Progressive Familial Intrahepatic Cholestasis Treatment & Management
- Author: Melissa Kennedy, MD; Chief Editor: Carmen Cuffari, MD more...
The general treatment of cholestasis applies to progressive familial intrahepatic cholestasis; please see the article Cholestasis for treatment information. The disease typically does not respond to any form of medical therapy. Some have reported success in treating patients with progressive familial intrahepatic cholestasis with ursodeoxycholic acid (20-30 mg/kg/d), which may be tried as an initial treatment. Other therapies for the symptomatic relief of pruritus include antihistamines, rifampin, and bile acid-binding agents.
Surgical therapy that diverts bile salts from the enterohepatic recirculation relieves pruritus in most patients, decreases serum bile salt levels, improves growth, and may delay the progression of disease with PFIC1 and PFIC2.[10, 11] The most common procedure, partial cutaneous biliary diversion, diverts gallbladder bile to a cutaneous ostomy. Patients typically drain 30-120 mL of bile per day, which is discarded. In a recent study following children with PFIC, 3 years after diversion procedure, 45% of patients had complete relief of pruritus, 27% had mild pruritus, and 27% experienced no relief.[8, 9, 10, 11, 12] This procedure must be done prior to the development cirrhosis to be effective. Alternatively, ileal bypass, a procedure in which the proximal ileum is attached to the cecum bypassing the distal 15% of the ileum and therefore avoiding ileal reabsorption of bile acids can be performed in patients that are not candidates for diversion. This procedure provides immediate relief similar the results seen in diversion, but cholestasis eventually returns in most patients.
Liver transplantation is indicated in patients with decompensated cirrhosis or with a failed diversion with debilitating pruritus. The clinical courses and outcomes for PFIC1 recipients after living-donor liver transplantation are still not that good when compared with PFIC2 recipients. Hori et al reported 14 PFIC patients who underwent living-donor liver transplantation, comprising 11 PFIC1 and 3 PFIC2 patients. Three of 11 PFIC1 recipients died, while the 3 recipients with PFIC2 survived. Liver transplantation is the only effective treatment of PFIC3.
Refer all patients to centers with expertise in pediatric hepatology.
The treatment of fat malabsorption principally involves dietary substitution. In an older patient, a diet rich in carbohydrates and proteins can be substituted for a diet containing long-chain triglycerides. This may not be possible for infants, for whom substitution of a formula containing medium-chain triglycerides may improve fat absorption and nutrition. However, this substitution has not been proven, and therapeutic formulas containing medium-chain triglycerides may not be worth the expense. Bile salt therapy to replace missing bile salts is not practical. Ursodeoxycholic acid, which is used to treat some cholestatic conditions, does not form mixed micelles and has no effect on fat absorption.
Pay careful attention to preventing fat-soluble vitamin deficiencies, accomplished by administering fat-soluble vitamins and monitoring the response to therapy. Administer vitamin E as tocopherol polyethylene glycol succinate (TPGS) to achieve sufficient absorption in the face of reduced intestinal bile salt concentrations.
No activity restrictions are needed until late stages of liver disease when precautions should be taken to avoid splenic injury.
Alissa FT, Jaffe R, Shneider BL. Update on progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr. 2008 Mar. 46(3):241-52. [Medline].
van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW, van de Graaf SF, Houwen RH. Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy. Best Pract Res Clin Gastroenterol. 2010 Oct. 24(5):541-53. [Medline].
Varma S, Revencu N, Stephenne X, Scheers I, Smets F, Beleza-Meireles A, et al. Retargeting of bile salt export pump and favorable outcome in children with progressive familial intrahepatic cholestasis type 2. Hepatology. 2015 Jul. 62 (1):198-206. [Medline].
Wang L, Dong H, Soroka CJ, Wei N, Boyer JL, Hochstrasser M. Degradation of the bile salt export pump at endoplasmic reticulum in progressive familial intrahepatic cholestasis type II. Hepatology. 2008 Nov. 48(5):1558-69. [Medline].
Espinosa Fernandez MG, Navas Lopez VM, Blasco Alonso J, Sierra Salinas C, Barco Galvez A. [Progressive familial intrahepatic cholestasis type 3. An MDR3 defect]. An Pediatr (Barc). 2008 Aug. 69(2):182-4. [Medline].
Delaunay JL, Durand-Schneider AM, Dossier C, Falguières T, Gautherot J, Anne DS, et al. A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3. Hepatology. 2015 Oct 17. [Medline].
Chen ST, Chen HL, Su YN, et al. Prenatal diagnosis of progressive familial intrahepatic cholestasis type 2. J Gastroenterol Hepatol. 2008 Sep. 23(9):1390-3. [Medline].
Liu C, Aronow BJ, Jegga AG, Wang N, Miethke A, Mourya R, et al. Novel resequencing chip customized to diagnose mutations in patients with inherited syndromes of intrahepatic cholestasis. Gastroenterology. 2007 Jan. 132(1):119-26. [Medline].
