Overall and cause-specific mortality in anorexia nervosa; impact of psychiatric comorbidity and sex in a 40-year follow-up study.

OBJECTIVE: This study investigates the overall and cause-specific mortality in males and females with anorexia nervosa (AN) from 1977 to 2018, focusing on the impact of psychiatric comorbidity on mortality risk, a less explored aspect despite a high prevalence in patients with AN. METHOD: We conducted a nationwide population-based cohort study in Denmark including all patients with AN (n = 14,774) with a median follow-up time of 9.1 years and a 1:10 age- and sex-matched general population comparison cohort. Using Cox proportional hazard model, we calculated adjusted hazard ratios (aHR) for death stratified by psychiatric comorbidity, sex, and age at AN onset and evaluated the causes of death using Fine and Gray sub-distribution hazard ratios (SHR). RESULTS: In patients with AN, the weighted average aHR for all-cause mortality was 4.5 [95% CI 4.1-4.9] with up to 40 years follow-up. Psychiatric comorbidity was present in 47% of patients with AN at index date, which was associated with a 1.9-fold increase in 10-year mortality compared with patients without comorbidity and a notably four-fold increase, when diagnosed at age 6-25 years. The mortality risk was similar according to sex. 13.9% of all deaths in patients with AN were due to suicide (SHR 10.7 [8.1-14.2]). The risk of dying of natural causes was increased with a SHR of 3.8 [95% CI 3.4-4.2]. DISCUSSION: The increased mortality risk in both males and females with AN and psychiatric comorbidity, particularly when diagnosed at young age, underscores the need for comprehensive treatment addressing both AN and coexisting psychiatric conditions. PUBLIC SIGNIFICANCE: The mortality in patients with anorexia nervosa (AN) is high and we show in our study that the mortality is doubled in the presence of psychiatric comorbidity particularly the first 10 years after diagnosis seen in both sexes and with suicide as a major cause of death. These findings stress the importance of detection and treatment of psychiatric comorbidities alongside the eating disorder to prevent fatal outcome.

Fracture Risk in Patients with Anorexia Nervosa Over a 40-Year Period.

Researchers have reported increased fracture risk in patients with anorexia nervosa (AN), but more knowledge on the long-term risk and the effects of age, male sex, and time-related changes is still needed. We examined the long-term (up to 40 years) fracture risk among patients with AN compared to a matched comparison cohort from the general population. We utilized data from the Danish Health Care Registers to identify 14,414 patients with AN (13,474 females and 940 males) diagnosed between 1977 and 2018, with a median age of 18.6 years and median follow-up time of 9.65 years. We calculated adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) using Cox regression analysis for overall and site-specific fracture risks. The overall aHR of any fracture was 1.46 [95% CI: 1.36 to 1.48], with an aHR of 1.50 [95% CI: 1.43 to 1.57] for females and 0.95 [95% CI: 0.82 to 1.1] for males. For specific fractures we found an association with femur fractures both in females 4.06 [95% CI: 3.39 to 4.46] and in males 2.79 [95% CI: 1.45 to 2.37] and for fractures of the spine (females 2.38 [95% CI: 2.00 to 2.84], males 2.31 [95% CI: 1.20 to 4.42]). The aHR of any fracture decreased from 1.66 [95% CI: 1.52 to 1.81] in the period from 1977 to 1997 to 1.40 [95% CI: 1.33 to 1.40] from 1998 to 2018. In conclusion, we found that AN was associated with a 46% increased risk of any fracture up to 40 years after diagnosis. We found no overall increased risk in males, but in both sexes we found a particularly high site-specific fracture risk in the spine and femur. Fracture risk decreased in recent decades, indicating that more patients with AN have been diagnosed with presumably less severe disease and that the earlier detection and intervention of AN in recent years may translate into a lower facture risk. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Metabolic improvement after gastric bypass correlates with changes in IGF-regulatory proteins stanniocalcin-2 and IGFBP-4.

