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).

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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; https://doi.org/10.1542/peds.2022-058859. Open Access: Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Good Review of Cholestatic Liver Diseases

SH Ibrahim et al. Hepatology 2022; 75: 1627-1646. Cholestatic liver diseases of genetic etiology: Advances and controversies

Table 1 lists more than 40 monogenic disorders of cholestasis. Examples:

  • Disorders of membrane transporter or polarity: PFIC1, PFIC2, PFIC3, Dubin-Johnson
  • Basolateral disorders: NTCP deficiency, Rotor syndrome, Organic solute transporter deficiency
  • Disorders of nuclear receptors: PFIC5
  • Disorders of intracellular trafficking: Arthrogryposis-renal dysfunction-cholestasis, PFIC6 microvillous inclusion (MYO5B gene), Osteo-oto-hepato-enteric, Fanconi renotubullar syndrome
  • Disorders of cytoskeletal and tight junction protein: PFIC4, Neonatal ichthyosis sclerosing cholangitis
  • Cholangiopathies-Ciliopathy: Neonatal sclerosing cholangitis, Nephronophthisis, Meckel-Joubert syndrome, renal cysts and diabetes syndrome, BASM
  • Cholangiopathies-Bile duct paucity: Alagille
  • Cholangiopathies-cholangiocyte channelopathy: Cystic Fibrosis
  • Hepatocellular disease: A1AT deficiency, mitochondrial depletion, mitochondrial translation defect, transaldolase deficiency
  • Inborn errors of metabolism -bile acids: BASD, bile acid conjugation defects, peroxisomal defects
  • Inborn errors of metabolism -carbohydrates: galactosemia, hereditary fructose intolerance
  • Inborn errors of metabolism -amino acids: tyrosinemia type 1

Key Points:

  • Low GGT genetic disorders (>25 genetic mutations) include canalicular transporter defects, basolateral transporter defects, intracellular trafficking defects, defects of cytoskeletal and tight junction protein, transaldolase deficiency, bile duct paucity, and inborn errors of metabolism.
  • The authors note that the timing and utility of a liver biopsy is changing due to the advent of rapid molecular testing.
  • Potential treatments are reviewed include ursodeoxycholic acid, IBAT inhibitors, cholic acid, biliary diversion, and liver transplantation.
  • Multidisciplinary evaluation is often needed in patients with Alagille. 87% have cardiac anomalies, up to 36% have/develop cerebral vasculopathy, 21% develop post-transplant renal dysfunction, and 22% develop spontaneous or procedure-associate systemic bleeding (need for hematology consultation). In addition, pathologic fractures are common; one report found the rate of femur fractures was 50 times that in the general population which is likely related to intrinsic bone defects (as well as cholestasis).

My take: With the widespread availability of genetic testing which is needed due to the numerous etiologies, the diagnosis of ‘idiopathic’ chronic cholestasis has decreased and targeted therapies have emerged.

Related article: L Matarazzo et al. JPGN 2022; 74; p e115-e121. MYO5B Gene Mutations: A Not Negligible Cause of Intrahepatic Cholestasis of Infancy With Normal Gamma-Glutamyl Transferase Phenotype

Key finding:

In this multicenter retrospective and prospective study was conducted in 32 children with cryptogenic intrahepatic cholestasis, whole exome sequencing identified 6 with MYO5B mutations.  The most common signs were pruritus, poor growth, hepatomegaly, jaundice, and hypocholic stools. 

Related blog post:

Good News Story: The Remarkable Hepatitis B Vaccine Story

W-Q He, GN Guo, C Li. Hepatology 2022; 75: 1566-1578. The impact of hepatitis B vaccination in the United States, 1999-2018

In the past 30 years, the hepatitis B vaccine has been included in infant immunization schedules in the U.S. The authors studied a large, comprehensive, and nationally representative data set (NHANES data from 1999-2018) to assess its efficacy.

