Survey of hepatitis B virus infection status after 35 years of universal vaccination implementation in Taiwan.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) vaccination programs in Taiwan are one of the earliest programs in the world and have largely reduced the prevalence of HBV infection. We aimed to demonstrate the vaccination efficacy after 35 years and identify gaps toward HBV elimination. METHODS: A total of 4717 individuals aged 1-60 years were recruited from four administrative regions based on the proportion of population distribution. Serum levels of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) levels were assessed. HBV viral load, genotypes and HBsAg 'ɑ' determinant variants were evaluated if indicated. RESULTS: After 35 years of vaccination, the overall seropositivity rates for HBsAg and anti-HBc in Taiwan were 4.05% and 21.3%, respectively. The vaccinated birth cohorts exhibited significantly lower seropositivity rates for both markers compared to the unvaccinated birth cohorts (HBsAg: 0.64% vs. 9.78%; anti-HBc: 2.1% vs. 53.55%, respectively; p < 0.0001). Maternal transmission was identified as the main route of HBV infection in breakthrough cases. Additionally, increased prevalences of genotype C and HBsAg escape mutants were observed. CONCLUSION: The 35-year universal HBV vaccination program effectively reduced the burden of HBV infection, but complete eradication of HBV infection has not yet been achieved. In addition to immunization, comprehensive screening and antiviral therapy for infected individuals, especially for pregnant women, are crucial strategies to eliminate HBV.

Tenofovir alafenamide or tenofovir disoproxil fumarate in pregnancy to prevent HBV transmission: Maternal ALT trajectory and infant outcomes.

BACKGROUND: The use of antiviral agents, specifically tenofovir disoproxil fumarate (TDF), in pregnant women to prevent mother-to-child HBV transmission is a key step towards hepatitis elimination. However, data on using tenofovir alafenamide (TAF) is insufficient. The frequent occurrence of postpartum ALT flares may impact the clinical implementation. METHODS: The maternal and infant outcomes were compared in multi-centre trials of high viral load HBsAg/HBeAg+ pregnant women receiving TAF or TDF from the third trimester until 2 weeks postpartum with intensive follow-ups. To explore the dynamic pre- and postpartum changes in ALT levels, we used a group-based trajectory model for analysing data of 332 women from three prospective studies. RESULTS: After treatment, the maternal HBV DNA levels significantly decreased from baseline to delivery: 7.87 ± 0.59 to 3.99 ± 1.07 Log10 IU/mL TAF (n = 78) and 8.30 ± 0.36 to 4.47 ± 0.86 Log10 IU/mL (TDF, n = 53), with viral load reductions of 3.87 versus 3.83 Log10 IU/mL. The HBsAg-positive rates among 12-month-old infants were 1.28% (1/78) versus 1.82% (1/55) respectively (p = 1.00). Of the TAF or TDF-treated mothers, 25.64% versus 16.98% experienced ALT > 2X ULN, and 11.54% versus 1.89% received extended antiviral treatment. Our model revealed four distinct ALT patterns: stable ALT (87.2%), moderate (8.0%) or marked (2.4%) postpartum flares, or prepartum elevations (2.4%). CONCLUSIONS: TAF effectively reduces mother-to-child HBV transmission, but prophylaxis failure still occurred in few cases. Postpartum ALT flares are common in women receiving TAF or TDF during pregnancy. Approximately 12.8% of mothers may require extended postpartum antiviral treatment. CLINICAL TRIAL NUMBER: NCT03695029 (ClinicalTrials.gov).

Clinical experience of infantile hepatic hemangioma.

