Sleep Medicine xxx (xxxx) xxx

Contents lists available at ScienceDirect

Sleep Medicine
journal homepage: www.elsevier.com/locate/sleep

Review Article

Sleep deprivation and its association with diseases- a review

Siaw Cheok Liew a, *, Thidar Aung b
a
Department of Clinical Competence, Perdana University-Royal College of Surgeons in Ireland, Kuala Lumpur, Malaysia
b
Department of Biochemistry, Perdana University-Royal College of Surgeons in Ireland, Kuala Lumpur, Malaysia

a r t i c l e i n f o a b s t r a c t

Article history: Sleep deprivation, a consequence of multiple health problems or a cause of many major health risks, is a
Received 1 May 2020 significant public health concern in this era. In the recent years, numerous reports have been added to
Received in revised form the literature to provide explanation and to answer previously unanswered questions on this important
8 July 2020
topic but comprehensive updates and reviews in this aspect remain scarce. The present study identified
Accepted 27 July 2020
Available online xxx
135 papers that investigated the association between sleep deprivation and health risks, including car-
diovascular, respiratory, neurological, gastrointestinal, immunology, dermatology, endocrine, and
reproductive health. In this review, we aimed to provide insight into the association between sleep
Keywords:
Sleep deprivation
deprivation and the development of diseases. We reviewed the latest updates available in the literature
Sleep and particular attention was paid to reports that detailed all possible causal relationships involving both
Chronic illness extrinsic and intrinsic factors that may be relevant to this topic. Various mechanisms by which sleep
Diseases deprivation may affect health were presented and discussed, and this review hopes to serve as a platform
for ideas generation for future research.
© 2020 Elsevier B.V. All rights reserved.

1. Introduction 2010 [5]. Sleep deprivation is now a recognised health problem in

The Irish proverb has it that a good laugh and a long sleep are the
best cures in the doctor's book. Sleep is an intricate state in physi-
ology, and we, humans, spend about a third of our lifetime sleeping.
Sleep has two distinctive states, the rapid eye movement (REM) and
non-rapid eye movement (NREM) [1]. Interestingly, to date, the
reasons why we need two states of sleep remain much debatable.
The National Institutes of Health recommends that, on average,
in a day, pre-school children require 10e12 h of sleep, 9 h for
schooling children and teenagers, and 7e8 h for adults [2]. During
sleep, there are numerous changes to the body concerning its
biological and physiological functions. The regulation of blood
pressure, heart rate, hormonal secretion, and immune defence
functions, cellular repair, temperature control, restoration of
memory capacity, and cognition, all happen during sleep [3,4].
Schoenborn & Adams reported that people sleep less now
compared to those in the past. Adults in the early 20th century
sleep on average about nine hours a day and those in the 1980s,
seven hours a day. On average, 3 in 10 adults sleep less than 7 h in
* Corresponding author. Department of Clinical Competence, Perdana University-
Royal College of Surgeons in Ireland, Block D, Level 1, MAEPS Building, MARDI
Complex, Jalan MAEPS Perdana, 43400, Serdang, Malaysia. Fax: þ603 8941 7661.
E-mail address: ctinalsc@hotmail.com (S.C. Liew).
this modern era. The prevalence of sleep deprivation, causing
excessive daytime sleepiness, is between 9% - 24%, and sleep
deprivation is one of the major causes for visits to the sleep clinics
[6,7].
We could be sleep deprived because of multiple factors. Lifestyle
factors such as shift work, stress, and the use of media and elec-
tronic devices before sleep have been reported to contribute to the
physiological alteration of melatonin secretion, which leads to
sleep deprivation [8,9]. The ageing process also disrupts the phys-
iology of sleep and reduces the total sleep time [10]. Patients with
sleep disorders such as insomnia, restless leg syndrome (RLS), pe-
riodic limb movements (PLM), and sleep breathing disorders (SBD)
are likely to suffer from sleep deprivation [11e16].
Long term sleep deprivation leads to the development of
physiological and neurobehavioral problems [17]. Major road traffic
accidents and occupational-related accidents and errors are some
examples of adverse events related to sleep deprivation [2]. The
consequences of sleep deprivation are immense. The development
of multiple health risks associated with sleep deprivation leads to a
reduction in one's quality of life and increases mortality [18]. Given
the pivotal role that healthy normal sleep plays in health, studies in
the area of sleep deprivation have surmounted in the past few
decades.
Numerous publications on sleep-related conditions have added
new information and explanation to the previously unanswered

https://doi.org/10.1016/j.sleep.2020.07.048
1389-9457/© 2020 Elsevier B.V. All rights reserved.

Please cite this article as: Liew SC, Aung T, Sleep deprivation and its association with diseases- a review, Sleep Medicine, https://doi.org/10.1016/
j.sleep.2020.07.048
2 S.C. Liew, T. Aung / Sleep Medicine xxx (xxxx) xxx
questions on this topic. Previous epidemiological and experimental
studies have reported the association of sleep deprivation and
diseases, albeit studies in some areas in this topic yielded incon-
clusive and inconsistencies in findings. It is timely that an updated
review is carried out now to look at updates currently available on
the association between sleep deprivation and its effect on health.
The focus of this study is to review the updated publications
available on the association between sleep deprivation and the
development of diseases and aimed to fill in the gap of knowledge
in this aspect. We also discussed the cascading factors that are
involved in the determination of these associations. We hope that
the results of this review could help to better inform various
stakeholders on the updates on this topic and provide a platform
for discussion on future research.
We will first review the most updated research articles and
experimental studies on each primary organ system that is affected
by sleep deprivation. Next, we will look into the limitations of these
studies. Finally, we will outline the future potential research focus
area in this aspect, offering recommendations to close the gap of
knowledge and merging the most valued expertise opinions that
are currently available.
1.1. Literature search and inclusion criteria
The literature search was performed using the PubMed data-
bases, Embase, Web of Science, and the Cochrane Library. A variety
of search terms were used (for example, sleep deprivation and
diseases, sleep deprivation and cardiovascular disease). Articles
suitable for this review were also searched from the reference lists
of these published papers. The articles included in this review are
original articles and relevant reviews that were published in En-
glish from January 2014 till March 2020. Articles are inclusive of all
studies that reported the experimental findings and reviews on
sleep deprivation and diseases. For the latest updates on the sys-
tematic reviews, a literature search from the Cochrane Database of
Systematic Reviews and Cochrane Central Register of Controlled
Trials (CENTRAL) was performed. The search terms were sleep
deprivation AND diseases, *Sleep Deprivation and inflammatory
diseases, *Sleep Deprivation and metabolic diseases, * Sleep
deprivation and gastrointestinal diseases, *Sleep deprivation and
cardiovascular diseases.
Suitable articles which contain only abstract publication, theses
and dissertation but were unpublished, articles which were pub-
lished in a language other than English and suitable articles not
within the time frame specified for this study were excluded from
this review.
We reviewed a total of 145 articles. Of these, 25 are related to
cardiovascular diseases, six are related to respiratory disease, 43 are
related to neurological diseases, 10 are related to gastrointestinal,
14 are related to immunological diseases, five are related to
dermatology and musculoskeletal diseases, 22 are related to
endocrine diseases, six are related to nephrology and urology, two
are related to reproduction and two are related to stress.
