Circulating Leptin Levels in Patients with Myalgic Encephalomyelitis Chronic Fatigue Syndrome and/or Fibromyalgia: a Systematic Review, 2021, Musker

Master of Clinical Science Thesis

Circulating Leptin Levels in Patients with Myalgic Encephalomyelitis Chronic Fatigue Syndrome and/or Fibromyalgia: a Systematic Review

Submitted for the degree of Master of Clinical Science By Michael Musker

March 2021

The University of Adelaide JBI, Faculty of Health and Medical Sciences

https://hekyll.services.adelaide.edu.au/dspace/bitstream/2440/130222/1/Musker2020_MClinSc.pdf

Abstract Title: Circulating Leptin levels in Patients with Myalgic Encephalomyelitis Chronic Fatigue Syndrome and/or Fibromyalgia: a Systematic Review

Objective: The objective of this thesis was to evaluate circulating levels of leptin in cases diagnosed with Myalgic Encephalomyelitis Chronic Fatigue Syndrome and/or Fibromyalgia Syndrome and to investigate the differences compared with healthy controls.

Background: Myalgic Encephalomyelitis Chronic Fatigue Syndrome is a condition that has major symptoms including self-reported fatigue, post exertional malaise and unexplained pain across the body. The widespread pain is measured in a systematic way and is often referred to as fibromyalgia. The two disorders have many similarities but their association with leptin has indicated that leptin may affect the role of proinflammatory cytokines and symptom severity.

Inclusion criteria: This thesis considered observational studies of varying study designs including prospective and retrospective cohort studies, case-control studies, time-series and analytical cross-sectional studies that included both cases and healthy comparators. Cases included a diagnosis of Myalgic Encephalomyelitis, Chronic Fatigue Syndrome and/or Fibromyalgia. Some consider Myalgic Encephalomyelitis to be a different condition from Chronic Fatigue Syndrome, but for the purpose of this thesis we will use a consistent format ‘Myalgic Encephalomyelitis Chronic Fatigue Syndrome’ without prejudice to the community perspective. Controls are those without this diagnosis, usually healthy participants. Only studies published in English were included due to limited resources for translation.

Methods: This systematic review is reported based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) checklist and follows JBI’s methodology for systematic reviews of etiology and risk. A comprehensive search strategy included PubMed, Embase, Scopus, Science Direct, and PsychINFO. Two reviewers screened, critically appraised eligible articles and extracted data using a standardised data extraction tool informed by the JBI System for the Unified Management, Assessment and Review of Information (SUMARI) software.

Data Synthesis: The authors completed a quantitative analysis that produced synthesised findings across studies using pooled effect sizes and confidence intervals of the measures provided.

Results: There were 12 case (n=649) vs control (n=658) studies combined (n=1307) in meta-analysis which demonstrated a small difference favouring a higher level of circulating leptin in cases compared to controls when using a standardised mean difference. There was an overall pooled difference of 0.39, with a 95% Confidence Interval 0.04 to 0.74, which was significant (p=0.029). The metaanalysis showed a high level of heterogeneity I2=86%. Re-expressing SMDs (Standardised Mean Difference) using the original units of leptin showed a pooled effect of 3.26 ng/mL (CI 0.33 ng/mL to 6.19 ng/mL).

Conclusions: Much of the literature describes the role of leptin as being part of an inflammatory response, but this systematic review did not find that studies could provide convincing evidence that leptin was higher in cases than controls. Although many studies indicated increased leptin in cases, there were two studies that reported lower leptin in cases compared to controls, four studies that showed no discernible difference, and six studies that indicated higher levels of leptin in cases. Individual study methodology varied between studies causing some difficulties in comparison. A series of investigative benchmarks and protocols need to be developed in relation to researching adipokines if exploration of biomarkers in these syndromes is to yield useful results. To provide clarity, clinical investigators need to use similar standardised practices and research methods to aid better comparison of experimental results between studies. A series of international standards and protocols needs to be developed, accepted, and cited across the literature as part of clinical operational procedures if we are to advance this area of research. A series of recommendations for future research has been made in chapter 5.