Endocrine Dysregulation in Septic Foals
ACVIM 2008
Ramiro E. Toribio, DVM, MS, PhD, DACVIM
Columbus, OH, USA

Sepsis

Sepsis, defined as the presence of pathogenic organisms or their toxins in blood or tissues, is the number one cause foal mortality. Major improvements in treating septic foals have been made in recent years; however, limited information on endocrine dysregulation during various pathological conditions in foals is available.

Endocrinopathies in human sepsis are typically manifested as hyperglycemia and hyperinsulinemia (insulin resistance), and/or insufficient production of adrenal corticosteroids, and/or decreased thyroid hormone concentrations, and/or abnormal parathyroid gland function. In recent years information on the association between other endocrine systems (leptin, adiponectin, resistin, natriuretic peptides, adrenomedullin, endothelin-1) and sepsis in other species has become available. In foals, information on endocrine dysregulation during disease is lacking. Current advances elucidating endocrine changes of critically ill humans has resulted in better patient care and survival; these improvements have occurred, in part, from the use of endocrine markers as prognostic indicators (procalcitonin, insulin, thyroid hormones, leptin, ACTH, cortisol, resistin) and from the development of innovative therapeutic agents targeting specific humoral systems (e.g., angiotensin-converting enzyme--ACE, endothelin-converting enzyme--ECE, neutral endopeptidase--NEP inhibitors, insulin, vasopressin agonists). Various research groups are currently working in elucidating endocrine aspects of the septic foal. The goal of this review is to provide an update on current information on endocrine dysregulation in the septic foal.

Arginine Vasopressin (AVP), Adrenocorticotrophin (ACTH), and Cortisol

The role of the hypothalamic-pituitary-adrenal (HPA) axis in fluid, electrolyte, energy, metabolism, and immune regulation is vital. Endocrine factors of the HPA include vasopressin/corticotrophin-releasing factor (hypothalamus), ACTH (anterior pituitary), and cortisol (adrenal). AVP is also part of the osmoregulatory/pressor systems. We, as well as others, believe that HPA dysfunction is frequent in septic foals.

Arginine Vasopressin

AVP is synthesized by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. In turn, AVP is stored in the posterior lobe of the pituitary (neurohypophysis) and released in response to hyperosmolality, hypotension, and stress. AVP also reaches the corticotrophs of the adenohypophysis. AVP interacts with V1 receptors in vascular smooth muscle to induce vasoconstriction, with V2 receptors in the renal collecting ducts to mediate its antidiuretic effects, and with V3 receptors in the corticotrophs of the pituitary gland to increase ACTH synthesis and release. AVP is an important ACTH secretagogue in horses. AVP is important for cardiovascular homeostasis where it is a systemic vasopressor, except in coronary, cerebral, and pulmonary arterial circulations where it induces vasodilation. We have documented that increased AVP concentrations are a frequent finding in septic foals (<72 hours old), and that the high AVP concentrations in most septic foals are not related to serum osmolality but rather to poor perfusion and severity of sepsis (stress, SIRS). Foals with the highest AVP concentrations had the highest ACTH concentrations and were more likely to die (OR=24). These findings indicate that most foals with sepsis had an increased hypothalamic-pituitary response that is not able to compensate for the systemic inflammatory status. It also indicates the need for prospective studies on the use of exogenous vasopressin or its agonists (desmopressin, terlipressin) as AVP concentrations are elevated in most of these foals.

ACTH

ACTH is released by the adenohypophysis in response to hypothalamic corticotrophin-releasing factor (CRF) and AVP. Other factors that directly increase ACTH release include low cortisol concentrations, cytokines, and endotoxin. Two recent studies evaluated ACTH concentrations in a large number of septic foals. Most septic foals had increased plasma ACTH concentrations and those with higher ACTH concentrations were more likely to die (OR=16). Some foals with low cortisol concentrations had low or normal ACTH concentrations indicating a poor pituitary response to stress. Many of the foals with high ACTH had normal cortisol concentrations indicating adrenal insufficiency. Relative impairment of adrenocortical response has been proposed to be an important in the pathogenesis of septic shock, and has been the basis for glucocorticoid administration in patients with adrenal insufficiency. There is limited data on relative adrenal insufficiency in foals and ongoing studies by various groups are addressing this question.

Cortisol

Cortisol is synthesized and released by the zona fasciculata of the adrenal gland in response to ACTH. Its major physiological functions are as an endogenous immunosuppressor, blood pressure regulator, and energy modulator. Cortisol is a physiological antagonist of insulin by decreasing glycogenesis, promoting lipolysis and breakdown of proteins, decreasing glucose uptake, inducing hyperglycemia, and increasing gluconeogenesis. Cortisol induces insulin resistance and hyperglycemia (relevant to foal sepsis). Cortisol inhibits the effects of IL-1 on the hypothalamus to secrete CRF. High cortisol concentrations in septic foals were recently documented in two independent studies. Septic foals with higher cortisol concentrations were more likely to die (OR=19). Most of these foals had higher cortisol concentrations when compared to healthy foals, but a number of them had either low/normal ACTH and cortisol concentrations, or high ACTH concentrations with normal cortisol concentrations (relative adrenal insufficiency). In support to relative adrenal insufficiency as a relevant problem in critically ill foals, the same studies found that septic foals had higher AVP/ACTH and ACTH/cortisol ratios than healthy foals. The accurate diagnosis of relative adrenal insufficiency requires the administration of exogenous ACTH.

