endocrinology (hypercalcemia in cats)

Question 1

what are the key role of calcium in normal physiological processes

Answer 1

calcium is important in:
- neuromuscular transmission
- enzyme activity
- blood coagulation
- muscle contraction (including skeletal, smooth and cardiac muscles)
- calcium mediates vascular smooth muscle contraction and maintains blood vessel tone and hence blood pressure
- calcium is the most abundant component of the skeleton

Question 2

list the three organ systems responsible for calcium homeostasis

Answer 2

gastrointestinal tract

kidneys

bones

Question 3

what are the hormones involved in calcium regulation

Answer 3

parathyroid hormone

calcitriol

calcitonin

Question 4

what are the PTH roles

Answer 4

PTH increases calcium reabsorption in the distal convoluted tubules of the kidney

PTH decreases phosphate reabsorption from the proximal tubules

PTH stimulates osteoclastic bone resorption and increases the number of osteoclasts on the bone surface to release calcium and phosphate from bone

Question 5

what are the calcitriol’s roles

Answer 5

calcitriol is the active form of vitamin D

it increases the absorption of calcium and phosphate from the GI tract and also reabsorption in the renal tubules

Question 6

what are the calcitonin’s roles

Answer 6

calcitonin is a potent calcium lowering hormone

it acts predominantly on bone to inhibit osteoclastic bone resorption

Question 7

describe briefly the process of calcium regulation

Answer 7

PTH is produced from chief cells in the parathyroid gland in response to ionised hypocalcemia

calcitriol is activated in the kidneys under the influence of the enzyme 1-alpha-hydroxylase
- cats have low levels of vitamin D in their skin
- unlike in humans, it is not synthetised in the skin in response to sunlight
- therefore, cats are dependent on dietary intake and vitamin D is often supplemented in pet foods

calcitonin is secreted from C cells in the thyroid gland in response to hypercalcemia

Question 8

describe the physiological response to hypercalcemia

Answer 8

the normal physiological response to hypercalcemia includes:
- decreased production of PTH from the parathyroid gland
- increased production of calcitonin from C cells in the thyroid gland
- decreased production of calcitriol in the kidneys due to direct inhibition and also decreased PTH production

this results in:
- reduced release of calcium and phosphate from bone due to reduced PTH concentrations
- increased renal excretion of calcium, due to decreased PTH and calcitriol concentrations
- decreased intestinal absorption of calcium due to decreased calcitriol concentration

Question 9

what is the risk with hypercalcemia

Answer 9

identification of hypercalcemia and implementation of appropriate therapy is important as soft tissue calcification is likely to occur if the calcium*phosphate product becomes increased (>5.6 mmol²/l²)

mineralisation of renal tissue may result in nephron injury causing a decline in renal function and azotemia

hypercalcemia may promote formation of calcium oxalate uroliths

hypercalcemia may play a role in pancreatitis

Question 10

describe all the forms of calcium in the body

Answer 10

approximately 99% of total body calcium is stored in bones in the form of hydroxyapatite crystals

extracellular calcium exists in three forms:
- ionised calcium: around 50%, it is the biologically active form

- complexed calcium: around 10%, it is complexed with anions such as phosphate, lactate or bicarbonate

- protein-bound calcium: around 40%, it is bound to proteins mainly albumin

Question 11

describe pre-analytical factors that can contribute to a low ionised calcium

Answer 11

results for ionised calcium are lower in heparinised blood samples compared with serum samples

kittens will have increased concentrations due to increased bone turnover until 12 months of age

exposure to air will lead to loss of CO2 and an increase in pH, this promotes calcium binding to protein and results in a decreased ionised calcium concentration

in acidemic patients, hydrogen ions will displace protein-bound calcium ions and increase the ionised calcium concentration

a cat with ionised calcium concentration > 1.40 mmol/l is generally considered to be hypercalcemic

Question 12

what are the clinical signs accompanying hypercalcemia

Answer 12

they are often vague and non-specific

lethargy and weakness may result from depressed excitability of muscular and nervous tissue

anorexia, vomiting and constipation may be a consequence of decreased contractility of the smooth muscle in the GI tract

muscle twitching and potentially seizures may be seen due to direct effects of hypercalcemia on the central nervous system

cardiac arrhytmias can also develop due to direct effects on cardiac tissue

PU/PD is less frequent than in dogs may be due to the higher capacity of cats to concentrate urine

Question 13

what are the main differentials for hypercalcemia

Answer 13

spurious results:
- non-fasted sampling
- hyperlipidemia
- hyperproteinemia
- hemoconcentration
- laboratory error
- physiological growth in young animals

hypercalcemia in cats is mostly idiopathic, with CKD and neoplasia also being common causes

hypoadrenocorticism and primary hyperparathyroidism are very rare in cats

Question 14

what would be your diagnostic approach for hypercalcemia

Answer 14

biochemistry
- ionised calcium should be measured to confirm hypercalcemia if total calcium is elevated
- hypercalcemia should be demonstrated to be persistent
- a cat with an ionised calcium concentration > 1.40 mmol/l is generally considered to be hypercalcemic
- full biochemical analysis should be undertaken including renal function and phosphate concentration

parathyroid hormone
- it allows to assess if hypercalcemia is parathyroid dependent or parathyroid independent
- the majority of cats will have parathyroid-independent hypercalcemia
- if the PTH concentration is in the upper two-third of the reference interval or is increased, it suggests a parathyroid-dependent cause

parathyroid hormone related peptide
- PTH-rp can be measured if malignancy is suspected
- normal value does not fully exclude neoplasia

vitamin D metabolites
- calcitriol and calcidiol can be measures
- calcitriol reflects metabolically active vitamin D
- calcidiol reflects cholecalciferol or ergocalciferol ingestion following hydroxylation

