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.
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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
2. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL.
Table 2 Clinical characteristics of the ‘high-risk’ obese
Overweight and obesity in the United States: prevalence
and trends, 1960–1994. Int J Obes 1998; 22:39–47.
3. International Agency for Research on Cancer, World Health
Abdominal obesity (increased waist–hip ratio)
Organization.2002 Weight control and physical activity. In:
Vainio H, Bianchini F, eds. International Agency for
High triglycerides and low HDL-cholesterol levels
Research on Cancer handbooks of cancer prevention,
vol 6. Lyon, France, IARC Press, 2002.
implications in lower-income countries. Public Health Nutr
5. Drenick EJ, Bale GS, Seltzer F, Johnson DG. Excessive
mortality and causes of death in morbidly obese men. JAMA
6. Build and Blood Pressure Study, 1959. Chicago, Society of
7. Keys A. Seven countries: a multivariate analysis of death
3 years, and resulted in a 58% reduction in diabetes
and coronary heart disease. Cambridge MA, Harvard
For morbidly obese persons with a high-risk
8. Waaler HT. Height, weight and mortality: the Norwegian
profile or the above-mentioned complications,
experience. Acta Med Scand Suppl 1984; 679:1–56.
who fail to lose weight, pharmacological adjunct
9. Build Study, 1979. Chicago, Society of Actuaries and
therapy and bariatric surgery should be considered.
association of Life Insurance Medical Directors of America,
This is supported by the results of two large
intervention studies with a relatively long-term
10. Lew EA, Garfinkel L. Variations in mortality by weight among
follow up. In the first, a randomized trial comparing
750,000 men and women. J Chronic Dis 1979; 32:564–76.
combined dietary intervention with orlistat (lipase
11. Lee IM, Manson JE, Hennekens CH, Paffenbarger RS. Body
inhibitor) and dietary intervention to dietary inter-
weight and mortality: a 27 year follow-up of middle-aged
vention alone, the combined therapy given for
4-year period, resulted in a 37% reduction in the
12. Lindsted K, Tonstad S, Kazma JW. Body mass index and
incidence of diabetes due to the effect in a subgroup
patterns of mortality amongst Seventh-day Adventist men.
Int J Obes 1991; 15:397–406.
of patients with impaired glucose tolerance.173In the second large study, 1703 obese patients
13. Wilcosky T, Hyde J, Anderson JJB, Bangdiwala S, Duncan B.
Obesity and mortality in the Lipid Research Clinic Program
who underwent bariatric surgery were followed for
Follow-Up Study. J Clin Epidemiol 1990; 43:743–52.
10 years, and compared to conventionally treated
14. Vandendbroucke JP, Mauritz BJ, deBruin A, Verheesen JH,
obese subjects. The surgery group lost significantly
van der Heide-Weisel C, van der Heide RM. Weight,
more weight and maintained the weight loss
smoking and mortality. JAMA 1984; 252:2859–60.
throughout the follow-up period and this weight
15. Menotti A, Descovich GC, Lanti M, Spagonolo A, Dormi A,
loss was accompanied by a significantly lower
Seccareccia F. Indexes of obesity and all causes mortality in
incidence of diabetes and hypertriglyceridemia.174
Italian epidemiology data. Prev Med 1993; 22:293–303.
The issues of safety, cost-effectiveness and quality
16. Manson JE, Willett WC, Stampfer MJ, Colditz GA, Hunter DJ,
of life, related to pharmacological and surgical
Hankinson SA, et al. Body weight and mortality among
therapies for obesity, are still debated, and an
women. N Engl J Med 1995; 333:677–85.
individual approach has been suggested.175 Before
17. Gu D, He J, Duan X, Reynolds K, Wu X, Chen J, Huang G,
establishing definite treatment guidelines, more
et al. Body weight and mortality among men and women inChina. JAMA 2006; 295:776–83.
large intervention studies, focusing on differentage groups and obesity-related comorbidities are
18. Bradley PJ. Is obesity an advantageous adaptation? Int J Obes
needed to address the long-term cost-effectivenessand quality of life associated with various treatment
19. Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG,
Commerford P, et al. Obesity and the risk of myocardial
infarction in 27000 participants from 52 countries: a casecontrol study. Lancet 2005; 366:1640–9.
