In general, disorders of bile acid synthesis can be divided into primary and secondary. Primary bile acid synthesis disorders are a group of inborn errors of metabolism due to congenital defects of enzymes that catalyze the chemical reactions in the synthesis of two primary bile acids namely chenodeoxycholic acid and cholic acid. The secondaries include disorders in transport of bile acid and also includes, but it is not limited to, low gamma-GT familial intrahepatic cholestasis, Smith-Lemli-Opitz syndrome, a problem with the supply of cholesterol, and Zellweger spectrum disorders, classified as peroxisomal disorders but participating in bile acid synthesis.Â
Epidemiology
BASDs are inherited metabolic diseases that interfere with the creation of bile acids. They are a limited category of cholestatic diseases in children, which compose only 1% to 2% of all such disorders, and these disorders are associated with an autosomal recessive pattern of inheritance. BASDs are not confined to any geographical area or any ethnic group of people. There is no known predisposing factor to BASDs. They usually manifest as progressive cholestasis in infancy and typical symptoms include jaundice, failure to thrive, and hepatomegaly. The following are some congenital defects in the synthesis of bile which can result in liver diseases later on in adulthood. BASDs are served equally in males and females but the clinical spectra may fifer depending on the enzyme defect. Knowledge about BASDs epidemiology is important for early detection and effective interventions, hence promoting well-being of people with such conditions. Â
Anatomy
Pathophysiology
Defects in synthesis of bice acids contribute to 1 to 2% of the cases of cholestatic disease in children and are autosomal recessive disorders. The severity of these defects depends on the type of enzymes, the deficiency of which is the cause of the illness. These diseases primarily affect neonates as the progressive cholestasis of infancy, but they can also manifest as acute liver disease in neonates, liver disease in childhood, or neonatal hepatitis. Fundamentally, a liver disease usually develops before the enzymatic anomalies lead to the formation of the cholestatic oxo-bile acids. Inherited defects in the synthesis of bile can also bring about a number of diseases in adults.Â
Etiology
Genetic mutations in the specific genes responsible for coding certain proteins of the body that are important in performing various body functions cause bile acid synthesis disorders. This disorder may be inherited in an autosomal recessive pattern. Alleles are recessive genetic disorders in which the same abnormal gene for a particular trait is passed from each parent, carrying with it a 25% risk of having an affected child with each pregnancy. Such a child has a 25% chance of getting normal genes from both parents and, correspondingly, has normal genetic information regarding this trait.
These disorders result from the faulty synthesis of the bile acids, principally chenodeoxycholic acid and cholic acid. The acids are synthesized in the live via a complex series of chemical reactions involving at least 17 enzymatic steps. Level with each of these disorders, participating respectively, is a gene for each respective enzyme, so if one enzyme is either missing or deficient, it disrupts the production of bile, which may result in a disorder of the synthesis of bile acid.
Abnormal formation of bile acids leads to improper or impeded flow of bile, resulting in malabsorption of dietary vitamins, fats, and other nutrients in the body and failure in the removal of wastes, cholesterol, toxins and bilirubin not properly excreted. This, under normal conditions, ends in malabsorption of essential nutrients, coupled with the accumulation of toxic materials in the body.
Genetics
Prognostic Factors
BASDs are genetically inherited diseases manifesting as complex syndromes in the liver that if untreated, can be lethal.Â
Clinical History
Symptoms and signs of this condition include:Â
Liver disease due to unknown reason
Dark-coloured urineÂ
Enlarged spleen or liverÂ
Poor growthÂ
Yellowing of eyes or skin, or jaundiceÂ
Vitamin deficiencyÂ
Strong-smelling and pale stoolÂ
Physical Examination
General appearance
Failure to thrive refers to inadequate weight gain and growth in infants and children, while irritability refers to signs of discomfort or distress.
Skin manifestation
Jaundice, pallor, and xanthomas are symptoms of high bilirubin levels causing yellowing of skin and eyes, potentially indicating anemia.
Abdominal manifestations
An enlarged liver is a condition known as hepatomegaly whereas splenomegaly is the increased size of the spleen, both are signs of late liver disease and these changes can be detected by placing hands under the rib cage.
