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Semin Liver Dis 2019; 39(02): 209-220
DOI: 10.1055/s-0039-1679918
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Mechanisms and Treatments of Pruritus in Primary Biliary Cholangitis

Raj A. Shah
1   Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington
,
Kris V. Kowdley
1   Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington
› Author Affiliations
Further Information

Publication History

Publication Date:
08 March 2019 (online)

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Abstract

Pruritus is a frustrating and sometimes debilitating symptom that commonly accompanies primary biliary cholangitis (PBC). The mechanism by which this symptom manifests remains elusive but extensive research has now shown that the itch is not just “weak pain” as had been the commonly held belief for decades. As this research now shines a light on the many diverse paths by which pruritus might be experienced, the necessity for a comprehensive approach to the symptom becomes clear. Understanding the interplay between the pathophysiology of PBC and delicately balanced neural circuitry is paramount to guiding the search for definitive treatment. Most relevant to providers today is the efficacy of currently available treatments and the side effects that may accompany them. Anion exchange resins, while remaining an important element in therapy, are no longer the only available medication to arrest pruritus. Rifampin, opioid antagonists, and other adjunctive therapies have quickly become a mainstay. Newer therapies such as the molecular adsorbent recycling system now also have a role in treatment. Increased recognition of these modalities may serve to alleviate the often debilitating pruritus experienced by patient suffering from PBC and might ultimately allow them to live more meaningful lives.

Keywords

pruritus - cholestasis - primary biliary cholangitis
 

  • References

  • 1 Ständer S, Steinhoff M, Schmelz M, Weisshaar E, Metze D, Luger T. Neurophysiology of pruritus: cutaneous elicitation of itch. Arch Dermatol 2003; 139 (11) 1463-1470
    PubMedGoogle Scholar
  • 2 Rishe E, Azarm A, Bergasa NV. Itch in primary biliary cirrhosis: a patients' perspective. Acta Derm Venereol 2008; 88 (01) 34-37
    CrossrefPubMedGoogle Scholar
  • 3 Mela M, Mancuso A, Burroughs AK. Review article: pruritus in cholestatic and other liver diseases. Aliment Pharmacol Ther 2003; 17 (07) 857-870
    CrossrefPubMedGoogle Scholar
  • 4 Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology 2019; 69 (01) 394-419
    PubMedGoogle Scholar
  • 5 Hirschfield GM, Beuers U, Corpechot C. , et al; European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017; 67 (01) 145-172
    CrossrefPubMedGoogle Scholar
  • 6 Talwalkar JA, Souto E, Jorgensen RA, Lindor KD. Natural history of pruritus in primary biliary cirrhosis. Clin Gastroenterol Hepatol 2003; 1 (04) 297-302
    CrossrefPubMedGoogle Scholar
  • 7 Huesmann M, Huesmann T, Osada N, Phan NQ, Kremer AE, Ständer S. Cholestatic pruritus: a retrospective analysis on clinical characteristics and treatment response. J Dtsch Dermatol Ges 2013; 11 (02) 158-168
    PubMedGoogle Scholar
  • 8 Bergasa N. The pruritus of cholestasis. J Hepatol 2005; 43 (06) 1078-1088
    CrossrefPubMedGoogle Scholar
  • 9 Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of pruritus. Br J Dermatol 2010; 162 (03) 587-593
    CrossrefPubMedGoogle Scholar
  • 10 Ikoma A, Steinhoff M, Ständer S, Yosipovitch G, Schmelz M. The neurobiology of itch. Nat Rev Neurosci 2006; 7 (07) 535-547
    CrossrefPubMedGoogle Scholar
  • 11 Hales P. Pruritus after epidural morphine. Lancet 1980; 2 (8187): 204
    PubMedGoogle Scholar
  • 12 Duffy BL. Itching as a side-effect of epidural morphine. Anaesthesia 1981; 36 (01) 67
    PubMedGoogle Scholar
  • 13 Ballantyne JC, Loach AB, Carr DB. Itching after epidural and spinal opiates. Pain 1988; 33 (02) 149-160
