Overview of bile acid synthesis disorders

Bile acid synthesis disorders (BASDs) are rare genetic conditions that can present as cholestasis, neurologic disease or fat-soluble-vitamin deficiencies. BASDs are responsible for 1-2% of cases of neonatal cholestasis.1

There are nine subtypes of BASDs, all of which result in an abnormal bile acid production and accumulation of bile acids and bile acid intermediaries.1

Bile acid synthesis disorders are classified as either primary or secondary:2

  • Primary BASDs arise from congenital deficiencies in the enzymes required for synthesising the two main bile acids: cholic acid and chenodeoxycholic acid
  • Secondary metabolic defects impacting primary bile acid synthesis include peroxisomal disorders, such as Zellweger spectrum disorder (ZSD), and Smith-Lemli-Opitz syndrome caused by a deficiency of Δ7-desaturase.
Only primary BASDs are covered here.

The two most frequent defects of primary bile acid synthesis disorders are:3

  • 3β-hydroxy-Δ5-C27-steroid dehydrogenase (3β-HSD) deficiency, due to mutations in the HSD3B7 gene
  • Δ4–3-oxosteroid-5β-reductase (Δ4–3-oxoR) deficiency due to mutations in the AKR1D1 gene.
See more

The mechanism of cholestasis and liver injury is thought to result from:2

  • failure to synthesize adequate amounts of primary bile acids that are essential to the promotion and secretion of bile, and
  • increased production of unusual bile acids with hepatotoxic potential.
The pathophysiology is explained in more detail in the section Pathophysiology

BASDs commonly manifest in infants as cholestasis and can mimic other neonatal liver diseases, including biliary atresia.1 They are sometimes also diagnosed in older children and young adults following unexplained cirrhosis.2

Mode of transmission

These rare, inborn BASDs result from autosomal recessive inheritance.3 The autosomal recessive inheritance pattern is illustrated in the following figure.

Autosomal recessive inheritance pattern

adapted from the Genetic Foundation 2019 4

MOM IS A CARRIER

DAD IS A CARRIER

(no condition)

(no condition)

Child has condition

25% HAVE THE CONDITION

75% OF CHILDREN DON'T HAVE THE CONDITION

Child doesn't have
condition & is not a carrier

Children don't have condition
but are carriers

NON-WORKING GENE

WORKING GENE

Epidemiology

The estimated prevalence of 3β-HSD and Δ4–3-oxoR deficiencies in Europe is 1.13 cases per 10 million:3

  • 4.02 cases per 10 million in France
  • 1.98 cases per 10 million in Italy
  • 1.69 cases per 10 million in the UK
However, the estimated prevalence in Europe is likely to be an under-representation due to unawareness of the existence of these diseases and the lack of specialised laboratory facilities.3

Diagnosis

Failure to diagnose and without treatment, they can result in progressive chronic liver disease or liver failure.1

Diagnosis can be difficult because many diseases manifest as neonatal cholestasis or chronic liver disease, and there are no specific clinical features or biomarkers allowing the specific identification of BASDs. However, most patients with BASDs present with:1,5
  • Normal or low total serum bile acid concentrations
  • Normal γ-glutamyl transpeptidase concentrations
  • No pruritus

These are distinctive features as patients with cholestatic liver disease usually have elevated total serum bile acids and γ-glutamyl transpeptidase levels and present with severe pruritus.1 Diagnosis is achieved by connecting certain clinical signs and laboratory results with family history and liver histology, and needs to be confirmed by urinary bile acid analysis with mass spectrometry and genetic testing.2 Further details are provided in the section Diagnosis

3β-hydroxy-Δ5-C27-steroid dehydrogenase (3β-HSD) deficiency

3β-HSD deficiency is caused by mutations in the HSD3B7 gene on chromosome 16p.1

Liver injury occurs because of inadequate synthesis of the normal bile acids required to stimulate bile flow and from the accumulation of toxic bile acids.1

