Document QgoXJXyYwpqoOzMD5QpRgVmz4

OV680V s * a 'r BIO-MEDICAL RESEARCH DOCUMENT DESCRIPTION FORM 63 68 69 76 Duplicate in all cards:--> year as-1961- File number [Right justify [Numeric only] 77 78 Sub-Index Code Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space 1 /]; J h' / ' sf /, '* 20 21 4/ 40 41 __________________ 60 11 _/ - /, ,-/v , / 61 62 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms, separated from each other with comma-space. Avoid other punctuation; do not abbreviate. 1_______ ___________________________________________ ._ __ _ 21 22 '//'/ l'.' - ( r'A/.` S' t '! T "r ' ;vv^ $ r ^/':'V 23 < ,r /'/-------- 24 Source (Journal, Vol., Number, Pages, Date ) 12 f /" S / / s- i 61 62 31 32 Brief Summary 12 10 SUMMARY: 61 62 61 62 63 64 R&S 108911 Liver Damage and Angiosarcoma in Vinyl Chloride Workers A Systematic Detection Program Laszlo Makk, MD; John L. Creech, MD; Joseph G. Whelan, Jr., MD; Maurice N. Johnson, MD 90002Q1 Recently, five cases of hepatic angiosarcoma were found in Louisville. All of the patients had worked in a plant engaged in the production of polyvi nyl chloride (FVC) from vinyl chloride. A systematic health surveillance pro gram was instituted to detect existing iiver damage or angiosarcoma and to find eariy signs of developing liver damage. A proiocol was devised that be gan with on-site phlebotomies done in the piant and progressed to sophis ticated hospital studies, if important abnormalities were found. All of the 1,183 employees of the plant were tested. Two new cases of he patic angiosarcoma ana three cases of portal fibrosis were discovered by this program at the initial screening. It is hoped that continuous health moni- v/ili ahnormniitiA^ wmlA stilt in a reversible or curable slate. (JAMA 230:64-63, 1974) ANGIOSARCOMA of the iiver is one of the rarest human malignant neo plasms, The annual incidence in the United States is about 21 cases per year. Recently, seven cases of angio sarcoma were discovered in Louis ville. These patients were scattered in various hospitals in the area and were cared for by their personal physi cians. Initially, one of us noted the diagnosis of angiosarcoma of the liver on a death certificate and recalled that three years earlier he had per formed a biopsy of n liver with the same diagnosis. After he found that both of these patients had worked in a plant engaged in the production of polyvinyl chloride (PVC), careful data collection was begun. Thorough From the depbrtments Of pathology (Dr Makk), surgery (Dr, Creech), and racJio'ogy (Dr Whelan). St, Anthony Hospital, and the Medical Department (Drs Creech and Johnson), 3 F Goodrich Co., Loutjvi'ie. Reprint requests to 13t3 St Anthony Place, Louisville, KY 402Cm (Dr. Makk; search of plant and area hospital meaicai records resulted in the dis covery of three more cases from ne cropsy reports recorded over a tenyear period. Two additional cases were diagnosed by biopsy in the past two months as a result of this pro gram. See also p 59. Each of the patients with angiosar coma who were under our care, and some without angiosarcoma, had fi brosis of portal areas and other path ologic changes apparent on liver biopsy specimens. None of these pa tients had any specific abnormal find ings on physical examination or rou tine laboratory tests. In view ol this, a systematic detection program was devised and instituted with three ob jectives: (1) to find any presently ex isting liver damage or angiosarcoma in workers exposed to vinyl chloride or its polymer,-., (2) to detect early liver damage, if possible while in a re versible state, with continuous health monitoring, and (3) to provide infor mation for preventive measures. Materials and Methods A program was designed whereby large numbers of workers could be screened for liver disease with rela tive ease. The significant abnormal ities were evaluated by a combine-., clinical, comprehensive laboratory, and roentgenographic study. The re sults of this evaluation served as a basis for the treatment of the pa tients (Fig 1). The initial laboratory procedure for detection way a 12- or 18-factor automated chemical analy sis. The 12-factor analysis consisted of tests for the following: calcium, in organic phosphorus, glucose, blood urea nitrogen (BUN), uric acid, cho lesterol, total