Circulating Cytokine Alterations in Children and Adolescents With Anorexia Nervosa: A Systematic Review

Objective The etiopathogenesis of Anorexia Nervosa (AN) remains unclear, with genetic, epigenetic, metabolic, neurobiological, environmental, and psychosocial factors implicated. Emerging evidence suggests inflammation may contribute to psychiatric disorders. Cytokine alterations have been associated with AN in adults, with some studies reporting differences compared to healthy controls (HCs); however, findings across systematic reviews and meta-analyses are inconsistent. Research in adolescent AN remains limited. This study aims to systematically review cross-sectional and longitudinal studies examining in vivo cytokine production in adolescents with AN compared to healthy controls. Method A comprehensive search of three databases (PubMed, MEDLINE, and ISI Web of Science) was conducted in accordance with PRISMA guidelines to identify human in vivo studies examining cytokine production in adolescents with AN. Extracted data included population characteristics (e.g., age, sex, mean mBMI/%IBW), cytokine measures, and key findings. Potential confounders (e.g., smoking and psychiatric co-morbidity) were also recorded. Results An initial search identified, 1,438 studies, of which 11 met inclusion criteria (5 cross-sectional,6 longitudinal studies), comprising 746 participants (402 with AN and 344 HCs). Across studies, in-vivo cytokine profiles in adolescents with AN were heterogeneous, with no consistent pro-inflammatory pattern observed. Findings for TNF-α, IL-6, IL-15, IL-1β, CRP, IL-2, IL-1, IL-8, and IL-6Rα varied across studies with reports of increased, decreased or unchanged levels relative to HCs at baseline. Longitudinal findings were similarly inconsistent, with most studies reporting normalization or no significant differences following weight restoration. Notably, IL-15 was elevated at baseline in 67% of studies in AN patients compared to HCs; among longitudinal studies, 50% reported persistent elevation in IL – 15 in those with AN after weight gain compared to HCs, while 50% reported normalization of IL-15 level in AN following weight restoration similar to that of HCs. Conclusion Cytokine alterations in adolescents differed from the more uniform pro-inflammatory profile reported in adults with AN, suggesting a heterogeneous immune profile in adolescents. While findings for key pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) were inconsistent, IL-15 was more consistently elevated in the limited studies assessing it, which might suggest a differential immune involvement in early illness stages. Potentially, a more mature immune system and longer chronicity of the illness is necessary to fully express a pro-inflammatory state. These findings should be interpreted cautiously given the paucity of studies and limited sample sizes. Further research is required to determine inflammation and cytokine regulation involvement in adolescent AN and their potential as biomarkers or therapeutic targets. Study registration information A meta-analysis of in-vivo cytokine production in children and adolescents with anorexia nervosa; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024530354 Diversity & Inclusion Statement We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure diversity in experimental samples through the selection of the cell lines. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science.