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Treatment of paediatric cholestasis due to canalicular transport defects: yet another step forward
  1. Jose J G Marin1,
  2. Roderick H J Houwen2
  1. 1 Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain
  2. 2 Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
  1. Correspondence to Professor Jose J G Marin, Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Campus Miguel de Unamuno, ED-S09, Salamanca 37007, Spain; jjgmarin{at}

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Paediatric cholestasis is a rare but devastating group of diseases that usually manifest in infancy or childhood by impaired bile secretion, due to either primary or secondary alterations affecting the liver secretory machinery, and that may progress to cirrhosis and liver failure. Although there is resemblance in clinical symptoms, the cause of these diseases can be completely different, which is important because it determines, among others, the response to treatment. For a specific subgroup of cholestatic diseases, namely those associated with canalicular transport defects, our pathophysiological understanding has been increased enormously over the last decade. In parallel, treatment options have been developed,1 and the article by Gordo–Gilart et al 2 yet takes another step forward.

Several transport proteins located at the canalicular membrane of hepatocytes are required to maintain the correct secretory function of the liver (figure 1). A crucial role is played by a member of the superfamily of ATP-binding cassette proteins, the bile salt export pump ABCB11 (formerly designated as BSEP), which accounts for the active transport of bile acids into the canalicular lumen and, hence, the generation of the osmotic gradient that drives canalicular bile flow.3 The correct functioning of this and other transporters requires specific physical-chemical characteristics at the canalicular membrane, where they are inserted, which are dependent, in part, on the asymmetry regarding aminophospholipid composition in both layers of this membrane. The flippase activity of ATP8B1 plays a key role in maintaining this asymmetry. Accordingly, ATP8B1 deficiency results in a reduced secretion and intrahepatocyte accumulation of bile acids, which leads to pathological conditions known in their mild and severe forms as benign recurrent intrahepatic cholestasis type 1 (BRIC-1) and progressive familial intrahepatic cholestasis type 1 (PFIC-1), respectively. Similar situations may occur by reduced expression, impaired membrane trafficking or synthesis of defective ABCB11, which leads to BRIC-2 or PFIC-2 depending on the severity of the deficiency.4 ,5 Once secreted into bile, the potential toxic effect of bile acids, due to their detergent activity at the high concentrations reached in bile (mM), is buffered by phospholipids, mainly phosphatidylcholine, which is continuously supplied by the floppase activity of ABCB4, which was formerly designated as multidrug resistance-associated protein 3 (MDR3). Interestingly, complementary function of FIC1 and MDR3 in maintaining canalicular membrane integrity has been reported.6 Lack of ABCB4 function leaves the apical plasma membrane of hepatocytes and cholangiocytes unprotected against the aggressive action of bile acids, which firstly impairs the function of the secretory machinery and subsequently damages the tissue by inducing necrosis and apoptosis of liver cells. Since phospholipid secretion into bile is also essential for biliary cholesterol secretion, as cholesterol dissolves much better in mixed micelles of bile salts and phospholipid than in pure bile salt micelles, ABCB4 indirectly determines biliary cholesterol output and, hence, affects cholesterol homeostasis,7 preventing cholelithiasis.8 Thus, mutations in ABCB4 give rise or predispose to several hepatobiliary disorders, among them low phospholipid associated cholelithiasis syndrome (LPAC), but more frequently to high GGT-associated cholestasis, that is, PFIC-3.1

Figure 1

Scheme of the function of the canalicular ATP-dependent proteins ATP8B1, ABCB11 and ABCB4. A mild deficiency of ATP8B1 will lead to benign recurrent intrahepatic cholestasis type 1 (BRIC-1); severe deficiency to progressive familial intrahepatic cholestasis type 1 (PFIC-1). BRIC-2, respectively PFIC-2, is caused by mild respectively severe ABCB11 deficiency. Deficiency of ABCB4 is associated with PFIC-3 and also with LPAC (low phospholipid associated cholelithiasis).

It was already known that the severity of PFIC-3 and the outcome of pharmacological therapy of this disorder vary among affected children. Earlier studies investigated the link between ABCB4 mutations, expression of the corresponding protein at the canalicular membrane and response to ursodeoxycholic acid (UDCA) treatment. Although patients with mild genotypes, including heterozygous mutations, generally had a favourable course, no absolute correlation could be found, and even some patients with severe mutations showed complete remission upon UDCA administration.9 ,10 The current study, although in a limited number of patients, now establishes a clear relationship between the impact of ABCB4 mutations on expression and activity of the corresponding protein and the clinical outcomes in PFIC-3. The authors suggest that one-third of functional ABCB4 may suffice to elicit a favourable response to UDCA treatment, whereas on the other hand, complete or near-complete loss of ABCB4-mediated phosphatidylcholine-translocating activity leads to a more severe condition evolving to end-stage liver disease and finally requiring liver transplantation. These findings have a practical interpretation because in children with an unambiguous diagnosis of PFIC-3, the detection of residual ABCB4 activity may help to predict a positive response to pharmacological treatment with UDCA. The study by Gordo–Gilart et al 2 also supports the suggestion that patients harbouring mutations affecting protein maturation and membrane targeting could potentially benefit from rescuing functional ABCB4 to the cell surface, using pharmacological chaperones.1

UDCA is also used in ATP8B1 and ABCB11 deficiency, however, without a consistent effect.1 Another compound that is frequently used in these and other cholestatic conditions, rifampicin, indirectly increases the 6α-hydroxylation of bile acids, that can subsequently be glucoronidated and excreted in the urine. Rifampicin might reduce or abolish pruritus in mild ATP8B1 and ABCB11 deficiency (BRIC1 and BRIC2), but not in severe phenotypes (PFIC1 and PFIC2), although current evidence is insufficient to formally substantiate this. Cholestyramine, a resin that binds bile salts in the intestinal lumen, reduces reabsorption of these compounds in the ileum, and could have some effect in BRIC, but not in PFIC. A much stronger effect is seen for biliary diversion, which can dramatically reduce the enterohepatic circulation of bile acids. A recent analysis1 indeed showed that the vast majority of patients with low GGT-associated cholestasis (effectively BRIC and PFIC type 1 and 2, although some rare patients might have mutations in other genes giving low GGT-associated cholestasis) have at least some benefit of this procedure. It seems logical to assume that for these two conditions too a genotype-phenotype-therapeutic effect relationship could be established, using the methods now proposed by Gordo–Gilart et al,2 with mild mutations giving some functioning protein at the canalicular membrane, making those patients good candidates for either supposedly weak (eg, rifampicin) or stronger interventions (eg, biliary diversion). With severe mutations, and no functioning protein, it is reasonable to assume that no bile acid will enter the bile canaliculi, making any of these interventions useless, and rendering the child a candidate for liver transplantation.


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  • Contributors Both coauthors contributed equally to the preparation of this commentary.

  • Competing interests None.

  • Provenance and peer review Commissioned; internally peer reviewed.

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