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Bile Acid Synthesis Disorders & Zellweger Spectrum Disorders

  • Bile Acid Synthesis Disorders (BASD) & Zellweger Spectrum Disorders (ZSD) are distinct sets of rare genetic disorders that can rob the body of its natural ability to make primary bile acids.
  • Bile acids help us digest by helping to absorb dietary fats, vitamins, and other nutrients and eliminate excess cholesterol, bilirubin, waste and toxins from the body.
  • Newborns are most often affected by these disorders, which put them at risk for serious liver disease or liver failure.
  • The most common sign of BASD is prolonged jaundice, or a yellowish color to the skin or white part of the eyes that lasts more than two weeks. This is primarily due to a condition known as cholestasis, which is a reduction or stoppage of bile flow.
  • ZSD has overlapping signs and symptoms affecting many parts of the body, and no one person with the disorder is identical.
  • It is important to diagnose and treat these disorders as early as possible, since starting therapy early on may lead to better outcomes.
  • To find out if a patient has a BASD or ZSD, healthcare professionals may run a variety of blood and/or urine tests that are confirmed by specialized lab testing.
  • Free genetic testing for cholestasis is available in the U.S. at no cost to patients, physicians, or insurers.

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). 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. Bile acids (and bile salts) are also produced by the liver, and are the key digestive components of bile. 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.

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. The lack of normal bile acid has a two-pronged impact:

  1. The interruption of bile flow from the liver to the small intestine, called cholestasis, presents as prolonged jaundice in 1 in 2,500 newborns; and
  2. Buildup of abnormal bile acids (toxic bile intermediaries) that can lead to liver disease.

 

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). 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.  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.

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.

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. Retrophin, a company that offers a treatment for BASD, 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 payers. The test detects an array of potential causes of cholestasis, many of which are life threatening.

Zellweger Spectrum Disorders

Zellweger Spectrum Disorders (ZSD) are genetic conditions are associated with bile acid synthesis that have overlapping signs and symptoms affecting many parts of the body, and with different degrees of severity.  Patients with ZSD have multi-organ disease and no one person with the disorder is identical. However, one commonality is that liver dysfunction is typically present among patients with severe forms of ZSD. 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.

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.

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 (a yellowish color to the skin or white part of the eyes) that lasts more than two weeks. Other signs and symptoms may include: poor growth; pale, foul-smelling stools; dark urine; enlarged liver or spleen; and liver disease.

A patient diagnosed with a ZSD may need regular testing of their liver function and monitoring. 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.

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