Effect of interferon therapy on glucose metabolism in children with chronic hepatitis B.

The aim of this study was to investigate the effect of interferon (IFN)-alpha treatment on glucose metabolism in children with chronic hepatitis B (CHB). Forty children with CHB received IFN 10 MU/m2 for six months. Oral glucose tolerance test, anti-insulin and anti-glutamic acid decarboxylase (GAD) antibody, fasting plasma C-peptide and insulin (FPI), postprandial insulin, homeostasis model assessment of insulin resistance (HOMA-IR), HOMA-cell, and glucose/insulin ratio (G/I) were measured before and after treatment. The last four parameters were also evaluated in healthy controls (n=42). In patients, fasting plasma glucose (FPG) and HOMA-IR levels were significantly lower than in controls (p = 0.001 and p = 0.020, respectively). There was a strong correlation between degree of liver disease and FPG. Two patients had hyperinsulinemia. HOMA-IR was suppressed in 7 patients enough to indicate increased sensitivity. FPI of 13 patients and HOMA-cell of 9 patients were lower than the minimum level of controls, features compatible with beta-cell hypofunction. Frequency of glucose metabolism abnormalities was not different before and after therapy. After therapy, only 1 patient developed anti-GAD antibody, and FPI of 8 children and HOMA-cell level of 9 children were lower than the minimum level of controls. Hyperinsulinemia was persistent in the same patients. We demonstrated that HBV-infected children had insulin sensitivity; however, no adverse effects of IFN on glucose homeostasis were seen.

A novel mutation of the GLUT2 gene in a Turkish patient with Fanconi-Bickel syndrome.

Fanconi-Bickel syndrome is a rare inherited disorder of carbohydrate metabolism. The disease is characterized by the association of a massive hepatomegaly due to glycogen accumulation, severe hypophosphatemic rickets and marked growth retardation due to proximal renal tubular dysfunction. Fanconi-Bickel syndrome is a single gene disease and is caused by defects in the facilitative glucose transporter 2 (GLUT2) gene (SLC2A2) on chromosome 3q26.1-26.3, which encodes for the glucose transporter protein 2 expressed in hepatocytes, pancreatic beta-cells, enterocytes, and renal tubular cells. Several mutations in a gene encoding a glucose transporter have been reported in patients with Fanconi-Bickel syndrome. Here we report a Turkish child who had a novel mutation that has not been described before and we discuss the knowledge regarding genetic mutations in this rare disease.

HLA types in Turkish children with celiac disease.

The aim of this study was to assess the distribution of human leukocyte antigen (HLA) groups in Turkish children with celiac disease (CD) and to investigate the association of HLA types and clinical manifestations of CD. Seventy-five children with CD were evaluated in two groups: Group I consisted of 45 classical celiac patients (15 males, 6.7+/-3.8 years); Group II consisted of 30 atypical celiac patients (9 males, 9.3+/-4.3 years). The control group consisted of 100 healthy renal transplantation donors. HLA typing was made serologically using standard lymphocytotoxicity techniques. HLA A29, B51, CW5, DR14, DR16, and DQ1 were the most common antigens in the control group. Frequency of HLA B13, CW7, B8, DR7, DR17 and DQ2 was higher in CD patients than in the control group (p<0.005, <0.05, <0.001, <0.001 and <0.001, respectively). The relative risks for HLA DQ2, B8, DR17 and B13 were 14.9, 13.6, 7.1 and 3.6, respectively. Frequency of HLA B35, DR11 and DQ7 was higher in classical CD than atypical CD, while a positive association was found between HLA B8 and atypical CD. A positive association was found between HLA B13, CW7 and DR17 in Turkish celiac patients in addition to HLA B8, DR7 and DQ2. This study also suggested that a correlation may exist between genotype and clinical manifestations.

A novel mutation in TRIM37 is associated with mulibrey nanism in a Turkish boy.

Mulibrey nanism is a rare autosomal-recessive disorder characterized by prenatal onset severe growth retardation and pericardial constriction associated with abnormalities of muscle, liver, brain and eye. More than 80% of previously reported patients are of Finnish origin in whom a founder mutation in the TRIM37 gene have been described. We report on a 7-year-old Turkish boy who presented with classical phenotypic features of mulibrey nanism. Mutation screening of the TRIM37 gene revealed that the proband had a homozygous two base pair deletion, c.1894_1895delGA, resulting in a frame-shift and a premature termination codon. Our proband is one of the rare examples of mulibrey nanism outside Finland and extends the mutation spectrum in this disorder.

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.

Horizontal transmission of hepatitis B virus in children with chronic hepatitis B.