Calcium, Magnesium, Parathyroid Hormone (PTH), Calcitonin (CT), and Parathyroid Hormone-Related Protein (PTHRP)

Calcium

Calcium has important structural and non-structural functions. It is essential for muscle contraction, hormone secretion, enzyme activation, cell division, neuromuscular excitability, and blood coagulation. A decrease in extracellular ionized calcium (Ca2+) concentration increases PTH secretion while an increase in Ca2+ decreases PTH and increases CT secretion. Ca2+ has minimal effect on PTHrP secretion.

Hypocalcemia, PTH, and Sepsis

Low ionized calcium (Ca2+) concentrations are a frequent abnormality in critically ill/septic adult horses, and a number of critically ill horses with hypocalcemia have parathyroid gland dysfunction (hypocalcemia and low/normal PTH). In equids hypocalcemia is associated with ileus, seizures, dyspnea, tetany, tremors, cardiac arrhythmias, and death. In a recent study we found that total and ionized hypocalcemia are frequent findings in septic foals. Although in that study we could not find a strong association between hypocalcemia and foal survival, there was a trend for foals with lower Ca2+ to die. In the same study we found that PTH concentrations in septic foals were variable, but foals with higher PTH concentrations were more likely to die (OR = 5.8). Although this appears to be an appropriate response to hypocalcemia, many of these foals had normocalcemia. A similar phenomenon has been documented in critically ill humans. We believe that this increase in PTH concentrations (with normocalcemia) is part of a systemic inflammatory response (we have also documented this phenomenon in horses with enterocolitis and with experimental endotoxemia). Recent research indicates that PTH has functions not related to calcium regulation but rather to immunomodulation, as PTH inhibits leukocyte function and phagocytic activity.

Neonatal Hypocalcemia

Research from our laboratory indicates that the development of hypocalcemia of sepsis in equids is mediated, in part, by IL-1, IL-6, and over-expression of the calcium-sensing receptor (CaR) in parathyroid cells. This results in decreased PTH mRNA expression, PTH mRNA stability, and decreased PTH secretion, which translates into a poor response to hypocalcemia (parathyroid gland dysfunction). These findings support that a systemic inflammatory response interferes with normal parathyroid gland function to regulate extracellular Ca2+ concentrations.

Idiopathic Neonatal Hypercalcemia

Anecdotal reports as well as clinical experience indicates that some critically ill foals, often premature, may develop hypercalcemia that cannot explained by hyperparathyroidism or renal dysfunction (hypercalcemia from renal failure is uncommon in foals). The pathogenesis of this condition remains unclear. We believe that placental insufficiency plays a role in this condition. Further, we have found that plasma PTHrP concentrations are increased in many of these foals, and PTHrP is important in placental and transepithelial calcium transport (unpublished). A similar condition has been documented in children but its pathogenesis remains unknown.

Calcitonin (CT) and Procalcitonin (PCT)

There is minimal information available on CT in horses and no data is available in foals. It has been proposed that increased CT (hypocalcemic hormone) concentration during sepsis is in part responsible for the development of hypocalcemia. When we measured serum CT concentrations in healthy and septic foals, we could not demonstrate statistical differences between groups, and could not find any association with serum Ca2+ concentrations. More relevant perhaps is the recent discovery that PCT, the precursor of CT, which is not detected in circulation of healthy individuals, is increased in critically ill/septic/endotoxemic humans. PCT is currently used in the clinical setting as a marker of sepsis, severity of disease, and likelihood of survival. Since no information on blood PCT concentrations was available in equids we cloned the equine CT gene (CALC I gene; NM_001081854) with the purpose of evaluating its role in equine sepsis and hypocalcemia. Even though there is a 90% homology between equine and human CT (human assays work in horses), the homology with PCT is lower (74%), making the use of human PCT assays unreliable. We evaluated the human BRAHMS PCT assay using serum from critically ill foals and endotoxemic horses and confirmed that the human assay does not detect equine PCT. As an alternative approach, we determined PCT gene expression in peripheral white blood cells and liver from septic foals and found increased PCT mRNA expression (unpublished). We do not believe that this increased PCT expression is associated with hypocalcemia but rather is an inflammatory response to sepsis.

Parathyroid Hormone-Related Protein (PTHrP)

PTHrP is considered a paracrine, autocrine, and intracrine factor that is important in cell differentiation, apoptosis, and transplacental calcium transport. Early studies in other species have shown that PTHrP concentrations increase during endotoxemia. When we measured plasma PTHrP concentrations in healthy, sick non-septic, and septic foals we could not demonstrate any association between plasma PTHrP and degree of sepsis.

