Updates on hypoadrenocorticism
This review will help you better recognize and treat affected patients.
Hypoadrenocorticism may be difficult to recognize because of its varied clinical presentation. Furthermore, it may not be first on your differential diagnosis list because it is a relatively uncommon endocrine disease in dogs. However, it is important to be able to quickly identify this disease since prompt diagnosis and treatment can result in an excellent long-term prognosis. To help you better recognize and treat affected patients, this review discusses the etiology, diagnosis, and treatment of the different types of hypoadrenocorticism in dogs.
TYPES OF HYPOADRENOCORTICISM
In the adrenal cortex, glucocorticoids are produced in the zona fasciculata and zona reticularis, and mineralocorticoids are produced in the zona glomerulosa. Glucocorticoid production is stimulated by ACTH from the pituitary gland. Mineralocorticoids, on the other hand, are released in response to either hypovolemia, which triggers the renin-angiotensin system, or hyperkalemia, which directly stimulates adrenocortical tissue.1,2
Photo by Mark McDonald
Hypoadrenocorticism, also known as Addison's disease, is caused by either destruction of the adrenal cortex (primary hypoadrenocorticism) or a lack of ACTH release from the pituitary gland (secondary hypoadrenocorticism).3 Primary hypoadrenocorticism may result in a deficiency of glucocorticoids, mineralocorticoids, or both.1-3 In our experience, some dogs that initially have primary glucocorticoid deficiency (i.e. adrenal dysfunction) alone will eventually develop mineralocorticoid deficiency, but there are reports of dogs with primary glucocorticoid deficiency having clinically adequate mineralocorticoid production for years after initial diagnosis.4-7 Secondary hypoadrenocorticism (i.e. pituitary dysfunction) results in glucocorticoid deficiency only. The mineralocorticoids are spared since ACTH has limited effect on the zona glomerulosa.3 Mineralocorticoid deficiency without concurrent glucocorticoid deficiency is rare in dogs.3
Immune-mediated destruction of the adrenal cortex is the most common cause of primary hypoadrenocorticism.2,3 Other less common causes include neoplasia, thromboembolism, and granulomatous disease.2 Secondary hypoadrenocorticism may develop from pituitary damage due to neoplasia, inflammation, or trauma.2,5,8 Iatrogenic hypoadrenocorticism may result from the administration of adrenocorticolytic drugs such as mitotane or long-term glucocorticoid therapy.9
Hypoadrenocorticism is most often diagnosed in young to middle-aged female dogs but has been recognized in both male and female dogs between 4 months and 14 years of age.6,8 Standard poodles, Portuguese water dogs, Great Danes, rottweilers, West Highland white terriers, and Wheaton terriers are some of the overrepresented breeds.8,10 Hypoadrenocorticism may be inherited in certain breeds, such as Portuguese water dogs, and a complete genetic evaluation of hypoadrenocorticism is being investigated in many breeds.10
Clinical signs and the findings from a physical examination, complete blood count (CBC), serum chemistry profile, and urinalysis vary depending on the type of deficiency present.