Key findings:

  • HBV vaccination was associated with reduced risk of all-cause mortality (HR, 0.78; 95% CI, 0.68–0.90) and cancer-related mortality (HR, 0.76; 95% CI, 0.58–1.00) 
  • The highest vaccination uptake was found among those born after 1991, at 86.5%.
  • Vaccinated participants had higher prevalence of vaccine-induced immunity than the unvaccinated (47.2% vs. 7.4%). Among those born after 1991, vaccine efficacy (VE) was found at 58% (95% CI, 18%–79%) overall and 85% for those aged ≥20 years (mean age, 22), whereas no effect was found among those born prior to 1990

Context for these findings is noted in the associated editorial (pgs 1365-1367):

HBV remains one of the most deadly viruses worldwide with nearly 1 million deaths yearly and nearly 300 million people chronically-infected. The vast majority of unvaccinated children less than 1 year of age become chronically-infected. In the U.S., 98% of children acquired HBV through vertical transmission “including 26% of pediatric cases who were born in the USA or Canada”

My take: This study shows that HBV vaccine maintains strong protection for 20 years and protects against cancer and death.

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Los Poblanos Ranch, Alburquerque

Efficacy of Sebelipase Alfa for Lysosomal Acid Lipase Deficiency

BK Burton et al. JPGN 2022; 74: 757-764. Open Access: Long-Term Sebelipase Alfa Treatment in Children and Adults With Lysosomal Acid Lipase Deficiency

This was open-label study of enzyme replacement therapy (ERT) in 31 children and adults with lysosomal acid lipase deficiency (LALD). Sebelipase Alfa, a recombinant human lysosomal acid lipase, was FDA approved in 2015 for LALD.

Key findings:

  • Liver biopsies showed mostly improved or stable histopathology at 48 and 96 weeks versus baseline. In addition, there was modest improvement in transaminases; median ALT and AST levels changed by −42.0 and −22.0 U/L, respectively.
  • Median low-density lipoprotein cholesterol levels decreased by 52.6 mg/dL, and median high-density lipoprotein cholesterol increased by 9.8 mg/dL. Though, 55% of the study population had concomitant lipid-modifying therapy
  • Two patients tested positive for nonneutralizing, anti-drug antibodies

In the associated commentary (pgs 726-727), the authors state this study showed that “in contrast to infantile disease, ERT is not universally beneficial in individuals with attenuated disease…[and] it is impossible to predict response to ERT.” Testing for LALD is recommended for infants with hepatomegaly, poor growth, diarrhea or adrenal insufficiency. In older groups, LALD needs to be considered in those with hepatomegaly, steatosis, and dyslipidemia.

My take: There are still many questions regarding ERT’s long-term benefit in individuals with LALD, especially those with mild disease.

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From NASPGHAN Newsletter

Type 2 Diabetes in Children with Nonalcoholic Fatty Liver Disease

JB Schwimmer et al. Clin Gastroenterol Hepatol 2022; DOI:https://doi.org/10.1016/j.cgh.2022.05.028. Pre-proof full text PDF:Incidence of Type 2 Diabetes in Children with Nonalcoholic Fatty Liver Disease

Methods: Children with NAFLD (n=892) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network were followed longitudinally. These children had a mean age of 12.8 years followed for a mean of 3.8 years 

Key findings:

  • At baseline, 63 (of 892) children had T2D, and during follow-up, an additional 97 children developed incident T2D, resulting in a period prevalence of 16.8 %.
  • Incident T2D was significantly higher in females versus males (HR 1.8 [1.0-2.8]), associated with BMI z-score (HR 1.8), and more severe liver histology including steatosis grade (HR 1.3), and fibrosis stage (HR 1.3).

My take: Children/adolescents with NAFLD need to be monitored for the development of T2D.

Related blog posts:

Thanks to David for picture of Portland Head Lighthouse

Wow, Your Liver Looks So Young!

I’ve had the good fortune to work with the same nurse, Bernadette, for 25 years. While I have joked with some patients, that in a few more years she will figure it all out, in fact, she has been terrific from day one. A few years ago, Bernadette enthusiastically told me that her physician had told her that she had the colon of a teenager; this sounds like a good thing.

