Exploring the Mechanisms of Recovery in Anorexia Nervosa through a Translational Approach: From Original Ecological Measurements in Human to Brain Tissue Analyses in Mice.

Anorexia nervosa (AN) is a severe eating disorder where caloric restriction, excessive physical activity and metabolic alterations lead to life-threatening situations. Despite weight restoration after treatment, a significant part of patients experience relapses. In this translational study, we combined clinical and preclinical approaches. We describe preliminary data about the effect of weight gain on the symptomatology of patients suffering from acute AN (n = 225) and partially recovered (n = 41). We measured more precisely physical activity with continuous cardiac monitoring in a sub-group (n = 68). Using a mouse model, we investigated whether a long-term food restriction followed by nutritional recovery associated or not with physical activity may differentially impact peripheral and central homeostatic regulation. We assessed the plasma concentration of acyl ghrelin, desacyl ghrelin and leptin and the mRNA expression of hypothalamic neuropeptides and their receptors. Our data show an effect of undernutrition history on the level of physical activity in AN. The preclinical model supports an important role of physical activity in the recovery process and points out the leptin system as one factor that can drive a reliable restoration of metabolic variables through the hypothalamic regulation of neuropeptides involved in feeding behavior.

Vitamin D Level Trajectories of Adolescent Patients with Anorexia Nervosa at Inpatient Admission, during Treatment, and at One Year Follow Up: Association with Depressive Symptoms.

(1) Background: Evidence has accumulated that patients with anorexia nervosa (AN) are at higher risk for vitamin D deficiency than healthy controls. In epidemiologic studies, low 25(OH) vitamin D (25(OH)D) levels were associated with depression. This study analyzed the relationship between 25(OH)D serum levels in adolescent patients and AN and depressive symptoms over the course of treatment. (2) Methods: 25(OH)D levels and depressive symptoms were analyzed in 93 adolescent (in-)patients with AN from the Anorexia Nervosa Day patient versus Inpatient (ANDI) multicenter trial at clinic admission, discharge, and 1 year follow up. Mixed regression models were used to analyze the relationship between 25(OH)D levels and depressive symptoms assessed by the Beck Depression Inventory (BDI-II). (3) Results: Although mean 25(OH)D levels constantly remained in recommended ranges (≥50 nmol/L) during AN treatment, levels decreased from (in)patient admission to 1 year follow up. Levels of 25(OH)D were neither cross-sectionally, prospectively, nor longitudinally associated with the BDI-II score. (4) Conclusions: This study did not confirm that 25(OH)D levels are associated with depressive symptoms in patients with AN. However, increasing risks of vitamin D deficiency over the course of AN treatment indicate that clinicians should monitor 25(OH)D levels.

Zinc Deficiency as a Reversible Cause of Heart Failure.

Zinc, an essential micronutrient, affects the heart by modulating cardiomyocyte oxidative stress and maintaining myocardial structure, among other mechanisms. In cross-sectional studies, patients with heart failure have often had zinc deficiencies, suggesting effects on the ongoing pathogenesis of heart failure. Low plasma and myocardial zinc levels may cause reversible cardiomyopathy in patients who have nutritional deficiencies. We present the case of a 24-year-old woman with anorexia nervosa and new-onset heart failure whose depressed left ventricular systolic function improved after zinc supplementation. To our knowledge, this is the first report of low plasma zinc levels as the chief cause of cardiomyopathy that resolved after zinc supplementation.

The potential role of the novel hypothalamic neuropeptides nesfatin-1, phoenixin, spexin and kisspeptin in the pathogenesis of anxiety and anorexia nervosa.

