Document 10xn7e0Rm1pQk9BYxKZbwKxD5

Progression of vinyl chloride induced hepatic fibrosis io angiosarcoma of the liver 307 varices to be the source of haemorrhage, and these-, 'absence of portal hypertension, and may then be were treated by injection sclerotherapy. The serum difficult to detect. It does not lead to a disturbance alkaline phosphatase and y-glutamyl transpeptidase of liver function tests and may even be missed on levels rose over the next three months to 334 IU/1 needle biopsy of the liver.1 Greyscale ultrasonogra and 106 RJ/1 respectively. Radioisotope liver scan phy is a useful diagnostic aid," but it has yet to be showed multiple filling defects consistent with used in a large industrial survey, and there are prob tumour deposits. Ascites and ankle oedema ably several unrecognised affected VCM workers. developed, and he died suddenly in January 1980 Stringent measures to control levels of exposure from an intraperitoneal bleed after a liver biopsy. should lead to eventual disappearance of non- Necropsy showed that a large haemorrhagic tumour, arThotic fibrosis. Those patients who already have occupying most of the right lobe of the liver, had the condition, however, are still at risk of developing ruptured into the peritoneum. Several smaller hepatic angiosarcoma in the future. haemorrhagic tumours were found elsewhere in the A problem highlighted by the second case is that liver. An enlarged spleen (wt 760 g) and thrombosed, angiosarcoma is, by definition, a vascular lesion, and oesphageal varices were also noted. Histology there is a risk of uncontrolled haemorrhage after sh wed the tumours to be angiosarcomas, with areas blind liver biopsy. We believe, therefore, that the of sinusoidal dilatation and portal fibrosis in unaf diagnosis should be sought either by laparoscopic fected areas of the liver. biopsy or by hepatic angiography. Discussion Vinyl chloride monomer is transformed by hepadc microsomal enzymes to toxic metabolites that coval ently bind to DNA.' After exposure to VCM hepatocytic proliferation, sinusoidal lining cell pro liferation, and focal sinusoidal dilatation occur1 and angiosarcoma may later develop from the sinusoidal lining ceils. Enlarged lipocytes may be seen in the space of Disse1; these cells are fibroblast precursors and can lay down collagen.' Hepatic fibrosis results and may be assodated with presinusoidal portal hypertension.11 It is commoner than angiosarcoma.2 Although fibrosis was found in tumour-free portions of the liver tissue from VCM workers dying of angiosarcoma,1 transition of hepatic fibrosis to angiosarcoma, although postulated,1 has not been observed. The two patients described here were originally included in a series of seven VCM workers with por tal hypertension.1 They were followed for five and 10 years respectively from the time of diagnosis of portal hypertension to death from angiosarcoma. During this period they were not further exposed to VCM. Their case histories indicate that hepatic fibrosis in a VCM worker may be a precursor of future malignant change and life-long follow-up is necessary. We know of only one other similar patient who died seven years after a portacaval shunt from an angiosarcoma.1 Non-tinhotic fibrosis can also occur in the We thank Dr D M D Evans and Professor Peter Scheuer for their help in interpreting the biopsy material. References 1 Creech JL. Johnson MN. Anpotarcoma of the liver in the mamifaaurc of polyvinyl chloride. JOM 1974:14:150-1. 1 Smith PM, Crossiey'lR, Williams DMJ. Portal hypertension in vinyl chloride monomer workers. Lancet 1976;ii:602-*. 1 Popper H. Malioni C, Selikoff U. Vinyl chloride-induced hepatic lesions in man and rodents. A comparison. Liver 1981;1:7-20. * Tamburro Of. The hepatic role in carbnogenesis and nj early detection--the vmvl chloride model. Yale J Biel Met 1978:51:67-80. * Popper H. Thomas LB. TeBes NC Falk H. Selikoff LI. Develop ment at hepatic angiosarcoma in man induced hv vinyl chloride, thoroirast and arsenic.Am J Pathol 1978:92:349-69. * Makk L. Delmore F, Creech JL. a e/. Oinica] and morphological pattern! of hepatic angiosarcoma in vjnyl dilolide workers. Cancer 197637:149-63. ' Ostermann-Golkar S. Hultmark D. Segertack D, tt aL Alkyla tion of DNA and protein in mice exposed to vinyl chloride. Biochem Biephys Res Common 1977;76:259-66. 