Feline parathyroid gland

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The concentration of calcium in the blood of mammals is ~10 mg/dL, with some variation due to species (eg, up to 13 mg/dL is normal in horses and rabbits), age, dietary intake, and analytic method. The blood calcium is composed of protein-bound and diffusible fractions. Diffusible calcium consists of calcium complexed to anions, such as phosphate and citrate, plus biologically active free (ionic) calcium.

The calcium ion is an essential structural component of the skeleton and plays a key role in muscle contraction, blood coagulation, enzyme activity, neural excitability, secondary messengers, hormone release, and membrane permeability. Precise control of calcium ion in extracellular fluids is vital to health. Three major hormones (PTH, vitamin D, and calcitonin) interact to maintain a constant concentration of calcium, despite variations in intake and excretion. Other hormones, such as adrenal corticosteroids, estrogens, thyroxine, somatotropin, and glucagon, may also contribute to the maintenance of calcium homeostasis.

Parathyroid Hormone

PTH is synthesized and stored in the chief cells of the parathyroid glands. Synthesis is regulated by a feedback mechanism involving the level of blood calcium (and, to a lesser degree, magnesium). In addition, biological amines, peptides, steroids, and several classes of drugs can influence PTH secretion.

The primary function of PTH is to control calcium concentration in the extracellular fluid, which it does by affecting the rate of transfer of calcium into and out of bone, resorption in the kidneys, and absorption from the GI tract. The effect on the kidneys is the most rapid, causing reabsorption of calcium and excretion of phosphorus. The major initial effect on bone is to mobilize calcium from the bone to the extracellular fluid; later, bone formation may be enhanced. PTH does not directly affect calcium absorption from the gut. Its effect is mediated indirectly by regulation of synthesis of the active metabolite of vitamin D.

Vitamin D

The second major hormone involved in the regulation of calcium metabolism and skeletal remodelling is vitamin D, which includes cholecalciferol (vitamin D₃ ) of animal origin, as well as ergocalciferol (vitamin D₂) of plant origin. Vitamin D has long been considered an essential dietary ingredient, but in several species, including sheep, cattle, horses, pigs, and humans, vitamin D can be formed in the skin from a cholesterol metabolite (7-dehydrocholesterol) after exposure to ultraviolet light. In contrast, dogs and cats are not able to synthesize vitamin D₃ adequately in the skin and are mainly dependent on dietary intake.

Vitamin D must be metabolically activated before it can function physiologically. The biologic actions of vitamin D depend on hydroxylation in the liver and kidney to form the biologically active 1,25-dihydroxyvitamin D (calcitriol). This conversion in the kidneys is the rate-limiting step in vitamin D metabolism, and it is partly responsible for the delay between vitamin D administration and expression of its biologic effects. PTH and conditions that stimulate its secretion, as well as hypophosphatemia, increase the formation of the active vitamin D metabolite. High circulating phosphorus concentrations have the opposite effect. Under certain conditions, prolactin, estradiol, placental lactogen, and possibly somatotropin have a similar enhancing effect. Increased secretion of these hormones, either alone or in combination, appears to be important in the efficient adaptation to the major calcium demands of pregnancy, lactation, and growth.

Calcitonin

Calcitonin is a 32-amino acid polypeptide hormone secreted by the parafollicular cells (C-cells) of the thyroid gland in mammals and by ultimobranchial tissue in avian and other non-mammalian species. The concentration of calcium ion in extracellular fluids is the principal stimulus for the secretion of calcitonin by C-cells. In hypercalcemia, the rate of secretion of calcitonin is increased greatly by rapid discharge of stored hormone from C-cells into interfollicular capillaries. Hyperplasia of C-cells occurs in response to long-term hypercalcemia. When blood calcium is lowered, the stimulus for calcitonin secretion is diminished. The storage of large amounts of preformed hormone in C-cells and rapid release in response to a moderate rise in circulating calcium probably reflect the physiologic role of calcitonin as an “emergency” hormone to protect against development of hypercalcemia.

Calcitonin exerts its effects by interacting with target cells, primarily in bone and kidney. The actions of PTH and calcitonin are antagonistic on bone resorption but synergistic on decreasing the renal tubular reabsorption of phosphorus. The hypocalcemic effects of calcitonin are primarily the result of decreased entry of calcium from the skeleton into plasma, resulting from a temporary inhibition of PTH-stimulated bone resorption. The hypophosphatemia develops from a direct action of calcitonin, which increases the rate of movement of phosphorus out of plasma into soft tissue and bone and inhibits the bone resorption stimulated by PTH and other factors. Although many effects have been attributed to calcitonin at pharmacologic doses, their physiologic relevance is suspect. Physiologically, calcitonin has at best a minor role in regulating blood concentrations of calcium. Neither chronically high (eg, as in animals with medullary thyroid cancer) nor chronically low (eg, as in animals after surgical removal of the thyroid gland) circulating calcitonin concentrations result in any alterations in the serum calcium concentration.

Hypercalcemia

The development of clinical signs from hypercalcemia depends on the magnitude of the calcium elevation, how quickly it develops, and its duration. Serum total calcium concentrations of ≤15 mg/dL may not be associated with systemic signs, but serum concentrations of >18 mg/dL are often associated with severe, life-threatening signs. Polydipsia and polyuria are the most common signs of hypercalcemia and result from an impaired ability to concentrate urine and a direct stimulation of the thirst centre. Anorexia, vomiting, and constipation can also develop as a result of decreased excitability of GI smooth muscle. Decreased neuromuscular excitability may lead to signs of generalized weakness, depression, muscle twitching, and seizures.