Due to the dynamic development of molecular neurobiology and bioinformatic methods several novel brain neuropeptides have been identified and characterized in recent years. Contemporary techniques of selective molecular detection e.g. in situ Real-Time PCR, microdiffusion and some bioinformatics strategies that base on searching for single structural features common to diverse neuropeptides such as hidden Markov model (HMM) have been successfully introduced. A convincing majority of neuropeptides have unique properties as well as a broad spectrum of physiological activity in numerous neuronal pathways including the hypothalamus and limbic system. The newly discovered but uncharacterized regulatory factors nesfatin-1, phoenixin, spexin and kisspeptin have the potential to be unique modulators of stress responses and eating behaviour. Accumulating basic studies revelaed an intriguing role of these neuropeptides in the brain pathways involved in the pathogenesis of anxiety behaviour. Nesfatin-1, phoenixin, spexin and kisspeptin may also distinctly affect the energy homeostasis and modulate food intake not only at the level of hypothalamic centres. Moreover, in patients suffered from anxiety and anorexia nervosa a significant, sex-related changes in the plasma neuropeptide levels occurred. It should be therefore taken into account that the targeted pharmacomodulation of central peptidergic signaling may be potentially helpful in the future treatment of certain neuropsychiatric and metabolic disorders. This article reviews recent evidence dealing with the hypothetical role of these new factors in the anxiety-related circuits and pathophysiology of anorexia nervosa.

Ghrelin activation and neuropeptide Y elevation in response to medium chain triglyceride administration in anorexia nervosa patients.

BACKGROUND & AIMS: Ghrelin, a peptide found in the stomach, increases appetite and fat-free mass while suppressing energy expenditure. Ghrelin requires modification by medium-chain triglycerides (MCTs) to exert its physiological effects. In this study, we investigated ghrelin activation and the resulting physiological changes following MCT administration. METHODS: Thirty participants were selected from among inpatients diagnosed with anorexia nervosa (AN). The patients were randomly divided into three groups by the MCT content of their nutritional supplement: (1) 'MCT high' (>6 g/day), (2) 'MCT moderate' (1-6 g/day), and (3) 'MCT low' (<1 g/day). Physical factors such as body weight and composition, as well as levels of nutrition-related serum factors such as acylated (active form) and desacyl (inactive form) ghrelin, leptin, growth hormone, insulin-like growth factor, and neuropeptide Y (NPY) were measured at weeks 0, 2, 4, and 6 of the treatment protocol. RESULTS: Significantly higher ghrelin activation was found in the 'MCT high' than in the 'MCT low' group (P < 0.05). The amount of consumed MCT had a curvilinear relationship with the active ghrelin level (P = 0.00). NPY levels in the 'MCT high' group were significantly more elevated than in the 'MCT low' group (P < 0.05). MCT administration did not significantly affect the remaining factors. CONCLUSIONS: This study clearly demonstrated that MCT activates ghrelin and increases NPY, suggesting that nutritional supplementation with MCT may be effective for the treatment of AN patients in an emaciated state.

[Atypical scurvy associated with anorexia nervosa]. / Scorbut atypique associé à une anorexie mentale.

INTRODUCTION: Scurvy, or "Barlow's disease", is a widely described disease involving cutaneous and mucosal lesions resulting from vitamin C deficiency. Herein, we report a case of scurvy in a 48-year-old woman that was unusual in its atypical cutaneous-mucosal presentation as well as its association with anorexia nervosa. PATIENTS AND METHODS: A 48-year-old woman treated for depression for several years was admitted to hospital for her impaired general state of health. Over the last year, she had presented palmoplantar rash and episodes of perimalleolar oedema. The clinical examination showed the patient to have wasting syndrome, with a BMI of 11.9kg/m2, lower-limb oedema, palmoplantar fissures, geographic tongue, telogen effluvium and purpuric petechiae on her right knee. However, no gingival bleeding was noted and there was no loss of tooth enamel. The remainder of the clinical examination was normal. Blood tests revealed extremely low vitamin C levels without any other associated deficiencies, as well as laboratory signs of cytolysis and anicteric cholestasis without inflammatory syndrome. The diagnosis of anorexia nervosa was made by psychiatrists, despite the unusual age of onset. Favorable clinical outcome was rapidly achieved via a one-month course of vitamin C supplements at a daily dose of 1g. DISCUSSION: The absence of classical buccal-dental symptoms and the presence of keratotic dermatosis with fissures and ulcers on the hands and feet are atypical in scurvy; however, this diagnosis was confirmed by the existence of purpura evoking capillary fragility, the patient's drastically low vitamin C level and the rapid subsidence of symptoms following treatment with oral vitamin C alone. Anorexia nervosa was doubtless the cause of deficiency. This situation is rare and a systematic review of the literature in Medline via PubMed showed that only three reports of scurvy associated with mental anorexia have been published since 1975.