20. Keys A, Fidanza P, Karvonen MJ, Kimura N, Taylor AL.
Indices of relative weight and obesity. J Chronic Dis 1972;
1. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence
21. Revicki DA, Israel RG. Relationship between body mass
and trends in obesity among US adults, 1999–2000. JAMA
indexes and measures of body adiposity. Am J Public Health
22. Kvist H, Chowdhury B, Grangard U, Tylen U, Sjostrom L.
38. Neter JE, Stam BE, Kok FJ, Grobbee DE. Influence of weight
Total and visceral adipose-tissue volumes derived from
reduction on blood pressure: a meta-analysis of randomized
measurements with computed tomography in adult men
controlled trials. Hypertension 2003; 42:878–84.
and women: predictive value. Am J Clin Nutr 1988;
39. Stevens VJ, Corrigan SA, Obarzenak E, Bernauer E, Cook NR,
Hebert P, et al. Weight loss intervention in phase 1 trials of
23. Lissner L, Odell PL, D’Agostino RB, Stokes J 3rd, Kreger BE,
Hypertension prevention. The TOHP collaborative research
Belanger AJ, et al. Variability of body weight and health
group. Arch Intern Med 1993; 153:849–58.
outcomes in the Framingham population. N Engl J Med
40. Modan M, Almog S, Fuchs Z, Chetrit A, Lusky A, Halkin H.
24. Diaz VA, Mainous AG III, Everett CJ. The association
response to antihypertensive drugs. Hypertension 1991;
between weight fluctuation and mortality: results from a
population-based cohort study. J Community Health 2005;
41. Grundy SM, Barnett JP. Metabolic and health complications
of obesity. Dis Mon 1990; 36:641–731.
25. Flegal KM, Graubard KI, Williamson DF, Gail MH. Excess
42. Datillo AM, Kris-Etherton PM. Effects of weight reduction on
deaths associated with underweight, overweight and obesity.
blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr
26. National Center for Health Statistics. Health, United States,
43. Krauss RM, Winston M. Obesity: impact on cardiovascular
2005 With Chartbook on Trends in the Health of Americans.
disease. Circulation 1998; 98:1472–6.
Hyatsville MD, National Center for Health Statistics, 2002.
Available at ].
44. Willett WC, Manson JE, Stampfer MJ, Colditz GA, Rosner B,
Speizer FE, et al. Weight, weight change and coronary heartdisease in women. Risk within the ‘normal’ weight range.
Williams DE, Flegal KM, et al. Secular trends in cardio-vascular disease risk factors according to body mass index in
45. Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ,
US adults. JAMA 2005; 293:1868–74.
Larson MG, et al. Obesity and the risk of heart failure. N EnglJ Med 2002; 347:305–13.
28. Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight
gain as a risk factor for clinical diabetes mellitus in women.
46. James WPT, Jackson-Leach R, Ni Mhurvhu, Kalamara E,
Shayeghi M, Rigby NJ, et al. Overweight and obesity (high
body mass index). In: Ezzati M, Lopez AD, Rodgers A,
29. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC.
Murray CJL, eds. Comparative quantification of health risks:
Obesity and fat distribution and weight gain as risk factors
global and regional burden of disease attributable to selected
for clinical diabetes in men. Diabetes Care 1994; 17:961–9.
major risk factors, vol. 1. Geneva, WHO, 2004:497–596.
30. Knowler WC, Pettitt DJ, Saad MF, Charles MA, Nelson RG,
47. McGill HC , Jr, McMahan CA, Herderick EE, Zieske AW,
Howard BV, et al. Obesity in the Pima Indians: its
Malcom GT, Tracy RE, et al. Obesity accelerates the
magnitude and relationship to diabetes. AmJ Clin Nutr
progression of coronary atherosclerosis in young men.
31. Tirosh A, Shai I, Tekes-Manova D, Israeli E, Pereg D,
48. Widlansky ME, Sesso HD, Rexrode KM, Manson JE,
Shochat T, et al. Normal fasting plasma glucose levels
Gaziano M. Body mass index and total and cardiovascular
and type 2 diabetes in young men. N Engl J Med 2005;
mortality in men with a history of cardiovascular disease.
Arch Intern Med 2004; 164:2326–32.
32. Sjostrom CD, Lissner L, Wedel H, Sjostrom L. Reduction in
49. Alpert MA. Obesity cardiomyopathy: pathophysiology and
incidence of diabetes, hypertension and lipid disturbances
evolution of the clinical syndrome. Am J Med Sci 2001;
after interventional weight loss induced by bariatric surgery:
the SOS Intervention Study. Obes Res 1999; 7:477–84.