protein, albumin, total bilirubin, alkaline phosphatase, lactic acid dehydrogenase (LDH), and se rum glutamic oxaloacetic transami nase (SGOT). The 18-factor analysis consisted of the preceding plus cre atine phosphokinase (CPK), creati nine, and serum electrolyte determi nations. The blood was drawn at the plant's Medical Department; trans portation, centrifugation, and test determinations were done promptly. If the initial laboratory results were normal, the tests were repeated in three months. If abnormalities not. related to the liver were found by any of the screening procedures, they were followed up according to their severity. If one liver-related abnor- G4 JAMA. Oct 7. 1974 * Vol 230, No 1 Liver Damage--Makk et a! V R&S 108912 Retest Three Months Later t Normal Remove From PVC Work. Advise To Abstain From Alcohol and Other Hepatotoxins Abnormal / N'' Normal -* Normal I No Action Riant Population t 12-or 18-Factor Analysis __ One Test *" Abnormal Retest Three Weeks Later 2 or More Tests Abnormal Jr Comprehensive Liver Profile Liver Scan Normal Abnormal Abnormal Abnormal Chest Roentgenogram Abnormal I Action As Indicated F Evaluate Normal Panangiography T -- Abnormal t Laparotomy and Biopsy Retest in 3 Mo Restudy as Indicated Resection ` f l . J , - * - It tllsJiW'UlUU Fig 1.--Liver disease detection protocol. mality was found, the 12-factor anal ysis was repeated in three weeks. If the single abnormality presisted, or if two or more liver-related abnormal ities were found on the initial labora tory tests, the patient underwent a comprehensive examination consist ing of tests for the following values: a 12-factor automated chemical analy sis, serum electrophoresis, LDH isoenzymes, fractionated alkaline phosphatase, direct and indirect bili rubin (if total level was elevated), se rum glutamic pyruvic transaminase (SGl'T), y-glutamic transpeplidase (GGTP), isocitrate dehydrogenase (ICD), (i-fetoprotcin (fctoglobulin), and carcinoembryonic antigen (CRA). Also, a complete blood cell count (CBC), platelet count, chest roentgen ogram, and liver and spleen scan were done. Abnormalities found in the initial 12-factor chemical analyses indicat ing the need for comprehensive pro -- - Table 1 ---Liver Enzyme and Bilirubin Results Test Alkaline phosphataso, mil (milliunits) /ml y-Glutamic transpeptidase, mll/ml Serum glutamic oxaloacetic transaminase, mll/ml Bilirubin, mg/100 ml Serum glutamic oxaloacetic transaminase, mll/ml Isocitrato dehydrouenase, mll/ml Lactic dehydrogenase, mU /ml No. of Patients Studied 72 70 68 72 73 59 72 No. (%] With Abnormal Values 35 (49.4) 31 (44.3) 19 (29.8) , Normal Range 3-35 6-28 4-25 19 (28.4) 13 (18.0) 0.15-1.0 12-40 9 (18.0) 8 (11.1) 0-7 90-225 Abnormal Range 87-135 29-575 27-559 1.1-2.6 48-150 8-88 237-475 files were grouped according to the following work areas: (1) PVC pro duction, (2) synthetic rubber produc tion, and (3) .all others (including maintenance, shipping, laboratory, and other salaried employees). Liver Abnormalities Dictated Hospital Studies If abnormal scan or other findings suggested serious liver disease or the possibility of angiosarcoma, the pa- JAMA, Oct 7, 1974 Vol 230, No 1 Liver Damage--Makk et al 65 Table 2.--Twelve-Factor Analysis Abnormalities and Comprehensive Screening Cases According To Work Area Work Area 12*Factor Analysis z--------------------- -----------------------( No. {%} With Total No. Abnormality No. (%) Co.T.pro- hensive Profile Needed Polyvinyl chlorideproduction____________ 274___________ 59 (21.5)__________ 2ti (9.8) Synthetic rubberproduction 203 58 (28.6) 14 (6.9) All other 7U6 1S9 (26.7) 35 (4.9) Total 1.183 306 (26.7) 75 (6.3) Case Mo. 1 2 3 4 5 6 7 Diagnosis Angiosarcoma Angiosarcoma Portal Fibrosis, fatty cnange Portal Fibrosis, moderate Portal Fibrosis, slight Normal Normal Angiographt Tumor right Ic cirrhosis Tumor, both Ir and cirrhos Normal Normal Normal *T Indicates elevated values; I. depressed values. tN Indicates normal values. 'V . v, t. Fig 2.--Technetium 99m sulfur colloid liver scan, anterior view. Typical filling defect in right lobe of liver. X Fig 3.--Hepatic arteriogram, six seconds. Circumferential tumor vessels are present in right lobe of liver (arrows). Main hepatic artery is normal size. Intrahepatic vessels are small and tortuous suggesting cirrhosis. !