PURPOSE: To describe the clinical presentation, treatment preference, and relevant complications of infantile hepatic hemangioma (IHH) in propranolol era. METHODS: The National Taiwan University Hospital integrated Medical Database (NTUH-iMD) was used to enroll twenty-one cases of IHH diagnosed from 2006 to 2020. Medical charts were retrospectively reviewed. RESULTS: In nine patients (42.9%), IHH was found incidentally, and in seven patients (33%), it was detected during postnatal self-paid ultrasonography. Focal disease was determined in 17 patients, multifocal disease in 1 patient, and diffuse disease in 3 patients. Patients with diffuse disease had a lower hemoglobulin level than patients with focal IHH (9.38 vs. 12.6 mg/dL, p = 0.045). Two patients had Kasabach-Merritt phenomenon (KMP), one had hypothyroidism, and one had both. All patients with KMP had focal hepatic hemangiomas. Among the 17 patients with focal IHH, nine were prescribed propranolol, one was treated by surgical resection of the tumor, and the others had expectant management. All patients with multifocal and diffuse IHH were administered propranolol. One infant (7.7%) treated with propranolol had bradycardia initially but it subsided after dose adjustment. CONCLUSIONS: Most IHH is found incidentally or detected during postnatal ultrasonography screening. Patients with large focal lesions should also be screened for associated complications. Propranolol is the drug of choice and a safe therapeutic option for IHH, especially for focal tumors >5 cm as well as multifocal and diffuse lesions.

Characterization of Hepatitis B Virus in Tenofovir-Treated and Untreated Chronically Infected Mothers and Their Immunoprophylaxis Failure Infants.

BACKGROUND: Maternal tenofovir disoproxil fumarate (TDF) therapy during late pregnancy can reduce mother-to-infant transmission of hepatitis B virus (HBV). We investigated HBV mutations associated with maternal TDF therapy and their role in infant immunonophylaxis failure (IPF). METHODS: Serum samples from untreated (n = 89) and TDF-treated (n = 68), highly viremic, chronically infected mothers and their infants were analyzed for HBV DNA by nested polymerase chain reaction (PCR) and direct sequencing. RESULTS: At delivery, compared with untreated mothers, TDF-treated mothers had a lower HBV DNA titer and a higher frequency of basal core promoter (BCP) gene mutations, but they had similar frequencies in pre-S/S and pre-core/core mutations. The 14 mothers harboring surface "a" determinant mutants did not transmit the mutants to their immunized infants. Such mutants were found in 3 of 13 IPF infants; the 13 mothers had wild-type hepatitis B surface antigen (HBsAg). In univariable analysis, maternal HBV DNA titer (odds ratio [OR]: 1.54; 95% confidence intervals [CI]: 1.02-2.33; P = .039), genotype C (OR: 4.18; 95% CI: 1.28-13.62; P = .018) and pre-S1 wild-type sequence (OR: 6.33; 95% CI: 1.85-21.68; P = .003) at delivery were associated with infant IPF. Multivariable analyses showed that maternal genotype C (OR: 3.71; 95% CI: 1.11-12.36; P = .033) and pre-S1 wild-type (OR: 6.34; 95% CI: 1.79-22.44; P = .004) were associated with infant IPF independently of maternal viremia. CONCLUSIONS: Along with high maternal HBV DNA titer at delivery, maternal genotype C and pre-S1 wild-type sequence were potential risk factors for infant IPF, although BCP mutations were not. The offspring of pregnant women harboring "a" determinant mutants as major strains seemed to be protected by immunoprophylaxis. CLINICAL TRIALS REGISTRATION: NCT01312012.

Baseline Hepatitis B Virus Surface Antigen Titers in Childhood Predict the Risk of Advanced Liver Fibrosis in Adulthood.

BACKGROUND & AIMS: Hepatitis B virus (HBV) surface antigen (HBsAg) is a marker of both HBV covalently closed circular DNA and integrated HBV genome, whereas the HBV core-related antigen (HBcrAg) indicates the transcriptional activity of covalently closed circular DNA. This study examined the relationship between HBsAg and HBcrAg titers in childhood and advanced fibrosis in adulthood. METHODS: We recruited 214 initially hepatitis B e antigen-positive chronic HBV-infected patients who were followed for a total of 6371 person-years. None of the patients were co-infected with hepatitis C or D virus. Serum HBsAg and HBcrAg titers were assessed at 10 and 15 years of age. Transient elastography was performed at a mean final age of 38.21 years to identify advanced fibrosis. RESULTS: Patients with advanced fibrosis in adulthood had a higher rate of genotype C HBV infection and a higher HBsAg titer at 10 and 15 years of age (P = .003, P = .03, and P = .005, respectively). The HBcrAg titer was not correlated with advanced fibrosis (P > .05). Receiver operating characteristic curve analysis showed that HBsAg cutoffs of >4.23 and >4.44 log10 IU/mL at 10 and 15 years of age, respectively, best predicted advanced fibrosis in the fourth decade of life (P = .001 and P < .001, respectively). In a multivariate analysis, both an HBsAg titer >4.44 log10 IU/mL at 15 years of age and HBV genotype C were predictors of advanced fibrosis (odds ratios, 15.43 and 4.77; P = .01 and P = .02, respectively). CONCLUSIONS: HBsAg titers in childhood predict the progression to liver fibrosis in adulthood.

