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4
Overview of the Comorbidity Between
Medical Illnesses and Overweight/Obesity
Christopher J. Nolan
The Global Burden of Disease (GBD) 2015 Obesity Collaborators
reported that, in 2015, a total of 107.7 million (5%) children and 603.7
million (12%) adults were obese in data assembled from 195 countries,
with a doubling since 1980 in many countries [1]. Furthermore, among
adults in 2015, overweight and obesity contributed to 4.0 million (7.1%
of total) deaths from any cause and 120 million disability-adjusted life
years (4.9% of total) globally [1]. Of major concern was the observa-
tion of rapid increases in obesity prevalence in young people, particularly
within middle-income countries such as China, Brazil and Indonesia [1,
2]. A younger onset of obesity is likely to be followed by earlier onset of
obesity-associated chronic diseases, such as type 2 diabetes (T2D), cardio-
vascular disease, renal disease, musculoskeletal disorders and some cancers
[1–3]. The rising prevalence of obesity in women of child-bearing age is
also adversely affecting pregnancy outcomes with transgenerational health
C. J. Nolan (
B
)
Australian National University, Canberra, ACT, Australia
e-mail: christopher.nolan@anu.edu.au
© The Author(s) 2020
R. Brown and E. Thorsteinsson (eds.), Comorbidity,
https://doi.org/10.1007/978-3-030-32545-9_4
79
80 C. J. Nolan
consequences [4, 5]. The 2018 Position Statement of the Obesity Society
states a case that obesity is a disease in its own right and that, in addition
to its effect to elevate the risk of premature mortality, it increases the risk
for the development of more than 200 comorbid chronic diseases [6].
Furthermore, obesity can adversely impact all systems of the body and all
stages of life (from in utero to old age).
4.1 Medical Illnesses
and Overweight/Obesity
Overweight and obesity areconditions in which there is excessive accumu-
lation of adipose tissue. The body mass index (BMI) (calculated as height
[m]/weight [kg]
2
) is used to classify the weight of adults into underweight
(<18.5 m/kg
2
), normal weight (18.5–24.9 m/kg
2
), overweight (25.0–
29.9 m/kg
2
), obese class I (30–34.9 m/kg
2
), class II (35–39.9 m/kg
2
)
and class III (≥40.0 m/kg
2
)[7]. For Asian and South Asian popula-
tions, lower BMI cut-offs for overweight (23.0–24.9 m/kg
2
) and obesity
(≥25.0 m/kg
2
) are used [8]. For children and teenagers, overweight is
defined as a BMI ≥85th and <95th percentile and obesity as a BMI ≥95th
percentile for children and teens of the same age and sex [9]. Obesity-
associated medical illnesses can be classified in various ways, according
to the body systems affected or according to whether they are a conse-
quence of systemic metabolic and inflammatory disturbances (Metabolic
Syndrome; MetS) or just the consequence of the mechanical effects of car-
rying excess weight. As links between MetS and an increasing number of
medical illnesses are being found, an overview of MetS will be addressed
next.
4.1.1 Metabolic Syndrome and Associated Medical
Illnesses
Strong associations between overweight/obesity, insulin resistance, hyper-
insulinaemia, glucose intolerance, hypertriglyceridaemia, reduced high-
density lipoprotein cholesterol and hypertension and their link to
4 Overview of the Comorbidity … 81
atherosclerotic cardiovascular disease (ASCVD) were described by Pro-
fessor Gerald Reaven in 1988 [10]. This clustering of factors was initially
named “Syndrome X” by Reaven and was later named the “Insulin Resis-
tance Syndrome” and “Metabolic Syndrome” (MetS), with MetS now
the most commonly used and accepted name [11]. The MetS has been
expanded to include additional factors such as central or visceral adipos-
ity, increased apolipoprotein B and small dense LDL particles (proathero-
genic), elevated plasma fibrinogen and plasminogen activator inhibitor
(PAI)-1 (prothrombotic), increased C-reactive protein and inflammatory
cytokines (systemic inflammation) and microalbuminuria [12, 13]. It is
well accepted that the clustered components of the MetS contribute to
the pathogenesis of conditions such as non-alcoholic fatty liver disease
(NAFLD), polycysticovarian syndrome (PCOS), T2D, andASCVD [12–
17]. MetS has also been associated with increased risk for chronic kidney
disease, cognitive impairment, obstr uctive sleep apnoea, chronic respira-
tory diseases and skin conditions [18–22]. The usefulness of a diagnosis
of MetS in predicting T2D and ASCVD, over its individual components,
has been questioned, but MetS is now listed as a disease entity (E88.81)
in the International Classification of Diseases-10 (ICD-10) [10, 23].
