Diseases of the Parathyroid Glands

The control of calcium and phosphate metabolism is vital as these ions play an important role in many physiologic processes. Calcium is necessary for intracellular reactions, including muscle contraction, nerve cell activity, the release of hormones through the process of exocytosis, and activation of numerous enzymes [1]. Inorganic phosphate also functions as an important hydrogen ion buffering system in blood. Organic phosphate is an important part of the cell, including the plasma membrane and intracellular components including nucleic acids, ATP, and AMP. The regulation of calcium involves control of the movement of calcium between the extracellular fluid and three body organs: bone, gastrointestinal tract, and kidneys [2].

Parathyroid Hormone

The main endocrine organ involved in the control of calcium and phosphate metabolism is the parathyroid gland. Four parathyroid glands are present in the cat and the dog. The external parathyroid lies at the cranial-lateral pole of the thyroid gland, and the internal parathyroid gland rests medially within the thyroid parenchyma. Vascular supply to the parathyroid glands is provided via branches of the thyroid artery and vein [3]. During embryologic development, fragments of parathyroid tissue may migrate and be present ectopically in peritracheal fascia to the thoracic inlet or cranial mediastinum [4]. Parathyroid hormone (PTH), primarily an 84-amino acid, single-chain polypeptide, is synthesized, stored, and secreted by the chief cells of the parathyroid glands [1].

The effect of PTH is to increase calcium and decrease phosphate concentrations in extracellular fluids. PTH has direct effects on bone and kidney metabolism of calcium and indirect effects on gastrointestinal metabolism of calcium [5]. The initial effect of PTH on bone is to promote the transfer of calcium across the osteoblast osteocyte membrane. PTH acts on the distal convoluted tubules of the kidneys to increase absorption of calcium and decrease renal phosphate reabsorption through an effect on the proximal tubules. PTH is involved also in the activation of vitamin D at the kidney level. PTH mediates the absorption of calcium from the gut indirectly through its effect on vitamin D. PTH secretion is controlled by free (ionized) calcium concentrations in blood; decreases in calcium stimulate PTH secretion, and increases in calcium turn off secretion [1].

Hyperparathyroidism

Hypercalcemia can be caused by a variety of etiologies including hypercalcemia of malignancy, hyperparathyroidism, granulomatous disease, osteoporosis, hypoadrenocorticism, chronic renal disease, and hypervitaminosis D [5]. The initial signs of hypercalcemia are polydipsia and polyuria resulting from impaired response of distal renal tubules to antidiuretic hormone (ADH). Listlessness, depression, and muscle weakness result from depressed excitability of neuromuscular tissue. Mild gastrointestinal signs of hypercalcemia include inappetence, vomiting, and constipation [6]. In cats, neoplasia, renal failure, and urolithiasis are the most common conditions associated with hypercalcemia [7].

The diagnostic approach to hypercalcemia consists of ruling out the most common cause, which is hypercalcemia of malignancy. Lymphosarcoma and adenocarcinoma of the anal sac, tumors that are commonly associated with hypercalcemia, secrete a PTH-like hormone that increases bone resorption and inhibits renal tubular reabsorption of phosphorus [1,8]. A thorough history and physical examination including lymph node and rectal examination, CBC, serum chemistry profile, urinalysis, and chest/abdominal radiographs are necessary to search for underlying neoplastic processes. Once a diagnosis of neoplasia has been excluded, the next differential for hypercalcemia is chronic renal failure. This is the most difficult to exclude because other causes of hypercalcemia may result in renal damage owing to soft tissue mineralization of the kidneys.

Therefore, an animal with hypercalcemia, azotemia, and hyperphosphatemia could suffer from primary hyperparathyroidism or primary renal failure with secondary renal hyperparathyroidism. Furthermore, patients with hypercalcemia secondary to renal disease may also exhibit elevations in intact PTH. Diagnosis of primary hyperparathyroidism is based on the findings of hypercalcemia (preferably ionized), hypophosphatemia, high-normal to elevated serum parathormone concentrations, and a mass in the cervical region. Intact PTH, using a sandwich assay validated for use in the dog and cat, should be measured [9]. It should be emphasized that a normal PTH concentration in the presence of elevated total and/or ionized calcium is "inappropriate" for the calcium level and would be considered diagnostic for primary hyperparathyroidism. For suspected cases of hypercalcemia of malignancy in which the diagnostic approach has failed to identify a neoplastic process, PTH-related protein (PTH-rp) concentrations may be measured [6,9].