2. Sleep deprivation and cardiovascular disorders
The Framingham Heart Study in 2008 started the use of the
concept termed “Heart Age”. Heart Age is a concept, which is
believed to be the simplest way to communicate the risk of car-
diovascular disease to the public. Heart Age is the age-predicted for
a person's heart or vascular system, accounting for the person-
specific overall cardiovascular risk profile. Excess Heart Age (EHA)
is defined as the difference between Heart Age (predicted heart age
based on the individual cardiovascular risk profile) and the actual
biological age of the individual. The lowest EHA was observed in
Please cite this article as: Liew SC, Aung T, Sleep deprivation and its association with diseases- a review, Sleep Medicine, https://doi.org/10.1016/
j.sleep.2020.07.048
adults that sleep 7 h per night. Sleep duration of less than or more
than 7 h was seen to be associated with an increased EHA [19].
Sleep deprivation, therefore, has an unfavourable effect on the
cardiovascular system, and the repercussions are enormous. In this
section of the review, we explored the relationship between sleep
deprivation and cardiovascular functions.
2.1. Autonomic nervous system
One of the functions of sleep is in the regulation of the auto-
nomic nervous system. The autonomic nervous system plays a vital
role in the physiological regulation process of cardiovascular
functions. The suprachiasmatic nucleus works to regulate rest and
wakefulness and is maintained through the autonomic nervous
system. The system relies heavily on external cues such as sleep,
daylight exposure, daytime activities, and food intake to function.
These cues are blunted by sleep deprivation, resulting in an
elevated sympathetic nervous system activity.
Sleep deprivation results in impaired autonomic function, which
leads to cardiovascular problems [20]. Heart Rate Recovery (HRR) is
the return of heart rate after exercise. HRR represents the function
of autonomic regulation, and its impairment is proposed as a
prognostic indicator of increased cardiovascular mortality. Cincin
et al. investigated the HRR on healthy individuals who had a good
night sleep and after a night of sleep deprivation. These healthy
individuals were subjected to a treadmill exercise test. The study
demonstrated that acute sleep deprivation is associated with a
reduction of HRR and was associated with the impairment in the
autonomic regulation of heart rate in healthy individuals [21].
The autonomic nervous system regulates blood pressure. A
reduction of about 10e20% of blood pressure reading is usually
seen during sleep. In sleep deprivation, the occurrence of blood
pressure dipping is loss at night, resulting in a higher nocturnal
systolic blood pressure. Matthews et al. reported that suboptimal
sleep is associated with hypertension and diabetes in the Native
Hawaiian/Pacific Islanders (NHPI), Blacks, and Whites residents of
the United States [22]. A study by Kuetting et al. found that in shift
workers and medical practitioners who have periods of sleep
deprivation, this has led to a significant increase in blood pressure
reading and other cardiovascular parameters such as heart rate and
contractility, and stress hormone secretion [23].
Studies on the association between the impact of sleep depri-
vation on autonomic nervous system yielded contradictory and
inconclusive findings. While several studies reported the associa-
tion between sleep deprivation and increased in heart rate and
blood pressure, many other studies reported the lowering effect of
heart rate and no changes to the parasympathetic activity. A recent
study by Stomko et al. found a reduction in the systolic and diastolic
blood pressure readings of sleep-deprived pre-hypertensive and
hypertensive individuals in the study. The same study also reported
that parameters such as the duration of sleep deprivation and
baseline blood pressure readings could determine the hemody-
namic changes to blood pressure during sleep deprivation [24,25].
The disorder of the autonomic nervous system following sleep
deprivation has been reported to play a crucial role in the devel-
opment of cardiac arrhythmias. Heart rate variability (HRV) is a
regulator for cardiac autonomic control and has shown a significant
reduction in activity after a period of sleep deprivation. Statin
functions to regulate the autonomic nervous system and has anti-
inflammatory properties. In a study by Chen et al. participants
were administered statin 48 h before sleep deprivation, and the
effects on HRV and cardiac arrhythmia were investigated. This
study suggested that the use of a lipid-lowering drug, statin, in
healthy sleep-deprived individuals could improve arrhythmia. The
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authors cautioned that findings in this study should be replicated
by other extensive studies in this aspect to test its true validity [26].
2.2. Glucose and lipid metabolism
The risk of cardiovascular disease is increased with the disrup-
tion of blood pressure and salt regulation, fluid homeostasis,
glucose metabolism, and an increase in stress hormone secretion
[27e34]. Sleep deficiency does not only lead to problems with the
regulation of blood pressure and heart rate, but it also disrupts
glucose and lipid metabolism. Prolonged disturbed sleep leads to
glucose intolerance, insulin insensitivity and resistance thus in-
creases the susceptibility to type 2 diabetes. In sleep deprivation,
leptin, a hormone that controls satiety is suppressed, and ghrelin, a
hormone that increases appetite is stimulated. These responses, if
prolonged, would lead to weight gain.
A review by Cappuccio et al. concluded that the development of
risk factors for cardiovascular diseases such as diabetes, hyperten-
sion, heart disease, stroke, might be a result of sleep deprivation.
These poor health outcomes are risk factors for premature death
[35]. A report by Deng et al. supported the finding by Cappuccio
et al. Deng et al. also reported the association between sleep
deprivation and a significant increase in central obesity and
metabolic syndrome, a higher level of fasting glucose, blood pres-
sure, and triglycerides and a reduction in the level of high-density
lipoprotein-cholesterol [36]. A retrospective, longitudinal study
reported that individuals with sleep duration of less than 6 h a
night had a higher non-fatal cardiovascular events and was asso-
ciated with obesity [37].
There are contradictory reports on the effect of longer sleep
hours on cardiovascular risks in the literature. Deng et al. reported
that in participants with longer sleep duration, there was an as-
sociation with a lower prevalence of hypertriglyceridemia and
metabolic syndrome [36]. On the contrary, a review by Jike et al.
reported an interesting finding whereby a long sleep duration is
associated with adverse cardiovascular health outcomes and
increased mortality [38].
2.3. Atherosclerosis and ischaemia
Chronic sleep deprivation has been reported to be associated
with the development of atherosclerotic condition. The dysfunc-
tional vascular endothelial was reported to be one of the critical
pathological processes that contributed to the disease development
[39,40]. Bain et al. reported that short sleep duration is associated
with cardiovascular diseases as a result of impaired NO-mediated
endothelium vasodilation [41]. Nitric oxide (NO) is a vasodilator
which effectively acts as an antioxidant and has both anti-
atherogenic and anti-inflammatory functions. It also regulates the
uptake of glucose and modulates insulin sensitivity. Chronic sleep
loss has been reported to be correlated to dysfunctional NO-
mediated endothelium-dependent vasodilation which was
observed to have contributed to multiple adverse cardiovascular
risk factors and diseases such as diabetes, hypertension, and stroke.
Similarly, Jiang et al. in a laboratory study, investigated the
mechanism and effects of rapid eye movement (REM) sleep
deprivation on endothelial dysfunction and blood pressure of
middle-aged rats. The study concluded that sleep deprivation could
induce endothelial dysfunction and hypertension. The pathological
changes seen were reported to be inhibited by the supplementation
of L-arginine. The results demonstrated that with supplementation
of L-arginine, there was a reduction in blood pressure, augmenta-
tion of the NO level in the aorta and increased vasodilation [42].
Another contributory factor to atherosclerosis is the prolonged
build-up of arterial wall lipid plaques, and inflammatory responses
Please cite this article as: Liew SC, Aung T, Sleep deprivation and its association with diseases- a review, Sleep Medicine, https://doi.org/10.1016/
j.sleep.2020.07.048
3
have been proposed to augment its pathogenesis. A report by Aho
et al. documented that prolonged sleep deprivation is known to
activate immune responses, and this process is contributory to the
development of atherosclerosis [43]. A study by Sauvet et al. tried to
determine whether seven weeks of exercise would be able to limit
cardiovascular dysfunction in young men caused by total sleep
deprivation. The study reported that exercise training, especially
the combination of moderate to high intensity training, is associ-
ated with an improvement in vascular dysfunction caused by sleep
deprivation. This study also reported that exercises are associated
with the reduction in the inflammatory responses that were
induced in sleep deprivation [44].
