Search

Background & Aims: Hepatitis B virus (HBV) genotypes may be related to severity of liver disease and treatment response. The aims of this nationwide study were to determine the prevalence of HBV genotypes in the United States and the association between HBV genotypes and patient demographics, mode of infection, and clinical status., Methods: A total of 694 consecutive chronic HBV-infected patients seen in 17 U.S. liver centers during a 1-year period were enrolled. Demographic, clinical, and laboratory data were collected. Sera were tested for HBV genotyping, precore, and core promoter variants by line-probe assays., Results: All 7 HBV genotypes (A-G) were found, with genotypes A and C the most common. The prevalence of HBV genotypes was different in different regions of the United States. A strong correlation was found between HBV genotypes and ethnicity. HBV genotype A was prevalent among white and black patients, whereas genotypes B and C were most common among Asian patients. The predominant genotype among patients born in the United States, Europe, the Far East, and Southeast Asia were A, D, C, and B, respectively. Genotypes A and C were associated with a higher prevalence of hepatitis B e antigen. Precore variant was detected in 27% of patients and core promoter variant in 44% of patients., Conclusions: Our study suggests that the epidemiology of HBV infection in the United States may have changed over time as a result of immigration from countries with a high prevalence of HBV infection. HBV genotypes may account for the heterogeneity in disease manifestations among patients with chronic HBV infection.

Background & Aims: Chronic hepatitis B is a leading cause of death worldwide. To identify patients who might require urgent liver transplantation despite antiviral therapy, we investigated the determinants of early mortality in a large cohort of patients with decompensated chronic hepatitis B treated with lamivudine., Methods: One hundred fifty-four North American patients with decompensated chronic hepatitis B received lamivudine for a median of 16 months. Univariate and multivariate Cox regression modeling was used to develop a model of 6-month mortality., Results: A biphasic survival pattern was observed, with most deaths occurring within the first 6 months of treatment (25 of 32, 78%) because of complications of liver failure. The estimated actuarial 3-year survival of patients who survived at least 6 months was 88% on continued treatment. In multivariate modeling, elevated pretreatment serum bilirubin and creatinine levels as well as the presence of detectable hepatitis B virus (HBV) DNA (by the bDNA assay) pretreatment were significantly associated with 6-month mortality. An equation approximating the probability of early mortality was developed from these variables., Conclusions: Our data demonstrate a distinct alteration in the slope of the survival curve after 6 months of lamivudine treatment for decompensated chronic hepatitis B. An equation consisting of 3 widely available pretreatment laboratory parameters was developed that can be used to predict the likelihood of early death in patients receiving lamivudine for decompensated chronic hepatitis B. These observations may help identify patients who can be stabilized with suppressive antiviral therapy vs. those who require urgent liver transplantation.

Acute flares in chronic hepatitis B are common and may be caused by a number of identifiable and potentially treatable factors. The common link for many of these exacerbation episodes is a change in the immunologic response to hepatitis B virus (HBV), and this may have no identifiable cause or be triggered by an increase in viral replication or genotypic change. It is important to keep in mind the clinical situations in which patients are at increased risk of reactivated infection and secondary exacerbations. Reactivation is frequently induced by medical treatments such as cancer chemotherapy, antirejection drugs used in organ transplantation, and corticosteroids. The immunologic flares that often result from sudden withdrawal of these medications can be life-threatening unless recognized and treated promptly with antivirals, and there is increasing experience that preemptive antiviral treatment can diminish their occurrence and improve the outcome. The experience with lamivudine and other nucleoside analogues has increased our understanding of the molecular events behind hepatitis flares that occur when chronic hepatitis B is treated with drugs that potently inhibit HBV DNA polymerase. However, not all flares are explainable by events related to HBV infection alone. Depending on the population studied, as many as 20%-30% of flares may be caused by infection with other hepatotropic viruses, and this situation may inhibit HBV replication. Proper understanding of the etiology and effective treatment of acute flares in chronic hepatitis B requires an appreciation of high-risk clinical situations, assessment of HBV replication status, and testing for other viruses when appropriate.

