Hemodynamic studies were performed in 5 vinyl chloride monomer workers in whom splenomegaly or thrombocytopenia was detected during a screening ...
00165085/78/7502-020~02.~/0
Vol. 75, No.
GASTROENTEROLOGY 751206-211,1978
Copyright0 1978by the AmericanGastroenterological Association
PORTAL HYPERTENSION MONOMER WORKERS A hemodynamic
2
Printed in USA.
IN VINYL
CHLORIDE
study L. M. BLENDIS, M.D.,
F.R.C.P.
CC!), P. M. SMITH, M.D.,
M.R.C.P.,
B. W. LAWRIE, M.B.,
F.R.C.R.,
M. R. STEPHENS, M.D.,
M.R.C.P.,
W. D. EVANS, M.A.,
M. INST.P
Welsh National School of Medicine, University of Toronto, Canada
Cardiff, Wales, and Department
AND
of Medicine,
Hemodynamic studies were performed in 5 vinyl chloride monomer workers in whom splenomegaly or thrombocytopenia was detected during a screening program at a major chemical plant. Three patients had portal hypertension and collateral venous circulations, with intrasplenic pressures between 20 and 29 mm Hg and normal wedged hepatic venous pressures, but the gradient between the wedged and free hepatic vein pressures was also increased. Splenic blood flows were increased in both hypertensive and normotensive patients. There was no correlation between the splenic blood flow and the portal pressure or the presence of portal fibrosis. The portal hypertension associated with vinyl chloride exposure is mainly presinusoidal in type, and may be attributed to an abnormality of the portal vein radicles, or hepatic sinusoids. At the time that acre-osteolysis was being described in workers involved in the polymerization of vinyl chloride monomer,‘* 2 attention was also drawn to nonspecific changes in liver function and structure,3 which were eventually shown to be related to hepatic fibrosis, splenomegaly , and portal hypertension.4 This was soon followed by the discovery of angiosarcoma of the liver in a few of these workers,5 and the total number of recorded cases to date is more than 50. In a large scale survey of vinyl chloride monomer workers in South Wales,6 5 men were found with abnormalities suggestive of portal hypertension. The results of the investigations in these patients are reported here. Methods A full clinical history was obtained from all 5 patients, with particular emphasis on symptoms of gallstone dyspepsia, alcohol consumption, drugs, and presence of hepatitis B surface antigen and antibody. The 5 patients (table 1) were admitted for investigation by radiology, esophagogastroscopy, splenic venography, liver biopsy, and hemodynamic studies. The latter included measurement of free and wedged hepatic vein pressures via right heart catheterization using the inferior vena cava as the zero reference value. Satisfactory wedging of the hepatic vein was confirmed by a sudden change in the venous wave pattern with the appearance of arterial spikes and the specific radiographic appearance after the injection of a small amount of contrast material. Finally, the mean wedged pressure was recorded and the catheter was Received June 16, 1977. Accepted March 15, 1976. Address requests for reprints to: Dr. L. M. Blendis, Room 112, University Wing, Toronto General Hospital, 585 University Avenue, Toronto, Ontario, Canada M5G lL7. The authors thank Mr. A. R. Richards for help with the spleen blood flows and Dr. D. M. J. Williams for referring the patients.
withdrawn slowly with a sharp drop in pressure, signifying a change from wedge to free pressures. This was repeated three times, wedging in three different positions. Intrasplenic pressure was recorded before splenic venography after insertion of a “Longdwell” catheter. The intrasplenic position of the catheter was verified by an injection of a small amount of contrast material after the initial puncture, and two further pressures were recorded after slight (approximately 0.5 cm) withdrawals of the catheter tip and a mean value was taken, the extension of the midaxillary line as an approximation of the right atrium being taken as the zero reference point. Splenic blood flow in milliliters per 100 g per min was measured using splenic artery boluses of radioxenon in normal saline to saturate the spleen, with external monitoring of the radioactive washout curve.’ Splenic volume was estimated using a gamma camera with data processing and denatured gymT~labeled red cells.a From the slope of the washout curve and the volume and density of the spleen, the total splenic blood flow in milliliters per minute could then be derived. Hepatic blood flow was estimated using a continuous infusion of indocyanine green and measuring the extraction of this dye across the liver.y Liver biopsies were performed using the Truecut Vim Silverman needle. The investigations in this study were performed with the patient’s fullest cooperation, not only for the purpose of documenting the presence or absence and degree of portal hypertension suggested by unexplained splenomegaly and thrombocytopenia, its etiology and pathogenesis, but also for possible medico-legal implications. Therefore, in all cases informed consent was obtained for each person investigated, i.e., liver biopsy, splenic venography, and hemodynamic measurements, using routine consent forms.
