Disorders of calcium--hyper and hypocalcemia; parts 1 & 2 (Proceedings)

Normal calcium homeostasis

The hormones that dictate calcium regulation include parathyroid hormone (PTH), active vitamin D (1,25 dihydroxycholecalciferol), and calcitonin. Parathyroid hormone functions include mobilization of Ca++ from the bone, and promotion of vitamin D conversion from 25 (OH) cholecalciferol to 1,25-dihydroxycholecalciferol (active vitamin D). Active vitamin D (calcitriol) increases renal and gastrointestinal calcium reabsorption and mobilizes calcium ion from the bone. As calcium and active vitamin D levels normalize in plasma, negative feedback occurs to reduce production of PTH. Calcitonin is made in the thyroid parafollicular cells and inhibits bone reabsorption and increases Ca++ loss in urine.

Plasma calcium in circulation is partly bound to protein, and partly diffusible. The protein bound form is mostly bound to albumin, and the diffusible form is mostly ionized (free), and includes a small quantity that is complexed to anions. Protein-bound and ionized calcium are usually present in equal amounts; however changes in other electrolytes and pH can alter this proportion or increase the proportion of complexed calcium. For example, plasma proteins become more ionized with alkalosis, causing increase of the protein-bound form of calcium. Calcium is maintained in the bloodstream by an interaction of absorption from the bone, gastrointestinal tract, and renal absorption or excretion.

Vitamin D is a group of closely related sterols produced by the action of ultraviolet light on certain provitamins in the skin. When exposed to ultraviolet light, 7-dehydrocholesterol eventually becomes vitamin D3 (cholecalciferol). Vitamin D3 is also absorbed in the intestines from dietary sources. Inter-species differences dictate whether dietary source vitamin D or skin-produced vitamin D is the predominant source. For example, non-haired species like reptiles obtain most vitamin D via skin production, whereas dogs and cats rely primarily on intestinal absorption for vitamin D. Cholecalciferol is transferred in the plasma to the liver, converted to 25-hydroxycholecalciferol, and then to 1, 25-dihydroxycholecalciferol (calcitriol) in the renal proximal tubular cells. Calcitriol increases serum calcium primarily by facilitating calcium reabsorption from the gastrointestinal tract, but also increases bone reabsorption in concert with PTH. Formation of calcitriol in the renal tubules is regulated by feedback from Ca++ and phosphorous, and facilitated by PTH.

Chief cells of the parathyroid glands secrete PTH in response to low total or ionized calcium or low calcitriol. Parathyroid hormone is an 84 amino acid sequence as released from the parathyroid gland. In circulation, PTH is cleaved in circulation with the 1-34 amino acid sequence (the n terminal) end being the active hormone sequence. Plasma half-life is 10 minutes. PTH acts on bone to increase reabsorption and mobilize calcium. PTH receptors can bind PTH or parathyroid- hormone related protein (PTHrP). Secretion of PTH is regulated by circulating ionized calcium through a direct negative feedback mechanism.  Magnesium is required to maintain normal PTH secretory responses. Hypomagnesemia can cause diminished PTH release resulting in diminished end-organ response, and hypocalcemia.

Calcitonin is a calcium-lowering hormone secreted by the parafollicular cells of the thyroid gland. Calcitonin contains 32 amino acid residues; however the order of amino acids varies from one species to the next. Half-life is <10 minutes in people. Calcitonin lowers calcium by inhibiting bone reabsorption. Salmon calcitonin, which is produced as a pharmaceutical for treatment of hypercalcemia, is more than 20 times more active in people than human calcitonin.

Causes of Hypercalcemia

Hypercalcemia of any degree identified on a serum biochemical profile represents a medical emergency. Mild hypercalcemia may be associated with few clinical signs and be slowly progressive; however hypercalcemia can cause acute renal failure and death. Rapidity of onset and degree of hypercalcemia both dictate severity of clinical presentation. Differential diagnosis for hypercalcemia includes neoplasia, primary hyperparathyroidism, hypervitaminosis D, systemic mycoses, hypoadrenocorticism, delayed renal excretion, and idiopathic.

