• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

ATP8B1 Deficiency

Synonym: FIC1 Deficiency

, MD, , PhD, and , MD.

Author Information
, MD
Institute of Liver Studies
King's College Hospital
London, United Kingdom
, PhD
Liver Center Laboratory and Institute for Human Genetics
Department of Medicine
University of California, San Francisco
San Francisco, California
, MD
Division of Pediatric Gastroenterology, Hepatology, and Nutrition
Children’s Hospital of Pittsburgh
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania

Initial Posting: ; Last Update: March 20, 2014.

Summary

Disease characteristics. ATP8B1 deficiency encompasses a phenotypic spectrum ranging from severe to intermediate to mild, based on an individual’s clinical findings and laboratory test results, including liver biopsy.

Severe ATP8B1 deficiency is characterized by onset of symptoms of cholestasis (pruritus and attacks of jaundice) within the first few months of life. Secondary manifestations such as coagulopathy (due to vitamin K deficiency), malabsorption, and poor weight gain may present earlier than age three months. Without surgical intervention, cirrhosis and evolution to end-stage hepatic failure and death usually ensue before the third decade.

Mild ATP8B1 deficiency is characterized by intermittent episodes of cholestasis manifest as severe pruritus and jaundice; chronic liver damage does not typically develop. In contrast to patients in whom bouts of cholestasis are induced only by particular triggers known to increase risk of cholestasis (drug exposure, shifts in hormonal milieu [including those resulting from ingestion of contraceptive drugs or from pregnancy], coexistent malignancy), some or all bouts of cholestasis in individuals with mild ATP8B1 deficiency have different or unknown triggers.

Diagnosis/testing. The diagnosis of ATP8B1 deficiency is suspected based on clinical and laboratory findings (often including liver biopsy findings), and confirmed by identification of biallelic ATP8B1 mutations.

Management. Treatment of manifestations: Standard pharmacologic therapies for pruritus associated with cholestasis (e.g., ursodeoxycholic acid, cholestyramine, and/or rifampin) may be temporarily effective but in the long term are relatively ineffective in severe disease. Nutritional therapy and supplementation of fat-soluble vitamins are useful in severe cholestasis. In severe disease, partial external biliary diversion (PEBD) surgery may reduce pruritus. In some individuals it even slows or reverses progression of hepatic fibrosis. Alternative surgical procedures include ileal exclusion, partial internal biliary diversion, and external diversion with a button device. When liver disease fails to respond to this type of surgery or progresses to cirrhosis in patients with severe ATP8B1 deficiency, orthotopic liver transplantation (LTX) is necessary for long-term survival; however, particular complications are relatively common after LTX.

Additional treatment options are available for milder disease, including temporary measures such as nasobiliary drainage and extracorporeal liver support therapy, which may shorten a bout of cholestasis.

Genetic counseling. ATP8B1 deficiency is inherited in an autosomal recessive manner. The parents of an affected individual are generally obligate carriers of a disease-causing mutation. Intrahepatic cholestasis of pregnancy (ICP) has been reported occasionally in mothers of some individuals with ATP8B1 deficiency. At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

GeneReview Scope

ATP8B1 Deficiency: Included Disorders
  • Mild ATP8B1 deficiency
  • Severe ATP8B1 deficiency

For synonyms and outdated names see Nomenclature.

Diagnosis

ATP8B1 deficiency encompasses a phenotypic spectrum ranging from severe to intermediate to mild, based on an individual’s clinical findings and laboratory test results, including liver biopsy.

Severe ATP8B1 deficiency should be considered in children with unremitting cholestasis (typically beginning within the first few months of life) manifest as jaundice, failure to thrive, and/or hemorrhage (due to the coagulopathy of vitamin K deficiency) that has evolved into cirrhosis and end-stage liver disease or that appears likely to evolve to that stage if untreated.

Mild ATP8B1 deficiency should be considered in persons with intermittent manifestations of intrahepatic cholestasis. Although the first episode of cholestasis in infancy may herald disease anywhere along the phenotypic continuum, the older the age at the first episode, the less likely the individual is to develop severe disease.

In mild-to-moderate ATP8B1 deficiency the age at onset of the first episode of cholestasis and the length of episodes and length of disease-free intervals between episodes vary greatly. Episodes of cholestasis typically involve jaundice and pruritus; however, milder episodes may include pruritus only.

“Triggers” for episodes of intrahepatic cholestasis in patients with intermittent cholestasis may include intercurrent illness, ingestion of a drug, or a shift in hormonal milieu (endogenous or exogenous in origin). Paraneoplastic cholestasis must be considered.

Other manifestations (malaise, abdominal discomfort, loose stools) lack specificity.

Extrahepatic manifestations in ATP8B1 deficiency include hearing loss, pancreatitis, pancreatic insufficiency, kidney stones, and resistance to parathyroid hormone [de Pagter et al 1976, Bull et al 1998, Nagasaka et al 2004, Stapelbroek et al 2009, Pawlikowska et al 2010, Folvik et al 2012]. Patients may have diarrhea not solely attributable to fat malabsorption [Davit-Spraul et al 2010, Pawlikowska et al 2010]. Children with severe ATP8B1 deficiency typically manifest failure to thrive and poor growth, beyond that expected in cholestasis alone [Pawlikowska et al 2010]; puberty may also be delayed.

Testing

Laboratory Studies Consistent with ATP8B1 Deficiency

Serum studies consistent with severe ATP8B1 deficiency. See Table 1.

  • Low-to-normal serum γ-GT (gamma-glutamyltranspeptidase) activity despite conjugated hyperbilirubinemia and/or severe pruritus
    Note: (1) Because γ-GT activity is elevated in most types of cholestasis, forms of cholestasis in which γ-GT is not elevated are called ‘low-γ-GT cholestasis.’ (2) Low-to-normal serum γ-GT activity despite conjugated hyperbilirubinemia is also found in disorders of bile acid synthesis and in disorders of bile acid conjugation. See Fast-atom bombardment ionization mass spectrometry (FAB-MS) analysis of urine.
  • Serum concentrations of cholesterol are usually not elevated (an unusual finding in cholestasis).
  • Serum concentrations of total bile acids are elevated, often markedly so [Davit-Spraul et al 2010, Pawlikowska et al 2010].

Serum studies consistent with mild ATP8B1 deficiency. γ-GT activity is low despite hyperbilirubinemia (see Table 1).

Table 1. Clinical Biochemistry Test Results in ATP8B1 Deficiency

PhenotypeSerum γ-GT ActivitySerum Concentration of CholesterolSerum Concentration of Total Bile AcidsSerum Concentration of Conjugated Bilirubin
Severe Low to normal 1 Low to normal 1
(HDL low, oxidized LDL high, triglycerides high) 2
Markedly elevatedHigh early with resolution and subsequent elevation with end-stage liver disease
Mild Low to normal 3Usually low to normal during symptomatic periods 4Markedly elevated during symptomatic periods – normal between episodesNormal between episodes; variable increases during symptomatic periods

1. Usually elevated in cholestatic liver disease; see Serum studies consistent with severe ATP8B1 deficiency.

2. Nagasaka et al [2005], Nagasaka et al [2009], Pawlikowska et al [2010]

3. May be elevated at onset or at resolution of an episode of cholestasis

4. Detailed study of one individual with mild ATP8B1 deficiency demonstrated low HDL and other lipid abnormalities during a bout of cholestasis [Nagasaka et al 2007].

Fast-atom bombardment ionization mass spectrometry (FAB-MS) analysis of urine. Normal bile acid species present in elevated concentrations indicate normal bile acid synthesis and conjugation. In ATP8B1 deficiency FAB-MS shows elevated levels of normal bile acid species without unusual bile acid species.

Gas-chromatography / FAB-MS analysis of bile. Depletion of dihydroxy-bile acid species (principally chenodeoxycholic acid) is compatible with ATP8B1 deficiency [Tazawa et al 1985, Emerick et al 2008].

Note: Such analyses of bile and urine should be conducted, if possible, more than two weeks after the last administration of ursodeoxycholic acid (see Management). The presence of this choleretic, an exogenous dihydroxy-bile acid, in bile and urine samples may make interpretation of results more difficult.

Sweat chloride. Concentration of electrolytes in sweat may be elevated.

Liver Biopsy

Findings typical of severe ATP8B1 deficiency at presentation are bland intracanalicular cholestasis and scant intrahepatocytic cholestasis.

  • At presentation, individuals with ATP8B1 deficiency generally do not have underlying hepatobiliary structural abnormalities; such abnormalities may develop as the disease evolves. Although inflammation, fibrosis, ductular reaction (bile ductular proliferation), and signs of injury to hepatocytes are not features in early stages of severe ATP8B1 deficiency, they develop over months to years [Bull et al 1997]. As the disease progresses, fibrosis of portal tracts develops; centrilobular fibrosis, with perivenular and pericellular accentuation, is generally seen; and bridging fibrosis, both portal-portal and portal-central, supervenes. Neocholangiolar metaplasia in centrilobular regions may make it difficult to distinguish draining venules from portal venules. When cirrhosis evolves, its pattern is micronodular.
  • None of the usual signs of injury to hepatocytes in cholestatic disorders of infancy (swelling of hepatocytes, rarefaction of hepatocyte cytoplasm, multinucleation of large hepatocytes (“giant-cell change”), and necrosis of individual hepatocytes) is typical of severe ATP8B1 deficiency. Instead, the usual findings are small, tidy-appearing hepatocytes and varying degrees of rosetting of hepatocytes around variably dilated - even pseudoacinar - lumina of bile canaliculi (“bland intralobular cholestasis”, principally intracanalicular rather than hepatocellular). Similar findings are present in mild ATP8B1 deficiency during episodes of cholestasis.
  • Although hepatocytes with three or four nuclei may rarely be encountered, cytoplasmic volume per nucleus is not increased: Multinucleate cells are different from “giant cells”, an important distinction.
  • The bile within canalicular lumina generally appears wispy or pale, unlike the khaki-colored pigment typical in other forms of cholestasis.
  • Coarsely granular canalicular bile may be found on transmission electron microscopy (TEM), although treatment with ursodeoxycholic acid may alter this finding. Bile is not ultrastructurally abnormal in mild ATP8B1 deficiency when cholestasis is not present.
  • Bile ducts are small and inconspicuous and may appear hypoplastic, with interlobular biliary-tract radicles that are only a cell or two broad in cross-section, a characteristic best ascribed to lack of trophic bile flow. Paucity of interlobular bile ducts, however, is not seen.

