OVERVIEW: What every practitioner needs to know

Anorexia nervosa is a serious disorder with significant medical complications and psychiatric co-morbidities. Anorexia nervosa is life-threatening and has the highest mortality rate of any psychiatric disorder. Anorexia nervosa frequently appears during the teen years, but may also develop during childhood. The disorder affects both girls and boys. Anorexia nervosa is treatable. Early recognition and timely intervention based on a developmentally appropriate and evidence-based inter-disciplinary team approach is the standard of care. To date, family-based treatment is the most effective first-line psychological outpatient treatment.

Are you sure your patient has Restrictive Anorexia Nervosa? What are the typical findings for this disease?

Restriction of energy intake relative to requirements leading to significantly low body weight in the context of age, sex, developmental trajectory, and physical health. Significantly low weight is defined as a weight that is less than minimally normal or, for children and adolescents, less than that minimally expected.
Intense fear of gaining weight or of becoming fat, or persistent behavior that interferes with weight gain, even though at a significantly low weight.
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Disturbance in the way in which one’s body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or persistent lack of recognition of the seriousness of the current low body weight.

What are the common physical signs and symptoms of Restrictive Anorexia Nervosa?

Signs: weight loss, amenorrhea or menstrual dysfunction, pubertal delay or interruption, arrested or poor linear growth, lanugo hair (extra fine, downy hair growth), thinning of hair, dry skin, yellow discoloration of skin, pitting or ridging of nails, bone fractures, hypothermia, bradycardia, hypotension, acrocyanosis, peripheral edema, systolic murmur sometimes associated with mitral valve prolapse, irritability or mood changes.
Symptoms: cold intolerance, dizziness or light-headedness, fainting, chest pain, early satiety, abdominal bloating, abdominal pain or discomfort, fatigue, constipation, muscle weakness, muscle cramps, decreased concentration, poor memory.

What behaviors may provide clues that a child or adolescent has a diagnosis of Restrictive Anorexia Nervosa?

Frequent weighing
Excessive exercise
Wearing baggy clothing
Frequent excuses for not eating
Cutting food in small pieces
Irritability
Social isolation

Who is typically affected by Restrictive Anorexia Nervosa?

Approximately 85%-90% of those affected are females in mid-adolescence (13-15 years).
Estimated prevalence in young women is 0.3% to 0.5%.
In children and adolescents <12 years old, approximately 17% are male.
Both genders and all racial and ethnic backgrounds are affected.

What other disease/condition shares some of these symptoms?

Gastrointestinal: inflammatory bowel disease, celiac disease
Endocrine: hyperthyroidism, diabetes mellitus, Addison’s disease
Rheumatologic: systemic lupus erythematosus
Neurologic: central nervous system lesions (hypothalamic or pituitary tumors)
Infections: tuberculosis, HIV
Malignancy: leukemia, lymphoma
Collagen vascular disease
Cystic fibrosis
Psychiatric disorders including mood disorders, anxiety disorders, somatization, and psychosis

What conditions commonly co-exist in Restrictive Anorexia Nervosa?

Anxiety disorderss
Obsessive-compulsive disorder
Depression

What causes this disorder to develop at this time?

The etiology is complex and multifactorial, with a combination of biological, developmental, psychological, and socio-cultural factors contributing to the development of the disorder. The exact nature of these interactive processes remains incompletely understood.
Family, twin, and molecular genetic studies suggest that the biological vulnerability might be genetic. To date, no single gene or combination of genes have been identified.
Disturbances in a number of different neurotransmitters such as serotonin, norepinephrine, and dopamine may also exist.
Weight concerns and societal emphasis on thinness are pervasive in westernized societies, and adolescent girls tend to be particularly vulnerable to these influences.

What are potential risk factors for Restrictive Anorexia Nervosa?

