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Obesity is now so common within the World's population that it is beginning to replace undernutrition and infectious diseases as the most significant contributor to ill health. Major advances in the understanding of overweight and obesity confirm that they constitute an important medical condition. A better understanding of the genetic contribution to both weight gain and the intra-abdominal distribution of fat (central obesity) is identifying certain ethnic groups and susceptible families who are specifically at risk.

Obesity causes or exacerbates a large number of health problems, both independently and in association with other diseases1. In particular, it is associated with the development of type 2 diabetes mellitus, coronary heart disease, an increased incidence of certain forms of cancer, obstructive sleep apnoea, and osteoarthritis of large and small joints. The Build and Blood Pressure Study has shown that the adverse effects of excess weight tend to be delayed, sometimes for 10 years or longer2. Life insurance data and epidemiological studies confirm that increasing degrees of overweight and obesity are important predictors of decreased longevity3. In the Framingham Heart Study, the risk of death within 26 years increased by 1% for each extra pound [0.45kg] increase in weight between the ages of 30 years and 42 years, and by 2% between the ages of 50 years and 62 years4. Despite this evidence, many clinicians continue to consider obesity to be a self-inflicted condition of little medical significance.
Obesity can no longer be regarded simply as a cosmetic problem affecting certain individuals but must be considered an epidemic requiring effective measures for its prevention and management. The object of this chapter is to detail the pathophysiology of a number of important medical problems caused by obesity and present a system for the clinical assessment of an overweight or obese patient.

CLINICAL PROBLEMS CAUSED BY OVERWEIGHT AND OBESITY

Increasing body fatness is accompanied by profound changes in physiological function. These changes are, to a certain extent, dependent on the regional distribution of adipose tissue. Generalised obesity results in alterations in total blood volume and cardiac function while the distribution of fat around the thoracic cage and abdomen restricts respiratory excursion and alters respiratory function. The intra-abdominal visceral deposition of adipose tissue, which characterises upper body obesity, is a major contributor to the development of hypertension, elevated plasma insulin concentrations and insulin resistance, hyperglycaemia and hyperlipidaemia. The alterations in metabolic and physiological function that follow an increase in adipose tissue mass are predictable when considered in the context of normal homeostasis.

Obesity and type 2 diabetes mellitus

Obesity is characterised by elevated fasting plasma insulin and an exaggerated insulin response to an oral glucose load5. Overall fatness and the distribution of body fat influence glucose metabolism through independent but additive mechanisms. Increasing central obesity is accompanied by a progressive increase in the glucose and insulin response to an oral glucose challenge with a positive correlation being observed between increasing upper body (central) obesity and measures of insulin resistance. Post hepatic insulin delivery is increased in upper body obesity leading to more marked peripheral insulin concentrations that, in turn, lead to peripheral insulin resistance.
Different fat depots vary in their responsiveness to hormones that regulate lipolysis and this also varies according to fat distribution6. In both men and women, the lipolytic response to noradrenaline is more marked in abdominal than gluteal or femoral adipose tissue7 . Cortisol may also contribute to this enhanced lipolysis by further inhibiting the anti-lipolytic effect of insulin. These factors contribute to an exaggerated release of free fatty acids (FFA) from abdominal adipocytes into the portal system8. FFA have a deleterious effect on insulin uptake by the liver and contribute to the increased hepatic gluconeogenesis and hepatic glucose release observed in upper body obesity. Insulin insensitivity is not confined to adipocytes with the process being accentuated by skeletal muscle insulin resistance.
The elevation in plasma FFA concentration, particularly postprandially when they are usually suppressed by insulin, leads to an inappropriate maintenance of glucose production and an impairment of hepatic glucose utilisation (impaired glucose tolerance). Reduced hepatic clearance of insulin leads to increased peripheral [systemic] insulin concentrations and to a further down-regulation of insulin receptors.
In the initial phases of this process, the pancreas can respond by maintaining a state of compensatory hyperinsulinaemia with gross decompensation of glucose tolerance being prevented (figure 1).

