Review
The effect of sleep on gastrointestinal functioning in
Lancet Gastroenterol Hepatol
2020; 5: 616–24
Lynn Health Science Institute,
University of Oklahoma Health
Sciences Center, Oklahoma
City, OK, USA
(Prof W C Orr PhD); Department
of Medicine, Metrohealth
Medical Center and Case
Western Reserve University,
Cleveland, OH, USA
(Prof R Fass MD); Children’s
Hospital Colorado, University
of Colorado School of Medicine,
Aurora, CO, USA
(S S Sundaram MD); and
Department of Pediatrics,
Johns Hopkins School of
Medicine, Baltimore, MD, USA
(A O Scheimann MD)
Correspondence to:
Dr Ann O Scheimann, Division of
Pediatric Gastroenterology and
Nutrition, Johns Hopkins School
of Medicine, Baltimore,
MD 21287–2631, USA
ascheima@jhmi.edu
616 www.thelancet.com/gastrohep Vol 5 June 2020
common digestive diseases
William C Orr, Ronnie Fass, Shikha S Sundaram, Ann O Scheimann
Sleep quality and sleep disorders affect symptom manifestation and the pathogenesis of digestive diseases. Sleep is
largely regulated by the light–dark cycle and associated circadian rhythms. These occurrences are closely regulated
through several mechanisms with direct effects on the gastrointestinal tract. Misalignment of the circadian system is
a common cause of sleep complaints, which play an important role in the presentation of many gastrointestinal
disorders. This Review will focus on sleep disorders and how these alterations in sleep play an important role in many
commonly encountered digestive diseases, such as gastro-oesophageal reflux disease, irritable bowel syndrome,
inflammatory bowel disease, and non-alcoholic fatty liver disease. Therapeutic interventions focusing on resolving
sleep disorders could optimise treatment and improve quality of life in these patients.
Introduction understanding of the importance of sleep in the
The value of good sleep is often underappreciated in pathogenesis of gastrointestinal diseases, within focuses
clinical medicine. Sleep is an integral part of the on common digestive diseases, such as gastro-oesop­hageal
circadian day–night cycle, and both sleep and the reflux disease, irritable bowel syndrome (IBS),
intrinsic properties of the circadian cycle influence inflammatory bowel disease (IBD), and non-alcoholic
gastrointestinal functioning. Sleep quality affects fatty liver disease (NAFLD).
perceived wellbeing and physiological functioning in
patients with underlying digestive1 and liver diseases.2 Biological clocks in the control of physiology
One study3 has docu­mented a significant relationship and behaviour
between subjective ratings of sleep disturbance and To clearly understand sleep mechanisms, it is necessary
gastro­intestinal symptoms. This finding would suggest to appreciate that sleep exists as part of a 24 h cycle that is
that obtaining a sleep history should be a standard largely regulated by the inexorable oscillation of light and
component of the gastrointestinal evaluation for every dark. Light and dark cycles arising from the rotation of
patient. As will be noted in this Review, sleep disorders the Earth are a dominant influence on living organisms.
are an integral part of several digestive diseases that are Periodic oscillations of light and dark provide the basis
commonly encountered, and good sleep quality is for physiological clocks, which are ubiquitous in human
crucial to quality of life. physiology and behaviour. The alignment of sleeping and
A brief sleep history should consist of focused ques­ waking with the circadian cycle is crucial for the
tions to assess the overall quality of a patient’s sleep. The establishment of a healthy sleep cycle. Misalignment of
presence of morning drowsiness, daytime sleep­ iness, these environmental changes (eg, occuring among shift
and snoring with intermittent pauses in breathing can workers) frequently causes sleep disturbances and sleep-
provide useful information in approaching and under­ related symptoms such as insomnia.4 The fluctuations of
standing the chief digestive symptoms. A history of cognitive perfor­mance and energy over a 24 h period, and
excessive daytime sleepiness and snoring can itself be the urge to sleep after 14–16 h of wakefulness, are familiar
indicative of sleep apnoea, particularly in patients with daily experiences. Less obvious, however, is how
obesity, who commonly present with symptoms of biological clocks are interwoven into nearly every aspect
gastro-oesophageal reflux disease. Because sleep is an of physiological functioning, from cells to organs. Well
amnestic occurrence, and patients often deny sleep known physiological cycles include the sleep–wake cycle,
complications (as they cannot hear their snoring or the 24 h temperature cycle, and the secretion of cortisol.
