Disrupted sleep-wake rhythms linked to liver disease progression

FrontiersDec 4 2024

The prevalence of MASLD (metabolic dysfunction-associated steatotic liver disease) is exploding in most regions of the world, boosted by increased obesity and sedentary lifestyles. MASLD (formerly known as non-alcoholic fatty liver disease) is already the most common liver disorder: it affects 30% of adults and between 7% and 14% of children and adolescents, and this prevalence is predicted to rise to more than 55% of adults by 2040. People with MASLD run a heightened risk of diabetes, hepatocellular carcinoma, non-liver cancers, chronic kidney disease, age-related muscle loss, and cardiovascular disease.

Earlier studies have implicated disturbances in the circadian clock and in the sleep cycle in the development of MASLD. But the American Academy of Sleep Medicine has recommended that objective measures – rather than subjective ones such as sleep questionnaires – be used to prove this hypothetical link between disorders of sleep and the circadian rhythm, MASLD, and MASH. MASH is a more severe form of MASLD, where the liver suffers damage from inflammation and tissue scarring, caused by abnormal accumulation of fat.

"Here we show for the first time with an objective method, 24/7 actigraphy, that the sleep-wake rhythm in patients with MASLD does indeed differ from that in healthy individuals: those with MASLD demonstrated significant fragmentation of their nightly sleep due to frequent awakenings and increased wakefulness," said Dr Sofia Schaeffer, a postdoctoral researcher at the University of Basel and Basel's University Center for Gastrointestinal and Liver Diseases, and the corresponding author of a new study in Frontiers in Network Physiology.

Actigraphy involves tracking gross motor activity with a sensor worn on the wrist.

Don't lose any sleep

Between 2019 and 2021, Schaeffer and colleagues recruited 46 adult women and men diagnosed with either MASLD, MASH, or MASH with cirrhosis. A further eight patients with non-MASH-related liver cirrhosis served as comparisons, while a second comparator group consisted of 16 age-matched healthy volunteers. Each study participant was equipped with an actigraph, to be worn at all times, which tracked light, physical activity, and body temperature.

Participants visited the clinic as outpatients at the start, midpoint, and end of the four-week follow-up. Both at the start and end of this period, they underwent clinical investigation, were interviewed through sleep questionnaires about their sleep habits. They also kept a sleep diary.

All patients with MASLD were obese, and 80% had metabolic syndrome. Patients with MASLD further had significantly higher levels of triglycerides, fasting glucose, and insulin in their blood than healthy participants, but lower levels of total cholesterol, 'bad' LDL cholesterol, and 'good' HDL cholesterol.

Rude awakening

Actigraph measurements didn't reveal any differences between patients with MASLD and healthy participants when it came to things such as sleep duration or the amount of time spent in bed.

But importantly, the actigraphs showed that patients with MASLD woke 55% more often at night, and lay 113% longer awake after having first fallen asleep, compared to healthy volunteers. Patients with MASLD also slept more often and longer during the day. Sleep patterns and quality as measured by actigraph were similarly impaired in patients with MASH, MASH with cirrhosis, and non-MASH-related cirrhosis.

Subjectively, patients with MASLD self-reported their disrupted and inefficient sleep as shorter sleep with a delayed onset. In their sleep diaries, 32% of patients with MASLD reported experiencing sleep disturbances caused by psychological stress, compared to only 6% of healthy participants.

We concluded from our data that sleep fragmentation plays a role in the pathogenesis of human MASLD. Whether MASLD cause sleep disorders or vice versa remains unknown."

Dr. Sofia Schaeffer, Postdoctoral Researcher, University of Basel

"The underlying mechanism presumably involves genetics, environmental factors, and the activation of immune responses – ultimately driven by obesity and metabolic syndrome."

Schaeffer and colleagues also tried to improve the sleep of participants with a single sleep hygiene education session, performed at the study's midpoint. Here, they were taught practical measures to improve their sleep habits. However, the results showed that the session didn't improve the actigraphy or self-reported measures of sleep quality and quantity.

"A single sleep hygiene education session didn't suffice to sustainably impact on the circadian rhythm in either patients with MASLD or healthy controls. Future studies should explore perpetual sleep counselling sessions or interventions such as light therapy in combination with other lifestyle changes to improve the sleep-wake cycle in patients with MASLD," recommended Dr Christine Bernsmeier, a professor at the University of Basel and the study's senior author.