Humoral hypercalcemia of malignancy

Certain neoplastic cells produce a PTH related protein (PTHrP) that binds with PTH receptors to cause hypercalcemia. This is commonly known as humoral hypercalcemia of malignancy, and typically results in a rapid onset of hypercalcemia with marked clinical signs. Neoplasias associated with this syndrome include lymphosarcoma (LSA, most commonly in dogs), apocrine gland adenocarcinoma of the anal sac, multiple myeloma, malignant mammary adenocarcinoma, nasal adenocarcinoma, thyroid carcinoma, GI or vaginal squamous cell carcinoma, and others. In cats, humoral hypercalcemia of malignancy is most commonly associated with squamous cell carcinoma. Hypercalcemia associated with LSA in dogs is a negative prognostic indicator, and is frequently associated with cranial mediastinal lymph node involvement. Solid bone tumors such as osteosarcoma that were previously thought to result in hypercalcemia from bone destruction now are suspected to cause hypercalcemia by the humoral mechanism.

Primary hyperparathyroidism

Primary hyperparathyroidism usually results from parathyroid adenoma, however parathyroid carcinoma and parathyroid hyperplasia cause similar clinical signs. Parathyroid adenomas occur most frequently in dogs and cats greater than 10 years of age, and Keeshond dogs and Siamese cats are overrepresented. Hypercalcemia with primary hyperparathyroidism tends to be slowly progressive over months to years. The low-grade persistent hypercalcemia can cause calcium-containing urinary calculi that are sometimes diagnosed prior to recognition of hypercalcemia. Parathyroid adenocarcinoma is sometimes associated with dramatic hypercalcemia. Parathyroid hyperplasia is the result of chronic stimulation of parathyroid glands to produce PTH, and is associated with lack of vitamin D (typically associated with failure of ultraviolet light exposure in pet reptiles), intake of feedstuffs with low calcium: phosphorous ratio (nutritional secondary hyperparathyroidism), or poor renal production of calcitriol (renal secondary hyperparathyroidism).

The secondary causes of hyperparathyroidism should result in a normal serum calcium and are not typically included in differentials for hypercalcemia; however in renal secondary hyperparathyroidism the parathyroid glands can undergo an adenomatous transformation causing poor response to negative feedback leading to excessive PTH and hypercalcemia. This is known as tertiary hyperparathyroidism, and is relatively uncommon. Nutritional secondary hyperparathyroidism is not a cause of hypercalcemia. Severe nutritional secondary hyperparathyroidism can lead to hypocalcemia when there is insufficient stored calcium from bone depletion.

Hypervitaminosis D

Hypervitaminosis D occurs secondary to ingestion of an active form of Vitamin D (e.g. cholecalciferol rodenticide or human pharmaceutical intoxication, dietary supplementation, day-blooming jessamine ingestion, or iatrogenic following treatment of hypoparathyroidism,) Vitamin D is metabolized into the active form (if not already in an active form) to increase GI uptake and bone reabsorption of calcium.

Systemic mycoses

Macrophages in chronic granulomatous diseases produce a vitamin D-like compound to cause hypercalcemia. Systemic fungal diseases are the most common cause of this form of hypercalcemia, and include blastomycosis, histoplasmosis, and coccidiomycosis.

Delayed renal excretion

Hypoadrenocorticism and chronic renal failure result in hypercalcemia via an unknown pathogenesis. Chronic renal failure could result in tertiary hyperparathyroidism to result in hypercalcemia as described above, or could be associated with mild increases in serum total calcium from changes in excretion. Hypercalcemia is sometimes seen with moderate to severe hypoadrenocorticism (Addison's), and most likely occurs from dehydration and poor renal excretion.

Idiopathic hypercalcemia of cats

Idiopathic hypercalcemia is the most common cause of hypercalcemia in cats. Duration of hypercalcemia can be months to years, and is sometimes asymptomatic. Weight loss, anorexia, vomiting, and constipation can be seen. Affected cats are predisposed to formation of calcium-containing urinary stones. Longhaired cats seem to be predisposed.

