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A Systematic Review and Meta-Analysis Finds Increased Blood Levels of All Forms of Ghrelin in Both Restricting and Binge-Eating/Purging Subtypes of Anorexia Nervosa.
Seidel, M, Markmann Jensen, S, Healy, D, Dureja, A, Watson, HJ, Holst, B, Bulik, CM, Sjögren, JM
Nutrients. 2021;(2)
Abstract
Anorexia nervosa (AN) is a severe psychiatric condition associated with high mortality and chronicity. The hunt for state, trait, subtyping, and prognostic biomarkers is ongoing and the orexigenic hormone ghrelin and its different forms, acyl ghrelin and desacyl ghrelin, have been proposed to be increased in AN, especially in the restrictive subtype. A systematic literature search was performed using established databases up to 30 November 2020. Forty-nine studies met inclusion criteria for cross-sectional and longitudinal meta-analyses on total ghrelin, acyl ghrelin, and desacyl ghrelin. All forms of ghrelin were increased in the acute stage of anorexia nervosa during fasting compared to healthy controls. Previous notions on differences in ghrelin levels between AN subtypes were not supported by current data. In addition, a significant decrease in total ghrelin was observed pre-treatment to follow-up. However, total ghrelin levels at follow-up were still marginally elevated compared to healthy controls, whereas for acyl ghrelin, no overall effect of treatment was observed. Due to heterogeneity in follow-up designs and only few data on long-term recovered patients, longitudinal results should be interpreted with caution. While the first steps towards a biomarker in acute AN have been completed, the value of ghrelin as a potential indicator of treatment success or recovery status or its use in subtype differentiation are yet to be established.
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Body composition in anorexia nervosa: Meta-analysis and meta-regression of cross-sectional and longitudinal studies.
Hübel, C, Yilmaz, Z, Schaumberg, KE, Breithaupt, L, Hunjan, A, Horne, E, García-González, J, O'Reilly, PF, Bulik, CM, Breen, G
The International journal of eating disorders. 2019;(11):1205-1223
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OBJECTIVE Clinically, anorexia nervosa (AN) presents with altered body composition. We quantified these alterations and evaluated their relationships with metabolites and hormones in patients with AN longitudinally. METHOD In accordance with PRISMA guidelines, we conducted 94 meta-analyses on 62 samples published during 1996-2019, comparing up to 2,319 pretreatment, posttreatment, and weight-recovered female patients with AN with up to 1,879 controls. Primary outcomes were fat mass, fat-free mass, body fat percentage, and their regional distribution. Secondary outcomes were bone mineral density, metabolites, and hormones. Meta-regressions examined relationships among those measures and moderators. RESULTS Pretreatment female patients with AN evidenced 50% lower fat mass (mean difference [MD]: -8.80 kg, 95% CI: -9.81, -7.79, Q = 1.01 × 10-63 ) and 4.98 kg (95% CI: -5.85, -4.12, Q = 1.99 × 10-28 ) lower fat-free mass, with fat mass preferentially stored in the trunk region during early weight restoration (4.2%, 95% CI: -2.1, -6.2, Q = 2.30 × 10-4 ). While the majority of traits returned to levels seen in healthy controls after weight restoration, fat-free mass (MD: -1.27 kg, 95% CI: -1.79, -0.75, Q = 5.49 × 10-6 ) and bone mineral density (MD: -0.10 kg, 95% CI: -0.18, -0.03, Q = 0.01) remained significantly altered. DISCUSSION Body composition is markedly altered in AN, warranting research into these phenotypes as clinical risk or relapse predictors. Notably, the long-term altered levels of fat-free mass and bone mineral density suggest that these parameters should be investigated as potential AN trait markers. RESUMENOBJETIVO Clínicamente, la anorexia nervosa (AN) se presenta con alteraciones en la composición corporal. Cuantificamos estas alteraciones y evaluamos longitudinalmente su relación con metabolitos y hormonas en pacientes con AN. MÉTODO: De acuerdo con las pautas PRISMA, realizamos 94 meta-análisis en 62 muestras publicadas entre 1996-2019, comparando hasta 2,319 pacientes mujeres en pre-tratamiento, post-tratamiento, y recuperadas en base