Figure 1. A schematic illustration of the effect of increasing abdominal fatness that results in a vicious cycle of events leading to pancreatic islet cell decompensation and type diabetes. The initial process is decreased insulin sensitivity with increasing hepatic glucose production and reduced insulin uptake. This results in systemic hyperinsulinaemia with skeletal muscle insulin resistance - this, in turn, leads to additional demands on the islet cells to release more insulin.

With ever increasing plasma concentrations of FFA, the insulin resistant individual cannot continue to maintain this state of compensatory hyperinsulinaemia, and hyperglycaemia prevails. Hyperinsulinaemia and insulin resistance are both significant correlates of a dyslipoproteinaemic state and contribute to the characteristic alterations of plasma lipid profile associated with obesity: elevated fasting plasma triglyceride concentration, reduced HDL-cholesterol, marginal elevations of cholesterol and LDL-cholesterol concentrations and increased number of apo-B carrying lipoproteins9.
Prospective population studies confirm a close association between increasing body fatness and type 2 diabetes. In the Nurses Cohort Study, BMI was the dominant predictor of the risk of diabetes after adjustment for age10. In the nurses, the risk of diabetes was increased fivefold for those with a BMI of 25, 28-fold with BMI of 30 and 93-fold for those women with a BMI of 35 or greater. Women who gained 8 to 10.9kg in weight during the period of study had 2.7-fold increased risk of diabetes compared to women of stable weight. Similarly, the risk of diabetes in men increases for all BMI levels of 24 or above. The risk of diabetes, adjusted for age, is 2.2-fold for a BMI between 25 - 26.9, 6.7-fold for a BMI between 29 and 30, and 42-fold for those with a BMI of 35 or greater11. The distribution of fat tissue is also independently associated with diabetes: a waist circumference of >40 inches (102 cm.) increases the risk of diabetes 3.5-fold even after controlling for the BMI12.

Obesity and the Metabolic / Insulin Resistance Syndrome

In 1988 Reaven coined the term Syndrome X to refer to the clustering of (abdominal) obesity, hypertriglyceridaemia, reduced levels of HDL cholesterol, hyperinsulinaemia, glucose intolerance and hypertension13. To this basic cluster of abnormalities have been added further metabolic alterations that include increased atherogenic small, dense LDL particles, elevated apo B concentrations and raised plasminogen activator inhibitor-1 (PAI-1). The syndrome is now referred to as the Metabolic Syndrome or Insulin Resistance Syndrome, the latter identifying the likely pivotal biochemical abnormality. Reaven estimated that the prevalence of insulin resistance within the sedentary adult population of North America is approximately 25% and closely linked to central (visceral) obesity. Several cohort studies have confirmed that upper body (visceral) obesity is associated with greater cardiovascular morbidity and mortality than obesity itself (14,15).

Cardiovascular function in obesity

The effects of increased body fatness on cardiovascular function are predictable. Total body oxygen consumption is increased due to an expanded lean tissue mass as well as the oxidative demands of metabolically active adipose tissue, and this is accompanied by an absolute increase in cardiac output. However, the values are within the normal range when they are normalised to body surface area16. The total blood volume in obesity is increased in proportion to body weight. This increase in blood volume contributes to an increase in the left ventricular pre-load and an increase in resting cardiac output17. The increased demand for cardiac output is achieved by an increase in stroke volume while the heart rate remains comparatively unchanged. The obesity-related increase in stroke volume results from an increase in diastolic filling of the left ventricle18. The volume expansion and increase in cardiac output lead to structural changes of the heart. The increase in left ventricular filling results in an increase in the left ventricular cavity dimension and an increase in wall stress. As left ventricular dilatation is accompanied by myocardial hypertrophy, the ratio between ventricular cavity radius and wall thickness is preserved. This thickening of the wall with dilatation results in eccentric hypertrophy. Left ventricular mass increases directly in proportion to BMI or the degree of overweight19. The blood pressure is a function of cardiac output and the vascular resistance against which the blood is pumped - systemic vascular resistance. An elevated cardiac output is common with moderate obesity but not all obese patients are hypertensive. However, in those subjects where systemic resistance is increased, the combination of hypertension and obesity results in an increase of ventricular wall dimensions disproportionate to the chamber radius and this leads, in time, to concentric hypertrophy20 (Figure 2).