Clinical Signs of Hypercalcemia

Clinical signs of hypercalcemia may be absent to severe, and are dictated by the rapidity of onset and severity of increase of calcium. Common signs include polyuria, polydipsia, listlessness, weakness, exercise intolerance, and lower urinary tract disease, while less common signs include vomiting, constipation, stiff gait, or pathologic fractures.

Polyuria and polydipsia are the predominant clinical signs. When serum calcium exceeds 12-14 mg/dl, renal calcium reabsorptive capacity becomes overwhelmed, leading to hypercalciuria. Polyuria occurs due to nephrogenic diabetes insipidus (NDI); ADH receptors become insensitive due to alteration in cyclic AMP (cAMP) response from increased calcium filtration. The obligate polyuria causes compensatory polydipsia. Renal failure ensues due to glomerular changes, direct toxicity of calcium on tubular cells, volume depletion and tubular ischemia, and renal mineralization. In longstanding cases, urolithiasis occurs secondary to chronic hypercalciuria. Animals are also predisposed to urinary tract infections.

Physical examination findings in the hypercalcemic patient are dictated by the underlying disease (e.g. peripheral lymphadenopathy in lymphosarcoma), or examination may be normal. The importance of a thorough physical examination cannot be overemphasized. Parathyroid gland enlargement is not typically detectable on cervical palpation in dogs; however cats can present with a cervical mass which might be mistaken for an enlarged thyroid gland. Rectal examination should be performed in every hypercalcemic patient to identify apocrine gland adenocarcinoma of the anal sac as a cause. Anal sac tumors can be quite small and still produce PTHrP, so thorough palpation can only be performed following expression of the anal sacs if the sacs are full.

Diagnostic Testing for Hypercalcemia

Medical database workup to include complete blood count, serum biochemical profile, ionized calcium evaluation, urinalysis, and radiographs should be performed in every hypercalcemic patient. Complete blood count is often unrewarding, but can show changes consistent with lymphosarcoma or chronic granulomatous disease. Serum biochemical profile should be carefully evaluated to show evidence of renal dysfunction or electrolyte changes consistent with hypoadrenocorticism. Phosphorous concentration can help to differentiate various causes of hypercalcemia in that hypervitaminosis D or renal failure results in increase of both calcium and phosphorous resulting in elevations of both while primary hyperparathyroidism or humoral hypercalcemia of malignancy would be expected to increase phosphorous excretion and cause low-normal to low phosphorous concurrent with hypercalcemia.

Calcium on serum biochemical profile is total calcium, which normally represents 50% ionized calcium, and 50% protein-bound calcium. Ionized calcium is the metabolically active form, and should be performed to differentiate clinically significant hypercalcemia from alterations of calcium proportions in blood. Ionized calcium measurement has become widely available through commercial laboratories, and in some in-house chemistry analyzers and point-of care analyzers. Ionized calcium should be increased with primary hyperparathyroidism or hypercalcemia of malignancy. Chloride becomes elevated due to PTH-induced proximal tubular bicarbonate reabsorption, leading to increased calcium reabsorption with mild proximal renal tubular acidosis. Chronic, persistent hypercalcemia causes renal failure, and renal failure can be a cause of hypercalcemia. Therefore, azotemia can be seen. Isosthenuria should occur with hypercalcemia due to nephrogenic diabetes insipidus. Hematuria, pyuria, bacteriuria, crystalluria all may be significant findings, and should be followed up with a urine culture.

Thoracic and abdominal radiographs are indicated in diagnostic workup of any patient with hypercalcemia to evaluate bone conformation, assess for lytic bone lesions, and screen for neoplasia. Abdominal ultrasound is also useful to evaluate for neoplasia, chronic kidney failure, and lower urinary calculi or cystitis. Cervical ultrasound may identify parathyroid enlargement.

