What is Resistant Hypercalcemia?
Hypercalcemia is a condition where the amount of calcium in your blood is higher than normal. This typically means serum calcium– the amount of calcium in your blood– is over 10.5 mg/dl, or ionized calcium– the tested amount of calcium in the blood– is over 5.3 mg/dl. Normal serum calcium levels are usually between 9.0 and 10.5 mg/dl, but these levels can vary depending on the lab that tests the blood. About 45% of the calcium in your blood is free or ionized, almost half is tied up with a protein called albumin, and about 10% is partially bonded with small particles like phosphate and citrate.
Dehydration or the process of having a high concentration of blood cells, which can occur during blood drawing, could falsely increase total serum albumin levels and hence lead to falsely elevated total serum calcium levels. However, ionized calcium levels may still be normal. Changes in blood pressure can also alter the binding of calcium with albumin. For instance, alkalosis, a condition where your body fluids have too much base (alkali), can strengthen the calcium–albumin binding, while acidosis, a condition where there’s too much acid in your body fluids, can weaken the binding. Conditions that cause low serum albumin levels, such as malnutrition or liver cirrhosis, can lead to falsely low reported calcium levels. Therefore, it’s important to adjust calcium levels to account for abnormal serum albumin levels before hypercalcemia can be diagnosed.
There are different levels of hypercalcemia:
1. Mild hypercalcemia: serum calcium ranging between 10.5 and 11.9 mg/dl.
2. Moderate hypercalcemia: serum calcium level ranging between 12 mg/dl and 13.9 mg/dl.
3. Hypercalcemic crisis: serum calcium level above 14 mg/dl.
Resistant hypercalcemia refers to a situation where calcium levels remain high despite multiple treatment methods, or if treatment needs to be re-applied within two weeks of the initial treatment.
What Causes Resistant Hypercalcemia?
High levels of calcium in the blood, or hypercalcemia, can be caused by different things. These include endocrine disorders, different types of cancer, inflammatory diseases, some medications, and a lack of physical movement. There are also specific types of hypercalcemia that don’t respond to initial treatment, which can be caused by having an overactive parathyroid gland as well as certain types of cancer.
Hypercalcemia can be split into two types, both linked to different endocrine (hormonal) disorders.
The first type is due to endocrine disorders that overproduce parathyroid hormones (which control the calcium level in our bodies). This could include:
* Disorders that affect the parathyroid glands, which could be sporadic (meaning they happen randomly), happening within a family, or associated with tumors.
* Familial hypocalciuric hypercalcemia, a genetic disorder that can cause high levels of calcium in the blood.
* Tertiary hyperparathyroidism, which happens as a result of long-term kidney disease or high calcium levels linked to the treatment of other conditions.
The second type of hypercalcemia isn’t related to an overproduction of parathyroid hormones. Instead, it can be caused by other conditions such as:
* Underactive thyroid (hypothyroidism)
* A tumor of the adrenal glands (pheochromocytoma)
* Underactive adrenal glands (hypoadrenalism)
* A tumor producing too much vasoactive intestinal peptide (VIPoma)
* Jansen metaphyseal chondrodysplasia, a rare genetic bone disorder.
On the other hand, cancer-related hypercalcemia accounts for 90% of cases in hospital. It could be linked to a high or normal level of parathyroid hormones. Solid cancers like breast, lung, kidney, lymphoma, and some forms of leukemia could cause an elevated parathyroid hormone level. Lung, ovarian, and thyroid cancers are associated with normal parathyroid hormone levels.
Various medications can cause hypercalcemia, for example, lithium, aminophylline/theophylline, tamoxifen, vitamins A and D, certain diuretics, and acid reducers.
In addition, some infectious or autoimmune conditions can trigger hypercalcemia as a side effect of inducing vitamin D production outside the kidneys. These could include conditions like sarcoidosis, Wegener’s granulomatosis, histoplasmosis, tuberculosis, cytomegalovirus infections, and HIV.
Hypercalcemia in children can be due to idiopathic infantile hypercalcemia or Williams syndrome, which are specific pediatric disorders. People with restricted mobility, due to conditions like a spinal injury, can also develop hypercalcemia. This happens because their bones start to break down faster, releasing more calcium into the blood.
Risk Factors and Frequency for Resistant Hypercalcemia
Hypercalcemia is a disease that is fairly common, particularly in older women, affecting about 3% of those over 60. The main causes of hypercalcemia are malignancy-related and hyperparathyroidism, accounting for around 90% of all cases.
- Malignancy-related hypercalcemia is predominantly found in patients who are hospitalized.
- Hyperparathyroidism-related hypercalcemia primarily occurs in an outpatient setting.
- Among the different types of malignancy-related hypercalcemia, Humoral Hypercalcemia of Malignancy is the most common, making up about 80% of these cases.
