Anorexia Nervosa, Bulimia Nervosa, and Other Eating Disorders

c h a p t e r
29
Anorexia Nervosa, Bulimia
Nervosa, and Other Eating
Disorders
Irina Kowalska, Monika Karczewska-Kupczewska, Marek Strączkowski, and Robert T. Rubin
“A young woman thus afflicted, her clothes scarcely hanging together on

her anatomy, her pulse slow and slack, her temperature two degrees below
the normal mean, her bowels closed, her hair like that of a corpse—dry and
lustreless, her face and limbs ashy and cold, her hollow eyes the only vivid
thing about her—this wan creature whose daily food might lie on a crown
piece, will be busy with mother’s meetings, with little sister’s frocks, with
university extension and with what you please else of unselfish effort, yet on
what funds God only knows.”1
CHAPTER OUTLINE
HISTORY AND EPIDEMIOLOGY, 499 CENTRAL NERVOUS SYSTEM–RELATED
DIAGNOSIS, 500 NEUROPEPTIDES, ADIPOCYTOKINES, AND
GENETICS, 502 GASTROINTESTINAL HORMONES, 508
GENERAL PHYSICAL AND LABORATORY Neuropeptide Y and Peptide YY, 508
FINDINGS, 503 Leptin, 509
NEUROIMAGING, 504 Adiponectin, 510
NEUROENDOCRINOLOGY, 505 Macrophage Inhibitory Cytokine-1, 511
The Hypothalamo-Pituitary-Gonadal Axis, 505 Ghrelin, 511
The Hypothalamo-Pituitary-Adrenal Axis, 506 Cholecystokinin, 511
The Hypothalamo-Pituitary-Thyroid Axis, 506 Melanocortin and Corticotropin-Releasing
The Growth Hormone Axis, 506 Hormone, 512
Insulin Sensitivity, 507 Vasopressin and Oxytocin, 512
Bone, 507 Opioid Peptides, 512
Brain-Derived Neurotrophic Factor, 513
TREATMENT, 513
KEY POINTS
• A norexia nervosa is a serious psychiatric disorder that commonly begins during
adolescence or young adulthood and leads to multiple endocrine and metabolic
complications.
• The three cardinal diagnostic criteria for anorexia nervosa include: restriction of energy
intake that leads to significantly low body weight; persistent fear of becoming fat or
demonstration of behavior that interferes with gaining weight; and disturbed perception
of body weight.
• The main diagnostic criteria for bulimia nervosa include: recurrent episodes of binge
eating with an inappropriate compensatory behavior to prevent weight gain that
occur at least once a week for 3 months, and the persistence of those disturbances not
exclusively during episodes of anorexia nervosa.
498
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29 ANOREXIA NERVOSA, BULIMIA NERVOSA, AND OTHER EATING DISORDERS 499
KEY POINTS—cont’d
• A bnormal endocrine profiles and responses to challenges observed in anorexic patients
are the consequences of prolonged starvation and malnutrition and revert to normal
after weight recovery.
• Osteopenia and osteoporosis are recognized as serious complications of anorexia
nervosa that are not completely reversible after nutritional rehabilitation and could
have an impact on patients later in life.
• Multiple changes in neuropeptides, adipocytokines, and gastrointestinal hormones are
connected with disturbed perception of hunger and satiety, abnormal eating behavior,
energy homeostasis, and psychopathologic features in anorexic and bulimic patients.

Anorexia nervosa (AN) and bulimia nervosa (BN) are such patients kept their body weight somewhat below
eating disorders that have been recognized for hundreds normal but not to the same extent as AN patients. They
of years, yet their etiologies remain poorly understood.2-9 also tended not to develop amenorrhea and were more
Both illnesses carry significant physical and psychologi- active sexually. Russell considered BN to be an “ominous
cal morbidity, and in the case of AN, death can occur in variant” of AN, in that comorbid depressive symptoms
severe, untreated cases. Early recognition and aggressive were often severe and distressing, leading to a high risk
treatment thus are particularly important. Because the for suicide.
physical manifestations of these illnesses are so promi- In the 1990s, there were opposing views about
nent, most patients have their first encounters with non- whether to treat binge eating disorder (BED) as a sepa-
psychiatric physicians. Lengthy diagnostic workups for rate entity. Since 1994, BED became a provisional eat-
underlying physical illness may be conducted, and a psy- ing-disorder diagnosis and was included in the appendix
chiatric disturbance may be considered only when the of the fourth edition text revision of the Diagnostic and
results of the workup do not fit a known physical illness. Statistical Manual of Mental Disorders (DSM-IV-TR).18
The careful application of psychiatric diagnostic criteria In the Diagnostic and Statistical Manual of Mental Dis-
for AN and BN permits these illnesses to be suspected orders, Fifth Edition (DSM-5) published in 2013, BED
early in the medical workup and facilitates referral to was recognized as a separate category of eating disorders
the psychiatric specialist in a manner acceptable to the with proposed diagnostic criteria.19 In common with BN,
patient and family. patients with BED experience recurrent episodes of binge
eating; however the compensatory behavior (e.g., purg-
ing) is absent in BED. The other differences between BED
HISTORY AND EPIDEMIOLOGY and BN include age of onset, gender (males are affected
AN and BN are diseases primarily of adolescent girls; more frequently than in BN), association with obesity
approximately 95% of AN cases are female.10 Although (BED occurs in overweight and obese individuals), and
there is documentary evidence of AN occurring in the psychiatric comorbidities. Family and twin studies sug-
Middle Ages, the first medical accounts appeared in the gest a genetic background of BED.20
17th century as A Discourse upon Prodigious Abstinence Eating disorders are relatively rare in the general popu-
by John Reynolds in 1669 and Phthisiologia; or, a Trea- lation. However, the seriousness of medical complications
tise of Consumptions by Richard Morton in 1689.3,11,12 and the impact of these disorders on the affected indi-
AN as a modern clinical entity derives from publica- viduals’ quality of life and that of their families, warrant
tions in 1873 by Charles Lasègue and William Gull, who recognition and careful evaluation. Additionally, patients
referred to the illness as hysterical anorexia,13,14 and with eating disorders very often deny their illness, which
Gull’s publication in 1874 entitled Anorexia Nervosa.15 can influence the results of epidemiological studies. The
Bliss and Branch3 commented, “It is revealing to note the reported incidence of AN has varied between about 0.5
extraordinary differences in the description of the same and 15 cases per 100,000 population per year.21-23 The
condition by the two men. While Gull’s comments were large variation is related to the diagnostic criteria used,
as direct and precise as a pathologic report, Lasègue con- the methods of case ascertainment, and the population
veyed a sense of the spirit and feeling of these people, the studied (e.g., clinic versus community). In a British study
nuances of their disturbed relationships, and the subtle- concerning the incidence of eating disorders in primary
ties of their intrapsychic turmoil” (p. 14). The early 20th- care, the age-standardized annual incidence of eating dis-
century history of AN primarily involves its distinction orders increased from 32.3 in 2000 to 37.2 in 2009.24
from physical illnesses such as Simmonds’ cachexia.16 The incidence of AN remained stable during the observa-
Although binge eating (bulimia) has long been recog- tion period.24 The observed increase was mainly related
nized as part of the symptomatology of AN, BN as a dis- to the higher incidence of eating disorder not otherwise
tinct syndrome was first proposed by Russell in 1979.17 specified (EDNOS) in the last third of the decade.24 While
He elaborated two criteria for BN: an irresistible urge to the overall incidence of AN is considered to be stable, the
overeat followed by self-induced vomiting or purging, trend toward higher incidence is observed among young
and a morbid fear of becoming fat. In common with AN, girls from 15 to 19 years of age.24,25 The prevalence of AN
500 PART 4 OBESITY, ANOREXIA, AND NUTRITION
ranges from 0.5% to 1.0% among females, with males TABLE 29-1 DSM-5 Diagnostic Criteria
being affected about one tenth as frequently, although for Anorexia Nervosa
the prevalence has been considerably higher in some
studies.22,23 A population-based study conducted in six A. Restriction of energy intake relative to requirements, leading
European countries showed a lifetime prevalence of AN to a significantly low body weight in the context of age, sex,
in adult female patients of 0.9%.26 A meta-analysis of 42 developmental trajectory, and physical health. Significantly low
studies revealed the crude mortality rate in AN (due to all weight is defined as weight that is less than minimally normal
or, for children and adolescents, less than that minimally
causes of death) to be 5.9%, which is substantially greater expected.
than that for female inpatients and for the general popu- B. Intense fear of gaining weight or of becoming fat, or persistent
lation.27 In two more recent studies, standardized mortal- behavior that interferes with weight gain, even though at a
ity ratios for patients with AN of 5.9% (meta-analysis of significant low weight.
C. Disturbance in the way in which one’s body weight or shape is
36 studies) 28 and 6.2% (retrospective cohort studies)29 experienced, undue influence of body weight or shape on self-
were reported. One in five individuals with AN who died evaluation, or persistent lack of recognition of the seriousness
had committed suicide.28 Although there is agreement of of the current low body weight.
higher premature mortality rate in AN, it is still unknown Restricting type: During the last 3 months, the individual has
which factors predict higher mortality. Previous findings not engaged in recurrent episodes of binge-eating or purging
behavior (i.e., self-induced vomiting or the misuse of laxatives,
pointed out older age at hospital admission, history of diuretics, or enemas). This subtype describes presentations in
attempted suicide, longer duration of the disease, psychi- which weight loss is accompanied primarily through dieting,
atric comorbidity, and desire for lower weight at admis- fasting, and/or excessive exercise.
sion as the factors influencing mortality.29,30 A recent Binge-eating/purging type: During the last 3 months, the individu-
al has engaged in recurrent episodes of binge-eating or purging
study shed additional light on the predictors of mortality behavior (i.e., self-induced vomiting or the misuse of laxatives,
in AN.31 This longitudinal observation (a median total diuretics, or enemas).
follow-up time of 20 years) revealed that apart from the
Current Severity
long duration of the disease, substance abuse, low body
mass index (BMI), and poor social adjustment raise the The minimum level of severity is based, for adults, on current
risk for mortality in AN.31 body mass index (BMI) or, for children and adolescents, on
BMI percentile. The ranges below are derived from World
The prevalence of BN varies between 2% and Health Organization categories of thinness in adults; for chil-
4%.22,23,32,33 In the quoted meta-analysis of 36 studies, dren and adolescents, corresponding BMI percentiles should be
a standardized mortality ratio for BN was 1.9%.28 Both used. The level of severity may be increased to reflect clinical
AN and BN, as well as subsyndromal anorexia and buli- symptoms, the degree of functional disability, and the need for
supervision.
mia, are far more common in certain groups of young Mild: BMI ≥17kg/m2
women, notably athletes and ballet dancers, where occu- Moderate: BMI ≥16-16.99 kg/m2
pational demands place a premium on thinness. Primary Severe: BMI ≥15-15.99 kg/m2
and secondary amenorrheas in these individuals are Extreme: BMI <15 kg/m2
extraordinarily common. Overweight and obesity are Reprinted with permission from the Diagnostic and statistical manual
common comorbidities of BED, which has an estimated of mental disorders, 5th edition. Arlington, VA: American Psychiatric
prevalence rate between 0.7% and 3%.34 Association, 2013.
