Skip to main content
PMC home page
Postgraduate Medical Journal logoLink to Postgraduate Medical Journal
. 2002 Jul;78(921):404–407. doi: 10.1136/pmj.78.921.404

Fatigue in cholestatic liver disease—a perplexing symptom

D Kumar 1, R Tandon 1
PMCID: PMC1742427  PMID: 12151655

Abstract

Fatigue is an important symptom and a quality of life determinant in patients with cholestatic liver disease. The pathogenesis of fatigue is obscure, although alterations in central neurotransmission and peripheral muscle dysfunction have been incriminated. No effective treatment is available at present. The available literature on fatigue in cholestatic liver disease is reviewed.

Full Text

The Full Text of this article is available as a PDF (81.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bailey S. P., Davis J. M., Ahlborn E. N. Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue. J Appl Physiol (1985) 1993 Jun;74(6):3006–3012. doi: 10.1152/jappl.1993.74.6.3006. [DOI] [PubMed] [Google Scholar]
  2. Bakheit A. M., Behan P. O., Dinan T. G., Gray C. E., O'Keane V. Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. BMJ. 1992 Apr 18;304(6833):1010–1012. doi: 10.1136/bmj.304.6833.1010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barofsky I., Legro M. W. Definition and measurement of fatigue. Rev Infect Dis. 1991 Jan-Feb;13 (Suppl 1):S94–S97. doi: 10.1093/clinids/13.supplement_1.s94. [DOI] [PubMed] [Google Scholar]
  4. Bearn J., Wessely S. Neurobiological aspects of the chronic fatigue syndrome. Eur J Clin Invest. 1994 Feb;24(2):79–90. doi: 10.1111/j.1365-2362.1994.tb00971.x. [DOI] [PubMed] [Google Scholar]
  5. Bergasa N. V., Jones E. A. The pruritus of cholestasis: potential pathogenic and therapeutic implications of opioids. Gastroenterology. 1995 May;108(5):1582–1588. doi: 10.1016/0016-5085(95)90709-2. [DOI] [PubMed] [Google Scholar]
  6. Bergasa N. V., Mehlman J. K., Jones E. A. Pruritus and fatigue in primary biliary cirrhosis. Baillieres Best Pract Res Clin Gastroenterol. 2000 Aug;14(4):643–655. doi: 10.1053/bega.2000.0109. [DOI] [PubMed] [Google Scholar]
  7. Bluthé R. M., Sparber S., Dantzer R. Modulation of the behavioural effects of interleukin-1 in mice by nitric oxide. Neuroreport. 1992 Feb;3(2):207–209. doi: 10.1097/00001756-199202000-00022. [DOI] [PubMed] [Google Scholar]
  8. Bonaz B., Taché Y. Water-avoidance stress-induced c-fos expression in the rat brain and stimulation of fecal output: role of corticotropin-releasing factor. Brain Res. 1994 Mar 28;641(1):21–28. doi: 10.1016/0006-8993(94)91810-4. [DOI] [PubMed] [Google Scholar]
  9. Britton D. R., Britton K. T. A sensitive open field measure of anxiolytic drug activity. Pharmacol Biochem Behav. 1981 Oct;15(4):577–582. doi: 10.1016/0091-3057(81)90212-4. [DOI] [PubMed] [Google Scholar]
  10. Cauch-Dudek K., Abbey S., Stewart D. E., Heathcote E. J. Fatigue in primary biliary cirrhosis. Gut. 1998 Nov;43(5):705–710. doi: 10.1136/gut.43.5.705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dunn A. J., Berridge C. W. Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain Res Brain Res Rev. 1990 May-Aug;15(2):71–100. doi: 10.1016/0165-0173(90)90012-d. [DOI] [PubMed] [Google Scholar]
