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Medical issues in the patient with anorexia nervosa
Eating Behaviors 2 (2001) 293 – 305
Medical issues in the patient with anorexia nervosa David Leonard, Philip S. Mehler* Department of Internal Medicine, Denver Health, Denver, CO, USA University of Colorado Health Sciences Center, Denver, CO, USA
1. Introduction Most medical complications of anorexia nervosa are a direct result of the malnutrition and weight loss that defines this illness. Few organ systems are spared the progressive deterioration that marks the clinical course of anorexia nervosa. The aggregate annual mortality rate associated with anorexia nervosa is more than 12 times higher than the annual death rate of all causes of death for women 15–24 years old in the general population (Sullivan, 1995).
2. Dermatologic complications In patients with anorexia nervosa, the skin is typically dry and scaly. There is often soft, downy hair growth, referred to as lanugo hair, on the sides of the face, the back, and on the arms and legs. Although the exact cause of the lanugo hair growth is unknown, it is not a sign of virilization. Moreover, it always recedes with weight restoration. Hair loss and brittle nails are also common findings. Starvation-associated pruritus and dry skin are caused by decreased sebaceous gland activity. These patients often have a yellow tinge to their skin. In the past, it was assumed that this was attributable to high circulating levels of beta-carotene. This is of no clinical significance, and more recent studies have not found hypercarotenemia (Mehler & Lezotte, 1998).
* Corresponding author. Denver Health, 660 Bannock Street, Denver, CO 80204, USA. Tel.: +1-303-4363234; fax: +1-303-436-5772. E-mail address: [email protected] (P.S. Mehler). 1471-0153/01/$ – see front matter D 2001 Elsevier Science Ltd. All rights reserved. PII: S 1 4 7 1 - 0 1 5 3 ( 0 1 ) 0 0 0 5 8 - 7
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3. Cardiovascular The heart was once thought to be spared the ill effects of starvation. However, based on research during World War II, we now know that half of the deaths occurring in anorexia nervosa are due to cardiovascular complication (Neumarker, 1997). A significant proportion of these deaths occur during refeeding, highlighting the need for careful management of this phase of treatment. The cardiovascular abnormalities found in anorexia nervosa are listed in Table 1, but it is unclear to what extent these findings are markers for cardiovascular complications. In fact, some of these findings, specifically bradycardia and reduced blood pressure to levels as low as 70–80, are actually normal adaptations to starvation. Bradycardia with heart rates as low as 25–30 beats/min (bpm) may be seen in severe anorexia nervosa accompanied by excessive weight loss, and may be an appropriate energy conserving adaptation (Keys, Brozek, Henschel, Mickelsen, & Taylor, 1950; Mehler, 2001). Despite a case report of heart block causing bradycardia in an anorexia nervosa patient with syncope (Gould, Reddy, Singh, & Zen, 1980), evidence suggests that neuronal vagal hyperactivity rather than conduction abnormalities usually mediate the bradycardia seen in anorexia nervosa. Power spectral analysis (PSA) of beat-to-beat heart rate variability is a proxy method used to estimate vagal and sympathetic input to the heart. Using PSA, studies have shown increased vagal tone in supine anorexia nervosa patients as well as during 24-h monitoring (Kollai, Bonyhai, Jokkel, & Szonyi, 1994; Kreipe, Goldstein, DeKing, Tipton, & Kempski, 1994; Petretta et al., 1997). Kreipe et al. (1994) also found that anorexia nervosa patients on standing had an exaggerated increase in sympathetic tone compared to
Table 1 Cardiovascular findings in anorexia nervosa Structural Decreased LV mass Decreased LV volume Mitral valve prolapse Vertical rotation of the heart Hemodynamic Hypotension (low blood pressure) Bradycardia (heart rate < 60 bpm) ? Decrease cardiac output ? Decrease LV function Electrocardiographic QT prolongation Right axis deviation Low-voltage QRS ST segment depression T wave flattening Arrhythmias
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controls. However, that excessive sympathetic output was offset by a smaller than expected decrease in parasympathetic tone on standing, which may account for the common symptoms of orthostatic hypotension, dizziness, and decreased exercise tolerance seen in anorexia nervosa (Kollai et al., 1994). Rechlin, Weis, Ott, Bleichner, and Joraschky (1998) found diminished sympathetic tone in supine anorexia nervosa patients less than 75% of ideal body weight (IBW), but not in anorexia nervosa patients greater than 75% of IBW. These studies suggest that the bradycardia seen in anorexia nervosa is mediated by altered autonomic function, which returns to normal with weight gain. With judicious refeeding and careful attention to maintaining normal levels of electrolytes, sinus bradycardia resolves appropriately (Kay et al., 1990) and thus in and of itself does not necessarily warrant cardiac monitoring. Prolonged QT interval on an EKG has been proposed as a risk factor for fatal arrhythmias in anorexia nervosa patients. Studies are conflicting as to the prevalence of QT prolongation in anorexia nervosa, ranging from 0% to over 50% (Cooke et al., 1994; Durakovic, Durakovic, & Korsic, 1994; Panagiotopoulos, McCrindle, Hick, & Katzman, 2000; Swenne & Larsson, 1999). Furthermore, whether prolonged QT is actually a causative factor in anorexia nervosa death is unknown. In a case study by Isner, Roberts, Heymsfield, and Yager (1985) of three patients who died of anorexia nervosa, all had prolonged QT prior to admission, and all three likely died of fatal arrhythmias. In a case study of five anorexic patients whose admissions where complicated by cardiac arrhythmias in four of the patients, all had prolonged QT (Beumont & Large, 1991). Each patient also developed severe hypophosphatemia during refeeding, and the two who died were also taking tricyclic antidepressants. These findings suggest that prolonged QT in the setting of electrolyte abnormality or tricyclic antidepressants may have been a contributing factor in the deaths. However, it is unclear to what extent the prolonged QT interval itself is a marker for sudden death. The mechanisms underlying the prolonged QT interval in anorexia nervosa are not well understood. QT dispersion, a measure of QT interval variation between leads, may be increased in anorexia nervosa. QT dispersion reflects unsynchronous repolarization (Cooke & Chambers, 1995) and facilitates EADs (early after depolarizations), which are thought to give rise to ventricle arrhythmias. Bradycardia in the setting of prolonged QT may also facilitate development of EADs (Tan, Hou, Lauer, & Sung, 1995). Thus, it is theoretically possible that bradycardia in anorexia nervosa patients with prolonged QT could confer increased risk for ventricular arrhythmias. Two intriguing studies by Swenne (2000) and Swenne and Larsson (1999) suggest that QT prolongation is caused by the ‘‘catabolic state of anorexia nervosa per se,’’ and furthermore that reversing the catabolic state with judicious refeeding results in prompt resolution of the QT prolongation. The first study showed that QT prolongation and dispersion were a function of the final rate of weight loss that correlates with an active catabolic state. The second study of 32 patients in whom 18 had prolonged QTs, demonstrated normalization of the QT intervals within 3 days of refeeding with only an average weight increase of 133 g/ day. Of note, no electrolyte abnormalities occurred. This suggests that QT prolongation can be corrected by reversing the catabolic state, long before significant weight gain occurs.
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A higher prevalence of mitral valve prolapse is found in anorexia nervosa patients than in controls (De Simone et al., 1994; Johnson, Humphries, Shirley, Mazzoleni, & Noonan, 1986) and may be due to valvulo-ventricular disproportion in which the valvular structures do not undergo the same decrease in size as the ventricles during starvation (Schocken, Holloway, & Powers, 1989). It usually resolves with weight restoration. A study of 43 patients with anorexia nervosa demonstrated a higher rate of arrhythmias in the 16 patients found to have mitral valve prolapse (Johnson et al., 1986). Despite these findings, it is unclear whether the higher prevalence of mitral valve prolapse in anorexia nervosa is associated with increased cardiovascular mortality, but it may be associated with chest pain and palpitations. In addition, patients with anorexia nervosa may have the following EKG findings: bradycardia, right axis deviation, diminished QRS voltage, flattened T waves, QT prolongation, and minor and complex arrhythmias. To what extent these findings are markers for sudden death is unclear (Table 1).
4. Refeeding One of the greatest periods of increased cardiac risk actually occurs during the early phases of refeeding and weight restoration in anorectic patients who are more than 10% below their IBW. Left ventricular (LV) mass in anorexia nervosa has been shown to be reduced by 20% when compared to healthy thin controls, and reduced by 35% compared to normal weight controls (De Simone et al., 1994). Conflicting data exist on whether LV function is also reduced in anorexia nervosa. Kahn, Halls, Bianco, and Perlman (1991) studied eight anorexia nervosa patients with radionuclide ventriculography before and after regaining 5–10% of their weight. All eight patients had normal rest and exercise LV function before refeeding, and all but one had normal LV function after refeeding. Half were noted to have regional wall motion abnormalities of unclear significance. De Simone et al. (1994), on the other hand, found reduced cardiac output in anorexia nervosa patients compared to controls. Lands, Pavilanis, Charge, and Coates (1992) evaluated maximum work capacity (Wmax) in 9 anorexia nervosa patents and 10 controls. Although 6/9 patients compared to 2/10 controls had reduced Wmax as predicted for age and height, Wmax and cardiac output were normal when adjusted for percent of IBW. This suggests that the diminished cardiac output reflects reduced lean body mass and not a primary cardiac abnormality. Even if weight-adjusted cardiac output is normal, in the setting of significantly reduced LV mass and decreased preload, heart failure can be precipitated during the early phases of refeeding because of fluid overload, increased oxygen demand, and reduced LV dysfunction. Fluid overload often occurs during refeeding if fluid and nutritional repletion are given too aggressively (Birmingham, Alothman, & Goldner, 1996; Melchior, 1998; Solomon & Kirby, 1990). Increased oxygen demand results from the anabolic state associated with refeeding. All of these can overwhelm the diminished capacity of the weakened heart muscle. Hypophosphatemia, a frequent complication of overly aggressive carbohydrate
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repletion, can also cause LV systolic dysfunction and heart failure (Kohn, Golden, & Shenker, 1998; Solomon & Kirby, 1990).
