Table of Contents  

Thompson: Intrahepatic cholestasis

Several multisystem syndromes associated with neonatal-onset cholestatic liver disease have been described. In addition, a rapidly growing number of defective genes have been found to underlie cholestatic disorders with onset in all age groups.

Alagille syndrome has been clinically defined as intrahepatic cholestasis with a variable spectrum of other features; notably involving facies, and the heart, eyes and bones. The defect lies in the Notch signalling pathway, with the majority of patients having heterozygous mutations in Jagged1, a Notch ligand.1,2 A few patients instead have mutations in NOTCH2. The mutations are not fully penetrant, with family members having a partial, sometimes trivial, phenotype. Mutations in NOTCH2 are probably less penetrant than those in JAG1. The combination of cardiac disease, notably peripheral pulmonary stenosis, with end-stage liver disease can make these patients particularly difficult to manage and may preclude liver transplantation.

Progressive familial intrahepatic cholestasis (PFIC) is a useful clinical description that has been steadily unravelled into distinct phenotypes; it has been the discovery of the different genetic defects that has made this possible. However, in each case it has also become clear that there are later-onset variants, and that even presentation in adulthood does not preclude progression to end-stage liver disease.

The bile salt export pump (BSEP) is the main transporter of bile salts from the hepatocytes into bile. Complete failure of bile acid transport leads to severe, unremitting liver disease, with extreme pruritus. Presentation is in the first few months of life, with giant cell hepatitis and normal serum levels of gamma-glutamyltranspeptidase.3 Severe BSEP deficiency is associated with a 15% risk of hepatocellular carcinoma (HCC), particularly in the first 5 years of life.4 Individuals with no BSEP protein are at three times higher risk than BSEP-deficient patients;5 the same group is also at risk of post-liver transplant graft dysfunction as a result of alloantibodies blocking the function of BSEP in the donor organ.6

Multidrug resistance protein 3 (MDR3) is a transporter, similar to BSEP, but essential for the entry of phospholipids into bile.7 A reduction in MDR3 function results in reduced lipids and increased free bile acid concentration.8 This results in cholangiopathy, although this may be microscopic and not apparent on radiographs. Mild cases benefit significantly from administration of ursodeoxycholic acid. Individuals with biallelic mutations generally present in childhood. Those with reduced function from both alleles, or even just complete loss of function from one allele, can present with progressive liver disease in adulthood.9 Both HCC and cholangiocarcinoma complicate late disease.

Familial intrahepatic cholestasis 1 is a protein that contributes to the maintenance of plasma membrane lipid asymmetry. Deficiency of this transporter leads to cholestasis and abnormalities in other epithelia, which can give rise to diarrhoea, pancreatic and renal tubular dysfunction and deafness, all to a very variable degree.10,11 The multisystem nature of the disease means that liver transplantation is less satisfactory than in the previous two conditions.

Tight junction protein 2 (TJP2 deficiency) was recently identified as a cause of PFIC.12 TJP2 is, in fact, cytosolic and links transmembrane components of the tight junction with the cytoskeleton. Most early-onset patients require transplantation. It is now evident that some of the longer-term survivors have developed extrahepatic disease, which is probably not surprising given the ubiquitous need for tight junctions in epithelia.



Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 1997; 16:243–51.


Oda T, Elkahloun AG, Pike BL, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 1997; 16:235–42.


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; 20:233–8.


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; 44:478–86.


Strautnieks SS, Byrne JA, Pawlikowska L, et al. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology 2008; 134:1203–14.


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.


Smit JJ, Schinkel AH, Oude Elferink RP, et al. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 1993; 75:451–62.


de Vree JM, Jacquemin E, Sturm E, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci USA 1998; 95:282–7.


Jacquemin E, De Vree JM, Cresteil D, et al. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 2001; 120:1448–58.


Bull LN, van Eijk MJ, Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 1998; 18:219–24.


Klomp LW, Vargas JC, van Mil SW, et al. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology 2004; 40:27–38.


Sambrotta M, Strautnieks S, Papouli E, et al. Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet 2014; 46:326–8.

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