50. Chakko S, Alpert MA, Alexander JK. Obesity and ventricular
33. Sjostrom L, Lindroos AK, Peltonen M, Torgerson J,
function in man: diastolic function. In: Alpert MA,
Bouchard C, Carlsson B, et al. Lifestyle, diabetes and
Alexander JK, eds. The Heart and Lung in Obesity.
cardiovascular risk factors 10 years after bariatric surgery.
51. Zarich SW, Kowalchuk GJ, McGuire MP, Benotti PN,
34. Willett WC, Dietz WH, Colditz GA. Guidelines for healthy
Mascioli EA, Nesto RW. Left ventricular filling abnormalities
in asymptomatic morbid obesity. Am J Cardiol 1991;
35. Huang Z, Willett WC, Manson JE, Rosner B, Stampfer MJ,
Speizer FE, et al. Body weight, weight change and risk for
52. Pascual M, Pascual DA, Soria F, Vicente T, Hernandez AM,
hypertension in women. Ann Intern Med 1998; 128:81–8.
Tebar FJ, et al. Effects of isolated obesity on systolic and
diastolic left ventricular function. Heart 2003; 89:1152–6.
Kannel WBl. Overweight and obesity as determinants of
cardiovascular risk; the Framingham experience. Arch Intern
Ganguzza A, Parrinello G, et al. Left ventricular diastolic
and systolic function in normotensive obese subjects:
37. Schillaci G, Pasqualini L, Vaudo G, Pirro M, Gemelli F,
influence of degree and duration of obesity. Eur Heart J
De Sio M, et al. Effect of body weight changes on 24-hour
blood pressure and left ventricular mass; a 4-year follow-up.
54. Yong CY, O’Moore-Sullivan T, Leano R, Byrne N, Beller E,
Marwick TH. Alteration of left ventricular myocardial
characteristics associated with obesity. Circulation 2004;
and risk of stroke in apparently healthy women. Circulation
55. Peterson LR, Waggoner AD, Schechtman KB, Meyer T,
71. Larsson B, Svardsudd K, Welin L, Wilhelmsen L, Bjontorp P,
Gropler RG, Barzilai B, et al. Alterations in left ventricular
Tibblin G. Abdominal adipose tissue distribution, obesity
structure and function in young healthy obese women.
and risk of cardiovascular disease and death: 13 year follow
Assessment by echocardiography and tissue Doppler imag-
up of participants in the study of men born in 1913. Br Med J
ing. J Am Coll Cardiol 2004; 43:1399–404.
56. Curtis JP, Selter JG, Wang Y, Rathore SS, Jovin IS,
72. Walker S, Rimm E, Ascherio A, Kawachi I, Stampfer M,
Jadbabaie F, et al. The obesity paradox. Body mass index
Willet W. Body size and fat distribution as predictors of
and outcomes in patients with heart failure. Arch Intern Med
stroke among US men. Am J Epidemiol 1996; 144:1143–50.
73. Tanne D, Medalie JH, Goldbourt U. Body fat distribution and
57. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE,
long-term risk of stroke mortality. Stroke 2005; 36:1021–5.
Selby JV, et al. Prevalence of diagnosed atrial fibrillation in
74. Kales A, Cadieux RJ, Bixler EO, Soldatos CR, Vela-Bueno A,
adults: national implications for rhythm management and
Misoul CA, et al. Severe obstructive sleep apnea-I:onset,
stroke prevention: the anticoagulation and risk factors in
clinical course and characteristics. J Chronic Dis 1985;
atrial fibrillation (ATRIA study). JAMA 2001; 285:2370–5.
58. Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ,
75. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S.
Wolf PA. Independent risk factors for atrial fibrillation in
The occurrence of sleep-disordered breathing among
a population-based cohort: the Framingham Heart Study.
middle-aged adults. N Engl J Med 1993; 328:1230–5.
76. Davies RJO, Ali NJ, Stradling JR. Neck circumference and
59. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE.
other clinical features in the diagnosis of the obstructive
The natural history of atrial fibrillation: incidence, risk factors
sleep apnoea syndrome. Thorax 1992; 47:101–5.
and prognosis in the Manitoba follow-up study. Am J Med1995; 98:476–84.
77. Katz I, Stradling J, Slutsky AS, Zamel N, Hoffstein V.
Do patients with obstructive sleep apnea have thick necks?
60. Ruigomez A, Johansson S, Wallander MA, Rodriguez LA.
Am Rev Respir Dis 1990; 141:1228–31.
Incidence of chronic atrial fibrillation in general practice andits treatment pattern. J Clin Epidemiol 2002; 55:358–63.