Musculoskeletal system manifestations
Vitamin D deficiency can cause bone deformities, as in the case of rickets or osteomalacia. Muscle weakness may be caused by malnutrition or deficiencies in certain vitamins.
Neurological examination
Developmental delays in children and peripheral neuropathy are symptoms of vitamin E deficiency causing tingling, numbness, or weakness in the extremities.
Lifestyle changes cannot cure BASDs. It is focused on the specific characteristics of a patient’s pathophysiological symptoms and mainly depends on a multidisciplinary approach. In 2015, CAA was approved as the first pharmacological treatment for pediatric as well as adult BASDs due to defects of single enzymes and patients with peroxisomal disorders.Cholic acid, being one of the oral bile acid therapies is used to treat BASDs replaces the primary bile acids which are lacking in the body. In some instances, other treatments may not work, hence calling for a liver transplant.Â
by Stage
by Modality
Chemotherapy
Radiation Therapy
Surgical Interventions
Hormone Therapy
Immunotherapy
Hyperthermia
Photodynamic Therapy
Stem Cell Transplant
Targeted Therapy
Palliative Care
modification-of-the-environment
Positive results from bile acid disorders can be obtained by giving the patient a supportive and safe environment. These are supplemented with special diet and nutritional supplementation to support liver function and to replace the malabsorption of fats. Furthermore, another equally relevant factor is having a strict regime in terms of medication and access to medications at any time. Moreover, a clean and hygienically maintained living space with good living conditions are very essential for the prevention of infections and reduction of stress. The customization in physical activity programs and psychosocial support can make a huge difference in the quality of life of patients with BASDs.Â
Use of bile acid replacement therapy
Cholbam: This is a bile acid indicated for treating disorders of bile acid synthesis and peroxisomal disorders.Â
Chenodeoxycholic acid: This is a primary bile acid that is synthesized in the liver and used to treat cholelithiasis. It is particularly used to treat people with deficiency of sterol 27-hydroxylased deficiency.Â
The process involves a clinical evaluation, laboratory testing, genetic testing, imaging studies, and a liver biopsy to assess symptoms, medical history, liver function, and potential enzyme defects.Â
Initial treatment and stabilizationÂ
The aspect of treating the signs includes removal of jaundice, itchy and stunted growths as well as starting oral bile acid therapy that will deal with lack of main bile acids. Moreover, one can change diet patterns and include fat-soluble vitamins in their meals.Â
Long-term managementÂ
Monitoring has to be done on a regular basis. One must adhere to medications, provide necessary dietary support and proactively manage any potential complications in order to maintain proper function of the liver, growth and development.Â
Advanced interventionsÂ
Liver transplantation may be considered in severe cases of declining liver function, while genetic counselling provides information and support for families regarding inheritance patterns and future pregnancy risks.Â
Indicated for Disorders due to Bile Acid Synthesis
10-15 mg/kg every day orally or in divided two times a day
Peroxisomal Disorder
10-15 mg/kg every day orally or in divided two times a day
Note:
For the Familial hypertriglyceridemia require a 10% enhancement in the recommended dose to account for losses because of its malabsorption; 11-17 mg/kg every day orally or in divided two times a day
Indicated for Disorders due to Bile Acid Synthesis
Age >3 weeks
10-15 mg/kg every day orally or in divided two times a day
Age <3 weeks
Safety and efficacy not established
Peroxisomal Disorder
Age >3 weeks
10-15 mg/kg every day orally or in divided two times a day
Age <3 weeks
Safety and efficacy not established
Note:
For the Familial hypertriglyceridemia require a 10% enhancement in the recommended dose to account for losses because of its malabsorption; 11-17 mg/kg every day orally or in divided two times a day
»
Home » CAD » Disorders due to Bile Acid Synthesis
Disorders due to Bile Acid Synthesis
Updated :
October 3, 2024
In general, disorders of bile acid synthesis can be divided into primary and secondary. Primary bile acid synthesis disorders are a group of inborn errors of metabolism due to congenital defects of enzymes that catalyze the chemical reactions in the synthesis of two primary bile acids namely chenodeoxycholic acid and cholic acid. The secondaries include disorders in transport of bile acid and also includes, but it is not limited to, low gamma-GT familial intrahepatic cholestasis, Smith-Lemli-Opitz syndrome, a problem with the supply of cholesterol, and Zellweger spectrum disorders, classified as peroxisomal disorders but participating in bile acid synthesis.Â
BASDs are inherited metabolic diseases that interfere with the creation of bile acids. They are a limited category of cholestatic diseases in children, which compose only 1% to 2% of all such disorders, and these disorders are associated with an autosomal recessive pattern of inheritance. BASDs are not confined to any geographical area or any ethnic group of people. There is no known predisposing factor to BASDs. They usually manifest as progressive cholestasis in infancy and typical symptoms include jaundice, failure to thrive, and hepatomegaly. The following are some congenital defects in the synthesis of bile which can result in liver diseases later on in adulthood. BASDs are served equally in males and females but the clinical spectra may fifer depending on the enzyme defect. Knowledge about BASDs epidemiology is important for early detection and effective interventions, hence promoting well-being of people with such conditions. Â
Defects in synthesis of bice acids contribute to 1 to 2% of the cases of cholestatic disease in children and are autosomal recessive disorders. The severity of these defects depends on the type of enzymes, the deficiency of which is the cause of the illness. These diseases primarily affect neonates as the progressive cholestasis of infancy, but they can also manifest as acute liver disease in neonates, liver disease in childhood, or neonatal hepatitis. Fundamentally, a liver disease usually develops before the enzymatic anomalies lead to the formation of the cholestatic oxo-bile acids. Inherited defects in the synthesis of bile can also bring about a number of diseases in adults.Â
Genetic mutations in the specific genes responsible for coding certain proteins of the body that are important in performing various body functions cause bile acid synthesis disorders. This disorder may be inherited in an autosomal recessive pattern. Alleles are recessive genetic disorders in which the same abnormal gene for a particular trait is passed from each parent, carrying with it a 25% risk of having an affected child with each pregnancy. Such a child has a 25% chance of getting normal genes from both parents and, correspondingly, has normal genetic information regarding this trait.
These disorders result from the faulty synthesis of the bile acids, principally chenodeoxycholic acid and cholic acid. The acids are synthesized in the live via a complex series of chemical reactions involving at least 17 enzymatic steps. Level with each of these disorders, participating respectively, is a gene for each respective enzyme, so if one enzyme is either missing or deficient, it disrupts the production of bile, which may result in a disorder of the synthesis of bile acid.
Abnormal formation of bile acids leads to improper or impeded flow of bile, resulting in malabsorption of dietary vitamins, fats, and other nutrients in the body and failure in the removal of wastes, cholesterol, toxins and bilirubin not properly excreted. This, under normal conditions, ends in malabsorption of essential nutrients, coupled with the accumulation of toxic materials in the body.
BASDs are genetically inherited diseases manifesting as complex syndromes in the liver that if untreated, can be lethal.Â
Symptoms and signs of this condition include:Â
Liver disease due to unknown reason
Dark-coloured urineÂ
Enlarged spleen or liverÂ
Poor growthÂ
Yellowing of eyes or skin, or jaundiceÂ
Vitamin deficiencyÂ
Strong-smelling and pale stoolÂ
General appearance
Failure to thrive refers to inadequate weight gain and growth in infants and children, while irritability refers to signs of discomfort or distress.
Skin manifestation
Jaundice, pallor, and xanthomas are symptoms of high bilirubin levels causing yellowing of skin and eyes, potentially indicating anemia.
Abdominal manifestations
An enlarged liver is a condition known as hepatomegaly whereas splenomegaly is the increased size of the spleen, both are signs of late liver disease and these changes can be detected by placing hands under the rib cage.
Musculoskeletal system manifestations
Vitamin D deficiency can cause bone deformities, as in the case of rickets or osteomalacia. Muscle weakness may be caused by malnutrition or deficiencies in certain vitamins.
Neurological examination
Developmental delays in children and peripheral neuropathy are symptoms of vitamin E deficiency causing tingling, numbness, or weakness in the extremities.
