Diseases of the parathyroid glands (Proceedings)

Calcium is involved in many cellular and extracellular processes that include neuromuscular transmission, muscle contraction/tone, hormone secretion, bone homeostasis, coagulation, membrane transport systems, and other cell regulatory pathways. Calcium is measured as ionized (active form, roughly 50%) or total (ionized + albumin bound + anion bound). The extracellular fluid ionized calcium is tightly regulated by interactions between the parathyroid glands, bone, the intestinal tract, and kidneys. Parathyroid hormone (PTH) is secreted by the chief cells of the parathyroid glands primarily in response to low extracellular ionized calcium.1 Increased ionized calcium stops the secretion of PTH. Parathyroid hormone stimulates calcium and phosphorus absorption from the bone via increased activity of osteoclasts.1 Parathyroid hormone increases calcium reabsorption in the distal convoluted tubule and decreases phosphorus reabsorption in the proximal renal tubules so more calcium is retained and more phosphorus lost.1 Parathyroid hormone also increases the production of 1,25-dihydroxyvitamin D by the kidneys which increases calcium absorption from the intestinal tract. 1,25-dihidroxyvitamin D also provides negative feedback to the parathyroid glands. Vitamin D3 (cholecalciferol) is produced from 7-dehydrocholesterol which is found in high concentration in the skin. Vitamin D3 is then converted to 25-hydroxyvitamin D in the liver and 25-hydroxyvitamin D is converted to 1,25-dihydroxyvitamin D in the kdineys. 1,25-dihydroxyvitamin D inhibits its own synthesis. Hypercalcemia also inhibits 1,25-dihydroxyvitamin D. High serum ionized calcium, in addition to inhibiting PTH secretion, stimulates calcitonin release from the C cells of the thyroid gland. Calcitonin decreases serum calcium and phosphorus by decreasing osteoclastic activity within the bone. Calcitonin also promotes phosphorus excretion via inhibition of phosphorus reabsorption in the proximal renal tubules.

Differentials for Hypercalcemia

     • Lab error

     • Granulomatous disease - infectious

          o Coccidioidiomycosis

          o Blastomycosis

          o Histoplasmosis

          o Aspergillosis

          o Schistosomiasis

     • Increased osteoclastic activity

     • Granulomatous disease

          o Septicemia

          o Neoplasia

     • Primary hyperparathyroidism

     • Vitamin D toxicosis

     • Hypoadrenocorticism

     • Renal Failure (Acute & Chronic)

     • Nutritional Secondary Hyperparathyroidism

     • Iatrogenic

     • Idiopathic (cats)

     • Neolpasia

          o Lymphosarcoma*

          o Apocrine gland anal sac adenocarcinoma*

          o Multiple myeloma*

          o Other carcinomas

          o Melanoma

          o Testicular interstitial cell tumors

          o Thymoma

Primary Hyperparathyroidism

Etiology

Primary hyperparathyroidism (PHPTH) is an uncommon disease in dogs and very rare in cats. Most masses are single adenomas with less than 10% occurring as adenocarcinomas. There is a report of a single cat with bilateral cystadenomas and primary hyperparathyroidism. There have also been reports of hyperplasia of the parathyroid glands in dogs and cats leading to PHPTH.

Signalment

This is a disease that typically affects middle aged to older dogs and cats. There is no sex predilection. In the Keeshonden, PHPTH is inherited as an autosomal dominant trait. There is also a single report of an inherited form of PHPTH in German shepherd dog littermates.

Clinical Findings

Clinical signs may be absent and hypercalcemia found incidentally. In fact in one group of dogs with PHPTH, 88/210 owners brought their dogs in to be evaluated for reasons unrelated to PHPTH.2 The most common signs are polyuria, polydipsia, decreased appetite, weight loss, lethargy, and lower urinary tract signs. Vomiting, diarrhea, constipation, seizures, and renal osteodystrophy are less common.Signs may be present for months to years prior to presentation. Cats most often present with anorexia, lethargy and vomiting. Parathyroid glands are normally not palpable in dogs and cats. Masses are not palpable in dogs with PHPTH but may be in cats.

