Hypoadrenocorticism. Marc Bercovitch DVM, Dip. ACVIM. Adrenal anatomy and hormone actions/regulation

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1 Hypoadrenocorticism Marc Bercovitch DVM, Dip. ACVIM Adrenal anatomy and hormone actions/regulation The adrenal gland is composed of an outer cortex and an inner medulla. Catecholamines are secreted by the inner medullary area. The outer cortex can be divided into 3 zones: the zona glomerululosa, the zona fasiculata and the zona reticularis. The outermost zona glomerulosa provides precursors for the zona fasiculata and reticularis. This zone also produces and secretes mineralocorticoid hormone. Aldosterone is a mineralocorticoid produced and secreted by the zona glomerulosa. Its main actions are sodium and water retention and potassium excretion by the kidney. It is the main hormone responsible for renal potassium loss. Angiotension II is the most important stimulus for aldosterone release. Increased serum potassium levels also stimulate Aldosterone release. The zona fasiculata secretes glucocorticoid hormones and the inner most cortical area, the zona reticularis, primarily secretes sex hormones. Cortisol secretion by the zona fasciculate is regulated by pituitary release of ACTH. Actions of cortisol include increased vascular sensitivity to catecholamine, maintenance of vascular tone, maintenance of vascular integrity, maintenance of normoglycemia by increased gluconeogenesis and lipolysis and decreased peripheral utilization of glucose, and increases erythropoiesis. Etiology Adrenocortical failure can result from primary, secondary or iatrogenic processes. Primary Hypoadrenocorticism is thought to be most commonly due to immune destruction of all three layers of the adrenal cortex. Other reported causes are infiltrative fungal disease (blastomycosis, histoplasmosis) neoplasia (Lymphosarcoma), and hemorrhage/infarcts. An atypical form of primary Hypoadrenocorticism results in early or selective destruction of the zona fasculata resulting in only a cortisol deficiency. These patients may or may not progress to typical primary Hypoadrenocorticism resulting in both glucocorticoid and mineralocorticoid deficiency. Iatrogenic Hypoadrenocorticism can result from the medical destruction of the adrenal cortex secondary to medication (Lysodren or Trilostane) or the acute discontinuation of exogenous glucocorticoid therapy. Secondary Hypoadrenocorticism results from a decreased or absent release of ACTH from the pituitary gland. This results in selective atrophy of the zona fasiculata and reticularis resulting in a cortisol deficiency without a concurrent mineralocorticoid deficiency. Signalment Hypoadrenocorticism typically affects young to mid-aged dogs form 4-5 years old; however, it can affect dogs of any age and has been reported to occur in dogs as young as 4 weeks old. There tends to be a female predisposition with the exception of standard poodles, Portuguese water dogs and bearded collies where it equally affects male and female dogs. Nova Scotia duck

