Document p6GnY7Koz6ja02a1JpQE3oxE

'130 . Annals New York Academy of Sciences 48. Duoois, P., ?. Amblaso, B. De Biomcourt & J. Leorand. 1972, Acropaihlc polyvinylique professlonnelle, Dull. Soc. Franc. Dermatol. Syphillgr. 79i 197. 49. Eckarot. ft. E. St R. Hihdin. 1973. The health hazards of plastics. J, Occupa tional hied. 15: 808. 50. Edmondson, H. A., R. U Peters, H. H. Frankel Sl S. Oorowskj. 1967. The early stage oi liver injury in the alcoholics. Medicine 46: 119. 51! Europachshie. 1972. Handclsblait GmbH. Dllsseldorf, West Germany. 'k'^,yu-*32~f*muu l, T_i V -Cxupanyi-fiajnhrmorc, Md. 53. Filatova, V. S. St E. Sit. Gronsbero. 1957. SaniUmo-gigieDiteskie usloviya Iruda v proifvodstve polikhlorvinilovol smolyt 1 meryl ikh ozdorovlenlya. Gigtena Sanit, No. 1: 38. 54. Fiutova, V. S., L. I. BaukHonova St B. Sit. Gronsoero. 1958. GlgJcniJeskaya kharakrerisiikp proizvodstva khloristovo vinija. Gigtena Truda Prof. Zabolevaniya 2(11: 6, 55. Filatova. V. S.. 6. Sit. Gronsbero, N. A. Smirnova, E. A. StuLova St 1. V. OaesCKSvic. 1965. Voproiyi gigienyi Iruda i sostoyanie zdorov'ya reboiikh, unyatyikh na proizvoastve latcEinovo poHvfniJkhlorida. Glglena Truda Proi. Zabolcvsniya 9: 9. 56. Filatova. V. S. 3t, V. A. ANTONVuuttNKo. 1971. Gigieni&cftMya usloviya (rude ( professional'naya ubolevacmost* reboiikh proizvodstva suipenzionnovo poll- vinilkhiorida v dinamike za ryad tet. Giglena Truda Prof. Zabolevaniya 15(4); 32. Fischer, J., H. MuNOSCiteNKi R, Wolf. 1965. MilzszInUgraphle mil l-Bromamcrcu,-; ("'tifi.J-hydroxypropan (BMHPJl Fortschr. GebJete Rcentgenstrahlen Nuklcanncd. 103:a-*. 58. Fischer. J., R. Wolf St H. Gamm. 1973. Die Milzszintigraphie. Dlsch. Arztebl. No. 7:401. n.n^C \ IQ AS T.iry./.^ nf ftvgg / rl.> 1 T -- ^^J^Jiir-jT^lrfcipphavtt Outtipauy.-Philadalphlty Ta. ~ 60. Gitsios, C. T. 1971. Aero-osteolysis in PVC workers. Med. Bull. Stand. Oil Co. 31(1): 49. 61. GOnther. O. 1956. Die Kunststoffe und ihre arbeitsmedizinische Dedeuiung. ZeMr. Arbeitinied. 61 156. 62. Harris, D. K. 1953. Health problems in the manufacture and use of plastics. Brit, l.ltvi. Med. I0i255. 63. Harris, D. K. 1W. G. P. AOaaij. 1967. Aero-osteolysis occurring in men engaged in the polymerization of vinyl chloride. Brit. Med. J. 3t 712. 64. Hcnsciiler, D,, Ed. 1972/1973. GesundheitsschKdllche ArbeitsstoiTe. Toxlkolo* gisch-arbeitsmedizintsche BegrUndungcn von MAK-Werien (Maximale Arbeit*plMi Konzeiurationen). Vedtg Chernte. Weinheim, West Germany. 65. HERat.6, K. 196). Polyvlnylchlorid. }n UUmanna EncyklopSdie tier lechnjschen Chemie. W. Foerit, Ed. 3rd edit. Vol. 14. Urban Sl schwareenberg. Milnchen, West Germany. 66. Hervieux St Tessier. 1959. Quei^ues observations d'exBosftfon e( d'intoWrance aux dfrivls vioyliquis et aux rlsmcs fthoxyllque*. Aren. Maladies Profess. lOt 61. 67. Uek, F. L. 1970. Portal hypertension in the presence of normal liver morphology, Ann. N Y. Acad. Sd. 17oifl}s 11 J. 66. (NVEaNATiofrAL Labour Office. 1971. Encyclopaedia of Occupational Health and Safety. Geneva, Switzerland. Vol. 1: 387. 69. International Labour Office. 1972. Encyclopaedia of Occupational Health and Safety. Geneva, Switzerland. Vol. II: 1467. 1I1 tnim."-*5- H1. I**1 H-'narnu*'1 t,yf,T?a*V^nii T ^an^-TuTICOiUlif. Volt lU-TaRieeiag Syndrom umf Aitrcosteolysen bel Arbeitern der PVC-herstcUenden Industrie Deut. Med. V-'ceftreur. 97: 1922. I^QSOGfrZ Marsteller tt oi.: Splenonv - iml rhlr-ri.U imljll Schiff, Ed. I.B. vrueiuuH. *w* rll. Kluge, T., H. Sowmersciiild Sl A. Flat sion. Surgery 68t 294. 78. Kramer, C. G. A J. E, Mutchler. 1972. menial measurements for workers exp Assoc.}. 33: 19. 79. Lanoi*. C.-E,, S. JOhe, G, Stein St G. chlorid-Krankhcil--cine beruisbedingtc med. 32: [, < 80. Leake. C, D. 1934. The role of pbarmac vhesU. 1. Am. Med. Assoc. 102*, l. ft h~ I rnmi*. fti I76fi fhrmit und TmiiltnHi - JUUel GermatryT 82. Lf8vrc, M. }. 1972. Internationales Syr Industrie, 27-29 April 1972, Ludwigsh 83. Lehmann. K. D. St F, Flurv, Eds. 1931 schen Lbsungsmitul. Julius Springer, B 84. LesTeb, D,, L A, GreEnoero St W. R. pealed exposures of humans and rats ti 24:265. 85. Lindner, H. 1973. Laparoscopy in alcohc 64; 842. 86. MacSween, R. N. M., J. M. Vetters, stone St A. T. Sanoison. 1973. Haer 1. Pathol. 109: 39. gj< Matren, It. grtk,Rrilr~gnrcnuTT. I964r Amair. dI^UTll!!TiuU ttTg~t^ 88. Maltonj. C.. M. Caespt i P. J. R. Burci on Cancer Detection and Prevention Medica Ini. Congr. Ser. No. 275. 89. Marin, A,, 1. Strauss. R, MicuiELS. J, I Acro-ost6olyse d'orijine profesjionncl contre le fthumatume, stance du 18 ja 90. MarkovviT2, S. S.r C, J. McDoN*'r, *'* enpationaj ecroostcolysis. Art [0 ; 91. Marsteller, 11. J., W. K. Let Rohnex 6e G. Veltman. 197 *4 1" In der PVC'Produktlon, Dcut 92. MAsnokumo, E., A. M. Fisf halation toxicity of vinyl chit I.Ji 394; Bull, Hyg. Jir 244. Ol LI B_tQ60 fVrnpnii Raftirnora) Msh '** 94. McCord, C. P. 1970. A new o 12: 234. 95. Muxet-siN. W. p., H. A. Eon Reywocos. 1965. Extra- and (hepatoportal sclerosis). Ann. 96. MlSOELO, V., H. J. SrOLtMAN Vinytchlorld-Polymerisaie un 48t 425. 97. hiORRil, J. T. Htot 3t A. E. Ann. Rheumatic Diseases 31: 98. Nettleship, A. St W. J. Fink. I thorotren. Am. t. Clin, Patlio H W H 0^ CO VO 99. Oettel, II. 1963. Gewerbetoxikologie Polymetijale eliloriedcr Atliykiie. Jn BFG36138 14 Toxic and Drug-Induced Hepatitis GERALD KLATSKIN, m.d. Hepatotoxins, a heterogeneous group of naturally occurring and synthetic chemical 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 pathlogenesis, all such lesions share a number of features in common. Characteristically, they (1) exhibit a distinc tive histologic pattern for any given hepatotoxin, (2) vary in severity in direct relation to the dose, (3) can be elicited in all indi viduals, (4) are reproducible in experimen tal arntnak and (5) appear after a pre dictable and usually brief latent period fol lowing exposure. In many instances, hepatotoxins 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 sensi tizing agents rather than hepatotoxins. Ac cordingly, a distinction must be drawn between drug-induced and toxic hepatitis. The features that characterize the lesions of drug-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 therapy, the latent penrioda boeing borniefr in some individuals and long in others; (5) the 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 the lesions are accompanied by extrahe patic manifestations of hypersensitivity, such as fever, rash, arthralgia and eosinophilia. A few drugs, such as chloroform, are true 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^ in the etiology of hepatitis, especially when^ the latter develops during a long coursefA of treatment, or after an extended laitteennt*tQ period. NOTICE THIS MATERIAL MAY BE PROTECTED BY COPYRIGHT LAW 1TTJIE 17 as. CODE) >atitis iod being brief in g in others; (5) the le lesions is more at of extrahepatic me instances, and others; (6) often mied by extrahepersensitivity, such nd eosinophilia. iloroform, are true the typical lesions , like the organic sensitizing agents id as hepatotoxins hiding some C-17 'roids and certain graphy, interfere nay give rise to actional disorders ampanied 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 5 administration gents. This posld in evaluating linistered drugs especially when a long course xtended latent Toxic Hepatitis 499 have demonstrated that carbon tetrachlo ride alters the permeability of the mito chondria of the hepatic cells, resulting in loss of diphosphopyridine nucleotide (DPN) and a decrease in the activity of the DPN- linked dehydrogenases of the Krebs cycle. In addition, there is a concomitant fall in adenosine triphosphate (ATP)17* and un coupling of oxidative phosphorylation.1111171 Biochemical13* and electron microscopic174 studies indicate that the mitochondria of the liver swell and fill with lipid under these conditions. Phosphorus172 and heliotrine134 produce similar effects, but whether these occur in other forms of toxic hepatitis is not known. That carbon tetrachloride can attack the mitochondria directly has been established in in vitro experiments.111-135 However, anoxia produces similar effects, so that the in vivo changes in mitochondrial enzymatic activity observed following carbon tetra chloride poisoning have been attributed by some to ischemia.51* The latter interpreta tion is open to question, but there can be lit tle doubt that mitochondrial damage does not constitute the initial event that leads to necrosis, since other histologic,530,334 biochemical3** and electron microscopic8*3 changes can be demonstrated much earlier. Recent studies suggest that the primary site of action of carbon tetrachloride is in the endoplasmic reticulum,800, ** a complex of cystoplasmic structures which are the source or the microsomes obtained on cen trifugal fractionation of the cells. These play a role in protein synthesis118 and in certain conjugating systems355 and possibly in lipid metabolism.900 Marked dilatation of the cistemae of the endoplasmic reticulum on electron microscopy608 and inhibition of mi crosomal enzymatic activities5** are de monstrable early in the course of carbon tetrachloride poisoning, before morphologic or functional changes in the mitochondria are evident. Interestingly, carbon tetrachlo ride8** and other hepatotoxins, such as diplasm by autolytic enzymes.TM The results methylnitrosamine,345 inhibit the in vitro of more recent studies support this view but incorporation of labeled amino adds into attach special importance to enzyme sys- protein by the microsomes of the liver. This supports the view that the inhibition of pro tein synthesis by hepatotoxins is responsible for the subsequent alterations in znitocbon- 500 Toxic and Drug-Induced Hepatitis drial morphology and function that ulti mately lead to cellular necrosis.69 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 respirabon and oxidabve phosphorylation in mitochondria,"44 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.28' 323 According to Himsworth, this effect is dependent upon a specific defi ciency of cystine.322 Moreover, ne 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, he 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 tbe 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 die hepatic necrosis induced by bromobenzene, and the fact that bromobenzene couples with cysteine before it is acetylated and excreted as mercapturic acid,3* lend support to the hypothesis that hepatotoxins injure the liver by inducing a relative deficiency of sulfur-containing aminn 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.198 However, direct measure ments have failed to demonstrate a fall in the glutathione content of the liver follow They rep< ing carbon tetrachloride poisoning.202 More over, it is difficult to reconcile this hypoth that block hepatic esis with the observation that a dietary de against hi ficiency of sulfur-containing amino acids in mitoch will not produce hepatic necrosis unless the seen folio diet is also deficient in vitamin E287-288-325 ing. How' and factor 3,**- 684 a naturally occurring or that the ganically bound selenium compound found due to tl in many tissues and foods.85 Indeed, that it wi Schwarz has shown that the protective ef induced J fects of methionine and cystine are depend perature ent not upon their content of sulfhydryl Interes groups but rather upon the presence of dilatation trace amounts of selenium.*5 ment of Ethionine, by trapping adenosine in $- rather thi adenosvlethionine, depletes the liver of instance ATP, leading to inhibition of protein syn the area thesis and accumulation of triglyceride.220 agent, ns Since all of these effects can be prevented via the j by intraperitoneal injection of ATP or its ever, the precursors, the inhibition of protein syn by hepat thesis is related to the depletion of hepatic ferences ATP. However, this is not the case in car the varic bon tetrachloride poisoning, since ATP in by zonal jection prevents the decline in hepatic ATP, of hepat but does not prevent inhibition of protein This pos synthesis.351 tions in Vascular Factors. Alterations in the intra cells foui lobular circulation may play a role in the Accorc pathogenesis of toxic hepatitis. Exposure to duces he carbon tetrachloride, for example, produces ability' of an immediate but transient intralobular acids.324 vasoconstriction, which, as exposure contin carbon t ues, is followed by a more sustained ob mia, it is literation of the sinusoids, possibly as a containii consequence of hepatocellular swelling. This methion has been demonstrated both by the quartz- against i rod transillumination technic7 and by in- oxygen i trasplenic India ink injection.288 Calvert and Lmportai Brody have attributed the vasoconstriction se can to stimulation of the central sympathetic biochem areas resulting in a prolonged discharge of On th the peripheral sympathetic nervous system urement and increased secretion of epinephrine.112 method' Since the degenerative changes and ne an imp crosis produced by carbon tetrachloride and challeng a number of other agents occur in the cen- a role in trilobular areas where the circulation is most necrosis impaired, many investigators have attrib chloride uted the lesions to ischemia.285,788 Evi ing to t dence in support of this hypothesis has been brought forward by Calvert and Brody.112 Cr blood fi using tl ^G36l4o c Toxic Hepatitis 501 of the liver followooisonirig.20* More- ncrfle this hypothi that a dietary de aling amino acids necrosis unless the /itamin E287,298-325 irally occurring ori compound found foods.065 Indeed, the protective efystine are dependtent of sulfhydryl the presence of m.665 j adenosine in Stes the liver of n of protein synof triglyceride.220 can be prevented >n of ATP or its of protein synjletion of hepatic : the case in carg, since ATP ini in hepatic ATP, bition of protein ions in the intraay a role in the ids. Exposure to mple, produces ent intralobular exposure contine sustained ob, possibly as a ar swelling. This \ by the quartzicTM and by inu*88 Calvert and vasoconstriction *al sympathetic sd discharge of nervous system epinephrine.1*2 langes and netrachloride and cur in the cenmlation is most s have attribiia.285'TM Evi-hesis has been and Brody.11* They reported that cordotomy, a procedure that blocks sympathetic stimuli ana 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.572 Interestingly, allyl formate, which causes dilatation of the sinusoids without impair ment of circulation, produces peripheral rather than centrilobular necrosis.633 In this < instance the principal point of attack is in the area of maximal concentration of the agent, namelv, where it enters the lobule via the portal tract at its periphery. Howj ever, the distribution of lesions produced | by hepatotoxins may be determined by dif- I ferences in the susceptibility of the cells in 1 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.879 According to Himsworth, ischemia pro duces hepatic necrosis bv limiting the avail ability of circulating sulfur-containing amino , acids.324 If the hepatic necrosis produced by ) 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 oxygen tension would appear to be a more important factor, inasmuch as anoxemia per se can produce similar histologic400 and biochemical318 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.7*8 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 alkaloids630,870 and massive doses of arsphenamine,34 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.304- 8*0, 870 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 medullaiy stimulation,11* (2) depres sion of fatty acid oxidation in the fiver due to a reduction in available DPN17* and ATP173 that follows mitochondrial damage, and 3) inhibition of the normal mechanism for the transport of triglyceride out of the fiver, presumably because of injury to the endoplasmic reticulum.800 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 fiver, 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 nonesterifiea fatty acids from the isolated epididymal fat pad while carbon tetrachloride does not,080 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 S O O S O G t'Z BFG36143 302 Toxic and Drug-Induced Hepatitis mobilize f:aattty acids by some other mecha- ence suggests that the same is true cf nism. Indeed, the elevated levels of free man, but the evidence is not nearly as con fatty acids found in the plasma following vincing. In general, starvation and high-fat the administration of such agents31 support diets enhance, whereas high-carboydrate this view. and high-protein diets protect against the Dianzani has reported that carbon tetra hepatotoxic effects of these agents. However, chloride uncouples oxidative phosphoryla in the case of many hepatotoxins the effects tion and lowers the ATP content of the liver of diet are not known. Moreover, the results before it produces fatty infiltration.173 Since of changing a single dietary constituent are ATP is essential in the activation of fatty difficult to interpret, unless due considera acid oxidation, he postulates that the ac tion is given to concomitant changes in the cumulation of fat is secondary to a reduc other components and caloric value of the tion in its rate of oxidation. This view has diet, and to their effect on net food intake- been disputed by two groups of investi factors that frequently have been neglected gators who have shown that the fat content in toxicity studies. of the liver rises before there is any uncou Even a relatively brief period of starvation pling of oxidative phosphorylation111'600 or increases the severitv of" tne heeppsatic damage impairment of octoanate oxidation,99 and produced by carbon tetrachloride238 and that this effect is not abolished by prevent chloroform.167 High-fat diets enhance their ing mitochondrial damage with ethylene- toxicity to an even greater extent.60-543 In diaminetetraacetate.111 contrast, carbohydrate appears to protect the Carbon tetrachloride, in addition to rais liver against injury by these and other ing the concentration of lipid in the liver, agents.80- *a lowers the plasma level of triglyceride and The effects of protein are variable, de inhibits the hyperlipema induced by intra pending not only on the nature of the hepa- venously infected Triton.00 From this, Reck- totoxin but also on other factors. Thus, pro nagel and associates concluded that fat ac tein deficiency increases the susceptibility cumulates because of damage to the mecha of the liver to damage by chloroform306 but nism normally responsible for the transport not by carbon tetrachloride.187 Similarly, a of triglyceride out of the liver.900 Moreover, surplus of protein protects against the he on the basis of indirect evidence, they have patic effects of chloroform506 but not against proposed that the most likely locus for this those of carbon tetrachloride187 or many mechanism is the membranous component other agents.185 The protective action of of the endoplasmic reticulum. Smuckler, protein also depends in part on the nutri Iseri and Benditt, who are in essential agree tional status. Thus, supplements are far more ment with this view, attribute the block in effective in preventing chloroform injury in triglyceride transport more specifically to the depleted animal than they are in the the depressed synthesis of protein required animal with normal protein stores.167 The for lipid conjugation.6* A number of obser source of protein is another factor that may- vations support this concept. The most im portant of these are that on electron micros influence contrast the results. with other PpM*roetaeti,nfso, raecxtaumaVlplyle,anin copy, the earliest findings in the liver fol hances the toxicity of some agents.81 lowing carbon tetrachloride administration other dietary constituents are of interest are cystic dilatation of the rough endo in connection with toxic hepatitis, not only plasmic reticulum and dislocation of the for their possible therapeutic value but also ribosomes from its membranes,697 and that for the cfues that they may provide to the these changes are accompanied by an inhi mechanisms involved in the actions of hepa bition of ribosomal protein697 and plasma totoxins. Of these, choline, methionine, cys lipoprotein67 synthesis. tine and tocopherol have received the great Nutritional Factors. The susceptibility of est attention. animals to hepatotoxins is greatly influenced Choline accelerates the removal of excess by their nutritional status. Clinical experi fat deposited in the liver as a result of car bon ing unc hav aga car not i tox stotail At car the crc he 3 fol Al bo ca im efl ve BFG36144 Toxic Hepatitis 503 e same is true of is not nearly as courvation and high-fat bon tetrachloride40 or phosphorus60 poison ducing a relative deficiency of sulfhydryl ing but does not prevent hepatic necrosis groups in essential enzyme systems of the under these conditions. Some investigators liver.185 Accordingly, it is believed that low high-carboydrate protect against the e agents. However, atoto.'dns the effects loreover, the results have reported that choline partially protects against the mitochondrial injury induced by carbon tetrachloride,136 but this effect has not been confirmed by others.111 Methionine protects against chloroform protein diets potentiate the toxic effects of these agents by hastening such depletion. The failure to demonstrate a fall in nepatic glutathione following carbon tetrachlo ride2"- casts doubt on the validity of this tary constituent are Jess due consideratant changes in the caloric value of the m net food intake-- iave been neglected toxicity both in protein-depleted507 and stock-fed animals.103 However, it is not cer tain that the site of its action is in the liver. At least in protein-depleted animals given carbon tetrachloride, methionine increases the survival time by preventing renal ne interpretation. An alternative possibility that has received relatively little attention is that protein depletion increases the apparent toxicity of such agents by retarding the re generation of injured hepatic cells. At one time, the glycogen concentration crosis-89 rather than by protecting against of the liver was thought to be the major fac period of starvation hepatic damage.184 In conjunction with tor that determined its susceptibility to in the hepatic damage alpha-tocopherol supplements, methionine jury. This concept was responsible for the Jtrachloride235 and also prevents the development of cirrhosis widespread adoption of high-carbohydrate diets enhance their following chronic selenium poisoning.669 diets in the therapy of hepatic disease. It is ter extent.80- 343 ln Alpha-tocopherol alone protects against car now known that the protective action of pears to protect the bon tetrachloride toxicity in rats on low- carbohydrate depends on its protein-sparing these and other casein diets. Prolongation of survival in this effect and its tendency to reduce hepatic t instance probably is not due to any hepatic lipids and not on an increase in hepatic t are variable, de effect, since liver damage is not pre glycogen.272 nature of the hepa- vented.341 Contributory Factors. Ethyl alcohol po factors. Thus, pro- Cystine has not been studied as extern-, tentiates the hepatotoxic effects of chloro the susceptibility sivelv as the other dietary constituents dis form,631 carbon tetrachloride,40* phos ' chloroform50* but cussed. It affords some protection against phorus228 and certain other chlorinated ide.187 Similarly, a the hepatotoxic effects of chloroform in the hy drocarbons.60 Since all of these agents are ts against the he- protein-depleted dog but is inferior to meth highly soluble in lipid solvents, it has been i50* but not against ionine in this respect600 and has no effect suggested that ethanol, by serving as a ve loride187 or many in other forms of toxic hepatitis.185 hicle, facilitates either their absorption from tective action of i The precise way in which dietary factors the intestinal tract or their penetration and part on the nutri affect susceptibility to hepatotoxins is not storage in cells.637 ments are far more known, but there is suggestive evidence that In experimental animals, injection of rela loroform injury in indicates that they may do so by altering tively innocuous bacteria greatly enhances 1 they are in the either the fat content of the liver or the size the hepatotoxic effects of chloroform and ein stores.167 The of its protein stores. In general, suscepti phosphorus and produces a type of mid- Jr factor that may bility is enhanced by diets that lead to an in zonal or massive necrosis that is not seen t, for example, in crease in hepatic fat or depletion of protein in uncomplicated poisoning with these sins, actually eri and is reduced by those that produce the agents.542 It has been proposed that under te agents.81 reverse changes.27* The heightened suscepti these conditions the hepatotoxins alter the ats are of interest bility associated with fatty infiltration of the permeability of the vessels in the liver and tepatitis, not only tic value but also 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 ly provide to the toxins in fat185-272 Obviously, this cannot plavs a similar role in man is not known. e actions of hepa- account for increased toxicity of agents that Anoxia increases the hepatotoxic effects methionine, cys- are relatively insoluble. As noted, it has of certain anesthetic agents.632 This would ^ceived the great- been postulated that some hepatotoxins, and appear to be an additive rather than a syner particularly the chlorinated hydrocarbons, gistic effect, since anoxemia per se can pro removal of excess produce hepatic necrosis by interacting with duce serious liver injury.208-490 s a result of car j sulfur-containing amino adds, thereby in- In experimental animals, antecedent he- 24905007 BFG36145 504 Toxic and Drug-Induced Hepatitis patic injury renders the liver more suscep tible to further damage by other agents!