Figure 2. Summary of the events affecting the cardiovascular system that is initiated by increasing body weight. An increased circulating blood volume creates additional demands upon the heart to maintain a normal cardiac output. The process results in re-modeling of the left ventricle with eccentric hypertrophy - if there is a concomitant increase in systemic blood pressure, the process is followed by concentric hypertrophy typical of hypertensive heart disease.

The cardiovascular adaptation to the increased intravascular volume of obesity may not completely restore normal haemodynamic function. Marked systolic dysfunction occurs when the ventricle can no longer adapt to volume overload. Dilatation of the left ventricle cavity radius leads to a decline in ventricular contractility. Despite an elevation of cardiac output, obese individuals have been shown to have depressed myocardial contractility proportional to excess weight21. With left ventricular hypertrophy, reduced ventricular compliance alters the ability of the chamber to accommodate an increased volume during diastole and this results in diastolic dysfunction. A combination of systolic and diastolic dysfunction progresses to clinically significant heart failure. Body weight, independent of several traditional risk factors, was directly related to the development of congestive cardiac failure in the Framingham Heart Study22.

In addition to congestive cardiac failure, the presence of left ventricular hypertrophy has been associated with a greater risk of morbidity and mortality from coronary heart disease, CHD and sudden death as well as abnormal heart rhythms, arrhythmias. In the Nurse's Cohort Study the risk of CHD increased twofold for women with a BMI between 25 to 28.9 and 3.6-fold for a BMI >2923. In the Framingham Heart Study, the 26 year incidence of CHD in women and men was related proportionately to excess weight. In this study the incidence of CHD increased by a factor of 2.4 in obese women and a factor of two in obese men under the age of 50 years24. The independent risk of CHD attributed to obesity in multivariate analysis may reflect other important mediators such as upper body fat, altered rheology and haemostasis, hyperinsulinaemia or sleep apnoea.

Haemostasis and obesity

The haemostatic system plays an important role in the pathogenesis of atherosclerotic plaques and associated complications. A pro-thrombotic environment and/or a situation where thrombus is not cleared will predispose to the development of atherosclerosis and its clinical sequelae.
Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of fibrinolysis. PAI-1 binds to and inactivates tissue plasminogen activator (t-pa) and urokinase-like plasminogen (u-pa), the main activators of plaminogen. As PAI-1 levels increase, plasminogen activation is reduced and consequently fibrin accumulates. In this situation the balance is in favour of thrombosis - high concentrations of PAI-1 are likely to favour the development of atheroscelorosis and its acute complications. Furthermore, the prognostic value of PAI-1 appears to be related to its association with the Metabolic Syndrome25. Results from animal and human studies suggest that adipose tissue may be an important source of PAI-1 and be responsible for elevated concentrations in obese subjects; as fat mass increases so does PAI-1 production26. There is evidence that elevated adipose tumour necrosis factor-a (TNF-a), as found in obesity, may increase PAI-1 mRNA expression in adipose tissue. Moreover, the production of PAI-1 from the liver appears to be regulated by insulin - chronic hyperinsulinaemia is associated with increased PAI-1 mRNA expression27.
PAI-1 levels are positively correlated with the degree of obesity as judged by BMI and waist circumference. This correlation is confirmed by computerised tomography (CT) measurements of visceral fat mass28. PAI-1 concentration is additionally positively correlated with each of the variables that make up the metabolic syndrome: central obesity, hypertension, hypertriglyeridaemia and low HDL cholesterol concentration29.
Fibrinogen is also considered an important predictor of coronary heart disease and future cardiovascular events and may have a direct role in the atherosclerotic process. Fibrinogen stimulates smooth muscle proliferation and migration, is a component of atherosclerotic plaques, promotes platelet aggregation, and is a major contributor to blood viscosity. Increased fibrinogen levels contribute directly to a procoagulant state and thereby favour the development of atherosclerosis30. In a number of studies increased fibrinogen levels appear to be correlated with increasing BMI, most particularly in women31.