Glucocorticoids are important for maintaining homeostasis, especially during stress. They play a role in metabolizing glucose, fats, and proteins; stimulating erythropoiesis; and regulating the immune system.1,6 The most common clinical signs of glucocorticoid deficiency include lethargy, weakness, anorexia, weight loss, vomiting, and diarrhea (Table 1).4,7,11 Other less common clinical signs include polyuria and polydipsia, exercise intolerance, and seizures.7,12 Clinical signs may be intermittent and associated with stressful events such as boarding, grooming, and medical evaluation. Physical examination findings in dogs with glucocorticoid deficiency are nonspecific and can include weakness and thin body condition.6
Table 1: Clinical Signs in Dogs with Glucocorticoid or Glucocorticoid and Mineralocorticoid Deficiency*
Gastrointestinal (GI) signs are common in dogs with glucocorticoid deficiency because glucocorticoids are important for maintaining GI mucosal health, GI motility, and colonic sodium absorption.1,7,8 Hypocortisolemia may potentiate mucosal ulceration and hemorrhage as a result of decreased vascular integrity.6 Exercise intolerance or seizures may develop if severe hypoglycemia occurs; however, hypoglycemia is typically mild.12
Common findings on a CBC include normocytic, normochromic, nonregenerative anemia and a lack of a stress leukogram (Table 2).7 Glucocorticoids, along with other hormones, stimulate erythropoiesis, so glucocorticoid deficiency may result in anemia. GI hemorrhage can further contribute to anemia in dogs with hypocortisolemia.6,7,11 A lack of a stress leukogram most commonly manifests as a normal or increased lymphocyte count with or without eosinophilia.5,6
Table 2: Laboratory Findings and Their Proposed Pathogenesis in Dogs with Glucocorticoid Deficiency or Glucocorticoid and Mineralocorticoid Deficiency*
Serum chemistry profile abnormalities in dogs with glucocorticoid deficiency include hypoalbuminemia, hypocholesterolemia, hypoglycemia, and mild hyponatremia.6,7 Impaired absorption of nutrients, protein-losing enteropathy, and decreased albumin production may contribute to the hypoalbuminemia.13 Hypocholesterolemia is thought to result from altered lipid absorption.6 Hypoglycemia may be due to blunted gluconeogenesis and increased glucose uptake and use by peripheral tissues.6,12 Mild hyponatremia may develop because of decreased vasopressin secretion and blunted colonic sodium absorption. In healthy dogs, glucocorticoids inhibit vasopressin release; therefore, with glucocorticoid deficiency, inappropriate vasopressin secretion may cause water retention and result in a dilutional hyponatremia.1,7
Mineralocorticoids promote sodium and water retention and potassium excretion to regulate intravascular volume and serum potassium concentrations, respectively.1 The clinical signs associated with mineralocorticoid deficiency can range from mild to severe.8 Dogs with mineralocorticoid deficiency may have a history of weakness, lethargy, polyuria and polydipsia, tremors, or collapse.1,8 Most of these clinical signs are the result of hypovolemia, hypotension, or hyperkalemia. Hyponatremia may alter resting membrane potentials of skeletal muscle, leading to tremors.1 Physical examination findings may include weakness, mild to severe dehydration, hypothermia, weak pulses, and bradycardia.4,8
The classic serum chemistry profile abnormalities associated with mineralocorticoid deficiency are hyponatremia and hyperkalemia since mineralocorticoids regulate sodium reabsorption and potassium excretion in the renal tubules (Table 2). Hyponatremia can be exacerbated by hypovolemia-induced vasopressin release and free water retention.1 A sodium to potassium ratio < 27:1 is consistent with mineralocorticoid deficiency; however, many diseases can decrease the sodium to potassium ratio in dogs. Thus, a low sodium to potassium ratio is not specific for hypoadrenocorticism or mineralocorticoid deficiency.14
Mineralocorticoid deficiency alone has a minimal effect on CBC results. Typically, CBC abnormalities in dogs with hypoadrenocorticism are related to either glucocorticoid deficiency or another underlying disease process.
Glucocorticoid and mineralocorticoid deficiency
Dogs with concurrent glucocorticoid and mineralocorticoid deficiency may have a combination of any of the previously mentioned clinical signs (Table 1), physical examination findings, and clinicopathologic abnormalities (Table 2). Other abnormalities include hypochloremia, azotemia, metabolic acidosis, hypercalcemia, and increased alanine aminotransferase and aspartate aminotransferase activities.4,7,8,15 Hypovolemia and consequential hypoperfusion of the kidneys or liver may result in prerenal azotemia or increased alanine aminotransferase and aspartate aminotransferase activities, respectively.1,8 The hyponatremia may lead to medullary washout and dilute urine, often in the face of dehydration.8
Take care when categorizing azotemia in patients with mineralocorticoid deficiency since many dogs will have isosthenuria or minimally concentrated urine in the face of prerenal azotemia. Lactic acid production and decreased renal hydrogen ion secretion contribute to metabolic acidemia.4 Hypercalcemia may develop because of decreased renal excretion of calcium and hemoconcentration, but the exact pathogenesis is unknown.15
OTHER CLINICAL FINDINGS
Several imaging and electrocardiographic findings may be recognized in dogs with hypoadrenocorticism. However, not all dogs with hypoadrenocorticism will have these diagnostic findings.
