Transient or Inconsequential Hypercalcemia

Inconsequential hypercalcemia does not cause injury, resolves rapidly, or is only mild. Dehydration can result in mild hypercalcemia attributed to hemoconcentration. Furthermore, dehydration and volume contraction stimulate increased sodium and calcium reabsorption in the kidneys. An increased serum concentration of protein, especially albumin, can result in an increased serum tCa concentration as more calcium binds to protein. Dehydration in dogs is occasionally associated with serum tCa concentrations of 12.0 to 13.5 mg/dL that rapidly return to normal after dehydration is corrected. Increased serum tCa and decreased iCa concentrations can occur transiently after plasma transfusion because of excess citrate-calcium ion complexes.³⁸⁵

Hypoadrenocorticism

Hypoadrenocorticism is the second most common cause of hypercalcemia in dogs (after malignancy), accounting for 11% to 45% of cases in five studies,^{115,166,314,586,614} but no cases were reported in one study.⁴⁶ Hypercalcemia was reported in 28% to 31% of dogs with glucocorticoid- and mineralocorticoid-deficient hypoadrenocorticism,^442,445 in some dogs with glucocorticoid-deficient hypoadrenocorticism,³²⁸ and in 1 of 10 cats.⁴⁴³ In a study of 36 dogs with hypoadrenocorticism, 42% had an increase in tCa, but only 22% had increases in both iCa and tCa.³ The ionized hypercalcemia was typically mild, but a few dogs exhibited moderate to severe hypercalcemia. In eight dogs with hypoadrenocorticism, tCa was elevated in all eight, but iCa was elevated in only five of seven dogs in which iCa was measured.²²¹ PTH was within or below the reference range in all dogs, 25-hydroxyvitamin D was within or below the reference range in all dogs, and calcitriol was within the reference range in seven of eight dogs. Hypoadrenocorticism is rarely recognized in cats, and hypercalcemia is present in only 8% of cases.³⁵ Hypercalcemia was present in one cat with iatrogenic secondary hypoadrenocorticism and diabetes mellitus.⁵⁴¹ Magnitude of hypercalcemia was greatest in the most severely affected dogs, but the mechanism is unknown. A correlation between the degree of hyperkalemia and hypercalcemia was detected when the serum potassium concentration was greater than 6.0 to 6.5 mEq/L, and serum tCa concentration was often 11.4 to 13.5 mg/dL.¹⁷⁸ Increases in serum iCa may or may not develop in hypoadrenocorticism.⁵⁹⁵ Serum tCa concentration rapidly returns to normal after 1 to 2 days of corticosteroid replacement therapy in dogs,⁴⁴² and IV volume expansion can return serum calcium concentration to normal within a few hours. Hypoadrenocorticism should always be included in the differential diagnosis of hypercalcemia, because the clinical signs of hypoadrenocorticism and hypercalcemia are similar.

Chronic Renal Failure

The findings of hypercalcemia and primary renal azotemia pose a special diagnostic problem because hypercalcemia can cause renal failure or develop as a consequence of CRF. Serum PTH concentration is often increased in patients with hypercalcemia related to renal failure, and these animals must be differentiated from those with primary hyperparathyroidism. Serum iCa concentration is increased in primary hyperparathyroidism but is usually normal or low in patients with CRF.^118,314

Deleterious effects of hypercalcemia occur in patients with renal failure only if it is associated with increases in serum iCa concentration. Consequently, clinical signs of hypercalcemia are uncommon in CRF patients, and measurement of serum iCa concentration to assess calcium status in CRF patients is critical. In CRF patients, the serum tCa measurement incorrectly assessed iCa status in 36% of dogs and 32% of cats.^518,519 The use of the “adjusted tCa” value incorrectly assessed iCa status in approximately 53% of dogs with CRF. In dogs, serum tCa measurement or adjusted tCa measurement overestimated hypercalcemia and underestimated hypocalcemia. In cats with CRF, serum tCa measurement overestimated normocalcemia and underestimated hypercalcemia. Thus, to accurately assess calcium status in patients with CRF, iCa concentration must be directly measured.

Fewer than 10% of all dogs with CRF have increased serum iCa concentrations. In one study, approximately 6% exhibited ionized hypercalcemia.¹¹⁸ In a recent study of 490 dogs with CRF, 9% exhibited hypercalcemia, 55% were normocalcemic, and 36% were hypocalcemic based on serum iCa concentrations.⁵¹⁹ In another recent study of dogs with hypercalcemia, 17% were diagnosed with renal failure and were hypercalcemic based on their iCa concentration.³⁷⁵ Of these dogs, 89% had chronic renal failure and 11% had acute renal failure. Cats with CRF appear to have a higher incidence of ionized hypercalcemia as compared with dogs. In 102 cats with CRF, 29% were hypercalcemic, 61% were normocalcemic, and 10% were hypocalcemic based on iCa concentration.⁵¹⁸

Many dogs and cats with CRF have normal serum tCa concentrations.^147,183,380 Hypercalcemia based on measurement of serum tCa concentration occurs sporadically in dogs and cats with CRF and is usually listed as second or third in frequency of causes of hypercalcemia in dogs. Elevated tCa occurs in up to 14% of dogs with CRF, with a range of 12.1 to 15.2 mg/dL.^{118,183,314,405} In 71 hypercalcemic cats, CRF was noted in 38%.⁵¹¹ In cats with CRF, the reported incidence of serum total hypercalcemia ranged from 11.5%¹⁴⁷ to 58%.²⁷

The incidence of elevated tCa increases with severity of azotemia. In 73 cats with CRF, serum tCa was increased in 8%, 18%, and 32% of those with mild, moderate, or severe azotemia, respectively.²⁷ However, increases in serum iCa do not show a strong association with the degree of azotemia.¹³⁴ In 47 of the previous 73 cats with CRF, iCa was increased in 0%, 9%, and 6% of those with mild, moderate, or severe azotemia, respectively.²⁷ Hypercalcemia was also not correlated with serum phosphorus concentration in dogs with experimental renal failure.^419,583

The parathyroid glands must be present for hypercalcemia to develop,⁵⁸³ and partial parathyroidectomy ameliorates hypercalcemia in some dogs with CRF.¹⁸³ Treatment of dogs with CRF and hypercalcemia with low-dose calcitriol to reduce PTH synthesis and secretion can result in decreased iCa concentration. Low-dose calcitriol therapy does not appreciably increase intestinal calcium absorption.^401,402 In patients with CRF, increased serum PTH concentration (renal secondary hyperparathyroidism) contributes to the progression of renal disease.⁴⁰² Oral administration of low doses of calcitriol reduces toxic concentrations of PTH, improves quality of life, reduces progression of renal disease, and leads to prolongation of life.^403,524

Some cases of ionized hypercalcemia and CRF may be associated with the use of calcium carbonate intestinal phosphate binders. In these cases, serum iCa concentration rapidly returns to normal after discontinuation of treatment. In humans with CRF, therapeutic use of calcitriol is limited by development of hypercalcemia in patients also being treated with calcium-based dietary phosphorus binders.^126,403 In veterinary medicine, use of aluminum-based phosphorus binders or sevelamer largely precludes this problem.¹⁰ “Noncalcemic analogues” of calcitriol have been developed for use in humans,⁵³⁹ such as paricalcitol, 22-oxacalcitriol (OCT), and doxercalciferol.¹⁵⁵ These analogues have a very short half-life (several minutes), and this short half-life is responsible for their weak stimulation of intestinal calcium absorption. Doses of noncalcemic analogues needed to suppress PTH synthesis are approximately eightfold higher than that of calcitriol⁵³⁹ and are up to 12 times the cost. If hypercalcemia develops with calcitriol therapy, a twice-weekly dosing strategy of calcitriol is used. This dosing regimen will suppress PTH but be much less effective at stimulating intestinal calcium absorption. Noncalcemic analogues are not needed and are financially impractical in veterinary medicine.

