Eating disorders are serious psychiatric disorders characterized by abnormal eating or weight-control behaviors . Eating disorders can strongly impair physical health and are associated with markedly increased mortality compared with the general population. Among all psychiatric disorders, anorexia nervosa is associated with the highest mortality rates . In fact, more than 50% of all deaths in anorexia nervosa patients are caused by medical complications that are predominantly starvation-related . The physical damage involves nearly all bodily systems, and its severity generally depends on the extent and duration of weight loss. Further causes of medical complications in anorexia nervosa are secondary to purging behaviors, which are present in the purging subtype of anorexia nervosa. The medical complications of bulimia nervosa and binge eating disorder (BED) are mostly caused by excessive bingeing and potential consequences of associated obesity, or in bulimia nervosa also by purging behaviors.
This is a focused narrative update on the physical comorbidities associated with eating disorders, targeting important recent findings within the last 2 years. We focused on reviewing the different types of comorbidities, their clinical relevance, as well as recommended monitoring and management strategies.
Medical comorbidities and complications are frequent in individuals with eating disorders, requiring clinical attention. As an example, Fig. 1 shows the frequency of selected medical findings in a large sample of adult inpatient-residential eating disorder patients .
Clearly, to improve short-term and long-term outcomes in individuals with eating disorders, the specific eating disorder must be diagnosed and treated according to existing guidelines. However, at the same time the treatment team must assess for and manage physical abnormalities that are often prevalent and often the direct consequence of the specific eating disorder. Table 1 summarizes medical findings and their suggested management in eating disorders, as well as serious complications and risk of fatality.
LIFE-THREATENING MEDICAL FINDINGS AND THEIR MANAGEMENT
Among the most dangerous physical findings in eating disorders are severe electrolyte disturbances including hypophosphatemia and the associated risk of refeeding syndrome, and hypoglycemia with subsequent liver failure. Severe imbalances of different electrolytes are often caused by excessive purging or sometimes due to excessive drinking of water. The most common electrolyte imbalances are hyponatremia and hypokalemia. Among the life-threatening complications of these electrolyte imbalances are cardiac arrhythmias and seizures. An important risk factor for serious arrhythmias is QTc-interval prolongation. Recent evidence from the largest study on ECG changes in anorexia nervosa patients summarized that QTc-interval prolongation is not necessarily an inherent feature of eating disorders, but rather associated with electrolyte disturbances or side effects of psychotropic medications [5▪]. If electrolytes are carefully monitored, the cardiovascular findings in patients’ with extreme anorexia nervosa, such as bradycardia, hypotension, myocardial atrophy, pericardial effusion, are rarely alone cause of fatal complications. Severe hypokalemia may also cause renal failure and require haemodialysis. Another serious condition can be hypophosphatemia, which can reach life-threatening proportions in relation to starvation and can be aggravated during refeeding if phosphate and thiamine are not adequately supplemented . Initially, refeeding causes a change from a catabolic to an anabolic metabolism, and concomitant hyperparathyreoidism may contribute to the development of hypophosphatemia. This process can lead to a critical drop in the intracellular concentration of ATP and the energy supply of the cells . Thiamine acts as a coenzyme for transketolase, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes, enzymes which play a fundamental role for intracellular glucose metabolism . Clinical consequences range from severe organ dysfunction and rhabdomyolysis to seizures, delirium, coma and death .
Monitoring and management of electrolyte disturbances is therefore one of the most important aspects of the initial diagnosis and medical management of eating disorders. Phosphate and thiamine supplementation during refeeding of severely malnourished patients with anorexia nervosa can be life saving.
A further and common life-threatening complication of extreme anorexia nervosa is hypoglycemia, which may lead to coma and death as a result of starvation and hepatic failure and consecutive impairment of gluconeogenesis .
Gastrointestinal symptoms are extremely common in eating disorders, but rarely the cause of fatal complications, apart from liver necrosis in end-stage starvation [10,11]. In rare cases, reduced gastrointestinal motility may lead to serious complications, such as gastric dilatation or rupture or paralytic ileus or subileus when psychotropic medications are used that have anticholinergic potential that may further impair motility (e.g. olanzapine, quetiapine) .
