Importance of fatigue and its measurement in chronic liver disease

Abstract

The mechanisms of fatigue in the group of people with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are protean. The liver is central in the pathogenesis of fatigue because it uniquely regulates much of the storage, release and production of substrate for energy generation. It is exquisitely sensitive to the feedback controlling the uptake and release of these energy generation substrates. Metabolic contributors to fatigue, beginning with the uptake of substrate from the gut, the passage through the portal system to hepatic storage and release of energy to target organs (muscle and brain) are central to understanding fatigue in patients with chronic liver disease. Inflammation either causing or resulting from chronic liver disease contributes to fatigue, although inflammation has not been demonstrated to be causal. It is this unique combination of factors, the nexus of metabolic abnormality and the inflammatory burden of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis that creates pathways to different types of fatigue. Many use the terms central and peripheral fatigue. Central fatigue is characterized by a lack of self-motivation and can manifest both in physical and mental activities. Peripheral fatigue is classically manifested by neuromuscular dysfunction and muscle weakness. Therefore, the distinction is often seen as a difference between intention (central fatigue) versus ability (peripheral fatigue). New approaches to measuring fatigue include the use of objective measures as well as patient reported outcomes. These measures have improved the precision with which we are able to describe fatigue. The measures of fatigue severity and its impact on usual daily routines in this population have also been improved, and they are more generally accepted as reliable and sensitive. Several approaches to evaluating fatigue and developing endpoints for treatment have relied of biosignatures associated with fatigue. These have been used singly or in combination and include: physical performance measures, cognitive performance measures, mood/behavioral measures, brain imaging and serological measures. Treatment with non-pharmacological agents have been shown to be effective in symptom reduction, whereas pharmacological agents have not been shown effective.

Keywords: Fatigue, Chronic liver disease, Non-alcoholic fatty liver diseases, Non-alcoholic steatohepatitis, Measurement, Patient-reported outcomes

Core tip: Fatigue is prevalent, persistent and complex in people with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis. Fatigue can be analyzed in terms of peripheral and central fatigue, increasing precision of evaluation while elucidating causes and improving treatment. The liver is central to the pathogenesis of fatigue, which in our view, is dependent upon energy regulation. Biosignatures for fatigue are being tested that reflect metabolic and inflammatory pathways of relevance. Non-pharmacological treatments including weight loss, aerobic and resistance exercise are effective in treating fatigue in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis. Pharmacological agents to date have not been shown to have a significant/reliable effect in reducing fatigue.