Peter P. Kintzer,     Westbrook, Maine

Mark E. Peterson,     New York, New York

Cause

Primary hypoadrenocorticism results from destruction or atrophy of the adrenal cortices and usually results in a deficiency of both glucocorticoid and mineralocorticoid secretion. Causes include idiopathic spontaneous (probably immune-mediated) primary hypoadrenocorticism (Addison’s disease), iatrogenic disease resulting from mitotane or trilostane therapy, and very rarely adrenocortical destruction resulting from granulomatous disease, metastatic neoplasia, or hemorrhage.

A subset of dogs with primary hypoadrenocorticism have glucocorticoid deficiency, based on the findings of low basal and adrenocorticotropic hormone (ACTH)–stimulated serum cortisol values but normal serum sodium and potassium concentrations. This has been referred to as “atypical” hypoadrenocorticism. It has recently been reported that most dogs with “atypical” hypoadrenocorticism actually do not have measurable aldosterone levels (Mueller et al, 2007). In other words, most “atypical” cases do have aldosterone deficiency (as well as cortisol deficiency) and so are not so atypical after all. This has important implications as far as treatment recommendations are concerned. These dogs appear to maintain normal serum electrolyte concentrations by an alternative, aldosterone-independent, yet-to-be-defined mechanism. In most of these dogs electrolyte abnormalities eventually develop, but a few dogs do not develop serum electrolyte changes when followed for many months or years.

Secondary hypoadrenocorticism is caused by insufficient pituitary ACTH production and the resultant atrophy of the zona fasciculata of the adrenal cortices. The result is deficient glucocorticoid secretion; mineralocorticoid secretion is preserved. Causes include iatrogenic disease resulting from overly rapid discontinuation of long-term and/or high-dose glucocorticoid therapy, pituitary or hypothalamic lesions, or idiopathic isolated ACTH deficiency.

Diagnosis

Although most affected dogs present in young to middle age, naturally occurring hypoadrenocorticism has been reported in dogs ranging from 2 months to 14 years of age. A genetic predilection has been confirmed in standard poodles, leonbergers, and bearded collies and suggested in certain breeds such as Nova Scotia duck tolling retrievers, Portuguese water spaniels, Great Danes, rottweilers, and wheaten and West Highland white terriers. Female dogs are about twice as likely to develop naturally occurring hypoadrenocorticism as males.

The historical findings, clinical signs, and laboratory abnormalities associated with spontaneous hypoadrenocorticism are well described (Tables 53-1 and 53-2). The severity and duration of clinical signs vary greatly among cases, from the acute life-threatening addisonian crisis to the chronic intermittent or waxing and waning signs seen in some dogs with chronic hypoadrenocorticism. Many of the historical and clinical findings are nonspecific and also occur in many more common diseases, particularly gastrointestinal and renal disorders. No set of findings is pathognomonic for canine hypoadrenocorticism. A high index of suspicion is needed to recognize some cases, particularly those with normal serum electrolyte concentrations. Findings that should heighten this suspicion include a waxing/waning course, previous response to fluid or glucocorticoid therapy, and exacerbation of clinical signs in stressful situations.

The classic electrolyte abnormalities associated with spontaneous primary hypoadrenocorticism are hyperkalemia and hyponatremia and are seen in more than 80% of affected dogs. Prior treatment with fluids, steroids, or both may mask serum electrolyte changes. Therefore one should never exclude a diagnosis of primary hypoadrenocorticism in a dog suspected of having hypoadrenocorticism on a basis of normal serum electrolyte concentrations alone. Also, some dogs with secondary hypoadrenocorticism caused by isolated pituitary ACTH deficiency are hyponatremic with normal potassium concentrations. Although Addison’s disease is often the first disorder thought of when these electrolyte abnormalities are found, the presence of hyperkalemia and hyponatremia cannot be relied on for the diagnosis of canine hypoadrenocorticism. Indeed these electrolyte abnormalities may be associated with a wide variety of diseases more common than hypoadrenocorticism, including gastrointestinal disorders, renal disease, effusive disorders, and acidosis (see Web Chapter 16).

Definitive diagnosis of hypoadrenocorticism requires demonstration of inadequate adrenal reserve. This is done by performing an ACTH stimulation test, considered the gold standard for diagnosis of hypoadrenocorticism. The preferred method is to determine serum cortisol concentrations before and 1 hour after the intravenous administration of 5 µg/kg of cosyntropin (Cortrosyn). Following reconstitution, the solution, when refrigerated, is stable for at least 4 weeks. Otherwise the remaining solution can be divided into aliquots and frozen.

If cosyntropin is not available, the ACTH stimulation test can also be performed by determining the serum cortisol concentration before and after the intramuscular injection of 2.2 U/kg of ACTH gel. ACTH gel (usually 40 U/ml) is available from several compounding pharmacies. The bioavailability and reproducibility of all these formulations have yet to be carefully evaluated. A study in dogs by Kemppainen, Behrend, and Busch (2005) using four compounded ACTH gels demonstrated increases in serum cortisol concentrations comparable to cosyntropin injection 1 hour after intramuscular injection of each of the four formulations but considerable variation at 2 hours after injection. The investigators recommended determining serum cortisol concentrations at both 1 and 2 hours post-ACTH administration when using a compounded ACTH gel. The determination of a third cortisol level would likely offset any presumed cost saving derived from using the compounded product. The potential for lot-to-lot variability in compounded ACTH gel formulations has not been evaluated. Therefore one should consider assessing the activity of each new vial by performing an ACTH stimulation test on a normal dog.

