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Liver disease associated with canalicular transport defects: Current and future therapies

  • Janneke M. Stapelbroek
    Affiliations
    Department of Paediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Post-Box 85090, 3508 AB, Utrecht, The Netherlands

    Department of Metabolic and Endocrine Diseases, University Medical Centre Utrecht, and Netherlands Metabolomics Centre, Utrecht, The Netherlands
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  • Karel J. van Erpecum
    Affiliations
    Department of Gastroenterology, University Medical Centre Utrecht, Utrecht, The Netherlands
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  • Leo W.J. Klomp
    Affiliations
    Department of Metabolic and Endocrine Diseases, University Medical Centre Utrecht, and Netherlands Metabolomics Centre, Utrecht, The Netherlands
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  • Roderick H.J. Houwen
    Correspondence
    Corresponding author. Address: Department of Paediatric Gastroenterology [KE.01.144.3], Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Post-Box 85090, 3508 AB, Utrecht, The Netherlands. Tel.: +31 88 75 55555; fax: +31 88 75 55342.
    Affiliations
    Department of Paediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Post-Box 85090, 3508 AB, Utrecht, The Netherlands
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Open AccessPublished:November 23, 2009DOI:https://doi.org/10.1016/j.jhep.2009.11.012
      Bile formation at the canalicular membrane is a delicate process. This is illustrated by inherited liver diseases due to mutations in ATP8B1, ABCB11, ABCB4, ABCC2 and ABCG5/8, all encoding hepatocanalicular transporters. Effective treatment of these canalicular transport defects is a clinical and scientific challenge that is still ongoing. Current evidence indicates that ursodeoxycholic acid (UDCA) can be effective in selected patients with PFIC3 (ABCB4 deficiency), while rifampicin reduces pruritus in patients with PFIC1 (ATP8B1 deficiency) and PFIC2 (ABCB11 deficiency), and might abort cholestatic episodes in BRIC (mild ATP8B1 or ABCB11 deficiency). Cholestyramine is essential in the treatment of sitosterolemia (ABCG5/8 deficiency). Most patients with PFIC1 and PFIC2 will benefit from partial biliary drainage. Nevertheless liver transplantation is needed in a substantial proportion of these patients, as it is in PFIC3 patients. New developments in the treatment of canalicular transport defects by using nuclear receptors as a target, enhancing the expression of the mutated transporter protein by employing chaperones, or by mutation specific therapy show substantial promise. This review will focus on the therapy that is currently available as well as on those developments that are likely to influence clinical practice in the near future.

      Abbreviations:

      ABC (adenosine triphosphate-binding-cassette), PC (phosphatidylcholine), PS (phosphatidylserine), PFIC (progressive familial intrahepatic cholestasis), BRIC (benign recurrent intrahepatic cholestasis), GGT (gamma-glutamyl transpeptidase), ICP (intrahepatic cholestasis of pregnancy), LPAC (low-phospholipid associated cholelithiasis syndrome), DJS (Dubin Johnson syndrome), UDCA (ursodeoxycholic acid), PXR (pregnane X receptor), MARS (extracorporal albumin dialysis), PBD (partial biliary diversion), IB (ileal bypass), PEBD (partial external biliary diversion), PIBD (partial internal biliary diversion), NBD (nasobiliary drainage), FXR (farnesoid X receptor), 6-ECDCA (6-ethyl chenodeoxycholic acid), PPAR (peroxisome proliferator activator receptor), CAR (constitutive androstane receptor), CF (cystic fibrosis), 4-PBA (4-phenylbutyrate acid), CFTR (cystic fibrosis transmembrane conductance regulator)

      Keywords

      Introduction

      The process of primary bile formation occurs at the canalicular membrane predominantly through the action of transporters belonging to the adenosine triphosphate-binding-cassette (ABC) family [
      • Oldham M.L.
      • Davidson A.L.
      • Chen J.
      Structural insights into ABC transporter mechanism.
      ,
      • Borst P.
      • Elferink R.O.
      Mammalian ABC transporters in health and disease.
      ] (Fig. 1A). Secretion of bile salts, phosphatidylcholine (PC) and cholesterol is mediated by ABCB11 (BSEP), ABCB4 (MDR3) and ABCG5/8, respectively. Excretion of organic anions is mediated by other members of the ABC-family such as ABCC2 (MRP2). In addition, ATP8B1 (FIC1), a P4 P-type ATPase, is essential for a proper composition of the canalicular membrane, and thus for normal bile flow [
      • Bull L.N.
      • van Eijk M.J.
      • Pawlikowska L.
      • DeYoung J.A.
      • Juijn J.A.
      • Liao M.
      • et al.
      A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis.
      ].
      Figure thumbnail gr1
      Fig. 1Medical treatment of canalicular transport defects. (A) Schematic representation of bile formation at the canalicular membrane. ATP8B1 (FIC1) is essential for normal bile flow, probably through maintaining an asymmetric distribution of phospholipids between the inner and outer leaflet of the canalicular membrane. Secretion of bile salts into the canaliculus by the bile salt export pump ABCB11 (BSEP) is the main driving force for bile flow, with water following through osmotic forces. ABCB4 (MDR3) and ABCG5/8 induce secretion of phosphatidylcholine and cholesterol, respectively. These lipids form mixed micelles with the bile salts and protect membranes lining the biliary tract against detergent bile salts. ABCC2 (MRP2) mediates efflux of a broad range of organic anions. As indicated most ABC transporters are probably organized in microdomains enriched in sphingomyelin and cholesterol. (B) Left panel: the effect of UDCA in the hepatocyte. The hydrophilic ursodeoxycholic acid (UDCA) partly replaces the endogenous cytotoxic hydrophobic bile salts. In addition, by inducing expression of ABCB11, and ABCB4, UDCA stimulates hepatobiliary secretion of bile salts and protective phospholipids. The up-regulation of ABCC4 (MRP4) induces the efflux of conjugated bile acids across the basolateral membrane. Right panel: rifampicin (RIF) activates PXR regulated transcription of CYP3A4. This stimulates 6α-hydroxylation of bile salts, which can be excreted at the basolateral membrane via ABCC4 (MRP4), with subsequent excretion in the urine. In addition, the conjugation and excretion of bilirubin is enhanced through induction of UGT1A1 and ABCC2 (MRP2). (C) Cholestyramine binds bile salts in the intestinal lumen and interrupts the enterohepatic circulation of bile salts by reducing re-absorption and stimulating faecal excretion. N, nucleus; TJ, tight junction.
      Bile formation at the canalicular membrane is a delicate process and any inaccuracy may have devastating consequences. This is illustrated by inherited liver diseases caused by mutations in any of the hepatocanalicular transporters described above. In this review, we give recommendations for the treatment of canalicular transport defects based on current evidence. In addition, this review focuses on the developments that are likely to influence clinical practice in the near future.

      Canalicular transport defects in liver disease

      Phospholipid-flippases ATP8B1 (FIC1)