Since the 1980s, large-scale twin and family studies
have suggested that eating disorders are familial.35,36
There is cross-transmission between AN and BN, and First Diagnosed in Infancy, Childhood and Adolescence,”
they appear to share a common vulnerability, but the a category that no longer exists in the DSM-5) and places
transmissible elements remain elusive. Twin and family elimination disorder (also listed in DSM-IV in “Disorders
studies suggest that major depressive disorder and sub- Usually First Diagnosed in Infancy, Childhood and Ado-
stance dependence most likely do not share a common lescence”) as a new independent classification outside the
etiology with the eating disorders. The genetic contribu- feeding and eating disorders. In addition, brief descrip-
tion is likely predisposing rather than determining, in that tions and preliminary diagnostic criteria are provided for
sociocultural circumstances, as well as personal psycho- several conditions connected with disturbances in eating
logical stressors, are risk factors.37,38 The risk for devel- behavior under “Other Specified Feeding and Eating Dis-
oping AN is higher in female twins than in male twins, orders.”19 This category includes atypical AN, BN of low
but male members of opposite-sex pairs have almost the frequency and/or limited duration, BED of low frequency
same risk as female twins.39 This suggests that an intra- and/or limited duration, purging disorder, and night eat-
uterine factor, such as sex steroid hormones, also influ- ing syndrome.19 The main intention of introducing the
ences the development of AN. new classification for Feeding and Eating Disorders and
providing the diagnostic criteria was to minimize the
diagnosis of EDNOS and facilitate clinical diagnosis.
DIAGNOSIS The DSM-5 criteria for AN, BN, and BED highlight
The DSM-5 provides the current clinical criteria for AN the many identifiable behavioral and psychological
(Table 29-1), BN (Table 29-2) and BED. In addition, the aspects of these illnesses.40 If the patient and family are
new DSM-5 classification includes the clinical criteria for queried about these aspects, considerable information
pica, rumination, and avoidant/restrictive food intake pointing toward the diagnosis can be gleaned, psychiat-
disorder (listed in the DSM-IV in “Disorders Usually ric consultation can be considered early in the diagnostic
TABLE 29-2 DSM-5 Diagnostic Criteria for

Bulimia Nervosa
A. R
ecurrent episodes of binge eating. An episode of binge eating
is characterized by both of the following:
1. E ating, in a discrete period of time (e.g., within any 2-hour
period), an amount of food that is definitely larger than
most people would eat during a similar period of time and
under similar circumstances.
2. A sense of lack of control over eating during the episode
(e.g., a feeling that one cannot stop eating or control what
or how much one is eating).
B. R
ecurrent inappropriate compensatory behavior in order to
prevent weight gain, such as self-induced vomiting; misuse of
laxatives, diuretics, enemas, or other medications; fasting; or
excessive exercise.
C. The binge eating and inappropriate compensatory behaviors
both occur, on average, at least once a week for 3 months.
D. S elf-evaluation is unduly influenced by body shape and weight.
E. T
he disturbance does not occur exclusively during episodes of
anorexia nervosa.
Current Severity
The minimum level of severity is based on the frequency of inap-
propriate compensatory behaviors (see below). The level of
severity may be increased to reflect other symptoms and the
degree of functional disability.
Mild: An average of 1-3 episodes of inappropriate compensatory
behaviors per week.
Moderate: An average of 4-7 episodes of inappropriate compen-
satory behaviors per week. Figure 29-1 Extreme cachexia in an anorexia nervosa patient. (From
Severe: An average of 8-13 episodes of inappropriate compensa- Bliss EL, Branch CHH: Anorexia nervosa: its history, psychology, and
tory behaviors per week. biology. New York: Paul B. Hoeber, 1960.)
Extreme: An average of 14 episodes of inappropriate compensa-
tory behaviors per week.
Reprinted with permission from the Diagnostic and statistical manual to herself to be either at an acceptable weight or even
of mental disorders, 5th edition. Arlington, VA: American Psychiatric fat. Indeed, initiation of treatment by insisting on the
Association, 2013. patient’s eating can lead to purging behavior that did not
occur prior to treatment. How inflexible a given patient
process, and specialized and expensive laboratory testing may be in refusing to gain weight, however, can vary
often can be avoided. considerably.41
The main difference in the new criteria for AN listed A corollary of this is the third criterion, disturbance of
in the DSM-5 is deletion of the DSM-IV Criterion D the experience of one’s body weight or shape (e.g., undue
requiring amenorrhea for AN diagnosis. The rationale influence of body weight or shape on self-evaluation/
for this is that this criterion cannot be applied for males, self-esteem and/or denial of the seriousness of the weight
premenarchal females, females taking contraceptives, and loss), even though there may be clear adverse physical
postmenopausal women.19 There is also some change sequelae, for example, secondary amenorrhea. For the
to Criterion A: “Refusal to maintain body weight” is endocrinologist, questions that should be asked of the
replaced by “restriction of energy intake relative to patient and family to address these psychological and
requirements, leading to significantly low body weight.”19 behavioral aspects of AN include the following (adapted
According to the DSM-5, three cardinal features must be from the Structured Clinical Interview for DSM-IV Axis
present to diagnose AN: restriction of energy intake that I Disorders):42
leads to significantly low body weight (Criterion A), per-
sistent fear of becoming fat or behavior that interferes How much do you weigh now?
with gaining weight (Criterion B), and disturbed percep- How tall are you?
tion of body weight (Criterion C) (see Table 29-1). As What foods do you eat?
illustrated in Figure 29-1, the cachexia can be severe, Why do you limit yourself to those foods?
and, as mentioned, self-starvation can lead to death. If Do you feel you are fat now?
the onset is in childhood or early adolescence, there may Are you concerned that you might become fat if you
be a failure to make the expected weight gain during the ate more?
active growth phase. The restriction of energy intake that Do you weigh less than other people think you should
prevents weight gain or maintains body weight is rooted weigh?
psychologically in the second criterion, an intense fear Do you need to be very thin in order to feel good about
of gaining weight or of becoming fat, even though the yourself?
patient is underweight. There is a subjective distortion of Has anyone told you it can be dangerous to be as thin
body image such that the emaciated individual appears as you are?
What kinds of things do you do to keep from gaining Comorbid symptoms of depression and anxiety occur
weight? with some frequency in both AN and BN and should
Have you ever made yourself vomit or take laxatives, be assessed, because their persistence during treatment
enemas, or water pills? How often? may portend poorer outcomes.46-52 Symptoms of depres-
How much do you exercise? sion and anxiety are exaggerated by malnutrition and
Before now, were you having periods? Were they regu- improved with nutrition. AN patients with obsessive-
lar? When did they stop? compulsive disorder (OCD) tend to have an obsessional
need for symmetry/exactness and compulsions toward
For BN, the distinguishing features are uncontrol- ordering and arranging.53 Mild to moderate negative
lable binge eating of a definitely larger-than-normal mood states and obsessive symptoms can persist after
amount of food (Criterion A) that is clearly repetitive recovery in both anorexic and bulimic individuals,54,55
(Criterion C). In the DSM-5 criteria for BN, the fre- suggesting that these traits may contribute to the patho-
quency of binge eating and the compensatory behavior genesis of eating disorders.56 As well, comorbid impulse
in BN has been reduced from at least twice a week for control disorders (ICD), the most common being compul-
3 months to once weekly.19 Here too, ones sense of self sive buying disorder and kleptomania, occur more fre-
is unduly influenced by weight and body shape (Crite- quently in individuals with binge eating subtypes and are
rion D). Compensatory behaviors such as self-induced associated with greater use of laxatives, diuretics, appe-
vomiting, purging, fasting between binges, and exercise tite suppressants, and fasting.57
are invoked to prevent weight gain (Criterion B). The There also is a high incidence of comorbid OCD in
frequency and chronicity of the bingeing, and espe- anorexic and bulimic women and their families, as well
cially the compensatory behaviors, help distinguish BN as increased rates of AN and BN in persons with primary
from overeating in general. And because binge eating OCD. It may be that the core eating disorder symptoms
and purging can occur as part of AN as a subtype, a (e.g., fear of fatness, pursuit of thinness) are a specific
Criterion E for BN is that it does not occur exclusively type of obsession. Symmetry, ordering, and perfection-
during episodes of AN. Recent findings support the lon- ism are the most common target symptoms in women
gitudinal distinction between AN and BN, but they may with AN and BN and often persist after recovery. Leck-
not support the AN subtyping schema.43,44 BED also man and others58 delineated four symptom dimensions
is being distinguished from BN18,19,45 because obesity of OCD, one of which was symmetry and ordering; these
rather than inanition often results, and the endocrino- occurred most commonly in men. OCD in men and eat-
logic and other metabolic changes are different from ing disorders in women may be gender-specific expres-
those of AN and BN. sions of a common psychobiology related to obsessions
For the endocrinologist, questions that should be with symmetry and ordering compulsions.
asked of the patient and family to address the criteria for A recent systematic review of eight studies has demon-
BN include the following (adapted from the Structured strated that the prevalence of autism spectrum disorders
Clinical Interview for DSM-IV Axis I Disorders):42 is significantly higher in populations with eating disor-
ders compared with those in healthy controls.59 It has
Do you have times when your eating gets out of con- been reported that these disorders affect about 20% of
trol? Tell me about these times. patients with AN. Additionally, patients with attention-
During these times, do you often eat within a 2-hour deficit hyperactivity disorder may present with symptoms
period what most people would regard as an unusual of eating disorders.60
amount of food?
Can you give me an example of the kinds and amounts GENETICS
of food that you might eat during one of these times?
