Parathyroid Tumors

+ Anatomy

• Parathyroid glands are salmon-coloured and distinct from the thyroid glands
• 1 external and 1 internal parathyroid gland per thyroid gland
• External parathyroid gland is on the cranial pole of the thyroid gland and external to its capsule
• Internal parathyroid gland are within the thyroid capsule in the caudal and medial aspects of the thyroid
• External parathyroid gland is vascularized by a branch of the cranial thyroid artery
• Ectopic parathyroid tissue is present in 35%-50% of cats and 6%-100% of dogs and can be located anywhere from the base of the tongue to the heart base

+ General Considerations

• Primary hyperparathyroidism is caused by excessive secretion of PTH from the parathyroid glands due to hyperplasia, benign adenoma, or malignant ADC of the parathyroid glands
• Parathyroid neoplasia is uncommon in dogs and rare in cats
• 4 parathyroid glands (1 internal and 1 external on both thyroid glands)
• Hyperplastic or adenomatous changes can be observed in multiple parathyroid glands
• 7% (5/72) dogs with primary hyperthyroidism have multiple parathyroid gland involvement, but only 1 involved all 4 parathyroid glands (multiple parathyroid gland involvement common in Keeshond)
• Secondary hyperplasia should be investigated if all 4 parathyroid glands are enlarged
• Neoplastic or hyperplastic parathyroid gland is usually palpable although surrounding thyroid tissue may make assessment difficult
• Histopathology: hyperplasia, adenoma, and ADC (rare)
• Differentiation of hyperplasia from adenoma is difficult
• Ectopic parathyroid tissue has been identified in the cranial mediastinum

+ Pathophysiology

• Parathyroid neoplasia causes excessive and autonomous PTH secretion from parathyroid chief cells
• Increased circulating levels of PTH results in:
• Increased calcium and phosphorus release from bone
• Increased calcium reabsorption and phosphorus excretion by the kidneys
• Increased calcium and phosphorus absorption in the intestines

+ Signalment

• Cats: Siamese over-represented
• Dogs: Keeshond while GSD, Poodles, and Labrador and Golden Retrievers are over-represented

+ Clinical Features

• Clinical signs are caused by a slow and progressive increase in serum calcium
• Polyuria-polydipsia is a common finding in dogs because of poor response of tubular cells to ADH
• Renal changes include interstitial nephritis and nephrocalcinosis
• Hypercalcemia induces vasoconstriction of afferent renal arterioles and decreases GFR
• Other findings include weakness, lethargy, inappetance, and calcium-based urolithiasis with UTI
• Lethargy, weakness, GI signs, and constipation are common findings in cats and is caused by decreased excitability of GI smooth muscle

+ Diagnosis

• Diagnosis of parathyroid hyperplasia or neoplasia has previously been a rule-out diagnosis followed by confirmation with surgical biopsy
• Primary hyperparathyroidism diagnosed in dogs when neoplasia and hypoadrenocorticism excluded
• Primary hyperparathyroidism diagnosed in cats when non-parathyroid neoplasia and CRF excluded
• However, validated assays and ultrasonography have facilitated the diagnosis of primary hyperparathyroidism

+ Serum Biochemistry

• Mildly to markedly elevated serum total and ionized calcium caused by excessive autonomous secretion of PTH from the hyperplastic or neoplastic parathyroid glands
• 50% of serum calcium is protein bound and hence diseases causing increased albumin or total protein may increase calcium measurements
• 45% of serum calcium is unbound, ionized, and metabolically active
• Other abnormalities on serum biochemistry include low to normal serum phosphorus and mild to moderate increases in ALP secondary to bone resorption
• Uncomplicated primary hyperparathyroidism: normal renal function and isosthenuric or hyposthenuric urine
• However, prolonged hypercalcemia may affect renal function

+ Parathyroid Hormone Assay

• Serum PTH levels may be normal to increased in cats and dogs with primary hyperparathyroidism
• Parathyroid hyperplasia suspected if normal serum PTH and increased ionized calcium

+ Ultrasonography

• Cervical ultrasonography can routinely identify parathyroid nodules < 5 mm
• Parathyroid nodules < 4 mm more likely to be primary or secondary parathyroid hyperplasia
• Parathyroid nodules ≥ 4 mm more likely to be parathyroid adenoma or carcinoma

+ Nuclear Scintigraphy

• Technetium-99m-sestamibi radionucleide scans can accurately identify parathyroid masses in humans
• Nuclear scintigraphy has the potential additional advantage of identifying ectopic parathyroid tissue
• However, technetium-99m-sestamibi only has an 11% sensitivity, 50% specificity, and 27% overall accuracy for detecting and localizing hyper-functional parathyroid tissue (0% sensitivity for parathyroid hyperplasia and 25% sensitivity for parathyroid adenoma)
• Sensitivity, specificity, and accuracy are greater in humans when scintigraphy combined with ultrasonograph