1 Sdtaffner F. Popper H. Selikoff LI. Initial features of vinyl chloride (VQ hepatic injury. Gastroenterology 1976;72:A35. * Kent G. Gay S, Inouye T. Bahu R, Minick OT, Popper H. Vita min A containing lipocytes and formation of type III collagen in Hvcr injury. Proc Nail Acad Sd USA 1976:73:3719-22. ' Blendii LM, Smith PM. Laurie BW, Stephens MR, Evan WD. Portal hypertension in vinyl chloride monomer workers. A hemodvnamic ttudv. Gastroenterology 1978;75:206-11. " William! DMJ. Smith PM. Taylor KJW. Crowley IR, Duck BW. Monitoring liver disorder! in vinyl chloride monomer workers using grevscaie ultrasonography. BrJlnd Med 197633:1527. R&S 116712 British Journal of Industrial Medicine 1982;39:306-307 r*T fjfffuc Progression of vinyl chloride induced hepatic fibrosis to angiosarcoma of the liver D B JONES AND P M SMITH From the Department of Gastroenterology, Uandough Hospital, Penarth, S Glamorgan, UK abstract Two vinyl chloride monomer (VCM) workers, who developed non-cirrhotic portal fibrosis and portal hypertension, died from angiosarcoma of the liver five and ten years later respectively, despite withdrawal from occupational exposure. We suggest that non-rirthotic por tal fibrosis caused by exposure to VCM is potentially premalignant and that those workers who already have the condition should be carefully monitored. Since the original communication by Creech and results showed a normal scrum bilirubin with a Johnson' there have been several further case reports of vinyl chloride monomer (VCM) induced angiosarcoma of the liver. A commoner hepatic raised alkaline phosphatase (201 IU/1) and y-giutamy? transpeptidase (83 IU/1). Radioisotope liver scan showed a small liver with no filling defects lesion is non-drrhotic portal fibrosis3 leading to por and needle liver biopsy showed a well-pronounced tal hypertension. It has been suggested that this micronodular cirrhosis with no evidence to tumour. lesion may be a precursor to angiosarcoma He responded to protein restriction and lactulose formation,3-3 but there has been only one report of a and was discharged. Within a week of discharge he patient with documented hepatic fibrosis developing was readmitted with an endoscopically confirmed angiosarcoma at a later date.* We describe two bleeding duodenal ulcer. After this, he lapsed into further cases. hepatic coma and died. Necropsy showed multiple malignant tumours in the liver (wt 1130 g), one of Case reports whit* was haemorrhagic. Histologically, a great variety of liver cell lesions were present, some resem CASE 1 bling angiosarcomas, some hepatocartiuomas, and A 60-year old white man initially presented in 1969 some adenomas. There were also atypical sinusoidal to the dermatology department with a skin eruption. cells and fibrosis in the non-mmorous parts of the Examination at that time showed anaemia, thrombo liver. cytopenia, hepatosplenomegaly, and occult faecal blood loss. He had an occupational history of expos CASE 2 ure to VCM at high concentration for seven years A 49-year-old man with a 12-year history of expos while working as a polycleaner and a blowdown ure to vinyl chloride monomer while working as a recovery operator. After two haematemeses, barium spray drier bagger, premix operator, and paste studies and splenic venography confirmed portal charging operator was, during a factory survey of hypertension and oesophageal varices, and he process workers in 1974, found to have thrombo underwent an end-to-side ponocaval shunt. At cytopenia. This was later shown to be due to laparotomy the liver looked nodular, but operative hvpersplenism and presinusoidal portal hyperten liver biopsy showed non-dnhoric portal fibrosis sion. He was otherwise well and drank five pints of only. Over the next four years the patient developed beer a night. Liver function test results were normal chronic portosystemic encephalopathy and maturity apart from a raised y-glutamyl transpeptidase level onset diabetes mellitus that was treated with oral of 82 IU/1. Varices were shown by barium studies hypoglvcaemic agents. In May 1980 he presented and endoscopy, and liver biopsy showed fatty with worsening mental deterioration, hepatic foetor, change and slight non-cirrhotic portal fibrosis. Two asterixis, and an enlarging liver. Liver function test years later the patient developed insulin dependent diabetes mellitus, but otherwise remained well until Received 5 October 1981 Accepted 20 November 1981 October 1979 when he presented with a large haematemesis. Endoscopy confirmed oesophageal 306 Pro. CD -4 Dis- Vin mic