Mineralocorticoid Before Glucocorticoid Deficiency in a Dog with Primary Hypoadrenocorticism and Hypothyroidism

Introduction

Primary hypoadrenocorticism (Addison’s disease) is a well described and well recognized clinical entity in dogs characterized by deficiency of glucocorticoid (cortisol) and mineralocorticoid (aldosterone) secretion from the adrenal cortex.^1–5 Typically, dogs are diagnosed with primary hypoadrenocorticism by demonstration of a subnormal cortisol response to provocative testing with adrenocorticotropic hormone (ACTH).^3,5,6 The dog profiled in this case report initially presented with normal ACTH-stimulated cortisol responses despite classic clinical and electrolyte abnormalities consistent with Addison's disease. Subnormal serum aldosterone concentrations were confirmed. Within 6 wk, the dog also developed glucocorticoid deficiency fulfilling all criteria of Addison's disease, yet illustrating an unusual presentation for this endocrinopathy.

Case Report

A 3 yr old castrated male Doberman pinscher weighing 42 kg presented to the Cornell University Hospital for Animals with a 3 wk history of intermittent head and neck tremors, weight loss, poor appetite, increased thirst, and lethargy. Head tremors (< 10 sec in duration) were associated with activity. On physical examination, the dog was alert with muscle wasting (epaxial, shoulder, temporal) and crusting cutaneous lesions (periocular, mandibular). Neurologic assessments were normal. Laboratory testing included a complete blood count (CBC), serum biochemistry, and urinalysis. The CBC disclosed a normal hematocrit (44%; reference range, 41–60%), normal leukocyte count (8.8 × 10³/μL; reference range, 5.7–14.2 × 10³/μL) with normal differential distribution, and erythrocyte microcytosis (mean corpuscular volume was 63 fL; reference range, 66–76 fL). Serum biochemistry (Na, potassium, chloride, total protein, albumin, globulin, blood urea nitrogen, creatinine, glucose, Ca, phosphorous, total bilirubin, cholesterol, iron, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, and amylase) disclosed hyponatremia (131 mEq/L; reference range, 142–151 mEq/L), hypochloremia (96 mEq/L; reference range, 107–117 mEq/L), normokalemia (5.0 mEq/L; reference range, 3.9–5.3 mEq/L), mild hypercalcemia (11.7 mg/dL; reference range, 9.3–11.6 mg/dL), hyperphosphatemia (5.8 mg/dL; reference range, 2.8–5.3 mg/dL), hyperalbuminemia (4.8 g/dL; reference range, 3.1–4.1 g/dL), increased alanine aminotransferase (183 U/L; reference range, 25–106 U/L), and hypercholesterolemia (396 mg/dL; reference range, 124–335 mg/dL). Urine specific gravity was 1.028 with a negative dipstick reading and inactive sediment. An electrocardiogram was within normal limits. Ionized hypercalcemia (1.42 mmol/L; reference range, 1.18–1.37 mmol/L) was measured. An ACTH stimulation test, performed by measuring serum cortisol concentrations before and 1 hr after IV administration of cosyntropin^a (5 μg/kg), was within normal limits. Serum cortisol before and after ACTH administration was 5.6 μg/dL (reference range, 1.8–4.9 μg/dL) and 15.2 μg/dL (reference range, 6–16 μg/dL), respectively. The dog was discharged for continued monitoring and observation.

One week later, with unchanged clinical signs, physical exam findings, and neurologic status, bacterial folliculitis of the head and neck was diagnosed and cephalexin^b (25 mg/kg per os [PO] q 12 hr) was prescribed. A CBC and serum biochemistry disclosed erythrocyte microcytosis (mean corpuscular volume was 63 fL), hyponatremia (125 mEq/L), hypochloremia (98 mEq/L), hyperkalemia (6.0 mEq/L), increased blood urea nitrogen (35 mg/dL; reference range, 8–30 mg/dL), normal creatinine (1.0 mg/dL; reference range, 0.5–1.3 mg/dL), hypercalcemia (12.3 mg/dL), ionized hypercalcemia (1.42 mmol/L), hyperphosphatemia (6.4 mg/dL), hyperalbuminemia (5.0 g/dL), and hypercholesterolemia (424 mg/dL). Testing of thyroid function revealed an increased thyroid stimulating hormone concentration (0.847 ng/mL; reference range, 0–0.5 ng/mL), but normal total and free thyroxine (T₄) concentrations (1.63 μg/dL; reference range, 1.5–3 μg/dL and 1.22 ng/dL; reference range, 0.7–2.5 ng/dL, respectively). Repeat ACTH stimulation testing (including aldosterone assessments) revealed baseline and 1 hr post-ACTH stimulated serum cortisol concentrations of 2.42 μg/dL and 10.2 μg/dL, respectively. Subnormal serum aldosterone was documented (baseline was < 11 pg/mL [reference range, 11–150 pg/mL] and 1 hr post-ACTH stimulated was 36.68 pg/mL [reference range, 100–250 pg/mL]). Diagnosis of mineralocorticoid deficiency warranted treatment with the short-acting mineralocorticoid fludrocortisone acetate^c (0.01 mg/kg PO q 24 hr).