An increased risk of developing a second MetS-associated disease has
been shown in patients who already have one of the diseases. Thus,
if a woman has PCOS, her risk of developing T2D is about fourfold
higher than for women without PCOS [24–26]. Similarly, if a person has
NAFLD, the risk for the person of having a non-fatal or fatal cardiovas-
cular disease event is increased 1.6–2.6-fold depending on the severity of
the NAFLD [27]. For these reasons, a good understanding of the mech-
anisms underlying the MetS, including a unifying mechanism, if this in
fact exists, is critically important.
The issue of identifying a unifying mechanism underlying the MetS is
not trivial, as this would enable the development of better focussed preven-
tive and therapeutic strategies for the syndrome and its associated comor-
bidities. Insulin resistance and visceral adiposity have most often been
proposed to be the unifying mechanism [12, 23]. However, we recently
proposed an alternative view that insulin hypersecretion in response to an
adverse environment,such as that associated with a Westernised lifestyle, is
82 C. J. Nolan
primary and that the resultant hyperinsulinaemia drives the other compo-
nents of the MetS [11]. Another recent and very interesting hypothesis is
that the MetS is the consequence of a disturbance in the circadian rhythm
[28]. Congruent with the multidirectional causality of comorbidities asso-
ciated with obesity and the circadian rhythm hypothesis, Zimmet et al.
state that evidence is mounting that connects disturbances in circadian
rhythm with key components of the MetS and its associated conditions
including sleep disturbance, depression, steatohepatitis and cognitive dys-
function [28].
4.1.2 Overweight-/Obesity-Associated Medical
Illnesses According to Body Systems
Endocrine System
Many endocrine conditions including hypothyroidism, Cushing’s dis-
ease, hypothalamic/pituitarydisorders, monogenetic causes of obesity(e.g.
melanocortin 4 receptor deficiency) and obesity syndromes (e.g. Prader–
Willi) can contribute to overweight and obesity and need to be considered
in the clinical assessment of overweight and obese patients [29–33]. How-
ever, it is much more common for overweight and obesity to contribute
to the occurrence of endocrine diseases, in particular PCOS, gestational
diabetes mellitus (GDM) and T2D [34, 35]. As discussed in the previous
section, PCOS and T2D are strongly associated with the MetS.
PCOS is estimated to affect 3–10% of women who present with one or
more of: (i) oligomenorrhoea or amenorrhoea, (ii) hirsutism and/or acne
as a consequence of hyperandrogenism, (iii) infertility or (iv) an inciden-
tal finding of multiple ovarian cysts very often associated with overweight
or obesity [36, 37]. In a systematic review and meta-analysis of women
with PCOS, overweight and obesity was reported to have a pooled esti-
mated prevalence of 61% (95% CI: 54–68%), with a very wide variation
in prevalence between the studies (from 6 to 100%) depending on the
populations included [38]. Psychological disorders are very commonly
reported comorbidities of PCOS, with affected women having higher
4 Overview of the Comorbidity … 83
rates of low self-esteem, depression, anxiety, disordered eating and psy-
chosexual dysfunction than women without PCOS [39–41].Therateof
hospital admissions for women with PCOS in a Western Australian pop-
ulation in comparison with women without PCOS was markedly higher
including for conditions such as T2D, cardiovascular diseases, psycholog-
ical disorders including self-harm and fertility disorders [42].
