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ATP8B1 Deficiency: Understanding PFIC1, BRIC1 and the Role of Genetic Testing

Medically reviewed by Brandon Colby, MD, last reviewed

ATP8B1 deficiency

ATP8B1 deficiency is an inherited liver condition in which bile does not flow normally out of the liver (cholestasis). It ranges from a severe form that starts in infancy, called progressive familial intrahepatic cholestasis type 1 (PFIC1), to a milder form with episodes of itching and jaundice, called benign recurrent intrahepatic cholestasis type 1 (BRIC1). ATP8B1 deficiency is inherited in an autosomal recessive pattern, and the diagnosis is confirmed when genetic testing finds disease-causing variants in both copies of the ATP8B1 gene.

Understanding ATP8B1 Deficiency

ATP8B1 deficiency is a genetic condition that affects how bile moves out of the liver. Bile helps the body digest fats and absorb fat-soluble vitamins. When bile builds up in the liver instead (cholestasis), it can cause intense itching, yellowing of the skin and eyes (jaundice) and, over time, liver damage. The condition occurs along a spectrum. The severe form, PFIC1, usually begins in the first months of life and can progress to cirrhosis and liver failure without treatment. The mild-to-moderate form, BRIC1, causes episodes of itching and jaundice that can last weeks to months, separated by symptom-free periods that can last months to years. Some people move along the spectrum over time, and a form that starts out episodic can become persistent.

The ATP8B1 gene provides instructions for making a protein that moves certain fats (phospholipids) from one side of a cell membrane to the other. This helps keep liver cell membranes stable and protects them from damage by bile acids. Because the protein is found in many tissues, the condition can affect other parts of the body too. Hearing loss is common across the spectrum, and some people have chronic diarrhea, poor growth, low levels of vitamins A, D, E and K, or pancreatitis. Researchers first linked the ATP8B1 gene to both PFIC1 and BRIC1 in a 1998 study.

Diagnosing ATP8B1 Deficiency

A liver specialist may suspect the condition when blood tests show cholestasis with high bile acid levels but a normal or low level of the liver enzyme gamma-glutamyltransferase (GGT), which is unusual for most causes of cholestasis. Imaging, and sometimes a liver biopsy, helps rule out other causes such as a blockage of the bile ducts. According to GeneReviews, the diagnosis is established when genetic testing finds disease-causing variants in both copies of ATP8B1 in a person with these findings. Testing may use a multigene panel for cholestatic liver disease or broader exome or genome sequencing. Finding variants of uncertain significance does not confirm or rule out the diagnosis, so results should be interpreted by a specialist or genetic counselor.

Uses of Genetic Testing for ATP8B1 Deficiency

Genetic testing for ATP8B1 deficiency can be helpful in several ways:

  1. Confirming the Diagnosis: Finding disease-causing variants in both copies of ATP8B1 confirms the condition and helps distinguish it from other inherited forms of cholestasis that can look similar, such as those linked to the ABCB11 or TJP2 genes.
  2. Guiding Care: A confirmed diagnosis helps the care team plan monitoring, including regular hearing tests for everyone with the condition, nutrition and growth checks, and awareness of medicines and situations that can trigger cholestasis or affect hearing.
  3. Testing Family Members: When both parents are carriers, each brother or sister of an affected child has a 25% chance of also being affected. Once the family's variants are known, testing relatives can help identify those who would benefit from early monitoring.
  4. Family Planning: Carriers usually do not have the condition themselves, so many families learn they are carriers only after a child is diagnosed. Genetic counseling can help families understand their chances of having an affected child and the reproductive options available, including prenatal and preimplantation genetic testing.
  5. Research: Genetic information helps researchers understand how different ATP8B1 variants affect disease severity and supports the development of new treatments.

Get Tested With Whole Genome Sequencing

Whole genome sequencing reads nearly all of your DNA, including the ATP8B1 gene and other genes linked to inherited liver conditions. Sequencing's Kit Bundles include a Whole Genome Sequencing kit and Next Gen Disease Screening, which screens your DNA for genetic variants linked to more than 15,000 conditions. You can download your results and share them with your doctor or a genetic counselor.

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Frequently Asked Questions About ATP8B1 Deficiency

What is ATP8B1 deficiency?

