Drug disposition in patients with HBsAg-positive chronic liver disease

Chronic infection with hepatitis B virus (HBV) results in a spectrum of hepatic abnormalities ranging from minimal liver dysfunction to severe liver failure. These patients provide an opportunity to examine the relationship between the evolution of the liver disease and the ability to metabolize drugs. We have examined hepatic drug disposition in patients with chronic persistent hepatitis, chronic active hepatitis, and cirrhosis due to HBV infection. Four model drugs were used: two low-extraction capacity-limited drugs (antipyrine and aminopyrine) and two high-extraction flow-limited drugs (ICG and lidocaine). The disposition of the four drugs tested was comparable to that of healthy controls in patients with chronic persistent hepatitis, chronic active hepatitis, and mild cirrhosis. In patients with severe cirrhosis (as defined by the presence of ascites, encephalopathy, or large esophageal varices), there was a significant impairment in the aminopyrine breath test (–31%) and in the clearance of antipyrine (–53%), lidocaine (–49%), and ICG (–54%). These results indicate that impairment of drug clearance occurs only late in the evolution of HBV-related chronic liver disease. This is in keeping with the known slow and insidious progression of the disease.Supported by grants from the Medical Research Council of Canada, The Canadian Liver Foundation and the Fonds de Recherche en Santé du Québec     

HLA-DR antigens in HBsAg-positive chronic active liver disease with and without associated delta infection

The A, B, C and DR locus specificities of the human leukocyte antigens system (HLA) were determined in 45 delta-positive and 44 delta-negative Italian patients, all with HBsAg-positive chronic active liver disease; controls were 526 healthy Italian blood donors matched for age, sex and geographical origin. HLA-A, B, C gene frequencies were not significantly changed. In delta-positive patients, the frequencies of the DR locus specificities were: DR2, 37.8%; DR3, 20%; DR4, 11.1%. In the delta-negative patients, the frequencies were: DR2, 13.6%; DR3, 36.4%; DR4, 0%. Control frequencies were: DR2, 19.4%; DR3, 17.1%; DR4, 18.5%. The corrected p values of the differences between controls and delta-positive patients were: DR2, pc = 0.046; DR3, pc = NS (not significant); DR4, pc = NS. The corrected p values of the differences between controls and delta-negative patients were: DR2, pc = NS; DR3, pc = 0.03; DR4, pc = 0.002. These findings show that: (a) DR3, a genetic marker of autoimmunity, might assist the establishment of chronic HBsAg liver disease in the absence of delta superinfection; (b) DR2 is linked with failure to clear the delta agent, and (c) DR4 may protect from virus B persistence. Identification of adventitious factors such as delta may help uncover a subgroup of HBsAg carriers who are genetically predisposed to develop chronic liver disease.     

Prevalence of anti-HCV among Chinese patients with acute and chronic liver disease

To assess whether the hepatitis C virus plays an important role in Chinese patients with acute and chronic liver disease, antibodies to HCV (anti-HCV) were measured by enzyme immunoassay in 67 patients with type A and B acute viral hepatitis, 165 patients with non-A, non-B (NANB) hepatitis, 438 patients with chronic hepatitis, 200 patients with postnecrotic liver cirrhosis, 72 patients with alcoholic liver disease, 55 patients with non-alcoholic fatty liver, 24 patients with toxic and drug-induced hepatitis, and 20 patients with other chronic liver diseases. Anti-HCV was not detected in sera from patients with type A and B acute viral hepatitis, toxic and drug-induced hepatitis, primary biliary cirrhosis, Wilson's disease, or lupoid hepatitis. The anti-HCV prevalence was found to be highest in patients with NANB hepatitis (59% in sporadic and 73.2% in transfusion-associated), 16.4% in non-alcoholic fatty liver, 5.6% in alcoholic liver disease, 6.8% in chronic hepatitis, and 16% in postnecrotic liver cirrhosis. In patients with chronic hepatitis, the anti-HCV prevalence was significantly higher in HBsAg-negative (15/34, 44.1%) than in HBsAg-positive cases (15/404, 3.7%; P less than 0.0001). The results indicate that HCV is a major agent of NANB hepatitis and plays an important role in HBsAg-negative chronic liver disease in Taiwan.     

Prevalence of antibodies to hepatitis C virus among Saudi patients with chronic liver diseases.

