Medical Consequences of Obesity

OBESITY

Medical Consequences of Obesity

Major complications of overweight and obesity, and approximate relative risks at BMI > 27–30 kg/m2 Hirsutism 2 Sweating ↑

Stroke 1.6 Low mood, poor self-esteem ↑

I Packianathan N Finer Hypertension 2.9 Coronary heart disease 2.5 Thromboembolism 1.5 Heart failure 1.5

Hypoventilation ↑ Sleep apnoea ↑ Breathlessness 3.5

Obesity is chronic disease with important health and psychosocial consequences. The medical complications affect almost every body system (Figure 1). Evidence for these risks comes from both cross-sectional surveys and large, prospective studies following cohorts of men and women over decades. Body mass index (BMI) is most commonly used to determine obesity in such epidemiological studies, though waist circumference (or waist:hip ratio) is increasingly important.

Breast cancer 1.3 Infertility ↑ Pregnancy problems 2 Cancer of uterus 4.6 Menorrhagia 1.8

Gallstones 2.7 Cancer of colon 1.5 Cancer of pancreas 1.6 Kidney disease ↑

Mortality Many studies have reported a ‘U-shaped’ or ‘J-shaped’ curve relating BMI to mortality. The greater mortality at low BMI is partly explained by the association of smoking and pre-existing illness with low body weight. The link between BMI and mortality weakens with increasing age, partly because of the increasing prevalence of diseases that increase mortality and also cause weight loss, and partly because harmful visceral fat deposition is greater at lower BMI and there is an increasing bias in BMI that fails to reflect adiposity. A recent analysis of the Framingham Heart Study confirmed that life expectancy is reduced in the overweight and obese. A 40-year-old man or woman with a BMI of more than 30 kg/m2 can expect to lose an average of 7 years of life compared with a normal-weight individual (Figure 2); this is equivalent and additive to the risks of smoking.

Diabetes mellitus 10 Dyslipidaemia 1.5 Hyperinsulinaemia ↑↑ 1

Central or upper body fat distribution, as measured by waist circumference, is an independent risk factor for the development of type 2 diabetes (Figure 5). Visceral obesity is associated with insulin resistance, which is present at the level of the peripheral tissues (muscle and adipose tissue) and the liver (Figure 6) (see page 27). Insulin resistance is primarily caused by post-receptor defects (impaired autophosphorylation of tyrosine kinase, the enzyme responsible for glucose transport, oxidation and storage)

Type 2 diabetes The link between type 2 diabetes and obesity is strong within and between ethnic and population groups (Figure 3); about 75% of patients are overweight or obese. In Europe and North America, the risk of type 2 diabetes begins to increase from BMI 22 kg/m2 in women and 24 kg/m2 in men; in Asian populations, the risk begins to increase at BMIs of 1–2 kg/m2 lower. Weight gain also carries a risk. In men aged 40–75 years followed for 5 years, the risk of diabetes was 6.4-fold greater in those who had a BMI of 27 kg/m2 at age 21 years and, independently, 3.5-fold greater in those who gained 9 kg from that age (Figure 4). The relative risk of developing diabetes increases by 25% for every 1 kg/m2 increase in BMI above 22 kg/m2.

Years of life lost in men and women who are obese (BMI > 30 kg/m2) at age 40 years, relative to the non-obese (BMI 18.5–24.9 kg/m2) Female non-smoker Female smoker

Male non-smoker Male smoker

Years of life lost relative to BMI 18.5–24.9 kg/m2

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I Packianathan is Clinical Research Fellow at the Luton and Dunstable Hospital, Luton, UK.

8 6 4 2 0

Obese (all) N Finer is Clinical Director of the Wellcome Trust Clinical Research Facility, Cambridge, UK, Honorary Consultant in Obesity Medicine at Addenbrooke’s Hospital, Cambridge and Senior Research Associate at the University of Cambridge.

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Osteoarthritis 2 Gout 3 Varicose veins ↑

Obese (without hypertension/diabetes)

Source: Peeters A et al. Ann Intern Med 2003; 138: 24–32.