Age and female gender
Early childhood eating problems
Weight concerns or negative body image
Dieting
Perinatal adverse events (prematurity, small for gestational age, cephalohematoma)
Personality traits such as perfectionism, anxiety, low self-esteem, obsessionality
Early puberty
Chronic illness
Physical and sexual abuse
Family history of an eating disorder or other mental health disorder
Competitive athletics, i.e., gymnastics, ice skating, ballet, wrestling

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Hematological

Complete blood count (CBC) and differential: leukopenia, anemia, thrombocytopenia

Erythrocyte sedimentation rate (ESR): decreased ESR; if elevated, consider alternate diagnosis
Chemistry

Electrolytes (sodium, potassium, chloride, calcium, magnesium, phosphate): hypernatremia if dehydrated, hyponatremia if water-loading, hypocalemia, hypophosphatemia (most commonly occurs with low body weight in the context of refeeding), hypomagnesemia

Nutrients: decreased vitamin A, decreased serum zinc, decreased serum copper, decreased serum iron
Gastrointestinal (GI)

Liver enzymes and function: elevated aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)

Lipid profile: increased cholesterol
Endocrine

Thyroid studies: normal thyroid stimulating hormone (TSH), normal or slightly low thyroxine (T4), often low triiodothyronine (T3)

Gonadotropins: low basal levels of LH, FSH, pre-pubertal LH secretory pattern

Sex steroids: low estrogen in females, low testosterone in males

Prolactin: normal

Growth hormone: decreased insulin-like growth factor (IGF-1), normal or elevated growth hormone (GH)

Cortisol: normal or elevated
Renal and metabolic

Urinalysis: increased specific gravity if dehydrated, alkaline urine, hematuria, proteinura

Blood urea nitrogen: elevated

Creatinine: elevated

Blood gas: metabolic alkalosis

Glucose: low
Cardiac

12-lead electrocardiogram (ECG): bradycardia, low-voltages, prolonged QTc interval, T wave inversion, ST depression

Would imaging studies be helpful? If so, which ones?

Dual-energy X-ray absorptiometry (DXA) to measure bone mineral density: low bone mineral density
Echocardiogram: decreased cardiac size, mitral valve prolapse
Upper GI tract series: delayed gastric emptying

What are the indications for hospitalization?

Weight <75% median body mass index (BMI) for age and sex
Significant bradycardia (heart rate (HR) <50 during day (<45 beats/min at night)
Hypotension (<90/45 mm Hg)
Significant orthostatic changes (decrease in systolic blood pressure >20 mm Hg or increase in HR >35)
ECG abnormalities (e.g., prolonged QTc >0.44 msec, severe bradycardia, or other arrhythmias)
Dehydration
Electrolyte disturbance (hypokalemia, hyponatremia, hypophosphatemia)
Hypothermia (body temperature <96°F, 35.6°C)
Acute medical complications of malnutrition (e.g., syncope, seizures, cardiac failure, pancreatitis)
Delayed or arrested growth
Delayed or arrested pubertal development
Acute food refusal
Uncontrollable bingeing and purging
Failure of outpatient treatment
Comorbid psychiatric or medical condition that prohibits or limits appropriate outpatient treatment (e.g., severe depression, suicidal ideation, obsessive compulsive disorder, type 1 diabetes mellitus)

If you are able to confirm that the patient has Restrictive Anorexia Nervosa, what treatment should be initiated?

