Hepatitis B virus antigens in liver tissue in hepatocellular carcinoma and advanced chronic liver disease,relationship to liver cell dysplasia

ABSTRACT— Hepatitis B surface (HBs) and core (HBc) antigens (Ag) were studied in liver tissue in HBsAg seropositive patients with chronic liver disease complicated (n=32) and not complicated (n=36) by hepatocellular carcinoma. Both groups were matched by age, sex and underlying disease. There was no qualitative and quantitative difference in tissue HBsAg between the two groups. However, HBcAg was significantly less in quantity in hepatocytes of patients with hepatocellular carcinoma compared to chronic liver disease without cancer. Serum hepatitis B e antigen tested by radioimmunoassay was also less frequently positive in patients with hepatocellular carcinoma. These findings seem to suggest that hepatitis B virus replication becomes less active in the process of hepatocarcinogenesis. The relationship between intrahepatic hepatitis B antigens and liver cell dysplasia was also studied. In hepatocellular carcinoma, tissue hepatitis B antigens often coexisted in the same liver having liver cell dysplasia, but no such association was observed in chronic liver disease without cancer. However, no indication was obtained that the dysplastic cells harbor HBsAg more frequently than non-dysplastic cells.     

Status of hepatitis B virus DNA in alcoholic liver disease: a study of a large urban population in the United States

Two reports have shown hepatitis B virus DNA in serum and liver tissue in alcoholic liver disease with negative serum HBsAg, suggesting a pathogenetic role for hepatitis B virus. We studied hepatitis B virus DNA in serum and liver from three groups of alcoholic patients; (Group 1) 50 patients without liver disease, (Group 2) 108 patients with alcoholic liver disease and (Group 3) five patients with alcoholic liver disease and hepatocellular carcinoma. Serum was tested for HBsAg, anti-hepatitis B core and anti-hepatitis B surface by radioimmunoassay and hepatitis B virus DNA by direct spot hybridization. Liver tissue from Groups 2 and 3 (113 patients) was examined by Southern blot analysis using 32P-labeled hepatitis B virus DNA clone from pBR322. Controls were 21 patients with chronic hepatitis B virus (14 patients with chronic active hepatitis, seven patients with cirrhosis and hepatocellular carcinoma). Serum and tissue were analyzed for hepatitis B virus DNA. Hepatitis B virus DNA was not detected in either serum or liver tissue in any of the 163 patients (Groups 1 to 3). In contrast, among the controls, hepatitis B virus DNA was present in the serum of 15 of the 21. Tissue DNA in those with chronic active hepatitis revealed 10/14 with free hepatitis B virus DNA, two with integrated sequences and two with no viral sequences. All seven patients with hepatocellular carcinoma had integrated viral DNA sequences in the tumor tissues. From these results, it appears that hepatitis B virus does not play a role in the pathogenesis of alcoholic liver disease.     

Biologic significance of the detection of HBsAg and HBcAg in liver and tumor from 204 HBsAg-positive patients with primary hepatocellular carcinoma

Hepatitis B virus surface and core antigens (HBsAg, HBcAg) were examined in the resected primary hepatocellular carcinoma from 204 patients who had HBsAg in serum. Ninety patients had small (less than 5 cm) and 114 had large hepatocellular carcinoma (greater than 5 cm). HBsAg was detected in hepatocellular carcinoma in 65 cases (32%) and HBcAg in 30 cases (14.7%); hepatitis B virus antigens were more frequently detected in small (HBsAg in 42.2% and HBcAg in 20%) than in large hepatocellular carcinoma (HBsAg 23.7% and HBcAg 10.5%). These results suggest that replicative forms of hepatitis B virus DNA may exist in hepatocellular carcinoma more frequently than previously believed and that the malignant hepatocytes can support hepatitis B virus replication. A lymphocytic infiltration in hepatocellular carcinoma was more often observed in hepatocellular carcinoma expressing HBsAg (71%) or HBcAg (63%) than in hepatocellular carcinoma with no detectable HBsAg (26%) or HBcAg (37%), p less than 0.01. The reaction was mild in the majority (85%) of the cases. These findings suggest that hepatitis B virus antigen expression in hepatocellular carcinoma can provoke a local immune response. The most striking finding was that patients with hepatitis B virus antigens in small hepatocellular carcinoma had a 5-year survival rate (13%) lower than that (50%) of the antigen-negative patients (p less than 0.05). In contrast, patients with a marked local immune response in hepatocellular carcinoma, regardless of the viral antigen status, had significantly better 5-year survival rates (43%) than those with no or a mild lymphocytic reaction (18%). These findings indicate that a marked immune response in hepatocellular carcinoma is a favorable prognostic sign.(ABSTRACT TRUNCATED AT 250 WORDS)     