Radiographic changes may include microcardia, a narrowed caudal vena cava or descending aorta, hypoperfused lung fields, and microhepatia. These findings are secondary to hypovolemia.3,16,17 Rarely, megaesophagus is recognized.6,16 Bilateral atrophy of the adrenal glands may be noted on ultrasonographic evaluation.17
Atrial standstill, ventricular premature contractions, atrial fibrillation, or atrioventricular block may be documented in patients with hyperkalemia when the serum potassium concentration is > 7 mmol/L.2,3 In severe cases, ventricular fibrillation or asystole may develop.18
There are two methods to assess adrenal function: dynamic testing and measurement of basal cortisol concentrations (Table 3).
Table 3: Diagnostic Test Results in Dogs with Hypoadrenocorticism*
ACTH stimulation test. Dynamic testing with an ACTH stimulation test is the gold standard for diagnosing cortisol deficiency.1 The test compares plasma cortisol concentrations before and after stimulation with synthetic ACTH (cosyntropin).1 Natural ACTH (ACTH gel) can also be used, but because of limited availability and the potential to induce immunologic reactions, cosyntropin is preferred.19
To perform an ACTH stimulation test, collect a blood sample to measure a baseline cortisol concentration. Then give 0.25 mg/dog of cosyntropin intramuscularly or intravenously, and collect a blood sample 60 or 90 minutes later to measure the post-ACTH cortisol concentration.1 In healthy dogs, similar post-cosyntropin serum cortisol concentrations are obtained regardless of whether cosyntropin is given intravenously or intramuscularly or whether samples are collected 60 or 90 minutes after cosyntropin administration.20 A post-ACTH plasma cortisol concentration < 2 μg/dl indicates a lack of an appropriate response and is diagnostic for hypoadrenocorticism.1
To minimize the cost of cosyntropin, an intravenous dose of 0.005 mg/kg may be used since this dose results in a similar degree of stimulation in healthy dogs and dogs with hyperadrenocorticism.19,21 Reconstituted cosyntropin can be stored frozen (-4 F [-20 C]) in plastic syringes for up to six months.22 Although no published data confirming this exist, some veterinarians store reconstituted cosyntropin in the refrigerator (39.2 F [4 C]) for up to 24 hours without a perceived change in potency.
Basal cortisol concentration. Measuring a basal cortisol concentration has been proposed as a diagnostic test for hypoadrenocorticism in dogs. In one study of 13 dogs with hypoadrenocorticism and 110 healthy dogs, a basal cortisol concentration ≤ 1 μg/dl had a sensitivity of 100% and specificity of 98.2% for hypoadrenocorticism.23 The same study found that using a cutoff of ≤ 2 μg/dl for the basal cortisol concentration had a negative predictive value of 100%.23 These data indicate that basal cortisol concentrations can be used to rule out hypoadrenocorticism in dogs with appropriate clinical signs that are not receiving drugs that could potentially alter cortisol secretion such as glucocorticoids, mitotane, trilostane, or ketoconazole. However, given the low disease prevalence of hypoadrenocorticism in dogs, this test had a poor positive predictive value.23 Since basal cortisol concentrations have a poor positive predictive value and hypoadrenocorticism requires life-long therapy, ACTH stimulation testing is still the test of choice for definitively diagnosing hypoadrenocorticism in dogs.
CAR. The ratio of basal cortisol concentration to endogenous ACTH concentration (CAR) is an additional method to diagnose primary hypoadrenocorticism.24 The reference interval CAR in healthy dogs is 1.1 to 26.24 Dogs with primary hypoadrenocorticism should have low cortisol and high ACTH plasma concentrations, resulting in a low CAR. In one study of 22 dogs with primary hypoadrenocorticism, the CAR was 0.003 to 0.17, well below the reference interval.24
This test allows for a specific diagnosis of primary hypoadrenocorticism in dogs with a single blood sample. Since endogenous ACTH concentrations will be low in dogs with secondary hypoadrenocorticism, CAR does not help differentiate normal dogs from dogs with secondary hypoadrenocorticism.
