Document kD579Q078Qp96OXw5r93p8KQJ

130 Annals New York Academy of Sciences 48. Ducois, P,, P. Amblard, B. De Bionicolfrt 4 J. Leorand, 1972. Acropalhlc polyvinyliquc professionnelle, Bull. Soc. Franc. Dermatol. Syphillgr. 79* 197. 49. EcKAROr, ft. E. 4 R. Hindin. 1973. The health hatardi of plastics. J. Occupa tional hied. 15t 808. 30. Edmondson, 11. A., R. L. Peters H. H. Frankel 4 S. Bokowski. 1967. Tbe early stage of liver injury in the alcoholics. Medicine 46s 119. SL EuropacsikmiS. 1972. Handelsblatt GmbH. DOsseldorf, West Germany. Ruami r I. T. I9S7 TnHnOna) 2ad-*dii' Thi -Gosnpanyt-BaltimorerMd. 53. Filatova, V. S. 4 E. Sir. Gronsbero. 1957. Samtamo-BigicniCcskic usloviya truda v proizvodstvc polikhlorvinilovoi smotyl I mcryi ikh ozdorovlcniyn, Gigicna Sanit. No. t: 38. 54. Filatova, V. S.. L. 1. Balakhonova 4 E. Sts. Gronsbero. 1958. Gigieniteskaya kharakieristika proirvodstva khloristovo vinila. Gigicna Truda Prof. Zabolevaniya 2(1): 6. 55. Filatova, V. S,, E. Sm. Gronsoero, N. A. Smirnova, B. A. Stulova a 1/ V. Oresckevic- 1965. Voprosyl gigienyi truda 1 sostoyanle zdorov'ya raboJikh. zanyatyiklt na proitvodsive lateksnovo poUvlnilkhtorida. Glgiena Truda Prof. Zabulevaniya 9t 9. 56. Filatov*, V. S. 4 V. A. Antonyuzhenxo. 1971. Glgieniteskiye usloviya truda I profcsiional'naya tabolevaemost' raboilkh proizvodstva suspenziOnnovo pollvinilkhlorida v dlnamlke za ryad let. Gigjena Truda Prof. Zabolevaniya 15(4): 32. 57. Fischer, J., H. Munoschenk 4 R. Wolf. 1965. Milzsziniigraphie mil 1-Bromomercuri (u,Hg)-2-hydroxypropan (BMHP). Forischr. Gebiete Roentgcnstrahlen Nuktearined. 103: 349. 58. Fischer, J., R. Wolf 4 If. Gamm. 1973, Die Milzizintigraphic. Duch. Arztebl. No. 7: 401. (8o>i< ,1 |f|f<\ Tnmnrt nf Ihe liviT la (sf ||ir Ibm 1 TtITTiT, Ttl 9fd edit, J. D. Lipptin.'OnCumpanr.-Philftitelphia, Pj. -- 60. GitsiOS, C. T. 1971. Aero-osteolysis in PVC workers. Med. Bull. Stand. Oil Co. 31(1); 49. 61. GOntiier, O. 1956. Die KunslstoiTc und ihre arbeitsmeduinische Bedeutung. Zentr. Arbcitsmed. 6; 156. 62. Harris, D. K. 1953. Health problems (n the manufacture and use of plastics. Bril. I nd. MeJ. 10; 255. t>3, Harris, D, K. 4 W, G. F. Adams. 1967, Acro-osteolysis occurring in men engaged in the polymerization of vinyl chloride. Brit. Med. J. 3i 712. 64. HensCHler, D.. Ed. 1972/1973. GesundheitsscMdllche Acbettsstofle, Toxikoio* gisch-arbeitsmedizinische Begrllndungen von MAK-Werten (Maximale Arbeits- plaiz-Konzentrationen). Verlag Chemie. Weinheim, West Germany. 65. Herri.6, K, 1961, Polyvlnylchlorld. fn Ullmanns Encyklopidie deT technischen * Chemie. W. Foerst, Ed. 3rd edit, Vol. |4. Urban 4 Scfwarzenbcrg. Mllnchen, West Germany. 66. Hervieux 4 Tessier. 1959. Quelques observations d'exposltlon et d'intolirance aux dlrivls vinylique* ei tux rfsines fthoxyliques. Aren. Maladies Profess. 20i 61. 67. Iuer, F. L. 1970. Portal hypertension in the presence of normal liver morphology. Ann. N.Y. Acad. Set. 176(1): 115. 68. International Labour Office. 1971. Encyclopaedia of Occupational Health and Safety. Geneva, Switzerland. Vol. I: 387. 69. International Labour Office. 1972. Encyclopaedia of Occupational Health and Safety. Geneva, Switzerland. Vol. II: 1467. htTS.D^lb63. lUloj^rnmed^hydsocarbonti I. 71. JaviW. N. 3. !S?70. Clinical and experimental aspects of sulphobromophthaleln and related compounds. In Progress in Liver Disease. H. Popper 4 F. Schaffner, Eds. Voi. fir. Or-r.c 4 Stratton. New York, N.Y. 73. 1 upAlt, /. D.. A. .1. X. McLean 4 E. K, McLean. 1970. Biochemical mechanisms of liver injury. Am. J. Med. 49* 609. 73. lima, S. 4 C. 'i. Lmnos. 1972. Sklerodermlcartlgc Hautverlinderungen, Raynaud- Syndrcm vnd / .`trccsteolysen bei Arbcitern der PVC-herstcllcnden Industrie. Dent. M?c*. Vrvc;:?e.vr. 97* 1922. Marstelier e( aL: Splenomcgaiic 74. Kelly, R. E.(l97pVinyl chloride and acrooste 858. SchilT, Ed. 3rd edit. J. D, Lippincoll Company. 76. Klinge, 0, 4 H. W. Altmann. 1971. Morpbolo Med, Wochschr. 113; 1529. 77. Kluge, T., H. Sommerschild 4 A. Flatwark. sion. Surgery 68: 294. 78. Kramer, C. G. I. S. hlurchler. 1972. The cc mental measurements for workers exposed |i Assoc. J, 33: 19. 79. Lange, C.-E., S, JUiie, G. Stein & G. Vlltm. chlorid-Krankheit--<iite beru/sbedingle Systei mcd. 32: I. B0. LEAKe. C. D. 1934. The role of pharmacology i thesia. J. Am. Med. Assoc. 102; 1. n1 1 *T '"*! Pn (<I66 ........ TnnitMltwpir -Arr ^U^Al-GerrrriTtyr 32. iit-ivse, M. 7. 1972. Iniernalionoles Sympoiioi Industrie, 27-29 April 1977, Ludwigshafen, ? 8j. Lihimann, K. B. 4 F. Flurt, Eds. 193B. Toxi jcben Lbsungsmltlel. Julius Springer. Berlin, C i4. Lester, D., L. A. GrEEnuero 4 W. R, Adam: pealed exposures of humans and rats to vinyl 24:265. 95, Lindner. If. 1973. Laparoscopy in atcohol-induc 54: 832. 86. MacSween, R. N. M., J. M. Vetters! S. K. STONe 4 A. T. Sandison. 1973. Haemangio- 1. Pathol. 109: 39. It. C. 4 ft. L. giLL-mm. 196h4nJua und^PruL'g.stng uf~P|gim 88. MALTONt, C., M. Crespi 4 P. J. R. Durcii, Eds. on Cancer Detection and Prevention, Bolo Mcdlca I at. Congr. Ser. No. 275. 89. Marin, A., J. Strauss, R. Michels, I. P. Beni Acro-os<6olyse d'originc professionnelle (Tra contre le Rhumaiisme, sdance du 18 janvicr l 90. Markowjtz, S. S., C. J. McDonald, u/ Petu cupational acroosteolysis. Arch. D> a 91. Marsteller. H. J., W. K. Lelbaci* Roiiner 4 G. Veltman, 1973. Cl in der PVC-Pcoduktioti. Devi. Mr 92. Mastromatteo, E., A. M. fisher, halation toxicity of vinyl chlorid J. 5: 394; Bull. Hyg. 36t 244. Q* Af!VFB< LI-B- 1Q69 nr-rnpalion nalttmofrMdr-- 94. McCord, C. P. 1970. A new occ M 12:234. 0) 95. Mikkelsen, W. P., H. A. EOAtc Reynolds. 1965. Extra- and i H (hepatoportal sclerosis). Ann. 96. MJSGELD. V.. H. J. STOLPAtAN (71 Vinylchlorid-Polymerisatc ur 48:425. i 97. Moruus, 3. S., T, Htvt 4 A. E M I Ann. Rheumatic Diseases S' H 98. Nettlesiiip, A. 4 W. J. Fink CO thorotrast. Am. J. Clin. Pali 99. OnTiiL, JL 1963. Gewerbetoxikoiopic a Polymerisaic chlorierter Athylene. 7/j Ullm: -*>v Letters to the Editor Readers are invited to submit letters for publication in this department. Submit to Ir ving R. Tabershaw, M.D., Editor, P.O. Box 772, Berke!ey, Calif. 94701. Letters should be typewritten, double spaced, and should be designated "for Publication". Vinyl Chloride and Acroosteolysis The excellent review of the article "Occupational Acroosteolysis" in the August issue (p 670) contains an error in the nonmedical field The statement is made that cleaning of the polymerization reactors for vinyl chloride resins must be done by hand. This is in error, as solvent cleaning and steam cleaning, which ob viate the necessity of the workers en tering the kettle to carry out the cleaning is a technology that has existed for some time, and, of course, has been ex panding since the advent of oc cupational acroosteolysis. It is of interest that in those installations where this method of cleaning has been carried out there is no acroosteolysis in their PVC workers. R. Emmet Kelly, M.D. Box 526 St. Louis, Mo. 63166 lypersusceptibility and Genetic Problems The recent article entitled, "Hypersusceptibility and Genetic Problems in Occupational Medicine--A Consensus Report," by Stokinger and Scheel1 makes a number of assertions with regard to work published from our laboratory and which require clarification. While the authors state that they ". . . . have tried to present a cross section .... without author bias," it is evident that their paper represents their personal opinion. The authors make reference to our paper2 and note that it is unique in that it is the only paper that examines serum alpha-1 antitrypsin levels in an industrial situation. They proceed to discredit the paper by quoting a letter to the editor of IAMA5 but omit to refer to our reply which followed on the same page.4 Fur thermore, we should also like to point out that the very comments we made about methodology in our reply were recently raised by others in a recent sym posium.5 -.......... - - ------- Of further interest, is that about the rime our study was completed, Fagerhol id Laurell6 reported on their crossed- immunoelectrophoresis phenotyping to detect genetic variants relative to alpha-1 antitrypsin deficiency. Subsequently, in a 858 paper by Talamo et al7 it was shown that with the exception of the homozygote deficient (PiZZ), no correlation between serum trypsin inhibitory capacity (TIC), or concentration, and the heterozygous phenotype was obtained whether or not obstructive pulmonary disease was present Overlapping quantitative values were reported including those with variants PiMM, PiMS and PiMZ. In our study we also found it impossible to separate heterozygotes from normal by means of TIC determinations. Talamo et al7 go on to state that, "the clinical im portance of intermediate serum alpha-1 antitrypsin deficiency remains un certain." The recent studies by Galdston et ala implicating leukocyte lysosomal proteases, as well as, the studies of Starkey9 and Werb10 on the inhibition of cathepsins and coliagenase by the alpha2 macroglobulin fraction may prove to be relevant; it is certainly too early to tell. There is another matter raised by Stokinger and Scheel to which we should like to address ourselves. The authors make comment on the poor reception by industry of "genetic" testing. The reason for this may be that a "cause and effect" relationship between genetic predisposition and industrial disease has not been demonstrated. In deed there is no biological phenomenon which is not in part a result of heredity; man is a "colossal variant" What is required in this important area of research is more quantitative studies and more facts rather than glib and facile ex planations. An examination of the five (5) genetic tests and criteria suggested by Stokinger and Scheel suggests that their opinions are based on hypothesis rather than fact. Serum alpha-7 antitrypsin deficiency. -- With respect to the heterozygote state, no definite association between predisposition and occurrence of bron chopulmonary disorders has been established - especially in an industrially-oriented environment The comments by Robin11 are particularly relevant in this connection. Furthermore, with respect to prevalence, we should like to remind the authors that Eriksson12 found only four (4) homozygote deficients after screening a random population of 6995; and only two (2) of the four had any history of emphysema. Would this be considered by the authors a relatively high prevalence in a work ing population? We hardly think so, although we still feel that the test should be performed. Furthermore, it should be Stated that we know of no study in dicating "respiratory irritants" in con junction with alpha-1 antitrypsin deficiency may predispose to chronic obstructive pulmonary disease. Giucose-6-Phosphate Dehydrogenase De//c/ency. -- The relatively high prevalence of heterozygotes for glucose6-phosphate dehydrogenase deficiency appears to be the primary reason that this test should be performed rather than the "promise" of detecting chronic "pilltakers;" the individuals in the latter category are more in need of psychiatric counseling than genetic testing. Fur thermore, the effects due to chemical exposure and those due to genetic variations should be delineated. While the drug induced anemias can com pound the situation when a genetic deficiency is present, the nature of the effects of these compounds on the erythrocyte is varied and complex. This is especially true in a redox system where the integrity of the cell membrane is clearly dependent on the integrity of the thiol (-SH) groups. Thus urea, a common nitrogen-containing metabo lite, which is freely diffusable through the erythrocyte ceil membrane and a strong proton binder (pK in the neigh borhood of 1CH4) does not, to the best of our knowledge, have any potentiating effect on those with glucose-6phosphate dehydrogenase deficiency disease. CSz Genetic Testing. -- The genetic risks in predisposition to CS2 have never been clearly delineated; no genetic criteria relevent to CS2 susceptibility have been determined. Furthermore, as the authors themselves noted, the available data (large spread in values) make the use of TETD for genetic testing highly questionable. The rate of for mation of metabolic products from TETD may not be a consequence of a genetic "defect" per se. Isocyanate Genetic Testing.-- The im munologic testing for isocyanate allergic NOTICE THIS MATERIAL MAY BE PROTECTED BY COPYRIGHT LAW (TITLE 17 U.S. CODE) 130 Annals New York Academy of Sciences 48. Ducois, P., P. Amblaad, Q. De Bionicourt k J. Leorand. 1972. Acropalhle polyvinyUque profewlonnelle. Butt. Soc. Franc. Dcmulol. Syphillgr. *791 197. 49. Ectkioanrfdllt\M, (-eftad. .Ei1..r6.:Jot8a0Ro8.. Hihdin. 1973. The health hazards of plastics. 1. Occupa- 50. Edmondson, It, A., R. L. Peters. H. H. Franxel k S. Bonowsxi. 1967. The early stage of liver injury in the alcoholics. Medicine 46; 119. 5L Europacuemie. 1972. Handelsblatl GmbH. DUsscldorf, West Germany. 'If I T Tl 1957 TnH^^rial JTh. m.lliao>-X-W{tHTw-- v -Corapanyi-Baltimere, Md. 53. Filatova, V, 2. <1 E. Sit. Gronsbero. 1957. Sanilamo-gigieniieskie usloviya truda v proifvodslve polikhlorvinilovol smolyl I meryl ikh O2dorovlcnlya. Glgiena Sanit, No. 1: 38. 54. Filatova, V, S., L. I. BalaxHonova k E. Sii. Gronsbero. 1958. Glgicniieskaya kharakteristika proizvodstva khloristovo vinila. Gigiena Truda Prof. Zabolevaniya 2(1): 6. 55. Filatova, V, S., 6. Sit. Gronsbero, N. A. Smirnova, E. A. Sttjlova k l. V. Oresckevic. (965. Voprosyi gigienyi truda i sostoyanie ztlorov'ya rabotikh, zanyatyikh na proizvodstve lateksnovo pollvinilkhlorida. Gigiena Truda Prof. Zabolevaniya 9: 9. 56. Filatova, V. S. k V, A. AntonyuzheKKO. 1971. Gigleniiesklye usloviya truda I professional'nay* zaboievaemosi' raboiikh proizvodstva suspenzionnovo pollvinilkhlorida v dinamike za ryad let. Gigiena Truda Prof. Zabolevaniya 15(4): 32. 57. Fischer, J,, H. Mundschenk Jt R. Wait. 1965. Miizszintigraphle nut l-Broaiomercuri ("'tM-l-hydroxypropan (BMHP). Fortschr. Gebiete Roentgcnstrahlen Nukleanned. 103: mr. 58. Fischer, J., R. Wolf k H. Gamm. 1973. Die Milzszinilgraphie. Dtsch. Arztebl, A No. 7: 401. poi 1^2 TM C.. xm___ - - T,<rn-r-*-n--f !W l|l|vT^ff lAa~ nlttnn n1,1 rtJj1hI_Hif. L.,'ffCtTtlT, SO. ' 9*4-ediir-Jr-Urk:ipplireutl`Cuiiipaiiy.^htiad*lphi>7 Pa. 60. Gitsios. C. T. l?7l. Aero-osteolysis In PVC workers. Med. Bull. Stand. Oil Co. 31(l):49. 61. GOntiier. O. 1956. Die Kunstsioffe und ihre arbcitsmedizinische Bedcutung. Ztntr. Arbeiismtd. 6: 156. 62. Harris, D. K. 1953. Health problems in the manufacture and use of plastics. Bril. J. Ind. Med. lOi 255. 63. Harris, 13. K. Jt%V. G. F. Adams. 1967. Acro-osteolysls occurring Ip men engaged in the polymerization of vinyl chloride. Bril. Med. J. 3i 712. 64. Henschlek, D., Ed. 1972/1973. GcsundheitsschSdllche Arbeltsstoffe. Toxikolo- gisch-arbeitsmedizmlsche Bcgrbndungen von MAK*Werten (Maximal Arbelts- plniz-Konzeniraiionen). Verlag Chemie. Weinheim, West Germany. "e 65. Hurm.b, K. 1963. Polyvlnylchlorid. In Ullmanns Encyklopadie der technlschen Chemie. W. Foerst, Ed. 3rd edit. Vol. 14. Urban & Schwartenberg. Milnchen, West Germany. 66. Uervieux 6s Tessier. 1959. Quelques observations d'expositlon et d'intolfrance aux dirivis virfyliques et aux r6s:ne$ fthoxyliques. Aren. Maladies Profess. 20t 61. 61. UtR, F. L. 1970. Portal hypertension in the presence of normal liver morphology, Ann. N.Y. Acad. Sci. 176(1): 115. 68. International Labour Office. 1971. Encyclopaedia of Occupational Health and Safety. Geneva, Switzerland. Vo). I: 387. 69. International Labour Office. 1972. Encyclopaedia of Occupational Health and Safety. Geneva, Switzerland. Vol. If; 1467. A ... Hh-ImJh, S. Di 1M3 U-1............. ' ------ ^d-TcrTtk0i0^. V -e<Jviu.cTuLiJ;i:,.-;rj; fiew Turk, 14.7. 71. Iavitt, N. B. 1970. Clinical and experimental aspects of sulphubromophthaieln and related compounds, in Progress in Liver Disease. H. Popper k F. Schaffner, Eds. Vol. HI. Ctjp.c k StriHon. New York, N.Y. 72- Judah. J. D,, A. E. M. McLean k E, K. McLean. J970. Biochemical mechanisms of liver injury. Am. f. Med. 49t 6Q9. 73. JOiie, S. k C. o. Lance. 1972. Sklerodermleanige HautverMndervngen, Raynaud- Syndrom urd Ax.-ccstcolysen bel Arbeilern der PVC-hersleUeittlett lauusltie. Dcui. Med. V'cchwiir. 97s 1922. tOOSOGLZ Marsteller et al.\ Splenomegalic 1 ^ Ul ii ---- 75, Klatsxin, OQim^Toxic and drug induced ncpaii Schiff, Ed. 3rHedit. J. B. Lippincott Company. P 'll. Kluge, T., H. Sommerschild k A. Flatmarx. 15 sion, Surgery 68t 294. 78. Kramer, C, G. k J. E. Mutcmler. 1972. The cor mental measurements for workers exposed to Assoc. 1. 33: 19. 79. Lanou, C.-E., S. JOne, G. SrtliN k G. Vcltma; chlorid-Krankheit--eine berufsbedinfile System mcd. 32t 1. / 80. Leake, C. D. 1934. The role of pharmacology in the&iit. J. Am. Med. Assoc. 102: 1. 01 T ronif R, 1*166 Thrmi* nml Tonilrnfncii--ifri-- '-ilUet-GemraTTyr 82. LtrfevRZ, M. J. 1972. Internationales Symposion Industrie, 27-29 April 1972, Ludwigshafen. At 83. Lehmann, K. D. k F. Flury, Eds. 1938. Toxik schen Ldsungsmittel. Julius Springer. Berlin, G 84. Lester, D., L. A. Greenoero k W. R. Adams. pcated exposures of humans and rats to vinyl c 24; 265. 85. Lindner, >!. 1973. Laparoscopy in alcohol-inducc 64: 842. 86. MacSween, R. N. M,, J. M. Vetters, S. K. F stone Jt A, T. Sandison. 1973. Haemangio-e I. Pathol. 109: 39. 8-7, Mac.tx)4, ](, 12, a. Rr L. ZibuiuisV 196 ti ImluU* in th^P^udu^jiuit^ntl^Trejgnliig uf" Plaetiu 88. Maltonj, C., M. Crespi Jt P.-J. R. Duncu, Eds. i on Cancer Detection and Prevention, Boiog Medica Ini. Congr. Ser. No. 275. 89. Marin, A., J. StraUSs, R. Michiels, J. P. Beno Acro-ostiolyse d'origine professionnelle (Trav conue le Rhumatisme, stance du 18 janvicr 19 90. Markowit2, S. S., C. J. McDon". cupalionai acroosteoiysis. Art w 91. Maasteluui, H. J., W. K. Lei ^Rohner Jt G. Veltman. 197 in der PVC-Produktion. Deut 92. Mastromatteo, E,, A. M. Fish halation toxicity of vinyl chk I. 5: 394; Bull. Hyg. 36: 244. *)3 KUVPM4 Vt 1> ]Q69 Grrnpntl _Oa tlfmf | f I * " = Q 94. McCord, C. P. 1970. A new o 12:234. 95. Mjkkelsen, W, P.. H. A. Edm Reynolds. 1965. Extra- and (hepatoportal sclerosis). Ann. 96. Misceld. V. H. J. Stolpman H gO cn go VinyJchlortd-Polymemate un 48; 425. c* 97. Morris, J. S.. T. Httjt k A. E. 03 Ann. Rheumatic Diseases 31; 98. Nettlesihf, A. k W. J. Fink. 1 ^0 ihorotrast. Am. J. Clin. Patho 99. Oettel, H. 1963. Gewerbetoxikologie und PI Polymerisate chiorierter Alhylene. In Ullma Toxic and Drug-Induced Hepatitis GERALD KLATSKIN, m.d. Hepatotoxins, a heterogeneous group of therapy, the latent period being brief in naturally occurring and synthetic chemical some individuals and long in others; (5) the agents, produce a variety of lesions in the liver that are classified as forms of toxic hepatitis. Although they may differ in mor phology and pathogenesis, all such lesions histologic pattern of the lesions is more variable, resembling that of extrahepatic biliary obstruction in some instances, and that of viral hepatitis in others; (6) often share a number of features in common. the lesions are accompanied by extrahe Characteristically, they (1) exhibit a distinc patic manifestations of hypersensitivity, such tive histologic pattern for any given hepato- as fever, rash, arthralgia and eosinophilia. toxin, (2) vary in severity in direct relation A few drugs, such as chloroform, are true to the dose, (3) can be elicited in all indi viduals, (4) are reproducible in experimen tal animals and (5) appear after a pre dictable and usually brief latent period fol lowing exposure. In many instances, hepato toxins behave as general protoplasmic poi sons and affect not only the liver but also other tissues. Carbon tetrachloride and phosphorus are typical examples in this group. Many drugs can injure the liver, yet, paradoxically, few are true hepatotoxins. As is shown later, most drugs that produce he patic damage appear to behave as sensitizing agents rather than hepatotoxins. Ac cordingly, a distinction must be drawn between drug-induced and toxic hepatitis. The features that characterize the lesions of dme-induced. hepatitis and serve to dis tinguish them from those of toxic hepatitis may be summarized as follows: (1) they cannot be reproduced in animals: (2) only a small fraction of exposed individuals are susceptible to this type of hepatic injury; (3) neither the occurrence of such lesions nor their severity can be correlated with the amount of drug consumed; (4) the appear ance of the lesions bears no constant tem poral relationship to the institution of drug hepatotoxins and produce the typical lesions of toxic hepatitis. Others, like the organic arsenicals, may behave as sensitizing agents under some conditions and as hepatotoxins under others. A number of drugs, including some C-17 alpha alkyl substituted steroids and certain agents used for cholecystography, interfere with bile secretion and may give rise to jaundice. However, the functional disorders they produce are not accompanied by he patic necrosis or inflammation or by evi dence of hypersensitivity, so that these drugs are neither true hepatotoxins nor sen sitizing agents, and must be considered separately. Transmission of the hepatitis virus by means of improperly sterilized syringes con taminated with blood constitutes one of the hazards of parenteral drug therapy and has been reported following the administration of a variety of therapeutic agents. This pos sibility must be borne in mind in evaluating the role of parenterally administered drugs^j in the etiology of hepatitis, especially whenjfs. the latter develops during a long coursefA of treatment, or after an extended latent^ period. 498 NOTICE THIS MATERIAL MAY BE PROTECTED BY COPYRIGHT LAW rrntE 3 7 us. code) i Toxic Hepatitis 499 >atitis iod being brief in g in others; (5) the le lesions is more at of extrahepatic me instances, and others; (6) often arued by extrahepersensitivity, such nd eosinophilia. iloroform, are true the typical lesions t like the organic sensitizing agents td as hepatotoxins lu*' some C-17 iroiu-> and certain )graphv, interfere nay give rise to actional disorders }mpanied by heation or by evi, so that these :totoxins nor sen: be considered patitis virus by :ed syringes conitutes one of the therapy and has 3 administration gents. This posld in evaluating linistered drugs especially when a long course steaded latent TOXIC HEPATITIS have demonstrated that carbon tetrachlo Pathogenesis ride alters the permeability of the mito chondria of the hepatic cells, resulting in I Several mechanisms have been proposed loss of diphosphopyridine nucleotide (DPN) j to account for the actions of hepatotoxins. and a decrease in the activity of the DPN- These include: (1) disturbances in protein linked dehydrogenases of the Krebs cycle. synthesis and energy production in the liver In addition, there is a concomitant fall in restilting from direct injury to hepatic cell adenosine triphosphate (ATP)173 and un membranes, or metabolic alterations in es coupling of oxidative phosphorylation.111,171 sential constituents of the hepatic cell; (2) Biochemical138 and electron microscopic174 impairment of hepatic blood flow, leading studies indicate that the mitochondria of to ischemic necrosis, secondary to swelling the liver swell and fill with lipid under these of the hepatic parenchyma, or to stimula conditions. Phosphorus172 and heliotrine134 tion of the sympathetic nervous system; and produce similar effects, but whether these (3) alterations in lipid metabolism. occur in other forms of toxic hepatitis is Considering that hepatotoxins differ mark not known. edly in chemical structure, it is highly im- That carbon tetrachloride can attack the ! probable that they all attack the liver in the same way. The uniformity of the biochemi cal findings in the liver after exposure to mitochondria directly has been established in in vitro experiments.111*135 However, anoxia produces similar effects, so that the i hepatotoxins of diverse character suggests I that, although these agents probably initiate 1 cellular injury in different ways, the subse- in vivo changes in mitochondrial enzymatic activity observed following carbon tetra chloride poisoning have been attributed by ' quent chain of biochemical events leading some to ischemia.816 The latter interpreta to necrosis follows a common pathway. tion is open to question, but there can be lit Several factors, including the nutritional tle doubt that mitochondrial damage does state, alcoholism, pre-existent liver disease not constitute the initial event that leads and infection, modify the effects of hepato to necrosis, since other histologic,830,334 toxins and are of importance in the patho biochemical598 and electron microscopic698 genesis of toxic hepatitis (see below). changes can be demonstrated much earlier. Some hepatotoxins attack the liver exclu Recent studies suggest that the primary sively, though they enter cells elsewhere in site of action of carbon tetrachloride is in the bodv. The reason for this is not clear. the endoplasmic reticulum,00*696 a complex I Since many of these agents are degraded or of cystoplasmic structures which are the ! otherwise chemically altered in the liver, it source of the microsomes obtained on cen ! has been proposed that their metabolites are trifugal fractionation of the cells. These play ] responsible for their specific hepatic ac- a role in protein synthesis118 and in certain l lions.480 Alternative possibilities that must conjugating systems358 and possibly in lipid j be considered are that agents of this type metabolism.9"'1 Marked dilatation of the cis- are concentrated in the liver, or attack en temae of the endoplasmic reticulum on zymes peculiar to the liver. electron microscopy696 and inhibition of mi Direct Effects on Cell Membranes. More crosomal enzymatic activities596 are de than 60 vears ago Wells suggested that hep- monstrable early in the course of carbon [ atotoxins produce cellular injury and death tetrachloride poisoning, before morphologic by inactivating essential oxidative enzyme or functional changes in the mitochondria 1 systems, leading to cessation of anabolic are evident. Interestingly, carbon tetrachlo processes and ultimate dissolution of cyto ride696 and other hepatotoxins, such as di- plasm bv autolytic enzymes.TM The results methylnitrosamine,345 inhibit the in vitro of more recent studies support this view but incorporation of labeled amino acids into attach special importance to enzyme sys protein by the microsomes of the liver. This tems concerned with energy production and supports the view that the inhibition of pro protein synthesis. tein synthesis by hepatotoxins is responsible Christie and Judah13* and others111*172 for the subsequent alterations in mitochon 500 Toxic and Drug-Induced Hepatitis drial morphology and function that ulti mately lead to cellular necrosis.66 In both carbon tetrachloride744 and thioacetamide poisoning250 the calcium content of the hepatic cells increases rapidly. Since high concentrations of calcium produce swelling, loss of potassium and inhibition of respiration and oxidative phosphorylation in mitochondria,744 it is possible that agents of this type contribute to hepatic injury by altering the permeability of the cell mem branes, permitting excess calcium to enter and attack the mitochondria. Several investigators have suggested that carbon tetrachloride damages the endoplas mic reticulum by enhancing the peroxida tion of its structural lipids.597 Indirect Metabolic Effects. Diets that are deficient in sulfur-containing amino acids produce massive hepatic necrosis in the rat.268,323 According to Himsworth, this effect is dependent upon a specific defi ciency of cystine.322 Moreover, he suggests that lesions of this type are induced not only by dietary restriction but also by a relative deficiency of cystine as a consequence of excessive losses or increased demands. As examples, be cites the hepatic lesions of trinitrotoluene poisoning, which he attrib utes to the combination of cystine with free nitrous groups, and to the increased de mand for cystine imposed by a raised meta bolic rate, and the lesions of chronic sele nium poisoning, which he believes are also dependent upon a relative deficiency of cys tine, created in this instance by the substi tution of selenium for sulfur. The observation that protein deficiency enhances and that supplements of methio nine or cysteine inhibit the hepatic necrosis induced by bromobenzene, and the fact that bromobenzene couples with cysteine before it is acetvlated and excreted as mercapturic acid,388 lend support to die hypothesis that hepatotoxins injure the liver by inducing a relative deficiency of sulfur-containing amino acids. According to Drill, a defi ciency of this type could lead to hepatic ne crosis by interfering with intracellular en zymatic oxidation-reduction systems de pendent upon an adequate supply of sulfhydryl groups.185 However, direct measure ments have failed to demonstrate a fall in the glutathione content of the liver follow, They report ing carbon tetrachloride poisoning.202 More that blocks ? over, it is difficult to reconcile this hypoth hepatic va esis with the observation that a dietary de against hep ficiency of sulfur-containing amino acids in mitochon will not produce hepatic necrosis unless the seen followi diet is also deficient in vitamin E287,288,325 ing. Howev and factor S,**3- 664 a naturally occurring or that the pr ganically bound selenium compound found due to the in many tissues and foods.605 Indeed, that it will t Schwarz has shown that the protective ef induced he fects of methionine and cystine are depend perature is ent not upon their content of sulfhydryl Interestir groups but rather upon the presence of dilatation c trace amounts of selenium.685 ment of c Ethionine, by trapping adenosine in S- rather than adenosvlethionine, depletes the liver of instance tb ATP, leading to inhibition of protein syn the area ol thesis and accumulation of triglyceride.220 agent, nam Since all of these effects can be prevented via the pot by intraperitoneal injection of ATP or its ever, the < precursors, the inhibition of protein syn by hepatot thesis is related to the depletion of hepatic ferences in ATP. However, this is not the case in car the varioui bon tetrachloride poisoning, since ATP in bv zonal c jection prevents the decline in hepatic ATP, of hepatot but does not prevent inhibition of protein This possil synthesis.351 tions in tl Vascular Factors. Alterations in the intra cells found lobular circulation may play a role in the Accordir pathogenesis of toxic hepatitis. Exposure to duces heps carbon tetrachloride, for example, produces ability of d an immediate but transient intralobular acids.324 If vasoconstriction, which, as exposure contin carbon tet ues, is followed by a more sustained ob mia, it is u literation of the sinusoids, possibly as a containing consequence of hepatocellular swelling. This methionin< has been demonstrated both by the quartz- against thi rod transillumination technic766 and by in- oxvgen tei trasplenic India ink injection.265 Calvert and important Brody have attributed the vasoconstriction se can pi to stimulation of the central sympathetic biochemic areas resulting in a prolonged discharge of On the the peripheral sympathetic nervous system urements i and increased secretion of epinephrine.112 method of Since the degenerative changes and ne an impla: crosis produced by carbon tetrachloride and challenger a number of other agents occur in the cen- a role in tl trilobular areas where the circulation is most impaired, many investigators have attrib *1 necrosis fc chloride a uted the lesions to ischemia.25, 768 Evi ing to thi dence in support of this hypothesis has been blood flo\ brought forward by Calvert and Brody.112 using the Toxic Hepatitis 501 of ' > liver followpc .jirig.202 Moreloncile this hypothi that a dietary de aling amino acids necrosis unless the ritamin E287,28a-825 irally occurring or1 compound found foods.065 Indeed, the protective efystine are depend ent of sulfhydryl the presence of m.665 ; adenosine in S- tes die liver of n of protein svnof triglyceride.526 can be prevented m of ATP or its of protein syndetion of hepatic : the case in carg, since ATP in? in hepatic ATP, bition of protein iky A the intraay .ole in the itis. Exposure to ample, produces ent intralobular exposure contine sustained ob, possibly as a ar swelling. This l by the quartzic766 and by ini.265 Calvert and vasoconstriction :al sympathetic sd discharge of nervous system epinephrine.112 langes and netrachloride and cur in the cenailation is most s have attribiia.285'766 Evithesis has been and Brody.112 They reported that cordotomy, a procedure that blocks sympathetic stimuli and prevents hepatic vasoconstriction, fully protects against hepatic necrosis and the alterations in mitochondrial enzymatic activity usually seen following carbon tetrachloride poison ing. However, Plaa and Larson have shown that the protective effect of cordotomy is due to the hypothermia it produces, and that it will not prevent carbon tetrachlorideinduced hepatic necrosis if the body tem perature is maintained at 36 C.5"2 Interestingly, allyl formate, which causes dilatation of the sinusoids without impair ment of circulation, produces peripheral rather than centrilobular necrosis.655 In this < instance the principal point of attack is in the area of maximal concentration of the agent, namely, where it enters the lobule via the portal tract at its periphery. How ever, the distribution of lesions produced by hepatotoxins may be determined by dif ferences in the susceptibility of the cells in the various zones of the liver rather than by zonal differences in the concentration of hepatotoxin or by circulatory changes. This possibility is suggested by the varia tions in the biochemical activities of the cells found in different parts of the lobule.675 According to Himsworth, ischemia pro duces hepatic necrosis bv limiting the avail ability of circulating sulfur-containing amino , acids.334 If the hepatic necrosis produced by I carbon tetrachloride is the result of ische mia, it is unlikely that a deficiency of sulfurcontaining amino acids plays a role, since methionine supplements do not protect against this type of hepatic injury.184 A low i oxygen tension would appear to be a . more important factor, inasmuch as anoxemia per se can produce similar histologic40 and biochemical516 lesions. On the basis of hepatic blood flow meas urements in the intact rat, using the Grayson * method of internal thermal conductivity with an implanted thermocouple, Stoner has challenged the concept that ischemia plays a role in the development of central hepatic necrosis following exposure to carbon tetra chloride and other toxic agents.725 Accord ing to this investigator, the impairment of blood flow previously observed by others, using the India ink injection method or the technic of quartz-rod transillumination, can be attributed to the anesthesia and laparot omy required in such experiments.726 It is difficult to reconcile Stoners observations with other indirect evidence pointing to a circulatory disturbance.112 A number of agents, including urethane,180 some - senecio alkaloids630,670 and massive doses of arsphenamine,394 appear to produce hepatic lesions by injuring the blood vessels of the liver, leading either to increased vas cular permeability and extravasation of blood180 or to thromboses.334, e3-070 Fatty Infiltration. One of the striking fea tures of the hepatic lesions produced by car bon tetrachloride and a number of other toxic agents is an accumulation of fat within the parenchymal cells. This phenomenon has been variously attributed to (1) mobilization of nonesterified fatty acids from adipose tis sue, as a consequence of sympathetic and adrenal medullary stimulation,112 (2) depres sion of fatty acid oxidation in the liver due to a reduction in available DPN172 and ATP173 that follows mitochondrial damage, and 3) inhibition of the normal mechanism for the transport of triglyceride out of the liver, presumably because of injury to the endoplasmic reticulum.600 The concept that carbon tetrachloride mo bilizes lipid from the depots by stimulating the sympathetic nervous system and adrenal medulla, and thus produces fatty infiltration of the liver, stems from the observation of Calvert and Brody that adrenalectomy di minishes and cordotomy prevents this ef fect.112 More direct evidence indicative of fat mobilization has been obtained in an imals whose depot fats were labeled with deuterium prior to carbon tetrachloride ad ministration.41 The observation that the ad ministration of epinephrine increases the release of nonesterified fatty acids from the isolated epididymal fat pad while carbon tetrachloride does not,660 and the failure of adrenalectomy to protect against carbon tetrachloride-induced fatty infiltration in some experiments,10 appear to be inconsist ent with the theory that fat mobilization is mediated by sympathetic stimulation and increased epinephrine secretion. However, this does not exclude the possibility that carbon tetrachloride and other hepatotoxins 502 Toxic and Drug-Induced Hepatitis mobilize fatty acids by some other mecha nism. Indeed, the elevated levels of free fatty adds found in the plasma following the administration of such agents351 support this view. Dianzani has reported that carbon tetra chloride uncouples oxidative phosphoryla tion and lowers the ATP content of the liver before it produces fatty infiltration.173 Since ATP is essential in the activation of fatty acid oxidation, he postulates that the ac cumulation of fat is secondary to a reduc tion in its rate of oxidation. This view has been disputed by two groups of investi gators who have shown that the fat content of the liver rises before there is any uncou pling of oxidative phosphorylation111- 300 or impairment of octoanate oxidation,599 and that this effect is not abolished by prevent ing mitochondrial damage with ethylenediaminetetraacetate.111 Carbon tetrachloride, in addition to rais ing the concentration of lipid in the liver, lowers the plasma level of triglyceride and inhibits the hyperlipema induced by intra venously injected Triton.00 From this, Recknagel and associates concluded that fat ac cumulates because of damage to the mecha nism normally responsible for the transport of triglyceride out of the liver.600 Moreover, on the basis of indirect evidence, they have proposed that the most likely locus for this mechanism is the membranous component of the endoplasmic reticulum. Smuckler, Iseri and Benditt, who are in essential agree ment with this view, attribute the block in triglyceride transport more specifically to the depressed synthesis of protein required for lipid conjugation.698 A number of obser vations support this concept. The most im portant of these are that on electron micros copy, the earliest findings in the liver fol lowing carbon tetrachloride administration are cystic dilatation of the rough endo plasmic reticulum and dislocation of the ribosomes from its membranes,697 and that these changes are accompanied by an inhi bition of ribosomal protein897 and plasma lipoprotein897 synthesis. Nutritional Factors. The susceptibility of animals to hepatotoxins is greatly influenced by their nutritional status. Clinical experi ence suggests that die same is true of man, but the evidence is not nearly as con vincing. In general, starvation and high-fat diets enhance, whereas high-carboydrate and high-protein diets protect against the hepatotoxic effects of these agents. However, in the case of many hepatotoxins the effects of diet are not known. Moreover, the results of changing a single dietary constituent are difficult to interpret, unless due considera tion is given to concomitant changes in the other components and caloric value of the diet, and to their effect on net food intakefactors that frequently have been neglected in toxicitv studies. Even a relatively brief period of starvation increases the severitv of the hepatic damage produced by carbon tetrachloride230 and chloroform.167 High-fat diets enhance their toxicity to an even greater extent80-543 In contrast, carbohydrate appears to protect the liver against injury by these and other agents.80- 543 The effects of protein are variable, de pending not only on the nature of the hepatotoxin but also on other factors. Thus, pro tein deficiency increases the susceptibility of the liver to damage by chloroform508 but not by carbon tetrachloride.187 Similarly, a surplus of protein protects against the he patic effects of chloroform506 but not against those of carbon tetrachloride187 or many other agents.195 The protective action of protein also depends in part on the nutri tional status. Thus, supplements are far more effective in preventing chloroform injury in the depleted animal than they are in the animal with normal protein stores.167 The source of protein is another factor that may influence the results. Meat, for example, in contrast with otherr proteins, actually en hances the toxicity ot some agents.81 Other dietary constituents are of interest in connection with toxic hepatitis, not only for their possible therapeutic value but also for the c:Ilues that they may provide to the mechanisms involved in the actions of hepa totoxins, Of these, choline, methionine, cys tine and tocopherol have received the great est attention. Choline accelerates the removal of excess fat deposited in the liver as a result of car bon t ing bi under have i again carbo not b Me toxici stocktain t At le carbc the s crosis hepai alphs also folio' Alph bon casei insta effec vent Ci sivel cuss< the ! prot lonu in o T! affe< kno indi eith of i bilil cret and rev< bilil live at 1 toxi acc are bee par pro sulJ ** i Toxic Hepatitis 503 e same is true of is r nearly as conrva. . and high-fat is high-carboydrate protect against the ise agents. However, atotoxins the effects foreover, the results tary constituent are iless due consideratant changes in the caloric value of the in net food intake-- tave been neglected period of starvation die hepatic damage strachloride235 and diets enhance their ter extent.80- 543 jn 'pears to protect the these and other i are variable, de nature of the hepafactors. Thus, pro- the susceptibility ' chloroform506 but ide.'8. Similarly, a *s ' 'nst the hei506 . not against loride187 or many ?tective action of part on the nutri ments are far more loroform injury in l they are in the ein stores.167 The sr factor that may t, for example, in sins, actually enle agents.81 ats are of interest epatitis, not only -tic value but also ly provide to the e actions of hepa- methionine, cysJceived the great- removal of excess is a result of car bon tetrachloride40 or phosphorus69 poison- during a relative deficiency of sulfhydryl ing but does not prevent hepatic necrosis groups in essential enzyme systems of the under these conditions. Some investigators Uver.185 Accordingly, it is believed that low have reported that choline partially protects protein diets potentiate die toxic effects of against the mitochondrial injury induced by these agents by hastening such depletion, carbon tetrachloride,135 but this effect has The failure to demonstrate a fall in hepatic not been confirmed by others.111 glutathione following carbon tetrachlo- Methionine protects against chloroform ride2"2 casts doubt on the validity of this toxicity both in protein-depleted507 and interpretation. An alternative possibility that stock-fed animals.103 However, it is not cer- has received relatively little attention is that ' tain that the site of its action is in the liver, protein depletion increases the apparent At least in protein-depleted animals given toxicity of such agents by retarding the re carbon tetrachloride, methionine increases generation of injured hepatic cells, the survival time by preventing renal ne- At one time, the glycogen concentration crosis239 rather than by protecting against of the liver was thought to be the major fac- hepatic damage.184 In conjunction with tor that determined its susceptibility to in- alpha-tocopherol supplements, methionine jury. This concept was responsible for the also prevents the development of cirrhosis widespread adoption of high-carbohydrate following chronic selenium poisoning.869 diets in the therapy of hepatic disease. It is Alpha-tocopherol alone protects against car- now known that the protective action of j bon tetrachloride toxicity in rats on low- carbohydrate depends on its protein-sparing | casein diets. Prolongation of survival in this effect and its tendency to reduce hepatic j instance probably is not due to any hepatic lipids and not on an increase in hepatic effect, since liver damage is not pre- glycogen.272 vented.341 Contributory Factors. Ethyl alcohol po- Cystine has not been studied as exten- tentiates the hepatotoxic effects of chloro- sivelv as the other dietary constituents dis- form,631 carbon tetrachloride,409 phos- cussed. It affords some protection against pborus228 and certain other chlorinated the hepatotoxic effects of chloroform in the hydrocarbons.60 Since all of these agents are protein-depleted dog but is inferior to meth- highly soluble in lipid solvents, it has been ionine in this respect506 and has no effect suggested that ethanol, by serving as a ve in other forms of toxic hepatitis.185 hide, facilitates either their absorption from i The precise way in which dietary factors the intestinal tract or their penetration and affect susceptibility to hepatotoxins is not storage in cells.637 known, but there is suggestive evidence that In experimental animals, injection of rev indicates that they may do so by altering lively innocuous bacteria greatly enhances either the fat content of the liver or the size the hepatotoxic effects of chloroform and of its protein stores. In general, suscepti- phosphorus and produces a type of mid- bility is enhanced by diets that lead to an in- zonal or massive necrosis that is not seen crease in hepatic fat or depletion of protein in uncomplicated poisoning with these and is reduced by those that produce the agents.342 It has been proposed that under reverse changes.272 The heightened suscepti- these conditions the hepatotoxins alter the bility associated with fatty infiltration of the permeability of the vessels in the liver and liver is thought to depend, in some instances thus permit organisms to gain access to the at least, on the solubility of many hepato- parenchymal cells. Whether or not infection toxins in fat.185-272 Obviously, this cannot plays a similar role in man is not known, account for increased toxicity of agents that .Anoxia increases the hepatotoxic effects are relatively insoluble. As noted, it has of certain anesthetic agents.632 This would been postulated that some hepatotoxins, and appear to be an additiv e rather than a syner- particularly the chlorinated hydrocarbons, gistic effect, since anoxemia per se can pro- produce hepatic necrosis by interacting with duce serious liver injury.208, 490 I sulfur-containing amino acids, thereby in- In experimental animals, antecedent he- 24905007 504 Toxic and Drug-Induced Hepatitis patic injury renders the liver more suscep tible to further damage by other agents.80 This may account, in part, for the apparent synergistic effects of chronic alcoholism, in fection and anoxia in toxic hepatitis. Pathology The morphologic features of toxic hepa titis vary, depending on the agent, its dose and the route of administration. Usually, the acute hepatic lesions are distributed uni formly throughout the lobules, are arranged in a zonal pattern and show all stages of parenchymal degeneration from simple swelling to acute necrosis, with relatively little inflammatory reaction. Often fatty in filtration is a prominent feature. In the case of many hepatotoxins, the intralobular dis tribution of the lesions is distinctive. Thus, they characteristically occur in the centrilobular zones in carbon tetrachloride114 and chloroform784 intoxication and in the peri portal zones in phosphorus poisoning.324 However, the distribution may vary in some forms of toxic hepatitis. Occasionally, the lesions extend beyond the confines of the individual lobules and give rise to areas of massive necrosis, as, for example, in poison ing with die Amanita phaUoides toxin190 and some of the chlorinated naphthalene and diphenyl compounds.281 Curiously, agents that produce zonal lesions seldom give rise to massive hepatic necrosis, even when large doses are administered. In experimental ani mals, for example, even lethal doses of car bon tetrachloride or chloroform fail to pro duce this type of lesion unless they are injected directly into the portal circula tion.118 Carbon tetrachloride poisoning in man may be an exception. The writer has seen two instances of acute poisoning--one by ingestion and the other by inhalation-- that were associated with subacute hepatic necrosis and subsequent postnecrotic scar ring. As a rule, acute toxic hepatitis of the zonal type is a self-limited lesion that goes on to complete recovery without residuals. However, if the exposure to a hepatotoxin is continuous or is repeated at intervals that do not permit full recovery on each occasion, a diffuse fibrosis may ensue and terminate in a picture closely resembling Laennec's cirrhosis.114 When necrosis is zonal, regen eration proceeds in an orderly fashion within the confines of an intact reticulum by pro liferation of the remaining viable cells in the same lobule, thereby restoring the normal lobular architecture. However, this is not possible in massive hepatic necrosis, in which regeneration must proceed from dis tant lobules bordering the zones of necrosis. Large masses of parenchymal cells are formed which compress the intervening ne crotic zones, containing intact reticuhim, blood vessels and bile ducts, into broad bands. This produces the condition variously described as toxic cirrhosis, postnecrotic scarring with nodular hyperplasia and healed massive or subacute hepatic necrosis. Prolonged exposure to hepatotoxins, in cluding carbon tetrachloride,203-215 selen ium53* and others, induces hepatomas in experimental animals. Although cirrhosis usually precedes the appearance of these tumors, it is not known whether necrosis and regeneration of parenchymal cells are essential for their development.215 Theo retically at least, hepatotoxins can induce hepatomas in man. However, no authen ticated cases have been reported. Clinical Features Characteristically, the clinical manifesta tions of hepatic injury do not become evi dent for a variable interval following expo sure to hepatotoxins. In acute poisoning with agents such as carbon tetrachloride and chloroform, the latent period is relatively brief, usually not exceeding a day or two, and is well corre lated with the evolution of the lesion micro scopically. Although histologic evidence of hepatocellular injury can be demonstrated within a few hours, necrosis does not reach its peak for a period of 48 hours.114-7S4 Following repeated exposure to relatively small doses of certain hepatotoxins, there may be a long interval before signs of cir rhosis become clinically evident.5"4 This does not constitute a period of true latency, sincav it is possible to demonstrate the presence progressive lesions histologically at a ver early stage.114 The delayed appearance q symptoms in this instance is prooably relate to trie fact that the slowly progressive d> Toxic Hepatitis 505 osis is zonal, regend< Tashion within :t reuculum by proQg viable cells in the estoring the normal owever, this is not epatic necrosis, in rt proceed from disae zones of necrosis, nchymal cells are the intervening neg intact reticulum, ducts, into broad ; condition variously rhosis, postnecrotic hvperplasia and ate hepatic necrosis. :o hepatotoxins, in.loride,208,215 selenuces hepatomas in Although cirrhosis ppearance of these n whether necrosis `enchvmal cells are elopment.215 Theootoxins can induce iwever, no autheni reported. ZAT S clinical manifestalo not become evival following expo- ith agents such as td chloroform, the y brief, usually not . and is well correof the lesion microtologic evidence of n be demonstrated osis does not reach 18 hours.114- 784 posure to relatively hepatotoxins, there before signs of cirvident.574 This does ' true latency, since ate the presence of logically at a very fed appearance of is probably related rly progressive de struction of the parenchyma is accompanied by compensatory hepatocellular regeneration. Symptoms Not all of the clinical manifestations in acute toxic hepatitis are the consequence of liver injury, many being related to the extrahepatic pharmacologic and toxic ef fects of hepatotoxins. In many instances it is difficult to distinguish between the symp toms of hepatic and extrahepatic origin, and occasionally the latter predominate. Signs of renal damage and gastrointestinal irrita tion are especially common. The usual clinical picture resembles that - of viral hepatitis, except for the absence of preicteric fever and constitutional symptoms. Anorexia, nausea and vomiting are the prin cipal symptoms, and jaundice and hepato. megalv are the major physical findings. In | mild cases, jaundice may be absent. Usually, / the icterus is accompanied by bilirubinuria, ' but acholic stools are rare. In severely poisoned patients with massive or subacute hepatic necrosis, the clinical manifestations tend to be more severe and may include such unusual features as intense abdominal pain, coffee-ground vomitus, a rapid decrease in the size of the liver, as cites, edema, hemorrhagic phenomena, som nolence and coma. j As noted, repeated exposure to hepa totoxins mav produce cirrhosis. The clinical course in such cases is variable. In some, there are repeated episodes of acute hepa titis before frank signs of cirrhosis become evident, whereas in others the onset is insidious without antecedent symptoms of acute hepatic injury. Unless the exposure to a hepatotoxin is recognized, the former may be mistaken for relapsing viral hepatitis with posthepatitic cirrhosis, and the latter for | Laennecs or some other type of cirrhosis. Except in the most severely affected cases, recovery from acute toxic hepatitis tends to be more rapid and is less likely to be fol lowed by sequelae than in viral hepatitis. However, the ultimate prognosis depends as much upon the accompanying extrahepatic lesions as upon the state of the liver. Thus, for example, in carbon tetrachloride poison ing, the hepatic lesions may be mud and heal, while those in the kidney are extensive and lead to progressive renal failure and death. Laboratory Features The results of liver function tests are simi lar to those found in acute viral hepatitis, except that abnormalities of cephalin-cholesterol flocculation and thymol turbidity are less common.580 This difference may be re lated to the relative paucity of inflammatory cells in the lesions of toxic hepatitis. Although liver function tests are of limited value in distinguishing between toxic and viral hepatitis, they can be of great assistance in detecting the early signs of liver injury following known or suspected exposure to hepatotoxins, and in evaluating the severity and the progress of the lesion once it is established. In this connection, the serum transaminase level, because of its sensitivity and the relative ease with which it can be determined, is the most useful single screen ing test available. Treatment If the patient is seen immediately after exposure, an attempt should be made to re move any remaining traces of hepatotoxin from the intestinal tract by lavage and ca tharsis, or by hyperventilation in the case of toxic vapors. However, such measures are seldom successful once signs of toxic hepa titis are evident, because of the relatively long period of latency between exposure and the appearance of clinical manifestations. In the case of industrial hepatotoxins, it is important to keep all exposed personnel under close surveillance, preferably with periodic tests of hepatic function, and to remove such individuals from the contami nated environment at the first sign of func tional impairment. Antidotes. A number of chemical agents protect against the injurious effects of hepa totoxins in experimental animals.185 Only a few have been tested in man, and these have proved to be of no value in the treat ment of toxic hepatitis. This is not sur prising, since in most experiments these agents have been used prophylactically rather than therapeutically. BAL (2,3-dimercaptopropanol) would 506 Toxic and Drug-Induced Hepatitis appear to be an ideal antidote in the early management of toxic hepatitis due to com pounds of gold and arsenic, since it com bines both with free and tissue-bound metal lic ions to form relatively innocuous, soluble thiometal complexes which are excreted readily by the kidneys. However, the results of treatment in man have been disappoint ing.186 No doubt this is attributable to the fact that in most instances BAL has been tried in patients with hypersensitivity reac tions induced by organic arsenical or gold compounds rather than in those with toxic hepatitis. Since other chemical agents that protect against hepatotoxins in animals also contain sulfhydryl groups, their effectiveness has been attributed to a sulfhydryl-sparing action in essential enzyme systems. How ever, some of the nonsulfhydryl analogues of these agents are equally effective,102 so that their mode of action is unknown. Reports indicating that antihistamines protect against the hepatotoxic effects of thioacetamide, possibly by preventing mito chondrial swelling,366 and that adrenergic blocking agents protect against carbon tetrachloride poisoning by preventing he patic ischemia112 suggest new approaches to the treatment of toxic hepatitis. Although these agents have not been tried in man, if they do prove to be effective, they will have to be used within a-few hours of ex posure to the hepatotoxin. Diet. There are no well-controlled studies establishing the efficacy of dietotherapy in the management of toxic hepatitis in man, the rationale for such treatment being based almost exclusively on the results of animal experiments and on experience with other tvpes of liver disease. Most experimental studies of the interre lationships between dietary factors and the actions of hepatotoxins have been concerned with the influence of the antecedent nutri tional status on the incidence and the sever ity of hepatic injury following intoxication, and not with the effects of diet on the regen eration and the repair of the inj'ured liver-- the major considerations in the treatment of toxic hepatitis. This is an important distinc tion, since it does not follow that a dietary constituent that protects against the hepato toxic effects of an agent necessarily facilitates recovery once such inj'ury has occurred. The effect of protein in chloroform poison ing is a case in point. Here there seems to be little doubt that protein depletion enhances toxicity and that protein supplements under these conditions are protective, even if given some hours after exposure.