Clinical Gastroenterology and Hepatology
Volume 10, Issue 2 , Pages 103-105, February 2012

Fatigue in Cirrhosis: Is Transplant the Answer?

Liver Unit, Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada

published online 07 November 2011.

Article Outline

 

Fatigue is a complex symptom that encompasses a range of complaints including malaise, exhaustion, lethargy, and loss of motivation and social interest. Chronic fatigue is common in the general population, affecting up to 20%.1 Many chronic diseases are associated with fatigue including rheumatoid arthritis, systemic lupus erythematosus,2 and multiple sclerosis.3 Fatigue is often a major factor in the reduction of quality of life associated with chronic disease. Furthermore, the symptom of fatigue does not typically correlate with traditional markers of disease activity, severity, disability, or clinical disease subtype.4, 5 The exact frequency of fatigue in patients with chronic liver disease is variable; however it does constitute the most common complaint.6, 7, 8 Any physician who manages patients with chronic liver disease will acknowledge the presence of fatigue in this patient population. However, because of difficulties in measuring and treating fatigue, it is often minimized.

The study by Kalaitzakis and colleagues9 in this issue of Clinical Gastroenterology and Hepatology follows cirrhotic patients longitudinally pre- and post liver transplantation. As expected, fatigue was greater in patients with cirrhosis as compared with the general population. Additionally, the degree of fatigue was related to the severity of cirrhosis; specifically, patients with higher Child–Pugh classification scores had more severe fatigue.

When discussing fatigue, it is important to differentiate between central and peripheral fatigue.4, 5 Peripheral fatigue, classically manifested by neuromuscular dysfunction and muscle weakness, does not appear to be the main factor in patients with liver disease in the absence of decompensated cirrhosis or liver failure. In comparison, central fatigue is characterized by difficulty performing physical and mental activities: a lack of self-motivation.10 Central fatigue is often associated with an increased perceived effort for tasks.

The prevalence of fatigue varies depending on the specific form of liver disease. Fatigue is well characterized in chronic cholestatic liver diseases including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis.11 In fact, fatigue is present in 50% to 80% of patients with PBC and can often be the presenting symptom.12, 13, 14 Fatigue in PBC has been shown to be a poor prognostic factor, as patients with higher fatigue scores had reduced survival.13 The predominance of fatigue in hepatitic liver pathology is less clearly defined, with chronic hepatitis C,7, 15, 16 autoimmune hepatitis,17 and nonalcoholic fatty liver disease5 the most commonly reported. Additionally, the discussion of fatigue in patients with chronic liver disease must be placed in the context of a diagnosis with an uncertain prognosis and associated social stigma. This patient population also frequently has coexisting psychological issues, including depression and anxiety.18 The presence of hepatic encephalopathy compounds this further. Therefore, the clinical expression of fatigue encompasses complex interactions with biological, psychosocial, and behavioral processes.11 This is supported in the current study where fatigue was highest amongst cirrhotic patients that were unemployed or disabled; again showing the complexity of the clinical picture in this group of patients. Patients with the highest level of fatigue had the lowest described quality of life. Additionally, a significant proportion of patients in the study had anxiety or depression, which dramatically improved post liver transplant.

