Angela Vegnente

Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B†

One year of lamivudine treatment results in increased hepatitis B e antigen (HBeAg) seroconversion and serum hepatitis B virus (HBV) DNA negativity in children with chronic hepatitis B and high serum alanine aminotransferase concentrations. Two hundred seventy‐six children who participated in a 1‐year randomized, placebo‐controlled study of lamivudine were enrolled in a 24‐month, open‐label extension. Patients were stratified into two groups based on HBeAg status at week 48 of the previous study: 213 HBeAg‐positive children were entered into a treatment arm, and 63 HBeAg‐negative children were entered into an observation arm to evaluate durability of HBeAg loss. In the treatment arm, 28 of 133 (21%) children previously treated with lamivudine and 23 of 77 (30%) children who previously received placebo achieved the primary end point: virological response (VR) (HBeAg loss and HBV DNA negativity) at month 24. The incidence of YMDD (tyrosine, methionine, aspartate, aspartate) mutations at month 24 was 64% (66/103) in the children previously treated with lamivudine and 49% (34/70) in those previously treated with placebo. The incidence of VR at month 24 was 5% (5/100) for patients with YMDD mutant HBV and 54% (39/72) for patients without. The durability of response in the observation arm was 89% (48/54) at month 24. In conclusion, further clinical response was seen over the 24‐month open‐label study period in children who had not initially achieved a VR after 12 months of lamivudine treatment. However, the incidence of YMMD mutations increased over time and resulted in lower response rates. VR was maintained in most patients who had initially responded to lamivudine in the first 12 months. (HEPATOLOGY 2006;43:225–232.)

Re‐evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease

The diagnosis of Wilson disease (WD) is challenging, especially in children. Early detection is desirable in order to avoid dramatic disease progression. The aim of our study was to re‐evaluate in WD children with mild liver disease the conventional diagnostic criteria and the WD scoring system proposed by an international consensus in 2001. Forty children with WD (26 boys and 14 girls, age range = 1.1‐20.9 years) and 58 age‐matched and sex‐matched patients with a liver disease other than WD were evaluated. Both groups were symptom‐free and had elevated aminotransferases as predominant signs of liver disease. In all WD patients, the diagnosis was supported by molecular analysis, the liver copper content, or both. A receiver operating characteristic (ROC) analysis of ceruloplasmin at the cutoff value of 20 mg/dL showed a sensitivity of 95% [95% confidence interval (CI) = 83%‐99.4%] and a specificity of 84.5% (95% CI = 72.6%‐92.6%). The optimal basal urinary copper diagnostic cutoff value was found to be 40 μg/24 hours (sensitivity = 78.9%, 95% CI = 62.7%‐90.4%; specificity = 87.9%, 95% CI = 76.7%‐95%). Urinary copper values after penicillamine challenge did not significantly differ between WD patients and control subjects, and the ROC analysis showed a sensitivity of only 12%. The WD scoring system was proved to have positive and negative predictive values of 93% and 91.6%, respectively. Conclusion: Urinary copper excretion greater than 40 μg/24 hours is suggestive of WD in asymptomatic children, whereas the penicillamine challenge test does not have a diagnostic role in this subset of patients. The WD scoring system provides good diagnostic accuracy. (HEPATOLOGY 2010.)

Side effects of alpha-interferon therapy and impact on health-related quality of life in children with chronic viral hepatitis.

BACKGROUND Interferon (IFN) is standard therapy for chronic viral hepatitis in children. The aim of this study was to evaluate the side effects of alpha-interferon (IFN) in 94 consecutive children (58 males; age range, 3 to 14 years) affected by chronic viral hepatitis treated with different schedules ranging from 3 to 10 MU and from 3 to 12 months, and the impact of this therapy on health-related quality of life. METHODS Side effects were evaluated with clinical and laboratory examinations and were recorded on a diary card. The health-related quality of life was evaluated with a modified version of the Sickness Impact Profile. RESULTS All patients experienced at least one adverse reaction to IFN treatment; 80% had more than five side effects. There were no life-threatening reactions. Three children experienced severe reactions (febrile seizure, severe hypertransaminasemia and relapsing episodes of epistaxis, respectively) that required permanent IFN withdrawal. Another child had a febrile seizure requiring temporary IFN withdrawal. In seven children the neutrophil count fell below 1000/mm3 and promptly increased when IFN was temporarily discontinued. The remaining children had mild or moderate clinical and/or laboratory adverse reactions. Age, sex, viral etiology of chronic hepatitis and response to therapy were not significantly associated with the appearance of side effects. The pre-IFN health-related quality of life was good in all children; it deteriorated significantly during IFN therapy and returned to basal standards within 3 months after IFN withdrawal. No patient required suspension of IFN therapy because of worsening of health-related quality of life. CONCLUSION Children have a low risk of developing severe IFN-induced side effects. Adverse reactions and worsening of health-related quality of life were tolerable and did not seem to be a limiting factor for IFN therapy in young candidates.