Elevated plasma concentrations of bacterial ClpB protein in patients with eating disorders.

OBJECTIVE: Caseinolytic protease B (ClpB) produced by Enterobacteria, such as Escherichia coli, has been identified as a conformational mimetic of α-melanocyte-stimulating hormone (α-MSH), an anorexigenic and anxiogenic neuropeptide. In mice, ClpB induces α-MSH cross-reactive antibodies and activates anorexigenic brain neurons. In patients with eating disorders (ED), anti-ClpB and anti-α-MSH antibodies correlate with psychopathological traits. However, it is not known if ClpB is present in human plasma including ED patients. METHODS: Plasma concentrations of ClpB were measured using a recently developed ClpB immunoassay in female patients with anorexia nervosa, bulimia nervosa, and binge-eating disorder and compared with healthy participants, all characterized by the Eating Disorder Inventory-2 (EDI-2) scale. RESULTS: We found that ClpB was readably detectable in plasma of healthy participants and ED patients and that its concentrations were elevated in ED patients, without significant differences in patient's subgroups. Plasma ClpB concentrations correlated with the EDI-2 scores, with α-MSH as well as with plasma levels of anti-ClpB and anti-α-MSH antibodies. DISCUSSION: These data revealed that bacterial ClpB is naturally present in human plasma and that its concentrations can be elevated in ED patients and associated with ED-related psychopathological traits. These results support a link between bacterial ClpB and the ED pathophysiology. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:805-808).

Alteration in serum klotho levels in anorexia nervosa patients.

BACKGROUND & AIMS: Klotho is a trans-membrane protein which can be shed to act as a hormone; its blood levels may be regulated by the GH/IGF-1 axis. Klotho deficient mice exhibit short lifespan and characteristics of aging and malnutrition, including decreased fat and muscle mass, osteopenia, and impaired fertility. As anorexia nervosa (AN) is characterized by malnutrition and GH resistance, we hypothesized klotho levels would be altered in AN, and aimed to assess klotho levels in undernourished AN patients and changes in klotho following weight rehabilitation. PARTICIPANTS AND METHODS: 19 adolescent female AN inpatients (aged 16.1 ± 1.8 years) admitted to an inpatient service for eating disorders in a tertiary center were recruited. Blood samples were obtained on admission and after weight restoration (interval 4.0 ± 2.3 months) and analyzed for klotho, IGF-1, calcium, phosphorus, and alkaline phosphatase. RESULTS: Klotho levels on admission were lower than expected for age, and correlated with lumbar spine BMD Z-score (r = -0.81, p < 0.001) and alkaline phosphatase levels (r = 0.66, p = 0.003) but not with age, height-SDS, weight-SDS, BMI-SDS, or serum calcium, phosphorus and IGF-1 levels. Both IGF-1 and klotho levels increased significantly during hospitalization (IGF-1: 44 ± 17 nmol/l to 53 ± 11 nmol/l, p = 0.008; klotho: 1061 ± 421 pg/ml to 1519 ± 781 pg/ml, p = 0.008). CONCLUSIONS: Klotho levels are low in the acute stage of AN and increase with nutritional rehabilitation. Low klotho on admission may be secondary to low IGF-1 levels and may contribute to the clinical manifestations of AN. The role of klotho in the pathophysiology of AN and as a novel marker of disease severity should be further explored.