Findings in mild ATP8B1 deficiency during an episode of cholestasis resemble those at presentation in severe ATP8B1 deficiency.

Immunohistochemical analysis may be available on a research basis (see Molecular Genetics).

Laboratory Studies Diagnostic of ATP8B1 Deficiency

Identification of biallelic ATP8B1 mutations confirms the diagnosis of ATP8B1 deficiency (see Table 2).

Table 2. Summary of Molecular Genetic Testing Used ATP8B1 Deficiency

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
ATP8B1Sequence analysis 4Sequence variants 5Unknown
Deletion/duplication analysis 6Exonic or whole-gene deletions and duplicationsSee footnote 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. For alleles associated with ATP8B1 deficiency in different populations, see Molecular Genetics and Pauli-Magnus et al [2005].

6. Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Exonic and multiexonic deletions have been reported in affected individuals (see Table A, HGMD).

Testing Strategy

To confirm/establish the diagnosis of ATP8B1 deficiency in a proband

1.

Standard clinical-biochemistry tests in cholestasis, including serum γ-GT activity, serum cholesterol concentration, and serum bile acid concentration. Cholestasis, as manifest by direct hyperbilirubinemia and/or hypercholanemia, in the setting of a normal to low γ-GT for age suggests ATP8B1 or ABCB11 deficiency (see Differential Diagnosis). Absence of pruritus and/or near normal serum bile acid concentrations suggests a bile acid synthesis or conjugation defect.
Notes: Bilirubin levels may not be an accurate marker of cholestasis. Substantially elevated aminotransferase activity values at presentation with progressive familial intrahepatic cholestasis (PFIC) suggest ABCB11 deficiency rather than ATP8B1 deficiency [Pawlikowska et al 2010].

2.

FAB-MS analysis of urine to evaluate for a defect in bile acid synthesis or conjugation

3.

Liver biopsy before initiation of ursodeoxycholic acid (UDCA) therapy (or 2 weeks following withdrawal of UDCA). Liver tissue should be routinely processed and examined by light microscopy. A sample should be primarily fixed for transmission electron microscopy.
Note: Liver biopsy may not be necessary if a sib has been definitively diagnosed or if the proband is from an ethnic group in which the disease is relatively common. Genotyping is essential in these cases as a means of confirming a diagnosis.

4.

Molecular genetic testing

Clinical Description

Natural History

ATP8B1 deficiency encompasses a phenotypic spectrum ranging from severe through intermediate to mild, based on an individual’s clinical findings and laboratory test results, including liver biopsy.

Severe ATP8B1 deficiency is characterized by infantile onset of intermittent cholestasis that progresses to cirrhosis, hepatic failure, and death. Mild 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 at biopsy. 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) [van Ooteghem et al 2002].

Extrahepatic disease manifestations. Some individuals with ATP8B1 deficiency (severe or mild) have:

Less well-documented extrahepatic manifestations for which patients may be at increased risk include:

  • Pneumonia. Because cardiolipin can disrupt surfactant function within pulmonary alveoli and because ATP8B1 depletes cardiolipin, ATP8B1 deficiency could increase the risk for (or severity of) pneumonia by increasing alveolar cardiolipin [Pawlikowska et al 2010, Ray et al 2010].
  • Delayed puberty.

Severe ATP8B1 Deficiency

Severe ATP8B1 deficiency is characterized by onset of symptoms of cholestasis (pruritus and attacks of jaundice) within the first few months of life. Secondary manifestations such as coagulopathy (due to vitamin K deficiency), malabsorption, and poor weight gain may present earlier than age three months.

Malnutrition plays a role in growth retardation; however, symmetric somatic growth failure and delayed puberty may be manifestations of the systemic nature of ATP8B1 deficiency.

Without surgical intervention (see Management), cirrhosis and evolution to end-stage hepatic failure and death usually ensue before the third decade.

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, variability has been noted, even within a single family [Bourke et al 1996, Bull et al 1999, Klomp et al 2004].

The age and type of symptoms at onset vary among individuals. Affected children typically present in the first year of life with severe pruritus with or without jaundice [Pawlikowska et al 2010]. The onset of pruritus is difficult to pinpoint because detection depends on an infant's ability to scratch in a coordinated manner. Irritability may be an initial manifestation of pruritus in some infants. Some individuals have been treated for long periods for chronic dermatologic conditions because of long-standing pruritus without typical hallmarks of liver disease.

Although children may initially experience episodes of severe cholestasis followed by disease-free intervals, cholestasis eventually becomes nonremitting. Pruritus is typically severe and persistent; jaundice is often intermittent. Pruritus is disproportionately severe for the degree of hyperbilirubinemia, but proportional to the elevation in serum bile acids. Typical features of chronic liver disease, including (but not limited to) those that emanate from complications of portal hypertension, may develop.

Growth retardation becomes evident in early childhood. This may be secondary to nutritional complications of cholestasis, which typically result in weight loss out of proportion to loss of linear growth. Alternatively, symmetric failure to thrive, consistent with a somatic defect in growth, may be manifest [Pawlikowska et al 2010].

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).

Complications of nutritional deficiencies can result in significant morbidity and mortality, especially hemorrhage secondary to vitamin K deficiency. Specific monitoring for, and treatment of, fat-soluble vitamin (A, D, E, and K) deficiency is essential (see Management).

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). Episodes of epistaxis (in the absence of a coagulopathy or thrombocytopenia) may occur. Significant skin excoriations, caused by constant scratching, are frequent.

Coarsened, stubby hands and fingers have been reported in individuals with genetically undefined PFIC [Ooi et al 2001]. This feature has been encountered in children with genetically confirmed severe ATP8B1 deficiency [B Shneider, personal observation], as has nail dystrophy [Bourke et al 1996, Klomp et al 2004].

As ATP8B1 is expressed in a broad range of tissues, ATP8B1 deficiency can lead to systemic disease manifestations. Liver-related complications are the major consequences of severe ATP8B1 deficiency in most individuals. Some individuals may also manifest abnormalities of pancreatic and intestinal function [Pawlikowska et al 2010]. These may come more prominently to attention after orthotopic liver transplantation (LTX), as secretory diarrhea, pancreatitis, and persistence of growth retardation [Egawa et al 2002, Lykavieris et al 2003, Knisely 2004, Miyagawa-Hayashino et al 2009, Davit-Spraul et al 2010, Hori et al 2011].

Defects in the composition of membranes of enterocyte microvilli have been reported with ATP8B1 deficiency, and it has been suggested that these underlie diarrhea [Verhulst et al 2010].

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

Mild ATP8B1 Deficiency

Mild 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.

In contrast to individuals in whom bouts of cholestasis are induced only by particular triggers known to increase risk of cholestasis (drug exposure, shifts in hormonal milieu [including those resulting from ingestion of contraceptive drugs or from pregnancy], coexistent malignancy), some or all bouts of cholestasis in individuals with mild ATP8B1 deficiency have different or unknown triggers.

In truly mild disease, chronic liver damage does not develop; however, in some individuals, ATP8B1 deficiency initially appears mild, but clinical monitoring over time or detection of fibrosis on liver biopsy indicates disease of intermediate severity [van Ooteghem et al 2002, van Mil et al 2004a].

Penetrance

Mutations underlying severe ATP8B1 deficiency are likely fully penetrant; however, variable expressivity may be observed among sibs with the same mutation(s).

ATP8B1 mutations that usually confer mild episodic ATP8B1 deficiency can occasionally be found in individuals who have not had cholestasis despite having reached an age by which even mild disease is usually manifest; such findings indicate that such mutations can be incompletely penetrant [Klomp et al 2004].

Genotype-Phenotype Correlations

Often, but not always, disease severity can be predicted if a mutation is known; as may be expected, mutations likely to severely impair ATP8B1 structure and/or function (e.g., nonsense and frameshift mutations and large deletions) are more often found in individuals with severe disease.

Missense mutations, which may have lesser impact on ATP8B1 structure/function, are found more commonly in individuals with mild disease [Klomp et al 2004].

The p.Ile661Thr mutation, which is frequently detected in persons with mild disease and of European descent, appears occasionally to be non-penetrant; however, it is also occasionally found in compound heterozygous form in persons with severe disease [Klomp et al 2004].

Family members with the same ATP8B1 mutations 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.

Nomenclature

Nomenclature for the conditions described in this GeneReview is in flux: the understanding of disease mechanisms is in transition from reliance on phenotypic features (giving rise to the PFIC and BRIC nomenclature), through the genetic mapping of disease loci (giving rise to the PFIC1 and BRIC1 nomenclature), to the identification of disease genes and the recognition of a continuum of disease severity (giving rise to severe and mild ATP8B1 deficiency nomenclature).

In this review, we have used the term:

  • ‘ATP8B1 deficiency’ to encompass the entire spectrum of severity of disease associated with ATP8B1 deficiency.
  • ‘Severe ATP8B1 deficiency’ to designate disease that may previously have been termed ‘progressive familial intrahepatic cholestasis type 1’ (PFIC1) or ‘severe FIC1 (familial intrahepatic cholestasis 1) deficiency.’ (The gene symbol initially assigned to ATP8B1 was FIC1. The gene symbol ATP8B1 was assigned as understanding of ATPase gene families increased.)
  • ‘Mild ATP8B1 deficiency’ to designate disease that may previously have been termed ‘benign recurrent intrahepatic cholestasis type 1’ (BRIC1) or ‘mild FIC1 (familial intrahepatic cholestasis 1) deficiency.’

Severe ATP8B1 deficiency in individuals of Amish ancestry was previously called Byler disease, after the kindred in which PFIC was first described [Clayton et al 1969].