*07 However, there is no evidence to show that such sup plements hasten recovery when adminis tered after overt signs of liver disease have appeared. Moreover, the protective action of most dietary constituents, including pro tein, have been demonstrated in depleted animals, so that no conclusions are war ranted regarding their therapeutic value in well-nourished individuals with toxic hep atitis. Also, it cannot be assumed that be cause a dietary constituent protects against one hepatotoxin it will necessarily do so against all. This is well illustrated in the case of protein, which protects the depleted animal against chloroform506 but not against carbon tetrachloride187 intoxication. Finally, in assessing the results of animal experiments, care must be exercised in dis tinguishing between the effects of dietarv measures on survival and their effects on the liver per se, since the former may be related to extrahepatic factors. Thus, in carbon tetrachloride poisoning, methionine in creases survival by preventing renal injurv but has no effect on liver damage.288 The impressive results of dietotherapy in Laennec's cirrhosis have encouraged its adoption in other forms of liver disease, in cluding viral and toxic hepatitis. Although this practice is reasonable, there is no con clusive evidence to indicate that dietary measures are effective in any type of liver injury other than that associated with nu tritional deficiency. In the absence of more precise informa tion regarding the most efficacious form of treatment in toxic hepatitis, it would seem logical to provide a diet rich in protein and carbohydrate on the principle that protein is required for tissue regeneration and is spared when adequate nonprotein calories are provided. Although there is no evidence to indicate that the addition of fat to a wellbalanced protein-containing diet is in any way deleterious to the injured liver, fat may be poorI anorexia of hepati it is dif Later, h proves, li cream, c aged, sir diet and high cal weight 1< follow ar Obvioi statemen caloric ri based or rather th With this that 70 fr ories con There is i protein i in cirrhos mav actu advancec of blood; protein c not impe liver inju vere ano parentera any ill eJ a numbei linistere face igc seessarily facilitates 'h injury has occurred. >tein in chloroform poisontit. Here there seems to be rotein depletion enhances rotein supplements under e protective, even if given - exposure-507 However, :e to show that such suprecovery when adminisigns of liver disease have er, the protective action nstituents, including proemonstrated in depleted ao conclusions are warheir therapeutic value in ividuals with toxic heplot be assumed that be- istihient protects against : will necessarily do so well illustrated in die ich protects the depleted reform500 but not against e187 intoxication, ing the results of animal oust be exercised in disn the effects of dietary il and their effects on the le f er mav be related ctor*. Thus, in carbon Dning, methionine in preventing renal injury m liver damage,289 isults of dietotherapy in have encouraged its irms of liver disease, inDxic hepatitis. Although onable, there is no con> indicate that dietary ive in any tvpe of liver lat associated with nu- more precise informanost efficacious form of epatitis, it would seem diet rich in protein and principle that protein ie regeneration and is ate nonprotein calories gh there is no evidence ddition of fat to a wellitaining diet is in any e injured liver, fat may Toxic Hepatitis 507 be poorly tolerated during the period of anorexia and indigestion in the early stages of hepatitis and has the disadvantage that it is difficult to administer parenterally. Later, however, when the appetite im proves, liberal use of fat in the form of milk, cream, cheese and eggs should be encour aged, since it makes for a more palatable diet and facilitates the maintenance of a high caloric intake, thus preventing the weight loss and the debility that so often follow an attack of acute hepatitis. Obviously, from what has been said, any statements regarding the precise protein and caloric requirements in toxic hepatitis are based on personal opinion and experience rather than on well-documented evidence. With this reservation in mind, it is suggested that 70 to 80 Gm. of protein and 3,000 cal ories constitute an adequate dietary intake. There is no evidence to indicate that a larger protein intake is more efficacious. Studies in cirrhosis507 suggest that excessive amounts may actually be harmful in the presence of advanced liver disease, by raising the level of blood ammonia. In prescribing protein for the patient with toxic hepatitis, due consideration must be given to the status of the kidneys, since hepatotoxins not infrequently produce acute tubular necrosis. In such cases, measures designed to reduce nitrogen retention and to attain a normal internal environment take precedence over the less urgent needs of the liver. Usually this entails omission of dietary protein, provision of sufficient carbo hydrate and fat calories to minimize en dogenous protein breakdown, and careful regulation of fluid and electrolyte balance. Fortunately, the relatively brief period of protein deprivation usually required does not impede recovery from the associated liver injury. Similarly, individuals with se vere anorexia and vomiting who require parenteral feedings do not appear to suffer any ill effects when protein is omitted for a number of days. Although parenterally ad ministered amino acids can be utilized in the face of severe hepatic injury,199 often they are poorly tolerated, so that their use is not recommended unless the situation de mands long-term parenteral feeding. From a practical standpoint, it is often difficult to achieve an intake of 3,000 calo ries during the first few days of an acute hepatitis, even if the diet is supplemented with parenterally administered glucose. This need not cause concern, since die easily at tainable level of 2,000 calories usually suf fices to tide the patient over this acute phase without compromising his chances of re covery or leading to any significant degree of malnutrition. When all or most of the calories must be administered by the parenteral route, there is an advantage in using relatively concen trated solutions of glucose. Provided that the infusion rate is slow, concentrations of 15 per cent can be infused over long periods of time without significant losses of glucose in the urine or the development of thrombo phlebitis. In experimental animals, vitamin B12 given prophylactically protects the liver against carbon tetrachloride injury.581 How ever, there is no evidence to indicate that vitamins administered following toxic in jury to the liver facilitate recovery. There fore, there would appear to be no rationale for supplementing the diet in the treatment of toxic hepatitis, except possibly in in stances where the antecedent diet has been deficient, or where prolonged parenteral feedings of vitamin-free glucose may pre cipitate an acute deficiency state. The effects of methionine and choline in experimental animals have encouraged the use of these agents in the treatment of toxic hepatitis.48, 201 However, there is no con vincing clinical evidence to show that these dietary supplements have any therapeutic value in well-nourished individuals. The principles governing the management of the cirrhosis that occasionally follows toxic hepatitis are essentially the same as those for Laennec's cirrhosis and therefore require no further discussion. However, the response to dietotherapy is likely to be far less impressive in the toxic type, since nu tritional factors are either lacking or are of subsidiary importance in its pathogenesis. Bed Rest. Although the importance of bed rest has not been established, it is rec ommended that the patient with acute toxic hepatitis be kept in bed until hepatic func tion returns to normal on the principle that 24905011 508 Toxic and Drug-Induced Hepatitis immobilization may facilitate repair of the injured liver by enhancing its blood flow and by reducing the metabolic demands made upon it. DRUG-INDUCED HEPATITIS Classification Most drugs that injure the liver appear to do so by inducing a hypersensitivity reac tion, but a few behave as true hepatotoxins. Methyltestosterone and a number of other substituted derivatives of testosterone com prise a special category whose actions are difficult to classify. The features that dis tinguish between these three groups of drugs are discussed at the beginning of this chapter. The morphologic changes and the clinical manifestations in drug-induced hepatitis may be predominantly tnose of hepatocellu lar injury or those of cholestasis, but in many instances features of both types are evident. The synthetic androgens and ana bolic agents also produce cholestasis, but the lesions differ in some respects from those seen in other forms of drug-induced hepatitis. Pathogenesis Surprisingly little is known about the mechanisms responsible for the dev elopment of drug-induced hepatitis, chiefly because the lesions are not reproducible in animals. Studies in man have been limited in scope, being largely concerned with the clinical, functional and morphologic features of the established lesion rather than with the fundamental disturbances that provoke he patic injury. Hepatocellular Injury. As pointed out, the few drugs that qualify as true hepato toxins, such as chloroform, behave like other hepatotoxins in that they injure the liver in all individuals given sufficiently large doses, exhibit the same effects in experimental ani mals and produce a distinctive type of zonal hepatic necrosis following a predictable and usually brief latent period. Characteristi cally, the extent of the lesions varies with the dose. In contrast, most other drugs that affect the liver produce a type of hepatic injury (1) that cannot be induced in all in dividuals, (2) that is not reproducible in animals, (3) whose morphologic features are more variable and less distinctive than in toxic hepatitis, (4) in which neither the occurrence nor the extent of the lesions can be correlated with the amount of drug con sumed, and (5) in which the latent period is variable and unpredictable. The sporadic nature of the susceptibility to drug-induced hepatitis and the frequency with which the hepatic lesions are accom panied by manifestations of hypersensitivity, such as fever, rash and eosinophilia, suggest that drug reactions of this type are allergic in nature. Longcope454 and Chase132 have emphasized the similarities between drug reactions and serum sickness and have pro posed that both represent forms of acquired hypersensitivity, a view that is supported by the observations of Landsteiner,411-4l2,413 Rich612, 914 and others.733- 777 Of particular interest in this connection is the fact that simple chemical compounds can serve as antigens and induce hypersensitivity,412,733 and that the tissue changes in drug reac tions closely resemble those of experimental anaphylaxis.311,615 Although the theory of acquired hyper sensitivity is based on an impressive body of evidence, some aspects of drug reactions ap pear to be inconsistent. These include the rarity with which circulating antibodies and skin hypersensitivity can be demonstrated, the inconstancy of the interval between the first exposure to a drug and the development of a reaction, and the variable character of the clinical manifestations. In contrast, the anaphylactic type of hypersensitivity seen in serum sickness and under experimental con ditions in animals is characterized by read ily demonstrable circulating antibodies and skin sensitivity, an immediate reaction to the antigen in the sensitized host, and a re sponse that is distinctive for the species.913 Even in the delayed or tuberculin type of hypersensitivity, the interval between the injection of an antigen and the appearance of a reaction in a sensitive host is usually not longer than 24 to 48 hours, and skin hypersensitivity can be demonstrated with great regularity. At present, our knowledge of drug reaction is too fragmentary to ac-  Drug-Induced Hepatitis 509 be.induced in all iono* reproducible in me jlogic features less distinctive than in which neither the snt of the lesions can amount of drug conich the latent period lictable. of the susceptibility tis and the frequency c lesions are accom1s of hypersensitivity, eosinophilia, suggest this tvpe are allergic and Chase132 have rities between drug rkness and have pront forms of acquired that is supported by andsteiner,411,412-413 r33, 77; q particular don is the fact that ounds can serve as /persensitivity,412-733 anges in drug reaclose of experimental of acquired hyperi iro^essive body of >f c reactions ap- These include the iting antibodies and n be demonstrated, aterval between the nd the development ariable character of ns. In contrast, the ersensitivity seen in r experimental conracterized by readting antibodies and lediate reaction to ized host, and a re} for the species.013 .* tuberculin type of erval between the nd the appearance ive host is usually 18 hours, and skin demonstrated with mt, our knowledge Vagmentary to ac count for these discrepancies, although sev eral possibilities may be considered. Since simple chemical compounds require con jugation with protein before they can serve as antigens,411-413-7" it is conceivable that variations in the length of the latent period are related to differences in the speed with which such conjugates are formed, and that failure to demonstrate circulating antibodies and skin sensitivity may be due to the use of inappropriately conjugated antigens in testing. Differences in the metabolic pathways followed by drugs may determine the readi ness with which antigens are produced and hence account for variations in individual - susceptibility. Although drug reactions occur more frequently in individuals with an al lergic background, differences in suscepti bility cannot be attributed to hereditarv constitutional factors alone, since the vast majority of reactions occur in individuals with no such background. The feature of drug hypersensitivity most difficult to explain is the extreme variability of its manifestations. Whv such hypersensi tivity is expressed as a fever and a rash in one individual, as hepatitis in another, and as a depression of myelopoiesis in a third, or why some drugs produce one or another of these manifestations more frequently than any of the others is completely unknown. Certainly, in experimental anaphylactic hy persensitivity, there is far less individual variation, and the nature of the sensitizing agent plays no significant role in determin ing the character of the reaction. Since the lesions are thought to be the consequence of an antigen-antibody reaction on or within cells,311 it has been suggested that the mani festations of hypersensitivity depend on the distribution of antibody within the tissues. Closely related to this problem is the I question of how the hepatic lesions are pro duced in drug reactions. Buckley105 and Follis233 have presented convincing evidence to show that the hepatic cells do not partici pate in experimental anaphylactic reactions, and that the focal necrosis and inflammation seen in the liver under such conditions308,433 are the consequence of vascular injury. Al though vascular lesions can be demonstrated in some cases of drug hypersensitivity,243 often the nature of the lesions suggests di rect injury to the hepatic parenchymal cells. This raises the question of whether drug reactions may not be more closely related to the delayed tuberculin type of hypersen sitivity, the type usually induced by infec tion, and characterized by sensitization of the tissues generally and by the absence of demonstrable circulating antibodies. Chase, who has studied this problem, believes that both the immediate anaphylactic and de layed tuberculin types of hypersensitivity may play a role in drug reactions.132 How ever, this has not been established, so that, for the present at least, drug reactions must be considered a unique form of hyper sensitivity. Some drugs, such as iproniazid, produce hepatic lesions that are indistinguishable from those of viral hepatitis.577 The possi bility that agents of this type enhance the susceptibility to intercurrent infection with the hepatitis virus or light up latent infec tion in carriers has been considered but has not been investigated. In differentiating between hepatotoxic and sensitizing drugs, and in evaluating the potential hazards of therapy with such agents, two generalizations are worth bear ing in mind. First, if a drug produces he patic injury in man but fails to do so in other species, it is likelv to prove to be a sensitizing agent and may be expected to produce other manifestations of hypersen sitivity. Second, if it gives rise to extrahepatic manifestations of hypersensitivity in some individuals, it can be predicted that sooner or later it will produce hepatitis in others. Cholestasis. Manv drugs, such as chlorpromazine, produce a tvpe of hepatitis, gen erally classified as cholestatic, in which the clinical and the laboratory features resem ble those of extrahepatic biliary obstruction. Characteristically, the liver shows evidence of bile stasis but few signs of hepatocellu lar injury. An inflammatory reaction in the portal triads is a constant feature, except in the type of cholestatic jaundice produced by methvltestosterone and other substituted derivatives of methyltestosterone. Drug-induced cholestatic hepatitis has been variously attributed to (1) subtle toxic 510 Toxic and Drug-Induced Hepatitis injury to the hepatic parenchymal cells, leading to increased viscosity of the bile and occlusion of the canaliculi712 or to swell ing of the parenchyma and compression of the canaliculi441; (2) toxic injury to the canalicular membranes of the parenchy mal cells, resulting in effacement or distor tion of their microvilli, secondary stasis and inspissation of bile, and ultimate dilatation and rupture of the canaliculi into the spaces of Disse647'ei9; and (3) a hypersensitivity reaction with injury to both the parenchy mal cells and small bile ducts.807 In support of the view that drugs of this type may be hepatotoxic, it has been demonstrated that in the rat chlorpromazine depresses Bromsulphalein excretion25 and enhances the hepatotoxic effects of ethionine.579 How ever, direct measurements have failed to demonstrate any alterations in bile flow883 and administration of massive doses of chlorpromazine for periods up to 6 months has not produced significant hepatic lesions or jaundice in such animals.579 These ob servations taken together with the fact that patients may recover from cholestatic hepa titis while still taking the offending drug,655 or may develop the disorder a week or two after discontinuing its use,354 appear to be inconsistent with the interpretation that these agents are hepatotoxic. As in hepato cellular type of drug-induced hepatitis, many features of the cholestatic type point to an underlying hypersensitivity reaction. These include its sporadic occurrence in patients receiving such drugs, the immu nity of animals and the frequency of its association with fever,373 rash141 and eosinophilia.176 ` The mode of action of methyltestosterone and other substituted derivatives of testos terone would appear to differ fundamen tally from that of other drugs that produce cholestatic hepatitis. Although jaundice de velops only sporadically following large doses of methyltestosterone781 or norethandrolone,194-649 the regular occurrence of Bromsulphalein retention in man313-308 and of reduced bile flow23 and alterations in the electron microscopic appearance of the canaliculi650 in the rat suggest that these compounds behave more like hepatotoxins than sensitizing agents. Consistent with this interpretation is the fact that they do not provoke an inflammatory reaction in the liver or produce clinical manifestations of hypersensitivity, such as fever, rash or eosinopbilia. However, they differ from most hepatotoxins in that they do not pro duce hepatic necrosis. Available evidence suggests that they interfere with bile excre tion bv some unknown mechanism. Since the plasma levels of conjugated bili rubin and alkaline phosphatase are invari ably elevated, it is generally agreed that regurgitation of bile is the major factor re sponsible for the development of jaundice in cholestatic hepatitis. Several mechanisms have been invoked to account for the reflux of bile under these conditions: (1) occlu sion of the canaliculi by inspissated bile.712 (2) dilatation and ultimate rupture of the canaliculi into the spaces of Disse,647 (3) obstruction of the small bile radicles in the portal triads by inflammatory exudate711 and (4) increased permeability of the eholangioles.329 Since each parenchymal cell is drained by several canaliculi and all canalic uli are arranged in a complex network of intercommunicating channels, it is highlv improbable that the scattered bile thrombi seen in cholestatic hepatitis obstruct the flow of bile significantly. Although the possibility of rupture of the canaliculi into the spaces of Disse cannot be excluded with certainty, electron micro scopic studies have failed to demonstrate such communications even under condi tions of complete biliary obstruction.298 Occlusion of the cholangioles by inflam matory exudate is often cited as an impor tant factor in the pathogenesis of druginduced cholestasis. However, this has not been established histologically and appears unlikely, since the inflammatory reaction in the portal triads usuallv is less intense than in the hepatocellular tvpe of drug-induced hepatitis and is totally absent in some cases. Except in rare instances in which actual necrosis of the cholangioles has been dem onstrated,807 there is no direct evidence that these structures are abnormally permeable under conditions of cholestasis. One possibility that has received insuffi cient attention is that drugs may produce cholestasis by affecting the bilirubin trans- 24905014 * < Drug-Induced Hepatitis 511 t \ they do not ry reaction in the l manifestations of as fever, rash or they differ from vt thev do not proAvailable evidence ere with bile excienechanism. 5 of conjugated hmphatase are invarilerally agreed that he major factor reipment of jaundice Several mechanisms count for the reflux ditioos: (1) ocC\^ inspissated bile,'12 late rupture of the es of Disse,647 (3) bile radicles in the imatorv exudate*11 eability of the choparenchymal cell is culi and all canalicomplex network of innels, it is highly ttered bile thrombi )at-; obstruct the ty of rupture of the es of Disse cannot aty, electron microled to demonstrate iven under condiobstruction.288 angioles by rnflamcited as an impormgenesis of drugtvever, this has not gically and appears imatorv reaction in is less intense than pe of drug-induced isent in some cases. ;es in which actual Dies has been demiirect evidence that lormally permeable lestasis. ias received insuffiirugs may produce the bilirubin trans port system and permeability of the hepatic parenchymal cells, thus permitting the reflux of conjugated bilirubin from the cells and/or the canaliculi into the lymph spaces and the sinusoids. That cellular disturbances of this tvpe can occur in the absence of histologic abnormalities is evident from the elegant in vivo studies of bile secretion carried out . by Hanzon, using direct microscopy of the liver following the injection of uranin, a fluorescent dye that is excreted in the bile.302 Similarly, reflux of bile from the canaliculi into the lymph spaces via the cytoplasm of the parenchymal cells has been confirmed by electron microscopy.208 More direct evi dence suggestive of altered permeability of the hepatic cells in cholestatic hepatitis is the rise in the serum transaminase level that often occurs in the absence of overt hepatic necrosis. Of interest are studies on the patho*. genesis of "geel-dikkop," a naturally occurI ring form of cholestatic hepatitis seen in v South African sheep that feed on the poi sonous plant Lippia rehmanni.620 Rimington and associates have shown that in the rab bit, icterogenin, a triterpene acid derivative of this plant, suppresses bile secretion and blocks the excretion of intravenously in jected conjugated and unconjugated bili rubin without producing histologic abnor malities in the liver.613 They interpret these observations as evidence of a defect in the f transport of bilirubin through the hepatic cells and suggest that icterogenin may alter : cell permeability, permitting regurgitation ' of bile from the canaliculi. 1 Pathology | Drugs may give rise to a variety of lesions, | depending on their mode of action. True ' hepatotoxins, such as chloroform, produce s parenchymal necrosis, degeneration and fatty infiltration with a distinctive zonal pattern in the lobules, and little or no in flammatory reaction. In contrast, sensitizing drugs give rise to hepatocellular and/or cholestatic lesions that differ from those seen in toxic hepatitis. In the hepatocellular type, produced by agents like the sulfonamides,243 the liver shows scattered foci of parenchymal necro (sis and a diffuse inflammatory reaction that usually is most intense in the portal triads. Bile stasis is an inconstant but common fea ture, whereas deposition of fat is rare. Oc casionally, the portal triads contain granulomata, some of which may involve vessel walls.243,517 Some drugs, such as iproniazid and cinchophen, cause lesions that are in distinguishable from those of viral hepatitis and occasionally involve large masses of parenchyma, producing the picture of sub acute or massive hepatic necrosis.377 A fatal outcome is relatively common in this group; in survivors, healing of the liver may be ac companied by scarring and the develop ment of postnecrotic cirrhosis. Many sensitizing drugs, such as chlorpromazine, produce hepatic lesions in which bile stasis, particularly in the pericentral bile canaliculi, is the predominant feature. Usually, the portal triads are infiltrated to a variable degree with mononuclear, poly morphonuclear and eosinophilic leukocytes. The absence of hepatocellular necrosis and intralobular inflammation is generally em phasized as a characteristic feature of druginduced cholestatic hepatitis. However, care ful study of biopsy specimens frequently reveals such changes, although not to the same extent as in the hepatocellular type.383, 307 In the writer's experience no sharp dis tinction can be drawn between the lesions of cholestatic and hepatocellular hepatitis. Although cholestasis may predominate in the one and parenchymal damage in the other, most cases show evidence of both. The hepatitis produced by some drugs may be of the cholestatic type in some individ uals and of the hepatocellular type in others. Usually, recovery from cholestatic hepa titis is relatively prompt and without resid uals. However, the disease may run a pro longed course with persistent jaundice and hepatomegaly, occasionally accompanied by splenomegaly, hypercholesterolemia301 and xanthomatosis.70, 329,724 This svndrome has been reported following hypersensitivity re actions to the axsphenamines301,724 sul fanilamide,68 thiouracil,253 neocinchophen70 and chlorpromazine.520 Although ultimate recovery without significant residuals occurs and is said by some594 to be the rule, there are well-documented instances of slowly progressive periportal inflammation and 24905015 512 Toxic and Drug-Induced Hepatitis fibrosis leading ultimately to the develop ment of biliary cirrhosis.82-70,383-528 Both the clinical and the histologic findings in such cases bear a remarkable resemblance to those described in primary biliary cir rhosis. This suggests the interesting possi bility that, in some instances, unrecognized reactions to drugs are important in the pathogenesis of this otherwise obscure disease. The hepatic lesions produced by methyltestosterone and other substituted deriva tives of testosterone are characterized by pericentral canalicular bile stasis and thus resemble those of drug-induced cholestatic hepatitis. However, they differ in that they show no significant hepatocellular damage or inflammatory reaction.94-181 Rarely, drugs of this type produce peliosis hepatis,274- 378 an unusual disorder that may be fatal in which the parenchyma of the liver is studded with blood-filled cystic spaces lined by endothelial or hepatic pa renchymal cells. Focal necrosis, vasculitis and agonal congestion have been invoked as possible factors in the pathogenesis of this lesion. Clinical Features The interval between the first exposure to a drug and the onset of a reaction involving the liver tends to be longer and is less pre dictable than in toxic hepatitis. Reactions of this type are seen most commonly be tween the 2nd and 5th week, but may occur as early as the 1st day or only after many months of drug administration. Occasion ally, the reaction appears as long as a week or two after cessation of therapy.328 Variations in the period of latency appear to be dependent on host factors rather than on the nature of the agent involved. In previously exposed individuals, readminis tration of a drug may provoke a reaction following the first dose, presumably because of antecedent sensitization. However, simi lar immediate reactions are seen occasion ally in individuals with no history of previ ous exposure.426 It is difficult to account for such cases on the basis of hypersensitivity unless it is assumed that inadvertent con tact with the drug or with some chemically related compound has occurred in the past. Symptoms Not infrequently, the onset of drug-in duced hepatitis is heralded by the abrupt appearance of constitutional manifestations of hypersensitivity, such as fever, chills, a morbilliform or urticarial rash, pruritus and arthralgia. Often these are accompanied by anorexia and nausea, and less commonly by vomiting and abdominal pain. Jaundice and dark urine become evident within a few days and usually are accompanied by en largement and tenderness of the liver. Splenomegaly is seen occasionally but is less common than in viral hepatitis. Acholic stools and pruritus are frequent findings in cholestatic hepatitis but are inconstant fea tures in the hepatocellular type. In some cases the onset of jaundice is insidious without antecedent or accompany ing constitutional symptoms. This is the rule in the type of cholestatic hepatitis produced by methyltestosterone and other substituted derivatives of testosterone and may be seen in other forms of drug-induced hepatic injury. Liver damage may occur in the absence of jaundice. This is illustrated by the fre quency with which Bromsulphalein reten tion,419 rises in the serum levels of alkaline phosphatase383 and transaminase,649 and his tologic changes in the liver383 can be dem onstrated in die course of drug reactions un accompanied by jaundice or other overt clinical signs of hepatic involvement. Usually, prompt withdrawal of the offending drug is followed within a few days by subsidence of fever and other constitutional manifestations. However, the signs of hepa titis clear more slowly, usually requiring 2 to 3 weeks for full resolution. Occasion ally, they persist for many weeks or even months. Protracted cholestatic jaundice may be ac companied by progressive enlargement of the liver and the spleen, intractable pruri tus and xanthomatosis,92'70'529 features in distinguishable from those of so-called pri mary biliary cirrhosis. In a few instances, cirrnosis has been demonstrated histologi cally,92' T0' 529 but in others the inflamma tory reaction and fibrosis in the liver have been less extensive, and apparent clinical recovery ha come in th< the histolo levels of Si cholesterol of the jaum with docu tends to ru other form; Drugs st and cincho that reseml sionallv pr> patic necrc clinical ma stances are complicate elude sue! abdominal rapid decre edema, he lence and course is d covery taki of postnecr plasia. If t logically, t] such cases signs of ci years later, more prok signs of 1 may ensue usually is rhage from rent infecti In the h hepatitis, t are identic; hepatitis, of serum common. The typ cholestatic of extrahej for the occ transamina ease. Char; in serum b fraction pi rubin in th 24905016 Drug-Induced Hepatitis 513 c *ug-inr tiic abrupt anifestations ver, chills, a pruritus and jmpanied by ommonly by faundice and 'ithin a few mied by en~ t the liver, nally but is .titis. Acholic \t findings in constant fea- jaundice is accompanyus is the rule .tis produced r substituted may be seen ced hepatic the absence - by the frebalein retenls r' Vkaline *e\ ud hiscan be demreactions un- other overt ement. the offendfew days by constitutional igns of hepa' requiring 2 o- Occasion al^ or even ce may be acargement of ctable pruri- feahires ino-called priw instances, d histologile mflamma* Uver have rent clinical recovery has occurred.684 The ultimate out come in the latter group is uncertain, since the histologic abnormalities and the raised . levels of serum alkaline phosphatase and cholesterol usually persist despite clearing of the jaundice and xanthomatosis. In cases with documented cirrhosis, the disease tends to run a more benign course than in other forms of biliary cirrhosis. Drugs such as iproniazid, pyrazinamide and cinchophen, which give rise to lesions that resemble those of viral hepatitis, occa sionally produce subacute or massive he patic necrosis. As might be expected, the clinical manifestations under these circum. stances are usually more severe than in unJ complicated acute hepatitis, and may in clude such unusual features as intense abdominal pain, coffee-ground vomitus, a rapid decrease in the size of the liver, ascites, edema, hemorrhagic phenomena, somno lence and coma. Occasionally, the clinical course is deceptively benign, apparent rej covery taking place despite the occurrence of postnecrotic scarring and nodular hyper plasia. If the liver is not examined histo logically, the true nature of the lesion in such cases may not become evident until signs of cirrhosis appear months or even years later. Usually, however, the course is more prolonged and is characterized by signs of hepatic decompensation. Death i may ensue in a few weeks or months and I usually is due to hepatic failure, hemor rhage from esophageal varices or intercur rent infection. i Laboratory Features In the heptocellular type of drug-induced i hepatitis, the results of liver function tests ; are identical with those seen in acute viral hepatitis, with the exception that high levels of serum alkaline phosphatase are more | common. The typical biochemical pattern in the I cholestatic type of hepatitis resembles that of extrahepatic biliary obstruction, except for the occurrence of high levels of serum transaminase early in the course of the dis ease. Characteristically, there is an increase in serum bilirubin involving the conj'ugated j fraction predominantly, excretion of bili] rubin in the urine, a decrease in the output of urobilinogen in the feces, and a sharp rise in the serum levels of alkaline phos phatase and cholesterol. With few excep tions, thymol turbidity and cephalin-cholesterol flocculation remain normal. In the pro tracted form of cholestatic hepatitis, par ticularly in cases complicated by xantho matosis, the concentration of cholesterol rises to high levels, often above those seen in extrahepatic biliary obstruction or pri mary biliary cirrhosis.594 Studies with acetate-l-14C indicate that the rate of choles terol and phospholipid synthesis under these conditions is greatly increased.529 Both the serum alkaline phosphatase and cholesterol attain high levels relatively early in the dis ease, a point that may help to distinguish between drug-induced cholestasis and bili ary obstruction. Eosinophilia is an inconstant feature of drug reactions but, when present, may be an important clue to the etiology in druginduced hepatitis. Usually, the leukoevte count is normal or moderately elevated, but leukopenia and agranulocytosis are seen oc casionally.838 Treatment Prompt withdrawal of the offending agent is of prime importance in the management of drug-induced hypersensitivity reactions, since this alone may abort the reaction and prevent serious injury to the liver and the bone marrow. However, once provoked, re actions of this type may run a fulminant and even fatal course despite the absence of further exposure to the drug. Although ACTH and adrenal cortical steroids are useful in other allergic diseases, their efficacy in drug-induced hepatitis has not been established. Nevertheless, since favorable results have been reported in a few instances,159,712 it would appear reason able to employ these agents in severe druginduced hepatitis that does not respond to drug withdrawal and simple supportive measures, or when continued administra tion of the offending drug is urgently needed. Since a serious reaction may follow even a single small dose, it is unwise to readminister drugs that have previously provoked manifestations of hypersensitivity unless the 24905017 514 Toxic and Drug-Induced Hepatitis indications are urgent. Successful! desen sitization with graded doses has been re ported,7W* 772 but it is difficult to evaluate the efficacy of this procedure, since drug reactions may subside spontaneously de spite continued administration of the offend ing agent534-W5- 888 or may fail to recur when drug therapy is resumed following recovery.783 If desensitization is attempted, concomitant steroid therapy early in the course may help prevent reactions.765 In general, the principles of treatment are the same as for toxic hepatitis and are dis cussed elsewhere. In the protracted form of cholestatic hep atitis, special measures may be required to control intractable pruritus, diarrhea and the tendency to decalcification of the bones. Methyltestosterone and norethandrolone re lieve the pruritus,594 but may intensify the jaundice. Although there is no conclusive evidence to indicate that this retards ulti mate recovery, it is probably wiser to use cholestyramine, a resin that binds bile acids and prevents their reabsorption from the in testinal tract.122 Because of the malabsorp tion that usually accompanies the impair ment of bile flow in prolonged cholestasis, vitamin D deficiency and decalcification of the bones may ensue. Accordingly, supple ments of vitamin D and calcium should be prescribed to avoid this complication. Diar rhea related to malabsorption of fat may be partially alleviated by reducing the fat con tent of the diet, but this is done only if the diarrhea is troublesome, since it may lead to wasting. Prophylaxis Since the potential hazard of sensitization cannot be evaluated in animals, all new drugs must be considered suspect until proved to be otherwise by prolonged trial in man. If a drug gives rise to any of the manifestations of hypersensitivity, one can be reasonably confident that sooner or later it will produce hepatitis. Although it is not possible to predict the susceptibility to drug reactions, the hazard appears to be somewhat greater in indi viduals with an allergic background, par ticularly those with a history of a previous reaction to other drugs. Indeed, during a reaction, patients may exhibit hypersensi tivity to a wide variety of unrelated agents. For that reason it is best to stop all medi cations until the reaction subsides and then, if necessary, resume their use one at a time. Patients receiving sensitizing drugs should be watched carefully for early signs of a re action. If fever, rash or pruritus occur, the medication should be stopped immediately, at least until other possible causes can be excluded. In the case of patients given agents known to produce serious reactions involving the liver, the serum alkaline phos phatase and transaminase should be tested at weekly intervals during the first 2 months, the period of greatest risk. SPECIAL FEATURES OF AGENTS CAPABLE OF PRODUCING LIVER INJURY Hepatotoxins comprise such a hetero geneous group with respect to their chem ical structure and mode of action that thev are difficult to classify in any logical or orderly manner. For convenience, therefore, the following section is arranged alphabet ically. The agents selected for discussion bv no means constitute a complete inventory of substances that can injure the liver, but most of those known to produce toxic hep atitis in man are included. ACCIDENTAL AND INDUSTRIAL POISONING Beryllium Inhalation of beryllium compounds may provoke either an acute pneumonitis or a chronic granulomatous reaction in the lung. The former, which is more common, follow s exposure to most of the beryllium dusts and fumes encountered in industry, appears after a relatively brief incubation period, is char acterized pathologically by an exudation of mononuclear cells into the alveoli and usuually resolves completely within 4 months. In contrast, the chronic disease develops chiefly following exposure to beryllium oxide, appears after a relatively long latent period, ranging from a month to 15 years, is characterized pathologically by a diffuse 24905013 Accidental and Industrial Poisoning 515 ** exl' 't hypersensiif v dated agents, rt: to stop all medi. subsides and then, r use one at a time, itizing drugs should early signs of a re pruritus occur, the jpped immediately, ;ib!e causes can be of patients given >e serious reactions erum alkaline phosse should be tested g the first 2 months, sk. IS OF AGENTS RODUCING JURY >e such a heteroaect to their chemof action that they in any logical or venience, therefore, arranged alphabetjd for discussion by mp1 ' inventory of jure <e liver, but produce toxic hep- ) INDUSTRIAL ING OM m compounds may i pneumonitis or a eaction in the lung, re common, follows beryllium dusts and lustry, appears after tion period, is charby an exudation of he alveoli and usuy within 4 months, ic disease develops sure to beryllium :latively long latent lonth to 15 years,303 gically by a diffuse granulomatous reaction that closely re sembles sarcoidosis and runs a chronic pro gressive course that often terminates fa tally.71*- 750 Not infrequently, the disease is accompanied by hepatosplenomegaly, a raised level of serum gamma globulin, a negative tuberculin reaction, hypercalcuria and renal stones,303 features that may make the differentiation from sarcoidosis exceed ingly difficult. Although acute and chronic berylliosis are considered distinct clinical and morpho logic entities, it has been suggested, on the basis of autopsv studies, that the chronic granulomatous lesion represents a late de velopment in the evolution of the acute pneumonic process.105 This view is difficult to reconcile with the observation that, while the inhalation of beryllium compounds pro vokes an acute pneumonitis, neither inhala. tionT" nor parenteral administration688 of . such agents produces granulomas in the } lungs of experimental animals. Several features of the granulomatous re action suggest that it results from sensi tization to beryllium. These include its sporadic occurrence in exposed individuals, the long period of latency, the disparity between the amount of beryllium found in the lungs and the severity of the lesions718 and the immunity of experimental animals. The fact that patch tests with beryllium salts provoke a granulomatous inflammatory re action in the skin of affected individuals170701 lends support to the sensitization theory. However, the possibility that beryllium can provoke a granulomatous reaction in the lung by some direct action cannot be ex cluded with certainty, since subcutaneous . injections of beryllium produce granulomas both locally291-696 and in regional lymph nodes.251 Berylliosis may be acquired in any occu pation involving the handling of beryllium or its compounds. Metal workers who ma chine beryllium or alloys high in beryllium content, and manufacturers of ceramics, radio tubes and neon signs are the principal victims.702 The use of beryllium phosphorus in fluorescent bulbs was discontinued in 1949, so that this no longer constitutes the hazard it once did.30* Individuals who live within a 3-mile radius of a beryllium plant may acquire the disease as a consequence of prolonged exposure to low concentra tions of beryllium-containing dust and fumes emitted from smoke stacks.133-180 In advertent intoxication occurs also in individ uals who come in contact with the contami nated clothing of beryllium workers.189-303 A variety of hepatic lesions are found in fatal cases of both forms of pulmonary berylliosis. These do not occur with any degree of regularity, nor do they give rise to overt signs of liver disease. In the acute pneumonic type, centrilobular necrosis is the principal finding.103- 750 Hepatic necrosis also occurs in animals after intravenous in jections of beryllium compounds.886 How ever, the lesions produced tend to be midzonal in location and do not occur when the beryllium is administered by the respiratory route.722 Therefore, the centrilobular ne crosis in man may be due not to the local toxic action of beryllium but rather to the passive congestion and anoxia that occur terminally in acute beryllium pneumonitis. In the delayed form of chronic beryllium intoxication, small granulomata, similar to those in the lung, are often found scattered throughout the fiver.133- 180-750 These are in distinguishable from the lesions seen in sar coidosis and a number of other related dis eases.385 Chronic passive congestion of the liver secondary to cor pulmonale and heart failure is another abnormality found with some frequency. In rare instances the liver mav exhibit central and midzonal necrosis,189 severe parenchymatous degeneration189 and a diffuse fibrosis.105 Whether or not these are directly related to the effects of beryl lium is not known. Both the clinical features and the histo logic findings in berylliosis may be indistin guishable from those of sarcoidosis. Usually, a history of exposure to beryllium suffices for differentiation, but in doubtful cases a patch test may be required for confirmation. In this test a small gauze square moistened w-ith a I or 2 per cent solution of beryllium sulfate or nitrate is applied to the skin for 48 hours. On removal of the patch, patients with berylliosis exhibit an area of erythema, induration and scaling which may persist for a number of weeks. Biopsy of the skin 24905019 516 Toxic and Drug-Induced Hepatitis late in the course of the reaction shows sarcoid-like granulomas with small zones of central necrosis,701 From the evidence available, this test appears to be sensitive and specific.170, 701 Carbon Tetrachloride Because of its widespread use as a solvent, fire-extinguisher and cleaning agent, carbon tetrachloride is an important cause of toxic hepatitis. Poisoning usually follows inhala tion of the vapor in a poorly ventilated en closed space but also occurs after its inges tion. It is not known whether it is absorbed significantly through the skin. It has been suggested on the basis of autopsy690 evi dence that liver injury is more common after ingestion than after inhalation of car bon tetrachloride. However, this has not been borne out in all studies.514 Susceptibility. In animals, as little as 0.02 ml. of carbon tetrachloride/kg. can produce histologically demonstrable hepatic lesions. On the basis of experiments carried out on criminals awaiting execution,178 it would appear that only slightly larger doses (5 ml.), well within the antihelminthic thera peutic range, occasionally produce similar lesions in man. Although these are usually not detectable clinically, there are marked individual differences in susceptibility, so that even small doses of carbon tetrachloride occasionally inflict serious injury. Fatal in toxication has been reported after the in gestion of as little as 1.5 ml.,437 yet recovery has followed poisoning with amounts in excess of 100 ml.423 With respect to the toxic level of car bon tetrachloride in the atmosphere, it is obviously a function not only of the concen tration but also of the duration of exposure. On the basis of animal experiments it has been estimated that a concentration in ex cess of 0.01 per cent in air is required to produce clinically detectable intoxication in individuals chronically exposed to carbon tetrachloride vapor in their work.608 The time-dose relationships under other condi tions have not been worked out. Alcohol Ingestion. Clinical and experi mental evidence indicates that alcohol greatly increases the susceptibility to carbon tetrachloride. In one autopsy series,*14 for example, 11 of 12 fatal cases of accidental poisoning occurred in alcoholics. Similarly, are ev. a maxi of 34 individuals being treated for hook is acti worm infestation with small doses of carbon recovei tetrachloride, the only 2 instances of toxicity ever, t were encountered in alcoholics.691 Results an incr of animal experiments confirm these clinical observations.409 long af returns The mechanism underlying this synergism succurr is not known, but it has been suggested that days fc alcohol, by virtue of its solvent properties, of liver enhances the absorption of carbon tetra ing ma chloride from the intestinal tract409 and Mass facilitates its penetration and storage in be reca cells,631 or it renders the liver more sus unless ceptible to injury by increasing its fat con directly tent.514 Another possibility is that carbon has see tetrachloride is oxidized to phosgene and necrosk then undergoes condensation with ethanol bon tetr to form etnylchloroformate, a compound recover allegedly more toxic than carbon tetrachlo scarring ride.263 Renai None of these theories alone, however, fatal ea accounts for the fact that alcohol enhances The prii the toxicity of both ingested and inhaled changes carbon tetrachloride, that it increases the and cell severity of injury in both the liver and support] kidney, and that the increased susceptibility active r is seen in chronic alcoholics who have not lium.514 been drinking immediately prior to poison The f ing.314 Moreover, whereas alcohol enhances chloride the acute toxic effects of carbon tetrachlo terest ai ride, it does not increase the severity of individu the hepatic lesions in chronic poisoning.410 days. Cl Nutritional Status. Susceptibility to car a fibrino bon tetrachloride also appears to depend forma tio on the nutritional status. In animals, in walls, ai anition235 and high-fat diets80 increase the lining cr toxicity of carbon tetrachloride, whereas, to renal surprisingly, low-protein diets do not.187 those se The importance of these factors in man has failure, not been investigated. show ed Pathologic changes in fatal cases of car bronchoj: bon tetrachloride poisoning314 closely re thought semble those described in experimental an tion and imals.114 rect effec The hepatic lesions are characterized bv right-side diffuse fatty degeneration and necrosis of panies th the centrilobular parenchyma, collapse of Areas reticulum, hemorrhage and leukocytic in 'be seen.3 filtration. Regeneration occurs early and to the kid proceeds from intact cells at the periphery observed of the lobule. In animals cytologic changes ure.28 As Accidental and Industrial Poisoning 517 il > _o accidental alc^.iolics. Similarly, ig treated for booksmall doses of carbon 2 instances of toxicity alcoholics.88* Results confirm these clinical are evident within a few hours and reach a maximum in 24 to 48 hours; regeneration is active by the 3rd day, and histologic recovery is complete by the 14th day. How ever, the hepatic cells continue to exhibit an increased susceptibility to further injury long after their microscopic appearance has returned to normal.331 Individuals who have ;rlying this synergism > been suggested that ts solvent properties, on of carbon tetratestinal tract408 and ion and storage in the liver more susicreasing its fat conility is that carbon id to phosgene and isation with ethanol nnate, a compound an carbon tetrachlo- succumbed to renal failure as long as 18 days following intoxication still show signs of liver injury,514 which suggests that heal ing may occur more slowly in man. Massive hepatic necrosis is rare. It will be recalled that the same is true in animals, unless the carbon tetrachloride is injected directly into the portal vein.116 The writer has seen two instances of subacute hepatic necrosis following a single exposure to car bon tetrachloride.383 Although these patients recovered clinically, residual postnecrotic scarring was evident on biopsy. Renal lesions are invariably present in ies alone, however, j fatal cases and may be the cause of death. lat alcohol enhances The principal findings include degenerative igested and inhaled changes in the tubules, the presence of heme bat it increases the and cellular casts, cellular infiltration of the both the liver and supporting connective tissue, and signs of reased susceptibility active regeneration in the tubular epithe 10I vho have not tely j-/rior to poison- lium.514 The pulmonary findings in carbon tetra- as alcohol enhances I chloride poisoning are of considerable in- rf carbon tetrachlo- * terest and are seen with great regularity in ase the severity of j individuals who survive for longer than 8 hronic poisoning.410 days. Characteristically, the alveoli exhibit isceptibility to car- a fibrinous exudate with pseudomembrane appears to depend formation, fibroblastic thickening of their us. In animals, in walls, and proliferation of their epithelial diets80 increase the | lining cells.754 These appear to be related achloride, whereas, to renal insufficiency and are identical with n diets do not.187 those seen in other forms of acute renal factors in man has failure. In addition, the lungs frequently 'show edema, hemorrhage, congestion and i fatal cases of car-ning514 closely re in experimental an- bronchopneumonia, features that are thought to be the result of shock, infec tion and other factors unrelated to the dijrect effects of carbon tetrachloride. Often, 'e characterized bv right-sided dilatation of the heart accom m and necrosis of panies these pulmonary changes. diyma, collapse of 1 Areas of atypical focal pancreatitis may and leukocytic in- :be seen.514 These too appear to be related occurs early and to the kidney damage, since they have been Is at the periphery observed in other types of acute renal fail * cytologic changes ure.28 As a rule, the lesions are limited in extent and severity and do not give rise to overt symptoms. Clinical manifestations of acute carbon tetrachloride poisoning relate to (1) the general toxic and pharmacologic effects of the agent, (2) liver damage or (3) renal injury. Although any of these may predom inate, careful examination usually discloses evidence of all three. Often the three groups of symptoms overlap, so that it may be im possible to specify their origin. The general toxic and pharmacologic ef fects of the poison are the first to become evident. Usually, they appear within a few hours but may be delayed for as long as a day. With large oral doses and, more com monly following inhalation of toxic fumes, the onset may be immediate. The most frequent symptoms during this period in clude dizziness, headache, nausea and vomiting. In more severe cases, there may be confusion, abdominal cramps, diarrhea, generalized muscle pain and vasomotor col lapse. Occasionally, exposure to a high con centration of fumes results in a deep but transient narcosis due to the anesthetic properties of the agent. Death seldom oc curs during this initial period. Occasionally, even fatal doses of carbon tetrachloride do not produce immediate symptoms, so that the first signs of intoxication are delayed until hepatic or renal involvement becomes evident some days later. Clinical signs of liver involvement appear 2 to 4 days after intoxication, or a day or two after the maximum injury demonstrable histologically. Jaundice and hepatomegaly are the principal clinical manifestations; however, it is evident from autopsy find ings514 that extensive hepatic necrosis may occur without producing either. Therefore, it is important to check the functional stasis of the Uver in evaluating the severity of car bon tetrachloride intoxication. The gastro intestinal symptoms which appear shortly after exposure usually increase as the signs of liver damage become evident. In gen eral, the severity of the poisoning is cor related with the depth of jaundice. How ever, death from renal failure may occur with little or no clinical evidence of hepatic injuiy.514,8SM>*706 Autopsy studies indicate that the kidneys 518 Toxic and Drug-Induced Hepatitis are involved about as frequently as the liver, and in many cases renal failure dom inates the clinical picture.514,690 It has been suggested that there is an inverse relation ship between the severity of the lesions in the kidneys and the liver.514 Most deaths attributable to hepatitis occur during the 1st week, whereas those due to renal fail ure occur in the 2nd and 3rd weeks.754 However, as indicated, usually there is evi dence of both hepatic and renal injury in all cases. Even in mild intoxication, the urine usually contains albumin and casts during the first few days. In more severe cases, oliguria appears between the 2nd and 4th days and men may progress to complete anuria. Azotemia is common and occasionally is accompanied by hypertension. During the period of oliguria the specific gravity tends to become fixed at a level of 1.010, and often the urine contains a significant num ber of red blood cells and polymorphonu clear leukocytes. In some cases, however, the urine shows little, other than a reduced volume and a low specific gravity, despite the presence of severe azotemia. The close resemblance of the clinical picture to that in other forms of acute tubular necrosis has been emphasized.706 However, dehydration due to fluid losses from the intestinal tract often plays an important role in the develop ment of azotemia and must be taken into consideration in planning therapy. Not infrequently peripheral and pulmo nary edema supervene as the azotemia pro gresses. While cardiac failure may be re sponsible for this complication in some cases, often faulty regulation of fluid and electrolyte balance is the cause. The dysp nea, cyanosis and signs of consolidation that appear terminally are due usually to the pulmonary lesions associated with azotemia described previously. Occasionally, acute julmonary edema is seen immediately fol- Jowing exposure to carbon tetrachloride. This is thought to be the result of the direct irritant effect of the agent on the alveoli. Prognosis. It is difficult to predict the outcome in any given case of carbon tetra chloride poisoning. In general, the outlook is favorable if jaundice is mild and the signs of renal impairment are minimal or absent. However, the prognosis should be guarded early in the course of mild hepatitis, since the appearance of renal failure may be de layed for a number of days and then ter minate fatally. If the patient survives the 1st week he is not likely to die of hepatic failure. Similarly, if azotemia is not evident by the end of the 1st week it is unlikely to develop later, so that the outlook for re covery is excellent. If the initial effects of acute carbon tetra chloride poisoning are survived, the signs of hepatitis usually subside in 2 to 4 weeks, a period slightly longer than that required for morphologic restitution of the liver in experimental animals.114 As a rule, there are no residuals, but in occasional cases healing of extensive lesions is followed by post necrotic scarring.583 Recovery from renal in jury is somewhat slower but is always com plete. Occasionally, cirrhosis follows re peated exposure to subclinical toxic doses of carbon tetrachloride,574 as in experi mental animals.114 The clinical picture in such cases does not differ significantly from that in other types of cirrhosis, so that the diagnosis depends almost entirely on the history of exposure. Early recognition of this condition is important, since the cir rhotic lesion may be reversible in its earlv stages if further exposure to the toxin is prevented.114 Treatment. The general principles of treatment are outlined on pages 505-508. As mentioned, there is no evidence to indicate that supplements of protein, methionine or choline exert any therapeutic effect in the well-nourished individual. However, it is possible that they may be of benefit in mal nourished individuals if given immediately after intoxication. A wide variety of chemically unrelated substances, including tocopherol,340 glu tathione,102 sodium thiomalate,102 sodium malate,102 sodium thioglycoilate,,y- sodium glycocollate,10- vitamin Bi2!SI and adren ergic blocking agents112 reportedly protect animals against the toxic effects of carbon tetrachloride when given prophijlactically. However, they have not been tried as thera peutic agents, and their mode of action is not understood'. Hemodialysis is effective in the manage ment of 1 tetrachk Cm Becau ties, the diphenv. sulation Howeve. that the dustry. most fr consists thalenes tetrachlc it has b< naphtha! directly is enhai small an alcohol.6 Althoi mav leiu inhalatio agent di or the cc atitis pr often ter necrosis Charactc the dev rexia an< longed e it is he] acneforrr recognize the chloi hepatom and then size of t disease r usually death wi Occasi and dcat liver suj abdomin; in such i patic nei pancreati 727 is not Few ca Accidental and Industrial Poisoning 519 sh 1 be guarded nilt .epatitis, since . failure may be de days and then ter>atient survives the Iv to die of hepatic temia is not evident eek it is unlikely to the outlook for re- : acute carbon tetraarvived, the signs of e in 2 to 4 weeks, than that required tion of the liver in r As a rule, there are isional cases healing followed by postovery from renal in but is always comrrhosis follows rejclinical toxic doses e,574 as in experi- clinical picture in gr significantly from irrhosis, so that the ost entirely on the arly recognition of tar ince the cirvei. in its early ure to the toxin is aeral principles of >n pages 505-508. As evidence to indicate rtein, methionine or peutic effect in the lal. However, it is oe of benefit in mal: given immediately hemicallv unrelated tocopherol,340 gluiomalate,102 sodium ;Iycollate,102 sodium B12581 and adren: reportedly protect ic effects of carbon en proph ijlactically. been tried as therar mode of action is tive in the manage ment of severe renal failure due to carbon tetrachloride poisoning.283 Chlorinated Naphthalenes and Diphenyls Because of their unique physical proper ties, the chlorinated naphthalenes and the diphenvls make ideal materials for the in sulation of electrical wire and condensers. However, they are such potent hepatotoxins that they are no longer widely used in in dustry. The commercial product employed most frequently, and known as Halowax, consists of a mixture of chlorinated naph thalenes and at one time contained carbon tetrachloride as a solvent. Experimentally, it has been shown that the toxicity of the naphthalenes and the diphenyls is related directlv to their degree of chlorination and is enhanced greatly by the presence of small amounts of carbon tetrachloride and alcohol.80 Although ingestion of these compounds may lead to poisoning,80 most cases follow inhalation of fumes given off by the molten agent during the soldering of condensers or the coating of wires.279 The type of hep atitis produced . is unusually severe and often terminates fatally in subacute hepatic necrosis or postnecrotic cirrhosis.231'2`9-l2` Characteristically, the onset is insidious with the development of general debility, ano rexia and nausea and usually follows pro longed exposure to the toxin. Occasionally, it is heralded by the appearance of an acneform rash (chloracne), one of the wellrecognized signs of toxicity in handlers of the chlorinated naphthalenes. Jaundice and hepatomegaly appear a week or two later and then are followed by a decrease in the size of the liver, ascites and edema. The disease runs a chronic downhill course and usually terminates in hepatic coma and death within a few months. Occasionally, the lesion is more fulminant, and death due to massive necrosis of the liver supervenes within 2 weeks. Severe abdominal pain is a characteristic feature in such cases. Whether this is due to he patic necrosis or to the associated acute pancreatitis described by several authors231T8T is not known. Few cases of nonfatal hepatitis have been reported, and no follow-up studies are avail able to indicate whether recovery without residuals is possible. The remarkable toxicity of the chlorinated naphthalenes and the diphenyls for the liver has also been ob served in animals, who show the same tend ency toward massive necrosis seen in man.60 In contrast with carbon tetrachloride, the chlorinated naphthalenes do not produce renal lesions in animals.80 However, nephro sis has been reported as an occasional com plication in man.727 Copper Acute copper sulfate poisoning may fol low its ingestion with suicidal intent,136 or its application as a topical astringent and antiseptic agent in the treatment of wounds, dermatitis or burns.337 Doses of 10 or 15 mg. may produce signs of toxicity, and as little as 1 Cm. may be fatal, although the usual lethal dose is approximately 10 Gm. The principal lesions produced by copper sulfate include an erosive, hemorrhagic gas tritis and enteritis, centrilobular hepatic necrosis with bile stasis, and renal tubular necrosis. In addition, it frequently produces severe intravascular hemolysis. Soon after ingesting copper sulfate, pa tients note a metallic taste and experience epigastric pain, nausea, vomiting and diar rhea. In severe poisoning, hypotension and shock may ensue. Not infrequently, jaun dice appears on the 2nd or the 3rd day, and may be due to either hepatocellular necrosis or hemolysis, or both. The hepa tocellular type of jaundice tends to be severe, and usually is accompanied by en largement and tenderness of the liver, and significant abnormalities of hepatic func tion. As a rule, hemolytic jaundice is mild, even when hemolysis is severe and asso ciated with hemoglobinuria. Many patients exhibit transient oliguria, hemoglobinuria and microscopic hematuria, but in some, renal failure is severe and progressive. In one large series, the mortality rate was approximately 15 per cent.136 Deaths within the first 24 hours usually are attributable to shock, whereas those that occur later are due to hepatic or renal failure, or both. As might be anticipated, the concentra tion of copper is increased in the serum, (IN N 520 Toxic and Drug-Induced Hepatitis but is even greater in whole blood, due to the unusual avidity of red cells for copper. In at least one case, the level of cerulo plasmin in the serum was greatly ele hepatic cells in the rat when administered at low-dose levels for long periods of time.847 However, overt hepatic injury has not been reported in man. the selective methylnitrosa metabolite fc vated.337 Penicillamine therapy in this case enhanced the urinary excretion of copper, reduced the concentrations of serum copper and ceruloplasmin, and appeared to alle viate the clinical manifestations of toxicity. Corticosteroids also are alleged to be effec tive in the management of acute copper sulfate poisoning.284 Dimethylnitrosamine Severe toxic hepatitis can follow exposure to dimethylnitrosamine, an agent once used to inhibit corrosion. In the 2 cases reported by Freund, daily exposure to the fumes produced massive hepatic necrosis after 1 month and 12 days, respectively.245 The Accidental of iron is an children, whc tablets of fe belief that ti In fatal ca The possibility that chronic copper poi onset was abrupt with abdominal cramps, stomach and soning plays a role in the pathogenesis of nausea, vomiting and jaundice and was periportal pi the hepatic lesions in Wilsons disease is followed within 2 weeks by the appearance fattv infiltral suggested by the high concentrations of of ascites. The less severely ill patient ap sions mav b copper found in the liver. However, with parently recovered after a prolonged course, Vomiting few exceptions,46 attempts to produce cir but jaundice recurred in 16 months, and companied rhosis in animals by the chronic admin the liver remained large and indurated, poisoning. Ii istration of copper salts have failed.232 which suggests that postnecrotic cirrhosis coma and d< DDT and Other Insecticides developed. The other patient died in the Occasionally 6th week following an acute illness char patients whc DDT (2,2bis[p-chlorophenylJ-l,l,l-tri- acterized by deepening jaundice, intractable Prompt la chlorethane) can produce central necrosis ascites and progressive enlargement of the dium bicarb* of the liver in animals,833 and is thus gen liver and the spleen. Postmortem examina deferoxamin' erally regarded as a potential hepatotoxin tion revealed extensive hepatocellular ne travenous rc in man. However, despite its widespread crosis, a diffuse inflammatory reaction with ment of acu use as an insecticide, it has rarely been re a predominance of round cells and histio There app ported as a cause of toxic hepatitis. In one cytes, and periportal hemorrhages. longed exce instance, the accidental ingestion of 120 Dimethylnitrosamine exhibits the same hemosideros ml. of a 5 per cent solution in kerosene pro propensity for producing massive hepatic question of duced hepatomegaly, gastrointestinal bleed necrosis and ascites in experimental animals, to hemochr ing, oliguria, coma and death.693 Autopsy both when it is administered by inhala Although pr revealed extensive central necrosis and tion245- 388 and when it is given orally39 or duces hemo' periportal fatty infiltration of the liver and intraperitoneally.30-39 The lesions, which rats, it does severe tubular degeneration and necrosis are characterized by extensive centrilob- on an adequ of the kidneys. Since DDT alone does not ular and midzonal eosinophilic necrosis, re hemoehrorru produce renal damage,833 it was suggested semble those of carbon tetrachloride poi dividuals wl that the kerosene used as a solvent was an soning but are more sharply circumscribed, iron therapc important factor in the pathogenesis of the show more hemorrhage and are devoid of the possibil lesions. hydropic or other slightly damaged cells.39 chronic ane In another case, exposure to DDT used Small doses given over a long period pro important r as an insecticide produced jaundice in an duce a fatal form of cirrhosis in the rat.39 rhosis. Simi individual with an underlying cirrhosis.437 In addition, they may give rise to tumors of hemochr Rarely, DDT serves as a sensitizing agent. in the liver, kidney and lung.481 Bantu/7 wh In one such case, it produced periarteritis .Although evidence indicates that follow cessive,769 n nodosa.321 At autopsy, the liver showed en ing its administration dimethylnitrosamine tors as mal Uv: largement due to congestion, periportal fatty is uniformly distributed through the body the principa infiltration and a large, thrombosed vein. water and enters all cells freely, its toxic brewed beei A number of other chlorinated hydrocar actions are limited to the liver exclusively.490 bons used as insecticides, such as chlordane. This, taken together with the fact that it dieldrin, lindane and toxaphene, produce exhibits no in oifro effects on the metabolic Industrial characteristic alterations in the cytoplasm of activities of the liver,30-345 suggests that dioxide dusl 24305 Accidental and Industrial Poisoning 521 be. [ministered long periods of epatic injury has the selective hepatotoxic actions of dimethylnitrosamine may depend upon some metabolite formed in the liver.30*345- 48-432 Iron 5AMEVE Accidental poisoning with compounds 1 follow exposure of iron is an important problem in young agent once used children, who not infrequently ingest coated 2 cases reported tablets of ferrous sulfate in the mistaken re to the fumes belief that they are candies.33*-33T-4l5- 457 necrosis after 1 In fatal cases, the principal autopsy find jectively.245 The ings are congestion and ulceration of the dominal cramps, stomach and small intestine, and striking indice and was periportal parenchymal necrosis and mild - the appearance v ill patient ap- rolonged course, 16 months, and i fatty infiltration in the liver.457 Similar le | sions may be produced in animals.457 , j Vomiting and diarrhea, occasionally ac companied by melena, occur soon after and indurated, poisoning. In severe cases, shock, acidosis, ecrotic cirrhosis ^ coma and death follow in rapid succession. ?nt died in the Occasionally, mild jaundice is observed in tte illness char- patients who survive. dice, intractable J Prompt lavage of the stomach with so irgement of the [ dium bicarbonate and the administration of ortem examioa- deferoxamine, by both the gastric and in ^atocellular ne- travenous routes, are effective in the treat y reaction with ment of acute ferrous sulfate poisoning.357 ells ~nd bistio- There appears to be no doubt that a pro *rb. longed excessive intake of iron leads to ibits the same hemosiderosis of the liver. However, the aassive hepatic question of whether or not it can give rise mental animals, to hemochromatosis remains unresolved. red by inhala- Although prolonged iron administration, pro ven orally3* or duces hemochromatosis in choline-deficient lesions, which rats, it does not do so in animals maintained sive centrilob- on an adequate diet,165 Several instances of lie necrosis, re- hemochromatosis have been reported in in rachloride poi- dividuals who have taken large amounts of circumscribed, iron therapeutically,573 but in such cases, are devoid of the possibility cannot be excluded that imaged cells34 chronic anemia and other factors play an ig period pro- important role in the development of cir s in the rat3* rhosis. Similarly, the increased incidence rise to tumors ?48I s that follow- of hemochromatosis in the South .African Bantu,87 whose dietary intake of iron is ex cessive,74 mav be attributable to such fac lylnitrosamine tors as malnutrition and alcoholism, since 3gh the body . the principal source of iron excess is home sely, its toxic brewed beer.88 exclusively.480 5 fact that it Manganese the metabolic Industrial workers exposed to manganese suggests that dioxide dust and fumes are subject to pneu monia217 and a highly characteristic neuro logic disorder that closely resembles the progressive lenticular degeneration of Wil sons disease.119-,31-217 Because of the pos sible relationship of the neurologic changes in Wilson's disease to the associated cirrho sis, it has been suggested that a similar hepatic lesion may be responsible for the neurologic disorder in chronic manganese poisoning.131 The observation that repeated injections of soluble manganese salts pro duce cirrhosis in animals supports this hy pothesis.226- 340 However, a complete review of all the reported cases of manganese poi soning in. man217-763 discloses only one in stance in which a biliary cirrhosis is said to have been demonstrated.125 Therefore, it is highly improbable that the type of chronic manganese poisoning encountered in indus try produces liver injury. Phosphorus With the legal prohibition of the use of elemental yellow phosphorus in the manu facture of matches in this country, acute phosphorus poisoning has become relatively rare. Currently, most cases are due to inges tion of roach paste408-474 or rat poison.408 In the Orient, where yellow phosphorus matches are still in use, the incidence of poisoning is high. As might be expected, the victims are often children. As little as 15 mg. of yellow phosphorus can produce signs of toxicity, and 60 mg. has caused death.273 Some roach pastes con tain more than 1 Gm.