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Front Page : Library : ACVIM 2003 : ACVIM-Small Animal : Hypercalcemia and Hypocalcemia Back to ACVIM-Small Animal Back to Table of Contents
Clinical Disorders of Hypercalcemia and Hypocalcemia in Dogs and Cats ACVIM 2003 Dennis J. Chew, DVM, DACVIM; Patricia A. Schenck, DVM, PhD; Jordan Q. Jaege, DVM, MS Columbus, OH 18273048
An alteration in serum calcium is typically first noted when total calcium (tCa) is measured as part of a biochemistry profile. Abnormalities in tCa warrant further diagnostic investigation. First it should be verified that the abnormality is repeatable. If the abnormality is repeatable, ionized calcium (iCa) should be measured for an accurate assessment of calcium status. Total or adjusted tCa are not reliable measurements of calcium status, especially in cases of hypercalcemia, as noted by a high degree of diagnostic discordance between total, adjusted, and ionized calcium measurements.
HYPERCALCEMIA Small increases in ionized serum calcium concentration can have adverse consequences in some animals whereas others with a similar or greater degree of hypercalcemia may not manifest obvious clinical signs. A mild degree of hypercalcemia may not be immediately dangerous and there is time to establish a definitive diagnosis before starting treatment. In those with severe clinical signs associated with hypercalcemia, diagnostic and therapeutic efforts may need to proceed concurrently. Interaction with serum phosphorus is important, as those with a tCa (mg/dL) times phosphorus concentration product greater than 70 are most likely to have severe tissue changes associated with mineralization. Hypercalcemia can be toxic to all body tissues, but major deleterious effects are on the kidneys, nervous system, and cardiovascular system. Most animals with tCa greater than 15.0 mg/dL will show systemic signs, and those with tCa concentrations greater than 18.0 mg/dL are critically ill. Hypercalcemias can be classified as parathyroid-dependent (primary hyperparathyroidism), or parathyroid-independent (normal parathyroid gland). In hypercalcemic dogs, neoplasia is the most common diagnosis, followed by hypoadrenocorticism, primary hyperparathyroidism, and chronic renal failure. Approximately 70% of hypercalcemic dogs are also azotemic, with azotemia uncommon only in dogs with hyperparathyroidism. In hypercalcemic cats, neoplasia is second to renal failure. Polydipsia, polyuria, and anorexia are the most common clinical signs attributed to hypercalcemia, though depression, weakness, vomiting, and constipation can also occur. Uncommonly, cardiac arrhythmias, seizures, and muscle twitching are observed. Severe hypercalcemia that has developed rapidly (hypervitaminosis D) can result in death. Cats with hypercalcemia do not display polyuria, polydipsia or vomiting as commonly as do dogs with a similar degree of hypercalcemia. Cats with idiopathic hypercalcemia may have no obvious clinical signs.
HYPERPARATHYROIDISM Hyperparathyroidism is divided into primary, renal secondary, nutritional secondary, tertiary and atypical causes. Detection of increased PTH concentration is dependent on measurement with a validated intact PTH molecule assay. Primary Hyperparathyroidism Primary hyperparathyroidism is characterized by excessive secretion of PTH in relation to increased iCa concentration (parathyroid-dependent hypercalcemia). Primary hyperparathyroidism is not common in dogs, and is less common in cats. Dogs with primary hyperparathyroidism are older with a mean age of about 10 years; the mean age in cats is near 13 years old. There is no sex predisposition, but occurs more frequently in the Keeshond, Dachshund, Golden Retriever, Poodle, Labrador Retriever, Siberian Husky, Rhodesian Ridgeback, and Australian Shepherd. Most reported cases in cats have been in Siamese. Primary hyperparathyroidism is normally caused by a solitary parathyroid gland adenoma that is not palpable in most dogs, but is usually palpable in the cat.
