Hcl085 565.580

Q J Med 2006; 99:565–579doi:10.1093/qjmed/hcl085 From the 1Department of Internal Medicine C and 2Metabolic Unit, Kaplan Medical Centre,Rehovot, Israel IntroductionThe prevalence of overweight and obesity is Initial data from actuarial studies of more than increasing worldwide.1 A comparison of data from 4 million men and women showed a direct positive 1976–802 with that from 1999–2000 shows that the association between body weight and overall prevalence of overweight (defined as body mass mortality rates.6 Subsequent studies confirmed index, BMI, of 25–29.9 kg/m2) increased from 46% increased mortality risk above a certain threshold, to 64.5%, and the prevalence of obesity (BMI but found a U-shaped association between weight 530 kg/m2) doubled to 30.5%. The epidemic of and mortality.7,8 In the Build study,9 there was obesity is not just isolated to the US, but is a higher mortality in lean subjects, but there worldwide,3,4 including less affluent countries.4 was no adjustment for smoking. The American Cancer Society found a much stronger association including genetic, metabolic, behavioural and between leanness and mortality, specifically cancer environmental. The rapid increase in prevalence mortality, in the group of smokers compared to suggests that behavioural and environmental influ- ences predominate, rather than biological changes.
The Harvard Alumni Study11 was a prospective We summarize data from many studies evaluating cohort study of more than 19 000 middle-aged men.
the impact of obesity on mortality and morbidity, It also noted a U-shaped relation between BMI discuss some controversies and provide practical and mortality after adjustment for age, cigarette guidelines for managing obese patients.
smoking and physical activity. However, afterexcluding those who had ever smoked and thosewho died within the first 5 years of follow-up, there was no evidence for increased mortality in those mortality was noted in those who weighed 20% Direct associations between obesity and several diseases, including diabetes mellitus, hypertension, A direct relationship between BMI and mortality dyslipidaemia and ischaemic heart disease, are well was also described in a cohort of more than 8000 recognized. Despite this, the relationship between Seventh Day Adventists, with the lowest mortality body weight and all-cause mortality is more rate found in men with a BMI <22.3 kg/m2.12 This controversial. A very high degree of obesity group is usually lean by choice, and therefore their (BMI 535 kg/m2) seems to be linked to higher leanness is less likely to be the result of cigarette mortality rates,5 but the relationship between more modest degrees of overweight and mortality is increased risk of mortality in women. There have Address correspondence to Dr S.D.H. Malnick, Department of Internal Medicine C, Kaplan Medical Centre,Rehovot 76100, Israel. email: [email protected] ! The Author 2006. Published by Oxford University Press on behalf of the Association of Physicians.
All rights reserved. For Permissions, please email: [email protected] been some reports that did not find a relationship and for effect modification by age, they found an between BMI and mortality in women,13–15 but increased mortality associated both with being due to the small number of endpoints occurring underweight and with being obese. Notably, the in these cohorts, these studies lacked sufficient increased mortality was found in subjects with a power. Several larger studies showed a significant BMI 535 kg/m2, but there was no increase in association between body weight8–10 or BMI and mortality in the in the less obese groups. In addition, mortality.16 Notably, the Nurses’ Health Study, there was a decline in the relative risk of mortality showed a U-shaped relationship between BMI and according to BMI categories from NHANES I to all-cause mortality.16 Another recent study found a U-shaped association between weight and This finding suggests that the attenuation in the mortality in a large cohort of Chinese men and strength of the association between obesity and mortality is related to the improvement in the There are several explanations for the discrepan- standard medical care that has resulted in reduced cies observed in the above epidemiological studies.