al peso con hasta 1,879 controles. Las principales medidas fueron masa grasa, masa libre de grasa, porcentaje de grasa corporal y su distribución regional. Las medidas secundarias fueron densidad mineral ósea, metabolitos y hormonas. Las meta-regresiones examinaron las relaciones entre esas medidas y moderadores. RESULTADOS Las pacientes femeninas con AN pre-tratamiento mostraron un 50% menos de masa grasa (MD: -8.80 kg, CI 95%: -9.81, -7.79, Q = 1.01 × 10-63 ) y 4.98 kg (CI 95%: -5.85, -4.12, Q = 1.99 × 10-28 ) menos de masa libre de grasa, con masa grasa preferentemente almacenada en la región del tronco durante la recuperación temprana del peso (4.2%, CI 95%: -2.1, -6.2, Q = 2.30 × 10-4 ). Aunque la mayoría de los rasgos regresaron a los niveles vistos en los controles sanos después de la restauración del peso, la masa libre de grasa (MD: -1.27 kg, CI 95%: -1.79, -0.75, Q = 5.49 × 10-6 ) y la densidad mineral ósea (MD: -0.10 kg, CI 95%: -0.18, -0.03, Q = 0.01) permanecieron significativamente alteradas. DISCUSIÓN: La composición corporal es marcadamente alterada en la AN, lo que garantiza la investigación en estos fenotipos como predictores de riesgo clínico o de recaída. Notablemente, la alteración a largo plazo de los niveles de masa libre de grasa y densidad mineral ósea sugieren que estos parámetros debe ser investigados como potenciales rasgos indicadores de AN.
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Significant Locus and Metabolic Genetic Correlations Revealed in Genome-Wide Association Study of Anorexia Nervosa.
Duncan, L, Yilmaz, Z, Gaspar, H, Walters, R, Goldstein, J, Anttila, V, Bulik-Sullivan, B, Ripke, S, , , Thornton, L, et al
The American journal of psychiatry. 2017;(9):850-858
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OBJECTIVE The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. METHOD Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h2SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes. RESULTS Results were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h2SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. CONCLUSIONS Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.
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Oxidative stress and antioxidant levels in patients with anorexia nervosa: A systematic review and exploratory meta-analysis.
Solmi, M, Veronese, N, Manzato, E, Sergi, G, Favaro, A, Santonastaso, P, Correll, CU
The International journal of eating disorders. 2015;(7):826-41
Abstract
OBJECTIVE To systematically review and meta-analyze oxidative stress and antioxidant markers in anorexia nervosa (AN). METHODS Electronic PubMed search from database inception until 12/31/2013. Out of 1062 hits, 29 studies comparing oxidative stress/antioxidant markers between patients with AN and healthy controls (HCs) with a total of 1,729 participants (AN = 895, HCs = 834) were eligible. Data about oxidative stress and antioxidant markers, independent of their source, were extracted. We calculated random effects standardized mean differences (SMDs) as effect size measures for outcomes reported in ≥5 studies; others were summarized descriptively. RESULTS Compared to HCs, AN patients showed significantly higher apolipoprotein B (ApoB) levels (studies = 7; n = 551; SMD = 0.75; p = .0003, I(2) = 74%), with higher age being associated with higher ApoB (Coefficient: 0.61 ± 0.15, p < .0001), whereas BMI (p = .15) and measurement method (p = .70) did not moderate the results. Serum albumin levels were similar between AN and HCs (studies = 13; n = 509; SMD =-0.19; 95%CI: -0.62 to 0.24; p = .38; I(2) = 81%), with neither age (p = .84) nor BMI (p = .52) being significant moderators. Lower superoxide dismutase levels were reported in 2 studies, while findings for vitamin A and its metabolites were inconclusive. In single studies, patients with AN had significantly higher catalase and nitric oxide (NO) parameter levels (platelet NO, exhaled NO and nitrites), such as lower glutathione and free cysteine levels, compared to HCs. DISCUSSION AN appears to be associated with some markers of increased oxidative stress. Additional research is needed to discern whether oxidative stress is a potential cause or effect of AN, and whether treatments improving oxidative stress could be useful in AN.