Influence of a fermented protein-fortified dairy product on serum insulin-like growth factor-I in women with anorexia nervosa: A randomized controlled trial.

BACKGROUND & AIMS: Patients with anorexia nervosa (AN) have low serum IGF-I levels that may contribute to a lower bone mineral mass. We investigated the effects of a fermented, protein-fortified, dairy product on serum IGF-I levels in patients with AN during an in-hospital refeeding program. METHODS: In this multicenter, randomized, double-blind, placebo-controlled, clinical trial conducted at 3 university hospitals and 3 private clinics in France and Switzerland, 62 women recently admitted with confirmed AN and with a baseline low serum IGF-I level were randomized to 2 daily isocaloric fresh cheese pots containing either 15 g/150 g or 3 g/150 g (controls) of protein for 4 weeks. The primary outcome was the change in IGF-I levels. RESULTS: In the primary intention-to-treat analysis, mean serum IGF-I levels increased during the intervention phase from 22.9 ± 1.5 to 28.6 ± 1.3 nmol/L (means ± SEM) (+20.2%) in the intervention group and from 20.2 ± 1.2 to 25.7 ± 1.5 nmol/L (+16.8%) in controls. In a preplanned analysis of covariance with repeated measures, the between-group difference was close to statistical significance (P = 0.071). In a post-hoc mixed-regression model analysis, the difference was statistically significant (4.9 nmol/l increase; P = 0.003), as was the change of the ratio IGF-I/IGF-BP3 (P=0.004). There was no between-group difference in biochemical markers of bone turnover (osteocalcin, P1NP, CTX) or in serum parathyroid hormone level. Serum calcium levels slightly increased during the intervention phase in the higher protein group (P = 0.02). IGF-BP2 decreased significantly more in the intervention group during the follow up period at week 4 after supplements cessation (P = 0.019). CONCLUSIONS: Intake of a fermented, protein-fortified, isocaloric dairy product during 4 weeks may slightly increase serum IGF-I levels in women with AN, without significant changes in bone turnover markers. CLINICAL TRIAL REGISTRATION NUMBER: NCT01823822 (www.clinicaltrials.gov).

Strong relationship between vitamin D status and bone mineral density in anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is associated with impaired bone health and low bone mineral density (BMD) as a consequence of an inadequate peak bone mass in adolescence and bone loss in young adulthood. The vitamin D status with its implications for bone health in patients affected by AN has only been examined previously in small studies. OBJECTIVE: To evaluate the prevalence of vitamin D deficiency and test the hypothesis that patients with AN and vitamin D deficiency might have worse bone metabolism and lower bone density as compared with AN with adequate vitamin D repletion. DESIGN: We analysed the vitamin D status and bone metabolism in a large cohort (n=89) of untreated patients affected by AN, with amenorrhoea. RESULTS: Vitamin D deficiency is widespread in untreated patients with AN: 16.9% had 25OH vitamin D levels below 12 ng/ml, 36% below 20 ng/ml and 58.4% below 30 ng/ml. PTH values were higher and BMD at both femoral sites were lower in patients with vitamin D<20 ng/ml. Progressively higher values of BMD were observed by 4 ranks of 25 OH vitamin D values (severe deficiency: <12 ng/ml, deficiency: ≥12 ng/ml and <20 ng/ml, insufficiency: ≥20 and <30 ng/ml and normal: ≥30 ng/ml). In patients with severe vitamin D deficiency BMD at the hip were significantly lower than that measured in groups with values over 20 ng/ml (p<0.001 for trend). The level of significance did not change for values adjusted for BMI or body weight. CONCLUSION: We found a strong relationship between vitamin D status and hip BMD values with additional benefits for those with 25OHD levels above 20 ng/ml. Our results support the design of a randomized placebo-controlled clinical trial on the effect of vitamin D on BMD in patients with AN. The second point, whether 25OHD should be above 20 or 30 ng/ml remains a discussion point.

