Bile Acid Synthesis Disorder

Bile acid synthesis disorders are rare genetic conditions that disrupt the body’s ability to produce normal bile acids, leading to serious liver problems and other complications that can affect people from infancy through adulthood.

Table of contents

• What is bile acid synthesis disorder?
• Disease identification codes
• Causes and inheritance
• Types of bile acid synthesis disorders
• Signs and symptoms
• How the condition is diagnosed
• Treatment options
• How common is the condition
• Outlook for patients

What is bile acid synthesis disorder?

Bile acid synthesis disorders are a group of rare metabolic conditions caused by problems with the enzymes that make bile acids in the liver^[1]. Bile acids are special chemicals that the body makes from cholesterol to help digest fats and absorb certain vitamins from food^[3].

When someone has a bile acid synthesis disorder, their body cannot produce normal bile acids. Instead, abnormal and potentially toxic bile acid compounds build up^[4]. This causes cholestasis, a condition where bile cannot flow properly from the liver to the small intestine^[6].

Without normal bile acids, the body struggles to digest fats and absorb important fat-soluble vitamins like A, D, E, and K^[4]. The abnormal bile acids and other substances that accumulate can damage the liver and potentially other organs^[1].

Disease identification codes

10088265
C0400973
Not specified in sources

BASD, BASDs, inborn errors of bile acid metabolism, bile acid synthesis defects

Causes and inheritance

Bile acid synthesis disorders are genetic conditions caused by mutations, or changes, in specific genes^[5]. These genetic changes prevent the body from making the enzymes needed to produce normal bile acids^[8].

The conditions are inherited in an autosomal recessive pattern^[4]. This means a person must inherit two copies of the changed gene—one from each parent—to develop the disorder^[5]. Parents who each carry one copy of the changed gene typically do not show symptoms themselves but can pass the condition to their children^[4].

Types of bile acid synthesis disorders

Nine different enzyme problems have been identified that cause bile acid synthesis disorders, and seven of these lead to liver cholestasis^[1]. The disorders can be classified as primary, which result from defects in genes directly involved in bile acid production, or secondary, which stem from defects in genes for bile acid transport or other related processes^[3].

The seven main types that cause liver cholestasis include^[1]:

• 3-beta-hydroxy-C27-steroid oxidoreductase deficiency (also called BAS defect type 1 or CBAS1), which is the most common form^[1]
• Delta4-3-oxosteroid-5-beta reductase deficiency (BAS defect type 2)
• Oxysterol 7alpha-hydroxylase deficiency (BAS defect type 3)
• 2-methylacyl-CoA racemase deficiency (BAS defect type 4)
• Trihydroxycholestanoic acid (THCA) CoA oxidase deficiency
• Bile acid CoA ligase deficiency and defective amidation
• Cerebrotendinous xanthomatosis

Additionally, there are secondary bile acid synthesis disorders associated with peroxisomal disorders, such as Zellweger spectrum disorders^[3]. Peroxisomes are important structures inside cells, and when they don’t work properly, it affects bile acid production along with many other body functions.

Signs and symptoms

The signs and symptoms of bile acid synthesis disorders can begin at different ages, from the first weeks of life through adulthood^[1]. The severity and specific symptoms can vary greatly depending on which enzyme is affected^[5].

The most common early sign is jaundice, a yellowing of the skin and the whites of the eyes that lasts more than two weeks^[6]. Infants with the condition often fail to gain weight and grow at the expected rate, a problem called failure to thrive^[4].

Because the body cannot properly absorb fats, affected individuals may have steatorrhea—pale, foul-smelling stools that contain excess fat^[4]. The urine may appear dark, like tea^[6].

The inability to absorb fat-soluble vitamins leads to several complications^[1]:

• Vitamin A deficiency can cause night blindness and vision problems
• Vitamin D deficiency can lead to rickets, a condition where bones become soft and weak^[4]
• Vitamin E deficiency may cause neurological problems
• Vitamin K deficiency results in a bleeding diathesis, meaning the blood does not clot properly, leading to easy bruising and bleeding^[1]

Liver-related symptoms include an enlarged liver (hepatomegaly) and an enlarged spleen (splenomegaly)^[3]. Blood tests typically show elevated liver enzymes, indicating the liver is not working properly^[6].