    CrossrefPubMedGoogle Scholar
  • 14 Benson JL, Campbell HE, Phillips CN. Opioid-induced pruritus. Consult Pharm 2015; 30 (04) 221-227
    CrossrefPubMedGoogle Scholar
  • 15 Brull SJ, Atanassoff PG, Silverman DG, Zhang J, Lamotte RH. Attenuation of experimental pruritus and mechanically evoked dysesthesiae in an area of cutaneous allodynia. Somatosens Mot Res 1999; 16 (04) 299-303
    CrossrefPubMedGoogle Scholar
  • 16 Yosipovitch G, Fast K, Bernhard JD. Noxious heat and scratching decrease histamine-induced itch and skin blood flow. J Invest Dermatol 2005; 125 (06) 1268-1272
    CrossrefPubMedGoogle Scholar
  • 17 Nilsson HJ, Levinsson A, Schouenborg J. Cutaneous field stimulation (CFS): a new powerful method to combat itch. Pain 1997; 71 (01) 49-55
    CrossrefPubMedGoogle Scholar
  • 18 Ward L, Wright E, McMahon SB. A comparison of the effects of noxious and innocuous counterstimuli on experimentally induced itch and pain. Pain 1996; 64 (01) 129-138
    CrossrefPubMedGoogle Scholar
  • 19 Green AD, Young KK, Lehto SG, Smith SB, Mogil JS. Influence of genotype, dose and sex on pruritogen-induced scratching behavior in the mouse. Pain 2006; 124 (1-2): 50-58
    CrossrefPubMedGoogle Scholar
  • 20 Kuraishi Y, Nagasawa T, Hayashi K, Satoh M. Scratching behavior induced by pruritogenic but not algesiogenic agents in mice. Eur J Pharmacol 1995; 275 (03) 229-233
    PubMedGoogle Scholar
  • 21 Thomsen JS, Petersen MB, Benfeldt E, Jensen SB, Serup J. Scratch induction in the rat by intradermal serotonin: a model for pruritus. Acta Derm Venereol 2001; 81 (04) 250-254
    CrossrefPubMedGoogle Scholar
  • 22 Shimada SG, Shimada KA, Collins JG. Scratching behavior in mice induced by the proteinase-activated receptor-2 agonist, SLIGRL-NH2. Eur J Pharmacol 2006; 530 (03) 281-283
    CrossrefPubMedGoogle Scholar
  • 23 Shimada SG, LaMotte RH. Behavioral differentiation between itch and pain in mouse. Pain 2008; 139 (03) 681-687
    CrossrefPubMedGoogle Scholar
  • 24 LaMotte RH, Dong X, Ringkamp M. Sensory neurons and circuits mediating itch. Nat Rev Neurosci 2014; 15 (01) 19-31
    CrossrefPubMedGoogle Scholar
  • 25 Ikoma A. Updated neurophysiology of itch. Biol Pharm Bull 2013; 36 (08) 1235-1240
    CrossrefPubMedGoogle Scholar
  • 26 Jacoby A, Rannard A, Buck D. , et al. Development, validation, and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis. Gut 2005; 54 (11) 1622-1629
    CrossrefPubMedGoogle Scholar
  • 27 Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjörk HE. Specific C-receptors for itch in human skin. J Neurosci 1997; 17 (20) 8003-8008
    CrossrefPubMedGoogle Scholar
  • 28 Meng J, Steinhoff M. Molecular mechanisms of pruritus. Curr Res Transl Med 2016; 64 (04) 203-206
    PubMedGoogle Scholar
  • 29 Andrew D, Craig AD. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 2001; 4 (01) 72-77
    PubMedGoogle Scholar
  • 30 Namer B, Carr R, Johanek LM, Schmelz M, Handwerker HO, Ringkamp M. Separate peripheral pathways for pruritus in man. J Neurophysiol 2008; 100 (04) 2062-2069
    CrossrefPubMedGoogle Scholar
  • 31 Reddy VB, Iuga AO, Shimada SG, LaMotte RH, Lerner EA. Cowhage-evoked itch is mediated by a novel cysteine protease: a ligand of protease-activated receptors. J Neurosci 2008; 28 (17) 4331-4335
    CrossrefPubMedGoogle Scholar
  • 32 Sun Y-G, Chen Z-F. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 2007; 448 (7154): 700-703
    PubMedGoogle Scholar
  • 33 Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF. Cellular basis of itch sensation. Science 2009; 325 (5947): 1531-1534
    CrossrefPubMedGoogle Scholar
  • 34 Ikoma A, Rukwied R, Ständer S, Steinhoff M, Miyachi Y, Schmelz M. Neuronal sensitization for histamine-induced itch in lesional skin of patients with atopic dermatitis. Arch Dermatol 2003; 139 (11) 1455-1458
    PubMedGoogle Scholar
  • 35 Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288 (5472): 1765-1769
    CrossrefPubMedGoogle Scholar