NONLIFE THREATENING MEDICAL FINDINGS AND THEIR RELEVANCE FOR MANAGEMENT
Many medical findings, especially in anorexia nervosa but also in bulimia nervosa, such as abnormal findings of skin, hair, teeth, bone or endocrine findings, can be frequently observed (Table 1 ). This includes elevated inflammatory cytokines and oxidative stress markers, predominantly in anorexia nervosa, which are markers of global physical stress that contributes to the overall physical ill-health and predisposes to physical morbidities [13–15]. However, these findings are not acutely life-threatening and are usually reversible with weight restoration and the cessation of purging behavior. Many of these symptoms may impair individual well being and make affected persons looking physically ill and prematurely old. The assessment of various medical symptoms and the confrontation of patients with the link between these subjectively burdensome physical symptoms and disturbed eating behavior can increase the willingness to seek psychotherapeutic treatment for the eating disorder. It is therefore recommended to carefully diagnose all medical findings in patients with eating disorders and to explain these findings to the patients to support their insight into their eating disorder representing a serious condition with the potential for adverse long-term consequences.
This situation is especially true for children and adolescents and their caregivers since eating disorders at this early age may also have serious consequences for growth and development, fertility, bone density and other aspects of future physical ill-health .
RECENT EVIDENCE ON LONG-TERM-CONSEQUENCES OF MEDICAL FINDINGS
In the last few years, there have been new findings about negative long-term effects of hormonal changes on fertility, childbearing or cardiovascular mortality. These findings complement existing knowledge about adverse long-term and sometimes irreversible effects on physical health even after remission.
Kärkkäinen, Mustelin  studied the long-term health-related consequences of disordered eating behaviors of young adults at age 24, using data of the population-based FinnTwin16 cohort study. Disordered eating behaviors at age 24 were associated cross-sectionally and prospectively with poorer self-rated health, higher BMI, larger waist circumference and greater psychological distress in both sexes. Adjusting for baseline BMI and potential confounders, disordered eating behaviors predicted poor self-rated health in men. In a recent epidemiologic survey of 36 309 adults in the USA, eating disorder diagnoses were significantly associated with medical conditions . Anorexia nervosa was associated with fibromyalgia, cancer, anemia and osteoporosis, while BED was associated with diabetes, hypertension, high cholesterol and triglycerides, that is known medical correlates of obesity. In this study, bulimia nervosa was not significantly associated with any somatic conditions. A newer study, however, yielded different results. In a longitudinal cohort study, women hospitalized for bulimia nervosa were followed up for 12 years from 2006 to 2018 to identify incidences of cardiovascular disease and death [19▪▪]. The comparison group consisted of women hospitalized for pregnancy-related events. The study's findings suggested that bulimia nervosa is associated with an increased long-term risk of any cardiovascular disease, such as ischemic cardiac events and conduction disorders, as well as with death among women. The authors suggested that women with a history of bulimia nervosa should be screened regularly for ischemic cardiovascular disease and may benefit from prevention of and treatment for cardiovascular risk factors.
Eating disorders, especially anorexia nervosa, are regularly associated with multiple endocrine disturbances, and with amenorrhea in women. During recent years, long-term-follow-up studies investigated the enduring consequences of eating disorders on reproductive outcomes, finding that a history of both anorexia nervosa and bulimia nervosa was associated with delayed first birth and lower parity [20▪]. The adverse long-term effects on fertility were stronger in anorexia nervosa, with an 81% reduced parity compared with the general population.
Finally, most of the medical findings of patients with BED are a consequence of overweight and obesity, which are associated with multiple medical consequences. A recent review of studies on medical complications in BED concluded that BED and the loss of eating control in children may independently increase the likelihood of developing components of the metabolic syndrome .
Recommended physical monitoring strategies in patients with eating disorders are summarized in Table 2.