Cardiac ischaemic event is one of the leading comorbidity
worldwide. Ischaemic changes were reported to be associated and
more pronounced in women with sleep deprivation of less than 5 h
[45]. A similar phenomenon was observed in an experimental
laboratory study by Jeddin et al. It was reported that there was an
alteration to the function of the hearts of these experimental rats in
this study. Rats that were subjected to sleep deprivation showed a
significant increase in heart rate and weak haemodynamic recovery
after an ischaemic event [46].
3. Sleep deprivation and respiratory disorders
3.1. Sleep deprivation and alteration to respiratory physiology
It is well-reported that sleep affects breathing. The control of the
central respiratory system, airway resistance and muscular
contractility differs during sleep and the state wakefulness [47].
There are limited studies in the literature that explored the effects
of sleep deprivation on the respiratory system. Previous studies are
primarily focussed on the effect of respiratory disorders on sleep
deprivation. The relationship between sleep deprivation and res-
piratory disorders is like a vicious cycle, commonly observed as a
cause-and-effect phenomenon, where respiratory conditions lead
to sleep loss and sleep loss further augments the respiratory
conditions.
Cardiorespiratory coupling (CC) describes the influence of
respiration on heart rate and blood pressure, a correlative rela-
tionship between the autonomic and respiratory physiological
systems [48]. A study that analysed CC and explored the relation-
ship between respiratory oscillations and cardiac cycle suggested
that CC was not influenced by moderate sleep loss [49]. Interest-
ingly, there are reports in the literature that documented the as-
sociation between sleep apnoea in those who work in professions
that are prone to sleep deprivation such as shift workers [50e52].
Rault et al. documented that in healthy adults that were sub-
jected to one-night of sleep deprivation, a reduction in the respi-
ratory motor output was observed. This observation was postulated
to be a result of the altered cortical command for respiration and a
significant reduction in inspiration endurance [53]. The respiratory
motor output induces the phrenic motor neurons that trigger the
activation of diaphragm and accessory muscles of breathing. It was
found that in increased respiratory load, additionally, the premotor
cortex was activated. This led to an increased in inspiratory muscle
activation. Task failure sets in when inspiratory effort could not
overcome the demand of inspiratory load. In task failure, there
could be a reduction in respiratory motor output, a reduction in
inspiratory muscles contractility or both. In this study by Rault et al.
healthy participants were asked to breathe as long as possible until
task failure was achieved. It was found that in sleep-deprived
participants, time to task failure was shorter than typical
participants.
4 S.C. Liew, T. Aung / Sleep Medicine xxx (xxxx) xxx
3.2. Sleep deprivation and inflammatory airway conditions
A review conducted on circadian based inflammatory responses
and implications on respiratory diseases concluded that immune
responses were more robust in late second phase of the night and
early hours in the morning. The heightened disease severity and
augmented inflammatory responses in obstructive airway diseases
and allergic rhinitis were demonstrated to be higher during these
hours. The level of pro-inflammatory and anti-inflammatory cyto-
kines were elevated during rest time and activity time, respectively.
This review has indicated that the circadian rhythm is associated
with the modulation of immune cell production, release, and in
gene expression in cells. Circadian disruption is associated with the
dysregulation of immune responses which can ultimately disrupt
the circadian rhythms [54].
Asthma is a Th2 mediated intermittent airway hyper-
responsiveness with increased IgE levels. Sleep deprivation has
been reported to alter the modulation of Th1 and Th2 and has been
previously reported to augment neutrophilic responses. Filho et al.
conducted an experimental study to test the hypothesis which
suggest that sleep deprivation could induce neutrophilic-driven
asthma in already allergic prone individuals. Mice with sleep
deprivation were found to have a higher incidence of severe airway
inflammation than those with normal sleep. A higher level of
neutrophils was also found in the sleep-deprived group of mice
[55].
4. Sleep deprivation and neurological disorders
4.1. Memory, cognition, and behavioural changes
4.1.1. Memory decline in sleep deprivation
Sleep deprivation is associated with the reduction in cognitive
function and caused memory decline [56]. It was suggested that the
disruption of the intracellular cyclic adenosine monophosphate
(cAMP)-protein kinase A (PKA) signalling is associated with mem-
ory impairment and neuronal plasticity in the hippocampus.
Disruption to the cAMP-PKA signalling is correlated to the changes
in cAMP response element-binding protein (CREB)-mediated gene
transcription. Similarly, this disruption is associated with the al-
terations of neurotrophic signalling process and the expression of
the glutamate receptor, which cascaded the down-regulation of cell
turnover and neurogenesis in the hippocampus. Chronically, this
process was observed to be associated with cognitive decline and
psychiatric illnesses [57].
The cognitive control of attention, emotion regulation and
working memory are all part of a set of basic psychologic processes
called Executive Functions (EFs). A Cochrane systematic review and
exploratory meta-analysis performed on the association between
EFs and insomnia has identified that insomnia exerts a negative
impact on EFs, especially on the aspect of working memory [58]. It
is fascinating to find that caffeine and modafinil have been put
forward as beneficial treatment options in the maintenance of
recognition memory in sleep deprivation. Caffeine was observed to
prevent the down-regulation of synaptophysin and synapsin I
proteins in sleep deprivation, whereas modafinil reduced the
down-regulation of both the synaptophysin and synapsin I protein
and also the PSD-95 proteins in the hippocampus [59].
Melatonin (N-acetyl-5-methoxytryptamine) is found in almost
all living things, and in human, melatonin is released from the pi-
neal gland. Melatonin is suppressed during the day (light phase)
and activated during the night (dark phase) of the day. Melatonin
has a neuroprotective role. Melatonin acts as an antioxidant to help
reduce the emergence of free radicals and it augments the meta-
bolism of reactive oxygen species. There are reports that
Please cite this article as: Liew SC, Aung T, Sleep deprivation and its association with diseases- a review, Sleep Medicine, https://doi.org/10.1016/
j.sleep.2020.07.048
documented the association between memory impairment sec-
ondary to sleep deprivation and the accumulation of oxidative
stress. In an experimental study on mice, melatonin treatment was
documented to improve memory impairment secondary to sleep
deprivation [56].
In experimental animal studies, numerous reports have recor-
ded the pathological effects of sleep deprivation on memory. The
likely mechanism for the adverse effects that sleep deprivation
have on memory is not fully understood, but the alteration on
neurotransmission systems is seen as a possible explanation.
Emotional memory is regulated by Gastrin Releasing Peptide (GRP),
a neuropeptide which is a memory regulator through the neuro-
transmission system. In a recent animal study conducted on Wistar
rats, it was reported that memory impairment caused by sleep loss
was not improved by intraperitoneal (IP) administration of bomb-
esin, a gastrin-releasing peptide (GRP) agonist [60]. In another
experimental study on adult rats, it has been shown that sleep
deprivation of more than 6 h induced alterations in neuronal ac-
tivity in a few areas of the brain, namely the lateral hypothalamus,
the paraventricular nucleus, the arcuate nucleus, and the
mammillary bodies. Adverse effects of sleep deprivation could be
seen to last up to 48 h [61].
Sleep deprivation is also known to induce low-grade neuro-
inflammation. In an experimental study on sleep-deprived Wistar
rats, it tested the hypothesis that chronic sleep deprivation would
induce memory impairment due to neuroinflammation. This study
concluded that chronic sleep deprivation caused an increase in pro-
inflammatory cytokines. The brains of these sacrificed rats that
were subjected to molecular studies have also shown evidence of a
low-grade neuroinflammation. These rats, on observation, showed
a higher anxiogenic behaviour and memory impairment compared
to the controls. The findings of this study provided some insight
into the role of cytokines, astrocytes and microglial cells in the
pathogenesis of neuroinflammation in chronic sleep deprivation
[62].