Ionized hypercalcemia occurs in patients with CRF who receive excessive doses of calcitriol. Hypercalcemia is very uncommon in animals treated with the lower dosages of calcitriol (2.5 to 4.0 ng/kg daily). If hypercalcemia is caused by excessive calcitriol, the serum tCa concentration decreases during the week after its discontinuation. Most CRF patients who develop an elevated tCa during low-dose calcitriol treatment have normal or low serum iCa concentrations. Serum tCa concentration may not decrease when calcitriol is discontinued if the increased serum tCa concentration is caused by increased complexed calcium.

The mechanisms of increased serum tCa concentration in CRF have not been well characterized.^{183,314,478,583} In dogs with CRF, serum total hypercalcemia, and normal iCa concentrations, the increase in serum tCa is caused by an increase in the complexed calcium fraction.⁵¹⁷ In CRF, organic anions such as citrates, phosphates, lactates, bicarbonates, and oxalates are capable of complexing with calcium. Complexed calcium accounted for 24% of serum tCa in those dogs with CRF and elevated serum tCa as compared with 11% in those dogs with CRF and low serum tCa. Increased PTH-mediated bone resorption as a consequence of CRF could increase serum tCa concentration. If elevated iCa is also present, then the reduced GFR caused by loss of renal mass could cause increased iCa concentration as the filtered load of calcium declines. Hyperplasia of the parathyroid gland chief cells could account for increased PTH secretion and serum calcium concentration because chief cells secrete small amounts of PTH that are nonsuppressible regardless of serum iCa concentration.²¹⁴

Tertiary hyperparathyroidism refers to the condition of a subset of patients with CRF who develop ionized hypercalcemia and excessive PTH secretion that is not inhibited by high serum iCa concentration. It is likely that such patients had high PTH concentrations in association with normal or low serum iCa concentration (renal secondary hyperparathyroidism) earlier in the clinical course of CRF. Autonomous secretion of PTH from the parathyroid gland is unlikely, but the set-point for PTH secretion may be altered in CRF such that higher concentrations of iCa are necessary to inhibit PTH secretion.²¹⁵ Decreased serum calcitriol concentrations, decreased numbers of calcitriol receptors in the parathyroid gland, and decreased calcitriol-VDR interactions with chief cell DNA caused by uremic toxins may contribute to this increase in set-point,^75,266,435 as may decreased levels of the calcium receptor, which both establish the set-point and depend on calcitriol functionality for synthesis of its mRNA from the parathyroid cells’ DNA.⁹⁹ Ten dogs with CRF and increased serum tCa concentration were compared with those with normal serum tCa concentration (Fig. 6-12). Serum amino-terminal PTH concentration was markedly increased in both groups of uremic dogs, but those with increased tCa had higher PTH concentrations. Calcitriol concentration was decreased to a similar extent in both groups. It was proposed that the hypercalcemic and more markedly hyperparathyroid uremic dogs might have had greater calcitriol receptor (VDR) deficits in their parathyroid cells, which would lead to poorly controlled PTH synthesis and chief cell hyperplasia.⁴⁰⁵ Deficient calcitriol functionality caused by VDR deficits would also lead to calcium receptor deficits and the “set-point” elevations involved in the observed hypercalcemia.⁹⁹

Figure 6-12 Comparison of biochemical data for dogs with renal failure and hypercalcemia or normocalcemia. Dogs with renal failure were normalized for age and had similar concentrations of serum creatinine, phosphorus, and calcitriol. Serum concentrations of PTH were greater in the hypercalcemic dogs than in the normocalcemic dogs. Data are mean ± SEM. For normal and hypercalcemic uremic dogs, n = 10; for normocalcemic uremic dogs, n = 20. Significant differences were *P <.0001 (from normal) and **P <.02 (from normocalcemic uremia PTH) by Student t test.

(From Nagode LA, Steinmeyer CL, Chew DJ, et al. Hyper- and normo-calcemic dogs with chronic renal failure: relations of serum PTH and calcitriol to parathyroid gland Ca⁺⁺ set-point. In: Norman AW, Schaefer K, Grigoleit HG, et al, editors. Vitamin D 1988. Chemical, biochemical and clinical endocrinology. Berlin: Walter de Gruyter & Co, 1988: 799–800.)

Aluminum accumulation in the development of hypercalcemia in dogs or cats with renal disease being treated with aluminum-containing intestinal phosphate binders has not been investigated despite the fact that such treatment is common. Experimental dogs exposed to aluminum developed mild hypercalcemia within minutes of a single intravenous injection. During chronic daily exposure to aluminum during a period of weeks, serum calcium concentration progressively increased, and azotemia developed.²⁴²

Two of 15 cats with CRF developed hypercalcemia while eating a phosphate-restricted veterinary diet designed for treatment of renal failure. Hypercalcemia in these cats was associated with a decrease in serum phosphorus and low or undetectable PTH concentrations. Serum calcium returned to normal, and PTH and phosphorus increased with the feeding of a maintenance diet.²⁹

Cancer-Associated Hypercalcemia

The most common cause of hypercalcemia in dogs is cancer-associated hypercalcemia. Cancer is third in frequency of association with hypercalcemia in cats. There are three mechanisms (Fig. 6-13) of increased serum calcium concentration induced by neoplasms: (1) HHM, (2) hypercalcemia induced by metastases of solid tumors to bone (local osteolytic hypercalcemia [LOH]), and (3) hematologic malignancies growing in the bone marrow (LOH).^479,480

Figure 6-13 Pathogenesis of cancer-associated hypercalcemia. Humoral and local forms of cancer-associated hypercalcemia increase circulating concentrations of calcium by stimulation of osteoclastic bone resorption and increased renal tubular reabsorption of calcium.

Humoral Hypercalcemia of Malignancy

HHM is a syndrome associated with many tumors in people and animals.⁴⁸⁰ Characteristic clinical findings in patients with HHM include hypercalcemia, hypophosphatemia, hypercalciuria (often with decreased fractional calcium excretion), increased fractional excretion of phosphorus, increased nephrogenous cyclic adenosine monophosphate (cAMP), and increased osteoclastic bone resorption. Hypercalcemia is induced by humoral effects on bone, kidneys, and possibly the intestine (Fig. 6-14).⁴⁸¹ Increased osteoclastic bone resorption is a consistent finding in HHM and increases calcium release from bone. The kidneys play a critical role in the pathogenesis of hypercalcemia because PTHrP stimulates calcium reabsorption, which binds and activates renal PTH-PTHrP receptors. The level of renal function in the patient may also contribute to the development of hypercalcemia. Animals with dehydration or impaired renal function are more susceptible to developing hypercalcemia or may have more severe hypercalcemia because of decreased renal excretion of calcium. In some forms of HHM, increased serum 1,25-dihydroxyvitamin D concentrations may increase calcium absorption from the intestine.⁴⁸⁹

Figure 6-14 Humoral factors such as parathyroid hormone-related protein (PTHrP), interleukin-1 (IL-1), tumor necrosis factors (TNFs), or transforming growth factors (TGFs) produced by tumors induce humoral hypercalcemia of malignancy (HHM) by acting as systemic hormones and stimulating osteoclastic bone resorption or increasing tubular reabsorption of calcium.