5. Refeeding the anorectic patient Therefore, frequent clinical assessments are very important especially during the more severe phases and the early weeks of refeeding. The mainstay of treatment involves nutritional repletion. A simple tenet, which must be followed, is ‘‘start low and go slow.’’ Referral to a dietician for their ongoing involvement in the weight restoration process are important components of the treatment plan. In general, the goal should be to effectuate a 1- to 2-lb weight gain per week, to within 90% of IBW. There are two basic ways to proceed. The patient can either be empirically started on a 800–1000-kcal diet plan with incremental 200–300-kcal increases every 4–5 days until adequate calories are attained to sustain consistent weight gain, or the dietitian can specifically calculate resting energy expenditure (REE) by obtaining an indirect calorimetry test or by calculating REE with the Harris – Benedict equation. The value obtained is then multiplied by an activity factor of 1.2–1.4, depending on how active the patient is, to ascertain the basal energy expenditure. Regardless of which approach is used, the dietician must work closely with the patient to craft a well-balanced and palatable diet plan with which the patient will comply, and which promotes successful and consistent weight gain. In general, at least for the first few weeks of treatment, these patients should be weighed at least once a week. There are many different perturbations on this main theme. Some programs supplement oral diets with liquid calorie drinks to achieve the daily caloric goal; others revert to enteral feeding through daily placement of small caliber nasogastric tubes or a percutaneous enterogastrostomy tube for more refractory cases, or even rarely, utilize total parenteral nutrition (Mehler & Weiner, 1993). Standard oral diet plans are the preferred method. The clinical complication seen during the early stages of refeeding is referred to as the refeeding syndrome. It is a well-recognized phenomenon that is most graphically manifested by cardiovascular collapse and even death following oral, enteral, or parenteral intake of large amounts of highly caloric nutrients, especially those high in glucose. The mechanism of the critically important hypophosphatemia is due to a shift of phosphate from the extracellular space to the intracellular one during refeeding. The transition to an anabolic state with refeeding results in the incorporation of phosphate into newly synthesized tissue and a depletion of serum phosphate and adenosine triphosphate. The result is a reduction in cardiac capacity and stroke volume. This sobering syndrome is completely preventable as long as refeeding is started slowly, and caloric increases are modest during the first few weeks. The dietitian’s expertise to accurately calculate caloric needs is invaluable. Assiduously monitoring serum electrolytes, especially phosphorous, every few days during the early refeeding period will prevent the development of this syndrome. In addition, it is important to monitor the patient for any
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sustained increase in pulse rate above their baseline and for the development of peripheral edema. These can be harbingers of imminent cardiac decompensation.
6. Endocrine complications Anorexia nervosa has profound and widespread effects on the endocrine system. Glucose metabolism is often disturbed. Mild hypoglycemia is common. Severe hypoglycemia denotes a poor prognosis (Rich, Caine, Findling, & Shaker, 1990). The pathogenesis of hypoglycemia reflects depletion of hepatic glycogen stores and gluconeogenic substrates superimposed on a chronically malnourished state along with excessive exercise. Abnormalities on thyroid function tests are often present in the form of the euthyroid sick syndrome and need not be treated. Serum levels of L-thyroxine (T4) are normal to low, as are levels of triiodothyronine (T3). Levels of thyroid-stimulating hormone are normal, but levels of reverse T3 are increased. This syndrome does not require specific treatment because with resolution of anorexia nervosa, all these thyroid indicators return to normal. Similarly, leukopenia (low white blood cell count) and mild anemia, may also be present, but once again resolve with weight gain (Mehler & Howe, 1995). Moreover, anorectic patients who lose weight exclusively by restricting intake have normal electrolyte levels until the very late stages of illness. The presence of hypokalemia, or metabolic alkaloses should raise concern that the anorectic patient may be surreptitiously purging through vomiting or diuretic abuse (Greenfield, Mickley, Quinlan, & Roloff, 1995; Mehler, 1998).
7. Amenorrhea Secondary amenorrhea occurs in over 95% of women with anorexia nervosa. The amenorrhea of anorexia nervosa is characterized by low circulating levels of the pituitary gonadotrophs (follicular-stimulating hormone, FSH, and luteinizing hormone, LH) despite low estrogen levels. There is a reversion to a prepubertal state with blunted LH and FSH secretion secondary to a decrease in the pulsatility of gonadotropin-releasing hormone. Withdrawal bleeding after a progestin challenge does not occur. These abnormalities are part of a global hypothalamic dysfunction associated with loss of weight and body fat. Men with anorexia nervosa also have hypogonadism and low testosterone levels. In addition, low leptin levels, emotional unrest, and excessive exercise may play a role in its pathogenesis. Resumption of menses in anorexia nervosa is an important issue because it marks a substantial improvement in their clinical status and it would dissuade clinicians from using additional hormonal therapy. The general rule is that a weight approximately 90% of IBW is the average weight at which return of menses will occur within 6 months in most women with anorexia nervosa (Mehler, Eckel, & Donahoo, 1999). This generally correlates with higher estradiol levels. In 10–15% of patients, the amenorrhea persists despite weight gain and is likely attributable to unresolved emotional issues. It is important to advise these
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patients that despite their amenorrheic state, anorectic patients are not totally protected from pregnancy and contraception should be utilized.
8. Osteoporosis Over 50% of female patients with anorexia nervosa have osteoporosis (Golden, Jacobson, Schebandach, et al., 1997). Although it was thought that the amenorrhea experienced by anorectic patients was devoid of adverse consequences, this thinking has radically changed. Osteoporosis is one of the most serious clinical concerns that accompanies amenorrhea and weight loss. The peak bone mass achieved as a young adult is a major determinant of bone density and fracture risk. Anorexia nervosa is associated with markedly reduced bone density, especially at the lumbar spine but also at the proximal femur and distal radius (Bachrach, Guido, Katzman, Litt, & Marcus, 1990; Biller, Saxes, Herzog, Holzmman, & Klibanski, 1989; Davies et al., 1990; Powers, 1999; Rigotti, Nussbaum, Herzog, & Neer, 1984). A recent study showed that the long-term risk of any fracture is elevated 2.9-fold (Rigotti, Neer, Skates, Herzog, & Nussbaum, 1991). This could cause major widespread problems since anorexia nervosa is the third most common chronic condition in adolescence after obesity and asthma (Lucas, Melton, Crowson, & O’Fallon, 1999). The marked degree of osteopenia in anorexia nervosa is based on a number of factors. While estrogen deficiency and its resultant amenorrhea are involved, other factors contribute. This became increasingly clear after trials with estrogen replacement surprisingly failed to result in improvement in bone density (Klibanski, Biller, Schoenfeld, Herzog, & Saxe, 1995; Lucas, Beard, O’Fallon, & Kurland, 1991; Ward, Brown, & Treasure, 1997). Further, the severity of osteopenia in anorexia nervosa is dependent on lean body mass not the duration of estrogen deficiency (Hegenroeder, 1995). Hypercortisolemia has been reported in anorexia (Grinspoon et al., 1999). Reduced levels of insulin-like growth factor I (Soyka, Grinspoon, Kevitsky, Herzog, & Klibanski, 1999) along with excessive exercise may also be involved (Cumming, 1996). Because anorexia nervosa appears to be a low-turnover state associated with increased bone resorption and high serum cortisol levels, and therefore different from the osteopenia of postmenopausal women, the routine usage of estrogen to attenuate bone loss must be reconsidered (Grinspoon et al., 2001; Hotta et al., 2000; Lennkh et al., 1999) Given the unclear exact etiology of osteopenia in anorexia nervosa, along with the at best minimal benefit from estrogen, the primary goal of treatment must be to restore weight and avoid bone loss. Normalized weight is the best predictors of bone density (Goebel, Schweiger, Kruger, & Fichter, 1999). This must be discussed with the patient in the early phases of treatment because as anorexia nervosa becomes more chronic, an increase in body weight may be insufficient to completely restore bone mineral density (Baker, Roberts, & Towell, 2000). Calcium supplementation (1500 mg/day) along with vitamin D (400 IU/day) should be prescribed, especially if cortisol excess is indeed involved in the pathogenesis of osteoporosis (Sambrook, Birmingham, & Kelly, 1993). There are currently no definitive data in anorexia nervosa to support the utilization of bisphosphonates, although they too have been
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found to be beneficial to prevent corticosteroid-induced osteoporosis (Adachi et al., 1997). Clinicians should closely monitor bone mineral density levels with bone densitometry in moderate to severe anorexia especially once amenorrhea has occurred. If abnormal, it should be repeated every 1–2 years to monitor the effectiveness of therapy. When the bone density is found to be osteopenic, or frankly osteoporotic, despite adequate calcium and vitamin D, consideration should be given to more aggressive therapies, such as bisphosphonates or nasal calcitonin given the lifelong risk of fractures (Kulak & Bilezikian, 1999). Bone markers, such as the resorption marker N-telopeptide, may also be used to assess the effectiveness of therapy because they stabilize more rapidly than does bone mineral density (Cummings et al., 2000; Greenspan, Parker, & Ferguson, 1998).
