Maria Grazia Marazzi

Long-Term Course of Chronic Hepatitis C in Children: From Viral Clearance to End-Stage Liver Disease

BACKGROUND & AIMS The natural course of chronic hepatitis C (CHC) in children is not well understood. The aim of this study was to assess the long-term course of CHC in a large sample of otherwise healthy children. METHODS From 1990 to 2005, 504 consecutive antihepatitis C virus (HCV)-positive children were enrolled at 12 centers of a national observatory and were followed up retrospectively/prospectively. RESULTS Putative exposure was perinatal in 283 (56.2%) cases, parenteral in 158 (31.3%), and unknown in 63 (12.5%). At baseline, 477 (94.6%) cases were HCV RNA seropositive, 118 (24.7%) of which were treated with standard interferon alpha. Ten years after putative exposure, the outcome in 359 HCV RNA-positive, untreated patients was (1) undetectable viremia in 27 (7.5%) (by Cox regression analysis, spontaneous viral clearance was independently predicted by genotype 3 [hazard ratio 6.44; 95% confidence interval: 2.7-15.5]) and (2) persistent viremia in 332 (92%) cases. Six of these 332 cases (1.8%) progressed to decompensated cirrhosis (mean age, 9.6 years). This latter group included 5 Italian children perinatally infected with genotype 1a (4 of the mothers were drug users). Thirty-three (27.9%) treated patients achieved a sustained virologic response. CONCLUSIONS Over the course of a decade, few children with chronic HCV infection cleared viremia spontaneously, and those who did were more likely to have genotype 3. Persistent viral replication led to end-stage liver disease in a small subgroup characterized by perinatal exposure, maternal drug use, and infection with HCV genotype 1a. Children with such features should be considered for early treatment.

Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations.

In this study, we report further results of mutation analysis of the ATP7B gene in Wilson disease (WD) patients of Mediterranean origin. A total of 136 WD chromosomes, 73 of which were of Italian, 43 of Turkish, 18 of Sardinian, and two of Spanish origin, were analysed and the mutation characterised in 84.5% of them. We found 50 different mutations of which 19 are novel, including three nonsense, one frameshift, and 15 missense mutations. The mutations detected were rare and mostly found in the compound heterozygous state together with other mutations and only rarely in homozygosity. Most of these mutations lie in the transmembrane and ATP binding loop regions. These data expand our knowledge of both the structure-function relationships of the WD protein and the molecular pathology of WD, thus improving our capability of prevention and genetic counselling.

Serum transaminases in children with Wilson's disease.

Objectives: The response of serum transaminase levels to penicillamine and zinc treatment in Wilson’s disease is poorly understood. The aim of this multicenter retrospective study was to evaluate transaminase levels after penicillamine and zinc treatment in children with Wilson’s disease. Patients and Methods: One hundred and nine patients with Wilson’s disease (median age at diagnosis, 7.2 years; range, 1 to 18 years), treated for at least 12 months and observed in the last 20 years at 11 Paediatric Departments were studied. Clinical, laboratory and histologic features at diagnosis and initial treatment were recorded. Efficacy parameters were normalization of serum transaminase level and improved clinical and/or laboratory signs. One hundred and two patients had clinical or laboratory signs of liver disease. Results: Fifty-six of 87 patients (64%) given penicillamine normalized serum alanine aminotransferase (ALT) levels within a median of 17 months (range, 2 to 96 months). Of the 29 patients with persistent hyper-ALT, 17 (59%) switched to zinc; only four of these normalized ALT on zinc within a median period of 38 months (range, 7 to 48 months). Eleven (50%) of the 22 patients given zinc alone normalized ALT within a median period of 6 months (range, 1 to 36 months). Of the 11 patients with persistent hyper-ALT, five switched to penicillamine. Three of the five normalized ALT within a median period of 6 months (range, 6 to 9 months). Overall, in penicillamine-treated and zinc-treated patients with persistent hypertransaminasemia, ALT decreased from a basal median of 236 IU/L (range, 54 to 640 IU/L) to a median of 78 (range, 46 to 960 IU/L) at the end of follow-up (P = 0.0245). Poor compliance was suspected in only 10% of cases. No predictive factor of persistent hypertransaminasemia was identified. Liver disease did not worsen in any patient during the study. Conclusions: Although the efficacy of penicillamine and zinc is well documented, it is notable that a subset of children with Wilson’s disease-related liver disease (36%) had hypertransaminasemia despite appropriate treatment with penicillamine or zinc.

An Epidemiological Survey of Hepatitis C Virus Infection in Italian Children in the Decade 1990–1999

Background A retrospective–prospective survey of Italian children with hepatitis C virus (HCV) infection was planned in 1998 to explore the epidemiologic features of infection during the past decade. Methods Anti-HCV–positive patients (or HCV RNA–positive infants) aged 1 month to 16 years, consecutively observed in 20 pediatric Institutions, were considered. An anonymous epidemiologic questionnaire based on clinical records was used. Results From 1990 through March 1999, 606 patients were observed (296 boys, average age 5.8 years). Maternal infection (46% of cases) and blood transfusions (34%) were the most frequent risk factors. Of 279 infected mothers, 61% did not recall a putative source of infection (by history, many could possibly have had exposure through routes such as therapeutic injections with nondisposable material), whereas 94 (34%) admitted drug abuse, including 49 (17%) coinfected with human immunodeficiency virus (HIV). Only 157 (26%) children were born after 1991: 90% of their mothers were infected (11% were HIV coinfected vs. 25% mothers of older children, P < 0.01). Conclusions Maternal infection is a prominent source of pediatric HCV infection in Italy. The fact that most mothers had a history of covert exposure to HCV, probably through percutaneous routes that are no longer operating, and that the number of those with HIV coinfection has decreased suggests that the frequency of pediatric infection could decrease in the future.

Management of chronic hepatitis C in childhood: The impact of therapy in the clinical practice during the first 2 decades

BACKGROUND AND AIM Treatment of chronic hepatitis C in children is controversial and its role in the clinical practice is unknown. We retrospectively investigated the impact of treatment in a large cohort of children with chronic hepatitis C over the past 20 years. METHODS 376 hepatitis C virus RNA positive children were recruited consecutively in five Italian centres since 1990 and followed for 1-17 years. RESULTS 86 (23%) subjects were treated: 73 with recombinant interferon alone and 13 with pegylated-interferon and ribavirin. Sustained clearance of hepatitis C virus RNA was observed in 25% of the former, in 92% of the latter and in 9% of untreated cases (p < 0.001). Loss of viraemia was recorded in all children with genotype 2-3 and in 6 of 7 with hepatitis C virus genotype 1 treated with combination therapy. At last evaluation 45% of patients were young adults and 15% had cleared viraemia. Overall, 152 (40%) were putative candidates to therapy. CONCLUSIONS Few Italian children with chronic hepatitis C have been treated in the past 20 years. The poor propensity to spontaneous clearance of viraemia and the efficacy of combination therapy should encourage to consider treatment in attempt to shorten the duration of viral replication.