Lifestyle changes cannot cure BASDs. It is focused on the specific characteristics of a patient’s pathophysiological symptoms and mainly depends on a multidisciplinary approach. In 2015, CAA was approved as the first pharmacological treatment for pediatric as well as adult BASDs due to defects of single enzymes and patients with peroxisomal disorders.Cholic acid, being one of the oral bile acid therapies is used to treat BASDs replaces the primary bile acids which are lacking in the body. In some instances, other treatments may not work, hence calling for a liver transplant.Â
Gastroenterology
Positive results from bile acid disorders can be obtained by giving the patient a supportive and safe environment. These are supplemented with special diet and nutritional supplementation to support liver function and to replace the malabsorption of fats. Furthermore, another equally relevant factor is having a strict regime in terms of medication and access to medications at any time. Moreover, a clean and hygienically maintained living space with good living conditions are very essential for the prevention of infections and reduction of stress. The customization in physical activity programs and psychosocial support can make a huge difference in the quality of life of patients with BASDs.Â
Gastroenterology
Cholbam: This is a bile acid indicated for treating disorders of bile acid synthesis and peroxisomal disorders.Â
Chenodeoxycholic acid: This is a primary bile acid that is synthesized in the liver and used to treat cholelithiasis. It is particularly used to treat people with deficiency of sterol 27-hydroxylased deficiency.Â
Gastroenterology
Diagnosis and initial assessmentÂ
The process involves a clinical evaluation, laboratory testing, genetic testing, imaging studies, and a liver biopsy to assess symptoms, medical history, liver function, and potential enzyme defects.Â
Initial treatment and stabilizationÂ
The aspect of treating the signs includes removal of jaundice, itchy and stunted growths as well as starting oral bile acid therapy that will deal with lack of main bile acids. Moreover, one can change diet patterns and include fat-soluble vitamins in their meals.Â
Long-term managementÂ
Monitoring has to be done on a regular basis. One must adhere to medications, provide necessary dietary support and proactively manage any potential complications in order to maintain proper function of the liver, growth and development.Â
Advanced interventionsÂ
Liver transplantation may be considered in severe cases of declining liver function, while genetic counselling provides information and support for families regarding inheritance patterns and future pregnancy risks.Â
In general, disorders of bile acid synthesis can be divided into primary and secondary. Primary bile acid synthesis disorders are a group of inborn errors of metabolism due to congenital defects of enzymes that catalyze the chemical reactions in the synthesis of two primary bile acids namely chenodeoxycholic acid and cholic acid. The secondaries include disorders in transport of bile acid and also includes, but it is not limited to, low gamma-GT familial intrahepatic cholestasis, Smith-Lemli-Opitz syndrome, a problem with the supply of cholesterol, and Zellweger spectrum disorders, classified as peroxisomal disorders but participating in bile acid synthesis.Â
BASDs are inherited metabolic diseases that interfere with the creation of bile acids. They are a limited category of cholestatic diseases in children, which compose only 1% to 2% of all such disorders, and these disorders are associated with an autosomal recessive pattern of inheritance. BASDs are not confined to any geographical area or any ethnic group of people. There is no known predisposing factor to BASDs. They usually manifest as progressive cholestasis in infancy and typical symptoms include jaundice, failure to thrive, and hepatomegaly. The following are some congenital defects in the synthesis of bile which can result in liver diseases later on in adulthood. BASDs are served equally in males and females but the clinical spectra may fifer depending on the enzyme defect. Knowledge about BASDs epidemiology is important for early detection and effective interventions, hence promoting well-being of people with such conditions. Â
Defects in synthesis of bice acids contribute to 1 to 2% of the cases of cholestatic disease in children and are autosomal recessive disorders. The severity of these defects depends on the type of enzymes, the deficiency of which is the cause of the illness. These diseases primarily affect neonates as the progressive cholestasis of infancy, but they can also manifest as acute liver disease in neonates, liver disease in childhood, or neonatal hepatitis. Fundamentally, a liver disease usually develops before the enzymatic anomalies lead to the formation of the cholestatic oxo-bile acids. Inherited defects in the synthesis of bile can also bring about a number of diseases in adults.Â
Genetic mutations in the specific genes responsible for coding certain proteins of the body that are important in performing various body functions cause bile acid synthesis disorders. This disorder may be inherited in an autosomal recessive pattern. Alleles are recessive genetic disorders in which the same abnormal gene for a particular trait is passed from each parent, carrying with it a 25% risk of having an affected child with each pregnancy. Such a child has a 25% chance of getting normal genes from both parents and, correspondingly, has normal genetic information regarding this trait.
