Fu-Chen Huang

Pediatric fulminant hepatic failure in endemic areas of hepatitis B infection: 15 years after universal hepatitis B vaccination

To investigate the role of hepatitis B virus (HBV) infection in pediatric fulminant hepatic failure (FHF) after the launch of universal HBV vaccination, the authors analyzed the data from patients with FHF collected from a nationwide collaborative study group. Children aged 1 month to 15 years who were diagnosed with FHF (62 males and 33 females) between 1985–1999 were included. HBV infection (hepatitis B surface antigen [HBsAg] and/or immunoglobulin M hepatitis B core antibody [IgM anti‐HBc] seropositive) accounted for 46% (43 of 95 cases) of all the cases of FHF. The average annual incidence of FHF in the time period 1985–1999 was 0.053/100,000 in the group of patients ages 1–15 years and 1.29/100,000 in those patients age < 1 year. Approximately 61% (58 of 95 cases) of all FHF cases were infants. The percentage of HBV infection was found to be higher in infants (57%) compared with children ages 1–15 years (27%) (P = 0.004). The incidence rate ratio of those patients age < 1 year to those ages 1–15 years was 54.2 for HBV‐positive FHF and 15.2 for HBV‐negative FHF. Maternal HBsAg was found to be positive in 97% of the infants with HBV‐positive FHF, and hepatitis B e antigen (HBeAg) was found to be negative in 84% of these infants. Approximately 74% of all HBV‐positive FHF patients and 81% of the infantile HBV‐positive patients had been vaccinated. In conclusion, within the first 15 years of universal vaccination, HBV was found to rarely cause FHF in children age > 1 year but remained a significant cause of FHF in infants. HBV‐positive FHF was prone to develop in infants born to HBeAg‐negative, HBsAg‐carrier mothers; these infants had not received hepatitis B immunoglobulin according to the vaccination program in place. (HEPATOLOGY 2004;39:58–63.)

Long-term follow-up of duodenal ulcer in children before and after eradication of Helicobacter pylori.

BACKGROUND Helicobacter pylori is a well-known cause of chronic antral gastritis and plays an important role in the pathogenesis of peptic ulcer disease in adults. However, because of the relatively low incidence of duodenal ulcer in childhood, few studies have been directed specifically at the relation between the treatment of H. pylori infection and duodenal ulcer in children. An evaluation in a larger patient population is necessary to draw a conclusion. METHODS Twenty-six children with duodenal ulcer and H. pylori antral gastritis received triple therapy (amoxicillin, bismuth, and metronidazole) to investigate whether eradication of the organisms can promote healing and prevent relapse of the ulcers in children. Endoscopic examinations were performed before, 2 months, and 12 months after the beginning of treatment. RESULTS H. pylori infection was eradicated in 25 (96%) of the 26 patients who underwent upper endoscopic follow-up. Clinical improvement and ulcer healing were achieved in 24 (92%) of 26 children. During a mean follow-up of nearly 2 years, the annual ulcer relapse rate was estimated to be 9%. CONCLUSIONS Triple therapy is the treatment of choice for endoscopically proven duodenal ulcer and histologically proven H. pylori antral gastritis in children. It strongly supports a causal relation between H. pylori and duodenal ulcer disease in children.

Lamivudine treatment in maternally transmitted chronic hepatitis B virus infection patients

Background : Lamivudine treatment in chronic carriers who acquired hepatitis B virus through maternal transmission were investigated.

Factors affecting the mortality of pediatric fulminant hepatic failure in relation to hepatitis B virus infection

Aim:  To investigate the factors affecting the outcome of fulminant hepatic failure (FHF) in children in relation to hepatitis B virus (HBV) infection.

Genome-Wide Association Study Identifies Novel Susceptibility Genes Associated with Coronary Artery Aneurysm Formation in Kawasaki Disease