Within 4 days of starting treatment, electrolyte concentrations improved. Fludrocortisone acetate was discontinued and desoxycorticosterone pivalate ([DOCP^d], 1 mg/kg) was administered subcutaneously. Twelve days later, electrolyte concentrations were normal and the dog had gained 2.5 kg. Twenty-eight days after the single dose of DOCP, the head tremors had resolved but lethargy and vomiting were noted. Serum biochemistry parameters were within reference ranges, but repeat baseline and ACTH-stimulated serum cortisol concentrations were subnormal (0.847 μg/dL and 0.892 μg/dL, respectively) and an elevated endogenous ACTH concentration was noted (135 pg/mL; reference range, 0–25 pg/mL). Repeat assessment of thyroid function confirmed primary hypothyroidism (T₄ was 0.63 μg/dL, free T₄ was 0.54 ng/dL, and thyroid stimulating hormone was 0.936 ng/mL). The dog was prescribed DOCP (1 mg/kg subcutaneously q 28 days) and prednisone (0.25 mg/kg PO q 24 hr for 1 wk then 0.1 mg/kg PO q 24 hr), thyroid supplementation (0.01 mg/kg levothyroxine^e PO q 12 hr). The dog continued to receive the cephalosporin antibiotic as prescribed for 10 more days for the bacterial folliculitis.

Periodic reassessments over 29 mo have confirmed normal activity and resolution of head tremors. The DOCP and thyroid supplementation were continued as described previously and the prednisone dosage was titrated to 0.05 mg/kg PO q 24 hr.

Discussion

Hypoadrenocorticism can be classified as either primary (caused by bilateral adrenocortical destruction) or secondary (resulting from diminished pituitary production of ACTH).^1–4 Typically, primary hypoadrenocorticism results in both glucocorticoid (cortisol) and mineralocorticoid (aldosterone) deficiencies because of widespread adrenocortical destruction. Secondary hypoadrenocorticism reflects decreased pituitary ACTH secretion resulting in atrophy of adrenocortical tissue producing glucocorticoids (i.e., the zona fasciculata and zona reticularis). Mineralocorticoid production from the zona glomerulosa continues unhindered because aldosterone secretion is relatively independent of ACTH.^1,4

Atypical Addison’s disease describes a syndrome associated with glucocorticoid deficiency without concurrent mineralocorticoid deficiency (and the resultant electrolyte imbalances). Dogs with primary hypoadrenocorticism not evidencing mineralocorticoid insufficiency are classified as atypical Addisonians.^3,4,7,8 The majority of dogs with primary hypoadrenocorticism have pervasive destruction of all zones of the adrenal cortex associated with an immune-mediated process.³ In those with atypical presentations, mineralocorticoid deficiency would be expected to eventually develop, but many cases never evidence classic electrolyte abnormalities.⁸ The case described herein uniquely demonstrated the opposite scenario with mineralocorticoid deficiency preceding glucocorticoid insufficiency.

Laboratory abnormalities classically, but variably, associated with typical canine Addison’s disease include hyperkalemia, hyponatremia, hypochloremia, azotemia, hypercalcemia, hypoglycemia, hypocholesterolemia, hypoalbuminemia, erythrocyte microcytosis, nonregenerative anemia, and a reverse stress leukogram.^1,3–5 Electrolyte abnormalities are caused by aldosterone deficiency, whereas hypercalcemia, hypoglycemia, hypocholesterolemia, and hematologic changes are attributed to deficient cortisol.³ Either low aldosterone or cortisol may contribute to hypovolemia and hypoperfusion leading to azotemia.³ Some of the biochemical (hypercholesterolemia) abnormalities in the dog described herein also likely reflect the emerging primary hypothyroidism. The cause of the mild ionized hypercalcemia prior to the documented cortisol deficiency in this dog remains unclear. Definitive diagnosis of hypoadrenocorticism generally requires documentation of subnormal cortisol before and after administration of synthetic ACTH.^3,5,6,8,9 Differentiation as primary hypoadrenocorticism is usually confirmed by one or more of the following: classic electrolyte abnormalities, concurrent aldosterone deficiency, or increased endogenous ACTH concentrations.^3,5,10,11

