Got milk? The clinical approach to hypercalcemia (Proceedings)

Small animal patients presenting with a primary complaint of hypercalcemia can often be a diagnostic challenge. Typically, the clinical signs are insidious and nonspecific. A thorough work-up, sometimes necessitating repetition in diagnostic steps may be required to determine the etiology of the hypercalcemia. Treatment should be directed toward resolution of the underlying disease.

Calcium is an important electrolyte in the body and performs two main functions: maintenance of tooth and bone structure and as an important intracellular second messenger. In the latter role, Ca2+ controls many cellular processes including muscle contraction, nerve function, blood coagulation, enzyme activity, cell secretion, and cell adhesion. There is a large concentration gradient of Ca2+ between the extracellular fluid and cell cytoplasm; this favors Ca2+ entry into the cell to activate signal transduction processes. Serum calcium exists in three forms: 50% is ionized (physiologically-active form), 45% is protein bound (primarily albumin and to a lesser extent globulin), and 5% is complexed to anions (citrate, bicarbonate, phosphate, or lactate). The skeletal structure holds a huge reserve of calcium, containing >99% of calcium, mostly in the mineral phase.

Serum ionized calcium is regulated within a narrow range that is controlled by two principal hormones: parathyroid hormone (PTH) and the active form of vitamin D, calcitriol. PTH, synthesized by the chief cells of the parathyroid gland, acts on the bone to increase resorption and calcium mobilization. It also works on the kidney to increase calcium reabsorption and decrease phosphorous reabsorption, and to increase the formation of calcitriol. The net result of PTH secretion is to increase calcium and decrease phosphorous in the serum. Vitamin D is formed from cholesterol precursors in the skin by the action of sunlight. The active form, calcitriol, is formed in the kidney. Vitamin D works primarily on the intestine to increase calcium and phosphorous absorption. The net effect of vitamin D is to increase plasma calcium and phosphorous. Calcitonin is used pharmacologically for treatment of hypercalcemia, although its exact physiologic role is under debate. It is regulated by GI hormones and is probably important in controlling postprandial hypercalcemia. It also appears to be important in calcium regulation in immature animals. It probably is a minor player in the day-to-day regulation of plasma calcium.

Causes of hypercalcemia

The most common cause of hypercalcemia in dogs and cats is malignancy. The neoplastic diseases reported to cause hypercalcemia include lymphoma, anal sac apocrine cell adenocarcinoma, multiple myeloma, mammary carcinoma, thymoma, oral melanoma hepatoblastoma, chronic lymphocytic leukemia, and nasal carcinoma, with lymphoma being the most common. Hypercalcemia seen with malignant disease probably results primarily from enhanced osteoclastic bone resorption mediated by factors systemically released by neoplastic cells. One such factor has been has been identified in the dog as parathyroid hormone related protein (PTHrP) which is identical to PTH at the N-terminal region and can bind with equal affinity to PTH receptors. By activating PTH receptors, PTHrP causes hypercalcemia by a similar mechanism as that of an excess of PTH. Osteolysis from primary bone tumors are a rare cause of hypercalcemia.

Other common disorders associated with hypercalcemia are hypoadrenocorticism chronic renal failure, and urolithiasis in cats. Although in these retrospective studies, a significant number of Addisonian animals were reported to be hypercalcemic, the pathogenesis of the hypercalcemia is unknown. Dogs and cats with chronic renal failure demonstrate hypercalcemia uncommonly, and it is thought that decreased renal calcium excretion and PTH-mediated osteoclastic activity from renal secondary hyperparathyroidism may be responsible. In the cat, idiopathic hypercalcemia of mild to moderate severity has been described. In some cases it has been associated with calcium oxalate urolithiasis and has resolved with discontinuation of an urinary acidification diet. The pathogenesis of hypercalcemia with this condition is unknown.

