Therapeutics for Pruritus in Cholestatic Liver Disease: Many Treatments but Few Cures

Autoimmune, Cholestatic, and Biliary Diseases (S Gordon and C Bowlus, Section Editors)
  • 13 Downloads
Part of the following topical collections:
  1. Topical Collection on Autoimmune, Cholestatic, and Biliary Diseases

Abstract

Purpose of Review

Pruritus in cholestatic liver disease is commonly encountered and difficult to eradicate. It has a major impact on quality of life and thus is important to address. This article reviews current and future treatment options for cholestatic pruritus.

Recent Findings

In the last 5 years, the pathogenesis of cholestatic itch has been further clarified via studies of serum autotaxin, which correlates with severity of symptoms and decrease in patients on therapy. New medications under development include apical sodium-dependent bile acid transporters (maralixibat, GSK2330672), fibrates (bezafibrate), and κ-opioid receptor agonists (nalfurafine hydrochloride).

Summary

While many treatments are available to treat this vexing condition, data to support consistent and dramatic improvement with any one medication is lacking. However, with so many options and several new medications under investigation in clinical trials, symptom relief is an achievable goal for many patients.

Keywords

Itch Primary biliary cholangitis Primary biliary cirrhosis Primary sclerosing cholangitis Bile 

Notes

Compliance with Ethical Standards

Conflict of Interest

Mark Pederson declares no conflicts of interest.