Severe ATP8B1 deficiency in individuals of Inuit ancestry was previously called Greenland childhood cholestasis or Greenland familial cholestasis [Nielsen et al 1986, Ornvold et al 1989, Eiberg & Nielsen 1993].

Prevalence

The prevalence of ATP8B1 deficiency is unknown. It has been considered rare, but 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. Outside certain restricted populations (e.g., the Amish and Inuit), no specific population is known to be at a higher risk for ATP8B1 deficiency, although certain mutant alleles are more prevalent in particular populations.

Carrier frequencies for ATP8B1 deficiency are unknown, except for the Greenland Inuit in whom the carrier frequency of the mutation p.Asp554Asn appears quite high. Population studies indicate that the frequency of this disease allele varies regionally in Greenland; the frequency of the mutated allele is high enough to warrant routine screening, reaching 0.16 in Ittoqqortoormiit, and 0.23 in Kuummiut, both in East Greenland [Eiberg & Nielsen 1993, Eiberg et al 2004, Nielsen & Eiberg 2004, Andersen et al 2006].

Differential Diagnosis

Differential diagnosis most relevant in suspected ATP8B1 deficiency relates to other forms of cholestatic liver disease typically characterized by low or normal serum γ-GT levels. Low or normal serum γ-GT levels distinguish this group of disorders from the much more common and diffuse differential diagnosis of cholestasis in the setting of an elevated serum γ-GT level. Some individuals are diagnosed with PFIC accompanied by high serum γ-GT levels, and in some such individuals, mutation in ABCB4 (encoding MDR3) has been identified. Elevated serum γ-GT activity generally allows this form of pediatric cholestasis to be distinguished from ATP8B1 deficiency.

Relevant cholestatic liver diseases with low or normal serum γ-GT activity include the following:

ABCB11 deficiency. ABCB11 encodes ABCB11, also known as bile salt export pump (BSEP). Severe ABCB11 deficiency is also called PFIC type 2 (PFIC2); mild ABCB11 deficiency is also called BRIC type 2 (BRIC2). The clinical features of ABCB11 deficiency resemble in large part those of ATP8B1 deficiency; differences that facilitate differential diagnosis are discussed below.

Mutation in ABCB11 can lead to retention of bile salts within hepatocytes and to lack of bile salts within canalicular lumina. The detergent effect of bile salts is required for elution of γ-GT from canalicular walls into bile. Lack of intracanalicular bile salts thus has as a consequence that bile leaking between damaged hepatocytes into plasma does not carry with it eluted γ-GT. Serum γ-GT activity in ABCB11 deficiency thus is not elevated.

Early in disease, histopathologic findings in ABCB11 deficiency differ from those in ATP8B1 deficiency. In the former, retained bile salts within hepatocytes damage intrahepatocytic structures, manifest on histopathologic study of liver tissue as swelling, giant-cell change, and necrosis of hepatocytes. Moderate inflammation, varying degrees of fibrosis and elevations in serum transaminase activity accompany this parenchymal injury [Davit-Spraul et al 2010, Pawlikowska et al 2010]. Accumulations of bile pigment are found in hepatocytes as well as in lumina of bile canaliculi. Ultrastructural study of canalicular bile does not identify coarse granularity [Bull et al 1997]. Immunohistochemical study finds ectoenzymes, like γ-GT, expressed along canalicular walls, while expression of ABCB11 is often deficient. (ABCB11 is usually well expressed along bile canaliculi in ATP8B1 deficiency.)

In severe disease, results of some laboratory studies of serum at disease presentation differ between ATP8B1 and ABCB11 deficiencies. For example, serum transaminase activity values are higher at presentation in children with ABCB11 deficiency, consistent with the histopathologic findings indicating more inflammatory disease [Davit-Spraul et al 2010, Pawlikowska et al 2010]. At disease presentation, serum alkaline phosphatase activity is generally higher in severe ATP8B1 deficiency, while serum albumin, bile acid, and alphafetoprotein concentrations tend to be higher in severe ABCB11 deficiency [Davit-Spraul et al 2010, Pawlikowska et al 2010]. Sweat test results (at presentation or later) are more likely to be abnormal in ATP8B1 deficiency than in ABCB11 deficiency [Pawlikowska et al 2010].

Without normal ABCB11/BSEP function, post-hepatic bile (sampled from gallbladder or at ampulla of Vater) is deficient in bile salts [Emerick et al 2008]. Deficiency of primary bile salts in such bile thus can suggest either ATP8B1 deficiency or ABCB11 deficiency.

ABCB11 is expressed only at the apical (bile-canaliculus) membrane of hepatocytes. Mutation in ABCB11 thus leads to primary effects only within the liver. Those effects, with hepatocyte damage, lead to cholestasis. Secondary effects of cholestasis, such as pruritus and malabsorption, are like those of ATP8B1 deficiency. As expected for a disorder caused by mutation in a gene expressed only in hepatocytes, however, the primary manifestations of ABCB11 deficiency are limited to the liver, and extrahepatic disease manifestations are less common than in ATP8B1 deficiency. For example, while gallstone disease is more common in children with severe ABCB11 deficiency than in those with severe ATP8B1 deficiency, children with ATP8B1 deficiency appear more likely to manifest hearing loss, pancreatic disease, diarrhea, rickets, and poor growth [Davit-Spraul et al 2010, Pawlikowska et al 2010]. In contrast to ATP8B1 deficiency, after LTX in ABCB11 deficiency, diarrhea, pancreatitis, and steatosis of the allograft are not described.

ABCB11 deficiency is associated with hepatobiliary malignancy (both hepatocellular carcinoma and cholangiocarcinoma) in childhood [Knisely et al 2006, Scheimann et al 2007, Strautnieks et al 2008]. A single report of pancreatic adenocarcinoma against a background of ABCB11 deficiency has appeared [Bass et al 2010]. Malignancy is not a reported feature of ATP8B1 deficiency.

Some patients with ABCB11 deficiency who undergo LTX develop antibodies against ABCB11 [Keitel et al 2009, Jara et al 2009, Maggiore et al 2010, Siebold et al 2010]. The proportion of transplanted patients who develop such antibodies is unknown. In some such patients, these antibodies impede ABCB11 function and cholestasis develops. The proportion of such patients also is unknown. Disease ascribed to formation of antibodies against ATP8B1 after LTX in patients with ATP8B1 deficiency has not been reported.

Locus heterogeneity for low γ-GT PFIC and BRIC. Evidence indicates the existence of an additional disease locus (or loci) for low γ-GT PFIC and BRIC. Some individuals diagnosed on clinical and histopathologic evidence as having PFIC or BRIC do not show linkage to either ATP8B1 or ABCB11; others, on sequencing of both of these genes, have no detectable mutation [Bull et al 1997, Floreani et al 2000, Strautnieks et al 2001]. Mutation of TJP2, implicated in hypercholanemia [Carlton et al 2003], underlies some such instances of low γ-GT PFIC [Sambrotta et al 2014].

Inborn errors of bile acid biosynthesis. Synthesis of cholic and chenodeoxycholic acids (the principal human bile acids) from cholesterol comprises several steps, involving cytoplasmic, mitochondrial, and peroxisomal sites [Bove et al 2000]. Mutation in single genes that encode individual pathway enzymes thus may cause disease [Setchell et al 1998, Honda et al 1999, Bove et al 2000, Clayton et al 2002, Grange et al 2002, Setchell et al 2003]. Precursor bile acids are likely poor substrates for ABCB11 and thus accumulate in hepatocyte cytoplasm where they cause damage; cholestasis ensues. Although lack of primary bile salts in bile (see ABCB11 deficiency) precludes rises in serum γ-GT activity, γ-GT is well expressed along canalicular walls in the livers of such patients. For disorders of bile-acid conjugation, see Familial hypercholanemia.

Familial hypercholanemia (FHC) is a disorder with the hallmark feature of fluctuating, but often extremely elevated, concentrations of bile acids in serum. Affected individuals often manifest pruritus, malabsorption of fat-soluble vitamins, and failure to thrive. Most do not become jaundiced. Causative mutations in four genes, TJP2, BAAT, SLC27A5, and EPHX1, have been identified [Carlton et al 2003, Zhu et al 2003, Chong et al 2012]. BAAT and SLC27A5 encode enzymes involved in bile acid conjugation. Defects in bile acid conjugation can be identified by MS-FAB analysis of urine. Non-conjugated bile acids are poor substrates for ABCB11; they also can traverse cell membranes more readily than can conjugated bile acids. Thus, failure of serum γ-GT to rise in BAAT deficiency and SLC27A5 deficiency likely results from lack of detergent activity in canalicular bile. TJP2 is a scaffold protein in tight junctions, and the reported mutation is proposed to increase the permeability of tight junctions with regard to bile acids. EPHX1 is implicated in hepatocyte uptake of bile acids from plasma.

Smith-Lemli-Opitz syndrome (SLOS) can secondarily lead to low γ-GT cholestasis [Grange et al 2002] via decreased synthesis of bile acid precursors. SLOS can be diagnosed biochemically through measurement of serum concentrations of dehydrocholesterol and cholesterol.

Nonspecific failure of bile acid production. As in adulthood [Kajiwara et al 1991], acute hepatic failure in infancy can be associated with low γ-GT cholestasis, which is ascribed to nonspecific failure of bile acid production. In this situation, as in primary defects of bile acid synthesis, the detergent effect of bile acids is lacking. Thus, γ-GT is not likely to be eluted by bile from the surface membranes of cells in contact with bile and cannot reflux into plasma. Currently, acute and severe neonatal liver disease is not a known presentation of genetically documented ATP8B1 or ABCB11 deficiency; malabsorption-associated failure to synthesize proteins that require vitamin K as a cofactor must be distinguished from hepatocellular loss and failure to synthesize a broader range of proteins such as albumin and transferrin.