Patients Gray scale ultrasonography in all patients suggested enlargement of the spleen and subsequently was confirmed by gamma camera imagery of denatured YY”l’c-labeled red cells. 206
PORTAL
August 1978
HYPERTENSION
IN VINYL
The industrial histories of each patient were taken and are shown in table 1. However because of the possibility of polyvinyl chloride liver disease, all 5 patients had been removed from exposure by at least 1 year before hepatic investigations. Exposure levels at the plant have been drastically reduced in recent years and now do not normally exceed 5 ppm. Patient 1. This 49-year-old symptomless man had been exposed to vinyl chloride from 1962 to 1974. There was no history of hepatitis and his alcoholic consumption was 2 to 4 pints of beer per night. The mode of presentation, length of exposure to vinyl chloride, and initial hematology results are shown in table 2. During a survey in 1974 he was found to have thrombocytopenia and hepatosplenomegaly. Barium swallow demonstrated esophageal varices, and splenic venography showed a patent portal vein, varices around the gastric fundus, and an abnormal intrahepatic venous pattern. In January 1976 he passed melena stools, the hemoglobin level falling to 10.9 g per 100 ml. This was treated conservatively. At the time of this investigation the hemoglobin level had risen to 13.7 g per TABLE 1, Industrial
Patient no.
histories of 5 patients in polyvinyl chloride (PVC) plants Type of work mo
Spray drier bagger Premix operator Paste blowdown operator Paste charging operator Paste operator Polycleaner Paste blowdown operator Paste charging operator Dispersion flow operator Spray drier bagger Premix operator Paste blowdown operator Paste charging operator Spray drier bagger Premix operator Paste blowdown operator Paste charging operator Spray drier bagger Polycleaner Paste blowdown operator Dispersion drier operator Dispersing charging operator Latex operator Relief charge hand
LI MC MC MC LI HC MC MC MC LI MC MC MC LI MC MC MC LI HC MC MC MC MC LI
14 27 25 56 24 24 9 186 9 14 27 25 66 14 5 24 75 16 7 29 20 47 24 24
” Abbreviations are: LI, light intermittent exposure at less than 50 ppm of PVC in working atmosphere; MC, medium constant exposure at between 50 and 200 ppm of PVC in working atmosphere; HC, high constant exposure at greater than 200 and up to 1500 ppm of PVC in working atmosphere.
CHLORIDE
Age
sex
Length of exposure
data in vinyl chloride disease
Mode of presentation
Yr 1
49
M
2 3 4 5
59 34 43 42
M M M M
12 19 11 10 16
207
WORKERS
100 ml but he complained of lethargy and backache. Laboratory test results were: hepatitis B surface antigen test, negative, bromosulfophthalein , 10% retention at 45 min; albumin, 4.3 g per 100 ml; globulin, 2.8 g per 100 ml; bilirubin, 0.6 mg per 100 ml; asparate transaminase (SGOT), 30 IU (normal up to 32); alkaline phosphatase, 3.0 (normal up to 18 Bodansky units; y-glutamyl transpeptidase (GT), 82 IU (normal up to 45); serum glutamic pyruvic transaminase (SGPT), 25 IU (normal up to 35). Prothrombin time and protein electrophoresis were normal, smooth muscle and mitochondrial antibodies were negative, and abdominal X-ray and ultrasound showed no evidence of gallstones. Patient 2. This 59-year-old man worked as a polycleaner for 2 years and as a charging operator for 19 years, being exposed to vinyl chloride gas throughout. He presented to his general practitioner in December 1970, complaining of intermittent ankle swelling for 18 months and was noted to have clubbing, which had apparently been present for 25 years. There was no history of hepatitis, and alcohol consumption was 3 to 5 pints of beer per day. Radiology showed mild degenerative changes only in the left ankle joint with no evidence of acre-osteolysis. Further investigations in April 1974, including bronchoscopy and esophagoscopy were normal, but liver function tests were slightly abnormal: serum bilirubin, 1.0 mg per 100 ml; alkaline phosphatase, 