*0 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 tetrachloride11* and chloroformTM intoxication and in the peri portal zones in phosphorus poisoning.334 However, the distribution may vary in some forms of toxic hepatitis. Occasionally, the lesions extend beyond the confines of die individual lobules and give rise to areas of massive necrosis, as, for example, in poison ing with the Amanita phalloides toxin100 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.110 Carbon tetrachloride poisoning in man may be an exception. The writer has seen two instances oi 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 reticulum, 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,208-215 selen ium384 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.114-784 Following repeated exposure to relatively small doses of certain hepatotoxins, there may be a long interval before signs of cir rhosis become clinically evident.574 This does not constitute a period of true latency, sincdTW it is possible to aemonstrate the presence progressive lesions histologically at a ve. early stage.114 The delayed appearance symptoms in this instance is probably relat to the fact that the slowly progressive d BpG36l46 C:' 4' a<jng is zonal, regen* derly fashion within reticulum by proug viable cells in the estoring the normal owever, this is not epatic necrosis, in ;t proceed from disie zones of necrosis, nchvmal cells are the intervening neg intact reticulum, ducts, into broad ; condition variously rhosis, postnecrotic * hvperplasia and ate hepatic necrosis. 0 hepatotoxins, inloride,203-215 selenuces hepatomas in Although cirrhosis Dpearance of these a whether necrosis enchymal cells are elopment.215 Theootoxins can induce .wever, no authen1 reported. MATURES clinical manifestao not become evival following expo- ith agents such as id chloroform, the y brief, usually not , and is well correof the lesion micro* tologic evidence of a be demonstrated osis does not reach 18 hours.114-794 posure to relatively lepatotoxins, there before signs of cirvident.574 This does : true latency, since ate the presence of logically at a very ired appearance of is probably related 'ly progressive de struction of the parenchyma is accompanied by compensatory hepatocellular regenera tion. 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 i preicteric fever and constitutional symptoms. ] Anorexia, nausea and vomiting are the prinj cipal svmptoms, and jaundice and hepato- I: 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. ; As noted, repeated exposure to hepa totoxins may produce cirrhosis. The clinical course in sucn 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 i Laennec's 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 mild and Toxic Hepatitis 505 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 ana 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 24905009 BFG36147 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.188 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,38* 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 injured 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 injury 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.507 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 or 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 chloroform908 but not against carbon tetrachloride1*7 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 pot anorex of hep it is < Later, proves, cream, aged, j diet ai high c weight follow Obvi statena caloric based rather Withtl that 70 ones ct There i protein in cirrh mavv" ac advanc of bloo- In pi toxic h given i hepatoi tubular design* to atta take pr of the 1 dietary hydrate dogeno regulat Fortum protein not im liver in vere ai parent* any ill a numb i- Lgent necessarily facilitates \ injury has occurred. tetri in chloroform poisont. Here there seems to be rotein depletion enhances rotein supplements under e protective, even if given r exposure.507 However, :e to show that such suprecovery when adminisigns of liver disease have er, the protective action nstituents, including proemonstrated in depleted 10 conclusions are warheir therapeutic value in ividuals with toxic heplot be assumed that beistituent protects against : will necessarily do so ; well illustrated in the ich protects the depleted reform500 but not against e18T intoxication, ing the results of animal mist be exercised in disn the effects of dietary il and their effects on the ie former may be related ctors. Thus, in carbon ning, methionine inpreventing renal injury 3n liver damage.28* 2sults of dietotherapy in have encouraged its irms of liver disease, in>xic hepatitis. Although onable, there is no con> indicate that dietary ive in any type of liver lat associated with nu- moreprecise informanost efficacious form of epatitis, it would seem diet rich in protein and principle that protein te regeneration and is ate nonprotein calories fh there is no evidence dition of fat to a wellltaining 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 mat 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 Cm. 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 cirrhosis387 suggest that excessive amounts may actually be harmful in the presence of advanced liver disease, by raising die 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 free of severe hepatic injury,1** 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 the 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 prophylacticaUu protects the liver against carbon tetrachloride injury.381 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 BFG36149 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. Tne morphologic changes and the clinical manifestations in drug-induced hepatitis may be predominantly those 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. Pathocen-esis Surprisingly little is known about the mechanisms responsible for the development 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 hepatotoxins, 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 (1) that cannot be induced in all individuals, (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, *t2-413 Rich412'614 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.*11,415 Although the theory of acquired hyper sensitivity is based on an impressive body of evidence, some aspects of dnig reactions ap pear to be inconsistent. These include the rarity with which circulating antibodies and sltin 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.613 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- bednduced in all innot reproducible in morphologic features less distinctive than in which neither the snt of the lesions can amount of drug con* ich the latent period lictable. of the susceptibility tis and the frequency c lesions are accomis of hypersensitivity, eosinophilia, suggest this type are allergic and Chase132 have rities between drug -kness and have pront forms of acquired that is supported by .andsteiner,411-412* 418 r33,777 q particular don is the fact that ounds can serve as persensitivity,412, 738 inges in drug reaclose of experimental of acquired hyperi impressive body of )f drug reactions ap- These include the ting antibodies and q 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 i2ed host, and a re5 for the species.818 tuberculin type of erval between the nd the appearance ive host is usually 18 hours, and skin demonstrated with nt, our knowledge ragmentary to ac Drug-Induced Hepatitis 509 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,4"- 41S- 777 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 sensitivitv 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 hereditary 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. Why 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, mere is fax less individual variation, and the nature of the sensitizing agent plavs 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,811 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 question of how the hepatic lesions are pro duced in drug reactions. Buckley103 and FolIis288 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 likely to prove to be a sensitizing agent and may be expected to produce other manifestations of hypersen sitivity. Second, if it gives rise to extra- hepatic manifestations of hypersensitivity in some individuals, it can be predicted that sooner or later it will produce hepatitis in others. Cholestasis. Many drugs, such as chlor- promazine, produce a type 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 methvltestosterone. Drug-induced cholestatic hepatitis has been variously attributed to (1) subtle toxic iw s o s b z BFG36151 510 Toxic and Drug-Induced Hepatitis injury to the hepatic parenchymal cells, lifting to increased viscosity of the bile and occlusion of the canaliculim 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 ana rupture of the canaliculi into the spaces of Disse647, w8; 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 flow 583 and administration of massive doses of chlorpromazine for periods up to 6 months has not produced significant hepatic lesions or jaundice in such animals.570 These ob servations taken together with the fact that patients may recover from cholestatic hepa titis while still taking the offending drug,50 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 rash147 and eosinophilia." ` 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,1*4'w* the regular occurrence of Bromsuiphalein retention in man313,308 and of reduced bile flow23 and alterations In the electron microscopic appearance of the canaliculi850 in the rat suggest that these compounds behave more like hepatotoxins than sensitizing agents. Consistent with this interpretation is the fact that they do r rovoke an inflammatory reaction in t ver or produce clinical manifestations hypersensitivity, such as fever, rash eosinophilia. However, they differ frc most hepatotoxins in that they do not pi duce hepatic necrosis. Available evidec suggests that they interfere with bile exc tion by some unknown mechanism. Since the plasma levels of conjugated b rubin and alkaline phosphatase are Lnva ably elevated, it is generally agreed tl regurgitation of bile is the major factor sponsible for the development of jaund; in cholestatic hepatitis. Several mechanis have been invoked to account for the refl of bile under these conditions: (1) occ sion of the canaliculi by inspissated bile, (2) dilatation and ultimate rupture of t canaliculi into the spaces of Disse,**7 ( obstruction of the small bile radicles in ( portal triads by inflammatory exudate and (4) increased permeability of the cl langioles.82 Since each parenchymal cell drained by several canaliculi and ail canal uli are arranged in a complex network intercommunicating channels, it is higl improbable that the scattered bile thron seen in cholestatic hepatitis obstruct l flow of bile significantly. Although the possibility of rupture of l canaliculi into the spaces of Disse cam be excluded with certainty, electron mic scopic studies have failed to demonstr; such communications even under con tions of complete biliary obstruction.298 Occlusion of the cholangioles by infla matory exudate is often cited as an imp tant factor in the pathogenesis of dr. induced cholestasis. However, this has i been established histologically and appe; unlikely, since the inflammatory reaction the portal triads usually is less intense th in the hepatocellular type of drug-induc hepatitis and is totally absent in some cas Except in rare instances in which acti necrosis of the cholangioles has been de onstrated,807 there is no direct evidence tl these structures are abnormally perineal under conditions of cholestasis. One possibility that has received insu cient attention is that drugs may prodt cholestasis by affecting the bilirubin tra 24905014 4 ** Drug-Induced Hepatitis 511 t that they do not * reaction in the , manifestations of as fever, rash or they differ from it they do not proAvailable evidence sre with bile excrenechanism. 5 of conjugated biliphatase are invarilerally agreed that he major factor reipment of jaimdice Several mechanisms count for the reflux ditions: (1) occluinspissated bile,712 iate rupture of the es of Disse,047 (3) bile radicles in the unatorv exudate711 eabilitv of the choparenchymal cell is euli and all canalicomplex network of innels, it is highly ttered bile thrombi latitis obstruct the 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 type 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,-98 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 occurj ring form of cholestatic hepatitis seen in i South African sheep that feed on the poi sonous plant Lippia rehmanni.20 Rimington and associates have shown that in the rab bit, icterogenin, a trlterpene 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 r of rupture of die malities in the liver.813 They interpret these es of Disse cannot nty, electron micro- observations as evidence of a defect in the j transport of bilirubin through the hepatic led to demonstrate ven under condi- cells and suggest that icterogenin may alter cell permeability, permitting regurgitation obstruction.28 angioles by inflam- 1 of bile from the canaliculi. cited as an imporlogenesis of drug- ivever, this has not Really and appears amatory reaction in is less intense than pe of drug-induced ?sent in some cases. :es in which actual ales has been demlirect evidence that tormally permeable lestasis. as received insuffiIrugs may produce the bilirubin trans Pathology Drugs may give rise to a variety of lesions, depending on their mode of action. True hepatotoxins, such as chloroform, produce ! 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 gran- ulomata, some of which may involve vessel walls.245*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.577 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 canalicmi, 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, 807 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' 528,724 This svndrome has been reported following hypersensitivity re actions to the arsphenamines301-724 sul fanilamide,52 thiouracil,253 neocinchophen70 and chlorpromazine.52 Although ultimate recovery without significant residuals occurs and is said by some504 to be the rule, there are well-documented instances of slowly progressive periportal inflammation ana 24905015 512 Toxic and Drug-Induced Hepatitis fibrosis leading ultimately to the develop ment of biliary cirrhosis.*1'70, *** s" 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.*4*-781 Rarefy, drugs of this type produce peliosis hepatis,274* *T* an unusual disorder that mav 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 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 methyltestosteroue 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. Inis is illustrated by the fre quency with which Bromsulphalein reten tion,41* rises in the serum levels of alkaline phosphatase3*3 and transaminase,*4* and his tologic changes in the liver3*3 can be dem onstrated in the course of drug reactions un accompanied by jaundice or other overt clinical signs of hepatic involvement. Usually, prompt withdrawal of the offend ing drug is followed within a few days by recovery come in the histo levels oi cholestei of the ja with dc tends to other foi Drugs and cine that rese sionallv patic ne clinical i stances t complies elude si abdomin rapid dec edema, lence an course i* covery t of postm plasia. I logically such caj signs of years lat more signs oi may ens usually rhage fr rent infe ally, the reaction appears as long as a week subsidence of fever and other constitutional or two after cessation of therapy.32* manifestations. However, the signs of hepa In the Variations in the period of latency appear titis clear more slowly, usually requiring 2 to be dependent on host factors rather than to 3 weeks for full resolution. Occasion on the nature of the agent involved. In ally, they persist for many weeks or even hepatitis are iden hepatitis previously exposed individuals, readminis months. of semi tration or a drug may provoke a reaction Protracted cholestatic jaundice may be ac common following the first dose, presumably because companied by progressive enlargement of The t of antecedent sensitization. However, simi the liver and the spleen, intractable pruri cholesta E ? - lar immediate reactions are seen occasion tus and xanthomatosis,*2'70-529 features in ally in individuals with no history of previ distinguishable from those of so-called pri of extra for the ous exposure.42* It is difficult to account for mary biliary cirrhosis. In a few instances, transam such cases on the basis of hypersensitivity cirrhosis has been demonstrated histologi ease. Cli nnlftss it is assumed that inadvertent con- cally,*2, 70-528 but in others the inflamma in serun tact with the drug or with some chemically tory reaction and fibrosis in the liver have fraction related compound has occurred in the past. been less extensive, and apparent clinical rubin in 249051)16 BpG36l54 Drug-Induced Hepatitis 513 of drug-intbe abrupt jnifestations ver, chills, a pruritus and unpanied by ommonly by faundice and athin a few mied by enf the liver, oally but is .titis. Acholic it findings in constant fea- : jaundice is accompanylis is the rule ,tis produced r substituted may be seen ced hepatic the absence . by the frehalein retents of alkaline e,849 and his-an be demeactions un- other overt ement 5f the offendfew days by constitutional igos of hepa' requiring 2 n. Occasion?eks or even ce may be aclargement of ctable pruri- features in>o-called pri!w instances, ed histologi>e inflammaie liver have rent rliniraf recovery has occurred.5*4 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 hepatic necrosis. As might be expected, the clinical manifestations under these circumI stances are usually more severe than in un* J complicated acute hepatitis, and may in- | elude such unusual features as intense I 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 reS 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. Laboratory Features In the heptocellular type of drug-induced j 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 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 conjugated 1 fraction predominantly, excretion of bili rubin in me 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 cepbalin-choles terol 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-l4C indicate that the rate of choles terol and phospholipid synthesis under these conditions is greatly increased.52* 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 leukocyte count is normal or moderately elevated, but leukopenia and agranulocytosis are seen oc casionally.635 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,1S9*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 readmin ister drugs that have previously provoked manifestations of hypersensitivity unless the ^TOSOGfcZ 514 Toxic and Drug-Induced Hepatitis indications are urgent. Successful! desen sitization with graded doses has been re ported,78- 771 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 agent334- *** or may fail to recur when drug therapy is resumed following recovery.785 If desensitization is attempted, concomitant steroid therapy early in the course may help prevent reactions.785 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,554 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 die 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 mav 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 indivictuals with an allergic background, par ticularly those with a nistory of a previous reaction to other drugs. Indeed, during a reaction, patients may exhibit hypersensitivity to a wide variety of unrelated agents. For that reason it is best to stop all medications until the reaction subsides and then, if necessary, resume their use one at a time. Patients receiving sensitizing drugs should be watched carefuuy for early signs of a reaction. If fever, rash or pruritus occur, the medication should be stopped immediatelv, 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 phosphatase 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 heterogeneous group with respect to their chemical 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 alphabetically. The agents selected for discussion by 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, follows exposure to most of the beryllium dusts and fumes encountered in industry, appears after a relatively brief incubation period, is characterized pathologically by an exudation of mononuclear ceils 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,3"3 is characterized pathologically by a diffuse { ' j , , , . ( ; , ] } < ^ ] ` < ' ] . { < , \ { i i ] j ( j j , j , , , , j | 2490501 * Accidental and Industrial Poisoning 515 * exhibit hypersensif unrelated agents. to stop all medi- subsides and then, . r use one at a time, itizing drugs should early signs of a repruritus occur, the 3pped immediately, ;ible causes can be of patients given x serious reactions erum alkaline phosse should be tested g the first 2 months, sk. granulomatous reaction that closely re sembles sarcoidosis and runs a chronic pro gressive course that often terminates fatally.71*-758 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 mav 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 autopsy studies, that the chronic granulomatous lesion represents a late de velopment in the evolution of the acute 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*160 In advertent intoxication occurs also in individ uals who come in contact with the contami nated clothing of beryllium workers.108*803 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.185,738 Hepatic necrosis also occurs in animals after intravenous in jections of beryllium compounds.868 How pneumonic process.185 This view is difficult ever, the lesions produced tend to be mid- iS OF AGENTS to reconcile with the observation that, while zonal in location and do not occur when the RODUCING the inhalation of beryllium compounds pro beryllium is administered by the respiratory JURY vokes an acute pneumonitis, neither inhala route.722 Therefore, the centrilobular ne ;e such a hetero- l tion1-- nor parenteral administration68 of such agents produces granulomas in the crosis in man may be due not to the local toxic action of beryllium but rather to the pect to their chem- j lungs of experimental animals. passive congestion and anoxia that occur of action that they ' Several features of the granulomatous re terminally in acute beryllium pneumonitis. in any logical or action suggest that it results from sensi In the delayed form of chronic beryllium venience, therefore, tization to beryllium. These include its intoxication, small granulomata, similar to arranged alphabet- sporadic occurrence in exposed individuals, those in the lung, are often found scattered ?d for discussion by the long period of latency, the disparity throughout the liver.133*1S8-758 These are in mplete inventory of between the amount of beryllium found in distinguishable from the lesions seen in sar jure the liver, but produce toxic hep- the lungs and the severity of the lesions718 coidosis and a number of other related dis and the immunity of experimental animals. eases.335 Chronic passive congestion of the The fact that patch tests with beryllium salts liver secondary to cor pulmonale and heart provoke a granulomatous inflammatory re failure is another abnormality found with ) INDUSTRIAL ING UM m compounds may } pneumonitis or a eaction in the lung, re common, follows beryllium dusts and lustrv, appears after tion period, is charbv an exudation of he alveoli and usuy within 4 months, ic disease develops sure to beryllium datively long latent lonth to 15 years,303 gically by a diffuse action in the skin of affected individuals170' some frequency. In rare instances the liver 701 lends support to the sensitization theory. may exhibit central and midzonal necrosis,188 However, the possibility that beryllium can severe parenchymatous degeneration168 and firovoke a granulomatous reaction in the a diffuse fibrosis.185 Whether or not these ung by some direct action cannot be ex are directly related to the effects of beryl cluded with certainty, since subcutaneous lium is not known. injections of beryllium produce granulomas both locally281*880 and in regional lymph nodes.281 Berylliosis may be acquired in any occu pation involving the handling of beryllium or its compounds. Metal workers who ma 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 chine beryllium or alloys high in beryllium patch test may be required for confirmation. content, and manufacturers of ceramics, In this test a small gauze square moistened radio tubes and neon signs are the principal with a 1 or 2 per cent solution of beryllium victims.702 The use of beryllium phosphorus sulfate or nitrate is applied to the skin for in fluorescent bulbs was discontinued in 48 hours. On removal of the patch, patients 1949, so that this no longer constitutes the with berylliosis exhibit an area of erythema, hazard it once did.30* Individuals who live induration and scaling which may persist within a 3-mile radius of a beryllium plant for a number of weeks. Biopsy of the skin 8 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 autopsy00 evi dence that liver injury is more common after ingestion than after inhalatioa 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 nas been reported after the in gestion of as little as 1.5 ml.,437 yet recovery nas followed poisoning with amounts in excess of 100 ml.44* 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,914 for example, 11 of 12 fatal cases of accidental poisoning occurred in alcoholics. Similarly, of 34 individuals being treated for hook worm infestation with small doses of carbon tetrachloride, the only 2 instances of toxicity were encountered in alcoholics.801 Results of animal experiments confirm these clinical observations.400 The mechanism underlying this synergism is not known, but it has been suggested that are a mi is a< reco ever. an n long retui succi days alcohol, by virtue of its solvent properties, of lb enhances the absorption of carbon tetra chloride from the intestinal tract400 and facilitates its penetration and storage in cells,831 or it renders the liver more sus ceptible to injury by increasing its fat con tent.514 Another possibility is that carbon tetrachloride is oxidized to phosgene and then undergoes condensation with ethanol to form etnylchloroformate, a compound allegedly more toxic than carbon tetrachlo ride.233 ' None of these theories alone, however, accounts for the fact that alcohol enhances the toxicity of both ingested and inhaled carbon tetrachloride, that it increases the severity of injury in both the liver and kidney, and that die increased susceptibility is seen in chronic alcoholics who have not mlu be re unles direc has s necrc bon t recov scam flei fatal The f chan^ and c suppc active lium. been drinking immediately prior to poison ing.514 Moreover, whereas alcohol enhances the acute toxic effects of carbon tetrachlo ride, it does not increase the severity of the hepatic lesions in chronic poisoning.410 The chlori terest indivi days, Nutritional Status. Susceptibility to car bon tetrachloride also appears to depend on the nutritional status. In animals, in anition235 and high-fat diets80 increase the toxicity of carbon tetrachloride, whereas, surprisingly, low-protein diets do not187 The importance of these factors in man has not been investigated. Pathologic changes in fatal cases of car bon tetrachloride poisoning514 closely re semble those described in experimental an imals.114 The hepatic lesions are characterized by diffuse fatty degeneration and necrosis of the centrilobular parenchyma, collapse of reticulum, hemorrhage and leukocytic in filtration. Regeneration occurs early and proceeds from intact cells at the periphery of the lobule. In animals cytologic changes a fibri forma walls, lining to rem those failure show broncl thougf tion at rect ef right-si panies Are; be see: to the I observ< ure.SsM . BpG36l58 Accidental and Industrial Poisoning 517 tl cases of accidental alcoholics. Similarly, j treated for hook- small doses of carbon % instances of toxicity alcoholics.