The pathophysiology of fatigue is complex. Animal models and clinical studies have documented that chronic liver inflammation is associated with changes in the central nervous system (CNS) that manifest as behavioral modifications.19 The inflamed liver communicates with the brain and results in altered brain function. Abnormal central neurotransmission gives rise to behavioral changes in the absence of pathologic CNS tissue damage.20, 21, 22 The neurotransmitters that have been implicated in central fatigue include coricotropin-releasing hormone (CRH),23 serotonin,24 and noradrenaline.25 In fact, pharmacologic targeting of serotonin has proven to be advantageous in managing fatigue in some patients with liver disease.26, 27 In addition to altered neurotransmission, the liver can communicate with the brain via neural, immune cell, or cytokine-driven routes. The liver is innervated by vagal nerve afferents that respond to immune mediators such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interleukin-6.28, 29 Activated vagal nerves project to different regions of the brain, potentially driving subsequent behavior changes. However, it is likely that this neural pathway plays only a minor role in mediating fatigue in the setting of chronic liver disease because post liver transplant patients (in which the liver is deinnervated) often report little change in their fatigue30; a finding also supported by this current study. Inflammatory mediators and cytokines within the circulation can also interact with their cognate receptors, expressed on the surface of cerebral endothelial cells, to activate their corresponding signaling pathways and subsequently stimulate cells within the brain parenchyma through the release of secondary messengers, including prostaglandins and nitric oxide.31, 32 The CNS is protected by a blood-brain barrier which is impermeable to large, hydrophilic cytokine molecules. However, the circumventricular organs are regions of the brain that lack an intact blood-brain barrier. The fenestrated capillaries allow the passage of inflammatory molecules that can then activate microglia, resident immune cells of the brain.33, 34 Finally, glial cells and neurons within the brain are capable of producing de novo cytokines that can mediate behavior effects, including fatigue.32, 35

The basal ganglia is comprised of 6 nuclei that project to the limbic system and frontal cortex. Fatigue has been linked to alterations in neural activity within the basal ganglia.10 Magnetic resonance imaging (MRI) studies in PBC patients have demonstrated increased signal intensity in the basal ganglia in patients with high fatigue levels.36 A recent study using MRI and voxel-based morphometry, which measures brain tissue density and concentration, found a decrease in brain density in certain areas in patients with cirrhosis.37 The brain areas found to have scores most indicative of decreased brain density were the frontal and parietal regions and putamen for gray matter, and the cingulate gyrus and temporal and frontal regions for white matter. Interestingly, many of these brain areas overlap structurally and/or functionally with the basal ganglia. Intriguingly, post liver transplant patients in this study also had areas of decreased brain density, even several months after transplantation. Cirrhosis had not recurred in these patients, suggesting that neurological injury may be persistent, or at least very slow to improve. The study by Kalaitzakis and colleagues9 is unique as it longitudinally documents fatigue in patients before and after liver transplantation. In concordance with the above-mentioned MRI study, Kalaitzakis et al9 found that fatigue improved post liver transplantation, but only in a minority of patients. The degree of fatigue was still significantly higher than the control population. No specific etiologies of posttransplant fatigue were identified in this study and further work is warranted in this area.

Fatigue in the advanced stages of chronic liver disease is challenging to study due to potential overlap with symptoms associated with hepatic encephalopathy (HE). HE ranges from subtle neuropsychiatric disturbances, only apparent by performing psychometric testing (minimal HE), to varying degrees of confusion, stupor, and coma.38 However, HE is not a requirement for the development of changes within the CNS in patients with chronic inflammatory liver disease. Traditionally, HE was attributed to the toxic effects of ammonia on astroglial cells,39 with hyperammonemia leading to the accumulation of glutamine within astrocytes, causing brain edema due to osmotic stress.40 However, recent attention has focused on the role of systemic inflammation in the development of HE, possibly acting synergistically with ammonia toxicity, including blood-brain cytokine transfer and receptor-mediated cytokine signal transduction.41, 42 These proinflammatory mechanisms are similar in many ways to the pathophysiology underlying behavioral changes and fatigue in the setting of liver inflammation and/or cirrhosis.

Fatigue is a complex and prevalent symptom in patients with chronic liver disease. Several pathophysiological mechanisms for explaining the development of fatigue have been generated; however, our understanding of fatigue in patients with liver disease is still incomplete. Moreover, the issue of fatigue in these patients is even more problematic given the recent findings that liver transplantation often does not completely alleviate this debilitating symptom. Future studies will be imperative to further examine factors predictive of fatigue in post liver transplant patients, and should help to inform us as to potential therapeutic interventions which could be instituted in order to improve fatigue in this clinical setting. Importantly, studies such as that reported by Kalaitzakis et al9 will help us to counsel patients more effectively with regards to expectations post liver transplantation; including that their fatigue potentially may not be significantly improved.

