Background: Cholestatic liver diseases (CD) account for 11% of all liver transplantations (LT) in the Eurotransplant region. Despite the excellent long-term outcome that is considerably superior to all other indications for LT, transplant surgeons and physicians face nowadays - in the era of MELD (Model of End-Stage Liver Disease)-based allocation, organ shortage, and extended allocation policies - more and more challenges in this patient cohort, especially since there is no curative medical treatment for these entities. Methods: Based on a literature review and personal experience in liver transplantation for CD, we show the status quo of indication, allocation, and outcome as well as potential strategies to overcome long waiting times and organ shortage. Results: Concerning graft and patient survival, CD remain the ‘best indications' for LT. Since the implementation of MELD-based allocation results in patients with primary sclerosing cholangitis (PSC) could be preserved on good levels only by the implementation and revision of standard exceptions. Recurrence of PSC after LT remains a challenge for transplant surgeons and physicians. New data has kindled a debate on biliary reconstruction in LT for PSC. Promising data on living donor LT motivate to push the boundaries in this direction. Conclusion: CD are excellent indications for liver transplantation since excellent long-term outcomes are achievable when the transplant is performed at the right time. The decisions concerning evaluation, listing, and allocation should be made by an interdisciplinary team of gastroenterologists and transplant surgeons.

Keywords:
Cholestatic liver disease, Primary biliary cirrhosis, Primary sclerosing cholangitis, Liver transplantation
1.
Adam R, Karam V, Delvart V, et al: Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol 2012;57:675-688.
2.
Lindkvist B, Benito de Valle M, Gullberg B, Bjornsson E: Incidence and prevalence of primary sclerosing cholangitis in a defined adult population in Sweden. Hepatology 2010;52:571-577.
3.
Mendes F, Lindor KD: Primary sclerosing cholangitis: overview and update. Nat Rev Gastroenterol Hepatol 2010;7:611-619.
4.
Chapman R, Fevery J, Kalloo A, et al: Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51:660-678.
5.
European Association for the Study of the Liver: EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237-267.
6.
Tischendorf JJ, Hecker H, Kruger M, Manns MP, Meier PN: Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am J Gastroenterol 2007;102:107-114.
7.
Williamson KD, Chapman RW: Primary sclerosing cholangitis. Dig Dis 2014;32:438-445.
8.
Alswat K, Al-Harthy N, Mazrani W, Alshumrani G, Jhaveri K, Hirschfield GM: The spectrum of sclerosing cholangitis and the relevance of IgG4 elevations in routine practice. Am J Gastroenterol 2012;107:56-63.
9.
Mendes FD, Jorgensen R, Keach J, et al: Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol 2006;101:2070-2075.
10.
Bergquist A, Ekbom A, Olsson R, et al: Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 2002;36:321-327.
11.
Boberg KM, Lind GE: Primary sclerosing cholangitis and malignancy. Best Pract Res Clin Gastroenterol 2011;25:753-764.
12.
Trauner M, Halilbasic E, Baghdasaryan A, et al: Primary sclerosing cholangitis: new approaches to diagnosis, surveillance and treatment. Dig Dis 2012;30(suppl 1):39-47.
13.
Fevery J, Verslype C, Lai G, Aerts R, Van Steenbergen W: Incidence, diagnosis, and therapy of cholangiocarcinoma in patients with primary sclerosing cholangitis. Dig Dis Sci 2007;52:3123-3135.
14.
Lutz H, Trautwein C, Tischendorf JW: Primary sclerosing cholangitis: diagnosis and treatment. Dtsch Arztebl Int 2013;110:867-874.
15.
Boberg KM, Bergquist A, Mitchell S, et al: Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand J Gastroenterol 2002;37:1205-1211.
16.
Melum E, Buch S, Schafmayer C, et al: Investigation of cholangiocarcinoma associated NKG2D polymorphisms in colorectal carcinoma. Int J Cancer 2008;123:241-242.
17.
Melum E, Karlsen TH, Schrumpf E, et al: Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms. Hepatology 2008;47:90-96.
18.
Darwish Murad S, Kim WR, Harnois DM, et al: Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology 2012;143:88-98.e3; quiz e14.
19.
Gershwin ME, Mackay IR: The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology 2008;47:737-745.
20.
Carbone M, Neuberger JM: Autoimmune liver disease, autoimmunity and liver transplantation. J Hepatol 2014;60:210-223.
21.
Raczynska J, Habior A, Paczek L, Foroncewicz B, Pawelas A, Mucha K: Primary biliary cirrhosis in the era of liver transplantation. Ann Transplant 2014;19:488-493.
22.
Kopycinska J, Kempinska-Podhorodecka A, Haas T, et al: Activation of FoxO3a/Bim axis in patients with Primary Biliary Cirrhosis. Liver Int 2013;33:231-238.