BACKGROUND: Pregnancy-associated plasma protein-A (PAPP-A) is an enzyme that increases IGF-activity through cleavage of IGF-binding proteins (IGFBPs), primarily IGFBP-4, whereby bound IGF-I becomes released as a free molecule. The enzymatic activity of PAPP-A is irreversibly suppressed by the glycoprotein stanniocalcin-2 (STC2). Pre-clinical and clinical studies suggest that the STC2 - PAPP-A - IGFBP-4 axis is important in controlling local IGF-action. STC2, PAPP-A and IGFBP-4 are expressed in adipose tissue, and as bariatric surgery markedly reduces the amount of fat, we found it relevant to study the impact of Roux-en-Y gastric bypass (RYGB) on circulating concentrations of this IGF-regulatory network. METHODS: Analysis of fasting blood samples from 20 obese subjects, hereof 10 with preoperative type 2 diabetes, investigated before RYGB, and 1 week, 3 months and 12 months post-surgery. Members of the IGF-system were analyzed by immunoassays, bioactive IGF by cell-based IGF-I receptor activation assay. We compared changes in IGF-system components with changes in fasting plasma insulin and glucose, and HbA1c. RESULTS: PAPP-A remained unchanged, but STC2 decreased following RYGB (p < 0.05). The PAPP-A substrate IGFBP-4 declined (p < 0.01), whereas levels of PAPP-A specific IGFBP-4 fragments increased (p < 0.05), indicating an increased PAPP-A enzymatic activity post-RYGB. Further, the reduction in intact IGFBP-4 correlated with increased levels of bioactive IGF (p < 0.05). In multivariable regression analyses, an improved glucose metabolism correlated with reductions in STC2 and IGFBP-4, and with increases in bioactive IGF and IGF-I (p < 0.05). CONCLUSION: After 12 months, RYGB caused reduced serum concentrations of intact IGFBP-4 and STC2, whereas serum PAPP-A remained at pre-operative levels. However, concentrations of PAPP-A generated IGFBP-4 fragments increased, pointing to an overall increased PAPP-A enzymatic activity following RYGB. Notably, reductions in intact IGFBP-4 and STC2 associated with improvements in glucose metabolism. Therefore, we propose that STC2 and IGFBP-4 are involved in the metabolic improvement that follows RYGB.

Relationship between biochemical and symptomatic hypoglycemia after RYGB. Responses to a mixed meal test: a case-control study.

BACKGROUND: Postprandial hypoglycemia is a relatively common complication after Roux-en-Y gastric bypass (RYGB). The cause remains incompletely understood, and the association between biochemical hypoglycemia and hypoglycemic symptoms is unclear. OBJECTIVES: To evaluate the association between postprandial hormonal responses and biochemical and symptomatic hypoglycemia after RYGB. SETTING: University Hospital, Denmark. METHODS: A case-control study with 3 groups: (1) RYGB group with postprandial hypoglycemic symptoms (HS), n = 13; (2) RYGB-group with no symptoms of hypoglycemia (NHS), n = 13; and (3) nonoperated body mass index-matched controls (CON), n = 7. Plasma glucose (PG) and hormonal responses (insulin, glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon) were measured after a mixed meal test (MMT), and hypoglycemic symptoms were determined by a questionnaire. The primary outcomes were differences in subjective and biochemical responses related to hypoglycemia among the 3 groups. RESULTS: Nadir PG was lower (3.1 versus 4.0 mmol/L (56 versus 72 mg/dL); P = .0002) and peak insulin higher in HS than NHS patients (1073 versus 734 pmol/L; P = .0499). Of the 13 patients with a peak insulin >850 pmol/L, 8 patients developed symptoms whereas only 2 out of the 13 patients with peak insulin ≤850 pmol/L developed symptoms, corresponding to an odds ratio of 12 (1.8; 81.7). Post hoc analyses comparing all RYGB patients with biochemical hypoglycemia after the MMT (nadir glucose ≤3.0 mmol/L [54 mg/dL]) with those with glucose >3 mmol/L (54 mg/dL) revealed a difference in both peak insulin (1138 versus 760 pmol/L; P = .042) and peak glucagon-like peptide-1 (182 versus 86 pmol/L; P = .016) concentrations. CONCLUSIONS: Patients with HS had lower nadir PG and higher insulin responses than NHS patients after MMT. Regarding PG, PG ≤3.0 mmol/L (54 mg/dL) was the best discriminator of having hypoglycemic symptoms after the MMT. However, high insulin level seems the most important predictor for having both biochemical and symptomatic hypoglycemia.