3β-hydroxy-Δ5-C27-steroid oxydoreductase and
Δ4-3 oxosteroid 5β-reductase deficiencies

These deficiencies are part of a group of diseases called primary bile acid synthesis disorders (BASD). Deficiency in 3β-hydroxy-Δ5-C27-steroid oxidoreductase (or dehydrogenase/isomerase) may also be called 3β-HSD deficiency, or BAS defect type 1. Deficiency in Δ4-3-oxosteroid-5β reductase may also be called Δ4-3-oxoR, or 5β-reductase deficiency, or BAS defect type 2.

When were these diseases discovered?

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.

The development of new medical analysis techniques made it possible to identify and diagnose these diseases from 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.

What are deficiencies in 3β-HSD and Δ4-3-oxoR?

Deficiencies in 3β-HSD and Δ4-3-oxoR are inherited autosomal recessive diseases that are part of the ten or so BASDs identified to date. They correspond to a lack of one of the two enzymesEnzyme: Protein that activates or accelerates the chemical reactions of the body, 3β-HSD or Δ4-3-oxoR. These enzymesEnzyme: Protein that activates or accelerates the chemical reactions of the body 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 toxic intermediates accumulating in the liver causing its deterioration.

 

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

What are the figures?

Bile acid synthesis disorders are responsible for approximately 1 to 2% of cholestasisCholestase: Decrease or cessation of bile secretion in neonates [1]. In Europe, the prevalencePrévalence: Number of patients identified in a population at a given time of 3β-HSD and Δ4-3-oxoR deficiencies is at least 1.13 cases per 10 million people [2]:

 

  • 0.99 per 10 million people for 3β-HSD deficiency [2],
  • 0.14 per 10 million people for Δ4-3-oxoR deficiency [2].
FRANCE
4.02 per 10 million people [2]
ITALY
1.98 per 10 million people [2]
UK
1.69 per 10 million people [2]

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

 

  • 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.

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 genesGene: Portion of DNA constituting a functional unit, referred to as “mutated”.

The genesGene: Portion of DNA constituting a functional unit are carried by the DNADNA: Essential constituent of chromosomes and structure containing genetic information present in the chromosomeschromosome: Condensed structure consisting largely of DNA. Each chromosomechromosome: Condensed structure consisting largely of DNA exists in pairs, and during embryonic development, people inherit half of their mothers’ chromosomeschromosome: Condensed structure consisting largely of DNA and half of their fathers’ chromosomeschromosome: Condensed structure consisting largely of DNA. Therefore, 50% of every person’s DNADNA: Essential constituent of chromosomes and structure containing genetic information, and therefore their genesGene: Portion of DNA constituting a functional unit, 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 genesGene: Portion of DNA constituting a functional unit (a mutated geneGene: Portion of DNA constituting a functional unit from the mother and a mutated geneGene: Portion of DNA constituting a functional unit from the father), that is, to say two identical allelesallele: A variant version of a gene.

FOR EVERY PREGNANCY*, A CHILD HAS THE FOLLOWING RISKS:
25%
25

 

  • Inheriting both mutated alleles
  • Developing the disease
  • Transmitting a mutated allele to offspring
50%
50

 

  • Inheriting one mutated allele (healthy carrier)
  • No development of the disease
  • Possibly transmitting a mutated allele to offspring
25%
25

 

  • 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:

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

How do these diseases work?

Bile acids play a role in regulating their own production. They exert a negative feedback 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.
on their synthesis pathway, that is to say that when the amount produced is sufficient, synthesis is stopped.
3β-HSD and Δ4-3-oxoR are enzymes that play a role at the beginning of 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 main functions of primary bile acids:

  • 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 bilirubinBilirubin: Yellow pigment present in bile. , and medicinal product metabolites
  • Facilitates the absorption of fat-soluble vitamins fat-soluble vitamins: Vitamins soluble in fats but not in an aqueous medium (in water). These are vitamins A, D, E and K. and lipids in the intestines

The pathophysiological consequences are as follows

  1. Absence of primary bile acids
  2. Accumulation of intermediate hepatotoxic and cholestatic bile acids
  3. 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.
  4. Primary bile acids negative feedback defect:
    • 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?

These diseases may be suspected based on a combination of clinical and laboratory signs, and histological signs 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.

