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Anorexia Nervosa is a disorder characterized by aberrant patterns of feeding behavior and weight
regulation. The patients suffer from disturbances in attitude toward weight and shape as well as their
body image and perception of their body shape. There is an inexplicable fear of weight gain and an
unrelenting obsession of fatness, even in the face of increasing cachexia. Patients refuse to maintain
body weight over a minimal normal weight for age and height and they exhibit denial of the seriousness of
this low body weight. In post-menarcheal females, there is an absence of at least the last three of her
Two subtypes of this disorder exist, the binge eating/purging subtype and the restricting subtype. The
patient suffering from the binge eating/purging subtype engages in recurrent episodes of binge eating or
purging behavior during the episodes of anorexia. The restricting subtype is characterized by scrupulous
restriction of food intake with the absence of the binge eating and purging
The cause of the disorder is presumed to be complex and multiply influenced by developmental, social,
and biological processes, but the exact interaction among these processes remains incompletely
understood. It is certain that cultural attitudes toward standards of physical attractiveness have
relevance to the psychopathy of eating disorders, but it is unlikely that the cultural influences in
pathogenesis are very prominent. For example, dieting behavior and striving to be thin are commonplace
in many industrialized countries but anorexia nervosa's lifetime prevalence among females is estimated
0.1% - 0.7% (Kaye, W.,2000).
In addition to this, numerous clear descriptions of anorexia date from the middle of the nineteenth
century, suggesting that factors other than our current culture have an etiologic role in the development
of the disorder (Klump, K., 2001). Anorexia has a relatively stereotypic clinical presentation, sex
distribution, and age-of-onset, which supports the possibility of some biological vulnerability, while
highlighting the fact that the genetic diathesis for eating abnormalities is likely to be highly polygenic with a
multitude of genetic traits contributing to its development (Klump, K., 2001). It has been suggested that
there may be a gradual accumulation of risk factors, which only manifest themselves during the stress of
adolescence (Karwautz, R., 2001).
These proposed risk factors appear to be both extrinsic and intrinsic. The extrinsic factors include
adverse experiences while the intrinsic focus on genetic vulnerability. They have been proposed to act
either as fundamental etiological risk factors (predisposing), as triggers for the illness (precipitating), or
to prolong and exacerbate the illness (maintaining). Due to the complexity, it is unlikely that each risk
factor can be classified in this way. Prospective studies which use a design sensitive to both genetic and
environmental factors will be the only way to clarify these issues (Karwautz,
Throughout the literature, a general agreement exists that the results of twin and family studies suggest a
genetic vulnerability to anorexia nervosa and model-fitting of data obtained from twin studies suggests
that non-shared factors, such as differential experiences and genes are of greater importance than
shared factors in anorexia nervosa (Karwautz, R., 2001).
Several developmental and early environmental factors seem to increase the risk of developing the
eating disorder. While the risk of pre-term birth and faddy eating in childhood have been shown to be
linked to partial cases of anorexia, parental and personal obesity, dieting in family members, and adverse
comments about weight/shape or eating were not seen to be antecedents for anorexia nervosa
(Karwautz, R., 2001). None of the risk factors implicated so far appear to be necessary or sufficient to
account for the development of anorexia nervosa. Inconsistent results highlight the need for additional
population-based twin studies to clarify findings and determine the generalizability of heritability estimates
from clinical samples (Klump, K., 2001).
Anorexia is widely assumed to have a complex, multi-factorial etiology, yet psychological theories of
pathogenesis have largely prevailed in explanatory paradigms which were presented in the recent
decades (Kaye, W.,2000). This disorder occurs frequently in association with Axis I psychiatric
disorders, mood and anxiety disorders in particular. These disorders have no evident connection to
cultural attitudes relating to body weight, and are commonly associated with biological disturbances in the
system as their cause. In addition, it has been suggested that there may be a gradual accumulation of
risk factors which only manifest themselves during the stress of adolescence (Karwautz, R., 2001) as
opposed to purely psychological causes for this disorder.
The stereotypical onset for anorexia nervosa coincides with the developmental changes which take
place during puberty. This occurrence has been hypothesized to be due to genetic relationships between
eating abnormalities and the ovarian hormones activated during puberty. A study was conducted
involving 11 year old cohorts were divided into pre- and postpubertal twin groups to more closely examine
the effect of puberty on the heritability of the characteristic traits and behaviors of anorexia (Klump, K.,
2001). The results demonstrated increased heritability in postpubertal relative to prepubertal twins who
were the same age provided strong evidence of potential pubertal activation of the heritability of eating
abnormalities that may be mediated by ovarian hormones. These findings are important for highlighting
not only developmental differences in genetic effects but also the potential role of ovarian steroids in the
heritability of the disorder (Klump, K., 2001).
