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Twenty-seven carriers of the hepatitis B surface antigen who underwent liver transplantation in Italy and Belgium for terminal Hepatitis delta virus (HDV) cirrhosis were investigated. In 22 of the patients, HDV infection recurred. Two patients died of coexisting HDV and hepatitis B virus (HBV) reactivation. Four patients who died of unrelated causes were found to have HDV without signs of HBV reactivation. Five patients (18%) cleared both HBV and HDV after transplantation with no evidence of hepatitis (mean follow-up, 29 months). In many surviving patients, HDV infection recurred early without signs of HBV reactivation. Disease returned in the 11 HDV-infected patients in whom HBV also recurred. Histological hepatitis did not recur during an interim of 12-33 months in the 5 HDV-infected patients in whom HBV did not return. The overall medium-term survival in patients with HDV who underwent transplantation was 77.7%. Liver transplantation offers patients with HDV a hope of cure from disease despite a high risk of reinfection. In the transplantation setting, HDV can cause subclinical infections without any apparent assistance from HBV; these infections become symptomatic only if and when HBV reactivates. Thus, HDV may not be in itself pathogenic but requires cooperation from HBV to cause the appearance of the disease.

Background: Small clinical trials are necessary when there are difficulties in recruiting enough patients for conventional frequentist statistical analyses to provide an appropriate answer. These trials are often necessary for the study of rare diseases as well as specific study populations e.g. children. It has been estimated that there are between 6,000 and 8,000 rare diseases that cover a broad range of diseases and patients. In the European Union these diseases affect up to 30 million people, with about 50% of those affected being children. Therapies for treating these rare diseases need their efficacy and safety evaluated but due to the small number of potential trial participants, a standard randomised controlled trial is often

The case of a young woman with GB virus C/hepatitis G virus (GBV-C/HGV) infection and with a severe exacerbation of chronic hepatitis of unknown etiology during pregnancy is described. In the offspring, severe neonatal hepatitis with subsequent mild chronic liver disease of at least 16-month duration was followed by the development of antibodies to the envelope protein (E2) of GBV-C/HGV, suggesting that the child was recovering from GBV-C/HGV infection. There was an improvement in clinical and biochemical parameters in the mother following delivery and alpha-interferon therapy was associated with a transient biochemical response.

Immunohistochemical detection of hepatitis B core antigen (HBcAg), a reliable marker of hepatitis B virus (HBV) replication, is routinely performed in chronic hepatitis B on paraffin-embedded liver biopsies regardless of fixation technique. Due to sensitivity discrepancies observed in the HbcAg immunodetection, we prospectively investigated the role of the type of fixative solution (formalin versus Bouin's solution) in 32 consecutive patients with chronic hepatitis B. Results were compared with those of serum HBV-DNA determined by liquid hybridization. The biopsy core was divided into two parts, one immersed in 4% buffered formalin and the other in Bouin Alien's solution for 24 hours before paraffin embedding. HbcAg immunodetection, performed with a rabbit polyclonal antibody, was revealed by the streptavidin-biotin peroxidase method. Nuclear HBcAg positivity, observed in 21 cases, was solely confined to formalin fixed material in five cases and was more intense after formalin than after Bouin's solution fixation in the 16 other cases. Cytoplasmic HBcAg positivity, observed in 15 cases, was solely confined to formalin fixed material in 12. Eleven cases remained negative whichever the fixation, seven of these being also serum HBV-DNA negative. Conversely, all but three cases positive by immunohistochemistry were serum HBV-DNA positive, the three exceptions being serum anti-HBe positive. In conclusion, formalin fixation is significantly superior to Bouin's solution fixation for HBcAg immunodetection. With regard to HBV replication, the sensitivity of this detection is at least similar to that obtained with serum HBV-DNA determined by liquid hybridization.

