However, the rigorous examination of fatigue as a symptom in viral hepatitis has only recently received scientific scrutiny. Fatigue in PBC does not correlate with disease severity. 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 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.
Furthermore, in experimental liver disease in rats we have identified a number of abnormalities in the central systems which control the stress response. 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. 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. 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.