Figen Ozcay

Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency

Hepatocellular carcinoma (HCC) is rare in young children. We attempted to see if immunohistochemical and mutational‐analysis studies could demonstrate that deficiency of the canalicular bile acid transporter bile salt export pump (BSEP) and mutation in ABCB11, encoding BSEP, underlay progressive familial intrahepatic cholestasis (PFIC)—or “neonatal hepatitis” suggesting PFIC—that was associated with HCC in young children. We studied 11 cases of pediatric HCC in the setting of PFIC or “neonatal hepatitis” suggesting PFIC. Archival liver were retrieved and immunostained for BSEP. Mutational analysis of ABCB11 was performed in leukocyte DNA from available patients and parents. Among the 11 nonrelated children studied aged 13‐52 months at diagnosis of HCC, 9 (and a full sibling, with neonatal hepatitis suggesting PFIC, of a tenth from whom liver was not available) had immunohistochemical evidence of BSEP deficiency; the eleventh child did not. Mutations in ABCB11 were demonstrated in all patients with BSEP deficiency in whom leukocyte DNA could be studied (n = 7). These mutations were confirmed in the parents (n = 14). With respect to the other 3 children with BSEP deficiency, mutations in ABCB11 were demonstrated in all 5 parents in whom leukocyte DNA could be studied. Thirteen different mutations were found. In conclusion, PFIC associated with BSEP deficiency represents a previously unrecognized risk for HCC in young children. Immunohistochemical evidence of BSEP deficiency correlates well with demonstrable mutation in ABCB11. (HEPATOLOGY 2006;44:478–486.)

Severe bile salt export pump deficiency : 82 different ABCB11 mutations in 109 families

BACKGROUND & AIMS Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. METHODS Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. RESULTS Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]). CONCLUSIONS With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential.

Helicobacter pylori Infection in Turkish Children: Comparison of Diagnostic Tests, Evaluation of Eradication Rate, and Changes in Symptoms after Eradication

Background.  Helicobacter pylori infection is most frequently acquired in childhood. After this organism is eradicated, the rate of reinfection is low. Thus, it is very important to diagnose and treat the disease appropriately in childhood, and to be able to assess eradication with certainty. Eradication of H. pylori infection is reported to reduce or eliminate abdominal pain and dyspeptic symptoms in children.

Neurological complications of liver transplantation in pediatric patients: A single center experience

Abstract:  Neurologic complications (NCs) are a significant cause of morbidity and mortality in patients who undergo liver transplantation (LT). The aim of this study was to evaluate the incidence and type of NCs and associated factors in pediatric LT patients. We retrospectively reviewed NCs in the medical records of 40 consecutive infants, children, and adolescents who underwent LT at our institution. The subjects consisted of 23 boys and 17 girls (median age, 8.5 ± 0.85 yr; range, 11 months to 17 yr). The indications for LT were Wilsons disease in 10 patients, fulminant hepatic failure (FHF) in nine, and other types of chronic liver disease in 21. NCs were found in 14 patients (35%). Those 14 individuals experienced a total of 16 episodes of NCs (two separate episodes in two of the patients). The most common NCs were seizure (seven episodes in six patients) and posterior leukoencephalopathy syndrome (PLES; five episodes in four patients). Seizure was the presenting symptom in three episodes of PLES. Two episodes of diffuse encephalopathy were observed in two patients, and two episodes of psychiatric symptoms occurred in two patients. We also noted one episode of tremor in one patient, one episode of acute dystonic reaction in one patient, and one episode of headache in one patient. Patients with Wilsons disease had a higher incidence of NCs (60%) than did patients without Wilsons disease (26.7%); however, this difference was not significant. The incidence of NCs was 44% in patients with FHF and 35% in those without FHF. That difference also was not significant. Immunosuppressive agents were the primary cause of 13 of the 16 episodes of NC. Uremia with hypertension, hypoxia, and hypomagnesemia caused one neurologic episode each. NCs, which are frequent in the first 30 days after pediatric LT, did not affect survival in this group. NCs were reversed by the discontinuation or reduction of immunosuppressive agents in 12 episodes, correction of hypomagnesemia and the reduction of immunosuppressive agents in one episode, and the correction of uremia and hypertension in one episode. Refractory epilepsy developed in one patient, and death unrelated to NCs occurred in one. The mortality rate was 7.1% (n = 1) in patients with NCs and 15.4% (n = 4) in those without NCs (p = 0.64). NCs are an important complication after LT. It is essential that each transplantation team collaborate with pediatric neurologists to ensure the rapid and accurate diagnosis of NCs in infants, children, and adolescents after LT and to prevent the delay of appropriate treatment.

