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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.

— 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.

In this article, the gross pathology of varices and supplying veins are described comparing esophageal varices and varices of the cardia and fundus of the stomach. The angioarchitecture of the lower esophagus is such that normally very thin parallel veins in the lamina propria mucosae in the palisade zone become enlarged in portal hypertension and join the few larger submucosal veins to form esophageal varices. Enlarged parallel veins come to pile up and join the submucosal veins at an acute angle, rendering this area vulnerable to rupture. Most ruptures occur in this critical area. The basic differences between esophageal and gastric varices are the layers in which the varicose veins form: the lamina propria mucosae and submucosa in the esophageal varices and the submucosa in gastric varices. While cardiac veins and varices are continuous with esophageal varices, fundic varices develop independently as part of a splenogastrorenal shunt that runs through the stomach wall, having rare communications with other veins. The fundic varix is so large in caliber that when it ruptures, the muscularis mucosae and lamina propria are penetrated with massive bleeding. The treatment of varices calls for complete thrombosis of all varicose veins, and merits and demerits of available treatment modalities are discussed based on autopsies from the pathologic point of view. Because of the large size, the management of fundic varices is difficult, and the new technique called balloon-occluded retrograde transvenous obliteration for occluding fundic varices is discussed.

The Budd-Chiari syndrome was primarily described as hepatic vein thrombosis within the liver, but it now includes inferior vena cava (IVC) thrombosis and other conditions that cause hepatic vein outflow obstruction. This author and several others maintain that primary hepatic vein thrombosis and primary IVC thrombosis represent two different clinical disorders. Primary thrombosis of the IVC most commonly occurs in its hepatic portion, which seems to be predisposed to thrombosis and has been called membranous obstruction of IVC, because the thrombus organizes into a fibrous and frequently membranous occlusion of the IVC. The hepatic vein orifices are affected to varying degrees, resulting in congestive liver damage. The cause of IVC thrombosis may be a hypercoagulable state such as coagulation factor deficiency and myeloproliferative disorders, but is more often idiopathic. In Nepal, it is endemic with a suspected association with infections. To consider IVC thrombosis and the congestive liver damage as a disease entity, this author proposes the term obliterative hepatocavopathy, separate from hepatic vein thrombosis. Clinically obliterative hepatocavopathy is less severe in its acute phase compared with hepatic vein thrombosis, but it aggravates occlusion of hepatic vein orifices with recurrent thrombosis. Primary hepatic vein thrombosis and obliterative hepatocavopathy display different hemodynamics of the hepatic veins, IVC, and portal vein; dilatation of the subcutaneous veins in the body trunk is more pronounced in obliterative hepatocavopathy because the ascending lumbar vein becomes the major collateral route. Congestive liver cirrhosis develops after a long clinical course that may be complicated by hepatocellular carcinoma.

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).

ビタミンC測定法, および血中の総ビタミンC値の基準値 (参考値) を検討した。健康な女子大生ボランティア54人に, 3日間の食事調査の後, 採血し, ビタミンCを1日200mg含む一定の試験食を3日間供した。3日後に再び採血を行い, 得られた血漿のビタミンC濃度を測定した。測定は3カ所の施設でHPLC法 (お茶の水女子大学, テイジンエスアールラボ) およびアスコルビン酸オキシダーゼ法 (東邦大学) を用いて行い, 各施設での測定値の比較も行った。総ビタミンC濃度の試験食摂取前値と後値では平均値に有意な差はみられないが, 後値ではばらつき (標準偏差) が小さくなり, ビタミンCの一定量摂取が, 血中濃度に影響を与えることが示唆された。前値でビタミンC濃度が低値にあった学生では, ビタミンCを1日200mg, 3日間摂取することで, 血中濃度は0.62mg/dL以上の範囲に入った。異なる測定方法による施設間差は認められず, 従って, 統計的に95%の信頼範囲から血中総ビタミンC濃度の基準値は0.70-1.38mg/dL (HPLC/ECD法) となった。この値は栄養所要量算出の際に基準とした値 (0.7mg/dL)とも一致した。

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.