AIM: To determine the possible routes of intrafamilial transmission pattern in pediatric cases of chronic hepatitis B virus (HBV) infection. METHODS: In this descriptive retrospective study, 302 children with chronic HBV infection from 251 families and their parents attending the Social Security Children's Hospital and Doctor Sami Ulus Children's Hopsital in Ankara between December 1998 and May 2000, were enrolled in. Screenings and diagnosis of chronic HBV infections were established according to the Consensus 2000. RESULTS: In the studied 302 children with chronic HBV infection, mothers of 38% and fathers of 23% were HBsAg positive. The HBsAg positivity in at least two siblings of the same family was 61% when both parents were HBsAg positive. CONCLUSION: It is well known that horizontal transmission is quite common in countries where Hepatitis B Virus is moderately endemic. To our best knowledge, this is the largest series observed regarding the horizontal transmission in pediatric chronic HBV infection in Turkey. It is necessary to expand the preventive programs to target not only the newborn period but also all stages of childhood.

Progressive familial intrahepatic cholestasis with normal GGT level appearing with lichenification and enlargement of hands and feet.

Progressive familial intrahepatic cholestasis is a serious disease of the liver, known as Byler disease, characterized by hepatocellular cholestasis. Severe pruritus and high serum bile acid concentrations are the most important diagnostic criteria of this autosomal recessive inherited disease. Here, we present a five-year-old boy with lichenification and enlargement of hands and feet as a sign of progressive familial intrahepatic cholestasis due to severe pruritus.

Comparison of antiviral effect of lamivudine with interferon-alpha2a versus -alpha2b in children with chronic hepatitis B infection.

AIM: To compare additive efficacy of combination therapy including interferon (IFN)-alpha2a+lamivudine (3TC) to IFN-alpha2b+3TC in children with chronic hepatitis B virus (HBV) infection. MATERIAL AND METHODS: Chronic hepatitis B infection was determined by presence of HBsAg, HBeAg and HBV DNA in serum screened at 3 months intervals for at least 1 year, serum alanine transaminase (ALT) levels more than 1.5-times the upper normal limit and chronic hepatitis with histological activity index (HAI) more than 6 by liver biopsy. Sixty-three children with chronic hepatitis B infection were treated randomly with thrice-weekly subcutaneous injections of 5 MU/m2 recombinant IFN-alpha2a (n=29) or recombinant IFN-alpha2b (n=34) with the same dose, intervals for 6 months. Patients also received 3TC (4 mg/kg/day, max 100 mg/day) orally daily combined with IFN and continued for 12 months. End of therapy response was defined as ALT normalization, HBV DNA clearance and HBe/anti-HBe seroconversion. Breakthrough infection was determined as re-emergence of HBV DNA in serum after its clearance. Response rate, incidence of side effects and breakthrough infection were compared between IFN-alpha2a+3TC- and IFN-alpha2b+3TC-treated patients. RESULTS: Response rate was 44.8% (n=13) with IFN-alpha2a+3TC and 47.1% (n=16) with IFN-alpha2b+3TC (P=1.0). No significant difference was found in respect to the DNA clearance (P=0.32), anti-HBe (P=1.0), anti-HBs (P=0.09) seroconversion and response rates (P=1.0) between the groups. Breakthrough infection was detected in 1 (3.4%) case on IFN-alpha2a and none of the cases on IFN-alpha2b (P=0.46). All of the patients experienced flu-like symptoms, malaise and fatigue; however, side effect interfering with therapy was not encountered. CONCLUSION: No significant difference was found in response rates achieved by combination therapies based on IFN-alpha2a and IFN-alpha2b. Clinical efficacy of 3TC and two different IFN subtypes was found similar.

Nonobstructive neonatal cholestasis: clinical outcome and scoring of the histopathological changes in liver biopsies.

The clinical outcome of nonobstructive neonatal cholestasis (NC) cases varies greatly and the prognosis is generally unpredictable. In this study, we aimed to evaluate the prognostic benefits of qualitative analysis of histopathological changes in nonobstructive NC cases. A total of 28 nonobstructive NC cases (18 neonatal hepatitis; 10 intrahepatic bile duct paucity) were studied. We analyzed the relationship between histopathological and clinical parameters. Hepatic inflammation, bridging necrosis, pericellular fibrosis, giant cell transformation, and extramedullary hematopoiesis were evaluated and scored according to their absence or presence in each case. The sum of the histopathological scores was accepted as "total pathological injury score." The height percentiles, the presence and the degree of hepatomegaly and ascites, and serum alanine aminotransferase (ALT), albumin, and bilirubin levels and prothrombin time were also evaluated and scored. The patients were divided into 2 clinical course groups considered "good" or "bad" according to the total clinical scores. For statistical analysis, Pearson's chi-square test, Mann-Whitney U-test, and receiver operating characteristic curve were used. We found a statistically significant negative relation between the clinical course and total pathological injury score (P = 0.042) and pericellular fibrosis (P = 0.016). In conclusion, during the interpretation of liver biopsies of nonobstructive NC, scoring of histopathological changes should be done for assessing the clinical prognostic outcome.

