Association of CNR1 and FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia nervosa: evidence for synergistic effects

Endocannabinoids modulate eating behavior; hence, endocannabinoid genes may contribute to the biological vulnerability to eating disorders. The rs1049353 (1359 G/A) single nucleotide polymorphism (SNP) of the gene coding the endocannabinoid CB1 receptor ( CNR1 ) and the rs324420 (cDNA 385C to A) SNP of the gene coding fatty acid amide hydrolase (FAAH), the major degrading enzyme of endocannabinoids, have been suggested to have functional effects on mature proteins. Therefore, we explored the possibility that those SNPs were associated to anorexia nervosa and/or bulimia nervosa. The distributions of the CNR1 1359 G/A SNP and of the FAAH cDNA 385C to A SNP were investigated in 134 patients with anorexia nervosa, 180 patients with bulimia nervosa and 148 normal weight healthy controls. Additive effects of the two SNPs in the genetic susceptibility to anorexia nervosa and bulimia nervosa were also tested. As compared to healthy controls, anorexic and bulimic patients showed significantly higher frequencies of the AG genotype and the A allele of the CNR1 1359 G/A SNP. Similarly, the AC genotype and the A allele of the FAAH cDNA 385C to A SNP were significantly more frequent in anorexic and bulimic individuals. A synergistic effect of the two SNPs was evident in anorexia nervosa but not in bulimia nervosa. Present findings show for the first time that the CNR1 1359 G/A SNP and the FAAH cDNA 385C to A SNP are significantly associated to anorexia nervosa and bulimia nervosa, and demonstrate a synergistic effect of the two SNPs in anorexia nervosa.     

The Endocrinopathies of Anorexia Nervosa

ObjectiveTo describe the hormonal adaptations and alterations in anorexia nervosa.MethodsWe performed a PubMed search of the English-language literature related to the pathophysiology of the endocrine disorders observed in anorexia nervosa, and we describe a case to illustrate these findings.ResultsAnorexia nervosa is a devastating disease with a variety of endocrine manifestations. The effects of starvation are extensive and negatively affect the pituitary gland, thyroid gland, adrenal glands, gonads, and bones. Appetite is modulated by the neuroendocrine system, and characteristic patterns of leptin and ghrelin concentrations have been observed in anorexia nervosa. A thorough understanding of refeeding syndrome is imperative to nutrition rehabilitation in these patients to avoid devastating consequences. Although most endocrinopathies associated with anorexia nervosa reverse with recovery, short stature, osteoporosis, and infertility may be long-lasting complications. We describe a 20-year-old woman who presented with end-stage anorexia nervosa whose clinical course reflects the numerous complications caused by this disease.ConclusionsThe effects of severe malnutrition and subsequent refeeding are extensive in anorexia nervosa. Nutrition rehabilitation is the most appropriate treatment for these patients; however, it must be done cautiously. (Endocr Pract. 2008;14:1055-1063)     

Resting tachycardia, a warning sign in anorexia nervosa: case report

Background

Among psychiatric disorders, anorexia nervosa has the highest mortality rate. During an exacerbation of this illness, patients frequently present with nonspecific symptoms. Upon hospitalization, anorexia nervosa patients are often markedly bradycardic, which may be an adaptive response to progressive weight loss and negative energy balance. When anorexia nervosa patients manifest tachycardia, even heart rates in the 80–90 bpm range, a supervening acute illness should be suspected.

Case presentation

A 52-year old woman with longstanding anorexia nervosa was hospitalized due to progressive leg pain, weakness, and fatigue accompanied by marked weight loss. On physical examination she was cachectic but in no apparent distress. She had fine lanugo-type hair over her face and arms with an erythematous rash noted on her palms and left lower extremity. Her blood pressure was 96/50 mm Hg and resting heart rate was 106 bpm though she appeared euvolemic. Laboratory tests revealed anemia, mild leukocytosis, and hypoalbuminemia. She was initially treated with enteral feedings for an exacerbation of anorexia nervosa, but increasing leukocytosis without fever and worsening left leg pain prompted the diagnosis of an indolent left lower extremity cellulitis. With antibiotic therapy her heart rate decreased to 45 bpm despite minimal restoration of body weight.