9. Fertility Women who have recovered from anorexia do not have an increased incidence of infertility. These complications are only increased in women with an active eating disorder (Bulik, 1999; Conti, Abraham, & Taylor, 1998; Frako & Walton, 1993). Of note, despite their amenorrhea, patients with anorexia nervosa can become pregnant. Contraceptives should therefore be recommended if the possibility of an unwanted pregnancy exists. Interestingly, patients with anorexia nervosa may demonstrate a reduction in their eating disorder symptoms during pregnancy (Blais et al., 2000), but may relapse after delivery due to conflicts about changes in body shape (Fahy, 1991; Mehler, 2000).
10. Gastrointestinal Patients with anorexia nervosa frequently have such gastrointestinal complications as delayed gastric emptying and decreased intestinal motility, both of which produce an exaggerated sense of postprandial fullness, early satiety, abdominal pain, and constipation (Stracher, Bergman, Steiner-Mittelbach, Kiss, & Abatzi, 1994). Alterations in antral motility, which have been thought to be responsible for delayed gastric emptying, seem to resolve with weight gain. Feelings of postprandial fullness may frustrate initial attempts at weight restoration. A concerted effort should be made to determine whether these common gastrointestinal complaints are functional or are caused by an organic abnormality. If the latter is the case, treatment with prokinetic agents may be successful. Acute gastric dilatation, which is sometimes accompanied, by duodenal dilatation, has also been reported during early refeeding of severely anorexic patients. The gastric dilatation is characterized by rapid onset of nausea, vomiting, pain, and abdominal distention. Chronic constipation is another frequently reported complaint. In the absence of a history of laxative abuse, this complication is typically caused by reflex hypofunctioning of the colon secondary to inadequate food intake. Rarely, rectal impaction can occur for similar reasons.
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These problems can usually be resolved with patience and the addition of high-fiber foods to the diet. Abnormalities of the pancreas are infrequent, although severe protein–calorie malnutrition may precipitate functional and structural abnormalities. Refeeding pancreatitis, which typically occurs during the early stages of the refeeding process, is the most commonly reported complication. Some investigators have suggested that priming of the ductal system with inspissated secretions during starvation may set the stage for refeeding pancreatitis. A clear association between liver disease and anorexia nervosa has never been defined. Slight elevations of serum transaminase levels may indicate that refeeding of a starved patient needs to be slowed. Such elevations are usually reversible.
11. Inpatient hospitalization No controlled trials have been performed to define with certainty when inpatient hospitalization is indicated. Generally, anorexia nervosa is classified as mild, moderate, or severe based on the percentage decrement below IBW (Table 2). Most authorities agree that when a patient’s weight has fallen into the severe range (25 –30% below IBW) that hospitalization is generally indicated. In addition, hospitalization is recommended for patients whose weight loss is rapidly progressive, as well as for those with serious electrolyte disorders, cardiac arrhythmias, and perhaps for newly attained heart rates less than 30–35 bpm especially if not sinus rhythm. The presence of a serious comorbid psychiatric illness or incapacitating obsessions and compulsions also should be considered for inpatient hospitalization (Practice guidelines for the treatment of patients with eating disorders, 2000). Once hospitalized, refeeding in a structured environment, with specialized staff who are familiar with the unique features of eating disordered patients, is recommended. Notwithstanding the constraints of managed care organizations, proper medical treatment should aim for the attainment of 85–90% of IBW. There is solid evidence that suggest, that if a patient with anorexia nervosa can be hospitalized until this amount of weight is gained and maintained for a few days, that relapses in the following 5 years are significantly reduced compared to when they are discharged at a much lower weight. However, the decision to hospitalize patients must be carefully deliberated for each individual case with judicious input from an internist and mental health professional who is very familiar with anorexia nervosa, because lengthy admission might interfere with the potential for long-term recovery (Gowers, Weetman, Shore, Hossain, & Elvins, 2000).
Table 2 Severity of anorexia nervosa Mild Moderate Severe a
10% below IBW a 20% below IBW a > 30% below IBW a
IBW is calculated as 100 lb for a height of 5 ft tall and 4 – 5 lb for every additional inch.
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12. Summary Anorexia nervosa is associated with multiple medical complications. These patients require treatment by a multidisciplinary team that should include medical input (Weiner, 1999). The severity of the illness dictates the levels of appropriate input and care. The primary care physician has a valuable role in pointing out the reality and severity of this chronic psychiatric illness while monitoring and assessing the patient’s physical status (Walsh, Wheat, & Freund, 2000).
References Adachi, J., Bensen, W. G., Brown, J., Hanley, D., Hudsman, A., Josse, R., Kendler, D. L., Lentle, B., Olszynski, W., Ste-Marie, L. G., Tenenhouse, A., & Chines, A. A. (1997). Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. New England Journal of Medicine, 337, 382 – 387. Bachrach, L. K., Guido, D., Katzman, D. L., Litt, I. F., & Marcus, R. (1990). Decreased bone density in adolescent girls with anorexia nervosa. Pediatrics, 86, 440 – 447. Baker, D., Roberts, R., & Towell, T. (2000). Factors predictive of bone mineral density in eating disordered women: a longitudinal study. International Journal of Eating Disorders, 27, 29 – 35. Beumont, P. J., & Large, M. (1991). Hypophosphatemia, delirium and cardiac arrhythmia in anorexia nervosa. Medical Journal of Australia, 155, 519 – 522. Biller, B. M. K., Saxes, U., Herzog, D. B., Holzman, S., & Klibanski, A. (1989). Mechanisms of osteoporosis in adult and adolescent women with anorexia nervosa. Journal of Clinical Endocrinology and Metabolism, 68, 548 – 552. Birmingham, C. L., Alothman, A. F., & Goldner, E. M. (1996). Anorexia nervosa: refeeding and hypophosphatemia. International Journal of Eating Disorders, 20, 211 – 213. Blais, M. A., Becker, A. E., Flores, A. T., Nussbaum, K. M., Greemwood, D. N., & Herzog, D. D. (2000). Pregnancy: outcome and impact on a cohort of eating disordered women. International Journal of Eating Disorders, 27, 140 – 149. Bulik, C. M. (1999). Intensive prenatal care for pregnant anorexic patients. Journal of Clinical Psychiatry, 60, 130 – 135. Conti, J., Abraham, S., & Taylor, A. (1998). Eating behavior and pregnancy outcome. Journal of Psychosomatic Research, 44, 465 – 477. Cooke, R. A., & Chambers, J. B. (1995). Anorexia nervosa and the heart. British Journal of Hospital Medicine, 54, 313 – 317. Cooke, R. A., Chambers, J. B., Singh, R., Todd, G. J., Smeeton, N. C., Treasure, J., & Treasure, T. (1994). QT interval in anorexia nervosa. British Heart Journal, 72, 69 – 73. Cumming, D. (1996). Exercise-associated amenorrhea, low bone density and estrogen replacement therapy. Archive of Internal Medicine, 156, 2193 – 2195. Cummings, S. R., Palmero, C., Wallace, R., Pearson, J., Eckert, S., & Black, D. (2000). Monitoring osteoporosis recovery with bone density. JAMA, Journal of the American Medical Association, 283, 1318 – 1321. Davies, K. M., Pearson, P. H., Huseman, C. A., Greger, N. G., Kimmel, D. K., & Recker, R. R. (1990). Reduced bone mineral in patients with eating disorders. Bone, 11, 143 – 147. De Simone, G., Scalfi, L., Galderisi, M., Celentano, A., Di Biase, G., Tammaro, P., Garofalo, M., Mureddo, G. F., de Devitiis, O., & Contaldo, F. (1994). Cardiac abnormalities in young women with anorexia nervosa. British Heart Journal, 71, 287 – 292. Durakovic, Z., Durakovic, A., & Korsic, M. (1994). Changes of the corrected QT interval in the electrocardiogram of patients with anorexia nervosa. International Journal of Cardiology, 45, 115 – 120. Fahy, T. A. (1991). Eating disorders in pregnancy. Psychological Medicine, 21, 577 – 580.