*1 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 irlying this synergism i been suggested that ts solvent properties, on of carbon tetratestinal tract40* and ion and storage in the liver more susicreasing its fat conlility is that carbon id to phosgene and isation with ethanol mate, a compound an carbon tetrachlo- succumbed to renal failure as long as IS days following intoxication still show signs of liver injury,514 which suggests that heal ing mav 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.110 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 nes alone, however, lat alcohol enhances igested and inhaled hat it increases the both the liver and reased susceptibility jolics who have not tely prior to poison- alcohol enhances f carbon tetrachloase the severity of hronic poisoning.410 jsceptibility to car- appears to depend us. In animals, in diets80 increase the achloride, whereas, n diets do not.107 i factors in man has fatal cases and may be the cause of death. The principal findings include degenerative changes in the tubules, the presence of heme and cellular casts, cellular infiltration of the supporting connective tissue, and signs of active regeneration in the tubular epithe lium.514 The pulmonary findings in carbon tetra chloride poisoning are of considerable in terest and are seen with great regularity in individuals who survive for longer than 8 days. Characteristically, the alveoli exhibit a fibrinous exudate with pseudomembrane formation, fibroblastic thickening of their walls, and proliferation of their epithelial lining cells.754 These appear to be related to renal insufficiency and are identical with those seen in other forms of acute renal failure. In addition, the lungs frequently show edema, hemorrhage, congestion and i fatal cases of ear 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 di rect effects of carbon tetrachloride. Often, *e characterized bv m and necrosis of diyma, collapse of and leukocytic in- right-sided dilatation of the heart accom panies these pulmonary changes. Areas of atypical focal pancreatitis may 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.20 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 ings511 that extensive hepatic necrosis may occur without producing either. Therefore, it is important to check the functional stasis of the liver 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 injury.514, ** Autopsy studies indicate that die kidneys 24905021 518 - Toxic and Drug-Induced Hepatitis are involved about as frequently as the However, the prognosis should be guarded liver, and in many cases renal failure dom early in the course of mild hepatitis, since inates die clinical picture.514* ** It has been the appearance of renal failure may be de suggested that there is an inverse relation layed for a number of days and then ter ship between the severity of the lesions minate fatally. If the patient survives the in die kidneys and the liver.514 Most deaths 1st week he is not likely to die of hepatic attributable to hepatitis occur during the failure. Similarly, if azotemia is not evident 1st week, whereas those due to renal fail by the end of the 1st week it is unlikely to ure occur in the 2nd and 3rd weeks.754 develop later, so that the outlook for re However, as indicated, usually there is evi covery is excellent. dence of both hepatic and renal injury in all If the initial effects of acute carbon tetra cases. Even in mild intoxication, the urine chloride poisoning are survived, the signs of usually contains albumin and casts during hepatitis usually subside in 2 to 4 weeks, the first few days. In more severe cases, a period slightly longer than that required oliguria appears between the 2nd and 4th for morphologic restitution of the liver in days and then may progress to complete experimental animals.114 As a rule, there are anuria. no residuals, but in occasional cases healing Azotemia, is common and occasionally is of extensive lesions is followed by post accompanied by hypertension. During the necrotic scarring.38* Recovery from renal in period of oliguria the specific gravity tends jury is somewhat slower but is always com to become fixed at a level of 1.010, and plete. Occasionally, cirrhosis follows re often the urine contains a significant num peated exposure to subclinical toxic doses ber of red blood cells and polymorphonu of carbon tetrachloride,574 as in experi clear leukocytes. In some cases, however, mental animals.114 The clinical picture in the urine shows little, other than a reduced . such cases does not differ significantly from volume and a low specific gravity, despite that in other types of cirrhosis, so that the the presence of severe azotemia. The close diagnosis depends almost entirely on the resemblance of the clinical picture to that history of exposure. Early recognition of in other forms of acute tubular necrosis has this condition is important, since the cir been emphasized.705 However, dehydration rhotic lesion may be reversible in its earlv due to fluid losses from the intestinal tract stages if further exposure to the toxin is often plays an important role in the develop prevented.114 ment of azotemia and must be taken into Treatment. The general principles of consideration in planning therapy. treatment are outlined on pages 505-508- As Not infrequently peripheral and pulmo mentioned, there is no evidence to indicate nary edema supervene as the azotemia pro that supplements of protein, methionine or gresses. While cardiac failure may be re choline exert any therapeutic effect in the sponsible for this complication in some well-nourished individual. However, it cases, often faulty regulation of fluid and possible that they may be of benefit in mal electrolyte balance is the cause. The dysp nourished individuals if given immediately nea, cyanosis and signs of consolidation that after intoxication. appear terminally are due usually to the A '.vide variety of chemically unrelated pulmonary lesions associated with azotemia substances, including tocopherol,340 glu described previously. Occasionally, acute tathione,10* sodium tbiomalate,102 sodium pulmonary edema is seen immediately fol malate,102 sodium thioglycollate,102 sodium lowing exposure to carbon tetrachloride. glycocollate,102 vitamin B12551 and adren This is thought to be the result of the direct ergic blocking agents112 reportedly protect irritant effect of the agent on the alveoli. animals against die toxic effects of carbon Prognosis. It is difficult to predict the tetrachloride when given prophylactically. outcome in any given case of carbon tetra However, they have not been tried as thera chloride poisoning. In general, the outlook peutic agents, and their mode of action is is favorable if jaundice is mild and the signs not understood. of renal impairment are minimal or absent. Hemodialysis is effective in the manage ment tetrac atitis often necros Chara the d rexia in sue patic panen 727 is Fev BFG36160 Accidental and Industrial Poisoning 519 should be guarded 'Id hepatitis, since allure may be de* days and then ter>atient survives the ment of severe renal failure due to carbon tetrachloride poisoning.883 Chlorinated Naphthalenes and Diphenyls ly to die of hepatic Because of their unique physical proper temia is not evident ties, the chlorinated naphthalenes and the eek it is unlikely to diphenyls make ideal materials for the in the outlook for re* sulation of electrical wire and condensers. : acute carbon tetraarvived, the signs of e in 2 to 4 weeks, than that required tion of the liver in As a rule, there are tsional cases healing followed by postovery from renal in but is always comrrhosis follows rejclinical toxic doses e,574 as in expericlinical picture in er significantly from irrhosis, so that the ost entirely on the arly recognition of 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.'*0 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 tant, since the dr- often terminates fatally in subacute hepatic versible in its early necrosis or postnecrotic cirrhosis.231- 27e-727 're to the toxin is Characteristically, the onset is insidious with the development of general debility, ano aeral principles of rexia and nausea and usually follows pro >n pages 505-308. As longed exposure to the toxin. Occasionally, evidence to indicate it is heralded by the appearance of an itein, methionine or acneform rash (chloracne), one of the well- peutic effect in the recognized signs of toxicity in handlers of lal. However, it is the chlorinated naphthalenes. Jaundice and oe of benefit in mal- 1 hepatomegaly appear a week or two later r given immediately and then are followed by a decrease in the j size of the liver, ascites and edema. The hemicallv unrelated | disease runs a chronic downhill course and tocopherol,340 glu- 1 usually terminates in hepatic coma and iomalate,102 sodium death within a few months. ;IycoUate,tt>2 sodium Occasionally, the lesion is more fulminant, Bi2581 and adren` reportedly protect ic effects of carbon en prophylacticaUy. 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 been tried as thera- patic necrosis or to the associated acute r mode of action is pancreatitis described by several authors231- 727 is not known. tive in the manage- 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.80 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,138 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 Cm. 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.138 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. 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 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.234 The possibility that chronic copper poi soning plays a role in the pathogenesis of the hepatic lesions in Wilsons disease is suggested by the high concentrations of copper found in the liver. However, with few exceptions,48* attempts to produce cir rhosis in animals by the chronic admin istration of copper salts have failed.432 DDT and Other Insecticides DDT (2,2bis(p-chlorophenyIj-1,1,1-tri- chlorethane) can produce central necrosis of the liver in animals,333 and is thus gen erally regarded as a potential hepatotoxin in man. However, despite its widespread use as an insecticide, it has rarely been re ported as a cause of toxic hepatitis. In one instance, the accidental ingestion of 120 ml of a 5 per cent solution in kerosene pro duced hepatomegaly, gastrointestinal bleed ing, oliguria, coma and death.**3 Autopsy revealed extensive central necrosis and periportal fatty infiltration of the liver and severe tubular degeneration and necrosis of the kidneys. Since DDT alone does not produce renal damage,*38 it was suggested that the kerosene used as a solvent was an important factor in the pathogenesis of the lesions. In another case, exposure to DDT used as an insecticide produced jaundice in an individual with an underlying cirrhosis.437 Rarely, DDT serves as a sensitizing agent. In one such case, it produced periarteritis nodosa.321 At autopsy, the liver showed en largement due to congestion, periportal fatty infiltration and a large, thrombosed vein. A number of other chlorinated hydrocar bons used as insecticides, such as chlordane, dieldrin, lindane and toxaphene, produce characteristic alterations in the cytoplasm of hepatic cells in the rat when administered at low-dose levels for long periods of time.*47 However, overt hepatic injury has not been reported in man. Dimethylnithosamine 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,24* The onset was abrupt with abdominal cramps, nausea, vomiting and jaundice and was followed within 2 weeks by the appearance of ascites. The less severely ill patient ap parently recovered after a prolonged course, but jaundice recurred in 16 months, and the liver remained large and indurated, which suggests that postnecrotic cirrhosis developed. The other patient died in the 6th week following an acute illness char acterized by deepening jaundice, intractable ascites and progressive enlargement of the liver and the spleen. Postmortem examina tion revealed extensive hepatocellular ne crosis, a diffuse inflammatory reaction with a predominance of round cells and histio cytes, and periportal hemorrhages. Dimethylnitrosamine exhibits the same propensity for producing massive hepatic necrosis and ascites in experimental animals, both when it is administered by inhala tion245- 3a* and when it is given orally3* or intraperitoneally.30-39 The lesions, which are characterized by extensive centrilobular and midzonal eosinophilic necrosis, re semble those of carbon tetrachloride poi soning but are more sharply circumscribed, show more hemorrhage and are devoid of hydropic or other slightly damaged cells.3* Small doses given over a long period pro duce a fetal form of cirrhosis in the rat.3* In addition, they may give rise to tumors in the liver, kidney and hmg.4*1 Although evidence indicates that follow ing its administration dimethylnitrosamine is uniformly distributed through the body water and enters all cells freely, its toxic actions are limited to the liver exclusively.48* This, taken together with the feet that it exhibits no in vitro effects on the metabolic activities of the liver,30-343 suggests that the sele methylni metaboli Accidt of iron i children, tablets c belief th In fati ings are stomach periport; fatty infi sions m<a Vomit: compani poisouin; coma an Occasion patients Promp dium bic deferoxa travenou ment of There longed ' hemosidi question to hemt Althougl duces h rats, it d< on an ad hemoehr dividual: iron the the pos: chronic importar rhosis, S of hemo Bantu,'7 cessive,7' tors as i the prim brewed 1 Indust dioxide < BFG36I62 24305ffi2 Accidental and Industrial Poisoning 521 ben administered 'Og periods of -patic injury has the selective hepatotoxic actions of di- methylnitrosamine may depend upon some metabolite formed in the fiver.30'345- 48-482 i. Iron SAMXNE Accidental poisoning with compounds i follow exposure of iron is an important problem in young, agent once used children, who notInfrequently ingest coated 2 cases reported tablets of ferrous sulfate in the mistaken re to the fumes belief that they are candies.33*-351, *15- 457 necrosis after 1 In fatal cases, the principal autopsy find jeetively..243 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 fatty infiltration in the liver.4*7 Similar le y ill patient ap- j sions may be produced in animals.457 rolonged course, Vomiting ana diarrhea, occasionally ac 16 months, and companied by melena, occur soon after and indurated, I poisoning. In severe cases, shock, acidosis, ecrotie cirrhosis i coma and death follow in rapid succession. ?nt died in the Occasionally, mild jaundice is observed in (te illness char- I patients who survive. dice, intractable ' Prompt lavage of the stomach with so irgement of the { dium bicarbonate and the administration of ortem examina- deferoxamine, by both the gastric and in- patocellular ne- , travenous routes, are effective in the treat y reaction with ment of acute ferrous sulfate poisoning.357 ells and histio- There appears to be no doubt that a pro Thages. longed excessive intake of iron leads to ibits the same hemosiderosis of the liver. However, the issive hepatic question of whether or not it can give rise nental animals, to hemochromatosis remains unresolved. red by mhala- Although prolonged iron administration pro ven orally** or duces hemochromatosis in choline-deficient lesions, which ' rats, it does not do so in animals maintained sive centrilob- on an adequate diet.465 Several instances of iic necrosis, re- hemochromatosis have been reported in in achloride poi- dividuals who have taken large amounts of circumscribed, iron therapeutically,373 but in such cases, are devoid of the possibility cannot be excluded that -maged cells.** . chronic anemia and other factors play an *g period pro- . important role in the development of cirs in the rat** j rhosis. Similarly, the increased incidence rise to tumors of hemochromatosis in the South African Bantu,97 whose dietary intake of iron is ex s that follow- cessive,7** may be attributable to such fac- tyhaitrosamine > tors as malnutrition and alcoholism, since 3gh die body ' the principal source of iron excess is home sely, its toxic brewed beer.** exclusively.48* s 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 son's disease.119,131217 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.228- 246 However, a complete review of all the reported cases of manganese poi soning in man217-783 discloses only one in stance in which a biliary cirrhosis is said to have been demonstrated.125 Therefore, it is highly improbable that the tvpe 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 paste409- 474 or rat poison.4** 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 Cm. 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.4'*9 Red phosj horns, 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 Tone and Drug-Induced Hepatitis even before characteristic tissue changes common, and the urine usually contains al and myoc can be demonstrated histologically.*** bumin, casts and red blood cells. renal hemt Symptoms. The initial symptoms, includ The latter part of the course is character faces and ing nausea, vomiting, epigastric burning, ized by coma, delirium and vasomotor col are also se abdominal pain and diarrhea, usually occur lapse and, as indicated, death occurs to is due to immediately following the ingestion of ward the end of the 1st week. grain, fora phosphorus or within a few hours. These are Occasionally, even severely poisoned indi produced due to the local action of the poison in the viduals appear to recover completely. How ing seleniu gastrointestinal tract. However, when symp ever, one such case, followed by serial bi A more toms do not appear for hours or days, they opsies of the liver over a period of 3 months, as the "bli are related to the systemic effects of ab showed evidence of incomplete healing and whose fee sorbed phosphorus. progressive fibrosis, a lesion similar to that content. \ Shortly after phosphorus is ingested, the seen in animals with chronic phosphorus testine an breath has a garlic-luce odor, and the feces poisoning,*85 How often this type of post the princij are luminescent in the dark, features that necrotic fibrosis and cirrhosis follows acute congested may be of great diagnostic importance. phosphorus poisoning in man is not known. but frank < In severe poisoning, shock and coma fol Pathology. At autopsy the liver is en In some low the initial symptoms in rapid succession, larged and exhibits extensive periportal fatty gestion of and death may ensue within 48 hours. More infiltration and degenerative changes in the only hepa commonly, however, the systemic effects are parenchymal cells, occasionally accompanied adenomas evident I to 3 davs after phosphorus is in by a mild inflammatory reaction in the por Himswo gested, and death occurs during the 1st tal triads. In one case seen by the writer, ity betwet week. Although it is highly probable that marked periportal bile stasis and pseudo selenium \ no tissue is wholly exempt, the liver and duct formation were outstanding Features tal dieteti the kidneys suffer the most severe injury late in the course of the disease. Massive gested ths and manifest the most striking structural necrosis of the parenchyma is said to quence of and functional changes. As in other severe occur437 but is exceedingly rare. The lesion containing intoxications, tissue damage is so wide in experimental phosphorus poiso ling485 is placement spread that often it is difficult to determine similar, but cellular necrosis is a more promi protein.322 the site of origin of any given symptom. nent feature. The renal tubules and the myo and meth The manifestations of systemic intoxica cardium also show degenerative changes would ap tion include intractable vomiting, often with and fatty infiltration. However, blood-streaked material, diarrhea, abdomi Treatment. Gastric lavage with a dilute vent liver nal cramps and severe prostration. Signs of solution of copper sulfate (0.25 Cm. in a doubt on severe liver injury can always be demon glass of water) and a magnesium sulfate Of spec strated, although hepatomegaly and jaun purge are recommended to rid the intesti question c dice may not develop. Jaundice seldom ap- nal tract of any remaining traces of phos seleniferoi Ejars before the 4th day and may be de- phorus. Unfortunately, these are effective yed for over a week. The prognosis is only if given within the first few hours. in man. J areas exci somewhat better when jaundice appears Treatment is largely supportive, as out nium in tl late. As in other forms of severe hepatitis, lined previously. Choline hastens the re nificant e the urine contains bilirubin, and the feces moval of fat from the liver in phosphorus to date w tend to become pale, which indicate that poisoning.89 However, its therapeutic value of hepatic bile secretion is suppressed. Not infre would appear to be negligible, since it does quently, hemorrhages occur into the skin not prevent hepatic injury. Semi and the mucous membranes, presumably A nun fa due to the associated fall in die prothrombin and fibrinogen levels of the plasma. Other Selenium In areas where the selenium content of genera Se contain p; features of severe hepatic failure can occa the soil is high, livestock develop "alkali atotoxic. ! sionally include edema, hypoglycemia, tyrosinuria and an increase in serum amino nitrogen. Usually the kidneys are affected equally severely. Oliguria and azotemia are disease," a chronic illness characterized by emaciation, loss of hair, lameness and sloughing of the hoofs.323 At autopsy, the principal findings are cirrhosis of the liver Asia and disease ai horses th< upon the 249 52S BFG36164 Accidental and Industrial Poisoning 523 isually contains al> x>d cells. >urse is charactermd vasomotor col- death occurs toeek. irely poisoned indi completely. Howavved by serial bijeriod of 3 months, nplete healing and ion similar to that ironic phosphorus this type of postlosis follows acute man is not known. ' the liver is enive periportal fatty ive changes in the nallv accompanied eaction in the por;en bv the writer, tasis and pseudotstanding Features : disease. Massive hyma is said to ly rare. The lesion us poisoning48* is is is a more promilules and the myojnerative changes age with a dilute 3 (0.25 Cm. in a lagnesium sulfate to rid the intesti:g traces of phoslese are effective it few hours, ipportive, as out' hastens the reer in phosphorus therapeutic value ible, since it does i ?nhim content of c develop "alkali characterized by lameness and At autopsy, the hosis of the liver {and myocarditis. Glomerulonephritis, ad1 renal hemorrhages, erosion of the joint sur faces and ulceration of the intestinal tract ' are also seen in some instances. The disease I 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. A more acute form of poisoning, known 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 H adenomas and low-grade carcinomas.534 Himsworth has emphasized the similarj ity between the hepatic lesions in chronic selenium poisoning and those of experimenj 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 placement of sulfur by selenium in plant protein.323 The protective action of casein and methionine in animals fed selenium would appear to support this hypothesis. However, the fact that cvstine 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, ! to date none of these has shown evidence : of hepatic or other disease.892 Senecio and Related Alkaloids A number of plants belonging to the genera Senecio, Crotalaria and Heliotropium - 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- *58-911 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 Chian syndrome.870 Both in animals871 and in man,970 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 iiicifolius and burcheUi, two weeds commonly known as ragwort.