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— A follow-up study of acute non-A, non-B post-transfusion hepatitis with a mean follow-up period of 30 months was carried out in 24 patients in whom liver biopsy was done within 3 months of onset. Of the 24, 13 patients (54%) developed chronic biochemical liver disease with elevated serum aminotransferases for more than 6 months, and in 11 the elevated liver enzymes were normalized within 6 months. Although there were no statistically significant differences in the mean peak values of liver enzymes, length of incubation period and number of transfusions between the chronic and resolved groups, the former tended to have a slow rise and multiple peaks of serum liver enzymes. Analysis of the liver biopsies made in the acute phase revealed that limiting plate erosion, hepatocellular degeneration, and poor regenerative activities were indicative of subsequent transition to chronicity. Multiple biopsies were taken in five patients who were followed for an average of 29 months, and the subsequent histological diagnosis was chronic persistent hepatitis in two, chronic active hepatitis in two and cirrhosis in one.

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.

Five autopsy cases of peliosis hepatis occurring as a late complication of thorotrast (ThO2) liver disease are described. The liver contained many blood-filled cystic spaces of various sizes. Marked sinusoidal dilatation, disruption of cell cords and reticulin fiber framework, and cystic dilatation of sinusoids seem to represent the developmental stages of peliosis hepatis in sequence. Of the five cases, two had no other liver disease except for hepatic fibrosis, and the other three had associated neoplasms, such as angiosarcoma, hepatocellular carcinoma, cholangiocarcinoma, benign hemangioma, and their combinations. Peliosis hepatis seemed to have directly contributed to the patient's death in four cases. The most characteristic clinical feature was the fulminant terminal course with massive ascites, deep jaundice, and hepatic failure, often accompanied by hepatorenal syndrome and tendency to hemorrhage. Liver function study suggested progressive hepatic insufficiency with reduction in serum albumin, prothrombin and the clearance rate for test dyes, and increase in bilirubin. Clinical diagnosis was almost impossible without biopsy.

— The etiology of idiopathic portal hypertension (IPH) is not known. To obtain clues to the pathogenesis, an attempt was made to produce a hepatic lesion similar to that in IPH by repeated injections of aggregated killed non-pathogenic E. coli directly into the portal vein. In the treated dogs, histology of the liver showed dense fibrosis in the portal tract and an aberrant vasculature around the portal area after 1 month. Portal pressure was elevated and middle-to-small-sized portal branches were decreased in number as studied by portography. These changes closely mimic those seen in human IPH. The possibility is discussed that chronic entrance of an antigen such as bacteria from the intestine to the portal venous system plays an etiologic role in IPH.

Aims: The early stage of hepatocarcinogenesis is not well understood pathologically and clinically. The present study was designed to define small (early) hepatocellular carcinoma (HCC) angiographically using the angio-helical computed tomography (CT) system. Methods: Arterial portography CT and hepatic arteriography CT were carried out in 29 patients in whom small HCC ≤ 20 mm was detected during follow-up. Results: There were 17 males and 12 females, aged 47 to 85 years. The offending virus was hepatitis B in four, hepatitis C in 24 and no virus marker in one case. The follow-up period varied from less than a year to 17 years, averaging 6.4 years. The underlying disease was cirrhosis in 12 and chronic hepatitis in 17 cases. The mass was solitary in 16 and multiple in 13 cases, while the size of the mass ranged from 8-20 mm. All lesions were low in attenuation on arterial portography CT, and in 23 of 30 lesions hepatic arteriography CT showed high attenuation, suggesting arterial blood supply. In the remaining 7 cases, lesions were perhaps in the transition from portal to arterial. Conclusions: It was concluded that HCC develops frequently in a liver with chronic hepatitis, often muticentrically, and that early HCC lesions are more often overt HCC already with arterial blood supply, rather than extremely well-differentiated supplied by the portal vein as generally believed.

