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8:51
Anorexia Nervosa: Current

Status and Future Directions
Evelyn Attia
Weill Cornell Medical College and Columbia Center for Eating Disorders,
Columbia University Medical Center, New York, New York; email: ea12@columbia.edu
Annu. Rev. Med. 2010. 61:42535
Key Words
The Annual Review of Medicine is online at

med.annualreviews.org
eating disorders, treatment, epidemiology, neurobiology, medication
This articles doi:

10.1146/annurev.med.050208.200745
Abstract
c 2010 by Annual Reviews.

Copyright
All rights reserved
0066-4219/10/0218-0425$20.00
Anorexia nervosa (AN) is a serious mental illness categorized by a failure to maintain a minimally normal weight, a fear of gaining weight or
becoming fat, and preoccupations about body shape or weight. AN is
associated with signicant morbidity and a mortality rate as high as that
seen in any psychiatric illness. Biological factors, including genetic predisposition, appear to play a role in the development of AN. Treatment
is challenging both because interventions with clear empirical support
have not been identied and because individuals affected by AN are
typically reluctant to undergo weight restoration. Preliminary studies
suggest that family-based treatment may be useful for younger patients
with AN. Treatment development for adults with AN and pursuit of
neurobiological correlates of AN remain high-priority research areas.
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OVERVIEW

Purging: in
discussions of eating
disorders, purging
refers to behaviors
intended to rid the
body of ingested
calories. These include
vomiting and abuse of
medications such as
laxatives or emetics
Anorexia nervosa (AN) is a serious mental

illness estimated to affect 0.5%1% of females
during their lifetime and approximately one
tenth as many males (1). AN is associated with
a crude mortality rate of 5.6% per decade of
illness (3), a rate as high as that seen in any psychiatric illness. AN is characterized by an avid
pursuit of thinness and a failure to maintain
a minimally normal weight. These behaviors
are accompanied by preoccupying thoughts of
food, weight, and body shape, including fear
of being or becoming fat. The two subtypes
of AN described in DSM-IVrestricting (R)
and binge-eating/purging (BP)distinguish
patients who solely reduce their intake from
those whose behaviors include purging (i.e.,
vomiting, or misuse of laxatives, diuretics,
or other purgatives), with or without bingeeating (4). The core symptom of low weight
distinguishes AN-BP from bulimia nervosa,
an eating disorder characterized by recurrent
and frequent episodes of binge eating and
inappropriate compensatory behaviors aimed
to prevent weight gain.
AN is not a new illness. Some regard early
reports of religious asceticism and fasting behavior, such as that seen in St. Catherine of
Siena, as examples of AN (5), and a condition
with the core features of AN was characterized as an illness in the seventeenth century
by Richard Morton. The syndrome was formally identied and labeled almost simultaneously by Europeans Charles Lasegue in 1873
and William Gull, who named the condition
anorexia nervosa in 1874 (6).
EPIDEMIOLOGY
An epidemiologic study published in 2006,
which had collected data for >50 years in one
region of the United States, reported an average AN incidence of 8 per 100,000 per year, and
point prevalence of 0.3% in young females (7).
Incidence rates appear to have increased consistently during the twentieth century, but it is
not known whether this represents more individuals being affected by the illness or simply
426
Attia
larger numbers entering the health care system,