78. Smith PL, Gold AR, Meyers DA, Haponik EF, Bleecker ER.
Weight loss in mildly to moderately obese patients
61. Wilhelmsen L, Rosengren A, Lappas G. Hospitalizations of
with obstructive sleep apnea. Ann Intern Med 1985;
atrial fibrillation in the general male population : morbidity
and risk factors. J Intern Med 2001; 250:382–9.
62. Wang TJ, Parise H, Levy D, D’Agostino RB Sr, Wolf PA,
Burman ED, Longmore DB. Sites and sizes of fat deposits
Vasan RS, et al. Obesity and the risk of new-onset atrial
around the pharynx in obese patients with obstructive sleep
fibrillation. JAMA 2004; 292:2471–7.
apnoea and weight matched controls. Eur Respir J 1989;
63. Gami AS, Pressman G, Caples SM, Kanagala R, Gard JJ,
Davison DE, et al. Association of atrial fibrillation and
80. Schwartz AR, Gold AR, Schubert N, Stryzak A, Wise RA,
obstructive sleep apnea. Circulation 2004; 110:364–7.
Permutt S, et al. Effect of weight loss on upper airway
64. Jood K, Jern C, Wilhelmsen L, Rosengren A. Body mass index
collapsibility in obstructive sleep apnea. Am Rev Respir Dis
in mid-life is associated with a first stroke in men: a
prospective population study over 28 years. Stroke 2004;
81. Weiss ST, Shore S. Obesity and asthma: directions for
research. Am J Respir Care Med 2004; 169:963–8.
65. Kurth T, Gaziano JM, Berger K, Kase CS, Rexrode KM,
82. Thomson CC, Clark S, Camargo CA Jr. Body mass index and
Cook NR, et al. Body mass index and the risk of stroke in
asthma severity among adults presenting to the emergency
men. Arch Intern Med 2002; 162:2557–62.
department. Chest 2003; 124:795–802.
66. Suk SH, Sacco RI, Boden-Albala B, Cheun JF, Pittmann JG,
83. Canargo CA Jr, Weiss ST, Zhang S, Willett WC, Speizer FE.
Elkind MS, Palk MC. Abdominal obesity and risk of ischemic
Prospective study of body mass index, weight change and
stroke: the Northern Manhattan Stroke Study. Stroke 2003;
risk of adult-onset asthma in women. Arch Intern med 1999;
67. Rexrode KM, Hennekens CH, Willet WC, Colditz GA,
84. Guerra S, Wright AL, Morgan WJ, Sherrill DL, Holberg CJ,
Stampfer MJ, Rich-Edwards JW, et al. A prospective study
Martinez FD. Persistence of asthma symptoms during
of body mass index, weight change and risk of stroke in
adolescence: role of obesity and age at onset of puberty.
Am J Respir Crit Care Med 2004; 170:78–85.
68. Millionis HJ, Goudevenos J, Seferiadis K, Elisaf MS.
85. Aaron SD, Fergusson D, Dent R, Chen Y, Vandemheen KL,
Association between body mass index and risks in elderly
Dales RE. Effect of weight reduction on respiratory function
patients with a first-ever acute ischemic stroke. Arch Intern
and airway reactivity in obese women. Chest 2004;
69. Song YM, Sung J, Davey Smith G, Ebrahim S. Body mass
86. Litonjua AA, Sparrow D, Celedon JC, DeMolles D,
index and ischemic and hemorrhagic stroke; a prospective
Weiss ST. Association of body mass index with the
study in Korean men. Stroke 2004; 35:831–6.
development of methacholine airway hyperresponsive-
70. Kurth T, Gaziano JM, Rexrode KM, Kase CS, Cook NR,
ness in men:the Normative Aging Study. Thorax 2002;
Manson JE, Buring JE. Prospective study of body mass index
87. Shore SA, Fredberg JJ. Obesity, smooth muscle and
104. Hampel H, Abraham NS, El-Serag HB. Meta-analysis:
airway hyperresponsiveness. J Allergy Clin Immunol 2005;
obesity and the risk for gastroesophageal relux disease
and its complications. Ann Intern Med 2005; 143:199–211.
88. Canoy D, Luben R, Welch A, et al. Abdominal obesity and
105. Stampfer MJ, Maclure KM, Colditz GA, Manson JE,
respiratory function in men and women in the EPIC-Norfolk
Willett WC. Risk of symptomatic gallstones in women
Study, United Kingdom. Am J Epidemiol 2004; 159:1140–9.
with severe obesity. Am J Clin Nutr 1992; 55:652–8.
