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.
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 & 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.
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.
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.
Taiwan began a universal hepatitis B virus (HBV) vaccination program for infants in July 1984. The seroprevalence of hepatitis B surface antigen (HBsAg) decreased from 9.8% before the vaccination ...program to less than 1% by 25 years afterward. We continued to monitor HBV infections in this population.
We conducted a series of serologic and epidemiologic surveys in the Taipei metropolitan area every 5 years from 1984 through 2014. From January 1 through December 31 of 2014, we collected serum samples from 4605 apparently healthy individuals (ages: 287 were <3 y, 405 were 3-6 y, 675 were 7-12 y, 686 were 13-18 y, 468 were 18-22 y, and 2084 were 22-50 y). All subjects were tested for HBsAg, its antibody (anti-HBs), and hepatitis B core antibody (anti-HBc). We performed genotype and viral load analyses for patients who tested positive for anti-HBc.
Of vaccinated participants (age, <30 y; n = 3299), 0.5% tested positive for HBsAg, 47.4% tested positive for anti-HBs, and 4.5% tested positive for anti-HBc. Of unvaccinated participants (age, 30-50 y, n = 1306), 6.7% tested positive for HBsAg (P < .0001), 69.4% tested positive for anti-HBs, and 44.1% tested positive for anti-HBc. One occult HBV infection was found in each age group. Among subjects positive for HBsAg younger than age 30, 77% were born to mothers positive for HBsAg.
Based on a series of serologic and epidemiologic surveys performed in the Taipei metropolitan area, 6.7% of persons born before the universal HBV vaccination program were positive for HBsAg, compared with 0.5% of those born afterward. Most subjects positive for HBsAg younger than age 30 were born to mothers positive for HBsAg.
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.
Background & Aims Mother-to-infant transmission is the major cause of hepatitis B virus (HBV) infection among immunized children. There has been much debate about screening pregnant women and ...administering hepatitis B immunoglobulin (HBIG) to newborns. We analyzed the rate of HBV infection among children born to hepatitis B surface antigen (HBsAg)-positive mothers and whether HBIG administration reduces transmission. Methods We analyzed data from 2356 children born to HBsAg-positive mothers, identified through prenatal maternal screens. In addition to HBV vaccines, HBIG was given to all 583 children with hepatitis B e antigen (HBeAg)-positive mothers and to 723 of 1773 children with HBeAg-negative mothers. Serology tests for HBV were performed from 2007 to 2009, when children were 0.5–10 years old. Results A significantly greater percentage of children with HBeAg-positive mothers tested positive for antibodies against the hepatitis B core protein (16.76%) and HBsAg (9.26%) than children with HBeAg-negative mothers (1.58% and 0.29%, respectively; P < .0001 and <.001). Among the HBV-infected children, the rate of chronicity also was higher among children with HBeAg-positive mothers than children with HBeAg-negative mothers (54% vs 17%; P = .002). Similar rates of antibodies against the hepatitis B core protein (0.99% and 1.88%; P = .19) and HBsAg (0.14% and 0.29%; P = .65) were noted in children born to HBeAg-negative mothers who were or were not given HBIG. Infantile fulminant hepatitis developed in 1 of 1050 children who did not receive HBIG (.095%). Conclusions Children born to HBeAg-positive mothers are at greatest risk for chronic HBV infection (9.26%), despite immunization. Administration of HBIG to infants born to HBeAg-negative mothers did not appear to reduce the rate of chronic HBV infection, but might prevent infantile fulminant hepatitis. Screening pregnant women for HBsAg and HBeAg might control mother-to-infant transmission of HBV.
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