Advertisement

Medical Complications of Anorexia Nervosa and Bulimia

      Abstract

      Anorexia nervosa and bulimia nervosa are serious psychiatric illnesses related to disordered eating and distorted body images. They both have significant medical complications associated with the weight loss and malnutrition of anorexia nervosa, as well as from the purging behaviors that characterize bulimia nervosa. No body system is spared from the adverse sequelae of these illnesses, especially as anorexia nervosa and bulimia nervosa become more severe and chronic. We review the medical complications that are associated with anorexia nervosa and bulimia nervosa, as well as the treatment for the complications. We also discuss the epidemiology and psychiatric comorbidities of these eating disorders.

      Keywords

      Clinical Significance
      • Anorexia nervosa and bulimia have many medical complications associated with them.
      • In anorexia nervosa, the medical complications are due to weight loss and malnutrition.
      • In bulimia, the medical complications are due to the mode and frequency of purging.
      • Most complications are reversible with early effective treatment.
      Anorexia nervosa and bulimia nervosa are serious psychiatric illnesses with substantial morbidity and mortality. Anorexia nervosa is the psychiatric illness with the highest mortality rate.
      • Sullivan P.F.
      Mortality in anorexia nervosa.
      • Harris E.C.
      • Barraclough B.
      Excess mortality of mental disorder.
      • Emborg C.
      Mortality and causes of death in eating disorders in Denmark 1970-1993: a case register study.
      • Nielsen S.
      Epidemiology and mortality of eating disorders.
      • Mehler P.S.
      • Krantz M.
      Anorexia nervosa medical issues.
      • Guarda A.S.
      Treatment of anorexia nervosa: insights and obstacles.
      • Herpertz-Dahlmann B.
      Adolescent eating disorders: definitions, symptomatology, epidemiology and comorbidity.
      Mortality also is increased in patients with bulimia nervosa.
      • Crow S.J.
      • Peterson C.B.
      • Swanson S.A.
      • et al.
      Increased mortality in bulimia nervosa and other eating disorders.
      In both anorexia nervosa and bulimia nervosa, much of the increased mortality rate is attributable to the medical complications inherent to these 2 illnesses.
      Although anorexia nervosa and bulimia nervosa are defined as separate disorders in the psychiatric Diagnostic and Statistical Manual 5th Edition,
      • American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders.
      they both fall into the category of disordered eating, driven by an irrational fear of normal body weight and a desire for thinness, and leading to body image distortion.
      • Andersen A.
      • Yager J.
      Eating disorders.
      Cultural ideals of beauty and thinness may incite the development of disordered eating in vulnerable individuals, who have a genetic predisposition toward anxiety and perfectionism.
      • Lulé D.
      • Schulze U.M.E.
      • Bauer K.
      • et al.
      Anorexia nervosa and its relation to depression, anxiety, alexithymia and emotional processing deficits.
      Both starvation and purging may initially calm these feelings of anxiety and reduce obsessions and compulsions via a serotonergic neuronal pathway.
      • Kaye W.H.
      • Fudge J.L.
      • Paulus M.
      New insight into symptoms and neurocircuit function in anorexia nervosa.
      • Zink C.F.
      • Weinberger D.R.
      Cracking the moody brain: the rewards of self- starvation.
      During the course of anorexia nervosa and bulimia nervosa, comorbid mental disorders also emerge as a result of altered neurotransmitter metabolism or endocrine changes that result from caloric deprivation.
      • Pollice C.
      • Kaye W.H.
      • Greeno C.G.
      • Weltzin T.E.
      Relationship of depression, anxiety and obsessionality to state of illness in anorexia nervosa.
      • McAdams C.J.
      • Krawczyk D.C.
      Impaired neuronal processing of social attribution in anorexia nervosa.
      • Neufang S.
      • Specht K.
      • Hausman M.
      • et al.
      Sex differences and the impact of steroid hormones on the developing human brain.
      • Rothemund Y.
      • Buchald C.
      • Georgiewa P.
      • et al.
      Compulsivity predicts fronto striatal activation in severely anorectic individuals.
      Approximately 50% of adolescent patients with anorexia nervosa meet criteria for at least 1 comorbid psychiatric illness.
      • Bühren K.
      • Schwarte R.
      • Fluck N.
      • et al.
      Comorbid psychiatric disorders in female adolescents with first-onset anorexia nervosa.
      Eating disorders are strongly associated with mood and anxiety disorders, and the type and severity of these comorbidities are increased in patients who have the most severe eating disorders.
      • Aspen V.
      • Weisman H.
      • Nafiz N.
      • et al.
      Psychiatric comorbidity in women presenting across the continuum of disordered eating.
      • Hudson J.L.
      • Hiripi E.
      • Pope Jr., H.G.
      • Kessler R.C.
      The prevalence and correlates of Eating Disorders in the National Comorbidity Survey Replication.
      • Swanson S.A.
      • Crow S.J.
      • LeGrange D.
      • et al.
      Prevalence and correlates of eating disorders in adolescents. Correlates from the national comorbidity survey. Replication adolescent survey.
      • Brown T.A.
      • Haedt-Matt A.A.
      • Keel P.K.
      Personality pathology in purging disorder and bulimia nervosa.
      • Rossiter E.M.
      • Agras W.S.
      • Telch C.F.
      • Schneider J.A.
      Cluster B personality disorder characteristics predict outcome in patients with bulimia nervosa.
      In addition, patients with bulimia nervosa who have comorbid borderline personality disorder have poorer outcomes than those without borderline personality disorder when both groups are treated with psychotherapy and pharmacotherapy.
      • Herzog T.A.
      • Hartmann A.
      • Sandholz A.
      • Stammer H.
      Prognostic factors in outpatient therapy of bulimia.
      • Button E.J.
      • Chadalavada B.
      • Palmer R.L.
      Mortality and predictors of death in a cohort of patients presenting to an eating disorders service.
      Psychiatric comorbidity, as well as a history of suicidal or self-harm ideation, and comorbid mental illnesses all confer an increased risk of death in patients with eating disorders.
      • Button E.J.
      • Chadalavada B.
      • Palmer R.L.
      Mortality and predictors of death in a cohort of patients presenting to an eating disorders service.
      • Franko D.L.
      • Keel P.K.
      • Dorer D.J.
      • et al.
      What predicts suicide attempts in women with eating disorders?.
      • Keel P.K.
      • Dorer D.J.
      • Eddy K.T.
      • et al.
      Predictors of mortality in eating disorders.
      • Papadopoulos F.C.
      • Ekbom A.
      • Brandt L.
      • et al.
      Excess mortality, causes of death and prognostic factors in anorexia nervosa.
      Problems socializing and difficulties with being assertive are factors that contribute to maintaining an eating disorder.
      • Raykos B.C.
      • McEvoy P.M.
      • Carter O.
      • Fursland A.
      • Nathan P.
      Interpersonal problems across restrictive and binge-purge samples: data from a community-based eating disorders clinic.
      Temperament traits of harm avoidance, combined with high reward dependence, are protective factors seen more commonly in patients who recover from eating disorders.
      • Atiye M.
      • Miettunen J.
      • Raevuori-Helkamaa A.
      A meta-analysis of temperament in eating disorders.
      Treatment of anorexia nervosa and bulimia nervosa is multidimensional. In addition to nutritional rehabilitation, cognitive-behavioral psychotherapy and family therapy have been shown to be effective in treating patients with anorexia nervosa,
      • Brauhardt A.
      • de Zwaan M.
      • Hilbert A.
      The therapeutic process in psychological treatments for eating disorders: a systematic review.
      although the benefit of these therapies have been noted primarily in the weight maintenance phase of treatment.
      • Yager J.
      • Devlin M.J.
      • Halmi K.A.
      • et al.
      Practice Guideline for the Treatment of Patients with Eating Disorders.
      There is only minimal to moderate evidence that psychiatric medications are efficacious in treating patients with anorexia nervosa. Despite the prevalence of mood and anxiety symptoms in patients with anorexia nervosa, medications used to treat these conditions are not necessarily useful treatment adjuncts for reducing the symptoms of anorexia nervosa. In one study, fluoxetine assisted in preventing relapse in weight-restored patients with anorexia nervosa.
      • Kaye W.H.
      • Nagata T.
      • Weltzin T.E.
      • et al.
      Double-blind placebo controlled administration of fluoxetine in restricting and purging type anorexia nervosa.
      However, this finding was not replicated in a subsequent study.
      • Walsh B.T.
      • Kaplan A.S.
      • Attia E.
      • et al.
      Fluoxetine after weight restoration in anorexia nervosa: a randomized controlled trial.
      Although there may be evidence for using antidepressants in the weight maintenance phase, antidepressants do not ameliorate eating disorder pathology in patients who are acutely underweight.
      • deVos J.
      • Houtzager L.
      • Katsaragaki G.
      • et al.
      Meta-analysis on the efficacy of pharmacotherapy versus placebo on anorexia nervosa.
      The poor response to antidepressants is believed to result from starvation-induced abnormalities in serotonin receptors.
      • Kaye W.H.
      • Frank G.K.
      • Bailer U.F.
      • Henry S.E.
      Neurobiology of anorexia nervosa: clinical implications of alterations of the function of serotonin and other neuronal systems.
      In addition to concerns regarding the efficacy of antidepressants in patients with anorexia nervosa, there is also considerable debate as to the efficacy of antipsychotics in treating their symptoms. Low-dose antipsychotic medications may be useful in treating delusional beliefs regarding body image, intense ruminations about food, and the hyper-arousal and anxiety induced by having to face weight restoration.
      • Hay P.J.
      • Claudino A.M.
      Clinical psychopharmacology of eating disorders: a research update.
      • Flament M.F.
      • Bissada H.
      • Spettigue W.
      Evidence-based pharmacotherapy of eating disorders.
      Although atypical antipsychotic medications promote weight gain in normal-weight individuals, they do not have this effect in patients with anorexia nervosa.
      • deVos J.
      • Houtzager L.
      • Katsaragaki G.
      • et al.
      Meta-analysis on the efficacy of pharmacotherapy versus placebo on anorexia nervosa.
      • McKnight R.F.
      • Park R.J.
      Atypical antipsychotics and eating disorders: a review.
      However, patients with eating disorders may not accept reassurance in this regard. Despite the paucity of associated weight gain, there remains concern that the risk of using these medications outweighs their potential benefit.
      • Kishi T.
      • Kafantaris V.
      • Sunday S.
      • et al.
      Are antipsychotics effective for the treatment of anorexia nervosa? Results from a systematic review and meta-analysis.
      First-generation antipsychotics (typical antipsychotics) lower the seizure threshold. Side effects of second-generation antipsychotics (atypical antipsychotics), such as orthostasis, prolonged rate-corrected QT (QTc), and hepatotoxicity, are of concern.
      Despite continued debate regarding the usefulness of pharmacotherapy in patients with anorexia nervosa, pharmacotherapy for bulimia is well established. Fluoxetine (at doses of ≥60 mg) is approved by the Food and Drug Administration for bulimia nervosa, and other selective serotonin reuptake inhibitors (as well as other classes of antidepressants) have been found to be useful in treating patients with bulimia nervosa.
      • Yager J.
      • Devlin M.J.
      • Halmi K.A.
      • et al.
      Practice Guideline for the Treatment of Patients with Eating Disorders.
      • Hay P.J.
      • Claudino A.M.
      Clinical psychopharmacology of eating disorders: a research update.
      The effect of fluoxetine in treating the symptoms of bulimia nervosa seems to be independent of its effects on mood and is reportedly related to the effects of the medication on satiety, thereby reducing binge eating.
      • Goldstein D.J.
      • Wilson M.G.
      • Ashcroft R.C.
      • et al.
      Effectiveness of pharmacotherapy in bulimia nervosa regardless of comorbid depression.
      • Walsh B.T.
      • Agras W.S.
      • Devlin M.J.
      • et al.
      Fluoxetine for bulimia nervosa following poor response to psychotherapy.
      Cognitive behavioral therapy is a well-established psychotherapeutic treatment for bulimia nervosa.
      • Yager J.
      • Devlin M.J.
      • Halmi K.A.
      • et al.
      Practice Guideline for the Treatment of Patients with Eating Disorders.
      • Serpell S.
      • Stobie B.
      • Fairburn C.G.
      • et al.
      Empirically-supported and non-empirically supported therapies for bulimia nervosa: retrospective patient ratings.