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Frako, D. K., & Walton, B. E. (1993). Pregnancy eating disorders. International Journal of Eating Disorders, 13, 41 – 48. Goebel, G., Schweiger, U., Kruger, R., & Fichter, M. M. (1999). Predictors of bone mineral density in patients with eating disorders. International Journal of Eating Disorders, 25, 143 – 150. Golden, H. N., Jacobson, M. S., Schebandach, J., Solanto, M. V., Hertz, S. M., & Shenker, I. R. (1997). Resumption of menses in anorexia nervosa. Archive of Pediatric Adolescent Medicine, 151, 16 – 21. Gould, L., Reddy, C. V., Singh, B. K., & Zen, B. (1980). Evaluation of cardiac conduction in anorexia nervosa. Pacing and Clinical Electrophysiology, 3, 660 – 665. Gowers, S. G., Weetman, J., Shore, A., Hossain, F., & Elvins, R. (2000). Impact of hospitalization on the outcome of adolescent anorexia nervosa. British Journal of Psychiatry, 176, 138 – 141. Greenfield, D., Mickley, D., Quinlan, D. M., & Roloff, P. (1995). Hypokalemia in outpatients with eating disorders. American Journal of Psychiatry, 152, 60 – 63. Greenspan, S. L., Parker, R. A., & Ferguson, L. (1998). Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy. Journal of Bone Mineral Research, 13, 1431 – 1438. Grinspoon, S., Miller, K., Coyle, C., Krempin, J., Herzog, D., & Klibanski, A. (1999). Severity of osteopenia in estrogen deficient women with anorexia nervosa. Journal of Clinical Endorcrinology and Metabolism, 84, 2049 – 2055. Grinspoon, S., Thomas, E., Pitts, S., Gross, E., Mickley, D., Miller, K., Herzog, D., & Klibanski, A. (2001). Prevalence and predictors of regional osteopenia in women with anorexia nervosa. Annals of Internal Medicine, 133, 790 – 794. Hegenroeder, A. C. (1995). Bone mineralization, hypothalamic amenorrhea and sex steroid therapy in female adolescents. Journal of Pediatrics, 126, 683 – 689. Hotta, M., Fukada, I., Sato, K., Hizuka, N., Shibasaki, T., & Takano, K. (2000). The relationship between bone turnover and body weight, serum insulin growth factor-I and serum IGF-binding protein levels in patients with anorexia nervosa. Journal of Clinical Endocrinology and Metabolism, 85, 200 – 206. Isner, J. M., Roberts, W. C., Heymsfield, S. B., & Yager, J. (1985). Anorexia nervosa and sudden death. Annals of Internal Medicine, 102, 49 – 52. Johnson, G. L., Humphries, L. L., Shirley, P. B., Mazzoleni, A., & Noonan, J. A. (1986). Mitral valve prolapse in patients with anorexia nervosa and bulimia. Archive of Internal Medicine, 146, 1525 – 1529. Kahn, D., Halls, J., Bianco, JA., & Perlman, S. B. (1991). Radionuclide ventriculography in severely underweight anorexia nervosa patients before and during refeeding therapy. Journal of Adolescent Health, 12, 301 – 306. Kay, W. H., George, D. T., Gwirtsman, H. E., Jimerson, D. C., Goldstein, D. S., Ebert, M. H., & Lake, C. R. (1990). Isoproterenol infusion test in anorexia nervosa: assessment of pre- and post-beta-noradrenergic receptor activity. Psychopharmacology Bulletin, 26, 355 – 359. Keys, A., Brozek, J., Henschel, A., Mickelsen, O., & Taylor, H. L. (1950). The biology of human starvation, vol. 1. Minneapolis, University of Minnesota Press. Klibanski, A., Biller, B. M., Schoenfeld, D. A., Herzog, D. B., & Saxe, V. C. (1995). The effects of estrogen administration on trabecular bone loss in anorexia nervosa. Journal of Clinical Endocrinology and Metabolism, 80, 898 – 904. Kohn, M. R., Golden, N. H., & Shenker, I. R. (1998). Cardiac arrest and delirium: presentations of the refeeding syndrome in severely malnourished adolescents with anorexia nervosa. Journal of Adolescent Health, 22, 239 – 243. Kollai, M., Bonyhay, I., Jokkel, G., & Szonyi, L. (1994). Cardiac vagal hyperactivity in adolescent anorexia nervosa. European Heart Journal, 15, 1113 – 1118. Kreipe, R. E., Goldstein, B., DeKing, D. E., Tipton, R., & Kempski, M. H. (1994). Heart rate power spectrum analysis of autonomic dysfunction in adolescents with anorexia nervosa. International Journal of Eating Disorders, 16, 159 – 165. Kulak, C. A. M., & Bilezikian, J. P. (1999). Bone mass measurement in identification of women at risk for osteoporosis. International Journal of Fertility, 44, 269 – 278.
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Lands, L., Pavilanis, A., Charge, T. D., & Coates, A. L. (1992). Cardiopulmonary response to exercise in anorexia nervosa. Pediatric Pulmonology, 13, 101 – 107. Lennkh, C., Zwaan, M., Bailer, V., Strnad, A., Nagy, C., el-Giamal, N., Wiesnagrotzki, S., Vytiska, E., Huber, J., & Kasper, S. (1999). Osteopenia in anorexia nervosa: specific mechanisms of bone loss. Journal of Psychiatric Research, 33, 349 – 356. Lucas, A. R., Beard, C. M., O’Fallon, W. M., & Kurland, L. T. (1991). 50-year trends in the incidence of anorexia nervosa in Rochester, Minn. American Journal of Psychiatry, 148, 917 – 922. Lucas, A. R., Melton, J., Crowson, C. S., & O’Fallon, W. M. (1999). Long-term fracture risk among women with anorexia nervosa. Mayo Clinic Proceedings, 74, 972 – 977. Mehler, P. S. (1998). Electrolyte disorders in bulimia. Eating Disorders: the Journal of Treatment and Prevention, 6, 65 – 68. Mehler, P. S. (2000). Eating disorders. In: R. V. Lee, L. A. Barbour, P. E. Garner, & E. Keely (Eds.), Medical care of the pregnant patient (1st ed., pp. 140 – 148). Philadelphia, PA: ACP Press. Mehler, P. S. (2001). Diagnosis and care of patients with anorexia nervosa in primary care settings. Annals of Internal Medicine, 134, 1048 – 1059. Mehler, P. S., Eckel, R. H., & Donahoo, W. T. (1999). Leptin levels in restricting and purging anorectics. International Journal of Eating Disorders, 26, 189 – 194. Mehler, P. S., & Howe, S. E. (1995). Serious fat atrophy with leukopenia in anorexia nervosa. American Journal of Hematology, 49, 171 – 172. Mehler, P. S., & Weiner, K. L. (1993). Anorexia nervosa and total parenteral nutrition. International Journal of Eating Disorders, 14, 297 – 305. Melchior, J. C. (1998). From malnutrition to refeeding during anorexia nervosa. Current Opinion Clinical Nutrition Metabolic Care, 1, 481 – 485. Neumarker, K. J. (1997). Mortality and sudden death in anorexia nervosa. International Journal of Eating Disorders, 21, 205 – 212. Panagiotopoulos, C., McCrindle, B. W., Hick, K., & Katzman, D. K. (2000). Electrocardiographic findings in adolescents with eating disorders. Pediatrics, 105, 1100 – 1105. Petretta, M., Bonaduce, D., Scalfi, L., de Filippo, E., Marciano, F., Migauz, M. L., Themistoclakis, S., Ianniciello, A., & Cantaldo, F. (1997). Heart rate variability as a measure of autonomic nervous system function in anorexia nervosa. Clinical Cardiology, 20, 219 – 224. Powers, P. S. (1999). Osteoporosis and eating disorders. Journal of Pediatric Adolescent Gynecology, 12, 51 – 57. Practice guidelines for the treatment of patients with eating disorders. (2000). American Journal of Psychiatry, 157, 1 – 39. Rechlin, T., Weis, M., Ott, C., Bleichner, F., & Joraschky, P. (1998). Alterations of autonomic cardiac control in anorexia nervosa. Biological Psychiatry, 43, 358 – 363. Rich, L. M., Caine, M. R., Findling, J. W., & Shaker, J. L. (1990). Hypoglycemic coma in anorexia nervosa. Archive of Internal Medicine, 150, 894 – 895. Rigotti, M. A., Neer, R. M., Skates, S. J., Herzog, D. B., & Nussbaum, S. R. (1991). The clinical course of osteoporosis in anorexia nervosa: a longitudinal study of cortical bone mass. JAMA, Journal of the American Medical Association, 265, 1133 – 1138. Rigotti, N. A., Nussbaum, S. R., Herzog, D. B., & Neer, R. M. (1984). Osteoporosis in women with anorexia nervosa. New England Journal of Medicine, 311, 1601 – 1606. Sambrook, P., Birmingham, J., & Kelly, P. (1993). Prevention of corticosteroid osteoporosis, a comparison of calcium, calcitrol and calcitonin. New England Journal of Medicine, 328, 1747 – 1752. Schocken, D. D., Holloway, J. D., & Powers, P. S. (1989). Weight loss and the heart. Effects of anorexia nervosa and starvation. Archive of Internal Medicine, 149, 877 – 881. Solomon, S. M., & Kirby, D. F. (1990). The refeeding syndrome: a review. Journal of Parenteral and Enteral Nutrition, 14, 90 – 97. Soyka, L. A., Grinspoon, S., Kevitsky, L. L., Herzog, D. B., & Klibanski, A. (1999). The effects of anorexia
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nervosa on bone metabolism in female adolescents. Journal of Clinical Endocrinology and Metabolism, 84, 4489 – 4496. Stracher, G., Bergman, H., Steiner-Mittelbach, G., Kiss, A., & Abatzi, T. A. (1994). Primary anorexia nervosa gastric emptying and antral motor activity. International Journal of Eating Disorders, 14, 297 – 305. Sullivan, P. F. (1995). Mortality in anorexia nervosa. American Journal of Psychiatry, 152, 1073 – 1074. Swenne, I. (2000). Heart risk associated with weight loss in anorexia nervosa and eating disorders: electrocardiographic changes during the early phase of refeeding. Acta Paediatrica, 89, 447 – 452. Swenne, I., & Larsson, P. T. (1999). Heart risk associated with weight loss in anorexia nervosa and eating disorders: risk factors for QT interval prolongation and dispersion. Acta Paediatrica, 88, 304 – 309. Tan, H. L., Hou, C. J., Lauer, M. R., & Sung, R. J. (1995). Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Annals of Internal Medicine, 122, 701 – 714. Walsh, J. M., Wheat, M. E., & Freund, K. (2000). Detection, evaluation and treatment of eating disorders—the role of the primary care physician. Journal of General Internal Medicine, 15, 577 – 590. Ward, A., Brown, N., & Treasure, J. (1997). Persistent osteopenia after recovering from anorexia nervosa. International Journal of Eating Disorders, 22, 71 – 75. Weiner, K. (1999). Multidisciplinary team treatment: working together. In: P. S. Mehler, & A. E. Andersen (Eds.), Eating disorders: a guide to medical care and complications ( pp. 27 – 43). Baltimore: Johns Hopkins University Press.
