Disorders of bile acid synthesis

Abstract

Inborn errors of bile acid synthesis can produce life-threatening cholestatic liver disease (which usually presents in infancy) and progressive neurological disease presenting later in childhood or in adult life. Both types of disease can often be treated very effectively with bile acid replacement therapy and it is therefore important to diagnose these disorders as early as possible. The cholestatic disease in infancy is characterised by conjugated hyperbilirubinaemia with raised transaminases but normal γ-glutamyl transpeptidase and a biopsy showing a giant cell hepatitis. There is usually evidence of fat-soluble vitamin malabsorption. The neurological presentation often includes signs of upper motor neurone damage (spastic paraparesis). The most useful screening test for many of these disorders is analysis of urinary cholanoids (bile acids and bile alcohols); this is usually now achieved by electrospray ionisation tandem mass spectrometry. The disorders that are discussed in this review are: 3β-hydroxysteroid-Δ5-C27-steroid dehydrogenase deficiency, Δ4-3-oxosteroid 5β-reductase deficiency, sterol 27-hydroxylase deficiency (cerberotendinous xanthomatosis, CTX), oxysterol 7α-hydroxylase deficiency (including one form of hereditary spastic paraparesis) and the amidation defects, bile acid-CoA: aminoacid N-acyltransferase (BAAT) deficiency and bile acid-CoA ligase deficiency. The disorders of peroxisome biogenesis and peroxisomal β-oxidation that affect bile acid synthesis will be covered in the review by Ferdinandusse et al.

Measurement of Transport Activities of 3β-Hydroxy-Δ⁵-bile Acids in Bile Salt Export Pump and Multidrug Resistance-Associated Proteins Using LC-MS/MS

“…3,16,17) Ichimiya et al and Clayton investigated the bile acid profiles in urine of patients with HSD3B7 deficiency using FAB-MS, ESI-MS, and GC-MS methods and reported that sulfated 3β-hydroxy-Δ 5 -bile acids and their glycine conjugates were the major bile acids excreted in urine of the patients. 10,15) The present study demonstrated that hMRP3 vesicles have high affinities for 3-sulfated 3β-hydroxy-Δ 5 -bile acids. hMRP3 may play a key role in the excretion of conjugated 3β-hydroxy-Δ 5 -bile acids.…”

“…7,10,15) In the present study, various conjugated bile acids (Fig. 1) were used as substrates of membrane vesicles for the following experiments.…”

“…1, are the major bile acids excreted in the urine of patients with 3β-hydroxy-Δ 5 -C 27 -steriod dehydrogenase/isomerase (HSD3B7) deficiency. [7][8][9][10][11][12][13][14][15] Deficiency of this enzyme is thought to cause chronic liver injury in childhood. [7][8][9][10][11] The above ABC transporters may play key roles in excretion of these 3β-hydroxy-Δ 5 -bile acids from the liver.…”

Detection of Δ4-3-oxo-steroid 5β-reductase deficiency by LC–ESI-MS/MS measurement of urinary bile acids

“…Some of the first inborn errors in these pathways were detected nearly 30 years ago [2,3] acid biosynthetic pathway. Since that time, inborn errors of bile acid formation involving isolated defects in most of the enzymes in the biosynthetic pathway have been reported [4]. However, such enzymatic defects are extremely rare.…”

“…Chenodeoxycholic acid and cholic acid, the normal primary bile acids in man are nearly undetectable. However, because gene alterations cannot be found in the majority of patients excreting increased amounts of these urinary 4 -3-oxo-bile acids, it was eventually recognized that such abnormal bile acids could also accumulate and be excreted in urine in children with severely damaged liver functions [4]. This turned out to be the case for the first Japanese patient with possible 4 -3-oxo-steroid 5␤-reductase deficiency [6].…”