Azza Karrar

Fatigue in chronic liver disease: exploring the role of the autonomic nervous system

This issue of Liver International has published an article by Dyson et al., which presents data implicating the sympathetic nervous system as a potentially significant contributor and pathogenetic factor for fatigue (1). Given the prevalence and importance of this line of research, we propose to discuss some general aspects of fatigue, its taxonomy and place the findings reported by Dyson et al. in this context. What is meant by ‘fatigue’? The Oxford English Dictionary defines fatigue as ‘lassitude or weariness resulting from either bodily or mental exertion’ or . . . ‘as a condition of muscles, organs, or cells characterized by a temporary reduction in power or sensitivity following a period of prolonged activity or stimulation’. (2) This definition, commonly held, helps confirm the view that there may be both physical and mental contributors to fatigue, but it implies that fatigue ‘results’ from exertion, prolonged activity or stimulation, a view not held by those who study fatigue. (3). Fatigue is a symptom that certainly may result from exercise, work and activities of daily living. However, it can also be associated with a variety of illnesses and their treatments. In fact, several illnesses and syndromes use fatigue as a diagnostic criterion (rheumatic diseases, multiple sclerosis et al.) and as a key measure of disease activity and severity or successful treatment. (4) Well-defined chronic illnesses and cancer have fatigue as a prevalent and prominent associated condition. (5) These kinds of fatigue have specific criteria that must be met. Additionally, fatigue can be idiopathic, having no obvious ‘objective’ basis or identifiable ‘cause’. Examples of idiopathic fatigue include multisystem disease or chronic fatigue syndrome (CFS). The evaluation and treatment of fatigue present at least two significant challenges to clinicians. The first is diagnostic and requires assessments of symptoms, performance measures, laboratory and other physiological measures. The second pertains to taxonomy and depends on using standard evaluations, namely patient self-reports, to assess the pattern, severity and quality of fatigue. It requires one to interpret patient self-reports. Self-reports often use generic phrases (e.g. ‘I lack energy’ or ‘It is difficult to get going in the morning’) or more specific phrases (e.g. I tire walking up stairs). A useful construct, although still not universally accepted, is to divide fatigue into two separate entities. One is peripheral, or physical, fatigue and the other central, or mental, fatigue. Peripheral fatigue results from a decline in muscle function originating from non-central nervous system mechanisms. (6) Fatigue is worsened by low physical fitness and chronic illnesses. These conditions may intensify fatigue to levels that limit physical and social functioning and severely diminish health-related quality of life. The other is central fatigue, defined as ‘the failure to initiate and/or sustain attentional tasks and physical activities requiring self-motivation’, thus emphasizing a cognitive component. (7) Fig. 1 illustrates the overlap and distinctions of central and peripheral fatigue with regards to both measurement and symptomatic presentation. The value gained using specific constructs would enable a treatment plan to be targeted towards a particular organ system(s), making treatment more effective. Researchers have struggled to better assess and understand the aetiology and classification of fatigue within different illness groups. The largest area of difficulty is criterion variance, the inability to classify patients into the two diagnostic categories (peripheral and central fatigue). This is in part dependent upon measurement and the sensitivity and specificity of the instruments. Dyson et al. have contributed to the understanding of fatigue in chronic liver disease by demonstrating an association between sympathetic over-activity, increased cardiac output and primary sclerosing cholangitis. The association between autonomic dysfunction and fatigue has been identified in people with primary biliary cirrhosis (PBC) (8), nonalcoholic fatty liver disease and chronic hepatitis C (9) and CFS (10), suggesting this is a multidomain phenomenon, one of which may be autonomic dysfunction. Activated immune cells secrete cytokines that influence central nervous system activity, which, in turn, activates output through the peripheral nervous system to regulate the magnitude of an immune response. (11) It is possible that dysregulation of this line of communication between the nervous and immune systems might contribute to disease development and progression. The sympathetic nervous sys-

Anti-adipocyte antibody response in patients with non-alcoholic fatty liver disease.

A significant number of autoantibodies have been reported in patients with non‐alcoholic fatty liver disease (NAFLD) patients. In the present study, our aim was to assess the role of disease and cell‐specific antibodies, namely anti‐adipocyte antibodies (anti‐AdAb) in patients with NAFLD and non‐alcoholic steatohepatitis (NASH).

The levels of monoamine neurotransmitters and measures of mental and emotional health in HCV patients treated with ledipasvir (LDV) and sofosbuvir (SOF) with or without ribavirin (RBV)

AbstractMental and emotional health (MEH) impairment is commonly encountered in hepatitis C patients. Although the exact mechanism remains unknown, alterations in neurotransmitter and cytokine levels maybe associated with hepatitis C virus (HCV)-related MEH issues.The aim of the study was to assess association of serum biomarkers with self-reports of MEH in HCV patients before treatment and after achieving sustained virologic response (SVR).The HCV genotype-1-infected patients who achieved SVR at 12 weeks after treatment with ledipasvir (LDV)/sofosbuvir (SOF) ± ribavirin (RBV) were selected. Frozen serum samples from baseline, end of treatment (EOT), and posttreatment week 4 (PTW4) were used to assay 16 cytokines and monoamine neurotransmitters. Validated self-reports were used to assess MEH.Hundred patients were evaluated. Mean age was 53 years (57% male, 86% white). Compared with baseline, emotional well-being and emotional health significantly increased by EOT, and role emotional, emotional well-being, and emotional health significantly increased at PTW4 in the RBV-containing arm (P < 0.05). In patients taking LDV/SOF + RBV, serotonin levels were significantly decreased at PTW4 compared with baseline (P = 0.046). Compared with baseline, there were significant decreases in interleukin (IL)-10 levels at EOT and PTW4 in both treatment groups. The changes in IL-8 also differed significantly between LDV/SOF + RBV and LDV/SOF groups (P < 0.05). Changes in dopamine and tryptophan levels at EOT correlated with increasing emotional health scores, whereas changes in monocyte chemoattractant protein-1 at EOT and IL-8 at PTW4 correlated with increasing mental health scores. The neurotransmitters and cytokines were found to be independent predictors of MEH scores in multiple regression analysis.Cytokine and neurotransmitter changes are associated with mental and emotional health. Patient-reported outcome scores change during and after treatment.