Impact of critical illness on cholesterol and fatty acids: insights into pathophysiology and therapeutic targets.

Critical illness is characterized by a hypercatabolic response encompassing endocrine and metabolic alterations. Not only the uptake, synthesis and metabolism of glucose and amino acids is majorly affected, but also the homeostasis of lipids and cholesterol is altered during acute and prolonged critical illness. Patients who suffer from critically ill conditions such as sepsis, major trauma, surgery or burn wounds display an immediate and sustained reduction in low plasma LDL-, HDL- and total cholesterol concentrations, together with a, less pronounced, increase in plasma free fatty acids. The severity of these alterations is associated with severity of illness, but the underlying pathophysiological mechanisms are multifactorial and only partly clarified. This narrative review aims to provide an overview of the current knowledge of how lipid and cholesterol uptake, synthesis and metabolism is affected during critical illness. Reduced nutritional uptake, increased scavenging of lipoproteins as well as an increased conversion to cortisol or other cholesterol-derived metabolites might all play a role in the decrease in plasma cholesterol. The acute stress response to critical illness creates a lipolytic cocktail, which might explain the increase in plasma free fatty acids, although reduced uptake and oxidation, but also increased lipogenesis, especially in prolonged critical illness, will also affect the circulating levels. Whether a disturbed lipid homeostasis warrants intervention or should primarily be interpreted as a signal of severity of illness requires further research.

Impact of Hydrocortisone and of CRH Infusion on the Hypothalamus-Pituitary-Adrenocortical Axis of Septic Male Mice.

PURPOSE: Sepsis is hallmarked by high plasma cortisol/corticosterone (CORT), low adrenocorticotropic hormone (ACTH), and high pro-opiomelanocortin (POMC). While corticotropin-releasing hormone-(CRH) and arginine-vasopressin (AVP)-driven pituitary POMC expression remains active, POMC processing into ACTH becomes impaired. Low ACTH is accompanied by loss of adrenocortical structure, although steroidogenic enzymes remain expressed. We hypothesized that treatment of sepsis with hydrocortisone (HC) aggravates this phenotype whereas CRH infusion safeguards ACTH-driven adrenocortical structure. METHODS: In a fluid-resuscitated, antibiotics-treated mouse model of prolonged sepsis, we compared the effects of HC and CRH infusion with placebo on plasma ACTH, POMC, and CORT; on markers of hypothalamic CRH and AVP signaling and pituitary POMC processing; and on the adrenocortical structure and markers of steroidogenesis. In adrenal explants, we studied the steroidogenic capacity of POMC. RESULTS: During sepsis, HC further suppressed plasma ACTH, but not POMC, predominantly by suppressing sepsis-activated CRH/AVP-signaling pathways. In contrast, in CRH-treated sepsis, plasma ACTH was normalized following restoration of pituitary POMC processing. The sepsis-induced rise in markers of adrenocortical steroidogenesis was unaltered by CRH and suppressed partially by HC, which also increased adrenal markers of inflammation. Ex vivo stimulation of adrenal explants with POMC increased CORT as effectively as an equimolar dose of ACTH. CONCLUSIONS: Treatment of sepsis with HC impaired integrity and function of the hypothalamic-pituitary-adrenal axis at the level of the pituitary and the adrenal cortex while CRH restored pituitary POMC processing without affecting the adrenal cortex. Sepsis-induced high-circulating POMC may be responsible for ongoing adrenocortical steroidogenesis despite low ACTH.