Alagille Syndrome | Alpha-1 Antitrypsin Deficiency | Bile Acid Synthesis Defects | Mitochondrial Hepatopathies | > PFIC (Progressive Familial Intrahepatic Cholestasis)

Progressive Familial Intrahepatic Cholestasis (PFIC)

Definition

Maintenance of normal bile flow is dependent in part upon a complex system of specific transport proteins that are found in a polarized distribution in the liver and intestine. Inherited defects in the genes for some of these transporters lead to cholestasis, which can result in a clinical syndrome generally referred to as Progressive Familial Intrahepatic Cholestasis (PFIC). PFIC was initially described as a clinical and not as a genetic entity. In its most characteristic form, PFIC involved cholestasis presenting in the first year of life. The cholestasis was persistent and led to progressive liver injury. Imaging and other invasive studies did not reveal evidence of extrahepatic bile duct obstruction or disease - thus the label of intrahepatic disease. In many of the early descriptions, the disease was identified in multiple relatives, hence the term familial. In a broad sense, using the initial clinical definition PFIC has the potential to include a very large spectrum of liver disease.

The most well understood forms of PFIC, which are the subject of investigation by CLiC, involve inherited defects in three specific genes (Table 1).

FIC1 Disease. PFIC1 has been the label assigned to individuals who have defects in the Familial Intrahepatic Cholestasis 1 gene (FIC1 = ATP8B1). This disease was initially described as two distinct clinical entities, Byler Disease and Benign Recurrent Intrahepatic Cholestasis (BRIC). Both diseases are the result of abnormalities in FIC1. Current thinking is that the diseases vary due to differing severity of the underlying defect in FIC1, with milder defects being present in BRIC. The exact function of FIC1 is not known. FIC1 may mediate the flopping of aminophospholipids from the outer to inner hemi-leaflet of the canalicular lipid bilayer. Some studies indicate that FIC1 may influence the expression of bile acid transporters via effects on the transcription factor, farnesoid X receptor. Other studies suggest that FIC1 may alter the composition of membranes and therefore alter transporter function.

BSEP Disease. PFIC2 was initially described in children with a disease that resembled Byler’s disease, but could not be ascribed to defects in FIC1. Gene linkage and basic investigations of bile acid transport led to the discovery that PFIC2 was the result of defects in the canalicular bile salt export pump (BSEP = ABCB11). BRIC-like disease has also been described in children and adults with genetic defects in BSEP. BSEP plays a critical role in transporting bile acids from inside the hepatocyte into the bile canaliculus and thus it is not surprising that inherited defects in this gene lead to cholestatic liver disease. 

MDR3 Disease. PFIC3 was initially discovered in knock-out mice and then identified in children with a distinct form of PFIC, characterized by high serum levels of gamma glutamyl transpeptidase activity (gGTP). The elevation in serum gGTP was in distinct contrast to the normal or low levels of gGTP that characterize the prior two forms of PFIC. The underlying gene that is defective in PFIC3, encoding multidrug resistance-associated protein 3 (MDR3 = ABCB4), has been shown to facilitate canalicular phospholipid excretion into bile.

The nomenclature for these diseases is in part historical and confusing in light of molecular advances in our understanding of PFIC as a whole. Going forward, CLiC has agreed to designate these diseases on the basis of the names of the defective protein that underlies the disease. Thus PFIC 1, 2, and 3 will be henceforth referred to as FIC1, BSEP, and MDR3 disease, respectively.

Table 1

Abbreviations: PFIC - progressive familial intrahepatic cholestasis, BRIC - benign recurrent intrahepatic cholestasis, GFC - Greenland familial cholestasis, ICP - intrahepatic cholestasis of pregnancy.