89. Peters-Golden M, Swern A, Bird SS, Hustad CM, Grant E,
Edelman JM. Influence of body mass index on the response
Borges Da Silva B. Impact of rapid weight reduction on
to asthma controller agents. Eur Respir J 2006; 27:495–503.
risk of cholelithiasis after bariatric surgery. Obes Surg 2003;
90. Locke GR III, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ
III. Risk factors associated with symptoms of gastroesopha-
107. Malnick SD, Beergabel M, Knobler H. Non-alcoholic fatty
geal reflux. Am J Med 1999; 106:642–9.
liver: a common manifestation of a metabolic disorder.
91. Murray L, Johnston B, Lane A, Harvey I, Donovan J, Nair P.
Relationship between body mass and gastro-oesophageal
108. Hamaguchi M, Kojima T, Takeda N, Nakagawa T,
reflux symptoms: the Bristol Helicobacter Project. Int J
Taniguchi H, Fujii K, et al. The metabolic syndrome as a
predictor of nonalcoholic fatty liver disease. Ann Intern
92. Nilsson M, Johnsen R, Ye W, Hveem K, Lagergren J, et al.
Obesity and estrogen as risk factors for gastroesophageal
109. Suzuki A, Lindor K, St Saver J, Lymp J, Mendes F, Muto A,
reflux symptoms. JAMA 2003; 290:66–72.
et al. Effect of changes on body weight and lifestyle
93. Delgado-Aros S, Locke GR 3rd, Camilleri M, Talley NJ,
in nonalcoholic fatty liver disease. J Hepatol 2005;
Fett S, Zinsmeister AR, et al. Obesity is associated with
increased risk of gastrointestinal symptoms: A population-
110. Ong JP, Elariny H, Collantes R, Younoszai A, Chandhoke V,
based study. Am J Gastroenterol 2004; 99:1801–6.
Reines HD, et al. Predictors of non-alcoholic steatohepatitis
94. Nandurkar S, Locke Gr 3rd, Fett S, Zinsmeister AR,
and advanced fibrosis in morbidly obese patients. Obes
Cameron AJ, Talley NJ. Relationship between body
mass index, diet, exercise and gastroesophageal reflux
111. Hart DJ, Spector TD. The relationship of obesity, fat
symptoms in a community. Aliment Pharmacol Ther 2004;
distribution and osteoarthritis in women in the general
population: The Chingford Study. J Rheumatol 1993;
95. Diaz-Rubio M, Moreno-Elola-Olaso C, Rey E, Locke GR
3rd, Rodriguez-Artalejo F. Symptoms of gastro-oesophageal
112. Cicuttini FM, Baker JR, Spector TD. The association of
reflux: Prevalence, duration, severity and associated symp-
obesity with osteoarthritis of the hand and knee in women:
toms in a Spanish population. Aliment Pharmacol Ther
a twin study. J Rheumatol 1996; 23:1221–6.
113. Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JJ.
96. Lagergren J, Bergstrom R, Nyren O. No relation between
Weight loss reduces the risk for symptomatic knee
body mass and gastro-oesophageal reflux symptoms in a
osteoarthritis in women. The Framingham Study. Ann
Swedish population-based study. Gut 2000; 47:26–9.
97. Andersen LI, Jensen G. Risk factors for benign oesophageal
114. Vainio H, Bianchini F, eds. International Agency for Cancer
disease in a random population sample. J Intern Med 1991;
handbook of cancer prevention, vol. 6. Weight control and
physical activity. Lyon, IARC, 2002.
98. Wilson LJ, Ma W, Hirshcowitz BI. Association of obesity
115. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ.
with hiatal hernia and esophagitis. Am J Gastroenterol
Overweight, obesity and mortality from cancer in a
prospectively studied cohort of US adults. N Engl J Med
99. Chang CS, Poon SK, Lien HC, Chen GH. The incidence of
reflux esophagitis among the Chinese. Am J Gastroenterol
116. Danaei G, Vander Hoorn S, Lopez AD, Murray CJL,
100. Ruhl CE, Everhart JE. Overweight but not high dietary fat
collaborating group. Causes of cancer in the world:
intake increases risk of gastroesophageal reflux disease
comparative risk assessment of nine behavioural and
hospitalization: the NHANES I epidemiologic follow up
environmental risk factors. Lancet 2005; 366:1784–93.
study. First national health and Nutrition Examination
117. Huang Z, Hankinson SE, Colditz GA, Stampfer MJ,
Survey. Ann Epidemiol 1999; 9:424–35.