BACKGROUND The therapeutic results of nonsurgical treatment for patients with hepatocellular carcinoma (HCC) have been poor, and improved treatments are needed. The authors recently developed a new technique called angiographic subsegmentectomy for the treatment of patients with small HCC. METHODS The technique includes confirming the diagnosis of small HCC using a helical computed tomography (CT) scan combined with an angiography system for identifying the tumor-feeding subsegmental hepatic artery, injecting lipiodol containing farmorubicin until it enters the portal vein in sufficient amounts, and injecting sponge particles into the hepatic artery for embolization. Occlusion of the hepatic artery with gel particles and occlusion of the portal vein by lipiodol induce infarction necrosis, which encompasses the entire tumor and the surrounding liver parenchyma. RESULTS The treatment was given to 23 patients with 30 HCC tumors that measured < 20 mm in greatest dimension. It was successful in all 23 patients. Serum alanine aminotransferase levels were elevated to a significant level in the majority of patients after treatment, mild ascites developed in three patients, and the patients complained of pain and fever posttreatment that were controlled readily. No patients developed hepatic failure. Only one patient developed recurrent disease posttreatment at 1.5 years, for a recurrence rate of 5% at 1 year and 6.6% at 1.5 years, a rate that has never been achieved with other treatment modalities. CONCLUSIONS Angiographic subsegmentectomy is a novel treatment for patients with small HCC. The results indicated that it is equivalent to undergoing small resection and is superior to conventional arterial chemoembolization. Cancer 2003;97:1051–6. © 2003 American Cancer Society. DOI 10.1002/cncr.11106

Portal hypertension occurs in a number of disorders other than cirrhosis and they are collectively called non-cirrhotic portal hypertension (NCPH). The common causes of NCPH include idiopathic portal hypertension (IPH), non-cirrhotic portal fibrosis (NCPF) and extrahepatic portal venous thrombosis (EHPVT). Other causes include schistosomiasis, hepatic venous outflow tract obstruction, veno-occlusive disease and congenital hepatic fibrosis. Patients with IPH and EHPVT present with upper gastrointestinal bleeding, splenomegaly, ascites after gastrointestinal bleeding, features of hypersplenism, growth retardation and jaundice due to portal biliopathy. The diagnosis is usually made by abdominal ultrasound, upper gastrointestinal endoscopy, normal liver function tests and normal liver histology. Variceal bleeding in NCPH has lower mortality as compared with cirrhosis because of better liver functions in NCPH. Treatment for NCPH includes primary prophylaxis for variceal bleeding and prevention of repeat bleeding using drugs like beta-blockers, endoscopic sclerotherapy and endoscopic band ligation of varices. In patients with uncontrolled variceal bleeding or symptomatic hypersplenism, porto-systemic shunt surgery or splenectomy are required.

Part 2 of this review discusses DNA damage in biliary epithelial cells in the development of cholangiocarcinoma, alterations in cell kinetics of biliary epithelial cells, biliary epithelial mitoinhibition, and apoptosis that includes the role of Bcl-2, transforming growth factor-beta, telomerase activities and deregulation of Ras and p53, cancer-associated antigens in cholangiocarcinoma, precancerous lesions, stroma formation and angiogenesis, cancer invasion, cell-cell and cell-matrix interactions, and the mechanism of evasion from immune surveillance. These discussions are followed briefly by treatments such as photodynamic therapy, and surgical approaches comparing resection and liver transplantation.

This review describes the early chronological events in the pursuit of a treatment for pernicious anaemia, and the subsequent discovery of vitamin B12 and the intrinsic factor. It details Castle's experiments which established the theory of extrinsic and intrinsic factors as hemopoietic principles, and describes the studies on purification of the anti-pernicious anaemia principle from liver tissue that terminated in the crystallization of vitamin B12 and identification of its coenzyme forms. Biochemical purification and characterization of the intrinsic factor secreted by the gastric parietal cells, and two other vitamin B12 proteins, R-binder (transcobalamin I, haptocorrin), and transcobalamin II, are discussed in detail. The biochemical reactions in micro-organisms and humans in which vitamin B12 is involved are then briefly reviewed, and finally and briefly the immunological basis of pernicious anaemia is discussed.

