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Low-GT Familial Intrahepatic Cholestasis

[Includes: ATP8B1-Related Intrahepatic Cholestasis; ABCB11-Related Intrahepatic Cholestasis]

Summary

Disease characteristics. Low-GT (gamma-glutamyltranspeptidase) familial intrahepatic cholestasis occurs as a spectrum ranging from severe to mild. Individuals with the severe forms of low-GT familial intrahepatic cholestasis (PFIC1 and PFIC2) typically begin to exhibit symptoms of cholestasis (pruritus and attacks of jaundice) within the first few months of life; secondary manifestations such as malabsorption, greasy stools, and poor weight gain may present earlier than three months of age. Initially episodes of severe cholestasis are followed by disease-free intervals; eventually, cholestasis becomes non-remitting. Pruritus is typically severe and persistent. Growth retardation becomes evident in early childhood. Cirrhosis, hepatic failure, and death usually ensue within the first two decades of life in the absence of surgical intervention. Benign recurrent intrahepatic cholestasis (BRIC1 and BRIC2) are the milder forms of low-GT familial intrahepatic cholestasis, and are characterized by episodes of cholestasis, severe pruritus, and jaundice; chronic liver damage does not develop. Some heterozygous women experience intrahepatic cholestasis of pregnancy (ICP), in which symptoms typically appear during the third trimester and resolve postpartum.

Diagnosis/testing. The diagnosis of PFIC1 and PFIC2 is primarily based on clinical and laboratory findings. Low-to-normal serum GT activity despite conjugated hyperbilirubinemia is the hallmark of PFIC1 and PFIC2, as GT activity is elevated in most types of cholestasis. Serum cholesterol concentration is low to normal. Serum concentration of total bile acids is elevated. Fast-atom bombardment ionization mass spectrometry (FAB-MS) analysis of urine shows normal bile acid species and indicates normal bile acid synthesis. Liver biopsy at initial presentation shows either bland intracanalicular cholestasis or "neonatal hepatitis" with portal-tract fibrosis and bile ductular proliferation; underlying hepatobiliary structural abnormalities are not present, but may develop over time. Either coarsely granular canalicular bile or amorphous canalicular bile may be found on transmission electron microscopy (TEM). PFIC1 is caused by mutations in the ATP8B1 gene (also termed FIC1); PFIC2 is caused by mutations in the ABCB11 gene (also termed BSEP). Although clinical, histopathologic, and ultrastructural differences between PFIC1 and PFIC2 have been observed, it is not possible to distinguish between the two without molecular genetic testing. Molecular genetic testing for mutations in the ATP8B1 and ABCB11 genes is available on a clinical basis.

Management. Low-GT familial intrahepatic cholestasis is generally refractory to medical treatment. Standard therapies for pruritus associated with cholestasis may be temporarily effective but in the long term are relatively ineffective. Nutritional therapy includes infant formulas with significant proportions of medium chain triglycerides, which can be absorbed relatively independent of bile flow. Fat-soluble vitamin supplementation using special preparations of vitamin E is useful in severe cholestasis. Partial biliary diversion (PBD) surgery in individuals with severe disease interrupts the enterohepatic circulation of bile acids and reduces pruritus; in some individuals it even slows or reverses progression to hepatic fibrosis. Types of PBD include cutaneous cholecystostomy, cholecysto-jejuno-cutaneostomy, and cholecysto-appendico-cutaneostomy. An alternative surgical procedure is ileal exclusion.

When liver disease progresses to cirrhosis or fails to respond to PBD, orthotopic liver transplantation (OLTX) is necessary for long-term survival; Bile acid chelators and clonidine may ameliorate diarrhea after OLTX. Surveillance for malignancy may include annual ultrasonography in children who have not undergone OLTX. Persons with mild ATP8B1-related intrahepatic cholestasis have responded to temporary catheterization of the common bile duct.

Genetic counseling.  Low-GT familial intrahepatic cholestasis is inherited in an autosomal recessive manner. The parents of a proband are generally obligate carriers of a disease-causing mutation. Intrahepatic cholestasis of pregnancy has been reported in the mothers of some individuals with severe ATP8B1-related intrahepatic cholestasis and PFIC of undetermined subtype. 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. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk family members is available on a clinical basis if the mutations have been identified in the proband. Prenatal testing is clinically available for families in which the 1660G>A (D554N) mutation in ATP8B1 has been identified. Prenatal testing for other mutations may be available through laboratories offering custom prenatal testing.

