Tag Archives: inborn error of bile acid metabolism

Dr. William Balistreri: Whatever Happened to Neonatal Hepatitis (Part 1)

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Recently Dr. Balistreri gave our group an excellent lecture. I have taken some notes and shared some slides. There may be inadvertent omissions and mistakes in my notes.

In my view, Dr.Balistreri’s contributions to our field of pediatric gastroenterology, hepatology and nutrition are unsurpassed by any other individual. This is due to his leadership roles (division director, president of AASLD and NASPGHAN), his editor roles (Journal of Pediatrics, and JPGN), his extensive publications/research including sentinel discoveries in bile acid pathophysiology and treatment, and through education (lectures and mentorship).

Key points:

  • Fifty years ago, ~65% of neonatal cholestasis cases were poorly understood and lumped together under the heading of “Idiopathic Neonatal Hepatitis” (INH). The discovery of Alpha-One Antitrypsin (A1AT) Deficiency was instrumental, indicating that there were specific medical diseases mislabeled as INH
  • A1AT deficiency proved that many cases were NOT “idiopathic,” NOT necessarily “neonatal,” and NOT “hepatitis”
  • Currently, less than 10% of infants with neonatal cholestasis are unspecified. Dr. Balistreri’s goal has been to make sure every patient receives a precise diagnosis
  • Now more than 90 genetic conditions have been recognized as causing neonatal cholestasis
  • The journey of unraveling the reasons for neonatal cholestasis includes the referral of two infants from Atlanta by Dr. Saripkin to Cincinnati. These infants who had an older sibling who had died at 4 months of age were determined to have an inborn error of bile acid metabolism. Subsequently, they were treated successfully with cholic acid which suppressed production of toxic precursors via feedback inhibition
  • There are 11 steps in the conversion of cholesterol to bile acids; thus, it was hypothesized and later proven that there would be many other inborn errors of bile acid metabolism

Related blog posts:

Variability in Inborn Errors of Bile Acid Metabolism

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There is significant variability in the presentation of the most common inborn error of bile acid metabolism, 3β-hydroxy-Δ5-C27-steroid oxidoreductase (3β-HSD) deficiency (Molho-Pessach V et al, Hepatology 2012; 55: 1139-45).  

This report investigated a 24-year-old women from Iran with idiopathic cirrhosis and a strong family history of idiopathic cirrhosis, as well as a 32-year-old first-cousin who had a self-limited liver disease (resolved at age 9).  A genome-wide analysis of 2.4 million single nucleotide polymorphisms was performed in the patient and cousin and compared to a healthy relative.  The investigators were able to identify regions of homozygosity  that was present in the proband and cousin but not the healthy relative; one of these regions corresponded to a gene encoding 3β-HSD.  Subsequent, sequence analysis revealed a specific frameshift mutation and high levels of 3β-hydroxy-Δ5 using mass spectrometry.

For me, this report has two take home points:

  • As with a lot of diseases, 3β-HSD can have variable phenotypic expression and may present beyond infancy.  Its diagnosis remains important because a timely diagnosis allows effective treatment with bile acid replacement.
  • More ‘idiopathic’ diseases will be unmasked with new molecular tools, especially when investigators combine these tools with careful history-taking and family history.

Additional references:

  • w/u for bile acid defects: FAB-MS fast atom bombardment mass spectrometry
    **stop URSO 5 days before test
  • http://www.orpha.net/data/patho/Pro/en/InbornErrorsBileAcidMetabolism-FRenPro11194v01.pdf. Online review article from Heubi JE, et al, reprinted with permission from Thieme Medical Publishers (Seminars Liver Dis. 2007 Aug;27(3):282-294) Homepage at www.thieme.com.“At the Cincinnati Children‘ Hospital Medical Center, more than 130 patients have been identified with defects, accounting for 1% to 2% of the cases of unexplained liver disease in infants and children.”
  • -Gastroenterology 2009; 137: 1310.  Long-term good efficacy of cholic acid for primary defects in bile acid synthesis.
  • -Hepatology 2009; 39: 1403.  Review defects in bile acid synthesis.