Expression of hepatitis B surface antigen subtypes in liver of patients with hepatocellular carcinoma; comparison of subtypes in serum and liver.

To clarify the discrepancy in hepatitis B surface antigen (HBsAg) subtypes present in the serum and liver, as well as among hepatocytes, liver specimens which were resected from 37 HBsAg-positive patients with hepatocellular carcinoma (HCC) were examined. We evaluated HBsAg and the subtypic determinants of HBsAg and hepatitis B core antigen (HBcAg) using the peroxidase-antiperoxidase (PAP) staining method. Hepatitis B antigens were more frequently detected in small tumors (HBsAg in 67%. HBcAg in 40%) than in large ones (HBsAg in 36%, HBcAg in 14%). The prevalence of each subtypic determinant in the HBsAg positive non-tumorous vs. tumorous areas was 100% vs. 67% in a, 100% vs. 57% in d, 100% vs. not tested in y, 100% vs. 53% in r and 25% vs. 0% in w (a, d, y, r and w represent subtypic determinants). There was virtually no difference in a set of subtypic determinants between the serum and liver. However, there were some variations in a set of subtypic determinants among the hepatocytes. On the other hand, liver tissue of compound subtype adyr in serum contained both cells with a,d,r and with a,y,r as well as a few cells with a,d,y,r. These findings suggest that HBV genomes in hepatocytes of type B chronic liver disease may differ genetically among cells even in the same liver tissue.     

Clinicopathological features of hepatocellular carcinoma--comparison of hepatitis B seropositive and seronegative patients

Clinicopathological features were studied in 113 non-alcoholic patients with histology-proven hepatocellular carcinoma, of whom 35 were positive for hepatis B virus surface antigen (HBsAg), 23 were negative for all seromarkers for hepatitis B virus, and 55 were negative for HBsAg, but positive for anti-HBs and/or anti-core antibody (anti-HBc) with low titers. It was found that the age of the patient at the time of diagnosis was significantly lower in HBsAg cases than in the other two groups. Serum alpha-fetoprotein levels were often normal or below 100 ng/ml in the seronegative cases, and its measurement less frequently served as a diagnostic clue. Otherwise, clinically there was no difference between the three groups except for more frequent liver disease within the second degree of kinship in the HBsAg patients. Histopathological study of the livers showed that there were more expanding type hepatocellular carcinomas in the seronegative cases as compared with the HBsAg positive cases. There was no autoimmune chronic liver disease in these patients. These observations and data seem to indicate that there are certain differences between HBsAg positive and seronegative hepatocellular carcinomas. Since most patients had progressive liver disease, it is likely that many of these seronegative cases had chronic non-A, non-B viral disease, which is very common in Japan. It may be inferred further that non-A, non-B hepatitis virus is less carcinogenic as compared with hepatitis B virus.     

Occult hepatitis B virus infection in patients with chronic liver disease due to hepatitis C virus and hepatocellular carcinoma in Brazil

BACKGROUND: The prevalence and consequences of occult HBV infection in patients with chronic liver disease by HCV remain unknown. AIMS: To evaluate the prevalence of occult HBV infection in a population of HCV-infected patients with hepatocellular carcinoma. METHODS: The serum samples were tested for HBV DNA by nested PCR and liver tissue analysis was carried out using the immunohistochemical technique of 66 HBsAg-negative patients: 26 patients with chronic hepatitis by HCV (group 1), 20 with hepatocellular carcinoma related to chronic infection by HCV (group 2) and 20 with negative viral markers for hepatitis B and C (control group). RESULTS: Occult HBV infection was diagnosed in the liver tissue of 9/46 (19.5%) HCV-infected patients. Prevalence of occult B infection was evaluated in the HCV-infected patients with and without hepatocellular carcinoma, and there were seven (77.7%) of whom from group 2, conferring a 35% prevalence of this group. No serum sample was positive for HBV DNA in the three groups. CONCLUSION: Occult infection B is frequently detected in liver tissue of HCV-infected patients, especially in cases of hepatocellular carcinoma. However large studies are needed to confirm that co-infection could determine a worse progress of chronic liver disease in this population.     