Diagnosis

Clinical Diagnosis

Low-GT (gamma-glutamyltranspeptidase) familial intrahepatic cholestasis occurs as a spectrum ranging from severe to mild. Forms intermediate to the better characterized severe and mild ends of the spectrum are also observed.

Severe forms.  Progressive familial intrahepatic cholestasis, types 1 and 2:

• Type 1 [PFIC1; severe FIC1 (familial intrahepatic cholestasis 1) deficiency] caused by mutations in ATP8B1

• Type 2 [PFIC2; severe BSEP (bile salt export pump) deficiency] caused by mutations in ABCB11

Mild forms.  Benign recurrent intrahepatic cholestasis, types 1 and 2:

• Type 1 [BRIC1; mild FIC1 (familial intrahepatic cholestasis 1) deficiency] caused by mutations in ATP8B1

• Type 2 [BRIC2; mild BSEP (bile salt export pump) deficiency] caused by mutations in ABCB11

Note: Deficiency of FIC1 or of BSEP is defined as "severe" or "mild" clinically, based upon the severity of a particular individual's illness. Laboratory testing results, including findings on liver biopsy, are taken into account when assessing severity.

The diagnosis of severe forms should be considered in children with primary evidence of cholestasis (severe pruritus and attacks of jaundice) and its secondary effects (progressive hepatic dysfunction and fibrosis/cirrhosis, growth retardation). Children with severe forms typically begin to exhibit symptoms of cholestasis within the first few months of life, while later presentation is typically observed in individuals with milder disease. Other clinical manifestations related to fat and fat-soluble vitamin malabsorption, including hemorrhage from vitamin K deficiency, greasy stools, and lack of weight gain, may present at variable ages including the newborn period. Severe forms eventually evolve to end-stage liver disease.

Milder forms may manifest as intrahepatic cholestasis with intermittent clinical manifestations.

Testing

Table 1. Liver Function Test Results in Low-GT Familial Intrahepatic Cholestasis Phenotype Serum GT Activity Serum Concentration of Cholesterol Serum Concentration of Total Bile Acids Serum Concentration of Conjugated Bilirubin Severe Low to normal  1 Low to normal  1 Markedly elevated High early with resolution and subsequent elevation with end-stage liver disease Mild Low to normal Usually low to normal during symptomatic periods Markedly elevated during symptomatic periods Normal between episodes; variable increases during symptomatic periods

1. Usually elevated in most other types of cholestatic liver disease

Fast atom bombardment ionization mass spectrometry (FAB-MS) analysis of urine.  Normal bile acid species, and hence normal bile acid synthesis

Analysis of bile (by gas chromatography/FAB-MS).  Depletion of dihydroxy-bile acid species (principally chenodeoxycholic acid) suggests PFIC.

Note: Such analysis should be conducted, if possible, when recent administration (within two weeks) of the exogenous dihydroxy-bile acid and choleretic ursodeoxycholic acid has not potentially confused the issue.

Other Tests

Concentration of electrolytes in sweat may be elevated.

Liver biopsy.  At initial presentation, individuals with progressive familial intrahepatic cholestasis do not have underlying hepatobiliary structural abnormalities; such abnormalities may develop as the disease evolves.

• Light microscopy of liver tissue from individuals with severe forms of progressive familial intrahepatic cholestasis at initial presentation shows either bland intracanalicular cholestasis or "neonatal hepatitis" with portal-tract fibrosis and bile ductular proliferation. As the disease progresses, liver biopsy demonstrates progressive fibrosis and, eventually, cirrhosis.

• Transmission electron microscopy (TEM) shows either coarsely granular canalicular bile or amorphous canalicular bile.

Note: It appears that individuals with coarsely granular bile typically have "bland intracanalicular cholestasis" at presentation, while individuals with amorphous bile typically have "neonatal hepatitis" with portal-tract fibrosis and bile ductular proliferation at presentation. These features have tentatively been correlated with PFIC1 and PFIC2 respectively [Bull et al 1997 , Chen et al 2002 , Chen et al 2004]; further studies to evaluate such associations definitively are underway.

Immunohistochemical and molecular-biologic studies to document absence of gene product within hepatocytes or elsewhere are research tools at present. Testing for absence of mRNA or protein in appropriate tissues (FIC1 in liver or intestine - BSEP in liver) may yield a specific diagnosis in individuals with mutations associated with marked reduction in steady-state mRNA or protein levels.

