Inflammatory cytokines and anorexia nervosa: A meta-analysis of cross-sectional and longitudinal studies

Objective: Although inflammation is increasingly implicated in psychiatric disorders, less is known about its role in anorexia nervosa (AN), an illness with low body mass index (BMI).

Methods: We performed a systematic PubMed literature search until 12/31/2013 and meta-analyzed cross-sectional and longitudinal studies comparing circulating pro- and anti-inflammatory cytokines between patients with anorexia nervosa (AN) and healthy controls (HCs) (1) before and (2) after weight gain, and (3) within AN patients before and after weight gain. Standardized mean differences (SMDs)± 95% confidence intervals (CIs) for results from ≥ 2 studies were calculated.

Results: Of 999 initial hits, 22 studies with 924 participants (AN=512, HCs=412) were eligible. Compared to HCs, tumor necrosis factor (TNF)-alpha (SMD=0.35, 95%CI=0.09-0.61, p=0.008), interleukin (IL)1-beta (SMD=0.51, 95%CI=0.18-0.84, p=0.003), IL-6 (SMD=0.43, 95%CI=0.11-0.76, p=0.009), and TNF-receptor-II (SMD=0.42, 95%CI:0.07-0.78, p=0.02) were significantly elevated in AN, while C-reactive protein (SMD=-0.53, 95%CI=-.77, -0.28, p<0.0001) and IL-6 receptor (SMD=-0.85, 95%CI=-1.33, -0.36, p=0.0006) were significantly decreased. No differences were found for TNF-receptor I and TGF-β. Across a subset of eight longitudinal studies (AN=152, HCs=129), significant weight gain (baseline BMI=15.4 ± 1.5, endpoint BMI=18.2 ± 1.6, p<0.0001) was not associated with significant changes in TNF-α, IL-6 and IL1-β. However, after weight gain, IL-6 was not different anymore compared to HCs (SMD=0.06, 95%CI=-0.32, 0.45, p=0.75). In meta-regression, shorter illness duration (p=0.0008), but not younger age (p=0.71) significantly moderated greater IL-6 levels.

Conclusion: Despite abnormally low BMI, AN seems to be associated with increased inflammatory cytokines. Whether specific elevated cytokines represent trait or state markers of AN, and whether they could be treatment targets requires further study.