Frequently Asked Questions
Q: What are Bile Acid Synthesis Deficiency Diseases and how are they related?
A: Bile Acid Deficiency Diseases are characterized by progressive liver failure caused by the inability to produce normal bile acids essential for the elimination of toxic byproducts of metabolism from the body, as well as food breakdown into essential nutrients. Bile acids are chemicals produced in the liver that flow into the intestines to solubilize fat to allow its absorption through the intestines.
Bile acids are made from cholesterol acted upon by proteins called enzymes, which are coded in a person's DNA molecules, to produce the final product needed for normal bile flow and digestion. If there are genetic defects or mutations in the DNA that are translated into defective enzymatic proteins, then the defective enzymes may make abnormal bile acid molecules, which cannot facilitate absorption of fats and vitamins. Researchers have identified 17 different enzymes necessary for the bile acid synthetic pathway. A defective enzyme at any one of these 17 steps can result in the synthesis of abnormal (non-functional) enzymes, consequently making abnormal bile acid molecules and/or inhibiting synthesis of bile acids.
Mutations in the genes responsible for the enzymes that make bile acid molecules usually are found in the genes inherited from the patient's parents.
Q: What causes Bile Acid Synthesis Deficiency Diseases?
A: Children with inborn genetic errors in any one of the 17 multiple enzymes responsible for production of bile acids can suffer what is referred to collectively as Bile Acid Deficiency Diseases. The characteristic clinical symptoms of inborn genetic errors include poor growth, yellow jaundice in the skin and eyes, enlarged spleen and/or liver, spontaneous bleeding, vitamin deficiencies, and poor liver function.
Most of the patients with inborn genetic errors have cholestasis, where the flow of bile from the liver is blocked. The symptoms associated with cholestasis include clay or white colored stools, dark urine, nausea, an inability to digest certain foods, and other symptoms.
Depending on the nature of the inborn genetic error in the enzymes, in the bile acid production pathway, patients may survive for a limited time. Untreated patients may die early in infancy, early childhood, or adulthood from progressive liver failure caused by the accumulation of toxic abnormal bile acids. Characteristically, untreated patients suffer severe liver scarring -- clinically termed "cirrhosis."
Since many, if not all, of the above described clinical symptoms are also associated with other types of liver diseases, diagnosis of whether an infant or child has a Bile Acid Deficiency Disease must be done by specialized diagnostic laboratories. Specific diagnosis of Bile Acid Deficiency Disease in a patient is made by the laboratory analysis of body fluids (bile, blood, and urine) using fast atom bombardment-mass spectroscopy (FAB-MS) and gas chromatography mass spectroscopy (GC-MS). The Council can provide information as to where these diagnostic methods are available and how to contact these laboratories and see if your patient's sample may be sent.
Q: How frequently do Bile Acid Synthesis Deficiency Diseases occur?
A: Bile acid synthetic defects are uncommon genetic disorders that have been classified as a rare orphan diseases. There are 9 inborn genetic errors that researchers have described, 7 of which lead to liver cholestasis. The overall number of infants and children suffering from bile acid deficiencies is unknown, but is estimated by medical experts to be one per 80,000 new births. It is estimated that bile acid enzyme pathway defects are responsible for 1-2% of cases of unexplained liver disease in infants, children, and adolescents.
The age at diagnosis is variable. Most Bile Acid Deficiency Diseases are diagnosed in infancy with liver cholestasis, while some are diagnosed later in childhood with unexplained liver disease or in adulthood with neurological disease. Infants and children may suffer from complications secondary to fat malabsorption and fat-soluble vitamin deficiencies, including rickets, bleeding, neurologic deficits and other consequences of vitamin A or E deficiency disorders.
Unless diagnosed and treated appropriately, the associated liver diseases may be life threatening. Bile Acid Deficiency Diseases are treatable in the early disease stages by replacement of deficient primary bile acids with an investigational oral drug composed of bile acid salts; however, in patients with severe liver cirrhosis caused by bile acid deficiency diseases they may require liver transplantation. Information on various investigational new drug treatments under clinical study are also available on the National Institutes of Health (NIH) website at clinicaltrials.gov.
Q: How are inborn genetic errors of Bile Acid Synthesis Deficiency Diseases treated?
A: There is no US Food and Drug Administration (FDA) approved treatment for any of the inborn genetic errors of bile acid deficiency diseases. In 1994, FDA authorized Dr. James Heubi and Dr. Kenneth D.R. Setchell to initiate an open label clinical trial in 1994 under an Investigational New Drug application to treat identified patients with Bile Acid Deficiency Diseases with an experimental oral formulation of bile acid salts; this program is still active. Other clinical studies that patients can enter are also listed on the NIH website, clinicaltrials.gov.