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Basics ⬇

Outline

BASICS

Definition!!navigator!!

Serum total calcium concentration greater than the reference interval.

Pathophysiology!!navigator!!

  • PTH, calcitonin, and vitamin D act in conjunction with the intestine, bone, kidneys, and parathyroid glands to maintain calcium homeostasis. The calcium-sensing receptor, found in cell types that secrete calciotropic hormones, is central to calcium regulation and detects changes in ionized calcium.
  • Calcium absorption occurs primarily in the proximal small intestine. Serum calcium concentration is more dependent on the amount of dietary calcium and less dependent on vitamin D.
  • The kidney is important in calcium regulation; horses excrete a larger proportion of absorbed calcium in the urine than other mammals do. Calcium is also eliminated through sweat, milk, and feces.
  • Disturbances in calcium homeostasis leading to hypercalcemia occur with organ dysfunction, abnormalities in hormonal balance and control, administration of vitamin D products or ingestion of plants containing vitamin D-like compounds, or production of a parathyroid hormone analog in certain malignancies.
  • With CRF, ability of the kidney to excrete calcium is compromised, causing hypercalcemia especially in horses on a high calcium diet.
  • Hypercalcemia of malignancy is associated with certain types of neoplasia. Tumor cells produce and secrete PTHrP or related products, causing increased osteoclastic bone resorption and renal resorption of calcium.
  • Hypercalcemic states can lead to widespread soft tissue mineralization

Systems Affected!!navigator!!

General Comments

Although uncommon, metastatic calcification may develop with hyperphosphatemia and concurrent hypercalcemia (hypervitaminosis D) when the calcium x phosphorus product (in mg/dL) is greater than 70. Vasculature of lungs, pleura, kidneys, endocardium, and stomach are prone.

Cardiovascular

ECG changes associated with increased serum calcium progress from bradycardia to tachycardia to ventricular fibrillation.

Endocrine/Metabolic

Hypercalcemia stimulates calcitonin release from thyroid C-cells, which acts by decreasing osteoclastic bone resorption as a compensatory mechanism to decrease plasma calcium concentration.

GI

Possible decreased contractility of GI smooth muscle. Constipation may occur.

Renal

Soft tissue mineralization may occur with concurrent hypercalcemia and hyperphosphatemia.

Genetics!!navigator!!

N/A

Incidence/Prevalence!!navigator!!

N/A

Geographic Distribution!!navigator!!

N/A

Signalment!!navigator!!

Renal Disease

Dependent on the underlying cause.

Hypercalcemia of Malignancy

  • Lymphoma is a common neoplasm in horses.
  • Horses with lymphoma are typically young to middle-aged (5–10 years).
  • SCC generally occurs in older animals.
  • Cutaneous SCC more commonly occurs on nonpigmented areas, so Appaloosas, Paints, and some draft breeds are predisposed

Signs!!navigator!!

General Comments

Dependent on the underlying cause.

Historical Findings

  • With renal disease/failure, poor performance and/or weight loss, mild colic signs or abnormal urination may be noted. Recent or long-term nephrotoxic medications (e.g. NSAIDs, aminoglycosides) may be included in the history.
  • With lymphoma, weight loss, lethargy, edema, recurrent fever, and/or lymphadenopathy may be present.
  • With gastric SCC, horses may exhibit signs of esophageal obstruction (e.g. dysphagia, ptyalism, choke), and/or have a prolonged history of halitosis, anorexia and weight loss. Intraabdominal SCC may cause chronic weight loss and intermittent colic.
  • Horses with hypervitaminosis D may exhibit limb stiffness and painful flexor tendons and suspensory ligaments.
  • Primary hyperparathyroidism is rare; history may include anorexia, weight loss, or changes in facial bone structure

Physical Examination Findings

Renal Disease

  • Ventral edema—frequently seen with glomerulonephritis.
  • Oral ulcerations.
  • Hematuria or PU/PD.
  • On rectal palpation, some horses with AKI may have enlarged painful kidneys; horses with CRF may have small kidneys with irregular surface

Neoplasia

  • Cutaneous SCC—proliferative/erosive masses or nonhealing wounds in the periorbital region, genitalia, lips, nose, or anus; during late/advanced stages, signs might be referable to location of metastasis.
  • Abdominal mass might be palpated per rectum in cases of metastatic SCC or GI lymphoma.
  • Gastric SCC—weight loss, halitosis.
  • Lymphoma: dependent on location of tumor (e.g. cutaneous GI, mediastinal or multicentric)

Primary Hyperparathyroidism

Bone remodeling (osteodystrophy of facial bones).

