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4 Overview of the Comorbidity … 89
women has been found to be associated with an increased risk of fracture
[117, 118]. With the increasing prevalence of obesity and high morbidity
associated with fractures, there is much research interest in determining
the effects of obesity on bone health and interactions with muscle mass
and strength.
Dermatological System
The skin of overweight and obese individuals is prone to infection, includ-
ing lower limb cellulitis, as a consequence o f venous stasis and lym-
phoedema, hidradenitis suppurativa and intertrigo particularly due to
candidiasis, but often the consequence of mixed bacterial and fungal infec-
tions [22].T2D further increases the risk of these infections [119]. Related
to hyperinsulinaemia and the MetS in overweight/obese individuals are
the skin conditions of acanthosis nigricans and psoriasis [22, 120]. In
addition for women with PCOS, due to hyperandrogenism, is increased
prevalence of acne and hirsutism [22]. Obesity may also be associated with
an increased risk of melanoma and non-melanoma skin cancers [121].
Reproductive System
Overweight and obesity is associated with reduced fer tility as a conse-
quence of PCOS, as discussed earlier in Sect. 4.1. Psychological distress
that is associated with infertility in obese women, already with low self-
esteem and high rates of anxiety anddepression, is a significant issue [122].
Once pregnant, the rates of adverse pregnancy outcomes for obese women
are substantially increased; the rates of GDM and hypertensive disorders
of pregnancy are increased three–fourfold, and rates of caesarean section
and hospital stay greater than 5 days are increased twofold [123, 124]. For
their neonates, rates of macrosomia and admission to the neonatal inten-
sive care unit are increased about twofold [123, 124]. Obesity, particularly
in association with hyperglycaemia, is associated with higher rates of con-
genital malformations [123, 125]. Importantly, maternal overweight and
obesity were recently reported to be the highest-ranking modifiable risk
90 C. J. Nolan
factors for stillbirth [126]. Importantly, maternal obesity is also a deter-
minant of the next-generation obesity [127].
Haematological Diseases
In a National Hospital Discharge Survey, the relative risk of deep venous
thrombosis and pulmonary embolism, comparing obese to non-obese
patients, was 2.5 (95% CI, 2.49–2.51) and 2.21 (95% CI, 2.20–2.23)
[128]. Factors that may contribute include an increased prevalence of
venous insufficiency, greater immobility and MetS-linked hypercoag-
ulability due to increased systemic inflammation and increased pro-
coagulation factors, such as plasminogen activator type 1, von Willebrand
factor, fibrinogen and increased platelet activation [129, 130]. Associa-
tions between obesity and iron deficiency are also reported [131]. Obe-
sity has also been linked to increased risk of haematological malignancies
including myeloma, chronic myeloid leukaemia and acute lymphoblastic
leukaemia [132].
Cancer
Evidence is now sufficient to indicate a relationship between obesity and
the following cancers: oesophagus, gastric cardia, colon and rectum, liver,
gallbladder, pancreas, breast in menopausal women, body of uterus, kid-
ney, meningioma, thyroid and multiple myeloma [133]. Other malignan-
cies (e.g. melanoma) are also likely increased [133]. Of further concern
is a recent report which suggests that obesity-related cancer is increasing
in successively younger birth cohorts in the USA [134]. Efforts to under-
stand the contributing mechanistic factors to the association of obesity
with these cancers are ongoing.
Mental Health
Obesity and mental health disorders are both common. Increasing evi-
dence suggests that their coexistence is the result of more than simple
overlap [135]. Overweight and obesity have also been reported to be
4 Overview of the Comorbidity … 91
associated with the increased prevalence of attention deficit hyperactivity
disorder, mood disorders, anxiety, binge eating disorder, post-traumatic
stress disorder, including from childhood sexual abuse, and schizophre-
nia [136–141]. Medications used to treat mental health disorders (e.g.
antidepressants) can also contribute to weight gain [142]. The potential
for bidirectional causal relationships between mental health disorders and
overweight and obesity is a particular focus of attention in other chapters
of this book.
4.2 Overweight/Obesity Comorbidities
and Causal Linkages
An understanding of the likely causality underpinning the linkages
between comorbid conditions isimportant, asthis will permit the targeting
of interventions to reduce their co-occurrence and/or detrimental impacts
on health. With respect to overweight and obesity, and its large number
of potential comorbid conditions, breaking down the likely causality into
different stages of disease is worthwhile, including: (i) early (i.e. prior to
the development of irreversible end-organ injury); (ii) middle (i.e. during
the development of irreversible end-organ injury); and (iii) late stage (i.e.
presence of established end-organ disease comorbidities).