A Pilot Study of Biliary Atresia Newborn Screening Using Dried Blood Spot Matrix Metalloproteinase-7.

OBJECTIVES: Timely diagnosis is a critical challenge and is associated with improved survival of biliary atresia (BA) patients. We aimed to measure matrix metalloproteinase-7 (MMP-7) levels in BA patients within 3 days of birth using the dried blood spot (DBS) method and evaluate its potential as a screening tool. METHODS: The study enrolled 132 patients, including 25 patients diagnosed with BA and 107 non-BA patients with other congenital or perinatal conditions from the National Taiwan University Children Hospital. The stored DBS samples collected from 48 to 72 hours of life were retrieved from newborn screening centers. MMP-7 on the DBS was quantified using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: The MMP-7 levels of BA patients on the DBS were significantly higher than those of non-BA patients (19.2 ± 10.4 vs 5.6 ± 2.7 ng/mL, P value < 0.0001). MMP-7 levels in non-BA patients, including 5 patients with hepatobiliary structural anomaly, 9 patients with intrahepatic cholestasis, and 93 patients with other perinatal diseases, were 11.6 ± 4.2 ng/mL, 6.9 ± 3.0 ng/mL, and 5.2 ± 2.1 ng/mL, respectively. The DBS MMP-7 level showed good accuracy for identifying BA, with an area under the curve of 93.7% [95% confidence interval (CI): 87.7%-99.7%]. The MMP-7 cutoff at 8.0 ng/mL showed a sensitivity of 92.0% (95% CI: 75.0%-98.6%) and specificity of 92.5% (95% CI: 85.9%-96.1%) for detecting BA from other congenital or perinatal diseases. CONCLUSIONS: MMP-7 DBS analysis can be used to distinguish BA from other conditions as early as 3 days of age.

Universal Infant Hepatitis B Virus (HBV) Vaccination for 35 Years: Moving Toward the Eradication of HBV.

A universal hepatitis B virus (HBV) vaccination program has been implemented in Taiwan since 1984. A total of 1611 individuals in Taipei were enrolled to monitor long-term efficacy. The prevalences of hepatitis B surface antigen (HBsAg) and hepatitis B core antibody in the vaccinated birth cohort were lower than in those born before 1984 (0.4% vs 7.7%, and 2.2% vs 50.8%, respectively; P < .0001). Three vaccine-failure carriers all were born to HBsAg-carrier mothers, probably due to no antiviral intervention during pregnancy. Occult HBV infection was rare in the postvaccination era. High vaccination coverage, comprehensive HBV screening, and antiviral agents for pregnant mothers will be essential to eliminate HBV transmission.

Hepatitis B virus X gene impacts on the innate immunity and immune-tolerant phase in chronic hepatitis B virus infection.

