DIAGNOSIS AND TREATMENT
Initial treatment included a 400-ml bolus of 0.9% sodium chloride solution given intravenously over two hours (30 ml/kg/hr)
followed by prednisolone sodium succinate (18.4 mg/kg IV), which was administered immediately after completion of an ACTH
stimulation test. Intravenous fluid therapy with 0.9% sodium chloride solution was continued at 6.5 ml/kg/hr after the initial
bolus. We administered cefazolin (30 mg/kg intravenously, two doses, 10 hours apart) and famotidine (0.75 mg/kg orally b.i.d.
for the duration of hospitalization) to prevent sepsis due to bacterial translocation and ulceration secondary to compromised
gastrointestinal mucosal integrity, which commonly occurs with hypoadrenocorticism.3
The ACTH stimulation test results were available the next day (day 8) and confirmed hypoadrenocorticism. The resting cortisol
concentration was 0.5 µg/dl (reference range = 0.5 to 5.5 µg/dl), and the two-hour post-stimulation cortisol concentration
was 0.4 µg/dl (reference range = 5.5 to 20 µg/dl). We treated the dog with a mineralocorticoid, desoxycorticosterone pivalate
(Percorten—Novartis Animal Health; 2.2 mg/kg given intramuscularly), and glucocorticoids. Dexamethasone sodium phosphate (0.22
mg/kg intravenously) was administered once. The patient then began eating, so we switched to treatment with oral prednisone
(1.5 mg/kg orally once a day).
Clinical signs resolved, and serum chemistry profile abnormalities, including the hypercalcemia, improved after three days
of treatment for hypoadrenocorticism (Table 1, day 9). After four days of hospitalization, the patient was eating well and the ocular discharge had resolved, so the patient
was released to the owner. Prednisone (0.73 mg/kg b.i.d.) and famotidine (0.73 mg/kg b.i.d.) were prescribed as initial home
care. We emphasized the importance of strict compliance with future desoxycorticosterone pivalate injections and prednisone
At reevaluation (day 14), the patient was doing well. Its energy level and appetite had improved, and it had gained 1.3 lb
(0.6 kg) since being released from hospital. Most serum chemistry profile results, including the calcium concentration, were
normal (Table 1, day 14).
Initially, the patient was evaluated every 30 days, and more recently, it has been evaluated every 60 to 90 days. The results
of intermittent serum chemistry profiles, including electrolytes, have been normal. Treatment includes desoxycorticosterone
pivalate every four weeks, and the oral prednisone has slowly been tapered to a physiological dose of 0.3 mg/kg daily. We
instructed the owner to increase the prednisone dose in times of stress, such as boarding or illness. The patient is a clinically
normal 2.5-year-old dog.
Hypoadrenocorticism, or Addison's disease, is an endocrine disorder most commonly resulting from atrophy and destruction of
the adrenal cortices. This deterioration leads to a deficiency of glucocorticoids alone or both glucocorticoids and mineralocorticoids.3,4
Many causes of this disease have been identified in people, including adrenal gland destruction (often autoimmune), tuberculosis,
human immunodeficiency virus, adrenoleukodystrophy, and congenital adrenal hypoplasia.5,6 In dogs, primary hypoadrenocorticism is usually due to autoimmune destruction of the adrenal glands.3 Less common causes include granulomatous disease, infarction, neoplastic metastasis, amyloidosis, trauma, and iatrogenic
causes.3 Natural secondary hypoadrenocorticism is due to a lack of ACTH production by the pituitary glands, which rarely occurs in
Hypoadrenocorticism is most common in young to middle-aged female dogs, but it also occurs in neonatal and pediatric dogs.3,7,8 Standard poodles, West Highland white terriers, great Danes, Leonbergers, Labrador retrievers, and Portuguese water dogs
are overrepresented breeds.3,8
The link between hypoadrenocorticism and hypercalcemia
Addison's disease may cause electrolyte abnormalities including mild to moderate hypercalcemia.9,10 Hypercalcemia is noted at the time of diagnosis in 29% of patients with hypoadrenocorticism.3 The severity of hypercalcemia in Addison's disease is typically proportional to the clinical severity of adrenal insufficiency.7,9 Although the exact mechanism of hypercalcemia associated with hypoadrenocorticism remains uncertain, the following theories
have been postulated8,11,12 :
1. Dehydration leads to hemoconcentration and a relative increase in proteins that bind calcium.
2. Hyponatremia due to mineralocorticoid deficiency increases the affinity of plasma proteins for calcium. This increased
protein binding of calcium leads to an elevated serum calcium concentration.