Background and Aims: Studies of the hepatic artery are scarce. We have observed that hepatic artery calcification is very uncommon in patients with hyperparathyroidism that expedites calcification. Methods: Plain abdominal CT was studied in 221 patients on chronic hemodialysis. Control consisted of 442 sex- and age-matched patients with other diseases. Calcification was graded as a percentage of the entire wall circumference for the aorta, and as a percentage of the entire length of the hepatic and splenic arteries from the celiac trunk to the hilum of each organ. Results: Aortic calcification was seen in 79.2% of male dialysis patients, 22.1% of controls, 74.1% of female dialysis patients and 17.3% of controls (P < 0.0001). Hepatic artery calcification was seen in only 13 dialysis patients. The degree of calcification of the abdominal aorta was correlated with the length of hemodialysis period (P = 0.008), but not with serum calcium, serum phosphate or their product. Although serum parathormone levels were not correlated with calcification, seven of eight dialysis patients with hepatic artery calcification had very high parathormone levels. Conclusions: The hepatic artery is far less frequently calcified than are the abdominal aorta and splenic artery. This may be a teleologic phenomenon of the liver.

Confusion prevails throughout the world regarding the definition and classification of the Budd-Chiari syndrome. The original patients (Budd and Chiari) described had hepatic vein thrombosis, but this syndrome now encompasses various hepatic venous outflow blocks, of which membranous obstruction of the inferior vena cava (IVC) is the most common. This author has been suggesting that the classical Budd-Chiari syndrome or hepatic vein thrombosis and membranous obstruction of IVC or primary thrombosis of IVC at its hepatic portion are epidemiologically, pathologically and clinically different, and that they should be treated as two clinical entities that are not to be mixed. The two diseases have a different onset, different clinical manifestations and a different natural history. Whereas hepatic vein thrombosis is a severe disease with an acute onset, IVC thrombosis presents mildly at onset, but it recurs and eventually turns into a fibrous occlusion of IVC of varying thickness or stenosis of a various degree. The fibrous IVC occlusion is found as a mysterious thin membrane, but is more often much thicker than a membrane, and therefore 'membrane' is a misnomer. Although the genesis is not established, formation of a thin membrane may be an outcome of recurrent thrombosis. The past congenital vascular malformation theory no longer holds, because the disease occurs mostly in adulthood, and transformation of thrombosis into a membrane has now been well documented pathologically as well as clinically. This author suggests that a term 'obliterative hepatocavopathy' replace membranous obstruction of IVC, the term 'Budd-Chiari syndrome' be abandoned, and that primary hepatic venous outflow block be divided into primary hepatic vein thrombosis and primary IVC thrombosis (obliterative hepatocavopathy).

Background: The TT virus (TTV), a new DNA virus found in Japan from a patient with post-transfusion hepatitis non-A-non-G, is frequently positive in the sera of patients with liver disease. It is not established whether this virus causes liver damage. We studied the frequency of superinfection of this virus and hepatitis C virus (HCV) known to be endemic among haemodialysis patients, and the possible deleterious effect of TTV on HCV-induced chronic liver disease. Methods: We used primers from a conservative region in the TTV genome (Okamoto, 1998) to detect TTV. Sera from 163 dialysis patients positive for anti-HCV and 77 dialysis patients negative for anti-HCV (control) were tested. Results: TT Virus positivity was 35% among HCV antibody (anti-HCV)-positive patients and 45.4% among anti-HCV-negative patients. TT Virus positivity was unrelated to the length of haemodialysis or amounts of blood the patients had received in the past. More anti-HCV-positive patients had a history of transfusion, but TTV positivity was not as closely associated with transfusion as anti-HCV positivity. The severity of chronic liver disease was estimated from peak serum alanine aminotransferase levels in the preceding 6 months. Among anti-HCV positives, TTV-positive patients tended to have less active disease; at least there was no indication that TTV superinfection aggravated chronic hepatitic C in long-term dialysis patients. Four of 35 anti-HCV-negative, TTV-positive patients had chronic active liver disease, while none of the anti-HCV-negative and TTV-negative patients did. Conclusions: TT Virus infection is prevalent among haemodialysis patients. Its transmission occurs not only by blood transfusion, but also by non-parenteral infection. Superinfection of TTV does not exert deleterious effects on the liver disease induced by HCV. However, it may cause chronic hepatitis in a limited number of patients, but remains dormant most of the time. Triple infection, HCV and TTV plus HBV or HGV (one case each), did not cause severe liver disease.

