Zellweger Spectrum Disorders

Liver involvement in Zellweger spectrum disorders

Zellweger spectrum disorders are inherited conditions that have overlapping signs and symptoms, affect many parts of the body, and have different degrees of severity. Patients with Zellweger spectrum disorders have multiorgan disease and no one patient is exactly identical.1 Liver involvement is nearly universal in patients with Zellweger spectrum disorders. The overall incidence varies; however, in the United States, it has been estimated that 1 in 50,000 live births are diagnosed with a form of peroxisomal disorder including Zellweger spectrum disorders.2,3

In Zellweger spectrum disorders 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.1,2,4 Partial or complete loss of peroxisomes leads to a buildup of abnormal bile acids which can be toxic to the liver.1

Types of Zellweger spectrum disorders
Three different syndromes have been historically described.5

Cholestasis presents as jaundice in infants

What leads to an inability to make bile acids?

A mutation (change in DNA) in any of the genes responsible for making the enzymes necessary for normal production of bile acids leads to a buildup of abnormal bile acids,6,7 which may be toxic to the liver. If left untreated, buildup of toxic bile acids may result in progressive liver disease.6,8

Bile acids

The role of bile acids

What are bile acids and why are they important?

One of the primary functions of the liver is to produce bile and bile acids. Bile is a fluid that contains water, certain minerals, and other materials including bile salts, lipids, cholesterol, and an orange-yellow pigment (bilirubin). Bile helps with digestion and absorption of dietary fats, vitamins, and other nutrients and in the elimination of excess cholesterol, bilirubin, waste, and toxins from the body.8,9

Bile acids and bile salts are the key digestive components of bile. Cholic acid (KOE-lik AS-id) and chenodeoxycholic acid (KEE-noe-dee-OX-i-KOL-ik AS-id) are the primary bile acids produced by the liver.8 They enable the liver to work normally by8,10

  • Promoting bile flow
  • Assisting with absorption of the fats and vitamins from the food we eat
  • Eliminating cholesterol from the body

Abnormal bile flow and bile production often result in malabsorption of vital nutrients and the accumulation of toxic materials in the body.6,8

1. Wanders RJ, Ferdinandusse S. Peroxisomes, peroxisomal diseases, and the hepatotoxicity induced by peroxisomal metabolites. Curr Drug Metab. 2012;13:1401-1411.  2. Braverman NE, D’Agostino MD, Maclean GE. Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev. 2013;17:187-196.  3. Steinberg SJ, Raymond GV, Braverman NE, Moser AB. Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum. http://www.ncbi.nlm.nih.gov/books/NBK1448. Updated May 10, 2012. Accessed June 4, 2015.  4. 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.  5. 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.  6. 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.  7. Fischler B, Lamireau T. Cholestasis in the newborn and infant. Clin Res Hepatol Gastroenterol. 2014;38:263-267.  8. Heubi JE, Setchell K, Bove KE. Inborn errors of bile acid metabolism. Semin Liver Dis. 2007;27(3):282-294.  9. PubMed Health. How does the gallbladder work? http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072570/. Updated November 7, 2012. Accessed January 8, 2016.  10. CHOLBAM® (cholic acid) capsules, for oral use [prescribing information]. San Diego, CA: Retrophin, Inc.; March 2015.

Indication and Usage
CHOLBAM® is a bile acid indicated for:

  • Treatment of bile acid synthesis disorders due to single enzyme defects
  • Adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders in patients who show signs and symptoms of liver disease, steatorrhea (fatty stools), or complications from decreased fat soluble vitamins absorption (A, D, E, K)

Limitation of Use:
The safety and effectiveness of CHOLBAM® on extrahepatic manifestations of bile acid synthesis disorders due to single enzyme defects or peroxisomal disorder including Zellweger spectrum disorders have not been established.

Important Safety Information
Warnings and Precautions—Exacerbation of Liver Impairment

  • Monitor liver function and discontinue CHOLBAM® (cholic acid) in patients who develop worsening of liver function while on treatment.
  • Monitor AST, ALT, GGT, alkaline phosphatase, bilirubin, and international normalized ratio (INR) every month for the first 3 months, every 3 months for the next 9 months, every 6 months during the next 3 years and annually thereafter. Administer the lowest dose that effectively maintains liver function.
  • Discontinue CHOLBAM® if liver function does not improve within 3 months of starting treatment, if complete biliary obstruction develops, or if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis; continue to monitor liver function and consider restarting at a lower dose when parameters return to baseline.

Adverse Reactions
In the CHOLBAM® clinical trials, diarrhea was the most common adverse reaction in approximately 2% of the patient population. All other adverse reactions are less than or equal to 1% of the patient population.

Drug Interaction

  • Bile Salt Efflux Pump (BSEP) Inhibitors (eg, cyclosporine): Avoid concomitant use; if concomitant use is necessary, monitor serum transaminases and bilirubin.
  • Bile Acid Resins and Aluminum-Based Antacids: Take CHOLBAM® at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin or aluminum-based antacids.

Pregnancy
No studies in pregnant women or animal reproduction studies have been conducted with CHOLBAM®. Women who become pregnant during CHOLBAM® treatment are encouraged to call 1-844-202-6262.

Lactation
Endogenous cholic acid is present in human milk. Clinical lactation studies have not been conducted to assess the presence of CHOLBAM® in human milk, the effects of CHOLBAM® on the breastfed infant, or the effects of CHOLBAM® on milk production.

There are no animal lactation data and no data from case reports available in the published literature.

Overdosage
In the event of overdose (elevated GGT and ALT), the patient should be monitored and treated symptomatically.

Elevated serum gamma glutamyltransferase (GGT) and serum alanine aminotransferase (ALT) may indicate CHOLBAM® overdose. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline.

Please see full prescribing information for CHOLBAM® (cholic acid) 50 mg and 250 mg capsules.

To report SUSPECTED ADVERSE REACTIONS, contact Retrophin, Inc. at 1-877-659-5518 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.