7.5 Bodansky units; SGOT, 40 IU, y-GT, 43 IU. Other tests were: hepatitis B surface antigen test, negative; albumin, 4.2 g per 100 ml; globulin, 2.5 g per 100 ml; prothrombin time normal; tests for antinuclear, rheumatoid, mitochondrial, and smooth muscle antibodies, negative; protein electrophoresis, normal; straight X-ray and ultrasound showed no evidence of gallstones. A large spontaneous splenorenal shunt with a patent portal vein was seen on splenic venography (fig. 1). Patient 3. This 34-year-old man, who had been exposed to vinyl chloride for 11 years was symptom-free when seen. There was no history of hepatitis and alcohol consumption was about 1 pint of beer per day. On examination there was no abnormality, but a platelet count of 60,000 per cu mm led to his admission for further investigation. Laboratory tests were: hepatitis B surface antigen, negative; smooth muscle and mitochondrial antibody test, negative; electrophoresis, normal; albumin, 3.8 g per 100 ml; globulin, 2.7 g per 100 ml; bilirubin, 1.0 mg per 100 ml; SGOT, 28 IU; alkaline phosphatase, 3.3 Bodansky units; y-GT, 49 IU; bromosulfophthalein, 7% at 45 min; transferrin, 400 mg per 100 ml; prothrombin time, normal. Barium swallow and upper gastrointestinal endoscopy demonstrated esophageal varices. A splenic venogram showed a patent portal vein and normal intrahepatic pattern with a slight tilling of esophageal varices. Straight abdominal X-ray and ultrasound showed no evidence of gallstones. Patient 4. This 43-year-old man had been exposed to vinyl chloride for 10 years and was symptomless. There was no history of hepatitis and alcohol consumption was 2 to 3 pints of beer per day. On examination there was no abnormality. Straight abdominal X-rays suggested splenomegaly and he was therefore admitted for investigation. Laboratory tests
TABLE 2. Clinical and hematological Patient no.
MONOMER
Thrombocytopenia; hepatosplenomegaly Intermittent ankle swelling, clubbing Thrombocytopenia Splenomegaly (abdominal X-ray) Splenomegaly (ultrasound)
Hemoglobin
WBC
Platelet5
gllO0 ml
x 103/nm”
X I03/mm3
13.7 12.1 15.4 15.3 15.3
3.1 4.2 6.1 5.5 5.5
39 90 61 136 145
BLENDZS
208
ET AL.
Vol. 75, No. 2
FIG. 1. Splenic venogram demonstrating massive esophageal varices and spontaneous splenorenal shunt in patient 2. were: prothrombin time and protein electrophoresis, normal; albumin, 4.4 g per 100 ml; globulin, 2.5 g per 100 ml; bilirubin, 0.9 mg per 100 ml; barium meal showed no evidence of varices. Straight abdominal X-ray and ultrasound showed no evidence of gallstones. Patient 5. This 42-year-old patient, who had been exposed to vinyl chloride for 16 years, was symptom-free. There was no history of hepatitis and alcohol consumption was about 1 pint of beer per week. There was no abnormality on examination. He was found to have an unconjugated hyperbilirubinemia with serum total bilirubin, 2.8 mg per 100 ml and conjugated bilirubin, 0.4 mg per 100 ml; albumin, 5.4 g per 100 ml; globulin, 1.7 g per 100 ml (nicotinamide test: at 2 hr the bilirubin rose to 3.3 mg per 100 ml with 0.6 mg of conjugated and at 4 hr the bilirubin had fallen to 2.5 mg per 100 ml, of which 0.6 mg were conjugated); SGOT, 18 III; alkaline phosphatase, 18 Bodansky units; +y-GT, 14 IV, prothrombin time, normal. Red cell and bone marrow morphology was normal. Tests of red cell function showed a normal hemoglobin of 15.5 g per 100 ml with a reticulocyte count of 1% in a normal film. Autohemolysis was 7% at 48 hr (upper limit of normal 4%), consistent with mild red cell abnormality in association with liver disease and hyperbilirubinemia. Barium swallow, esophagoscopy, and splenic venography were normal. Straight Xray of abdomen and ultrasound failed to show gallstones.
Liver Histology Patient 1. Liver structure was well preserved with a slight excess of fatty change. There was no major increase in fibrous tissue, but diffuse increase in reticulin around the sinusoids with focal dilatation.