Liver Disease

The liver disease that develops in PFIC is in large part the result of the effects of hepatocellular accumulation of bile acids. Intracellular accumulation of bile acids can lead to liver injury by a number of mechanisms including both direct toxicity and pathologic activation of signal transduction pathways. In FIC1 disease biliary excretion of bile acids is diminished, potentially as a result of decreased although not absent expression of BSEP. Other factors, which are currently under investigation, are also likely to play a role in the pathogenesis of the cholestasis in FIC1 disease. In light of the fact that interruption of canalicular excretion of bile acids is not absolute, the rate of progression to end-stage liver disease in FIC1 disease may be slower than that in BSEP disease. In severe forms of BSEP disease, BSEP expression and function are completely absent. Hepatocellular bile acid excretion can only occur through alternative and quantitatively insufficient pathways. As such there is pronounced accumulation of hepatocellular bile acids and rapidly progressive liver disease. End-stage liver disease in severe BSEP disease can occur in the first one or two years of life. The pathogenesis of liver disease in MDR3 disease is somewhat different from that in the other two forms of PFIC. In MDR3 disease, phospholipids in canalicular bile are deficient or absent. This leads to the formation of a toxic bile that is rich in unmicellized bile salts, which in turn contributes to the pathogenesis of a progressive intrahepatic cholangiopathy. The resulting liver disease results from the cholestasis and inflammatory response that are generated by this cholangiopathy. In addition, hepatocellular injury in MDR3 disease is the result of hepatocellular bile salt accumulation.

Clinical Features

The typical presenting clinical features of the severe forms of these diseases are jaundice and/or pruritus. Life-threatening hemorrhage, secondary to cholestasis-related vitamin K deficiency, can also be a dramatic early presentation of PFIC. Genetic advances have allowed identification of individuals with less severe mutations in these genes and there is a growing appreciation that the clinical spectrum of disease in PFIC is quite diverse.

Profound, medical therapy resistant pruritus is one of the most common early manifestations of all three of these forms of PFIC. Irritability may be an early manifestation of pruritus in infants who cannot scratch. Typically scratching begins between 6 and 12 months of age. The scratching is constant and has profound effects on quality of life for both the patient and family. Many children may not have jaundice and the pruritus is incorrectly ascribed to atopy or dermatitis.

The initial laboratory findings in childen with PFIC can make identification of liver disease problematic. The cholestasis in these children is characterized by marked elevations in serum bile acid levels. This can be in the setting of near normal serum bilirubin, normal gGTP, normal serum cholesterol and only mild elevation in serum aminotransferase values. Since serum bile acid concentrations are not routinely determined it may initially be difficult to appreciate that these children have significant cholestasis. In MDR3 disease gGTP is elevated. As liver disease in these children progresses, the biochemical parameters become more typical for chronic liver disease and can include elevated bilirubin and aminotransferase values.

The cholestasis in PFIC is associated with malabsorption of fat and fat-soluble vitamins. Thus failure to thrive is a common early feature of disease that results from malabsorption of long chain fats in either breast milk or many commercial infant formulas. Complications of fat-soluble vitamin deficiencies (A, D, E and K) can also be seen. Hemorrhage secondary to vitamin K deficiency and rickets from vitamin D deficiency are the most dramatic and acute problems. Long-term complications of deficiencies of the other fat-soluble vitamins are well described and include neuropathy and visual problems.

Children with PFIC develop end-stage liver disease in a manner akin to other forms of progressive cholestatic liver disease. Portal hypertension develops secondary to the development of biliary cirrhosis. All of the typical sequelae of portal hypertension have been described in PFIC, including growth failure, ascites, and variceal hemorrhage. Hepatocellular carcinoma and cholangiocarcinoma have developed in children with PFIC, and appear to be a significant risk in children with BSEP disease. Synthetic liver failure is a late manifestation of these diseases.

Diagnosis

Definitive diagnosis of a specific form of PFIC is dependent upon identification of characteristic genetic defects.  At present much diagnosis is provisional based upon surrogate markers that are also under investigation; commercial-laboratory testing via mutational analysis is available at several sites, principally, in North America, through Baylor College of Medicine (http://www.bcm.edu/geneticlabs/tests/alltests.html). The typical patient with either FIC1 or BSEP disease has profound symptomatic cholestasis (as documented by marked elevation of serum bile acids) with normal or low serum levels of gGTP. At present, it is not certain if one can readily distinguish FIC1 from BSEP disease by surrogate testing, and with some forms of treatment distinction may not be essential. Assessment of risk of malignancy and of likely response to liver transplantation (see below for treatment and prognosis) are features, however, that likely are strongly disease-associated. Absent canalicular staining for BSEP, FIC1, or MDR3 is highly suggestive of BSEP disease, FIC1 disease, and MDR3 disease, respectively, as is lack of these genes’ mRNA within appropriate tissues. FIC1 disease is systemic and thus certain nonhepatic features suggest FIC1 disease rather than BSEP disease. Children with FIC1 disease may have somatic growth problems, hearing problems, recurrent respiratory problems, elevated sweat chloride, recurrent pancreatitis, diarrhea that is independent of the cholestasis, and post-transplant steatosis and intractable diarrhea. BSEP disease appears to be a liver specific disease and may be associated with an increased risk of liver cancer. BRIC related to defects in BSEP may be associated with cholelithiasis. Early on, FIC1 disease appears to lead to relatively less hepatocellular injury than BSEP disease.  There is a sense that progression to end-stage liver disease occurs more quickly in BSEP disease, although this impression needs to be confirmed in prospective analyses of the clinical course of children with genetically defined disease.

