“That’s fine in practice, but how does it work in theory?”
I heard this quote while visiting the University of Chicago. A recent (really cool) study reminded me of this quote because of the interplay between predictions of the effects of a genetic defect in bile acid conjugation and the actual clinical presentation of 10 pediatric patients (Gastroenterol 2013; 144: 945-55).
Background: Bile acid synthesis from cholesterol requires 17 enzymatic reactions in different cellular compartments of the hepatocyte. These steps are tightly regulated. All of the steps are vulnerable to genetic defects, some of which have been recognized for a long time. The final step occurs in the peroxisome and is 2-part mediated by bile acid-CoA ligase enzyme (SLC27A5) and bile acid-CoA:amino acid N-acyltransferase (BAAT). This latest study examines the final step of primary bile acid synthesis in which there is conjugation with amino acids. Conjugation of bile acids improves absorption of lipids including fat-soluble vitamins.
Results: Ten patients with severe fat-soluble vitamin deficiency (five with rickets) were carefully analyzed. Levels of urinary bile acids showed increased unconjugated forms (79%). In addition, there was an absence of glycine and taurine conjugates in the urine, bile, and serum. In the 8 patients with duodenal bile analysis, >95% of bile acids were unconjugated which was too low for efficient lipid absorption. Typically, glycine and taurine conjugates account for >95% of bile acids secreted in bile. On mass spectrometry, there was a marked presence of a dominant ion at m/z 407 which represents cholic acid. The investigators also performed molecular analysis and identified mutations in BAAT in 7 of 8 who had available DNA.
Clinical features:
- Hepatomegaly in 3 of 10
- Age at diagnosis: 3mo-14 years
- Elevated aminotransferase: 4 of 10
- Low GGT
- Liver failure/transplant in one patient
- All 10 had fat-soluble vitamin deficiency
- None had diarrhea (which had been theorized)
Thus, patients had variable liver disease ranging from none to severe.
Take-home message(s):
Specific genetic defects have been identified in the final steps of bile acid production. Abnormal urine mass spectrometry may increase the suspicion for mutations in BAAT (or SLC27A5). Breakdown in any of these bile acid synthesis steps can lead to fat-soluble vitamin deficiency. Potential treatment with primary conjugated bile acids (e.g.. glycocholic acid) should improve fat-soluble vitamin absorption in these patients.
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