Question 15

what findings in urinalysis could be suggestive of hypercalcemia

Answer 15

presence of calcium oxalate crystals or uroliths could suggest hypercalcemia (or ethylene glycol toxicity)

Question 16

why is diagnostic imaging useful

Answer 16

thoracic and abdominal imaging can be helpful in screening for neoplasia or granulomatous lesions

soft tissue calcification can occur when calcium*phosphate product is > 5.6 mmol²/l²

the kidneys and gastric mucosa are the predominant organs to be affected and this may be visualised on X-ray or CT images

X-ray may also identify calcium oxalate nephroliths, ureteroliths or cystoliths

Question 17

what treatment could be implemented in patients with a severe acute rise in calcium concentration

Answer 17

promoting diuresis
- IV fluid therapy and furosemide (1-2 mg/kg q 8-12h) administration
- isotonic saline is the fluid of choice as it does not contain calcium
- furosemide acts to inhibit calcium reabsorption in the loop of Henle
- thiazide diuretics should not be used as these enhance the reabsorption of calcium in the renal distal tubules

Question 18

can glucocorticoids be used to treat hypercalcemia

Answer 18

glucocorticoids reduce bone resorption, decrease intestinal absorption and increase renal excretion of calcium

avoid steroids if the underlying etiology remains unclear

prednisolone 0.5-1 mg/kg q 12-24 h

dexamethasone 0.1-0.2 mg/kg/24h

Question 19

how bisphosphonates can be helful in treating hypercalcemia

Answer 19

bisphophonates exert their activity by reducing the number and activity of osteoclasts

alendronate 5-20 mg/cat PO q 7 days administered after fasting to optimise GI absorption

Question 20

how calcitonin can be useful in hypercalcemia

Answer 20

calcitonin has short-lived effects and may be associated with side effects

used in emergency if needed 4-6 UI/kg SC q 8-12h

salmon calcitonin is the most potent form available

Question 21

how a dietary change could be useful for treating hypercalcemia

Answer 21

dietary change is one of the most important aspects of management in cats with idiopathic hypercalcemia

high fiber diets can be fed to bind intestinal calcium, thus reducing its absorption

wet diets can also be helpful in promoting diuresis and generally have a lower calcium content than dry diets
- diets formulated for management of calcium oxalate urolithiasis may be considered as these are restricted in calcium and decrease urinary acidification

diets containing < 200mg/100 kcal of calcium and with Ca:P ratio < 1.4:1 are recommended
- Chia seed (2g/cat/day) could be tried as they respect this nutritional profile

Question 22

how would you manage hypercalcemia associated with CKD

Answer 22

in cats with early and mid-stage CKD, iCa is normal or low and total calcium is normal or increased
- this is the result of increased phosphate concentration associated with reduced renal clearance forming complexes with ionised calcium

reduce phosphate retention through feeding a renal diet that is restricted in protein and phosphate

intestinal phosphate binders without calcium salt can be used

it is important to note that some cats can develop hypercalcemia when being fed a renal diet
- increased phosphate intake may lead to resolution of hypercalcemia

Question 23

how would you manage hypercalcemia associated with hyperparathyroidism

Answer 23

if primary hyperparathyroidism is confirmed, the abnormal parathyroid tissue should be surgically resected with close monitoring for development of hypocalcemia or recurrent laryngeal nerve damage

in nutritional hyperparathyroidism it is low calcium or an altered calcium:phosphate ratio in the diet that stimulates productionn of PTH
- it is not generally associated with hypercalcemia
- it may be recognised more commonly with the increasing popularity of feeding bone and raw food diets. It is the same with all-meat diets
- nutritional secondary hyperparathyroidism is typically associated with a predominantly meat diet, as they are low in calcium but high in phosphate which stimulates PTH production

Question 24

explain malignacy associated hypercalcemia

Answer 24

less common in cats than in dogs

hypercalcemia ca develop through humoral mechanisms or through osteolytic mechanisms

primary bone neoplasia is rarely associated with hypercalcemia

squamous cell carcinoma and lymphoma are the two most common neoplasms associated with hypercalcemia

both total and ionised calcium are increased and therefore, PTH concentration should be low

Question 25

explain hypercalcemia associated with hypervitaminosis D

Answer 25

there is typically a parallel increase in calcium and phosphate concentration

PTH concentration will be low

the presence of soft tissue calcifications may be more suggestive of vitamin D toxicity as both calcium and phosphate rise in parallel, resulting in an increased calcium*phosphate product

Question 26

explain hypercalcemia associated with granulomatous disease

Answer 26

uncommon cause of hypercalcemia

hypercalcemia can result from granulomatous inflammation because macrophages can synthesize calcitriol without negative feedback regulation

calcitriol can be high and calcium normal

hypercalcemia has been associated with mycobacteria, FIP, toxoplasmosis, nocardiosis, cryptococcosis and actinomyces rhinitis

Question 27

explain the link between hyperthyroidism and hyperparathyroidism

Answer 27

60-80% of cats with hyperthyroidism have concurrent hyperparathyroidism

total and iCa concentrations tend to be either normal or slightly decreased

hyperphosphatemia is more frequently observed
- these findings are most likely due to the effects of thyroid hormone on bone turnover and renal excretion

hypocalcemia and/or hyperphosphatemia will cause compensatory increase in PTH secretion