Hypercalcemia

Jack MacKenzie, DVM, DACVIM
Chicago Veterinary Internal Medicine and Oncology

In General:
1. Ionized (non-protein bound) Calcium is regulated and maintained through relationships between active Vitamin D3, Phosphorous, Parathyroid Hormone, and Calcitonin
2. iCa= 55%, Protein-bound Ca= 35% and complexed Ca= 10%
3. With decreased calcium levels, you will get the following:
a. Increase PTH production, thus increased Vitamin D3 synthesis, which in turn has a negative feedback on addition PTH production
b. With Increased PTH production you get the following:
i. Increased bone resorption of calcium and phosphorous
ii. Increased kidney calcium reabsorption and increased kidney phosphorous excretion
iii. Increased calcium and phosphorous GI absorption
4. High calcium and/or phosphorous levels will cause the opposite effects as #2

HyperCalcemia Differentials
1. Neoplasia
a. In some forms of cancer, Hypercalcemia comes from production of Parathyroid hormone related protein (PTHrP), a peptide similar to PTH, which effect bone and renal tubular resorption of Calcium
b. Other tumors may met to the bone elaborating local factors that cause bone (thus calcium) resorption
c. In dogs, neoplastic hypercalcemia is primarily from LSA and Anal Sac Apocrine gland adenocarcinoma, while in cats, neoplastic hypercalcemia is most commonly associated with LSA and SCC
i. LSA: 20% of dogs are hypercalcemic
ii. Multiple Myeloma: B-cell or plasma cell origin, with 17% associated with hypercalcemia
iii. Apocrine gland adenocarcinoma: Hypercalcemia in 27%, and those with hypercalcemia found to have shorter survival times (256d versus 584 days)
iv. Mammary adenocarcinoma: time of spay can influence development of disease with those with OHE prior to first heat <0.05%, after first estrus 8% then plateaus at 26% thereafter
v. Other tumors include nasal adenocarcinoma, SCC of GI or vulva, and thyroid carcinoma

2. Renal Failure
a. Renal secondary hyperparathyroidism
i. nephron loss and decreased GFR promotes renal phosphorous retention, causing a decreased iCa concentration and inhibits Vit D3 production
ii. With hypocalcemia and low Vit. D3 levels, get increased PTH production, and adjustment of Ca and Phosphorous back to normal
iii. However, with continued renal function decline, get continued PTH secretion and thus hypercalcemia
b. Hypercalcemia
i. Most dogs with CRF have normal to low calcium, only occasionally hypercalcemia
ii. Tertiary Hyperparathyroidism: chronic stimulation of the parathyroid gland in asso. With renal failure results in hyperplasia and autonomous secretion of PTH as the setpoint for calcium level is “reset” thus iCa levels no longer inhibit PTH secretion
iii. Decreased renal excretion of calcium

3. Primary Hyperparathyroidism
a. Neoplasia: benign functional adenomas cause 86% of canine and feline PHP, and are usually solitary
b. Hyperplasia of the parathyroid gland implies that more than 1 gland is abnormal
c. Pathogenesis
i. PTH is secreted in excess regardless calcium levels causing hypercalcemia, hypophosphatemia, hypercalciuria and phosphaturia
ii. Hypercalcemia is further aggravated by increased Vit. D through increased PTH
iii. Renal calcification occurs if Ca x Phosph >70, but since phosphorous is usually low in PHP, may not occur with this disease
d. Signalment:
i. older dog (>10.5y) endocrine disorder with Keeshond overrepresented
ii. 7 Cats (primarily Siamese) have been reported
e. Clinical Signs:
i. Tumors not usually palpable in dogs but may be in the cat
ii. Most are in good health with clinical signs related to hypercalcemia

4. Hypoadrenocortiscism
a. Increased renal tubular reabsorption of calcium, and increased protein-binding affinity for calcium

5. Hypervitaminosis D
a. See significant hypercalcemia and hyperphosphatemia
b. Plants: Cestrum diurnum (day blooming jessamine), Solanum malacoxylon (night shade)
c. Rodenticides: Quintox®, Rampage®, Rat-be-gone®Mouse-be-gone®

