Document NpQxpg5aEY9pXRyXgwgVdMGp

Noncirrhotic Portal Fibrosis S. K. SAMA. M.O. S. BHARGAVA. M.O.. D.M.R.D. N. GOPI NATH. M.S. J. R. TALWAR. M.S. N. a NAYAK. M.O. B. N. TANDON. M.D. K. L. WIG. F.R.C.P. New Delhi, India In India noncirrhotic portal fibrosis (portal hypertension without demonstrable intrahepatic or extrahepatic obstruction) ac counted for seventy-five (25 per cent) of 300 cases of portal hypertension studied by us. The majority of patients presented with marked splenomegaly of long duration and recurrent hemorrhage from esophageal varices (usually well tolerated), with minimal features of hepatocellular failure. There was an increase of alpha- globulin, beta globulins and immunoglobulin G (IgG). Hemodynamically, two significant findings were a marked gradient between the splenic pressure and wedged hepatic vein pressure, and a normal hepatic blood flow; in some patients wedged hepatic vein pressure was high. Roentgenologically, there was dilatation and tortuosity of the portal and splenic veins, with massive varices and hepatofugal collaterals. The intrahepatic vascular pattern was not much distorted, in contrast to cirrhosis. At shunt surgery the gross appearance of the liver varied from near normal to irregular nodularity re sembling cirrhosis. There was at times shrinkage of the left lobe and hypertrophy of the right lobe. A needle biopsy speci men of the liver showed nonspecific changes, i.e., small focal areas of necrosis and regeneration, focal infiltrates, Kupffer cell hyperplasia and portal scars of varying size. Wedge biopsy and autopsy specimens revealed focal occlusive changes in the medium-sized radicals of the portal vein, changes considered specific for this disease. Electron microscopy revealed widening and collagenization of the space of Disse, with laying down of large collagen bundles in and around the sinusoids. Shunt surgery was performed in twenty-six patients. The op erative mortality was 10.7 per cent. Splenorenal shunt was better tolerated than portocaval shunt but was associated with postoperative bleeding in 18.75 per cent of the cases. From the Departments of Medicine, Radi ology. Thoracic Surgery and Pathology, AllIndia Institute of Medical Sciences, New Delhi 16. India. Requests for reprints should be addressed to Dr. S. K. Same, Department of Medicine. All-India Institute of Medical Sciences, Ansari-Nagar, New Delhi I6, India. Manuscript received Sep tember 1.1970. The syndrome of portal hypertension without demonstrable intrahepatic or extrahepatic obstruction, first described in India by Ramalingaswami, Wig and Sama [1], is now a well recognized entity [2]. A similar disease has been reported in the literature under various names [3-11], but investigators in India have de cided to designate this entity noncirrhotic portal fibrosis [12]. Since its first description in 1962, seventy-five cases of non cirrhotic portal fibrosis have been studied in detail at the AllIndia Institute of Medical Sciences. We report on the clinical, biochemical, roentgenologic, hemodynamic, immunologic, his- BFG36695ICO TVm American Journal of ModWna NONCIRRHOTIC PORTAL FIBROSIS -- SAMA ET AL. tologic and ultrastructural features of this dis ease. MATERIAL AND METHODS The diagnosis of noncirrhotic portal fibrosis was estab lished in seventy-five of a total of 300 cases of portal hypertension studied on the basis of the following criteria: (1) definite clinical and/or roentgenologic evidence of portal hypertension; (2) patent extrahepatic portal venous system on splenoportovenogram; (3) adequate liver biopsy specimen showing no evidence of cirrhosis of the liver [13]. A detailed history and physical examination were ob tained in each case. Special attention was given to mode of onset, history of malaria, umbilical sepsis, dietary habits, alcoholism, ingestion of hepatotoxins and herbal medicines, presenting symptoms, and size of the liver and spleen. Liver function studies including serum bilirubin, albumin, globulins, alkaline phospha tase, thymol turbidity and serum glutamic pyruvic acid transaminase (SGPT) were carried out in all cases. A standard bromsulfalein test and l,a> rose bengal hepatogram before and after stress with bromsulfalein [14] were obtained in twenty cases. A barium swallow roentgenogram for the detection of esophageal varices and a splenoportovenogram were available in all cases. Wedged hepatic vein pressure was measured in forty-four cases and splenic pressure in forty-six cases. Both pressures were recorded in twenty-seven cases. The mid-thoracic line was taken as the zero line cf reference for all pressure measurements. Estimated hepatic blood flow was determined with indocyanine green by single injection technic [15] in twenty-seven cases and with radioactive gold [16] in twenty cases. Percutaneous needle biopsy of the liver was per formed with