Two patients with ectopic liver are described. In one patient, a small ectopic liver attached to the gastric serosa developed hepatocellular carcinoma (HCC). The preoperative diagnosis was an alpha-fetoprotein (AFP)-producing carcinoma and a malignant ulcer of the stomach. Total gastrectomy and esophago-jejunostomy were performed. The tumor that measured 4 x 2 x 2 cm contained an AFP-producing HCC and normal liver tissue. In another patient who had alcoholic cirrhosis, ectopic liver on the serosa of the gallbladder was found to have the same histological changes as the mother liver. A survey of the literature disclosed more than 20 cases in which HCC developed outside the liver; the liver did not have HCC. By contrast, there was only one report on HCC occurring in the liver in the presence of a noncancerous, relatively large accessory liver lobe. Because ectopic liver does not have a complete vascular and ductal system as a normal liver, it is perhaps functionally handicapped and more prone to hepatocarcinogenesis.

Budd-Chiari syndrome (BCS) was initially defined as a symptomatic occlusion of the hepatic veins, but subsequent reports on various obliterative changes that occur in the hepatic portion of the inferior vena cava (IVC) and hepatic vein orifices have resulted in a broadened and ambiguous definition. Membranous obstruction of the inferior vena cava has been regarded by many as a congenital vascular malformation, but its relation to the classical BCS has remained obscure. With modern imaging and recent histological study of new cases, membranous obstruction of the IVC is now considered to be a sequela to thrombosis. How to classify various forms of occlusion and stenosis of the IVC and hepatic vein ostia is a major challenge. In this review, we emphasize that primary hepatic vein thrombosis (classical Budd-Chiari) and an obliterative disease predominantly affecting the hepatic portion of the IVC, both of which account for most patients with venous outflow block, are clinically quite different. In the West, the former is more common than the latter, which constitutes the vast majority of cases of outflow block in developing countries such as Nepal, South Africa, China, and India. The latter is frequently complicated by hepatocellular carcinoma (HCC), and primary hepatic vein thrombosis is not. The major cause of thrombosis is a hypercoagulable state in hepatic vein thrombosis, but more of the latter cases are idiopathic. The clinical presentation of the latter is milder, and onset is frequently inapparent, whereas the former is more severe, sometimes causing acute hepatic failure. Markedly enlarged subcutaneous veins over the body trunk characterize the latter. We propose that these two disorders be clinically distinguished with a suggested term "obliterative hepato-cavopathy" for the latter against classical BCS.

混合型 (Mixed type) クリオグロブリン血症 (クリオと略) がC型肝炎ウイルス (HCV) 感染と密接に関係していることが最近明らかになった. また維持透析患者中のHCV感染率が極めて高いことはよく知られている. そこで我々は透析患者中のクリオの頻度, C型肝炎感染との関係ならびに臨床意義について検討した.三愛記念病院で1997年4月現在透析中の患者531名の血清についてクリオを調べ, 対照として千葉大学第1内科の外来で経過観察中の慢性C型肝炎患者242名, および健康成人183名について血清のクリオを調べた. その結果, HCV感染の慢性透析患者170名中30.6%, 慢性C型肝炎患者中29.8%, HCV感染のない透析患者中10.8%, および健康成人中0%にクリオが証明された. 過去6か月以内に透析に入った腎不全患者30名中4名がHCV抗体陽性, 中1名がクリオ陽性, 26名はHCV抗体陰性, 中4名 (15%) がクリオ陽性であった. クリオ陽性患者は陰性患者にくらべて平均午齢は若かった. なお生成するクリオ沈澱量は透析患者では対照にくらべ, また他の報告の量より遥かに低かった. 輸血歴, 透析期間とクリオとの間には相関は無かった. クリオ陽性患者には皮膚のかゆみの訴えが多かった. HCV抗体陽性患者につき肝機能, HCVウイルス量を検討したが, クリオ陽性患者と陰性患者間に差は無かった. 維持透析患者は非透析患者にくらべHCV感染に起因するクリオ発現率は低く, クリオの生成能は低く, クリオに起因する臨床症状は著しくなく, クリオが肝疾患を悪化させるという所見は得られなかった. 透析患者の中のかなりの数の者は透析前よりクリオをもっており, またクリオを有する患者は若い年齢で透析に入るように思われる.