• How specifically such studies can establish that primary defects in ATP8B1 or ABCB11 underlie the absence of gene product is not yet known. It may be that defects in other genes, or defects in the processing of the gene product owing to acquired disease, can produce partial phenocopies. When BSEP cannot be identified in persons with PFIC, correlation with demonstrated mutation in ABCB11 has been near-uniform [Jansen et al 1999]. BSEP expression also has been found in samples from individuals with PFIC known to be caused by a mutation in ATP8B1 [Alvarez et al 2004].
• Parallel studies with respect to FIC1 have yet to be conducted. Unlike BSEP, FIC1 is expressed in a wide range of tissues, so testing of protein and/or mRNA expression may be possible in non-hepatic tissue samples.
• The expression of immunohistochemically demonstrable gene product in forms of BRIC has yet to be evaluated. Ultrastructural observations in BRIC suggest similarities between PFIC1 and BRIC1, as well as between PFIC2 and BRIC2, but these are anecdotal.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory's work; listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. —ED.

Genes.  Two genes are associated with low-GT familial intrahepatic cholestasis:

• ATP8B1 (FIC1 deficiency / disease)
• ABCB11 (BSEP deficiency / disease)

Other loci.   Some individuals diagnosed on clinical and histopathologic evidence as having PFIC1 or BRIC do not show linkage to either ATP8B1 or ABCB11, indicating the existence of additional disease loci [Bull et al 1997 , Floreani et al 2000 , Strautnieks et al 2001 , Carlton et al 2003].

Molecular genetic testing: Clinical uses

• Confirmation of diagnosis
• Carrier detection
• Prenatal diagnosis

Molecular genetic testing: Clinical methods

• ATP8B1.  Over 50 distinct mutations in ATP8B1 have been reported in PFIC1 [Bull et al 1998 , Klomp et al 2000 , Egawa et al 2002 , Chen et al 2002 , Klomp et al 2004].

  • Individuals of Amish ancestry (in whom the disease was originally described [Clayton et al 1969]) are homozygous for a 923G>T / G308V mutation [Bull et al 1998].
  • Affected individuals of Inuit ancestry from eastern Nunavut (the Canadian Arctic) and both West and East Greenland are homozygous for a 1660G>A / D554N mutation [Klomp et al 2000].
  • Affected individuals of Dominican ancestry have been found to be homozygous for a 1993G>T / E665X mutation [Klomp et al 2004].
  • Most individuals of European descent with BRIC in whom ATP8B1 mutations are identified have the 1982T>C / I661T mutation on one or both alleles [Bull et al 1998 , Tygstrup et al 1999 , Klomp et al 2004].
  • To date, other mutations in ATP8B1 have been detected in persons from only one or a small number of families each.

• ABCB11.  Various mutations in ABCB11 have been reported in individuals with BSEP deficiency [Strautnieks et al 1998 , Jansen et al 1999 , Chen et al 2002 , Goto et al 2003 , Knisely et al 2005].

Table 2 summarizes molecular genetic testing for this disorder.

Table 2. Molecular Genetic Testing Used in Low-GT Familial Intrahepatic Cholestasis Test Method Population Mutations Detected Mutation Detection Rate Test Availability Sequence analysis Amish with severe disease G308V mutation in ATP8B1 100% Clinical Inuit  1 with severe disease D554N mutation in ATP8B1 100% Dominican with severe disease E665X mutation in ATP8B1 Unknown European with mild disease I661T Unknown; to date, found in ~80% of European-origin individuals with BRIC1  2 All others ATP8B1 sequence alterations Unknown ABCB11 sequence alterations Clinical

1. Klomp et al 2000 , Eiberg et al 2004 , Nielsen & Eiberg 2004 2. Most individuals with BRIC of European ancestry in whom an ATP8B1 mutation was identified have this mutation on at least one allele; also occasionally detected in compound heterozygous form in individuals with more severe disease.

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy for a Proband

1. Standard liver function tests including serum GT activity, serum cholesterol concentration, and serum bile acid concentration

   Note: Bilirubin levels may not be an accurate marker of cholestasis. Highly elevated aminotransferase-activity values at presentation may suggest BSEP disease rather than FIC1 disease; this point is under study.

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 two weeks after withdrawal of UDCA). Liver tissue should be examined by light microscopy. If at all possible, a sample of liver tissue should be snap-frozen at bedside for eventual molecular-biologic studies and a sample should be primarily fixed for transmission electron microscopy.

