Sleep Disruption and Daytime Sleepiness Correlating with Disease Severity and Insulin Resistance in Non-Alcoholic Fatty Liver Disease: A Comparison with Healthy Controls

Abstract

Background & aims: Sleep disturbance is associated with the development of obesity, diabetes and hepatic steatosis in murine models. Hepatic triglyceride accumulation oscillates in a circadian rhythm regulated by clock genes, light-dark cycle and feeding time in mice. The role of the sleep-wake cycle in the pathogenesis of human non-alcoholic fatty liver disease (NAFLD) is indeterminate. We sought to detail sleep characteristics, daytime sleepiness and meal times in relation to disease severity in patients with NAFLD.

Methods: Basic Sleep duration and latency, daytime sleepiness (Epworth sleepiness scale), Pittsburgh sleep quality index, positive and negative affect scale, Munich Chronotype Questionnaire and an eating habit questionnaire were assessed in 46 patients with biopsy-proven NAFLD and 22 healthy controls, and correlated with biochemical and histological parameters.

Results: In NAFLD compared to healthy controls, time to fall asleep was vastly prolonged (26.9 vs. 9.8 min., p = 0.0176) and sleep duration was shortened (6.3 vs. 7.2 hours, p = 0.0149). Sleep quality was poor (Pittsburgh sleep quality index 8.2 vs. 4.7, p = 0.0074) and correlated with changes in affect. Meal frequency was shifted towards night-times (p = 0.001). In NAFLD but not controls, daytime sleepiness significantly correlated with liver enzymes (ALAT [r = 0.44, p = 0.0029], ASAT [r = 0.46, p = 0.0017]) and insulin resistance (HOMA-IR [r = 0.5, p = 0.0009]) independent of cirrhosis. In patients with fibrosis, daytime sleepiness correlated with the degree of fibrosis (r = 0.364, p = 0.019).

Conclusions: In NAFLD sleep duration was shortened, sleep onset was delayed and sleep quality poor. Food-intake was shifted towards the night. Daytime sleepiness was positively linked to biochemical and histologic surrogates of disease severity. The data may indicate a role for sleep-wake cycle regulation and timing of food-intake in the pathogenesis of human NAFLD as suggested from murine models.

Fig 1. Sleep characteristics detailed in patients with Non-alcoholic fatty liver disease (NAFLD) and controls.

(A) Sleep latency (minutes; left) was significantly prolonged in NAFLD compared to controls; sleep duration was significantly reduced (hours; right). (B) The chronotype did not significantly differ between NAFLD and controls, Munich Chronotype Questionnaire (MCTQ; left) and sleep quality was poor (Pittsburgh Sleep Quality Index [PSQI]; right). A score ≤ 5 is considered good sleep quality. (C) Positive and negative affect scale (PANAS): Negative affect was significantly higher in patients (left). Positive affect did not differ (right). Controls (n = 22), NAFLD (n = 46; simple steatosis [n = 12]; Non-alcoholic steatohepatitis [NASH, n = 34]). *, p<0.05; **, p<0.001.

Fig 2. Timing of food-intake differs between NAFLD patients and controls.

The percentage of patients vs. controls having meals at different times during the day and night. Compared to controls meal times in NAFLD patients were shifted towards the night (p = 0.001, generalised linear mixed model). Controls (n = 22); NAFLD (n = 44).

Fig 3. Daytime sleepiness in patients with Non-alcoholic fatty liver disease (NAFLD) is linked to insulin resistance and elevated liver enzymes.

(A) Daytime sleepiness, assessed by the Epworth Sleepiness scale (ESS) was observed more often in NAFLD but median scales did not differ significantly from controls. An ESS score ≤10 is considered normal. (B-D) Daytime sleepiness is positively correlated with clinical and biochemical parameters in patients with NAFLD/NASH. Graphs showing ESS correlations with (B) BMI (kg/m²), (C) parameters of insulin resistance: HOMA-IR, glucose (mmol/l), insulin (μU/ml) and (D) liver enzymes: Gamma-glutamyl transpeptidase (GGT, U/l), Aspartate aminotransferase (ASAT, U/l) and Alanine aminotransferase (ALAT, U/l). Spearman correlations.

Fig 4. Daytime sleepiness is higher in patients with advanced fibrosis.

Daytime sleepiness, assessed by the Epworth Sleepiness scale (ESS) was plotted against the stage fibrosis (NAFLD activity score) in patients with fibrosis (F1-F4). *, p<0.05.