      ATP8B1 is thought to specifically translocate phosphatidylserine (PS) from the outer to the inner leaflet of plasma membranes, causing the outer leaflet to be enriched in PC, sphingomyelin and cholesterol [
      • Paulusma C.C.
      • Folmer D.E.
      • Ho-Mok K.S.
      • de Waart D.R.
      • Hilarius P.M.
      • Verhoeven A.J.
      • et al.
      ATP8B1 requires an accessory protein for endoplasmic reticulum exit and plasma membrane lipid flippase activity.
      ,
      • Pomorski T.
      • Lombardi R.
      • Riezman H.
      • Devaux P.F.
      • van M.G.
      • Holthuis J.C.
      Drs2p-related P-type ATPases Dnf1p and Dnf2p are required for phospholipid translocation across the yeast plasma membrane and serve a role in endocytosis.
      ,
      • Ujhazy P.
      • Ortiz D.
      • Misra S.
      • Li S.
      • Moseley J.
      • Jones H.
      • et al.
      Familial intrahepatic cholestasis 1: studies of localization and function.
      ,
      • Cai S.Y.
      • Gautam S.
      • Nguyen T.
      • Soroka C.J.
      • Rahner C.
      • Boyer J.L.
      ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained.
      ]. Cholesterol has a high affinity for sphingomyelin, and both are thought to be preferentially located in laterally separated microdomains (previously called lipid rafts). These microdomains offer protection against the detergent action of bile salts in the canalicular lumen and are essential for normal function of transmembrane transporters [
      • Amigo L.
      • Mendoza H.
      • Zanlungo S.
      • Miquel J.F.
      • Rigotti A.
      • Gonzalez S.
      • et al.
      Enrichment of canalicular membrane with cholesterol and sphingomyelin prevents bile salt-induced hepatic damage.
      ,
      • Paulusma C.C.
      • Groen A.
      • Kunne C.
      • Ho-Mok K.S.
      • Spijkerboer A.L.
      • Rudi de W.D.
      • et al.
      Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport.
      ,
      • Paulusma C.C.
      • Dewaart D.R.
      • Kunne C.
      • Mok K.S.
      • Oude Elferink R.P.
      Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content.
      ]. Recent evidence indicates that canalicular ABC-transporters are indeed localized within these microdomains [
      • Ismair M.G.
      • Hausler S.
      • Stuermer C.A.
      • Guyot C.
      • Meier P.J.
      • Roth J.
      • et al.
      ABC-transporters are localized in caveolin-1-positive and reggie-1-negative and reggie-2-negative microdomains of the canalicular membrane in rat hepatocytes.
      ]; therefore, disruption of lipid asymmetry and reduction of cholesterol content in the apical membrane decreases the function of resident proteins such as the bile salt export pump ABCB11, resulting in cholestasis [
      • Paulusma C.C.
      • Groen A.
      • Kunne C.
      • Ho-Mok K.S.
      • Spijkerboer A.L.
      • Rudi de W.D.
      • et al.
      Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport.
      ,
      • Paulusma C.C.
      • Dewaart D.R.
      • Kunne C.
      • Mok K.S.
      • Oude Elferink R.P.
      Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content.
      ]. In addition, the canalicular membrane in both humans and mice with ATP8B1/Atp8b1 deficiency develops a decreased resistance to hydrophobic bile salts, evidenced by an enhanced biliary recovery of phospholipids, cholesterol and canalicular ectoenzymes in bile [
      • Paulusma C.C.
      • Groen A.
      • Kunne C.
      • Ho-Mok K.S.
      • Spijkerboer A.L.
      • Rudi de W.D.
      • et al.
      Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport.
      ,
      • Bull L.N.
      • Carlton V.E.
      • Stricker N.L.
      • Baharloo S.
      • DeYoung J.A.
      • Freimer N.B.
      • et al.
      Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity.
      ,
      • Groen A.
      • Kunne C.
      • Jongsma G.
      • van den O.K.
      • Mok K.S.
      • Petruzzelli M.
      • et al.
      Abcg5/8 independent biliary cholesterol excretion in Atp8b1-deficient mice.
      ]. It is likely that this damage to the canalicular membrane adds to the cholestasis.
      ATP8B1 deficiency (formerly FIC1 disease) is an autosomal recessive condition characterized by mutations in the ATP8B1 gene [
      • Bull L.N.
      • van Eijk M.J.
      • Pawlikowska L.
      • DeYoung J.A.
      • Juijn J.A.
      • Liao M.
      • et al.
      A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis.
      ,
      • Klomp L.W.
      • Vargas J.C.
      • van Mil S.W.
      • Pawlikowska L.
      • Strautnieks S.S.
      • van Eijk M.J.
      • et al.
      Characterization of mutations in ATP8B1 associated with hereditary cholestasis.
      ,
      • Klomp L.W.
      • Bull L.N.
      • Knisely A.S.
      • van Der Doelen M.A.
      • Juijn J.A.
      • Berger R.
      • et al.
      A missense mutation in FIC1 is associated with Greenland familial cholestasis.
      ]. Patients with ATP8B1 deficiency may present in infancy or early childhood with progressive familial intrahepatic cholestasis type 1 (PFIC1) [
      • Klomp L.W.
      • Bull L.N.
      • Knisely A.S.
      • van Der Doelen M.A.
      • Juijn J.A.
      • Berger R.
      • et al.
      A missense mutation in FIC1 is associated with Greenland familial cholestasis.
      ,
      • Bourke B.
      • Goggin N.
      • Walsh D.
      • Kennedy S.
      • Setchell K.D.
      • Drumm B.
      Byler-like familial cholestasis in an extended kindred.
      ,
      • Clayton R.J.
      • Iber F.L.
      • Ruebner B.H.
      • McKusick V.A.
      Byler disease. Fatal familial intrahepatic cholestasis in an Amish kindred.
      ,
      • Nielsen I.M.
      • Ornvold K.
      • Jacobsen B.B.
      • Ranek L.
      Fatal familial cholestatic syndrome in Greenland Eskimo children.
      ] or later in life with episodes of cholestasis and intractable pruritus: benign recurrent intrahepatic cholestasis type 1 (BRIC1) [
      • Brenard R.
      • Geubel A.P.
      • Benhamou J.P.
      Benign recurrent intrahepatic cholestasis. A report of 26 cases.
      ,
      • De Koning T.J.
      • Sandkuijl L.A.
      • De Schryver J.E.
      • Hennekam E.A.
      • Beemer F.A.
      • Houwen R.H.
      Autosomal-recessive inheritance of benign recurrent intrahepatic cholestasis.
      ,
      • Summerskill W.H.
      • Walshe J.M.
      Benign recurrent intrahepatic “obstructive” jaundice.
      ,
      • Tygstrup N.
      • Steig B.A.
      • Juijn J.A.
      • Bull L.N.
      • Houwen R.H.
      Recurrent familial intrahepatic cholestasis in the Faeroe Islands. Phenotypic heterogeneity but genetic homogeneity.
      ]. PFIC1 and BRIC1 are in fact two ends of a clinical spectrum, as is illustrated by patients who initially present with episodic cholestasis but progress to permanent cholestasis in time [
      • Klomp L.W.
      • Vargas J.C.
      • van Mil S.W.
      • Pawlikowska L.
      • Strautnieks S.S.
      • van Eijk M.J.
      • et al.
      Characterization of mutations in ATP8B1 associated with hereditary cholestasis.
      ,
      • van Mil S.W.
      • Klomp L.W.
      • Bull L.N.
      • Houwen R.H.
      FIC1 disease: a spectrum of intrahepatic cholestatic disorders.
      ,
      • van Ooteghem N.A.
      • Klomp L.W.
      • van Berge-Henegouwen G.P.
      • Houwen R.H.
      Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.
      ]. During a cholestatic episode, all patients have low serum concentrations of gamma-glutamyl transpeptidase (GGT) in combination with high serum bile salt levels. Liver biopsies of PFIC1 patients show bland cholestasis with characteristic coarse and granular bile on the ultra-structural level [
      • Bull L.N.
      • Carlton V.E.
      • Stricker N.L.
      • Baharloo S.
      • DeYoung J.A.
      • Freimer N.B.
      • et al.
      Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity.
      ,
      • Knisely A.S.
      Progressive familial intrahepatic cholestasis: a personal perspective.
      ]. ATP8B1 is localized on the canalicular membrane of the hepatocyte [
      • Ujhazy P.
      • Ortiz D.
      • Misra S.
      • Li S.
      • Moseley J.
      • Jones H.
      • et al.
      Familial intrahepatic cholestasis 1: studies of localization and function.
      ,
      • Eppens E.F.
      • van Mil S.W.
      • De Vree J.M.
      • Mok K.S.
      • Juijn J.A.
      • Oude Elferink R.P.
      • et al.
      FIC1, the protein affected in two forms of hereditary cholestasis, is localized in the cholangiocyte and the canalicular membrane of the hepatocyte.
      ,
      • van Mil S.W.
      • van Oort M.M.
      • van dB I.
      • Berger R.
      • Houwen R.H.
      • Klomp L.W.
      Fic1 is expressed at apical membranes of different epithelial cells in the digestive tract and is induced in the small intestine during postnatal development of mice.
      ], but its expression is even more abundant in other tissues [
      • Bull L.N.
      • van Eijk M.J.
      • Pawlikowska L.
      • DeYoung J.A.
      • Juijn J.A.
      • Liao M.
      • et al.
      A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis.
      ,
      • Harris M.J.
      • Arias I.M.
      FIC1, a P-type ATPase linked to cholestatic liver disease, has homologues (ATP8B2 and ATP8B3) expressed throughout the body.
      ], where it can also be found at the apical membranes of polarized cells [
      • Eppens E.F.
      • van Mil S.W.
      • De Vree J.M.
      • Mok K.S.
      • Juijn J.A.
      • Oude Elferink R.P.
      • et al.
      FIC1, the protein affected in two forms of hereditary cholestasis, is localized in the cholangiocyte and the canalicular membrane of the hepatocyte.
      ,
      • van Mil S.W.
      • van Oort M.M.
      • van dB I.
      • Berger R.
      • Houwen R.H.
      • Klomp L.W.
      Fic1 is expressed at apical membranes of different epithelial cells in the digestive tract and is induced in the small intestine during postnatal development of mice.
      ,
      • Stapelbroek J.M.
      • Peters T.A.
      • van Beurden D.H.
      • Curfs J.H.
      • Joosten A.
      • Beynon A.J.
      • et al.
      ATP8B1 is essential for maintaining normal hearing.
      ]. This is consistent with a proposed general cellular function of ATP8B1 and with extrahepatic features such as persistent short stature [
      • Bourke B.
      • Goggin N.
      • Walsh D.
      • Kennedy S.
      • Setchell K.D.
      • Drumm B.
      Byler-like familial cholestasis in an extended kindred.
      ], diarrhoea [
      • Bourke B.
      • Goggin N.
      • Walsh D.
      • Kennedy S.
      • Setchell K.D.
      • Drumm B.
      Byler-like familial cholestasis in an extended kindred.
      ,
      • Chen H.L.
      • Chang P.S.
      • Hsu H.C.
      • Ni Y.H.
      • Hsu H.Y.
      • Lee J.H.
      • et al.
      FIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low gamma-glutamyltranspeptidase levels.
      ,
      • Lykavieris P.
      • van M.S.
      • Cresteil D.
      • Fabre M.
      • Hadchouel M.
      • Klomp L.
      • et al.
      Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation.
      ], pancreatitis [
      • Tygstrup N.
      • Steig B.A.
      • Juijn J.A.
      • Bull L.N.
      • Houwen R.H.
      Recurrent familial intrahepatic cholestasis in the Faeroe Islands. Phenotypic heterogeneity but genetic homogeneity.
      ,
      • Knisely A.S.
      • Agostini R.M.
      • Zitelli B.J.
      • Kocoshis S.A.
      • Boyle J.T.
      Byler’s syndrome.
      ], sensorineural hearing loss [
      • Stapelbroek J.M.
      • Peters T.A.
      • van Beurden D.H.
      • Curfs J.H.
      • Joosten A.
      • Beynon A.J.
      • et al.
      ATP8B1 is essential for maintaining normal hearing.
      ,
      • Oshima T.
      • Ikeda K.
      • Takasaka T.
      Sensorineural hearing loss associated with Byler disease.
      ] and an abnormal sweat composition [
      • Bourke B.
      • Goggin N.
      • Walsh D.
      • Kennedy S.
      • Setchell K.D.
      • Drumm B.
      Byler-like familial cholestasis in an extended kindred.
      ,
      • Knisely A.S.
      • Agostini R.M.
      • Zitelli B.J.
      • Kocoshis S.A.
      • Boyle J.T.
      Byler’s syndrome.
      ], which are frequently present in patients with ATP8B1 deficiency. Heterozygous mutations in ATP8B1 can be found in patients with intrahepatic cholestasis of pregnancy (ICP), a liver disorder that is characterized by pruritus and raised serum bile salt levels during pregnancy or use of oral contraceptives [
      • Mullenbach R.
      • Bennett A.
      • Tetlow N.
      • Patel N.
      • Hamilton G.
      • Cheng F.
      • et al.
      ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy.
      ,
      • Painter J.N.
      • Savander M.
      • Ropponen A.
      • Nupponen N.
      • Riikonen S.
      • Ylikorkala O.
      • et al.
      Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy.
      ] (Table 1).
      Table 1Canalicular transporters and canalicular transport defects.
      Canalicular transporter (synonym)Canalicular transport defect (synonym)Disease characteristicsBiochemical and histological characteristicsDisease associated with heterozygous canalicular transport defect
      ATP8B1 (FIC1)ATP8B1 deficiency (FIC1 disease PFIC1, Byler disease and Greenland familial cholestasis, BRIC1, Tygstrup-Summerskill and Walshe cholestasis)Spectrum of intrahepatic cholestasis comprising PFIC1 and BRIC1High serum bile salts but low GGT concentrations. Liver biopsy: bland cholestasis with coarse and granular bileICP
      PFIC1: progressive intrahepatic cholestasis, pruritus and in some patients extrahepatic symptoms
      BRIC1: episodic cholestasis, pruritus and in some patients extrahepatic symptoms. In between episodes no symptoms
      ABCB11 (BSEP)ABCB11 deficiency (PFIC2, BRIC2)Spectrum of intrahepatic cholestasis comprising PFIC2 and BRIC2High serum bile salts but low GGT concentrations. Liver biopsy: portal-tract fibrosis, bile duct proliferation and amorphous canalicular bileICP, drug induced cholestasis, transient neonatal cholestasis
      PFIC2: progressive intrahepatic cholestasis, pruritus and in some patients cholelithiasis
      BRIC2: episodic cholestasis, pruritus and in some patients cholelithiasis. In between episodes no symptoms
      ABCB4 (MDR3)ABCB4 deficiency (PFIC3)Progressive intrahepatic cholestasis, high serum GGT concentrations. Pruritus less prominentHigh serum bile salts and high GGT concentrations. Liver biopsy: fibrosis and marked bile duct proliferationICP, drug induced cholestasis, transient neonatal cholestasis LPAC
      ABCC2 (MRP2)Dubin Johnson syndromeAsymptomatic but in some patients gastrointestinal symptomsHigh serum conjugated bilirubin concentrations. Liver biopsy: dark blue or black due to pigmentation
      ABCG5/8SitosterolemiaXanthomas, arthralgias and premature coronary artery diseaseHigh serum sitosterols with relatively low cholesterol concentration. Liver biopsy: unknown
      PFIC, progressive familial intrahepatic cholestasis; BRIC, benign recurrent intrahepatic cholestasis; GGT, gamma-glutamyl transpeptidase; ICP, intrahepatic cholestasis of pregnancy; LPAC, low-phospholipid associated cholelithiasis syndrome.

      Bile salt transporter ABCB11 (BSEP)

      Since bile flow is largely dependent on bile salt excretion, it is not surprising that a deficiency of ABCB11, the main bile salt transporter, can cause a severe autosomal recessive cholestatic syndrome that is hard to distinguish from ATP8B1 deficiency. Patients may present with progressive intrahepatic cholestasis in the first decade of life that rapidly leads to liver failure (PFIC2) [
      • Strautnieks S.S.
      • Bull L.N.
      • Knisely A.S.
      • Kocoshis S.A.
      • Dahl N.
      • Arnell H.
      • et al.
      A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis.
      ,
      • Strautnieks S.S.
      • Byrne J.A.
      • Pawlikowska L.
      • Cebecauerova D.
      • Rayner A.
      • Dutton L.
      • et al.
      Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.
      ]. However, ABCB11 deficiency also represents a phenotypic spectrum, with episodic cholestasis (BRIC2) as the mild manifestation [
      • Jansen P.L.
      • Strautnieks S.S.
      • Jacquemin E.
      • Hadchouel M.
      • Sokal E.M.
      • Hooiveld G.J.
      • et al.
      Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis.
      ,
      • Lam C.W.
      • Cheung K.M.
      • Tsui M.S.
      • Yan M.S.
      • Lee C.Y.
      • Tong S.F.
      A patient with novel ABCB11 gene mutations with phenotypic transition between BRIC2 and PFIC2.
      ,
      • Takahashi A.
      • Hasegawa M.
      • Sumazaki R.
      • Suzuki M.
      • Toki F.
      • Suehiro T.
      • et al.
      Gradual improvement of liver function after administration of ursodeoxycholic acid in an infant with a novel ABCB11 gene mutation with phenotypic continuum between BRIC2 and PFIC2.
      ,
      • van Mil S.W.
      • van der Woerd W.L.
      • van der B.G.
      • Sturm E.
      • Jansen P.L.
      • Bull L.N.
      • et al.
      Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11.
      ]. Biochemically, serum concentrations of bile salts are markedly elevated, but GGT concentrations remain low [
      • Knisely A.S.
      Progressive familial intrahepatic cholestasis: a personal perspective.
      ,
      • Thompson R.
      • Strautnieks S.
      BSEP: function and role in progressive familial intrahepatic cholestasis.
      ]. Histological characteristics of the liver, with portal-tract fibrosis, bile duct proliferation and amorphous canalicular bile may distinguish ABCB11 from ATP8B deficiency [
      • Knisely A.S.
      Progressive familial intrahepatic cholestasis: a personal perspective.
      ]. In addition, ABCB11/Abcb11 localization is restricted to the canalicular membrane of hepatocytes [
      • Strautnieks S.S.
      • Bull L.N.
      • Knisely A.S.
      • Kocoshis S.A.
      • Dahl N.
      • Arnell H.
      • et al.
      A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis.
      ,
      • Gerloff T.
      • Stieger B.
      • Hagenbuch B.
      • Madon J.
      • Landmann L.
      • Roth J.
      • et al.
      The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver.
      ,
      • Keitel V.
      • Burdelski M.
      • Warskulat U.
      • Kuhlkamp T.
      • Keppler D.
      • Haussinger D.
      • et al.
      Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis.
      ] and no extrahepatic symptoms are described. In contrast, cholelithiasis is often observed, probably due to biliary bile salt concentrations that are too low to solubilise all biliary cholesterol [
      • Jansen P.L.
      • Strautnieks S.S.
      • Jacquemin E.
      • Hadchouel M.
      • Sokal E.M.
      • Hooiveld G.J.
      • et al.
      Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis.
      ,
      • van Mil S.W.
      • van der Woerd W.L.
      • van der B.G.
      • Sturm E.
      • Jansen P.L.
      • Bull L.N.
      • et al.
      Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11.
      ]. Also, hepatocellular carcinoma or cholangiocarcinoma may be a complication of ABCB11 deficiency [
      • Knisely A.S.
      • Strautnieks S.S.
      • Meier Y.
      • Stieger B.
      • Byrne J.A.
      • Portmann B.C.
      • et al.
      Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.
      ,
      • Scheimann A.O.
      • Strautnieks S.S.
      • Knisely A.S.
      • Byrne J.A.
      • Thompson R.J.
      • Finegold M.J.
      Mutations in bile salt export pump (ABCB11) in two children with progressive familial intrahepatic cholestasis and cholangiocarcinoma.
      ]. Heterozygous mutations in ABCB11 are described in drug induced cholestasis [
      • Lang C.
      • Meier Y.
      • Stieger B.
      • Beuers U.
      • Lang T.
      • Kerb R.
      • et al.
      Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury.
      ], ICP [
      • Dixon P.H.
      • van Mil S.W.
      • Chambers J.
      • Strautnieks S.
      • Thompson R.J.
      • Lammert F.
      • et al.
      Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy.
      ,
      • Meier Y.
      • Zodan T.
      • Lang C.
      • Zimmermann R.
      • Kullak-Ublick G.A.
      • Meier P.J.
      • et al.
      Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump.
      ,
      • Pauli-Magnus C.
      • Lang T.
      • Meier Y.
      • Zodan-Marin T.
      • Jung D.
      • Breymann C.
      • 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.
      ] and transient neonatal cholestasis [
      • Hermeziu B.
      • Sanlaville D.
      • Girard M.
      • Leonard C.
      • Lyonnet S.
      • Jacquemin E.
      Heterozygous bile salt export pump deficiency: a possible genetic predisposition to transient neonatal cholestasis.
      ] (Table 1).

