Association of Serum Biomarkers With Fatigue in Patients With Chronic Liver Disease

Abstract

Background and Aims: Fatigue is a common symptom of chronic liver diseases (CLD), including non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CH-C). The mechanisms or correlates of fatigue in these patients have not been well studied. We aimed to determine if there is a correlation between self-reports of physical activity associated fatigue (peripheral fatigue) or more global lack of energy and motivation (central fatigue); with serum markers of inflammation, or with abnormalities of glucose and lipid metabolism. Methods: 31 untreated patients (age 52.5 ±6.8 years, 66.7% male, BMI 32.4 ± 5.5, 26.7% DM, 0% cirrhosis) with CLD (biopsy proven NAFLD or CH-C with viremia) participated in the study. Fasting blood samples were obtained and were assessed for levels of cytokines (IL-6, IL-8, and TNF-α), serotonin, C-peptide insulin, liver enzymes (AST, ALT), glucose, and lipids (triglycerides, total cholesterol, HDL, LDL, and the non-HDL fraction). Cytokines, serotonin, and C-peptide insulin were measured by ELISA following the manufacturer's protocols. The remaining parameters were measured by the Cholestech LDX system. Selfreports included standardized and valid measures of depression (short form of CES-D), vitality/energy (vitality subscale of the SF36) and level of activity (Human Activity Profile). Patients were then divided into tertiles by MET value. The middle third was omitted from further analysis; the remaining top third (those with MET >8.8, representing strenuous activity) and bottom third (those with MET 7 and a transformed vitality index score <45. Only patients meeting these criteria were defined as having central fatigue. Groupwise comparisons were made by Mann-Whitney test, and correlations were assessed by Spearman Rho. Results: In comparison to CLD patients without peripheral fatigue, CLD patients who had peripheral fatigue (n=23) had significantly elevated serum levels of IL-6 (7.2±13.5 pg/mL vs. 1.6±0.74 pg/mL, p<0.01) and IL-8 (22.8±11.2 vs. 15.7±6.8 pg/mL, p<0.05); respectively. In terms of central fatigue, the ratio of AST/ALT was significantly lower in CLD patients with central fatigue than those CLD patients without central fatigue (0.862±0.166 vs. 1.118±0.283, p= 0.004). Conclusions: The current study demonstrates that a substantial majority of patients with CLD report significant peripheral fatigue. This type of fatigue is linked to elevated serum levels of IL-6 and IL-8, implying an inflammatory component present in patients with peripheral fatigue but not in those with central fatigue. Further study into the nature and extent of fatigue associated with CLD is warranted.