In addition to the correlation between pubertal genetic activation, there has also been research involving
the association between Axis I psychological disorders and anorexia nervosa. One study in-particular
aimed to demonstrate the increased association between major depression and anorexia nervosa in
women (Wade, T., 2000). It was noted that in recent studies, lifetime major depression has been
reported in about 50% of the women with anorexia nervosa and the rates of major depression are
elevated in the first-degree relatives of women with anorexia nervosa. This co-morbidity has been
debated, and some authors contend that anorexia nervosa and major depression share a common
etiology, while others suggest that the liability for anorexia nervosa is distinct from that operating in the
transmission of affective disorders (Wade, T., 2000). A twin study was used in order to isolate the
phenotype of the subjects and to determine the effects of environment versus genetics. The interviewers
were blind to any information about the twins to avoid bias. To increase the statistical power of this study
of a disorder with such a low prevalence, a broad definition of anorexia nervosa was adopted. This
expansion of the definition of anorexia nervosa allowed the researchers to obtain useful estimates of the
genetic and environmental contributions to the liability of anorexia nervosa. The correlation was found to
be less than unity; therefore separate genes appear to contribute uniquely to the liability for anorexia
nervosa and major depression (Wade, T., 2000). This suggests that there is in fact a genetic component
in the development of anorexia, but the results of this study were claimed to be slightly ambiguous
(Wade, T., 2000). The causes of this ambiguity shall be discussed in the
Considering the abundance of results that lean toward a genetic component in the development of
anorexia nervosa, researchers have begun to directly examine the genetic influences through
association and linkage studies. Particularly, the relative influence of a specific gene or genetic marker
on the development of eating disorders was studied. This is accomplished by comparing the frequency of
the alleles from the parents to the children with anorexia. Linkage analysis is used to identify contributing
genetic loci by examining allele sharing among family members at several genetic markers across the
genome, examining all identified genetic markers in the genome (Klump, K.,
An additional strategy used to examine genetic influences utilizes association studies. There is evidence
linking anorexia to monoamine functioning, which has led researchers to target serotonin and
dopamine-related genes in association analysis. Several studies have shown an increase in the -1438/A
allele of the 5-HT receptor gene in anorexic women when compared with controls. However, additional
studies have failed to show significant associations in subjects with anorexia as well as increased allele
frequencies of the dopamine D3 and D4 receptor genes in anorexic relatives to the control subjects
(Klump, K., 2001).
The pathology of anorexia has been attributed to the roles of weight control, feeding, and energy
expenditure, which has led researchers to examine genes related to these processes and their influence
on the development of the disorder. Several studies have been conducted examining the genetic risk
factors involved in the development of anorexia nervosa disclosing a relation between a polymorphism in
the promoter region of the 5HT2A gene (-1438G/A) and the presence of anorexia (Karwautz, R., 2001).
This mutation results in a trait-related disturbance of serotonin that could contribute to restricted eating,
behavior over-control, and obsessive exactness.
Brain serotonergic systems have been reported to regulate eating behaviors. The pharmacological
enhancement of serotonin (5HT) transmission generally leads to increased satiety. This is supported by
evidence of reduction in meal size, rate of eating, and body weight. The brain's hypothalamic 5HT
pathways are involved in post-ingestive satiety, and pre-meal administration of 5HT agonist drugs has
been proven to decrease food intake (Nishiguchi, N., 2001).
These pharmacological studies appear to support the involvement of functional alteration of
neurotransmission due to genetic polymorphisms of serotonergic receptors in the modulation of eating
and the development of eating disorders, particularly anorexia nervosa (Nishiguchi, N., 2001). In addition
to these studies, numerous researchers have succeeded in replicating the original finding that the
frequency of the -1438A/G polymorphism was significantly higher in patients with anorexia than in control
subjects. Evidence against these findings, however, has also been reported; thus, the association is
controversial (Nishiguchi, N., 2001).
In addition to the investigations involving serotonergic receptors, researchers have also been exploring
the possibility of involvement of dopamine receptors in anorexia nervosa. Dopamine is suspected to be
involved in the physiology of the disorder, amenorrhea, and the anticipation of heeding in humans. It has
also been implicated in the clinical symptoms of hyperactivity, distortion of body image, and the reward
and reinforcement processes (7).
Reinforcement is considered to be an addictive feature that could constitute a core symptom of anorexia
nervosa, exemplified in the characteristic lack of control involved in the disorder. The dopamine receptor
(D3) gene is expressed in restricted limbic areas such as the nucleus accumbens and the island of
Calleja. This suggests that this dopamine receptor could be more specifically involved in the
pathogenesis of anorexia nervosa. The mesolimbic mesocortical dopaminergic circuits innervate the
ventral striatum, notably the nucleus accumbens, which is one of the essential substrates for reward and
reinforcement behavior (Bruins-Slot, L., 1998). Although the research leans toward involvement of the
D3 receptor in the development of anorexia, no significant difference was found between allellic
distribution of this polymorphism in anorexia nervosa and a control group. Two factors, small sample size
and the fact that the sample population was distinguished by the clinical specifications of anorexia
nervosa limit this conclusion (Bruins-Slot, L., 1998).
