Jae Sung Ko

Clinical and Histological Features of Nonalcoholic Fatty Liver Disease in Children

BackgroundNonalcoholic fatty liver disease (NAFLD) is becoming more frequently diagnosed as the prevalence of obesity in children increases rapidly.AimThe aim of this study was to investigate the correlation of clinical findings with histopathologic features in children with NAFLD.MethodsWe reviewed the clinical data and liver histology results of children with biopsy-proven NAFLD at Seoul National University Hospital. NAFLD was classified as simple steatosis, type 1 nonalcoholic steatohepatitis (NASH), characterized by ballooning degeneration and perisinusoidal fibrosis, or type 2 NASH, characterized by portal inflammation and portal fibrosis.ResultsAmong 80 total patients, 84% were male. All patients were obese or overweight. Insulin resistance was present in 96% of children. Perisinusoidal fibrosis was noted in 45% of children and portal fibrosis was noted in 77%. Simple steatosis was present in 22% of children, type 1 NASH in 34%, and type 2 NASH in 44%. No differences were found among NAFLD subtypes or NAFLD activity score with regard to sex, blood pressure, or levels of aminotransferase, fasting lipid, or insulin. Children with NASH were older and had higher body mass index than those with simple steatosis. Patients with type 2 NASH had higher body mass index and advanced fibrosis compared with patients with type 1 NASH.ConclusionsObesity and older age are associated with development of NASH. Type 2 NASH is the most common form and associated with a greater severity of obesity and advanced fibrosis.

Noninvasive Parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease

AIM To evaluate the noninvasive parameters and hepatic fibrosis scores in obese children with nonalcoholic fatty liver disease (NAFLD). METHODS A total of 77 children diagnosed with NAFLD via liver biopsy were included and divided into 2 subgroups according to the histopathologic staging of hepatic fibrosis: mild (stage 0-1) vs significant fibrosis (stage 2-4). Clinical and laboratory parameters were evaluated in each patient. The aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, AST/platelet ratio index (APRI), PGA index, Forns index, FIB-4, NAFLD fibrosis score, and pediatric NAFLD fibrosis index (PNFI) were calculated. RESULTS No clinical or biochemical parameter exhibited a significant difference between patients with mild and significant fibrosis. Among noninvasive hepatic fibrosis scores, only APRI and FIB4 revealed a significant difference between patients with mild and significant fibrosis (APRI: 0.67 ± 0.54 vs 0.78 ± 0.38, P = 0.032 and FIB4: 0.24 ± 0.12 vs 0.31 ± 0.21, P = 0.010). The area under the receiving operating characteristic curve of FIB4 was 0.81, followed by Forns index (0.73), APRI (0.70), NAFLD fibrosis score (0.58), AST/ALT ratio (0.53), PGA score (0.45), and PNFI (0.41). CONCLUSION APRI and FIB4 might be useful noninvasive hepatic fibrosis scores for predicting hepatic fibrosis in children with NAFLD.

Clinical features of congenital portosystemic shunt in children

Clinical features, images, complications, treatments, and prognosis of 10 children with congenital portosystemic shunt (CPSS) were reviewed. Nine children were diagnosed with intrahepatic shunts while one presented with extrahepatic shunt. CPSS was detected by prenatal ultrasonography in four infants. Three infants presented with galactosemia without an enzyme deficiency. Two children presented with mental retardation and attention deficit hyperactivity disorder. Pulmonary hypertension developed in two patients. Spontaneous closure occurred in four infants with intrahepatic shunts including patent ductus venosus. The shunts were closed using transcatheter embolizations in four patients with intrahepatic shunts. Conclusion: Intrahepatic shunts may close spontaneously. Transcatheter embolization is effective for the treatment of symptomatic intrahepatic shunts.

Tufting Enteropathy with EpCAM Mutations in Two Siblings.

Tufting enteropathy is a rare autosomal recessive disorder presenting with early-onset severe intractable diarrhea. The epithelial cell adhesion molecule gene (EpCAM) has recently been identified as the gene responsible for tufting enteropathy. Based on histology, a diagnosis of tufting enteropathy was made in two Korean siblings. They developed chronic diarrhea and failure to thrive. They had a broad nasal bridge and micrognathia. Duodenal and colonic biopsies showed villous atrophy, disorganization of surface enterocytes, and focal crowding resembling tufts. Protracted diarrhea continued and so cyclic parenteral nutrition was supplied. The sister had juvenile rheumatoid arthritis. Mutation analysis of EpCAM identified two compound heterozygous mutations in these siblings: 1) a donor splicing site mutation in intron 5 (c.491+1G>A) and 2) a novel nonsense mutation in exon 3 (c.316A>T, Lys106X). Analysis of EpCAM will be useful for genetic counseling and prenatal diagnosis of tufting enteropathy.

Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency in Korean Infants

Citrin is a liver-type mitochondrial aspartate-glutamate carrier encoded by the SLC25A13 gene, and its deficiency causes adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Here, the authors investigated clinical findings in Korean infants with NICCD and performed mutation analysis on the SLC25A13 gene. Of 47 patients with neonatal cholestasis, three infants had multiple aminoacidemia (involving citrulline, methionine, and arginine) and galactosemia, and thus were diagnosed as having NICCD. Two of these three showed failure to thrive. The laboratory findings showed hypoproteinemia and hyperammonemia, and liver biopsies revealed micro-macrovesicular fatty liver and cholestasis. The three patients each harbored compound heterozygous 1,638-1,660 dup/ S225X mutation, compound heterozygous 851del4/S225X mutation, and heterozygous 1,638-1,660 dup mutation, respectively. With nutritional manipulation, liver functions were normalized and catch-up growth was achieved. NICCD should be considered in the differential diagnosis of cholestatic jaundice in Korean infants.