cardiovascular mortality in recent years. Age- There may be an adverse effect of leanness and adjusted death rates from heart disease (per leanness can be a surrogate marker of underlying 100 000 population) declined from 412.1 in 1980 diseases.18 The possibility that there may be some to 240.8 in 2002.26 In addition, there was a beneficial effect of mild degree of excess body decrease in the prevalence of hypercholesterolemia weight on overall survival, also cannot be entirely and smoking, but not of diabetes, between 1960–62 ruled out. For example, in the INTERHEART study, and 1999–2000.27 These changes occurred despite high hip circumference had a negative predictive the marked increase in the prevalence of obesity value for myocardial infarction, while high waist circumference was associated with high rates ofmyocardial infarction, implying that consideringonly the BMI and ignoring fat distribution may bemisleading.19 Weight or BMI may be relatively low in an elderly person with little lean body mass relative to adipose tissue. The correlations between BMI and There is a strong association between obesity and more direct measures of adiposity (e.g. underwater type 2 diabetes mellitus, in both genders and all ethnic groups. Data from the Nurses’ Health Study Furthermore, reported correlations between waist– showed an age-adjusted relative risk of 40 for hip ratios and visceral adipose tissue volume diabetes in women with a BMI 531 kg/m2, com- pared with women with a BMI <22 kg/m2.28 Other limitations of several epidemiological studies are: partial adjustment for confounding A similar risk was shown for men in the Health factors (such as physical fitness, type of diet, family Professionals Follow-up Study: a BMI of 535 kg/m2 history, weight cycling, use of diet drugs, economic was associated with an age-adjusted relative status), inclusion of self-reported data, not taking risk for diabetes of 60.9, compared with a BMI of into account the age of onset of obesity and not <23 kg/m2.29 In addition, weight gain appears to estimating the obesity-attributable mortality. It has precede the development of diabetes. In the Pima been estimated that the excess mortality associated Indians, a group with a high incidence of type 2 with obesity in the Framingham study is due to the diabetes, body weight was shown to increase by effect of weight cycling, and that participants with 30 kg from a mean of 60 kg to a mean of 90 kg in stable body weights were not at increased risk.23 the years prior to the diagnosis of diabetes.30 The A similar finding has been reported in the National importance of obesity as a risk factor for diabetes in the presence of other risk factors is underlined by a recent report from Israel. In a cohort of relatively Flegal et al. recently made an estimation of young men in the Israel Defence Forces who relative risks of mortality associated with different were subjected to regular physical examinations, levels of BMI from the nationally representative the combination of a fasting plasma glucose in NHANES I, II and III, and applied these relative the high-normal range (91–99 mg/dl) and a BMI risks to the distribution of BMI and other covariates of 430 kg/m2 was associated with a hazard ratio from NHANES 1999–2002 data to estimate attrib- of 8.29 for developing diabetes, compared to those utable fractions and number of excess deaths related men with a BMI <25 kg/m2 and a fasting plasma to obesity.25 After adjusting for confounding factors Hypertension is strongly linked to obesity. The In addition to the link between obesity and mortality Swedish Obesity Study showed hypertension to be from cardiovascular disease, obesity is associated present at baseline in 44–51% of obese sub- with increased risks of coronary artery disease, heart jects.32,33 In the Nurses’ Health Study, BMI at age 18 years and in mid-life were both positivelyassociated with the occurrence of hypertension.34,35 Furthermore, weight gain was also associated with An increased risk of coronary artery disease (CAD) an increased risk. The relative risk for developing in the overweight was apparent in both the hypertension in women who gained 5–9.9 kg was Framingham Heart Study and the Nurses Health 1.7, and in those who gained 425 kg, the relative Study.6,34,36,43,44 In the Nurses Health Study, risk was 5.2.34 Similar findings in men were the adjusted relative risk for CAD (taking BMI apparent in the Health Professionals Study.29 It has of 21 kg/m2 as a reference value) increased been estimated from the Framingham Health from 1.19 at a BMI of 21–22.9 kg/m2 to 3.56 Study that excess body weight may account for up at a BMI 429 kg/m2.33,45 The Asia-Pacific Cohort to 26% of cases of hypertension in men and 28% Collaboration Study, involving 4300 000 adults followed up for almost 7 years, found a 9% increase Not only is obesity linked with hypertension, in ischaemic-heart disease events for each unit but weight loss in obese subjects is associated with change in BMI.46 In addition, obesity was associated a decline in blood pressure.35 In a 4-year follow-up with both fatty streaks and raised atherosclerotic of 181 overweight hypertensive patients, a 10% lesions in the right coronary and left anterior weight loss was independently associated with a 4.3/3.8 mmHg decrease in 24-h ambulatory blood pressure monitoring.37 A meta-analysis of 25 random- In patients with pre-existing heart disease, ized controlled trials that enrolled nearly 5000 however, the relationship between obesity and participants found that both systolic and diastolic cardiovascular mortality is not as strong. A subgroup blood pressures fell by approximately 1 mmHg for analysis from the Physicians Health Study compar- each kg weight loss.38 The anti-hypertensive effect ing cardiovascular mortality in men with a BMI of of weight loss is independent of race or gender.39 22.0–24.9 kg/m2 vs. those with a BMI 428 kg/m2, Furthermore, chronic obesity reduces the efficacy did not find a significant increase on multivariate Heart failureThe relationship between obesity and heart failure Obesity is associated with an unfavourable lipid is complex. In the Framingham Study, almost 6000 profile. Lipid abnormalities related to obesity individuals without a history of heart failure (mean include an elevated serum concentration of choles- age 55 years) were followed for a mean of 14 years.