Incidence of hepatitis B virus infection in alcoholic liver disease,HBsAg negative chronic active liver disease and primary liver cell cancer in Britain

ABSTRACT— A study has been undertaken to determine the incidence of serum markers of hepatitis B virus (HBV) infection in British caucasian patients with biopsy-proven alcoholic liver disease (n = 56), HBsAg negative chronic active liver disease (CALD) (n = 47) and primary liver cell cancer (PLCC) (n = 27), compared to a hospital control population without liver disease (n = 112). No increased incidence of any serum marker of HBV infection was found in alcoholic liver disease or in ‘lupoid’ CALD (antinuclear factor positive 1:40 and/or smooth muscle antibody positive > 1:40). In contrast, the incidence of antibody to HB surface and core antigens was significantly increased (p<0.05) in patients with cryptogenic CALD. The incidence of hepatitis B surface antigen and antibodies to HB core and ‘e’ antigens was significantly increased (p<0.005) in PLCC.     

Expression of hepatitis B surface antigen subtypes in liver of patients with hepatocellular carcinoma; comparison of subtypes in serum and liver

ABSTRACT— To clarify the discrepancy in hepatitis B surface antigen (HBsAg) subtypes present in the serum and liver, as well as among hepatocytes, liver specimens which were resected from 37 HBsAg-positive patients with hepatocellular carcinoma (HCC) were examined. We evaluated HBsAg and the subtypic determinants of HBsAg and hepatitis B core antigen (HBcAg) using the peroxidase-antiperoxidase (PAP) staining method. Hepatitis B antigens were more frequently detected in small tumors (HBsAg in 67%, HBcAg in 40%) than in large ones (HBsAg in 36%, HBcAg in 14%). The prevalence of each subtypic determinant in the HBsAg positive non-tumorous vs. tumorous areas was 100% vs. 67% in a, 100% vs. 57% in d, 100% vs. not tested in y, 100% vs. 53% in r and 25% vs. 0% in w (a, d, y, r and w represent subtypic determinants). There was virtually no difference in a set of subtypic determinants between the serum and liver. However, there were some variations in a set of subtypic determinants among the hepatocytes. On the other hand, liver tissue of compound subtype adyr in serum contained both cells with a,d,r and with a,y,r as well as a few cells with a,d,y,r. These findings suggest that HBV genomes in hepatocytes of type B chronic liver disease may differ genetically among cells even in the same liver tissue.     

Relationship of pre-S encoded antigens in liver and clinical manifestations of chronic hepatitis B infection

Pre-S1 and pre-S2 encoded antigens of hepatitis B virus were localized in liver tissue using monoclonal antibodies. They were found to be exclusively expressed in the cytoplasm of liver cells. Cell bound pre-S1 encoded protein was often detected in patients with chronic liver disease and viremia. Only a small number of the HBsAg positive cells also contained pre-S1 antigen. There was no correlation with nuclear HBcAg. Livers of non-viremic HBsAg carriers contained many HBsAg expressing liver cells, that were frequently also positive for pre-S2 encoded protein but contained no detectable pre-S1 encoded protein at all. It remains open whether cell bound pre-S2 containing proteins of middle size have a significance for pathogenesis, as they are present in individuals with chronic liver disease as well as in healthy HBsAG carriers, and may be associated with both increased and normal liver enzymes. Cell bound pre-S1 antigen with viremia may, however, be involved in the maintenance of viremia and liver disease.     

Hepatitis C virus infection in chronic liver disease in Bombay.