Marlyn J. Mayo reports grants from Glaxo Smith Kline, Shire, Intercept, and Pfizer, outside the submitted work.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Lawley T, Yancey K. Approach to the patient with a skin disorder. In: Kasper D, Hauser S, Longo D, Jameson JL, Loscalzo J, editors. In Fauci A BE. Harrison’s Principles of Internal Medicine USA: The McGraw-Hil Companies; 2008. p. 308–12.Google Scholar
  2. 2.
    Jin X, Khan T. Quality of life among patients suffering from cholestatic liver disease-induced pruritus: a systematic review. J Formos Med Assoc. 2016;115:689–702.CrossRefPubMedGoogle Scholar
  3. 3.
    Benito de Valle M, Rahman M, Lindkvist B, Bjornsson E, Chapman R, Kalaitzakis E. Factors that reduce health-related quality of life in patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2012;10(7):769–75 e2.  https://doi.org/10.1016/j.cgh.2012.01.025.CrossRefPubMedGoogle Scholar
  4. 4.
    Marchesini G, Bianchi G, Amodio P, Salerno F, Merli M, Panella C, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology. 2001;120(1):170–8.  https://doi.org/10.1053/gast.2001.21193.CrossRefPubMedGoogle Scholar
  5. 5.
    Poupon RE, Chretien Y, Chazouilleres O, Poupon R, Chwalow J. Quality of life in patients with primary biliary cirrhosis. Hepatology. 2004;40(2):489–94.  https://doi.org/10.1002/hep.20276.CrossRefPubMedGoogle Scholar
  6. 6.
    Stanca CM, Bach N, Krause C, Tandon N, Freni MA, Gutierrez JA, et al. Evaluation of fatigue in U.S. patients with primary biliary cirrhosis. Am J Gastroenterol. 2005;100(5):1104–9.  https://doi.org/10.1111/j.1572-0241.2005.41315.x.CrossRefPubMedGoogle Scholar
  7. 7.
    Younossi Y, Kiwi M, Boparai N, Price L, Guyatt G. Cholestatic liver diseases and health-related quality of life. Am J Gastroenterol. 2000;95:497–502.CrossRefPubMedGoogle Scholar
  8. 8.
    Lens S, Leoz M, Nazal L, Bruguera M, Pares A. Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int. 2014;34(2):197–203.  https://doi.org/10.1111/liv.12290.CrossRefPubMedGoogle Scholar
  9. 9.
    •• Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631–43.  https://doi.org/10.1056/NEJMoa1509840. A phase 3 study demonstrating the efficacy of obeticholic acid for the treatment of PBC experiencing suboptimal response to UDCA. CrossRefPubMedGoogle Scholar
  10. 10.
    •• Reig A, Sese P, Pares A. Effects of Bezafibrate on Outcome and Pruritus in Primary Biliary Cholangitis With Suboptimal Ursodeoxycholic Acid Response. Am J Gastroenterol. 2018;113(1):49–55.  https://doi.org/10.1038/ajg.2017.287. A trial of 48 patients demonstrating the beneficial effects of long-term bezafibrate effects in patients with PBC experiencing suboptimal response to UDCA. CrossRefPubMedGoogle Scholar
  11. 11.
    Kronsten V, Fitzpatrick E, Baker A. Management of cholestatic pruritus in paediatric patients with alagille syndrome: the King's College Hospital experience. J Pediatr Gastroenterol Nutr. 2013;57(2):149–54.  https://doi.org/10.1097/MPG.0b013e318297e384.CrossRefPubMedGoogle Scholar
  12. 12.
    Rishe E, Azarm A, Bergasa N. Itch in primary biliary cirrhosis: a patients’ perspective. Acta Derm Venereol. 2008;88:34–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Alighieri D. Inferno. New York: Race Point Publishing; 2015.Google Scholar
  14. 14.
    Peddicord S. FDA approves Ocaliva for rare, chronic liver disease. 2016.Google Scholar
  15. 15.
    •• Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015;148(4):751–61 e8.  https://doi.org/10.1053/j.gastro.2014.12.005. A phase 3 study demonstrating the efficacy of obeticholic acid for the treatment of PBC experiencing suboptimal response to UDCA. CrossRefPubMedGoogle Scholar
  16. 16.
    Mason A, Luketic V, Lindor K, Hirschfield G, Gordon S, Mayo M, et al. 2 Farsenoid-X receptor agonists: a new class of drugs for the treatment of PBC? An international study evaluating the addition of INT-747 to ursodeoxycholic acid. J Hepatol. 2010;52(Suppl):S1–2.CrossRefGoogle Scholar
  17. 17.
    Patrick DL, Bush JW, Chen MM. Methods for measuring levels of well-being for a health status index. Helth Serv Res. 1973;8:228–45.Google Scholar
  18. 18.
    Pincus T, Bergman M, Sokka T, Roth J, Swearingen C, Yazici Y. Visual analogue scale in formats other than a 10 cm horizontal line to assess pain and other clinical data. J Rheumatol. 2008;35(8):1550–8.PubMedGoogle Scholar
  19. 19.