Pedunculated hepatocellular carcinoma (HCC) or extrahepatic growth of HC C is an uncommon but not rare pathological form, but its genesis is unknown. Right-sided adrenal metastases of HCC that were abutting on or about to fuse with the right hepatic lobe were resected in three patients. The masses seemed to have originated in the para-adrenal tissue, leaving the adrenal gland intact. They were partially supplied by the hepatic artery as well as by the suprarenal artery. Four cases of autopsied pedunculated HCC of the right lobe were also studied. The mass was protruding caudad from the noncancerous parenchyma of the right lobe. Postmortem angiography carried out on one liver showed that only a small portion of the mass toward the liver was supplied from the hepatic artery. These observations suggest that some, perhaps most, of the right-sided pedunculated HCCs represent fusion of the right lobe and para-adrenal or adrenal metastatic HCC. This phenomenon may be explained by possible transport of cancer cells toward the right adrenal gland through the so-called adrenohepatic fusion, a relatively common anatomical change in advanced age.

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.

Most patients infected with hepatitis C virus (HCV) develop chronic hepatitis. Unfortunately, the pathological evolution of this disease over time is not completely understood. We studied 70 HCV-positive patients, from whom 2 to 10 liver biopsy specimens (mean, 3.9) had been obtained during an interval of 1 to 26 years (mean, 8.8 years). Each biopsy specimen was evaluated independently by four pathologists who each provided a numerical score for the grade of portal/periportal necroinflammation (0-4), grade of lobular necroinflammation (0-4), their sum (final grade), and the stage of fibrosis (1-4). The scores were correlated with progression of disease, if any, and transition to cirrhosis. During follow-up, 35 patients (50%) developed cirrhosis. Cirrhosis developed in all patients with a high final grade (> or = 5) of necroinflammation on initial biopsy who were followed for 10 years and in 96% of patients with an intermediate final grade (3.5-4.9) who were followed for 17 years. Only 30.4% of patients with low final grade (< or = 3.4) on initial biopsy developed cirrhosis after 13 years. All patients with evidence of septal fibrosis with incomplete nodularity (stage 3.0-3.4) in the initial biopsy progressed to unequivocal cirrhosis by 10 years. The rate of progression to cirrhosis was accelerated in patients whose initial biopsies showed high-grade and -stage lesions. This study demonstrates the importance of grading and staging liver biopsy lesions in chronic hepatitis C, particularly for patients with high-grade necroinflammation, septal fibrosis, and regions of modularity on initial biopsy who are at high risk of developing advanced cirrhosis in the ensuing decade.

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.

Background/Aims: A problem in pharmacotherapy for bleeding varices in portal hypertension is non-responders. The aim of this study was to elucidate the features of hemodynamic response to vasopressin in the gastroesophageal collateral vein in patients with esophageal varices. Methods: Flow velocity in the portal and the collateral left gastric vein was measured with an echo-Doppler flowmeter before and during infusion of vasopressin, 0.2 U/min, in 41 patients with cirrhois and esophageal varices. Results: The decrease in flow velocity in the left gastric vein with vasopressin (–29±25%) was significantly smaller than that in the portal vein (–56±20%). There was no or only minimal change in flow velocity in the left gastric vein in 39% of the patients, especially in those with large-size varices. In 28 patients examined by portal catheterization, changes in flow velocity in the left gastric vein were correlated with portal pressure, and portal pressure in non-responders was significantly higher than that in responders (non-responders: 363±49, responders: 312±41 mmH 2 O, p Conclusions: It was concluded that hepatofugal blood flow in the gastroesophageal collateral is not readily reduced by vasopression. However, as the study was performed in a stable condition without variceal bleeding, whether these hemodynamic features will apply during acute variceal bleeding in patients who are known to have a poor hemodynamic response to vasopressin remains to be elucidated.