Interferon-α Treatment of Chronic Hepatitis C in Children with Hemophilia

Background In children with hemophilia, hepatitis C virus (HCV) is the major cause of chronic liver disease. In this study, long-term efficacy of interferon-&agr; was studied to determine the factors that predict a sustained response to interferon therapy in young children with hemophilia who have chronic hepatitis C. Methods Seventeen Korean children with hemophilia and chronic hepatitis C were treated with 3.7 million units/m2 of interferon-&agr;2a three times weekly for 6 months. Liver biopsy, pretreatment serum HCV RNA quantitation with competitive reverse transcription assay, and HCV genotyping with reverse hybridization assay were performed. Results Hepatitis C virus genotypes 1a, 1b, and 2a were found in three (18%), five (29%), and six (35%) patients, respectively. Interferon-&agr; was well tolerated, and the frequency of bleeding did not increase. Of the 17 patients, 7 (41%) had a sustained response for 3 years after the end of therapy. Patients with a sustained response had lower pretreatment serum HCV RNA levels. One (13%) of eight patients with genotype 1 and five (83%) of six with genotype 2 had a sustained response (P < 0.05). Conclusions Interferon-&agr; treatment of chronic hepatitis C in children with hemophilia was safe and effective in producing sustained responses. The pretreatment serum HCV RNA level and viral genotype may be predictive factors for sustained response to interferon therapy.

Genetically confirmed Wilson disease in a 9-month old boy with elevations of aminotransferases.

Wilson disease (WD) is an autosomal recessive disorder of copper transport caused by alteration of the adenosine triphosphatase 7B gene. It is rare to diagnose WD below the age of three years. Molecular genetic testing is one of the most important diagnostic methods and may confirm the diagnosis in equivocal cases. We report a case of a 9-mo old boy with WD who presented as chronic hepatitis. Genetic analysis showed compound heterozygotes of p.G1186S and c.4006delA.

Aberrant CpG Island Hypermethylation in Pediatric Gastric Mucosa in Association With Helicobacter pylori Infection

CONTEXT Helicobacter pylori infection is primarily acquired during childhood and persists throughout life in the absence of eradication with antibiotics. Helicobacter pylori infection induces methylation in the promoter CpG island loci in gastric epithelial cells. Thus, aberrant CpG island hypermethylation in gastric epithelial cells likely occurs early in life, although there are no existing data supporting this notion. OBJECTIVES To identify whether aberrant CpG island hypermethylation occurs in pediatric stomach mucosa in association with H pylori infection and to compare methylation profiles of samples from pediatric and adult stomach tissues. DESIGN We analyzed pediatric (n = 47) and adult (n = 38) gastric mucosa samples for their methylation status in 12 promoter CpG island loci using the MethyLight assay and compared the number of methylated genes and the methylation levels in individual genes between H pylori -positive and H pylori -negative sample results and between pediatric and adult samples. RESULTS The average number of methylated genes was significantly higher in H pylori -infected pediatric samples than in H pylori -negative pediatric samples (3.4 versus 0.3, P < .001) and in H pylori -infected adult samples than in H pylori -negative adult samples (7.6 versus 0.9, P < .001). Seven genes showed significantly higher methylation levels in H pylori -infected pediatric samples than in H pylori -negative pediatric samples (all values were P < .05). CONCLUSIONS These results indicate that CpG island hypermethylation occurs in pediatric gastric mucosa in association with H pylori infection and that the genes affected by H pylori -associated hypermethylation were similar in pediatric and adult samples.

Clinical Application of Liver MR Imaging in Wilson’s Disease

Objective To determine whether there is a correlation between liver MR findings and the clinical manifestations and severity of liver dysfunction in patients with Wilsons disease. Materials and Methods Two radiologists retrospectively evaluated MR images of the liver in 50 patients with Wilsons disease. The Institutional Review Board approved this retrospective study and informed consent was waived. MR images were evaluated with a focus on hepatic contour abnormalities and the presence of intrahepatic nodules. By using Fishers exact test, MR findings were compared with clinical presentations (neurological and non-neurological) and hepatic dysfunction, which was categorized by the Child-Pugh classification system (A, B and C). Follow-up MR images were available for 17 patients. Results Contour abnormalities of the liver and intrahepatic nodules were observed in 31 patients (62%) and 25 patients (50%), respectively. Each MR finding showed a statistically significant difference (p < 0.05) among the three groups of Child-Pugh classifications (A, n = 36; B, n = 5; C, n = 9), except for splenomegaly (p = 0.243). The mean age of the patients with positive MR findings was higher than that of patients with negative MR findings. For patients with Child-Pugh class A (n = 36) with neurological presentation, intrahepatic nodules, surface nodularity, and gallbladder fossa widening were more common. Intrahepatic nodules were improved (n = 8, 47%), stationary (n = 5, 29%), or aggravated (n = 4, 24%) on follow-up MR images. Conclusion MR imaging demonstrates the contour abnormalities and parenchymal nodules of the liver in more than half of the patients with Wilsons disease, which correlates with the severity of hepatic dysfunction and clinical manifestations.

Does the Diagnostic Accuracy of the 13C‐Urea Breath Test Vary with Age Even After the Application of Urea Hydrolysis Rate?

Background: Endogenous CO2 production may be a possible explanation for higher false‐positive results reported for 13C‐urea breath test (UBT) in children below 6 years. In this study, we evaluated whether age affects the diagnostic accuracy of the 13C‐UBT even after the application of urea hydrolysis rate (UHR) in children.