% of phosphorus,474 so that the ingestion of as little as 5 Gm. may be fatal. The severity of the poisoning in the average case is well illustrated by the mortality rate of 75 per cent among 16 cases reported from the Charity Hospital in New Orleans.408 Red phosj bonis, another form of the ele ment, is relatively nontoxic apparently be cause it is insoluble and nonvolatile. Yellow phosphorus is also poorly soluble but is readily dispersed into an aqueous colloidal solution and is volatile.273 Although the hepatic manifestations of phosphorus poisoning are of special interest, phosphorus is a potent general protoplasmic poison and may be lethal within 10 hours. 522 Toxic and Drug-Induced Hepatitis even before characteristic tissue changes can be demonstrated histologically.408 Symptoms. The initial symptoms, includ ing nausea, vomiting, epigastric burning, abdominal pain and diarrhea, usually occur immediately following the ingestion of phosphorus or within a few hours. These are due to the local action of the poison in the gastrointestinal tract. However, when symp toms do not appear for hours or days, they are related to the systemic effects of ab sorbed phosphorus. Shortly after phosphorus is ingested, the breath has a garlic-like odor, and the feces are luminescent in the dark, features that mav be of great diagnostic importance. In severe poisoning, shock and coma fol low the initial symptoms in rapid succession, and death may ensue within 48 hours. More commonly, however, the svstemic effects are evident 1 to 3 davs after phosphorus is in gested, and death occurs during the 1st week. Although it is highly probable that no tissue is wholly exempt, the liver and the kidneys suffer the most severe injury and manifest the most striking structural and functional changes. As in other severe intoxications, tissue damage is so wide spread that often it is difficult to determine the site of origin of any given svmptom. The manifestations of svstemic intoxica tion include intractable vomiting, often with blood-streaked material, diarrhea, abdomi nal cramps and severe prostration. Signs of severe liver injury can always be demon strated, although hepatomegaly and jaun dice may not develop. Jaundice seldom ap pears before the 4th day and may be de layed for over a week. The prognosis is somewhat better when jaundice appears late. As in other forms of severe hepatitis, the urine contains bilirubin, and the feces tend to become pale, which indicate that bile secretion is suppressed. Not infre quently, hemorrhages occur into the skin and the mucous membranes, presumably due to the associated fall in die prothrombin and fibrinogen levels of the plasma. Other features of severe hepatic failure can occa sionally include edema, hypoglycemia, tyrosinuria and an increase in serum amino nitrogen. Usually the kidneys are affected equally severely. Oliguria and azotemia are common, and the urine usually contains al bumin, casts and red blood cells. The latter part of the course is character ized by coma, delirium and vasomotor col lapse and, as indicated, death occurs to ward the end of the 1st week. Occasionally, even severely poisoned indi viduals appear to recover completely. How ever, one such case, followed by serial bi opsies of the liver over a period of 3 months, showed evidence of incomplete healing and progressive fibrosis, a lesion similar to that seen in animals with chronic phosphorus poisoning.485 How often this type of post necrotic fibrosis and cirrhosis follows acute phosphorus poisoning in man is not known. Pathology. At autopsy the liver is en larged and exhibits extensive periportal fatty infiltration and degenerative changes in the parenchymal cells, occasionally accompanied bv a mild inflammatory reaction in the por tal triads. In one case seen by the writer, marked periportal bile stasis and pseudo duct formation were outstanding features late in the course of the disease. Massive necrosis of the parenchyma is said to occur437 but is exceedingly rare. The lesion in experimental phosphorus poiso ring455 is similar, but cellular necrosis is a more promi nent feature. The renal tubules and the myo cardium also show degenerative changes and fatty infiltration. Treatment. Gastric lavage with a dilute solution of copper sulfate (0.25 Cm. in a glass of water) and a magnesium sulfate purge are recommended to rid the intesti nal tract of any remaining traces of phos phorus. Unfortunately, these are effective only if given within the first few hours. Treatment is largely supportive, as out lined previously. Choline hastens the re moval of fat from the fiver in phosphorus poisoning.60 However, its therapeutic value would appear to be negligible, since it does not prevent hepatic injurv. Selenium In areas where the selenium content of the soil is high, livestock develop "alkali disease," a chronic illness characterized by emaciation, loss of hair, lameness and sloughing of the hoofs.3-3 At autopsy, the principal findings are cirrhosis of the liver and myocari renal hemorr faces and ul are also seen is due to inj grain, forage produced in ing selenium A more ac as the "blinc whose feed content. My< testine and the principal congested an but frank cin In some s gestion of s* only hepatic adenomas an Himswortl ity between selenium poi tal dietetic gested that quence of a: containing a placement c protein.322 1 and methioi would appe However, th vent liver da doubt on thi Of special question of seleniferous in man. Inc areas excret nium in the nificant exp to date non of hepatic oi Sexeci A numb genera Sene contain pyn atotoxic. In Asia and M disease are horses that : upon the d Accidental and Industrial Poisoning 523 jsusdlv contains alx> 11s. xjurse is characterind vasomotor col- death occurs toeek. rely poisoned indi completely. Howawed bv serial bijeriod of 3 months, nplete healing and ion similar to that ironic phosphorus this type of postlosis follows acute man is not known. r the liver is enive periportal fatty ive changes in the nallv accompanied saction in the porien by the writer, tasis and pseudotstanding features t disease. Massive hyma is said to iy rare. The lesion ns poisoning485 is is is more promidu id the myomerative changes age with a dilute 2 (0.25 Gm. in a lagnesium sulfate to rid the infesti ng traces of phoslese are effective >t few hours, ipportive, as out; hastens the reer in phosphorus therapeutic value ,ible, since it does and myocarditis. Glomerulonephritis, ad renal hemorrhages, erosion of the joint sur faces and ulceration of the intestinal tract are also seen in some instances. The disease ; is due to ingestion of selenium-containing grain, forage or vegetation, and can be re, produced in experimental animals by add ing selenium salts to the diet, i A more acute form of poisoning, known I as the "blind staggers," is seen in animals | whose feed is unusually high in selenium ; content. Myocarditis, ulceration of the inj testine and erosion of the long bones are the principal findings. Usually, the liver is congested and shows focal areas of necrosis, but frank cirrhosis is rare. In some strains of rats, the chronic in gestion of seleniferous grain produces not only hepatic necrosis and fibrosis but also ,, adenomas and low-grade carcinomas.534 Himsworth has emphasized the similarI ity between the hepatic lesions in chronic ' selenium poisoning and those of experiinen| tal dietetic massive necrosis and has sug- | gested that the former may be the conse quence of an induced deficiency of sulfurcontaining amino acids related to the re 1 placement of sulfur bv selenium in plant protein.32- The protective action of casein and methionine in animals fed selenium would appear to support this hypothesis. However, the fact that cystine does not pre vent liver damage in such experiments casts doubt on this interpretation. Of special interest, to the clinician is the question of whether or not the ingestion of seleniferous grain leads to hepatic damage in man. Individuals living in seleniferous areas excrete appreciable amounts of sele nium in the urine, which indicates that sig nificant exposure has occurred. However, i to date none of these has shown evidence : of hepatic or other disease.692 Senecio and Belated Alkaloids t snium content of c develop "alkali characterized by lameness and At autopsy, the hosis of the liver A number of plants belonging to the genera Senecio, Crotalaria and Heliotroptum ' contain pvrrolizidine alkaloids that are hepatotoxic. In South Africa, Australia, Central Asia and Norway outbreaks of severe liver disease are encountered in sheep, cattle and horses that feed on these plants. Depending upon the degree and the duration of expo sure, affected animals exhibit signs of either acute hepatic necrosis or cirrhosis. Similar lesions are reproducible in experimental animals.591, 58,871 Occasionally, humans fall victim to this type of poisoning, but in man the senecio alkaloids produce an unusual form of liver disease in which the clinical and pathologic features resemble those of the Chiari syndrome.070 Both in animals071 and in man,6"0 protein deficiency enhances the toxicity of these agents. In South Africa, senecio poisoning has been reported in poorly nourished white Europeans who consume bread made of imperfectly winnowed wheat contaminated with the seeds of Senecio ilicifolius and burcheUi, two weeds commonly known as ragwort.670- 792 A similar form of toxic hepa titis affects natives of Central Asia who eat cereal grains contaminated with the seeds of Heliotropium lasiocarpine.we Evidence suggests that the use of native "bush teas" containing extracts of Senecio and Crotalaria retusia for medicinal purposes mav be re sponsible for the development of venoocclusive disease of the liver in Jamaican children.730 A similar explanation has been invoked to account for the common occur rences of cirrhosis in the children of West Bengal and Madras, India.360 However, in this instance, there is contradictory evidence pointing to the hepatitis virus as the re sponsible agent.3 Pathologic Findings. In fatal cases of senecio poisoning, the principal findings are enlargement of the liver, widespread fibrous occlusion of the central and the sublobular veins, and intense congestion and destruc tion of the centrilobular parenchyma. Usu ally, the stroma is uninvolved, and there is little or no inflammatory reaction. Organ ized thrombi may be demonstrable in the larger hepatic veins. In more chronic cases, there is, in addition, fibrosis and round cell infiltration of the portal zones, giving rise to the picture of cirrhosis.070,732 It is gen erally agreed that the primary lesion is in the vessels, and that the parenchymal changes are secondary to intense conges tion. However, there is uncertainty whether the fibrous occlusion of the central and sub lobular veins follows a proliferative endophlebitis or is the end-result of thrombosis 524 Toxic and Drug-Induced Hepatitis and organization. Similar lesions have been described in the veno-occlusive disease of the liver seen in Jamaica.93 The hepatic changes induced by senecio alkaloids in experimental animals are more variable than in man. Although some inves tigators have demonstrated alterations in the blood vessels with secondary conges tion, atrophy and fibrosis of the paren chyma,318- 30'785 others have shown that these agents may provoke acute centrilobular necrosis and cirrhosis by a direct action.108,13-*> 858 In the more chronic lesion, there is striking enlargement of the hepatic cells, a feature thought to be characteristic of senecio poisoning, and indicative of a metabolic defect which prevents cellular division and thus leads to loss of cells and ultimate fibrosis.106 Of particular interest is the fact that in the rat a single small dose of senecio alkaloid may, after a latent period of several weeks during which no necrosis is evident, give rise to a chronic progressive hepatic lesion terminating in a picture re sembling postnecrotic cirrhosis.658, 059 Clinical Features.870-792 In acute senecio poisoning, the onset is sudden with gnaw ing and colicky epigastric pain, followed within a few davs by a rapidly developing ascites. The liver enlarges and within a few weeks becomes firm. Jaundice is an incon stant feature and, in one series at least, oc curred in only 2 of 12 cases.670 Vomiting and diarrhea are present in about a third of cases. Splenomegaly appears to be unusual despite the obvious development of portal hvpertension. Occasionally, there is lowgrade fever late in the disease. In severe poisoning, there may be early vasomotor collapse, followed later by hematemesis and melena. Usually, the clinical course is prolonged and is characterized by rapid reaccumula tion of ascites, recurrent attacks of abdomi nal pain, and cachexia. Hypoproteinemia is common, but edema is an inconstant find ing. In approximately half the cases, death occurs within 1 to 3 months. Despite the apparent progressive downhill course in the remaining patients, clinical recovery ultimately takes place over a period of sev eral months up to 2 years. Whether or not healing of the hepatic lesions is complete in such cases is not known, since reports of long-term follow-up biopsy studies are not available. Mild cases of intoxication probably occur, but have not been described in the liter ature. The clinical picture of veno-occlusive dis ease in children resembles that of senecio poisoning.93, 730 However, an acute onset is not nearly as common, hepatosplenomegalv and other signs of cirrhosis appearing insidi ously in many cases. Also splenomegaly and jaundice are seen more frequently. The mor tality rate is high; hepatocellular failure and hematemesis account for most deaths. Treatment. No specific therapy is avail able, so that treatment is supportive and directed at maintaining nutrition and con trolling the ascites. TETRACHLO RETKA N*E Of all the chlorinated hydrocarbons, tetrachlorethane is by far the most toxic. During World War I it was used widely as a solvent for cellulose acetate, chiefly in the "dope" used in varnishing the canvas surfaces of airplanes and, to a lesser extent, in the manufacture of rayon and lacquers. How ever, it proved to be so toxic that it was abandoned as soon as a suitable substitute (amyl acetate) was found. During World War II it was used again, since it was the only satisfactory solvent for impregnating clothing with materials that neutralized poisonous gases.286 Despite the imposition of stringent engineering and hygienic con trols. signs of toxicity were encountered once again in a high proportion of workers exposed to the agent. However, the control measures prevented serious intoxication, so that no fatalities resulted.285 Intoxication usually follows inhalation of the agent but may occur also following its absorption from the skin or the intestinal tract. For reasons that are not entirely clear, females are more susceptible than males, and in both sexes intoxication is more com mon after the age of 30.2S6 The toxic level of tetrachlorethane in the atmosphere is estimated to be in excess of 10 parts per million for individuals exposed for long periods. The odor, which closely resembles that of carbon tetrachloride, is readily de- 21905028 Accidental and Industrial Poisoning 525 known, since reports of i biopsy studies are not tectable at a concentration of 25 parts per million.2*5 xicuwjn probably occur, described in the liter- Pathologic Findings. The principal patho logic finding in fatal cases is a subacute or massive hepatic necrosis with preservation re of veno-occlusive dis;embles that of senecio vever, an acute onset is on, hepatosplenomegalv rrhosis appearing insidiAlso splenomegaly and jre frequently. The morjpatocellular failure and it for most deaths. Decific therapy is availnent is supportive and oing nutrition and con- of the stroma, marked fatty infiltration of surviving parench\Tnal cells, absence of he patocellular regeneration, and active pro liferation of bile ducts.707 The early lesions in nonfatal cases have not been described. Fatty degenerative changes are also seen in the renal tubules and mvocardium. Es sentially the same lesions have been ob served in rats exposed to tetrachlorethane vapor.707- 7S0 Symptoms. The earlv symptoms of tetra chlorethane intoxication are of two types: gastrointestinal and neurologic.2SS Follow ing exposure to low concentrations of the SLORETTHANE ' vapor for a number of weeks, there is an ted hydrocarbons, tetra- insidious onset of anorexia, nausea and vom r the most toxic. During iting, or of headache, giddiness, drowsiness used widely as a solvent ( and paresthesias. These mav occur singlv 3, chiefly in the "dope" | or in combination and often are associated the canvas surfaces of ; with hepatomegaly and impairment of liver a lesser extent, in the function. Jaundice is also present in approxi on and lacquers. How- mately 10 per cent of such individuals. Oc be so toxic that it was casionally, jaundice appears before other as a suitable substitute symptoms develop. Prompt cessation of ex 5 f During World posure to the contaminated environment at aga.,1, since it was the ilvent for impregnating this stage results in rapid recovery, usually within a period of less than a month. Of erials that neutralized possible diagnostic significance in early tox Despite the imposition icity is the tendency for the absolute and `ring and hygienic con- relative number of large monocytes in the city were encountered peripheral blood to increase.509 li proportion of workers In more heavily exposed individuals, the it. However, the control onset is similarly delaved and gradual, but ! serious intoxication, so gastrointestinal symptoms, hepatomegaly ulted.255 and jaundice are constant findings and usu lly follows inhalation of ally are associated with tenderness of the occur also following its liver and weight loss. Not infrequently, the e skin or the intestinal jaundice is intense and persists for weeks at are not entirely clear, and even months following the last expo susceptible than males, sure to tetrachlorethane. Recovery is possi itoxication is more com- ble at this stage,5"9 but some individuals 30.286 The toxic level ; run a progressive downhill course, develop in the atmosphere is ascites ana die of hepatic failure.789 These excess of 10 parts per are the cases that, at autopsy, show sub uals exposed for long acute hepatic necrosis and postnecrotic scar which closely resembles ring. ichloride, is readily de Prognosis. Before the toxicity of tetra chlorethane was fully understood and ap propriate protective measures instituted, the exposure tended to be heavy and often was continued long after signs of intoxication had appeared. As a result, the hepatitis pro duced was unusually severe. In one such series of 70 cases, for example, the mortality rate was 17 per cent.420 In contrast, no fa talities were seen in a more recently studied group of 55 cases encountered in a care fully supervised plant. Moreover, the dis ease was so mild that only 6 of the 55 de veloped jaundice.295 Toluene This aromatic hydrocarbon derived from coal tar is widely used in industry, espe cially in the manufacture of paints and lac quers. Although it shares the excellent sol vent properties of its homologue benzene, it is far less toxic. In individuals exposed to the high concentrations usually encoun tered during spray painting, toluene appears to exert no significant ill-effects. Hepatomegaly and mild macrocytic anemia are relatively frequent findings, but no instances of frank toxic hepatitis or aplastic anemia have been reported.278 The nature of the hepatic enlargement has not been inves tigated. However, in animals exposed to similar concentrations of toluene, both the liver and kidneys show mild degenerative changes.699 Trinitrotoluene (TNT) Munition workers exposed to TNT are subject to a number of toxic manifestations of which hepatitis and aplastic anemia are the most important.449- *92,551 Functional disturbances of the gastrointestinal, circu latory and central nervous systems, and local irritation of the respiratory tract and the skin are often troublesome but rarely give rise to serious difficulty. Absorption is chiefly from the skin and, to a lesser extent, from the mucous membranes.38'420 The presence on the skin of oil and grease, in which TNT is soluble, enhances absorp tion and increases the chances of intoxica tion.38, 515 It is generally stated that inhala tion of the fumes is without danger,513 but this view is not shared by some au thorities.492 Clinical Features. The hepatitis produced 526 Toxic and Drug-Induced Hepatitis by TNT has many unusual features, few of which have been adequately explained. Among these are the following: (1) Only a small proportion of individuals exposed to TNT develop hepatitis.492 ( 2) Signs of he patic damage usually appear onlv after many weeks of exposure192 or, in some in stances, not until several months after ces sation of exposure.788 ( 3) The disease is almost always severe, being characterized by a prolonged course and a high fatality rate. (4) Massive and subacute necrosis of the liver occur far more frequently and re semble the lesions of idiopathic acute yellow atrophy far more closely than almost any other known tvpe of toxic hepatitis.324,719 T- (5) It is difficult to reproduce the lesion in animals,322 an unusual circumstance for an agent presumed to be a true hepatotoxin. In many respects these unusual features are reminiscent of the hypersensitivity type of hepatitis produced by drugs such as cinchophen. However, the chemical struc ture ofTNT and its failure to produce other manifestations of hypersensitivity make it highly improbable that it is a sensitizing agent. Himsworth has suggested that the long latent period, the occurrence of massive he patic necrosis, and the failure to reproduce the lesion in animals on normal diets may indicate that TNT injures the liver indirectly by inducing a relative deficiency of sulfurcontaining amino acids.322 In support of this hypothesis, he has pointed out that TNT raises the metabolic rate and thus in creases the demand for protein, that at least 2 of its 3 isomers combine with amino acids and make them unavailable, and that by reducing the protein content of the diet it is possible to reproduce TNT hepatitis in experimental animals. However, the isomer of TNT that does not combine with amino acids also produces toxic hepatitis, and a low-protein intake favors the development of hepatic necrosis in experimental animals only when the diet is high in fat. The latter observation suggests the possibility that the peculiarities of TNT toxicity may be related to the fat solubility of the agent. Possibly dietary fat enhances the absorp tion of TNT from the intestinal tract and favors Us retention in the liver at high con centrations by producing fatty infiltration. Similarly, the enhanced absorption of TNT from the skin in the presence of grease38*515 mav account for the sporadic occurrence of intoxication in groups of apparently equally exposed individuals. As for the long latent period, it does not necessarily point to an induced nutritional deficiency, as indicated, but mav reflect a slow cumulative intoxica tion with an agent that is absorbed rela tively slowlv. In cases where the signs of liver disease appear weeks or months after the last exposure to TNT. it is possible that the initial injury incurred during exposure is asvmptomatic, and that the lesion pro duced is progressive. Symptoms. Usually, the onset of symp toms is insidious, with anorexia, nausea and vomiting. Jaundice appears within 2 weeks and often is followed bv hepatomegaly. In severe cases, abdominal pain is a prominent feature, and the liver mav be small. The course tends to be prolonged and often is complicated by the development of ascites and hemorrhagic phenomena. Occasionally, there is an associated disturbance of the hemopoietic svstem, as evidenced by severe leukopenia,719 macrocvtic anemia719 or aplas tic anemia.551 Both hyperplastic719 and aplastic492 bone marrows have been de scribed, suggesting that the changes in the peripheral blood mav be due to a matura tion arrest in some cases. Prognosis. The outcome is unpredictable. In most cases reported in the literature death has occurred within a few weeks of acute massive necrosis of the liver324,4!`or after prolonged hepatic failure resulting from postnecrotic cirrhosis.720,788 However, some individuals with TNT hepatitis re cover. Unfortunately, little is known about the nature of the lesion in this group or its ultimate fate. In one 3-vear follow-up studv of 17 such cases,720 there were no clinical residuals, which suggests that the initial lesion was zonal rather than massive. How ever, reports of postnecrotic cirrhosis be coming evident as long as 10 years after apparent recoverv from TNT hepatitis324illustrate that the scarred postnecrotic liver mav be difficult to recognize clinically and n ' He liver at high conroc ag fatty infiltration, lanced absorption of TNT he presence of grease38, 515 the sporadic occurrence of sups of apparently equally <ils. As for the long latent ot necessarily point to an al deficiency, as indicated, slow cumulative intoxica nt that is absorbed rel eases where the signs of ear weeks or months after to TXT, it is possible that incurred during exposure and that the lesion pro- ive. aally, the onset of sympwith anorexia, nausea and >e appears within 2 weeks wed by hepatomegaly. In )minal pain is a prominent liver may be small. The >e prolonged and often is he development of ascites phenomena. Occasionally, dated disturbance of the in, as evidenced by severe crc 'c anemia719 or aplasloti -ivperplastic719 and marrows have been deig that the changes in the may be due to a matura- } cases. outcome is unpredictable, sported in the literature ;d within a few weeks of ?crosis of the liver32-1,492 1 hepatic failure resulting cirrhosis.720,788 However, with TNT hepatitis reely, little is known about lesion in this group or its >ne 3-vear follow-up study ,2 there were no clinical suggests that the initial ather than massive. Howpostnecrotic cirrhosis he 's long as 10 years after from TNT hepatitis324,788 scarred postnecrotic liver 3 recognize clinically and Anesthetic Agents 527 may decompensate unexpectedly years after its inception. It is highly probable that such lesions can be recognized much earlier by the use of sensitive tests of hepatic function and especially by needle biopsy of the liver. Vomitenc Sickness of Jamaica Native Jamaican children, usually from the age of .2 to 5 years are subject to an un usual disease characterized bv a sudden onset of severe vomiting, followed soon thereafter by convulsions and coma. Death ensues within 2 or 3 days in 80 per cent of cases. The principal findings at autopsy in clude fatty- infiltration of the liver and kid neys, hvperemia and petechial hemorrhages in the liver, spleen, heart, lungs and brain, and degenerative changes in the renal tu bules. The etiology is unknown. However, Hill has reviewed evidence suggesting that malnutrition and the toxic effects of the ackee fruit, cassava and yams mav play an important role in its pathogenesis.317 This disease is of particular interest be cause of its striking resemblance to the Reve svndrome (encephalopathy with fatty de generation of the viscera) first described in 1965.608 In the manv reports, the possibility of intoxication has been considered, but in none has a specific hepatotoxin been impli cated. A recent review suggests that the dis ease is of infectious origin, and possibly at tributable to a variety of viruses, including those of chicken pox, measles and mumps.127 ANESTHETIC AGENTS In evaluating the role of an anesthetic agent in the pathogenesis of postoperative hepatitis, due consideration must be given to the nature of the underlying disease, the degree of anoxia attained during anesthesia and the presence of such complicating fac tors as shock and infection, since each of these alone can produce liver injury. Chloroform Chloroform has the well-deserved reputa tion of being a dangerous hepatotoxin. Al though largely supplanted by other less toxic anesthetic agents, it is still used to some extent in various parts of the world for obstetric and minor surgical procedures. Most fatalities have followed prolonged anesthesia, especially during parturition, but deaths have occurred also after as little as & ounce of chloroform.238 Women under going prolonged labor appear to be peculi arly susceptible to this type of anesthetic death. This has been ascribed to the mal nutrition and the infection which so fre quently accompany such labors,837 a hy pothesis consistent with the experimental observation in animals that malnutrition272 r,i'7 and infection342 enhance the hepatotoxic effects of chloroform. From the paucity of reports dealing with nonfatal cases of chloroform hepatitis, it is easy to gain the erroneous impression that chloroform either injures the liver seriously or not at all. However, in animals even a 30-minute period of chloroform anesthesia causes significant impairment of hepatic function, which mav persist for as long as 8 davs.832 Clinical Features. The clinical manifesta tions of severe chloroform intoxication fol low a uniform pattern.258,637, 709 Character istically, the onset of symptoms is delayed for 24 to 72 hours following recovery from anesthesia. Drowsiness and vomiting then appear and are soon followed by jaundice. Vomiting is copious and often becomes coffee-ground in nature. By the 4th day the drowsiness usually progresses to coma, and in approximately half the cases is followed bv convulsions. Despite the regular occur rence of severe hepatic damage, jaundice fails to develop in some cases.709 Fever is unusual, except terminally. Azotemia and acidosis occur early and tend to increase in severity. Although these are usually associ ated with oliguria and albuminuria, in oc casional cases the urinary volume and the urea content are high,258 suggesting that the azotemia is related in part to the rapid breakdown of protein, rather than to renal failure and dehydration alone. Prognosis. Most severely intoxicated in dividuals die in 3 to 8 days, but an occa sional patient survives and goes on to com plete recovery. Residuals are unlikely in such cases, since the characteristic lesions seen at autopsy are zonal in type. Complete 528 Toxic and Drug-Induced Hepatitis recovery without scarring also occurs in the development of toxic hepatitis, so that animals exposed to nonfatal doses of chloro thev do not provide a sound basis for thesia in it are difficult form.784 treatment. since circu Individuals who are exposed to repeated doses of Chloroform at frequent intervals Cyclopropane tions in he] gical manij occasionally develop cirrhosis. In one such Transient alterations in hepatic function function. case described by Wilcox, small amounts of chloroform were inhaled daily over a period of 6 months, at the end of which time jaun have been observed following cyclopropane anesthesia. Usually, these are relatively minor, but in patients with liver disease they Halc Meth dice and hepatomegaly developed.789 Subse mav be more severe.242 Changes of similar In contrs quently, ascites and other signs of cirrhosis magnitude are seen following anesthesia hydrocarbo appeared, and death ensued in IS months. with ethyl ether. Since the degree of func 1,1,1-trifiuo: Pathology. At autopsy the liver is of nor tional impairment bears little relation to the patic necr mal size but may be small. Hepatocellular duration of anesthesia, it is highly probable cannot be c necrosis is invariably centrilobular in dis that such hepatic injury is the resault of cir theless, cas tribution and never massive. Vary ing frac culatory changes and trauma incidental to encounterei tions of the lobule are destroyed, but a small surgery rather than of cyclopropane toxicity. anesthetic.1 rim of intact cells is always present around the portal triads. The necrotic cells break Divinyl Ether been vario icity or hy] up into hvalinized fragments and undergo Because divinyl ether can produce centri fection wit lvsis, while the intact cells peripherally lobular necrosis in dogs,271 it is generally incidental f show marked fatty infiltration. As in other regarded as a potential hepatotoxin in man. In a rev tvpes of toxic hepatitis, the reticulum is not In the dog. the severity of the hepatic dam well-docurr destroyed and usually is infiltrated with a age produced is closely correlated with the ciated hep; number of phagocytic mononuclear cells at duration of anesthesia, the nutritional status sented con the sites of necrosis. The remaining hepatic and the degree of oxygenation.270-271 Ac is a sensitri cells show little evidence of regeneration. cordingly, certain precautions have been ducing hep Almost identical hepatic lesions have been recommended. These include administration hvpersensit described in the dog.784 of carbohvdrate preoperatively, limitation ble individ The changes in the kidney are less con of the duration of anesthesia to I hour, use of cases ol spicuous than in carbon tetrachloride poi of oxygen whenever the period of anes be attribui soning and usually consist of fatty infiltra thesia is to exceed 3k hour, and avoidance of sepsis 27 ar tion of the convoluted tubules. divinvl ether in patients with liver dis completes Susceptibility. During the past decade ease.592 Under these conditions, no instances fact that I considerable attention has been directed to of hepatic injury have been encountered in induced hi the interrelationships between the hepato- an extensive clinical experience with this cent,382 it toxic effects of chloroform and certain die- agent.582 Although it would be unwise to of the Nati tarv factors. In brief, starvation,272 protein- abandon this cautious attitude toward risk of ha depletion5"7 and a high fat intake543 increase divinyl ether, it should be recognized that proximatel the susceptibility to hepatic damage bv its hepatotoxicitv for man has not been As in th< chloroform, and diets rich in protein-'72 and proved, and that the human liver may be as induced b carbohydrate272 are protective when given resistant to it as the monkev's.271 as lpronnu prophylactically. Moreover, protein, methio nine and, to a lesser extent, cystine protect Ether (Diethyl Ether) mine,582 th halothane protein-depleted animals against chloro There are no clinical reports of toxic hepa from those form toxicity if given from 24 hours before titis follow ing ether anesthesia. However, reproducer to as late as 4 hours after anesthesia.5"-507 experimental evidence indicates that, in the The theoretical implications of these obser dog at least, ether can produce mild liver cellular nc reaction ar vations are discussed elsewhere. None of injury270 and transient impairment of he i ^ teristic. Th these experimental observations is con patic function.32 Bromsulphalein reten i a sensitizal cerned with the therapeutic effects of these tion144 and other functional derangements242 l V current ini supplements when administered following have been reported following ether anes S? stronglv si jA It * Anesthetic Agents 529 ^atitis, so that jn asis for patic function r cvclopropane are relatively er disease they iges of similar wg anesthesia esree of funcrelation to the iffhlv probable e result of ciri incidental to opane tonicity. iroduce centrit is generally otoxin in man. * hepatic damlated with the tritional status Joj, 270. 271 ^c- is have been administration eiy, limitation to )ur, use riou of ahesi avoidance of ith liver diss. no instances ncountered in nee with this be unwise to itude toward cognized that has not been ver mav be as .71 her) of toxic hepana. However, es that, in the ice mild liver rment of hehalein retenrangements242 g ether anes thesia in man also, but such observations the latent period between exposure to halo are difficult to interpret in terms of toxicity, thane and the onset of symptoms, the strik since circulatory disturbances and altera ing increase in the incidence of hepatitis tions in hepatic structure incidental to sur following multiple exposures, the frequency gical manipulation may also affect hepatic with which the nepatitis is accompanied by function. other manifestations of hypersensitivity, Halothane (Fluothane) and Methdxyflurane (Penthrane) such as chills, high fever, rash and eosinophilia, and, of particular significance, the regularity with which the hepatitis recurs In contrast to many other halogenated following re-exposure to halothane.382 hydrocarbons, halothane (2-bromo-2-chloro- Characteristically, the onset of halothane- 1,1,1-trifluoroethane) does not produce he- induced hepatitis is abrupt, with moderate j patic necrosis in animals364 and, hence, to high fever, often accompanied by chills, cannot be considered an hepatotoxin. Never- and occasionally by rash, arthralgia and j theless, cases of hepatic necrosis have been eosinophilia, In patients exposed to halo ] encountered in man following its use as an thane for the first time, the average interval | anesthetic.lwT- i08-128- 440 Such lesions have between anesthesia and the onset of symp I been variously ascribed to halothane tox- toms is approximately 7 days, with a range I icity or hypersensitivity, to intercurrent in- of 1 to 12 days. Following multiple expo 1 fection with the hepatitis virus, or to co sures, the latent period is shorter, averaging incidental factors unrelated to halothane. 3 days (1 to 10 davs). Jaundice appears 3 In a review based on an analysis of 41 or 4 days after the onset of fever, and usu ! well-documented cases of halothane-asso- ally deepens rapidly. Anorexia, nausea and \ ciated hepatic necrosis, the writer has pre vomiting are prominent features. Occasion sented convincing evidence that halothane ally, there is severe abdominal pain. Coffee- is a sensitizing agent, and is capable of pro ground vomitus, ascites, edema, somnolence ducing hepatitis and other manifestations of and coma usually indicate a fatal outcome, hypersensitivity in a few uniquely suscepti which occurs in approximately half the ble individuals.382 Judging from the number cases. of cases of hepatic necrosis that could not In contrast to viral hepatitis, the leuko be attributed to shock, cardiac failure or cyte count tends to be high. Biochemical sepsis,27 and making allowance for the in studies reveal abnormalities indicative of completeness of the autopsy data and the hepatocellular jaundice. However, signifi fact that the mortality rate in halothane- cant elevations of serum alkaline phospha induced hepatitis is approximately 50 per tase, negative cephalin-cholesterol floccula cent,382 it may be estimated from the data tion reactions and normal thymol turbidity of the National Halothane Study,734 that the values are more common than in viral risk of halothane-induced hepatitis is ap hepatitis. proximately 1 in 10,000. In the writer's experience, prednisone As in the hepatocellular type of hepatitis therapy has appeared to be effective when induced by other sensitizing drugs, such instituted before the onset of hepatic coma, as iproniazid, pyrazinamide and zoxazola- but has failed to prevent a fatal outcome in mine,592 the hepatic lesions seen following those with hepatic coma, even when used halothane anesthesia are indistinguishable in massive doses in conjunction with ex from those of viral hepatitis, and cannot be change transfusions. However, the number reproduced in animals. Extensive hepato of patients so treated is small, so that in cellular necrosis, an intense inflammatory sufficient data are available to assess the reaction and a high fatality rate are charac therapeutic value of corticosteroids and ex teristic. That the hepatitis is attributable to change transfusions. a sensitization reaction rather than to inter- Halothane has a number of advantages current infection with the hepatitis virus is over other anesthetic agents, not the least strongly suggested by the narrow limits of of which is that it is associated with a lower 530 Toxic and Drug-Induced Hepatitis overall postoperative mortality rate follow ing middle- and high-risk surgical proce dures.734 Since the degree to which halothane lowers the postoperative mortality from other causes is significantly greater than the estimated 0.005 per cent risk of fatal halothane-induced massive hepatic ne crosis, continued use of halothane as an anesthetic for such procedures would ap pear to be both reasonable and desirable. However, every effort should be made to reduce the risk of this complication by avoiding, whenever possible, the use of halothane in low-risk surgical procedures, in planned serial operations and in individ uals who have experienced an unexplained bout of fever or jaundice following a previ ous exposure to halothane. In this connec tion, it should be emphasized that the risk of halothane-induced hepatitis is twice as great following multiple exposures as it is following a single exposure.382 Methoxyflurane (Penthrane, 2,2-dichloro- 1,1-difluoroethyl methyl ether), a closely related halogenated ether, also may give rise to hepatic necrosis in susceptible indi viduals,38.8, 442 presumably by a similar mechanism, ana may provoke a serious re action in patients previously sensitized to halothane.440 Accordingly, one agent can not be substituted for the other once sensi tization has occurred. Evidence suggests that halothane may constitute an occupational hazard for occa sional, uniquely susceptible anesthetists or other operating-room personnel exposed to low concentrations or the agent in the course of their daily work. A recent report describes a young physician who experi enced an attack of acute hepatitis after hav ing served as an anesthetist for several months.93 Following full recovery, he was anesthetized with halothane for a few min utes to test his reaction to the agent. Within 5 hours he had shaking chills and fever fol lowed later by the appearance of eosinophilia and biochemical evidence of acute hepatitis. Another case seen by the writer involved an anesthetist who had had recur rent attacks of acute hepatitis that led to cirrhosis over a 5-year period.383 Almost all of the relapses had been ushered in by chills and fever that appeared within a few hours of the patient's return to work following prolonged convalescence and ultimate re covery from a preceding attack. Challenge with a non-anesthetic dose of halothane for 5 minutes produced chills and fever within 5 hours, and, within 4 hours, evidence of acute hepatitis, which was documented both biochemically and histologically. Tribromoethanol ( Avebtin) As a member of the halogenated hydro carbon group, Avertin might be expected to behave as a potent hepatotoxin. Actually, however, it produces only slight liver dam age in dogs89 and never has been implicated as a cause of toxic hepatitis in man. Never theless, it is generally assumed that liver disease contraindicates its use as an anes thetic agent, since the Bromsulphalein re tention that usually follows Avertin anes thesia, both in man144 and in experimental animals,89 is significantly enhanced in the presence of hepatic damage. A more urgent reason for exercising caution in the patient with liver disease is the danger of delayed recovery from anesthesia related to a de crease in the rate of Avertin detoxification.89 ANTIARTHEUTIC AGENTS CiNCHOPHEN Hepatitis is by far the most serious com plication of cinchophen therapy and is largely responsible for the decline in the use of this agent over the past 3 decades. Al though it occurs in less than 0.1 per cent of patients under treatment,703 the mortality rate is close to 50 per cent.950 This has encouraged a search for less toxic deriva tives of cinchophen, but these have proved to be no safer than the parent substance. Included in this group are neocinchophen (the ethyl ester of methyl cinchophen), farastan (mono-iodo-cinchophen), biloptin (di-iodo-cinchophen), oxiliodide (cincho phen hydroiodide) and guphen (the guaiacol ester of cinchophen ). Clinical Features. A number of features strongly suggest that the hepatitis produced by cinchophen is a manifestation of drug hypersensitivity. These include the follow ing: 1 t' rork following ce J'ultimate reog attack. Challenge lose of halothane for ills and fever within [ hours, evidence of ras documented both logically. ol (Avertin) halogenated hydro night be expected to jpatotoxin. Actually, nlv slight liver damhas been implicated atitis in man. Never- assumed that liver its use as an anesBromsulphalein rellows Avertin anesand in experimental ly enhanced in the nage. A more urgent mtion in the patient 5 danger of delayed ria related to a de ntin detoxification.89 IC .ENTS ?HEN e most serious com;n therapy and is he decline in the use past 3 decades. Als than 0.1 per cent lent,703 the mortality r cent.530 This has >r less toxic derivat these have proved e parent substance, are neocinchophen lethyl cinchophen), achophen), biloptin oxiliodide (cinchornd guphen (the hen). number of features t hepatitis produced nifestation of drug include the follow- Antiarthritic Agents 531 1. Frequently, the hepatitis is associated with other symptoms suggestive of an al lergic reaction, such as pruritus, rash, fever, arthralgia and edema.586,682 2. The ingestion of cinchophen some times is followed by sudden vasomotor col lapse, respiratory distress and syncope, a syndrome closely resembling an anaphy lactic reaction.42, 386, 682 3. Usually, there is a long latent period between the onset of drug therapy and the appearance of symptoms.51,778 4. The reactions are particularly likely to occur in individuals previously exposed to the drug.166 5. Neither the incidence nor the severity of the hepatitis can be correlated with the amount of cinchophen ingested. 6. There is a remarkable tendency for the lesion to progress after withdrawal of the drug.550 7. Even lethal doses of cinchophen fail to produce significant hepatic lesions in ex perimental animals.314, 421, 605 Skin tests for hypersensitivity are posi tive only occasionally,593,682 and the results of attempted passive transfer of antibody by the Prausnitz-KiistDer technic and of precipitin tests are uniformly negative.586, 682 However, as indicated, these are seldom positive in other types of drug hypersen sitivity. Usually, hepatitis appears after prolonged cinchophen therapy, often weeks or months following its institution. In occasional in stances, however, liver damage is not evi dent for as long as 6 months following cessa tion of drug ingestion.550 It is this long period of latency and the frequent occur rence of massive hepatic necrosis that have led to the suggestion that the injury to the liver may be based on an induced nutri tional deficiency,324 No clinical evidence supports this hvpothesis; indeed, the restric tion of protein and methionine in the diet does not overcome the natural resistance of animals to hepatic injury by cinchophen.344 Other possible interpretations of the sig nificance of prolonged latency are discussed elsewhere. Attempts have been made to correlate the development of cinchophen hepatitis with antecedent liver disease436 or impaired he patic function,436,593 on the theory that they may render the liver more susceptible to injury, or lead to the production of ab normal toxic metabolites. However, in ani mals, previous damage with toxic agents, such as chloroform and phosphorus, does predispose the liver to injury by cincho phen,42`-603 and as vet no toxic metabolites of cinchophen have been isolated. Pathologic Findings. The high mortality rate in this form of hepatitis is related to the frequent development of acute and sub acute massive necrosis of the liver. Almost invariablv postmortem examination reveals a small liver without significant nodulation, even when the patient has survived for a number of months.51, 426, 45- 56- 604 This re flects the fact that usually the destruction is extensive, and unaccompanied by hepato cellular regeneration. Most of the paren chymal cells have either undergone lysis or show severe degenerative changes, includ ing fattv infiltration, vacuolization and hya line necrosis. The inflammatory reaction is variable, being minimal in some cases and intense in others. As in other types of acute massive, hepatic necrosis, the reticulum framework is collapsed and condensed and the bile ducts show active regeneration. In older lesions, the areas of collapse are the site of connective tissue proliferation. Except for the frequent occurrence of degenerative changes in the epithelium of the renal tubules, and certain alterations to be expected as secondary manifestations of severe hepatic failure, there are no other morphologic signs of cinchophen toxicity. The nature of the hepatic lesions in nonfatal cases is not known, but there is no rea son to believe that it differs fundamentally from that seen at autopsy, except possibly In extent. This raises the question of whether or not restoration of the normal architec ture is possible following recovery. Of 3 such cases studied at the Mayo Clinic, 1 ex hibited a nodular liver at operation, and 2 had relapses subsequently that proved to be fatal.778 Therefore, it is possible that postnecrotic scarring is more frequent than is generally recognized. Symptoms. Usually, the onset is sudden, with anorexia, nausea and vomiting. These may be accompanied by chills and fever, 24905035 532 Toxic and Drug-Induced Hepatitis pruritus or urticaria. Jaundice usually fol lows within a few days but may be delayed for weeks or even months.778 Anicteric hep atitis has been described588, 778 but is rareThe jaundice increases in intensity, usually reaching its maximum in a few days and then persists. As might be expected from the nature of the hepatic lesion, bilirubinuria and pale or clay-colored stools are seen early. Al buminuria, cylindruria and oliguria are com mon, but severe renal failure is rare. The subsequent course is variable.778 Prognosis. In fulminant cases, the patient lapses into coma and dies of hepatic failure within the first few weeks. This is by far the most common type of death. Other cases run a chronic course, occasionally inter rupted by clinical remissions; ultimately ascites and edema develop and the patient dies within 6 months of hepatic failure or bleeding from esophageal varices. The most favorable cases improve slowly and go on to apparent recovery in 6 to 8 weeks. As indicated, the prognosis in this group must be guarded, since relapse and evidence of progression mav appear at a later date. In a recent report "cholangiolitic" cirrho sis with xanthomatosis, allegedly due to intrahepatic biliary' obstruction, appeared 18 years following neocinchophen therapy.70 There was no immediate reaction to the drug, but it was considered possible that an anicteric hepatitis had occurred and then progressed at a subclinical level for a num ber of years. This is a reasonable interpre tation, in the light of experience with other drug reactions, although it is difficult to ex clude alternative possibilities. DESACETYlJVfFTHYLCOLCHICINE ( CoLCEMIDE, DEMECOLCINE ) Desacetylmethylcolchicine, an alkaloid with antimitotic activity, is an effective thera peutic agent in acute gout and chronic mye logenous leukemia. It produces fewer gas trointestinal symptoms than colchicine. However, serious side reactions, including bone marrow depression, alopecia, fever, rash, stomatitis and jaundice, have been re ported.177 Hepatic involvement is relatively uncom mon and usually is of the cholestatic type.791 Although massive doses of desacetylmethylcolchicine can produce hepatic congestion and necrosis in rabbits,791 the character of the hepatic lesions and the associated symp toms seen in man suggest that they are due to drug sensitization. Gold The gold compounds used in rheumatoid arthritis frequently produce manifestations of toxicity. These fall into two groups: (1) anaphylactoid and febrile responses imme diately following an injection and (2) de layed reactions involving the skin, mucous membranes, gastrointestinal tract, liver, kid neys and hemopoietic system.21,157 It is not known whether these are due to drug in toxication or to sensitization, but the latter is generally considered more likely. Hepatitis is one of the less common com plications of gold therapy and is said to be clinically indistinguishable from the viral tvpe.S0T Since many of the cases reported have occurred in individuals undergoing group therapy in large outpatient clinics,307 it is possible that they represent instances of syringe-transmitted viral hepatitis. Un fortunately, no epidemiologic or histologic data are available to substantiate this. Massive hepatic necrosis is said to occur rarely,189 but in no reported cases has the diagnosis been established by postmortem examination. In the few fatalities that have been investigated,21 the changes in the liver were nonspecific, and no lesions suggestive of a hypersensitivity reaction have been de scribed. BAL is of some value in the. treatment of dermal reactions following gold therapy.48 Although it is worth a trial in all cases, it is not known whether it affects the course of more serious reactions involving the liver, kidney and hemopoietic svstem. Indomethacin (Indocin) Indomethacin [ l-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid], rarely produces hepatitis. In one reported fatal case, that of a 12-year-old Negro boy, pro fuse rectal bleeding and deep jaundice ap peared after 5 or 6 months of treatment with prednisone and indomethacin for se vere j'uveuile arthritis.374 The liver was en larged reveale creased positive action, time a deepen died 10 of the 1 zonal n fatty ir minima In a atomeg 3 wee! therap) An unu serum i high co color. 1 hue. Tf aminas^ but the lesterol centrilc mild fa tense n matory and th transan nisone of the i ered 6 tory ex this ca that in< biliverc or, alte deficier light b) It w< that in hepatoi though lished, is attri since i 2&he 1 Antiarthritic Agents 533 : desacetylmethylep congestion the character of associated sympthat they are due ed in rheumatoid ce manifestations two groups: (1) responses immetion and (2) dethe sldn, mucous il tract, liver, kid,m st. isr jt is not due to drug in)n, but the latter re likelv. `ss common comand is said to be from the viral e cases reported uals undergoing patient clinics,307 present instances tl hepatitis. Ungic or histologic ibstantiate this. s to occur ?d c<xj,es has the by postmortem alities that have -nges in the liver ions suggestive n have been de* the treatment of gold therapy.488 in all cases, it is ts the course of >lving the liver, tern. DOCEV) obenzoyl>5-mec acid], rarely reported fatal fegro boy, proJP jaundice ap5 of treatment ethacin for se liver was en larged and tender, and laboratory studies revealed marked hyperbilirubinemia, in creased levels of serum transaminase, a positive cephalin-cholesterol flocculation re action, prolongation of the prothrombin time and marked leukocytosis. Jaundice deepened progressively, and the patient died 10 days later. Postmortem examination of the liver revealed extensive centrflobular zonal necrosis with bile stasis, small-droplet fatty infiltration of the parenchyma and a minimal inflammatory reaction. In a second, nonfatal case, jaundice, hepatomegalv and abdominal pain were noted 3 weeks after the onset of indomethacin therapy for chronic rheumatoid arthritis.224 An unusual feature was the presence in the serum and urine of biliverdin in sufficiently high concentrations to render them green in color. The skin too had a distinct greenish hue. The serum levels of bilirubin and trans aminase were only moderately elevated, but those of alkaline phosphatase and cho lesterol were high. Liver biopsy revealed centrilobular degeneration and swelling, mild fatty infiltration, bile stasis and an in tense mononuclear and neutrophilic inflam matory reaction in both the parenchyma and the portal zones. Because the serum transaminase level continued to rise, pred nisone therapy was begun in the 4th week of the disease. The patient was fully recov ered 6 weeks later. There was no satisfac tory explanation for the biliverdinemia in this case, although the authors suggested that indomethacin inhibited the activity of biliverdin reductase in the liver and spleen, or, alternatively, that a congenital partial deficiency of the enzyme was brought to light by the development of hepatitis. It would appear from these two reports that indomethacin can give rise to either hepatocellular or cholestatic hepatitis. Al though the mechanism has not been estab lished, it is highly probable that hepatitis is attributable to a sensitization reaction, since indomethacin is known to produce other manifestations of hypersensitivity, such as rash, angioneurotic edema, asthma, leukopenia and thrombocytopenia. Phenylbutazone (Butazolidin) The high incidence of untoward reactions I to phenylbutazone limits its usefulness as an antiarthritic agent. n5> 717 Many of these, including rash, fever, agranulocytosis, throm bocytopenia, lymphadenopathy and swell ing of the salivary glands, appear to be manifestations of drug hypersensitivity. However, others, such as edema and peptic ulcer,400-030 are probably based on other mechanisms. Hepatitis is a relatively uncommon com plication of phenylbutazone therapy.213-4W713,7i5, 72i when it occurs, it is almost al ways accompanied by other manifestations indicative or drug sensitization. It is seen most frequently during the first 6 weeks of therapy but may occur at long as 10 days after the drug is withdrawn.213 Usually, the clinical and the laboratory features are those of acute hepatocellular disease with jaundice and hepatomegaly, buFrare instances of aiucteric'fTepafitis'Have been reported.721 Histologically, the "liver shows scattered parenchymal degeneration and necrosis and a polymorphonuclear and mononuclear inflammatory reaction in the portal triads.213 Although most patients re cover without residuals within 3 months, extensive hepatocellular necrosis with sub sequent postnecrotic cirrhosis may be seen occasionally.213 Rarely, the clinical and labo ratory picture is that of_ cholestatic hepa titis, but even in cases of this type the liver shows evidence of significant hepatocellular involvement.213 Several fatalities have been reported,213-494-7,3 but in only one of these was death clearly attributable to the hepatic lesion.213 Probenecid (Benemed) Fever, rash and other manifestations of drug sensitization occur in about 2 per cent of patients who receive probenecid and are seen almost exclusively in those given the drug intermittently.310 Hepatic involvement is rare, but one fatal case has been re ported.610 In this instance, mild hepatitis fol lowed a 2-year course of intermittent pro benecid therapy in a patient with an allergic background. Recovery followed withdrawal of the drug, but when it was readministered a month later it promptly produced asthma and rash followed by progressive jaundice, clay-colored stools, hepatomegaly. 