  12. Fisk J. D., Ritvo P. G., Ross L., Haase D. A., Marrie T. J., Schlech W. F. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis. 1994 Jan;18 (Suppl 1):S79–S83. doi: 10.1093/clinids/18.supplement_1.s79. [DOI] [PubMed] [Google Scholar]
  13. Goldblatt J., James O. F., Jones D. E. Grip strength and subjective fatigue in patients with primary biliary cirrhosis. JAMA. 2001 May 2;285(17):2196–2197. doi: 10.1001/jama.285.17.2196. [DOI] [PubMed] [Google Scholar]
  14. Goulis J., Leandro G., Burroughs A. K. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet. 1999 Sep 25;354(9184):1053–1060. doi: 10.1016/S0140-6736(98)11293-X. [DOI] [PubMed] [Google Scholar]
  15. Gross C. R., Malinchoc M., Kim W. R., Evans R. W., Wiesner R. H., Petz J. L., Crippin J. S., Klintmalm G. B., Levy M. F., Ricci P. Quality of life before and after liver transplantation for cholestatic liver disease. Hepatology. 1999 Feb;29(2):356–364. doi: 10.1002/hep.510290229. [DOI] [PubMed] [Google Scholar]
  16. Hagan P., Poole S., Bristow A. F. Endotoxin-stimulated production of rat hypothalamic interleukin-1 beta in vivo and in vitro, measured by specific immunoradiometric assay. J Mol Endocrinol. 1993 Aug;11(1):31–36. doi: 10.1677/jme.0.0110031. [DOI] [PubMed] [Google Scholar]
  17. Hart B. L. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev. 1988 Summer;12(2):123–137. doi: 10.1016/s0149-7634(88)80004-6. [DOI] [PubMed] [Google Scholar]
  18. Heathcote E. J., Cauch-Dudek K., Walker V., Bailey R. J., Blendis L. M., Ghent C. N., Michieletti P., Minuk G. Y., Pappas S. C., Scully L. J. The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. 1994 May;19(5):1149–1156. [PubMed] [Google Scholar]
  19. Huet P. M., Deslauriers J., Tran A., Faucher C., Charbonneau J. Impact of fatigue on the quality of life of patients with primary biliary cirrhosis. Am J Gastroenterol. 2000 Mar;95(3):760–767. doi: 10.1111/j.1572-0241.2000.01857.x. [DOI] [PubMed] [Google Scholar]
  20. Katsinelos P., Vasiliadis T., Xiarchos P., Patakiouta F., Christodoulou K., Pilpilidis I., Eugenidis N. Ursodeoxycholic acid (UDCA) for the treatment of amoxycillin-clavulanate potassium (Augmentin)-induced intra-hepatic cholestasis: report of two cases. Eur J Gastroenterol Hepatol. 2000 Mar;12(3):365–368. doi: 10.1097/00042737-200012030-00017. [DOI] [PubMed] [Google Scholar]
  21. Kent S., Bluthe R. M., Dantzer R., Hardwick A. J., Kelley K. W., Rothwell N. J., Vannice J. L. Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9117–9120. doi: 10.1073/pnas.89.19.9117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kent S., Bluthé R. M., Kelley K. W., Dantzer R. Sickness behavior as a new target for drug development. Trends Pharmacol Sci. 1992 Jan;13(1):24–28. doi: 10.1016/0165-6147(92)90012-u. [DOI] [PubMed] [Google Scholar]
  23. Khawli F. A., Reid M. B. N-acetylcysteine depresses contractile function and inhibits fatigue of diaphragm in vitro. J Appl Physiol (1985) 1994 Jul;77(1):317–324. doi: 10.1152/jappl.1994.77.1.317. [DOI] [PubMed] [Google Scholar]
  24. Koob G. F., Heinrichs S. C., Pich E. M., Menzaghi F., Baldwin H., Miczek K., Britton K. T. The role of corticotropin-releasing factor in behavioural responses to stress. Ciba Found Symp. 1993;172:277–295. doi: 10.1002/9780470514368.ch14. [DOI] [PubMed] [Google Scholar]
