Fatigue in liver disease: pathophysiology and clinical management

Abstract

Fatigue is the most commonly encountered symptom in patients with liver disease, and it has a significant impact on their quality of life. However, although some progress has been made with regard to the understanding of the processes which may generate fatigue in general, the underlying cause(s) of liver disease-associated fatigue remain incompletely understood. The present review describes recent advances which have been made in our ability to measure fatigue in patients with liver disease in the clinical setting, as well as in our understanding of potential pathways which are likely important in the pathogenesis of fatigue associated with liver disease. Specifically, experimental findings suggest that fatigue associated with liver disease likely occurs as a result of changes in neurotransmission within the brain. In conclusion, a reasonable approach to help guide in the management of the fatigued patient with liver disease is presented.

Figures

Figure 1

Corticotropin-releasing hormone (CRH) acts in its traditional role to stimulate adrenocorticotropic hormone (ACTH) release from the anterior pituitary gland. However, CRH release from nerve fibres projecting to areas within the brain stimulates behavioural activation and arousal

Figure 2

Serotonin-secreting nerves originate in the dorsal raphe nucleus within the midbrain and their axons project throughout the central nervous system. Activation of 5-hydroxytryptamine 1A (5HT1A) autoreceptors located on serotonin nerve cell bodies within the raphe nucleus results in a decrease in serotonin release from nerve terminals at the distal projection sites of these serotonergic nerves. ↓ Decrease

Figure 3

Neural transmission pathway for liver to brain signalling. Kupffer cells within the liver secrete proinflammatory mediators (eg, cytokines, prostaglandins) that activate vagal afferent nerves, which innervate the liver. Nerve impulses are then carried to the nucleus tractus solitarius (NTS) within the brainstem, which acts as a relay centre for the transmission of these impulses to areas throughout the brain. Stimulation of vagal afferent nerves can thereby result in alterations in neurotransmitter systems within the brain, which may give rise to central fatigue

Figure 4

Humoral transmission pathway for liver to brain signalling. Substances released within the circulation in the setting of liver disease (eg, cytokines, including tumour necrosis factor-alpha [TNFα]) activate the cerebral endothelial cells that make up the blood-brain barrier. Activated cerebral endothelial cells then secrete secondary messengers (eg, nitric oxide, prostaglandin E2) into the brain parenchyma, which induce changes in central neurotransmitter systems, which give rise to central fatigue