534 Toxic and Drug-Induced Hepatitis coma and ultimate death on the 27th day. Postmortem examination revealed massive hepatic necrosis involving the central and the midzonal areas predominantly, and a sparse portal inflammatory reaction with out evidence of vasculitis. ANTIBIOTICS Some antibiotics can injure the liver, either directly by a toxic action or indirectly by inducing a hypersensitivity reaction. However, many of the infections for which they are used also produce hepatitis, so that often it is difficult to evaluate the role of antibiotics when this complication occurs. Moreover, in prolonged therapy the possi bility of syringe-transmitted viral hepatitis must be considered. It has also become ap parent that broad-spectrum antibiotics favor the development of disseminated mycotic infections and the emergence of resistant strains of staphylococci, both of which may produce an acute suppurative focal hepa titis. Chloramphenicol (Chloromycetin) A small proportion of individuals on chloramphenicol therapy develop severe blood dyscrasias related to toxic depression of the bone marrow.304-133 In at least two instances, jaundice has been reported as a complication; in one of these it appeared after aplastic anemia developed and was due to an infection of the liver with staphy lococci and Candida, so that the drug was im plicated only indirectly.811 In the other, an individual with a history of penicillin sen sitivity in the past, nausea, vomiting and vertigo developed immediately following a second course of chloramphenicol.304 Jaun dice appeared on the third day and then cleared promptly. Signs of aplastic anemia did not become evident for 2 months. At autopsy 2 weeks later the liver was normal. Possibly the jaundice in this case was the result of a hypersensitivity reaction involv ing the liver. This would be consistent with the observation that chloramphenicol does not injure the liver in animals*4 or in pa tients with hepatitis.290 Routine biopsies in individuals without hepatic disease also have failed to demonstrate changes in the liver following chloramphenicol therapy.802 Chloramphenicol should be used with caution in patients with severe liver dis ease, since they are unusually prone to bone marrow depression.731 Their enhanced sus ceptibility to this complication appears to be related to the high levels of free chlor amphenicol that occur in the serum as a re sult of impaired conjugation in the liver and the slow rate at which the unconjugated form of the drug is excreted by the kidneys. Erythromycin Although erythromycin is relatively in nocuous so far as the liver is concerned, one of its esters, propionyl erythromycin ester of lauryl sulfate (Ilosone), produces typical cholestatic hepatitis in a small proportion of exposed individuals.388 Since the hepatitis not infrequently is accompanied by eosinophilia ana cannot be reproduced in experi mental animals, it is reasonable to assume that it is due to drug sensitization. The oc casional occurrence of urticaria and other rashes is consistent with this view. In most cases, jaundice appears between the 2nd and the 21st days of medication iind often is accompanied by abdominal distress, which may be colicky in nature.221 Charac teristically, thymol turbidity and cephalincholesterol flocculation are normal, while the serum bilirubin, alkaline phosphatase and transaminase levels rise. The signs and symptoms of liver disease promptly subside when the drug is withdrawn, but usually recur if it is administered a second time. Griseofulvin In mice, chronic administration of large doses of griseofulvin leads to the develop ment of hepatic and erythropoietic por phyria accompanied by enlargement of the liver, focal hepatocellular necrosis, ductular proliferation and deposition of pigment in Kupffer cells and bile ducts.188 The hepatic lesions have been ascribed by some investi gators to a direct toxic effect of griseo fulvin,37 and by others to overproductioi and increased biliary excretion of proto porphyrin, leading to its deposition in par enchymal and Kupffer cells and its precipi tation within the small intrahepatic bill BPnerig*^ ph ''ol therapy.802 ou* je used with th severe liver dis- sually prone to bone [heir enhanced susalication appears to levels of free chlorn the serum as a reigation in the liver ch the unconjugated eted bv the kidneys. UYCIN an is relatively iner is concerned, one erythromycin ester e), produces typical . small proportion of Since the hepatitis tnpanied by eosinoproduced in experiasonable to assume aisitization. The ocurticaria and other i this view. x appears between s of medication and abdominal distress, i w e.221 Characidit .nd cephalinare normal, while kaline phosphatase rise. The signs and e promptly subside irawn, but usually la second time. LVLY inistration of large ds to the develop?rythropoietic porenlargement of the r necrosis, ductular tion of pigment in icts.168 The hepatic d by some investi' effect of griseo* to overproduction xcretion of proto deposition in parUs and its precipi- intrahepatic bile Antibiotics 535 radicles, resulting in biliary obstruction and necrosis and died on the 13th day following secondary parenchymal changes.347 Rats, the onset of symptoms.98 The morphologic guinea pigs and rabbits are not susceptible changes in the liver were indistinguishable to these effects of griseofulvin. from those seen in fulminant viral hepatitis. Many patients receiving therapeutic doses of griseofulvin for tinea infections also show Oxacillin (Phostaphlin) increased protoporphyrin and copropor The semisvnthetic penicillin, sodium oxa phyrin in their feces and red blood cells.810 cillin, produces allergic reactions charac However, they do.not exhibit other bio terized bv fever,-rash, urticaria and eosinochemical evidence of hepatic injury.444- 6,9 philia in approximately 3 per cent of Several individuals with acute intermittent patients. In one such patient, the reaction porphyria given therapeutic doses of griseo was accompanied by tvpical cholestatic fulvin during a remission have experienced hepatitis that resolved in little over 3 a relapse.64- 601 In one of these, acute porphvria was accompanied bv mild Bromsulphalein retention and an increase in months.742 Oxacillin therapy occasionally is accom panied bv moderate elevation of serum serum transaminase.601 Griseofulvin may serve as a sensitizing agent and give rise to reactions character ized by fever, rash, urticaria and angio neurotic edema.268-710 In at least one in stance, cholestatic hepatitis resulted.05 glutamic oxalacetic transaminase.498 Since no details are available on the circumstances under which this occurs, it is not clear whether such alterations in serum trans aminase are due to drug toxicity or sensitiza tion, or to the underlying infection for Novobiocin which the drug is used. Therapeutic doses of novobiocin tend to Penicillin raise the level of unconjugated bilirubin in In 1 or 2 per cent of individuals given the serum,5* and occasionally give rise to penicillin, manifestations of hypersensitivity overt jaundice,154 especially in neonates.736 develop.427 Urticaria and other benign types Since hemolysis does not appear to be the factor responsible for this effect, it is highlv probable that the unconjugated hyperbili rubinemia is attributable, at least in part, to a defect in the hepatic uptake or conju gation of bilirubin. Attempts to establish the precise mechanism involved have been unsuccessful. In some strains of rats, novo biocin inhibits the uptake of bilirubin by the liver, but in others it does not.4 The fact that the hyperbilirubinemia seen in man usually is associated with abnormal reten tion of Bomsulphalein154 suggests that there is a defect in bile secretion in addition to impairment of bilirubin uptake or conju gation. Since, the hyperbilirubinemia occurs in the absence of detectable changes in he patic morphology,736 it would appear to be related to a functional disorder of pigment metabolism rather than to toxic injury. of skin rash predominate, but fatal cases of anaphvlactic shock,767- 791 exfoliative derma titis''87 and acute vasculitis65 also have been reported. Acute hepatitis is a relatively rare com plication, usually seen in association with exfoliative dermatitis.587- 757 In one such nonfatal case, the serum bilirubin and alka line phosphatase levels were moderately elevated, whereas cephalin-cholesterol floc culation and thymol turbidity remained nor mal.757 Biopsy of the liver revealed multiple foci of necrosis, diffuse infiltration of the parenchyma with histiocytes and neutro phils, proliferation of the reticuloendothelium, and portal exudates containing monocvtcs, eosinophils and neutrophils. Dubin has reported one instance of prolonged peni cillin-induced cholestatic hepatitis in which Not infrequently, novobiocin induces hy recovery occurred in one and a half years.191 persensitivity reactions characterized bv That the hepatitis provoked by penicillin fever, rash, pruritus and eosinophilia.98 is due to sensitization and not to hepato- Rarely, these may be accompanied by hepa toxicity is evident not only from the other titis. One such patient had massive hepatic 536 Toxic and Drug-Induced Hepatitis it is associated, but also by the fact that the lesions are not reproducible in animals,1'299 Rjlfamycin SV Large doses of rifamycin given intrave nously produce a transient increase in serum bilirubin and interfere with the excretion of Bromsulphalein.6 Most of the bilirubin is in the unconjugated form, but at the peak of the rise 25 per cent may be conjugated.4 In rats, rifamycin reduces the Tm for both conjugated and unconjugated bilirubin, and increases their concentration in the liver, which suggests that rifamycin competes with bilirubin for excretion.4 However, since the bilirubin retained in the serum is pre dominantly unconjugated, it is highly prob able that the drug also impairs the hepatic uptake of bilirubin. Streptomycin A variety of drug reactions may occur during streptomycin therapy.807 Some, such as disturbances of the 8th nerve and its nuclei, are clearly toxic in origin, whereas others, such as rash, fever and eosinophilia, are almost certainly manifestations of drug sensitization. The pathogenesis of the renal failure and the bone marrow depression that occur occasionally is not known. Several instances of jaundice have been reported following streptomycin therapy.607 Unfortunately, insufficient data are avail able to state whether these were due to an incidental infection with the hepatitis virus, a toxic reaction or the development of hy persensitivity. However, animal experi ments412 and studies of hepatic function607 and morphology802 in man suggest that streptomycin is not a hepatotoxin, and that if jaundice occurs during treatment it is likely to be due to a hypersensitivity reac tion, or to syringe-transmitted viral hep atitis. Tetracyclines Chlortetracycline (Aureomycin). Thera peutic doses of orally administered chlor tetracycline frequently produce a fine fatty vacuolization or the hepatic parenchyma that is readily reversible on stopping the drug.643-64V 802 However, the drug appears to have little effect on hepatic function, even in patients with antecedent liver dis ease,143, 674 so that the lesion probably has no clinical importance. Intravenous chlortetracycline, on the other hand, can produce significant liver damage, as evidenced by impairment of function, clinical jaundice and hepatomeg aly.45, 423-642 This is most likely to occur in individuals who have received excessively large doses intravenously in addition to oral medication,45, 428 but significant injury has been observed also after as little as I Gm. intravenously for 3 days.642 Conceivably, hepatitis in such cases is due to the asso ciated infection. However, the same type of injury has been produced experimentally in both man45 and animals,429 so that there is little reason to doubt that intravenous chlortetracycline is potentially hepatotoxic. Histologically, the liver shows the same type of fine fatty vacuolization seen after the oral administration of chlortetracycline, but the centrilobular cells tend to undergo autolysis and fragmentation, and bile thrombi are common.45, 428 In animals, inactivation of chlortetra cycline by heat does not abolish its toxicity for the liver, which suggests that the he patic lesions are due to a direct chemical effect and not to an indirect action related to chlortetracycline's antibiotic activity. Of special interest is the observation that chlortetracycline protects animals against the massive hepatic necrosis produced by low-sulfhydryl, low-tocopherol diets, an effect thought to be related to inhibition of the intestinal flora and a reduction in the formation of hypothetical hepatotoxic bac terial metabolites.290 On the principle that similar bacterial factors may be of impor tance in the pathogenesis of hepatic coma, chlortetracycline has been recommended as a therapeutic agent in that condition.222 On the whole, the results of this form of treat ment have been disappointing. Large doses of chlortetracycline also pro tect against the hepatic and the renal effects of choline deficiency in rats.47 The mecha nism of this action is not known but appears to be related to the antibacterial properties of the drug. Oxytetr vacuolizat curs with peutic doi orally or j eral davs.1 clinical si versible f< and gives nificant i] even in p; ease.383 Si in mice ar Severe ness are V ceiving o: casional d< ity hepatil as yet no s Tetracy ministered daily occ; tion of thi on hepatic Large < when gu women w may give .-.es.'eei, "S3 and morp the acute cases occt intravenoi; cvcline e.\i has been 1 Gm. da or orally.7 trimester victims of in the pos sionally in dren181 an ease is fat of cases. At postr parenchvn with fine v pearance. flammatior CD hepatocelh c no Kupffer c phagoevto: J'l. *' Antibiotics 537 ep function, >6dt.c liver dism probably has ictine, on the significant liver impairment of md hepatomegcely to occur in' ved excessively addition to oral cant injury has little as 1 Gm. 2 Conceivably, tie to the assothe same type experimentally so that there at intravenous ly hepatotoxic. > the same type n after the oral feline, but the 3ergo autolvsis i thrombi are of chlortetralish its toxicity i t the heireev chemical action related : activity, servation that imals against produced by ol diets, an i inhibition of uction in the )atotoxic bacprincipie that be of imporiepatic coma, immended as idition.222 On orm of treat- line also prorenal effects The mechabut appears al properties Oxytetracycline (Terramycin). Fine fatty eating antecedent necrosis and loss of par vacuolization of the hepatic parenchyma oc enchyma.405 In many cases, the kidneys curs with great regularity following thera show fatty vacuolization of the renal tu peutic doses of oxytetracycline given either bules and foci of cortical necrosis, unre orally or parenterally over a period of sev lated to underlying pyelonephritis, and in eral davs.845 The lesion appears to have no a high proportion there is evidence of acute clinical significance, since it is readily re pancreatitis.10' versible following withdrawal of the drug Inordinately high levels of tetracycline and gives rise to neither svmptoms nor sig have been found in the serum of patients nificant impairment of hepatic function, with tetracvcline-induced toxic hepatitis.783 even in patients with pre-existent liver dis- Accordingly, it has been suggested that im . ease.383 Similar lesions have been observed pairment of renal function related to pyelo in mice and do<js429 but not in rats.350 nephritis and diminished exti-acellular fluid Severe reactions resembling serum sick volume mav be important factors in the ness are known to occur in individuals re pathogenesis of this complication. In addi ceiving oxytetracycline,361 so that the oc tion, the possibility- has been considered that casional development of drug hypersensitiv pregnanev, bv enhancing the uptake and ity hepatitis is to be anticipated. However, diminishing the excretion of tetracycline by as vet no such cases have been reported. the liver, as it does in the case of Brom- Tetracycline (Achromycin). Orally ad- sulphalein, leads to an unusually high con | ministered tetracycline in doses up to 2 Gm. centration of the drug in the liver and thus daily occasionally produces fatty infiltra- renders it susceptible to toxic injury.783 | tion of the liver, but has no adverse effect The principal clinical manifestations are j on hepatic function.219 nausea, vomiting, abdominal pain and jaun ! Large doses of tetracycline, especially dice. Not infrequently the vomitus is coffee- j when given intravenously to pregnant ground in character. Evidence of renal fail women with complicating pyelonephritis, ure is common, and in some cases there are may give rise to severe hepatic injury.*05- signs of acute pancreatitis. Remarkably, the 585.881, '83 such women, both the clinical recoverv rate was SO per cent in one series and morphologic features mimic those of of 5 cases treated rigorously for acute pan the acute fattv liver of pregnancy. Most creatitis. In fatal cases, the patient lapses cases occur 3 to 5 days after the onset of into coma and dies within a few days. Fetal intravenous treatment with doses of tetra death occurs in 70 per cent of women who cycline exceeding 2 Gm. daily. However, it die, and in 40 per cent of those who sur has been reported after doses as small as vive.405 1 Gm. daily given either intravenously881 Laboratory studies reveal leukoevtosis, or orally.TM Although women in the third azotemia, evidence of acidosis, and a mod trimester of pregnancy are the principal erate elevation of the serum levels of bili victims of this complication, it may occur rubin, alkaline phosphatase and transami in the postpartum period and is seen occa nase. Usuallv, thvmol turbidity is normal, sionally in nonpregnant women565 and chil but the eephalin-cholesterol flocculation re dren181 and rarely in adult males. The dis- action tends to be strongly positive. In 1 ease is fatal in approximately 80 per cent many cases, the serum levels of amylase t of cases. and lipase are increased. IAt postmortem examination, most of die The occurrence of a Fanconi-Iike syn parenchymal cells of the liver are distended drome and features simulating disseminated with fine vacuoles, giving them a foamy ap- lupus erythematosus have been reported i pearance. Although foci of necrosis and in- following the use of degraded tetracy j flammation are not seen, the number of cline.732 These have not been accompanied hepatocellular nuclei is reduced and the by evidence of hepatic injury. Kupffer cells contain large amounts of The hepatotoxic properties of tetracycline phagocytosed debris and pigment, indi- have been confirmed in the rat.508 However, 24905041 538 Toxic and Drug-Induced Hepatitis in this species pregnancy does not appear to increase the susceptibility to hepatic injury. Triacetyloleamkjmycin (Cyclaniycin) A high proportion of individuals receiving triacetyloleandomycin in a dose of I Gm. daily for 2 to 4 weeks show variable al terations in hepatic function, including Bromsulphalein retention, cephalin-cholesterol flocculation, increased thymol turbid ity or a raised serum level of transaminase, alkaline phosphatase or bilirubin.'"3, 748, 749 Occasionally, these are associated with clin ically detectable jaundice, anorexia and mild discomfort in the epigastrium or right upper quadrant of the abdomen. Liver bi opsy in patients with drug-induced jaundice reveals moderate cholestasis, foci of hepato cellular degeneration, acidophilic bodies and a portal mononuclear inflammatory re action. Histologic changes in anicteric druginduced hepatitis are similar but less strik ing. Functional abnormalities clear in a few weeks following withdrawal of the drug, but recovery from structural changes in the liver is much slower. Usually, there is a prompt relapse on subsequent challenge with the drug. When given in doses of less than 1 Gm. daily and for periods of less than 2 weeks, triacetyloleandomycin appears to have no ill effects on the liver. The pathogenesis of the hepatic lesions induced by this agent is unknown. The fre quency with which functional abnormalities are produced, and their apparent dose de pendence suggest that triacetyloleandomycin is a hepatotoxin. However, the morphologic features of the hepatic lesions and the promptness with which they recur following challenge are more consistent with drug sensitization. In this connection, it may be of significance that this drug is known to produce other types of allergic reaction. ANTICONVULSANTS, MUSCLE RELAXANTS AND SEDATIVES Dilantin (Diphenylhydantoin Sodium) Approximately 15 per cent of epileptics maintained on Dilantin therapy for pro longed periods develop drug reactions. Those relating to the gums, the central nerv ous system and the gastrointestinal tract are almost certainly of toxic origin and usually can be controlled by adjusting the dose. On the other hand, skin reactions, which often are accompanied by fever and other con stitutional symptoms, appear to be mani festations of drug hypersensitivity and are far more serious. Although they often sub side despite continued drug administration, they occasionally give rise to exfoliative dermatitis129-4S7-7,50 or hemorrhagic ery thema multiforme621 and terminate fatally. Several instances of Dilantin-induced hepatitis have been reported.129,156,193,306 Without exception, these have occurred in association with other manifestations of hy persensitivity, such as rash, fever, lymphadenopathv and eosinophiiia. Occasionally such reactions are accompanied by hepatosplenovnegaly without jaundice.32,487 In most cases, the clinical and biochemical fea tures are those of hepatocellular jaundice with varying degrees of cholestasis. On biopsy, the liver shows evidence of diffuse injury, with foci of necrosis, acidophilic bodies, infiltration of both the parencnvma and portal triads with many mononuclear cells and eosinophils, and bile stasis.306 Oc casionally, hepatic necrosis is submassive in character and leads to hepatic coma and death.156 In one fatal case of Dilantininduced exfoliative dermatitis, there was, in addition to hepatic necrosis, necrosis of ar terioles and granuloma formation that in volved many tissues, including the liver.760 Mesantoin (3 methyl-5.5-ethvlphenvlhydantoin) Mesantoin, a compound closely related to Dilantin, mav give rise to fever, rash, Ivmphadenopathv and aplastic anemia,258 features that are generally regarded as mani festations of drug hypersensitivity. Minor alterations in hepatic function may be ob served under such conditions, but frank hepatitis has not been encountered.13 At least one instance of acquired hemolytic jaundice has been reported. 00 Nervanol (Phenvlethvlhvdantoin) Nirvanol, a compound closely related to Dilantin, \ tive and i regularly t action, cn eosinophili the reactio so that the country. / dence of 1 but no ir hepatitis t A review fatalities a tic doses < the drug 1 introducec ger of sei doubt mil1 and attra< biturates frequently as widely parent dif no signific The pri barbital r more seve dermatitis and bleed membran< are manif although rivatives, of metabo responsibl The ca: occurred tions.48*-7 showed e necrosis, ' ing cells changes i less striki ported,776 colored si associatio eruption. ^veeks. .The \v jnic h iction i Anticonvulsants, Muscle Relaxants and Sedatives 539 antral nervirifc. .al tract are origin and usually sting the dose. On ions, which often r and other conjear to be manijnsitivity and are a they often subig administration, se to exfoliative emorrhagic eryterminate fatally. Dilantin-induced rted.129,156,193,308 have occurred in dfestations of hvh, fever, lymph- lia. Occasionally inied by hepatoundice.32,487 In biochemical fea* cellular jaundice cholestasis. On dence of diffuse osis, acidophilic the parenchyma ny mononuclear >ile sis.308 Ocis . nassive in patic coma and se of Dilantintis, there was, in i, necrosis of armation that in'ing the liver.760 dhydantoin) closely related to fever, rash, istic anemia,255 garded as manilsitivity. Minor on may be ob3ns, but frank countered.13 At ired hemolytic itoin) sely related to Dilantin, was once widely used as a seda tive and in the treatment of chorea.211 It regularly produces a typical sensitization re action, characterized by fever, rash and eosinophilia, in 1 to 2 weeks. Occasionally, the reaction is severe and terminates fatally, so that the drug has been abandoned in this country. Agranulocytosis and autopsy evi dence of liver injury have been described, but no instances of clinically detectable hepatitis have been reported. Phenobarbetal A review of the literature records only 17 fatalities as a result of reactions to therapeu tic doses of phenobarbital.468 Since tons of the drug have been consumed since it was introduced into clinical medicine, the dan ger of serious reaction must be small. No doubt mild reactions are relatively common and attract little attention. The other bar biturates appear to produce reactions less frequently. However, none of them is used (as widely as phenobarbetal, so that the ap parent difference in their toxicity may have | no significance. The principal clinical features of phenobarbital reactions are fever and rash. In more severe cases, there may be exfoliative dermatitis, renal failure, signs of hepatitis, and bleeding from the skin and the mucous membranes. It is highly probable that these are manifestations of drug hypersensitivity, although it is held by some that phenol de rivatives, liberated during an abnormal type of metabolism in susceptible individuals, are responsible for tissue damage. The cases of hepatitis reported have all occurred in association with dermal reac tions.488- 776 In one of these,488 the liver showed extensive midzonal and periportal necrosis, with vacuolization of the remain ing cells. However, the hepatocellular changes in other fatal cases790 have been less striking. In the one nonfatal case re ported,776 moderately severe jaundice, claycolored stools and dark -urine occurred in association with a morbilliform and bullous eruption. Complete recovery followed within 3 weeks. The writer has seen one instance of chronic hepatitis following a phenobarbital reaction in a 7-year-old child. The onset was with rash, fever and splenomegaly. The rash subsided, except for residual pigmentation, but was followed by arthritis, lymphadenopathy, anemia and progressive hepatosplenomegaly. Biopsy of the liver at the end of 2 years revealed fibrosis of the portal tracts with an intense inflammatory exudate, composed of large reticulum cells, mono cytes 'and plasma cells, and evidence of mveloid metaplasia. Death occurred 2& years after onset. Unfortunately, permission for autopsy was not obtained. Phenurone ( Phenacetylurea ) Of all the antiepileptic drugs, Phenurone is the one most likely to produce hepa titis.183,239 One survey indicates that this complication occurs in approximately 2 per cent of patients under treatment, and that in approximately 10 per cent the disease is fatal.753 Bone-marrow depression753 and renal failure259-432 are equally serious com plications. Fever and rash occur somewhat more frequently but do not appear to be as lethal. Many clinical features suggest that these reactions are manifestations of drug hypersensitivity, which is consistent with the observation that Phenurone does not produce hepatic, renal or hemopoietic injurv in animals.817 As in the case of Dilantin, Phenurone may give rise to signs of true toxicitv in the gastrointestinal tract and the central nervous system.259,753 Careful screening of patients may reveal alterations in liver function before clinical signs of hepatitis appear.1 Therefore, it is probably wise to check the status of the liver with some simple test, such as the serum transaminase level, at frequent inter vals, and to stop treatment if any abnor mality is detected. As with other types of drug sensitivity, symptoms may appear as early as the first week of therapy, or not until many months have elapsed,124 so that close supervision is essential for as tong as treatment is continued. The pathologic changes found in fatal cases or hepatitis are not constantle3-432 In general, however, there is extensive nonzonal degeneration or necrosis of paren chymal cells with little inflammatory reac tion. Occasionally, the renal tubules also show severe degenerative changes.432 fO CoO cn o 4* 540 Toxic and Drug-Induced Hepatitis Tridione ( Trimethadione ) A high proportion of individuals receiv ing Tridione develop rash, leukopenia, or a characteristic type of visual disturbance.425 Rarely, hepatitis,417 nephrosis785 and fatal aplastic anemia477 may occur. In one pa tient with hepatitis,417 jaundice and exfolia tive dermatitis appeared 4 weeks after the onset of Tridione therapy and were associ ated with a leukemoid reaction in the bone marrow. Uneventful recovery took place in approximately I month. Except for the visual disturbances, which may be of toxic origin, it is generally be lieved that the side-effects of Tridione are due to drug hypersensitivity, an opinion consistent with the observation that the drug does not produce visceral lesions in animals.616 severe form of zoxazolamine-induced hepa titis who was treated with ACTH.359 The pathogenesis of this type of hepatitis is not known. Since zoxazolamine occasion ally produces a skin rash, the possibility of drug hypersensitivity must be considered. This is supported by the report that eosino phils predominated in the inflammatory exu date seen in the liver in one fatal case.123 However, in none of the other reported cases have there been any clinical or mor phologic features indicative of a sensitiza tion reaction. A direct hepatotoxic action appears unlikely, since zoxazolamine does not produce hepatic lesions in animals. CHEMOTHERAPEUTIC AGENTS USED IN INFECTION ZOXAZOLAMINE (FLEX1N) Zoxazolamine (2-amino-5-chlorobenzoxazole) was introduced as a muscle relaxant and later found to be an effective uricosuric agent. Occasionally it produces a form of acute hepatocellular necrosis characterized by clinical and morphologic features indis tinguishable from those of acute viral hep atitis.123- 330-359 Of the cases reported, most have terminated fatally with signs of mas sive hepatic necrosis.123-330> 456 Usually, the hepatitis appears following a period of drug administration that may be as short as 1 week or as long as 2 months. The onset is abrupt, with anorexia, nausea, vomiting and abdominal pain, which are followed within a few days by jaundice, dark urine and light stools. Fever is uncom mon. Enlargement and tenderness of the liver may be evident early in the course of the disease, but in severe cases, the liver soon shrinks in size and often is not pal pable. The laboratory findings are those of severe hepatocellular disease, although high levels of serum alkaline phosphatase may be seen.359 In fatal cases, there is rapid deep ening of the jaundice, fever and die devel opment of hepatic coma with death in 2 or 3 weeks. Prednisone and cortisone have proved to be ineffective in such cases.123-330 Full recovery within a period of 3 months has been reported in a patient with a less Antimony Although the inorganic compounds of antimony can injure die liver in animals,273 they do not appear to produce hepatitis in workers exposed to them in industry,287 Toxic doses of both the trivalent and the pentavalent organic antimonials induce fatty degeneration of the liver, kidneys and heart in patients undergoing treatment for kalaazar.728 However, frank hepatitis has been reported only in connection with the penta valent group.331, 532 Almost without excep tion, the jaundice in such cases has ap peared a month or two following comple tion of a course of intravenous injections. Therefore, these may represent instances of syringe-transmitted viral hepatitis. How ever, neither the clinical features nor the pathologic findings have been described in sufficient detail to permit definite conclu sions regarding their etiology. Antimony dimercaptosuccinate (Astiban), a trivalent antimonial used in the treatment of schistosomiasis, frequently raises the serum level of glutamic oxalacetic transaminase, and less commonly that of alkaline phosphatase.708-773 Since the oc currence of these changes appears to be correlated with the total dose employed, it is assumed that they are manifestations of hepatotoxicitv. However, biopsy studies of the liver in several patients undergoing treatment have failed to demonstrate sig- ca7 line-induced hepated ...th ACTH.359 is of this type of hepatitis 33 zoxazolamine occasion al rash, the possibility of vitv must be considered, bv the report that eosinod in the inflammatory exuliver in one fatal case.123 e of the other reported been any clinical or morindicative of a sensitizadirect hepatotoxic action since zoxazolamine does dc lesions in animals. RAPEUTIC AGENTS N INFECTION NTIMONY inorganic compounds of ire the liver in animals,273 ir to produce hepatitis in 0 them in industry.287 Doth the trivalent and the ic antimonials induce fatty le liver, kidneys and heart 501 reatment for kalafra._. hepatitis has been onnection with the pentaa Almost without excep2 in such cases has ap>r two following compleof intravenous injections, may represent instances tted viral hepatitis. Howclinical features nor the ;s have been described in > permit definite conclu?ir etiology. lercaptosuccinate (Astiantimonial used in the histosomiasis, frequently ivel of glutamic oxalacetic 1 less commonly that of ase.708-775 Since the oc: changes appears to be he total dose employed, t they are manifestations However, biopsy studies feral patients undergoing died to demonstrate sig Chemotherapeutic Agents Used in Infection 541 nificant lesions.TM No cases of overt hepa titis have been encountered in patients re ceiving this drug. It has been suggested that impairment of hepatic function during the treatment of schistosomiasis with antimonials is the re sult of an allergic reaction to products re leased from killed ova and worms, and that this can be prevented by concomitant ad ministration of prednisone.904 Consistent with this possibility is the observation that antimonial treatment of schistosomiasis not infrequently leads to an increase in eosinophilia and the appearance of fever and pruritus.708 Arsenic At one time it was thought that all types of arsenical hepatitis had a common patho genesis. However, arsenic can produce liver injury by: (1) a direct toxic action, (2) inducing a hypersensitivity reaction or (3) serving as a vehicle for the accidental trans mission of the hepatitis virus. In animals, massive doses of arsenic, in the form of either the organic compounds once used in the therapy of syphilis394- 851 or inorganic salts,762 produce acute necrosis of the liver. Depending on the circum stances, the lesions mav be massive,394 centri lobular051 or focal762 in distribution. The counterpart of this type of liver injury is not seen when intermittent therapy with small doses of the arsphenamines is used in the treatment of syphilis, but is common after short-term massive arsenotherapy.210424 Jaundice occurs in 1 to 4 per cent of pa tients on the latter regimen and, as might be expected, frequently is associated with other manifestations of acute arsenic tox icity, including fever, rash and cerebral symptoms. Usually recovery is rapid and complete. In contrast, healing of the lesions pro duced by the inorganic arsenates in animals often is followed by postnecrotic scarring and the picture of cirrhosis.762 A similar sequence is seen occasionally in individuals who have received potassium arsenite (Fowler's solution) for prolonged periods.239 Usually, the signs of cirrhosis in such cases develop insidiously without any recogniz able antecedent episode of acute hepatitis. A small proportion of individuals who are given small doses of the arsphenamines in termittently develop a reaction known as "erythema of the 9th day," or Milians syn drome.301- 624- 644 Usually, it appears several hours after the 2nd or 3rd injection (8th to 10th day of treatment) and is character ized by fever, rash, arthralgia and eosinophilia and, in some instances, by hepatitis, purpura and renal injury. The latter are par ticularly prone to occur if treatment is con tinued after the initial symptoms appear or is resumed following their subsidence. Al though the reaction was once thought to be of toxic origin,824-704 it is now generally agreed that it is due to drug sensitiza tion.301- 644 The hepatitis associated with Milians syn drome is of the classic cholestatic typeCharacteristically, jaundice appears on the 2nd or 3rd day of the reaction and usually is associated with anorexia, nausea and vom iting. The liver tends to enlarge, the spleen may be palpable, and itching is common. As the jaundice deepens, the stools become clav-colored, and the urine dark. The results of liver function tests, especially if carried out late in the disease, are more suggestive of extrahepatic biliary obstruction than they are of hepatocellular damage. Thus, the serum alkaline phosphatase and the choles terol levels tend to be high, while the cephalin-cholesterol flocculation reaction usually is negative. Liver biopsy at this stage reveals pericholangitis and bile stasis, with little or no evidence of parenchymal injury. The course of Milian's svndrome is vari able. Although uneventful recovery may occur within a few weeks, often it is delayed for many months. Rarely, it is complicated by the development of hepatic fibrosis and xanthomatosis of the skin,724 a syndrome difficult to distinguish from other tvpes of biliarv cirrhosis. By far the most common tvpe of hepatitis seen in individuals receiving any of the arsphenamines occurs 3 to 18 months after the onset of treatment.49- 704 There is now unequivocal experimental,460 histologic175 and epidemiologic644 evidence to show that the liver injury in this instance is due not to drug toxicity but rather to accidental syringe-transmission of the hepatitis virus. 542 Toxic and Drug-Induced Hepatitis No doubt most reported cases of massive hepatic necrosis286 and postnecrotic cirrho sis34* 173 following arsenotherapy also fall into this group. In animals, high-protein and high-carbohydrate diets given prophylacticalhj appear to protect against the hepatotoxic effects of arsenic.153- 303 However, claims for the thera peutic efficacy of cysteine and methionine supplements in postarsphenamine jaundice are based on unconvincing clinical evi dence.564 Moreover, there would appear to be little logic in attempting to "detoxify" arsenic in this situation, since the jaundice is usuallv due to viral hepatitis or to a sen sitization reaction. The results of treatment with BAL have been equivocal.196 Since BAL fixes and fa cilitates the removal of arsenic, it would appear to be a useful agent in the manage ment of true arsenic intoxication, such as occurs after massive arsphenamine therapy, and conceivably may be of value in sensi tization reactions when traces of the drug still remain.. However, it obviously has no place in the treatment of postarsphenamine jaundice due to the hepatitis virus. No doubt the inclusion of many such cases in treated groups has made the evaluation of therapy difficult. Inhalation of arsine (AsH3, arsenuretted hydrogen) usually is followed by the de velopment of jaundice, an effect due to an acute hemolytic reaction. Several instances of hepatitis following carbarsone therapy have been reported.535'. 588 These have been attributed to the hepatoxic effects of the drug itself or one of its hydrolvtic products, arsanilic acid, presuma bly formed during its storage or manufac ture.588 However, the hepatitis usuallv comes on abruptly following a relatively brief period of carbarsone administration at a low dose level, is typically cholestatic in type, almost alwavs is accompanied bv fever, and occasionally is associated with exfoliative dermatitis, features that strongly suggest that the drug is a sensitizing agent rather than an hepatotoxin. Atabrine Prolonged administration of small doses of atabrine occasionally gives rise to skin reactions. Rarely, these are accompanied by fulminant hepatitis, aplastic anemia or agranulocytosis.445 Similar reactions have been reported following intermittent thera peutic doses.11 It is not known whether these are due to a toxic effect or to drug sensitiza tion. Since patch tests may be positive,11 and since large doses do not ordinarily impair hepatic function109 a sensitization reaction is a distinct possibility. However, a direct toxic action cannot be excluded, since large doses of atabrine can produce hepatic necrosis in dogs.109 Bismuth The onlv instances of hepatitis reported following exposure to bismuth compounds have occurred in syphilitics given repeated injections over a long period of time. De scriptions of the clinical features and cer tain epidemiologic data in these cases sug gest svringe-transmission of the hepatitis virus. Ethionamide Ethionamide (alpha-ethyl-thioisonicotinamide), an effective agent in the treatment of tuberculosis, occasionally gives rise to acute hepatitis.14Ti 4,8 381* 369 The incidence of this complication is estimated to be 5 per cent.147 Diabetics appear to be particularly susceptible.147 Of the 18 cases reported up until 1964, 2 resulted in death from exten sive hepatic necrosis.147 Occasionally, this form of drug-induced hepatitis is unaccom panied bv jaundice.147 In addition, ethiona mide therapv may lead to alterations in he patic function without producing clinical signs of hepatitis.418 The onset, which occurs 1 to 8 months after starting treatment with ethionamide, is characterized by anorexia, nausea and vomiting, followed within a few days by dark urine and jaundice. Occasionally, these are accompanied by fever and rash. Usu allv, the signs of hepatitis regress following withdrawal of the drug, and recur when it is administered at a later date.520-561 How ever, hepatic functional abnormalities, in the absence of clinical signs of acute hepa titis, mav subside despite continued drug administration.4'8 In addition to hyperbilirubinemia, high levels of SGOT are mol turbidity, posi flocculation reactic values of serum a less constant featu eosinophilia occurs. The histologic ! biopsy147 resemble atitis. The occurrence c philia in some patit hepatic lesions and usually provoked b that ethionine-indu festation of a hypei view is not shared i attribute this com] infection with the h Is Izoniazid (isoni Rimifon, Pyrizidin widelv used in the l is a potential hepa longed administrat to 25.0 rrig./kg. for fatty degeneration jaundice.839 The rr in man (2 to 10 m affect hepatic func however, thev ind> produce fever, rai hepatitis.67- 142- ->9t-{ out exception, the ported in individi Other sensitizing ' para-aminosalicvlic to isoniazid. Althc tivitv to isoniazid such cases bv provi the hepatitis or fe' lowing recovery, tl excluded that initi duced bv PAS. In : which isoniazid alo hepatitis, there wa cedent reaction to The clinical and the hepatitis prodn ble those of viral 1 recovery follows v However, at least t- reported.142,502 In 1 24905046 If are accompanied itil iplastic anemia or Similar reactions have >wing intermittent theranot known whether these fleet or to drug sensitizatests may be positive,11 loses do not ordinarily action109 a sensitization ^ possibility. However, a cannot be excluded, since rine can produce hepatic ismuth ;es of hepatitis reported to bismuth compounds yphilitics given repeated mg period of time. Delinical features and cerdata in these cases suglission of the hepatitis IONAMIDE ha*ethvl-thioisonicotinaagent in the treatment of anally gives rise to acute 5*1.3*9 jhe incidence of t ated to be 5 per ppear to be particularly he 18 cases reported up in death from exten ds.147 Occasionally, this ed hepatitis is unaccom147 In addition, ethiona!ead to alterations in henout producing clinical i occurs 1 to 8 months nent with ethionamide, ' anorexia, nausea and within a few days by dice. Occasionally, these y fever and rash. Usupatitis regress following irug, and recur when it i later date.520-501 How:ional abnormalities, in cal signs of acute hepadespite continued drug yperbilirubinemia, high Chemotherapeutic Agents Used in Infection 543 levels of SGOT are the rule. Increased thy mol turbidity, positive cephalin-cholesterol flocculation reactions and relatively high values of serum alkaline phosphatase are less constant features. In a few patients, eosinophilia occurs. The histologic features found on liver biopsy147 resemble those seen in viral hep atitis. The occurrence of fever, rash and eosino philia in some patients, the character of the hepatic lesions and the prompt recurrence usually provoked by drug challenge suggest that ethionine-induced hepatitis is a mani festation of a hypersensitivity reaction. This view is not shared by some authorities, who attribute this complication to intercurrent infection with the hepatitis virus. ISONIAZID Izoniazid (isonicotinic acid hydrazide, Rimifon, Pyrizidin, Nydrazid), an agent widely used in the treatment of tuberculosis, is a potential hepatotoxin. In animals, pro longed administration of large doses (17.5 to 25.0 mg./kg. for 4 to 5 weeks) produces fatty degeneration of the liver and overt jaundice.*39 The much smaller doses used in man (2 to 10 mg./kg.) do not appear to affect hepatic function.212-025 Occasionally, however, they induce hypersensitivity and produce fever, rash and, less commonly, hepatitis.*57- U2-29*302*39,)- 809 Almost with out exception, the hepatitis has been re ported in individuals who have received other sensitizing drugs, and particularly para-aminosalicylic acid (PAS), in addition to isoniazid. Although evidence of sensi tivity to isoniazid has been established in such cases by provoking an exacerbation of the hepatitis or fever with a test dose fol lowing recovery, the possibility cannot be excluded that initial sensitization was in duced by PAS. In several reported cases in which isoniazid alone appeared to produce hepatitis, there was a history of an ante cedent reaction to PAS.87-009 The clinical and laboratory features of the hepatitis produced by isoniazid resem ble those of viral hepatitis. As a rule, full recovery follows withdrawal of the drug. However, at least two fatal cases have been reported.142,302 In one instance, drug ther apy was reinstituted 1 month after a reac tion accompanied by jaundice. This pro voked an exacerbation which was followed several months later by a fatal massive hem orrhage from esophageal varices. Postmor tem examination revealed postnecrotic cir rhosis thought to be related to the ante cedent drug reactions.502 In the second case, a patient being treated for sarcoidosis with prednisolone and isonicotinic acid, acute hepatitis with clinical, laboratory and histologic features undistinguishable from those of viral hepa titis, appeared on the 30th day of treat ment.142 Following withdrawal of the drug, full recovery occurred within 2 months. Isoniazid was restarted 10 days later, and the patient continued to take prednisolone. On the 45th day of treatment there was a recurrence of acute hepatitis with rapidly deepening jaundice followed by hepatic coma and death on the 21st day. Autopsy revealed a small liver (900 Gm.) and signs of submassive hepatic necrosis. Although the hepatitis tends to recur when isoniazid therapy is resumed, oral de sensitization has been successful in a num ber of cases87 The closely related isopropyl derivative of isonicotinic acid, iproniazid (Marsilid), was abandoned as an antituberculosis agent soon after it was introduced, since it proved to be more toxic than isoniazid. However, its potential for producing serious hepato cellular injury was not fully appreciated until it was reintroduced as an antidepres sant. The features of this type of hepatitis are described in the section on Psychopharmacologic Agents. Nitrofurantoin ( Furadantin) Nitrofurantoin, when given in large doses, often produces gastric irritation with nau sea and vomiting. Less commonly, it gives rise to sensitization reactions characterized by fever, rash, angioneurotic edema, hemo lytic anemia or leukopenia. In at least one instance, such a reaction was accompanied by cholestatic hepatitis.214 The patient, a female, experienced fever and rash during her second course of treatment with nitro furantoin. On resuming treatment 2 months later, she had an exacerbation of fever, 544 Toxic and Drug-Induced Hepatitis maculopapular rash, pruritus and eosinophilia within 24 hours, and 4 days later was found to be jaundiced. The liver was en larged and tender, and tests of hepatic func tion were typical of cholestasis with mod erate elevation of serum bilirubin, high alkaline phosphatase and cholesterol, mild elevation of serum transaminase and nega tive flocculation reactions. Liver biopsy re vealed severe centrolobular bile stasis, foci of parenchymal necrosis and inflammation, and enlargement of the portal tracts with ductular proliferation ana an exudate con taining numerous neutrophils, eosinophils and lymphocytes. Full recovery, except for mild residual Bromsulphalein retention, oc curred within 7 weeks. Paha-aminosalicylic Acid (PAS) Both toxic and allergic reactions may complicate the course of PAS therapy. Toxic reactions, which are due to the local irritant action of the drug in the gastrointestinal tract, are common but seldom necessitate interruption of treatment. Allergic reactions, which are far more serious, occur in ap proximately 2 to 5 per cent of patients. Usu ally, such reactions appear between the 3rd and 6th weeks of medication and are char acterized by fever, rash, eosinophilia and lymphadenopathy.435*9881772 Other less com mon manifestations of hypersensitivity in clude hepatitis/58, 435- 4T3, 688 Loeflier's syn drome,772 neutropenia,435 atypical lympho cytosis435 and renal damage.158 A history of antecedent allergy is relatively common.688 As a rule, the onset of hepatitis is pre ceded by other manifestations of PAS sen sitivity, such as fever and rash. The prin cipal clinical features include jaundice, dark urine and enlargement and tenderness of the liver. Occasionally, hepatosplenomegaly occurs without jaundice.435 Most cases show a marked increase in serum alkaline phos phatase and abnormalities in the cephalincholesterol flocculation and thymol turbid ity reactions.435 Usually, recovery ensues in 4 to 5 weeks. Histologically, the liver shows scattered foci of hepatocellular necrosis, bile stasis and an inflammatory reaction that is most intense in the portal triads.688 A few fatal cases have been reported.54, 546688 In these, death has occurred in 2 to 7 weeks with clinical and morphologic signs of massive hepatic necrosis. Occasionally, patch tests are positive/38 which supports the view that PAS-induced hepatitis is due to hypersensitivity. Of in terest in this connection, is the report of positive L.E. tests in the serum of a 32-yearold patient who had a severe reaction to PAS characterized by fever, urticaria, lym phadenitis, anicteric hepatitis and acute myocardial infarction/1 Although successful desensitization has been reported in a few instances/58-348, 772 it is difficult to exclude the possibility of spontaneous desensitization in such cases/72 Moreover, reinstitution of drug therapv often is followed by prompt recurrence of symptoms. As pointed out, reactions to PAS not in frequently are associated with or followed by the development of sensitivity to other drugs.140-688 It is not clear whether these are indicative of cross-sensitization or of multiple independent sensitizations. PVRAZINAMIDE ( AlDIXAMIDE ) In combination with isoniazid, pyrazinamide is one of the most effective agents used in the treatment of tuberculosis. How ever, its usefulness is limited by its tend ency to produce hepatitis when adminis tered alone368 or in combination with other drugs/17- 464, MS-862 A review of the litera ture indicates that jaundice occurs in ap proximately 3 per cent of patients receiv ing a daily dose of 40 mg./kg. of bodv weight. Evidence suggests that smaller doses are less likely to affect the liver.518 Usually, the hepatitis occurs late in the course of treatment, most commonly during the 6th month, but occasionally as early as the 2nd. Its duration and severity are vari able; some patients develop mild jaundice and recover within a week, whereas others run a severe aud protracted course. Several fatalities have been reported.464 The clinical and laboratory features are those of acute hepatocellular disease. Rarely, in nonfatal cases of unusual severity, the jaundice is accompanied by ascites.484 Bi opsy in such cases reveals a marked inflam matory reaction involving both the paren chyma and the portal triads, focal areas of hepatoc stasis.38 curred < massive on port) Alter; demons zinamic rupt th are disc minatio nection if treal transarr avoidec It is product or by in massive pa tic n< is not k persons Howevi patic le sitizatio The r (stilbar dine), and c agents ment o: sis,379 a multiple tomveo; they pr kidneys cem ovi Trans svmptoi mg the Usually utes an drug sic the diss distribu quentlv The nei followir is due ti sensory Then 348 Chemotherapeutic Agents Used in Infection 545 nr hologic signs ris. >$ts are positive,158 r that PAS-induced rsensitivity. Of in1, is the report of serum of a '32-yearsevere reaction to ver, urticaria, lym`patitis and acute iesensitization has instances,159- 54S-772 the possibility of du in such cases.772 of drug therapy mpt recurrence of >ns to PAS not in. with or followed ensitivity to other ?ar whether these ensitization or of situations. JJtN'AMIDE ) oniazid, pyrazinat effective agents ube dosis. Howrite y its tendis when adminisnation with other lew of the literaice occurs in apf patients receivmg./kg. of body sts that smaller * the liver.518 ccurs late in the commonly during anally as early as severity are vari>p mild jaundice s whereas others d course. Several d.464 :ory features are x disease. Rarely, ual severity, the >y ascites.494 Bii marked inflam- both the paren ts, focal areas of hepatocellular necrosis and marked bile mg./kg. daily or every other day in amounts stasis.383 In a fatal case in which death oc up to 6.0 Gm.) do not ordinarily cause any curred on the 8th day of illness,464 there was significant depression of hepatic or renal massive hemorrhagic necrosis of the liver function in man.22 However, in experimen on portmortem examination.383 tal animals, larger doses have produced Alterations in hepatic function may be severe fatty infiltration of the liver, degen demonstrable during the course of pyra- eration of the convoluted tubules of the zinamide therapy.484* 568 It is wise to inter kidnevs, and renal failure,787 rupt therapy as soon as such abnormalities Similar lesions were observed at autopsy are discovered. Serum transaminase deter in a 7-vear-old girl with systemic blastomy minations are particularly useful in this con cosis who received 7.65 Gm. of 2-hvdroxy- nection. Indeed, it has been reported that stilbamidine intravenously over a 36-day if treatment is stopped as soon as the period.538 Each injection was followed by transaminase level rises, hepatitis can be headache, nausea and fever. Twenty-four avoided.519 hours after her last dose of 450 mg., which It is not known whether pyrazinamide in retrospect was considered excessive, she produces hepatitis by a direct toxic action had a convulsion, followed by fever and or by inducing a sensitization reaction. Since enlargement of the liver. Death occurred massive doses of the drug can produce he on the 4th day. At the height of the reac patic necrosis in dogs,623 and since the drug tion the serum bilirubin was 1.4 mg./lOO is not known to produce other signs of hy ml.; cephalin-cholesterol flocculation, 4+; >. persensitivity, a toxic action appears likely. and thymol turbidity, 9 units. However, the histologic features of the he A number of years ago a fulminant tvpe , patic lesion are more consistent with a sen of hepatitis was observed in patients under sitization reaction. going stilbamidine therapy for kala-azar in Stilbamidine the Sudan.379 Characteristically, the symp toms occurred from 1 to 3 months following The 4,4'-diamidino derivatives of stilbene cessation of therapy. At autopsy, the out (stilbamidine), diphenyl ether (phenami- standing findings were extensive eentrilobu- dine), diphenoxypropane (propamidine) lar necrosis ana fatty infiltration of the liver. and diphenoxypentane (pentamidine), In some cases, the lesions closely resembled agents once used exclusively in the treat those of acute yellow atrophy. The hepa ment of trypanosomiasis22 and leishmania titis was attributed to an increase in the tox sis,379 are of value in the management of icity of the drug related to its storage and multiple myeloma,22 actinomycosis,503 blas- exposure to light. tomvcosis657 and tic douloureux. Because Subsequently, the increase in the toxicity they produce lesions in the liver and the of stilbamidine on exposure to light was kidneys of animals,787 there has been con confirmed in animals.36,247 However, in cern over their possible toxic effects in man. none of the experiments reported were the Transient vasomotor and gastrointestinal long latent period and centrilobular hepatic symptoms are common immediately follow necrosis reproduced. In retrospect, these ing the first few injections of stilbamidine. deaths were probablv due to syringe-trans Usually, these subside within a few min mitted viral hepatitis, especially since the utes and may be avoided by injecting the disease was prevalent in the Sudan at the drug slowly.00-379 Of greater importance is time. the dissociated sensory disturbance over the distribution of the trigeminal nerve that fre Sulfonamides quently follows prolonged therapy.22-379 The sulfonamides fall into the category The neuropathy appears from 2 to 3 months of drugs that can produce hepatic injury, following cessation of the medication and both by direct toxic action and by the in is due to toxic degeneration of the principal duction of a hypersensitivity reaction. From sensory nucleus or the 5th cranial nerve. a clinical point of view, however, only the Therapeutic doses of stilbamidine (2 to 3 latter gives rise to serious consequences. 546 Toxic and Drug-Induced Hepatitis Prolonged administration of sulfonamides to animals leads to the development of focal inflammatory, degenerative and necrotic lesions in liver, kidneys, myocardium and lungs.1*4, 244 Similar lesions have been ob served in a high proportion of individuals who have received sulfonamides shortly before death.244, 501 These are thought to be manifestations of true drug intoxication. The depression in hepatic function,18,774 and the occasional occurrence of hepatitis in individuals without other signs of hyper sensitivity773 have also been attributed to the toxic effects of the drug. However, the fact that these can seldom be correlated with the amount of drug ingested raises the question of whether they may not be related to some other factor, such as infection or sensitization. A variable proportion of individuals, de pending on the particular sulfonamide de rivative employed, develop a reaction char acterized bv fever, rash, and signs of vis ceral and bone marrow injury. Although the clinical manifestations often suggest in volvement of a single organ, postmortem ex amination usually reveals widespread in flammatory and necrotic lesions in many of the viscera and blood vessels.243,517 Occa sionally, identical lesions are found in indi viduals who have received sulfonamides but have not had clinical manifestations of a drug reaction.243 The clinical and morpho logic features of such reactions resemble those of serum sickness so closely that it is difficult to escape the conclusion that they are allergic in nature,*24,454, 812 even thouogh attempts to demonstrate specific antibodies have been unsuccessful.294 Acute hepatitis occurs in about 0.6 per cent of patients undergoing sulfanilamide therapy1,21 130,138, 229> 254,294,452'517, 641 and somewhat less frequently in individuals who receive sulfathiazole,130 sulfadiazine,130,314 sulfamethoxypvridine (Kynex),750 sulfa methoxazole (Gantanol),102 sulfadimethoxine (Madribon) ,216 and other sulfonamide derivatives. The incidence and severity of the hepatitis cannot be correlated with the amount of drug administered. In most in stances, the onset is within the first 2 weeks but may be delayed until the 6th week of therapy, or even later.*41 Rarely, hepatitis and other manifestations of sensitization do not become evident until a number of weeks have elapsed following cessation of medi cation.254 Approximately one quarter of these reactions occur in individuals who have been exposed previously to the drug. Usually, the onset of symptoms is sudden, with fever, anorexia, nausea and vomiting; they may be accompanied by a rash. Jaun dice appears on the 3rd to 6th day but may be delaved for as long as 2 weeks. The liver enlarges and often is tender. Occasionally, there is splenomegaly. Dark urine and acholic stools are the rule, at least early in the course. The laboratory features, which are those of hepatocellular damage, are not distinctive, except that the serum alkaline phosphatase level may be very high.234, 750 Most cases go on to slow recovery, but a few patients lapse into coma and die of hepatic failure.02, 138, 254, 3l4, 51T' 641 Death mav occur as earlv as the 5th day314 or may be delayed for several months.*2 Often, ascites is present when the course is chronic. In mild cases of sulfonamide-induced hepatitis, a diffuse inflammatory reaction involves all portions of the liver, with scat tered foci of hepatocellular necrosis750 and bile stasis. Occasionally, granulomata are seen.216 In fatal cases, the liver is small and shows evidence of massive necrosis of the parenchyma, collapse of the stroma and an inflammatory reaction in the portal triads.62i3s. 3i4. sit Individuals who die of more gen eralized reactions show scattered areas of hepatic necrosis, foci of inflammatory cells, and spotty necrosis of vessels. The exudate, which is composed of large mononuclear cells, is predominantly perivascular and periportal in location.243, 517 Sinjilar lesions may be found in the myocardium, kidneys, bone marrow, skin and other tissues. It has been suggested that pre-existent hepatic disease renders the liver more sus ceptible to further injury by the sulfona mides.130, 773 Autopsy experience does not bear this out. Moreover, there is no clinical evidence that sulfonamides increase hepatic dysfunction in such individuals.566 However, cirrhotics appear to be peculiarly suscepti ble to the other toxic effects of sulfonamides, particularly in the it is probably wise disease. Acute hemolyt: follow the ingestio give rise to jaunt taken for a manife occur earlv in the especially after : pyridine administr The etiology ol of sulfonamide tb may be due to the cipitated drug cn the drug or to se last ripe is most o hepatitis. (Amithiozone, p-r thiose; Tibione, used u cuiosis. is generall hepatotoxin. Althc hepatic function16 the liver218 have effects, there have hepatitis. The oth icity, which inc rash165 and agraro the drug may be is consistent wit even massive dost chvmatous or bon mals.383, 706 Similar alteratioj symptoms of sen* served following tf zone (p-fomwlac zone), a compoi Tibione.687 CYTOTOXIC SUPPRES Ante Azathioprine (I purine antagonist, actions as 6-merca which it is derived an immunosuppre; 2 4905050 Cytotoxic and Immunosuppressive Agents 547 gr ^Ur Rarely, hepatitis [on' * sensitization do ntL lumber of weeks ng cessation of mediitelv one quarter of r in individuals who reviously to the drug, if symptoms is sudden, nausea and vomiting; mied bv a rash. Jaunrd to 6th day but may r as 2 weeks. The liver tender. Occasionally, ly. Dark urine and rule, at least early in atory features, which llular damage, are not it die serum alkaline y be very high.254-750 slow recovery, but a ito coma and die of SM.3U.MT, Ml Death the 5th day31* or may ral months.92 Often, the course is chronic, sulfonamide-induced iflammatory reaction f the liver, with scatllular necrosis730 and lly, nulomata are the er is small and ssive necrosis of the :>f the stroma and an in the portal triads.62vho die of more genn scattered areas of f inflammatory cells, vessels. The exudate, : large mononuclear y perivascular and ,3,317 Similar lesions lyocardium, kidneys, other tissues, ed that pre-existent : the liver more susiry by the sulfonai.xperience does not there is no clinical des increase hepatic viduals.586 However, peculiarly susceptiJcts of sulfonamides, particularly in the kidney.408, 386 Therefore, it is probably wise to avoid their use in liver disease. Acute hemolytic reactions occasionally follow the ingestion of the sulfonamides and give rise to jaundice, which may be mis taken for a manifestation of hepatitis. These occur early in the course of treatment and especially after sulfanilamide and sulfapvridine administration.452 The etiology of the renal complications of sulfonamide therapy is complex. Lesions may be due to the mechanical Effects of pre cipitated drug crystals, the toxic action of , the drug or to sensitization reactions. The last type is most often associated with drug hepatitis. TlBIO.VE (Amithiozone, p-Ac-etvlaminobenzaldehyde thiosemicarbazone) Tibione. used in the treatment of tuber] culosis, is generally regarded as a potential ! hepatotoxin. Although minor alterations in j hepatic function185 and fatty infiltration of * the liver21- have been described as toxic 1 effects, there have been no reports of acute * hepatitis. The other manifestations of tox icity, which include nausea, vomiting, rash163 and agranulocvtosis,585 suggest that the drug may be a sensitizing agent. This is consistent with the observation that even massive doses fail to produce paren chymatous or bone marrow lesions in ani mals.5"- 7?