   Note: Liver biopsy may not be necessary if a sibling has been definitively diagnosed.

4. Molecular genetic testing

   • In certain populations (Amish, Inuit), mutation detection can replace steps 1-3 above.
   • Within a sibship, mutation detection can replace steps 1-3 above if disease-associated mutations have already been identified in one affected individual.
   • Until chip-based testing for candidate genes is in use, for most individuals (other than those in the groups identified immediately above), selection of which gene to screen will continue to depend on results of clinical laboratory, histopathologic, and (perhaps) expression studies, as definitive screening for mutations is expected to be both time consuming and expensive.

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in ATP8B1 and ABCB11.

Clinical Description

Natural History

Severe Forms of Low-GT Familial Intrahepatic Cholestasis

The age and mode of onset of symptoms vary in individuals with PFIC. Affected children typically present in the first year of life with severe pruritus with or without jaundice. The onset of pruritus is difficult to pinpoint because detection depends upon an infant's ability to scratch in a coordinated manner. Irritability may be an initial manifestation of pruritus in some infants. In some children, the initial symptom is loose, foul-smelling, greasy stools, usually present from birth. 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, hepatosplenomegaly may develop.

Growth retardation becomes evident in early childhood.

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. Significant morbidity and mortality may result from complications of nutritional deficiencies (especially hemorrhage secondary to vitamin K deficiency).

Hepatocellular carcinoma was reported at between two and three years of age in several individuals with genetically undefined PFIC [Alonso et al 1994 , Moore et al 1997]. Follow-up studies reveal that some [Sándorf et al 1976 , Moore et al 1997] but not all [Ugarte & Gonzalez-Crussi 1981] of these instances of hepatocellular carcinoma can be attributed to severe BSEP deficiency [Knisely et al 2005].

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 (resulting from vitamin E deficiency). Episodes of epistaxis (in the absence of a coagulopathy or thrombocytopenia) may occur. Significant skin excoriations, caused by constant scratching, often occur.

Coarsened, stubby hands and fingers have been reported in individuals with genetically undefined PFIC [Ooi et al 2001].

Although it has been thought that the abnormalities in severe FIC1 and BSEP deficiency are restricted to the liver, data suggest that, at least in some individuals, pancreatic and intestinal function may be abnormal as well. This is evidenced by the observation, in some individuals with severe FIC1 deficiency, of post-transplant secretory diarrhea, pancreatitis, and persistence of growth retardation [Knisely 2004 , Lykavieris et al 2003]. Post-transplant steatohepatitis may also occur in individuals with FIC1 disease.

Some individuals with PFIC have sensorineural hearing loss.

Although onset in the first year of life, with progression to cirrhosis by the end of the first decade of life, is the typical course in children with severe FIC1 and BSEP disease, variability has been noted. Whitington et al (1994) reported children with rapidly progressive cholestasis leading to cirrhosis within the first year of life, as well as two children who exhibited few symptoms of cholestasis until their teenage years. In the latter two cases, BRIC could have been suspected; however, both individuals had siblings with typical PFIC. (Of note, it is unknown whether the two individuals had FIC1 deficiency, BSEP deficiency, or an as-yet genetically uncharacterized form of PFIC.) In addition, once severe cholestasis was evident, they had a progressive course typical of PFIC. Thus, both more severe and milder forms of PFIC exist, as evidenced by these clinical observations. This conclusion is supported by the fact that cases of PFIC, BRIC, and disease of intermediate severity can each be caused by mutations in the same genes, ATP8B1 [Bull et al 1998 , Chen et al 2002 , Egawa et al 2002 , van Ooteghem et al 2002] or ABCB11 [Strautnieks et al 1998 ; van Mil, van der Woerd et al 2004].

Mild Forms of Low-GT Familial Intrahepatic Cholestasis

Benign recurrent intrahepatic cholestasis (BRIC).  Mutations in ATP8B1 account for some cases of BRIC [Sinke et al 1997 , Bull et al 1998 , Floreani et al 2000]. BRIC is characterized by episodes of cholestasis, severe pruritus, and jaundice without extrahepatic bile duct obstruction. Episodes may last from weeks to months. Symptom-free intervals may last from months to years. Chronic liver damage does not develop. BRIC can be distinguished from PFIC only by long-term clinical monitoring or by liver biopsy; if hepatic fibrosis is present, BRIC is excluded. Disease of intermediate severity (in terms of both clinical presentation and anatomic-pathologic findings) between BRIC and PFIC is being recognized [van Ooteghem et al 2002 ; van Mil, van der Woerd et al 2004].

