Fibrosing cholestatic hepatitis in a transplant recipient with hepatitis B virus precore mutant

A patient with hepatitis B virus (HBV) precore mutant (seropositive for hepatitis B surface antigen [HBsAg], anti-hepatitis B e antigen [HBeAg], and HBV DNA) who underwent orthotopic liver transplantation for end-stage liver disease is described. Sequencing of the HBV precore region of the pretransplant serum sample confirmed the presence of the precore stop-codon mutant (G-->A mutation in codon 1896) only. The patient received HBV immunoglobulin prophylaxis for 6 months but HBV recurred thereafter with a mild hepatitic flare, and he remained seropositive for HBsAg, anti-HBe, and HBV DNA. The initial hepatitic illness resolved in 3 months. The patient remained well for another 16 months before presenting with fibrosing cholestatic hepatitis (FCH). During his entire initial hepatitic flare, quiescent period, and final FCH phase, he remained seropositive for HBsAg, anti-HBe, and HBV DNA. Moreover, sequencing of the serum HBV DNA in final FCH phase showed the presence of the identical HBV precore mutant. Immunohistochemical staining showed extensive expression of HBsAg/pre-S1, pre-S2, and hepatitis B core antigen, but HBeAg was scarcely detectable. This case illustrates that (1) recurrence of HBV precore mutant infection can occur in liver; (2) it can give rise to FCH; and (3) hepatic accumulation of HBeAg is not essential for the development of FCH.     

Effect of human leukocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis

Four patients with chronic hepatitis B infection and chronic active hepatitis were treated with human leukocyte interferon. Three of them had consistently elevated levels of circulating Dane-particle markers, including Dane-particle-associated DNA polymerase activity, hepatitis B core antigen and Dane-particle-associated DNA. Parenteral interferon administration at a dosage between 6.0 X 10(3) and 17 X 10(4) U per kilogram per day was associated with a rapid and reproducible fall in all Dane-particle markers in the three patients. The suppressive effect was transient when the interferon was given for 10 days or less but appeared to be more permanent when administration was prolonged for a month or more. In addition, long-term interferon therapy was associated with a marked fall in hepatitis B surface antigen in two of three patients and a disappearance of e antigen in two of two patients. Interferon may be useful in limiting carrier infectivity or eradicating chronic infection.     

Long-term outcome of chronic hepatitis B in heart transplant recipients

BACKGROUND: Hepatitis B is common in organ transplant recipients. It adversely affects the prognosis after liver and kidney transplantation. The long-term outcome of hepatitis B virus (HBV) infection in heart transplant recipients has not been studied before. METHODS: Between July 1984 and June 1993, 436 patients underwent heart transplantation at the Hannover Medical School. A total of 345 patients survived for more than 1 year and were included in this study. Of these, 74 were found to be hepatitis B surface antigen (HBsAg)-positive during follow-up; 69 acquired HBV infection at known time points 25+/-17 months after transplantation, and 5 had already been infected before heart transplantation. Mean follow-up was 105 (range, 25-157) months. RESULTS: Patients developed significant alanine aminotransferase (ALT) elevations after HBV infection, which peaked and then remained above normal. Preinfection levels of ALT were 15.4+/-6.4 U/L, peak values were 71.2+/-47.2 U/L, and mean values after HBV infection were 28.9+/-14.6 U/L. All patients remained HBsAg-positive. Thirteen patients (18%) became HBeAg-negative during follow-up, 10 with negative quantitative HBV-DNA assays. Mean HBV-DNA levels in the remaining patients were 292+/-267 (range, 0-978) pg/ml. Thirty-four patients died during follow-up (45.9%) compared to 78/271 (28.8%) in the control group (P=0.008). Six of the HBsAg-positive patients (17.1%) died of liver failure 6.2-10.6 years (mean, 8.6) after transplantation. Histology of 25 HBsAg-positive patients more than 5 years after infection revealed severe fibrosis or cirrhosis in 14 (56%), mild fibrosis in 9 (36%), and chronic hepatitis without fibroproliferation in 2 (8%). CONCLUSIONS: Hepatitis B infection after heart transplantation leads to chronic liver disease in the majority of the affected patients, causing cirrhosis in more than 55% within the first decade after transplantation. Liver failure is a common cause of death in the infected group of patients. Active HBV vaccination is mandatory for all organ transplant candidates, in particular before heart transplantation.     

