What is congenital bile acid synthesis disorder?

Congenital bile acid synthesis disorder is a rare inherited metabolic disease caused by congenital defects in enzymes essential for synthesizing two bile acids (cholic acid and chenodeoxycholic acid), leading to impaired bile acid synthesis.

Most cases are autosomal recessive disorders, accounting for about 1%–2% of infantile cholestatic diseases.

What are the causes of congenital bile acid synthesis disorder?

Congenital bile acid synthesis disorder is primarily an autosomal recessive genetic disease associated with enzyme deficiencies in bile acid synthesis, including:

• 3β-hydroxy-C27-steroid dehydrogenase/isomerase (HSD3B7) deficiency;
• △4-3-oxosteroid 5β-reductase (AKR1D1) deficiency;
• Oxysterol 7α-hydroxylase (CYP7B1) deficiency;
• α-methylacyl-CoA racemase (AMACR) deficiency;
• Sterol 27-hydroxylase (CYP7A1) deficiency;
• 12α-hydroxylase deficiency.

Who is most susceptible to congenital bile acid synthesis disorder?

Congenital bile acid synthesis disorder is a genetic metabolic disease, primarily affecting children.

What are the clinical manifestations of congenital bile acid synthesis disorder?

Clinical presentations vary depending on the underlying enzyme deficiency:

• HSD3B7 deficiency: Jaundice, hepatosplenomegaly, steatorrhea; older children may show rickets, growth retardation, with or without pruritus.
• AKR1D1 deficiency: Severe jaundice, dark urine, clay-colored stools, steatorrhea, growth impairment, rickets, hepatosplenomegaly, coagulopathy (no pruritus); often presents with severe neonatal cholestasis and liver failure.
• CYP7B1 deficiency: Rare (only 2 reported cases), with severe neonatal cholestasis, hepatosplenomegaly, pale stools (no pruritus).
• AMACR deficiency: Neonatal fat-soluble vitamin (25-OH-D, vitamin E) deficiency, bloody stools, mild cholestatic liver disease.
• CYP7A1 deficiency (cerebrotendinous xanthomatosis): Symptoms typically appear in adulthood (20s–30s); progressive neurological dysfunction, dementia, ataxia, cataracts, xanthomas in brain/tendons.
• 12α-hydroxylase deficiency: Neonates—severe hypoglycemia and cholestasis; children—steatorrhea and chronic constipation.

Which department should be consulted for congenital bile acid synthesis disorder?

Departments: Pediatrics, Hepatobiliary-Pancreatic Surgery, Pediatric Surgery.

How is congenital bile acid synthesis disorder diagnosed?

Diagnosis combines clinical symptoms, lab tests, imaging, and biopsy, confirmed by urinary bile acid analysis and genetic testing:

• Lab tests: Elevated conjugated bilirubin, transaminases; normal γ-GT; giant cell hepatitis on biopsy.
• Urinary bile acid analysis (tandem mass spectrometry): Primary diagnostic method.
• Genetic testing: Targets genes like CYP7A1, HSD3B7, AKR1D1, CYP7B1, etc.

How is congenital bile acid synthesis disorder treated?

Treatment aims to supplement primary bile acids, suppress toxic metabolite production:

• Medication: Oral primary bile acids (cholic acid, chenodeoxycholic acid, ursodeoxycholic acid) improve symptoms/biomarkers if started early.
• Personalized therapy:
  • AKR1D1 deficiency: Chenodeoxycholic/cholic acid preferred over ursodeoxycholic acid.
  • AMACR deficiency: Supplement bile acids + fat-soluble vitamins; restrict phytol intake.
  • CYP7A1 deficiency: Chenodeoxycholic acid reduces cholestanol; statins may be combined.
• Liver transplantation for drug-refractory or advanced cases.

What is the prognosis of congenital bile acid synthesis disorder?

Early diagnosis and treatment often yield good outcomes. Delayed intervention may lead to liver failure, necessitating transplantation or causing death.

How to prevent congenital bile acid synthesis disorder?

Preventive measures for this genetic disorder include:

• Avoid consanguineous marriage; undergo premarital screening.
• Regular prenatal checkups and diagnostic tests during pregnancy.
• Genetic counseling for families with affected children planning another pregnancy.