Anorexia nervosa

Anorexia nervosa is an eating disorder characterized by refusal to maintain a healthy body weight and an obsessive fear of gaining weight, often coupled with a distorted self image which may be maintained by various cognitive biases that alter how the affected individual evaluates and thinks about her or his body, food and eating. Persons with anorexia nervosa continue to feel hunger, but deny themselves all but very small quantities of food. The average calorific intake of a person with anorexia nervosa is 600-800 calories per day, but in extreme cases self-starvation is more extreme. It is a serious mental illness with a high incidence of comorbidity and the highest mortality rate of any psychiatric disorder.

It can affect men and women of all ages, races, socioeconomic and cultural backgrounds. Anorexia nervosa occurs in the ratio of 1:10 in males:females.

The term anorexia nervosa was established in 1873 by Sir William Gull, one of Queen Victoria's personal physicians. The term is of Greek origin: a (α, prefix of negation), n (ν, link between two vowels) and orexis (ορεξις, appetite), thus meaning a lack of desire to eat.

Signs and symptoms
A person with anorexia nervosa may exhibit a number of signs and symptoms, some of which are listed below. The type and severity vary in each case and may be present but not readily apparent. Anorexia nervosa and the associated malnutrition that results from self-imposed starvation, can cause severe complications in every major organ system in the body.

It should be noted that some of the possible signs listed below (Russell's sign, scarring of knuckles, purging/self-induced vomiting and use/abuse of laxatives, diet pills, i.e., and swollen cheeks/enlargement of the salivary glands) are signs primarily of bulimia, which is a condition that often occurs simultaneously with anorexia.

Causes
Studies have hypothesized that the continuance of disordered eating patterns may be epiphenomena of starvation. The results of the Minnesota Starvation Experiment showed that normal controls exhibit many of the behavioral patterns of anorexia nervosa when subjected to starvation. This may be due to the numerous changes in the neuroendocrine system, which results in a self perpetuating cycle. Studies have suggested that the initial weight loss such as dieting may be the triggering factor in developing AN in some cases, possibly due to an already inherent predisposition toward AN. One study reports cases of AN resulting from unintended weight loss that resulted from varied causes such as a parasitic infection, medication side effects, and surgery. The weight loss itself was the triggering factor.

Biological

 * Obstetric complications: various prenatal and perinatal complications may factor into the development of AN such as maternal anemia, diabetes mellitus, preeclampsia, placental infarction, and neonatal cardiac abnormalities. Neonatal complications may also have an influence on harm avoidance, one of the personality traits associated with the development of AN.
 * Genetics: anorexia nervosa is believed to be highly heritable, with estimated inheritance rates ranging from 56% to 84%.   Association studies have been performed, studying 128 different polymorphisms related to 43 genes including genes involved in regulation of eating behavior, motivation and reward mechanics, personality traits and emotion. Consistent associations have been identified for polymorphisms associated with agouti related peptide, brain derived neurotrophic factor, catechol-o-methyl transferase, SK3 and opioid receptor delta-1. In one study, variations in the norepinephrine transporter gene promoter were associated with restrictive anorexia nervosa, but not binge-purge anorexia. Recent studies have advanced the theory that the sex difference in incidence and the common onset at the age of puberty may reflect an abnormal response of the brain to anorexic (feeding suppressing) effects of the female sex hormone, estrogen.  This viewpoint has been recently supported by a report that abnormal forms of the estrogen receptor are more common in women with anorexia nervosa of the restricting type.
 * epigenetics: Epigenetic mechanisms: are means by which genetic mutations are caused by environmental effects that alter gene expression via methods such as DNA methylation, these are independent of and do not alter the underlying DNA sequence. They are heritable, as was shown in the Överkalix study, but also may occur throughout the lifespan, and are potentially reversible. Dysregulation of dopaminergic neurotransmission and Atrial natriuretic peptide homeostasis due to epigenetic mechanisms, has been implicated in various eating disorders. "We conclude that epigenetic mechanisms may contribute to the known alterations of ANP homeostasis in women with eating disorders."
 * serotonin dysregulation; particularly high levels in those areas in the brain with the 5HT1A receptor - a system particularly linked to anxiety, mood and impulse control. Starvation has been hypothesized to be a response to these effects, as it is known to lower tryptophan and steroid hormone metabolism, which might reduce serotonin levels at these critical sites and ward off anxiety. Other studies of the 5HT2A serotonin receptor (linked to regulation of feeding, mood, and anxiety), suggest that serotonin activity is decreased at these sites. There is evidence that both personality characteristics associated with AN, and disturbances to the serotonin system are still apparent after patients have recovered from anorexia.
 * Brain-derived neurotrophic factor (BDNF) is a protein that regulates neuronal development and neuroplasticity, it also plays a role in learning, memory and in the hypothalamic pathway that controls eating behavior and energy homeostasis. BDNF amplifies neurotransmitter responses and promotes synaptic communication in the enteric nervous system. Low levels of BDNF are found in patients with AN  and some comorbid disorders such as major depression.  Exercise increases levels of BDNF
 * leptin and ghrelin; leptin is a hormone produced primarily by the fat cells in white adipose tissue of the body it has an inhibitory (anorexigenic) effect on appetite, by inducing a feeling of saiety. Ghrelin is an appetite inducing (orexigenic) hormone  produced in the stomach and the upper portion of the small intestine. Circulating levels of both hormones are an important factor in weight control. While often associated with obesity both  have been implicated in the pathophysiology of anorexia nervosa and bulimia nervosa.
 * cerebral blood flow (CBF); neuroimaging studies have shown reduced CBF in the temporal lobes of anorectic patients, which may be a predisposing factor in the onset of AN.


