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).
Background & Aims Immunoprophylaxis reduces but does not completely eradicate hepatitis B virus (HBV) transmission. This prospective study aims at assessing the rate and risk factors of maternally ...transmitted HBV infection. Methods We enrolled 303 mother-infant pairs with positive maternal hepatitis B surface antigen (HBsAg) under current immunization program. Maternal viral load was determined by a real-time PCR-based assay. The children were tested for HBsAg at 4–8 months and/or 1–3 years of age. Rates of HBV infection were estimated using a multivariate logistic regression model. Results HBeAg-positive mothers (81/303, 26.7%) had higher viral loads than HBeAg-negative mothers (7.4 ± 1.9 vs. 2.7 ± 1.4 log10 copies/ml, p <0.0001). Ten children, born to HBeAg-positive mothers with high viral load (median, 8.4; range, 6.5–9.5 log10 copies/ml), were chronically infected. After adjustment for maternal age, birth type, factors related to maternal-fetal hemorrhage, gestational age, infant gender, birth weight, timeliness of vaccination, and feeding practice, maternal viral load was significantly associated with risk of infection (adjusted odds ratio for each log10 copy/ml increase, 3.49; 95% confidence interval (CI), 1.63–7.48; p = 0.001). The predictive rates of infection at maternal viral load levels of 7, 8, and 9 log10 copies/ml were 6.6% (95% CI, 0.5–12.6%; p = 0.033), 14.6% (95% CI, 5.6–23.6%; p = 0.001), and 27.7% (95% CI, 13.1–42.4%; p <0.001), respectively. Conclusions Additional strategies to further reduce transmission should be considered in mothers with a viral load above 7–8 log10 copies/ml.
Background: A genome-wide association study identified variants in or near patatin-like phospholipase domain-containing-3 (PNPLA3), neurocan (NCAN), lysophospholipase-like 1 (LYPLAL1), glucokinase ...regulatory protein (GCKR), and protein phosphatase 1 regulatory subunit 3b (PPP1R3B) that were strongly associated with nonalcoholic fatty liver disease (NAFLD) in adults of European ancestry.Objective: We examined these genetic variants in obese children and tested whether their effects on NAFLD are significant in the Taiwanese Han Chinese population.Design: We genotyped PNPLA3 rs738409, NCAN rs2228603, LYPLAL1 rs12137855, GCKR rs780094, and PPP1R3B rs4240624 in 797 obese children aged 7–18 y. NAFLD was identified by liver ultrasonography. We analyzed the effect of these genetic variants on NAFLD.Results: NAFLD was identified in 24% of the recruited obese children. We found significant associations with NAFLD at variants in PNPLA3 and GCKR but not in NCAN, LYPLAL1, and PPP1R3B. Multiple logistic regression analysis showed that, after control for the effects of age- and sex-adjusted body mass index, waist-to-hip ratio, sex, and PNPLA3 rs738409 polymorphism, the variant GCKR rs780094 TT genotype independently increased the OR of NAFLD by 1.997 (95% CI: 1.196, 3.335; P = 0.008) compared with the CC genotype. Subjects with the variant GCKR rs780094 TT genotype had a higher mean serum alanine aminotransferase concentration than did those with the CC genotype (30.8 ± 34.7 compared with 22.2 ± 18.6 IU/L; P = 0.01).Conclusions: By studying the genetic variants of obese Taiwanese children, we confirmed that the genetic variants in GCKR rs780094 and PNPLA3 rs738409, but not in NCAN rs2228603, LYPLAL1 rs12137855, and PPP1R3B rs4240624, are associated with an increased risk of NAFLD. GCKR and PNPLA3 variants are the common genetic factors that may confer susceptibility to NAFLD in obese individuals across multiple ethnic groups. This trial was registered at clinicaltrials.gov as NCT00274183.
Background & Aims Hepatitis B virus (HBV) infection was hyperendemic in Taiwan before the implementation of the universal infant hepatitis B immunization program, which was launched in 1984. Five ...previous seroepidemiologic surveys were conducted at 0, 5, 10, 15, and 20 years after the launch of the vaccination program. Methods We enrolled 3332 subjects younger than 30 years of age, with approximately 100 of them in each age cohort. Subjects were recruited voluntarily from schools and other institutions in Taipei, as in previous surveys. HBV seromarkers included hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) and hepatitis B core antigen (anti-HBc). HBV DNA levels were measured in anti-HBc positive/HBsAg negative subjects (anti-HBc only). Results The HBsAg, anti-HBs, and anti-HBc seropositive rates were very different between subjects born after the program in 2009 and the baseline group in 1984 (0.9% vs. 10%, 55.9% vs. 24.5%, and 7.0% vs. 28%, respectively). In this 6th survey, we showed that HBsAg prevalence further decreased in the vaccinated cohorts. A positive maternal HBsAg status was found in 86% of vaccine failures. Serum HBV DNA was detected in 4.2% (6/142) of anti-HBc positive/HBsAg negative subjects, with a low level of HBV DNA. All of these six subjects’ HBV were genotype C. Conclusions The universal infant HBV immunization program in Taiwan has completed its 25-year follow-up and its efficacy in young adults is clear. The continued decrease in HBsAg prevalence suggests that the elimination of HBV infection is becoming a reality.
Jaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of ...bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis.
The major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway.
Understanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.
Background/Aims
There are substantial genetic components contributing to the susceptibility of nonalcoholic fatty liver disease (NAFLD). It has recently been reported that the rs641738 C>T variant in ...the membrane‐bound O‐acyltransferase domain‐containing protein 7 (MBOAT7) gene increased severity of NAFLD in adults of European descent. We aimed to test the hypothesis that MBOAT7 rs641738 variant would increase hepatic steatosis and hepatocellular injury in obese children.