Chronic hepatitis B infection is a serious health threat in the Asia-Pacific area. A consensus meeting on the treatment of chronic hepatitis B infection was conducted in Hong Kong, in August 1997. It was generally agreed that treatment of chronic hepatitis B infection should be based on the understanding of the natural history of chronic hepatitis B infection. To date, interferon alpha is the only Food and Drug Administration (FDA)-approved form of therapy for chronic hepatitis B infection. The overall response in Asian patients is unsatisfactory: approximately 15-20% will clear hepatitis B e antigen, but less than 5% will clear hepatitis B surface antigen. Newer immunomodulatory therapies are under trial. In contrast, nucleoside analogues, such as lamivudine (pending FDA approval) and famciclovir, have been shown to be potent suppressors of hepatitis B viral replication; however, their role as monotherapy in the treatment of chronic hepatitis B infection remains to be defined. Also, the issues of resistance to nucleoside analogues and withdrawal rebound need to be carefully studied. The future direction of therapy in chronic hepatitis B infection is probably a combination of nucleoside analogues or nucleoside analogues with immunomodulatory therapy.

It is known that patients on chronic haemodialysis are frequently infected with hepatitis C virus (HCV). It has recently been found that GB virus-C (GBV-C) and hepatitis G virus frequently coinfect patients with HCV. This study aimed at elucidating the clinical implications of GBV-C infection among haemodialysis patients who have and do not have HCV infection. GBV-C RNA was detected in sera of randomly selected 98 anti-HCV-positive and 85 -negative patients on dialysis by reverse transcription-polymerase chain reaction using two sets of amplification primers made from the reported sequences of the non-structural protein 3 and 5' untranslated regions. In these patients, liver function tests were carried out at regular intervals. There were six patients who were coinfected with HCV and GBV-C and three who had only GBV-C RNA. All had a history of past blood transfusion. The onset of mild hepatitis was identified in three HCV-negative patients; elevation of alanine aminotransferase (ALT) following blood transfusion was very mild but recognizable, and aspartate aminotransferase (AST) was higher than ALT. In two of six coinfected patients, the onset of liver disease was recognized with a peak ALT of 72 and 90 IU/L, respectively. Two of these six were Amplicore (HCV-RNA) negative and asymptomatic, two had low-grade HCV viraemia and two moderate-grade HCV viraemia. Of the 98 anti-HCV-positive cases, 41 were thought to have had nosocomial infection of HCV or non-A, non-B virus; none of them had GBV-C. GBV-C RNA was negative in nine patients who had chronic non-A-E hepatitis. GBV-C infection was detected in 6.1% of anti-HCV-positive and in 3.5% of -negative dialysis patients. All had blood transfusion in the past, and there was no evidence of patient-to-patient spread of GBV-C in hospital. The liver disease was very mild and self-limited in GBV-C infection alone. The natural history of coinfected patients may be similar to that of those with chronic HCV infection, but the liver disease appears to be milder.

Although less common than oesophageal varices in portal hypertension, gastric fundal varices carry a higher mortality rate when they rupture. They are less amenable to sclerotherapy. We have developed a minimally invasive balloon-occluded retrograde transverse obliteration (B-RTO) procedure to treat gastric fundal varices. B-RTO involves inserting a balloon catheter into an outflow shunt (gastric-renal or gastric-vena caval inferior) via the femoral or internal jugular vein. Blood flow is then blocked by inflating the balloon, and 5% ethanolamine oleate iopamidol is injected in a retrograde manner. The embolized gastric varix subsequently disappears. B-RTO was performed in 32 patients with gastric varices. Follow-up endoscopies were performed at intervals of 2-4 months for an average observation period of 14 months. Eradication of the varices has been confirmed in 31 of 32 patients. No recurrence occurred in any patients in the follow-up period. There were no significant changes in liver function after the procedure. We conclude that B-RTO is a safe and effective procedure for the treatment of gastric fundal varices.