Vitamin D status in anorexia nervosa: A meta-analysis.

OBJECTIVE: In anorexia nervosa (AN), osteoporosis and osteopenia are common, which have been associated with low circulating levels of vitamin D (VitD) in other settings. We aimed to meta-analyze cross-sectional studies reporting on VitD parameters in patients with AN and healthy controls (HCs). METHOD: Electronic PubMed search from database inception until December 31, 2013 and meta-analysis of cross-sectional studies comparing serum levels of 25-hydroxyvitamin D (25OH-D), 1,25-dihydroxyvitamin D (1,25OH-D) and dietary VitD between patients with AN and HCs, before or after VitD supplementation. We calculated random effects standardized mean differences (SMDs) ±95% confidence intervals (CIs) as effect size measures. RESULTS: Out of 1,739 initial hits, 15 studies with a total of 927 participants (AN = 408 and HCs = 519) were meta-analyzed. In the unsupplemented state, both serum 25OH-D (studies = 4; n = 168; SMD = -0.43; 95%CI: -0.83 to -0.03; p = .03) and 1,25OH-D levels (studies = 4; n = 113; SMD = -1.06; 95%CI: -1.47 to -0.66; p < .00001) were significantly lower in AN than HCs. In AN patients treated with cholecalciferol supplementation, serum 25OH-D levels were significantly higher than in HCs (studies = 5; n = 449; SMD = 0.66; 95%CI: 0.01-1.31; p = .05). Paradoxically, despite lower 25OH-D and 1,25OH-D levels, AN patients reported similar intake of VitD compared to HCs (studies = 6; n = 314; SMD = 0.33; 95%CI: -0.16, 0.81; p = .19). DISCUSSION: Although AN patients reported similar dietary VitD intake compared to HCs, AN patients had significantly lower 25OH-D and 1,25OH-D levels without supplementation. Conversely, supplementation with cholecalciferol fully normalized VitD serum levels. Future studies are needed to clarify the role of VitD supplementation in AN for improving bone health.

Vitamin K deficiency evaluated by serum levels of undercarboxylated osteocalcin in patients with anorexia nervosa with bone loss.

BACKGROUND & AIMS: Osteoporosis is a chief complication in patients with anorexia nervosa. Serum levels of undercarboxylated osteocalcin reflect serum and bone vitamin K deficiency. We investigated vitamin K status in patients with anorexia nervosa to help establish prevention and treatment recommendations for osteoporosis. METHODS: Fifty-four female amenorrheic patients with anorexia nervosa (29 restricting-type and 25 binge eating/purging type) (age, 28.0 (26.7-31.1) (mean (95% CI)) years; body mass index, 14.8 (14.1-15.5) kg/m(2), duration of illness; 107.3 (88.5-126.0) months) and 15 age-matched healthy females were included in this study. We measured serum levels of undercarboxylated osteocalcin, biochemical and nutritional markers, and bone metabolic markers. Dietary vitamin K intake was evaluated by a questionnaire. RESULTS: Lumbar bone mineral density and T-scores in patients with anorexia nervosa were 0.756 (0.721-0.790) g/cm(2) and -2.4 (-2.1 to -2.7), respectively, indicating bone loss. Serum levels of undercarboxylated osteocalcin in patients with anorexia nervosa were significantly higher than those of controls. The 17% of restricting type and 40% of binge eating/purging type anorexia nervosa patients, serum levels of undercarboxylated osteocalcin were higher than 4.5 ng/ml and were diagnosed with vitamin K deficiency. Serum levels of undercarboxylated osteocalcin correlated significantly and negatively with vitamin K intake in patients with anorexia nervosa. CONCLUSIONS: Patients with anorexia nervosa had vitamin K deficiency. Since a supplement of vitamin K might be effective for maintaining bone quality, we provide recommendations regarding vitamin K intake for prevention and treatment of osteoporosis in patients with AN.