RECENT FINDINGS REGARDING THE MEDICAL MANAGEMENT OF MEDICAL ABNORMALITIES IN PATIENTS WITH EATING DISORDERS
Nutritional management of anorexia nervosa patients
Accelerated instead of slow refeeding
It was previously assumed that starting the refeeding process with low initial caloric intake (1200 kcal/day) and advancing slowly by 200 kcal every other day would prevent the potentially life-threatening refeeding syndrome. However, a more recent systematic review supported higher calorie approaches in mildly and moderately malnourished patients under close medical monitoring . In addition in 103 extremely malnourished adults targeting higher caloric intake (i.e., 2000 kcal/day at the initiation of treatment) was not associated with refeeding complications when closely monitoring and supplementing phosphate and thiamine, but with normalization of weight and starvation-related laboratory abnormalities [23▪▪]. Accelerated refeeding led to rapid normalization of abnormal laboratory values (Fig. 2a–c, 4-week course of creatine kinase, aspartate transferase and phosphate). Accelerated refeeding leads to quicker reversal of underweight, which is a positive predictor of mid-term and long-term outcomes . Although there is still no international consensus on refeeding practices in patients with anorexia nervosa, recent data suggest that the ‘start slow’ approach may be outdated .
Food composition and route of intake
So far, there is very little research on the ideal macronutrient content and route of delivery for patients with anorexia nervosa. While Kohn et al. suggested to reduce carbohydrate content to decrease the risk of refeeding syndrome, to our knowledge, no randomized controlled trial comparing refeeding protocols with different macronutrient composition has been performed. Refeeding practices also seem to be a result of different patient characteristics (i.e. with respect to the degree of malnutrition), settings (i.e. medical or psychiatric wards), healthcare systems (i.e. long vs. short inpatient care) as well as traditional and regional developments over time. Some institutions focus on quick normalization of eating behavior by introducing oral and well balanced nutrition on the first day of treatment which was feasible even in extremely malnourished adults [23▪▪]. Other authors describe a range of benefits achieved by administering a nasogastric tube, such as less electrolyte imbalances and cardiac disturbances , decreased frequency and severity of binge/purge episodes, and, in particular in combination with higher caloric refeeding, potential reduction of anxiety, gastric distention, abdominal pain and early satiety . A systematic review examining the role of nasogastric feeding concluded that contrary to common concerns, nasogastric tube feeding was not associated with an increased risk for adverse outcomes, well tolerated by the patients, and effectively increased caloric intake and weight gain, both in adolescents and adults [28,29]. However, to date, there are still insufficient, well designed, controlled studies to conclude on the superiority of nasogastric tube vs. oral refeeding in patients with anorexia nervosa.
Some clinical symptoms that are observed in anorexia nervosa could be partially explained by micronutrient deficiencies [30▪]. For example, Suzuki et al. described an association between zinc deficiency and restrictive eating behavior; cases of sensory neuropathy were found in anorexia nervosa patients with vitamin B12 deficiency ; fasting can cause neurological complications due to severe vitamin B1 deficiency . Hanachi et al.[30▪] determined micronutirent status in 374 severely malnourished anorexia nervosa patients and found that zinc deficiency was most prevalent (64.3%), followed by vitamin D (54.2%), copper (37.1%), selenium (20.5%), vitamin B1 (15%), vitamin B12 (4.7%) and vitamin B9 (8.9%). The authors concluded that micronutrients status of anorexia nervosa patients should be monitored and supplemented to prevent deficiency-related complications and improve nutritional status. Prospective studies are needed to explore the symptoms and consequences of each deficiency, which can aggravate the prognosis during recovery.
Prevention and treatment of bone loss
Osteopenia and osteoporosis are common medical findings in anorexia nervosa and their degree depends on the extent and duration of weight loss and starvation . As standard measures, supplementation with vitamin D and calcium are recommended. Dual energy x-ray absorbtiometry (DXA) is the measure of choice to diagnose bone mass density. Major causes of osteopenia and osteoporosis are the endocrine dysregulation associated with underweight, that is hypercortisolism and estrogene deficiency and vitamin D and calcium deficiency.