If the cause of hypercalcemia is not evident following physical examination and medical database evaluation, PTH, PTHrP, and vitamin D should be measured. The physiologic response to hypercalcemia is to stop production of PTH; therefore the hypercalcemic animal should have low PTH. It is critically important to evaluate these hormone levels in the presence of hypercalcemia. If calcium has been rendered normal with therapy, the clinician should wait until hypercalcemia returns to submit PTH and PTHrP testing. Primary hyperparathyroidism is diagnosed by finding hypercalcemia, with normal or elevated PTH. Parathyroid hormone should be low or undetectable and PTHrP elevated in hypercalcemia of malignancy. Vitamin D assay is available to identify intoxication if history of toxin ingestion is not known. Parathyroid hormone-related protein assay is available. If diagnostic testing is supportive of humoral hypercalcemia of malignancy in a patient without obvious neoplasia, bone marrow aspiration, lymph node aspiration, abdominal ultrasound, and hepatic biopsy should be considered.

Therapy for Hypercalcemia

Acute management of the hypercalcemic patient is aimed at correcting the hypercalcemia while investigating the cause of the disorder. Treatment to control hypercalcemia is indicated when dehydration, azotemia, cardiac arrhythmia, neurologic dysfunction, or weakness exists. Mild and slowly progressive hypercalcemia in which the animal is stable (normally hydrated) can sometimes be managed on an outpatient basis while diagnostic tests are pending.

Initial management with critical hypercalcemia consists of intravenous fluid therapy for rehydration, and to maximize calcium excretion. Failure to normalize marked hypercalcemia can predispose to acute renal failure; therefore, inpatient management is recommended. The fluid of choice is 0.9% sodium chloride (NaCl) since it promotes calciuresis by increasing renal tubular flow rate. Correct any existing dehydration before proceeding with further therapy. Following rehydration, loop diuretics such as furosemide may be administered to inhibit calcium reabsorption at the thick ascending limb of the loop of Henle.

Administration of furosemide will exacerbate renal injury if the patient is not appropriately volume expanded. The dose of furosemide is 5mg/kg IV bolus initially, followed by intermittent boluses as needed to normalize calcium. Thiazide diuretics are not indicated since they decrease renal calcium excretion. If no response occurs within 24 hours of initiation of furosemide therapy and the patient is still appropriately hydrated, calcitonin therapy is indicated. The drug is weak and short-acting, and loses effectiveness over time. Salmon calcitonin (Calcimar® solution) is the most potent form available, and is a relatively costly drug. A variety of dosing regimens have been reported (4.5 U/kg SQ q8h, 8 U/kg SQ q24h, 5 U/kg SQ q12h in dogs, 4 U/kg IM q12h in cats).

Glucocorticoids are effective at lowering calcium by inducing remission of LSA, as well as limiting hypercalcemia for other reasons (e.g. vitamin D intoxication, granulomatous disease). Once remission is induced, LSA becomes extremely difficult to definitively diagnose. Therefore, avoid administration of glucocorticoids until diagnosis is confirmed. Positive response to corticosteroids does not confirm neoplasia. Mechanisms of action of corticosteroids include reducing bone resorption and decreasing intestinal resorption. Prednisone is dosed at 2mg/kg BID.

Surgery aimed at finding abnormal parathyroid tissue is indicated when PTH is elevated. The goal is to identify all four parathyroid glands, and distinguish disease in one gland (most consistent with adenoma or carcinoma) versus multiple glands (primary or secondary hyperplasia). Solitary gland disease results in atrophy of other glands due to negative feedback. Negative exploratory indicates parathyroid disease elsewhere than the cervical region, or alternate diagnosis (e.g. malignancy). Postoperative hypocalcemia should be anticipated, and treatment provided if necessary.

For chronic or noncurable hypercalcemia (e.g. nonresectable neoplasia, vitamin D intoxication), a class of drugs called bisphosphonates can be considered. Bisphosphonates lower calcium by reducing osteoclast activity and function. In people, these treatments are most commonly used to normalize calcium in humoral hypercalcemia of malignancy. Side effects in people include renal impairment, and nausea and esophageal reflux with the oral form. Hydration status should be normalized prior to initiating this therapy. In dogs, pamidronate has been used to treat hypercalcemia from vitamin-D containing rodenticide ingestion, congenital hyperparathyroidism, and humoral hypercalcemia of malignancy. Cats with idiopathic hypercalcemia have been treated with bisphosphonates. Intravenous injection is typically used to lower calcium initially; whereas oral treatment can be used long term. Oral therapy should not be associated with feeding. Drugs used either experimentally or clinically in dogs include pamidronate, clodronate, and etidronate. Pamidronate can be administered at 1.3 mg/kg in 0.9% NaCl delivered as a 2 hour intravenous infusion, and repeated in 1-3 weeks. Clodronate has been administered at 20-25 mg/kg as a 4 hour intravenous infusion.