Kawasaki disease (KD) or Kawasaki syndrome is known as a vasculitis of small to medium-sized vessels, and coronary arteries are predominantly involved in childhood. Generally, 20–25% of untreated with IVIG and 3–5% of treated KD patients have been developed coronary artery lesions (CALs), such as dilatation and aneurysm. Understanding how coronary artery aneurysms (CAAs) are established and maintained in KD patients is therefore of great importance. Upon our previous genotyping data of 157 valid KD subjects, a genome-wide association study (GWAS) has been conducted among 11 (7%) CAA-developed KD patients to reveal five significant genetic variants passed pre-defined thresholds and resulted in two novel susceptibility protein-coding genes, which are NEBL (rs16921209 (P = 7.44 × 10−9; OR = 32.22) and rs7922552 (P = 8.43 × 10−9; OR = 32.0)) and TUBA3C (rs17076896 (P = 8.04 × 10−9; OR = 21.03)). Their known functions have been reported to associate with cardiac muscle and tubulin, respectively. As a result, this might imply their putative roles of establishing CAAs during KD progression. Additionally, various model analyses have been utilized to determine dominant and recessive inheritance patterns of identified susceptibility mutations. Finally, all susceptibility genes hit by significant genetic variants were further investigated and the top three representative gene-ontology (GO) clusters were regulation of cell projection organization, neuron recognition, and peptidyl-threonine phosphorylation. Our results help to depict the potential routes of the pathogenesis of CAAs in KD patients and will facilitate researchers to improve the diagnosis and prognosis of KD in personalized medicine.

Hepcidin-Induced Iron Deficiency Is Related to Transient Anemia and Hypoferremia in Kawasaki Disease Patients

Kawasaki disease (KD) is a type of systemic vasculitis that primarily affects children under the age of five years old. For sufferers of KD, intravenous immunoglobulin (IVIG) has been found to successfully diminish the occurrence of coronary artery lesions. Anemia is commonly found in KD patients, and we have shown that in appropriately elevated hepcidin levels are related to decreased hemoglobin levels in these patients. In this study, we investigated the time period of anemia and iron metabolism during different stages of KD. A total of 100 patients with KD and 20 control subjects were enrolled in this study for red blood cell and hemoglobin analysis. Furthermore, plasma, urine hepcidin, and plasma IL-6 levels were evaluated using enzyme-linked immunosorbent assay in 20 KD patients and controls. Changes in hemoglobin, plasma iron levels, and total iron binding capacity (TIBC) were also measured in patients with KD. Hemoglobin, iron levels, and TIBC were lower (p < 0.001, p = 0.009, and p < 0.001, respectively) while plasma IL-6 and hepcidin levels (both p < 0.001) were higher in patients with KD than in the controls prior to IVIG administration. Moreover, plasma hepcidin levels were positively and significantly correlated with urine hepcidin levels (p < 0.001) prior to IVIG administration. After IVIG treatment, plasma hepcidin and hemoglobin levels significantly decreased (both p < 0.001). Of particular note was a subsequent gradual increase in hemoglobin levels during the three weeks after IVIG treatment; nevertheless, the hemoglobin levels stayed lower in KD patients than in the controls (p = 0.045). These findings provide a longitudinal study of hemoglobin changes and among the first evidence that hepcidin induces transient anemia and hypoferremia during KD’s acute inflammatory phase.

Interferon-gamma Genetic Polymorphism and Expression in Kawasaki Disease.

AbstractKawasaki disease (KD) is a systemic vasculitis of unknown etiology. IFNG gene encoding interferon (IFN)-&ggr;, produced by natural killer cells and T cells, has been suggested to play an important role in the immunopathogenesis of Kawasaki disease. The aim of this study was to examin the correlation of gene polymorphisms of the IFNG gene and plasma levels of IFN-&ggr; in KD patients and their outcomes.A total of 950 subjects (381 KD and 569 controls) were recruited. Three tagging single-nucleotide polymorphisms (rs2069718, rs1861493, rs2069705) were selected for TaqMan allelic discrimination assay. Clinical phenotypes, coronary artery lesions (CAL), coronary artery aneurysms (CAA) and intravenous immunoglobulin (IVIG) treatment outcomes were collected for analysis. Plasma IFN-&ggr; levels were also measured with an enzyme-linked immunosorbent assay.Polymorphisms of the IFNG gene were significantly different between the normal controls and KD patients. The G allele of rs1861493 conferred a better response to IVIG treatment in KD patients. AA allele frequencies of rs1861493 were also associated with a significantly higher risk of CAA in KD patients. Furthermore, the plasma IFN-&ggr; level was lower in the AA allele than in the GG allele of rs1861493 both before and after IVIG treatment in KD patients.This study provides the first evidence supporting an association between IFNG gene polymorphisms, susceptibility of KD, IVIG responsiveness, and plasma IFN-&ggr; levels in KD patients.