Background & Aims: It has been reported that patients with chronic renal failure have low serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels as a result of vitamin B 6 deficiency. Chronic hepatitis C is common among patients undergoing hemodialysis, and low aminotransferase levels cause diagnostic problems. The aim of this study was to determine the cause of hypoaminotransferasemia. Methods: Serum levels of vitamin B 6 and its coenzyme were reassessed in relation to AST and ALT levels in patients undergoing long-term hemodialysis using high-performance liquid chromatography. Results: The mean (±SD) serum AST and ALT levels in 304 patients negative for hepatitis B surface antigen and anti-hepatitis C virus were 9.2 ± 2.4 and 7.4 ± 1.7 IU/L, respectively. In 556 normal adults, they were 22.7 ± 5.4 and 18.0 ± 4.0 IU/L, respectively ( P 6 and pyridoxal-5′-phosphate levels in patients undergoing dialysis were not reduced compared with the control, although occasionally patients had low levels. The AST and ALT assay reagents in Japan do not contain added pyridoxal-5′-phosphate; addition of pyridoxal-5′-phosphate (0.1 mmol/L) to the reagent significantly increased measurements to similar extents in both groups. Conclusions: Serum AST and ALT levels in patients undergoing dialysis are very low, but they are not a result of vitamin B 6 deficiency. The upper normal limits of AST and ALT levels in patients undergoing dialysis should be reduced considerably, and these levels should be interpreted with caution in the diagnosis of liver disease.

The Japanese Ministry of Health and Welfare Research Committee on Aberrant Portal Blood Flow carried out an epidemiological survey and clinical study on Budd-Chiari syndrome in 1990. In the primary survey for determining the prevalence of the disease, a questionnaire was sent to all major hospitals throughout Japan and 160 cases seen in 1989 were compiled. More epidemiological details were obtained in 87 of these 160 cases. The number of patients with Budd-Chiari syndrome in this country was estimated to be about 300 (prevalence of 2.4/million) with about 20 new cases occurring every year. In the clinical study, 157 authentic cases of Budd-Chiari syndrome studied in 15 years (1975-89) were analyzed. There were 87 males (average age, 36.4 years) and 70 females (46.5 years), and the average period from the likely onset to the first medical consultation was 6.6 years, suggesting that these patients were mostly chronic cases. The main clinical features were hepatomegaly, leg edema, ascites and venous dilatation over the trunk. Abdominal pain was recorded in only four (2.5%). There were 16 (10.2%) with known identifiable etiologies. Of the patients 93% showed an obstructing lesion of various thickness in the hepatic portion of the inferior vena cava. Only nine (5.7%) had hepatic vein obstruction without caval lesions. Thus, the majority of Budd-Chiari syndrome patients in Japan are idiopathic, having an obstructing lesion in the inferior vena cava. The main causes of 33 deaths (21%) were liver failure, variceal bleeding and hepatocellular carcinoma. Hepatocellular carcinoma occurred in 10 (6.4%) in the 15-year period. However, the incidence of Budd-Chiari syndrome among all cases of hepatocellular carcinoma was less than 1% in the survey made by the Liver Cancer Study Group of Japan.

Little is known about radiological aspects of hepatic artery calcification. For this reason, the sonographic features of calcified hepatic arteries were studied in patients with chronic renal failure who frequently develop tissue calcification due to hyperparathyroidism.Ultrasound was performed in 314 patients on dialysis who underwent examination of the liver, spleen and kidney twice in the past 4 years and were reevaluated with particular attention to acoustic shadowing. Abdominal CT was carried out in 219 of these 314 patients, and ultrasound findings were reevaluated with reference to CT findings.A large acoustic shadow was seen in the hilum that corresponded to the calcified hepatic artery on CT in 8 patients, and in another 9, a similar large shadow was seen in the hilum without CT confirmation. Acoustic shadows of various sizes were definitely or most likely due to arterial calcification within the liver in 36 patients. The strength of shadow depended on the angle at which the ultrasound beam hit the artery. Probable calcification of small arteries accompanying portal veins was seen in 70 patients. These changes are different from those due to pneumobilia and biliary tract diseases.Calcification of the hepatic artery can be identified by its acoustic shadow.

