Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Pruritus associated with cholestasis

Raoul Poupon, MD
Sanjiv Chopra, MD, MACP
Section Editor
Keith D Lindor, MD
Deputy Editor
Shilpa Grover, MD, MPH, AGAF


Cholestasis is seen with many hepatobiliary disorders that produce extrahepatic biliary obstruction and/or intrahepatic biliary disruption. One particularly troublesome symptom associated with cholestasis is pruritus, which can range in severity from mild, to moderate (in which sleep is disturbed), and to extreme (in which the lifestyle of the patient is completely disrupted).

This topic will review the pathogenesis, clinical manifestations, diagnosis, and management of cholestasis-associated pruritus. The disorders associated with cholestasis are discussed elsewhere. (See "Intrahepatic cholestasis of pregnancy" and "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)" and "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis" and "Drug-induced liver injury" and "Clinical manifestations and diagnosis of cholangiocarcinoma" and "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis".)

The following discussion is consistent with 2009 guidelines from the American Association for the Study of Liver Diseases [1] and the European Association for the Study of the Liver [2] on the management of primary biliary cholangitis (previously referred to as primary biliary cirrhosis) and cholestatic liver disease, respectively.


Pruritus may develop in patients with cholestasis due to any cause. It may be seen with primary biliary cholangitis (previously referred to as primary biliary cirrhosis), primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, biliary obstruction, chronic viral hepatitis, cirrhosis, prolonged drug-induced cholestasis, and inherited cholestasis syndromes (eg, progressive familial intrahepatic cholestasis and benign recurrent intrahepatic cholestasis [3]).

The frequency with which pruritus is seen in these conditions is variable [3]:

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Apr 10, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology 2009; 50:291.
  2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009; 51:237.
  3. Bunchorntavakul C, Reddy KR. Pruritus in chronic cholestatic liver disease. Clin Liver Dis 2012; 16:331.
  4. Jones EA, Bergasa NV. The pruritus of cholestasis: from bile acids to opiate agonists. Hepatology 1990; 11:884.
  5. Bolier R, Oude Elferink RP, Beuers U. Advances in pathogenesis and treatment of pruritus. Clin Liver Dis 2013; 17:319.
  6. Schoenfield, L, Sjovall, J, Perman E. Bile acids on the skin of patients with pruritic hepatobiliary disease. Nature 1967; 213:93.
  7. Varadi DP. Pruritus induced by crude bile and purified bile acids. Experimental production of pruritus in human skin. Arch Dermatol 1974; 109:678.
  8. Kirby J, Heaton KW, Burton JL. Pruritic effect of bile salts. Br Med J 1974; 4:693.
  9. Murphy GM, Ross A, Billing BH. Serum bile acids in primary biliary cirrhosis. Gut 1972; 13:201.
  10. Ghent CN, Bloomer JR, Klatskin G. Elevations in skin tissue levels of bile acids in human cholestasis: relation to serum levels and topruritus. Gastroenterology 1977; 73:1125.
  11. Ghent CN. Pruritus of cholestasis is related to effects of bile salts on the liver, not the skin. Am J Gastroenterol 1987; 82:117.
  12. Bergasa NV. Treatment of the Pruritus of Cholestasis. Curr Treat Options Gastroenterol 2004; 7:501.
  13. Thornton JR, Losowsky MS. Plasma leucine enkephalin is increased in liver disease. Gut 1989; 30:1392.
  14. Spivey J, Jorgensen R, Gores G, et al. Serum met-enkephalin levels in patients with primary biliary cirrhosis correlate with severity of disease but not pruritus. Gastroenterology 1992; 102:A892.
  15. Thornton JR, Losowsky MS. Opioid peptides and primary biliary cirrhosis. BMJ 1988; 297:1501.
  16. Bernstein JE, Swift R. Relief of intractable pruritus with naloxone. Arch Dermatol 1979; 115:1366.
  17. Summerfield JA. Naloxone modulates the perception of itch in man. Br J Clin Pharmacol 1980; 10:180.
  18. Kremer AE, Martens JJ, Kulik W, et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 2010; 139:1008.
  19. Oude Elferink RP, Kremer AE, Martens JJ, Beuers UH. The molecular mechanism of cholestatic pruritus. Dig Dis 2011; 29:66.
  20. Kremer AE, van Dijk R, Leckie P, et al. Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions. Hepatology 2012; 56:1391.
  21. Talbot TL, Schmitt JM, Bergasa NV, et al. Application of piezo film technology for the quantitative assessment of pruritus. Biomed Instrum Technol 1991; 25:400.
  22. Tandon P, Rowe BH, Vandermeer B, Bain VG. The efficacy and safety of bile Acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus. Am J Gastroenterol 2007; 102:1528.
  23. Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol 2009; 15:2049.
  24. Glantz A, Reilly SJ, Benthin L, et al. Intrahepatic cholestasis of pregnancy: Amelioration of pruritus by UDCA is associated with decreased progesterone disulphates in urine. Hepatology 2008; 47:544.
  25. Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy. Gastroenterology 2005; 129:894.
  26. Palma J, Reyes H, Ribalta J, et al. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo. J Hepatol 1997; 27:1022.
  27. Binder T, Salaj P, Zima T, Vítek L. Randomized prospective comparative study of ursodeoxycholic acid and S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis of pregnancy. J Perinat Med 2006; 34:383.
  28. Roncaglia N, Locatelli A, Arreghini A, et al. A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-l-methionine in the treatment of gestational cholestasis. BJOG 2004; 111:17.
  29. DATTA DV, SHERLOCK S. Treatment of pruritus of obstructive jaundice with cholestyramine. Br Med J 1963; 1:216.
  30. Kuiper EM, van Erpecum KJ, Beuers U, et al. The potent bile acid sequestrant colesevelam is not effective in cholestatic pruritus: results of a double-blind, randomized, placebo-controlled trial. Hepatology 2010; 52:1334.
  31. Bergasa NV. The pruritus of cholestasis. J Hepatol 2005; 43:1078.
  32. Wiertelak EP, Maier SF, Watkins LR. Cholecystokinin antianalgesia: safety cues abolish morphine analgesia. Science 1992; 256:830.
  33. Podesta A, Lopez P, Terg R, et al. Treatment of pruritus of primary biliary cirrhosis with rifampin. Dig Dis Sci 1991; 36:216.
  34. Ghent CN, Carruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial. Gastroenterology 1988; 94:488.
  35. Khurana S, Singh P. Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials. Liver Int 2006; 26:943.
  36. Imam MH, Gossard AA, Sinakos E, Lindor KD. Pathogenesis and management of pruritus in cholestatic liver disease. J Gastroenterol Hepatol 2012; 27:1150.
  37. Bergasa NV, Alling DW, Talbot TL, et al. Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Ann Intern Med 1995; 123:161.