Methods
A total of 831 obese children aged 7‐15 years were recruited. Hepatic steatosis was measured by ultrasonography. Because PNPLA3 rs738409, GCKR rs780094 and TM6SF2 rs58542926 variants are known to confer susceptibility to NAFLD, we assessed the influence of MBOAT7 rs641738 on hepatic steatosis, and serum levels of CK‐18 fragment (a biomarker of hepatocellular injury and apoptosis for NAFLD) after adjusting the effects of PNPLA3, GCKR and TM6SF2 polymorphisms.
Results
Of the recruited obese children, 22.7% had hepatic steatosis. PNPLA3 rs738409, GCKR rs780094 and TM6SF2 rs58542926 variants were independent risk factors of hepatic steatosis and elevated ALT levels. In contrast, MBOAT7 rs641738 variants, neither heterozygous nor homozygous genotypes, were not associated with hepatic steatosis, insulin resistance, lipid levels and liver enzymes. The multiple linear regression model revealed that after adjusting for age, gender, body mass index z score, PNPLA3 rs738409 and GCKR rs780094 variants, but not MBOAT7 rs641738, were associated with serum levels of CK‐18 fragment.
Conclusions
The variant MBOAT7 rs641738 genotype is not associated with hepatic steatosis and serum levels of CK‐18 fragment in obese Taiwanese children.
Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, ...hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as “neonatal intrahepatic cholestasis caused by citrin deficiency” (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose‐free and medium‐chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long‐term follow‐up of NICCD patients into adolescence and adulthood.
Citrin deficiency: a metabolic disorder causing neonatal cholestasis and steatosis.
What is Known
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disorder caused by SLC25A13 gene mutations that may recover or progress to liver cirrhosis.
SLC25A13 gene mutations may have a late‐onset phenotype causing neuropsychiatric symptoms in adulthood.
What is New
Citrin deficiency has been described in several countries beyond Asia and should be considered in the differential diagnosis of all infants with cholestasis and growth failure.
A genetic diagnosis, which is now widely available, is the most reliable tool to confirm citrin deficiency, given the significant variability in both clinical manifestations and genetic mutations.
Early diagnosis and treatment results in improved growth and better patient outcomes.
Background Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma. This population-based study aimed to investigate whether prevention of hepatocellular carcinoma by the ...universal Taiwanese HBV vaccine program, launched in July 1984, has extended beyond childhood and to identify the predictors of hepatocellular carcinoma for vaccinated birth cohorts. Methods Data on 1958 patients with hepatocellular carcinoma who were aged 6–29 years at diagnosis in Taiwan between 1983 and 2004 were collected from two national hepatocellular carcinoma registries. Age- and sex-specific incidence among vaccinated and unvaccinated birth cohorts were analyzed by using Poisson regression models. All statistical tests were two-sided. Records of 64 hepatocellular carcinoma patients and 5 524 435 HBV vaccinees who were born after the initiation of the vaccination program were compared for HBV immunization characteristics during infancy and prenatal maternal hepatitis B surface antigen (HBsAg) and e antigen (HBeAg) serostatus. Results Hepatocellular carcinoma incidence was statistically significantly lower among children aged 6–19 years in vaccinated compared with unvaccinated birth cohorts (64 hepatocellular cancers among vaccinees in 37 709 304 person-years vs 444 cancers in unvaccinated subjects in 78 496 406 person-years, showing an age- and sex-adjusted relative risk of 0.31, P < .001, for persons vaccinated at birth). The risk of developing hepatocellular carcinoma for vaccinated cohorts was statistically significantly associated with incomplete HBV vaccination (for those who received fewer than three doses of HBV vaccine, odds ratio OR = 4.32, 95% confidence interval CI = 2.34 to 7.91); with prenatal maternal HBsAg seropositivity (OR = 29.50, 95% CI = 13.98 to 62.60); with prenatal maternal HBeAg seropositivity (with administration of hepatitis B immunoglobulin at birth, OR = 5.13, 95% CI = 2.24 to 11.71; and without it, OR = 9.43, 95% CI = 3.54 to 25.11). Conclusion The prevention of hepatocellular carcinoma by this HBV vaccine extends from childhood to early adulthood. Failure to prevent hepatocellular carcinoma results mostly from unsuccessful control of HBV infection by highly infectious mothers.
Chronic hepatitis B virus (HBV) infection in endemic areas usually starts since infancy and early childhood and persists lifelong. The clinical course varies among different chronic infected ...subjects. Majority of chronic HBV infected children present with immune-tolerant status initially, experience the immune clearance phase with various degree of liver injury during or beyond puberty, and then enter the inactive phase after hepatitis B e antigen (HBeAg) seroconversion. Part of them may have HBV DNA titers elevation with hepatitis flare after HBeAg seroconversion, the so call HBeAg-negative hepatitis flare. Liver cirrhosis, and even hepatocellular carcinoma may develop afterward.The complex course of chronic HBV infection is associated with the age/route of viral acquisition, host factors such as immune and endocrine factors, viral factors, and host-viral interactions. The adrenarche and puberty onset modulate the start of immune clearance and the severity of liver inflammation in chronic HBV infected children. The genotype and phenotype of human cytokines, innate immunity, and human leukocyte antigens are also associated with the onset of immune clearance of HBV and severity of inflammation. Immune escape HBV mutant strains, emerged during the immune clearance phase under host immune surveillance, may cause different impacts on viral biosynthesis, host immune responses, and clinical course.Early events in childhood during chronic HBV infection may serve as important predictors for the later outcome in adulthood. Understanding the mechanisms triggering liver inflammation and their long-term impacts may enhance the development of better and earlier therapeutic strategies for patients with chronic HBV infection.
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