Intrahepatic cholestasis of pregnancy (ICP).  Obligate carriers of ATP8B1 mutations have been reported to experience ICP [Clayton et al 1969 , Bull et al 1998] as have obligate carriers from families in which ATP8B1 and ABCB11 status has not been evaluated [Whitington et al 1994]. Putative ABCB11 or ATP8B1 mutations have been identified in a small proportion of women affected with ICP from families in which PFIC has not been diagnosed [Pauli-Magnus et al 2004 , Mullenbach et al 2005 , Painter et al 2005]. Both low-GT and high-GT ICP are characterized by cholestasis, pruritus, and sometimes jaundice during pregnancy. Symptoms typically appear during the third trimester and resolve spontaneously postpartum; ICP confers an increased risk of fetal complications. Affected women generally do not experience symptoms between pregnancies and do not develop chronic liver damage.

Genotype-Phenotype Correlations

Correlation between FIC1 and BSEP.  Although significant phenotypic overlap between FIC1 and BSEP disease occurs, clinical, biochemical, histopathologic, and ultrastructural differences have been noted. It is unknown at this time if clinical, biochemical, histopathologic, or ultrastructural differences among individuals with different ATP8B1 mutations and/or among individuals with different ABCB11 mutations result from the effect of different mutations on gene function, or are the result of other genetic and/or environmental factors. Thorough studies correlating genotype and phenotype are needed to confirm these observations.

• Bull et al (1997) reported differences in liver tissue (on light microscopy and TEM) and bile acid composition among individuals with PFIC1 whose disease was linked to 18q21-q22 and individuals whose disease was not.
• Nine individuals (all Amish, seven known to be members of the Byler kindred in which PFIC was first described) whose disease was linked to 18q21-q22 (presumed to have ATP8B1 mutation[s]) had coarsely granular bile and, at presentation, bland intracanalicular cholestasis, while four individuals (two sets of siblings) whose disease was not linked to 18q21-q22 had amorphous or finely filamentous bile and, at presentation, "neonatal hepatitis."
• Two of the nine individuals with disease linked to 18q21-q22 and one pair of siblings with disease not linked to this locus were reported to have a concentration of chenodeoxycholic acid in bile that was lower than normal, while the other two siblings were reported to have a concentration of chenodeoxycholic acid in bile that was only slightly reduced. Evidence now suggests that differences on microscopy of liver in individuals with PFIC1 and PFIC2 correlate with mutations in ATP8B1 or ABCB11. Depletion of chenodeoxycholic acid in bile, however, appears common to individuals with PFIC1 and individuals with PFIC2.
• It has been suggested that individuals with PFIC1 can develop pancreatitis, steatohepatitis, and secretory diarrhea in the absence of steatorrhea after orthotopic liver transplantation (OLTX), while individuals with PFIC2 do not.
• Growth retardation in individuals with PFIC1 may not resolve after OLTX [Knisely 2004 , Lykavieris et al 2003].

Severe versus mild disease.  In individuals with severe BSEP disease, usually little BSEP can be demonstrated in tissue specimens. Such studies have yet to be systematically carried out for FIC1 disease.

Often, but not always, severity or mildness of disease can be predicted if a mutation is known. Family members with the same mutations in the same genes do not always have disease of the same clinical severity. In addition, clinical severity can change. A child with mild disease, diagnosed as having BRIC1 or BRIC2, may in adulthood develop severe disease that would be better classified as PFIC1 or PFIC2.

Nomenclature

In general, nomenclature for the conditions described in this GeneReview is problematic and is expected to undergo change in the ensuing years.

Severe FIC1 deficiency in individuals of Amish ancestry was previously called Byler disease, after the kindred in which PFIC was first described.

Severe FIC1 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 exact prevalence of low-GT familial intrahepatic cholestasis is unknown. It has been considered rare, but misdiagnosis or imprecision in diagnosis in the past may have contributed to an underestimation of its prevalence. First described as Byler's disease in children of Amish descent [Clayton et al 1969], it has now been described in individuals of all races and many ethnicities. Outside certain restricted demes (the Amish, the Inuit), no specific population seems to be at a higher risk for either FIC1 or BSEP deficiency, although population-specific mutations may exist.

