Comorbidity pp 79-114 | Cite as

Overview of the Comorbidity Between Medical Illnesses and Overweight/Obesity

  • Christopher J. NolanEmail author


Overweight and obesity are major contributors to the total global burden of chronic diseases due to the consequences of their associated comorbid conditions which can affect all systems of the body. These comorbidities are often considered to be consequence of the excess weight with unidirectional causality; however, causality is almost certainly multidirectional with roles for both physical and psychological factors. In this chapter, an overview of overweight- and obesity-related medical illnesses, categorised according to the body systems affected, is provided. Some focus is directed towards the role of the metabolic syndrome in these illnesses. The importance of causality of comorbid conditions at early, middle and late stages of disease is emphasised, as interventions targeting causalities at each of these times are likely to have the greatest impact on lessening the burden of overweight and obesity on affected individuals.

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 observation 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), cardiovascular disease, renal disease, musculoskeletal disorders and some cancers [1, 2, 3]. The rising prevalence of obesity in women of child-bearing age is also adversely affecting pregnancy outcomes with transgenerational health 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 are conditions in which there is excessive accumulation 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/kg2), normal weight (18.5–24.9 m/kg2), overweight (25.0–29.9 m/kg2), obese class I (30–34.9 m/kg2), class II (35–39.9 m/kg2) and class III (≥40.0 m/kg2) [7]. For Asian and South Asian populations, lower BMI cut-offs for overweight (23.0–24.9 m/kg2) and obesity (≥25.0 m/kg2) 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 consequence of systemic metabolic and inflammatory disturbances (Metabolic Syndrome; MetS) or just the consequence of the mechanical effects of carrying 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, hyperinsulinaemia, glucose intolerance, hypertriglyceridaemia, reduced high-density lipoprotein cholesterol and hypertension and their link to atherosclerotic cardiovascular disease (ASCVD) were described by Professor Gerald Reaven in 1988 [10]. This clustering of factors was initially named “Syndrome X” by Reaven and was later named the “Insulin Resistance 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 adiposity, increased apolipoprotein B and small dense LDL particles (proatherogenic), 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), polycystic ovarian syndrome (PCOS), T2D, and ASCVD [12, 13, 14, 15, 16, 17]. MetS has also been associated with increased risk for chronic kidney disease, cognitive impairment, obstructive sleep apnoea, chronic respiratory diseases and skin conditions [18, 19, 20, 21, 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, 25, 26]. Similarly, if a person has NAFLD, the risk for the person of having a non-fatal or fatal cardiovascular 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 mechanisms 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 preventive and therapeutic strategies for the syndrome and its associated comorbidities. 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 primary and that the resultant hyperinsulinaemia drives the other components 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 associated 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 dysfunction [28].

4.1.2 Overweight-/Obesity-Associated Medical Illnesses According to Body Systems

Endocrine System

Many endocrine conditions including hypothyroidism, Cushing’s disease, hypothalamic/pituitary disorders, 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, 30, 31, 32, 33]. However, 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 incidental 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 estimated 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 rates of low self-esteem, depression, anxiety, disordered eating and psychosexual dysfunction than women without PCOS [39, 40, 41]. The rate of hospital admissions for women with PCOS in a Western Australian population in comparison with women without PCOS was markedly higher including for conditions such as T2D, cardiovascular diseases, psychological disorders including self-harm and fertility disorders [42].

Worldwide, approximately 415 million people are diagnosed with 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]. Gestational 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, 44, 45, 46, 47]. Strengthening the linkage between obesity and Alzheimer’s disease is post-mortem findings of increased amounts of Alzheimer’s disease-associated biomarkers, amyloid β and tau, in the hippocampal tissue of elderly patients 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, 50, 51, 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, 56, 57, 58, 59, 60].

Less appreciated is the association between obesity and both autonomic dysfunction and peripheral polyneuropathy [43]. Obesity is associated with an imbalance in the autonomic nervous system with increased sympathetic compared to parasympathetic activity [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 dysmetabolic effects [61, 62, 63]. Interestingly, while diabetes is a major contributor 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 presence 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 cardiovascular 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 protected 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].

Obesity is also an established risk factor for heart failure, including heart failure with both preserved and reduced ejection fraction, often in the absence of evident coronary artery disease [69, 70, 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, hypertension, obstructive sleep apnoea and obesity hypoventilation syndrome, as well as ASCVD [70, 72, 73, 74, 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 pulmonary disease (COPD), asthma, obstructive sleep apnoea and obesity hypoventilation syndrome [77]. More severe categories of obesity result in restrictive lung impairment, as shown by lower total lung volume, forced vital capacity (FVC) and forced expiratory volume in 1-second (FEV1) measurements; that can be attributed to intraabdominal 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 factors 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].