Inter-disciplinary Team Approach: An inter-disciplinary team skilled and knowledgeable in working with children and adolescents with eating disorders and their families is imperative.
Treatment Setting: Depending on the patient and family circumstance, may include inpatient (see indications for hospitalization), outpatient, day hospital, or residential treatment.
Medical Intervention: If indicated, admission to hospital for reversal of acute medical complications and ongoing monitoring of biochemical markers and cardiac status, especially during nutritional rehabilitation. Patient should have ongoing medical monitoring while an outpatient, in day hospital, or residential treatment.
Nutritional Intervention: Effective treatment of adolescents with AN always starts with nutritional rehabilitation. Research supports initiating higher caloric prescriptions (~1400 kcal/day) with close medical monitoring for inpatient nutritional rehabilitation in adolescents who are mildly (% mBMI 80-90%) and moderately malnourished (% mBMI 70-79%). This nutritional rehabilitation has not been associated with increased risk for refeeding syndrome under close medical monitoring with electrolyte correction as needed. Further, this type of nutritional rehabilitation has been associated with shorter hospital stays and increases in the rate of weight gain without increasing rates of refeeding syndrome. To date, there is insufficient evidence to support higher caloric prescriptions in severely malnourished inpatients (% mBMI <70%). Thus, lower calorie approaches with slow advancement still has a role. Inpatient weight gain of 1-2 kg/week normalizes cardiovascular instability, but the time to physiological stability is highly variable. Attempts should be made to achieve weight gain through the oral route, however, short-term nasogastric feeding may be necessary in some patients. Consider supplementation with calcium (1300-1500 mg/day), vitamin D, and multivitamin as necessary. Consultation with a dietitian regarding caloric requirements should be considered. Weight restoration (and in girls, the return of normal menstrual function) is the treatment of choice for amenorrhea and low bone mineral density.
Psychological Intervention: Evidence supports the efficacy of family-based treatment as the first-line outpatient psychological treatment for adolescents with anorexia nervosa.
Pharmacological Treatment: Some adolescents may benefit from the use of psychotropic medications. Common medications used to treat symptoms of Restrictive Anorexia Nervosa and comorbid psychiatric disorders such as anxiety, obsessive-compulsive disorder, and depression include selective serotonin reuptake inhibitors (SSRIs). The use of atypical antipsychotic medications to treat adolescents with Restrictive Anorexia Nervosa has recently been explored. The data in adolescents is encouraging although it has been limited to case series and case reports.

What are the adverse effects associated with each treatment option?

Cardiovascular collapse, arrhythmias, altered mental status, and death can occur in malnourished patients aggressively renourished with parenteral or enteral nutrition. The greatest risk for refeeding syndrome occurs during the first week of nutritional rehabilitation; however, delirium can occur during or after the second week.

Refeeding syndrome is associated with intracellular shifts of phosphate, potassium, calcium, and magnesium, resulting in hypophosphatemia, hypokalemia, hypocalcemia, and hypomagnesemia. Refeeding hypophosphatemia can occur with nutritional rehabilitation and is correlated with the degree of malnutrition. Electrolytes should be monitored daily for the first week after initiation of feeding. Electrolyte supplementation should be given as indicated.

What are the possible outcomes of Restrictive Anorexia Nervosa?

Adolescents with Restrictive Anorexia Nervosa can fully recover; however, the time to full recovery can range from 2 to 6 years.

Factors associated with good prognosis include:

Short duration of illness
Early identification and intervention
Early onset (<14 yrs.)
No comorbid psychiatric diagnoses
Supportive family

The mortality rate ranges from 2% to 8%. The most common causes of death are suicide and the medical complications of starvation. Clinical and laboratory findings associated with sudden cardiac death include prolonged QTc interval, decreased serum phosphate concentration, and severe emaciation (<70% median BMI).

What complications might you expect from the disease or treatment of the disease?

Fluid and electrolyte-related

Dehydration

Hypokalemia

Hyponatremia

Hypophosphatemia

Hypomagnesemia

Hypogylcemia
Cardiovascular

Sinus bradycardia or arrhythmia

Orthostatic hypotension or tachycardia

Ventricular dysrhythmias

Reduced myocardial contractility

Sudden death

Mitral valve prolapse

Cardiomyopathy (secondary to ipecac use)

ECG abnormalities including low voltage, prolonged QTc interval, prominent U waves