--til i*fl liitSpfcdl JW* , Fig 4.--Hepatic arteriogram, ten seconds, portal venous phase; Circumferential tumor stain is present with a central area of radioluccncy (arrows). Stain persisted through the late poital hepatogram phase, up to 34 seconds. tients were hospitalized and hepatic panangiography was performed, con sisting of hepatcsplenic arterio gram and phlcbogram with free and wedged hepatic pressure measure ments. The hepatic arteriogram was performed by the Seldinger tech nique.' A mixLure of diatrizcate so dium and diatrizcate meglumine (Renogr?fin-76) was user! as contrast medium. If the angiograms demon strated findings suggestive of a tu mor, open-liver biopsy was advised with consideration of hepatic lobec tomy, if so indicated at exploration. If angiosarcoma was limited to one lobe, a biopsy specimen of the unin volved lobe was obtained first to eval uate the extent of fibrosis or other damage and render diagnosis by fro zen section. Then, a biopsy specimen of the tumor was obtained and stud ied likewise. If the uninvolved lobe had no no table disease, lobectomy of the neo plastic lobe was to be performed. If the nonneoplastic lobe was diseased (ie, showed fibrosis t.o a degree that lobectomy might have led to liver failure), or if the angiosarcoma in volved both lobes, chemotherapy was to be considered. On biopsy, a wedge and deep Vim-Silverman needle specimen was obtained from each lobe when no gross tumor was found. In the presence of neoplasm, only wedge biopsies were taken. Results Screening profiles were obtained from 1,1S3 employees by the 12- or 1H- 66 JAMA, Oct 7, 1974 Vol 230, No 1 Liver Damage--Mnkk et al J3 8 V) o 00 (0 CO Table 3.--Tissue, Roentgenologic, and Laboratory Examination Correlation Liver Scan Filling defect and cirrhosis Filling defect, both lobes Alkaline Phosphate t T y-Glutamie Transpetidase tr t Level of Serum Glutamic Pyruvic Transaminase A I Bilirubin t NN Suggestive cf cirrhosis r t T t Suggestive of cirrhosis t T i N ' Suggestive oi cirrhosis T rNN Normal 4 NNN Normal T NNN Serum Glutamic Oxaloacetic Transaminase T Lactic Dehydrogenase Nt tt tN NN NN NN NN Platelet Count l T N N N N N factor chemical analysis. Of these, 75 isoenzyme 1. Splenomegaly with abnormal liver (6.3ro) had either two liver-related ab Fetoglobulin determinations gave scan was present in three patients. normalities on the initial screening or normal results in all cases. Results of Hepatic panangiography was per one such abnormality that persisted. carcinoembryonic antigen radio formed in seven patients. Rv pan- These patients had comprehensive immunoassays were normal in all pa angiography, two of the liver scan evaluations. One patient had initial tients, with one marginal result in a filling defects were found to be tu screening in the plant, further eval patient who smoked. Complete blood mors (Fig 3 and 4). The anomalous po uation and biopsy elsewhere, and cell counts disclosed normal values for sition of the gallbladder in one case, then was transferred to our institu tion for further studies. Results of al- r'n'T'Tt C'nrt'T* t :i ^U 4 1 , 1 X, LJ I t~ hemoglobin, hematocrit, red blood ceil (RBC) count, and corpuscular indexes 111 Cdl.fl }MUcnL 1* UUl paiitMIlt) IKlU and dilatated short gastric and collat eral portal veins in another cerrelat1 with the defects on the scans. 11 irubin, SGOT, ICD, and LDH slight to moderate granulocytosis. other angiograms were normal. examinations are listed in Table 1. One patient showed relative lym Of the six splenic arteriograms, Significant Biochemical Findings phocytosis. Twenty-three patients two showed splenomegaly; one of showed slight, and seven moderate, these with multiple splenic aneu Other tests of the comprehensive monocytosis. Three patients had mod rysms and the other, intrasplenic ar liver profile yielded the following sig erately increased eosinophil counts. terial strictures. The other four were nificant results: moderately elevated One patient had thrombocytopenia normal. total pr, 'in values were found in with a platelet count of 98,000/cu three patients with a similar eleva mm, and another had thrombocytosis Surgical Findings tion in y-glohulin content. Serum with a count of 750,000/cu mm (nor Exploratory laparotomy was per electrophoresis showed slight to mod mal range, 140,000 to 440,000). The formed in seven patients; in two, an erate increase in 7-globulin in 11 pa number of 12-factor abnormalities giosarcoma was found. Resection tients. The /?