23.
Corpechot C, Chretien Y, Chazouilleres O, Poupon R: Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. J Hepatol 2010;53:162-169.
24.
Gershwin ME, Selmi C, Worman HJ, et al: Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 2005;42:1194-1202.
25.
Poupon R: Primary biliary cirrhosis: a 2010 update. J Hepatol 2010;52:745-758.
26.
Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ: Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997;113:884-890.
27.
Lindor KD: Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med 1997;336:691-695.
28.
Olsson R, Boberg KM, de Muckadell OS, et al: High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology 2005;129:1464-1472.
29.
Lindor KD, Kowdley KV, Luketic VA, et al: High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009;50:808-814.
30.
Gross CR, Malinchoc M, Kim WR, et al: Quality of life before and after liver transplantation for cholestatic liver disease. Hepatology 1999;29:356-364.
31.
Mells GF, Pells G, Newton JL, et al: Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study. Hepatology 2013;58:273-283.
32.
Pells G, Mells GF, Carbone M, et al: The impact of liver transplantation on the phenotype of primary biliary cirrhosis patients in the UK-PBC cohort. J Hepatol 2013;59:67-73.
33.
Dickson ER, Grambsch PM, Fleming TR, Fisher LD, Langworthy A: Prognosis in primary biliary cirrhosis: model for decision making. Hepatology 1989;10:1-7.
34.
Freeman RB Jr, Gish RG, Harper A, et al: Model for end-stage liver disease (MELD) exception guidelines: results and recommendations from the MELD Exception Study Group and Conference (MESSAGE) for the approval of patients who need liver transplantation with diseases not considered by the standard MELD formula. Liver Transpl 2006;12(suppl 3):S128-136.
35.
German Medical Association: Richtlinien zur Organtransplantation gem. § 16 Abs. 1 S. 1 Nrn. 2 u. 5 TPG. Dtsch Arztebl 2012;108:A662-674.
36.
Klose J, Klose MA, Metz C, et al: Outcome stagnation of liver transplantation for primary sclerosing cholangitis in the Model for End-Stage Liver Disease era. Langenbecks Arch Surg 2014;399:1021-1029.
37.
Schlitt HJ, Loss M, Scherer MN, et al: Current developments in liver transplantation in Germany: MELD-based organ allocation and incentives for transplant centres (Article in German). Z Gastroenterol 2011;49:30-38.
38.
Weismuller TJ, Fikatas P, Schmidt J, et al: Multicentric evaluation of model for end-stage liver disease-based allocation and survival after liver transplantation in Germany - limitations of the ‘sickest first'-concept. Transpl Int 2011;24:91-99.
39.
Deutsch M, Papatheodoridis GV, Tzakou A, Hadziyannis SJ: Risk of hepatocellular carcinoma and extrahepatic malignancies in primary biliary cirrhosis. Eur J Gastroenterol Hepatol 2008;20:5-9.
40.
Harada K, Hirohara J, Ueno Y, et al: Incidence of and risk factors for hepatocellular carcinoma in primary biliary cirrhosis: national data from Japan. Hepatology 2013;57:1942-1949.
41.
Shibuya A, Tanaka K, Miyakawa H, et al: Hepatocellular carcinoma and survival in patients with primary biliary cirrhosis. Hepatology 2002;35:1172-1178.
42.
Harnois DM, Gores GJ, Ludwig J, Steers JL, LaRusso NF, Wiesner RH: Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer? J Hepatol 1997;27:512-516.
43.
Welsh FK, Wigmore SJ: Roux-en-Y choledochojejunostomy is the method of choice for biliary reconstruction in liver transplantation for primary sclerosing cholangitis. Transplantation 2004;77:602-604.
44.
Pandanaboyana S, Bell R, Bartlett AJ, McCall J, Hidalgo E: Meta-analysis of Duct-to-duct versus Roux-en-Y biliary reconstruction following liver transplantation for primary sclerosing cholangitis. Transpl Int 2015;28:485-491.
45.
Neuhaus P: Live donor/split liver grafts for adult recipients: when should we use them? Liver Transpl 2005;(suppl 2):S6-9.
46.
Chen CL, Kabiling CS, Concejero AM: Why does living donor liver transplantation flourish in Asia? Nat Rev Gastroenterol Hepatol 2013;10:746-751.
47.
Harihara Y, Makuuchi M, Kawarasaki H, et al: Initial experience with living-related liver transplantation at the University of Tokyo. Transplant Proc 1998;30:129-131.
48.
Waki K, Sugawara Y, Mizuta K, Fujita H, Kadowaki T, Kokudo N: Living-donor liver transplantation at the University of Tokyo, 1996-2011: the impact of HLA matching and a positive crossmatch on long-term survival and tolerance. Clin Transpl 2011;223-235.