4.2.1 Early-Stage Causal Linkages Between
Overweight/Obesity Comorbidities
In the early stages of overweight and obesity, prior to the development of
end-organ medical comorbidities, the key questions in regard to causality
of the comorbidity relate to factors contributing to excess weight gain
and determining the presence or absence of the MetS. For comorbidities
that can contribute to excess weight gain, it is important to first consider
medical conditions or therapies that are known to cause obesity, such as
chromosomal abnormalities (e.g. Prader–Willi syndrome), monogenetic
causes of obesity (e.g. Alstrom syndrome), endocrine diseases (e.g. Cush-
ing’s disease, hypothyroidism, testosterone deficiency) and obesogenic
92 C. J. Nolan
drugs (e.g. glucocorticoids, clozapine) [143, 144]. For the majority, how-
ever, the causality of obesity is complex with likely interactions between
genetics (polygenic), epigenetics influenced by the early life environment
and an obesogenic environment (e.g. sociocultural circumstances, food
availability, need for exercise, environmental chemicals such as endocrine
disrupters, gut microbiome) being implicated [144]. The likelihood of
bidirectional causality between psychological illness (e.g. depression, per-
sonality disorders, post-traumatic stress disorder) and obesity needs to
be considered due to the effects of psychological illness on behaviour
that can influence weight gain (e.g. diet choices, sleep hygiene, sedentary
behaviour) and of obesity which can affect psychological well-being (e.g.
reduced self-esteem) [145–148].
As discussed in the above section, MetS is involved in the pathogenesis
of a large percentage of obesity comorbidities, including PCOS, NAFLD,
T2D and ASCVD [11]. For this reason, prevention of MetS via interven-
tions that target its causes may reduce the prevalence of comorbid diseases
that are associated with overweight and obesity. However, the unifying
mechanism of causation of MetS is not agreed upon. Insulin resistance
and central adiposity have most often been proposed, although werecently
suggested that insulin hypersecretion in response to poor diet and lack of
exercise is very much an upstream event in its causation, with the resul-
tant hyperinsulinaemia likely driving t he other components of the MetS
[11, 12, 23]. Nonetheless, the underlying determinants of the develop-
ment of MetS, even if there is a main driver such as hyperinsulinaemia,
are undoubtedly complex and may include genetic factors, epigenetic fac-
tors as a consequence of early life environment, and the effects of other
comorbidities, in particular, psychological illnesses and disturbances in
the circadian rhythm [11, 28, 149].
In particular, MetS has been found to be associated with depression
across BMI categories and independent of age, smoking status, socioeco-
nomic factors and lifestyle [150]. A systematic review and meta-analysis
of 29 studies with >150,000 participants clearly confirmed this linkage
between depression and MetS [151]. Patients with metabolic syndrome
had a higher prevalence of depression than patients without metabolic syn-
drome (unadjusted odds ratio with a pooled estimate of 1.42 (95% CI,
1.28–1.57)) [151]. Bidirectional causation is likely, as 11 studies, with
4 Overview of the Comorbidity … 93
depression as the outcome, reported an adjusted odds ratio of 1.27 (95%
CI, 1.07–1.57); whereas 12 studies, with MetS as the outcome, reported
an adjusted odds ratio of 1.34 (95% CI, 1.18–1.51) [151]. When 9 stud-
ies with new-onset depression cases were aggregated, the odds ratio for
depression as the outcome, if MetS was present as opposed to not present,
was even higher at 1.49 (95% CI, 1.19–1.87) [151]. Taken together, the
results suggest that depression and MetS are associated with a 25–30%
increased risk of the other condition, especially the new onset of depres-
sion.
More broadly,MetS has been posited to be caused by disturbances in the
circadian rhythm, with alterations in central and peripheral physiological
clocks affecting sleep and eating behaviour, as well as body temperature
(BT). The circadian rhythm disturbances are likely to be the consequence
of the modern-day environment [28, 146, 152]. For example, light pol-
lution at night within cities and the greater individual use of electronic
screen devices into the night are proposed to be major contributors to the
dysregulation [152, 153]. Interestingly, in related research, the incidence
rate of diabetes has been shown to increase with higher outdoor ambi-
ent temperature, based on a meta-analysis of the relationship between
mean annual temperature and diabetes incidence from 1996 to 2009 for
each US state separately, and a meta-analysis of the association between
mean annual temperature and the global prevalence of glucose intolerance.