Worldwide, approximately415 million people are diagnosedwith T2D,
a condition that contributes in a major way to global disease burden
through microvascular complications (e.g. retinopathy, nephropathy and
neuropathy), macrovascular complications (e.g. coronary artery disease,
stroke and peripheral vascular disease) and premature mortality [34]. Ges-
tational diabetes, defined as carbohydrate intolerance that is diagnosed
during pregnancy, is associated with increased risk of adverse pregnancy
outcomes and increased long-term health risks for both the mother and
her children [35].
Neurological System
Associations between obesity, and sometimes underweight, with impaired
cognitive function and dementia are increasingly being reported, although
with some inconsistencies between studies [43–47]. Strengthening the
linkage betweenobesity and Alzheimer’sdisease is post-mortem findings of
increased amounts of Alzheimer’s disease-associated biomarkers, amyloid
β
and tau,in thehippocampal tissueof elderlypatients with morbid obesity
compared to those of normal weight [48]. Furthermore, imaging studies
have shown obesity to be associated with atrophy of frontal, temporal and
subcortical regions of the brain, including the hippocampus [49–52]. In
particular, grey matter is more atrophied and this can even be detected in
children and adolescents with obesity [53, 54]. The mechanisms involved
are not well understood, but systemic inflammation and dyslipidaemia,
associated with the MetS, and obstructive sleep apnoea, all of which are
aggravated by obesity, have been implicated [55–60].
Less appreciated is the association between obesity and both autonomic
dysfunction and peripheral polyneuropathy [43]. Obesity is associated
84 C. J. Nolan
with an imbalance in the autonomic nervous system with increased sym-
pathetic comparedto parasympatheticactivity [43]. Increased sympathetic
nervous system activity in obese individuals can affect the cardiovascular
system by increasing heart rate, vascular tone and blood pressure, and
it also increases adipose tissue lipolysis with elevated non-esterified fatty
acids release into the circulation which contributes to a range of dys-
metabolic effects [61–63]. Interestingly, while diabetes is a major con-
tributor to peripheral sensory neuropathy, non-glycaemic MetS factors
have also been shown to contribute to this complication independently of
glycaemia [64].
Cardiovascular System
Obesity is a heterogenous condition, particularly with respect to the pres-
ence of MetS and its related features. At one end of the continuum are the
metabolically healthy obese (MHO) individuals with no features of MetS,
who might be expected to have a low risk of events from ASCVD. At the
other end of the continuum are metabolically unhealthy obese (MUO)
individuals with significant MetS. MUO individuals have increased car-
diovascular disease risk factors such as hypertension, prediabetes or T2D,
dyslipidaemia, impaired fibrinolysis and systemic inflammation [64, 65].
The Whitehall II cohort study with 17 years of follow-up, showed in a
fully adjusted model, that compared with metabolically healthy normal-
weight (MHNW) individuals, MUO individuals were at increased risk of
both ASCVD (HR 2.44, 95% CI, 1.85–3.21) and T2D (6.92, 95% CI,
5.43–8.81), as would be expected [66]. However, increased risks (hazards
ratios) for MHO compared to MHNW individuals for both ASCVD
(1.95, 95% CI: 1.37–2.77) and T2D (3.25, 95% CI: 2.32–4.54) were
also shown [66]. Of note, there was an excess risk in MUO compared to
MHO for T2D (HR 1.98, 95% CI, 1.39–2.83), but not ASCVD (1.23,
95% CI, 0.81–1.87) [66]. In a larger study, with shorter follow-up of
3.6 years, those individuals with MHO were again shown not to be pro-
tected compared to MUO individuals from the increased occurrence of
myocardial infarction [67]. Thus, MHO should not be considered to be
a benign condition when it comes to cardiovascular health [68].
