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  • Pediatric Gastroenterology, Hepatology and Nutrition (兒童腸胃科)
  • Pediatrics (小兒科/部)
  • Clinical Associate Professor (臨床副教授)
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Research Outline      2014-10-31 13:10:15

1. Hepatitis B virus (HBV) infection:

1-1. Natural course of chronic HBV infection

We investigated the predictive effect of serial serum ALT and spontaneous HBeAg seroconversion age in chronic HBV infected children. During the chronic course of HBV infection, the median remaining times to spontaneous HBeAg seroconversion were 8.35, 5.14, 4.25, 3.95 and 2.80 years after the ALT levels crossed 20, 30, 40, 60, and 150 IU/L, respectively. The incidence rate of spontaneous HBeAg seroconversion within 6 months when a subject entered the phase of ALT between 60 and 150 IU/L was 5.57 times that of the phase with ALT < 60 IU/L.
1-2. Host genetic background and chronic HBV infection: course of HBeAg and HBsAg seroclearance/seroconversion
1-2-1. Impact of host immune system
Cytokines are suspected to play roles in the complex immune response in the process of spontaneous HBeAg seroconversion. Based on a prospective cohort study design, we had identified single nucleotide polymorphisms at rs3212217 of IL-12β, and rs1800896 of IL-10 gene were significantly correlated with the age of spontaneous HBeAg seroconversion. Serum IL -10 level and inducible IL-12 level (PBMC in vitro HBcAg stimulation) were significantly higher in subjects with favorable cytokine genotype and predicting earlier spontaneous HBeAg seroconversion.
We further demonstrated the IL-10 and IL-12β mRNA abundances were positively correlated with IFN-γ expression levels in human liver. IFN-γ mRNA abundance was associated with lower furin, and higher PD-1/PD-L1 mRNA levels in liver tissue from HBeAg-positive patients. IFN-γ enhanced PD-L1 expression in hepatoma cells. In HepG2.2.15 cells, IFN-γ further suppressed furin and HBeAg expression. Furin inhibition and knockdown in HepG2.2.15 cells also down-regulate HBeAg and HBsAg biosynthesis. IFN-γ, downstream to IL-12 and IL-10, may modulate the inflammatory response to avoid excessive hepatocyte damage through the enhancement of PD-1/PD-L1 expression, whereas furin suppression may contribute to a reduction in HBeAg/HBsAg biosynthesis.
The HBV Precore/Core Gene Carboxyl Terminal Mutations, P135Q, emergence during the inflammatory phase was associated with HBeAg-seroconversion. It was associated with altered HBV capsid assembly, HBeAg biosynthesis, and reduced human immune responses following HBeAg-seroconversion. The G/G genotype at the IL-10 rs1800896 polymorphism associated with higher A2189C mutations, lower HBV viral load at immune inflammatory phase, and earlier spontaneous HBeAg seroconversion than A allele carriers.
Human TLR genes polymorphisms were assessed in 278 HBeAg-positive chronic HBV infected patients. T allele at TLR5 rs5744174 and C allele at TLR9 rs5743836 promoter predicted earlier HBeAg seroconversion. The T allele carriers at TLR5 rs5744174 predicted higher IFN-γ secretion, and the G allele carriers at TLR4 rs4986790 predicted spontaneous HBsAg seroclearance and seroconversion.

1-2-2. Impact of human hormone system
We investigated androgen factors in chronic HBV infected males in Taiwan from puberty to young adulthood. We identified that, earlier onset of puberty and V allele carrier at SRD5A2 V89L polymorphism sites associated with earlier onset age of spontaneous HBeAg seroconversion. Earlier onset of puberty also associated with higher serum ALT before HBeAg seroconversion and more HBV viral load decrement from puberty to young adulthood.
Earlier menarche is associated with earlier spontaneous HBeAg seroconversion in chronic HBV infected females. Higher serum DHEAS levels at puberty predicts more HBV viral titer decrement, and younger age of spontaneous HBeAg seroconversion in both genders.

2. Biliary Atresia (BA) and Liver transplantation:
2-1. Biliary atresia
Poor humoral immune response to recombinant HBV vaccine in BA infants as compared with healthy control had been identified. The long term protection against HBV is non-inferior to healthy population once the effective humoral immune response had been established after the primary vaccination.
Humoral immunogenicity to Measles, Rubella, and Varicella zoster virus vaccine in BA children were also noted to be inferior than age- and gender-matched counterparts after primary standard vaccination program. In BA patients, serum IL-12p40 levels before the Kasai operation were higher in the subjects with a 3-month jaundice-free status than in those without. The pre-operative IL-12p40 level was a good predictive biomarker of clinical outcome in children with BA undergoing the Kasai operation.
2-2. Pediatric liver transplantation
We had assessed the risk factors of PTLD in our hospital and identify the navity of EBV and transplantation before 1 year old are two important independent risk factors in Taiwan. More aggressive monitoring of EBV status in these subjects should be applied in Taiwan to avoid the occurrence of the serious complication.

3. Hepatoblastoma:
We conducted a genome wide scaning of genomic DNA from subjects with hepatoblastoma and identified some specific chromosomal microdeletion in 5p15.33 and 6q12.2. The change in 6q12.2 is correlated with tumor size at the initial presentation, and the change in 5p15.33 is correlated with patient survival and native liver survival in our subjects.

4. Gastrointestinal motility:
We investigated the role of MII-pH in diagnosing sliding hiatal hernia in GERD children. We demonstrated the ratio of reflux episodes detected by pH-probe to that by impedance probes >1 was more frequently noted in sliding hiatal hernia children than non-sliding hiatal hernia children. The sensitivity and specificity of this diagnostic tool to predict sliding hiatal hernia in GERD children are 93.8% and 79.6%, respectively.