Joao Felipe De Brito Galvao,     Downers Grove, Illinois

Dennis J. Chew,     Columbus, Ohio

Larry A. Nagode,     Columbus, Ohio

Patricia A. Schenck,     Lansing, Michigan

Pathophysiology and Differential Diagnosis

Hypoparathyroidism is a state of absolute or relative deficit of parathyroid hormone (PTH) secretion that can be permanent or transient. Hypocalcemia and clinical signs referable to low ionized calcium concentration are the hallmarks of advanced hypoparathyroidism. This endocrine disorder is an uncommon cause of hypocalcemia in dogs and cats (Web Box 22-1), but it is the only condition requiring acute and chronic treatment to alleviate clinical signs associated with hypocalcemia. Hypoparathyroidism in dogs is most commonly an idiopathic or primary condition, whereas surgical removal or injury during thyroidectomy to correct hyperthyroidism is the most common cause in cats. Rarely, transient hypoparathyroidism can occur after correction of long-standing hypercalcemia (e.g., subsequent to removal of an adenocarcinoma of the apocrine gland of the anal sac or treatment of lymphosarcoma). In humans with idiopathic hypoparathyroidism, a variety of mutations have been identified that affect PTH production or PTH receptors (pseudohypoparathyroidism), but these conditions have not been described in dogs or cats. The treatment for hypoparathyroidism is the same, regardless of cause or genetic defect.

Inappropriately low levels of PTH cause hypocalcemia, hyperphosphatemia, and decreased levels of 1,25-dihydroxycholecalciferol (calcitriol). Hypocalcemia is explained by increased urinary loss (hypercalciuria), reduced bone mobilization, and decreased intestinal absorption as a result of decreased calcitriol formation during periods of low PTH levels. Hyperphosphatemia results from decreased urinary loss of phosphorus (hypophosphaturia), which overcomes decreased bone mobilization and low intestinal absorption of phosphorus during periods of decreased PTH levels. PTH is a potent stimulator, and phosphorus is a potent inhibitor of the 25(OH)-cholecalciferol–1α-hydroxylase system in the renal tubules, the last step in vitamin D activation. Consequently, the absence of PTH and the presence of hyperphosphatemia work together to decrease renal synthesis of calcitriol (i.e., active vitamin D). Decreased levels of calcitriol contribute to hypocalcemia largely through decreased intestinal calcium absorption. A component of hypocalcemia unrelated to low PTH levels is increased uptake of calcium into bone after rapid correction of long-standing hyperparathyroidism or hyperthyroidism, both of which are associated with loss of bone calcium before treatment (hungry bone syndrome).

Magnesium also plays a role in PTH production. Severe magnesium depletion blunts maximal PTH secretion, increases end-organ resistance to PTH, and also may impair calcitriol synthesis.

Veterinary patients with hypoparathyroidism can be divided into three categories: (1) those with absence or destruction of parathyroid glands, (2) those with sudden correction of chronic hypercalcemia, or (3) those with suppressed secretion of or responsiveness to PTH without parathyroid gland destruction. The most common category of hypoparathyroidism in dogs and cats is that associated with the absence or destruction of the parathyroid glands.

Clinical Signs

Clinical signs related to hypocalcemia are identical, regardless of the underlying cause. Decreased serum ionized calcium concentration increases excitability of neuromuscular tissue, which accounts for many of the clinical signs of hypoparathyroidism. Mild decreases in serum ionized calcium may result in no obvious clinical signs. The duration, magnitude, and rate of the decrease in serum calcium interact to determine the severity of clinical signs. In its most severe forms, hypocalcemia can cause death from harmful circulatory effects (hypotension and decreased myocardial contractility) and respiratory arrest from paralysis of respiratory muscles. Serum total calcium concentration below 4 mg/dl can cause death, especially if the decline was rapid.

Other electrolyte and acid-base abnormalities can either magnify or diminish the signs of hypocalcemia. Correction of hypokalemia may precipitate the onset of clinical signs of hypocalcemia when hypocalcemia is present concurrently. Respiratory alkalosis after exercise or excitement also may increase the clinical signs of hypocalcemia as ionized calcium shifts to the protein-bound fraction. Rapid infusion of sodium bicarbonate with resulting metabolic alkalosis causes a similar decrease in ionized calcium.

Clinical signs of primary hypoparathyroidism from hypocalcemia include seizures, muscle tremors or fasciculations, muscle cramping, stiff gait, and behavioral changes (restlessness, excitation, aggression, hypersensitivity to stimuli, disorientation) (Web Box 22-2). Most seizures resolve without treatment but often recur despite treatment with anticonvulsants. Growling attributable to pain or behavior change and intense rubbing of the face with the paws or on the ground commonly are observed. These signs are attributed to either paresthesia or pain from facial muscle spasms. Hyperthermia may be caused by increased muscular activity; lethargy, anorexia, and weakness may be noted, especially in cats. Polyuria and polydipsia occur in some cases as a result of psychogenic mechanisms or renal injury from hypercalciuria. Anterior and posterior lenticular cataracts occur in some affected dogs and cats, and prolapse of the third eyelid sometimes is seen with acute hypocalcemia in cats. Vomiting, abdominal pain, and diarrhea occasionally have been noted in patients with primary hypoparathyroidism.

Seizures caused by hypocalcemia appear different than those associated with idiopathic epilepsy. With hypocalcemia, seizures often are preceded by apprehension or nervousness, and affected animals may remain partially conscious and retain urinary continence during the seizure. Clinical signs caused by acute postoperative hypocalcemia after parathyroidectomy are similar in dogs and cats relating to excitation of neuromuscular tissue. Focal twitching of facial muscles and whiskers may be noticed before more generalized muscle tremors or seizures. Clinical tetany typically occurs when total calcium concentration declines to 6 mg/dl or less.

Diagnosis

Hypocalcemia has numerous causes (see Web Box 22-1). The approach to diagnosis of the cause of hypocalcemia is described in Web Figure 22-1. Primary hypoparathyroidism is the only disorder characterized by hypocalcemia, elevated serum phosphorus, and low PTH concentration, along with normal renal function. Decreased serum calcium with increased serum phosphorus may be seen in nutritional or renal secondary hyperparathyroidism, after phosphate-containing enema administration, and in tumor lysis syndrome; however, PTH concentration is increased in all of these conditions. A presumptive diagnosis of hypoparathyroidism can be made on the basis of decreased serum calcium, high serum phosphorus, normal renal function, and the absence of an obvious alternative diagnosis. The definitive diagnosis of hypoparathyroidism requires the finding of a PTH concentration below or within the reference range concurrently with hypocalcemia because hypocalcemia should provide a strong stimulus to the normal parathyroid glands to secrete PTH to a level above the reference range. Primary hypoparathyroidism requires lifelong treatment; thus confirmation of the diagnosis with PTH measurement is recommended highly. Because magnesium depletion can cause functional hypoparathyroidism measurement of serum ionized magnesium concentration also is recommended because more than 75% of dogs and cats with primary hypoparathyroidism have marginal or low serum ionized magnesium concentrations.