4.1.2. Cognitive decline in sleep deprivation
Sleep deprivation hampers one's ability to respond to external
stimuli promptly. The reduction in responses are attributed to poor
vigilant attention; a feature believed to be a part of the processes in
cognition. In a study by Zhang et al. the psychomotor vigilance test
(PVT) was used to examine vigilant attention and cognitive insta-
bility in sleep deprivation. A satisfactory PVT depends on sustained
vigilant attention and a robust functioning of the motor systems. In
this study, it was reported that sleep deprivation was correlated to
the disruption of the cerebellar functions and the impairment of
psychomotor vigilance. Individuals with reduced psychomotor
vigilance and cognitive instability have difficulty in maintaining
task performance on a daily basis [63]. In an in vivo study on rats,
sleep deprivation caused a decreased in neuronal excitability. The
reduction in neuronal excitability was postulated to be the cause
that leads to functional deterioration in daily activities [64].
Cognitive instability could be seen in some conditions such as
dementia, ageing, Attention Deficit Hyperactivity Disorders (ADHD)
and similarly, has been reported in those with sleep deprivation.
The effect of sleep deprivation on cognitive inability is seen as a
series of lapses in performance and not as a total impairment in
task performance. Previous studies have demonstrated that
cognitive instability is a result of lapses in the integrity of structural
brain function, in particular, the white matter. The recent study by
Zhu et al. suggested that white matter differences in every indi-
vidual is correlated to the differences in PVT seen with cognitive
instability in sleep deprivation [65].
Hilaire et al. investigated the impact of chronic variable sleep
deficiency (CVSD) on overall sleepiness and neurocognitive
 S.C. Liew, T. Aung / Sleep Medicine xxx (xxxx) xxx
performance in healthy male adults. The CVSD model, which is
sleep deprivation interspersed with a period of recovery, is believed
to be more realistic a representation of experiences of sleep in the
general population. In this experimental study, participants were
given a baseline of sleep opportunity for 10 h with a subsequent
three cycles of two opportunities of a 3- hour sleep each, followed
by a final one 10-hour sleep opportunity. It was found that there
was a gradual decline in the participants' neuro-behavioural per-
formance after each cycle. Some recoveries were seen following
each extended sleep opportunity in each cycle. This study
concluded that although there were some signs of performance
recovery seen following a period of adequate sleep, subsequent
sleep deprivation escalated a manifestation of deterioration of
cognitive function [66].
During sleep, there is an increase in the volume of interstitial
space and that allows higher glymphatic system clearance of waste
generated in the brain. Dysfunctional glymphatic pathway due to
sleep deprivation results in the inadequate clearance of the waste
from the brain and the accumulation of harmful by-products such
as amyloid plaque deposition, leading to cognitive impairment.
Recent studies have found that continuous theta-burst stimulation
(cTBS) which is a form of repetitive transcranial magnetic stimu-
lation (rTMS) could aid in eliciting quality sleep and help to mini-
mise emotional and cognitive impairment secondary to sleep
deprivation. Liu et al. conducted an experimental animal study
which looked at the effect of cTBS on the glymphatic system and
explored the mechanism of action that cTBS has on cognition in
sleep-deprived experimental animals. The study reported that cTBS
induced a higher than usual waste clearance in sleep-deprived
mice. The study concluded a protective element of cTBS against
neuronal dysfunction induced by sleep deprivation [67].
The prevalence of sleep deprivation is high in university stu-
dents. About 71% of university students were found to acquire less
than 8 h of sleep daily. Despite the high prevalence of sleep
deprivation in university students, limited studies could be found
that focussed on this group of individuals. There are reports that
documented the association between sleep deprivation and
reduced cognitive performance in university students. A meta-
analysis by Ma et al. concluded that sleep deprivation is associ-
ated with a reduction of brain activity [68]. Patrick et al. recently
conducted a study to investigate the effect of a night of sleep
deprivation on both motor and cognitive functions on university
students. Interestingly, this study found that the impact of sleep
deprivation was more significant on the physical function and not
the cognitive ability of these university students [69].
4.1.3. Behavioural changes in sleep deprivation
Sleep deprivation is often seen to be associated with neuro-
behavioural and neurodevelopmental problems, a common finding,
especially in children and adolescents. Neurobehavioural issues
that are of great concern in children include aggressive behaviour,
hyperactivity, emotional lability, and socialisation problem. Chil-
dren and adolescents are getting less sleep in this era, owing to the
increasing burden of academic work, enhanced use of technology
and the unlimited entertainment and social pursuits. A cross-
sectional study that was conducted in the Icelandic adolescents
reported that, despite an increment in total sleep time during non-
school days in these adolescents, a majority still did not achieve the
recommended sleep hours [70]. A study conducted in a sleep clinic
in Japan provided data that demonstrated a high prevalence of
insufficient sleep syndrome in patients aged 20 and below [71].
Sare et al. hypothesised that sleep deprivation, especially in
children, could lead to the alterations in plasticity, which has a
long-lasting impact on behaviour. Sleep plays a crucial role in brain
development and in synaptic plasticity. The cellular functions of
Please cite this article as: Liew SC, Aung T, Sleep deprivation and its association with diseases- a review, Sleep Medicine, https://doi.org/10.1016/
j.sleep.2020.07.048
5
plasticity such as myelination, protein synthesis, cellular detoxifi-
cation and synapse formation are disrupted in sleep deprivation. In
an experimental laboratory study, Sare et al. investigated the effect
of sleep deprivation on the behaviour of mice. The study demon-
strated that sleep deprivation was found to cause social and
behavioural abnormalities in mice, with male gender predisposi-
tion to poor recovery, post-sleep recovery [72]. A review on this
topic revealed that some studies have shown that the recovery
period for the adverse effects caused by acute sleep deprivation was
a two complete night sleep. Similarly, some other studies have
shown that sleep deprivation may cause long-term unwanted
adverse effects [73].
Sleep deprivation is known to be associated with emotional
instability and reduce inhibition. Previous studies have shown that
individuals do display aggressive behaviour and impulsivity with
sleep loss, especially aggression following provocation. MacDonald
et al. explored the behavioural and sex hormones changes in adult
men and women post sleep deprivation. The pattern of sleep loss
designed for this experiment was tailored to mimic real-life expe-
riences. The aggressive behaviour post sleep deprivation was seen
with the different phases of the menstrual cycle in women. The
follicular phase has seen a higher incidence of reactive aggression
in sleep-deprived women. The control group showed a higher
aggressive behaviour in the luteal phase. This study also docu-
mented a reduction in reactive aggression in men with mild sleep
deprivation when compared to those with normal sleep [74].
4.2. Alzheimer's disease
Chronic sleep deprivation is a reported risk factor for Alz-
heimer's Disease (AD). In an experimental study on mice by Zhao
et al. the results indicated that mice with sleep deprivation
demonstrated alteration to the amyloid-b (Ab) protein precursor
processing. Chronic sleep deprivation was also seen to be a cause in
the increasing cortical Ab plaque deposition and the acceleration in
the pathogenesis of AD in wild-type mice [75]. An interesting study
on fruit flies yielded similar results, suggesting that sleep loss and
the increase in Ab were shown to cause neural excitability, which in
turn, led to further Ab accumulation [76]. Similarly, another study
by Qiu et al. concluded the presence of senile plaques and an
increased in amyloid-b (Ab 1e42) level in the brains of the
experimented sleep-deprived mice. The study also reported that
the phosphorylated tau protein level was found to be elevated in
these mice. Consequently, observational impaired cognitive per-
formance was seen in the experimented mice [77].