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Prevalence of type 2 diabetes increases with weight

Age-adjusted relative risk

East Pakistan Malaysia El Salvador Guatemala Venezuela Uruguay

7.5

Costa Rica

5.0

Nicaragua Honduras 2.5

30 25 20 15 10 5 0

Panama

0 70

80

90

100

110

120

130

< 21

140

% Mean standard weight Source: West K M. Diabetes 1970; 19: 656–63.

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and, to a lesser extent, a receptor defect. High levels of tumour necrosis factor α in obese individuals have been shown to inhibit autophoshorylation of tyrosine kinase and could have an important role in the development of insulin resistance. Initially, insulin resistance is compensated for by increased insulin secretion by pancreatic β cells, to maintain normal glucose homeostasis at the expense of hyperinsulinaemia. When the β cells ‘burn out’ and insulin secretion cannot match the increasing insulin resistance, impaired glucose tolerance and frank diabetes develop.

< 29

< 31

≥ 35

< 91

< 96.3

≥ 96.4

30 25 20 15 10 5 0

< 71

< 75.9

< 81

< 86

5

The relationship between visceral obesity and insulin resistance ↑ Tumour necrosis factor α

Upper body fat Visceral obesity ↑ Waist circumference

Post-receptor defect

Insulin resistance

Receptor defect

Adipose tissue

Muscle

Liver

Relative risk of developing type 2 diabetes (adjusted for age and BMI at age 18 years) during 14 years of follow-up increases with weight gain Weight change (kg)

< 27

Source: Carey V J et al. Am J Epidemiol 1997; 145: 614–19.

The most common and most deleterious effects of obesity are on the cardiovascular system, and include hypertension, heart failure, coronary heart disease (CHD) and stroke associated with disorders of lipids and haemostasis. Left ventricular (LV) mass – there is a direct relationship between BMI and LV mass, representing an adaptation to the increased cardiac output required to meet the high metabolic demands of greater body mass. The total circulating volume expands, causing an increase in pre-load and LV end-diastolic

Increased insulin secretion by pancreas

Weight loss Hyperinsulinaemia Weight gain

0

2

4

6

8

10

12

Compensated

14

Normal glucose tolerance

Relative risk of developing diabetes over 14 years Source: Colditz G A et al. Ann Intern Med 1995; 122: 481–6.

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< 25

Waist circumference (cm)

Cardiovascular system

> 20 11–19.9 5–10.9 < 5, < 5 5–7.9 8–10.9 11–19.9 > 20

< 23

BMI (kg/m2) Age-adjusted relative risk

Prevalence of diabetes (%)

Age-adjusted models of type 2 diabetes risk according to BMI and waist circumference

Uncompensated

Impaired glucose tolerance and diabetes

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volume. Cardiac output is a function of heart rate and stroke volume, and, because heart rate in obesity remains relatively constant, the increase in cardiac output is effected by an increase in stroke volume. As stated in Starling’s law (force of contraction is directly proportional to the initial length of muscle fibre), the increased end-diastolic volume causes LV dilatation, myocardial hypertrophy and, initially, improved myocardial contractility. A process of eccentric hypertrophy, in which the ratio between LV wall thickness and chamber cavity radius is preserved, maintains cardiac reserve. The increased LV mass seen in obesity also results from fatty infiltration of epicardial fat into the myocardium (and may have a role in the arrhythmias associated with obesity). Hypertension and heart failure – more than one-third of obese adults have hypertension (blood pressure ≥ 140/90 mm Hg) – twice the prevalence in those with BMI less than 25 kg/m2. It has been estimated that, for every 10% increase in weight, there is a blood pressure increase of 6 mm Hg systolic and 4 mm Hg diastolic. Hypertension in the obese develops secondary to increased sodium retention and vascular resistance related to changes in the renin–angiotensin system, insulin resistance and increased peripheral sympathetic nervous system activity (Figure 7). Increased sympathetic activity correlates with 24-hour urinary excretion of noradrenaline, which in turn directly correlates with BMI, waist:hip ratio, glucose and fasting insulin levels. The combination of eccentric LV hypertrophy and hypertension leads eventually to heart failure. Several studies have identified congestive heart failure as a common complication of obesity and an important cause of death. Even in the absence of hypertension, obesity-related cardiac structural changes can lead to ‘obesity cardiomyopathy’. CHD is also associated with weight gain and obesity. The Nurses’ Health Study showed a clear relationship between CHD and elevated BMI, even when controlling for age, smoking, menopausal status and family history. The risk of CHD increased from BMI 22–23 kg/m2, and was doubled at 25–28.9 kg/m2 and more than three times higher above 29 kg/m2 compared with the risk at BMI less than 21 kg/m2. In UK men, the risk of CHD increases by 10% with every 1 kg/m2 increase in BMI above 22 kg/m2. However, waist circumference may be a better predictor of susceptibility to CHD; measurements of more than 94 cm in men and 80 cm in women identify individuals at a risk similar to that in those with BMI more than 25 kg/m2. In men and women with a waist circumference of more than 102 cm or 88 cm respectively, the risk of CHD is similar to that at BMI more than 30 kg/m2.