the Vim-Silverman's needle. Adequate biopsy material was obtained at least once in each case. In twenty cases, wedge biopsy was carried out at operation. During the period of study seven cases came to autopsy. Ultrastructural studies were made in nine patients. The standard technic for electron microscopic study was used [17]. In twenty patients, serum protein fractions were studied by cellulose-acetate paper electrophoresis [18] and immunoglobulins by Sephadex* G 200 column chromatography [19]. RESULTS Noncirrhotic portal fibrosis constituted 25 per cent of the total cases of portal hypertension in this series. The maximum incidence of the disease was noted in the second, third and fourth decades (Table I). The mean age was 32.5 years at the time of first presentation and 25.2 years at the onset. The majority of the patients were male. TABLE 1 Age Distribution in Seventy-Fhre Cases of Nondrrhotic Portal Fibrosis Age Croup (y <10 11-20 21-30 31-40 41-50 50+ Sex (no.) Male Female 11 12 3 17 1 12 4 10 3 83 Total 2 15 18 16 13 11 This may have been due to the lesser number of beds for female patients in the hospital and does not indicate true predilection for the male sex. The male:female patient ratio in the hospital is 7:2. Most of the patients were from northern India, a few were from other parts of the country. The disease affected the poor and the middle class. The very poor who came to the hospital with severe malnutrition were not affected. Only three patients had been addicted to alcohol, thirty had been tak ing indigenous drugs. A past history of jaundice was elicited in nine cases (12 per cent); the inter val between the onset of symptoms and the history of jaundice varied from one to twenty-five years, with a mean of seven and a half years. A history suggestive of malaria was present in twelve cases, and of diarrhea and dysentery in ten. Associated pulmonary tuberculosis was present in three and recurrent thrombophlebitis in one case. Clinical Features. Forty of seventy-five patients (53.3 per cer,;) had splenomegaly as their first symptom. Splenic enlargement was either ob served by the patients or pointed out by the doctor during examination for minor ailments, usually years before the appearance of other symptoms. In nineteen patients (25.3 per cent) sudden hematemesis without any previous symptoms marked the onset of their illness. Gradual abdominal dis- TABLE II Clinical Features Clinical Features Splenomegaly (average enlargement 8.57 cm) Hematemesis (average 2.3 episodes) Ascites Palpable liver (average 3.40 cm) Pain in splenic area Engorged abdominal veins Gynecomastia Palmer erythema Scanty pubic and axillary hair Clubbing Cares No. % 75 100 39 52.0 31 41.3 48 64.0 24 32.0 18 24.0 4 5.3 2 2.6 2 2.6 2 2.6 NONC1RRHOTTC PORTAL FIBROSIS -- SAMA CT AL. TABLE III liver Function Tests Uvei Function Tests Serum total proteins (gm %) Serum albumin (gm %) Normal (>3.75 gm %) Mild hypoalbuminemia (between 3.1 and 3.7S gm %) Moderate hypoalbuminemia (between 2 and 3 gm %) Severe hypoalbuminemia 2 gm %) Serum globulins (gm %) Alkaline phosphatase (King-Armstrong units) Thymol turbidity SGPT 0*M/ml/hr/40X) Serum bilirubin (mg %) No. Mem Cases SO. 75 $.3 0.84 ...75 3.2 0.43 3S 20 ... 19 0 ... ... 75 3.1 0.63 75 12.9 6.5 7S 5.7 3.6 7S 1.9 1.2 75 0.78 0.43 tention due to ascites initiated the illness in ten cases (13.3 per cent). The onset of illness in the remaining six cases (8 per cent) was with vague abdominal symptoms, pallor or weakness. Among those whose illness started with hematemesis, ascites or other symptoms, a large spleen was invariably found on examination. The mean duration of illness at the time of first observation was 7.15 years. The clinical features at the time of first presentation are shown in Table II. Splenomegaly was noted in all patients. The size of the spleen varied from 2 to 27 cm with a mean of 8.57 cm. Recurrent pain in the region of the splenic mass was a complaint of twenty-four patients (32.0 per cent). Severe hematemesis oc curred in thirty-nine patients (52 per cent); it was recurrent in a majority of the patients, with an average of 2.3 episodes and a maximum of twelve episodes. Gastrointestinal hemorrhage was usually well tolerated and did not lead to encephalopathy. Engorged abdominal veins were present in eigh teen cases (24 per cent). Ascites was present in thirty-one cases (41.3 per cent); it was mild in seventeen, moderate in eleven and severe in three. Ascites was considered mild when only shifting dullness was elicited, mod erate when a fluid wave could also be demon strated, and severe when the patient had ab dominal or respiratory discomfort. The liver was palpable in forty-eight cases (64 per cent) and varied in size from 1 to 10 cm, with an average of 3.40 cm. It was smooth, firm and nontender. Signs and symptoms of hepatocellular failure