Hypocalcemia

Low serum calcium must be interpreted in light of disorders causing a change in the proportion of protein-bound to ionized calcium. Decrease in the protein-bound calcium in circulation with normal ionized calcium should not result in clinical signs of hypocalcemia. Both clinical signs and ionized calcium measurement can help to differentiate clinically significant hypocalcemia from an incidental finding. True hypocalcemia is the result of insufficient circulating parathyroid hormone (PTH), inadequate active Vitamin D, or sudden binding of ionized calcium making it unavailable.

Clinical Signs

Clinical signs of hypocalcemia are often episodic, and commonly include muscle tremors, fasciculations, seizures, tetany, status epilepticus, facial rubbing, paw chewing, and behavior changes. Less common symptoms include panting, pyrexia, lethargy, depression, anorexia, third eyelid prolapse, posterior lenticular cataracts, tachycardia, QT interval lengthening, polyuria, polydipsia, hypotension, respiratory arrest, and death. Symptoms occur acutely or chronically. Neurologic symptoms tend to progress. Physical examination may be normal except for neurologic or behavioral abnormalities.

Diagnostic evaluation should include screening tests to rule out common causes for hypocalcemia. Identification of hypocalcemia on a serum chemistry panel should be interpreted in light of hypoalbuminemia and should be confirmed with ionized calcium measurement if clinical signs are not consistent with diagnosis. Magnesium assessment should be performed to identify hypocalcemia secondary to hypomagnesemia.

Treatment of Hypocalcemia

Treatment consists of administration of emergency therapy to address life-threatening clinical signs of hypocalcemic tetany, as well as chronic therapy to maintain calcium in the normal range. Emergency therapy should be initiated prior to obtaining results from all diagnostic testing if clinical signs are severe (tetany, seizures). Therapy for hypocalcemic tetany requires initial treatment with calcium salts. Calcium content varies widely among preparations, and milligram doses recorded in the literature apply to elemental calcium content of the product. Calcium chloride is extremely irritating if administered perivascularly, therefore calcium gluconate is more frequently utilized in veterinary practice. Excessively rapid calcium administration can cause bradycardia; therefore EKG should be evaluated throughout administration. The doses given are guidelines: administration by the intravenous route should be given by slow injection until clinical signs are controlled, and not be strictly dictated by a published dose.

Intravenous therapy should control symptoms of hypocalcemic tetany for 1 to 12 hours, depending upon the underlying cause of the hypocalcemia. In some cases, the cause of hypocalcemia will resolve (e.g. eclampsia). Intravenous continuous calcium therapy and oral vitamin D supplementation should be initiated when the original cause of hypocalcemia cannot be quickly resolved (idiopathic or iatrogenic hyperparathyroidism). Continuous intravenous infusion of calcium is recommended at 60-90 mg/kg/day of elemental calcium, until oral calcium and vitamin D maintain calcium. Intermittent injections of calcium are less ideal due to fluctuations of serum calcium. Calcium preparations should not be added to bicarbonate-containing fluids because precipitation may occur.

Vitamin D is recommended to control calcium in hypoparathyroidism. Lifelong vitamin D therapy is indicated in primary hypoparathyroidism, and some cases of iatrogenic hypoparathyroidism. Iatrogenic hypoparathyroidism secondary to surgical thyroidectomy should resolve within 12 weeks; otherwise, parathyroid damage is considered permanent. Available vitamin D preparations vary in activity. Ergocalciferol, the least expensive of the available compounds, is also the least metabolically active. Dihydrotachysterol is a synthetic vitamin D analogue intermediate in activity between ergocalciferol and calcitriol.  Calcitriol is the most metabolically active form of vitamin D, has the shortest onset of activity, and is the most potent. Compared to other commercially available vitamin D analogues, ergocalciferol is 500 times less potent than dihydrotachysterol, and 1000 times less active than calcitriol.