Other problems – obese individuals are more prone to thrombosis, stroke and myocardial infarction. Altered rheology is also seen, and levels of clotting factors VII and X are elevated.

Metabolic syndrome Metabolic syndrome is discussed on page 27.

Respiratory dysfunction Dyspnoea and breathlessness at rest and particularly on exertion are common complaints of the obese. These symptoms arise partly because of the mechanical effects of excess weight on respiratory compliance (stiffness of the thoracic cage). Greater weight imposes higher ventilatory demands, to meet the greater consumption of oxygen on exercise; these demands are usually met by an increased ventilatory rate sufficient to maintain arterial oxygen and carbon dioxide levels. End-expiratory lung volume is reduced at rest in obesity because of the mechanical load on the chest wall, but does not decrease normally in response to exercise, impairing the normal increase in mechanical advantage of the diaphragm and the balance between inspiratory and expiratory muscles. This latter impaired exercise response seems to account for the symptoms of breathlessness, even in patients who maintain normal gas exchange. In the early stages of obesity, compensatory mechanisms operate to maintain a eucapnic state through increased central respiratory drive, which may increase 3–4-fold. These mechanisms fail to meet the demand as weight increases, however, and pulmonary hypoventilation develops that can lead to more severe cardiorespiratory compromise (Figure 8). Obstructive sleep apnoea (OSA) and obesity–hypoventilation syndrome (OHS) – OSA is a common feature of morbid obesity. It is characterized by disturbed sleep at night and somnolence during the day (with a tendency to fall asleep while resting or driving). The patient’s partner may report snoring and episodes of apnoea at night. The causes are partly mechanical (reduced upper airway dimensions and shape changes through fat deposition, large tongue, reduction of lung volume from abdominal obesity). However, it seems clear that impaired muscle tone of the upper airway muscles and a possible afferent sensory defect (from chronic airway vibration and occlusion) are also important determinants. In practice, some degree of OSA occurs in all men with a neck circumference of more than 42 cm. OSA is defined as repetitive cessation of airflow at the mouth or nostrils for 10–15 seconds during sleep secondary to collapse of the upper airway at the level of the pharynx. Respiratory efforts continue against the obstruction, but terminate when the apnoea produces hypoxaemia sufficient to rouse the patient from sleep (Figure 9). Traditionally, OSA was considered clinically significant only in those suffering five or more episodes per hour or 40 episodes in 7 hours, but this definition may be too narrow. Disruption of normal sleep and frequent arousals lead to excessive daytime sleepiness and neuropsychiatric manifestations including irritability, aggressive behaviour, short-term memory loss and impaired concentration. The repeated episodes of hypoxaemia can result in pulmonary hypertension, polycythaemia and cor pulmonale. OHS may precede OSA. The principle feature is persistent hypercapnia, which may not be present in OSA. OHS clearly overlaps

Proposed mechanisms by which hyperinsulinaemia contributes to hypertension • Vasodilatation • Increased sympathetic nervous system activity, directly and from vasodilatation • Increased renal tubular ‘salt sensitivity’, sodium retention • Increased renal sodium/hydrogen exchange • Lower free fatty acids stimulating aldosterone secretion • Vascular smooth muscle cell proliferation • Atherosclerosis increasing vascular rigidity

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lasted more than 6 years and involved more than 7000 children aged 4–17 years), the fattest children were 77% more likely to suffer symptoms of asthma. It was suggested that increased weight might lead to inflammation in the respiratory tract, which could be the key factor in inducing asthma, but it is impossible to determine whether these children were obese as a result of asthma (possibly because they took less exercise) or whether obesity caused their asthma. In a multivariate analysis, the relative risk of adult-onset asthma was strongly associated (P = 0.001) with BMI. Using the strictest case definition of asthma (subjects who reported physiciandiagnosed asthma within 1 month of symptom onset, plus use of a prescribed long-term, preventive asthma medication in the last year), nurses who had gained more than 25 kg in weight since the age of 18 years had the highest relative risk (4.7) for the development of asthma.