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Clinical signs are either mild (e.g., lethargy, polydipsia, polyuria, weakness) or may be absent. More prominent and serious clinical signs occur when hyperparathyroidism with severe hypercalcemia is long-standing, often in association with renal failure. Calcium-containing urolithiasis occurs in about 30% of dogs with primary hyperparathyroidism and may also be seen in cats. The diagnosis of primary hyperparathyroidism is easy in dogs and cats that exhibit increased iCa, increased PTH, and normal renal function. Additional support is provided by an increased serum alkaline phosphatase, low serum phosphorus, increased calcitriol, undetectable PTHrP, and calciumcontaining urolithiasis. The diagnosis of primary hyperparathyroidism is not easy when iCa is elevated but PTH concentration is still within the reference range. In these instances, the concentration of PTH should be deemed inappropriately high in comparison to the degree of hypercalcemia. In cases that are difficult to interpret, repeat analysis of iCa and PTH within several weeks will typically show a trend of increasing iCa and PTH. Ultrasonography of the neck may be helpful in the diagnosis of primary hyperparathyroidism, but requires an ultrasound unit with a high frequency transducer in the 7.5- to 10-MHz range to achieve the necessary level of resolution. Renal Secondary Hyperparathyroidism Progressive loss of nephron mass in renal failure reduces the ability of kidney to synthesize calcitriol. Lack of calcitriol accounts for the development of secondary hyperparathyroidism, and results in overproduction of PTH. Early on, the increased synthesis and secretion of PTH is considered an adaptive change that increases iCa and decreases serum phosphorus into the normal range. However, chronic high levels of PTH may be detrimental to a variety of tissues including kidneys, bone, and brain. Most dogs and cats with mild to moderate azotemia attributable to chronic renal disease have renal secondary hyperparathyroidism. PTH concentration does not correlate with the level of azotemia or phosphorus, and thus PTH must be accurately measured to confirm a diagnosis of secondary hyperparathyroidism. Serum phosphorus is often increased, and iCa is normal to low. Renal secondary hyperparathyroidism is confirmed when high levels of PTH are associated with intrinsic renal failure (azotemia, submaximal urine concentration, renal imaging changes, proteinuria, cylindriuria). Some animals with CRF have PTH levels within the normal range; since the range for PTH may be large, it is likely that PTH may still be elevated relative to a previously lower level. Nutritional Secondary Hyperparathyroidism Diets deficient in calcium or vitamin D, or have excessive phosphorus (such as all meat diets) result in increased PTH levels as a compensatory mechanism to restore calcium/phosphorus balance. Clinical signs are usually referable to the skeletal system with developmental abnormalities in young growing cats and dogs. Severe osteopenia and hypocalcemia may be observed clinically as pathologic fractures, muscle twitching, and seizures. PTH levels can be quite elevated in association with low to normal serum calcium, low to normal serum phosphorus, slightly increased calcitriol, and low 25(OH) vitamin D levels. This condition still occurs sporadically following the uninformed feeding of mostly muscle meat diets. It is likely that more such cases will be encountered with the increasing popularity of the "BARF" diet (bones and raw food, or biologically appropriate raw food). Tertiary Hyperparathyroidism Tertiary hyperparathyroidism is a term that refers to a subset of CRF patients that develop elevated iCa along with elevated PTH levels. The setpoint for iCa becomes altered, and elevations of iCa do not inhibit PTH production. It is likely that these patients had secondary hyperparathyroidism earlier in the clinical course of CRF. It is difficult to distinguish primary hyperparathyroidism from tertiary since both have increased PTH and iCa concentrations. Decreases in expression of the vitamin D receptor may play a role in tertiary hyperparathyroidism. Imaging of the parathyroid glands may be helpful since a single nodule indicates primary hyperparathyroidism, whereas tertiary hyperparathyroidism will have enlargement of all four glands. Atypical Hyperparathyroidism in Hyperthyroid Cats Over 75% of cats with hyperthyroidism have been noted to have high levels of PTH. Serum iCa and creatinine are lower than normal, and serum phosphorus is higher than normal. Hyperthyroid cats have been noted at times to have hyperphosphatemia without azotemia. Whether or not the high PTH levels return to normal following treatment and conversion to euthyroidism is not known. Phosphorus inhibition of calcitriol production may allow for increased PTH synthesis and secretion. The clinical significance of these observations is not yet known.