Endogenous ACTH concentrations. After definitive diagnosis, endogenous ACTH concentrations may be used to differentiate primary from secondary cortisol deficiency.1 Since dogs with primary glucocorticoid deficiency may develop a mineralocorticoid deficiency whereas dogs with secondary glucocorticoid deficiency should not, differentiating primary from secondary hypoadrenocorticism may help guide clinical monitoring.3,13 Dogs with pituitary dysfunction resulting in secondary hypoadrenocorticism should have low endogenous ACTH concentrations. On the other hand, dogs with primary hypoadrenocorticism should have a normally functioning pituitary gland, so their ACTH concentrations should be increased in response to hypocortisolemia.1
Mineralocorticoid deficiency is easily diagnosed based on recognizing hyperkalemia and hyponatremia (Table 3).1 Dogs with a cortisol deficiency that lack hyponatremia and hyperkalemia do not have a clinically important mineralocorticoid deficiency, so additional diagnostic testing for aldosterone deficiency is rarely indicated.
Measuring the basal aldosterone concentration is not a reliable way to diagnose aldosterone deficiency because of an overlap in the concentrations between healthy dogs and those with an aldosterone deficiency.24 The post-ACTH stimulation aldosterone concentration has been investigated as a means to assess zona glomerulosa function, but findings are inconsistent and vary with a dog's age.25,26
The main method of documenting mineralocorticoid deficiency, besides recognizing hyperkalemia and hyponatremia, is the aldosterone to renin ratio.24 The reference interval for this ratio in healthy dogs is 0.1 to 1.5.24 In a normal dog, hypovolemia stimulates renin with resultant aldosterone secretion. Dogs that have a mineralocorticoid deficiency due to adrenal dysfunction should have low aldosterone and high renin plasma concentrations and, consequently, a low aldosterone to renin ratio. In one study, dogs with primary hypoadrenocorticism (both glucocorticoid and mineralocorticoid deficiency) had ratios ranging from 0.002 to 0.08.24
The clinical presentation for hypoadrenocorticism can vary from mild, vague clinical signs to severe critical illness. For dogs that present with mild clinical signs, maintenance therapy may be initiated immediately. Dogs that present in crisis will require more aggressive initial management.
The initial main objectives of therapy in critically ill dogs are reversing life-threatening arrhythmias, administering intravascular volume resuscitation, replacing glucocorticoids, and correcting hyperkalemia (Table 4).9
Table 4: Emergency Treatment of Critically Ill Dogs with Hypoadrenocorticism*
Administer fluid therapy
With these objectives in mind, place an intravenous catheter, and administer intravenous fluids, typically 0.9% sodium chloride solution. Many patients will require aggressive fluid resuscitation to correct hypovolemia, and their fluid requirements will fluctuate over the first few days of therapy.2 Tailor the amount of intravenous fluid administered to the patient's specific needs based on the evaluation of physiologic end points such as heart rate, blood pressure, central venous pressure, and mental status. For dogs with life-threatening cardiac arrhythmias secondary to hyperkalemia, initiate immediate treatment (see "Treat hyperkalemia").
It is essential that glucocorticoids are administered with an intravenous injection of dexamethasone sodium phosphate, prednisolone sodium succinate, or hydrocortisone phosphate when hypoadrenocorticism is suspected in a critically ill dog (Table 4).13 Continue injectable glucocorticoids until maintenance therapy is instituted.
ACTH stimulation test timing. Ideally, an ACTH stimulation test should be performed before you administer glucocorticoids. However, glucocorticoids should not be withheld pending the results of the test. If an ACTH stimulation test cannot be performed immediately, administer glucocorticoids until hypoadrenocorticism is confirmed. Dexamethasone is an ideal glucocorticoid in this situation since it is rapid-acting and, unlike other glucocorticoids, will not directly interfere with the cortisol assay.9,13 A single intravenous injection of dexamethasone at ≤ 1 mg/kg does not significantly decrease post-ACTH stimulation plasma cortisol concentrations 24 hours after dexamethasone administration in dogs.27
Although 5 mg/kg dexamethasone administered intravenously significantly decreases post-ACTH stimulation plasma cortisol concentrations 24 hours after the dexamethasone administration (control dogs' cortisol concentrations 15.1 ± 3.1 μg/100 ml; dexamethasone-treated dogs' cortisol concentrations 10.6 ± 1.7 μg/100 ml), this degree of suppression would be unlikely to result in an inappropriate diagnosis of hypoadrenocorticism.27 However, it is important to consider that long-term glucocorticoid administration will eventually lead to adrenal cortical atrophy and a lack of cortisol production post-ACTH stimulation. For this reason, ACTH stimulation testing should be performed as soon as possible in any dog suspected of having hypoadrenocorticism, and the results should be interpreted in light of previous exogenous glucocorticoid administration.
