1. Disease characteristics
1.1 Name of the disease (synonyms)
1. Progressive familial intrahepatic cholestasis type 2 (PFIC2).
2. Bile salt export pump (BSEP) deficiency.
3. Initially reported under the name Byler syndrome.
Byler syndrome refers to normal gamma-glutamyltransferase (GGT) level chronic intrahepatic cholestasis observed in children usually during the first year of life.1 Later, PFIC1 (Byler disease)2 and PFIC23 were identified. The terms PFIC2 or BSEP deficiency should be used preferentially.
1.2 OMIM# of the disease
1.3 Name of the analysed genes or DNA/chromosome segments
ATP-binding cassette sub-family B or ABCB11.
Chromosome 2q24.3–2q31.1 (g.169487695-169596079).
1.4 OMIM# of the gene(s)
1.5 Mutational spectrum
More than 100 mutations have been reported, mostly point mutations (missense, nonsense and splicing) located throughout the gene’s 27 exons, but also small deletions, insertions and duplications.4, 5, 6, 7, 8
Mutations of ABCB11 can be found in the NHLBI ESP Exome Variant Server database (http://evs.gs.washington.edu/EVS/).
1.6 Analytical methods
Bidirectional ABCB11 gene sequencing of coding exons and their flanking intronic junctions (RefSeq accession number NM_003742.2).
As BSEP expression is virtually restricted to hepatocytes, transcripts of ABCB11 can only be studied on liver biopsy.
When the analysis fails to identify both mutant alleles, a search for (partial) gene deletion or duplication by multiplex ligation-dependant probe identification may be considered.
1.7 Analytical validation
Independent sequencing of both strands of DNA (forward and reverse).
When heterozygosity for two mutations is found, testing of the patient’s parents is recommended to confirm that the defect is biallelic.
In case of newly identified variation, a polymorphism has to be excluded by testing a set of at least 100 control chromosomes of the same ethnic origin. Pathogenicity of such novel variations has to be tested by in silico prediction methods. Moreover, protein stability and trafficking may be studied in cell lines on a research basis. Concerning splice site variants, their pathogenic nature should be studied by cDNA analysis.
1.8 Estimated frequency of the disease
(Incidence at birth (‘birth prevalence’) or population prevalence. If known to be variable between ethnic groups, please report):
The population prevalence of PFIC2 is unknown.
However, it is estimated around 1/100 000 births.
1.9 Diagnostic setting
Comment: PFIC2 is due to defects in the ABCB11 gene, encoding the BSEP protein, resulting in impaired biliary bile acid secretion, which leads to decreased bile flow and bile salt accumulation in hepatocytes with ongoing severe hepatocellular damage. Transmission is autosomal recessive. PFIC2 should be suspected in children with a clinical history of cholestasis of unknown origin after exclusion of other main causes of cholestasis presenting with normal serum GGT activity and high serum bile acid concentration.1 Usually, serum α-fetoprotein level is elevated and alanine aminotransferase values are over fivefold the upper limit of normal.7 Liver ultrasonography is usually normal but may reveal a huge gallbladder and sometimes biliary stones. Microscopy of the liver reveals canalicular and hepatocellular cholestasis, the absence of true ductular proliferation with only periportal biliary metaplasia of hepatocytes, pronounced lobular and portal fibrosis and inflammation, hepatocellular necrosis and giant cell transformation. BSEP immunostaining helps for diagnosis as it is usually negative in patients with PFIC2.5, 7, 9 When performed, cholangiography shows a normal biliary tree and allows bile collection. Biliary lipid analysis reveals dramatically decreased biliary bile salt concentration. Genotyping confirms the diagnosis. In the setting of neonatal cholestasis with normal serum GGT activity, normal serum level of bile acid suggests primary bile acid synthesis defects. When bile acid concentrations in serum are elevated in cholestasis with normal serum GGT activity of early infancy, the two main differential diagnostic considerations are PFIC1 and liver disease related to mitochondrial respiratory chain disorders.