terol, low-density-lipoprotein (LDL) cholesterol, The risk of developing heart failure was two-fold very low density lipoprotein (VLDL) cholesterol, higher in obese individuals, compared with subjects triglycerides and apolipoprotein B, as well as with a normal body-mass index.45 On multivariate analysis adjusting for risk factors including hyper- (HDL) cholesterol.41 The mechanism(s) underlying tension, coronary artery disease and left ventricular this dyslipidaemia are not fully understood but hypertrophy, there was an excess risk of 5% in men involve the combination of insulin resistance and and 7% in women for each 1 point increase in BMI.
hyperinsulinaemia stimulating hepatic triglyceride It was estimated that 11% of the cases of heart synthesis from an increased adipose tissue under- going enhanced lipolysis. This leads to postprandial hypertrigyceridaemia, smaller and denser LDL Individuals with obesity have a form of cardio- myopathy attributed to chronic volume overload, In a comprehensive meta-analysis, weight loss increased left ventricular wall stress and compensa- of 1 kg decreased serum total cholesterol by 0.05 mmol/l and LDL cholesterol by 0.02 mmol/l, studies have reported abnormal diastolic func- and increased HDL cholesterol by 0.009mmol/l.42 tion50,51 without abnormal systolic function.52,53 Recently, however, in a study comparing the of 11% for ischaemic stroke was found for each transthoracic echocardiography findings of the 1 point increase in BMI.69 In the Physicians Health heart of overweight or obese subjects with non- Study of 21 414 US physicians, those with a BMI obese controls, subtle changes in systolic function 530 kg/m2 had a relative risk of 1.95 for an were observed in parameters such as myocardial ischaemic stroke and 2.25 for a haemorrhagic velocity and strain index even when conventional stroke. Each 1 point increase in BMI resulted in a 2D echo found a normal ejection fraction.54 These 6% increase in the relative risk for total stroke.65 In changes were more prominent in the patients who a study from Sweden of 7402 apparently healthy had a BMI 435 kg/m2, compared to the less obese men aged 47–55 years, followed up over a 28-year patients. Similar findings have been reported in period, BMI 430 kg/m2 resulted in a hazard ratio obese young women (21–37 years of age).55 of 1.78 for ischaemic stroke, but not haemorrhagic Elevated BMI, however, appears to be associated stroke.64 In these studies, the increased risk for with an improved survival in patients with con- stroke persisted, although attenuated, after adjusting gestive heart failure (CHF).56 In the large Digitalis for concomitant risk factors such as hypertension, Obese women also have an increased risk for (BMI 430 kg/m2) had a mortality hazards ratio of stroke. Data from the Women’s Health Study of 0.88 compared to a control group of BMI 18.5–24.9 39 053 women with self-reported weight and height, on multivariate analysis. This has been termed the found a hazards ratio of 1.72 for ischaemic stroke in women with BMI 430 kg/m2 compared to thosewith BMI <25 kg/m2.70 There was no significant relationship between BMI and haemorrhagic stroke.