Sleep-breathing abnormalities in obesity

An increased amount of fat in the chest wall and abdomen has a predictable effect on the mechanical properties of the chest and the diaphragm and leads to an alteration of respiratory excursions during inspiration and expiration, reducing lung volume and altering the pattern of ventilation to each region. The increased mass of fat additionally leads to a decrease in compliance of the respiratory system as a whole. All of these changes are significantly exaggerated when an obese person lies flat. The mass loading effect of fat requires an increased respiratory muscle force to overcome the excessive elastic recoil and an associated increase in the elastic work of breathing. The obesity-related changes in respiratory function are most important during sleep32,33.

During Rapid Eye Movement (REM) sleep, there are decreases in voluntary muscle tone with reduced arterial oxygen saturation and a rise in carbon dioxide in all individuals but are especially marked in obese subjects. Irregular respiration and occasional apnoeic episodes often occur in lean people during REM sleep but obesity, with its influence on respiratory mechanics, increases their frequency and may result in severe hypoxia with resultant cardiac arrhythmias. Studies of obese men and women have demonstrated that the obstruction occurs in the larynx and is associated with loss of tone of the muscles controlling tongue movement. Relaxation of the genioglossus muscle allows the base of the tongue to fall back against the posterior pharyngeal wall occluding the pharynx. This results in a temporary cessation of breathing (apnoea) and associated transient fall in arterial oxygen saturation concentration, hypoxia. It is not uncommon to observe very low oxygen saturation values during REM sleep in some obese men while their awake arterial gases are normal34. By contrast, pre-menopausal obese women show relatively minor alterations during sleep with a decrease in arterial oxygen saturation of less than 7% without apnoea. After the menopause, the changes seen in obese women become more marked with the reduction in oxygen saturation during sleep being >7% and being accompanied by apnoeic episodes35. A minority of obese patients develop a situation characterised by a marked depression in both carbon dioxide (hypercapnic) and hypoxic respiratory drives accompanied by abnormal and irregular pattern of breathing during sleep and (eventually) in the waking state36. Characteristically, such individuals show frequent and prolonged episodes of sleep apnoea - sleep is disturbed with frequent awakening related to the resumption of breathing following an apnoeic episode. Daytime somnolence soon intervenes accompanied by persistent hypoxia / hypercapnia, pulmonary hypertension (superimposed upon an increased circulatory volume) and right-sided cardiac failure (figure 3). Such changes constitute the clinical manifestation of the obesity-hypoventilation syndrome (formerly known as the Pickwickian syndrome).

Figure 3. An illustration of the vicious circle of events that begin with nocturnal hypoventilation and arterial oxygen desaturation and end in persisting daytime hypercapnia and sustained pulmonary hypertension. With time, right ventricular failure supervenes - the obesity-hypoventilation syndrome.

In the Swedish Obese Subjects study, which examined 3034 subjects with BMI>35, over 50% of men and one third of women reported snoring and apnoea. In contrast, 15.5% of Swedish men of comparable age were self-reported habitual snorers37.
A number of groups have reported an increased risk of myocardial infarction and stroke in sleep apnoea. Snoring is a strong risk factor for sleep-related strokes while sleep apnoea symptoms increases the risk for cerebral infarction38.