Alpha interferon therapy in children with chronic active hepatitis B and delta virus infection

Two children with chronic hepatitis B virus and delta virus infection were treated with alpha interferon. Both tolerated the therapy without complications, and one demonstrated clearance of the infection and development of immunity.     

Chronic hepatitis B virus infection in south Auckland

AIM: Previous studies have identified high prevalence rates of hepatitis B infection in New Zealand Maori, Pacific Island and Asian populations within New Zealand. However, the true impact of chronic hepatitis B virus (HBV) infection on health resources has not been evaluated. This study was designed to determine the incidence of serious sequelae of chronic HBV infection in a high prevalence community. METHODS: All patients treated for HBV-related conditions at Middlemore Hospital from January 1995 to January 1997 were identified through discharge coding and laboratory records. Demographic characteristics and laboratory results, including liver function tests, hepatitis serology and liver histology were recorded. Number of admissions, average length of stay and survival were calculated from Casemix data. RESULTS: During the study period, 215 patients were referred for management of hepatitis B infection, of whom 179 had persistently elevated aminotransferases. Forty six percent of patients were hepatitis B 'e' antigen (HBeAg) negative, and 21% of these had delta co-infection (all Samoan). Liver biopsy was performed in 87 patients with raised aminotransferases. No features of chronic hepatitis were found in 5%, mild chronic hepatitis in 30%, moderate to severe chronic hepatitis in 44% and cirrhosis in 22%. Fifty five patients were admitted to hospital during the two year period with an HBV-related diagnosis, with an average length of stay of 12.2 days compared to 4.9 days for all other medical and surgical admissions during this period (p < 0.001). Twenty eight of the 55 subsequently died, 20 from hepatocellular carcinoma. CONCLUSIONS: Chronic hepatitis B infection is associated with significant morbidity and mortality in Maori, Pacific Islanders and Asians living in South Auckland. Screening of these high risk populations with vaccination of noninfected individuals should reduce the incidence of these serious sequelae and eventually lead to eradication of HBV.     

Cutaneous vasculitis after hepatitis B vaccination with recombinant vaccine in a renal transplant patient

BACKGROUND: Cutaneous vasculitis is a known complication of hepatitis B vaccination with recombinant vaccine. CASE REPORT: A renal transplant recipient with the HLD-DR4 susceptibility antigen developed histologically proven cutaneous vasculitis with serum antibodies after vaccination with anti-hepatitis B recombinant vaccine. The skin manifestation, evolved favorably after discontinuation of the immunization and bed rest. DISCUSSION: This case suggests that anti-hepatitis B vaccination with recombinant vaccine can produce cutaneous vasculitis in renal transplant recipients. The vaccination strategy in this population should be revisited.     

Variations of hepatitis B virus core gene sequence in Western patients with chronic hepatitis B virus infection