Signs and Symptoms of Resistant Hypercalcemia
Hypercalcemia is a medical condition where there is too much calcium in your blood. It is important to pay attention to the signs and symptoms associated with hypercalcemia, as well as any underlying conditions that might be causing it. A simple way to remember these symptoms is with the following mnemonic:
- Bone pain, including unexpected fractures
- Groans, representing symptoms like nausea and vomiting
- Stones, often referring to kidney stones
- Moans, standing for general feelings of unease and fatigue
- Psychiatric overtones, like confusion and depression
Hypercalcemia can affect body functions in various ways, depending on how severe it is and how long it has been present. These effects can include:
- Renal (kidney) issues: Increased urination and thirst, dehydration, kidney stones, calcification in the kidneys, and kidney failure
- Gastrointestinal (stomach and intestines) issues: Loss of appetite, abdominal pain, nausea, vomiting, indigestion, peptic ulcers, constipation, and inflammation of the pancreas
- Neuromuscular (nervous and muscle) issues: Depression, lethargy, cognitive dysfunction (trouble thinking clearly), coma, and fatigue
- Cardiac (heart) issues: Shortening of the QT interval (a measure of time in the heart’s electrical cycle), Heart blockages, slow heart rhythms, and high blood pressure
Testing for Resistant Hypercalcemia
The first step in diagnosing high blood calcium levels, or hypercalcemia, is to verify these levels by repeating the tests. What’s important is balancing the total serum calcium with albumin levels. Albumin is a protein, and certain conditions that lead to low protein, like kidney syndrome, malnutrition, and certain bowel diseases, can lead to low albumin, which means total blood serum levels are lower too. It’s also important to distinguish between actual hypercalcemia and pseudo hypercalcemia by checking the levels of ionized calcium and the levels of corrected calcium. In more severe cases of hypercalcemia, it may be necessary to start giving intravenous fluids while waiting for the repeated calcium levels to be confirmed.
Usually, most cases of hypercalcemia are due to overworking parathyroid glands or cancer. Small rises in calcium levels persisting for months or years are usually not due to cancer. However, if the hypercalcemia comes on rapidly and the levels are very high, cancer could be the cause. In such cases, doctors will screen for possible cancers like kidney, lung, and breast cancers, lymphoma, leukemia, and a blood cell cancer called multiple myeloma.
After it is confirmed that you have hypercalcemia, doctors will then differentiate between hypercalcemia that is parathyroid hormone (PTH) dependent and non-PHT dependent. This can be done by measuring both PTH and PTHrP levels. Low or normal levels of PTH in the presence of hypercalcemia may indicate cancer. Cases where PTH levels are mid-to-high normal or high, with concurrent hypercalcemia, typically suggest overactive parathyroid glands. Interestingly, some cancers can produce their own PTH. If PTHrP levels are found to be low, doctors may check for vitamin D-mediated hypercalcemia by measuring 1,25 dihydroxy- vitamin D levels. If both PTHrP levels and vitamin D levels are low, then the cause of the hypercalcemia should be sought elsewhere. Tests for other diseases, like multiple myeloma, an overactive thyroid, vitamin A toxicity, or bone cancer, might then be considered.
Doctors will also review your medications and possibly stop any suspected to raise calcium levels. If you are a newborn or an infant with unusual physical features and diagnosed with hypercalcemia, tests for Williams or Murk Jansen syndrome may be carried out quickly.
Often, hypercalcemia affects the heart’s electrical activity, causing changes in the EKG readings. In these cases, doctors might order imaging examinations to check for possible cancerous growths. In resistant hypercalcemia cases, especially when other tests haven’t clarified the cause, doctors might explore the neck surgically.
Treatment Options for Resistant Hypercalcemia
Hypercalcemia of malignancy refers to high calcium levels in the blood linked to cancer, which is usually an urgent situation demanding immediate medical attention. In cases where the hypercalcemia is not severe (less than 12 mg/dL), doctors generally focus on treating the underlying condition causing the high calcium levels. However, if the calcium levels are high or resistant to normal treatments, more aggressive solutions are needed.
Staying well-hydrated and restoring fluids are crucial for every patient dealing with severe hypercalcemia. Fluid restoration helps improve the excretion of calcium in urine and reduces the reabsorption of sodium and calcium. After receiving enough fluids, patients may be given a diuretic medication that prompts the elimination of calcium in the kidneys. It is important to continuously monitor the patient’s fluid intake and output during this process.
Certain medications, known as antiresorptive agents, help manage resistant hypercalcemia by preventing the action of cells that break down bone, thus limiting the release of calcium. Some commonly used antiresorptive agents include bisphosphonates. Another medication, calcitonin, works quickly and safely to inhibit bone resorption and increase calcium elimination. It may be used along with bisphosphonates in cases of severe hypercalcemia. Denosumab, a type of antibody, is also effective in controlling hypercalcemia that does not respond to bisphosphonates.