4 Overview of the Comorbidity … 85
Obesity is also an established riskfactor for heart failure,including heart
failure with both preserved and reduced ejection fraction, often in the
absence of evident coronary artery disease [69–71]. For example, within
5881 participants in the Framingham Heart Study with mean follow-up
of 14 years, there was an increase in the risk of heart failure of 5% for men
and 7% for women for each BMI increment of 1 [69]. Pathophysiological
factors that are proposed to contribute to cardiac disease include increased
sympathetic nervous system activity, increased cardiac output, hyperten-
sion, obstructive sleep apnoea and obesity hypoventilation syndrome, as
well as ASCVD [70, 72–75]. Surprisingly, the mortality risk of overweight
and obese adults (class I and II) with heart failure is lower than that of
normal and underweight adults with comparable severity heart failure, a
phenomenon called the “obesity paradox” [70, 76]. This difference may
be a consequence of more or different pathologies that contribute to heart
failure in leaner compared to obese individuals.
Respiratory System
Obesity has been shown to be a risk factor for chronic obstructive pul-
monary disease (COPD), asthma, obstructive sleep apnoea and obesity
hypoventilation syndrome [77]. More severe categories of obesity result
in restrictive lungimpairment, as shown bylower totallung volume, forced
vital capacity (FVC) and forced expiratory volume in 1-second (FEV1)
measurements; that can be attributed tointraabdominal fat compromising
the functioning of the diaphragm and the thoracic chest wall fat impeding
thoracic compliance [77, 78].
In a meta-analysis, the odds ratio for incident asthma in overweight
and obese subjects versus normal weight were, respectively, 1.38 (95%
CI, 1.17–1.62) and 1.92 (95% CI, 1.43–2.59) [79]. The mechanistic fac-
tors contributing to this association are not well understood, but obesity-
associated changes in lung function, altered diet composition, microbiome
changes, MetS and epigenetic factors may be involved [80]. Furthermore,
obese subjects with asthma are likely to have more symptoms, increased
frequency and severity of flare-ups, slower response to treatments and
decreased quality of life [80].
86 C. J. Nolan
Of 3631 participants from the multicenter prospective cohort study
Genetic Epidemiology of COPD (COPDGene) who had COPD
confirmed by spirometry, 35% of participants were obese [81]. Further-
more, obesity in individuals with COPD was associated with reduced
respiratory-specific and general quality of life, reduced 6-min walk dis-
tance, increased dyspnoea and greater odds of severe acute exacerbation of
COPD [81]. However, there is again an obesity paradox with respect to
mortality from COPD. In a study of 1659 COPD patients for a median
of just over 3 years, while BMI was inversely related to FEV1/FVC and
hyperinflation, with U-shaped relationships with dyspnoea and exercise
capacity, the cr ude mortality rate was 60, 43, 37, 36 and 28% from the
lowest to highest BMI groups (p < 0.0001) [82].
Higher rates of obstructive sleep apnoea are associated with obesity, as
assessed by BMI, waist circumference and neck circumference, in addition
to male gender and older age [83–85]. This is an important obesity con-
dition, as it contributes to excessive daytime tiredness, including falling
asleep while driving and at work, depression, cognitive decline, systemic
hypertension, heart failure and higher mortality [56, 73, 86–89]. Thus,
obstructive sleep apnoeacontributes significantly to the comorbid medical
and psychological illnesses of obesity.
Obesity hypoventilation syndrome, also known as Pickwickian syn-
drome, is defined as the triad of obesity, daytime hypoventilation and
sleep-disordered breathing in the absence of an alternative neuromuscu-
lar, mechanical or metabolic explanation for hypoventilation [90, 91].
Obesity hypoventilation syndrome is associated with very poor quality of
life and substantially increased risk of mortality [90, 91].
Gastroenterological and Hepatic System
Obesity is associated with the greater prevalence of gastro-oesophageal
reflux disease (GORD) and Barrett’s oesophagus, cholelithiasis, pancreati-
tis, NAFLD including non-alcoholic steatohepatitis (NASH) and various
gastroenterological and hepatic cancers.
GORD is one of the most common conditions affecting the gastroen-
terological tract estimated to be present in 10–20% of European and US
4 Overview of the Comorbidity … 87
populations, with its prevalence being more than doubled in obese indi-
viduals [92, 93]. With respect to obesity and Barrett’s oesophagus, one
study established that for each 5-unit increase in BMI, the risk of Barrett’s
oesophagus increased by 35% [94]. As Barrett’s oesophagus is a precur-
sor to adenocarcinoma of the oesophagus, it is not a surprise that obesity
is also associated with higher rates of this oesophageal malignancy, with
estimates of a fivefold increase for individuals with class III obesity [95].