BACKGROUND AND AIMS: The immunologic features involved in the immune-tolerant phase of chronic hepatitis B (CHB) virus (HBV) infection are unclear. The hepatitis B virus X (HBx) protein disrupts IFN-ß induction by downregulating MAVS and may destroy subsequent HBV-specific adaptive immunity. We aimed to analyse the impacts of genetic variability of HBx in CHB patients on the immune-tolerant phase during long-term follow-up. METHODS: Children with CHB in the immune-tolerant phase were recruited and followed longitudinally. HBx gene sequencing of infecting HBV strains was performed, and the effects of HBx mutations on the immune-tolerant phase were assessed. Restoration of the host immune response to end the immune-tolerant phase was investigated by immunoblotting, immunostaining, ELISA and reporter assays of MAVS/IFN-ß signalling in liver cell lines, patient liver tissues and the HBV plasmid replication system. RESULTS: A total of 173 children (median age, 6.92 years) were recruited. Patients carrying HBx R87G, I127V and R87G + I127V double mutations exhibited higher cumulative incidences of immune-tolerant phase breakthrough (p = .011, p = .006 and p = .017 respectively). Cells transfected with HBx R87G and I127V mutants and pHBV1.3-B6.3 replicons containing the HBx R87G and I127V mutations exhibited statistically increased levels of IFN-ß, especially under poly(I:C) stimulation or Flag-MAVS cotransfection. HA-HBx wild-type interacted with Flag-MAVS and enhanced its ubiquitination, but this ability was diminished in the R87G and I127V mutants. CONCLUSIONS: HBx suppresses IFN-ß induction. R87G and I127V mutation restored IFN-ß production by preventing MAVS degradation, contributing to curtailing the HBV immune-tolerant phase in CHB patients.

Fourteen-day sequential therapy is superior to 7-day triple therapy as first-line regimen for Helicobacter pylori infected children.

BACKGROUND/PURPOSE: Helicobacter pylori infection is one of the most common causes of peptic ulcer disease among children. This study is aimed to investigate the eradication rate of 14-day sequential therapy and the antibiotic resistance of H. pylori in children. METHODS: Eighty-seven treatment-naïve children (55 males; median age, 13.5 years) with H. pylori infection from January 2009 to August 2019 were recruited in this study. The status of H. pylori infection was confirmed by culture or histology with the aid of urea rapid test or C-13 urea breathe test. Patients treated with either triple therapy for 7 days or 14 days, or sequential therapy for 14 days was analyzed retrospectively. RESULTS: Thirty-eight (43.7%) patients received 14-day sequential therapy, 24 (27.6%) patients received 14-day triple therapy and the remaining 25 (28.7%) patients received 7-day triple therapy. The eradication rate of 14-day sequential therapy was significantly superior to 7-day triple therapy (97.4% vs. 80%, p = 0.032), and tended to be better than 14-day triple therapy (83%, p = 0.07). Of the 54 patients with available antibiotic resistance data, the resistant rate of clarithromycin, metronidazole, levofloxacin, and amoxicillin were 22.2%, 16.7%, 9.1% and 2.2%, respectively. Clarithromycin resistance demonstrated an inverse association with eradication success (Odds ratio = 0.017, p < 0.001). CONCLUSION: In treatment-naïve children with H. pylori infection, 14-day sequential therapy is superior to triple therapy, and achieve a high eradication rate (above 90%) in an area of high clarithromycin resistance.

Is the rating result reliable? A new approach to respond to a medical trainee's concerns about the reliability of Mini-CEX assessment.

PURPOSE: Whether the rating result of mini-clinical evaluation exercise (Mini-CEX) for rating clinical skills is reliable is of a medical trainee's great concerns. The objectives of this study were to analyze the test-retest reliability, interrater reliability and internal consistency reliability of Mini-CEX. METHODS: Three clinical scenarios, each played by a standardized patient and resident, were developed and videotaped. A group of assessors were recruited to rate the resident's clinical skills using Mini-CEX with a nine-point grading scale in each videotaped clinical scenario. Each assessor was required: (1) to watch the videotaped clinical scenarios a sequential order; (2) to rate each medical trainee's clinical skills in each clinical scenario for two rating sessions, and there must be a minimum three-week interval between the first and the second Mini-CEX rating session. RESULTS: A total of 38 assessors participated in this study. This study showed that: (1) an assessor carried out similar rating reuslts under the same clinical performance based on an acceptable test-retest reliability (Pearson's correlation coefficients = 0.24-0.76, P value=<0.01-0.14); (2) assessors gave similar rating results to a medical trainee's clinical performance based on a good interrater reliability (intra-class correlation coefficient = 0.57-0.83, P value=<0.01-0.03); and (3) the items reflected unidimensionally a construct-a medical trainee's clinical skills based on an excellent internal consistency reliability (Cronbach's alpha = 0.92-0.97). CONCLUSION: This study convincingly showed that Mini-CEX is a reliable assessment tool for rating clinical skills, and can be widely used to assess medical trainees' clinical skills.