Any patient with hyperkalemia-induced clinical signs or electrocardiographic signs of cardiotoxicity should receive immediate therapy with intravenous 10% calcium gluconate (Table 4). Calcium gluconate affects the transmembrane potential of myocardial cells, protecting the heart from potassium's toxic effects.2,9 The protective effect will last 30 to 60 minutes, which should allow enough time for other potassium-lowering therapies to start working.9 All patients with hyperkalemia should be given intravenous fluid therapy. Fluid diuresis lowers serum potassium concentrations through dilution and by promoting renal potassium excretion. For patients with mild hyperkalemia and no signs of cardiotoxicity, intravenous fluid therapy alone may correct hyperkalemia.3
For patients with moderate to severe hyperkalemia or signs of cardiotoxicity, additional treatments such as dextrose with or without insulin or sodium bicarbonate are indicated. Insulin drives potassium into the cells, lowering serum potassium concentrations. Insulin should always be administered with dextrose (Table 4). In nondiabetic patients, dextrose may be given to stimulate endogenous insulin release with less risk of iatrogenic hypoglycemia.2 Similarly, sodium bicarbonate drives potassium into the cells, lowering serum potassium concentrations.9 Monitor patients with moderate to severe hyperkalemia with an electrocardiogram (ECG) and serial serum potassium concentration measurements.
Additional treatment considerations
Metabolic acidosis is almost always corrected with intravenous fluid therapy alone.3 However, for patients with a severe acidemia (pH < 7.1) that is unresponsive to volume resuscitation, sodium bicarbonate can be administered.4 For patients with clinically important hypoglycemia, dextrose can be administered.3,4 Make sure to monitor patients for acute renal failure and treat appropriately.9
Myelinolysis of the central thalamus may develop after rapid correction of chronic hyponatremia in dogs.28 Clinical signs of this neurologic condition develop five days after rapid correction and include obtundation, ataxia, tetraparesis, decreased sensory perception, and hypermetria.28 To avoid myelinolysis, correction of chronic hyponatremia should not exceed a 10 to 12 mEq/L increase in serum sodium concentration in a 24-hour period.28
Hypoadrenocorticism is a dynamic condition, and a patient's status may rapidly change, resulting in a life-threatening situation. Careful serial monitoring of physical examination parameters, blood pressure, central venous pressure, an ECG, urine production, serum electrolytes, and renal parameters is prudent. Once appropriate treatment is initiated, many worrisome clinicopathologic abnormalities such as azotemia, hyponatremia, and hyperkalemia will resolve.
Once a patient's hemodynamic parameters and electrolytes have stabilized and the patient is eating and drinking, initiate maintenance therapy.
Since mineralocorticoid deficiency alone is rare, almost all dogs with hypoadrenocorticism require glucocorticoid supplementation. Prednisone or prednisolone is used to maintain glucocorticoid replacement and is initially started at 0.2 mg/kg daily (Table 5); adjust the dose based on clinical signs.3
Table 5: Maintenance Treatment of Dogs with Hypoadrenocorticism*
Other oral, short-acting glucocorticoids may be used as well, and you should adjust the dose based on the relative potency of that particular glucocorticoid (Table 6). For example, dexamethasone has about seven times more glucocorticoid activity than prednisone does. Thus, you would divide the prednisone dose by seven to determine the equivalent dexamethasone dose. Avoid long-acting depot formulations of injectable glucocorticoids because of varied serum concentrations and durations of action. The dose of glucocorticoids should be at least doubled during periods of stress such as grooming and medical evaluation.3,4 Clinical signs such as anorexia, lethargy, vomiting, or diarrhea indicate inadequate glucocorticoid administration.1
Table 6: Glucocorticoid and Mineralocorticoid Properties*
If mineralocorticoid deficiency causing hyperkalemia and hyponatremia is present, institute treatment with desoxycorticosterone pivalate (DOCP) (Percorten—Novartis Animal Health) or fludrocortisone acetate (Table 5).