Causes!!navigator!!

Renal Disease

  • Hyper-, hypo-, or normocalcemia occurs with AKI.
  • Hypercalcemia in AKI or CRF is more apt to develop in horses fed high-calcium rations.
  • AKI may progress to CRF. Causes—glomerulonephritis from immune complex deposition (e.g. streptococcal infection, equine infectious anemia), nephrotoxins (e.g. aminoglycosides, NSAIDs, vitamin K3, heavy metals [especially mercury], hemoglobin, myoglobin), chronic urinary tract obstruction, interstitial nephritis, amyloidosis, pyelonephritis, nephrolithiasis and ureterolithiasis, and congenital abnormalities (e.g. renal hypoplasia or polycystic kidneys)

Neoplasia

  • The most common paraneoplastic finding in horses is hypercalcemia.
  • Tumors associated with hypercalcemia—lymphoma, SCC, multiple myeloma, adrenocortical carcinoma, malignant mesenchymoma of the ovary, and ameloblastoma

Hypervitaminosis D

Hypercalcemia from increased GI absorption and bone resorption is associated with ingestion of plants containing vitamin D-like substances (Solanum spp., Cestrum diurnum, Trisetum flavescens) or administration of vitamin D.

Exercise

Because calcium is present in sweat, plasma concentrations may be reduced with large volumes of sweat loss.

Primary Hyperparathyroidism (Rare)

Parathyroid adenoma, parathyroid hyperplasia, carcinoma.

Neonatal Hypercalcemia and Asphyxia (Rare)

Asphyxia; may be associated with placental insufficiency and excessive PTHrP.

Granulomatous Disease (Rare)

Hypercalcemia due to unregulated production of calcitriol by macrophages may be seen in horses with idiopathic systemic granulomatous disease.

Risk Factors!!navigator!!

See Signalment and Causes.

Diagnosis ⬆ ⬇

Outline

DIAGNOSIS

Differential Diagnosis!!navigator!!

See Causes.

CBC/Biochemistry/Urinalysis!!navigator!!

  • Azotemia (increased serum Cr and urea nitrogen concentrations) and isosthenuria (USG 1.008–1.015) support the diagnosis of renal disease, but other causes of azotemia with concurrent PU/PD must be ruled out.
  • Hypophosphatemia, mild hyponatremia and hypochloremia, and normo- or hyperkalemia can be present.
  • Moderate to marked proteinuria is common with glomerulonephritis.
  • Suspect urinary tract infection with moderate to many leukocytes in urine sediment.
  • Hypercalcemia without concurrent azotemia or isosthenuria implies causes other than renal; suspect neoplasia.
  • Consider vitamin D intoxication with concurrent hypercalcemia and hyperphosphatemia. Hyperphosphatemia is the earliest abnormality and may be more reliable for indicating hypervitaminosis D in oversupplementation than hypercalcemia. Hyperphosphatemia may be absent in plant intoxication. USG may be low

Other Laboratory Tests!!navigator!!

  • Measurement of ionized calcium concentration by ion-selective electrodes requires special sample handling (collected in anaerobic conditions and analyzed promptly) and is becoming more readily available.
  • With suspected primary hyperparathyroidism, measurement of PTH is indicated

Imaging!!navigator!!

Ultrasonography of kidneys during CRF may reveal increased echogenicity (i.e. fibrosis) and is useful in assessing abnormalities (e.g. polycystic kidneys).

Other Diagnostic Procedures!!navigator!!

  • Fine needle aspiration or tissue biopsy of masses (endoscopic or ultrasonography guided) are indicated for establishing the diagnosis of neoplasia.
  • Abdominal or thoracic fluid cytology may reveal neoplastic cells.
  • Renal biopsy sometimes is useful in determining the cause of renal disease

Pathologic Findings!!navigator!!

Dependent on the underlying cause.

Treatment ⬆ ⬇

Outline

TREATMENT

Diet!!navigator!!