ATP8B1 deficiency is an inherited liver condition that causes bile to build up in the liver (cholestasis). It ranges from a severe form that starts in infancy, called PFIC1, to a milder episodic form, called BRIC1. Hearing loss is common across the spectrum.

Are PFIC1, BRIC1 and Byler disease the same condition?

These names describe different presentations of the same condition, called ATP8B1 deficiency. PFIC1 refers to the more severe form, with persistent cholestasis and progressive liver disease, while BRIC1 refers to the generally milder form, with recurring episodes of cholestasis. Byler disease is an older name for PFIC1, which was first described in an Amish extended family. These conditions are caused by disease-causing variants in the ATP8B1 gene.

How is ATP8B1 deficiency inherited?

It is inherited in an autosomal recessive pattern, which means a person has the condition when both copies of the ATP8B1 gene carry a disease-causing variant. Parents of an affected child are usually carriers. When both parents are carriers, each child has a 25% chance of being affected, a 50% chance of being a carrier and a 25% chance of inheriting neither variant.

What are the symptoms?

Common symptoms include intense itching, jaundice and pale stools. The severe form can also cause diarrhea, poor growth, easy bleeding or bruising from low vitamin K, and liver scarring. In the milder form, symptoms come in episodes that may be triggered by illness, certain medicines or hormonal changes. Talk to your doctor if you or your child has ongoing itching or jaundice.

How is ATP8B1 deficiency diagnosed?

A liver specialist may suspect ATP8B1 deficiency when blood tests show cholestasis with high bile acid levels and a normal or low GGT level. The diagnosis is confirmed when genetic testing finds disease-causing variants in both copies of the ATP8B1 gene. A genetic counselor can help interpret the results.

How is ATP8B1 deficiency treated?

Treatment depends on severity and is guided by a liver specialist. It can include medicines to relieve itching, including IBAT inhibitors approved for PFIC, nutrition support and vitamin supplements, surgery to divert bile flow, and in some cases liver transplantation. Regular hearing tests are recommended for everyone with the condition. In some people, diarrhea can continue or worsen after a liver transplant, so families should discuss this with their care team.

Can carriers of one ATP8B1 variant have symptoms?

Carriers usually do not have ATP8B1 deficiency. However, research suggests carriers may have a higher chance of developing cholestasis during pregnancy (intrahepatic cholestasis of pregnancy), and a case report suggests newborn carriers may be more likely to have temporary cholestasis. Let your doctor or obstetrician know if ATP8B1 deficiency runs in your family.

Does Sequencing test for this condition?

Whole genome sequencing reads nearly all of your DNA, including the ATP8B1 gene discussed in this article. Sequencing's Kit Bundles include Next Gen Disease Screening, which screens your DNA for genetic variants linked to more than 15,000 conditions. Results describe variants, not a diagnosis, so share them with your doctor or a genetic counselor.

Where can I find support or a specialist?

The PFIC Advocacy and Resource Network (PFIC Network) supports people and families affected by PFIC, including ATP8B1 deficiency, and keeps a directory of hospitals familiar with treating PFIC. GeneReviews also has an expert written overview of ATP8B1 deficiency. All are listed in the resources below.

Resources

These organizations and resources are provided for education and support. They are not endorsements or medical advice.

References

  1. Bull LN, Morotti R, Squires JE. ATP8B1 deficiency. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 2001 [updated 2021 Sep 9]. NCBI Bookshelf: NBK1297
  2. Bull LN, van Eijk MJ, Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet. 1998;18(3):219-224. PMID: 9500542
  3. Klomp LW, Vargas JC, van Mil SW, et al. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology. 2004;40(1):27-38. PMID: 15239083
  4. van Wessel DBE, Thompson RJ, Gonzales E, et al. Impact of genotype, serum bile acids, and surgical biliary diversion on native liver survival in FIC1 deficiency. Hepatology. 2021;74(2):892-906. doi:10.1002/hep.31787
  5. Deeks ED. Odevixibat: first approval. Drugs. 2021;81:1781-1786. PMID: 34499340
  6. Dixon PH, Sambrotta M, Chambers J, et al. An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy. Sci Rep. 2017;7:11823. PMID: 28924228

This article is for education and is not a substitute for professional medical advice, diagnosis, or treatment. Talk to a qualified healthcare provider or genetic counselor about your own health.