Reproductive function in obesity

The association between obesity and abnormalities of reproductive function is well recognized, with decreased libido and impotence commonly seen in extremely overweight men, and increased incidence of dysfunctional uterine bleeding and amenorrhoea being reported in obese women.
Subnormal plasma testosterone concentrations and reduced sex hormone binding globulin [SHBG] levels occur in massively obese men, with an inverse relationship between plasma testosterone and body weight. In these men it has been proposed that elevated plasma oestrogens, which result from increased aromatization of androgen precursors by adipose tissue, results in a negative feedback on the hypothalamo-pituitary axis with subnormal luteinizing hormone [LH] and follicle stimulating hormone [FSH] levels39.

In obese women, raised plasma testosterone and androstenedione concentrations are frequently found with a reduced SHBG and increased ratio of oestrone to oestradiol; it is of interest that a similar pattern of changes of sex steroid concentration and binding are found in women with the polycystic ovary [PCO] syndrome, many of whom are obese. In contrast to the women with the PCO syndrome, obese women have a normal LH and FSH response to direct stimulation by LH releasing hormone [LHRH] and normal gonadotrophin release following the administration of clomiphene, which acts through the hypothalamus40. In obese subjects weight loss not only reverses the biochemical changes but frequently results in the reappearance of menses41.
The precise aetiology of these changes is unclear but evidence points to a peripheral effect of adipose tissue on steroid secretion. Androgen production from the adrenal cortex and ovaries is increased in obesity. This is associated with increased metabolic clearance of testosterone and dihydrotestosterone. Adipose tissue may serve both as a reservoir and a site for steroid metabolism with androgens being irreversibly aromatised to oestrogen or reversibly converted to other androgens42. There are two possible explanations for this obesity-related increase in androgen production. The first is hypothalamic-pituitary-gonadal and adrenal compensation for the increased clearance of sex steroids. The alternative is an increase in ovarian and adrenal production stimulated by other factors such as insulin, and a consequent reduction in hepatic production of SHBG. Independently, increased androgen levels may stimulate upper body fat deposition with an additional increase in steroidal metabolic clearance through adipose tissue sequestration and metabolism43.

Hepatic function and obesity

Non alcoholic steatohepatitis (NASH) is an emerging clinical problem among obese subjects particularly those with central obesity. 40% of patients with NASH are overweight or obese, 20% have type 2 diabetes and 20% hyperlipidaemic44. The development of the characteristic pathological changes within the liver are intimately related to the various clinical and biological markers of the metabolic syndrome - BMI, waist circumference, hyperinsulinaemia, hypertriglyceridaemia, and impaired glucose tolerance. The diagnosis of NASH rests on characteristic histolological features that include substantial fat infiltration, necroinflammation and fibrosis in the absence of alcohol as a cause for the disease. In NASH the ratio of serum alanine transaminase (ALT) to aspartate transaminase (AST) is always >1 whereas the ratio in alcoholic liver disease is almost always <145. Histological evidence of fibrosis and/or cirrhosis is seen in up to 50% of patients with most patients, who initially show fibrosis, developing cirrhosis after 10 years - it has been suggested that "cryptogenic cirrhosis" represents "burnt out" NASH46. A liver biopsy is necessary to make a diagnosis and is important for therapeutic and prognostic reasons - ultrasound scanning of the liver is not sufficiently sensitive to be diagnostic.
The causative factors inducing necrosis, inflammation and fibrosis within the liver include oxidative stress and subsequent lipid peroxidation, factors associated with abnormal cytokine production and factors associated with disordered fat metabolism and insulin resistance.
The two metabolic abnormalities most strongly associated with NASH are insulin resistance and an increase supply of free fatty acids to the liver (see section 2.1 ). There is evidence that NASH associated with obesity and type 2 diabetes is due primarily to peripheral insulin resistance and consequential hyperinsulinaemia47. Insulin blocks hepatic mitochondrial fatty acid oxidation and results in an increased concentration of intracellular fatty acids that may be directly toxic or lead to oxidative stress. The link between central obesity and liver injury may be explained by the fact that fatty acids are mobilised more rapidly from visceral (central) than subcutaneous fat and drain directly to the liver via the portal vein.
Weight loss is generally associated with a reduction in the severity of the biochemical abnormalities and a regression of the steatosis. Nevertheless, sudden weight loss or "weight cycling" (weight loss followed by weight regain) may predispose to NASH48.