Medical issues in the patient with anorexia nervosa David Leonard, Philip S. Mehler* Department of Internal Medicine, Denver Health, Denver, CO, USA University of Colorado Health Sciences Center, Denver, CO, USA
1. Introduction Most medical complications of anorexia nervosa are a direct result of the malnutrition and weight loss that defines this illness. Few organ systems are spared the progressive deterioration that marks the clinical course of anorexia nervosa. The aggregate annual mortality rate associated with anorexia nervosa is more than 12 times higher than the annual death rate of all causes of death for women 15–24 years old in the general population (Sullivan, 1995).
2. Dermatologic complications In patients with anorexia nervosa, the skin is typically dry and scaly. There is often soft, downy hair growth, referred to as lanugo hair, on the sides of the face, the back, and on the arms and legs. Although the exact cause of the lanugo hair growth is unknown, it is not a sign of virilization. Moreover, it always recedes with weight restoration. Hair loss and brittle nails are also common findings. Starvation-associated pruritus and dry skin are caused by decreased sebaceous gland activity. These patients often have a yellow tinge to their skin. In the past, it was assumed that this was attributable to high circulating levels of beta-carotene. This is of no clinical significance, and more recent studies have not found hypercarotenemia (Mehler & Lezotte, 1998).
* Corresponding author. Denver Health, 660 Bannock Street, Denver, CO 80204, USA. Tel.: +1-303-4363234; fax: +1-303-436-5772. E-mail address: [email protected] (P.S. Mehler). 1471-0153/01/$ – see front matter D 2001 Elsevier Science Ltd. All rights reserved. PII: S 1 4 7 1 - 0 1 5 3 ( 0 1 ) 0 0 0 5 8 - 7
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3. Cardiovascular The heart was once thought to be spared the ill effects of starvation. However, based on research during World War II, we now know that half of the deaths occurring in anorexia nervosa are due to cardiovascular complication (Neumarker, 1997). A significant proportion of these deaths occur during refeeding, highlighting the need for careful management of this phase of treatment. The cardiovascular abnormalities found in anorexia nervosa are listed in Table 1, but it is unclear to what extent these findings are markers for cardiovascular complications. In fact, some of these findings, specifically bradycardia and reduced blood pressure to levels as low as 70–80, are actually normal adaptations to starvation. Bradycardia with heart rates as low as 25–30 beats/min (bpm) may be seen in severe anorexia nervosa accompanied by excessive weight loss, and may be an appropriate energy conserving adaptation (Keys, Brozek, Henschel, Mickelsen, & Taylor, 1950; Mehler, 2001). Despite a case report of heart block causing bradycardia in an anorexia nervosa patient with syncope (Gould, Reddy, Singh, & Zen, 1980), evidence suggests that neuronal vagal hyperactivity rather than conduction abnormalities usually mediate the bradycardia seen in anorexia nervosa. Power spectral analysis (PSA) of beat-to-beat heart rate variability is a proxy method used to estimate vagal and sympathetic input to the heart. Using PSA, studies have shown increased vagal tone in supine anorexia nervosa patients as well as during 24-h monitoring (Kollai, Bonyhai, Jokkel, & Szonyi, 1994; Kreipe, Goldstein, DeKing, Tipton, & Kempski, 1994; Petretta et al., 1997). Kreipe et al. (1994) also found that anorexia nervosa patients on standing had an exaggerated increase in sympathetic tone compared to
Table 1 Cardiovascular findings in anorexia nervosa Structural Decreased LV mass Decreased LV volume Mitral valve prolapse Vertical rotation of the heart Hemodynamic Hypotension (low blood pressure) Bradycardia (heart rate < 60 bpm) ? Decrease cardiac output ? Decrease LV function Electrocardiographic QT prolongation Right axis deviation Low-voltage QRS ST segment depression T wave flattening Arrhythmias
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controls. However, that excessive sympathetic output was offset by a smaller than expected decrease in parasympathetic tone on standing, which may account for the common symptoms of orthostatic hypotension, dizziness, and decreased exercise tolerance seen in anorexia nervosa (Kollai et al., 1994). Rechlin, Weis, Ott, Bleichner, and Joraschky (1998) found diminished sympathetic tone in supine anorexia nervosa patients less than 75% of ideal body weight (IBW), but not in anorexia nervosa patients greater than 75% of IBW. These studies suggest that the bradycardia seen in anorexia nervosa is mediated by altered autonomic function, which returns to normal with weight gain. With judicious refeeding and careful attention to maintaining normal levels of electrolytes, sinus bradycardia resolves appropriately (Kay et al., 1990) and thus in and of itself does not necessarily warrant cardiac monitoring. Prolonged QT interval on an EKG has been proposed as a risk factor for fatal arrhythmias in anorexia nervosa patients. Studies are conflicting as to the prevalence of QT prolongation in anorexia nervosa, ranging from 0% to over 50% (Cooke et al., 1994; Durakovic, Durakovic, & Korsic, 1994; Panagiotopoulos, McCrindle, Hick, & Katzman, 2000; Swenne & Larsson, 1999). Furthermore, whether prolonged QT is actually a causative factor in anorexia nervosa death is unknown. In a case study by Isner, Roberts, Heymsfield, and Yager (1985) of three patients who died of anorexia nervosa, all had prolonged QT prior to admission, and all three likely died of fatal arrhythmias. In a case study of five anorexic patients whose admissions where complicated by cardiac arrhythmias in four of the patients, all had prolonged QT (Beumont & Large, 1991). Each patient also developed severe hypophosphatemia during refeeding, and the two who died were also taking tricyclic antidepressants. These findings suggest that prolonged QT in the setting of electrolyte abnormality or tricyclic antidepressants may have been a contributing factor in the deaths. However, it is unclear to what extent the prolonged QT interval itself is a marker for sudden death. The mechanisms underlying the prolonged QT interval in anorexia nervosa are not well understood. QT dispersion, a measure of QT interval variation between leads, may be increased in anorexia nervosa. QT dispersion reflects unsynchronous repolarization (Cooke & Chambers, 1995) and facilitates EADs (early after depolarizations), which are thought to give rise to ventricle arrhythmias. Bradycardia in the setting of prolonged QT may also facilitate development of EADs (Tan, Hou, Lauer, & Sung, 1995). Thus, it is theoretically possible that bradycardia in anorexia nervosa patients with prolonged QT could confer increased risk for ventricular arrhythmias. Two intriguing studies by Swenne (2000) and Swenne and Larsson (1999) suggest that QT prolongation is caused by the ‘‘catabolic state of anorexia nervosa per se,’’ and furthermore that reversing the catabolic state with judicious refeeding results in prompt resolution of the QT prolongation. The first study showed that QT prolongation and dispersion were a function of the final rate of weight loss that correlates with an active catabolic state. The second study of 32 patients in whom 18 had prolonged QTs, demonstrated normalization of the QT intervals within 3 days of refeeding with only an average weight increase of 133 g/ day. Of note, no electrolyte abnormalities occurred. This suggests that QT prolongation can be corrected by reversing the catabolic state, long before significant weight gain occurs.
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A higher prevalence of mitral valve prolapse is found in anorexia nervosa patients than in controls (De Simone et al., 1994; Johnson, Humphries, Shirley, Mazzoleni, & Noonan, 1986) and may be due to valvulo-ventricular disproportion in which the valvular structures do not undergo the same decrease in size as the ventricles during starvation (Schocken, Holloway, & Powers, 1989). It usually resolves with weight restoration. A study of 43 patients with anorexia nervosa demonstrated a higher rate of arrhythmias in the 16 patients found to have mitral valve prolapse (Johnson et al., 1986). Despite these findings, it is unclear whether the higher prevalence of mitral valve prolapse in anorexia nervosa is associated with increased cardiovascular mortality, but it may be associated with chest pain and palpitations. In addition, patients with anorexia nervosa may have the following EKG findings: bradycardia, right axis deviation, diminished QRS voltage, flattened T waves, QT prolongation, and minor and complex arrhythmias. To what extent these findings are markers for sudden death is unclear (Table 1).
4. Refeeding One of the greatest periods of increased cardiac risk actually occurs during the early phases of refeeding and weight restoration in anorectic patients who are more than 10% below their IBW. Left ventricular (LV) mass in anorexia nervosa has been shown to be reduced by 20% when compared to healthy thin controls, and reduced by 35% compared to normal weight controls (De Simone et al., 1994). Conflicting data exist on whether LV function is also reduced in anorexia nervosa. Kahn, Halls, Bianco, and Perlman (1991) studied eight anorexia nervosa patients with radionuclide ventriculography before and after regaining 5–10% of their weight. All eight patients had normal rest and exercise LV function before refeeding, and all but one had normal LV function after refeeding. Half were noted to have regional wall motion abnormalities of unclear significance. De Simone et al. (1994), on the other hand, found reduced cardiac output in anorexia nervosa patients compared to controls. Lands, Pavilanis, Charge, and Coates (1992) evaluated maximum work capacity (Wmax) in 9 anorexia nervosa patents and 10 controls. Although 6/9 patients compared to 2/10 controls had reduced Wmax as predicted for age and height, Wmax and cardiac output were normal when adjusted for percent of IBW. This suggests that the diminished cardiac output reflects reduced lean body mass and not a primary cardiac abnormality. Even if weight-adjusted cardiac output is normal, in the setting of significantly reduced LV mass and decreased preload, heart failure can be precipitated during the early phases of refeeding because of fluid overload, increased oxygen demand, and reduced LV dysfunction. Fluid overload often occurs during refeeding if fluid and nutritional repletion are given too aggressively (Birmingham, Alothman, & Goldner, 1996; Melchior, 1998; Solomon & Kirby, 1990). Increased oxygen demand results from the anabolic state associated with refeeding. All of these can overwhelm the diminished capacity of the weakened heart muscle. Hypophosphatemia, a frequent complication of overly aggressive carbohydrate
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repletion, can also cause LV systolic dysfunction and heart failure (Kohn, Golden, & Shenker, 1998; Solomon & Kirby, 1990).