Histologic and ultrastructural analysis of the liver may be useful in distinguishing FIC1 from BSEP disease. In severe forms of the two disorders -- those that present in infancy with cholestasis that persists, rather than in later life, or with cholestasis that comes and goes -- FIC1 disease appears less likely than is BSEP disease, at presentation, to be associated with elevations in serum concentrations of transaminase activity. This is associated, at biopsy, with more pronounced hepatocellular disarray, edema, giant-cell change, and even hepatocellular necrosis ("neonatal hepatitis") in BSEP disease (BSEP H and E - Image 1) than in FIC1 disease. Indeed, hepatocytes in FIC1 disease tend to be tidy and compact (FIC1 H and E - Image 2). Severe BSEP disease also is associated with a lack of immunohistochemically demonstrable BSEP at canalicular margins (BSEP immunohistochemistry 1 - disease - Image 3 and BSEP immunohistochemistry 2 - control - Image 4) although molecules of similar structure, such as multiple drug resistance protein 2 (MRP2), are unremarkably expressed along canaliculi in patients with severe BSEP disease (MRP2 immunohistochemistry BSEP disease - Image 5) Transmission electron microscopy in FIC1 disease may identify coarsely granular "Byler bile" (FIC1 disease canalicular ultrastructure - Image 6), while transmission electron microscopy in BSEP disease may identify loose, amorphous, or dense bile (BSEP disease canalicular ultrastructure - Image 7).

MDR3 disease should be suspected in children with progressive cholestasis who have an elevated gGTP and no evidence of extrahepatic bile duct disease. In patients with severe disease biliary phospholipid concentrations are markedly reduced and there may be an absence of serum lipoprotein X. Some individuals with partial defects in MDR3 appear to have more subtle hepatic presentations. This can include cholestasis of pregnancy, intrahepatic lithiasis, biliary cirrhosis, and perhaps “small duct primary sclerosing cholangitis.” At present, without genetic testing, it is not possible to make a definitive diagnosis of MDR3 disease. Absent canalicular staining for MDR3, like deficiency of biliary phospholipid, is highly suggestive of MDR3 disease

Treatment

The treatment of PFIC includes standard nutritional approaches for fat and fat-soluble vitamin malabsorption due to cholestasis and therapies for end-stage liver disease. Certain aspects of the management of the cholestasis in PFIC are unique and are described here. Initially, the pruritus associated with PFIC is the most prominent and debilitating symptom. Standard medical approaches ( e.g. , cholestyramine, ursodeoxycholic acid, antihistamines, rifampin, and opioid antagonists) to the pruritus are minimally if at all successful. Surgical interruption of the enterohepatic circulation of bile acids can be a very effective therapy in children with PFIC. It can completely ameliorate the pruritus, can normalize serum markers of liver disease, and can prevent progression of liver disease. The exact mechanism by which this works is not known, although preliminary data suggests that intestinal reabsorption of bile acids is enhanced in cholestasis with a more pronounced and potentially pathologic response in FIC1 disease. The most commonly used surgical procedure for PFIC is partial external biliary diversion. This involves using a small segment of intestine to form a conduit between the gallbladder and abdominal wall. Using this approach, 30 to 50% of bile excreted by the liver drains externally through the ostomy and is discarded. An alternative and less well-characterized approach for interrupting the enterohepatic circulation of bile acids involves partial ileal exclusion. A blind loop is formed with the distal 20% of the small intestine and the proximal limb of the intestine is anastomosed to the cecum. This bypasses the terminal ileum, where most bile acids are reabsorbed. These procedures were initially described for children with low gGTP forms of PFIC. At present, there is a unproven sense that these procedures are more effective for FIC1 than for BSEP disease. Preliminary data indicates that patients with less severe mutations in BSEP may be responsive to partial external biliary diversion. The relatively high risk for the development of hepatocellular carcinoma in BSEP deficiency may warrant surveillance by ultrasonography and serum measurements of alpha fetoprotein.

