ATP8B1 Deficiency

In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
[updated ].


Clinical characteristics: The phenotypic spectrum of ATP8B1 deficiency ranges from severe through moderate to mild. Severe ATP8B1 deficiency is characterized by infantile-onset cholestasis that progresses to cirrhosis, hepatic failure, and early death. Although mild-to-moderate ATP8B1 deficiency initially was thought to involve intermittent symptomatic cholestasis with a lack of hepatic fibrosis, it is now known that hepatic fibrosis may be present early in the disease course. Furthermore, in some persons with ATP8B1 deficiency the clinical findings can span the phenotypic spectrum, shifting over time from the mild end of the spectrum (episodic cholestasis) to the severe end of the spectrum (persistent cholestasis). Sensorineural hearing loss (SNHL) is common across the phenotypic spectrum.

Diagnosis/testing: The diagnosis of ATP8B1 deficiency is established in a proband with suggestive clinical and laboratory findings and biallelic pathogenic variants in ATP8B1 identified by molecular genetic testing.

Management: Treatment of manifestations: Cholestasis: pharmacotherapy is ineffective regardless of disease severity. In severe disease: the primary surgical therapy is interruption of the enterohepatic circulation which can reduce pruritus and slow or reverse the progression to hepatic fibrosis; when cirrhosis is present, liver transplantation may be the definitive therapy. Notably for some, secretory diarrhea can continue or worsen following liver transplantation. In mild-to-moderate disease, nasobiliary drainage and extracorporeal liver support may hasten the end of an episode of cholestasis. Pruritus: in severe disease pharmacotherapy has historically been ineffective; however, recent US Food and Drug Administration approval of ileal bile acid transporter inhibitors to treat pruritus introduces a novel therapeutic approach that holds great promise. Other options include UVB light therapy and plasmapheresis. In mild-to-moderate disease, pharmacotherapy may be efficacious. Secretory diarrhea can require IV fluids or more palliative interventions. Poor growth may require medium-chain triglyceride-based formulas; fat-soluble vitamin deficiencies are treated symptomatically. SNHL is managed per standard protocols.

Surveillance: Routine monitoring of cholestasis, liver disease, pruritus, growth, and nutrition per treating hepatologist; routine audiograms for all individuals with ATP8B1 deficiency whether known to be symptomatic or not.

Agents/circumstances to avoid: Potentially ototoxic agents; oral contraceptive agent therapies can induce and/or exacerbate episodes of cholestasis.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment, surveillance, and awareness of agents and circumstances to avoid.

Genetic counseling: ATP8B1 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ATP8B1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a heterozygote (carrier), and a 25% chance of inheriting both normal alleles. Once the ATP8B1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Publication types

  • Review