How often do these times occur? Eating disorders in both women and men are familial,
Do you do anything to counteract the effects of eating as shown by both family and twin studies.61-66 The heri-
that much—like making yourself vomit; taking laxa- tability of both AN and BN has been estimated between
tives, enemas, or water pills; strict fasting between 33% and 84%.67 Recent findings corroborate previous
periods of eating a lot of food; or exercising a lot? research implicating the transition from early to mid-ado-
How important is your body shape and size in how lescence as a critical time for the emergence of a genetic
you feel about yourself? diathesis for disordered eating.68 Studies of the genetics of
AN and BN have been primarily by linkage analysis and
These questions and those regarding AN should be association studies. In linkage analysis, correlations are
phrased in a way that is comfortable to both the health determined between the occurrence of a disease in fami-
care professional and the patient. The patient should lies and the inheritance of specific chromosomal regions
also be asked if this is the first time these behaviors have in those families. In association studies, nucleotide poly-
occurred or if there have been past episodes; in the case morphisms are searched for in specific candidate genes
of the latter, a careful history taking about each episode, suggested by chromosomal linkage studies and/or the
its severity and duration, and treatments and their success known functions of the gene product.
should be done. This information may yield important Linkage studies in AN and BN families have suggested
clues as to how to approach the patient therapeutically susceptibility genes on several chromosomes, but the
during the current episode. strength of the associations has depended on the diagnostic
stringency of the cases. For example, in 192 families with to AN, high blood cholesterol concentration is observed
at least one affected relative pair with AN, BN, and related in AN patients despite emaciation. These findings sug-
eating disorders, modest linkage was found with a marker gest that altered cholesterol metabolism might increase
on chromosome 4.69 However, when the analysis was the susceptibility to AN, but further studies are needed to
restricted to 37 families in which at least two relatives confirm this hypothesis.
had a diagnosis of the restricting subtype of AN (without One published study demonstrated the results of the
bingeing and purging), there was a much stronger linkage genome-wide association study (GWAS) in AN, but due
to a marker on chromosome 1p. With reference to specific to relatively small statistical power, no conclusion about
behavioral traits, two variables were identified in a sample common gene variation was made.78
of 196 families with an AN proband: drive for thinness Thus, although the familial clustering of both AN and
and obsessionality.70 When these variables were incorpo- BN is clear, there is no clear evidence that single nucleotide
rated into a linkage analysis, there again was highly sig- polymorphisms in any of the aforementioned genes are
nificant linkage to a region on chromosome 1, as well as closely related to either of these eating disorders. Recent
linkages of lesser significance to regions on chromosomes findings and wider availability of the new techniques of
2 and 13. In contrast, linkage analysis of 308 families with molecular biology open a new area of investigation to
a BN proband yielded a high linkage score to chromo- elucidate the genetic background of eating disorders.
some 10.71 In a subset of 133 families in which two or
more BN members reported self-induced vomiting, an GENERAL PHYSICAL AND LABORATORY FINDINGS
even higher linkage was found to a region on chromosome
10p. Another region on chromosome 14q was suggestive The general physical and laboratory findings of AN
of linkage. These studies can serve to suggest specific chro- and BN are presented in Tables 29-3 and 29-4, respec-
mosomal regions for association studies. tively.79,80 Metabolic changes and medical complications
Gene association studies performed in AN have so far occur secondary to chronic starvation and malnutrition
produced only a few replicable observations. These candi- and to bingeing and purging.7,80-82 Malnutrition-associ-
date gene studies have targeted neurotransmitter systems ated disturbances as severe as pulmonary bronchiectasis
(opioid, serotonergic, dopaminergic receptors), brain- and emphysema have been reported.83 Cardiac compli-
derived neurotrophic factor (BDNF), genes controlling cations are also well recognized in patients with eating
hormones and proteins related to food intake or energy disorders, including the more common abnormalities of
metabolism such as the uncoupling proteins UCP-2 and bradycardia, orthostatic hypotension, and (although less
UCP-3, fat tissue obesity gene (FTO), pro-opiomelanocor- common) the risk for more serious abnormalities, includ-
tin (POMC), the melanocortin-4 receptor (MC4R), leptin, ing prolongation of the QT interval and silent pericardial
ghrelin, agouti-related protein (AgRP), neuropeptide Y effusion.84
(NPY), cholecystokinin (CCK), the β3-adrenergic recep- Gastrointestinal (GI) disturbances occur in both AN
tor, estrogen receptors, and tumor necrosis factor. How- and BN.85 Delayed gastric emptying and delayed colonic
ever, for the majority of the studied genes, the results have transit time resulting in constipation are common in
been inconsistent.72,73 Promising data have been obtained AN patients and are associated with complaints of early
for BDNF, delta 1 opioid receptor (OPDR1), and AgRP.72 satiety, bloating, and abdominal distension, leading the
The OPDR1 gene is responsible for mediating the hedonic patient to feel fat and avoid eating. GI disturbances in
component of feeding, and disruption of the signal could BN include increased gastric capacity, decreased gastric
contribute to AN.73 An important set of studies regards the relaxation, delayed gastric emptying, and abnormal func-
potential role of BDNF gene variation in AN. BDNF regu- tion of the enteric autonomic nervous system. Abnor-
lates neuronal plasticity and plays a role in the neuronal malities of GI function in AN and BN are reversible to
survival. Animal studies showed that BDNF has metabolic various degrees with improvement in the underlying dis-
properties, influences food intake, and is connected with orders. Treatments targeted at these abnormalities, such
physical activity. Moreover, Val66Met polymorphism of as agents to improve gastric emptying in AN and neu-
the BDNF gene has been studied in psychiatric disorders. rotransmitter modulators to reduce bingeing in BN, have
All these data indicate its possible role in triggering and/or met with varying success and require further study.
maintaining AN by influencing eating behavior, metabolic Increasing recognition is being given to osteopenia as
disturbances, and psychiatric traits of the disorder. Previ- an early and serious complication of AN.86-89 Adoles-
ous data demonstrated the association between Val66Met cence is a time when optimal bone mineralization sup-
polymorphism of the BDNF gene with AN in family-based porting physical growth is critical, and adolescent girls
studies from eight European countries.74 It has also been with AN have relatively poor bone mineral accrual. Sev-
demonstrated that blood BDNF levels are modulated by eral factors contribute to osteopenia in AN, including
BDNF gene variation.75 However, a recent meta-analysis estrogen, androgen, and insulin-like growth factor defi-
of Val66Met polymorphism of the BDNF gene revealed ciency; elevated cortisol, and peptide YY (PYY); excessive
no association with AN.76 exercise; and nutritional deficiencies. Multifaceted treat-
Intriguing data about variation in the epoxide hydro- ment of AN is required to restore bone mineral density to
lase 2 (EPHX2) gene and its possible role in anorexics have the normal range.
been suggested.77 EPHX2 codes for an enzyme known to The electrolyte disturbances of AN and BN depend
regulate cholesterol metabolism, and, although it is not on whether purging is primarily by vomiting or by
known how EPHX2 variants influence the susceptibility abuse of laxatives or diuretics (or both) and can be life
TABLE 29-3 Physical and Laboratory Findings TABLE 29-4 Physical and Laboratory Findings
in Anorexia Nervosa in Bulimia Nervosa
Physical Physical
Cachexia, emaciation, dehydration, shock or impending shock Usually well groomed with good hygiene
Covert infectious processes, immunologic problems late in Usually normal weight or mild to moderate obesity
process Generalized or localized edema of lower extremities
Xerosis (dry, scaly skin), desquamation, yellowish palms and Swelling of parotid and other salivary glands
soles Bruises and lacerations of posterior pharynx, scar/callus forma-
Scalp and pubic hair loss, lanugo, increased pigmented body hair tion over dorsum of hands (Russell’s sign) secondary to
Hypothermia, decreased metabolic rate, bradycardia, hypotension induced vomiting
Acrocyanosis (circulatory changes resulting in cold, blue, and Dental enamel discoloration and dysplasia secondary to vomiting
occasionally sweaty hands and feet) of gastric acid
Bradypnea (respiratory compensation for alkalosis) Pyorrhea and other gum disorders
Edema of lower extremities, heart murmur (infrequent) Diminished reflexes, muscle weakness, paralysis, infrequently
Signs of estrogen deficiency (dry skin, osteoporosis, small uterus peripheral neuropathy
and cervix, dry vaginal mucosa) and androgen deficiency (no Muscle cramping (with induced hypoxia or positive Trousseau’s
acne or oily skin) sign)
Signs of hypokalemia (hypotension, weak pulse, arrhythmias,
Chemical decreased cardiac output, poor-quality heart sounds; shortness
Normal laboratory results early in process of breath; ileus, abdominal distension, acute gastric dilatation;
Elevated BUN secondary to dehydration depression, mental clouding)
Hypercarotenemia Additional physical features of anorexia nervosa, if food restric-
Elevated serum cholesterol early in process; may decrease later tion is part of syndrome
Decreased plasma transferrin, complement, fibrinogen, prealbu- Chemical
min; usually normal protein and albumin:globulin ratio
Elevated serum lactic dehydrogenase and alkaline phosphatase Uncomplicated bulimia
Depressed serum magnesium, calcium, phosphorus, the last a late No abnormalities reported; possible abnormal glucose metabo-
and ominous sign lism
Possibly depressed plasma zinc, urinary zinc, and copper Bulimia with vomiting
Metabolic alkalosis (hypochloremia, elevated serum bicarbonate)
Hematologic Hypokalemia (secondary to metabolic alkalosis)
Panleukopenia with relative lymphocytosis Hypovolemia with secondary hyperaldosteronism (also contrib-
Thrombocytopenia (causing purpura) utes to hypokalemia), pseudo-Bartter’s syndrome
Very low erythrocyte sedimentation rate Bulimia with vomiting and purging (laxatives or diuretics)
Mild anemia; severe anemia (rare and late in process), especially All the above findings, plus:
with rehydration Decreased body potassium secondary to diarrhea and renal losses
Metabolic acidosis with spuriously normal serum potassium
Adapted from Comerci GD: Medical complications of anorexia nervosa Hypokalemic nephropathy (urine concentrating deficit)
and bulimia nervosa. Med Clin North Am 74:1293-1310, 1990; Hypokalemic myopathy (including cardiomyopathy)
and Mitchell JE, Crow S: Medical complications in adolescents with Hypo- or hypercalcemia, hypomagnesemia, hypophosphatemia
anorexia nervosa: a review of the literature. Curr Opin Psychiatry
19:438-443, 2006. Adapted from Comerci GD: Medical complications of anorexia nervosa
and bulimia nervosa. Med Clin North Am 74:1293-1310, 1990.
threatening. The medical management of these cases

can be complex and must be individualized. Refeeding that all hematologic alterations reverse after nutritional
syndrome may occur in severely malnourished patients rehabilitation.