Classification of obesity-related respiratory compromise Stage 1 – BMI < 27 kg/m2 • Normal forced vital capacity • Reduced end-expiratory reserve volume • Low-normal PaCO2 • Recumbancy in sleep may impair ventilation and vascular perfusion • Impaired exercise capacity Stage 2 – BMI 27–35 kg/m2 • Restrictive defect, forced vital capacity 80% predicted • Reduced lung and chest wall compliance • End-expiratory reserve volume almost equals closing volume • Ventilation/perfusion mismatch • Increased alveolar–arterial gradient • Impaired gas exchange during sleep • Mild daytime hypercapnia indicative of sleep-disordered breathing • Dsypnoea on exercise and at rest Stage 3 – BMI > 35 kg/m2 • Pulmonary hypertension and right heart failure • Hypercapnoea • Obesity–hypoventilation syndrome • Obstructive sleep apnoea

Gallstones The incidence of gallstones is greater in obese women, but the relationship is not strong in men. The risk is increased twofold in those with a BMI of 30 kg/m2 and sevenfold at BMI more than 45 kg/m2. Mechanisms include increased cholesterol synthesis, reduced bile acids, changes in cholesterol:bile acid ratio and impaired motility in the gallbladder, probably as a consequence of impaired responsiveness of the gallbladder to cholecystokinin.

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Psychosocial Obese individuals face discrimination in education, work, health care and social relationships. In a US study of 16–24-year-olds followed for 7 years, women who were overweight at the start of the study completed fewer years at school, were less likely to be married, had lower household incomes and experienced higher rates of household poverty (see page 7). In contrast, overweight men in the study were only less likely to be married. The obese often receive a lower standard of education than their thinner counterparts and perform less well in educational environments. Obese students tend to complete fewer years at school and, in the USA, obese women are about 65% less likely to be accepted by their first-choice college than are thinner students, even when they have the same grades. Several studies have shown a general reluctance to employ obese individuals. In a recent study of job recruitment decisions, obese applicants and applicants with diabetes were both less likely to be hired than ‘healthy’ applicants, but for different reasons – the obese applicants were considered to have poor work habits and were thought more likely to have emotional and interpersonal problems. It is clear that obesity is considered a social stigma, though ethnicity is an important confounding factor. Obese women tend to suffer greater prejudice than obese men; studies have shown that obese women have more difficulty being upwardly mobile and relating to others. Psychological and emotional distress appears to be more common in the obese, though most studies have not found increased psychiatric morbidity. Obese individuals seeking treatment in clinics report a high degree of emotional disturbance, and also binge-eating behaviour, but are a biased sample. u

Obstructive sleep apnoea

Loud snoring

Upper airways obstruction

Airway patency restored

Cessation of airflow

Arousal Progressive asphyxia Reduced PO2

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with other respiratory diseases such as chronic bronchitis and emphysema. OHS and OSA can be confirmed by polysomnographic studies and measurements of arterial oxygen and carbon dioxide levels. Asthma – recent research has suggested a link between obesity and asthma. In the US National Health and Nutrition Study (which