To find out the prevalence of antibody of hepatitis C virus (anti-HCV) in patients with chronic liver disease in Bombay, sera from 126 patients (93 men, 33 women; aged 9-70 years, mean 39.7) with chronic liver disease (cirrhosis 103, cirrhosis with hepatocellular carcinoma 3, chronic active hepatitis 20) were tested for HBsAg and anti-HCV antibody. HBsAg positive sera were tested for anti-delta antibody and IgM anti-HBc. All the tests were carried out by ELISA. Of 126 patients, 51 (40.5%) were HBsAg positive, 49 (38.8%) alcoholic and 21 (16.6%) anti-HCV positive. The prevalence of anti-HCV in HBsAg positive, alcoholic and cryptogenic (HBV negative and no alcohol) liver disease patients was 13.7%, 14.7% and 20.5% respectively. Of 21 anti-HCV antibody positive patients, 8 (38%) had received blood transfusions previously. HCV is present in 15-20% of patients with chronic liver disease in Bombay.     

Specificities of serum alpha-fetoprotein in HBsAg+ and HBsAg- patients in the diagnosis of hepatocellular carcinoma.

Serum alpha-fetoprotein level is often elevated in patients with chronic liver disease and patients with hepatocellular carcinoma. One of the most difficult problems frequently encountered in practice is differentiating hepatocellular carcinoma from chronic liver disease. This study investigated the specificity and predictive value positive of serum alpha-fetoprotein at various levels in the diagnosis of hepatocellular carcinoma, using 54 patients with histologically proven hepatocellular carcinoma and 200 patients with chronic liver disease (40 patients with chronic active hepatitis and 160 patients with cirrhosis) as nontumor controls. Among 254 patients, 170 (66.9%) were HBsAg+. A wide range of overlap (from 0 to 6,400 ng/ml) in the distribution of serum alpha-fetoprotein levels between hepatocellular carcinoma and chronic liver disease patients was observed mainly among HBsAg+ patients. In contrast, the overlapping range of serum alpha-fetoprotein levels between HBsAg- patients with hepatocellular carcinoma and chronic liver disease was remarkably narrow (from 0 to 200 ng/ml). Therefore the specificity and predictive value positive of alpha-fetoprotein at a given level were significantly lower in HBsAg+ than in HBsAg- patients, especially when alpha-fetoprotein was between 25 and 200 ng/ml. The specificities of alpha-fetoprotein at 200 ng/ml and 400 ng/ml in HBsAg+ patients were 79.8% and 91.5%, respectively, whereas these specificities were both 100% in HBsAg- patients. The predictive values positive at 200 ng/ml and 400 ng/ml in HBsAg+ patients were 53.6% and 72.5%, respectively, in contrast to 100% at both levels in HBsAg- patients. The serum alpha-fetoprotein level, which showed a predictive value positive of 95% in HBsAg+ hepatocellular carcinoma patients, was 3,200 ng/ml, whereas that in HBsAg- hepatocellular carcinoma patients, was 200 ng/ml. We conclude that serum HBsAg status should be considered when serum alpha-fetoprotein is measured as an independent test to diagnose hepatocellular carcinoma, and suggest that regular serum alpha-fetoprotein determination may be more useful in HBsAg- patients with chronic liver disease for the early diagnosis of hepatocellular carcinoma than in HBsAg+ patients.     

Clearance of HBsAg in seven patients with chronic hepatitis B.

The natural history of chronic hepatitis B patients who spontaneously cleared serum HBsAg was investigated. A total of 351 patients with chronic hepatitis B were observed in our hospital for at least 3 yr. Seven of these patients became HBsAg negative during the follow-up period. HBsAg disappeared within 6 mo (range = 11 to 169 days, mean = 70 days) after acute elevation of ALT. ALT levels as high as 500 IU were found in three patients, whereas such elevation was not demonstrated in the other four patients. After the disappearance of HBsAg, ALT levels returned to normal in all patients. With one exception, all patients seroconverted to antibody to HBsAg; however, hepatitis B virus DNA remained detectable in serum using the polymerase chain reaction in five patients. The titer of percent inhibition of antibody to HBcAg gradually decreased to less than 70% when a 1:200 dilution of the serum of six patients was used. Four of the patients had active liver disease develop: two had chronic active hepatitis and two had cirrhosis. Three of these four patients subsequently had hepatocellular carcinoma develop. These findings suggest that patients may suffer complications of chronic hepatitis even after normalization of transaminase activities and after the clearance of HBsAg. Thus hepatitis B virus should be considered as a possible factor associated with hepatocellular carcinoma even in the absence of HBsAg, particularly if serum hepatitis B virus DNA persists.     

