Bile Acid Synthesis Disorders

Bile Acid Synthesis Disorders (BASDs) are rare genetic conditions that affect the production of bile acids in the liver. Bile acids play a crucial role in digesting fats and absorbing essential nutrients from our food. In this article, we’ll provide a comprehensive overview of BASDs, including their types, causes, symptoms, diagnostic tests, treatments, and medications, all explained in simple and easy-to-understand language.

Bile acids are essential compounds that help our bodies digest dietary fats. They are produced in the liver and stored in the gallbladder until needed. When you eat, your gallbladder releases bile acids into your small intestine to aid in the digestion and absorption of fats and fat-soluble vitamins. However, in individuals with BASDs, there are problems with the production or processing of bile acids, which can lead to various health issues.[rx]

Bile acid synthesis disorders (BASDs) are a group of rare metabolic disorders characterized by defects in the creation (synthesis) of bile acids. Bile acids are chemical compounds found in the liver that have several roles in the body including promoting the flow and excretion of bile and assisting in the intestinal absorption of fat and fat-soluble vitamins. Bile acids are formed from cholesterol and, therefore, bile acid synthesis serves as the main pathway in breaking down and eliminating cholesterol from the body (cholesterol degradation). [rx]The failure to produce normal or functional bile acids results in the accumulation of abnormal bile acids and other substances that normally would be broken down (intermediary metabolites) within the body. The resulting accumulation of abnormal bile acids, intermediary metabolites and cholesterol in the body can damage certain organ systems. The main symptom of most (but not all) BASDs is interruption or suppression of the flow of bile from the liver (cholestasis) and fat-soluble vitamin malabsorption. [rx]Additional symptoms such as progressive neurological disease may develop in certain cases and can occur in the absence of liver disease. In many cases, symptoms or signs are present at birth or during the newborn period. If untreated, the more severe forms of these disorders can eventually progress to cause life-threatening complications such as scarring of the liver (cirrhosis) and liver failure. Many of these disorders can be successfully treated by replacing the missing bile acids (bile acid replacement therapy). BASDs are caused by mutations in specific genes; most of these mutations are inherited in an autosomal recessive pattern.[rx]

Types of Bile Acid Synthesis Disorders

There are several types of BASDs, each with its own specific genetic mutations and characteristics. Here are some of the most common types:

1. Primary Bile Acid Synthesis Disorders (PBASDs): These disorders result from genetic mutations that disrupt the primary synthesis of bile acids in the liver.
2. Secondary Bile Acid Synthesis Disorders (SBASDs): SBASDs occur when there is an issue with the conversion of primary bile acids into secondary bile acids.
3. Atypical Bile Acid Synthesis Disorders (ABASDs): These disorders are less common and involve unique genetic mutations that affect bile acid synthesis.
4. Transporter Deficiency Disorders: In some cases, the problem lies in the transport of bile acids within the body.

Causes of Bile Acid Synthesis Disorders

BASDs are primarily caused by genetic mutations that disrupt the normal process of bile acid production and metabolism. Here are 20 possible causes of these disorders:

1. Inherited Genetic Mutations: Most BASDs are inherited from one or both parents who carry specific genetic mutations related to bile acid synthesis.
2. De Novo Mutations: In some cases, BASDs can occur due to spontaneous genetic mutations not inherited from parents.
3. Enzyme Deficiencies: Genetic mutations can lead to deficiencies in enzymes required for bile acid synthesis.
4. Abnormal Transporter Proteins: Issues with transporter proteins can disrupt bile acid transport.
5. Metabolic Disorders: Some metabolic conditions may lead to secondary bile acid synthesis disorders.
6. Liver Diseases: Liver diseases like cirrhosis or hepatitis can affect bile acid production.
7. Medications: Certain medications can interfere with bile acid synthesis.
8. Premature Birth: Babies born prematurely may have underdeveloped bile acid systems.
9. Infections: Severe infections can disrupt bile acid metabolism.
10. Inflammatory Bowel Disease: Conditions like Crohn’s disease can affect bile acid absorption.
11. Cystic Fibrosis: This genetic disorder can lead to issues with bile acid processing.
12. Gallbladder Removal: Surgery to remove the gallbladder can alter bile acid release.
13. Malabsorption Disorders: Conditions that affect nutrient absorption can also impact bile acids.
14. Cholestasis: A condition where bile flow is obstructed, leading to bile acid buildup.
15. Pancreatic Disorders: Issues with the pancreas can affect fat digestion and bile acid synthesis.
16. Malnutrition: Poor nutrition can impact the body’s ability to produce bile acids.
17. Alcohol Abuse: Excessive alcohol consumption can harm the liver and bile acid production.
18. Hormonal Imbalances: Certain hormonal imbalances can affect bile acid synthesis.
19. High Cholesterol: Elevated cholesterol levels can influence bile acid metabolism.
20. Environmental Factors: Exposure to toxins or pollutants may play a role in some cases.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.[rx]

