Section 3 Obesity,Diabetes Mellitus,

and Metabolic Syndrome

401 Pathobiology of Obesity

Stephen 0'Rahilly, I. Sadaf Farooqi

haipose tissue evolved as a solution to the challenge of the intermitet

avalability of food. At times when food is plentiful, excess hrriesig
converted
droplets
to
triglycerides and stored in the unilocular
the that OCcupy most of efficiently
the volume of fat cells. and
When ncvei
gheent
triglyceride
which provide an is rapidly broken
down to free fatty acids the but

energy source to other sites throughout

Monev,
inenvironments where food is abundant and when indi- highest prevalence at 56.9%. There has been a marked increase in the 3081
vibuk
tendto he sedentary, the chronic excess of energy intake over Drevalence of obesity over time. For example, between 1976 and 1980,
leads to obesity. The risks of becoming obese under those
gendture
the NHANES survey reported a prevalence of 14.5%, indicating anear
n umslanc and of developing the illnesses associated with obesity threefold increase over the past 40 years.
prcatlybetween individuals, with that variation having a strong This trend is seen globally. According to the WHO, obesity has
gntic
basis.
nearly tripled worldwide sincé 1975. In 2016, >1.9 billion adults aged
(DEFINTTION OF OBESITY AND 218years old were overweight. Of these, >650 milion were obese; 39%
OVERWEIGHT of adults aged 18 years old were overweight in 2016, and 13% were
Ohesityisdcfinedlas astate of excess adiposetissue mass that adversely
shealth. The. direct measurement of fat mass is not something weight Most
obese. of the kills
and obesity world'smore
population livesunderweight.
people than in countries where over
thilisreadihy undertaken in routine clinical practice, so a proxy mea-
bod massindex (BMI), is generally used. This is calculated as During this time, one of the most striking changes has beenCHAPTER
in the
urethe prevalence of obesity in children. In children, the relationship between
neihheighr' (in kg/m²) (Fig. 401-1). BMI-based
andoverweight have been established based on definitions
of
associations obe-
BMI and body fat varies considerably with age and with pubertal mat
with
morbidities and excess mortality. These definitions have uration; however, when adjusted for age and sex, BM is areasonable
been
etain
onstudies of predominantly white, Western populations, proxy for fat mass. Using age- and sex-specific BMl cutoffs(overweight
401
largely
dthere is growing evidence that the relationship between BMI and >91st percentile; obesity >99th percentile), in 2019, the WHO
Ased esti
Pathobiology
adreseeoutcomes may be different in peoplefrom other ethnic groups, mated that 38 million children under the age of 5were overweight or
DSUall"inthe direction of worse health outcomes being seen at lower obese, and in 2016, they reported that 340 million children and adoles
Pels offBMI. The World Health Organization(WHO) defines a BMI cents aged5-19 were overweight or obese.
30kgIm' as the cutoff point for robesity, while individuals with values
PHYSIOLO GIC REGULATION OF
25and 30 kg/m² are classified as overweight. For individuals ENERGY BALANCE of
Obesity
verymuscular body habitus, the BMI may overestimate the Discussions about obesity so frequently focus on the issues of personal
not of body fat. For anyfat given BMI, women will generally have a choice or the obesogenic environment that it can be easy to forget that
than men.
Higher percentage of body the amount of stored energy in our bodies is subject to homeostatic
The axtent to which different adipose depots expand in response control by fundamental physiologic processes essential to our survival.
whronic overnutrition varies markedly between people. In general, In the 1940s, it was demonstrated that rodents defend their level of
imales store more fat in subcutaneous tissues, especialy on buttocks, body fat; once returned to ad libitum diets after a short period of
thichs, and upper arms, whereas men are more prone to store fat in enforced caloric restriction or excess, animals either overconsumed or
uzabdominal and truncal subcutaneous sites. Asimple measure of underconsumed calories until they returned to their previous status.
it distzbution is provided by a measurement of the waist-to -hip ratio. Since that time, research has progressively dissected the signals that
biependent of how obese aperson is, a waist-to -hip ratio >0.9 in sense nutrient stores and the contents of our diets and how this infor
wOmen and >1.0 in men is associated with adverse health outcomes mation is integrated to control hunger, satiety, and the expenditure of
ach as type 2diabetes and dyslipidemia. energy. The key locus for the integration of these signals is the hypo
thalamus, an area of the brain at least partially outside the blood-brain
LEPIDEMIOLOGY barrier that facilitates its ability to receive hormonal signals and com
le amnal National Health and Nutrition Examination Survey bine these with sensory, cognitive, and other neural inputs.
NHANES) provides an ongoing record of the prevalence of obesity in The hypothalamus receives two broad types of hormonal signals
be United States. 2017-2018, 42.4% of US. adults aged 220 years old relevant to energy balance (Fig. 401-2). The circulating concentration
Rit obese with no significant differences in prevalence by age group. of leptin, a peptide hormone produced by fat cells, increases as fat
Na Hispanic black people had the highest prevalence of obesity at stores increase and declines as fat stores are depleted. Importantly,
B%, flowed by Hispanic (44.8%), non-Hispanic white (42.2%), under conditions of caloric restriction, circulating leptin levels fall
Ton-fFispanic Asian (17.4%) people. In the United States, Asians faster than the disappearance of fat. Humans born without functional
rscit ahighly heterogeneous group encompassing both East and leptin or leptin receptors, although normal weight at birth, become
Asia as well as a substantial Filipino community. The risks of severely obese from an early age, largely as a result of an intense insa
and its complications may differ greatly between people from tiable appetite. Clearly, areduction of leptin below normal level is a
parts of Asia; in general, the prevalence of obesity is some powerfül stimulus to food intake and largely explains the rebound
a igher in women than in men, with black women having the overeating and weight regain that occurs after aperiod of starvation
or dieting, The hypothalamus also receives hormonal signals that are
more immediately related to the amount and type of food that has been
ingested. Peripheral hormones such as cholecystokinin (CCK) from
Body Mass Index
(weight in kg/height in meters squared)GTSC
the stomach, glucagon-like peptide 1(GLP-1) and gastric inhibitory
polypeptide (GIP) from enteroendocrine cells of the small intestine,
and peptide YY (PYY) and oxyntomodulin from the large intestine are
secreted in response to eating a meal and/or the presence of nutrients
in the intestinal lumen. Their release together with neural signals from
the vagus nerve and the enteric nervous system contributes to satiety,
often indirectly acting on the hypothalamus via projections from the
brainstem. Insulin, produced by the pancreas in response to carbo
hydrate and protein-rich meals, also has effects on the hypothalamic
neurons controlling energy balance.
The propeptide pro-opiomelanocortin (POMC) is expresed in
a highly restricted population of hypothalamic neurons that project
widely throughout the brain (Fig. 401-3). These neurons are respon
Obese sive to the endocrine signals described above and are critical the
wergnt Normal weight
18.5-24.9
Overweight
25-29.9 >30.0

Heath Organization
regulation of energy balance. The POMC-derived peptides a- and
PB-melanocyte-stimulating hormone (MSH) act on the melanocortin
obesity. The World 4receptor (MCAR)to regulate both food intake and aspects ot energy
Delinit ons
tybased ofoverweight and(BMI), which is calculated as weight in expenditure that are influenced by the sympathetic nervous system.
on body mass
dby the height
index
in meters squared.
3082
responsive to metabolic
other type of cell is
store
of the
fat safely in this fircealquilyremdeesnigtnse,d Nat
specimanner,
adverse and
likely caused notconsequences
by having of obesitymany
too
adipocytes but by much fatin
Hypothalamus Brainstem being forced to take
new fat cells can be up and "nonprofes ional"
store fat.
-10% of our tat cellmade in adulthood v
Leptin
Vagus nerve every year. population turns m
Ghrelin + THE CAUSES OF
Adipose OBESITY:ANDAN
INTERACTION OF GENES
tissue ENVIRONMENT
For a person to become
must exceed energy obese, energy intake
expenditure in amanner
that is sufficiently sustained
GLP14 to result in the
CCK accumulation of a large excess of triglyceride
in adipose tissue. As obesity is a
cumulative
Insulin pathology, if energy intake exceeds energy
Amylin expenditure by even a small amount
tle as 7 kcal/d), this is sufficient to
(as li:
PYY develop
OXM obesity Over a matter of years or decades.
Pancreas Even where obesity is common, there are
many people who are not overweight. co
nomic and social factors are likely to play a
now role as there are more normal-weight people
bod in wealthier and more socially advantaged
ogroups, at least in Western societies. It is also
bosmuzrouEsbau true, however, that because of discrimination,
FIGURE 401-2 The homeostatic regulation of body weight. In most 1o obese people may become socially and eco
people, body
periods of time despite fluctuations in the amout of food we eat and the weight remains stable over long nomically isadvantaged, which complicates
homeostatic regulation of body weight is controlled by the neurons in the amount of activity we undertake. This interpretation of that data. We can, however,
hypothalamus, which receive
signals from adipose tissue such as leptin and neural and
Glucagon-like peptide 1(GLP1) and cholecystokinin hormonal signals from the gut in response tohormonal state with considerable certainty that genetic
peptide YY (PYY) and oxyntomodulin (0XM) from the large (CCK)from enteroendocrine cells of the small intestinemeals.
and factors play a major role in predisposing per
or the presence of nutrients in the intestinal intestine are secreted in response to eating a meal and/ ple to arange of adiposity. We knowthis from
lumen. Their release, together with neural signals from the vagus
nerve and the enteric nervous system, contributes to satiety, a large number of studies comparing ideni
brainstem. Insulin, produced by the pancreas in response to acting on the and hypothalamus via projections from the cal and nonidentical twins. It is particulary
bythe action of some of the gut hormones, also
has
carbohydrate- protein-rich meals and potentiated tellingly that the degree of adiposity in adut
balance. The release of the hormone effects on the hypothalamic neurons controlling energy
by acting on hypothalamic neurons asghrelin from the stomach increases in the
wellas on receptors in the brainstem. unfed state and induces appetite
life of identical twins brought up in diterent
families is very similar between the twins but
is not at all correlated with that of the adop
tive siblings with whom they were raised
y-MSH, acting mostly through the MC3 receptor, appears to
controlling linear growth and the disposition ofplay
of a role in
intolean versus fat tissues. Signaling
more
nutrients
THE RELATIVE ROLESOF EXCESS INTAKE AND
LOWER ENERGY EXPENDITURE IN CONFERRING
through both these melanocortin
receptors is also subject to negative control BIOLOGIC PREDISPOSITION expenditur
neurons, which make and release agouti-related by a different population of Do these heritable factors influence energy intake, energy
ropeptide Y(NPY), and the inhibitory peptide (AGRP), neu or both? It is clear that by the time a person is obesethe amountno
tyríc acid (GABA). AGRP actively switches neurotransmitter
off melanocortiny-aminobu
less. than a
energy they expend in the resting state is more, notweight by dieting
Leptin, which suppress food intake,
neurons and inhibits NPY/AGRP neurons. simultaneously stimulatesreceptors.
POMC
obese person. However, if an obese person loses
there is some evidence that they tend to be more "energy
efticient
Vintermsof
ho"
highly sensitive to signaling through this systemHuman energy balance is than a person who has never been obese, particularlymuscular activi:
genetic defect in just one of the two copies of theas people who have a many calories they burn during a defined bout of sone
aare by
prone to overeat (hyperphagia) and to gain weight.MC4R gene are very However, the effects are subtle. It seems verylikely that thereobesity
individuals who are predominantly predisposed Ito develop hypoty-
THEPHYSIOLOGY OF severe consis
NUTRIENT STORAGE IN virtue of a lower metabolic rate, but thus far, apartfrom
much moreBeneti
ADIPOSE TISSUE roidism, concrete examples are scarce. In Contrast, a
When energy intake exceeds energy expenditure, a small amount of tent predisposition to obesity is largely mediated through
the thethat
idea the contr
brains
and compelling body of evidence Supports
that excess energy is stored as glycogen in liver and individuals
if the imbalance is greater, skeletal
then our bodies are designed tomuscle. But of food intake. When studied in controlled settings and
be