Back to Article Outline

References 

  1. Bates DW , Schmitt W , Buchwald D , et al.  Prevalence of fatigue and chronic fatigue syndrome in a primary care practice . Arch Intern Med . 1993;153:2759–2765
  2. Omdal R , Mellgren SI , Koldingsnes W , et al.  Fatigue in patients with systemic lupus erythematosus: lack of associations to serum cytokines, antiphospholipid antibodies, or other disease characteristics . J Rheumatol . 2002;29:482–486
  3. Benedict RH , Wahlig E , Bakshi R , et al.  Predicting quality of life in multiple sclerosis: accounting for physical disability, fatigue, cognition, mood disorder, personality, and behavior change . J Neurol Sci . 2005;231:29–34
  4. Chaudhuri A , Behan PO . Fatigue in neurological disorders . Lancet . 2004;363:978–988
  5. Swain MG . Fatigue in chronic disease . Clin Sci (Lond) . 2000;99:1–8
  6. Milkiewicz P , Heathcote EJ . Fatigue in chronic cholestasis . Gut . 2004;53:475–477
  7. Poynard T , Cacoub P , Ratziu V , et al.  Fatigue in patients with chronic hepatitis C . J Viral Hepat . 2002;9:295–303
  8. Younossi ZM , Boparai N , Price LL , et al.  Health-related quality of life in chronic liver disease: the impact of type and severity of disease . Am J Gastroenterol . 2001;96:2199–2205
  9. Kalaitzakis E , Josefsson A , Castedal M , et al.  Factors related to fatigue in patients with cirrhosis before and after liver transplantation . Clin Gastroenterol Hepatol . 2012;10:174–181
  10. Chaudhuri A , Behan PO . Fatigue and basal ganglia . J Neurol Sci . 2000;179(S1–S2):34–42
  11. Swain MG . Fatigue in liver disease: pathophysiology and clinical management . Can J Gastroenterol . 2006;20:181–188
  12. Huet PM , Deslauriers J , Tran A , et al.  Impact of fatigue on the quality of life of patients with primary biliary cirrhosis . Am J Gastroenterol . 2000;95:760–767
  13. Jones DE , Bhala N , Burt J , et al.  Four year follow up of fatigue in a geographically defined primary biliary cirrhosis patient cohort . Gut . 2006;55:536–541
  14. Newton JL , Gibson GJ , Tomlinson M , et al.  Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence . Hepatology . 2006;44:91–98
  15. Wessely S , Pariante C . Fatigue, depression and chronic hepatitis C infection . Psychol Med . 2002;32:1–10
  16. Rodger AJ , Jolley D , Thompson SC , et al.  The impact of diagnosis of hepatitis C virus on quality of life . Hepatology . 1999;30:1299–1301
  17. Obermayer-Straub P , Strassburg CP , Manns MP . Autoimmune hepatitis . J Hepatol . 2000;32(1 Suppl):181–197
  18. McDonald J , Jayasuriya J , Bindley P , et al.  Fatigue and psychological disorders in chronic hepatitis C . J Gastroenterol Hepatol . 2002;17:171–176
  19. D'Mello C , Swain MG . Liver-brain inflammatory axis . Am J Physiol Gastrointest Liver Physiol . 2011;301:G749–G761
  20. Forton DM , Hamilton G , Allsop JM , et al.  Cerebral immune activation in chronic hepatitis C infection: a magnetic resonance spectroscopy study . J Hepatol . 2008;49:316–322
  21. Forton DM , Thomas HC , Murphy CA , et al.  Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease . Hepatology . 2002;35:433–439
  22. Pollak Y , Ovadia H , Orion E , et al.  The EAE-associated behavioral syndrome: I (Temporal correlation with inflammatory mediators) . J Neuroimmunol . 2003;137:94–99
  23. Clauw DJ , Chrousos GP . Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms . Neuroimmunomodulation . 1997;4:134–153
  24. Lucki I . The spectrum of behaviors influenced by serotonin . Biol Psychiatry . 1998;44:151–162