Impacts of the Percentage of Basal Core Promoter Mutation on the Progression of Liver Fibrosis After Hepatitis B e Antigen Seroconversion.

BACKGROUND: We investigated the relationships among the percentage of hepatitis B virus (HBV) mutations and liver fibrosis after hepatitis B e antigen (HBeAg) seroconversion. METHODS: We quantified the percentage of HBV mutants by pyrosequencing using serum samples obtained at inflammatory phase and after HBeAg seroconversion in 160 initially HBeAg-positive chronic HBV-infected patients. The relationships between antiviral agents, percentages of HBV mutations, and liver stiffness measurements (LSMs) were analyzed. RESULTS: We demonstrated that the percentages of A1762T/G1764A mutation are significantly higher in subjects with an LSM >7 kPa than in those with an LSM ≤7 kPa after HBeAg seroconversion. Hepatitis B e antigen seroconversion age is positively correlated with the percentages of A1762T/G1764A mutation at inflammatory phase before HBeAg seroconversion. Subjects who underwent interferon, entecavir, or tenofovir disoproxil fumarate therapy before HBeAg seroconversion possessed a lower percentage of A1762T/G1764A mutation after HBeAg seroconversion. The percentage of A1762T/G1764A ≥20% after HBeAg seroconversion was predictive of an LSM >7 kPa (hazard ratio = 6.37, P = .001). The presence of A1762T/G1764A led to downregulated messenger ribonucleic acid and protein levels of programmed-death ligand-1 (PD-L1) in hepatocytes. CONCLUSIONS: The percentage of A1762T/G1764A mutations after HBeAg seroconversion was associated with liver fibrosis. The A1762T/G1764A mutation may evoke hepatic inflammation by suppressing PD-L1 in hepatocytes.

Occult Hepatitis B Virus Infection in Immunized Infants Born to Untreated and Tenofovir-Treated Highly Viremic Mothers.

Tenofovir disoproxil fumurate (TDF) therapy during late pregnancy in highly viremic mothers can reduce residual overt hepatitis B virus (HBV) infections of their infants that occur despite immunoprophylaxis.1,2 Occult HBV infection (OBI) has been defined as the presence of HBV DNA in liver or sera in subjects seronegative for hepatitis B surface antigen (HBsAg).3 OBI has been found in varying proportions of immunized infants born to HBsAg-positive mothers.4-6 We aimed to investigate the impact of maternal TDF therapy during pregnancy on vertically acquired OBI.

Serum bile acid levels assist the prediction of biliary stricture and survival after liver transplantation in children.

Biliary stricture is an important biliary complication after liver transplant in children. We aimed to investigate the utility of serum bile acid levels for prediction of biliary stricture in children after liver transplant. This study enrolled 60 children who underwent liver transplantation at a mean age of 2.04±0.30 years; serum bile acid levels were surveyed in a cross-sectional design. These patients were followed regularly at our institute, and the clinical data were collected prospectively. The major indication of liver transplant in this pediatric cohort was biliary atresia (78.33%). During the follow-up period (3.08±0.30 years), nine patients (15%) developed biliary stricture after the check of serum bile acid. A receiver operating characteristic curve analysis yielded a serum bile acid cutoff of >40 µM for the prediction of biliary stricture (P = 0.002). A serum bile acid level >40 is the most important predictor of a biliary stricture after liver transplant (odds ratio=65.65, P = 0.003) after adjusting for gender and GGT levels. The phenomenon remained on Cox's proportional hazard survival analysis (hazard ratio =15.42, P = 0.001). The mortality risk after liver transplant was significantly higher in subjects with serum bile acid levels >40 µM than in those with levels ≤40 µM (log-rank test, P = 0.004).Conclusion: Serum bile acid levels can be used for non-invasive screening and prediction of biliary stricture and mortality in children after liver transplantation. What is Known: • Biliary stricture is a major biliary complication after pediatric liver transplantation, and we showed the serum bile acid level significantly associates with biliary stricture. What is New: • In this study, we demonstrated the serum bile acid level may assist in the early detection of biliary stricture and mortality non-invasively.

Risk factors and management for anastomotic stricture after surgical reconstruction of esophageal atresia.

