Divalent Electrolytes: Calcium, Magnesium, Phosphorus

What are the 3 key players of Ca regulation?

1) PTH

2) Vitamin D

3) Calcitonin

PTH will increase ____________, but decrease ____________

calcium

phosphorus

Vitamin D will ___________ both calcium and phosphorus.

increase

Calcitonin will ___________ both calcium and phosphorus.

decrease

PTH is going to affect what three organs?

bone, kidney, and gut

When serum calcium is decreased, how does PTH respond and affect the bone?

increase resorption of bone by stimulating osteoclasts - this will release Ca and PO4 from the bone

When serum calcium is decreased, how does PTH respond and affect the kidney?

it will increase calcium renal reabsorption, but will decrease phosphorus reabsorption

What is the affect of vitamin D on the kidney, bone, and gut?

it will increase renal reabsorption of calcium and phosphorus

it will increase bone resorption and release of calcium and phosphorus

it will increase absorption of calcium and phosphorus in the gut

When serum calcium is decreased, how does PTH respond and affect the gut?

PTH affects the gut indirectly

it will increase vitamin D formation by the kidney, and then vitamin D will directly promote absorption of calcium and phosphorus in the gut.

How does increased Ca and PO4 affect vitamin D?

once Ca and PO4 are elevated enough - it will prevent further conversion of vitamin D into its active form

What is the active form of vitamin D?

calcitriol (1,25-dihydroxycholecalciferol)

When serum calcium is increased, how does Calcitonin respond and affect the bone?

calcitonin will decrease osteoclast activity, meaning bone resorption is decreased and release of calcium and phosphorus from the bone is inhibited

When serum calcium is increased, how does Calcitonin respond and affect the kidney?

promotes excretion of calcium and phosphorus from the kidneys

When serum calcium is increased, how does Calcitonin respond and affect the gut?

it don't

When serum calcium is increased, how does PTH & vitamin D formation respond?

PTH decreases

Vitamin D formation decreases

If vitamin D is increased, Ca should be ____________ and P should be __________

increased

increased

If PTH/PTHrP is increased, Ca should be ____________ and P should be ___________

increased

decreased

If PTH is decreased, Ca should be ____________ and P should be ___________

decreased

increased

If you observed Ca and PO4 to both be increased, or both be increased - what substances/hormones are predominating to cause this effect?

Vitamin D

or Calcitonin

If you observed Ca to be increased and PO4 to be decreased or visa versa - what substances/hormones are predominating to cause this effect?

PTH/PTHrP

What is the biologically active form of calcium?

unbound - free calcium

What are the 3 forms of Ca that are present in the blood and are measured in total calcium?

1) Free ionized calcium (50%) (referred to iCa in the notes)

2) Protein-bound, mostly to albumin (40-45%)

3. Anion-complex-bound (e.g., bound to citrate, phosphate, etc) (5-10%)

Why should we not use EDTA/Citrate tubes if we want to perform a chem panel?

EDTA/Citrate will chelate the divalent cations and chem panel results would show really really decreased Ca and Mg

If EDTA/Citrate tubes are used, what will Ca, Mg, and K end up looking like on your chem panel?

Ca and Mg will be drastically decreased

K will be drastically increased

If no obvious cause for major or ̄ tCa: Send sample off for a calcium panel - what 5 things will this panel measure?

tCa

iCa

PTH

PTHrP

VitaminD

Increased absorption in gut, reabsorption in kidney, and mobilization from bone of Ca leads to _____________.

hypercalcemia

What's a mnemonic to help us remember potential causes of hypercalcemia?

Goshdarnit

What are two primary clinical signs of hypercalcemia?

Soft tissue calcification

PU/PD

What are two conditions where soft tissue calcification is seen secondary to hypercalcemia?

- Vitam D toxicity

- renal failure

What explains PU/PD as a clinical sign of hypercalcemia?

Calcium inhibits the action of ADH

without ADH, patients cannot concentrate their urine well --> loss of water in urine --> stimulate thirst

If calcium x phosphorus product is greater than 70, this often occurs in what two instances?

Vitamin D toxicity

Renal failure

What is the most common cause of marked hypercalcemia?

Humoral hypercalcemia of malignancy

What is humoral hypercalcemia of malignancy?

it just means marked hypercalcemia due to cancer

What substance is the primary humoral factor that instigates humoral hypercalcemia of malignancy?

PTHrP (Parathyroid hormone related protein)

What are the two most common tumors associated with humoral hypercalcemia of malignancy?

1) Lymphoma (usually T cell)

2) Anal sac adenocarcinoma

What are the expected findings for Ca, PTH, PTHrP and PO4 in cases of humoral hypercalcemia of malignancy?