Ghrelin and anorexia nervosa: a psychosomatic perspective.

Anorexia nervosa (AN) is a serious medical illness associated with gastrointestinal, metabolic, and psychological complications, and there are no effective pharmacologic treatments for the condition. Recent studies have suggested that the regulatory peptides, including ghrelin, are involved in the pathologic feeding behavior of AN. Previous studies have indicated that plasma total ghrelin and acyl ghrelin levels in patients with AN are higher than in controls, and the ratio of des-acyl ghrelin to acyl ghrelin in AN tend to be higher than in controls. In addition, ghrelin has been reported to stimulate appetite and food intake in various diseases, including chronic heart failure, chronic obstructive pulmonary disease, and cancer. Because it is speculated that difficulties in resolving the underlying psychological condition preclude reversal of the pathologic feeding behavior in AN, ghrelin is expected to be applied in a clinical setting as a new treatment. In this review, we describe the role of ghrelin in the pathophysiology and potential treatment of AN along the gut-brain axis.

Ghrelin, appetite and gastric electrical stimulation.

Ghrelin is a peptide hormone produced mainly by the stomach and has widespread physiological functions including increase in appetite. The stimulation of the ghrelin system represents a potential therapeutic approach in various disorders characterized by deficient ghrelin signaling or by low appetite. This stimulation may be achieved via pharmacological targeting of the ghrelin receptor with synthetic ghrelin or ghrelin mimetics or via increased endogenous ghrelin production. Recently, it was demonstrated that gastric electrical stimulation (GES) with Enterra parameters results in increased ghrelin production in rats. Furthermore, recent data revealed putative role of ghrelin-reactive immunoglobulins in the modulation of the ghrelin signaling which can be also stimulated by GES. Here, we review the links between GES and ghrelin in existing GES experimental and clinical applications for treatment of gastroparesis, functional dyspepsia or obesity and discuss if GES can be proposed as a non-pharmacological approach to improve ghrelin secretion in several pathological conditions characterized by low appetite, such as anorexia nervosa or anorexia-cachexia syndrome.

Is glycyrrhizin sensitivity increased in anorexia nervosa and should licorice be avoided? Case report and review of the literature.

OBJECTIVE: Hypokalemia is a potentially life-threatening electrolyte disturbance in anorexia nervosa and is most frequently caused by purging behavior. We report a case of severe hypokalemia in anorexia nervosa induced by daily ingestion of approximately 20 g of licorice. METHODS: To confirm the diagnosis of licorice-induced pseudohyperaldosteronism, a re-exposure trial was performed. RESULTS: Cessation of the licorice intake normalized plasma potassium, renin, and aldosterone levels and the urine cortisol/cortisone ratio. Re-exposure confirmed the diagnosis. The pronounced response to a relatively low daily dose of licorice suggests high glycyrrhizin sensitivity. CONCLUSION: Patients with anorexia nervosa not only have decreased food intake but also selective and sometimes bizarre eating habits that, in association with increased sensitivity to glycyrrhizin, may cause severe hypokalemia.

Micronutrient deficiencies and supplementation in anorexia and bulimia nervosa: a review of literature.

Anorexia and bulimia nervosa are characterized by unbalanced eating patterns that include inadequate dietary intake of various nutrients. Conservation mechanisms resulting from starvation and/or self-prescribed nutrient supplements can result in laboratory values that appear within normal limits. These artificially inflated values drop to dangerous levels in some patients once rehydration and refeeding begin. Electrolyte status must be closely monitored during this time to prevent complications. Other micronutrient deficiencies can be corrected with adequate dietary intake, but patients with eating disorders are unlikely to consume such an adequate diet immediately upon entering treatment, so they may benefit from supplementation. Depleted nutrient stores require longer supplementation than acute inadequacies in nutrient intake. This review compiles the findings reported to date regarding micronutrient deficiencies and supplementation for patients with anorexia and bulimia. Because of the widely varying eating practices from patient to patient and the current lack of data controlling for nutrient self-supplementation, nutrition assessment performed by a nutrition professional via food intake history may be more practical than laboratory tests and more accurate than current food intake for determining potential micronutrient deficiencies.

