Bile Acid Synthesis Disorders

Overview 

Bile acid synthesis disorders (BASDs) are a group of rare genetic disorders that affect the production of bile acids in the liver. Bile acids help you to digest and absorb fats and certain vitamins from your food. They also help in the production and excretion of bile, which is a fluid made by the liver that aids the overall digestion process.

BASDs are caused by mutations (changes in the DNA) in certain genes that are linked to the production of bile, which causes the process of bile acid production to be defective. This leads to a wide range of symptoms, from mild yellowing of the skin (jaundice) to life-threatening consequences like liver failure. Jaundice is a symptom of cholestasis, which is a condition that causes obstructed flow of bile. However, many of these disorders can be treated by replacing the missing bile acids. Early detection and management of the condition can improve patient outcomes.

What are bile acids, and why are they important? 

Bile acids are molecules that are made in the liver from cholesterol and then released into bile (a fluid made in the liver to aid digestion). The two main bile acids made by the liver are called cholic acid and chenodeoxycholic acid. 

Bile acids have many roles in aiding digestion and absorption. This includes: 

• Assisting the absorption of fats and fat-soluble vitamins 
• Breaking down and eliminating cholesterol (a type of fat) from the body 
• Promoting the flow and excretion of bile

People with BASDs are unable to produce bile acids adequately, which means that they get a build-up of abnormal toxic by-products (intermediate compounds). These intermediate compounds would usually be converted into fully formed bile acids in a healthy person. The build-up of these toxic compounds, along with obstructed bile flow and impaired absorption of bile acids, can harm the body and cause various symptoms. 

Causes of BASDs

Bile acid synthesis disorders are genetic conditions that are caused by mutations in certain genes. These particular genes code for enzymes (a special type of protein) that are involved in the process of producing bile acids. A mutation in a gene that codes for these enzymes can lead to non-functional, absent or deficient amounts of these enzymes. This impacts the production of bile acids and leads to the build-up of toxic intermediate bile acids.

Inheritance of BASDs

BASDs are inherited disorders, which means that they are passed down in the genes from parents to children. BASDs are inherited in an autosomal recessive pattern. Every individual has two genes for every trait. In an autosomal recessive condition, if you only have one gene that is abnormal and the other is normal, you will not experience symptoms of the condition but you will be a carrier of the condition (you can ‘carry’ the condition to pass down to your children). This is because the normal gene will compensate for the abnormal one. However, if you inherit two abnormal genes (one from each parent), you will have a BASD that is associated with that gene. So, having two copies of the abnormal gene is necessary for you to inherit BASDs.

For two parents who are carriers of BASDs, with each pregnancy, there is a: 

• 25% chance that their child will have a BASD
• 50% chance that their child will inherit an abnormal gene from only one parent and be a carrier of BASD
• 25% chance that their child will inherit a normal gene from each parent and be unaffected

Types of BASDs

There are a total of 9 types of BASDs, which all cause abnormal bile acid production and the build-up of intermediate bile acids.

All nine of these subtypes can fall into the category of primary or secondary BASDs:

• Primary BASDs occur when the enzymes involved in producing the two main types of bile acids, cholic acid and chenodeoxycholic acid, are missing or not working properly from birth
• Secondary BASDs occur due to problems in the process of making the primary bile acids. One example includes Smith-Lemli-Optiz syndrome, which is a disorder that impairs the body’s supply of cholesterol, which in turn means there’s less cholesterol for the synthesis of bile acids.

Primary BASDs can be caused by a deficiency of the enzyme that produces cholic acid or the enzyme that makes chenodeoxycholic acid. 

The estimated prevalence of these two defects is 1.69 cases per 10 million in the UK. However, the actual prevalence is likely to be more than this as many cases are left undiagnosed. 

Signs and symptoms 

The age of onset, type of symptoms, and rate of progression vary between individuals depending on the specific genetic defect underlying the cause of their BASD. Most cases are identified in infancy or childhood, but some milder cases don’t present until adulthood.