Background/aims: Interferon treatment causes a sustained loss of virus replication only in a proportion of patients with chronic hepatitis B. This study investigated whether genomic variations in the precore/core gene of hepatitis B virus affect the response to interferon alfa., Methods: The precore/core region was sequenced in 46 serum samples obtained before, during, and after interferon treatment of 12 patients., Results: In 23 samples from 7 responders (group A), there were 24 missense mutations, whereas in 23 samples from 5 patients who did not respond or relapsed after treatment (group B), there were 141 missense mutations (P < 0.001). All group B patients had cirrhosis, but only 2 of 7 patients in group A had cirrhosis (P = 0.026). Substitutions in amino acids 21-27 of the core protein, known to diminish HLA-A2-restricted cytotoxic T-cell function, were found in all nonresponders but in none of the responders. No significant changes occurred in the precore/core region in responders after seroconversion to antibody to hepatitis B e antigen, but multiple variations persisted in group B during treatment and new mutations appeared with the relapse of hepatitis., Conclusions: Specific mutations in the core protein that can interfere with T-cell function occur frequently in patients with advanced chronic hepatitis B and may affect the response to interferon.

Background: Recurrent hepatitis B after liver transplantation may be complicated by fibrosing cholestatic hepatitis. This syndrome is associated with rapid graft failure and is characterized by ballooning degeneration of hepatocytes and abundant viral antigen expression., Methods: To study this disorder further, in situ hybridization studies were performed on 36 liver biopsy specimens from 14 transplanted patients with recurrent hepatitis B and 18 nontransplanted controls with chronic hepatitis B. Biopsy specimens were scored for histological features and intensity of riboprobe hybridization signal to hepatitis B virus (HBV) DNA and RNA., Results: HBV DNA hybridization signals of 2+ to 3+ intensity were observed in 53% of the posttransplant biopsies but none of the nontransplanted samples (P < 0.001). HBV RNA signals of this intensity were found in 42% of the transplant biopsy specimens compared with 17% of the nontransplant specimens (P < 0.07). Features of fibrosing cholestatic hepatitis were noted in 12 biopsies; 11 of these displayed RNA signals of 2+ to 3+ intensity (92%) compared with 4 of 24 (17%) biopsy specimens without this diagnosis (P < 0.001). The level of hepatocyte RNA correlated with the extent of hepatocellular ballooning (P < 0.007)., Conclusions: These data suggest that fibrosing cholestatic hepatitis is associated with enhanced hepatitis B virus transcription and support a cytopathic role for the virus in the development of this syndrome.

Background: Hepatic histological responses described in hepatitis C virus (HCV) infection include bile duct damage, lymphoid follicles and/or aggregates in portal tracts, large- and small-droplet fat, Mallory body-like material in hepatocytes, liver cell dysplasia and multinucleation, and activation of sinusoidal inflammatory cells. The specificity of these lesions for HCV infection is uncertain., Methods: In two multicenter trials of recombinant interferon alfa therapy for chronic hepatitis C and B, the frequency of these eight lesions in pretherapy and posttherapy liver biopsy specimens was examined to determine the set of features, if any, that distinguishes HCV from hepatitis B virus (HBV) infection. The lesions were scored in 317 HCV biopsy specimens and 299 HBV specimens., Results: Stepwise logistic regression determined a set of three features more likely to be seen in HCV than in HBV infection: bile duct damage [odds ratio (OR), 4.7; 95% confidence interval (Cl), 1.8-12.3], lymphoid follicles and/or aggregates (OR, 2.4; 95% Cl, 1.2-4.7), and large-droplet fat (OR, 2.4; 95% Cl, 1.4-4.1). A fourth lesion, Mallory body-like material, was seen only in HCV biopsy specimens (OR, 71.6; 95% Cl, 4.4-996.1)., Conclusions: These four histological lesions are useful pathological parameters in the diagnosis of liver disease caused by HCV.

Thirty-eight patients with chronic active hepatitis type B received antiviral therapy. In one trial, 22 patients were randomized to either no treatment or treatment with a 28-day cycle of adenine arabinoside 5' monophosphate (ARA-AMP); in a second trial, 13 patients were randomized to no treatment or treatment with two 28-day cycles of ARA-AMP separated by a 4-wk rest interval; during a third trial, 11 individuals were treated with 8 wk of prednisone therapy followed by 28 days of ARA-AMP therapy. The response rate (73%) to the regimen with prednisone was significantly greater than that achieved in the first or second trial (0% and 15%, respectively). The data indicate that the combination of short-term prednisone and ARA-AMP therapy may offer more promise for successful treatment of chronic active hepatitis type B than does ARA-AMP alone. Synergism may possibly occur by the combined effects of immune rebound provided by corticosteroid withdrawal and the inhibition of viral proliferation by ARA-AMP.

