Cortisol in sickle cell disease: a systematic review and meta-analysis

Abstract

Cortisol plays a critical role in the biological link between psychosocial stress and health outcomes; however, the methods for assessing cortisol and the biopsychosocial correlates of this stress hormone among individuals with sickle cell disease (SCD) are not well developed. This review aimed to systematically evaluate the current literature for cortisol measurement and methodology among individuals with SCD and synthesize findings of biopsychosocial correlates in this population. A systematic search of medical databases was conducted, resulting in 20 studies meeting inclusion criteria, involving 710 participants with SCD and 454 control participants without SCD. Cortisol was primarily measured using serum (k = 10) and plasma (k = 8), and few studies used salivary (k = 1) or hair (k = 1) measurements. Most studies investigated cortisol in comparison with a control group (k = 14). Qualitative findings were inconsistent, and quantitative meta-analytic data (k = 12) imply no significant difference in cortisol in SCD participants relative to healthy controls (serum Hedges g = -1.51, 95% confidence interval [CI], -3.99 to 0.97; plasma Hedges g = -0.72; 95% CI, -1.56 to 0.13). Additionally, studies examined cortisol in comparison with adrenal standards (k = 5), responses to adrenocorticotropic hormone stimulation (k = 7), and correlations with vaso-occlusive crises (k = 3) and disease severity (k = 3). Few studies explored medication (k = 2) or behavioral correlates (k = 1) of cortisol. Finally, no study investigated the influence of psychosocial stressors on cortisol levels. There is a clear need for high-quality observational research to clarify cortisol findings in SCD and identify psychosocial correlates and biomedical outcomes.

Graphical abstract

Figure 1.

A theoretical biopsychosocial framework for SCD that illustrates the cyclical physiological and behavioral pathways through which psychosocial stressors influence SCD morbidities. This framework is intended to guide research on the bidirectional mechanisms linking stressors, stress responses, and health outcomes. Physiological pathways: when the brain perceives a stressor, physiological stress-related biomarkers (glucocorticoids, catecholamines, and cytokines) are released to repond to the stressor and gain allostasis. Experiences with chronic and recurrent acute psychosocial stressors can result in dysregulated diurnal stress response patterns and elevated systemic inflammation. Inflammatory outcomes can then lead to increased hemolysis and SCD morbidities. Conversely, anemic conditions and systemic ischemia associated with SCD morbidities could theoretically result in further dysregulation of the stress response system via pathophysiological mechanisms. Behavioral pathways: experiences with chronic and recurrent acute psychosocial stressors and dysregulated stress response biomarkers can also result in depressed mood and withdrawn behaviors, resulting in disengagement in care and increased SCD morbidities. Conversely, elevated SCD morbidities are associated with increased disease-related stressors such as school or work absences, peer or family conflict, and health care bias, which can further result in dysregulated stress responses.

Figure 2.

PRISMA flow diagram detailing study selection.

Figure 3.

Meta-analytic summary statistics and forest plots. (A) Studies assessing plasma cortisol relative to a healthy control group. (B) Studies assessing serum cortisol relative to a healthy control group. HK, Hartung-Knapp method; SE, standard error; SMD, standardized mean difference.