either because of better illness recognition by
clinicians or better treatment acceptance by individuals with AN (7). A recent study using a
community sample obtained by household interview estimated a somewhat higher lifetime
prevalence rate for AN at 0.9% among women
and 0.3% among men (8). Most prevalence and
incidence rates have been obtained using North
American and European samples, but AN has
also been reported in non-Western countries
(911).
PHENOMENOLOGY AND
COURSE OF ILLNESS
AN generally presents in middle to late adolescence, although cases in childhood and early
adolescence are increasingly recognized (12).
Primary care clinicians are often the rst professionals to identify and evaluate new cases of
AN (13). For most patients, the core features of
AN are ego-syntonic (not experienced as symptomatic), especially at the time of illness onset.
Therefore, few seek out specialist practitioners
unless referred by pediatricians, school personnel, or concerned family members. Individuals with AN present with recent weight loss
or, in a growing child or adolescent, the failure
to achieve expected weight gainaccompanied
by changes in eating behaviors including food
restriction, secretive eating, vomiting or other
purging after eating, and excessive exercise. In
addition, patients with AN endorse or demonstrate behaviors that support beliefs that they
are fat despite being underweight, or would
become fat if they ate normally, and maintain
other overvalued ideas about body shape and
weight. Many female patients with AN experience an interruption in menstrual activity, although there is increasing evidence that the
presence of amenorrhea does not meaningfully
distinguish the clinical status of individuals with
the symptoms of AN (1416).
Medical signs and symptoms commonly associated with AN include vital-sign changes
consistent with a hypometabolic state, such
as bradycardia, hypotension, and hypothermia.

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AN is associated with leukopenia and, less

commonly, anemia or pancytopenia (17). Electrolyte abnormalities may be present, including hypokalemia in individuals with vomiting
or laxative use, and hyponatremia in individuals
who ingest large quantities of water and other
non-nutritive beverages. Clinicians should not
be reassured by normal laboratory values, as
individuals with AN will commonly have normal values despite depleted stores of multiple
nutrients, vitamins, and minerals. Endocrine
changes associated with AN include low levels of estrogen and testosterone, with amenorrhea developing in many of the previously
menstruating females and decreased libido in
both females and males (18). Additionally, hypercortisolemia is present in most low-weight
individuals with AN (18). Bone mineral density
is affected in both males and females, with osteopenia and/or osteoporosis developing after
periods as little as one year of illness (19), which
is likely related to the hormonal abnormalities
seen in AN. Notably, bone mineral density does
not appear to improve in response to estrogenreplacement therapy in underweight individuals with AN (20, 21). Prolonged QT interval,
as measured by electrocardiogram, is one of the
more worrisome signs associated with AN, as it
has been associated with sudden death (22) and
may add to an individuals vulnerability to arrhythmia if medications known to prolong QT
interval are utilized. Less commonly, hepatic
transaminase levels may be elevated, and renal insufciency may be present in AN; these
ndings are generally associated with more severe cases. Patients with AN, including those
who minimize concern about other physical
changes, may report hair loss, skin changes, or
constipation, providing the clinician with evidence of nutritional deciencies and opportunities for clinical intervention.
Psychological symptoms commonly associated with AN include distractibility, depression, anxiety, agitation, sleep disturbance, obsessionality, and compulsivity. As described in
the landmark study of semistarvation by Keys
and colleagues (23), these symptoms are also
seen in non-eating-disordered individuals who
undergo caloric restriction and substantial

weight loss and therefore are best understood
as being secondary to the state of semistarvation. Although some individuals may report
psychological symptoms that predate the onset of the eating disorder, these symptoms generally worsen with malnutrition and improve
signicantly with nutritional rehabilitation and
weight restoration (24).
Most of what is known about ANs course
of illness has been obtained from samples of
patients seeking clinical treatment. Therefore,
published information about the course of AN
may describe the more serious cases that warrant medical intervention. There is clearly a
range of severity in cases of AN from single episodes that respond to a rst attempt at
weight restoration to chronic courses characterized by substantial morbidity lasting decades. A
bleak recovery rate30% of individuals with
AN achieving full recovery by a median of
90 months of follow-upwas described by
Herzog and colleagues (25). Keski-Rahkonen
et al. found that 67% of individuals with AN
identied in a community sample achieved full
recovery at ve years (26). Among a sample of
patients identied by general practitioners as
new cases of AN, van Son and colleagues report
that 55% of those initially diagnosed with AN
restricting type and 57% of those with bingeeating/purging type were considered to be recovered after a mean of 4.8 years (27). In a
meta-analysis using 119 outcome studies conducted during the second half of the twentieth century, composed of 5590 patients, Steinhausen (28) found full recovery in 46.9% of
the patients, 33.5% were categorized as somewhat improved, and 20.8% were still diagnosed
with AN at the time of follow-up assessment.
A longer follow-up period was associated with
higher recovery rates among surviving patients.
Across follow-up studies, younger patients have
signicantly better outcomes, and early identication and intervention are recommended
whenever possible (28).
As mentioned, mortality rates are notably
high for AN and are signicantly higher than
that described among individuals with bulimia
www.annualreviews.org Anorexia Nervosa
Eating disorder: a
persistent disturbance
of eating or eatingrelated behavior that
results in the altered
consumption or
absorption of food and
that signicantly
impairs physical or
psychosocial
functioning. The
disturbance is not
secondary to any
recognized general
medical disorder or
any other psychiatric
disorder (67)
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6 December 2009