Bile acid synthesis disorders result from improper synthesis of bile acids, particularly the two primary bile acids, cholic acid and chenodeoxycholic acid. The principal bile acids are synthesized by the liver through a series of complex chemical reactions involving at least 17 enzymatic steps. These reactions mainly occur within specialized liver cells known as hepatocytes. Each “step” requires a corresponding specialized protein known as an enzyme. Each gene associated with a bile acid disorder creates (encodes) a specific enzyme. When a gene that encodes a bile acid enzyme is mutated, it leads to low levels of functional versions of the corresponding enzyme. When one enzyme in the process is absent or deficient, it leads to diminished production of bile and potentially a bile acid synthesis disorder.[rx]

One of the main functions of bile acids is to promote the flow of bile. Abnormal bile acid formation results in improper or hampered bile flow. Bile is created in the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body: it aids in digestion and absorption of dietary fats, vitamins, and other nutrients and it aids in the elimination of excess cholesterol, bilirubin, waste, and toxins from the body. Therefore, a problem with normal bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.[rx]

3-beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency is caused by mutations of the HSD3B7 gene on short arm of chromosome 16 (16p11.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.[rx]

Delta4-3-oxosteroid 5-beta-reductase deficiency is caused by mutations in the AKR1D1 gene located on the long arm of chromosome 7 (7q33).[rx]

Oxysterol 7-alpha-hydroxylase deficiency is caused by mutations in the CYP7B1 gene located on the long arm of chromosome 8 (8q12.3).

Alpha-methylacyl-CoA racemase deficiency is caused by mutations in the AMACR gene located on the short arm of chromosome 5 (5p13.2).

Sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis) is caused by mutations in the CYP27A1 gene located on the long arm of chromosome 2 (2q35).[rx]

Amino acid n-acyltransferase deficiency is caused by mutations in the BAAT gene located on the long arm of chromosome 9 (9q31.1).

Bile acid CoA ligase deficiency is caused by mutations in the SLC27A5 gene located on the long arm of chromosome 19 (19q13.43).[rx]

Symptoms of Bile Acid Synthesis Disorders

BASDs can manifest in various ways, and the symptoms may vary depending on the type and severity of the disorder. Here are 20 common symptoms:

1. Jaundice: Yellowing of the skin and eyes due to the buildup of bilirubin.
2. Itchy Skin: Pruritus, or severe itching, is a common symptom.
3. Fatigue: Individuals may feel tired and weak.
4. Poor Growth: Children with BASDs may experience stunted growth.
5. Dark Urine: Urine can appear dark due to excess bilirubin.
6. Pale Stools: Stools may be light-colored or gray.
7. Abdominal Pain: Some individuals may have abdominal discomfort.
8. Nausea and Vomiting: Digestive issues can lead to these symptoms.
9. Weight Loss: Unintentional weight loss can occur.
10. Diarrhea: Frequent loose stools may be a sign of BASDs.
11. Osteoporosis: Weak bones due to impaired fat-soluble vitamin absorption.
12. Vitamin Deficiencies: BASDs can lead to deficiencies in vitamins A, D, E, and K.
13. Gallstones: An increased risk of gallstones is associated with BASDs.
14. Joint Pain: Some individuals may experience joint discomfort.
15. Delayed Puberty: Adolescents may experience delayed onset of puberty.
16. Hepatomegaly: Enlargement of the liver can occur.
17. Splenomegaly: Enlargement of the spleen may also be present.
18. Fatty Liver: Accumulation of fat in the liver can lead to non-alcoholic fatty liver disease (NAFLD).
19. Hepatic Fibrosis: Scarring of the liver tissue can develop.
20. Neurological Symptoms: In severe cases, neurological problems can arise.