Some patients with BSEP deficiency present with benign recurrent intrahepatic cholestasis type 2 (BRIC2, OMIM 605479).10 They suffer from bouts of cholestasis and liver pathological examination, when performed, shows only minimal fibrosis. In some patients, BSEP deficiency initially presents as BRIC2 and an evolution towards a PFIC2 phenotype is observed illustrating that BSEP deficiency represents a phenotypic continuum from BRIC2 to PFIC2.7 Life-long specialised medical follow-up is mandatory.
Monoallelic mutation of ABCB11, predisposes to drug-induced cholestasis (DIC), intrahepatic cholestasis of pregnancy type 2,11, 12 transient neonatal cholestasis13 and biliary lithiasis.7 Specialised medical follow-up should also be offered to heterozygous patients (mainly those who are symptomatic).
2. Test characteristics
2.1 Analytical sensitivity
(proportion of positive tests if the genotype is present)
2.2 Analytical specificity
(proportion of negative tests if the genotype is not present)
2.3 Clinical sensitivity
(proportion of positive tests if the disease is present)The clinical sensitivity can be dependent on variable factors such as age or family history. In such cases, a general statement should be given, even if a quantification can only be made case by case.
2.4 Clinical specificity
(proportion of negative tests if the disease is not present)The clinical specificity can be dependent on variable factors such as age or family history. In such cases, a general statement should be given, even if a quantification can only be made case by case.
2.5 Positive clinical predictive value
(life-time risk to develop the disease if the test is positive)
There is no case report of an asymptomatic person harbouring two predictedly pathogenic mutations in biallelic state. In case of known disease-causing mutations, virtually 100% of affected individuals develop cholestasis. However, PFIC2 constitute the severe side of the clinical spectrum of BSEP deficiency and some patients may suffer from BRIC2. Evolution of BRIC2 patients towards a PFIC2 phenotype has been reported.7 In approximately half patients with PFIC2, liver transplantation is required before adulthood.
2.6 Negative clinical predictive value
(probability not to develop the disease if the test is negative)Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered.
Index case in that family had been tested:
Index case in that family had not been tested:
3. Clinical Utility
3.1 (Differential) diagnostics: the tested person is clinically affected
(To be answered if in 1.9 ‘A’ was marked)
3.1.1 Can a diagnosis be made other than through a genetic test?
3.1.2 Describe the burden of alternative diagnostic methods to the patient
A combined clinical, biochemical, radiological and histological approach associated with liver immunostaining and biliary lipid analysis can allow a PFIC2 diagnosis in most cases. However, invasive procedures, which can only be performed in few centers with a high level of expertise – such as liver biopsy and bile collection by endoscopic retrograde cholangiopancreatography or by direct vesicular puncture – are required. The use of genetic study to confirm clinicopathologic diagnoses – made through study of clinical, biochemical, imaging-study and histopathologic findings, with immunostaining and ultrastrucuture evaluation – is generally prudent.
3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged?
3.1.4 Will disease management be influenced by the result of a genetic test?
3.2 Predictive setting: the tested person is clinically unaffected but carries an increased risk based on family history
(To be answered if in 1.9 ‘B’ was marked).
3.2.1 Will the result of a genetic test influence lifestyle and prevention?
If the test result is positive (please describe).
If the test result is negative (please describe).
3.2.2 Which options in view of lifestyle and prevention does a person at-risk have if no genetic test has been done (please describe)?
3.3 Genetic risk assessment in family members of a diseased person
(To be answered if in 1.9 ‘C’ was marked).
3.3.1 Does the result of a genetic test resolve the genetic situation in that family?
If the two disease-causing mutations have been identified in the diseased person, family members with a negative test are not at risk for being affected.
3.3.2 Can a genetic test in the index patient save genetic or other tests in family members?
Yes: in case of a known familial mutation, carriership can be confirmed or excluded.
3.3.3 Does a positive genetic test result in the index patient enable a predictive test in a family member?
As BSEP deficiency at a heterozygous status predisposes to develop intrahepatic cholestasis of pregnancy type 2, drug-induced cholestasis, transient neonatal cholestasis and also biliary lithiasis, a predictive test can be offered to family members.