and endocrine disturbances were uncommon. Gyneco mastia was seen in four cases (5.3 per cent), pal mar erythema in two (2.6 per cent), scanty pubic and axillary hair in two (2.6 per cent); jaundice and spider angioma were not observed. Clubbing of the fingers was present in two cases (2.6 per cent). Hematologic Data. Most of the patients were anemic. Anemia was mild in fifteen patients, mod erate in forty-four and severe in nine [20]. It was usually normocytic, normochromic or normocytic hypochromic. No case of macrocytic anemia was seen. Bone marrow examination carried out in fifteen cases disclosed hypercellular marrow with relative erythroid hyperplasia in all. Leukopenia was present in fifteen cases, thrombocytopenia in twenty-four and pancytopenia in nine. Routine liver function tests in the majority of the patients disclosed only minor alterations. The mean serum albumin was 3.2 : 0.43, the mean serum globulin was 3.1 0.63 gm per cent. Mild to moderate hypoalbuminemia was seen in thirty- nine of seventy-five patients (52 per cent). Thymol turbidity, alkaline phosphatase and SGPT levels were not significantly altered (Table 110- No pa tient had a serum bilirubin level above 2 mg at the time of first presentation. Bromsulfalein retention was normal (less than 8 per cent) in forty per cent of the cases, mildly increased (between 8 and 16 per cent) in another 40 per cent and markedly increased (retention above 16 per cent) in only 20 per cent. Im rose bengal hepatogram showed a TABLE IV lu> Rose Bengal Hepatograms With and Without Stress Subjects NoloI Cues TV, (mis) Mem IE Rate of liver Uptake/Minute* Mem S.E Maximum Uptake DO Mem SX Time of Peak liver Activity ie Minutes Mem S.E Normal Noncrrrhob'c portal fibrosis a 20 lm Rose Bengal Hepatogram 4.18S 0.31 15.2 0.616 6.25 0.49 10.95 0.94 P<0.01 P <0.001 17.04 10.71 P <0.001 0.828 0.54 Normal Noncrrrhotic portal fibrosis Mean Differanca in 1"* Rosa Bengal and Stress Hepatograms U 0.45 0.16 0.8 0.72 -0.39 20 2.16 0.43 -2.93 0.72 -2.a P <0.001 P <0.001 P<0.02 0.09 0.69 Expressed as per cent increase over initial counts. 22.38 30.5 P <0.001 2.5 9.5 P<0.01 1.44 1.11 1.33 2.a 162 The American Journal of Medicine NONCIRRHOTIC PORTAL FIBROSIS--SAMA ET Al_ TABLE V Serum Protein Tractions in Cases of Nonclrrhotlc Portal Fibrosis Subjects Sephadex G-200 Gravitational Method 1st Fraction 2nd Fraction 3rd Fraction Mean S.D. Mean S.0. Mean S.D. Cellulose Acetate Paper Electrophoresis Alpha, Alpha, Globulin Globulin Mean S.D. Mean S.0. Beta Globulin Mean S.0L Gamma Globulin Mean S.D. Normal 12.8 0.25 Noncirrhotic portal fibrosis 10.0 0.90 P = 0.01 39.9 0.29 46.0 1.20 P <0.001 47.0 0.29 45.0 ..1. .10 4.1 0.29 4.5 ...0.13 8.2 0.45 9.3 0.34 P = 0.06 10.5 0.48 13.3 0.36 P <0.001 21 0.74 23 .0...75 NOTE: Al results are given in percentages, significant alteration of hepatocellular function in 75 per cent of cases. The hepatogram was en tirely normal in five cases. The mean value for all the parameters of hepatocellular function, i.e., T 1/2, rate of liver uptake per minute, maximum uptake expressed as percentage of the injected dose and time of peak liver activity was signifi cantly abnormal as compared to the controls (Table IV)* Stress hepatogram was abnormal in all the cases studied. This included five patients with normal rose bengal hepatogram and eight patients with normal bromsulfalein excretion. Further, the abnormality of the I131 rose bengal hepatogram was significantly accentuated after stress with brom sulfalein. Bromsulfalein stress did produce slight alteration in the parameters of hepatocellular func tion in the control group also, but this was rela tively insignificant Cellulose acetate paper electrophoresis revealed a significant elevation of alpha, and beta globulins. Relative increase of IgG (second fraction) and decrease of IgM (first fraction) was observed in Sephadex G 200 column chromatography (Table V). Roentgenologic Investigations. Esophageal varices were demonstrated in fifty-one cases (68 per cent). The varices were usually marked and extended to the lower and middle third of the esophagus in the majority. Splenoportovenogram revealed varices and collaterals in the gastro esophageal area. There was dilatation of the main portal vein and portal vein radicles (Figure 1). The splenic vein was dilated and tortuous. Extensive collaterals made interpretation of the state of the major intrahepatic vessels difficult. Small portal vein branches showed gentle curves in some pa tients. There was no kinking or deformity. The normal complement of small branch filling was present, and the sinusoidal phase was usually dense compared to the patchy sinusoidal phase seen in cirrhosis. Hemodynamic Studies. Mean wedged hepatic vein pressure was 12.74 6.16 mm Hg, which is significantly higher than in the controls (P <0.001). It was, however, not