Major methylation alterations on the CpG markers of inflammatory immune associated genes after IVIG treatment in Kawasaki disease

BackgroundKawasaki disease (KD) is an autoimmune disease preferentially attacking children younger than five years worldwide. So far, the principal treatment to KD is the administration of Intravenous immunoglobulin (IVIG). Although DNA methylation plays important regulation roles in diseases, few studies investigated the regulation roles of DNA methylation in KD.MethodsIn this study, we focused not only on the DNA methylation alterations resulted from KD onset but also on DNA methylation alterations resulted from IVIG administration. To do so, we investigated the effects of KD’s onset and IVIG administration on CpG marker’s methylation alterations.ResultsWe first found that DNA methylation alterations reflecting disease onset or IVIG administration are contributed mainly by the CpG markers on autosomes. In addition, we also demonstrated that some CpG markers carry methylation alteration among samples, forcing the expression abundance of the downstream genes to be also altered and negatively correlated with methylation profile. Finally, compared with KD’s onset, IVIG administration brings stronger impact on methylation alteration. And, such alterations were conducted mainly by hyper-methylating CpG markers, forcing the corresponding genes to keep lower expression levels. Moreover, the genes regulated by the altered CpG markers with IVIG administration are enriched in the pathways associated with inflammatory immune response.ConclusionsIn summary, our result provides researchers with another way into the regulation mechanism through which IVIG represses excessive inflammatory responses.

Infantile Hepatitis B in Immunized Children: Risk for Fulminant Hepatitis and Long-Term Outcomes

Background Infantile hepatitis B after neonatal immunoprophylaxis is a rare yet distinct disease. This study aimed to analyze the long-term outcomes and risk factors in immunized infants with hepatitis B. Methods The clinical parameters and outcomes of 41 infants born after universal immunization, and admitted for HBV-positive hepatitis were studied. All patients were followed for at least 6 months (median  = 4.4 years, range 0.6–18.1 years). Patient survival, changes of HBsAg and HBeAg status, and complications were analyzed. Results Among the 41 cases (32 males, 9 females), 21 presented with fulminant hepatitis (FH), and 20 with non-fulminant hepatitis (NFH). Ninety-five percent (36/38) of the mothers were positive for hepatitis B surface antigen (HBsAg). Multivariate analyses revealed younger age of onset (age <7 months) and negative maternal hepatitis B e antigen (HBeAg) were associated with FH (p = 0.03 and p = 0.01, respectively). An infantile fulminant hepatitis B risk score using maternal/infant HBeAg positivity and onset age was proposed. Among the FH cases, the rate of mortality, HBsAg clearance, and chronic HBV infection were 47.6%, 38.1%, and 14.3%, respectively. Among the NFH cases, 35% developed chronic infection. Of the 9 chronically infected children received long-term follow-up, 8 had HBeAg seroconversion before 4 years of age. One case of FH developed hepatocellular carcinoma 14 years later. Conclusions Maternal HBsAg + /HBeAg- and early onset age were risk factors for FH in immunized infants. A significant portion of patients with FH or NFH evolve to chronic HBV infection, with HBeAg seroconversion in young childhood. Close surveillance for hepatocellular carcinoma is warranted in patients surviving infantile hepatitis B.

Helicobacter pylori infection and duodenal ulcer in children and adolescents.

To investigate the relationship between H. pylori infection and duodenal ulcer in children and adolescents, the markers of H. pylori infection were studied in 22 children and adolescents who had duodenal ulcers and were followed prospectively (Group A). Another 36 patients with gastrointestinal symptoms, but without ulcer, were also studied for comparison (Group B). Antral and duodenal tissues were biopsied and analyzed for the presence of H. pylori using three standard methods: urease test, culture and histology. The specific IgG antibody against H. pylori positivity using the ELISA method were also analysed. By these three methods, H. pylori positivity in the antral tissues, chronic active antral gastritis, and seroprevalence rate were found to be much higher in Group A than Group B. However, a similar trend was not found in the duodenal tissues. H. pylori was found in four of five patients during postoperative follow-up for duodenal ulcer. Among the four patients, no duodenal ulcer but chronic active gastritis was detected endoscopically in three who received vagotomy. Only the one who received simple closure of the perforated duodenal ulcer had a recurrent duodenal ulcer. It was concluded that a close relationship among duodenal ulcer, chronic active gastritis and H. pylori is present in children and adolescents.