store that to eat more

mutation
excess energy in a more carry genetic variants that predispose to obesity tendwhen the arenow
This fat is more efficient efficient way as triacylglycerol
(triglyceride). less demonstrable
because, unlike not need has readily satiated. Thisis very1readily data
accompanying water, and when metabolized,glycogen,
it does predisposition, but similar eftects.
it generates almost three a major effect on obesity Smaller
times more energy per gram than does in the case of common genetic variants with
cells) have evolved to contain a highly carbohydrate. Adipocytes (fat emerging ENVIRONMENTAL FACTORS P.REDISPOSING
specialized organelle, the unilo
cular fat droplet, which holds the triglyceride downad
phospholipid that contains all the componentswithin a single-layer of TO OBESITY
to lay beliet
the
that make and breakdown triglycerides in a needed for enzymes Obesity cannot exist in the absence of sufficient foodleadslo
manner that is rapidly maintain excess fat stores. That fact not infrequenly
 There is much current investigation 3033
entromedial Paraventricular into other environmental factors that
Ventro
nucleus
nucleus might influence the development of obe
sity. Heated debates continue about the
Reduced food optimal balance of macronutrients in the
BDNF Intake
MC4R
diet to maintain normal weight and good
Increased energy health. Much of this revolves around the
a/B-MSH AGRP expenditure potential benefits of reducing the relative
proportion of carbohydrates in the diet
(Chap. 402). There seems to be reason
Arcuate SIM1
able consensus that, in the short CHAPTER
term,
nucleus
diets that are rich in protein and fat
and lower in carbohydrates more readily
POMC AGRP result in quick weight loss. This may be
because the appetite-suppressing gut hor 401
mones discussed above increase more in
Hypothalamus LEPR LEPR Pathobiology
response to protein than to carbohydrate,
thus inducing earlier satiation. However,
longer-term studies to date are less com
pelling, and the long-term increases in
protein and fat intake are not without at of
least theoretical risks. Agrowing body Obesity
of
evidence suggests that exposures early in
life, either in utero or in early postnatal life,
might "program" individuals to develop
obesity and/or cardiometabolic disease
through effects that are often attributed
Hypothalamus to "epigenetics" (Chap. 483). This is an
attractive idea, and if true, it would mean
that time-limited and affordable inter
ventions early in life might have lifelong
benefits. Inevitably, it will take time to see
if the promise of such interventions will
Adipose be fulflled. Much excitement has been
Leptin tissue
generated by the increasing recognition of
the diversity of our intestinal microbiome,
s otddanos which clearly has relevance to gastrointes
tinal health (Chap. 471). At present, it is
riüURE 401-3 Hypothalamic pathways regulating body weight. Neurons in the hypothalamus regulate energy intake premature to ascribe any significant role
and expenditure in response to leptin and other hormones. In the fed state, leptin stimulates primary neurons in the to the human microbiome in obesity or its
tuae nucleus of the hypothalamus that express pro-opiomelanocortin (POMC). The POMC-derived peptides a and
Pelanocyte-stimulatíng hormone (MSH) act on the melanocortin 4 receptor (MC4R) expressed on neurons in the adverse consequences.
ENTICular nucleus to reduce enerqy intake and increase energy expenditure. At the same time, leptin inhibits
these and WHY DOESNTLEPTIN
Sexpressing agouti-related peptide (AGRP), which switches off melanocortin receptors. Whenare disrupted by PREVENT OBESITY?
Ay molecules, such as brain-derived neurotrophic factor (BDNF) and single minded-1 (SIM1),
Hented mutations, affected individuals have hyperphagia and severe obesity. Leptin is known to suppress food intake,
and its levels rise as fat stores expand. So
why does thìs not prevent us from becom
be principal cause of obesity must be either the obese person's ing obese? The most plausible explanation lies in the evolutionary his
of excess caloric intake or their conscious choice tory of leptin and the fact that it appears to defend strongly against the
therole
l9bprioritizeOf the immediate pleasures of eating over the long-term loss of body fat stores, with a fall in circulating leptin below a persons
health harms associated with obesity. Taken to extremes, these views habitual level being a powerful stimulus to food intake, whereas the
0engender serious social, economic, and medical discrimination response to rises in leptin above the normal level is less pronounced.
ginst obese people. It is clear that genetic factors, howeverimportant At higher levels of leptin,administering extra amounts of the hormone
Uey are in an individual's predispositionto obesity,cannot explain the may have no discernible effect at all-a phenomenon that has come
marked irncrease in obesity prevalencethat has occurred in the past few to be called leptin resistance. It is important to remember that even
tecades.We have totoexplain become increas- though a person appears to be leptin resistant, some leptin action is
tey dbesogenic an environment
look tothat phenomenon. In has
that most developed and occurring; otherwise, the person would become as insatiably hungry
and progressively obese as someone with congenital leptin deficiency
tveeIore,vveeralgospinprovided
g havecountbeeninries,largerenergy-dense
aggressively marketed, made cheaper
and highly palatable food and
than ever
portions, and made available ubiquitously
(see below). It also seems likely that asubgroup of people may have
relatively low leptin levels, which plays arole inthe etiology of their
the reduction inandphys- obesity. There are likely other hormonal signals produced in severe
thang continuouslnature
y.
dactivity in WOrk been combined
Thisandhas domestic with mechanization
life due to the obesity that, unlike leptin, continue to exert a suppressive effect on
in the food intake and help to ensure that the expansion of adipose tissue does
control of our external not
Of employment. Even the less energy
become indefinitely cumulative.
erature by cooling has meant
artdriving
ificial the recentTakenincrease in obesity. It isimportant
kpeMajndeodr factorsthermoregul
on
heating and
together, these are likely to be
mber,
ation.substantial proportion of the populace SINGLE-GENE DISORDERS LEADING TO OBESITY
The assessment of severely obese children and, indeed, adults should be
ans normalhowever weight, that
undera these circumstances and alarge part of directed at screening for potentially treatable endocrine and neurologic
conditions and identifying genetic conditions so that appropriate
attributable to their geneticgoodfortune.
 3084
TABLE 401-1 Classical Genetic Obesity Syndromes TABLE 401-2 Obesity Syndromes due to
Controlling Energy Homeostasis Pathways Mutations in
SYNDROME INHERITANCE ADDITIONAL CLINICAL FEATURES
Hypotonia, failure to thrive in infancy, GENE AFFECTED INHERITANCE Genes
Prader-Willi Autosomal
dominant developmental delay, short stature,
hypogonadotropic hypogonadism,
Leptin Autosomal
recessive ADOITIOhyperNAL phagiCLINIaC,ALfrFgEnueATmI
Severe
Autosomal
sleep disturbance, obsessive behavior
Short stature in some, skeletal defects,
ihypogonadi
nfections, hypogonadot
s m, mi ld rnie
Albright's hereditary
osteodystrophy dominant developmental delay, shortened
metacarpals; hormone resistance
Leptin receptor Autosomal hypothyroihyperdismphagia, franuarm
Severe
recessive
when mutation on maternally inherited
allele
ihypogonadi
nfections, hypogona
sm, milddotogie,
PART 12 Bardet-Biedl Autosomal Syndactyly/brachydactyly/polydactyly, Proopiomelanocortin Autosomal hypothyroidism
recessive developmentaldelay, retinal
dystrophy or pigmentary retinopathy,
recessive
Hyperadrenalphagicrisis
or a, choldueestatoticACTHjaurge
Cohen's Autosomal
hypogonadism, renal abnormalities
Facial dysmorphism, microcephaly,
Prohormone convertase1Autosomal defiSmalcile-bowel
ncy, paleenteskinropatandhy. rad a
logyand recessive hypotonia, developmental delay,
recessive
postprandial hypoglycemia.
Carpenter's Autosomal
retinopathy
Acrocephaly, brachydactyly,
hypot
hypogonadi
Insipidus
hyroidissm,m, centACTHral dideaicbieetnegty
recessive developmental delay, congenital Carboxypeptidase E Autosomal
heart defects; growth retardation, recessive
hypogonadism
Melanocortin 4receptor Autosomal
Alström's Autosomal
recessive
Progressive cone-rod dystrophy,
sensorineural hearing loss, dominant Hyperphagi
growth a, accelerated Iineg
Single-minded 1 Autosomal
lism hyperinsulinemia,early type 2diabetes
mellitus, dilated cardiomyopathy, dominant Hyperphagia,
growth, speechaccel
and
erated lineg
pulmonary, hepatic and renal fibrosis delay, autistic traits language
Tubby BDNF
Autosomal
recessive
Progressive cone-rod dystrophy, Autosomal
dominant Hyperphagia, developmental telay,
hearing loss hyperactiity, behavioral problens
TrkB
including aggression
genetic counseling and, in some cases, treatment can be started. Clin Autosomal Hyperphagia, speech and
dominant language delay, variable
ically, it remains useful to categorize the genetic obesity
as those with dysmorphism and/or developmental delay syndromes
and those
developmental delay, hyperacthity,
behavioral problems including
without these features (Tables 401-1 and 401-2). Although individ aggression
ually these monogenic disorders are rare, cumulatively, up to 20% of SH2B1 Autosomal | Hyperphagia, disproportionate
children with severe obesity have rare chromosomal abnormalities dominant hyperinsulinemia, early type 2
and/or highly penetrant genetic mutations that drive their obesity. diabetes mellitus, behavioral
This figure is likely to increase with wider accessibility to genetic problems including aggressian
testing and as new genes are identified. A genetic diagnosis can Abbreviations: ACTH, adrenocorticotropic hormone: BDNE, brain-derived
inform management (many such patients find it very difficult to lose neurotrophic factor; SH2B1, Src-homology-2 (SH2) B-adaptor protein-1 (SHB1;
weight through diet and exercise) and can inform clinical decision TrkB, tropomyosin receptor kinase B.
making regarding the use of bariatric surgery (feasible in some;
risk in others) (Chap. 402). There are a number of drugs in high a syndrome known as Albright's hereditary osteodystrophy (i0
clinical
trials targeted specifically at patients with genetic obesity syndromes. (Chap. 412). Maternal transmission of GNASI mutationsdefectslea pls
AHO (characterized
Specifically, setmelanotide, a MCAR agonist, has been used effectively resistance to several byhormones short:stature, obesity, andskeletal Nhers
in phase 2/3 clinical trials in children who are (e-g., parathyroid hormone),Thecniz
genetically deficient in paternal transmission leads only to the AHOphenotype.
POMC or the leptin receptor. It is also being explored for the treatment spectrum is very broad, and some patients may present with
of other genetic obesity syndromes affecting the melanocortin
pathway. alone. diseasechura
CLASSICAL SYNDROMIC DISORDERS Bardet-Biedl syndrome is arare autosomal recessiveretinal drstnn
A number of syndromes were identified by clinicians long
before terized by obesity, developmental delay. polydactyly, renal
abnormauio
their exact genetic cause was known. In these syndromes, obesity is or pigmentary retinopathy, hypogonadism, and in>20
gens
The same clinical from mutationsclinical fatu
associated with a stereotyped set of other anomalies, often neurode features can arise
velopmental in type. The precise genetic basis for the majority of these which disrupt signaling in primary cilia. Overlapping syndromes(Table
syndromes is now known. Prader-Willi syndrome (PWS) is the most are seen in a number of other genetic obesity
common syndromic cause of obesity, with an estimated prevalence of DISORDERS OF LEpTIN-MELANOCORII oflert
~1 in 25,000. It is an autosomal dominant disorder caused by
deletion
of an imprinted region on the paternal chromosome 15 (Chap. 466). SIGNALING
action
homat
Homozygous mutations that disrupt the production r with
The characteristic clinical features are hypotonia, feeding difficulties Children
in infancy, developmental delay, are rare but result in a disorderthat is treatable.rapid weight aninte
hyperphagia (increased food intake),hypogonadotropic
and obesity. hypogonadism,
Children with PWS
gous loss-of-function leptin mutationssevere
first few months of life,
have
obesity dueto
with
foodsetie
deficen
are short with reduced lean body mass and resulting in
tures resembling those seen in growth hormone (GH)increased fat mass, fea drive to eat (hyperphagia) and impaired satiety leptin
recombinantepl
deficiency; GH meal. Congenital Sinly