      Medical Complications of Anorexia Nervosa

      Anorexia nervosa can adversely affect almost every body system. The complications arise as a direct result of weight loss and malnutrition. However, there are no studies that define which body mass index is associated with a particular medical complication. The eyes may be affected by lagophthalmos, wherein the eyelids do not totally cover the eye during sleep, resulting in irritation to the cornea and mild ocular discomfort.
      • Gaudiani J.L.
      • Braverman J.M.
      • Mascolo M.
      • Mehler P.S.
      Lagophthalmos in severe anorexia nervosa: a case study.
      Treatment involves taping the eyes shut at night after first applying a sterile lubricant.

      Gastrointestinal

      Dysphagia can frustrate the ingestion of oral calories during the early stages of refeeding. It is due to weakened and uncoordinated pharyngeal muscles. As a result, patients may experience coughing with eating or have a history of aspiration pneumonia. The diagnosis is made by a modified barium swallow test, and the treatment depends on weight restoration and input from a speech therapist to define proper food consistencies.
      • Holmes S.R.
      • Gudridge T.A.
      • Gaudiani J.L.
      • Mehler P.S.
      Dysphagia in severe anorexia nervosa: a case report.
      Patients with anorexia nervosa have significantly slowed gastric emptying at their nadir weights that is accompanied by early satiety, nausea, and bloating.
      • Benini L.
      • Todesco T.
      • Dalle Grave R.
      • Deiorio F.
      • Salandini L.
      • Vantini I.
      Gastric emptying in patients with restricting and binge/purging subtypes of anorexia nervosa.
      This gastroparesis ultimately resolves with weight gain, but symptoms may respond early on to low-dose, short-term use of metoclopramide before meals. Acute gastric dilatation is a serious condition that can lead to gastric perforation if not recognized early.
      • Mascolo M.
      • Dee E.
      • Townsend R.
      • Brinton J.T.
      • Mehler P.S.
      Severe gastric dilatation due to superior mesenteric artery syndrome in anorexia nervosa.
      It can occur independently as an isolated finding in the early phases of refeeding or as a result of the superior mesenteric artery syndrome.
      • Welsch T.
      • Buchler M.W.
      • Kienle P.
      Recalling superior mesenteric artery syndrome.
      Superior mesenteric artery syndrome is defined by the extrinsic compression of the third portion of the duodenum by the superior mesenteric artery, due to loss of a fatty tissue pad that normally maintains the angle between the superior mesenteric artery and the aorta. Significant left upper quadrant abdominal pain with eating, emesis during the meal, and early satiety should prompt an evaluation for gastric dilatation or superior mesenteric artery syndrome via an abdominal radiograph or computed tomography scan. Treatment of superior mesenteric artery syndrome is aimed at weight restoration to reconstitute the fat pad. This can be achieved by a soft or liquid oral diet or by enteral feeds via a nasojejunal tube or a percutaneously placed one.
      • Le Moigne F.
      • Lamboley J.L.
      • Vitry T.
      • et al.
      Superior mesenteric artery syndrome: a rare etiology of upper intestinal obstruction in adults.
      Acute gastric dilation is first treated by gastric decompression with a nasogastric tube, followed by treatments similar to those used in superior mesenteric artery syndrome. Just as there is slowing of the proximal gastrointestinal tract, there is also slowing of colonic function, resulting in constipation as an accompanying symptom in anorexia nervosa.
      • Zipfel S.
      • Sammet I.
      • Rapps N.
      • Herzog W.
      • Herpertz S.
      • Martens U.
      Gastrointestinal disturbances in eating disorders: a clinical and neurobiological aspects.
      Osmotic laxatives are useful along with reassurance that the patient's prior bowel pattern should return over a few weeks with ongoing progressive nutritional rehabilitation.
      Elevated liver transaminases occur frequently at patients' nadir weights.
      • Miller K.K.
      • Grinspoon S.K.
      • Ciampa J.
      • Hier J.
      • Herzog D.
      • Klibanski A.
      Medical findings in outpatients with anorexia nervosa.
      This generally represents apoptosis, a programmed hepatocyte death as a result of malnutrition. Aspartate aminotransferase and alanine aminotransferase are the most frequently affected in a range of 2 to 4 times elevated, but severe elevations also have been reported to occur.
      • De Caprio C.
      • Alfano A.
      • Senatore I.
      • Zarrella L.
      • Pasanisi F.
      • Contaldo F.
      Severe acute liver damage in anorexia nervosa: two case reports.
      Alanine aminotransferase is more elevated than aspartate aminotransferase. The prevalence of liver enzyme abnormalities correlates with lower body mass index, hypoglycemia, and the development of refeeding hypophosphatemia.
      • Brown C.A.
      • Sabel A.L.
      • Gaudiani J.L.
      • Mehler P.S.
      Predictors of hypophosphatemia during refeeding of patients with severe anorexia nervosa.
      Progressive nutritional support will resolve these elevations over the first few weeks of refeeding. Typically, alkaline phosphatase and bilirubin are not affected. Less frequently, elevations of aspartate aminotransferase and alanine aminotransferase may be due to steatosis as a result of actual refeeding. A liver ultrasound can help elucidate the cause because in steatosis, a fatty enlarged liver will be noted.
      • Narayanan V.
      • Gaudiani J.L.
      • Harris R.H.
      • Mehler P.S.
      Liver function test abnormalities in anorexia nervosa – cause or effect.