 * autoimmune system; Autoantibodies against neuropeptides such as melanocortin have been shown to affect personality traits associated with eating disorders such as those that influence appetite and stress responses.


 * Nutritional deficiencies
 * Zinc deficiency may play a role in Anorexia. It is not thought responsible for causation of the initial illness but there is evidence that it may be an accelerating factor that deepens the pathology of the anorexia. A 1994 randomized, double-blind, placebo-controlled trial showed that zinc (14 mg per day) doubled the rate of body mass increase compared to patients receiving the placebo.

Environmental
Sociocultural studies have highlighted the role of cultural factors, such as the promotion of thinness as the ideal female form in Western industrialized nations, particularly through the media. A recent epidemiological study of 989,871 Swedish residents indicated that gender, ethnicity and socio-economic status were large influences on the chance of developing anorexia, with those with non-European parents among the least likely to be diagnosed with the condition, and those in wealthy, white families being most at risk. People in professions where there is a particular social pressure to be thin (such as models and dancers) were much more likely to develop anorexia during the course of their career, and further research has suggested that those with anorexia have much higher contact with cultural sources that promote weight-loss.

There is also evidence to suggest that patients who have anorexia nervosa can be characterised by Alexithymia and also a deficit in certain emotional functions. A research study showed that this was the case in both adult and adolescent anorexia nervosa patients.

There is a high rate of reported child sexual abuse experiences in clinical groups of who have been diagnosed with anorexia. Although prior sexual abuse is not thought to be a specific risk factor for anorexia, those who have experienced such abuse are more likely to have more serious and chronic symptoms.

Relationship to autism
Since Gillberg's (1985) and others initial suggestion of relationship between anorexia nervosa and autism,  a large scale longitudinal study into teenage onset anorexia nervosa conducted in Sweden confirmed that 23% of people with a long-standing eating disorder are on the autism spectrum. Those on autism spectrum tend to have a worse outcome, but may benefit from the combined use of behavioural and pharmacological therapies tailored to ameliorate autism rather than anorexia nervosa per se. Other studies, most notably research conducted at the Maudsley Hospital UK, furthermore suggest that autistic traits are common in people with anorexia nervosa, shared traits include e.g. executive function, autism quotient score, central coherence, theory of mind, cognitive-behavioural flexibility, emotion regulation and understanding facial expressions.