Renal disease—salt restriction is indicated if ventral edema develops, and a diet of high-quality carbohydrates (e.g. corn, oats), roughage (e.g. grass hay), and free access to fresh water is recommended. Avoid feeds high in protein or calcium.

Surgical Considerations!!navigator!!

Surgical excision, local chemotherapy, radiotherapy, cryosurgery, or hyperthermia are options with some localized tumors.

Medications ⬆ ⬇

Outline

MEDICATIONS

Drug(s) of Choice!!navigator!!

AKI (Hypercalcemia Less Likely)

  • IV fluid therapy/diuresis.
  • Discontinue nephrotoxic drugs

CRF

  • Good nutritional support and free access to fresh water, fluids and electrolytes, salt blocks if edema is absent (restrict if hypertension or edema develops), and vitamin B complex.
  • Anabolic steroids may help to prevent muscle wasting.
  • With severe hypercalcemia, administration of physiologic saline with loop diuretics (e.g. furosemide) will promote urinary calcium excretion

Hypervitaminosis D

Removal of the source of vitamin D, fluid diuresis, corticosteroid administration, and low calcium and phosphorus feeds.

Contraindications!!navigator!!

  • Do not feed hypercalcemic horses legume hays or high-calcium rations.
  • Fluid therapy for hypercalcemic horses should be devoid of calcium.
  • Thiazide diuretics promote renal resorption of calcium.
  • Avoid aminoglycoside antibiotics and NSAIDs if possible

Precautions!!navigator!!

N/A

Possible Interactions!!navigator!!

N/A

Alternative Drugs!!navigator!!

N/A

Follow-up ⬆ ⬇

Outline

FOLLOW-UP

Patient Monitoring!!navigator!!

Renal disease—serial biochemistries.

Prevention/Avoidance!!navigator!!

  • Judicious use of nephrotoxic drugs.
  • Ultraviolet-blocking fly masks in horses with nonpigmented facial skin

Possible Complications!!navigator!!

Soft tissue mineralization.

Expected Course and Prognosis!!navigator!!

  • Supportive therapy may prolong life substantially in polyuric (urine output > 18 mL urine/kg/day), stabilized patients.
  • With CRF, serum Cr concentration > 5 mg/dL indicates a marked decline in glomerular filtration rate. A grave prognosis is associated with serum Cr concentrations > 10 mg/dL.
  • Unless cutaneous or localized, neoplasia carries a guarded to poor prognosis.
  • Removal of vitamin D sources may result in recovery of hypervitaminosis D with time, but with soft tissue mineralization in the heart or kidney, the prognosis is poor

Miscellaneous ⬆ ⬇

Outline

MISCELLANEOUS

Associated Conditions!!navigator!!

N/A

Age-Related Factors!!navigator!!

N/A

Zoonotic Potential!!navigator!!

N/A

Pregnancy/Fertility/Breeding!!navigator!!

Increased calcium concentration in mammary secretions is a good indicator of impending parturition.

Synonyms!!navigator!!

  • Hypercalcemia of malignancy—humoral hypercalcemia of malignancy, pseudohyperparathyroidism
  • Metastatic calcification—soft tissue mineralization

Abbreviations!!navigator!!

  • AKI = acute kidney injury
  • Cr = creatinine
  • CRF = chronic renal failure
  • GI = gastrointestinal
  • NSAID = nonsteroidal anti-inflammatory drug
  • PTH = parathyroid hormone
  • PTHrP = parathyroid hormone-related peptide
  • PU/PD = polyuria/polydipsia
  • SCC = squamous cell carcinoma
  • USG = urine specific gravity

Suggested Reading ⬆ ⬇

Aguilera-Tejero E. Calcium homeostasis and derangements. In: Fielding CL, Magdesian KG, eds. Equine Fluid Therapy. Ames, IA: Wiley, 2015:55–75.

Toribio RE. Parathyroid gland, calcium and phosphorus regulation. In: Smith BP, ed. Large Animal Internal Medicine, 5e. St. Louis, MO: Elsevier Mosby, 2015:1244–1252.

Author(s) ⬆ ⬇

Author: Karen E. Russell

Consulting Editor: Sandra D. Taylor

Additional Further Reading ⬆

Click here for Additional Further Reading