Some patients may develop inflammation of the liver or chronic liver disease (cirrhosis)^[4]. If left untreated, the condition can progress to liver failure in childhood^[4].

How the condition is diagnosed

Diagnosing bile acid synthesis disorders begins with a medical history and physical examination^[5]. Because these conditions are rare and can cause a variety of symptoms, they may not be immediately suspected^[19].

Doctors typically perform blood tests to check liver function, including measurements of^[5]:

• Direct bilirubin
• Alanine transaminase (ALT) and aspartate transaminase (AST)
• Gamma glutamyltransferase (GGT)
• Primary bile acids

The definitive diagnosis is made through specialized testing. The most important diagnostic tool is mass spectrometry, which analyzes urine, serum, and bile samples to detect abnormal bile acids^[1]. Two specific techniques used are liquid secondary ionization mass spectrometry (LSIMS) and gas chromatography-mass spectrometry (GC-MS)^[1].

Genetic testing can identify specific mutations in the genes responsible for bile acid production^[5]. This testing uses panels that screen for various genes known to cause cholestasis.

For families who have had a previously affected child, most bile acid synthesis defects can be diagnosed before birth from embryonic tissue^[1]. Screening of urine from suspected newborn cases can be done in the first days of life, allowing treatment to begin before serious complications develop^[1].

Treatment options

The main treatment for bile acid synthesis disorders is oral bile acid therapy, which involves taking bile acid supplements by mouth to replace the bile acids the body cannot make^[5].

Cholic acid is the primary treatment option. It was approved in 2015 as the first treatment for both pediatric and adult patients with bile acid synthesis disorders caused by single enzyme defects^[5]. Cholic acid works by creating a bile acid pool that stimulates bile flow and helps the body absorb fats^[1]. It also helps suppress the production of toxic bile acid intermediates^[1].

Another medication sometimes used is ursodeoxycholic acid (UDCA). While this treatment creates a bile acid pool, it does not suppress production of toxic intermediates as effectively and is not as good at facilitating fat absorption as cholic acid^[1].

For some specific types of bile acid synthesis disorders, such as type 3, cholic acid does not appear to be effective^[1]. In another form called type 4, glycocholic acid therapy is considered the treatment of choice^[1].

Treatment must be tailored to each patient’s specific symptoms and may require coordination among a team of medical specialists^[5]. Patients receiving treatment need regular laboratory testing to monitor liver function^[6].

Some patients who do not respond to bile acid therapy or who have developed severe liver damage may ultimately require a liver transplant^[5].

How common is the condition

Bile acid synthesis disorders are very rare. The overall estimated prevalence is around 1 to 9 cases per 1,000,000 people^[1].

These conditions are thought to account for 1% to 3% of all cases of neonatal cholestasis, which is jaundice that appears in newborns^[5]. Neonatal cholestasis itself occurs in about 1 in 2,500 births^[5].

Inborn errors in bile acid synthesis probably account for 1% to 2% of cases of unexplained liver disease in infants, children, and adolescents^[1].

Among all the types of bile acid synthesis disorders, 3-beta-hydroxy-C27-steroid oxidoreductase deficiency (type 1) is the most common^[4].

Outlook for patients

The outlook for patients with bile acid synthesis disorders depends heavily on early diagnosis and treatment^[5]. If left untreated, these conditions often lead to progressive liver disease, cirrhosis, and premature death in childhood^[4].

Early identification and prompt initiation of treatment with bile acid therapy may lead to better outcomes^[5]. With proper treatment, many patients can experience improvement in liver function and prevention of serious complications^[7].

Bile acid synthesis disorder is a lifelong condition for which there is no cure^[9]. Patients require ongoing treatment and monitoring throughout their lives. The treatment helps manage symptoms and slow disease progression, but the underlying genetic problem remains.

It is important to diagnose and treat bile acid synthesis disorders as early as possible, since untreated patients may develop serious liver disease or liver failure that could require a liver transplant^[5].