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. There are nine subtypes of BASDs, classified either as primary or secondary: 
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. Early diagnosis of these disorders is essential.
The two most frequent ones responsible for chronic liver disease are: 
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. 
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.
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. 
Bile acid synthesis disorders are responsible for approximately 1 to 2% of cholestasis in neonates.
In Europe, the prevalence of 3β-HSD and Δ4-3-oxoR deficiencies is at least 1.13 cases per 10 million people: 
However, it is possible that these prevalences may be underestimated because of the rarity of the diseases and because: 
1.98 per 10 million people
4.02 per 10 million people
1.69 per 10 million people
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.
*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: 
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.
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
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.
Absence of primary bile acids
Accumulation of intermediate hepatotoxic and cholestatic bile acids
Intestinal malabsorption of fats and fat-soluble vitamins
Defect in the negative feedback of primary bile acids :
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.
(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.
(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.
Analysis of bile acids in urine by mass spectrometry(3)
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]
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.
Early diagnosis of these diseases is therefore essential.
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.
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.
Protein that activates or accelerates the chemical reactions of the body
Essential constituent of chromosomes and structure containing genetic information
Condensed structure consisting largely of DNA
Decrease or cessation of bile secretion
A variant version of a gene
Portion of DNA constituting a functional unit
Soluble in fats, oils
Vitamins soluble in fats but not in an aqueous medium (in water). These are vitamins A, D, E and K.
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.
Increase in the volume of the liver
Increase in the volume of the spleen
Presence of fats in the stools
Aspartate Aminotransferase – a transaminase enzyme
Alanine Aminotransferase – a transaminase enzyme
Gamma Glutamyl Transpeptidase – a liver enzyme
Itchy skin sensation
Liver condition characterized by tissue reorganisation and cell damage
Increased blood bilirubin levels
Number of patients identified in a population at a given time
Yellow pigment present in bile
 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.
 Heubi JE, Setchell KDR, Bove KE. Inborn errors of bile acid metabolism. Clin Liver Dis 2018;22:671-87
 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
 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.
 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.
 Monte MJ, et al. Bile acids: Chemistry, physiology, and pathophysiology. World J Gastroenterol 2009; 15(7): 804-816
 van Mil SW, Houwen RH, Klomp LW. Genetics of familial intrahepatic cholestasis syndromes. J Med Genet 2005;42:449-63.
 Bile acid synthesis disorders. NORD: National Organization for Rare Disorders, 2017. (Accessed April, 2020, at https://rarediseases.org/rare-diseases/bile-acid-synthesis-disorders/.)