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When the Results say High Blood Calcium

Calcium is a mineral we have all heard about as we have been told to drink our milk for adequate calcium since we were children. Women are encouraged to supplement calcium, not just in pregnancy but virtually throughout adulthood in hope of staving off osteoporosis. Calcium is not only important as a component of bone; it is also involved in the contraction of all muscle tissue from the skeletal muscles that move our limbs voluntarily to the involuntary muscles that move our intestinal contents to our heart muscle that beats regularly and tirelessly throughout life.

There’s more.

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 percent of blood calcium is present as ionized calcium.

Bound calcium is also circulating in the bloodstream but it is not floating around freely. Instead, it is 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 percent 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

When the body needs to raise blood ionized calcium levels, the sources it may draw from are the bones (where calcium is stored as mineral), the intestine (where the calcium we eat enters our bodies), and the kidney (where excess calcium is dumped into urine). We can regulate how much dietary calcium is allowed to enter from the GI tract. We can cause our bones to relinquish stored calcium quickly or slowly as our needs dictate. When we want to drop the ionized calcium level, our kidneys are able to remove circulating calcium, including it in our urine so that it can be happily flushed away.

These processes are controlled by two hormones: parathyroid hormone (affectionately called PTH) and calcitriol (affectionately known as vitamin D). Calcitriol acts to enhance calcium absorption into the body from the intestine, promote release of calcium from bone, and cause the kidney to avoid dumping calcium. This adds up to higher blood ionized calcium. PTH also acts to mobilize bone calcium and shut off renal calcium dumping. This also adds up to more blood ionized calcium.

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

Elevated blood calcium starts when the bones receive an inappropriate message to mobilize their calcium. This message is either from excess parathyroid hormone (as might be produced by a parathyroid gland tumor) or from high amounts of parathyroid hormone-related protein (see later). When calcium is removed from the bones, all that is left is a fibrous scaffold that is not really strong enough to support us. Our bones break and even fold.

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:

• A tumor excessively producing PTH-rP. Such tumors include: lymphoma, anal sac carcinoma, mammary tumors, and multiple myeloma. It is possible for other tumors to secrete PTH-rP in high amounts but it is rare. The common tumors should be sought first. Lymphoma (lymphatic cancer) is probably by far the most common cause of elevated calcium in dogs.
  
  
• Parathyroid gland tumor secreting PTH.
  
  
• Kidney failure (altering the calcium and phosphorus balance). It should be noted that kidney failure causes hypercalcemia, and hypercalcemia causes kidney failure. It will be difficult to determine which came first but since kidney failure tends to progress rapidly when there is hypercalcemia, this puts more of a rush on the testing sequence.
  
  
• Addison's disease (hypoadrenocorticism - a deficiency in adrenal steroid hormones).
  
  
• Vitamin D Poisoning (some newer rat poisons use vitamin D analogs – the good news is that you would usually know if rat poison was in the pet’s environment or if the pet had gotten into such a product).
  
  
• Quintox and Rampage are two brands of rat poison using Vitamin D analogs. Others include Rat-B-Gone and Mouse-B-Gone.
  
  
• Fungal disease (certain fungal infections cause tissues to calcify, especially lung tissue, and be associated with elevated blood calcium levels).
  
  
• Idiopathic hypercalcemia -(rare in dogs, common in cats) - meaning that after a complete work-up of tests, no cause can be found. Frustratingly, this is the most common cause of hypercalcemia in cats, though it is an extremely rare situation for dogs. Most cats in this situation show no clinical signs from their elevated calcium (versus dogs who almost always have marked thirst) though 15% of cats will have bladder stones (usually calcium oxalate stones).

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.
Total calcium is what is usually reported on a blood panel, but it is ionized calcium (the actual active portion of calcium) that we care about. If total calcium is elevated but ionized calcium is normal then we are done testing. Sometimes excessive fat circulating in blood will increase total calcium. Sometimes an elevation in blood pH will raise total calcium and sometimes a dehydrated patient will have a high total calcium. If ionized calcium is not elevated, our patient does not have a hypercalcemia problem.

