Liver Briefs: Hep C Undertreated, Mystery Hepatitis Pediatric Cases, & AAP Hyperbilirubinemia Guidelines

Yesterday’s link to a funny 2 minute eulogy did not work right and has been fixed. Here is the updated link and it should work: Humor: Eulogy

In response to this video, Steven Liu sent me a link to a a Weird Al Yankovic:YouTube: Word Crimes. This link would probably be helpful for those reviewing a poorly-written journal submission when providing feedback (& hopefully not sent to anyone trying to provide information via a GI blog).


USA Today (8/9/22): Fewer than a third of insured Americans with hepatitis C receive timely treatment, CDC study shows

“More than 95% of people infected with hepatitis C can be cured with a simple course of antivirals…[the CDC] looked at nearly 50,000 insured patients diagnosed with hepatitis C between January 2019 and October 2020 and found less than one-third received treatment within a year of their diagnosis, according to the study published Tuesday in the Morbidity and Mortality Weekly Report...Treatment was lowest among patients who had state-administered Medicaid plans, with about 23% receiving it. About 28% people covered by Medicare and 35% with private insurance received treatment within the year.”

“Cases of hepatitis C rates have skyrocketed as the opioid epidemic worsens, jumping from an estimated 2,700 infections in 2011 to 57,500 infections in 2019, according to the CDC.”

NY Times (7/26/22): Viral Infections and Gene Variant Are Linked to Child Hepatitis Cases

“Two small studies…suggest a possible explanation for the hepatitis cases: In a small subset of children with this particular gene variant, dual infections with A.A.V.2. (adeno-associated virus 2) and a helper virus, often an adenovirus, trigger an abnormal immune response that damages the liver….As of July 8, 1,010 probable cases had been reported from 35 countries, according to the World Health Organization”

AR Kemper et al. Pediatrics 2022; Open Access: Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation

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Genetic Diseases and Newborn Unconjugated Hyperbilirubinemia

H Mel et al. J Pediatr 2022; 243: 53-60. Clinical and Genetic Etiologies of Neonatal Unconjugated Hyperbilirubinemia in the China Neonatal Genomes Project

Methods: The researchers used targeted panel sequencing data on 2742 genes including known unconjugated hyperbilirubinemia genes in 1412 neonates (in China). Exclusion criteria included gestational age <35 weeks and congenital malformations. 37% had severe unconjugated hyperbilirubinemia (reaching threshold recommended for exchange transfusion)


  • 45 (3%) of the cohort had genetic findings related to their unconjugated hyperbilirubinemia. 26 had variants associated with G6PD deficiency and eight had variants in UGT1A1 (which can cause Gilbert syndrome or Crigler-Najjar syndrome)
  • 11 of 45 of genetic findings were due to more obscure causes including to RBC membrane defects, n=5 (ANK1, SPTB) and due to metabolic/biochemical disorders (GCDH, MMACHC, MUT, DUOX2, DUOXA2, MOCS1)
  • Known clinical causes of hyperbilirubinemia were identified for 68% of patients. The most common clinical cause of unconjugated hyperbilirubinemia group was infection (15%). Other clinical causes included breastfeeding (n=154, 11%), extravascular hemorrhage (147, 10%), hemolytic disease (104, 7%) and inadequate feeding (82, 6%)

My take: About 3% of infants in this cohort had underlying genetic causes contributing to their jaundice; three-fourths of those with a genetic condition had either a variant of G6PD or UGT1A1

Related blog posts:

Valley of Fires, New Mexico. The darker areas are lava.

Elevated Bilirubin in Newborns with Down Syndrome

Elevated bilirubin in newborns with Down syndrome has been previously reported but the frequency has not been well-described.  A recent retrospective report (TM Bahr J Pediatr 2020; 219; 140-5) compared 357 neonates with Down syndrome to 377,368 controls.

Key findings:

  • Compared with control subjects, neonates with Down syndrome had 4.7 times the risk of having an initial total serum bilirubin exceeding the 95th percentile (23.5% vs 5.0%), 8.9 times the need for phototherapy (62.2% vs 7.0%) and 3.6 times the readmission rate for jaundice (17.4 vs 4.8 per 1000 live births).

The authors note that the basis for the increased risk of hyperbilirubinemia may be early hemolysis related to “neocytolysis” which is due to destruction of RBCs following a change from low to high oxygen exposure. Other factors could include slower bilirubin conjugation/elimination and poor feeding.

My take: This study indicates that infants with Down syndrome have a substantial risk of hyperbilirubinemia.  And, while you are checking a bilirubin, it is worthwhile to obtain a direct bilirubin as cholestasis is increased in infants with Down syndrome too; the latter is often transient and/or associated with other organ involvement.