Diagnostic Tests for Bile Acid Synthesis Disorders

Diagnosing BASDs involves a series of tests to assess liver function, bile acid levels, and genetic mutations. Here are 20 common diagnostic tests:

1. Liver Function Tests: Blood tests to evaluate liver enzymes and function.
2. Bile Acid Quantification: Measuring the levels of bile acids in blood and urine.
3. Genetic Testing: Identifying specific genetic mutations related to BASDs.
4. Ultrasound: Imaging to visualize the liver, gallbladder, and bile ducts.
5. Liver Biopsy: A small tissue sample is taken from the liver for examination.
6. MRCP (Magnetic Resonance Cholangiopancreatography): An MRI of the bile ducts.
7. ERCP (Endoscopic Retrograde Cholangiopancreatography): A procedure to examine the bile ducts.
8. CT Scan: Imaging to assess the liver and surrounding structures.
9. FibroScan: Measures liver stiffness to assess fibrosis.
10. Esophagogastroduodenoscopy (EGD): Examines the upper gastrointestinal tract.
11. Small Bowel Biopsy: A sample of the small intestine may be taken.
12. Stool Fat Test: Detects fat malabsorption in stools.
13. Vitamin Levels: Blood tests to check for deficiencies in fat-soluble vitamins.
14. Fasting Serum Bile Acids: Measures bile acid levels after fasting.
15. Gastrointestinal Transit Studies: Evaluates the movement of food through the digestive tract.
16. X-ray: May be used to assess the gallbladder.
17. Cholescintigraphy: Imaging to check gallbladder function.
18. Liver Function Panel: Blood tests for liver enzymes and bilirubin.
19. Gallbladder Ultrasound: Focuses on gallbladder health.
20. MRI Liver Elastography: Measures liver stiffness as a sign of fibrosis.

Treatments for Bile Acid Synthesis Disorders

Managing BASDs typically involves dietary changes, medications, and, in severe cases, liver transplant. Here are 30 treatments and interventions:

1. Bile Acid Replacement Therapy: Supplements with synthetic bile acids to aid digestion.
2. Fat-Soluble Vitamin Supplements: Vitamin A, D, E, and K supplements as needed.
3. High-Fat Diet: Some individuals may require a higher fat intake to aid absorption.
4. Ursodeoxycholic Acid (UDCA): Medication to reduce bile acid buildup.
5. Cholestyramine: A resin that binds to bile acids, reducing their absorption.
6. Fibrates: Medications that can help with fat metabolism.
7. Antibiotics: May be prescribed to treat bacterial overgrowth in the small intestine.
8. Dietary Modifications: Adjusting the diet to minimize symptoms.
9. Low Cholesterol Diet: Reducing dietary cholesterol intake.
10. Low-FODMAP Diet: May help manage gastrointestinal symptoms.
11. Avoiding Alcohol: Eliminating or limiting alcohol consumption.
12. Liver Transplant: In severe cases, a liver transplant may be necessary.
13. Pain Medication: Managing abdominal pain as needed.
14. Anti-Itch Medication: Medications to relieve itching.
15. Nutritional Support: Ensuring proper nutrition through dietary guidance.
16. Lifestyle Changes: Promoting a healthy lifestyle to manage symptoms.
17. Monitoring Growth: Tracking growth in children with BASDs.
18. Regular Check-ups: Frequent medical follow-ups for ongoing care.
19. Physical Therapy: Supportive therapy for joint pain or mobility issues.
20. Counseling: Emotional support for coping with chronic illness.