-globulin value was and comprehensive profiles according could not be carried out in one patient slightly lowered in six patients. to work areas is listed in Table 2. because of the extent of neoplasm. In In 32 patients with elevated alka line phosphatase values, 15 had in Radiological Studies the other patient, angiosarcoma was limited to one lobe, but because of creased liver fractions. In 37 patients Seventy-four patients had liver portal fibrosis in the other lobe, resec with normal levels of alkaline scans: 11 01 those scans (M.S76) were tion was deferred. phosphatase, fractionation was also abnormal, and 2 were borderline. Six In three patients, varying degrees performed. Thirteen showed relative patients had filling defects (Fig 2). of portal fibrosis was found on lap elevation of liver fractions. Eight of Three of these and another five pa arotomy. Of the remaining two pa 72 patients (11.lrc) showed elevated tients had irregularities suggestive of tients, one had a cholecystectomy, the 3J values for total LDH. Four of those cirrhosis. Spleen scans were per other an incisional hernia repair. fie had isoenzyme 4; two, isoenzyme 5; formed concurrently with liver scans Liver biopsy was performed con W and one, isoenzyme 3 elevation; one in 71 patients. comitantly on each. Both of these liv had normal isoenzyme proportions. Three patients had had splenec ers were essentially normal oil biopsy o 00 Of CD cases with normal LDH val tomies in the past. Nine patients and on laboratory testing. Correla --tol ues, -14 showed relative elevation in (12.7'f') had enlargement of the spleen tion of biopsy, roentgenographic, level of isoenzyme 1 (GS.7',7); two. rela to 22 cm (normal spleen size is consiu- and laboratory findings is given in tive isoenzyme 5; and one, relative ered less than 14 cm in length1). Table 3, JAMA, Oct 7, 1974 Vol 230, No 1 Liver Damage--Makk et al G7 *1 R&S 108915 Chest roentgenograms and labora tory examinations not related to liver function disclosed only occasional ab normalities. These were followed up appropriately. All were within the findings expected from a screening of this size male adult population. No lung tumors were found. Comment Nonueoplastic liver damage in polyvinyl chloride production workers has been reported.1' Acro-osteolysis was also observed In such workers.1 Viola et ah' reported the development of skin, lung, and bone neoplasms in rats exposed to vinyl chloride. Mal- toni7 reported hepatic angiosarcomas and other neoplasms in rats exposed to high doses of vinyl chloride. To our knowledge, the Louisville cases are the first recognized human angiosar comas of the liver associated with working in vinyl chloride monomer polymerization. Creech and Johnson' reported the first angiosarcoma of the liver among vinyl chloride workers. Block" also reported on the subject; or.e of our cases is included in his re port. The report of Falk et al (p 59) ... i i . .... . c j-i-; _ Vil tiiti V^lUUltUvi^V Ui H4 4-J Ul.1C.UdV also includes two cases of angiosar coma discovered with our program. As the results indicate in Table 2, the percentage of abnormalities on the 12-factor examination seems higher than would be expected among a presumably healthy working popu lation. These results also indicate that a somewhat smaller proportion of persons engaged in PVC production had abnormalities on initial 12-factor analysis than either those who worked in synthetic rubber produc tion or all other workers in the plant. However, considerably larger num bers and percentages of the PVC workers had liver disease serious enough to warrant comprehensive profiles. All the patients who needed angiography, the two patients with angiosarcoma, and two of the three with portal fibrosis had worked in PVC production. In our experience, the logistics of this program worked well from on site screening to sophisticated test ing. This surveillance discovered two new, otherwise unsuspected angiosar comas of the liver and three cases of portal fibrosis. The good correlation between norma! liver biopsies and es sentially normal liver function tests in cases 6 and 7 was reassuring. In addition