Celiac disease with various presentations.

BACKGROUND: Celiac disease (CD) has a wide clinical spectrum from malabsorption syndrome to extra intestinal presentations. A total of 45 children with CD presented with mainly chronic diarrhea (n :23), anemia (n: 12), and short stature (n: 10) were evaluated in this study. The aim was to find common parameters of CD with various presentations. METHODS: Basic anthropometric, biochemical and hematological parameters in cases with CD with various presentations were compared. RESULTS: It was found that children with CD presenting with chronic diarrhea were younger. There was no significant difference in hemoglobin levels in children with CD presenting with anemia. Children with CD with short stature had significantly lower serum vitamin B(12) levels and lower levels of height standard deviation scores, bone age delay, and alkaline phosphatase. CONCLUSIONS: It was concluded that children, especially infants with chronic diarrhea with CD, may not be affected with generalized malabsorption. Anemia and short stature are frequent findings in cases with CD whether they are main presenting symptoms or not. Children with CD presenting with short stature may have lower levels of vitamin B(12) than other presentations.

Detection of Cryptosporidium parvum infection in childhood using various techniques.

BACKGROUND: The protozoan parasite Cryptosporidium parvum, which causes acute gastroenteritis in both humans and animals, has become an important pathogen all over the world. C. parvum may cause asymptomatic or symptomatic acute infections of the digestive system in immunocompetent subjects, but life-threatening disease in immunocompromised hosts. The aim of this study was to determine the usefulness of conventional microscopic staining techniques in the detection of C. parvum. For this purpose, 50 unselected immunocompetent asymptomatic children were evaluated for C. parvum during routine upper endoscopy. MATERIAL/METHODS: Duodenal aspirates and duodenal biopsy samples from 37 girls and 13 boys, between the ages of 2 and 18 years, obtained by gastrointestinal upper endoscopy and concomitant stool samples were examined with different staining techniques. RESULTS: Two stool samples and one duodenal aspirate were positive for C. parvum, but we could not demonstrate C. parvum in any duodenal biopsy samples. Dyspepsia was the primary indication for upper endoscopy in the patient with positive duodenal aspirate sample. CONCLUSIONS: These findings indicate that there is a low asymptomatic carrier rate in immunocompetent subjects with no involvement of intestinal villius attachment in the duodenum. We also conclude that C. parvum is an infrequent parasite in asymptomatic subjects, most probably due to a very low prevalence of HIV positivity in Turkey.

Current therapeutic approaches in childhood chronic hepatitis B infection: a multicenter study.

BACKGROUND AND AIM: The aim of the present study was to compare the therapeutic efficacy of three different regimens in childhood chronic hepatitis B (CHB) infection. METHODS: A total of 182 children with CHB infection were prospectively allocated to three random groups. Sixty-two patients in the first group received high-dose interferon (IFN)-alpha 2b (10 MU/m2) thrice/weekly alone for 6 months. In the second (n = 60) and third groups (n = 60), IFN-alpha was used for 6 months (5 MU/m2) thrice/weekly in combination with lamivudine (LAM) (4 mg/kg, maximum 100 mg/day) for 12 months. Lamivudine was started simultaneously with IFN in the second group, while it was started 2 months prior to IFN injections in the third group. RESULTS: The initial mean alanine aminotransferase (ALT) values for the first, second and third groups were 109 +/- 93 IU/L, 101 +/- 64 IU/L and 92 +/- 42 IU/L, respectively (P > 0.05). At the end of the therapy, ALT values decreased to 82 +/- 111 IU/L, 38 +/- 41 IU/L and 29 +/- 16 IU/L in groups 1, 2 and 3, respectively. The mean ALT value of the first group was significantly different to the second and third groups (P = 0.046 and P = 0.002, respectively) at the end of the therapy and these differences were found to be sustained after 18 months. However, results in the second and third groups were similar (P > 0.05). There were no significant differences in HBeAg clearance and anti-HBe seroconversion at the initial stage, 12 months and 18 months between the three groups (P > 0.05). Hepatitis B virus (HBV) DNA clearance in the first group was different from the second and third groups, while the second and third groups had similar HBV DNA clearance ratios at 12 and 18 months. No significant difference was found in the complete response (normalization of ALT, clearance of HBV DNA and seroconversion of anti HBe) ratios of all groups (at 12 months: 28.8, 45.5, 35.8% and at 18 months 33.3, 49 and 34% in groups 1, 2 and 3, respectively, P > 0.05). CONCLUSIONS: Although the ALT normalization and HBV DNA clearance ratios of IFN plus LAM combination groups were better than the high-dose IFN-alpha monotherapy group, no significant difference was found in the complete response ratios of all three groups.