Hunter DJ, Manson JE, et al. Dual effects of weight
101. Furukawa N, Iwakiri R, Koyama T, Okamoto K, Yoshida T,
and weight gain on breast cancer risk. JAMA 1997;
Kashiwagi Y, et al. Proportion of reflux esophagitis in 6010
Japanese adults: prospective evaluation by endoscopy.
118. McTiernan A. Obesity and cancer: the risks, science,
J Gastroenterology 1999; 34:441–4.
and potential management strategies. Oncology 2005;
102. Nilsson M, Lundegardh G, Carling L, Ye W, Lagergren J.
Body mass and reflux esophagitis: an oestrogen-dependent
119. Otake S, Takeda H, Suzuki Y, Fukui T, Watanabe S,
association? Scand J Gastroenterol 2002; 37:626–30.
Ishihama K, et al. Association of visceral fat accumulation
103. El-Serag HB, Graham DY, Sattia JA, Rabeneck L. Obesity is
an independent risk factor for GERD symptoms and erosive
evidence for participation of insulin resistance. Clin
esophagitis. Am J Gastroenterol 2005; 100:1243–50.
120. Stoll BA. Western nutrition and the insulin resistance
139. Fox CS, Larson MG, Leip EP, Culleton B, Wilson PW,
syndrome: a link to breast cancer. Eur J Clin Nutr 1999;
Levy D. Predictors of new-onset kidney disease in a
community-based population. JAMA 2004; 291:844–50.
140. Solerte SB, Fioravanti M, Schifino N, Ferrari E. Effects of
Castiglione-Gertsch M, Goldhirsch A. Relation between
diet-therapy on urinary protein excretion albuminuria and
chemotherapy dose, oestrogen receptor expression and
renal haemodynamic function in obese diabetic patients
body-mass index. Lancet 2005; 366:1108–10.
with overt nephropathy. Int J Obes 1989; 13:203–11.
122. Gortmaker SL, Must A, Perrin JM, Sobol AM, Dietz WH.
Social and economic consequences of overweight in
Gibbons LW, Paffenbarger RS Jr, Blair SN. Relationship
adolescence and young adulthood. N Engl J Med 1993;
between low cardiorespiratory fitness and mortality in
normal-weight, overweight and obese men. JAMA 1999;282:1547–53.
123. Rosik CH. Psychiatric symptoms among prospective
bariatric surgery patients: rates of prevalence and their
142. Lee CD, Blair SN, Jackson AS. Cardiorespiratory fitness,
relation to social desirability, pursuit of surgery, and
body composition and all-cause and cardiovascular disease
follow-up attendance. Obes Surg 2005; 15:677–83.
mortality in men. Am J Clin Nutr 1999; 69:373–80.
124. Stunkard AJ. Binge-eating disorder and the night-eating
143. Haapanen-Niemi N, Miilunpalo S, Pasanen M, Vuori I,
syndrome. In: Wadden TA, Stunkard AJ, eds. Handbook on
Oja P, Malmberg J. Body mass index, physical inactivity
obesity treatment. Guilford Press, New York, 2002:107–21.
and low level of physical fitness as determinants ofall-cause
125. Dietl J. Maternal obesity and complications during
follow-up of middle-aged and elderly men and women.
pregnancy. J Perinat Med 2005; 33:100–5.
Int J Obes Relat Metab Disord 2000; 24:1465–74.
126. Green BB, Weiss NS, Darling JR. Risk of ovulatory infertility
144. Wessel TR, Arant CB, Olson MB. Relationship of physical
in relation to body weight. Fertil Steril 1988; 50:721–6.
activity vs. Body mass index with coronary artery disease
127. Esposito K, Giugliano F, Di Palo C, Giugliano G, Marfella R,
and cardiovascular events in women. JAMA 2004;
D’Andrea F, et al. Effect of lifestyle changes on erectile
dysfunction in obese men: a randomized controlled trial.
145. Bogardus C, Lillioja S, Mott DM, Hollenbeck C, Reaven G.
Relationship between degree of obesity and in vivo insulin
128. Esposito K, Giugliano D. Obesity, the metabolic syndrome,
action in man. Am J Physiol 1985; 248:E286–91.
and sexual dysfunction. Int J Impot Res 2005; 17:391–8.