this program provided a wealth of base-line liver function test results and other health information. These data formed the basis of a con tinuing health monitoring program for these workers. GGTP Reflects Extent of Damage Of the liver function tests, the GGTP determination seemed to be most useful in detecting abnormal ities and reflecting the extent of liver lesions by the degree of elevation. Alkaline phosphatase, SGPT, SGOT, LDH, and bilirubin tests were also useful. The large number of LDH1 isoenzyme elevations are noteworthy, but they merit further study before specific significance can be attached to them. Fetoglobulin and carcino- embryonic antigen determinations were normal. No test was specific for angiosarcoma. The liver function studies appeared to reflect quite well the extent of liver damage, except in patient 2, where this correlation was tr t i i.,.' , .. jjl/ui . nc iutu CALcnanc , , .................... .... and only slight elevation in LDH val ues on the initial screening that per sisted. This prompted his astute per sonal physician to request more sophisticated studies and biopsy ex amination. It is therefore quite im portant than even borderline abnor malities bo carefully followed up. Scans and Angiograms Liver scans and angiographic stud ies corresponded well with results of laboratory tests and biopsy examina tions in the detection of cirrhosis, even in early stages. When roentgenographic studies indicated cirrhosis, the concomitant histopathologic ex amination disclosed a peculiar fibro sis of the portal areas instead of cir rhosis. It is our understanding that when communications refer to cir rhosis in the context of this condition, the histological findings arc those of a peculiar portal fibrosis and Ivupffer cell hyperplasia. Hepatic panangiographv with pressure measurements as described by Viamontc ct al1" was very helpful in the differentiation of neoplastic from nonneeplastic lesions that appeared as a filling defect on scanning. It also proved helpful in the preoperative evaluation of the extent of the tumor. In addition to angiogra phy in selected cases, we are planning liver biopsies through the right jugu lar vein as described by Rosch et al.1' The experience gained from this study enabled us to modify our method. We added GGTP and SGPT determinations to the 12-factor initial examination. Tests for fetoglobulin, ICD, and carcinoembryonic antigen as w'cll as electrophoresis were de leted from our comprehensive profile. Until specific tests for hepatic angio sarcoma or vinyl chloride-induced liver damage are available, in our ex perience such a surveillance program of laboratory testing, roentgenographic examinations, and clinical evaluation will help to detect liver damage in an early, possibly rever sible or curable state. James T. Kurfees, MO, Anchorage, Ky, gave permission for inclusion of the results from one of ms patients in this study. . References 1. Seldinger SI: Catheter replacement of the needle in percutaneous arteriography. Acfa /fadial 39:363-376, 1933. 2. Siegel RM, Becker DV, Hurley JR: Eval uation of spleen size during routine liver imag ing with '-"'Tc and scintillation camera. J Nuct Med 11.GS9-692, 1970, 3. Marsteller HJ, et al: Chronisch-toxischc-leberschaden bei arbeitom in dor PVC-production Dtsch Med Woehcnxchr 93:2311-2314, 1973. 4. Suctu T, Drojam T, Vakvskai M: Etude des maladies dues au chloride do vinyl. Mad Lav 53:261-271, 1%7. 5. Wilson RH, et al: Occupational acroostcolysis: Report of 31 cases. JAMA 201:577, 1967. 6. Viola PL Bigotti A, Caputo A: Oncogenic response of rat skin, lung, and hones to vinyl chloride. Cancer Rea 31:516-522, 1971. 7. MaltoniC: Exhibit 6. Judge Myall's hearing on oncogenic potential of vinyl chloride 43-63, 1974. 8. Creech JL, Johnson MN; Angiosarcoma of liver in the manufacture of polyvinyl chloride. J Ormp Mt<! 16.150-151. 1971. 9. Block JR: Angmsarwina of the liver follow ing vinyl chloride exposure. JAMA 229.53-54, 1974, 10 Viamontc MJ, Warren WD, Foroman JJ: Liver panangiography in the assessment of por tal hypertension in liver cirrhosis, Radittl Clin Xarth .-bn 8*147-167, 1970. H, Kosch J. et ah Tran\jugular approach to liver biopsy and transhepatie cholangiography. 4V flnyl J Sin! 289.227-231. 1973. 6B JAMA, Oct 7. 1974 Vo! 230, No 1 Liver Damage--Makk el al