Patient 2. Normal biopsy. Patient 3. There was a slight increase in fibrous tissue of portal tracts with minor reticulin condensation but with no cirrhosis. Kupffer cells and hepatocytes were normal. There was slight extension of fibrous tissue into surrounding parenchyma. Patient 4. No biopsy. Patient 5. A defninite increase in collagen in portal areas which is extensive with fine fibrosis linking portal tracts (fig. 2). In a few areas the central veins and portal areas are also linked by fibrous tissue. Basic liver architecture is intact. Kupffer cells are slightly more prominent than normal.
Hemodynamics Portal hypertension was present in 3 of the patients with net intrasplenic pressures of 20 to 29 mm Hg (table 3, fig. 3). However, the sinusoidal pressure as assessed by the wedged hepatic vein pressure was normal, and the drop in pressure from the portal vein to sinusoids was 10 mm Hg or more, the normal gradient being less than 5 mm Hg. This is indicative of presinusoidal portal hypertension. There was also a greater than the normal 5-mm Hg pressure difference between the wedged and free hepatic vein pressure in these patients and this was associated with a slight elevation in the postsinusoidal resistance in 2 of them (table 3). Four patients had increased total spleen blood flows ranging from 332 to 813 ml per min, the upper limit of normal being 300 ml per min. The highest flow occurred in the patient with the largest spleen and was the only case associated with an increased hepatic blood flow (1070 ml per min per m*), despite a significant collateral circulation (table 3). In the other
PORTAL
August 1978
FIG. 2.
Pa-
Liver biopsy fibrosis
Varices or co11aterals
i _ + ND ++
++ ++ ++ _
TABLE 3. Hemodynamic Mean Pressures”
ISP
WHVP mm
1 2 3 4 5
Normalrange 0 Abbreviations
IN VINYL
CHLORIDE
MONOMER
209
WORKERS
Reticulin stain of a liver biopsy showingextensionof fibroustrabeculaeas seen in patient 5 (magnification,x 300). ____
tient no.
HYPERTENSION
FHVP
studies in vinyl chloride disease
Cardiac index
liters/minim’
Hg
Spleen wt &?
Spleen blood flow ml/lOOg/min
nllmin
20 22 29 12 12
10 9 11 7 7
2 3 1 2 3
4.4 4.8 5.5 4.3 4.3
984 532 1525 302 623
91 74 137 93
484 1050 414 580
3-15
5-12
l-4
2.5-4.5
120-300
60-120
100-300
are: ISP, intrasplenic
Estimated ~ hepa~;cJlood
Resistance Postsinusoidal
Splenic
dyneslseclcm-Y
mllminlm2
787 645 1070
457 400 410
748
237
20 4.8 12.0 11.5
150-400
22-65
300-800
pressure; WHVP, wedged hepatic vein pressure; FHVP, free hepatic vein pressure.
patients moderate splenomegaly and increased splenic blood flows were associated with normal hepatic blood flows. Splenic resistance in all patients was reduced. The cardiac index was either increased or at the upper level of normal, but pulmonary artery and right atria1 pressures were normal. Discussion Could the liver disease in these patients be attributed to another etiology? All 5 patients drank alcohol in the form of beer but in very moderate amounts for that area and only 1 of the patients had any histological changes associated with alcoholism. None of the patients had a history of hepatitis or biliary dyspepsia, and investigations for hepatitis B surface antigen and gallstones
were negative. Furthermore, the liver “function” tests indicated good liver function as far as the serum albumin levels and prothrombin time results were concerned, but bromosulfophthalein excretion was significantly impaired in 1 of the 2 patients tested (patient 11, a finding already described in vinyl chloride disease. This patient also had an elevated GT level, a highly sensitive enzyme commonly found elevated in anyone exposed to enzyme-inducing agents, such as alcohol, but not necessarily indicating liver damage. Finally, patient 5 had an unconjugated hyperbilirubinemia, which rose further with nicotinamide, but had otherwise normal liver function tests and evidence of slightly increased red cell fragility. The presence of hepatic fibro-
210
BLENDIS ET AL.