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Impaired decision-making in symptomatic anorexia and bulimia nervosa patients: a meta-analysis.
Guillaume, S, Gorwood, P, Jollant, F, Van den Eynde, F, Courtet, P, Richard-Devantoy, S
Psychological medicine. 2015;(16):3377-91
Abstract
BACKGROUND Impaired decision-making is a potential neurocognitive phenotype of eating disorders. It is therefore important to disentangle the decision-making deficits associated with the eating disorder subtypes and determine whether this putative impairment is a state or trait marker of the disease or more related to starvation. We systematically reviewed the literature on decision-making in eating disorders and conducted a meta-analysis to explore its role in anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED). METHOD A search of the Medline and EMBASE databases and article references was performed. A total of 23 studies (2044 participants) met the selection criteria. When the Iowa gambling task (IGT) was used in at least three of the studies, a meta-analysis was run. RESULTS IGT performance was significantly worse in patients with an eating disorder diagnosis (AN, BN or BED) compared with healthy controls, indicating that eating disorders have a negative effect on decision-making. Hedges' g effect sizes were moderate to large (-0.72 in AN, -0.62 in BN, and -1.26 in BED). Recovered AN patients had IGT scores similar to those of healthy controls. Restrictive AN patients had significantly lower IGT net scores than purging AN patients, and both AN subtypes had worse performances than healthy controls. Age and body mass index did not explain results. CONCLUSIONS Decision-making was significantly altered in patients with eating disorders. Poor decision-making was more pronounced during the acute phase than in the recovered state of AN. Nutritional status during the acute phase of the disease did not seem to influence decision-making skills.
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Vitamin D status in anorexia nervosa: A meta-analysis.
Veronese, N, Solmi, M, Rizza, W, Manzato, E, Sergi, G, Santonastaso, P, Caregaro, L, Favaro, A, Correll, CU
The International journal of eating disorders. 2015;(7):803-13
Abstract
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.
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Executive functions in anorexia nervosa.
Jáuregui-Lobera, I
Nutricion hospitalaria. 2014;(3):500-7
Abstract
INTRODUCTION The pathophysiologic mechanisms that account for the development and persistence of anorexia nervosa (AN) remain unclear. With respect to the neuropsychological functioning, the executive functions have been reported to be altered, especially cognitive flexibility and decision-making processes. OBJECTIVES The aim of this study was to review the current state of the neuropsychological studies focused on anorexia nervosa, especially those highlighting the executive functions. METHODS This was done by means of a searching process covering three relevant electronic databases, as well as an additional search on references included in the analysed papers. Eventually we have to mention other published reviews and a hand-search. RESULTS AND DISCUSSION Comparing AN patients and healthy controls the results remain controversial and so remains the comparison of different eating disorders with respect to the neuropsychological dysfunction. The role of variables such as depression, anxiety and obsessionality needs to be clarified. There seems to be some base to state that some commonalities exist in the so-called extreme weight conditions (anorexia, obesity). The link between neuropsychological dysfunction in AN and biomarkers remains unclear. The role of neuropsychological deficits in AN, as initial factors or simply as mere consequences, remains unclear too. The link between the body image disturbances and the neuropsychological dysfunction needs to be clarified. The similarities between the AN neuropsychological dysfunction and that found in other mental disorders may be considered up to date as a mere approach. The same applies to the relationship between the AN patients' neuropsychological performance and personality or gender.
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Anorexia nervosa and the Val158Met polymorphism of the COMT gene: meta-analysis and new data.
Brandys, MK, Slof-Op't Landt, MC, van Elburg, AA, Ophoff, R, Verduijn, W, Meulenbelt, I, Middeldorp, CM, Boomsma, DI, van Furth, EF, Slagboom, E, et al
Psychiatric genetics. 2012;(3):130-6
Abstract
OBJECTIVES This study aimed to test the association between the Val158Met polymorphism (rs4680) of the catechol-O-methyl transferase gene and anorexia nervosa (AN). METHODS First, an association study on two cohorts (306 cases and 1009 controls from Utrecht, and 174 cases and 466 controls from Leiden/NTR) was performed. Subsequently, the results were integrated into a meta-analysis, together with all the case-control and family-based studies, which were testing the same hypothesis and were available in the literature. Altogether, eight studies (11 datasets) were included in this meta-analysis, with a total of 2021 cases, 2848 controls, and 89 informative (heterozygous) trios. RESULTS The present association studies found no association between AN and rs4680 when testing the allelic contrast [Utrecht odds ratio (OR)=1.14, P=0.14; Leiden OR=1.02, P=0.85]. There was an indication of an association under the dominant model of genetic effect in the Utrecht cohort (for the Met allele, OR=1.42, P=0.03). Nevertheless, the meta-analyses of both the allelic contrast and the dominant effect were nonsignificant (the allelic pooled OR=1.03, P=0.42 and the dominant pooled OR=1.1, P=0.18). The meta-analyses were performed under the fixed-effect model and there was no significant heterogeneity among the effect sizes. CONCLUSION Meta-analytically combined evidence from the present genotypings and the literature search shows that the effect sizes are homogeneous across studies and that rs4680 is not associated with AN.
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Effect on bone health of estrogen preparations in premenopausal women with anorexia nervosa: a systematic review and meta-analyses.
Sim, LA, McGovern, L, Elamin, MB, Swiglo, BA, Erwin, PJ, Montori, VM
The International journal of eating disorders. 2010;(3):218-25
Abstract
OBJECTIVE Because estrogen therapies are widely prescribed for amenorrhea associated with anorexia nervosa (AN), we conducted a systematic review and meta-analyses to estimate the influence of estrogen preparations (EP) on bone mineral density in women with AN. METHOD Prospective cohort studies and randomized clinical trials (RCTs) comparing the effect of EP use to no treatment or placebo on bone mineral density and bone fractures were included. Independent reviewers selected studies for inclusion and extracted study characteristics, markers of methodologic quality, and outcomes for the intention-to-treat population. RESULTS Using random-effects meta-analyses and inconsistency across trials using the I(2) statistic, data were combined across two eligible prospective cohort studies and four RCTs; none reported effects on bone fractures. Compared with placebo or no treatment, low quality evidence found EPs have a moderate effect on bone mineral density in the lumbar spine [ES (effect size) 0.33, 95% CI (confidence interval) 0.09, 0.56; I(2) = 0%)], but no significant effect on the femoral neck (ES 0.13, 95% CI -0.16, 0.43; I(2) = 0%). There were no significant treatment-subgroup interactions. DISCUSSION In general, EPs have uncertain benefit and should be avoided by women with AN in whom the success of weight and nutritional rehabilitation is judged by menses resumption.
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Long-term mortality in anorexia nervosa: a report after an 8-year follow-up and a review of the most recent literature.
Signorini, A, De Filippo, E, Panico, S, De Caprio, C, Pasanisi, F, Contaldo, F
European journal of clinical nutrition. 2007;(1):119-22
Abstract
OBJECTIVE To evaluate long-term mortality rate of anorexia nervosa (AN) patients in a southern Italy population compared to the most recent literature. DESIGN Retrospective and review setting. PATIENTS AND INTERVENTIONS One hundred and forty-seven female AN patients, consecutively admitted from 1994 to 1997 to the Outpatient Unit, were re-examined between June and November 2003. Our data are compared with 10 other studies published since 1988. RESULTS One hundred and twenty-three deaths in 2240 patients, amounting to a total mortality rate of 5.25% were reported in the literature. Deaths due to suicide, AN-related and AN-unrelated diseases were 1.20, 3.07 and 0.98%, respectively. After correcting for unrelated deaths, mortality rate was 4.27%. In our 8-year follow-up, we found a mortality rate of 2.72% (1.82% after correcting for unrelated deaths). Standardized mortality ratio was 9.7. CONCLUSION We interpret our favourable findings as a consequence of an integrated, clinical-nutritional and psychiatric approach. Finally, considering AN demographic characteristics, that is young female subjects in Westernized societies, mortality rate is confirmed to be dramatically high.