Increased risk of somatic diseases following anorexia nervosa in a controlled nationwide cohort study

OBJECTIVE: To assess the risk of somatic diseases in connection with anorexia nervosa (AN). METHOD: This matched cohort study was based on Danish registries of all patients born 1961-2008 with a first-time diagnosis of AN in 1994-2018 at age 8-32 and matched controls without an eating disorder. For 13 somatic disease categories, time from inclusion date to time of first somatic diagnosis, accounting for censoring, was studied by use of time-stratified Cox models. RESULTS: A total of 9985 AN patients born 1961-2008 and 49,351 controls were followed for a median (interquartile range) of 9.0 (4.4-15.7) years. During the first 2 years after entry there was a 60% higher hazard for any somatic disease among patients with AN than among controls, while the ratio from three to 11 years was reduced to 1.18. Regardless of age at diagnosis, the hazard among patients and controls were no different at approximately a decade after diagnosis of AN and the cumulative risk for patients for 12 of 13 disease categories was always higher or no less that for controls. For all disease categories, the hazard ratio (HR) was higher when close to entry. For most disease categories, age at diagnosis of AN did not modify the effect. DISCUSSION: While around 90% of all individuals had any somatic disease at the end of follow-up, the cumulative incidence over time was higher for patients with AN than for controls. Large HRs were seen in the early years after diagnosis during which patients require extensive medical interventions. PUBLIC SIGNIFICANCE: Based on Danish registries, a large sample of almost 10,000 patients with AN born 1961-2008 and almost 50,000 matched controls were followed for a median of 9 years. While around 90% of all individuals had any somatic disease at the end of follow-up, the cumulative incidence over time was higher for patients with AN than for controls

GDF15 is an exercise-induced hepatokine regulated by glucagon and insulin in humans

ObjectiveGrowth differentiation factor (GDF)-15 is implicated in regulation of metabolism and circulating GDF15 increases in response to exercise. The source and regulation of the exercise-induced increase in GDF15 is, however not known.MethodPlasma GDF15 was measured by ELISA under the following conditions: 1) Arterial-to-hepatic venous differences sampled before, during, and after exercise in healthy male subjects (n=10); 2) exogenous glucagon infusion compared to saline infusion in resting healthy subjects (n=10); 3) an acute exercise bout with and without a pancreatic clamp (n=6); 4) healthy subjects for 36 hours (n=17), and 5) patients with anorexia nervosa (n=25) were compared to healthy age-matched subjects (n=25). Tissue GDF15 mRNA content was determined in mice in response to exhaustive exercise (n=16).ResultsThe splanchnic bed released GDF15 to the circulation during exercise and increasing the glucagon-to-insulin ratio in resting humans led to a 2.7-fold (P<0.05) increase in circulating GDF15. Conversely, inhibiting the exercise-induced increase in the glucagon-to-insulin ratio blunted the exercise-induced increase in circulating GDF15. Fasting for 36 hours did not affect circulating GDF15, whereas resting patients with anorexia nervosa displayed elevated plasma concentrations (1.4-fold, P<0.05) compared to controls. In mice, exercise increased GDF15 mRNA contents in liver, muscle, and adipose tissue.ConclusionIn humans, GDF15 is a “hepatokine” which increases during exercise and is at least in part regulated by the glucagon-to-insulin ratio. Moreover, chronic energy deprivation is associated with elevated plasma GDF15, which supports that GDF15 is implicated in metabolic signalling in humans

Ghrelin and its potential in the treatment of eating/wasting disorders and cachexia

The gastrointestinal “hunger” hormone ghrelin is the only known circulating peripheral molecule with the ability to decrease body fat utilization and to increase body weight gain. Accordingly, due to ghrelin’s effects to promote food intake while decreasing energy expenditure ghrelin may offer potential as a drug for treatment of eating/wasting disorders and cachexia. Therapeutic potential of ghrelin and ghrelin analogues to promote food intake and body weight gain was recently indicated in several clinical studies. The recent discovery of the ghrelin O-acyltransferase as the key enzyme responsible for ghrelin acylation has further deepened our understanding of ghrelin activation, thereby paving the way for more efficient targeting of the ghrelin pathway. Here, we summarize the current knowledge pertaining to the potential of the endogenous ghrelin system as a drug target for the treatment of eating/wasting disorders and cachexia

Treatment of anorexia nervosa:A multimethod investigation translating experimental neuroscience into clinical practice

Background Anorexia nervosa (AN) is a severe psychiatric condition and evidence on how to best treat it is limited. Objectives This programme consists of seven integrated work packages (WPs) and aims to develop and test disseminable and cost-effective treatments to optimise management for people with AN across all stages of illness. Methods WP1a used surveys, focus groups and a pre–post trial to develop and evaluate a training programme for school staff on eating disorders (EDs). WP1b used a randomised controlled trial (RCT) [International Standard Randomised Controlled Trial Number (ISRCTN) 42594993] to evaluate a prevention programme for EDs in schools. WP2a evaluated an inpatient treatment for AN using case reports, interviews and a quasi-experimental trial. WP2b used a RCT (ISRCTN67720902) to evaluate two outpatient psychological therapies for AN. WP3 used a RCT (ISRCTN06149665) to evaluate an intervention for carers of inpatients with AN. WP4 used actimetry, self-report and endocrine assessment to examine physical activity (PA) in AN. WP5 conducted a RCT (ISRCTN18274621) of an e-mail-guided relapse prevention programme for inpatients with AN. WP6 analysed cohort data to examine the effects of maternal EDs on fertility and their children’s diet and growth. WP7a examined clinical case notes to explore how access to specialist ED services affects care pathways and user experiences. Finally, WP7b used data from this programme and the British Cohort Study (1970) to identify the costs of services used by people with AN and to estimate annual costs of AN for England. Results WP1a: a brief training programme improved knowledge, attitudes and confidence of school staff in managing EDs in school. WP1b: a teacher-delivered intervention was feasible and improved risk factors for EDs in adolescent girls. WP2a: both psychological therapies improved outcomes in outpatients with AN similarly, but patients preferred one of the treatments. WP2b: the inpatient treatment (Cognitive Remediation and Emotional Skills Training) was acceptable with perceived benefits by patients, but showed no benefits compared with treatment as usual (TAU). WP3: compared with TAU, the carer intervention improved a range of patient and carer outcomes, including carer burden and patient ED symptomatology. WP4: drive to exercise is tied to ED pathology and a desire to improve mood in AN patients. PA was not increased in these patients. WP5: compared with TAU, the e-mail-guided relapse prevention programme resulted in higher body mass index and lower distress in patients at 12 months after discharge. WP6: women with an ED had impaired fertility and their children had altered dietary and growth patterns compared with the children of women without an ED. WP7a: direct access to specialist ED services was associated with higher referral rates, lower admission rates, greater consistency of care and user satisfaction. WP7b: the annual costs of AN in England are estimated at between £45M and £230M for 2011. Conclusions This programme has produced evidence to inform future intervention development and has developed interventions that can be disseminated to improve outcomes for individuals with AN. Directions for future research include RCTs with longer-term outcomes and sufficient power to examine mediators and moderators of change. Trial registration Current Controlled Trials ISRCTN42594993, ISRCTN67720902, ISRCTN06149665 and ISRCTN18274621