  25. Krähenbühl S., Talos C., Lauterburg B. H., Reichen J. Reduced antioxidative capacity in liver mitochondria from bile duct ligated rats. Hepatology. 1995 Aug;22(2):607–612. doi: 10.1002/hep.1840220234. [DOI] [PubMed] [Google Scholar]
  26. Kumar D., Tandon R. K. Use of ursodeoxycholic acid in liver diseases. J Gastroenterol Hepatol. 2001 Jan;16(1):3–14. doi: 10.1046/j.1440-1746.2001.02376.x. [DOI] [PubMed] [Google Scholar]
  27. Lindor K. D., Dickson E. R., Baldus W. P., Jorgensen R. A., Ludwig J., Murtaugh P. A., Harrison J. M., Wiesner R. H., Anderson M. L., Lange S. M. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology. 1994 May;106(5):1284–1290. doi: 10.1016/0016-5085(94)90021-3. [DOI] [PubMed] [Google Scholar]
  28. Lindor K. D., Poupon R., Poupon R., Heathcote E. J., Therneau T. Ursodeoxycholic acid for primary biliary cirrhosis. Lancet. 2000 Feb 19;355(9204):657–658. doi: 10.1016/S0140-6736(05)72401-6. [DOI] [PubMed] [Google Scholar]
  29. Lindor K. D., Therneau T. M., Jorgensen R. A., Malinchoc M., Dickson E. R. Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology. 1996 May;110(5):1515–1518. doi: 10.1053/gast.1996.v110.pm8613058. [DOI] [PubMed] [Google Scholar]
  30. Linthorst A. C., Flachskamm C., Müller-Preuss P., Holsboer F., Reul J. M. Effect of bacterial endotoxin and interleukin-1 beta on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: an in vivo microdialysis study. J Neurosci. 1995 Apr;15(4):2920–2934. doi: 10.1523/JNEUROSCI.15-04-02920.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Metcalf J. V., Mitchison H. C., Palmer J. M., Jones D. E., Bassendine M. F., James O. F. Natural history of early primary biliary cirrhosis. Lancet. 1996 Nov 23;348(9039):1399–1402. doi: 10.1016/S0140-6736(96)04410-8. [DOI] [PubMed] [Google Scholar]
  32. Minami M., Kuraishi Y., Yamaguchi T., Nakai S., Hirai Y., Satoh M. Immobilization stress induces interleukin-1 beta mRNA in the rat hypothalamus. Neurosci Lett. 1991 Feb 25;123(2):254–256. doi: 10.1016/0304-3940(91)90944-o. [DOI] [PubMed] [Google Scholar]
  33. Otterness I. G., Seymour P. A., Golden H. W., Reynolds J. A., Daumy G. O. The effects of continuous administration of murine interleukin-1 alpha in the rat. Physiol Behav. 1988;43(6):797–804. doi: 10.1016/0031-9384(88)90379-4. [DOI] [PubMed] [Google Scholar]
  34. Paradis V., Kollinger M., Fabre M., Holstege A., Poynard T., Bedossa P. In situ detection of lipid peroxidation by-products in chronic liver diseases. Hepatology. 1997 Jul;26(1):135–142. doi: 10.1053/jhep.1997.v26.pm0009214462. [DOI] [PubMed] [Google Scholar]
  35. Poupon R. E., Bonnand A. M., Chrétien Y., Poupon R. Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology. 1999 Jun;29(6):1668–1671. doi: 10.1002/hep.510290603. [DOI] [PubMed] [Google Scholar]
  36. Poupon R. E., Lindor K. D., Cauch-Dudek K., Dickson E. R., Poupon R., Heathcote E. J. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 1997 Sep;113(3):884–890. doi: 10.1016/s0016-5085(97)70183-5. [DOI] [PubMed] [Google Scholar]
  37. Prince M. I., James O. F., Holland N. P., Jones D. E. Validation of a fatigue impact score in primary biliary cirrhosis: towards a standard for clinical and trial use. J Hepatol. 2000 Mar;32(3):368–373. doi: 10.1016/s0168-8278(00)80385-2. [DOI] [PubMed] [Google Scholar]