The treatment of PFIC includes standard nutritional approaches for fat and fat-soluble vitamin malabsorption due to cholestasis and therapies for end-stage liver disease. Certain aspects of the management of the cholestasis in PFIC are unique and are described here. Initially, the pruritus associated with PFIC is the most prominent and debilitating symptom. Standard medical approaches (e.g., cholestyramine, ursodeoxycholic acid, antihistamines, rifampin, and opioid antagonists) to the pruritus are minimally successful if at all. Surgical interruption of the enterohepatic circulation of bile acids can be a very effective therapy in children with PFIC. Nasobiliary drainage of bile may accomplish the same thing on a temporary basis and has been used in adults with BRIC. These procedures can completely ameliorate the pruritus, can normalize serum markers of liver disease, and can prevent progression of liver disease. The exact mechanism by which this works is not known, although preliminary data suggests that intestinal reabsorption of bile acids is enhanced in cholestasis with a more pronounced and potentially pathologic response in FIC1 disease. The most commonly used surgical procedure for PFIC is partial external biliary diversion. This involves using a small segment of intestine to form a conduit between the gallbladder and abdominal wall. Using this approach, 30 to 50% of bile excreted by the liver drains externally through the ostomy and is discarded. An alternative and less well-characterized approach for interrupting the enterohepatic circulation of bile acids involves partial ileal exclusion. A blind loop is formed with the distal 15% of the small intestine and the proximal limb of the intestine is anastomosed to the cecum. This bypasses the terminal ileum, where most bile acids are reabsorbed. These procedures were initially described for children with low-gGTP forms of PFIC. At present, there is a unproven sense that these procedures are more effective for FIC1 than for BSEP disease. Preliminary data indicate that patients with less severe mutations in BSEP may be responsive to partial external biliary diversion. Interruption of the enterohepatic circulation of bile acids may also be effective for other forms of intrahepatic cholestasis, namely Alagille syndrome. The risk for the development of hepatocellular carcinoma in BSEP deficiency may warrant surveillance by ultrasonography and serum measurements of alpha fetoprotein.

Prognosis

The prognosis for children with PFIC can be quite variable. It can be influenced by the genetic abnormality (both the specific gene mutated and the severity of the mutation) and the therapeutic approaches used. Complete analyses of genotype and clinical course are not yet available so these statements must be viewed as preliminary. Severe defects in BSEP and MDR3 disease are typically associated with an unremitting form of cholestasis that is minimally if at all responsive to medical and surgical therapies, short of liver transplantation. End-stage liver disease typically evolves in the first five to ten years of life. Liver transplantation appears to be “curative” for these disorders as both diseases appear to be primarily liver specific. In contrast, FIC1 defects lead to multisystem disease, which is expected in light of the wide-spread tissue distribution of the FIC1 gene product. Liver transplantation in children with FIC1 disease has unmasked interesting and difficult issues in the post-transplant course. The most notable and incapacitating problem has been the development of intractable diarrhea  This is not seen in most patients, but can be especially problematic when it occurs. Steatosis commonly develops in the liver graft. Recurrent pancreatitis is also problematic for some children after liver transplantation. Growth problems may not fully resolve in children with FIC1 disease after liver transplantation. Thus liver transplantation, while effective for pruritus, may not be an optimal therapy for children with FIC1 disease. Surgical interruption of the enterohepatic circulation appears to be preferable to liver transplantation in FIC1 disease. Overall, with optimal surgical intervention the long-term prognosis for children with PFIC is excellent.

References

General reviews

Molecular basis of intrahepatic cholestasis.
Carlton VE, Pawlikowska L, Bull LN. Ann Med. 2004;36: 606-17

Genetic defects in hepatocanalicular transport.
Thompson R, Jansen PL. Semin Liver Dis. 2000;20: 365-72.

Progressive familial intrahepatic cholestasis: a personal perspective.
Knisely AS. Pediatr Dev Pathol. 2000;3:113-25. 