Conclusions

Bradycardia is a characteristic feature of anorexia nervosa particularly with significant weight loss. When anorexia nervosa patients present with nonspecific symptoms, resting tachycardia should prompt a search for potentially life-threatening conditions.     

Integrated circuits and molecular components for stress and feeding: implications for eating disorders

Eating disorders are complex brain disorders that afflict millions of individuals worldwide. The etiology of these diseases is not fully understood, but a growing body of literature suggests that stress and anxiety may play a critical role in their development. As our understanding of the genetic and environmental factors that contribute to disease in clinical populations like anorexia nervosa, bulimia nervosa and binge eating disorder continue to grow, neuroscientists are using animal models to understand the neurobiology of stress and feeding. We hypothesize that eating disorder clinical phenotypes may result from stress‐induced maladaptive alterations in neural circuits that regulate feeding, and that these circuits can be neurochemically isolated using animal model of eating disorders.     

Classification of feeding and eating disorders: review of evidence and proposals for ICD-11

Current classification of eating disorders is failing to classify most clinical presentations; ignores continuities between child, adolescent and adult manifestations; and requires frequent changes of diagnosis to accommodate the natural course of these disorders. The classification is divorced from clinical practice, and investigators of clinical trials have felt compelled to introduce unsystematic modifications. Classification of feeding and eating disorders in ICD-11 requires substantial changes to remediate the shortcomings. We review evidence on the developmental and cross-cultural differences and continuities, course and distinctive features of feeding and eating disorders. We make the following recommendations: a) feeding and eating disorders should be merged into a single grouping with categories applicable across age groups; b) the category of anorexia nervosa should be broadened through dropping the requirement for amenorrhoea, extending the weight criterion to any significant underweight, and extending the cognitive criterion to include developmentally and culturally relevant presentations; c) a severity qualifier "with dangerously low body weight" should distinguish the severe cases of anorexia nervosa that carry the riskiest prognosis; d) bulimia nervosa should be extended to include subjective binge eating; e) binge eating disorder should be included as a specific category defined by subjective or objective binge eating in the absence of regular compensatory behaviour; f) combined eating disorder should classify subjects who sequentially or concurrently fulfil criteria for both anorexia and bulimia nervosa; g) avoidant/restrictive food intake disorder should classify restricted food intake in children or adults that is not accompanied by body weight and shape related psychopathology; h) a uniform minimum duration criterion of four weeks should apply.     

Muscle dysmorphia: a critical review of the proposed criteria

While body-image related disorders such as anorexia nervosa have focused on thinness, only recently have clinical criteria for a disorder that centers around muscularity--muscle dysmorphia--been proposed. An individual affected by muscle dysmorphia is overly concerned with his or her degree of muscularity.This preoccupation is manifested in the individual's behavior (excessive weight lifting, excessive attention to diet, social impairment).This article examines the historical aspects and proposed criteria for muscle dysmorphia and contrasts them with those of anorexia nervosa. While the authors of the proposed criteria have suggested that muscle dysmorphia be classified as a subcategory of body dysmorphic disorder, both the historical and clinical aspects of this syndrome are more consistent with its classification as an obsessive-compulsive disorder.     

Identifying Predictors of Activity Based Anorexia Susceptibility in Diverse Genetic Rodent Populations