Tau accumulation drives the neurodegeneration process in AD.
The intracellular fluid (ISF) and cerebrospinal fluid (CSF) tau level
were reported to be higher in sleep deprivation [78]. In another
experiment by Di Meco et al., sleep-deprived mice showed a sig-
nificant reduction in their memory and cognitive ability. These
mice also showed a reduction in the phosphorylation of tau, which
led to the increase of the insoluble form. In addition, this study
reported a reduction of the postsynaptic density protein 95 and an
elevated level of glial fibrillary acidic protein in the experimented
mice [79].
Shokri-Kojori et al. found that sleep deprivation reduced the
brain clearance of Ab and resulted in its accumulation, even after
just a night of reduced sleep [80]. Similar findings were reported by
Yulug et al. [81]. Chen et al. reported that the modulation of the b-
amyloid (Ab)-related metabolism accelerated the progression of
AD, as seen in the increase in expression of Ab1-42 and Ab1-40 [82].
The results by Chen et al. were supported by a research done by Wei
et al. which concluded that sleep deprivation increased the plasma
Ab40 levels and a reduction of the Ab42/Ab40 ratio [83]. A rando-
mised controlled trial conducted by Ooms et al. concluded that
6 S.C. Liew, T. Aung / Sleep Medicine xxx (xxxx) xxx
sleep deprivation resulted in an increased in the morning level of
Ab42, which could potentially escalate the risk of AD [84]. In
another study that investigated the role of amyloid-b oligomers
(AbOs), toxins and its contributory role in memory impairment in
AD, the results showed that sleep deprivation posed a higher brain
vulnerability to AbOs [85].
Polymerisation of soluble extra-cellular amyloid-beta (eAb) into
its insoluble form, the amyloid fibrils, is linked to the pathogenesis
of AD. During sleep, the (eAb) is removed twice as much by the
glymphatic system, in which interstitial fluid is also drained from
the brain. Melatonin, a peptide hormone, significantly elevated
during sleep, functions to inhibit the polymerisation of eAb [86].
Melatonin (N-acetyl-5-methoxytryptamine) is an antioxidant
which is produced in the pineal gland and other organs. In sleep-
deprived rats, melatonin was also demonstrated to offer anti-
oxidative and protective effects. A higher level of 4-
hydroxynonenal (4-HNE) and 7,8-dihydro-8-oxo-deoxyguanine
(8-oxo-dG), both known as the markers of oxidative stress, were
observed in sleep-deprived rats. The level of these markers were
normalised with melatonin treatment [87].
Increased in the phagocytic functions of brain cells can lead to
neurodegeneration which is a risk for developing AD. Bellesi et al.
demonstrated in an experimental study that astrocytes in brains of
mice which were kept under various condition of sleep deprivation
yielded increased phagocytic activity. In this study, microglial
phagocytosis was solely identified in chronic sleep loss. A pro-
longed state of microglial activation secondary to sleep deprivation
is harmful to the function of the brain. The Mertk and crk were the
astrocytic genes associated with phagocytosis and were found to be
raised in sleep deprivation [88,89].
4.3. Stroke and global cerebral ischaemia/reperfusion
Stroke is a major cause for disability, and it increases the
morbidity and mortality rate in adults. The primary known risk
factors for stroke are hypertension, diabetes, hyper-
cholesterolaemia, atrial fibrillation, smoking, and transient
ischaemic attack. Sleep deprivation has been reported to be asso-
ciated with stroke. A review by Patyar and Patyar suggested the
association between sleep duration and the risk of developing
health problems such as diabetes and hypertension, which are in-
dependent risk factors for stroke. The review concluded that there
was a significant correlation between shortened and longer sleep
duration with the risk of acquiring a stroke. The review also re-
ported that sleep deprivation augments the pro-inflammatory
cytokine responses that heightened neuroinflammation and
impair the recovery from ischaemia [90]. In an experimental study
that investigated the effects of sleep deprivation on mortality in
mice with permanent cerebral hypoperfusion, it was reported that
poor prognosis was seen in those with sleep deprivation after a
cerebrovascular event [91]. Interestingly, similar to the report
documented by Patyar and Patyar, a prospective research and meta-
analysis by Leng et al. reported that a persistent, extended period of
sleep is associated with a doubled risk of stroke compared to those
with a persistent average sleep duration [92].
Global cerebral ischemia/reperfusion is a syndrome that
occurred after a sudden, rapid loss of cerebral blood flow in patients
who suffer from a cardiac arrest or a haemodynamic shock.
Neuronal death is the pathological hallmark of this syndrome and it
leads to multiple repercussions such as memory impairment and
learning difficulties. Previous experimental studies on ischaemic
mice have demonstrated that brain-derived neurotrophic factor
(BDNF) could promote neurogenesis in these mice, thereby
improve cognitive function. In a current study by Chen et al. it was
reported that the hippocampal BDNF level was increased in the
Please cite this article as: Liew SC, Aung T, Sleep deprivation and its association with diseases- a review, Sleep Medicine, https://doi.org/10.1016/
j.sleep.2020.07.048
short term sleep-deprived global ischaemic rats, and this promoted
neurogenesis [93].
4.4. Neurotransmitters and neuromodulators in sleep deprivation
Our current knowledge on the mechanism regarding the
neurological interplay in sleep deprivation is still limited. In the
literature, there are numerous studies conducted on this topic but
research outcomes have yielded contradictory and inconclusive
findings. The complexity of network surrounding sleep physiology
and the involvement of multiple neurotransmitters and neuro-
modulators in its course, pose a great challenge and inflict much
difficulty in the designing of a research to answer the multiple
queries that are at hand on this aspect. In this segment, we explored
some updates available in the literature on neurotransmitters and
neuromodulators that are linked to sleep deprivation.
Orexin is a neurotransmitter, found abundantly in the peri-
fornical area of the brain, and is activated during wakefulness.
During rapid eye movement (REM) and non-rapid eye movement
(NREM) sleep stages, the orexin-A (Orx-A) neurotransmitters/Orx-
ergic neurons are inactivated. Mehta et al. reported that in sleep
deprivation, there was a significant increase in the level of Orx-A
level in the brain, especially in locus coeruleus (LC), cortex, and
posterior hypothalamus (PH). Levels were seen to normalise after
adequate sleep was restored. The fluctuating level of these neuro-
transmitters at these regions of the brain during the different
phases of sleep was postulated to be responsible for the changes in
general health [94]. A randomised controlled trial by Olsson re-
ported that unlike in animal study, it was found that in human,
short term sleep deprivation caused an increase in cerebrospinal
fluid (CSF) orexin level with no other remarkable biomarkers
findings in the CSF [95].
Monoaminergic pathways have been reported to be linked to
the modulation of the sleep-wake pattern. The monoamine level
changes with circadian rhythm and in different stages of sleep with
the highest level seen in wakefulness and reduces in slow-wave
sleep and lowest in rapid eye movement stage. The review by
Menon et al. concluded that although monoamines are believed to
aid wakefulness, interestingly, the highest level of monoamine in
this study was found during the active dark phase of sleep rather
than during the inactive light phase of wakefulness. It was also
reported that the level of monoamine which fluctuates throughout
the normal sleep stages, was disrupted in sleep deprivation. This
phenomenon was also postulated to be hazardous to general well-
being [96].
Adenosine is known to regulate sleep and noradrenaline for
wakefulness. Adenosine is the inhibitory neuromodulator that
promotes sleepiness, especially in prolonged sleep loss. The accu-
mulation of adenosine in the basal forebrain inhibited the neurons
in this part of the brain and its associated areas in the cortex.
