Diagnostic procedures (Proceedings)

Calcium

     • Bone mineralization (skeletal structure)

     • Ion transport across cells

     • Cell contractility and secretion

     • Hormone secretion

     • Cell growth and division

     • Neuromuscular transmission

Serum calcium

     • 55% bound to albumin

     • 35% ionized (active and regulated) form

     • 10% "complexed" (to citrate, lactate, bicarbonate, phosphate)

Serum biochemical profile measures total calcium

Parathyroid hormone

     • Parathyroid gland = main endocrine organ involved in control of Ca/P metabolism

     • PTH actions

          o Ca and P reabsorption from bone

          o Increases Ca but decreases P reabsorption in kidneys

               • Potent phosphaturic action*

          o Increases activity of vit. D

               • Increased absorption of Ca and P in GI

     • Principle hormone in fine minute-to-minute blood calcium regulation

          o Released in response to hypocalcemia

          o Release inhibited by increased iCa, vit D

Vitamin D

     • Activated vitamin D (calcitriol) increases Ca concentration by increasing absorption of Ca from the intestine, and by enhancing PTH action on bone and kidney.

     • Cholecalciferol Calcidiol Calcitriol

     • Vitamin D actions

          o Increases GI absorption of Ca and P **

          o Increases bone reabsorption

     • Increases renal reabsorption

Note: pH effects

          o ACIDOSIS increases IONIZED CALCIUM

          o ALKALOSIS decreases IONIZED CALCIUM

Analytes for calcium status

     • Total calcium

     • Ionized calcium

     • Inorganic phosphorus

     • Parathyroid hormone (PTH)

     • Parathyroid hormone related peptide (PTHrp)

     • Vitamin D

Disorders of calcium

     • Hypocalcemia

     • Hypercalcemia

       (refer to both total calcium abnormalities and ionized calcium abnormalities)

Hypocalcemia: hypoalbuminemia

     • 55% of calcium is bound to albumin

     • When albumin decreases, TOTAL calcium decreases

     • Ionized calcium stays the same

     • Benign

     • Very common: most common cause of decreases in total calcium!

Correction formulas

     • Use of correction formulas is not recommended

     • Ionized calcium should be measured if true hypocalcemia is suspected

     • (that said, if albumin is low, it is likely the reason for the hypocalcemia)

Common causes of true hypocalcemia

     • Renal failure (acute and chronic)

     • Pancreatitis

     • Eclampsia

Renal failure and hypocalcemia

     • Decreased calcitriol formation by kidney

          o Decreased intestinal absorption of calcium

          o PTH is less effective at releasing Ca from bone

     • Increased phosphorus will decrease Ca (mass action, less important)

Eclampsia

     • 1-3 weeks post partum

     • Small breed dogs

     • Loss of calcium in milk/skeletal development

     • Seizures, trembling, twitching, shaking, and stiffness

     • Treatment is IV calcium gluconate

Uncommon causes of hypocalcemia

     • Hypoparathyroidism

     • Ethylene glycol toxicosis

     • Nutritional secondary Hyperparathyroidism

     • Intestinal malabsorption (Yorkies)

     • Phosphate-containing enemas (Fleet)

     • Citrate toxicity (blood transfusions)

     • Hypovitaminosis D

     • Inadequate calcium intake

     • Excess phosphorus

Clinical signs of hypocalcemia

     • Signs occur when IONIZED calcium is low

     • Nervousness, anorexia, stilted gait

     • Hyperventilation, numbness

     • Generalized tetany, seizures

Hypercalcemia

     • Increased total calcium

     • Increased ionized calcium

     • Can serve as a marker of disease AND can cause disease

Hypercalcemia

     • Estimate of overall occurrence

          o 1.5% of all cases in one private diagnostic lab

     • Significance of hypercalcemia

          o Approx. 25% are young, growing animals

          o Approx. 60% are transient (therefore not worked up)

          o Approx. 15% persistent and pathological

Transient (inconsequential) hypercalcemia

     • Post prandial

     • Dehydration

     • Lipemia (laboratory artifact)

     • Young, growing dogs

     • Addison's disease (hypoadrenocorticism)

Hypoadrenocorticism

     • Second most common cause of hypercalcemia in dogs

     • Total Ca increased +/- ionized calcium

     • May be caused by increased renal reabsorption of calcium

     • Responds to corticosteroid treatment and/or volume replacement

Causes of true hypercalcemia

     • Hypercalcemia of malignancy: most common

     • Primary hyperparathyroidism

     • Idiopathic hypercalcemia of cats (diet?, rx pred)