increased in all the patients (Figure 2). The splenic pressure was markedly increased in almost all the patients, with a mean value of 20.2 6.80 mm Hg (Figure 2). In twenty-seven patients in whom both wedged hepatic vein pressure and splenic pressure were recorded, the gradient between the two was de termined. The pressure gradient of each patient is represented in Figure 3. The mean gradient was 8.84 4.8 mm Hg which indicates a significant increase in presinusoidal resistance. The results of hepatic blood flow studies are shown in Table VI. The mean estimated hepatic blood flow for the group was 1,433 ml/minute/Ms of the body sur face area, by the indocynanine green method. Ex pressed as percentage of cardiac output the mean value was 31.8 3.94 per cent. These values are slightly, not significantly, higher than normal. There was a wide variation in hepatic blood flow among individual patients. Estimated hepatic blood flow was above 1,500 ml/minute/M3 body surface area in thirteen cases (48 per cent), 1,000 to 1,499 in eight cases (30 per cent) and less than 1,000 in six cases (22 per cent). Hepatic blood flow was also estimated by radioactive gold (Table VII) in twenty patients and twenty-one controls. Figure 1. Splenoportovenogram of a patient with noncirrhotic portal fibrosis showing marked collaterals and dilatation of portal and splenic veins. 24952004 163 NONORRHOTtC PORTAL FIBROSIS -- SAMA ET AL. *2; 2* 22 20 i r* i Z M I M S * t * meaii zO (Or* r { .T T a a aa a MEAN 12 74 21 It XCAN QUOKNT.a (4140 aaaa Figure 3. Gradient between splenic pressure and wedged hepatic vein pressure. W.N.V.P. (44 CASES) S.E. (44CASCS) Figure 2. Wedge hepatic vein end splenic pressure in nondrrhotic portal fibrosis. TABLE VI Estimated Hepatic Blood Flow (EHBF) in Normal Subjects and in Patients with Noncirrhotic Portal Fibrosis Subjects Mem EHBF (mi/nm/M1) Standard Mem EHBF as Standard Error of XofCarduc Error of Mem Output Mem Normal portal fibrosis 1.2U (5) 42.69 2-5(5) 187.94 M.W V*9/ 1.89 P >0.05 P>0.10 NOTE: Figures in parentheses represent number of cases. Figure 4. Liver specimen from a patient with noncir rhotic portal hypertension. Note the extensive and marked fibrosis, predominantly confined to portal areas. The left lobe is atrophic and the surface presents a scarred ap pearance reminiscent of cirrhosis. TABU VII Hepatic Blood F1ow-An> Uver "K" Values in Normal Subjects and in Patients with Noncirrhotic Portal Fibrosis Subjects No. Mem Standard Mem Cases -r Deviate Error Normal 21 0.357 0.04S 0.010 Nondrrhotic portal fibrosis 20 0.374 0.147 0.017 NOTE: Normal versus nondrrhotic portal fibrosis. P not sig nificant. Figure. 5. Characteristic change in large intrahepatlc portal vein radicle. The intime shows irregular thicken ing. Compare with artery on the right Masson trichrome stain, original magnification X 120. ) Tho American Journal at Modidno BFG36699 NONCIRRHOTIC PORTAL FIBROSIS --SAMA CT AL The results are expressed as disappearance rate constant "K" which represents the fraction of the total blood volume perfusing the liver [16]. The mean "K" in control subjects was 0.357 0.048; in noncirrhotic portal fibrosis it was 0.374 0.147, which is not significantly different from that in control subjects. Histopathologic Studies. The gross appearance of the liver was noted in thirty-one patients either at the time of operation or at autopsy. In general, the normal luster of the liver was lost, it felt firm and had linear pale scars in some areas due to mild thickening of the capsule. The surface varied from normal to distinctly nodular, resembling cirrhosis (Figure 4). It was smooth in fourteen pa tients, granular in seven and nodular in ten. The nodularity was more often seen on the under sur face and left lobe of the liver. In one patient there was a large hump-like elevation of one lobe with atrophy of the other. In patients who came to autopsy, inspection of the cut surface of the liver showed that the nodu larity was more in the subcapsular regions. Deep inside, the cut surface appeared normal in some and showed thin irregular scars in others. The larger portal tracts were thickened by fibrosis. Nodular transformation of the entire liver was seen in only one case. Microscopically, in the needle biopsy specimens, the normal architecture of the liver was fairly well preserved except for variably increased fibrosis in the portal tract and small focal areas of necrosis and regeneration in the liver parenchyma. In some there was focal infiltration with inflammatory cells in the lobule or in the portal tracts. Varying de grees of portal scarring were seen in a majority of the cases. The fibrosis was mostly confined to the portal areas, sometimes linking them up. The wedge biopsy specimens showed thickened cap sules with prominent portal fibrosis in the subcapsular region. The subcapsular fibrosis at