Clinical signs and laboratory results

Most patients with 3β-HSD deficiency are neonates, although age at onset can vary, ranging from 8 weeks to 3 years, with in some cases the disorder even manifesting in adolescents and adults.6 The clinical presentation is also variable.1,2 Typical features may include:1,2,6

  • Progressive jaundice
  • Increased aminotransferase levels, conjugated hyperbilirubinaemia, a normal γ-glutamyl transpeptidase level, a low or normal total serum bile acid concentration
  • Hepatomegaly (common), with or without splenomegaly
  • Pruritus (usually absent)
  • Malabsorption with resulting steatorrhoea, fat-soluble-vitamin deficiency, poor growth, and rickets

The variability of the clinical course of early-onset disease can be illustrated by jaundice initially resolving in some patients who then later in life present with persistent small duct injury or progressive liver disease eventuating in cirrhosis, death, or transplantation.2

Histological signs

The histopathology of 3β-HSD deficiency varies with patient age and correlates with the mode of presentation and rate of disease progression. In the infant, liver histology includes giant cell hepatitis, canalicular bile plugs, hepatocyte bile stasis and portal tract inflammation with varying degrees of fibrosis. In older infants and children, liver biopsy samples may show less pronounced features of giant cell transformation and cholestasis; however, fibrosis becomes more prominent in the portal and periportal areas, and cirrhosis may be present.1,2

Δ4-3-oxosteroid-5β-reductase (Δ4-3-oxoR) deficiency

Δ4-3-oxoR (also known as 5β-reductase) deficiency is an autosomal recessive deficiency of the Δ4-3-oxosteroid-5β-reductase enzyme – encoded by the AKR1D1 gene – causing defective synthesis of the bile acid steroid nucleus.1

Clinical signs and laboratory results

The disorder typically presents as neonatal cholestasis. Δ4-3-oxoR deficiency is characterised by increased concentrations of aminotransferases, conjugated hyperbilirubinaemia, normal γ-glutamyl transpeptidase activity and coagulopathy that worsens with disease progression.2

The clinical presentation is similar to that of 3β-HSD deficiency; however, the average age at diagnosis of Δ4-3-oxoR deficiency patients is 3 months.2 In contrast to 3β-HSD deficiency, infants with Δ4-3-oxoR deficiency tend to present more severe liver disease with rapid progression to cirrhosis and death without intervention.2 Liver failure occurs rapidly, accounting for a 50% mortality rate in infants in whom diagnosis is delayed.1 Neonatal liver failure resembling neonatal haemochromatosis is an alternative clinical presentation and is thought to be caused by an impairment in iron excretion, which is usually enhanced by bile acids.1

Histological signs

The histopathology of Δ4-3-oxoR deficiency is typical of neonatal hepatitis including giant cell hepatitis, pseudo-acinar transformation, hepatocellular and canalicular cholestasis, and extramedullary haematopoiesis.1

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

2. Heubi JE, Setchell KDR, Bove KE. Inborn errors of bile acid metabolism. Clin Liver Dis 2018;22:671-87.

3. Jahnel J, Zöhrer E, Fischler B, et al. Attempt to determine the prevalence of two inborn errors of primary bile acid synthesis: results of a European survey. J Pediatr Gastroenterol Nutr 2017;64:864-8.

4. Autosomal recessive. Genetic Support Foundation, 2019. (Accessed April, 2020, at https://www.geneticsupport.org/genetics-101/inheritance-patterns/autosomal-recessive/.)

5. Bile acid synthesis disorders. NORD: National Organization for Rare Disorders, 2017. (Accessed April, 2020, at https://rarediseases.org/rare-diseases/bile-acid-synthesis-disorders/.)

6. Protocole national de diagnostic et de soins : Déficits de synthèse des acides biliaires primaires. Centre de Référence Coordonnateur de l’Atrésie des Voies Biliaires et des Cholestases Génétiques; 2019.


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