BACKGROUND/PURPOSE: Anastomotic stricture (AS) is a major morbidity of patients with esophageal atresia (EA) after surgical reconstruction. Our study determined the risk factors of AS after EA reconstruction. The therapeutic efficacy and complications of esophageal dilatation for children with AS were also evaluated. METHODS: Forty children treated for EA between January 2008 and December 2018 were included in this retrospective analysis. Esophageal dilatation was performed when AS was diagnosed. The therapeutic effect of esophageal dilatation was determined based on nutritional status, as assessed by the weight-for-age z-score. RESULTS: Sixteen EA patients developed AS. A gap >1.5 cm between the esophageal pouches (P = 0.02) in patients with EA and type A EA was a risk factor for developing AS. A mean of 7.7 sessions of esophageal dilatation were performed per patient, and no complications occurred. The nutritional status of EA children with AS after dilatation was not inferior to that of the children without AS at the 6-month follow-up. CONCLUSION: A gap >1.5 cm between the esophageal pouches and type A EA are risk factors for AS after esophageal reconstruction. Esophageal dilatation is both safe and effective for managing strictures and improves nutritional status in EA children with AS.

Long-term growth and bone development in children of HBV-infected mothers with and without fetal exposure to tenofovir disoproxil fumarate.

BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) is the preferred treatment to prevent maternal transmission of HBV, owing to its efficacy and safety. However, data are lacking on the long-term safety outcomes in children following fetal exposure to TDF. METHODS: Children participating in a prospective, multisite trial of maternal TDF treatment during late pregnancy were recruited for follow-up visits once a year. Growth parameters, serum biochemistry, HBV serology, and bone mineral density (BMD) by dual-energy x-ray absorptiometery scan were measured. RESULTS: One hundred and twenty-eight children, 71 in the TDF and 57 in the control group, completed 255 follow-up visits at the age of 2 to 7 (median, 4.08) years. No differences in z-scores for weight-for-age (0.26 ± 0.90 vs. 0.22 ± 0.99, p = 0.481), z-scores for height-for-age (0.20 ± 1.02 vs. 0.25 ± 0.98, p = 0.812), and estimated glomerular filtration rate (169.12 ± 50.48 vs. 169.06 ± 34.46 ml/min/1.73m2, p = 0.479) were detected. After adjustment for age, sex and HBV status by multiple linear regression, children in the TDF and control group had comparable levels of serum calcium, phosphorus, bone-specific alkaline phosphatase, calcidiol and BMD of lumbar spines (0.55 ± 0.01 vs. 0.57 ± 0.01 g/cm2, p = 0.159) and left hip (0.56 ± 0.01 vs. 0.56 ± 0.01 g/cm2, p = 0.926). CONCLUSIONS: Children of HBV-infected mothers who did or did not receive tenofovir disoproxil fumarate treatment during late pregnancy had comparable long-term growth, renal function, and bone development up to 6-7 years after delivery. CLINICAL TRIAL NUMBER: NCT01312012 (ClinicalTrials.gov) LAY SUMMARY: Currently there are insufficient long-term safety data in children born to mothers who took antiviral agents during pregnancy to prevent mother-to-infant transmission of hepatitis B virus (HBV). In this study, we found that children of HBV-infected mothers who did or did not receive tenofovir disoproxil fumarate treatment during late pregnancy had comparable long-term growth, renal function, and bone development up to 6-7 years after delivery.

Baseline Level of Hepatitis B Core Antibody Predicts Spontaneous Hepatitis B e Antigen (HBeAg) Seroconversion in HBeAg-Positive Children With a Normal Alanine Aminotransferase Level.