The relative risk of cholelithiasis over 18 years of follow-up inthe Nurses’
Health Study (age 35–60 years at baseline) was increased sevenfold in
people with BMIs ≥45.0 kg/m
2
[96]. Use of very-low-calorie diets and
bariatric surgery which can result in rapid weight loss are also associated
with increased incidence of symptomatic gall stone disease in obese indi-
viduals [97, 98]. Acute pancreatitis has been shown to be increased in
relation to visceral adiposity [99]. Furthermore, the severity of pancreati-
tis and risk of mor tality are increased in association with morbid obesity
[100, 101].
Non-alcoholic fatty liver disease complicates obesity, but only 10–25%
of fatty livers show steatohepatitis (NASH), an inflammatory liver dis-
ease associated with the MetS that can lead to cirrhosis and progress onto
hepatocellular carcinoma [15, 102, 103]. In association with the obesity
epidemic, the prevalence of NAFLD continues to increase worldwide, esti-
mated to affect 20–40% of the population. Weight loss of even 10% with
improved diet and exercise can significantly improve indices of NAFLD
and NASH, but this is often difficult to achieve for affected individuals
[103].
Renal System
T2D is well known to cause nephropathy, and its contribution to the bur-
den ofchronic kidney disease and end-stagerenal disease is increasing.This
is asa consequenceof increasedT2Dprevalence, includingat youngerages,
and success in reducing deaths from ASCVD in T2D patients, such that
people now live longer with T2D [104]. Obesity, independent of T2D,
has also been proposed to be a contributor to the increasing prevalence of
chronic kidney disease [105]. A meta-analysis showed that, compared with
88 C. J. Nolan
normal-weight individuals, overweight and obese individuals had elevated
risk for chronic kidney disease, with respective relative risks of 1.40 (95%
CI, 1.30–1.50) and 1.83 (95% CI, 1.57–2.13) [106]. Hypertension, dys-
lipidaemia, hyperinsulinaemia and systemic inflammation, all features of
the MetS, have been implicated as pathogenic factors in obesity-related
chronic kidney disease [20, 105].
Musculoskeletal System
Obesity is associated with increases in the occurrence of osteoarthritis,
possibly rheumatoid arthritis, sarcopaenic obesity, and a higher hip frac-
ture risk [107–110]. For obesity and osteoarthritis, weight-loaded joints,
in particular the knee, are affected, with increasing evidence pointing
to synergistic effects of biomechanical issues and systemic inflammation
associated with central adiposity in its pathogenesis [111]. The Fram-
ingham study provided evidence for an association between obesity and
knee osteoarthritis, with the relationship stronger in women (relative risk
heaviest quintile of weight compared to the lightest 3 quintiles at base-
line: 2.07, 95% CI: 1.67–2.55) than in men (1.51, 95% CI: 1 .14–1.98)
[112]. Treatment of knee osteoarthritis with total knee joint replacement
is associated with an increased risk of surgical complications, in particular
infection, and this risk is higher in patients with sarcopaenic obesity (con-
currence of obesity and reduced muscle mass) [113]. Additionally, obesity
and osteoarthritis comorbidity are associated with worse physical activity
scores, low quality of life and increased disability [114].
Although study results are not consistent, obesity may be associated
with an increase in the development of rheumatoid arthritis. Obesity is
also associated withgreater subjective measures of disease activity and poor
treatment response, but less destructive joint disease and mortality [107,
115]. Uncertainty exists as to whether the poorer treatment response in
obese individuals with rheumatoid arthritis is due to less efficiency of the
medications or is a consequence of subjective reporting differences [107].
Evidence also points to increased risk of hip fracture in association with
central adiposity, but reduced risk of vertebral fractures in obese men, with
no difference in obese women [110, 116]. Sarcopaenic obesity in men and