times was so prominent that differentiation from cirrhosis became difficult. Needle biopsy speci mens from deeper regions in such cases helped to exclude cirrhosis. The small portal veins were in conspicuous and .often replaced by several small vascular channels embedded in the scar tissue. In a few of the wedge biopsy specimens and in all the autopsy material, in addition to these relatively nonspecific lesions, occlusive changes in the portal vein radicles were seen. Large and medium-sized portal vein branches showed thickening of the wall due to subendothelial increase of collagen tissue, reducing the lumen to approximately half of its normal size (Figure 5). This thickening was so striking that in the routinely stained sections it was frequently difficult to differentiate the vein from the artery. In some livers removed at autopsy large intrahepatic portal veins showed definite evidence of thrombosis and recanalization. These changes were focal in distribution and were seen in deep wedge biopsy specimens and autopsy specimens but not in the needle biopsy specimens. Examination of the ultrastructure of the liver consistently showed abnormalities in the space of Disse, perisinusoidal space and the cell mem branes in all the nine cases. There was widening of the space of Disse ar.d the intercellular space. The widening in the space of Disse was essentially due to the laying down of collagen bundles which were prominent in the parasinusoidal space and in some areas also spread to the intercellular spaces (Figure 6A). Well developed mesenchymal cells were seen close to the collagen bundles. In some areas an attempt at capillarization of sinu soids by the development of endothelial lining was noticed. The microvilli at the cell membranes fac ing the sinusoids were abundant. The cell mem brane between the hepatocytes showed develop ment of microvilli (Figure 6B). The nuclear and all the intracytoplasmic components of the hepato cytes were normal. Response to Treatment. In general, it was pos sible to control the ascites and to improve the gen eral condition and anemia by symptomatic treat ment. Hematemesis was recurrent, and while in the hospital the patients stood the bleeding well. However, two patients showed gradual but per sistent deterioration. In these the ascites gradu ally became less amenable to diuretic therapy. Ultimately, five years and eight years after the onset of their illness, both had severe ascites, mild icterus and a marked deterioration in liver func tion tests. Both died in the hospital of hepatic coma precipitated in one by hematemesis. Surgical Management. In all, twenty-eight pa tients were operated on for gastrointestinal bleed ing. Splenorenal shunt was performed in sixteen cases. There was only one death during the im mediate postoperative period, giving an operative mortality of 6.25 per cent. This patient had hema temesis on the third postoperative day and died of peripheral circulatory failure and hepatic coma. In the remaining fifteen patients the operative procedure was uneventful. In two patients serum hepatitis developed three months after the opera tion. One of them died of hepatic coma, the other recovered completely.-Three patients (18.75 per Vrimt 51. Aocnst 1971 BFG36700 165 I(U99d9 2435200? NONCIRRHOTIC PORTAL FIBROSIS SAMA ET At. cent) had severe hematemesis five months, three years and four years after the operation; two of these died of bleeding in the hospital. Hema temesis precipitated hepatic coma in one, the other died of peripheral circulatory failure. One pa tient had grade II encephalopathy and is being maintained on antibiotics. The remaining twelve patients are well, with a follow-up of six months to four years. Portocaval shunt was performed in nine pa tients. Two died (22.2 per cent) during the im mediate postoperative period due to hepatic coma. Autopsy was performed in one of these patients. The liver showed extensive ischemic necrosis. Dur ing follow-up one patient had serum hepatitis, with complete recovery. One had severe en cephalopathy and died of hepatic coma one year after the operation. The six surviving patients have been followed up for one to ten years and are asymptomatic. Splenectomy with transgastric resection of varices was performed in three patients. Huge splenomegaly and hypersplenism were the main indications. There was no operative death. One died one and a half months after the operation, ^ue to severe hematemesis. COMMENTS Noncirrhotic portal fibrosis has been described in the literature under various names from all over the world. A series of seventy cases has been reported from Japan [8], twenty-four from Uganda [21] and seventeen from the United States [9]. Iber [2] considers that 3 to 5 per cent of the pa tients with portal hypertension in the West may have this disease. In India, Ramalingaswami, Wig and Sama [1], while describing the dinicopathologic classification of intrahepatic portal hypertension, reported sixteen cases of this syn drome. Later, noncirrhotic portal fibrosis was re corded by others in India [4--7,12]. The clinical picture of noncirrhotic portal fi brosis is characterized by a long history of spleno megaly, which marks the onset of illness in many cases. Recurrent hematemesis is frequent and is usually well tolerated. Mild to moderate ascites occurs in 41 per cent of the cases and is easily amenable to diuretic therapy. The lower incidence of ascites reported earlier from this center is due to the fact that patients with histologically non. specific changes and ascites as the predominant symptom (type II) were not included in the descrip tion of the splenomegalic type of portal hyperten- ion (type III), which is now recognized as non cirrhotic portal fibrosis. Mild to moderate anemia and hypersplenism are common. A comparatively higher incidence of hematemesis (90 per cent) and a low incidence of ascites reported by Basu et al. [5] and Boyer et al. [7] may be related to selected material referred for surgery. Other features of hepatocellular failure are uncommon. Jaundice does not occur except during the terminal stages or transiently following hematemesis in some pa tients. The course of the disease is relatively be nign and is compatible with long life in most pa tients. There is mild hypoalbuminemia, but other rou tine liver function tests are within normal limits. The bromsulfalein test helps to differentiate cases of noncirrhotic portal fibrosis from cirrhosis. In noncirrhotic portal fibrosis the bromsulfalein test is either normal or shows retention of less than 16 per cent in a majority of the patients; in cirrhosis retention in most of the patients is above 16 per cent. Other investigators have also reported pres ervation of liver function tests in this disease [7]. I131 rose bengal hepatogram after stress with bromsuifalein is a more sensitive liver function test and was found to be uniformly abnormal in non cirrhotic portal, fibrosis. There is a rise in alpha, and beta globulin levels, but a similar increase is observed in cirrhosis of the liver. IgG was found to be increased in noncirrhotic portal fibrosis but usually normal in cirrhosis and extrahepatic ob struction. Splenoportovenograms show dilatation of the portal and splenic veins. Similar findings have been reported by Boyer et al. [7] and Williams et at. [10]. Narrowing and constriction of the main branches and poor visualization of peripheral ves sels reported by Boyer et al. [7] and Williams et al. [10] was not consistently seen in this study. Bhardwaj et al. [12] reported additional changes in the intrahepatic portal vein radicals viz. selec tive dilatation of the left main branch of the portal vein, sudden narrowing (cut-off sign) of major intrahepatic branches, truncated peripheral termi nals and a granular pattern in place of secondary branching with occasional pooling of dye in the distended portal vein branches. Hemodynamic studies have indicated normal estimated hepatic blood flow, increased splenic pressure and significant presinusoidal resistance. However, there was marked variation in the esti mated hepatic blood flow and the gradient between the splenic pressure and wedged hepatic vein pres sure among different patients. Similar hemodynamicfindings have been reported by other investi- Volume 51. August 1971 167 BFG36702 V L noncirrmotk: naeosis--sama et al gators [7.12]. However, Williams et al. [10] found increased blood flow in their patients; wedged hepatic vein pressure was above 10 mm Hg in twenty-three of forty-four patients. The clinical features of patients with and without raised wedged hepatic vein pressure were similar. Histologically there is a varying degree of portal fibrosis, with focal areas of necrosis and cellular infiltration with chronic inflammatory cells. These changes are all nonspecific. The specific anatomic lesions of this disease not observed in cirrhosis or extrahepatic obstruction are (1) occlusive changes in the intrahepatic portal vein radicals, which are focal in distribution, and (2) diffuse collagenization of the space of Disse and perisinusoidal space on electron microscopy. Obliterative portovenopathy can explain the presinusoidal resistance but fails to account for raised wedged hepatic vein pressure and normal estimated hepatic blood flow. Similar findings of raised wedged hepatic vein pressure and normal estimated hepatic blood flow have been reported in portal hypertension due to schisto somiasis in which the anatomic lesion is certainly presinusoidal [22]. It has been argued that when the obstruction is presinusoidaL. the increased hepatic arterial flow compensates for diminished portal venous flow, and as the disease progresses secondary changes occur in