As noted above, obesity is linked to hypertension, Similar results were found in 116 759 women in coronary artery disease, diabetes mellitus, left the Nurses’ Health Study.67 In this study there was ventricular hypertrophy, left atrial enlargement and a non-significant inverse relationship between CHF. Hypertension, left atrial enlargement and obesity and haemorrhagic stroke. It is unclear why congestive heart failure are all strongly linked to there is no relationship between haemorrhagic atrial fibrillation (AF).57,58 Despite the close relation- stroke and obesity, but it may be linked to the ship between obesity and several of the risk factors lower number of cases in each of the trials, for AF, a clear relationship between AF and obesity has only recently been established. Previous However, not all studies have shown an associa- epidemiologic studies produced conflicting results tion between BMI and stroke,71,72 and recent data as to whether AF is linked to obesity. This may be suggest that central fat accumulation is a stronger due to short-term follow-up, failure to account risk factor for stroke than overall obesity. In a report for interim cardiovascular events and/or lack of from the Israeli Ischemic Heart Disease Study of 9151 male civil servants, trunk body fat was a Data from the Framingham Heart Study62 show predictor of stroke mortality, independent of BMI, a correlation between the risk of developing AF and blood pressure, smoking, socioeconomic status and BMI. In multivariate analysis, adjusting for interim myocardial infarction or heart failure, every increaseof 1 point in BMI was associated with a 4% increase in the risk of AF. In addition, there was a gradual increase in left atrial size as BMI increased. The Obesity is a major risk factor for obstructive sleep relationship between BMI and AF was not significant apnoea (OSA). Over 75% of patients with OSA are after adjusting for left atrial diameter, suggesting reported to be 4120% of ideal body weight.74 a physiological link between obesity and left atrial Epidemiological evidence from the Wisconsin diameter. In addition there is an association Sleep Cohort Study showed that sleep apnoea between obstructive sleep apnoea and AF,63 and risk increased significantly with obesity.75 A neck as will be discussed below, obesity and obstructive circumference 417 inches, which is correlated with obesity, has also been highly correlated with OSA.76,77 In addition, mild-to-moderate weightloss can substantially improve sleep apnoea.79 Obesity is linked to an increased risk of stroke in Obesity probably contributes to OSA via multiple both men and women.64–69 In a study of 234 863 mechanisms. Increased fat deposits in tissues Korean men aged 40–64 years, an adjusted hazard surrounding the upper airway in obese patients may directly impinge on the airway lumen.80 large population-based studies did not find any Upper-body fat deposits may increase airway collapsibility and interfere with the function of the Several studies have examined the relationship inspiratory and expiratory muscles that maintain between GORD and oesophageal erosions. Three airway calibre. Upper airway collapsibility also reported a moderate positive association,98–100 one decreases after weight loss in obese patients reported no association,101 and one found a positive association in women but not in men.102 In a recentstudy in 453 patients, obese patients were 2.5 times as likely as patients with a BMI <25 kg/m2 to have The prevalence of asthma is increased in overweight either reflux symptoms or oesophageal erosions.103 subjects,82 and obese or overweight subjects Since there is a link between GORD and oesoph- account for 75% of emergency department visits ageal adenocarcinoma, the connection between for asthma.83 Longitudinal studies indicate that GORD and obesity deserves further investigation.
obesity antedates asthma, and that the relative risk A recent meta-analysis found a significant associa- of incident asthma increases with increasing tion between obesity and the risk for GORD obesity.84,85 In addition, morbidly obese asthmatic symptoms, erosive oesophagitis and oesophageal subjects studied after weight loss demonstrate decreased severity of asthma symptoms.85 Obesityalso appears to be a risk factor for airway hyper- responsiveness.86 The relationship between obesityand asthma is underlined by the finding that obesity Obesity is associated with cholelithiasis. In the is a strong predictor of the persistence of childhood Nurses’ Health Study, women with BMI <24 kg/m2 asthma into adolescence.5 Potential mechanisms had an incidence of symptomatic gallstones of for this relationship include obesity-related changes approximately 250 per 100 000 person-years of in lung volumes, systemic inflammation and other follow-up.105 Women with BMI 445 kg/m2 had a adipocyte-derived factors that might alter airway seven-fold increase in risk for gallstones compared smooth muscle function and promote airway to women with BMI <24 kg/m2. Women with BMI 430 kg/m2 had a yearly gallstone incidence of Recently, the relationship between respiratory 41% and those with BMI 545 kg/m2 had a rate function and obesity has been examined in the of approximately 2% per year. Similar data were EPIC-Norfolk cohort in Norfolk, UK.88 This group found in men in the Health Professionals Study.34 included 9674 men and 11 876 women aged 45–79 Notably however, there is an increased risk for cholelithiasis in patients who lose weight rapidly.