Low prevalence of vitamin D deficiency among adolescents with anorexia nervosa.

UNLABELLED: Fifty adolescents with AN and 200 healthy girls underwent vitamin D screening. Girls with AN reported exceptional compliance with vitamin D supplementation and PTH concentrations were lower. Vitamin D deficiency was less common in the group with AN, but when race was considered, the trend was no longer significant. INTRODUCTION: The objective of this study was to determine whether patients with anorexia nervosa (AN) are more compliant with supplementation and have a lower prevalence of vitamin D deficiency than healthy controls. METHODS: Fifty adolescents with AN and 200 controls were compared using anthropometric and lifestyle data, serum 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) concentrations, and prevalence of vitamin D deficiency. RESULTS: The prevalence of deficiency (<20 ng/mL) was 2% in the AN group vs. 24% among controls (p = 0.003). 25OHD was similar among white participants with AN and white controls (39.5 vs. 36.0 ng/mL, p = 0.20), but higher than in non-white controls (20.6 ng/mL). Significantly more girls with AN reported vitamin D supplementation (86%) than the full control (14%) or white subgroup (27%) (p < 0.001). Participants with AN had lower PTH concentrations than controls, (27.8 vs. 47.4 pg/mL, p = 0.009), a trend that lost significance after age and race adjustment (41.7 pg/mL, p = 0.12). CONCLUSIONS: Compared to healthy controls, adolescents with AN had a lower prevalence of vitamin D deficiency and PTH concentration. However, 25OHD and PTH concentrations were similar after adjustment for race and age. The trend of lower PTH levels in adolescents with AN, accompanied by exceptional compliance with supplementation, may have bone health implications for these patients.

Treatment of anorexia nervosa is associated with increases in bone mineral density, and recovery is a biphasic process involving both nutrition and return of menses.

BACKGROUND: Recovery from osteoporosis in anorexia nervosa (AN) is uncertain. OBJECTIVE: The purpose of this study was to understand the changes in bone mineral density (BMD) in women with AN and the mechanisms of recovery from osteopenia. DESIGN: We studied BMD and markers of bone formation and resorption, osteocalcin and N-telopeptide (NTX), in patients with AN (n=28) who were following a behavioral weight-gain protocol. RESULTS: Anorexic patients experienced significant percentage increases in BMD (4.38 +/- 7.48% for spine; 3.77 +/- 8.8% for hip; P<0.05 for both) from admission until recovery of 90% ideal body weight, achieved over 2.2 mo. NTX concentrations were higher in patients with AN at admission than in healthy control subjects (n=11; 69.0 +/- 31.09 and 48.3 +/- 14.38 nmol/mmol creatinine, respectively; P<0.05) and in reference control subjects (n=30; 69.0 +/- 31.09 and 37.0+/-6.00 nmol/mmol creatinine, respectively; P<0.001). In weight-recovered subjects with AN, osteocalcin increased (from 8.0 +/- 3.05 to 11.2 +/- 6.54 ng/mL; P<0.05), whereas NTX remained elevated (from 69.0 +/- 31.09 to 66.7 +/- 45.5 nmol/mmol creatinine; NS). A decrease in NTX (from 70.7 +/- 40.84 to 45.9 +/- 22.72 nmol/mmol creatinine; NS) occurred only in the subgroup of subjects who regained menses with weight recovery. CONCLUSIONS: Nutritional rehabilitation induces a powerful anabolic effect on bone. However, a fall of NTX and a shift from the dominant resorptive state, which we postulate involves full recovery, may involve a hormonal mechanism and require a return of menses. Nutritional rehabilitation appears to be critical to bone recovery and may explain the ineffectiveness of estrogen treatment alone on BMD in the cachectic state.