Prevalence of hepatitis C antibody in patients with chronic liver disease and hepatocellular carcinoma in Korea

Summary. To investigate the contribution of hepatitis C virus (HCV) to chronic liver disease and hepatocellular carcinoma (HCC) in Korea, antibodies to HCV (anti-HCV) were tested by enzyme immunoassay in 1759 patients with chronic liver disease and HCC, and in 808 healthy adults. The prevalence of anti-HCV was 1.6% in 808 controls. Anti-HCV was present in 32 (7.7%) of 418 hepatitis B surface antigen (HBsAg)-positive and 128 (53.1%) of 241 HBsAg-negative patients with chronic hepatitis, 16 (6.0%) of 265 HBsAg-positive and 90 (30.5%) of 295 HBsAg-negative patients with liver cirrhosis, and 16 (4.8%) of 330 HBsAg-positive and 61 (29.0%) of 210 HBsAg-negative patients with HCC. Antibodies to hepatitis B core antigen (anti-HBc) were present in 80–88% of patients who were seropositive for anti-HCV and seronegative for HBsAg. Among the sera from 114 patients with HBsAg-negative and anti-HCV-positive chronic liver diseases, HBV DNA and HCV RNA were detected by polymerase chain reaction (PCR) in 54 (47.4%) and 61 (53.3%), respectively. Both HBV DNA and HCV RNA were detected in 4 (4.4%) samples. The mean age of the patients with both HBsAg and anti-HCV was not different from that of patients who were seropositive for HBsAg alone. These findings indicate that current and/or past HBV infection is still the main cause of chronic liver disease in Korea. Although multivariate analysis showed that anti-HCV is a risk factor for chronic hepatitis, cirrhosis of the liver and HCC, PCR data for HBV DNA and HCV RNA indicate that HCV infection plays only a minor role in HBsAg-positive as well as in HBsAg-negative liver disease and does not accelerate the development of HCC in HBV carriers.     

Hepatitis Be antigen and antibody in chronic liver diseases and hepatocellular carcinoma

The presence of hepatitis Be antigen (HBeAg) and antibody (anti-HBe) was investigated by immunodiffusion in 144 patients with chronic liver disease, and 129 with hepatocellular carcinoma (HCC). Most of the patients were HBsAg-positive. In 62 patients with chronic active viral hepatitis B, 17 (27%) were positive for HBeAg and 25 (40%) for anti-HBe. HBeAg and anti-HBe were not related to the degree of histological activity or serum alanine aminotransferase activities, but were related more frequently to higher HBsAg titer and younger age; whereas anti-HBe generally correlated in an opposite manner. Two patients seroconverted from HBeAg to anti-HBe in 13 and 20 months respectively. HBs antigenemia was not eliminated in either HBeAg or anti-HBe positive patients. The prolonged interval in seroconversion and an age-related declining frequency of HBeAg, accompanied by a reciprocal increase in anti-HBe in chronic infection, suggest anti-HBe as a chronologic indicator in HBs antigenemia in chronic HBsAg carriage. In HCC, regardless of coexisting cirrhosis, a predominant frequency of anti-HBe (62%) was found as in cirrhosis (54%), suggesting longstanding HBsAg carriage in these patients.     

