Anorexia Nervosa in vivo cytokine production: a systematic review

Introduction: The underlying psychobiology that contributes to Anorexia Nervosa (AN) onset and disease progression remains unclear. New research is emerging suggesting a possible link between inflammation and a variety of mental illnesses. Alterations of cytokines may play a role in the pathogenesis of AN. Some studies have found differences in the cytokine profile of those with AN compared to healthy controls, but results are heterogeneous. The aim of this work was to systematically review existing studies investigating in-vivo cytokine production in those with AN before and after weight restoration compared to controls.Methods: A comprehensive literature search of four electronic databases (PubMed, PsychInfo, EMBASE and CINAH) was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines to identify human in-vivo studies investigating the relationship between AN and cytokine production. Data extracted from included studies related to population characteristics (e.g. age, gender, mean mBMI/%IBW), cytokine measurement and relevant findings. Confounding factors (e.g. smoking status, co-morbid mental illness, menstruation status) were also collected.Results: 36 studies were eligible for this systematic review of which the majority were conducted in Europe (77.8%) and involved female subjects (97.2%). Those with AN ranged in age from 13 to 47 years and had an illness duration of 3 months to 24 years. 15 candidate cytokines and 3 receptors were identified (TNF-alpha, IL-6, IL-1B, CRP, IL-2, IL-7, IL-10, IFN-gamma, TNF-R2, IL-1 alpha, IL-15, TNF-R1, IL-17, IL-18, TGF-B1, IL-12, IL-6R and TGF-B2) exploring in-vivo levels in patients with AN and comparing to controls. TNF-alpha and IL-6 were the most extensively studied with IL-6 being significantly elevated in 4 out of 8 (50%) of longitudinal studies when comparing AN patients at baseline compared to post weight restoration. Following weight restoration, there was no difference in IL-6 levels when comparing to HC in 7 of 8 (87.5%) longitudinal studies examined.Conclusions: The most promising cytokine potentially involved in the pathogenesis of AN appears to be IL-6, and possibly TNF-alpha pathways. The heterogeneity of clinical and methodology factors impedes the generalizability of results. Future studies may wish to address these methodological shortcomings as alterations in cytokine levels in AN could act as therapeutic targets assisting with weight restoration and psychopathology and may offer diagnostic potential.