  38. Wolfhagen FH, Sternieri E, Hop WC, et al. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 1997; 113:1264.
  39. Bergasa NV, Schmitt JM, Talbot TL, et al. Open-label trial of oral nalmefene therapy for the pruritus of cholestasis. Hepatology 1998; 27:679.
  40. Terg R, Coronel E, Sordá J, et al. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study. J Hepatol 2002; 37:717.
  41. Jones EA, Neuberger J, Bergasa NV. Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions. QJM 2002; 95:547.
  42. McRae CA, Prince MI, Hudson M, et al. Pain as a complication of use of opiate antagonists for symptom control in cholestasis. Gastroenterology 2003; 125:591.
  43. Browning J, Combes B, Mayo MJ. Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol 2003; 98:2736.
  44. Mayo MJ, Handem I, Saldana S, et al. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology 2007; 45:666.
  45. Zylicz Z, Krajnik M, Sorge AA, Costantini M. Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial. J Pain Symptom Manage 2003; 26:1105.
  46. Simons FE, Watson WT, Chen XY, et al. The pharmacokinetics and pharmacodynamics of hydroxyzine in patients with primary biliary cirrhosis. J Clin Pharmacol 1989; 29:809.
  47. Talwalkar JA, Souto E, Jorgensen RA, Lindor KD. Natural history of pruritus in primary biliary cirrhosis. Clin Gastroenterol Hepatol 2003; 1:297.
  48. Batta AK, Salen G, Mirchandani R, et al. Effect of long-term treatment with ursodiol on clinical and biochemical features and biliary bile acid metabolism in patients with primary biliary cirrhosis. Am J Gastroenterol 1993; 88:691.
  49. Poupon RE, Chrétien Y, Poupon R, Paumgartner G. Serum bile acids in primary biliary cirrhosis: effect of ursodeoxycholic acid therapy. Hepatology 1993; 17:599.
  50. Heathcote EJ, Cauch-Dudek K, Walker V, et al. The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994; 19:1149.
  51. Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med 1997; 336:691.
  52. Matsuzaki Y, Tanaka N, Osuga T, et al. Improvement of biliary enzyme levels and itching as a result of long-term administration of ursodeoxycholic acid in primary biliary cirrhosis. Am J Gastroenterol 1990; 85:15.
  53. Stellaard F, Bolt MG, Boyer JL, Klein PD. Phenobarbital treatment in primary biliary cirrhosis. Differences in bile acid composition between responders and nonresponders. J Lab Clin Med 1979; 94:853.
  54. Bloomer JR, Boyer JL. Phenobarbital effects in cholestatic liver diseases. Ann Intern Med 1975; 82:310.
  55. Hegade VS, Kendrick SF, Dobbins RL, et al. Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. Lancet 2017; 389:1114.
  56. Hanid MA, Levi AJ. Phototherapy for pruritus in primary biliary cirrhosis. Lancet 1980; 2:530.
  57. Cerio R, Murphy GM, Sladen GE, MacDonald DM. A combination of phototherapy and cholestyramine for the relief of pruritus in primary biliary cirrhosis. Br J Dermatol 1987; 116:265.
  58. Bergasa NV, Link MJ, Keogh M, et al. Pilot study of bright-light therapy reflected toward the eyes for the pruritus of chronic liver disease. Am J Gastroenterol 2001; 96:1563.
  59. Lauterburg BH, Taswell HF, Pineda AA, et al. Treatment of pruritus of cholestasis by plasma perfusion through USP-charcoal-coated glass beads. Lancet 1980; 2:53.
  60. Cohen LB, Ambinder EP, Wolke AM, et al. Role of plasmapheresis in primary biliary cirrhosis. Gut 1985; 26:291.
  61. Alallam A, Barth D, Heathcote EJ. Role of plasmapheresis in the treatment of severe pruritus in pregnant patients with primary biliary cirrhosis: case reports. Can J Gastroenterol 2008; 22:505.
  62. Hegade VS, Krawczyk M, Kremer AE, et al. The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study. Aliment Pharmacol Ther 2016; 43:294.
  63. Borgeat A, Wilder-Smith O, Mentha G, Huber O. Propofol and cholestatic pruritus. Am J Gastroenterol 1992; 87:672.
  64. Walt RP, Daneshmend TK, Fellows IW, Toghill PJ. Effect of stanozolol on itching in primary biliary cirrhosis. Br Med J (Clin Res Ed) 1988; 296:607.
  65. Neff GW, O'Brien CB, Reddy KR, et al. Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease. Am J Gastroenterol 2002; 97:2117.
  66. Macia M, Avilés J, Navarro J, et al. Efficacy of molecular adsorbent recirculating system for the treatment of intractable pruritus in cholestasis. Am J Med 2003; 114:62.
  67. Doria C, Mandalá L, Smith J, et al. Effect of molecular adsorbent recirculating system in hepatitis C virus-related intractable pruritus. Liver Transpl 2003; 9:437.
  68. Bellmann R, Graziadei IW, Feistritzer C, et al. Treatment of refractory cholestatic pruritus after liver transplantation with albumin dialysis. Liver Transpl 2004; 10:107.
  69. Parés A, Cisneros L, Salmerón JM, et al. Extracorporeal albumin dialysis: a procedure for prolonged relief of intractable pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol 2004; 99:1105.