  • 36 Schmelz M, Hilliges M, Schmidt R. , et al. Active “itch fibers” in chronic pruritus. Neurology 2003; 61 (04) 564-566
    CrossrefPubMedGoogle Scholar
  • 37 Ikoma A, Handwerker H, Miyachi Y, Schmelz M. Electrically evoked itch in humans. Pain 2005; 113 (1-2): 148-154
    CrossrefPubMedGoogle Scholar
  • 38 Fukuoka M, Miyachi Y, Ikoma A. Mechanically evoked itch in humans. Pain 2013; 154 (06) 897-904
    CrossrefPubMedGoogle Scholar
  • 39 Carey Jr JB, Williams G. Relief of the pruritus of jaundice with a bile-acid sequestering resin. JAMA 1961; 176 (05) 432-435
    CrossrefPubMedGoogle Scholar
  • 40 Van Itallie TB, Hashim SA, Crampton RS, Tennent DM. The treatment of pruritus and hypercholesteremia of primary biliary cirrhosis with cholestyramine. N Engl J Med 1961; 265 (10) 469-474
    CrossrefPubMedGoogle Scholar
  • 41 Kirby J, Heaton KW, Burton JL. Pruritic effect of bile salts. BMJ 1974; 4 (5946): 693-695
    CrossrefPubMedGoogle Scholar
  • 42 Varadi DP. Pruritus induced by crude bile and purified bile acids. Experimental production of pruritus in human skin. Arch Dermatol 1974; 109 (05) 678-681
    CrossrefPubMedGoogle Scholar
  • 43 Quist RG, Ton-Nu HT, Lillienau J, Hofmann AF, Barrett KE. Activation of mast cells by bile acids. Gastroenterology 1991; 101 (02) 446-456
    CrossrefPubMedGoogle Scholar
  • 44 Alemi F, Kwon E, Poole DP. , et al. The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest 2013; 123 (04) 1513-1530
    CrossrefPubMedGoogle Scholar
  • 45 Lieu T, Jayaweera G, Zhao P. , et al. The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology 2014; 147 (06) 1417-1428
    CrossrefPubMedGoogle Scholar
  • 46 Bergasa NV. The pruritus of cholestasis: from bile acids to opiate agonists: relevant after all these years. Med Hypotheses 2018; 110: 86-89
    CrossrefPubMedGoogle Scholar
  • 47 Cipriani S, Renga B, D'Amore C. , et al. Impaired itching perception in murine models of cholestasis is supported by dysregulation of GPBAR1 signaling. PLoS One 2015; 10 (07) e0129866
    CrossrefPubMedGoogle Scholar
  • 48 Murphy GM, Ross A, Billing BH. Serum bile acids in primary biliary cirrhosis. Gut 1972; 13 (03) 201-206
    CrossrefPubMedGoogle Scholar
  • 49 Ghent CN, Bloomer JR, Klatskin G. Elevations in skin tissue levels of bile acids in human cholestasis: relation to serum levels and to pruritus. Gastroenterology 1977; 73 (05) 1125-1130
    CrossrefPubMedGoogle Scholar
  • 50 Ghent CN, Bloomer JR. Itch in liver disease: facts and speculations. Yale J Biol Med 1979; 52 (01) 77-82
    PubMedGoogle Scholar
  • 51 Chanarin I, Szur L. Letter: relief of intractable pruritus in polycythaemia rubra vera with cholestyramine. Br J Haematol 1975; 29 (04) 669-670
    CrossrefPubMedGoogle Scholar
  • 52 Silverberg DS, Iaina A, Reisin E, Rotzak R, Eliahou HE. Cholestyramine in uraemic pruritus. BMJ 1977; 1 (6063): 752-753
    CrossrefPubMedGoogle Scholar
  • 53 Gittlen SD, Schulman ES, Maddrey WC. Raised histamine concentrations in chronic cholestatic liver disease. Gut 1990; 31 (01) 96-99
    CrossrefPubMedGoogle Scholar
  • 54 Nakamura A, Yamazaki K, Suzuki K, Sato S. Increased portal tract infiltration of mast cells and eosinophils in primary biliary cirrhosis. Am J Gastroenterol 1997; 92 (12) 2245-2249
    PubMedGoogle Scholar
  • 55 Farrell DJ, Hines JE, Walls AF, Kelly PJ, Bennett MK, Burt AD. Intrahepatic mast cells in chronic liver diseases. Hepatology 1995; 22 (4, Pt 1): 1175-1181
    PubMedGoogle Scholar
  • 56 Cowden JM, Zhang M, Dunford PJ, Thurmond RL. The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation. J Invest Dermatol 2010; 130 (04) 1023-1033
    CrossrefPubMedGoogle Scholar
  • 57 Dunford PJ, Williams KN, Desai PJ, Karlsson L, McQueen D, Thurmond RL. Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus. J Allergy Clin Immunol 2007; 119 (01) 176-183
    CrossrefPubMedGoogle Scholar
  • 58 Lucey MR, Neuberger JM, Williams R. Primary biliary cirrhosis in men. Gut 1986; 27 (11) 1373-1376