The prevalence of antibodies against hepatitis C virus (anti-HCV) was determined in 55 patients with chronic liver diseases including liver cirrhosis (42 patients), liver cirrhosis and hepatocellular carcinoma (8 patients), and chronic active hepatitis (4 patients). A total of 63.6% of these patients were positive for anti-HCV, a significantly higher prevalence than the rate of 3.9% observed in 488 asymptomatic volunteers. Of the 42 patients with liver cirrhosis 16 (38.1%) had positive anti-HCV without any markers of hepatitis B virus (HBV), while 12 (28.6%) had markers of neither HCV nor HBV infection. Our findings suggest that HCV infection may play a significant role in the pathogenesis of chronic liver disease in Saudi Arabia, which is an area of endemic HBV infection. Screening for anti HCV should be considered mandatory in patients with chronic liver disease (CLD) especially where the etiology appears obscure.     

Prevalence of hepatitis C virus antibodies in chronic liver disease and hepatocellular carcinoma patients in India

The prevalence of antibodies to hepatitis C virus (HCV) was investigated in 129 patients with chronic liver disease (85 with chronic active hepatitis and 44 with cirrhosis) and 53 patients with hepatocellular carcinoma. The commercially available second generation anti-HCV enzyme immunoassay kit was used. Antibodies to hepatitis C virus were detected in 16.2% of the patients with chronic liver disease and in 15.1% with hepatocellular carcinoma. Of the HCV positive patients in all groups 51.7% were positive for hepatitis B virus (HBV) markers indicating present or past infection. Prevalence of HBV markers in all the three groups (CAH, cirrhosis and HCC) was higher as compared with anti-HCV prevalence. These results suggest that HCV infection may not be a major cause of chronic liver disease and hepatocellular carcinoma in India and indicate the presence of other aetiological agents.     

Immunosuppressive treatment of HBsAg-positive chronic liver disease: significance of HBeAg

In a randomized clinical trial in 148 patients of azathioprine vs. prednisone treatment of chronic aggressive hepatitis and/or nonalcoholic cirrhosis, 20 were HBsAg positive on entry. In this subgroup sequential serum samples were investigated for HBs and HBe markers by radioimmunoassay. At the time of evaluation, 13 patients were still alive; their median age was 53 years (25 to 72) and median follow-up time was 46 months (23 to 82). Of 16 patients with cirrhosis, 5 of 7 with persistence of HBeAg died, compared with 2 of 9 with anti-HBe. In three patients with anti-HBe, HBeAg reappeared several times with simultaneous rise in transaminase values. The overall survival was 65% after 5 years. The prognosis of HBsAg-positive chronic liver disease seemed to depend on the presence of cirrhosis and HBeAg rather than on improvement in biochemical activity during immunosuppressive treatment.     

Prevalence of hepatitis A virus antibodies in patients with chronic liver diseases.

OBJECTIVE: The age of persons with hepatitis A virus (HAV) infection in the general population has risen; these persons are at increased risk of clinically severe disease, especially patients with chronic liver disease. The aim of the present study was to analyze the prevalence of total antibodies against HAV in patients with chronic liver disease. METHODS: In a prospective study carried out between September 1998 and June 1999, 180 patients seen in the chronic liver disease outpatient department were studied. The prevalence of total anti-HAV antibodies was determined by age group, etiology and degree of histological damage, and according to the antecedents of risk for parenteral infection. A nonconditional logistic regression model was fitted with anti-HAV positivity as the dependent variable. RESULTS: Mean age was 44.1 years, with an anti-HAV prevalence of 77.2% (varying from 42.9% in the 21-25-year-old group to more than 83% in patients > 56-years old). Differences across groups regarding other categories (histological damage, etiology and history of parenteral or drug use) were not statistically significant, but the probability of anti-HAV positivity increased with age and a history of drug addiction. CONCLUSIONS: The prevalence of total anti-HAV antibodies is high among patients with chronic liver disease. We therefore recommend this test before vaccination against HAV, until current recommendations on universal childhood vaccination are implemented, in order to prevent hepatitis A epidemics in the general population.     

