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Mechanisms of Disease: inborn errors of bile acid synthesis

Abstract

Inborn errors of bile acid synthesis are rare genetic disorders that can present as neonatal cholestasis, neurologic disease or fat-soluble-vitamin deficiencies. There are nine known defects of bile acid synthesis, including oxysterol 7α-hydroxylase deficiency, Δ4-3-oxosteroid-5β-reductase deficiency, 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency, cerebrotendinous xanthomatosis (also known as sterol 27-hydroxylase deficiency), α-methylacyl-CoA racemase deficiency, and Zellweger syndrome (also known as cerebrohepatorenal syndrome). These diseases are characterized by a failure to produce normal bile acids and an accumulation of unusual bile acids and bile acid intermediaries. Individuals with inborn errors of bile acid synthesis generally present with the hallmark features of normal or low serum bile acid concentrations, normal γ-glutamyl transpeptidase concentrations and the absence of pruritus. Failure to diagnose any of these conditions can result in liver failure or progressive chronic liver disease. If recognized early, many patients can have a remarkable clinical response to oral bile acid therapy.

Key Points

  • Defects in bile acid synthesis most commonly present as neonatal cholestasis or neonatal hepatitis, but can present as chronic liver disease in older children

  • Unlike most cholestatic diseases, patients with bile acid synthesis defects generally have the hallmark features of low or normal serum bile acid levels, normal or minimally increased γ-glutamyl transpeptidase levels and lack of pruritus

  • Deficiency of Δ4-3-oxosteroid-5β-reductase can present as either neonatal cholestasis or as liver failure that resembles neonatal hemochromatosis; it has a 50% mortality in infants when diagnosis is delayed

  • Deficiency of 3β-hydroxy-Δ5-C27-steroid dehydrogenase is the most common defect of bile acid synthesis, presenting both as neonatal cholestasis and as chronic liver disease in older patients

  • Cerebrotendinous xanthomatosis is a lipid storage disorder that presents with symptoms of progressive neurologic dysfunction in the second or third decade of life and occasionally as neonatal cholestasis; it can be treated with oral bile acids

  • Early recognition and diagnosis of bile acid synthesis defects is important as these disorders are often readily treatable with oral bile acid therapy

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Figure 1: Bile acid synthesis occurs by two pathways, the classic 'neutral' pathway and the alternative 'acidic' pathway.
Figure 2: Liver histology in a patient aged 12 weeks with oxysterol 7α-hydroxylase deficiency.
Figure 3: Liver histology in a patient aged 6 weeks with Δ4-3-oxosteroid 5β-reductase deficiency.
Figure 4: Liver histology in a patient aged 6 months with 3β-hydroxy-Δ5-C27 steroid dehydrogenase deficiency.

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Acknowledgements

RJS and SSS are supported by NIH grants U54DK078377, UO1DK062453 and RR00069.

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Sundaram, S., Bove, K., Lovell, M. et al. Mechanisms of Disease: inborn errors of bile acid synthesis. Nat Rev Gastroenterol Hepatol 5, 456–468 (2008). https://doi.org/10.1038/ncpgasthep1179

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