Mutation analysis of ATP7B gene in Turkish Wilson disease patients: identification of five novel mutations.

Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene that encodes a P-type copper transporting ATPase. The aim of this study was to screen and detect mutations of the ATP7B gene in unrelated Turkish Wilson disease patients (n = 46) and control group (n = 52). Mutations were screened and detected by DNA sequencing. 30 out of 46 patients had mutations. 24 different Wilson disease related mutations were identified in those patients. The distribution of mutations in ATP7B gene was as follow: 17 missense, 3 nonsense, 1 silent, 3 frameshift (1 insertion, 2 deletion). None of them were not found in the control group. Five out of 24 mutations were found to be novel. Four of them were missense (c.2363C > T, c.3106G > A, c.3451C > T, c.3733C > A). The last one was deletion (c.3111delC). 10 single nucleotide polymorphisms (SNPs) given in the literature were found in both control and patients groups. Moreover one new polymorphism in exon 18 (c.3727G > A) not reported previously was discovered in both groups. It was striking that most of the mutations were found in exons 8, 12-14. This is the first study covering Turkish Wilson disease patients and control groups for mutation screening in all the coding regions of ATP7B gene by DNA sequencing method and adding five new mutations and one polymorphism into the HUGO Wilson disease mutation database.

Lamivudine and adefovir resistance in children and young adults with chronic hepatitis B.

OBJECTIVE: Long-term lamivudine (LAM) and adefovir (ADV) treatment has been found to induce the emergence of drug-resistant hepatitis B virus (HBV) in a significant number of patients with chronic hepatitis B (CHB) infection. The aim of our study was to evaluate the LAM and ADV mutations detected in our patient group. MATERIALS AND METHODS: Twenty-four patients diagnosed with CHB were enrolled in this study. The patient group consisted of those who had received 6 months of treatment with interferon-alpha and who did not response to this therapy. Patients were evaluated based on virologic and serologic response to therapy, and were classified as responders or non-responders. The treatment of non-responders continued with LAM (3mg/kg/d, maximum 100mg/d). Due to a lack of response to treatment, ADV (10mg/g) was added to the treatment regimen of eight young adult patients. The mutations associated with HBV drug resistance were investigated using reverse hybridization methods and PCR. RESULTS: The mutation studies indicated that 14 (58.4%) of the patients had resistance. Three patients developed ADV-associated mutations (A181T), one after 18 months of ADV; the other two had undergone 18 and 36 months of LAM therapy without ADV exposure. Although the average LAM treatment period of the patients with LAM resistance was longer than for those in whom no resistance was detected, no statistically significant difference was found. CONCLUSIONS: HBV treatment with nucleoside analogues results in the development of mutant strains, leading to drug resistance. Therefore genotypic resistance testing is important in planning and monitoring HBV treatment.

Infectious complications in pediatric liver transplantation candidates.

We analyzed infections that occurred within one month prior to LT, identified factors associated with their occurrence and effect of infections on post-transplant mortality. The study group included 40 consecutive children who underwent LT. Sites and types of infection and culture results were recorded prospectively. IID was assessed. Risk factors for the infectious events were analyzed. Forty infection episodes were found in 24 patients (60%); 90% were bacterial, 7.5% fungal, and 2.5% viral. Overall, IID was 38.2 per 1000 patient days. Sites of bacterial infection were urinary tract in 13 events (36.1%) and blood stream in 11 events (30.5%). Bacteremia (culture positive infection episodes) was identified in 19 events (52.7%). Gram-negative isolates were twice as frequent as Gram-positive infections (63.1% vs. 36.9%). Risk factors for the infectious complications were young age, low body weight, prior abdominal surgery, chronic liver disease related to biliary problems, presence of ascites, portal hypertension and cirrhosis, and high PELD score (p < 0.05 for all). Infectious complications in pediatric LT candidates are common. Preventive measures are important not only to reduce the infectious complications but also to prevent the post-operative mortality.

Acute hemorrhagic edema of infancy: a case report.

Acute hemorrhagic edema of infancy is a rare vasculitic syndrome affecting young children. Although presentation is dramatic and striking, it is a benign disorder. A 9-month-old boy with fever, rhinorrhea, edema, and purpuric lesions involving the face, oral mucosa, ears, and extremities was presented.