Noradrenaline neurons are neuromodulator that promotes wake-
fulness., especially the locus coeruleus noradrenaline. The activity
of this noradrenaline is most abundant during the awake state,
reduces during the non-rapid eye movement state and diminishes
at rapid eye movement stage of sleep. In an experiment on a sleep-
deprived rat model, it was reported that changes to the adenosine
and noradenosine receptors, which were predicted to be a long
term phenomenon, were observed in chronic sleep deprivation.
The changes to these receptors were seen to contribute to cognitive
impairments observed in sleep deprivation [97].
5. Sleep deprivation and gastrointestinal disorders
Sleep deprivation induces the pro-inflammatory markers. The
higher level of cytokines was reported to be associated with some
 S.C. Liew, T. Aung / Sleep Medicine xxx (xxxx) xxx
of the gastrointestinal diseases [98]. The reduction in melatonin
levels in sleep-deprived mice caused an elevated level of pro-
inflammatory cytokines and the reduction of anti-inflammatory
cytokines, which led to colonic mucosal injury [99]. Polidarova
et al. reported that the disturbance to the circadian system and
sleep deprivation induced the pro-inflammatory responses in the
colonic mucosa [100]. Similarly, it was reported in a study by Carra
et al. that the reduction of immunity and the induction of systemic
inflammation were the risks of gingival inflammation. These
physiological processes were seen to be associated with the degree
of seriousness of the periodontal disease seen in patients with sleep
deprivation [101,102].
The research in the area of sleep deprivation and the integrity of
the gastrointestinal barrier is scarce. REM sleep deprivation was
previously reported to cause an alteration of the innate immune
response. A recent study reported that sleep deprivation caused an
acute inflammatory response in the gastric mucosa. Ibarra-
Coronado et al. conducted a study to investigate the immune
response against the helminth parasite T. spiralis in sleep depriva-
tion. The study concluded that sleep deprivation resulted in a sig-
nificant increase in the number of eosinophils in the villi and the
periglandular area. This study also reported a reduction in mast cell
regulation. These changes are suggestive of an alteration to the
dynamic integrity of the mucosal barrier [103].
An experimental study on mice found that sleep deprivation
caused liver inflammation and hepatocytes apoptosis [104]. Sus-
tained reduction in sleep duration and an increment in nap hours
during the day were associated with non-alcoholic fatty liver dis-
ease (NAFLD) [105]. A study conducted in the Japanese population
reported the association of sleep deprivation and the risk of NAFLD
in Japanese women, especially in those who had increased body
adiposity [106].
Previous studies have documented the relationship between
sleep loss and irritable bowel syndrome (IBS). The pathophysiology
for this relationship is not fully known and explained. It was pro-
posed that the changes to the noradrenergic signalling pathway is
responsible for the condition. Hence, alpha 2-adrenoceptors has
been brought forward as a potential treatment option for this
condition. A recent animal model study by Yaoita et al. that sleep
deprivation of the REM stage contributed to the increased gastro-
intestinal tract movement symptoms in IBS. This study also docu-
mented that sleep-deprived mice had a reduction in the function of
alpha2A-adrenoceptor [107].
6. Sleep deprivation and immunological and genetic
responses
6.1. Sleep deprivation and immunological disorders
Sleep, the status of our immune system and the strength of our
defence system are inter-linked [108]. Sleep deprivation increases
the pro and anti-inflammatory markers [109]. Raised inflammatory
markers, like C-reactive protein (CRP) and interleukin-6 (IL-6),
were seen in disturbed sleep and sleep deprivation [110]. The
decreased level of mature neutrophils found in sleep deprivation
postulated the need to study the link between sleep deprivation
and susceptibility to infections [111]. Sleep deprivation is reported
to cause cellular inflammation in young adults, whereas, in older
adults, sleep deprivation results in a reduced toll-like receptor 4
that contributes to the acquirement of infectious diseases [112]. The
increase in the interplay of autoimmune antibodies was also re-
ported to be associated with the development of autoimmune
diseases such as systemic lupus erythematosus and rheumatoid
arthritis [113].
Please cite this article as: Liew SC, Aung T, Sleep deprivation and its association with diseases- a review, Sleep Medicine, https://doi.org/10.1016/
j.sleep.2020.07.048
7
In an animal model, it was found that experimental mice that
were sleep-deprived over some time, continued to show signs of
neuroinflammation and apoptosis and microglial activation despite
three months' post-recovery [114]. There are a number of evidence
in the literature documenting the effect of chronic sleep depriva-
tion on inflammatory cells, but limited information could be found
in the literature that documents the effect of fragmented sleep on
acute inflammation. Dumaine et al. investigated the effect of
varying duration of intermittent or fragmented sleep on pro-
inflammatory (IL-1b, TNF-a), anti-inflammatory (TGF-b1) cytokine
and corticosterone level in mice. The study concluded that sleep
fragmentation of 24hr duration considerably caused an increase in
the pro-inflammatory and stress hormones level in the periphery.
Ironically, this study also reported that sleep fragmentation
induced an anti-inflammatory cytokine in the brain [115].
6.2. Sleep deprivation and protein functions and genetic disorders
Restorative sleep plays a significant role in the repair and reju-
venation processes of the body. Sleep deprivation has been re-
ported to be associated with the alteration to the metabolic
function such as alteration to the redox metabolism which leads to
a higher susceptibility to diseases. A study by Trivedi et al.
measured the effect of sleep deprivation on the levels of antioxi-
dants, glutathione, ATP, cysteine, and homocysteine levels and
found that these parameters were significantly reduced after sleep
deprivation. Antioxidants and glutathione both function to protect
cells from damage caused by free radicals. Cysteine and homocys-
teine levels are involved in DNA methylation. These changes were
postulated to contribute to the development of diseases, especially
neurological disorders [116].
The processes of DNA damage and repair are mediated by
numerous cellular conditioning and events. Chronic sleep loss is
reported to trigger oxidative stress and it could generate an in-
crease in DNA damage and hampers its repair. Both of these un-
wanted processes contributed to the development of illnesses. In a
study which utilised urinary 8-hydroxydeoxyguanosine as a sur-
rogate marker of DNA damage reported that in sleep-deprived shift
workers, it was found that sleep deprivation was associated with
respiratory infections [117]. A recent study by Cheung et al. in shift
workers documented that sleep deprivation was associated with
DNA damage. DNA repair was impaired in these participants [118].
Drosophila melanogaster, fruit flies, has continuously been used
in experiments to investigate sleep disorders owing to the simi-
larity of its characteristics to mammals. In an experiment by
Rodrigues et al. utilising fruit flies that were subjected to sleep
deprivation, it has been shown that mitochondrial changes were
found in these insects. This study also reported that in these fruit
flies with sleep deprivation, there was a reduction in the antioxi-
dant defence, an increased in ROS production and in apoptosis.
Some changes in gene expression were also observed [119].
Ma et al. investigated the level of common serum proteins that
were found in chronic sleep deprivation. Four potential bio-
markers have been identified in this study, and these are specific
for sleep deprivation. These biomarkers are KNG1 (Kininogen1),
PFN1 (Profilin-1), PKM (Pyruvate kinase M1/M2) and protein CLU
(Clusterin). KNG1 is an inflammatory mediator found in the
plasma kallikrein-kinin system that inhibits the aggregation of
thrombocytes. KNG1 also enhances brain inflammation, induces
leakage in the bloodebrain barrier and generates microvascular
thrombosis. PFN1 is an actin-binding protein and was reported to
play a part in vascular atherosclerosis and promotes cardiac hy-
pertrophy. PKM modulates the final stage in glycolysis and has a
significant role in metabolism. PKM also greatly enhance cell
proliferation and plays a part in cardiac function. CLU is expressed
8 S.C. Liew, T. Aung / Sleep Medicine xxx (xxxx) xxx
in several conditions, notably during cell stress and tissue injury
and helps to salvage reversibly damaged cardiomyocytes in cardiac
disease [120].