Gallium nitrate is another medication used to manage high levels of calcium by reducing bone reshaping and therefore, calcium levels. However, it should not be used in patients with kidney failure as it could worsen their condition. In cases of hypercalcemia resistant to usual treatments, Hydrocortisone may also be used. Freshening up fluids and monitoring electrolytes are crucial during this treatment.
In critical cases where calcium levels are dangerously high and don’t respond to other treatments, or in patients with kidney disease, hemodialysis may be required. This process involves a machine cleaning a patient’s blood to remove excess calcium and other waste products. Furthermore, under emergencies, drugs like cinacalcet can be given as it acts on the calcium-sensing receptors, leading to a decrease in the secretion of a hormone that increases calcium levels.
In cases of hypercalcemia that don’t respond to medical treatments, an emergency surgery to remove the parathyroid glands (parathyroidectomy) might be necessary. A similar surgery could also be an elective procedure for benign tumors of the parathyroid gland. Criteria for surgery in primary hyperparathyroidism generally includes high levels of calcium in the blood, bone and renal issues, and age less than 50 years.
What else can Resistant Hypercalcemia be?
If you’re showing symptoms similar to those of hypercalcemia, it could be due to other medical conditions. These might include:
- Azotemia: a condition with high levels of nitrogen waste products in the blood
- Hypernatremia: a condition characterized by high sodium levels in the blood
- Hypermagnesemia: a condition marked by high magnesium levels in the blood
- Hyperphosphatemia: a condition where there is an excessive amount of phosphate in the blood
- Hyperkalemia: a condition of elevated levels of potassium in your blood
- Hyperparathyroidism: a condition where the parathyroid glands, which regulates calcium in your body, are overactive.
What to expect with Resistant Hypercalcemia
The outcome of hypercalcemia, or having high calcium levels in the blood, largely depends on what is causing it. If hypercalcemia is due to a non-threatening health issue, the outlook is often good. For example, hypercalcemia caused by an overactive parathyroid gland (hyperparathyroidism) is generally less severe and may persist for an extended period.
Instances of mild hypercalcemia are infrequently fatal if managed correctly. However, hypercalcemia linked to cancer is more serious, as it usually shows up in the advanced stages of the disease. This situation unfortunately often involves multiple visits to the emergency room and frequent hospital stays.
Hypercalcemia can be fatal in patients where a type of protein called PTHrP is produced outside of the parathyroid glands (ectopic PTHrP production). These patients usually live only a few weeks or months. Also, when cancer spreads to the bones causing them to break down (osteolytic metastases), it can become deadly due to nerve compression and other complications related to the bone structure.
Possible Complications When Diagnosed with Resistant Hypercalcemia
: Hypercalcemia, or an excessive amount of calcium in your blood, can cause problems due to the condition and its treatment. Seriously high levels of calcium are a medical emergency that needs quick attention to prevent dangerous outcomes, including deep dehydration, heart problems, and effects on the nervous system.
Not dealing with hypercalcemia can cause changes to your heart rhythm. Your electrocardiogram (test that checks how your heart is functioning) may show flattened T-waves, small extensions of the QRS and PR intervals, and presence of Q-wave.
Continuously high levels of calcium in the blood may form crystals and eventually turn into calcium stones in the kidneys. Hypercalcemia can affect the way kidneys self-regulate, cause a condition called diabetes insipidus, and lead to increased serum osmolality and other metabolic disruptions, leading to prerenal kidney injury with reduced capability of the glomerulus (part of the kidney) to filter and the kidney’s ability to get rid of waste.
Hypercalcemia can cause osteoporosis, a disease where bones become weak, due to the resorption (or absorption into the bloodstream) of calcium from the bone. Persistent osteoclast activity (cells that break down bone) can lead to thinner bones, and problems such as fractures and loss of height. Extremely high levels of calcium can cause conditions ranging from delirium and confusion to dementia and coma, which can be fatal in severe cases.
Complications of Hypercalcemia:
- Heart problems, including abnormal rhythms
- Deep dehydration
- Nervous system issues
- Kidney stones due to precipitation of calcium
- Kidney injury resulting in reduced functioning
- Osteoporosis due to bone resorption
- Thinning of bones and its complications like fractures and height loss
- Mental health problems including delirium, confusion, dementia, and coma
- Potential fatality in extreme cases
Preventing Resistant Hypercalcemia
It’s very important for patients to understand the cause of their disease, especially if their high calcium levels are related to cancer. Frequently, a team of specialists in cancer care, kidney health, and hormone disorders need to work together to provide the best possible treatment. It’s also important for patients to know that severe high calcium levels can be life-threatening.
Patients should also be informed about all the possible treatment options. These might include blood cleansing through a process known as hemodialysis, or surgery to remove the parathyroid glands (parathyroidectomy). Those options are particularly important to discuss if the high calcium levels continue despite treatment.