Malignancies that are commonly associated with HHM in dogs include T-cell lymphoma and adenocarcinomas derived from the apocrine glands of the anal sac.^{22,36,479,607,615} In a retrospective study of 109 dogs with hypercalcemia, 58% had hypercalcemia due to underlying neoplasia. Lymphosarcoma was present in 78% of these patients, with 11% diagnosed with carcinoma and 6% diagnosed with anal sac adenocarcinoma.³⁷⁵ Dogs with cancer and HHM are expected to have shorter survival. In addition, sporadic cases of HHM occur in dogs with thymoma, myeloma, melanoma, or carcinomas originating in the lungs, pancreas, thyroid gland, skin, mammary gland, nasal cavity, and adrenal medulla.^{61,458,479-481} Tumors associated with hypercalcemia in cats include lymphosarcoma, multiple myeloma, squamous cell carcinoma, bronchogenic carcinoma/adenocarcinoma, osteosarcoma, fibrosarcoma, undifferentiated sarcoma, undifferentiated renal carcinoma, anaplastic carcinomas of the lungs and diaphragm, and thyroid carcinoma.* Lymphosarcoma and squamous cell carcinoma are the two most common causes of hypercalcemia in cats.⁵¹¹ Of 11 hypercalcemic cats with lymphosarcoma, two each had renal, generalized, gastrointestinal, or mediastinal involvement, and one each had laryngeal, nasal, or cutaneous disease.^{61,119,161,167,511} Squamous cell carcinoma has been found in mandibular, maxillary, pulmonary, and ear canal locations.^{61,270,299,511}

Excessive secretion of biologically active PTHrP plays a central role in the pathogenesis of hypercalcemia in most forms of HHM, but cytokines such as IL-1, TNF-α, and transforming growth factor (TGF)-α and -ß or calcitriol may have synergistic or cooperative actions with PTHrP (see Fig. 6-14). Before PTHrP was identified, it was recognized that tumors associated with HHM induced a syndrome that mimicked primary hyperparathyroidism with secretion of a PTH-like factor that was antigenically unrelated to PTH.^396,606 PTHrP binds to the N-terminal PTH-PTHrP receptor in bone and the kidneys but does not cross-react immunologically with native PTH (Fig. 6-15). PTHrP stimulates adenylyl cyclase and increases intracellular calcium in bone and the kidneys cells by binding to and activating the cell membrane PTH-PTHrP receptors. This binding results in stimulation of osteoclastic bone resorption, increased renal tubular calcium reabsorption, and decreased renal tubular phosphate reabsorption. IL-1 stimulates bone resorption in vivo and in vitro and is synergistic with PTHrP.^364,480 TGF-α and -ß can stimulate bone resorption in vitro and have been identified in tumors associated with HHM, including adenocarcinomas derived from apocrine glands of the anal sac in dogs.³⁷⁴

Figure 6-15 Parathyroid hormone-related protein (PTHrP) induces many of the effects of parathyroid hormone (PTH) by interacting with the PTH receptor in bone and kidneys and activating adenylyl cyclase (AC) to form cyclic AMP (cAMP) and phospholipase C (PLC) to form inositol triphosphate (IP₃) and diacylglycerol (DAG) from phosphatidylinositol (PIP₂). Stimulation of the PTH receptor results in increased osteoclastic bone resorption and renal tubular reabsorption of calcium, inhibition of renal tubular reabsorption of phosphorus, and stimulation of renal production of 1,25-dihydroxyvitamin D₃ (calcitriol).

Lymphoma

Hypercalcemia is found in 20% to 40% of dogs with lymphoma (Fig. 6-16).^321,342 Most dogs with lymphoma and hypercalcemia have HHM because increased osteoclastic resorption is present in bones without evidence of tumor metastasis. Lymphoma is an uncommon cause of mild HHM in ferrets.²⁹⁰ Lymphomas associated with HHM are usually of the T-cell type.⁶⁰⁷ T-cell lymphoma occurred in 22% of dogs with lymphoma, and hypercalcemia only occurred in dogs with CD4⁺ lymphoma in one study.⁵⁰² The pathogenesis of hypercalcemia in dogs with lymphoma and HHM resembles that occurring in humans with lymphoma or leukemia induced by human T-cell lymphotropic virus type I (HTLV-I). Neoplastic cells from humans with HTLV-I-induced lymphoma have increased PTHrP production.⁴⁷¹

Figure 6-16 Lateral (A) and ventrodorsal (B) thoracic radiographs of a 5-year-old boxer dog with hypercalcemia of malignancy caused by mediastinal lymphoma (arrows). Severe hypercalcemia (serum total calcium concentration, 20.6 mg/dL) was detected on initial presentation.

(From Chew DJ, Carothers M. Hypercalcemia. Vet Clin North Am Small Anim Pract 1989;19:265–287.)

Most dogs with lymphoma and hypercalcemia have T-cell lymphoma.^561,607 Dogs with T-cell lymphoma were significantly more likely to have early relapse and death compared with those with B-cell lymphoma. Shorter remissions and survival times have been noted by others for T-cell lymphoma compared with B-cell lymphoma in dogs.²²⁵ In another study, 46 (32.8%) of 140 lymphomas were classified as T cell in origin, and 16 of these dogs (35%) were hypercalcemic.¹⁹⁶ In 37 dogs with lymphoma and hypercalcemia, calcium concentration was not related to prognosis; mean remission was 10.4 months, and median remission was 6 months.⁴⁷⁷ The presence of a mediastinal mass had an adverse effect on remission in these hypercalcemic dogs. Serum tCa concentration may return to normal despite minimal reduction in tumor mass following chemotherapy, as happened in 5 of 12 dogs with lymphoma and initial hypercalcemia.⁶¹⁰ The finding of hypercalcemia in dogs with lymphoma was not prognostic for survival or time to remission, but T-cell origin lymphoma did adversely affect prognosis.^298,561,590

Most dogs with lymphoma and HHM have increased circulating PTHrP concentrations, but concentrations are lower than those in dogs with carcinomas and HHM, and PTHrP concentrations are not correlated with serum calcium concentration (Fig. 6-17).⁴⁸⁹ Elevated PTHrP concentrations were found in 12 of 14 dogs with underlying malignancy, but was within the reference range in 17 normocalcemic dogs with lymphoma.³⁶⁹ Epithelial T-cell cutaneous lymphoma (mycosis fungoides) has been associated with hypercalcemia in one dog, but histopathology failed to detect PTHrP in the neoplastic cells.⁴⁴ These findings indicate that PTHrP is an important marker of HHM in dogs with lymphoma but is not the sole humoral factor responsible for stimulation of osteoclasts and development of hypercalcemia. It is likely that cytokines such as IL-1 or TNF function synergistically with PTHrP to induce HHM in dogs with lymphoma (see Fig. 6-14).^479,480

Figure 6-17 Circulating N-terminal parathyroid hormone-related protein (PTHrP) concentrations in normal dogs (CONTROL); dogs with hypercalcemia (>12 mg/dL) and anal sac adenocarcinomas (CAC), lymphoma, or miscellaneous tumors (MISC TUMOR); and dogs with normocalcemia (<12 mg/dL) and anal sac adenocarcinomas, lymphoma, or miscellaneous tumors.

(From Rosol TJ, Nagode LA, Couto CG, et al. Parathyroid hormone-related protein, parathyroid hormone, and 1,25-dihydroxyvitamin D in dogs with cancer-associated hypercalcemia. Endocrinology 1992;131:1157–1164.)

Some dogs and human patients with lymphoma and hypercalcemia have increased serum calcitriol concentrations, which may contribute to the induction of hypercalcemia.^489,527 Some lymphocytes contain the 1α-hydroxylase (similar to that found in renal tubules) that converts 25-hydroxyvitamin D to the active metabolite 1,25-dihydroxyvitamin D (calcitriol). Therefore, lymphomas that retain this capability may synthesize excessive calcitriol, which could increase calcium absorption from the intestinal tract and facilitate development of hypercalcemia.

An early report indicated that a mediastinal mass was detected in most dogs with lymphoma and hypercalcemia.³⁷⁸ However, a recent report indicates that the presence of a cranial mediastinal mass was not required for development of hypercalcemia in dogs, and mediastinal masses were not disproportionately more common in those dogs with hypercalcemia.⁵⁴

Canine Adenocarcinoma Derived from Apocrine Glands of the Anal Sac

The adenocarcinoma derived from apocrine glands of the anal sac of dogs consistently fulfills the criteria for HHM.^377,379,473 This tumor appears primarily in middle-aged (mean, 10 years) dogs and rarely metastasizes to bone. Clinical signs are referable to hypercalcemia (polyuria, polydipsia, anorexia, and weakness), a mass in the perineum (tenesmus, ribbon-like stools, increased odor, and protruding mass), a mass in the sublumbar region, or more distant metastases. Apocrine adenocarcinomas often require rectal and anal sac palpation to confirm their presence because their sizes range from 7 mm to 6 × 8 cm (Fig. 6-18). Dogs with this tumor and HHM have hypercalcemia (tCa, 12 to 24 mg/dL); hypophosphatemia; decreased immunoreactive PTH concentration; increased urinary excretion of calcium, phosphorus, and cAMP; and increased osteoclastic bone resorption.^36,379,615 This tumor should not be confused with the common perianal adenomas or the uncommon perianal adenocarcinomas that arise from the circumanal glands and have entirely different biologic behavior. Perianal adenomas and adenocarcinomas affect primarily male dogs and are not associated with hypercalcemia.⁵⁹¹

Figure 6-18 Hypercalcemia of malignancy associated with apocrine gland adenocarcinoma of the anal sac in an elderly female dog. Transverse section of the anal sac and associated malignancy (arrows).