entl hep life: ang linii spa> and and hyp Alt of ang ang obs .1 inti tal 10 por Du: VC fibr fun nec pat shu N i Progression of vinyl chloride induced hepatic fibrosis to angiosarcoma of the liver 307 varices to be the source of haemorrhage, and these were treated by injection sclerotherapy. The serum alkaline phosphatase and y-glutamyl transpeptidase levels rose over the next three months to 334 IU/1 tnd 106 IU/1 respectively. Radioisotope liver scan >howed multiple filling defects consistent with umour deposits. Ascites and ankle oedema leveloped. and he died suddenly in January 1980 rom an intraperitoneal bleed after a liver biopsy. Necropsy showed that a large haemorrhagic tumour, occupying most of the right lobe of the liver, had ruptured into the peritoneum. Several smaller naemorrhagic tumours were found elsewhere in the iver. An enlarged spleen (wt 760 g) and thrombosed oesphageal varices were also noted. Histology showed the tumours to be angiosarcomas, with areas of sinusoidal dilatation and portal fibrosis in unaf fected areas of the liver. absence of portal hypertension, and may then be difficult to detect. It does not lead to a disturbance of liver function tests and may even be missed on needle biopsy of the liver.- Greyscale ultrasonogra phy is a useful diagnostic aid," but it has yet to be used in a large industrial survey, and there are prob ably several unrecognised affected VCM workers. Stnngent measures to control levels of exposure should lead to eventual disappearance of non cirrhotic fibrosis. Those patients who already have the condition, however, are still at risk of developing hepatic angiosarcoma in the future, A problem highlighted by the second case is that angiosarcoma is, by definition, a vascular lesion, and there is a risk of uncontrolled haemorrhage after blind liver biopsy. We believe, therefore, that the diagnosis should be sought either by laparoscopic biopsy or by hepatic angiography. Discussion Vinyl chloride monomer is transformed by hepatic microsomal enzymes to toxic metabolites that coval ently bind to DNA.' After exposure to VCM hepatocytic proliferation, sinusoidal lining cell pro liferation, and focal sinusoidal dilatation occur5 and angiosarcoma may later develop from the sinusoidal lining cells. Enlarged lipocytes may be seen in the space of Disse"; these cells are fibroblast precursors and can lay down collagen.1' Hepatic fibrosis results and may be associated with presinusoidal portal hypertension,'0 It is commoner than angiosarcoma.; Altho' fibrosis was found in tumour-free portions of the :iver tissue from VCM workers dying of angiosarcoma,' transition of hepatic fibrosis to angiosarcoma, although postulated,' has not been observed. The two patients described here were originally included in a scries of seven VCM workers with por tal hypertension.' They were followed for five and 10 years respectively from the time of diagnosis of portal hypertension to death from angiosarcoma. Durina this period they were not further exposed to VCM "heir case histories indicate that hepatic fibrosis in a VCM worker may be a precursor of future malignant change and life-long follow-up is necessary. We know of only one other similar patient who died seven years after a portacaval shunt from an angiosarcoma.4 Non-cirrhotic fibrosis can also occur in the We thank Dr D M D Evans and Professor Peter Scheuer for their help in interpreting the biopsy material. References 1 Creech JL. Johnson MN. Angiosarcoma of the liver in the manu facture of pofwinyt chlonde. JOSf 1974;16:15<M. * Smith PM. Crossley IR, Williams DMJ. Portal hypertension m vinyl chloride monomer workers. Lancet 1976;ii;602-4 * Popper H. Maltom C. Seltkoff TJ. Vinyl chloride*induced hepatic lesions in man and rodents. A comparison. Liver j 081,1:7-20. 4Tamburro CH. The hepatic role in carcinogenesis and its early detection--ihe vinvl chloride model. Yale J Biot Med l978;51,67-80, ' Popper H. Thomas LB. Telles NC, Falk H. Selikoff JJ. Develop ment of hepatic angiosarcoma m man induced bv vinvl chloride, thorotrasi and arsenic. .4/m J Pathol I978:92:34st-fty, * Makk L. Delmore F. Creech JL.etui. Clinical and morphological pattern* of hepatic angiosarcoma in vinyl chloride workers. Cancer 197*.37` 149-03. 