Bile Acid Synthesis Disorder - A Quick Guide

Introduction

Bile acid synthesis disorders are a category of rare genetic disorders that account for up to one to two percent of cases of neonatal cholestasis, a disease characterized by the development of conjugated or direct hyperbilirubinemia within the initial months after birth. The majority of individuals with inborn errors of bile acid synthesis have a notable clinical response to oral bile acid therapy. Disorders of bile acid synthesis are grouped into primary or secondary. Primary BASDs are caused by congenital deficiencies in enzymes that catalyze the chemical reactions required to synthesize the two main bile acids, cholic acid, and chenodeoxycholic acid. Secondary disorders encompass low gamma-GT familial intrahepatic cholestasis and MDR3 deficiency (known as primary familial intrahepatic cholestasis), Smith-Lemli-Opitz syndrome, which hinders the cholesterol supply in the body, and Zellweger spectrum disorders, which are categorized as peroxisomal disorders but are also involved in the synthesis of bile acid.

What Are the Signs and Symptoms?

• Cholestasis occurs in these disorders due to intrahepatic defects of the bile duct rather than bile duct defects outside the liver (extrahepatic).

• Yellow discoloration of the skin and mucous membranes, sclera of the eyes (jaundice), failure to gain weight, and growth deficiency are all symptoms of cholestasis.

• Hepatomegaly (enlargement of the liver) and splenomegaly (enlargement of the spleen) may also occur. Prolonged, severe itchiness (pruritus) is frequent in other cholestasis-causing disorders but uncommon in people with BASDs.

• Due to bile flow suppression, affected individuals may also experience diarrhea, excess fats in the stools (steatorrhea), and pale or clay-colored stools (acholic stools).

• Some of the symptoms of cholestasis are caused by an inability of the digestive system to absorb fat properly, fat-soluble vitamins, and other nutrients (malabsorption).

• Malabsorption causes vitamin deficiency, which can cause rickets, a condition characterized by softened, weakened bones (vitamin D deficiency), problems in the vision (deficiency of vitamin A), poor cooperation, and developmental delay in development (vitamin E deficiency of vitamin E), and clotting defects, resulting in easy bleeding and bruising (vitamin K deficiency).

• In some cases, if left untreated, liver abnormalities can lead to serious life-threatening risks such as fibrous scar tissue (fibrosis) formation and regeneration of the liver with scarring (cirrhosis), high blood pressure in the liver's main vein (portal hypertension), and abnormal fluid retention and swelling in the abdomen (ascites). Liver disease can eventually lead to liver failure.

What Are the Various Deficiencies?

1. 3-Beta-Hydroxy-Delta-5-C27-Steroid Oxidoreductase Deficiency - This condition is known as 3HSD deficiency or bile acid synthesis defect 1. It is thought to be the most common type of BASD. This clinical picture can vary widely. In general, affected children will develop cholestasis and malabsorption of fat-soluble vitamins (along with other abnormalities caused by vitamin deficiency) during infancy. If left untreated, the liver disease progresses.

2. Oxysterol 7-Alpha-Hydroxylase Deficiency - This condition is known as five beta-reductase deficiency or bile acid synthesis defect 2. This disorder has similar symptoms to three beta-dehydrogenase deficiencies, but it is usually more severe and, if left untreated, can quickly advance to cirrhosis and liver failure. Five beta-reductase deficiency can manifest as neonatal cholestasis or liver failure, similar to neonatal hemochromatosis.

3. Oxysterol 7-Alpha-Hydroxylase Deficiency - This condition is also known as bile acid synthesis defect 3. Affected infants have developed severe neonatal cholestasis, coagulopathy (a disease that affects the blood's ability to clot), hepatosplenomegaly (liver and spleen are enlarged), and, if untreated, cirrhosis and liver failure early in life.

4. Alpha-Methylacyl-CoA Racemase (AMACR) Deficiency - This condition is known as 2-methyl acyl-CoA racemase deficiency or bile acid synthesis defect 4. The disorder was first identified in three adults suffering from sensory-motor neuropathy, a disease caused by disease of the peripheral nerves (those located outside the central nervous system) that regulate pain, temperature, and muscle coordination. Sensory motor neuropathy can lead to abnormal sensations like numbness or pricking in the arms and legs, muscle weakness, and balance and coordination issues. Adults with this disorder may be asymptomatic till the sensory-motor neuropathy develops; they could have mild liver disease in children.

5. Sterol 27-Hydroxylase Deficiency (Cerebrotendinous Xanthomatosis) - Cerebrotendinous xanthomatosis (CTX) is extremely variable and grouped into a wide range of potential abnormalities. Initially, the disorder was thought to be a neurological disorder of abnormality in the fat storage (lipid) that was unrelated to liver disease. CTX can cause cholestatic liver disease in children, which can be severe or mild, and resolve on its own in people who may later develop other side effects of the disorder, such as neurological disease.

6. Trihydroxycholestanic Acid (THCA) Co-A Oxidase Deficiency - This disorder has been reported in several individuals. It is characterized primarily by neurological findings such as ataxia (a category of disease that affects coordination, balance, and speech), often manifested in three and a half years old. This type of BSAD has not been linked to liver disease.

7. Amidation Defects - The final step in bile acid synthesis is connecting (conjugating) two amino acids, glycine and taurine. This step is characterized by ‘defective bile acid amidation because of the failure to conjugate with glycine and taurine,’ or, more simply, amidation defects. Two disorders have been identified under this category.

• Bile Acid Co-A Ligase Deficiency - This condition is distinguished by neonatal cholestasis, malabsorption of fat and fat-soluble vitamins, and growth failure.
• Amino Acid N-Acyltransferase Deficiency - Individuals who were affected established pruritus, variable growth deficiency, and fat malabsorption of fat.

What Are the Standard Therapies?

• BASD treatment focuses on the particular symptoms that each experiences. A team of specialists may be required to work on the condition. Affected individuals and their families should need genetic counseling.

• Many affected people have responded dramatically to treatment by reintroducing one of the body's missing primary bile acids (bile acid replacement therapy).

• This therapy entails orally taking one of the two primary bile acids, cholic acid or chenodeoxycholic acid. Replacement of missing bile acids has improved or normalized liver function in people with specific BASDs.

Conclusion

Bile acid synthesis defects are a growing group of serious hepatic disorders. Clinically, these conditions represent several other underlying causes of neonatal cholestasis and chronic liver disease, and arriving at a diagnosis requires a high index of clinical suspicion. Early detection is critical because most of these abnormalities can be effectively treated with bile acid replacement therapy.