3. Decreased renal function and decreased glomerular filtration rate due to hypovolemia lead to increased tubular calcium
reabsorption and decreased calcium excretion.
4. Increased serum calcium interferes with sodium and water retention in the distal renal tubules. A compensatory increase
of sodium reabsorption then occurs in the proximal tubule, which is associated with an increase in calcium reabsorption.
5. Since glucocorticoids antagonize vitamin D activity, glucocorticoid deficiency, as with hypoadrenocorticism, can result
in increased intestinal absorption and increased bone resorption of calcium. Glucocorticoids may alter osteoblast differentiation
in a manner that has not been identified. Thus, a lack of glucocorticoids may cause an increase in calcium resorption from
Many or all of these factors likely play a role in hypercalcemia associated with hypoadrenocorticism. The puppy in this report
may have been at a higher risk to develop hypercalcemia because it had increased bone turnover due to growth.
The serum calcium concentration on presentation in the patient in this case was 26.8 mg/dl (reference range = 8.8 to 11.4
mg/dl), almost double that of previously reported concentrations of hypercalcemia associated with hypoadrenocorticism. Reported
ranges of calcium concentrations in dogs with hypoadrenocorticism are 6.8 to 15.9 mg/dl (reference range = 8.5 to 11.5 mg/dl),7 12 to 14.9 mg/dl (reference range = 8.5 to 11.6 mg/dl),9 and—the highest reported value—16.7 mg/dl (reference range = 8.5 to 11.5 mg/dl).11
Hypercalcemia has toxic effects on all cell types, with clinically important effects on the heart and the nervous, gastrointestinal,
and renal systems. Dogs with hypercalcemia commonly experience polyuria, polydipsia, anorexia, lethargy, and weakness.13 The development of these clinical signs depends on the severity and rate of development of hypercalcemia.13
Differential diagnoses for hypercalcemia
Hypercalcemia in dogs has many differential diagnoses other than hypoadrenocorticism, including primary hyperparathyroidism,
acute and chronic renal failure, vitamin D toxicosis, nutritional secondary hyperparathyroidism, granulomatous diseases, neoplasia
(e.g. carcinomas, lymphoma, multiple myeloma, melanoma), hyperthyroidism, and spurious laboratory results.14 Mild elevations in serum calcium concentrations (11 mg/dl) may occur in dogs up to 3 months of age because of normal bone
growth.13 A small percentage of normal young dogs may have serum calcium concentrations as high as 12 mg/dl, possibly as high as 15
mg/dl.13 One published reference range for serum calcium concentrations in pediatric dogs is 10.6 to 11.7 mg/dl.15 No calcium or vitamin D supplements had been added to the high-quality commercial diet of the patient in this report.
Total serum calcium is the sum of ionized calcium (the biologically active form), protein-bound calcium, and complexed calcium.
Spurious hypercalcemia can occur because of lipemia, hemolysis, dehydration, and acidosis and can also occur in young animals,
postprandial samples, and samples containing EDTA anticoagulant.16 This puppy's calcium concentration was measured and verified at a commercial veterinary laboratory from a fasted, nonlipemic,
nonhemolyzed sample that contained no anticoagulant. Dehydration may have increased the total serum calcium concentration
in this patient. Ionized calcium concentrations help differentiate between spurious and true hypercalcemia. However, as previously
stated, the financial limitations of the owners prevented this additional testing.
In this patient, primary hyperparathyroidism and secondary hyperparathyroidism due to renal failure were initially considered
as differential diagnoses for hypercalcemia. Ideally, ionized calcium and parathyroid hormone concentrations would have been
measured. However, because of the rapid, complete, and sustained resolution of hypercalcemia after treatment for hypoadrenocorticism,
we thought no further testing was indicated.