      Cardiac

      As noted earlier, anorexia nervosa has the highest mortality of any psychiatric disorder. Sudden cardiac death along with other medical complications and suicide account for approximately 60% of the deaths. The exact cause of sudden death in anorexia nervosa remains unknown. Autopsy studies do not reveal evidence of obstructive coronary artery disease.
      • Arnette E.N.
      • Isner J.M.
      • Redwood D.R.
      • et al.
      Coronary artery narrowing in coronary heart disease: a comparison of cineangiographic and necropsy findings.
      It has been postulated that alterations in cardiac conduction and repolarization contribute to heightened mortality though a single unifying mechanism. Generally, bradycardia is noted in patients and reflects heightened vagal tone in the setting of substantial weight loss. This often recovers with restoration of body weight. A resting heart rate of less than 60 beats per minute, for example, was seen in 95% of patients in a consecutive series.
      • Yahalom M.
      • Spitz M.
      • Sandler L.
      • Heno N.
      • Roguin N.
      • Turgeman Y.
      The significance of bradycardia in anorexia nervosa.
      Sinus bradycardia in and of itself does not require specific therapy, but current guidelines recommend hospitalization for a heart rate less than 40 beats per minute. High-grade atrioventricular block is exceedingly rare and suggests underlying structural heart disease that may be unrelated to anorexia nervosa itself. Temporary pacemakers are rarely required. Persistent junctional rhythm has been described among patients with severe anorexia nervosa, which may be extinguished with exercise.
      • Krantz M.J.
      • Gaudianni J.
      • Johnson V.
      • Mehler P.S.
      Exercise electrocardiography extinguishes persistent junctional rhythm in a patient with severe anorexia nervosa.
      • Kossaify A.
      Management of sinus node dysfunction with junctional escape rhythm in a case of anorexia nervosa.
      Patients may present with prolongation of the QTc interval on surface electrocardiography, and a commonly held belief was that this is the primary cause of sudden cardiac death. However, this relationship is confounded by concurrent QTc-prolonging medications and depletion of serum potassium and magnesium levels. In a series of patients with severe anorexia nervosa, marked QTc interval prolongation (>500 ms) was actually uncommon in the absence of contributing factors.
      • Krantz M.J.
      • Sabel A.
      • Sagar U.
      • et al.
      Factors influencing QT prolongation in hospitalized patients with severe anorexia nervosa.
      Facchini and colleagues
      • Facchini M.
      • Sala L.
      • Malfatto G.
      • Bragato R.
      • Redaelli G.
      • Invitti C.
      Low-K+ dependent QT prolongation and risk for ventricular arrhythmia in anorexia nervosa.
      observed 29 patients with anorexia and found marked QTc prolongation in only 2 individuals.
      • Facchini M.
      • Sala L.
      • Malfatto G.
      • Bragato R.
      • Redaelli G.
      • Invitti C.
      Low-K+ dependent QT prolongation and risk for ventricular arrhythmia in anorexia nervosa.
      Both had profound hypokalemia, and after potassium repletion, the QTc interval normalized. Therefore, to date, an independent causal pathway among anorexia nervosa, QTc prolongation, torsade de pointes, and sudden cardiac death has not been demonstrated. Expectant management of delayed repolarization is generally adequate and includes electrolyte repletion, discontinuation of QTc-prolonging medications, and serial 12-lead electrocardiography.
      Severe anorexia nervosa is also known to change cardiac structure. Many patients develop left ventricular atrophy and subsequent annular changes that lead to mitral valve prolapse. Patients occasionally develop pericardial effusions, which are generally self-limited and resolve with weight restoration. Among the most prominent cardiovascular structural abnormalities is a substantial reduction in left ventricular myocardial mass with preserved left ventricular systolic function. This is generally reversible with refeeding. One study demonstrated myocardial fibrosis/scar manifested by late gadolinium enhancement on magnetic resonance imaging in approximately one quarter of patients.
      • Oflaz S.
      • Yucel B.
      • Oz F.
      • et al.
      Assessment of myocardial damage by cardiac MRI in patients with anorexia nervosa.
      Although echocardiographic atrophy and fibrosis by magnetic resonance imaging have been demonstrated, histologic abnormalities in the heart have been poorly characterized until very recently: A published autopsy report showed left ventricular atrophy with endocardial and interstitial fibrosis, focal myxoid material deposition with mast cells, and increased cytoplasmic lipofuscin.
      • Lamzabi I.
      • Syed S.
      • Reddy V.B.
      • Jain R.
      • Harbhajanka A.
      • Arunkumar P.
      Myocardial changes in a patient with anorexia nervosa: a case report and review of literature.
      Although most cardiac structural abnormalities are reversible in this condition, the presence of myocardial scar suggests that malignant arrhythmias remain a possible mechanism of increased mortality in this disease.

      Pulmonary

      As opposed to the cardiac system, the lungs are not adversely affected for the most part. There seem to be some pulmonary function test abnormalities associated with anorexia nervosa that are similar to those seen with emphysemia.
      • Gardini G.G.
      • Boni E.
      • Todisco P.
      Respiratory function in patients with anorexia nervosa.
      It is not clear whether this impairment recedes with refeeding. Spontaneous pneumothorax has been reported in anorexia nervosa along with prolonged air leaks.
      • Biffl W.
      • Narayanan V.
      • Gaudiani J.L.
      • Mehler P.S.
      The management of pneumothorax in patients with anorexia nervosa.

      Hematology

      As anorexia nervosa becomes worse, there is trilinear hypoplasia causing anemia, leukopenia, and thrombocytopenia. Anemia occurs in 40% of these patients, with leukopenia noted in 30% and thrombocytopenia in approximately 10%.
      • Hutter G.
      • Ganepola S.
      • Hofmann W.K.
      The hematology of anorexia nervosa.
      The cytopenia are due to gelatinous marrow transformation with atrophy of the normal fat content in the marrow and replacement by a mucopolysacharide.
      • Muhajir M.
      Gelatinous transformation of bone marrow in a patient with anorexia nervosa.
      Typically, iron deficiency is not found, and red cell indices are normal. Although often neutropenic, surprisingly, these patients do not appear to be more susceptible to infectious complications.
      • Nova E.
      • Samartin S.
      • Gomez S.
      • Morande G.
      • Marcos A.
      The adaptive response of the immune system to the particular malnutrition of eating disorders.
      However, they also do not manifest a typical febrile response to infections and inflammatory markers are suppressed, which can cause a delay in the diagnosis of an infection.
      • Brown R.F.
      • Bartrop R.
      • Beaumont P.
      • Birmingham C.L.
      Bacterial infections in anorexia nervosa: delayed recognition increases complication.
      The cytopenias resolve with weight restoration; growth factors are not indicated in anorexia nervosa.
      • Sabel A.
      • Gaudiani J.
      • Statland B.
      • Mehler P.S.
      Hematological abnormalities in severe anorexia nervosa.
      Plasma levels of vitamin B12 and folate recently have been found to be increased. The increase is artificial because it was found to be due to hepatocyte dysfunction with leakage of the vitamins from these cells.
      • Corbetta F.
      • Tremolizzo L.
      • Conti E.
      • et al.
      Paradoxical increase of plasma vitamin B12 and folates with disease severity in anorexia nervosa.