+ Conservative Management

• Emergency management of hypercalcemia is rarely required in animals with primary hyperparathyroidism
• Symptomatic therapy should:
• Promote external loss of calcium
• Increase renal excretion of calcium
• Inhibit bone release of calcium
• Isotonic sodium chloride will ameliorate dehydration, expand extracellular fluid volume, increase GFR, increase calciuresis and natriuresis, and decrease calcium reabsorption by kidneys
• Furosemide and other loop diuretics can be used following rehydration to limit calcium reabsorption in ascending loop of Henle
• Corticosteroids can be used to inhibit prostaglandin, osteoclast-activating factor, vitamin D, and intestinal calcium absorption if the cause of hypercalcemia of malignancy is determined
• Salmon calcitonin (4.5 U/kg q 8 hr SC) rapidly reduces serum calcium levels, but this effect is transient
• Other treatments for severe hypercalcemia include mithramycin, bisphosphonates, and gallium nitrate

+ Percutaneous Ultrasound-Guided Ethanol Injection

• Ultrasound-guided injection of 96% ethanol into the parathyroid nodule
• Percutaneous injection of ethanol results in coagulative necrosis and vascular thrombosis
• Serum calcium, phosphorus, and PTH normalized within 5 days in all 8 dogs
• Complications: hypocalcemia in 50% (4/8), recurrence in 13% (1/8) after 1 month, and mild dysphonia

+ Percutaneous Ultrasound-Guided Radiofrequency Heat Ablation

• Ultrasound-guided radiofrequency heat ablation of parathyroid glands
• Radiofrequency treatment ablates tissue by thermal necrosis
• Number of treatments: 1 in 6 dogs, 2 in 2 dogs, and unsuccessful in 3 dogs
• Serum ionized and total calcium levels normalized within 48 hours in all 8 successfully treated dogs
• Serum PTH decreased within 24 hours in all 8 successfully treated dogs
• Hypocalcemia developed in 63% (5/8) successfully treated dogs and all required treatment
• complication: transient and mild dysphonia

+ Parathyroidectomy

• Position: dorsal recumbency with neck extended and towel placed under neck
• Ventral midline skin incision from larynx to manubrium
• Skin incision continued through subcutaneous tissue and oblique fibres of sphincter coli muscle
• Sternohyoideus muscles are exposed and separated in midline to expose trachea
• Thyroid glands normally located immediately caudal to larynx on medial aspect of sternothyroideus muscles
• Abnormal parathyroid gland is usually well-defined at 1 pole of the thyroid gland
• Abnormal parathyroid gland is removed by blunt dissection
• Thyroidectomy is rarely required
• Remaining parathyroid glands are usually atrophied and will result in postoperative hypocalcemia
• Parathyroid hyperplasia is the most common cause of enlargement of all 4 parathyroid glands and removal of 1-3 parathyroid glands may ameliorate clinical signs of hypercalcemia
• Complete cervical area is examined for ectopic tissue if there is no evidence of parathyroid gland enlargement

+ Postoperative Management

• 58% of dogs become hypocalcemic after surgical resection of a single parathyroid tumor
• Muscular (i.e., fasciculations, ataxia, and pain), cardiac (i.e., arrhythmias), and GI responses may be observed with sudden decrease in calcium following chronic adaption to severe hypercalcemia
• Suppressed parathyroid glands require 14-21 days to recover function
• Postoperative support of calcium homeostasis is correlated with degree of preoperative hypercalcemia
• Dogs with preoperative calcium > 14 mg/dL present a high risk and are managed with vitamin D and calcium supplementation to maintain calcium levels in low normal range for several days prior to gradual weaning
• Dogs with preoperative calcium < 14 mg/dL present a low risk for clinical hypocalcemia and should be hospitalized and monitored twice daily until calcium > 8.5 mg/dL
• Permanent vitamin D and calcium supplementation will be required if all 4 parathyroid glands are resected
• Hypocalcemia develops within 1-5 days of surgery
• Clinical signs: restlessness, weakness, muscle tremors, twitching, tetany, and seizures
• Treatment of hypocalcemia includes:
• 10% calcium gluconate (0.5-1.5 mg/kg IV) at over 10-20 minutes initially
• 10% calcium gluconate (10 ml added to 250 ml maintenance solution) at 60 ml/kg/day
• Maintenance with oral calcium gluconate (3-4 ml diluted 1:1 with isotonic saline q 6-8 hrs or 0.2-0.5 g/cat)
• Maintenance with vitamin D analogue dihydrotachysterol (0.015 mg/kg q 12 hr PO for 2 days, 0.01 mg/kg q 12 hr PO for 2 days, and then maintained at 0.005 mg/kg q 12 hr and tapered over 4-8 weeks)
• ± calcitriol, which is an alternative to dihydrotachysterol, for prophylactic treatment of hypocalcemia (25 μg/cat or 0.05 μg/kg for dogs > 5 kg q 24 hr for 3 days and then tapered)
• Permanent hypoparathyroidism is likely if calcium does not return to normal within 14-21 days
• Spontaneous resolution of hypoparathyroidism due to reversible damage or hypoxia resulting from thyroidectomy or compensation by accessory parathyroid tissue

+ Prognosis

• Prognosis is excellent for uncomplicated primary hyperparathyroidism with normal renal function following definitive therapy (i.e., percutaneous ablation or surgical resection)
• Prognosis is guarded for animals with compromised renal function as renal function will only improve marginally following resolution of hypercalcemia