Liver transplantation for acute liver failure due to toxic agent ingestion in children.

ALF is characterized by sudden onset, impaired liver function, jaundice and encephalopathy, without previous liver disease. We analyzed the patients who underwent LT due to toxic agent induced ALF to raise community awareness about preventing the toxic agent induced ALF. Five children (three boys, two girls) underwent LT due to toxic agent ingestion. Toxic agents were mushroom poisoning (n = 2), Datura stramonium (n = 1), yellow phosphorous (n = 1) and INH (n = 1). On admission, one patient had stage IV, two had stage III and two had stage II hepatic encephalopathy but worsened during the follow-up. One patient had renal failure, and three patients required mechanical ventilation. Three patients underwent LRLT and others from a DD. Post-operative complications were managed by supportive managements successfully, and overall all the patients are alive (100% survival) without any organ sequelae. Although outcome of these patients are excellent, ALF may be prevented in these cases by educating the public about consuming mushrooms and toxic effects of wild plants, prohibiting fireworks and serial liver enzyme measurements after initiating INH.

Therapeutic efficacy of sequential and simultaneous treatments with interferon-alpha and lamivudine in children with chronic hepatitis B.

BACKGROUND: Interferon (IFN)-alpha and lamivudine (LAM), a nucleoside analog, are frequently used drugs for the treatment of chronic hepatitis B (CHB), and their combined therapy has been shown to be effective. The purpose of the present study was to examine the therapeutic efficacy of sequential and simultaneous combination therapies of IFN-alpha and LAM in children with CHB. METHODS: A total of 45 children with CHB, whose antibody status was positive for hepatitis B surface antigen (HBsAg), hepatitis B envelope antigen (HBeAg), and HBV-DNA at least for 6 months; who had alanine aminotransferase (ALT) levels 1.5-fold higher than normal and hepatic activity index scores higher than 6, were allocated to two groups. The first group included 24 children who were given standard dose IFN-alpha (5 MU/m(2) s.c., thrice weekly) for 6 months, followed by LAM (4 mg/kg per day per oral, maximum 100 mg/day) for an additional 6 months (sequential therapy group). The second group included 21 children who were given IFN-alpha and LAM therapy simultaneously for 6 months and who continued with LAM alone for another 6 months (simultaneous therapy group). Partial response was defined as normalization of ALT and eradication of HBV-DNA. Complete response was defined as normalization of ALT, eradication of HBV-DNA and e seroconversion. Non-responders were defined as having positive HBV-DNA and abnormal ALT levels. Sustained response was defined as absence of HBsAg and presence of hepatitis B surface antibody (anti-HBs). RESULTS: The mean age of the sequential therapy group was 12.7 +/- 4.1 years, and 16 (66.7%) of the patients were male. The mean age of the simultaneous therapy group was 14.8 +/- 4.6 years, and 15 (71.4%) were male. In the first group, 13 patients (54.2%) were non-responders; partial response was observed in five patients (20.8%), and complete response was seen in six patients (25%). Despite the occurrence of e seroconversion, normalization of ALT was not achieved in one case. In the second group, which consisted of 21 patients, 11 subjects (52.4%) were non-responders; partial response was observed in one case (4.8%), and complete response was seen in seven (33.3%). Sustained response was found in two patients (9.5%). There were no significant differences between the groups (P > 0.05). CONCLUSION: When the therapeutic efficiency of two different treatment regimens applied for 1 year was evaluated in childhood CHB therapy, it was remarkable that there was a sustained response and a higher complete response in group 2, although there was no considerable difference between the therapy results of both groups.

Infliximab treatment of pediatric refractory Crohn's disease: a case report.

