Different natural courses of chronic hepatitis B with genotypes B and C after the fourth decade of life.

AIM: To investigate the different impact of genotypes B and C on the development of liver cirrhosis (LC) among different age groups of patients with chronic hepatitis B (CH-B). METHODS: We examined the outcome of 121 patients with CH-B, divided by age and genotype. Univariate analyses were used to compare different groups. The Cox proportional hazard model was employed to evaluate factors affecting the development of LC. RESULTS: In patients < 30 years old, there were no significant predictors for development of LC. However, in patients > or = 30 years old, genotype C was the only significant predictor. In the genotype C group, 8 of 12 patients who progressed to LC were 30-49 years old at initial diagnosis of chronic hepatitis (7 patients were positive for HBeAg). In the genotype B group, 4 of 8 patients who developed LC were > or = 50 years old at initial diagnosis and were HBeAg-negative. CONCLUSION: The rate of development of LC was comparable in patients infected with genotypes B and C when CH-B occurred at < 30 years old. However, CH-B patients infected with genotype C showed poor prognosis if they were 30-49 years old and were positive for HBeAg. Age-specific natural course of CH-B should be considered when patients with CH-B are treated with antiviral drugs.

Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease.

AIM: Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), and progresses to the end stage of liver disease. Biochemical markers of liver fibrosis are strongly associated with the degree of histological liver fibrosis in patients with chronic liver disease. However, data are few on the usefulness of markers in NAFLD patients. The aim of this study was to identify better noninvasive predictors of hepatic fibrosis, with special focus on markers of liver fibrosis, type VI collagen 7S domain and hyaluronic acid. METHODS: One hundred and twelve patients with histologically proven NAFLD were studied. RESULTS: The histological stage of NAFLD correlated with several clinical and biochemical variables, the extent of hepatic fibrosis and the markers of liver fibrosis were relatively strong associated. The best cutoff values to detect NASH were assessed by using receiver operating characteristic analysis: type VI collagen 7S domain > or =5.0 ng/mL, hyaluronic acid > or =43 ng/mL. Both markers had a high positive predictive value: type VI collagen 7S domain, 86% and hyaluronic acid, 92%. Diagnostic accuracies of these markers were evaluated to detect severe fibrosis. Both markers showed high negative predictive values: type VI collagen 7S domain (> or =5.0 ng/mL), 84% and hyaluronic acid (> or =50 ng/mL), 78%, and were significantly and independently associated with the presence of NASH or severe fibrosis by logistic regression analysis. CONCLUSION: Both markers of liver fibrosis are useful in discriminating NASH from fatty liver alone or patients with severe fibrosis from patients with non-severe fibrosis.

A rare association of primary biliary cirrhosis and pernicious anemia.

Primary biliary cirrhosis is often associated with autoimmune diseases. However, an association between primary biliary cirrhosis and pernicious anemia has rarely been reported. We report a patient with primary biliary cirrhosis associated with pernicious anemia and autoimmune gastritis. The patient was a 64-year-old Japanese woman who had been diagnosed as having primary biliary cirrhosis 5 years previously. She was readmitted with jaundice and macrocytic anemia. The diagnosis of pernicious anemia was confirmed by the low level of serum vitamin B12 and the presence of anti-parietal cell antibody and anti-intrinsic factor antibody. Pernicious anemia should be regarded as a possible complication of primary biliary cirrhosis.

Monitoring low level hepatitis B virus by a newly developed sensitive test.

We have recently developed a sensitive quantitative test for hepatitis B virus (HBV) DNA using a real-time polymerase chain reaction (HBV RTD DIRECT), which can detect HBV DNA levels as low as 10(0.7) copies/ml. The aim of this study was to explore the significance of viremia changes below the detection limit of the other currently developed sensitive assays, transcription-mediated amplification and hybridization protection assay (TMA-HPA) and Amplicor HBV Monitor. The subjects consisted of 11 patients with chronic liver disease type B who showed undetectable test results of HBV DNA by TMA-HPA or Amplicor HBV Monitor during the observation period. A total of 150 serial serum samples were examined for viremia level by HBV RTD DIRECT: 139 were positive and 11 were negative. HBV RTD DIRECT could detect viremia in 72 of 78 serum samples negative for HBV DNA by TMA-HPA, or in 38 of 43 serum samples negative for HBV DNA by Amplicor HBV Monitor. The HBV DNA level was gradually increased from its lowest level before the spontaneous reactivation of hepatitis or the emergence of YMDD mutant during lamivudine treatment. However, such a phenomenon was not revealed by either TMA-HPA or the Amplicor HBV Monitor test.

