Disorders of Bile Acid Synthesis

Bile acid synthesis defects often result in a deficiency of the primary bile acids—cholic acid and chenodeoxycholic acid—that are needed for absorption of fats and fat-soluble vitamins. Fat malabsorption leads to steatorrhea and growth retardation, and the fat-soluble vitamin deficiency can lead to coagulation defects and rickets. As bile acids are needed for bile flow, their deficiency can cause cholestasis, jaundice, and liver disease. In addition to the bile acid deficiency, accumulation of bile acid intermediates or their derivatives can cause other symptoms including progressive neurological disease. Bile acid synthesis defects can present from the neonatal period to adulthood. When a bile acid synthesis defect is suspected, bile acid analysis by tandem mass spectrometry in plasma and urine should be performed. As most bile acid synthesis defects have a characteristic bile acid profile, bile acid analysis can readily identify the underlying disorder, but for some disorders genetic analysis is required. Besides supplementation of the fat-soluble vitamins, bile acid replacement therapy can be beneficial in most of the bile acid synthesis disorders. This not only restores the bile acid pool but also strongly reduces the production of toxic bile acid intermediates by feedback inhibition of the bile acid synthesis pathway.