Hypoadrenocorticism in the Dog and Cat: An Overview

Katy M. Groover, DVM; Kenneth S. Latimer, DVM, PhD; Perry J. Bain, DVM, PhD; Carla L. Jarrett, DVM, MS; Kevin S. Stiffler, DVM

Class of 2004 (Groover) and Department of Pathology (Latimer), Department of Anatomy and Radiology (Jarrett), and Department of Small Animal Medicine and Surgery (Stiffler), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Incidence and Etiology of Hypoadrenocorticism

Hypoadrenocorticism, also know as Addison’s disease, is an uncommon endocrine disorder in dogs and is rarely observed in cats. Hypoadrenocorticism occurs most commonly in young to middle-aged dogs (average age of 4 years) of any breed with a predilection for females. A familial relationship has been demonstrated in Standard Poodles and a breed predilection to develop hypoadrenocorticism exists for the Bearded Collie, Airedale Terrier, Basset Hound, German Shepherd Dog, German Shorthaired Pointer, Great Dane, Saint Bernard, Springer Spaniel, and West Highland White Terrier. In cats, hypoadrenocorticism has been reported in young to middle age animals; neither a sex or breed predilection has been observed.¹

Hypoadrenocorticism is characterized by insufficient production of mineralocorticoids (primarily aldosterone) by the adrenal cortex (Fig. 1). Mineralocorticoids regulate body water and electrolyte homeostasis by promoting renal retention of sodium and excretion of potassium and/or glucocorticoids (cortisol). Hypoadrenocorticism usually results from disease affecting both adrenal cortices and requires destruction of 85-90% of the adrenocortical cells before clinical signs of glucocorticoid and mineralocorticoid deficiency become obvious. Two types of adrenocortical insufficiency exist and are designated as primary hypoadrenocorticism and secondary hypoadrenocorticism.

Figure 1. Histologic section of the adrenal gland, demonstrating the three zones of the cortex (zona glomerulosa, zona fasiculata and zona reticularis ) and the medulla (hematoxylin and eosin stain, 2.5x magnification).

Primary hypoadrenocorticism occurs from destruction of the adrenal cortex with resultant atrophy and fibrosis (Fig. 2). In humans, the most common cause is immune-mediated destruction of the adrenal cortex.^2,3 In dogs, the etiology usually is unknown but an immune-mediated is suspected. This form of disease is termed idiopathic hypoadrenocorticism. Other causes of primary hypoadrenocorticism include iatrogenic destruction of the adrenal cortex from Lysodren (o,p'DDD) therapy for Cushing’s disease (common), adrenal hemorrhage or infarction (rare), fungal infection (rare), trauma (rare), effacement of the adrenal gland by metastatic neoplasia (rare), and surgical adrenalectomy (uncommon). Regardless of the cause of primary hypoadrenocorticism, the results of the disease are a deficiency of mineralocorticoid and glucocorticoid production by the adrenal cortices, as well as an increased plasma concentration of adrenocorticotropic hormone (ACTH) due to the absence of negative feedback on the pituitary secretion of this hormone. The possibility exists that the outermost layer of the adrenal cortex (zona glomerulosa), which is responsible for mineralocorticoid production, may be spared. This condition results only in a glucocorticoid deficiency with an atypical presentation of primary Addison’s disease (hypoadrenocorticism).

Figure 2. Small adrenal glands from a dog that developed hypoadrenocorticism following treatment for Cushing's disease with o,p'DDD.