30 25 \
20 -
0
NORMAL
RANGE
0
PORTAL
HYPERTENSION
0
NORMOTENSIVE
I" 15E E io5OINTRASPLENIC PRESSURE mm Hg
WEDGED HEPATIC VEIN PRESSURE mm Hg
FREE HEPATIC VEIN PRESSURE mm Hg
FIG. 3. Portal pressure profile in patients with polyvinyl liver disease.
chloride
sis makes the diagnosis of Gilbert’s syndrome difficult to sustain unless it coexisted with vinyl chloride monomer related liver damage. In contrast there can be little doubt of the exposure of all 5 patients in this series to vinyl chloride. The length of exposure is similar to that recorded in several series of workers who developed angiosarcomata. Our patients had less heavy exposure, only one having a period as polycleaner, but for the majority of time they were exposed to concentrations of from 50 to 200 ppm, and there are apparently at least two claims of angiosarcoma formation in rats exposed to only 50 ppm. lo The commonest liver abnormality in vinyl chloride workers is now thought to be liver fibrosis, with or without bile duct proliferation, and lymphocytic infiltration. The fibrosis may connect adjacent portal tracts as perilobular fibrosis or extend toward the central veins.‘O, I1 In angiosarcomatous patients there may be an increase in sinusoidal lining cells, dilatation of sinusoids, perisinusoidal fibrosis, and abnormalities in hepatocyte morphology. However when patients were removed from exposure the changes in hepatocytes and sinusoidal lining cells had disappeared, but the fibrosis, and in 1 case bile duct proliferation, persisted.lO~ l1 This may explain the absence of most of the described histological changes attributed to vinyl chloride exposure in our patients, apart from hepatic fibrosis. In addition, it is important to point out that wedge biopsies have revealed more abnormal histology than have percutaneous needle biopsies. l2Our patients had no evidence of angiosarcomatous change, and the sinusoidal dilatation and atypical sinusoidal liming cells in particular are thought to represent a precursor malignant stage.13 The failure to show a relationship between hepatic fibrosis and portal hypertension in these patients could be attributed to the fact that the liver biopsy may not be truly representative of the total liver architecture
Vol. 75, No. 2
and the irregular distribution of portal fibrosis in vinyl chloride workers is now well described. Nevertheless the virtual “inverse relationship” found in these patients in that the lowest pressure occurred in the patient with the most fibrosis suggests that portal fibrosis is not a major factor in the pathogenesis of portal hypertension in these patients. However, the fibrosis in these patients may be perisinusoidal in distribution,“, l4 resembling that described in arsenic intoxication,15 and may have been missed on percutaneous biopsy in this series. It has been suggested that the splenomegaly is a consequence of prolonged exposure to vinyl chloride with stimulation of splenic cells.” This might result in decreased splenic resistance and increased splenic and thus hepatic blood flow, leading to presinusoidal portal hypertension. However, with the exception of 1 patient in this series, spleen blood flow was only moderately elevated and there was no correlation between spleen or liver blood flow and the portal pressure. The presence of a collateral circulation bypassing the liver might blur this relationship, although in patients with portal hypertension and esophageal varices associated with splenomegaly caused by blood dyscrasias, there was a significant relationship between the increased spleen and hepatic blood flows and wedged hepatic vein pressure, suggesting that the increased flow was an important factor in the portal hypertension in those patients.16In this group of blood dyscrasia patients and in patients with idiopathic tropical splenomegaly and portal hypertension,17 postsinusoidal resistance was normal or diminished, whereas in the 3 patients with portal hypertension described here, the postsinusoidal resistance was slightly increased or at the upper limit of normal. These results differ from a previous report in which corrected sinusoidal pressures were normal. la However, these patients had angiosarcomas and elevated inferior vena cava pressures, which were not found in the present series. The findings here are similar to the hemodynamic profile in patients with Felty’s syndrome and portal hypertension,‘y suggesting abnormalities within the liver rather than increased splenic and hepatic blood flow as the major factor in the development of portal hypertension. Several workers have reported a “cut-ofI” of small portal venous radicles on hepatic venography in noncirrhotic portal hypertension,20-22including 1 patient with vinyl chloride disease.22These