treatment decreases body fat and increases linear growth and muscle can be behavior soon after the end of a of
ass

mass and is now standard of care in this condition. Low levels of treated with subcutaneous injections to weight
homozygousmutations
lead
in

brain and
expression of the neuropeptide oxytocin and the nerve growth factor clinical which reduce hunger, increase satiety,with leptintre
Brain-derived neurotrophic factor (BDNF) in PWS patients have sug leptin features are seen in patients responsivetooccuseva in
they are not rarely
gested new therapeutic opportunities for these patients. receptor gene, but
(Table 401-2). Normal pubertal development
biohemkal
Inherited or de novo (not found in either parent) deticiency, with is
sue e

another imprinted gene, GNASI, which encodes Gsa mutations in with leptin or leptin hypogonadisn. receptor
Howevet.
lhere
protein, cause of hypogonadotropic
 3085
delayedbut spontaneous onset of menses in asmall number of Hypothalamic Damage The hypothalamic regions that con-
leptin receptor-deficient adults. Leptin treatment permits trol energy balance can be disrupted by tumors (such as cranio
pubertal development, suggesting that leptin is a per- pharyngiomas), inflammatory masses, or after a severe head injury
MmATSoNof (Chap. 379). In such cases, there is often some accompanying evidence
factorforthe development of puberty.
Homorygous compound heterozygous mutations in POMC of disruption of the hormonal functions of the anterior or posterior
hyperphagia produced
and early-onset obesity. As adrenocorticotropic pituitary, although it may be subtle and the history of hyperphagja and
often short. It is worth noting that in common obesity,
Iinthe pituitary gland by cleavage from weight gain is
c(ÀCTH)is present with
syrmone
also isolated ACTH deficiency (neonatal GH levels in response to provocative testing may be somewhat lower
AMG patients
hpoglnemia and cholestatic jaundice). In the skin, POMC-derived structural
than normal, of a
but this does not necessarily suggest the presence
nelanocortin peptides act on melanocortin 1 receptors to induce lesion.
mentation. For this reason, the lack of POMC-derived peptides CHAPTBR
ADVERSE CONSEQUENCES OF OBESITY
ohesepatients
with POMC deficiency results in hypopigmentation
in hair, which is more noticeable in people of Caucasian Mechanistic Considerations Obesity is associated with a wide
skinand hair. Prohormone convertase 1(PCSK1) morbidity and mortality 401
who often have red
Ancestry
1zyme involved in the cleavage of POMCinto ACTH, which is range of pathologies that can adversely impactrelated, at least in part, to
(Chap. 408). Some of these consequences are
s e r dleavedto make a-MSH by carboxypeptidase E. Impaired the direct mechanical or gravitational effects of the expanded Pathobiology
fat mass
essingoffPOMC contributes to the hyperphagic severe early-onset
who also have
itself (Fig. 401-4). However, the principal mechanisms behind many of
and ACTH deficiency in people lacking PCSKI to be due to the expanded fat
the complications of obesity are less likely chronic
bmoonadotropic hypogonadism, postprandial hypoglycemia (due to mass itself but more closely related to the state of overnutrition
dprocesing of proinsulin to insulin), and a neonatal enterop-
impaired
itself and its effects on tissues throughout the body.
in Parly childhood. Heterozygous mutations that impair the func As people become obese, one of the first and most prominent biochem of Obesity
severe early-onset ical abnormalities that develops is the need for increased circulating
Han of MC4R are found in 5-6% of patients with population, homeostasis. This state
hesy and at a frequency of ~l in 300 in the general concentrations of insulin to maintain glucose
obe
contribute
naling this the most common gene in which variants manner, with
to
of insulin resistance generally worsens with a greater degreeIt isof more
hesiy MC4R mutations are inherited in a co-dominant sity, but there is a high degree of interindividual variability.
zriable penetrance and expression in heterozygous carriers; homozy prominent when fat is distributed more centrally. Insulin resistance/
often hyperphagic from
gUS Carriers are severely obese. Patients arehave increased lean mass hyperinsulinemia is likely to play a major role in the predisposition to
iaty childhood and hyperinsulinemic and metabolic endocrine and cardiovascular diseases seen more frequently
and increased linear growth. in obesity and may even play a role in the predisposition of obese peo
ple to develop certain cancers.
IGENETICSUBTYPES OF OBESITY ASSO
CIATED The main sites of insulin action in the body are the liver and skeletal
of the
WITH NEUROBEHAVIORAL ABNORMALITIES muscle. Thus, for insulin resistance to be discernible at the level
gene that whole body, the action of insulin must be disturbed in one or both of
both PWS patients and patients with mutations in SIM1 (a would do
ats downstream of MC4R) exhibit a spectrum of behavioral
abnor these tissues. It seems unlikely that an expanded fat cell massresistance?
nalties that overlap with autism-like features that could be related to that directly. How then does obesity lead to a state of insulin
kduced oxytocin signaling (Table 401-2). Mutations affecting BDNF
speech
al ts receptor tropomyosin receptor kinase B (TrkB) causeas hyper Dementia
aa anguage delay, hyperphagia, and severe obesity, as well Stroke
kUy autistic traits, and impaired short-term memory. Interestingly, Sleep apnea
iommon variant in BDNF(V66M), found in heterozygous form in
and neu
nof the population, is associated with a number of traitsChromoso
ychiatric disorders incuding anxiety and depression. Hypertension
mal deletion andImutations affecting Src-homolog-2 (SH2) B-adaptor Hypertriglyceridemia
severe,
Prolein-1 (SH2B1) are associated with dominantly inherited,
early-onset
Ischemic heart disease
ote Obesity, disproportionate insulin resistance, Gallstones Heart failure
2diabetes, and behavioral l problems including aggressive behavior. Esophagitis Cancer of esophagus,
Type 2 colon, endometrium,
DISORDERS pancreas, kidney
LOBESITY SECONDARY 1TO OTHER
may gain
diabetes
NAFLD
Endocrine
Iand become
obese,
Patients with hypothyroidism
Disorders although it is rarely the sole cause of severe
function in PCOS
thesty, It is nonetheless always to measure
prudent
thyroid
thyroid-stimulating
yaient t presenting with obesity. Measurement of thyroid,
Wmone Tare(TSH)secondary
will detect significant primary
hypothyroidism,
disease of the
additional measurement of
gain can also be a
Arthritis
Gout
hyroxine levels is Weight
needed (Chap. 383).
the presence of
WeyoSnsetnatinngeous feature of Cushing's syndrome. Clinically,marked
bruising, livid striae, myopathy, and centripetal
hypercor-
itrbutionfromof common body fat help
obesity. This condition
endogenous
to distinguish true is usually reasonably
approximate cortisol
MitaMuisogdluhcitofnobyrwardrates to(24-hdiagnoseurine
based on tests that suppression of serum
free cortisol) orthe
(Chap. 386). Occasionally,
iventa effectsdexametof adiposity
hasone
in severelyobese
metabolism can make
FIGURE 401-4 Obesity-related complications. The expanded
characterizes obesity predisposes certain obesity-related
osteoarthritis of knees, reflux esophagitis, and obstructive sleep
fat mass that
complications (e.g.,
apnea) directly
the metabolic, endocrine,
through its mass and/or volume. However, in the case ofFurther
on glucocorticoid tests, including and cardiovascular complications, the link is less clear. research is needed
more sophisticated
interpret results, andof cortisol, necessary to estab- to establish whether some features of the expandedaspects fat mass influence the