Sleep deprivation may have caused changes at the molecular
level, ie, DNA, RNA, and protein level and all these changes in gene
transcription and protein synthesis are associated to disorders seen
in circadian rhythm disruption [121]. In sleep-deprived individuals,
metabolomic analysis revealed a lower circulating LDL levels. This
finding suggests that modification to the cholesterol pathways
could have occurred at the level of gene expression [43].
7. Sleep deprivation and dermatological and musculoskeletal
disorders
Sleep deprivation adversely modifies the metabolic and in-
flammatory pathway. Inconsistent results on the effect of sleep
deprivation and a decline in musculoskeletal parameters have
recently been reported. Osteopenia is defined as bone mineral
density (BMD) 1e2.5 SD and sarcopenia, the relative skeletal
muscle mass >1 SD. Both osteopenia and sarcopenia are more
prevalent in middle-aged individuals. The decline in BMD alone is a
likely determinant of fracture risk in osteopenia and sarcopenia.
Lucassen et al. conducted a study to examine the associations be-
tween quality, duration and timing of sleep with osteopenia and
sarcopenia. The study concluded that sleep deprivation, poor
quality and late sleep were associated with the development of
osteopenia and sarcopenia, especially in men and women who are
middle-aged [122].
It has been previously documented that sleep deprivation
hampers the ability for task performance that requires high energy
expenditure. A study on a group of healthy young men with a 36-
hour sleep deprivation reported that sleep deprivation caused
muscle damage, reduced the antioxidant levels, and increased lipid
peroxidation. These deteriorations were seen to normalise after
12 h of recovery [123].
Sleep deprivation was reported to exacerbate the early stage of
psoriasis flare-up due to the exacerbation of skin inflammation
secondary to the increasing level of pro-inflammatory cytokines
[124]. An interesting finding by Li et al. concluded that sleep
deprivation caused dry eyes [125]. Sleep deprivation also augments
the production of senescence-associated secretory phenotype,
which contributes to ageing [126].
8. Sleep deprivation and metabolic and endocrine disorders
8.1. Sleep deprivation and obesity
Epidemiological studies have found that sleep restriction was
associated with an increase in excessive intake of food and weight
gain [127]. The increase in the ghrelin hormones, an appetite
stimulant, and the altered metabolic regulation, are all associated
with the impairment of metabolism and weight changes seen in
sleep deprivation [128]. The hyper-activation of the food stimuli
pathway in the brain that is induced by sleep-deprivation accen-
tuates the risk of obesity. The amygdala and anterior insula in the
cortex respond to most food-related stimuli and contribute to the
emotion of food craving. In optimal sleep, the amygdala and insula
remain to be minimally activated. In sleep deprivation, the anterior
insula was found to be highly activated, but the activity in the
amygdala remained normal [129].
Sleep deprivation is one of the triggering factors for obesity and
insulin resistance. The acute-phase protein serum amyloid A (SAA)
has recently been reported to play a significant role in obesity. In
acute inflammation, the SAA production is augmented in the liver
and adipose tissue. SSA has a growth factor-like property and is also
Please cite this article as: Liew SC, Aung T, Sleep deprivation and its association with diseases- a review, Sleep Medicine, https://doi.org/10.1016/
j.sleep.2020.07.048
able to adhere to the toll-like receptors (TLRs). These processes
enabled SAA proliferation to pre-adipocytes and are involved in
inflammatory and metabolic processes. A recent research by Oli-
veira et al. investigated the link between sleep loss and the regu-
lation of SAA. The study concluded that there is a rise in serum
amyloid A (SAA) in healthy human participants of the study who
were sleep-deprived for two nights. An increase in the SAA level
was postulated to be harmful to health and could lead to obesity
and insulin resistance [130].
8.2. Sleep deprivation and glucose homeostasis
Sleep deprivation was found to have an increased effect on
glucose homeostasis [131e133]. Sleep deprivation also resulted in
an altered metabolism in which adequate sleep recovery of more
than 20 days may reverse the adverse effects [134]. In an experi-
mental study, sleep-deprived mice had a better glycaemic control
after sleep recovery [135]. A review article that summarised the
adverse effects on the health of those who were on shift work
indicated a strong association between sleep deprivation and type
2 diabetes, obesity, heart disease, and cancer [136]. Similar findings
were found in a study that looked at the dose-dependent response
of sleep deprivation [137]. In a cross-sectional study conducted by
Bhaskar et al. at an outpatient department, insomnia was found to
be associated with ageing and diabetes [138]. A study by Moraes
et al. concluded that the reduction of insulin level in sleep depri-
vation did not induce an increase in the level of hypothalamic in-
sulin level. This phenomenon was suggested to be linked to the
altered metabolism seen in sleep deprivation [139]. Interestingly,
caffeinated coffee was found to have severe adverse effects on
glucose homeostasis, especially in those who were sleep-deprived
[140].
Chronic sleep loss, especially during the early morning, has the
most deleterious effect on glucose metabolism and increases in-
sulin resistance [141]. Insulin resistance is associated with the
elevation of the level of non-esterified (ie, free) fatty acid (NEFA).
The level of NEFA has a diurnal variation with the highest level
normally observed at night. Sleep deprivation was found to elevate
the level of NEFA at night and in the early morning, caused a rise in
the incidence of impaired fasting glucose, therefore, increasing the
risk of diabetes, especially in men [142,143]. Shorter sleep duration
(<6 h) is associated with the increase risk of obesity [144]. A study
in China reported an association between short sleep duration and
the development of obesity in Chinese men [145]. Sleep deprivation
was also associated with obesity in children [146].
8.3. Sleep deprivation and cortisol
Numerous studies in the past have demonstrated a relationship
between sleep deprivation and the elevated cortisol level. Previous
studies have also documented the relationship between sleep
deprivation and mental disorders. Cortisol exerts an excitatory
input to the central nervous system. The feeling of euphoria
increased anxiety, delusional experiences and insomnia are the
effects of elevated cortisol level. Song et al. measured the serum
cortisol level in sleep deprivation and correlated that to the mental
health of participants in their study. In this study by Song et al. the
serum cortisol level, which was found to be elevated in sleep
deprivation, significantly affect mental health and could possibly
play a part in the pathogenesis of manic disorder [147].
8.4. Sleep deprivation and melatonin
Sleep deprivation in children is a serious problem and a pro-
longed sleep deprivation may lead to severe metabolic dysfunction.
 S.C. Liew, T. Aung / Sleep Medicine xxx (xxxx) xxx
Melatonin, a pineal hormone, plays an integral part in metabolic
homeostasis. Melatonin synthesis is aided by the norepinephrine-
mediated calcium influx and the activation of protein kinase A
(PKA). It is well known that melatonin level induces a substantial
effect on circadian rhythmicity. Melatonin also exerts considerable
influence on the modulation of the immune system, the pursuit of
free radical scavenging and antioxidative activity. Chen et al.
investigated the role of sleep deprivation in calcium expression and
the effect on melatonin production. The study documented the
significantly reduced calcium and pineal signalling; hence, the
reduction in melatonin production and the altered metabolic
function post sleep deprivation. The authors also recommended
that melatonin could be utilised as a treatment option to counteract
metabolic deficiencies in children with sleep deprivation [148].