apneic pauses themselves), input from family members Whereas some physiological functions are strongly
can help reveal sleep problems. There are brief influenced by the environmental light–dark cycle, others
questionnaires regarding quality of life and sleep are not. The most obvious physiological function that is
disorders, as well as useful tools for focusing on any not influenced by the light–dark cycle is the circadian
sleep disorder. These instruments and methods to temperature cycle, which persists in the absence of a
evaluate sleep in patients with gastrointestinal symptoms light–dark oscillation. The environmental light–dark
are reviewed elsewhere.3 cycle and social cues, such as eating and daytime social
Various physiological systems regulate the sleep–wake interactions, serve to link this endogenous cycle to a 24 h
cycle to include intrinsic circadian rhythms and complex cycle that is entrained to the external environment. In the
neural mechanisms. This Review focuses on the absence of these light–dark and social cues, the
relationship between altered sleep and circadian endogenous clock has a period of slightly longer than
rhythms, as well as their effect on gastrointestinal 24 h, which advances by a small amount each day,
functioning. The ultimate goal is to enhance resulting in a free-running cycle.5

Circadian functioning can also be controlled by genetic
and neuronal mechanisms. The core molecular
mach­inery of the circadian clock resides in most organs
and tissues of the body, including the heart, kidneys,
liver, and gut. The primary markers of the circadian clock
are core body temperature and the secretion of the sleep
hormone melatonin from the pineal gland. Normal
cycles in the secretion of melatonin, social interaction,
and food ingestion are powerful determinates of healthy
clock functioning.6 The proper orches­ tration and
synchronisation of these biological oscillations are
essential for health, and their misalign­ment is reflected
in the pathogenesis of many disease processes.7,8 Thus, a
clear understanding of the control mechanisms driving
these biological clocks will greatly enhance the ability of
physicians to understand disease mechanisms and
provide optimal care of patients.
Biological clocks in healthy gastrointestinal
functioning
Circadian oscillations have been identified in numerous
organ systems in the human body, including the secretion
of insulin, leptin, liver enzymes, blood pressure, and
the sleep-promoting hormone melatonin.5 Core body
temp­era­ture has a well-described circadian cycle with a
peak in the later part of the day and a trough in the middle
of the normal sleeping interval (according to a standard
24 h day that matches normal light–dark oscillation).
Endocrine and behavioural functions, such as reaction
time, memory, and mood, oscillate in similar 24 h cycles.8,9
Another important circadian marker is melatonin
secretion, which is inhibited by light and stimulated by
dark through retinal hypothalamic signal­ ling to the
suprachiasmatic nucleus and relays to the superior
cervical ganglion and pineal gland.