*70- 792 A similar form of toxic hepa titis affects natives of Central Asia who eat cereal grains contaminated with the seeds of Heliotropium lasiocarpine.109 Evidence suggests that the use of native "bush teas" containing extracts of Senecio and Crotalaria retusia for medicinal purposes may be re sponsible for the development of venoocclusive disease of the liver in Jamaican children.734 A similar explanation has been invoked to account for the common occur rences of cirrhosis in the children of West Bengal and Madras, India.384 However, in this instance, there is contradictory evidence pointing to the hepatitis virus as the re sponsible agent.8 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 parenchvma. 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.870- 792 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-occhisive disease of the liver seen in Jamaica.** The hepatic changes induced by senecio alkaloids in experimental animals are more variable than in maa Although some inves tigators have demonstrated alterations in the blood vessels with secondary conges tion, atrophy and fibrosis of the paren chyma,318, 792 others have shown that these agents may provoke acute centrilobular necrosis and cirrhosis by a direct action.106,134,858 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.108 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.638, 838 Clinical Features.670,792 In acute senecio poisoning, the onset is sudden with gnaw ing and colickv epigastric pain, followed within a few days bv 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.870 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 bv 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-occhisive dis ease in children resembles that of senecio poisoning.03*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. Tetrachlorethane Of all the chlorinated hydrocarbons, tetra chlorethane 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 onlv 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 30,286 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- 24905028 TiTiV.1 Vi'i'i Accidental and Industrial Poisoning 525 known, since reports of > biopsy studies are not 'cation probably occur, described in die liter- re of veno-occlusive dis sembles that of senecio vever, an acute onset is on, hepatosplenomegaly rrhosis appearing insidi. Also splenomegaly and re frequently. The morepatocellular failure and it for most deaths, pecific therapy is availnent is supportive and oing nutrition and con- HLOBTTHANE .ted hydrocarbons, tetrar the most toxic. During used widely as a solvent s, chieflv in the "dope" the canvas surfaces of a lesser extent, in the on and lacquers. Howbe so toxic that it was as a suitable substitute s found. During World . again, since it was the rent for impregnating trials that neutralized Despite the imposition ;ring and hvgienic con:.city were encountered h proportion of workers it However, the control l serious intoxication, so ulted.285 lly follows inhalation of occur also following its e skin or the intestinal iat are not entirely clear, susceptible than males, itoxication is more comof 30.TM The toxic level in the atmosphere is excess of 10 parts per uals exposed for long which closely resembles ichioride, is readily de tectable at a concentration of 25 parts per million.2** Pathologic Findings. The principal patho logic finding in fatal cases is a subacute or massive hepatic necrosis with preservation of the stroma, marked fatty infiltration of surviving parenchymal cells, absence of he patocellular regeneration, and active pro liferation of bile ducts.77 The early lesions in nonfatal cases have not been described. Fatty degenerative changes are also seen in the renal tubules and myocardium. Es sentially the same lesions have been ob served in rats exposed to tetrachlorethane vapor.707- 789 Symptoms. The early symptoms of tetra chlorethane intoxication are of two types: gastrointestinal and neurologic.285 Follow ing exposure to low concentrations of the vapor for a number of weeks, there is an insidious onset of anorexia, nausea and vom iting, or of headache, giddiness, drowsiness and paresthesias. These may occur singly or in combination and often are associated with hepatomegaly and impairment of liver function. Jaundice is also present in approxi mately 10 per cent of such individuals. Oc casionally, jaundice appears before other symptoms develop. Prompt cessation of ex posure to the contaminated environment at this stage results in rapid recovery, usually within a period of less than a month. Of possible diagnostic significance in early tox icity is the tendency for the absolute and relative number of large monocytes in the peripheral blood to increase.50 In more heavily exposed individuals, the onset is similarly delaved and gradual, but gastrointestinal symptoms, hepatomegaly and jaundice are constant findings and usu ally are associated with tenderness of the liver and weight loss. Not infrequently, the jaundice is intense and persists for weeks and even months following the last expo sure to tetrachlorethane. Recovery is possi ble at this stage,509 but some individuals run a progressive downhill course, develop ascites and die of hepatic failure.789 These are the cases that, at autopsy, show sub acute hepatic necrosis and postnecrotic scar ring. 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/20 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.29* 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. Hepato megaly and mild macrocytic anemia are relatively frequent Endings, 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 kidnevs show mild degenerative changes.99 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.448* TM*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,515 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.493 (2) Signs of he patic damage usually appear only after many weeks of exposure492 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 :-l) (5) It is difficult to reproduce the lesion in animals,333 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 cincbophen. 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.323 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 its 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 grease38,3,5 may 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 slowly. 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 as\mptomatic, 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 may be small. The course tends to be prolonged and often is complicated by the development of ascites and hemorrhagic phenomena. Occasionallv. there is an associated disturbance of the hemopoietic svstem, as evidenced by severe leukopenia,7^ macrocytic anemia719 or aplas tic anemia.351 Both hyperplastic719 and aplastic49 bone marrows have been de scribed, suggesting that the changes in the peripheral blood may 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. Unfortunatelv, little is known about the nature of the lesion in this group or its ultimate fate. In one 3-year 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 recovery from TNT hepatitis324-7'' illustrate that the scarred postnecrotic liver may be difficult to recognize clinically and Anesthetic Agents 527 ,n in the liver at high con-oducing fatty infiltration. need absorption of TNT ne presence of grease38,515 the sporadic occurrence of oups of apparently equally als. 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 TNT, it is possible that incurred during exposure and that the lesion pro- ive. ually, the onset of sympwith anorexia, nausea and appears within 2 weeks wed by hepatomegaly. In >minal pain is a prominent liver may be small. The >e prolonged and often is be development of ascites phenomena. Occasionally, sated disturbance of the m, as evidenced by severe crocytic anemia719 or aplasloth hvperplastic719 and marrows have been deg that the changes in the may be due to a maturai cases. outcome is unpredictable, sported in the literature ?d within a few weeks of xerosis of the liver324, 492 i hepatic failure resulting cirrhosis.729,788 However, with TNT hepatitis reely, little is known about lesion in this group or its me 3-year follow-up study l2 there were no clinical suggests that the initial ather than massive. Howpostnecrotic cirrhosis he 's long as 10 years after from TNT hepatitis324, TM scarred postnecrotic liver 5 recognize clinically and may decompensate unexpectedly years after obstetric and minor surgical procedures. its inception. It is highly probable that such Most fatalities have followed prolonged lesions can be recognized much earlier by anesthesia, especially during parturition, but the use of sensitive tests of hepatic function deaths have occurred also after as little as and especially by needle biopsy of the liver. H ounce of chloroform.258 Women under Vomittnc Sickness of Jamaica going prolonged labor appear to be peculi arly susceptible to this type of anesthetic Native Jamaican children, usually from death. This has been ascribed to the mal the age of 2 to 5 years are subject to an un nutrition and the infection which so fre usual disease characterized bv a sudden quently accompany such labors,637 a hy onset of severe vomiting, followed soon pothesis consistent with the experimental thereafter by convulsions and coma. Death observation in animals that malnutrition272- ensues within 2 or 3 days in 80 per cent of 397 and infection342 enhance the hepato- cases. The principal findings at autopsy in toxic effects of chloroform. clude fatty infiltration of the liver and kid From the paucitv of reports dealing with neys, hyperemia and petechial hemorrhages nonfatal cases of chloroform hepatitis, it is in the liver, spleen, heart, lungs and brain, easy to gain the erroneous impression that and degenerative changes in the renal tu chloroform either injures the liver seriouslv bules. The etiology is unknown. However, or not at all. However, in animals even a Hill has reviewed evidence suggesting that 30-minute period of chloroform anesthesia I malnutrition and the toxic effects of the causes significant impairment of hepatic ackee fruit, cassava and yams may play an function, which may persist for as long as important role in its pathogenesis.317 8 davs.932 (This disease is of particular interest be Clinical Features. The clinical manifesta cause of its striking resemblance to the Reve tions of severe chloroform intoxication fol syndrome (encephalopathy with fatty delow a uniform pattern.258,637, 709 Character generation of the viscera) first described in istically, the onset of symptoms is delaved 1965.808 In the many reports, the possibility for 24 to 72 hours following recovery from of intoxication has been considered, but in anesthesia. Drowsiness and vomiting then none has a specific hepatotoxin been impli appear and are soon followed by jaundice. cated. A recent review suggests that the dis Vomiting is copious and often becomes ease is of infectious origin, and possiblv at coffee-ground in nature. By the 4th dav the tributable to a variety of viruses, including drowsiness usually progresses to coma, and those of chicken pox, measles and mumps.127 in approximately half the cases is followed by convulsions. Despite the regular occur ANESTHETIC AGENTS rence of severe hepatic damage, jaundice fails to develop in some cases.TM Fever is In evaluating the role of an anesthetic unusual, except terminally. Azotemia and agent in the pathogenesis of postoperative acidosis occur early and tend to increase in hepatitis, due consideration must be given severity. Although these are usually associ to the nature of the underlying disease, the ated with oliguria and albuminuria, in oc degree of anoxia attained during anesthesia casional cases the urinary volume and the and the presence of such complicating fac urea content are high,258 suggesting that the tors as shock and infection, since each of azotemia is related in part to the rapid these alone can produce liver injury. breakdown of protein, rather than to renal failure and denydration alone. Chloroform Prognosis. Most severely intoxicated in Chloroform has the well-deserved reputa dividuals die in 3 to 8 days, but an occa tion of being a dangerous hepatotoxin. Al sional patient survives and goes on to com though largely supplanted bv other less plete recovery. Residuals are unlikely in toxic anesthetic agents, it is still used to such cases, since the characteristic lesions some extent in various parts of the world for seen at autopsy are zonal in type. Complete *0 HLV] a&iifeg 528 Toxic and Drug-Induced Hepatitis recovery without scarring also occurs in animU exposed to nonfatal doses of chloro form.754 Individuals who are exposed to repeated doses of Chloroform at frequent intervals occasionally develop cirrhosis. In one such case described by Wilcox, small amounts of chloroform were inhaled daily over a period of 6 months, at the end of which time jaun dice and hepatomegaly developed.75 Subse quently, ascites and other signs of cirrhosis appeared, and death ensued in 18 months. Pathology. At autopsy the liver is of nor mal size but may be small. Hepatocellular necrosis is invariably centrilobular in dis tribution and never massive. Varying frac tions of the lobule are destroyed, but a small rim of intact cells is always present around the portal triads. The necrotic cells break up into hvalinized fragments and undergo lysis, while the intact cells peripherally show marked fatty infiltration. As in other types of toxic hepatitis, the reticulum is not destroyed and usually is infiltrated with a number of phagocytic mononuclear cells at the sites of necrosis. The remaining hepatic cells show little evidence of regeneration. Almost identical hepatic lesions have been described in the dog.784 The changes in the kidney are less con spicuous than in carbon tetrachloride poi soning and usually consist of fatty infiltra tion of the convoluted tubules. Susceptibility. During the past decade considerable attention has been directed to the interrelationships between the hepatotoxic effects of chloroform and certain die tary factors. In brief, starvation,272 proteindepletion507 and a high fat intake343 increase the susceptibility to hepatic damage by chloroform, and diets rich in protein273 and carbohydrate272 are protective when given prophylacticaUu. Moreover, protein, methio nine and, to a lesser extent, cystine protect protein-depleted animals against chloro form toxicity if given from 24 hours before to as late as 4 hours after anesthesia.506-507 The theoretical implications of these obser vations are discussed elsewhere. None of these experimental observations is con cerned with the therapeutic effects of these supplements when administered following the development of toxic hepatitis, so that they do not provide a sound basis for treatment. thesia in are diffic since cir Cyclopropane Transient alterations in hepatic function have been observed following cyclopropane anesthesia. Usually, these are relatively dons in 1 ;al mai iction. Ha minor, but in patients with liver disease they Me mav be more severe.242 Changes of similar In cor magnitude are seen following anesthesia hydrocar with ethyl ether. Since the degree of func 1,1,1-trifli tional impairment bears little relation to the patic ne duration of anesthesia, it is highly probable cannot b< that such hepatic injury is the result of cir theless, c culatory changes and trauma incidental to encounte surgery rather than of cyclopropane toxicity. anesthed Divinyl Ether been vai icity or l Because divinvl ether can produce centri fection \ lobular necrosis in dogs,271 it is generally incidents regarded as a potential hepatotoxin in man. In a r In the dog, the severity of the hepatic dam well-doci age produced is closely correlated with the ciated hf duration of anesthesia, the nutritional status sented o and the degree of oxygenation.270-271 Ac is a sensi cordingly, certain precautions have been ducing h recommended. These include administration hvperser of carbohydrate preoperatively, limitation ble indiv of the duration of anesthesia to 1 hour, use of oxygen whenever the period of anes of cases be attril thesia is to exceed J* hour, and avoidance of divinyl ether in patients with liver dis sepsis,-' complete ease.52 Under these conditions, no instances of hepatic injury have been encountered in an extensive clinical experience with this agent.52 Although it would be unwise to abandon this cautious attitude toward divinyl ether, it should be recognized that its hepatotoxicity for man has not been fact thai induced cent,352 i of the Ni risk of 1 proximal As in i proved, and that the human liver may be as resistant to it as the monkev's.-71 Ether (Diethyl Ether) induced as ipron mine,432 halothan There are no clinical reports of toxic hepa titis following ether anesthesia. However, experimental evidence indicates that, in the dog at least; ether can produce mild liver injurv270 and transient impairment of he patic function.632 Bromsulphalein reten tion144 and other functional derangements242 have been reported following ether anes- from the reproduc cellular reaction eristic. ' t ^ a sensiti: current i S strongly rT Anesthetic Agents 529 patitis, so that nod basis for paHr function ' cyclopropane are relatively er disease they iges of similar no anesthesia egree of funcrelation to the ighly probable e result of ciri incidental to opane toxicity. coduce cenbri.t is generally otoxin in man. hepatic dam* lated with the tritional status ion.270- 271 Acis have been administration aly, limitation to 1 hour, use nod of anes- avoidance of ith liver diss. no instances ocountered in oce with this be unwise to itude toward cognized that has not been ver may be as -T1 HER) of toxic heparia. However, es that, in the ice mild liver rment of hebalein retenrangements242 5 ether anes- thesis 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 hepatitis is accompanied by function. other manifestations of hypersensitivity, Halothane ( Fluothane) and Mcthoxyflurane (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 patic necrosis in animals34 and, hence, to high fever, often accompanied by chills, cannot be considered an hepatotoxin. Never and occasionally by rash, arthralgia and 41 theless, cases of hepatic necrosis have been encountered in man following its use as an eosinophilia. In patients exposed to halo thane for the first time, the average interval anesthetic.1*7-12S- 440 Such lesions have between anesthesia and the onset of symp been variously ascribed to halothane tox toms is approximately 7 days, with a range icity or hypersensitivity, to intercurrent in of 1 to 12 days. Following multiple expo 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 days}. 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 Decrosis 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 bv 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,582 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- Hadothane 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 24905033 BFG36171 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.32 Methoxyflurane (Penthrane, 2,2-dichloro1,1-difluoroethyl methyl ether), a closely related halogenated ether, also may give rise to hepatic necrosis in susceptible indi viduals,386- 442 presumably by a similar mechanism, and 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 of 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.34 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 (Avektin) 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 dogs" 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.9 ANTIARTHRITIC AGENTS ClNCHOPHEN Hepatitis is by far the most serious com- Ilication 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.530 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 (cincbophen hydroiodide) and guphen (the guaiacol ester of cinchophen). Clinical Features. A number of features strongly suggest that the hepatitis produced C I by cinchophen is a manifestation of drug WC hypersensitivity. These include the follow ing: im .V ... ' Ati Ji i to work following re and`ultimate reg attack. Challenge lose of halothane for ills and fever within [ hours, evidence of ?as documented both logically. on (Avertin) halogenated hydronight be expected to jpatotoxin. Actually, nlv slight liver damhas been implicated ititis in man. Never- assumed that liver its use as an anesBromsulphalein rellows Avertin anesand in experimental fy enhanced in the nage. A more urgent mtion in the patient 3 danger of delayed da related to a de ntin detoxification.8* IC AGENTS 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 c cent.550 This has >r less toxic derivat these have proved e parent substance, are neoeinchophen iethyl cinchophen), xhophen), biloptin oxiliodide (cinchosnd guphen (the hen). number of features i 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.58-582 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.42,586, 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.168 5. Neither the incidence nor the severity of the hepatitis can be correlated with the amount or cinchophen ingested. 0. There is a remarkable tendency for the lesion to progress after withdrawal of the drug.55 7. Even lethal doses of cinchophen fail to produce significant hepatic lesions in ex perimental animals.3*4, *21,605 Skin tests for hypersensitivity are posi tive only occasionally,5*3, 882 and the results of attempted passive transfer of antibody by the Prausnitz-Kustner technic and of precipitin tests are uniformly negative.586,883 However, as indicated, these are seldom positive in other types of drug hypersen sitivity. Usuallv, 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 hypothesis; 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 disease488 or impaired he- padc function,488,588 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,421,605 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 invariably postmortem examination reveals a small liver without significant nodulation, even when the patient has survived for a number of months.51,428,450,580,604 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 {>rurittis or urticaria. Jaundice usually fol- Although massive doses of desacetylmethvi- ows within a few days but may be delayed colchicine can produce hepatic congestion for weeks or even months.778 Anicteric hep and necrosis in rabbits 781 the character of atitis has been described*88,778 but is rare. the hepatic lesions and the associated symp The jaundice increases in intensity, usually toms seen in man suggest that they are due reaching its maximum in a few days and to drug sensitization. then persists. As might be expected from the nature of Gold the hepatic lesion, bilirubimiria and pale The gold compounds used in rheumatoid or clay-colored stools are seen early. Al arthritis frequently produce manifestations buminuria, cylindruria and oliguria are com of toxicity. These fall into two groups: (1) mon, but severe renal failure is rare. The anaphylactoid and febrile responses imme subsequent course is variable.778 diately following an injection and (2) de Prognosis. In fulminant cases, the patient layed reactions involving the skin, mucous lapses into coma and dies of hepatic failure membranes, gastrointestinal tract, liver, kid within the first few weeks. This is by far the neys and hemopoietic system.21,157 It is not most common type of death. Other cases known whether these are due to drug in run a chronic course, occasionally inter toxication or to sensitization, but the latter rupted by clinical remissions; ultimately is generally considered more likely. ascites and edema develop and the patient Hepatitis is one of the less common com dies within 6 months of hepatic failure or plications of gold therapy and is said to be bleeding from esophageal varices. The most clinically indistinguishable from the viral favorable cases improve slowly and go on type.307 Since many of the cases reported to apparent recovery in 6 to 8 weeks. As have occurred in individuals undergoing indicated, the prognosis in this group must group therapy in large outpatient clinics,307 be guarded, since relapse and evidence of it is possible that they represent instances progression mav appear at a later date. of syringe-transmitted viral hepatitis. Un In a recent report "cholangiolitic" cirrho fortunately, no epidemiologic or histologic sis with xanthomatosis, allegedly due to in- data are available to substantiate this. trabepatic biliarv obstruction, appeared 18 Massive hepatic necrosis is said to occur sears following neocinchophen therapy.70 rarely,189 but in no reported cases has the There was no immediate reaction to the diagnosis been established by postmortem drug, but it was considered possible that an examination. In the few fatalities that have anicteric hepatitis had occurred and then been investigated,21 the changes in the liver progressed at a subclinical level for a num were nonspecific, and no lesions suggestive ber of years. This is a reasonable interpre of a hvpersensitivity reaction have been de tation, in the light of experience with other scribed. drug reactions, although it is difficult to ex BAL is of some value in the. treatment of clude alternative possibilities. Desacet^xmethylcolckicine (COLCEMIDE, DeMECOLCDTE) dermal reactions following gold therapy.4*8 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, Desacetybnethvlcolchicine, an alkaloid kidney and hemopoietic system. with antimitotic activity, is an effective thera peutic agent in acute gout and chronic mye logenous leukemia. It produces fewer gas Indomethacin ( Indoclv ) Indomethacin [l-(p-chlorobenzovl)-5-me- trointestinal symptoms than colchicine. thoxy-2-methylindole-3-acetic acid], rarely However, serious side reactions, including produces hepatitis. In one reported fatal bone marrow depression, alopecia, fever, case, that of a 12-year-old Negro boy, pro rash, stomatitis and jaundice, have been re- fuse rectal bleeding and deep jaundice ap ported.177 peared after 5 or 6 months of treatment Hepatic involvement is relatively uncom with prednisone and indomethacin for se mon and usually is of the cholestatic type.781 vere juvenile arthritis.374 The liver was en larged reveal crease positiv action, time : deepei died 1 of the zonal i fatty i minim In a atome; 3 wee therap An un serum high c color, hue. T amina: but th lestero centril mild f tense i mator and t) transa; nisone of the ered 6 tory e this Ci that ii biliver or, alt deficie light b It v that ii liepatc thougl lishea, is atti since r l^COf -O , cn 1 -C3 BFG36174 v'{ ***:' : desacetylmethylepadc congestion be character of associated sympthat they are due ed in rheumatoid ce manifestations two groups: (I) responses immetion and (2) dethe skin, mucous il tract, liver, Idd;m.21 157 It is not due to drug in>n, but the latter re likely. ss common comand is said to be t from the viral e cases reported uals undergoing patient clinics,507 Dresent instances il hepatitis. Ungic or histologic ubstantiate this, is said to occur ed cases has the by postmortem .alities that have inges in the liver ;sions suggestive >n have been de- the treatment of gold therapy.485 in all cases, it is ts the course of jiving the liver, tem. toon) obenzoyl)-5-metc acid], rarely reported fatal 'Jegro boy, proep jaundice ap is of treatment lethacin for see 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 centrilobular zonal necrosis with bile stasis, small-droplet fatty infiltration of the parenchyma and a minimal inflammatory reaction. In a second, nonfatal case, jaundice, hep atomegaly and abdominal pain were noted 3 weeks after the onset of indomethacin therapy for chronic rheumatoid arthritis."