Further delineation of the molecular pathology of Wilson disease in the Mediterranean population

This study presents the update results of an ongoing project on the delineation of the spectrum of mutations at the Wilson disease (WD) gene in WD patients of Mediterranean origin. In studying 59 patients, of whom were 26 Continental Italians, 22 Sardinians, 9 Turkish, and 2 Albanians, we have found 31 novel and three known mutations. Of the novel mutations, 3 are deletions, two nonsense, 2 splice or consensus splice site, and 24 missense. The large majority of the missense mutations lie in evolutionary conserved regions of the WD gene of documented functional importance. Most of our patients were compound heterozygotes, and only a few were homozygotes. In addition, three polymorphisms were detected. By adding the new data to those previously reported by our group, we have to date detected 85% of mutations in the WD chromosomes from Continental Italians, 30% from Sardinians, 81.7% from Turkish and 66.7% from Albanians. Most of the mutations characterized are rare, and only a limited number are common. Of the common mutations 5 were found in Continental Italians, two in Sardinians and a single one in Turkish. Because there are so many causative mutations of the disease, the preclinical and prenatal diagnosis of WD should be carried out by a combination of mutation and linkage analysis. Hum Mutat 12:89–94, 1998.

Safety and immunogenicity of hepatitis A vaccine in infants: a candidate for inclusion in the childhood vaccination programme

Forty-eight infants received a single dose (720 ELISA units = 0.5 ml) of inactivated hepatitis A vaccine at the fifth month of age with booster at the 11th month of age, together with the second and third doses of the vaccines compulsory under Italian law (diphtheria, tetanus, oral polio and hepatitis B). Overall, the seroconversion rate was 100%. The anti-HAV geometric mean titre (GMT) reached 3,021 mIU/ml in infants born to anti-HAV-negative mothers, but only 399 mIU/ml in infants born to anti-HAV-positive mothers. Hepatitis A vaccine was immunogenic, safe and well tolerated without significant side-effects. There seems to be no reason for not including it in childhood vaccination programmes particularly in low endemic HAV areas.

Chronic Hepatitis C in Childhood: An 18-Year Experience

BACKGROUND The long-term outcome of chronic hepatitis C (CHC) has not been well studied, both for untreated and interferon-treated children. The aim of this study was to evaluate the long-term outcome of disease in a large series of children with CHC. METHODS Clinical, biochemical, virological, and histological features were evaluated in all children (age, 2-18 years) with CHC who did not have concomitant disease and who attended at our hospitals liver unit during the period of 1986-2004. RESULTS One hundred twenty-five children with CHC were studied. All patients remained free of symptoms throughout the period of observation. On the basis of transaminase levels during the first year of positivity for antibodies to hepatitis C virus (HCV), children were divided into 2 groups: patients with hypertransaminasemia (100 patients, all of whom had detectable HCV RNA), and those with normal transaminases (25 patients; 16 had viremia and 9 did not have viremia). Sustained clearance of viremia was achieved in 38% of the patients treated with interferon, compared with 12% of untreated children (P<.05). A sustained response to therapy was obtained in 64.7% of children infected with an HCV genotype other than genotype 1 and in 24.2% of those infected with HCV genotype 1 (P<.05). Histological lesions were mild in all 64 patients who underwent liver biopsy. No linear correlation was found between duration of disease and progression of fibrosis. Examination of a follow-up liver biopsy specimen revealed cirrhosis only in 1 (4.7%) of 21 children. CONCLUSIONS Children with CHC were symptom free and had a morphologically mild liver disease. Interferon therapy may be effective for patients infected with HCV genotypes other than genotype 1, whereas lower response rates are expected for HCV genotype 1-infected children. The real impact of therapy on long-term outcome remains to be established.