changes were noted in 1 of our 3 patients with portal hypertension, the rest exhibiting a normal intrahepatic pattern. Thus, diminution of the size of portal vein branches within the portal tracts may be responsible for the portal hypertension, as has been suggested for the patients with chronic arsenic poisoning.23Portal vein radical constriction may be related to extension of perisinusoidal fibrosis previously described. The limitation of the hepatic fibrosis to the portal tracts, with sparing of the parenchymal cells, is reflected in the normality of the liver function tests, and also in the excellent progress of 3 vinyl chloride workers who have undergone a portacaval shunt for bleeding varices. l2 Although angiosarcoma is the most feared hepatic
A u/just 1978
PORTAL
HYPERTENSION
IN VINYL
complication of exposure to vinyl chloride monomer, and some examples of angiosarcoma with coexistant hepatic fibrosis have been described, several patients with fibrosis have been followed for up to 8 years without deterioration of liver function.12 The more frequent complication in these patients is the development of portal hypertension and esophageal variceal bleeding. This study indicates that these patients are unlikely to benefit from splenectomy alone, but because the liver function is good, these patients should tolerate portacaval anastomosis well. REFERENCES 1. Cordier JM, Fievez C, Lefevre MJ, et al: Acre-osteolyse at lesions cutanees associes chez deux ouvriers affects au nettoyage d’autoclaves. Cah Med Trav 4:3-39, 1966 2. Harris DK, Adams WGF: Acre-osteolysis occurring in men engaged in the polymerisation of vinyl chloride. Br Med J 3:712714. 1967 3. Pushin GA: Affection of the liver and bile ducts in workers engaged in the production of some types of plastics. Sov Med 28132-135, 1965 4. Marsteller HJ, Lelback WK, Muller R, et al: Chronisch-toxische Leberschaden bei Arbeitern in der PVC-produktion. Dtsch Med Wochenschr 982311-2314, 1973 5. Creech JL, Johnson MN: Angiosarcoma of the liver in the manufacture of polyvinyl chloride. J Sot Occup Med 16:150-151, 1974 6. Williams DMJ, Smith PM, Taylor KJW, et al: Monitoring liver disorders in vinyl chloride monomer workers using greyscale ultraaonography. Br J Ind Med 33:152-157, 1976 Williams R, Condon RE, Williams HS, et al: Splenic blood flow in cirrhosis and portal hypertension. Clin Sci 34:441-452, 1968 Roberts JG, Wisbey ML, Newcombe RG, et al: Prediction of human spleen size by computer analysis of splenic scintigrams. Br J Radio1 49:151-155, 1976 Leevy CM, Mender&all CL, Lesko W, et al: Estimations of hepatic blood flow with indocyanine green. J Clin Invest 41:169-
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176, 1962 10. Berk PD, Martin JF, Young RS, et al: Vinyl chloride-associated liver disease. Ann Intern Med 84:717-731, 1976 11. Thomas LB, Popper H, Berk PD, et al: Vinyl chloride induced liver disease from idiopathic portal hypertension (Banti’s syndrome) to angiosarcoma. N Engl J Med 292:17-22, 1975 12. Smith PM, Crossley IR, Williams DMJ: Portal hypertension in vinyl-chloride production workers. Lancet 2:602-604, 1976 13. Falk H, Creech JL, Heath CW, et al: Hepatic disease among workers at a vinyl chloride polymerization plant. JAMA 230:5963, 1974 14. Weinbren K: Histopathology of liver lesions associated with exposure to vinyl chloride monomer. Proc R Sot Med 69:299-303, 1976 15. Huet PM, Guillaume E, Cote J, et al: Noncirrhotic presinusoidal portal hypertension associated with chronic arsenical intoxication. Gastroenterology 68:1270-1277, 1975 16. Blendis LM, Banks DC, Ramboer C, et al: Spleen bloodflow and splanchnic haemodyanamics in blood dyserasia and other splenomegalies. Clin Sci 38:73-84, 1970 17. Williams R, Parsonson A, Somers K, et al: Portal hypertension in idiopathic tropical splenomegaly. Lancet 1:329-333, 1966 18. Whelan JG, Creech JL, Tambutto CH: Angiographic and radionuclide characteristics of hepatic angiosarcoma found in vinyl chloride workers. Radiology 118:549-557, 1976 19. Blendis LM, Parkinson MC, Shilkin KB, et al: Nodular regenerative hyperplasia of the liver in Felty’s syndrome. Q J Med 43:25-32, 1974 20. Boyer JL, Sengupta KP, Biswas SK, et al: Idiopathic portal hypertension. Comparison with portal hypertension of cirrhosis and extrahepatic portal vein obstruction. Ann Intern Med 66:4168, 1967 21. Zeegen R, Stansfeld AG, Dawson AM, et al: Prolonged survival after portal decompression of patients with noncirrhotic intrahepatic portal hypertension. Gut 11:610-617, 1970 22. Villeneuve JP, Huet PM, Joly JG, et al: Idiopathic portal hypertension. Am J Med 61:459-464, 1976 23. Morris JS, Schmid M, Newman S, et al: Arsenic and noncirrhotic portal hypertension. Gastroenterology 66:86-94, 1974