Carrier frequencies for low-GT familial intrahepatic cholestasis are unknown, except among the Greenland Inuit, in whom the carrier frequency of the D554N mutation in FIC1 appears to be quite high. A population study indicates 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 a high of 0.16 in Ittoqqortoormiit [Eiberg & Nielsen 1993 , Eiberg et al 2004 , Nielsen & Eiberg 2004].

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Numerous specific causes of childhood cholestasis exist, some of them heritable. Most of them, however, are associated with high serum GT activity during cholestatic periods and can be eliminated from differential diagnostic consideration on this basis. Unlike most other forms of infantile or childhood cholestasis, low-GT familial intrahepatic cholestasis is associated with serum GT activity and cholesterol concentrations that are normal or disproportionately low when compared with serum bile acid concentration.

Disorders with low serum GT activity during cholestasis include:

• Inborn errors of bile acid biosynthesis.  Synthesis of cholic and chenodeoxycholic acids (the principal bile acids in people) from cholesterol has 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 [Clayton et al 1987 , Setchell et al 1988 , Buchmann et al 1990 , Jacquemin et al 1994 , Setchell et al 1998 , Honda et al 1999 , Bove et al 2000 , Clayton et al 2002 , Grange et al 2002 , Setchell et al 2003].

• Familial hypercholanemia (FHC) is a newly identified disorder with the hallmark feature of fluctuating, but often extremely elevated, concentrations of bile acids in serum. Individuals often manifest pruritus, malabsorption of fat-soluble vitamins, and failure to thrive. Most do not become jaundiced. Causative mutations in three genes, TJP2, BAAT, and EPHX1, have been identified [Carlton et al 2003 , Zhu et al 2003]. BAAT encodes an enzyme involved in bile acid conjugation; defects in bile acid conjugation can be identified biochemically.

• 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 GT, and ichthyosis [Eastham et al 2001]. Mutations in VPS33B have been identified in individuals with ARC syndrome [Gissen et al 2004]. In general, the extrahepatic findings strongly suggest the clinical diagnosis [Bull et al 2006].

• Smith-Lemli-Opitz syndrome (SLOS) can secondarily lead to low-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-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, 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 low-GT familial intrahepatic cholestasis; 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.

• Microvillus inclusion disease (MVID).  In individuals with MVID, it appears that disordered surface membranes in the biliary tract lessen the access of bile to GT, which is not eluted into bile and cannot reflux into plasma. Since treatment-refractory diarrhea is a feature of MVID and may be a feature of low-GT familial intrahepatic cholestasis, light and TEM of small-bowel mucosa biopsy specimens may be required to evaluate apical enterocytes for deficient brush border and intracytoplasmic microvillus-lined inclusions [Peters et al 2001].

Management

Evaluations at Initial Diagnosis to Establish the Extent of Disease

Standard biochemical liver testing, imaging, and biopsy should be performed to assess the degree of liver disease associated with low-GT familial intrahepatic cholestasis.

Particular attention should be paid to assessing for evidence of portal hypertension as this finding may have implications for possible surgical interventions.

Treatment of Manifestations

Medical therapy.  Although various medical therapies have been tried in individuals with severe low-GT familial intrahepatic cholestasis to alleviate symptoms and to stop or reverse the progression of liver damage, these disorders have, for the most part, been refractory to medical treatment. Standard therapies 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 controlling the pruritus associated with PFIC [Whitington et al 1994]. In addition, no data suggest that these therapies alter the progression to end-stage liver disease.

Special attention needs to be paid to nutritional therapy for individuals with PFIC. Infant formulas should contain significant proportions of medium-chain triglycerides, which can be absorbed relatively independent of bile flow. Fat-soluble vitamin supplementation using special preparations of vitamin E (tocopherol polyethylene glycol succinate [TPGS]) can be especially useful in severe cholestasis.

Surgical therapy

• Partial biliary diversion (PBD).  Since liver damage in severe low-GT familial intrahepatic cholestasis is thought to result from a build-up of bile acids in the liver, surgery to interrupt enterohepatic circulation of bile acids has been used in individuals with severe low-GT familial intrahepatic cholestasis. Studies have shown such surgery to be successful in reducing pruritus, with slowed or even reversed progression to hepatic fibrosis in some individuals with severe disease [Felberbauer et al 2000 , van Ooteghem et al 2002]. Methods of interrupting the enterohepatic circulation of bile acids reported successful in severe low-GT familial intrahepatic cholestasis include cutaneous cholecystostomy, cholecysto-jejuno-cutaneostomy, cholecysto-appendico-cutaneostomy, and the internal diversion approach of ileal exclusion [Emond & Whitington 1995 , Hollands et al 1998 , Ismail et al 1999 , Rebhandl et al 1999 , Melter et al 2000]. The value of analyses of relative efficacy of various forms of PBD in severe low-GT familial intrahepatic cholestasis [Kalicinski et al 2003] and of descriptions of change, after PBD in PFIC, in hepatic architecture and bile composition [Kurbegov et al 2003] is vitiated by failure to correlate observations with genetic findings.