GB virus C (GBV-C) has been detected in Belgian hemodialysis patients. To study their genomic diversity and phylogenetic relationship, a 592 nucleotide fragment extending from the 5' non-coding region to part of the E1 gene of the GBV-C genome was amplified and sequenced from 12 Belgian hemodialysis patients in two different centers. Together with strains from different geographical origins, these sequences were analyzed phylogenetically using three different methods. A consistent tree topology was obtained with all methods. Three GBV-C genotypes were observed with two subtypes in type 2 and a questionable subtyping in type 1. Except for one isolate falling into type 1 cluster which mainly consists of African strains, all the other Belgian strains clustered within the type 2a branch. Two GBV-C isolates in two patients from the same hemodialysis center clustered together closely, suggesting a nosocomial transmission. In view of their long branch length, it seems unlikely that the other Belgian strains evolved recently from a common ancestor. Our results indicate that the major type circulating among Belgian hemodialysis patients seems to be 2a, which is usual for Europe and North America, but that the African type 1 also exists to a minor extent. Although patient to patient transmission of GBV-C in Belgian hemodialysis centers did occur, it may not account for the majority of infections.

BACKGROUND: The cause of fulminant hepatitis (FH) in children is unexplained in up to 50% of cases. We report parvovirus B19 as an agent associated with FH in children and compare clinical characteristics of these patients with those of age-matched patients with FH of other origin. METHODS: 45 patients presented with FH. No cause was apparent in 21 patients. Parvovirus B19 genome was retrospectively sought by PCR in serum collected at admission in 41 patients. FINDINGS: Parvovirus B19 genome was detected in serum from four of 21 patients with unexplained FH (four of 11 younger than 5 years). No B19 DNA was detected in serum from patients with other types of FH or from 82 patients with biliary atresia. Parvovirus B19 IgM was detected in one of the four patients. Patients with parvovirus B19 infection had significantly lower bilirubin concentrations than age-matched patients with FH due to hepatitis A (nine) or other causes (nine) (poisoning with amanita excluded). All patients with parvovirus B19 survived without orthotopic liver transplantation, with restoration of normal liver function within 17 days. INTERPRETATION: In patients younger than 5 years with FH of unexplained origin, evidence of acute parvovirus B19 was associated with a distinct clinical pattern. In particular, low bilirubin concentrations and rapid recovery of liver function without transplantation were distinctive features.

The few studies concerning HCV genotypes in hemodialyzed patients concerned small groups of patients, issued from single units. Using the RFLP typing method in the 5' non-coding region (5' NCR), we performed the genotyping of HCV strains of 80 patients issued from 14 Belgian dialysis units. Forty-seven of the 80 patients were also tested by Inno-Lipa II (Innogenetics, Gent, Belgium). Sixty-four of 80 patients (80%) were infected with subtype 1b, 2 (2.5%) with subtype 1a, 6 (7.5%) with subtype 2a and 1 (1%) with subtype 2b; 6 patients (7.5%) showed a type 4 and 2 patients (2.5%) a type 5 infection, respectively. Only 1 patient (1%) showed a mixed infection (1a and 1b). In the 47 patients tested by both methods, we observed a very good agreement (98%) between RFLP and Inno-Lipa II's results. Our multicentric study detected HCV genotypes 4 or 5 in 8/80 (10%) of hemodialyzed patients in Belgium. The substantial prevalence of these genotypes could not be fully explained by a nosocomial spread of HCV infection: indeed, four patients belonged to dialysis units located in different cities, and two appeared infected with distinct subtypes in a same unit. Thus, the discovery of a "rare" HCV genotype in several hemodialyzed patients does not always point to nosocomial HCV transmission.

The mode of contamination, presentation, clinical evolution and liver histology of 10 native Belgian patients with chronic hepatitis B likely due to a peculiar viral strain, the so called precore mutant hepatitis B virus were reviewed. This viral strain first described in Southern European regions is characterized by a mutation of a single base change at nucleotide 1896 in the preterminal codon of the precore region which creates a stop codon that prevents the production of HBeAg. In this setting, abnormal liver biochemistry and active viral replication as evidenced by HBV DNA positivity often coincides with a serological profile similar to that observed in healthy HBsAg carriers. Our data indicate that chronic hepatitis related to such a viral strain may be observed in a native Belgian population. This unusual presentation of chronic hepatitis B should thus be kept in mind when interpreting atypical sero-biochemical features, evaluating the risk of infectivity and the potential benefit of antiviral therapy.