Clinical/biochemical/histology

Clinical and biochemical findings in progressive familial intrahepatic cholestasis.
Whitington PF, Freese DK, Alonso EM, Schwarzenberg SJ, Sharp HLJ. Pediatr Gastro Nutr 1994;18:134-41

Histologic pathology of progressive familial intrahepatic cholestasis. Alonso EM, Snover D, Whitington PF, Montag A, Freese DK. J Pediatr Gastro Nutr 1994;18:128-33. 

Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity.
Bull LN, Carlton VE, Stricker NL, Baharloo S, DeYoung JA, Freimer NB, Magid MS, Kahn E, Markowitz J, DiCarlo FJ, McLoughlin L, Boyle JT, Dahms BB, Faught PR, Fitzgerald JF, Piccoli DA, Witzleben CL, O'Connell NC, Setchell KD, Agostini RM Jr, Kocoshis SA, Reyes J, Knisely AS. Hepatology. 1997; 26:155-64.

Liu C, Aronow BJ, Jegga AG, Wang N, Miethke A, Mourya R, Bezerra JA. Novel resequencing chip customized to diagnose mutations in patients with inherited syndromes of intrahepatic cholestasis. Gastroenterology 2007;132:119-126.

Jung C, Driancourt C, Baussan C, Zater M, Hadchouel M, Meunier-Rotival M, Guiochon-Mantel A, et al. Prenatal molecular diagnosis of inherited cholestatic diseases. J Pediatr Gastroenterol Nutr 2007;44:453-458.

FIC1 Disease

A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis.
Bull LN, van Eijk MJ, Pawlikowska L, DeYoung JA, Juijn JA, Liao M, Klomp LW, Lomri N, Berger R, Scharschmidt BF, Knisely AS, Houwen RH, Freimer NB. Nat Genet. 1998;18: 219-24.

Recurrent familial intrahepatic cholestasis in the Faeroe Islands. Phenotypic heterogeneity but genetic homogeneity.
Tygstrup N, Steig BA, Juijn JA, Bull LN, Houwen RH. Hepatology. 1999;29:506-8.

FIC1 disease: a spectrum of intrahepatic cholestatic disorders.
van Mil SW, Klomp LW, Bull LN, Houwen RH. Semin Liver Dis. 2001;21:535-44.

Characterization of mutations in ATP8B1 associated with hereditary cholestasis.
Klomp LW, Vargas JC, van Mil SW, Pawlikowska L, Strautnieks SS, van Eijk MJ, Juijn JA, Pabon-Pena C, Smith LB, DeYoung JA, Byrne JA, Gombert J, van der Brugge G, Berger R, Jankowska I, Pawlowska J, Villa E, Knisely AS, Thompson RJ, Freimer NB, Houwen RH, Bull LN. Hepatology. 2004 40:27-38.

A mouse genetic model for familial cholestasis caused by ATP8B1 mutations reveals perturbed bile salt homeostasis but no impairment in bile secretion.
Pawlikowska L, Groen A, Eppens EF, Kunne C, Ottenhoff R, Looije N, Knisely AS, Killeen NP, Bull LN, Elferink RP, Freimer NB. Hum Mol Genet. 2004 15;13:881-92.

Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity.
Chen F, Ananthanarayanan M, Emre S, Neimark E, Bull LN, Knisely AS, Strautnieks SS, Thompson RJ, Magid MS, Gordon R, Balasubramanian N, Suchy FJ, Shneider BL
Gastroenterology. 2004 126: 756-64

Paulusma CC, Groen A, Kunne C, Ho-Mok KS, Spijkerboer AL, Rudi de Waart D, Hoek FJ, et al. Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport. Hepatology 2006;44:195-204.

BSEP Disease

A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis.
Strautnieks SS, Bull LN, Knisely AS, Kocoshis SA, Dahl N, Arnell H, Sokal E, Dahan K, Childs S, Ling V, Tanner MS, Kagalwalla AF, Nemeth A, Pawlowska J, Baker A, Mieli-Vergani G, Freimer NB, Gardiner RM, Thompson RJ. Nat Genet. 1998;20:233-8.

The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver.
Gerloff T, Stieger B, Hagenbuch B, Madon J, Landmann L, Roth J, Hofmann AF, Meier PJ. J Biol Chem. 1998;273(16):10046-50.

Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis.
Jansen PL, Strautnieks SS, Jacquemin E, Hadchouel M, Sokal EM, Hooiveld GJ, Koning JH, De Jager-Krikken A, Kuipers F, Stellaard F, Bijleveld CM, Gouw A, Van Goor H, Thompson RJ, Muller M. Related Articles, Gastroenterology. 1999;117:1370-9.