meweni sagsurinfeature
theß diagnosis
diurnal rhythm confidence.mayWeight
of
with
patients with
be
gain can also be
insulinoma, driven largely by
eal more frequently than normal to avoid hypoglycemia.
the
development of these complications or whether other
overnourished state, such as excess fat outside the fat depot,
of the chronically
are more relevant.
NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovarian syndrome.
One hypothesis suggests a leading role for the Chronic Imbalance of energy Intake
inflammation that occurs in the adipose tissue in Energy expenditure
obesity (Fig. 401-5). This undoubtedly happens,
as there are more macrophages in obese than Expansion of adipose tlssue depots
nonobese adipose tissues, and this is associated
with higher levels of inflammatory markers in
the circulation of obese people. The majority of
macrophages in obese adipose tissue are found
in clusters around dead or dying adipocytes,
s0 it appears that these cells are clearing debris Adipose tissue
after cell death. Studies in animal models provide Inflammation
strong support for the notion that this inflam imforitecontiUrgsr
d fa cal
matory state is mechanistically linked to insulin
resistance, but evidence from humans for this is
not as strong.
An alternative hypothesis is that as individuals
becomes more obese they become less able to
safely store nutrients in their adipose tissue and Inflammatory Storage of lipid in
cytokines
begin to redirect macronutrients to other tissues nonadipose tissue
that are not designed for fat storage and may be
damaged by the nutrient excess. This certainly Defective
in
glucose handling
liver and muscle
happens to people who are born with a lack of
adipose tissue (lipodystrophy) who, early in life,
develop severe verSions all the metabolic com Insulin resistance/compensatory hyperinsulinemia
plications that are seen in obesity as they have FIGURE 401-5 How does obesity cause metabolic disease?
no safe depot in which to store excess nutrients. comolications of obesity and underlies and precedes many ot its Insulin resistance is one of ho w
There are stronger human data from both genetic and production of glucose by the adverse health consequences Tha
to insulin, and this results in a mostimportant tissues,muscle and liver, respectively, become lers
and pharmacologic studies for the existence of main theories for the Compensatory increase in insulin secretion from the pancreas. There
the latter mechanism. How ectopic fat leads to other association of obesity with insulin resistance.
cells that are more abundant in obese adip0se In the first, products of macroohatt
insulin resistance and other damaging effects is routes,inflammatory
disturb insulin's action in muscle and liver cells. In the tissue can, through paracrine or et
still a puzzle, but it is very likely a major driver of become less able to take on excessive calories, which end upsecond, as adipose storage deposts fl n
being stored as S
pathology associated with obesity. muscle and liver, which are not primarily designed to store nutrients of this ectopic lipid in tissues srctz
stronger for the latter hypothesis. type. The evidence in huaS:
Metabolic Complications DYSLIPIDEMIA
The insulin resistance of obesity is frequently asso
ciated with dyslipidemia characterized by high circulating triglycerides irritation and can also become infected with fungi. Insulin resitzaz
and low high-density lipoprotein cholesterol (Chap. 407). Occasionally, hyperinsulinemia is associated with acanthosis nigricans, wher za
the hypertriglyceridemia may be severe enough to put the patient at such as axilla, groin, and the back of neck develop velvety byars
risk of pancreatitis. Although there is a relationship between obesity mentation. Hidradenitis suppurativa is apotentially disabling sunt
and raised circulating levels of low-density lipoprotein cholesterol dition strongly associated with obesity. It is characterized by rerure
(which is the major risk factor for coronary artery disease), genetic boils often with chronically draining sinus tracts affecting stin r
factors independent of obesity and the type of dietary fat consumed containing apocrine sweat glands.
probably have an even greater impact.
FATTY LIVER DISEASE Obesity is Cardiovascular Complications Obese people, evenitheyd
strongly associated with the pres have diabetes, have increased morbidityand mortality from ahen
ence of ectopic fat in hepatocytes. This can progress to nonalcoholic rombotic vascular disease, including coronary artery
steatohepatitis (NASH), which can progress to the fibrosis, which stroke. The factors that result in this are complex and involve mae
is a precursor to cirrhosis (Chap. 343). The reported incidence of prevalence of hypertension, dyslipidemia, and insuln ln
NASH-related cirrhosis and of hepatocellular carcinoma has increased hyperinsulinemia. The rare condition of thrombotic throm
markedly in step with the increase in the prevalence of obesity in ado Purpura, Which causes microvascular platelet thrombosis, thromy
lescents and adults. topenia, and hemolytic anemia due to the presence of abnormay
associated withobeait
TYPE 2 DIABETES The insulin resistance characteristic of the over von Willebrand factor multimers, is strongly
nourished state strongly predisposes to the development of type 2 Independent of occlusive arterial disease, obese people
characterized
diabetes in people who, largely for genetic reasons, are less able to increased risk of heart failure, particularly
fbrilation, the most comi
by diastolic dysfunction, and of atrial
maintain the high levels of insulin secretion over many decades.
Impaired glucose tolerance and type 2 diabetes are among the most arrhythmia. is
À
Comaxu

common complications of obesity (Chap. 403). Exertional dyspnea

Respiratory Complications increased requiredtomo
obesity, contributed to by the work diaphrag
Endocrine Complications In females, the insulin resistancel onthetofsofttised
greater mass as well as impacts of pressure
hyperinsulinemia frequently found in obesity strongly predisposes thoracic cage on chest wall compliance. Enlargement airways a
aroundthe byporentilai
factor
to the development of polycystic ovaries, characterized by irregular
the mouth and throat and adipose depots
apnea, although
other
menstruation, anovulatory infertility, and hirsutism due to hyperan ute to the high prevalence of sleep nocturnal
drogenism. In males, obesity is more often associated with a degree of contribute to some forms, where central
central hypogonadism, where low circulating testosterone is associated also occurs.
esophagitisisthem
oaune
with levels of luteinizing hormone and follicle-stimulating hormone particularjy
that do not rise appropriately to compensate for the testosterone-de Gastrointestinal Disorders Reflux
complication of obesity biliuryca
ficient state mon gastrointestinal pressure. Gallstones
risksof
in those with high intraabdominal increased
Dermatologic Complications
with excessive skin Obesity
folds that can cause can through
discomfort result in mechanical
problems common in obese
cholecystitis, people,andbringing
pancreatitis, gallbladder cancer.
 3087
amatologic Disorders Osteoarthritis of the knce and gout
most common theumatologic conditions cdearly associ-
Evaluationand
wihobesity. Interestingly, despite obesity being described as a
nlamnatorrstate, there is no evidence for an increase in rheu- 402 Management of Obesity
arthritis or the seronegative arthritides among people who are
n/ Robert F. Kushner

Obesity is a risk factor for a number of common cancers.

recently been calculated that, at least in some countries, More than 70% of U.S.adults are considered to be overweight or have
t has
overtaken
ismoking as the greatest risk factorfor developing obesity, and the prevalence of obesity is increasing rapidly in most of
wNhas research has found that as the BMI
increases 5 kg/m', by CHAPTER
Recent
a mortalityincreases by 10%. The largest effects are on colorec-
the industrialized world. Children and adolescents also are becoming
more obese, indicating that the current trends will accelerate over
r andpancreatic cancer, adenocarcinoma of the esophagus,
kdhey, time. Obesity is associated with an increased risk of multiple health
women, endometrial carcinoma. The recent rapid increase inproblems, including hypertension, type 2 diabetes, dyslipidemia, 402
prevalenceof esophageal adenocarcinoma is likely related to the obstructive sleep apnea, nonalcoholic fatty liver disease, degenerative
* recentincrease in reflux esophagitis due tothe raised intraab- health
rked joint disease, and some malignancies. Thus, it isimportant for Bvaluation
pressure (with or without hiatus hernia) characteristic of care providers to identify, evaluate, and treat patients for obesity and
sominal
ntral
ohesity: associated comorbid conditions.

Responseto Infection
The factttthat obesity can influence the out- EVALUATION and
infections has become very apparent with the COVID- Health care providers should screen all adult patients for obesity and
ofsome Management
Srandemic. Ohese patients have asubstantially worse outcome if offer intensive counseling and behavioralininterventions to promote sus-
shtedbySARS-Cov-2 through mechanisms that are as yet unclear. tained weight loss. The four main steps the evaluation of obesity, as
epatients also appear to
wound
be more susceptible to bacterial described below, are (1) a focused obesity-related history that includes
(2) a
gtcionsand postoperative sepsis. lifestyle questions about diet, physical activity, sleep, and stress;
obesity; (3) of
physical esxamination to determine the degree and type of
There is increasing assessment of comorbid conditions; and (4) assessment of the patient's
Obesity
Disorders of the Central Nervous System
ndencethat obesity is arisk factor for dementia in later life, although readiness to adopt lifestyle changes.
that risk is mediated is not clear. Idiopathic intracranial hyperten The Obesity-Focused History The first step in taking an obe
obesity.
msa rare disorder that is strongly associated with sity-focused history is to approach the topic in a sensitive manner. The
reason for this concern is that the word obesity is a highly charged,
ICONCLUSION emotive term. It has a significant pejorative meaning for many patients,
sir is amedical disorder that has been greatly increasing in prey- leaving them feeling judged and blamed when labeled as such. This is
other chronic dis
iat due to environmental factors that are
ubiquitous in developed not the case when patients are told that they have prefer that clinicians
mind that hypertension. Patients
zideveloping countries. However, it is important to bear in
people is atrib
eases such as diabetes or
terms such as weight, excess weight, body
isa highly heterogeneous condition, which in somegenetic variation use more neutral words or
stigmatizing terms
underlying
zDe entirely to genetic causes, and that people. It is a serious con mass index (BMI), or unhealthy weight, versus more
mgy influences the risk of obesity in alloutcomes such as obesity, morbid obesity, or fatness. address the following seven
un leading tomultiple adyerse health and considerable Information from the history should
pathogenesis increases, questions:
nan sufering, As our understanding of its compassion
duy to treat obese patients with understanding and What factors contribute to the patient's obesity?
prevention
ab develop new and better options or its treatment and How is the obesity affecting the patient's health?
sNythy of emphasis. risk from obesity?
What is the patient's level ofdifficult
What does the patient find about managing weight?
FURTHER READING NEngl What are the patient's goals and expectations? management program?
SAZZA Ket al: Myths, presumptions, and facts about obesity. Is the patient motivated to begin a weight
need?
Med 368-446, 2013. What kind of help does the patient
of obesity in humans. n: are promoted by
IS, O' R AHILLY S: The genetics Dartmouth, 2000. Although the vast majority of cases of obesity patterns, the his
Pingold KR et al (eds). Endotext. control of energyMA,balance.
South Nat behavioral factors that affect diet and physical activity
evaluation. Disor
tLDMAN1754,TM:2019.
Veab Leptin andthee endocrine tory may suggest secondary causes that merit further hypothyroidism,
ovarian syndrome,
pathophysiology, and ders to consider include polycystic
hypothalamic disease. Drug-induced weight
SFIELD SB, WADDEN TA: Mechanisms, 2017. and
Cushing's syndrome, considered. Common causes include medica
Tagenent tof Engl J Med 376:1492,
RL et al: obesity. inNenergy expenditureresultingfrom
altered gain also should be
tions for diabetes (insulin,
sulfonylureas, thiazolidinediones), steroid