      Musculoskeletal

      Osteoporosis is common in anorexia nervosa and occurs early in the disease.
      • Kraeft J.J.
      • Uppot R.N.
      • Heffess A.M.
      Imaging findings in anorexia nervosa.
      Decreased bone density is evident after just 1 year of anorexia nervosa, notwithstanding the relatively young age of these patients. The risk of subsequent fragility fractures is markedly elevated both in adults and in adolescents with anorexia nervosa.
      • Faje A.T.
      • Fazeli P.K.
      • Miller K.K.
      • et al.
      Fracture risk and areal bone mineral density in adolescent females with anorexia nervosa.
      • Vestergaard P.
      • Emborg C.
      • Stovving R.K.
      • Hagen C.
      • Moseklide L.
      • Brixen K.
      Fractures in patients with anorexia nervosa – a nationwide register study.
      Fracture incidence increases soon after diagnosis of anorexia nervosa and remains so many years later. This is one of the rare complications of anorexia nervosa, which may leave irreversible damage even after recovery. Thus, there is a need for obtaining bone density testing in all patients with a disease duration of more than 1 year. In contrast to postmenopausal osteoporosis, in anorexia nervosa the loss of bone mineral density is due to both decreased bone formation along with increased bone resorption. Also, trabecular bone is more affected than cortical bone. Yet, the exact etiologic factors involved in their loss of bone density are not clear. Putative factors include the overlap between the normal accrual of peak bone mass and the age of onset of anorexia nervosa, along with the typical hypogonadal state, elevated cortisol levels, and growth hormone resistance found in anorexia nervosa, as described next.
      There are currently no treatments specifically approved for the osteoporosis of anorexia nervosa. Weight gain and resumption of menses are key and associated with significant increases in spine and hip bone mineral density.
      • Miller K.K.
      • Lee E.E.
      • Lawson E.A.
      • et al.
      Determinants of skeletal loss and recovery in anorexia nervosa.
      However, estrogen therapy does not seem to be of much value in anorexia nervosa. Many randomized controlled trials have found it to be ineffective, a fact that is underappreciated in the medical community.
      • Klibanski A.
      • Biller B.M.
      • Schoenfeld D.A.
      • Herzog D.B.
      • Saxe V.C.
      The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa.
      • Stokosh G.R.
      • Friedman A.J.
      • Wu S.C.
      • Kamin M.
      Effects of oral contraceptive on bone mineral density in adolescent females with anorexia nervosa.
      • Golden N.H.
      • Lanzkowsky L.
      • Schebendach J.
      • Palestro C.J.
      • Jacobson M.S.
      • Shenker I.R.
      The effect of estrogen progestin treatment on bone density in anorexia nervosa.
      Also, the withdrawal bleeding associated with its use can mislead patients into believing they are getting better. Transdermal estrogen patches have shown promising results in adolescents.
      • Misra M.
      • Katzman D.
      • Miller K.K.
      • et al.
      Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa.
      Calcium and vitamin D by themselves do not restore bone density.
      • Mehler P.S.
      • Mackenzie T.D.
      Treatment of osteopenia and osteoporosis in anorexia nervosa. A systematic review of the literature.
      Bisphosphonates have been shown to be effective in anorexia nervosa with an increase of 3% to 4% in spine bone mineral density after 12 months of treatment.
      • Golden N.H.
      • Iglesias E.A.
      • Jacobson M.S.
      • et al.
      Alendronate for the treatment of osteopenia in anorexia nervosa.
      Recently, teriparatide, a recombinant parathyroid hormone, has demonstrated favorable effects in this population.
      • Fazeli P.K.
      • Wang I.S.
      • Miller K.K.
      • et al.
      Teriparatide increases bone formation and bone mineral density in adult women with anorexia nervosa.
      There are no data as yet with denosumab.
      • Zaher S.
      • LeBoff M.
      • Lewiecki M.
      Denosumab for the treatment of osteoporosis.
      Testosterone therapy may be effective in male patients with anorexia nervosa who also have low serum testosterone levels. Male patients with anorexia nervosa actually have more severe degrees of osteoporosis then their female counterparts.
      • Mehler P.S.
      • Sabel A.L.
      • Watson T.
      • Andersen A.E.
      High risk of osteoporosis in male patients with eating disorders.

      Endocrine

      There are multiple endocrine abnormalities associated with anorexia nervosa. Most patients, both female and male, are hypogonadal because of reversion to a prepubertal state wherein pulsatile hypothalamic gonadotropin-releasing hormone secretion is reduced, causing low levels of follicle stimulating hormone and luteinizing hormone.
      • Devlin M.J.
      • Walsh B.T.
      • Katz J.L.
      • et al.
      Hypothalamic-pituitary-gonadal function in anorexia nervosa.
      Thus, amenorrhea is noted commonly in most, but not all female patients with anorexia nervosa. Leptin may have a causal role in the amenorrhea.
      • Miller K.K.
      • Grinspoon S.
      • Gleysteen S.
      • et al.
      Preservation of neuroendocrine control of reproductive function despite under nutrition.
      Resumption of menses generally occurs at the weight that the periods ceased or at more than 90% of ideal body weight.
      • Golden N.H.
      • Jacobson M.S.
      • Schebendach J.
      • et al.
      Presumption of menses in anorexia nervosa.
      However, some patients have prolonged amenorrhea even after weight restoration, and fertility may be permanently adversely affected.
      • Jocangeli F.
      • Masala S.
      • Staar Mezzasalma F.
      • et al.
      Amenorrhea after weigh recovery in anorexia nervosa: role of body composition and endocrine abnormalities.
      In male patients with anorexia nervosa, the low testosterone levels affect potency, libido, and muscle strength.
      Cortisol levels have been noted to be elevated because of both increased adrenal production and decreased renal clearance.
      • Lo Sauro C.
      • Ravaldi C.
      • Cabras P.L.
      • et al.
      Stress, hypothalamic-pituitary-adrenal axis and eating disorders.
      Growth hormone levels also are noted to be elevated, but insulin growth factor-1 levels are low, indicating a state of growth hormone resistance.
      • Golden N.H.
      • Kreitzer P.
      • Jacobson M.S.
      • et al.
      Disturbance in growth hormone secretion and action in adolescents with anorexia nervosa.
      Most patients have thyroid function abnormalities that closely mimic sick euthyroid syndrome. These resolve with weight gain.
      • Utiger R.D.
      Altero thyroid function in non-thyroidal illness and surgery. To treat or not to treat.
      Hypoglycemia occurs as anorexia nervosa becomes more severe, as a result of depleted hepatic glycogen stores. It is a poor prognostic sign that requires close monitoring.
      • Rich L.M.
      • Caine M.R.
      • Findling J.W.
      • Shader J.L.
      Hypoglycemic coma in anorexia nervosa.
      There is also evidence that type 1 diabetes may be related to the development of anorexia nervosa, although the specifics are inconclusive.
      • Baechle C.
      • Castillo K.
      • Strasburger K.
      Is disordered eating behavior more prevalent in adolescents with type 1 diabetes then in their respective peers?.
      However, what is clear is that some of these insulin-dependent diabetic patients realize that they can induce weight loss via reducing their use of insulin, thereby causing hyperglycemia and a resultant osmotic diuresis. This accelerates microvascular complications.
      • Wisting L.
      • Frossland D.H.
      • Skrivarhaug T.
      • Dahl-Jorgenson K.
      • Ro O.
      Disturbed eating behavior and commission of insulin in adolescents receiving insulin treatment.

      Neurologic

      Brain atrophy changes occur as a result of the malnutrition of anorexia nervosa. Neurocognitive functioning may be permanently impaired even though brain atrophy improves with weight restoration.
      • Roberto C.A.
      • Mayer L.E.
      • Brickman A.M.
      • et al.
      Brain tissue volume changes following weight gain in anorexia nervosa.
      Both gray and white matter are affected.

      Dermatologic

      There are multiple skin changes that occur in anorexia nervosa. These include xerosis, lanugo hair growth on the spine and sides of the face, thinning of the hair, acrocyanosis, and perniosis. Increased acne and carotenoderma also have been described.
      None of these are signs of virilization, but rather are related to reduced subcutaneous tissue or to the body's attempt to maintain core temperature and prevent heat loss. They all resolve with weight gain.

