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HYPERCALCEMIA IN DOGS
WHEN THE RESULTS SAY HIGH BLOOD CALCIUM
Calcium is used as a messenger to activate enzymes and regulate all sorts of body functions. Calcium is such a crucial component of our biochemistry that virtually any complete blood panel, whether human or veterinary will include a measurement of calcium. Our bodies go to tremendous lengths to regulate our blood calcium levels within a very narrow range. We need a storage source to draw upon for when we need more circulating calcium as well as a system to unload excess
HOW CALCIUM IS ORGANIZED IN OUR BODIES:
Calcium exists in several states in our bodies depending on whether it is being used or stored. “Ionized Calcium” is circulating free in the bloodstream and is active or ready to be used in one of the numerous body functions requiring calcium. The amount of ionized calcium in the blood is tightly regulated. Too much is dangerous. Too little is dangerous. About 50% of blood calcium is present as ionized calcium.
“Bound Calcium” is also circulating in the bloodstream but it is not floating around freely. It is instead, being carried by molecules of albumin (a blood protein whose job is to transport substances that don’t freely dissolve in blood) or complexed with other ions. About 40% of blood calcium is bound (i.e. carried by albumin or complexed with another ion). Ionized calcium and bound calcium added together are called "total calcium." This value is reported on most blood chemistry panels. Total calcium refers to the total calcium in the bloodstream, not the total calcium in the body.
Calcium is also stored in the minerals of bone. We do not usually think of bone as more than just scaffolding but living bone is a surprisingly active tissue. One of its functions is to store calcium and when calcium is needed, it can be mobilized from the bone. Normally there is plenty of calcium and such mobilization does not significantly weaken the bone structure but if excess calcium is mobilized, bone can be depleted and softened.
ADJUSTING CALCIUM LEVELS
What keeps calcium from rising higher and higher? Calcitriol shuts off PTH production in the parathyroid glands. PTH is necessary for activation of vitamin D/calcitriol. Essentially these two hormones shut each other off.
The sequence of events might be this: blood ionized calcium begins to drop. The parathyroid glands sense this and release PTH. Ionized calcium begins to rise. When PTH levels are high enough, vitamin D/calcitriol is activated. With active vitamin D/calcitriol on the scene, ionized calcium begins to rise even more. When enough vitamin D/calcitriol has been activated, the parathyroid glands shut of PTH production and PTH/calcitriol blood levels begin to drop. When PTH levels are low enough, vitamin D/calcitriol activation ceases. With both PTH and active vitamin D/calcitriol levels low, calcium levels begin to drop until they drop low enough to activate the whole system over again.
WHY HIGH CALCIUM LEVELS ARE BAD:
Our kidneys normally would perceive these high calcium levels and attempt to unload as much calcium as possible into the urine. If parathyroid hormone levels are high, the kidneys are completely prevented from doing so. Without the ability to unload calcium, the kidney’s system for water and sodium conservation is impaired. The result is excessive urine production (and often excessive thirst to match). In time, the excess calcium levels going through the kidney are damaging and kidney failure results. Calcium begins to deposit in all the body’s soft tissues actually mineralizing them. This is a painful and inflammatory process.
So how can this system that seems so perfect get all screwed up and allow blood calcium level to rise so high? One common monkey wrench in the works is excess Parathyroid Hormone-Related Protein.
WHAT IS PARATHYROID HORMONE-RELATED PROTEIN?
This substance, abbreviated “PTH-rP,” is produced by numerous body tissues and has actions similar to those of Parathyroid Hormone. It is a normal substance in the body; however, some tumors produce it in very high amounts. When it is present in such very high amounts, blood calcium becomes dangerously high. Detecting PTH-rP is a sign that a cancer is afoot somewhere in the body.
WHAT CAUSES HYPERCALCEMIA?
Given the feedback system described, the list is rather short:
WHAT TESTS COME NEXT?
Back to the patient with an elevated calcium level that needs to be tracked down. Often the elevated calcium is found as an unpleasant surprise on a screening test for a patient that, at least at first glance, seems normal.
STEP ONE: Make sure to check ionized calcium.
STEP TWO: Double check the patient for obvious disease that might elevate calcium.