(From Chew DJ, Meuten DJ. Disorders of calcium and phosphorus metabolism. Vet Clin North Am Small Anim Pract 1982;12:411–438.)

Hypercalcemia was present at the time of diagnosis in 80% to 100% of affected dogs in early studies.^357,360 Recent reports in dogs with earlier detection note the incidence of hypercalcemia to be lower, at 33%,⁴⁹⁶ 27%,⁶¹⁵ and 53% of cases.³⁶ Early reports also noted a strong bias toward the occurrence of this tumor in female dogs, but equal sex distribution has been more recently noted.⁶¹⁵ In some instances, the finding of hypercalcemia during routine serum biochemistry testing prompts rectal palpation and subsequent discovery of an apocrine gland adenocarcinoma. Surgical removal or radiation therapy of the adenocarcinoma results in rapid return to normal of serum calcium and phosphorus concentrations, increased serum PTH concentration, and decreased calcitriol concentration.⁴⁸⁹ Postsurgical survival of dogs with apocrine gland adenocarcinoma and hypercalcemia ranged from 2 to 21 months, with a mean of 8.8 months. Sublumbar metastases occur in a high percentage (72%) of affected dogs and are associated with recrudescence of the biochemical alterations in serum and urine.³⁶ In one study, dogs with hypercalcemia and anal sac adenocarcinoma had shorter survival times compared with normocalcemic dogs with this tumor (356 vs. 584 days)⁶¹⁵; in another study, survival was not influenced by the presence of hypercalcemia.³⁶

Most dogs with HHM have increased concentrations of circulating PTHrP (see Fig. 6-17). Plasma concentrations of PTHrP are highest (10 to 100 pmol/L) in dogs with apocrine adenocarcinomas of the anal sac and sporadic carcinomas associated with HHM.⁴⁸⁹ Serum calcium concentrations in affected dogs correlate well with circulating PTHrP concentrations, which is consistent with the concept that PTHrP plays a primary role in the pathogenesis of HHM in these dogs. Dogs with apocrine adenocarcinomas and normocalcemia may have increased plasma PTHrP concentrations (2 to 15 pmol/L), but the concentrations are lower than those in dogs with hypercalcemia.

Some dogs with apocrine adenocarcinomas have inappropriate concentrations (normal or increased) of calcitriol for the degree of hypercalcemia.⁴⁸⁹ This finding suggests that the humoral factors produced by the neoplastic cells are capable of stimulating renal 1α-hydroxylase and increasing the formation of calcitriol even in the presence of increased serum calcium concentration. PTH concentrations were not increased in hypercalcemic dogs and were significantly lower than those observed in dogs with primary hyperparathyroidism. Parathyroid glands from dogs with apocrine adenocarcinoma were atrophic or inactive, and there was nodular hyperplasia of C cells in the thyroid glands because of prolonged hypercalcemia.³⁷⁹

Primary Hyperparathyroidism

Primary hyperparathyroidism is an uncommon cause of hypercalcemia in dogs^40,87 and is even less common in cats.^141,285 In hypercalcemic cats, primary hyperparathyroidism was found in 4 of 71 cases.⁵¹¹ Excessive and inappropriate secretion of PTH by the parathyroid glands relative to the serum iCa concentration characterizes this condition. In a review of 210 dogs with primary hyperparathyroidism, all dogs had hypercalcemia, and 65% had hypophosphatemia. BUN and serum creatinine concentrations were within or below the reference range in 95% of cases. Serum PTH concentration was within the reference range in 73% of dogs. Primary hyperparathyroidism was caused by a solitary parathyroid gland adenoma in approximately 90% of dogs, whereas parathyroid gland carcinoma and parathyroid gland hyperplasia each accounted for 5% of cases in one large series.¹⁷⁸ Adenomas occurred with nearly equal frequency in the external and internal parathyroid glands in one study,⁴⁰ but external gland adenomas predominated in another report in dogs.⁶¹⁹ Idiopathic parathyroid gland hyperplasia may affect one or more glands and has been reported in six older dogs.¹⁴³ Although remnant parathyroid tissue may be found in the cranial mediastinum near the base of the heart, neoplastic transformation has not been reported at this site in dogs or cats. An ectopic parathyroid gland adenoma cranial to the thoracic inlet has been described in one dog.⁶¹⁸ In cats, the underlying lesion is typically benign, owing to an adenoma, bilateral cystadenomas, or hyperplasia,^{141,172,511,550} but unilateral or bilateral carcinomas have also been diagnosed.^{178,285,353,452}

Primary parathyroid gland hyperplasia has been reported in two German shepherd dog puppies.⁵⁶⁸ Diffuse hyperplasia was present in all four parathyroid glands. In retrospect, this family of German shepherd dogs probably had an inactivating mutation in the gene for the calcium-sensing receptor. Mutations in one or both of the calcium-sensing receptor genes in humans result in familial hypocalciuric hypercalcemia or neonatal severe hypercalcemia, respectively, because of an inadequate ability to sense extracellular calcium concentration and coordinate the appropriate cellular response.⁴⁵⁴ The affected puppies had a disease syndrome that mimicked neonatal severe hypercalcemia in humans. Neonatal severe hypercalcemia is lethal unless total parathyroidectomy is performed early in life to markedly reduce increased PTH concentrations.

Dogs with primary hyperparathyroidism are older: in one review of 210 dogs with primary hyperparathyroidism, the mean age of affected dogs was 11.2 years (range, 6 to 17 years);¹⁷⁷ in another study, the mean age of affected dogs was 10.5 years (range, 5 to 15 years).¹⁷⁸ The mean age in affected cats was 12.9 years (range, 8 to 15 years).²⁸⁵ No sex predisposition has been noted, but keeshonds constituted 36% of affected dogs, and five of eight cats were Siamese.³⁸⁰ Parathyroid gland masses usually cannot be palpated in dogs, but 50% of cats with primary hyperparathyroidism had a palpable cervical mass.^141,285 Clinical signs related to hypercalcemia are either mild (e.g., lethargy, polydipsia, polyuria, and weakness) or absent in many affected dogs.^40,178 In one study, most owners of affected dogs were not convinced that their dogs had a serious illness,⁴⁰ but some owners retrospectively recognized subtle signs after hypercalcemia resolved.¹⁷⁸ In 210 dogs with primary hyperparathyroidism, the most common clinical signs were related to urinary tract infections or urolithiasis.¹⁷⁷ No abnormalities were noted in 71% of dogs. Urinary tract infection was present in 29% and urolithiasis was present in 31% of dogs in this study. Other studies have shown that calcium-containing uroliths (calcium phosphate, calcium oxalate, or mixtures) occurred in approximately 30% of dogs and in a cat with primary hyperparathyroidism.^178,300,353 Urolithiasis is attributed to hypercalcemia and subsequent hypercalciuria. Interestingly, hypercalcemia arising from other causes has not been associated with urolithiasis except in cats with idiopathic hypercalcemia (IHC).⁵²⁰ More prominent clinical signs and serious consequences can occur when hyperparathyroidism and severe hypercalcemia are long standing and associated with renal failure.^115,116

