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bile acid synthesis diseases

Wednesday 4 June 2003

Definition: Bile acid synthetic defects are uncommon genetic disorders that are responsible for approximately 2% of persistent cholestasis in infants.

Inborn errors of bile acid synthesis are rare genetic disorders that can present as neonatal cholestasis, neurologic disease or fat-soluble-vitamin deficiencies.

There are nine known defects of bile acid synthesis, including:

- oxysterol 7α-hydroxylase deficiency
- Δ4-3-oxosteroid-5β-reductase deficiency
- 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency
- cerebrotendinous xanthomatosis (sterol 27-hydroxylase deficiency)
- α-methylacyl-CoA racemase deficiency
- Zellweger syndrome (cerebrohepatorenal syndrome).

These diseases are characterized by a failure to produce normal bile acids and an accumulation of unusual bile acids and bile acid intermediaries.

Individuals with inborn errors of bile acid synthesis generally present with the hallmark features of normal or low serum bile acid concentrations, normal γ-glutamyl transpeptidase concentrations and the absence of pruritus.

Failure to diagnose any of these conditions can result in liver failure or progressive chronic liver disease. If recognized early, many patients can have a remarkable clinical response to oral bile acid therapy.

There diseases result from defects in bile acid synthesis

- CBAS1 is caused by mutation in the gene encoding 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase (HSD3B7; MIM.607764) on chromosome 16p.

- CBAS2 (MIM.235555) is caused by mutation in the delta(4)-3-oxosteroid 5-beta-reductase gene (AKR1D1; 604741) on chromosome 7q32.

- CBAS3 (MIM.603711) is caused by mutation in the 7-alpha hydroxylase gene (CYP7B1) on chromosome 8q21;

- CBAS4 (MIM.214950), caused by mutation in the AMACR gene (MIM.604489) on chromosome 5.

The inheritance of these defects is autosomal and recessive. The resulting liver diseases vary from mild to severe, depending on the particular alteration.

The most common clinical presentation is progressive cholestasis of infancy, although other clinical manifestations, such as advanced liver disease at birth, neonatal hepatitis or the development of liver disease in later childhood, can also occur.

When the enzymatic defect results in an accumulation of toxic monohydroxylated and/or unsaturated oxo-bile acids, many of which are cholestatic, the progression of liver disease is usually rapid.

Recent evidence suggests that certain cholestatic liver diseases in adults may also be due to an inherited defect in bile acid biosynthesis.

Diagnosis is accomplished by analysis of the profile of bile acid species and their precursors and/or metabolites in body fluids, using laboratory techniques such as fast atom bombardment-mass spectroscopy and gas chromatography-mass spectroscopy.

Early diagnosis is critical for these patients, because several of these disorders can be successfully treated with the dietary addition of bile acids.

This has a dual purpose: first, to replace the essential primary bile acids absent, and second, to down-regulate bile acid synthesis by negative feedback inhibition, thus reducing the production of abnormal toxic intermediate metabolites by hepatocytes bearing the defect.

As will be commented below in detail, inborn errors affecting the enzymes involved both in the modification of the sterol nucleus and the side-chain, as well as in side-chain amidation, have been identified.

Moreover, the absence or impaired function of peroxisomes also results in alterations in bile acid metabolism that accompany the other signs characterizing each syndrome.


1. anomalies of the modification of the sterol nucleus of bile acids

- defect in cholesterol 7α-hydroxylase (CYP7B1) (CBAS3 - MIM.603711)
- defect in oxysterol 7α-hydroxylase
- defect in 3β-hydroxy-C27-steroid dehydrogenase/isomerase (HSD3B7) (CBAS1 - MIM.607765)
- defect in δ-4-3-oxosteroid 5β-reductase (AKR1D1) (CBAS2 - MIM.235555)

2. defects in the modification of the side-chain of bile acids

Several inborn errors affecting single enzymes involved in the modification of the cholesterol side-chain to produce C24 bile acids have been identified. Additionally, because β-oxidation of the side-chain occurs in peroxisomes, peroxisomal disorders can also affect bile acid synthesis, accompanying other manifestations typical of each syndrome.

- defect in sterol 27-hydroxylase
- defect in 25-hydroxylase
- defect in alpha methylacyl-CoA racemase (AMACR) (CBAS4 - MIM.214950)

3. peroxisomal diseases (or Zellweger syndrome or cerebrohepatorenal syndrome).

Apart from AMACR, other peroxisomal enzymes involved in the beta-oxidation of the bile acid side-chain are branched-chain acyl-CoA oxidase, D-bifunctional protein and sterol carrier protein X (SCPx).

4. defects in bile acid conjugation (HPID:15088)

Defective bile acid conjugation (bile acid amidation), which is characterized by a complete absence of glycine and taurine conjugates of bile acids in biological fluids and a predominance of unconjugated CA, with small proportions of sulfate and glucuronide conjugates, has been reported.


- analysis of body fluids (bile, blood, and urine) using

  • fast atom bombardment-mass spectroscopy (FAB-MS)
  • gas chromatography-mass spectroscopy (GC-MS)


Four single enzymes involved in modification of the sterol nucleus and in five steps in modification of the side-chain to form cholic acid and chenodeoxycholic acids, the primary bile acids.

In three of four known defects of sterol nucleus modification, liver disease is progressive.

Progression of liver disease is most rapid when the defect results in accumulation of toxic monohydroxy and unsaturated oxo-bile acids. Liver disease may be transient, delayed in onset and mild.

Reduced bile flow caused by atypical bile acids contributes to cholestasis and may be the dominant factor in defects of side-chain synthesis, peroxisomal abiogenesis and S-L-O syndrome.

Pathological findings

- intralobular cholestasis with giant cell transformation
- necrotic hepatocytes including giant cell forms
- hepatitic injury confined to the portal limiting plate
- smallest bile ductules may be injured and where fibrosis typically develops. Interlobular bile ducts are usually spared.


- nonspecific changes with the possible exception of unusual canalicular morphology


- Mechanisms of disease: Inborn errors of bile acid synthesis. Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Nat Clin Pract Gastroenterol Hepatol. 2008 Aug;5(8):456-68. PMID: 18577977

- Bove KE, Heubi JE, Balistreri WF, Setchell KD. Bile acid synthetic defects and liver disease: a comprehensive review. Pediatr Dev Pathol. 2004 Jul-Aug;7(4):315-34. PMID: 15383928