In this paper, the recent development in the study of the epidemiology of hepatocellular carcinoma (HCC) and the diagnosis of adenomatous hyperplastic nodules as a putative preneoplastic lesion are discussed. Other clinical features of HCC will not be included here.

This study, aimed at elucidating the epidemiological features of primary liver carcinoma developing in non-cirrhotic livers, was based on 25 103 autopsies performed between 1975 and 1984 in Trieste, Italy. These autopsies correspond to approximately 70% of all deaths that occurred in this area. Various factors allegedly related to carcinomas were analysed in reference to our previous study on cirrhotic livers and in comparison with 5603 autopsies in Kurume, Japan. There were 28 cases of hepatocellular carcinoma (HCC), 16 of cholangiocellular carcinoma (CCC) not associated with cirrhosis in Trieste, and 48 HCC and 19 CCC in Kurume. On the basis of our findings, it was concluded that cirrhosis, regardless of its cause, is the main pathogenetic factor in HCC; it is responsible for a much higher frequency (14.2:1) than in non-cirrhotic livers, as well as for early occurrence of tumours (an average of 6 years earlier in cirrhotic liver) in Trieste. Patients in Trieste were older than those in Japan, and the frequency of HCC among all autopsies was much greater in the latter. By contrast, the influence of cirrhosis on cholangiocellular carcinoma (CCC) was negligible, as such association appeared purely coincidental or absent. The incidence of CCC among autopsies was greater in Japan. Our data on CCC were not sufficient to demonstrate any clear aetiopathogenetic association between this tumour and alcohol abuse and hepatitis B virus (HBV) infection, except for a possible aetiological role of gallstones. The frequency of CCC relative to HCC was greater in Trieste than in Japan; the incidence of HCC was much less in Trieste, whereas CCC was more frequent in Japan.

A 59 year old man with cirrhosis presented with encephalopathy and hyper-ammonaemia. T1 weighted magnetic resonance imaging demonstrated a large void tubular structure connecting the right posterior portal vein branch and the inferior vena cava through the right hepatic lobe inferiorly, and cine-mode imaging showed a flow within this channel. Clearly in this patient a significant portion of the portal venous blood was being shunted into the inferior vena cava, causing encephalopathy. The exact origin of this channel is not known, but several possibilities are discussed. It is also predicted that similar previously unknown large intrahepatic shunts will be discovered increasingly with the availability of modern imaging techniques.

Percutaneous ethanol injection (PEI) was applied to 120 lesions in 95 patients with hepatocellular carcinomas (HCC) smaller than 3 cm in the past 6 years. All main target tumours, in 67 patients who had been followed by sonography for more than 6 months after PEI, decreased in size; 28 tumours (41.8%) became undetectable and have remained so until now. The 1-, 2-, 3-, 4- and 5-year survival rates calculated by the Kaplan-Meier method were 93%, 81%, 65%, 52% and 28% respectively. These survival rates were better than those of patients with HCC smaller than 3 cm who did not receive anticancer treatment (P less than 0.01). The survival of patients of the Child's A or Child's B status was better than that of those with Child's C disease. Recurrence occurred in areas within the liver different from the original lesion in 34% in one year, 61% in two years and 66% in three years after PEI. PEI was then repeated in 61% of such patients.

