Adrenal insufficiency occurring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels

This review discusses some of the mechanisms through which alcohol (EtOH) alters the activity of the hypothalamic-pituitary-adrenal (HPA) axis. In adult rats, acute EtOH treatment increases plasma ACTH and corticosteroids levels primarily by stimulating the release of corticotropin-releasing factor (CRF) and possibly vasopressin (VP) from nerve terminals in the median eminence. Increased CRF gene transcription in the hypothalamus may also be important. The HPA axis remains activated during chronic EtOH exposure, although habituation may take place. Changes in the responsiveness of hypothalamic neurons, a phenomenon itself dependent in part on a number of intermediate secretagogues, as well as decreased pituitary responsiveness to VP, all play a role. Finally, the activity of the HPA axis is influenced by exposure to EtOH during embryonic development, with mature offspring showing hyporesponsiveness to many stimuli. These altered responses appear to be caused in part by changes in the synthesis/release CRF, possibly under the influence of nitric oxide. CRF, VP, ACTH, and corticosteroids are important regulators of the immune system, behavior, metabolic pathways, and reproductive parameters. Alcohol therefore may influence such functions through the pathological secretion of these hormones. A better understanding of the mechanisms through which the drug alters their release thus may permit the development of therapies designed to alleviate some of the consequences of alcoholism.

Alcohol stimulates ACTH secretion in the rat: mechanisms of action and interactions with other stimuli.

Restraint stress-induced thymic involution and cell apoptosis are dependent on endogenous glucocorticoids

Brown adipose tissue (BAT) and brown-like cells in white adipose tissue (WAT) can dissipate energy through thermogenesis, a process mediated by uncoupling protein 1 (UCP1). We investigated whether stress hormones ACTH and corticosterone contribute to BAT activation and browning of WAT. ACTH and corticosterone were studied in male mice exposed to 4 or 23°C for 24 h. Direct effects were studied in T37i mouse brown adipocytes and primary cultured murine BAT and inguinal WAT (iWAT) cells. In vivo effects were studied using (18)F-deoxyglucose positron emission tomography. Cold exposure doubled serum ACTH concentrations (P=0.03) and fecal corticosterone excretion (P=0.008). In T37i cells, ACTH dose-dependently increased Ucp1 mRNA (EC50=1.8 nM) but also induced Ucp1 protein content 88% (P=0.02), glycerol release 32% (P=0.03) and uncoupled respiration 40% (P=0.003). In cultured BAT and iWAT, ACTH elevated Ucp1 mRNA by 3-fold (P=0.03) and 3.7-fold (P=0.01), respectively. In T37i cells, corticosterone prevented induction of Ucp1 mRNA and Ucp1 protein by both ACTH and norepinephrine in a glucocorticoid receptor (GR)-dependent fashion. ACTH and GR antagonist RU486 independently doubled BAT (18)F-deoxyglucose uptake (P=0.0003 and P=0.004, respectively) in vivo. Our results show that ACTH activates BAT and browning of WAT while corticosterone counteracts this.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.14-254839

Direct activating effects of adrenocorticotropic hormone (ACTH) on brown adipose tissue are attenuated by corticosterone

The purpose of this work was to compare the plasma adrenocorticotropin (ACTH), corticosterone and interleukin-6 (IL-6) responses that rats of the outbred Sprague-Dawley strain obtained from two differ

Sprague-Dawley rats obtained from different vendors exhibit distinct adrenocorticotropin responses to inflammatory stimuli.

The biologic activity of ACTH and related peptides on peripheral blood mononuclear cells is altered by the presence of dexamethasone.

Toxic Epidermal Necrolysis [TEN] is life-threatening condition with mortality rate of 30-60%. Most common etiology of TEN is drug induced. Though Anaphylactic [Type I Hypersensitivity] reactions have been reported with Iron Sucrose, we present first case of TEN [Type IV Hypersensitivity], associated with Iron Sucrose along with Anti-tuberculosis treatment [ATT], to our knowledge. Iron Sucrose is considered relatively safer than other iron formulations. After 48 hours of administering Intravenous Iron Sucrose [20 mg in 200 ml N.S] infusion [first day], patient developed TEN symptoms [third day]. He was taking first line ATT drugs since past one month for Pulmonary Tuberculosis. On basis of history, 80-90% Body Surface area involvement, positive Nikolsky sign and laboratory findings, patient was diagnosed with drug induced TEN [fifth day]. For TEN management, ATT was withdrawn and patient was treated with intravenous Dexamethasone, Piperacillin/Tazobactam, Metronidazole, Pantoprazole, Intravenous fluids with dermatologically supportive local applications and patient was monitored. Patient died due to septic shock despite all resuscitative measures [seventh day]. Causality assessment (WHO UMC scale and Naranjo scale) was ‘Possible’ for both Iron Sucrose and ATT drugs. No improvement in patient’s condition after withholding ATT and short duration between Iron sucrose and symptoms of TEN onset suggests an increased likelihood of TEN induction by Iron sucrose. However, either ATT or Iron Sucrose could trigger TEN in presence of other drug. Improved understanding by physicians of these relatively unknown life-threatening ADR’s and interactions can aid in early identification and enhanced vigilance in future scenarios. 
Keywords: WHO UMC Scale, SCORTEN score, Naranjo scale, Anaphylactic reactions 

K. Aggarwal

Papers

The biologic activity of ACTH and related peptides on peripheral blood mononuclear cells is altered by the presence of dexamethasone.

A A Rare Case Report of Toxic Epidermal Necrolysis with Iron Sucrose/first line Anti-tuberculosis Treatment Drugs