Secondary hypoadrenocorticism results from hyposecretion of glucocorticoids by the two innermost layers of the adrenal cortex (zona fasiculata and zona reticularis). In secondary hypoadrenocorticism, decreased secretion of ACTH by the pituitary occurs directly or as a consequence of decreased release of corticotropin releasing hormone (CRH) by the hypothalamus. Dogs with secondary hypoadrenocorticism usually do not have mineralocorticoid deficiency because ACTH has little trophic effect on the zona glomerulosa.⁴ Although rare, spontaneous disease may result from destructive lesions of the pituitary or hypothalamus including neoplasia, inflammation, or trauma. The most common of these possibilities is a large pituitary tumor that ultimately may result in simultaneous hypofunction of other endocrine organs such as the thyroid gland.¹ A more common cause of secondary hypoadrenocorticism is iatrogenic disease. Long term glucocorticoid administration may suppress ACTH secretion by the pituitary, resulting in atrophy of the adrenal glands. Cats may also develop adrenocortical atrophy after receiving megestrol acetate.¹

Clinical Signs of Hypoadrenocorticism

The clinical signs of hypoadrenocorticism are nonspecific and may be mistakenly attributed to a variety of common diseases such as renal disease, gastrointestinal disorders (i.e., Trichuris vulpis infestation), acute pancreatitis, and metabolic acidosis. The severity and duration of hypoadrenocorticism varies between dogs; the majority of patients have a history of chronic progressive medical problems for up to one year.³ Some dogs are presented in an acute adrenal crisis that constitutes a medical emergency. In either situation, most dogs often exhibit clinical signs prior to presentation that can be attributed to hypoadrenocorticism, but were not severe enough to warrant serious concern by the owner. Historically, owners observe anorexia (89%), lethargy (88%), weight loss (42%), vomiting (72%), diarrhea (36%), shaking or shivering (23%), weakness (69%), and/or collapse (29%). Physical findings include depression (87%), lethargy (88%), dehydration (42%), poor body condition (82%), bradycardia (25%), weak femoral pulses (22%), hypothermia (34%), abdominal pain (6%), melena or hematochezia (17%), and collapse (29%).^2,3 Most clinical findings can be associated with mineralocorticoid and/or glucocorticoid deficiency that can result in severe hypotonic dehydration due to excessive sodium loss and potassium retention.

Diagnostic Findings in Hypoadrenocorticism

The major diagnostic findings in hypoadrenocorticism are presented in Table 1.

Table 1. Clinicopathologic findings in hypoadrenocorticism.

Whenever a patient presents with bradycardia an electrocardiogram (ECG) should be performed. The ECG may demonstrate cardiac conduction disturbances related to hyperkalemia and immediate therapy can be instituted. The typical appearance of an ECG due to hyperkalemia may not always be present due to other concurrent electrolyte abnormalities, metabolic acidosis, and decreased tissue perfusion. ECG abnormalities that may be associated with hyperkalemia are presented in Table 2.

Table 2. Electrocardiogram (ECG) abnormalities associated with hyperkalemia.

Figure 3. Normal electrocardiogram from a healthy dog. The P wave and QRS complex are apparent. Normal rhythm is associated with a normal heart rate.	Figure 4. Electrocardiogram from a dog with hypoadrenocorticism and hyperkalemia. Bradycardia, an absence of P waves, and tall, peaked T waves are apparent.

Survey radiographs of dogs with hypoadrenocorticism may have one or more of the following abnormalities including microcardia, a narrow descending aorta or caudal vena cava, small cranial lobar pulmonary artery, hypoperfusion of the lung fields, and microhepatica.⁶ The severity of these changes usually reflects the severity of hypovolemia. These radiographic findings are not specific for hypoadrenocorticism but reflect hypovolemia of any origin.

Figure 5. Lateral (left) and ventrodorsal (right) survey thoracic radiographs of a dog with microcardia (a small cardiac shadow) secondary to hypoadrenocorticism and severe hypovoluemia.

Megaesophagus occasionally has been observed and is thought to originate from abnormal electrolyte levels that interfere with normal neuromuscular function or from decreased cortisol concentrations that result in muscular weakness.² Megaesophagus usually resolves following treatment of hypoadrenocorticism, but the presence of this condition is important in initial management of the patient.⁴

Ultrasound examination of the adrenal glands may be of benefit when hypoadrenocorticism is suspected in a critically ill patient.⁷ Ultrasound studies may demonstrate shorter and thinner adrenal glands in dogs with hypoadrenocorticism. Both poles of the left adrenal may be considerably thinner than normal, while the right adrenal gland may appear straight, losing its characteristic peanut shape. The two layer internal structure (cortex and medulla) of the adrenal gland may not be visualized on ultrasound examination of dogs with hypoadrenocorticsm.