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is an autosomal recessive condition characterized by Fanconi-type aminoaciduria, degeneration of anterior horn cells (i.e., lower motor neurons), conjugated hyperbilirubinemia without elevated γ-GT, and ichthyosis [Eastham et al 2001]. Mutations in VPS33B and VIPAR have been identified in individuals with ARC syndrome [Gissen et al 2004, Cullinane et al 2010]. In general, the extrahepatic findings strongly suggest the diagnosis [Bull et al 2006]. The proteins encoded by VPS33B and VIPAR subserve trafficking of various species, including γ-GT and ABCB11, to the canalicular membrane. Failure of γ-GT activity to rise in ARC syndrome, despite cholestasis, thus likely is multifactorial.

Microvillus inclusion disease (MVID). Mutations in MYO5B underlie this disorder of intracellular trafficking in which apical membranes of enterocytes in particular are poorly assembled [Müller et al 2008]. In individuals with MVID usual microvillus-lined inclusions are not seen in apical cytoplasm of hepatocytes. Evidence for abnormal composition or population of hepatocellular apical membranes, however, is provided by poor expression of γ-GT along bile canaliculi [Peters et al 2001; AS Knisely, personal observations]. Cholestasis in MVID is most often precipitated by parenteral alimentation but also may occur after small-bowel transplantation. In both settings, abnormal composition of canalicular membranes likely increases susceptibility to cholestasis, with failure of γ-GT to rise reflecting lack of γ-GT expression.

Drug-induced cholestasis and intrahepatic cholestasis of pregnancy (ICP). Cholestasis with symptoms like those of ATP8B1 deficiency may develop on exposure to a drug (including contraceptive drugs); cholestasis generally improves when the implicated drug is withdrawn. Similarly, the altered hormonal milieu and/or greater physiologic demands of pregnancy induce some women to develop intrahepatic cholestasis of pregnancy (ICP), in which symptoms typically appear during the third trimester and resolve after delivery. ICP is characterized by cholestasis manifest as pruritus with elevated serum bile acid levels, occasionally accompanied by jaundice. ICP confers an increased risk of fetal complications. Women with ICP generally do not experience symptoms between pregnancies and do not develop chronic liver damage. The frequency with which ATP8B1 mutation predisposes to drug-induced cholestasis is not known.

Malignancy. Cholestasis with symptoms like those of ATP8B1 deficiency may rarely develop in association with malignancy (paraneoplastic cholestasis). This phenomenon should be borne in mind when evaluating intrahepatic cholestasis that is first manifest after infancy. Instances of paraneoplastic cholestasis associated with ATP8B1 mutation are not yet described.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations at Initial Diagnosis

To establish the extent of hepatobiliary disease and needs in an individual diagnosed with ATP8B1 deficiency, the authors recommend the following:

  • Standard biochemical assays of hepatocellular function and of hepatobiliary injury
  • Imaging studies of the liver, with liver biopsy if indicated by the findings on imaging studies or biochemical assays
  • Assessment for evidence of portal hypertension to weigh implications for surgical intervention

Treatment of Manifestations

Pharmacologic Therapy

Severe ATP8B1 deficiency. Although various medical therapies to alleviate symptoms and to stop or reverse the progression of liver damage have been tried, this disorder has, for the most part, been refractory to pharmacologic treatment. Standard treatments for pruritus associated with cholestasis (including choleretic agents such as phenobarbital and ursodeoxycholic acid [UDCA], cholestyramine, rifampin, antihistamines, carbamazepine, UV-B light therapy, and plasmapheresis) have been relatively ineffective in the long term. In addition, no data suggest that these therapies alter progression to end-stage liver disease.

Mild ATP8B1 deficiency. Some medications, including rifampicin, UDCA, and bile acid binding resin [Folvik et al 2012, Mizuochi et al 2012, Uegaki et al 2008] may have some efficacy.

Nutritional Therapy and Supplementation

Severe ATP8B1 deficiency

  • Special attention must be paid to nutritional therapy which includes infant formulas with significant proportions of medium chain triglycerides, which can be absorbed relatively independent of bile flow.
  • Nasogastric tube feeding has been useful in some infants.
  • Fat-soluble vitamin supplementation using special preparations of vitamin E (e.g., tocopheryl polyethylene glycol-1000 succinate) is useful in severe cholestasis. Individual supplementation may be required to insure adequate levels of fat-soluble vitamins.

Other Approaches

Mild ATP8B1 deficiency. Additional temporary approaches such as nasobiliary drainage [Stapelbroek et al 2006, Toros et al 2012] and extracorporeal liver support therapy [Huster et al 2001, Saich et al 2005, Walensi et al 2012] may hasten the end of an episode of cholestasis. Note: Because some of these studies involved individuals with a clinical – but not a molecular – diagnosis of BRIC, it is uncertain whether their disease was due to mutation in ATP8B1 or in a different gene.

Interruption of the enterohepatic circulation of bile acids. Since liver damage in severe ATP8B1 deficiency is thought to result from a build-up of bile acids in the liver, surgical interruption of the enterohepatic circulation of bile acids has been used as therapy. Such surgery can successfully reduce pruritus, with slowed or even reversed progression to hepatic fibrosis in some individuals [Felberbauer et al 2000, van Ooteghem et al 2002].

Surgical approaches reported to be successful in severe disease include [Hollands et al 1998, Ismail et al 1999, Rebhandl et al 1999, Melter et al 2000, Bustorff-Silva et al 2007, Clifton et al 2011]:

  • Partial external biliary diversion (PEBD) in which the gallbladder apex is anastomosed to one end of a segment of bowel while the other end is used to create a cutaneous stoma from which bile is then drained and discarded*, interrupts the enterohepatic circulation of bile acids and reduces pruritus. In some individuals it even slows or reverses progression to hepatic fibrosis.

    *PEBD includes cutaneous cholecystostomy, cholecysto-jejuno-cutaneostomy, cholecysto-appendico-cutaneostomy.
  • The internal biliary bypass approach of cholecystojejunocolic anastomosis.

Alternative surgical procedures include ileal exclusion, external diversion with a button device, and biliary diversion to the colon.

Note: Which surgical procedure is most helpful in severe ATP8B1 deficiency is unknown, although PEBD is the most commonly performed surgery. As most studies of responses to these procedures in individuals diagnosed with PFIC [Kalicinski et al 2003, Kurbegov et al 2003] have been performed in genetically uncharacterized patients, differences in response that may depend on which disease gene is mutated or on the severity of the functional effects of different mutations have not been assessed.

Liver transplantation (LTX). Individuals with severe ATP8B1 deficiency whose liver disease progresses to decompensated cirrhosis, may require LTX for long-term survival. Individuals whose disease does not respond to surgical interruption of the enterohepatic circulation may also be candidates for LTX.

In some individuals with severe ATP8B1 deficiency, LTX constitutes definitive therapy; however, in others secretory diarrhea in the absence of steatorrhea continues or worsens after LTX [Knisely 2004, Lykavieris et al 2003]. The diarrhea can be severe and may require intravenous fluid administration. Bile acid chelators [Egawa et al 2002] may ameliorate diarrhea after LTX, as they may divert bile produced by the allograft away from the native gut [Usui et al 2009, Nicastro et al 2012]. Clonidine has palliated diarrhea after LTX in some patients [Kocoshis et al 2005].

Somatic growth failure can occur and may not be responsive to LTX.

Pancreatitis and steatohepatitis can occur after otherwise successful LTX [Egawa et al 2002, Lykavieris et al 2003, Miyagawa-Hayashino et al 2009, Davit-Spraul et al 2010, Hori et al 2011]. Steatohepatitis can be progressive and lead to cirrhosis. Both steatosis and diarrhea may respond when PEBD is used to divert the flow of bile from the allograft away from the native gut (which expresses functionally defective ATP8B1) [Usui et al 2009, Nicastro et al 2012].

Extrahepatic manifestations. Persons with sensorineural hearing loss may require hearing aids [Stapelbroek et al 2009, Pawlikowska et al 2010].

Prevention of Primary Manifestations

Severe ATP8B1 deficiency. Surgical interruption of the enterohepatic circulation should be the primary therapy in individuals with severe ATP8B1 deficiency unless cirrhosis is present, in which case LTX should be considered.

Mild ATP8B1 deficiency. LTX appears difficult to justify in patients with mild, intermittently manifesting ATP8B1 deficiency. The role of surgical interruption of the enterohepatic circulation in mild ATP8B1 deficiency is unclear.

Prevention of Secondary Complications

Fat-soluble vitamin supplementation is a key aspect of the management of the cholestasis seen in ATP8B1 deficiency. Vitamin supplementation is necessary to alleviate malabsorption of fat-soluble vitamins. Vitamin K administration in the newborn period is of critical importance.

Medium chain triglyceride based formulas may be useful in the prevention and/or treatment of growth failure.

Surveillance

Periodic monitoring for fat-soluble vitamin deficiency is recommended.

Hearing screening is recommended at five-year intervals in individuals with no symptomatic evidence of hearing deficits.

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.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Administration of 4-phenylbutyrate, a modifier of protein configuration, has improved expression/function of ATP8B1 in vitro [van der Velden et al 2010]. Extension to clinical use is under study [Gonzales & Jacquemin 2010].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

ATP8B1 deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • A case report suggests that ATP8B1 heterozygotes may be at increased risk for transient neonatal cholestasis [Jacquemin et al 2010].

Offspring of a proband

  • The offspring of an individual with ATP8B1 deficiency are obligate heterozygotes (carriers) for a mutant allele.
  • The carrier frequencies of ATP8B1 mutations 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 mutation 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.
  • A case report suggests that ATP8B1 heterozygotes may be at increased risk for transient neonatal cholestasis [Jacquemin et al 2010].