Laboratory Evaluation

There are no significant abnormalities on the CBC. Total serum calcium is increased consistently. Ionized calcium is increased in most animals but may be normal. Phosphorus is usually low or low normal. Kidney values may be elevated in dogs and catsIf renal values are increased they present a diagnostic dilemma, is this an animal with renal failure and a secondary form of hyperparathyroidism? Does this animal have concurrent renal disease and PHPTH? Or is this an animal with PHPTH and renal disease secondary to mineralization? Typically dogs with CRF have hyperphosphatemia and a normal to low ionized calcium whereas with PHPTH phosphorus is normal to low with an increase in ionized and total calcium. With PHPTH, urine may be minimally concentrated, isosthenuric or hyposthenuric. Liver enzymes are elevated in some dogs and cats with PHPTH.Uroliths and urinary tract infections are fairly common in dogs so calcium-containing crystalluria, hematuria, pyuria, proteinuria, and bacteruria may also be present. Urinary tract infections and calculi are rare in cats.

Assays for PTH currently utilized are either a two-site immunoradiomimetric assay or sandwich ELISA available and validated for the dog and cat. PTH is normal to increased in dogs and cats with PHPTH.2 The importance is that as calcium increases PTH should decrease, which does not occur with PHPTH.

Diagnostic Imaging

Radiography may be used to evaluate for other causes of hypercalcemia, concurrent disease, urinary tract calculi and boney changes (renal osteodystrophy). Local invasion and distant metastases have not been reported with malignant tumors. Parathyroid tumors are readily identifiable utilizing ultrasoundParathyroid adenomas are round, hypoechoic and tend to be over 4 mm in size. Hyperplastic nodules (CRF, nutritional secondary) tend to be smaller than adenomas.15,20 The majority of animals have a single enlarged parathyroid but a few have 2 enlarged parathyroid glands.

Treatment

Dogs and cats with PHPTH are typically stable so emergency treatment is rarely necessary. In some cases medical management prior to surgery may be necessary if dehydration (prerenal azotemia), renal azotemia, neurologic signs, or dramatic weakness are present. Medical management consists of correction of dehydration and administration of diuretics, glucocorticoids and bisphosphonates as needed to control signs and minimize heypercalcemia. Intravenous fluid diuresis may correct mild hypercalcemia and 0.9% saline is the fluid of choice because it promotes calciuresis (sodium competes with calcium for reabsorption). Care must be taken in animals with renal disease to avoid volume overload. Loop diuretics can be given for mild to moderate hypercalcemia once animals have been rehydrated. Furosemide, a potent loop diuretic, is used most often. Furosemide inhibits calcium reabsorption in the thick ascending loop of Henle.2 Glucocorticoids are highly effective in decreasing calcium secondary to lymphosarcoma and multiple myeloma but are also used for mild to moderate hypercalcemia seen with PHPTH. Glucocorticoids decrease intestinal absorption of calcium, reduce bone resorption and increase renal excretion of calcium.2 Bisphosphonates inhibit osteoclasts but because intestinal absorption is poor they are administered IV.2 Bisphosphanates are effective in moderate to severe hypercalcemia.2 Calcitonin decreases osteoclast activity and can be administered in cases of severe, unresponsive hypercalcemia.2,22 Typically in treating hypercalcemia of unknown origin, saline and loop diuretics are given until lymphosarcoma is ruled out or if the hypercalcemia is unresponsive to these treatments. At this time glucocorticoids and bisphosphonates are considered. As mentioned previously, most animals with PHPTH do not require medical management for stabilization.

Surgery is the treatment of choice for parathyroid tumors. Masses should be identified with ultrasound pre-operatively because a few are not identifiable at surgery. Saline diuresis and furosemide are recommended prior to surgery for animals with moderate or severe hypercalcemia. External glands may be removed without thyroid tissue but removal of internal parathyroid glands requires removal of the corresponding thyroid lobe. If malignant neoplasia is suspected, the corresponding thyroid lobe should also be removed.