    CrossrefPubMedGoogle Scholar
  • 59 Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol 2009; 15 (17) 2049-2066
    CrossrefPubMedGoogle Scholar
  • 60 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 (07) 632-641
    CrossrefPubMedGoogle Scholar
  • 61 Glantz A, Reilly SJ, Benthin L, Lammert F, Mattsson LÅ, Marschall HU. Intrahepatic cholestasis of pregnancy: amelioration of pruritus by UDCA is associated with decreased progesterone disulphates in urine. Hepatology 2008; 47 (02) 544-551
    PubMedGoogle Scholar
  • 62 Imam MH, Gossard AA, Sinakos E, Lindor KD. Pathogenesis and management of pruritus in cholestatic liver disease. J Gastroenterol Hepatol 2012; 27 (07) 1150-1158
    CrossrefPubMedGoogle Scholar
  • 63 Lloyd-Thomas HGL, Sherlock S. Testosterone therapy for the pruritus of obstructive jaundice. BMJ 1952; 2 (4797): 1289-1291
    CrossrefPubMedGoogle Scholar
  • 64 Alva J, Iber FL. Relief of the pruritus of jaundice with methandrostenolone and speculations on the nature of pruritus in liver disease. Am J Med Sci 1965; 250: 60-65
    CrossrefPubMedGoogle Scholar
  • 65 Lesurtel M, Soll C, Humar B, Clavien PA. Serotonin: a double-edged sword for the liver?. Surgeon 2012; 10 (02) 107-113
    CrossrefPubMedGoogle Scholar
  • 66 Schwörer H, Ramadori G. Improvement of cholestatic pruritus by ondansetron. Lancet 1993; 341 (8855): 1277
    PubMedGoogle Scholar
  • 67 Raderer M, Müller C, Scheithauer W. Ondansetron for pruritus due to cholestasis. N Engl J Med 1994; 330 (21) 1540
    PubMedGoogle Scholar
  • 68 Jones EA, Molenaar HAJ, Oosting J. Ondansetron and pruritus in chronic liver disease: a controlled study. Hepatogastroenterology 2007; 54 (76) 1196-1199
    PubMedGoogle Scholar
  • 69 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 Manage 2012; 44 (05) 725-730
    CrossrefPubMedGoogle Scholar
  • 70 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 (12) 2736-2741
    CrossrefPubMedGoogle Scholar
  • 71 Mayo MJ, Handem I, Saldana S, Jacobe H, Getachew Y, Rush AJ. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology 2007; 45 (03) 666-674
    CrossrefPubMedGoogle Scholar
  • 72 Boozalis E, Khanna R, Kwatra SG. Selective serotonin reuptake inhibitors for the treatment of chronic pruritus. J Dermatol Treat 2018; 29 (08) 812-814
    CrossrefPubMedGoogle Scholar
  • 73 Bautista DM, Wilson SR, Hoon MA. Why we scratch an itch: the molecules, cells and circuits of itch. Nat Neurosci 2014; 17 (02) 175-182
    PubMedGoogle Scholar
  • 74 Richardson BP. Serotonin and nociception. Ann N Y Acad Sci 1990; 600 (01) 511-519 , discussion 519–520
    CrossrefPubMedGoogle Scholar
  • 75 Bautista DM, Jordt SE, Nikai T. , et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 2006; 124 (06) 1269-1282
    CrossrefPubMedGoogle Scholar
  • 76 Morita T, McClain SP, Batia LM. , et al. HTR7 mediates serotonergic acute and chronic itch. Neuron 2015; 87 (01) 124-138
    CrossrefPubMedGoogle Scholar
  • 77 Akiyama T, Ivanov M, Nagamine M. , et al. Involvement of TRPV4 in serotonin-evoked scratching. J Invest Dermatol 2016; 136 (01) 154-160
    CrossrefPubMedGoogle Scholar
  • 78 Basbaum AI, Fields HL. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 1984; 7 (01) 309-338
    CrossrefPubMedGoogle Scholar
  • 79 Millan MJ. Descending control of pain. Prog Neurobiol 2002; 66 (06) 355-474
    CrossrefPubMedGoogle Scholar
  • 80 Zhao ZQ, Liu XY, Jeffry J. , et al. Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling. Neuron 2014; 84 (04) 821-834
    CrossrefPubMedGoogle Scholar
  • 81 Barry DM, Munanairi A, Chen ZF. Spinal mechanisms of itch transmission. Neurosci Bull 2018; 34 (01) 156-164
    CrossrefPubMedGoogle Scholar
  • 82 Weisshaar E, Ziethen B, Gollnick H. Can a serotonin type 3 (5-HT3) receptor antagonist reduce experimentally-induced itch?. Inflamm Res 1997; 46 (10) 412-416
    CrossrefPubMedGoogle Scholar