Oral calcium supplementation is most important initially before the vitamin D preparation takes effect. Calcium content in normal diets is appropriate for maintenance in the presence of vitamin D; however supplemental calcium is important prior to onset of vitamin D activity in the hypoparathyroid patient. Similar to intravenous preparations, oral supplements are dosed on elemental calcium. Calcium carbonate is the most commonly used supplement since it contains the highest quantity of elemental calcium.

Patients with primary hypoparathyroidism are subject to fluctuations in calcium levels, and require regular evaluation throughout life. Daily evaluation of serum calcium is indicated at the time of diagnosis for initial management, and tapering of intravenous calcium supplementation when oral calcium and vitamin D supplementation have been initiated. Following initial stabilization, weekly calcium evaluation should be sufficient, with the client monitoring for signs of hypocalcemia and hypercalcemia at home. After at-home stabilization, recheck every 3 months is appropriate to adjust drug therapy. Calcium should be maintained at the low end of the reference range, since iatrogenic hypercalcemia is undesirable.

Primary hypoparathyroidism requires lifelong therapy. Prognosis is unknown, but is improved by avoiding episodes of iatrogenic hyperparathyroidism that cause hypercalcemia and renal injury. Following surgical removal of a parathyroid adenoma, or iatrogenic hypoparathyroidism following thyroidectomy, hypoparathyroidism is expected until the remaining parathyroid glands are no longer suppressed from chronic negative feedback. This may occur from as soon as 2 weeks, to as long as 3 months postoperatively. Dogs usually require treatment for 6-12 weeks postoperatively. Initial taper of vitamin D can be attempted 1 month postoperatively. If calcium levels fall, the previous dose should be reinstituted, and another taper attempted in one month. If the patient cannot be tapered within three months, lifelong therapy will most likely be needed.

Causes of Hypocalcemia Common Uncommon Rare Hypoalbuminemia (ionized usually normal) Hypoparathyroidism (primary or iatrogenic secondary to treatment of hyperparathyroidism) EDTA anticoagulent sample Chronic renal failure (ionized usually normal) Ethylene glycol intoxication Blood transfusions (citrated anticoagulant) Puerperal tetany (eclampsia) Phosphate enema administration Rapid administration of phosphate-containing solutions Acute renal failure Following bicarbonate administration Hypovitaminosis D Acute pancreatitis Soft tissue trauma or rhabdomyolysis Severe starvation, intestinal malabsorption     Hypomagnesmia     Infarction of parathyroid adenoma     Nutritional secondary hyperparathyroidism     Acute Ca-free fluid administration

Drug Preparation Elemenatal Ca++ Dose Comment Ca++ gluconate 10% 9.3 mg/ml 0.5-1.5 ml/kg slow IV to effect; 5-15 mg/kg/hr IV; 1-2 ml/kg diluted 1:1 with saline SQ t.i.d. Stop IV infusion if bradycardiac; maintain Ca++; May give SQ Ca++ chloride 10% 27.2 mg/ml 5-15 mg/kg/hr IV Extremely caustic perivascularly

Preparation Daily Dose Time until Maximum Effect Time to Resolve Toxicity Ergocalciferol Initial: 4000-6000 U/kg/day; Maintenance: 1000-2000 U/kg once daily to once weekly 5-21 days 1-18 weeks Dihydrotachysterol Initial: 0.02-0.03 mg/kg/day; Maintenance: 0.01-0.02 mg/kg q24-48 hrs 1-7 days 1-3 weeks Calcitriol Initial: 20-30 ng/kg/day x 3-4 days; Maintenance: 5-15 ng/kg/day 1-4 days 2-7 days

Drug % Ca++ avail Preparation Dose Comment Ca++ carbonate 40 Many sizes 25-50 mg/kg/day Most common Ca++ lactate 13 325, 650 mg tablet 25-50 mg/kg/day   Ca++ chloride 27 Powder 25-50 mg/kg/day GI irritant Ca++ gluconate 10 Many sizes 25-50 mg/kg/day