* Similar alterations in hepatic function and symptoms of sensitization have been ob served following the administration of Myvizone (p-formvlacetanilide thiosemicarba zone), a compound closely related to Tibione.8*7 CYTOTOXIC AND IMMUNO SUPPRESSIVE AGENTS Anttmetabolites Azathioprine (Imuran). Azathioprine, a purine antagonist, has the same therapeutic actions as 6-mercaptopurine (6-MP), from which it is derived, but is more effective as an immunosuppressive agent.52 Although it is metabolized to 6-MP,209 it appears to be less toxic.840 In dogs, doses or 3.5 to 5.0 mg./kg. daily for periods up to 60 days raise the serum levels of alkaline phospha tase and transaminase, and produce minor degrees of focal hepatocellular necrosis and degeneration, increased mitotic activity, central congestion, bile stasis and, in some cases, cholangitis, pericholangitis and peri portal fibrosis.729 Several instances of apparent hepatotoxicitv have been reported in man. In a series of 46 patients given azathioprine for a va riety of "autoimmune" diseases, one case of biopsy-documented cholestatic hepatitis was encountered in a patient who had received the drug for 178 days in doses up to 350 mg. daily.150 The relationship of the hepatitis to azathioprine in this case was uncertain, because the patient had also taken prochlor perazine, a known cholestatic agent. In an other group of 3 patients being treated with azathioprine for - active chronic hepatitis, jaundice was encountered in one, a young girl who had received 4 mg./kg.476 The hy perbilirubinemia in this case was unaccom panied by other biochemical evidence of hepatocellular injury, and subsided despite continued drug administration. 6-Mercaptopurine (6-MP, Purinethol). A significant number of patients with leu kemia treated with 6-MP in doses exceed ing 2.5 mg./kg. daily exhibit manifestations of hepatotoxicity.204,469 These may appear as early as 2 weeks or as late as 2 years after treatment is begun. Usually, signs of hepatic injury appear abruptly, with jaundice, dark urine, light stools and enlargement and tenderness of the liver. Often these are associated with other manifestations of drug toxicity-, espe cially oral lesions and leukopenia. The serum levels of bilirubin, alkaline phospha tase and transaminase are elevated, and, occasionally, thymol turbidity and cephalincholesterol flocculation are abnormal. The jaundice tends to clear rapidly when drug administration is discontinued. Usually, reinstitution of 6-MP therapy provokes a re currence.204 Rarely, the hepatitis is progres sive and terminates fatally. Patients with active chronic liver disease 24905051 548 Toxic and Drug-Induced Hepatitis appear to be peculiarly susceptible to the bepatotoxic effects of 6-MP. In one such case, a dose of only 1.5 mg./kg. given daily for 3 weeks produced fatal hepatic necrosis and marked cholestasis accompanied by hepatic coma, renal failure and terminal shock.402 Of 12 other patients with active chronic hepatitis, most of whom were given 1.5 to 2.5 mg./Kg. of 6-MP daily, half ex hibited jaundice within 2 to 4 weeks.479 An unusual feature in this group was the fact that the hyperbilirubinemia was unaccom panied by other biochemical evidence of hepatocellular injury, and cleared spon taneously despite continued administration of the drug. In a nonfatal case seen by the writer, liver biopsy revealed enlargement of the portal triads with marked ductular proliferation, an intense neutrophilic and lvmphocvtic in flammatory reaction, marked bile stasis and many periportal acidophilic bodies. Post mortem examination of the liver in a per sonally studied fatal case revealed extensive loss of parenchyma, marked pleomorphism of the remaining hepatocytes, gross distor tion of the parenchymal plate pattern, pseu doduct formation and marked bile stasis. Experiments in animals confirm that 6-MP is an hepatotoxin.137 However, the doses re quired to produce hepatic lesions in the rat and the dog are considerably higher on a weight basis than those in man. Methotrexate (Amethopterin). Metho trexate, an antagonist of folic acid metabo lism widely used in the treatment of leu kemia, lymphoma, ocular inflammatory dis ease and psoriasis, frequently produces bio chemical evidence of hepatic injur)',31 and occasionally gives rise to overt clinical signs of liver disease.145, 545,738,741 The functional abnormalities, the severity of which appears to be dose related, are reversible if detected early.316 However, drug treatment, if con tinued, may give rise to progressive hepatic injury leading to the development of cir rhosis.145-73B-741 Formerly the hepatic fibro sis seen under such conditions was attrib uted to resolution of leukemic infiltrates in the portal triads with secondary collapse.145 However, this is unlikely since similar le sions have been reported in a patient with psoriasis who had received methotrexate in termittently over a 2 year period.543 Chil dren given the drug for acute leukemia ap pear to be more susceptible to severe he patic injury than adults. In a series of 10 patients with acute leu kemia receiving intermittent intensive treat ment with methotrexate, increased serum transaminase and Bromsulphalein retention were observed in 9, and hyperbilirubinemia in 2, functional abnormalities that were maximal following completion of each 5-dav course of treatment, and tended to regress during drug-free periods.316 There were no accompanying signs or symptoms of hepatic injurv, but liver biopsy revealed infiltration of the portal and periportal zones with neu trophils and mononuclear cells, occasional binucleate hepatocytes, and, less commonlv, bile stasis, fatty infiltration and portal fibro sis. Similar but less severe functional and histologic abnormalities were encountered in 8 of 12 patients with ocular inflammatorv disease treated less intensively with metho trexate every 4th day for 6 weeks.316 Of 7 children with acute leukemia treated with methotrexate by Colsky and associ ates,143 all 5 who had a satisfactory remis sion and remained under treatment for 6 to 14 months developed hepatomegaly and ascites; at postmortem examination portal fibrosis was extensive, and in 3 instances it had progressed to cirrhosis. Jaundice was not a prominent feature, but hyperbilirubi nemia was present in all cases. In another group of 32 children given methotrexate for acute leukemia, 7 devel oped anorexia, vomiting, hepatosplenomegalv, ascites and edema after 3 to 10 months of treatment.736 Jaundice was observed in only one. Liver biopsy in 4 of the children revealed swelling and pleomorphism of the parenchymal cells, evidence of regenera tion activity, acidophilic necrosis of some cells, and portal fibrosis with ductular pro liferation and round cell infiltration. When cyclophosphamide was substituted for methotrexate, fluid retention and hepatosplenomegaly regressed. Alkylating Agents Chlorambucil (Leukeran). Evidence sug gests that chlorambucil, a derivative of ni trogen mustard, is hepatotoxic in man. In one leuk dice drug At i this pato bile ture R; tizin tvpe man morl of ti vom whic amb later meg whe N. In tl area amn somi heps one dise; shov auto dice -eff icity tests of tl injur apy. stati thoS' volv O' histi that infill heps fed*TM f-Jard Jgthe rt-aii 'Jl A 3*ctic J^ear N> Food Poisoning 549 >ar "period.545 Chilac* leukemia aptil .o severe he ats with acute leuent intensive treat, increased serum jlphalein retenb'on hyperbilirubinemia rahties that were ?tion of each 5-day tended to regress 3,8 There were no mptoms of hepatic ivealed infiltration al zones with neur cells, occasional id, less commonly, i and portal Bbrore functional and vere encountered ular inflammatory ivelv vrith methoweeks.318 leukemia treated ilsky and associatisfactory remisreatment for 6 to ipatomegaly and :arr 'tion portal h -nstances it is. Jaundice was rnt hvperbilirubises. - children given ikemia, 7 develepatosplenomegr 3 to 10 months *vas observed in 1 of the children morphism of the ce of regeneratecrosis of some th ductular pro stration. When substituted for fro and hepato- SNTS >. Evidence suglerivative of ni>xic in man. In one series of patients with chronic lymphatic leukemia ana lymphoma, 6 exhibited jaun dice after having received 6 to 15 mg. of the drug daily for periods of 18 to 75 days.17 At postmortem examination, the livers in this group showed varying degrees of he patocellular necrosis, degenerative changes, bile stasis and portal fibrosis. In 2, the pic ture was that of postnecrotic cirrhosis. Rarely, chlorambucil serves as a sensi I tizing agent and gives rise to an allergic type of hepatitis. In one such case, a voung man with chronic lymphatic leukemia, a imorbilliform rash appeared on the 15th dav of treatment, and was followed bv nausea, vomiting, abdominal pain and jaundice which lasted for 3 weeks.3!>2 When chlor ambucil therapy was resumed 2 months later, the rash, abdominal pain and hepato megaly recurred promptly, and subsided * when the drug was withdrawn, t Nitrogen Mustard (Mechlorethamine). * In the cat, nitrogen mustard produces focal \ areas of hepatic necrosis, but in most other animals the liver is not affected.276 There is | some uncertainty regarding the possible hepatotoxic effects of the drug in man. In 1 one study, 3 of 50 patients with Hodgkin's disease treated with nitrogen mustard showed miliary foci of hepatic necrosis at autopsy, and 2 of the 4 cases with jaun dice appeared to get worse under treatment --effects that were attributed to drug tox icity.160 However, in another investigation, tests of hepatic function and needle biopsy of the liver failed to show anv evidence of injury that could be ascribed to chemother apy.809 Moreover, the clinical and functional status of the liver appeared to improve in those cases with antecedent hepatic in volvement. Obviouslv, it is difficult to interpret the i histologic and functional changes in a liver that is already the site of lymphomatous infiltration. Although the possibility of a hepatotoxic action cannot be excluded, the benefits to be derived from nitrogen mus tard outweigh its possible dangers, so that j the presence of hepatic lesions is not a con traindication to therapy. A recent report of a hypersensitivity re action to nitrogen mustard leading to ap pearance of erythema multiforme,84 suggests the possibility that, rarely, the drug gives rise to an allergic type hepatitis. To date there have been no reports of hepatic injury following the use of triethylenemelamine (TEM). Urethane (Ethyl Carbamate) Occasionally, patients undergoing pro longed therapy with urethane develop fatal massive hepatic necrosis, manifested clin ically with jaundice, ascites and hepato megaly.230- 312,496-5-11 Careful study of ure thane toxicity in experimental animals sug gests that the hepatocellular changes are secondary to vascular injury, with resultant extravasation of edema fluid and blood between the sinusoids and the parenchymal cells.180 In one reported case, an elderly woman with suspected multiple myeloma, signs of decompensated cirrhosis appeared after 6 years of continuous daily treatment with urethane.365 FOOD POISONING Aflatoxlv A large number of deaths associated with hepatic lesions have been encountered in turkey poults and other farm animals fed peanut (groundnut) meal contaminated with the fungus Aspergillus flavus.162 The agent responsible for the hepatic lesions has been identified as afiatoxin, a product of the fungus. The lesions have been reproduced in a wide variety of experimental animals.",7n-737 Protein deficiency enhances the hepatotoxic effects of afiatoxin. The hepatic lesions are characterized by focal hepato cellular necrosis, fatty infiltration, striking ductular proliferation and centrilobular endophlebitis. Prolonged administration of afiatoxin may give rise to cirrhosis or hepatoma. As yet, afiatoxin has not been implicated in human disease, but on the basis of ex perience with animals, it has been sug gested that contamination of food crops by A. flavus, and possibly other fungi, plays a role in the pathogenesis of cirrhosis and hepatoma, particularly in malnourished populations.182 550 Toxic and Drug-Induced Hepatitis Eppin'c Jaundice Occasionally, foodstuffs are contaminated during handling and shipment. A good ex ample is the epidemic of jaundice reported from Epping, England, which was traced to the ingestion of bread baked with flour contaminated with 4,4'-diaminodiphenylmethane, an aromatic amine used as a hard ener for epoxy resin.385 The flour had been contaminated during shipment in a van carrying a broken container of the amine. In most of the 84 patients involved, the onset was sudden with intermittent, severe abdominal pain that resembled biliary colic. This was followed 2 or 3 days later by rigors and an obstructive-like jaundice, pruritus and hepatomegaly. Usually, jaundice cleared in 4 to 6 weeks; in several patients, it per sisted for 3 or 4 months. ITie biochemical changes were variable, suggesting biliary obstruction in some, and hepatocellular dis ease in others. Moderate eosinophilia was present in half the cases, but the total leuko cyte count remained normal. The principal histologic features in the liver were portal inflammation with numer ous eosinophils, cholangitis, cholestasis and minimal hepatocellular necrosis. In more prolonged jaundice, the picture resembled that of viral hepatitis. Minimal portal scar ring was observed following recovery. There were no deaths in the group. Mushroom Poisoning (Mycetismus) Some 70 or 80 species of mushrooms are known to be toxic for man, but only one, Amanita phalloides, affects the liver. The others produce gastroenteritis, muscarinic effects, acute hemolysis and disorders of the central nervous system. The unusual toxicity of A. phalloides is attested by the 50 per cent mortality rate which follows its ingestion.237 Types of Toxin. Two types of toxin iso lated from A. phalloides are: phallin. a thermolabile ghicoside with hemolytic prop erties, and amanitatoxin, a thermostable agent which characteristically produces fatty degeneration and necrosis of the liver, kidneys and myocardium.238 Since phallin is destroyed readily by cook ing and during ingestion, it probably plays little role in human poisoning, although its effects can be easily demonstrated in ani mals when administered by the parenteral route.-116 There is general agreement, there fore, that all of the manifestations of A. phalloides poisoning are due to amanita toxin, which has been identified as a mix ture of cylic polypeptides.788 Phallin and amanitatoxin are antigenic and can produce specific antibodies in ani mals.238 However, the antigenicity of ama nitatoxin is weak, so that it has not been possible to develop a potent antiserum for use in treatment. Pathologic Changes. The principal patho logic changes in fatal cases are found in the liver, kidneys and central nervous system.191'' 753 As a rule, the liver is small and exhibits massive hepatocellular necrosis, intralobular hemorrhage and an acute inflammatory exu date. The parenchymal cells are heavily in filtrated with fat. droplets and do not un dergo the type of rapid autolysis seen in many other forms of massive hepatic ne crosis. The kidneys show varying degrees of swelling, degeneration and fatty infiltration of the tubular epithelium and congestion of the glomeruli. The principal findings in the central nerv ous system include widespread toxic swell ing of the cerebral ganglion cells, scattered small punctate hemorrhages and perivascu lar lymphocytic exudates. Not infrequently, the mvocardium also shows fatty infiltration and degeneration. Symptoms. Characteristically, the onset of symptoms following the ingestion of A. phalloides is delayed for 6 to 15 hours. In contrast, most other poisonous mush rooms produce symptoms within the first few hours. Nausea, vomiting, severe ab dominal cramps and diarrhea appear in rapid succession and usually are followed within 24 hours by severe prostration, signs of dehydration and vasomotor collapse. In severe cases, coma supervenes, and death ensues in 3 to 8 days. Usually jaundice ap pears on the 3rd day758 but mav be absent, even in individuals who survive for several days and then succumb to severe hepatic necrosis.180 Enlargement and tenderness of the liver and splenon Signs of rei Early in the bumin, cast oliguria anc spasms and minally. Th the central postmortem, experiments cemia is a fa rhagic phen< common tha toms but do I Prognosis, tients with s injury may i to predict tl Nevertheless azotemia an tem involvef able progno: able, in som days, and ir Few long-tei carried out, the recovery complete. I been report' stances,322 s occur more recognized. I Therapy. ; treatment fc eral support! ; importance ! initial critic vasomotor o velopment < These inclu and electrob blood, and t terally adm caloric requ glycemia. G: rid die gasti maining trac Ipjocedures n there is (stion of CStnptoms. I Mophylactic 52 V! * 1 Hormonal and Metabolic Agents 551 on' although its rpc ated in ani>by the parenteral I agreement, theremanifestations of re due to amanitalentified as a mix- 57S )xin are antigenic antibodies in aniitigenicitv of amait it has not been tent antiserum for and splenomegaly are inconstant findings. Signs of renal injury are always present. Early in the course, the urine contains al bumin, casts and red blood cells; later, oliguria and azotemia supervene. Clonic spasms and convulsions may develop ter minally. These are generally attributed to the central nervous system lesions found postmortem,190 but evidence based on dog experiments suggests that severe hypogly cemia is a factor in some instances. Hemor: rhagic phenomena and anemia are far less ! common than hepatorenal and neural svmp- le principal patho;s are found in the nervous system.190small and exhibits crosis, intralobular inflammatory e.vuslls are heavily ins and do not un- autolvsis seen in issive hepatic ne- , toms but do occur occasionally. Prognosis. Even the most gravely ill pa- j tients with signs of severe hepatic and renal j injury may recover,TM so that it is difficult 'to predict the outcome in any given case. Nevertheless, vasomotor collapse, increasing azotemia and signs of central nervous sys tem involvement usually denote an unfavor' able prognosis. The recovery period is variable, in some instances being as short as 10 i days, and in others as long as 6 weeks.758 xving degrees of d fatty infiltration n and congestion Few long-term follow-up studies have been 1 carried out, so that it is not known whether | the recover)' from hepatic injury is usually . complete. However, hepatic fibrosis has 0 ti entral nervpread toxic swellon cells, scattered jes and perivascu- been reported as a sequela in several in stances,322 so that residual damage may occur more frequently than is generally recognized. Therapy. Although there is no specific myocardium also treatment for A. phalloides poisoning, gen 1 degeneration. Really, the onset eral supportive measures are of the greatest importance in tiding the patient over the the ingestion of initial critical period of dehydration and :or 6 to 15 hours, vasomotor collapse, and the subsequent de poisonous mush* within the first iting, severe aburhea appear in ally are followed prostration, signs lotor collapse. In k'enes, and death tally jaundice aptt may be absent, arvive for several ;o severe hepatic velopment of hepatic and renal failure. These include careful regulation of fluid and electrolyte balance, transfusion of whole blood, and the provision of sufficient parenterally administered glucose to meet the caloric requirements and to prevent hypo glycemia. Gastric lavage and saline purges rid the gastrointestinal tract of possible re maining traces of mushroom; however, these procedures are of doubtful value, since usu ally there is a long interval between the in gestion of mushrooms and the onset of mess of the liver symptoms. However, they may be of value prophylactically in individuals who have partaken of a bad lot of mushrooms, but are not vet ill. HORMONAL AND METABOLIC AGENTS Androgens and Related Anabolic Acents Methyltestosterone, norethandrolone and a number of other C-17 alpha alkyl substi tuted steroids occasionally produce an un usual form of cholestatic jaundice. Charac teristically, there are no accompanying clini cal signs of hypersensitivity or histologic evidence of an inflammatorv reaction in the liver, features usually seen in most other forms of drug-induced cholestatic hepatitis. Since Bromsulphalein retention can be dem onstrated in a high proportion of individ uals given large doses, it is generally be lieved that agents of this type interfere with the excretion of bile, probablv as the result of a direct toxic action. Norethandrolone produces these effects more readily than any other steroid in this group.4''9 Neither tes tosterone and its esters, such as the phenvlproprionate,313 nor the closely related com pound, norandrolone,799 exhibit any adverse effect on the liver. Most of the substituted derivatives of tes tosterone stimulate the synthesis of creatine and increase the urinary excretion of cre atinine.489 Although this effect parallels Bromsulphalein retention, the correlation in individual cases is not close. Neither the mechanism of increased creatine synthesis nor its relationship to altered hepatic func tion is known. Methyltestosterone. Considering the fre quency with which methyltestosterone is prescribed and the small number of cases of cholestatic jaundice reported,97-23S-781 it is evident that the incidence of this com plication is relatively low. However, when used as an antipruritic agent in obstructive jaundice, it invariably raises the level of serum bilirubin.449 Daily doses of -30 to 100 mg. for periods of 1 to 5 weeks produce sig nificant Bromsulphalein retention without other signs of hepatic dysfunction in a high proportion of normal subjects and patients without evidence of antecedent liver dis ease.313* 489 Much of the Bromsulphalein re- 24905055 552 Toxic and Drug-Induced Hepatitis tained in the serum is in the conjugated form.1*1 This has been interpreted as evi dence that methyltestosterone interferes with the excretion but not with the conjuga tion of the dye. However, studies of Brom sulphalein clearance in individuals receiv ing norethandrolone show that the uptake of dye by the liver also is impaired, so that the effects of steroids of this type may not be limited to impairment of dye transport out of the hepatic cells.419 In patients who develop jaundice, the liver snows marked centrilobular bile stasis with little or no evidence of parenchymal damage or inflammatory reaction. In one re ported case with prolonged jaundice, biopsy of the liver showed simple cholestasis at the end of 3 weeks, and signs of early biliary cirrhosis, confirmed by gross inspection of the liver, at 11 weeks.15 Usually, symptoms appear between the 2nd and 5th months of medication but may be seen as earlv as the 8th day. The onset is characterized by malaise, nausea and other gastrointestinal disturbances. Jaun dice follows within a few days to 4 weeks and is accompanied by dark urine, acholic stools and hepatomegaly. Splenomegaly and pruritus are seen in some cases. Usually, the serum alkaline phosphatase level is significandy elevated, but this is an inconstant finding. In contrast, the serum cholesterol level, the cephalin-cholesterol flocculation reaction and thymol turbidity tend to re main within normal limits. Often, the jaundice is intense, but usually complete recovery ensues within 3 months. One fatality has been reported,399 In this case, jaundice appeared after 7 weeks of methyltestosterone therapy at a dose level ' of 30 mg. daily. The jaundice persisted and was complicated by progressive dehydration and metabolic acidosis which resulted in death at the end of 2 months. Postmortem examination revealed centrilobular hepato cellular degeneration with marked bile stasis. Norethandrolone (27<*-etbyl-19-nortestosterone, Nilevar). The effects of norethan drolone on the liver are essentially the same as those produced by methyltestosterone but tend to be more intense. In a high proportion of individuals receiving this drug in daily doses of 25 to 60 mg., impairment of Bromsulphalein excretion can be demon strated in 1 to 3 weeks, depending on the dose.398,649 Less commonly, there may be an increase in serum alkaline phosphatase398 and glutamic oxalacetic transaminase.349 Much of the Bromsulphalein retained in the serum is conjugated,120 which has been cited as evidence in support of the concept that norethandrolone interferes with the ex cretion rather than with the conjugation of the dye.489 In the rat, a similar defect in bilirubin excretion can be demonstrated.23 Since electromicroscopic studies of the liver in both man and the rat have shown that norethandrolone regularly produces dilatation of the canaliculi and effacement of their microvilli without any concomitant change in the appearance of the cytoplasm, it has been proposed that these anatomic alterations are responsible for the chole stasis and the impairment of Bromsulphalein excretion induced by this drug.650 However, clearance studies in man419 indicate that norethandrolone interferes with both the excretion and uptake of Bromsulphalein bv the liver. This suggests that the action of the drug is not limited to the canalicular membranes. The resulting functional de rangement is selective and does not affect indocyanine-green clearance.419 Only a few instances of overt cholestatic jaundice have been reported,194-274-649 but from the relatively high incidence observed in some series,194-649 one may anticipate that many more cases will be encountered as norethandrolone is used more widely, and that they will be seen more frequently than in the case of methyltestosterone ther apy. The interval between the onset of nor ethandrolone administration and the ap pearance of jaundice is unpredictable and may range from 2 weeks849 to 10 months.274 Usually, the jaundice is accompanied by an increase in serum alkaline phosphatase,t94*74, 649 an(j not infrequently there is a rise in the serum glutamic oxalacetic transami nase level649 and a positive cephalin-choles terol flocculation reaction.274-649 In some cases, the jaundice is intense and resolves relatively slowly.194- 649 Histologically, the liver shows centrilobular bile stasis with bile thrombi in the canaliculi, bile staining of the KupJ degeneratia Similar cha ally accomj portal triad and nuclear tive activity icteric indi lone.398 At least ported. Bot ure followii ethandrolon marked cho patocellular Because of necrosis in ( complicating virus was ir sented in si not convinci: Other Sul terone. Bror observed fo methandrosti rone, methi oxtjmesteront methyltestosi progestatiom ethinyl-19-no norethijnodrt (10)estren-3dition, rnetha the serum lei aminase.489 C the problem the observat and synthetic glucuronide fiver.342 Cholestatic after methylt reported in drone752 ant methyl-I9-noi A ^VIethimazo M}e, Tapazo in appr ^hts,43 and fi ewnCbnsitizinjj a ** Hormonal and Metabolic Agents 553 'i n* 'mpairment of the Kupffer cells and secondary feathery n ,__ . be demon- degeneration of the parenchymal cells.649 iepending on the Similar changes of lesser degree, occasion yi there may be ally accompanied by lymphocvtosis of the ne phosphatase398 portal triads, focal hepatocellular necrosis nsaminase.849 and nuclear changes indicative of regenera ialein retained in tive activity, have been encountered in non- which has been icteric individuals receiving norethandro- jrt of the concept | lone.393 feres with the ex- At least two fatalities have been re- he conjugation of ported. Both patients died of hepatic fail- similar defect in j ure following a prolonged course of nor- 5 demonstrated.23 ethandrolone and at autopsy exhibited c studies of the marked cholestasis, varying degrees of he- s rat have shown | patocellular necrosis and peliosis hepatis. gularlv produces j Because of the extensive character of the li and effacement necrosis in one case, it was assumed that a : any concomitant : complicating infection with the hepatitis of the cytoplasm, | virus was involved, but the evidence pre- it these anatomic : sented in support of this interpretation is le for the chole- ] not convincing. of Bromsulphalein i Other Substituted Derivatives of Testos drug.650 However, terone. Bromsulphalein retention has been a419 indicate that observed following the administration of ;s with both the I methandrostenolone (17a-methyltestoste- bromsulphalein by rone, methandienone, Dianabol),799 flu- chat the action of oxijmesterone (9a-9uoro-ll/3-hydroxy-17a- to the canalicular methyltestosterone, Halotestin)369 and the ng ctional de- progestational agents, norethindrone (17a- id <_^es not affect ethinyl-19-nortestosterone, Norlutin), and ice.419 norethijnodrel (17a-ethvnvl-17/3-hydroxy-5 >f overt cholestatic >rted,194- 274> 648 but ncidence observed le may anticipate ill be encountered ised more widely, m more frequently vitestosterone thern the onset of nortion and the apunpredictable and 849 to 10 months.274 iccompanied by an ne phosphatase,194atly there is a rise (10)estren-3-one norethisterone).533 In ad dition, methandrostenolone frequently raises the serum level of glutamic oxalacetic trans aminase.459 Of interest in connection with the problem of jaundice in the newborn is the observation that most of the natural and synthetic progestational steroids inhibit glueuronide transferase activity in the liver.342 Cholestatic jaundice resembling that seen after methyltestosterone therapy has been reported in patients receiving norethindrone752 and methylestrenalone (17aEnethyl-19-nortestosterone) .363 ixalacetic transamive cephalin-choleson.274- 649 In some itense and resolves Histologically, the it bile stasis with Antithyroid Drugs Methimazole (l*methy!-2-mercaptoimidazole, Tapazole) produces rash and urti caria in approximately 5 per cent of pa tients,43 and for that reason is thought to be iliculi, bile staining a sensitizing agent. Less commonly, it gives rise to agranulocytosis and cholestatic hepa titis028- 681 or cholestatic hepatitis alone.491 Propylthiouracil. Rare instances of fatal generalized periarteritis with secondary in volvement of the liver463 and transient hepa tocellular jaundice in association with fever and neutropenia448 have been reported. Pre sumably, such reactions are due to hyper sensitivity. Thiouracil. Fever, rash, arthralgia, lymphadenopathy, agranulocytosis and swelling of the salivary glands--features suggestive of sensitization--have been observed in pa tients receiving thiouracil.248-233> 338-557 Less commonly, this drug produces hepatitis.253we, '''7 The latter may be of the cholestatic type,253 but in at least one case which proved to be fatal the liver was greatly re duced in size and showed focal and central hepatocellular necrosis and bile stasis.336 Thiourea produces fever, rash, leukopenia and other manifestations of drug sensitiza tion more frequently than does thiouracil.557 Rarely, it gives rise to periarteritis nodosa. In one such case, the manifestations of gen eralized vascular disease were accompanied by deep jaundice, which at autopsv ap peared to be related to intrahepatic ar teritis.260 Corticosteroids In experimental animals, large doses of cortisone produce scattered foci of hepato cellular necrosis, and enhance the hepatotoxic effects of carbon tetrachloride.743 In addition, thev give rise to fatty infiltration of the liver, an effect attributable to in creased mobilization of fatty acids from adipose tissue depots.320 Fatty infiltration of the liver has been ob served following the administration of ther apeutic doses of cortisone in man.714 In a child given large doses of prednisone and hydrocortisone for 11 weeks, marked fatty infiltration of the liver was associated with massive fat embolism which resulted in sud den death.319 Dinitrophenol Occasionally, small doses of dinitrophenol produce an acute cholestatic hepatitis.685 Although it has not been possible to dem onstrate skin sensitivity or the presence of 24905057 554 Toxic and Drug-Induced Hepatitis circulatory antibodies in such cases;493 it is with bile secretion,646 but other steroids in highly probable that the hepatitis is due to this group also affect the liver. drug hypersensitivity. The reasons for be In animals, massive doses of stilbestrol lieving so include the following: (1) hepa (diethylstilbestrol), a nonsteroidal synthetic titis may be associated with an urticarial estrogen, produce hepatic necrosis,495 rash,685 (2) the clinical and laboratory fea whereas small doses impair Bromsulphalein tures closely resemble those seen in the hy excretion,251 as in the case of the steroidal persensitivity type of arsenical hepatitis,885 estrogens. However, there is no evidence (3) even fatal doses of dinitrophenol do not that the therapeutic doses used in man are produce significant alterations in the liver, hepatotoxic.241-4S8,495 either in experimental animals739 or in Most oral contraceptives contain a mix man,576-740 and (4) other common manifes ture of a synthetic progestin and a syn tations of drug hypersensitivity, including thetic estrogen, usually in a ratio of ap angioneurotic edema, neutropenia, renal in proximately 10:1 or greater. Not infre jury and arthritis, have been reported.20,459 quently, both components are C-17 alpha Large doses of dinitrophenol often stain alkyl substituted 19-nor-steroids. The agents the tissues yellow, due to the color of the most commonly employed include the pro drug itself. This must be distinguished from gestins, norethindrone (norethisterone, 17- true icterus. ethinyl-19-nortestosterone, Norlutin), nor- Estrogenic and Progestational Agents ethynodrel (17a-ethinyl-5[ 10]-estraeneolone), ethynodiol diocetate (17a-ethinvl-4- Natural Estrogens. Both estradiol and its estraenediol diacetate), or lynestrenol metabolite estriol, when given in relatively (ethinylestranol; 17/3-hydroxv-17a-ethinvI- Targe doses, produce abnormal Bromsulpha- estr-4-ene) in doses of 1 to 10 mg. and the lein retention, an effect attributable pri estrogens, ethinyl estradiol or its 3-methvl marily to a defect in the transport of dye ether, mestranol, in doses of 0.05 to 0.15 mg. out of the hepatic cell.524 In addition, estra As might be anticipated from the behavior diol raises the serum level of alkaline phos of their constituents in animals, oral con phatase, but has no effect on serum bili traceptives give rise to alterations in hepatic rubin or other parameters of hepatic func function in a significant number of healthv tion, and does not alter the microscopic ap women, the principal abnormality; mild pearance of the liver.525 Bromsulphalein retention, occurring in 20 It has been suggested that the alterations to 40 per cent of individuals tested.539 The in hepatic function that occur late in preg serum alkaline phosphatase is elevated far nancy are related to the accompanying less frequently. That the action of the oral marked increase in estrogen production. contraceptives on the liver is not always Natural Progestins. In contrast to the limited to inhibition of bile secretion is evi natural estrogens, neither progesterone nor dent from the fact that occasionally' thev its metabolite pregnanedioi impairs hepatic raise the level of serum transaminase, an function, as judged by Bromsulphalein clear effect that suggests hepatocellular injury.*8 ance in the rat.251 Menopausal women may be more suscepti Synthetic Estrogens, Progestins and Oral ble to this type of reaction, although in Contraceptives. As in the case of the syn most cases reported the dose employed has thetic androgens, a wide variety of syn been larger than that used for contracep thetic estrogens and progestins impair the tion.205, 7-3 With large doses, the serum hepatic excretion of Bromsulphalein, possi transaminase level rises with regularity, and bly by interfering with the uptake and trans may be accompanied by hyperbilirubine port of the dye in the liver.251 If given in mia; liver biopsy in such individuals re sufficiently large doses, they may produce veals centrilobular necrosis, either with or other biochemical and histologic evidence without cholestasis.723 of hepatic injury and cholestasis.723 The 17- Almost 100 cases of jaundice have been alpha alkyl 19-nor-steroids interfere most reported in women receiving oral contra- TV. ' i.',' :.i * * Hormonal and Metabolic Agents 555 it o&er steroids in li loses of stilbestrol isteroidal synthetic patic necrosis,495 iir Bromsulphalein se of the steroidal re is no evidence s used in man are es contain a mixjestm and a synin a ratio of apeater. Not infre:s are C-17 alpha eroids. The agents l include the proirethisterone, 17a, Norlutin), norl-5[10]-estraeneoLe (17a-ethinyl-4- or lynestrenol Iroxv-lTa-ethinvl- o 10 mg. and the >1 or its 3-methyl >f 0.05 to 0.15 mg. from the behavior nimals, oral conrati^s in hepatic iur. of healthy onormality, mild occurring in 20 ils tested.339 The e is elevated far ction of the oral t is not always ; secretion is evi>ccasionally thev transaminase, an cellular injury. e more susception, although in se employed has i for contracepises, the serum h regularity, and hyperbilirubineindividuals re, either with or idice have been ing oral contra ceptives.539* 544 However, considering the and Ovulen (ethynodiol diacetate 1 mg. + widespread use of these agents, the inci mestranol 0.1 mg.). dence of this complication must be exceed Available evidence suggests that the ingly low. Genetic or other constitutional estrogenic component is responsible for the factors may be of importance in determin jaundice produced by oral contraceptives. ing susceptibility to this form of jaundice. Thus, following recovery from such jaun- This is suggested by the observation that, .dice, challenge with mestranol provokes a in approximately 40 per cent of cases, previ- relapse, whereas administration of such ous pregnancies have been accompanied by progestational components as norethvnodrel (manifestations of cholestasis,5*39-344 a com or lynestrenol does not.8- 736 In contrast to plication of pregnancv that mav have a the synthetic estrogens, the natural estrogen i hereditary basis.293 In this connection, it is estradiol does not induce jaundice in such j noteworthy that the largest number of cases cases, although it mav raise the level of ! of contraceptive-induced jaundice have serum transaminase and cause bromsul ' been reported from Scandinavia415- 747 and phalein retention.736 > Chile,544 areas where the incidence of the The other manifestations of hepatic dys j cholestasis of pregnancv also is relatively function encountered in women receiving ; high. oral contraceptives also appear to be due j The initial symptoms of contraceptive- primarily to the synthetic estrogens con j induced cholestasis--malaise, anorexia and tained in these agents.'6-205 However, at J nausea--appear after 2 weeks to several high dose levels, synthetic progestins mav , months of medication. Jaundice, pruritus, be even more injurious to the liver than the dark urine and pale stools follow within a estrogens.'-3 Also, there is some evidence few days to 2 weeks. These are unaccom that the estrogens and progestins in oral panied bv fever, rash or adenopathv. In a contraceptives act synergistically in produc few cases, the liver enlarges, but the spleen ing hepatic dvsfunction.723 does not. Usually, the serum levels of bili Since mestranol produces jaundice and rubin and transaminase are only moderately other manifestations of hepatic dysfunction elevated, but deep jaundice and levels of much more readily than norethvnodrel, at transaminase in excess of 1,000 units have least at the dose levels found in oral con been reported.344- 747 Often, the serum alka traceptives, though both agents are C17 line phosphatase remains normal, but in alpha alkyl substituted steroids, alkylation some cases it rises significantlv.544 On bi- at the C-17 position cannot be the onlv opsv, the liver shows centrilobular canalicu lar and intracellular bile stasis, focal hepato cellular degeneration and necrosis, and a scanty parenchymal and portal inflamma tory reaction.344-747 Cessation of contracep tive therapy is followed by gradual re covery over a period of several weeks. Re lapses have been reported following re sumption of such therapy.747 j Impairment of hepatic function and j jaundice have been reported following the ] use of most oral contraceptives, including i Enovid (norethvnodrel 2.5-10 mg. + I mestranol 0.075-0.15 mg.), Lyndiol ( ethinyl- ] estrenol 5 mg. -j- mestranol 0.15 mg.), structural determinant of hepatotoxicity in this group of compounds. As further evi dence of this, estradiol, a nonalkvlated steroid, also impairs hepatic function.324- 736 In addition to alkylation at the C-17 posi tion, the presence of a phenolic A ring ap pears to be a factor in determining the potential of C-18 steroids for blocking Bromsulphalein excretion,. and may ac count for mestranols unusual activity in this respect.231 It has been suggested that hypersensitivity plays a role in the case of synthetic estrogens and progestins that pro duce signs of hepatocellular injury.646 This appears highly improbable, since large doses of lynestranol, particularly when forti Anovlar (norethindrone acetate 2.5 mg. + fied with mestranol, produce such injury ethinylestradiol 0.05 mg.), Ortho-Novum with regularity.723 (norethindrone 2 mg. -f- mestranol 0.1 mg.) Although some estrogenic and progesta- 24905059 556 Toxic and Drug-Induced Hepatitis tional steroids inhibit hepatic glucuronyl transferase in vitro,34S there is no evidence that they play a role in the biliary ex cretory defects induced by oral contra ceptives. However, pregnane-3 (alpha),20(beta)-diol, an unusual metabolite of progesterone secreted only rarely in human breast milk, inhibits glucuronyl transferase in vitro, and gives rise to severe and pro longed unconjugated hyperbilirubinemia in young infants fed such milk.24 Oral contraceptives appear to enhance the susceptibilitv to thromboembolic dis ease,4"4 and several instances of the BuddChiari syndrome have been reported in young women who have used these agents for periods ranging from 2 weeks to 2 years.1384,27a*' 8354T05a- 7184 Usually, the dis ease has proved fatal, but in one case re covery followed withdrawal of the drug.7l)5sL Hypoglycemic Agents Biguanidines. Synthalin (decamethylenediguanidine), one of the first oral hypo glycemic agents to be used in the treatment of diabetes mellitus, was abandoned soon after its introduction because it produces severe hepatic injurv both in animals and in man.33* Other compounds of this tvpe in current use do not appear to share this property and have not been implicated as etiologic factors in drug hepatitis.401 These include phenethylformamidinyliminourea (phenformin, DBI), amylformamidinyliminourea (DBB) and Lsoamylformamidinij}iminourea (DBC). Carbulamide (l-butyl-3-sulfonylurea, BZ55) Of the several sulfonvlureas introduced as hvpoglvcemic agents in the treatment of diabetes mellitus, carbutamide is the least desirable because of the frequency with which it evokes reactions. These are of the same tvpe produced bv the closely related sulfonamides, and include fever, rash, agranulocytosis, hemolytic anemia and hepatitis, manifestations suggestive of drug sensitization.380 Several fatalities have been reported, death being due to acute myocarditis,""* hepatitis,113 exfoliative dermatitis380 and bone marrow depression.380 The most strik ing finding in these cases has been the presence of foci of necrosis with miliary granulomata scattered through the viscera, of the type seen in patients with sulfon amide reactions.243 In one of these cases, the biochemical findings were those of chole static hepatitis, but hepatic failure ensued, and autopsy revealed a difFuse hepatitis with numerous areas of hepatocellular necrosis and bile stasis.113 Similar but less extensive changes have been observed in nonfatal cases.113 Chlorpropamide (l-propyl-3-( [p-chlorobenzenesulfonyi] )urea, Diabinese). One of the chief drawbacks to the use of chlor propamide as a hypoglycemic agent is the frequency with which it produces chole static hepatitis.100-202-207, 6lJ3 The incidence of this complication has been estimated to be approximately 0.5 per cent.003 However, in some series, transient but significant ele vations of the serum alkaline phosphatase level have been observed in as many as 25 per cent of patients under treatment with this drug.755 Usually, after 2 to 6 weeks of chlorpropa mide therapy, the hepatitis is ushered in with anorexia, nausea and vomiting. Soon thereafter dark urine, jaundice and claycolored stools appear. Fever, rash, pruritus, eosinophilia and hepatomegaly are common but inconstant findings. Although the regu lar occurrence of hyperbilirubinemia with high serum levels of alkaline phosphatase and cholesterol indicates a cholestatic form of jaundice, it is evident from the rise in SCOT003 and the positive cephalin-cholesterol flocculation reactions202, 603 seen in some cases that the cholestasis may be ac companied bv significant hepatocellular in jury, as in manv other forms of cholestatic hepatitis. Histologic studies of the liver bear this out. Characteristically, there is centrilobular bile stasis with bile-staining of the hepatic and Kupffer cells, plus an inflamma tory reaction in the portal triads with polymorjjlionuclear leukocytes, eosinophils and monoevtes.100-202, 207, 6"3 However, not in frequently the parenchyma shows feathery degeneration,603 small foci and necrosis603 and evidence of increased hepatocellular regenerative activity.297 Full recovery is to be anticipated in 1 to 3 months. The sporadic occurrence of the hepatitis in patients with which fever and the drug ti mals3S~- 658 a sensitizii toxin. In s of the druj tack of cl does not pi necessarily nism but n desensitizai Of pract diabetics w jaundice dc mide.297,603 Metahexj zenesulfon> cin), anoth jaundice in tients,755 a progressive ported.340 The clini of the hepa 540. 755 rtncj others.179, 3t foci of he nantlv cent some instar the portal stasis.179, 300 cellular inju the results show, in a significantly aminase300- 475, 755 an(J cholesterol I In fatal c picture is t sis.540 One a of lesion ha: was respon postnecrotic It is not c jures the liv tl|nductio TjJf^ sporad aQ^the occii rsdfffr in pati distent w Hormonal and Metabolic Agents 557 'j ( the viscera, ti< with sulfon- eTot uiese cases, the are those of choleitic failure ensued, a' diffuse hepatitis of hepatocellular 13 Similar but less been observed in jropyl-3-( [p-chloro- in patients given the drug, the frequency with which the jaundice is accompanied by fever and eosinophilia, and the failure of the drug to produce hepatic lesions in ani mals337, 050 suggest that chlorpropamide is a sensitizing agent rather than a hepato toxin. In some instances, readministration of the drug following recovery from an at | tack of chlorpropamide-induced hepatitis does not provoke a relapse.202 This does not that large doses produce hepatic lesions in experimental animals35 suggests that, under some circumstances, metahexamide may be have as a hepatotoxin. Tolbutamide (I-butyl-3-([p-tolylsulfonyl])urea, Orinase). Of the sulfonylureas used as hypoglycemic agents tolbutamide appears to evoke drug-reactions least frequently. In an early report on 400,000 patients re ceiving this agent, no instances of drug- Diabinese). One of necessarily exclude a sensitization mecha induced hepatitis or alterations in hepatic the use of chlor- j nism but may be indicative of spontaneous function are recorded.1'8 However, since cemic agent is the it produces ehole61,3 The incidence been estimated to cent.6l>3 However, but significant elecaline phosphatase 1 in as many as 25 ler treatment with j desensitization. Of practical importance is the fact that ` diabetics who recover from chlorpropamide jaundice do not relapse when given tolbuta j mide.29'- 603 / Metahexamide (N-[3-amino-4-methylben- zenesulfonvlj-N'-cyclohexylurea, Euglv- ; ein), another of the sulfonureas, produces j jaundice in approximately 1 per cent of pa tients/55 and at least 2 fatalities from then, several cases have been encountered. In one series of 1,500 patients given tolbutamide, 4 instances of liver injury were encountered.01 One of these, a patient with pre-existent cirrhosis, had a 2-week episode of jaundice following 3 months of drug therapy. In another, death from hepatic failure occurred after 12 months of treat ment; postmortem examination revealed mild portal cirrhosis with superimposed ?eks of chlorpropatitis is ushered in ad vomiting. Soon lundice and clayver, rash, pruritus, lega1" are common Vlt gh the reguiilirubinemia with raline phosphatase a cholestatic form t from the rise in e cephalin-choles>ns202, 003 seen in ^stasis mav be ac- hepatocellular inrms of cholestatic es of the liver bear y, there is centriile-staining of the plus an inflamma- 1 triads with polys, eosinophils and However, not inla shows feathery ci and necrosis603 ed hepatocellular progressive hepatic failure have been re ported.540 The clinical features of the hepatitis are of the hepatocellular type in some cases4755-mi. 735 and of the cholestatic type in others.170- 300 Histologically, the liver shows foci of hepatocellular necrosis, predomi nantly centrilobular in distribution, and, in some instances, an inflammatory reaction in the portal triads and evidence of bile stasis.1*9 3W- 540 This combination of hepato cellular injury and cholestasis is reflected in the results of laboratory tests which often j show, in addition to hyperbilirubinemia, significantly elevated serum levels of transaminase3"'*' 475 and alkaline phosphatase300its, 755 ;incl a strongly positive cephalin- cholesterol flocculation reaction. In. fatal cases, the clinical and pathologic picture is that of subacute hepatic necro sis.540 One apparent recovery from this type of lesion has been reported.540 In another it was responsible for the development of postnecrotic cirrhosis.755 It is not dear whether metahexamide in jures the liver by a direct toxic action or bv the induction of a hypersensitivity reaction. acute hepatitis. In the 2 remaining cases, the outstanding features were fever, thrombocvtopenic purpura, hepatosplenomegaly, Bromsulphalein retention and elevation of the serum alkaline phosphatase level. These appeared 1 and 6 months, respectively, after treatment was started. Biopsy of the liver in one of the cases revealed fatty infiltra tion. Recover)' followed withdrawal of the drug in one case and administration of hydrocortisone in the other. Several instances of typical cholestatic hepatitis have been encountered in indi viduals who have received tolbutamide for periods ranging from 1 to 24 months.31, 230 Prompt recovery has followed withdrawal of the drug. In one case, continued adminis tration of tolbutamide for 2 months after jaundice appeared resulted in chronic cholestasis with the development of clinical and functional features and histologic changes in the liver that closely resembled those seen in primarv biliarv cirrhosis.280 On histologic examination, the liver showed cholestasis, destructive cholangitis and cholangiolitis, and disappearance of the interlobular ducts. Exploratory laparotomy, mticipated in I to The sporadic occurrence of the hepatitis to exclude biliary obstruction, was fol and the occasional development of fever and lowed by massive bleeding from gastric e of the hepatitis rash in patients receiving the drug753 are and esophageal microsal ulcerations, hepatic consistent with the latter. However, the fact coma and dead). 558 Toxic and Drug-Induced Hepatitis Since tolbutamide occasionally gives rise to allergic reactions, it is possible that the hepatitis it produces also is a manifestation of hypersensitivity. However, in none of the cases reported has the hepatitis been accom panied by fever, rash or eosinophilia. METABOLIC DISTURBANCES Hyperthermia. Sustained elevation of the body tempera ture at a high level often produces severe liver damage. Approximately 20 per cent of individuals subjected to an artificially in duced fever of 41.5 C. (106.7 F.) for 7 hours develop clinical jaundice,466 and an even higher proportion exhibit an increase in serum bilirubin."71 Similar evidence of hepatic damage is seen also in association with the hyperpyrexia of heatstroke315,708 and other febrile diseases. Hyperpyrexia of sufficient severity and duration may be fatal.82,275,788 The prin cipal findings at autopsy include hemor rhages into the skin, mucous membranes and serosal surfaces, and severe degenera tive changes and necrosis in the liver, kid neys and adrenals.275 All patients who die later than the 2nd day exhibit jaundice and severe centrilobular hepatic necrosis. Super ficially, the lesions resemble those in ful minant viral hepatitis. However, there is little or no inflammatory reaction, and the hepatic cells do not show the characteristic rapid and complete autolysis seen in that disease. Cases that run a more prolonged course may show evidence of hepatocellular and bile duct proliferation. Usually, the changes in the liver are the predominant lesion after the first 48 hours, so that they probably have an important bearing on the ratal outcome. In patients that die sooner, the hepatic parenchyma shows cloudy swell ing, hydropic vacuolization and fatty in filtration and may be more seriously injured functionally than is evident histologically. This is suggested by the observation that the serum bilirubin invariably rises within 4 hours of the onset of hyperpyrexia.771 Pathogenesis of the hepatic injury in hy perpyrexia is not well understood. It is gen erally believed that anoxia and alterations in essential enzymatic reactions are the major factors responsible for tissue injury.275 The importance of anoxia has been disputed on the grounds that continuous oxygen ad ministration does not prevent liver dam age.466 However, this is not a valid objec tion, since oxygen therapy does not over come the anoxemia of hyperpyrexia.771 Shock and dehydration may be additional factors in some instances but are certainly not the essential ones. Clinical manifestations of the hepatitis466 are difficult to distinguish from those due to the other effects of hyperthermia. Nausea and vomiting occur early and usually are followed on the 2nd or 3rd day by jaundice and hepatomegaly. There is an early in crease in the urinary excretion of urobilino gen, and later the urine contains bile. Only occasionally, however, are the stools acholic. In severe cases, there may be central nerv ous svstem disturbances, vasomotor col lapse and signs of renal failure. Purpuric manifestations have been emphasized, par ticularly in heatstroke,798 although they may occur in other types of hyperpyrexia.275 These appear to be related to the combined effects of a low prothrombin level, a reduc tion in platelets and an increase in capil lary fragility.798 Pleural effusions, ascites and edema are not rare in fatal cases.82, 275 Recovery without residual liver damage occurs in the vast majority of cases. The ap pearance of shock, anasarca, renal failure and neurologic disturbances are omens of a fatal outcome. Hyperthyroidism A high proportion of individuals with hy perthyroidism show evidence of liver d-amage. In fatal cases, the incidence of sig nificant hepatic lesions may be as high as 90 per cent,30 and in those who survive the frequency of functional impairment is equally great. In both instances, the severity of the abnormalities correlates closely with the intensity and duration of the under lying thyroid disease. Nevertheless, it is by no means certain that the changes in the liver are due to the direct effects of the thvToid hormone; indeed, other possible in terpretations are held to be more likely. A variety of hepatic lesions occur in pa tients who die plications.50-11 tatty metamor crosis, usually ally massive, (3) atrophy denced by a < liver, {4) ver rhosis. Excep similar changi massive doses ine.237-310 Ne\ maintain that specific, and t attributed to t Weller desc as a patchy lyi tion in the po bv proliferatio development < on the other hi lesion is venou of the lobules normal pressui branches of th tal vein.519 Ac follows resemb gestive failure centered arour stead of the ce subscribe to ei and most reg; quence of fatt hepatic cells.112 Almost even has been inve; centration of si of Bromsulpha tolerance for the prothrombi nificant numbe th\Toidism.295' 4 turbances have mals with expei roidism.188 The levulose toleran in carbohydrate but there is litt wher abnormal ramage. The pathogei imnd in hypert lbject. The clo Metabolic Disturbances 559 're :>ns are the for ussue injury.-75 i has been disputed dnuous oxygen ad- irevent liver dam- not a valid objec- f does not overlvperpyrexia.771 mav be additional > but are certainly ; of the hepatitis466 i from those due to erthermia. Nausea v and usually are ;d day by jaundice e is an early inetion of urobilinoiontains bile. Only ; the stools acholic, y be central nervvasomotor col- failure. Purpuric emphasized, par ilthough they may F hyperpyrexia.275 d to the combined ain level, a reduc ing ;e in capilefruoions, ascites a fatal cases.92, 275 ual liver damage of cases. The aprca, renal failure ^es are omens of D1SM lividuals with hynce of liver damincidence of sigay be as high as ' who survive the impairment is nces, the severity lates closely with n of the underertheless, it is bv t changes in the ct effects of the >ther possible ine more likely, ons occur in pa tients who die of thyrotoxicosis and its com severity of the hepatic damage and the in plications.59, U5> 519,673 These include: (1) tensity and the duration of the hyperthy fatty metamorphosis, (2) hepatocellular ne roidism suggests that excessive amounts of crosis, usually focal or central, but occasion thvroid hormone are bepatotoxic/'" How ally massive, as in acute yellow atrophy, ever, studies based on liver biopsy material (3) atrophy of the parenchyma, as evi indicate that, in the absence of complica denced by a decrease in the weight of the tions, even severe hyperthyroidism may not liver, (4) venous congestion ana (5) cir produce significant alterations in hepatic rhosis. Except for cirrhosis and atrophy, structure or function.322,571 This has led similar changes are seen in animals given some to the conclusion that the lesions massive doses of thyroid extract or thyrox found at autopsv are either coincidental or ine.257, 310 Nevertheless, some investigators the result of complications. maintain that most of the lesions are non Although there is little doubt that infec specific, and that only the cirrhosis can be tion, shock and cardiac failure are responsi , attributed to the hyperthyroid state. ble for liver damage in many instances, the Weller describes the characteristic lesion incidence of these factors in nonfatal cases as a patchy lymphocytic inflammatory reac appears to be too low to account for the fre tion in the portal triads, which is followed quency with which hepatic involvement bv proliferation of connective tissue and the can be demonstrated. For that reason many | development of cirrhosis.779 Moschcowitz, investigators regard liver injury as a mani j on the other hand, believes that the primary festation of hyperthyroidism but attribute lesion is venous congestion at the periphery the deleterious effect of the thyroid hor of the lobules due to a disturbance in the mone to some indirect action. Experimental normal pressure relationships between the evidence indicates that hyperthyroidism in branches of the hepatic artery and the por creases the susceptibility of the liver to in tal vein.318 Accordingly, the cirrhosis that jury by anoxia,471 infection668 and toxic . follows resembles that seen in chronic con- agents.472 At one time these effects were * gestive failure, except that the fibrosis is thought to depend on a fall in liver glyco centered around the interlobular septa in gen.189, 803 However, more recent studies in stead of the central veins. Few pathologists dicate that these effects cannot be attributed subscribe to either of these interpretations, to changes in hepatic glycogen.472 and most regard the fibrosis as a conse Another interpretation is that hyperthy quence of fatty infiltration and necrosis of roidism induces a relative nutritional defi hepatic cells.115 ciency bv increasing the demands for cer Almost every test of liver function that tain essential dietary constituents.183,322 has been investigated, including the con Although this might lead to fatty infiltra centration of serum bilirubin, the excretion tion and cirrhosis, it would not account for of Bromsulphalein and hippuric acid, the the zonal and focal hepatic necrosis seen in tolerance for galactose and levulose, and hyperthvroidism. No one mechanism ac the prothrombin level, is abnormal in a sig counts satisfactorily for all the tvpes of liver nificant number of individuals with hvper- injury encountered in hyperthyroidism. th\Toidism.29S- 470, 478 Similar functional dis The clinical significance of these hepatic turbances have been demonstrated in ani lesions is difficult to evaluate. Ordinarily, mals with experimentally induced hyperthy they give rise to no overt signs of liver dis roidism.188 The decrease in galactose and ease, except for occasional hepatomegaly, levulose tolerance may be due to alterations but in approximately 20 per cent of fatal in carbohydrate metabolism or absorption, cases they produce jaundice.50 Therefore, it but there is little reason to doubt that the would seem reasonable to assume that ex other abnormalities are indicative of liver tensive lesions contribute to a fatal out damage. come. At one time, it was believed that they The pathogenesis of the hepatic lesions were responsible for thyrotoxic crises. How found in hyperthyroidism is a controversial ever, this view has been abandoned for lack subject. The close relationship between the of supporting evidence.470 560 Toxic and Drug-Induced Hepatitis PSYCHOPHARMACOLOGIC AGENTS A wide variety of drugs used as tran quilizers and antidepressants give rise to re actions, some of which affect the liver. The lesions produced may be either cholestatic or hepatocellular in type, depending on the nature of the agent, but in both instances the process appears to be due to drug sensi tization rather than to any direct hepatotoxic effect. In dealing with agents of this type, the physician should recognize that, while alterations in chemical structure may reduce the frequency with which certain drugs produce hepatitis, they rarely, if ever eliminate this hazard completely. Ac cordingly, all newly introduced substituted derivatives of drugs known to provoke re actions involving the liver should be con sidered suspect, at least until prolonged ex perience proves them to be innocuous. Phenothiazine Derivatives Cholestatic hepatitis has been reported more frequently after chlorpromazine {Thor azine) than any of the other phenothiazine derivatives used as tranquilizing agents. However, it is difficult to compare the haz ards of the drugs in this group, since few of the newer phenothiazine derivatives have been used as extensively as chlorpromazine. Chlorpromazine (Thorazine) Hydrochlo ride. Published statistics indicate that the incidence of cholestatic hepatitis in patients given chlorpromazine is 1 to 2 per cent.141354.451 However, the findings on serial bi opsy of the liver and the results of serial determinations of serum alkaline phospha tase and glutamic oxalacetic transaminase suggest that the incidence of anicteric re actions involving the liver is 20 to 50 per cent.176,676, 763 Since the occurrence of such reactions is not dependent on the dose, and since the hepatic changes are not repro ducible in animals,579,695 chlorpromazine cannot be classified as a true hepatotoxin. Schnack has reported that chlorpromazine reduces the biliary excretion of BSP in rats, and interprets this as evidence of hepatotoxicity.654 However, others have not con firmed this observation.198 Moreover, it has been found that, in the rat, chlorpromazine does not inhibit the biliary secretion of indo cyanine green or bilirubin,306 reduce the rate of bile flow,683 or raise the pressure within the common hepatic duct.683 Frequently, reactions are accompanied bv fever, rash and eosinophilia141, 451 and less commonly by agranulocytosis451 and a posi tive patch test.434 Taken together with the fact that the drug can produce contact der matitis,434 these features strongly suggest that chlorpromazine is a sensitizing agent. However, as in many other drug reactions, attempts to demonstrate circulating anti body to chlorpromazine,83 or to establish the presence of other immunologic abnormali ties431 have met with failure. According to some reports antecedent liver disease predisposes to the development of cholestatic hepatitis.373 However, this has not been borne out in other studies.176 As in the case of many other drug reactions, females appear to be more susceptible than males. Usually, chlorpromazine jaundice appears between the 2nd and 4th week of therapy. Although it is uncommon in patients who have received the drug for less than a week, it has been reported following 1 day of ther apy794 and even after a single dose.'35 In such cases, and occasionally in others,207 354 the onset of jaundice may be delayed for as long as 2 weeks following withdrawal of the drug. Only rarely are reactions of this type seen after the 5th week of drug admin istration.373 In patients who have recovered from chlorpromazine-induced hepatitis, re administration of the drug produces a prompt relapse in some44,407'54)0 but not in others.44-407 Moreover, recovery from chlor promazine hepatitis may ensue despite con tinued administration of the drug,653-689 a course of events generally attributed to spontaneous desensitization. In most cases, the onset of chlorproma zine hepatitis is abrupt with fever and mild constitutional symptoms, which are fol lowed in 1 to 4 days by jaundice, dark urine and clay-colored stools.354- 373- 4B1* 782 Occa sionally, the fever is accompanied by a rash and by chilly sensations or frank shaking chills. Pruritus may precede the appearance of jaundice and often is a troublesome late manifestation. Anorexia, nausea, vomiting and abdominal pain are common but sel- ti jin,305 reduce the m or raise the pressure i ,hepatic duct.683 ions are accompanied by jinophilia141-451 and less uilocytosis4 '1 and a posifaken together with the ran produce contact .der-. atures strongly suggest e is a sensitizing agent, nv other drug reactions, istrate circulating antizine,83 or to establish the mmunologic abnormalih failure. me reports antecedent oses to the development tis.373 However, this has in other studies.178 As v other drug reactions, e more susceptible than nazine jaundice appears d 4th week of therapy, mmon in patients who ug for less than a week, following 1 day of therer single dose.