    Price DD, Busch FM, Long S, Harkins SW. A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating. Pain. 1994;56:217–26.CrossRefPubMedGoogle Scholar
  20. 20.
    Reich A, Heisig M, Phan NQ, Taneda K, Takamori K, Takeuchi S, et al. Visual analogue scale: evaluation of the instrument for the assessment of pruritus. Acta Derm Venereol. 2012;92(5):497–501.  https://doi.org/10.2340/00015555-1265.CrossRefPubMedGoogle Scholar
  21. 21.
    Reich A, Riepe C, Anastasiadou Z, Medrek K, Augustin M, Szepietowski JC, et al. Itch assessment with visual analogue scale and numerical rating scale: determination of minimal clinically important difference in chronic itch. Acta Derm Venereol. 2016;96(7):978–80.  https://doi.org/10.2340/00015555-2433.CrossRefPubMedGoogle Scholar
  22. 22.
    Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of pruritus. Br J Dermatol. 2010;162(3):587–93.  https://doi.org/10.1111/j.1365-2133.2009.09586.x.CrossRefPubMedGoogle Scholar
  23. 23.
    Ward L, Wright E, McMahon SBA. Comparison of the effects of noxious and innocuous counterstimuli on experimentally induced itch and pain. Pain. 1996;64:129–38.CrossRefPubMedGoogle Scholar
  24. 24.
    Ochoa J, Torebjork E. Sensations evoked by intraneural microstimulation of C nociceptor fibres in human skin nerves. J Physiol. 1989;415:583–99.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Schmelz M, Schmidt R, Bickel A, Handwerker H, Torebjork H, Specific C. Receptors for itch in human skin. J Neurosci. 1997;17:8003–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjork HE, Handwerker HO. Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neuro-Oncol. 2003;89:2441–8.Google Scholar
  27. 27.
    Patel KN, Dong X. Itch: cells, molecules, and circuits. ACS Chem Neurosci. 2011;2(1):17–25.  https://doi.org/10.1021/cn100085g.CrossRefPubMedGoogle Scholar
  28. 28.
    • Kremer AE, Feramisco J, Reeh PW, Beuers U, Receptors OERP. Cells and circuits involved in pruritus of systemic disorders. Biochim Biophys Acta. 2014;1842(7):869–92.  https://doi.org/10.1016/j.bbadis.2014.02.007. An excellent review of the molecular mechanisms and neurological pathways involved in cholestatic pruritus. CrossRefPubMedGoogle Scholar
  29. 29.
    Sun YG, Chen ZF. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature. 2007;448(7154):700–3.  https://doi.org/10.1038/nature06029.CrossRefPubMedGoogle Scholar
  30. 30.
    Jinks SL, Carstens E. Responses of superficial dorsal horn neurons to intradermal serotonin and other irritants: comparison with scratching behavior. J Neuro-Oncol. 2002;87:1280–9.  https://doi.org/10.1152/jn.00431.2001.Google Scholar
  31. 31.
    Kittaka H, Uchida K, Fukuta N, Tominaga M. Lysophosphatidic acid-induced itch is mediated by signalling of LPA5 receptor, phospholipase D and TRPA1/TRPV1. J Physiol. 2017;595(8):2681–98.  https://doi.org/10.1113/JP273961.CrossRefPubMedGoogle Scholar
  32. 32.
    Nelson L, Vergnolle N, D'Mello C, Chapman K, Le T, Swain MG. Endogenous opioid-mediated antinociception in cholestatic mice is peripherally, not centrally, mediated. J Hepatol. 2006;44(6):1141–9.  https://doi.org/10.1016/j.jhep.2005.11.043.CrossRefPubMedGoogle Scholar
  33. 33.
    Alemi F, Kwon E, Poole DP, Lieu T, Lyo V, Cattaruzza F, et al. The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest. 2013;123(4):1513–30.  https://doi.org/10.1172/JCI64551.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Datta DV, Sherlock S. Cholestyramine for the long term relief of the pruritus complicating intrahepatic cholestasis. Gastroenterology. 1966;50:323–32.  https://doi.org/10.1016/S0016-5085(66)80071-9. PubMedGoogle Scholar
  35. 35.
    Di Padova C, Tritapepe R, Rovagnati P, Rossetti S. Double-blind placebo-controlled clinical trial of microporous cholestyramine in the treatment of intra- and extra-hepatic cholestasis: relationship between itching and serum bile acids. Methods Find Exp Clin Pharmacol. 1984;6:773–6.PubMedGoogle Scholar
  36. 36.
    Appleby VJ, Hutchinson JM, Davies MH. Safety and efficacy of long-term nasobiliary drainage to treat intractable pruritus in cholestatic liver disease. Frontline Gastroenterol. 2015;6(4):252–4.  https://doi.org/10.1136/flgastro-2014-100489.CrossRefPubMedGoogle Scholar
  37. 37.
    • Hegade VS, Krawczyk M, Kremer AE, Kuczka J, Gaouar F, Kuiper EM, 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(2):294–302.  https://doi.org/10.1111/apt.13449. Evaluated the safety and effectiveness of nasobiliary drainage in 27 patients with refractory cholestatic pruritus. CrossRefPubMedGoogle Scholar
