Canine hypoadrenocorticism: managing difficult cases (Proceedings)

Hypoadrenocorticism (Addison's disease) results from failure of the adrenal glands to secrete glucocorticoids and mineralocorticoids. Most cases of hypoadrenocorticism are due to primary adrenal failure, resulting in deficiency of usually both cortisol and aldosterone from the adrenal cortex. More rarely, Addison's disease may be due to pituitary dysfunction resulting in a failure of ACTH secretion and pure glucocorticoid deficiency (secondary adrenal failure). In secondary hypoadrenocorticism, mineralocorticoid secretion is expected to be normal.

Clinical signs

Signalment

Seventy percent of dogs diagnosed with hypoadrenocorticism are female, and most are young to middle-aged dogs (mean 4 - 5 years). The disease is heritable in the Standard Poodle, Bearded Collie, Portuguese water dog and the Nova Scotia Duck Tolling Retriever (NSDTR) and in these breeds no obvious sex predisposition is evident. In the Standard Poodle, Portuguese Water dog, and NSDTR, the disease appears to be inherited as an autosomal recessive trait. Incidence of hypoadrenocorticism in the NSDTR is estimated to affect 1.4% of the population while in the Standard Poodle 8.6% of poodles in one study were affected.

History and physical examination

Clinical signs may be either acute or gradual in onset and often wax and wane. Owners may not realize how long their dog has been ill until treatment results in a dramatic improvement in activity level. Since 85-90% of adrenal reserve must be depleted before clinical signs are observed, it may require a stressful event to trigger clinical illness. Clinical signs may be very vague. Anorexia, vomiting, lethargy/depression, weakness, weight loss, diarrhea, shaking/shivering, polyuria, polydipsia, and abdominal pain may be observed. Most of these clinical signs can occur due to glucocorticoid deficiency alone. If mineralocorticoids are also deficient, the clinical signs tend to be more severe and polyuria, polydipsia, hypovolemic shock, collapse and dehydration are often present. Less common clinical signs include acute gastrointestinal hemorrhage, and seizures due to hypoglycemia or electrolyte derangement. The physical examination may be normal or may reveal lethargy, weakness, dehydration, bradycardia, weak pulses, decreased capillary refill time, and other evidence of hypovolemic shock

Diagnostic testing

Clinical pathology

A complete blood count may reveal a nonregenerative normocytic normochromic anemia, or the hematocrit may be increased due to dehydration. Eosinophilia, neutrophilia or lymphocytosis occur in only 20-30% of dogs with hypoadrenocorticism, but lack of a stress leukogram in a dog with systemic illness is common. A chemistry profile may reveal hyponatremia, hypochloremia, hyperkalemia, hypercalcemia, and hyperphosphatemia. These changes occur due to aldosterone deficiency with a resultant failure of the kidneys to conserve sodium. Other possible serum biochemical abnormalities include hypoalbuminemia, hypocholesterolemia, hypoglycemia, and increased liver enzymes. Specific gravity of the urine is commonly less than 1.030. The changes on the minimum data base in dogs with hypoadrenocorticism may initially mimic other disorders such as renal failure, hepatic disease, gastrointestinal disease, or insulinoma.

Serum electrolyte abnormalities

The majority of dogs with hypoadrenocorticism have the classic electrolyte changes of hyponatremia and hyperkaelina due to aldosterone deficiency. It is now recognized however, that a subset of dogs with hypoadrenocorticism lack these changes. In a retrospective study of dogs with hypoadrenocorticism, 24% of dogs lacked hyponatremia and hyperkalemia. In a study of 25 NSDTR, 32% lacked electrolyte abnormalities at the time of diagnosis. Reasons for normal electrolytes include secondary hypoadrenocorticism due to decreased ACTH secretion, selective destruction of the zona fasciculata and reticularis, or early stage disease in which there has not yet been complete destruction of the zona glomerulosa. Dogs with glucocorticoid deficient hypoadrenocorticism tend to be older, have a longer duration of clinical signs, and are more likely to be anemic, hypoalbuminemic and hypocholesterolemic. It is important for clinicians to recognize that an absence of the characteristic electrolyte changes does not exclude a diagnosis of hypoadrenocorticism. Conversely reliance on measurement of electrolytes alone for diagnosis of hypoadrenocorticism can be misleading, because there are many other causes of these electrolyte changes.

Na:K ratio

The Na:K ratio is usually low in dogs with hypoadrenocorticism, and this ratio may be useful to guide emergency diagnosis and treatment while waiting for definitive test results.