This is also a good time to review the basic lab work where the elevated total calcium was discovered. Renal insufficiency/kidney failure is the third most common cause of hypercalcemia. Basic blood work should readily pick this up. A significantly elevated globulin level, a red flag for multiple myeloma, also should be evident on basic lab work if it is present. Multiple myeloma is a type of blood cancer that produces excessive antibodies Serum electrophoresis (another blood test) will be helpful in ruling this in or out if globulin levels are consistent.
STEP THREE: ACTH STIMULATION TEST FOR ADDISON'S DISEASE (OR AT LEAST A BASELINE CORTISOL LEVEL)
STEP FOUR: Run a PTH level, and a PTH-rP Level
If a PTH-rP level is high, this is a strong indicator of cancer and we just need to find out where. Usually lymphoma would be the culprit but, as mentioned, many other tumors are on the list of possibilities.
The constellation of these tests will tell us if we must search for a parathyroid tumor, search for another type of tumor, treat for Addison’s disease, or attempt to manage the kidney disease.
STEP FIVE: The Tumor Search
We are looking for a tumor that is not readily apparent and lymphoma is the most common. Again, we would like to reserve the most expensive and the most invasive testing for last in case they are not necessary. With this in mind, the following would be a reasonable sequence:
It should be obvious from this discussion that treatment of hypercalcemia is highly dependent on finding the underlying cause and treating that. One might ask is there nothing that can be done to control hypercalcemia during all this testing. The answer is “yes and no.” Treating the hypercalcemia is likely to interfere with the testing (see below). It is very important to do one's best to find an underlying tumor if there is one but we also need to protect the kidneys from damage by the high levels of calcium going through them.
Reducing the amount of calcium entering the body can be helpful in restoring blood calcium levels to normal and there are several approaches. Obviously, if a primary cause of the hypercalcemia is found, a diet appropriate for that disease is best. Lightly salting food may be helpful as salt encourages the kidneys to dump calcium though this method remains untested for the treatment of hypercalcemia. Supplementing the diet with fiber has been shown to be helpful in some studies but not helpful in others. While the jury is still out on fiber supplementation, adding fiber certainly would not be harmful and is something that might be used. Diets formulated for patients with kidney insufficiency or for the prevention of calcium oxalate bladder stones are restricted in calcium and may also be helpful. If a couple of months on a therapeutic diet has not been helpful or if the ionized calcium level is especially high, it is important to add in more aggressive therapy.
Bone is shaped by osteocytes (cells that make new bone) and osteoclasts (cells that dissolve bone). The osteocytes and osteoclasts work together to sculpt and build bone in the correct shape. When osteoclasts dissolve bone, they release calcium into the bloodstream which is just what we do not want in a hypercalcemic patient. The bisphosphonate drugs, developed for women needing treatment for osteoporosis, can be used to suppress the activity of osteoclasts, potentially reducing blood calcium levels. Alendronate is the usual oral veterinary product and it is used once a week. Zoledronate is given as an IV infusion.
It might seem like prednisolone is useful in treating almost any disease. When it comes to hypercalcemia, prednisolone enables the kidney to dump extra calcium and potentially bring dangerously elevated calcium levels down to normal. There is a very important downside here, however. Lymphoma remains the most common cause of hypercalcemia by far. Lymphoma cells are killed by prednisolone and a short-term remission is induced. This sounds like it would be a good thing but in fact, it is not. If the hypercalcemic patient is put on prednisolone before proper testing has been done, a lymphoma may be almost impossible to find thus making it almost impossible to reach a definitive diagnosis. Worse still, the remission achieved by prednisolone alone is short-lived and leaves the tumor resistant to other chemotherapy drugs (thus making a long term remission all the more difficult to achieve). For this reason, prednisolone treatment is a last resort and is only used when testing has been exhausted.
Hospitalization on intravenous fluids will help maintain blood flow to the damaged kidneys and may be useful. In general fluids not containing calcium are used.
Low doses of furosemide also help remove calcium from the blood stream but one must be careful not to allow the patient to get dehydrated since furosemide is a diuretic (meaning it increases urine production).
As one can see a surprise elevated calcium test is not something to ignore. Testing must be swiftly performed so that treatment can be initiated without fear of making diagnosis impossible. If you have further questions about hypercalcemia or the conditions leading to it, do not hesitate to ask your veterinarian.
Page last updated: 11/22/2021