Gunaydin M, Tander B, Demirel D, Caltepe G, Kalayci AG, Eren E, et al. Different techniques for biliary diversion in progressive familial intrahepatic cholestasis. J Pediatr Surg. 2015 Aug 22. [Medline].
van der Woerd WL, Kokke FT, van der Zee DC, Houwen RH. Total biliary diversion as a treatment option for patients with progressive familial intrahepatic cholestasis and Alagille syndrome. J Pediatr Surg. 2015 Jul 27. [Medline].
Jankowska I, Socha P. Progressive familial intrahepatic cholestasis and inborn errors of bile acid synthesis. Clin Res Hepatol Gastroenterol. 2012 Jun. 36(3):271-4. [Medline].
Kalicinski PJ, Ismail H, Jankowska I, Kaminski A, Pawlowska J, Drewniak T. Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal bypass. Eur J Pediatr Surg. 2003 Oct. 13(5):307-11. [Medline].
Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, et al. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology. 2006 Aug. 44(2):478-86. [Medline].
Ekinci S, Karnak I, Gurakan F, et al. Partial external biliary diversion for the treatment of intractable pruritus in children with progressive familial intrahepatic cholestasis: report of two cases. Surg Today. 2008. 38(8):726-30. [Medline].
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. J Pediatr Surg. 2008 Jul. 43(7):1312-20. [Medline].
Usui M, Isaji S, Das BC, et al. Liver retransplantation with external biliary diversion for progressive familial intrahepatic cholestasis type 1: A case report. Pediatr Transplant. 2008 Sep 10. [Medline].
Alonso EM, Snover DC, Montag A, et al. Histologic pathology of the liver in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr. 1994 Feb. 18(2):128-33. [Medline].
Yang H, Porte RJ, Verkade HJ, De Langen ZJ, Hulscher JB. Partial external biliary diversion in children with progressive familial intrahepatic cholestasis and Alagille disease. J Pediatr Gastroenterol Nutr. 2009 Aug. 49(2):216-21. [Medline].
Hori T, Egawa H, Takada Y, et al. Progressive familial intrahepatic cholestasis: a single-center experience of living-donor liver transplantation during two decades in Japan. Clin Transplant. 2011 Sep. 25(5):776-785. [Medline].
Bull LN, van Eijk MJ, Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet. 1998 Mar. 18(3):219-24. [Medline].
Davis AR, Rosenthal P, Newman TB. Nontransplant surgical interventions in progressive familial intrahepatic cholestasis. J Pediatr Surg. 2009 Apr. 44(4):821-7. [Medline].
de Vree JM, Jacquemin E, Sturm E, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci U S A. 1998 Jan 6. 95(1):282-7. [Medline].
Deleuze JF, Jacquemin E, Dubuisson C, et al. Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis. Hepatology. 1996 Apr. 23(4):904-8. [Medline].
Emond JC, Whitington PF. Selective surgical management of progressive familial intrahepatic cholestasis (Byler's disease). J Pediatr Surg. 1995 Dec. 30(12):1635-41. [Medline].
Hollands CM, Rivera-Pedrogo FJ, Gonzalez-Vallina R, et al. Ileal exclusion for Byler's disease: an alternative surgical approach with promising early results for pruritus. J Pediatr Surg. 1998 Feb. 33(2):220-4. [Medline].
Jacquemin E. Progressive familial intrahepatic cholestasis. J Gastroenterol Hepatol. 1999 Jun. 14(6):594-9. [Medline].
Jacquemin E, Hermans D, Myara A, et al. Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis. Hepatology. 1997 Mar. 25(3):519-23. [Medline].
Jansen PL, Strautnieks SS, Jacquemin E, et al. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology. 1999 Dec. 117(6):1370-9. [Medline].
Strautnieks SS, Bull LN, Knisely AS, et al. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet. 1998 Nov. 20(3):233-8. [Medline].
van Mil SW, van der Woerd WL, van der Brugge G, et al. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology. 2004 Aug. 127(2):379-84. [Medline].
Wagner M, Trauner M. Transcriptional regulation of hepatobiliary transport systems in health and disease: implications for a rationale approach to the treatment of intrahepatic cholestasis. Ann Hepatol. 2005 Apr-Jun. 4(2):77-99. [Medline].
Whitington PF, Freese DK, Alonso EM, et al. Clinical and biochemical findings in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr. 1994 Feb. 18(2):134-41. [Medline].
Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology. 1988 Jul. 95(1):130-6. [Medline].
Strautnieks SS, Byrne JA, Pawlikowska L, Cebecauerová D, Rayner A, Dutton L, et al. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology. 2008 Apr. 134(4):1203-14. [Medline].
|ATP8B1||FIC 1 (ATP8B1)||Increased phospholipid membrane instability leads to decreased bile acid transport||Low||Extrahepatic manifestations: diarrhea, pancreatitis, hearing loss|
|ABCB11||BPEP||Mutation in bile acid export pump (BSEP) leads to cholestasis||Low||Increased risk of hepatobiliary malignancies|
|ABCB4||MDR3||Decreased phospholipid concentration in bile leads to destabilized micelles within ductules causing inflammation/destruction and eventually cholestasis||High||Onset of cholestasis tends to be later in life|