  38. 38.
    Freedman MRH, Holzbach RT, Ferguson DR. Pruritus in cholestasis: no direct causative role in bile acid retention. Am J Med. 1981;70(5):1011–6.CrossRefPubMedGoogle Scholar
  39. 39.
    Murphy GM, Ross A, Billing BH. Serum bile acids in primary biliary cirrhosis. Gut. 1972;13:201–6.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kremer AE, Martens JJ, Kulik W, Rueff F, Kuiper EM, van Buuren HR, et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology. 2010;139(3):1008–18, 18 e1.  https://doi.org/10.1053/j.gastro.2010.05.009.CrossRefPubMedGoogle Scholar
  41. 41.
    Kremer AE, van Dijk R, Leckie P, Schaap FG, Kuiper EM, Mettang T, et al. Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions. Hepatology. 2012;56(4):1391–400.  https://doi.org/10.1002/hep.25748.CrossRefPubMedGoogle Scholar
  42. 42.
    Kremer AE, Gonzales E, Schaap FG, Oude Elferink RP, Jacquemin E, Beuers U. Serum Autotaxin activity correlates with pruritus in pediatric cholestatic disorders. J Pediatr Gastroenterol Nutr. 2016;62(4):530–5.  https://doi.org/10.1097/MPG.0000000000001044.CrossRefPubMedGoogle Scholar
  43. 43.
    Kremer AE, Bolier R, Dixon PH, Geenes V, Chambers J, Tolenaars D, et al. Autotaxin activity has a high accuracy to diagnose intrahepatic cholestasis of pregnancy. J Hepatol. 2015;62(4):897–904.  https://doi.org/10.1016/j.jhep.2014.10.041.CrossRefPubMedGoogle Scholar
  44. 44.
    Berstein JE, Switft R. Relief of intractable pruritus with naloxone. Arch Dermatol. 1979;115:1366–7.  https://doi.org/10.1001/archderm.1979.04010110058029.CrossRefGoogle Scholar
  45. 45.
    Thornton JR, Losowsky MS. Methionine enkephalin is increased in plasma in acute liver disease and is present in bile and urine. J Hepatol. 1989;8:53–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Bergasa NV, Alling DW, Vergalla J, Jones EA. Cholestasis in the male is associated with naloxone-reversible antinociception. J Hepatol. 1994;20:85–90.CrossRefPubMedGoogle Scholar
  47. 47.
    Spivey JR, Jorgensen RA, Gores GJ, Lindor KD. Methionine-enkephalin concentrations correlate with stage of disease but not pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol. 1994;89(11):2028–32.PubMedGoogle Scholar
  48. 48.
    Gittlen SD, Schulman ES, Maddrey WC. Raised histamine concentrations in chronic cholestatic liver disease. Gut. 1990;31:96–9.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Duncan JS, Kennedy HJ, Triger DR. Treatment of pruritus due to chronic obstructive liver disease. Br J Med. 1984;289:22.CrossRefGoogle Scholar
  50. 50.
    Glantz A, Rielly SJ, Benthin L, Lammert F, Mattsson L, Marschall HU. Intrahepatic cholestasis of pregnancy: amelioration of pruritus by UDCA is associated with decreased progesterone disulfates in urine. Hepatology. 2008;47:544–51.CrossRefPubMedGoogle Scholar
  51. 51.
    Bacq Y, le Besco M, Lecuyer AI, Gendrot C, Potin J, Andres CR, et al. Ursodeoxycholic acid therapy in intrahepatic cholestasis of pregnancy: results in real-world conditions and factors predictive of response to treatment. Dig Liver Dis. 2017;49(1):63–9.  https://doi.org/10.1016/j.dld.2016.10.006.CrossRefPubMedGoogle Scholar
  52. 52.
    • Grand’Maison S, Durand M, Mahone M. The effects of ursodeoxycholic acid treatment for intrahepatic cholestasis of pregnancy on maternal and fetal outcomes: a meta-analysis including non-randomized studies. J Obstet Gynaecol Can. 2014;36(7):632–41.  https://doi.org/10.1016/s1701-2163(15)30544-2. A meta-analysis of 11 randomized controlled trials examining the safety and effectiveness of UDCA for the treatment of intrahepatic cholestasis of pregnancy. CrossRefPubMedGoogle Scholar
  53. 53.
    Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ, et al. Primary biliary cirrhosis. Hepatology. 2009;50(1):291–308.  https://doi.org/10.1002/hep.22906.CrossRefPubMedGoogle Scholar
  54. 54.
    •• European Assocaition for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cirrhosis. J Hepatol. 2017;67:145–72. Recently updated guidelines from the European Association for the Study of the Liver on the management of PBC. CrossRefGoogle Scholar
  55. 55.
    Scaldaferri F, Pizzoferrato M, Ponziani FR, Gasbarrini G, Gasbarrini A. Use and indications of cholestyramine and bile acid sequestrants. Intern Emerg Med. 2013;8:205–10.CrossRefPubMedGoogle Scholar
