Carmen Diaz

Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period

BACKGROUND/AIMS Chronic hepatitis B virus infection can lead to cirrhosis and hepatocellular carcinoma, particularly in men over 40 years of age and in areas where childhood-onset infection is common. The sequence of events from paediatric infection to severe disease in adults is only partially known. The aim of this study was to evaluate the evolution of chronic hepatitis B acquired in childhood during 20 years of follow-up. PATIENTS One hundred and eighty-five consecutive, otherwise healthy, Caucasian children were enrolled in Padua (Italy) and in Madrid (Spain) between 1975 and 1985, and followed for an average period of 13 years; 168 were hepatitis B e antigen (HBeAg) positive and five had cirrhosis. RESULTS Thirty patients received steroids or levamisole and 21 interferon, but treatment did not significantly influence HBeAg clearance. Overall, two (1.1%) children, with initial cirrhosis, developed hepatocellular carcinoma and the other three (1.6%) cirrhotic patients became asymptomatic carriers of infection after anti-HBe seroconversion and biochemical remission; 14 (7.5%) children maintained HBeAg positive hepatitis; 155 (83.8%) became asymptomatic carriers of infection after anti-HBe seroconversion and biochemical remission; six (3.2%) experienced reactivation of liver disease and viral replication after remission and five (2.7%) maintained biochemical features of liver damage after HBeAg clearance. Only 6% cleared hepatitis B surface antigen. CONCLUSIONS Even considering the bias of treatment, the large majority of Caucasian children with chronic hepatitis B became asymptomatic carriers of infection with normal alanine amino-transferase during the first 20 years of observation. Cirrhosis is an early, rare complication, and a risk factor for hepatocellular carcinoma. A subgroup of patients who experienced reactivation or maintained liver damage after HBeAg clearance seems to be at greater risk for disease progression during adult life.

Posttransfusion and community-acquired hepatitis C in childhood

Following a longitudinal study of chronic non-A, non-B hepatitis in Italy and Spain, we evaluated the epidemiologic and clinical features of chronic hepatitis C in 77 consecutively observed children (35 male; mean age, 4 years) without underlying systemic diseases. All subjects were positive for antibody to hepatitis C virus in serum by second-generation tests. Forty-six patients had received blood transfusions in the perinatal period; 12 had a mother with antibodies to HCV in serum (five of these mothers were drug users or partners of a drug user); seven had a history of putative percutaneous exposure; and 12 had not been exposed to any risk factors for viral hepatitis. At presentation, only 22% were symptomatic, mean alanine-aminotransferase levels were three times the upper normal value, and liver histology showed active disease in only nine of 28 cases (32%). During a mean observation period of 6 years, only 11 of 57 patients (19%) complained of symptoms and 11 of 40 cases (27%) had histologic features of active hepatitis. Two patients had severe hepatitis with associated cirrhosis. However, only six of 57 cases (10%) achieved sustained biochemical remission. The clinical features and the outcome were similar in both the posttransfusion and the community-acquired cases. These results indicate that transfusions in the perinatal period are the single most important cause of hepatitis C in otherwise healthy children. Community-acquired cases represent an heterogeneous epidemiologic group in which maternal transmission, whether perinatal or postnatal, could be relevant. Histologically severe hepatitis and cirrhosis seem to be an infrequent feature of chronic hepatitis C virus infection in childhood and adolescence, in spite of persistent liver damage.

Efficacy and Safety of Peginterferon-α2b and Ribavirin Combination Therapy in Children With Chronic Hepatitis C Infection

Background: Interferon (IFN)-&agr;2b plus ribavirin is approved for treatment of hepatitis C in children; however, little is known about efficacy and tolerability of pegylated IFN (PEG-IFN)-&agr;2b in this population. The objective of this study was to test the efficacy and safety of PEG-IFN-&agr;2b plus ribavirin in children with chronic hepatitis C. Methods: Thirty children 3–16 years of age who had detectable hepatitis C virus (HCV) RNA for ≥3 years after exposure and elevated alanine aminotransferase values received PEG-IFN-&agr;2b 1.0 &mgr;g/kg/wk plus ribavirin 15 mg/kg/d for 24 weeks (genotype 2/3) or 48 weeks (genotype 1/4). The primary endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA (<50 IU/mL) at week 24 of follow-up. Results: SVR was achieved in 50% of patients (3/3 genotype 3; 12/27 genotype 1/4). At week 12, 52% of patients were HCV RNA negative and 72% had a >2 log10 decrease in viral load, compared with baseline; 87% and 71% of these patients, respectively, attained an SVR. Therapy was discontinued in 3 patients as a result of adverse events. No patient required ribavirin dose reduction; PEG-IFN-&agr;2b dose was reduced in 23% of patients to manage neutropenia. Conclusions: Combination therapy with PEG-IFN-&agr;2b and ribavirin treatment was effective in children with chronic hepatitis C. Virologic status at week 12 identified future responders and nonresponders. PEG-IFN-&agr;2b and ribavirin were reasonably well tolerated, with no unexpected or permanent adverse effects. Further studies are needed to identify the optimum treatment regimen for this patient population.

Heterozygous ABCB4 mutations in children with cholestatic liver disease.

Monoallelic defects in ABCB4, which encodes the canalicular floppase for phosphatidylcholine MDR3, have been encountered in association with a variety of hepatobiliary disorders, particularly in adult subjects. In this study, we examined the presence of heterozygous ABCB4 variants in a cohort of children with chronic cholestasis and assessed the pathogenicity of the missense changes identified.