It is not clear whether baseline hepatitis B core antibody (anti-HBc) level in hepatitis B e antigen (HBeAg)-positive children with a normal alanine aminotransferase (ALT) level is predictive of spontaneous HBeAg seroconversion. We investigated the correlation between anti-HBc level and the natural course of chronic hepatitis B (CHB) virus (HBV) infection in children, particularly the ability of baseline anti-HBc level to predict spontaneous HBeAg seroconversion during long-term follow-up. HBeAg-positive children with untreated CHB and a normal ALT level were followed longitudinally. Anti-HBc level was determined by double-sandwich immunoassay. Effects of anti-HBc levels and other parameters on spontaneous HBeAg seroconversion and the natural course of CHB were assessed. A total of 182 children (106 males) with a median age at enrollment of 10.6 years (interquartile range [IQR], 10.3-15.3) were followed for a median of 19.8 years (IQR, 11.9-21.9). Spontaneous HBeAg seroconversion occurred in 85 children (46.7%) during the follow-up. A baseline anti-HBc titer of >500 IU/mL (hazard ratio [HR] = 2.81), HBV genotype B and B + C (HR = 3.46), and a baseline hepatitis B surface antigen titer of ≤4.8 log10  IU/mL (HR = 3.09) were predictive of spontaneous HBeAg seroconversion, based on multivariable survival analysis (P < 0.001). In cases remaining HBeAg positive, their anti-HBc levels increased gradually during follow-up because of ongoing inflammation. Conclusion: Baseline anti-HBc level is predictive of spontaneous HBeAg seroconversion in HBeAg-positive children with a normal ALT level. Anti-HBc level reflects anti-HBV immune response in the HBeAg-positive normal ALT phase of CHB.

Bilirubin level 1 week after hepatoportoenterostomy predicts native liver survival in biliary atresia.

BACKGROUND: To determine a very early predictive biomarker after hepatoportoenterostomy (HPE) for the prediction of native liver survival in biliary atresia (BA) patients. METHODS: A retrospective chart review was conducted of BA patients in our hospital between August 2000 and April 2019. The serum total bilirubin (T-bil), direct bilirubin, and gamma-glutamyl transferase level 1 week after HPE were analyzed. The clinical outcome predictors were investigated. RESULTS: A total of 90 BA patients were recruited. Receiver operating characteristic curve analysis showed that a post-HPE 1-week T-bil level ≤4.85 mg/dL predicted jaundice-free after HPE (P = 0.02). BA patients with a post-HPE 1-week T-bil ≤4.85 mg/dL were more likely to be jaundice-free within 3 months of HPE (odds ratio = 3.53; P = 0.006). Kaplan-Meier plot analysis showed that the likelihood of native liver survival and jaundice-free native liver survival were significantly higher in BA subjects with a post-HPE 1-week T-bil ≤4.85 mg/dL than in other subjects (P = 0.01 and 0.01, respectively). CONCLUSIONS: The serum post-HPE 1-week T-bil level may predict the long-term outcome in BA patients. A post-HPE 1-week T-bil ≤4.85 mg/dL correlated with better native liver survival and jaundice-free native liver survival in BA patients.

Dysregulation of liver developmental microRNA contribute to hepatic carcinogenesis.

BACKGROUND/PURPOSE: To investigate the role of microRNA (miRNA) dysregulation in liver cancer by assessing the miRNA profiles of human hepatic stem cells (HpSCs), marker-carrying human hepatoblastoma (HB) cells, and hepatocellular carcinoma (HCC) cells vs. those of fetal hepatocytes. METHODS: We subjected human HCC and HB tumor specimens to immunohistochemical (IHC) staining for markers of HpSCs. We analyzed the miRNA patterns of HpSCs, HCC cells, HB cells, and fetal hepatocytes using microarray analysis, with confirmation via quantitative real-time polymerase chain reaction. The roles of the miRNAs in liver cancer stem cells (CSCs) were also elucidated. RESULTS: The epithelial cell adhesion molecule (EpCAM) was the most prevalent HpSCs marker in human HB and HCC tumor cells and hepatoma cells. EpCAM-positive HB and HCC cells exhibited greater self-renewal and tumorigenicity than their EpCAM-negative counterparts or EpCAM-positive fetal hepatocytes. In EpCAM-positive fetal hepatocytes, miR-126 expression level increased with gestational age. The EpCAM-positive HB cells exhibited downregulation of miR-126 in comparison to EpCAM-positive fetal hepatocytes. An miR-126 mimic reduced sphere and colony formation in, and induced apoptosis of, HB cells. In comparison to EpCAM-positive fetal hepatocytes, EpCAM-positive HCC cells exhibited downregulation of miR-126, miR-144, and miR-451. Transfection of miR-126, miR-144, and miR-451 induced apoptosis of, and reduced sphere and colony formation in, HCC cells. CONCLUSION: Dysregulation of liver developmental miRNAs, which exert a tumor suppressant effect, in EpCAM-positive HpSCs may contribute to liver carcinogenesis by promoting the transformation of HpSCs to CSCs of HB and HCC.