Heterogeneity of the hepatitis B virus (HBV) core gene has been reported to be associated with the presence of active liver disease in Japanese patients with chronic HBV infection. This study evaluated the significance of HBV core gene heterogeneity in Western patients with chronic HBV infection. The hepatitis B virus precore/core gene from 45 patients (inactive:active liver disease ratio 16:29) was amplified from serum by polymerase chain reaction (PCR). Gel electrophoresis was employed to detect large deletions. The PCR amplicons from 13 patients (all HBV serotype adw but with a different spectrum of liver disease) were cloned and sequenced. Hepatitis B surface antigen (HBsAg) serotypes were tested by enzyme immunoassay (EIA) and hepatic expression of HBV antigens was assessed by immunohistochemistry. The HBV core gene was amplified from the serum of all 45 patients. Three patients had mixed infection with both precore mutant and wild-type HBV and all three had active liver disease. No patient had a large deletion of the HBV core gene. Hepatitis B virus core gene sequence variations were more common in the midcore region and there was no difference in the number of silent and missense substitutions between those with inactive and active liver disease. There was no correlation between the nucleotide or encoded amino acid substitutions and the clinical and biochemical parameters, including the subsequent response to interferon-alpha therapy (n = 37) or hepatic HBV antigen expression. Variation of the HBV core gene was not found to be preferentially associated with active liver disease in Western patients with chronic HBV infection. The pattern of hepatitis B core gene variation is in accord with the genomic organization of HBV.     

Hepatitis B virus infection, hepatitis B vaccine, and hepatitis B immune globulin

Hepatitis B virus (HBV) infection is a major health problem in the United States; in 1995, approximately 128,000 cases occurred. Transmission of HBV occurs primarily by blood exchange (eg, by shared needles during injection drug use) and by sexual contact. Persons infected early in life are much more likely to become chronically infected than those infected during adulthood: as many as 90% of infants infected perinatally develop chronic infection and up to 25% will die of HBV-related chronic liver disease as adults. Clinical signs of acute hepatitis occur in about 50% of infected adults but in only 5% of infected preschool-aged children. In the United States, hepatitis B vaccine is currently made by recombinant DNA technology using baker's yeast. Preexposure vaccination results in protective antibody levels in almost all infants and children (> 95%) and healthy adults younger than 40 years of age (> 90%). The most common adverse event following administration of hepatitis B vaccine is pain at the injection site, which occurs in 13% to 29% of adult and 3% to 9% of children. A comprehensive hepatitis B vaccination policy is now recommended that includes (1) routine infant vaccination; (2) catch-up vaccination of 11- to 12-year-olds who were not previously vaccinated; (3) catch-up vaccination of young children at high risk for infection; (4) vaccination of adolescents and adults based on lifestyle or environmental, medical, and occupational situations that place them at risk; and (5) prevention of perinatal HBV infection.     

The elimination of hepatitis B virus infection: changing seroepidemiology of hepatitis A and B virus infection in Okinawa, Japan over a 26-year period

Serial changes in hepatitis A virus (HAV) and B virus (HBV) markers were determined from 1970 to 1996 in healthy Japanese residents of a rural area of Okinawa, Japan. All 190 serum samples taken in 1970, 791 in 1980, 708 in 1988, and 523 in 1996 from residents 0 to more than 60 years of age were tested for antibody to HAV (anti-HAV), antibody to hepatitis B core antigen (anti-HBc), and hepatitis B surface antigen (HBsAg). The age-adjusted prevalences of anti-HAV and anti-HBc decreased significantly from 83.9% and 74.9%, respectively, in 1970 to 39.7% and 36.6%, respectively, in 1996. In residents < or = 29 years of age, the prevalences of anti-HAV and anti-HBc decreased significantly from 65.3% and 83.8%, respectively, in 1970 to 0.7% and 8.2%, respectively, in 1996. The age-adjusted HBsAg prevalence decreased significantly from 8.2% in 1980 to 4.1% in 1988. These results indicate that exposure to HAV and HBV infections among Okinawa residents less than 29 years of age is decreasing, probably because of improvements in socioeconomic conditions since 1970. Infection with HBV may be eliminated there in the near future.     