1 Ostermann-Golkar S. Hulimark D, Segerbaek D. et aL Alky la tum of DNA and protein in mice exposed to vinyl chloride. Biochern firs Comntun 1977;76:259-0*. I Schaffner F, Popper H. Selikoff IJ Initial features of vinvl chloride (VC) hepanc injury, Ciiwi/w/iffTo/oi\ 1976,72:A35 * Kent G. Gav S. Inouyc T. Bahu R, Mmiek OT. Popper H Vita min A containing lipoevtcs and formation of npe III collagen in liver m/urv, Pmc Sail Acad Sit lfSA 197*;73 3719-22 Blcndis LM, Smith PM. Laune BW. Stephens MR, Evans WD Portal hypertension m vinyl chloride monomer workers A hemodynamic study. Gastroenter<dotfv ] 978.75:20*-! 1. II Williams DMJ. Smith PM. Taylor KJW. Crossley IR, Duck BW Monitoring liver disorders in vinvl chloride monomer winkers using grevseafe ultrasonographs Br J hid Med 1976.33: J 52- 7. British Journal of Industrial Medicine 1982;39:306-307 Progression of vinyl chloride induced hepatic fibrosis to angiosarcoma of the liver D B JONES AND P M SMITH From the Department of Gastroenterology, Llandough Hospital, Penarth, S Glamorgan, UK abstract Two vinyl chloride monomer (VCM) workers, who developed non-cirrhotic;__ lttBB|and died from angiosarcoma of the liver five and ten years later respectively, despitewithdrawal from occupational exposure. We suggest that non-cirrhotic por tal fibrosis caused by exposure to VCM is potentially premalignant and that those workers who already have the condition should be carefully monitored. Since the original communication by Creech and results showed a normal serum bilirubin with a Johnson' there have been several further case raised alkaline phosphatase (201 IU/1) and reports of vinyl chloride monomer (VCM) induced y-glutamyl transpeptidase (83 IU/1). Radioisotope angiosarcoma of the liver. A commoner hepatic liver scan showed a small liver with no filling defects lesion is non-cirrhotic portal fibrosis1 leading to por and needle liver biopsy showed a well-pronounced tal hypertension. It has been suggested that this micronodular cirrhosis with no evidence to tumour. lesion may be a precursor to angiosarcoma He responded to protein restriction and lactulose formation.J*5 but there has been only one report of a and was discharged. Within a week of discharge he patient with documented hepatic fibrosis developing was readmitted with an endoscopically confirmed angiosarcoma at a Inter date.6 We describe two bleeding duodenal ulcer. After this, he lapsed into further cases. hepatic coma and died. Necropsy showed multiple malignant tumours m the liver (wt 1130g), one of Case reports which was haemorrhagic. Histologically, a great variety of liver cell lesions were present, some resem CAM-. 1 bling angiosarcomas, some hepatocarcinomas. and A 60-year old white man initially presented in 1969 some adenomas. There were also atypical stnusoida to the dermatology department with a skin eruption. cells and fibrosis in the non-tumorous parts of the Examination at that time showed anaemia, thrombo liver. cytopenia. hepatosplcnomegaly. and occult faecal blood loss. He had an occupational history of expos case : ure to VCM at high concentration for seven years A 49-year-old man with a 12-year history of expos while working as a polycleaner and a blowdown ure to vinyl chloride monomer while working as a recovery operator. After two haemaiemeses, barium spray drier bagger, premix operator, and paste studies and splenic venography confirmed portal charging operator was. during a factory survex of hypettension and oesophageal varices, and he process workers in 1974, found to have thrombo underwent an end-lo-side portocaval shunt. At cytopenia. This was later shown to be due to laparotomy the liver looked nodular, but operative hyperxplenism and prcstnusoidal portal hyperten liver biopsy showed non-cirrhotic poital fibrosis sion. He was othetwise well and drank five pints of only. Over the next four years the patient developed beer a night. Liver function test results were normal chtome portosystemic encephalopathy and maturity apart from a raised y-glutamyl iranspeptidase level onset diabetes mellitus that was treated with oral of 82 IU/1. Varices were shown by barium studies hypoglyeaemic agents. In May 1980 he presented and endoscopy, and liver biopsy showed fatty with worsening mental deterioration, hepatic foetor, change and slight non-cirrhotic portal fibrosis. Two aster)ms. and an enlarging liver. Liver function test years later the patient developed insulin dependent diabetes mellitus, but otherwise remained well until Kcii'IM-iI 1 OOi'l'tT i on t WcpuM -U Nos ember l^HJ October 1979 when lie presented with a large haematemesis. Endoscopv confirmed oesophageal 306