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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”

Fatigue and Liver Disease

Fatigue as a Symptom of Liver Disease

Mark G. Swain, MD
Assistant Professor of Medicine
University of Calgary


A) What is Known About Fatigue in Liver Disease?

i) Viral Hepatitis

Fatigue as a symptom which is commonly observed in patients seen in the clinic with chronic viral hepatitis, and fatigue can be incapacitating in some patients. However, the rigorous examination of fatigue as a symptom in viral hepatitis has only recently received scientific scrutiny.

Anecdotally, fatigue has been reported to occur in approximately 5% to 10% of patients with hepatitis C and does not appear to be associated with the severity of the associated liver disease. Recently Davis showed that patients with hepatitis C had a reduced quality of life which did not appear to improve with viral clearance after a interferon treatment.1 Furthermore, Foster et al have documented, by using a validated questionnaire, that patients with hepatitis C have a significant impairment in their energy level.2 Interestingly, patients with chronic hepatitis B did not exhibit fatigue scores any different than control subjects. Hepatitis C patients with a history of intravenous drug abuse (IVDA) had worse fatigue scores than hepatitis C patients with no history of IVDA, but both groups had significant reductions in energy when compared with normal controls. Moreover, fatigue scores did not correlate with the severity of hepatitis as measured by hepatic histology or ALT.


ii) Cholestatic Liver Disease

Fatigue, lethargy and malaise commonly occur in patients with the cholestatic liver diseases, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Fatigue occurs in up to 86% of patients with PBC3 and 75% of patients with PSC4 and has a significant impact on their quality of life. In PBC, fatigue constitutes the worst symptom in almost 50% of patients. Moreover, fatigue scores in 25% of PBC patients are similar to those documented in patients with multiple sclerosis. Fatigue in PBC does not correlate with disease severity. Fatigue in PBC is central, not peripheral, in origin.5

B) Possible Mechanisms of Fatigue Genesis in Liver Disease

The specific cause(s) of central fatigue are poorly characterized; however, a number of causes of central fatigue have been suggested and investigated in patients with chronic fatigue syndrome. These theories identify sustained dysregulation of the stress response system which arise secondary to chronic physical and immune stress and which eventually lead to central changes characterized by blunting of the stress response. This blunting of the stress response has been repeatedly implicated in the genesis of fatigue in diseases characterized by chronic fatigue. These chronic stressors can be modified by psychological cofactors which modulate symptom development.6 These theories may be applicable to the genesis of central fatigue in patients with liver disease.

Liver disease constitutes a chronic uncontrollable stress to the patient. This chronic stress can be in the form of physical, emotional and/or immune stress. Furthermore, in experimental liver disease in rats we have identified a number of abnormalities in the central systems which control the stress response. Specifically we have identified decreased hypothalamic corticotropin-releasing hormone (CRH) levels and release in rats with cholestatic liver disease and this deficit in central CRH release leads to defective CRH-mediated behaviours in these animals. CRH is the main central activator of the stress response in rodents and humans and defective central CRH release has been implicated in the genesis of fatigue in the chronic fatigue syndrome.

In addition, we have identified augmented central responsiveness of cholestatic rats to the fatigue-ameliorating effects elicited by serotonin receptor activation (specifically 5HT1A receptors). Given that serotonin activates the stress response by stimulating central CRH release, these results are consistent with enhanced sensitivity to serotonin-induced CRH release in cholestatic rats as mediating the beneficial effects of serotonin receptor activation upon fatigue in these animals. Chronic immune activation leads to hypercytokinemia in patients with chronic liver disease.7 Prolonged exposure of the brain to elevated circulating cytokine levels can lead to a blunting of the stress response which has been implicated in the genesis of fatigue. We have identified elevated circulating cytokine levels in cholestatic rats and have also found a blunting of the activation of the stress response in cholestatic rats produced by acute immune activation and by exogenous cytokine administration. These results suggest that a blunting of immune activation of the stress response in liver disease may contribute to the genesis of fatigue in patients with chronic liver disease.


C) Treatment of Fatigue in the Patients with Liver Disease

i) Rule out Other Causes of Fatigue: · renal (BUN, Cr, lytes)
· anemia (CBC)
· electrolyte (Mg2+, Ca2+)
· thyroid (TSH)

ii) Rule out Depression:
· If patient is depressed consider treatment of depression and observe for improvement of fatigue

iii) Future Directions:
· CRH agonists
· centrally active serotonin receptor (5HT1A) agonists
· anti-cytokines


. Davis GL, Balart LA, Schiff ER, et al. Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile. Clin Ther 1994;16(2):334-43.
3. Foster GR, Goldin RD, Thomas HC, et al. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology 1998;27(1):209-12.
4. Huet P-M, Deslauriers J. Impact of fatigue on quality of life of patients with primary biliary cirrhosis (PBC). Gastroenterology 1996;110:A1215.
5. Lindor KD, Wiesner RH, MacCarty RL, et al. Advances in primary sclerosing cholangitis. Am J Med 1990;89(1):73-80.
6. Jalan R, Gibson H, Lombard MG. Patients with PBC have central but no peripheral fatigue. Hepatology 1996;24:A162.
7. Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms. Neuroimmunomodulation 1997;4(3):134-53.
8. Tilg H, Wilmer A, Vogel W, et al. Serum levels of cytokines in chronic liver disease. Gastroenterology 1992;103(1):264-74.