Kunio Okuda’s research while affiliated with Chiba University and other places

Autologous immune complex nephritis was successfully produced in guinea pigs with the iniection of gold (Sodium aurothiomalate). Gold was iniected once a week for 9-14 weeks, into 18 Hurtley guinea pigs. One to two weeks after first injection, the urine protein patterns showed typical tubular pro-teinuria in 14 (82%) out of 17 cases determined by sodium dodecyl sulfate gel electrophoresis. Tubular basement membrane (TBM) antigen was detected in urine samples from 15(88%) out of 17 cases. Two months after the final injection, massive proteinuria had broken out in four cases. Especially in the urine from one case, which contained, more than 1, 000 mg protein per dl. Morphological examinations of kidney from this case revealed characteristic manifestations of both typical interstitial changes as defined to immune complex nephritis. The glomerular deposits as well as tubular epithelial cells were specifically stained with anti-guinea pigs IgG by direct immunofluorescence methods. Eluate from the diseased kidney also stained specifically renal tubular cells of normal guinea pig by indirect immu nofluorescence. Circulating antitubular cell antibody and resoective antigen were detected in this case. These results indicate that glomerular changes as well as interstitial changes had occured in gold treated guinea pigs, and the glomerular injury might certainly be mediated by the immune complexess composed of tubular epithelial antigen and host antibody. It will be further suggested that the ex-creted tubular antigen from the damaged tubular cells would lead to auto-antibody and/or immune-e complexes formation which cause glomerular injury.

It has been shown that hepatitis C virus (HCV) infection is closely associated with mixed type cryoglobulinaemia. It is also known that HCV infection is rampant among chronic haemodialysis patients. We studied 531 renal failure patients on maintenance dialysis including 170 with positive HCV antibodies for cryoglobulinaemia, and its incidence was compared with controls which consisted of 242 chronic hepatitis C patients without renal failure and 183 healthy adults. Cryoglobulinaemia was present in 30.6% of dialysis patients with HCV infection, 10.8% of dialysis patients without HCV infection, 29.8% of patients with chronic hepatitis C without renal failure, and 0% of healthy adults. Among the 30 new renal failure patients who were started on dialysis within 6 months, four were positive for HCV antibodies, and one of them had cryoglobulinaemia; of the 26 HCV-negative patients, four (15%) were cryoglobulinaemic. The cryocrit values among dialysis patients were much lower than those of the control cases and other reports on non-dialysis cases. Patients with cryoglobulinaemia were generally younger compared with patients negative for this condition. There was no correlation between cryoglobulinaemia and past blood transfusion, underlying disease or length of dialysis. Cryoglobulinaemic patients seem to develop renal failure at relatively young ages and a considerable proportion of cryoglobulinaemic dialysis patients may have already had cryoglobulinaemia at the time of the start of haemodialysis. There was no indication that the presence of cryoglobulin in serum adversely affects the liver disease nor increases serum virus load in HCV-infected dialysis patients. Thus, it was concluded that although HCV infection has a certain role in the development of cryoglobulinaemia in dialysis patients, they develop cryoglobulinaemia less frequently and produce cryoglobulin to a lesser degree in the presence of HCV infection as compared with non-dialysis patients.

The pathomorphological changes of intrahepatic portal veins were studied in 19 autopsy cases of idiopathic portal hypertension (IPH), and the pathogenesis of portal sclerosis was discussed by the observations on the human and experimental materials. The degree and morphological appearance of intimal lesions vary from vessel to vessel. Fibrocellular proliferation of subendothelial tissue and incorporation of organized mural thrombi were suggested as the cause of intimal thickening in the portal veins. Animal experiment showed that injury of portal vein wall was followed by intimal hyperplasia and/ or incorporation of mural thrombi, and resulted in portal sclerosis similar to that of IPH liver. The cause of portal phlebosclerosis in IPH can not be explained by passive congestion alone. There might be a certain possibility of direct injurious effect in the vessel wall in the pathogenesis of portal lesions of IPH. The following pathogensis of portal sclerosis in IPH is postulated: phlebosclerotic changes of the portal veins are initiated by injury to the vessel wall due to unknown cause (s) and accelerated by secondary thrombosis and/ or mechanical injury due to increased portal pressure.TA PATHOL. JPN. 35: 299–314, 1985.

ABSTRACT— Six autopsy cases of the rare, diffuse type of hepatocellular carcinoma (HCC), as classified gross anatomically according to the strict definition, have been studied. The prominent clinical feature was the rapid deterioration of the patient's general condition, terminating in hepatic failure. The liver size enlarged quickly, at a perceptible speed, often accompanied by abdominal pain. Diagnosis of this particular type of HCC was difficult, and celiac angiography and scintiscan of the liver were only suggestive when considered together with other laboratory data. Hepatitis B surface antigen was positive in all three patients in whom it was tested. The entire liver was studded with minute, uniformly sized tumor nodules, evenly distributed throughout. Some of them were grossly indistinguishable from cirrhotic nodules. All livers had an underlying cirrhosis which was characterized by relatively small regenerative nodules with thin stromas. Large portal branches at the hilum contained tumor thrombi in all patients, except for one case in which left lobectomy was followed by intraportal dissemination. Histologically, all tumor nodules represented intrahepatic metastases via the portal vein system. Tumor cells were poorly differentiated. These findings suggest that the diffuse type of HCC most frequently, if not always, represents intrahepatic, widespread portal metastases which have occurred within a short period of time.

