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Congenital bile acid synthesis defect, type 2

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Other Names: CBAS2; Cholestasis with delta(4)-3-oxosteroid 5-beta-reductase deficiency

Congenital bile acid synthesis defect type 2 is a disorder characterized by cholestasis, a condition that impairs the production and release of a digestive fluid called bile from liver cells. Bile is used during digestion to absorb fats and fat-soluble vitamins, such as vitamins A, D, E, and K. People with congenital bile acid synthesis defect type 2 cannot produce (synthesize) bile acids, which are a component of bile that stimulate bile flow and help it absorb fats and fat-soluble vitamins. As a result, an abnormal form of bile is produced. If left untreated, congenital bile acid synthesis defect type 2 typically leads to cirrhosis and death in childhood.

Epidemiology

The prevalence of congenital bile acid synthesis defect type 2 is unknown. Together, all congenital defects of bile acid synthesis are thought to have a prevalence of 1 to 9 per million people.

Cause

Mutations in the AKR1D1 gene cause congenital bile acid synthesis defect type 2. The AKR1D1 gene provides instructions for making an enzyme called 3-oxo-5- beta(β)-steroid 4-dehydrogenase. This enzyme is found in certain liver cells that produce bile acids. Bile acids are produced from cholesterol in a multi-step process. The 3-oxo-5-β-steroid 4-dehydrogenase enzyme is responsible for the third step in that process, which converts 7alpha(α)-hydroxy-4-cholesten-3-one to 7α-hydroxy-5 β-cholesten-3-one.

AKR1D1 gene mutations result in a 3-oxo-5-β-steroid 4-dehydrogenase enzyme with severely reduced function. Without enough functional enzyme, the conversion of 7α-hydroxy-4-cholesten-3-one to 7α-hydroxy-5 β-cholesten-3-one is impaired. The 7α-hydroxy-4-cholesten-3-one instead gets converted into abnormal bile acid compounds that cannot be transported out of the liver into the intestine, where the bile acids are needed to absorb fats and fat-soluble vitamins. As a result, cholesterol and abnormal bile acids build up in the liver and fat-soluble vitamins are not absorbed, which contribute to the signs and symptoms of congenital bile acid synthesis defect type 2.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

The signs and symptoms of congenital bile acid synthesis defect type 2 often develop in infancy. Affected infants usually have a failure to gain weight and grow at the expected rate (failure to thrive) and yellowing of the skin and eyes (jaundice) due to impaired bile flow and a buildup of partially formed bile. Excess fat in the feces (steatorrhea) is another feature of congenital bile acid synthesis defect type 2. As the condition progresses, affected individuals can develop liver abnormalities including inflammation or chronic liver disease (cirrhosis). Some individuals with congenital bile acid synthesis defect type 2 cannot absorb certain fat-soluble vitamins, which can result in softening and weakening of the bones (rickets) or problems with blood clotting that lead to prolonged bleeding.

Diagnosis

Diagnostic methods Diagnosis is based on urine analysis using liquid secondary ionization mass spectrometry (LSIMS) and gas chromatography - mass spectrometry (GC-MS).

LSIMS urine analysis reveals elevated amounts of delta(4)-3-oxo bile acids including 3-oxo-7alpha-hydroxy-4-cholenoic and 3-oxo-7alpha, 12alpha-dihydroxy-4-cholenoic acids. Increased production of delta4-3-oxo bile acids occurs in infants during the first few weeks of life and in patients with end-stage liver disease of other causes. It is important to perform repeat LSIMS urine analysis as, on rare occasions, a resolution of the liver disease occurs with disappearance of atypical bile acids.

Differential diagnosis

Differential diagnoses include progressive familial intrahepatic cholestasis, diseases that present with neonatal cholestasis, which includes alpha-1-antitrypsin deficiency (ZZ phenotype), tyrosinemia type 1, biliary atresia, choledochal cyst, cystic fibrosis, Alagille syndrome, galactosemia and hereditary fructose intolerance or diseases that present with growth failure (panhypopituitarism) (see these terms).

Antenatal diagnosis

Antenatal diagnosis can be established by analysis of embryonic tissue when there has been a previously identified sibling. Urine LSIMS on siblings of affected patients may be performed in the first neonatal days and therapy begun before serious morbidity develops.

Treatment

Treatment is based on oral bile acid therapy, which leads to gradual resolution of biochemical and histologic abnormalities and prevents progression of the disease. Cholic acid therapy creates a pool of bile acids which stimulates bile flow and facilitates fat soluble vitamin absorption and suppresses atypical bile acid synthesis thereby reducing the production of toxic bile acid metabolic intermediates.

Ursodeoxycholic acid (UDCA) may be used but is not the therapy of choice because UDCA does not suppress atypical bile acid synthesis and the toxic metabolites that may injure the liver continue to be produced. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

  • cholic acid (Brand name: Cholbam)Treatment of bile acid synthesis disorders due to single enzyme defects and as adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption.

Prognosis

With early treatment, the long-term prognosis is excellent. If a patient is identified with advanced liver disease, cholic acid therapy may not be effective and liver transplantation may be required. Without treatment, the condition is generally fatal.

NIH genetic and rare disease info

Congenital bile acid synthesis defect, type 2 is a rare disease.

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