In normal dogs administration of a supraphysiologic dose of ACTH produces a rise in serum cortisol to values usually above 10 µg/dl (275 nmol/L). In contrast, dogs with hypoadrenocorticism have an absent or blunted response to ACTH administration. Basal and post-ACTH serum cortisol concentrations are less than 1 µg/dl (27 nmol/L) in over 75% of dogs and less than 2 µg/dl (55 nmol/L) in virtually all dogs with primary hypoadrenocorticism. Although the post-ACTH serum cortisol concentration may be as high as 2 to 3 µg/dl in a few dogs with secondary hypoadrenocorticism, the great majority of these dogs also have ACTH-stimulated cortisol concentrations of less than 2 µg/dl.

The ACTH stimulation test using intravenous cosyntropin can be performed during institution of initial treatment if dexamethasone is used for glucocorticoid replacement since dexamethasone does not interfere with the cortisol assay. If prednisone, prednisolone, methylprednisolone, or hydrocortisone has been administered, these treatments must be discontinued, and glucocorticoid supplementation changed to dexamethasone for at least 24 hours before ACTH stimulation testing. ACTH gel cannot be used in dehydrated or hypovolemic patients since impaired absorption may lead to inaccurate results. Alternatively, testing can be delayed until after the patient is stabilized.

A study in dogs compared an in-house cortisol assay (SNAP Cortisol) with a reference laboratory chemiluminescent assay; there was a very good correlation between the two assays. The in-house assay is particularly useful when a rapid determination of the presence of hypoadrenocorticism is desired, such as differentiating in an emergency patient between an addisonian crisis and a disease with a poorer prognosis such as acute renal failure.

Based on recent work (Lennon et al, 2007), a resting serum cortisol concentration above 2 µg/dl would make a diagnosis of hypoadrenocorticism very unlikely in a dog that had not recently received one or more doses of glucocorticoids. However, a low resting serum cortisol concentration is not diagnostic of hypoadrenocorticism and an ACTH stimulation test is necessary to confirm the diagnosis.

Secondary hypoadrenocorticism can be differentiated from atypical primary hypoadrenocorticism by measurement of a plasma ACTH level. Plasma ACTH is high (>500 pg/ml) with primary hypoadrenocorticism and undetectable-to-low with secondary hypoadrenocorticism. ACTH is labile; therefore the diagnostic laboratory performing the assay should be consulted for appropriate sample handling instructions. Plasma for ACTH determination must be collected before instituting therapy, especially glucocorticoid treatment. Even a relatively low dose of glucocorticoid may reduce previously high ACTH concentrations into the normal-to-low reference range; thus the results must be interpreted in conjunction with a careful drug history. To properly evaluate the endogenous ACTH test result, the dog ideally should not have received any form of steroid treatment in the preceding weeks. If plasma ACTH is measured in a dog that has received recent glucocorticoid treatment, a false-positive diagnosis of secondary hypoadrenocorticism may result.

Recently an alternate approach was proposed for assessing the pituitary-glucocorticoid axis in dogs by measuring basal cortisol and plasma ACTH concentrations and then calculating a cortisol-to-ACTH ratio (Javadi et al, 2006). Similarly the renin-angiotensin-aldosterone system was assessed by determining the basal plasma concentrations of aldosterone and plasma renin activity and then calculating an aldosterone-to-renin ratio.

Dogs with primary hypoadrenocorticism have low basal concentrations of cortisol with high plasma ACTH concentrations. In contrast, dogs with secondary hypoadrenocorticism have low plasma cortisol concentrations with low plasma ACTH concentrations. Therefore dogs with primary hypoadrenocorticism have much lower cortisol-to-ACTH ratios than do normal dogs or dogs with secondary hypoadrenocorticism, with little to no overlap in ratio values.

In states of aldosterone deficiency such as primary hypoadrenocorticism, the inability to retain sodium leads to hypovolemia, which subsequently stimulates renin release. Thus dogs with primary hypoadrenocorticism have low basal concentrations of aldosterone with high plasma renin activity. In secondary hypoadrenocorticism aldosterone secretion is not decreased; therefore plasma renin activity remains relatively normal. Accordingly, dogs with primary hypoadrenocorticism have much lower aldosterone-to-renin ratios than do normal dogs or dogs with secondary hypoadrenocorticism, again with little to no overlap in ratio values.

The advantage of using cortisol-to-ACTH and aldosterone-to-renin ratios is that such measurement of endogenous hormone variables in a single blood sample allows for the specific diagnosis of primary hypocortisolism and primary hypoaldosteronism. A dynamic stimulation test is not required. The use of these paired-hormone ratios generally allows for clear differentiation between primary and secondary hypoadrenocorticism; this dual assessment is particularly relevant when isolated hormone deficiency is suspected (i.e., isolated glucocorticoid deficiency or isolated mineralocorticoid deficiency).

Disadvantages of this approach to diagnosis include the considerable expense to measure plasma concentrations of cortisol, ACTH, aldosterone, and renin activity, as well as sample handling, including the absolute necessity of collecting blood for measurement of hormone and renin concentrations before any fluid or steroid treatment. Furthermore, it may be difficult to find a laboratory that can accurately measure plasma renin activity in dogs.