Other family members. Each sib of an obligate carrier is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in a family are known.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Liver Foundation
    75 Maiden Lane
    Suite 603
    New York NY 10038
    Phone: 800-465-4837 (Toll-free HelpLine); 212-668-1000
    Fax: 212-483-8179
    Email: info@liverfoundation.org
  • Canadian Liver Foundation (CLF)
    2235 Sheppard Avenue East
    Suite 1500
    Toronto Ontario M2J 5B5
    Canada
    Phone: 800-563-5483 (toll-free); 416-491-3353
    Fax: 416-491-4952
    Email: clf@liver.ca
  • Childhood Liver Disease Research and Education Network (ChiLDREN)
    The Children's Hospital, Section of Pediatric Gastroenterology/Hepatology/Nutrition
    13123 East 16th Avenue
    Suite B290
    Aurora CO 80045
    Phone: 720-777-2598
    Fax: 720-777-7351
    Email: hines.joan@tchden.org
  • Children's Liver Disease Foundation (CLDF)
    36 Great Charles Street
    Birmingham B3 3JY
    United Kingdom
    Phone: +44 (0) 121 212 3839
    Fax: +44 (0) 121 212 4300
    Email: info@childliverdisease.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. ATP8B1 Deficiency: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for ATP8B1 Deficiency (View All in OMIM)

211600CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 1; PFIC1
243300CHOLESTASIS, BENIGN RECURRENT INTRAHEPATIC, 1; BRIC1
602397ATPase, CLASS I, TYPE 8B, MEMBER 1; ATP8B1

ATP8B1

Gene structure. ATP8B1 has a coding sequence of 3,753 bp and consists of 27 coding exons (NM_005603.4) [Bull et al 1998]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Over 80 mutations in ATP8B1 have been reported to date. While a complete tabulation of all reported ATP8B1 mutations is beyond the scope of this article, for examples see: Bull et al [1998], Klomp et al [2000], Egawa et al [2002], Chen et al [2002], Klomp et al [2004], Liu et al [2010], Davit-Spraul et al [2010], Matte et al [2010].

Table 3. ATP8B1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.625C>Ap.Pro209ThrNM_005603​.4
NP_005594​.1
c.923G>Tp.Gly308Val
c.1660G>Ap.Asp554Asn
c.1982T>Cp.Ile661Thr
c.1993G>Tp.Glu665Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. ATP8B1 codes for a 1,251 amino acid protein. ATP8B1 is a member of a subfamily of P-type ATPase genes. Other members of this family encode proteins that may function in the transport of aminophospholipids from the outer to the inner leaflet of plasma membranes [Tang et al 1996]. Initial functional studies suggest that ATP8B1 may function as an aminophospholipid flippase [Ujhazy et al 2001], but other functions are not excluded [Verhulst et al 2010].

Studies of RNA and protein expression indicate that 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.

Abnormal gene product. Immunostaining for ATP8B1 has been conducted on a research basis in snap-frozen tissue; immunostaining for this protein in formalin-fixed, paraffin-embedded (“routinely processed”) tissue is not available. In its stead, immunostaining of routinely processed liver for canalicular antigens (ectoenzymes in particular, including γ-GT) can suggest deficiency of ATP8B1 function or expression; instability of the canalicular membrane in ATP8B1 disease leads to loss of expression of ectoenzymes. Such loss of expression of ectoenzymes is not a feature in other forms of intrahepatic cholestasis without elevated γ-GT activity.

Assessment of tissue for ATP8B1 mRNA or ATP8B1 protein content has been conducted on a research basis only.

Some studies indicate that decreased or absent ATP8B1 function is associated with diminished activity of the farnesoid X-receptor [Alvarez et al 2004, Chen et al 2004, Frankenberg et al 2008, Martinez-Fernandez et al 2009, Chen et al 2013]. The farnesoid X-receptor directly activates bile salt export pump (BSEP) and indirectly inactivates intestinal bile acid transport.

A mouse model homozygous for a mutation orthologous to that present in humans with severe disease was generated [Pawlikowska et al 2004]. When challenged with a bile salt-supplemented diet, these mice develop biochemical manifestations of cholestasis and liver injury, as well as hepatomegaly; however, histologic abnormalities are less severe than those observed in individuals with ATP8B1 deficiency. Additional studies of this mouse model support: (1) the hypothesis that ATP8B1 deficiency results in abnormal distribution of phosphatidylserine between the membrane leaflets of the canalicular (apical) membrane of the hepatocyte and (2) the proposition that ATP8B1 deficiency results in decreased resistance of this membrane to the detergent effects of bile salts, consequently contributing to increased extraction of cholesterol, phospholipid, and ectoenzymes from this membrane, and decreased function of transporters within this membrane, including BSEP [Pawlikowska et al 2004, Paulusma et al 2006, Groen et al 2008]. Some in vitro studies also support this model (see, e.g., Cai et al [2009]).

Other studies suggest additional/alternative hypotheses regarding the function of ATP8B1. One study suggests that ATP8B1 may be involved in cardiolipin import into the cell [Ray et al 2010]. Another study reports a role for ATP8B1 in apical membrane organization that is independent of its presumed flippase activity [Verhulst et al 2010]. Inquiry into the functional roles of ATP8B1 continues to be an active area of research.