To determine if the presence of hepatitis B e antigen (HBeAg) and elevated DNA polymerase activity in the serum of chronic HBeAg carriers indicate increased contagiousness in a household setting, the household contacts of 74 carriers were prospectively evaluated for serologic evidence of hepatitis B infection. Thirty of the HBsAg carriers had HBeAg and 44 had anti-HBe. Twenty-eight HBeAg-positive carriers regularly demonstrated elevated DNA polymerase when serially drawn serum samples were analyzed. None of the anti-HBE-positive carriers demonstrated elevation of DNA polymerase activity. Both household contacts of HBeAg-positive and anti-HBe-positive carriers demonstrated serologic evidence of hepatitis B infection (HBsAg, anti-HBs, and anti-HBc). However, infection was significantly more frequent among spouses and sexual partners of carriers who had either HBeAg (P less than 0.001) or elevated DNA polymerase activity (P less than 0.001). Thus, the data indicate that a particular subpopulation of spouses and sexual partners of hepatitis B carriers are at significantly greater risk for acquiring infection.

A patient with pulmonary tuberculosis and a constricting transverse colon lesion on barium enema was found at colonoscopy to have a 1.5 X 3.0 cm ulcer with irregular, edematous borders. Multiple colonoscopic biopsies of the ulcer revealed acid-fast bacilli with absence of granulomas. Previously, the diagnosis of colonic tuberculosis had been thought to require laparotomy for confirmation. The authors now suggest that colonoscopic biopsy may be a desirable alternative in selected cases.

The clinical value of an enzyme-linked immunosorbent assay for the detection of immunoglobulin M (IgM) antibody to hepatitis B core antigen (anti-HBc IgM) was evaluated by testing serum samples from the following groups of patients: (a) 27 individuals who had been diagnosed as having acute hepatitis B virus (HBV) infection, (b) 29 hepatitis B surface antigen (HBsAg) carriers, (c) 6 subjects with acute non-B hepatitis, and (d) 10 HBsAg-negative but anti-HBc-positive subjects who were suspected of being index cases for the intimate transmission of HBV. Whereas 24 of the 27 individuals with presumed acute HBV infection exhibited anti-HBc IgM, only 2 of 29 HBsAg carriers were found to be positive. Hepatitis B surface antigen persisted during an 8-mo observation period in 3 anti-HBc IgM-negative subjects with acute HBsAg-positive hepatitis. Before anti-HBc IgM testing, it was considered that these cases had evolved to the HBsAg carrier state. However, the regular demonstration of anti-HBc IgM in acute type B hepatitis, as well as the failure to detect this antibody in the majority of HBsAg carriers, led to reclassification of these cases as probable instances of acute non-A, non-B or delta-agent hepatitis superimposed on the HBsAg carrier state. Through additional testing, the diagnosis of non-A, non-B (NANB) infection was confirmed in 2 of these cases, and delta-agent infection was identified in the third. None of the non-B hepatitis cases exhibited anti-HBc IgM. However, 5 of the 10 suspected type B index cases were anti-HBc IgM-positive, indicating that they were very recently infected and most likely had infected their cohabiting sexual partners. The results from this study indicate that testing for anti-HBc IgM may improve serodiagnostic accuracy when acute NANB and delta-agent hepatitis occur in previously unrecognized HBsAg carriers. Moreover, it may be a useful test in defining potential high risk sources of exposure to HBV.

Excretory liver function was analyzed in 10 healthy volunteers and 28 subjects with acute or chronic liver injury following intravenous administration of 99mtechnetium p-isopropyl iminodiacetic acid. Hepatobiliary transit of this agent was quantitated at 5-min intervals for a total of 60 min. Indices of total liver activity, liver cell uptake, liver parenchymal clearance, and bile duct clearance of 99mtechnetium p-isopropyl iminodiacetic acid were calculated from time--activity curves over heart, liver, extrahepatic bile ducts, and gallbladder. Seven subjects with acute viral hepatitis, 15 with extrahepatic biliary obstruction, and 6 with intrahepatic cholestasis were evaluated. Compared with healthy volunteers, a significant (p less than 0.0001) reduction in total liver activity and liver parenchymal clearance was demonstrated in all patient groups. Major resolution in all liver-derived indices, particularly total liver activity, occurred during convalescence from hepatitis and after biliary drainage. Nonmeasurable bile duct clearance always indicated a diagnosis of extrahepatic obstruction in cholestatic subjects, and this index normalized in subjects following biliary drainage. Whereas visual assessment of 99mtechnetium p-isopropyl iminodiacetic acid scans provided limited, useful information about the functional status of the liver, quantitative temporal analysis proved to be a much more effective technique.