CVC Highlights: Atypical Addison's: How will I know?

Corticosteroids could be deemed the most important hormones in the body, given their effect on the homeostasis of every organ and system. Cortisol controls many processes; at physiologic concentrations, it benefits wound healing, prevents diuresis, and promotes normal gastrointestinal (GI) function. Cortisol acts to maintain cardiac output and systemic blood vessel tone, thereby maintaining blood pressure.

The rise and fall of cortisol in response to stress and illness is also vital to the fight-or-flight response, healing, and recovery. Corticosteroids are necessary for a normal response to catecholamines and inhibit inducible nitric oxide synthesis (iNOS), countering inflammatory-driven vasodilation. A recent study looking at basal cortisol concentrations in patients with parvovirus infection showed that cortisol values at 48 hours after presentation were very predictive of mortality.1 All puppies had initial increases in cortisol, but patients whose cortisol concentrations had dropped at 48 hours were more likely to survive than those whose had not.

Dr. Jennifer E. Waldrop

NOT YOUR NORMAL ABNORMAL

Atypical Addison's disease is "the great pretender" in veterinary medicine. While the stereotypical Addisonian patient loses function of the entire adrenal cortex, in the atypical case only portions of the zones are affected, resulting in a variety of clinical presentations.

Glucocorticoid deficient-only hypoadrenocorticism, the most common atypical form, has recently been documented in up to 45% of all hypoadrenocorticism patients.2 Most patients with atypical Addison's disease are not mineralocorticoid-deficient and maintain normal sodium/potassium ratios throughout their lives. Furthermore, current literature3 supports the finding that patients with atypical Addison's disease generally do not develop typical Addison's disease, despite older suspicions to the contrary.

WHEN TO SUSPECT ATYPICAL ADDISON'S

Suspect atypical Addison's disease in dogs that are not getting better despite appropriate therapy, especially if there is an absence of a stress leukogram. Lack of a stress leukogram is an important finding that should not be ignored in an obviously sick patient.

Dogs with chronic GI signs or those presenting for evaluation of signs of another disorder (trauma, GI infection, rickettsial infection) that are sicker than would be expected should raise your level of suspicion. These dogs may be permanently hypoadrenal and cannot respond to illness appropriately. It is easy to focus on the primary illness in these cases and fail to notice signs such as

• Mild hyperkalemia or a low sodium/potassium ratio

• Hypoglycemia

• Eosinophilia

• Hypocholesterolemia

• Lack of a stress leukogram

• Profound weakness despite aggressive fluid therapy

• Peripheral vasoconstriction and poor perfusion (extremely cool feet with a normal core body temperature).

These abnormalities, seemingly small blips on the radar, should signal the need to look further.

Another form of atypical disease is a temporary hypoadrenal condition termed critical illness-related corticosteroid insufficiency (CIRCI). CIRCI should be suspected in critically ill patients that are hypotensive despite adequate fluid resuscitation and are vasopressor-dependent or have inadequate responses to vasopressors. CIRCI occurs more commonly in patients with sepsis or traumatic brain injury.

DIAGNOSIS

ACTH stimulation test

The ACTH stimulation test is the gold standard for diagnosing Addison's disease. A pre- and post-ACTH cortisol concentration ≤ 2 µg/dl is diagnostic for Addison's disease (the absolute cut-offs may vary slightly by laboratory).4 In patients that are tested early in disease progression, the cortisol concentrations may be slightly higher, but "flat-line" cortisol responses may still be seen (e.g. pre-ACTH 3 µg/dl, post-ACTH 3.5 µg/dl). Retesting these patients in 30 days may reveal more definitive results.

Remember, it is important to avoid using any corticosteroid other than dexamethasone when considering an ACTH stimulation test. Other corticosteroids are chemically similar to cortisol and interfere with the measurement of cortisol concentrations at the laboratory. In my experience, oral prednisone can increase the cortisol measurement in as little as half an hour.

Basal cortisol concentration

Basal cortisol concentration measurement is less expensive to perform; however, measuring basal cortisol concentrations is not preferred for diagnosing atypical Addison's disease because cortisol concentrations normally fluctuate throughout the day, may be below the reference range in clinically normal animals, and may not decline in patients with CIRCI. For screening, a basal cortisol concentration may be run if Addison's disease is suspected (and the patient is not too sick) and the client cannot afford an ACTH stimulation test. If the cortisol concentration is > 2 µg/dl, the patient is unlikely to have Addison's disease, but if the cortisol concentration is < 2 µg/dl, a traditional ACTH stimulation test must be performed.5

TREATMENT

If the patient is in shock, administration of dexamethasone (0.1 mg/kg intravenously) is imperative initially. If the patient is not in life-threatening shock and after samples for ACTH stimulation testing have been collected, I recommend that atypical Addison's disease be treated with injectable prednisolone (0.2 to 0.5 mg/kg/day intramuscularly or subcutaneously; usually must be compounded) and changed to the oral form when able (can be given twice a day or once a day). I find this protocol, which is based on a combination of personal experience and published recommended dosages, to benefit most of my patients with atypical Addison's disease. Ill patients that develop CIRCI may only require one or two doses of prednisone or dexamethasone given the long-lasting effects (up to 48 hours) of these corticosteroids.

Patients with atypical Addison's disease that are not being treated in the hospital should be prescribed the lowest dose of oral prednisolone (0.1 to 0.5 mg/kg/day) to treat clinical signs. Long-term treatment of hypoadrenal disorders with overly high doses of corticosteroids will increase the likelihood of comorbidity secondary to iatrogenic Cushings.

Jennifer E. Waldrop, DVM, DACVECC

Animal Critical Care and Emergency Services

11536 Lake City Way NE

Seattle, WA 98125

REFERENCES

1. Schoeman JP, Goddard A, Herrtage ME. Serum cortisol and thyroxine concentrations as predicators of death in critically ill puppies with parvoviral diarrhea. J Am Vet Med Assoc 2007;231(10):1534-1539.

2. Sadek D, Schaer M. Atypical Addison's disease in the dog: a retrospective survey of 14 cases. J Am Anim Hosp Assoc 1996;32(2):159-163.

3. 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.

4. Ettinger SJ, Feldman EC. Textbook of veterinary internal medicine, 6th ed. St. Louis, Mo: Saunders Elsevier, 2005;1619.

5. 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.