Metabolic and Endocrine Changes in Critical Illness
World Small Animal Veterinary Association World Congress Proceedings, 2014
Johan P. Schoeman, BVSc, MMedVet, PhD, DSAM, DECVIM-CA
Professor of Small Animal Internal Medicine, Head of the Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, South Africa

Over the past few decades, we have come to understand the inextricable link between the endocrine, immune and nervous systems - a field dubbed as psychoneuroimmunology. In this paradigm, one system is subject to the vicissitudes of the other in the form of several intricate feedback loops, such that conditions affecting the one have far-reaching effects on the other. Likewise, critical illness (especially sepsis and septic shock) is mostly accompanied by inflammation - a state that best exemplifies the abovementioned intricate relationship between the immune and endocrine systems, in particular. During this state, cytokines and other inflammatory mediators, such as IL-1β, IL-6 and TNF-alpha, exert their effects locally at the level of various endocrine glands and centrally by affecting hypothalamic and pituitary function. In turn, the hypothalamic-pituitary axis represents the epitome of systems integration by acting as a neuroendocrine control unit, in essence, directing the physiology of survival in an abnormal internal environment.

This paper will explicate some of the metabolic and endocrine changes occurring within the body in response to critical illness and inflammation, with a specific focus on the hypothalamic-pituitary adrenal and -thyroidal axes. First and foremost, it is important to understand the ubiquitous influence of the endocrine glands on every organ system in the body. In this regard, important clinical endpoints such as blood pressure, electrolyte concentrations and glycaemic changes are markedly influenced by the endocrine system.

The Hypothalamic-Pituitary-Adrenal Axis in Critical Illness

Several factors that challenge the immune system, such as infectious agents, trauma or tissue inflammation, also activate the HPA axis. Since the late 1950s, human critical care physicians have noted the link between adverse outcome and high peripheral serum cortisol concentrations.1 A condition, originally coined relative adrenal insufficiency, entered the literature and was said to represent a state of normal-to-elevated basal serum cortisol concentrations accompanied by a blunted response to ACTH.2 This sparked a plethora of studies on the diagnosis of this state and on the risks and benefits of corticosteroid supplementation in critical illness3 - a debate that is still raging to this day. Ultimately, an uneasy consensus emerged that a critical illness condition does indeed exist that manifests as systemic hypotension, refractoriness to fluid loading and vasopressors, yet showing corticosteroid responsiveness. This systemic hypotension during critical illness may be due to down-regulation of smooth muscle adrenergic receptors, the expression of which is modulated by glucocorticoids. The above condition was later termed critical illness-related corticosteroid insufficiency and was purported to represent a state of insufficient corticosteroid-mediated down-regulation of inflammatory transcription factors.4 Its aetiology, however, remains only partially elucidated, and several cytokines have been implicated in this reversible dysfunction of the HPA axis. In this regard, TNF-alpha has been shown to impair both pituitary CRH-mediated ACTH release and ACTH-stimulated cortisol synthesis in the adrenal gland. In addition, its diagnosis still remains elusive, in that the dose of diagnostic ACTH and the appropriate response to ACTH in critical illness is controversial and almost impossible to predict, given the ill-defined magnitude of stress and inflammation and the nature and scope of individual response to critical illness. Treatment is mainly based on clinical diagnosis and confirmed retrospectively by subsequent response to corticosteroid therapy.

Lately, however, the very notion that there is a "required" plasma cortisol concentration to match the severity of a stimulus has been questioned, and the term "sick euadrenal syndrome" has been proposed.5 Supporting this paradigm, most severely ill humans at the greatest risk of mortality tend to have predictably high serum cortisol concentrations, commensurate with the degree of inflammation and/or stress that they are subjected to, but there is no corresponding relationship between mortality and lower cortisol concentrations. Hypercortisolaemia is thus seen as an essential component of the stress response to noxious stimuli, especially hypotension, serving to restore homoeostasis and act as a biomarker of severity and not as adequacy of response. Similarly, changes have been observed in the canine critical illness models of canine babesiosis and parvoviral infection.6,7

Secreted glucocorticoids have certain, relatively uniform, effects on the immune system. They reduce the number of circulating lymphocytes and eosinophils, while increasing neutrophil numbers, with the nett result of leukocytosis in species exhibiting a preponderance of neutrophils (such as dogs). In fact, glucocorticoids not only reduce total lymphocyte counts, but they also suppress the activity of B cells and cytotoxic T cells. For example, glucocorticoids decrease the synthesis of interleukin 1 by macrophages and that of IL 2 by helper T cells - cytokines, which in turn are needed for the optimal function of macrophages, helper T cells, B cells and cytotoxic T cells. However, glucocorticoids are by no means the only compounds secreted by the HPA axis that influence immunocompetence.