ght. NChanges (clozapine, olanzapine, risperidone),

RsKWeiFACTOR hormones, antipsychotic agents
1995.
Eng! J Med 332:621,(NCD-RISC): Worldwidetrends
mood stabilizers (lithium), antidepressants (tricyclics, monoamine
from 1975 drugs
index,CCoLLABORATION overweight, and obesity mirtazapine), and antiepilepticsuch
bdy-mas underweight, population-based
, measurement
analysis of 22416 adolescents, and adults. Lancet
ies in pooledmillion
oxidase inhibitors, paroxetine,
(valproate, gabapentin, carbamazepine).
nonsteroidal anti-inlammatory drugs and
Other medications,
calcium channel blockers,
as

1289 children,
observations on the causes may cause peripheral edema but do not increase body fat.
physical activity patterns may reveal
S: 2016: Some
Harveian Oration Clin Med(Lond) 16:551, 2016. The patient'scurrent diettheand
development of obesity and may iden

Aonseauences of obesity. factors that contribute to treatment. Physical fitness, in particular,

is an important
target for
tify behaviors topredictor
BMI and body composition
of all-cause mortality rate
independent of
and highlights the importance of
exercise history during examination as well
as
taking
a physical activity and
emphasizing physical activity as a treatment approach.
 3088
TABLE 402-1 Cassiñcation of Welght Status and Disesse Risk TABLE 402-3 Obesity-Related Orggan Systems
ratoryReview
RODY MASS INDEX OBESITY Cardiovascular
CLASSIFHCATION
Underweight
(kg/m'
<185
CLASS OISEASE RISK
Hypertension
Congestive heart failure
RespiDyspnea
Healthy weight 18.5-249 Cor pulmonale
Obstructive sla p apnag
Overweight
Obesity
Obesity
250-29.9
30 0-349
35.0-39.9
Increased
High
Very high
Varicose veins
Pulmonary embolism HvPiAsthmacpkowivecnktiilaantiosnyndsryonmdraome
Coronary artery disease
Extreme obesity Extremely high Endocrine Gastrointestinal
NonaCholGastreolcleiosthholoipahisicasgefaatly lrveelurxdidisytt
PART 12 Source Adapted with permission from WHO Consultetion on Obesity (1997): Metabolic syndrome
Geneva, Switzerland), World Health Organization. Division of Noncommunicable
Diseases &World Health Organization. Programme of Nutrition, Family and Type 2diabetes
Reproductive Health (1998). Obesity: preventing and managing the global epidemic: Dyslipidemia
report of a WHO Consultation on Obesity, Geneva, 3-5 June 1997. World Health
Organization. htps:/apps. who.intirisbitstream/handle/10665/63854/WHO_NUT Polycystic ovarian syndrome Hernias
Colon cancer
ology
and NCD 98 1 %28p159-276%29. pdf?sequence-2&isAllowed=y
Musculoskeletal
Hyperuricemia and gout Genitourinary
Inquiring about sleep health that addresses regularity, duration, Immobility Urinary stress incontinence
efficiency, and satisfaction is also important. Although the mechanisms
are uncertain, sleep deprivation is associated with metabolic alterations
Osteoarthritis (knees and hips)
Low back pain
ObesHypogonadi
ity-relastemd (gmloalmee)rulopathy
in appetite regulation, sympathetic nervous system overactivity, insulin Breast and uterine cancer
Carpal tunnel syndrome
sensitivity, and changes in circadian rhythm. Stress may also contribute
Psychological
Pregnancy complications
bolism obesity, in part due to activation of the adrenal cortical axis and Neurologic
elevated cortisol levels and its impact on emotional health and behav Depression/low self-esteem
iors. This historicinformation is best obtained by the combination of a Body image disturbance
Stroke
questionnaire and an interview. Social stigmatization
Idiopathic intracranial hypertaroy
Meralgia paresthetica
BMIand Waist Circumference Three key anthropometric mea Integument Dementia
surements are important in evaluating the degree of obesity: weight, Striae distensae
height, and waist circumference. The BMI, calculated as weight (kg)/ Stasis pigmentation of legs
height (m) or as weight (b)/height (in)? x 703, is used to classify Lymphedema
weight status and risk of disease (Table 402-1). BMI is highly correlated Cellulitis
with body fat and is related to disease risk. Lower BMI thresholds for
overweight and obesity have been proposed for the Asia-Pacific region Intertrigo, carbuncles
since this population appears to be at risk for glucose and lipid abnor Acanthosis nigricans
malities at lower body weights. Acrochordons (skin tags)
Excess abdominal fat, assessed by measurement of waist circum Hidradenitis suppurativa
ference, is independently associated with a higher risk for metabolic
syndrome, diabetes mellitus, and cardiovascular disease. Measurement
of the waist circumference is a surrogate for visceral adipose tissue
and should be performed in the horizontal plane above the iliac crest risk factors, and index of suspicion. For allpatients, atast
(Table 402-2). profile (total, low-density lipoprotein, and high-densty
cholesterol and triglyceride levels), chemistry panel, andP
Obesity-Associated Comorbid Conditions The evaluation of hemoglobin should be performed, and blood pressurerelatedoat
comorbid conditions should be based on presentation of symptoms, Symptoms and diseases that are directly or indirectly
Although individuals vary, tht
SIty are listed in Table 402-3.
and severity of organ-specific comorbid conditions usualy
TABLE 402-2 Ethnic-Specific Cutpoint Values for Waist increasing levels of obesity.
ETHNIC GROUP
Circumference underw
WAIST CIRCUMFERENCE Patient Efforts are patiens
Europeans Identifying the High-Risk identify
develop more practical and useful assessments tto AnalogousW
Men >94 cm (>37 in) alone
are at high risk in addition to using BMI heartfailued
Women >80 cm (>31.5 in) staging systems commonly used for congestive Endazi
South Asians and Chinese of Clinical(AC
kidney disease, the American AssociationEndocrinology
Men >90 cm (>35 in) (AACE) and the American College of obesity
Women >80 cm (>31.5 in) lines advocate a simple and clinically useful ind
system that is based on ethnic-specific cutoffs
BMI 402-1)S¡
Japanese (Fig.
Men >85 cm (>33.5 in)
assessment for adiposity-related complicationsorobeseby.2 ard
assigned to individuals who are overweight l and ati
Women cation but have no complications, whereas stagesBMI oratea
classih
>90 cm (>35 in)
Ethnic South and Central Use South Asian as individuals who are overweight or obese by(stage
Americans specific data are recommendations
available. until more
have one or more mild-moderate complications
functionalstaging
Sub-Saharan Africans Use European data until more specific data severe complication (stage 2). Adifferent System(EQ
are available. obesity, called the Edmonton Obesity Staging (
Eastern Mediterranean Use European data until more specific data individuals with obesity into fivegraded categories
three
domains-l
independent
and Middle Eastern (Arab) are available. along
morbidity and health-risk profile staging occurs.
populstions
tional, and mental. In this system,
Source KG Alberti, P Zimmet, JShaw; IDF Epidemiology Task Force to Change
Group The metabolic syndrome-a new worldwide Consensus Assessing the Patient's Readiness
patient is not ce
definition. Lancet 366:1059, 2005. lifestyle changes
nitiate when the
 3089
Stage 0 Stage 1 Stage 2
No Mild- moderate Severe
complioations Complications complications

BMI 25 29.9 BMI >25 BMI >25

BMI
BMI 30

Treatment/ Secondary Tertiary Tertiary

prevention Prevent complications Treat complications Treat complcations CHAPTER

Lifestyle Lifestyle Lifestyle

Suggested Consider medication Plus medication 402
therapy consider surgery
Evaluation
" Metabolically healthy " Pre-hypertension "Prediabetes
obese " Hepatic steatosis "Metabolic syndrome
" No biomechanical OSA with AHI5-30 " Type 2 diabetes and
complications and mild symptoms " NASH
Examples Osteoarthritis with Hypertension Management
" OSA with symptoms or AHI >30
WOMAC score 1-5
Osteoarthritis with WOMAC score
5-10 or knee replacement surgery

of Clinical Endocrinology clinical practice guidelines. AHI, apnea-hypopnea index; BMI, body of
NIDE A12-1 Staging the severity of obesity using the American Association
apnea; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index (a patient-reported
Obesity
ndey: NASH, nonalcoholic steatohepatitis; 0SA, obstructive sleep
function). (Data from WT Garvey et al: American Association of Clinical Endocrinologists and American
ne measure for oste0arthritis registering pain, stiffness, and
ene of Endocrinologycomprehensive clinical practice guidelines for medical care of patients with obesity, Endocr Pract 22 (Suppl 3):1, 2016.)