The purpose of this study was to develop the technique of intra-operative portal angioscopy using a portal angioscope, and to demonstrate its potential use in the therapy for patients with hepatocellular carcinoma (HCC) bearing a portal thrombus. Portal angioscopes, Olympus BF3C10 and CHFP10 of a diameter of 3.5 mm and 4.8 mm, respectively, were used during operation in five dogs, two patients with hepatic metastasis from colon cancer and three patients with HCC having a portal tumour thrombus. The portal vein and hepatic artery were ligated simultaneously, and the angioscope was immediately introduced under direct vision through a small portal venotomy. Blood in the portal vein was almost fully diverted by infusion of heparinized saline through a channel of the angioscope at a rate of 3 mL/min in dogs and 5 mL/min in patients with hepatic metastasis. Rates of 6 mL/min and 10 mL/min in dogs and patients, respectively, were adequate to clear completely the portal vein of blood. In patients with HCC, portal tumour thrombectomy was performed with a Fogarty balloon catheter by suctioning thrombi through a channel of the fibrescope after visual study of the portal thrombus. Observation and treatment of portal thrombus by angioscopy may become an important part of surgical treatment of HCC with portal invasion, but further technical improvement is desirable before this technique becomes a routine procedure.

A 45-year-old man with hepatocellular carcinoma who developed intravascular coagulation following complete tumor regression by chemotherapy is described. After 2 doses of 10 mg of Mitomycin C given into the hepatic artery at the time of selective angiography, and 16 intravenous doses of 5-fluorouracil and Mitomycin C, 2 doses per week, subjective symptoms and hepatomegaly disappeared. Alpha-fetoprotein became negative and a remarkable change in tumor size and vasculature was noted in the arteriogram. Three months after chemotherapy, the patient developed thrombocytopenia, intravascular hemolysis, and acute renal failure. Autopsy disclosed a 8 × 7 × 5 cm solitary, encapsulated hepatocellular carcinoma in the right lobe. The tumor was surrounded by a thick capsule and completely necrotized. Neither intrahepatic invasion nor extrahepatic metastasis was observed. In the kidney, generalized fibrin thrombi were seen in the afferent arterioles of glomeruli as accounted for by intravascular coagulation.

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.

The pathologic findings of 232 consecutive cases of hepatocellular carcinoma (HCC) autopsied during the past ten years at Kurume, Japan, were analyzed from the point of view of global epidemiology, in relation to clinical feature, and in regard to incidence, age, sex, etiologic factors, size of liver, changes in noncancer parenchyma, gross type of tumor, extrahepatic metastases, intravascular and intraductal growths, cancer cell histology, hepatitis B surface antigen (HBsAg) in hepatocytes and cancer cells, liver cell dysplasia, and frequency and clinicopathologic characteristics of minute HCC. Furthermore, postmortem hepatic arteriography and portography were done in 152 livers for comparison with gross anatomy and celiac angiograms. It was found that: (1) epidemiologically, HCC in Japan is distinct from that in the West that it is frequently encapsulated, livers are generally small because of frequent and advanced cirrhosis and small cancer, minute HCC, is not uncommon at autopsy, cirrhosis most commonly associated is the one with thin stroma and medium size nodules, and micronodular cirrhosis is very rare despite frequent alcohol abuse; (2) HCC is increasing in incidence; (3) HBsAg is frequently found in parenchyma; (4) liver cell dysplasia is indirectly related to HBsAg with no evidence for premalignancy; (5) the lung is the most frequent site of metastasis but peritoneal dissemination is unusual; (6) intraportal tumor growth is very common and the hepatic vein is less frequently affected; (7) growth in the major bile duct is frequently associated with intraportal growth and clinically presents as obstructive jaundice; and (8) tumor is supplied solely by arteries and celiac arteriograms are closely correlated with gross pathologic findings.

The effects of human alpha and beta interferons (IFN) on the production of HBsAG by PLC/PRF/5 cells, an HBsAg-producing human hepatoma cell line, were studied in the exponential and stationary phases of cell growth. When exponential phase cells were treated with 100 or 1,000 U of IFN per ml for 48 hr. the amount of HBsAg in the culture medium decreased. The number of cells and the synthesis of DNA and proteins were also reduced by the IFN treatment. These results suggested that IFN did not affect the production of HBsAg specifically in exponential phase cells. When cells in the stationary phase were similarly treated with IFN, HbsAg production was not inhibited nor did the number of cells decrease. To examine the antiviral state induced by IFN in PLC/PRF/5, induction of 2'5'-oligo (A) synthetase and susceptibility to two kinds of viruses were examined. The 2'5'-oligo (A) synthetase activity was increased in an IFN-dose dependent manner. Susceptibility to vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV) was decreased by treatment with 10 and 100 U of IFN per ml for 20 hr. It was concluded that IFN-alpha and IFN-beta induce 2'5'-oligo (A) synthetase and the antiviral state, but do not inhibit HBsAg production by PLC/PRF/5 cells.

