Diseases of the Parathyroid Gland and Calcium Metabolism

Chapter 32 Diseases of the Parathyroid Gland and Calcium Metabolism



Patricia A. Schenck, Dennis J. Chew



NORMAL CALCIUM METABOLISM


Calcium is required for many intracellular and extracellular functions, as well as for skeletal support. Ionized calcium is required for enzymatic reactions, membrane transport and stability, blood coagulation, nerve conduction, neuromuscular transmission, muscle contraction, vascular smooth muscle tone, hormone secretion, bone formation and resorption, control of hepatic glycogen metabolism, and cell growth and division. Normal homeostatic control mechanisms usually maintain serum ionized calcium concentration within a narrow range.



Distribution of Calcium


Calcium in plasma or serum exists in three fractions: ionized (free calcium), complexed, and protein bound.




Key Point


Ionized calcium is the biologically active fraction of serum total calcium.



• Ionized calcium: This is the biologically active fraction of calcium and accounts for approximately 55% of the total serum calcium concentration in dogs.

• Complexed calcium: Complexed calcium accounts for approximately 10% of the total serum calcium concentration in dogs but may be elevated in chronic renal failure (CRF). Complexed calcium may be bound to anions such as lactate, phosphate, bicarbonate, sulfate, citrate, and oxalate.

• Protein-bound calcium: Protein-bound calcium accounts for approximately 35% of the total serum calcium concentration. Albumin is the primary protein bound to calcium. Protein binding is affected by changes in pH, with increased binding as pH increases and decreased binding as pH decreases.


Regulation of Calcium


Regulation of serum calcium concentration is complex and requires the integrated actions of parathyroid hormone (PTH), vitamin D metabolites, and calcitonin. The intestine, kidney, and bone are the major target organs affected by calcium regulatory hormones. The skeleton provides a major supply of calcium and phosphorus when intestinal absorption and renal reabsorption are inadequate to maintain normal serum calcium concentration.



Parathyroid Hormone


PTH is synthesized and secreted by chief cells of the parathyroid gland in response to a decrease in ionized calcium concentration. The most important biologic effects of PTH are as follows:


• Increase the blood calcium concentration

• Increase tubular reabsorption of calcium, resulting in decreased loss of calcium in the urine

• Increase bone resorption and numbers of osteoclasts on bone surfaces

• Accelerate the formation of 1,25-dihydroxyvitamin D3 (calcitriol) by the kidney



Key Point


The net effects of PTH are to increase serum ionized calcium and to decrease serum phosphorus concentrations.



Calcitonin


Calcitonin is synthesized by C cells in the thyroid gland and is secreted in response to hypercalcemia and to a calcium-rich meal. The effects of calcitonin on normal calcium homeostasis are considered minor. The major target site for calcitonin is bone, where it inhibits resorption of calcium and phosphorus.



Vitamin D Metabolites


The cholecalciferol (vitamin D3 of animal origin) metabolites 25-hydroxyvitamin D3 (calcidiol) and 1,25-dihydroxyvitamin D3 (calcitriol) are the most important vitamin D metabolites. These metabolites may also be derived from ergocalciferol (vitamin D2 of plant origin), and are equally bioactive. Dogs and cats inefficiently photosynthesize vitamin D in their skin and consequently are dependent on vitamin D in their diet. Hydroxylation of vitamin D occurs in the liver to produce 25-hydroxyvitamin D. This 25-hydroxyvitamin D is further hydroxylated in the proximal tubule of the kidney to form calcitriol.



Calcitriol


Calcitriol is the only active metabolite of vitamin D. Calcitriol increases serum calcium and phosphorus concentrations and acts on the intestine, kidney, and bone.


• Bone: Calcitriol stimulates osteoclastic calcium mobilization and resorption of bone.

• Intestine: Calcitriol increases calcium, phosphorus, and magnesium absorption.

• Kidney: Calcitriol increases renal tubular resorption of calcium and phosphorus.



Key Point


The net effect of calcitriol is to increase both serum ionized calcium and serum phosphorus concentrations.



DIAGNOSTIC TESTS OF CALCIUM


METABOLISM


Measurement of total calcium, ionized calcium, and hormones of calcium metabolism aid in the diagnosis of calcium disorders (see Tables 32-1 and 32-2).



Table 32-1 EXPECTED CHANGES IN CALCEMIC HORMONES AND SERUM BIOCHEMISTRY IN HYPERCALCEMIA DISORDERS

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Table 32-2 EXPECTED CHANGES IN CALCEMIC HORMONES AND SERUM BIOCHEMISTRY IN HYPOCALCEMIA DISORDERS

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Total Serum Calcium


Total serum calcium is part of most routine serum profile evaluations. However, ionized calcium concentration does not parallel total calcium concentration, and thus ionized calcium concentration must be measured for an accurate assessment of calcium status. Total calcium is usually measured using a colorimetric method and may be spuriously elevated if hyperlipemia or hemolysis is present.



Adjusted Total Calcium Values


Formulas to adjust serum total calcium to albumin or total protein concentration have been published for dogs. Due to a high level of diagnostic discordance between adjusted total calcium and ionized calcium concentrations, the use of these formulas is discouraged.



Ionized Calcium Concentration



• Ion-selective methods are available in some laboratories. Special handling of serum or heparinized plasma is necessary to prevent lowering of ionized calcium due to pH increases. Serum samples appear to be stable for 72 hours at 4°C if handled anaerobically. Some laboratories have developed species-specific pH adjustment formulas to allow measurement of aerobically handled samples.

• A handheld analyzer is also available for cage-side analyses. Heparinized whole blood is used for measurement; for best results, a standard quantity of dry heparin and blood should be utilized for each assay.


Parathyroid Hormone


The PTH molecule is composed of three portions: amino-terminus, mid-molecule, and carboxy-terminus. The amino-terminus is the biologically active portion of the molecule. An intact PTH assay (a two-site assay) provides accurate determination of PTH concentration. PTH fragments are excreted by the kidneys. In animals with renal failure, concentration of inactive fragments may increase. Only an intact PTH assay should be used in patients with renal disease or failure. Serum or separated plasma samples can be assayed but should be kept refrigerated or frozen prior to assay.



Parathyroid Hormone-Related Protein


The parathyroid hormone-related protein (PTHrP) is a hormone secreted by some malignant neoplasms in animals with hypercalcemia. This hormone can bind to PTH receptors in the kidneys and bone and result in humoral hypercalcemia of malignancy (HHM). Separated plasma samples can be assayed but should be kept refrigerated or frozen prior to assay.



Vitamin D Metabolites



• 25-hydroxyvitamin D3 (calcidiol)
• Metabolites of vitamin D3 are chemically identical in all species. Calcidiol concentration is a good indicator of vitamin D3 ingestion and can be used to diagnose hypovitaminosis or hypervitaminosis D. Serum or separated plasma can be assayed, but samples should be protected from degradation due to exposure to light.

• 1,25-dihydroxyvitamin D3 (calcitriol)
• Calcitriol is the most active vitamin D metabolite, and it circulates in low concentrations. Assays have been developed for calcitriol but are not readily available due to cost.


HYPERCALCEMIA



Defining Criteria



• Serum total calcium concentration
• Dogs: >12.0 mg/dl (3.0 mmol/L)

• Cats: >11.0 mg/dl (2.75 mmol/L)

• Serum ionized calcium concentration
• Dogs: >5.8 mg/dl (1.45 mmol/L)

• Cats: >5.6 mg/dl (1.40 mmol/L)

• Young dogs may have a mild hypercalcemia (usually <13.0 mg/dl total serum calcium concentration) related to skeletal growth.

• Hyperlipemia and/or hemolysis of the sample may result in spurious elevations of calcium.



Key Point


Severe clinical signs are associated with a serum total calcium concentration >18 mg/dl.



Etiology


Hypercalcemia may be parathyroid-dependent (pri-mary hyperparathyroidism) or parathyroid-independent (normal functioning of the parathyroid gland).


• In parathyroid-independent hypercalcemia, elevated ionized calcium concentration causes suppression of PTH production. On analysis, ionized calcium concentration is elevated, and PTH concentration is in the lower part of or below the reference range. PTHrP concentration may be elevated if there is a tumor producing PTHrP. Concentration of 25-hydroxyvitamin D3 may be elevated in cases of vitamin D toxicity.

• Parathyroid-dependent hypercalcemia (primary hyperparathyroidism) is characterized by elevated ionized calcium concentration without the appropriate suppression of PTH production due to a PTH-secreting tumor of the parathyroid gland.

See Table 32-3 for a list of hypercalcemia-related conditions.



Table 32-3 CONDITIONS ASSOCIATED WITH HYPERCALCEMIA



Nonpathologic Conditions


Hyperlipemia


Non-fasted serum samples


Young growing dogs


Laboratory error or improper handling of sample



Transient Conditions


Hemoconcentration


Hyperproteinemia



Pathologic Conditions


Parathyroid-dependent hypercalcemia


Primary hyperparathyroidism


Parathyroid-independent hypercalcemia


Malignancy-associated hypercalcemia


Lymphoma


Adenocarcinoma of the apocrine glands of the anal sac


Multiple myeloma


Metastatic bone tumors


Miscellaneous tumors (lymphocytic leukemia, mammary carcinoma, fibrosarcoma, pancreatic adenocarcinoma, testicular interstitial cell tumor, lung carcinoma, squamous cell carcinoma, thyroid adenocarcinoma, osteosarcoma)


Hypoadrenocorticism


Renal failure


Hypervitaminosis D


Cholecalciferol (rodenticide) toxicity


Dovonex ingestion


Iatrogenic due to dietary supplementation


Houseplants (Cestrum diurnum, Solanum malacoxylon, Trisetum flavescens)


Granulomatous disease (blastomycosis, schistosomiasis)


Grape toxicity


Bone lesions (sepsis, disuse osteoporosis)


Severe hypothermia


Idiopathic hypercalcemia in cats



Clinical Signs


Clinical signs in hypercalcemia depend on the magnitude of the calcium elevation, how quickly the hypercalcemia developed, and the duration of the hypercalcemia. Serum total calcium concentrations of <15 mg/dl (<3.75 mmol/L) may not be associated with systemic signs; however, serum total calcium concentrations of >18 mg/dl (>4.5 mmol/L) are often associated with severe life-threatening signs. Soft tissue mineralization may occur with prolonged hypercalcemia when the product of total calcium (mg/dl) times serum phosphorus (mg/dl) equals 70 or greater.


• Polydipsia and polyuria are the most common signs of hypercalcemia in dogs due to direct stimulation of the thirst center and a decreased ability of the kidneys to concentrate urine.

• Anorexia, vomiting, and constipation can result from decreased excitability of gastrointestinal smooth muscle.

• Generalized weakness may develop from decreased muscle excitability.

• Depression, muscle twitching, and seizures can occur as neurologic manifestations.

• Cardiac arrhythmias can develop from direct effects on the myocardium or secondary to cardiac mineralization.



Key Point


Polydipsia and polyuria are the most common clinical signs of hypercalcemia.



Diagnosis


Abnormalities depend on the underlying cause, severity, and duration of hypercalcemia (see later under “Conditions Associated with Hypercalcemia”).



History and Physical Examination



• A complete history and thorough physical examination are essential for diagnosing the cause of hypercalcemia. Obtain dietary history to assess the possibility of over-supplementation or under-supplementation with vitamin D.


Laboratory Tests



• Perform a complete blood count (CBC) and serum chemistry profile, and consider tests such as serum ionized calcium, PTH, 25-hydroxyvitamin D, and PTHrP concentrations. Collect samples for diagnostic testing prior to treatment.


Radiography and Ultrasound



• Soft tissue mineralization of the kidneys, heart, lungs stomach, and other tissues may be detected.

• Abdominal masses, mediastinal masses, pulmonary lesions suggestive of metastasis, or lymph node enlargement especially in the tracheobronchial region may be visualized.


Electrocardiography



• Prolongation of the PR interval, shortening of the QT interval, and cardiac arrhythmias (ventricular fibrillation) may develop with severe hypercalcemia.


Principles of Treating Hypercalcemia




Key Point


The definitive treatment for hypercalcemia is to remove the underlying cause.


Unfortunately, the etiology may not be apparent, and supportive measures must be taken to decrease the serum calcium concentration (see Table 32-4 for specific drugs and dosage recommendations). Supportive measures may include the following.



Table 32-4 TREATMENT OF HYPERCALCEMIA

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Volume Expansion


Volume expansion with IV 0.9% NaCl solution decreases hemoconcentration and encourages renal calcium loss by improving glomerular filtration rate and sodium excretion, resulting in less calcium resorption.



Loop Diuretics



• Diuretics such as furosemide increase calcium excretion; however, high doses may be needed. Diuretic use in a dehydrated patient is contraindicated because volume contraction and further hemoconcentration may worsen the hypercalcemia.

• Thiazide diuretics, which decrease calcium excretion by the kidneys, are contraindicated.


Sodium Bicarbonate


Sodium bicarbonate given as an IV bolus or as a continuous infusion has been shown to decrease serum total and ionized calcium concentration. Although the magnitude of calcium reduction is mild, alkalosis favors the binding of ionized calcium to protein, resulting in a decrease in ionized calcium. Sodium bicarbonate therapy is more beneficial when combined with other treatments and is reserved for life-threatening situations.



Glucocorticoids



• Glucocorticoids decrease bone resorption of calcium, decrease intestinal calcium absorption, and increase renal calcium excretion. These effects are non-specific and lead to a mild decrease in the magnitude of hypercalcemia.

• Glucocorticoids often cause a substantial decrease in serum calcium concentration when hypercalcemia is secondary to lymphoma, myeloma, hypervitaminosis D, or hypoadrenocorticism.



Key Point


The use of glucocorticoids prior to determination of the etiology of hypercalcemia may make definitive diagnosis difficult, especially for lymphoma and myeloma.



Calcitonin


Calcitonin can be useful during treatment of cholecalciferol toxicity. For calcitonin to decrease serum calcium, multiple injections per day are required. Long-term side effects include anorexia and vomiting, and diminished effectiveness of calcitonin treatment may occur over time. Use calcitonin only when other treatments have not adequately lowered serum calcium.



Bisphosphonates (Diphosphonates)


These compounds inhibit osteoclastic bone resorption.


• Etidronate (Didronel, Norwich Eaton) has been used with some success as an oral agent for long-term control of hypercalcemia, but it is not well absorbed.

• Intermittent IV injections of pamidronate (Aredia, Novartis) are effective for the control of vitamin D toxicity, hyperparathyroidism, and malignancy-associated hypercalcemia. Clodronate is an alternative.

• Since bisphosphonates have nephrotoxic potential, use these after rehydration. Use IV fluids during and for several hours after treatment with bisphosphonates.


Mithramycin


This drug is a potent inhibitor of osteoclastic bone resorption; however, mithramycin has been associated with many serious side effects, such as thrombocytopenia, hepatic necrosis, renal necrosis, and hypocalcemia, and is no longer recommended.



Peritoneal Dialysis


Using a calcium-free dialysate, this procedure can be considered as a last resort when other methods fail to decrease serum calcium concentration.



CONDITIONS ASSOCIATED WITH


HYPERCALCEMIA


For a complete list of conditions associated with hypercalcemia, see Table 32-3.



Hypercalcemia Associated with Malignancy




Key Point


Malignancy-associated hypercalcemia is the most common cause of persistent hypercalcemia in dogs and the third most common cause in cats.


Hypercalcemia primarily results from increased osteoclastic bone resorption and increased renal tubular resorption. Rarely, increased intestinal absorption also may play a role. Factors that may be produced by tumors and result in humoral hypercalcemia of malignancy include PTH, PTHrP, transforming growth factor, calcitriol, prostaglandin E2, osteoclast-activating factor, and other cytokines (interleukin-1, interleukin-2, and gamma interferon).


• In dogs, lymphoma, adenocarcinoma of the apocrine glands of the anal sac, and multiple myeloma are the most common tumors associated with hypercalcemia.

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Aug 27, 2016 | Posted by in SMALL ANIMAL | Comments Off on Diseases of the Parathyroid Gland and Calcium Metabolism

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