In dogs, hypercalcemia is most commonly associated with malignancy, hypoadrenocorticism (Addison’s disease), and renal disease. Less common causes of hypercalcemia in dogs include primary hyperparathyroidism, vitamin D toxicosis, granulomatous disease, and miscellaneous conditions. In cats, renal failure, neoplasia, and a recently recognized syndrome of idiopathic hypercalcemia are the most common causes of hypercalcemia.

         a) Hypercalcemia of malignancy

Malignancy is the most common cause of persistent hypercalcemia in dogs and is a common cause in cats. In hypercalcemia of malignancy, the hypercalcemia primarily results from increased osteoclastic bone resorption, but increased renal tubular resorption and increased intestinal absorption may also play a role. Factors that may be produced by tumors and result in humoral hypercalcemia of malignancy include PTH, PTH-related protein, transforming growth factor, 1,25-dihydroxyvitamin D, prostaglandin E₂, osteoclast-activating factor, and other cytokines (interleukin-1, interleukin-2, and g-interferon). Although many tumors have been associated with hypercalcemia in humans, in dogs malignancy-associated hypercalcemia has been most commonly linked to lymphoma, adenocarcinoma of the apocrine glands of the anal sac, and multiple myeloma. Other tumors (thymoma, squamous cell carcinoma, nasal carcinoma, hemangiosarcoma, and undifferentiated adenocarcinoma) have also been associated with hypercalcemia in dogs. In cats, humoral hypercalcemia of malignancy occurs less frequently than in dogs but has been reported with squamous cell carcinoma, multiple myeloma, and lymphoproliferative diseases.

         b) Hypercalcemia Associated with Hypoadrenocorticism

         c) Renal failure

         d) Primary hyperparathyroidism

         e) Hypervitaminosis D

Vitamin D toxicity refers to the effects of excessive intake of bioactive metabolites of vitamin D. Toxicity caused by ergocalciferol (vitamin D₂ ) or cholecalciferol (vitamin D₃) can occur from excessive dietary supplementation (most common in young growing dogs) for treatment of primary hypoparathyroidism. Both of these forms of vitamin D have a slow onset of action and prolonged duration, making correct dosing difficult. Treatment is directed at discontinuing the supplement or decreasing the dose of vitamin D. Toxicity caused by calcitriol (1,25-dihydroxyvitamin D), the most active form of vitamin D, most commonly occurs following treatment of primary hypoparathyroidism. Calcitriol is also the active ingredient in some rodenticides, but these products are no longer widely available, at least in the USA.

          f) Granulomatous Disease

Hypercalcemia associated with granulomatous disease arises from an alteration of endogenous vitamin D metabolism. Macrophages activated in response to granulomatous inflammation can develop the capability to convert vitamin D precursors to the active form of vitamin D (i.e., calcitriol) in an unregulated manner. A similar alteration of vitamin D metabolism in humans may explain hypercalcemia in non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, and lymphomatoid granulomatosis.

In companion animals, hypercalcemia related to granulomatous disease has been reported in disseminated histoplasmosis, blastomycosis, coccidiomycosis, tuberculosis, and schistosomiasis. Animals with hypercalcemia related to granulomatous disease are expected to have high serum concentrations of ionized calcium and low values for PTH. Serum calcium concentrations return to normal with treatment (ie, antifungal drugs and surgical removal).

         g) Idiopathic Hypercalcemia of Cats

In recent years, a hypercalcemia syndrome in cats has emerged. Affected cats range in age from 2-13 yr, with no gender predilection. Clinical signs are nonspecific and may include vomiting, weight loss, anorexia, lethargy, and evidence of lower urinary tract disease. Crystalluria or calcium oxalate urolithiasis is often an underlying cause of the urinary tract signs. Many affected cats have received urine-acidifying diets.

The most consistent laboratory abnormality is hypercalcemia (high total and ionized calcium concentration), usually accompanied by normal serum phosphorus and normal renal function. In cats with idiopathic hypercalcemia, diagnostic evaluation does not identify malignancy, primary hyperparathyroidism, or vitamin D excess.

Treatment options include dietary modification, glucocorticoids, or both. A high-fiber diet is thought to be beneficial because the fiber content may decrease availability of dietary calcium for absorption. If dietary modification is unsuccessful, some cats respond to treatment with prednisone, administered at an initial dose of 5 mg bid and increased to 10 mg bid, if needed. If a response occurs, the prednisone dose can be tapered to the minimum daily dosage required to maintain normocalcemia.

          h) Houseplants

Certain house plants (eg, Cestrum diurnum [the day-blooming jessamine], Solanum malacoxylon , Triestum flavescens ) may contain a substance similar to vitamin D that may cause hypercalcemia when ingested.

          i) Osteolytic Lesions

Hypercalcemia resulting from tumour invasion or metastasis to bone develops very rarely in animals. Primary bone tumors (eg, osteosarcoma) and neoplastic cells within the bone marrow (eg, multiple myeloma) may occasionally produce hypercalcemia. The mechanisms whereby bony neoplasia may produce hypercalcemia include mechanical destruction by the infiltrating cells (as occurs with metastatic tumors and osteosarcoma) and local production of osteoclast-activating factor (as occurs with multiple myeloma). Bacterial and mycotic osteomyelitis can also occasionally produce hypercalcemia. The hypercalcemia may result from direct bone lysis or may be mediated by bone-resorbing factors (eg, prostaglandins, osteoclast-activating factor).