      Medical Complications of Bulimia

      Self-Induced Vomiting

      Although the mortality rate associated with bulimia is less than in anorexia nervosa, it is also elevated because of the severe electrolyte and acid base alterations that can be associated with purging behaviors. Ninety percent of the purging behaviors found in bulimia are self-induced vomiting or the abuse of stimulant laxatives. With self-induced vomiting, the complications can be divided into the local adverse effects of vomiting and the electrolyte-acid base abnormalities that can ensue as this behavior becomes more extreme. Excessive vomiting can lead to persistent gastric acid reflux leading to dysphagia and dyspepsia. Treatment is cessation of this behavior and the administration of proton pump inhibitors. Whether patients with bulimia should be screened for Barrett's esophagus is not clear.
      • Denholm M.
      • Jankowski J.
      Gastroesophageal reflux disease and bulimia nervosa—a review of the literature.
      There have been reports of esophageal malignancy in bulimia.
      • Dessureault S.
      • Coppola D.
      • Weitzner M.
      • Powers P.
      • Karl R.C.
      Barrett's esophagus and squamous cell carcinoma in a patient with psychogenic vomiting.
      But, even screening for Barrett's esophagus is the general population with reflux has recently been questioned because of lack of proof of efficicacy.
      • Spechler S.J.
      • Souza R.F.
      Barrett's esophagus.
      Hematemesis is usually due to the limited Mallory-Weiss tears. Epistaxis and subconjunctival hemorrhages are self-limited, but recurrent epistaxis in a young female patient should raise the question of covert bulimia. Perimolysis refers to erosion of the dentin and enamel on the lingual service of the teeth due to repeated exposure to stomach acid.
      • Uhlen M.M.
      • Tveit A.B.
      • Stenhagen K.R.
      • Mulic A.
      Self-induced vomiting and dental erosion–a clinical study.
      Likewise, oral mucositis and cheilitis are found in these patients from the recurrent vomiting. Recommended therapies include oral hygiene, such as gentle brushing and use of a fluoride mouthwash.
      • Christensen G.J.
      Oral care for patients with bulimia.
      Acid exposure also causes damage to the larynx with inflammatory changes to the vocal cords and a hoarse voice.
      • Ferreira C.P.
      • Gama A.C.
      • Santos M.A.
      • Maia M.O.
      Laryngeal and vocal analysis in bulimic patients.
      Parotid gland enlargement, or sialadenosis, is a common feature of self-induced vomiting, although the precise mechanism remains elusive.
      • Coleman H.
      • Altini M.
      • Nayler S.
      • Richards A.
      Sialadenosis: a presenting sign in bulimia.
      Tissue examination of these parotid glands reveals large acini with prominent zymogen granules without other pathology. Of note, sialadenosis develops 3 to 4 days after the cessation of chronic excessive self-induced vomiting and can be distressing to a patient with bulimia whose focus on body image is exaggerated. The swelling is bilateral, with minimal tenderness. There may be elevation of the salivary isoamylase enzyme serum level.
      • Kinzl J.
      • Biebl W.
      • Herold M.
      Significance of vomiting for hyperamylasemia and sialadenosis in patients with eating disorders.
      Treatment ideally should be preemptive and composed of use of sialagogues such as tart candies, along with an anti-inflammatory medication and the frequent application of hot packs. Usually this will help prevent the elevation, or if started late, said treatment usually resolves the issue within 1 to 2 weeks. In rare cases, oral pilocarpine may be judiciously used to help resolve the sialadenosis.
      • Mehler P.S.
      • Wallace J.A.
      Sialadenosis in bulimia: a new treatment.
      The most dangerous medical complications of self-induced vomiting relate to the acid-base and electrolyte changes that ensue as a result thereof. These aberrations are the same that occur with abuse of diuretics as the preferred mode of purging, but in general those encountered with self-induced vomiting are more profoundly abnormal. The most common electrolyte abnormalities are a metabolic alkalosis and hypokalemia. With vomiting, this is due to loss of both acid and potassium in the vomitus, as well as from the volume-depleted state causing increased aldosterone secretion to sustain the blood pressure. This course of compensatory events is referred to as pseudo-Barrett's syndrome.
      • Bahia A.
      • Mascolo M.
      • Gaudiani J.L.
      • Mehler P.S.
      PseudoBartter syndrome in eating disorders.
      It predisposes these patients to a distressing propensity toward edema formation with the cessation of purging behaviors as well as if intravenous saline repletion is required and infused too quickly.
      • Trent S.A.
      • Moreira M.E.
      • Colwell C.B.
      • Mehler P.S.
      ED management of patients with eating disorders.
      These patients must be treated differently than, for example, a patient with acute gastroenteritis in need of intravenous saline, in whom it can be safely infused rather quickly.
      • Mascolo M.
      • Trent S.
      • Colwell C.
      • Mehler P.
      What the emergency room department needs to know when caring for patients with eating disorders.
      Although the protective elevated aldosterone levels will self-normalize after a few weeks of no ongoing purging behaviors, it is often purposeful to initiate spironolactone in a starting dose of 25 to 50 mg daily to both prevent and treat edema formation. The finding of hypokalemia, in an otherwise healthy young adult, is highly specific for the diagnosis of covert bulimia.
      • Wolfe B.E.
      • Metzger E.D.
      • Levine J.M.
      • Jimerson D.C.
      Laboratory screening for electrolyte abnormalities in bulimia nervosa.
      The potentially severe degrees of hypokalemia and metabolic-alkalosis and resulting cardiac arrhythmias that can develop in those who excessively purge are the likely reasons for the elevated mortality rate associated with bulimia nervosa.
      • Crow S.J.
      • Peterson C.B.
      • Swanson S.A.
      • et al.
      Increased mortality in bulimia nervosa and other eating disorders.
      Hypokalemia recently was reported to be especially dangerous in female persons, which is the gender mostly identified to have bulimia.
      • Jensen H.K.
      • Brabrand M.
      • Vinholt P.J.
      • Hallas J.
      • Lassen A.T.
      Hypokalemia in acute medical patients: risk factors and prognosis.
      Most patients with bulimia nervosa use their fingers to provoke vomiting. However, some abuse syrup of ipecac to accomplish this. This is even more dangerous because, emetine, the alkaloid in ipecac that induces vomiting, is a direct cardiac toxin.
      • Silber T.J.
      Ipecac syrup abuse, morbidity, and mortality: isn't it time to repeal its over-the-counter status?.
      This toxicity is cumulative. Each bottle of ipecac contains 30 mg of emetine and with a dose of just 1250 mg, there can be the development of an irreversible cardiomyopathy and severe congestive health failure.
      • Ho P.C.
      • Dweik R.
      • Cohen M.C.
      Rapidly reversible cardiomyopathy associated with chronic ipecac ingestion.

      Laxative Abuse

      Excessive laxative abuse is the other main mode of purging.
      • Koracs D.
      • Palmer R.L.
      The association between laxative abuse and other symptoms among adults with anorexia nervosa.
      Hypokalemia is again a potential risk of this behavior. However, in contrast to diuretics and self-induced vomiting, laxative abuse is initially associated with a hyperchloremic metabolic acidosis that eventually reverts to a state of metabolic alkalosis after a chronic volume-depleted state evolves. In addition to the electrolyte abnormalities, laxative abuse causes expected local gastrointestinal adverse effects, including rectal prolapse, diarrhea, hemorrhoids, and hematochezia.
      • Xing J.H.
      • Soffer E.E.
      Adverse effects of laxatives.
      • Malik M.
      • Stratton J.
      • Sweeney W.B.
      Rectal prolapse associated with bulimia nervosa: report of seven cases.
      There has long been a debate whether stimulant initiative can cause colorectal cancer.
      • Dukas L.
      • Willett W.C.
      • Colditz G.A.
      • Fuchs C.S.
      • Rosner B.
      • Giovannucci E.L.
      Prospective study of bowel movement, laxative use, and risk of colorectal cancer among women.
      One final and major complication of laxative abuse is the cathartic colon syndrome.
      • Muller-Lissner S.
      What has happened to the cathartic colon?.
      For many years, it has been known that stimulant laxatives, whose mechanism of action is based on stimulation of peristalsis via a direct effect on Auerbach's plexus in the colon, can cause permanent harm to these nerve plexi.
      • Smith B.
      Effect of irritant purgatives on the myenteric plexus in man and the mouse.
      As a result of chronic use, the colon is converted into an inert tube incapable of the propagation of fecal material and severe constipation ensues,
      • Joo J.S.
      • Ehrenpreis E.D.
      • Gonzalez L.
      • et al.
      Alterations in colonic anatomy induced by chronic stimulant laxatives: the cathartic colon revisited.
      which may necessitate a colectomy. The exact amount of time or quantity of abuse needed to cause the cathartic colon syndrome is unknown. Therefore, it is important to exhort these patients to cease abuse of laxatives that contain senna, cascara, phenolphthalein, or bisacodyl. The aforementioned edema formation that can develop also can be treated with spironolactone, and patient concerns about resultant constipation can be allayed with substitution of a judicious amount of an osmotic laxative.
      • Colton P.
      • Woodside D.B.
      • Kaplan A.S.
      Laxative withdrawal in eating disorders. Treatment protocol and 3 to 20 year follow up.
      • Chu E.S.
      • Gaudiani J.L.
      • Mascolo M.
      • et al.
      ACUTE center for eating disorders.
      Much less commonly, patients with bulimia purge via the use of enema type products.
      • Davies C.
      The use of phosphate enemas in the treatment of constipation.
      The main dangers from them are due to the electrolyte abnormalities previously mentioned but also the potential for fatal hyperphosphatemia from the sodium-phosphate active ingredients.
      • Ori Y.
      • Rozen-Zoi B.
      • Chagnac A.
      Fatalities and severe metabolic disorders associated with the use of sodium phosphate enemas.

      Conclusions

      Both anorexia nervosa and bulimia nervosa inherently have a litany of medical complications associated with them, although most of them are treatable after effective medical interventions and psychotherapy. To halt the disease process, a notable few are associated with permanent harm. Therefore, given the relatively young age of onset of these illnesses, there is an impelling need for informed medical treatment to help achieve a successful treatment outcome.