The natural course of hepatitis B and hepatitis C virus infection

Chronic hepatitis B and hepatitis C virus infections maintain a significant risk for the development of liver cirrhosis and hepatocellular carcinoma and cause a considerable morbidity in the population. Among patients with chronic HBV infection and histologically confirmed hepatitis the annual incidence of liver cirrhosis is 2%. The risk for hepatocellular carcinoma in chronic HBsAg carriers is elevated about 40-230 fold. 20-30% of patients with chronic HCV infection will develop cirrhosis over 20-30 years. Hepatocellular carcinoma evolves yearly in about 3% of patients with chronic HCV infection and cirrhosis, whereas HCV-carriers without cirrhosis usually do not develop hepatocellular carcinoma. The high incidence of serious sequelae warrants a regular surveillance of chronic virus carriers.     

Membranous glomerulonephritis associated with hepatitis C virus infection in renal transplant patients

BACKGROUND: Hepatitis C virus (HCV) infection has been described in association with various types of glomerular diseases, usually type I membranoproliferative glomerulonephritis and rarely membranous glomerulonephritis (MGN). In this article, we describe the first series of MGN exhibited in renal transplant patients and associated with HCV infection. METHODS: From January 1980 to December 1994, 2045 kidney transplantations were performed in our renal transplant units. A retrospective analysis demonstrated an overall 20% prevalence of HCV virus-positive patients; 409 transplanted patients were HCV positive (ELISA and RIBA). RESULTS: Fifteen patients developed an allograft MGN (3.66%) 24 months after renal transplantation. MGN appeared in the form of significant proteinuria (>1.5 g/24 h) with stable renal function. In all cases, graft biopsy demonstrated a thickening of the capillary wall, subepithelial electron-dense deposits, and IgG and C3 diffuse granular deposits along the basal membrane. Ten cases were considered de novo, two cases were considered recurrent MGN, and three cases were considered undetermined because the primary renal disease was chronic glomerulonephritis. All patients showed negative antinuclear antibodies and cryoglobulins, normal complement, and negative rheumatoid factors. During follow-up (an average of 2 years), 12 patients developed a progressive worsening of renal function, with increased serum creatinine and persistent proteinuria; 8 of the 12 patients returned to dialysis. Of the remaining three cases, two patients showed partial remission of nephrotic syndrome after high doses of steroids, and one patient persisted with stable renal function and proteinuria (<2 g/24 h.). CONCLUSIONS: In summary, HCV is preferentially associated with MGN in renal transplant patients, rather than with membranoproliferative glomerulonephritis as in the normal adult population. MGN associated with HCV infection has a similar clinical picture and outcome to posttransplant idiopathic de novo MGN, with persistent massive proteinuria and progressive deterioration of renal function.     

Malignant ventricular arrhythmia in a heart transplant patient

The authors describe a case of a 48-year old man living more than 9 years with a transplanted heart. Beside chronic complications (repeated rejection, gradual progression of renal and hepatic insufficiency, osteoporosis, marrow suppression), deterioration of cardiac insufficiency and angiographically documented coronary disease of the graft, there appeared haemodynamically severe persisting ventricular tachycardias degenerating into ventricular fibrillation. Frequent exacerbation of tachyarrhythmias despite the applied antiarrhythmic drugs (mexiletine, amiodarone) which were only partially effective, required repeated electrical cardioversions/defibrillations (totally 16 times). The patient in the clinical state of multi-organ failure which contraindicated retransplantation, died after almost 3 weeks after the appearance of malign arrhythmias. Electrophysiological characteristics of the transplanted heart modify the management of these patients.     

Immunoglobulin- and hepatitis B surface antigen-specific circulating immune complexes in chronic hepatitis B virus infection