Ca: increased

PTH: decreased

PTHrP: (+) if this is the factor secreted by tumor, (-) if it's another factor

PO4: if due to PTHrP, expect to be normal to decreased.

Primary hyperparathyroidism is often caused by what?

due to functional parathyroid neoplasia (usually adenoma) or idiopathic hyperplasia

What are the expected findings for Ca, PTH, PTHrP and PO4 in cases of primary hyperparathyroidism?

Ca: increased

PTH: increased

PTHrP: negative

PO4: normal to decreased

Are exogenous or endogenous sources the most common cause of vitamin D toxicity?

exogenous

What are examples of exogenous sources that can cause vitamin D toxicity?

- Rodenticides

- Donovex (psoriasis ointment)

- Plants

What are two examples of causes of an increase in endogenous vitamin D, leading to toxicity?

- Granulomatous disease

- neoplasia (rarely)

How does Granulomatous disease cause vitamin D toxicity?

macrophages produce 1,25 dihydroxycholecalciferol aka Vitamin D analogs, and it present at high enough concentrations --> vitamin D toxicity

What is the infectious agent of Schistosomiasis?

Heterobilharzia americana

How can schistosomiasis lead to hypercalcemia?

possibly related to granulomatous inflammation that causes hypercalcemia

rarely - these cases have increased PTHrP!

hypoadrenocorticism (Addison's) causes a ______ hypercalcemia. Does this resolve with treatment?

mild

yes

Acute and chronic kidney disease occasionally produce hypercalcemia in cats and dogs, possibly due to binding of Ca to retained anions and/or acidosis; for unknown reasons, it is especially common with ________ toxicity.

grape/raisin

________ excrete large amounts of calcium normally, so reduced renal excretion of calcium in horses due to renal disease often leads to ___________, particularly if they are on a high-Ca diet.

Horses

hypercalcemia

What is an idiopathic cause of mild hypercalcemia?

Idiopathic hypercalcemia of middle-aged cats

In cases of idiopathic hypercalcemia of middle-aged cats - what do you expect Ca levels to be?

mild to moderate hypercalcemia

What are some less common causes for mild to moderate hypercalcemia?

-- young, growing dogs

--Osteolytic lesions, e.g., myeloma, osteosarcoma, septic osteomyelitis

--Thiazide diuretics (promote resorption in distal tubules)

--Spurious (lab error or artifact due to lipemia or hemolysis)

--Increased protein-bound Ca due to multiple myeloma—extremely rare!

What are two common causes of mild hypercalcemia? which of these are prevalent in cats vs. dogs?

- Renal disease: both

- Addision's: dogs

What are two common causes of extreme hypercalcemia? which of these are prevalent in cats vs. dogs?

- Hypercalcemia of malignancy: both

- Primary hyperPTH: dogs

Secondary renal hyperparathyroidism leads to increased PTH due to _________ disease.

renal

Secondary renal hyperparathyroidism is mainly initiated by a(n) ____________ in vitamin D.

decrease

Explain how kidney disease can lead to secondary renal hyperparathyroidism

Tubular damage --> decreased GFR --> increase PO4 --> increase in FGF-23 --> decrease Vitamin D activation (& increase PO4 excretion) --> decrease ionized Ca --> increased PTH

What would be early findings of Ca, PO4, Vitamin D, and PTH in cases of secondary renal hyperparathyroidism?

Ca: normal

PO4: normal

Vitamin D: normal

PTH: increased

What would be later findings of Ca, PO4, Vitamin D, and PTH in cases of secondary renal hyperparathyroidism?

Ca: decreased

PO4: increased

Vitamin D: decreased

PTH: increased A LOT

What are some clinical signs of hypocalcemia?

- Muscle tremors, twitching, cramping

- Facial rubbing

- Seizures

- Stiff gait

- Aggressive and/or hypersensitive

- Biting or licking at paws

- Cattle: Weakness

How does decreased Ca2+ lead to increased excitability?

less calcium is present to stabilize Na+ channels so Na+ channels become more unstable/sensitive and will depolarize more easily

What is the most common cause of hypocalcemia/the first thing you should check for if you see hypocalcemia?

hypoalbuminemia

How does hypoalbuminemia affect iCa levels? what about total Ca levels?

iCa is unaffected

total Ca is decreased

If hypoalbuminemia is not causing the hypocalcemia, what three things should you consider?

1) Inadequate intestinal absorption

2) Excess urinary excretion

3) Inadequate mobilization from bone

What are the most common causes of hypocalcemia in dogs and cats?

Hypoalbuminemia

GI disease

Renal disease

Pancreatitis

Sepsis/critically ill

Eclampsia

If a dog or cat has severe hypocalcemia - what are the common causes to consider?

Primary hypoparathyroidism

Acute pancreatitis

Toxicity: ethylene glycol or cantharidin

Periparturient

Artifact (EDTA)

But all can be variable!

