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.