146. Stevens J, Cai J, Evenson KR, Thomas R. Fitness and
129. The Rotterdam ESHRE/ASRM-sponsored PCOS Consensus
fatness as predictors of mortality from all causes and
Workshop Group.Revised 2003 consensus on diagnostic
from cardiovascular disease in men and women in
criteria and long-term health risks related to polycystic
the lipid research clinics study. Am J Epidemiol 2002;
ovary syndrome. Fertil Steril 2004; 81:19–25.
130. Ehrmann DA. Medical Progress. Polycystic ovary syndrome.
147. Bassuk SS, Manson JE. Epidemiological evidence for
the role of physical activity in reducing risk of type 2diabetes and cardiovascular disease. J Appl Physiol 2005;
131. Pasulka PS, Bistrian BR, Benotti PN, Blackburn GL. The risks
of surgery in the obese patients. Ann Intern Med 1986;104:540–6.
148. Lillioja S, Mott DM, Spraul M, Ferraro R, Foley JE, Ferraro R,
Foley JE, Ravussin E, et al. Insulin resistance and
132. Dales RE, Dionne G, Leech JA, Lunau M, Schweitzer I.
insulin secretory dysfunction as precursors of non-
insulin dependent diabetes mellitus. N Eng J Med 1993;
following thoracic surgery. Chest 1993; 104:155–9.
133. Hall JC, Tarala RA, Hall JL, Mander J. A multivariate
149. Fontbonne AM, Eschwege EM. Insulin and cardiovascular
analysis of the risk of pulmonary complications after
disease. Paris Prospective Study. Diabetes Care 1991;
134. Brooks-Bunn JA. Predictors of post-operative pulmonary
150. Pyorala M, Miettinen H, Halonen P, Laakso M, Pyorala K.
complications following abdominal surgery. Chest 1997;
Insulin resistance syndrome predicts the risk of coronary
heart disease and stroke in healthy middle-aged men. The
135. McAlister FA, Khan NA, Straus SE, Papaioakim M,
22-year follow-up results of the Helsinki Policemen Study.
Fisher BW, Majumdar SR, et al. Accuracy of the
Arterioscler Thromb Vasc Biol 2000; 20:538–44.
preoperative assessment in predicting pulmonary risk
after nonthoracic surgery. Am J Resp Care Med 2003;
Dagenais GR, Moorjani S, et al. Hyperinsulinemia as an
independent risk factor for ischemic heart disease. N Engl J
136. Smetana GW. Preoperative pulmonary evaluation. N Engl J
152. Grundy SM, Cleeman JI, Daniel SR, Donato KA, Eckel RH,
137. Wiggins KJ, Johnson DW. The influence of obesity on the
Franklin BA, et al. Diagnosis and management of the
development and survival outcomes of chronic kidney
metabolic syndrome. An American Heart Association/
disease. Adv Chronic Kidney Dis 2005; 1:49–55.
National Heart, Lung, and Blood Institute scientific state-
138. Stengel B, Tarver-Carr ME, Powe NR, Eberhardt MS,
ment. Curr Opin Cardiol 2006; 21:1–6.
Brancati FL. Lifestyle factors, obesity and the risk of chronic
153. Laaka HM, Laaksonen DE, Lakka TA, Niskanen LK,
kidney disease. Epidemiology 2003; 14:479–87.
Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome
and total and cardiovascular disease mortality in middle-
gastric banding. Int J Obes Relat Metab Disord 2002;
154. Malik S, Wong ND, Franklin SF, Kamath TV, L’Italien GJ,
168. Klein S, Fontana L, Young VL, Coggan AR, Kilo C,
Pio JR, et al. Impact of the metabolic syndrome on mortality
Patterson BW, et al. Absence of an effect of liposuction
from coronary heart disease, cardiovascular disease, and
on insulin action and risk factors for coronary heart disease.
all causes in United States adults. Circulation 2004;
169. Elbein SC, Wegner k, Kahn SE. Reduced beta-cell
155. Wilson PWF, D’ Agostino RB, Parise H, Sullivan L,
compensation to the insulin resistance associated with
Meigs JB. Metabolic syndrome as a precursor of cardio-
obesity in members of caucasian familial type 2 diabetes
vascular disease and type 2 diabetes mellitus. Circulation
kindreds. Diabetes Care 2000; 23:221–7.