Hepatitis C virus (HCV) infection is aetiologically very closely associated with hepatocellular carcinoma (HCC). World-wide, hepatitis B virus infection is the predominant aetiological factor in developing countries, whereas in industrialized countries, HCV has a far more important role in hepatocarcinogenesis. The varying weights of the aetiological role of HCV infection are compared among countries. The speed of progression of chronic hepatitis C to cirrhosis, thenceforth to HCC, and certain discrepancies between an American study and the Japanese experience are described. The reason for the recent surge of HCV infection and subsequent increase in the incidence of HCC is also discussed. The genetic mechanism of HCV-induced hepatocarcinogenesis is still poorly understood.

Abstract Although the vast majority of hepatitis B surface antigen (HBsAg) carriers of the world inhabit South-east Asia, very little is known about delta infection in this area. Therefore, a serological and immunohistological study was made in the Tokyo-Chiba area. One of 58 (1.7%) HBsAg carriers had anti-delta antibody in a high titre in serum. Delta antigen was immuno-histologically localized in the liver in two of 146 (1.4%) HBsAg carriers studied. The antigen was strongly stained in the nuclei, and positive cells were diffusely scattered throughout the liver in both cases. Neither subject was an illicit drug user: one had travelled to Italy 10 years earlier and the other had a blood transfusion during a 5-year residence in Bangkok in the past. Thus, there is delta infection among non-intravenous drug users in Japan. Delta infection has been linked to severe liver damage, occasionally fatal. Once introduced, it could become epidemic in a country where hepatitis B virus infection is endemic, and might spread among non-drug users.

The diagnostic value of computed tomography (CT) scans in small hepatocellular carcinoma (HCC) (<5 cm) was studied in 82 patients. Dynamic scan was also made in 66 of them. Combined unenhanced and enhanced scans detected 87% of the lesions > 2 cm, but the detection rate was only 25% for lesions <1.5 cm. Diagnostic failure was due to isodensity of the mass and to technical artefacts. Diagnosis of the surrounding capsule and internal septa (partition) and demonstration of the typical pattern of density enhancement by dynamic scan proved useful in differentiating HCC from secondary cancers. On unenhanced CT, the density of the interior was subject to the histological changes of tumour such as bleeding, necrosis and fatty metamorphosis. Similarly, enhanced CT showed density changes suggestive of these histological changes. Dynamic scan proved particularly useful for lesions <3 cm because the typical density enhancement was frequently demonstrated in the arterial phase. It was concluded that unenhanced CT combined with dynamic scan has a high diagnostic value in small HCC and reflects histological changes.

Abstract A total of 184 cases of extrahepatic portal obstruction (EHPO), mostly demonstrated by intraoperative portography and studied at 17 institutes during the period 1957–1983, were compared with 469 cases of idiopathic portal hypertension (IPH) similarly studied. Of the cases of EHPO, there were 101 males and 83 females; 93 were under 20 years of age and the average age was 25.9 years (i.e. much younger than that of IPH cases). There were two age peaks, one before age 19 years and the other at age 40–49 years. One out of three adult cases had a history of abdominal surgery, but otherwise the aetiologic factor was difficult to elicit. Bleeding was the initial symptom in the majority, and splenectomy and haematological findings of hypersplenism were less pronounced compared with IPH. Liver function tests were almost always normal. The liver appeared normal macroscopically in 69% and histologically in 35%. The changes seen in the remainder were similar to those in IPH; they were less frequent in young patients than in cases above age 20 years. Compared with IPH, the wedged hepatic venous pressure in patients with EHPO was lower and the gradient from the portal venous pressure was greater. It is concluded that extrahepatic portal obstruction is less common compared with IPH in Japan, and that there are cases particularly among adults that present clinicopathological features very similar to those of IPH. It is unclear at present whether these two disorders represent two different disease entities, or whether they represent one disorder with differences in the site of involvement along the portal vein system.

Abstract Ten patients with cirrhosis, in whom small mass lesions were detected by imaging techniques and histological diagnosis of the resected specimens was difficult, are described. There were 17 grossly discrete lesions measuring 10 × 8 mm to 27 × 22 mm. Four were compatible with so-called adenomatous hyperplasia showing no histological features of malignancy, and eight were equivocal as to whether they were benign or malignant. The other five lesions (in four patients) were hepatocellular carcinoma, co-existing with apparently benign lesions. The eight equivocal lesions were eventually judged to be highly differentiated hepatocellular carcinomas. These benign-appearing lesions, found by advanced imaging in patients with cirrhosis, create a serious problem in regions where primary liver cancer is endemic among cirrhotics, and hepatic resection is the preferred treatment. It is possible that these lesions represent a transition from adenomatous hyperplasia occurring in cirrhotic livers to hepatocellular carcinoma through a histologically equivocal state and that the current morphological methods are inadequate for differentiating malignant from benign lesions.

Sixty-one patients, 41 with hepatocellular carcinoma and 20 with liver cirrhosis, were examined by dynamic computed tomography (CT) and all but one with hepatocellular carcinoma were examined by celiac angiography. Dynamic CT disclosed arterioportal shunting in eleven cases of hepatocellular carcinima and in one of cirrhotics. All of them were confirmed by angiography except one case in which angiography could not be performed. In ten of these eleven cases arterioportal shunt was adjacent to a mass lesion on dynamic CT, suggesting tumor invasion into the portal branch. In one with hepatocellular carcinoma, the shunt was remote from the mass. In one with cirrhosis, there was no mass. In these last two cases, the shunt might have been caused by prior percutaneus needle puncture. In another case of hepatocellular carcinoma, celiac angiography but not CT demonstrated an arterioportal shunt. Thus dynamic CT was nearly as diagnostic as celiac arterigraphy for the demonstration of arterioportal shunt due to portal invasion of hepatocellular carcinoma and percutaneus needle puncture.