The fundamental molecular basis of biological clocks
involves transcription–translation feedback loops, which
include several genes (PER1, PER2, PER3, CRY, CLOCK,
and BMAL).10 Moreover, specific gut functions, such as
intestinal permeability and colonic motility, have been
linked to specific CLOCK gene functions.11,12 These
oscillations are regulated by a feedback loop consisting of
several proteins with transcriptional or translational
interactions, which result in a 24 h circadian oscillation
in cells.5 The BMAL and CLOCK genes form a dimer that
is translocated into the nucleus, which attaches to an
enhancer box, which in turn stimulates production of
Per and Cry proteins. These proteins are translocated to
the cytoplasm, where they form a dimer that is
translocated into the nucleus and subsequently inhibits
further production of Per and Cry proteins. Cry proteins
also disinhibit BMAL and CLOCK genes. Through this
complex set of genetic interactions, CLOCK functioning
is maintained throughout the organism via interactions
with environmental cues, as well as actions of the
suprachiasmatic nucleus in relation to light–dark cycles
and the consequent secretion of the sleep-promoting
www.thelancet.com/gastrohep Vol 5 June 2020 617
Review
hormone melatonin. Vertebrates also produce melatonin
in other organs including skin, blood cells, and
enterochromaffin cells in the gastrointestinal tract,13,14
with high levels present in bile.15 Circadian rhythms
influence other aspects of digestive functioning,
including epithelial turnover (eg, of Wnt proteins and the
surface outer mucus layer), immune function (eg, Toll-
like receptors, macrophages, and dendritic cells), hepatic
metabolism, and gut peristalsis.16 During sleep, gastric
emptying is slower than during waking hours, with
decreased colonic motor activity.11 Hepatic metabolism is
similarly influenced by circa­ dian regulation, with
differential effects of macro­nutrient intake (eg, high-fat
diet, ketogenic diet) upon peripheral clocks.17 Diet and
time of food intake can substantially alter the circadian
cycle.7 Because circadian rhythms have apparent central
and local influences, alterations in sleep–wake cycling
are likely to affect the pathogenesis of digestive diseases.
Sleep–wake cycle and digestive functioning
Sleep disturbances can be prevalent in patients with both
gastro-oesophageal reflux disease and IBS.18 Numerous
physiological changes are associated with disturbed sleep,
with direct and indirect effects on gastrointestinal
functioning. For example, disturbed sleep has been
associated with visceral hyperalgesia in patients with
gastro-oesophageal reflux disease.19 Circadian misalign­
ment in shift workers has deleterious effects on digestive
functioning and other physiological functions, such as
leptin secretion and insulin resistance.20 The incidence of
IBS is notably increased in shift workers, especially in
those who work rotating shifts.4 One study21 showed that
33% of patients with sleep disturbance had IBS; after
adjusting for confounders, IBS was 1·6 times more likely
to occur in patients with sleep disturbance. These data are
of particular interest because sleep disturbances can
exacerbate visceral pain responses with resultant
worsening of symptoms of IBS.19,22 Regarding symptoms
of IBS, Chen and colleagues23 have shown enhanced
sensitivity to rectal distension among patients with
subjective sleep disturbance, as assessed by the Pittsburg
Sleep Quality Index (PSQI). Furthermore, proinflam­
matory cytokines are stimulated by poor sleep and might
help perpetuate symptoms in patients with IBS and IBD.24
Sleep disorders in patients with IBS and IBD
Sleep disorders are a common finding in patients with
IBS.23,25 Numerous studies have shown deleterious effects
of poor sleep in patients with IBS, accompanied by
exacerbation of symptoms after a night of poor sleep.19,26,27
Although several studies have documented subjective
sleep disturbance in patients with IBS, objective poly­
somno­graphic studies have produced variable results.25 A
study from our laboratory showed a significant increase
in rapid eye movement (REM) sleep in patients with IBS
using objective polysomnographic measures, but this
finding has not been validated by other investigators.28–30
 Review
Since polysomnography and other devices for collection
of physiological sleep data often have poor agreement
with subjective sleep measures, it is unsurprising that
there is discordance between objective and subjective
sleep data from patients with IBS.31 Rotating shift
workers, who commonly experience poor sleep, have an
increased incidence of IBS and abdominal pain,
independent of sleep quality.4 Melatonin treatment in
such patients has shown some symptom resolution.32 In
summary, poor sleep and circadian misalignment
contribute substantially to the pathogenesis of IBS and
could provide a future therapeutic strategy.