*35 In sic / in others,207-354 :e may be delayed for ollowing withdrawal of ly are reactions of this th week of drug adminUs who have recovered i-induced hepatitis, rehe drug produces a me44-40T-so but not in x, recovery from chlornay ensue despite con- i of the drug,855-889 a enerally attributed to ization. onset of chlorpromapt with fever and mild oms, which are fol>y jaundice, dark urine jls.334- 373.45i, 702 Qcca* vccompanied by a rash ions or frank shaking recede the appearance i is a troublesome late da, nausea, vomiting are common but sel Psychopharmacologic Agents 561 dom are severe. Hepatic enlargement and tenderness are inconstant findings. Rarely, the spleen is enlarged. Characteristically, the urine contains bile, and the serum shows a sharp rise in the levels of bilirubin, cholesterol, alkaline phos phatase and transaminase. In contrast, the thymol turbidity and cephalin-cholesterol flocculation reactions remain normal. Rarely, the latter are abnormal, and the serum glob ulins are increased. The principal histologic findings in the liver are bile stasis with intra-canalicular bile thrombi and bile-staining of the par enchymal and Kupffer cells in the centrilobular zones and a portal inflammatory exudate, consisting of polymorphonuclear leukocytes, monocytes and eosinophils.782",r Although the features of cholestasis have been emphasized, not infrequently the he patic parenchyma shows scattered foci of necrosis and evidence of increased regenera tive activity. The intensity and duration of jaundice are variable. Often, jaundice is mild and clears without residuals in 2 to 8 weeks. However, a significant number of cases with intense and prolonged jaundice have been reported.^-329- 348-373-31-529-584-700 The du ration of the disease in these individuals has ranged from 4 months to 5 years. Sev eral have exhibited portal fibrosis histo logically,348- 3*3-S29*594 and have had clini cal features suggestive of biliary cirrhosis, such as persistent pruritus and xanthomatosis S3.348.3. 528.770 According to Read and associates,594 lesions of this type are rever sible and never give rise to full-blown cir rhosis even though histologic abnormalities and raised levels of serum alkaline phos phatase and cholesterol may persist. How ever, this is not borne out by the course of events in the cases reported by Myers et al.529 and by Walker and Combes.770 In Myers' patient, portal hypertension and bleeding from esophageal varices developed 5 years after onset. At laparotomy for porta caval shunt, the liver was found to be cir rhotic.528 A similar case of chlorpromazineinduced biliary cirrhosis of 5-years' duration has been studied by Walker and Combes.770 The writer has had the privilege of examin ing serial biopsy sections of the liver from both of these patients and can vouch for the development of unequivocal advanced biliary cirrhosis. Several fatalities have been attributed to chlorpromazine hepatitis.77- 354- 628 However, in the 2 cases in which postmortem exami nation was carried out, unrelated compli cating factors could have played an impor tant role in the fatal outcome. The patient described by Boardman had mitral stenosis, severe congestive failure and a terminal purulent pericarditis.77 Sections of liver, which the writer has had the privilege of ex amining, show marked passive congestion and bile stasis. In Rodin and Robertsons case, death occurred on the 40th day of jaundice, following an unexplained episode of shock.628 The liver showed extensive centrilobular parenchymal necrosis with some degree of bile stasis. Whether the necrosis was attributable to the chlor promazine reaction or to the terminal epi sode of shock is not evident from the pub lished protocol. Because of the possible hazards involved, it is unwise to continue chlorpromazine therapy once the signs of a reaction appear or to resume such therapy following re covery from a reaction. Allegedly, crosssensitization reactions between chlorproma zine and other phenothiazines are rare.334 However, promazine occasionally produces cholestatic hepatitis in patients previously sensitized to chlorpromazine. Accordingly, once a reaction has occurred, caution should be exercised in substituting one phenothiazine for another. The effectiveness of cortisone in the man agement of chlorpromazine-induced hepa titis is in doubt. Favorable results have been reported in some cases159-712 but not in others.785 Mepazine (Pacatal). Mild jaundice has been observed in a few patients receiving mepazine.511 Prompt recovery has followed withdrawal of the drug. Presumably, the underlying lesion in such cases is a chole static hepatitis of the type produced by chlorpromazine. However, neither the histopathology nor the clinical features have as yet been reported. Although the incidence of this complication appears to be low, in one series of 76 patients given mepazine. 562 Toxic and Drug-Induced Hepatitis jaundice developed in 2, an incidence of 5.4 per cent.311 Perphenazine (Trilifon). At least two in stances of perphenazine-induced cholestatic hepatitis have been reported. In one, jaun dice appeared after 56 days of drug admin istration, and cleared within 3 weeks.148 In the other, the latent period was 60 days, and the duration of the hepatitis was longer, but full recovery occurred ultimately.*3 Prochlorperazine Maieate (Compazine). Cholestatic hepatitis with clinical and his tologic features indistinguishable from those produced by chlorpromazine has been ob served in patients receiving prochlorpera zine.497- 703 In addition, several cases of fatal drug-induced massive hepatic necrosis have been reported,148, 487 illustrating the fact that sensitizing agents that produce chole stasis occasionally give rise to serious hep atocellular disease. The hepatitis in one of these cases was accompanied by agranulo cytosis and thrombocytopenia.47 Promazine Hydrochloride (Sparine). This agent has no adverse effects on the liver in most individuals,37 but, rarely, it may give rise to cholestatic hepatitis. In 2 of the cases reported the patients had previously re ceived chlorpromazine. In one, the latter drug had induced hepatitis,74 whereas in the other it had been well tolerated.373 Al though cross-sensitization may have been a factor in both cases, there are instances in which promazine has failed to provoke a reaction in patients previously sensitized to chlorpromazine.74 Several fatalities have been attributed to promazine-induced agranulocytosis.284, 797 In one such case, the agranulocytosis was ac companied by jaundice.797 Death occurred on the 4th day, at which time the liver was infiltrated with fat It is not clear from the published protocol whether the hepatic le sions were attributable to the promazine re action or were produced by the antibiotics and cortisone used for several days prior to death. Thioridazine Hydrochloride (Mellaril). At least one case of cholestatic hepatitis and two instances of pruritus accompanied bv raised levels of serum transaminase and alkaline phosphatase have been reported in patients .receiving thioridazine hydrochlo ride.606 In two of these individuals there was evidence of an antecedent hepatic re action to chlorpromazine. In the third pa tient, the serum transaminase and alkaline phosphatase levels returned to normal de spite continued drug administration. Trifluoperazine Hydrochloride (Stelazine). Although this agent has been ad ministered to over a million patients, only 2 cases of cholestatic hepatitis have been reported.-9-300 One had a history of another drug reaction and chlorpromazine had been administered just prior to the use of trifluo perazine.20 Cholestatic jaundice appeared after 3 days of therapy and persisted for more than 6 months. The other patient re covered in 3 weeks.390 The writer has seen a patient with the tvpical features of early "primary" biliary cirrhosis, in whom the onset with pruritus and jaundice followed several months of intermittent trifluoperazine therapy.383 Whether or not the drug was responsible for the liver disease in this case is unknown. Monoamine Oxidase Inhibitors A number of monoamine oxidase inhibi tors, including iproniazid, isocarboxazid, nialamide, phenelzine and tranylcypromine (Parnate, Parstellazine) are widely used in the treatment of mental depression. All of these agents, with the exception of tranylcypromine, are, hydrazine derivatives and roduce a severe and often fatal form of epatitis in a small number of uniquely sus ceptible individuals. Since tranylcypromine is not a hydrazine derivative and does not affect the liver, it has been suggested that the propensity of the other drugs in this group to produce hepatic injury may be related to their hydrazine content rather than to their capacity to inhibit monoamine oxidase activity. For reasons discussed below, it is highly probable that the he patic lesions produced are attributable to drug sensitization rather than to a direct hepatotoxic action. In this connection, it is important to note that patients may react to several of the drugs in this group,333 so that it is hazardous to substitute one for the other once any of them has produced hepatitis. Iproniazid (l-isonicotinoyl-2-isopropylhy- drazine, Man duced as a cl treatment of abandoned be toxic than the effective com] acid hydrazid was revived potent antide potential for ] jury fully appi Characterisi a form of hep morphological that produced 829 Moreover, 1 and zoxazolan rise to massiv sis that often The reporte' tients receivin 1.4 per cent.621 total sales of lower,829 serial increases in se oxalacetic trai number of pat therapy were incidence of c siderably highi Since hepal pendently of < or the duratic and cannot b< animals,61 it is as an hepatotc of the hepatit it appears aft days to weeks drug,829 and ii a rash309,508 si a sensitizing a fever and eos tradictorv. Be semblance be induced hepal considered th; susceptibilitv lights up laten ^iirus. A repoi fcElffected indi\ Cfiemagglutinat C2>me support 01 viduals there ebt. at'hepatic ree. In the third paMnase and alkaline ined to normal dejninistration. Irochloride (Stelagent has been addHon patients, only lepatitis have been a history of another jromazine had been h the use of triftuojaundice appeared i and persisted for ae other patient re- a patient with the y "primary" biliary onset with pruritus d several months lerazine therapy.38 ug was responsible lis case is unknown. iSE Inhibitors nine oxidase inhibiizid, isocarboxazid, nd nylcypromine ) i. widely used ntal depression. All exception of tranyline derivatives and often fatal form of ber of uniquelv suskce tranylcypromine /ative and does not >een suggested that other drugs in this itic injury may be one content rather i inhibit monoamine reasons discussed 'bable that the heare attributable to ?r than to a direct his connection, it is patients may react in this group,333 so lbstitute one for the iem has produced dnoyI-2-isopropylhy- Psychopharmacologic Agents 563 drazine, Marsilid). Iproniazid was intro duced as a chemotherapeutic agent in the treatment of tuberculosis but was soon abandoned because it proved to be more toxic than the closely related and equally effective compound, isoniazid (isonicotinic acid hydrazide). Some years later its use was revived when it was found to be a potent antidepressant. Only then was its potential for producing serious hepatic injurv fully appreciated. Characteristically, iproniazid gives rise to a form of hepatitis that both clinically and morphologically is indistinguishable from that produced by the hepatitis virus.577, 578, 629 Moreover, like pyrazinamide, cinchophen and zoxazolamine, it not infrequently gives rise to massive or subacute hepatic necro sis that often proves fatal.240, 577,578,8291677 The reported incidence of hepatitis in pa tients receiving iproniazid is approximately 1.4 per cent.629 Although estimates based on total sales of the drug are considerably lower,329 serial studies demonstrating minor increases in serum bilirubin372 and glutamic oxalacetic transaminase552 in a significant number of patients suggest that if iproniazid therapy were not controlled carefully, the incidence of overt hepatitis would be con siderably higher. Since hepatitis appears to occur inde pendently of either the dose of iproniazid or the duration of its administration-'77, 629 and cannot be reproduced in experimental animals,81 it is difficult to classify iproniazid as an hepatotoxin. The sporadic occurrence of the hepatitis, the frequency with which it appears after a latent period of several days to weeks following withdrawal of the drug,629 and its occasional association with a rash369, 808 suggest that the drug may be a sensitizing agent However, the rarity of fever and eosinophilia appears to be con tradictory. Because of the remarkable re semblance between viral- and iproniazidinduced hepatitis, the possibility has been considered that the drug either enhances susceptibility to intercurrent infections or lights up latent infections with the hepatitis virus. A report indicating that a third of affected individuals exhibited a positive hemagglutination reaction308 appears to lend some support to this hypothesis. However, this observation has not been confirmed by others.383 If hepatitis is to develop, it does so most commonly after the 4th week of iproniazid therapy, but the interval may be as short as 4 days or as long as 6 months.629 In almost 20 per cent of cases, it appears 1 to 4 weeks after the cessation of drug administration. The onset may be abrupt, but more often it is insidious, with anorexia, weakness and malaise, occasionally accompanied by pru ritus. In contrast with viral hepatitis, there is no fever during the preicteric phase. Darkening of the urine is noted within a day or two and is followed by overt jaun dice which appears within 3 to 11 days of the onset.369 The stools become clay-colored in a high proportion of cases. Jaundice deepens rapidly, reaching a peak in 2 to 4 weeks and usually is more intense than in viral hepatitis. Early enlargement and ten derness of the liver are common and may be accompanied by splenomegaly. In fatal cases, the liver shrinks in size and can sel dom be palpated after the 1st week. Con comitantly, the jaundice deepens progres sively and often is associated with ascites, gastrointestinal bleeding, fever and termi nal hepatic coma. Death may occur as early as the 2nd week or not until several weeks later. In nonfatal cases, the course tends to be prolonged, often exceeding 3 months. Al though no cases of postnecrotic cirrhosis have been reported, subacute hepatic necro sis has been observed in a number of non fatal cases.577 On the basis of experience with lesions of this type, it can be predicted that some patients who apparently have re covered from an attack of iproniazid hepa titis will ultimately exhibit clinical or morphologic evidence of postnecrotic cir rhosis. Characteristically, the concentration of serum bilirubin rises markedly, usually to levels higher than those seen in most cases of viral hepatitis. Although serum glutamic oxalacetic transaminase activity is greatly increased, levels over 500 units are less com mon than in viral hepatitis. A strongly posi tive cephalin-cholesterol flocculation reac tion and increased thymol turbidity are common but inconstant findings. Raised 564 Toxic and Drug-Induced Hepatitis levels of serum alkaline phosphatase are seen more frequently than in viral hepatitis and in many cases reach the heights seen in cholestatic hepatitis. In fatal cases, the serum concentrations of albumin and choles terol tend to fall, while that of globulin rises. Often prothrombin activity is greatly de pressed in such cases. As noted, the morphology of the liver in Marsilid-induced hepatitis is indistinguish able from that in viral hepatitis, except that subacute and massive hepatic necrosis are more common. The mortalitv rate is approximately 20 per cent.629 Attempts to stem the downhill course in patients with massive hepatic ne crosis by administering corticosteroids or ACTH have generally met with failure.677' sn>i However, thev appear to have been more successful in less seriously ill patients with subacute hepatic necrosis.58,383 Whether or not cases of this type would have recovered spontaneously is unknown. Moreover, as pointed out, no data are available on the biopsy findings following recovery, so that the question of residual postnecrotic scar ring in such patients is unsettled. Isocarboxazid (Marplan). Although an analogue of iproniazid, this agent produces far fewer undesirable side reactions and thus far has caused only one case of hep atocellular jaundice.57 In this instance, svmptoms suggestive of an upper respira tory infection appeared 4 weeks after the institution of isocarboxazid administration. The preicteric phase was characterized by pruritus, a distaste for cigarettes and inter mittent right flank pain. Although jaundice did not become clinically evident until the 3rd week, dark urine and light stools were noted as early as the 3rd dav. The jaundice was moderate and cleared within 3 weeks. Serum bilirubin, alkaline phosphatase and transaminase showed modest increases, while the level of cholesterol was depressed. Thymol turbidity was increased, and the cephalin-cholesterol flocculation reaction was strongly positive. Phenelzine (Nardil). Severe hepatitis has been encountered in patients given phenel zine for periods of 18 days to 5 months.148, 332. 32 As jn hepatitis induced by iproniazid, the clinical features and the histologic find ings in the liver are indistinguishable from those of severe viral hepatitis. Death from massive hepatic necrosis within 3 weeks has occurred in 5 of 7 reported cases. Repeated exchange transfusions in one case,362 begun 12 hours after onset of coma, failed to re lieve the coma or to prevent death. Pheniprazine (beta-phenylisopropyl-hydrazine, Catron, Cavodil). Several instances of severe hepatitis have been reported in patients receiving pheniprazine for periods of 2 weeks to 7 months.52, 63,277, 333 In all respects, the clinical, laboratory, and mor phologic features have resembled those of iproniazid-induced hepatitis. Two of 6 re ported cases terminated fatally with mas sive hepatic necrosis.52,333 One of the pa tients with nonfatal hepatitis had previously had a mild attack of jaundice while taking iproniazid.333 In another, following recov ery from pheniprazine-induced hepatitis, administration of the monoamine oxidase inhibitor, nialamide (Niamid), provoked a relapse.333 Although the paucity of reports suggests that the incidence of hepatitis is low, in one series of 37 patients given pheniprazine for periods of 8 to 40 weeks, one developed se vere hepatitis and 4 others showed a sig nificant rise in SGOT.277 Other Psychopharmacolocic Drugs Chlordiazepoxide Hydrochloride (Lib rium). Typical cholestatic hepatitis has been encountered in at least 2 patients re ceiving chlordiazepoxide for 5 and 35 davs, respectively.2,1,0 In addition, elevations of SGOT in the absence of jaundice have been observed.335 Another closely related benzodiazepine derivative, diazepam (Valium), has been implicated in at least one nonfatal case of severe hepatic necrosis.148 However, since the patient involved has also received phenoxypropazine, the role played by diazepam is uncertain. Ectylurea (Nostyn). In the only reported case of hepatic injury induced bv ectyl urea, both the clinical and the histologic features were those of a mild cholestatic hepatitis.328 The onset was sudden, with anorexia, nausea and right upper abdomi nal pain, on the 14th day of therapy. Dark gu* * "hie from is. uth from un 3 weeks has rases. Repeated case,362 begun a, failed to re death. ylisopropyl-hyveral instances ?p reported in iie for periods 3.2T7.333 Jn a]J :ory, and morlbled those of Two of 6 re:!ly with masne of the paiad previously ; while taking lowing recovced hepatitis, unine oxidase ), provoked a ports suggests is low, in one sniprazine for developed seho* 1 a sig- cic Drucs loride (Libhepatitis has Z patients reand 35 days, elevations of ce have been nzodiazepine ), has been fatal case of wever, since ceived phenby diazepam nly reported d by ectylle histologic l cholestatic ldden, with ler abdomierapy. Dark Miscellaneous 565 urine, pruritus and faint icterus were noted mately 8 weeks after the appearance of a few days later. There was a modest in rash. Autopsy revealed massive destruction crease in serum bilirubin and glutamic of the hepatic parenchyma, collapse of re- oxalacetic transaminase and a marked rise ticulin, numerous lipofuscin-filled macro in the alkaline phosphatase level. In con phages and a mixed portal exudate of neu trast, the serum cholesterol concentration, thymol turbidity and cephalin-cholesterol flocculation reaction remained normal. All trophils, lymphocytes and histiocytes with occasional plasma cells and eosinophils, fea tures seen in other forms of massive hepatic symptoms subsided within 5 days. When necrosis produced by reactions to drugs. a single 300-mg. dose of ectylurea was given Considering the clinical features in this on 2 successive days approximately 3 weeks case, and the fact that imipramine and later there was an immediate relapse of desipramine produce rash, fever, eosino jaundice, pruritus and anorexia, which philia, thrombocytopenia and agranulocy cleared within a week. tosis, it is highly probable that the hepatic Im/pramine Hydrochloride (Tofranil). lesions they produce are attributable to Jaundice is a relatively uncommon compli drug sensitization. cation of imipramine therapy, and usually Meprobamate (Miltown, Equanil). This subsides promptly following withdrawal of agent, one of the most widely used tranquil the drug.19-Ul-327- 422- 484 In the few re izers, produces a variety of allergic reac ported cases in which the clinical features tions, including rash, fever, angioneurotic are described, jaundice appeared between edema, arthralgia and thrombocytopenic the 7th19 and 110th484 days of treatment, purpura.66 334 Although hepatic involve and was accompanied by fever19- 3~7 and ment in such reactions has not been re biochemical changes suggestive of chole- ported, the writer has seen 2 instances of stasis.19-327 The one available biopsy speci cholestatic jaundice in patients receiving men of the liver is said to have shown slight, meprobamate and has heard of 2 others. nonspecific inflammation in the paren chyma.19 In one series of 85 patients receiv ing imipramine, 19 exhibited a transient rise, MISCELLANEOUS in serum transaminase unaccompanied by jaundice.19 Apiol Derivatives The desmethyl analogue of imipramine, Apiol, a camphoraceous material derived desipramine hydrochloride (Norpramin, from parslev and an important constituent Pertofrane), also may give rise to jaun of manv illegal proprietary abortifacients, dice.152 Unfortunately, details of the illness produces hepatic injury in animals and oc in such cases are lacking. casionally has been implicated as a hepato- | From available data, it appears that both toxic agent in humans.435 However, in most * imipramine and desipramine usually pro- such cases, complicating factors such as I duce a cholestatic type of hepatitis. How- sepsis, hemolvsis and shock have made it j ever, in at least one instance, these agents difficult to assess the role of apiol in the j produced massive hepatic necrosis that was pathogenesis of the hepatic necrosis dem fatal.584 The patient involved noted the onstrated at autopsy. onset of rash 2 weeks after starting treat ment with imipramine. Substitution of Burns and Tannic Acid desipramine at this point aggravated the A variety of hepatic lesions have been ob dermatitis, so that drug treatment was dis served in individuals with extensive burns.58- continued 2 days later. Jaundice, fever and .*62.795 Animal experiments show that most mild eosinophilia appeared 6 weeks after of these can be attributed to tannic acid the onset of rash. The jaundice deepened therapv and possibly to infection.33,234,309 rapidly, the rash become exfoliative in char In dogs, extensive bums of the skin, if left acter, and ulcerations of the mucous mem untreated, are usually accompanied by cen branes appeared. Death occurred 2 weeks tral congestion and atrophy of the hepatic after the onset of jaundice and approxi parenchyma. However, if infection super 566 Toxic and Drug-Induced Hepatitis venes, or if tannic acid dressings are ap plied, central necrosis of the liver ensues,30* The presence of a burn is not essential for this effect for the same lesions occur when tannic acid is injected subcutaneously into normal animals.33,2341308 It seems unlikely that burns give rise to hepatic necrosis by reducing blood flow through the liver, since in dogs hepatic oxygen uptake is not reduced following burns.23 Severe liver damage, occasionally accom panied by jaundice and ascites, is also seen in patients with fatal burns that have been treated with tannic acid. The midzonal ne crosis and the Councilman bodies found in such cases closely resemble those of yellow fever.56 In contrast, untreated cases show only minor alterations in the staining qual ity of the parenchymal cells, varying de grees of fatty infiltration and centrilobular atrophy without necrosis.282 Impairment of hepatic function also has been reported fol lowing burns.785 However, the data do not indicate whether this occurs in the absence of infection and tannic acid therapy. Cabbamazepine (Tegretol) Carbamazepine (5-carbamyl-5H-diben2azepine) is chemically related to imipramine (Tofranil) and is used in the treat ment of epilepsy and trigeminal neuralgia. It is a sensitizing agent, having produced rash, the Stevens-Johnson syndrome and fatal aplastic anemia in a number of cases.588 In addition, it has been responsible for at least 2 instances of cholestatic hepa titis on the 7th and 20th day of drug ad ministration.538 Chlorothiazide Rarely, chlorothiazide gives rise to chole static hepatitis.182,3-18 In one case, itching was noted after only three 0.5 Gm. doses given at daily intervals.182 The drug was taken intermittently for an additional 2 weeks, at the end of which time jaun dice appeared. Except for pruritus, there were no associated svmptoms. The histo logic and laboratory features were consist ent with cholestatic hepatitis; but, because of uncertainty about the diagnosis, explora tory laparotomy was carried out, revealing a normal biliary tree. Full recovery occurred by the end of 2 months. In a second case, the jaundice was pro tracted, and was associated with a lesion re sembling biliary cirrhosis.348 The patient in volved took chlorothiazide daily for more than 2 years without ill effects. Two and one-half months after resuming therapy with chlorothiazide she noted the onset of low grade fever, pruritus, anorexia and jaundice. She continued taking the drug for 5 weeks. Liver function studies suggested obstructive jaundice, so that exploratory laparotomy was carried out in the 8th week. The biliary tract proved to be normal. Wedge biopsy of the liver revealed expanded portal tracts with numerous neutrophils and eosino- hils, granulomata, atypical ductular proferation and periportal parenchymal ne crosis, bile stasis and early fibrosis. Jaun dice and pruritus persisted for several months and then cleared. However, the serum alkaline phosphatase level remained high. The patient died of a cerebrovascular accident 16 months after the onset of jaun dice, and, at autopsy, the liver was nodular with portal fibrosis, nodular regeneration and a mononuclear reaction in the triads and septa. Cholecystography Dyes Bunamiodyl (Orabilex). In a high pro portion of individuals given bunamiodyl, a tri-iodophenyl compound, there is a transient increase in the indirect-reacting (uncon jugated) fraction of serum bilirubin by the next morning-92 The rise in total serum bili rubin, which at its peak reaches levels of 1.5 to 2.0 mg./lOO mL, returns to normal within 24 hours. Concomitantly, there is a transient increase in Bromsulphalein re tention.884 Although bunamiodyl inhibits bilirubin conjugation by rat liver in vitro, other ex perimental evidence suggests that the re tention of uneonjugatea bilirubin in the serum is due primarily to competitive in hibition of bilirubin excretion in bile,72 or impairment of bilirubin uptake by the liver.68 With respect to Bromsulphalein re tention, animal studies suggest that bu namiodyl impairs the hepatic uptake of dye.63 ec< /. occurred lundice was prol with a lesion re1,9 The patient ini daily for more effects. Two and ling therapy with he onset of low xia and jaundice, [rug for 5 weeks, ssted obstructive 'laparotomy was ?ek. The biliary . Wedge biopsy led portal tracts Is and eosino1 ductular proarenehvmal ne' fibrosis. Jaun2d for several However, the level remained cerebrovascular 2 onset of jauner was nodular it regeneration i in *he triads Dyes fn a high probunamiodyl a re is a transient cting (unconilirubin by the tal serum bili* ches levels of ras to normal tly, there is a mlphalein re mits bilirubin 'tro, other ex- that the rerubin in the unpetitive in* in bile,72 or take by the nlphalein reest that buc uptake of Miscellaneous 567 Iopanoic Acid (Telepaque) and Iodipamide (Cholografin), two other iodinated compounds used for cholecystography, also produce transient mild hyperbilirubinemia72 and Bromsulphalein retention,72-504 pre sumably by the same mechanisms involved in the case of bunamiodyl. In addition, in vitro studies,with iopanoic acid suggest that inhibition of the Bromsulphalein-glutathione conjugating system is a factor in the dye retention produced by this agent513 Rarely, orally administered cholecystogra phy dves produce reactions that appear to be allergic in nature. In one such case seen by the writer, the temperature rose sharply several hours after 3 Gm. of iopanoic acid was administered. Chills and fever con tinued for 6 days. A morbilliform rash and eosinophilta were noted in the 3rd dav. At the height of the jaundice the liver was en larged but not tender, serum bilirubin rose to 4.8 mg.S, serum alkaline phosphatase was 26 Bodansky units, thymol turbidity was 7 units, and the SGOT level was 60 units. The cephalin-cholesterol flocculation reaction remained normal Biopsy at this time revealed a diffuse mononuclear inflam matory' reaction involving all portions of the lobules and some of the central veins, and extensive centrilobular and periportal ne crosis. Repeat biopsy 2 months after the reaction revealed normal liver tissue. How ever, full clinical and functional recovery did not occur for another 3 months. Ethyl Alcohol As pointed out, alcohol enhances the hepatotoxic effects of agents such as carbon tetrachloride, chloroform and phosphorus. In addition, it appears to play a role in the pathogenesis of Laennec's cirrhosis. This raises the question of whether or not alco hol is a hepatotoxin. According to many au thorities, alcohol has no direct effect on the liver, but, when imbibed in excessive amounts, encourages a reduction in food consumption that leads to malnutrition, hepatic injury and, ultimately, to Laennec's cirrhosis. However, experimental studies in animals indicate that, apart from its effects on food consumption, alcohol raises the choline re quirement,384 increases fatty acid synthe sis,438 mobilizes fat from the depots to the liver595 and potentiates the development of nutritional cirrhosis.384 Moreover, even in healthy nonalcoholic individuals maintained on a high protein diet, alcohol administra tion leads to fatty infiltration of the liver, raises the serum transaminase level and produces ultrastructural changes suggestive of toxic injury.838 Whether or not these effects are implicated in the pathogenesis of Laennec's cirrhosis remains to be estab lished.292 For a more complete review of this subject see References 356 and 381. Male Fern Male fern extract, widely used in the treatment of tapeworm infestation, regu larly raises the level of the indirect-reacting (unconjugated) fraction of bilirubin in the serum and increases Bromsulphalein reten tion.537 These changes, which appear within 24 hours, are unaccompanied by alterations in serum alkaline phosphatase or transami nase, and subside within a few days. Usu ally, the alterations in serum bilirubin and Bromsulphalein are slight, but, occasion ally, overt jaundice or a high degree of Bromsulphalein retention may be produced. It has been suggested that male fern in terferes with the hepatic uptake of bili rubin and Bromsulphalein. However, the mechanism involved has not been ade quately investigated. Methyldopa (Aldomet) Abnormalities of hepatic function, includ ing Bromsulphalein retention, and raised levels of serum transaminase and alkaline phosphatase, occur in a small but significant number of patients receiving methvldopa in the treatment of hypertension.153 Those that appear within the first 10 days may be accompanied by fever and malaise, but more often they occur insidiously and with out symptoms during the first few months of therapy. As a rule, such functional ab normalities promptly revert to normal when the drug is withdrawn. Liver biopsy in sev eral patients has revealed foci of necrosis considered compatible with drug hyper sensitivity. In a few instances, the hepatic functional abnormalities produced by methyldopa have 568 Toxic and Drug-Induced Hepatitis been accompanied by mild jaundice that has cleared promptly on discontinuing medi cation.499 However, one instance of severe hepatitis has been reported.80* In this case, the clinical features and the histologic find ings in the liver were indistinguishable from those of viral hepatitis or those produced by drugs like iproniazid. The serum levels of bilirubin, glutamic oxalacetic transami nase and alkaline phosphatase reached peak values of 30 mg./lOO ml., 1120 units and 25 K-A units, respectively. On withdrawal of the drug, the hepatitis subsided, but the serum bilirubin level was still elevated on the 45th day. Considering that methyldopa can give rise to drug fever, agranulocytosis, thrombo cytopenia1*3 and Coombs' positive hemo lytic anemia,55 and that such reactions may be accompanied by a positive L.E. test and the appearance of rheumatoid factor in the serum,679 it is highly probable that the he patic lesions produced by this agent are due to drug hypersensitivity. Nicotinic Acid A significant number of patients on pro longed nicotinic acid therapy for hyper cholesteremia show minor degrees of Bromsulphalein retention and slight elevations of serum transaminase, lactic dehydrogen ase, and alkaline phosphatase.555 Raised levels of serum bilirubin are less common.354 Withdrawal of the drug is followed by prompt recovery. Evidence suggests that preparations designed to provide slow re lease of the drug may produce hepatic dys function more frequently than pure nico tinic acid.554 Liver biopsy studies in patients maintained on the drug for at least a year have revealed no abnormalities.556 Although several patients with altered hepatic func tion have shown a variety of histologic changes in the liver, their relationship to nicotinic acid therapy is uncertain since other etiologic factors nave been involved.555 At least two instances of apparent nico tinic acid-induced cholestatic hepatitis have been reported. In one, pruritus was noted after 13 months of drug therapy.622 Treat ment was interrupted for a month and then was resumed. Three months later there was a relapse of pruritus, accompanied this time by jaundice. There were no associated gas trointestinal or constitutional symptoms. The liver was enlarged but nontender, and serum bilirubin was increased to a level of 7.4 mg./lOO ml., only 1.0 mg. of which was of the direct-reacting type. There were ele vations of serum alkaline phosphatase to 45 K-A units and SGOT to 91 units; thymol turbidity and cephalin-cholesterol floccula tion were normal. The drug was stopped, and jaundice cleared in 3 weeks. In the second case, pruritus appeared sev eral weeks after a 15 month course of nico tinic acid had been discontinued.554 Jaun dice followed 8 days later, but there was no associated anorexia, nausea, vomiting, or hepatomegaly. Serum bilirubin rose to 7.0 mg./lOO ml., with a direct-reacting fraction of 5.4 mg., SGOT to 200 units, and serum alkaline phosphatase to 50 K-A units; thymol turbidity remained normal. Drug therapy was discontinued and jaundice cleared in 4 days. The pathogenesis of the hepatic dysfunc tion produced by nicotinic acid is not clear. Considering the absence of features sug gestive of an allergic reaction, it is unlikely that drug hypersensitivity is involved. Al though the occurrence of Bromsulphalein retention, the occasional development of pruritus and jaundice, and the absence of histologic changes in the liver suggest the type of functional cholestasis produced by agents like methyltestosterone, the fre quency of raised levels of serum transami nase is atypical and suggests a mild hepatotoxic action. Phenindione ( Phenylindandione, Hedulin, Danilone) Phenindione, a widely used anticoagulant, occasionally gives rise to reactions that ap pear to be allergic in nature. These are char acterized by fever, rash, granulocytopenia and/or eosinophilia and may be accom panied by a cholestatic type of hepatitis,99is-. 33,483, 583 and rarely by nephritis.99 a rule, the onset is abrupt during the 3rqpy 4th week of drug administration, but riffi occur as early as the 10th day and as latgffi the 9th week. Rarely, the reaction Miscellaneous 569 act >anied this time ;ere no associated gasistitutional symptoms, ed but nontender, and increased to a level of 1.0 mg. of which was type. There were elecaline phosphatase to )T to 91 units; thymol n-cbolesterol flocculale drug was stopped, in 3 weeks, pruritus appeared sevmonth course of nicoiiscontinued.354 Jaunater, but there was no nausea, vomiting, or bilirubin rose to 7.0 irect-reactmg fraction 200 units, and serum > 50 K-A units; thymol >rmal. Drug therapy jaundice cleared in the hepatic dysfuneinic acid is not clear, ice of features sugeacb'^n, it is unlikely vit) involved. AI; of rSromsulphalein nal development of and the absence of he liver suggest the lestasis produced bv tosterone, the fre: of serum transamigests a mild hepato- VYUNDAXDIONE, inilone) used anticoagulant, 0 reactions that apure. These are char1, granulocytopenia d may be accomtype of hepatitis,99, ' by nephritis.99 As >t during the 3rd or oistradon, but may 1 day and as late as '0 reaction appears a few days after withdrawal of the drug.483 Usually, resumption of therapy following recovery provokes a prompt relapse.99-483 Usually, hepatitis subsides following with drawal of the drug. In some cases, ACTH J and corticosteroids have appeared to hasten ; recovery.99,19T-483 Although some patients with allergic re actions to phenindione can tolerate other anticoagulants, such as ethyl biscoumacetate,73 relapses or exacerbations have been , reported following resumption of treatment , with acenoeoumarin (nicoumalone, Sinj trom).5*3 It is probably unwise, therefore, to use any agent in this group once a reac tion has occurred. PHENYLHYDRAZINE u The jaundice seen during phenvlhydrai zine therapy for polycythemia vera is due j primarily to the rapid hemolysis of erythro cytes. It has been suggested that prolonged (or excessive treatment also results in liver injury. This is based on the observation that ' massive doses produce fatty degeneration and centrilobular necrosis of the liver in rab bits,79 and that following repeated courses of treatment occasional patients develop cir rhosis.430 However, even prolonged admin istration of therapeutic doses does not im pair hepatic function, either in man101 or in animals,281 and following such treatment the liver shows no change other than mild hemosiderosis.14 There is no reason to im plicate phenylhydrazine as the etiologic fac tor in cirrhosis, since the lesion occurs spon taneously in untreated cases of polycy themia vera. POLYVIJCYI* PYRROLIDONE { PVP ) The intravenous administration of PVP, a synthetic plasma expander, is followed within a few months by the appearance in the Kupffer cells of globular basophilic de posits thought to be macromolecules of PVP.249 At least up to a year, the amount of phagocvtized material appears to increase with time. Occasionally, a mild inflamma tory reaction is associated with the deposi tion of PVP, but there is no flbrosis or evi dence of hepatocellular dysfunction. In ani mals given repeated injections of PVP, ag gregates of PVP-filled histiocytes accumu late in the parenchyma and then extend into the triads.248 Pressor Agents Although shock alone208 or shock associ ated with cardiac failure378 may produce centrilobular necrosis, the lesions are seldom massive.104 However, in patients given pres sor amines for the control of shock that ultimatelv proves to be fatal, the liver not infre quently shows large areas of infarction or extensive zones of hemorrhagic necrosis.104 It has been suggested that the pressor amines are responsible for such lesions by producing ischemia.104 Consistent with this view is the observation that in healthy dogs infusions of epinephrine, levarterenol, metaraminol, methoxamine, phenylephrine or mephentermine give rise to diffuse he patic necrosis.377 However, hemodynamic studies in the dog indicate that, under con ditions of hemorrhagic shock, vasopressor drugs like levarterenol increase hepatic ar terial blood flow.149 Although further study of the problem in man is needed, the latter observations sug gest that, under such conditions, pressor amines do not produce hepatic ischemia. However, it is possible that they lead to massive hepatic necrosis indirectly by pro longing survival under conditions of shock and thus permit lesions to develop that otherwise would not become manifest.104 Pyridine At one time, pyridine was used in the treatment of convulsive seizures and asthma and still is employed widelv in industry as a solvent and as a reagent in the synthesis of certain organic compounds. It can produce severe hepatic and renal injury in man,573 but the lesions have not been described. In the rat, pyridine produces both fatty in filtration and acute hepatic necrosis and, following prolonged administration, may give rise to cirrhosis.46 Methionine and cho line partially protect against the fatty in filtration and fibrosis but do not prevent the necrosis. Therefore, it has been sug gested that pyridine injures the liver, botn by a direct toxic action and by producing 570 Toxic and Drug-Induced Hepatitis an intrinsic nutritional deficiency, possibly by diverting methyl groups during its methylation. QUINETHAZONE (HyDROMOX) Jaundice has been reported in a patient receiving quinethazone, a nonmercurial diu retic, unrelated to the benzothiadiazines, used in the treatment of hypertension.350* In the case involved, asymptomatic mild scleral icterus, slight hepatomegaly and ele vation of the serum bilirubin to 3.3 mg./lOO ml., with a direct-reacting fraction of 1-5 mg., were noted after 7 weeks of drug ther apy. Other tests of hepatic function are said to have been normal. Liver biopsy revealed intracellular bile pigment granules in the centrilobular parenchyma, evidence of in creased regenerative activity and infiltration of the portal triads with mononuclear cells and eosinophils. A direct Coombs' test was positive on two occasions. The jaundice cleared rapidly when the drug was with drawn, but recurred within a week when treatment with quinethazone was resumed. Since the direct Coombs* test was posi tive in the case described, and reports indi cate that quinethazone occasionally pro duces rash, it may be a sensitizing agent. Radiation X-ray irradiation of the liver provokes more intense radiation sickness than irradi ation over any other area of the body. Al though it is clear from both experimental and clinical observations that irradiation can damage the liver, the symptoms of radi ation sickness do not appear to be depend ent upon hepatic injury, which suggests that they may be due to the indirect effects of irradiation. In some cases, intensive irradiation over the liver produces severe degeneration and necrosis of the intrahepatic bile ducts while sparing the parenchyma.126 Thus, the he patic parenchyma is thought to be relatively resistant to irradiation damage. However, in experimental animals, the parenchymal cells appear to be far more sensitive than the biliary epithelium when massive doses of x-ray are employed, the principal effects being degeneration and necrosis of hepatocytes by a direct action, and varying degrees of edema, hyperemia and leukocytic infil tration attributable to vascular damage.26 Smaller doses also affect the hepatic paren chyma, but the changes are more subtle.*41703 Similarly, in man, intensive irradiation (3,000 to 6,000 rads) over the liver pro duces severe damage, giving rise to a syn drome called "radiation hepatitis.**96,3a3>414 Characteristically, ascites and hepatosplenomegaly, occasionally accompanied by ab dominal pain and jaundice, appear 2 to 6 weeks following completion of a course of irradiation. The hepatic lesion may heal without residuals, lead to fibrosis of the liver or result in death. Histologically, the lesion is characterized by progressive fibrosis and obliteration of the central veins, and centrolobular conges tion, hemorrhage and atrophy of the par enchyma, features that closely resemble those of the veno-occlusive disease seen in Jamaica and produced by senecio alka loids.002 The concept that the vascular le sions precede and are responsible for the congestion and loss of hepatic parenchyma is open to question, since in some studies the parenchymal changes have been ob served prior to the appearance of hepatic venous occlusion.353 There is evidence that, in some cases, the lesions regress or heal without residuals after a period of 4 months.553,802 However, marked fibrosis may persist and often is accompanied by terminal jaundice.6 Rarely, such hepatic lesions may be complicated by stricture of the common duct or fibrosis of the pan creas.6 Surprisingly few changes in the liver were observed in atom bomb casualties.436 In in dividuals who survived for less than 6 weeks, the principal findings were central conges tion with atrophy of the hepatic paren chyma, and edema of the centra! veins. In those who survived longer, the liver ex hibited fatty infiltration. At least two radioactive materials used as therapeutic or diagnostic agents can pro duce liver injury: radioactive colloidal gold and thorium dioxide (Thorotrast). Although there are no clinical reports of liver injury following the use of radioactive colloidal gold, it produces severe midzonal hepatic necrosis in rats.33 The architecture of the li crosis az enchymi Althoug there is ascites varies fr Despi is convi trast ca rise to r disorder Hepa grees oi occurs i: who ha thorium splenog ally, th after a animals foci of much si number hepatic A wi< been ei ministn of appi often th been ol hepator heman^ liomas tion to have b sues, a cedent less we acute aplasth pura h tions ol All o tained cially ii of year the sp] none i< can be fs^jf the jpf the |j^he fib 4 Miscellaneous 571 and leukocytic infil- of the liver is grossly distorted, both by ne- due to radioactivity and not to a foreign- ''vascular damage.26 i the hepatic paren- crosis and by the transformation of the par- body reaction. The 75 ml. dose of 25 per enchyma to masses of bizarre giant cells, cent thorium dioxide solution required for s are more subtle.447* Although the lesion may resemble cirrhosis, hepatosplenography has been estimated to intensive irradiation there is no fibrosis. Clinically, jaundice and possess an alpha ray activity equivalent to over the liver pro ascites are evident prior to death. Survival that of 1.5 to 3.0 micrograms of radium.801 giving rise to a synn hepatitis."96* 353* 414 :es and hepatosplenoiccompanied by ab- varies from a few days to 7 months. Despite claims to-the contrary,800*801 there is convincing evidence to show that Tborotrast can produce hepatic injury and give In the course of its degradation, a series of other radioactive elements are produced, some of which emit beta and gamma rays in small quantity. Several of these have ldice, appear 2 to 6 letion of a course of tic lesion may heal to fibrosis of the liver rise to malignancy and certain hemopoietic disorders. Hepatosplenomegaly with varying degrees of fibrosis and cirrhosis of the liver occurs in a significant number of individuals been identified in the excreta and the ex pired air many years after the injection of Thorotrast.716 The carcinogenic potentiality of Thorotrast is also presumed to be related to its radioactivity, sion is characterized ; and obliteration of who have received large doses of colloidal thorium dioxide in the course of hepato* Transfusion Reactions ^entrolobular conges- splenography or angiography.12* 181* 252 Usu- Not infrequently, severe reactions to atrophy of the par- ally, the signs of hepatic disease appear transfusions of incompatible blood are ac- at closely resemble after a latent period of at least 15 years. In companied by jaundice, a manifestation al- nsive disease seen in animals, large doses of Thorotrast produce most certainly due to acute hemolysis. How- d by senecio alka- foci of hepatic necrosis and fibrosis in a ever, evidence suggests that hepatic injury that the vascular le- much shorter period of time.546 A significant plays a contributory role. In most fatal cases, ! responsible for the number of patients with the disease die of the liver shows areas of central necrosis,85* hepatic parenchyma hepatic failure. 269 and similar lesions have been produced ince in some studies A wide variety of malignant tumors have in dogs by injecting heterologous hemagglu- nges have been ob- been encountered following Thorotrast ad- tmins.559 Healing is followed by diffuse 5pe ce of hepatic ministration, usually after a latent period fibrosis in animals that survive, but a simi- There is evidence of approximately 20 years.11*536*562 Most lar sequence has not been described in man. he lesions regress or often these have involved the liver, and have The pathogenesis of the hepatic lesions in i after a period of 4 been of varying histologic types, including transfusion reactions is not well understood, er, marked fibrosis hepatoma, cholangiocarcinoma, sarcoma and Possibly they are related to shock, which l is accompanied by hemangioendothelioma. Hemangioendothe- is often present. It has also been suggested Rarely, such hepatic liomas are particularly frequent.161 In addi- that hepatic necrosis results from impaction tested by stricture of tion to those found in the liver, carcinomas of the sinusoids with agglutinated erythro fibrosis of the pan- have been encountered in many other tis- cytes. sues, although their relationship to ante- Jaundice may also follow the transfusion mges in the liver were 'b casualties.439 In inl for less than 6 weeks, were central congesthe hepatic parenthe central veins. In longer, the liver exn. tive materials used as tic agents can prooactive colloidal gold [ThoTotrast). no clinical reports of the use of radioactive uces severe midzonal s.393 The architecture cedent Thorotrast administration has been less well defined.161 Also, instances of both acute and chronic leukemia, lymphoma, aplastic anemia and thrombocytopenic purpura have been reported as late compucations of Thorotrast deposits.161 All of the injected thorium dioxide is retained in the reticuloendothelium, and espedaily in the liver and spleen. Over a period of years, some may shirt from the liver and the spleen to adjacent lymph nodes, but none is excreted. Although large particles can be demonstrated in the Kupffer cells of the liver and in the reticuloendothelium of the spleen, it is generally believed that the fibrosis that occurs in these organs is of well-matched blood. This complication, designated by some as "benign postoperative intrahepatic cholestasis,*652 is seen most commonly during the postoperative course of patients who have been transfused with bank blood.3t0* 57*65Z*672 However, it may also occur after transfusions administered to patients with severe trauma or bums.672 The writer has seen one instance following multiple transfusions in a patient with chronic renal failure who was undergoing periodic hemodialysis. Characteristically, the jaundice appears on the 1st to the 6th postoperative day, increases over the next few days and then clears within a week or two. Both the direct-reacting (conjugated) 24905075 572 Toxic and Drug-Induced Hepatitis and indirect-reacting (unconjugated) frac tions of serum bilirubin are increased, and are associated with bilirubinuria, but acholic stools and pruritus do not occur. Raised levels of serum alkaline phosphatase and transaminase are common but inconstant findings. Usually, peak values of serum bilirubin are under 10 mg./lOO ml., but concentrations of 25 to 40 mg./lOO ml. have been reported.370,652 Histologically, the liver shows centrilobular bile stasis which, occasionally, is accompanied by focal hepatic necrosis and degenerative changes.370,652 In cases with elevated levels of serum alkaline phosphatase, the clinical features may suggest obstructive jaundice. As a rule, the jaundice is asymptomatic and appears to have no adverse effect on the clinical course. Fatalities have been reported in cases of severe postoperative jaundice, but, in these, death has been due primarily to other factors.370 The possibility that the cholestasis in such cases has played a con tributory role cannot be excluded. The jaundice seen following the trans fusion of matched blood is clearly not due primarily to hemolysis. Although not proved, the mechanism involved appears to be re lated to two factors: first, a disturbance in hepatic secretory function (cholestasis) sec ondary to impairment of hepatic blood flow related to the effect of surgery, anesthesia, congestive heart failure, shock, trauma or sepsis, and second, a large increase in the load of bilirubin presented to the liver as a result of hemolysis of transfused blood. units, glutamic pyruvic transaminase 375 units, alkaline phosphatase 15.3 Sigma units, thymol turbidity 9 units and cephalincholesterol flocculation 3+. Biopsy of the liver revealed centrilobular bile stasis, foci of parenchymal necrosis, proliferation of Kupffer cells, enlargement and inflammation of the portal triads and rare acidophilic bodies. Jaundice cleared rapidly following cessa tion of drug therapy, but the serum bili rubin was still slightly elevated when last studied at the end of 3 weeks. Considering that this agent occasionally gives rise to allergic manifestations, such as rash, it is highly probable that the hepa titis described was another manifestation of drug hypersensitivity. Tripelennamine (Pyribenzamine) Hydrochloride A brief report implicates Pyribenzamine as a cause of cholestatic hepatitis.*4 In the patient involved, an obstructive-like jaun dice appeared during the course of treatment with the drug. Exploratory laparotomy failed to demonstrate any evidence of extrahepatic biliary obstruction. On biopsy, the liver showed centrilobular bile thrombi, foci of hepatocellular degeneration and ne crosis and an inflammatory reaction. The jaundice persisted for 5 months, but then cleared. Follow-up clinical and biochemical studies several months later revealed no residuals. , Trimethobenzamide Hydrochloride (Tigan) Thus far, only one instance of hepatitis has been attributed to trimethobenzamide hydrochloride, an agent widely used as an antiemetic and for the control of motion sickness.84 The patient involved noted the onset of jaundice and dark urine, accom panied by epigastric discomfort, anorexia and nausea, on the 5th day of drug admin istration. The jaundice deepened over the next few davs and then began to fade. The results of hepatic function tests were con sistent with hepatocellular jaundice, peak values being: serum bilirubin 14.9 mg./lOO mL, glutamic oxalacetic transaminase 660 REFERENCES 1. Abbott, J. A., and Schwab, R. S.: The serious side effects of the newer antiepi leptic drugs; their control and prevention, New Engl. J. Med. 242:943, 1950- 2. Abbruzzese, A., and Swanson, J.: Jaun dice after therapy with chlordiazepoxide hydrochloride, New Engl. J. Med. 273: 321, 1965. 3. Achar, S. T., Raju, V. B., and Sriramachari, S.: Indian childhood cirrhosis, J. Pediat. 57:744,1960. 4. Acocella, G., and Billing, B. H.: Effect drugs on the hepatic transport of bilirubirr^ in McIntyre, N., and Sherlock, S.: (edsgft Therapeutic Agents and the Liver, p. Oxford, Blackwell Scientific Pub., 1965?* o vl 0) *9 ruv^ transaminase 375 aha 15.3 Sigma units, 9 units and cephalintion 3-f-. Biopsy of the ilobular bile stasis, foci jcrosis, proliferation of ement and inflammation s and rare acidophilic rapidly following cessa>y, but the serum biliitly elevated when last 3 weeks. this agent occasionally manifestations, such as obable that the hepaoother manifestation of ( Pyribexzamine ) CHLORIDE ilicates Pyribenzamine atic hepatitis.74 In the obstructive-like jaunr the course of treat- xploratory laparotomy : any evidence of exstruction. On biopsy, ilob- W bile thrombi, deg ration and nenatory reaction. The 5 months, but then lical and biochemical is later revealed no l J l CNCES l Schwab, R. S.: The of the newer antiepi:ontrol and prevention, 242:943,1950. id Swanson, J,: Jaunwith chlordiazepoxide ' Engl. J. Med. 273: Y` B- and Srirama- j hildhood cirrhosis, T. lling, B. H.: Effect of transport of bilirubin I Sherlock, S.: (eds.) and the Liver, p. 1, cientific Pub., 1965. 5. -----------: The effect of rifamycin SV on bile pigment excretion in rats. Gastro enterology 49:526,1965. 6. Acocella, G., Nicolis, F. B., and Tenconi, L. T.: The effect of an intravenous infu sion of rifamycin SV on the excretion of bilirubin, Bromsulphalein, and indocva- nine green in man, Gastroenterology 49: 521, 1965. ' .. 7. Adams, R. H,,, and Combes, B.: Viral hepatitis during pregnancy, J.A.M.A. 292:195, 1965. 8. Adlercreutz, H., and Ikonen, E.: Oral contraceptives and liver damage, Brit. Med. J. 2:1133, 1964. 9. Adlercreutz, H., Svanborg, A., and An- berg, A.: Recurrent jaundice in preg nancy. II. A study of estrogens and their conjugation in late pregnanev. Am. J. Med. 42:341, 1967. 10. Agostini, C., Perm, A., and Fonnesu, A.: Toxic fatty liver in adrenaleetomized rats, Brit. J. Exp. Path. 42:617, 1960. 11. Agress, C. M.: Atabrine as a cause of fatal exfoliative dermatitis and hepatitis, J.A.M.A. 232:14, 1936. 12. Aizawa, M., Kobavashi, H., Maruvama, K., and Hagihara, K.: Two cases of cir rhotic liver associated with Thorotrast, deposit, Acta path. jap. 22:615, 1960. 13. Alexander, H. L.: Reactions with Drug Therapv, p. 167, Philadelphia, Saunders, 1955. 14. Allen, N. W., and Banker, N. W.: Ex periments with phenvlhvdrazine; patho logic anatomv, Ann. Int. Med. T.683, 1928. 15. Almaden, P. J., and Ross, S. W.: Jaun dice due to methvj testosterone therapv, Ann. Int. Med. 40:146, 1954. 16. Ambrus, C. M., Siderin, C. N., Johnson, G. C-, and Harrison, J. W. E.: Toxicitv of penicillin and Aureomycin in guinea pigs, Antibiot. Chemother. 2;521. 1952. 17. Amromin, G. D., Deliman. R. M., and Shanbrom, E.: Liver damage after chem otherapy for leukemia and lvmphoma, Gastroenterology 42:401, 1962. 18. Andersch, M. A.: Hepatic damage asso ciated with sulfonamide therapv in in fants and children. II, Changes in liver function test during sulfonamide therapv, Ann. Int. Med. 29:622, 1943. 19. Andersen. H-, and Kristiansen, E. S.: Tofranil treatment of endogenous depres sions, Acta psvchiat. scand. 34:387, 1959. 20. Anderson, H. H., Reed, A. C., and Emer son, G. A.: Toxicity of alpha dinitrophe- References 573 nol; report of a case, JA.M.A. 101:1053, 1933. 21. Anderson, N. L., and Palmer, W. L.: The danger of gold salt therapy; report of a fatal case, J.A.M.A. 115:1627, 1940. 22. Aral, H., and Snapper, I.: The influence of stilbamidine upon kidney function, liver function and peripheral blood in multiple myeloma; neurological sequelae of stilbamidine therapy. New York J. Med. 47:1867, 1947. 23. Arias, I. M.: Effect of norethandrolone on hepatic metabolism of bilirubin bv normal and Gunn rats, Clin. Res. 8:367 1960. 24. Arias, I. M., Gartner, L. M., Seifter, S., and Furman M.: Prolonged neonatal un conjugated hyperbilirubinemia associated with breast feeding and a steroid, pregnane-3(alpha),20(beta)-diol, in maternal milk that inhibits glucuronide formation in vitro, J. Clin. Invest. 43:2037, 1964. 25. Arias, I. M., Jankelson, O. M., and Zamcheck, N.: The effect of chlorpromazine on the excretion of Bromsulphalein (BSP) in human bile, Clin. Res. 4:144, 1956. 26. Ariel, I. M.: The effect of single massive doses of roentgen radiation upon the liver; an experimental studv, Radiologv 57:561, 1951. 27. Babior, B, M., and Davidson, C. S.: Post operative massive liver necrosis: a clini cal and pathological study. New Engl. J. Med. 276:645,1967. 28. Baggenstoss, A. H.: The pancreas in uremia: a histopathologic study, Am. J. Path. 24:1003, 1948. 29. Bailev, B. H., and Kay, R. E.: Prolonged phenothiazine hepatitis; report of a case, Am. J. Psvchiat. 117:557, 1960. 30. Bailie, M. J., and Christie, G. S.: The acute toxic action of dimethvlnitrosamine on liver cells, Biochem. J. 72:473, 1959. 31. Baird, R. W., and Hull, J. G-: Chole static jaundice from tolbutamide, Ann. Int. Med. 53:194, 1960. 32. Bajoghli, M.: Generalized Ivmphadenopathv and hepatosplenomegaly induced by diphenvlhvdantoin. Pediatrics 28:943, 1961. * 33. Baker, R. D., and Handler, P.: Animal experiments with tannic acid suggested bv the tannic acid treatment of bums, Ann. Surg. 228:417, 1943. 34. Baldridge, C. W.: The relationship be tween antisvphilitic treatment and toxic cirrhosis. Am. J. Med. Sci. 288:685, 1934. 35. Bander, A.: Pharmacological studies of 574 Toxic and Drug-Induced Hepatitis the sulfonylureas, Ann. N. Y. Acad. Sci. 32:508, 1959. 36. Barber, H. J., Slack, R., and Wien, R-: Increase in toxicity of stdbamidine solu tion on exposure to light. Nature 151: 107,1943. 37. Barich, L. I... Schwara, J.. Barich, D. J., and Horowitz, M. G.t Toxic liver dam age in mice after prolonged intake of ele vated doses of griseofulvin, Antibiot. Chemother. 11:566, 1961. 