Hepatitis B viral DNA in infected human liver and in hepatocellular carcinoma

Blot-hybridization analysis of DNA forms from hepatitis B virus (HBV) in the liver of chronic carriers of hepatitis B surface antigen (HBsAg) has revealed the presence of both relaxed and closed circular viral DNA and of novel viral DNA-RNA hybrid molecules in patients with complete virions, with the hepatitis B e antigen (HBeAg), or with both, in serum. One carrier of HBsAg with no detectable virus or HBeAg in his serum had small amounts of free viral DNA in his liver sample, a finding suggesting the potential for production of complete virus; another such carrier had only HBV DNA integrated in cellular DNA and, thus, may have lost the ability to replicate virus. The liver sample of one of eight patients with antibodies to HBsAg in his serum, but no HBsAg, contained small amounts of free viral DNA. Analysis of tissue from hepatocellular carcinoma revealed evidence for integrated viral DNA sequences in multiple-cellular DNA sites, and stoichiometric analysis suggested that the tumors were monoclonal in origin. These results demonstrate the presence of a new form of HBV in infected human liver and reveal that serological profiles are not always a reliable guide in determining the presence of potentially infectious forms of HBV in the liver.     

Detection, by three techniques, of hepatitis B surface antigen (HBsAg) and determination of HBsAg and anti-HBs titres in patients with chronic liver disease.

The sensitivities of three technqiues used to detect serum hepatitis B surface antigen (HBsAg) were compared in 411 patients with various types of chronic liver disease. Counterimmunoelectrophoresis proved an unreliable test. Two haemagglutination technqiues were slightly less sensitive than radioimmunoassay but were more rapidly performed. Less sensitive techniques were particularly unreliable in active liver disease where HBsAg titres were low. HBsAg was detected in patients with chronic persistent hepatitis, alcoholic liver disease, chronic active liver disease with or without cirrhosis, and primary liver cell carcinoma. Forty-six of the 68 (68%) HBsAg positive subjects were males coming from outside the United Kingdom. The HBsAg titres in 13 subjects with chronic persistent hepatitis were significantly higher (P less than 0-001) than those in 43 subjects with chronic active liver disease. Corticosteroid therapy did not alter the HBsAg titre significantly. None of the 28 HBsAg positive subjects studied serially for up to two years cleared HBsAg from the serum. Anti-HBs was examined by passive haemagglutination and found in 35 subjects, 26 of whom had no evidence of liver disease, 80% came from abroad. Anti-HBs was believed to be of epidemiological rather than of pathological importance.     

High-level expression of hepatitis B viral antigens in fibrosing cholestatic hepatitis.

The expression of hepatitis B viral antigens was quantified in liver tissue from four transplant recipients with fibrosing cholestatic hepatitis (FCH) and compared with five other transplant recipients who did not develop this syndrome and 30 patients with chronic hepatitis B virus (HBV) infection. As measured by radioimmunoassays, the liver tissue from patients with FCH had significantly greater amounts of both hepatitis B surface antigen (HBsAg) and nucleocapsid antigens than to transplant patients without this syndrome (P less than 0.01) or patients with chronic HBV infection (P less than 0.001). Intrahepatic expression of pre-S1/pre-S2 in FCH was also extensive with a distribution parallel to that of HBsAg. High-level expression of intrahepatic HBsAg and hepatitis B core antigen in the explanted liver was associated with subsequent development of FCH in the liver graft, suggesting that viral/host factors may also be important. This pattern of intrahepatic hepatitis viral antigen expression, by analogy with Chisari's transgenic mice model and Roingeard's HBV-transfected HepG2 cell model, may be the cause of direct hepatocytopathic injury in this condition.     

Clinical features and etiology of hepatocellular carcinoma arising in patients with membranous obstruction of the inferior vena cava: in reference to hepatitis viral infection