9. Sleep deprivation and nephrology & urology disorders
The increasing prevalence of chronic kidney disease (CKD) is
alarming, and the prevalence is predicted to be about 14.4% in 2020
and 16.7% in 2030 [149]. It was reported that adults over 30 years in
the USA have a tendency to develop CKD in their lifetime. Literature
has conflicting reports on the association between sleep depriva-
tion and the risk of acquiring CKD [150,151]. The most recent meta-
analysis conducted by Cheungpasitporn et al. concluded that sleep
deprivation was associated with the risk of proteinuria, which is a
marker for kidney disease [152].
Argeri et al. investigated the impact of sleep deprivation on the
last few weeks of gestation on mice. Parameters measured were
blood pressure, renal function and morphology and the long term
effect of sleep deprivation on the female offspring of these
experimented mice. Previous studies have reported that environ-
mental alterations during the crucial stages of intrauterine growth
predispose the growing foetus to adverse health problems. Sleep
deprivation in the last week of pregnancy for rats, which is the
critical phase for kidney maturation, showed that male offspring of
these sleep-deprived rats had reduced nephron and were hyper-
tensive [153]. In the current study by Argeri et al. on female
offspring of the experimental pregnant rats, it was demonstrated
that similar to the study by Thomal et al. adult female offspring of
these sleep-deprived rats developed renal dysfunction and increase
blood pressure [154].
The disturbance of the regular circadian rhythm compounding
with chronic insufficient sleep may result in tumorigenesis. The
impairment of the physiological, metabolic, and behavioural pro-
cesses, especially in shift workers, led to various research con-
ducted in this aspect. Multiple studies have concluded an
association between chronic sleep deprivation and breast cancer
[155e157]. Some epidemiological studies on sleep deprivation and
prostate cancer reported varying and contradictory findings on its
association [158,159]. A recent large prospective study conducted in
Sweden reported that there was no association between the
duration of sleep or chronic sleep deprivation with prostate cancer
[160].
10. Sleep deprivation and reproductive disorders
It remains a challenge to conduct studies on human reproduc-
tion. Experimental animal studies, especially in male rats, have
documented numerous findings on sexual dysfunctions associated
with sleep deprivation. In an animal study conducted by Alvarenga
et al. it was reported that sleep deprivation contributed to the
alteration of the spermatic function in rats. The sleep-deprived
group of mice had decreased sexual behaviour, lower testosterone
levels, and lower sperm viability levels [161].
Please cite this article as: Liew SC, Aung T, Sleep deprivation and its association with diseases- a review, Sleep Medicine, https://doi.org/10.1016/
j.sleep.2020.07.048
9
The current health care research need, identified by the U.S.
Department of Health and Human Services' Healthy People 2020,
lies in the limited available data regarding the under-studied
research group, the sexual minority individuals. A study in the
sexual minority adults (LGBT) revealed that this group of adults
have a higher prevalence of sleep deprivation. The shortened sleep
duration was also seen to be associated with adverse health effects
in this community [162].
11. Stress and sleep deprivation
Limited information could be found in the literature on the
impact of chronic stress on sleep deprivation. Stress response is
often accompanied by a cascade of physiological changes to ensure
the continuum of existence. Social stress had been documented to
affect the slow-wave activity (SWA) during non-rapid eye move-
ment (NREM) sleep. In an experimental study by Olini et al. that
investigated the effect of chronic stress on subsequent consecutive
sleep, it was demonstrated that adult mice in this randomised
control trial exhibited homeostatic dysregulation in sleep after
subjected to a 10-day trial of chronic social stress. Sleep-deprived
mice showed augmented sleep pressure (the need for sleep), as
seen in the slow-wave activity during NREM. The study also
demonstrated that during the recovery period, sleep-deprived mice
showed an increase in REM sleep [163].
Lu et al. investigated the relationship between Emotional Sta-
bility (ES) and the effect of sleep deprivation on cardiovascular
functions during stress. Emotional Stability (ES) is one of the Big
Five personality traits that refers explicitly to susceptibility for
emotional negativity and increased anxiety. Previous research in
this area have reported inconsistent results on the relationship
between ES and cardiovascular responses during stress. In this
recent study by Lu et al. the cardiovascular parameters (blood
pressure, heart rate, cardiac output, and total peripheral resistance)
of the participants in the study, both with and without sleep
deprivation were continuously monitored while they were sub-
jected to a stressful computer-based test. The study concluded that
sleep deprivation led to inadequate cardiovascular (blood pressure,
cardiac output) responses to stress, especially for those with a low
ES [164].
12. Study limitations
We failed to include a majority of systematic reviews and trials
from Cochrane databases. Studies published in the Cochrane da-
tabases were mainly based on randomised controlled trials that
focused on the effects of treatments/interventions on sleep depri-
vation and sleep-related disorders rather than the effect of sleep
deprivation on the systemic diseases. Similar reasons for the in-
clusion of limited meta-analysis reports in this review.
References from animal experiments were included in this re-
view to elaborate on the various effects of sleep deprivation at
molecular and cellular levels. Experimental studies were included
due to the limitations on human studies in specific pathological
processes of diseases discussed in this review.
An evidence-based approach could not be made to each of the
studies included in this review for various reasons. We could only
adopt the format of a scoping review, aiming to derive and collect
updated information on sleep deprivation and health disorders
from the literature. However, we hope that our review could serve
as a useful piece of information that add knowledge to improve
understanding and awareness on sleep deprivation and its associ-
ated disorders. In our future work, we would like to adopt a sys-
tematic review approach to this topic to ensure that the best
evidence is retrieved.
10 S.C. Liew, T. Aung / Sleep Medicine xxx (xxxx) xxx
13. Conclusions
It is evident from the review that sleep deprivation contributes
to poor health outcomes. Detrimental effects on health outcomes
could be seen with sleep duration that is less than 7 h a night. Both
physiological and pathological modulation that occur due to sleep
deprivation could be better explained in some diseases compared
to others. Extensive studies on the effects of sleep deprivation and
cardiovascular, neurological, endocrine, and immunological health
outcomes had been rigorously conducted. Results from these
studies provided explanation on the adverse effects of sleep
deprivation on health, and the pathological processes involved
were generally well outlined.
Experimental studies on animals are crucial in the determinant
of disease processes. Specific disease processes were better studied
via this method when human avenue for the same could not be
achieved. Shreds of evidence on the association between sleep
deprivation and other health outcomes such as reproduction,
nephrology, and urology remain scarce. Investigations into these
outcomes would be much needed and valued.
It is alarming that literature reported a global decline in sleep
hours in this modern society, despite reports on the immense
public health issues that sleep deprivation pose. Eventually,
guidelines on recommended sleep hours per night for children,
teenagers, adults, elderly should be explicitly made known to the
public. There is a substantial amount of evidence on adverse effects
of sleep deprivation, therefore, awareness of the importance of
adequate sleep, which is often a neglected aspect of health pro-
motion should be emphasised.
Research priorities
It is recommended that future research should concentrate on
the following areas:
1. Assess the true worldwide prevalence of sleep deprivation,
extensive data to be gathered from more countries worldwide.
2. Study the disease predisposition of sleep deprivation in chil-
dren, teenagers, adults, and the elderly.
3. Investigate the best education strategies that could help educate
the public on sleep hygiene and behavioural change to comply
with the recommended sleep requirement.
Financial support
None.
CRediT authorship contribution statement
Siaw Cheok Liew: Conceptualization, Methodology, Writing -
original draft, Writing - review & editing. Thidar Aung: Method-
ology, Writing - original draft, Writing - review & editing.
Conflict of interest
The authors declare no conflict of interest.
The ICMJE Uniform Disclosure Form for Potential Conflicts of
Interest associated with this article can be viewed by clicking on the
following link: https://doi.org/10.1016/j.sleep.2020.07.048.
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