MASS VACCINATION AGAINST HEPATITIS B IN INFANTS IN ITALY

A field trial currently underway in an area near Naples Italy where hepatitis B is endemic is providing support for a new vaccination protocol that involves administering hepatitis B vaccine at 3 and 5 months of age with a booster at 11 months. This protocol saves 1 dose of vaccine and also allows hepatitis B vaccine to be administered at the same time as immunization against diphtheria tetanus and poliomyelitis. Measurement of anti-hepatitis B surface antigen titers in the 110 Italian infants vaccinated according to this protocol to date revealed seroconversion rates of 93.6% immediately before the 11 month booster and 96.3% 2 months after the booster injection. In addition to being effective this protocol has been highly acceptable. 99% of mothers in the area have complied with the immunization program and have welcomed the opportunity to obtain protection for their children against hepatitis B at the same time that other immunizations are administered. On the basis of these findings the Italian health authorities have adopted the new protocol for routine use in areas highly endemic for hepatitis B infection. The World Health Organization has also recommended that hepatitis B vaccine be offered at the same time as other childhood immunizations.

Chronic hepatitis in childhood: the spectrum of the disease.

During a multicentre study of chronic hepatitis in childhood diagnosed by biopsy, the spectrum of the disease has been evaluated in 196 consecutive patients, including 157 from Northern Italy and 39 from Southern Italy. Only 31% of patients in the former group and 27% in the latter were symptomatic when first seen: the majority of cases being seen after familial screenings for hepatitis B virus (HBV) markers or during intercurrent infections, thus suggesting that the frequency of chronic hepatitis in childhood might be largely underestimated in our area. In Southern and Northern Italy 83% of symptomatic and 95% of asymptomatic patients were hepatitis B surface antigen (HBsAg) positive in serum; only 15 (8.3%) of these children were born to mothers known to be HBsAg positive at delivery, but a high circulation of HBV was found in their families: in fact more than 65% of household contacts in Northern Italy and more than 90% in Southern Italy had serological evidence of past or ongoing HBV infection. These data indicate that, although familial screenings for HBV could have enhanced the percentage of HBsAg positive asymptomatic cases, chronic hepatitis in Italian children is mainly caused by HBV infection acquired in the familial setting through horizontal transmission. Such findings also emphasise the importance of mass vaccination of infants as the most effective means to prevent chronic type B hepatitis in childhood in our area. Among HBsAg positive children 55% had histological features of chronic active hepatitis and 85% were hepatitis Be antigen (HBeAg) positive in serum. Anti-HBe positive hepatitis was significantly more frequent in Southern than in Northern Italy in parallel with the significantly higher prevalence (17%) of hepatitis delta virus infection in that area. Of the 16 HBsAg negative cases included in the study three had autoimmune hepatitis, three Wilsons disease, one alpha1 antitrypsin deficiency, and nine had cryptogenic hepatitis, often associated to mild liver lesions resembling those seen in our adult patients with chronic non-A, non-B hepatitis unrelated to percutaneous exposure.

Predictive Value of Epstein-Barr Virus Genome Copy Number and BZLF1 Expression in Blood Lymphocytes of Transplant Recipients at Risk for Lymphoproliferative Disease

Epstein-Barr virus (EBV) genome numbers and RNA transcripts from the immediate-early EBV gene BZLF1 were monitored by means of polymerase chain reaction in peripheral blood lymphocytes (PBLs) of 44 children who received liver transplants. The 2 tests were compared, using several parameters to assess their value as predictors of posttransplantation lymphoproliferative disease (PTLD). All patients were infected with EBV. BZLF1 mRNA was positive in 70% of patients, with highest expression in those with largest virus load. Four patients developed PTLD that could not be unequivocally diagnosed by any of the parameters considered alone. Sensitivity of EBV genome number (>/=40,000 EBV copies/10(5) PBLs) and BZLF1 mRNA (BZLF1:glyceraldehyde-3-phosphate-dehydrogenase ratio >/=0.5) was 100%. Specificity of each of the 2 tests alone (98% and 58%, respectively) improved (to 100% and 83%, respectively) when measurement of serum IgG level was included. Because decreased virus load, but not BZLF1 mRNA expression, accurately predicted favorable responses of PTLD to therapy, monitoring of EBV genome numbers alone appears sufficient in children with liver transplants.

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.