Studies addressing circadian alignment and sleep
disturbance in patients with IBD have shown that
alterations in day–night rhythms could play a part in the
pathology of gastrointestinal disease. Such alterations
upregulate circulating cytokines, which trigger sleep
disruption, resulting in further increases of circulating
cytokine concentrations.33 This process creates a self-
perpetuating condition that contributes directly to the
pathogenesis of IBD. Several studies have provided
evidence that these self-perpetuating conditions could
play an important role not only in the pathogenesis of
IBD, but also in the disease flares that are characteristic
of the disease.34 In-vitro data from animal models have
provided further insight into the relationship between
colitis and sleep disruption. Administration of dextran to
mice in conjunction with acute and chronic sleep
deprivation created histological evidence of colitis.35
In studies that examine IBD, sleep disturbances are
most often measured by subjective instruments rather
than polysomnography. Whereas numerous studies
about IBS assess sleep via subjective and objective
polysomno­ graphic measures, few polysomnography
studies have been done in patients with IBD. Clinical
studies in patients with IBD have shown that subjective
sleep disturbances are common and might play an
important role in symptom exacerbations. Ranjbaran
and colleagues36 evaluated sleep disturbance via the
PSQI in a large population of patients with IBD. They
found that patients with IBD reported sleep disturbances
more often than did participants in the healthy control
group, and that there was a correlation between sleep
disturbance and severity of disease. Sleep duration has
been shown to affect the incidence of ulcerative colitis,
with higher incidence of ulcerative colitis among
individuals with subjective sleep durations of less than
6 h or greater than 9 h.37 Furthermore, in patients who
report poor sleep on sleep scales such as the PSQI,
subsequent symptom flares are significantly more
likely.38 Patients with abnormal PSQI scores had a
positive predictive value of 83% for histological
inflammatory activiy on tissue biopsy samples.38 This
value is most likely due to sleep disturbances that
increase the expression of inflammatory cytokines,
which in turn enhance sleep disturbance, creating a
vicious cycle of sleep disturbance and inflammatory
618 www.thelancet.com/gastrohep Vol 5 June 2020
cytokine production.34,39 One study40 examined whether
patients with IBD could be affected by chronotype—that
is, the tendency towards peak functioning in the early
morning versus late morning or early afternoon.40
Patients with IBD tended to have a late rather than early
chronotype and experience greater sleep deprivation
than did healthy control participants, with minimal
demonstrable effects and questionable clinical signifi­
cance.41 Although insomnia is a frequent subjective
complaint, polysomnography is rarely used as a
diagnostic tool. Three of the discussed studies33,34,39
provide strong docu­ mentation that optimal care of
patients with IBS and IBD could be facilitated by
recognising and resolving sleep disturbances and
possible circadian misalignment.
The first-line treatment of sleep disorders in patients
with IBS and IBD centres on the control of disease
symptoms associated with the sleep disturbance. Thus,
control of symptoms is paramount and often results in
substantial improvement of sleep quality. However,
there is also an element of learned behaviour in these
patients because of the creation of so-called conditioned
insomnia from prolonged periods of poor sleep. The
treatment of conditioned insomnia might require the
assistance of a multidisciplinary approach, including a
sleep physician, clinical psychologist, and psychiatrist to
manage behavioural and pharmacological aspects of
optimal treatment.