Animal studies are very useful in detection of early disease indicators and in unravelling the pathophysiological processes underlying core psychiatric disorder phenotypes. Early indicators are critical for preventive and efficient treatment of progressive psychiatric disorders like anorexia nervosa. Comparable to physical hyperactivity observed in anorexia nervosa patients, in the activity-based anorexia rodent model, mice and rats express paradoxical high voluntary wheel running activity levels when food restricted. Eleven inbred mouse strains and outbred Wistar WU rats were exposed to the activity-based anorexia model in search of identifying susceptibility predictors. Body weight, food intake and wheel running activity levels of each individual mouse and rat were measured. Mouse strains and rats with high wheel running activity levels during food restriction exhibited accelerated body weight loss. Linear mixed models for repeated measures analysis showed that baseline wheel running activity levels preceding the scheduled food restriction phase strongly predicted activity-based anorexia susceptibility (mice: Beta  =  −0.0158 (±0.003 SE), P<0.0001; rats: Beta  =  −0.0242 (±0.004 SE), P<0.0001) compared to other baseline parameters. These results suggest that physical activity levels play an important role in activity-based anorexia susceptibility in different rodent species with genetically diverse background. These findings support previous retrospective studies on physical activity levels in anorexia nervosa patients and indicate that pre-morbid physical activity levels could reflect an early indicator for disease severity.     

Anorexia nervosa,amenorrhea, and adaptation

Female mammals under stress or in poor physical condition often delay puberty or otherwise suppress reproduction. This capacity is adaptive because it enables females to avoid reproduction when environmental conditions are not conducive to the survival of offspring. Because amenorrhea is one of the key diagnostic criteria for this condition, anorexia nervosa is discussed in an evolutionary context. It is suggested that anorexia nervosa may delay puberty in girls who are disposed to early maturity. Since there is some evidence that early and late maturers have different life histories in modern societies, the reproductive delay associated with anorexia nervosa exhibits features compatible with an evolved reproductive strategy. Insofar as anorexia nervosa is a modern phenomenon, it is unlikely that the syndrome per se is the result of selection. Rather, anorexia nervosa appears to be a reflection of the female ability to alter maturation rates and reproductive function in response to environmental conditions.     

Anorexia nervosa viewed as an extreme weight condition: genetic implications

In anorexia nervosa, psychopathological features and reduced body weight are inseparable, suggesting a prominent role of behavioral factors in achievement and maintenance of extreme underweight. Due to the considerably higher prevalence of this eating disorder in females, anorexia nervosa contributes to the left end of the distribution of the body mass index, especially in the female sex. By reviewing the relevant literature we examined whether genetic research in anorexia nervosa can profit from considering this disorder as an extreme weight condition. For this purpose we compared genetic studies pertaining to both anorexia nervosa and the heritability of the body mass index. Whereas previous genetic studies in anorexia nervosa have mostly concentrated on the assessment of the familial psychopathology, further studies are warranted that additionally attempt to analyze the complex phenotype body weight in relatives of affected probands. Further insight into pathogenetic mechanisms underlying anorexia nervosa might be gained by contrasting the epidemiological, psychopathological and prognostic factors with those in severe obesity. Thus, epidemiological studies suggest that females are more likely to develop both extreme underweight and extreme obesity. A possible explanation for this phenomenon is that the, on average, higher percentage of total body weight composed of fat mass might predispose females towards the development of both extreme weight conditions.     

Human pancreatic polypeptide responsiveness to insulin-induced hypoglycemia in anorexia nervosa

Patients with anorexia nervosa occasionally suffer from hypoglycemic comas. We investigated the role of human pancreatic polypeptide (HPP) in insulin-induced hypoglycemia (0.1 U/kg of regular insulin). Ten female patients with anorexia nervosa (20.7 +/- 2.0 years, mean +/- SEM; 34.9 +/- 1.7 kg, mean +/- SEM) and 8 age-matched female controls (20.9 +/- 0.6 years, 51.5 +/- 0.8 kg) were tested. In the patients with anorexia nervosa, testing was performed before and after the restoration of body weight (45.0 +/- 0.8 kg). There was no significant difference in glucose nadir between patients with anorexia nervosa and the control subjects. However, glucose recovery from nadir was delayed in patients with anorexia nervosa. In anorexia nervosa patients, the plasma pancreatic glucagon responses to insulin-induced hypoglycemia did not differ from those of the controls. Results also showed, however, that HPP responses to insulin-induced hypoglycemia were significantly higher in patients with anorexia nervosa than in controls (p less than 0.01). The increased HPP responses were still present after the restoration of body weight in anorexia nervosa patients. A complete body weight recovery or a longer period of time may be required to normalize the HPP response to insulin-induced hypoglycemia in patients with anorexia nervosa, after the restoration of body weight.     