      References

        • Sullivan P.F.
        Mortality in anorexia nervosa.
        Am J Psychiatry. 1995; 152: 1073-1074
        • Harris E.C.
        • Barraclough B.
        Excess mortality of mental disorder.
        Br J Psychiatry. 1999; 173: 11-53
        • Emborg C.
        Mortality and causes of death in eating disorders in Denmark 1970-1993: a case register study.
        Int J Eat Disord. 1999; 25: 243-251
        • Nielsen S.
        Epidemiology and mortality of eating disorders.
        Psychiatr Clin North Am. 2001; 24: 201-214
        • Mehler P.S.
        • Krantz M.
        Anorexia nervosa medical issues.
        J Womens Health. 2003; 12: 331-340
        • Guarda A.S.
        Treatment of anorexia nervosa: insights and obstacles.
        Physiol Behav. 2008; 94: 113-120
        • Herpertz-Dahlmann B.
        Adolescent eating disorders: definitions, symptomatology, epidemiology and comorbidity.
        Child Adolesc Psychiatr Clin N Am. 2009; 18: 31-47
        • Crow S.J.
        • Peterson C.B.
        • Swanson S.A.
        • et al.
        Increased mortality in bulimia nervosa and other eating disorders.
        Am J Psychiatry. 2009; 166: 1342-1346
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        5th ed. American Psychiatric Publishing, Arlington, VA2013: 338-345
        • Andersen A.
        • Yager J.
        Eating disorders.
        in: Saddock B.J. Saddock V.A. Kaplan and Saddock's Comprehensive Textbook of Psychiatry. 8th ed. Lippincott, Williams and Wilkins, Philadelphia2005: 2002-2021
        • Lulé D.
        • Schulze U.M.E.
        • Bauer K.
        • et al.
        Anorexia nervosa and its relation to depression, anxiety, alexithymia and emotional processing deficits.
        Eat Weight Disord. 2014; 19: 209-216
        • Kaye W.H.
        • Fudge J.L.
        • Paulus M.
        New insight into symptoms and neurocircuit function in anorexia nervosa.
        Nat Rev Neurosci. 2009; 10: 573-584
        • Zink C.F.
        • Weinberger D.R.
        Cracking the moody brain: the rewards of self- starvation.
        Nat Med. 2010; 16: 1382-1383
        • Pollice C.
        • Kaye W.H.
        • Greeno C.G.
        • Weltzin T.E.
        Relationship of depression, anxiety and obsessionality to state of illness in anorexia nervosa.
        Int J Eat Disord. 1997; 21: 367-376
        • McAdams C.J.
        • Krawczyk D.C.
        Impaired neuronal processing of social attribution in anorexia nervosa.
        Psych Res. 2011; 194: 57-63
        • Neufang S.
        • Specht K.
        • Hausman M.
        • et al.
        Sex differences and the impact of steroid hormones on the developing human brain.
        Cereb Cortex. 2009; 19: 464-473
        • Rothemund Y.
        • Buchald C.
        • Georgiewa P.
        • et al.
        Compulsivity predicts fronto striatal activation in severely anorectic individuals.
        Neuroscience. 2011; 197: 242-250
        • Bühren K.
        • Schwarte R.
        • Fluck N.
        • et al.
        Comorbid psychiatric disorders in female adolescents with first-onset anorexia nervosa.
        Eur Eat Disorders Rev. 2013; 22: 39-44
        • Aspen V.
        • Weisman H.
        • Nafiz N.
        • et al.
        Psychiatric comorbidity in women presenting across the continuum of disordered eating.
        Eat Behav. 2014; 15: 686-693
        • Hudson J.L.
        • Hiripi E.
        • Pope Jr., H.G.
        • Kessler R.C.
        The prevalence and correlates of Eating Disorders in the National Comorbidity Survey Replication.
        Biol Psychiatry. 2007; 61: 348-358
        • Swanson S.A.
        • Crow S.J.
        • LeGrange D.
        • et al.
        Prevalence and correlates of eating disorders in adolescents. Correlates from the national comorbidity survey. Replication adolescent survey.
        Arch Gen Psychiatry. 2011; 68: 714-723
        • Brown T.A.
        • Haedt-Matt A.A.
        • Keel P.K.
        Personality pathology in purging disorder and bulimia nervosa.
        Int J Eat Disord. 2011; 44: 735-740
        • Rossiter E.M.
        • Agras W.S.
        • Telch C.F.
        • Schneider J.A.
        Cluster B personality disorder characteristics predict outcome in patients with bulimia nervosa.
        Int J Eat Disord. 1993; 13: 349-357
        • Herzog T.A.
        • Hartmann A.
        • Sandholz A.
        • Stammer H.
        Prognostic factors in outpatient therapy of bulimia.
        Psychother Psychosom. 1991; 56: 48-55
        • Button E.J.
        • Chadalavada B.
        • Palmer R.L.
        Mortality and predictors of death in a cohort of patients presenting to an eating disorders service.
        Int J Eat Disord. 2010; 43: 387-392
        • Franko D.L.
        • Keel P.K.
        • Dorer D.J.
        • et al.
        What predicts suicide attempts in women with eating disorders?.
        Psychol Med. 2004; 34: 843-853
        • Keel P.K.
        • Dorer D.J.
        • Eddy K.T.
        • et al.
        Predictors of mortality in eating disorders.
        Arch Gen Psychiatry. 2003; 60: 179-183
        • Papadopoulos F.C.
        • Ekbom A.
        • Brandt L.
        • et al.
        Excess mortality, causes of death and prognostic factors in anorexia nervosa.
        Br J Psychiatry. 2009; 194: 10-17
        • Raykos B.C.
        • McEvoy P.M.
        • Carter O.
        • Fursland A.
        • Nathan P.
        Interpersonal problems across restrictive and binge-purge samples: data from a community-based eating disorders clinic.
        Eat Behav. 2014; 15: 449-452
        • Atiye M.
        • Miettunen J.
        • Raevuori-Helkamaa A.
        A meta-analysis of temperament in eating disorders.
        Eur Eat Disord Rev. 2015; 23: 88-99
        • Brauhardt A.
        • de Zwaan M.
        • Hilbert A.
        The therapeutic process in psychological treatments for eating disorders: a systematic review.
        Int J Eat Disord. 2014; 47: 565-584
        • Yager J.
        • Devlin M.J.
        • Halmi K.A.
        • et al.
        Practice Guideline for the Treatment of Patients with Eating Disorders.
        3rd ed. American Psychiatric Association, Washington, DC2006
        • Kaye W.H.
        • Nagata T.
        • Weltzin T.E.
        • et al.
        Double-blind placebo controlled administration of fluoxetine in restricting and purging type anorexia nervosa.
        Biol Psychiatry. 2001; 49: 644-652
        • Walsh B.T.
        • Kaplan A.S.
        • Attia E.
        • et al.
        Fluoxetine after weight restoration in anorexia nervosa: a randomized controlled trial.
        JAMA. 2006; 295: 2605-2612
        • deVos J.
        • Houtzager L.
        • Katsaragaki G.
        • et al.
        Meta-analysis on the efficacy of pharmacotherapy versus placebo on anorexia nervosa.
        J Eat Disord. 2014; 2: 27
        • Kaye W.H.
        • Frank G.K.
        • Bailer U.F.
        • Henry S.E.
        Neurobiology of anorexia nervosa: clinical implications of alterations of the function of serotonin and other neuronal systems.
        Int J Eat Disord. 2005; 37: S15-S19
        • Hay P.J.
        • Claudino A.M.
        Clinical psychopharmacology of eating disorders: a research update.
        Int J Neuropsychopharmacol. 2012; 15: 209-222
        • Flament M.F.
        • Bissada H.
        • Spettigue W.
        Evidence-based pharmacotherapy of eating disorders.
        In J Neuropsychopharmacol. 2012; 15: 189-207
        • McKnight R.F.
        • Park R.J.
        Atypical antipsychotics and eating disorders: a review.
        Eur Eat Disord Rev. 2010; 18: 10-21
        • Kishi T.
        • Kafantaris V.
        • Sunday S.
        • et al.
        Are antipsychotics effective for the treatment of anorexia nervosa? Results from a systematic review and meta-analysis.
        J Clin Psychiatry. 2012; 73: e757-e766
        • Goldstein D.J.
        • Wilson M.G.
        • Ashcroft R.C.
        • et al.
        Effectiveness of pharmacotherapy in bulimia nervosa regardless of comorbid depression.
        Int J Eat Disord. 1999; 25: 19-27
        • Walsh B.T.
        • Agras W.S.
        • Devlin M.J.
        • et al.
        Fluoxetine for bulimia nervosa following poor response to psychotherapy.
        Am J Psychiatry. 2000; 157: 1332-1334
        • Serpell S.
        • Stobie B.
        • Fairburn C.G.
        • et al.
        Empirically-supported and non-empirically supported therapies for bulimia nervosa: retrospective patient ratings.