Additional studies suggest that several heritable characteristics are commonly co-morbid with anorexia
and may share genetic transmission with the disorder (Klump, K., 2001). These disorders include anxiety
disorder or traits, body weight, and possibly major depression. Anorexics also tend to exhibit high levels
of harm avoidance, stress reactivity, and negative emotionality. It has been speculated that phenotypic
similarities between these traits and the rigidly preserving, obsessional, and anxiety-reducing character
of the anorexic's dietary restraint may be based on shared genetic and environmental factors (Kaye, W.,
2000). The moderately heritable characteristics of these conditions suggest that etiologic relationships
may be genetic (Klump, K., 2001). This is because genetic rather than environmental influences seem to
underlie phenotypic and familial relationships. But the results also indicate the presence of other genetic
influences on eating abnormalities that are independent of genes influencing personality characteristics
(Klump, K., 2001).
One study inparticular researched the prevalence anorexia nervosa in a controlled family study.
Their goal was to uncover the relationship between anorexia and genetics as well as its
relationship with the personality traits described above. They found that a higher lifetime
prevalence of the disorder in first-degree relatives of probands than in first-degree relatives of
psychiatric and normal controls (Kaye, W.,2000). They also uncovered a higher prevalence of
the obsessional personality traits, suggesting that obsessional traits may manifest the effects of
a genotype that increases susceptibility to anorexia (Kaye, W.,2000).
A number of other family studies have provided a necessary step in determining whether the
disorder is genetic by establishing whether it clusters among biologically related individuals. In
general, these studies have found an increased rate of eating disorders in relatives compared to
control relatives. The findings from the largest and most reliable studies suggest a 7-12-fold
increase in the prevalence of anorexia in relatives of eating-disordered probands (Klump, K.,
2001). However, given that first-degree relatives share genes and environments, these studies
are unable to differentiate genetic versus environmental causes for familial clusters. The
researchers have turned to twin studies to disentangle genetic and environmental effects
(Karwautz, R., 2001).
Reviews of twins with anorexia have consistently found an increased concordance rate for
eating disorders in monozygotic twins when conpared to dizygotic (Bruins-Slot, L., 1998). The
vulnerability component of anorexia nervosa that can be attributed to genetic influences, has
been estimated around 76% using evidence from these studies. They are able to differentiate
genetic from environmental effects by comparing similarity for a trait disorder between identical
and fraternal twins. The heritability estimates are similar to those found in studies of
schizophrenia and bipolar disorder, suggesting that anorexia may be as genetically influenced as
disorders traditionally viewed as biological (Klump, K., 2001). Although this information seems
promising, the findings of twin studies are inconsistent and difficult to interpret. The estimates for
the heritability of liability to anorexia nervosa is be 0% to 70%. Methodological reasons for this
variability include issues of, definition of phenotype, diagnostic reliability, violation of the equal
environments assumption, and small sample sizes (Klump, K., 2001).
Together the results suggest significant genetic and non-shared environmental influence on
anorexic pathology and that findings from patient-based samples are generalizable to individuals
in the general population, despite the low prevalence of this disorder in the population (Klump, K.,
2001). This disorder is complex and probably results from an interaction of genetic and
environmental factors, and an aetiological study should include both parameters (Karwautz, R.,
2001). The best design would be a prospective study but a sample size of 20,000-10,000 would
be needed to obtain 100 cases of the disorder. Alternative strategies would be to sample high
risk groups, but such approaches would require the preliminary identification of appropriate
measure and risk factors from retrospective analysis (Karwautz, R., 2001).
Bruins-Slot, L., Gorwood, P., et. al. "Lack of Association between Anorexia Nervosa and D3
Dopamine Receptor Gene." Society of Biological Psychology, 1998.
Nishiguchi, N., Matsushita, S., et. al. "Association between 5HT2A Recpetor Gene Promoter
Region Polymorphosm and Eating Disorders in Japanese Patients." Society of Biological
Wade, T., Bulik, C., et. al. "Anorexia Nervosa and Major Depression: Shared Genetic and
Environmental Risk Factors." The American Journal of Psychiatry, 2000.
Klump, K., Miller, K, et. al. "Genetic and Environmental Influences on Anorexia Nervosa
Syndromes in a Population-Based Twin Sample." Psychological Medicine, 2001.
Karwautz, A., Rabe-Hesketh, S., et. al. "Individual-Specific Risk Factors for Anorexia Nervosa: A
Pilot Study Using a Discordant Sister-Pair Design." Psychological Medicine,
Klump, K., Kaye, W., et. al. "The Evolving Genetic Foundations of Eating Disorders." Psychiatric
Clinics of North America, 2001.
Kaye, W., Lilenfeld, L., et. al. "A Search for Susceptibility Loci for Anorexia Nervosa: Methods
and Sample Design." Society of Biological Psychiatry, 2000.
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