In BASD, the failure to produce enough primary bile acids to promote the flow of bile leads to a condition called cholestasis. The symptoms associated with this condition include: 

• Yellowing of the skin (jaundice) 
• Delayed growth
• Enlargement of the liver (hepatomegaly)
• Enlargement of the spleen (splenomegaly) 
• Diarrhoea or pale-coloured stools 

Some of the symptoms associated with BASD are linked to vitamin deficiencies, as the disorder impairs the absorption of fats and fat-soluble vitamins (vitamins A, D, E and K) in the digestive system. The symptoms associated with vitamin deficiency include: 

• Vision problems (vitamin A deficiency)
• Rickets, a condition causing soft, weakened bones (vitamin D deficiency)
• Poor coordination and developmental delays (vitamin E deficiency) 
• Blood clotting problems leading to easy bleeding and bruising (vitamin K deficiency)
• Neurological diseases (vitamin E deficiency or build-up of cholesterol-like substances in the brain) 

If BASDs are left untreated, they can lead to life-threatening conditions in some cases. These include: 

• Scar tissue on the liver (fibrosis)
• High blood pressure in the main vein of the liver (portal hypertension) 
• Abdominal swelling (ascites) 
• Liver failure 

Diagnosis of BASDs

If your child is experiencing the symptoms listed above, they may have a BASD, and you must see a doctor. The doctor will ask about your child’s medical history and perform a clinical examination to look for clinical signs, such as jaundice. However, the symptoms of BASD can also present in other liver disorders, so it is important to do further diagnostic testing to rule out other potential causes. 

Some of the specific diagnostic tests that may be conducted to diagnose BASDs include:

• Liver biopsy (surgically removing a tiny piece of liver tissue and analysing it under a microscope) 
• Laboratory analysis of body fluids (e.g. bile, blood and urine) 
• Molecular genetic testing (detecting specific mutations in genes known to cause BASDs)¹

Early detection and diagnosis of BASDs is vital, as without treatment, these conditions can lead to progressive chronic liver disease or liver failure.^1,2

Management and treatment 

The treatment of BASD varies based on symptoms, and an effective treatment plan may require the collaborative effort of many different specialities such as paediatricians, liver specialists and neurologists.¹

Many people with BASDs have seen dramatic improvements in their health in response to bile acid replacement therapy. This treatment has shown the potential to improve and even normalise liver function. The mechanism of bile acid replacement therapy works by replacing one of the missing primary bile acids (cholic acid and chenodeoxycholic acid), through oral administration.^1,2 

However, whilst most BASDs respond well to bile acid replacement therapy, it does not work for all types of BASD. Some individuals may require alternative or additional medications to achieve the optimal outcome.²

Treatment for BASDs may also include vitamin supplementation of fat-soluble vitamins A, D, E and K. These vitamins, alongside other nutrients, may be deficient in individuals with BASDs as their absorption is impacted due to impaired bile acid function. 

Individuals who do not respond to bile replacement therapy or any other treatments may require a liver transplant as a last resort. A liver transplant comes with risks and postoperative complications. After a liver transplant, individuals have to take medication (immunosuppressants) to prevent rejection of the transplanted liver.

Genetic counselling is recommended for individuals with BSADs and their families to help them understand how the condition is inherited, make family planning decisions, explore potential treatment options, and provide psychosocial support.^1,2 

Summary 

Bile acid synthesis disorders (BASDs) are rare genetic conditions that disrupt the production of bile acids in the liver. These disorders arise from mutations in the genes responsible for bile acid production, resulting in impaired bile flow and accumulation of toxic intermediate bile acids. This can cause various symptoms, ranging from mild to severe. If BASDs are left untreated, they can lead to life-threatening complications, like liver failure. However, treatments like bile acid replacement therapy have shown promising results in improving patient outcomes. 

The treatment approach varies between individuals and different types of BASDs, with some more severe cases requiring vitamin supplementation and even liver transplants. Genetic counselling is also important for affected families, as BASDs are genetic and can be passed down from parents to children. Through greater awareness and the timely detection and treatment of BASDs, we can optimise the outcome for individuals with the condition.