Supplementing estrogene (transdermally) has therefore been recommended in anorexia nervosa to reduce the risk of bone loss. Many patients with anorexia nervosa are using oral contraceptives, which has been criticized for several reasons. First, earlier studies did not prove a protective effect of oral contraceptives on bone mineral density in anorexia nervosa . Second, combined hormonal contraceptives induce cyclic bleeding and may therefore disguise that weight loss causes amenorrhea. This masking may negatively impact on the motivation for further weight gain. In a recent cross-sectional analysis of 301 adult females with anorexia nervosa (99 on oral contraceptives) and 121 age matched healthy controls, however, whole body, lumbar spine, femoral neck, hip and radius bone mineral density values (DEXA and bone turnover markers) were systematically higher in anorexia nervosa patients taking vs. not taking oral contraceptives [35▪]. These differences even persisted after multiple adjustments. The data further showed that bone mineral density preservation improved with longer durations of oral contraceptives use and shorter delays between disease onset and the start of oral contraceptives. The authors concluded from their data that oral contraceptives might be prescribed for young women with anorexia nervosa to limit bone loss. Although prospective data are sorely needed, the so far rather critical restraint toward oral contraceptives in anorexia nervosa must be challenged.
The gut microbiome and eating disorders
There is a growing body of literature that implicates a potential role of the gut microbiota in the cause and progression of eating disorders [36,37▪]. Gut bacteria may act on the gut–brain axis altering appetite control and brain function as part of the genesis of eating disorders . As the illnesses progress, extreme feeding patterns and psychological stress potentially feed back to the gut ecosystem, which can further compromise physiological, cognitive and social functioning. However, the microbiome is a quite complex entity and initial studies analyzing altered microbiomes in patients with anorexia nervosa have reported heterogeneous results [37▪]. As alterations of the microbiome in anorexia nervosa patients persist after short-term weight restoration , microbiome-directed interventions could become an adjunctive treatment, for example, by special nutritional supplies, use of probiotics or prebiotics or drugs influencing the microbiome .
New findings on the pharmacotherapy of anorexia nervosa
One aspect of medical management of eating disorders is the use of psychotropic medications [40,41] that are a key treatment approach for many psychiatric illnesses. However, the role of psychotropic medications in the treatment of eating disorders differs somewhat from that in other psychiatric disorders. For all eating disorders, psychopharmacological agents should not be a primary treatment approach, but rather a potential adjunctive treatment embedded in nutritional and psychotherapeutic treatment approaches. Current evidence for the efficacy of psychotropic medications and regulatory approval differs across eating disorders. Numerous studies have shown some efficacy of antidepressants for bulimia nervosa. High-dose fluoxetine (i.e. 60 mg/day) is the standard of care medication approach for bulimia nervosa. Fluoxetine is approved as pharmacotherapy for bulimia nervosa in many countries. There are also many studies showing moderate effects of antidepressants on symptoms of BED, but with apparently little effect on body weight change. There is also evidence for the efficacy of stimulants for BED and lisdexamfetamine is approved for treatment of BED in the USA.
Regarding anorexia nervosa, for a long-time studies with psychopharmacological agents had been negative . Recently a placebo-controlled randomized controlled trial (RCT) was conducted in 152 adult outpatients with anorexia nervosa with a mean BMI of 16.7 kg/m2 who received either olanzapine 5–10 mg/day (mean = 6.2 mg/day) or placebo for 16 weeks [43▪▪]. The study documented a modest therapeutic effect of olanzapine on BMI, but not on psychological symptoms. Importantly, different from nonanorexia nervosa populations [44,45], olanzapine was not associated with cardiometabolic adverse effects on the lipid and glucose metabolism. This is an important new finding, because for the first time a significant therapeutic effect of a pharmacological agent has been shown in patients with anorexia nervosa in a large RCT. Olanzapine may therefore be a new therapeutic option for anorexia nervosa patients who do not respond to standard nutritional and psychotherapeutic treatment and who accept and tolerate this treatment.
