Fatigue in chronic liver disease: New insights and therapeutic approaches

Abstract

The management of fatigue associated with chronic liver disease is a complex and major clinical challenge. Although fatigue can complicate many chronic diseases, it is particularly common in diseases with an inflammatory component. Fatigue can have both peripheral (i.e., neuromuscular) and central (i.e., resulting from changes in neurotransmission within the brain) causes. However, fatigue in chronic liver disease has strong social/contextual components and is often associated with behavioural alterations including depression and anxiety. Given the increasing awareness of patient-reported outcomes as important components of treatment outcomes and clinical research, there is a growing need to better understand and manage this poorly understood yet debilitating symptom. Although several pathophysiological mechanisms for explaining the development of fatigue have been generated, our understanding of fatigue in patients with chronic liver disease remains incomplete. A better understanding of the pathways and neurotransmitter systems involved may provide specific directed therapies. Currently, the management of fatigue in chronic liver disease can involve a combined use of methods to beneficially alter behavioural components and pharmacological interventions, of which several treatments have potential for the improved management of fatigue in chronic liver disease. However, evidence and consensus are lacking on the best approach and the most appropriate biochemical target(s) whilst clinical trials to address this issue have been few and limited by small sample size. In this review, we outline current understanding of the impact of fatigue and related symptoms in chronic liver disease, discuss theories of pathogenesis, and examine current and emerging approaches to its treatment.

The challenges of primary biliary cholangitis: What is new and what needs to be done

“…Additional symptoms include sicca complex, abdominal pain, arthralgia, restless legs, sleeplessness, depression and cognitive dysfunction (233,234). Symptomatic patients have a worse prognosis (2).…”

“…Autonomic dysfunction, which is very common in PBC, correlates with fatigue and is more pronounced in females than in males (14). As PBC is an organ-specific disease, fatigue may be triggered in the brain by the diseased liver via unknown signaling pathways (234). It has been suggested that liver inflammation produces brain changes via neural, humoral (in parts of the brain lacking an intact blood-brain-barrier) and immune-mediated routes, leading to microglia activation in the brain and eventually to changes in neurotransmission in the basal ganglia, the main drivers of fatigue syndrome (234).…”

PBC‐10: a short quality of life measure for clinical screening in primary biliary cholangitis

“…Typical PBC‐related symptoms include fatigue, pruritus, dry eyes and mouth, and occasional abdominal and bone pain . Fatigue can be profound and persistent, and is typically unrelated to histological stage or activity of the disease …”

“…3,4 Fatigue can be profound and persistent, and is typically unrelated to histological stage or activity of the disease. [5][6][7] Recent years have seen significant evolution in the treatment of PBC. Furthermore, the importance of health-related quality of life (HRQoL) 8 is widely appreciated, and approaches to the management of the symptoms contributing to HRQoL, most notably pruritus, continues to improve.…”

The efficacy of levocarnitine treatment in relieving fatigue in patients with cirrhosis but without overt hepatic encephalopathy: a prospective non-randomized controlled study

“…A useful construct is to consider fatigue as two separate entities: peripheral fatigue and central fatigue [10]. Peripheral fatigue results from neuromuscular dysfunction originating from noncentral nervous system mechanisms and most commonly manifests as weakness in clinical examinations [11][12][13].…”