The diagnostic workup to confirm primary hyperparathyroidism often begins with the fortuitous finding of increased serum calcium concentration on routine clinical chemistry testing.¹⁷⁸ The diagnosis of primary hyperparathyroidism is easy in dogs and cats that have increased serum tCa concentration, normal renal function, and increased concentration of immunoreactive PTH. The appropriateness of the PTH concentration must be interpreted in relation to the serum iCa concentration. Additional support for the diagnosis of primary hyperparathyroidism is provided by the finding of increased serum iCa concentration, increased serum ALP, low serum phosphorus concentration, increased or normal calcitriol concentration, undetectable PTHrP, and calcium-containing uroliths. The most consistent laboratory abnormality in dogs with primary hyperparathyroidism is increased serum calcium concentration.¹⁷⁸

Hypercalcemia results from a combination of effects following PTH binding to receptors in kidneys and bone. PTH also acts indirectly to increase serum iCa concentration by enhancing renal conversion of 25-hydroxyvitamin D to calcitriol. Hypophosphatemia secondary to PTH-enhanced urinary excretion of phosphorus was observed in 5 of 21 dogs.⁴⁰ Serum phosphorus concentration is typically low,¹⁷⁸ and calcitriol concentrations were mildly increased or in the high-normal range in three of four dogs with primary hyperparathyroidism.⁴⁸⁹

The diagnosis of primary hyperparathyroidism is more challenging when PTH is within the reference range. A PTH concentration in the upper part of the reference range in association with hypercalcemia is inappropriate. Confirmed primary hyperparathyroidism has been noted in dogs and cats with hypercalcemia and reference range PTH concentrations.^178,285 In a cat with persistent hypercalcemia related to primary hyperparathyroidism, PTH concentration was increased on two occasions but within the reference range on five other occasions.¹⁴¹ PTH concentrations measured in blood collected from either the left or right jugular vein did not differ, and sampling from a specific side was not valuable for localizing the site of an enlarged parathyroid gland.¹⁸⁰ Circulating PTHrP concentrations were undetectable in six dogs with primary hyperparathyroidism.⁴⁸⁹

Ultrasonography of the neck is helpful in the diagnosis of primary hyperparathyroidism in dogs and cats, but it requires an ultrasound unit with a high-frequency (7.5- to 10-MHz) transducer to achieve the necessary level of resolution rather than the widely available 5- or 7.5-MHz units used for abdominal studies.^178,618 With a 10-MHz linear transducer, the parathyroid glands of normal dogs can routinely be identified especially in larger dogs.⁴⁶⁹ Parathyroid gland masses greater than 5 mm can usually be identified, and some masses as small as 2 mm may be detected. Enlarged parathyroid glands are expected to be hypoechoic or anechoic, well marginated, and easily contrasted with thyroid tissue. False-positive results are rare, but false-negative findings may occur. Ultrasonography correctly identified the presence and location of a solitary parathyroid gland mass in 10 of 11 dogs in a prospective study in which the mass was confirmed at surgery.¹⁸⁰ Sonography identifies the location of the parathyroid gland tumor and allows presurgical planning.

Double-phase scintigraphy of the parathyroid glands using ^99mTc sestamibi was useful in the diagnosis of parathyroid gland adenoma in initial reports from two dogs.^362,626 In a study of 15 dogs with hypercalcemia, scintigraphy correctly identified 3 of 3 dogs with hypercalcemia of malignancy as negative for hyperfunctioning parathyroid glands.³⁶¹ Scintigraphy identified only one of six dogs with a parathyroid gland adenoma and only one of six dogs with parathyroid hyperplasia. Based on these results, parathyroid gland scintigraphy is not recommended to identify abnormal parathyroid glands because of very poor sensitivity and specificity.

Surgical exploration of the cervical region in patients with parathyroid gland adenoma or carcinoma usually reveals enlargement of one parathyroid gland, and the remaining three are small or impossible to identify because hypercalcemia results in atrophy of normal parathyroid tissue. Primary parathyroid gland hyperplasia may affect more than one gland, and clinical signs can recur if only the largest gland is removed surgically. Parathyroid gland tumors may be difficult to identify if the tumor is embedded in fat or if it arises from the internal parathyroid gland. Failure to visualize a parathyroid gland tumor is rarely attributed to the occurrence of a tumor in ectopic parathyroid tissue. Methylene blue infusion to enhance visualization of parathyroid glands should be reserved for patients in whom a tumor is strongly suspected but not readily identified during surgery because clinically relevant side effects of methylene blue administration include hemolytic anemia and acute renal failure.¹⁸⁵ In 47 dogs with primary hyperparathyroidism treated with parathyroidectomy, 94% of surgeries resulted in control of hypercalcemia.⁴⁶⁴ Hypercalcemia resolved within 1 to 6 days, and remained within the reference range for a median of 561 days. The use of a rapid PTH assay for intraoperative measurement of PTH may be helpful to demonstrate a decrease in PTH concentration after excision of autonomously secreting parathyroid tissue.²³³

Ultrasound-guided chemical ablation was used safely and effectively as an alternative treatment to surgery in eight dogs with a solitary parathyroid gland mass and hypercalcemia.³³⁶ Serum tCa and iCa concentrations were within reference ranges 24 hours after treatment in seven dogs and within 5 days in one dog. Transient hypocalcemia developed in four dogs during the first 5 days after treatment; one dog required treatment for hypocalcemic tetany. Dysphonia was noted in two of eight dogs in this study, but Horner syndrome, laryngeal paralysis, and death were not encountered as has been described with ethanol injection of thyroid glands of hyperthyroid cats.^213,592,612 It is likely that the low volume of ethanol injected into a single parathyroid mass provides less potential for leakage beyond the parathyroid mass. In a review of treatment of 110 dogs with primary hyperparathyroidism, 72% of ethanol ablation procedures resulted in a control of hypercalcemia.⁴⁶⁴ Hypercalcemia resolved in 1 to 4 days, and remained within normal limits for a median of 540 days.

Ultrasonographically guided radiofrequency heat ablation of parathyroid masses in dogs has become the preferred treatment at some referral hospitals. In one study, 11 dogs with either one or two masses on ultrasonography were treated by radiofrequency heat following anesthesia and insertion of a 20-gauge over-the-needle catheter into the mass.⁴⁵⁵ Hypocalcemia developed in five of the eight successfully treated dogs, all of which required treatment. The only other adverse effect was a transient voice change in one dog. In 49 dogs with primary hyperparathyroidism treated with heat ablation, 90% of procedures resulted in a control of hypercalcemia.⁴⁶⁴ Hypercalcemia resolved in 1 to 6 days, and remained within normal limits for a median of 581 days.

Hypervitaminosis D

Hypervitaminosis D refers to toxicity resulting from excess cholecalciferol (vitamin D₃) or ergocalciferol (vitamin D₂). Metabolites of vitamin D can also exert toxicity, and the term hypervitaminosis D has been extended clinically to include toxicity from 25-hydroxyvitamin D, dihydrotachysterol, and 1,25-dihydroxyvitamin D (calcitriol), as well as newer analogues of calcitriol. Vitamin D toxicity is better referred to as 25-hydroxyvitamin D toxicity, because vitamin D is rapidly transformed into this metabolite in vivo.¹⁹⁹ Vitamin D and its immediate metabolite, 25-hydroxyvitamin D, have little biologic activity at physiologic concentrations because they have low binding affinity for the VDR. Pharmacologic concentrations of 25-hydroxyvitamin D that occur during hypervitaminosis D exert hypercalcemic effects, because 25-hydroxyvitamin D competes with calcitriol for binding to the VDR in target tissues.^162,404 Hypercalcemia results from increased intestinal absorption of calcium, but increased osteoclastic bone resorption and calcium reabsorption from renal distal tubules may also contribute.