as a result of severe shifts in fluids and electrolytes, in In bulimic patients, the increased prevalence of poly-
particular phosphate, from extracellular to intracellular cystic ovary morphology/polycystic ovary syndrome has
spaces. These electrolyte shifts can lead to cardiovascu- been reported.93 Another study conducted in hirsute
lar, neurologic, and hematologic complications and can women revealed that 12.6% were diagnosed with BN.94
be associated with significant morbidity and mortality.90 Additionally, a Swedish study indicated that fertility is
Comerci79 presented detailed case histories of an anorexic significantly reduced in anorexic women.95 Another study
and a bulimic patient, including critiques of their treat- pointed out that the birth weight of offspring was lower in
ment, which highlight the intricacies of successful medical mothers with AN, and the group with BN had the higher
management of these disorders. rates of miscarriagies.96 However, a more recent finding
Hematologic alterations in AN are also of clinical found no differences in mean children birth weight in AN
importance. Review of the relevant studies that reported and BN mothers.97
the frequency of hematologic changes in total blood cell
count demonstrated that almost 30% of AN patients NEUROIMAGING
have anemia and leukopenia, and about 5% to 10% have
thrombocytopenia.91 Hematologic abnormalities are This is a growing area of eating-disorders research
more frequent in severe AN.92 Anemia is characterized supported by major improvements in imaging tech-
by normal values of MCV, ferritin, folic acid, and vita- nology.98,99 In AN, enlargement of cortical sulci and
min B12. The observed hematologic changes are related to subarachnoid spaces suggestive of cerebral, and on occa-
the bone marrow atrophy or starvation-mediated gelati- sion cerebellar, atrophy have been reported, the changes
nous marrow transformation.91,92 It is of importance being positively correlated with poor neuropsychological
test performance and being reversible to varying degrees levels are elevated in both AN and BN,120 indicating that
with weight gain.100-102 Reduced gray matter volume in bulimic patients are nutritionally depleted despite their
the anterior cingulate cortex has been reported in AN normal body weight.121
compared to healthy controls, the amount of the decrease
being correlated with illness severity.103 Studies in recov- The Hypothalamo-Pituitary-Gonadal Axis
ered AN and BN patients have differed, showing either The relationship of starvation and eating disorders to
persistent alterations or normalization of gray- and neuroendocrine function is most clearly seen for the pitu-
white-matter volumes.104,105 itary-gonadal axis. Amenorrhea is very common in AN,
With regard to CNS metabolites, proton magnetic res- and oligomenorrhea occurs in 50% of bulimic individu-
onance spectroscopy (1H-MRS) indicates higher ratios of als. Table 29-5 lists the major endocrine disturbances that
choline-containing compounds to creatine and N-acety- occur in AN and BN.117,122-124 The secondary amenorrhea
laspartate, as well as reduced myoinositol, in the fron- is a direct result of altered gonadotropin secretion. Serum
tal white matter and occipital gray matter in association sex hormone-binding globulin may be increased, and both
with decreased BMI, suggesting starvation-associated estrogen and testosterone are decreased.125 Additionally,
increased cell membrane turnover.106 Consistent with
these findings, phosphorus MRS (31P-MRS) has shown
altered phosphodiester and phosphomonoester peaks in
malnourished anorexics, suggesting that reduced body
TABLE 29-5 Neuroendocrine Disturbances in
mass alters CNS cellular membrane phospholipid metab-
Anorexia Nervosa and Bulimia Nervosa
olism.107 Reduced blood flow in frontal, parietal, and
frontotemporal cortex, as shown by single photon emis- Anorexia Bulimia
sion computed tomography (SPECT), has been reported Nervosa Nervosa
in AN, which reverted to normal perfusion with clinical
Hypothalamo-Pituitary-Gonadal Axis
remission.108 Another SPECT study suggested reduced
blood flow in the anterior cingulate in patients with Plasma gonadotropins (LH, FSH) ↓ ↓
Plasma estradiol ↓↓ ↓
AN compared to controls, both before and after weight Plasma testosterone ↓ ?
restoration.109 LHRH stimulation of LH ↓ ↓
Functional neuroimaging (fMRI) also is delineating LHRH stimulation of FSH ↔ ↔
activation of limbic and paralimbic areas that may be Hypothalamo-Pituitary-Adrenocortical Axis
involved with calorie fear, including exaggerated activa-
tion of the caudate and reduced activation of the insula Plasma and CSF cortisol ↑ ↑
Plasma ACTH ↔ ↔
to taste stimuli in women recovered from AN compared CSF ACTH ↓ ↔ (↓ when
to normal women.110,111 These areas also have been abstinent)
implicated as neural substrates of obsessive-compulsive CSF CRH ↑ ?
and depressive symptoms.112 Decreased food-stimu- CRH stimulation of ACTH ↓ ?
ACTH stimulation of cortisol ↑ ?
lated activation of several cortical areas has also been Dexamethasone suppression test 50%-90% 20%-60%
shown by fMRI in chronically ill anorexics, compared nonsup- nonsup-
to those exhibiting long-term recovery.113 Positron pression pression
emission tomography (PET) imaging has demonstrated Hypothalamo-Pituitary-Thyroid Axis
reduced 5-HT1A and 5-HT2A receptor binding in
frontal, parietal, and occipital cortex in both AN and Plasma T4 ↓ ↔ (↓ when
abstinent)
BN patients, which may persist after recovery in both Plasma T3 ↓↓ ↓
conditions.8,114,115 Plasma Reverse T3 ↑ ↔ (↓ when
abstinent)
Plasma TSH ↓ ↓ (↑ when
NEUROENDOCRINOLOGY abstinent)
CSF TRH ↓ ?
Abnormal hormone profiles and responses to challenge TRH stimulation of TSH ↓ ↓
are closely related to the “starvation” status of AN and
Other Neuroendocrine Axes
BN patients.116-119 Hormone abnormalities also may be
present (but to a lesser extent) in normal-weight women Growth hormone ↑ ↑
with BN. The presence of starvation in AN is evident IGF-1 ↓ ↔
Prolactin ↔ ↓
from the weight loss, but it may not be recognized in Prolactin response to serotonergic ↓ ↓
normal-weight BN. Although bulimic women often challenge
maintain a normal weight, they do so by restricting food Melatonin ↑ ?
intake when not bingeing and purging, and they often Insulin sensitivity ↔ ?
have poorly balanced meals. Starvation-induced deple- ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing
tion of hepatic glycogen stores results in free fatty acids hormone; CSF, cerebrospinal fluid; FSH, follicle-stimulating
and ketone bodies replacing glucose as the primary hormone; LH, luteinizing hormone; LHRH, luteinizing hormone–
releasing hormone; IGF-1, insulin growth factor 1, T4, thyroxine;
energy source. This shift from glycogenolysis to lipoly- T3, triiodothyronine; TRH, thyrotropin-releasing hormone; TSH,
sis and ketogenesis is associated with an increase in free thyroid-stimulating hormone; ↑, increased; ↓, decreased; ↔, un-
fatty acids and their metabolites. β-Hydroxybutyric acid changed;?, insufficient or conflicting data.
low fat mass could also contribute to the hypoestrogenic Taken together, the pituitary-adrenocortical findings
state in AN by limiting extraovarian conversion of andro- indicate a mild to moderate activation of this hormone
gens to estrogens.126 As indicated in Table 29-3, there are axis in AN and BN. As well, plasma neuroactive steroids
physical signs of severe estrogen deficiency. The lutein- are reported to be elevated in untreated women with both
izing hormone (LH) response to LH-releasing hormone AN and BN.138
stimulation is blunted, but the follicle-stimulating hor-
mone (FSH) response is usually normal. The gonadotro- The Hypothalamo-Pituitary-Thyroid Axis
pin secretion pattern in adult AN women resembles that With reference to the hypothalamo-pituitary-thyroid axis,
of prepubertal girls. Studies on gonadotropin secretion, starvation leads to considerably decreased plasma free
which reflects gonadotropin releasing hormone (GnRH) triiodothyronine (T3) concentrations, along with some-
secretion, revealed a very low plasma level of LH dur- what decreased plasma free thyroxine (T4) and increased
ing the day and night without a pulsatile pattern of LH plasma reverse T3 concentrations. This represents the
secretion. This can result from impaired GnRH pulsatil- “euthyroid sick syndrome” hormone profile.139-143 The
ity, which could be related to significant loss of adipose decreased circulating T3 helps reduce energy expenditure
tissue and altered hormonal and adipocytokines profiles and minimizes muscle protein catabolism into amino
in AN.127 acids for gluconeogenesis. CSF thyrotropin-releasing
BN patients also may have decreased gonadotropin hormone (TSH) also appears to be reduced in AN.144
secretion if they have lost 15% or more of their body When bingeing, bulimic patients generally have normal
weight, but they usually have normal circulating gonado- thyroid indices with perhaps reduced T3 and TSH con-
tropins and continue their menses. centrations; however, when they stop bingeing, their
pituitary-thyroid axis function resembles that of anorexic
The Hypothalamo-Pituitary-Adrenal Axis patients.145,146
With reference to the hypothalamic-pituitary-adrenal Resting energy expenditure (REE) measured in anorexic
cortical (HPA) axis (see Table 29-5), the abnormalities patients appears to be significantly lower in comparison
in AN and in reduced-weight BN123,128,129 are strikingly to healthy controls,147,148 which might be considered
similar to those occurring in 30% to 50% of patients an adaptive mechanism to chronic starvation linked to
with major depression.123,130,131 In accordance with the low T3. A close relationship between REE and T3
this is the observation of a positive correlation between has been reported.147 In addition, results from a refeed-
serum cortisol level and scores of anxiety and depres- ing study conducted in AN patients pointed out that an
sive symptoms in AN.132 Circulating cortisol is increased increase of REE during the recovery period was related to
at all times of the day and night, but the amplitude and the changes in T3. This supports the hypothesis about the
timing of its circadian rhythm are preserved. Circulating role of T3 in the regulation of energy hemostasis.147 REE
adrenocorticotropic hormone (ACTH) is usually normal is mostly a function of the activity of lean body mass,
when determined by radioimmunoassay, as it is in major which is metabolically more active than fat tissue. Data
depression; the more specific immunoradiometric assay published regarding AN indicate that a decrease in REE is
for ACTH1-39 has shown decreased ACTH in major independent of fat free mass (FFM).147,148 Recent findings
depression,133 which also could be the case for ACTH1- have added new information about potential factors influ-
39 in these eating disorders. Cerebrospinal fluid (CSF) encing energy expenditure in anorexic patients.148 The
ACTH concentrations appear to be decreased, but CSF role of interleukin 6 (IL-6) and soluble forms of its mem-
corticotropin-releasing hormone (CRH) concentrations brane receptor and glycoprotein 130 in the regulation
may be increased,123,129 as may be CSF vasopressin,123,134 of energy hemostasis in AN has been demonstrated.148
a secretagogue for ACTH in addition to CRH,135 which All these data suggest that mass-independent alterations
appears to play a greater role in stress states than under could be of importance in the regulation of REE in AN.
normal conditions.136
Stimulation and suppression tests of the HPA axis have The Growth Hormone Axis
been conducted mainly in AN, and they are in accord Insulin-like growth factor type 1 (IGF-1) concentrations
with the baseline hormone findings. The ACTH response are low in both AN and BN, which is consistent with
to CRH administration is reduced, undoubtedly second- diminished IGF-1 production in the liver during fasting.