        J Eat Disord. 2013; 1: 41
        • Gaudiani J.L.
        • Braverman J.M.
        • Mascolo M.
        • Mehler P.S.
        Lagophthalmos in severe anorexia nervosa: a case study.
        Arch Ophthalmol. 2012; 130: 928-930
        • Holmes S.R.
        • Gudridge T.A.
        • Gaudiani J.L.
        • Mehler P.S.
        Dysphagia in severe anorexia nervosa: a case report.
        Int J Eat Disord. 2012; 45: 463-466
        • Benini L.
        • Todesco T.
        • Dalle Grave R.
        • Deiorio F.
        • Salandini L.
        • Vantini I.
        Gastric emptying in patients with restricting and binge/purging subtypes of anorexia nervosa.
        Am J Gastroenterol. 2004; 99: 1448-1454
        • Mascolo M.
        • Dee E.
        • Townsend R.
        • Brinton J.T.
        • Mehler P.S.
        Severe gastric dilatation due to superior mesenteric artery syndrome in anorexia nervosa.
        Int J Eat Disord. 2015; 48: 532-534
        • Welsch T.
        • Buchler M.W.
        • Kienle P.
        Recalling superior mesenteric artery syndrome.
        Dig Surg. 2007; 24: 149-156
        • Le Moigne F.
        • Lamboley J.L.
        • Vitry T.
        • et al.
        Superior mesenteric artery syndrome: a rare etiology of upper intestinal obstruction in adults.
        Gastroenterol Clin Biol. 2010; 34: 403-406
        • Zipfel S.
        • Sammet I.
        • Rapps N.
        • Herzog W.
        • Herpertz S.
        • Martens U.
        Gastrointestinal disturbances in eating disorders: a clinical and neurobiological aspects.
        Auton Neurosci. 2006; 129: 99-106
        • Miller K.K.
        • Grinspoon S.K.
        • Ciampa J.
        • Hier J.
        • Herzog D.
        • Klibanski A.
        Medical findings in outpatients with anorexia nervosa.
        Arch Intern Med. 2005; 165: 561-566
        • De Caprio C.
        • Alfano A.
        • Senatore I.
        • Zarrella L.
        • Pasanisi F.
        • Contaldo F.
        Severe acute liver damage in anorexia nervosa: two case reports.
        Nutrition. 2006; 22: 572-575
        • Brown C.A.
        • Sabel A.L.
        • Gaudiani J.L.
        • Mehler P.S.
        Predictors of hypophosphatemia during refeeding of patients with severe anorexia nervosa.
        Int J Eat Disord. 2015 Apr 2; ([Epub ahead of print])
        • Narayanan V.
        • Gaudiani J.L.
        • Harris R.H.
        • Mehler P.S.
        Liver function test abnormalities in anorexia nervosa – cause or effect.
        Int J Eat Disord. 2010; 43: 378-381
        • Arnette E.N.
        • Isner J.M.
        • Redwood D.R.
        • et al.
        Coronary artery narrowing in coronary heart disease: a comparison of cineangiographic and necropsy findings.
        Ann Intern Med. 1979; 91: 350-356
        • Yahalom M.
        • Spitz M.
        • Sandler L.
        • Heno N.
        • Roguin N.
        • Turgeman Y.
        The significance of bradycardia in anorexia nervosa.
        Int J Angiol. 2013; 22: 83-94
        • Krantz M.J.
        • Gaudianni J.
        • Johnson V.
        • Mehler P.S.
        Exercise electrocardiography extinguishes persistent junctional rhythm in a patient with severe anorexia nervosa.
        Cardiology. 2011; 120: 217-220
        • Kossaify A.
        Management of sinus node dysfunction with junctional escape rhythm in a case of anorexia nervosa.
        Turk Kardiyol Dern Ars. 2010; 38: 486-488
        • Krantz M.J.
        • Sabel A.
        • Sagar U.
        • et al.
        Factors influencing QT prolongation in hospitalized patients with severe anorexia nervosa.
        Gen Hosp Psychiatry. 2011; 34: 173-177
        • Facchini M.
        • Sala L.
        • Malfatto G.
        • Bragato R.
        • Redaelli G.
        • Invitti C.
        Low-K+ dependent QT prolongation and risk for ventricular arrhythmia in anorexia nervosa.
        Int J Cardiol. 2006; 106: 170-176
        • Oflaz S.
        • Yucel B.
        • Oz F.
        • et al.
        Assessment of myocardial damage by cardiac MRI in patients with anorexia nervosa.
        Int J Eat Disord. 2013; 46: 862-866
        • Lamzabi I.
        • Syed S.
        • Reddy V.B.
        • Jain R.
        • Harbhajanka A.
        • Arunkumar P.
        Myocardial changes in a patient with anorexia nervosa: a case report and review of literature.
        Am J Clin Pathol. 2015; 143: 734-737
        • Gardini G.G.
        • Boni E.
        • Todisco P.
        Respiratory function in patients with anorexia nervosa.
        Chest. 2009; 136: 1356-1360
        • Biffl W.
        • Narayanan V.
        • Gaudiani J.L.
        • Mehler P.S.
        The management of pneumothorax in patients with anorexia nervosa.
        Patient Saf Surg. 2010; 4: 1-4
        • Hutter G.
        • Ganepola S.
        • Hofmann W.K.
        The hematology of anorexia nervosa.
        Int J Eat Disord. 2009; 42: 293-300
        • Muhajir M.
        Gelatinous transformation of bone marrow in a patient with anorexia nervosa.
        Int J Hematol. 2013; 97: 157-158
        • Nova E.
        • Samartin S.
        • Gomez S.
        • Morande G.
        • Marcos A.
        The adaptive response of the immune system to the particular malnutrition of eating disorders.
        Eur J Clin Nutr. 2002; 56: S34-37
        • Brown R.F.
        • Bartrop R.
        • Beaumont P.
        • Birmingham C.L.
        Bacterial infections in anorexia nervosa: delayed recognition increases complication.
        Int J Eat Disord. 2005; 37: 261-265
        • Sabel A.
        • Gaudiani J.
        • Statland B.
        • Mehler P.S.
        Hematological abnormalities in severe anorexia nervosa.
        Ann Hematol. 2013; 92: 605-609
        • Corbetta F.
        • Tremolizzo L.
        • Conti E.
        • et al.
        Paradoxical increase of plasma vitamin B12 and folates with disease severity in anorexia nervosa.
        Int J Eat Disord. 2015; 48: 317-322
        • Kraeft J.J.
        • Uppot R.N.
        • Heffess A.M.
        Imaging findings in anorexia nervosa.
        AJR Am J Roentgenol. 2013; 200: 328-334
        • Faje A.T.
        • Fazeli P.K.
        • Miller K.K.
        • et al.
        Fracture risk and areal bone mineral density in adolescent females with anorexia nervosa.
        Int J Eat Disord. 2014; 47: 458-466
        • Vestergaard P.
        • Emborg C.
        • Stovving R.K.
        • Hagen C.
        • Moseklide L.
        • Brixen K.
        Fractures in patients with anorexia nervosa – a nationwide register study.
        Int J Eat Disord. 2002; 32: 301-308
        • Miller K.K.
        • Lee E.E.
        • Lawson E.A.
        • et al.
        Determinants of skeletal loss and recovery in anorexia nervosa.
        J Clin Endocrinol Metab. 2011; 91: 2931-2937
        • Klibanski A.
        • Biller B.M.
        • Schoenfeld D.A.
        • Herzog D.B.
        • Saxe V.C.
        The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa.
        J Clin Endocrinol Metab. 1995; 80: 898-904
        • Stokosh G.R.
        • Friedman A.J.
        • Wu S.C.
        • Kamin M.
        Effects of oral contraceptive on bone mineral density in adolescent females with anorexia nervosa.
        J Adolesc Health. 2006; 39: 819-827
        • Golden N.H.
        • Lanzkowsky L.
        • Schebendach J.
        • Palestro C.J.
        • Jacobson M.S.
        • Shenker I.R.
        The effect of estrogen progestin treatment on bone density in anorexia nervosa.
        J Pediatr Adolesc Gynecol. 2002; 15: 135-143
        • Misra M.
        • Katzman D.
        • Miller K.K.
        • et al.
        Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa.
        J Bone Miner Res. 2011; 26: 2430-2438
        • Mehler P.S.
        • Mackenzie T.D.
        Treatment of osteopenia and osteoporosis in anorexia nervosa. A systematic review of the literature.
        Int J Eat Disord. 2009; 42: 195-201
        • Golden N.H.
        • Iglesias E.A.
        • Jacobson M.S.
        • et al.
        Alendronate for the treatment of osteopenia in anorexia nervosa.
        J Clin Endocrinol Metab. 2005; 90: 3179-3184
        • Fazeli P.K.
        • Wang I.S.
        • Miller K.K.
        • et al.
        Teriparatide increases bone formation and bone mineral density in adult women with anorexia nervosa.
        J Clin Endocrinol Metab. 2014; 99: 1322-1329
        • Zaher S.