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REFERENCES Carey V J, Walters E E, Colditz G A et al. Body Fat Distribution and Risk of Non-insulin-dependent Diabetes Mellitus in Women: The Nurses’ Health Study. Am J Epidemiol 1997; 145: 614–19. Colditz G A, Willett W C, Rotnitzky A et al. Weight Gain as a Risk Factor for Clinical Diabetes Mellitus in Women. Ann Intern Med 1995; 122: 481–6. Davies R J, Stradling J R. The Relationship between Neck Circumference, Radiographic Pharyngeal Anatomy, and the Obstructive Sleep Apnoea Syndrome. Eur Respir J 1990; 3: 509–14. de la Maza M P, Estevez A, Bunout D et al. Ventricular Mass in Hypertensive and Normotensive Obese Subjects. Int J Obes Relat Metab Disord 1994; 18: 193–7. He J, Ogden L G, Bazzano L A et al. Risk Factors for Congestive Heart Failure in US Men and Women: NHANES I Epidemiologic Follow-up Study. Arch Intern Med 2001; 161: 996–1002. Manson J E, Willet W C, Stampfer M J. The Nurses’ Health Study: Body Weight and Mortality among Women. N Engl J Med 1997; 333: 677–85. Peeters A, Barendregt J J, Willekens F et al. Obesity in Adulthood and its Consequences for Life Expectancy: A Life-table Analysis. Ann Intern Med 2003; 138: 24–32. Young S Y, Gunzenhauser J D, Malone K E et al. Body Mass Index and Asthma in the Military Population of the Northwestern United States. Arch Intern Med 2001; 161: 1605–11.

Management of Obesity and Overweight M E J Lean

The emergence of obesity as a distinct disease presents new issues for health services, and often personal conflicts for doctors relating to the aims and potential demands of treatment. The justification for treating obesity is founded on its enormous cost to health services (including drugs for conditions resulting from weight gain) coupled with evidence of the benefits of weight loss. There is less well-documented evidence for benefits of weight loss than for the association between obesity and secondary diseases, partly as a consequence of the limited number of studies that have induced and maintained weight loss long enough to provide such data, and partly because uncritical dismissal of interventions that did not ‘cure’ obesity by achieving normal body weight. More recently, it has been recognized that modest weight loss leads to major long-term health gains, and the emphasis has shifted towards weight maintenance.

FURTHER READING Inoue S, Zimmet P. The Asia–Pacific Perspective: Redefining Obesity and its Treatment. Sydney: Health Communications Australia. www.diabetes.com.au/downloads/obesity_report.pdf (The epidemiology and health consequences of obesity in Asia.) National Institutes Of Health National Heart, Lung and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. NIH Publication No. 98-4083 September 1998. Bethesda: National Institutes of Health, 1998. www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns.pdf (This large, evidence-based report on obesity provides a wealth of information on all aspects of the disease.) Nature Insight 2000; 404. (An entire issue devoted to obesity, including medical aspects, genetics and treatment.) UK National Audit Office. Tackling Obesity in England. HC 220 Session 2000–2001: 15 February 2001. London: HMSO, 2001. www.nao.gov.uk/publications/nao_reports/00-01/0001220.pdf (Details the costs of obesity to the NHS and makes recommendations on initiatives across government to address the problem.)

Aims and criteria of success in weight management Most individuals gain weight gradually during adult life, reaching a plateau at about 60 years of age. The rate of weight gain varies; the average is 15–20 kg between age 20 and 60 years. In those who become obese, a gain of 1–2 kg/year is average and 5–10 kg/year is common. Only a few individuals maintain a body mass index (BMI) of less than 25 kg/m2 throughout their adult M E J Lean is Professor of Human Nutrition at the University of Glasgow, UK, and Honorary Consultant Physician at Glasgow Royal Infirmary.

What’s new ? • Adult obesity (BMI > 30 kg/m2) has exceeded the WHO definition of an epidemic (> 15% worldwide) • Correcting physical inactivity is increasingly seen as the vital first step in effective weight management • Weight loss of 5–10 kg sustained for 4 years by modest dietary change, moderate physical activity and orlistat reduces the incidence of diabetes by 30–60% • Long-term (2-year) trials of sibutramine and orlistat show sustained weight loss of about 12–13 kg, with improvements in all risk factors • Major weight loss after gastric surgery for obesity tends to be followed by regain after 2–3 years, but with sustained health benefits including prevention of diabetes

Practice points • Obesity reduces life expectancy by about 7 years in 40-year-old men and women • Obesity is an important risk factor for cardiovascular diseases including CHD, heart failure and stroke • Weight gain, obesity and a large waist circumference are potent predictors of later development of type 2 diabetes • Respiratory complications of obesity are common; sleep apnoea is predicted by neck circumference > 42 cm

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