Infliximab is a monoclonal antibody that targets TNF-alpha and has been shown to be effective for the management of steroid-dependent or refractory Crohn's disease. It is an effective therapy in adult patients, but experience in children is limited. We report a case of Crohn's disease which was refractory to the conventional treatment. A 14-year-old boy was admitted to the hospital with arthralgia and oral and perianal lesions. On physical examination his body weight was below the 3rd percentile, and height was between the 3rd-10th percentiles. He had elevated erythrocyte sedimentation rate and C-reactive protein and decreased hemoglobin, hematocrit and albumin levels. Barium enema and computerized abdominal tomography revealed a markedly distended small bowel with a narrowed area just above the ileocecal valve and terminal ileum. There was no mucosal pathology in his colonoscopic study. A regimen of prednisolone was begun with a diagnosis of Crohn's disease. In the first month of therapy the patient experienced progressive worsening of his symptoms, and azathioprine was added to the treatment in the second month. As he had exacerbation of his symptoms and worsening laboratory tests, infliximab infusions (5 mg/kg/d) were administered intravenously (at 0, 2 and 6 weeks) at the end of the 8th week. At the 6th week of treatment including two infusions of infliximab at 0 and 2 weeks, clinical and laboratory response occurred. The only side effect of the treatment was pneumonia, which was seen after the 6th week of the therapy. In conclusion, infliximab appears to be an effective and safe therapy for childhood refractory Crohn's disease.

Impact of liver transplantation on renal function of patients with congenital hepatic fibrosis associated with autosomal recessive polycystic kidney disease.

Congenital hepatic fibrosis (CHF) is an uncommon autosomal recessive malformation. It may be associated with extrahepatic manifestations such as polycystic kidney disease. The main consequence is portal hypertension and bleeding from varices. Despite liver transplantation as a therapeutic option for this patient, long-term impact of liver transplantation on renal functions of patients with autosomal recessive polycystic kidney disease with associated liver disease is not well known. In this study, we aimed to analyze the patient's renal function after liver transplantation by creatinine clearance, glomerular filtration rate, and renal resistive indexes. Between March 1997 and September 2002, three of 50 orthotopic liver transplantation (OLT) were performed because of CHF associated with ARPKD at Ege University Organ Transplantation and Research Center. Baseline immunosuppression consisted of prednisone and cyclosporine A (CSA). The mean follow-up of the patients was 2.1 yr. Blood urea and creatinine levels were decreased after operation in all patients and remained within the normal range at the sixth and 12th month, whereas the level of the third patient were increased at the 18th month. RRI values of patients were not found different at the sixth month whereas, RRI values of patients were decreased at the 12th month and remained unchanged at the 18th month of follow-up. During the study period hypertension developed in one patient at the 16th month and resolved with antihypertensive treatment and decreasing dosage of CSA. Kidney function has remained satisfactory in all of the patients despite the use of cyclosporine. OLT can provide good survival in patients with CHF associated with ARPKD.

Our experience with fulminant hepatic failure in Turkish children: etiology and outcome.

Fulminant hepatic failure is a rare and devastating event during childhood. The etiology of liver failure is reported to change according to age and geographical location. We aimed to investigate, retrospectively, causes and outcome of fulminant hepatic failure in Turkish children. Thirty-four children with fulminant hepatic failure were analysed by means of etiology and outcome. Etiological factor, clinical presentation, encephalopathy stage and biochemical parameters were correlated with outcome. Acute viral hepatitis was detected in 12 cases (35.2 per cent) and hepatitis A was the most commonly detected cause among cases with fulminant hepatic failure (n = 9, 26.4 per cent). Hepatitis B and non A-E infection were diagnosed in two (5.8 per cent) and one (2.9 per cent) cases, respectively. Wilson's disease was defined in four patients (12.5 per cent). Budd-Chiari syndrome (2.9 per cent), autoimmune hepatitis (2.9 per cent) and mushroom poisoning (2.9 per cent) were other detected causes of fulminant hepatic failure in this group. No viral, metabolic, toxic or anatomic reason could be detected in the remaining 15 (44.1 per cent) patients and they were evaluated as cryptogenic. Mortality was 67.6 per cent (23 cases). Encephalopathy grade, total and indirect bilirubin levels were found to be significantly higher in patients who died (p = 0.004, p = 0.03, p = 0.04). Seven patients could have been transplanted (two cadavaric, five living related) and the mortality of this group was 28.5 per cent (n = 2). It was concluded that fulminant hepatitis A virus (HAV) infection is the most common detectable cause of fulminant hepatic failure in Turkish children.