Prevalence of anti-HCV antibodies in patients with chronic liver disease and its relationship to HBV and HDV infections

Summary The prevalence of anti-HCV, anti-HDV and of HBV markers has been investigated in a series of 209 consecutive patients (age 18–74 years) with chronic liver disease. Among 155 HBsAg negative patients (53 chronic hepatitis cases and 102 cirrhosis cases), anti-HCV were found in 69% of the cases. 67% of the 155 patients also carried anti-HBc, with no difference between patients positive or negative for anti-HCV. Among the 54 HBsAg positive patients, 10 (18.5%) also had anti-HCV, 22 (40.7%) were anti-HDV positive and 12 (22.2%) had serum HBV-DNA. One patient had concomitant anti-HDV and anti-HCV and another presented anti-HCV and serum HBV-DNA. 21/54 patients had liver cirrhosis on presentation and among these 17 (81%) were anti-HCV and/or anti-HDV positive. On the whole, 123/209 patients had liver cirrhosis on presentation and in 107 of them HCV infection may have played a role.

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Prävalenz von anti-HCV-Antikörpern bei Patienten mit chronischer Leberkrankheit und ihre Beziehung zu Infektionen mit HBV und HDV

Zusammenfassung Bei 209 nacheinander eingewiesenen Patienten mit chronischer Leberkrankheit (Alter 18 bis 74 Jahre) wurde die Prävalenz von anti-HCV, anti-HDV und HBV-Markern bestimmt. Anti-HCV fand sich in 69% von 155 HBsAg-negativen Patienten (55 mit chronischer Lebererkrankung und 102 mit Zirrhose). 67% dieser 155 Patienten wiesen auch anti-Hbc im Serum auf, wobei sich zwischen anti-HCV positiven und-negativen Patienten kein Unterschied feststellen ließ. Bei den 54 HBsAg-positiven Patienten fanden sich zehn (18,5%) die auch anti-HCV-positiv waren, 22 (40,7%) waren auch anti-HDV-positiv und bei 12 (22,2%) konnte im Serum HBV-DNA nachgewiesen werden. Bei einem Patienten fand sich gleichzeitig anti-HDV und anti-HCV, bei einem anderen anti-HCV und HBV-DNA im Serum. Bei 21 von 54 Patienten wurde bei Aufnahme eine Leberzirrhose festgestellt, davon waren 17 (81%) anti-HCV und/oder anti-HDV-positiv. In der Gesamtgruppe von 209 Patienten hatten 123 bei Aufnahme eine Leberzirrhose und in 107 dieser Fälle hatte HCV möglicherweise eine pathogenetische Bedeutung.

     

Toxic neuropathy after adenine arabinoside treatment in chronic HBsAg-positive liver disease.

A 62-year-old woman with hepatitis-B-surface-antigen-positive hepatic cirrhosis presented with weakness and paresthesias over the distal part of the limbs in the course of adenine arabinoside 5'-monophosphate (ARA-AMP) treatment, and recovered spontaneously after several weeks of drug withdrawal. Electrophysiological and histological studies demonstrated axonal neuropathy. Although the patient received a relatively low total dose (120 mg/kg), her age and advanced liver disease may have played a role in the ARA-AMP neurotoxicity.     

Prevalence of restless legs syndrome in Japanese patients with chronic liver disease

Aim: Sleep disturbance is a major complication in patients with chronic liver disease, but causes are unclear. The aim of this study was to clarify the prevalence of restless legs syndrome (RLS) in Japanese chronic liver disease patients and investigate the influence on sleep and quality of life. Methods: The study included 149 consecutive outpatients with chronic liver disease at Nagasaki University Hospital between September 2008 and March 2010. The presence of RLS was evaluated by a written survey using the questionnaire for the epidemiological surveillance of the international RLS research group in 2003. In addition, 89 cases, including all RLS patients, were evaluated for sleep quality and health-related quality of life. Sleep quality was evaluated by using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI), and health-related quality of life was evaluated by the Japanese SF-36 Health Survey. Result: Twenty-five of the 149 patients (16.8%) fulfilled the diagnostic criteria for RLS. The median global PSQI score of the RLS group was significantly higher than the non-RLS group (9 vs 5, P < 0.01). The number of poor sleepers (global PSQI score, >5) in the RLS group was significantly higher than in the non-RLS group (P < 0.05). In SF-36, the mental component summary score of the RLS group was 43.8 ± 10.8, which was significantly lower than the non-RSL group (49.8 ± 10.5; P < 0.05). Conclusion: This is the first report that clarifies the prevalence of RLS in Japanese chronic liver disease patients. RLS worsens quality of sleep and life in chronic liver disease patients.     