Related blog post: Neonatal cholestasis and Down syndrome

Island Ford Nat’l Recreation Area/Chattahoochee River, Sandy Springs

Unbound Bilirubin and Prematurity

A recent prospective study (SB Amin, H Wang. J Pediatr 2018; 192: 47-52) indicates that premature infants have lower bilirubin binding affinity which could place them at risk for neurological complications.

Background: Very high levels of unconjugated bilirubin can lead to bilirubin-induced neurotoxicity/kenricterus.  There is increased susceptibility in newborns, particularly premature infants.  Unbound bilirubin (not bound to protein) can cross blood-brain barrier.  However, unbound bilirubin, rather than total serum bilirubin, is a better predictor of abnormal neurological outcomes.

Key findings:

  • Among 166 infants, peak unbound bilirubin significant correlated with bilirubin-albumin binding affinity (Ka) (r=-0.44, P=.001)
  • Gestational age was a significant modifier for the association between Ka and peak unbound bilirubin.
  • Peak unbound bilirubin was primarily associated with a decrease in binding affinity in infants ≤30 weeks gestational age

Implications of study: “Phototherapy as a sole intervention may be insufficient in preventing or reducing bilirubin-induced neurotoxicity”

My take: If there is low bilirubin binding affinity, among premature infants ≤30 weeks gestational age, some neurologic toxicity could occur even with bilirubin levels that have been considered safe previously.

Related blog posts:

Bright Angel Trail, Grand Canyon

Assessing Neonatal Jaundice with Smartphone App

A recent study (Taylor JA, et al. Pediatrics 2017; 140 (3) e20170312) reports on the effectiveness of a smartphone app, BiliCam, to detect total serum bilirubin (TSB) in a diverse sample of newborns < 7 days old.  Thanks to Ben Gold for this reference.

BiliCam uses a calibration card which is placed on the infant’s sternum to standardize the color (and jaundice) reading in the photo; the image goes via the internet to a server for analysis.

Key findings:

  • Estimated bilirubin levels using BiliCam were compared with TSB levels in 530 newborns which included 20.8% African American,, 26.3% Hispanic and 21.2% Asian American
  • The overall correlation was 0.91 were similar among all ethnic groups with correlations ranging from 0.88 to 0.92
  •  The sensitivity of Bilicam was 84.6% is for identifying infants with a TSB in the high-risk zone of the Bhutani nomogram. The sensitivity was 100% for identifying TSB > 17 mg/dL. Specificities were 75.1% adn 76.4% respectively.

For more commentary on this article: AAP Journals Blog: Bilirubin phone apps –our future calls!

My take: This article indicates that a digital image with Smartphone app analysis is much more accurate in detecting jaundice that a visual assessment.

In brief: Pediatric HCV trial, Exercise for NAFLD, and Urso for Unconjugated Hyperbilirubinemia

Schwarz et al. JPGN 2016; 62: 93-96.  This study showed that all 21 children who had achieved a sustained virological response with PEG-interferon/ribavirin maintained an SVR during followup of 4.4-7.0 years.  Hopefully, new direct-acting highly effective oral agents will be approved in pediatrics and make this study less relevant.

U.S. Food and Drug Administration approved Zepatier (elbasvir and grazoprevir) Jan 28, 2016

Anderson et al. JPGN 2016; 62: 110-17.  Participants (n=2612) from a large longitudinal study with prospectively collected data were followed. “The adolescents who are more active in late childhood have lower risk of ultrasound scan fatty liver and lower ϒ-gluamyl transferase levels.”  In addition, they showed that more activity was correlated with lower fat mass in adolescence.

Saki et al. JPGN 2016; 62: 97-100. In a double-blind randomized clinical trial of 80 neonates with unconjugated hyperbilirubinemia, treatment with added ursodeoxycholic acid (5 mg/kg/dose BID) resulted in improved clearance of bilirubin compared to phototherapy alone. At 12, 24 and 48 hours, total bilirubin in the treatment group was 12, 10 and 9.8 respectively compared with 14.4, 12.5, and 10.1 for the control group.  Furthermore, the mean time for phototherapy to decrease bilirubin to <10 was 15.5 hours in the treatment group compared with 44.6 hours in the control group.  This study, if confirmed, could result in shorter hospital stays.

Old Town, San Juan

Old Town, San Juan

Hyperbilirubinemia and Central Apnea

Briefly noted: “Unbound Unconjugated Hyperbilirubinemia is Associated with Central Apnea in Premature Infants” J Pediatr 2015; 166: 571-5.  This was a prospective observational study with 100 27-33 gestational infants.  The group with central apnea had higher unconjugated hyperbilirubinemia (UB).  The authors speculate that UB could cause neurotoxicity via central chemoreceptors and more aggressive treatment of UB with phototherapy could be needed.