What is the most likely cause of hypocalcemia in a horse?

Colic

Colic

Colic

Cantharidin

Other than colic - what is a potential cause of hypocalcemia in horses?

Cantharidin toxicity

Ingestion of oxalate- containing plants

What are the two most common causes of hypocalcemia in cattle?

- milk fever

- endotoxemia and GI disease (LDA, vagal indigestion)

What are some primary causes of hypoparathyroidism?

Parathyroid damage: surgery, inflammation

You would expect patients with primary hypoparathyroidism to be ______phosphatemic and _____magnesemic.

hyper

hypo

Why is it that in primary hypoparathyroidism, phosphate is increased?

because of a lack of PTH to promote urinary phosphorus excretion

Acute pancreatitis commonly results in ______calcemia that can range from mild to marked

hypo

Chronic kidney disease in dogs, cats, and ruminants often results in mild ______calcemia.

hypo

Why is it that renal disease can lead to hypocalcemia?

mostly due to decrease vitamin D (which is activated in the kidney) - this leads to decreased reabsorption of Ca in renal tubules.

However, if renal disease is caused by ethylene glycol toxicity, a _________ _____________ is often seen due to chelation of calcium by an oxalate metabolite

marked hypocalcemia

How can milk fever cause hypocalcemia?

in cattle—sudden demand for Ca during lactation and Ca is met with an inadequate response to PTH, as well as potentially decreased intestinal absorption of Ca due to anorexia.

How can eclampsia cause hypocalcemia?

results from an demand for Ca, often combined with an inadequate response to PTH:

(dogs, horses and sheep)—associated with peak lactation; tetany typically observed

Preparturient hypocalcemia (cats)—1-2wks prior to parturition

How do malabsorption syndromes lead to hypocalcemia?

malabsorption of Ca and vitamin D; examples include protein-losing enteropathy and exocrine pancreaticinsufficiency. Albumin loss also contributes to the hypocalcemia

How can colic cause hypocalcemia in horses?

While the mechanism is not entirely understood, it is thought to be endotoxin-related. This mechanism may also be observed in other species.

If there is a herd outbreak of colic, what might you suspect is the cause? What would you expect their calcium levels to be?

Cantharidin toxicity from eating blister beetle-contaminated alfalfa hay

Hypocalcemia

What is one of the greatest factors determining phosphorus concentration?

GFR

Other than GFR, what are three other factors that play a role in regulating Phosphorus concentration?

hormonal regulation

cellular shifting

dietary intake

What four hormones/substances play a role in regulating phosphorus?

PTH

Vit D

Calcitonin

Growth hormone

What are four steps to approaching phosphorus evaluation?

1) What is the calcium doing?

2) How do the renal parameters to look?

3) Is unusual diet or GI disease present?

4) Could there be a shift between ICF and ECF?

If Ca & P move together: Consider problem with ____________ or (unlikely) _________

vitamin D

calcitonin

If Ca & P move in opposite directions: Consider _______ or _________

PTH

PTHrP

PTH and Calcitonin will _____________ phosphorus concentrations, as long as GFR is adequate

decrease

Growth hormone ____________ renal reabsorption of phosphorus.

increases

What explains the normal elevation in phosphorus in young animals?

growth hormone present

Vitamin D overall, ____________ phosphorus concentration.

increases

What is the most common cause on increased phosphorus concentration?

decreased renal excretion

Degree of increased phosphorus generally parallels ___________, except in horses.

azotemia

What are two possible renal causes for hypophosphatemia?

increased renal excretion due to diruesis or damaged/defective proximal tubular cells.

What is a dietary/GI cause of hyperphosphatemia?

increased intestinal absorption due to a a low Ca:PO4 ratio or phosphate enemas

What is a dietary/GI cause of hypophosphatemia?

decreased intestinal absorption due to anorexia, malabsorption, or phosphorus-binding agents.

What's the purpose of phosphorus binding agents? and how can they play a role in hypophosphatemia?

These decrease intestinal absorption of PO4, although usually they are being administered because of hyperphosphatemia, and it is rare that administration would cause hypophosphatemia.

In reference to cellular shifting, hyperphosphotemia can occur when there is increased ____________ phosphorus. (extracellular/intracellular)

extracellular

What are potential causes of increased extracellular phosphorus concentrations?

anything that can cause it to be released from cell:

- severe cell lysis

- acidosis

- delayed sample porocessing

In reference to cellular shifting, hypophosphotemia can occur when there is increased ____________ phosphorus. (extracellular/intracellular)

intracellular

What are potential causes of increased intracellular phosphorus concentrations?

- hyperinsulinism

- glucose infusion

- respiratory alkalosis (increases RBC glycolysis)

Growth hormone can cause ___________ renal reabsorption of phosphorus.

increased