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.

Suggestive Findings

ATP8B1 deficiency should be suspected in individuals with the following clinical findings, laboratory findings, histologic findings on liver biopsy, and family history.

While mild-to-moderate and severe phenotype classifications have been proposed, ATP8B1 deficiency occurs along a continuous spectrum of severity.

Establishing the Diagnosis

The diagnosis of ATP8B1 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in ATP8B1 identified by molecular genetic testing (see Table 2). If molecular genetic testing is not available, see the histologic findings associated with ATP8B1 deficiency in Histologic Findings (pdf).

Note: Identification of biallelic ATP8B1 variants of uncertain significance (or identification of one known ATP8B1 pathogenic variant and one ATP8B1 variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.

Molecular genetic testing approaches can include gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of ATP8B1 deficiency has not been considered may be more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

ATP8B1 deficiency encompasses a phenotypic spectrum ranging from severe through moderate to mild. Severe ATP8B1 deficiency is characterized by infantile-onset cholestasis that progresses to cirrhosis, hepatic failure, and death. Mild-to-moderate ATP8B1 deficiency was initially thought to involve intermittent symptomatic cholestasis with a lack of hepatic fibrosis; however, some persons with clinically diagnosed mild disease have hepatic fibrosis on biopsy. Furthermore, in some persons with ATP8B1 deficiency the clinical findings can span the phenotypic spectrum, shifting over time from the mild end (episodic cholestasis) to the severe end of the spectrum (persistent cholestasis) [van Ooteghem et al 2002].

Family members with the same ATP8B1 pathogenic variants do not always have disease of the same clinical severity. In addition, clinical severity can change over time: mild disease diagnosed in childhood may progress in adulthood to severe disease [Morris et al 2015, Squires et al 2017].

Severe ATP8B1 deficiency. The age and onset of manifestations of severe ATP8B1 deficiency vary among affected individuals. Affected children typically present in the first year of life, often with severe pruritus and jaundice [Pawlikowska et al 2010, Morris et al 2015]. The onset of pruritus is often difficult to pinpoint because detection depends on an infant's ability to scratch in a coordinated manner; thus, in some infants irritability may be an initial manifestation of pruritus. Some individuals have been treated for long periods for chronic dermatologic conditions because of longstanding pruritus without typical findings of liver disease.

Secondary manifestations such as coagulopathy (due to vitamin K deficiency), malabsorption, and poor weight gain may present earlier than age three months.

While onset in the first year of life with progression to cirrhosis by the end of the first decade of life is typical in severe ATP8B1 deficiency, both interfamilial and intrafamilial variability have been noted among affected individuals with the same pathogenic variants [Bourke et al 1996, Bull et al 1999, Klomp et al 2004, Morris et al 2015, Squires et al 2017, van Wessel et al 2021].

Mild-to-moderate ATP8B1 deficiency is characterized by intermittent episodes of cholestasis, severe pruritus, and jaundice in the absence of extrahepatic bile duct obstruction. Episodes may last from weeks to months. Symptom-free intervals may last from months to years. Individuals may have variable or unknown triggers for some or all bouts of cholestasis.

In truly mild disease, chronic liver damage does not develop; however, in some individuals in whom ATP8B1 deficiency initially appears mild, clinical monitoring over time or detection of fibrosis on liver biopsy may indicate disease of moderate severity [van Ooteghem et al 2002, van Mil et al 2004a]. More recently, ATP8B1 pathogenic variants have been reported in some adults with cryptogenic cirrhosis, suggesting further broadening of the phenotypic spectrum of ATP8B1 deficiency to include development of liver disease beyond the first decades of life [Vitale et al 2018].

See Table 3 for an overview of the distinguishing features of the severe and mild-to-moderate phenotypes.

Cholestasis. Although children with the severe phenotype may initially experience episodes of severe cholestasis followed by disease-free intervals, cholestasis eventually becomes constant. Triggers that increase the risk of cholestasis may include intercurrent illness, drug exposure, shifts in hormonal milieu (including those resulting from ingestion of contraceptive drugs and/or pregnancy), and coexistent malignancy.

Pruritus is typically severe and persistent; jaundice is often intermittent. While pruritus is disproportionately severe for the degree of hyperbilirubinemia, it is proportional to the elevation in serum bile acids. Significant skin excoriations, caused by constant scratching, are frequent.

