Comparison of two different regimens of combined interferon-alpha2a and lamivudine therapy in children with chronic hepatitis B infection.

AIM: To evaluate the efficacy of two regimens of combined interferon-alpha2a (IFN-alpha2a) and lamivudine (3TC) therapy in childhood chronic hepatitis B. METHODS: A total of 177 patients received IFN-alpha2a, 9 million units (MU)/m2 for 6 months. In group I (112 patients, 8.7 +/- 3.5 years), 3TC (4 mg/kg/day, max 100 mg) was started simultaneously with IFN-alpha2a, in group II (65 patients, 9.6 +/- 3.8 years) 3TC was started 2 months prior to IFN-alpha2a. 3TC was continued for 6 months after antiHBe seroconversion or stopped at 24 months in nonresponders. RESULTS: Baseline alanine aminotransferase (ALT) was 134.2 +/- 34.1 and 147.0 +/- 45.3; histological activity index (HAI) was 7.4 +/- 2.7 and 7.1 +/- 2.3; and HBV DNA levels were above 2,000 pg/ml in 76% and 66% of patients in groups I and II, respectively (P > 0.005). Complete response was 55.3% and 27.6% in groups I and II, respectively (P < 0.01). AntiHBe seroconversion was higher and earlier, and HBV DNA clearance was earlier in group I (P < 0.05). HBsAg clearance was 12.5% and 4.6% and antiHBs seroconversion was 9.8% and 6.2% in groups I and II, respectively (P > 0.05). Breakthrough occurred in 17.9% and 24.6%; breakthrough times were 15.9 +/- 4.6 and 14.1 +/- 5.1 months; and relapse rates were 6.8% and none in groups I and II, respectively (P > 0.05, P > 0.05, P > 0.05). Responders had higher HAI (HAI > 6) and higher pre-treatment ALT than non-responders. CONCLUSION: Simultaneous 3TC+IFN-alpha2a yields a higher response and earlier antiHBe seroconversion and viral clearance than consecutive combined therapy. Relapse rate is low. Predictors of response are high basal ALT and high HAI scores. 3TC can be administered for 24 months without any side effect and breakthrough rate is comparable with previous studies.

Mannose-binding lectin gene polymorphism and chronic hepatitis B infection in children.

BACKGROUND/AIMS: Mannose-binding lectin (MBL) is a member of innate immune system that activates complement system through lectin pathway. MBL deficiency is associated with susceptibility to infectious diseases. In this study, the relation between MBL gene polymorphism and chronic hepatitis B infection in children is evaluated. PATIENTS AND METHODS: The study included 67 children with chronic hepatitis B and 99 healthy controls. The hepatitis B patients were divided into immuntolerant, chronic inactive, and treatment groups according to their laboratory findings. MBL gene codon 52, 54, and 57 polymorphisms were studied with polymerase chain reaction in all patients and controls. The associations of MBL gene polymorphism with clinical, laboratory, and histopathologic findings were evaluated. RESULTS: Homozygous codon 54 polymorphism of MBL was found significantly higher in chronic hepatitis B patients than controls. Rate of the polymorphism was similar in all groups and, responsive and nonresponsive patients in the treatment group. CONCLUSIONS: The hepatitis B patients who are homozygous for codon 54 of MBL are prone to develop chronic infection. Longitudinal studies with larger groups are needed.

Do liver IL-12 levels predict sustained response to IFN-alpha therapy in children with chronic hepatitis B?

The aim of this study is to investigate the immunoregulatory role of interleukin-12 and interferon-gamma in children with chronic hepatitis B who are treated with interferon-alpha therapy. The patients were divided into 2 groups: Group I included 16 children with naive chronic replicative hepatitis B infection, and Group II included 6 children who are inactive hepatitis B virus (HBV) carriers. Group I received interferon-alpha subcutaneously (10 mU/m(2)/dose), 3 times a week during 4 months. Initial serum alanine aminotransferase (ALT) levels, hepatitis B serologic markers, serum interleukin-12 and interferon-gamma levels were measured. In Group I, laboratory tests were re-evaluated in the second and fourth months. Liver biopsy was performed in all patients and samples were used for tissue interleukin-12 level evaluation and histopathological examination. Hepatic activity index (HAI) and serum interferon-gamma were significantly higher in Group I (P < 0.05). Initial tissue interleukin-12 levels in Group I were low but a significant increase was observed at the fourth month (P < 0.05). While responder patients in Group I had marked elevation of tissue interleukin-12 levels, nonresponders did not reveal considerable changes at the fourth month evaluation. A negative correlation was found between serum HBV-DNA copies and interferon-gamma levels prior to therapy (P < 0.01, r: -0.66). The analysis of cytokine levels with serum transaminases demonstrated a positive correlation between the tissue interleukin-12 levels at the fourth month and serum ALT levels at the beginning and second month of the therapy (r: 0.77, P < 0.05 and r: 0.92, P < 0.05, respectively). This is the first study emphasizing the relationship between tissue cytokine levels and therapy success. Understanding the course of chronic hepatits B in the pediatric population will help us to clarify some debates on the treatment.

Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization.

Arthrogryposis, renal dysfunction and cholestasis syndrome (ARC) is a multisystem disorder associated with abnormalities in polarized liver and kidney cells. Mutations in VPS33B account for most cases of ARC. We identified mutations in VIPAR (also called C14ORF133) in individuals with ARC without VPS33B defects. We show that VIPAR forms a functional complex with VPS33B that interacts with RAB11A. Knockdown of vipar in zebrafish resulted in biliary excretion and E-cadherin defects similar to those in individuals with ARC. Vipar- and Vps33b-deficient mouse inner medullary collecting duct (mIMDC-3) cells expressed membrane proteins abnormally and had structural and functional tight junction defects. Abnormal Ceacam5 expression was due to mis-sorting toward lysosomal degradation, but reduced E-cadherin levels were associated with transcriptional downregulation. The VPS33B-VIPAR complex thus has diverse functions in the pathways regulating apical-basolateral polarity in the liver and kidney.

Infantile hepatic hemangioendothelioma: clinical presentation and treatment.

BACKGROUND/AIMS: Hepatic hemangioendotheliomas are rare tumors in childhood. We report our 10-years' experience in a tertiary health center. METHODS: This retrospective analysis included eight patients with infantile hepatic hemangioendothelioma. RESULTS: The median age at diagnosis was 24 days (age range: 1 to 70 days) and the female/male ratio was 5/3. The main symptoms were abdominal distention and respiratory distress. Cutaneous hemangiomas were present in four cases. Three infants had Kasabach-Merritt syndrome. Four cases had single hepatic tumors while the others had multiple. The tumor size ranged from 2 cm to 10 cm in diameter. These lesions were located equally in the right and left hepatic lobes, and three babies had bilobar involvement. Most of the multifocal hepatic tumors were associated with skin hemangiomas. Treatment options were assessed individually. Systemic prednisolone therapy (2 mg/kg/d) was commenced in six patients. Five patients responded to corticosteroids. One boy with Kasabach-Merritt syndrome did not respond to this therapy. Interferon-alpha (1 million units (MU)/m2/day) was started, and the daily dose of the drug was increased up to 10 MU/m2, administered 3 times per week, until clinical improvement was achieved. The response was very good and we observed only constitutional adverse symptoms. Two cases were operated; one died from intraoperative bleeding. Other patients were alive and well for 11 to 66 months. Overall survival was 87% in our series. CONCLUSIONS: The treatment approaches depend on the center's experience. A multidisciplinary approach is required for the best treatment option.