Normal glands often atrophy due to the negative feedback of calcium on normal tissue so temporary hypocalcemia may occur lasting weeks to months. It may take up to 6 days for the calcium to drop so calcium should be monitored once to twice daily for 7 days. There is some evidence that the higher the calcium pre operatively, the more likely hypocalcemia is to develop post operatively. It is also likely the more chronic the hypercalcemia, the more likely hypocalcemia is to develop. For this reason, some surgeons start vitamin D therapy prior to surgery. It is important to remember that signs of tetany can occur with variable degrees of hypocalcemia. Although hypocalcemia occurs in cats post operatively, clinical hypocalcemia does not. Intravenous calcium gluconate is utilized to stabilize calcium in animals with clinical signs related to hypocalcemia. For a more thorough discussion of the treatment of acute hypocalcemia and tetany see hypoparathyroidism below.

Vitamin D therapy is utilized in the perioperative period as well. As discussed previously, some surgeons administer vitamin D prior to surgery in anticipation of hypocalcemia. There are three forms which have been used in veterinary medicine. Ergocalciferol (Vitamin D2) is the cheapest but least potent formulation. Ergocalciferol can be started at 4,000 to 6,000 U/kg daily. Because of its long half life this form of vitamin D takes the longest to affect serum levels (5 to 14 days) and correction of hypercalcemia can take 1 to 4 weeks with cessation which is why this form of vitamin D is not preferred.

Dihydrotachysterol (DHT) is a synthetic vitamin D analogue that raises calcium more quickly than ergocalciferol (in 1 to 7 days). DHT is more expensive and more potent than ergocalciferol. The starting dose is 0.03 mg/kg/day divided twice daily to desired effect then taper by 0.01 mg/kg/day as needed. If hypercalcemia occurs, improvement in serum calcium should be noted 4 to 14 days after cessation.

1,25-dihydroxyvitamin D (calcitriol) is the most potent form of vitamin D with the shortest half life. Effects of calcitriol are seen within 2 to 4 days of administration. The dose is 20 to 40 ng/kg/day initially then tapered to 10 to 20 ng/kg/day and then reduced every 2 weeks to every fourth day before discontinuing. This is the most expensive formulation but hypercalcemia is corrected within 24 to 48 hours with cessation. Generic forms of calcitriol are available and may make treatment less expensive. Oral calcitriol is the formulation used most commonly pre-operatively. Calcitriol is initiated 24 hours before surgery for severe hypercalcemia (> 18 mg/dl), after surgery for moderate hypercalcemia (14 mg/dl to 18 mg/dl) and whenever post operative calcium drops below normal.

Oral calcium is given to animals with hypocalcemia as soon as the animal is able to eat post operatively.A more extensive discussion of oral calcium is given below. Most dogs and cats go home on oral calcium and some form of vitamin D. Oral calcium is weaned first followed by oral calcitriol over several months. The goal is to keep the total, or ionized, calcium just below normal or low normal to stimulate normal tissue. If all parathyroids have or may have been removed permanent calcitriol therapy may be required. No other complications occur with surgical parathyroidectomy in dogs but Horner's syndrome and voice change have been reported in one cat.

Percutaneous ethanol and heat radiofrequency ablation have been performed with ultrasound guidance. In a study comparing surgery, heat ablation and ethanol ablation in 110 dogs with PHPTH, hypercalcemia resolved in 44/47 dogs after surgical parathyroidectomy. In 12/15 dogs a single ethanol ablation was successful and in 43/48 dogs a single heat ablation was successful. Heat ablation and surgery had similar results but ethanol ablation was only slightly less successful. Hypocalcemia was the most common side effect and occurred in 37% of dogs but only 11% of dogs developed clinical signs. Additional side effects include cough, bark change and Horner's syndrome.

Prognosis

In the absence of renal disease these animals do well. Occasionally signs can recur due to the presence of another parathyroid tumor.

Primary Hypoparathyroidism

Background

Signs of hypocalcemia most often relate to the neuromuscular systems. Calcium is necessary for acetylcholine release at the neuromuscular junction, stabilization of nerve cell membranes and is involved in muscle contraction. Low calcium results in more excitable neurons and spontaneous firing that may appear as tetany. Hypocalcemia, in most labs, is a total calcium less than 9 mg/dl and ionized less than 1.1 mmol/L but tetany occurs with a total calcium less than 7 mg/dl and ionized less than 0.7 mmol/L.