  38. Reid M. B., Stokić D. S., Koch S. M., Khawli F. A., Leis A. A. N-acetylcysteine inhibits muscle fatigue in humans. J Clin Invest. 1994 Dec;94(6):2468–2474. doi: 10.1172/JCI117615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schwartz J. E., Jandorf L., Krupp L. B. The measurement of fatigue: a new instrument. J Psychosom Res. 1993 Oct;37(7):753–762. doi: 10.1016/0022-3999(93)90104-n. [DOI] [PubMed] [Google Scholar]
  40. Schwörer H., Hartmann H., Ramadori G. Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists: effectiveness of ondansetron. Pain. 1995 Apr;61(1):33–37. doi: 10.1016/0304-3959(94)00145-5. [DOI] [PubMed] [Google Scholar]
  41. Schwörer H., Hartmann H., Ramadori G. Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists: effectiveness of ondansetron. Pain. 1995 Apr;61(1):33–37. doi: 10.1016/0304-3959(94)00145-5. [DOI] [PubMed] [Google Scholar]
  42. Segreti J., Gheusi G., Dantzer R., Kelley K. W., Johnson R. W. Defect in interleukin-1beta secretion prevents sickness behavior in C3H/HeJ mice. Physiol Behav. 1997 Jun;61(6):873–878. doi: 10.1016/s0031-9384(96)00611-7. [DOI] [PubMed] [Google Scholar]
  43. Sokol R. J., Devereaux M., Khandwala R. A. Effect of dietary lipid and vitamin E on mitochondrial lipid peroxidation and hepatic injury in the bile duct-ligated rat. J Lipid Res. 1991 Aug;32(8):1349–1357. [PubMed] [Google Scholar]
  44. Sokol R. J., McKim J. M., Jr, Goff M. C., Ruyle S. Z., Devereaux M. W., Han D., Packer L., Everson G. Vitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochenodeoxycholic acid in the rat. Gastroenterology. 1998 Jan;114(1):164–174. doi: 10.1016/s0016-5085(98)70644-4. [DOI] [PubMed] [Google Scholar]
  45. Sokol R. J., Winklhofer-Roob B. M., Devereaux M. W., McKim J. M., Jr Generation of hydroperoxides in isolated rat hepatocytes and hepatic mitochondria exposed to hydrophobic bile acids. Gastroenterology. 1995 Oct;109(4):1249–1256. doi: 10.1016/0016-5085(95)90585-5. [DOI] [PubMed] [Google Scholar]
  46. Spadaro F., Dunn A. J. Intracerebroventricular administration of interleukin-1 to mice alters investigation of stimuli in a novel environment. Brain Behav Immun. 1990 Dec;4(4):308–322. doi: 10.1016/0889-1591(90)90034-n. [DOI] [PubMed] [Google Scholar]
  47. Sternberg E. M., Glowa J. R., Smith M. A., Calogero A. E., Listwak S. J., Aksentijevich S., Chrousos G. P., Wilder R. L., Gold P. W. Corticotropin releasing hormone related behavioral and neuroendocrine responses to stress in Lewis and Fischer rats. Brain Res. 1992 Jan 20;570(1-2):54–60. doi: 10.1016/0006-8993(92)90563-o. [DOI] [PubMed] [Google Scholar]
  48. Sumida S., Tanaka K., Kitao H., Nakadomo F. Exercise-induced lipid peroxidation and leakage of enzymes before and after vitamin E supplementation. Int J Biochem. 1989;21(8):835–838. doi: 10.1016/0020-711x(89)90280-2. [DOI] [PubMed] [Google Scholar]
  49. Swain M. G., Beck P., Rioux K., Le T. Augmented interleukin-1beta-induced depression of locomotor activity in cholestatic rats. Hepatology. 1998 Dec;28(6):1561–1565. doi: 10.1002/hep.510280616. [DOI] [PubMed] [Google Scholar]
  50. Swain M. G., Beck P., Rioux K., Le T. Augmented interleukin-1beta-induced depression of locomotor activity in cholestatic rats. Hepatology. 1998 Dec;28(6):1561–1565. doi: 10.1002/hep.510280616. [DOI] [PubMed] [Google Scholar]