Both the synthesis of beta-endorphins by the anterior pituitary gland and the release of vasopressin and oxytocin from the neurohypophysis are increased in response to challenges to homoeostasis. Beta-endorphins enhance T cell proliferation, whereas both vasopressin and oxytocin stimulate helper T cells to produce more interferon gamma - a cytokine that activates macrophages and NK cells. The situation is further complicated by the fact that vasopressin and oxytocin, in concert with catecholamines, also stimulate the secretion of ACTH and B-endorphins from their mutual precursor pro-opiomelanocortin. In fact, it is not possible to make specific predictions concerning the effect, for example, of a given serum cortisol concentration on a particular individual patient, given the varied pathways and substances modulating the effect that disease states has on immune function. Alas, there is a big difference between describing complexity and understanding it; and, therefore, unless we have reproducible observations that yield consistent predictions, we do not truly understand the system. Nevertheless, the magnitude of their aberrations and a prolonged failure of the hormones of the HPA axis to return to baseline, have been consistent indications of disease severity in both humans and dogs.

Further elucidation of the underlying pathophysiological mechanisms of these HPA axis aberrations is ongoing. The author is currently investigating the response of a given species (in this case the dog) to several different disease states (parvovirus infection, babesiosis, snakebite, bite wounds and blunt trauma) and consistent, reproducible patterns are emerging.

The Hypothalamic-Pituitary-Thyroidal Axis in Critical Illness

The thyroid gland originates as a thickened plate of epithelium in the floor of the pharynx. It is intimately related to the aortic sac in its development, thus leading to accessory thyroid tissues being found in mediastinal structures, especially in dogs. The thyroid is the largest of the endocrine glands that functions exclusively as an endocrine gland.8 T4 and T3 are the major secretory products of the thyroid gland and act on many different target cells in the body. Much of the biological activity of the thyroid hormones is the results of monodeiodination of T4 to T3. Under certain conditions, such as starvation or inflammation, thyroxine is preferentially monodeiodinated to reverse T3, a biologically inactive from, which is thought to provide a mechanism to attenuate the metabolic effects of thyroid hormones on peripheral tissues.

The overall effect of thyroid hormones are to increase the basal metabolic rate, make more glucose available by increasing glycolysis, gluconeogenesis, and glucose absorption from the intestines; stimulate new protein synthesis; increase lipid metabolism; activate lipoprotein lipase and increase the sensitivity of adipose tissue to lipolysis; stimulate heart rate, cardiac output and blood flow.9 Serum total thyroxine concentrations have found a place in the prediction of both human and animal outcome from critical illness, with a continued downward trend taken as a harbinger of death and the converse as an indication of recovery.6,7,10

Other Metabolic Changes

Serum potassium concentrations are tightly regulated and aberration of this electrolyte is arguably the most common problem encountered in critically ill patients. Various other acid-base abnormalities and other electrolyte changes are also common, the scope of which is beyond the word limit of this paper. For a good review, please consult the reference list. Both hypo- and hyperglycaemia has been described in critical illness. Glucose has multiple essential effects on inflammation and resultantly on epithelial integrity and coagulation and is a subject of intense research.11,12


1.  Melby JC, Spink WW. Comparative studies on adrenal cortical function and cortisol metabolism in healthy adults and in patients with shock due to infection. J Clin Invest. 1958;37:1791–1798.

2.  Barquist E, Kirton O. Adrenal insufficiency in the surgical intensive care unit patient. J Trauma. 1997;42:27–31.

3.  Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. J Am Med Assoc. 2002;288:862–871.

4.  Marik PE. Critical illness-related corticosteroid insufficiency. Chest. 2009;135:181–193.

5.  Venkatesh B, Cohen J. Adrenocortical (dys)function in septic shock - a sick euadrenal state. Best Pract Res Clin Endocrinol Metab. 2011;25:719–733.

6.  Schoeman JP, Goddard A, Herrtage ME. Serum cortisol and thyroxine concentrations as predictors of death in critically ill puppies with parvoviral diarrhea. J Am Vet Med Assoc. 2007;231:1534–1539.

7.  Schoeman JP, Rees P, Herrtage ME. Endocrine predictors of mortality in canine babesiosis caused by Babesia canis rossi. Vet Parasitol. 2007;148:75–82.

8.  Capen CC. Comparative anatomy and physiology of the thyroid. In: Braverman LE, Utiger RD, eds. Werner and Ingbar's The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, PA: Lippincot-Raven; 2000:20–44.

9.  Lima FR, Gervais A, Colin C, Izembart M, Neto VM, Mallat M. Regulation of microglial development: a novel role for thyroid hormone. J Neurosci. 2001;21:2028–2038.

10. Angelousi AG, Karageorgopoulos DE, Kapaskelis AM, Falagas ME. Association between thyroid function tests at baseline and the outcome of patients with sepsis or septic shock: a systematic review. Eur J Endocrinol. 2011;164:147–155.

11. Knieriem M, Otto CM, Macintire D. Hyperglycemia in critically ill patients. Compend Contin Educ Vet. 2007;29:360–372.

12. Langouche L, Mesotten D, Vanhorebeek I. Endocrine and metabolic disturbances in critical illness: relation to mechanisms of organ dysfunction and adverse outcome. Verh K Acad Geneeskd Belg. 2010;72:149–163.


Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Johan P. Schoeman, BVSc, MMedVet, PhD, DSAM, DECVIM-CA
Department of Companion Animal Clinical Studies
Faculty of Veterinary Science
University of Pretoria
Pretoria, South Africa

MAIN : Critical Care : Metabolic Changes
Powered By VIN