Effect of Congenital Heart Disease on Renal Function in Childhood

Background: Nephropathy is a well-known complication of congenital heart disease (CHD), and the risk of developing renal impairment is particularly high in patients with cyanotic CHD. Most investigations of renal impairment in CHD have involved patients 20 years and older. This study investigated renal tubule function in pediatric patients with CHD, and compared findings in cyanotic and acyanotic groups. Methods: Twenty children with acyanotic CHD, 23 children with cyanotic CHD, and 13 healthy children were enrolled. Blood and early morning urine samples were collected from each subject to measure urinary concentrations of sodium, microalbumin, creatinine, β2-microglobulin, and N-acetyl-β-D-glucosaminidase (NAG). Results: The age and sex distributions in the three groups were similar. Median fractional excretion of sodium (FeNa) and urinary NAG/creatinine were significantly higher in the cyanotic group than in the control group (p = 0.022 and p = 0.002, respectively). There were no statistically significant differences among the groups with respect to urinary β2-microglobulin/creatinine, urinary microalbumin/creatinine or glomerular filtration rate. Conclusion: Tubular injury can be detected before glomerular injury occurs even within the first decade of life in patients with cyanotic CHD.

Hepatocellular carcinoma in Wilson's disease: A rare association in childhood

Abstract:  Wilsons disease is a hereditary disorder of copper metabolism that results in the accumulation of copper in the body, primarily in the liver, brain, and cornea. Hepatocellular carcinoma, in contrast to other causes of cirrhosis, is seldom associated with Wilsons disease. We present a 12‐yr‐old boy with Wilsons disease in whom hepatocellular carcinoma was incidentally diagnosed in the pathologic specimen examined after liver transplantation.

A family with Jeune syndrome.

Abstract  Jeune syndrome is a rare autosomal recessive disease characterized by narrow thoracic cage and short-limbed dwarfism. Seventy percent of affected individuals die in early childhood from pulmonary hypoplasia and respiratory distress due to the small size of the thorax. Growth retardation and chronic renal insufficiency due to nephronophthisis may occur in patients who survive the respiratory failure. We report a family that exhibited clinically heterogeneous features of Jeune syndrome. The 6-year-old male proband presented with skeletal deformities and chronic renal failure. A kidney biopsy revealed that nephronophthisis was the cause of the patient’s kidney failure,and we diagnosed Jeune syndrome. A retrospective diagnosis of Jeune syndrome was also established for the proband’s older sister, who haddied of renal failure at 8 years of age. The oldest female child in the family alsohad thoracic deformity, and the father and paternal uncle were both of short stature and exhibited brachydactyly. Their renal function and blood pressure were normal. The findings in this family are important in that they demonstrate the clinical heterogeneity of Jeune syndrome and underline the association of renal disease with this syndrome.

Effect of iron deficiency anemia on renal tubular function in childhood

Abstract.Little is known about renal function in children with iron deficiency anemia. The purpose of this study was to investigate renal tubular function in these children. We compared renal tubular function in 20 children with iron deficiency anemia with 20 healthy age-matched controls. Blood and urine samples were obtained for hematological and biochemical analysis. Mean fractional excretion of sodium and mean urinary N-acetyl-β-D-glucosaminidase/creatinine were significantly higher in the children with iron deficiency anemia than in controls (P<0.05). Hemoglobin levels were negatively correlated with urinary N-acetyl-β-D-glucosaminidase/creatinine (r= -0.44, P=0.015), but were not correlated with fractional excretion of sodium (r= -0.29, P=0.13). There was no correlation between urinary N-acetyl-β-D-glucosaminidase/creatinine and fractional excretion of sodium (r=0.32, P=0.09). The results suggest that children with iron deficiency anemia have impaired renal tubular function.

Type I diabetes mellitus, Hashimoto's thyroiditis and celiac disease in an adolescent with Down syndrome.

The prevalence of autoimmune diseases such as autoimmune thyroiditis, type I diabetes mellitus (DM), and celiac disease (CD) is higher in patients with Down syndrome (DS, or trisomy 21) than in the general population. 1,2 However, there are only a few published reports of coexistent autoimmune thyroid disease, type I DM and CD in a DS patient. 3 Here we describe the case of an adolescent boy with DS who was diagnosed with Hashimoto’s thyroiditis, type I DM and CD.

The Use of Levetiracetam in a Child with Nonconvulsive Status Epilepticus

Levetiracetam is an antiepileptic drug that was shown to be effective in various seizure types. Experience with this agent for treating status epilepticus is just emerging. To the best of our knowledge, there is no report in the literature regarding its use in children with nonconvulsive status epilepticus. We here report a liver-transplanted child with nonconvulsive status epilepticus who responded well to oral levetiracetam treatment.