Table 1.
Genetic, biochemical and clinical features of bile acid synthesis defects.
| Enzyme defect | Gene encoding the affected enzyme (reference) | Urine bile acid profile | serum bile acid profile | Clinical features |
|---|---|---|---|---|
| Oxysterol 7α-hydroxylase deficiency | CYP7B14 | ↑ Sulfate and glycosulfate conjugates of 3β-δ5-monohydroxy bile acids Absence of primary bile acids | Extremely high levels of bile acids, primarily 3β-δ5-monohydroxy bile acids | Neonatal hepatitis (single reported case; unrecognized cases could be due to prenatal or early-postnatal death) |
| Δ4-3-oxosteroid-5β-reductase deficiency | AKR1D1(SRD5B1)20 | ↑ 3-oxo-δ4 bile acids ↑ Allo bile acids ↓ Primary bile acids |
↑ 3-oxo-δ4 bile acids ↑ Allo bile acids ↓ Primary bile acids |
Neonatal hepatitis with rapid progression to liver failure Neonatal hemochromatosis |
| 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency | HSD3B738,39 | ↑ Dihydroxy & trihydroxy cholenoic acids ↓ Primary bile acids |
↓ or absence of primary bile acids | Neonatal hepatitis Late-onset liver disease Malabsorption |
| Cerebrotendinous xanthomatosis (sterol 27-hydroxylase deficiency) | CYP27A148 | ↑ Plasma cholestanol: cholesterol ratio | ↑ Bile alcohol glucuronides | Progressive neurologic dysfunction in 2nd–3rd decade of life Chronic diarrhea Bilateral juvenile cataracts Neonatal cholestasis |
| Alpha methylacyl-CoA racemase deficiency | AMACR gene on chromosome 5p13.2-q11.171 | ↑ C27 trihydroxycholestanoic and pristanic acid ↓ Primary bile acids |
↑ C27 trihydroxycholestanoic and pristanic acid ↓ Primary bile acids Normal long-chain fatty acids and phytanic acid |
Adult onset peripheral neuropathy Neonatal cholestasis with considerable fat-soluble-vitamin deficiency |
| Zellweger syndrome (cerebrohepatorenal syndrome) | 12 PEX gene mutations; PEX1 mutations are the most common. |
Atypical monohydroxy, dihydroxy and trihydroxy C27 bile acids ↓ Primary bile acids |
↑ Long-chain fatty acids ↑ Cholestanoic and pipecolic acid ↑ C29 dicarboxylic acid ↓ Primary bile acids |
Craniofacial abnormalities Neuronal migration defects Polycystic kidneys Chronic liver disease Bony abnormalities |
| Bile acid conjugation defects | BAAT and BAL97,98 | Absence of glycine and/or taurine conjugates. Presence of cholic glucouronidates and/or sulfates and unconjugated cholic acid |
↑ Unconjugated cholic and deoxycholic acid Absence of chenodeoxycholic acid |
Transient neonatal cholestasis Fat-soluble-vitamin deficiencies |