Assessment LIFESTYLE MANAGEMENT

pfrustration and may hamper future weight-loss efforts. psychi Obesity care involves attention to three essential elements of
life
and support, stressful life events,
ncudes patient motivation and behavior modification.
tic status, time availability and constraints, and appropriateness of style: dietary habits, physical activity,disease of energy imbalance,
viewed as the balance of two Because obesity is fundamentally a
Bals and expectations. Readiness can be desire to change; and all patients must learn how and when energy is consumed
(diet),
mosing forces: (1) motivation, or the patient's (physical activity), and how to
resistance, or the patient's resistance to change. how and when energy is expendedtheir daily lives (behavioral ther
to use the moti incorporate this information into
Ahelpful method to begin a readiness assessment ispatient's interest shown to result in a modest
apy). Lifestyle management has beencompared
ional interviewing technique of anchoring" the technique, (typically 3-5 kg) weight loss when with no treatment
Confidence to change on a numerical scale. With thisbeing not so
with 0 or usual care.
De patient is asked to rate-on a scale from 0to 10, is to reduce overall
ortant (or confident) and 10 being very important (or confident) Diet Therapy The primary focus of dietthetherapy
American Heart Associ
about losing weight at this calorie consumption. Guidelines from
Bor her level of interest in and confidence also serves Cardiology/The Obesity Society (AHA/
Ihis exercise helps establish readiness to change and ation/ American College of calorie deficit of
ibasis for further dialogue. ACC/TOS) recommend initiating treatment with a diet. Alterna
500-750 kcal/d compared with the patient's habitual 1500-1800 kcal/d
tively, a diet of 1200-1500 kcal/d for women and can be prescribed.
body weight)
for men (adjusted for the individual'sgoal of losing ~1-2 lb/week. The
IREATMENT This reduction is consistent with a substitutions or
ObesIHE GOAL
iry OF calorie deficit can be instituted through dietary
alternatives, Examples include choosing
consuming
smaller
more
portion sizes, eating
whole-grain cereals,
he
THERAPY improve obesity-related more fruits and vegetables, reducing
skimmed dairy products, fats and
prim ary goals of treatment are to reduce the risk of devel- selecting leaner cuts of meat and
and other foods with added
Cümorbid conditions and quality oflife and consumption of fried foods
Information obtained sugar-sweetened beverages. It is
ngfuture -related complications.and diagnostic tests is oils,and drinking water instead ofremains patient centered and that
Iom obesity-
the history, physical examination, important that dietary counseling measurable, agreed upon,
plan(Fig. 402-2).
Wed to determine risk and develop a treatment and which
patient the selected goals are SMART (specific,
The of how aggressively to treat the risk status, expec- realistic, timely).
de cision
Oalities to use determined by the patient's
is patients who are
deemed The macronutrient composition
of the diet will vary with the
condition. The 2020 U.S. Depart
ions, and availableresources. Not all patient's preference and medical 332),
alone does
treated, since BMIdistribution, ment of Agriculture Dietary Guidelines for Americans (Chap.applied
BMI need to be reduction, can be
directly screening
O, body fat and risk
which focus on health promotion overweight
measure body fat, distinguish However, patients who
to treatment of patients who are or obese. The recom
an health status. and who would bene- diet rich in whole grains,
Weent I with individuals comorbidities
obesity-reelated should be managed proactively.
mendations include maintaining a decreasing
fruits, vegetables, and dietary fiber; sodium intake to
low-fat dairy products; and
forweigobesi
ht-losS
intervention management and <2300 mg/d; consuming fat-free orfat intake to <10% of daily cal
with lifestyle depending on
always beginsbariatric
ty
dude pharmacotherapy or
an
surgery,
initial weight-loss
goal keeping added sugars and saturated
ories. Applicationof these guidelines to specific
calorie goals can be
Calegory Setting
(Tableis402-4).
6 months a realistic target.
 9090

Patient
Measure welght BMI25-29.9 (overweight) Assess and treat risk
encounter
helght; calculate 30-34.9 (class Iobese) Yes factors for CVD and
or 35-39.9 (class lobese) BMI 225
BMI
or 40(class IlIl obese), obesity-related
comorbidties and lartya
histonan
PART 12 Evaluation
No

Treatment
BMI 18.5-24.9 No, insufficient risk Asses ne
to \ose weinht
BM 230 or BMI
gy
mand
Measure weight
and calculate BMI
Advise to
avoid weight gain;
wth isk fctort25-s h:
annually or more address and treat
frequently other risk factors
Yes

OAMO -No, not yet ready Assess

readinitestyie
to make ess
High-intensity changes to achieve
Follow-up and comprehensive weight loss
weight loss lifestyle
JAM intervention
maintenance
Yes, ready
Alternative
delivery of lifestyle
Yes intervention Determine weight los
and heath goals and
Intensive behavioral intervention strategjes
treatment; reassess Yes
and address
Weight loss medical or other
25% and sufficient contributory factors; Weight loss
Comprehensive
improvement consider adding or No >5% and sufficient
in health targets lifestyle intervention
reevaluating obesity improvement in health
alone or with adunctve
pharmacotherapy,
and/or refer to
targets therapies (BMI30 0r
an experienced 227 with comorbidiy)
No
bariatric surgeon
Continue intensive
medical management BMI 240 or BMI 235 with
of CVD risk factors comorbidity.
Offer referral to an experienced BMI30 or BMI 27 with
and obesity-related comorbidity-option for adding
conditions; weight bariatric surgeon for consultation and
evaluation as an adjunct to pharmacotheapy as an adjunct
management options to comprehensive lifestyle
comprehensive lifestyle intervention intervention

FIGURE 402-2 Treatment

algorithm-chronic disease management model for primary care of patients with overweightand obesity. This alaorithm appliesto the
of overweight and obesíty and
Administration. (Reproduced wisubsequent
th permissiondecisions
from MDbased
Jensenon that
et al: assessment. BMI indicates
2013 AHA/ACCTOS quidelinehodyfor themass.management
index: CVD. ofcardiovascular
overweight and obesityinsdults A
disease,
American College of Cardiology/American Heart Association task force on practice quidelines and The Obesity Society. Circulation 129/25Supo ruts 2:SI2,20

TABLE 402-4 A'Guide to Opting for Treatment for Obesity

TREATMENT BMICATEGORY (kg/m)

25-26.9 27-29.9 35-309
Diet, exercise, behavioral therapy 30-34.9
With comorbidities With comorbidities
Pharmacotherapy With comorbidities
Surgery Withcomorbidities
Source: Reproduced with permission from U.S. Department of Health and Human Services Public Health Service, National Institute or Health National Heart
Institute. The Practical Guide ldentification, Evaluation, and Treatment of Overweight and Obesity in Adults. NIH Publication Number 00-4084. October2000.
 3091
the websitewww.choosemyplate,gov. Since portion control the patient to wear a pedometer or accelerometer to monitor total
hemost diflicult strategies for patients to manage, the use accumulation of steps or kcal expended as part of the activities of
don

orared
Iproductssuch as meal relacements is asimple and daily living is a useful strategy. Step counts are highly correlated
suggestion. Examples include frozen entrees, protein with activity level. Studies have demonstrated that lifestyle activities
and bars. Use of meal replacements in the diet has been are as effective as structured exercise programs for improving cardi
tin a 7-8% weight loss. orespiratory fitness and weight loss. Ahigh level of physical activity
Niunenous)andomizedtrials comparing diets of different macro- (>300 min of moderate-intensity activity per week) is often needed
tcomposition(e.g., low--carbohydrate, low-fat, Mediterra- to lose weight and sustain weight loss. These exercise recommen
rshownthat weighttloss depends primarily on reduction dations are daunting to most patients and need to be implemented
caloricintakeand adherence tothe prescribed diet, not the gradually. Consultation with an exercise physiologist or personal
wN proportions of carbohydrate, fat, and protein in the diet. CHAPTER
trainer may be helpful.
aCTONUtrient composition will ultimately be determined Behavioral Therapy Cognitive behavioral therapy is used to help
taste
patient's preferences, cooking style, and culture. How-
thepatient'ss underlying
the medical problems are also important change and reinforce new dietary and physical activity behaviors.
dingthe recommended dietary composition. The dietary Strategies include self-monitoring techniques (e.g., journaling, 402
weighing, and measuring food and activity); stress management;
will vary according to the patient's metabolic profile stimulus control (e.g., using smaller plates, not eating in frontBvaluation
of
Trs, AConsultation with aregistered dietitian for med the television or in the car), social support; problem solving; and
nutritiontherapy is particularly useful in considering patient cognitive restructuring to help patients develop more positive and
trenceanddtreatment of comorbid diseases.
Anotherdietary approach to consider is based on the concept of realistic thoughts about themselves. When recommending any
behavioral lifestyle change, the patient should be asked to identify and
density,which refers to the number of calories (ie., amount what, when, where, and how the behavioral change will be Management
per
A
enerygy)afood contains per unittof weight. People tend to ingest
aOnstantvolume of food regardless of caloric or macronutrient
formed. The patient should keep a record of the anticipated behav
nnent.Adding water orfber to afood decreases its energy density ioral change so that progress can be reviewed at the next office visit.
Because these techniques are time consuming to implement, their
kiacreasing weight without affecting caloric content. Examples of supervision is often undertaken by ancillary office staff, such as an
ewith low energy density include soups, fruits, vegetables, oat of
advanced practice provider or registered dietitian. Obesity
a.andegglean meats. Dry foods and high-fat foods such asSpretzels,
tes, yolks, potato chips, and red meat have a high energy PHARMACOTHERAPY
niy: Diets containing low-energy-dense foods have been shown Adjuvant pharmacologic treatments should be considered for
uOntrol hunger and thus to result in decreased caloric intake and patients with aBMI 30 kg/m² or for patients with a BMI >27 kg/m
ht loss. who have concomitant obesity-related diseases and for whom
Ocasionaly, very-low-calorie diets (VLCDs) are prescribed as a dietary and physical activity therapy has not been successful. When
imof aggressive dietary therapy. The primary purpose of aVLCD an antiobesity medication is prescribed, patients should be actively
sto promote a rapid and significant (13- to 23-kg) short-term engaged in alifestyle program that provides the strategies and skills
t os over a3- to 6-month period. The proprietary formulas needed to use the drug effectively since such support increases total
igned for this purpose typically supply S800 kcal, 50-80 g of
Min, and 100% of the recommended daily intake for vitamins
weight loss.
Medications for obesity fall into two major categories: those that
minerals. According to a review by the National Task Force on affect appetite and those that inhibit gastrointestinal fat absorp
eHhevention and Treatment of Obesity, indications for initiating tion. Since 2012, four new appetite-controlling medications were
NLCD include the involvement of well-motivated individuals who approved by the U.S. Food and Drug Administration (FDA) with
Emoderately to severely obese, have failed at more conservative an indication for chronic weight management, although one was
0aches to weight loss, and have a medical condition that would voluntarily withdrawn in February 2020. These medications work
kncdiately improved with rapid weight loss. These conditions biologically to suppress appetite, affecting hunger, satiety, and
k pory controlled type 2 diabetes, hypertriglyceridemia, response to highly rewarding foods, thus making it easier for
CTVe sleep apnea, and symptomatic peripheral edema. In the patients to follow their dietary intentions to restrict caloric intake.
ECT tial of patients with type 2diabetes and obesity, alow In addition, one capsule that is considered a medical device was
ormula diet (825-853 kcal•d) was administered for 3months marketed in 2020.
8by astructured monthly program. At 12 months, almost
dhe participants achieved remission to a nondiabetic state Centrally Acting Medications This class of medications affects
vEre not taking antidiabetic drugs. Use of formula diets should satiety (feeling of fullness after a meal), hunger (the biologic sensa
by trained practitioners in a medical care setting tion that prompts eating), and craving (intense desire for aspecific
etEScrmediibcedal monitoring and high-intensitylifestyle intervention food). By controlling appetite, these agents help patients reduce
ae rovided. caloric intake without a sense of deprivation. The target site for
the actions of these medications is primarily the hypothalamus
ical Activity Therapy Although exercise alone is only mod- and reward centers in the central nervous system (Chap. 401).
yetective for weight loss, the combination off dietary modifi- The classic sympathomimetic adrenergic agents (benzphetamine,
anddexercise is the most effective behavioral approach for the phendimetraine, diethylpropion, mazindol, and phentermine)
ent of obesity. The mosttimportant role of exercise appears to function by stimulating norepinephrine release or by blocking its
Ue maintenance of the weight loss. The 2018 Physical Activity reuptake. Among these agents, phentermine is the most commonly
for Americans (www.health,gov/paguidelines) recom- prescribed; there are limited long-term data on its effectiveness.
A 2002 review of six randomized, placebo-controlled trials of
adults vigorous--intensity min of moderate-intensity
awek ofshould engagein 150aerobic physical activity per phentermine for weight control found that patients lost 0.6-6.0
additional kg of weight over 2-24 weeks of treatment. The most
weterablphysiy cal activity
spread throughout the week. Focusing
into the normal daily
should
routine
be
on simple
through
suggested.
common side effects of the amphetamine-derived agents are rest
lessness, insomnia, dry mouth, constipation, and increased blood
ls inchude travel, and domestic
brisk walking, work
using the stairs, doing housework pressure and heart rate.
itis important
PHEN/TPMisacombination drug that contains acatecholamine
AwOdk, and engaging in sports. Additionally, with all-cause releaser (phentermine) and an anticonvulsant (topiramate). Topira
sedentary
and behavior, which is associated
disease mortality in
adults. Asking mate is approved by the FDA as an anticonvulsant for the treatment
cardiovascular
 s092 TABLE 402-5 Cinical Trias for Antiobesity Medications
PHEN/TPM NALTREXONE SR/BUPROPION SR