Magnesium

Magnesium is an important cofactor for enzymatic activation, metabolism of carbohydrates, fats, and proteins, energy metabolism, cell membrane function, nerve function, muscle contraction, and cell proliferation. As Ca2+, ionized magnesium (Mg2+) is the active form of magnesium. Calcium regulation, including PTH release, PTH receptor activation, and renal vitamin D (1,25 dihydroxyvitamin D3) activation requires Mg2+. Thus, hypomagnesemia and Mg2+ depletion can lead to hypocalcemia. We have shown that ionized hypomagnesemia is a consistent finding in critically ill horses and it is associated with equine mortality. We have documented hypomagnesemia in septic foals (25%); however, unlike other species, we could not demonstrate an association between hypomagnesemia and foal survival. The mechanisms for the development of hypomagnesemia in critically ill/septic patients are multifactorial and poorly understood. Decreased gastrointestinal absorption as well as Mg2+ shift into the intracellular compartment from hyperinsulinemia and increased vasopressin concentrations have been proposed as the main causes of hypomagnesemia of sepsis. We have documented both hyperinsulinemia and hypervasopressinemia in sepsis foals.

Energy Metabolism

Although information from human neonatal critical medicine has clearly influenced foal intensive care medicine, in particular to regard of endocrine interventions, limited information on the endocrine aspects of the foal energy metabolism is available. Several humoral factors are important in energy regulation including insulin, glucagon, glucocorticoids, leptin, adiponectin, resistin, ghrelin, and growth hormone. Unfortunately, many of the commercially available assays to measure these hormones are not validated or do not work in horses.

Insulin

Extensive work exists on serum insulin concentrations and the insulin response to changes in glucose concentrations in healthy and premature foals, and the effect of insulin on other hormones (ACTH, cortisol, catecholamines) in foals. Human clinical trials have shown that tight a control of hyperglycemia with insulin can improve survival in selected ICU patients. Despite subjective reports on serum insulin concentrations and its potential therapeutic value in critically ill foals, information is lacking on the energy metabolism of the septic foal. It is believed that both insulin deficiency and insulin resistance are common in critically ill foals. Insulin affects and is affected by leptin and the HPA axis in healthy horses. Preliminary work in our laboratory confirms the importance of insulin dysregulation in foal sepsis. When we compared insulin concentrations between septic, sick non-septic, and healthy foals, we found that insulin concentrations were statistically higher in septic foals (unpublished), although we did not find an association with survival. Many hyperinsulinemic foals had normoglycemia indicating sepsis-mediated insulin resistance. A number of these foals had hypoglycemia/normoglycemia/hyperglycemia with normoinsulinemia and may benefit from insulin administration, in particular those under glucose infusion. An important point from this study is that hyperinsulinemia is a frequent finding in septic foals. Measuring insulin in septic foals is warranted to address its relationship to other endocrine and body systems, its association to survival, and to substantiate its therapeutic use.

Leptin

Leptin is an adipocyte-derived satiety factor and the key regulator of food intake and body weight. It is predominantly expressed in adipose tissue and its plasma levels correlate well with body fat mass. Leptin concentrations are elevated during experimental human and animal endotoxemia, and during SIRS and sepsis. Leptin has pro and anti-inflammatory properties, and it is a mediator of the central effects of sepsis (anorexia, depression, hyperthermia). Limited information is available on leptin in horses; however, it is known that insulin and glucocorticoids increase plasma leptin concentrations in adult horses. Leptin concentrations are low in newborn foals, likely to enhance hunger. No information on leptin in sick or septic foals is available; however, work from our group indicates that plasma leptin concentrations are associated with foal sepsis (preliminary work). Based on its relationship with different body systems (HPA, insulin, thyroid hormones, insulin, immunity), we believe that measuring leptin concentrations in septic foals is well justified.

Thyroid Hormones

Transient central hypothyroidism is documented in septic humans. Whether low thyroid hormone (TH) concentrations (non-thyroidal illness syndrome/euthyroid sick syndrome) represents an adaptive or a maladaptive response to severe illness in any species remains unclear. Information on TH concentrations in healthy foals is available; however, other than individual cases, foals with congenital hypothyroidism, and one abstract on premature/sick foals, information on septic foals is minimal. Newborn foals have higher (up to ten fold) TH concentrations than adults. One study (Breuhaus, ACVIM 2005) found that premature foals had significantly lower TH serum concentrations and an exaggerated thyroid-stimulating hormone (TSH) response to TRH stimulation when compared to normal foals. Information in sick foals remains inconclusive. The author concluded that premature and sick foals experience non-thyroidal illness syndrome (primarily low T3). Although hypothyroidism is a rare condition in foals, determining the association between THs, foal sepsis, survival, energy metabolism, and other endocrine systems is warranted.

References

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Speaker Information
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Ramiro Toribio, DVM, MS, PhD, DACVIM
The Ohio State University
Columbus, OH


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