6. Miscellaneous Other causes of Hypercalcemia
a. Young animals: also see increased phsophrous
b. Granulomatous disease: systemic mycoses, panniculitis, injection site granulomas, all due to production of calcitriol by granulomatous tissue
c. Osteomyelitis: bacterial or fungal causes
d. Lab artifact: ex. Hypoalbuminemia will decrease total but not ionized calcium levels

7. Feline Hypercalcemia
a. Less common than dogs
b. Anorexia and lethargy are the primary clinical signs
c. Primary causes are neoplasia (LSA, SCC, MM, Lymphoproliferative disease), renal failure, Urolithiasis (Ca oxalate as well as secondary to primary hyperparathyroidism) and Idiopathic
d. Idiopathic:
i. Young to middle aged cats, with increased total and iCa levels, with PTH and Vit. D levels normal
ii. Unknown etiology although it’s speculated that dietary acidification can lead to chronic metabolic acidosis, increased bone resorption, elevated iCa and hypercalciuria
iii. Clinically irrelevant in most cases although may occasionally see GI upset and weight loss.

8. Clinical signs
a. PU/PD
i. most common sign in dogs
ii. excessive calcium decreases renal tubular response to ADH (NDI) and impairs renal tubular sodium reabsorption causing medullary washout
b. Renal Failure
i. Hypercalcemia can cause OR be the cause of Renal failure
ii. Nephrocalcinosis with CaxP >70, seen also at heart and lungs
iii. Ca > 15mg/dl can cause renal afferent arteriole vasoconstriction, thus renal ischemia and decreased GFR
c. Depression and weakness
i. Hypercalcemia causes decreased excitability of nervous tissue, and occasional shivering and twitching
d. Gastrointestinal signs
1. anorexia, vomiting, constipation via decreased excitability of smooth muscle
e. Urolithiasis
i. Hypercalciuria from PHP predisposes calcium containing uroliths

9. Diagnosis of Hypercalcemia causes
a. CBC: usually non-specific
b. Hypercalcemia
i. rule out artifact (lipemia, hemolysis and dehydration) and lab error
ii. Hypoalbuminemia?
• corrected Ca for hypoalbuminemia = 3.5-albumin + measured total calcium, dogs only
• corrected values are NOT accurate determinations of iCa
c. iCa:
i. Hypercalcemia without elevated iCa is NOT of significant clinical concern, as the iCa is the metabolically active component (and drive for PTH secretion)
ii. Increased by acidosis, decreased by alkalosis
d. Magnitude of Hypercalcemia
i. severe: PHP and hypervitaminosis D
e. Phosphorous
i. Low/normal with PHP
ii. High with Hypervitamonosis D, renal failure and osteolysis
f. Azotemia: differentiate pre-renal versus renal versus post-renal (obstruction/uroliths)
g. Increased ALP: seen with young animals, neoplasia and PHP
h. Urinalysis:
ii. check specific gravity. Usually low secondary to multiple reasons including Polydipsia, medullary washout, NDI, etc.
iii. UTI often noted with PHP (alkaline urine)
iv. Calculi
v. Proteinuria: multiple myeloma
vi. Consider Fungal antigen (Blastomycoses, Histoplasmosis)
i. Radiographs: neoplasia and osteomyelitis as well as other evidence in thoracic and abdominal radiographs
j. Ultrasound: Parathyroid and abdominal
k. +/- Lymph node aspirate, ACTH Stim, Malignancy panel (PTH, PTHrP, iCa)

10. Treatment
a. Saline diuresis: restoration of ECF decreases Na reabsorption and promotes renal calcium excretion. Watch for progressing Hypokalemia
b. Lasix: inhibits calcium reabsorption in ascending loop of henle and enhances calciuric effect of fluid therapy
c. Glucocorticoids: decrease bone resorption, decrease renal and GI Ca absorption, and are lympholytic to LSA
d. Salmon Calcitonin: decreases osteoclast activity and drops calcium in 4-12 hours (primarily for Vit. D toxicity)
e. Bisphosphanates (Pamidronate): decrease osteoclastic activity and function
f. Bicarbonate: shift iCa to protein-bound decreasing metabolically active iCa levels
g. For Feline Idiopathic:
i. High fiber or alkalinizing diets (W/D) monitoring iCa levels
ii. Glucocorticoids for those non-responsive to prednisone
h. For PHP:
i. Surgery monitoring post-op for iatrogenic hypoparathyroidism for 7 days

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