No. of participants (ITT-L0CF)

BMI (kg/m)
EQUIP
1230
>35
CONQUER
2487
27-45
COR-I
1742
30-45
COR-I!
1496
30-45
COR-BMO0
793
30-45
SCALE
3131
LRAGUTI0F
Age (yl 18-70 18-70 18-65 18-65 18-65 1
Comorbid conditions (cBrdiovBscular and >2 >1 21
Metabolic)
Mean weight loss (%) with treatment vs 10.9 vs 1.6 7.8 vs 1.2 |6.1 vs 1.3 6.5 vs 1.9 9.3 vs 5.1
PART 12 placebo 8.0 vs2.6
Placebo-subtracted weight loss (%) 9.3 6.6 4.8 4.6 4.2
Categorical change in 5% weight loss with 66.7 vs 17.3 62 Vs 21 48 vs 16 50.5 vs 17.1 66.4 vs 42.5
treatment vs placeb0 63.2 vs Z1.1
logyand Study completion rate, treatment vs 66.4 vs 52.9 69 vs 57 50 54
placebo (%) 57.9 vs 58.4
71.9 vs 64.4
Note: EQUIP, PHENTPM= 15/92 mg dose; CONQUER, PHEN/TPM =7.5/46 mg dose.
Abbreviations: BMI, body mass index; ITT-LOCF, intention to treat, last observation carried forward;
PHENTPM,
phentermine/topiramate extended release.
of epilepsy and for the prophylaxis of migraine headaches. Weight
Naltrexone
antagonist andSR/bupropion
loss was identified as an unintended side effect of SR
a mild reuptake (NB) aof
olism is a
topiramate
during cdinical trials for epilepsy. The mechanism responsible for nephrine, inhibitor combination oí an go
Individually, naltrexonedopamiis ne and norbe
weight loss is uncertain but is thought to be mediated through the FDA for therespectively.
drug's modulation of y-aminobutyric acid receptors, inhibition of treatment
of the effects of
of alcohol dependence and forapprtohved
e
carbonic anhydrase, and antagonism of glutamate. PHEN/TPM
has undergone two l-year pivotal randomized,
exogenously
pion is approved as an administered opioids, wherex h
double-blind trials of efficacy and safety: EQUIPplacebo-controlled, a combination antidepressant and smoking
drug, each component works in consort: ai.cessat ion
In a third study, SEQUEL, 78% of and CONQUER. stimulates secretion of buyrpt
ued to receive their blinded treatment CONQUER participants contin from POMC, whereas a-mel a nocyte-stim ulatin g hormone NE
for an
participants received diet and exercise counseling.additional year. All effects of opioid receptorsnaltrexone blocks the feedback inhihr
activated by the ß-endorphin reast:
bers, eligibility, characteristics, and weight-loss Participant num the hypothalamus, thus allowing the inhibitory etiects of XKM:
played in Table 402-5. Intention-to-treat 1-year outcomes are dis reduce food intake.
weight loss for PHEN/TPM was 9.3% placebo-subtracted
(15-mg/92-mg dose) and
The medication has undergone three
randomized, placi
6.6% (7.5-mg/46-mg dose), respectively, controlled, double-blnd trials for efficacy and safety.
QUER trials. Clinical and statistical in the EQUIP and CON Partiäjatve
randomized to receive NB (8 mg/90 mg two tablets bid) or laa
were seen in selected cardiovasculardose-dependent improvements in the three COR studies. Whereas
surements that were related to the weight and metabolic outcome mea participants received stand:
ized nutritional and exercise counseling
loss, The most common in CORI and CU
adverse events experienced by the a more intensive behavior modification program wS ps
paresthesias, dry mouth, drug-randomizedandgroup were in COR-BMOD (able 402-5), Intention-to-treat 1-year pak
Because of an increased riskconstipation,
of congenitaldysgeusia, insomnia.
fetal oral-cleft formation subtracted weight loss was 4.8%, 5.1%, and 4.2%, respee
from topiramate, women of the COR-I, COR-II, and COR-BMOD trials. Clinical and
pregnancy test before treatment childbearing age should havea negative canie
and monthly
effective contraception consistently during thereafter and use dose-dependent improvements
cular and metabolic were seen inthatselected
outcome measurements were
Lorcaserin was approved by the FDA formedication therapy. the weight loss. However, the medication led to slighti
agement in 2012 and taken off the market in chronic weight man
2020, Lorcaserin was smaller decreases blood pressure and pulse thanplactu
developed as a selective 5-HT2, receptor agonist most common adverse events experienced bythe drug-rnie
selectivity ~15 times of 5-HT2, receptors and with a functional
5-HT2, receptors. Thisthatselectivity 100 times
'is important, since the that of
groups were nausea, constipation, headache, vomiting
diarrhea, insomnia, and dry mouth.
duced valvulopathy drug-in ghxat
that were removed from documented
the
with two other
serotonergic agents Liraglutide, the fourth new medication, is toahuna
peptide-1 (GLP-1) analogue with 97% homology
ramine--was due
on cardiac valvular
market--fenfluramine
to activation of the
5-HT2,
and dexfenflu
receptors that was previously approved for the treatment ot
interstitial cells.
receptor, lorcaserin is thought to decreaseBy food activating theexpressed
5-HT2.
doses up to 1.8 mg once daily, In addition tolraghutde
its inhán

pro-opiomelanocortin (POMC) system of neurons. intake through the hormone (glucose-induced insulin secretion),
and stimulates
Lorcaserin underwent gastric emptying and glucagon Secretion toreduc
two randomized, tors in the arcuate nucleus of the hypothalamus
double-blind trials for efficacy and safety. placebo-controlled, Liraglutide has undergone three saletx
randomized
Prty

placebo-subtracted Intention-to-treat
the two pivotal trials.weight loss was 3.6% and 3.0%, respectively, in
1-year controlled, double-blind trials for efficacy and aihy)a
SC
Modest
with the weight loss were seen instatistical improvements consistent were randomized to receive liraglutide (3.0 without disbe mg

abolic selected cardiovascular and met cebo for initial weight loss--SCALE(patients for weight
outcome
vascular outcomemeasurements.
trial found thatHowever,
more
a
postmarketing cardio SCALE Diabetes (patients with(SCALE
nance after initial weight loss
diabetes)-or
Maintenance)
cOunselingh
(7.7%) were diagnosed with cancer patients taking lorcaserin
aae
ar