Zucker et al. (2007) proposed that conditions on the autism spectrum make up the cognitive endophenotype underlying anorexia nervosa and appealed for increased interdisciplinary collaboration (see figure to right). A pilot study into the effectiveness Cognitive Behaviour Therapy, which based its treatment protocol on the hypothesised relationship between anorexia nervosa and an underlying autistic like condition, reduced perfectionism and rigidity in 17 out of 19 participants.

Medical
The initial diagnosis should be made by a competent medical professional. There are multiple medical conditions, such as viral or bacterial infections, hormonal imbalances, neurodegenerative diseases and brain tumors which may mimic psychiatric disorders including anorexia nervosa. According to an in depth study conducted by psychiatrist Richard Hall as published in the Archives of General Psychiatry:'''
 * Medical illness often presents with psychiatric symptoms.
 * It is difficult to distinguish physical disorders from functional psychiatric disorders on the basis of psychiatric symptoms alone.
 * Detailed physical examination and laboratory screening are indicated as a routine procedure in the initial evaluation of psychiatric patients.
 * Most patients are unaware of the medical illness that is causative of their psychiatric symptoms.
 * The conditions of patients with medically induced symptoms are often initially misdiagnosed as a functional psychosis.


 * There are a variety of tests that may aid in the diagnosis of AN and the assessment of possible secondary effects caused by AN upon the patient.


 * neuroimaging; via the use of various techniques such as PET scan, fMRI, MRI and SPECT imaging should be included in the diagnostic procedure for any eating disorder to detect cases in which a lesion, tumor or other organic condition has been either the sole causative or contributory factor in an eating disorder.


 * "we therefore recommend performing a cranial MRI in all patients with suspected eating disorders"(Trummer M et al.2002)","intracranial pathology should also be considered however certain is the diagnosis of early-onset anorexia nervosa. Second, neuroimaging plays an important part in diagnosing early-onset anorexia nervosa,..".(O'Brien et al.''2001).

Psychological
Anorexia nervosa is classified as an Axis I disorder in the Diagnostic and Statistical Manual of Mental Health Disorders (DSM-IV). Published by The American Psychiatric Association. The DSM-IV should not be used by laypersons to diagnose themselves.




 * DSM-IV-TR: diagnostic criteria for AN includes intense fear of gaining weight, a refusal to maintain body weight above 85% of the expected weight for a given age and height, and three consecutive missed periods and either refusal to admit the seriousness of the weight loss, or undue influence of shape or weight on one's self image, or a disturbed experience in one's shape or weight. There are two types: the binge-eating/purging type is characterized by overeating or purging, and the restricting type is not.
 * Criticism of DSM-IV There has been criticisms over various aspects of the diagnostic criteria utilized for anorexia nervosa in the DSM-IV. Including the requirement of maintaining a body weight below 85% of the expected weight and the requirement of amenorrhea for diagnosis; some women have all the symptoms of AN and continue to menstruate. Those who do not meet these criteria are usually classified as eating disorder not otherwise specified this may affect treatment options and insurance reimbursments. The validity of the AN subtype classification has also been questioned due to the considerable diagnostic overlap between the binge eating/ purging type and the restricting type and the propensity of the patient to switch between the two.


 * ICD-10: The criteria are similar, but in addition, specifically mention:
 * 1) The ways that individuals might induce weight-loss or maintain low body weight (avoiding fattening foods, self-induced vomiting, self-induced purging, excessive exercise, excessive use of appetite suppressants or diuretics).
 * 2) If onset is before puberty, that development is delayed or arrested.
 * 3) Certain physiological features, including "widespread endocrine disorder involving hypothalamic-pituitary-gonadal axis is manifest in women as amenorrhoea and in men as loss of sexual interest and potency. There may also be elevated levels of growth hormones, raised cortisol levels, changes in the peripheral metabolism of thyroid hormone and abnormalities of insulin secretion".

Differential diagnoses
There are various medical and psychological conditions that have been misdiagnosed as anorexia nervosa, in some cases the correct diagnosis was not made for more than ten years. In a reported case of achalasia misdiagnosed as AN, the patient spent two months confined to a psychiatric hospital.