Medications for Bile Acid Synthesis Disorders

Various medications may be prescribed to manage the symptoms and complications of BASDs. Here are 20 common drugs used in treatment:

1. Ursodiol (Actigall): A bile acid supplement to aid digestion.
2. Cholestyramine (Questran): Binds to bile acids to reduce absorption.
3. Rifaximin (Xifaxan): Antibiotic used to treat bacterial overgrowth.
4. Vitamin A Supplements: To address vitamin A deficiency.
5. Vitamin D Supplements: For individuals with vitamin D deficiency.
6. Vitamin E Supplements: To manage vitamin E deficiency.
7. Vitamin K Supplements: To address vitamin K deficiency.
8. Fibrates (Gemfibrozil, Fenofibrate): Medications to help with fat metabolism.
9. Loperamide (Imodium): Used to control diarrhea.
10. Analgesics (Pain Relievers): For managing abdominal pain.
11. Antihistamines: To relieve itching.
12. Proton Pump Inhibitors (PPIs): Reduces stomach acid production.
13. Pancreatic Enzyme Replacement: Helps digest fats.
14. Metronidazole (Flagyl): Antibiotic for managing bacterial overgrowth.
15. Dexamethasone: May be used to reduce inflammation.
16. Allopurinol: Used in some cases to manage uric acid levels.
17. Bile Acid Sequestrants: Medications that bind to bile acids.
18. Acetaminophen (Tylenol): For pain relief when needed.
19. Anti-Inflammatory Drugs: To manage inflammation in some cases.
20. Immunosuppressants: May be prescribed for severe cases.

In 2015, Cholbam (cholic acid) was approved as the first treatment for pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects, and for patients with peroxisomal disorders (including Zellweger spectrum disorders). Cholbam is marketed by Retophin Pharmaceuticals.[rx]

Cholic acid replacement therapy has proven beneficial in treating individuals with 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency; delta4-3-oxosteroid 5-beta-reductase deficiency; and alpha-methylacyl-CoA racemase deficiency. Most affected individuals experience a correction of all liver functions over a period of several weeks or months.[rx]

Cholic acid replacement therapy is not used for amidation defects because these individuals do not lack cholic acid. These two disorders can be treated with commercially available bile acids from health food stores under the name of Ox Bile available in 125 and 500 mg capsules through health food stores or through internet sources. This preparation is approximately 75% glycocholic acid. Glycocholic acid has proven effective in treating individuals with amino acid n-acyltransferase deficiency.[rx]

Cholic acid replacement therapy is not effective for the treatment of oxysterol 7-alpha-hydroxylase deficiency. Ursodeoxycholic acid worsened the condition. Two infants reported in the medical literature were successfully treated by a liver transplant and one with chenodeoxycholic acid.[rx]

Chenodeoxycholic and cholic acid have been used to treat individuals with sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis). This therapy has led to significant improvement in affected individuals. It tends to be most effective when given in conjunction with a drug that inhibits HMG-CoA reductase, an enzyme that plays a role the creation (biosynthesis) of cholesterol in the liver. There are concerns that treatment with an HMG-CoA reductase inhibitor could boost the activity of receptors for low-density lipoprotein (LDL) cholesterol, thereby increasing cholesterol uptake and potentially worsening CTX.[rx]

Ursodeoxycholic acid has provided short-term benefit to some individuals with BSADs. However, its long-term benefit is limited because it cannot compensate for the basic underlying defects and ultimately affected individuals experience continued formation of abnormal bile acids and toxic metabolites.

Treatment of BASDs is also symptomatic and supportive. For example, supplemental treatment with vitamins and nutrients is essential for individuals with malabsorption. Such treatment may include restoring vitamins A, D, E, and K.[rx]

Conclusion

Bile Acid Synthesis Disorders are complex conditions that can have a significant impact on a person’s health. Understanding the types, causes, symptoms, diagnostic tests, treatments, and medications associated with BASDs is crucial for both patients and healthcare providers. While these disorders can be challenging to manage, advancements in medical science offer hope for improved diagnosis and treatment options in the future. If you or a loved one suspect you may have a BASD, it’s essential to seek medical evaluation and ongoing care to optimize your health and well-being.

 

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. Thank you for giving your valuable time to read the article.

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