On average, age-adjusted diabetes incidence increased by 0.314 (95%
CI, 0.194–0.434) per 1000 US cases for each 1 °C increase in temper-
ature, whereas the global prevalence of glucose intolerance increased by
0.17% (95% CI, 0.107–0.234%) per 1 °C rise in temperature and the
relationships persisted after adjustment for obesity [154]. Further, in a
recent review [155], it was reported that diabetes places patients at greater
risk for heat-related illness (e.g. heat stress or exercise-induced) due to
an impaired capacity to dissipate heat. In particular, affected individuals
have low skin blood flow and sweating responses during heat exposure,
which may adversely affect cardiovascular regulation and glycaemic con-
trol, especially in patients with poor glycaemic control and/or diabetes
complications. Taken together, the results suggest that an elevated BT
94 C. J. Nolan
(due to ambient warming) is linked to the onset and progression of dia-
betes, whereas cold exposure might have therapeutic potential. Neverthe-
less, behavioural mechanisms are also likely to be involved in causing the
overweight-/obesity-related comorbidities. For example, night shift-work
rostering isknown to be strongly associated with overweight, obesity, MetS
and MetS-related diseases [156]. Further, the strong linkages between the
disturbances in circadian rhythm, BT regulation, psychological disorders,
overweight/obesity and the MetS are suggestive of multidirectional causal-
ity [28, 146, 157].
4.2.2 Middle-Stage Causal Linkages Between
Overweight/Obesity Comorbidities
Once overweight/obesity with/without MetS is established, the resultant
biomechanical and/or MetS-related factors including hyperinsulinaemia,
systemic inflammation, dyslipidaemia, dysglycaemiaand hypertensioncan
cause end-organ damage and disease states affecting all bodily systems,
such as those listed in Sect. 4.1.2. A causative link between MetS-related
factors and PCOS, T2D, NAFLD and ASCVD is well established [10,
11]. Thus, it is not surprising that the presence of one of the MetS-related
disease statesis associated withthe greater likelihoodof the others [24–27].
Furthermore, bidirectional causality between the MetS-related conditions
is also very likely [158]; and MetS features have been implicated in many
other disease states including chronic kidney disease, dementia, arthritis,
psoriasis and various malignancies [20, 58, 120, 159, 160].
It is well known that diabetes is a direct cause of comorbidities that
result from hyperglycaemia-induced microvascular and macrovascular tis-
sue injury, such as eye disease, kidney disease, foot complications and
macrovascular disease [5]. NAFLD complicated by NASH is well known
to cause liver cirrhosis and is a strongly linked causative factor for hep-
atocellular carcinoma [103, 161]. While depression and T2D often co-
occur and may be predictive of each other, evidence of the mechanisms by
which bidirectional causation occurs is lacking [162]. However, obstruc-
tive sleep apnoea is well known to aggravate hypertension and contribute
to cerebrovascular and cardiovascular diseases [18, 86]. Osteoarthritis of
4 Overview of the Comorbidity … 95
the lower limbs can result in reduced mobility, and this will make weight
loss more difficult, reduce overall cardiorespiratory fitness and increase the
challenges in managing overweight/obesity-associated conditions such as
T2D [163, 164].
Nevertheless, it is possible that overweight/obese patients and those
with diabetes will have more than a single comorbidity; and as discussed
in Chapters 7–9, several or more risk factors may exert effects on different
aspects of a person’s health and there may be some degree of overlap in
the likely cause/s of the comorbid conditions. An example by which a risk
factor for one comorbid illness can influence the outcome of another is
the effect of elevated BT on outcomes of stroke. In a prospective study
of 390 stroke patients, mortality was higher and outcome was worse in
the patients with hyperthermia on admission, relative to those with mild
hypothermia. BT was independently related to keystroke outcome mea-
sures such as infarct size, mortality and the severity of stroke using an
established stroke scale on discharge [165]. Thus, established morbidities
of overweight and obesity can increase the risk and severity of comorbidi-
ties, with bidirectional and sometimes multidirectional causality being
often evident.