correlated across the entire spectrum of the waist- Gallstone formation after bariatric surgery has been hip ratio in both men and women, and this relation reported to affect about 38% of patients.106 persisted after adjustment for BMI. This suggeststhat abdominal obesity may impair respiratory Non-alcoholic fatty liver disease (NAFLD) function, and more so than generalized obesity.
NAFLD is increasing in prevalence in developed Furthermore, a post-hoc analysis of a database countries, and is one of the most common causes of four previous placebo-controlled studies of of cryptogenic cirrhosis. It is strongly linked to the monteleukast or inhaled beclomethasone, showed metabolic syndrome, of which obesity is a central a lower placebo response and also a lower response component, and is in fact regarded as the hepatic to inhaled corticosteroid, with increasing BMI, manifestation of the metabolic syndrome.107,108 whereas response to monteleukast was not affected NAFLD is a spectrum of diseases ranging from simple steatosis to steatohepatitis and cirrhosis, with all of its concomitant complications. Patientswith NAFLD especially those with mainly steatosis, respond favourably to weight reduction, and a Gastrooesophageal reflux disease (GORD) is a recent large study showed that achieving 55% common disorder that has been linked to obesity.
weight reduction by lifestyle modifications was Most population-based studies supported this asso- associated with improvement and even normal- ciation in studies conducted in the US, UK, ization of liver enzymes in subjects with impaired Norwegian and Spanish populations,90–95 and two of these studies showed a gradual increase in GORD Interestingly, waist–hip ratio is an independent symptoms as BMI increased.90,91 However, two predictor of advanced fibrosis at liver biopsy.110 in the USA could account for 14% of all cancerdeaths in men and 20% in women.
There is a marked increase in osteoarthritis in the In a systematic review and meta-analysis from the obese. It is most common in the knees and the Comparative Risk Assessment Project evaluating ankles, which may be a consequence of trauma data on 7 million deaths from cancer, 2.43 million related to the excess body weight. In a study of over were attributable to potentially modifiable risk 1000 women, the age-adjusted odds ratio of factors, including overweight and obesity. For every risk factor, they calculated the population knee, as determined by X-ray, was 6.2 for BMI attributable fraction (PAF), estimating the propor- <23.4 kg/m2 and 18 for BMI 426.4 kg/m2. When tional reduction in cancer death if the risk factor was BMI <23.4 kg/m2 was compared to BMI 23.4– reduced. The corresponding PAF for over-weight 26.4 kg/m2, the odds ratios for osteoarthritis were and obesity was: 11% for colon and rectum cancers; increased: 2.9 fold for the knee, 1.7 fold for 5% for breast cancer; 40% for uterine cancer.116 carpometacarpal joint, 1.5 fold for the distal In the Nurses’ Health Study, obesity and weight interphalangeal joint, and 1.2 fold for the proximal gain had differing effects on the risk of breast cancer interphalangeal joint.111 A co-twin control study in premenopausal and postmenopausal women.117 noted that each one kg increase in weight was Premenopausal women with BMI 426 kg/m2 had associated with an increased risk of radiographic lower mortality from breast cancer. In addition, features of osteoarthritis at the knee and carpo- weight gain after the age of 18 years was not associated with increased risk of breast cancer Not only is obesity associated with osteoarthritis, before menopause, but was a risk factor after but weight loss is associated with a decreased risk menopause. In postmenopausal women who had of osteoarthritis. A study of 800 women showed never taken oestrogen hormone replacement ther- that a decrease in BMI of 2 kg/m2 or more in the apy, the relative risk of developing breast cancer preceding 10 years decreased the odds for devel- was 1.6 if they had gained 10–20 kg and 2.0 if they oping osteoarthritis by 450%.113 This benefit was had gained 420 kg, compared to women with also present in those women with a BMI 425 kg/m2 minimal weight gain. Women who were taking and thus at high risk of osteoarthritis.