Paediatric orthotopic liver transplant recipients may develop chronic hepatitis after surgery. To investigate the role of hepatitis C virus in this pathology a cohort of 249 paediatric orthotopic liver transplant recipients was studied. Sixteen children (6.4%) were found to have chronic hepatitis C virus hepatitis after orthotopic liver transplantation. All but one of them had serum transaminase values which were persistently raised two to eight times the upper limit of normal. Thirteen were positive for both serology and serum hepatitis C virus RNA. Serum hepatitis C virus RNA detection occurred five to 33 months before hepatitis C virus antibodies. Liver tissue hepatitis C virus RNA and hepatitis C virus core antigen were detected in five. In one patient, tissue hepatitis C virus core antigen was detected when other tests for hepatitis C were negative. Two patients had positive human cytomegalovirus serum antibodies and RNA before transplantation. Although serum hepatitis C virus RNA was not detected after transplantation, serum enzyme immunosorbent assay and tissue core antigen were still detectable in both patients. In another child, serum hepatitis C virus RNA was positive and hepatitis C virus core antigen was found on a liver biopsy specimen but antihepatitis C virus antibodies were negative as well as liver hepatitis C virus RNA. No patient developed severe liver disease or cirrhosis during a follow up of up to 72 months. It is concluded that hepatitis C virus is a significant cause of morbidity after paediatric orthotopic liver transplantation. Diagnosis cannot rely on serological testing only. The patients remained stable on follow up, but longer prospective histological studies remain necessary to establish prognosis.

We investigated a group of Belgian HCV-100 Elisa positive volunteer blood donors for potential sources of contamination and the presence of liver biochemical abnormalities. In addition, results of serological testing and liver biochemistry of their related blood products recipients were also analysed. In blood donors, anti-HCV-100 repeat reactive rate was 0.77% with a 34% rate of abnormal liver function tests. A potential source of parenteral exposure was found in all donors with RIBA-confirmed HCV-100 positivity. Among recipients, anti-HCV-100 RIBA-2 positive blood product donations were associated with RIBA-2 seroconversion, a history of transfusion in donors being of high predictive value of infectivity.

The mode of contamination, presentation, clinical evolution and liver histology of 10 native Belgian patients with chronic hepatitis B likely due to a peculiar viral strain, the so called precore mutant hepatitis B virus were reviewed. This viral strain first described in Southern European regions is characterized by a mutation of a single base change at nucleotide 1896 in the preterminal codon of the precore region which creates a stop codon that prevents the production of HBeAg. In this setting, abnormal liver biochemistry and active viral replication as evidenced by HBV DNA positivity often coincides with a serological profile similar to that observed in healthy HBsAg carriers. Our data indicate that chronic hepatitis related to such a viral strain may be observed in a native Belgian population. This unusual presentation of chronic hepatitis B should thus be kept in mind when interpreting atypical sero-biochemical features, evaluating the risk of infectivity and the potential benefit of antiviral therapy.

To investigate the effect of high doses of cytosine arabinoside (AraC) on liver function in non-A, non-B hepatitis, we prospectively followed 11 leukemic patients with posttransfusion hepatitis at the time of conditioning before bone marrow transplantation. Diagnosis of non-A, non-B hepatitis was based on a sustained elevation of serum alanine aminotransferase (ALT) (greater than or equal to 2.5 times the upper limit of normal), negative serology for hepatitis A and B viruses, cytomegalovirus and Epstein-Barr virus and, in eight out of nine surviving patients, on antihepatitis C sero-conversion. Conditioning included high dose AraC (3 g/m(2)/12 h) on day -6 and day -5, cyclophosphamide (60 mg/kg) on day -4 and day -3 and total body irradiation (day -1, 800 cGy). Ten out of 11 patients exhibited a striking reduction in ALT level already apparent within 24 h following AraC administration and sustained until day + 29. Mean (+/- SD) ALT level on day -6 was 242( +/- 138)IU/l; on day -3, 161 ( +/- 100) IU/l (P < 0.001); and on day + 4, 60( +/- 27) IU/l. After day + 29, a progressive rise in ALT concentrations was again observed in all patients. High doses of AraC might thus exert a potent inhibitory effect on HCV replication in vivo which warrants further investigation.