2 trolling retrievers are also a breed predisposed to Hypoadrenocorticism but this breed tends to be affected at a younger age on average 2.5 years old. Clinical Signs and Physical Exam The clinical signs associated with Hypoadrenocorticism tend to be non-specific, vague, and wax and wane. Most often the systems affected are the cardiovascular, intestinal, renal, or nervous systems. Signs may be gradual in onset and there can be an acute exacerbation of a more chronic problem. Additionally, any pet with recurrent vague signs that responds to general supportive care should be considered a potential hypoadrenocortical dog. Signs typically observed are anorexia, lethargy, vomiting/regurgitation, weight loss, polyuria, polydipsia, hematemesis/hematochezia/melena, or ataxia/seizures/coma. Signs tend to be more severe and shock, collapse and dehydration more prevalent with mineralocorticoid deficient patients. Upon physical exam these patients may be anywhere from mildly dehydrated to hypotensive shock. A prolonged capillary refill time and poor pulse may also be observed. Bradycardia with an associated hypotension should immediately raise concern for hyperkalemia and Hypoadrenocorticism. Laboratory Changes Hyperkalemia, hyponatremia and hypochloremia occur independently or together especially with primary disease. Hyperkalemia and hyponatremia result from an aldosterone deficiency with primary disease causing an increase in sodium wasting and increased potassium retention via the kidneys. Gastrointestinal signs associated with Hypoadrenocorticism also exacerbate the hyponatremia. A sodium: potassium ratio of < 15:1 is strongly suggestive of Hypoadrenocorticism. It is very important to remember that normal electrolytes do not exclude a diagnosis of Hypoadrenocorticism as this is reported to happen in as many as 30% of hypoadrenocortisolemic patients. The clinician must also consider other potential causes of hyperkalemia and/or hyponatremia including severe gastrointestinal disease, renal failure/uroabdomen, liver failure, heart failure, chylothorax, intestinal parasites, academia and artifact secondary to hemolysis, thrombocytosis, and lipemia. Other noted laboratory changes may include hypercalcemia, hypoalbuminemia, hypocholesterolemia and a non-regenerative anemia. Anemia, hypoalbuminemia, hypocholesterolemia, or hypoglycemia and lack of a stress leukogram are more commonly seen with secondary/atypical disease and warrants further testing for Hypoadrenocorticism. Diagnostic test Diagnostic tests performed are a blood pressure, electrocardiogram, baseline cortisol level, ACTH stimulation test if indicated, and potentially endogenous ACTH levels. Hypotension is the result of renal sodium and water loss leading to a severe decrease in extracellular volume, which is exacerbated by concurrent sodium and water loss from intestinal signs. Hyperkalemia can lead to decreased myocardial function and decreased cardiac output which also contributes to the hypotension. Lastly, Cortisol enhances vascular sensitivity to catecholamines (endogenous or exogenous) and is vital to the maintenance of vascular integrity and tone. Thus the cortisol deficiency not only contributes to the pathogenesis of hypotension in hypoadrenocortical patients but the lack of cortisol replacement therapy may hamper efforts to correct the hypotension.

3 Typical changes seen on an electrocardiogram secondary to hyperkalemia include a tall tented T wave, bradycardia, a prolonged P-R interval (first degree heart block), a prolonged QRS, S-T segment depression and atrial standstill. Baseline cortisol values are very useful in excluding a diagnosis of Hypoadrenocorticism. A baseline cortisol value of greater than 2 mcg/dl essentially excludes a diagnosis of adrenal insufficiency. A baseline coritsol level below 2 mcg/dl is an indication to perform a full ACTH stimulation tests. Cortrosyn at a dose of 5 mcg/kg (max of 250mcg) is given intravenously and a post sample is collected in 1 hour. If using compounded gel 1 and 2 hour post samples should be obtained. Your baseline Cortisol level is your pre-injection value. Ideally these tests should be performed prior to the administration of any exogenous glucocorticoids. Prednisone is detected as cortisol in the assay and should not be given if possible. If need be cortisol levels can be obtained about 36 hours after administration. If it is necessary to administer steroids prior to performing a baseline cortisol or ACTH stimulation test in a critical patient thought to have Hypoadrenocorticism then Dexamethasone is preferred. This is not detected as cortisol by the assay and doses as high as 5mg/kg have been shown to not alter the results of an ACTH stimulation tests in an acute setting. The vast majority of dogs with Hypoadrenocorticism have both a baseline and post stimulation cortisol level below 1 mcg/dl. About 25% of hypoadrenocortisolemic patient will have a post stimulation value between 1 mcg/dl and 2 mcg/dl but virtually all will have both pre and post values below 2 mcg/dl. Evaluation of an endogenous ACTH level has been advocated to distinguish atypical primary hypoadrenocortisolemic patients that may progress to a more typical form requiring mineralocorticoids supplements in addition to gluocorticoid supplements from secondary hypocortisolemic patients that will not. Samples should be obtained prior to any steroid administration. Theoretically with atypical primary hypoadrenocorticism the endogenous ACTH level should be very high (> 500 pg/ml) and low to undetectable levels are found with secondary disease. Endogenous ACTH is very labile and falsely decreased levels can occur. Additionally in one study of 11 dogs with glucocorticoid only deficient hypoadrenocorticism 9 of the 11 dogs were found to have atypical primary disease based on an elevated endogenous ACTH level. However, only 1 dog progressed to typical primary disease necessitating the addition of mineralocorticoids. Treatment of an acute adrenal crisis Identification and early intervention is imperative for the treatment of an acute adrenal crisis. These patients may be severely dehydrated, hypotensive, and in a state of shock. The hallmark of treatment is aggressive fluid support, replacement of hormonal deficit and correction of metabolic abnormalities. 0.9 % saline is the crystalloid fluid of choice and initially is administered at ml/kg for the first 1-2 hours and then as clinically indicated. Care should be taken not to correct the hyponatremia faster than meq/dl/day. Rapidly acting glucocorticoids such as Dexamethasone Sodium-Phosphate are given at super-physiological doses, 2-4 mg/kg IV, to help improve vascular and intestinal integrity. These super-physiological doses may need to be given every 2-6 hours. Dexamethasone is not detected as cortisol so if clinically indicated it can be administered prior to obtaining a baseline cortisol or performing an ACTH stimulation test.