Vitamin D intoxication and hypercalcemia may result from excessive dietary supplementation or may be caused iatrogenically during the treatment of hypoparathyroidism. Accurate dosing with cholecalciferol and ergocalciferol is difficult because they have a slow onset and prolonged duration of action.^40,530 Hypercalcemia developed in 7 of 16 hypoparathyroid dogs during treatment with vitamin D and calcium salt supplementation.⁴⁰ Ingestion of toxic plants that contain glycosides of calcitriol (e.g., Cestrum diurnum, Solanum malacoxylon, and Trisetum flavescens) is a potential cause of hypercalcemia in small animals.⁴²⁸ Vitamin D toxicity associated with ingestion of C. diurnum has been reported in a cat.¹⁵¹ C. diurnum, day-blooming jessamine, has achieved increasing popularity as a house plant and should not be confused with jasmine, which is an indoor climbing plant without active vitamin D metabolites.⁸⁵

A diagnosis of hypervitaminosis D in dogs and cats increased with the introduction of cholecalciferol-containing rodenticides in 1985, but this source of intoxication is less common today. Cholecalciferol bait is delivered as pellets that are palatable to some animals and are very toxic when ingested. One manufacturer claimed a low hazard to dogs (oral median lethal dose, 88 mg/kg), but toxicity at a lower dosage (10 mg/kg) was demonstrated.^162,228 High-risk groups include dogs weighing 12 kg or less and those younger than 9 months. Recovery from previous cholecalciferol toxicity can be a risk factor for subsequent occurrence because removal of the source from the premises may not be possible.¹¹² Toxicity in four cats has also been reported.^390,441 One reason for the few reports of vitamin D toxicity in cats is that they appear to be resistant to cholecalciferol toxicity when the diet is otherwise complete and balanced.⁵³⁴

Clinical signs are usually vague and include anorexia, lethargy, vomiting, tremors, constipation, and polyuria. These signs are usually attributed to the effects of hypercalcemia. Hypercalcemia is reversible with early and aggressive therapy by providing enough time for 25-hydroxyvitamin D to be eliminated from the body.^107,149,162 Death occurred in approximately 45% of dogs after developing hypercalcemia from hypervitaminosis D in early reports,^{162,228,344,500} but the survival rate was higher in dogs of a later series.¹⁰⁷

Hypercalcemia usually develops within 24 hours after ingestion,²²⁸ and hypercalcemia is often severe unless serum samples were obtained within 24 hours of ingestion. Mild hyperphosphatemia is often noted. Azotemia is initially absent but can develop subsequently. Serum creatinine concentration usually is less than 3 mg/dL unless treatment has been delayed, in which case azotemia may be marked. It may take as long as 72 hours for azotemia to develop as a result of renal lesions caused by hypercalcemia. Measurement of serum 25-hydroxyvitamin D concentration can provide conclusive evidence for hypervitaminosis D after exposure to cholecalciferol or ergocalciferol. Serum concentrations of 25-hydroxyvitamin D were increased to at least twice the upper limit of normal, with a mean concentration approximately 10 times the normal in dogs with hypervitaminosis D¹⁰⁷ and were increased for weeks to months in some instances.¹⁴⁹ In ten episodes of cholecalciferol intoxication, concentrations of cholecalciferol were increased above the normal range for 10 to 61 days.¹¹² The half-life for cholecalciferol was 29 days in experimental dogs.⁵⁰⁰ Serum calcitriol concentrations were also increased early in the syndrome,¹⁰⁷ but suppression of calcitriol synthesis occurs later.

Hypervitaminosis D with hypercalcemia, azotemia, high concentrations of 25-hydroxyvitamin D, and/or renal calcification has been described in cats from Japan fed fish-based commercial cat food.^236,391,509 Cholecalciferol content of these diets exceeded the dietary requirements of vitamin D by more than 100 times. Renal disease and failure occurred within 4 to 14 months in a large number of cats fed a commercial cat food containing 30 times the vitamin D requirement.³⁹² All commercial cat foods provide vitamin D in excess of the minimal requirements, and there is no regulated upper limit on the quantity of vitamin D that can be included. Other factors may modulate the toxicity of hypervitaminosis D, such as increased dietary calcium and phosphorus or dietary reduction in magnesium.⁵³⁴ Hypervitaminosis D with hypercalcemia, high concentrations of serum 25-hydroxyvitamin D and calcitriol concentrations have been described in two dogs that consumed a commercial diet containing more than 100 times the manufacturer-stated vitamin D concentration.³⁷⁰ Accidental oversupplementation of commercial dog and cat foods with excessive vitamin D resulted in a large recall of products in 2006.

Hypercalcemia attributed to the effects of increased calcitriol occasionally occurs during calcitriol treatment in animals with hypoparathyroidism and rarely during treatment of renal secondary hyperparathyroidism. When hypercalcemia is observed, it is usually in patients given doses more than 3.5 ng/kg daily. Discontinuation of calcitriol should result in normocalcemia within 1 week. Dosing with calcitriol at twice the daily dosage every other day up-regulates fewer intestinal epithelial cells for calcium absorption and decreases the chance for further development of hypercalcemia. No adverse effects were noted when using this intermittent dosing protocol in one study in 20 cats.²⁶³ Formulation errors have also been encountered in which the concentration of calcitriol in a compounded product was too high. There are no veterinary preparations of calcitriol; thus, the available preparations of calcitriol must be diluted in pharmaceutical oils for appropriate dosing. Hypercalcemia has also been encountered when dosing errors have been made (mg/kg amounts given as opposed to ng/kg amounts). High serum concentrations of calcitriol have been observed in some dogs with lymphoma and hypercalcemia,⁴⁸⁹ but it is not clear whether the excess calcitriol was synthesized by the tumor or by the kidneys under stimulation of PTHrP.

Topical ointments containing potent vitamin D analogues (calcipotriene) for treatment of human psoriasis can result in hypercalcemia when toxic quantities are ingested by dogs.* Minimal toxic dose is 10 μg/kg; minimal lethal dose is 65 μg/kg; and the oral LD50 is between 100 and 150 μg/kg in dogs.²³⁴ In 25 dogs with calcipotriene ingestion, 28% died and 50% experienced AIRF. Phosphorus, tCa, and iCa are elevated with calcipotriene toxicity.^230,234 The affinity of calcipotriene for vitamin D-binding protein is much lower than that of calcitriol; thus, free calcipotriene is readily available for binding to VDRs. The rapid binding to VDRs accounts for the rapid onset of hypercalcemia and hyperphosphatemia and also for the rapid catabolism of calcipotriene. Hypercalcemia decreases after several days rather than being prolonged for weeks to months as seen in cholecalciferol toxicity. Exposure to calcipotriene has not yet been reported in cats, although there are several anecdotal reports of cats that developed hypercalcemia after licking calcipotriene from their owner’s skin. Telephone calls to animal poison control centers indicate that exposure to this ointment has been increasing in dogs.³⁵⁴ Whether calcipotriene cross-reacts with calcitriol in the measurement of vitamin D metabolites has not yet been determined, but it is not detected by methods to measure 25-hydroxyvitamin D.

Granulomatous Disease

Hypercalcemia can result from calcitriol synthesis by activated macrophages during granulomatous inflammation. Normal macrophages express 1α-hydroxylase activity (which converts 25-hydroxyvitamin D to calcitriol) when stimulated by interferon or lipopolysaccharide. Macrophages in granulomatous inflammation express such activity without stimulation.¹⁵⁹ Blastomycosis is a granulomatous disease in dogs that is occasionally (5% to 14% of cases) associated with hypercalcemia. Hypercalcemia is usually mild but can be severe.^15,150 In a study of 38 dogs with blastomycosis, 5% had elevated serum iCa but only 2.6% had elevated serum tCa.¹³² In this study, 61% of dogs with blastomycosis had low serum tCa, but no dogs were hypocalcemic based on serum iCa concentration, showing an overestimation of hypocalcemia based on serum tCa measurement. Reports of granulomatous diseases associated with hypercalcemia include a dog with gastric pythiosis,³²³ a dog with granulomatous lymphadenitis,³⁷² two cats with disseminated histoplasmosis²⁵⁰ and dogs with coccidioidomycosis or schistosomiasis.^178,581 In one dog with schistosomiasis, PTHrP levels were undetectable,⁴⁷⁶ but in two other dogs with schistosomiasis, PTHrP levels were increased with no malignancy found at necropsy.¹⁹⁷ In cats, elevated calcitriol concentrations were documented in cases of Nocardia and atypical mycobacteria infection.³⁶⁸ Cats with blastomycosis, cryptococcosis, actinomyces, and injection site granulomas (Chew and Peterson, unpublished observations on injection site granuloma)^368,511,547 have been noted with hypercalcemia possibly because of enhanced synthesis of calcitriol.¹⁵⁰ Severe hypercalcemia was observed in association with noninfectious granulomatous dermatitis in two dogs in which excess synthesis of calcitriol was suspected (Kwochka and Chew, unpublished observations). PTH, PTHrP, and 25-hydroxyvitamin D concentrations were not increased. Hypercalcemia resolved as the inflammation subsided. In a dog with granulomatous lymphadenitis, serum PTH concentration was low but serum calcitriol concentration was elevated.³⁷² Nodular panniculitis with hypercalcemia has been reported in dogs, and calcitriol concentrations were two to three times the normal in one instance.^166,448

Idiopathic Hypercalcemia of Cats

Hypercalcemia may be less common in cats than in dogs, although the incidence of hypercalcemia from primary care practices is not reported. Within the past 10 years, IHC has been recognized in cats^365,381 and is now the most common cause of ionized hypercalcemia in cats in the United States. Even though some suggest that IHC is a local geographic phenomenon,¹⁷⁸ it is widespread across the United States and is being recognized in other parts of the world.