the sinusoids and space of Disse which may be responsible for raised wedged hepatic vein pressure [23]. However, the obliterative portovenopathy is a patchy lesion most often missed in a needle biopsy specimen, whereas the perisinusoidal fibrosis, easily observed in 600 to 700 A thick sections of needle biopsy speci mens. is a more diffuse change. It is possible that the primary lesion in this disease is collagenization in the perisinusoidal regions and space of Disse. Obliterative venopathy may be secondary to portal hypertension produced by perisinusoidal fibrosis. Alternatively, the same etiologic factor simulta neously produces changes in the intrahepatic rad icles of the portal vein and perisinusoidal area. The variation in the severity of changes at these two sites explains the variation in hemodynamic findings. Splenorenal shunt seems to give better results than portocaval shunt On correlating the results of shunt operation with estimated hepatic blood flow, interesting observations were made. There were three deaths in the immediate postoperative period. Estimated hepatic blood flow was mea sured in two of these three patients and was one and a half to two times the normal. Such increase in hepatic blood flow was not observed in any other patient operated upon. It is possible that sudden cessation of portal blood was not tolerated by the liver in these patients with higher blood flow. Autopsy performed on one of them demon strated extensive ischemic necrosis of the liver. Even in cases of cirrhosis Warren et al. [24] reported poor results of surgery in patients when the blood flow was relatively high. When evaluat ing the results of shunt surgery in noncirrhotic portal fibrosis it is therefore important to take into consideration the initial estimated hepatic blood s flow and the fall in estimated hepatic blood flow after the operation. Three patients had hematemesis after operation. Two of them died despite conservative treatment in the hospital. Such high mortality due to bleeding was not seen in this disease before surgery. An operative mortality of 10.7 per cent, high risk of serum hepatitis and high mortality due to postshunt bleeding in a relatively benign condition makes one wonder whether the accepted indications for surgery in cirrhosis can be applied to this group. To evaluate the role of surgery in this disease it is necessary to have a control group of patients on conservative management The natural history of noncirrhotic portal fibro sis is not known. The disease seems to have a protracted benign course, but progressive hepatic fibrosis may lead to severe impairment of liver functions with fatal results in a few patients, as was observed in four cases in the present series. The pathogenesis of noncirrhotic portal fibro sis is unknown. It may be the result of abdomi nal sepsis with thrombophlebitis and repeated embolization into the portal circulation. This pro cess may have been initiated in childhood with sepsis. It is extremely difficult to obtain an accu rate history of umbilical sepsis from adult patients. Alternatively, these lesions may be due to some unknown toxin with a specific action on the portal vein radicles and space of Disse. The toxin may be bacterial or parasitic, or may be ingested by the patients as indigenous drugs or as adulterants in food, similar to the specific herbal toxins for hepatic venous system in veno-occlusive disease. ACKNOWLEDGMENT We are grateful to Dr. V. Ramalingaswami, principal investigator of noncirrhotic portal fibro sis in India, for initiating and guiding this study and to the Department of Cardiology of the AllIndia Institute of Medical Sciences for help in hemodynamic studies. J BFG36703its Th American Journal of Mtdldno NONCIRRHOTIC PORTAL FIBROSIS -- SAMA ET At- REFERENCES 1. Ramalingaswamt V, Wig KL, Sama SK: Cirrhosis of livar in Northern India. Arch Intern Med (Chicago) 110:350.1962. 2. Iber FL: Obliterative portal venopathy of the liver and idiopathic portal hypertension. Ann Intern _ Med 71:660.1969. 3. Wig KL, Tandon BN, Bhargava S, Sama SK, Nayak, NC: Portal hypertension with particular reference to the non-cirrhotic type. Bull AIIMS 2:152,19681 4. Nayak NC, Ramalingaswami V: Obliterative portovenopathy of the liver associated with so-called idiopathic portal hypertension in tropical spleno megaly. Arch Path (Chicago) 87: 359,1969. 5. Basu AK. Boyer J, Basu Mullick KC, Sen Gupta KP: Noncirrhotic portal fibrosis with portal hyperten sion. Clinical and functional studies with results of operation. Part I. Indian J Med Res 55: 336, 1967. 6. Basu Mullick KC, Sen Gupta KP, Basu AK, Biswas SK, Pal NC, Boyer J: Noncirrhotic portal fibrosis with portal hypertension. Part II. Histological studies. Indian J Med Res 55:351, 1967. 