5. Refeeding the anorectic patient Therefore, frequent clinical assessments are very important especially during the more severe phases and the early weeks of refeeding. The mainstay of treatment involves nutritional repletion. A simple tenet, which must be followed, is ‘‘start low and go slow.’’ Referral to a dietician for their ongoing involvement in the weight restoration process are important components of the treatment plan. In general, the goal should be to effectuate a 1- to 2-lb weight gain per week, to within 90% of IBW. There are two basic ways to proceed. The patient can either be empirically started on a 800–1000-kcal diet plan with incremental 200–300-kcal increases every 4–5 days until adequate calories are attained to sustain consistent weight gain, or the dietitian can specifically calculate resting energy expenditure (REE) by obtaining an indirect calorimetry test or by calculating REE with the Harris – Benedict equation. The value obtained is then multiplied by an activity factor of 1.2–1.4, depending on how active the patient is, to ascertain the basal energy expenditure. Regardless of which approach is used, the dietician must work closely with the patient to craft a well-balanced and palatable diet plan with which the patient will comply, and which promotes successful and consistent weight gain. In general, at least for the first few weeks of treatment, these patients should be weighed at least once a week. There are many different perturbations on this main theme. Some programs supplement oral diets with liquid calorie drinks to achieve the daily caloric goal; others revert to enteral feeding through daily placement of small caliber nasogastric tubes or a percutaneous enterogastrostomy tube for more refractory cases, or even rarely, utilize total parenteral nutrition (Mehler & Weiner, 1993). Standard oral diet plans are the preferred method. The clinical complication seen during the early stages of refeeding is referred to as the refeeding syndrome. It is a well-recognized phenomenon that is most graphically manifested by cardiovascular collapse and even death following oral, enteral, or parenteral intake of large amounts of highly caloric nutrients, especially those high in glucose. The mechanism of the critically important hypophosphatemia is due to a shift of phosphate from the extracellular space to the intracellular one during refeeding. The transition to an anabolic state with refeeding results in the incorporation of phosphate into newly synthesized tissue and a depletion of serum phosphate and adenosine triphosphate. The result is a reduction in cardiac capacity and stroke volume. This sobering syndrome is completely preventable as long as refeeding is started slowly, and caloric increases are modest during the first few weeks. The dietitian’s expertise to accurately calculate caloric needs is invaluable. Assiduously monitoring serum electrolytes, especially phosphorous, every few days during the early refeeding period will prevent the development of this syndrome. In addition, it is important to monitor the patient for any
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sustained increase in pulse rate above their baseline and for the development of peripheral edema. These can be harbingers of imminent cardiac decompensation.
6. Endocrine complications Anorexia nervosa has profound and widespread effects on the endocrine system. Glucose metabolism is often disturbed. Mild hypoglycemia is common. Severe hypoglycemia denotes a poor prognosis (Rich, Caine, Findling, & Shaker, 1990). The pathogenesis of hypoglycemia reflects depletion of hepatic glycogen stores and gluconeogenic substrates superimposed on a chronically malnourished state along with excessive exercise. Abnormalities on thyroid function tests are often present in the form of the euthyroid sick syndrome and need not be treated. Serum levels of L-thyroxine (T4) are normal to low, as are levels of triiodothyronine (T3). Levels of thyroid-stimulating hormone are normal, but levels of reverse T3 are increased. This syndrome does not require specific treatment because with resolution of anorexia nervosa, all these thyroid indicators return to normal. Similarly, leukopenia (low white blood cell count) and mild anemia, may also be present, but once again resolve with weight gain (Mehler & Howe, 1995). Moreover, anorectic patients who lose weight exclusively by restricting intake have normal electrolyte levels until the very late stages of illness. The presence of hypokalemia, or metabolic alkaloses should raise concern that the anorectic patient may be surreptitiously purging through vomiting or diuretic abuse (Greenfield, Mickley, Quinlan, & Roloff, 1995; Mehler, 1998).
7. Amenorrhea Secondary amenorrhea occurs in over 95% of women with anorexia nervosa. The amenorrhea of anorexia nervosa is characterized by low circulating levels of the pituitary gonadotrophs (follicular-stimulating hormone, FSH, and luteinizing hormone, LH) despite low estrogen levels. There is a reversion to a prepubertal state with blunted LH and FSH secretion secondary to a decrease in the pulsatility of gonadotropin-releasing hormone. Withdrawal bleeding after a progestin challenge does not occur. These abnormalities are part of a global hypothalamic dysfunction associated with loss of weight and body fat. Men with anorexia nervosa also have hypogonadism and low testosterone levels. In addition, low leptin levels, emotional unrest, and excessive exercise may play a role in its pathogenesis. Resumption of menses in anorexia nervosa is an important issue because it marks a substantial improvement in their clinical status and it would dissuade clinicians from using additional hormonal therapy. The general rule is that a weight approximately 90% of IBW is the average weight at which return of menses will occur within 6 months in most women with anorexia nervosa (Mehler, Eckel, & Donahoo, 1999). This generally correlates with higher estradiol levels. In 10–15% of patients, the amenorrhea persists despite weight gain and is likely attributable to unresolved emotional issues. It is important to advise these
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patients that despite their amenorrheic state, anorectic patients are not totally protected from pregnancy and contraception should be utilized.
8. Osteoporosis Over 50% of female patients with anorexia nervosa have osteoporosis (Golden, Jacobson, Schebandach, et al., 1997). Although it was thought that the amenorrhea experienced by anorectic patients was devoid of adverse consequences, this thinking has radically changed. Osteoporosis is one of the most serious clinical concerns that accompanies amenorrhea and weight loss. The peak bone mass achieved as a young adult is a major determinant of bone density and fracture risk. Anorexia nervosa is associated with markedly reduced bone density, especially at the lumbar spine but also at the proximal femur and distal radius (Bachrach, Guido, Katzman, Litt, & Marcus, 1990; Biller, Saxes, Herzog, Holzmman, & Klibanski, 1989; Davies et al., 1990; Powers, 1999; Rigotti, Nussbaum, Herzog, & Neer, 1984). A recent study showed that the long-term risk of any fracture is elevated 2.9-fold (Rigotti, Neer, Skates, Herzog, & Nussbaum, 1991). This could cause major widespread problems since anorexia nervosa is the third most common chronic condition in adolescence after obesity and asthma (Lucas, Melton, Crowson, & O’Fallon, 1999). The marked degree of osteopenia in anorexia nervosa is based on a number of factors. While estrogen deficiency and its resultant amenorrhea are involved, other factors contribute. This became increasingly clear after trials with estrogen replacement surprisingly failed to result in improvement in bone density (Klibanski, Biller, Schoenfeld, Herzog, & Saxe, 1995; Lucas, Beard, O’Fallon, & Kurland, 1991; Ward, Brown, & Treasure, 1997). Further, the severity of osteopenia in anorexia nervosa is dependent on lean body mass not the duration of estrogen deficiency (Hegenroeder, 1995). Hypercortisolemia has been reported in anorexia (Grinspoon et al., 1999). Reduced levels of insulin-like growth factor I (Soyka, Grinspoon, Kevitsky, Herzog, & Klibanski, 1999) along with excessive exercise may also be involved (Cumming, 1996). Because anorexia nervosa appears to be a low-turnover state associated with increased bone resorption and high serum cortisol levels, and therefore different from the osteopenia of postmenopausal women, the routine usage of estrogen to attenuate bone loss must be reconsidered (Grinspoon et al., 2001; Hotta et al., 2000; Lennkh et al., 1999) Given the unclear exact etiology of osteopenia in anorexia nervosa, along with the at best minimal benefit from estrogen, the primary goal of treatment must be to restore weight and avoid bone loss. Normalized weight is the best predictors of bone density (Goebel, Schweiger, Kruger, & Fichter, 1999). This must be discussed with the patient in the early phases of treatment because as anorexia nervosa becomes more chronic, an increase in body weight may be insufficient to completely restore bone mineral density (Baker, Roberts, & Towell, 2000). Calcium supplementation (1500 mg/day) along with vitamin D (400 IU/day) should be prescribed, especially if cortisol excess is indeed involved in the pathogenesis of osteoporosis (Sambrook, Birmingham, & Kelly, 1993). There are currently no definitive data in anorexia nervosa to support the utilization of bisphosphonates, although they too have been
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found to be beneficial to prevent corticosteroid-induced osteoporosis (Adachi et al., 1997). Clinicians should closely monitor bone mineral density levels with bone densitometry in moderate to severe anorexia especially once amenorrhea has occurred. If abnormal, it should be repeated every 1–2 years to monitor the effectiveness of therapy. When the bone density is found to be osteopenic, or frankly osteoporotic, despite adequate calcium and vitamin D, consideration should be given to more aggressive therapies, such as bisphosphonates or nasal calcitonin given the lifelong risk of fractures (Kulak & Bilezikian, 1999). Bone markers, such as the resorption marker N-telopeptide, may also be used to assess the effectiveness of therapy because they stabilize more rapidly than does bone mineral density (Cummings et al., 2000; Greenspan, Parker, & Ferguson, 1998).
