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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@example.com
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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
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GEOGRAPHY Breadth of Study Key Stage 1 • During the key stage, pupils should be taught the Knowledge, skills and understanding through the study of two localities: a) The locality of the school. b) A locality either in the United Kingdom or overseas that has physical and/or human features that contrast with those in the locality of the school. • In their study of localities, pupi
Clinical features, pathophysiology, and treatment of medication-overuse headache Medication-overuse headache (MOH) is a chronic headache disorder deﬁ ned by the International Headache Society Lancet Neurol 2010; 9: 391–401 as a headache induced by the overuse of analgesics, triptans, or other acute headache compounds. The population- See In Context page 349 based prevalence of MOH