• Nasobiliary diversion.  Persons with mild ATP8B1-related intrahepatic cholestasis have responded (with rapid resolution of cholestatic episodes) to temporary catheterization of the common bile duct with transnasal catheter drainage. Whether this approach is effective in mild ABCB11-related intrahepatic cholestasis has not been assessed [Stapelbroek et al 2006].

Orthotopic liver transplantation (OLTX).  Individuals with severe low-GT familial intrahepatic cholestasis whose liver disease progresses to cirrhosis require OLTX for long-term survival. In addition, individuals who are not responsive to surgical interruption of the enterohepatic circulation may also be candidates for liver transplantation. In some individuals with severe low-GT familial intrahepatic cholestasis, OLTX is a definitive therapy. However, in others, secretory diarrhea in the absence of steatorrhea has been observed to continue after OLTX, and in some, growth retardation persists [Knisely 2004 , Lykavieris et al 2003]. Pancreatitis and steatohepatitis can occur after otherwise successful OLTX. OLTX carries with it problems of its own, following in particular from the immunosuppression necessary for allograft survival.

Prevention of Primary Manifestations

It has been suggested that surgical interruption of the enterohepatic circulation should be the primary therapy in individuals with severe low-GT familial intrahepatic cholestasis unless cirrhosis is present or unless hepatic fibrosis progresses in spite of biliary diversion [Emond & Whitington 1995]. Long-term follow-up is necessary to determine if this surgery can preclude the need for liver transplantation in some individuals. The effects of this surgery on the long-term risk of developing hepatocellular carcinoma are not known, although most clinicians feel the risk is markedly reduced after successful surgery.

Prevention of Secondary Complications

Vitamin supplementation (see above) is necessary to alleviate malabsorption of fat-soluble vitamins.

Bile acid chelators [Egawa et al 2002] and clonidine [Kocoshis et al 2005] may ameliorate diarrhea after OLTX.

Surveillance

Although no specific recommendations currently exist regarding serologic or imaging-study monitoring for hepatocellular carcinoma in individuals with severe low-GT familial intrahepatic cholestasis, appropriate clinical management should address the risk of malignancy. Although not proven to be completely effective, annual surveillance ultrasonography in children with their native liver and low-GT cholestasis may be reasonable.

Testing of Relatives at Risk

Clinically significant PFIC is rarely silent and thus individuals who have evidence of cholestasis should undergo assessment similar to that provided the proband.

Therapies Under Investigation

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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

Low-GT familial intrahepatic cholestasis is inherited in an autosomal recessive manner.

Risk to Family Members

This section is written from the perspective that molecular genetic testing for this disorder is available on a research basis only and results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis. —ED.

Parents of a proband

• The parents of a proband are generally obligate carriers of a disease-causing mutation.
• Intrahepatic cholestasis of pregnancy (ICP) has been reported in the mothers of some individuals with severe ATP8B1-related intrahepatic cholestasis [Clayton et al 1969 , Bull et al 1998] and PFIC of undetermined subtype [Whitington et al 1994]. Putative ABCB11 or ATP8B1 mutations have been identified in a small proportion of women with ICP from families in which PFIC has not been diagnosed [Pauli-Magnus et al 2004 ; Mullenbach et al 2005 ; Painter et al 2005]. The risk of developing ICP in women who are heterozygous for an ABCB11 or ATP8B1 mutation is unknown.

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.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Offspring of a proband

• The offspring of an individual with ATP8B1-related intrahepatic cholestasis or ABCB11-related intrahepatic cholestasis are obligate heterozygotes (carriers) for a mutant allele.
• The carrier frequencies of ATP8B1 and ABCB11 mutations are unknown. Given that severe low-GT familial intrahepatic cholestasis is relatively uncommon, however, the likelihood that an individual with severe low-GT familial intrahepatic cholestasis would have children with a carrier is low. Exceptions would include populations in which a founder mutation is present, such as the Amish population in which severe ATP8B1-related intrahepatic cholestasis was first described. Offspring of an affected proband and a carrier have a 50% chance of being affected and a 50% chance of being carriers.