Evidence-based
treatment: a clinical
treatment with
documented efcacy
obtained from
research studies. The
use of evidence-based
treatments is growing
in all areas of health
care in an effort to
reduce errors and
improve health
Cognitive behavioral
therapy (CBT): a
psychotherapeutic
approach that helps a
patient identify and
interrupt patterns of
cognition and
associated behaviors
that may contribute to
problem symptoms
involving thoughts,
feelings, and/or
behaviors
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8:51
nervosa. A recent study using hospital discharge

and death registries in Sweden found a standardized mortality ratio (SMR) of 6.2 (95% CI
5.57.0) among a sample of 6009 individuals
diagnosed with AN after an inpatient hospitalization. In other words, the numbers of deaths
among individuals with AN occurred at approximately six times the rate expected in the general
population. AN, substance abuse, and suicide
were the most commonly listed causes of death
in this sample (2). Additionally, AN appears to
carry its high risk of mortality for many years
after initial illness presentation. Papadopoulos
and colleagues found SMR remained high for
20 years following rst hospitalization (2), and
in a meta-analysis of results from 42 studies that
reported on mortality, Sullivan found an aggregate mortality rate of 5.6% per decade of illness
(3).
TREATMENT
Treatment for AN remains a challenge, as no
treatment has clear empirical support. The
paucity of evidence-based treatment for AN
likely results from several factors, including
general challenges inherent to the work with
this clinical population, rather than from problems specic to any one therapeutic approach.
The fact that AN is a relatively uncommon disease makes it difcult to recruit adequate samples for study in the context of traditional clinical trials typically conducted at one or a few
collaborative sites. Patients with AN are reluctant to participate in treatments with the
goal of weight restoration, making recruitment
and retention particularly challenging (29). The
comprehensive and intensive treatments commonly used to help patients recover from the
acute manifestations of AN are complex and
expensive, making studies of these commonly
used interventions difcult. Among the clinical trials that have been conducted, many have
used structured treatment programs such as
inpatient and day-treatment units to conduct
medication trials. These settings include adequate medical and psychiatric support for participants undergoing weight restoration, and
Attia
the controlled and structured environment in

which participants are residing probably improves compliance. Unfortunately, using structured environments has made it difcult to
determine whether medication interventions
offer benet for AN compared to placebo, since
they are studied within comprehensive and intensive treatment programs that are known to
improve weight and a range of associated psychiatric symptoms.
Many medications, mostly antidepressants,
have been examined in AN by small randomized clinical trials, which have been extensively
reviewed elsewhere (30, 31). The majority have
failed to report a clear benet of medication versus placebo. However, Bissada and colleagues
found that among a sample of 34 women with
AN attending a day-treatment program, olanzapine was better than placebo at helping patients achieve normal weight, shorten time to
reach normal weight, and decrease symptoms
of obsessionality (32). Although this study is
limited by a small sample size and the use of a
highly structured and specialized day-treatment
program, this nding deserves replication.
Clinical trials of psychotherapies have failed
to identify effective interventions for underweight adults with AN. A provocative nding
was reported by McIntosh and colleagues, who
described signicantly improved clinical outcome among 56 outpatients with AN assigned
to receive a control treatment composed of clinical management and supportive psychotherapy in comparison to patients receiving cognitive behavioral therapy (CBT) and interpersonal therapy (IPT) (33). This studys strengths
included its randomized clinical trial design,
while its limitations included the low weights of
subjects in all study groups at the end of the trial,
its modest sample size and signicant drop-out
rate (only 35 subjects completed the 20-session
study).
For children and adolescents with AN, preliminary data support the efcacy of a specic
form of family-based therapy. Russell and colleagues established that younger patients with
a shorter duration of illness achieved far better clinical outcomes (including weight one year