ary to enhanced negative feedback on the pituitary cor- Circulating growth hormone (GH) is increased, likely
ticotrophs exerted by elevated circulating cortisol. The owing to both diminished feedback of IGF-1 on GH
cortisol response to ACTH administration is increased, secretion and primary hypothalamic dysfunction.149-152
suggesting increased secretory capacity of the adrenal Prolonged starvation blocks GH action; thus resistance
cortex. The low-dose dexamethasone (DEX) suppression to GH is observed in AN. Misra and colleagues have
test is abnormal in 50% to 90% of anorexics and in 20% documented that adolescent girls with AN had increased
to 60% of bulimics, depending on weight loss. Because basal and pulsatile secretion of GH and low plasma
DEX acts primarily at the pituitary, ACTH and cortisol IGF-1 levels.153 GH secretion correlated inversely with
escape from DEX suppression suggest increased suprapi- the measurements of nutritional status (BMI, fat mass,
tuitary stimulation of corticotrophs by CRH and vaso- plasma leptin), suggesting that hypothalamic control of
pressin (AVP). CRH may be more influential than AVP GH secretion might be nutritionally regulated in AN.151
in stimulating the HPA axis in AN, because the cortisol Additionally, plasma ghrelin level, a potent GH secre-
response to exogenous AVP administration is blunted.137 tagogue, was higher in AN.153 Further support for the
GH resistance in AN was provided by the results from unfavorable adaptive metabolic changes, could influence
an interventional study, where supraphysiologic doses energy homeostasis. However, it has been discovered that
of recombinant human GH (rhGH) were given to AN anorexic patients demonstrate normal metabolic flex-
patients.154 The main conclusion from this study is that in ibility (the ability of skeletal muscles to switch between
malnourished anorexic patients, even a supraphysiologic oxidation of lipids as an energy fuel during fasting to
GH level does not stimulate IGF-1 secretion. The poten- the oxidation of carbohydrates during insulin stimulated
tial consequences of GH resistance include muscle atro- conditions), which makes an argument for the preserved
phy, growth failure, and bone loss.155 It should be noted insulin sensitivity in AN.162
that in the refeeding study, an improvement in nutritional
status was accompanied by an increase in IGF-1 plasma Bone
level, as well as IGF-1 bioactivity. Osteopenia and osteoporosis are recognized as serious
It is suggested that the resistance to GH in AN can complications in AN, which could have an impact on
be mediated by fibroblast growth factor 21 (FGF21).152 quality of life. Chronic malnutrition observed in anorex-
FGF21 is a hormone that is induced by fasting and exerts ics influences bone metabolism, bone mineral density
diverse beneficial effects on energy balance and insulin (BMD), and fracture incidence. Published data indicate
sensitivity.156 In animal models, FGF21 causes resistance that changes in bone mass are not fully reversed after
to GH in the liver by reducing the active form of signal nutritional rehabilitation in AN and might persist over a
transducer and activator of transcription 5 (STAT5), an lifetime, conferring the high cumulative risk for fracture
important mediator of GH action.157 In AN, elevated of 57% for a follow-up of 40 years after diagnosis.165
plasma concentration of FGF21 has been demonstrated. The BMD of different parts of the skeleton (e.g., lumbar
Moreover, FGF21 was associated positively with GH, spine, femoral neck, hip) estimated by dual-energy x-ray
and inversely with IGF-1, which indirectly supports the absorptiometry (DXA), is lower in anorexics, with the
hypothesis that FGF21 can be a mediator for GH resis- highest prevalence of osteopenia/osteoporosis observed in
tance in AN.152 the lumbar spine. Z-score compares the individual’s bone
Circulating prolactin is usually unchanged in AN and density to the mean for age and gender, whereas T-score
may be reduced in BN. Prolactin responses to serotoner- compares it to the mean bone density for young adults.166
gic challenges are diminished in both AN and BN,158-160 The prevalence of osteopenia was reported to be 92%
suggesting decreased CNS serotonergic neurotransmitter and osteoporosis 32% in adult women with AN.167 In
function.115 Circulating melatonin has been reported as adolescent girls, lumbar spine Z-scores of <–1 occur in
both unchanged and increased in AN and as unchanged 41% of anorexics, and Z-scores of < –2 are present in
in BN.161 9%, compared to 19% and 2%, respectively, in con-
trols.168 Optimal bone mineralization is not achieved in
Insulin Sensitivity anorexics. Importantly, the vitamin D and PTH levels are
One of the cardinal features of AN is a significant loss of normal in AN, indicating that other factors than vitamin
adipose tissue. Adipose tissue is considered to be an active D deficiency or primary hyperparathyroidism are respon-
organ expressing and secreting a variety of bioactive sub- sible for low bone mass in AN. The pathogenesis of bone
stances that could influence metabolism, insulin sensitiv- loss in AN is not clearly elucidated. In adult women with
ity, and energy expenditure. It is generally accepted that AN, both impaired bone formation and increased bone
adipose tissue plays an important role in the pathogen- resorption have been reported together with altered bone
esis of insulin resistance. An example is obesity, which microarchitecture, indicating that factors in addition to
is associated with insulin resistance and thus increased low estrogen are responsible for the low bone mass.169
risk for type 2 diabetes mellitus. However, the lack of Low lean body mass; the marked deficiency of adipose
adipose tissue observed in lipodystrophic syndromes is tissue; duration of amenorrhea; decrease in estrogen, tes-
also accompanied by extreme insulin resistance, which tosterone, leptin, IGF-1, and insulin; and increase in cor-
emphasizes the significance of fat tissue in energy homeo- tisol and PYY are recognized as a factors contributing to
stasis. This raises the question of whether the significant low bone mass in AN.166-170 Bone mass in anorexics is
reduction of fat tissue observed in AN has an impact on also influenced by the age of diagnosis; adult women who
glucose metabolism. Metabolic abnormalities in anorexic develop AN during adolescence have lower BMD in com-
patients are not clear. Studies regarding insulin sensitiv- parison to those who develop AN in adult life, indicating
ity in anorexic patients have conflicting results. Insu- the importance of the pubertal age for bone formation.166
lin-stimulated glucose disposal has been reported to be Taking into account the problem of high risk for
normal,162 decreased,163 or enhanced164 in AN. More- fracture in women with AN, several therapeutic strat-
over, data concerning nonoxidative glucose metabolism, egies have been studied to prevent or delay the bone
which is reflected mainly in muscle glycogen synthesis, loss in anorexics. Treatment with vitamin D, calcium,
differ between studies; diminished163 and normal non- oral estrogen, oral contraceptives, dehydroepiandros-
oxidative pathways of glucose metabolism in AN have terone sulfate, or testosterone has been proven to be
been reported.162 The inconsistent results of these studies ineffective in increasing bone mass in AN (reviewed in
may be attributed to differences in the techniques used 166,170).166,170 Treatment with supraphysiologic doses
for evaluating insulin action and/or characteristics of of rhGH also did not influence the markers of bone for-
the studied groups. Notably, the longer duration of the mation. The intervention that had an impact on mark-
disease, which reflects prolonged severe starvation and ers of bone formation and improved BMD was therapy
with rhIGF-1.171,172 Of note, in the study performed with TABLE 29-6 Central Nervous System
adolescent anorexics, the rhIGF-1 was administered for 9 Neuropeptide Disturbances in Anorexia Nervosa
days and markers of bone formation were estimated.172 and Bulimia Nervosa
However, in a randomized study performed with adult
AN women, 9 months of rhIGF-1 administration was Anorexia Bulimia
effective in increasing bone density. Furthermore, bone Nervosa Nervosa
density increased to the greatest extent in the group in CSF neuropeptide Y ↑ ↔
which rhIGF-1 was combined with oral contraceptives, Plasma neuropeptide Y ↑ ↑
suggesting that oral contraceptives may augment the CSF peptide YY ↔ ↔
IGF-1 effect on bone mass.171 A recent study showed ↑ ↑ During
that a physiologic dose of oral or transdermal estrogen absti-
nence
increases BMD in adolescent anorexics.173 Additionally, Plasma peptide YY ↑ ↔
a randomized placebo-controlled study demonstrated Plasma ghrelin ↑ ↑
the efficacy of the bisphosphonate, risedronate, in adult Plasma leptin ↓ ↓
women with anorexia nervosa, however bisphosphonates CSF leptin ↓ ?
Plasma adiponectin ↑ ↑
should be used with caution in women of reproductive ↓ ?
age.174 Review of the data indicates that nutritional reha- Plasma macrophage inhibitory cytokine - 1 ↑ ?
bilitation with sustained weight recovery accompanied by Plasma cholecystokinin ? ↓
restorations of regular menses are the strongest factors CSF cholecystokinin ? ↓
influencing improvement in bone mass.175 CSF β-endorphin ↓ ↓
CSF dynorphin ↔ ↔
The effect of reduced caloric intake on these endocrine CSF vasopressin ↑ ↑
systems has been studied in healthy individuals.176,177 Plasma brain derived neurotrophic factor ↓ ?
When healthy women were starved, plasma gonadotro-
↑, Increased; ↓, decreased; ↔, unchanged; ?, insufficient or conflicting
pin concentrations declined. The women also experienced data.
increased circulating concentrations of cortisol and GH
and decreased plasma T3 concentrations despite normal
plasma T4—the “euthyroid sick syndrome” hormone and neuromodulators, including monoamines and neu-
profile. The endocrine abnormalities associated with star- ropeptides that influence hunger and satiety.8,9,129,179
vation in the healthy female subjects reversed with the Compounds such as norepinephrine, serotonin, insulin,
resumption of normal eating. opioids, NPY and PYY, leptin, CRH, vasopressin, and
The endocrine changes in both AN and BN revert to the orexins/hypocretins contribute to regulating the rate,
normal with successful treatment of these illnesses, indi- duration, and size of meals, as well as the selection of
cating that the endocrine changes are “state” markers carbohydrates and protein.180-182
of the metabolic stress of starvation and malnutrition. Neuropeptides were initially determined to be regula-
It should be emphasized that in addition to its effects tors primarily of hypothalamic functions such as food
on hormone secretion, starvation can lead to abnormal and water consumption and metabolism, sexuality, sleep,
psychological states. Semistarvation of male conscien- body temperature, pain sensation, and autonomic func-
tious objectors to military service was associated with tion. These compounds also have been localized to other
increased irritability, labile mood, depression, decreased areas of the CNS besides the hypothalamus and pituitary
concentration, decreased libido, and decreased motor gland, where they appear to regulate complex human
activity,178 and starvation and malnutrition can exagger- mental functions such as mood, obsessionality, attach-
ate the comorbid psychiatric symptoms of AN and BN. ment formation, and risk-taking and addictive behaviors.
These changes reinforce the concept of starvation-related Some of the behavioral disturbances occurring during
“state” changes influencing both the behavioral and the starvation therefore may be related to alterations in func-
endocrine aspects of eating disorders. tion of neuropeptides throughout the CNS. These peptide
systems work together multiply in overlapping CNS path-
CENTRAL NERVOUS SYSTEM–RELATED ways that influence the spectrum of energy balance states.
