Bile acid synthesis disorders (BASD) are rare genetic conditions that can present as cholestasis, neurologic disease or fat-soluble-vitamin deficiencies. They are responsible for 1-2% of cases of neonatal cholestasis.[1] There are nine subtypes of BASDs, classified either as primary or secondary: [2]

  • Primary BASDs arise from congenital deficiencies in the enzymes required for synthesizing 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.

What are primary bile acid synthesis disorders?

Primary bile acid synthesis disorders (BASD) are genetic autosomal recessive diseases. They are associated with mutations in the coding genes for enzymes involved in the biosynthesis of primary bile acids (cholic acid and chenodeoxycholic acid). They are rare causes of liver disease in children that can occur at any age (from birth to adolescence). They usually present as cholestatic jaundice and/or liver failure.[3] Early diagnosis of these disorders is essential. The two most frequent ones responsible for chronic liver disease are: [3]
  • 3β-hydroxy-Δ5-C27-steroid oxidoreductase (or dehydrogenase/isomerase) deficiency; may also be called 3β-HSD deficiency, or BAS defect type 1.
  • Δ4-3-oxosteroid-5β reductase deficiency; may also be called Δ4-3-oxoR, or 5β-reductase deficiency, or BAS defect type 2.

They correspond to a lack of one of the two enzymes, 3β-HSD or Δ4-3-oxoR, which are involved in the transformation of cholesterol into primary bile acids in liver cells. When they are missing, cholesterol transformation is incomplete which leads to the absence of production of primary bile acids and accumulation of toxic intermediates in the liver causing its deterioration. [3]

These enzyme deficiencies are very rare liver diseases, diagnosed in most cases in infants and children. However, the possibility of diagnosing these diseases in older children or in adults should not be ruled out. The scientific literature describes a few cases of patients diagnosed with 3β-HSD deficiency in adulthood following unexplained cirrhosis.

Did you know? 

For a long time, bile acid synthesis disorders were confused with other liver diseases grouped under the name “progressive familial intrahepatic cholestasis” in the French literature, or under the names “progressive familial cholestatic cirrhosis”, “fatal familial intrahepatic cholestasis”, “Byler syndrome”, “Byler’s disease”, and “progressive familial intrahepatic cholestasis” in the Anglo-Saxon literature.

Thanks to the development of new medical analysis techniques allowing analysis of urinary bile acids, it is now possible to identify and diagnose these diseases since the 1980s. Deficiencies in 3β-HSD and Δ4-3-oxoR were identified respectively in 1987 and 1988. Their genetic origins were only confirmed in the 2000s. [3]

What are the figures?

Bile acid synthesis disorders are responsible for approximately 1 to 2% of cholestasis in neonates.[4]
In Europe, the prevalence of 3β-HSD and Δ4-3-oxoR deficiencies is at least 1.13 cases per 10 million people: [5]

  • 0.99 per 10 million people for 3β-HSD deficiency,
  • 0.14 per 10 million people for Δ4-3-oxoR deficiency.

However, it is possible that these prevalences may be underestimated because of the rarity of the diseases and because: [5]

  • The potential inexperience of physicians in these diseases can make diagnosis complicated: some patients may go undiagnosed or may be misdiagnosed;
  • The number of specialized medical laboratories that can confirm the diagnosis is limited.

Italie

1.98 per 10 million people

FRANCE

4.02 per 10 million people

UK

1.69 per 10 million people

How are these diseases transmitted?

Deficiencies in 3β-HSD and Δ4-3-oxoR are genetic diseases with autosomal recessive inheritance. They are due to abnormal genes, referred to as “mutated”.

The genes are carried by the DNA present in the chromosomes. Each chromosome exists in pairs, and during embryonic development, people inherit half of their mothers’ chromosomes and half of their fathers’ chromosomes. Therefore, 50% of every person’s DNA, and therefore their genes, come from their mother and 50% come from their father. 

Because of the autosomal recessive nature of these diseases, for them to develop, a person has to inherit two mutated genes (a mutated gene from the mother and a mutated gene from the father), that is, to say two identical alleles.