placebo (7.1%). The trial was compared to All received diet and exercise
participants
conducted in 12,000those
overweight
taking a and SCALE Maintenance, Were dyslipdemuik
5years. Arange of cancer patients over patients or
types
types of cancers occurring morewas reported, with several different had treated or untreated hypertensionweight loss
frequently in the lorcaserin group,
including pancreatic, colorectal, and to-treat 1-year placebo-subtracted Maintenake
lung. respectively, in the SCALE andSCALE M
 3093
and
ynlonnscular metabolic outcome measUrements; however, of ~9-10%, whereas placebo recipients have a 4-6% weight loss.
heart rate. The most
small increase in common adverse Because orlistat is minimally (<1%) absorbed from the gastroin
incude naUsca, diarrhea, constipation, and vomiting. GLP-1 testinal tract, it has no systemic side effects. The drug's tolerability
should not be prescribed in patients with a family or per-
cancer or multiple endocrine
is related to the malabsorption of dietary fat and the subsequent
historyof medullary thyroid passage of fat in the feces. Adverse gastrointestinal effects, including
/ flatus with discharge, fecal urgency, fatty/oily stool, and increased
haynoringthenewantiobesity medications,the FDA introduced defecation, are reported in at least 10% of orlistat-treated patients.
provisionwithimportant clinical relevance: a prescriptiontrial These side effects generally are experienced early, diminish as
ASSesseffectiveness. Response to these medications should patients control their dietary fat intake, and only infrequently cause
weekss of treatment for PHEN/TPM (or 16 weeks patients to withdraw from clinical trials. When taken concomi
oRKANSPdaBter12 since these
BAnd liraglutide medications are uptitrated during CHAPTER402
tantly psyllium mucilloid is helpful in controlling orlistat-induced
month) Determining responsiveness at 3 or 4 months is gastrointestinal side efects. Because serum concentrations of the
*find hoc observed| trial data that patients who did not fat-soluble vitamins Dand E and B-carotene may be reduced by
on the postamount off weight early in treatment were less suc-
a respecified -
orlistat treatment, vitamin supplements are recommended to pre
lyear: For PHEN/TPM, if the patient has not lost at least 3% vent potential deficiencies. Orlistat was approved for over-the
yweight at 3 months, the clinician can either escalate the dose counter use in 2007.
Rasess progress at 6 months or discontinue treatment entirely. Evaluation
medication should be discontinued ifthe patient has not Oral Device Gelesis100 is a nonsystemic, water-soluble gel that
ArNB,the
itleast5%offbody weight. The corresponding responsive target was approved by the FDA in 2019. In the stomach, the capsule
wlinglutide is a46 weight loss. releases the cellulose microgel, which absorbs water and forms and
hipherally Acting Medications Orlistat is a synthetic hydroge-
a matrix with the consistency of food, occupying ~25% of the
Management
stomach. In the large intestine, it is broken down by enzymes and
ad derivative of a naturally occurring lipase inhibitor, lipostatin, the cellulose is excreted. Gelesis100 and placebo were evaluated
it roduced by the mold Streptomyces toxytricini. This drug
mtent, slowly reversible inhibitor of pancreatic, gastric, and
over 24 weeks in patients with BMI of 27 to s40 kg/m² and fasting
plasma glucose of 90-145 mg/dL. Intention-to-treat, 24-week,
sharlester lipases and phospholipase A,, which are required for placebo-subtracted weight loss was 2.1% (6.4 vs 4.4%). Gelesis100 of
bwiosis of dietary fat into fatty acids and monoacylglycerols. treatment had no apparent increased safety risks. The capsules are
Obesity
isat acts in the lumen of the stomach and small intestine by approved for patients with a BMI of 225 kg/m', with or without
iming acovalent bond with the active site of these lipases. Taken comorbidities.
itherapeutic dose of 120 mg tid, orlistat blocks the digestion and
SURGERY
sumion of -30% of dietary fat. After discontinuation of the drug,
Ed at content usually returns to normal within 48-72 h. Bariatric surgery (Fig. 402-3) can be considered for patients with
Maltiyle randomized, double-blind, placebo-controlled stud severe obesity (BMI>40 kg/m?) or for those with moderate obesity
save shown that, after 1year, orlistat produces a weight loss (BMI 235 kg/m²) associated with a number of comorbid conditions.

150 cm

C100 cm

D
C for surgicalI manipulation of the gastrointestinal tract. A. Laparoscopic adjustable
operativeinterventions used
procedures. Examples of Roux-en-Y gastric bypass. D. Biliopancreatic diversion with duodenal switch. E. Biliopancreatic diversion.
 3094
Weight-los$ surgeries have traditionally been classified into three The mortality rate from
categories on the basis of anatomic changes: restrictive, restrictive but varies with the procedure,bariatric surgery
conditions, and the experience the
malabsorptive, and malabsorptive. More recently, however, the
clinical benefits of bariatric surgery in achieving weight loss and
of
common surgical complications the patsurientg'iscalage and
alleviating metabolic comorbidities have been attributed largely include stomal team.
ginal ulcers (occurring in 5-15% of
longed nausea and vomiting after patients) thatstenosis
to changes in the physiologic responses of gut hormones, bile acid
the diet to solid foods. These eating or
metabolism, the microbiota, and adipose tissue metabolism. Met
abolic effects resulting from bypassing the foregut include altered endoscopic balloon dilation and acidcomplications typiincabialylity
are treat
responses of ghrelin, GLP-1, peptide YY3-36, and oxyntomodulin.
Additional effects on food intake and body weight control may be
tively. For patients who
banding, there are no undergo
intestinal
suppressicon therapy
laparoscopi tes
than mechanical reduction absorptive adjustable
e:
PART 12
attributed to changes in vagal signaling. The loss of fat mass, partic
ularly visceral fat, is associated with multiple metabolic, adipokine,
and inflammatory changes that include improved insulin sensi
in gastric
selective deficiencies are uncommon size
and abnormalties
outloW.
unbalanced. In contrast, the restrictive-unless eating habits
h

tivity and glucose disposal; reduced free fatty acid flux; increased
adiponectin levels; and decreased interleukin 6, tumor necrosis
factor a, and high-sensitivity C-reactive protein levels.
carry an increased risk for

malabsorptive
calcium, and micronutrient
B,,, iron, folate,
procedures
vitamin D.
require Patie
-malabdesfoicrpietnicviees proceti
nts with
of wita
olism
logyand Restrictive surgeries limit the amount of food the stomach can these micronutrients. lifelong restricm
supplementation
hold and slow the rate of gastric emptying. Laparoscopic adjustable Intraluminal Gastric Balloons Three in
gastric banding is the prototype of this category. The first banding approved for weight loss that are gastric balloon deits a
device, the LAP-BAND, was approved for use in the United States in
2001. In contrast to previous devices, this band has a diameter that
either placed in the
endoscopically (the REHAPE and ORBERA o

is adjustable by way of its connection toareservoir that is implanted (OBALON). Efficacy of the devices at 6 months,
f devices) or Swalve
under the skin. Injection of saline into the reservoir and removal weighted-mean percent weight loss, was 9.7%, based and theonacm
posik by
of saline from the reservoir tighten and loosen the band's internal subtracted percent weight loss was 5.6%. The
only for up to 6 months of use in adults with adevices are amm by
diameter, respectively, thus changing the size of the gastric opening. Adyerse effects include nausea, vomiting, and BMI of 30-4 m
Although the mean percentage of total body weight lost at 5 years abdominal pain
is estimated at 20-25%, longer-term follow-up has been more dis
appointing, leading to near abandonment of the procedure. In the FURTHER READING
laparoscopicsleeve gastrectomy, the stomach is restricted by stapling ApoVIAN CM et al: Pharmacological management of obeait:
and dividing it vertically, removing ~80% of the greater curvature Endocrine Society clinical practice guideline. J Clin Endacrm
and leaving a slim banana-shaped remnant stomach along the lesser Metab 100:342, 2015.
curvature. Weight loss after this procedure is superior to that after GARVEY WT et al: American Association of Clinical Endocrinoloes
laparoscopic adjustable gastric banding. and American College of Endocrinology Comprehensive dmd
The three
the elements restrictive-malabsorptive bypass procedures combine
of gastric restriction and selective practice guidelines for medical care of patients with obesty hà:
Pract 22(suppl 3):1, 2016.
Roux-en-Y gastric bypass, biliopancreatic diversion,malabsorption:
and biliopan JENSEN MD et al: 2013 AHA/ACC/TOS guideline for the manage
creatic diversion with duodenal switch (Fig. 402-3). Roux-en-Y is
the most commonly undertaken and most of overweight and obesity in adults: Areport of the Americzn le
cedure. These procedures accepted bypass pro
are routinely performed by laparoscopy. of Cardiology/American Heart Association Task Force on a
These procedures generally produce a 30-35% average total Guidelines and The Obesity Society. Circulation 129(suppl 3
2014.
body weight loss at 12-18 months followed by variable weight OBESITY CANADA: Canadian Adult Obesity Clinical Gue
regain thereafter. Significant improvement
related comorbid conditions, including typein 2multiple obesity (CPGs). Available at https://obesitycanada.calguidelines. s
tension, dyslipidemia, obstructive sleep apnea, diabetes, hyper December 25, 2020.
and long-term cardiovascular events, has been quality of life,
analysis of controlled clinical trials comparingreported. A meta
versus no surgery showed that surgery was bariatric surgery
reduced odds ratio (OR) risk of global mortalityassociated
(OR=
with a
0.55),
diovascular death (OR = 0.58), and all-cause mortality (OR = car
Among the observed 0.70).
vention and treatment ofimprovements in comorbidities, the pre
Diabetes Mellitus:
type 2
ric surgery have garnered the diabetes resulting from bariat
from the Swedish Obese Subjectsmost attention. Fifteen-year data
study demonstrated a marked
reduction (i.e., by 78%) in the incidence
403 Diagnosis, Classification,
opment among obese patients who of type 2 diabetes devel
underwent bariatric sur
and Pathophysiology
gery. Multiple randomized controlled studies Alvin C. Powers, Kevin D.
Niswende)
weight loss and more have shown greater
5 years among surgical improved glycemic control from 1 and Carmella Evans-Molina
ventional patients than among patients
medical A retrospective cohort receiving con
adults with diabetestherapy.
7metabali

found that, overall, 68.2% ofstudy of >4000 common dstint

rienced an initial complete remission of type 2 patients expe Diabetes mellitus (DM) refers to a group of Several
5 years after surgery.
However, among these patients, diabetes within hyperglycemia.
ders that share the phenotype of interaction of genetics a
lators

redeveloped type diabetes within 5 years. Patients withone-third

2
stage type 2diabetes (ie.,
of DM are DM.
caused by a complex etiologyofthesecretion,
earlier mental factors. Depending on thereduced
duration disease, and withthoselower
who do not need insulin, with shorter
uting to hyperglycemia include production.The
insulin Pathoptrs Ab
better
seen inimprovement after bariatric hemoglobin A,) appear to have I
trenmenus
glucose utilization, and increased glucosesecondary So
surgery. The
diabetes after bariatric surgery is thought rapid improvement causes
dysregulation associated with DM that
restriction, reduced insulin to be due to caloric impose
changes in multiple organ systemsand on the end-stuge
glucose homeostasis broughtresistance, and surgery-specific effects health
about by alteration of gut on on the individual with diabetes cause of
hormones. the United States, DM is the leading