High serum and urinary unconjugated bile acid concentrations are associated with homozygous mutation in bile acid coenzyme A: Amino acid N-acyltransferase (BAAT)

Abstract

The final step in bile acid synthesis involves conjugation with the amino acids glycine and taurine. Conjugated bile acids have low pKa values and self-associate efficiently to form micelles and facilitate fat absorption. Recently, we discovered two Amish children, aged 2 and 5, with pruritus, fat malabsorption and vitamin K coagulopathy and high serum bile acid concentrations. Both showed homozygous mutation in BAAT, an enzyme that conjugates bile acids with glycine and taurine. Total serum bile acid concentrations were elevated (53.05 and 9.55 mg/ml, respectively; 1.4 mg/ml in control children, and 53.4 and 45.6 mg/ml after treatment with 300 mg/day ursodeoxycholic acid). No amino acid conjugates were found. in contrast, a cholestaric pauent with BRIC (due to a mutation in FIC1) showed elevated serum bile acid concentrations (151 mg/ml) that were almost entirely (96%) amino acid conjugated. Urinary bile acid outputs in the Amish patients were 30.3 and 17.3 mg/ml, respectively, with 18 and 34% unconjugated and the rest as glucuronide/sulfates. The patient with BRIC had 192.1 mg/ml bile acids in the anne, but more than 50% were glycine and taurine conjugated. These resuhs suggest that the bile salt export pump has a requirement for amino acid conjugated bile acids in order to transport them from liver into the bile. Patients that are homozygous for BAAT mutation show high levels of serum unconjugated bile acids and increased urinary excretion of bile acids, composed chiefly of unconjugated and glucuronidated/sulfated bile acids, in contrast, patients with BRIC also show elevated serum and urinary bile acids, but these are predominantly conjugated with glycine and taurine. The presence of unconjugated bile acids leads to their backup and overflow into the serum and excretion into urine. Clinically, elevated serum unconjugated bile acids are associated with pruritus while the deficiency of amino acid conjugated bile acids in the intestine results in tat malabsorption and vitamin K coagulopathy.