There are various other psychological issues that may factor into anorexia nervosa, some fulfill the criteria for a separate Axis I diagnosis or a personality disorder which is coded Axis II  and thus are considered comorbid to the diagnosed eating disorder. Axis II disorders are subtyped into 3 "clusters", A, B and C.The causality between personality disorders and eating disorders has yet to be fully established. Some people have a previous disorder which may increase their vulnerability to developing an eating disorder. Some develop them afterwards. The severity and type of eating disorder symptoms have been shown to affect comorbidity. BDD is a chronic and debilitating condition which may lead to social isolation, major depression, suicidal ideation and attempts. Neuroimaging studies to measure response to facial recognition have shown activity predominately in the left hemisphere in the left lateral prefrontal cortex, lateral temporal lobe  and left parietal lobe showing hemispheric imbalance in information processing. There is a reported case of the development of BDD in a 21 year old male following an inflammatory brain process. Neuroimaging showed the presence of new atrophy in the frontotemporal region.
 * Body dysmorphic disorder (BDD) is listed as a somatoform disorder that affects up to 2% of the population. BDD is characterized by excessive rumination over an actual or perceived physical flaw. BDD has been diagnosed equally among men and women. While BDD has been misdiagnosed as anorexia nervosa, it also occurs comorbidly in 25% to 39% of AN cases.

The distinction between the diagnoses of anorexia nervosa, bulimia nervosa and eating disorder not otherwise specified (EDNOS) is often difficult to make as there is considerable overlap between patients diagnosed with these conditions. Seemingly minor changes in a patient's overall behavior or attitude can change a diagnosis from "anorexia: binge-eating type" to bulimia nervosa. It is not unusual for a person with an eating disorder to "move through" various diagnoses as his or her behavior and beliefs change over time.

Treatment
Treatment for anorexia nervosa tries to address three main areas. 1) Restoring the person to a healthy weight; 2) Treating the psychological disorders related to the illness; 3) Reducing or eliminating behaviours or thoughts that originally led to the disordered eating.
 * Diet and Nutrition
 * Zinc supplementation has been shown in various studies to be beneficial in the treatment of AN even in patients not suffering from zinc deficiency, by helping to increase weight gain.


 * Essential fatty acids:The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been shown to benefit various neuropsychiatric disorders. There was reported rapid improvement in a case of severe AN treated with ethyl-eicosapentaenoic acid (E-EPA) and micronutrients. DHA and EPA supplementation has been shown to be a benefit in many of the comorbid disorders of AN including: attention deficit/hyperactivity disorder (ADHD), autism, major depressive disorder (MDD), bipolar disorder, and borderline personality disorder. Accelerated cognitive decline and mild cognitive impairment (MCI) correlate with lowered tissue levels of DHA/EPA, and supplementation has improved cognitive function.
 * Nutrition counseling
 * Medical Nutrition Therapy;(MNT) also referred to as Nutrition Therapy is the development and provision of a nutritional treatment or therapy based on a detailed assessment of a person's medical history, psychosocial history, physical examination, and dietary history.


 * Medication
 * Olanzapine: has been shown to be effective in treating certain aspects of AN including to help raise the body mass index and reduce obsessionality, including obsessional thoughts about food.


 * Psychotherapy/Cognitive remediation
 * Cognitive behavioral therapy (CBT) – "The term 'cognitive-behavioral therapy (CBT); is a very general term for a classification of therapies with similarities. There are several approaches to cognitive-behavioral therapy". CBT is an evidence based approach which in studies to date has shown to be useful in adolescents and adults with anorexia nervosa.


 * Acceptance and commitment therapy: A type of CBT, has shown promise in the treatment of AN" participants experienced clinically significant improvement on at least some measures; no participants worsened or lost weight even at 1-year follow-up."

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Stroop Test: Used in Cognitive Remediation Therapy. Naming the color of the first set of words is easier and quicker than the second set.