Pericardial effusion

Congestive heart failure
Renal

Increased blood urea nitrogen

Increased creatinine

Decreased glomerular filtration rate

Renal calculi

Edema

Renal concentrating defect

Urinary incontinence
Gastrointestinal

Delayed gastric emptying

Constipation

Elevated liver enzymes

Fatty liver

Superior mesenteric artery syndrome

Rectal prolapse

Gallstones
Hematological

Anemia

Leukopenia

Thrombocytopenia
Endocrine or metabolic

Primary or secondary amenorrhea

Pubertal delay

Sick euthyroid syndrome (low T3)

Hypercortisolism

Partial diabetes insipidus

Elevated cholesterol

Elevated cortisol

Hypoglycemia

Low bone mineral density

Increased risk of bone fracture
Skin

Lanugo hair

Edema

Acrocyanosis
Neurologic

Generalized muscle weakness

Seizures secondary to metabolic abnormalities

Peripheral neuropathies

Syncope

Structural brain changes

Cognitive deficits across a broad range of neuropsychological domains, i.e., verbal, memory, cognitive efficiency.

What is the Evidence?

Garber, AK, Sawyer, SM, Golden, NH.. “A Systematic Review of Approaches to Refeeding in Patients with Anorexia Nervosa”. Int J Eat Disord. vol. 49. 2016. pp. 293-310. (Findings support higher caloric approaches to refeeding in mildly and moderately malnourished hospitalized adolescents under close medical monitoring.)

Golden, NH, Katzman, DK, Sawyer, SM, Ornstein, RM. “Update on the medical management of eating disorders in adolescents”. J Adolesc Health.. vol. 56. 2015. pp. 370-5. (The medical practitioner has an important role to play in the management of adolescents with eating disorders and must be up-to-date on the changing epidemiology of eating disorders, revised diagnostic criteria, newer methods of assessing degree of malnutrition, more aggressive approaches to refeeding, and current approaches to managing low bone mass.)

Golden, NH, Katzman, DK, Sawyer, SM, Ornstein, RM. “Position Paper of the Society for Adolescent Health and Medicine: medical management of restrictive eating disorders in adolescents and young adults”. J Adolesc Health.. vol. 56. 2015. pp. 121-5. (This paper proposes evidence-based methods for determining degree of malnutrition, advocates for standardization of terminology, and consistency in the use of terms referring to ideal, expected or medial body weight, and supports more aggressive approaches to refeeding and the use of family-based therapy as a first-line psychological treatment for adolescent with anorexia nervosa.)

Lock, J, Le Grange, D, Agras, WS. “Randomized clinical trial comparing family-based treatment with adolescent-focused individual therapy for adolescents with anorexia nervosa”. Arch Gen Psychiatry. vol. 67. 2010. pp. 1025-32. (Family-based therapy has been found to be effective in the adolescent age group.)

Misra, M, Golden, NH, Katzman, DK.. “State of the art systematic review of bone disease in anorexia nervosa”. Int J Eat Disord.. vol. 49. 2016. pp. 276-292. (The safest and most effective strategy to improve bone health in AN is normalization of weight with restoration of menstrual function.)

Ongoing controversies regarding etiology, diagnosis, treatment

Controversy exists as to whether fluoxetine prevents relapse in adolescents with anorexia nervosa.

One study reported that fluoxetine prevented relapse in older adolescents with anorexia nervosa who have attained 85% of their expected body weight (Kaye WH, Nagata T, Weltzin TE, et al. Double-blind placebo-controlled administration of fluoxetine in restricting- and restricting-purging-type anorexia nervosa. Biol Psychiatry 2001;49:644-52).

A more recent study failed to demonstrate any benefit from fluoxetine in weight-restored patients with anorexia nervosa (Walsh BT, Kaplan AS, Attia E, et al. Fluoxetine after weight restoration in anorexia nervosa: a randomized controlled trial. JAMA 2006;295:2605-12).

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Restrictive Anorexia Nervosa