References

Literature Cited

  1. Alvarez L, Jara P, Sanchez-Sabate E, Hierro L, Larrauri J, Diaz MC, Camarena C, De la Vega A, Frauca E, Lopez-Collazo E, Lapunzina P. Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1. Hum Mol Genet. 2004;13:2451–60. [PubMed: 15317749]
  2. Andersen S, Okkels H, Krarup H, Laurberg P. Geographical clustering and maintained health in individuals harbouring the mutation for Greenland familial cholestasis: A population-based study. Scand J Gastroenterol. 2006;41:445–50. [PubMed: 16635913]
  3. Bass LM, Patil D, Rao MS, Green RM, Whitington PF (2010) Pancreatic adenocarcinoma in type 2 progressive familial intrahepatic cholestasis. BMC Gastroenterol 13;10:30. [PMC free article: PMC2841578] [PubMed: 20226067]
  4. Bourke B, Goggin N, Walsh D, Kennedy S, Setchell KD, Drumm B. Byler-like familial cholestasis in an extended kindred. Arch Dis Child. 1996;75:223–7. [PMC free article: PMC1511711] [PubMed: 8976662]
  5. Bove KE, Daugherty CC, Tyson W, Mierau G, Heubi JE, Balistreri WF, Setchell KD. Bile acid synthetic defects and liver disease. Pediatr Dev Pathol. 2000;3:1–16. [PubMed: 10594127]
  6. Bull LN, Carlton VE, Stricker NL, Baharloo S, DeYoung JA, Freimer NB, Magid MS, Kahn E, Markowitz J, DiCarlo FJ, McLoughlin L, Boyle JT, Dahms BB, Faught PR, Fitzgerald JF, Piccoli DA, Witzleben CL, O'Connell NC, Setchell KD, Agostini RM, JrKocoshis SA, Reyes J, Knisely AS. Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity. Hepatology. 1997;26:155–64. [PubMed: 9214465]
  7. Bull LN, Juijn JA, Liao M, van Eijk MJ, Sinke RJ, Stricker NL, DeYoung JA, Carlton VE, Baharloo S, Klomp LW, Abukawa D, Barton DE, Bass NM, Bourke B, Drumm B, Jankowska I, Lovisetto P, McQuaid S, Pawlowska J, Tazawa Y, Villa E, Tygstrup N, Berger R, Knisely AS, Freimer NB. Fine-resolution mapping by haplotype evaluation: the examples of PFIC1 and BRIC. Hum Genet. 1999;104:241–8. [PubMed: 10323248]
  8. Bull LN, Mahmoodi V, Baker AJ, Jones R, Strautnieks SS, Thompson RJ, Knisely AS. VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype. J Pediatr. 2006;148:269–71. [PubMed: 16492441]
  9. Bull LN, van Eijk MJ, Pawlikowska L, DeYoung JA, Juijn JA, Liao M, Klomp LW, Lomri N, Berger R, Scharschmidt BF, Knisely AS, Houwen RH, Freimer NB. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet. 1998;18:219–24. [PubMed: 9500542]
  10. Bustorff-Silva J, Sbraggia Neto L, Olímpio H, de Alcantara RV, Matsushima E, De Tommaso AM, Brandão MA, Hessel G. Partial internal biliary diversion through a cholecystojejunocolonic anastomosis--a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report. J Pediatr Surg. 2007;42:1337–40. [PubMed: 17706492]
  11. Cai SY, Gautam S, Nguyen T, Soroka CJ, Rahner C, Boyer JL. ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained. Gastroenterology. 2009;136:1060–9. [PMC free article: PMC3439851] [PubMed: 19027009]
  12. Carlton VE, Harris BZ, Puffenberger EG, Batta AK, Knisely AS, Robinson DL, Strauss KA, Shneider BL, Lim WA, Salen G, Morton DH, Bull LN. Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nat Genet. 2003;34:91–6. [PubMed: 12704386]
  13. Chen F, Ananthanarayanan M, Emre S, Neimark E, Bull LN, Knisely AS, Strautnieks SS, Thompson RJ, Magid MS, Gordon R, Balasubramanian N, Suchy FJ, Shneider BL. Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity. Gastroenterology. 2004;126:756–64. [PubMed: 14988830]
  14. Chen F, Ghosh A, Shneider BL. Phospholipase D2 Mediates Signaling by ATPase Class I Type 8B Membrane 1. J Lipid Res. 2013;54:379–85. [PMC free article: PMC3588867] [PubMed: 23213138]
  15. Chen HL, Chang PS, Hsu HC, Ni YH, Hsu HY, Lee JH, Jeng YM, Shau WY, Chang MH. FIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low gamma-glutamyltranspeptidase levels. J Pediatr. 2002;140:119–24. [PubMed: 11815775]
  16. Chong CP, Mills PB, McClean P, Gissen P, Bruce C, Stahlschmidt J, Knisely AS, Clayton PT. Bile acid-CoA ligase deficiency--a new inborn error of bile acid metabolism. J Inherit Metab Dis. 2012;35:521–30. [PubMed: 22089923]
  17. Clayton PT, Verrips A, Sistermans E, Mann A, Mieli-Vergani G, Wevers R. Mutations in the sterol 27-hydoxylase gene (CYP27A) cause hepatitis of infancy as well as cerebrotendinous xanthomatosis. J Inherit Metab Dis. 2002;25:501–13. [PubMed: 12555943]
  18. Clayton RJ, Iber FL, Ruebner BH, McKusick VA. Byler disease. Fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child. 1969;117:112–24. [PubMed: 5762004]
  19. Clifton MS, Romero R, Ricketts RR. Button cholecystostomy for management of progressive familial intrahepatic cholestasis syndromes. J Pediatr Surg. 2011;46:304–7. [PubMed: 21292078]
  20. Cullinane AR, Straatman-Iwanowska A, Zaucker A, Wakabayashi Y, Bruce CK, Luo G, Rahman F, Gürakan F, Utine E, Ozkan TB, Denecke J, Vukovic J, Di Rocco M, Mandel H, Cangul H, Matthews RP, Thomas SG, Rappoport JZ, Arias IM, Wolburg H, Knisely AS, Kelly DA, Müller F, Maher ER, Gissen P. Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization. Nat Genet. 2010;42:303–12. [PubMed: 20190753]
  21. Davit-Spraul A, Fabre M, Branchereau S, Baussan C, Gonzales E, Stieger B, Bernard O, Jacquemin E. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology. 2010;51:1645–55. [PubMed: 20232290]
  22. de Pagter AGF, van Berge Henegouwen GP, Huinink TB, Brandt KH. Familial benign recurrent intrahepatic cholestasis. Gastroenterology. 1976;71:202–7. [PubMed: 939378]
  23. Demeilliers C, Jacquemin E, Barbu V, Mergey M, Paye F, Fouassier L, Chignard N, Housset C, Lomri NE. Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation. Hepatology. 2006;43:1125–34. [PubMed: 16628629]
  24. Eastham KM, McKiernan PJ, Milford DV, Ramani P, Wyllie J, van't Hoff W, Lynch SA, Morris AA. ARC syndrome: an expanding range of phenotypes. Arch Dis Child. 2001;85:415–20. [PMC free article: PMC1718974] [PubMed: 11668108]
  25. Egawa H, Yorifuji T, Sumazaki R, Kimura A, Hasegawa M, Tanaka K. Intractable diarrhea after liver transplantation for Byler's disease: successful treatment with bile adsorptive resin. Liver Transpl. 2002;8:714–6. [PubMed: 12149765]
  26. Egawa H, Yorifuji T, Sumazaki R, Kimura A, Hasegawa M, Tanaka K. Intractable diarrhea after liver transplantation for Byler's disease: successful treatment with bile adsorptive resin. Liver Transpl. 2002;8:714–6. [PubMed: 12149765]
  27. Eiberg H, Nielsen IM. Linkage studies of cholestasis familiaris groenlandica/Byler-like disease with polymorphic protein and blood group markers. Hum Hered. 1993;43:250–6. [PubMed: 8344670]
  28. Eiberg H, Norgaard-Pedersen B, Nielsen IM. Cholestasis Familiaris Groenlandica/Byler-like disease in Greenland--a population study. Int J Circumpolar Health. 2004;63 Suppl 2:189–91. [PubMed: 15736649]
  29. Emerick KM, Elias MS, Melin-Aldana H, Strautnieks S, Thompson RJ, Bull LN. Bile composition in Alagille Syndrome and PFIC patients having Partial External Biliary Diversion. BMC Gastroenterol. 2008;8:47. [PMC free article: PMC2585081] [PubMed: 18937870]
  30. Eppens EF, van Mil SW, de Vree JM, Mok KS, Juijn JA, Oude Elferink RP, Berger R, Houwen RH, Klomp LW. FIC1, the protein affected in two forms of hereditary cholestasis, is localized in the cholangiocyte and the canalicular membrane of the hepatocyte. J Hepatol. 2001;35:436–43. [PubMed: 11682026]
  31. Felberbauer FX, Amann G, Rebhandl W, Huber WD. Follow-up after partial external biliary diversion in familial cholestasis of infancy. J Pediatr Gastroenterol Nutr. 2000;31:322. [PubMed: 10997384]
  32. Floreani A, Molaro M, Mottes M, Sangalli A, Baragiotta A, Roda A, Naccarato R, Clementi M. Autosomal dominant benign recurrent intrahepatic cholestasis (BRIC) unlinked to 18q21 and 2q24. Am J Med Genet. 2000;95:450–3. [PubMed: 11146465]
  33. Folvik G, Hilde O, Helge GO. Benign recurrent intrahepatic cholestasis: review and long-term follow-up of five cases. Scand J Gastroenterol. 2012;47:482–8. [PubMed: 22229830]
  34. Frankenberg T, Miloh T, Chen FY, Ananthanarayanan M, Sun AQ, Balasubramaniyan N, Arias I, Setchell KD, Suchy FJ, Shneider BL. The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor. Hepatology. 2008;48:1896–905. [PMC free article: PMC2774894] [PubMed: 18668687]
  35. Gissen P, Johnson CA, Morgan NV, Stapelbroek JM, Forshew T, Cooper WN, McKiernan PJ, Klomp LW, Morris AA, Wraith JE, McClean P, Lynch SA, Thompson RJ, Lo B, Quarrell OW, Di Rocco M, Trembath RC, Mandel H, Wali S, Karet FE, Knisely AS, Houwen RH, Kelly DA, Maher ER. Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. Nat Genet. 2004;36:400–4. [PubMed: 15052268]
  36. Gonzales E, Jacquemin E. Mutation specific drug therapy for progressive familial or benign recurrent intrahepatic cholestasis: a new tool in a near future? J Hepatol. 2010;53:385–7. [PubMed: 20537422]
  37. Grange DK, deMello DE, Hart MH, Kelley RI, Knisely AS, Nwokoro NA, Sotelo-Avila C. Cholestatic liver disease in Smith-Lemli-Opitz syndrome. Proc Greenwood Genet Center. 2002;21:48–9.
  38. Groen A, Kunne C, Jongsma G, van den Oever K, Mok KS, Petruzzelli M, Vrins CL, Bull L, Paulusma CC, Oude Elferink RP. Abcg5/8 independent biliary cholesterol excretion in Atp8b1-deficient mice. Gastroenterology. 2008;134:2091–100. [PubMed: 18466903]
  39. Hollands CM, Rivera-Pedrogo FJ, Gonzalez-Vallina R, Loret-de-Mola O, Nahmad M, Burnweit CA. Ileal exclusion for Byler's disease: an alternative surgical approach with promising early results for pruritus. J Pediatr Surg. 1998;33:220–4. [PubMed: 9498390]
  40. Honda A, Salen G, Shefer S, Batta AK, Honda M, Xu G, Tint GS, Matsuzaki Y, Shoda J, Tanaka N. Bile acid synthesis in the Smith-Lemli-Opitz syndrome: effects of dehydrocholesterols on cholesterol 7alpha-hydroxylase and 27- hydroxylase activities in rat liver. J Lipid Res. 1999;40:1520–8. [PubMed: 10428990]