4 Metabolic complications of an acute adrenal crisis also include hyperkalemia, hypoglycemia and academia. Hyperkalemia can be a life threatening complication of a hypo adrenal crisis that warrants immediate attention. Regular insulin ().5 U/kg) can be given along with dextrose (2-3 grams/unit insulin). Half of the dextrose is administered as an intravenous bolus and the remainder given as a CRI over 4-6 hours. This will induce an intracellular shift of serum potassium levels thereby reducing serum levels. If more immediate intervention is required for cardioprotection then 10% calcium gluconate ( 0.1 mg/kg) can be administered intravenously over minutes; however, the effect is short lived lasting on the order of less than 30 minutes. While administering calcium gluconate an electrocardiogram should be monitored for signs of bradycardia, S-T segment elevation or a shortened Q-T interval. Hypoglycemia is treated with ml/kg of 50% dextrose diluted with saline and administered as an intravenous bolus. 2.5% to 5.0% dextrose is the added to the replacement fluids as indicated. Acidemia usually resolves after fluid resuscitation. The goal is to have a venous ph of greater than 7.2 and a bicarbonate level of greater than 12 mmol/l. If the ph remains below 7.1 then bicarbonate therapy should be considered the dose is calculated as [0.3 x body weight in kg] x [24 measured HCO3]. One-quarter to one-half of the calculated dose is given over 4-6 hours. Very close monitoring of the patient in an acute crisis is vital to a successful outcome. At least every 30 minutes an exam should be performed as well as a blood gas, blood pressure and electrolyte assessment. Chronic therapy of Hypoadrenocorticism Mineralocorticoid replacement is only indicated for pets with primary hypoadrenocorticism showing the requisite electrolyte changes. Mineralocorticoid supplementation can be given orally, Fludrocortisone, or as an injection of DOCP (Percorten) either intramuscularly or subcutaneously. A typical dose for DOCP would be 2.2 mg/kg SQ about every 25 days. Electrolytes should be assessed at day 12 and 25. If they are abnormal at day 12 then the next dose should be increased by 10% and if they are only abnormal at day 25 then the dose should be decreased by 2 days. Dogs with atypical primary Hypoadrenocorticism may progress to the more typical disease requiring mineralocorticoids supplements too but this may take months to years to occur if it ever progresses to that point and this rarely happens. Glucocorticoids replacement therapy is indicated for pets with primary hypoadrenocorticism, secondary Hypoadrenocorticism, and atypical primary Hypoadrenocorticism. Physiological doses of Prednisone, 0.2 mg/kg/day, are administered to all hypo adrenal dogs. However, during times of stress higher doses may be indicated. Some patients with primary Hypoadrenocorticism may require lower doses of glucocorticoids in conjunction with their Mineralocorticoid supplements and occasionally the glucorticoid may even be able to be discontinued except during times of stress. Conclusion The clinician must understand the hypoadrenocorticism is a vague disease that is easily overlooked. This disease must be considered in any patient that is hypotensive and bradycardic. Additionally it should be considered in any patient with intestinal signs, no stress leukogram and either hypoalbuminemia, hypoglycemia or hypocholesterolemia. One must remember that

5 normal electrolytes do not exclude a diagnosis of hypoadrenocorticism. With early recognition and intervention this is a very treatable disease.