9. Fertility Women who have recovered from anorexia do not have an increased incidence of infertility. These complications are only increased in women with an active eating disorder (Bulik, 1999; Conti, Abraham, & Taylor, 1998; Frako & Walton, 1993). Of note, despite their amenorrhea, patients with anorexia nervosa can become pregnant. Contraceptives should therefore be recommended if the possibility of an unwanted pregnancy exists. Interestingly, patients with anorexia nervosa may demonstrate a reduction in their eating disorder symptoms during pregnancy (Blais et al., 2000), but may relapse after delivery due to conflicts about changes in body shape (Fahy, 1991; Mehler, 2000).
10. Gastrointestinal Patients with anorexia nervosa frequently have such gastrointestinal complications as delayed gastric emptying and decreased intestinal motility, both of which produce an exaggerated sense of postprandial fullness, early satiety, abdominal pain, and constipation (Stracher, Bergman, Steiner-Mittelbach, Kiss, & Abatzi, 1994). Alterations in antral motility, which have been thought to be responsible for delayed gastric emptying, seem to resolve with weight gain. Feelings of postprandial fullness may frustrate initial attempts at weight restoration. A concerted effort should be made to determine whether these common gastrointestinal complaints are functional or are caused by an organic abnormality. If the latter is the case, treatment with prokinetic agents may be successful. Acute gastric dilatation, which is sometimes accompanied, by duodenal dilatation, has also been reported during early refeeding of severely anorexic patients. The gastric dilatation is characterized by rapid onset of nausea, vomiting, pain, and abdominal distention. Chronic constipation is another frequently reported complaint. In the absence of a history of laxative abuse, this complication is typically caused by reflex hypofunctioning of the colon secondary to inadequate food intake. Rarely, rectal impaction can occur for similar reasons.
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These problems can usually be resolved with patience and the addition of high-fiber foods to the diet. Abnormalities of the pancreas are infrequent, although severe protein–calorie malnutrition may precipitate functional and structural abnormalities. Refeeding pancreatitis, which typically occurs during the early stages of the refeeding process, is the most commonly reported complication. Some investigators have suggested that priming of the ductal system with inspissated secretions during starvation may set the stage for refeeding pancreatitis. A clear association between liver disease and anorexia nervosa has never been defined. Slight elevations of serum transaminase levels may indicate that refeeding of a starved patient needs to be slowed. Such elevations are usually reversible.
11. Inpatient hospitalization No controlled trials have been performed to define with certainty when inpatient hospitalization is indicated. Generally, anorexia nervosa is classified as mild, moderate, or severe based on the percentage decrement below IBW (Table 2). Most authorities agree that when a patient’s weight has fallen into the severe range (25 –30% below IBW) that hospitalization is generally indicated. In addition, hospitalization is recommended for patients whose weight loss is rapidly progressive, as well as for those with serious electrolyte disorders, cardiac arrhythmias, and perhaps for newly attained heart rates less than 30–35 bpm especially if not sinus rhythm. The presence of a serious comorbid psychiatric illness or incapacitating obsessions and compulsions also should be considered for inpatient hospitalization (Practice guidelines for the treatment of patients with eating disorders, 2000). Once hospitalized, refeeding in a structured environment, with specialized staff who are familiar with the unique features of eating disordered patients, is recommended. Notwithstanding the constraints of managed care organizations, proper medical treatment should aim for the attainment of 85–90% of IBW. There is solid evidence that suggest, that if a patient with anorexia nervosa can be hospitalized until this amount of weight is gained and maintained for a few days, that relapses in the following 5 years are significantly reduced compared to when they are discharged at a much lower weight. However, the decision to hospitalize patients must be carefully deliberated for each individual case with judicious input from an internist and mental health professional who is very familiar with anorexia nervosa, because lengthy admission might interfere with the potential for long-term recovery (Gowers, Weetman, Shore, Hossain, & Elvins, 2000).
Table 2 Severity of anorexia nervosa Mild Moderate Severe a
10% below IBW a 20% below IBW a > 30% below IBW a
IBW is calculated as 100 lb for a height of 5 ft tall and 4 – 5 lb for every additional inch.
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12. Summary Anorexia nervosa is associated with multiple medical complications. These patients require treatment by a multidisciplinary team that should include medical input (Weiner, 1999). The severity of the illness dictates the levels of appropriate input and care. The primary care physician has a valuable role in pointing out the reality and severity of this chronic psychiatric illness while monitoring and assessing the patient’s physical status (Walsh, Wheat, & Freund, 2000).
References Adachi, J., Bensen, W. G., Brown, J., Hanley, D., Hudsman, A., Josse, R., Kendler, D. L., Lentle, B., Olszynski, W., Ste-Marie, L. G., Tenenhouse, A., & Chines, A. A. (1997). Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. New England Journal of Medicine, 337, 382 – 387. Bachrach, L. K., Guido, D., Katzman, D. L., Litt, I. F., & Marcus, R. (1990). Decreased bone density in adolescent girls with anorexia nervosa. Pediatrics, 86, 440 – 447. Baker, D., Roberts, R., & Towell, T. (2000). Factors predictive of bone mineral density in eating disordered women: a longitudinal study. International Journal of Eating Disorders, 27, 29 – 35. Beumont, P. J., & Large, M. (1991). Hypophosphatemia, delirium and cardiac arrhythmia in anorexia nervosa. Medical Journal of Australia, 155, 519 – 522. Biller, B. M. K., Saxes, U., Herzog, D. B., Holzman, S., & Klibanski, A. (1989). Mechanisms of osteoporosis in adult and adolescent women with anorexia nervosa. Journal of Clinical Endocrinology and Metabolism, 68, 548 – 552. Birmingham, C. L., Alothman, A. F., & Goldner, E. M. (1996). Anorexia nervosa: refeeding and hypophosphatemia. International Journal of Eating Disorders, 20, 211 – 213. Blais, M. A., Becker, A. E., Flores, A. T., Nussbaum, K. M., Greemwood, D. N., & Herzog, D. D. (2000). Pregnancy: outcome and impact on a cohort of eating disordered women. International Journal of Eating Disorders, 27, 140 – 149. Bulik, C. M. (1999). Intensive prenatal care for pregnant anorexic patients. Journal of Clinical Psychiatry, 60, 130 – 135. Conti, J., Abraham, S., & Taylor, A. (1998). Eating behavior and pregnancy outcome. Journal of Psychosomatic Research, 44, 465 – 477. Cooke, R. A., & Chambers, J. B. (1995). Anorexia nervosa and the heart. British Journal of Hospital Medicine, 54, 313 – 317. Cooke, R. A., Chambers, J. B., Singh, R., Todd, G. J., Smeeton, N. C., Treasure, J., & Treasure, T. (1994). QT interval in anorexia nervosa. British Heart Journal, 72, 69 – 73. Cumming, D. (1996). Exercise-associated amenorrhea, low bone density and estrogen replacement therapy. Archive of Internal Medicine, 156, 2193 – 2195. Cummings, S. R., Palmero, C., Wallace, R., Pearson, J., Eckert, S., & Black, D. (2000). Monitoring osteoporosis recovery with bone density. JAMA, Journal of the American Medical Association, 283, 1318 – 1321. Davies, K. M., Pearson, P. H., Huseman, C. A., Greger, N. G., Kimmel, D. K., & Recker, R. R. (1990). Reduced bone mineral in patients with eating disorders. Bone, 11, 143 – 147. De Simone, G., Scalfi, L., Galderisi, M., Celentano, A., Di Biase, G., Tammaro, P., Garofalo, M., Mureddo, G. F., de Devitiis, O., & Contaldo, F. (1994). Cardiac abnormalities in young women with anorexia nervosa. British Heart Journal, 71, 287 – 292. Durakovic, Z., Durakovic, A., & Korsic, M. (1994). Changes of the corrected QT interval in the electrocardiogram of patients with anorexia nervosa. International Journal of Cardiology, 45, 115 – 120. Fahy, T. A. (1991). Eating disorders in pregnancy. Psychological Medicine, 21, 577 – 580.