Nutritional deficiencies. Complications of nutritional deficiencies can result in significant morbidity and mortality in individuals with the severe phenotype. Prolonged malabsorption of fat-soluble vitamins may lead to easy bruising or bleeding (caused by vitamin K deficiency), rickets (caused by vitamin D deficiency), and neurologic abnormalities (caused by vitamin E deficiency). In contrast, vitamin A levels – when measured – are often normal or elevated; supplementation is rarely required [Morris et al 2015, Squires et al 2017].

Poor growth becomes evident in early childhood. While this may be secondary to nutritional complications of cholestasis (which typically result in weight loss out of proportion to the decreased rate of linear growth), children with severe ATP8B1 deficiency typically manifest failure to thrive and poor growth beyond that expected in persons with cholestasis alone [Pawlikowska et al 2010].

Diarrhea. The profound diarrhea that can accompany ATP8B1 deficiency may also contribute to poor growth. Mechanisms are complex and may involve both pancreatic insufficiency and the extrahepatic (dys)function of ATP8B1 in the terminal ileum. Importantly, the diarrhea may persist or even worsen following liver transplantation [Davit-Spraul et al 2010, Pawlikowska et al 2010, Verhulst et al 2010, Folvik et al 2012, Bull et al 2018, Henkel et al 2021].

Chronic liver disease including (but not limited to) those resulting from complications of portal hypertension may develop. Cirrhosis and its attendant complications, including hepatic failure and death, typically ensue in the absence of surgical intervention such as partial biliary diversion or liver transplantation (see Management).

Post-transplantation steatohepatitis may also occur, and may evolve into cirrhosis [Lykavieris et al 2003, Miyagawa-Hayashino et al 2009, Davit-Spraul et al 2010, Hori et al 2011, Henkel et al 2021].

Extrahepatic disease manifestations are attributed to the widespread tissue distribution of ATP8B1. Some individuals with ATP8B1 deficiency have:

• Sensorineural hearing loss, most pronounced at higher frequencies and often detected in late adolescence and early adulthood, which can progress with time. Hearing loss is attributed to defects in the composition of membranes of inner ear cilia [Stapelbroek et al 2009, Pawlikowska et al 2010].
• Pancreatitis or pancreatic exocrine insufficiency [Tygstrup et al 1999, Davit-Spraul et al 2010, Pawlikowska et al 2010, Folvik et al 2012, Bull et al 2018]

Rare extrahepatic findings can include the following:

• Resistance to parathyroid hormone [Nagasaka et al 2004]
• Kidney stones or acute renal failure [Tygstrup et al 1999, Folvik et al 2012]
• Delayed puberty [Bull et al 2018]
• Epistaxis in the absence of a coagulopathy or thrombocytopenia
• Nail dystrophy [Bourke et al 1996, Klomp et al 2004]

Genotype-Phenotype Correlations

Disease severity generally correlates with variant type:

• Pathogenic variants likely to severely impair ATP8B1 structure and/or function (e.g., nonsense and frameshift variants and large deletions) are more often found in individuals with severe disease.
• Missense variants, which may have a lesser effect on ATP8B1 structure/function, are found more commonly in individuals with mild disease [Klomp et al 2004]. Of note, in individuals with a severe phenotype, the number of predicted protein-truncating variants (i.e., 0, 1, or 2) does not predict survival with native (i.e., non-transplanted) liver [van Wessel et al 2021].
• The p.Gly308Val pathogenic variant (frequently associated with the Old Amish kindred in which the disease was initially described) and the p.Asp554Asn variant (seen with Greenland familial cholestasis, typically present in early childhood) are associated with disease progression often necessitating surgical intervention (see Management) [Klomp et al 2000, Morris et al 2015, Squires et al 2017].
• The p.Ile661Thr pathogenic variant, which is frequently detected in persons of European descent with mild disease, appears occasionally to be non-penetrant, but is also occasionally found in compound heterozygous form in persons with severe disease [Klomp et al 2004].

Nomenclature

In this review, the term "ATP8B1 deficiency" is used to encompass the full phenotypic spectrum ranging from severe ATP8B1 deficiency to intermediate to mild ATP8B1 deficiency.