Gastro-oesophageal reflux and sleep
Because gastro-oesophageal reflux disease involves the
oesophagus and other proximal organs (ie, larynx,
oropharynx, and the bronchi), symptoms of gastro-
oesophageal reflux disease might have a systemic effect
leading to sleep disturbances. There is a bidirectional
relationship between gastro-oesophageal reflux disease
and sleep, in which gastro-oesophageal reflux disease
adversely affects sleep by awakening patients during the
night or, more commonly, causes multiple short amnestic
arousals with resultant sleep fragmentation.42 In turn,
poor sleep might adversely affect gastro-oesophageal
reflux disease by enhancing perception of intra-
oesophageal stimuli, such as gastric acid (centrally
mediated sensitisation) and an increase in the exposure of
the oesophagus to gastric acid, possibly by altering the
ghrelin and leptin ratio.43,44 This relationship creates a
vicious cycle in which gastro-oesophageal reflux disease
leads to poor sleep and poor sleep exacerbates disease
(figure). Epidemiological studies have shown that 65% of
patients with gastro-oesophageal reflux disease have both
daytime and night-time symptoms.45–48 Only about 13% of
patients with gastro-oesophageal reflux disease experience
only night-time symptoms. 47–57% of patients with
gastro-oesophageal reflux disease reported that heartburn
specifically awakened them from sleep during the
night.48–50 By contrast, 25% of the general population
reported having heartburn symptoms during sleep time.50

In a large survey of 1 000 participants, 75% of patients with
gastro-oesophageal reflux disease reported that symptoms
affected their sleep, 63% believed that heartburn prevented
them from sleeping well, 42% were unable to sleep
through a full night, 34% needed to take naps during the
day, and 34% were sleeping in a seated position (to
alleviate symptoms).48 Night-time reflux might lead to
insomnia, snoring, tossing and turning, and even
nightmares.50 Gastro-oesophageal reflux disease might
also affect a patient’s sleep experience by causing
nocturnal cough, choking, wheezing, sore throat, and
breathlessness.51,52 Unfortunately, rather than being
viewed as an essential part of clinical assessment, sleep
disturbances due to gastro-oesophageal reflux disease are
rarely recognised in clinical practice and rarely elicited by
physicians despite their profound effect on patients’
quality of life and work productivity.53,54
Alterations in oesophageal physiology during sleep
might accentuate the effect of gastro-oesophageal reflux
on the oesophageal mucosa, leading to increased severity
of disease and sleep disturbances. Patients with night-
time reflux are more likely to develop severe erosive
oesophagitis, peptic stricture, oesophageal ulceration,
extra-oesophageal manifestations, Barrett’s oesophagus,
and adenocarcinoma of the oesophagus.55–57 The panel
summarises various physiological alterations that occur
during sleep, which predispose to gastro-esophageal
reflux.58–60 The ramifications of these physiological changes
during sleep include prolonged clearance of acid from the
oesophagus (regardless of the pH value) and volume of
the refluxate, leading to an increase in time of exposure to
acid from the stomach and elevated migration of acid to
the proximal oesophagus. Two primary mechanisms are
responsible for sleep distur­bances in patients with gastro-
oesophageal reflux disease: conscious awakenings
associated with symp­toms, and short amnestic arousals
that are not associated with symptoms but might still lead
to sleep fragmentation.61 Acid reflux events are more
commonly associated with short rather than long amnestic
arousals, which tend to occur during sleep stage 2 and
rarely also during the REM sleep period.62 In a study
of patients with gastro-oesophageal reflux disease,63
90% experienced at least one conscious awakening during
sleep, and 52% of arousals were associated with acid
reflux events. In addition, only 16% of the conscious
awakenings associated with acid reflux were also
associated with symptoms related to gastro-oesophageal
reflux disease, suggesting that awakenings alone during
sleep could be the sole presentation of gastro-oesophageal
reflux disease.63 In 86% of the awakenings, the awakening
preceded the reflux event. The duration of acid reflux
events that occurred after awakening was considerably
shorter than the duration of acid reflux events that
preceded the awakening. This difference is probably
because during awakening the normal defence
mechanisms against gastro-oesophageal reflux could be
initiated, such as swallowing with subsequent primary
www.thelancet.com/gastrohep Vol 5 June 2020 619
Review
Sleep deficiency
Alters
• Proton pump inhibitors Oesophageal • Ramelteon
• Surgery physiology • Melatonin
Increases
GORD symptoms
Figure: The different therapeutic pathways that can disrupt the vicious cycle between gastro-oesophageal
reflux disease and sleep
GORD=gastro-oesophageal reflux disease.