Atypical responses to morphine in mice: a possible relationship to anorexia nervosa?

According to our previously proposed auto-addiction hypothesis of chronic anorexia nervosa, patients become addicted to an initial period of dieting through endogenous opioid mediated mechanisms. Morphine causes hyperactivity and anorexia in the mouse, symptoms of anorexia nervosa but responses opposite to those of most species including rats and normal human subjects. This suggests that the atypical opioid systems in the mouse may resemble those of the chronic anorexia nervosa patient in contrast to those of most species including the normal human. Characterization of this atypical opioid system may be useful in understanding the pathophysiology of anorexia nervosa.     

Risks of all‐cause and suicide mortality in mental disorders: a meta‐review

A meta‐review, or review of systematic reviews, was conducted to explore the risks of all‐cause and suicide mortality in major mental disorders. A systematic search generated 407 relevant reviews, of which 20 reported mortality risks in 20 different mental disorders and included over 1.7 million patients and over a quarter of a million deaths. All disorders had an increased risk of all‐cause mortality compared with the general population, and many had mortality risks larger than or comparable to heavy smoking. Those with the highest all‐cause mortality ratios were substance use disorders and anorexia nervosa. These higher mortality risks translate into substantial (10‐20 years) reductions in life expectancy. Borderline personality disorder, anorexia nervosa, depression and bipolar disorder had the highest suicide risks. Notable gaps were identified in the review literature, and the quality of the included reviews was typically low. The excess risks of mortality and suicide in all mental disorders justify a higher priority for the research, prevention, and treatment of the determinants of premature death in psychiatric patients.     

Epidemiology of Anorexia Nervosa in Men: A Nationwide Study of Finnish Twins

Background

To examine the epidemiology of anorexia nervosa in men, we screened Finnish male twins born in 1975–79.

Methods and Findings

Men (N = 2122) from FinnTwin16 birth cohorts were screened for lifetime eating disorders by a questionnaire. The screen positives (N = 18), their male co-twins (N = 10) and those with lifetime minimum BMI≤17.5 (N = 21) were administered the Structured Clinical Interview for DSM-IV anorexia nervosa. The incidence rate of anorexia nervosa for the presumed peak age of risk (10–24y) was 15.7 per 100 000 person-years; its lifetime prevalence was 0.24%. All probands had recovered from eating disorders, but suffered from substantial psychiatric comorbidity, which also manifested in their co-twins. Additionally, male co-twins displayed significant dissatisfaction with body musculature, a male-specific feature of body dysmorphic disorder.

Conclusions

Anorexia nervosa in males in the community is more common, transient and accompanied by more substantial comorbidity than previously thought.     

Serum leptin levels in patients with anorexia nervosa before and after partial refeeding, relationships to serum lipids and biochemical nutritional parameters.

Leptin is a protein hormone produced by adipocytes that provide information about the body fat content. It was previously reported that serum leptin levels were decreased in patients with anorexia nervosa in comparison with healthy control subjects. The aim of our study was to compare serum leptin levels in patients with anorexia nervosa (n=11, initial mean BMI=15.4 kg/m2) before and after partial recovery with control age-matched subjects (n=11, mean BMI= 20.3 kg/m2) and to study the relationships of leptin levels, serum lipids and biochemical nutritional parameters. We found that serum leptin concentrations in patients with anorexia nervosa were significantly reduced in comparison with control subjects (3.61 vs 9.37 ng.ml(-1), p<0.01). Serum cholesterol, triglycerides, total protein and albumin in patients with anorexia nervosa either before or after partial recovery did not differ from the control group. After partial recovery, a significant increase in serum leptin was observed (4.83 vs 3.61 ng.ml(-1), p<0.05), but the values still remained significantly lower than in the control group (p<0.01) Leptin levels correlated positively with the body mass index in the control group and anorexia nervosa group before recovery. The correlation with BMI in the anorexia nervosa group after refeeding was not significant. No significant correlation was found between leptin concentrations and serum lipids, total protein, albumin and prealbumin, respectively. Serum leptin thus represents a sensitive parameter that reflects the nutritional status in patients with anorexia nervosa suitable for long-term follow up during refeeding therapy.     