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following discharge) in family therapy than did

similar patients assigned to individual therapy
(34). Robin and colleagues supported this initial nding in their study of 22 outpatient adolescents with AN randomly assigned to receive
either family or individual therapy (35). Most
recently, Lock and colleagues examined a specic family-based therapy (36) that empowers
parents to help refeed their adolescent with AN
and found this approach useful in helping patients to achieve a normal weight and improved
psychological status at 6 and 12 months (37).
Although evidence is limited for effective
treatment interventions in AN, the behavioral disturbances and serious medical and psychiatric sequelae among these patients have
spurred the development of behaviorally oriented treatment programs that are reliable in
helping patients normalize weight and associated symptoms acutely (38). Behavioral programs may be offered in several different treatment settings, including outpatient, intensive
day treatment, or inpatient, and have in common the focus on behavioral improvement.
Programs attempt to help the patient change
behaviors by ensuring regular eating, increasing
the amount of food consumed, exposing the patient to a variety of foods and amounts, and providing psychosocial support and reinforcement.
A structured refeeding plan that includes sufcient calories (generally 30004000 kcal/day) is
needed for consistent weight gain. Successful
behavioral programs generally achieve weight
gain at rates of 12 lbs/week in outpatient programs and 34 lbs/week in inpatient programs
(38, 39).
Behavioral management programs are well
tolerated by most patients with AN. An uncommon but serious adverse effect associated
with this treatment is refeeding syndrome, the
medically precarious and potentially fatal state
of uid and electrolyte imbalance that can occur with aggressive refeeding in the context
of semistarvation. Specically, refeeding syndrome is associated with the development of
signicant and rapid peripheral edema, hypophosphatemia, and hypomagnesemia, and it
may progress to include congestive heart failure
and acute mental status change (40). Refeeding syndrome is not common in AN treatment,
likely because patients are otherwise generally
healthy adolescents and young adults and have
often maintained their low weight for an extended time (rather than suddenly stopped eating or acutely decreased weight), and because
eating-disorder treatment programs typically
initiate refeeding in a graduated fashion. Individuals with AN may be at risk for developing
refeeding syndrome if, upon presentation, they
demonstrate or report the following symptoms:
very low weight (BMI < 16 kg/m2 ), substantial weight loss within the past four weeks, little
or no caloric intake for ten days or more, use
of diuretics or laxatives, or low blood levels of
potassium or essential minerals (40, 41). Initial
refeeding should include vitamin supplementation and close medical monitoring, with frequent weights, physical exams, and assessments
of serum electrolytes, as well as a baseline electrocardiogram. Low levels of phosphorus, magnesium, or calcium should prompt supplementation of therapeutic minerals (40).
RELAPSE PREVENTION
Although behavioral treatment programs can
help AN patients normalize their weight, relapse rates are high following weight restoration (42). Because medications and psychotherapies may be less benecial during the acute
phase of AN treatment owing to the effects
of starvation on neural processes, and because
of the high relapse rates, several investigators
have focused on relapse prevention strategies
for AN. In a sample of 33 weight-restored
women with AN recently discharged from a
specialized inpatient program, Pike et al. found
that CBT was more successful than nutritional
counseling at keeping patients in treatment and
maintaining weights not requiring rehospitalization (43). A nonrandomized trial by Carter
et al. also supported CBT as more helpful
than treatment as usual for assisting patients in
maintaining BMI > 17.5 kg/m2 without bingeeating and purging during the year following
weight restoration (44). Some preliminary data
BMI (body mass