  • 83 Weisshaar E, Ziethen B, Röhl FW, Gollnick H. The antipruritic effect of a 5-HT3 receptor antagonist (tropisetron) is dependent on mast cell depletion--an experimental study. Exp Dermatol 1999; 8 (04) 254-260
    PubMedGoogle Scholar
  • 84 Tian B, Wang XL, Huang Y. , et al. Peripheral and spinal 5-HT receptors participate in cholestatic itch and antinociception induced by bile duct ligation in rats. Sci Rep 2016; 6: 36286
    CrossrefPubMedGoogle Scholar
  • 85 Gupta MA, Gupta AK, Schork NJ, Ellis CN. Depression modulates pruritus perception: a study of pruritus in psoriasis, atopic dermatitis, and chronic idiopathic urticaria. Psychosom Med 1994; 56 (01) 36-40
    CrossrefPubMedGoogle Scholar
  • 86 Warnock JK, Morris DW. Adverse cutaneous reactions to antidepressants. Am J Clin Dermatol 2002; 3 (05) 329-339
    CrossrefPubMedGoogle Scholar
  • 87 Sannicandro TJ, Farrar MC, Markowitz JS. Selective serotonin reuptake inhibitor-induced rash: case report and review of the literature. Pharmacotherapy 2002; 22 (04) 516-518
    CrossrefPubMedGoogle Scholar
  • 88 Cederberg J, Knight S, Svenson S, Melhus H. Itch and skin rash from chocolate during fluoxetine and sertraline treatment: case report. BMC Psychiatry 2004; 4: 36
    CrossrefPubMedGoogle Scholar
  • 89 U. S. Food and Drug Administration/FDA Adverse Event Reporting System. Washington, DC: 2014
    PubMed
  • 90 Thornton JR, Losowsky MS. Plasma methionine enkephalin concentration and prognosis in primary biliary cirrhosis. BMJ 1988; 297 (6658): 1241-1242
    CrossrefPubMedGoogle Scholar
  • 91 Bergasa NV, Rothman RB, Vergalla J, Xu H, Swain MG, Jones EA. Central mu-opioid receptors are down-regulated in a rat model of cholestasis. J Hepatol 1992; 15 (1-2): 220-224
    CrossrefPubMedGoogle Scholar
  • 92 Swain MG, Rothman RB, Xu H, Vergalla J, Bergasa NV, Jones EA. Endogenous opioids accumulate in plasma in a rat model of acute cholestasis. Gastroenterology 1992; 103 (02) 630-635
    CrossrefPubMedGoogle Scholar
  • 93 Phan NQ, Bernhard JD, Luger TA, Ständer S. Antipruritic treatment with systemic μ-opioid receptor antagonists: a review. J Am Acad Dermatol 2010; 63 (04) 680-688
    CrossrefPubMedGoogle Scholar
  • 94 Thornton JR, Losowsky MS. Opioid peptides and primary biliary cirrhosis. BMJ 1988; 297 (6662): 1501-1504
    CrossrefPubMedGoogle Scholar
  • 95 Wolfhagen FHJ, Sternieri E, Hop WCJ, Vitale G, Bertolotti M, Van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 1997; 113 (04) 1264-1269
    CrossrefPubMedGoogle Scholar
  • 96 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) 2028-2032
    PubMedGoogle Scholar
  • 97 Owczarek D, Garlicka M, Pierzchała-Koziec K, Skulina D, Szulewski P. Met-enkephalin plasma concentration and content in liver tissue in patients with primary biliary cirrhosis [in Polish]. Przegl Lek 2003; 60 (07) 461-466
    PubMedGoogle Scholar
  • 98 Bergasa NV, Liau S, Homel P, Ghali V. Hepatic Met-enkephalin immunoreactivity is enhanced in primary biliary cirrhosis. Liver 2002; 22 (02) 107-113
    CrossrefPubMedGoogle Scholar
  • 99 Li X, Zhu J, Tao Y, Tao K. Elevated endogenous opioids in obstructive jaundice: The possible skin mechanisms. Med Hypotheses 2018; 116: 119-121
    CrossrefPubMedGoogle Scholar
  • 100 Tao KM, Tao Y, Chen CY. , et al. Proteinase-activated receptor 1 contributed to up-regulation of enkephalin in keratinocytes of patients with obstructive jaundice. Anesthesiology 2014; 121 (01) 127-139
    CrossrefPubMedGoogle Scholar
  • 101 Liu XY, Liu ZC, Sun YG. , et al. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 2011; 147 (02) 447-458
    CrossrefPubMedGoogle Scholar
  • 102 Phan NQ, Lotts T, Antal A, Bernhard JD, Ständer S. Systemic kappa opioid receptor agonists in the treatment of chronic pruritus: a literature review. Acta Derm Venereol 2012; 92 (05) 555-560
    CrossrefPubMedGoogle Scholar
  • 103 Dawn AG, Yosipovitch G. Butorphanol for treatment of intractable pruritus. J Am Acad Dermatol 2006; 54 (03) 527-531
    CrossrefPubMedGoogle Scholar