Gallstones and Obesity

Gallbladder disease is a well-recognised complication of obesity. Increasing BMI is associated with a substantially increased risk of the development of gallstones; women with a BMI >45 kg/m2 have a sevenfold increase compared to normal weight women49. In men, it appears that the presence of visceral obesity is a stronger risk factor than body weight per se. It appears likely that a solubility defect leading to supersatuation of gallbladder bile is the primary reason for the increased occurrence of gallstones in obesity - obese subjects have higher bile saturation indices than non-obese individuals, possibly because of hepatic secretion of cholesterol into bile.
The risk of gallstone formation increases in the obese during rapid weight loss and it is suggested that extremely low intakes of dietary fat impairs contraction of the gallbladder thereby leading to stasis and increased lithogenicity50.

Obesity and risk of certain cancers

Certain forms of cancer are more common in obese subjects: colorectal and prostate in obese men, carcinoma of the gallbladder, breast and endometrium in obese women. The increased incidence is more prominent for those with upper body fat distribution at lower degrees of obesity and is thought to be a direct consequence of hormonal changes. The incidence of gastrointestinal cancers (such as colorectal and gall bladder) appear to be associated with increased body weight or obesity in some, but not all, studies while renal cell carcinoma has consistently been associated with overweight and obesity especially in women51,52. In addition to overall obesity, intraabdominal fat distribution and adult weight gain have been independently associated with increased risk of breast cancer53.
Adipose tissue contains high levels of aromatase, the enzyme that converts androgens into oestrogens: accumulation of adipose tissue may lead directly to a rise in oestrogen levels. Such a modulation may explain the rising incidence of breast and endometrial cancer in post-menopausal women in the face of a declining concentration of SHBG; reduced levels of SHBG are concomitantly associated with increased concentrations of bioavailable oestrogen. In addition, increased concentrations of free fatty acids have been reported to increase levels of free oestradiol by displacing oestradiol from SHBG54. Oestrogens serve as growth factors for both breast and endometrial cancers and fat cells serve as a source of androstenedione, which is converted into oestrogens.

Osteoarthritis and obesity

Osteoarthritis is the most prevalent joint disorder of an aging population. The knee is the principal large joint to be targeted by osteoarthritis (OA) and it results in disabling knee symptoms in an estimated 10% of patients older than 55 years, a quarter of whom are severely disabled55. The risk of disability attributable to OA alone is as great as that due to heart disease and greater than that due to any other medical disorder in the elderly. A recognised risk factor for the development of OA is obesity because of increased biomechanical forces directed at the joint surfaces. Joint alignment of the knee (varus or valgus alignment) influences the progression of knee OA: the degree of radiographic tibiofemoral narrowing correlates with increasing BMI in those subjects with varus knees56. It appears that varus mal-alignment is a local factor that predisposes the knee to the adverse biomechanical effects of obesity irrespective of whether mal-alignment precedes or follows OA.

Obesity and other associated medical complications

Obesity may be associated with the development of other medical complications. These include gastro-oesophageal reflux secondary to a hiatus hernia, skin problems including oppositional intertrigo, lower limb oedema and varicose veins, excessive sweating, and increased frequency of psychological and psychiatric problems. In addition, the major limiting factor for most obese subjects is breathlessness on minor exertion such as climbing stairs and walking uphill.