Rarer etiologies of hypercalcemia in the dog and cat include primary hyperparathyroidism and hypervitaminosis D. Primary hyperparathyroidism may result from parathyroid hyperplasia, adenoma or adenocarcinoma, which are all rare in small animals. Hypervitaminosis D, most commonly results from vitamin D-containing rodenticides or medications, but may be seen with over supplementation with vitamin D, especially in small dogs being given human vitamins. Infectious and inflammatory disorders such as blastomycosis, coccidioidomycosis, feline granulomatous disease, endometritis, and schistosomiasis rarely are reported to cause hypercalcemia in dogs and cats. A recent report also details hypercalcemia following renal transplantation in the cat.

Clinical signs

How does one recognize a hypercalcemic patient? The clinical presentation of hypercalcemia can range from the animal with no clinical abnormalities in which hypercalcemia was found on a routine chemistry to a severly weak or even comatose one. Usually, the clinical signs of hypercalcemia are insidious and so mild that many owners fail to recognize that there is anything wrong with their pet. The most common clinical sign of hypercalcemia is polyuria/polydipsia (PU/PD). This is a direct effect of hypercalcemia on the concentrating ability of the kidney; however, hypercalcemia can also cause acute or chronic renal failure, also resulting in PU/PD. Hypercalcemic animals may also present with signs of lower urinary tract disease since they are predisposed to urinary tract infections and the formation of calcium uroliths. Other less commonly recognized clinical signs include: muscle weakness/atrophy, depression, anorexia, vomiting, constipation, bone pain, pathological fractures, and cardiac arrhythmias. Signs related to specific tumors may also be present.

Evaluating the Hypercalcemic Patient

The clinical approach to the diagnosis of the hypercalcemic patient requires patience and thoroughness. A detailed history should be obtained and questions regarding the possible exposure to rodenticides should be included. Owners should also be questioned about any nutritional supplementation they may be using that may contain vitamin D. The first thing that needs to be established is that the patient is truly hypercalcemic. Since approximately ½ of the plasma calcium is complexed or protein-bound, the total calcium level must be evaluated in light of the serum albumin concentration. In dogs, a correction formula has been established as follows: corrected serum calcium = total serum calcium - serum albumin + 3.5. This formula is not reliable in the cat. A recent study demonstrates that the correction formula does not reflect true calcium status in up to 37% of dogs and 55% of dogs with chronic renal failure. A more accurate way to determine serum calcium levels is to measure ionized calcium in the serum. It is this form that the body regulates through PTH and Vitamin D activity. In addition, by measurement of this value, discrepancies resulting from abnormal serum protein levels are eliminated. Unfortunately, many practices do not have the ability to do this in house, but appropriately handled samples can be sent to outside laboratories.

Once the presence of hypercalcemia has been established, ruling in or out the differential diagnoses listed above should be attempted. Physical examination should be thorough and include palpation of the neck area for parathyroid masses. Although this is a low-yield procedure since the majority of parathyroid masses are too small to be palpated externally. Peripheral lymph nodes should be carefully evaluated for size and firmness, changes in which may indicate the presence of lymphoma. Abdominal palpation should be thorough including evaluation for masses and kidney size. Skeletal pain should be noted that may signal the presence of bone disease. Anal sacs should be thoroughly palpated to check for the presence of anal sac adenocarcinoma.

Biochemical work-up should be initiated by a CBC, chemistry profile, and urinalysis. The leukogram may reveal a leukocytosis that may signal an infectious or inflammatory process. The presence of lymphocytosis or of abnormal lymphocytes may suggest the presence of lymphoma. The hemogram may reveal a nonregenerative anemia that may indicate the presence of chronic disease, renal failure,or bone marrow invasion of neoplastic cells. A chemistry profile will allow evaluation of azotemia that may indicate renal failure. The phosphorous concentration must be carefully evaluated since hypophosphatemia along with hypercalcemia may indicate hyperparathyroidism. Hyponatremia or hyperkalemia may suggest the presence of hypoadrenocorticism, and hyperglobulinemia may signal multiple myeloma or chronic infection. A urinalysis should always be performed in order to fully evaluate the chemistry profile. Unconcentrated samples or isosthenuria may reflect the lack of renal concentrating ability caused by direct effect of hypercalcemia and not necessarily the presence of renal failure. A sediment examination should be performed to determine the presence of crystalluria or urinary tract infection. Urine culture should be performed if indicated.

