Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2 gene variants analysis by high-throughput sequencing

J Gastroenterol. 2018 Aug;53(8):945-958. doi: 10.1007/s00535-017-1423-1. Epub 2017 Dec 13.


Background: Mutations in ATP-transporters ATPB81, ABCB11, and ABCB4 are responsible for progressive familial intrahepatic cholestasis (PFIC) 1, 2 and 3, and recently the gene for tight junction protein-2 (TJP2) has been linked to PFIC4.

Aim: As these four genes have been poorly studied in young people and adults, we investigated them in this context here.

Methods: In patients with cryptogenic cholestasis, we analyzed the presence of mutations by high-throughput sequencing. Bioinformatics analyses were performed for mechanistic and functional predictions of their consequences on biomolecular interaction interfaces.

Results: Of 108 patients, 48 whose cause of cholestasis was not established were submitted to molecular analysis. Pathogenic/likely pathogenic mutations were found in ten (21%) probands for 13 mutations: two in ATP8B 1, six in ABCB11, two in ABCB4, three in TJP2. We also identified seven variants of uncertain significance: two in ATP8B1, one in ABCB11, two in ABCB4 and two in TJP2. Finally, we identified 11 benign/likely benign variants. Patients with pathogenic/likely pathogenic mutations had higher levels of liver stiffness (measured by FibroScan®) and bile acids, as well as higher rates of cholestatic histological features, compared to the patients without at least likely pathogenic mutations. The multivariate analysis showed that itching was the only independent factor associated with disease-causing mutations (OR 5.801, 95% CI 1.244-27.060, p = 0.025).

Conclusions: Mutations in the genes responsible for PFIC may be involved in both young and adults with cryptogenic cholestasis in a considerable number of cases, including in heterozygous status. Diagnosis should always be suspected, particularly in the presence of itching.

Keywords: Bioinformatics analysis; Cryptogenic disease; Genetic variants; Pathogenic mutations; Progressive familial intrahepatic cholestasis.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / deficiency
  • ATP Binding Cassette Transporter, Subfamily B / genetics*
  • ATP Binding Cassette Transporter, Subfamily B, Member 11 / genetics*
  • Adenosine Triphosphatases / genetics*
  • Adolescent
  • Adult
  • Cholestasis / genetics
  • Cholestasis, Intrahepatic / complications
  • Cholestasis, Intrahepatic / genetics*
  • Elasticity Imaging Techniques
  • Female
  • Humans
  • Liver / diagnostic imaging
  • Male
  • Middle Aged
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Pruritus / etiology
  • Steroid Metabolism, Inborn Errors / genetics
  • Young Adult
  • Zonula Occludens-2 Protein / genetics*


  • ABCB11 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • TJP2 protein, human
  • Zonula Occludens-2 Protein
  • multidrug resistance protein 3
  • Adenosine Triphosphatases
  • ATP8B1 protein, human

Supplementary concepts

  • Bile acid synthesis defect, congenital, 1
  • Cholestasis, progressive familial intrahepatic 1
  • Cholestasis, progressive familial intrahepatic 2
  • Cholestasis, progressive familial intrahepatic 3