D. Leonard, P.S. Mehler / Eating Behaviors 2 (2001) 293–305
303
Frako, D. K., & Walton, B. E. (1993). Pregnancy eating disorders. International Journal of Eating Disorders, 13, 41 – 48. Goebel, G., Schweiger, U., Kruger, R., & Fichter, M. M. (1999). Predictors of bone mineral density in patients with eating disorders. International Journal of Eating Disorders, 25, 143 – 150. Golden, H. N., Jacobson, M. S., Schebandach, J., Solanto, M. V., Hertz, S. M., & Shenker, I. R. (1997). Resumption of menses in anorexia nervosa. Archive of Pediatric Adolescent Medicine, 151, 16 – 21. Gould, L., Reddy, C. V., Singh, B. K., & Zen, B. (1980). Evaluation of cardiac conduction in anorexia nervosa. Pacing and Clinical Electrophysiology, 3, 660 – 665. Gowers, S. G., Weetman, J., Shore, A., Hossain, F., & Elvins, R. (2000). Impact of hospitalization on the outcome of adolescent anorexia nervosa. British Journal of Psychiatry, 176, 138 – 141. Greenfield, D., Mickley, D., Quinlan, D. M., & Roloff, P. (1995). Hypokalemia in outpatients with eating disorders. American Journal of Psychiatry, 152, 60 – 63. Greenspan, S. L., Parker, R. A., & Ferguson, L. (1998). Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy. Journal of Bone Mineral Research, 13, 1431 – 1438. Grinspoon, S., Miller, K., Coyle, C., Krempin, J., Herzog, D., & Klibanski, A. (1999). Severity of osteopenia in estrogen deficient women with anorexia nervosa. Journal of Clinical Endorcrinology and Metabolism, 84, 2049 – 2055. Grinspoon, S., Thomas, E., Pitts, S., Gross, E., Mickley, D., Miller, K., Herzog, D., & Klibanski, A. (2001). Prevalence and predictors of regional osteopenia in women with anorexia nervosa. Annals of Internal Medicine, 133, 790 – 794. Hegenroeder, A. C. (1995). Bone mineralization, hypothalamic amenorrhea and sex steroid therapy in female adolescents. Journal of Pediatrics, 126, 683 – 689. Hotta, M., Fukada, I., Sato, K., Hizuka, N., Shibasaki, T., & Takano, K. (2000). The relationship between bone turnover and body weight, serum insulin growth factor-I and serum IGF-binding protein levels in patients with anorexia nervosa. Journal of Clinical Endocrinology and Metabolism, 85, 200 – 206. Isner, J. M., Roberts, W. C., Heymsfield, S. B., & Yager, J. (1985). Anorexia nervosa and sudden death. Annals of Internal Medicine, 102, 49 – 52. Johnson, G. L., Humphries, L. L., Shirley, P. B., Mazzoleni, A., & Noonan, J. A. (1986). Mitral valve prolapse in patients with anorexia nervosa and bulimia. Archive of Internal Medicine, 146, 1525 – 1529. Kahn, D., Halls, J., Bianco, JA., & Perlman, S. B. (1991). Radionuclide ventriculography in severely underweight anorexia nervosa patients before and during refeeding therapy. Journal of Adolescent Health, 12, 301 – 306. Kay, W. H., George, D. T., Gwirtsman, H. E., Jimerson, D. C., Goldstein, D. S., Ebert, M. H., & Lake, C. R. (1990). Isoproterenol infusion test in anorexia nervosa: assessment of pre- and post-beta-noradrenergic receptor activity. Psychopharmacology Bulletin, 26, 355 – 359. Keys, A., Brozek, J., Henschel, A., Mickelsen, O., & Taylor, H. L. (1950). The biology of human starvation, vol. 1. Minneapolis, University of Minnesota Press. Klibanski, A., Biller, B. M., Schoenfeld, D. A., Herzog, D. B., & Saxe, V. C. (1995). The effects of estrogen administration on trabecular bone loss in anorexia nervosa. Journal of Clinical Endocrinology and Metabolism, 80, 898 – 904. Kohn, M. R., Golden, N. H., & Shenker, I. R. (1998). Cardiac arrest and delirium: presentations of the refeeding syndrome in severely malnourished adolescents with anorexia nervosa. Journal of Adolescent Health, 22, 239 – 243. Kollai, M., Bonyhay, I., Jokkel, G., & Szonyi, L. (1994). Cardiac vagal hyperactivity in adolescent anorexia nervosa. European Heart Journal, 15, 1113 – 1118. Kreipe, R. E., Goldstein, B., DeKing, D. E., Tipton, R., & Kempski, M. H. (1994). Heart rate power spectrum analysis of autonomic dysfunction in adolescents with anorexia nervosa. International Journal of Eating Disorders, 16, 159 – 165. Kulak, C. A. M., & Bilezikian, J. P. (1999). Bone mass measurement in identification of women at risk for osteoporosis. International Journal of Fertility, 44, 269 – 278.
304
D. Leonard, P.S. Mehler / Eating Behaviors 2 (2001) 293–305
Lands, L., Pavilanis, A., Charge, T. D., & Coates, A. L. (1992). Cardiopulmonary response to exercise in anorexia nervosa. Pediatric Pulmonology, 13, 101 – 107. Lennkh, C., Zwaan, M., Bailer, V., Strnad, A., Nagy, C., el-Giamal, N., Wiesnagrotzki, S., Vytiska, E., Huber, J., & Kasper, S. (1999). Osteopenia in anorexia nervosa: specific mechanisms of bone loss. Journal of Psychiatric Research, 33, 349 – 356. Lucas, A. R., Beard, C. M., O’Fallon, W. M., & Kurland, L. T. (1991). 50-year trends in the incidence of anorexia nervosa in Rochester, Minn. American Journal of Psychiatry, 148, 917 – 922. Lucas, A. R., Melton, J., Crowson, C. S., & O’Fallon, W. M. (1999). Long-term fracture risk among women with anorexia nervosa. Mayo Clinic Proceedings, 74, 972 – 977. Mehler, P. S. (1998). Electrolyte disorders in bulimia. Eating Disorders: the Journal of Treatment and Prevention, 6, 65 – 68. Mehler, P. S. (2000). Eating disorders. In: R. V. Lee, L. A. Barbour, P. E. Garner, & E. Keely (Eds.), Medical care of the pregnant patient (1st ed., pp. 140 – 148). Philadelphia, PA: ACP Press. Mehler, P. S. (2001). Diagnosis and care of patients with anorexia nervosa in primary care settings. Annals of Internal Medicine, 134, 1048 – 1059. Mehler, P. S., Eckel, R. H., & Donahoo, W. T. (1999). Leptin levels in restricting and purging anorectics. International Journal of Eating Disorders, 26, 189 – 194. Mehler, P. S., & Howe, S. E. (1995). Serious fat atrophy with leukopenia in anorexia nervosa. American Journal of Hematology, 49, 171 – 172. Mehler, P. S., & Weiner, K. L. (1993). Anorexia nervosa and total parenteral nutrition. International Journal of Eating Disorders, 14, 297 – 305. Melchior, J. C. (1998). From malnutrition to refeeding during anorexia nervosa. Current Opinion Clinical Nutrition Metabolic Care, 1, 481 – 485. Neumarker, K. J. (1997). Mortality and sudden death in anorexia nervosa. International Journal of Eating Disorders, 21, 205 – 212. Panagiotopoulos, C., McCrindle, B. W., Hick, K., & Katzman, D. K. (2000). Electrocardiographic findings in adolescents with eating disorders. Pediatrics, 105, 1100 – 1105. Petretta, M., Bonaduce, D., Scalfi, L., de Filippo, E., Marciano, F., Migauz, M. L., Themistoclakis, S., Ianniciello, A., & Cantaldo, F. (1997). Heart rate variability as a measure of autonomic nervous system function in anorexia nervosa. Clinical Cardiology, 20, 219 – 224. Powers, P. S. (1999). Osteoporosis and eating disorders. Journal of Pediatric Adolescent Gynecology, 12, 51 – 57. Practice guidelines for the treatment of patients with eating disorders. (2000). American Journal of Psychiatry, 157, 1 – 39. Rechlin, T., Weis, M., Ott, C., Bleichner, F., & Joraschky, P. (1998). Alterations of autonomic cardiac control in anorexia nervosa. Biological Psychiatry, 43, 358 – 363. Rich, L. M., Caine, M. R., Findling, J. W., & Shaker, J. L. (1990). Hypoglycemic coma in anorexia nervosa. Archive of Internal Medicine, 150, 894 – 895. Rigotti, M. A., Neer, R. M., Skates, S. J., Herzog, D. B., & Nussbaum, S. R. (1991). The clinical course of osteoporosis in anorexia nervosa: a longitudinal study of cortical bone mass. JAMA, Journal of the American Medical Association, 265, 1133 – 1138. Rigotti, N. A., Nussbaum, S. R., Herzog, D. B., & Neer, R. M. (1984). Osteoporosis in women with anorexia nervosa. New England Journal of Medicine, 311, 1601 – 1606. Sambrook, P., Birmingham, J., & Kelly, P. (1993). Prevention of corticosteroid osteoporosis, a comparison of calcium, calcitrol and calcitonin. New England Journal of Medicine, 328, 1747 – 1752. Schocken, D. D., Holloway, J. D., & Powers, P. S. (1989). Weight loss and the heart. Effects of anorexia nervosa and starvation. Archive of Internal Medicine, 149, 877 – 881. Solomon, S. M., & Kirby, D. F. (1990). The refeeding syndrome: a review. Journal of Parenteral and Enteral Nutrition, 14, 90 – 97. Soyka, L. A., Grinspoon, S., Kevitsky, L. L., Herzog, D. B., & Klibanski, A. (1999). The effects of anorexia
D. Leonard, P.S. Mehler / Eating Behaviors 2 (2001) 293–305
305
nervosa on bone metabolism in female adolescents. Journal of Clinical Endocrinology and Metabolism, 84, 4489 – 4496. Stracher, G., Bergman, H., Steiner-Mittelbach, G., Kiss, A., & Abatzi, T. A. (1994). Primary anorexia nervosa gastric emptying and antral motor activity. International Journal of Eating Disorders, 14, 297 – 305. Sullivan, P. F. (1995). Mortality in anorexia nervosa. American Journal of Psychiatry, 152, 1073 – 1074. Swenne, I. (2000). Heart risk associated with weight loss in anorexia nervosa and eating disorders: electrocardiographic changes during the early phase of refeeding. Acta Paediatrica, 89, 447 – 452. Swenne, I., & Larsson, P. T. (1999). Heart risk associated with weight loss in anorexia nervosa and eating disorders: risk factors for QT interval prolongation and dispersion. Acta Paediatrica, 88, 304 – 309. Tan, H. L., Hou, C. J., Lauer, M. R., & Sung, R. J. (1995). Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Annals of Internal Medicine, 122, 701 – 714. Walsh, J. M., Wheat, M. E., & Freund, K. (2000). Detection, evaluation and treatment of eating disorders—the role of the primary care physician. Journal of General Internal Medicine, 15, 577 – 590. Ward, A., Brown, N., & Treasure, J. (1997). Persistent osteopenia after recovering from anorexia nervosa. International Journal of Eating Disorders, 22, 71 – 75. Weiner, K. (1999). Multidisciplinary team treatment: working together. In: P. S. Mehler, & A. E. Andersen (Eds.), Eating disorders: a guide to medical care and complications ( pp. 27 – 43). Baltimore: Johns Hopkins University Press.