Inborn error in primary bile acid synthesis

Progressive familial intrahepatic cholestasis (PFIC), types 1, 2 and 3, are due to defects in genes involved in bile secretion (FIC1, BSEP, MDR3). PFIC and inborn errors of bile acid synthesis (IEBAS) often present in infancy with cholestasis. The distinctive feature of PFIC 1 and 2 and IEBAS is a normal level of GGT, while IEBAS are suspected in patients with low plasma bile acids concentration. Molecular testing, urinary bile acid analysis (IEBAS), liver biopsy and immuno-staining are used for the diagnosis. Some patients with PFIC can be successfully treated with ursodeoxycholic acid or partial external biliary diversion. IEBAS is treated with cholic acid. Liver transplantation is required for cirrhosis with liver failure. Hepatocarcinoma has been reported in PFIC2.

Oral bile acid replacement has been shown to be an effective therapy in primary bile acid synthesis defects, but to date there have been no reports of the long-term effects of this therapy. The aim of the study was to evaluate the long-term effectiveness and safety of cholic acid (CA) therapy.

Fifteen patients with either 3beta-hydroxy-Delta(5)-C(27)-steroid oxidoreductase (3beta-HSD) (n = 13) or Delta(4)-3-oxosteroid 5beta-reductase (Delta(4)-3-oxo-R) (n = 2) deficiency confirmed by mass spectrometry and gene sequencing received oral CA and were followed up prospectively.

CA therapy was started at a median age of 3.9 years (range, 0.3-13.1 years). The median follow-up with treatment was 12.4 years (range, 5.6-15 years). The mean daily dose of CA was initially 13 mg/kg and was 6 mg/kg at last evaluation. During CA therapy, physical examination findings, laboratory test results, and findings on sonography normalized. Mass spectrometry analysis of urine showed that excretion of the atypical metabolites was reduced by 500-fold and 30-fold in 3beta-HSD and Delta(4)-3-oxo-R deficiency, respectively, and total urinary bile acid excretion decreased dramatically. Liver biopsies performed in 14 patients after at least 5 years of CA therapy showed marked improvement, especially in patients with the 3beta-HSD deficiency. CA was well tolerated with all children developing normally, including 2 women having 4 normal pregnancies during treatment.

Oral CA therapy is a safe and effective long-term treatment of the most common primary bile acid synthesis defects.

Bile acid concentrations are elevated in the blood of neonates with cholestatic hepatobiliary disorders providing a possible means of screening for treatable conditions including biliary atresia. A method is described for the determination of concentrations of conjugated bile acids in dried blood spots using electrospray ionization mass spectrometry. Bile acids were eluted from the blood spots using methanol containing, as internal standards, the taurine and glycine conjugates of D4-chenodeoxycholic acid and D4-cholic acid. The samples were then reconstituted in acetonitrile/water and injected by autosampler into the electrospray source operating in negative ion mode. Optimal conditions were determined for both single quadrupole and tandem mass spectrometry analysis. Blood spot bile acid profiles were studied in two groups of infants (< 1 y), a cholestatic group (conjugated bilirubin > 25 mumol/L; n = 49), and a control group (n = 96). The best discrimination between the two groups was provided by measurements of taurodihydroxycholanoates (normal < 5 mumol/L; cholestatic group 18-94 mumol/L) and glycodihydroxycholanoates (normal < 5 mumol/L; cholestatic group 11-66 mumol/L). The method can also be adapted to detect unusual bile acids which are diagnostic of inborn errors of bile acid synthesis and peroxisomal disorders. The method is fast, reliable, reproducible, and relatively cheap; however, much more work is required to determine whether it can be used for mass screening for cholestasis. It will be necessary to show that measurement of bile acid concentrations in blood spots obtained at 7-10 d can be used to detect infants who currently present with jaundice, pale stools, and dark urine during the first 6 mo of life.