* 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 5 centrilobular degeneration and swelling, l 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 die 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 eaema, asthma, leukopenia and thrombocytopenia. Phenylbutazone (Butazoudin) Thehigh incidence of untoward reactions ; Andarthridc Agents 533 to phenylbutazone limits its usefulness as an antiarthritic agent. ns>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,400-580 are probably based on other mechanisms. Hepatitis is a relatively uncommon com plication of phenylbutazone therapy.213, *** 7is, -is. 721 when it occurs, it is almost al ways accompanied by other manifestations indicative of 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, buTrare instances of anicteric~Hepafitis~Have been reported.727 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- **713 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.010 Hepatic involvement is rare, but one fatal case has been re ported.^8,0 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 readminis tered a month later it promptly produced asthma and rash followed by progressive jaundice, clay-colored stools, hepatomegaly. OS06t,Z BFG36l75 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.3**-433 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 indirectly311 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 oecome 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 animals694 or in pa tients with hepatitis.29* Routine biopsies in individuals without hepatic disease also have failed to demonstrate changes in the liver following chloramphenicol therapy.** Chloramphenicol should be used with caution in patients with severe liver disease, 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 relativelv in nocuous so far as the liver is concerned, one of its esters, propionyl erythromycin ester of lauryl sulfate (Ilosone), produces tvpical cholestatic hepatitis in a small proportion of exposed individuals.389 Since the hepatitis not infrequently is accompanied by eosinophilia and 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 and often is accompanied by abdominal distress, which may be colicky in nature.221 Charac teristically, thymol turbidity and cephalin- cholesterol flocculation are normal, while tiie 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. Gfiseofulvin In mice, chronic administration of large doses of griseofulvln 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.138 The hepatic lesions have been ascribed by some investi gators to a direct toxic effect of griseofulvin,37 and by others to overproduction 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 bilej Antibiotics 535 gVh'ei*n#"icol therapy.8* ould be used with severe liver dis- -rtally prone to bone HimV enhanced sus- radides, resulting in biliary obstruction and secondary parenchymal changes.847 Rats, guinea pigs and rabbits are not susceptible to these effects of griseofulvin. Many patients receiving therapeutic doses necrosis and died on the 13th day following the onset of symptoms.98 The morphologic changes in the liver were indistinguishable from those seen in fulminant viral hepatitis. alication appears to of griseofulvin for tinea infections also show Oxacillin (Pbostaphlin) levels of free chlor- increased protoporphyrin and copropor- The semisynthetic penicillin, sodium oxa n the serum as a re- phvrin in their feces and red blood cells.818 cillin, produces allergic reactions charac igation in the liver However, they do not exhibit other bio terized by fever,-rash, urticaria and eosino ch the unconjugated chemical evidence of hepatic injury.444- 818 philia in approximated 3 per cent of eted by the kidneys. Several individuals with acute intermittent patients. In one such patient, the reaction vrraN in is relatively in- porphyria given therapeutic doses of griseo was accompanied by typical cholestatic fulvin dining a remission have experienced hepatitis that resolved in little over 3 a relapse.84-801 In one of these, acute months.712 er is concerned, one ervthromycin ester porphvria was accompanied bv mild Brom- Oxacillin therapy oceasionallv is accom sulphalein retention and an increase in panied bv moderate elevation of serum e), produces typical small proportion of serum transaminase.801 glutamic oxalacetic transaminase.498 Since Griseofulvin may serve as a sensitizing no details are available on the circumstances Since the hepatitis agent and give rise to reactions character under which this occurs, it is not clear mpanied by eosino- ' ized bv fever, rash, urticaria and angio whether such alterations in serum trans 9produced in expert- j neurotic edema.28-T1 In at least one in aminase are due to drug toxicity or sensitiza asonable to assume stance, cholestatic hepatitis resulted.95 tion, or to the underlying infection for nsitization. The oc- 1 urticaria and other j Novobiocin which the drug is used. . this view. ^ Therapeutic doses of novobiocin tend to Penicillin * appears between j raise the level of unconjugated bilirubin in In 1 or 2 per cent of individuals given s of medication and the serum,59 and occasionally give rise to penicillin, manifestations of hypersensitivity abdominal distress, overt jaundice,154 especially in neonates.738 develop.427 Urticaria and other benign types i nature.221 Charac- Since hemolysis does not appear to be the of skin rash predominate, but fatal cases of iditv and cephalin- factor responsible for this effect, it is highly anaphvlactic shock,'7-791 exfoliative derma are normal, while dine phosphatase rise. The signs and e promptly subside frawn, but usually ! a second time. LVIN inistration of large ds to the developirvthropoietic porenlargement of the r necrosis, ductular tion of pigment in :cts.168 The hepatic d by some investi effect of griseoto overproduction xcretion of proto 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,738 it would appear to be related to a functional disorder of pigment metabolism rather than to toxic injury. Not infrequently, novobiocin induces hy persensitivity reactions characterized by titis-"87 and acute vasculitis5 also have been reported. Acute hepatitis is a relatively rare com plication, usually seen in association with exfoliative dermatitis.387- 737 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 normal.717 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 mono cytes, eosinophils and neutrophils. Dubin has reported one instance of prolonged peni cillin-induced cholestatic hepatitis in which recovery occurred in one and a half years.191 That the hepatitis provoked by penicillin deposition in par- fever, rash, pruritus and eosinophilia.98 is due to sensitization and not to hepato- ills and its precipi- Rarely, these may be accompanied by hepa toxicity is evident not only from the other intrahepatic bile titis. One such patient had massive hepatic 24905039 BpG36l77 538 Toxic and Drug-Induced Hepatitis it is associated, but also by the fact that the lesions are not reproducible in animals.1*-299 Rifamycin SV Large doses of rifamycin given intrave nously produce a transient increase in serum bilirubin and interfere with the excretion of Bromsulphalein.9 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.5 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.907 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 ments512 and studies of hepatic function907 and morphology90* 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 (Aureomycln). Thera peutic doses of orally administered chlor tetracycline frequently produce a fine fatty vacuolization of the hepatic parenchyma that is readily reversible on stopping the drug.943,945,802 However, the drug appears to have little effect on hepatic function, Oxyte even in patients with antecedent liver dis vacuolu ease,149, 974 so that the lesion probably has curs wii no clinical importance. peutic c Intravenous chlortetracycline, on the orally oi other hand, can produce significant liver eral da) damage, as evidenced by impairment of clinical function, clinical jaundice and hepatomeg- versible aly.45-429> 842 This is most likely to occur in and givi individuals who have received excessively nificant large doses intravenously in addition to oral even in medication,45,428 but significant injury has ease.293 been observed also after as little as 1 Gm. in mice intravenously for 3 days.042 Conceivably, Seven hepatitis in such cases is due to the asso ness are ciated infection. However, the same type ceiving of injury has been produced experimentally casional in both man45 and animals,42* so that there itv hepa is little reason to doubt that intravenom as yet n< chlortetracycline is potentially hepatotoxic. Tetrai Histologically, the liver shows the same type minister of fine fatty vacuolization seen after the oral daily o< administration of chlortetracycline, but the tion of I centrilobular cells tend to undergo autolysis on hepai and fragmentation, and bile thrombi are Large common.45,429 when i In animals, inactivation of chlortetra women cycline by heat does not abolish its toxicity may giv for the liver, which suggests that the he >S.08l77S patic lesions are due to a direct chemical and moi effect and not to an indirect action related the acui to chlortetracycline s antibiotic activity. cases oc Of special interest is the observation that intraven chlortetracycline protects animals against cvcline t the massive hepatic necrosis produced by has beei low-sulfhydryl, low-tocopherol diets, an i Gm. ( effect thought to be related to inhibition of or orall) the intestinal flora and a reduction in the trimestei formation of hypothetical hepatotoxic bac victims < terial metabolites.200 On the principle that in the p similar bacterial factors may be of impor sionally tance in the pathogenesis of hepatic coma, dren191 : chlortetracycline has been recommended as ease is i a therapeutic agent in that condition.222 On of cases. the whole, the results of this form of treat At poi ment have been disappointing. parench; Large doses of chlortetracycline also pro with fine tect against the hepatic and die renal effects *3 pearance of choline deficiency in rats.47 The mecha flammati nism of this action is not known but appears ^ ?hepatoce to be related to the antibacterial properties ^ ^Kupffer of the drug. ^ [Jphagocyi <5 bFG361 78 Antibiotics 537 epatic function, ident liver disi probably has tdine, on the significant liver impairment of md hepatomeg aly to occur in ved excessively addition to oral ^nt injury has little as 1 Gm. 2 Conceivably, ae to the assothe same type experimentally ** so that there at intravenous ly hepatotoxic. s the same type n after the oral ycline, but the lergo autolysis i thrombi are of chlortetralish its toxicity i that the heirect chemical action related activity, 'servation that imals against produced by ol diets, an > inhibition of uction in the latotoxic bacDrinciple that be of imporlepatic coma, unmended as idition.222 On orm of treat line also prorenal effects The mechabut appears al properties Oxytetracycline (Terramycin). Fine fatty vacuolization of the hepatic parenchyma oc curs with great regularity following thera peutic doses of oxytetracycline given either orally or parenterally over a period of sev eral days.45 The lesion appears to have no clinical significance, since it is readily re versible following withdrawal of the drug and gives rise to neither svmptoms nor sig nificant impairment of hepatic function, even in patients with pre-existent liver dis ease.383 Similar lesions have been observed in mice and dogs429 but not in rats.350 Severe reactions resembling serum sick ness are known to occur in individuals re ceiving oxytetracycline,31 so that the oc casional development of drug hypersensitiv ity hepatitis is to be anticipated. However, as yet no such cases have been reported. Tetracycline (Achromycin). Orally ad- | ministered tetracycline in doses up to 2 Gm. daily occasionally produces fatty infiltra- j tion of the liver, but has no adverse effect { on hepatic function.21* Large doses of tetracycline, especially j when given intravenously to pregnant . women with complicating pyelonephritis, may give rise to severe hepatic injury.<05sea. eel. *83 jn such women, both the clinical and morphologic features mimic those of the acute fatty liver of pregnancy. Most cases occur 3 to 5 days after the onset of intravenous treatment with doses of tetra cycline exceeding 2 Gm. daily. However, it has been reported after doses as small as 1 Gm. daily given either intravenously*1 or orally.733 Although women in the third trimester of pregnancy are the principal victims of this complication, it may occur in the postpartum period and is seen occa sionally in nonpregnant women55 and chtfdren11 and rarely in adult males. The dis ease is fatal in approximately 80 per cent of cases. At postmortem examination, most of the parenchymal cells of the liver are distended with fine vacuoles, giving them a foamy ap pearance. Although foci of necrosis and in flammation are not seen, the number of hepatocellular nuclei is reduced and the Kupffer cells contain large amounts of phagocytosed debris and pigment, indi cating antecedent necrosis and loss of par enchyma.405 In many cases, the kidneys show fattv vacuolization of the renal tu bules and foci of cortical necrosis, unre lated to underlying pyelonephritis, and in a high proportion there is evidence of acute pancreatitis.407' Inordinately high levels of tetracycline have been found in the serum of patients with tetracycline-induced toxic hepatitis.733 Accordingly, it has been suggested that im pairment of renal function related to pyelo nephritis and diminished extracellular fluid volume mav be important factors in the pathogenesis of this complication. In addi tion, the possibility has been considered that pregnancv, bv enhancing the uptake and diminishing the excretion of tetracycline by the liver, as it does in the case of Bromsulphalein, leads to an unusually high con centration of the drug in the liver and thus renders it susceptible to toxic injury.733 The principal clinical manifestations are nausea, vomiting, abdominal pain and jaun dice. Not infrequently the vomitus is coffeeground in character. Evidence of renal fail ure is common, and in some cases there are signs of acute pancreatitis. Remarkably, the recovery rate was SO per cent in one series of 5 cases treated vigorously for acute pan creatitis. In fatal cases, the patient lapses into coma and dies within a few days. Fetal death occurs in 70 per cent of women who die, and in 40 per cent of those who sur vive.405 Laboratory studies reveal leukocytosis, azotemia, evidence of acidosis, and a mod erate elevation of the serum levels of bili rubin, alkaline phosphatase and transami nase. Usually, thvmol turbidity is normal, but the cephalin-cholesterol flocculation re action tends to be strongly positive. In many cases, the serum levels of amylase and lipase are increased. The occurrence of a Fanconi-like syn drome and features simulating disseminated lupus erythematosus have been reported following the use of degraded tetracy cline.738 These have not been accompanied by evidence of hepatic injury. The hepatotoxic properties of tetracycline have been confirmed in the rat.303 However, W 2 53$ Toxic and Drug-Induced Hepatitis in this species pregnancy does not appear to increase the susceptibility to hepatic injury. Triacetyloleandomycin (Cyclamyon) A high proportion of individuals receiving triacetyloleandomycin in a dose of 1 Cm. 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.-'-3'7'18'749 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 I 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 me 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 dermatitis12- 4*7-780 or hemorrhagic ery thema multiforme21 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, lymphadenopathy and eosinophilia. Occasionally such reactions are accompanied by hepatosplenomegaly 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 fiver shows evidence of diffuse injury, with foci of necrosis, acidophilic bodies, infiltration of both the parenchyma 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.136 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.TM Mesantoin (3 methyl-5.5-ethylphenvlhydantoin) Mesantoin, a compound closely related to Dilantin, may give rise to fever, rash, lvmphadenopathy and aplastic anemia,2" 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.70 Nervanol (Phenvlethylhydantoin) Nirvanol, a compound closely related to Dilantix tive an< regular] action, eosinop the reac so that i country dence c but no hepatiti A rev fatalitie tic dost the dm introdu ger of doubt i and att biturab frequei as wid< parent no sign The barbita more si dermat and bU membr are ma althou rivatm of mets respond The occum lions.46 showee necrosi ing c< change less sti ported. colorec associa Anticonvulsants, Muscle Kelaxants and Sedatives 539 Ithe central nervntestinal tract are igin and usually Dilantin, was once widely used as a seda tive and in the treatment of chorea.311 It regularly produces a typical sensitization re iting the dose. On action, characterized by fever, rash and ions, which often eosinophilia, in 1 to 2 weeks. Occasionally, r and other con- the reaction is severe and terminates fatally, )ear to be mani- so that the drug has been abandoned in this jnsitivity and are country. Agranulocytosis and autopsy evi a they often sub- dence of liver injury have been described, ig administration, but no instances of clinically detectable se to exfoliative hepatitis have been reported. emorrhagic ex terminate fatally. Phenobarbital Dilantin-induced A review of the literature records only 17 121). 156. 193. 60S fatalities as a result of reactions to therapeu have occurred in tic doses of phenobarbital.468 Since tons of ifestations of hv- the drug have been consumed since it was h, fever, lymph- introduced into clinical medicine, the dan lia. Occasionally ger of serious reaction must be small. No inied by hepato- doubt mild reactions are relatively common undice.32-487 In | and attract little attention. The other bar- biochemical fea- ' biturates appear to produce reactions less I^ellular jaundice cholestasis. On frequently. However, none of them is used as widely as phenobarbital, so that the ap dence of diffuse parent difference in their toxicity may have osis, acidophilic no significance. the parenchyma The principal clinical features of pheno ny mononuclear barbital reactions are fever and rash. In >ile stasis.308 Oc- more severe cases, there may be exfoliative is submassive iD dermatitis, renal failure, signs of hepatitis, patic coma and and bleeding from the skin and the mucous ;e of Dilantin- membranes. It is highly probable that these tis, there was, in are manifestations of drug hypersensitivity, necrosis of ar- although it is held by some that phenol de mation that in- rivatives, liberated during an abnormal type ling the liver.780 of metabolism in susceptible individuals, are responsible for tissue damage. Thydantoin) The cases of hepatitis reported have all occurred in association witti dermal reac closely related tions.468, 778 In one of these,488 the liver to fever, rash, showed extensive midzonal and periportal istic anemia,253. necrosis, with vacuolization of the remain garded as mani- ing cells. However, the hepatocellular rsitivity. Minor changes in other fatal cases780 have been on may be ob- less striking. In the one nonfatal case re ans, but frank ported,778 moderately severe jaundice, clay- countered.1* At colored stools and dark urine occurred in ired hemolytic association with a morbilliform and bullous eruption. Complete recovery followed within 3 weeks. itoin) The writer has seen one instance of chronic hepatitis following a phenobarbital sely related to 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 myeloid metaplasia. Death occurred 2H 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, 258 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.733 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 in jury 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, 733 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,1-4 so that close supervision is essential for as long as treatment is continued. The pathologic changes found in fatal cases of hepatitis are not constant.183,432 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.438 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.424 Rarely, hepatitis,417 nephrosis744 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 [narrow. 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.81 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 (FlEXIN) 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* 33*359 Of the cases reported, most have terminated fatally with signs of mas sive hepatic necrosis.128*M0,458 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 the 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 the liver in animals,273 they do not appear to produce hepatitis in workers exposed to them in industry.287 Toxic doses of both the bivalent 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.431-532 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.709* 775 Since the oc currence of tnese 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-  *1 * >**' -`-S'- foitfi-aiiiiiiti; razolamine-induced hepawith ACTH 359 , of this type of hepatitis ce zoxazolamine occasionrfn rash, the possibility of vity must be considered, bv the report that eosinod in the inflammatory exuliver in one fatal case.123 ie of the other reported been any clinical or morindicative of a sensitizadirect hepatotoric action since zoxazolamine does tic lesions in animals. RAPEUTIC AGENTS N INFECTION JHIMONY inorganic compounds of ire the liver in animals,273 it to produce hepatitis in 0 them in industry.27 noth the bivalent and the ic antimonials induce fatty ie liver, kidneys and heart going treatment for kalafrank hepatitis has been 'nnection with the penta- Almost without exceps in such cases has ap?r two following compleof intravenous injections, may represent instances tted viral hepatitis. Howclinical features nor the ? have been described in 5 permit definite conclu?ir etiology. lercaptosuccinate (Asti- antimonial used in the histosomiasis, frequently :vel of glutamic oxalacetic 1 less commonly that of ase.708.7Ts Since the oc- 5 changes appears to be he total dose employed, t they are manifestations However, biopsy studies 'eral patients undergoing ided 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.804 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 syphilis3*4-051 or inorganic salts,782 produce acute necrosis of the liver. Depending on the circum stances, the lesions mav be massive,394 centrilobular831 or focal782 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 arsenotherapv.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 s\Tiiptoms. 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.782 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 9m day," or Milian's syn drome.301, 844 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- 844 The hepatitis associated with Milian's syn drome is of the classic cholestatic type. Characteristicallv, 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 clay-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 syndrome 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 types of biliarv cirrhosis. By far the most common type 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,480 histologic175 and epidemiologic844 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 T<ndc and Drug-Induced Hepatitis No doubt most reported cases of massive hepatic necrosis3** and postnecrotic cirrho sis4, 175 following arsenotherapy also fall into this group. In animals, high-protein and high-carbo hydrate diets given prophylacticalTy appear to protect against the hepatotoxic effects of arsenic.155-5"3 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 usually due to viral hepatitis or to a sen sitization reaction. The results of treatment with BAL have been equivocal.1*6 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 die 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 bv the de velopment of jaundice, an effect due to an acute hemohtic reaction. Several instances of hepatitis following carbarsone therapy have been reported.5*5, 588 These have been attributed to the hepatoxic effects of the drug itself or one of its hydrolytic products, arsanilic acid, presuma bly formed during its storage or manufac ture.588 However, the hepatitis usually comes on abruptly following a relatively brief period of carbarsone administration at a low dose level, is typically cholestatic in type, almost always is accompanied by fever, and occasionallv is associated with exfoliative dermatitis, features that strongly suggest that the drug is a sensitizing agent rather than an bepatotoxin. 