I was thinking about this comment about younger body parts after reading a recent article from The Washington Post (6/6/22): Your liver is younger than you think

Key points/excerpts:

  • “Research in the journal Cell Systems reveals that humans’ livers are forever young, clocking in at less than three years old despite their hosts’ biological age…”
  • “Researchers studied the livers of 33 adults who were between ages 20 and 84 when they died…When the scientists dated the cells, they found an average age of about three years regardless of the age of the person who generated the cells. The hepatocytes “show continuous and lifelong turnover, allowing the liver to remain a young organ,” they write.”
  • “Ninety-five percent of the cells with two complete sets of chromosomes turned over within a year, but up to 12 percent of a cell subtype that have more than one pair of chromosomes can survive up to a decade.”
  • “Our bodies produce about 700 million hepatocytes each day — not bad for a three-pound organ.”

My take: The liver is amazing and can stay young even when in older bodies.

Related blog post: Why the Liver is the King of Internal Organs

Liver Shorts: Malnutrition in Biliary Atresia, Cholestasis with ECMO, Impaired Cognition After Pediatric Liver Transplantation

JM Boster et al. Liver Transplantation 2022; 28: 483-492. Malnutrition in Biliary Atresia: Assessment, Management, and Outcomes Good review article. Malnutrition and sarcopenia negatively impact pretransplant, peritransplant, and posttransplant outcomes and survival in children with BA.

E Alexander et al. JPGN 2022; 74: 333-337. Clinical Implications for Children Developing Direct Hyperbilirubinemia on Extracorporeal Membrane Oxygenation Key findings: 36/106 (34%) children developed direct hyperbilirubinemia (DHB) on ECMO. Illness acuity scores were significantly higher in the DHB group on ECMO day 2 (P = 0.046) and day 7 (P = 0.01). Mortality rate was higher in the DHB group 72%, versus 29% in the control group (P < 0.001).

A Ostensen et al. J Pediatr 2022; 243: 135-141. Open Access: Impaired Neurocognitive Performance in Children after Liver Transplantation In this study with 65 participants, key findings:

  • Compared with the patients who underwent transplantation a age >1 year (n = 35), those who did so at age <1 year (n = 30) had a lower FSIQ (87.1 ± 12.6 vs 96.6 ± 13.8; P = .005) and lower verbal comprehension index (87.3 ± 13.8 vs 95.4 ± 13.0; P = .020).
  • Transfusion of >80 mL/kg (P = .004; adjusted for age at transplantation: P = .046) was also associated with detrimental effects on FSIQ.
  • No difference in IQ between tests was found in those patients tested more than once, indicating no significant improvement with more time after transplantation (first testing was at median of 4.1 years after transplantation and the second testing was at a median age of 6.7 years after transplantation)
  • “Our findings indicate that transplantation at early age has a pronounced effect on later neurocognitive impairment, and that this effect is separate from and more pronounced than the effect of cholestasis before transplantation.”

Related blog posts:

Onion Headline:

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)

Findings:

  • 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.

Sugary Beverage and Liver Stiffness in Healthy Adults

CW Leung, EB Tapper. Clin Gastroenterol Hepatol 2022; 20; 959-961. Sugar-sweetened Beverages Are Associated With Increased Liver Stiffness and Steatosis Among Apparently Healthy Adults in the United States

In this representative sample (2706 adults, median 37.9 years) from 2017-2018 NHANES, subjects without any known chronic disease had tow 24-hr dietary recalls collected and had liver stiffness measurements (LSM) and controlled attenuation parameters (CAP); LSM <7 kPa (using vibration-controlled transient elastography) was considered low risk for advanced fibrosis and CAP >248 dB/m were at risk for heaptosteatosis. Key findings:

  • 11% (n=305) had LSM >7.0 kPa and 46% (n=1254) had CAP >248 dB/m
  • Sugar-sweetened beverage (SSB) >2/day was associated with greater LSM (OR 2.30)
  • In mutlivariate analysis, consuming >1-2 sugar-sweetened servings per day was associated with elevated CAP (OR 1.51 compared to adults with SSB consumption
  • Limitations: this cross-sectional study cannot prove causality

My take: Even in healthy adults, SSB consumption is associated with detrimental changes in the liver.

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