38. Barnes, J. A. P.: Toxic jaundice in muni tion workers and troops, Brit. Med. J. 1:155, 1917. 39. Barnes, J. M., and Magee, P. N.: Some toxic properties of dimethylnitrosamine, Brit. J. Indust. Med. 21:167, 1954. 40. Barrett, H. M., Best, C H., MacLean, D. L., and Ridout J. H.: The effect of choline on the fatty liver of carbon tetra chloride poisoning, J. Phvsiol. 97: 103, 1939. 41. Barrett, H. M., Best, C. H., and Ridout, J. H.: A study of the source of liver fat using deuterium as an indicator, J. Physiol. 93:367,1938. 42. Barron, M.; Cinchophen poisoning: re port of a case of severe allergic reaction, J.A.M.A. 82:2010,1924. 43. Bartels, E. C., and Sjogren, R. W.: l-Methyl-2-mercaptoimidazole: a new ac tive antithyroid agent, J. Clin. Endocr. 11:1057,1951. 44. Bartholomew, L. G., Cain, J. C., Frazier, S. H., Petersen, M. C., Foulk, W. T., Soule, E. H., Fleisher, G. E., and Owen, C. A., Jr.: Effect of chlorpromazine on the liver. Gastroenterology 34:1096, 1958. 45. Bateman, J. C., Barberio, J. R., Cromer, J. K,, and Klopp, C. T.: Investigation of mechanism ana type of jaundice pro duced by large doses of parenterally ad ministered Aureomycin, Antibiot. Chemo ther. 3:1, 1953. 46. Baxter, J. H.: Hepatic and renal injury with calcium deposits and cirrhosis pro duced in rats by pyridine. Am, J. Path. 24:503, 1948. 47. Baxter, J. H., and Campbell, H.: Effects of Aureomycin on renal lesions, liver lipids, and tissue choline in choline de ficiency, Proc. Soc. Exp. Biol. Med. 80: 415,1952. 48. Beattie, J., Herbert, P. H., Wechtel, C., and Steele, C. W.: Studies on hepatic dysfunction. I. Carbon tetrachloride poi soning treated with casein digest and methionine, Brit. Med. J. J:209, 1944. 49. Beattie, J., and Marshall, J.; The aetiol ogy of post-arsphenamine jaundice, Brit. Med. J. 1:547, 1944. 50. Beaver, D. C., and Pemberton, J. DeJ.: The pathologic anatomy of the liver in exophthalmic goiter, Ann. Int. Med. 7687, 1933. 51. Beaver, D. C., and Robertson, H. E.: Specific character of toxic cirrhosis as observed in cinchophen poisoning; re view of five fatal cases, Proc. Mavo Clin 6:216, 1931. 52. Beer, D. T., and Schaffner, F.: Fatal jaundice after administration of betaphenvlisopropylhydrazine. Report of a case, J.A.M.A. 171:887, 1959. 53. Belfrage, S,, Ahlgren, I., and Axelson, S.: Halothane hepatitis in an anesthetist. Lancet 2:1466,1966. 54. Bellamy, W. E., Jr., Mauck, H. P., Jr., Hennigar, G. R., and Wigod, M.: Jaun dice associated with the administration of sodium p-aminosalicvlic acid; review of the literature and report of a case, Ann. Int. Med. 44:764, 1956. 55. Belle, M. S., and Mas, I. R.: Methyldopa and positive Coombs' test, J.A.M.A. 200: 900, 1967. 56. Belt, T. H.: Liver necrosis following bums, simulating the lesions of vellow fever, J. Path. Bact. 43:493, 1939. 57. Benack, R. T., and Lvnch, V.: Jaundice associated with isocarboxazid therapv, New Engl. J. Med. 264:294, 1961. 58. Benaim, S., and Dixon, M. F.: Jaundice associated with administration of ipronia zid. Report of two cases, Brit Med. J. 2:1068,1958. 59. Benhamou, J. P.: General discussion on drugs and the liver, in McIntyre, N., and Sherlock, S. (eds.): Therapeutic Agents and the Liver, p. 167, Oxford, Blackwell Scientific Publications, 1965. 60. Bennett, G. A., Drinker, C. K., and War ren, M. F-: Morphological changes in the livers of rats resulting from exposure to certain chlorinated hydrocarbons, J. Indust Hvg. Toxicol. 20:97, 1938. 61. Benson, W. M., Stefko, P. L., and Roe, M. D-: Pharmacologic and toxicologic observations on hvdrazine derivatives of isonicotinic acid (Rimifon, Marsilid), Am. Rev. Tuberc. 65:376. 1952. 62. Berger, S. S., and Applebaum, H. S.: Toxic hepatitis due to sulfanilamide; re- References 575 rath .*seia digest and port of a fatal case with histopathologic Med. J. 1:209, 1944. findings in the liver, J. Lab. Clin. Med. larshall, J.: The aetiol- 26:785, 1941. enamine jaundice, Brit 44. id Pemberton, J. DeJ.: aatomy of the liver in 63. Berkowitz, D., Rotman, M., Greenstein, R. H., and Sloane, N. G.: Occurrence of jaundice during perphenazine and betaphenvlisopropylhvdrazine, Am. J. Dig. er, Ann. Int. Med. 7: Dis. '6:160, 1961'. 64. Berman, A., and Franklin, R. L.: Pre nd Robertson, H. E.: cipitation of acute intermittent porphyria of toxic cirrhosis as bv griseofulvin therapy, J.A.M.A. 192: lophen poisoning; re- 1005,1965. :ases, Proc. Mavo Clin. 65. Berne, R. M.: An unusual sensitivity re action to penicillin; report of a case with Schaffner, F.: Fatal autopsv findings. New Engl. J. Med. 242: ministration of betairazine. Report of a -.887, 1959. 814, 1950. 66. Bernstein, C., and Kioto, S. D.: Aller genicity of tianquilizing drugs, J.A.M.A. ;n, I., and Axelson, S-: is in an anesthetist, 16-3:930, 1957. 67. Berte, S. J., Di Mase, J. D., and Chris 50. r., Mauck, H. P., Jr., nd Wigod, M.: Jaunth the administration salicylic acid; review j tianson, C. S.: Isoniazid, para-aminosalicylic acid, and streptomycin intoler ance in 1,744 patients: an analysis of reactions to single drugs and drug groups plus data on multiple reactions, type and nd report of a case, m, 1956. time of reactions, and desensitization. Am Rev. Resp. Dis. 90:508, 1964. as, I. R.: Methyldopa 1 68. Berthelot, P., and Billing, B. H.: Effect is test, J.A.M.A. 200: of bunamiodyl on hepatic uptake of sulfobromophthalein in the rat, Am. J. Physiol. r i sis following 212:395, 1966. he lesions of veDow 69. Best, C. H., MacLean, D. L., and Ridout, 48:493, 1939.' Lynch, V.: Jaundice J. H.: Choline and liver fat in phosphorus poisoning, J. Phvsiol. 83:275, 1935. >carboxazid therapy, 164:294,1961. 70. Bevans, M., and Batchelor, W. H.: Cholangiolitic cirrhosis with intrahepatic bili- con, M. F.: Jaundice arv tract obstruction and xanthomatosis. inistration of iproniacases, Brit. Med. J. Am. J. Med. 9:133,1950. 717 Bickers, J. N., Buechner, H. A., Hood, B. and Alvarez-Chiesa, G.: Hypersen eneral discussion on in McIntyre, N., and Therapeutic Agents 7, Oxford, Blackwell s, 1965. sitivity reaction to antituberculosis drugs with hepatitis, lupus phenomenon and myocardial infarction. New Engl. J. Med. 265:131, 1961. 72. Billing, B. H., Maggiore, Q., and Cartter, cer, C. K., and Warigical changes in the Ing from exposure d hydrocarbons, J. 20:97, 1938. '<o, P. L., and Roe, ?c and toxicologic azine derivatives of ifon, Marsilid), Am. .1952. tpplebaum, H. S.i > sulfanilamide; re M. A.: Hepatic transport of bilirubin, Ann. N. Y. Acad. Sci. jil:319, 1963. 73. Bingle, J., and Shine, I.: Phenindione sensitivity. Lancet 2:377, 1959. 74. Bjorneboe, M., Iversen, O., and Olsen, S.: Infective hepatitis and toxic jaundice in municipal hospital during a five-year period, Acta med. scancL 282:491, 1967. 75. Black-Sehaffer, B., Johnson, D. S., and Cobbel, W. G., Jr.: Experimental total midzonal hepatic necrosis. Am. J. Path- 26:397,1950. 76. Boake, W. C., Schade, S. G., Morrissey, J. F., and Schaffner, F.: Intrahepatic cholestatic jaundice of pregnancy fol lowed by Enovid-induced cholestatic jaundice; report of a case, Ann. Int. Med. 63:302, 1965. 77. Boardman, R. H.: Fatal case of toxic hepatitis implicating chlorpromazine, Brit. Med. J. 2:579, 1954. 78. Bodansky, M., Campbell, K., and Ball, E.: Changes in serum calcium, inorganic phosphate and phosphatase activity in pregnant women. Am. J. Clin. Path. 9: 36, 1939. 79. Bodansky, M., Marr, W. L., and Brind ley, P.: An experimental study of the action of phenylhydrazine hydrochloride and acetylphenylhydrazine (pyrodin) with reference to their use in the treat ment of polvcvthemia vera. Am. J. Clin. Path. 2:391,' 1932. 80. Bollman, J. L.: Protective value of foods in experimental cirrhosis, J.A.M.A. 222: 1413, 1943. 81. Bollman, J. L., and Mann, F. C.: The phvsiology of the impaired liver, Ergebn. Physiol. -38:445, 1936. 82. Bolt, R. J., Dillon, R. S-, and Pollard, H. M.: Interference with bilirubin excretion bv a gall-bladder dve (bunamiodyl). New Engl. J. Med. 265:1043, 1961. 83. Bolton, B. H.: Prolonged chlorpromazine jaundice. Am. J. Castroent. 48:497, 1967. 84. Borda, I., and Jick, H.: Hepatitis follow ing the administration of trimethobenzamide hydrochloride. Arch. Int. Med. 120: 371, 1967. 85. Bordley, J., Ill: Reactions following transfusion of blood, with urinarv sup pression and uremia. Arch. Int. Med. 47:288, 1931. 86. Borglin, N. E.: Oral contraceptives and liver damage, Brit. Med. J. 2:1289, 1965. 87. Bothwell, T. H., and Bradlow, B. A.: Siderosis in the Bantu: a combined histopathological and chemical studv. Arch. Path. 70:279, 1960. 88. Bothwell, T. H-, Seftel, H., Jacobs, P., Ton-ance, J. D., and Baumslag, N.: Iron overload in Bantu subjects: studies on die availability of iron in Bantu beer. Am. J. Clin. Nutr. 14:47, 1964. 89. Bourne, W., and Raginsky, B. B.: The effect of Avertin upon die normal and impaired liver. Am. J. Sure. 14:653 1931. 90. Bowesxoan, C.: A short report on the use *0 576 Toxic and Drug-Induced Hepatitis of 4:4'-diamidino stilbene in the treat ment of human sleeping sickness, Ann. Trop. Med. 34:217, 1940. 91. Bradley, R. F.: Role of oral blood sugar- lowering agents in the management of diabetes, Ann. N. Y, Acad. Sci. 52:513, 1959. 92. Bragdon, J. H.: The hepatitis of hyper thermia; report of a fatal case. New Engl. J. Med. 237:765, 1947. 93. Bras, G-, Jelliffe, D. B., and Stuart, K. L.: Veno-occlusive disease of liver with nonportal type of cirrhosis, occurring in Jamaica, Arch. Path. 57:285, 1954. 94. Brauer, M. J., McEvoy, B. F., and Mitus, W. J.: Hypersensitivity to nitrogen mus tards in the form of erythema multiforme: a unique adverse reaction. Arch. Int. Med. 120:499, 1967. 95. Breinstrup, H., and Sogaard-Andersen, J.: Intrahepatic cholestasis after griseofulvin therapy, Ugeskr. Laeg. 128:145, 1966. 96. Brick, I. B.; Effects of million volt irradi ation on the gastrointestinal tract, Arch. Int. Med. 96:26, 1955. 97. Brick, I. B., and Kyle, L. H.: Jaundice of hepatic origin during the course of methvl-testosterone therapv. New Engl. J. Med. 246:176, 1952. 98. Bridges, R. A., Berendes, H., and Good, R. A.: Serious reactions to novobiocin, J. Pediat. 50:579, 1957. 99. Brooks, R. H., and Calleja, H. B.: Der matitis, hepatitis and nephritis due to phenindiOne (phenvlindandione), Ann. Int. Med. 52:706, 1960. 100. Brown, G-, Zoidis, J., and Spring, M.: Hepatic damage during chlorpropamide . therapy, J.A.M.A. 170:2085, 1959. 101. Brown, G. E., and Griffin, H. Z.: The treatment of polycythemia vera (ery thremia) with phenylhydrazine, Arch. Int. Med- 38:321, 1926. 102. Brunschwig, A., Johnson, C., and Nichols, S.: Carbon tetrachloride injury of the liver. The protective action of certain compounds, Proc. Soc. Exp. Biol. Med. 60:388, 1945. 103. Brunschwig, A., Nichols, S., Bigelow, R. R., and Miles, J.: Sulfbydryl protection of the liver. Arch. Path. 40:81, 1945. 104. Brunson, J. G., Eckman, P. L., and Campbell, J. B,: Increasing prevalence of unexplained liver necrosis. New Engl. J. Med. 257:52, 1957. 105. Buckley, J. J., Buckley, S. M., and Gey, M. K.: Tissue culture studies on liver cells of anapbylactically (Arthus) sensi tized animals in the presence of the sensi tizing antigen. Bull. Johns Hopkins Hosp. 84:195, 1949. 106. Bull, L. B., and Dick, A. T.: The chronic pathological effects on the liver of the rat of the pyrrolizidfne alkaloids heliotrine, lasiocarpine and their N-oxides, J. Path. Bact. 78:483, 1959. 107. Bunker, J. P., and Blumenfeld, C. M.: Liver necrosis after halothane anesthesia: cause or coincidence? New Engl. J. Med. 268:531, 1963. 108. Burnap, T. K., Calla, S. J., and Vandam. L. D.: Anesthetic, circulatory and respi ratory effects of Fluothane, Anesthesiol ogy 19:307, 1958. 109. Butt, H. R., Hall, J. E., Watkins, C. H.. and Cragg, R. W.: Atabrine dihvdxochloride (quinacrine hvdrochloride) some observations on its toxicity and oa its use in the treatment of malaria, with particular reference to its effect on the liver, Gastroenterology 4:205, 1945. 110. Cacioppo, J., and Merlis, S.; Chlordiazepoxide hydrochloride (Librium) and jaun dice; report of a case, Am. j. Psvchiat. 127:1040, 1961. 111. Calvert, D. N., and Brody, T. M,,: Bio chemical alterations of liver function bv the halogenated hydrocarbons. I. In vitro and in vivo changes and their modifica tion bv ethvlenediamine tetraacetate, J. Pharmacol. Exp. Ther. 124:273, 1958. 112. ---------- : Role of the sympathetic ner vous system in CC14 hepatotoxicitv. Am. J. PhysioL 198:669, 1960. 113. Camerini-Davalos, R., Root, H. F., and Marble, A.: Clinical experience with carbutamide (BZ-55); a progress report, Diabetes 6:74, 1957. 114. Cameron, G. R.: Carbon tetrachloride cirrhosis in relation to liver regeneration, J. Path. Bact 42:1, 1936. 115. Cameron, G. R., and Karunaratne, W. A. E.: Liver changes in exophthalmic goitre, J. Path. Bact. 41:267, 1935. 116. Cameron, G. R., Karunaratne, W. A. E., and Thomas, J. C.: Massive necrosis ("toxic infarction") of the liver follow ing intra-portal administration of poisons, J. Path. Bact. 44:297, 1937. 117. Campagna, M., Calix, A. A., and Hauser, G: Observations on the combined use of pyrazinamide (Aldinamide) and isoniazid in the treatment of pulmonary tubercu- i' V iyla Uy (Arthus) sensim the presence of the sensi, Bull. Johns Hopkins Hosp. id Dick, A, T.: The chronic jffects on the liver of the rrolizidine alkaloids helio sine and their N-oxides, ). f:483, 1959. and Blumenfeld, C. M.: after halothane anesthesia: idence? New Engl. J. Med. . Calla, S. J., and Vandam, etic, circulatory and respiof Fluothane, Anesthesiol558. 'all, J. E., Watkins, C. H., W.: Atabrine dihvdroinacrine hydrochloride); ons on its toxicity and on treatment of malaria, with rence to its effect on the terologv 4:205, 1945. id Merlis, S.: Chlordiazepsride (Librium) and jaun- a case, Am. J. Psychiat. L. , and Brody, T. M.: Biotions of liver function by l h\ arbons. I. In vitro anges and their modificalediamine tetraacetate, J. . Ther. 124:273, 1958. of the sympathetic nerCCh hepatotoxicity. Am. 669, 1960. os, R., Root, H. F., and 'linical experience with Z-55); a progress report, 1957. t.: Carbon tetrachloride ion to liver regeneration, 2:1, 1936. and Karunaratne, W. hanges in exophthalmic Bact 41:267, 1935. Karunaratne, W. A. E., C.: Massive necrosis n") of the liver followdministration of poisons, 1:297, 1937. ^alix, A. A., and Hauser, on the combined use of ldinamide) and isoniazid of pulmonary tubercu losis; a clinical study. Am. Rev. Tuberc. 69:334, 1954. 118. Campbell, P. N., Greengard, O., and Kemot, B. A.: Studies on the synthesis of serum albumin by the isolated microsome fraction from rat liver, Biochem. J. 74: 107, 1960. 119. Canavan, M. N., Cobb, S., and Drinker, C. K.: Chronic manganese poisoning; report of a case with autopsv. Arch. Neurol. Psychiat. 32:501, 1934. 120. Carbone, J. V.: Personal communication to Marquardt, Fisher, Levy and Dow'ben.'*89 121. Carbone, J. V., Grodsky, G. M., and Hjelte, V.: Effect of hepatic dvsfunction on circulating levels of sulfobromophthalein and its metabolities, J. Clin. Invest. 33:1989, 1959. 122. Carey, J. B., and Williams, G.: Relief of j the pruritus of jaundice with a bile-acid | sequestering resin, J.A.M.A. 176:432, 1961. ] 123. Carr, H. J., Jr., and Knauer, Q. F.: Death due to hepatic necrosis in a pa tient receiving zoxazolamine. Report of a case and review of the literature, New Engl. J. Med. 264:977, 1961. 124. Carter, S., Sciarra, R., and Merritt, H. H.: Phenvlacetylurea in the treatment of convulsive seizures, Dis. Nerv. Svst. 11: 139, 1950. 125. Casamajor, L.: Cited bv von Oettingen.TM3 126. Case, J. T., and Warthin, A. S.: The occurrence of hepatic lesions in patients treated bv intensive deep roentgen irra diation, Am. J. Roentgenol. 12:27, 1924. 127. Case Records of the Massachusetts Gen eral Hospital: Reve's disease, with fattv change and peripheral zonal necrosis of the liver, toxic encephalopathv, and fattv change of renal tubules, New Engl. J. Med. 276:47, 1967. 128. Chadwick, D. A., and Jennings, R. C.: Massive hepatic necrosis associated with halothane anesthesia, Lancetl :793,1964. 129. Chaiken, B. H., Goldberg, B. I., and Segal, J. P.: Dilantin sensitivity; report of a case of hepatitis with jaundice, pvrexia and exfoliative dermatitis. New Engl. J. Med. 242:897, 1950. 130. Chaikin, N. W., and Chlenoff, S. O.: Acute hepatitis; Clinical observations in 63 cases. Am. J. Dig. Dis. 12:151, 1945. 131. Charles, J. R.: Manganese toxaemia; with special reference to the effects of liver feeding, Brain 50:30, 1927. References 577 132. Chase, M. W.: The allergic state m Dubos, R.: Bacterial and Mycotic Infec tions in Man, ed. 2, p. 168, Philadelphia, Lippincott, 1952. 133. Chesner, C.: Chronic pulmonary granu lomatosis in residents of a community near a beryllium plant; three autopsied cases, Ann. Int. Med. 32:1028, 1950. 134. Christie, G. S.: Liver damage in acute heliotrine poisoning. I. Structural changes, Aust. J. Exp. Biol. Med. Sci. 36:405, 1958. 135. Christie, G. S., and Judah, J. D.: Mech anism of action of carbon tetrachloride on liver cells, Proc. Rov. Soc. Biol. 142-B: 241, 1954. 136. Chutlani, H. K., Gupta., P. S., Gulati, S., and Gupta, D. N.: Acute copper sulfate poisoning. Am J. Med. 39:849, 1965. 137. Clarke, D. A., Philips, F. S., Sternberg, S. S., Stock, C. C., Elion, G. B., and Hitchings, G. H.: 6-Mercaptopurine: effects in mouse sarcoma 180 and in normal animals, Cancer Res. 13:593, 1953. 138. Cline, E. W.: Acute vellow atrophy of the liver following sulfanilamide medica tion, J.A.M.A. 121:2384, 1938. 138a. Clubb, A. W., and Ciles, C.: Budd-Chiari svndrome after oral contraceptives, Brit. Med. J. 1:252, 1968. 139. Coggeshall, H. C., and Greene, J. A.: The influence of desiccated thyroid gland, thvroxin. and inorganic iodine, upon the storage of glycogen in the liver of the albino rat under controlled conditions. Am. J. Physiol. 105:103, 1933. 140. Cohen, A. A., and Lawrence, S. H.: Combined hvpersensitivitv reaction to sodium para-aminosalicvlate and asso ciated antibacterial drug concurrently administered, Ann. Int. Med. 46:893, 1957. 141. Cohen, I. M., and Archer. J. D.: Liver function and hepatic complications in pa tients receiving chlorpromazine, J.A.M.A. 159:99, 955. 142. Cohen, R., Kaiser, M. H., and Thomson, R. V.: Fatal hepatic necrosis secondary to isoniazid therapv, J.A.M.A. 176:877, 1961. 143. Colbert, J. W., Jr., Bungaxds, L., and Knowlton, M.: Aureomvcin, Chloromy cetin and Terramvcin in treatment of acute viral hepatitis, Proc. Soc. Exp. Biol. Med. 79:339, 1952. 144. Coleman, F. P.: The effect of anesthesia 578 Toxic and Drug-Induced Hepatitis on hepatic function, Surgery 3:87, 1938. 145. Colsky, J., Greenspan, E. M., and War ren, T. N.: Hepatic fibrosis in children with acute leukemia after therapy with folic acid antagonists. Arch. Path. 59: 198, 1955. 146. Combes, B.: Personal communication. 147. Conn, H. O., Binder, H. J., and Orr, H. D.: Ethionamide-induced hepatitis: a review with a report of an additional case. Am. Rev. Resp. Dis. 90:542, 1964. 148. Cook, G. C., and Sherlock, S.: Jaundice and its relation to therapeutic agents. Lancet 1:175, 1965. 149. Corday, E., and Williams, J. H., Jr.: Effect of shock and of vasopressor drugs on the regional circulation of the brain, heart, kidney and liver. Am. J. Med. 29: 228, 1960. 150. Corley, C. C., Jr., Lessner, H. E., and Larsen, W. E.: Azathioprine therapy of "autoimmune" diseases. Am. J. Med. 41: 404, 1966. 151. Council on Drugs: Imipramine hydro chloride (Tofranil), J.A.M.A. 178:575, 1961. 152. -----------: A new antidepressant--desipramine hydrochloride (Norpramin, Pertofrane), j.A.M.A. 194:82, 1965. 153. ---------- - a new antihvpertensive--methvldopa (Aldomet), j.A.M.A. 186:504, 1963. 1-54. Cox, R. P., Foltz, E. L., Ravmond. S., and Drewyer, R.: Novobiocin jaundice. New Engl. J. Med, 261:139, 1959. lo5. Craven, E. B., Jr.: The importance of diet in preventing acute yellow atrophv during arsphenamioe treatment. Bull. Johns Hopkins Hosp. 48:131, 1931. 156. Crawford, S. E., and Jones, C. K.: Fatal liver necrosis and diphenvlhvdantoin sensitivity. Pediatrics 30:595, 1962. 157. Crosbv, G. J. V.: The "accidents" of gold treatment in rheumatoid arthritis. Lancet 1:1463, 1936. 158. Cuthbert. J.: Acquired idiosvncrasv to sodium p-aminosalicvlate, Lancet 2:209, 1950. 159. Cutts, M.: Chlorpromazine hepatitis treated with cortisone, Ann. Int. Med. 46:1160, 1957. 160. Damashek, W., Weisfuse, L., and Stein, L.: Nitrogen mustard therapy in Hodg kin's disease. Blood 4:338, 1949. 161. daSilva Horta, J., Abbatt, J. D., Cavolla Da Mbtta, L., and Roriz, M. L.: Malig nancy and other late effects following administration of Thorotrast, Lancet 2: 201, 1965. 162. Davidson, C. S.: Hepatotoxicity of foods: a consideration of the hepatotoxicity of a few phanerogams and cryptogams; 163. their possible influence in the pathogene sis of cirrhosis and hepatoma, Ann. N. Y. Acad. Sci. 104:1026, 1963. Davidson, D. T., Jr., and Lennox, W. G.: Phenacetylurea--phenurone--in epi lepsy, Dis. Nerv. Syst. 21:167, 1950. 164. Davis, H. A., Harris, L. C., Jr., and Schmeisser, H. C.: Tissue changes fol lowing prolonged administration of sul fanilamide in rats, Arch. Path. 25:750, 1938. 165. Davis, J. D., Netzer, S., Schwartz, J. A., and Pattison, E. H.: Tibione: laboratory and clinical studies, Dis. Chest 28:521, 1950. 166. Davis, J. S., Jr.: The relation of neo- cinchophen to the question of cinchophen toxicity. Am. J. Med. Sci. 184:555, 1932. 167. Davis, N. C., and Whipple, G. H-: The influence of fasting and various diets on the liver injurv effected bv chloroform anesthesia. Arch Int. Med. 23:612, 1919. ]68. DeMatteis, F., and Rimington, C.: Dis turbance of porphyrin metabolism caused bv griseofulvin in mice, Brit. J. Dermat. 75:91, 1963. 169. DeNardi, J. M., Van Ordstrand, H. 5., and Carmodv, M. G.: Chronic pulmon ary granulomatosis; report of 10 cases. Am. J. Med. 7:345, 1949. 170. DeNardi J. M., Van Ordstrand, H. S., Curtis, G. H., and Zielinski, J.: Beryl liosis: summary and survey of all clinical types observed in a twelve-vear period. Arch. Indust. Hvg. 8:1, 1953. 171. Dianzani, M. U: Uncoupling of oxida tive phosphorylation in mitochondria from fattv livers, Biochim. Biophvs. Acta 24:514, 1954. 172. -----------: Content and distribution of pyridine nucleotides in fatty livers, Bio chim. Biophvs. Acta 27:391, 1955. 173. -----------: The content of adenosine poly phosphates in fattv livers, Biochem. J. 65:116, 1957. 174. Dianzani, M. U., and Bahr, G. F-: Elec tron microscope investigation of mito chondria isolated from normal and stea* totic livers bv differential centrifugation, Acta path, microbiol. scand. 35:25, 1954. 175. Dibl thole J* v 176. Dick L.:$ in New 177. Ditt cold hem liter 178. Doc acti< livei 179. Dolj diat 82:1 180. Dol earl wit! refe gy ing, 181. Do> pati 188 182. Dre G. M.: tres Me 183. Dri live thv 184. -- ime tetr 90: L85. -- of Thi 186. Dri of inji Sci- 187. Dri J-: inti bv To: 188. Dr chc Bit T References 579 late,, effects following Tb'^trast, Lancet 2: fiepatotoxicity of foods: f the hepatotoxicity of ams and cryptogams; ience in the pathogene 1 hepatoma, Ann. N. Y. >26. 1963. Jr., and Lennox, W. a--phenurone--in epiSvst. 11:167, 1950. ;arris, L. C., Jr., and Tissue changes foladministration of sul- Arch. Path. 25:750, ;er, S- Schwartz, J. A., 1,:' Tibione: laboratory s, Dis. Chest 28:521, The relation of neo question of cinchophen kL Sci. 184:555, 1932. Whipple, G- H.: The a and various diets on fleeted bv chloroform rt. Med. 23:612, 1919. d Rimington, C.: Dis.-rin metabolism caused mice, Brit. J. Dermat. /ar istrand, H. S-, G-. chronic pulmon- s; report of 10 cases, >, 1949. Tan Ordstrand, H. S-, d Zielinski, J.: Beryld survey of all clinical a twelve-vear period, 8:1,1953.' Uncoupling of oxidaion in mitochondria iochim. Biopbys. Acta and distribution of js in fattv livers, Biora 17:391, 1955. mt of adenosine polyv livers, Biochem. J. nd Bahr, G. F.: Elecnvestigation of mitorom normal and stearential centrifugation, *L scand. -35:25, 1954. 175. Dible, J. H., and McMichael, J.: The pa thology of arseno-therapv jaundice, Brit. J. Vener. Dis. 19:102, 1943. 176. Dickes, R., Schenker, V., and Deutsch, L.: Serial liver-function and blood studies in patients receiving chlorpromazine. New Engl. J. Med. 256:1, 1957. 177. Dittman, W. A., and Ward. J. R.: Demecolcine toxicitv; a case report of severe hemopoietic toxicitv and a review of the literature, Am. J. Med. 27:519, 1959. 178- Dochertz, J. F., and Burgess, E.: The action of carbon tetrachloride on the liver, Brit. Med. J. 2:907, 1922. 179. Dolger, H.: An assessment of oral anti diabetic therapy, Ann. N. Y. Acad. Sci. 82:531, 1959. ' 180. Doljanski, L.. and Rosin, A.: Studies on earlv changes in the livers of rats treated with various toxic agents, with especial j reference to the vascular lesions; histolI ogv of the rat's liver in urethane poisoni ing, .Am. J. Path. 20:945, 1944. 181. Dowling, H. F., and Lepper, M. H.: He patic reactions to tetracycline, J.A.M.A. 788:307, 1964. 182. Drerup, A. L., Alexander, W. A., Lumb, G. D., Cummins, A. J., and Clark, G. M.: Jaundice occurring in a patient treated with chlorothiazide. New Engl. J. Med. 259:534. 1958. 183. Drill. V. A.: The effect of veast on the liver glvcogen of white rats during hvper` thyroidism, J. Xutr. 14:355, 1937. 184. ---------- : Methionine therapv in exper imental liver injury produced bv carbon tetrachloride, J. Pharmacol. Exp. Ther. 90:138, 1947. 185. --------- : Hepatotoxic agents: mechanism of action and dietarv interrelationship, Pharmacol. Rev. 4:1, 1952. 186. Drill, V. A., and Loomis. T. A.: Effect of methionine supplements on hepatic injurv produced bv carbon tetrachloride, Science 703:199, 1946. 187. Drill. V. A., Loomis, T. A., and Belford, J.: Effect of protein and carbohydrate intake on liver injurv produced in dogs bv carbon tetrachloride, J. Indust. Hvg. Toxicol. 29:180, 1947. 188. Drill, V. A., and Shaffer, C. B.: Serum cholesterol, serum phosphatase and Bromsulphalein retention in experimental hyperthyroidism. Gastroenterology 1: 308, 1943. 189. Driver, J. R., and Weller, J. N.: Unto ward results from the use of gold com pounds; report of a fatal case. Arch. Derm. Syph. 23:87, 1931. 190. Dubash, J., and Teare, D.: Poisoning by Amanita phalloides, Brit. Med. J. 1:45, 1946. 191. Dubin, I. N.: Unpublished data; cited by Dubin, I. N., Sullivan, B. H., Jr., LeGolvan, P. C., and Murphy, L. C., Am. J. Med. 29:55, 1960. 192. Dujovne, C. A., Chan, C. H., and Zim merman, H. J.: Sulfonamide hepatic injury: review of the literature and report of a case due to sufamethoxazole, New Engl. J. Med. 277:785, 1967. 193. Duma, R. J., Hendry, C. N., and Donahoo, J. S.: Hypersensitivity to diphenylhvdantoin (Dilantin): a case report with toxic hepatitis. Southern Med. J. 59:168, 1966. 194. Dunning, M. F.: Jaundice associated with norethandrolone (Nilevar) adminis tration, J.A.M.A. 767:1242, 1958. 195. Dutra; F. R.: The pneumonitis and gran ulomatosis peculiar to beryllium workers, Am. J. Path. 24:1137, 1948. 196. Eagle, H., and Magnuson, H. J.: The svstemic treatment of 227 cases of ar senic poisoning (encephalitis, dermatitis, blood dyscrasias, jaundice, fever) with 2,3-dimercaptopropanol (BAL), Am. J. Syph. 30:420, 1946. 197. East, E. N-, and Beamish, R- E.: Severe sensitivity reaction (hepatitis, dermatitis and pyrexia ) attributable to phenylin-danedione, Canad. Med. Ass. J. 77:1028, 1957. 198. Eckardt, E. T., and Plaa, G. L.: The effect of phenothiazine derivatives on the disappearance of sulphobromopthalein from mouse plasma, J. Pharmacol. Exp. Ther. 138:387, 1962. 199. Eckhardt, R. D., Faloon, W. W., and Davidson, C. S.: Improvement of active liver cirrhosis in patients maintained with amino acids intravenously as the source of protein and lipotropic substances, J. 200. Clin. Invest. 28:603, 1949. Eddy, J. H., Jr.: Carbon tetrachloride poisoning; preliminary report on the use of methionine in hepatitis, J.A.M.A. 128: 994, 1945. 201. Eden, E., and Harrison, D. D.: Studies in carbon tetrachloride poisoning. III. The possible role of sulphur amino acids 24905083 580 Toxic and Drug-Induced Hepatitis in detoxication, Aust. J. Exp. Biol. Med. 202. 203. Sci. <33:85, 1955. Editorial: Is alcohol hepatotoxic?. New EngL J. Med. 278:905, 1968. Edwards, J. E., and Dalton, A. J.: Induc tion of cirrhosis of the liver and of hepa tomas in mice with carbon tetrachloride, J. Nat. Cancer Inst. 3:19, 1942. 204. Einhom, M., and Davidsohn, I.; Hepat- otoxicity of mercaptopurine, J.A.M.A. 188:802, 1964. 205 Eisalo, A., Jarvinen, P. A., and Luukkainen, T.: Hepatic impairment during the intake of contraceptive pills: clinical trial with postmenopausal women, Brit. Med. J. 2:426, 1964. 206. Elion, G. B., Callahan, S., Bieber, S., Hitchings, C. H., and Rundles, R. W.: A summary of investigations with 6- [ (1- methvl-4-nitro-5-imidazoIvl) thiojpurine (B. W. 57-322), Cancer Chemother. Rep. 14:93, 1961. 207. Elkes, J., and Elkes, C.: Effect of chlor- promazine on the behaviour of chroni cally overactive psychotic patients, Brit. Med. J. 2:560, 1954. 208. Ellenberg, M., and Ossennan, K. E.: The role of shock in the production of central liver cell necrosis. Am. J. Med. 11:170, 1951. 209. Ellinger, F.: Response of the liver to ir radiation, Radiology 44:241, 1945. 210. Elliott, D. C., Baehr, G-, Shaffer, L. W., Usher, C. S., and Lough, S. A.: An evaluation of the massive dose therapv of earlv syphilis, J.A.M.A. 117:1160, 1941. 211. Ellis, F. A.: Reactions to Nirvanol, phenytoin sodium and phenobarbital; re port of a case of ectodermosis erosiva pluriorificalis following the ingestion of phenvtoln sodium. Southern Med. J. 36: 575, 1943. 212. Elmerdorf, D. F., Jr., Cawthon, W. V., Muschenheim, C., and McDermott, W.: The absorption, distribution, excretion and short-term toxicity of isonicotinic acid hvdrazide (nydrazid) in man. Am. Rev. Tuberc. 65:429, 1952. i 213. Engleman, E. P,, Krupp, M. A., Rine hart, J. F-, Jones, R. C., and Gibson, J. R.: Hepatitis following the ingestion of phenylbutazone, J.A.M.A. 156:98, 1954. ' 214. Emaelsteen, D., and Williams, R.-. Jaundice due to nitrofurantoin. Gastro enterology 41:590, 1961. 215. Eschenbremier, A. B., and Miller, E.: Liver necrosis and the induction of car bon tetrachloride hepatomas in strain A 216. mice, }, Nat. Cancer Inst 6:325, 1946. Espiritu, C. R., Kim, T. S., and Levine, R. A.: Granulomatous hepatitis associated with sulfadimethoxine hypersensitivity, 217. 218. 219. J.A.M.A. 202: 985, 1967. Fairhill, L. T., and Neal, P. A.: Indus trial manganese poisoning, Nat. Inst. Health Bull. No. 182, 1943. Falk, A.: Cited by Davis, J. D., et al.X9s Faloon, W. W., Downs, J. J., Duggan, K., and Prior, J. T.: Nitrogen and elec 220. trolyte metabolism and hepatic function and histology in patients receiving tetra cycline, Am. J. Med. Sci. 233:563, 1957. Farber, E., Shull, K. H., Villa-Trevino, S., Lombardi, B., and Thomas, M.: Biochemical pathology of acute hepatic adenosine-triphosphate deficiency. Nature 203:34, 1964. 221. Farmer, C. D., Hoffman, H. N., II, Shorter, R. G., Thurber, D. L., and Bartholomew, L. G.: Intrahepatic chole stasis associated with the Ingestion of ervthromvcm estolate (llosone). Gastro enterology 46:157, 1963. 222. Farquhar, J. D., Stokes, J., Jr., Whitlock, C. M., Jr., Bluemle, L. W., Jr., and Gambescia, J. M.: Studies on the use of Aureomvein in hepatic disease; a note on Aureomvcin therapv in hepatic coma. Am. J. Med. Sci, 220:166, 19S0. 223. Farrar, G. E-: Letter, Wveth Laborator ies, Philadelphia, Pa., Oct. 24, 1961. 224. Fenech, F. F., Bannister, W. H., and Grech. J. L.: Hepatitis with biliverdinaernia in association with indomethacin 225. therapv, Brit. Med. J. 3:155, 1967. Field. J. B., and Federman. D. D.: Sud den death in a diabetic subject during treatment with BZ-55 (carbutamide), Diabetes 6:67, 1957. 226. Findlav, C. M.: The experimental pro duction of biliarv cirrhosis by salts of manganese, Brit. J. Exp. Path. 5:92, 1924. 227. Finland. M., and Nichols, R. L.: Novo biocin, Antibiot. Chemother. 4:209,1957. 228. FischJer, G-: Uber experimentelle er- zeugte Lebercirrhose, Dtsch. Arch. klin. Med. 93:427, 1908. 229. Fitzgibbon, P., and Silver, B.: Toxic ne crosis of liver following use of sulfanila mide, Calif. West Med. 50:123, 1939. 230. Flanagan, J. F.: Toxic nephrosis and mass uretl 231. Flim lesio lene 232. Flini cher effec 49:c 233. Foil sues anin Bull 234. Fori acid Obs 235. Fori hou: and J. F 236. For< tutii Met 237. mus Am. 238. Fos: met I 239. Met Fra R. age 589 240. Fra wit] por 241- Fre Sos still 242. Fre Ber R. effe par pro An; 243. Fre pat cha che 19< Fre stit ant dn Fre References 581 B.. 1 Miller, E.: the x..auction of carepatomas in strain A er Inst. 6:325, 1946. n, T. S., and Levine, us hepatitis associated ane hvpersensitivity, 1967.^ Neal, P. A.: Indusoisoning, Nat. Inst. 12, 1943. Davis, J. D., et al.lss nvns, J. J., Duggan, : Nitrogen and elecand hepatic function ients receiving tetra. Sci. 233:563, 1957. C H., Villa-Trevino, and Thomas, M.: gy of acute hepatic tte deficiency. Nature offman, H. N., II, vurber, D. L., and : Intrahepatic choleth the ingestion of e (Uosone), Castro1963. ces, J., Jr., Whitlock, s, L. W., Jr., and tudi n the use of ic a ;e; a note on in hepatic coma, 0:166, 1950. *, Wveth Laborator, Oct. 24, 1961. nister, W. H., and titis with biliverdi- with indomethacin l 3:155, 1967. erman. D, D.: Sudetic subject during 55 (carbutamide), i experimental prorrhosis bv salts of Exp. Path. 5:92, :hols, R. L.: Novolother. 4:209,1957. experimentelle erDtsch. Arch. klin. ilver, B.: Toxic ne* ig use of sulfanilaJd. 50:123, 1939. ric nephrosis and massive heptic necrosis produced by urethan. Arch. Int. Med. 96:277, 1955. 231. Flinn, F. B., and Jarvik, N. E.: Liver lesions caused by chlorinated naphtha 232. 233. lene, Am. J. Hyg. 27:19, 1938. Flinn, F. B., and von Glahn, W. C.: A chemical and pathologic study of the effect of copper on the liver, J. Exp. Med. 49:5, 1929. Follis, R. H., Jr.: The metabolism of tis sues from anaphvlacticallv hypersensitive animals when antigen is added in vitro. Bull. Johns Hopkins Hosp. 92:371, 1953. 234. Forbes, J. C., and Evans, E. I.: Tannic acid and liver necrosis, Surg. Gvnec. 235. f Obstet. 76:612, 1943. Forbes, J. C., Leach, B. E., and Out house, E. L.: Studies on fat metabolism and susceptibility to carbon tetrachloride, J. Pharmacol. Exp. Ther. 72:202, 1941. 236. Ford. W. W.: The toxicological consti tution of Amanita phalloides, J. Exp. | Med. 8:437, 1906. ! 237. ---------- : A new classification of mycetis- ! mus (mushroom poisoning), Trans. Ass. Am. Phvs. 38:225, 1923. 238. Foss, G. L., and Simpson, S. L.: Oral methvltestosterone and jaundice, Brit. Med.' J. J :259, 1959239. Franklin, M., Bean, W. B., and Hardin, R. C.: Fowler's solution as an etiologic agent in cirrhosis, Am. J. Med. Sci. 219: 589, 1950. 240. Frantz, A. G.: Fatal jaundice associated with iproniazid (Marstlld) therapy; re port of a case, J.A.M.A. 267:987, 1958. 241. Freed, S. C., Rosenbaum, E. E.. and Soskin, $.: Alleged hepatotoxic action of stilbestrol, J.A.M.A. 115:2264, 1940. 242. French, A. B., Barss, T. P., Fairlie, C. S., Bengle, A. L., Jr., Jones, C. M., Linton, R. R., and Beecher, H. K.: Metabolic effects of anesthesia in man. V. Com parison of the effects of ether and cyclo propane anesthesia on the abnormal liver, Ann. Surg. 135:145, 1952. 243. French, A. J.: Hvpersensitivity in the j pathogenesis of the histopathologic changes associated with sulfonamide chemotherapy. Am. J. Path. 22:679, 1946. 244. French, A. J., and Weller, C. V.: Inter stitial myocarditis following the clinical and experimental use of sulfonamide drugs. Am. J. Path. 18:109, 1942. 245. Freund, H. A.: Clinical manifestations and studies in parenchymatous hepatitis, Ann. Int. Med. 10:1144, 1937. 246. Frommer, J.: The pathogenesis of reticu loendothelial foam cells; effect of poly vinylpyrrolidone on the liver of the mouse. Am. J. Path. 32:433, 1956. 247. Fulton, J. D.: Studies in chemotherapy; toxicity and therapeutic action of certain aromatic diamidines after exposure to light, Ann. Trop. Med. 37:48, 1943. 248. Cabrilove, J. L., and Kert, M. J.: Sensi tivity to thiouracil; report of 3 cases, J.A.M.A. 124:504, 1944. 249. Gall, E. A., Altemeier, W. A., Schiff, L., Hamilton, D. L., Braunstein, H., Giuseffi, J., Jr., and Freiman, D. G.: Liver lesions following intravenous administration of polwinvl pviTolidone (PVP), Am. J. Clin. Path. 23:1187, 1953. 250. Gallagher, C. H., Gupta, D. N., Judah, J. D., and Rees, K. R.: Biochemical changes in liver in acute thioacetamide intoxication, J. Path. Bact. 72:193, 1956. 251. Gallagher, T. F., Jr., Mueller, M. N., and Kappas, A.: Estrogen pharmacology. IV. Studies on the structural basis for estro gen-induced impairment of liver func tion, Medicine 45:471,1966. 252. Gardner, D. L., and Ogilvie, R. F.: The late results of injection of Thorotrast; two cases of neoplastic disease following contrast angiographv, J. Path. Bact. 78: 133, 1959. 253. Gargill, S. L., and Lesses, M, F.: Toxic reactions to thiouracil; report of cases with one fatalitv, J.A.M.A. 127:890, 1945. 254. Garvin, C. F.: Toxic hepatitis due to sulfanilamide, J.A.M.A. Ill:2283, 1938. 255. Carvin, J. S., and Gibbs, F. A.: Mesantoin toxicitv (a clinical note), Dis. Nerv. Syst. 11:48, 1950. 256. Cefter, W. I., Turnoff, D-, and Schnabel, T. G.: Unusuallv high icterus index in patient with fatal hepatic necrosis follow ing Mapharsen; case report. Am. J. Svph. 27:629, 1943. 257. Gerlei, F.: Necrose du foie consecutive a I'empoisonnement par la thyroxine, Ann. anat. path. 10:555, 1933. 58. Gibberd, G. F.: Delayed chloroform poisoning in obstetric practice, a clinical studv, with reports on three cases. Guv's Hosp. Rep. 85:142, 1935. 259. Gibbs, F. A., Everett, G. M., and Rich ards, R. K.: Phenurone in epilepsv, Dis. Nerv. Syst. 10:47,1949. 582 Toxic and Drug-Induced Hepatitis 260. Gibson, P. C., and Quinlan, J. T.: Peri arteritis nodosa in thiourea therapy. Lancet .2:108, 1945. 261. Giffin, H. Z., and Allen, E. V.: Experi ments with phenvlhydrazine; studies on renal and hepatic function and ervthro- ' poiesis, Ann. Int. Med. 2:677, 1928. 262. Gillman, J., and Gillman, T.: Structure of the liver in fatal bums, S. Afr. J. Med. Sci. 25:169, 1948. 263. Gilmore, J. P., and Fozzard, H. A.: Liver function following thermal injurv. Am. J. Physiol. 198:491, 1960. 264. Glaser, G. L., and Adams, D. A.: Agran ulocytosis with promazine administration: report of three cases, Ann. Tnt. Med. 48: 372, 1958. 265. Glynn, L. E., and Himsworth, H. P.: The intralobular circulation in acute liver injurv bv carbon tetrachloride, Clin. Sci. 6:235, 1948. 266. Glvnn, L. E., Himsworth, H. P., and Neuberger, A.: Pathological states due to deficiency of the sulphur-containing amino acids, Brit. J. Exp. Path. 26:326, 1945. 267. Gocher, T. E. P.: Antimony intoxication, Northw. Med. 44:92, 1945. 268. Goldblatt, S.: Severe reaction to griseofulvin: sensitivity investigation. Arch. Dermat. 83:936, 1961. 269. Goldring, W., and Graef, I.: Nephrosis with uremia following transfusion with incompatible blood: report of seven cases with three deaths. Arch. Int. Med. 58: 823, 1936. 270. Goldschmidt, S.. Ravdin, I. S., and Lucke, B.: Anesthesia and liver damage; protective action of oxvgen against the necrotizing effect of certain anesthetics on the liver, J. Pharmacol. Exp. Ther. 59:1, 1937. 271. Goldschmidt. S.. Ravdin, I. S., Lucke. B.. Muller, G. P., Johnston, C. G., and Ruigh, W L.: Divinvl ether; experi mental and chemical studies; J.A.M.A. 102:21, 1934. 272. Goldschmidt, S., Vars, H. M., and Rav din, I. S.: The influence of the foodstuffs upon the susceptibility of the liver to in jury by chloroform, and the probable mechanism of their action, J. Clin. Invest. 18:277, 1939. 273. Goodman, L., and Gilman, A.: The Pharmacological Basis of Therapeutics, New York, Macmillan, 2d ed., 1955. 274. Gordon, B. S., Waif, J., Krause, T., and Shai, F.: Peliosis hepatis and cholestasis following administration of norethandro lone. Am. J. Clin. Path. 33:156, 1960. 275. Gore, I., and Isaacson, N. H.: The pathology of hyperpyrexia; observations at autopsy in 17 cases of fever therapy, Am J. Path. 25:1029, 1949. 276. Graef, I., Kamofsky, D. A., Jager, V. B., Krichesky, B., and Smith, H. W.: The clinical and pathologic effects of nitro gen and sulfur mustards in laboratory animals. Am J. Path. 24:1, 1948. 276a. Grayson, M. J., and Reilly, M. C- T.: Budd-Chiari syndrome after oral contra ceptives, Brit. Med. J. 1:512, 1968. 277. Greenblatt, I. and Kahn, A.: Clinical toxicitv studies of a monoamine oxidase inhibitor, Ann. N. Y. Acad. Sci. 80:947, 1959278. Greenburg, L., Mayers, M. R., Hermann. H., and Moskowitz, S.: The effects of exposure to toluene in industrv, J.A.M.A. 118:573, 1942. 279. Greenburg, L., Mayers, M. R., and Smith, A. R.: The svstemic effects re sulting from exposure to certain chlori nated hvdrocarbons, J. Indust. Hvg. Toxicol. '21:29, 1939. 280. Gregory, D. H., Zaki, G. F-, Sarosi, G. A.. and Carey, J. B., Jr.: Chronic cholestasis Following prolonged tolbutamide admin istration: associated with destructive cho langitis and cholangiolitis, Arch. Path. 84.194, 1967. 281. Grier, R. S., Nash, P., and Freiman. D. G-: Skin lesions in persons exposed to bervllium compounds, J. Indust. Hvg. Toxicol. 30:228, 1948. 282. Griffith, R. S-: Eli Lillv Bulletin, August 23, 1961. 283. Cuild, W. R., Young, J. V:, and Merrill. J. P,: Anuria due to carbon tetrachlo ride intoxication, Ann. Int. Med. 48: 1221, 1958. 284. Gupta, P. S., Bhargava, S. P., and Sharma, M. L.: Cited by Holtzman et al.337 285. Guraev, R.: Tetrachlorethane intoxica tion: early recognition of liver damage and means of prevention, Gatsroenterology 1:1112, 1943. 286. ---------- : Useful procedures in early di agnosis of liver damage following ex posure to the chlorinated hydrocarbons. New Jork J. Med. 47:2566, 1947. 287. Gyorgy, P.: Relation of dietary factors References 5$3 jsis \ds and cholestasis liptsi.^aon of norethandro^lin. Path. 33:156, 1960. Isaacson, N. H.: The paperpvrexia; observations at cases of fever therapv, Am. >29, 1949. oofskv, D. A., Jager, V. B., , and Smith, H. W.: The jathologic effects of nitrour mustards in laboratory T. Path. 24:1, 1948. J., and Reilly, M. C. T.: ;vndrome after oral contraMed. J. 1:512, 1968. J., and Kahn, A.: Clinical >s of a monoamine oxidase i. N. Y. Acad. Sci. 80:947, ., Mavers, M. R., Hermann, kowitz, S.: The effects of >luene in industry, J.A.M.A. 2. L., Mavers, M\ R., and The svstemic effects re exposure to certain chloricarbons, J. Indust. Hyg. ,9, 1939. d., Zaki, G. F., Sarosi, G. A., . B., Jr.: Chronic cholestasis >lon tolbutamide admin>ciat<_ -vith destructive chocholangiolitis. Arch. Path. , Nash, P-, and Freiman, lesions in persons exposed compounds, J. Indust. Hvg. !28, 1948. .: Eli Lilly Bulletin, August ., Young, J. V., and Merrill, a due to carbon tetrachloition, Ann. Int. Med. 48: S., Bhargava, S. P., and L,: Cited bv Holtzman Tetrachlorethane intoxicarecognition of liver damage )f prevention, Gatsroenterol1943. ifui procedures in early dliver damage following exle chlorinated hydrocarbons, Med. 47:2566, 1947. Relation of dietary factors to liver injury, p. 67, Tr. 6th Liver In jury Conf., New York, Macy, 1947. 288- Gyorgy, P., and Goldblatt, H.: Further observations on the production and pre vention of dietary hepatic injury in rats, J. Exp. Med. 89:245, 1949. 289. Gyorgy, P., Seiiter, J., TomareHi, R. M., and Goldblatt, H.: Influence of dietary factors and sex on the toxicity of carbon tetrachloride in rats, J. Exp. Med. 83: 449, 1946. 290. Gyorgy, P., Stokes, J., Jr., and Gold blatt, H.: Antimicrobial agents in the prevention of experimental dietary injurv of the liver, Trans. Ass. Am. Phys. 64:289, 1951. 291. Haber, E., and Osborne, R. K.: Icterus and febrile reactions in response to isonicotim'c acid hvdrazine. Report of two cases and review of the literature. New Engl. J. Med. 260:417, 1959. 292. Hadlev, W. B., Kachadurian, A., and Marble, A.: Studies with chlorpropamide in diabetic patients, Ann. N. Y. Acad. Sd. 74:621, 1959. 293- Haemmerli, U. P.: Jaundice during preg nancy, with special emphasis on recurrent jaundice during pregnancy and its dif ferential diagnosis, Acta med. scand. Suppl. 444, 1966. 294. Hageman, P. O., and Blake, F. G.: A specific febrile reaction to sulfanilamide; drug fever, J.A.M.A. 109:642, 1937. 295. Haines, S. F., Magath, T. B, and Power, M. H.: The hippuric acid test in hyper thyroidism, Ann. Int. Med. 14:1225, 1941. 296. Hall, L., and Wharton, G. K.: Chlor amphenicol (Chloromycetin) in the treat ment of viral hepatitis. Gastroenterology 19:69, 1951. 297. Hamff, L. H., Ferris, H. A., Evans, E. C., and Whiteman, H. W.: The effects of tolbutamide and chlorpropamide on pa tients exhibiting jaundice as a result of previous chlorpropamide therapv,' Ann. N. Y. Acad. Sci. 74:820, 1959. 298. Hampton, J. C.: Electron microscopic studv of extrahepatic biliary obstruction in the mouse. Lab. Invest. 10:502, 1961. 299. Hamre, D. M., Rake, G., McKee, C. M., and MacPhillamy, H. B.: The toxicity of penicillin as prepared for clinical use. Am. J. Med. Sci. 206:642, 1943. 300. Hamwi, G. J., Skillman, T. G., Kruger, F. A., Roush, W. H., and Freedy, L. R.: Comparative pharmacology and clinical responses to metahexamide, Ann. N. Y. Acad. Sci. 82:547, 1959. 301. Hanger, F. M., and Gutman, A. B.: Postarsphenamine jaundice apparently due to obstruction of intrahepatic biliary tract, J.A.M.A. 115:263, 1940. 302. Hanzon, V.; Liver cell secretion under normal and pathologic conditions stud ied by fluorescence microscopy on living rats, Acta phvsiol. scand. 28, Supp. 101, 1952. 303. Hardy, H. L., and Stoeckle, J. D.: Beryl lium disease, J. Chron. Dis. 9:152, 1959. 304. Hargraves, M. M., Mills, S. D., and Heck, F. J.: Aplastic anemia associated with administration of chloramphenicol, J.A.M.A. 149:1293, 1952. 305. Hargreaves, T., and Lathe, G. H.: Drugs affecting biliary excretion, in McIntyre, N., and Sherlock, S. (eds.): Therapeutic Agents and the Liver, p. 9, Oxford, Blackwell Scientific Publ., 1965. 306. Harinasuta, U., and Zimmerman, H. J.: Diphenylhydantoin sodium hepatitis, J.A.M.A. 203:1015, 1968. 307. Hartfall, S. J,, and Garland, H. G.: Fur ther observations on the gold treatment of rheumatoid arthritis. Lancet 1:1459, 1936. 308. Hartley, G., Jr., and Lushbaugh, C. C.: Experimental allergic focal necrosis of the liver, Am. J. Path. 18:323, 1942. 309. Hartman, F. W., and Romence, H. L.: Liver necrosis in bums, Ann. Surg, 118: 402, 1943. 310. Hashimoto, H.: The heart in the experi mental hyperthyroidism with special ref erence to its histology, Endocrinology 5:579, 1921. 311. Hawn, C. V., and Janeway, C. A.: His tological and serological sequences in experimental hypersensitivity, J. Exp. Med. 85:571, 1947. 312. Hazlett, B. E., Taylor, H. E., and Whitelaw, D. M.: Fulminating hepatic necro sis in a patient with multiple myeloma treated with urethane. Report of a case. Blood 10:76, 1955. 313. Heaney, R. P., and Whedon, G. D.: Im pairment of hepatic Bromsulphalein clearance by two 17-substituted testosterones, J. Lab. Clin. Med. 52:169, 1958. 314. Herbert, P, A., and Scaricaciottoli, T. M.: Diffuse hepatitis necrosis caused by sulfadiazine. Arch. Path. 40:94, 1945. 315. Herman, R. H., and Sullivan, B. H., Jr.: 584 Toxic and Drug-Induced Hepatitis Heatstroke and jaundice, Am. J. Med. 27:154, 1959. 316. Hersh, E. M., Wong, V. G., Henderson, E. S., and Freireich, E. J.: Hepatotoxic effects of methotrexate, Cancer 19:600, 1966. 317. Hill, K. R.: The vomiting sickness of Jamaica: a review. West. Ind. Med. J. 1:243, 1952. 318. Hill, K. R., Stephenson, C. F., and Filshie, I.: Hepatic veno-occlusive disease produced experimentally in rats by the injection of monocrotaline. Lancet 2:623, 1958. 319. Hill, R. B., Jr.: Fatal fat embolism from steroid-induced fattv liver. New EngL J. Med. 265:318, 1961. 320. Hill, R. B., Jr., Droke, W, E., and Hays, A. P.: Hepatic lipid metabolism in cor tisone-treated rat, Exp. Molec. Path. 4: 320, 1965. 321. Hill, W. R., and Damiani, C. R.: Death following exposure to DDT, New Engl. J. Med. 235:897, 1946. 322. Himsworth, H. P.: Lectures on the Liver and Its Diseases, Cambridge, Mass., Har vard, 1947. 323. Himsworth, H. P., and Glynn, L. E.: Massive hepatic necrosis and diffuse hepatic fibrosis (acute yellow atrophy and portal cirrhosis): their production bv means of diet, Clin. Sci. 5:93, 1944. 324. -----------: Toxipathic and trophopathic hepatitis. Lancet 2:457, 1944. 325. Himsworth, H. P-, and Lindan, O.: Di etetic necrosis of the liver: the influence of a-tocopherol. Nature 163:30, 1949. 320. Hirsheimer, A.: The synthesis and ex cretion of hippuric acid in pregnancy, Am. J. Obstet. Gvnec. 29:395, 1935. 327. Hoaken, P. C. S.: Jaundice during imipramine treatment, Canad. Med. Ass. J. 90:1367, 1964. 328. Hochman, R., and Robbins, J. ].: Jaun dice due to ectvlurea. New Engl. J. Med. 259:583, 1958.' 329. Hoffbauer, F. W.: Clinical aspects of jaundice resulting from intrahepatic ob struction, J.A.M.A. 269:1453, 1959. 330. Hoffbauer, F. W., Nelson, O. L. N., Wag ner, D. J., and Knutsen, A.: Fatal liver necrosis in two patients receiving zoxazolamine, Gastroenterology 34:1048, 1958. 331. Hoffman, J., Himes, M. B., Klein, A., Poulos, V., and Post, J.: Responses of the liver to injury. Effect of previous in jury upon the healing pattern after acute carbon tetrachloride poisoning. Arch. Path. 62:96, 1956. 332. Holdsworth, C. D., Atkinson, M., Dossett, J. A., and Goldie, W.: Hepatitis caused by the newer amine-oxiaase-inhibiting drugs. Lancet 2:1459, 1961. 333. Holdsworth, C. D., Atkinson, M., and Goldie, W.: Hepatitis caused bv the newer amine-oxidase-inhibiting drugs, Lancet 2:621, 1961. 334. Hollister, L. E.: Allergic reactions to tranquilizing drugs, Ann. Int. Med. 49: 17, 1958. 335. Hollister, L. E., Motzenbecker, F. P., and Degan, R. O.: Withdrawal reactions from chlordiazepoxide ("Librium"), Psvchopharmacologia 2:63, 1961. 336. Holoubek, J. E., Mathews, W. R.. and Hollis, W. J.: Thiouracil hepatitis. Am. J. Med. 5:138, 1948. 337. Holtzman, N. A., Elliott, D. A., and Heller, R. H.: Copper intoxication: re port of a case with observations on ceru loplasmin, New Engl. J. Med. 275:347, 1966. 338. Hoppe, J. O., Marcelli, G. M. A., and Tainter, M. L.; A review of the toxicity of iron compounds. Am. J. Med. Sci. 230: 558, 1955. 339. Hornung, S.: Synthalin und Leberschadi- gung, Klin. Wschr. 7:69, 1928. 340. Hove, E. L.: Interrelation of a-tocoph- erol and protein metabolism; protective effect of vitamin E and certain nitroge nous compounds against CC14 poisoning in rats, Arch. Biochera. 27:467, 194S. 341. Hove, E. L., and Hardin, J. O.; Effect of vitamin E and CC14 on fat, respira tion and choline oxidase of rat livers, Proc. Soe. Exp. Biol. Med. 78:858, 1951. 342. Hsia, D. Y. Y., Dowben, R. M., Shaw, R., and Grossman, A.: Inhibition of glucuronosyl transferase by progestational agents from serum of pregnant women. Nature 287:693, 1960. 343. Hsia, D. Y., Riabov, S., and Dowben, R. M.: Inhibition of glucuronosyl trans ferase bv steroid hormone, Arch. Biochem. 103:181, 1963. 344. Hueper, W. C.: Toxicity and detoxifica tion of cinchophen; experimental studies, Arch. Path. 41:592, 1948. 345. Hultin, T., Arrhenius, E., Low, H-. and Magee, P. N.: Toxic liver injury. Inhibi tion by dimethylnitrosamine of incorpo ration of labelled amino acids into pro- References 585 aJinc item after acute >ride poisoning, Arch. }. Atkinson, M., Dossett, >, \V.: Hepatitis caused amine-oxidase-inhibiting 1459, 1961. D., Atkinson, M., and patitis caused by the idase-inhibiting drugs, 61. : Allergic reactions to gs, Ann. Int. Med. 49: teins of rat liver preparations in vitro, J. Biochem. 76:109, 1960. 346. Hurst, E. W., and Hurst, P. E.: The aetiology of hepato-lenticular degenera tion: experimental liver cirrhosis; poi soning with manganese, chloroform, phenvlhvdrazine, bile and guanidine, J. Path.' Bact 31:303, 1928. 347. Hurst, E. W., and Paget, G. E.: Proto porphyrin, cirrhosis and hepatoma in the livers of mice given griseofulvin, Brit. J. Dermatol. 75:105, 1963. 348. Hurt, P., and Wegmann, T.: Protrahier- 359. Jasper, H.: Jaundice in a patient receiv ing zoxazolamine (Flexin), Am. J. GastroenL 34:419, 1960. 360. Jeliffe, D. B., Bras, G., and Mukherjee, K. L.: Veno-occlusive disease of the liver and Indian childhood cirrhosis. Arch. Dis. Child. 32:369, 1957. 361. Johnston, T. G., and Cazort, A. G.-. Severe serum sickness reaction with cy anosis following Terramycin, Antibiot. Chemother. 3:481, 1953. 362. Jones, E. A., Gain, D., Clink, H. M., MacGillivray, M., and Sherlock, S.: He Motzenbecker, F. P., Withdrawal reactions >xide ("Librium"), Psvi 2:63, 1961. Mathews, W. R., and liouracil hepatitis. Am. 48. Elliott, D. A., and 'opper intoxication: re* h observations on ceruZngl J. Med. 275:347, ter Largactilikterus mit Ubergang in primare biliare Cirrhose, Acta hepatosplen. 8:87, 1961. 349. Huseby, K. O.: Jaundice with persisting pericholangiolitic inflammation in a pa tient treated with chlorthiazide; report of a case. Am. J. Dig. Dis. 9:439, 1964. 350. Hustead, A. P.: The effects of Terramycin on the rat liver. Thesis, Yale Uni versity, 1952. 350a. Hutchison, J. C., Roediger, P. M., and Werblin, M.: Cholestatic jaundice follow- patic coma due to acute hepatic necrosis treated by exchange blood-transfusion, Lancet 2:169, 1967. 363. Jones, N. L.; Hepatitis due to phenindione sensitivity, Brit. Med. J. 2:504, 1960. 364. Jones, W. M., Margolis, G., and Stephen, C. R.: Hepatotoxicity of inhalation anes thetic drugs. Anesthesiology 19:715, 1958. 365. Jonstam, R.: Urethane-induced hepatic failure, Acta med. scand. 170:701, 1961. arcelli, G. M. A., and l review of the toxicity s, Am. J. Med. Sci. 230: ' ing administration of quinethazone. Cur rent Therap. Res. 6:199, 1964. 351. Hyams, D. E., Taft, E. B., Drummey, G. D., and Isselbacher, K. J.: The pre 366. 367. Judah, J. D.: Effect of antihistamines on mitochondrial swelling and liver injury, Nature 185:390, 1960. Judah, J. D., and Rees, K. R.: Mecha vention of fatty liver by administration nism of action of carbon tetrachloride, hal d Leberschadi- of adenosine triphosphate. Lab. Invest. Fed. Proc. 18:1013, 1959. r. 7:w, 1928. errelation of ce-tocoph- 16:604, 1967. 368. Kahil, M. E., Fred, H. L., Brown, H., 352. Imhauser, K.: Hamstoffsynthese in der and Davis, J. S.: Acute fatty liver of metabolism; protective Fettleber, Arch. exp. Path. Pharmak. 145: pregnancy; report of two cases. Arch. E and certain nitroge- 120, 1929. Int. Med' 113:63, 1964. against CC14 poisoning i 353. Ingold, J. A., Reed, G. B., Kaplan, H. S., 369. Kahn, M., and Perez, V..- Jaundice asso rhem. 17:467, 1948. and Bagshaw, M. A.: Radiation hepatitis. ciated with the administration of ipronia Hardin, J. O.: Effect Am. J. Roentgenol. 93:200, 1965. zid. Report of nine cases. Am. J. Med. . CC14 on fat, respira- 354. Isaacs, B., Macarthur, J. G., and Taylor, 25:898, 1958. oxidase of rat livers, R. M.: Jaundice in relation to chlor- 370. Kantrowitz, P. A., Jones, W. A., Green- 01. Med. 78:858, 1951. promazine therapy, Brit. Med. J. 2:1122, berger, N. J., and Isselbacher, K.: Severe >o\vben, R. M., Shaw, 1955. postoperative hyperbilirubinemia simu , A.: Inhibition of glu- 355. Isselbacher, K.: Enzymatic mechanisms lating obstructive jaundice. New Engl. ase by progestational of hormone metabolism. II: Mechanism J. Med. 276:591, 1967. i of pregnant women, of hormonal glucuronide formation. Re 371. Karnofsky, D. A., Burchenal, J. J., Armi- 960. cent Progr. Hormone Res. 12:134, 1956. stead, G. C., Southam, C. M., Bernstein, X3V, S., and Dowben, 356. Isselbacher, K. J.,andGreenberger, N. J.: J. L., Craver, L. F., and Rhoads, C. P.: of glucuronosyl trans- Metabolic effects of alcohol on the liver, Triethylene melamine in the treatment hormone, Arch. Bio- New Engl. J. Med. 270:351, 402, 1964. of neoplastic disease; compound with 163. 357. Jacobs, J., Greene, H., and Gendel, B. R.: nitrogen-mustard-like activity suitable for oxicity and detoxifica- Acute iron intoxication. New Engl. J. oral and intravenous use. Arch. Int. Med. ; experimental studies, Med. 273:1124, 1965. 87:477,1951. 2. 1946. 358. Jacobson, K. H., Wheelwright, H. J., Jr., 372. Katz, R., Klinger, J., Silva, L., Rodriguez, ius, E., Low, H., and Clem, J. H., and Shannon, R. N.: Stud J., and Ducci, H.: Serial hepatic study in dc liver injury. Inhibi- ies on the toxicology of n-nitrosodi- patients treated with iproniazid, Ann. itrosamine of incorpo- methylamine vapor. Arch. Industr. Health N. Y. Acad. So. 80:898, 1959. amino acids into pro 12:617,1955. 373. Kelsey, J. R., Jr., Moyer, J. H., Brown, 586 Toxic and Drug-Induced Hepatitis W. G., and Bennett, H, D.; Chlorpromazine jaundice. Gastroenterology 29: 865, 1955. 374. Kelsey, W. M. and Scharyj, M.: Fatal hepatitis probably due to mdomethacin, j.A.M.A. 199:586, 1967. 375. Kemp, J. A.: jaundice occurring during administration of promazine, Gastro enterology 32:937, 1957. 376. Killip, 1., Ill, and Payne, M. A.: High serum transaminase activity in heart disease. Circulatory failure and hepatic necrosis. Circulation 21:646, 1960. 377. King, W. M.: Cited by Brunson et al.104 378. Kintzen, W., and Silny, J.: Peliosis hepatis after administration of fluoxymesterone, Canad. Med. Ass. J. 83:160, 1960. 379. Kirk, R., and Henry, A. J.: Observations on the toxicity of stilbamidme, Ann. Trop. Med. 38:99, 1944. 380. Kirtley, W. R.: Occurrence of sensitivity and side reactions following carbutamide. Diabetes 6:72, 1957. 381. Klatskin, G.: Alcohol and its relation to liver damage, Gastroenterology 41:443, 1961. 382. -----------: Mechanisms of toxic and drug- induced hepatic injury, in Fink, B. K. (ed.); Toxicity of Anesthetics, pp. 159172, Baltimore, Williams & Wilkms, 1^68. 383- -----------: Unpublished data. 384. Klatskin, G., Krehl, W. A., and Conn, H. O.: The effect of alcohol on the cho line requirement, J. Exp. Med. 100:605, 615, 1954. 385. Klatskin, G., and Yesner, R.: Hepatic manifestations of sarcoidosis and other granulomatous diseases, Yale J. Biol. Med. 23:207, 1950. 386. Klein, N. C., and Jeffries, G. H.: Hepato- toxicity after methoxyflurane administra tion, J.A.M.A. 197:1037, 1966. 387. Knick, B.; Clinical and experimental studies with chlorpropamide in diabetes mellitus, in normal individuals, and in nondiabetics with hepatic disease, Ann. N. Y. Acad. Sci. 74:858, 1959. 388. Koch-Weser, D., de la Huerga, J., and Popper, H.: Hepatic necrosis due to bromobenzene and its dependence upon available sulfur amino acids, Proc. Soc. Exp. Biol. Med. 79:196, 1952. 389. Kohlstaedt, K. G.: Propionyl erythromy cin ester lauryl sulfate and jaundice, J.A.M.A. 178:89, 1961. 390. Kohn, N., and Myerson, R. M.: Choles tatic hepatitis associated with trifluoper azine, New Engl. J. Med. 264:549, 1961. 391. Kohn, N. N., and Myerson, R. M.: Xanthomatous biliary cirrhosis following chlorpromazine. Am. J. Med. 31:665, 1961. 392. Koler, R. D., and Forsgren, A. L.: Hepa- toxicity due to chlorambucil; report of a case, J.A.M.A. 167:316, 1958. 393. Koletsky, S., and Gustafson, G.: Liver damage in rats from radioactive colloidal gold. Lab. Invest. 1:312, 1952. 394. Kolmer, J. A., and Luck6, B.: A study of the histologic changes produced ex perimentally in rabbits by arsphenamine. Arch. Derm. Syph. 3:483, 1921. 395. Kopelman, H., Scheuer, P. J-, and Williams, R.: The liver lesion of the Epping jaundice. Quart. J. Med. 35:533, 1966. 396. Korn, R. J.: Discussion, Second Marsilid Svmposium, May 8, 1958, Chicago, 111. 397. Korn, R. J., Rock, W., and Zimmerman, H. J-: Studies of hepatic function in patients receiving promazine, Am. J. Med. Sci. 235:431, 1958. 398. Kory, R. C., Bradley, M. H., Watson, R. N., Callahan, R., and Peters, B. J.: A six-month evaluation of an anabolic drug, norethandrolone, in underweight per sons. II: Bromsulphalein (BSP) reten tion and liver function. Am. J. Med. 26:243, 1959. 399. Koszalka, M. F.: Medical obstructive jaundice; report of a death due to methvltestosterone, J. Lancet 77:51, 1957. 400. Krainin, P.: Gastric ulcer with massive hemorrhage following use of phenylbuta zone; report of a case, J.A.M.A. 252:31, 1953. 401. Krall, L. P., and Bradley, R. F.: Clinical evaluation of formamidinyliminourea, a new biguanidine oral blood sugar lower ing compound: comparison with other hvpoglycemic agents, Ann. Int. Med. 50:586, 1959. 402. Krawitt, E. L., Stein, J. H., Kirkendall, W. M., and Clifton, J. A.: Mercaptopurine hepatotoxicity in a patient with chronic active hepatitis. Arch. Int. Med. 120:729, 1967. 403. Kreek, M. J., Sleisenger, M. H., and Jeffries, G. H.: Recurrent cholestatic jaundice of pregnancy with demonstrated estrogen sensitivity, Am. J. Med. 43:795, 1967. Jf References 587 g associated with trifluoper5ngl Med. 564:549, 1961. f ,, ` Myerson, R. M.: is biliary cirrhosis following ne. Am. J. Med. 31:665, and Forsgren, A. L.: Hepato chlorambucil; report of a L 167:316, 1958. and Gustafson, G.: Liver its from radioactive colloidal avert. 1:312, 1952. L, and Luck6, B.: A study logic changes produced ex in rabbits by arsphenamine, Syph. 3:483, 1921. H., Scheuer, P. J., and The liver lesion of the lice, Quart. J. Med. 35:553, Discussion, Second Marsilid May 8, 1958, Chicago, 111. Rock, W., and Zimmerman, ies of hepatic function in eiving promazine. Am. J. 5:431, 1958. , Bradley, M. H., Watson, ian R., and Peters, B. J.: A aluation of an anabolic drug, one, in underweight peromsulphalein (BSP) retenrer "ction, Am. J. Med. J. [. F.: Medical obstructive ort of a death due to methylJ. Lancet 77:51, 1957. Gastric ulcer with massive following use of phenvlbutaof a case, J.A.M.A. 152:31, and Bradlev, R. F.: Clinical f formamidinyliminourea, a dine oral blood sugar lowerad: comparison with other c agents, Ann. Int. Med. 3. L., Stein, J. H., Kirkendall, l Clifton, J. A.: Mercaptototoxicity in a patient with 'e hepatitis. Arch. Int. Med. 37. J., Sleisenger, M. H., and H.: Recurrent cholestatic wegnaney with demonstrated dtivity. Am. J. Med. 43:795, 404. Kreek, M. J., Weser, E., Sleisenger, M. H., and Jeffries, G. H.: Idiopathic cholestasis of pregnancy: the response to challenge with the synthetic estrogen, ethinyl estradiol. New Engl. J. Med. 277: 1391, 1967. 405.. Kunelis, C. T., Peters, J. L., and Ed mondson, H. A.: Fatty liver of pregnancy and its relationship to tetracycline ther apy, Am. J. Med. 38:359, 1965. 406. Kuzma,' J. F., and Polley, T. Z.: The role of the liver in renal sulfonamide complications. Am. J. Med. Sci. 214:651, 1947. 407. Labhardt,F.: Technique, side effects and complications of Largactil therapv, Schweiz. Arch. Neurol. Psvchiat. 73:338, 1954. 408. LaDue, J. S., Schenken, J. R., and Kuker, L. H.: Phosphorus poisoning; report of 16 cases with repeated liver biopsies in a recovered case, Am. J. Med. Sci. 208: 223, 1944. 409. Lamson, P. D., Gardner, G. H., Gustaf son, R. K., Maire, E. D., McLean, A. J., and Wells, H. S.: The pharmacologv and toxicology of carbon tetrachloride, J. Pharmacol. Exp. Ther. 22:215, 1923. 410. Lamson, P. D., and Wing, R.: Early cir rhosis of the liver produced in dogs by carbon tetrachloride, J. Pharmacol. Exp. Ther. 29:191, 1928. 411. Landsteiner, K.: Anaphvlactic shock by azo dyes, J. Exp. Med. 57:633, 1933. 412. Landsteiner, K., and Jacobs, J.: Studies on the sensitization of animals with simple chemical compounds; anaphylaxis induced bv arsphenamine, J. Exp. Med. 64:717, 1936. 413. Landsteiner, K., and vander Scheer, J.: Serological reactions with simple chemi cal compounds (precipitin reactions), J. Exp. Med. 56:399, 1932. 414. Lansing, A. M., Davis, W. M., and Brizel, H. E.; Radiation hepatitis. Arch. Surg. 96:878, 1968. 415. Large, H. L., Jr.: A case of iron intoxi cation caused by Roncovite with a note on striation of portal blood flow. Am. J. Clin. Path. 35:427, 1961. 416. Larsson-Cohn, U., and Stenram, U.: Liver ultrastructure and function in icteric and non-icteric women using oral contraceptive agents, Acta. med. scand. 181:257, 1967. 417. Leard, S. E., Greer, W. E. R., and Kauf 418. 419. 420. 421. 422. 423. 424. 425. 426. 427. 428. 429. man, I. C.: Hepatitis, exfoliative derma titis and abnormal bone marrow occur ring during Tridione therapy; report of case with recovery. New Engl. J. Med. 240:962, 1949. Lees, A. W,: Toxicity in newly diag nosed cases of pulmonary tuberculosis treated with ethionamide. Am. Rev, Resp. Dis. 88:347, 1963. Leevy, C. M., Cherrick, G. R., and Davidson, C. S.: Observations on norethandrolone-induced abnormalities in plasma decay of sulfobromophthalein and indocyanine green, J. Lab. Clin. Med. 57:918, 1961. Legge, T. M.: Toxic jaundice in muni tion workers and troops, Brit. Med. J. I: 155, 1917. Lehman, A. J., and Hanzlik, P. J.: Cinchophen toxicosis; results of experimen tal subacute and chronic cinchophen poi soning, Arch. Int Med. 52:471, 1933. Lehmann, H. E., Cahn, C. H., and deVerteuff, R. L.: The treatment of depressive conditions with imipramine, Canad. Psychiat. Ass. J. 3:155, 1958. Lehnherr, E. R.: Acute carbon tetra chloride poisoning; report of a case Arch. Int. Med. 56:98, 1935. Leifer, W., Chargin, L., and Hyman, H. T.: Massive dose arsenotherapy of early syphilis by intravenous drip method: re capitulation of the data (1933 to 1941) J.A.M.A. 117:1154, 1941. Lennox, W. G.: Tridione in the treat ment of epilepsv, J.A.M.A. 134:138 1947. Lenzer, A. R., Lockie, L. M., and Becker, C. F.: Acute yellow atrophy following cinchophen administration; report of case. New Engl. J. Med. 236:500, 1947. Lepper, M. H., Dowling, H. F., Robin son, J. A., Stone, T. E., Brickhouse, R. L., Caldwell, E. R., Jr., and Whelton, R. L.: Symposium on antibiotics; studies on hypersensitivity to penicillin; inci dence of reactions in 1303 patients, J. Clin. Invest. 