index): a measure of
weight in relation to
height, dened as a
persons weight in
kilograms divided by
the square of height in
meters
Behavioral
treatment: behavioral
treatment aims to
change behaviors of
illness by reinforcing
healthy behaviors.
Effective behavioral
treatments are clearly
and consistently
applied so patients are
well aware of
behavioral
expectations as well as
consequences of not
meeting expected goals
Relapse prevention:
relapse prevention for
AN refers to treatment
interventions designed
to maintain restored
weight, cessation of
eating-disorder
behaviors such as
purging, and other
improvements
achieved during an
initial phase of
treatment for acute
symptoms
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6 December 2009
Dual energy x-ray

absorptiometry: a
technology that uses a
low-radiation X-ray to
measure body
composition and bone
mineral density

Neurobiology: the
scientic study of
brain and nervous
system function
8:51
suggested uoxetine might be helpful for relapse prevention among patients with AN (45,
46); however, Walsh et al. found that uoxetine
was no more helpful than placebo at preventing
relapse during the rst year post-hospitalization
among 93 recently weight-restored women receiving CBT (47).
Additional research is needed to identify
denitive treatments for relapse prevention, but
recent ndings have suggested the importance
of identifying features present after acute treatment that are predictors of longer-term success
for individuals with AN. Mayer et al. examined
a sample of 32 weight-restored women over
the year following weight-restoration treatment. Individuals designated as a treatment
success (full, good, or fair outcome at study
completion) (n = 16) and those designated as
a treatment failure (poor outcome) (n = 10)
at one year following hospitalization were not
different in their BMI at the end of weightrestoration treatment. However, those in the
treatment success group had a statistically
signicantly higher percent of body fat measured by dual energy x-ray absorptiometry upon
weight restoration than did those who went on
to be treatment failures (48). In similar work,
with a partially overlapping sample, Schebendach et al. found that a measure of diet variety
and diet energy density from food records obtained prior to discharge correlated with clinical outcome during the year following hospitalization, with higher variety and density scores
being associated with good outcome (49).
BIOLOGY AND GENETICS

The etiology of AN is unknown, but accumulating evidence supports the idea that some type
of biological vulnerability contributes to the development of AN. Biological disturbances have
long been identied in association with AN, but
studies of patients during the acute phase of illness cannot discern whether such disturbances
are stable features present in those vulnerable
to developing AN, or changes resulting from
malnutrition. Investigations of the neurobiology of AN have therefore started to include
430
Attia
recovered individuals with a history of AN and

family members of affected individuals in an attempt to differentiate features that may be associated with the core illness and its development.
Genetic Vulnerability
Family studies have consistently demonstrated
that AN aggregates in families. Twin studies have observed higher concordance rates
in monozygotic than in dizygotic twin pairs
(50, 51), indicating a genetically mediated vulnerability to the development of the disease.
Additional data indicate that anxiety, obsessionality, and perfectionism appear to be associated with AN, are present prior to the development of the illness (52, 53), and are shared by
unaffected family members of individuals with
AN (54). These observations have been used to
support the hypothesis that heritable biological
features are associated with the development
of this challenging disorder. Although several
linkage and association studies have been conducted among individuals with AN (55), genetic studies of AN remain in the early phases.
Like many serious mental illnesses, AN is a
complex trait, and it is not likely that any one
DNA sequence is responsible for its development. Rather, the illness probably results from
an interaction of genetic, developmental, and
environmental factors.
Other Biological Factors

The involvement of monoamine neurotransmitters in regulating appetite and in regulating mood and anxiety motivated early investigations of CNS monoamine function in AN (56).
However, the results are somewhat difcult to
interpret because of the effects of starvation on
CNS function. Consequently, several investigators looking for biological features associated
with the illness have examined recovered AN
subjects, who are not affected by acute malnutrition. CNS serotonin (5-HT), dopamine,
and norepinephrine have been measured indirectly in recovered AN patients, using challenge tests (57, 58) and assays of monoamine

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metabolites present in cerebrospinal uid (56).