NEUROPEPTIDES, ADIPOCYTOKINES, AND Table 29-6 lists the major neuropeptide disturbances that
occur in AN and BN.8,9,118,129,134,183-186 These changes
GASTROINTESTINAL HORMONES represent an adaptive profile to weight loss specific to AN
Since the 1980s, the realization has evolved that the and are not present in constitutionally lean women.187
peripheral hormonal disturbances in AN and BN are a
consequence of the malnutrition associated with starva- Neuropeptide Y and Peptide YY
tion and bingeing, rather than being etiologic. Contem- These phylogenetically and structurally related peptides
poraneously, an understanding of how CNS neuronal share the same receptor family (Y1, Y2, Y4, Y5) and are
pathways contribute to starvation-induced alterations among the most potent stimulants of feeding behavior
in peripheral hormonal secretion has developed. The in animals, particularly for carbohydrate-rich foods.129
mechanisms for controlling food intake and energy NPY occurs in high concentrations in limbic structures,
homeostasis involve a complex interplay among periph- including the hypothalamus, and is present throughout
eral (taste, local autonomic influences on GI/neuropep- the cerebral cortex.188 NPY-producing cells in the arcu-
tides, vagal afferent nerves) and CNS neurotransmitters ate nucleus of the hypothalamus co-express AGRP and
are inhibited by leptin. NPY increases during hunger, falls treatment. Abnormally elevated CNS PYY activity in the
during meals, and acts on the paraventricular nucleus to abstinent bulimic may contribute to a persistent drive
mediate increased eating and reduce energy expenditure. toward bingeing, particularly a desire for sweet, high-
Its effect is counteracted by CRH, and a dynamic equilib- caloric foods.
rium between NPY and CRH neuronal activity appears
to be an important regulator of food intake. The Y1, Y2, Leptin
and Y5 subtypes of NPY receptors have been implicated Leptin is secreted primarily by adipocytes, but it can also
in the regulation of feeding.188 be found in other tissues like the placenta, testes, ova-
In contrast, PYY occurs in lower concentrations in the ries, hypothalamus, pituitary gland, and other organs.191
CNS, caudal brainstem, and spinal cord. PYY occurs in Leptin receptors (OB-R) are located throughout the
two forms and is primarily located in endocrine cells of body, suggesting that leptin could play a role in the regu-
the lower GI tract, where it helps mediate motility and lation of different processes. The primary role of leptin is
function. PYY1-36 is strongly orexigenic. PYY3-36, on to provide the CNS with a signal of the state of the body
the other hand, has particular affinity for the Y2 recep- energy balance, which helps to control appetite and food
tor, it increases in response to meals, and its actions are to intake, and to maintain a stable body weight. Current
decrease appetite and reduce food intake.189 data indicate that leptin is physiologically more impor-
Intracerebroventricular (ICV) NPY administration in tant as a sensor of energy deficiency rather than energy
animals produces many of the physiologic and behavioral excess.192 Leptin influences the appetite by inhibiting
changes associated with AN, including gonadal steroid- orexigenic pathways mediated by neurons expressing the
dependent effects on LH secretion, suppression of sexual melanocortin antagonists AGRP and NPY. Leptin regu-
activity, increased CRH in the hypothalamus, and hypo- lates energy balance by influencing fuel metabolism and
tension.129 Underweight AN patients have elevated CSF promoting fat oxidation in skeletal muscles and prevent-
NPY, likely a result of their malnourished status. In con- ing lipid accumulation in adipose tissue.191 Replacement
trast, such patients, whether underweight or recovered, therapy with leptin in patients with congenital leptin
have normal CSF PYY concentrations. CSF NPY returns deficiency and patients with lipodystrophy markedly
to normal with recovery, although patients with amenor- improved their insulin sensitivity and reduced hepatic
rhea may continue to have higher CSF NPY concentra- steatosis.193,194
tions. Elevated CSF NPY is not an effective stimulant of In rodents, defects in the leptin gene coding sequence,
feeding in underweight anorexics, as evidenced by their resulting in leptin deficiency and obesity, and defects in
resistance to eating and weight gain. Anorexics typically leptin receptors are associated with obesity. Treatment
display an obsessive and paradoxical interest in dietary with recombinant leptin reduces fat mass in both obese
intake and food preparation, and it may be that increased and normal-weight animals in a dose-dependent manner.
NPY activity in extrahypothalamic areas of the CNS con- In humans, serum leptin concentrations are positively cor-
tributes to these cognitions and behaviors. related with fat mass in individuals in all weight ranges.
ICV PYY administration in rats causes massive food Women tend to have higher serum leptin than men of the
ingestion to which tolerance does not develop, which same weight, presumably because of their higher propor-
prompted speculation that increased CNS PYY activity tion of body fat.195 Obesity in humans is not thought to be
may contribute to bulimia. CSF PYY concentrations in a result of leptin deficiency per se, but obesity may be asso-
normal-weight bulimic women when bingeing and vom- ciated with leptin resistance.195 Malnourished and under-
iting were similar to those of controls,129 whereas CSF weight AN patients have significantly reduced plasma and
PYY was significantly elevated in bulimic women after 1 CSF leptin concentrations compared with normal-weight
month of abstinence from bingeing and vomiting, com- controls,184,196-198 implying a normal physiologic response
pared to healthy volunteer women and AN patients. CSF to starvation. Reduced plasma/CSF leptin ratio has been
NPY concentrations were normal in the bulimic women, found in anorexics compared with controls, suggesting
in contrast to the elevated CSF NPY concentrations in that the proportional decrease in leptin with weight loss
the anorexic women. Plasma NPY and PYY concentra- is greater in plasma than in CSF. As in normal control
tions in AN and BN patients were not different from women, plasma leptin concentrations in anorexics are pos-
controls.190 In another study, plasma PYY in AN was itively correlated with body weight and fat mass, and they
significantly elevated.89 It should be noted that plasma are negatively correlated with physical activity.199 As men-
concentrations of these peptides do not necessarily accord tioned previously, leptin acts via its own receptors. The
with their CSF concentrations and may have peripheral soluble leptin receptor (sOB-R) is the main leptin-binding
effects unrelated to the CNS.9 For example, AN patients protein, and the ratio of serum leptin to sOB-R provides
may have normal CSF PYY concentrations, as noted ear- the measure of free leptin index (FLI), which is postulated
lier, but they also may have elevated plasma PYY concen- to be a more accurate determinant of leptin action.200 A
trations, which can contribute to the osteoporosis noted markedly reduced plasma leptin level with high plasma
in these individuals.86-89 concentration of sOB-R and lower FLI in AN have been
It is not known why CSF PYY is normal in bulimics demonstrated.201 This suggests that high sOB-R in AN
with chronic bingeing and vomiting and becomes ele- may reflect the upregulation of the sOB-R to suppress
vated after a period of abstinence. Whatever the cause, leptin action during energy deficiency. The weight recov-
this disturbance is of potential importance. Normal- ery in anorexic patients was connected with a decrease in
weight bulimia carries a high recidivism rate despite plasma sOB-R level with concomitant increase in plasma
total leptin level, but not with FLI. It should be noted that
menstrual recovery, but not weight recovery alone, was Adiponectin
associated with a significant increase in FLI.202 This sug- Adiponectin also is secreted by adipose cells.185 Circulat-
gests that the observed increase in FLI may indicate the ing levels are two to three times higher in women than in
important role played by free leptin in menstrual recov- men. It exists in three forms made up of different num-
ery in AN. During refeeding in AN patients, CSF leptin bers of trimers. Several studies indicate that adiponectin
concentrations increase to normal values before full weight has insulin-sensitizing, anti-atherogenic and anti-inflam-
restoration,184,202,203 possibly as a consequence of the rela- matory properties.209-212 The globular form of adipo-
tively rapid and disproportionate accumulation of fat dur- nectin appears to increase muscle sensitivity to insulin
ing refeeding, which could contribute to the resistance to by increasing fatty acid oxidation, similar to the effect
weight recovery. Preliminary evidence suggests that hyper- of leptin. It has also been reported that plasma adipo-
leptinemia is associated with an increased risk for recurrent nectin was positively correlated with glucose oxidation
weight loss204; higher plasma leptin level at the beginning and negatively correlated with lipid oxidation during
of the recovery period was a predictor for poor outcomes 1 hyperinsulinemia.213 Unlike leptin, however, circulating
year later in anorexic patients.204 This indicates the impor- adiponectin is inversely correlated with fat mass, being
tance of leptin response to weight gain in the prediction of decreased in obesity, type 2 diabetes mellitus, and coro-
the long-term outcome in anorexic patients. nary heart disease.209,211,212 There does not appear to be
Patients with BN appear to have significantly decreased a direct relationship between circulating leptin and adipo-
serum leptin following an overnight fast.184 During sus- nectin, in that decreasing serum leptin by acute fasting or
tained recovery from BN, serum leptin remains decreased increasing it by administration of physiologic or pharma-
compared to controls matched on amount of body fat. cologic doses had no effect on serum adiponectin.214 On
This finding, along with persistently decreased thyroid the other hand, ghrelin impairs adiponectin expression by
activity and elevated ghrelin in recovered BN patients, adipocytes.215
may result in decreased metabolic rate and a tendency In AN, adiponectin levels were increased in spite
toward weight gain contributing to the preoccupation of the marked deficiency of adipose tissue.162,164,216
with body weight that is characteristic of BN. Plasma adiponectin correlated negatively with BMI and
Leptin plays a role in the reproductive function. In ob/ percent of body mass in AN patients.164 Less severely
ob mice, chronic leptin treatment restores puberty and malnourished patients with AN binge eating/purging
fertility.191 It is assumed that leptin acts as a signal trig- type displayed a relatively modest increase in circulat-
gering puberty, thus linking adiposity with reproductive ing adiponectin, whereas a more prominent rise in this
function.205 Furthermore, in humans leptin deficiency is adipokine was found in severely malnourished AN
associated with hypogonadotrophic hypogonadism and restrictive type individuals. Interestingly, in other stud-
delayed puberty, which resolves after leptin treatment.193 ies, adiponectin levels in anorexic patients were not dif-
The administration of leptin to women with relative leptin ferent from controls 201,217 or decreased.218 It has been
deficiency and hypothalamic amenorrhea restores the suggested that increased adiponectin levels might play
function of the hypothalamic-pituitary-gonadal axis.206 a role in maintaining energy homeostasis under energy
In some anorexic patients, amenorrhea may occur before shortage conditions.219 Interesting information comes
significant weight loss, and leptin may be the mediating from the refeeding study. Adiponectin levels in anorexic
hormone. Weight loss generally causes circulating leptin women after weight recovery were similar to those of
concentrations to fall in proportion to the loss of body fat lean healthy female adolescents.216 In another report,
mass, but acute, fasting-induced weight loss can provoke an anorexic patient who reached a life-threatening state
a fall in leptin disproportionately greater than would be showed the lowest adiponectin level.217 Concurrently
expected from the amount of fat lost. This suggests that with improved nutrition and weight gain, the adiponec-
under conditions of intense food deprivation, leptin may tin level increased gradually until the BMI was about
instigate metabolic responses before a significant weight 16 kg/m2 and then decreased subsequently, as would be
or fat loss has occurred. Studies in rats and in patients with expected in lean healthy subjects.217 These data suggest
AN207 have suggested that hypoleptinemia also can trig- that there might be an optimal fat mass for adiponectin
ger semi-starvation-induced hyperactivity. Reduced leptin secretion.217
concentrations appear to be a critical signal that initiates In patients with generalized lipodystrophy, a very low
the neuroendocrine response to starvation, including lim- adiponectin level is observed, which makes the argument
iting procreation, decreasing thyroid thermogenesis, and for an intrinsic defect in adipocyte function.220 In con-