In IHC, serum calcium concentration may be increased for months to more than 1 year. In 427 cases of feline IHC, 46% had no clinical signs, 18% had mild weight loss with no other clinical signs, 6% had inflammatory bowel disease, 5% had chronic constipation, 4% were vomiting, and 1% were anorectic.⁵²⁰ Uroliths or renoliths were observed in 15%, and calcium oxalate stones were noted in 10% of cases. Cats ranged in age from 0.5 to 20 years, and long-haired cats accounted for 27% of the cases (compared with an overall submission rate of 14% from long-haired cats). There was no sex predilection. Serum iCa concentration was increased; PTH concentration was in the lower half of the reference range; and PTHrP was negative in all samples. Concentration of iMg was normal, and mean concentration of 25-hydroxyvitamin D was within the reference range. Calcitriol was measured in a small number of these cats and was suppressed. In another study, 1 of 7 cats exhibited an increased concentration of calcitriol, and 2 of 11 cats had increased PTHrP in the absence of underlying neoplasia following extensive diagnostic evaluation, survival for many months, and necropsy.³⁸¹ It appears that excessive PTH, 25-hydroxyvitamin D, or calcitriol concentration is not the cause of IHC in most cats. However, normal concentrations of calcitriol could result in hypercalcemia if there are mutations of the VDR or an increase in the number of calcitriol receptors. Normal concentrations of iMg indicate that PTH secretion is not inhibited by decreased or excess iMg.⁵²⁰ Renal function, based on BUN and serum creatinine concentration, is usually normal initially, but some cats develop CRF secondary to long-standing IHC.³⁸¹ Results of serology testing for feline leukemia virus and feline immunodeficiency virus have been negative, and serum thyroxine concentrations have been normal. Chronic acidosis could explain chronic elevations of iCa,¹²¹ but venous blood gas analysis has not revealed significant acid-base disturbances. Exploration of the cervical region has not identified primary hyperparathyroidism, and subtotal parathyroidectomy has not resolved hypercalcemia in cats in which this procedure was performed.³⁸¹

As many as 35% of cats with calcium oxalate urinary stones have hypercalcemia. Even though the specifics of the underlying diagnoses were not detailed,⁴²⁴ it is likely that most had IHC. The occurrence of ureterolithiasis in cats was very uncommon before 1993. Eleven cases of calcium oxalate ureterolithiasis were recently described in cats, and four had mild to moderate hypercalcemia.³¹⁹ It appears that the frequency of hypercalcemia in calcium oxalate stone-forming cats has decreased substantially (Lulich, personal communication, 2003).

Specific treatment for IHC is impossible because the pathogenesis remains unknown. Increased bone resorption, increased intestinal absorption, or decreased renal excretion of calcium or combinations of these mechanisms could be responsible for hypercalcemia. The feeding of increased dietary fiber decreased serum calcium in some cats³⁶⁵ but not in others.³⁸¹ The beneficial effect of a higher fiber diet may be because of decreased intestinal absorption of dietary calcium. The effects of fiber on intestinal absorption are complex and depend on the types and amounts of fiber in the diet and other nutrients present.

The feeding of veterinary renal diets may result in normocalcemia in some cats with IHC. These diets are generally low in calcium and phosphorus and are considered alkalinizing or at least less acidifying than maintenance diets. Some cats that show an initial decrease in serum calcium concentration following any type of dietary change will have a return to hypercalcemia over time.

In those cats that do not respond to a change in diet, prednisone therapy may result in a long-term decrease in iCa. The effects of glucocorticosteroid treatment may last for months to years in some cats with doses of 5 to 20 mg prednisone/cat/day. There is an escape from the effects of glucocorticosteroid treatment in some cats and a return to hypercalcemia despite maximal doses of prednisone. When dietary modification and treatment with prednisolone have been unsuccessful in resolving IHC, intravenous pamidronate treatment can be considered.

Beneficial effects from the chronic administration of subcutaneous fluids or oral furosemide to cats with IHC have not been evaluated. Treatment with calcimimetics could be of benefit. Calcimimetics interact with the calcium receptor and are effective in decreasing calcium, phosphorus, and PTH in human patients.⁵⁵

Uncommon Causes of Hypercalcemia

AIRF in dogs is occasionally associated with mild hypercalcemia. Hypercalcemia may occur more commonly after conversion of oliguria to polyuria, possibly as calcium salts that were deposited during oliguria are mobilized from soft tissues. Sudden improvement in renal function also may result in a rapid decrease of serum phosphorus concentration, changing mass law interactions between phosphorus and calcium and resulting in transient hypercalcemia. Mild hypercalcemia (11.5 to 12.5 mg/dL) is observed uncommonly in some dogs with severe oliguria and decreased GFR during intrinsic renal failure. Animals with severe hyperphosphatemia during AIRF usually have normal or low serum calcium concentrations.

Nonmalignant skeletal lesions are occasionally associated with hypercalcemia in dogs. Bacterial and fungal osteomyelitis can potentially result in hypercalcemia if the rate of osteolysis is sufficient.¹¹¹ Hypercalcemia associated with hepatozoonosis and skeletal involvement has been reported.³⁵¹ In 30 dogs with systemic aspergillosis, 27% had hypercalcemia.⁵²³ Neonatal septicemia has been associated with hypercalcemia on rare occasions in puppies after septic embolization of bone and subsequent osteolysis.¹¹¹ Mild hypercalcemia occurs in some dogs with hypertrophic osteodystrophy, and the hypercalcemia may be aggravated by ascorbic acid supplementation.⁵⁵⁸ Hypothermia has caused hypercalcemia in one cat.⁴²⁹ One cat with pancreatitis and hypercalcemia has been described, even though hypocalcemia is more common in cases of pancreatitis.²⁴⁷ In one report, a dog receiving intermittent calcium therapy for hypocalcemia developed hypercalcemia and acute pancreatic hemorrhage that may have been related to excessive calcium therapy.⁴⁰⁹ Dehydration may cause mild and reversible hypercalcemia, especially with normal kidney function. Disuse osteoporosis after prolonged immobilization can rarely contribute to the development of mild hypercalcemia because weight bearing is necessary to maintain the balance between new bone formation and resorption of old bone. Serum total hypercalcemia has been noted in a small percentage of hyperthyroid cats,^28,511 but iCa concentration is normal. In cats with untreated hyperthyroidism, mild ionized hypercalcemia that resolved following conversion to euthyroidism with treatment has been uncommonly noted (Chew, unpublished observations). Overuse of calcium-containing intestinal phosphate binders can occasionally cause hypercalcemia.¹¹¹ An unusual case of hypercalcemia was attributed to the chronic ingestion of calcium carbonate in the form of limestone rocks.²⁹⁶ Malignant histiocytosis in dogs was reported in association with hypercalcemia in one dog.⁵⁸⁶

The ingestion of large amounts of grapes or raisins may result in hypercalcemia. Seven of 10 dogs with renal failure associated with grape or raisin ingestion had increased serum tCa concentrations (12.3 to 26 mg/dL) and increased serum phosphorus (6.4 to 22 mg/dL) 24 hours to several days following ingestion.²³⁰ In four dogs, ingestion was estimated to be from 0.41 to 1.1 ounces of grapes or raisins per kilogram of body weight. Oliguria or anuria was noted in 5 of 10 dogs, and 5 of 10 dogs survived. These cases were clustered from 1999 to 2001, and raisin/grape toxicity had not been previously reported.