Overall, serotonergic activity appears higher in
individuals recovered from AN than in healthy
volunteers (59). Serotonin is thought to have
a central role in the control of appetite and
eating; therefore, any differences in serotonin
function identied among individuals with eating disorders are intriguing. Additionally, high
levels of serotonin metabolite 5-HIAA are seen
in some anxiety disorders such as obsessivecompulsive disorder (60), which raises the question of whether the disturbances in serotonin
function, if present premorbidly, are associated with the high degree of anxiety, vigilance,
obsessionality, and perfectionism seen among
many of the individuals who go on to develop
AN. Kaye and colleagues have hypothesized
that the caloric restriction central to acute AN
may be a reinforcing, symptom-relieving behavior in part because dieting is known to reduce plasma levels of the amino acid tryptophan, and tryptophan is the essential building
block of serotonin production (59).
Positron-emission tomography (PET) technology has allowed direct measurements of
neurotransmitter activity. Studies are complicated to interpret, because samples are small
and include individuals who are still underweight or who have comorbidities with known
disturbances in neurotransmitter activity, and
the ndings are sometimes inconsistent. Nevertheless, several groups have accumulated evidence that clinical samples of subjects with AN
are different from control subjects in serotonin
and dopamine receptor activity, suggesting that
these systems are dysregulated even following
recovery from the acute phase of illness (59).
A recent and intriguing line of investigation in AN has utilized cognitive activation
tasks and imaging of relevant neural circuits by
means of functional magnetic resonance imaging (fMRI). The observation that repetitive and
inexible behaviors are common in AN has
led investigators to develop studies that examine behaviors relevant to choosing, learning,
and adapting. Cognitive neuroscientists working with AN populations have specically measured set shifting, dened as the ability to move
back and forth between tasks or operations.

Impairment in set shifting has been observed
among patients with acute AN (61, 62), recovered AN patients (63, 64), and unaffected
sisters of individuals with AN (64), in comparison to healthy volunteers. Similarly, Steinglass et al. found that among 15 AN patients and 11 healthy controls, patients made
signicantly more perseverative errors on the
Wisconsin Card Sort Test, indicating a problem in set shifting (65). Holliday et al. argue that
this disturbance may represent an endophenotype for AN that is genetically mediated (64).
Zastrow and colleagues also found that AN
subjects had a higher error rate than controls
on a task that measured both behavioral and
cognitive set shifting. While AN subjects performed these tasks, fMRI demonstrated abnormalities in fronto-striatal circuitry, suggesting a
High baseline
anxiety
Functional magnetic
resonance imaging
(fMRI): a new
technique for studying
brain function. Brain
activity is examined by
tracking blood ow in
the brain during a
given task
High baseline
obsessionality
Cultural factors:
concerns about shape/weight
Anxiety about
food consumption,
food avoidance
Perfectionism
Rigid dieting practices
Diet with
low energy density
and limited variety
Weight loss
Figure 1
Traits of high baseline anxiety and obsessionality interact with environmental
factors such that patients develop maladaptive behaviors, including food avoidance, and rigid eating patterns (or dieting practices), and they experience high
levels of anxiety around eating. These behaviors are interrelated: Rigid dieting
leads to increased anxiety about food and vice versa. These behaviors result in a
diet that is low in fat (low energy density) and limited in variety, leading to weight
loss and a perpetuation of the symptoms of illness. (Adapted from Reference 68.)
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neurobiological mechanism for these cognitive