Histopathology of the adrenal gland usually demonstrates adrenal atrophy and fibrosis.⁸ In humans with autoimmune hypoadrenocorticism, mononuclear cell infiltrates (lymphocytes, plasma cells, and macrophages) may be observed within the adrenal cortex on histologic sections. Several reports have described mononuclear cell infiltrates in dogs in addition to adrenal atrophy and fibrosis indicating a possible immune-mediated component of the disease.³

Figure 6. Histologic section of an adrenal gland from a dog with hypoadrenocorticism. The adrenal cortex is diminished in width and contains a lymphocytic infiltrate. Hematoxylin and eosin stain, 40x magnification.

Diagnostic Confirmation of Hypoadrenocorticism

Although certain diagnostic findings may be suggestive of hypoadrenocorticism, specific disease diagnosis requires determination of plasma cortisol concentrations before and after an ACTH stimulation test. This test measures the ability of the adrenal cortex to secrete endogenous cortisol in reponse to exogenous ACTH. A blood sample is collected prior to administration of ACTH to determine the baseline plasma cortisol concentration. ACTH gel (20 U) is administered intramuscularly or synthetic ACTH (Cosyntropin, 250 micrograms or one reconstituted vial) is administered intramuscularly or intravenously (it also has been reported that an intravenous dose of 5-10 micrograms/kg of synthetic ACTH intravenously will yield comparable results).⁴

If synthetic ACTH is used, the post ACTH blood sample should be collected one hour after the injection is administered. If ACTH gel is used, the post ACTH blood sample should be collected two hours after the injection is administered. These collection times approximate the peak plasma cortisol concentration after administration of exogenous ACTH.²

If the patient presents in an acute adrenal crisis with hypovolemic shock, the ACTH stimulation test can be performed several hours after the patient is stabilized. If glucocorticoids are to be used in the initial treatment of such patients, dexamethasone sodium phosphate will not interfere with plasma cortisol determinations. Other glucocorticoids, such as prednisone and prednisolone, may cross react with the cortisol assay.⁷ If the patient has been on glucocorticoids prior to presentation, dexamethasone sodium phosphate should be administered as an alternative therapy at least 24 hours before performing the ACTH stimulation test. Severe hypovolemia, if present, may interfere with absorption of the intramuscular ACTH because of decreased tissue perfusion, produce inaccurate ACTH stimulation test data.⁴

When interpreting the results of the ACTH stimulation test, absolute cortisol values should be interpreted rather than relative increases in plasma cortisol concentration.⁹ The resting cortisol concentration may be low or within the reference interval. Administration of ACTH incites a subnormal or negative response in dogs with hypoadrenocorticism. Baseline and post-ACTH samples with cortisol concentrations of < 2 micrograms/dl are diagnostic for hypoadrenocorticism.^2,3 Occasionally in dogs that have incomplete destruction of the adrenal cortex, the post-ACTH cortisol concentration may be >2 micrograms/dl. The ACTH stimulation test does not differentiate between primary and secondary hypoadrenocorticism.⁹ In order to distinguish adrenal dependent from pituitary dependent disease in dogs with abnormally decreased ACTH stimulation test results and normal electrolyte concentrations, the endogenous plasma ACTH concentration should be measured.⁴ Dogs with primary hypoadrenocorticism will have an increased plasma ACTH concentration due to the absence of negative feedback on the pituitary from cortisol secretion by the adrenal cortex. Dogs with secondary hypoadrenocorticism will have very low to undetectable plasma ACTH levels due to destruction of the pituitary or hypothalamus.^1,9

The corticotropin releasing hormone (CRH) stimulation test also is available. This test may provide useful information my measuring endogenous plasma ACTH concentration. Dogs with primary hypoadrenocorticism will have ACTH levels that appear hyperresponsive to CRH. In contrast, dogs with secondary hypoadrenocorticism will not respond to CRH stimulation.⁹ If secondary hypoadrenocorticism is suspected, visualization of the pituitary should be attempted to determine the etiology of disease.¹

Treatment for Hypoadrenocorticism

Acute adrenocortical insufficiency should be treated as a medical emergency. If an Addisonian crisis is suspected based on initial evaluation, delaying treatment until all laboratory results are available could result in death. Before initiating therapy, both blood and urine samples should be collected for diagnostic evaluation.

