After perinatal transmission of hepatitis B virus, infants of anti-HBe positive HBsAg carrier mothers may develop fulminant hepatitis B. Previously it has been suggested, that fulminant hepatitis B ...in adults was associated with specific mutations in the HBV-genome. The aim of this study was to investigate, whether specific viral variants are associated with fulminant hepatitis B in young infants.
The complete HBV-genomes of five mothers and their infants with fulminant hepatitis were isolated from the sera, amplified and directly sequenced.
Between 6 and 43 base pair exchanges between the HBV genomes of the infants and their mothers were identified. The mutations spread over the entire virus genome. Nucleotide exchanges in the basic core promotor and precore region were identified in all cases. A heterogeneous virus population was detected in four mothers.
Many new mutations were proved to emerge during fulminant hepatitis B in infants, who had been perinatally infected. HBeAg negative variants were the predominant population in all children, whereas these mutants could only be detected as subpopulations in four mothers. The data suggest that the selection of a specific HBeAg negative viral strain may be associated with the development of fulminant hepatitis B in children.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological ...processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum (ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal glycosylation in plasma.
BackgroundHepatitis B virus (HBV) can be transmitted by blood donors and organ donors who are positive for antibody to HBV core antigen (anti-HBc) but negative for all other HBV markers. Therefore, ...we evaluated the risk of infection for babies of mothers with this serostatus MethodsA total of 2365 HBV surface antigen (HBsAg)–negative pregnant women were included in the study and screened for anti-HBc. Blood samples for screening were collected 1 day before or after delivery. Infants of mothers with positive anti-HBc test results were tested 3–4 months after birth ResultsOf 2365 mothers, 147 (6.2%) were anti-HBc positive. Follow-up tests were performed using samples from 105 children. Samples were tested for all HBV markers, including HBV DNA, which was evaluated using a highly sensitive polymerase chain reaction assay (Taq PCR). Seven children (6.6%) had markers of HBV infection; the Taq PCR detected HBV DNA in 5, and HBsAg was detected in the other 2 ConclusionsThis study shows that HBV can be transmitted perinatally even in the absence of HBsAg. None of the children developed chronic HBV infection. Further studies must determine whether routine immunization of infants at the age of 3 months gives enough protection against HBV infection or whether screening of pregnant women for HBV should be extended, with immunization of their newborns beginning immediately after birth
Peginterferon plus ribavirin is standard therapy for adults with chronic hepatitis C. As no data are available for children, the aim of the study was to evaluate the efficacy and tolerability of ...peginterferon alfa-2b in combination with ribavirin in chronically infected children. Genotypes, alanine aminotransferase levels, and different routes of viral transmission were considered. In an open-labeled, uncontrolled pilot study, 62 children and adolescents (range, 2-17 years) were treated with subcutaneous peginterferon alfa-2b at a dose of 1.5 microg/kg body weight once per week plus oral ribavirin (15 mg/kg x day) for 48 weeks. Sixty-one patients completed the study. Twenty-three children discontinued therapy after 6 months according to study protocol. Sustained viral response was documented in 22 (47.8%)of 46 patients with genotype 1, in 13 (100%) of 13 with genotype 2 or 3, in 1 of 2 with genotype 4, in 19 (70.4%) of 27 children with parenteral, in 12 (48%) of 25 with vertical, and in 5 of 9 with unknown route of infection. Overall, treatment was well tolerated. Nevertheless, some side effects were present in all treated patients. Eighty-three percent had leucopenia, but only 3 individuals required dose reduction and 10.3% developed thyroid autoantibodies and thyroid dysfunction. In conclusion, combination treatment of peginterferon alfa-2b with ribavirin showed encouraging results and was well tolerated in children and adolescents with chronic hepatitis C. Weekly dosing of peginterferon alfa-2b is a considerable advance for this age group. The treatment is not approved for children. Further controlled trials are needed.