7. Boyer JL, Sen Gupta KP, Biswas SK, Pal NC, Basu Mullick KC, Iber FL. Basu AK: Idiopathic portal hypertension. Comparison with portal hyperten sion of cirrhosis and extrahepatic portal vein ob struction. Ann Intern Med 66:41,1967. 8. Imanaga H. Yamamato S. Kuroyanagi Y: Surgical treatment of portal hypertension according to the state of intrahepatic circulation. Ann Surg 155: 42,1962. 9. Mikkelson WP. Eimondson HA, Peters RL. Redekar AG, Reynolds TB: Extra and intrahepatic pcrtal hypertension without cirrhosis (hepatoportal scle rosis). Ann Surg 162:602,1965. 10. Williams R, Parsonson A. Somers K. Hamilton PJS: Portal hypertension in idiopathic tropical spleno megaly. Lancet 1:329.1966. 11. Wig KL. Ramalingaswami V, Sama SK: Clinicopatho- logical classification of intrahepatic portal hyper tension (cirrhotic and non-cirrhotic). J Ass Physi cians India 14:411,1966. 12. Proceedings of the workshop on non-cirrhotic portal fibrosis. Indian Council of Medical Research 1969. 13. Havana Conference: Fifth Pan-American Congress of Gastroenterology, Havana. Cuba. Report of the Board of Classification and Nomenclature of Cir- rhosis of the Liver. Gastroenterology 31: 213, 1956. 14. Taplin GV, Meredith OM Jr. Kade H. Winter CC, Johnson 0: New radiodiagnostic techniques for investigating parenchymal and obstructive liver and kidney diseases. Proceedings of 2nd Inter national Conference on Peaceful Uses of Atomic Energy, Geneva 26:128,1958. 15. Dobson EL, Warner GF, Finney GR, Johnston ME: The measurement of liver circulation by means of the colloid disappearance rate. Liver Mood flow in normal young men. Circulation 7:690,1953. 16. Fellinger K, Hofer R, Vetter H: Radiocolloids in the study of hepatic circulation in man. Proceedings of 2nd International Conference on Peaceful Uses of Atomic Energy, Geneva 26:153,1958. 17. Tandon BN, Lakshminarayanan R, Bhargava S, Nayak NC, Sama SK: Ultrastructure of liver in non-cirrhotic portal fibrosis with portal hyperten sion. Gut 11:905,1970. 18. Zweig C, Whitaker JR: Paper Chromatography and Electrophoresis. New York, Academic Press. 1967. 19. Ftodin P, Killonder J: Fractionation of human serum proteins by gel filtration. Biochim Biophys Acta . 63:403.1962. 20. W.H.O. Technical Report Series 405,1968. 21. Leather HM: Portal hypertension and gross spleno megaly in Uganda. Brit Med J 1:15,1961. 22. Ramos OL, Saad F, Leser WP: Haemodynamic and liver function in hepatic schistosomiasis. Gastro enterology 47:241,1964. 23. Iber FL: Cause of portal hypertension. Amer J Med Sci 255: 217,1968. 24. Warren WD, Restrap JE, Respess JC, Mullee WH: The importance of haemodynamic studies in the management of portal hypertension. Ann Surg 158:387,1963. Volume 51, August 1971 BFG36704 CO cn o O 169 foz.9oaa a m *o Zj II C3 Q o c o. oo -o 3 c o is 3H<r535 =p-5^-? b =>t~2S* c(So<0o-, w -JC: (O &<v e<* s e> Sj ", ^5a=c 2-u"2 o 9o W-- 'ija * ' S 2.`:^2o: CO } CxO , ACr4 ! > >1= ! Il : 5v >o f ?. o . >. o^ e? = <iwMo J**vCJ2 OS' 5 23 *o 2 uxj tl U_c .. > S >* iaiiin>wii..-l,w uc s5 -5 J <* uc > w S3 X -ss X 3L o c a *V2) s ~ :0.-0J( Og .* N -t* g3 *S oo> *?:"!> i 5 cS < UwciJJZ* (-C-S-C ~ 3^o-5c >% u < CO * ccq -Q D r-' go 5 s* NHt Ov>JScE3j>co It;. So S = 0 ."K.'<g. "s, vi> oa.wus>potdoeu tj x A O " " a e g c fiiagiff 00^3 . s.x30 o 0^53 " sx; ,, TM =2~fcu >* o 2 Vi o s * ^'5 O-rf a. -MsCi-S/ S c > o 5< w oc"?uS t* O ; 3J- -< p . ^2|>-esal|r- wJ * , ?it 2* o 0Q3(5=a2.1a2 "If CO c c < 8 u. o.HI1' * SO. --a:crtTT t* -ic_>--> = > oc-t*T v a*I Si2-ir >-B i-tu.r 5 K'TrfitfJi ;.S > ; c .*2 i) . 0">'Tl-lr I " r> S;E' 2ca*" Q .oO cou.. S"---ctTf._ 1*4T.>J- . jc u uo aC M*iZZP2Piiicojzziontii|o1o2-*--0c|l-a2ig-a'jEj ?tC*;|o3fS.v2: ** ^>- crrn* -h. 'Ch _ "SsJjfsa1w0< . ddleJJS |SI&!l| sj- EZ >S -->5o 3V* A 0<Q O ae wj= _,tJO 23 sgB 02-0n XJ2 -5.3^ 2(5 >."0 S^2 ,,Ls01-5 ll2d s|j 2Q5"*-i'S0 S"vo . -> -- . OCU* ?> . Mw -a o 2 J5 oAVw) c,, g^ajo; -2 -I -" j>- i3S.2 si ,^7'S^TMf o--T. C-crOo-. --^ E--3"^Co>^<--. c-al^ o-g- (3 S 2 U,4<> > I-L e- SR IssoJI* n Eqq *H-fc w .1^ 1u> W3 'ss.ios _w .<- -0 Sn. " PcS.2 2^01>| <a, ^ <Z <JZ 3' Ct OS flC >-t)/CTQ BY (TTTLEl 7 (J.S.CODE) THE AMERICAN JOURNAL OK CASTROENTEHOLOCY Surugwu vt oJ-Kliidiitga In PutienU Injected will, Thorium Dioakle Sarugoca etal--Findings in PutienU InjecUxI w ith Thorium Dioxide THfc! AMJiU-.'A.\ jO UHNAL OK IMSTHOlSNTliMOLOCY I 111 I:o ill! ^ a* 3 U -.2 o S iM^3 *o-t2t ~1s> 8 8 1 H 1:1 i = s " S J"S 3 .*511*1 * jf|iip* &C > ? 3 3C _ vt s3i1* .2 a 11 -a i*filjzl I-ss s3-&i* hb! Iiti s r, J* a-o .So** Ji -O Q. THE AMERICAN JOURNAL OF GAS 1KOEN1EKOLOCY | -s***>.. Haruaoca et a/-Kindings in Patient* Injected w ilh Thorium Dioxide Sarugoca el o l-F in d in w In Fallouts Injw tod w llli Thorium Dioxido 900: . isJ c c o bfl O .2 o .2 asj SS23S8S 2 22g22" ifc-SHS-l-sS S <? M "3 53 - <o i* i ? ? ? s 9 s s ns?ns a"S > i jiJ s5 ^i3 a^a6 *1*3 -Ill Sg61 " 5 S-S-Ji Iff e" al 1 11 -i THE AMERICAN JOURNAL OF GA IOENTEROLOCY "235 ^'* aS--"33 .o