FOR EVERY PREGNANCY*, A CHILD HAS THE FOLLOWING RISKS:

0 %
  • Inheriting both mutated alleles
  • Developing the disease
  • Transmitting a mutated allele to offspring
0 %
  • Inheriting one mutated allele (healthy carrier)
  • No development of the disease
  • Possibly transmitting a mutated allele to offspring
0 %
  • Absence of mutated allele
  • No development of the disease
  • No transmission of a mutated allele to offspring

*If both parents are carriers of a mutated allele

As for any disease with autosomal recessive inheritance, parent consanguinity increases the risk of carrying the disease and developing it.

With 3β-HSD and Δ4-3-oxoR deficiencies, the mutated gene is carried by a non-sexual chromosome (neither the X nor the Y chromosome). The diseases are not linked to sex, they can affect both women and men. The following genes have been identified as being responsible for the development of these diseases when they are mutated: [3]

  • HSD3B7 gene for 3β-HSD deficiency,
  • AKR1D1 gene (formerly SRD5B1) for Δ4-3-oxoR deficiency.

What are bile acids?

Bile acids play a role in regulating their own production. They exert a negative feedback on their synthesis pathway: when the amount produced is sufficient, synthesis is stopped.

Bile [6]

  • Greenish-yellow biological fluid produced by the liver
  • Facilitates digestion, especially that of lipids and fat-soluble elements
  • 97% water
  • 3% of different non-aqueous elements of which bile acids are the major part

Primary bile acids [6]

  • Main constituents of bile
    • Cholic acid and chenodeoxycholic acid
  • Synthesized in liver cells from cholesterol
    • Involving about twenty different enzymes
  • Main functions:
    • Major route of cholesterol elimination
    • Provides the main driving force for the circulation and secretion of bile
    • Essential role in the elimination of toxic substances including bilirubin, and medicinal product metabolites
    • Facilitates the absorption of fat-soluble vitamins and lipids in the intestines

Enterohepatic circulation of bile acids [7]

Synthesis of the main constituent of bile, primary bile acids, from cholesterol in hepatocytes

Transportation of bile in the gall bladder through the biliary tract

Storage of bile in the gallbladder

Release of bile in the duodenum following bolus-related stimulation

Reabsorption of 95% of bile acids through the ileum and colon, transported through the portal vein to the liver, and 5% loss of bile acids in stools

How do these diseases work?

3β-HSD and Δ4-3-oxoR are enzymes that play an important role in the primary bile acid synthesis pathway. If they are deficient, synthesis of primary bile acids, which is essential for promoting biliary secretion, is prevented leading to accumulation of toxic bile acid precursors in the liver. This results in cholestasis, then liver cirrhosis or progressive and irreversible liver failure.

The pathophysiological consequences are as follows: [5]

Absence of primary bile acids

Accumulation of intermediate hepatotoxic and cholestatic bile acids

Intestinal malabsorption of fats and fat-soluble vitamins

  • Rickets due to lack of vitamin D,
  • Haemorrhage due to lack of vitamin K,
  • Neurological disorders due to lack of vitamin E,
  • Eye problems due to lack of vitamin A.

Defect in the negative feedback of primary bile acids :

  • Intermediate bile acids which are toxic for the liver continue to be produced and accumulate in the liver, aggravating the diseases.

How to recognize 3β-HSD and Δ4-3-oxoR deficiencies? [3-5]

These diseases may be suspected based on a combination of clinical and laboratory signs, and histological findings of the liver. Observed together, they should lead to a specific urine test and then a genetic test being conducted. Furthermore, since these diseases are inherited, it is important to look into the patient’s family history: cases of unexplained liver problems (or even deaths) in young children in the family can help with the diagnosis of BASD.

Clinical signs

  1. Cholestasis and/or hepatocellular insufficiency during the first months of life or in childhood(1)
    • Progressive and prolonged jaundice
    • Hepatomegaly, splenomegaly
    • Sings of liver failure
  2. And/or malabsorption syndrome
    • Steatorrhea
    • Clinical signs associated with fat-soluble vitamin deficiency: A, D, E, K (eye disorders, rickets, neurological disorders, haemorrhage)
  3. Or cirrhosis
  4. And no pruritus

(1) Exceptionally, the disease may be discovered late, in teenagers or adults; the possibility the patient may have the disease should be considered in case of unexplained liver cirrhosis.

LABORATORY SIGNS

  1. Elevation in serum transaminase levels (ALAT, ASAT)
  2. Conjugated hyperbilirubinemia
  3. NORMAL SERUM GGT ACTIVITY(2)
  4. Normal or low serum total bile acids

(2) Primary bile acids contribute to the release of GGT from the canalicular membrane to the blood. Except in special cases, given their absence, they do not lead to an increase in GGT levels in the blood.