oestrogen, however, did not have an increased risk The fact that osteoarthritis occurs more frequently of breast cancer associated with weight gain.
in non-weight-bearing joints suggests there are The data suggesting that obesity is one of the components of the obesity syndrome that alter causes for cancer are derived mainly from epide- cartilage and bone metabolism independent of miological studies, which cannot prove cause-effect relationship, and may be confounded by selectionbias. There are also limited data clarifying the underlying mechanisms for this association. It ispossible that the increased production of oestrogens The WHO International Agency for Research on by adipose tissue stromal cells, together with the Cancer has estimated that overweight and inactivity decrease of sex-steroid-binding globulin, is respon- account for from a quarter to a third of all cancers sible for the increased risk of endometrial and of the breast, colon, endometrium, kidney and perhaps breast cancer. Insulin resistance and increased levels of insulin-like growth factor-I Obesity also increases the likelihood of dying (IGF-I) may play a role in colon neoplasm.118–120 from cancer. A 16-year prospective study of Further studies evaluating the possible interaction between genetic background and obesity in the relative risk of death from cancer of 1.5 for men and development of specific type of cancers, are needed.
1.6 for women in the group with BMI 440 kg/m2 vs.
Obesity may also unfavourably influence the BMI 18.5–24.9 kg/m2.115 For both men and women, diagnosis of cancer and the response to therapy.
increasing BMI was associated with higher death The commonly accepted dose reduction of chemo- rates due to cancers of the oesophagus, colon and therapy in the obese may be deleterious. A review of rectum, liver, gallbladder, pancreas, kidney, non- four trials of treatment for breast cancer with a total of 2443 patients in whom the BMI was known, Men were also at increased risk for death from showed that obese patients received a lower dose stomach and prostrate cancer, while women were at of chemotherapy and had a worse outcome in the increased risk of death from cancers of the breast, group with oestrogen-receptor-negative tumours but cervix, uterus and ovary. On the basis of these data, not in the group with oestrogen-receptor-positive the authors estimated that overweight and obesity Obesity in the past was seen as a sign of wealth and In the light of the previously mentioned pulmonary wellbeing. This remains the case in many parts of changes associated with obesity, one might expect Africa, partly as a result of the HIV epidemic and its obesity to be a risk factor for post-operative associated wasting. However, in affluent countries there is a stigma associated with obesity in areas inconsistent. A review of ten series of obese patients such as education, employment and health care.
A survey of more than 10 000 adolescents found a similar 3.9% rate of post-operative pneumonia that women with a BMI above the 95th percentile and atelectasis to that in the general population.131 for age and sex completed fewer years of school In a prospective study of 117 patients undergoing (0.3 years), were 20% less likely to be married, thoracic surgery, there was no difference in the rate had lower household incomes and higher rates of of pulmonary complications when the patients household poverty compared to women who had were stratified by BMI.132 Contrasting findings not been overweight, independent of their baseline were found in a prospective study of 1000 patients socioeconomic status and aptitude test scores.122 undergoing laparotomy, in which BMI 425 kg/m2 Men who had been overweight were less likely to was an independent risk factor for postoperative pulmonary complications.133 Furthermore, in a In a group of 294 patients seeking consultation for prospective study of 400 patients undergoing bariatric surgery, half the patients had a psychiatric abdominal surgery, BMI 427 kg/m2 was one of six disorder and 29% had comorbidity. The highest prevalence rates were 29% for somatization, 18% tions.134 One possible explanation for the differ- for social phobia, 155 for hypochondriasis and 14% ences between these reports may be failure to distinguish between obesity and other comorbid In addition, eating disorders such as binge eating conditions. In a prospective study of 272 patients disorder and night eating syndrome have been referred for medical evaluation prior to non-thoracic surgery, using explicit criteria for postoperativepulmonary complications, the odds ratio was 4.1for patients with BMI 430 kg/m2, but this was no longer significant under multivariate analysis.135 A review of six studies encompassing a total of4536 patients found a similar risk of pulmonary Obesity during pregnancy is associated with an complications for both obese and non-obese gestational diabetes, pre-eclampsia, and deliverycomplications dystocia and higher rates of caesarean sections and infections. Maternal obesity may also be an The epidemic of obesity in the developed world has independent risk factor for neural tube defects and been associated with an increase in the prevalence fetal mortality. This subject has been reviewed of chronic kidney disease. It is however, unclear