  • 104 Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol Rev 2006; 86 (04) 1309-1379
    CrossrefPubMedGoogle Scholar
  • 105 Ossipov MH, Lai J, King T, Vanderah TW, Porreca F. Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers 2005; 80 (2-3): 319-324
    CrossrefPubMedGoogle Scholar
  • 106 Trivedi M, Bergasa NV. Serum concentrations of substance P in cholestasis. Ann Hepatol 2010; 9 (02) 177-180
    CrossrefPubMedGoogle Scholar
  • 107 Oehme P, Hilse H, Morgenstern E, Göres E. Substance P: does it produce analgesia or hyperalgesia?. Science 1980; 208 (4441): 305-307
    CrossrefPubMedGoogle Scholar
  • 108 Costa SK, Starr A, Hyslop S, Gilmore D, Brain SD. How important are NK1 receptors for influencing microvascular inflammation and itch in the skin? Studies using Phoneutria nigriventer venom. Vascul Pharmacol 2006; 45 (04) 209-214
    CrossrefPubMedGoogle Scholar
  • 109 Sun Y, Zhang W, Evans JF. , et al. Autotaxin, pruritus and primary biliary cholangitis (PBC). Autoimmun Rev 2016; 15 (08) 795-800
    CrossrefPubMedGoogle Scholar
  • 110 Hashimoto T, Ohata H, Momose K. Itch-scratch responses induced by lysophosphatidic acid in mice. Pharmacology 2004; 72 (01) 51-56
    CrossrefPubMedGoogle Scholar
  • 111 Kremer AE, Martens JJ, Kulik W. , et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 2010; 139 (03) 1008-1018 , 1018.e1
    CrossrefPubMedGoogle Scholar
  • 112 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 (08) 2681-2698
    CrossrefPubMedGoogle Scholar
  • 113 Tokumura A, Majima E, Kariya Y. , et al. Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem 2002; 277 (42) 39436-39442
    CrossrefPubMedGoogle Scholar
  • 114 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 (04) 1391-1400
    CrossrefPubMedGoogle Scholar
  • 115 Nakao M, Sugaya M, Suga H. , et al. Serum autotaxin levels correlate with pruritus in patients with atopic dermatitis. J Invest Dermatol 2014; 134 (06) 1745-1747
    CrossrefPubMedGoogle Scholar
  • 116 Nevens F, Andreone P, Mazzella G. , et al; POISE Study Group. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016; 375 (07) 631-643
    CrossrefPubMedGoogle Scholar
  • 117 Bocckino SB, Blackmore PF, Wilson PB, Exton JH. Phosphatidate accumulation in hormone-treated hepatocytes via a phospholipase D mechanism. J Biol Chem 1987; 262 (31) 15309-15315
    CrossrefPubMedGoogle Scholar
  • 118 Cooper AB, Wu J, Lu D, Maluccio MA. Is autotaxin (ENPP2) the link between hepatitis C and hepatocellular cancer?. J Gastrointest Surg 2007; 11 (12) 1628-1634 , discussion 1634–1635
    CrossrefPubMedGoogle Scholar
  • 119 Watanabe N, Ikeda H, Nakamura K. , et al. Both plasma lysophosphatidic acid and serum autotaxin levels are increased in chronic hepatitis C. J Clin Gastroenterol 2007; 41 (06) 616-623
    CrossrefPubMedGoogle Scholar
  • 120 Peyruchaud O. Novel implications for lysophospholipids, lysophosphatidic acid and sphingosine 1-phosphate, as drug targets in cancer. Anticancer Agents Med Chem 2009; 9 (04) 381-391
    CrossrefPubMedGoogle Scholar
  • 121 Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis. Lancet 2015; 386 (10003): 1565-1575
    CrossrefPubMedGoogle Scholar
  • 122 Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists. Ann Transl Med 2015; 3 (01) 5
    PubMedGoogle Scholar
  • 123 Makishima M, Okamoto AY, Repa JJ. , et al. Identification of a nuclear receptor for bile acids. Science 1999; 284 (5418): 1362-1365
    CrossrefPubMedGoogle Scholar
  • 124 D'Amore C, Di Leva FS, Sepe V. , et al. Design, synthesis, and biological evaluation of potent dual agonists of nuclear and membrane bile acid receptors. J Med Chem 2014; 57 (03) 937-954
    CrossrefPubMedGoogle Scholar
  • 125 Bassari R, Koea JB. Jaundice associated pruritis: a review of pathophysiology and treatment. World J Gastroenterol 2015; 21 (05) 1404-1413
    CrossrefPubMedGoogle Scholar
  • 126 Bosonnet L. Pruritus: scratching the surface. Eur J Cancer Care (Engl) 2003; 12 (02) 162-165