      Phosphatidylcholine transporter ABCB4 (MDR3)

      ABCB4 is expressed at the apical membrane of the hepatocyte [
      • Keitel V.
      • Burdelski M.
      • Warskulat U.
      • Kuhlkamp T.
      • Keppler D.
      • Haussinger D.
      • et al.
      Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis.
      ,
      • Smit J.J.
      • Schinkel A.H.
      • Mol C.A.
      • Majoor D.
      • Mooi W.J.
      • Jongsma A.P.
      • et al.
      Tissue distribution of the human MDR3 P-glycoprotein.
      ] and is essential for PC secretion into the bile [
      • Smith A.J.
      • Timmermans-Hereijgers J.L.
      • Roelofsen B.
      • Wirtz K.W.
      • van Blitterswijk W.J.
      • Smit J.J.
      • et al.
      The human MDR3 P-glycoprotein promotes translocation of phosphatidylcholine through the plasma membrane of fibroblasts from transgenic mice.
      ,
      • van Helvoort A.
      • Smith A.J.
      • Sprong H.
      • Fritzsche I.
      • Schinkel A.H.
      • Borst P.
      • et al.
      MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine.
      ]. A defective ABCB4 protein causes an imbalance in the composition of primary bile, with lack of PC and a surplus of bile salts, the latter damaging the canaliculus and small bile ducts, causing chronic and progressive liver disease [
      • De Vree J.M.
      • Jacquemin E.
      • Sturm E.
      • Cresteil D.
      • Bosma P.J.
      • Aten J.
      • et al.
      Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.
      ]. Mutations in ABCB4 are associated with progressive familial intrahepatic cholestasis type 3 (PFIC3) which, like the other PFIC types, inherits in an autosomal recessive pattern [
      • De Vree J.M.
      • Jacquemin E.
      • Sturm E.
      • Cresteil D.
      • Bosma P.J.
      • Aten J.
      • et al.
      Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.
      ,
      • Degiorgio D.
      • Colombo C.
      • Seia M.
      • Porcaro L.
      • Costantino L.
      • Zazzeron L.
      • et al.
      Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3).
      ]. In contrast to patients with PFIC1 and PFIC2, serum GGT levels are elevated. Liver histology reveals fibrosis (progressing to cirrhosis) and marked bile duct proliferation [
      • De Vree J.M.
      • Jacquemin E.
      • Sturm E.
      • Cresteil D.
      • Bosma P.J.
      • Aten J.
      • et al.
      Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.
      ]. There are no extrahepatic symptoms but heterozygous mutations can be encountered in unexplained cholestasis [
      • Gotthardt D.
      • Runz H.
      • Keitel V.
      • Fischer C.
      • Flechtenmacher C.
      • Wirtenberger M.
      • et al.
      A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults.
      ,
      • Ziol M.
      • Barbu V.
      • Rosmorduc O.
      • Frassati-Biaggi A.
      • Barget N.
      • Hermelin B.
      • et al.
      ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults.
      ] and many milder cholestatic conditions, such as ICP [
      • Dixon P.H.
      • Weerasekera N.
      • Linton K.J.
      • Donaldson O.
      • Chambers J.
      • Egginton E.
      • et al.
      Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking.
      ,
      • Pauli-Magnus C.
      • Lang T.
      • Meier Y.
      • Zodan-Marin T.
      • Jung D.
      • Breymann C.
      • 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.
      ,
      • Schneider G.
      • Paus T.C.
      • Kullak-Ublick G.A.
      • Meier P.J.
      • Wienker T.F.
      • Lang T.
      • et al.
      Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy.
      ,
      • Floreani A.
      • Carderi I.
      • Paternoster D.
      • Soardo G.
      • Azzaroli F.
      • Esposito W.
      • et al.
      Intrahepatic cholestasis of pregnancy: three novel MDR3 gene mutations.
      ,
      • Floreani A.
      • Carderi I.
      • Paternoster D.
      • Soardo G.
      • Azzaroli F.
      • Esposito W.
      • et al.
      Hepatobiliary phospholipid transporter ABCB4, MDR3 gene variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy.
      ,
      • Gendrot C.
      • Bacq Y.
      • Brechot M.C.
      • Lansac J.
      • Andres C.
      A second heterozygous MDR3 nonsense mutation associated with intrahepatic cholestasis of pregnancy.
      ,
      • Jacquemin E.
      • Cresteil D.
      • Manouvrier S.
      • Boute O.
      • Hadchouel M.
      Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy.
      ,
      • Mullenbach R.
      • Linton K.J.
      • Wiltshire S.
      • Weerasekera N.
      • Chambers J.
      • Elias E.
      • et al.
      ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancy.
      ,
      • Wasmuth H.E.
      • Glantz A.
      • Keppeler H.
      • Simon E.
      • Bartz C.
      • Rath W.
      • et al.
      Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene.
      ], drug induced cholestasis [
      • Lang C.
      • Meier Y.
      • Stieger B.
      • Beuers U.
      • Lang T.
      • Kerb R.
      • et al.
      Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury.
      ], transient neonatal cholestasis [
      • Jung C.
      • Driancourt C.
      • Baussan C.
      • Zater M.
      • Hadchouel M.
      • Meunier-Rotival M.
      • et al.
      Prenatal molecular diagnosis of inherited cholestatic diseases.
      ], and isolated and recurrent intrahepatic cholesterol gallstones, designated as LPAC (low-phospholipid associated cholelithiasis syndrome) [
      • Nakken K.E.
      • Labori K.J.
      • Rodningen O.K.
      • Nakken S.
      • Berge K.E.
      • Eiklid K.
      • et al.
      ABCB4 sequence variations in young adults with cholesterol gallstone disease.
      ,
      • Rosmorduc O.
      • Hermelin B.
      • Poupon R.
      MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis.
      ,
      • Rosmorduc O.
      • Hermelin B.
      • Boelle P.Y.
      • Parc R.
      • Taboury J.
      • Poupon R.
      ABCB4 gene mutation-associated cholelithiasis in adults.
      ,
      • Rosmorduc O.
      • Poupon R.
      Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene.
      ] (Table 1). The latter is characterized by gallstone disease at relatively young age (<40 yrs) persistent after cholecystectomy. The underlying mechanism is an insufficient concentration of PC in bile to form mixed micelles with cholesterol, resulting in cholesterol supersaturation and crystal formation. The wide clinical spectrum of ABCB4 deficiency is illustrated by a patient with a heterozygous mutation in ABCB4 described by Lucena et al. This patient presented with juvenile cholelithiasis, recurrently manifested ICP and finally developed biliary cirrhosis [
      • Lucena J.F.
      • Herrero J.I.
      • Quiroga J.
      • Sangro B.
      • Garcia-Foncillas J.
      • Zabalegui N.
      • et al.
      A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis.
      ].

      Organic anion transporter ABCC2 (MRP2)

      ABCC2 expression is found in the liver but also at the apical membranes of other polarized cells [
      • Keitel V.
      • Burdelski M.
      • Warskulat U.
      • Kuhlkamp T.
      • Keppler D.
      • Haussinger D.
      • et al.
      Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis.
      ,
      • Sandusky G.E.
      • Mintze K.S.
      • Pratt S.E.
      • Dantzig A.H.
      Expression of multidrug resistance-associated protein 2 (MRP2) in normal human tissues and carcinomas using tissue microarrays.
      ,
      • Schaub T.P.
      • Kartenbeck J.
      • Konig J.
      • Spring H.
      • Dorsam J.
      • Staehler G.
      • et al.
      Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma.
      ]. Its substrate specificity is broad and comprises organic anions, mainly conjugated compounds. ABCC2 has an important role in the excretion of bilirubin into bile and in the excretion of bile salts after their sulfation or glucuronidation [
      • Kamisako T.
      • Leier I.
      • Cui Y.
      • Konig J.
      • Buchholz U.
      • Hummel-Eisenbeiss J.
      • et al.
      Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2.
      ,
      • Akita H.
      • Suzuki H.
      • Ito K.
      • Kinoshita S.
      • Sato N.
      • Takikawa H.
      • et al.
      Characterization of bile acid transport mediated by multidrug resistance associated protein 2 and bile salt export pump.
      ]. Nevertheless, the mild hepatic phenotype and lack of extrahepatic symptoms in ABCC2 deficiency suggests that other transporters can complement its function. ABCC2 deficiency causes Dubin Johnson syndrome (DJS). This syndrome is an autosomal, recessively inherited disorder characterized by chronic or intermittent conjugated hyperbilirubinemia. Although some patients complain about gastrointestinal symptoms and drug metabolism might be different, there are no further symptoms. Plasma concentrations of liver enzymes are usually within the normal range, and there is no permanent liver damage. However, on macroscopic examination the liver itself appears dark blue or black due to pigmentation [
      • Corpechot C.
      • Ping C.
      • Wendum D.
      • Matsuda F.
      • Barbu V.
      • Poupon R.
      Identification of a novel 974C → G nonsense mutation of the MRP2/ABCC2 gene in a patient with Dubin-Johnson syndrome and analysis of the effects of rifampicin and ursodeoxycholic acid on serum bilirubin and bile acids.
      ,
      • Dubin I.N.
      • Johnson F.B.
      Chronic idiopathic jaundice with unidentified pigment in liver cells; a new clinicopathologic entity with a report of 12 cases.
      ,
      • Rastogi A.
      • Krishnani N.
      • Pandey R.
      Dubin-Johnson syndrome – a clinicopathologic study of twenty cases.
      ] (Table 1). So far, no associations between the heterozygous state and liver or other disease has been found [
      • Nies A.T.
      • Keppler D.
      The apical conjugate efflux pump ABCC2 (MRP2).
      ].

      Cholesterol transporter ABCG5/8

      ABCG5/8 is expressed at the apical membrane of liver and intestine [
      • Klett E.L.
      • Lee M.H.
      • Adams D.B.
      • Chavin K.D.
      • Patel S.B.
      Localization of ABCG5 and ABCG8 proteins in human liver, gall bladder and intestine.
      ]. The protein-complex consists of two half transporters, ABCG5 and ABCG8, that heterodimerise in the endoplasmic reticulum to become functionally active [
      • Graf G.A.
      • Li W.P.
      • Gerard R.D.
      • Gelissen I.
      • White A.
      • Cohen J.C.
      • et al.
      Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface.
      ,
      • Graf G.A.
      • Yu L.
      • Li W.P.
      • Gerard R.
      • Tuma P.L.
      • Cohen J.C.
      • et al.
      ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion.
      ]. The ABCG5/8 transporter has a major role in the biliary and intestinal excretion of cholesterol and plant sterols (mainly sitosterols) [
      • Berge K.E.
      • Tian H.
      • Graf G.A.
      • Yu L.
      • Grishin N.V.
      • Schultz J.
      • et al.
      Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.
      ,
      • Lee M.H.
      • Lu K.
      • Hazard S.
      • Yu H.
      • Shulenin S.
      • Hidaka H.
      • et al.
      Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.
      ]. Mutations in either ABCG5 or ABCG8 cause a rare autosomal recessive disease, sitosterolaemia. This disease is characterized by an increased retention of sitosterols by the intestine and a failure to secrete sterols into bile, resulting in high plasma sitosterol levels and accumulation of sterols in peripheral tissues and blood [
      • Berge K.E.
      • Tian H.
      • Graf G.A.
      • Yu L.
      • Grishin N.V.
      • Schultz J.
      • et al.
      Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.
      ,
      • Lee M.H.
      • Lu K.
      • Hazard S.
      • Yu H.
      • Shulenin S.
      • Hidaka H.
      • et al.
      Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.
      ,
      • Lam C.W.
      • Cheng A.W.
      • Tong S.F.
      • Chan Y.W.
      Novel donor splice site mutation of ABCG5 gene in sitosterolemia.
      ,
      • Heimerl S.
      • Langmann T.
      • Moehle C.
      • Mauerer R.
      • Dean M.
      • Beil F.U.
      • et al.
      Mutations in the human ATP-binding cassette transporters ABCG5 and ABCG8 in sitosterolemia.
      ]. Patients consequently present with tendon xanthomas, arthralgias and premature coronary artery disease, despite relatively low plasma levels of cholesterol [
      • Alam M.
      • Garzon M.C.
      • Salen G.
      • Starc T.J.
      Tuberous xanthomas in sitosterolemia.
      ,
      • Katayama T.
      • Satoh T.
      • Yagi T.
      • Hirose N.
      • Kurita Y.
      • Anzai T.
      • et al.
      A 19-year-old man with myocardial infarction and sitosterolemia.
      ,
      • Kolovou G.
      • Voudris V.
      • Drogari E.
      • Palatianos G.
      • Cokkinos D.V.
      Coronary bypass grafts in a young girl with sitosterolemia.
      ] (Table 1). Sporadically, haemolytic abnormalities are mentioned [
      • Rees D.C.
      • Iolascon A.
      • Carella M.
      • O’marcaigh A.S.
      • Kendra J.R.
      • Jowitt S.N.
      • et al.
      Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia.
      ]. Except for one patient with chronic active hepatitis and signs of cirrhosis, nothing is known about liver histology [
      • Miettinen T.A.
      • Klett E.L.
      • Gylling H.
      • Isoniemi H.
      • Patel S.B.
      Liver transplantation in a patient with sitosterolemia and cirrhosis.
      ]. The effect of being a heterozygous carrier for these mutations is not clear yet [
      • Hidaka H.
      • Nakamura T.
      • Aoki T.
      • Kojima H.
      • Nakajima Y.
      • Kosugi K.
      • et al.
      Increased plasma plant sterol levels in heterozygotes with sitosterolemia and xanthomatosis.
      ].

      Treatment of canalicular transport defects

      All liver diseases described above are due to mutations in genes encoding hepatocanalicular transporters. For most of these diseases the response to current medical therapy is either non-existent or of limited duration. Some agents have proven to be effective in specific situations, mainly by providing symptomatic relief.
      Nevertheless, most patients with progressive cholestasis eventually need surgical intervention. Even patients with the relative “benign” phenotypes of intrahepatic cholestasis (BRIC) may undergo invasive therapy, purely to improve quality of life [
      • Bourke B.
      • Goggin N.
      • Walsh D.
      • Kennedy S.
      • Setchell K.D.
      • Drumm B.
      Byler-like familial cholestasis in an extended kindred.
      ,
      • Tygstrup N.
      • Steig B.A.
      • Juijn J.A.
      • Bull L.N.
      • Houwen R.H.
      Recurrent familial intrahepatic cholestasis in the Faeroe Islands. Phenotypic heterogeneity but genetic homogeneity.
      ,
      • van Ooteghem N.A.
      • Klomp L.W.
      • van Berge-Henegouwen G.P.
      • Houwen R.H.
      Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.
      ].

      Current medical treatment

      The therapeutic strategies for cholestasis due to canalicular transport defects may target bile composition, bile salt toxicity and the secretion of bile salts. The ideal therapy should have anti-cholestatic, anti-fibrotic and anti-neoplastic properties. Ursodeoxycholic acid (UDCA), rifampicin and cholestyramine are amongst the most commonly used. Sometimes combination therapy is employed, but there is no evidence for any synergistic effect.

      UDCA

      The main therapeutic target of UDCA is the protection of hepatocytes and cholangiocytes by replacing endogenous, cytotoxic bile salts [
      • Lazaridis K.N.
      • Gores G.J.
      • Lindor K.D.
      Ursodeoxycholic acid ‘mechanisms of action and clinical use in hepatobiliary disorders’.
      ,
      • Paumgartner G.
      • Beuers U.
      Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited.
      ]. In addition, UDCA induces expression of functional transporters at transcriptional and post-transcriptional level and enhances bile flow, possibly through cholehepatic shunting [
      • Beuers U.
      • Bilzer M.
      • Chittattu A.
      • Kullak-Ublick G.A.
      • Keppler D.
      • Paumgartner G.
      • et al.
      Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver.
      ,
      • Dumont M.
      • Emmanuel J.
      • Serge E.
      Effect of ursodeoxycholic acid on the expression of the hepatocellular bile acid transporters (Ntcp and bsep) in rats with estrogen-induced cholestasis.
      ,
      • Fickert P.
      • Zollner G.
      • Fuchsbichler A.
      • Stumptner C.
      • Pojer C.
      • Zenz R.
      • et al.
      Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver.
      ,
      • Marschall H.U.
      • Wagner M.
      • Zollner G.
      • Fickert P.
      • Diczfalusy U.
      • Gumhold J.
      • et al.
      Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans.
      ,
      • Hofmann A.F.
      • Zakko S.F.
      • Lira M.
      • Clerici C.
      • Hagey L.R.
      • Lambert K.K.
      • et al.
      Novel biotransformation and physiological properties of norursodeoxycholic acid in humans.
      ,
      • van de Meeberg P.C.
      • van Erpecum K.J.
      • van Berge-Henegouwen G.P.
      Therapy with ursodeoxycholic acid in cholestatic liver disease.
      ]. A simplified illustration of the effect of UDCA in the hepatocyte can be found in Fig. 1B.
      More than half of the patients with high GGT-PFIC or proven PFIC3 responded to UDCA treatment [
      • Jacquemin E.
      • Hermans D.
      • Myara A.
      • Habes D.
      • Debray D.
      • Hadchouel M.
      • et al.
      Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis.
      ,
      • Jacquemin E.
      • De Vree J.M.
      • Cresteil D.
      • Sokal E.M.
      • Sturm E.
      • Dumont M.
      • et al.
      The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood.
      ,
      • Wanty C.
      • Joomye R.
      • Van H.N.
      • Paul K.
      • Otte J.B.
      • Reding R.
      • et al.
      Fifteen years single center experience in the management of progressive familial intrahepatic cholestasis of infancy.
      ] (Table 2A). Although in most reports this response was not further clarified we presume that it was characterized by at least partial improvement in serum transaminase levels and pruritus. Interestingly, those with missense mutations generally had a good response to UDCA therapy, while those with a premature stop codon showed no response [
      • Jacquemin E.
      • De Vree J.M.
      • Cresteil D.
      • Sokal E.M.
      • Sturm E.
      • Dumont M.
      • et al.
      The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood.
      ]. Therefore in patients with PFIC3 and a presumed residual function of the ABCB4 protein based on mutational analysis, UDCA is the therapy of choice.
      Table 2AUDCA treatment in hepatocanalicular transport defects.
      Hepatocanalicular defectNumber patientsOutcome (number patients)Reference
      PFIC undefined subtypes58Improvement (2)
      • Naveh Y.
      • Bassan L.
      • Rosenthal E.
      • Berkowitz D.
      • Jaffe M.
      • Mandel H.
      • et al.
      Progressive familial intrahepatic cholestasis among the Arab population in Israel.
      ,
      • Englert C.
      • Grabhorn E.
      • Richter A.
      • Rogiers X.
      • Burdelski M.
      • Ganschow R.
      Liver transplantation in children with progressive familial intrahepatic cholestasis.
      Partial improvement (0)
      No improvement (56)
      Low GGT-PFIC98Improvement (22)
      • Jacquemin E.
      • Hermans D.
      • Myara A.
      • Habes D.
      • Debray D.
      • Hadchouel M.
      • et al.
      Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis.
      ,
      • Wanty C.
      • Joomye R.
      • Van H.N.
      • Paul K.
      • Otte J.B.
      • Reding R.
      • et al.
      Fifteen years single center experience in the management of progressive familial intrahepatic cholestasis of infancy.
      ,
      • Morton D.H.
      • Salen G.
      • Batta A.K.
      • Shefer S.
      • Tint G.S.
      • Belchis D.
      • et al.
      Abnormal hepatic sinusoidal bile acid transport in an Amish kindred is not linked to FIC1 and is improved by ursodiol.
      ,
      • Ismail H.
      • Kalicinski P.
      • Markiewicz M.
      • Jankowska I.
      • Pawlowska J.
      • Kluge P.
      • et al.
      Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion.
      ,
      • Whitington P.F.
      • Freese D.K.
      • Alonso E.M.
      • Schwarzenberg S.J.
      • Sharp H.L.
      Clinical and biochemical findings in progressive familial intrahepatic cholestasis.
      ,
      • Bustorff-Silva J.
      • Sbraggia N.L.
      • Olimpio H.
      • de Alcantara R.V.
      • Matsushima E.
      • De Tommaso A.M.
      • et al.
      Partial internal biliary diversion through a cholecystojejunocolonic anastomosis – a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report.
      ,
      • Emerick K.M.
      • Elias M.S.
      • Melin-Aldana H.
      • Strautnieks S.
      • Thompson R.J.
      • Bull L.N.
      • et al.
      Bile composition in alagille syndrome and PFIC patients having partial external biliary diversion.
      ,
      • Kurbegov A.C.
      • Setchell K.D.
      • Haas J.E.
      • Mierau G.W.
      • Narkewicz M.
      • Bancroft J.D.
      • et al.
      Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile.
      ,
      • Yerushalmi B.
      • Sokol R.J.
      • Narkewicz M.R.
      • Smith D.
      • Karrer F.M.
      Use of rifampin for severe pruritus in children with chronic cholestasis.
      Partial improvement (12)
      No improvement (64)
      High GGT-PFIC46Improvement (20)
      • Jacquemin E.
      • Hermans D.
      • Myara A.
      • Habes D.
      • Debray D.
      • Hadchouel M.
      • et al.
      Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis.
      ,
      • Jacquemin E.
      • De Vree J.M.
      • Cresteil D.
      • Sokal E.M.
      • Sturm E.
      • Dumont M.
      • et al.
      The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood.
      ,
      • Wanty C.
      • Joomye R.
      • Van H.N.
      • Paul K.
      • Otte J.B.
      • Reding R.
      • et al.
      Fifteen years single center experience in the management of progressive familial intrahepatic cholestasis of infancy.
      Partial improvement (14)
      No improvement (12)
      BRIC12Improvement (0)
      • Brenard R.
      • Geubel A.P.
      • Benhamou J.P.
      Benign recurrent intrahepatic cholestasis. A report of 26 cases.
      ,
      • van Ooteghem N.A.
      • Klomp L.W.
      • van Berge-Henegouwen G.P.
      • Houwen R.H.
      Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.
      ,
      • Lykavieris P.
      • van M.S.
      • Cresteil D.
      • Fabre M.
      • Hadchouel M.
      • Klomp L.
      • et al.
      Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation.
      ,
      • Lam C.W.
      • Cheung K.M.
      • Tsui M.S.
      • Yan M.S.
      • Lee C.Y.
      • Tong S.F.
      A patient with novel ABCB11 gene mutations with phenotypic transition between BRIC2 and PFIC2.
      ,
      • Takahashi A.
      • Hasegawa M.
      • Sumazaki R.
      • Suzuki M.
      • Toki F.
      • Suehiro T.
      • et al.
      Gradual improvement of liver function after administration of ursodeoxycholic acid in an infant with a novel ABCB11 gene mutation with phenotypic continuum between BRIC2 and PFIC2.
      ,
      • Crosignani A.
      • Podda M.
      • Bertolini E.
      • Battezzati P.M.
      • Zuin M.
      • Setchell K.D.
      Failure of ursodeoxycholic acid to prevent a cholestatic episode in a patient with benign recurrent intrahepatic cholestasis: a study of bile acid metabolism.
      ,
      • Cancado E.L.
      • Leitao R.M.
      • Carrilho F.J.
      • Laudanna A.A.
      Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of gamma-glutamyl transpeptidase.
      ,
      • Metzelder M.L.
      • Petersen C.
      • Melter M.
      • Ure B.M.
      Modified laparoscopic external biliary diversion for benign recurrent intrahepatic cholestasis in obese adolescents.
      Partial improvement (2)
      No improvement (10)
      DJS2Improvement (1)
      • Corpechot C.
      • Ping C.
      • Wendum D.
      • Matsuda F.
      • Barbu V.
      • Poupon R.
      Identification of a novel 974C → G nonsense mutation of the MRP2/ABCC2 gene in a patient with Dubin-Johnson syndrome and analysis of the effects of rifampicin and ursodeoxycholic acid on serum bilirubin and bile acids.
      ,
      • Regev R.H.
      • Stolar O.
      • Raz A.
      • Dolfin T.
      Treatment of severe cholestasis in neonatal Dubin-Johnson syndrome with ursodeoxycholic acid.
      Partial improvement (0)
      No improvement (1)
      ‘‘Improvement”, indicates (almost complete) normalization of serum transaminases and/or bilirubin concentration and total relief of pruritus.
      ‘‘Partial improvement”, indicates no complete normalization of serum transaminases and/or bilirubin concentration with or without persistent pruritus.
      ‘‘No improvement”, indicates no response or deterioration of the symptoms.
      PFIC, progressive familial intrahepatic cholestasis; BRIC, benign recurrent intrahepatic cholestasis; DJS, Dubin Johnson syndrome; GGT, gamma-glutamyl transpeptidase. In the high GGT-PFIC subtype, 11 patient are reported twice
      • Jacquemin E.
      • Hermans D.
      • Myara A.
      • Habes D.
      • Debray D.
      • Hadchouel M.
      • et al.
      Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis.
      ,
      • Jacquemin E.
      • De Vree J.M.
      • Cresteil D.
      • Sokal E.M.
      • Sturm E.
      • Dumont M.
      • et al.
      The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood.
      .
      In patients with low GGT-PFIC or an undefined subtype of PFIC, the response to UDCA therapy was much less promising. Although in some reports serum transaminase levels and pruritus improved in about half of the patients upon UDCA [
      • Jacquemin E.
      • Hermans D.
      • Myara A.
      • Habes D.
      • Debray D.
      • Hadchouel M.
      • et al.
      Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis.
      ,
      • Wanty C.
      • Joomye R.
      • Van H.N.
      • Paul K.
      • Otte J.B.
      • Reding R.
      • et al.
      Fifteen years single center experience in the management of progressive familial intrahepatic cholestasis of infancy.
      ,
      • Morton D.H.
      • Salen G.
      • Batta A.K.
      • Shefer S.
      • Tint G.S.
      • Belchis D.
      • et al.
      Abnormal hepatic sinusoidal bile acid transport in an Amish kindred is not linked to FIC1 and is improved by ursodiol.
      ], in most studies UDCA was not effective [
      • Ismail H.
      • Kalicinski P.
      • Markiewicz M.
      • Jankowska I.
      • Pawlowska J.
      • Kluge P.
      • et al.
      Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion.
      ,
      • Naveh Y.
      • Bassan L.
      • Rosenthal E.
      • Berkowitz D.
      • Jaffe M.
      • Mandel H.
      • et al.
      Progressive familial intrahepatic cholestasis among the Arab population in Israel.
      ,
      • Whitington P.F.
      • Freese D.K.
      • Alonso E.M.
      • Schwarzenberg S.J.
      • Sharp H.L.
      Clinical and biochemical findings in progressive familial intrahepatic cholestasis.
      ,
      • Bustorff-Silva J.
      • Sbraggia N.L.
      • Olimpio H.
      • de Alcantara R.V.
      • Matsushima E.
      • De Tommaso A.M.
      • et al.
      Partial internal biliary diversion through a cholecystojejunocolonic anastomosis – a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report.
      ,
      • Emerick K.M.
      • Elias M.S.
      • Melin-Aldana H.
      • Strautnieks S.
      • Thompson R.J.
      • Bull L.N.
      • et al.
      Bile composition in alagille syndrome and PFIC patients having partial external biliary diversion.
      ,
      • Englert C.
      • Grabhorn E.
      • Richter A.
      • Rogiers X.
      • Burdelski M.
      • Ganschow R.
      Liver transplantation in children with progressive familial intrahepatic cholestasis.
      ,
      • Kurbegov A.C.
      • Setchell K.D.
      • Haas J.E.
      • Mierau G.W.
      • Narkewicz M.
      • Bancroft J.D.
      • et al.
      Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile.
      ,
      • Yerushalmi B.
      • Sokol R.J.
      • Narkewicz M.R.
      • Smith D.
      • Karrer F.M.
      Use of rifampin for severe pruritus in children with chronic cholestasis.
      ]. Even in patients with a mild phenotype (BRIC1, BRIC2), UDCA did not prevent or abort a cholestatic attack [
      • Brenard R.
      • Geubel A.P.
      • Benhamou J.P.
      Benign recurrent intrahepatic cholestasis. A report of 26 cases.
      ,
      • van Ooteghem N.A.
      • Klomp L.W.
      • van Berge-Henegouwen G.P.
      • Houwen R.H.
      Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.
      ,
      • Lykavieris P.
      • van M.S.
      • Cresteil D.
      • Fabre M.
      • Hadchouel M.
      • Klomp L.
      • et al.
      Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation.
      ,
      • Lam C.W.
      • Cheung K.M.
      • Tsui M.S.
      • Yan M.S.
      • Lee C.Y.
      • Tong S.F.
      A patient with novel ABCB11 gene mutations with phenotypic transition between BRIC2 and PFIC2.
      ,
      • Takahashi A.
      • Hasegawa M.
      • Sumazaki R.
      • Suzuki M.
      • Toki F.
      • Suehiro T.
      • et al.
      Gradual improvement of liver function after administration of ursodeoxycholic acid in an infant with a novel ABCB11 gene mutation with phenotypic continuum between BRIC2 and PFIC2.
      ,
      • Crosignani A.
      • Podda M.
      • Bertolini E.
      • Battezzati P.M.
      • Zuin M.
      • Setchell K.D.
      Failure of ursodeoxycholic acid to prevent a cholestatic episode in a patient with benign recurrent intrahepatic cholestasis: a study of bile acid metabolism.
      ,
      • Cancado E.L.
      • Leitao R.M.
      • Carrilho F.J.
      • Laudanna A.A.
      Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of gamma-glutamyl transpeptidase.
      ,
      • Metzelder M.L.
      • Petersen C.
      • Melter M.
      • Ure B.M.
      Modified laparoscopic external biliary diversion for benign recurrent intrahepatic cholestasis in obese adolescents.
      ] (Table 2A). Currently it is not possible to predict who would benefit from UDCA in low GGT cholestasis and it is doubtful whether UDCA has a place in the treatment of ATP8B1 or ABCB11 deficiency. Especially for patients with progression to severe liver disease, surgical management is needed as soon as possible.
      For DJS, two case-reports have been published with opposite effect. In one patient, serum bilirubin declined upon UDCA treatment, while in the other patient a combination of rifampicin with UDCA led to a dramatic rise in serum bilirubin and bile salt concentrations, which normalized once again after these medications were discontinued [
      • Corpechot C.
      • Ping C.
      • Wendum D.
      • Matsuda F.
      • Barbu V.
      • Poupon R.
      Identification of a novel 974C → G nonsense mutation of the MRP2/ABCC2 gene in a patient with Dubin-Johnson syndrome and analysis of the effects of rifampicin and ursodeoxycholic acid on serum bilirubin and bile acids.
      ,
      • Regev R.H.
      • Stolar O.
      • Raz A.
      • Dolfin T.
      Treatment of severe cholestasis in neonatal Dubin-Johnson syndrome with ursodeoxycholic acid.
      ] (Table 2A). For sitosterolaemia no clinical trials or case-reports have been published.
      UDCA treatment is safe, and except for the reversible effect in the DJS patient no serious side-effects have been described.
      Recently it was found that shortening of the side chains increases the therapeutic efficacy of UDCA [
      • Hofmann A.F.
      • Zakko S.F.
      • Lira M.
      • Clerici C.
      • Hagey L.R.
      • Lambert K.K.
      • et al.
      Novel biotransformation and physiological properties of norursodeoxycholic acid in humans.
      ]. This modified, so called norUDCA has already been proven to be more effective than the parent compound in a murine model of primary sclerosing cholangitis [
      • Fickert P.
      • Wagner M.
      • Marschall H.U.
      • Fuchsbichler A.
      • Zollner G.
      • Tsybrovskyy O.
      • et al.
      24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice.
      ].

      Rifampicin

      The primary effect of rifampicin is inducing CYP3A4 expression through activation of the xenosensor pregnane X receptor (PXR). This increases 6α-hydroxylation of bile salts, compounds which can subsequently be glucuronidated and excreted in the urine [
      • Marschall H.U.
      • Wagner M.
      • Zollner G.
      • Fickert P.
      • Diczfalusy U.
      • Gumhold J.
      • et al.
      Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans.
      ,
      • Wietholtz H.
      • Marschall H.U.
      • Sjovall J.
      • Matern S.
      Stimulation of bile acid 6 alpha-hydroxylation by rifampin.
      ]. In addition, conjugation and excretion of bilirubin is enhanced through induction of UGT1A1 and ABCC2 [
      • Marschall H.U.
      • Wagner M.
      • Zollner G.
      • Fickert P.
      • Diczfalusy U.
      • Gumhold J.
      • et al.
      Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans.
      ]. Enhanced expression of the latter might also be important for excretion of other, still unidentified pruritogenic compounds (Fig. 1B).
      In patients with low GGT-PFIC, rifampicin did not have any long lasting effect on serum concentration of bilirubin and transaminases, but reduced the pruritus in some patients [
      • Whitington P.F.
      • Freese D.K.
      • Alonso E.M.
      • Schwarzenberg S.J.
      • Sharp H.L.
      Clinical and biochemical findings in progressive familial intrahepatic cholestasis.
      ,
      • Bustorff-Silva J.
      • Sbraggia N.L.
      • Olimpio H.
      • de Alcantara R.V.
      • Matsushima E.
      • De Tommaso A.M.
      • et al.
      Partial internal biliary diversion through a cholecystojejunocolonic anastomosis – a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report.
      ,
      • Kurbegov A.C.
      • Setchell K.D.
      • Haas J.E.
      • Mierau G.W.
      • Narkewicz M.
      • Bancroft J.D.
      • et al.
      Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile.
      ,
      • Yerushalmi B.
      • Sokol R.J.
      • Narkewicz M.R.
      • Smith D.
      • Karrer F.M.
      Use of rifampin for severe pruritus in children with chronic cholestasis.
      ]. This marginal effect contrasts with the results obtained in patients with BRIC. After starting rifampicin treatment in seven patients, eighteen out of twenty-two episodes were completely aborted within several weeks [
      • van Ooteghem N.A.
      • Klomp L.W.
      • van Berge-Henegouwen G.P.
      • Houwen R.H.
      Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.
      ,
      • Cancado E.L.
      • Leitao R.M.
      • Carrilho F.J.
      • Laudanna A.A.
      Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of gamma-glutamyl transpeptidase.
      ,
      • Metzelder M.L.
      • Petersen C.
      • Melter M.
      • Ure B.M.
      Modified laparoscopic external biliary diversion for benign recurrent intrahepatic cholestasis in obese adolescents.
      ,
      • Balsells F.
      • Wyllie R.
      • Steffen R.
      • Kay M.
      Benign recurrent intrahepatic cholestasis: improvement of pruritus and shortening of the symptomatic phase with rifampin therapy: a case report.
      ] (Table 2B). Thus it seems that rifampicin can reduce pruritus in some patients with low GGT-PFIC, but might even induce remission in patients with BRIC. Nevertheless, rifampicin treatment should be used with caution because of its potential hepatotoxic effect.
      Table 2BRifampicin treatment in hepatocanalicular transport defects.
      Hepatocanalicular defectNumber patientsOutcome (number patients)Reference
      Low GGT-PFIC17Improvement (0)
      • Whitington P.F.
      • Freese D.K.
      • Alonso E.M.
      • Schwarzenberg S.J.
      • Sharp H.L.
      Clinical and biochemical findings in progressive familial intrahepatic cholestasis.
      ,
      • Bustorff-Silva J.
      • Sbraggia N.L.
      • Olimpio H.
      • de Alcantara R.V.
      • Matsushima E.
      • De Tommaso A.M.
      • et al.
      Partial internal biliary diversion through a cholecystojejunocolonic anastomosis – a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report.
      ,
      • Kurbegov A.C.
      • Setchell K.D.
      • Haas J.E.
      • Mierau G.W.
      • Narkewicz M.
      • Bancroft J.D.
      • et al.
      Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile.
      ,
      • Yerushalmi B.
      • Sokol R.J.
      • Narkewicz M.R.
      • Smith D.
      • Karrer F.M.
      Use of rifampin for severe pruritus in children with chronic cholestasis.
      Partial improvement (3)
      No improvement (14)
      BRIC7Improvement (5)
      • van Ooteghem N.A.
      • Klomp L.W.
      • van Berge-Henegouwen G.P.
      • Houwen R.H.
      Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.
      ,
      • Cancado E.L.
      • Leitao R.M.
      • Carrilho F.J.
      • Laudanna A.A.
      Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of gamma-glutamyl transpeptidase.
      ,
      • Metzelder M.L.
      • Petersen C.
      • Melter M.
      • Ure B.M.
      Modified laparoscopic external biliary diversion for benign recurrent intrahepatic cholestasis in obese adolescents.
      ,
      • Balsells F.
      • Wyllie R.
      • Steffen R.
      • Kay M.
      Benign recurrent intrahepatic cholestasis: improvement of pruritus and shortening of the symptomatic phase with rifampin therapy: a case report.
      Partial improvement (0)
      No improvement (2)
      DJS1Improvement (0)
      • Corpechot C.
      • Ping C.
      • Wendum D.
      • Matsuda F.
      • Barbu V.
      • Poupon R.
      Identification of a novel 974C → G nonsense mutation of the MRP2/ABCC2 gene in a patient with Dubin-Johnson syndrome and analysis of the effects of rifampicin and ursodeoxycholic acid on serum bilirubin and bile acids.
      Partial improvement (0)
      No improvement (1)
      ‘‘Improvement”, indicates the almost complete normalization of serum transaminases and/or bilirubin concentration and total relief of pruritus. For patients with BRIC “improvement” indicates the abortion of a cholestatic attack. ‘‘Partial improvement” indicates lack of complete normalization of serum transaminase concentration but improvement of pruritus. “No improvement” indicates lack of response or deterioration of the symptoms.
      PFIC, progressive familial intrahepatic cholestasis; BRIC, benign recurrent intrahepatic cholestasis; DJS, Dubin Johnson syndrome; GGT, gamma-glutamyl transpeptidase.
      The use of rifampicin in DJS has been described in one patient, but instead of reducing serum bilirubin concentrations, the conjugated bilirubinemia increased during treatment [
      • Corpechot C.
      • Ping C.
      • Wendum D.
      • Matsuda F.
      • Barbu V.
      • Poupon R.
      Identification of a novel 974C → G nonsense mutation of the MRP2/ABCC2 gene in a patient with Dubin-Johnson syndrome and analysis of the effects of rifampicin and ursodeoxycholic acid on serum bilirubin and bile acids.
      ] (Table 2B). It is not known whether rifampicin affects cholesterol homeostasis as well, but so far no experience with sitosterolaemia has been published.

