Hypercalcemia

WHEN THE RESULTS SAY HIGH BLOOD CALCIUM

boy drinking milkCalcium 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 involuntarymuscles 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% 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).

hare skeleton

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

toiletWhen the body needs to raise blood ionized calcium levels, the sources it may draw from are the bones (where calcium is stored as mineral), and the intestine (where the calcium we eat enters our bodies). 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. Essentially these two hormones shut eachother 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 is activated. With active vitamin D on the scene, ionized calcium begins to rise even more. When enough vitamin D has been activated, the parathyroid glands shut of PTH production and PTH blood levels begin to drop. When PTH levels are low enough, vitamin D activation ceases. With both PTH and active vitamin D 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 which 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 the most common cause of elevated calcium by far in dogs. Malignancy is the second most common cause of hypercalcemia in the cat.
     
  • 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 in the presence of hypercalcemia, this puts more a rush on the testing sequence.
     
  • Addison’s Disease (hypoadrenocorticism)
     
  • Vitamin D Poisoning (some newer rat poisons use Vitamin D analogs – the good news is that one would usually know if rat poison was in the pet’s environment or if the pet had gotten into such a product).

    quintox

    Rampage

    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, meaning that after a complete work-up of tests, no cause can be found. Frustratingly, this is the most common cause of hypercalcemia in the cat, 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: Repeat the calcium level to be sure it is really elevated.
One might ask why does this particular test need to be repeated when in almost all other types of testing, the results are simply believed to be true and repeating is not necessary. The answer is that calcium is special. The materials used in testing calcium are not as stable as those for other tests. Calcium in a sample can be falsely elevated by a recent meal, by excess fat in the bloodstream or damage to the blood cells of the sample. If possible a second sample is checked on an empty stomach to be absolutely sure the total calcium level is really elevated before proceeding with the work-up. Alternatively, an ionized calcium level might be run. Ionized calcium is the important portion of total calcium so if the total calcium level is high but ionized calcium is normal, it is not necessary to continue testing.

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. The patient will be back in the hospital for a fresh blood sample as above; this is the perfect opportunity to feel the throat carefully for a possible parathyroid growth, do a rectal exam to rule out anal gland tumor, 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.

STEP THREE: Run a PTH level, an ionized calcium level, and a PTH-rP Level and an ACTH Stimulation Test to rule out Addison’s Disease. If blood globulin levels are high run electrophoresis to rule out Multiple Myeloma.
Before launching a search for a hidden tumor (expensive and potentially invasive) it is probably worth exploring the non-invasive forms of testing first. The ACTH Stimulation test will require one or two hours in the hospital and is the only way to rule out the very treatable Addison’s Disease (an adrenal hormone deficiency) as a cause of the elevated calcium. In one study of 40 dogs with elevated calcium, 29% had Addison’s disease, making this condition a common cause of hypercalcemia (though not as common as Lymphoma and Parathyroid tumors). Multiple myeloma is a lymphoid tumor that produces high levels of antibodies. These tiny proteins that are normally so helpful in fending off infection, do nothing but cause trouble in multiple myeloma patients. A typical blood panel will include a blood globulin level (antibodies are a type of blood globulin). If this parameter is elevated, it is worth having an electrophoresis test done on the blood. If the globulin elevation stems from one single antibody type, a condition called "monoclonal gammopathy" is present. Monoclonal gammopathy is usually caused by either lymphoma or multiple myeloma (see the "tumor search" section below).

 

PTH level

ionized calcium

PTH-rP

 Parathyroid Tumor
 

very high to normal
A PTH level in the upper 50% of the "normal range" is not normal if blood calcium is high.

very high
 

very low

 Lymphoma
 

very low
 

very high
 

very high
 

 Anal Sac Tumor
 

very low
 

very high
 

very high
 

 Kidney Failure
 

very high
to normal

very low
to normal

very high
to normal

Idiopathic Hypercalcemia
 

normal to low
 

high
 

very low
 

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 FOUR: 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. 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.
     
  • If a thorough search for a tumor has been conducted and come up empty, sometimes a dose of a chemotherapy agent that does not directly affect calcium (usually vincristine or L-asparaginase) can be given provocatively. If the blood calcium level shows a drop in 3-5 days, one can assume a cancer such as lymphoma, or lymphoid leukemia can be presumed present).

Multiple myeloma is diagnosed based on finding two of the following signs:

  • monoclonal gammopathy in the blood (as described above).
     
  • a moth-eaten appearance to bones on radiographs (especially the vertebral bones).
     
  • the presence of abnormal proteins in the urine (called Bence-Jones proteins).
     
  • >5% cancer cells on a bone marrow tap or >10-20% plasma cells (the cells that produce antibodies) on a bone marrow tap.

Clearly the same tests as noted above will pick up most of the signs of myeloma as well as lymphoma.

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.

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. The pill requires some tricks to get it to absorb acceptably, including an 18 hour fast before it is given and a 4 hour fast after it is given.

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 a very important downside here, however. Lymphoma remains the most common cause of hypercalcemia by far. Lymphoma cells are killed by prednisone 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 prednisone 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 prednisone 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, prednisone 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.

Page last updated: 10/8/2014