Quantification of Serum Matrix Metallopeptide 7 Levels May Assist in the Diagnosis and Predict the Outcome for Patients with Biliary Atresia.

OBJECTIVE: To assess the diagnostic and prognostic usefulness of the serum matrix metallopeptidase-7 (MMP-7) level for biliary atresia in infants with cholestasis after hepatoportoenterostomy. STUDY DESIGN: We enrolled 100 infants with cholestasis (age, 43.56 ± 1.97 days; 62 males) with a direct bilirubin level of >1 mg/dL, of whom 36 (36%) were diagnosed with biliary atresisa. The MMP-7 levels in serum samples collected during the cholestasis workup and 6 months after hepatoportoenterostomy were assessed by enzyme-linked immunosorbent assay. We quantified liver fibrosis by Picro Sirius red staining of collagen in specimens from the 81 infants with cholestasis. RESULTS: Infants with biliary atresisa had a significantly higher serum MMP-7 level than that of non-biliary atresisa infants with cholestasis of equivalent age (P < .0001). Receiver operating characteristic analysis showed that a serum MMP-7 level of >1.43 ng/mL was predictive of biliary atresisa in infants with cholestasis (diagnostic accuracy, 88%). There was a positive correlation between the serum MMP-7 level and the severity of liver fibrosis (P = .0002). Survival analysis showed that the frequency of liver transplantation was significantly higher in infants with biliary atresisa with a serum MMP-7 level of >10.30 ng/mL compared with a serum MMP-7 level of ≤10.30 ng/mL after hepatoportoenterostomy (hazard ratio, 4.22; P = .02). CONCLUSIONS: The serum MMP-7 level, which reflects the severity of liver fibrosis and can be determined noninvasively, may facilitate the diagnosis of biliary atresisa among infants with cholestasis. Moreover, the serum MMP-7 level after hepatoportoenterostomy is associated with a need for liver transplantation in infants with biliary atresisa.

Transient elastography is useful in diagnosing biliary atresia and predicting prognosis after hepatoportoenterostomy.

We investigated the utility of transient elastography (TE) for diagnosing biliary atresia (BA) in cholestatic infants and predicting the outcome of BA. Forty-eight cholestatic infants (9-87 days of age) with direct bilirubin level >1 mg/dL were enrolled. Liver stiffness measurement (LSM) by TE was performed during the cholestasis workup, and 15 subjects were diagnosed as BA. We assessed liver histology using liver biopsies from 36 subjects and graded fibrosis status using the METAVIR score. BA infants had significantly higher LSM values and METAVIR scores than non-BA cholestatic infants. A receiver operating characteristic (ROC) curve analysis showed that an LSM >7.7 kPa was predictive of BA among cholestatic infants (sensitivity = 80%; specificity = 97%; area under the curve [AUC] = 85.3%; P = 0.0001). Cholestatic infants with an LSM >7.7 kPa were more likely to be diagnosed with BA (odds ratio [OR] = 128; P < 0.001). Very early measurement of LSM after hepatoportoenterostomy (HPE) is associated with occurrence of thrombocytopenia, splenomegaly, and esophageal varices 6 months post-HPE. Five of the BA subjects were awaiting or had received liver transplantation (LT), and they had a significantly higher LSM measured 1 week post-HPE than that in the other BA subjects (26.0 vs. 10.8 kPa; P = 0.006). A Cox proportional analysis demonstrated that the need for LT was significantly higher in BA subjects with LSM >16 kPa measured 1 week post-HPE than other BA subjects (hazard ratio [HR] = 10.16; P = 0.04). CONCLUSION: LSM assessment during the workup of cholestatic infants may facilitate the diagnosis of BA. LSM post-HPE may predict complications and the need for early LT in infants with BA. (Hepatology 2018).