24 consecutive AIDS patients with wasting, and who had never received anabolic therapies, were evaluated to determine their profile of sex hormones and whether transformation of testosterone (T) to the nuclear androgen, dihydrotestosterone (DHT), was impaired. Eleven (46%) patients had normal testosterone and DHT (group I), 10 (42%) had normal testosterone but low DHT (group II), and 3 (12%) had low testosterone and low DHT (group III). Age, prior opportunistic complications, symptoms, serum albumin, hemoglobin levels, and CD4 lymphocyte counts were similar in the groups. DHT was significantly lower (22.2 +/- 6.8 microg/dl) in group II compared with group I (50.8 +/- 15.3 microg/dl). The ratio of T/DHT, a measure of the conversion of testosterone to DHT, in group I was 15.1 +/- 3.5, which was within the range for eugonadal young men. In group II, the ratio was 22.3 +/- 1.5, indicating a defect in generation of DHT. Patients in group II had lost 9.2 +/- 3.5 kg compared with 5.6 +/- 2.6 kg in group I (p = .015). Thus, a syndrome of low DHT with normal testosterone was associated with significantly greater weight loss than in patients with normal testosterone and DHT. Further studies are needed to clarify whether low DHT is a result of AIDS wasting or is causally related to weight loss and whether androgen therapy in the form of DHT could reverse some of the metabolic changes associated with AIDS wasting.     

Prevention and control of hepatitis B virus infection in Singapore

Hepatitis B virus (HBV) accounted for 24% to 54% of the reported acute viral hepatitis cases in Singapore from 1982 to 1996. The prevalence of HBV infection, as indicated by the presence of markers of HBV, increased from 9.3% in children below 5 years of age to 54.6% in adults above 55 years. The overall hepatitis B surface antigen (HBsAg) prevalence was 5.7% for males and 3.4% for females, with the highest rate among the Chinese. About 39% of the HBsAg carriers were hepatitis B 'e' antigen positive. The main mode of transmission during the first year of life was perinatal, with 43% of the babies born to HBsAg-positive mothers developing the carrier state. Horizontal transmission within the infected household was significantly associated with sharing of personal and household articles. Based on the findings of seroprevalence surveys in various population groups and clinical trials on the safety, immunogenicity and efficacy of various doses and schedules with the plasma-based and yeast-derived hepatitis B vaccines in newborn babies, a national childhood hepatitis B vaccination programme was formulated and implemented in phases, starting with babies born to carrier mothers on 1 October 1985 and finally extending to all newborns on 1 September 1987. The hepatitis B prevention and control programme has been successful. During the period 1994 to 1996, more than 90% of children completed the full schedule of immunisation by below one year of age, and 85% had evidence of vaccination at school entry at age six. Follow-up of 2 cohorts of vaccinated children showed that perinatal transmission has been reduced by 80% to 100%. Horizontal transmission has also declined through other public health measures. The efficacy of the hepatitis B vaccine and the adequacy of reduced doses in the long-term protection of chronic carrier state have been shown in children and adults. The incidence of acute hepatitis B has declined from 10.4 per 100,000 in 1985 to 4.8 per 100,000 in 1996. There is a noticeable reduction in HBsAg prevalence in selected population (school children, national servicemen and antenatal women). The age-standardised incidence rate of primary liver cancer among males had also dropped from 27.8 per 100,000 per year during 1978 to 1982 to 19.0 per 100,000 per year during 1988 to 1992.     

Lymphocytotoxins in leprosy and in asymptomatic hepatitis B virus infection

Serum lymphocytotoxic antibodies (LCAs) were detected in 67% of Papua New Guinean lepromatous leprosy patients who were persistent carriers of hepatitis B surface antigen (HBsAg). Lymphocytotoxins were not associated with asymptomatic HBsAg in either healthy controls or tuberculoid leprosy patients. It was apparent that, although HBsAg itself is a poor indicator of in vitro lymphocytotoxicity, when the antigen occurred in a host with impaired immune response, lymphocytotoxicity, when the antigen occurred in a host with impaired immune response, lymphocytotoxicity was enhanced. In contrast to this finding, lepromatous leprosy patients without HBsAg had significantly depressed LCA production in comparison with tuberculoid patients and controls. The interaction between leprosy and hepatitis B virus was highly significant (P = 0.001) in an analysis of variance of cytotoxicity scores. It is proposed that the previously reported equivocal results regarding autoantibodies in leprosy patients may be explained by this unusual interaction between lepromatous leprosy and hepatitis B virus infection.