Disorder of bile acid synthesis (ORPHA:79168)
A group of sterol metabolism disorders due to enzyme deficiencies of bile acid synthesis (BAS) in infants, children and adults, with variable manifestations that include cholestasis, neurological disease, and fat malabsorption. Nine inborn errors have been described, 7 of which lead to liver cholestasis.
Epidemiology
Overall prevalence is unknown but estimated prevalence may be around 1-9/1,000,000 for overall BAS defects, excluding cerebrotendinous xanthomatosis. Inborn errors in BAS probably account for 1-2% of cases of unexplained liver disease in infants, children and adolescents.
Clinical description
Age at diagnosis is variable. Presentation may be in infancy with liver cholestasis, in childhood with unexplained liver disease or in adulthood with neurologic disease. Infants and children may present with complications secondary to fat malabsorption and fat-soluble vitamin deficiency including rickets, bleeding diathesis, neuroaxonal dystrophy and night blindness.
Etiology
The seven inborn errors of BAS leading to liver cholestasis include: 3-beta-hydroxy-C27-steroid oxidoreductase deficiency (BAS defect type 1) that is the most common, delta4-3-oxosteriod-5-beta reductase deficiency (BAS defect type 2), oxysterol 7alpha-hydroxylase deficiency (BAS defect type 3), 2-methylacyl-CoA racemase deficiency (BAS defect type 4;), trihydroxycholestanoic acid (THCA) CoA oxidase deficiency (see this term), bile acid CoA ligase deficiency and defective amidation (see this term), and cerebrotendinous xanthomatosis (see these terms). Cholesterol 7alpha-hydroxylase deficiency (see this term) leads to hypercholesterolemia without liver cholestasis. A reported defect in side chain oxidation in the alternate 25-hydroxylation pathway needs further confirmation.
Diagnostic methods
Diagnosis is based on serum hepatic enzyme and bilirubin profile, and analysis of urine, serum and bile using liquid secondary ionization mass spectrometry (LSIMS) and gas chromatography - mass spectrometry (GC-MS).
Differential diagnosis
The spectrumof differential diagnoses is large and is that of neonatal cholestasis, unexplained fat-soluble vitamin deficiency in infancy and childhood, unexplained liver disease in infancy, childhood and adolescence and unexplained neurologic disease in adults.
Antenatal diagnosis
Most defects can be diagnosed antenatally from embryonic tissue when there has been a previously affected sibling. Urine from suspected cases may be screened by LSIMS in the first neonatal days and therapy initiated before significant morbidity develops.
Management and treatment
Treatment is based on primary bile acid therapy. Cholic acid creates a bile acid pool that stimulates bile flow and fat absorption. It does not appear to be effective for type 3. Ursodeoxycholic acid (UDCA) therapy creates a bile acid pool, but does not suppress production of toxic intermediates and is not very effective at facilitating fat absorption. Glycocholic acid therapy is the treatment of choice for bile acid CoA ligase deficiency and defective amidation, improving fat absorption and growth.
Prognosis
Prognosis depends on the type of defect. In all defects that affect the steroid nucleus of the bile acid molecule, if untreated, progressive liver disease may develop or reduced intestinal bile acid concentrations may lead to serious morbidity or mortality. Long-term survival and clinical improvement is possible with early treatment. In those defects that affect the side chain, liver disease is milder and neurological disease may predominate.

                            Last update: 
                            January 2011


                            - Expert reviewer(s): 
                            Pr James HEUBI