The most important component of initial treatment is fluid therapy to restore blood volume. Most dogs in an acute crisis are severely hypovolemic due to the inability to retain sodium and water and excrete potassium. Intravenous 0.9% NaCl is the most appropriate choice for fluid replacement with the additional benefit of directly correcting the hyponatremia and hypochloremia. The dilutional effect of intravenous fluids also will decrease potassium concentrations in the blood. If 0.9% NaCl is unavailable, lactated Ringer's solution (LRS) may be used. The potassium concentration of LRS is only 4 mEq/L and is not detrimental to the patient because of the dilutional effect of fluid administration with improved renal perfusion and function. Fluid therapy should be instituted 60-80 ml/kg/hr for the first few hours until blood volume has been restored (this rate of fluid therapy is equivalent to that used to treat shock). Based on clinical status, response to treatment, urine output, and repeated electrolyte values, the fluid rate should be decreased to a maintenance rate over several days.^1-3

Intravenous glucocorticoids are also an important component of therapy but may be delayed initially if an ACTH stimulation test is planned. If delayed administration of glucocorticoids is not an option, dexamethasone sodium phosphate (2-4 mg/kg) may be given intravenously to prevent interference with the ACTH stimulation test.4 If the patient is vomiting, parenteral supplementation of glucocorticoids is continued every 2-6 hours or as needed based on the patient's clinical status.

Adequate fluid therapy and administration of intravenous glucocorticoids usually are sufficient to stabilize the patient until oral mineralocorticoid therapy can be instituted. If mineralocorticoid supplementation is needed in an acute crisis to restore normal electrolyte balance, an injection of desoxycorticosterone pivalate (2.2 mg/kg) can be given intramuscularly. If hydrocortisone succinate or cortisone is used as the initial parenteral glucocorticoid, sufficient mineralocorticoid activity is provided for 24 hours.¹ Rarely, additional therapy may be required to correct the hyperkalemia, hypoglycemia, and mild metabolic acidosis. If adequate fluid therapy and glucocorticoids do not correct the hyperkalemia and resultant cardiac conduction disturbances within the first 30-60 minutes of treatment, either a 10% glucose solution (4-10ml /kg body weight IV over 30-60 minutes) or regular insulin (0.5 U/kg) and glucose (3 g/U insulin) can be infused. Half of the total solution should be given as an intravenous bolus and the remainder of the solution should be added to the routine fluids and given over 6-8 hours.⁴ The electrocardiogram should be monitored until a normal cardiac rhythm returns. If the patient is not dehydrated and hypoglycemia continues to persist in the absence of hyperkalemia, 2.5% dextrose solution may be added to the fluid therapy.⁴ Metabolic acidosis usually is mild and is corrected with appropriate fluid therapy and increased renal perfusion. Sodium bicarbonate should be added to the intravenous fluids only if the serum concentration of bicarbonate decreases below 12 mEq/L or a blood pH of <7.2 is present. If sodium bicarbonate is administered, 25% of the calculated deficit should be administered over the first 6-8 hours.^2,4 This amount is usually sufficient to correct the acidosis.