The etiologic relationship of parasitic liver disease to primary liver cancer has long been debated. For this reason, a review of 4611 necropsies was carried out to determine the frequency with which hepatocellular carcinoma occurred in association with schistosomiasis. Of 227 cases of hepatocellular carcinoma, 24 (10.6%) were associated with schistosomiasis japonica. This was significantly higher than the incidence of this carcinoma without schistosomiasis (2.78%). The majority of the 24 cases exhibited the features of a mixed macronodular and micronodular cirrhosis (Gall's posthepatitic cirrhosis); this was super-imposed upon and caused a masking of schistosomiasis fibrosis. By radioimmunoassay hepatitis B antigen was positive in 27% of these cases. A review of the literature indicated that chronic schistosomiasis, on its own, is unlikely to be the cause of primary liver cell carcinoma. Histologic features resembling post-hepatitic cirrhosis combined with a high frequency of hepatitis B antigen suggest that viral hepatitis rather than S. japonicum is the more likely etiologic factor involved, or has a synergistic effect on carcinogenesis.

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.

Idiopathic (non-cirrhotic) portal hypertension is one of the major problems in developing countries, but the aetiology is not known. Two sisters with idiopathic portal hypertension diagnosed by percutaneous transhepatic catheterization of the portal vein and liver biopsy are reported. Both patients had large spontaneous portal-systemic shunts. This seems to be the first report of a familial aggregation of this disorder.

A total of 850 patients with hepatocellular carcinoma seen during the last 8 years were analyzed retrospectively for survival in relation to treatment and disease stage. A new staging scheme based on tumor size, ascites, jaundice and serum albumin was used. Clearly, the prognosis depended on disease stage. The median survival of 229 patients who received no specific treatment was 1.6 months, 0.7 month for Stage III patients, 2.0 months for Stage II, and 8.3 months for Stage I. The median survival of Stage I patients who had hepatic resection (n = 115) was 25.6 months and Stage II patients with resection (n = 42) was 12.2 months. In patients who had a small cancer (less than or equal to 25% of liver area in size) the median survival was 29.0 months. Survival of the surgically treated patients, which represented a highly selected group, was better than that of medically treated patients of a comparable stage. Median survival of Stage I medically treated patients (n = 124) was 9.4 months, for Stage II (n = 290) 3.5 months, and for Stage III (n = 50) 1.6 months. Medical treatment prolonged survival in Stage II and III patients, but not in Stage I. Transcatheter arterial embolization gave a better survival compared with chemotherapy, whether intra-arterial bolus administration of mitomycin C, systemic mitomycin C, or oral/rectal tegafur, in Stage II. Among various chemotherapeutic modalities, intra-arterial bolus injection was superior to systemic chemotherapy in survival in Stage II. In Stage III, chemotherapy improved survival as compared with no specific treatment. The major causes of death were hepatic failure and gastrointestinal bleeding, probably due to the coexistent advanced cirrhosis. These results in survival are much improved over the past reports, and the differences are probably a result of earlier diagnosis and frequent hepatic resections.

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.

A comparison of the gross pattern of hepatocellular carcinoma (HCC) was made using autopsy material from Japan (378 cases), the United States (90 cases), and South Africa (61 cases). The tumor could be placed in three major gross patterns only if subcategories of each were created. The common major patterns were expanding, spreading, and multifocal. There was a relationship of gross pattern to the presence or absence of prior liver disease, and there were differences in frequency of occurrence of the various gross types in the material from the above-mentioned countries.