Other terms used to refer to severe ATP8B1 deficiency

• Phenotype-based nomenclature: progressive familial intrahepatic cholestasis (PFIC)
• Phenotype and locus-based nomenclature: progressive familial intrahepatic cholestasis type 1 (PFIC1) or severe familial intrahepatic cholestasis 1 (FIC1) deficiency
• Ethnicity-based nomenclature: Byler disease (refers to severe ATP8B1 deficiency in individuals of Amish ancestry [Clayton et al 1969]) and Greenland childhood cholestasis or Greenland familial cholestasis (refers to severe ATP8B1 deficiency in individuals of Inuit ancestry [Nielsen et al 1986, Ornvold et al 1989, Eiberg & Nielsen 1993])

Other terms used to refer to mild ATP8B1 deficiency. Phenotype and locus-based nomenclature: benign recurrent intrahepatic cholestasis type 1 (BRIC1) or mild FIC1 deficiency

Prevalence

Collectively, the estimated prevalence for all progressive familial intrahepatic cholestasis (PFIC) disorders accompanied by high serum gamma-glutamyltranspeptidase (γ-GT) levels and, in individuals with biallelic ABCB4 pathogenic variants (PFIC3) is estimated at 1:50,000 to 1:100,000 births [Srivastava 2014]. The exact prevalence of ATP8B1 deficiency remains unknown. Although it has been considered rare, misdiagnosis or imprecise diagnosis may have contributed to underestimation of prevalence.

First described as Byler disease in children of Amish descent [Clayton et al 1969], it has now been reported in individuals of all races and many ethnicities. Except for certain populations (e.g., the Amish and Inuit) with increased consanguinity and founder variants (see Table 8), no other populations are known to be at a higher risk for ATP8B1 deficiency.

Carrier frequencies for ATP8B1 deficiency are unknown, except in the Greenland Inuit in whom the carrier frequency of the pathogenic variant p.Asp554Asn varies regionally. In East Greenland, the high carrier frequencies – which reach 0.16 in Ittoqqortoormiit and 0.23 in Kuummiut – warrant routine screening [Eiberg & Nielsen 1993, Eiberg et al 2004, Nielsen & Eiberg 2004, Andersen et al 2006].

Evaluations at Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ATP8B1 deficiency, all possible manifestations of this disorder (if not addressed as part of the evaluation that led to the diagnosis) should be included in the initial evaluation. See Table 5.

Treatment of Manifestations

Surveillance

Note: Monitoring for hepatobiliary malignancy has not been shown to be necessary in ATP8B1 deficiency.

Agents/Circumstances to Avoid

Susceptibility to sensorineural hearing loss in ATP8B1 deficiency may argue against use of aminoglycoside antibiotics or other potentially ototoxic agents.

Oral contraceptive therapy 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.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Cystic fibrosis transmembrane conductance regulator corrector compounds improved trafficking of mutated ATP8B1 protein in cell culture studies [van der Woerd et al 2016], providing support for the concept that these compounds may be suitable to be included in future therapeutic regimens for ATP8B1 deficiency.

Ileal bile acid transporter inhibitors have shown reduction in bile acid levels and reduced pruritus in children; various clinical trials are underway [Kamath et al 2020]. Recent FDA approval should prompt future real-world experience reports that are needed to better appreciate the true effectiveness of this therapy.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

ATP8B1 deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one ATP8B1 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an ATP8B1 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Intrahepatic cholestasis of pregnancy has been reported occasionally in mothers of individuals with ATP8B1 deficiency [Clayton et al 1969, de Pagter et al 1976, Bull et al 1998] (see Clinical Description).

Sibs of a proband

• 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.
• Although disease severity generally correlates with variant type, sibs with the same biallelic ATP8B1 pathogenic variants do not always have disease of the same clinical severity (see Clinical Description). In addition, clinical severity can change over time.
• ATP8B1 heterozygotes may be at increased risk for transient neonatal cholestasis and intrahepatic cholestasis of pregnancy (see Clinical Description, Manifesting Heterozygotes).