    CrossrefPubMedGoogle Scholar
  • 127 Datta DV, Sherlock S. Treatment of pruritus of obstructive jaundice with cholestyramine. BMJ 1963; 1 (5325): 216-219
    CrossrefPubMedGoogle Scholar
  • 128 Datta DV, Sherlock S. Cholestyramine for long term relief of the pruritus complicating intrahepatic cholestasis. Gastroenterology 1966; 50 (03) 323-332
    CrossrefPubMedGoogle Scholar
  • 129 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 (04) 1334-1340
    CrossrefPubMedGoogle Scholar
  • 130 Bergasa NV. Pruritus in primary biliary cirrhosis: pathogenesis and therapy. Clin Liver Dis 2008; 12 (02) 385-406 , x
    CrossrefPubMedGoogle Scholar
  • 131 Feramisco JD, Berger TG, Steinhoff M. Innovative management of pruritus. Dermatol Clin 2010; 28 (03) 467-478
    PubMedGoogle Scholar
  • 132 Calvori C, Frontali L, Leoni L, Tecce G. Effect of rifamycin on protein synthesis. Nature 1965; 207 (995) 417-418
    CrossrefPubMedGoogle Scholar
  • 133 Bachs L, Parés A, Elena M, Piera C, Rodés J. Effects of long-term rifampicin administration in primary biliary cirrhosis. Gastroenterology 1992; 102 (06) 2077-2080
    CrossrefPubMedGoogle Scholar
  • 134 Ghent CN, Carruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial. Gastroenterology 1988; 94 (02) 488-493
    CrossrefPubMedGoogle Scholar
  • 135 Podesta A, Lopez P, Terg R. , et al. Treatment of pruritus of primary biliary cirrhosis with rifampin. Dig Dis Sci 1991; 36 (02) 216-220
    CrossrefPubMedGoogle Scholar
  • 136 Kliewer SA, Moore JT, Wade L. , et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 1998; 92 (01) 73-82
    CrossrefPubMedGoogle Scholar
  • 137 Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 1998; 102 (05) 1016-1023
    CrossrefPubMedGoogle Scholar
  • 138 Kreek MJ, Garfield JW, Gutjahr CL, Giusti LM. Rifampin-induced methadone withdrawal. N Engl J Med 1976; 294 (20) 1104-1106
    CrossrefPubMedGoogle Scholar
  • 139 Meena N, Bartter T. Endosonography for mediastinal disease: esophageal ultrasound vs. endobronchial ultrasound. Endosc Int Open 2015; 3 (04) E302-E306
    Article in Thieme ConnectPubMedGoogle Scholar
  • 140 Prince MI, Burt AD, Jones DEJ. Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis. Gut 2002; 50 (03) 436-439
    CrossrefPubMedGoogle Scholar
  • 141 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 (08) 943-948
    CrossrefPubMedGoogle Scholar
  • 142 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 (07) 1528-1536
    CrossrefPubMedGoogle Scholar
  • 143 Bergasa NV, Talbot TL, Alling DW. , et al. A controlled trial of naloxone infusions for the pruritus of chronic cholestasis. Gastroenterology 1992; 102 (02) 544-549
    CrossrefPubMedGoogle Scholar
  • 144 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 (03) 161-167
    PubMedGoogle Scholar
  • 145 Bergasa NV, Schmitt JM, Talbot TL. , et al. Open-label trial of oral nalmefene therapy for the pruritus of cholestasis. Hepatology 1998; 27 (03) 679-684
    CrossrefPubMedGoogle Scholar
  • 146 Jones EA, Dekker LRC. Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis. Gastroenterology 2000; 118 (02) 431-432
    CrossrefPubMedGoogle Scholar
  • 147 Neuberger J, Jones EA. Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy. Eur J Gastroenterol Hepatol 2001; 13 (11) 1393-1394
    CrossrefPubMedGoogle Scholar
  • 148 Stange J, Hassanein TI, Mehta R, Mitzner SR, Bartlett RH. The molecular adsorbents recycling system as a liver support system based on albumin dialysis: a summary of preclinical investigations, prospective, randomized, controlled clinical trial, and clinical experience from 19 centers. Artif Organs 2002; 26 (02) 103-110
    CrossrefPubMedGoogle Scholar
  • 149 Parés A, Herrera M, Avilés 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 (02) 307-312
    CrossrefPubMedGoogle Scholar
  • 150 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 (05) 505-507
    CrossrefPubMedGoogle Scholar