These disorders result from the faulty synthesis of the bile acids, principally chenodeoxycholic acid and cholic acid. The acids are synthesized in the live via a complex series of chemical reactions involving at least 17 enzymatic steps. Level with each of these disorders, participating respectively, is a gene for each respective enzyme, so if one enzyme is either missing or deficient, it disrupts the production of bile, which may result in a disorder of the synthesis of bile acid.
Abnormal formation of bile acids leads to improper or impeded flow of bile, resulting in malabsorption of dietary vitamins, fats, and other nutrients in the body and failure in the removal of wastes, cholesterol, toxins and bilirubin not properly excreted. This, under normal conditions, ends in malabsorption of essential nutrients, coupled with the accumulation of toxic materials in the body.
BASDs are genetically inherited diseases manifesting as complex syndromes in the liver that if untreated, can be lethal.Â
Symptoms and signs of this condition include:Â
Liver disease due to unknown reason
Dark-coloured urineÂ
Enlarged spleen or liverÂ
Poor growthÂ
Yellowing of eyes or skin, or jaundiceÂ
Vitamin deficiencyÂ
Strong-smelling and pale stoolÂ
General appearance
Failure to thrive refers to inadequate weight gain and growth in infants and children, while irritability refers to signs of discomfort or distress.
Skin manifestation
Jaundice, pallor, and xanthomas are symptoms of high bilirubin levels causing yellowing of skin and eyes, potentially indicating anemia.
Abdominal manifestations
An enlarged liver is a condition known as hepatomegaly whereas splenomegaly is the increased size of the spleen, both are signs of late liver disease and these changes can be detected by placing hands under the rib cage.
Musculoskeletal system manifestations
Vitamin D deficiency can cause bone deformities, as in the case of rickets or osteomalacia. Muscle weakness may be caused by malnutrition or deficiencies in certain vitamins.
Neurological examination
Developmental delays in children and peripheral neuropathy are symptoms of vitamin E deficiency causing tingling, numbness, or weakness in the extremities.
Lifestyle changes cannot cure BASDs. It is focused on the specific characteristics of a patient’s pathophysiological symptoms and mainly depends on a multidisciplinary approach. In 2015, CAA was approved as the first pharmacological treatment for pediatric as well as adult BASDs due to defects of single enzymes and patients with peroxisomal disorders.Cholic acid, being one of the oral bile acid therapies is used to treat BASDs replaces the primary bile acids which are lacking in the body. In some instances, other treatments may not work, hence calling for a liver transplant.Â
Gastroenterology
Positive results from bile acid disorders can be obtained by giving the patient a supportive and safe environment. These are supplemented with special diet and nutritional supplementation to support liver function and to replace the malabsorption of fats. Furthermore, another equally relevant factor is having a strict regime in terms of medication and access to medications at any time. Moreover, a clean and hygienically maintained living space with good living conditions are very essential for the prevention of infections and reduction of stress. The customization in physical activity programs and psychosocial support can make a huge difference in the quality of life of patients with BASDs.Â
Gastroenterology
Cholbam: This is a bile acid indicated for treating disorders of bile acid synthesis and peroxisomal disorders.Â
Chenodeoxycholic acid: This is a primary bile acid that is synthesized in the liver and used to treat cholelithiasis. It is particularly used to treat people with deficiency of sterol 27-hydroxylased deficiency.Â
Gastroenterology
Diagnosis and initial assessmentÂ
The process involves a clinical evaluation, laboratory testing, genetic testing, imaging studies, and a liver biopsy to assess symptoms, medical history, liver function, and potential enzyme defects.Â
Initial treatment and stabilizationÂ
The aspect of treating the signs includes removal of jaundice, itchy and stunted growths as well as starting oral bile acid therapy that will deal with lack of main bile acids. Moreover, one can change diet patterns and include fat-soluble vitamins in their meals.Â
Long-term managementÂ
Monitoring has to be done on a regular basis. One must adhere to medications, provide necessary dietary support and proactively manage any potential complications in order to maintain proper function of the liver, growth and development.Â
Advanced interventionsÂ
Liver transplantation may be considered in severe cases of declining liver function, while genetic counselling provides information and support for families regarding inheritance patterns and future pregnancy risks.Â
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