increasing secretion of stress steroids. Hypoleptinemia is trast, in AN patients, despite low fat mass, high adipo-
the critical signal responsible for inhibition of kisspeptin nectin plasma levels have been reported,162,164,216,221 and
production in the arcuate region of hypothalamus. Kis- only critically malnourished AN patients have presented
speptin is a recently discovered factor responsible for with hypoadiponectinemia.217 This indicates that in AN
stimulation of GnRH neurons and involved in metabolic low adipose tissue mass is sufficient for adiponectin secre-
control of reproductive axis. The administration of leptin tion, and this adipocyte function is preserved. Even with
is known to upregulate kisspeptin expression in the hypo- all these data available, it is difficult to determine whether
thalamus. It could be an important mechanism explaining adiponectin plays a role in the pathogenesis of weight loss
inhibition of the hypothalamo-pituitary-gonadal axis in or whether changes of its concentration are a consequence
starvation.208 of chronic malnutrition in patients with AN.192
Adiponectin exerts an insulin-sensitizing effect. Despite in short-term meal initiation.230 Ghrelin is also involved
this, no relationship has been observed between adipo- in the long-term regulation of body weight, and its con-
nectin concentration and insulin sensitivity in AN,162,221 centration is low in obese individuals and high in lean
but in several studies increased insulin sensitivity was individuals.231 Plasma ghrelin levels are inversely corre-
accompanied by high adiponectin levels.164,221 lated with body weight and rise following weight loss in
Patients with BN also were found to have increased humans.231
circulating adiponectin concentrations, which were posi- Plasma total ghrelin levels are significantly elevated
tively correlated with the frequency of binge/vomiting in AN and return to normal level after weight recov-
episodes.222 In contrast, women with BED had reduced ery.232-235 On the other hand, ghrelin is not elevated
circulating adiponectin along with increased glucose, in constitutionally thin women with similar body mass
cholesterol, and triglycerides. In these patients, adipo- index as AN patients.233 Nutritional factors seem to play
nectin concentrations were not significantly related to the an important role in modulating ghrelin secretion. Fast-
frequency of their bingeing episodes. ing total ghrelin levels have been observed to decrease as
a result of meal intake236 and oral or intravenous admin-
Macrophage Inhibitory Cytokine-1 istration of glucose, but not through gastric distension
Another cytokine that could influence appetite is macro- by water.237 The postprandial ghrelin suppression could
phage inhibitory cytokine-1 (MIC-1), a member of the influence satiety perception and have an impact on modu-
transforming growth factor-β (TGF- β) superfamily. It is lating feeding behavior.192 A suppressive effect of glucose
expressed in various tissues, including activated macro- on acylated, nonacylated, and total ghrelin secretion was
phages and adipocytes.223 Clinical data show that MIC-1 observed in patients with AN in many studies.238,239 A
concentrations are elevated in patients with chronic decrease of plasma total ghrelin concentrations in AN
inflammatory conditions and in many types of cancer, thus subjects after a high-carbohydrate breakfast was also
suggesting a role for MIC-1 in the mediation of tumor- reported.240 However a loss of meal-induced decrease
induced anorexia and cachexia occurring in the late stages in plasma total ghrelin levels was also observed in AN,
of cancer.224 One of the possible mechanisms influencing suggesting an impaired suppression of hunger in this dis-
food intake is stimulation of anorexigenic pro-opiomel- ease.241 In humans, during a euglycemic hyperinsulinemic
anocortin (POMC) and inhibition of orexigenic NPY by clamp, circulating insulin levels similar to or higher than
MIC-1. There are two studies regarding plasma MIC-1 those occurring after meal ingestion have been reported
concentrations in AN consistently reporting an increased to suppress plasma concentrations of total, acylated, and
MIC-1 concentration in anorexic patients in comparison nonacylated ghrelin.242,243 In AN, an increased suppres-
to healthy controls.225,226 In one of the studies, partial sion of serum total ghrelin by hyperinsulinemia has been
realimentation significantly reduced serum MIC-1 con- observed.244 A marked decrease in serum total ghrelin
centrations in AN patients, but they still remained sig- was demonstrated in AN subjects and lean women, but
nificantly higher compared with controls.225 Additionally, the fall in serum total ghrelin was significantly higher in
it was observed that serum MIC-1 concentrations in AN AN in comparison with lean subjects. No significant dif-
patients correlated positively with the duration of the ill- ferences in insulin sensitivity between AN patients and
ness. In the other study, it was observed that hyperinsu- controls have been reported. In multiple regression analy-
linemia increased MIC-1 concentrations in AN but also sis, only fasting total serum ghrelin and the presence of
in obese and normal-weight women.226 It is hypothesized AN, but not insulin sensitivity, were independent predic-
that an increase in MIC-1 in AN might act as an addi- tors of the fall in serum total ghrelin during the clamp.
tional satiety signal and contribute to weight loss. These data suggest that this effect might be specific for
AN, however; its mechanism remains unclear. Increased
Ghrelin suppression of total serum ghrelin by insulin might lead
Ghrelin was discovered to be the endogenous ligand for to an increased and more rapid feeling of satiety in AN
the growth hormone (GH) secretagogue-receptor type 1a women.244 Fasting plasma ghrelin also has been reported
(GHS-R 1a).227-229 The stomach is the primary source of as elevated in BN patients compared to controls with sim-
circulating ghrelin, but it is also produced in small amounts ilar body mass index, suggesting that the abnormal eat-
by the CNS and other peripheral tissues.227-229 In turn, its ing behavior (bingeing and purging) influences circulating
secretion is inhibited by GH. Plasma total ghrelin includes ghrelin, as it can in the bingeing and purging subtype of
acylated and nonacylated ghrelin.227 The active form, acyl- AN.245,246 Ghrelin administration to medically ill patients
ated ghrelin, is a 28–amino acid peptide that contains an led to improved appetite, body composition, and muscle
n-octanoylated serine 3 (Ser-3) residue that is essential for wasting.247 Some researchers have shown that ghrelin
its action.229 Acylated ghrelin is a stimulator of GH release, administration to patients with AN has little influence on
but the major physiologic role of acylated ghrelin appears their appetite.248 Further studies demonstrated that AN
to be the control of food intake and energy homeostasis.229 subjects are sensitive to the appetite- stimulating effects
Ghrelin antagonizes the action of leptin, strongly stim- of exogenous ghrelin.249
ulates feeding and weight gain by promoting NPY and
AgRP, and has a number of other central and peripheral Cholecystokinin
neuroendocrine and metabolic actions. Circulating levels Cholecystokinin (CCK), secreted by the GI tract in
of ghrelin decrease with feeding and increase before food response to food intake,184 is known as the satiety hor-
intake. Ghrelin peaks before meals, suggesting its role mone250 because it is thought to signal satiety to the
CNS via vagal afferents. It is the most abundant peptide CRH also has central effects beyond the HPA axis; ICV
in the human brain.251 Exogenously administered CCK administration of CRH to animals produces physiologic
reduces food intake in humans. High postprandial levels and behavioral changes associated with AN, including
of CCK have been observed in girls with AN and may hypothalamic hypogonadism, decreased sexual activity,
aggravate the course of this disease by intensifying nau- decreased feeding behavior, and hyperactivity.129,184 The
sea and vomiting.252 To date, however, studies of CCK in anorexigenic action of leptin may be mediated at least
patients with AN have been inconsistent in their findings, partially through CRH.265 The anorexic activity of sero-
reporting normal or increased plasma CCK.253 A recent tonergic drugs appears to be through activation of POMC
study, which utilized a highly specific radioimmunoassay neurons in the arcuate nucleus, a circuit that is tonically
for plasma CCK demonstrated basal and postprandial regulated by leptin.266
plasma CCK levels in AN similar to controls.253 With an
initial weight gain of about 2 kg, fasting and postmeal Vasopressin and Oxytocin
CCK levels increased significantly but decreased again In addition to the effects of vasopressin on HPA axis reg-
with further weight improvement. This suggests that the ulation and free-water clearance by the kidney and the
higher plasma CCK level in the early phase of nutritional effects of oxytocin during the puerperium, these struc-
rehabilitation might be responsible for the premature feel- turally related neuropeptides are distributed throughout
ing of satiety in AN patients and could partially explain the CNS and function as long-acting neuromodulators of
the difficulties in increasing food intake at the beginning complex behaviors. The effects of vasopressin appear to
of weight recovery.253 It has been proposed that this phe- be reciprocal to those of oxytocin. Central administra-
nomenon be called the “hunger trap.” Adaptation of CCK tion of vasopressin to rats enhances memory consolida-
to low food intake in anorexic patients limits weight gain tion and retrieval, whereas administration of oxytocin
by increasing satiety even with moderate food intake.253 disrupts memory.129
Only with further weight improvement does the CCK In addition to abnormally high CSF vasopressin con-
release return to the normal level. In contrast, patients centrations123 and impaired osmoregulation of plasma
with BN appear to have reduced plasma, CSF, and lym- vasopressin,267 AN patients have reduced CSF oxytocin
phocyte CCK concentrations and diminished CCK secre- concentrations and impaired plasma oxytocin responses
tion following a test meal.254-256 It has been suggested to stimulation.129 These abnormalities tend to normalize
that patients affected by BN may suffer from an impaired after weight restoration, suggesting they are secondary
feeling of satiety; that is, the lack of negative feedback to to malnutrition or abnormal fluid balance, or both. In
terminate a meal could be responsible for binge eating. underweight anorexics, low CNS oxytocin might interact
In patients with BN, plasma CCK is decreased, and this with high CNS vasopressin to enhance the retention of
blunted postprandial CCK response may contribute to the cognitive distortions of the aversive consequences of eat-
diminished postingestive satiety that BN patients experi- ing, thereby reinforcing these patients’ perseverative pre-
ence.257 According to the published data, CCK release is occupation with the adverse consequences of food intake.
dependent on the macronutritent composition of food Lower postprandial oxytocin secretion in AN is associ-
choices, with protein being the most potent stimulator of ated with symptoms of anxiety and depression.268
the CCK response.258 A 2-week study involving patients Patients with normal-weight BN were found to have
with BN and BED demonstrated that the addition of a elevated CSF vasopressin concentrations but normal CSF
high-protein supplement to the diet resulted in less fre- oxytocin, both on admission and after 1 month of nutri-
quent binge eating episodes. It is suggested that CCK may tional stabilization and abstinence from bingeing and
mediate the effect of protein on satiety, and, thus, increas- purging.123 In these patients as well, high CNS vasopres-
ing the proportion of protein in the diet decreases the fre- sin might contribute to their obsessional preoccupation
quency of binge-eating episodes.259 with the aversive consequences of weight gain. Some
recovered bulimics may have continued elevation of CSF
Melanocortin and Corticotropin-Releasing Hormone vasopressin, perhaps related to a lifetime history of major
The central melanocortin system is important in the regu- depression.269
lation of energy balance.260,261 The key POMC-derived
alpha-melanocyte-stimulating hormone (α-MSH) is one Opioid Peptides
of the main anorexigenic anorexic mediators. The POMC CNS opioid agonists increase food intake, and opioid
gene is expressed in the hypothalamic arcuate nucleus. antagonists decrease food intake,123 suggesting that these
There are several transmembrane receptors for POMC- compounds may mediate some aspects of AN.123,129
derived molecules. Suppression of food intake is mainly Although assessment of brain opioid activity in vivo in
due to activation of MC4R, which is expressed in brain. humans is problematic because of the many CNS neuro-
The key MC4R agonist is α-MSH, and the antagonist is peptides with opioid activity and the multiplicity of CNS
AgRP, which has orexigenic activity.262 Plasma AgRP has opioid receptors, the CSF concentrations of some opi-
been reported as increased in AN, but plasma α-MSH has oid peptides have been determined in anorexic patients.