  56. 56.
    Kuiper EM, van Erpecum KJ, Beuers U, Hansen BE, Thio HB, de Man RA, 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(4):1334–40.  https://doi.org/10.1002/hep.23821.CrossRefPubMedGoogle Scholar
  57. 57.
    Hilal-Dandan R, Brunton LL. Goodman and Gilman’s manual of pharmacology and therapeutics, Second Edition. China: The McGraw-Hill Companies, Inc; 2014.Google Scholar
  58. 58.
    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(8):943–8.  https://doi.org/10.1111/j.1478-3231.2006.01326.x.CrossRefPubMedGoogle Scholar
  59. 59.
    Siemens W, Xander C, Meerpohl JJ, Buroh S, Antes G, Schwarzer G, et al. Pharmacological interventions for pruritus in adult palliative care patients. Cochrane Database Syst Rev. 2016;11:CD008320.  https://doi.org/10.1002/14651858.CD008320.pub3. PubMedGoogle Scholar
  60. 60.
    Li T, Chiang TYL. Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7alpha-hydroxylase gene transcription. Am J Physiol Gastrointest Liver Physiol. 2005;288(1):G74–84.CrossRefPubMedGoogle Scholar
  61. 61.
    Prince MI, Burt AD, Jones DEJ. Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis. Gut. 2002;50:436–9.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Martinez E, Collazos J, Myo J. Hypersensitivity reactions to rifampin: pathogenetic mechanisms, clinical manifestations, management strategies, and review of anaphylactic-like reactions. Medicine (Baltimore). 1999;78:361–9.CrossRefGoogle Scholar
  63. 63.
    Bergasa NV, Alling DW, Talbot T, Swain MG, Yurdaydin C, Turner M, et al. Effects of naloxone infusions in patients with pruritus of cholestasis. Ann Intern Med. 1995;123:161–7.CrossRefPubMedGoogle Scholar
  64. 64.
    Wolfhagen FKJ, Sternieri E, Hop WCJ, Vitale G, Bertolotti M, Van Buuren H. Oral naltrexone for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology. 1997;113:1264–9.CrossRefPubMedGoogle Scholar
  65. 65.
    Kumar N, Garg N, Bailey A. Opiate receptor antagonists for treatment of severe pruritus associated with advanced cholestatic liver disease. J Palliat Med. 2013;16:122–3.CrossRefPubMedGoogle Scholar
  66. 66.
    Mayo MJ, Handem I, Saldana S, Jacobe H, Getachew Y, Rush AJ. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology. 2007;45(3):666–74.  https://doi.org/10.1002/hep.21553.CrossRefPubMedGoogle Scholar
  67. 67.
    Thebaut A, Habes D, Gottrand F, Rivet C, Cohen J, Debray D, et al. Sertraline as an additional treatment for Cholestatic pruritus in children. J Pediatr Gastroenterol Nutr. 2017;64(3):431–5.  https://doi.org/10.1097/MPG.0000000000001385.CrossRefPubMedGoogle Scholar
  68. 68.
    Zylicz Z, Krajnik M, van Sorge AA, Costantini M. Paroxetine in the treatment of severe non-dermatological pruritus: a randomized controlled trial. J Pain Symptom Manag. 2003;26(6):1105–12.CrossRefGoogle Scholar
  69. 69.
    Antidepressants FRA. Black-box warning—10 years later. N Engl J Med. 2014;371(18):1666–8.  https://doi.org/10.1056/NEJMp1410540. CrossRefGoogle Scholar
  70. 70.
    Dillon S, Tobias JD. Ondansetron to treat pruritus due to cholestatic jaundice. J Pediatr Pharmacol Ther. 2013;18:241–6.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Raderer M, Muller C, Scheithauer W. Ondansetron for pruritus due to cholestasis. N Engl J Med. 1994;330:1540.  https://doi.org/10.1056/NEJM199405263302117.CrossRefPubMedGoogle Scholar
  72. 72.
    To TH, Clark K, Lam L, Shelby-James T, Currow DC. The role of ondansetron in the management of cholestatic or uremic pruritus—a systematic review. J Pain Symptom Manag. 2012;44(5):725–30.  https://doi.org/10.1016/j.jpainsymman.2011.11.007.CrossRefGoogle Scholar
  73. 73.
    European Association for the Study of the L. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51(2):237–67.  https://doi.org/10.1016/j.jhep.2009.04.009.CrossRefGoogle Scholar
  74. 74.
    Poropat G, Giljaca V, Stimac D, Gluud C. Bile acids for primary sclerosing cholangitis. Cochrane Database Syst Rev. 2011;1:CD003626.  https://doi.org/10.1002/14651858.CD003626.pub2.Google Scholar
  75. 75.
    Poupon R, Balkau B, Eschwege E, Poupon R. A multicenter, controlled trial of Ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med. 1991;324:1549–54.CrossRefGoogle Scholar
  76. 76.