      Cholestyramine

      Cholestyramine is a negative ion exchange resin that binds bile salts in the intestinal lumen, reduces re-absorption and stimulates faecal excretion of bile salts (Fig. 1C) [
      • Garbutt J.T.
      • Kenney T.J.
      Effect of cholestyramine on bile acid metabolism in normal man.
      ].
      Cholestyramine does not seem to be effective in patients with low GGT-PFIC or undefined subtypes of PFIC [
      • Naveh Y.
      • Bassan L.
      • Rosenthal E.
      • Berkowitz D.
      • Jaffe M.
      • Mandel H.
      • et al.
      Progressive familial intrahepatic cholestasis among the Arab population in Israel.
      ,
      • Whitington P.F.
      • Freese D.K.
      • Alonso E.M.
      • Schwarzenberg S.J.
      • Sharp H.L.
      Clinical and biochemical findings in progressive familial intrahepatic cholestasis.
      ,
      • Kurbegov A.C.
      • Setchell K.D.
      • Haas J.E.
      • Mierau G.W.
      • Narkewicz M.
      • Bancroft J.D.
      • et al.
      Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile.
      ,
      • Nakagawa M.
      • Tazawa Y.
      • Kobayashi Y.
      • Yamada M.
      • Suzuki H.
      • Konno T.
      • et al.
      Familial intrahepatic cholestasis associated with progressive neuromuscular disease and vitamin E deficiency.
      ,
      • Whitington P.F.
      • Whitington G.L.
      Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis.
      ]. For patients with BRIC the results are variable, varying from shortening of the cholestatic episodes [
      • van Ooteghem N.A.
      • Klomp L.W.
      • van Berge-Henegouwen G.P.
      • Houwen R.H.
      Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.
      ,
      • Uegaki S.
      • Tanaka A.
      • Mori Y.
      • Kodama H.
      • Fukusato T.
      • Takikawa H.
      Successful treatment with colestimide for a bout of cholestasis in a Japanese patient with benign recurrent intrahepatic cholestasis caused by ATP8B1 mutation.
      ,
      • Al Drees K.
      • Al Z.A.
      • Al A.A.
      • Abdulla A.
      Benign recurrent intrahepatic cholestasis in a Saudi child.
      ] to no effect at all [
      • Brenard R.
      • Geubel A.P.
      • Benhamou J.P.
      Benign recurrent intrahepatic cholestasis. A report of 26 cases.
      ,
      • van Ooteghem N.A.
      • Klomp L.W.
      • van Berge-Henegouwen G.P.
      • Houwen R.H.
      Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.
      ,
      • Cancado E.L.
      • Leitao R.M.
      • Carrilho F.J.
      • Laudanna A.A.
      Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of gamma-glutamyl transpeptidase.
      ,
      • Metzelder M.L.
      • Petersen C.
      • Melter M.
      • Ure B.M.
      Modified laparoscopic external biliary diversion for benign recurrent intrahepatic cholestasis in obese adolescents.
      ,
      • Odievre M.
      • Gautier M.
      • Hadchouel M.
      • Alagille D.
      Severe familial intrahepatic cholestasis.
      ] (Table 2C). Consequently cholestyramine seems to have no place in the treatment of PFIC, but it may be beneficial in patients with BRIC. Given the potentially better tolerability and higher efficacy of the new bile salt resin binders with other polymer structures, such as colesevalam [
      • Bays H.E.
      • Goldberg R.B.
      The ‘forgotten’ bile acid sequestrants: is now a good time to remember?.
      ], these drugs should be the topic of further investigations.
      Table 2CCholestyramine treatment in hepatocanalicular transport defects.
      Hepatocanalicular defectNumber patientsOutcome (number patients)Reference
      PFIC undefined subtypes23Improvement (0)
      • Naveh Y.
      • Bassan L.
      • Rosenthal E.
      • Berkowitz D.
      • Jaffe M.
      • Mandel H.
      • et al.
      Progressive familial intrahepatic cholestasis among the Arab population in Israel.
      ,
      • Nakagawa M.
      • Tazawa Y.
      • Kobayashi Y.
      • Yamada M.
      • Suzuki H.
      • Konno T.
      • et al.
      Familial intrahepatic cholestasis associated with progressive neuromuscular disease and vitamin E deficiency.
      ,
      • Whitington P.F.
      • Whitington G.L.
      Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis.
      Partial improvement (1)
      No improvement (22)
      Low GGT-PFIC34Improvement (0)
      • Whitington P.F.
      • Freese D.K.
      • Alonso E.M.
      • Schwarzenberg S.J.
      • Sharp H.L.
      Clinical and biochemical findings in progressive familial intrahepatic cholestasis.
      ,
      • Kurbegov A.C.
      • Setchell K.D.
      • Haas J.E.
      • Mierau G.W.
      • Narkewicz M.
      • Bancroft J.D.
      • et al.
      Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile.
      Partial improvement (0)
      No improvement (34)
      BRIC20Improvement (2)
      • Brenard R.
      • Geubel A.P.
      • Benhamou J.P.
      Benign recurrent intrahepatic cholestasis. A report of 26 cases.
      ,
      • van Ooteghem N.A.
      • Klomp L.W.
      • van Berge-Henegouwen G.P.
      • Houwen R.H.
      Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.
      ,
      • Cancado E.L.
      • Leitao R.M.
      • Carrilho F.J.
      • Laudanna A.A.
      Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of gamma-glutamyl transpeptidase.
      ,
      • Metzelder M.L.
      • Petersen C.
      • Melter M.
      • Ure B.M.
      Modified laparoscopic external biliary diversion for benign recurrent intrahepatic cholestasis in obese adolescents.
      ,
      • Uegaki S.
      • Tanaka A.
      • Mori Y.
      • Kodama H.
      • Fukusato T.
      • Takikawa H.
      Successful treatment with colestimide for a bout of cholestasis in a Japanese patient with benign recurrent intrahepatic cholestasis caused by ATP8B1 mutation.
      ,
      • Al Drees K.
      • Al Z.A.
      • Al A.A.
      • Abdulla A.
      Benign recurrent intrahepatic cholestasis in a Saudi child.
      ,
      • Odievre M.
      • Gautier M.
      • Hadchouel M.
      • Alagille D.
      Severe familial intrahepatic cholestasis.
      Partial improvement (2)
      No improvement (16)
      Sitosterolaemia13Improvement (12)
      • Alam M.
      • Garzon M.C.
      • Salen G.
      • Starc T.J.
      Tuberous xanthomas in sitosterolemia.
      ,
      • Hidaka H.
      • Nakamura T.
      • Aoki T.
      • Kojima H.
      • Nakajima Y.
      • Kosugi K.
      • et al.
      Increased plasma plant sterol levels in heterozygotes with sitosterolemia and xanthomatosis.
      ,
      • Belamarich P.F.
      • Deckelbaum R.J.
      • Starc T.J.
      • Dobrin B.E.
      • Tint G.S.
      • Salen G.
      Response to diet and cholestyramine in a patient with sitosterolemia.
      ,
      • Nguyen L.B.
      • Cobb M.
      • Shefer S.
      • Salen G.
      • Ness G.C.
      • Tint G.S.
      Regulation of cholesterol biosynthesis in sitosterolemia: effects of lovastatin, cholestyramine, and dietary sterol restriction.
      ,
      • Gregg R.E.
      • Connor W.E.
      • Lin D.S.
      • Brewer Jr., H.B.
      Abnormal metabolism of shellfish sterols in a patient with sitosterolemia and xanthomatosis.
      ,
      • Salen G.
      • Kwiterovich Jr., P.O.
      • Shefer S.
      • Tint G.S.
      • Horak I.
      • Shore V.
      • et al.
      Increased plasma cholestanol and 5 alpha-saturated plant sterol derivatives in subjects with sitosterolemia and xanthomatosis.
      ,
      • Cobb M.M.
      • Salen G.
      • Tint G.S.
      • Greenspan J.
      • Nguyen L.B.
      Sitosterolemia: opposing effects of cholestyramine and lovastatin on plasma sterol levels in a homozygous girl and her heterozygous father.
      ,
      • Salen G.
      • Starc T.
      • Sisk C.M.
      • Patel S.B.
      Intestinal cholesterol absorption inhibitor ezetimibe added to cholestyramine for sitosterolemia and xanthomatosis.
      Partial improvement (1)
      No improvement (0)
      “Improvement” indicates an almost complete normalization of serum transaminases, bilirubin and/or sterol concentration and total relief of pruritus. In BRIC “improvement” indicates the abortion of a cholestatic attack. “Partial improvement” indicates a lack of complete normalization of serum transaminases, bilirubin and/or sterol concentration with or without persistent pruritus. In patients with BRIC, “partial improvement” means reduction of pruritus. “No improvement” indicates a lack of response or deterioration of the symptoms.
      PFIC, progressive familial intrahepatic cholestasis; BRIC, benign recurrent intrahepatic cholestasis; GGT, gamma-glutamyl transpeptidase.
      There is no published evidence for cholestyramine treatment in high GGT cholestasis or DJS. However, extensive experiments are available for sitosterolaemia in which cholestyramine in combination with a diet low in cholesterol reduced the serum levels of plant sterols with improvement of clinical symptoms, such as reduction of xanthomas [
      • Alam M.
      • Garzon M.C.
      • Salen G.
      • Starc T.J.
      Tuberous xanthomas in sitosterolemia.
      ,
      • Hidaka H.
      • Nakamura T.
      • Aoki T.
      • Kojima H.
      • Nakajima Y.
      • Kosugi K.
      • et al.
      Increased plasma plant sterol levels in heterozygotes with sitosterolemia and xanthomatosis.
      ,
      • Belamarich P.F.
      • Deckelbaum R.J.
      • Starc T.J.
      • Dobrin B.E.
      • Tint G.S.
      • Salen G.
      Response to diet and cholestyramine in a patient with sitosterolemia.
      ,
      • Nguyen L.B.
      • Cobb M.
      • Shefer S.
      • Salen G.
      • Ness G.C.
      • Tint G.S.
      Regulation of cholesterol biosynthesis in sitosterolemia: effects of lovastatin, cholestyramine, and dietary sterol restriction.
      ,
      • Gregg R.E.
      • Connor W.E.
      • Lin D.S.
      • Brewer Jr., H.B.
      Abnormal metabolism of shellfish sterols in a patient with sitosterolemia and xanthomatosis.
      ,
      • Salen G.
      • Kwiterovich Jr., P.O.
      • Shefer S.
      • Tint G.S.
      • Horak I.
      • Shore V.
      • et al.
      Increased plasma cholestanol and 5 alpha-saturated plant sterol derivatives in subjects with sitosterolemia and xanthomatosis.
      ,
      • Cobb M.M.
      • Salen G.
      • Tint G.S.
      • Greenspan J.
      • Nguyen L.B.
      Sitosterolemia: opposing effects of cholestyramine and lovastatin on plasma sterol levels in a homozygous girl and her heterozygous father.
      ] (Table 2C). Chronic cholestyramine treatment may cause constipation, but no other serious complications have been found.

      Invasive treatment

      A few BRIC patients have been treated successfully with extracorporal albumin dialysis (MARS) [
      • Saich R.
      • Collins P.
      • Ala A.
      • Standish R.
      • Hodgson H.
      Benign recurrent intrahepatic cholestasis with secondary renal impairment treated with extracorporeal albumin dialysis.
      ,
      • Sturm E.
      • Franssen C.F.
      • Gouw A.
      • Staels B.
      • Boverhof R.
      • De Knegt R.J.
      • et al.
      Extracorporal albumin dialysis (MARS) improves cholestasis and normalizes low apo A-I levels in a patient with benign recurrent intrahepatic cholestasis (BRIC).
      ]. However biliary diversion and liver transplantation are the most commonly used invasive treatments.

      Biliary diversion

      Non-transplant surgical intervention can be effective in patients with intrahepatic cholestasis. Partial biliary diversion (PBD) or ileal bypass (IB) are two of these surgical interventions, in which PBD may be achieved by either a jejunal conduit from gallbladder to the abdominal wall (partial external biliary diversion; PEBD) [
      • Whitington P.F.
      • Whitington G.L.
      Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis.
      ], or one that connects the gallbladder to the colon (partial internal biliary diversion; PIBD) [
      • Bustorff-Silva J.
      • Sbraggia N.L.
      • Olimpio H.
      • de Alcantara R.V.
      • Matsushima E.
      • De Tommaso A.M.
      • et al.
      Partial internal biliary diversion through a cholecystojejunocolonic anastomosis – a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report.
      ]. Leaving the common bile duct intact, PBD establish only a partial diversion of bile (about 80%) while the remainder enters the duodenum. In IB, bile salt re-absorption is diminished by bypassing the small intestine at the terminal ileum through an ileocolonic anastomosis (Fig. 2) [
      • Hollands C.M.
      • Rivera-Pedrogo F.J.
      • Gonzalez-Vallina R.
      • Loret-de-Mola O.
      • Nahmad M.
      • Burnweit C.A.
      Ileal exclusion for Byler’s disease: an alternative surgical approach with promising early results for pruritus.
      ]. Although to a much stronger extent, the working mechanism of PBD is similar to cholestyramine – it reduces the accumulation of toxic bile salts by a reduction of the enterohepatic circulation.
      Figure thumbnail gr2
      Fig. 2Biliary drainage. Partial biliary diversion (PBD), or ileal bypass (IB), are two of non-transplant surgical interventions that interrupt the enterohepatic circulation of bile salts and can be effective in the treatment of canalicular transport defects. PBD may be achieved by either a jejunal conduit from gallbladder to the abdominal wall: partial external biliary diversion; PEBD, or one that connects the gallbladder to the colon: partial internal biliary diversion; PIBD. In IB, bile salt re-absorption is diminished by bypassing the terminal ileum through an ileocolonic anastomosis. A cholestatic attack in patients with BRIC may be aborted by endoscopically introducing a nasobiliary drain during a cholestatic episode (NBD).
      PEBD was initially described by Withington and Withington in 1988 [
      • Whitington P.F.
      • Whitington G.L.
      Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis.
      ]. This innovative technique was quickly adopted by other centres worldwide and so far sixteen additional case-reports/series addressing the effect and technique of PEBD in the treatment of PFIC have been published (Table 3). Except for one small series of five patients in which PEBD did not have any effect [
      • Wanty C.
      • Joomye R.
      • Van H.N.
      • Paul K.
      • Otte J.B.
      • Reding R.
      • et al.
      Fifteen years single center experience in the management of progressive familial intrahepatic cholestasis of infancy.
      ], all others report normalization or improvement of liver function in 75–100% of the patients with low GGT-PFIC, indicated by at least improved liver tests and reduced pruritus [
      • Ismail H.
      • Kalicinski P.
      • Markiewicz M.
      • Jankowska I.
      • Pawlowska J.
      • Kluge P.
      • et al.
      Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion.
      ,
      • Whitington P.F.
      • Freese D.K.
      • Alonso E.M.
      • Schwarzenberg S.J.
      • Sharp H.L.
      Clinical and biochemical findings in progressive familial intrahepatic cholestasis.
      ,
      • Emerick K.M.
      • Elias M.S.
      • Melin-Aldana H.
      • Strautnieks S.
      • Thompson R.J.
      • Bull L.N.
      • et al.
      Bile composition in alagille syndrome and PFIC patients having partial external biliary diversion.
      ,
      • Kurbegov A.C.
      • Setchell K.D.
      • Haas J.E.
      • Mierau G.W.
      • Narkewicz M.
      • Bancroft J.D.
      • et al.
      Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile.
      ,
      • Ekinci S.
      • Karnak I.
      • Gurakan F.
      • Yuce A.
      • Senocak M.E.
      • Cahit T.F.
      • et al.
      Partial external biliary diversion for the treatment of intractable pruritus in children with progressive familial intrahepatic cholestasis: report of two cases.
      ,
      • Emond J.C.
      • Whitington P.F.
      Selective surgical management of progressive familial intrahepatic cholestasis (Byler’s disease).
      ,
      • Melter M.
      • Rodeck B.
      • Kardorff R.
      • Hoyer P.F.
      • Petersen C.
      • Ballauff A.
      • et al.
      Progressive familial intrahepatic cholestasis: partial biliary diversion normalizes serum lipids and improves growth in noncirrhotic patients.
      ,
      • Ng V.L.
      • Ryckman F.C.
      • Porta G.
      • Miura I.K.
      • de C.E.
      • Servidoni M.F.
      • et al.
      Long-term outcome after partial external biliary diversion for intractable pruritus in patients with intrahepatic cholestasis.
      ,
      • Rebhandl W.
      • Felberbauer F.X.
      • Turnbull J.
      • Paya K.
      • Barcik U.
      • Huber W.D.
      • et al.
      Biliary diversion by use of the appendix (cholecystoappendicostomy) in progressive familial intrahepatic cholestasis.
      ,
      • Arnell H.
      • Bergdahl S.
      • Papadogiannakis N.
      • Nemeth A.
      • Fischler B.
      Preoperative observations and short-term outcome after partial external biliary diversion in 13 patients with progressive familial intrahepatic cholestasis.
      ,
      • Metzelder M.L.
      • Bottlander M.
      • Melter M.
      • Petersen C.
      • Ure B.M.
      Laparoscopic partial external biliary diversion procedure in progressive familial intrahepatic cholestasis: a new approach.
      ,
      • Yang H.
      • Porte R.J.
      • Verkade H.J.
      • De Langen Z.J.
      • Hulscher J.B.
      Partial external biliary diversion in children with progressive familial intrahepatic cholestasis and alagille disease.
      ]. The response in patients with an undefined subtype of PFIC seems to be less [
      • Englert C.
      • Grabhorn E.
      • Richter A.
      • Rogiers X.
      • Burdelski M.
      • Ganschow R.
      Liver transplantation in children with progressive familial intrahepatic cholestasis.
      ,
      • Kalicinski P.J.
      • Ismail H.
      • Jankowska I.
      • Kaminski A.
      • Pawlowska J.
      • Drewniak T.
      • et al.
      Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal bypass.
      ]. Liver biopsies post PEBD were performed in some patients and did not show further progression or even a resolution of hepatic morphologic abnormalities in all these patients [
      • Kurbegov A.C.
      • Setchell K.D.
      • Haas J.E.
      • Mierau G.W.
      • Narkewicz M.
      • Bancroft J.D.
      • et al.
      Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile.
      ,
      • Whitington P.F.
      • Whitington G.L.
      Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis.
      ,
      • Emond J.C.
      • Whitington P.F.
      Selective surgical management of progressive familial intrahepatic cholestasis (Byler’s disease).
      ,
      • Arnell H.
      • Bergdahl S.
      • Papadogiannakis N.
      • Nemeth A.
      • Fischler B.
      Preoperative observations and short-term outcome after partial external biliary diversion in 13 patients with progressive familial intrahepatic cholestasis.
      ]. Advanced disease and liver cirrhosis were proposed as the main causes of therapeutic failures, indicating that early surgical intervention in PFIC patients is essential. Three BRIC1 patients were treated with PEBD to improve quality of life rather than to prevent disease progression. In these patients PEBD aborted the cholestatic attack immediately but did not always prevent subsequent minor cholestatic episodes [
      • van Ooteghem N.A.
      • Klomp L.W.
      • van Berge-Henegouwen G.P.
      • Houwen R.H.
      Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.
      ,
      • Metzelder M.L.
      • Petersen C.
      • Melter M.
      • Ure B.M.
      Modified laparoscopic external biliary diversion for benign recurrent intrahepatic cholestasis in obese adolescents.
      ].
      Table 3Partial biliary drainage in hepatocanalicular transport defects.
      Hepatocanalicular defectNumber treatedOutcome (number patients)Reference
      PFIC undefined subtypes42Improvement (24)
      • Englert C.
      • Grabhorn E.
      • Richter A.
      • Rogiers X.
      • Burdelski M.
      • Ganschow R.
      Liver transplantation in children with progressive familial intrahepatic cholestasis.
      ,
      • Whitington P.F.
      • Whitington G.L.
      Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis.
      ,
      • Kalicinski P.J.
      • Ismail H.
      • Jankowska I.
      • Kaminski A.
      • Pawlowska J.
      • Drewniak T.
      • et al.
      Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal bypass.
      Partial improvement (5)
      Treatment by PEBDNo improvement (13)
      Low GGT-PFIC94Improvement (66)
      • Wanty C.
      • Joomye R.
      • Van H.N.
      • Paul K.
      • Otte J.B.
      • Reding R.
      • et al.
      Fifteen years single center experience in the management of progressive familial intrahepatic cholestasis of infancy.
      ,
      • Ismail H.
      • Kalicinski P.
      • Markiewicz M.
      • Jankowska I.
      • Pawlowska J.
      • Kluge P.
      • et al.
      Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion.
      ,
      • Whitington P.F.
      • Freese D.K.
      • Alonso E.M.
      • Schwarzenberg S.J.
      • Sharp H.L.
      Clinical and biochemical findings in progressive familial intrahepatic cholestasis.
      ,
      • Emerick K.M.
      • Elias M.S.
      • Melin-Aldana H.
      • Strautnieks S.
      • Thompson R.J.
      • Bull L.N.
      • et al.
      Bile composition in alagille syndrome and PFIC patients having partial external biliary diversion.
      ,
      • Kurbegov A.C.
      • Setchell K.D.
      • Haas J.E.
      • Mierau G.W.
      • Narkewicz M.
      • Bancroft J.D.
      • et al.
      Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile.
      ,
      • Ekinci S.
      • Karnak I.
      • Gurakan F.
      • Yuce A.
      • Senocak M.E.
      • Cahit T.F.
      • et al.
      Partial external biliary diversion for the treatment of intractable pruritus in children with progressive familial intrahepatic cholestasis: report of two cases.
      ,
      • Emond J.C.
      • Whitington P.F.
      Selective surgical management of progressive familial intrahepatic cholestasis (Byler’s disease).
      ,
      • Melter M.
      • Rodeck B.
      • Kardorff R.
      • Hoyer P.F.
      • Petersen C.
      • Ballauff A.
      • et al.
      Progressive familial intrahepatic cholestasis: partial biliary diversion normalizes serum lipids and improves growth in noncirrhotic patients.
      ,
      • Ng V.L.
      • Ryckman F.C.
      • Porta G.
      • Miura I.K.
      • de C.E.
      • Servidoni M.F.
      • et al.
      Long-term outcome after partial external biliary diversion for intractable pruritus in patients with intrahepatic cholestasis.
      ,
      • Rebhandl W.
      • Felberbauer F.X.
      • Turnbull J.
      • Paya K.
      • Barcik U.
      • Huber W.D.
      • et al.
      Biliary diversion by use of the appendix (cholecystoappendicostomy) in progressive familial intrahepatic cholestasis.
      ,
      • Arnell H.
      • Bergdahl S.
      • Papadogiannakis N.
      • Nemeth A.
      • Fischler B.
      Preoperative observations and short-term outcome after partial external biliary diversion in 13 patients with progressive familial intrahepatic cholestasis.
      ,
      • Metzelder M.L.
      • Bottlander M.
      • Melter M.
      • Petersen C.
      • Ure B.M.
      Laparoscopic partial external biliary diversion procedure in progressive familial intrahepatic cholestasis: a new approach.
      ,
      • Yang H.
      • Porte R.J.
      • Verkade H.J.
      • De Langen Z.J.
      • Hulscher J.B.
      Partial external biliary diversion in children with progressive familial intrahepatic cholestasis and alagille disease.
      Treatment by PEBDPartial improvement (11)
      No improvement (17)
      High GGT-PFIC1Improvement (0)
      • Wanty C.
      • Joomye R.
      • Van H.N.
      • Paul K.
      • Otte J.B.
      • Reding R.
      • et al.
      Fifteen years single center experience in the management of progressive familial intrahepatic cholestasis of infancy.
      Treatment by PEBDPartial improvement (0)
      No improvement (1)
      BRIC3Improvement (1)
      • van Ooteghem N.A.
      • Klomp L.W.
      • van Berge-Henegouwen G.P.
      • Houwen R.H.
      Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.
      ,
      • Metzelder M.L.
      • Petersen C.
      • Melter M.
      • Ure B.M.
      Modified laparoscopic external biliary diversion for benign recurrent intrahepatic cholestasis in obese adolescents.
      Treatment by PEBDPartial improvement (2)
      No improvement (0)
      PFIC undefined subtypes5Improvement (1)
      • Kalicinski P.J.
      • Ismail H.
      • Jankowska I.
      • Kaminski A.
      • Pawlowska J.
      • Drewniak T.
      • et al.
      Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal bypass.
      Partial improvement (0)
      Treatment by IBNo improvement (4)
      Low GGT-PFIC7Improvement (6)
      • Whitington P.F.
      • Freese D.K.
      • Alonso E.M.
      • Schwarzenberg S.J.
      • Sharp H.L.
      Clinical and biochemical findings in progressive familial intrahepatic cholestasis.
      ,
      • Hollands C.M.
      • Rivera-Pedrogo F.J.
      • Gonzalez-Vallina R.
      • Loret-de-Mola O.
      • Nahmad M.
      • Burnweit C.A.
      Ileal exclusion for Byler’s disease: an alternative surgical approach with promising early results for pruritus.
      Treatment by IBPartial improvement (0)
      No improvement (1)
      Low GGT-PFIC2Improvement (2)
      • Bustorff-Silva J.
      • Sbraggia N.L.
      • Olimpio H.
      • de Alcantara R.V.
      • Matsushima E.
      • De Tommaso A.M.
      • et al.
      Partial internal biliary diversion through a cholecystojejunocolonic anastomosis – a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report.
      Treatment by PIBDPartial improvement (0)
      No improvement (0)
      BRIC1Improvement (1)
      • Bustorff-Silva J.
      • Sbraggia N.L.
      • Olimpio H.
      • de Alcantara R.V.
      • Matsushima E.
      • De Tommaso A.M.
      • et al.
      Partial internal biliary diversion through a cholecystojejunocolonic anastomosis – a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report.
      Treatment by PIBDPartial improvement (0)
      No improvement (0)
      “Improvement” indicates an almost complete normalization of serum transaminases and/or bilirubin concentration and total relief of pruritus. “Partial improvement” indicates a lack of complete normalization of serum transaminases and/or bilirubin concentration and/or persistent pruritus. “No improvement” indicates a lack of response or deterioration of the symptoms.
      PFIC, progressive familial intrahepatic cholestasis; BRIC, benign recurrent intrahepatic cholestasis; GGT, gamma-glutamyl transpeptidase; PEBD, partial external biliary diversion; PIBD, partial internal biliary diversion; IB, ileal bypass.
      In the low GGT-PFIC subtype, four patient are reported double
      • Whitington P.F.
      • Freese D.K.
      • Alonso E.M.
      • Schwarzenberg S.J.
      • Sharp H.L.
      Clinical and biochemical findings in progressive familial intrahepatic cholestasis.
      ,
      • Whitington P.F.
      • Whitington G.L.
      Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis.
      .
      Another surgical technique for biliary drainage is IB, first described by Whitington et al. [
      • Whitington P.F.
      • Freese D.K.
      • Alonso E.M.
      • Schwarzenberg S.J.
      • Sharp H.L.
      Clinical and biochemical findings in progressive familial intrahepatic cholestasis.
      ] in patients who were not amenable for PEBD because of a previous cholecystectomy. An additional advantage of this procedure is the lack of an external fistula. However, after a short initial response, clinical symptoms recurred in half of the treated patients with low GGT- or an undefined subtype of PFIC within a year [
      • Hollands C.M.
      • Rivera-Pedrogo F.J.
      • Gonzalez-Vallina R.
      • Loret-de-Mola O.
      • Nahmad M.
      • Burnweit C.A.
      Ileal exclusion for Byler’s disease: an alternative surgical approach with promising early results for pruritus.
      ,
      • Kalicinski P.J.
      • Ismail H.
      • Jankowska I.
      • Kaminski A.
      • Pawlowska J.
      • Drewniak T.
      • et al.
      Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal bypass.
      ] (Table 3). This is probably due to secondary adaptation of the ileum to the resection and it was therefore concluded that IB is inferior to PEBD in patients with low GGT cholestasis.
      Recently, PIBD has been described in two teenage patients with PFIC and low GGT cholestasis. This technique combines the advantages of external drainage and ileal bypassing by partially interrupting enterohepatic circulation without an external biliary fistula. The initial clinical and laboratory results were very promising, but long-term follow-up is necessary to evaluate late results and complications [
      • Bustorff-Silva J.
      • Sbraggia N.L.
      • Olimpio H.
      • de Alcantara R.V.
      • Matsushima E.
      • De Tommaso A.M.
      • et al.
      Partial internal biliary diversion through a cholecystojejunocolonic anastomosis – a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report.
      ] (Table 3).
      In the few BRIC patients treated with PEBD, drainage immediately reduced pruritus and relieved cholestasis. Moreover, in the follow-up period just a few very short additional episodes were noticed [
      • van Ooteghem N.A.
      • Klomp L.W.
      • van Berge-Henegouwen G.P.
      • Houwen R.H.
      Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.
      ,
      • Metzelder M.L.
      • Petersen C.
      • Melter M.
      • Ure B.M.
      Modified laparoscopic external biliary diversion for benign recurrent intrahepatic cholestasis in obese adolescents.
      ] (Table 3). However the permanent character of PEBD makes it less appropriate to be used in a disorder that is only episodic. Based on these results we developed a temporary intervention: nasobiliary drainage (NBD) for which the first results were published in 2006 [
      • Stapelbroek J.M.
      • van Erpecum K.J.
      • Klomp L.W.
      • Venneman N.G.
      • Schwartz T.P.
      • van Berge-Henegouwen G.P.
      • et al.
      Nasobiliary drainage induces long-lasting remission in benign recurrent intrahepatic cholestasis.
      ]. Until now, in our centre a total of twelve cholestatic attacks in five BRIC1 patients were treated by NBD. This was established by endoscopically introducing a nasobiliary drain during a cholestatic episode (Fig. 2). In eight out of twelve treatments, pruritus totally resolved within 48 h and serum bile salt levels returned to normal or near normal levels. Failure of NBD was either due to practical difficulties when introducing the drain (one treatment) or progression of liver disease (three treatments in two patients who are now doing well after PEBD). Thus, for most cholestatic episodes in BRIC1, NBD is an effective therapy. Because in some patients there is a transition from episodic to progressive cholestasis, PEBD should be considered when NBD fails to resolve a cholestatic episode.
      Given the current evidence, PBD is the therapy of choice in patients with low GGT-PFIC, and should be performed as soon as possible after diagnosis to prevent liver damage. At present, large multicenter studies are in progress that investigate PBD results stratified for patients with ATP8B1 vs ABCB11 deficiency and in subpopulations with different mutations. It is to be expected that the current recommendations can be refined upon publication of these results. It is also important to realize that PBD induces the loss of considerable amounts of fluids and electrolytes, and patients might become dehydrated. Adequate and individualized electrolyte supplementations and fluid is mandatory in all patients with PBD. Finally complications from intestinal surgery as stoma prolaps and intestinal obstruction have been described.
      There is no evidence of the effect of non-transplant surgery in patients with other canalicular transport defects, except for one patient with ABCB4 deficiency who was unsuccessfully treated with PEBD [
      • Wanty C.
      • Joomye R.
      • Van H.N.
      • Paul K.
      • Otte J.B.
      • Reding R.
      • et al.
      Fifteen years single center experience in the management of progressive familial intrahepatic cholestasis of infancy.
      ].