STEP TWO: Double check the patient for obvious disease that might elevate calcium.
This is particularly important if the elevated total calcium was a surprise finding and the patient is no longer in the hospital. The patient will be back in the hospital for an ionized calcium level, as above; this is the perfect opportunity to feel the throat carefully for a possible parathyroid growth, do a rectal exam to rule out an anal gland tumor, and check all the lymph nodes for enlargement. Mammary glands should be carefully checked for growths. Obviously if any of these are found, we have a direction to pursue and further testing may not be needed but if nothing is found the biochemical tests listed below will be needed.

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 the pet has it. 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. Serum electrophoresis (a 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)
In one study of 40 dogs with elevated calcium, 29 percent had Addison’s disease, making this condition a common cause of hypercalcemia (though not as common as lymphoma and parathyroid tumors). Addison's disease (hypoadrenocorticism) is a deficiency in adrenal steroid hormones.It has been referred to as "The Great Imitator" because it can present in so many unusual ways and look like numerous other conditions. There are two ways to approach testing: a screening test and then a confirming test if the screening test is positive, OR jumping directly to the confirming test. The screening test involves a single cortisol level. If this level is greater than 2.5 mg/dl (0.069 mmol/L) then Addison's disease is ruled out and we can continue to STEP FOUR. If the level is less than 2.5 mg/dl (0.069 mmol/L), then an ACTH stimulation test is needed and the dog will need an hour or two in the hospital. The stimulation test assesses the dog's ability to respond to adrenal stimulation and results should definitively rule Addison's disease in or out.

STEP FOUR: Run a PTH level, and a PTH-rP Level
At this point, we are looking for a tumor. The PTH level will tell us if there is a parathyroid tumor. There may or may not be a palpable mass in the throat where the parathyroid glands are. Recall that parathyroid hormone acts to raise blood calcium levels. When blood calcium levels are high, parathyroid hormone production shuts down. If the PTH level is even in the upper 2/3 of the normal range in the face of high blood calcium levels, this is inappropriate and indicates a parathyroid tumor. Surgical exploration of the throat/neck area are indicated at this point.

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
At this point, we have done all the blood testing we can do and ruled out Addison’s disease, parathyroid tumor, and primary kidney disease. If we have an elevated PTH-rp level we have a high confidence level that cancer is afoot somewhere, even if we have not found it. Even if we do not have an elevated PTH-rp level, there is a good chance cancer is afoot somewhere. In either case, we need to find the tumor if we can.

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:

• Chest and Abdominal Radiographs to look for latent organ enlargement that might lead to the hidden tumor.
  
  
• A bone marrow tap (requires general anesthesia)
  
  
• Ultrasound of the belly to further look for hidden tumor and evaluate the kidneys.
  
  
• Some screening radiographs to look at bone quality.

Multiple myeloma is a kind of cancer associated with hypercalcemia. Many of its features might be detected in the course of this work up but it is helpful to remember that there are criteria to meet before making a diagnosis of multiple myeloma and some additional tests might be needed. This special type of cancer is diagnosed based on finding two of the following signs:

• monoclonal gammopathy in the blood (multiple myeloma is a tumor that produces antibodies. If electrophoresis of the blood proteins shows a large elevation of a single type of antibody, this is called a monoclonal gammopathy.)
  
  
• a moth-eaten appearance to bones on radiographs (especially the vertebral bones).
  
  
• abnormal proteins in the urine (called Bence-Jones proteins).
  
  
• greater than 5 percent cancer cells on a bone marrow tap or greater than 10-20 percent plasma cells, which produce antibodies, on a bone marrow tap.

Dietary Therapy

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.

Bisphosphonates

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.

Prednisone

It might seem like prednisone is useful in treating almost any disease. When it comes to hypercalcemia, prednisone enables the kidney to dump extra calcium and potentially bring dangerously elevated calcium levels down to normal. There is an 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.

Saline Diuresis

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.