The human bile salt export pump: characterization of substrate specificity and identification of inhibitors.
Byrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ. Gastroenterology. 2002 123:1649-58.

Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11.
van Mil SW, van der Woerd WL, van der Brugge G, Sturm E, Jansen PL, Bull LN, van den Berg IE, Berger R, Houwen RH, Klomp LW. Gastroenterology. 2004 Aug;127(2):379-84.

Scheimann AO, Strautnieks SS, Knisely AS, Byrne JA, Thompson RJ, Finegold MJ. Mutations in bile salt export pump (ABCB11) in two children with progressive familial intrahepatic cholestasis and cholangiocarcinoma. J Pediatr 2007;150:556-559.

Stieger B, Meier Y, Meier PJ. The bile salt export pump. Pflugers Arch 2007;453:611-620.

Suchy FJ, Ananthanarayanan M. Bile salt excretory pump: biology and pathobiology. J Pediatr Gastroenterol Nutr 2006;43 Suppl 1:S10-16.

MDR3 Disease

Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease.
Smit JJ, Schinkel AH, Oude Elferink RP, Groen AK, Wagenaar E, van Deemter L, Mol CA, Ottenhoff R, van der Lugt NM, van Roon MA, van der Valk MA, Offerhaus GJ, Berns AJ, Borst P. Cell . 1993 Nov 5;75(3):451-62.

Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.
de Vree JM, Jacquemin E, Sturm E, Cresteil D, Bosma PJ, Aten J, Deleuze JF, Desrochers M, Burdelski M, Bernard O, Oude Elferink RP, Hadchouel M. Proc Natl Acad Sci U S A . 1998 6;95:282-7.

The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood.
Jacquemin E, De Vree JM, Cresteil D, Sokal EM, Sturm E, Dumont M, Scheffer GL, Paul M, Burdelski M, Bosma PJ, Bernard O, Hadchouel M, Elferink RP.
Gastroenterology. 2001;120:1448-58.

MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis.
Rosmorduc O, Hermelin B, Poupon R. Gastroenterology. 2001;120:1459-67.

A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis.
Lucena JF, Herrero JI, Quiroga J, Sangro B, Garcia-Foncillas J, Zabalegui N, Sola J, Herraiz M, Medina JF, Prieto J. Gastroenterology. 2003;124:1037-42

Fickert P, Wagner M, Marschall HU, Fuchsbichler A, Zollner G, Tsybrovskyy O, Zatloukal K, et al. 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 2006;130:465-481.

Oude Elferink RP, Paulusma CC. Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein). Pflugers Arch 2007;453:601-610.

Trauner M, Fickert P, Wagner M. MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Semin Liver Dis 2007;27:77-98.

Therapies

Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis.
Whitington PF, Whitington GL. Gastroenterology, 1988;95:130-6.

Surgical management of progressive familial intrahepatic cholestasis. Emond JC,
Whitington PF. J Pediatr Surg 1995;30:1635-41. 

Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion.
Ismail H, Kalicinski P, Markiewicz M, Jankowska I, Pawlowska J, Kluge P, Eliadou E, Kaminski A, Szymczak M, Drewniak T, Revillon Y. Pediatr Transplant. 1999;3: 219-24.

Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile.
Kurbegov AC, Setchell KD, Haas JE, Mierau GW, Narkewicz M, Bancroft JD, Karrer Z, Sokol RJ. Gastroenterology. 2003;125:1227-34.

Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal bypass.
Kalicinski PJ, Ismail H, Jankowska I, Kaminski A, Pawlowska J, Drewniak T, Markiewicz M, Szymczak M. Eur J Pediatr Surg. 2003;13:307-11.

Stapelbroek JM, van Erpecum KJ, Klomp LW, Venneman NG, Schwartz TP, van Berge Henegouwen GP, Devlin J, et al. Nasobiliary drainage induces long-lasting remission in benign recurrent intrahepatic cholestasis. Hepatology 2006;43:51-53.

Metzelder ML, Bottlander M, Melter M, Petersen C, Ure BM. Laparoscopic partial external biliary diversion procedure in progressive familial intrahepatic cholestasis: a new approach. Surg Endosc 2005;19:1641-1643.

Updated: 30 May 2007

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