170. Carpenter CL, Ross RK, Paganini-Hill A, Bernstein L. Effect
156. McLaughlin T, Abbasi F, Cheal K, Chu J, Lamendola C,
of family history, obesity and exercise on breast cancer risk
Reaven G. Use of metabolic markers to identify overweight
among postmenopausal women. Int J Cancer 2003;
individuals who are insulin resistant. Ann Intern Med 2003;
171. Valdes AM, Wolfe ML, Tate HC, Gefter W, Rut A, Rader DJ.
157. Peeters A, Barendregt JJ, Willekens F, Mackenbach JP,
Association of traditional risk factors with coronary
Al Mamun A, Bonneux L; NEDCOM, the Netherlands
calcification in persons with a family history of premature
Epidemiology and Demography Compression of Morbidity
coronary heart disease: the study of the inherited risk of
Research Group. Obesity in adulthood and its conse-
coronary atherosclerosis. J Investig Med 2001; 49:353–61.
quences for life expectancy: a life-table analysis. Ann Intern
172. Knowler WC, Barret-Connor E, Fowler SE, Hamman RF,
Lachin JM, Walker EA, et al. Reduction in the incidence
158. Mark DH. Deaths attributable to obesity. JAMA 2005;
of type 2 diabetes with lifestyle intervention or metformin.
159. Gregg EW, Cheng YJ, Cadwell BL, Imperatore G,
173. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. Xenical
Williams DE, Flegal KM, Narayan KM, Williamson DF.
in the prevention of diabetes in obese subjects (XENDOS)
study; a randomized study of orlistat as an adjunct tolifestyle changes for the prevention of type 2 diabetes in
160. McLaughlin T, Abbasi F, Kim HS, Lamendola C, Schaaf P,
Reaven G. Relationship between insulin resistance, weight
loss, and coronary heart disease in healthy, obese women.
174. Sjostrom l, Lindroos AK, Peltonen M, Torgerson J,
Bouchard C, Carlsson B, et al. Lifestyle, diabetes, andcardiovascular risk factors 10 years after bariatric surgery.
161. Whiteman MK, Hillis SD, Curtis KM, McDonald JA,
Wingo PA, Marchbanks PA. Body mass and mortalityafter breast cancer diagnosis. Cancer Epidemiol Biomarkers
175. Mun WC, Blackburn GL, Matthews JB. Current status of
medical and surgical therapy for obesity. Gastroenterology2001;
162. Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG,
Commerford P, et al. Obesity and the risk of myocardial
176. Avenell A, Broom J, Brown TJ, Poobalan A, Aucott l,
infarction in 27000 participants from 52 countries: a case-
Stearns SC, et al. Systematic review of the long-term effects
control study. Lancet 2005; 366:1640–9.
and economic consequences of treatment for obesity andimplications for health improvement. Health Technol
163. Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E,
Sjostrom L. Distribution of adipose tissue and risk of
cardiovascular disease and death: a 12 year follow-up
177. Sharma AM. The obese patient with diabetes mellitus: from
of participants in the population study of women in
research targets to treatment options. Am J Med 2006;
Gothenburg Sweden. Br Med J 1984; 289:1257–61.
164. Kragelund C, Hassager C, Hildebrandt P, Torp-Pedersen C,
178. Lavie CJ, Milani RV. Effects of cardiac rehabilitation,
Kober L. TRACE study group. Impact of obesity on long-
exercise training, and weight reduction on exercise
term prognosis following acute myocardial infarction.
capacity, coronary risk factors, behavioral characteristics,
and quality of life in obese coronary patients. Am J Cardiol1997;
165. Folsom AR, Kushi LH, Anderson KE, Mink PJ, Olson JE,
Hong CP, et al. Associations of general and abdominal
179. Alpert MA. Management of obesity cardiomyopathy. Am J
obesity with multiple health outcomes in older women: the
Iowa Women’s Health Study. Arch Intern Med 2000;
180. Messier SP, Loeser RF, Miller GD, Morgan TM, Rejeski WJ,
Sevick MA, et al. Exercise and dietary weight loss in
166. Lebovitz HE, Banerji MA. Point: Visceral adiposity is
overweight and obese older adults with knee osteoarthritis;
causally related to insulin resistance. Diabetes Care 2005;
the Arthritis, Diet, and Activity Promotion Trial. Arthritis
167. Thorne A, Lonnqvist F, Apelman J, Hellers G, Arner P.
181. Christensen R, Astrup A, Bliddal H. Weight loss: the
A pilot study of long-term effects of a novel obesity
treatment of choice for knee osteoarthritis? A randomized
treatment: omentectomy in connection with adjustable
trial. Osteoarthritis Cartilage 2005; 13:20–7.
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