Hepatitis C serotypes in chronic hepatitis C of children

An enzyme linked immunosorbent assay has been recently developed which detects and distinguishes between infections with the three major hepatitis C virus (HCV) genotypes prevalent in Europe. Using this assay we have investigated the sera of 30 Italian and 37 Spanish children with chronic hepatitis C. Infection with HCV type 1 was found in 43% of Italian and 46% of Spanish children. Of the Italian children 7% were infected with HCV of type 2 and 7% had a mixed type 1/type 2 serotype. Infection with HCV type 3 was found in 7% of Italian and 8% of Spanish children while 36% of Italian and 46% of Spanish children had non-reactive sera. Serotype 3 was significantly more frequent in children with anti-HCV positive mothers (often drug abusers) than in those with percutaneous exposure (25% vs. 2%, p < 0.05). Mean alanine aminotransferase values were significantly higher in children with HCV type 1 than in those with non-reactive sera (P < 0.05). These results indicate a similar distribution of HCV serotypes in Italian and Spanish children. Serotype 1 is prevalent and associated with a more severe liver damage. The relevant proportion of non-reactive sera could be related to the existence of genetic variants different from those explored by the test and with low pathogenicity, or to a poor antibody response to viral antigens of the NS4 region in a consistent subgroup of children.

Unusual serum bile acid pattern in children with the syndrome of hepatic ductular hypoplasia

Fasting bile acids in serum of eight children with the syndrome of hepatic ductular hypoplasia were analyzed by gas chromatography. The children did not receive any kind of treatment during the month before the analysis. Serum concentrations of total bile acids ranged from 110.8-303.7 mumol/1. The predominant bile acids were chenodeoxycholic and cholic acids accounting for 62.8-86.5% of the total. The ratio of cholic acid to chenodeoxycholic acid ranged between 0.43 and 1.11. Monohydroxylated bile acids were found in increased amounts in all patients (5.1-23.9%), 3 beta-hydroxy-5-cholenoic acid being the major monohydroxylated bile acid (3.1-17.1%). Other unusual bile acids such as ursodeoxycholic acid and 12-oxo-3 alpha, 7 alpha-dihydroxy-5 beta-cholanoic acid (7.3-14.9%) were also detected. Neither 3 beta-hydroxy-5-cholenoic nor lithocholic acid levels were statistically correlated to cholic or chenodeoxycholic acids. However, a statistically significant correlation between total bile acid levels and 12-oxo-3 alpha, 7 alpha-dihydroxy-5 beta-cholanoic acid levels was found. These findings are interesting as far as the origin of the unusual bile acids found in this cholestatic syndrome is concerned. The large amounts of 3 beta-hydroxy-5-cholenoic acid measured in children with the syndrome of hepatic ductular hypoplasia could indicate the existence of an alternative fetal pathway of bile acid synthesis.

Liver Transplant in a Patient under Methylphenidate Therapy: A Case Report and Review of the Literature

Background. Methylphenidate (MPH) is widely used in treating children with attention-deficit-hyperactivity disorder. Hepatotoxicity is a rare phenomenon; only few cases are described with no liver failure. Case. We report on the case of a 12-year-old boy who received MPH for attention-deficit-hyperactivity disorder. Two months later the patient presented with signs and symptoms of hepatitis and MPH was discontinued, showing progressive worsening and developing liver failure and a liver transplantation was required. Other causes of liver failure were ruled out and the liver biopsy was suggestive of drug toxicity. Discussion. One rare adverse reaction of MPH is hepatotoxicity. The review of the literature shows few cases of liver injury attributed to MPH; all of them recovered after withdrawing the treatment. The probable mechanism of liver injury was MPH direct toxicity to hepatocytes. In order to establish the diagnosis of MPH-induced liver injury, we used CIOMS/RUCAM scale that led to an assessment of “possible” relationship. This report provides the first published case of acute MPH-induced liver failure with successful hepatic transplantation. Conclusions. It is important to know that hepatotoxicity can occur in patients with MPH treatment and monitoring the livers function is highly recommended.

Mineral metabolism disorders, vertebral fractures and aortic calcifications in stable kidney transplant recipients: The role of gender (EMITRAL study).

BACKGROUND AND OBJECTIVES The relationship between mineral metabolism disorders, bone fractures and vascular calcifications in kidney transplant recipients has not been established. METHOD We performed a cross-sectional study in 727 stable recipients from 28 Spanish transplant clinics. Mineral metabolism parameters, the semi-quantification of vertebral fractures and abdominal aortic calcifications were determined centrally. RESULTS Vitamin D deficiency (25OHD3<15ng/ml) was more common in female recipients at CKD-T stages I-III (29.6% vs 44.4%; p=0.003). The inverse and significant correlation between 25OHD3 and PTH was gender-specific and women exhibited a steeper slope than men (p=0.01). Vertebral fractures (VFx) with deformity grade ≥2 were observed in 15% of recipients. Factors related to VFx differed by gender; in males, age (OR 1.04; 95% CI 1.01-1.06) and CsA treatment (OR: 3.2; 95% CI: 1.6-6.3); in females, age (OR 1.07; 95% CI: 1.03-1.12) and PTH levels (OR per 100pg/ml increase: 1.27; 95% CI: 1.043-1.542). Abdominal aortic calcifications were common (67.2%) and related to classical risk factors but not to mineral metabolism parameters. CONCLUSIONS Vitamin D deficiency is more common among female kidney transplant recipients at earlier CKD-T stages, and it contributes to secondary hyperparathyroidism. Prevalent vertebral fractures are only related to high serum PTH levels in female recipients.