Lifetime corticosteroid maintenance therapy should be initiated for patients that have recovered from an acute adrenocortical crisis or for patients that present with chronic hypoadrenocorticism. Dogs with primary hypoadrenocorticism need lifetime supplementation with mineralocorticoid and, possibly, glucocorticoid. Fludrocortisone acetate (initial dose 0.015-0.02 mg/kg/day) can be given orally as a single daily dose or divided into two doses given 12 hours apart. Electrolyte concentrations should be monitored weekly and the dosage of fludrocortisone acetate may be increased in increments of 0.05-0.01 mg/day. Once electrolyte concentrations are stable, they should be monitored periodically for the first 3-6 months of treatment and then 1-2 times yearly thereafter. The final maintenance dose of fludrocortisone acetate is usually in the range of 0.02-0.03 mg/kg daily.^1,3

Adverse drug effects, development of drug resistance, or financial constraints may necessitate an alternative therapy to fludrocortisone acetate. Decreasing the dose of fludrocortisone acetate and adding salt to the diet¹ or using injectable desoxycorticosterone pivilate (DOCP, 2.2 mg/kg every 25 days IM or SQ) has been suggested. If DOCP is chosen as an alternative mineralocorticoid therapy, after the first 2 to 3 injections have been administered, electrolyte concentrations should be measured two, three, and four weeks post-injection to determine the drug's duration of action in the patient. The duration of action varies between dogs but is usually 3 to 4 weeks.⁴ Once electrolyte concentrations are stable, they should be monitored prior to each injection to allow adjustment of the drug dosage as needed.

Lifetime daily glucocorticoid maintenance is only required in 50% of dogs with primary hypoadrenocorticism that are being treated with fludrocortisone acetate; however, initial glucocorticoid therapy is recommended with oral prednisone or prednisolone (0.2mg/kg/day).³ During times of stress, dogs with hypoadrenocorticism may need 2 to 4 times the maintenance dose of glucocorticoids. Some dogs may be gradually tapered off of daily maintenance regimen of prednisone, but still require supplementation during stressful periods. Owner awareness of hypoadrenocorticism and recognition of stress are very important for correct drug supplementation and prevention of future Addisonian crises. Dogs with secondary hypoadrenocorticism only require lifetime supplementation with glucocorticoids. In addition, glucocorticoid dosages should be increased during stress.^2,3

Prognosis

The prognosis for primary hypoadrenocorticism is excellent if the disease is diagnosed early and appropriate therapy is instituted. The clinical prognosis of secondary hypoadrenocorticism depends on the etiology of the disease.

References

1. Rijnberk A (ed): Clinical Endocrinology of Dogs and Cats. Kluwer Academic Publishers, The Netherlands, 1996, pp. 61-73.

2. Feldman EC, Nelson RW: Canine and Feline Endocrinology and Reproduction, 2nd ed. W. B. Saunders Co., Philadelphia, 1996, pp. 267-305

3. Ettinger SJ, Feldman EC: Textbook of Veterinary Internal Medicine, 5th ed, vol 2. W. B. Saunders Co., Philadelphia, 2000, pp.1488-1498.

4. Kintzer PP, Peterson ME: Primary and secondary canine hypoadrenocorticism. Vet Clin N Am: Small Anim Pract 1997; 27:349-357.

5. Phillips SL, Polzin DJ: Clinical disorders of potassium homeostasis. Vet Clin N Am: Small Anim Pract 1998; 28:552.

6. Melian C, Stefanacci J, Peterson ME, Kintzer PP: Radiographic findings in dogs with naturally occurring primary hypoadrenocorticism. J Am Vet Med Assoc 1999

7. Hoeranf A, Reusch C: Ultrasonographic evaluation of the adrenal glands in six dogs with hypoadrenocorticism. J Am Vet Med Assoc 1999; 35: 214-218.; 35:208-212.

8. Tidwell AS, Penninck DG, Besso JG: Imaging of adrenal gland disorders. Vet Clin N Am: Small Anim Pract 1997; 27: 246.

9. Ferguson DC, Hoenig M: Endocrine system. In: Latimer KS, EA Mahaffey, KW Prasse. Duncan and Prasse's Veterinary Laboratory Medicine: Clinical Pathology, 4th ed. Iowa State Press, Ames, 2003, pp. 295-300

Acknowledgement

The image at top of manuscript, "Puppies 2" by Jenny Newland, is from All Posters.com

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