4.2.3 Late-Stage Causal Linkages Between
Overweight/Obesity Comorbidities
Interest in studying the impact of comorbidity and multimorbidity on
functional health loss and disability, mortality and costs in providing
health care has been increasing sharply [166–168]. The economic cost
of comorbidity is of major concern to health service providers [169]. Vari-
ous indices, such as the Charlson comorbidity index and Elixhauser score,
have been developed to permit the objective measurement of prognostic
comorbidity [170, 171]. Obese patients are more likely to have multi-
morbidity, particularly in older age groups, and the number of affected
individuals has increased in recent years due to the improved survival
for individual chronic disease components [172]. This is important, as
an increasing number of comorbid conditions is strongly associated with
poorer quality of life and the greater burden of disease costs. Obesity is
96 C. J. Nolan
also associated with increased risk of premature mortality, and this is a
direct consequence of its associated comorbidities [173, 174].
Sarcopaeniacandevelopasaconsequenceofageingaswellasmany
chronic diseases including obesity and MetS, COPD, chronic liver dis-
ease, inflammatory conditions including of the bowel and joints, diabetes,
other endocrine diseases, heart failure and advanced malignancies [175].
Mental health issues, poor nutrition and lack of exercise can also con-
tribute to sarcopaenia and are particularly relevant in sarcopaenic obesity
[176]. That is, as comorbidities increase as a consequence of the obesity,
the risk of obesity sarcopaenia increases [176]. Sarcopaenia is well known
to be associated with poor quality of life, disability and an increased risk of
mortality [176]. Of relevance, the relationship between high BMI groups
and mortality is strengthened when muscle mass is taken into considera-
tion, as low muscle mass is a likely a mediator of this effect [177]. For all
these reasons, sarcopaenia is likely to be causally linked to the poor out-
comes in overweight and obese individuals with multiple comorbidities
anditshouldbeafocusofintervention.
The effects of physical health multimorbidity on psychological health
are very strong. For example, in a survey of 7620 patients in primary care,
23% ofpatients with onechronic condition reported depression compared
to 41% of those with five or more conditions [178]. Of note, admissions
to hospital in patients with bipolar illness were more strongly linked to
other morbidities, in particular asthma and T2D, and patients with bipo-
lar illness as a comorbidity had a higher risk for in hospital mortality
[179]. Thus, as detailed throughout this book, the clinical outcomes for
patients with comorbid illnesses are generally worse than for the patients
with an uncomplicated (single) illness trajectory, especially patients with
overweight/obesity.
4 Overview of the Comorbidity … 97
4.3 Lessening the Burden of Comorbid
Illnesses in Overweight and Obese
Individuals
Lessening the burden of overweight and obesity on affected individualsand
health services is a major task that will take a very coordinated approach
from basic scientists, clinicians, public health practitioners and policy
makers. In this regard, a better understanding of the comorbid illnesses
that are associated with overweight and obesity is of major importance.
Clinicians need to appreciate the common co-occurrence of many of the
aforementioned comorbid conditions with overweight and obesity. There-
fore, patients need to be screened for the conditions and the conditions
should be managed as they arise as this is expected to improve the health
and well-being of the individuals.
However, key to success will be an improved understanding of the
likely causal relationships that exist between obesity and its comorbidi-
ties through scientific endeavours to enable the development of targeted
interventions. As MetS is an early driver of multiple obesity-associated
comorbidities, a thorough understanding of the mechanisms causing it is
of major importance. However, the causation of MetS is not so clear, as
discussed in Sect. 4.1, but interactions between genetic risk factors and
the modern environment, including poor lifestyle choices (e.g. poor diet,
physical inactivity), environmental toxin exposure, disrupted circadian
rhythm with abnormal body temperature regulation and sleep patterns,
are all likely to be involved.
Finally, it must be appreciated that the achievement of substantial and
sustained weight loss is difficult for obese individuals,with bariatricsurgery
showing the most success at present [180]. Of note, bariatric surgery has
been shown to substantially reduce the complications of obesity and it
reduces the risk of obesity-related comorbidities [181]. However, once
physical and psychological illnesses have developed in association with
obesity, health outcomes tend to worsen due to multidirectional harmful
interactions. Therefore, the management of established comorbidities in
obese patientsshould beby a multidisciplinary team of healthprofessionals
with expertise in managing complex illness.
98 C. J. Nolan
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