49.
Berg CL, Gillespie BW, Merion RM, et al: Improvement in survival associated with adult-to-adult living donor liver transplantation. Gastroenterology 2007;133:1806-1813.
50.
Kim SH, Lee SD, Kim YK, Park SJ: Pushing the frontiers of living donor right hepatectomy. World J Gastroenterol 2014;20:18061-18069.
51.
Mittler J, Pascher A, Jonas S, et al: Adult living donor liver transplantation: living donation of the right liver lobe. Langenbecks Arch Surg 2007;392:657-662.
52.
Singal AK, Guturu P, Hmoud B, Kuo YF, Salameh H, Wiesner RH: Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplantation 2013;95:755-760.
53.
Schoening WN, Buescher N, Rademacher S, et al: Twenty-year longitudinal follow-up after orthotopic liver transplantation: a single-center experience of 313 consecutive cases. Am J Transplant 2013;13:2384-2394.
54.
Duclos-Vallee JC, Sebagh M: Recurrence of autoimmune disease, primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis after liver transplantation. Liver Transpl 2009;15(suppl 2):S25-34.
55.
Fosby B, Karlsen TH, Melum E: Recurrence and rejection in liver transplantation for primary sclerosing cholangitis. World J Gastroenterol 2012;18:1-15.
56.
Moncrief KJ, Savu A, Ma MM, Bain VG, Wong WW, Tandon P: The natural history of inflammatory bowel disease and primary sclerosing cholangitis after liver transplantation - a single-centre experience. Can J Gastroenterol 2010;24:40-46.
57.
Vera A, Moledina S, Gunson B, et al: Risk factors for recurrence of primary sclerosing cholangitis of liver allograft. Lancet 2002;360:1943-1944.
58.
Alabraba E, Nightingale P, Gunson B, et al: A re-evaluation of the risk factors for the recurrence of primary sclerosing cholangitis in liver allografts. Liver Transpl 2009;15:330-340.
59.
Alexander J, Lord JD, Yeh MM, Cuevas C, Bakthavatsalam R, Kowdley KV: Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation. Liver Transpl 2008;14:245-251.
60.
Campsen J, Zimmerman MA, Trotter JF, et al: Clinically recurrent primary sclerosing cholangitis following liver transplantation: a time course. Liver Transpl 2008;14:181-185.
61.
Cholongitas E, Shusang V, Papatheodoridis GV, et al: Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation. Liver Transpl 2008;14:138-143.
62.
Jeyarajah DR, Netto GJ, Lee SP, et al: Recurrent primary sclerosing cholangitis after orthotopic liver transplantation: is chronic rejection part of the disease process? Transplantation 1998;66:1300-1306.
63.
Graziadei IW, Wiesner RH, Batts KP, et al: Recurrence of primary sclerosing cholangitis following liver transplantation. Hepatology 1999;29:1050-1056.
64.
Rowe IA, Webb K, Gunson BK, Mehta N, Haque S, Neuberger J: The impact of disease recurrence on graft survival following liver transplantation: a single centre experience. Transpl Int 2008;21:459-465.
65.
Carbone M, Mells GF, Alexander GJ, et al: Calcineurin inhibitors and the IL12A locus influence risk of recurrent primary biliary cirrhosis after liver transplantation. Am J Transplant 2013;13:1110-1111.
66.
Neuberger J, Gunson B, Hubscher S, Nightingale P: Immunosuppression affects the rate of recurrent primary biliary cirrhosis after liver transplantation. Liver Transpl 2004;10:488-491.
67.
Karlsen TH, Vesterhus M, Boberg KM: Review article: controversies in the management of primary biliary cirrhosis and primary sclerosing cholangitis. Aliment Pharmacol Ther 2014;39:282-301.
68.
Singh S, Loftus EV Jr, Talwalkar JA: Inflammatory bowel disease after liver transplantation for primary sclerosing cholangitis. Am J Gastroenterol 2013;108:1417-1425.
69.
Ho GT, Seddon AJ, Therapondos G, Satsangi J, Hayes PC: The clinical course of ulcerative colitis after orthotopic liver transplantation for primary sclerosing cholangitis: further appraisal of immunosuppression post transplantation. Eur J Gastroenterol Hepatol 2005;17:1379-1385.
70.
Indriolo A, Ravelli P: Clinical management of inflammatory bowel disease in the organ recipient. World J Gastroenterology 2014;20:3525-3533.
71.
Navaneethan U, Venkatesh PG, Mukewar S, et al: Progressive primary sclerosing cholangitis requiring liver transplantation is associated with reduced need for colectomy in patients with ulcerative colitis. Clin Gastroenterol Hepatol 2012;10:540-546.
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2015
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