  51. Swain M. G. Fatigue in chronic disease. Clin Sci (Lond) 2000 Jul;99(1):1–8. [PubMed] [Google Scholar]
  52. Swain M. G., Le T., Tigley A. W., Beck P. Hypothalamic nitric oxide synthase is depressed in cholestatic rats. Am J Physiol. 1997 May;272(5 Pt 1):G1034–G1040. doi: 10.1152/ajpgi.1997.272.5.G1034. [DOI] [PubMed] [Google Scholar]
  53. Swain M. G., Maric M. Defective corticotropin-releasing hormone mediated neuroendocrine and behavioral responses in cholestatic rats: implications for cholestatic liver disease-related sickness behaviors. Hepatology. 1995 Nov;22(5):1560–1564. [PubMed] [Google Scholar]
  54. Swain M. G., Maric M. Improvement in cholestasis-associated fatigue with a serotonin receptor agonist using a novel rat model of fatigue assessment. Hepatology. 1997 Feb;25(2):291–294. doi: 10.1002/hep.510250206. [DOI] [PubMed] [Google Scholar]
  55. Swain M. G., Patchev V., Vergalla J., Chrousos G., Jones E. A. Suppression of hypothalamic-pituitary-adrenal axis responsiveness to stress in a rat model of acute cholestasis. J Clin Invest. 1993 May;91(5):1903–1908. doi: 10.1172/JCI116408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Uehara A., Sekiya C., Takasugi Y., Namiki M., Arimura A. Anorexia induced by interleukin 1: involvement of corticotropin-releasing factor. Am J Physiol. 1989 Sep;257(3 Pt 2):R613–R617. doi: 10.1152/ajpregu.1989.257.3.R613. [DOI] [PubMed] [Google Scholar]
  57. Van Dam A. M., Bauer J., Tilders F. J., Berkenbosch F. Endotoxin-induced appearance of immunoreactive interleukin-1 beta in ramified microglia in rat brain: a light and electron microscopic study. Neuroscience. 1995 Apr;65(3):815–826. doi: 10.1016/0306-4522(94)00549-k. [DOI] [PubMed] [Google Scholar]
  58. Vuoristo M., Färkkilä M., Karvonen A. L., Leino R., Lehtola J., Mäkinen J., Mattila J., Friman C., Seppälä K., Tuominen J. A placebo-controlled trial of primary biliary cirrhosis treatment with colchicine and ursodeoxycholic acid. Gastroenterology. 1995 May;108(5):1470–1478. doi: 10.1016/0016-5085(95)90696-7. [DOI] [PubMed] [Google Scholar]
  59. Watson J. P., Jones D. E., James O. F., Cann P. A., Bramble M. G. Case report: oral antioxidant therapy for the treatment of primary biliary cirrhosis: a pilot study. J Gastroenterol Hepatol. 1999 Oct;14(10):1034–1040. doi: 10.1046/j.1440-1746.1999.01968.x. [DOI] [PubMed] [Google Scholar]
  60. Whimbey A. E., Denenberg V. H. Two independent behavioral dimensions in open-field performance. J Comp Physiol Psychol. 1967 Jun;63(3):500–504. doi: 10.1037/h0024620. [DOI] [PubMed] [Google Scholar]
  61. Wilson W. M., Maughan R. J. Evidence for a possible role of 5-hydroxytryptamine in the genesis of fatigue in man: administration of paroxetine, a 5-HT re-uptake inhibitor, reduces the capacity to perform prolonged exercise. Exp Physiol. 1992 Nov;77(6):921–924. doi: 10.1113/expphysiol.1992.sp003660. [DOI] [PubMed] [Google Scholar]
  62. Witt-Sullivan H., Heathcote J., Cauch K., Blendis L., Ghent C., Katz A., Milner R., Pappas S. C., Rankin J., Wanless I. R. The demography of primary biliary cirrhosis in Ontario, Canada. Hepatology. 1990 Jul;12(1):98–105. doi: 10.1002/hep.1840120116. [DOI] [PubMed] [Google Scholar]

Articles from Postgraduate Medical Journal are provided here courtesy of BMJ Publishing Group

RESOURCES