Epidemiology of primary biliary cirrhosis among women with elevated gamma-glutamyl transpeptidase levels in Okinawa, Japan.

We investigated the conditions among women who had an asymptomatic increase in serum gamma-glutamyl transpeptidase (gamma-GTP) levels, and the prevalence of primary biliary cirrhosis (PBC), in the general population. Among 4048 women who received their annual health check-up, 241 showed an elevated gamma-GTP level and were invited to participate in this study. Of the 241 women, 122 participated and were examined thoroughly, including for antimitochondrial antibody (AMA) and by using liver biopsy to make a clinical diagnosis. Six (4.9%) of the 122 women were AMA positive: five were diagnosed and one was suspected of having PBC. Another two women had the criteria of PBC despite being AMA negative. PBC was detected in 5.7% (95% confidence interval (CI), 1.6-9.9%) of asymptomatic women with raised gamma-GTP levels who were 6.0% of all 4048 women examined. The estimated prevalence of PBC in our area was 3400 per million women mainly over 40 years and 840 per million in the whole population. In 44% of women, the cause of chronic gamma-GTP elevation was unknown; they usually showed mild and non-specific histological change differing from their liver biochemical test results.

Metabolic syndrome is directly associated with gamma glutamyl transpeptidase elevation in Japanese women.

AIM: This study aimed to determine whether metabolic syndrome is directly or indirectly, through fatty liver, associated with elevated gamma-glutamyl transpeptidase (GGT) levels in Japanese women. METHODS: From 4 366 women who received their annual health check-up, 4 211 women were selected for analysis. All 4 211 women were negative for both hepatitis B surface antigen and antibody to hepatitis C virus. Clinical and biochemical variables were examined by using univariate and multivariate analysis. RESULTS: A raised GGT level (>68 IU/L) was seen in 258 (6.1%) of the 4 211 women. In univariate analysis, all variables examined (age, body mass index, blood pressure, hemoglobin concentration, fasting blood glucose, glycosylated hemoglobin A1c, cholesterol, triglyceride, and uric acid) were associated with the elevated GGT level, whereas in multivariate analysis, four variables (age > or =50 yr, hemoglobin > or =14 g/dL, triglyceride > or =150 mg/dL, and presence of diabetes) were significantly and independently associated with raised GGT level. Clinical variables predicting the presence of ultrasonographic evidence of fatty liver were also examined by multivariate analysis; four variables were associated with the presence of fatty liver: BMI > or =25 kg/m(2), hemoglobin > or =14 g/dL, triglyceride > or =150 mg/dL, and uric acid > or =7 mg/dL. There was no significant association between the raised GGT level and the presence of fatty liver. Hypertriglyceridemia was significantly and independently associated with both the raised GGT level and the presence of fatty liver. CONCLUSION: Metabolic syndrome seemed to be directly, not indirectly through fatty liver, associated with the raised GGT level in Japanese women.

Alanine aminotransferase (ALT) levels in a normal population and interferon therapy in chronic hepatitis C patients with normal ALT.

BACKGROUND/AIMS: The aims of this study were to determine the distribution of serum alanine aminotransferase levels in a normal population and to clarify whether interferon treatment is justified in HCV-infected patients with persistently normal alanine aminotransferase levels. METHODOLOGY: The distribution of alanine aminotransferase levels was examined among 949 normal subjects who were negative for hepatitis viruses, denied regular alcohol use. Nineteen patients with chronic hepatitis C and persistently normal alanine aminotransferase levels were treated with alpha interferon (six or ten million units thrice weekly for six months). RESULTS: Peaks of alanine aminotransferase distribution among the normal subjects were seen at 16-20 IU/L and 11-15 IU/L in males and females, respectively. Fourteen of the 19 patients who received interferon treatment had favorable factors of response to interferon (eight with low pretreatment virus load, four with HCV genotype 2 and two with both). A sustained virological response was achieved in eight (57%) of 14, and alanine aminotransferase levels decreased significantly to within the normal range after interferon treatment in six of eight. CONCLUSIONS: Patients with chronic hepatitis C and persistently normal alanine aminotransferase levels should be treated with high doses of interferon if they have favorable factors of response to interferon treatment.