Panel: Physiological alterations of the upper
gastrointestinal tract during sleep
• Marked decrease in (or absent) salivary secretion and flow
• Decrease in swallowing initiation
• Decrease in primary peristalsis
• Decrease in secondary peristalsis
• Decrease in upper oesophageal sphincter basal pressure
with deeper sleep
• Absent oesophago–upper oesophageal contractile reflex
• Diminished perception of intra-oesophageal stimuli
• Reduced gastric function
peristalsis and delivery of neutralising saliva to the distal
oesophagus. When patients with gastro-oesophageal
reflux disease transition from sleep to awakening in the
morning, this process is associated with a marked increase
in the number of gastro-oesophageal reflux events
immediately after awakening and before consumption of
a meal.64 This event, termed Risers’ reflux, is independent
of body positioning (recumbent or upright) and might
explain patients’ reports of symptoms related to gastro-
oesophageal reflux disease immediately after waking up
in the morning. Most previous studies were unable to
show differences in polysomn­ograms among the different
pheno­types of gastro-oesophageal reflux disease, or before
and after initiating antireflux treatment in patients with
gastro-oesophageal reflux disease. However, a spectral
analysis of sleep showed a shift in the electroencephalogram
power spectrum towards higher frequencies in patients
with heartburn and erosive oesophagitis than in patients
with functional heartburn.65 The higher alpha power and
the lower delta power in patients with erosive oesophagitis
than in patients with functional heartburn might suggest
a specific difference in sleep physiology between two
patient groups with heartburn as their predominant
symptom, with one group having a true gastro-oesophageal
reflux disease phenotype and the other a functional
oesophageal disorder. Overall, studies have shown that
 Review
gastro-oesophageal reflux disease might lead to sleep
disturbances and thus sleep deprivation. However, an
intriguing line of research suggests that sleep deprivation
might exacerbate gastro-oesophageal reflux disease
through two mechanisms: centrally mediated oesophageal
hypersensitivity and an increased degree of oesophageal
acid exposure through an effect of the satiety hormones.66,67
It appears that acute sleep deprivation might lead to
abnormal exposure to oeso­ phageal acid in healthy
individuals, probably through alteration in the relationship
between concentrations of ghrelin (which increases) and
leptin (which decreases), leading to increases in food
cravings and thus food consumption.44
An important mechanism that can lead to sleep
problems, but is frequently overlooked, is silent reflux.68
This clinical situation is encountered in individuals who
do not have typical or atypical manifestations of gastro-
oesophageal reflux disease, but who report sleep
disturbances and poor quality of sleep.69 Gastro-
oesophageal reflux has been shown to trigger these
problems, with sleep disturbances as the sole mani­
festation of gastro-oesophageal reflux disease in a subset
of patients.
The bilateral relationship between gastro-oesophageal
reflux disease and sleep provides an opportunity for
two completely different lines of therapy that can break
the vicious cycle (figure). Obviously, the focus has always
been on improving gastro-oesophageal reflux disease and
thereby restoring healthy sleep. This first-line therapy,
which primarily uses proton pump inhibitors, has been
shown—in many high-quality, randomised controlled
trials—to be efficient at reducing sleep disturbances and
enhancing sleep quality, thus improving quality of life in
patients who have gastro-oesophageal reflux disease with
night-time symptoms.70–73 However, most of the
aforementioned studies assessed only subjective sleep
parameters using patients’ diaries or validated question­
naires. Furthermore, it has been challenging to show
improvement in objective sleep parameters using
polysomnography in trials of proton pump inhibitors,
although polysomnography is not indicated to diagnose
poor sleep quality or insomnia. The beneficial effect of
anti-reflux surgery on sleep quality has also been
suggested in several small studies.74,75 The relationship
between refractory gastro-oesophageal reflux disease and
sleep disturbances, however, has been seldom addressed
in the literature.
A second-line approach is to improve sleep quality,
which might subsequently result in improvement of
symptoms related to gastro-oesophageal reflux disease.
