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Bile acid synthesis disorders (BASDs) are rare metabolic disorders characterized by defects in the synthesis of bile acids, which are crucial for cholesterol breakdown and the absorption of fats and fat-soluble vitamins. These disorders can lead to the accumulation of abnormal bile acids and intermediary metabolites, causing damage to various organs.

Classification

Bile Acid Synthesis Disorders are classified into two main categories: primary and secondary disorders, each with distinct characteristics and underlying causes.

Primary Bile acid synthesis disorders

Primary BASDs result from genetic mutations affecting enzyme directly involved in the biosynthetic pathways of bile acids. These disorders are typically autosomal recessive and lead to the production of atypical bile acids, causing liver dysfunction and other systemic effects. Some of the key primary BASDs include:

• 3β-Hydroxy-Δ5-C27-steroid Oxidoreductase Deficiency: caused by mutations in the HSD3B7 gene.
• Δ4-3-Oxosteroid 5β-Reductase Deficiency|Δ4-3-Oxosteroid 5β-Reductase Deficieny: results from mutations in the AKR1D1 gene (previously known as SRD5B1).
• Sterol 27-Hydroxylase Deficiency (Cerebrotendinous xanthomatosis): Caused by mutations in the CYP27A1 gene.
• Oxysterol 7α-Hydroxylase Deficiency: involves mutations in the CYP7B1 gene.

Secondary Bile acid synthesis disorders

Secondary BASDs are not caused by defects in bile acid synthesis enzymes but result from issues related to bile acid transport, metabolism, or supply of cholesterol precursors. These can be due to:

Bile acid transporter defects

Bile acid transporter defects occur when mutations affect the proteins responsible for transporting bile acids across cellular membranes, leading to their accumulation or improper reabsorption. These defects can result in cholestasis, liver injury, and systemic complications. Examples of bile acid transporter defects include:

• Low Gamma-GT Familial Intrahepatic Cholestasis (FIC): This condition involves mutations in genes encoding bile acid transporters, such as ATP8B1 or ABCB11. These mutations impair bile acid excretion from hepatocytes into the bile canaliculus, causing toxic bile acids to accumulate in the liver and leading to progressive liver damage.
• Progressive familial intrahepatic cholestasis (PFIC): PFIC refers to a group of genetic disorders caused by defects in bile salt export pump (BSEP) or other transporters. It results in severe cholestasis, jaundice, and liver fibrosis.

Cholesterol supply disorders

Cholesterol supply disorders are secondary conditions that limit the availability of cholesterol for bile acid synthesis, indirectly affecting bile acid production.

• Smith–Lemli–Opitz syndrome (SLOS): This disorder is caused by mutations in the DHCR7 gene, leading to a deficiency in 7-dehydrocholesterol reductase. This enzyme is essential for converting 7-dehydrocholesterol to cholesterol. The resulting cholesterol deficiency disrupts bile acid synthesis and causes developmental abnormalities.
• Zellweger spectrum disorders: These peroxisomal biogenesis disorders impair cholesterol metabolism by disrupting the conversion of sterols into precursors needed for bile acid synthesis. This results in reduced production of primary bile acids and accumulation of toxic intermediates.

Symptoms and signs

Bile Acid Synthesis Disorders present a range of symptoms, often beginning in infancy or early childhood. Jaundice, characterized by yellowing of the skin and eyes, is a common early sign. Growth deficiencies are prevalent, with affected individuals often failing to meet weight and height milestones due to malabsorption of fats and fat-soluble vitamins like A, D, E, and K. This can lead to Vitamin deficiencies, resulting in vision problems (vitamin A), rickets (vitamin D), neurological issues (vitamin E), and blood coagulation problems (vitamin K). Liver-related symptoms include hepatomegaly (enlarged liver) and splenomegaly (enlarged spleen), with elevated liver enzymes indicating liver dysfunction. Patients may experience cholestasis, a condition where bile flow is interrupted, leading to pale stools, dark urine, and sometimes severe itching. Steatorrhea, or excess fat in stools, is another symptom due to impaired fat digestion. In severe cases, BASDs can progress to liver failure if untreated. The variability in symptom onset and severity depends on the specific genetic defect involved.

Diagnosis

Diagnosing Bile Acid Synthesis Disorders (BASDs) requires a comprehensive approach due to their rarity and symptom overlap with other liver diseases. Physicians begin by suspecting BASDs in infants or children presenting with jaundice, unexplained liver disease, or fat-soluble vitamin deficiencies. Initial laboratory tests often include measuring serum bile acids.

Advanced diagnostic techniques involve mass spectrometry, Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and electrospray ionization-tandem mass spectrometry (ESI-MS/MS), to analyze bile acid profiles in urine and blood. These methods identify atypical bile acids and intermediates that accumulate due to enzyme deficiencies. Fast atom bombardment-mass spectrometry (FAB-MS) is another technique used to detect specific bile acid patterns indicative of BASDs. Genetic testing confirms the diagnosis by identifying mutations in genes responsible for bile acid synthesis enzymes.

Treatment

Treatment for BASDs primarily involves oral bile acid replacement therapy. Cholic acid, approved in 2015, is the standard treatment for patients with single enzyme defects and peroxisomal disorders. This therapy compensates for the lack of primary bile acids, restoring normal liver function and improving symptoms like jaundice and malabsorption.

In some cases, ursodeoxycholic acid may be used alongside cholic acid to enhance bile flow, although it is ineffective as a sole treatment. The dosage of cholic acid is carefully monitored to suppress abnormal metabolite production and improve liver biochemistry.

For patients unresponsive to medical therapy or with advanced liver disease, liver transplantation may be necessary. Early intervention with cholic acid has been shown to prevent progression to liver failure and improve long-term health outcomes, allowing many patients to lead normal lives into adulthood.

Epidemiology

Bile Acid Synthesis Disorders are rare conditions with limited epidemiological data available. The overall prevalence of BASDs is estimated to be between 1-9 cases per 1,000,000 people in the general population. However, this figure likely underestimates the true prevalence due to underdiagnosis and lack of awareness among healthcare providers.

BASDs are thought to account for approximately 1-2% of all childhood cholestatic disorders. In Europe, a study found a minimum estimated combined prevalence of 1.13 cases per 10 million people for two common types of BASDs

• 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency: 0.99 cases per 10 million
• Δ4-3-oxosteroid 5β-reductase deficiency: 0.14 cases per 10 million

These disorders affect males and females equally and can occur in individuals of any race or ethnicity. The age of onset varies, with presentations possible in infancy, childhood, or adulthood, depending on the specific type of BASD.

References

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• Diseases of liver
• Rare diseases