Preadipocyte factor-1 concentrations in patients with anorexia nervosa: the influence of partial realimentation

Preadipocyte factor-1 (Pref-1) is a member of epidermal growth-factor like family of proteins that regulates adipocyte and osteoblast differentiation. Experimental studies suggest that circulating Pref-1 levels may be also involved in the regulation of lipid and glucose metabolism and energy homeostasis. We hypothesized that alterations in Pref-1 levels may contribute to the ethiopathogenesis of anorexia nervosa or its underlying metabolic abnormalities. We measured Pref-1 concentrations and other hormonal, biochemical and anthropometric parameters in eighteen patients with anorexia nervosa and sixteen healthy women and studied the influence of partial realimentation of anorexia nervosa patients on these parameters. The mean duration of realimentation period was 46±2 days. At baseline, anorexia nervosa patients had significantly decreased body mass index, body weight, body fat content, fasting glucose, serum insulin, TSH, free T4, leptin and total protein. Partial realimentation improved these parameters. Baseline serum Pref-1 levels did not significantly differ between anorexia nervosa and control group (0.26±0.02 vs. 0.32±0.05 ng/ml, p=0.295) but partial realimentation significantly increased circulating Pref-1 levels (0.35±0.04 vs. 0.26±0.02 ng/ml, p<0.05). Post-realimentation Pref-1 levels significantly positively correlated with the change of body mass index after realimentation (r=0.49, p<0.05). We conclude that alterations in Pref-1 are not involved in the ethiopathogenesis of anorexia nervosa but its changes after partial realimentation could be involved in the regulation of adipose tissue expansion after realimentation.     

Salient components of a comprehensive service for eating disorders

Eating disorders are challenging and difficult to treat, because of the necessity of a multidisciplinary treatment team for effective outcomes and the high mortality rate of anorexia nervosa. An adequate initial assessment and evaluation requires a psychiatric assessment, a medical history and medical examination, a social history and an interview of family members or collateral informants. A comprehensive eating disorder treatment team includes a psychiatrist coordinating the treatment and appropriate medical physician specialists, nutritionists, and psychotherapists. An adequate outpatient eating disorder clinic needs to provide individual psychotherapy with cognitive behavioral techniques specific for anorexia nervosa and bulimia nervosa, family therapy, pharmacological treatment and the resources to obtain appropriate laboratory tests. Eating disorder patients requiring inpatient care are best treated in a specialized eating disorder inpatient unit. A cognitive behavioral framework is most useful for the overall unit milieu. Medical management and nutritional rehabilitation are the primary goals for inpatient treatment. Various group therapies can cover common core eating disorder psychopathology problems and dialectical behavior therapy groups can be useful for managing emotional dysregulation. Residential, partial hospitalization and day treatment programs are useful for transitioning patients from an inpatient program or for patients needing some monitoring. In these programs, at least one structured meal is advisable as well as nutritional counseling, group therapy or individual counseling sessions. Group therapies usually address issues such as social skills training, social anxiety, body image distortion or maturity fears. Unfortunately there is s paucity of evidence based randomized control trials to recommend the salient components for a comprehensive service for eating disorders. Experienced eating disorder clinicians have come to the conclusion that a multidisciplinary team approach provides the most effective treatment.     

Hypothalamic pituitary adrenal function in patients with anorexia nervosa.