        • LeBoff M.
        • Lewiecki M.
        Denosumab for the treatment of osteoporosis.
        Expert Opin Drug Metab Toxicol. 2015; 11: 461-470
        • Mehler P.S.
        • Sabel A.L.
        • Watson T.
        • Andersen A.E.
        High risk of osteoporosis in male patients with eating disorders.
        Int J Eat Disord. 2008; 41: 666-672
        • Devlin M.J.
        • Walsh B.T.
        • Katz J.L.
        • et al.
        Hypothalamic-pituitary-gonadal function in anorexia nervosa.
        Psychiatry Res. 1989; 28: 11-16
        • Miller K.K.
        • Grinspoon S.
        • Gleysteen S.
        • et al.
        Preservation of neuroendocrine control of reproductive function despite under nutrition.
        J Clin Endocrinol Metab. 2004; 89: 4434-4438
        • Golden N.H.
        • Jacobson M.S.
        • Schebendach J.
        • et al.
        Presumption of menses in anorexia nervosa.
        Adolesc Med. 1997; 151: 16-21
        • Jocangeli F.
        • Masala S.
        • Staar Mezzasalma F.
        • et al.
        Amenorrhea after weigh recovery in anorexia nervosa: role of body composition and endocrine abnormalities.
        Eat Weight Disord. 2006; 11: e20-26
        • Lo Sauro C.
        • Ravaldi C.
        • Cabras P.L.
        • et al.
        Stress, hypothalamic-pituitary-adrenal axis and eating disorders.
        Neuropsychobiology. 2008; 57: 95-100
        • Golden N.H.
        • Kreitzer P.
        • Jacobson M.S.
        • et al.
        Disturbance in growth hormone secretion and action in adolescents with anorexia nervosa.
        J Pediatr. 1994; 125: 655-660
        • Utiger R.D.
        Altero thyroid function in non-thyroidal illness and surgery. To treat or not to treat.
        N Engl J Med. 1995; 333: 1562-1567
        • Rich L.M.
        • Caine M.R.
        • Findling J.W.
        • Shader J.L.
        Hypoglycemic coma in anorexia nervosa.
        Arch Intern Med. 1990; 150: 894-898
        • Baechle C.
        • Castillo K.
        • Strasburger K.
        Is disordered eating behavior more prevalent in adolescents with type 1 diabetes then in their respective peers?.
        Int J Eat Disord. 2014; 47: 342-352
        • Wisting L.
        • Frossland D.H.
        • Skrivarhaug T.
        • Dahl-Jorgenson K.
        • Ro O.
        Disturbed eating behavior and commission of insulin in adolescents receiving insulin treatment.
        Diabetes Care. 2013; 36: 3382-3387
        • Roberto C.A.
        • Mayer L.E.
        • Brickman A.M.
        • et al.
        Brain tissue volume changes following weight gain in anorexia nervosa.
        Int J Eat Disord. 2011; 44: 406-410
      1. Strumia R. Eating Disorders and the Skin. Springer Publishing Company, New York2012
        • Denholm M.
        • Jankowski J.
        Gastroesophageal reflux disease and bulimia nervosa—a review of the literature.
        Dis Esophagus. 2011; 24: 79-85
        • Dessureault S.
        • Coppola D.
        • Weitzner M.
        • Powers P.
        • Karl R.C.
        Barrett's esophagus and squamous cell carcinoma in a patient with psychogenic vomiting.
        Int J Gastrointest Cancer. 2002; 32: 57-61
        • Spechler S.J.
        • Souza R.F.
        Barrett's esophagus.
        N Engl J Med. 2014; 371: 836-845
        • Uhlen M.M.
        • Tveit A.B.
        • Stenhagen K.R.
        • Mulic A.
        Self-induced vomiting and dental erosion–a clinical study.
        BMC Oral Health. 2014; 14: 92
        • Christensen G.J.
        Oral care for patients with bulimia.
        J Am Dent Assoc. 2002; 133: 1689-1691
        • Ferreira C.P.
        • Gama A.C.
        • Santos M.A.
        • Maia M.O.
        Laryngeal and vocal analysis in bulimic patients.
        Braz J Otorhinolaryngol. 2010; 76: 469-477
        • Coleman H.
        • Altini M.
        • Nayler S.
        • Richards A.
        Sialadenosis: a presenting sign in bulimia.
        Head Neck. 1998; 20: 758-762
        • Kinzl J.
        • Biebl W.
        • Herold M.
        Significance of vomiting for hyperamylasemia and sialadenosis in patients with eating disorders.
        Int J Eat Disord. 1993; 13: 117-124
        • Mehler P.S.
        • Wallace J.A.
        Sialadenosis in bulimia: a new treatment.
        Arch Otolaryngol Head Neck Surg. 1993; 119: 787-788
        • Bahia A.
        • Mascolo M.
        • Gaudiani J.L.
        • Mehler P.S.
        PseudoBartter syndrome in eating disorders.
        Int J Eat Disord. 2012; 45: 150-153
        • Trent S.A.
        • Moreira M.E.
        • Colwell C.B.
        • Mehler P.S.
        ED management of patients with eating disorders.
        Am J Emerg Med. 2013; 31: 859-865
        • Mascolo M.
        • Trent S.
        • Colwell C.
        • Mehler P.
        What the emergency room department needs to know when caring for patients with eating disorders.
        Int J Eat Disord. 2012; 45: 977-981
        • Wolfe B.E.
        • Metzger E.D.
        • Levine J.M.
        • Jimerson D.C.
        Laboratory screening for electrolyte abnormalities in bulimia nervosa.
        Int J Eat Disord. 2001; 30: 288-293
        • Jensen H.K.
        • Brabrand M.
        • Vinholt P.J.
        • Hallas J.
        • Lassen A.T.
        Hypokalemia in acute medical patients: risk factors and prognosis.
        Am J Med. 2015; 128: 60-67
        • Silber T.J.
        Ipecac syrup abuse, morbidity, and mortality: isn't it time to repeal its over-the-counter status?.
        J Adolesc Health. 2005; 37: 256-260
        • Ho P.C.
        • Dweik R.
        • Cohen M.C.
        Rapidly reversible cardiomyopathy associated with chronic ipecac ingestion.
        Clin Cardiol. 1998; 21: 780-783
        • Koracs D.
        • Palmer R.L.
        The association between laxative abuse and other symptoms among adults with anorexia nervosa.
        Int J Eat Disord. 2004; 36: 224-228
        • Xing J.H.
        • Soffer E.E.
        Adverse effects of laxatives.
        Dis Colon Rectum. 2001; 44: 1201-1209
        • Malik M.
        • Stratton J.
        • Sweeney W.B.
        Rectal prolapse associated with bulimia nervosa: report of seven cases.
        Dis Colon Rectum. 1997; 40: 1382-1385
        • Dukas L.
        • Willett W.C.
        • Colditz G.A.
        • Fuchs C.S.
        • Rosner B.
        • Giovannucci E.L.
        Prospective study of bowel movement, laxative use, and risk of colorectal cancer among women.
        Am J Epidemiol. 2000; 151: 958-964
        • Muller-Lissner S.
        What has happened to the cathartic colon?.
        Gut. 1996; 39: 486-488
        • Smith B.
        Effect of irritant purgatives on the myenteric plexus in man and the mouse.
        Gut. 1968; 9: 139-143
        • Joo J.S.
        • Ehrenpreis E.D.
        • Gonzalez L.
        • et al.
        Alterations in colonic anatomy induced by chronic stimulant laxatives: the cathartic colon revisited.
        J Clin Gastroenterol. 1998; 26: 283-286
        • Colton P.
        • Woodside D.B.
        • Kaplan A.S.
        Laxative withdrawal in eating disorders. Treatment protocol and 3 to 20 year follow up.
        Int J Eat Disord. 1997; 25: 311-317
        • Chu E.S.
        • Gaudiani J.L.
        • Mascolo M.
        • et al.
        ACUTE center for eating disorders.
        J Hosp Med. 2012; 7: 340-344
        • Davies C.
        The use of phosphate enemas in the treatment of constipation.
        Nurs Times. 2004; 100: 32-35
        • Ori Y.
        • Rozen-Zoi B.
        • Chagnac A.
        Fatalities and severe metabolic disorders associated with the use of sodium phosphate enemas.
        Arch Intern Med. 2012; 172: 263-265

      Linked Article

      • Use of Denosumab in a Patient with Chronic Anorexia Nervosa and Osteoporosis
        The American Journal of MedicineVol. 129Issue 2
        • Preview
          We read with interest the review of medical complication of patients with anorexia nervosa and bulimia by Westmoreland at al in The American Journal of Medicine.1 The experiences listed are similar to those encountered in our inpatient unit, which combines medical and psychiatric management in a single site.
        • Full-Text
        • PDF
      • The Reply
        The American Journal of MedicineVol. 129Issue 2
        • Preview
          I read with interest the letter to the editor from Jamieson in regard to using denosumab in a patient with anorexia nervosa.1
        • Full-Text
        • PDF