     • Renal disease (rare in small animals, common in horses)

     • Vitamin D toxicosis

     • Granulomatous inflammatory disease

     • Grape and raisin toxicosis (renal failure - 1/2-1 oz)

Hypercalcemia

     • PU/PD

     • Lethargy, weakness, constipation

     • Mineralization of soft tissue - when Calcium (mg/dL) x phosphorus (mg/dL) product > 60

     • Calcium containing uroliths

Primary hyperparathyroidism: dogs

     • Most often due to a solitary adenoma

     • Autonomously secreting PTH

     • Older dogs (>10)

Primary hyperparathyroidism: dogs

     • ⇑ total calcium

     • ⇑ ionized calcium

     • ⇑ PTH

     • ⇓ to normal phosphorus (can by high)

     • ⇑ to normal calcitriol

     • Undetectable PTHrp

Humoral hypercalcemia of malignancy

          o Humoral Hypercalcemia of Malignancy

          o Most common cause of hypercalcemia***

     • Apocrine gland adenocarcinoma of anal sac

     • Lymphoma

          o Others (carcinoma in cats)

     • Often associated with PTH-related protein (PTH-rP)

          o Can measure in dogs and cats

Hypervitaminosis d

     • Vitamin D toxicity

          o Over supplementation with dietary source

          o Rodenticides with Cholecalciferol

          o Plants containing vit D glycosides

               • Cestrum diurnum, Solanum malacoxylon

          o Granulomatous disease

               • Activation of vit D by macrophages

Hypervitaminosis d

     • Vitamin D increases Ca resorption from bone

     • Vitamin D increases Ca absorption from intestine

     • Vitamin D increases phosphorus absorption from intestine

     • Therefore, animals with hypervitaminosis D will have hypercalcemia AND hyperphosphatemia!

Chronic renal failure

     • Hypercalcemia is common in horses

     • Hypercalcemia seen in ~10% of dogs

          o iCa usually normal to low**

          o PTH often elevated

**this becomes important when distinguishing from hyperparathyroidism with secondary renal failure

Further diagnostics for hypercalcemia

     • Ionized calcium

     • CBC, serum chemistry profile, UA

     • Thorough physical exam

          o Palpate anal area, lymph nodes

          o Radiography/ultrasound (parathyroid glands)

     • Measure PTHrP

     • Measure PTH

     • Measure Vitamin D

Diagnostic approach

     • Cancer hunt

     • Renal disease?

     • Mass in cervical region?

     • History of vitamin D ingestion?

     • If still suspect neoplasia, PTH-rp

Phosphorus

     • Mineralization of bone

     • Critical for high-energy phosphoryl units of metabolic intermediates

     • Structural phosphoproteins and phospholipids.

     • Inorganic phosphate anions play a role in acid base metabolism

Phosphorus regulation

     • PTH decreases by decreasing renal tubular reabsorption

     • Calcitonin decreases by inhibiting PTH-stimulated bone resorption, increasing movement into tissues, and decreasing renal tubular resorption of phosphorus.

     • Vitamin D increases by stimulating absorption from intestine and kidney and inihibiting PTH synthesis.

Hypophosphatemia

     • Primary hyperparathyroidism (renal loss)

     • Hypercalcemia of malignancy (PTH-rp inhibits renal P reabsorption

     • Vitamin D deficiency

     • Respiratory alkalosis

     • Decreased intestinal absorption of P

     • Renal tubular defects (ie, Fanconi syndrome)

     • Chronic renal failure in horses

Remember: sequela of hyperca

     • Some causes of hypophosphatemia also cause hypercalcemia, such as primary hyperparathyroidism and hypercalcemia of malignancy.

     • Hypercalcemia may result in mineralization of the kidneys, with resulting decreased GFR, and subsequent normal or increased serum P concentrations.

Hyperphosphatemia

     • Decreased GFR, either as a result of prerenal azotemia (decreased blood flow to kidney), or renal disease is the most common cause of hyperphosphatemia.

     • Ruptured bladder or ureter, or urethral obstruction will also cause retention of phosphorus.

Hyperphosphatemia

     • Vitamin D intoxication

     • Excessive P intake

     • Primary hypoparathyroidism