In asymptomatic relatives with monoallelic mutation, information regarding the particular risks should be given. Specialised medical care (including UDCA treatment) and follow-up should be offered to symptomatic relatives with monoallelic mutation.
3.4 Prenatal diagnosis
(To be answered if in 1.9 ‘D’ was marked).
3.4.1 Does a positive genetic test result in the index patient enable a prenatal diagnosis?
Yes, prenatal diagnosis can be proposed if a disease-causing mutation has been identified in each parent.
4. If applicable, further consequences of testing
Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (Please describe).
Genetic counseling is always useful for the family.
Review of the analytical and clinical validity as well as of the clinical utility of DNA based.
Testing for mutations in the ABCB11 gene in diagnostic, predictive and prenatal settings and for risk assessment in relatives.
Davit-Spraul A, Gonzales E, Baussan C et al: Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis 2009; 4: 1.
Bull L, Eijk MJ, Pawlikowska L et al: A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 1998; 18: 219–224.
Strautnieks SS, Bull LN, Knisely AS et al: A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet 1998; 20: 233–238.
Jansen PLM, Strautnieks SS, Jacquemin E et al: Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology 1999; 117: 1370–1379.
Strautnieks SS, Byrne JA, Pawlikowska L et al: Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology 2008; 134: 1203–1214.
Knisely AS, Strautnieks SS, Meier Y et al: Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology 2006; 44: 478–486.
Davit-Spraul A, Fabre M, Branchereau S et al: ATP8B1 and ABCB11 analysis in 62 children with normal GGT PFIC: phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology 2010; 51: 1645–1655.
Pawlikowska L, Strautnieks S, Jankowska I et al: Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol 2010; 53: 170–178.
Evason K, Bove KE, Finegold MJ et al: Morphologic findings in progressive familial intrahepatic cholestasis 2 (PFIC2): correlation with genetic and immunohistochemical studies. Am J Surg Pathol 2011; 35: 687–696.
van Mil SW, van der Woerd WL, van der Brugge G et al: Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology 2004; 127: 379–384.
Pauli-Magnus C, Lang T, Meier Y et al: Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics 2004; 14: 91–102.
Pauli-Magnus C, Meier PJ, Stieger B : Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy. Semin Liver Dis 2010; 30: 147–159.
Hermeziu B, Sanlaville D, Girard M et al: Heterozygous bile salt export pump deficiency: a possible genetic predisposition to transient neonatal cholestasis. J Pediatr Gastroenterol Nutr 2006; 42: 7–8.
Jacquemin E, Hermans D, Myara A et al: Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis. Hepatology 1997; 25: 519–523.
Stapelbroek JM, van Erpecum KJ, Klomp LW et al: Liver disease associated with canalicular transport defects: current and future therapies. J Hepatol 2010; 52: 258–271.
Balistreri WF, Bezzera JA, Jansen P et al: Intrahepatic cholestasis: summary of an American association for study of liver diseases single-topic conference. Hepatology 2005; 42: 222–235.
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: 385–387.
Gonzales E, Grosse B, Cassio D et al: Successful mutation-specific chaperone therapy with 4-phenylbutyrate in a child with progressive familial intrahepatic cholestasis type 2. J Hepatol 2012; 57: 695–698.
Keitel V, Burdelski M, Vojnisek Z et al: 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: 510–517.
Jara P, Hierro L, Martínez-Fernández P et al: Recurrence of bile salt export pump deficiency after liver transplantation. N Engl J Med 2009; 361: 1359–1367.
This work was supported by EuroGentest2 (Unit 2: ‘Genetic testing as part of health care’), a Coordination Action under FP7 (Grant Agreement Number 261469) and the European Society of Human Genetics.
The authors declare no conflict of interest.
About this article
Cite this article
Gonzales, E., Spraul, A. & Jacquemin, E. Clinical utility gene card for: Progressive familial intrahepatic cholestasis type 2. Eur J Hum Genet 22, 572 (2014). https://doi.org/10.1038/ejhg.2013.187
Clinical phenotype and molecular analysis of a homozygous ABCB11 mutation responsible for progressive infantile cholestasis
Journal of Human Genetics (2018)