Increased plasma ammonia levels in patients with advanced cirrhosis have been attributed to reduced conversion of enteric ammonia to urea by the diseased liver and to entry of enteric ammonia into systemic circulation by way of portal-systemic shunts. Because single-pass extraction is high for portal venous ammonia, reduction of portal blood supply to hepatocytes may have detrimental effects on the hepatic extraction of ammonia. To assess how the development of intrahepatic portal-systemic shunts alters hepatic ammonia metabolism, we determined portal and hepatic venous ammonia levels along with measurements of intrahepatic portal-systemic shunts using 99mTc-macroaggregated albumin in 46 patients with portal hypertension. Hepatic venous ammonia levels in the groups of patients with idiopathic portal hypertension, Child class A cirrhosis and Child class B or C cirrhosis were 36 +/- 17, 75 +/- 26 and 93 +/- 52 micrograms/dl, respectively, in increasing order, and portal venous ammonia extraction rates as calculated with the equation (portal venous ammonia-hepatic venous ammonia)/portal venous ammonia x 100% were decreased in the same order (77% +/- 14%, 50% +/- 21%, 40% +/- 25%, respectively). Furthermore, we noted a significant negative correlation between the intrahepatic shunt indexes as calculated by counts per minute in lungs/counts per minute in lungs and liver x 100% and the ammonia extraction rates. It was noteworthy that among Child class C patients, the ammonia extraction rates were significantly lower in patients with high intrahepatic shunt indexes than in those with low shunt indexes. These results demonstrate a significant direct relationship between hepatic ammonia extraction rates and intrahepatic shunting in cirrhosis.

We analyzed the growth pattern of tumor masses and the survival of 39 asymptomatic Italian patients with a total of 59 small (≤ 5 cm in diameter) hepatocellular carcinomas arising from cirrhosis. The total length of the observation period ranged from 90 to 962 days, with an average of 364 ± 229 (mean ± S.D.). Doubling time ranged from 27.2 to 605.6 days (mean ± S.D., 204.2 ± 135; median = 171.6 days). Three different growth patterns were recognized: (a) tumors with no or very slow initial growth pattern (doubling time ＞ 200 days), 10 cases (37%); (b) tumors with declining growth rate over time, 9 cases (33.4%); and (c) tumors with almost constant growth rate, 8 cases (29.6%). Using the stepwise discriminant analysis, we found a score based on albumin, alcohol intake, number of nodules, echo pattern and histological type that allowed a correct prediction of short doubling time (≤ 150 days) in 55.6%, medium doubling time (151 to 300 days) in 60% and long doubling time (＞ 300 days) in 100% of cases. The estimated survival rate of the 39 patients, calculated by the Kaplan-Meier method was 81% at 1 yr, 55.7% at 2 yr and 21% at 3 yr. Stepwise discriminant analysis showed that a score based on sex, HBsAg status, alcohol consumption, ascites, γ-glutamyltranspeptidase, prothrombin time, Child-Pugh class and all the sonographicai parameters could predict 2-yr survival in 100% of cases. We conclude that great variability of growth patterns exists among and within small hepatocellular carcinomas. Prediction of subsequent growth rate is unreliable in most cases. The sonographical characteristics, together with the histological features, can, however, help in identifying cases with long doubling time (＞ 300 days). The discriminant analysis on survival of cirrhotic patients with small hepatocellular carcinomas demonstrates that the underlying liver disease plays a key role in the long-term survival probability.

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.

Forty-nine Japanese patients were enrolled in a randomized, placebo-controlled, double-blind trial of alpha-interferon for chronic non-A, non-B hepatitis: 24 patients received 3 million units of recombinant human alpha alpha-interferon (alpha-2a) thrice weekly for eight weeks, and 25 patients received placebo in a similar schedule. The mean serum alanine aminotransferase (ALT) dropped from 155 +/- 91 (SD) to 69 +/- 72 during interferon treatment, but remained unchanged (158 +/- 140 to 147 +/- 130) during placebo treatment (P less than 0.001). Serum ALT level fell to the normal range in 29% of interferon-treated patients, but in only 4% of placebo-treated patients. Pre- and posttreatment liver biopsies were obtained in all but one case. Average histological activity indices (HAI) were markedly improved in the interferon-treated group (9.5 +/- 3.7 to 7.0 +/- 4.3), but were unchanged in the placebo group (8.5 +/- 4.3 to 8.5 +/- 4.9). In addition, we compared the efficacy of interferon treatment between anti-hepatitis C virus (HCV) antibody positive and negative groups. Biochemical and histological improvements were similar and statistically significant in patients with and without antibody to hepatitis C virus. These data indicate that a eight-week course of alpha-interferon induces biochemical and histological improvement in more than half the patients with chronic non-A, non-B hepatitis.

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.