behavioral impairments (62).
A Possible Model for AN

There is accumulating evidence that individuals who develop AN have biologically mediated
disturbances that are present prior to the onset of illness and may contribute to a vulnerability to initiating and perpetuating the behaviors of illness, including caloric restriction (see
Figure 1). Psychological symptoms that are exacerbated by caloric restriction and weight loss,
such as anxiety, obsessionality, and social avoidance, may develop or worsen as the illness manifests, intensifying the cycle of thoughts and behaviors that dene AN.
FUTURE DIRECTIONS
AN remains a challenging disorder associated
with high rates of morbidity and mortality.
Neurobiological investigations are attempting
to identify factors that contribute to the
development and perpetuation of this illness.
Because of the paucity of empirically supported
treatments for AN, treatment development

research is currently under way at several
academic centers, much of it informed by
hypotheses generated from neurobiological
studies. Two large, multi-site clinical trials of
family-based treatment for adolescents with
AN are nearing completion ( J. Lock, personal
communication); studies aiming to replicate
and extend the ndings from Bissada et al.s
randomized clinical trial with olanzapine have
been initiated (E. Attia, unpublished data);
and pilot studies using psychotherapies based
on interventions useful in the treatment of
anxiety disorders are currently under way
(66). Translational research focusing on the
adaptation of ndings from feeding-behavior
studies performed in animals to humans is an
additional important area of future research.
Another is the identication of abnormalities in
reward circuits in AN and the potential overlap
with the neurobiology of substance abuse. The
application of newer methods (e.g., imaging
and genetics) and emerging perspectives on
the control of human behavior will lead to
important and clinically useful advances in our
understanding and treatment of AN.
SUMMARY POINTS
1. Anorexia nervosa (AN) is a serious mental illness characterized by failure to maintain
normal weight and by overvalued ideas about the importance about body shape and
weight.
2. AN is associated with substantial morbidity and a mortality rate as high as that seen in
any psychiatric illness.
3. Weight restoration is the most important treatment goal for individuals with AN. Associated psychological symptoms are likely to improve with nutritional rehabilitation.
4. There is a paucity of empirical support for particular psychotherapeutic or pharmacologic
interventions for individuals with AN, although it appears that family-based therapy
emphasizing weight restoration is helpful to children and adolescents with AN.
5. The etiology of AN remains unknown, although evidence suggests that biological factors
may contribute to an individuals vulnerability to the development of AN.
6. Treatment development and neurobiology remain critical areas for future research
regarding AN.
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Attia
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DISCLOSURE STATEMENT
Dr. Attia has received research support from Eli Lilly & Co.
ACKNOWLEDGMENT
Dr. Attia acknowledges the editorial assistance of Benny E. Chen, Joanna Steinglass, and Robyn
Sysko in the preparation of this manuscript.

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Annual Review of
Medicine

Contents
Volume 61, 2010
Using Genetic Diagnosis to Determine Individual

Therapeutic Utility
C. Thomas Caskey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Emotion Recollected in Tranquility: Lessons Learned
from the COX-2 Saga
Tilo Grosser, Ying Yu, and Garret A. FitzGerald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p17
Progressive Multifocal Leukoencephalopathy in Patients on
Immunomodulatory Therapies
Eugene O. Major p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p35
The Future of Antiplatelet Therapy in Cardiovascular Disease
Carlo Patrono and Bianca Rocca p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p49
Pharmacogenetics of Warfarin
Farhad Kamali and Hilary Wynne p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p63
Heparin-Induced Thrombocytopenia
Gowthami M. Arepally and Thomas L. Ortel p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p77
Regulation of Phosphate Homeostasis by PTH, Vitamin D, and FGF23
Clemens Bergwitz and Harald Juppner
p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p91
Alveolar Surfactant Homeostasis and the Pathogenesis of Pulmonary
Disease
Jeffrey A. Whitsett, Susan E. Wert, and Timothy E. Weaver p p p p p p p p p p p p p p p p p p p p p p p p p p p p 105
Diagnosis and Treatment of Neuropsychiatric Disorders
Katherine H. Taber, Robin A. Hurley, and Stuart C. Yudofsky p p p p p p p p p p p p p p p p p p p p p p p p p p p 121
Toward an Antibody-Based HIV-1 Vaccine
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HIV-1 Vaccine Development After STEP
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Growing Up with HIV: Children, Adolescents, and Young Adults with
Perinatally Acquired HIV Infection
Rohan Hazra, George K. Siberry, and Lynne M. Mofenson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 169
v
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H5N1 Avian Inuenza: Preventive and Therapeutic Strategies