Diminished responsiveness of homosexual men to antiviral therapy for HBsAg-positive chronic liver disease

To identify factors predicting response to antiviral therapy, we reviewed the clinical features of 38 male hepatitis B surface antigen (HBsAg) carriers who received adenine arabinoside or lymphoblastoid interferon. All patients were followed for one year or longer. Response was defined as loss of hepatitis B e antigen, hepatitis B virus DNA and DNA polymerase from the serum. Only 2 of 19 (11%) homosexual men responded, compared with 10 of 19 (53%) heterosexual men (P less than 0.02). Both responders in the homosexual group had received lymphoblastoid interferon. None of the 13 homosexual men, but 8 of 16 heterosexual men, responded to adenine arabinoside or its monophosphate (P less than 0.01). Responders to antiviral therapy had higher (P less than 0.05) serum levels of aspartate aminotransferase (median 115, range 51-344) than did non-responders (median 83, range 32-181). The decreased responsiveness of homosexual men to antiviral therapy may be a result of more severe immunologic abnormalities in homosexual than in heterosexual men with HBsAg-positive chronic liver disease.     

IgA-抗组织转谷氨酰胺酶抗体在慢性肝病患者中的表达

目的了解IgA-抗组织转谷氨酰胺酶（tTG）抗体在慢性肝病患者中的表达.方法以ELISA法检测26例慢性肝病患者（16例慢性肝炎,10例肝硬化）血清IgA-抗tTG抗体水平,结果＞10 AU为阳性.结果26例慢性肝病患者中有4例IgA-抗tTG抗体阳性（15.4%）,且该4例患者均为乙型肝炎肝硬化病例.Child-Pugh B级患者的抗体阳性水平略高于Child-Pugh A级.结论慢性肝病患者中存在较高的IgA-抗tTG抗体表达水平,且与门脉高压密切相关.     

Role of hepatitis C infection in chronic liver disease in Egypt

Hepatitis C virus (HCV) is considered the most common etiology of chronic liver disease (CLD) in Egypt, where prevalence of antibodies to HCV (anti-HCV) is approximately 10-fold greater than in the United States and Europe. Reported are results that show the role of HCV in both overt and occult CLD, the risk factors for CLD and for HCV infection, and the relative importance of chronic HCV, hepatitis B, or both in causing hepatic morbidity. Case patients included 237 new outpatients at the National Liver Institute. Controls comprised 212 sex- and age-matched neighbors without liver disease. Case patients were more likely than controls to report a history of blood transfusions, schistosomiasis, or parenteral therapy for schistosomiasis; to have anti-HCV, HCV RNA, hepatitis B surface antigen, and serum alanine aminotransferase (ALT) elevations; and to have abdominal ultrasound findings of cirrhosis, portal hypertension, and splenomegaly. Anti-HCV-positive case patients were more likely than anti-HCV-negative patients to be male, older, and farmers: to have received a blood transfusion or parenteral therapy for schistosomiasis; to have ALT elevations; and to have ultrasound findings of cirrhosis, portal hypertension, and spleen enlargement. Anti-HCV-positive controls were more likely than anti-HCV-negative controls to have received parenteral therapy for schistosomiasis. These data support the belief that HCV is the predominant cause of CLD in Egypt and suggest there is a large underlying reservoir of HCV-caused liver disease.     

Detection of hepatitis delta virus RNA in chronic liver disease

A series of 120 patients with chronic delta hepatitis virus (HDV) were investigated using a newly developed assay for the detection of serum delta RNA and this marker was correlated with other markers of HDV infection. The assay was shown to be both specific and sensitive and provides a direct non-invasive measurement of HDV infectivity. Serum HDV RNA was detected in 51.2% of all patients and in about 64% of those who were liver HDV antigen positive. Its presence was particularly associated with the early stages of the disease where it was found in 83% of cases with chronic active hepatitis (CAH) and progressively less common in CAH associated with cirrhosis and in inactive cirrhosis. The presence of both HBeAg (and HBV DNA) and high levels of HDV RNA in the sera of 5 of the patients analysed, clearly demonstrates simultaneous replication of both HBV and HDV. The serum HDV RNA 'slot blot' assay described in this study should prove invaluable in elucidating further the natural history of delta hepatitis and in monitoring antiviral therapy.