  25. Gold PW , Chrousos GP . The endocrinology of melancholic and atypical depression: relation to neurocircuitry and somatic consequences . Proc Assoc Am Physicians . 1999;111:22–34
  26. Kraus MR , Schäfer A , Schöttker K , et al.  Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study . Gut . 2008;57:531–536
  27. Piche T , Vanbiervliet G , Cherikh F , et al.  Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study . Gut . 2005;54:1169–1173
  28. Ek M , Kurosawa M , Lundeberg T , et al.  Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins . J Neurosci . 1998;18:9471–9479
  29. Goehler LE , Gaykema RP , Hansen MK , et al.  Vagal immune-to-brain communication: a visceral chemosensory pathway . Auton Neurosci . 2000;85:49–59
  30. McDonald C , Newton J , Lai HM , et al.  Central nervous system dysfunction in primary biliary cirrhosis and its relationship to symptoms . J Hepatol . 2010;53:1095–1100
  31. Bluthé RM , Layé S , Michaud B , et al.  Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice . Eur J Neurosci . 2000;12:4447–4456
  32. Park KM , Bowers WJ . Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction . Cell Signal . 2010;22:977–983
  33. Nadeau S , Rivest S . Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood-brain barrier . Neuroscience . 1999;93:1449–1464
  34. Ransohoff RM , Kivisäkk P , Kidd G . Three or more routes for leukocyte migration into the central nervous system . Nat Rev Immunol . 2003;3:569–581
  35. Rivest S , Lacroix S , Vallières L , et al.  How the blood talks to the brain parenchyma and the paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli . Proc Soc Exp Biol Med . 2000;223:22–38
  36. Forton DM , Patel N , Prince M , et al.  Fatigue and primary biliary cirrhosis: association of globus pallidus magnetisation transfer ratio measurements with fatigue severity and blood manganese levels . Gut . 2004;53:587–592
  37. Guevara M , Baccaro ME , Gómez-Ansón B , et al.  Cerebral magnetic resonance imaging reveals marked abnormalities of brain tissue density in patients with cirrhosis without overt hepatic encephalopathy . J Hepatol . 2011;55:564–573
  38. Ferenci P , Lockwood A , Mullen K , et al.  Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of gastroenterology, Vienna . Hepatology . 2002;3:716–721 1998
  39. Gabuzda GJ , Phillips GB , Davidson CS . Reversible toxic manifestations in patients with cirrhosis of the liver given cation-exchange resins . N Engl J Med . 1952;246:124–130
  40. Häussinger D , Kircheis G , Fischer R , et al.  Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema? . J Hepatol . 2000;32:1035–1038
  41. Shawcross DL , Shabbir SS , Taylor NJ , et al.  Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis . Hepatology . 2010;51:1062–1069
  42. Butterworth RF . Hepatic encephalopathy: a central neuroinflammatory disorder? . Hepatology . 2011;53:1372–1376

 Conflicts of interest The authors disclose no conflicts.

PII: S1542-3565(11)01165-7

doi:10.1016/j.cgh.2011.10.036

Refers to article:

  • Editorial Accompanies ArticleAdditional Online Content Available Factors Related to Fatigue in Patients With Cirrhosis Before and After Liver Transplantation , 12 August 2011

    Evangelos Kalaitzakis, Axel Josefsson, Maria Castedal, Pia Henfridsson, Maria Bengtsson, Irene Hugosson, Bengt Andersson, Einar Björnsson
    Clinical Gastroenterology and Hepatology February 2012 (Vol. 10, Issue 2, Pages 174-181.e1)

Clinical Gastroenterology and Hepatology
Volume 10, Issue 2 , Pages 103-105, February 2012

Article Tools