Clinical characteristics of patients with cryptogenic liver cirrhosis in Okinawa, Japan.

BACKGROUND/AIMS: The aims of the present study were to determine the prevalence of patients with cryptogenic liver cirrhosis, and to clarify the clinical characteristics of these patients, with special focus on obesity and type 2 diabetes mellitus. METHODOLOGY: For the case-control study, we selected age- and sex-matched control patients with cirrhosis of known etiology. RESULTS: Of 404 patients with liver cirrhosis, 40 (9.9%) were diagnosed as having cryptogenic cirrhosis. Of these 40 patients, 29 (73%) were female. The mean age was 66.1 +/- 8.9 (range 40-87 years old), and was significantly higher than that of either virus, or alcohol-related liver cirrhosis patients. Both obesity and type 2 diabetes mellitus were more common in patients with cryptogenic cirrhosis (53% and 40%, respectively) compared with the case-controls (20%, 18%, respectively). CONCLUSIONS: Cryptogenic liver cirrhosis accounted for approximately 10% of liver cirrhosis, and was associated with both obesity and type 2 diabetes mellitus. Nonalcoholic steatohepatitis sequelae may be the most important etiological factor in patients with cryptogenic liver cirrhosis in Okinawa, Japan, where virus-etiology is more predominant in liver cirrhosis compared with Western countries.

Difference in prognosis between patients infected with hepatitis B virus with genotype B and those with genotype C in the Okinawa Islands: a prospective study.

The factors contributing to the prognosis of hepatitis B virus (HBV)- related chronic liver disease were assessed prospectively in 72 patients with chronic hepatitis B confirmed clinically and pathologically. A comparative study was undertaken between patients infected with genotype B and those with genotype C. During the follow-up period, 13 (81.3%) of 16 patients with genotype B who were initially hepatitis B e antigen (HBeAg) positive became HBeAg negative and 14 (51.9%) of 27 with genotype C became HBeAg negative. HBeAg had been cleared in 8 (61.5%) of 13 patients with genotype B within the first 2 years of the follow-up, but in only one (7.1%) of 14 with genotype C (P < 0.05). Four (11.4%) of 35 patients with genotype B had progressed to cirrhosis, whereas, 12 (32.4%) of 37 patients with genotype C progressed to cirrhosis, including two patients with hepatocellular carcinoma. Multivariate analysis showed that difference in HBV genotype influenced significantly either the clearance of HBeAg or the development of cirrhosis. In conclusion, HBeAg was cleared from sera more frequently and earlier in patients with genotype B compared with those with genotype C, and development of cirrhosis occurred less frequently in patients with genotype B compared with those with genotype C. Thus, HBV genotypes may influence the prognosis of HBV-related chronic liver disease.

Preponderance of hepatitis B virus genotype B contributes to a better prognosis of chronic HBV infection in Okinawa, Japan.

The present study was designed to examine the distribution of hepatitis B virus (HBV) genotypes among patients at various stages of chronic liver disease type B in Okinawa Prefecture, Japan, where the prevalence of hepatitis B surface antigen is the highest in Japan despite the lowest mortality rate from primary liver cancer. Serum samples from 227 HBV carriers were determined for HBV genotype by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Five of 227 sera were negative for HBV DNA by nested PCR and were excluded from the genotype analysis. Genotype B was predominant in asymptomatic carriers (45/67, 67%), whereas genotype C was predominant in chronic liver disease: 49% (50/103) in patients with chronic hepatitis, 63% (20/32) in patients with cirrhosis, and 60% (12/20) in patients with hepatocellular carcinoma. The distribution of genotype B decreased with increasing liver disease severity. However, this tendency was seen among patients aged less than 50 years old, whereas the prevalence of genotype B was similar among carriers with various liver diseases who were older than age 50. In conclusion, HBV genotype B was prevalent and less frequent among patients with advanced liver disease, particularly in patients aged less than 50 years. These findings suggest that the preponderance of genotype B is responsible for the low mortality rate of primary liver cancer associated with HBV seen in Okinawa Prefecture, despite having the highest HBV carrier rate in Japanese.