Currently, there is no evidence for the use of antidepressants in anorexia nervosa. Notably, however, absence of evidence does not necessarily mean absence of an effect. Almost all studies with antidepressants and antipsychotics in anorexia nervosa apart from the olanzapine study by Attia et al.[43▪▪] had been underpowered. To date, there is no study with an antidepressant in anorexia nervosa with a sufficiently large sample size to detect significant differences. Such a study is urgently needed in the view of the frequent comorbidity of depression with anorexia nervosa and the fact that mean self-rated depression scores of patients with eating disorders are comparable with patients with depressive disorders .
Eating disorders are associated with many medical complications, which can even be fatal, especially in anorexia nervosa, and less frequently in bulimia nervosa. Most medical complications of BED are secondary to overweight/obesity, similar to the general population. Consideration and management of medical complications of eating disorders is not only important for short-term and long-term physical health, but also to foster insight and motivation for treatment in patients who may frequently be ambiguous towards or frankly against treatment. Some newer findings regarding refeeding, nutrition, hormone and antipsychotic treatment challenge traditional concepts of medical management and should be considered in the management of eating disordered patients aiming at improved overall outcomes. There is evidence for higher calorie refeeding protocols to accelerate weight gain in adolescent and adult patients [23▪▪,24,27]. This paradigm shift was included in recent guideline recommendations toward leaving the ‘start low, go slow’ approach, as this can underfeed patients and lead to severe consequences due to hypoglycemia and lack of energy required for renal and hepatic function as well as glucose metabolism .
Psychopharmacological treatment of the eating disorder per se should almost always be secondary to the medical management of complications of eating disorders, nutritional management and psychotherapy, as well as treatment of psychiatric comorbidities if those are not a consequence of the eating disorder. Whereas for bulimia nervosa and BED antidepressants and for BED also psychostimulants play a role as adjunctive treatment options within stepped-care approaches, new findings support the use of antipsychotics, such as olanzapine, for anorexia nervosa. Especially for anorexia nervosa, further studies with antipsychotics and antidepressants are of great interest in view of the high percentage of treatment-refractory cases and its high mortality risk.
In underweight patients osteoporosis and bone loss are common and usually diagnosed by DEXA radiography. Supplementation with vitamin D and calcium is recommended. Supplementing estrogene (transdermally) has been recommended in anorexia nervosa to reduce the risk of bone loss. Recent data suggest that young underweight women have better bone mineral density values (DEXA and bone turnover markers) when taking vs. not taking oral contraceptives [35▪].
The gut microbiome may play a role in the cause and progression of eating disorders [36,37▪], yet studies analyzing altered microbiome composition in patients with anorexia nervosa have reported heterogeneous results . Since alterations of the microbiome in anorexia nervosa patients persist after short-term weight restoration , microbiome-directed interventions could become an adjunctive treatment (nutrional supplies, probiotics or prebiotics or drugs influencing the microbiome), but, clearly, more studies are needed in this regard.
Eating disorders, and in particular anorexia nervosa, are associated with numerous physical complications that are sometimes life-threatening. These abnormalities require careful, multiprofessional assessment and treatment. There is growing evidence for adverse long-term consequences of anorexia nervosa and also bulimia nervosa on physical health and mortality. Recent advances focus on accelerated renutrition protocols, replacement of micronutirent deficiencies and the potential role of the microbiome in the pathogenesis and maintenance of at least some patients with eating disorders. Furthermore, there has been support for the utility of antidepressants for bulimia nervosa, stimulants for BED and antipsychotics for anorexia nervosa. However, the exact merit of these new and/or additional approaches for many patients or specific patient subgroups with eating disorders needs to be further established in prospective studies.
We would like to thank Mr Matthias Favreau for the literature research.
Financial support and sponsorship
Conflicts of interest
U.V., T.K. and V.H. have no conflicts of interest to declare. C.U.C. has been a consultant and/or advisor to or have received honoraria from: Alkermes, Allergan, Angelini, Boehringer-Ingelheim, Gedeon Richter, Gerson Lehrman Group, Indivior, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda and Teva. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus and Teva. He has received grant support from Janssen and Takeda. He is also a stock option holder of LB Pharma.
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