Results of initial biochemical screening may indicate a possible disease process that should be identified. For instance, in a hypercalcemic animal with hyperglobulinemia, multiple myeloma may be suspected and protein electrophoresis should be performed to identify a monoclomal gammopathy consistent with a plasma cell tumor. If sodium and potassium electrolyte imbalance is found, an ACTH-stimulation test should be performed to identify hypoadrenocorticism. However, in many cases, initial biochemical testing does not reveal a cause of the hypercalcemia and further investigation is required. Since neoplasia is the most common cause of hypercalcemia, this should be looked for. Reliable testing for PTHrP is available for the dog and cat and serum samples looking for the presence of this malignancy-related hormone should be submitted. Imaging studies should be performed to include radiographs of the chest to look for metastatic disease in the lungs and radiographs and/or ultrasound to look for evidence of meoplastic disease in the abdomen. Skeletal radiographs may be warranted to look for lytic bone lesions if multiple myeloma or bone disease is suspected. Any imaging abnormalities should be investigated further by histopathologic, cytologic or culture examination of tissue samples from the abnormal areas. These may be obtained using ultrasound-guided aspiration or biopsy technique or obtained surgically. If no evidence of neoplasia is found, a bone marrow aspirate should be examined for the presence of neoplasia as this may be the only place it can be found.

If results of the studies outlined above do not reveal the etiology of the hypercalcemia, parathyroid disease should be suspected. If the serum phosphorous level is low, this is further indication of hyperparathyroidism. Hyperparathyroidism may be diagnosed by measuring PTH hormone levels. An ionized calcium most be run on a sample obtained at the same time in order to evaluate the PTH level since PTH is regulated based on the serum Ca2+. In order to diagnose hyperparathyroidism, an inappropriately elevated PTH level must be detected as compared to serum Ca2+. Serum vitamin D levels can be checked to rule-out unobserved rodenticide ingestion or inadvertent supplementation with vitamins. If hyperparathyroidism is suspected, an ultrasound examination should be performed to try to identify a parathyroid tumor. Unfortunately, these lesions can be difficult to identify using ultrasound, although a recent report indicates better success using a high resolution method and suggests correlation of size of parathyroid lesion with disease. Scintigraphy using technetium may provide an additional, nonivasive imaging technique if nothing can be seen on ultrasound examination. In some cases, surgical exploration may be the only way to identify parathyroid disease.

Unfortunately, in some cases, the aforementioned work up fails to provide a diagnosis for the hypercalcemia. In this case, occult neoplasia or idiopathic hypercalcemia especially in the cat should be suspected. The animal may require repetition of previous bloodwork, imaging studies, and bone marrow examination in order to diagnose the condition. This can be frustrating for both the veterinarian and the owner, and the veterinarian must explain how difficult these cases can be to diagnose at times.

During the quest for diagnosis, the hypercalcemia must be addressed since hypercalcemia may result in tubular degeration and necroses of the kidney. Additionally, with elevations in serum phosphorous levels, hypercalcemia may lead to precipitation of calcium/phosphorous crystals in soft tissue structures. Treatment for hypercalcemia includes intravenous saline diuresis and lasix. In refractory cases, calcitonin is very effective in lowering serum calcium levels, although its effects are transitory. Although glucocorticoids also promote calciuresis and thus are effective in treating hypercalcemia, they should not be used until an etiology is determined since their use can confound the diagnosis of lymphoma, a chief rule-out for hypercalcemia. Bisphosphonates are a new class of drugs just starting to be used in veterinary medicine. Pamidronate and zolendronate has been used intravenously in dogs and cats with good results. These compounds are especially helpful in controlling bone pain associated with malignancies. Success has also been reported with oral alendronate; however, care must be taken to avoid esophagitis and stricture especially in cats.