  41. Hori T, Egawa H, Takada Y, Ueda M, Oike F, Ogura Y, Sakamoto S, Kasahara M, Ogawa K, Miyagawa-Hayashino A, Yonekawa Y, Yorifuji T, Watanabe K, Doi H, Nguyen JH, Chen F, Baine AM, Gardner LB, Uemoto S. Progressive familial intrahepatic cholestasis: a single-center experience of living-donor liver transplantation during two decades in Japan. Clin Transplant. 2011;25:776–85. [PubMed: 21158920]
  42. Huster D, Schubert C, Achenbach H, Caca K, Mössner J, Berr F. Successful clinical application of extracorporal albumin dialysis in a patient with benign recurrent intrahepatic cholestasis (BRIC). Z Gastroenterol. 2001;39 Suppl 2:13–4. [PubMed: 16215886]
  43. Ismail H, Kalicinski P, Markiewicz M, Jankowska I, Pawlowska J, Kluge P, Eliadou E, Kaminski A, Szymczak M, Drewniak T, Revillon Y. Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion. Pediatr Transplant. 1999;3:219–24. [PubMed: 10487283]
  44. Jacquemin E, Malan V, Rio M, Davit-Spraul A, Cohen J, Landrieu P, Bernard O. Heterozygous FIC1 deficiency: a new genetic predisposition to transient neonatal cholestasis. J Pediatr Gastroenterol Nutr. 2010;50:447–9. [PubMed: 20216097]
  45. Jara P, Hierro L, Martínez-Fernández P, Alvarez-Doforno R, Yánez F, Diaz MC, Camarena C, De la Vega A, Frauca E, Muñoz-Bartolo G, López-Santamaría M, Larrauri J, Alvarez L. Recurrence of bile salt export pump deficiency after liver transplantation. N Engl J Med. 2009;361:1359–67. [PubMed: 19797282]
  46. Kajiwara E, Akagi K, Tsuji H, Murai K, Fujishima M. Low activity of gamma-glutamyl transpeptidase in serum of acute intrahepatic cholestasis. Enzyme. 1991;45:39–46. [PubMed: 1687217]
  47. Kalicinski PJ, Ismail H, Jankowska I, Kaminski A, Pawlowska J, Drewniak T, Markiewicz M, Szymczak M. Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal bypass. Eur J Pediatr Surg. 2003;13:307–11. [PubMed: 14618520]
  48. Keitel V, Burdelski M, Vojnisek Z, Schmitt L, Häussinger D, Kubitz R. De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis. Hepatology. 2009;50:510–7. [PubMed: 19642168]
  49. Klomp LW, Bull LN, Knisely AS, van Der Doelen MA, Juijn JA, Berger R, Forget S, Nielsen IM, Eiberg H, Houwen RH. A missense mutation in FIC1 is associated with greenland familial cholestasis. Hepatology. 2000;32:1337–41. [PubMed: 11093741]
  50. Klomp LW, Vargas JC, van Mil SW, Pawlikowska L, Strautnieks SS, van Eijk MJ, Juijn JA, Pabon-Pena C, Smith LB, DeYoung JA, Byrne JA, Gombert J, van der Brugge G, Berger R, Jankowska I, Pawlowska J, Villa E, Knisely AS, Thompson RJ, Freimer NB, Houwen RH, Bull LN. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology. 2004;40:27–38. [PubMed: 15239083]
  51. Knisely AS. Progressive familial intrahepatic cholestasis: an update. Pediatr Dev Pathol. 2004;7:309–14. [PubMed: 15383927]
  52. Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, Bull LN, Pawlikowska L, Bilezikçi B, Ozçay F, László A, Tiszlavicz L, Moore L, Raftos J, Arnell H, Fischler B, Németh A, Papadogiannakis N, Cielecka-Kuszyk J, Jankowska I, Pawłowska J, Melín-Aldana H, Emerick KM, Whitington PF, Mieli-Vergani G, Thompson RJ. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology. 2006;44:478–86. [PubMed: 16871584]
  53. Kocoshis SA, Van Damme-Lombaerts R, Roskams T, Hupertz VF, Mazariegos GV, Squires RF, Bull LN, Knisely AS. Clonidine administration ameliorates diarrhea after liver transplantation in severe FIC1 / ATP8B1 disease (progressive familial intrahepatic cholestasis, type 1). Hepatology. 2005;42:474A–5A.
  54. Kurbegov AC, Setchell KD, Haas JE, Mierau GW, Narkewicz M, Bancroft JD, Karrer F, Sokol RJ. Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile. Gastroenterology. 2003;125:1227–34. [PubMed: 14517804]
  55. Liu LY, Wang XH, Wang ZL, Zhu QR, Wang JS. Characterization of ATP8B1 gene mutations and a hot-linked mutation found in Chinese children with progressive intrahepatic cholestasis and low GGT. Pediatr Gastroenterol Nutr. 2010;50:179–83. [PubMed: 20038848]
  56. Lykavieris P, van Mil S, Cresteil D, Fabre M, Hadchouel M, Klomp L, Bernard O, Jacquemin E. Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation. J Hepatol. 2003;39:447–52. [PubMed: 12927934]
  57. Maggiore G, Gonzales E, Sciveres M, Redon MJ, Grosse B, Stieger B, Davit-Spraul A, Fabre M, Jacquemin E. Relapsing features of bile salt export pump deficiency after liver transplantation in two patients with progressive familial intrahepatic cholestasis type 2. J Hepatol. 2010;53:981–6. [PubMed: 20800306]
  58. Martinez-Fernandez P, Hierro L, Jara P, Alvarez L. Knockdown of ATP8B1 expression leads to specific downregulation of the bile acid sensor FXR in HepG2 cells: effect of the FXR agonist GW4064. Am J Physiol Gastrointest Liver Physiol. 2009;296:G1119–29. [PubMed: 19228886]
  59. Matte U, Mourya R, Miethke A, Liu C, Kauffmann G, Moyer K, Zhang K, Bezerra JA. Analysis of gene mutations in children with cholestasis of undefined etiology. J Pediatr Gastroenterol Nutr. 2010;51:488–93. [PMC free article: PMC4090691] [PubMed: 20683201]
  60. Melter M, Rodeck B, Kardorff R, Hoyer PF, Petersen C, Ballauff A, Brodehl J. Progressive familial intrahepatic cholestasis: partial biliary diversion normalizes serum lipids and improves growth in noncirrhotic patients. Am J Gastroenterol. 2000;95:3522–8. [PubMed: 11151888]
  61. Miyagawa-Hayashino A, Egawa H, Yorifuji T, Hasegawa M, Haga H, Tsuruyama T, Wen MC, Sumazaki R, Manabe T, Uemoto S. Allograft steatohepatitis in progressive familial intrahepatic cholestasis type 1 after living donor liver transplantation. Liver Transpl. 2009;15:610–18. [PubMed: 19479804]
  62. Mizuochi T, Kimura A, Tanaka A, Muto A, Nittono H, Seki Y, Takahashi T, Kurosawa T, Kage M, Takikawa H, Matsuishi T. Characterization of urinary bile acids in a pediatric BRIC-1 patient: effect of rifampicin treatment. Clin Chim Acta. 2012;413:1301–4. [PubMed: 22525741]
  63. Mullenbach R, Bennett A, Tetlow N, Patel N, Hamilton G, Cheng F, Chambers J, Howard R, Taylor-Robinson SD, Williamson C. ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy. Gut. 2005;54:829–34. [PMC free article: PMC1774530] [PubMed: 15888793]
  64. Müller T, Hess MW, Schiefermeier N, Pfaller K, Ebner HL, Heinz-Erian P, Ponstingl H, Partsch J, Röllinghoff B, Köhler H, Berger T, Lenhartz H, Schlenck B, Houwen RJ, Taylor CJ, Zoller H, Lechner S, Goulet O, Utermann G, Ruemmele FM, Huber LA, Janecke AR. MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity. Nat Genet. 2008;40:1163–5. [PubMed: 18724368]
  65. Nagasaka H, Chiba H, Hui SP, Takikawa H, Miida T, Takayanagi M, Yorifuji T, Hasegawa M, Ota A, Hirano K, Kikuchi H, Tsukahara H, Kobayashi K. Depletion of high-density lipoprotein and appearance of triglyceride-rich low-density lipoprotein in a Japanese patient with FIC1 deficiency manifesting benign recurrent intrahepatic cholestasis. J Pediatr Gastroenterol Nutr. 2007;45:96–105. [PubMed: 17592371]
  66. Nagasaka H, Yorifuji T, Egawa H, Yanai H, Fujisawa T, Kosugiyama K, Matsui A, Hasegawa M, Okada T, Takayanagi M, Chiba H, Kobayashi K. Evaluation of risk for atherosclerosis in Alagille syndrome and progressive familial intrahepatic cholestasis: two congenital cholestatic diseases with different lipoprotein metabolisms. J Pediatr. 2005;146:329–35. [PubMed: 15756213]
  67. Nagasaka H, Yorifuji T, Hirano K, Ota A, Toyama-Nakagawa Y, Takatani T, Tsukahara H, Kobayashi K, Takayanagi M, Inomata Y, Uemoto S, Miida T. Effects of bezafibrate on dyslipidemia with cholestasis in children with familial intrahepatic cholestasis-1 deficiency manifesting progressive familial intrahepatic cholestasis. Metabolism. 2009;58:48–54. [PubMed: 19059530]
  68. Nagasaka H, Yorifuji T, Kosugiyama K, Egawa H, Kawai M, Murayama K, Hasegawa M, Sumazaki R, Tsubaki J, Kikuta H, Matsui A, Tanaka K, Matsuura N, Kobayashi K. Resistance to parathyroid hormone in two patients with familial intrahepatic cholestasis: possible involvement of the ATP8B1 gene in calcium regulation via parathyroid hormone. J Pediatr Gastroenterol Nutr. 2004;39:404–9. [PubMed: 15448432]
  69. Nicastro E, Stephenne X, Smets F, Fusaro F, de Magnée C, Reding R, Sokal EM. Recovery of graft steatosis and protein-losing enteropathy after biliary diversion in a PFIC 1 liver transplanted child. Pediatr Transplant. 2012;16:E177–82. [PubMed: 21672103]
  70. Nielsen IM, Eiberg H. Cholestasis Familiaris Groenlandica: an epidemiological, clinical and genetic study. Int J Circumpolar Health. 2004;63 Suppl 2:192–4. [PubMed: 15736650]
  71. Nielsen IM, Ornvold K, Jacobsen BB, Ranek L. Fatal familial cholestatic syndrome in Greenland Eskimo children. Acta Paediatr Scand. 1986;75:1010–6. [PubMed: 3564958]
  72. Ooi BC, Phua KB, Lee BL, Tan CE, Ng IS, Quak SH. Lichenification and enlargement of hands and feet: a sign of progressive familial intrahepatic cholestasis with normal gamma- glutamyl-transpeptidase. J Pediatr Gastroenterol Nutr. 2001;32:219–23. [PubMed: 11321400]
  73. Ornvold K, Nielsen IM, Poulsen H. Fatal familial cholestatic syndrome in Greenland Eskimo children. A histomorphological analysis of 16 cases. Virchows Arch A Pathol Anat Histopathol. 1989;415:275–81. [PubMed: 2503928]
  74. Painter JN, Savander M, Ropponen A, Nupponen N, Riikonen S, Ylikorkala O, Lehesjoki AE, Aittomaki K. Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy. Eur J Hum Genet. 2005;13:435–9. [PubMed: 15657619]
  75. Pauli-Magnus C, Stieger B, Meier Y, Kullak-Ublick GA, Meier PJ. Enterohepatic transport of bile salts and genetics of cholestasis. J Hepatol. 2005;43:342–57. [PubMed: 15975683]