  • 151 Cohen LB, Ambinder EP, Wolke AM, Field SP, Schaffner F. Role of plasmapheresis in primary biliary cirrhosis. Gut 1985; 26 (03) 291-294
    CrossrefPubMedGoogle Scholar
  • 152 Decock S, Roelandts R, Steenbergen WV. , et al. Cholestasis-induced pruritus treated with ultraviolet B phototherapy: an observational case series study. J Hepatol 2012; 57 (03) 637-641
    CrossrefPubMedGoogle Scholar
  • 153 Pinheiro NC, Marinho RT, Ramalho F, Velosa J. Refractory pruritus in primary biliary cirrhosis. BMJ Case Rep 2013; 2013 (13) 1-4
    CrossrefPubMedGoogle Scholar
  • 154 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 (08) 2117-2119
    CrossrefPubMedGoogle Scholar
  • 155 Gingold AR, Bergasa NV. The cannabinoid agonist WIN 55, 212-2 increases nociception threshold in cholestatic rats: implications for the treatment of the pruritus of cholestasis. Life Sci 2003; 73 (21) 2741-2747
    CrossrefPubMedGoogle Scholar
  • 156 Vrablík M, Češka R. Treatment of hypertriglyceridemia: a review of current options. Physiol Res 2015; 64 (Suppl. 03) S331-S340
    PubMedGoogle Scholar
  • 157 Reig A, Sesé P, Parés A. Effects of bezafibrate on outcome and pruritus in primary biliary cholangitis with suboptimal ursodeoxycholic acid response. Am J Gastroenterol 2018; 113 (01) 49-55
    CrossrefPubMedGoogle Scholar
  • 158 Corpechot C, Chazouillères O, Rousseau A. , et al. A placebo-controlled trial of bezafibrate in primary biliary cholangitis. N Engl J Med 2018; 378 (23) 2171-2181
    CrossrefPubMedGoogle Scholar
  • 159 Nakai S, Masaki T, Kurokohchi K, Deguchi A, Nishioka M. Combination therapy of bezafibrate and ursodeoxycholic acid in primary biliary cirrhosis: a preliminary study. Am J Gastroenterol 2000; 95 (01) 326-327
    CrossrefPubMedGoogle Scholar
  • 160 Iwasaki S, Ohira H, Nishiguchi S. , et al; Study Group of Intractable Liver Diseases for Research on a Specific Disease, Health Science Research Grant, Ministry of Health, Labour and Welfare of Japan. The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: a prospective, multicenter study. Hepatol Res 2008; 38 (06) 557-564
    CrossrefPubMedGoogle Scholar
  • 161 Levy C, Peter JA, Nelson DR. , et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther 2011; 33 (02) 235-242
    CrossrefPubMedGoogle Scholar
  • 162 Parés A. Therapy of primary biliary cirrhosis: novel approaches for patients with suboptimal response to ursodeoxycholic acid. Dig Dis 2015; 33 (02) (Suppl. 02) 125-133
    CrossrefPubMedGoogle Scholar
  • 163 Jones D, Boudes PF, Swain MG. , et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet Gastroenterol Hepatol 2017; 2 (10) 716-726
    PubMedGoogle Scholar
  • 164 Honda A, Ikegami T, Nakamuta M. , et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology 2013; 57 (05) 1931-1941
    CrossrefPubMedGoogle Scholar
  • 165 Bolier R, de Vries ES, Parés A. , et al; Netherlands Association for the Study of the Liver (NASL) Cholestatic Liver Diseases Study Group. Fibrates for the treatment of cholestatic itch (FITCH): study protocol for a randomized controlled trial. Trials 2017; 18 (01) 230
    CrossrefPubMedGoogle Scholar
  • 166 Lanzini A, De Tavonatti MG, Panarotto B. , et al. Intestinal absorption of the bile acid analogue 75Se-homocholic acid-taurine is increased in primary biliary cirrhosis, and reverts to normal during ursodeoxycholic acid administration. Gut 2003; 52 (09) 1371-1375
    CrossrefPubMedGoogle Scholar
  • 167 Hofmann AF. Inappropriate ileal conservation of bile acids in cholestatic liver disease: homeostasis gone awry. Gut 2003; 52 (09) 1239-1241
    CrossrefPubMedGoogle Scholar
  • 168 Al-Dury S, Wahlström A, Wahlin S. , et al. Pilot study with IBAT inhibitor A4250 for the treatment of cholestatic pruritus in primary biliary cholangitis. Sci Rep 2018; 8 (01) 6658
    CrossrefPubMedGoogle Scholar
  • 169 Hegade VS, Kendrick SFW, 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 (10074): 1114-1123
    CrossrefPubMedGoogle Scholar