Differentials for Hypocalcemia

     • Lab error

     • Iatrogenic

     • Hypoalbuminemia

     • Acute pancreatitis

     • Eclampsia

     • Chronic renal failure

     • Intestinal malabsorption

     • Acute renal failure

     • Ethylene glycol toxicosis

     • Phosphate-containing enemas

     • Primary hypoparathyroidism

     • Hypomagensemia

     • Nutritional secondary hypoparathyroidism

     • Chemotherapy

Etiology

Primary hypoparathyroidism is most commonly due to iatrogenic injury/removal during surgery for thyroid and parathyroid tumors. Naturally-occurring primary hypoparathyroidism is very rare and may be due to atrophy, dysgenesis or lymphocytic parathyroiditis.

Signalment

Naturally-occurring primary hypoparathyroidism is most common in young to middle-aged animals. There may be a female sex predilection but no apparent breed predisposition in dogs. The disease is more common in male vs. female cats.

Clinical Findings

Neuromuscular signs are variable in duration and exacerbated by stress or exercise. Clinical signs are often acute, episodic and include anxiety, lethargy, behavioral changes, facial rubbing (masseter & temporal mm cramping, tingling sensation), protruding nictitans, excessive grooming of extremities (tingling sensation), muscle twitching/spasms, rigid gait, and seizures (focal to diffuse). Additional, less common, signs include panting, tachyarrhythmias, bradyarrhythmias, ataxia, anorexia, vomiting, diarrhea, weight loss, and cataracts.

Laboratory Findings

Hypocalcemia is found in every case, both total and ionized. Hyperphosphatemia is also found in most cases. PTH is low or low normal which is inappropriate for concurrently low calcium.2

Treatment

Clinical signs often dictate the level of treatment. Obviously dogs and cats with low ionized calcium and clinical signs of tetany require emergent, aggressive treatment. For tetany the goal is to keep the total calcium above 7 mg/dl and the ionized above 0.7 mmol/L, levels in which signs are more common. For tetany 10% calcium gluconate (9 mg elemental calcium/ml) is usually given at 5 to 15 mg/kg over 20 minutes with ECG monitoringBradycardia, premature ventricular contractions and shortening of the Q-T interval are causes for discontinuation of IV infusion. Seizures will stop within a few minutes but anxiety, nervousness, panting, and tremors may take longer to resolve due to a lag between serum and csf concentrations Once tetany is controlled, diluted calcium gluconate (1:4 with saline) is given at 20 mg/kg QID subcutaneously. With every 48 hours of stable calcium (total 8 to 9.5 mg/dl), the dose frequency is reduced (QID –> TID –> BID –> daily). As an alternative to intermittent SC calcium, a CRI can be given at 2 to 4 mg/kg/hr. Calcium chloride is not recommended for IV or SC administration because it is irritating to subcutaneous tissues. Parenteral calcium is tapered once calcium is stabilized for 24 hours. Oral calcium and vitamin D therapy are started at this time. Oral calcium is given at 500 to 1000 mg/day in cats and 1000 to 4000 mg/day in dogs divided. There are numerous preparations available. Calcium carbonate is preferred because it does not irritate the intestinal tract (chloride formulations) and has the highest amount of elemental calcium per tablet (a 1000 mg tablet has 400 mg elemental calcium). Oral calcium is usually tapered prior to vitamin D because dietary calcium should be adequate to maintain normal serum calcium. Vitamin D is given indefinitely to animals with primary hyperparathyroidism unless due to parathyroidectomy and some parathyroid tissue remains. Doses and formulations of vitamin D were discussed previously. Regular monitoring of serum chemistry panels, including calcium and phosphorus, is recommended due to the risk of hypercalcemia and subsequent organ damage. Frequency of monitoring depends on serum calcium levels and the vitamin D formulation utilized. In general, animals are monitored at least once daily while in the hospital and for the first week then weekly for the first month. Calcium should be checked each time a change in medications is made to evaluate calcium. Long term monitoring every 3 months is recommended for stable patients on lifelong therapy. The goal is to maintain calcium between 8 and 10 mg/dl.

Prognosis

Therapy is usually necessary lifelong but the prognosis is good with treatment.

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