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.10* Bismuth The only 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 syringe-transmission of the hepatitis virus. Ethionamide Ethionamide (alpha-ethyl-thioisonicotinamide), an effective agent in the treatment of tuberculosis, occasionally gives rise to acute hepatitis.147,418- 52w- 561, 569 The incidence of this complication is estimated to be 5 per cent.147 Diabetics appear to be particularly susceptible.147 Of trie 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 by jaundice.147 In addition, ethiona mide therapy 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 ally, the signs of hepatitis regress following withdrawal of the drnug, 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, may subside despite continued drug administration.4 ,s In addition to hyperbilirubinemia, high levels of SGOT a mol turbidity, pc flocculation reac values of serum less constant fea eosinophilia occu The histologic biopsy147 resemb atitts. The occurrence philia in some pa hepatic lesions a usually provoked that ethionine-im festation of a hyj: view is not share* attribute this co infection with the Izoniazid (iso Rimifon, Pyrizic widely used in th is a potential he] longed administr to 25.0 mg./kg. f fatty degenerate jaundice.63* The in man (2 to 10 affect hepatic fu however, thev it produce fever, i hepatitis.87, 1+-- 29 out exception, t ported in indivi other sensitizing para-aminosalicy to isoniazid. Alt tivity to isoniazi such cases bv pr the hepatitis or lowing recovery, excluded that ir duced bv PAS. I which isoniazid ; hepatitis, there cedent reaction l The clinical a the hepatitis pro ble those of vira recovery follows However, at leas reported.142-504 I 249C 5046 -Jd i iwn'Tyj. .***. : i v * these are accompanied itis, aplastic anemia or jiroilar reactions have nving intermittent theranot known whether these ffect or to drug sensitizatests may be positive,11 Joses do not ordinarily action109 a sensitization it possibility. However, a :annot be excluded, since rine can produce hepatic ESXfUTH :es of hepatitis reported to bismuth compounds yphilitics given repeated jng period of time. Delinical features and cerdata in these cases suglission of the hepatitis IONAMIDE >ha-ethvl-thioisonicotinaagent in the treatment of onally gives rise to acute si. sot xhe incidence of estimated to be 5 per ppear to be particularly te 18 cases reported up sd in death from exten ds.147 Occasionally, this ed hepatitis is unaccom147 In addition, ethionaead to alterations in helout 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 t later date.220-381 Howional abnormalities, in cal signs of acute hepadespite continued drug yperbilirubinemia, high Chemotherapeutic Agents Used in Infection 543 levels of SCOT 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 bv some authorities, who attribute this complication to intercurrent infection with the hepatitis virus. Isoniazid Izoniazid (isonicotinic acid hydrazide, Rimifon, Pyrizidin, Nvdrazid), 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 fattv degeneration of the liver and overt jaundice.630 The much smaller doses used in man (2 to 10 mg./kg.) do not appear to affect hepatic function.212-823 Occasionally, however, they induce hypersensitivity and roduce fever, rash and, less commonly, epatitis.67-l4S- -,l-5o2- 39- 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.67-680 The clinical and laboratory features of the hepatitis produced by isoniazid resem ble those of viral hepatitis. As a rule, full I 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 saxcoidosis 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 desensitization has been successful in a num ber of cases67 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 frilly appreciated until it was reintroduced as an antidepres sant. The features of this type of hepatitis are described in the section on Psychopharmacologic Agents. Nitbofurantoix (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 4 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, ana enlargement of the portal tracts with ductular proliferation and an exudate con taining numerous neutrophils, eosinophils and lymphocytes. Full recovery, except for mild residual Bromsulphalein retention, oc curred within 7 weeks. Para-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-W8-772 Other less com mon manifestations of hypersensitivity in clude hepatitis,158-4331 473,888 Loefflers syn drome,772 neutropenia,435 atypical lympho cytosis435 and renal damage.138 A history of antecedent allergy is relatively common.'883 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.433 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.*88 A few fatal cases have been reported.54-54ft888 In these, death has occurred in 2 to 7 weeks with clinical and morphologic signs of massive hepatic necrosis. Occasionally, patch tests are positive,138 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.71 Although successful desensitization has been reported in a few instances,158- 548- 772 it is difficult to exclude the possibility of spontaneous desensitization in such cases.772 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.14*- 988 It is not clear whether these are indicative of cross-sensitization or of multiple independent sensitizations, PYRAZINAMIDE ( ALDLN'AMIDE ) 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 alone5*8 or in combination with other drugs.117-4**-5l8> 982 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.318 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 and protracted course. Several fatalities have been reported.494 The clinical and laboratory features are those of acute hepatocellular disease. Rarely, in nonfatal cases of unusual severity, the jaundice is accompanied by ascites.464 Biopsv in such cases reveals a marked inflam matory reaction involving both the paren chyma and the portal triads, focal areas of hept stasi OUT mas: on p A] dem zina rupt are mini nect if t tran avoi It prod or b; masj path is n< pers How path sitiz; Tl (stil dine and a?er men sis,37 mult tom> they kidn cem Tr svmj in? I Usm utes drug the ( distr quer The folio is dt sens< Tl 24905348 ii i t Chemotherapeutic Agents Used in Infection 545 morphologic signs hepatocellular necrosis and marked bile mg./kg. daily or every other day in amounts stasis.3** In a fatal case in which death oc up to 6.0 Cm.) do not ordinarily cause any .a are positive,13* curred on the 8th day of illness,4*4 there was significant depression of hepatic or renal vthat PAS-induced massive hemorrhagic necrosis of the liver function in man.22 However, in experimen ^sensitivity. Of in- on portmortem examination.3*3 tal animals, larger doses have produced 1, is the report of Alterations in hepatic function may be severe fatty infiltration of the liver, degen serum of a 32-year- demonstrable during the course of pyra- eration of the convoluted tubules of the severe reaction to zinamide therapy.4*4,388 It is wise to inter kidnevs, and renal failure.787 ver, urticaria, lym- rupt therapy as soon as such abnormalities - Similar lesions were observed at autopsy patitis and acute 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 Cm. of 2-hvdroxy- iesensitization has nection. Indeed, it has been reported that stilbamidine intravenously over a 36-day instances,158-54S-772 if treatment is stopped as soon as the period.538 Each injection was followed by the possibility of transaminase level rises, hepatitis can be headache, nausea and fever. Twenty-four on in such cases.772 of drug therapy avoided.513 hours after her last dose of 450 mg., which It is not known whether pvrazinamide in retrospect was considered excessive, she mpt recurrence of 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 >ns to PAS not in- massive doses of the drug can produce he on the 4th day. At the height of the reac with or followed patic necrosis in dogs,*23 and since the drug tion the serum bilirubin was 1.4 mg./lOO ensitivity to other is not known to produce other signs of hy- ml.; cephalin-cholesterol flocculation, 4-f-; ?ar whether these < persensiti\it\\ a toxic action appears likely. and thvmol turbidity, 9 units. ensitization or of However, the histologic features of the he A number of years ago a fulminant type isitizations. patic lesion are more consistent with a sen of hepatitis was observed in patients under sitization reaction. going stilbamidine therapy fur kala-azar in JJCNAMIDE ) oniazid, pyrazina- Stxlbamidike die Sudan.37* Characteristically, the symp toms occurred from 1 to 3 months following t effective agents The 4,4'-diamidino derivatives of stilbene cessation of therapy. At autopsy, the out uberculosis. How- (stilbamidine), diphenyl ether (phenami- standing findings were extensive centrilobu- lited by its tend- dine), diphenoxypropane (propamidine) lar necrosis ana fatty infiltration of the liver. when adminis- and diphenoxypentane (pentamidine), In some cases, the lesions closely resembled nation with other agents once used exclusively in the treat those of acute yellow atrophy. The hepa iew of the litera- ment of trypanosomiasis-- and leishmania titis was attributed to an increase in the tox ice occurs in ap- sis,37* are or value in the management of icity of the drug related to its storage and f patients receiv- multiple mveloma,22 actinomycosis,505 blas- exposure to light. mg./kg. of body tomvcosis*-"'7 and tic douloureux. Because Subsequently, the increase in the toxicity sts that smaller thev produce lesions in the liver and the of stilbamidine on exposure to light was :t the liver.5,8 kidneys of animals,781 there has been con confirmed in animals.3*-247 However, in tccurs late in the cern over their possible toxic effects in man. none of the experiments reported were the commonly during Transient vasomotor and gastrointestinal long latent period and centrilobular hepatic onally as early as symptoms are common immediately follow necrosis reproduced. In retrospect, these severity are vari- ing the first few injections of stilbamidine. deaths were probably due to syringe-trans op mild jaundice Usually, these subside within a few min mitted viral hepatitis, especially since the k, whereas others utes and mav be avoided by injecting the disease was prevalent in the Sudan at the d course. Several drug slowly.9*' 370 Of greater importance is time. 1 the dissociated sensory disturbance over the tory features are distribution of the trigeminal nerve that fre StZLFONAMIDES it disease. Rarely, quently follows prolonged therapy.22, 379 The sulfonamides fall into the category ual severity, the The neuropathy appears from 2 to 3 months of drugs that can produce hepatic injury, by ascites.4*4 Bi- following cessation of the medication and both by direct toxic action and by the in a marked inflaxn- is due to toxic degeneration of the principal duction of a hypersensitivity reaction. From both the paren sensory nucleus of the 5th cranial nerve. a clinical point of view, however, only the ts, focal areas of Therapeutic doses of stilbamidine (2 to 3 latter gives rise to serious consequences. G36i87 546 Toxic and Drug-Induced Hepatitis Prolonged administration of sulfonamides therapy, or even later.841 Rarely, hepatitis to animals leads to the development of focal and other manifestations of sensitization do particularly In t inflammatory, degenerative and necrotic not become evident until a number of weeks it is probably wi lesions in liver, kidneys, myocardium and have elapsed following cessation of medi disease. lungs.1*4*244 Similar lesions have been ob cation.254 Approximately one quarter of Acute hemol] served in a high proportion of individuals these reactions occur in individuals who follow the ingesi who have received sulfonamides shortly have been exposed previously to the drug. give rise to jau (a before death.244-501 These are thought to be Usually, the onset of symptoms is sudden, manifestations of true drug intoxication. with fever, anorexia, nausea and vomiting; taken for a mani occur earlv in tl The depression in hepatic function,18,774 they may be accompanied by a rash. Jaun especially after and the occasional occurrence of hepatitis dice appears on the 3rd to 6th day but may pyridine adminis in individuals without other signs of hyper be delayed for as long as 2 weeks. The liver The etiology sensitivity"73 have also been attributed to enlarges and often is tender. Occasionally, of sulfonamide I the toxic effects of the drug. However, the there is splenomegaly. Dark urine and may be due to tl fact that these can seldom be correlated acholic stools are the rule, at least early in cipitated drug < with the amount of drug ingested raises the the course. The laboratory features, which the drug or to question of whether they may not be related are those of hepatocellular damage, are not last ripe is most to some other factor, such as infection or distinctive, except that the serum alkaline hepatitis. I' sensitization. phosphatase level may be very high.234-738 ti A variable proportion of individuals, de Most cases go on to slow recovery, but a (Amithiozone, p pending on the particular sulfonamide de few patients lapse into coma and die of thio! 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 thev are allergic in nature,294, 434,812 even though attempts to demonstrate specific antibodies have been unsuccessful.294 Acute hepatitis occurs in about 0.6 per cent of patients undergoing sulfanilamide therapy,*2-13-I38, 2W- *432-317, 841 and hepatic failure.82- 138- 254- 3l4- 51T- 841 Death may occur as early as the 5th day314 or may be delayed for several months.82 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.218 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.82 i3s. 3n. 3it 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- 317 Similar lesions may be found in the myocardium, kidneys, Tibione, used culosis, is genen hepatotoxin. Alt hepatic function the liver218 havi effects, there hai hepatitis. The o icitv, which h rash183 and agra the drug mav b is consistent w even massive dc chymatous or b< mals.333-708 Similar alterat; symptoms of se served following zone (p-formyl zone), a comp Tibione.887 somewhat less frequently in individuals who bone marrow, skin and other tissues. receive sulfathiazole,130 sulfadiazine,130-314 It has been suggested that pre-existent sulfamethoxypyridine (Kynex) ,750 sulfa hepatic disease renders the liver more sus methoxazole (Gantanol),192 sulfadimeth- ceptible to further injury by the sulfona CYTOTOX SUPPR1 oxine (Madribon),31 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 mides.130- 773 Autopsy experience does not bear this out. Moreover, there is no clinical evidence that sulfonamides increase hepatic dvsfunction in such individuals.388 However, cirrhotics appear to be peculiarly suscepti ble to the other toxic effects of sulfonamiaes, An Azathioprine i purine antagonist actions as 6-mer which it is derivi an immunosuppi 4905050 r> Cytotoxic and Immunosuppressive Agents 547 er.84** Rarely, hepatitis ions of sensitization do ->til a number of weeks particularly in the kidney.40'368 Therefore, it is probably wise to avoid their use in liver g cessation of medi disease. ately one quarter of Acute hemolytic reactions occasionally r in individuals who follow the ingestion of the sulfonamides and reviously to the drug. give rise to jaundice, which may be mis f symptoms is sudden, taken for a manifestation of hepatitis. These nausea and vomiting; occur earlv in the course of treatment and inied bv a rash. Jaun- especially after sulfanilamide and sulfa- rd to 6th day but may pyridine administration.452 i as 2 weeks. The liver tender. Occasionally, The etiology of the renal complications j of sulfonamide therapv is complex. Lesions ly. Dark urine and J may be due to the mechanical Sects of pre rule, at least early in atory features, which llular damage, are not it the serum alkaline 1 cipitated drug crystals, the toxic action of the drug or to sensitization reactions. The last tvpe is most often associated with drug hepatitis. y be very high.254-750 Tibione slow recovery, but a (Amithiozone, p-Acetylaminobenzaldehyde jto coma and die of a*. ai4.5i7, Hi Death , thiosemiearbazone ) the 5th day314 or may ral months.62 Often, the course is chronic. sulfonamide-induced tflammatory reaction f the liver, with scatllular necrosis750 and Uy, granulomata are the liver is small and ssive necrosis of the f the stroma and an in the portal triads.82vho die of more genv scattered areas of f inflammatory cells, vessels. The exudate, 1 large mononuclear y perivascular and 317 Similar lesions lyocardium, kidneys, ; j ; , j | Tibione. used in the treatment of tuber culosis, is generally regarded as a potential hepatotoxin. Although minor alterations in hepatic function165 and fatty infiltration of the liver215 have been described as toxic effects, there have been no reports of acute hepatitis. The other manifestations of tox icity, which include nausea, vomiting, rash165 and agranulocvtosis,58* 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.5'55- 708 Similar alterations in hepatic function and symptoms of sensitization have been ob served following the administration of Myvi- zone (p-formylacetanilide thiosemicarba- zone), a compound closely related to Tibfcme.6*7 other tissues, ed that pre-existent the liver more susiry by the sulfona- CYTOTOXIC AND IMMUNO SUPPRESSIVE AGENTS ycperience does not , there is no clinical des increase hepatic viduals.568 However, peculiarly susceptiicts of sulfonamides. Antimetabolxtes 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.528 Although it is metabolized to 6-MP,208 it appears to be less toxic.848 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.72* Several instances of apparent hepatotoxicity have been reported in man. In a series of 46 patients given azathioprine for a va riety of "autoimmune" diseases, one case of biopsv-documented cholestatic hepatitis was encountered in a patient who had received the drug for 178 days in doses up to 350 mg. daily.'50 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.478 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.204-486 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, tight 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, thvmol turbidity and cephalincholesterol flocculation are abnormal The jaundice tends to clear rapidly when drug administration is discontinued. Usually, re institution 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 hepatotoxic effects of 6-MP. In one such case, a dose of only 1*5 mg.Ag. given daily for 3 weeks produced fatal hepatic necrosis and marked cholestasis accompanied by hepatic coma, renal failure ana terminal shock/02 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/75 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 nonfatai case seen by the writer, liver biopsy revealed enlargement of the portal triads with marked ductular proliferation, an intense neutrophilic and lymphocytic 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 nepatotoxin.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, lvmphoma, ocular inflammatory dis ease and psoriasis, frequently produces bio chemical evidence of hepatic injury,31* and occasionally gives rise to overt clinical signs of liver disease.14S* 545, *38- 741 The functional abnormalities, the severity of which appears to be dose related, are reversible if detected early.31* However, drug treatment, if con tinued, may give rise to progressive hepatic injury leading to the development of cirrhosis/45, 741 Formerly the nepatic fibro sis seen under such conditions was attrib uted to resolution of leukemic infiltrates In the portal triads with secondary collapse.143 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.545 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.31* 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 commonly, 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 inflammatory disease treated less intensively with metho trexate every 4th day for 6 weeks.31* Of 7 children with acute leukemia treated with methotrexate by Colsky and associ ates,145 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, hepatosplenomegaiv, ascites and edema after 3 to 10 months of treatment.738 Jaundice was observed in onlv 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 oi le di di A tfi F bi tv ti: tv m tn oi v< \v ai ta m w li aj ai sc hi O' d: si ai d ic It o ir a! st tl Vi h tl ir h 3* w? j Food Poisoning 549 ;ar period.5*5 Chilacute leukemia apfcible to severe he ats with acute leuent intensive treat* , increased serum rlphaletn retention hyperbilirubinemia lalities that were ation of each 5-day tended to regress 318 There were no mptoms of hepatic wealed infiltration ai zones with neur cells, occasional id, less commonly, 1 and portal fibrore functional and veTe encountered ular inflammatory ively with methoweelcs.318 ! leukemia treated ilslcy and associatisfactory remisreatment for 6 to ipatomegaly and :amination portal in 3 instances it is. Jaundice was Jt hvperbilinib!ses. I children given dcemia, 7 develepatosplenomegr 3 to 10 months 'vas observed in 1 of the children morphism of the ce of regeneraleorosis of some th ductular proifiltration. When substituted for on and hepato- 3TTS ). Evidence suglerivadve of niuric 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.,T 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. I Rarely, chlorambucil serves as a sensi tizing agent and gives rise to an allergic type of hepatitis. In one such case, a young 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.392 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, i Nitrogen Mustard (Mechlorethamine). * In the cat, nitrogen mustard produces focal | areas of hepatic necrosis, but in most other animals the liver is not affected.-78 There is ] some uncertainty regarding the possible hepatotoxic effects of the drug in man. In I one study, 3 of 50 patients with Hodgkin's 1 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 any evidence of injurv 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 l 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 i 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,94 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.23-312,496,541 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.'8 In one reported case, an elderly woman with suspected multiple mveloma, signs of decompensated cirrhosis appeared after 6 years of continuous daily treatment with urethane.365 FOOD POISONING Aflatoxin 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.1*2 The agent responsible for the hepatic lesions has been identified as aflatoxin, a product of the fungus. The lesions have been reproduced in a 'vide variety of experimental anirnals.479,737 Protein deficiency enhances the hepatotoxic effects of aflatoxin. The hepatic lesions are characterized by focal hepato cellular necrosis, fatty infiltration, striking ductular proliferation and centrilobular endophlebitis. Prolonged administration of aflatoxin may give rise to cirrhosis or hepatoma. As yet, aflatoxin 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.12 550 Toxic and Drug-Induced Hepatitis Epfing 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'-diaminodiphenyImethane, an aromatic amine used as a hard ener for epoxy resin.395 The flour had been contaminated during shipment in a van carrying a broken container of the amine. In most of the S4 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. The 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) little role in human poisoning, although its effects can be easily demonstrated in ani mals when administered by the parenteral route.23* 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.78* Phallin ana amanitatoxin are antigenic and can produce specific antibodies in ani mals.23* 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 svstem.10,>758 As a rule, the liver is small and exhibits massive hepatocellular necrosis, intralobular hemorrhage and an acute inflammatorv 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 myocardium also and splen Signs of i Early in t bumin, oliguria a spasms ax minally. 