Vomiting following ingestion of what appears to be a trivial quantity of raisins or grapes in some dogs leads to the development of AIRF usually within 48 hours. Not all dogs that consume grapes or raisins develop clinical signs or acute renal failure. Of 132 dogs reported with raisin or grape ingestion, 33 developed no clinical signs or azotemia, and 14 of 133 dogs developed clinical signs but no azotemia.¹⁶⁹ Of 132 cases, 43 dogs developed clinical signs and AIRF. The pathogenesis of nephrotoxicity associated with raisins and grapes remains unknown, but it is speculated that ochratoxin may be a toxic component.⁴⁴⁹ Tubular degeneration and necrosis of varying severity are consistently described and most pronounced in proximal tubules.^169,394

In some cases of grape or raisin ingestion with AIRF, mild to severe hypercalcemia develops, and in some dogs, serum tCa concentration can change dramatically from day to day during various treatments.³⁶³ With acute renal failure following ingestion of raisins or grapes, hypercalcemia was detected in 93% of affected dogs, and tCa ranged from 8 to 26 mg/dL.^169,230 Of 40 dogs, 23 (57.5%) survived, and 17 (42.5%) failed to survive; 15 of 23 underwent complete resolution of azotemia. Initial and peak serum tCa concentrations and initial and peak calcium X phosphorus products were significantly higher in those that did not survive as compared with those that did survive. Hypercalcemia was documented in 1 of 3 dogs evaluated within 24 hours of ingestion, in 2 of 8 dogs within 24 to 48 hours, and in 12 of 13 dogs evaluated for the first time 48 to 72 hours after ingestion. Total calcium concentration returned to the normal range in a median of 11 days (range, 2 to 51 days). Unfortunately, iCa measurements have yet to be reported for any dogs with raisin toxicity, AIRF, and hypercalcemia based on serum tCa. Because many dogs with severe AIRF have hyperphosphatemia, some of the increased serum tCa may be because of complex formation with phosphate. The observation that serum tCa concentration can dramatically increase or decrease daily during treatment suggests that its origin is related to extracellular or intravascular fluid volume dynamics.

A favorable outcome is possible in about 50% of cases, but several weeks of hospitalization with intensive fluid treatment is often needed in those with AIRF, especially if oliguric. About 50% of affected dogs can be expected to develop oliguria or anuria.^169,230,363 A case of AIRF with a fatal outcome occurred after ingestion of 450 grams of raisins in a vizsla dog despite intensive treatment, including peritoneal dialysis.⁴³⁷ Aggressive treatment has been recommended for any dogs suspected of having ingested large, or even small, quantities of grapes or raisins, including induction of emesis, gastric lavage, and administration of activated charcoal, followed by intravenous fluid therapy for a minimum of 48 hours.²³⁰ However, some dogs may consume relatively large quantities of grapes or raisins without development of ill effects.

Hypercalcemia was reported in a dog with a retained fetus and endometritis.²⁴⁸ Serum PTH was suppressed, and 25-hydroxyvitamin D concentration was within the normal range. Biopsy of the removed uterus documented neutrophilic inflammation but no granulomatous inflammation as a possible cause of the hypercalcemia. Serum iCa was normal 4 days after surgical removal of the uterus, and serum tCa was normal 6 weeks later.

Humoral hypercalcemia of benignancy is a phrase used to describe the association of humoral factors such as PTHrP and hypercalcemia in the absence of malignancy.^197,302 One dog with massive mammary gland hyperplasia, severe ionized hypercalcemia, and increased PTHrP in the absence of malignancy at necropsy has been observed (Chew, unpublished observations). This phenomenon has rarely been described in humans.^278,292

Philosophy of Treatment

There is no absolute serum calcium concentration that can be used as a guideline for the decision to treat hypercalcemia aggressively.^113,184 The magnitude of hypercalcemia, its rate of development, whether the serum calcium concentration is stable or progressively increasing, and the modifying effects of other electrolyte and acid-base disturbances must all be considered when deciding on a treatment plan. The clinical condition of the animal ultimately dictates how aggressive treatment should be, but a serum calcium concentration of 16 mg/dL or greater has been recommended as a basis for aggressive therapy.¹⁸⁴ Animals with serum calcium concentrations approaching 20 mg/dL should be considered candidates for crisis management. Animals with serum calcium concentrations less than 16 mg/dL may also require aggressive treatment, depending on the degrees of neurologic, cardiac, and renal dysfunction induced by the hypercalcemia and concurrent deleterious factors. Acidosis can magnify the effects of hypercalcemia at all serum calcium concentrations by shifting more calcium to the ionized fraction. The serum phosphorus concentration at the time of hypercalcemia is also an important modulating factor in clinical decision making because soft tissue mineralization is potentiated by hyperphosphatemia. Animals with rapid and progressive development of hypercalcemia usually display serious clinical signs that require aggressive therapy.

Definitive Therapy

Removal of the underlying cause is the definitive treatment for hypercalcemia. Most animals with pathologic hypercalcemia have an associated malignancy that is quickly diagnosed but often not readily treated. Complete excision of isolated neoplasms (e.g., apocrine gland adenocarcinoma of the anal sac and parathyroid gland adenoma) abolishes hypercalcemia. In animals with disseminated metastases, multicentric neoplasia, or nonresectable primary malignancy, the tumor burden and hypercalcemia may be decreased by appropriate chemotherapy, radiation therapy, and immunotherapy. Chemotherapy may disrupt neoplastic cellular metabolism to such an extent that the tumor may no longer be able to synthesize enough humoral factors to sustain hypercalcemia. Decreased serum calcium concentrations can occur despite a lack of obvious reduction in tumor size in these instances.

Antifungal treatment with amphotericin B, ketoconazole, or itraconazole effectively lowers increased serum calcium concentrations in dogs with systemic mycoses as the infectious agent is eradicated and inflammation resolves. For animals with hypercalcemia associated with hypoadrenocorticism, replacement therapy with mineralocorticoids and glucocorticoids after fluid volume replacement definitively manages the condition. Discontinuing all vitamin D supplementation in animals with hypervitaminosis D and hypercalcemia removes the external cause of intoxication, but excessive body stores of vitamin D may continue to contribute to hypercalcemia for several weeks.

Supportive Therapy

Supportive therapy is often necessary to decrease serum calcium concentration to a less toxic level while waiting for a definitive diagnosis to be established, for definitive treatment to reduce serum calcium concentration permanently, or for chronic management of hypercalcemia when the underlying cause cannot be removed. Box 6-3 and Table 6-3 list the general and specific treatments for the management of hypercalcemia. Unfortunately, no single treatment protocol is consistently effective for all causes of hypercalcemia. Consequently, regimens must be tailored for the individual patient. Supportive treatments reduce the magnitude of hypercalcemia by increasing renal calcium excretion, inhibiting bone resorption, promoting soft tissue deposition of calcium, causing a shift of intravascular calcium to other body compartments, promoting extrarenal calcium loss, reducing calcium transport across the gut, or some combination of these effects.^113,315,354

Table 6-3 Specific Treatment of Hypercalcemia

Initial Considerations for Treatment

Parenteral fluids, furosemide, sodium bicarbonate, glucocorticoids, or combinations of these treatments effectively reduce serum calcium concentrations in most animals. Repeatable serum hypercalcemia should be confirmed before prescribing aggressive treatments. It is not necessary to reduce serum calcium concentration to within normal limits, but substantial resolution of serious clinical signs may occur when serum tCa concentration decreases by as little as 1 to 3 mg/dL.