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PARATHYROID-INDEPENDENT HYPERCALCEMIA Malignancy-Associated Hypercalcemia Malignancy-associated hypercalcemia (MAH) includes local osteolytic hypercalcemia (LOH) and humoral hypercalcemia of malignancy (HHM). LOH involves local invasion and dissolution of bone by leukemia and multiple myeloma. HHM involves humoral substances elaborated by the tumor that act at sites distant from the tumor to increase the serum calcium. These calcemic factors increase osteoclastic bone resorption and increases renal tubular resorption of calcium leading to hypercalcemia. A number of calcemic factors can be elaborated by neoplastic tissue including PTHrP, interleukins, TNF and other cytokines. It appears that PTHrP is the most important of these humoral substances. Increased PTHrP concentration indicates that a malignancy is present; however the absence of detectable PTHrP does not rule out malignancy. The most common malignancies associated with hypercalcemia in dogs are lymphosarcoma (LSA) and anal sac apocrine gland adenocarcinoma. Thymoma and carcinomas of the lung, pancreas, skin, nasal cavity, thyroid, mammary gland, and adrenal medulla sporadically account for hypercalcemias in the dog. Other hematologic malignancies associated with hypercalcemia include multiple myeloma, lymphoma, myeloproliferative disease, and leukemia. In cats, the most common causes of MAH are LSA and squamous cell carcinoma (head and neck region). Leukemia, multiple myeloma, osteosarcoma, fibrosarcoma, undifferentiated sarcoma, and bronchogenic carcinoma have also been associated with MAH in the cat. Most cats with LSA and hypercalcemia are FeLV negative. Hypervitaminosis D Granulomatous diseases resulting in hypercalcemia include blastomycosis, histoplasmosis and other fungal diseases, dermatitis, panniculitis, and injection site granuloma. Hypercalcemia results from production of calcitriol by granulomatous tissue. Vitamin D toxicosis can result from oversupplementation with vitamin D3 , ingestion of plants containing calcitriol glycosides, cholecalciferol rodenticides, or calcipotriene (Dovonex速 antipsoriatic cream). Though not well documented, the ingestion of the popular houseplant day-blooming jessamine (Cestrum diurnum) is a potential cause of hypercalcemia in cats, as this plant contains calcitriol-like substances. Ingestion of calcipotriene has been reported as a cause of hypercalcemia in dogs but not in cats; anecdotes of the occurrence of hypercalcemia in cats following the licking of calcipotriene from human skin are emerging. In these cases iCa will be elevated, with suppression of PTH production. Oversupplementation with calcitriol used as a therapy for renal secondary hyperparathyroidism or hypoparathyroidism may also result in iCa elevation. Concentration of 25(OH)-D may be elevated in cases of oversupplementation of vitamin D3 , or cholecalciferol rodenticides. Hypoadrenocorticism Mild parathyroid-independent hypercalcemia with low PTH concentration is sometimes noted in hypoadrenocorticism. The mild hypercalcemia has little effect on the outcome of hypoadrenocorticism, and the magnitude of hypercalcemia parallels the severity of hyperkalemia and hypovolemia. The mechanism of hypercalcemia is unknown, and typically resolves with treatment of hypoadrenocorticism. Renal Failure The simultaneous discovery of hypercalcemia and primary chronic renal failure provides a great challenge in deciding the origin of the hypercalcemia. When tCa is high and iCa is normal or low, increased protein binding or binding to complexes (sulfates, lactates, phosphates, citrates) account for the disparity. In these instances, the increase in tCa is not considered dangerous to renal function. In those with increased iCa, adverse effect on renal function is of concern. Ionized hypercalcemia in conjunction with CRF is more common in cats than in dogs. In those with increased iCa, more effort to exclude an unrelated malignancy-associated hypercalcemia is needed. Cats with CRF may also have idiopathic hypercalcemia. Ionized hypercalcemia can result in CRF patients that are being treated with calcitriol for control of renal secondary hyperparathyroidism though this is unlikely at lower doses (2.5 to 3.5 ng/kg/day). If excessive action from calcitriol is causing the hypercalcemia, the hypercalcemia should resolve within 3 to 5 days after stopping calcitriol treatment. Treatment of CRF patients with aluminum-containing intestinal phosphate binders (aluminum hydroxide, aluminum carbonate) is a consideration for the development of hypercalcemia, as this can be associated with aluminum induced bone disease and reduced secretion of PTH. Tertiary hyperparathyroidism rarely develops in those with longstanding uncontrolled renal secondary hyperparathyroidism. Integration of the results of iCa measurement
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with calciotropic hormone levels (PTH, PTHrP, 25(OH)-D3, and 1,25(OH)2 -D3 ) is needed to achieve definitive diagnosis in many of these instances. Idiopathic Hypercalcemia of Cats A syndrome in young to middle-aged cats has emerged, where hypercalcemia occurs without obvious explanation. Serum total calcium is increased for months to more than one year, often without obvious clinical signs. Ionized calcium is increased, sometimes out of proportion to the increase in total serum calcium. Longhaired cats may be over represented in this syndrome. Vomiting and weight loss are the most common clinical signs. Most are nonazotemic, but may develop azotemia at a later date. Nephrocalcinosis is occasionally observed, as are uroliths in the kidney, ureter, and bladder. There is no evidence of malignancy based on radiography, abdominal ultrasonography, bone marrow evaluation, and in some instances, full necropsy. Serology for FeLV and FIV is negative, and T4 values are normal. PTH levels are within the reference range, PTHrP is not detectable, and 25-(OH)-D and calcitriol levels are within normal limits. Blood gas analysis reveals no major acid-base disturbance. An increase in dietary fiber has been reported to decrease serum calcium in affected cats in some reports. Challenge with prednisone therapy results in long-term decreases in iCa and tCa in some cats. There is concern that this treatment could increase hypercalciuria, which could subsequently enhance genesis of urinary calculi. However, the declining filtered load of calcium decreases as serum iCa declines, which offsets the enhanced formation of calculi. When dietary modification and challenge treatment with prednisolone have been unsuccessful in resolving hypercalcemia, bisphosphonate treatment should be considered. The cause(s) of idiopathic hypercalcemia in cats remains elusive. The role of dietary acidification, dietary magnesium restriction, and/or contribution of any specific dietary constituents deserve further consideration. It is conceivable that hypercalcemia develops only in a genetically susceptible population of cats. Other Causes of Hypercalcemia Nonmalignant skeletal lesions causing hypercalcemia include osteomyelitis (bacterial/mycotic), hypertrophic osteodystrophy (HOD), and disuse osteoporosis (immobilization). Other causes may include excessive use of intestinal phosphate binders, excessive calcium supplementation (calcium carbonate), hypervitaminosis A, milk-alkali syndrome, thiazide diuretics, acromegaly, thyrotoxicosis, postrenal transplantation, and aluminum exposure.