Imaging studies

Most untreated dogs with hypoadrenocorticism have one or more radiographic abnormalities on thoracic and abdominal radiographs including microcardia, small cranial lobar pulmonary artery, narrow posterior vena cava, or microhepatica. Occasional dogs may have evidence of megaesophagus. Most dogs with hypoadrenocorticism have a measurable reduction in size of the adrenal glands, and sometimes the adrenal glands cannot be identified on ultrasound.

Electrocardiogram

In dogs with hyperkalemia, abnormalities may be present on the electrocardiogram. These include a peaked T wave and shortening of the QT interval in mild hyperkalemia, widening of the QRS complex, decreased QRS amplitude, increased duration of the P wave, and increased P-R interval in moderate hyperkalemia, and loss of P waves and ventricular fibrillation or asystole in severe hyperkalemia.

Basal cortisol

Measurement a basal cortisol of >55 nmol/l is a useful test to exclude a diagnosis of hypoadrenocorticism. Measurement of a basal cortisol concentration is not adequate for confirmation of a diagnosis of hypoadrenocorticism, because some dogs have a low basal cortisol concentration but have an appropriate response to ACTH administration.

ACTH stimulation test

An ACTH stimulation test is necessary to confirm a diagnosis of hypoadrenocorticism because not all dogs with hypoadrenocorticism have the expected electrolyte changes, and because many other disorders may mimic the characteristic findings of Addison's disease. In dogs with hypoadrenocorticism, both the pre- and post- ACTH cortisol concentrations are usually less than 27 nmol/l, and both values should be less than the reference range for basal cortisol (usually 55 nmol/l) to confirm the diagnosis.

Acute treatment

Rapid treatment of dogs with suspected Addison's disease is vital especially if profound electrolyte abnormalities are present. Aims of treatment include correction of hypotension/hypovolemia, correction of electrolyte imbalances, provision of an immediate source of glucocorticoids, and correction of acidosis, hypoglycemia, and hypercalcemia.

The suggested procedure for dogs presenting with signs of hypovolemia in which Addison's disease is suspected is to immediately:

Place IV catheter in cephalic or jugular vein, and collect a blood sample for measurement electrolytes, and cortisol. Synthetic ACTH is then administered IV, and a second blood sample for measurement of cortisol collected 1 hour later. Fluid therapy (0.9% saline IV, 30 - 80 ml/kg/24 hours plus correction for dehydration) should be started immediately. Once the second blood sample has been collected, treatment with glucocorticoids can be begun if there is a high clinical suspicion of Addison's disease. If animal is in shock, administration of steroids should be at shock doses and this should take precedence over establishing an immediate diagnosis. The choice of mineralocorticoid depends upon the clinical status of patient (oral versus injectable), product availability, and confidence in diagnosis. In most cases electrolytes normalize with fluid therapy and glucocorticoids alone and immediate mineralocorticoid supplementation is not necessary. Long-term mineralocorticoid therapy can be initiated once the animal is stable and the diagnosis is confirmed. Other treatments that may be indicated in individual patients include synthetic colloids, blood transfusion, and IV dextrose. Parameters that should be monitored during treatment include serum electrolytes and acid-base status, urine output, ECG, blood pressure, and if possible central venous pressure. IV fluid therapy should be continued until the animal is fully rehydrated and oral intake is possible.

Maintenance therapy

Options for long term mineralocorticoid treatment include fludrocortisone or desoxycorticosterone pivalate. For both of these mineralocorticoids the dose should be titrated to effect. The dose of fludrocortisone typically needs to be increased over time whereas in many cases the dose of DOCP can be decreased over time. Dogs without electrolyte derangements do not require mineralocorticoid treatment, although electrolytes should be monitored frequently.

Prednisone is typically recommended for glucocorticoid replacement. The dose should then be tapered to the lowest dose that will control the clinical signs. It is important to avoid excess prednisone supplementation because this may result in manifestations of hyperadrenocorticism. Only 50% of dogs on fludrocortisone require supplemental prednisone, whereas most dogs on DOCP require prednisone at least every other day.

References

Famula TR; Belanger JM; et al. Heritability and complex segregation analysis of hypoadrenocorticism in the standard poodle. Journal of Small Animal Practice 2003;44:8-12.

Thompson AL; Scott-Moncrieff JC; et al. Comparison of classic hypoadrenocorticism with glucocorticoid-deficient hypoadrenocorticism in dogs: 46 cases (1985-2005). Journal of the Veterinary Medical Association 2007;230:1190-1194.

Adler JA; Drobatz KJ; et al. Abnormalities of serum electrolyte concentrations in dogs with hypoadrencorticism. Journal of Veterinary Internal Medicine 2007;21:1168-1173.

Hughes AM; Nelson RW; et al. Clinical features and heritability of hypoadrenocorticism in Nova Scotia Duck Tolling Retrievers: 25 cases (1994-2006). Journal of the Veterinary Medical Association 231:407,2007.