1 the centn postmortei experimen cemia is a rhagic ph< common tl toms but t Prognos tients wit! injury ma to predict Neverthel azotemia tem Lnvoh able progi able, in sc days, and Few long- carried on the recov< complete, been repc stances,322 occur mo recognizei Therap treatment Some 70 or 80 species of mushrooms are shows fatty infiltration and degeneration. eral supp( known to be toxic for man, but only one, Symptoms. Characteristically, the onset important Amanita phalloides, affects the liver. The of symptoms following the ingestion of initial cri others produce gastroenteritis, muscarinic A. phalloides is delayed for 6 to 15 hours. vasomotoi effects, acute hemolysis and disorders of In contrast, most other poisonous mush velopmen the central nervous system. The unusual rooms produce symptoms -within the first These inc toxicity of A. phalloides is attested by the few hours. Nausea, vomiting, severe ab and electr 50 per cent mortality rate which follows its dominal cramps and diarrhea appear in blood, am ingestion.237 rapid succession and usually are followed terally ac Types of Toxin. Two types of toxin iso within 24 hours by severe prostration, signs caloric re irti lated from A. phalloides are: phallin, a of dehydration and vasomotor collapse. In glycemia. thermolabile gtucoside with hemolytic prop erties, and amanitatoxin, a thermostable agent which characteristically produces fatty degeneration and necrosis of the liver, kidneys and myocardium.33* Since phallin is destroyed readily by cook ing and during ingestion, it probably plays severe cases, coma supervenes, and death ensues in 3 to 8 days. Usually jaundice ap pears on the 3rd day758 but may be absent, even in individuals who survive for several days and then succumb to severe hepatic necrosis.199 Enlargement and tenderness of the liver rid the g maining t JgJocedure there jstion o lptoms jphylac BFG36192 oning, although its nonstrated in aniyy the parenteral 1'agreement, theremanifestations of ire due to amanitadentified as a mix- 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 Dxm are antigenic ; antibodies in aniitigenicitv of amaat it has not been (tent antiserum for the central nervous system lesions found postmortem,190 but evidence based on dog experiments suggests that severe hvpoglycemia is a factor in some instances. Hemor rhagic phenomena and anemia are far less common than hepatorenal and neural svmp- he principal pathoes are found in the nervous system.199small and exhibits crosis, intralobular inflammatory exu* ells are heavily in:s and do not un autolysis seen in assive hepatic ne- , toms but do occur occasionally. Prognosis. Even the most gravely ill pa- j tients with signs of severe hepatic and renal i injury may recover,758 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 vari- i able, in some instances being as short as 10 ! days, and in others as long as 6 weeks.738 trying degrees of id fatty infiltration n and congestion Few long-term follow-up studies have been carried out, so that it is not known whether j the recovery from hepatic injury is usually , complete. However, hepatic fibrosis has n the central nerv- oread toxic swelljn cells, scattered *es and perivascu- been reported as a sequela in several in stances,^122 so that residual damage may occur more frequently than is generally recognized. Therapy. Although there is no specific mvocardium also treatment for A. phalloides poisoning, gen 1 degeneration, eral supportive measures are of the greatest ticallv, the onset importance in tiding the patient over the the ingestion of initial critical period of dehydration and For 6 to 15 hours, vasomotor collapse, and the subsequent de poisonous mush- velopment of hepatic and renal failure. s within the first These include careful regulation of fluid liting, severe ab- and electrolyte balance, transfusion of whole urhea appear in blood, and the provision of sufficient paren- ally are followed prostration, signs lotor collapse. In venes, and death uilly jaundice apit may be absent, arvive for several :o severe hepatic terally 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 prophylacticaUy in individuals who have Hormonal and Metabolic Agents 551 partaken of a bad lot of mushrooms, but are not vet ill. HORMONAL AND METABOLIC AGENTS Androgens and Related Anabolic Agents Methyltestosterone, norethandrolone and a number of other C-17 alpha alkvl 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 inflammatory 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."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,97-338> 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.*13, 489 Much of the Bromsulphalein re- 1 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 Bromsulphalein 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.*19 In patients who develop jaundice, the liver shows 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 4c Usually, symptoms appear between the 2nd and 5th mouths 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 sig nificantly 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.8** 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 (17cx-ethyl-19-nortestos- terone, Nilevar). The effects of norethan drolone on die 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 excretioa can be demon strated in 1 to 3 weeks, depending on the dose.398,849 Less commonly, there may be an increase in serum alkaline phosphatase898 and glutamic oxalacetic transaminase.849 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,*89 In the rat, a similar defect in bilirubin excretion can be demonstrated.23 Since electromicroscopic studies of the liver in both man and tne rat have shown that norethandrolone regularly produces dilatation of the canaliculi and enacement 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 man*19 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.*19 Only a few instances of overt cholestatic jaundice have been reported,19*-2T4- 949 but from the relatively high incidence observed in some series,19*- **9 one may anticipate that many more cases will be encountered as norethandrolone is used more widelv, 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.27* Usually, the jaundice is accompanied bv au increase in serum alkaline phosphatase,19427*, and not infrequently there is a rise in the serum glutamic oxalacetic transami nase level849 and a positive cephalin-choles terol flocculation reaction.27*-449 In some cases, the jaundice is intense and resolves relatively slowly.19*-919 Histologically, the liver shows centrilobular bile stasis with bile thrombi in the canaliculi, bile staining of the degene Similar ally ac portal and nu tive act icteric lone.398 At J< ported, ure foil ethandr marked patocell Because necrosis complic virus w sented aot com Other terooe. observe! metharu rone, n oxymest methylt* progesta ethinyl-] norethyr i 10)estr dition, m the serui aminase. the prob the obse and syntl ghicuron liver.3*2 Choles after me reported drone*58 methyl-li j^Vlethir M4e, Taj Q$ta in Qftits,*3 a CSbnsitizi K Hormonal and Metabolic Agents 553 mg., impairment of the Kupffer cells and secondary feathery {can be demon- degeneration of the parenchymal cells.849 epending on the Similar changes of lesser degree, occasion f, there may be ally accompanied by lymphocytosis of the ne phosphatase*98 portal triads, focal hepatocellular necrosis nsaminase.*49 and nuclear changes indicative of regenera lalein retained in tive activity, have been encountered in non- * which has been icteric individuals receiving norethandro- ,rt of the concept ; lone.398 feres with the ex- I At least two fatalities have been re- he conjugation of * ported. Both patients died of hepatic fail- similar defect in > ure following a prolonged course of nor- 2 demonstrated.23 l ethandrolone and at autopsy exhibited c studies of the f marked cholestasis, varying degrees of he- s rat have shown [ patocellular necrosis and peliosis hepatis. rlarly produces i Because of the extensive character or the 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 1 Other Substituted Derivatives of Testos drug.83'* However, terone. Bromsulphalein retention has been a11* indicate that observed following the administration of ;s with both the methandrostenolone (l7a-methyltestoste- bromsulphalein by rone, methandienone, Dianabol),79* ftu- bat the action of oxi/mesferone (9a>fiuoro-ll/3-hydroxy- 17a- to the canalicular methyltestosterone, Halotestin)3*9 and the ag functional de progestational agents, norethindrone (17a- ad does not affect ethinvl-19-nortestosterone, Norlutin), and ce.419 noretkynodrel (l7a-ethynyl-17/3-hydroxy-5 >f overt cholestatic (10)estren-3-one norethisterone).583 In ad rted,194-274-849 but dition, methandrostenolone frequently raises ncidence observed le may anticipate ill be encountered ised more widely, :n more frequently /Itestosterone therm the onset of nortion and the apunpredictable and 849 to 10 months.274 accompanied by an ne phosphatase,194atly there is a rise the serum level of glutamic oxalacetic trans aminase.4^ 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 norethindrone753 and methylestrenalone (17amethyI-19-nortestosterone ) xalacetic transamive cephalin-choleson.274-649 jn some Antithyroid Drugs Methimazole (l-methyl-2-mercaptoimida- itense and resolves Histologically, the it bile stasis with iliculi, bile staining zole, Tapazole) produces rash and urti caria in approximately 5 per cent of pa tients,43 and for that reason is thought to be a sensitizing agent. Less commonly, it gives rise to agranulocytosis and cholestatic hepatitis828' *1 or cholestatic hepatitis alone.491 Propylthiouracil. Rare instances of fatal generalized periarteritis with secondary in volvement of the liver-"*3 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, lymphadenopathv, agranulocytosis and swelling of the salivary glands--features suggestive of sensitization--have been observed in pa tients receiving thiouracil.248- 253338- 537 Less commonly, this drug produces hepatitis.253:i3tt- 3',T 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.338 Thiourea produces fever, rash, leukopenia and other manifestations of drug sensitiza tion more frequendy 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 autopsy ap peared to be related to intrahepatic ar teritis.299 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.329 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 II weeks, marked fatty infiltration of the liver was associated with massive fat embolism which resulted in sud den death.319 Dinttrophenol Occasionally, small doses of dinitrophenol produce an acute cholestatic hepatitis.*88 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,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: (I) hepa (diethylstilbestrol), a nonsteroidal synthetic titis may be associated with an urticarial estrogen, produce hepatic necrosis,493 rash,683 (2) the clinical and laboratory fea whereas small doses impair Bromsulphalein tures closely resemble those seen in the hy excretion,231 as in the case of the steroidal persensitivity type of arsenical hepatitis,685 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' 458' 495 either in experimental animals738 or in Most oral contraceptives contain a mix man,576, 740 and (-1) 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, 17a- true icterus. ethinyl-19-nortestosterone, Norlutin), nor- Estrocenic and Progestational Agents ethynodrel (17a-ethmyl-5[10]-estraeneolone), ethtjnodiol diacetate (17a-ethinyl-4- Natural Estrogens. Both estradiol and its estraenediol diacetate), or lynestrenol metabolite estriol, when given in relatively (ethinylestranol; 17/3-hydroxv-17a-ethinvI- large 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 aye 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 ora! 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 occasionallv thev its metabolite pregnanediol impairs hepatic raise the level of serum transaminase, an function, as judged by Bromsulphalein clear effect that suggests hepatocellular injurv.'* ance in the rat.-51 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 man that used for contracep thetic estrogens and progestins impair the tion.205- 723 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 biodiemical 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- BFG36196 Vv it other steroids in liver. ;es of stilbestrol steroidal synthetic patic necrosis,4** iir Bromsulphalein se of the steroidal re is no evidence Hormonal and Metabolic Agents 555 ceptives.53**544 However, considering the widespread use of these agents, the inci dence of this complication must be exceed- ingly low. Genetic or other constitutional factors may be of importance in determin ing susceptibility to this form of jaundice. This is suggested by the observation that, in approximately 40 per cent of cases, previ- and Ovulen (ethynodiol diacetate 1 mg. + mestranol 0.1 mg.). Available evidence suggests that the estrogenic component is responsible for the jaundice produced by oral contraceptives. Thus, following recovery from such jaun dice, challenge with mestranol provokes a relapse, whereas administration of such Not infre- Le )l 3-methyl >f 0.15 from the behavior nimals, oral conrations in hepatic umber of healthy ^normality, mild >ccurring in 20 als tested.539 The is elevated far iction of the oral ?r is not alwavs 5 secretion is evi- transaminase, an icellular injury.TM does not. Usually, the serum levels of bili rubin and transaminase are only moderately elevated, but deep jaundice and levels of transaminase in excess of 1,000 units have been reported.344* 747 Often, the serum alka line phosphatase remains normal, but in some eases it rises significantly.544 On bi opsy, the liver shows centrilobular canalicu lar and intracellular bile stasis, focal hepato cellular degeneration and necrosis, and a Since mestranol produces jaundice and other manifestations of hepatic dysfunction much more readily than norethynodrel, at least at the dose levels-found .in oral con traceptives, though both agents are C 17 alpha alkyl substituted steroids, alkylation at the C-17 position cannot be the only structural determinant of hepatotoxicity in this group of compounds. As further evi dence of this, estradiol, a nonalkviated tory reaction.344* 747 Cessation of contracep tive therapy is followed by gradual re- riod of several weeks Re. 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 may plays injury.848 24905059 BFG36197 556 ' Toxic and Drug-Induced Hepatitis tional steroids inhibit hepatic glucuronyl transferase in vitro,3** there is no evidence that they play a role in the biliary excretory 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 susceptibility to thromboembolic dis ease,4901 and several instances of the Budd- Chiari syndrome have been reported in voung women who have used these agents for periods ranging from 2 weeks to 2 years.13*4- -T84' 933*- "03"-7181 Usually, the dis ease has proved fatal, but in one case re covery followed withdrawal of the drug.705* 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 injury both in animals and in man.33* Other compounds of this type in current use do not appear to share this propertv and have not been implicated as etiologic factors in drug hepatitis.401 These include phenethylformamidinyliminourea (phenformin, DBl), amytformamidimjliminourea (DBB) and isoamylformamidinyh iminourea (DBC). Carbutamide (l-butyl-3-sulfonylurea, BZ55). Of the several suifonvlureas introduced as hypoglycemic 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 type produced by the closely related sulfonamides, and include fever, rash, agranulocytosis, hemolytic anemia and hepatitis, manifestations suggestive of drug sensitization.3* Several fatalities have been reported, death being due to acute myocarditis,--5 hepatitis,113 exfoliative dermatitis380 and bone marrow depression.3** 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."3 Chlorpropamide (I-propyl-3-( [p-chlorobenzenesulfonyl]) 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.ll>0- -2-207 603 The incidence of this complication has been estimated to be approximately 0.5 per cent.803 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 reactions32, 803 seen in some cases that the cholestasis may be ac companied by significant hepatocellular in jury, as in many 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 poly morphonuclear leukocytes, eosinophils and monocytes.100-202,207, **3 However, not in frequently the parenchyma shows feathery degeneration,003 small foci and necrosis803 and evidence of increased hepatocellular regenerative activity.27 Full recovery is to be anticipated in 1 to 3 months. The sporadic occurrence of the hepatitis in patie with wf fever ai the dru mals337- a sensit toxin. I of the <3 tack of does nol necessai nism bu desensit Of pr diabetic jaundice mide.27 Metal zenesulf cin), an jaundice tients,TM progress ported.5' The c of the h 340. 753 others.17 foci of nantlv c some ins the por stasis.179, cellular ; the resu show, ii significai amlnase3 4 75. 733 a cholestei In fat; picture i sis.540 Or of lesion was resj postnecn It is ni jures the tl|a$ndu< spo u(&the c :v _ _ lgh the viscera, tients with sulfon^of these cases, the Je those of choleiiic failure ensued. a1 diffuse hepatitis of hepatocellular 13 Similar but less 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 animals387-(K5* suggest that chlorpropamide is a sensitizing agent rather than a hepatotoxin. In some instances, readministration been observed in of the drug following recovery from an at tack of chlorpropamide-induced hepatitis jropyl-3-{ fp-chloro- | does not provoke a relapse.392 This does not Diabinese). One of necessarily exclude a sensitization mecha the use of chlor- j nism but may be indicative of spontaneous cemic agent is the it produces choleThe incidence been estimated to cent.81,3 However, but significant elecaline phosphatase 1 in as manv as *25 fer 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.297- 603 i Metahexamide (N-[3-amino-4-methylben- zenesulfonyl]-Nl-cyclohexylurea, Eugly' cin), another of the sulfonureas, produces * jaundice in approximately 1 per cent of pa tients,753 and at least 2 fatalities from jeks of chlorpropa- progressive hepatic failure have been re titis is ushered in t ported.340 ad vomiting. Soon j The clinical features of the hepatitis are urndice and clay* j of the hepatocellular type in some cases475- ver, rash, pruritus, | 540.735 an(j 0f the cholestatic type in legalv are common others.179,300 Histologically, the liver shows Ylthough the regu- foci of hepatocellular necrosis, predomi Diiirubinemia with nantly centrilobular in distribution, and, in aline phosphatase some instances, an inflammatory' reaction in a cholestatic form the portal triads and evidence of bile t from the rise in stasis.179-300,340 This combination of hepato e cephalin-choles- cellular injury and cholestasis is reflected in jns202*603 seen in the results of laboratory tests which often ^stasis may be ac- j show, in addition to hyperbilirubinemia, hepatocellular in- significantly elevated serum levels of trans >rms of cholestatic es of the liver bear aminase300- 473 and alkaline phosphatase300, 475, *55 anci a strongly positive cephalin- y, there is centri- cholesterol flocculation reaction. ile-staining of the In fatal cases, the clinical and pathologic plus an inflamma- picture is that of subacute hepatic necro 1 triads with poly- sis.340 One apparent recovery from this type s, eosinophils and of lesion has been reported.540 In another it However, not in- was responsible for the development of ia shows feathery postnecrotic cirrhosis.TM ci and necrosis603 It is not clear whether metahexamide in ed hepatocellular jures the liver by a direct toxic action or by the induction of a hypersensitivity reaction. anticipated in 1 to The sporadic occurrence of the hepatitis and the occasional development of fever and e of the hepatitis rash in patients receiving the drug735 are consistent with the latter. However, the fact Hormonal and Metabolic Agents 557 that large doses produce hepatic lesions in experimental animals30 suggests that, under some circumstances, metahexamide may be have as a hepatotoxin. Tolbutamide (l-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 druginduced hepatitis or alterations in hepatic function are recorded.179 However, since then, several cases have been encountered. In one series of 1,500 patients given tolbutamide, 4 instances of liver injury were encountered.91 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 acute hepatitis. In the 2 remaining cases, the outstanding features were fever, thrombo cytopenic 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. Recovery' 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.31,280 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 seeu in primary biliary cirrhosis.280 On histologic examination, the liver showed cholestasis, destructive cholangitis and cholangiolitis, and disappearance of the interlobular ducts. Exploratory laparotomy, to exclude biliary obstruction, was fol lowed by massive bleeding from gastric and esophageal microsal ulcerations, hepatic coma and death. T3QS06fcZ BFG36199 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,46* and an even higher proportion exhibit an increase in serum bilirubin.771 Similar evidence of hepatic damage is seen also in association with the hyperpyrexia of heatstroke315- 788 and other febrile diseases. Hyperpyrexia of sufficient severity and duration may be fatal.82, 273, 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 fatal 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.273 The importance of anoxia has been disputed on the grounds that continuous oxvgen ad ministration does not prevent liver dam age.166 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 hepatitis166 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 system disturbances, vasomotor col lapse and signs of renal failure. Purpuric manifestations have been emphasized, par ticularly in heatstroke,TM 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.788 Pleural effusions, ascites and edema are not rare in fatal cases.82'273 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 dam age. In fatal cases, the incidence of sig nificant hepatic lesions may be as high as 90 per cent,50 and in those who survive the frequency of functional impairment is equally great. In both instances, the severity of the abnormalities correlates closelv 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 thyroid hormone; indeed, other possible in terpretations are held to be more likely. A variety of hepatic lesions occur in pa tients who di plications.30-1 tatty metamc crosis, usually ally massive, (3) atrophy denced by a liver, (4) ve rhosis. Excej similar chanj massive dose; ine.257-310 Ne maintain thai specific, and attributed to Weller des as a patchy h tion in the p by proliferate development on the other t lesion is veno of the lobule: normal press* branches of t! tal vein.3 follows resem gestive failur centered arou stead of the c subscribe to < and most rej quence of fat hepatic cells.1 Almost eve has been inv' centration of of Bromsulph tolerance for the prothromt nificant numb thyroidism.293 turbances hav mals with exp< roidism.1*8 Th levulose tolera in carbohvdra but there is li vwher abnorm; ramage. The pathog iund in hype ibject. The c Metabolic Disturbances 559 joas been disputed tinuous oxygen ad.revent liver damnot a valid objecpy does not overt hvperpxrexia.771 may be additional ; but are certainly : of the hepatitis468 i from those due to erthermia. Nausea y and usually are d day by jaundice e is an early inetion of urobilinoxtntains bile. Only : the stools acholic. y be central nerv- vasomotor colfailure. Purpuric emphasized, paralthough they may : hyperpyrexia.275 d to the combined Din level, a reducincrease in capileffusions, ascites fatal cases.2*273 jal liver damage of cases. The aprca, renal failure :es are omens of DISM lividuals with hynce of liver damincidence of sig* ry be as high as : who survive the impairment is nces, the severity fates closely with n of the underertheless, it is bv > changes in the ct effects of the >ther possible ine more likely, ons occur in pa* dents who die of thyrotoxicosis and its com* severity of the hepatic damage and the in plications.3U-ll5-319, 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 thyroid hormone are hepatotoxic.30 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 and (5) cir produce significant alterations in hepatic rhosis. Except for cirrhosis and atrophy, structure or function.522* 571 This has led similar changes are seen in animals given some to the conclusion that the lesions massive doses of thyroid extract or thvrox- found at autopsv are either coincidental or ine.25"-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 by 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 j normal pressure relationships between the evidence indicates that hyperthyroidism in j branches of the hepatic artery and the por creases the susceptibility of the liver to in tal vein.319 Accordingly, the cirrhosis that jury by anoxia,471 infection338 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.130- -I>3 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.113 ciency by 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 hyperthyroidism. No one mechanism ac the prothrombin level, is abnormal in a sig counts satisfactorily for all the types of liver nificant number of individuals with hvper- injury encountered in hyperthyroidism. thvroidism.295* 47*473 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 thev give rise to no overt signs of liver dis roidism.163 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.479 BFG36201 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 nepatotoxic effect. In dealing with agents of this tvpe, the phvsician should recognize that, while alterations in chemical structure may reduce the frequency with which certain drugs produce hepatitis, thev rarelv, 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 alter 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 cent178-*78-785 Since the occurrence of such reactions is not dependent on the dose, and since the hepatic changes are not repro ducible in animals,57-895 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.854 However, others have not con firmed this observation.18 Moreover, it has been found that, in the rat, chlorpromazine does not inhibit the biliary secretion of indo cyanine green or bilirubin,308 reduce the rate of bile flow,883 or raise the pressure within the common hepatic duct.48* Frequently, reactions axe 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.178 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.735 In such cases, and occasionally in others,2*7-3''1 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, readministration of the drug produces a prompt relapse in some44,40T-500 but not in others.44-407 Moreover, recovery from chlor promazine hepatitis may ensue despite con tinued administration of the drug,885-889 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 I to 4 days by jaundice, dark urine and clay-colored stools.