 * Cognitive Remediation Therapy (CRT): is a cognitive rehabilitation therapy developed at King's College in London designed to improve neurocognitive abilities such as attention, working memory, cognitive flexibility and planning, and executive functioning which leads to improved social functioning. Neuropsychological studies have shown that patients with AN have difficulties in cognitive flexibility. In studies conducted at Kings College and in Poland with adolescents CRT was proven to be beneficial in treating anorexia nervosa, in the United States clinical trials are still being conducted by the National Institute of Mental Health on adolescents age 10-17 and Stanford University in subjects over 16 as a conjunctive therapy with Cognitive behavioral therapy.


 * Family therapy: various forms of family therapy have been proven to work in the treatment of adolescent AN including "Conjoint family therapy" (CFT), in which the parents and child are seen together by the same therapist, "separated family therapy" (SFT) in which parents and child attend therapy separately with different therapists. "Eisler's cohort show that, irrespective of the type of FBT, 75% of patients have a good outcome, 15% an intermediate outcome... ".
 * Maudsley Family Therapy: A 4 to 5 year follow up study of the Maudsley approach, shows full recovery at rates up to 90%.


 * Adjunctive/Alternate Therapies
 * Yoga: In preliminary studies indivualized yoga treatment has shown positive results for use as an adjunctive therapy to standard care. The treatment was shown to reduce eating disorder symptoms, including food preoccupation, which decreased immediately after each session. Scores on the Eating Disorder Examination decreased consistently over the course of treatment.
 * Acupuncture/Tui na: According to a study in China positive results were obtained in treating AN with a combination treatment utilizing acupuncture and Tui na, a form of manipulation therapy.


 * Experimental therapy
 * Marinol (dronabinol): a synthetic form of delta-9-THC a psychoactive compound extracted from the resin of the cannabis sativa plant is currently the subject of a clinical trial for use in the treatment of AN, the study is slated to end in 2011.
 * Ghrelin treatment: pilot studies have been concluded in the use of ghrelin infusion for the inhospital treatment of patients with AN. The results showed positive effect in the reduction of the associated gastrointestinal symptoms, an increase in appetite and energy intake without adverse effects.

Prognosis
The long term prognosis of anorexia is more on favorable side. The National Comorbidity Replication Survey was conducted among more than 9,282 participants throughout the United States, the results found that the average duration of anorexia nervosa is 1.7 years. "Contrary to what people may believe, anorexia is not necessarily a chronic illness; in many cases, it runs its course and people get better..."

In cases of adolescent anorexia nervosa that utilize Family treatment 75% of patients have a good outcome and an additional 15% show an intermediate yet more positive outcome. In a five year post treatment follow-up of Maudsley Family Therapy the full recovery rate was between 75% and 90%. Even in severe cases of AN, despite a noted 30% relapse rate after hospitalization, and a lengthy time to recovery  ranging from 57–79 months, the full recovery rate was still 76%. There were minimal cases of relapse even at the long term follow-up conducted between 10–15 years. The long-term prognosis of anorexia nervosa is changeable: one-fifth of patients stay severely ill. one-fifth of patients recover fully and three-fifth's of patients have a fluctuating and chronic course (Gelder, Mayou and Geddes 2005).

Epidemiology
Anorexia has an average prevalence of 0.3-1% in women and 0.1% in men for the diagnosis in developed countries. The condition largely affects young adolescent women, with between 15 and 19 years old making up 40% of all cases. Approximately 90% of people with anorexia are female. Anorexia nervosa is more prevalent in the upper social classes and it is declared to be rare in less developed countries (Gelder, Mayou and Geddes 2005).

History
The history of anorexia nervosa begins with early descriptions dating from the 16th and 17th centuries and the first recognition and description of anorexia nervosa as a disease in the late 19th century.

In the late 19th century, the public attention drawn to "fasting girls" provoked conflict between religion and science. Such cases as Sarah Jacob (the "Welsh Fasting Girl") and Mollie Fancher (the "Brooklyn Enigma") stimulated controversy as experts weighed the claims of complete abstinence from food. Believers referenced the duality of mind and body, while skeptics insisted on the laws of science and material facts of life. Critics accused the fasting girls of hysteria, superstition, and deceit. The progress of secularization and medicalization passed cultural authority from clergy to physicians, transforming anorexia nervosa from revered to reviled.