Overview

Bile Acid Synthesis Disorders due to single enzyme defects are a group of rare genetic disorders that affect the enzymes responsible for making normal, healthy bile acids. A mutation, or change, in one’s DNA prevents formation of normal bile acids and causes abnormal, toxic bile acids to build up. This disrupts bile production and flow from the liver to the small intestine. Individuals with BASD lack the ability to produce primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), and as a result produce abnormal bile acids which are known to be toxic for the liver. There are 2 broad classes of Bile Acid Synthesis Disorder: single enzyme defects and peroxisomal disorders. Single enzyme defects affect specific enzymes involved in the synthesis of bile acids.

Various types of BASD are responsible for 1% to 3% of neonatal cholestasis. The estimated prevalence of neonatal cholestasis is estimated at about 1 in 2500 births. These disorders have a considerably different presentation than that of most other cholestatic diseases.

Symptoms

Signs and symptoms to look for include:

  • Jaundice, or yellowing of the skin and eyes
  • Poor growth
  • Vitamin deficiencies (a lack of vitamins A, D, K, or E)
  • Enlarged liver or spleen
  • Liver disease from an unknown cause
  • Pale, strong-smelling stool
  • Dark-colored urine

The age of onset, specific symptoms, and rate of disease progression can vary greatly from one patient to another depending, in part, on the specific underlying defect. Although BASDs are usually detected in newborns or infants, milder forms of these disorders with later onset exist, including cases with onset during adulthood.

Causes

BASDs are an ultra-rare genetic disorder caused by mutations in specific genes. They are inherited autosomal recessive traits, meaning both parents are carriers of the gene defect.

Prevention

Since BASDs are caused by a genetic defect, there is no known cure. Early identification and initiation of treatment may lead to better outcomes as treatments exist for certain forms of this condition.

Diagnosis

To find out if a patient has a BASD, the doctor will probably begin by taking a medical history and doing a physical exam. In addition, he or she may do:

  • Blood and urine tests, including:
    • Direct bilirubin
    • Alanine transaminase (ALT)/aspartate transaminase (AST)
    • Gamma glutamyltransferase (GGT)
    • Primary bile acids
    • Blood and urine tests, including:
      • Direct bilirubin
      • Alanine transaminase (ALT)/aspartate transaminase (AST)
      • Gamma glutamyltransferase (GGT)
      • Primary bile acids
    • Confirmation by one of the following:
      • Mass spectrometry test of urine
      • Genetic testing using a panel of DNA that represents a diverse array of genes that may cause cholestasis.

If left untreated, BASDs can cause liver damage and eventually the liver may no longer work normally and a liver transplant may be necessary. It is important to diagnose and treat BASDs as early as possible, since untreated patients may develop serious liver disease/liver failure.

Treatment

Bile Acid Synthesis Disorders cannot be treated by lifestyle changes. The treatment of BASDs is directed toward the specific symptoms that are apparent in each individual and may require the coordinated efforts of a team of specialists. In 2015, 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. Oral bile acid therapy (e.g., cholic acid) replaces the primary bile acids that are absent in patients with BASD. Some patients who do not respond to other treatment options may ultimately require a liver transplant.

Prognosis

BASDs are rare genetic disorders that may lead to progressive liver disease and, if left untreated, premature death.