Nutrient intake in community-dwelling adolescent girls with anorexia nervosa and in healthy adolescents.

BACKGROUND: Adolescence is a common time for the onset of anorexia nervosa (AN), a condition associated with long-term medical and hormonal consequences. OBJECTIVE: The objective was to compare the nutrient intakes of community-dwelling girls with AN with those of healthy adolescents and to describe the associations between specific nutrient intakes and nutritionally dependent hormones. DESIGN: Nutrient intakes in 39 community-dwelling girls with AN and 39 healthy adolescents aged 12.1-18.7 y were determined by using 4-d food records. Fasting adiponectin, leptin, ghrelin, insulin, and insulin-like growth factor I (IGF-I) concentrations were measured. Indirect calorimetry was used to assess respiratory quotient and resting energy expenditure. RESULTS: In contrast with the control group, the AN group consumed fewer calories from fats (P < 0.0001) and more from carbohydrates (P = 0.0009) and proteins (P < 0.0001). Intake of individual fat components was lower and of dietary fiber higher in the AN group. No significant between-group differences were observed in dietary intakes of calcium, zinc, and iron; however, total intake was greater in the AN group because of greater supplement use (P = 0.006, 0.02, and 0.01, respectively). The AN group had greater intakes of vitamins A, D, and K and of most of the B vitamins, and significantly more girls with AN met the Dietary Reference Intake for calcium (P = 0.01) and vitamin D (P = 0.02) from supplement use. Fat intake predicted ghrelin, insulin, and IGF-I concentrations; carbohydrate intake predicted adiponectin. Resting energy expenditure was lower (P < 0.0001) and leisure activity levels higher in the AN group. CONCLUSIONS: Despite outpatient follow-up, community-dwelling girls with AN continue to have lower fat and higher fiber intakes than do healthy adolescents, which results in lower calorie intakes. Nutritionally related hormones are associated with specific nutrient intakes.

Prospective evaluation of leptin and neuropeptide Y (NPY) serum levels in girls with anorexia nervosa.

OBJECTIVES: The pathogenesis of anorexia nervosa (AN) remains still unclear. It has been reported that neuropeptides may play a role in the control of appetite and hormone release contributing to hormonal disturbances in AN. However the question if neuropeptide alterations are consequence or cause of malnutrition is still unresolved. METHODS: Serum leptin, neuropeptide Y (NPY) concentrations as well as hormones (FSH, LH, estradiol, cortisol and fT4) serum levels were prospectively estimated in 19 girls aged 11.7-17.7 years (mean 15.5 years) with anorexia nervosa (AN) at the admission to the hospital (baseline) and at follow-up after 7.21+ 2.32 months of treatment. The treatment consisted of hypercaloric diet, psychotherapy and vitamins supplementation. RESULTS: Mean leptin concentration significantly increased from 7.99 + 2.6 to 9.98 + 2.48 microg/ml (p<0.01), whereas mean NPY concentration significantly decreased from 34.10 + 9.81 to 29.6 + 8.04 pmol/l (p<0.01). Leptin/BMI ratio was constant, while NPY/BMI ratio decreased. There were no significant differences between leptin and NPY serum concentrations at baseline and follow-up in eumenorrheic vs. amenorrheic patients. Simple linear correlation analysis showed negative correlation between leptin and NPY concentrations at baseline (r=-0.67; p<0.05) and at follow-up (r=-0.76; p<0.05) only in eumenorrheic subgroup. There were no significant correlations between leptin, NPY and BMI and body weight values. CONCLUSIONS: 1) Serum concentration of leptin increases and serum concentration of NPY decreases significantly during the treatment of anorectic girls. 2) These changes do not correspond with increasing body weight and BMI suggesting disregulation of appetite and body weight control mechanisms in AN. 3) Altered neuroregulation of the neuropeptides (leptin and NPY) secretion may contribute persistent amenorrhea after weight gain in anorectic patients with low initial BMI.