whether obesity is a risk factor independent of Obesity is now estimated to be responsible for 6% of primary infertility.126 In men, there is a link Among NHANES III participants, the risk of either between impotence and increasing infertility, with incident end-stage renal disease or kidney-related abdominal obesity a particular risk.127,128 death was independently associated with a BMI Polycystic ovary syndrome (PCOS), the most 435 kg/m2, with a relative risk of 2.3 among those common endocrine disorder in women of repro- morbidly obese compared with normal weight ductive age, is characterized by a combination of persons, but risk was not increased for those chronic anovulation, polycystic ovary morphology classified as overweight or obese.138 In the and hyperandrogenism.129 Obesity and insulin Framingham study, patients who were obese at resistance are closely related with PCOS, and insulin baseline were more likely to have a decrease in resistance has a pivotal role in the pathogenesis of estimated glomerular filtration rate (GFR).139 Under this syndrome. Women with PCOS respond favour- multivariate analysis, increased baseline BMI was ably to weight loss, as well as to pharmacological significantly associated with progression to chronic treatment of insulin resistance, with decrease in kidney disease, with an odds ratio of 1.23 for each Notably, weight loss may preserve renal function.
syndrome, a cluster of abnormalities related to In a study of 24 type 1 and type 2 diabetics insulin resistance,153 was also associated with with nephropathy, a reduction in BMI from 33 increased risk of developing type 2 DM and CVD to 26 kg/m2 was associated with a decrease in large prospective studies.154–156 Population- in proteinuria from 1.3 to 0.623 g per 24 h, attributable risk estimates associated with the meta- bolic syndrome were 34%, 29% and 62% in men, and 16%, 8% and 47% in women, for CVD, CHD,and type 2 DM, respectively.157 The metabolicsyndrome includes known risk factors for CVD such as abdominal obesity, hypertension, glucose intolerance, high triglycerides and low HDL-cholesterol. In addition, some data suggest that Despite the mortality and morbidity associated with even after adjusting for these known risk factors, obesity described in previous sections, clinicians are the metabolic syndrome remains an independent well aware of the phenomenon of the healthy obese risk factor for CVD.158,159 Obese and overweight individual. Therefore, further characteristics that will people tend to be more insulin-resistant, yet only identify subsets of obese high-risk patients vs. obese about half have significant insulin resistance.160 Identifying obese insulin-resistant individuals indaily practice is of great importance, since weight reduction is especially beneficial in reducing CVD Several studies have shown that low physical fitness risk factors in this sub-group.160,161 Fortunately, and physical activity are independent predictors insulin resistance can be identified by relatively for all-cause mortality, CVD mortality and cardio- simple measures such as high fasting serum vascular events in lean and obese men and insulin levels or by high triglycerides and low women.141–144 In the Aerobics Center Longitudinal Study, unfit lean men had a higher risk for all-cause Obesity has been associated with increased risk and CVD mortality than men who were fit and of several types of commonly occurring cancer, obese.142 In a long-term prospective study of Finnish as noted above. In addition, obesity is associated men and women, low leisure time physical activity with both a higher rate of recurrence of breast and physical fitness, but not high BMI, were cancer and a worse prognosis.161 Interestingly, predictors of all-cause and CVD mortality.145 abdominal obesity and insulin resistance were However in another study conducted in men and shown to be associated with some types of cancer women, physical fitness, although associated with such as colon and breast neoplasia, suggesting that reduced mortality from CVD, did not completely one of the mechanisms linking obesity and cancer reverse the increased risk associated with obesity.146 is related to insulin-like growth factors.118–120 One of the mechanisms by which increasedphysical activity and fitness can reduce CVD risk and all-cause mortality is by modulating insulin The recently published INTERHEART study exam- sensitivity. In both Caucasians and Pima Indians, ined the predictive value for myocardial infarction maximal aerobic capacity is positively correlated of different obesity markers in427 000 subjects from with insulin action.147 Other protective mechanisms different ethnic groups, in 52 countries.162 It found of physical activity include: improvement of blood that waist–hip ratio was superior to BMI, having a pressure, atherogenic dyslipidaemia and inflam- graded and significant association with myocardial infarction that persisted after adjusting for the other function.148 The protective role of physical exercise known risk factors. BMI, in contrast, showed only a and fitness implies that physicians should at leastobtain a self-record of physical activity and fitness modest association, in some but not all populations, as part of assessing the risks associated with obesity.