DOCP. DOCP is a long-acting injectable mineralocorticoid given at a dosage of 2 mg/kg intramuscularly or subcutaneously about every 25 days.4,9,29 However, the duration of action can vary from 14 to 35 days,13 so adjust the dose and administration frequency as needed; many dogs require an increase in dose over the first six to 12 months after diagnosis.3 Monitor serum electrolyte concentrations 14, 21, and 28 days after DOCP administration and then as needed to determine DOCP's duration of action and efficacy.3 Typically, adjusting the dose or frequency by 10% will alleviate electrolyte abnormalities.
Many veterinarians prefer DOCP over fludrocortisone since DOCP is a long-acting injectable medication that circumvents problems with day-to-day owner compliance and drug bioavailability. DOCP has negligible glucocorticoid activity and should always be administered in conjunction with glucocorticoid therapy.13
Fludrocortisone. Fludrocortisone is a short-acting oral mineralocorticoid and is administered at a daily dose of 0.01 to 0.02 mg/kg.1,3,4,9 Similarly to DOCP, the dose should be adjusted based on serum electrolyte concentrations. The dose may be increased in 0.05- to 0.1-mg/day increments as needed based on serum electrolyte concentrations.3
Fludrocortisone has some glucocorticoid activity, but about 50% of dogs may need additional glucocorticoid supplementation.4 In some dogs, the amount of fludrocortisone that effectively maintains sodium and potassium concentrations may result in clinical signs of glucocorticoid excess such as polyuria and polydipsia.1,3 In this situation, consider administering DOCP and an oral glucocorticoid such as prednisone. When changing from fludrocortisone to DOCP, gradually taper the fludrocortisone over four to five days after DOCP is administered.1
Hypoadrenocorticism can be a frustrating disease since its presentation is often ambiguous. The disease can be life-threatening if not rapidly recognized and treated and requires lifelong management. Nevertheless, with good client compliance, the prognosis is favorable.2,13 Relative adrenal insufficiency, or RAI, is a condition that should be considered in any dog with sepsis and hypotension that is refractory to volume resuscitation (see "Relative hypoadrenocorticism: An emerging concern"). With additional research, early recognition of dogs with RAI and administration of appropriate therapy may decrease mortality in dogs with sepsis and possibly other forms of critical illness.
Relative hypoadrenocorticism: An emerging concern
Christine A. Gaydos, DVM
Webster Groves Animal Hospital
8028 Big Bend Blvd.
Webster Groves, MO 63119
Amy DeClue, DVM, MS, DACVIM
Department of Veterinary Medicine and Surgery
College of Veterinary Medicine
University of Missouri
Columbia, MO 65211
1. Feldman EC, Nelson RW. Hypoadrenocorticism. In: Canine and feline endocrinology and reproduction. 2nd ed. Philadelphia, Pa: WB Saunders, 1996;266-302.
2. Meeking S. Treatment of acute adrenal insufficiency. Clin Tech Small Anim Pract 2007;22(1):36-39.
3. Kintzer PP, Peterson ME. Primary and secondary canine hypoadrenocorticism. Vet Clin North Am Small Anim Pract 1997;27(2):349-357.
4. Greco DS. Hypoadrenocorticism in small animals. Clin Tech Small Anim Pract 2007;22(1):32-35.
5. Sadek D, Schaer M. Atypical Addison's disease in the dog: a retrospective study of 14 cases. J Am Anim Hosp Assoc 1996;32(2):159-163.
6. Lifton SJ, King LG, Zerbe CA. Glucocorticoid deficient hypoadrenocorticism in dogs: 18 cases (1986-1995). J Am Vet Med Assoc 1996;209(12):2076-2081.
7. Thompson AL, Scott-Moncrieff JC, Anderson JD. Comparison of classic hypoadrenocorticism with glucocorticoid-deficient hypoadrenocorticism in dogs: 46 cases (1985-2005). J Am Vet Med Assoc 2007;230(8):1190-1194.
8. Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979-1993). J Am Vet Med Assoc 1996;208(1):85-91.