BACKGROUND AND AIMS: Budd-Chiari syndrome (BCS) comprises hepatic vein thrombosis and inferior vena cava (IVC) obstruction known as membranous obstruction of the IVC (MOVC). The latter is frequently complicated by hepatocellular carcinoma (HCC).The etiology of MOVC-associated HCC in relation to hepatitis viral infection is not known. In this study, we investigated the clinical features and etiology of HCC in MOVC. METHODS: Membranous obstruction of IVC and HCC were diagnosed and studied by using imaging techniques. Sera from patients with MOVC, complicated by HCC, were examined for hepatitis viral antigens and antibodies (hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs), antibody to hepatitis B core antigen (anti-HBc) and third generation antibody to hepatitis C virus (anti-HCV)) and for hepatitis viral nucleic acids (hepatitis B virus (HBV)-DNA, hepatitis C virus (HCV)-RNA, hepatitis G virus (HGV)-RNA and TT virus DNA). RESULTS: We studied 12 patients with BCS who were seen between April 1968 and February 1999. All of them had MOVC. Hepatocellular carcinoma developed in three (25%) of them. There were no obvious differences in the clinical features and imaging findings concerning MOVC between patients with and without HCC. Hepatocellular carcinoma in these three patients showed no clear trend in clinical features and imaging findings. Of the hepatitis viral markers examined, HBsAg, anti-HBc and HBV-DNA were positive in only one of three patients with HCC and all of the viral markers were negative in the other two patients. CONCLUSIONS: Chronic congestion in the liver, caused by an outflow block of hepatic veins and subsequent histopathologic change, must have led to HCC in two patients without any hepatitis viral markers. Patients with MOVC should be followed closely as a high-risk group for HCC.     

Hepatocellular carcinoma without cirrhosis in Japanese patients

Hepatocellular carcinoma is closely associated with cirrhosis, but it also develops, although much less frequently, in a noncirrhotic liver. It is suspected, without supporting evidence, that hepatocellular carcinoma has a different etiology when associated and not associated with chronic liver disease. In this study, 66 noncirrhotic cases found among 618 autopsies for hepatocellular carcinoma (10.7%) were analyzed retrospectively. The noncirrhotic liver was histologically unremarkable in 3 cases and in the histologically evaluable 56 cases it had fibrosis of varying degrees or mild cellular infiltrate, or both, in the portal tract. There was one liver that had portal venous changes compatible with those in idiopathic portal hypertension (Banti's syndrome). In these noncirrhotic livers, the parenchymal cells were generally unremarkable except for liver cell dysplasia that was seen in 26.8%. Serum hepatitis B surface antigen was positive in only 7.4% in contrast to 26.6% in cirrhotic cases. Three histologically unremarkable cases had no clinical or histologic evidence of chronic liver disease; two involved painter-plasterers and one a farmer. The liver weight in these cases ranged from 4400 to 6180 g. In contrast, the average liver weight in cirrhotic cases was 1998 g. Noncirrhotic patients when compared with cirrhotic patients had better liver function tests and much less frequent varices. It was concluded that approximately 11% of hepatocellular carcinoma cases in Japan are noncirrhotic, the majority having some histologic changes in the portal tracts suggestive of past or ongoing chronic liver disease, and that there are rare cases that have no histologic changes in the liver.     

Thrombin and plasmin generation in patients with liver disease

Patients with liver disease frequently have multiple hemostatic abnormalities. Coagulation and fibrinolytic factors and inhibitors may decrease as the result of impaired synthesis and/or enhanced catabolism. In order to assess the actual degree of activation of coagulation and fibrinolytic systems in liver disease, plasma levels of thrombin-antithrombin III complex (TAT) and plasmin-alpha 2-antiplasmin complex (PAP) were measured together with cross-linked fibrin derivatives (XDP), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor (PAI-1) in 31 patients with liver disease (five patients with acute hepatitis, seven with chronic hepatitis, nine with liver cirrhosis, and ten with hepatocellular carcinoma). Mean plasma levels of TAT (mean 4.2 +/- SD 4.0 micrograms/L), PAP (0.7 +/- 0.7 mg/L), and XDP (374 +/- 518 micrograms/L) were significantly elevated in patients with liver disease as compared with normal subjects (TAT of 1.7 +/- 0.3 micrograms/L, PAP of 0.2 +/- 0.1 mg/L, and XDP of 30 +/- 14 micrograms/L; P less than 0.005). Plasma concentrations of t-PA and PAI-1 antigens were also elevated. When plotted by the disease categories, the magnitude of elevations of these parameters was variable among subgroups. Patients with acute hepatitis had considerably higher TAT levels. The mean PAP values were relatively high in chronic hepatitis and hepatocellular carcinoma, in which an elevation of the t-PA/PAI-1 ratio was observed. Although clearance of TAT and PAP should be evaluated in the future, these findings suggest that excessive amounts of thrombin and plasmin are actually generated in patients with liver disease.