ASSESSMENT OF THE OBESE PATIENT

Clinical assessment

Clinical setting: The usual principles for a medical consultation are applicable to the assessment of an overweight or obese patient. The consultation room must be properly equipped with larger than average chairs, access for wheelchairs for patients with mobility problems and medical equipment of appropriate size (examination couch, blood pressure cuff, weighing scales and tape measure).
< Insert Table 1 close to here >

Historical background: Table 1 outlines the areas of medical history that should be covered at the initial assessment. The history of weight gain should be described in detail to elucidate possible aetiological factors and to assess the patient's insight and understanding of the factors causing weight gain. It is also useful to distinguish childhood onset obesity from that occurring later in life either in relation to specific physiological 'critical periods' or illness. A number of syndromes are associated with childhood onset obesity but the longevity of history and the associated clinical features generally make such cases obvious. Disease involving the hypothalamus can often be distinguished from 'spontaneous' or 'simple' obesity by a shorter duration of weight gain and specific symptoms related to associated endocrine disturbances. The identification of the single gene disorders involving leptin and its signalling pathways are somewhat more difficult to distinguish from simple obesity but extreme weight gain from early childhood, a positive family history and continuing hyperphagia. The most common single gene disorder causing obesity, MC4R deficiency, is problematic as there are no pathognomonic features, but the diagnosis should be considered in cases of early-onset, familial obesity, usually with a clear dominant inheritance57.
The measurement of serum leptin is not recommended as a routine, but in cases of severe, early-onset obesity this should be undertaken, as, although rare, congenital leptin deficiency is a potentially treatable disorder.

Clinical examination: An outline of a scheme for the clinical examination is given in Table 2.

Height should be measured accurately using a stadiometer and weight measured by accurate scales calibrated against known weights. Fat distribution is assessed by measurement of the waist circumference and used to refine an assessment of risk for patients with a BMI of 25 to 34.9. Waist circumference is taken as the midpoint between the lower rib margin and the iliac crest. Waist circumference >90 cm in men and fasting plasma triglyceride are superior to the waist:hip ratio and BMI as screening tools for identifying abdominally obese men with an atherogenic dyslipidaemia of insulin resistance.
An examination of the skin is important: thin, atrophic skin is a feature of corticosteroid excess; acanthosis nigricans (pigmented, 'velvety', skin creases especially in the axillae) suggests insulin resistance; severe hirsutism in women may indicate the polycystic ovary syndrome. A neck circumference of >43cm (17 inches) indicates a likelihood of obstructive sleep apnoea while abnormal external gonadal status accompanied by intellectual impairment may suggest a rare genetic syndrome. Gastro-oesophageal reflux is a common cause of persistent cough in an obese patient.

Assessment of risk: An assessment of an obese patient's absolute risk status requires an assessment of associated disease conditions (established CHD, other atherosclerotic diseases, type 2 diabetes and sleep apnoea), other obesity-associated diseases such as gynaecological abnormalities, osteoarthritis, gallstones and stress incontinence, and cardiovascular risk factors. These will include cigarette smoking, hypertension, high-risk LDL-cholesterol (>4 mmol/l), low HDL-cholesterol (<1 mmol/l), impaired fasting blood glucose and family history of premature CHD. Patients can be classified as being of high absolute risk if they have three of these risk factors; such patients usually require specific management of risk factors.

Cigarette smoking: In the obese patient who smokes, smoking cessation is a major goal for risk management. A major obstacle to smoking cessation is the attendant weight gain. The weight gained with smoking cessation is less likely to produce negative health consequences compared to continued smoking.

Clinical investigation

The initial screening tests for the obese patient should include a full blood count (a raised MCV may be associated with an excessive alcohol intake, an increased PCV may be seen in obstructive sleep apnoea and occasionally in Cushing's syndrome), plasma urea and electrolytes (raised sodium and hypokalaemia in Cushing's), fasting blood glucose to exclude diabetes mellitus, and thyroid functions tests. The urine should be tested for protein.

Suspected cardiac abnormalities: It is important to identify those obese patients who are particularly at risk from cardiovascular complications at an early stage because the prognosis is poor once the disease becomes advanced. A high index of clinical suspicion is the most sensitive diagnostic test because an electrocardiogram, exercise ECG and trans-thoracic echocardiographs often lack diagnostic power due to difficulty in interpretation. Nevertheless, echocardiography and radionucleotide stress tests are generally helpful - severe exercise intolerance makes exercise ECGs rarely practical.