There have been several promising early trials targeting
sleep quality. A study in patients with gastro-oesophageal
reflux disease used zolpidem, a hypnotic drug that is
commonly used as a sleeping pill to induce and maintain
sleep. This study showed that even though the medication
reduced arousals associated with reflux events by more
than 50% compared with placebo, it also resulted in a
620 www.thelancet.com/gastrohep Vol 5 June 2020
significantly longer oesophageal acid clearance time than
placebo.76 In addition, patients can develop dependence on
zolpidem, requiring dose escalation over time. By contrast,
two other studies using different types of compounds to
improve sleep have suggested a beneficial effect on both
sleep and gastro-oesophageal reflux disease. Ramelteon,
which binds selectively to melatonin receptors MT1 and
MT2 in the suprachiasmatic nucleus, has been shown to
significantly improve daytime and night-time symptoms
of gastro-oesophageal reflux disease, sleep efficiency, and
sleep latency in patients with non-erosive reflux disease,
compared with placebo.77 Melatonin, as an adjunct therapy
to anti-reflux treatment or as sole therapy, has been
suggested to improve gastro-oesophageal reflux disease
through its preventive effects against oesophageal mucosal
injury and the progression from Barrett’s oesophagus to
adenocarcinoma of the oesophagus.78 Since improvement
in sleep disturbances related to gastro-oesophageal reflux
disease remains a treatment priority for physicians and
pharmaceutical companies, it is highly plausible that
future therapeutic approaches might require a combination
of anti-reflux and sleep-improving medication.
Sleep and NAFLD
Obstructive sleep apnoea affects 4–24% of men, 2–9% of
women, 3% of children, and up to 35% of the obese
population.79 This condition is characterised by snoring,
excessive daytime sleepiness, poor school and work
performance, and witnessed apnoeas. Moreover, patients
affected by obstructive sleep apnoea can have alterations
in cognitive function, mood disorders, increased hyper­
tension, cardiac disease, and stroke.79,80 Obstructive sleep
apnoea results in repeated episodes of upper airway
collapse, leading to cessation of airflow for 10 s or longer
(apnoea) or decreases in airflow for 10 s or longer.
Furthermore, this condition is associated with arousal
(hypopnoeas) detected on polysomnograms, which are
considered the gold standard for the diagnosis of
obstructive sleep apnoea.81 An apnoea-hypopnea index of
more than 5 is diagnostic of obstructive sleep apnoea
with concurrent symptoms, whereas an index of more
than 15 is diagnostic regardless of associated symptoms.81
There are several shared pathophysiological links
between obstructive sleep apnoea and NAFLD. Cellular
adaptations to hypoxia are dependent on the hypoxia
inducible factor (HIF), a constitutively-expressed trans­
cription factor composed of α and β subunits.82,83 In
normoxia, HIF is hydroxylated, allowing for proteasomal
degradation. However, during sustained or chronic
intermittent hypoxia, HIF is stabilised, translocates to the
nucleus, and exerts its effect as a key transcription
factor.83–85 HIF regulates the expression of multiple genes
that are important for oxygen transportation, angio­
genesis, proliferation, and metabolism, allowing cells to
counteract their hypoxic microenvironment. Findings
from murine models suggest that a dose–response
relationship exists between chronic intermittent hypoxia

and metabolic abnormalities, inducing insulin resistance
and increased systemic lipid concentrations in obese
mice.86,87 Chronic intermittent hypoxia also induces the
expression of lipogenic genes, including SREBP1c and
FASN, with selective inhibition of the HIF-1 pathway,
reducing hepatic triglyceride concentrations in transgenic
mice.88,89 Chronic intermittent hypoxia also induced
systemic and hepatic oxidative stress and lipid peroxidation
in both murine and human studies.82,90–92
Emerging evidence also shows a relationship between
clinical obstructive sleep apnoea and NAFLD. C57BL/6
mice that were fed a high-fat, high-cholesterol diet and
exposed to chronic intermittent hypoxia developed
significant increases in aminotransferases and histological