Aldosterone is a mineralocorticoid essential for regulation of water, Na, and potassium balance, exerting effects at the level of the renal tubule, intestinal mucosa, and sweat and salivary glands.^3,12 Secretion of aldosterone is stimulated by hyperkalemia or volume depletion via the renin-angiotensin system. In humans, drugs documented to affect either the release or actions of aldosterone include nonsteroidal anti-inflammatory medications, angiotensin-converting enzyme inhibitors, potassium sparing diuretics, heparin, and trimethoprim-sulfa drugs.¹³ Aldosterone deficiency with normal cortisol concentration has been reported in people with hyporeninemic hypoaldosteronism.^13,14 In that syndrome, lack of renin production by the kidney fails to activate the angiotensin system to invoke aldosterone secretion.¹⁴ The eventual documentation of hypocortisolemia in the dog described herein is disparate with the diagnostic criteria of hyporeninemic hypoaldosteronism.¹⁴ Hyperreninemic hypoaldosteronism has been described in people with Addison’s disease as well as humans with inborn errors of adrenal biosynthesis and hypotensive critically ill patients.^12,15 One study in dogs with primary hypoadrenocorticism also reported low aldosterone concentrations concurrent with increased plasma renin activity.⁹ Although overlap in values with clinically normal dogs was noted, the aldosterone-to-renin ratio was capable of distinguishing normal from Addisonian dogs.⁹ Isolated mineralocorticoid deficiency attributable to hyperreninemic hypoaldosteronism has been described in one dog. The ACTH-stimulated cortisol response was normal in that dog, but was not sequentially reevaluated.¹² Renin activity was not measured in the dog described herein because the assay was not available as a diagnostic test in the USA.

Pseudohypoadrenocorticism has been described in dogs with primary gastrointestinal disease (most frequently associated with diarrhea from trichuriasis).¹⁶ Those animals have hyponatremia and/or hyperkalemia associated with normal cortisol response to ACTH.¹⁶ Dogs with pseudohypoadrenocorticism have baseline and ACTH-stimulated aldosterone concentrations that are either normal or increased.¹⁷

Addison’s disease is most prevalent in young to middle-aged female dogs with over-representation of several breeds (e.g., Great Danes, Portugese water dogs, rottweilers, standard poodles, West Highland white terriers, and soft-coated wheaten terriers).^1,3,4 Clinical signs are typified by vomiting, weight loss, lethargy, and anorexia.^1,3,4 Although not a typically affected breed, the dog described herein demonstrated many common clinical signs of hypoadrenocorticism. The described head tremors, identified in Doberman pinschers as an idiopathic syndrome, have not been associated with either adrenal insufficiency or hypothyroidism.¹⁸ Nevertheless, the head tremors resolved with successful management of this dog’s endocrinopathies. It is possible that either the electrolyte abnormalities or developing thyroid dysfunction exacerbated head tremors in this dog; however, they also may have spontaneously resolved.

Treatment of Addison’s disease requires replacement of deficient mineralocorticoids and glucocorticoids.^2,3,5 Parenteral DOCP (a synthetic mineralocorticoid) and physiologic glucocorticoid replacement using prednisone are commonly advised. Although the dose of DOCP recommended by the manufacturer is 2.2 mg/kg q 25 days (either intramuscularly or subcutaneously), some dogs achieve adequate control with lower amounts and longer dosing intervals. The dog in this report required less than half the recommended dose and maintained normal serum Na and potassium concentrations for > 2 yr. Fludrocortisone acetate, an oral medication having both mineralocorticoid and glucocorticoid properties, alternatively may be prescribed.^2,3,5 With negligible glucocorticoid effects at recommended doses, DOCP would not be expected to interfere with glucocorticoid production, which is why it was used early in this case for management of the hypoaldosterone-driven electrolyte aberrations (D. Reece, DVM, Novartis Animal Health, Greensboro, NC, written communication, April 29, 2011). The subsequent demonstration of increased endogenous ACTH concentration further confirmed development of primary adrenal glucocorticoid insufficiency.

Diagnosis of concurrent primary hypoadrenocorticism and hypothyroidism is consistent with Schmidt’s syndrome caused by immune-mediated destruction of both the adrenal cortices and thyroid tissue.^19,20 Endocrine monitoring of other tissues has been advised in concern for development of polyendocrine immune-mediated insufficiency affecting the endocrine pancreas and parathyroid glands.³

Conclusion

The dog reported herein demonstrated progressive development of Addison’s disease with mineralocorticoid deficiency preceding glucocorticoid insufficiency. Consideration of this unique presentation warrants repeat ACTH stimulation for cortisol assessment when electrolyte abnormalities due to isolated hypoaldosteronism are identified.