Déficit en 3β-HSD et Déficit en Δ4-3-oxoR

CLINICAL SIGNS +

CholestasisCholestasis: decrease or cessation of bile secretion and/or hepatocellular insufficiency during the first months of life or in childhood*

– Progressive and prolonged jaundice

Hepatomegaly Hepatomegaly: Increase in the volume of the liver, splenomegalysplenomegaly: Increase in the volume of the spleen

– Sings of liver failure
– And/or malabsorption syndrome
Stéatorrhée Stéatorrhée: Diarrhée graisseuse

– Déficience en vitamines liposolubles : A, D, E, K (problème de vision, rachitisme, troubles neurologiques, hémorragie)

– Ou cirrhose cirrhose: Affection du foie caractérisée par une réorganisation tissulaire et une altération des cellules

+

ABSENCE DE PRURITPRURIT: Sensation de démangeaison cutanée

Signes biologiques +

– Elévation des transaminases sérique (ALAT ALAT: Alanine Aminotransférase – enzyme faisant partie des transaminases
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, ASAT ASAT: Aspartate Aminotransférase – enzyme faisant partie des transaminases)

Hyperbilirubinémie Hyperbilirubinémie Augmentation du taux de bilirubine dans le sang (principal colorant de la bile, c’est un pigment biliaire jaune) conjuguée

TAUX SERIQUE DE GGT GGT: Gamma Glutamyl Transpeptidase– enzyme hépatique
NORMAL**

Taux sérique d’acide biliaire normal ou bas

Signes histologiques du foie

– Cholestase canaliculaire, sans prolifération des canaux biliaires et avec parfois des signes d’hépatite à cellules géantes

– Portail et fibrose lobulaire avec caractéristiques de fibrose septale ou de cirrhose, selon le stade

  1. CholestasisCholestasis: Decrease or cessation of bile secretion. and/or hepatocellular insufficiency during the first months of life or in childhood*
    • Progressive and prolonged jaundice
    • Hepatomegaly Hepatomegaly: Increase in the volume of the liver, splenomegalysplenomegaly: Increase in the volume of the spleen
    • Sings of liver failure
  2. And/or malabsorption syndrome
    • Steatorrhea Steatorrhea: Presence of fats in the stools
    • Clinical signs associated with fat-soluble vitamin deficiency: A, D, E, K (eye disorders, rickets, neurological disorders, haemorrhage)
  3. Or cirrhosis cirrhosis: Liver condition characterized by tissue reorganisation and cell damage
  4. And no pruritusPruritus: Itchy skin sensation

CLINICAL SIGNS

LABORATORY SIGNS

  1. Elevation in serum transaminase levels (ALAT ALAT: Alanine Aminotransferase – a transaminase enzyme, ASAT ASAT: Aspartate Aminotransferase – a transaminase enzyme)
  2. Conjugated hyperbilirubinemia hyperbilirubinemia Increased blood bilirubin levels
  3. NORMAL SERUM GGT GGT: Gamma Glutamyl Transpeptidase – a liver enzyme ACTIVITY **
  4. Normal or low serum total bile acids
  1. Cases of unexplained liver problems
  2. Deaths in young children
  3. Inbreeding

FAMILY HISTORY

HISTOLOGICAL SIGNS

  1. Canalicular cholestasis, without bile duct proliferation and 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 ***

A genetic test

Sequencing of the genes involved in the diseases

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

The possibility that a patient may have one of these deficiencies should therefore be considered in an individual with conjugated hyperbilirubinemia, increased transaminase levels, normal serum GGT activity, normal total serum bile acid levels, and more specifically, with signs of fat-soluble vitamin malabsorption, cholestasis with no pruritus, and/or prolonged or progressive jaundice.

Patients with Δ4-3-oxoR deficiency have more severe liver damage than patients with 3β-HSD deficiency and more rapid progression to hepatic failure.

Early diagnosis of these diseases is therefore essential because if they are not treated quickly, they can lead to liver cirrhosis, liver transplantation or even death of the patient.

Are there treatments for these diseases?

It is important that patients, once they have been diagnosed and appropriate treatment has been instituted, be followed regularly by a specialist physician.

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.

References:

[1] 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.

[2] 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.

Useful links

Rare disease

A disease is considered to be rare when it affects a small number of people. For example, in Europe, a disease is considered rare when it affects less than 1 person in 2 000*. A disease may even be qualified as ultra-rare when it affects less than 1 in 50 000 people**. In general, the prevalence of a rare disease is so low that a multidisciplinary medical approach (collaboration between professionals from different medical disciplines) is required.

    *threshold value adopted by the Programme of Community Action on Rare diseases in 1999-2003
    **threshold value adopted by the National Institute for Health and Care Excellence (NICE) in the United Kingdom