Bile Acid Synthesis Disorders &
Zellweger Spectrum Disorders
One of the primary functions of the liver is to produce bile, a fluid that contains water, certain minerals, and other materials including bile salts, lipids, cholesterol, and an orange-yellow pigment (bilirubin).1 Bile aids in digestion and absorption of dietary fats, vitamins, and other nutrients and in the elimination of excess cholesterol, bilirubin, waste and toxins from the body.2
Bile acids (and bile salts) are also produced by the liver, and are the key digestive components of bile.2 Cholic acid and chenodeoxycholic acid are the primary bile acids that enable the liver to work normally by promoting bile flow, as well as assisting with absorption of the fats and vitamins from the food we eat, and eliminating cholesterol from the body.2,3,4
Defects in bile acid synthesis are caused by inherited disorders affecting the enzymes that make bile acids. A mutation (change in DNA) in any of the genes responsible for making these enzymes could lead to abnormal bile flow and bile production, often resulting in malabsorption of vital nutrients and the buildup of toxic materials in the body.2,3
The lack of normal bile acid has a two-pronged impact:
- The interruption of bile flow from the liver to the small intestine, called cholestasis, presents as prolonged jaundice in 1 in 2,500 newborns;5 and
- Buildup of abnormal bile acids (toxic bile intermediaries) that can lead to liver disease.3
Bile Acid Synthesis Disorders Due to Single Enzyme Defects
There are two distinct sets of genetic disorders associated with defects in bile acid synthesis: Bile Acid Synthesis Disorders (BASD) that are due to single enzyme defects and Zellweger Spectrum Disorders (ZSD).2
The most common sign of BASD is prolonged jaundice (a yellowish color to the skin or white part of the eyes) that lasts more than two weeks.6,7 Other signs and symptoms may include: poor growth; deficiencies of vitamins A, D, K, or E; pale, foul-smelling stools; dark urine; enlarged liver or spleen; and liver disease from an unknown cause.2,7,8,9
It is important to diagnose and treat BASD as early as possible, since untreated patients may develop serious liver disease or liver failure. Early identification and initiation of therapy may also lead to better outcomes.2,10
To find out if a patient has a BASD, healthcare professionals may run a variety of blood and/or urine tests that are confirmed by specialized lab testing.2,7,11,12,13 Retrophin is invested in the well-being of patients with rare liver diseases and has partnered with Emory Genetics Laboratory to offer the most comprehensive genetic test for cholestasis in the U.S. at no cost to patients, physicians, or insurance companies. The test is easy to use and detects an array of potential causes of cholestasis, many of which are life threatening. Learn more about this cholestatic genetic test offered to qualified patients at no charge.
One of the primary bile acids normally produced in the liver is called cholic acid.1 Since patients with these disorders do not properly produce this substance, they may be treated with a replacement therapy, which can help restore normal liver function.10 Learn more about an FDA-approved bile acid replacement therapy for BASD due to single enzyme defects.
Zellweger Spectrum Disorders
Zellweger Spectrum Disorders (ZSD) are genetic conditions associated with bile acid synthesis that have overlapping signs and symptoms affecting many parts of the body, and with different degrees of severity.14 Patients with ZSD have multi-organ disease and no one person with the disorder is identical.14 However, one commonality is that liver dysfunction is typically present among patients with severe forms of ZSD.15
The overall incidence of ZSD varies; however, in the U.S., it has been estimated that one in 50,000 live births are diagnosed with one such ZSD, known as Peroxisomal Biogenesis Disorder.16,17
With ZSD there is a problem with specialized compartments of cells, called peroxisomes, which are especially important during the final steps of bile acid production in the liver. Partial or complete loss of peroxisomes leads to a buildup of abnormal bile acids, which can be toxic to the liver.14
In addition to the neurologic abnormalities often associated with these conditions, a notable sign of ZSD, as it relates to the liver, is prolonged jaundice that lasts more than two weeks.6,7 Other signs and symptoms may include: poor growth; pale, foul-smelling stools; dark urine; enlarged liver or spleen; and liver disease.5,16,17,18
A patient diagnosed with ZSD may need regular testing of their liver function and monitoring.4,14,17 A patient with no signs of liver involvement should be monitored regularly for any changes.