Liver failure is a heterogeneous condition which may be fatal and the primary cause is frequently unknown. We investigated mitochondrial oxidative phosphorylation in patients undergoing liver ...transplantation. We studied 45 patients who had liver transplantation due to a variety of clinical presentations. Blue native polyacrylamide gel electrophoresis with immunodetection of respiratory chain complexes I-V, biochemical activity of respiratory chain complexes II and IV and quantification of mitochondrial DNA (mtDNA) copy number were investigated in liver tissue collected from the explanted liver during transplantation. Abnormal mitochondrial function was frequently present in this cohort: ten of 40 patients (25 %) had a defect of one or more respiratory chain enzyme complexes on blue native gels, 20 patients (44 %) had low activity of complex II and/or IV and ten (22 %) had a reduced mtDNA copy number. Combined respiratory chain deficiency and reduced numbers of mitochondria were detected in all three patients with acute liver failure. Low complex IV activity in biliary atresia and complex II defects in cirrhosis were common findings. All six patients diagnosed with liver tumours showed variable alterations in mitochondrial function, probably due to the heterogeneity of the presenting tumour. In conclusion, mitochondrial dysfunction is common in severe liver failure in non-mitochondrial conditions. Therefore, in contrast to the common practice detection of respiratory chain abnormalities in liver should not restrict the inclusion of patients for liver transplantation. Furthermore, improving mitochondrial function may be targeted as part of a complex therapy approach in different forms of liver diseases.
Treatment with alfa-interferon alone yielded poor results in children with chronic hepatitis C and was not generally recommended. Owing to limited experience with combination therapy in children, the ...aim of the study was to evaluate the efficacy and tolerability of alfa-interferon 2b in combination with ribavirin in these patients with different routes of viral transmission. In an uncontrolled pilot study, 41 children and adolescents ranging from 3 to 16 years were treated with alfa-interferon at a dose of 3 or 5 MU/m
2 3 times weekly in combination with oral ribavirin (15 mg/kg/d) for 12 months. The mode of infection was unknown in 4, parenterally transmitted in 16, and vertically transmitted in 21 children. Forty patients completed the study. Eleven children, who remained hepatitis C virus (HCV)-RNA positive 6 months after the beginning, discontinued therapy. One boy stopped treatment because of side effects. At the end of treatment 25 patients were HCV-RNA negative (61%). All individuals remained HCV-RNA negative during the 6-month follow-up period. Nine of 15 children with parenteral (56.3%), 14 of 21 with vertical (66.6%), and 2 of 4 with unknown route of infection responded. Side effects included minor clinical signs such as fever, flu-like symptoms, anorexia, and more severe signs (21.4%) such as the development of thyroid autoantibodies and impairment of thyroid function. In conclusion, combination of alfa-interferon with ribavirin seems to be an important advance in the treatment of chronic hepatitis C in children and adolescents. This also is true for both vertically infected patients and for individuals with normal transaminase levels before therapy. (H
EPATOLOGY 2002;36:1280-1284.)
Untreated, progressive familial intrahepatic cholestasis (PFIC) results in fibrosis, cirrhosis, and liver failure. It has been shown that partial external biliary diversion (PEBD) may prevent from ...liver transplantation in patients without cirrhosis. The aim of this study is to present a new laparoscopic technique using a button instead of a bowel conduit for PEBD.
Two boys with PFIC (patient 1, 17 months; patient 2, 12 years) underwent laparoscopic button cholecystostomy using a 3-trocar technique by insertion of a 14 French MIC KEY button (Kimberly-Clark Worldwide, Inc, Draper, Utah, United States) at the gallbladder fundus secured with two absorbable purse-string sutures. Beside the suitability of the procedure, end points included course of serum bile acids, total bilirubin, liver enzymes, and pruritus at a follow-up of 6 months.
No complications related to the operation occurred. Relieve of pruritus was achieved in both the children, due to adequate bile drainage during a follow-up period of 6 months. In patient 2, a 10-mm gallstone was removed simultaneously. In patient 1, serum bile acids decreased from 12.3 to 6.6 µmol/L and in patient 2, serum bile acids decreased from 106.3 to 2.9 µmol/L. Total bilirubin, aspartate amino transferase, alanine amino transferase, and gamma-glutamyltransferase are kept in normal ranges during follow-up. Patient's and parent's acceptance with the button was excellent.
Laparoscopic button cholecystostomy is a simple, safe, and sufficient technique for PEBD in patients with PFIC. It achieves an adequate bile flow with consecutive relief of pruritus and avoids an enteric anastomosis.
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