9. Schaer M. The treatment of acute adrenocortical insufficiency in the dog. J Vet Emerg Crit Care 2001;11:7-14.
10. Oberbauer AM, Bell JS, Belanger JM, et al. Genetic evaluation of Addison's disease in the Portuguese Water Dog. BMC Vet Res 2006;2:15.
11. Rogers W, Strauss J, Chew D. Atypical hypoadrenocorticism in three dogs. J Am Vet Med Assoc 1981;179(2):155-158.
12. Lane IF, Matwichuk CL, Carpenter LG, et al. Profound postanesthetic hypoglycemia attributable to glucocorticoid deficiency in 2 dogs. Can Vet J 1999;40:497-500.
13. Herrtage ME. Hypoadrenocorticism. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 6th ed. St. Louis, Mo: Elsevier, 2005;1612-1622.
14. Pak SI. The clinical implication of sodium-potassium ratios in dogs. J Vet Sci 2000;1(1):61-65.
15. Peterson ME, Feinman JM. Hypercalcemia associated with hypoadrenocorticism in sixteen dogs. J Am Vet Med Assoc 1982;181(8):802-804.
16. Melián C, Stefanacci J, Peterson ME, et al. Radiographic findings in dogs with naturally-occurring primary hypoadrenocorticism. J Am Anim Hosp Assoc 1999;35(3):208-212.
17. Hoerauf A, Reusch C. Ultrasonographic evaluation of the adrenal glands in six dogs with hypoadrenocorticism. J Am Anim Hosp Assoc 1999;35(3):214-218.
18. Riesen SC, Lombard CW. ECG of the month. Atrial fibrillation secondary to hypoadrenocorticism. J Am Vet Med Assoc 2006;229(12):1890-1892.
19. Kerl ME, Peterson ME, Wallace MS, et al. Evaluation of a low-dose synthetic adrenocorticotropic hormone stimulation test in clinically normal dogs and dogs with naturally developing hyperadrenocorticism. J Am Vet Med Assoc 1999;214(10):1497-1501.
20. Behrend EN, Kemppainen RJ, Bruyette DS, et al. Intramuscular administration of a low dose of ACTH for ACTH stimulation testing in dogs. J Am Vet Med Assoc 2006;229(4):528-530.
21. Frank LA, DeNovo RC, Kraje AC, et al. Cortisol concentrations following stimulation of healthy and adrenopathic dogs with two doses of tetracosactrin. J Small Anim Pract 2000;41(7):308-311.
22. Frank LA, Oliver JW. Comparison of serum cortisol concentrations in clinically normal dogs after administration of freshly reconstituted versus reconstituted and stored frozen cosyntropin. J Am Vet Med Assoc 1998;212(10):1569-1571.
23. Lennon EM, Boyle TE, Hutchins RG, et al. Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005). J Am Vet Med Assoc 2007;231(3):413-416.
24. Javadi S, Galac S, Boer P, et al. Aldosterone-to-renin and cortisol-to-adrenocorticotropic hormone ratios in healthy dogs and dogs with primary hypoadrenocorticism. J Vet Intern Med 2006;20(3):556-561.
25. Willard MD, Refsal K, Thacker E. Evaluation of plasma aldosterone concentrations before and after ACTH administration in clinically normal dogs and in dogs with various diseases. Am J Vet Res 1987;48(12):1713-1718.
26. Goy-Thollot I, Decosne-Junot C, Bonnet JM. Influence of aging on adrenal responsiveness in a population of eleven healthy beagles. Res Vet Sci 2007;82(2):195-201.
27. Kemppainen RJ, Sartin JL, Peterson, ME. Effects of single intravenously administered doses of dexamethasone on response to the adrenocorticotropic hormone stimulation test in dogs. Am J Vet Res 1989;50(11):1914-1917.
28. Churcher RK, Watson ADJ, Eaton A. Suspected myelinolysis following rapid correction of hyponatremia in a dog. J Am Anim Hosp Assoc 1999;35(6):493-497.
29. McCabe MD, Feldman EC, Lynn RC, Kass PH. Subcutaneous administration of desoxycorticosterone pivalate for the treatment of canine hypoadrenocorticism. J Am Anim Hosp Assoc 1995;31(2):151-155.
30. Cohn LA. Glucocorticoid therapy. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 6th ed. St. Louis, Mo: Elsevier, 2005;503-508.