Against a Pandemic
Suryaprakash Sambhara and Gregory A. Poland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 187
Revascularization for Coronary Artery Disease: Stents Versus Bypass
Surgery
Spencer B. King III, John Jeffrey Marshall, and Pradyumna E. Tummala p p p p p p p p p p p p p 199
Controversies in the Use of Drug-Eluting Stents for Acute Myocardial
Infarction: A Critical Appraisal of the Data
Rahul Sakhuja and Laura Mauri p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 215
Arrythmogenic Cardiomyopathy: Etiology, Diagnosis, and Treatment

Srijita Sen-Chowdhry, Robert D. Morgan, John C. Chambers,
and William J. McKenna p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 233
Contemporary Use of Ventricular Assist Devices
Cesare M. Terracciano, Leslie W. Miller, and Magdi H. Yacoub p p p p p p p p p p p p p p p p p p p p p p p p p p 255
Stress Cardiomyopathy
Yoshihiro J. Akashi, Holger M. Nef, Helge Mollmann, and Takashi Ueyama p p p p p p p p p p p 271
Stem Cells in the Treatment of Heart Disease
Stefan Janssens p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 287
Biological Mechanisms Linking Obesity and Cancer Risk:
New Perspectives
Darren L. Roberts, Caroline Dive, and Andrew G. Renehan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 301
Hepatocellular Carcinoma: Novel Molecular Approaches for
Diagnosis, Prognosis, and Therapy
Augusto Villanueva, Beatriz Minguez, Alejandro Forner, Maria Reig,
and Josep M. Llovet p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317
Molecular Diagnosis and Therapy of Kidney Cancer
W. Marston Linehan, Gennady Bratslavsky, Peter A. Pinto, Laura S. Schmidt,
Len Neckers, Donald P. Bottaro, and Ramaprasad Srinivasan p p p p p p p p p p p p p p p p p p p p p p p p p p 329
Myelodysplastic Syndromes
Bart L. Scott and H. Joachim Deeg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 345
Nanotechnology Applications in Surgical Oncology
Sunil Singhal, Shuming Nie, and May D. Wang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 359
Emerging Molecular Targets for the Treatment of Nonalcoholic Fatty
Liver Disease
Giovanni Musso, Roberto Gambino, and Maurizio Cassader p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 375
Metabolic Surgery to Treat Type 2 Diabetes: Clinical Outcomes
and Mechanisms of Action
Francesco Rubino, Philip R. Schauer, Lee M. Kaplan, and David E. Cummings p p p p p p p p 393
vi
Contents
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Genetic Aspects of Pancreatitis

David C. Whitcomb p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 413
Anorexia Nervosa: Current Status and Future Directions
Evelyn Attia p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 425
Structural Variation in the Human Genome and its Role in Disease
Pawel Stankiewicz and James R. Lupski p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 437

Surgical Innovations Arising from the Iraq and Afghanistan Wars

Geoffrey S.F. Ling, Peter Rhee, and James M. Ecklund p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 457
Medicare Part D: Ongoing Challenges for Doctors and Patients
Gretchen Jacobson and Gerard Anderson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 469
Indexes
Cumulative Index of Contributing Authors, Volumes 5761 p p p p p p p p p p p p p p p p p p p p p p p p p p p 477
Cumulative Index of Chapter Titles, Volumes 5761 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 481
Errata
An online log of corrections to Annual Review of Medicine articles may be found at
http://med.annualreviews.org/errata.shtml
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