Congenital bile acid synthesis defect type 2

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

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.

The signs and symptoms of congenital bile acid synthesis defect type 2 often develop in infancy. Affected infants usually have difficulty gaining weight and growing at the expected rate (faltering weight). They may also have 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.

If left untreated, congenital bile acid synthesis defect type 2 typically leads to cirrhosis and death in childhood.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

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 and family implications

From: MedlinePlus Genetics, National Library of Medicine

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.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

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.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal enzyme/coenzyme activity · Very frequent (99-80%)

Concentration or activity of an enzyme is above or below the limits of normal in the blood circulation.

Giant cell hepatitis · Very frequent (99-80%)

Chronic hepatitis characterized by parenchymal inflammation with formation of large multinucleated hepatocytes in response to a variety of insults to the liver.

Hyperbilirubinemia · Very frequent (99-80%)

An increased amount of bilirubin in the blood.

Abnormal serum bile acid concentration · Frequent (79-30%)

A deviation from the normal concentration of serum bile acid concentration.

Abnormality of the coagulation cascade · Frequent (79-30%)

An abnormality of the coagulation cascade, which is comprised of the contact activation pathway (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway) as well as cofactors and regulators.

Cholestasis · Frequent (79-30%)

Impairment of bile flow due to obstruction in bile ducts.

Dark urine · Frequent (79-30%)

An abnormal dark color of the urine.

Elevated circulating alkaline phosphatase concentration · Frequent (79-30%)

Abnormally increased serum levels of alkaline phosphatase activity.

Other findings in the same source

From: Orphanet

Additional reported features include Elevated circulating hepatic transaminase concentration (Frequent (79-30%)); Extramedullary hematopoiesis (Frequent (79-30%)); Failure to thrive (Frequent (79-30%)); Fat malabsorption (Frequent (79-30%)); Hepatic steatosis (Frequent (79-30%)); Hepatomegaly (Frequent (79-30%)); Increased circulating lactate dehydrogenase concentration (Frequent (79-30%)); Jaundice (Frequent (79-30%)); Low levels of vitamin E (Frequent (79-30%)); Postnatal growth retardation (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Congenital bile acid synthesis defect type 2 is Hepatology, with a hepatologist / gastroenterologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• What is known about the cause and extent of liver involvement?
• Which medicines, supplements or exposures should be reviewed?
• What follow-up is appropriate for the specific diagnosis and stage?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.