HYPOCALCEMIA The most common association of hypocalcemia based on tCa is that encountered with hypoalbuminemia. This may or may not be associated with changes in iCa. Clinically important hypocalcemia is characterized by a below normal concentration of iCa. Clinical signs associated with hypocalcemia include muscle tremors and fasciculation, facial rubbing, muscle cramping, stiff gait, seizures, restlessness, aggression, hypersensitivity, disorientation, panting, pyrexia, lethargy/depression, anorexia, tachycardia, and prolapse of the third eyelid (cats). Hypocalcemia can be parathyroid-dependent (primary hypoparathyroidism), or parathyroid-independent. Causes of parathyroid-independent hypocalcemia include eclampsia, pancreatitis, ethylene glycol intoxication, acute or chronic renal failure, phosphate enemas, hypovitaminosis D, intestinal malabsorption, hypomagnesemia, tumor lysis syndrome, or citrate anticoagulant-containing blood transfusions.
PRIMARY HYPOPARATHYROIDISM Primary hypoparathyroidism is uncommon in dogs and cats, and occurs mostly in young adults. Miniature Schnauzers, Miniature Poodles, terriers, Labrador Retrievers, and German Shepherd Dogs are more commonly affected. In primary hypoparathyroidism, the parathyroid gland is unable to produce PTH due to lymphoplasmacytic destruction. As a result, primary hypoparathyroidism is characterized by decreased iCa, with an inappropriately low PTH concentration. Iatrogenic hypoparathyroidism may also occur when the parathyroid glands become damaged or are removed during surgery of the neck. The decrease in PTH production may be transient, or may be permanent. Transient hypoparathyroidism is common post-thyroid surgery in cats and occurs after 20 to 30% of thyroid surgeries.
PARATHYROID INDEPENDENT HYPOCALCEMIA Eclampsia
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Eclampsia is a condition that occurs in the lactating bitch or queen during the first three weeks post-partum, and is most common in small dogs. The rapidity of calcium utilization for milk production overwhelms the ability to maintain serum iCa, and hypocalcemia results. Calcium supplementation of the pregnant bitch may predispose by causing atrophy of the parathyroid glands. Respiratory alkalosis caused by panting may also help to decrease serum iCa. Renal Failure Decreased iCa occurs in some cases of chronic renal failure, but these patients rarely show clinical signs of hypocalcemia. Hypocalcemia may occur in acute post-renal renal failure in male cats with urethral obstruction. In these cases, the rapid increase in serum phosphorus binds iCa causing acute hypocalcemia. Intoxication with ethylene glycol may also result in hypocalcemia. Serum calcium is chelated by metabolites of ethylene glycol, causing hypocalcemia. Pancreatitis Hypocalcemia is sometimes seen in acute pancreatitis. Hypocalcemia is mild, and clinical signs related to hypocalcemia are unlikely. Lipase that leaks from the pancreas causes saponification of peripancreatic fat, resulting in mild hypocalcemia.
SPEAKER INFORMATION (click the speaker's name to view other papers and abstracts submitted by this speaker) Dennis J. Chew, DVM, DACVIM CVM The Ohio State University 601 Vernon L. Tharp St. Columbus, OH 43210-1089 Jordan Q. Jaeger, DVM, MS Carolina Veterinary Specialists 2225 Township Rd. Charlotte, NC 28273 Patricia Schenck, DVM, PhD AHDL, Endocrinology Micigan State University A-46 Veterinary Medicine Center East Lansing, MI 48824
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