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 available on a clinical basis once the disease-causing mutations have been identified in the proband.

Related Genetic Counseling Issues

Family planning.  The optimal time for determination of genetic risk and clarification of carrier status is before pregnancy.

DNA banking.  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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal diagnosis for pregnancies at risk for ATP8B1-related intrahepatic cholestasis caused by the 1660G>A (D554N) mutation is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. Both disease-causing alleles of an affected family member must be confirmed to be the 1660G>A (D554N) mutation in ATP8B1 before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

No laboratories offering molecular genetic prenatal testing of most mutations causing ATP8B1-related intrahepatic cholestasis and ABCB11-related intrahepatic cholestasis are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering custom prenatal testing, see .

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

Molecular Genetics of Low Gamma-GT Familial Intrahepatic Cholestasis

Locus Name	Gene Symbol	Chromosomal Locus	Protein Name
PFIC1	ATP8B1	18q21	FIC1 (Familial intrahepatic cholestasis type 1)
PFIC2	ABCB11	2q24	Bile salt export pump

Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.

OMIM Entries for Low Gamma-GT Familial Intrahepatic Cholestasis

211600  CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC 1; PFIC1  243300  CHOLESTASIS, BENIGN RECURRENT INTRAHEPATIC; BRIC  601847  CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC 2; PFIC2  602397  ATPase, CLASS I, TYPE 8B, MEMBER 1; ATP8B1  603201  ATP-BINDING CASSETTE, SUBFAMILY B, MEMBER 11; ABCB11  605479  CHOLESTASIS, BENIGN RECURRENT INTRAHEPATIC, AUTOSOMAL DOMINANT

Genomic Databases for Low Gamma-GT Familial Intrahepatic Cholestasis

Gene Symbol	Entrez Gene	HGMD	GeneCards	GDB	GenAtlas
ATP8B1	602397	ATP8B1	ATP8B1	453352	ATP8B1
ABCB11	603201	ABCB11	ABCB11	9864786	ABCB11

For a description of the genomic databases listed, click here.

ATP8B1

Normal allelic variants: The gene has a coding sequence of 3,753 bp and consists of 27 coding exons [Bull et al 1998].

Pathologic allelic variants: Over 50 mutations in ATP8B1 have been reported to date [Bull et al 1998 , Klomp et al 2000 , Chen et al 2002 , Egawa et al 2002 , Klomp et al 2004].

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 code for 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]. Studies of RNA and protein expression indicate that ATP8B1 is widely expressed; ATP8B1 is present in the canalicular membrane of hepatocytes and in 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, van Oort et al 2004].

Abnormal gene product: Recent studies indicate that abnormal FIC1 function is associated with diminished activity of the farnesoid X-receptor [Alvarez et al 2004 , Chen et al 2004]. The farnesoid X-receptor directly activates BSEP and indirectly inactivates intestinal bile acid transport. One hypothesis is that FIC1 deficiency is associated with diminished hepatocellular excretion of bile acids [Alvarez et al 2004 , Chen et al 2004] and abnormally high intestinal reabsorption of bile acids [Chen et al 2004]. A mouse carrying a mutation in Atp8B1 has been generated [Pawlikowska et al 2004]

ABCB11

Normal allelic variants: The gene has a coding sequence of 3,963 bp and consists of 27 coding exons [Strautnieks et al 1998].

Pathologic allelic variants: Over 30 mutations in ABCB11 have been reported to date [Strautnieks et al 1998 , Jansen et al 1999 , Chen et al 2002 , Goto et al 2003 , Pauli-Magnus et al 2005]. Immunohistochemical studies of liver tissue from individuals with known mutations in ABCB11 have confirmed that 11 mutations (1 nonsense mutation, 2 1-bp deletions, and 8 missense mutations) result in loss of canalicular expression of the ABCB11 gene product, BSEP [Jansen et al 1999]. The converse — that persons with known loss of canalicular expression of BSEP can reliably be shown to harbor mutations in ABCB11 — has been demonstrated: each of the 19 parents available in a study of ten unrelated children with histochemically evaluated PFIC2 was found to be a heterozygote for one of 13 mutations (6 splicing defects, 3 missense mutations, 3 nonsense mutations, and 1 1-bp deletion were found) [personal observations, Knisely et al 2005].