Patients with liver involvement may have one or more of the following: elevated liver function tests; pale, foul-smelling stools; or poor growth, or failure to thrive, caused by an inability to absorb fat soluble vitamins like vitamins A, D, E, and K. Learn more about an FDA-approved adjunctive therapy for ZSD patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption.
The following organizations may be a resource for information and support for people with Bile Acid Synthesis Disorders and Zellweger Spectrum Disorders, as well as those around them:
The mission of the Global Foundation for Peroxisomal Disorders is to fund and promote Peroxisomal Disorder research and to assist families and professionals through educational programs and support services related to Zellweger Spectrum Disorders.
Global Genes is a non-profit patient advocacy organization working to eliminate the challenges of rare disease by building awareness, educating the global community, and providing critical connections and resources that equip advocates to become activists for their disease. Global Genes promotes the needs of the rare disease community under a unifying symbol of hope – the Blue Denim Genes Ribbon™. Numerous tools, resources and educational events can be found on the Global Genes website www.globalgenes.org.
The National Organization for Rare Disorders (NORD) is a unique federation of voluntary health organizations dedicated to helping people with rare "orphan" diseases and assisting the organizations that serve them. NORD is committed to the identification, treatment and cure of rare disorders through programs of education, advocacy, research and service. In the US, NORD is also the official sponsor of Rare Disease Day, an annual global observance that raises awareness of rare diseases and elevates them into the public consciousness as an important health issue that cannot be ignored.
EURORDIS is a non-governmental patient-driven alliance of more than 700 rare disease patient organisations in more than 60 countries. EURORDIS strives to build a strong pan-European community of patient organisations and people living with a rare disease, to be their voice at the European level, and - directly or indirectly - to fight against the impact of rare diseases on their lives. EURORDIS leads global efforts for Rare Disease Day and the online social platform for people living with or affected by a rare diseases RareConnect. EURORDIS represents the voice of an estimated 30 million people living with a rare disease in Europe. Follow @eurordis or see the EURORDIS Facebook page. For more information visit: www.eurordis.org.
- PubMed Health. How Does the Gallballder Work? Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072570/. Last accessed: July 28, 2016.
- Heubi JE, Setchell K, Bove KE. Inborn errors of bile acid metabolism. Semin Liver Dis. 2007;27(3):282-294.
- Setchell KDR. Adolf Windaus Prize Lecture 2004. Defects in bile acid synthesis—specific and treatable causes of metabolic liver disease. In: Paumgartner G et al, eds. Bile Acid Biology and Its Therapeutic Implications. Proceedings of the Falk Symposium 141 (XVIII Internationale Bile Acid Meeting) held in Stockholm, Sweden, June 18-19, 2004. Netherlands: Springer; 2005:1-15.
- CHOLBAM® (cholic acid) capsules, for oral use [prescribing information]. San Diego, CA: Retrophin, Inc.; March 2015.
- Fischler B, Lamireau T. Cholestasis in the newborn and infant. Clin Res Hepatol Gastroenterol. 2014;38:263-267.
- Bove KE, Heubi JE, Balistreri WF, Setchell KD. Bile acid synthetic defects and liver disease: a comprehensive review. Pediatr Dev Pathol. 2004;7:315-334.
- McKiernan PJ. Neonatal cholestasis. Semin Neonatol. 2002;7:153-165.
- Haas D World J Gastroenterol 2012.
- Clayton PT J Inherit Metab Dis 2011.
- Setchell KD, Heubi JE. Defects in bile acid biosynthesis—diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2006;43:S17-S22.
- Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2004;39:115-128.
- Gonzales E, Gerhardt MF, Fabre M, et al. Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy. Gastroenterology. 2009;137(4):1310-1320.
- Mignarri A, et al. J Inherit Metab Dis. 2014;37:421-429.
- Wanders RJ, Ferdinandusse S. Peroxisomes, peroxisomal diseases, and the hepatotoxicity induced by peroxisomal metabolites. Curr Drug Metab. 2012;13:1401-1411.
- Braverman NE, Raymond GV, Rizzo WB, et al. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117(3):313-321.
- Braverman NE, D’Agostino MD, Maclean GE. Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev. 2013;17:187-196.
- Steinberg SJ, Raymond GV, Braverman NE, Moser AB. Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum.
- Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of Disease: inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008;5(8):456-468.