Suspected respiratory abnormalities: The "gold standard" for the assessment of sleep-breathing abnormalities is an overnight sleep study (polysonography) with sleep staging, measures of airflow at the nose/mouth, measures of respiratory effort, oxygen saturation and simultaneous ECG and electromyography. The sleep study should report the number of respiratory events, such as apnoea, and the degree of oxygen desaturation. Overnight oximetry (which can be performed in outpatients) will detect repetitive oxygen desaturation and may be diagnostic in some patients. However, its use is limited because it does not record apnoeic episodes.

Suspected endocrine abnormalities: It is important to consider the likelihood of an endocrine disorder in an obese patient before embarking upon a series of tests of endocrine function. Such investigations cannot be justified unless there is good historical and clinical evidence to support a diagnosis other than simple obesity.

Possible Cushing's syndrome in an obese patient: A common clinical problem is excluding Cushing's syndrome in patients with obesity. The usual screening test is the measurement of urinary free cortisol concentration in a 24-hour urine collection. If the results are equivocal then a dexamethasone suppression test is appropriate. This is most conveniently done by giving 1mg as a single dose or, if a formal "low dose" dexamethasone suppression test is indicated, 0.5mg 6-hourly. Blood for cortisol is taken before and after 48 hours at 0900h; the subsequent cortisol is suppressed by at least 50% of its original value in obesity. Corticotrophin-releasing hormone (CRH) has been demonstrated to stimulate ACTH secretion in normal weight human subjects and patients with Cushing's disease but not in the ectopic ACTH syndrome. In obesity, the cortisol and ACTH release after CRH are comparable to that seen in normal weight subjects which contrasts with the generally excessive rise seen in pituitary-dependent Cushings or the absence of a response found in an adrenal adenoma or ectopic ACTH. Thus, a combination of low-dose dexamethasone suppression with CRH test may provide the most sensitive and specific method for differentiating Cushing's syndrome.

Possible pituitary dysfunction in an obese patient: Subtle changes in anterior pituitary function may be associated with extreme obesity. Such changes, which should be taken into account when evaluating the results from anterior pituitary tests. Results from investigations that make pituitary dysfunction unlikely are as follows:

• Absence of physical / clinical signs suggestive of hypopituitarism or a genetic cause for obesity;
• Normal free thyroxine and TSH;
• Normal plasma LH and FSH;
• Normal plasma prolactin.

The measurement of serum leptin is not recommended as a routine, but in cases of severe, early-onset obesity this should be undertaken, as, although rare, congenital leptin deficiency is a potentially treatable disorder.
If pituitary disease is suspected imaging of the pituitary should be performed either by magnetic resonance imaging (MRI) or by computerised axial tomography (CAT) scanning.

Diagnostic tests for other possible causes or associations of obesity: These investigations will depend largely on clinical suspicion and may include:

• 75-g oral glucose tolerance test with measurement of fasting plasma insulin in acanthosis nigricans;
• fasting serum lipid profile with measurement of total cholesterol, triglycerides, HDL and LDL cholesterol;
• serum urate.

SUMMARY OF CLINICAL PROBLEMS CAUSED BY OBESITY

Figure 4 summarises the pathophsyiological mechanisms that lead to the major clinical problems associated with obesity. The figure identifies an increasing adipocyte (fat) mass as the central factor. This results in an increasing mechanical "strain" on important body systems and alterations in metabolic function resulting in hyperinsulinaemia and insulin resistance.

Figure 4. A schematic representation of the relationship between increasing fat mass and the development of medical problems either as a direct result of a mechanical "strain" or due to associated metabolic changes.

Weight loss (with a reduction in fat mass) will result in either an alleviation of many of these problems, or their resolution if achieved at an early stage. Too often, unfortunately, medical intervention occurs too late when the complications are established, and irreversible.