-134-37a-451-792 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- ffG36202 Fsychophannaeologlc Agents 561 Bilirubin,305 reduce the f or raise the pressure i-hepatic duct683 ions are accompanied by sinophilia141,451 and less mlocytosis151 and a posi- raJcen together with the an produce contact den atures strongly suggest e is a sensitizing agent, nv other drug reactions, istrate circulating antizine,33 or to establish the mimmologic 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 a single dose.735 In sionally in others,207,354 .'e may be delayed for jllowing withdrawal of [y are reactions of this th week of drug admin* its who have recovered ^-induced hepatitis, rehe drug produces a me44-407. 500 But not in r, recovery from chlornay ensue despite coni of the drug,855, 888 a enerally attributed to ization. onset of chlorpromapt with fever and mild oms, which are fol* iy jaundice, dark urine >ls.8S4'373- * 783 Occaiccompanied by a rash ions or frank shaking recede the appearance i is a troublesome late da, nausea, vomiting are common but set 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- phata.se and transaminase. In contrast, the thvmol 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 centri- lobular zones and a portal inflammatory exudate, consisting of polymorphonuclear leukocytes, monocytes and eosinophils.784' **" 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.*3-328'J'*3- 3731 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*373,328-584 and have had clini- cal features suggestive of biliary cirrhosis, such as persistent pruritus and xanthomato- sis.33' 348< 391-34#'770 According to Read and associates,584 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 al529 and by Walker and Combes.770 In Mvers' 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 chlorpromazine- induced 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 far the development of unequivocal advanced biliary cirrhosis. Several fatalities have been attributed to chlorpromazine hepatitis.77*3M*626 However, in the 2 cases in which postmortem examrnation was carried out, unrelated complieating factors could have played an important 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 examining, show marked passive congestion and bite stasis. In Rodin and Robertsons case, death occurred on the 40th day of jaundice, following an unexplained episode of shock.828 The liver showed extensive centrilobular parenchymal necrosis with some degree of bile stasis. Whether the necrosis was attributable to the chlorpromazine reaction or to the terminal episode of shock is not evident from the published 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 recovery from a reaction. Allegedly, cross sensitization reactions between chlorpromazine 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 management of chlorpromazine-induced hepatitis is in doubt. Favorable results have been reported in some cases138-712 but not in others.785 Mepazine (Pacatal). Mild jaundice has been observed in a few patients receiving mepazine.311 Prompt recovery has followed withdrawal of the drug. Presumably, the underlying lesion in such cases is a cholestatic hepatitis of the type produced by chlorpromazine. However, neither the histo- pathology 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, BFG36203 562 Toxic and Drug-Induced Hepatitis jaundice developed in 2, an incidence of 5.4 per cent511 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.153 Prochlorperazine Maleate (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* 709 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.467 Promazine Hydrochloride (Sparine). This agent has no adverse effects on the liver in most individuals,397 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.379 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.764 Several fatalities have been attributed to promazine-induced agranulocytosis.264- 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 tne 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 by 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.-9-390 One had a history of another drug reaction and chlorpromazine had been administered just prior to the use of trifluo perazine.29 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 typical 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 tranyl cypromine, are. hydrazine derivatives and produce a severe and often fatal form of hepatitis 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 difogs 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-isomcotinoyI-2-isopropyIhy- -fe **# individuals there t *dent'hepatic reV In the third pamnase and alkaline toed to normal deministration. Irochloride (Stelagent has been adiflion patients, only lepatitis have been a history of another promazine had been io the use of trifluojaundice appeared r and persisted for ae other patient re- a patient with the y primary" biliary onset with pruritus d several months erazine therapy.388 ug was responsible iis case is unknown. \se Inhibitors nine oxidase inhibitzid, isocarboxazid, nd tranylcypromine ) are widely used ntal depression. All exception of tranyline derivatives and often fatal form of ber of uniquely susice tranylcypromine native and does not )een suggested that other drugs in this itic injury may be cine content rather inhibit monoamine reasons discussed bable that the heare attributable to X than to a direct his connection, it is patients may react in this group,333 so ibstitute one for the lem has produced dnoyl-2-isopropylhy- Psychopharmacologic Agents 563 drazine, Marsilld). Iproniazid was intro duced as a cheznotberapeutic 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 hvdrazide). 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 in jury 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> 329 Moreover, like pvrazinamide, cinchophen and zoxazolamine, it not infrequently gives rise to massive or subacute hepatic necro sis that often proves fatal.240, 377* 578, *** 377 The reported incidence of hepatitis in pa tients receiving iproniazid is approximately 1.4 per cent.689 Although estimates based on total sales of the drug are considerably lower,629 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 administration577,629 and cannot be reproduced in experimental animals,61 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 rash39*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 reaction396 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.39 The stools become day-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 assodated 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 \z 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 mortality rate is approximately 20 per cent.82 Attempts to stem the downhill course in patients with massive hepatic ne crosis by administering corticosteroids or ACTH have generally met with failure.*" 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/'7 In this instance, symptoms 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 day. 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, 32.3 As in 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,3*2 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* 53, 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 previousK had a mild attack of jaundice while taking iproniazid.333 In another, following recov ery from pheniprazine-induced hepatitis, administration or 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 Fsychopharmacolocic 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.2,110 In addition, elevations of SGOT in the absence of jaundice have been observed.333 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 ` 1 At I..1JW'- BFG36206 guishable from is. Death from n 3 weeks has rases. Repeated base,362 begun a, failed to redeath. y-lisopropyl-hyveral instances n reported in ne for periods 3, 277. 333 fn aU ory, and moribled those of Two of 6 relly with masne of the paiad previously ; while taking lowing recovced hepatitis, imine oxidase ), provoked a sorts suggests is low, in one miprazine for developed sehowed a sig- iic Drugs Joride (Libhepatitis has 2 patients reand 35 days, elevations of ce have been nzodiazepine ), has been fatal case of wever, since ceived phenby diazepam nly reported d by ectylie histologic l cholestatic ldden, with ?er abdomierapy. Dark Miscellaneous 565 urine, pruritus and faint Icterus were noted a few days later. There was a modest in crease in serum bilirubin and glutamic oxalacetic transaminase and a marked rise in the alkaline phosphatase level In con trast, the serum cholesterol concentration, thymol turbidity and cephalin-cholesterol flocculation reaction remained normal. AU symptoms subsided within 5 days. When a single 300-mg. dose of ectvlurea was given on 2 successive days approximately 3 weeks later there was an immediate relapse of jaundice, pruritus and anorexia, which cleared within a week. Imipramine Hydrochloride (Tofranil). Jaundice is a relatively uncommon compli cation of imipramine therapy, and usually subsides promptly following withdrawal of the drug.1*-15'- 32T- 422-484 In the few re ported cases in which the clinical features are described, jaundice appeared between the 7th19 and 110th484 days of treatment, and was accompanied by fever19-327 and biochemical changes suggestive of cholestasis.19-327 The one available biopsy speci men of the liver is said to have shown slight, nonspecific inflammation in the paren chyma.19 In one series of 85 patients receiv ing imipramine, 19 exhibited a transient rise, in serum transaminase unaccompanied by jaundice.19 The desmethvl analogue of imipramine, desipramine hydrochloride (Norpramin, Pertofrane), also may give rise to jaun dice.152 Unfortunately, details of the illness in such cases are lacking. From available data, it appears that both imipramine and desipramine usually pro duce a cholestatic type of hepatitis. How ever, in at least one instance, these agents produced massive hepatic necrosis that was fatal.584 The patient involved noted the onset of rash 2 weeks after starting treat ment with imipramine. Substitution of desipramine at this point aggravated the dermatitis, so that drug treatment was dis continued 2 days later. Jaundice, fever and mild eosinophiHa appeared 6 weeks after the onset or rash. Tne jaundice deepened rapidly, the rash become exfoliative in char acter, and ulcerations of the mucous mem branes appeared. Death occurred 2 weeks after the onset of jaundice and approxi mately 8 weeks after the appearance of rash. Autopsy revealed massive destruction of the hepatic parenchyma, collapse of reticulin, numerous lipofuscin-filled macro phages and a mixed portal exudate of neu trophils, lymphocytes and histiocytes with occasional plasma cells and eosinophils, fea tures seen in other forms of massive hepatic necrosis produced by reactions to drugs. Considering the clinical features in this case, and the fact that imipramine and desipramine produce rash, fever, eosinophilia, thrombocytopenia and agranulocy tosis, it is highly probable that the hepatic lesions they produce are attributable to drug sensitization. Meprobamate (Miltown, Equanil). This agent, one of the most widely used tranquil izers, produces a variety of allergic reac tions, including rash, fever, angioneurotic edema, arthralgia and thrombocytopenic purpura.'*8-334 Although hepatic involve ment in such reactions has not been re ported, the writer has seen 2 instances of cholestatic jaundice in patients receiving meprobamate and has heard of 2 others. MISCELLANEOUS Apiol Derivatives Apiol, a camphoraceous material derived from parsley and an important constituent of many illegal proprietary abortifacients, produces hepatic injury in animals and oc casionally has been implicated as a hepatotoxic agent in humans.433 However, in most such cases, complicating factors such as sepsis, hemolysis and shock have made it difficult to assess the role of apiol in the pathogenesis of the hepatic necrosis dem onstrated at autopsy. Burns and Tannic Acid A variety of hepatic lesions have been ob served in individuals with extensive burns.56, 282.795 Animal experiments show that most of these can be attributed to tannic acid therapy and possibly to infection.33-234-309 In dogs, extensive burns of the skin, if left untreated, are usually accompanied by cen tral congestion and atrophy of the hepatic parenchyma. However, if infection super 569 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 bum is not essential for this effect for the same lesions occur when tannic acid is injected subcutaneously into normal animals.33' ^ 303 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.283 Severe liver damage, occasionally accom panied by jaundice and ascites, is also seen in patients with fatal bums 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.54 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.362 Impairment of hepatic function also has been reported fol lowing bums.TM However, the data do not indicate whether this occurs in the absence of infection and tannic acid therapy. Carbamazepine (Tegretol,) Carbarnazepine (5-carbamyl-5H-dibenzazepine) is chemically related to imipraniine (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.58* 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.58* Chlorothiazide Rarely, chlorothiazide gives rise to chole static hepatitis.182'349 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.34* 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 phils, granulomata, atypical ductular pro liferation 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.82 The rise in total serum bili rubin, which at its peak reaches levels of 1.5 to 2.0 mg./IOO 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 unconjugated bilirubin in the serum is due primarily to competitive in hibition of bilirubin excretion in bile,73 or impairment of bilirubin uptake by the liver.88 With respect to Bromsulphalein re tention, animal studies suggest that bunamiodyl impairs the hepatic uptake of dye.88 v ecovery- occurred undice was prot with a lesion re The patient in daily for more jffects. Two and ling therapy with he onset of low ria and jaundice. Irug for 5 weeks. 3sted obstructive laparotomy was ?ek. The biliary . Wedge biopsy led portal tracts Is and eosino1 ductular proarenchvmal ne fibrosis. Jaun*d for several However, the level remained cerebrovascular ; onset of jauner was nodular ir regeneration i in the triads Dyes .n a high probunamiodyl, a re is a transient cting (unconilirubin by the )tal serum biliches levels of ms to normal tly, there is a nalphalein re- ibits bilirubin 'iro, other ex- that the rerubin in the impetitive ini in bile,73 or take by the mlphalein 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,72-1,04 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 agent.513 Rarely, orally administered cholecystogra phy dyes 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 eosinophilia were noted in the 3rd day. At the height of the jaundice the liver was en larged but not tender, serum bilirubin rose to 4.8 mg.2, 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 Laennecs 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 Laennecs 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,4*8 mobilizes fat from the depots to the liver55 and potentiates the development of nutritional cirrhosis.3*4 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.638 Whether or not these effects are implicated in the pathogenesis of Laennecs cirrhosis remains to be estab lished.202 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.137 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.133 Those that appear within the first 10 days may be accompanied by fever and malaise, but more often thev 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.4" 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 cytopenia158 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,879 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.554 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.550 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 have 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.022 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 mat drug hypersensitivity is involved. Al though tne 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, Heduun, 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,99i9T. 33,4M, 583 arKj rarely by nephritis." a rule, the onset is abrupt during the 4th week of drug administration, but rttfy occur as early as the 10th day and as latdgs the 9th week. Rarely, the reaction app^fts Miscellaneous 569 accompanied thfo time 'ere no associated gas.titutional symptoms, ed but nontender, and increased to a level of 1.0 mg. of which was tvpe. There were de cline phosphatase to >T to 91 units; thymol n-cbolesterol floccula te drug was stopped, in 3 weeks, pruritus appeared sevmonth course of nicodiscontinued.534 Jairnater, but there was no nausea, vomiting, or bilirubin rose to 7.0 irect-reacting fraction 200 units, and serum > 50 K-A units; thymol jrmai Drug therapy jaundice cleared in die hepatic dysfuncinic acid is not clear, ice of features sugeaction, it is unlikely vity is involved. Al; of Bromsulphalein nal development of and the absence of he liver suggest the lestasis produced by tosterone, the fre- of serum transamigests a mild hepato- ntundandione, untlon'e) used anticoagulant, 0 reactions that apure. These are charh granulocytopenia d may be accomtype of hepatitis,**' by nephritis." As >t during the 3rd or oistration, but may 1 day and as late as e reaction appears a few days after withdrawal of the drug.48* UsuaOv, resumption of therapy following recovery provokes a prompt relapse.**-483 Usually, hepatitis subsides following with drawal of the drug. In some cases, ACTH and corticosteroids have appeared to hasten ! recovery."* 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 acenocoumarin (nicoumalone, Sintrom).5*3 It is probably unwise, therefore, to use any agent in this group once a reac tion has occurred. Phenylhydrazine 0 The jaundice seen during phenvlhydra! zine therapy for polvcvthemia vera is due j primarily to the rapid hemolysis of erythro cytes. It has been suggested that prolonged 1 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,201 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. POLYVINYL PYRROLLDONE (PVT) 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 phagocytized material appears to increase with time. Occasionally, a mild inflamma tory reaction is associated with the deposi tion of PVP, but there is no fibrosis or evi dence of hepatocellular dysfunction. In ani mals given repeated injections of PVP, ag gregates of PVP-fiUed 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 ulti mately 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, tevarterenol, 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 widely 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,575 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.48 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, both 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 benzothiadiazioes, 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 L5 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 die indirect Sects of irradiation. In some cases, intensive irradiation over the liver produces severe degeneration and necrosis of the intrahepatic bile ducts while sparing the parenchyma.12* 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 binary 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.2* Smaller doses also affect the hepatic paren chyma, but the changes are more subtle.*47- TM 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."98- 35S-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 centra] 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.802 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.358 There is evidence that, in some cases, the lesions regress or heal without residuals after a period of 4 months.388- ** However, marked fibrosis may persist and often is accompanied bv terminal jaundice.9* Rarely, such hepatic lesions may be complicated by stricture of the common duct or fibrosis of the pan creas.9* Surprisingly few changes in the liver were observed in atom bomb casualties.439 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 central 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 racnoactive colloidal gold, it produces severe midzonal hepatic necrosis in rats.398 The architecture of the crosis enchyi Althoi there ascites varies Des is con trast i rise tc disord Hej grees occur: who 1 thorn] splen< ally, after arums foci < much numb hepat A% been minis of aj often been hepal hema lioma tion I have sues, cedei less i acute aplas pura tions All taine ciallj of ye the : none can $>f th *>f tl ^he I 36212 to! leukocytic infilvascular damage.2* jt the hepatic pawn s'are more subtle.447. Intensive irradiation over the liver pro giving rise to a synn hepatitis/'96' 333,414 es and hepatosplenoiccompanied by abidice, appear 2 to 0 letion of a course of tic lesion may heal to fibrosis of the liver sion is characterized ; and obliteration of ntrolobular congesatrophy of the parat closely resemble osive disease seen in d by senecio aBcathat the vascular le> responsible for the hepatic parenchyma ince in some studies ages have been objpearance of hepatic There is evidence he lesions regress or after a period of 4 er, marked fibrosis l is accompanied by barely, such hepatic icated by stricture of fibrosis of the pan- uoges in the liver were b casualties.439 In ini for less than 6 weeks, were central conges: the hepatic parenthe central veins. In longer, the liver exn. tive materials used as stic agents can prooactive colloidal gold [Thorotrast). no clinical reports of die use of radioactive uces severe midzonal s.8** The architecture Miscellaneous 571 of die liver is grossly distorted, both by ne crosis and by the transformation of die par enchyma to masses of bizarre giant cells. Although the lesion may resemble cirrhosis, there is no fibrosis. Clinically, jaundice and ascites are evident prior to death. Survival varies from a few days to 7 months. Despite claims to the contrary,800,801 there is convincing evidence to show that Thoro trast can produce hepatic injury and give rise to malignancy ana certain hemopoietic disorders. Hepatosplenomegaly with varying de grees of fibrosis and cirrhosis of the liver occurs in a significant number of individuals who have received large doses of colloidal thorium dioxide in the course of hepatosplenography or angiography.12, 181, 232 Usu ally, the signs of hepatic disease appear after a latent period or at least 15 years. In animals, large doses of Thorotrast produce foci of hepatic necrosis and fibrosis in a much shorter period of time.348 A significant number of patients with the disease die of hepatic failure. A wide variety of malignant tumors have been encountered following Thorotrast ad ministration, usually after a latent period of approximately 20 years.181,33e-382 Most often these have involved the liver, and have been of varying histologic types, including hepatoma, cholangiocarcinoma, sarcoma ana hemangioendothelioma. Hemangioendothe liomas are particularly frequent.181 In addi tion to those found in the liver, carcinomas have been encountered in many other tis sues, although their relationship to ante cedent Thorotrast administration has been less well defined.181 Also, instances of both acute and chronic leukemia, lymphoma, aplastic anemia and thrombocytopenic pur pura have been reported as late complica tions of Thorotrast deposits.181 All of the injected thorium dioxide is re tained in the reticuloendothelram, and espe cially in the liver and spleen. Over a period of years, some may shift 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 reticuloenaothetium of the spleen, it is generally believed that the fibrosis that occurs in these organs is due to radioactivity and not to a foreignbody reaction. The 75 mL dose of 25 per cent thorium dioxide solution required for hepatosplenography has been estimated to possess an alpha ray activity equivalent to that of 1.5 to 3.0 micrograms of radium.801 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 been identified in the excreta and the ex pired air many years after the injection of Thorotrast.718 The carcinogenic potentiality of Thorotrast is also presumed to be related to its radioactivity. Transfusion Reactions Not infrequently, severe reactions to transfusions of incompatible blood are ac companied by jaundice, a manifestation al most certainly due to acute hemolysis. How ever, evidence suggests that hepatic injury plays a contributory role. In most fatal cases, the liver shows areas of central necrosis,88, 288 and similar lesions have been produced in dogs by injecting heterologous hemagglu tinins.38* Healing is followed by diffuse fibrosis in animals that survive, but a simi lar sequence has not been described in man. The pathogenesis of the hepatic lesions in transfusion reactions is not well understood. Possibly they are related to shock, which is often present. It has also been suggested that hepatic necrosis results from impaction of the sinusoids with agglutinated erythro cytes. Jaundice may also follow the transfusion of well-matched blood. This complication, designated by some as "benign postoperative intrahepatic cholestasis,** is seen most commonly during the postoperative course of patients who have been transfused with bank blood.370,870, w2,872 However, it may also occur after transfusions administered to patients with severe trauma or burns.*72 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 bitirubinuria, 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./100 ml., but concentrations of 25 to 40 mg./lOO ml. have been reported.370,053 Histologically, the liver shows centrilobular bile stasis which, occasionally, is accompanied by focal hepatic necrosis and degenerative changes.370- 032 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-K 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.74 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 ana 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 days 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. 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