Hypothalamic pituitary adrenal function was studied in 14 patients with anorexia nervosa. Although basal plasma cortisol levels in the morning were elevated in most cases, basal plasma ACTH levels were not suppressed. Oral administration of 1 mg dexamethasone 10 hr before blood sampling failed to suppress plasma ACTH and cortisol levels in most patients with anorexia nervosa. Apparent biological half-life of exogenous cortisol was prolonged in all 4 patients with anorexia nervosa tested. The cortisol response to insulin-induced hypoglycemia and exogenous ACTH appeared to be blunted in these patients. It is concluded that anorexia nervosa has dysfunctions of hypothalamic pituitary adrenal axis, especially an abnormal feedback mechanism on ACTH secretion.     

Atypical endogenous opioid systems in mice in relation to an auto-addiction opioid model of anorexia nervosa

We have proposed that the atypical opioid system in the mouse may be representative of that in the anorexia nervosa patient and may account for a biological predisposition to the disorder. This is in the context of our auto-addiction model of anorexia nervosa in which endogenous opioids play a critical role in its etiology. Morphine activation of the endogenous opioid systems increases food intake and causes sedation in most species, including normal humans and rats. In contrast in BALB/C mice, morphine causes anorexia and hyperactivity, which we suggest may be true in the anorexia nervosa patient. A variety of atypical opioid systems have been demonstrated in different mouse strains, based on other responses. The present study examines these strains with reference to the responses relevant to our anorexia nervosa model. Three patterns are described--anorexia with hyperactivity (BALB/C and C57BL/6J mice), anorexia without hyperactivity (DBA/J mice), and a biphasic curve with hyperphagia at low doses and anorexia and hyperactivity at higher doses (CF-1 mice). Only female mice were used. These atypical opioid systems may reflect a spectrum of biological predispositions to the disorder. These strain differences may also provide useful correlations of the genetic determinants of various opiate responses and provide useful comparisons in characterizing the essential features responsible for the atypical responses.     

Effect of management of patients with Anorexia and Bulimia nervosa on symptoms and impulsive behavior

The aim of the study was to provide further and up to date information on the evaluation of the management of Anorexia and Bulimia nervosa at the Eating Disorders Unit (EDU) of the Ljubljana Psychiatric Clinic, based upon detailed assessment of the eating disorders specific and non specific symptoms of impulsive behaviors, highly correlated with these entities. 34 female patients with anorexia (restrictive or purgative type) and 38 female patients with Bulimia nervosa (purgative or non-purgative type) undergoing hospital treatment at the EDU were evaluated upon admission, as well as upon discharge and three and six months after discharge, using the Eating Disorder Questionnaire. Upon discharge a marked decrease in the overall symptoms was noted. The differences in symptoms incidences between the two groups were significantly specific for the individual form of eating disorder, especially upon admission, and were more pronounced in anorexia group. In later measurements, performed during the period of three and six months after discharge, a mild trend of increase in the disorder specific symptoms was detected in both groups, but was not statistically significant. In addition to binging on food, striking, quarreling and spending sprees are characteristics of patients with eating disorders, which in particular apply to the Bulimia nervosa group. Apart from the disorder specific symptoms, impulsive behavior was also reduced during study period, while the difference in its occurrence between the two groups gradually became non-significant. The management of patients with eating disorders at the EDU was successful in both groups, confirmed by an intense reduction of the disorder specific symptoms, impulsive behavior and increased stability recorded three and six months after discharge. The study strongly suggests that the effect of treatment regime for eating disorders can be predicted by careful assessment of the relevant symptoms and impulsive behavioral patterns.     

Transcultural aspects of eating disorders: A critical literature review

A review of studies addressing anorexia nervosa and bulimia nervosa among Native Americans, African-Americans, Hispanics, Asians, Africans, and Middle Easterners yielded only 35 studies, of which 22 were qualitative case reports, three were clinical quantitative studies, and ten were non-clinical quantitative studies. The case studies reported symptoms similar to those of Caucasian patients, and eating disorders were reported in all SES classes. The clinical studies, all reported from Asian countries, described a number of cases for eating disorders quite different from one another. The non-clinical quantitative studies reported a number of cases consistent with the ranges previously reported for controlled samples of non-clinical Caucasian populations. We found few or no quantitative studies on eating disorders from Hispanic, Middle Eastern, African, or Asian countries other than Japan.