Elsevier

Psychoneuroendocrinology

Volume 51, January 2015, Pages 237-252
Psychoneuroendocrinology

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

https://doi.org/10.1016/j.psyneuen.2014.09.031Get rights and content

Highlights

  • We conducted a meta-analysis of 22 studies (N = 924) regarding inflammatory cytokines in patients with anorexia nervosa (AN) vs. healthy controls (HCs), as well as before and after weight gain.

  • We found that despite abnormally low BMI, AN seems to be associated with significantly elevated inflammatory cytokines compared to HCs, especially TNF-α, IL-6 and IL1-β.

  • Significant weight gain with an endpoint mean BMI below 18.5 was not associated with significant changes in TNF-α, IL-6 and IL1-β, but after weight gain, IL-6 was not different from HCs anymore.

  • Shorter illness duration, but not younger age, was associated with significantly higher IL-6.

  • Future studies should examine whether elevated inflammatory cytokines are trait or state markers of AN, and whether inflammatory cytokines could be treatment targets in AN.

Summary

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.

Introduction

Anorexia nervosa (AN) is an eating disorder with point prevalence ranging from 0.28 to 2.0% (Jaite et al., 2013, Favaro et al., 2003). AN is characterized by high drop-out rates (Dejong et al., 2012) and frequently only partial response to available therapies in outpatient- and in patient settings (Hay, 2013, Goddard et al., 2013) being a chronic disease that is associated with high mortality (Hoang et al., 2014, Smink et al., 2013, Meczekalski et al., 2013). Many factors seem to be involved in its pathogenesis (Herpertz-Dahlmann et al., 2011), including genetic factors (Gamero-Villarroel et al., 2014, Hinney and Volckmar, 2013, Kim et al., 2014), perinatal insults and childhood abuse (Favaro et al., 2010), impulsivity, obsessive-compulsive personality traits (Anderluh et al., 2003, Lavender et al., 2013), and perfectionism (Halmi et al., 2012). Moreover orexigenic and anorexigenic signals and autoantibodies that react with appetite-regulating neuropeptides and peptides of the adipose tissue are thought to play a role in deregulated eating behaviors (Smitka et al., 2013).

Inflammation is increasingly recognized as being associated with several major psychiatric disorders, including schizophrenia (Kirkpatrick and Miller, 2013, Miller et al., 2011, Stojanovic et al., 2014, Suvisaari and Mantere, 2013, Fineberg and Ellman, 2013), bipolar disorder (Modabbernia et al., 2013), depression (Liu et al., 2012, Hiles et al., 2012, Dowlati et al., 2010) and autism (Mitchell and Goldstein, 2014), as well as suicidal behaviors (Serafini et al., 2013). However, less systematic attention has been paid to pro-inflammatory cytokines in AN, and anti-inflammatory mediators have been almost neglected in literature covering AN (Pomeroy et al., 1994, Allende et al., 1998, Corcos et al., 2001).

Moreover, while evidence suggests that the use of anti-inflammatory agents may be helpful in schizophrenia (Nitta et al., 2013, Keller et al., 2013), bipolar disorder (Soczynska et al., 2009, Rosenblat et al., 2014), and depression (Rosenblat et al., 2014, Raison et al., 2013, Na et al., 2014), no randomized controlled trial is available about the use of these drugs in AN, even though anti-TNF alpha agents have been suggested as a therapy for AN (Khalil et al., 2011). Furthermore, most psychiatric disorders are associated with increased BMI, overweight and obesity compared to the general population (De Hert et al., 2011) and abnormally high BMI is a strong correlate of pro-inflammatory status confounding the relationship between psychiatric illness and inflammation (Manu et al., 2014). Therefore, AN presents a unique opportunity to test the relationship between inflammatory markers and a specific psychiatric disorder in which abnormally low BMI would predict lower levels of inflammatory cytokines.

A role of inflammation in AN is suggested by several lines of evidence. Animal models demonstrated that several pro-inflammatory cytokines lead to early satiety through interaction with hypothalamic neuropeptides. Interleukin(IL)-6 and IL-1-beta have anorexigenic effects, interacting with leptin (Iwasa et al., 2011, Wallenius et al., 2002, Señarís et al., 2011, Sadagurski et al., 2010), while tumor necrosis factor (TNF)-alpha promotes the production of anorexigenic peptides (Inui, 2001, Nakai et al., 1999). Human data support this preclinical evidence. For example, different inflammatory mediators are known to reduce hunger leading to anorexia as observed in many chronic diseases (Scheede-Bergdahl et al., 2012), and case reports of patients affected by AN demonstrated significant weight gain and psychopathological improvement when inflammatory pathways were suppressed by immunosuppressive therapies (Solmi et al., 2013, Barber et al., 2003). However, it remains unclear how inflammation may interact with neuropeptide Y, an orexigenic peptide, which could play a role in binge-purging behaviors (Hargrave and Kinzig, 2012) and which has been reported to being elevated in AN (Sedláčková et al., 2011), with cholecystokinin, a neuropeptide possibly playing a role in the adaptation of appetite to low food intake in AN (Cuntz et al., 2013), or with leptin, the “satiety hormone”, which has been consistently reported being decreased in AN (Terra et al., 2013).

Finally, inflammation can be associated with depression, which is an important comorbidity in AN (Hughes et al., 2013). Since anorexia is a symptom of depression, the association between AN and depression could partially explain why patients with AN can resist extreme starvation.

To the best of our knowledge, a systematic review and quantitative meta-analysis of studies comparing major inflammatory mediators between AN patients and healthy controls is lacking. The same is true for a meta-analysis of cytokine levels before and after a weight gain/restoration in AN. We therefore aimed to conduct a meta-analysis of inflammatory markers in patients affected by AN compared to healthy controls and in response to weight gain.

Section snippets

Search strategy

We conducted an electronic literature search in PubMed without language restriction from data base inception until 12/31/2013 for studies comparing serum levels of inflammatory cytokines between healthy controls (HCs) and patients with AN diagnosed according to DSM-IV (i) before weight gain and (ii) after weight gain in AN patients, and (iii) within patients with AN before and after weight gain. Controlled vocabulary terms (MeSH) and the following keywords were used in the search strategy:

Results

The search identified 999 potentially eligible studies, of which 912 were excluded after title and abstract review. Full texts of 88 articles were read, and references of relevant papers were screened. Altogether, 22 studies were included in the meta-analysis (Fig. 1).

Discussion

To our knowledge, this is the first meta-analysis investigating serum inflammatory cytokines in patients affected by AN compared to HCs, and before and after weight regain (BMI > 17.5 kg/m2). Results from this meta-analysis of 22 studies and 924 participants (AN = 512 and HCs = 412) indicate that TNF-α, soluble TNF-Receptor-II, IL1-β, and IL6 were significantly elevated in patients compared with HCs, while CRP and soluble IL6-Receptor levels were significantly lower in AN patients compared to HCs.

Role of funding source

None.

Contributors

Conception and design of the study: Correll. Acquisition of data: Solmi, Veronese; Analysis and interpretation of data: Correll, Solmi, Veronese. Draft of the article: Solmi, Sergi, Manzato. Revision for important intellectual content: Favaro, Santonastaso. Approval of the final version: Correll, Manzato, Santonastaso.

Conflict of interest statement

Drs. Solmi, Veronese, Favaro, Santonastaso, Sergi and Manzato have nothing to disclose.

Dr. Correll has been a consultant and/or advisor to or has received honoraria from: Actelion, Alexza; American Academy of Child and Adolescent Psychiatry, Bristol-Myers Squibb, Cephalon, Eli Lilly, Genentech, GersonLehrman Group, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, National Institute of Mental Health, Janssen/J&J, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda, Teva, and Vanda.

Acknowledgements

We thank the following authors for providing unpublished data for this meta-analysis: Komorowska-Pietrzykowska R., Jiskra J., Misra M., Richart C., Karczewska-Kupczewska M., Oświęcimska J, Pomeroy C., and Brambilla F.

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