  76. Paulusma CC, Groen A, Kunne C, Ho-Mok KS, Spijkerboer AL, Rudi de Waart D, Hoek FJ, Vreeling H, Hoeben KA, van Marle J, Pawlikowska L, Bull LN, Hofmann AF, Knisely AS, Oude Elferink RP. Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport. Hepatology. 2006;44:195–204. [PubMed: 16799980]
  77. Pawlikowska L, Groen A, Eppens EF, Kunne C, Ottenhoff R, Looije N, Knisely AS, Killeen NP, Bull LN, Elferink RP, Freimer NB. A mouse genetic model for familial cholestasis caused by ATP8B1 mutations reveals perturbed bile salt homeostasis but no impairment in bile secretion. Hum Mol Genet. 2004;13:881–92. [PubMed: 14976163]
  78. Pawlikowska L, Strautnieks S, Jankowska I, Czubkowski P, Emerick K, Antoniou A, Wanty C, Fischler B, Jacquemin E, Wali S, Blanchard S, Nielsen IM, Bourke B, McQuaid S, Lacaille F, Byrne JA, van Eerde AM, Kolho KL, Klomp L, Houwen R, Bacchetti P, Lobritto S, Hupertz V, McClean P, Mieli-Vergani G, Shneider B, Nemeth A, Sokal E, Freimer NB, Knisely AS, Rosenthal P, Whitington PF, Pawlowska J, Thompson RJ, Bull LN. Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol. 2010;53:170–8. [PMC free article: PMC3042805] [PubMed: 20447715]
  79. Peters J, Lacaille F, Horslen S, Thompson RJ, Jaffe R, Brousse N, Wisecarver J, Knisely AS. Microvillus inclusion disease treated by small bowel transplantation: Development of progressive intrahepatic cholestasis with low serum concentrations of g-glutamyl transpeptidase activity. Hepatology. 2001;34:213A.
  80. Ray NB, Durairaj L, Chen BB, McVerry BJ, Ryan AJ, Donahoe M, Waltenbaugh AK, O'Donnell CP, Henderson FC, Etscheidt CA, McCoy DM, Agassandian M, Hayes-Rowan EC, Coon TA, Butler PL, Gakhar L, Mathur SN, Sieren JC, Tyurina YY, Kagan VE, McLennan G, Mallampalli RK. Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia. Nat Med. 2010;16:1120–7. [PubMed: 20852622]
  81. Rebhandl W, Felberbauer FX, Turnbull J, Paya K, Barcik U, Huber WD, Whitington PF, Horcher E. Biliary diversion by use of the appendix (cholecystoappendicostomy) in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr. 1999;28:217–9. [PubMed: 9932861]
  82. Saich R, Collins P, Ala A, Standish R, Hodgson H. Benign recurrent intrahepatic cholestasis with secondary renal impairment treated with extracorporeal albumin dialysis. Eur J Gastroenterol Hepatol. 2005;17:585–8. [PubMed: 15827452]
  83. Sambrotta M, Strautnieks S, Papouli E, Rushton P, Clark BE, Parry DA, Logan CV, Newbury LJ, Kamath BM, Ling S, Grammatikopoulos T, Wagner BE, Magee JC, Sokol RJ, Mieli-Vergani G, Smith JD, Johnson CA, McClean P, Simpson MA, Knisely AS, Bull LN, Thompson RJ. Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet. 2014;46:326–8. [PMC free article: PMC4061468] [PubMed: 24614073]
  84. Savander M, Ropponen A, Avela K, Weerasekera N, Cormand B, Hirvioja ML, Riikonen S, Ylikorkala O, Lehesjoki AE, Williamson C, Aittomäki K. Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy. Gut. 2003;52:1025–9. [PMC free article: PMC1773695] [PubMed: 12801961]
  85. Scheimann AO, Strautnieks SS, Knisely AS, Byrne JA, Thompson RJ, Finegold MJ. Mutations in bile salt export pump (ABCB11) in two children with progressive familial intrahepatic cholestasis and cholangiocarcinoma. J Pediatr. 2007;150:556–9. [PubMed: 17452236]
  86. Schneider G, Paus TC, Kullak-Ublick GA, Meier PJ, Wienker TF, Lang T, van de Vondel P, Sauerbruch T, Reichel C. Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy. Hepatology. 2007;45:150–8. [PubMed: 17187437]
  87. Setchell KD, Heubi JE, Bove KE, O'Connell NC, Brewsaugh T, Steinberg SJ, Moser A, Squires RH. Liver disease caused by failure to racemize trihydroxycholestanoic acid: gene mutation and effect of bile acid therapy. Gastroenterology. 2003;124:217–32. [PubMed: 12512044]
  88. Setchell KD, Schwarz M, O'Connell NC, Lund EG, Davis DL, Lathe R, Thompson HR, Weslie Tyson R, Sokol RJ, Russell DW. Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease. J Clin Invest. 1998;102:1690–703. [PMC free article: PMC509117] [PubMed: 9802883]
  89. Siebold L, Dick AA, Thompson R, Maggiore G, Jacquemin E, Jaffe R, Strautnieks S, Grammatikopoulos T, Horslen S, Whitington PF, Shneider BL. Recurrent low gamma-glutamyl transpeptidase cholestasis following liver transplantation for bile salt export pump (BSEP) disease (posttransplant Recurrent BSEP disease). Liver Transpl. 2010;16:856–63. [PubMed: 20583290]
  90. Stapelbroek JM, Peters TA, van Beurden DH, Curfs JH, Joosten A, Beynon AJ, van Leeuwen BM, van der Velden LM, Bull L, Oude Elferink RP, van Zanten BA, Klomp LW, Houwen RH. ATP8B1 is essential for maintaining normal hearing. PNAS. 2009;106:9709–14. [PMC free article: PMC2700994] [PubMed: 19478059]
  91. Stapelbroek JM, van Erpecum KJ, Klomp LW, Venneman NG, Schwartz TP, van Berge Henegouwen GP, Devlin J, van Nieuwkerk CM, Knisely AS, Houwen RH. Nasobiliary drainage induces long-lasting remission in benign recurrent intrahepatic cholestasis. Hepatology. 2006;43:51–3. [PubMed: 16374853]
  92. Strautnieks S, Byrne J, Knisely A, Bull LN, Sokal E, Lacaile F, Vergani G, Thompson R. There must be a third locus for low GGT PFIC. Hepatology. 2001;34:240A.
  93. Strautnieks SS, Byrne JA, Pawlikowska L, Cebecauerová D, Rayner A, Dutton L, Meier Y, Antoniou A, Stieger B, Arnell H, Ozçay F, Al-Hussaini HF, Bassas AF, Verkade HJ, Fischler B, Németh A, Kotalová R, Shneider BL, Cielecka-Kuszyk J, McClean P, Whitington PF, Sokal E, Jirsa M, Wali SH, Jankowska I, Pawłowska J, Mieli-Vergani G, Knisely AS, Bull LN, Thompson RJ. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology. 2008;134:1203–14. [PubMed: 18395098]
  94. Tang X, Halleck MS, Schlegel RA, Williamson P. A subfamily of P-type ATPases with aminophospholipid transporting activity. Science. 1996;272:1495–7. [PubMed: 8633245]
  95. Tazawa Y, Yamada M, Nakagawa M, Konno T, Tada K. Bile acid profiles in siblings with progressive intrahepatic cholestasis: absence of biliary chenodeoxycholate. J Pediatr Gastroenterol Nutr. 1985;4:32–7. [PubMed: 3981365]
  96. Toros AB, Ozerdenen F, Bektaş H, Sari ND. A case report: nasobiliary drainage inducing remission in benign recurrent intrahepatic cholestasis. Turk J Gastroenterol. 2012;23:75–8. [PubMed: 22505385]
  97. Tygstrup N, Steig BA, Juijn JA, Bull LN, Houwen RH. Recurrent familial intrahepatic cholestasis in the Faeroe Islands. Phenotypic heterogeneity but genetic homogeneity. Hepatology. 1999;29:506–8. [PubMed: 9918928]
  98. Uegaki S, Tanaka A, Mori Y, Kodama H, Fukusato T, Takikawa H. Successful treatment with colestimide for a bout of cholestasis in a Japanese patient with benign recurrent intrahepatic cholestasis caused by ATP8B1 mutation. Intern Med. 2008;47:599–602. [PubMed: 18379143]
  99. Ujhazy P, Ortiz D, Misra S, Li S, Moseley J, Jones H, Arias IM. Familial intrahepatic cholestasis 1: studies of localization and function. Hepatology. 2001;34:768–75. [PubMed: 11584374]
  100. Usui M, Isaji S, Das BC, Kobayashi M, Osawa I, Iida T, Sakurai H, Tabata M, Yorifuji T, Egawa H, Uemoto S. Liver retransplantation with external biliary diversion for progressive familial intrahepatic cholestasis type 1: a case report. Pediatr Transplant. 2009;13:611–4. [PubMed: 18785905]
  101. van der Velden LM, Stapelbroek JM, Krieger E, van den Berghe PV, Berger R, Verhulst PM, Holthuis JC, Houwen RH, Klomp LW, van de Graaf SF. Folding defects in P-type ATP 8B1 associated with hereditary cholestasis are ameliorated by 4-phenylbutyrate. Hepatology. 2010;51:286–96. [PubMed: 19918981]
  102. van Mil SW, van der Woerd WL, van der Brugge G, Sturm E, Jansen PL, Bull LN, van den Berg IE, Berger R, Houwen RH, Klomp LW. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology. 2004a;127:379–84. [PubMed: 15300568]
  103. van Mil SW, van Oort MM, van den Berg IE, Berger R, Houwen RH, Klomp LW. Fic1 is expressed at apical membranes of different epithelial cells in the digestive tract and is induced in the small intestine during postnatal development of mice. Pediatr Res. 2004b;56:981–7. [PubMed: 15496606]
  104. van Ooteghem NA, Klomp LW, van Berge-Henegouwen GP, Houwen RH. Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum. J Hepatol. 2002;36:439–43. [PubMed: 11867191]
  105. Verhulst PM, van der Velden LM, Oorschot V, van Faassen EE, Klumperman J, Houwen RH, Pomorski TG, Holthuis JC, Klomp LW. A flippase-independent function of ATP8B1, the protein affected in familial intrahepatic cholestasis type 1, is required for apical protein expression and microvillus formation in polarized epithelial cells. Hepatology. 2010;51:2049–60. [PubMed: 20512993]
  106. Walensi M, Canbay A, Witzke O, Gerken G, Kahraman A. Long-term therapy of a patient with summerskill-walshe-tygstrup syndrome by applying prometheus® liver dialysis: a case report. Case Rep Gastroenterol. 2012;6:550–6. [PMC free article: PMC3433004] [PubMed: 22949896]
  107. Zhu QS, Xing W, Qian B, von Dippe P, Shneider BL, Fox VL, Levy D. Inhibition of human m-epoxide hydrolase gene expression in a case of hypercholanemia. Biochim Biophys Acta. 2003;1638:208–16. [PubMed: 12878321]

Chapter Notes

Author History

Laura N Bull, PhD (2001-present)
AS Knisely, MD (2001-present)
Benjamin L Shneider, MD (2006-present)
Kelly A Taylor, MS, CGC; Vanderbilt University (2001-2006)

Revision History

  • 20 March 2014 (me) Comprehensive update posted live
  • 13 August 2008 (cd) Revision: prenatal diagnosis available for ABCB11 mutations
  • 26 May 2006 (cd) Revision: prenatal testing available for 1660G>A (D554N) mutation in ATP8B1
  • 15 February 2006 (me) Comprehensive update posted to live Web site
  • 15 July 2003 (me) Comprehensive update posted to live Web site
  • 15 October 2001 (me) Review posted to live Web site
  • 24 April 2001 (kt) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1297PMID: 20301474
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...