    Jorgensen R, Angulo P, Dickson R, Lindor K. Results of long-term ursodiol for treatment of patients with primary biliary cirrhosis. Am J Gastroenterol. 2002;97(97):2647–50.CrossRefPubMedGoogle Scholar
  77. 77.
    Yin Q, Li J, Xia Y, Zhang R, Wang J, Lu W, et al. Systematic review and meta-analysis: bezafibrate in patients with primary biliary cirrhosis. Drug Des Devel Ther. 2015;9:5407–19.  https://doi.org/10.2147/DDDT.S92041.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Bolier R, de Vries ES, Pares A, Helder J, Kemper EM, Zwinderman K, et al. Fibrates for the treatment of cholestatic itch (FITCH): study protocol for a randomized controlled trial. Trials. 2017;18(1):230.  https://doi.org/10.1186/s13063-017-1966-8. CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Metreau JM, Bismuth H, Franco D, Dhumeaux D. Effect of phenobarbital in a case of extrahepatic cholestasis. Gastroenterology. 1975;68:567–71.PubMedGoogle Scholar
  80. 80.
    Shneider BL, Morris A, Vockley J. Possible phenylacetate hepatotoxicity during 4-phenylbutyrate therapy of Byler disease. J Pediatr Gastroenterol Nutr. 2016;62(3):424–8.  https://doi.org/10.1097/MPG.0000000000001082.CrossRefPubMedGoogle Scholar
  81. 81.
    Simons FER, Watson WTA, Chen XY, Minuk GY, Simons KJ. The pharmacokinetics and pharmacodynamics of hydroxyzine in patients with primary biliary cirrhosis. J Clin Pharmacol. 1989;29:809–915.CrossRefPubMedGoogle Scholar
  82. 82.
    Simons FER, Watson WTA, Minuk GY, Simons KJ. Cetirizine pharmacokinetics and pharmacodynamics in primary biliary cirrhosis. J Clin Pharmacol. 1993;33:949–54.CrossRefPubMedGoogle Scholar
  83. 83.
    Pares A, Herrera M, Aviles J, Sanz M, Mas A. Treatment of resistant pruritus from cholestasis with albumin dialysis: combined analysis of patients from three centers. J Hepatol. 2010;53(2):307–12.  https://doi.org/10.1016/j.jhep.2010.02.031.CrossRefPubMedGoogle Scholar
  84. 84.
    Oldakowska-Jedynak U, Jankowska I, Hartleb M, Jirsa M, Pawlowska J, Czubkowski P, et al. Treatment of pruritus with Prometheus dialysis and absorption system in a patient with benign recurrent intrahepatic cholestasis. Hepatol Res. 2014;44(10):E304–E8.  https://doi.org/10.1111/hepr.12262. CrossRefPubMedGoogle Scholar
  85. 85.
    Tsipotis E, Shuja A, Jaber BL. Albumin dialysis for liver failure: a systematic review. Adv Chronic Kidney Dis. 2015;22(5):382–90.  https://doi.org/10.1053/j.ackd.2015.05.004. CrossRefPubMedGoogle Scholar
  86. 86.
    Martin P, DiMartini A, Feng S, Brown R Jr, Fallon M. Evaluation for liver transplantation in adults: 2013 practice guideline by the AASLD and the American Society of Transplantation. Hepatology. 2014;59(3):1144–65.CrossRefPubMedGoogle Scholar
  87. 87.
    Khungar V, Goldberg DS. Liver transplantation for Cholestatic liver diseases in adults. Clin Liver Dis. 2016;20(1):191–203.  https://doi.org/10.1016/j.cld.2015.08.011.CrossRefPubMedGoogle Scholar
  88. 88.
    •• Hegade VS, Kendrick SFW, Dobbins RL, Miller SR, Thompson D, Richards D, 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(10074):1114–23.  https://doi.org/10.1016/s0140-6736(17)30319-7. A phase 2 study of a novel ileal bile acid transporter inhibitor, GSK2330672, that demonstrated effectiveness in the treatment of cholestatic pruritus. CrossRefPubMedGoogle Scholar
  89. 89.
    •• Mayo MJ, Pockros P, Jones D, Bowlus C, Levy C, Patanwala I, et al. Clarity: a phase 2, randomized, double-blind, placebo-controlled study of lopixibat chloride (formerly Lum001), a novel apical sodium-dependent bile acid transporter inhibitor, in the treatment of primary biliary cirrhosis associated with itching. J Hepatol. 2016;64(2):S197.  https://doi.org/10.1016/s0168-8278(16)00146-x. A phase 2 study of a different novel ileal bile acid transporter inhibitor, lopixibat (now maralixibat) that showed improvement in cholestatic pruritus though was not statistically significant. CrossRefGoogle Scholar
  90. 90.
    •• Kumada H, Miyakawa H, Muramatsu T, Ando N, Oh T, Takamori K, et al. Efficacy of nalfurafine hydrochloride in patients with chronic liver disease with refractory pruritus: a randomized, double-blind trial. Hepatol Res. 2017;47:972–82. A phase 3 trial of a novel κ-opioid recent agonist, nalfurafine hydrochloride, demonstrating effectiveness in the treatment of cholestasis pruritus. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Digestive and Liver DiseasesUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations