Ca, Phos, Mg, and Parathyroid Disease

Question 1

The hormones involved in regulating Ca metabolism include:

Answer 1

Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (vitD), and calcitonin

Question 2

Describe the role of PTH in Ca and Phos metabolism.

Answer 2

PTH is secreted by parathyroid gland chief cells and increases Ca concentrations by mobilizing Ca from the bone. It also increases Ca reabsorption in the distal tubules of nephrons and increases urinary phosphate (phos) excretion.

Question 3

Describe Vit D metabolism in dogs and cats.

Answer 3

After ingestion and uptake, vit D (cholecalciferol) is first hydroxylated in the liver to 25(OH)D3 (calcidiol), and then it is further hydroxylated to 1,25(OH)2D3 (calcitriol) by the proximal tubular cells of the kidney. This final hydroxylation by the 1α-hydroxylase enzyme system to form active calcitriol is under tight regulation and is influenced primarily by serum PTH, calcitriol, phosphorus, ionized calcium, and fibroblast growth factor 23 (FGF-23) concentrations. Decreased levels of phosphorus, calcitriol, and calcium promote calcitriol synthesis, and increased levels of these substances all cause a decrease in calcitriol synthesis. Increased PTH has a potent effect to enhance calcitriol synthesis, whereas FGF-23 inhibits the synthesis of calcitriol.

Question 4

Describe the role of Vit D in Ca and Phos metabolism.

Answer 4

Calcitriol primarily acts on the intestine, bone, kidney, and parathyroid gland. In the intestine, calcitriol enhances the absorption of calcium and phosphate at the level of the enterocyte. In the bone, calcitriol promotes bone formation and mineralization by regulation of proteins produced by osteoblasts. In addition, calcitriol is also necessary for normal bone resorption because of its effect on osteoclast differentiation. In the kidney, calcitriol acts to inhibit the 1α-hydroxylase enzyme system, as well as promote calcium and phosphorus reabsorption from the glomerular filtrate. In the parathyroid gland, calcitriol acts genomically to inhibit the synthesis of PTH.

Question 5

Describe the role of calcitonin in Ca and Phos metabolism.

Answer 5

Calcitonin is secreted by the thyroid gland parafollicular C cells. It acts mostly on the bone to inhibit osteoclastic bone resorption activity but also decreases renal tubular reabsorption of calcium.

Question 6

True or false: yperCa interferes with synthesis of antidiuretic hormone, leading to an inability to concentrate urine and polyuria/polydipsia (PU/PD).

Answer 6

True

Question 7

Provide a comprehensive list of differential diagnoses for hypercalcemia

Answer 7

1. Malignancy [Lymphoma, AGASACA,
   Multiple myeloma, Miscellaneous tumors (squamous cell carcinoma, osteosarcoma, lung carcinoma, mammary carcinoma, malignant melanoma, metastatic bone tumors)]
2. Primary hyperparathyroidism
3. Hypoadrenocorticism
4. Chronic kidney disease
5. Granulomatous disease
6. Hypervitaminosis D
7. Cholecalciferol rodenticide intoxication
8. Excessive dietary supplementation
9. Ingestion of human medication containing calcitriol
10. Idiopathic (cats)
11. Bone lesions
12. Hyperlipidemia
13. Juvenile dogs
14. Hyperproteinemia
15. Lab error

Question 8

Describe how CKD can alter calcium homeostasis.

Answer 8

CKD is associated with decreases in 1-alpha-hydroxylase synthesis and phos retention, which inhibits its enzymatic action. These lead to reduced concentrations of vitD which, in turn, leads to decreased GI Ca absorption, subclinical decreases in circulating Ca and stimulation of PTH synthesis. These responses initially maintain normoCa but as CKD progresses, they may become insufficient and hypoCa can ensue. While CKD is typically associated with normoCa or hypoCa, a small number of affected animals can become hyperCa. The etiology of CKD and hyperCa is poorly understood but may be due to autonomous secretion of PTH, a raised set point for Ca autoregulation, or increased binding of Ca to retained anions

Question 9

True or False: In cats, CKD and malignancy (especially squamous cell carcinoma) are the most frequent causes of hyperCa.

Answer 9

True

Question 10

Provide a comprehensive list of differential diagnoses for hypocalcemia

Answer 10

1. Hypoalbuminemia
2. Acute and chronic kidney failure
3. Hypoparathyroidism
4. Eclampsia
5. Protein-losing enteropathies
6. Pancreatitis
7. Exocrine pancreatic insufficiency
8. Trauma
9. SIRS
10. Phosphate-containing enemas
11. Tumor lysis syndrome
12. Hypomagnesemia
13. Hypovitaminosis D
14. Nutritional secondary hyperparathyroidism
15. Chelating agents (e.g., EDTA)

Question 11

Provide a comprehensive list of differential diagnoses for hyperphosphatemia

Answer 11

1. Young growing healthy animals
2. Hypervitaminosis D
3. AKI or CKD
4. Hypoparathyroidism
5. Excessive dietary intake
6. Osteolytic bone lesions
7. Uroabdomen
8. Hyperthyroidism
9. Hyperadrenocorticism
10. Metabolic acidosis
11. Tumor cell lysis syndrome
12. Iatrogenic (e.g., phosphate-enemas, IV phos)
13. Lab error

Question 12

Provide a comprehensive list of differential diagnoses for hypophosphatemia

Answer 12

1. Primary hyperparathyroidism
2. Malignancy-associated hypercalcemia
3. Diabetic ketoacidosis
4. Vitamin D deficiency
5. Decreased dietary intake
6. Renal tubular disorders
7. Respiratory and metabolic alkalosis
8. Iatrogenic (e.g., phosphate binders, parenteral glucose, or sodium bicarbonate administration)

Question 13

List important drugs used for treatment of hypercalcemia.

Answer 13

1. IVF (0.9% NaCl)
2. Furosemide
3. Glucocorticoids
4. Sodium bicarbonate
5. Bisphosphonates
6. Calcimimetics (Cinacalcet)
7. Calcitonin-salmon

Question 14

How does furosemide treat hypercalcemia?

Answer 14

Furosemide enhances urinary calcium loss

Question 15

How do glucocorticoids treat hypercalcemia?

Answer 15

Glucocorticoids lead to reduced bone resorption, decreased intestinal calcium absorption, and increased renal calcium excretion.

Question 16

How do bisphosphonates treat hypercalcemia?

Answer 16

Bisphosphonates decrease osteoclastic activity, thus decreasing bone resorption. These include zoledronate and pamidronate.

Question 17

How do calcimimetics treat hypercalcemia?

Answer 17

These drugs activate the calcium-sensing receptor and thus decrease PTH secretion.

Question 18

True or False: Patients with decreased total calcium concentrations but normal ionized calcium concentrations require no treatment.

Answer 18

True

Question 19

List acute therapies for patients with hypocalcemia warranting treatment.

Answer 19

1. Ca-gluconate or Ca-chloride IV over 10-20 min.
2. Initiate Vit D supplementation
3. Oral Ca carbonate (more for long-term management)

Question 20

Which form of Vit D is administered for supplementation and why?

Answer 20

Calcitriol because it has a quick onset of action, short plasma half-life, and relatively short biological effect half-life.

Question 21

True or False: Magnesium is a coenzyme for the membrane-bound sodium-potassium ATPase pump and functions to maintain the sodium-potassium gradient across all membranes.

Answer 21

True. Calcium ATPase and proton pumps also require magnesium.

Question 22

Describe magnesium homeostasis.

Answer 22

Magnesium homeostasis is achieved through intestinal absorption and renal excretion. Absorption occurs primarily in the small intestine (jejunum and ileum), with little or no absorption occurring in the large intestine. The loop of Henle and the distal convoluted tubule are the main sites of magnesium reabsorption in the kidney. The kidney is the main regulator of serum magnesium concentration and total body magnesium content; regulation is achieved by both glomerular filtration and tubular reabsorption.

Question 23

List the major roles of phosphorus in homeostasis.

Answer 23

1. Maintenance of normal bone and teeth matrix in the form of hydroxyapatite.
2. Regulation of tissue oxygenation by way of 2,3-di-phosphoglycerate (2,3-DPG), which decreases the affinity of oxygen to hemoglobin.
3. Support of cellular membrane structure and ionic charge via phospholipids.
4. Mitochondrial production of ATP through the electron transport system by phosphoproteins.
5. Buffering acidotic conditions in the body.

Question 24

What is the role of phosphatonins in phosphate homeostasis?

Answer 24

Phosphatonins are circulating substances that increase renal phosphate excretion. Fibroblast growth factor 23 (FGF-23) is a phosphatonin that is heavily involved in the regulation of phosphate and vitamin D homeostasis.

Question 25

How does hemolysis occur secondary to hypophosphatemia?

Answer 25

This occurs because of decreased concentrations of red blood cell ATP and 2,3-DPG, spherocytosis, red cell membrane rigidity, and shorted red blood cell survival in some cats and dogs. Decreased intracellular 2,3-DPG also impairs the release of oxygen by hemoglobin to tissues, leading to tissue hypoxia

Question 26

Describe the pathogenesis of hyperphosphatemia in CKD patients.

Answer 26

Hyperphosphatemia inhibits 1α-hydroxylase activity and stimulates the secretion of PTH. Conversion of vitamin D to its active metabolite, calcitriol, is catalyzed by 1α-hydroxylase. Decreased calcitriol reduces intestinal absorption of phosphate; however, increased PTH enhances intestinal absorption and urinary excretion of phosphate, resulting in a small net effect of increased phosphate excretion. Calcitriol concentrations are subsequently restored by increased PTH. Initially, this restores serum phosphate; however, when PTH decreases, serum phosphate increases because of a decreased glomerular filtration rate and the cycle continues to preserve phosphate balance. Eventually, as CKD progresses, maximal inhibition of phosphate tubular reabsorption is surpassed, causing persistent hyperphosphatemia. As the number of functional tubular cells decreases, renal calcitriol synthesis tapers, and the magnitude of hyperphosphatemia progresses despite increased PTH.