28:826, 1949. Lepper, M. H., Wolfe, C. K., Zimmer man, H. J., Caldwell, E. R., Jr., Spies, H. W., and Dowling, H. F.: Effect of large doses of Aureomycin on human liver, Arch. Int. Med. 88:271, 1951. Lepper, M. H., Zimmerman, H. J., Carroll, G., Caldwell, E. R., Jr., Spies, H. W., Wolfe, C. K., and Dowling, H. F.: 588 Toxic and Drug-Induced Hepatitis Effects of large doses of Aureomycin, Terramycin and chloramphenicol on livers of mice and dogs. Arch. Int Med. 88:284,1951 430. Levi, E.: Ober die Ursache der Leber- cirrhose bei Polycythamie Leberschadigung durch Phenylhydrazintherapie, Z. klin. Med. 100:177, 1924. 431. Levine, R. A., Briggs, G. W., and Lowell, D. M.: Chronic chlorpromazine cholan- giolitic hepatitis; report of a case with immunofiuorescent studies. Gastroenter ology 50:665, 1966. 432. Levy, R. W., Simmons, D. J., and Aaronson, S.: Fatal hepatorenal syndrome as sociated with phenurone therapv, New Engl. J. Med. 242:933, 1950. 433. Lewis, C. N., Putnam, L. E., Hendricks, F. D., Kerlan, I., and Welch, H.; Chlor amphenicol (Chloromycetin) in relation to blood dvscrasias with observations on other drugs, Antibiot. Chemother. 2:601, 1952. 434. Lewis, G. M., and Sawickv, H. H.: Con tact dermatitis from chlorpromazine. Report of two cases, J.A.M.A. 157:909, 1955. 435. Lichtenstein, M. R., and Cannemever, W.: Severe para-aminosalicylic acid hy persensitivity simulating mononucleosis or hepatitis, J.A.M.A. 152:606, 1953. 436. Lichtman, S. S.: Toxic hepatitis ascribed to the use of cinchophen; illustration of the analgesic effect of jaundice in long standing rheumatoid arthritis, J. Mt. Sinai Hosp. 6:199, 1939. 437. -----------: Diseases of the Liver, Gall bladder and Bile Ducts, ed. 2, Philadel phia, Lea & Febiger, 1949. 438. Lieber, C. S.r and Schmid, R.: The effect of ethanol on fattv acid metabolism; stimulation of fattv acid svnthesis m vitro, J. Clin. Invest. 40:394, 1961. 439. Liebow, A. A., Warren, S., and DeCoursev, E.: Pathology of atomic bomb casu alties, Am. J. Path. 25:853, 1949. 440. Lindenbaum, J., and Leifer, E.: Hepatic necrosis associated with halothane anes thesia, New Engl. J. Med. 268:525, 1963. 441. Lindsay, S., and Skahen, R-: Jaundice due to chlorpromazine (Thorazine) ther apy. A histological study of the hepatic lesions in five patients, Arch. Path. 61: 84,1956. 442. Lischner, M. W., MacNabb, G. M., and Galambos, J. T.; Fatal hepatic necrosis following surgery: Possible relation to metboxyflurane anesthesia. Arch. Int Med. 120:725, 1967. 443. Little, D. M., Barbour, C. M., and Given, J. B.: The effects of fluothane, cyclopro pane, and ether anesthesias on liver func tion, Surg. Gynec. Obstet. 107:712,19-58. 444. Livingood, C. S., Brannen, M., Orders, R. L., Kopstein, J. B., and Rebuck, J. W.: Effect of prolonged griseofulvin admin istration on liver, hematopoietic system, and the kidnev, Arch. Dermat. 82:760 1960. 445. Livingood, C. S., and Dieuaide, F. R.: Untoward reactions attributable to atabrine, J.A.M.A. 229:1091, 1945. 446. Livingston, H. J-, and Livingston, S. F.: Agranulocytosis and hepatocellular jaun dice; toxic reactions following propyl thiouracil therapy, J.A.M.A. 135:422 1947. 447. Livingston, K. E., and McCallion, D. J.: The immediate effects of severe local X irradiation on the liver of the hamster, Canad. J. Med. Sci. 30:571, 1952. 448. Livingstone-Learmonth, A., and Cun ningham, B. M.: Observations on the ef fects of tri-nitrotoluene on ' women workers. Lancet 2:261, 1916. 449. Lloyd-1Thomas, H. G. L., and Sherlock, S.: Testosterone therapy for the pruritus of obstructive jaundice, Brit. Med. J. 2: 1289, 1952. 450. Loewentbal, L. J. A., MacKav, W. A., and Lowe, E. C.: Two cases of acute yellow atropbv of the liver following ad ministration of Atophan, Brit. Med. J. 1: 592, 1928. 451. Lomas, J., Boardman, R. H., and Markowe, M.: Complications of chlorpro mazine therapv in 800 mental-hospital patients. Lancet 2:1144, 1955. 452. Long, P. H., Haviland, J. W.f Edwards, L. B., and Bliss, E. A.: The toxic mani festations of sulfanilamide and its deriva tives with reference to their importance in the course of therapv, J.A.M.A. 225: 364, 1940. 453. Longcope, W. T.: Cirrhosis of the liver produced bv chronic protein intoxication, Trans. Ass. Am. Phys. 28:497, 1913. 454. -----------: Serum sickness and analogous reactions from certain drugs, particularly the sulfonamides, Medicine 22:251, 1943. 455. Lowenstein, L., and Bailew, D. H.: Fatal acute hemolytic anemia, thrombocyte- '7J*t V,ii,Wx . :v>* rexy: Possible relation to sv a*psthesia, Arch. Int. ,'lf Barboar, C. M., and Given, :cts of fluothane, cyclopror anesthesias on liver funciec. Obstet. 107:712,1958. S., Brannen, M., Orders, i, J. B., and Rebuck, ]. W.: jnged griseofulvin adminer, hematopoietic system, v. Arch. Dermat. 81:760, S., and Dieuaide, F. R.: ;-tions attributable to ata. 159:1091, 1945. J., and Livingston, S. F.: > and hepatocellular Jaunictions following propvlapy, J.A.M.A. 135:422, E., and McCallion, D. J.: effects of severe local X the liver of the hamster, Sci. 30:571, 1952. umonth. A., and Cun.: Observations on the eftitrotoluene on women t 2:261, 1916. H. G. L., and Sherlock, } therapv for the pruritus aundice, Brit. Med. J. 2: J. MacKay, W. A., C.: Two cases of acute of the liver following ad* Mophan, Brit. Med. J. 1: dman, R. H., and Markiplications of chlorpro- in 800 mental-hospital 1:1144, 1955. iviland, J. W., Edwards, , E. A.: The toxic manianilamide and its deriva?nce to their importance therapy, J.A.M.A. 115: 7: Cirrhosis of the liver onic protein intoxication, Phys. 28:497, 1913. sickness and analogous Jrtain drugs, particularly es. Medicine 22:251, rad Ballew, D. H.: Fatal anemia, thrombocyto- : References 589 penic purpura, nephrosis and hepatitis 6-mercaptopurine therapy. Blood 14:80, resulting from ingestion of a compound 1959. containing apiol, CanacL Med. Ass. J. 470. Mclver, M. A.: Liver changes in hyper 78:195, 1958. thyroidism, Surgery 12:654, 1942. 456. Lubell, D. L.: Fatal hepatic necrosis 471. -----------: Deleterious effects of anoxia associated with zoxazolamine therapy, on the liver of the hvperthyroid animal. N. Y. State J. Med. 62:3807, 1962. Arch; Surg. 46:171, 1943. 457. Luongo, M. A., and Bjomson, S. S.: The 472. Mclver, M. A., and Winter, E. A.: Fur liver in ferrous sulfate poisoning: a report ther studies on increased susceptibility to of three fatal cases in children and an chloroform poisoning produced in the experimental study. New Engl. J. Med. albino rat bv injection of crystalline thy 251:995, 1954. roxin, J. Clin. Invest. 21:191, 1942. 458. MacBrvde, C. M., Castrodale, D., Loef- 473. McKendrick, C. D. W.: Toxic hepatitis fel, E., and Freedman, H.: The svnthetic from para-aminosalicvlie acid, Lancet 2: estrogen diethylstilbestrol; clinical and 668, 1951. experimental studies, J.A.M.A. 117:1240, 474. McLean, S., MacDonald, A., and Sulli 1941. van, R. C.: Acute phosphorus poisoning 459. MacBrvde, C. M., and Taussig, B. L.: from the ingestion of roach paste; report Functional changes in liver, heart and of a fatal case in a child, J.A.M.A. 93: muscles, and loss of dextrose tolerance 1789, 1929. resulting from dinitrophenol, J.A.M.A. 475. Mach, B., Field, R. A., and Taft, E. B.: 105:13, 1935. Metahexamide jaundice; report of a case. 460. MacCallum, F. O.: Transmission of arsenotherapy jaundice bv blood: failure of faeces and nasopharvngeal washings, Lancet 1:342, 1945. 461. McCloskey, J. F.: Protective action of chlorophyll on hepatic necrosis in rats. Am. J. Clin. Path. 21:723, 1951. 462. McCloskey, J. F., and McGehee, E. H.: Effect of subcutaneous and intraoral ad ministration of carbon tetrachloride on the liver of the rat. Arch. Path. 49:200, 1950. 463. McCormick, R. V.: Periarteritis occur ring during propylthiouracil therapy. J.A.M.A. 144:1453, 1950. 464. McDermott, W., Ormond, L., Muschenheim, C., Deuschle, K., McCune, R. M., Jr., and Tompsett, R.: Pyraxinamideisoniazid in tuberculosis. Am. Rev. Tuberc. 69:319, 1954. 465. MacDonald, R. A., and Pechet, G. S.: Experimental hemochromatosis in rats, Am. J. Path. 46:85, 1965. New Engl. J. Med. 261:438, 1959. 476. Mackav, I. R., Weiden, $., and Ungar, B.: Treatment of active chronic hepatitis and lupoid hepatitis with 6-mercaptopurine and azothioprine. Lancet 1:899, 1964. 477. Mackav, R. P., and Gottstein, W. K.: Aplastic anemia and agranulocytosis fol lowing Tridione; a fatal case, J.A.M.A. 132:13, 1946. 478. Maddock, W. G., Pedersen, S-, and Col- ler, F. A.: Studies of the blood chemistry in thvroid crisis, J.A.M.A. 109:2130, 1937.' 479. Madhaven, T. V., Survanaravana Rao, K., and Tulpule, P. G.: Effect of dietary protein level on susceptibility of monkeys to aflatoxin liver injurv, Indian J. Med. Res. 53:984, 1965. 480. Magee, P. N.: Toxic liver injury. The metabolism of dimethvlnitrosamine, Biochem. J. 64:676, 1956'. 481. Magee, P. N., and Barnes, J. \L: Induc tion of kidnev tumours in the rat with 466. MacDonald, R. M.: Toxic hepatitis in fever therapy, Canad. Med, Ass. 51:445, 1944. dimethylnitrosamine (N-nitrosodimethvlamine), J. Path. Bact. 84:19, 1962. 482. Magee, P. N., and Lee, K. Y.: Experi 467. McFarland, R. B.: Fatal drug reaction mental toxic liver injury by some nitros- associated with prochlorperazine (Com pazine), Am. J. Clin. Path. 40:284, 1963. 468. McCeaehy, T. E., and Bloomer, W. E.: amines, Ann. N. Y. Acad. Sci. 104:916, 1963. 483. Makous, N., and Vander Veer, J. B.: The phenobarbital sensitivity syndrome. Severe drug sensitivity reaction to phen- Am. J. Med. 14:600, 1953. 469. Mcllvane, S. K., and MacCarthy, J. D.: indione (phenylindandione), J.A.M.A. 155:739, 1954. Hepatitis in association with prolonged 484. Malitz, S., Wilkens, B., and Esecover, 24905033 590 Toxic and Drug-Induced Hepatitis H.: Preliminary evaluation of Tofranil in a combined in-patient and out-patient setting, Canad. Phychiat. Ass. J. 4:S152, 1959. 485. Mallory, F. B.: Phosphorus and alco holic cirrhosis. Am. J. Path. 9:557, 1933, 486. Mallory, F, B., and Parker, F., Jr.: Ex perimental copper poisoning, Am. J. Path. 7:351, 1931. 487. MandeJbaum, H-, and Kane, L. J.: Di lantin sodium poisoning report of a case with dermatitis exfoliativa, pvrexia and hepatic and splenic enlargement, Arch. Neurol. Psychiat. 45:769, 1941. 488. Margolis, H. M., and Caplan, P. S.: BAL in treatment of toxicitv from gold, Ann. Int. Med. 27:353, 1947. 489. Marquardt, G. H., Fisher, C. I., Levy, P., and Dowben, R. M.: Effect of ana bolic steroids on liver function tests and creatine excretion, J.A.M.A. 175:851, 1961. 490. Martin, G. H., Bunting, C. H., and Lovenhart, A. S.: The morphological, changes in the tissues of the rabbit as a result of reduced oxidations, J. Pharma col. Exp. Ther. 8:112, 1916. 491. Martinez-Lopez, J. I., Greenberg, S. E., and Kling, R. R.: Drug-induced hepatic injury during methimazole therapv. Gastroenterology 43:84, 1962. 492. Martland, H. S.: Tri-nitro-toluene poi soning, J.A.M.A. 68:835, 1917. 493. Matzger, E.: Can sensitivity to dinitrophenol be determined bv skin tests?, JAM A,J03:25JL--1934, 494. Qviauer, ETF.: The toxic effects of phenyl butazone (ButazolidinJ"' review of the literature and report of the twentv-third death following its use. New Engl. J. \ted. 253:404, J955. 495. Mazer, C., Israel, S. L., and Ravetz, E.: The synthetic estrogen stilbestrol; experi mental and clinical evaluation, J.A.M.A. 126:675, 1941. 496. Meacham, G. C., Tillotson, F. W., and Heinle, R, W.: Liver damage after pro longed urethane therapy, Am. J. Clin. Path. 22:22, 1952. 497. Mechanic, R. C., and Meyers, L.: Chlor- promazine-type cholangitis; report of a case occurring after the administration of prochlorperazine. New Engl. J. Med. 259:778, 1958. 498. Medical Letter on Drugs and Thera peutics, Oxacillin 4:29,1962. 499. -----------: Methyldopa 6:47, 1964. 499a. Medical Research Council: Risk ot throm boembolic disease in women taking oral contraceptives: a preliminary communi cation to the Medical Research Council by a subcommittee, Brit, Med. J. 2:355 1967. 500. Melrose, A. G., and Roy, J. R.: Late prognosis of chorpromazine jaundice Brit. Med. J. 2:818, 1959. 501. Menten, M. L., and Andersch, M. A.: Hepatic damage associated with sulfona mide therapy in infants and children: morphologic pathology, Ann. Int. Med 29:609, 1943. 502. Merritt, A. D., and Fetter, B. F.: Toxic hepatic necrosis (hepatitis) due to iso niazid; report of a case with cirrhosis and death due to hemorrhage from esopha geal varices, Ann. Int. Med. 50:804. 1959. 503. Messinger, W. J., and Hawkins, W. B.: Arsphenamine liver injury modified b> diet. Protein and carbohydrate protective ' but fat injurious. Am. J. Med. Sci. 199: 216, 1940. 504- Meyer, R. R.: Effect of iopanoic acid on the sulfobromophthalein test, J.A.M.A. 294:343, 1965. 505. Miller, J. M., Long, P. H., and Schoenbach, E. B.: Successful treatment of actinomvcosis with "stilbamidine," J.A. M.A. 150:35, 1952. 506. Miller, L. L., Ross, J. F., and Whipple, G, H.: Methionine and cystine, specific protein factors preventing chloroform liver injurv in protein depleted dogs. Am. J. Med. Sd. 200:739, 1940. 507. Miller, L. L., and Whipple, G. H.: Liver injury, liver protection, and sulfur metab olism; methionine protects against chloroform liver injury even when given after anesthesia, J. Exp. Med. 76:421. 1942. 508. Miller, S. E. P., MacSween, R. N. M - Glen, A. C. A., Tribedi, K., and Moore, F. M. L.: Experimental studies on the hepatic effects of tetracycline, Brit. J. Exp. Path. 28:51, 1967. ' 509. Minot, C. R., and Smith, L. W.: The blood in tetrachlorethane poisoning, Arch. Int. Med. 28:687, 1921. 510. Mistilis, S. P., Skyring, A. P., and Goul- ston, J. M.: Effect of long-term tetra cycline therapy, steroid therapy and colectomy in pericholangitis associated with ulcerative colitis, Aust. Ann. Med. 14:286, 1965. 4*. References 591 Risk -i. thromen taking oral ary communiearch Council vied. J. 2:355, 511. 512. Mitchell, P. H., Sykes, P., and King, A.r Effects of "Pacatal" on symptoms in chronic psvchotic female in-patients, Brit Med. j. 1:204, 1957. Molftor, H., Graessle, O. E., Kuna, S., Mushett, C. W., and Silber, R. H.: Some 525. gens, Trans. Ass. Am. Phys. 77:248, 1964. ----------: Estrogen pharmacology. I. The influence of estradiol and estriol on he patic disposal of sulfobromophthalein (BSP) in man, J. Clin. Invest. 43:1905, , J. R.: Late ine jaundice, toxicological and pharmacological prop erties of streptomycin, J. Pharmacol. Exp. Ther. 86:151,' 1946. 1964. 526. Murray, J. E., Merrill, J. P., Harrison, J. H., Wilson, R. E., and Dammin, C. J.: ersch, M. A.: with sulfonaand children; in. Int. Med. 513. Monroe, L. S., and Longmore W. J.: Inhibition of sulfobromophthalein (BSP) conjugation with gluatathione by iopanoic acid (Telepaque), Gastroenterology 50:396. 1966. 527. Prolonged survival of human-kidnev homografts bv immunosuppressive drug therapv. New Engl. J. Med. 268:1315, 1963. * Muschenheim, C., McDermott, W., B. F.: Toxic ) due to isoi cirrhosis and from esophaled. 50:804, /kins, W. B.: modified bv ate protective ed. Sci. 299: anoic acid on ist, J.A.M.A. and Schoentrea^ -mt of lidi J.A.- nd Whipple, tine, specific chloroform :d dogs. Am. G. H.: Liver ulfur metabrts against when given ed. 76:421, 514. Moon, H. D.: The pathology of fatal I carbon tetrachloride poisoning with spe cial reference to the histogenesis of the (hepatic and renal lesions, Am. J. Path. 26:1041. 1950. I 515. Moore. B.: Toxic jaundice in munition I workers and troops, Brit. Med. J. 2:155, 1917. j 516. Moore. K. E., and Brodv, T. M.: Func| tional changes in liver mitochondria fol- ! lowing in situ anoxia, Am. J. Phvsiol. j 198:677, 1960. 517. More, R. H., McMillan, G. C., and Duff, G. L,: The pathology- of sulfonamide allergy in man. Am. J. Path. 22:703, 19467 518. Momssev, J. F., and Rubin, R. C.: The detection of pvrazinamide-induced liver damage bv serum enzvme determina- | tions. Ann. Rev. Resp. Dis. 80:855, 1959. | 519. Moschcowitz, E.: Pathogenesis of cir rhosis of the liver occurring in patients with diffuse toxic goitre, Arch. Int. Med. 78:497, 1946. 520. Moulding, T. S., Jr., and Goldstein, S.: Hepatotoxicitv due to ethionamide, Am. | Rev. Resp. E>is. 86:252, 1962. 521. Mount, F. W., Wunderlich, G. S., Mur McCune, R., Deuschle, K., Ormond, L., and Tompsett, R.: Pvrazinamide-isoniazid in tuberculosis. III. Results in 58 patients with pulmonarv lesions one vear after the start of therapv. Am. Rev. Tuberc. 70:743. 1954. 528. Mvers, f. D.; Personal communication. Dec., 1961. 529. Mvers, J. D., Olson, R. E,, Lewis, J. H., and Moran, J. T.: Xanthomatous biliarv cirrhosis following chlorpromazine, with observations indicating overproduction of cholesterol, hvperprothrombinemia, and the development of portal hyper tension, Trans. Ass. Phvns 70:243, 1957. 530. Mvren, J.: Injurv of liver tissue in mice after single injections of carbon tetra chloride, Acta path, microbiol, scand., Supp. 116, 1956. 531. Napier, L. E.: The pentavalent com pounds of antimonv in the treatment of kala-azar; aminostiburea; an analysis of the treatment in 52 cases, Indian J. Med. Res. 26:141, 1928. 532. -----------: The oentavalent compounds of antimonv in the treatment of kala-azar; urea-stibamine; an analysis of the treat ment in 70 consecutive cases, Indian J. Med. Res. 26:901, 1929. , R. N. M., and Moore, dies on the ne, Brit. J. ray, F. J., and Ferebee, S. H.: Hepatic toxicitv of pyrazinamide used with iso- niazid in tuberculous patients. A United States Public Health Service Tuberculo sis Therapv Trial, Am. Rev. Resp. Dis. 533. Nelson, A. A., Draize, T. H., Woodward, G., Fitzhugh, O. G., Smith, R. B., Jr., and Calverv, H. O.: Histopathological changes following administration of DDT to several species of animals. Pub. - W.: The poisoning, l. , and Goulterm tetraierapy and associated 80:371, 1959. 522. Movitt, E. R., Gersth, B., and Davis, A. j E.: Needle fiver biopsy in thvrotoxicosis, . Arch. Intem. Med. 92:729, 1953. j 523. Moxon, A. L., and Rhian, M.: Selenium ! poisoning, Physiol. Rev. 23:305, 1943. 524. Mueller, M. N., and Kappas, A.: Impair 534. 535. Health Rep. 59:1009, 1944. Nelson, A. A., Fitzhugh, O. G., and Cal- verv, H. O.: Liver tumours following cir rhosis caused bv selenium in rats. Cancer Res. 3:230, 1943. Nelson, R. S.: Hepatitis due to carbarsone; report of two cases, J.A.M.A. 160: Ann. Med. ment of hepatic excretion of sulfo 764, 1956. bromophthalein (BSP) by natural estro 536. Nettleship, A., and Fink, W. J.: Neo- MmMMM 592 Toxic and Drug-Induced Hepatitis plasms of the liver following injection of Thorotrast, Am. J. Clin. Path. 35:422, 1981. 537. Nosslin, B.: Bromsulphalein retention and jaundice due to unconjugated bili rubin following treatment with male fern extract, Seand. J. Clin. Lab. Invest. 15, Suppl. 69:206, 1963. 538- Oberman, J. W., and Gilbert, E. F.: The toxicity of 2-hvdroxvstilbamidine: prob able fatal toxic reaction during treatment of blastomvcosis, Ann. Int. Med. 48: 1401, 1958'. 539. Ockner, R. K., and Davidson, C. S.: He patic effects of oral contraceptives. New Engl. J. Med. 276:331, 1967. 540. O'Donovan, C. J. O.: Toxicity of Euglvcin (metahexamide), Circular letter from the Upjohn Co., Kalamazoo, Mich., May 13, 1959. 541. Ohier, R. L., Houghton, J. D., and Molonev, W. C.: Urethane toxicitv; report of a case of hepatic necrosis apparently due to urethane, New Engl. J. Med. 243:984, 1950. 542. Opie, E- L.: On the relation of combined intoxication and . bacterial infection to necrosis of the liver, acute vellow atro phy and cirrhosis, J. Exp. Med. 12:367, 1910. 543. Opie, E. L., and Alford, L. B.: The in fluence of diet upon necrosis caused bv hepatic and renal poisons. I. Diet and hepatic lesions of chloroform, phos phorus, or alcohol, J. Exp. Med. 22:1, 1915. 544. Orellana-Alcalde, J. M., and Dominguez, J. P.: Jaundice and oral contraceptive drugs. Lancet 2:1278, 1966. 545. O'Rourke, R. A., and Eckert, G. E.: Methotrexate-induced hepatic injury In an adult: a case report, Arch. Int. Med. 113:191, 1964. 546. Orr, C. R., Popoff, G. D., Rosedale, R. S., and Stephenson, B. R.: A studv of the effect of thorium dioxide sol injected in rabbits. Radiology 30:370, 1938. 547. Ortega, P-, Hayes, W. J,, jr., and Dur ham, W. F.: Pathologic changes in the liver of rats after feeding low levels of various insecticides. Arch. Path, 64:614, 1957. 548- Paine, D.: Allergic reactions to paraaminosalicvlic acid; report of six cases. Arch. Int/Med. 96:768, 1955. 549. ---------- : Fatal hepatic necrosis associated with aminosalicylic acid; review of the literature and report of a case J.A.M.A. 167:285, 1958. 550. Palmer, W. L., Woodall, P. S., and Wang, K. C.: Cmchophen and toxic necrosis of the liver; a survey of the problem, Trans. Am. Phys. 51:381, 1936. 551. Panton, P. N.: Toxic jaundice in muni tion workers and troops, Brit. Med. J. 1; 157, 1917. Pare, C. M. B., and Sandler, M.: Acute hepatic necrosis following iproniazid therapv. Value of glutamic-oxaloacetic transaminase estimation in early detec tion, Lancet 1:282, 1959. 553. Parrv, C. R., and West, G. H., Jr.: Cited bv Marquardt et al.489 554. Parsons, W. B., Jr.: Studies of nicotinic acid use in hypercholesteremia: changes in hepatic function, carbohydrate tol erance and uric acid metabolism. Arch. Int. Med. 107:653, 1961. Use of nicotinic acid to reduce serum lipid levels, J. Am. Geriat. Soc. 10-. 850, 1962. 556. Parsons, W. B., Jr., and Flinn, J. H.: Reduction of serum cholesterol levels and beta-lipoprotein cholesterol levels by nicotinic acid, Arch. Int. Med. 103:783, 1959. oo i . Paschkis, K. E., Cantarow, A., RaVcoff, A. E., Walkling, A. A., and Tourish, W. J.: Thiourea and thiouracil in treatment of thvrotoxicosis, J. Clin. Endocr. 4:179, 1944558. Patwardhan. M. V., Ramalin?aswami. V., Suramachari, S., and Patwardhan, V. N.: Nutritional factors in toxic liver in jury. I. Biochemical and histological studv of liver injury produced bv carbon tetrachloride in normal rats, Indian J. Med. Sci. 7:533, 1953. 559. Pearce, R. M.: Experimental cirrhosis of the liver, T- Exp. Med. 8:64, 1906. 560. Permar. H. H., and Goehring, H. D.: Cinchophen poisoning; report of two cases with histologic observations, Arch. Int. Med. 52:398, 1933. 561. Pernod, J.: Hepatic tolerance of ethiona mide, Am. Rev. Resp. Dis. 92:39, 1965. 562. Person, D. A., Sargent, T., and Isaac, E.: Thorotrust-induced carcinoma of the liver; a case report including results of whole bodv counting. Arch. Surg. 88: 503, 1964, Peters, J. H., Randall, A. H., Jr., Men- deloff, J., Peace, R., Coberlv, J. C., and Hurley, M. B.: Jaundice during adminis- trati End 564. Pete A. J The jaun acid 565. Pete kels. cycl nanl J-S .566. Pete lane com the 567 Phil G. J droi pati cert Eng 568. Phil burj sohi mid ber< 195 569. Phil mid 896 570. Picl rub: terc Ope Klir 571. Pipi in t 439 572. Plas bod fore cen 302 573. Plei Me- e a*"5 report of a case, *5, Woodall, P. S., and Cinchophen and toxic liver; a survev of the Am. Phys. 52:381, 1936. Toxic jaundice in munii troops, Brit. Med. J. 1: and Sandler, M.: Acute is following iproniazid of glutamic-oxaloacetic timation in earlv detec;82, 1959. d West, G. H., Jr.: Cited t al.4S9 Jr.: Studies of nicotinic ?reholesteremia: changes ;tion, carbohvdrate tolacid metabolism. Arch. :53, 1961. nicotinic acid to reduce i, J. Am. Geriat. Soc. 10: Jr., and Flinn, J. H.: erum cholesterol levels rein cholesterol levels bv rch. Int. Med. 203:783, Cantarow, A., Rakoff, A. A., and Tourish, W. 1 tb \cil in treatment J. v .. Endocr. 4:179, V., Ramalineaswami, S-, and Pahvardhan, V. 'actors in toxic liver inmical and histological .irv produced bv carbon normal rats, Indian J. 1953. xperimental cirrhosis of Med. 8:64, 1906. and Goehring, H. D.: :oning; report of two >gic observations. Arch. , 1933. nc tolerance of ethionalesp. Dis. 92:39, 1965. Urgent, T., and Isaac, luced carcinoma of the )rt including results of iting. Arch. Surg. 88: idall, A. H,, Jr., MenR., Coberly, J. C., and undice during adminis References 593 tration of methylestrenolone, J. Clin. Endocr. 28:114, 1958. 564. Peters, R. A., Thompson, R. H. S-, King, A. J., Williams, D. I., and Nicol, C. S.: The treatment of post-arsphenamine jaundice with sulfur-containing aminoacids, Quart. J. Med. 14:35, 1945. 565. Peters, R. L., Edmondson, H. A., Mikkelsen, W. P., and..Tatter, D.: -Tetra cycline-induced fatty liver in nonpreg nant patients: a report of six cases, Am. J. Surg. 113:622, 1967. 566. Peterson, O. L., Deutsch, E., and Fin land, M.: Therapv with sulfonamide compounds for patients with damage to the liver. Arch. Int. Med. 72:594, 1943. 567. Phillips, G. B., Schwartz, R., Gabuzda, G. J., Jr., and Davidson, C. S.: The syn drome of impending hepatic coma in patients with cirrhosis of the liver given certain nitrogenous compounds, New Engl. J. Med. 247:239, 1952. 568. Phillips, S., Larkin, J. C., Jr., Litzenburger, W. L., Horton, G. E., and Haimsohn, J. S.: Observations on pyrazina- mide (aldinamide) in pulmonary tu berculosis, Am. Rev. Tuberc. 69:443, 1954. 569. Phillips, S., and Tashman, H.: Ethiona mide jaundice. Am. Rev. Resp. Dis. 87: 896, 1963. 570. Pichmayer, I., and Stich, W.: Der bili- rubinostatische Ikterus, eine neue Ikterusform beim Zusammentreffen von Operation, Narkose und Bluttransfusion, Klin. Wschr. 40:665, 1962. 571. Piper, J., and Poulsen, E.: Liver biopsy in thyrotoxicosis, Acta med. scand. 127: 439, 1947. 572. Plaa, G. L., and Larson, R. E.: Role of body temperature in the protection af forded against CC14 hepatotoxicity by cervical cordotomy. Gastroenterology 46: 302, 1964. 573. Pletcher, W. D., Brody, G. L-, and Meyers, M. C.: Hemochromatosis follow ing prolonged iron therapy in a patient with hereditary nonspherocytic hemo lytic anemia. Am. J. Med. Sci. 246:2.1, 1963. 574. Poindexter, C. A., and Greene, C. H.: Toxic cirrhosis of the liver; report of a case due to long continued exposure to carbon tetrachloride, J-A.M.A. 102: 2015, 1934. 575. Pollack, L. J., Finkebnan, I., and Arieff, A. J.: Toxicity of pyridine in man. Arch. Int. Med. 71:95, 1943. 576. Poole, F. E., and Haining, R. B.: Sudden death from dinitrophenol poisoning, re port of a case with autopsy, J.A.M.A. 202:1141, 1934. 577. Popper, H.: Pathologic findings in jaun dice associated with iproniazid therapy, J.A.MA 168:2235, 1958. 578. -----------: Hepatic injury in patients who have received iproniazid, Ann. N. Y. Acad. Sci. 80:928, 1959, 579. Popper, H-, Dubin, A., Bruce, C., Kent, G., and Kushner, D.: Effect of chlorpromazine upon experimental hepatic in jury, J. Lab. Clin. Med. 49:767, 1957. 580. Popper, H., and Franklin, M.: Diagnosis of hepatitis by histologic and functional laboratory means, J.A.M.A. 237:230, 1948. 581. Popper, H., Koch-Weser, D., and Szanto, P. B.: Protective effect of vitamin B12 upon hepatic injury produced by carbon tetrachloride, Proc. Soc. Exp. Biol. Med. 72:688, 1949. 582. Popper, H., Rubin, E., Gardiol, D., Schaffner, F., and Paranetto, R.: Druginduced liver disease: a penalty for progress. Arch. Int. Med. 115:128, 1965. 583. Portal, R, W., and Emanuel, R. W.: Phenindione hepatitis complicating anti coagulant therapv, Brit. Med. J. 2:1318, 1961. 584. Powell, W. J., Jr., Koch-Weser, J., and Williams, R. A.: Lethal hepatic necrosis after therapy with imipramine and desipramine, J.A.M.A. 206:642, 1968. 585. Preheim, D. V., and Peck, M. E.: Agran ulocytosis due to amithiazone therapy. Am. Rev. Tuberc. 65:339, 1952. 586. Quick, A. J.: The probable allergic na ture of cinchophen poisoning, with spe cial reference to the Arthus phenomenon and with precautions to be followed in cinchophen therapy. Am. J. Med. Sci. 287:115, 1934. 587. Rabinovitch, J., and Snitkoff, M. C.: Acute exfoliative dermatitis and death following penicillin therapv, J.A.M.A. 233:496, 1948. 588. Radke, R. A., and Baroody, W. G.: Carbarsone toxicity: a review of the literature and report of 45 cases, Ann. Int Med. 47:418, 1957. 589. Ramsay, I. D.: Carbamazepine-induced jaundice, Brit Med. J. 4:155, 1967. 590. Randolph, H., and Joseph, S.: Toxic 594 Toxic and Drug-Induced Hepatitis hepatitis with jaundice occurring in a patient treated with isoniazid, J.A.M.A. 152:38, 1953. 591. Ratnoff, O., and Mirick, C.: Influence of sex upon lethal effects of hepatotoxic alkaloid, monocrotaline. Bull. Johns Hopkins Hosp. 84:507, 1949. 592. Ravdin, I. S., Eliason, E. L., Coates, C. M., Holloway, T. B., Ferguson, L. K., GiU, A. B., and Cooke, T, J.: Divinyl ether; report of its further use as a gen eral anaesthetic, J.A.M.A. 108:1163, 1937. 593. Rawls, W. B., Gruskin, B. J., Ressa, A. A., and Gordon, A. S.: The relation be tween skin sensitivity, liver function, leucopenic index, and toxic effects from dnchophen, J. Lab. Clin. Med. 24:597, 1939. 594. Read, A. E., Harrison, C. V., and Sher lock, S.: Chronic chlorpromazine jaun dice, with particular reference to its relationship to primary biliarv cirrhosis, Am. J. Med. 31:249, 1961. 595. Rebou^as, G., and Isselbacher, K. J.: Studies on the pathogenesis of the etha nol-induced fatty liver. I. Synthesis and oxidation of fatty acids by the liver, J. Clin. Invest. 40:1355, 1961. 596. Recknagel, R. O.: Depression of glucose6-phosphatase activity in carbon tetra chloride fattv liver. Fed. Proc. 19:137, 1960. 597. Recknagel, R. O., and Ghoshal, A. K.: Lipoperoxidation as a vector in carbon tetrachloride hepatotoxicity. Lab. Invest. 15:132, 1966. 598. Recknagel, R. O., and Litteria, M.: Biochemical changes in carbon tetrachloride fatty liver; concentration of carbon tetra chloride in liver and blood. Am. J. Path. 36:521, 1960. 599. Recknagel, R. O., and Lombardi, B.: Cited by Recknagel et al.600 600. Recknagel, R. O., Lombardi, B., and Schotz, M. C.: A new insight into patho genesis of carbon tetrachloride fat infil tration, Proc. Soc. Exp. Biol. Med. 104: 608, 1960. 601. Redeker, A. G., Sterline, R. E., and Bronow, R. S.: Effect of griseofulvin in acute intermittent porphyria, J.A.M.A. 188:466, 1964. 602. Reed, G. B., Jr., and Cox, A. J., Jr.: The human liver after radiation injury, a form of veno-occlusive disease. Am. J. Path. 48:597, 1966. 603. Reichel, J., Goldberg, S. B., Ellenberg, M., and Schaffner, F..- Intrahepatic cholestasis following administration of chlorpropamide; report of a case with electron miscroscopic observations. Am. J. Med. 28:654, 1960. 604. Reicble, H. S.: Toxic cirrhosis of liver due to cinchopben, Arch. Int. Med. 44: 281, 1929. 605. -----------: Cinchophen poisoning: an attempt to produce toxic cirrhosis of the liver in rats. Arch. Int. Med. 49:215, 1932. 606. Reinhart, M. J., Benson, R. M., Kwass, S. K., and Storey, W. F.: Suggestive evidence of hepatotoxicitv concomitant with thioridazine hydrochloride use, J.A.M.A. 197:767, 1966. 607. Report to Council on Pharmacy &. Chem istry, A.M.A.: The effects of strepto mycin on tuberculosis in man; prelimi nary statement, J.A.M.A. 135:634, 1947. 608. Reye, R. D. K., Morgan, G., and Baral, J.: Encephalopathy and fatty degenera tion of the viscera: a disease entity of childhood. Lancet 2:749, 1963. 609. Reynolds, E.: Isoniazid jaundice and its relationship to iproniazid jaundice. Tu bercle 43:375, 1962. 610. Reynolds, E. S., Schlant, R. C., Gonick, H. C-, and Dammin, G. J.: Fatal mas sive necrosis of the liver as a manifesta tion of hvpersensitivitv to probenecid. New Engl. J. Med. 256:592, 1957. 611. Rheingotd, J. J., and Spurting, C. L.: Chloramphenicol and aplastic anemia, J.A.M.A. 149:1301, 1952. 612. Rich, A. R.: The role of hypersensitivity in periarteritis nodosa as indicated by seven cases developing during serum sickness and sulfonamide therapy. Bull. Johns Hopkins Hosp. 71:123, 1942. 613- ---------- : The Pathogenesis of Tuber culosis, Springfield, 111., Thomas, 1944. 614. -----------: Hypersensitivity' to iodine as a cause of periarteritis nodosa. Bull. Johns Hopkins Hosp. 77:43, 1945. 615. Rich, A. R., and Gregory, J. E.: The experimental demonstration that peri arteritis nodosa is a manifestation ef hypersensitivity. Bull. Johns Hopkins Hosp. 72:65, 1943. 616. Richards, R. K.: Cited by Lennox, W. G* 11 617. Richards, R. K., and Everett, G. M.: .r , Cited by Tyler and King.763 j 618. Rimington, C., Heikel, T., Knight, B. C., ^ j ^!  References 595 rg, 0 B., Ellenberg, ;r> * Intrahepatic ,g administration of port of a case with >ic observations, Am. 60. oxic cirrhosis of liver Arch. hit. Med. 44: hen poisoning: an toxic cirrhosis of the 1. Int. Med. -49:215, enson, R. M., Kwass, , W. F.: Suggestive rotoxicitv concomitant hvdroebloride use, 1966. on Pharmacy & Chem\e effects of streptolosis in man; prelimii.M.A. 135:634, 1947. lorgan, G., and Baral, y and fatty degeneraa: a disease entity of 3:749, 1963. liazid jaundice and its oniazid jaundice, Tu>2. ichlant, R. C., Gonick, nin, G. J.: Fatal mase lr is a manifesta;itivTv. to probenecid, d. 256:592, 1957. and Spurling, C. L.: and aplastic anemia, 1, 1952. role of hypersensitivity jdosa as indicated by eloping during serum inamide therapv. Bull. ?sp. 71:123, 1942. ithogenesis of Tuberd. 111., Thomas, 1944. :nsitivitv to iodine as arteritis nodosa. Bull, losp. 77:43, 1945. 1 Gregory, J. E.: The nonstration that pen is a manifestation ef Bull. Johns Hopkins 3. Cited by Lennox, W. and Everett, C. M.: ad King.753 eikel, T,, Knight, B. C., Williams, E. J., and Ritchie, H. D.: Studies on biliary excretion in the rabbit: effect of icterogenin on bile flow and the excretion of bilirubin, phylloerythrin, 1 coproporphvrin, alkaline phosphatase, 1 and Bromsulphalein, Gastroenterology i 38:796. 1960. 619- Rimington, C., Morgan, P. N., Nichofls, K-. Everall, J. D., and Davies, R. R.: Griseofulvin administration and porphy rin metabolism: a survev, Lancet 2:318, 1963. 620. Rimington, C., Quin, J. I., and Roets, G. C. S.: Studies upon the photosensitiza tion of animals in South Africa. X. The icterogenic factor in geel-dikkop. Isola tion of active principles from Lippia rehmanni pears, Onderstepoort J. Vet. Sci. 9:225, 1937. 621. Ritchie, E. B., and Kolb, W.: Reaction to sodium diphenvl hvdantoinate (Dilantin sodium); hemorrhagic erythema multiforme terminating fatallv. Arch. Derm. Syph. 46:856, 1942. 622. Rivin, A. U.: Jaundice occurring during nicotinic acid therapv for hypercholes teremia, J.A.M.A. 170:2088, 1959. 623. Robinson, H. J.r Siegal, H., and Pietrowski, J. J.: Toxicity of pyrazinamide, Am. Rev. Tuberc. 70:423, 1954. 624. Robinson, S. S.: "Erythema of the ninth 1 day"; complicated by acute hepatitis and jaundice on continuation of arsphena- mine therapv, Arch. Derm. Svph. 37: 1031, 1938.' 625. Robitzek, E. H., and Selikoff, I. J.: Hydrazine derivatives of isonicotinic acid (Rimifon, Marsilid) in the treatment of active progressive caseous-pneumonic tu berculosis; preliminary report. Am. Rev. Tuberc. 65:402, 1952. 626. Rodin, A. E., and Robertson, D. M.: Fatal toxic hepatitis following chlorpromazine therapy; report of a case with autopsy findings, Arch. Path. 66:170, 1958. 627. Roman, B.: Acute vellow atrophy of the liver. Arch. Path. 4:399, 1927. 628. Rosenbaum, H., and Reveno, W. S.: Agranulocvtosis and toxic hepatitis from methimazole, J.A.M.A. 152:27, 1953. 629. Rosenblum, L. E., Korn, R. J., and Zim merman, H. J-: Hepatocellular jaundice as a complication of iproniazid therapv. Arch. Int. Med. 105:583, 1960. 630. Rosenfeld, I., and Beath, O. A.: Tissue changes induced bv Senecio riddelii, Am. J. Clin. Path. 75:407, 1945. 631. Rosenthal, S. M.: Some effects of alcohol upon the normal and damaged liver, J. Pharmacol. Exp. Ther. 38:291, 1930. 632. Rosenthal, S. M., and Bourne, \V.: The effect of anesthetics on hepatic function, J.A.M.A. 90:377, 1928. 633. Rosin, A., and Doljanski, L.: Studies on the earlv changes in the livers of rats treated with various toxic agents, with especial reference to the vascular lesions; the histology of the rat's liver in allvl formate poisoning. Am. J. Path. 22:317, 1946. 634. ---------- : Pvroninophilic structures of liver cells in carbon tetrachloride poison ing, Proc. Soc. Exp. Biol. Med. 62:62, 1946. 635. Roth, L. G.: Infectious hepatitis in preg nancy, Am. J. Med. Sci. 225:139 1953. 635a. Rothwell-Jackson, R. L.: Budd-Chiari svndrome after oral contraceptives, Brit. Med. J. 1:252, 1968, 636. Rotstein, J., Frick, P. S., and Schiele, B. C.: Agranulocvtosis associated with chlorpromazine therapy, Arch. Int. Med. 96:781,1955. 637. Rovston, G. D.: Delaved chloroform poisoning following delivery. Am. J. Obstet, Gvnec. 10:808, 1925. 638. Rubin, E., and Lieber, C. S-: Alcoholinduced hepatic injury in non-alcoholic volunteers. New Engl. J. Med. 278:870, 1968. 639. Rubin, B., Hassert, G. L., Jr., Thomas, B. G. H., and Burke, J. C.: Pharmacol ogy of isonicotinic acid hvdrazide (nvdrazid). Am. Rev. Tuberc. 65:392, 1952. 640. Rundles, R. W., Laszlo, J-, Itoga, T-, Hobson, J. B., and Garrison, F. E., Jr.: Clinical and hematologic studv of 6f (l-methvM-nitro-5-imidozolvl) thiol pu rine (B. W. 57-322) and related com pounds, Cancer Chemother. Rep. 14:99, 1961. 641. Russell, H.: Acute toxic necrosis of the liver following the use of sulfanilamide, Ann. Int. Med. 74:168, 1940. 642. Rutenburg, A. M., and Pinkes, S.: The hepatotoxicitv of intravenous Aureomv- cin. New Engl. J, Med. 247:797, 1952. 643. Saint, E. G., and Joske, R. A.: A note on fatty change in liver complicating Aureomycin therapy, Med. J. Aust. 1: 222, 1953. 644. Salaman, M. H., King, A. J., Williams, 24905098 596 Toxic and Drug-Induced Hepatitis D. I., and Nicol, C. S.: Prevention of jaundice resulting from anti-syphilitic treatment. Lancet -2:7, 1944. 645. Sborov, V. M., and Sutherland, D. A.: Fatty liver following Aureomycin and Terramycin therapy in chronic hepatic disease, Gastroenterology 18:598, 1951. 646. Schaffner, F.: The effect of oral contra ceptives on the liver, J.A.M.A. 198:1019, 1966. 647. Schaffner, F., and Popper, H.: Electron microscopic study of human cholestasis, Proc. Soc. Exp. Biol. Med. 101:777, 1959. 648. -----------: Morphologic studies of cho lestasis, Gastroenterology 87:565, 1959. 649. Schaffner, F., Popper, H., and Chesrow, E.: Cholestasis produced by the adminis tration of norethandrolone, Am. J. Med. 26:249, 1959. 650. Schaffner, F. Popper, H., and Perez, V.: Changes in bile canaliculi produced by norethandrolone: electron microscopic study of human and rat liver, ]. Lab. Clim Med. 56:623, 1960. 651. Schifrin, A.: Der Einfluss qualitativ ver- schiedener Emahrungsformen auf die dureh Salvarsan hervorgerufenen Lebernekrosen, Virchow's Arch. path. Anat. 287:175, 1932. 652. Schmid, M., Hefti, M. L., Gatticker, R., Kistler, H. J., and Senning, A.: Benign postoperative intrahepatic cholestasis. New Engl. J. Med. 272:545, 1965. 653. Schmidt, H. R., and Herold, L.: Leber- funktionsprufungen bei der Hvperemesis gravidarum, Arch. Gynaek. 156:463, 654. 1934. Schnack, H.: Zur Aetiologie des Chlorpromazin-Bcterus: Tierexperimentelle und klinische Beobachtungen, Path. Micro biol. 27:419, 1964. 655. Schneider, E. M., Daugherty, C., and DeVore, J. K.: Chlorpromazine jaundice; the effect of continued chlorpromazine ingestion in the presence of chlorproma zine jaundice. Southern, Med. J. 51:287, 1958. 656. Schneider, J. A., Salgado, E. D., Jaeger, D., and Delahunt, C.: The pharmacology of chlorpropamide, Ann. N. Y. Acad. Sci. 74:427, 1959. 657. Schoenbach, E. B., Miller, J. M., Gins berg, M., and Long, P. H.: Systemic blastomycosis treated with stilbamidine; a preliminary report, J.A.M.A. 146:1317, 1951. 658. Schoental, R., and Magee, P. N.: Chronic liver changes in rats after a single dose of lasiocarpine, a pyrrolizidine (senecio) alkaloid, J. Path. Bact 74:305, 1957. 659. -----------: Further observations on the subacute and chronic liver changes in rats after a single dose of various pyrrolizidine (senecio) alkaloids, J. Path. Bact 78:471, 1959. 660. Schotz, M. C., and Recknagel, R. O.: Effect of carbon tetrachloride on release of free fatty acids by rat adipose tissue, Proc. Soc. Exp. Biol. Med. 103:398 1960. 661. Schultz, J. C., Adamson, J. S., Jr., Work man, W. W., and Norman, T. D.: Fatal liver disease after intravenous administra tion of tetracycline in high dosage, New Engl. J. Med. 269:999,1963. 662. Schwartz, W. S., and Moyer, R. E.: The chemotherapy of pulmonary tuberculosis with pvrazinamide used alone and in combination with streptomycin, paraaminosalicylic acid or isoniazid. Am. Rev. Tuberc. 70:413, 1954. 663. Schwarz, K.: A hitherto unrecognized factor against dietary necrotic liver de generation in American yeast (factor 3), Proc. Soc. Exp. Biol. Med. 78:852, 1951. 664. -----------: Casein and factor 3 in dietarv necrotic liver degeneration; concentration of factor 3 from casein, Proc. Soc. Exp. Biol. Med. 80:319, 1952. 065, -----------: Factor 3, selenium and vita min E, Nutr. Rev. 18:193, 1960. 666. Scott, J. K.: Pathologic anatomy of acute experimental beryllium poisoning. Arch. Path. 45:354, 1948. 667. Seakins, A., and Robinson, D. S.: The effect of the administration of carbon tetrachloride on the formation of plasma lipoproteins in the rat, Biochem. J. 86: 401, 1963. 668. Sealy, W. C,: The induction of liver necrosis in rabbits bv the combination of experimental hyperthyroidism and Shope papilloma, Ann. Surg. 113:572, 1941. 669. Sellers, E. A., You, R. W., and Lucas, C. C.: Lipotropic agents in liver damage produced by selenium or carbon tetra chloride, Proc. Soc. Exp. Biol. Med. 75: 118,1950. 670. Selzer, G., and Parker, R. G. F.: Senecio poisoning exhibiting as Chiari's syn drome; report on 12 cases. Am. J. Path. 27:885, 1951. 871. Selzer, N.: Ai poisoni 14. 19i 672. Sevitt, transfu jects, I 673. Shaffer hypert 1940. 674. Shaffei J. the us< Aureoi titis, A 675. Shank H., K hetero (quan chem. 676. Shay, proms prevei alkali] alacet 32:57 677. Shay, necro Ann. ' 678. Sheel yellm poiso 47:4i 679. Sheri ringb and i Arch 680. Shiel Mac* tion buta: 681. Ship] zole Int. 682. Shor hyp* and 193J 683. Shoi gens heps Biol Shol hart due dye 264 p References 597 .get N.: Chronic after a single dose rolizidine {senecio) 1 74:305, 1957. iservations on the c liver changes in e of various pyrrolloids, J. Path. Bact. Reck-iagel, R, O.: (chloride on release rat adipose tissue, il. Med. 103:398, on, J. S., Jr., Work man, T. D.: Fatal ivenous administra. high dosage. New i, 1963. Mover, R. E-: The nonarv tuberculosis lsed alone and in tieptomycin, para- or isoniazid, Am. 1954. lerto unrecognized r necrotic liver dein veast (factor 3), Med. 78:852, 1951. factor 3 in dietary atic oncentration in, c. Soc. Exp. 952. selenium and vita: 193, 1960. ic anatomy of acute m poisoning. Arch. binson, D- S-: The istration of carbon donation of plasma it, Biochem. J. 86: induction of liver >v the combination perthvroidism and on. Surg. 213:572, R. W,, and Lucas, *nts in liver damage m or carbon tetraExp. BioL Med. 75: I r, R. G. F.: Senecio , as Chians syncases. Am. J. Path. 671. Selzer, G., Parker, R. G. F., and Sapeika, N.: An experimental study of senecio poisoning in rats, Brit. J. Exp. Path. 32: 14. 1951. Sevitt, S.: Hepatic jaundice after blood transfusions in injured and burned sub jects, Brit. J. Surg. 46:68, 1958. 673. Shaffer, J. M.: Disease of the liver in hvperthvToidism, Arch. Path. 29:20, 1940. 674. Shaffer, J. M., Farquhar, J. D., Stokes, J., Jr., and Sborov, V. M.: Studies on the use of Aureomycin in hepatic disease; Aureomydn therapy in acute viral hepa titis, Am. J. Med. Sci. 220:1, 1950. 675. Shank, R. E., Morrison, G., Cheng, C. H., Karl, I., and Schwartz, R.; Cell heterogeneity within the hepatic lobule (quantitative histochemistry), J. Histochem. Cytochem. 7:237, 1959. 676. Shay, H., and Siplet, H-: Studv of ehlorpromazine jaundice, its mechanism and prevention. Special reference to serum alkaline phosphatase and glutamic oxalacetic trasaminase. Gastroenterology 32:571, 1857. 677. Shay, H., and Sun, D. C. H.: Massive necrosis of the liver following iproniazid, Ann. Int. Med. 49:1246, 1958. 678. Sheehan, H. L.: The pathology of acute yellow atrophy and delayed chloroform poisoning, J. Obstet. Gynaec. Brit. Emp. 47:49, 1940. 679. Sherman, J. D., Love, D. E., and Har rington, J. F.: Anemia, positive lupus and rheumatoid factors with methvldopa, Arch. Int. Med. 120:321, 1967. 680. Shields, W. E., Adamson, N. E., Jr., and MacGregor, J. B.: Peptic ulcer perfora tion following administration of phenyl butazone, J.A.M.A. 152:28, 1953. 681. Shipp, J. C.: Jaundice during methima* zole ("Tapazole"} administration, Ann. Int. Med. 42:701, 1955. 682. Short, C- L., and Bauer, W.: Cinchophen hvpersensitiveness; report of four cases and a review, Ann. Int. Med. 6:1449, 1933. 683. Shorter, R. G., Bollman, J. L., and Baggenstoss, A. H.: Pressures in common hepatic duct of the rat, Proc. Soc. Exp. Biol. Med. 102:682, 1959. 684. Shotton, R., Carpenter, M., and Rine hart, W. B.r Bromsulphalein retention due to administration of a gall-bladder dye (bunamiodyl). New Engl. J. Med. 264:550, 1961. 685. Sidel, N.: Dinitrophenol poisoning caus ing jaundice: report of a case, J.A.M.A. 103:254, 1934. 686. Silverman, S. B., and Erickson, C. C.: Subcutaneous beryllium granuloma. Arch. Path. 50:63, 1950. 687. Simmons, G. Hobson, L. B., Resnick, A., DeNicola, R., and Bennett, R. H.: Human pharmacology of p-formylacetanilide thiosemicarbazone (Mivizone), Am. Rev. Tuberc. 62:128, 1950. 688. Simpson, D. C., and Walker, J. H.: Hy persensitivity to para-aminosalicvlic acid. Am. J. Med' 29:297, 1960. 689. Skromak, S. Schreader, C. J., O'Neill, J. F., and Ciccone, E. F,: Observations of chlorpromazine induced jaundice with continued use of the drug. Am. J. Med. Sd. 234:85, 1957. 690. Smetana, H.: Nephrosis due to carbon tetrachloride. Arch. Int. Med. 63:760, 1939. 691. Smillie, W. G., and Pessoa, S. B.: Treat ment of hookworm disease with carbon tetrachloride, Am. J. Hyg. 3:35, 1923. 692. Smith, M. I.: Chronic endemic selenium poisoning; review of the more recent field and laboratory studies,' J.A.M.A. 116:562, 1941. 693. Smith, N. J.: Death following accidental ingestion of DDT; experimental studies, J.A.M.A. 136:469, 1948. 694. Smith, R. M., Josvln, D. A., Gruhzit, O. M., McLean, I. W., Jr., Penner, M. A., and Ehrlich, J.: Chloromycetin: biologi cal studies, J. Bact. 55:425, 1948. 695. Smith, Kline and French Laboratories Bulletins (Philadelphia): Thorazine, Nov., Dec., 1954. 696. Smuckler, E. A., Iseri, O. A., and Ben- ditt, E. P.: Studies on carbon tetrachlo ride intoxication. I. The effect of carbon tetrachloride on incorporation of labelled amino acids into plasma proteins, Bio chem. Biophvs. Res. Commun. 5:270, 1961. 697. ---------- : An intracellular defect in pro tein synthesis induced by carbon tetra chloride, J. Exp. Med. 116:55, 1962. 698. Smyth, H. F.: Safe practices in the in dustrial use of carbon tetrachloride, J.A.M.A. 107:1683, 1936. 699. Smvth, H. F., and Smvth, H. F., Jr,: In halation experiments with certain lacquer solvents, J. Indust. Hyg. 10:261, 1928. 700. Snapper, I., Marks, D., Schwartz, L., and Hollander, L.: Hemolytic anemia second- 24905100 598 Toxic and Drug-Induced Hepatitis ary fo Mesantoin, Ann. Int. Med. 39:619, M. Elkind, M., and Carp, S.: Phenylbuta 1953. zone therapy of arthritis and other pain 701. Sneddon, I. B.: Berylliosis: a case report, ful musculoskeletal disorders, J.A.M.A. Brit Med. J. 1:1448, 1955. 150:1087, 1952. 702. ---------- : Bervllium disease. Postgrad. 716. Stenstrom, W.: Elimination of radioac Med. J. 34:262, 1958. tive elements by patients and rabbits 703. Snyder, R. G-, Traeger, C. H., Zoll, C. A., Kelly, L. C., and Lust, F. J.: The after injection of Thorotrast, Radiology 37:698, 1941. use of cinchophen in the treatment of| 7lY. Stephens, C. A., Jr., Yeoman, E, E., Hol chronic arthritis, J. Lab. Clin. Med. 21: brook, W. P., Hill, D. F., and Goodin, 541, 1936. W. L.: Benefits and toxicity of phenylbu 704. Soffer, L. J.: Postarsphenamine jaundice. Am. J. Syph. 21:309, 1937. tazone (Butazolidin) in rheumatoid ar_thritis,jlA1M!A^.150:ia84,..1952. 705. Solomon, F. A., Jr., and Compagna, F. 718. Sterner, j". H., and Eisenbud, M.: Epi A.: Jaundice due to prochlorperazine demiology of beryllium intoxication. {Compazine K Am. J. Med. 27:840, Arch. Industr. Hyg- 4:123, 1951. 1959. 718a. Sterup, K., and Mosbech, J.: Budd-Chiari 705a. Somayaji, B. N., Eeles, B. N., Paton, A., syndrome after taking oral contraceptives, and Parker, R. G. F-: Budd-Chiari syn Brit. Med. J. 4:660, 1967. drome after oral contraceptives, Brit. 719. Stewart, M. J.: Toxic jaundice in muni Med. J. 1:53, 1968. tion workers and troops, Brit. Med. J. 1. 706. Spain, D. M., Childress, W. G., and Fish 156, 1917. ier, J. S.: The effect of 4-acetvlaminoben- 720. ---------- : AtTopby of the liver, Brit. Med. zal thiosemicarbazone (tibione) on ex J. 2:584, 1920. perimental tuberculosis in guinea pigs,.. 721. Stifel, J. L., and Burnheimer, J. C.: Am. Rev. Tuberc. 62:144, 1950. Agranulocytosis following administration 707. Spillsbury, B. H.: Toxic jaundice in mu of phenylbutazone (Butazolidin); report nition workers and titoops, Brit. Med. J. of a case, J.A.M.A. 152 :555, 1953. 1:156, 1917. 722. Stokinger, H. E., Sprague, G. F., Ill, 70S. Spingarn, C. L., Edelman, M. H., Wave, Hall, R. H., Ashenburg, N. J., Scott, J. ]. D., Donoso, E., and Gregory, C-: Ob K., and Steadman, L. T.: Acute inhala servations on the treatment of schistoso tion toxicity of beryllium. I. Four defini miasis Mansoni with antimonv dimercap- tive studies of beryllium sulfate at ex tosuccinate (TWSb), Am. J. Med. 34: posure concentrations of 100, 50, 10 and 477, 1963. 1 mg. per cubic meter, Arch. Industr. 709. Slander, H. J.: Delayed chloroform poi Hvg. 1:379, 1950. soning, Am. J. Obstet. Gvnec. 23:882, 723. Stoll, B. A., Andrews, J. T., and Mot- 1932. teram, R-: Liver damage from oral con 710. Steagall, R. W., Jr.: Severe reaction to traceptives, Brit. Med. J- 1:960, 1966. griseofulvin. Arch. Dermat. 88:218, 724. Stolzer, B. L., Miller, G., White, W. A., 1963. and Zuckerbrod, M.: Postarsenical ob 711. Steigmann, F., and Popper, H.: Intra- structive jaundice complicated by xantho hepatic obstructive jaundice. Gastro matosis and diabetes mellitus, Am. J. enterology 1:645, 1943. Med. 9:124, 1950. 712. Stein, A. A., and Wright, A.; Hepatic 725. Stoner, H. B.: The mechanism of toxic pathologv in jaundice due to chlorpro- hepatic necrosis, Brit. J. Exp. Path. 37: mazine, J.A.M.A. 161:508, 1956. 176, 1956. 713. Steinberg, G. L., Bohrod, M. G., and 726. -----------: The effect of anaesthesia and Roodenburg, A. I.: Agranulocvtosis fol laparotomy on the blood-flow through lowing phenylbutazone (Butazolidin) the necrotic liver, Brit. J. Surg. 45:81, therapv; report of a fatal case, J.A.M.A. 1957. 152:33, 1953. 727. Strauss, N.: Hepato-toxic effects follow 714. Steinberg, H., Welb, W. M., and Rafskv, ing occupational exposure to Halowax H. A.: Hepatomegaly with fatty infiltra (chlorinated hydrocarbons). Rev. Gas tion secondary to cortisone tberapv. Case troenterol. 11:381, 1944. report. Gastroenterology 21:304, 1952 728. Struthers, E. B., Chang, H. H., Lin, L. 715. Steinbrocker, O., Berkowitz, S., Ehrlich, C., and Ch' en, J. T.: Antimony in the References 599 irp, 'henylbutaitis ana other painlisorders, J.A.M.A. nation of radioac- ` tients and rabbits jrotrast, Radiology eoman, E. E., HolF., and Goodin, <icitv of phenvlbuin rheumatoid ar- 084. 1952. ;senbud, M.: Epiium intoxication, 23, 1951. h, J.; Budd-Chiari ral contraceptives, 7. jaundice in muni:, Brit. Med. J. i: < ` liver, Brit. Med. mheimer, J. C.: lg administration tazolidin); report :555, 1953'. gue, G. F., Ill, N. J., Scott, J. / ve inhala- i. I. ar definin sulfate at ex100, 50, 10 and , Arch. Industr. [. T., and Mot? from oral con- 1:960, 1966.* , White, W. A., ostarsenical ob:ated bv xantholellitus, Am. J. lanism of toxic Exp. Path. 37: naesthesia and d-flow through P. Surg. 45:81, effects followe to Halowax s). Rev. Gas- I. H., Lin, L. j jtimony in the treatment of kala-azar, and its toxic ef fects, Chinese Med. J. 47:1421, 1933. 729. Stuart, F. P., Torres, E., Hester, W. J., Dammin, G. J., and Moore, F. D.: Or thotopic autotransplantation and allo transplantation of the liver: functional and structural patterns in the dog, Ann. Surg. 165:325, 1967. 730. Stuart, K. L., and Bras, G.: Veno-occlusive disease of the liver. Quart. J. Med. 26:291, 1957. 731. Suhrland, L. G., and Weisberger, A. S.: Chloramphenicol toxicitv in liver and re nal disease, Arch. Tnt. Med. 112:747, 1963. 732. Sulkowski, S. R., and Haserick, J. R.: Simulated svstemic lupus ervthematosus from degraded tetracvcline, J.A.M.A. 189:152, 1964. 733. Sulzberger, M. R.. and Simon, F. A.: Asrphenamine hvpersensittveness in guinea pigs; experiments demonstrating (A) the regional geographic variabilitv in susceptibility to sensitization (B) the chemical specificity of the hvpersensitivitv; and (C) variation in the sensitizing proclivities (sensitization index) of dif ferent brands, J. Allergy 6:39, 1934. 734. Summary of the National Halothane Study.- Possible association between halo thane anesthesia and postoperative he patic necrosis, J.A.M.A. 197:775, 1966. 735. Sussman, R. M., and Summer, P.: Jaun dice following the administration of 50 mg. of chlorpromazine. New Engl. J. Med. 253:499, 1955. 736. Sutherland, J. M., and Keller, W. H.: .Novobiocin and neonatal hyperbilirubi nemia; an investigation of the relation ship in an epidemic of neonatal hyper bilirubinemia, Am. J. Dis. Child. 101: 447,1961. 737. Svoboda, D., Grady, H. J., and Higginson, J.: Aflatoxin B| injury in rat and monkey liver. Am. J. Path. 49:1023, 1966. 738. Taft, L. I.: Methotrexate induced hepa titis in childhood leukemia, Israel J. Med. Sci. 1:823, 1965. 739. Tainter, M. L., and Cutting, W. C.: Mis cellaneous actions of dinitrophenol; re peated administrations, antidotes, fatal doses, antiseptic tests and actions of some isomers, J. Pharmacol. Exp. Then 49:187, 1933. 740. Tainter, M. L., and Wood, D. A.: A case of fatal dinitrophenol poisoning, J.A.M.A. 102:1147, 1934. 741. Talerman, A., and Thompson, R. B.: He patic fibrosis in a child possiblv due to prolonged methotrexate, J. Clin. Path. 19:81, 1966. 742. Ten Pas, A., and Quinn, E. L.: Chole static hepatitis following the administra tion of sodium oxacillin, J.A.M.A. 191: 674, 1965. 743. Tanvol, H., and Rehfuss, M. E.: Hepatotoxic effect of cortisone in experimen tal animals, Am. J. Dig. Dis. 22:169, 1955. 744. Thiers, R. E., Revnolds, E. S., and Vallee, B. L.: The effect of carbon tetra chloride poisoning on subvellular metal distribution in rat liver, J. Biol. Chem. 235:2130. 1960. 745. Thomas, E. W., Landv, S., and Cooper. C.: Reactions to penicillin therapv for svphilis, 1- Invest. Derm. 10:77, 1948. 746. Thomas. S. F.. Henrv, G. W., and Kapplan, H. S.: Hepatolienographv: past, present and future. Radiology 57:669, 1951. 747. Thulin, K. E., and Nermark, J.: Seven cases of jaundice in women taking an oral contraceptive, Anovlar, Brit. Med. J. 1:584, 1966. 748. Ticktin, H. E., and Robinson, M. M.: Effects of some antimicrobial agents on the liver, Ann. N. Y. Acad. Sci. 104: 1080, 1963. 749. Ticktin, H. E., and Zimmerman, H. J.: Hepatic dysfunction and jaundice in pa tients receiving triacetvloleandomvcin, New EngL J. Med. 267:964, 1962. ' 750. Tisdale, \V. A.: Focal hepatitis, fever and skin rash following therapv with sulfamethoxvpvridazine, a long-acting sulfonamide, New Engl. J. Med. 258: 687, 1958. 751. Tulloch, J. A.: A multiplicity of reac tions to carbutamide (BZ-55) therapv; report of a case, Diabetes 7:316, 1958. 752. Tvler, E. T., and Olson, H. J.: Fertilitv promoting and inhibitory effects of new steroid hormonal substances, J.A.M.A. 169:1843, 1959. 753. Tyler, M. \V., and King, E. Q.: Phena- cemide in treatment of epilepsv, J.A.M.A. 147:17, 1951. 754. Umiker, W., and Pearce, J.: Nature and genesis of pulmonary alterations in car bon tetrachloride poisoning. Arch, Path. 55:203, 1953. 600 Toxic and Drug-Induced Hepatitis 755. Unger, R. H., Madison, L. L., and Car ter, N. W.: Relative effectiveness of newer oral agents in the regulation of diabetic patients imperfectly controlled by tolbutamide studied within the frame work of a tentative subclassification of the disease, Ann. N. Y. Acad. Sci. 82: 570, 1959. 756. Urban, E., Frank, B. W., and Kem, F. Jr.: Liver dysfunction with mestranol but not with norethyndrel in a patient with Enovid-induced jaundice, Ann. Int. Med. 65:598, 1968. 757. Valdivia-Barriga, B., Feldman, A., and Orellana, J.: Generalized hypersensitivity with hepatitis and jaundice after the use of penicillin and streptomycin, Castroenterologv 45:114, 1963. 758. Vander Veer, J. B., and Fairley, D. L.: Mushroom poisoning (mycetismus); re port of four cases. Arch. Int. Med. 55: 773, 1935. 759- Van Ordstrand, H. S.: Current concepts of beryllium poisoning, Ann. Int. Med. 35:1203, 1951. 760. Van Wyk, J. J., and Hoffman, C. R.: Periarteritis nodosa; a case of fatal ex foliative dermatitis resulting from "Dilan tin sodium" sensitization. Arch. Int. Med. 51:605, 1948. 761. Velasco, H. A., and Sokal, J. E,: Cho lestatic jaundice in association with desacetylmethvlcolchicine. Report of a case, New Engi. J. Med. 260:1280, 1959. 762. VonGlahn, W. C., Flinn, F. B., and Keim, W. F., Jr.: Effect of certain arsenates on the liver. Arch. Path. 25: 488, 1938. 763. von Oettingen, W. F.: Manganese: its distribution, pharmacology and health hazards. Physiol. Rev. 15:175, 1935. 764. Waitzkin, L.: Hepatic dvsfunction dur ing promazine therapv, New Engl. J. Med. 257:276, 1957. 765. -----------: Probable hepatic allergy to chlorpromazine and deliberate desensiti zation, Ann. Int. Med. 53:116, 1960. 766. Wakim, K. G., and Mann, F, C.: Effect of experimental cirrhosis on the intra- hepatic circulation of blood in the intact animal. Arch. Path. 33:198, 1942. 767. Waldbott, G. L.: Anaphylactic death from penicillin, J.A.M.A. 139:526, 1949. 768. Waldo, J. F., and Tyson, J. T.: Hyper sensitivity to penicillin, J. Clin. Invest. 28:1039,' 1949. 769. Walker, A. R. P., and Arvidsson, U. B.: Iron intake and haemochromatosis in the Bantu, Nature 166:438, 1950. 770. Walker, C. O., and Combes, B.: Biliary cirrhosis induced by chlorpromazine. Gastroenterology 51:631, 1966. 771. Wallace, J., and Bushby, S. R. M.: Physiological and biochemical changes following hypertherm treatment, Brit, f, Vener. Dis. 19:155, 1943. 772. Warring, F. C., Jr., and Howlett, K. S.: Allergic reactions to para-aminosalicylic acid; report of seven cases, including a case of Loeffler's syndrome. Am. Rev Tuberc. 65:235, 1952. 773. Watson, C- J.: The effect of sulfanila mide upon the liver. Surgery 5:616 1939. 774. Watson, C. J-, and Spink, W. W.: Effect of sulfanilamide and sulfapyridine on hemoglobin metabolism and hepatic function. Arch. Int. Med. 65:825, 1940. 775. Waye, J. D., Donoso, E., Spingam, C. L., and Edelman, M. H.: Cardiotoxic effects of antimony dimercaptosuccinate in schistosomiasis; with special reference to coexistent hepatic dvsfunction. Am. J. Cardiol. 10:829, 1962/ 776. Weber, F. P.: A case of morbilliform and bullous eruption with jaundice, from Luminal, in a choreic child, Brit. J. Child. Dis. 22:280, 1925. 777. Wedum, A. G.: Immunological specific ity of sulfonamide azoproteins, J. Infect Dis. 70:173, 1942. ' 778. Weir, J. F., and Comfort, M. W.: Toxic cirrhosis caused bv cinchophen. Arch. Int. Med. 52:685, 1933. 779. Weller, C. V.: Hepatic pathology in exophthalmic goiter, Ann. Int. Med. 7: 543, 1933. 780. Wells, H. G.: Delayed chloroform poi soning: allied conditions: a note on die cause of the anatomic and clinical changes observed, J.A.M.A. 46:341, 1906. 781. Werner, S. C., Hanger, F. M., and Kritzler, R. A.: Jaundice during methyl tes tosterone therapv. Am. J. Med. 5:325, 1950. 782. Werther, J. L., and Korelitz, B. I.: Chlorpromazine jaundice; analysis of twenty-two cases. Am. J. Med. 22:351, 1957. 783. Whalley, P. J., Adams, R. H., and Combes, B.: Tetracycline toxicity in pregnancy: liver and pancreatic dvs function, J.A.M.A. i89:357, 1964. fj Store RL EEC* KJ S J... C Ord * ioe l-DEC-94 @ 12:17 Needs By: fiber: 1117445 itie: MED WOCHSCHR <S V O O E5 Slot O A To location: ;CAOOStaffer: N v- luae: 113 Issue: ISSN/ISSN: DATE: 1971 AGES: 1529w itle: MORPHOLGIE TOXISCHER HEPATOSEN... thor: KLINGE, 0 Note: CAQN Pag Count 4 Reason Not Filled w Hua.: 5393 w ce 1: 5393 C8 2: BAN Ord X3X&'7rOO Es Slot O-4-SW References 601 784. Whipple, C. H., and Sperry, J. A.: dno, J. T.: Purpuric manifestations of Chloroform poisoning; liver necrosis and heat stroke; studies of prothrombin and Biliarv repair. Bull. Johns Hopkins Hosp. 20; platelets in twelve cases. Arch. Int. Med. jmazine. 278, 1909. 77:27, 1946. 785. White, J. C.: Nephrosis occurring during 799. Wynn, V., Landon, J., and Kawerau, E.: R. M.: trimethadione therapy, J.A.M.A. 139: Studies on hepatic function during meth- changes 376, 1949. andienone therapv, Lancet 1:69, 1961. Brit. J. 786. Wieland, T., Schmidt, C., and Wirth, L.: 800. Yater, W, M., and Coe, F. O.; Ten years' Cber die Giftstoffe des KnoIIenblatter- experience with Thorotrast hepatosple- t, K. S.: pilzes VIII, Justus Liebig's Ann. Chem. nographv; Ann. Int. Med. 18:350, 1943. salicylic hiding a 577:215,1952. 801. Yater, W. M., and Whitmore, E. R.: 787. Wien, R., Freeman, W., and Scotcher, Histopathologic study of tissues of 65 m. Rev. N. M.: The metabolic effects produced patients injected with thorium dioxide bv certain aromatic diamidines. Arm. sol for hepatosplenography, with a fol ulfanila- Trop. Med. -37:19, 1943. low-up studv of 10 old cases. Am. J. 5:616, 788. Wilcox, W. W.: Toxic jaundice, Lancet Med. Sci. 195:198, 1938. 2:1, 1931. 802. Yesner, R., and Kunkel, P.: Preliminary Effect 789. -----------: Toxic jaundice. Lancet 2:57, observations on the effect of Aureomvcin, dine on - 1931. Terramvcin, Tibione, combined Tibione hepatic 5, 1940. 790. Wile, M. J., and Benson, J. A.: Exfolia tive dermatitis due to phenobarbital with and Streptomycin and Chloromvcetin on the morphology of the liver in man, Yale pingam, fatal outcome; report of two cases, Ann. J. Biol. Med. 2-3:299, 1951. rdiotoxic Int. Med. 13:1243, 1940. 803. Youmans, J. B., and Warfield, L. M.: uccinate 791. Wilenskv, A. O.: Fatal delayed anaphv- Liver injury in thyrotoxicosis as evi eference lactic shock after penicillin, J.A.M.A. denced bv decreased functional efficiency. , Am. J. -j 1-31:1384, 1946. Arch. Int. Med. 37:1, 1926. billiform 792. Wilmot, F. C., and Robertson, G. W.: 804. Zakv, A., Dorrv, L., and Salam, A.: The Senecio disease, or cirrhosis of the liver protective action of prednisone on the ee, from J. Chdd. due to senecio poisoning, Lancet 2:848, 1920. liver during tartar emetic treatment of bilharzial cirrhosis, J. Trop. Med. Hyg. 793. Wilson, M. E., and Stowell, R. E.: Cvto- 66:188, 1963. spe Jogical changes following roentgen irra 505. Zardav, Z., Rosenthal, W. S., and Wolff, . Infect. diation of the liver in mice, J. Nat. Can F. W.: Severe liver toxicitv after methvl- cer Inst. 1-3:1123, 1953. dopa, N. Y. State J. Med. 67:1897, 1967. Toxic 1- 794. Woldman, E. E., and Fishman, D.: 506. Zeffren, J. L., and Sherrv, S.: Effects of i, Arch. Intrahepatic obstructive jaundice follow prolonged tolbutamide therapv on he logv in Med. 7: ing the administration of 75 mg. of chJorpromazine, Ann. Int. Med. 47:332, 1957. patic function and serum cholesterol of adult diabetic patients. Metabolism 6: 504, 1957. )rm poi; on the clinical 46:341, 795. Wolff, W. A., Elkinton, J. R., and 507. Zelman, $.: Liver cell necrosis in chlor- Rhoads, J. E.: Liver damage and dex promazine jaundice (allergic cholangio- * trose tolerance in severe bums, Ann. litis); a serial studv of twentv-six needle Surg. 112:158, 1940. biopsv specimens in nine patients. Am. 796. Woods, W. W.: The changes in the kid J. Med. 27:708, 1959. id Kritzthv! tes- neys in carbon tetrachloride poisoning, and their resemblance to those in the "crush svndrome," J. Path. Bact. 58:767, 808. Zetzel, L., and Kaplan, H.: Liver damage concurrent with iproniazid administra tion, New Engl. J. Med. 258:1209, 1958. . '5:325, 1946. 809. Zimmerman, H. J., Alpert, L. K., and , 797. Woodward, D. J., and Solomon, J. D.: Howe, J. S.: The effect of nitrogen mus B. I.: Fatal agranulocytosis occurring during tard (bis-/?-chlorethyl amine) on liver lysis of promazine (Sparine) therapy, J.A.M.A. function and structure in patients with 22:351, 162:1308, 1956. neoplastic disease, J. Lab, Clin. Med. 798. Wright, D. O., Reppert, L. B., and Cut- 40:387, 1952. H., and