Offspring of a proband

• Unless the reproductive partner of an affected individual also has ATP8B1 deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ATP8B1.
• The carrier frequencies of ATP8B1 pathogenic variants are unknown; however, given that ATP8B1 deficiency is uncommon, the likelihood that an individual with ATP8B1 deficiency would have children with a carrier is low. Exceptions include populations in which a founder variant is present, such as the Amish or Greenland Inuit populations.* Offspring of an affected individual and a carrier have a 50% chance of being affected and a 50% chance of being carriers.
  * See Table 8 for information on founder variants in these populations.
• ATP8B1 heterozygotes (carriers) may be at increased risk for transient neonatal cholestasis and intrahepatic cholestasis of pregnancy (see Clinical Description, Manifesting Heterozygotes).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ATP8B1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ATP8B1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and of reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the ATP8B1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ATP8B1 encodes ATP8B1, a member of the P4 subfamily of P-type ATPases; these proteins function as phospholipid "flippases," translocating phospholipids from the outer to the inner leaflet of plasma membranes [Andersen et al 2016], helping to maintain the normal asymmetric distribution of lipids between the two membrane leaflets. Although early studies suggested that ATP8B1 translocates phosphatidylserine, more recent work suggests phosphatidylcholine is the preferred substrate of ATP8B1 [Paulusma et al 2006, Paulusma et al 2008, Takatsu et al 2014]. Lack of ATP8B1 function may result in abnormal lipid composition of the membrane bilayer, increasing membrane vulnerability to damage by canalicular bile acids, impairing function of membrane proteins (including the bile salt export pump), and potentially impairing vesicular transport and membrane trafficking [Paulusma et al 2009, Andersen et al 2016]. ATP8B1 may also play a role in FXR signaling; however, findings differ between studies. ATP8B1 may be involved in the innate immune response [van der Mark et al 2017].

ATP8B1 is widely expressed, including in the liver, small intestine, colon, pancreas, stomach, bladder, heart, lung, kidney, and gallbladder. ATP8B1 is present in the canalicular membrane of hepatocytes and in the apical membrane of cholangiocytes within the liver, as well as at the apices of enteric epithelia [Bull et al 1998, Eppens et al 2001, Ujhazy et al 2001, van Mil et al 2004b, Demeilliers et al 2006]. The broad expression pattern of ATP8B1 may explain the finding of some extrahepatic disease features in ATP8B1 deficiency.

For a broader review of this discussion, see Bull & Thompson [2018].

Mechanism of disease causation. Loss of function

Author Notes

James E Squires, MD, MS joined the faculty at the Children's Hospital of Pittsburgh in 2015, where he is an associate professor in pediatrics, director of the pediatric advanced/transplant hepatology fellowship, and associate medical director of Hepatology. Dr Squires remains active in both clinical and research pursuits. He is a co-investigator in the Children Liver Disease Research Network (ChiLDReN), an NIH-funded consortium working to improve the lives of children with rare cholestatic liver diseases. He is also a member of the Society of Pediatric LIver Transplant (SPLIT), a multifaceted organization focused on improving outcomes for children receiving liver transplantation. He is the Clinical Lead for the Starzl Network for Excellence in Liver Transplantation, a novel learning health network of leading pediatric transplant institutions committed to continuous improvement until every child can achieve a long and healthy life, and has received funding from the Patient-Centered Outcomes Research Institute (PCORI) to advance this work. Other current interests include metabolic liver disease, acute liver failure, and liver transplant. Website: www.pediatrics.pitt.edu

Author History

Laura N Bull, PhD (2001-present)
AS Knisely, MD; King's College Hospital (2001-2021)
Raffaella Morotti, MD (2021-present)
Benjamin L Shneider, MD; Children's Hospital of Pittsburgh (2006-2021)
James E Squires, MD, MS (2021-present)
Kelly A Taylor, MS, CGC; Vanderbilt University (2001-2006)

Revision History

• 9 September 2021 (bp) Comprehensive update posted live
• 20 March 2014 (me) Comprehensive update posted live
• 13 August 2008 (cd) Revision: prenatal testing available for ABCB11
• 26 May 2006 (cd) Revision: prenatal testing available for 1660G>A (D554N) mutation in ATP8B1
• 15 February 2006 (me) Comprehensive update posted live
• 15 July 2003 (me) Comprehensive update posted live
• 15 October 2001 (me) Review posted live
• 24 April 2001 (kt) Original submission

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