and the association was not significant after furtheradjustments. This study confirms (and extends to different populations) the results of previous studies, showing that simple measures of waist or waist–hipratio are closely related with CVD risk.163–165 Insulin resistance and the compensatory hyper- insulinemia, are strongly associated with increased increased visceral adipose tissue known to be risk for type 2 diabetes, CVD and CHD mortality in more metabolically active, releasing free fatty large epidemiological studies.149–152 The metabolic to insulin resistance.166 In a study comparing Table 1 Obesity-associated complications that respond removal of 1 kg visceral fat at bariatric surgery with bariatric surgery alone, there was a significantimprovement in insulin sensitivity in those patients while removal of subcutaneous tissue had no effect on insulin sensitivity.168 Therefore, assessment of visceral fat accumulation by measuring waist–hip ratio should be part of the routine assessment of The gene-environment interaction is known to playa role in multiple diseases. Obesity is associated NAFLD, non-alcoholic fatty liver disease.
with many comorbidities, and an interactionbetween obesity and a positive family history hasbeen shown in several of these associated illnesses.
data describing a U-shaped association, with excess In individuals with a strong family history of diabetes mortality in both under-weight and severe obesity, and increased BMI, reduced beta-cell compensation while milder degrees of overweight do not show to the insulin resistance associated with obesity was increased rates. In addition, improved standards of found, increasing the risk for developing type 2 medical care may attenuate the effect of obesity on diabetes.169 BMI was strongly associated with breast life expectancy. The economic burden of providing cancer risk among women with a strong family this medical care to increasing numbers of obese history of breast cancer, but only weakly associated subjects cannot however be dismissed.
in those women without a family history.170 In Not all obese patients will develop complications.
women with a family history of premature coronary Further characterization of physical activity and artery disease, BMI was an independent predictor fitness, fat distribution, insulin resistance and family of coronary artery calcification.171 Further studies history of obesity-related diseases, can identify the are needed to elucidate the possible interactions obese person who is at increased risk. The age of between obesity and genetic background, but onset of obesity also needs to be taken into account, obtaining a family history may be helpful in as the life-long risk of developing obesity-related assessing the risk of the individual obese patient.
complications is higher in early-onset comparedwith late-onset obesity.
We suggest the following scheme for the manage- ment of the patient with obesity. Firstly, for patients Obesity is linked with a large range of medical who suffer from obesity-related complications complications. There is evidence that obesity is not listed in Table 1 that have been shown to respond only related to conditions such as diabetes, hyper- favourably to weight loss, we recommend that tension, heart disease, obstructive sleep apnoea, dietary consultation be part of the treatment plan.
asthma, non-alcoholic fatty liver disease, osteo- Secondly, since not all obese subjects will arthritis and polycystic ovary syndrome, but also develop associated morbidities, we list clinical that weight reduction has beneficial effects and characteristics that are of assistance in identifying therefore is an integral part of treating these those asymptomatic obese people who have a morbidities (Table 1). Although there is a significant particularly high risk for developing obesity-related association between certain types of cancer and complications (Table 2). The rationale of focusing obesity, the inherent limitation of epidemiological the effort to achieve weight reduction in this high- studies in establishing causality, together with the risk group, is based on data from studies such as lack of intervention studies, underline the need for the large Diabetes Prevention Program, in which further studies before the role of obesity in cancer is 3234 non-diabetic overweight or obese patients with elevated glucose levels were randomized Another controversial issue is the association to placebo, lifestyle modification program or metformin. The lifestyle modification program was researchers believe that obesity will shorten the life aimed at achieving 7% weight loss and 150 min of expectancy of obese populations, there are other physical activity per week. This program lasted for 2. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL.
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