Primary Hyperparathyroidism

Dogs with primary hyperparathyroidism may present asymptomatically or with polydipsia, polyuria, and weakness as well as with urinary tract signs attributable to urolithiasis and infection [10-12]. The most common clinical signs observed in cats with hypercalcemia are anorexia and lethargy [13]. The majority of dogs have parathyroid adenomas or parathyroid hyperplasia with rare carcinomas reported [14]. If primary hyperparathyroidism is suspected, several imaging modalities, including ultrasonography, CT scan and scintigraphy may be utilized if a palpable neck mass is not present. Parathyroid scintigraphy has been shown to have poor sensitivity and specificity [15]. Ultrasonography may better delineate the side and size of parathyroid mass present [16]. Additionally, percutaneous ultrasound-guided techniques may be used to ablate masses. Radiofrequency as well as chemical ablation have been reported. Although these techniques have proven to be safe and effective, the potential risk factors include hypocalcemia and laryngeal paralysis. Additionally, repeat injections may be required for successful treatment [17,18].

Prior to surgical intervention, diuresis with normal saline may be instituted to lower serum calcium levels. For severe hypercalcemia, furosemide (in a well hydrated animal), glucocorticoid, or calcitonin therapy may be indicated [5]. Administration of glucocorticoids should be delayed until a definitive diagnosis has been made as administration may interfere with the ability to confirm lymphosarcoma histologically [1]. Bisphosphonates have been used to slow hypercalcemia in humans; they function by inhibiting osteoclast function and viability [19].

Surgery requires a full ventral neck exploration to evaluate both external and internal parathyroid glands bilaterally. Additionally, the whole cervical region to the thoracic inlet should be evaluated for ectopic parathyroid tissue. If all four glands are enlarged owing to parathyroid hyperplasia, excision of one to three of the glands may reduce the associated hypercalcemia [3]. Visualization of the abnormal parathyroid tissue may be aided with intravenous new methylene blue infusion, although Heinz body anemia is a risk factor of administration [20]. Patients should be monitored postoperatively for renal failure and signs of hypocalcemia, which include panting, twitching, or tremors. Development of postoperative renal failure in dogs has been found, in one study, to be more likely to develop in dogs with a higher initial calcium level [12]. Hypocalcemia occurs in up to 58% of dogs after surgery owing to negative feedback and suppression of the remaining glands from elevated PTH levels [14]. Dogs with higher initial calcium levels (> 14 mg/dl) are more likely to become clinically hypocalcemic after surgery [1]. Calcium, in the form of vitamin D (dihydrotachysterol) or calcitriol (1,25(OH)2D3), supplementation should be instituted pre- or postoperatively and continued until calcium levels normalize over 2 to 8 weeks. Long-term prognosis after parathyroidectomy, if renal damage has not occurred, is favorable [11-14].

Hypoparathyroidism

The classic biochemical findings in animals with hypoparathyroidism are hypocalcemia (both total and ionized) and hyperphosphatemia with an inappropriately low PTH level. Other causes of hypocalcemia include iatrogenic (post-thyroidectomy) hypoparathyroidism, chronic and acute renal failure, acute pancreatitis, hypoalbuminemia, puerperal tetany (eclampsia), ethylene glycol intoxication, intestinal malabsorption, and nutritional secondary hyperparathyroidism [21]. The absence of PTH results in urinary calcium loss, decreased calcium mobilization from bone, and decreased intestinal absorption of calcium [22]. The majority of clinical signs are attributable to low circulating ionized calcium, leading to neuromuscular excitability [21]. Early signs of hypocalcemia are nonspecific and include anorexia, facial rubbing, nervousness, and a stiff gait. Later signs progress to cardiac arrhythmias, hyperventilation, and finally, generalized tetany and/or seizures [21].

Diagnosis of primary hypoparathyroidism is achieved by obtaining a complete blood count, chemistry profile, urinalysis, ionized calcium and magnesium levels, as well PTH level. Serum or plasma PTH concentrations should be measured on a freshly drawn sample in a fasted animal. Handling of the sample is crucial to appropriate diagnosis, as PTH is prone to degradation if subjected to warm temperatures [9].

Treatment of hypoparathyroidism is directed at the underlying cause. In animals that undergo bilateral thyroidectomy, it is possible to autotransplant parathyroid tissue by sectioning the glands and implanting them within adjacent neck musculature [3]. Glands maybe functional within 2 weeks of transplantation [23]. Medical therapy for hypoparathyroidism may require intravenous calcium administration for an acute crisis or permanent vitamin D supplementation in chronic cases [24].