not been different from control values.263 Underweight anorexics were found to have significantly
The hypercortisolism in AN and BN is most likely reduced CSF β-endorphin concentrations compared with
due to hypersecretion of CRH, which is most probably a healthy volunteers.129 CSF β-endorphin concentrations
response to weight loss per se; the change in CRH is likely remained significantly below normal after short-term
mediated through the central melanocortin system.264 weight restoration but returned to normal after long-term
weight restoration. A downregulation in opioid circuits or that the disturbances are secondary to malnutrition or
a hyposensitivity at receptor sites could lead to a passive weight loss, or both, and are not etiologic, although once
or active resistance to eating. CSF β-endorphin concentra- established, the disturbances may perpetuate some of the
tions also have been shown to be reduced in women with symptomatology, providing a biological dimension to
BN.129 CSF dynorphin concentrations have been reported the question why many anorexics and bulimics cannot
as normal in all stages of AN and BN.123,129 easily reverse their illness. Secondary symptoms such as
A disturbance in CNS opioid function also may con- dysphoric mood, obsessions, and compulsions related to
tribute to the neuroendocrine abnormalities in AN and behaviors other than eating may be exaggerated by CNS
BN (e.g., disturbances in HPA and pituitary-gonadal axis neuropeptide alterations and cause the primary illness to
function).123,129 Brain opioid pathways inhibit ACTH be more refractory to treatment. That the neuropeptide
and cortisol release in humans, and they suppress pul- disturbances eventually become normal during long-term
satile gonadotropin secretion in rats and in sexually recovery suggests that treatment of AN and BN must be
mature humans. Underweight anorexics frequently have sustained for months after weight normalization to rec-
a blunted response of LH secretion to opiate antagonists, tify the many physiologic disturbances.
and weight restoration tends to normalize this response.123
The failure of opioid antagonists to increase LH secre- TREATMENT
tion in underweight anorexics suggests that another neu-
rotransmitter system (or systems) may be responsible for Treatment of the eating disorders continues to be com-
this neuroendocrine disturbance. plex and difficult. In a 20-year follow-up of AN patients,
about one third rated their outcomes as good, one third
Brain-Derived Neurotrophic Factor as intermediate, and one third as poor.280 Cognitive-
Along with the peripheral endocrine changes in pituitary behavioral, educational, psychodynamic, and psycho-
and target-gland hormones in AN and BN, multiple neu- pharmacologic treatments have been used with varying
ropeptide disturbances occur when patients engage in degrees of long-term success.281,282 As is often the case in
pathologic eating behaviors and become malnourished, the management of psychiatric patients, a combination of
as reviewed earlier. The list of neuropeptides involved therapies is used under the rationale that moderate suc-
continues to increase. cesses with individual treatments might be at least addi-
BDNF is widely and abundantly expressed in the central tive, if not synergistic in their overall effectiveness. The
nervous system.270 BDNF influences neuronal growth, dif- American Psychiatric Association practice guideline on
ferentiation, synaptic plasticity, and neuronal survival and the treatment of eating disorders discusses the spectrum
is also involved in cognitive function, mainly in the pro- of options and emphasizes developing individualized
cesses of learning and memory. Several lines of evidence treatment plans for weight restoration in the least restric-
support the essential role played by BDNF in eating behav- tive setting that is likely to be effective.281
ior and body weight regulation. BDNF knockout mice There have been more large-scale, randomized, con-
develop obesity and hyperphagia and hyperleptinemia.271 trolled clinical treatment trials in BN than in AN or
In db/db mice, central or peripheral BDNF administration BED.25,283-286 Controlled treatment studies of AN have
has resulted in a decrease in food intake and an increase shown the efficacy of various psychological therapies in
in energy expenditure, and has corrected hyperglyce- promoting weight gain in acutely ill patients287-290 and in
mia and hyperinsulinemia.272,273 Data regarding serum preventing relapse following restoration of normal body
BDNF concentrations in AN patients are conflicting. weight.290,291 Substantial improvement in body mass and
Some researchers have reported a normal serum BDNF psychosocial adjustment can be achieved in many anorexic
concentration,274,275 whereas other reports showed lower subjects through cognitive-behavioral, psychoeducational,
serum BDNF in AN patients versus control subjects.276-278 and family therapy techniques, with or without dietary
However, the results of meta-analysis showed significantly counseling. Therapeutic gains have not been as robust in
decreased plasma BDNF in AN.279 Lower serum BDNF patients with more chronic disability. Specialized eating
was observed in bulimic patients. Serum BDNF corre- disorders hospital units offer combinations of enforced
lated positively with BMI and plasma leptin concentra- weight-gain regimens along with a range of psychosocial
tions in anorexic patients, while negative correlations were treatments. Compulsory in-hospital treatment often is
observed between BMI and some features of anorexic effective over the short term and can achieve a weight gain
behavior (i.e., “drive for thinness” and “body dissatis- of 2 to 4 pounds per week.292-296 Recent data concerning
faction” and “Global Severity Index”).274 The significant nutritional therapy indicate that the composition of mac-
correlation of serum BDNF with some psychopathologic ronutrients (less than 40% calories from carbohydrates) is
features of the disorder has been demonstrated.275,276 Par- important in preventing refeeding syndrome in anorexic
tial weight recovery in AN was not accompanied by an patients.297 Moreover, the higher-calorie diets may have a
increase in serum BDNF.274,276 Long-term weight recovery beneficial effect on weight recovery in AN.298
caused an increase in serum BDNF in AN patients in com- Serotonin uptake–inhibiting antidepressant drugs
parison to severely malnourished subjects,274,277 which (SUIs) also show some promise. As noted earlier, seroto-
indicates that complete weight restoration is needed to nergic neurotransmission appears to be compromised in
increase BDNF levels in anorexic patients. eating disorders, including a possible underlying hypersen-
The slow correction of these neuropeptide distur- sitivity in AN that may be partially ameliorated by self-
bances with weight restoration in AN and BN implies starvation and a subsensitivity in BN that is responsive to
SUI-mediated increases in serotonergic activity.296,299,300 depression.284 Low serum T4 may predict poor treatment
SUIs are relatively ineffective in weight-reduced AN outcome.309 Combined treatment may have an advantage
patients,300 possibly because of reduced intake of trypto- over CBT alone in reducing binge eating and purging, but
phan, the amino-acid precursor of serotonin, with con- the incremental benefit is modest. Remaining questions
sequently diminished serotonin production. After weight include the length of continuation of psychosocial and
restoration in AN and improved serotonin production, SUIs antidepressant therapies needed to sustain gains achieved
such as fluoxetine possibly can reduce obsessionality and during acute treatment, the mechanisms underlying the
the incidence of relapse, although a large, well-controlled possibly synergistic effects of combined treatment, the
study comparing fluoxetine and placebo in weight-restored predictors of differential treatment outcomes, the reasons
patients found no significant benefit to medication during for a more rapid decay of acute antidepressant treatment
the year following nutritional rehabilitation.299 Atypical effects in BN compared to major depression, and the
neuroleptics also may have some utility, not only to reduce anticipated effects of crossing over to alternative modali-
anxiety and delusional thinking, but also because they ties of treatment when initial treatment fails.284
promote weight gain.301,302 A meta-analysis concerning Pharmacotherapies for BED, as distinct from BN, also
treatment with antipsychotic drugs did not reveal the clear are being investigated. Antiepileptic drugs such as topi-
benefit of these drugs in anorexic patients.303 The bingeing ramate and zonisamide, serotonin/norepinephrine uptake
and purging subtype of AN may have a poorer prognosis inhibitors such as sibutramine, and antiobesity agents
that the restricting subtype, and weight restoration alone such as the lipase inhibitor orlistat have shown promise
is unlikely to be effective in the bulimic subtype of AN.304 in regard to weight reduction and reduction in binge eat-
Improved treatment of AN remains of great clinical and ing.310-315 Novel pharmacologic interventions for eating
public health importance, in that it is a chronic, relapsing disorders also are being evaluated, such as peptide hor-
illness with substantial and costly medical morbidity. Yet, mones, ghrelin agonists, NPY-1 and NPY-5 antagonists,
overall, no pharmacologic intervention for AN thus far orexin receptor antagonists, CRH-2 receptor antagonists,
has had a significant impact on weight gain or its psycho- histamine-3 receptor antagonists, MC4R antagonists,
logical features. Based on current evidence, managing AN β3-adrenoceptor agonists, serotonin-2A receptor antago-
patients only with medications is inappropriate and often nists, and GH agonists.314
associated with high dropout rates. The difficulties faced by clinicians in the treatment
Controlled treatment studies of BN have shown the of AN, BN, and BED are also impacted by the trends in
efficacy of both antidepressant medications284,285 and health care delivery that reduce access to extended care in
psychological therapies, especially cognitive-behavioral specialty inpatient and outpatient facilities. These external
therapy (CBT), in reducing both the frequency of binge- forces may compromise efforts to reverse the debilitating
ing and purging and the severity of body dissatisfaction, and sometimes life-threatening behavioral and biological
pursuit of thinness, and perfectionism.284,305-307 How- symptoms and sequelae of these illnesses. Endocrinolo-
ever, medication alone rarely produces full remission; gists are best advised to seek psychiatric specialist consul-
many patients require multiple medication trials before tation early in the evaluation of patients with these eating
achieving clinically significant improvement. There have disorders, not just to aid in their differential diagnosis
been significant dropout rates in clinical trials, and relapse but, importantly, to help plan the complex therapeutic
during continuation therapy is high. approaches currently known to offer the best outcomes.
CBT alone produces higher rates of full remission in
BN than does antidepressant monotherapy.284 Even so, Acknowledgements
40% to 60% of patients receiving CBT remain symptom- The authors are grateful to Melita L. Daley and Carolyn
atic to some degree after acute treatment.284,285 Interper- Nguyen for their contributions to this chapter in previous
sonal therapy (IPT) that strictly avoids direct reference editions.
to abnormal eating attitudes or dietary behaviors may
achieve long-term benefits in controlling binge eating and • For your free Expert Consult eBook with biblio-

purging equal to those obtained with CBT.308 graphic citations as well as the ability to take notes,
How long to continue treatment in BN once binge eat- highlight important content, search the full text, and
ing abates, in order to minimize relapse, remains undeter- more, visit http://www.ExpertConsult.Inkling.com.
mined. With antidepressant continuation therapy, the risk
for relapse may be higher than in patients with unipolar
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Anorexia Nervosa, Bulimia Nervosa, and Other Eating Disorders

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Anorexia Nervosa, Bulimia Nervosa, and Other Eating Disorders

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c h a p t e r

“A young woman thus afflicted, her clothes scarcely hanging together on

TABLE 29-2 DSM-5 Diagnostic Criteria for

threatening. The medical management of these cases

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