FAMILY HISTORY

  1. Cases of unexplained liver problems
  2. Deaths in young children
  3. Consanguineous parents

HISTOLOGICAL SIGNS

  1. Canalicular cholestasis
    • Without bile duct proliferation
    • Sometimes with signs of giant cell hepatitis
  2. Portal and lobular fibrosis with features of septal fibrosis or cirrhosis, depending on the stage

Confirmation of diagnosis

A specific urine diagnostic test

Analysis of bile acids in urine by mass spectrometry(3) 

+

A genetic test

Sequencing of the genes involved in the diseases

(3) If you are a healthcare professional and have difficulties getting the specific diagnostic tests performed, do not hesitate to contact us for more information.

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;8]

  • Normal or low total serum bile acid concentrations
  • Normal γ-glutamyl transpeptidase concentrations
  • No pruritus

Patients with Δ4-3-oxoR deficiency are similar to patients with 3β-HSD deficiency. However, the average diagnosis is 3 months in patients with Δ4-3-oxoR versus 3 months to 14 years in patients with 3β-HSD deficiency. [1-2] They also tend to have more severe liver diseasethan patients with 3β-HSD deficiency and more rapid progression to cirrhosis and death without intervention.[2]

Early diagnosis of these diseases is therefore essential.

What about treatment of these diseases?

Early diagnosis is important because these disorders can be treated. Without treatment, there is a 50% mortality rate of Δ4-3-oxoR deficiency infants for whom diagnosis is delayed. [1-4]

Treatment should be initiated in a specialised environment, where the patient should also be monitored. In between visits to the reference centre specialist, the paediatrician or GP may treat intercurrent diseases in consultation with the specialist at the reference centre.[3]

Follow-up includes regular visits and regular blood and urine tests. The frequency of the visits varies according to the state of each patient and at the physician’s discretion. It is important to take medical treatments continuously because stopping them may lead to the reappearance of symptoms and further deterioration of the liver.

Useful links for primary BASD

GLOSSARY

Enzyme
Protein that activates or accelerates the chemical reactions of the body

DNA
Essential constituent of chromosomes and structure containing genetic information

Chromosome
Condensed structure consisting largely of DNA

Cholestasis
Decrease or cessation of bile secretion

Allele
A variant version of a gene

Gene
Portion of DNA constituting a functional unit

Liposoluble
Soluble in fats, oils

Fat-soluble vitamins
Vitamins soluble in fats but not in an aqueous medium (in water). These are vitamins A, D, E and K.

Feedback
Feedback is a feedback control of an effect on its cause: the system acts on itself 
Feedback can have different effects:
– Positive: that is to say, it increases the activity of the source.
– Negative: hat is to say, it reduces the activity of the source.

Hepatomegaly

Increase in the volume of the liver

Splenomegaly
Increase in the volume of the spleen

Steatorrhea
Presence of fats in the stools

ASAT
Aspartate Aminotransferase – a transaminase enzyme

ALAT
Alanine Aminotransferase – a transaminase enzyme

GGT
Gamma Glutamyl Transpeptidase – a liver enzyme

Pruritus
Itchy skin sensation

Cirrhosis
Liver condition characterized by tissue reorganisation and cell damage

Hyperbilirubinemia
Increased blood bilirubin levels

Prevalence
Number of patients identified in a population at a given time

Bilirubin
Yellow pigment present in bile

References

[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] 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

[4] K E Bove, J E Heubi, W F Balistreri , K D R Setchell. Bile acid synthetisis defects and liver disease : a comprehensive review. Pediatric and Developmental Pathology; 2004 (7), 315-334.

[5] J Jahnel, E Zohrer, B Fischler, L D’Antiga, D Debray, A Dezsofi, et al. Attempt to determine the prevalence of two inborn errors of primary bile acid synthesis: results of a european survey. JPGN, 2017 (64), 864–868.

[6] Monte MJ, et al. Bile acids: Chemistry, physiology, and pathophysiology. World J Gastroenterol 2009; 15(7): 804-816

[7] van Mil SW, Houwen RH, Klomp LW. Genetics of familial intrahepatic cholestasis syndromes. J Med Genet 2005;42:449-63.

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