evidence of hepatic inflammation and fibrosis.90 Several
human studies have also shown an association between
obstructive sleep apnoea and NAFLD, whereby NAFLD
was variably defined by liver enzyme elevation, radiological
findings, and histology. The severity of obstructive sleep
apnoea influences the histological disease severity of
NAFLD, with an odds ratio of 2·68 (95% CI 1·23–5·82) for
severe versus mild-to-moderate obstructive sleep apnoea
for the presence of advanced fibrosis in biopsy-proven
NAFLD.93 Severe obstructive sleep apnoea (defined as an
apnoea-hypopnea index >30) is also related to alanine
aminotransferase, independent of age, sex, diabetes, body-
mass index, and waist circumference.94 In children,
obstructive sleep apnoea was present in 91% of children
with obesity and increased aminotransferase concen­
trations,95 and in 68% of children with biopsy-proven non-
alcoholic steatohepatitis.96 Moreover, in paediatric NAFLD,
amino­transferase elevation and histological severity are
asso­ciated not only with obstruction, but also with the
severity of hypoxia, as measured by the oxygen nadir and
the time spent with oxygen saturations of less than 90%.97
Continuous positive airway pressure (CPAP) is
considered the gold standard for treatment of obstructive
sleep apnoea. Given the association between obstructive
sleep apnoea and NAFLD, there is burgeoning interest in
the application of CPAP to treat NAFLD as well.
Observational studies in adults and children have shown
a significant reduction in aminotransferase concen­
trations after CPAP treatment for 3–12 months.98–100 By
contrast, two small randomised studies of adults, which
used CPAP versus sham CPAP for less than 3 months,
did not find differences in amino­ transferase concen­
trations.101,102 Pooled data from a meta-analysis on the
efficacy of CPAP for improving liver enzyme concen­
trations in patients with obstructive sleep apnoea found
that a decrease in aminotransferase concentrations
required CPAP treatment duration of longer than
3 months.103 These intriguing data clearly suggest the
need for future clinical trials that are well designed and
that focus on CPAP in patients who have NAFLD with
obstructive sleep apnoea. In the meantime, screening
patients with NAFLD for obstructive sleep apnoea seems
a reasonable practice.
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Review
Search strategy and selection criteria
Search criteria were based on existing personal preferences
and citations of articles from PubMed. We did not perform a
systematic review of the literature.
Conclusions
Circadian rhythm pathways play an important role in
gastrointestinal functioning, inflammation, metabolic
regulation, and hormone signalling. Alterations in sleep
quality have an effect on quality of life, either directly—as
shown in gastro-oesophageal reflux disease—and
indirectly, as suggested in patients with IBD and IBS.
Sleep disorders, such as sleep apnoea, have known effects
on blood pressure and executive functioning. Emerging
animal and human research suggests that hypoxaemia
associated with sleep apnoea and alterations in the sleep–
wake cycle could have effects on the pathogenesis and
progression of NAFLD through hypoxia-inducible factors
and circadian effects on liver metabolism.
Therapeutic interventions targeting sleep dysregu­
lation and treatment for sleep apnoea warrant
consideration for further research in patients with
digestive and liver diseases. Further studies are needed
to address the role of sleep alteration and visceral
hypersensitivity in patients with IBS and IBD, as well as
effects of sleep-targeting therapies on short-term and
long-term clinical outcomes. Since sleep disturbance
and circadian misalignment can influence the patho­
genesis and manifestations of disease, assessment of
sleep quality and therapeutic interventions targeting
sleep–wake patterns will probably emerge as important
adjuncts to optimise patient care.
Contributors
AOS developed the manuscript, RF contributed to the figure, and all
authors contributed to the writing and editing of the manuscript.
Declaration of interests
We declare no competing interests.
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