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]. Furthermore, obesity in individuals with COPD was associated with reduced respiratory-specific and general quality of life, reduced 6-min walk distance, 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 crude 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, 84, 85]. This is an important obesity condition, 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, 87, 88, 89]. Thus, obstructive sleep apnoea contributes significantly to the comorbid medical and psychological illnesses of obesity.

Obesity hypoventilation syndrome, also known as Pickwickian syndrome, is defined as the triad of obesity, daytime hypoventilation and sleep-disordered breathing in the absence of an alternative neuromuscular, 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, pancreatitis, NAFLD including non-alcoholic steatohepatitis (NASH) and various gastroenterological and hepatic cancers.

GORD is one of the most common conditions affecting the gastroenterological tract estimated to be present in 10–20% of European and US populations, with its prevalence being more than doubled in obese individuals [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 precursor 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 in the Nurses’ Health Study (age 35–60 years at baseline) was increased sevenfold in people with BMIs ≥45.0 kg/m2 [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 individuals [97, 98]. Acute pancreatitis has been shown to be increased in relation to visceral adiposity [99]. Furthermore, the severity of pancreatitis and risk of mortality 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 disease 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, estimated 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 burden of chronic kidney disease and end-stage renal disease is increasing. This is as a consequence of increased T2D prevalence, including at younger ages, 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 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, dyslipidaemia, 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 fracture risk [107, 108, 109, 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 Framingham 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 baseline: 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 (concurrence 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 with greater 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 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, including lower limb cellulitis, as a consequence of venous stasis and lymphoedema, hidradenitis suppurativa and intertrigo particularly due to candidiasis, but often the consequence of mixed bacterial and fungal infections [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 fertility as a consequence 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 and depression, 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 intensive care unit are increased about twofold [123, 124]. Obesity, particularly in association with hyperglycaemia, is associated with higher rates of congenital malformations [123, 125]. Importantly, maternal overweight and obesity were recently reported to be the highest-ranking modifiable risk factors for stillbirth [126]. Importantly, maternal obesity is also a determinant 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 hypercoagulability 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]. Associations between obesity and iron deficiency are also reported [131]. Obesity has also been linked to increased risk of haematological malignancies including myeloma, chronic myeloid leukaemia and acute lymphoblastic leukaemia [132].


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, kidney, meningioma, thyroid and multiple myeloma [133]. Other malignancies (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 understand 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 evidence suggests that their coexistence is the result of more than simple overlap [135]. Overweight and obesity have also been reported to be 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 schizophrenia [136, 137, 138, 139, 140, 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 is important, as this 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. Cushing’s disease, hypothyroidism, testosterone deficiency) and obesogenic drugs (e.g. glucocorticoids, clozapine) [143, 144]. For the majority, however, 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, personality 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, 146, 147, 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 interventions 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 we recently suggested that insulin hypersecretion in response to poor diet and lack of exercise is very much an upstream event in its causation, with the resultant hyperinsulinaemia likely driving the other components of the MetS [11, 12, 23]. Nonetheless, the underlying determinants of the development of MetS, even if there is a main driver such as hyperinsulinaemia, are undoubtedly complex and may include genetic factors, epigenetic factors 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, socioeconomic 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 syndrome (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 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 studies 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 depression.

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 pollution 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 ambient 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 temperature, 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 control, especially in patients with poor glycaemic control and/or diabetes complications. Taken together, the results suggest that an elevated BT (due to ambient warming) is linked to the onset and progression of diabetes, whereas cold exposure might have therapeutic potential. Nevertheless, behavioural mechanisms are also likely to be involved in causing the overweight-/obesity-related comorbidities. For example, night shift-work rostering is known 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 causality [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, dysglycaemia and hypertension can 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 states is associated with the greater likelihood of the others [24, 25, 26, 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 tissue 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 hepatocellular 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, obstructive sleep apnoea is well known to aggravate hypertension and contribute to cerebrovascular and cardiovascular diseases [18, 86]. Osteoarthritis of 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 measures 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 comorbidities, 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, 167, 168]. The economic cost of comorbidity is of major concern to health service providers [169]. Various 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 multimorbidity, 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 also associated with increased risk of premature mortality, and this is a direct consequence of its associated comorbidities [173, 174].

Sarcopaenia can develop as a consequence of ageing as well as many chronic diseases including obesity and MetS, COPD, chronic liver disease, 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 contribute 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 consideration, 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 outcomes in overweight and obese individuals with multiple comorbidities and it should be a focus of intervention.

The effects of physical health multimorbidity on psychological health are very strong. For example, in a survey of 7620 patients in primary care, 23% of patients with one chronic 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 bipolar 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.

4.3 Lessening the Burden of Comorbid Illnesses in Overweight and Obese Individuals

Lessening the burden of overweight and obesity on affected individuals and 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. Therefore, 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 comorbidities 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 bariatric surgery 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 patients should be by a multidisciplinary team of health professionals with expertise in managing complex illness.


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© The Author(s) 2020

Authors and Affiliations

  1. 1.Australian National UniversityCanberraAustralia

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