      Liver transplantation

      Because of the high risk of complications and the life-long need for immune-suppressive therapy, liver transplantation should be reserved for patients who have established liver cirrhosis at the time of presentation or who have progressive liver disease despite treatment. Unfortunately, for many patients with the severe form of ATP8B1, ABCB11 and ABCB4 deficiency, liver transplantation is still the only option.
      Independent of the subtype of PFIC, the survival rate after transplantation ranges from 61–92% in the 80ths and early 90ths [
      • Whitington P.F.
      • Freese D.K.
      • Alonso E.M.
      • Schwarzenberg S.J.
      • Sharp H.L.
      Clinical and biochemical findings in progressive familial intrahepatic cholestasis.
      ,
      • Emond J.C.
      • Whitington P.F.
      Selective surgical management of progressive familial intrahepatic cholestasis (Byler’s disease).
      ,
      • Soubrane O.
      • Gauthier F.
      • Devictor D.
      • Bernard O.
      • Valayer J.
      • Houssin D.
      • et al.
      Orthotopic liver transplantation for Byler disease.
      ] to 75–100% more recently [
      • Lykavieris P.
      • van M.S.
      • Cresteil D.
      • Fabre M.
      • Hadchouel M.
      • Klomp L.
      • et al.
      Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation.
      ,
      • Wanty C.
      • Joomye R.
      • Van H.N.
      • Paul K.
      • Otte J.B.
      • Reding R.
      • et al.
      Fifteen years single center experience in the management of progressive familial intrahepatic cholestasis of infancy.
      ,
      • Ismail H.
      • Kalicinski P.
      • Markiewicz M.
      • Jankowska I.
      • Pawlowska J.
      • Kluge P.
      • et al.
      Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion.
      ,
      • Englert C.
      • Grabhorn E.
      • Richter A.
      • Rogiers X.
      • Burdelski M.
      • Ganschow R.
      Liver transplantation in children with progressive familial intrahepatic cholestasis.
      ,
      • Aydogdu S.
      • Cakir M.
      • Arikan C.
      • Tumgor G.
      • Yuksekkaya H.A.
      • Yilmaz F.
      • et al.
      Liver transplantation for progressive familial intrahepatic cholestasis: clinical and histopathological findings, outcome and impact on growth.
      ,
      • Bassas A.
      • Chehab M.
      • Hebby H.
      • Al S.M.
      • Al H.H.
      • Al Z.A.
      • et al.
      Living related liver transplantation in 13 cases of progressive familial intrahepatic cholestasis.
      ,
      • Cutillo L.
      • Najimi M.
      • Smets F.
      • Janssen M.
      • Reding R.
      • de Ville de G.J.
      • et al.
      Safety of living-related liver transplantation for progressive familial intrahepatic cholestasis.
      ,
      • Egawa H.
      • Yorifuji T.
      • Sumazaki R.
      • Kimura A.
      • Hasegawa M.
      • Tanaka K.
      Intractable diarrhea after liver transplantation for Byler’s disease: successful treatment with bile adsorptive resin.
      ,
      • Khan I.
      • Al-Shaqrani M.A.
      • Arain Z.B.
      • Al-Hebbi H.A.
      • Wali S.H.
      • Bassas A.F.
      One hundred and thirty-seven living donor pediatric liver transplants at Riyadh Military Hospital. Results and outlook for future.
      ,
      • D’Antiga L.
      • Moniz C.
      • Buxton-Thomas M.
      • Cheeseman P.
      • Gray B.
      • Abraha H.
      • et al.
      Bone mineral density and height gain in children with chronic cholestatic liver disease undergoing transplantation.
      ,
      • Usui M.
      • Isaji S.
      • Das B.C.
      • Kobayashi M.
      • Osawa I.
      • Iida T.
      • et al.
      Liver retransplantation with external biliary diversion for progressive familial intrahepatic cholestasis type 1: a case report.
      ,
      • Miyagawa-Hayashino A.
      • Egawa H.
      • Yorifuji T.
      • Hasegawa M.
      • Haga H.
      • Tsuruyama T.
      • et al.
      Allograft steatohepatitis in progressive familial intrahepatic cholestasis type 1 after living donor liver transplantation.
      ]. However, most follow-up periods do not yet exceed 3 years. Transplantation improved cholestasis-related symptoms like itching, malnutrition and liver function in almost all surviving patients. Due to the lack of cadaver donors, living-related liver transplantation is often used in patients with PFIC. Although it was feared that the heterozygous status of the parent donor would affect the results unfavourably, complications and survival rates of these types of transplantation in PFIC patients are similar to living-related transplantations for non-genetic liver diseases such as biliary atresia [
      • Cutillo L.
      • Najimi M.
      • Smets F.
      • Janssen M.
      • Reding R.
      • de Ville de G.J.
      • et al.
      Safety of living-related liver transplantation for progressive familial intrahepatic cholestasis.
      ,
      • Khan I.
      • Al-Shaqrani M.A.
      • Arain Z.B.
      • Al-Hebbi H.A.
      • Wali S.H.
      • Bassas A.F.
      One hundred and thirty-seven living donor pediatric liver transplants at Riyadh Military Hospital. Results and outlook for future.
      ]. However, in some PFIC patients, symptoms of cholestasis may recur after several years. Apart from the usual long-term complications after liver transplantation, such as chronic rejection and conduit stricture, in PFIC this may also be due to allo-immunization of the recipient against the ATP8B1, ABCB11 or ABCB4 protein located in the (heterozygous) donor liver [
      • Davit-Spraul A.
      • Gonzales E.
      • Baussan C.
      • Jacquemin E.
      Progressive familial intrahepatic cholestasis.
      ].
      The ATP8B1 protein is abundantly expressed outside the liver, e.g. in the intestine [
      • Bull L.N.
      • van Eijk M.J.
      • Pawlikowska L.
      • DeYoung J.A.
      • Juijn J.A.
      • Liao M.
      • et al.
      A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis.
      ,
      • van Mil S.W.
      • van Oort M.M.
      • van dB I.
      • Berger R.
      • Houwen R.H.
      • Klomp L.W.
      Fic1 is expressed at apical membranes of different epithelial cells in the digestive tract and is induced in the small intestine during postnatal development of mice.
      ] and correction of the liver defect by transplantation will not cure the extrahepatic symptoms, such as diarrhoea. Indeed, in a substantial proportion of PFIC1 patients, diarrhoea exacerbates when biliary bile salt secretion is restored after liver transplantation. In these patients, liver biopsies revealed severe steatosis [
      • Lykavieris P.
      • van M.S.
      • Cresteil D.
      • Fabre M.
      • Hadchouel M.
      • Klomp L.
      • et al.
      Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation.