Endocrine and metabolic alterations in response to systemic inflammation and sepsis: a review article

Abstract

Severe sepsis is cognate with life threatening multi-organ dysfunction. There is a disturbance in endocrine functions with alterations in several hormonal pathways. It has frequently been linked with dysfunction in the hypothalamic pituitary-adrenal axis (HPA). Increased cortisol or cortisolemia is evident throughout the acute phase, along with changes in the hypothalamic pituitary thyroid (HPT) axis, growth hormone-IGF-1 axis, insulin-glucose axis, leptin, catecholamines, renin angiotensin aldosterone axis, ghrelin, glucagon, hypothalamic pituitary gonadal (HGA) axis, and fibroblast growth factor-21. These changes and metabolic alterations constitute the overall response to infection in sepsis. Further research is essential to look into the hormonal changes that occur during sepsis, not only to understand their potential relevance in therapy but also because they may serve as prognostic indicators.

Keywords: Endocrine; Hormones; Inflammation; Metabolism; Sepsis; Septic shock.

Fig. 1

HPA-Axis in Acute Sepsis: (Original figure) The hypothalamus releases CRH, which stimulates pituitary ACTH secretion. This leads to cortisol release from the adrenal cortex. Pro-inflammatory cytokines released during sepsis stimulate CRH and ACTH secretion promoting hypercortisolemia. Cortisol maintains vascular tone, catecholamine sensitivity, and endothelial integrity. ACTH Adrenocorticotropic Hormone, CRH Corticotropin-releasing Hormone, IL-5 Interleukin-5, IL-6 Interleukin-6, TNF-α Tumor Necrosis Factor-Alpha

Fig. 2

HPT-Axis in Acute and Chronic Sepsis. (Original figure) The hypothalamus releases TRH which stimulates TSH secretion leading the thyroid gland release of active T3 and less active T4 (which is converted to T3 in the periphery). Cytokines and other factors acting in acute sepsis mainly affect the type 1 deiodinase responsible for converting T4 to T3 in the peripheral tissue, decreasing T3 while T4 and TSH remain the same and rT3 is increased. In chronic sepsis, the central HPT-axis is affected causing a decrease in T3, T4, TSH, and rT3. Legend: TRH Thyrotropin-releasing Hormone, TSH Thyroid Stimulating Hormone, T4 Thyroxine, T3 Triiodothyronine, rT3 Reverse Triiodothyronine

Fig. 3

Actions of Insulin: Proinflammatory and Anti-inflammatory responses Figure modified from Open access (International Immunopharmacology) permissible to re-use under a CC-BY 4.0 license)

Fig. 4

RAAS inhibitors and cecal ligation and puncture. Kaplan Mier survival curves in rats. (n = 10 rats/group except CLP-nontreated group (n = 20 rats) * Statistically Significant difference compared from Sham (p < 0.05), # Statistically Significant difference compared from CLP (p < 0.05). CLP = Cecal ligation and puncture, Spi = Spironolactone, Los = Losartan, Ram = Ramipril. Figure modified from Open access (Fundamental & Clinical Pharmacology) permissible to re-use under a CC-BY 4.0 license)

Fig. 5

Leptin levels in control and different stages of sepsis (Acute and Prolonged phase) A: Statistically significant difference from controls, C: statistically significant difference from acute sepsis values. The leptin levels in patients with acute sepsis were higher than in controls (10.2 ± 2.5 vs. 4.1 ± 1.2 ng/ml, p = 0.01). Leptin in non-survivors was almost twofold higher than in survivors (14.35 ± 7.44 vs. 7.48 ± 1.9 ng/ml, but this difference did not reach statistical significance. A statistically significant decline in patient leptin levels was found during prolonged sepsis (from 10.2 ± 2.5 to 6.25 ± 1.7 ng/ml, p = 0.001). Controls (n = 13) Septic patients (n = 30) Survivors (n = 18) non-survivors (n = 12) Figure modified from Open access (IN VIVO journal) permissible to re-use under a CC-BY 4.0 license)