Hypercalcemia

Original Editors - Whitney Browning & Natalie Elliott from Bellarmine University's Pathophysiology of Complex Patient Problems project.

Top Contributors - Whitney Browning, Natalie Elliott, Elaine Lonnemann, Admin, Lucinda hampton, 127.0.0.1, WikiSysop and Kim Jackson  

Definition/Description

Hypercalcemia is characterized by elevated calcium levels in the blood. It may include symptoms associated with the musculoskeletal, neurological, cardiovascular, and gastrointestinal systems. Hypercalcemia is often a sign or symptom of other disease occurring within the body. Normal calcium levels range from 8.2-10.2 mg/dL. Mild hypercalcemia occurs when this level raises to 12mg/dL and severe hypercalcemia is classified as serum calcium at 14mg/dL.

Prevalence

Hypercalcemia is a common medical emergency and between 20-40% of patients suffering from cancer can develop this during the course of their disease. It is considered the most common serious electrolyte presenting in adults with malignancies. This disorder often occurs in cases of metastatic bone disease with osteolytic lesion, breast cancer and myeloma. This is related to an increase in bone resorption caused by tumor cell production of parathyroid hormone-related protein that stimulates osteoclasts. It is also associated with primary hyperparathyroidism which occurs in 25 per 100,000 individuals and 75 per 100,000 hospitalized patients. This condition is the most common cause of mild hypercalcemia and can be treated through outpatient care. More than 50,000 cases occur in the U.S. each year. 

The incidence of hyperparathyroidism is considerably higher in women, thus suggesting women are at greater risk of developing hypercalcemia. The annual incidence in women older than 65 years is 250 per 100,000, although elevations in calcium levels related to cancer have no sex predominance. Also, with an increase in age, the incidence of hyperparathyroidism rises just as the rate of malignancy and the malignancy-associated hypercalcemia increases as well.

Characteristics/Clinical Presentation

System	Signs/symptoms
Musculoskeletal	Muscle pain, tenderness, and weakness Muscle spasms Bone pain (worse at night and with weight-bearing) Pathological fracture
Central Nervous System	Drowsiness, lethargy, coma Irritability, personality changes Confusion Headaches Depression, memory loss, difficulty concentrating Visual disturbances Balance/coordination problems Changes in deep tendon reflexes (hypo/hyperreflexia) Change in muscle tone ( in individuals with pre-existing neurological condition) Positive Babinski and/or clonus reflex Changes in bowel/bladder function
Gastrointenstinal	Anorexia (loss of appetite) Nausea/vomiting Constipation Dehydration Excessive thirst
Cardiovascular	Hypertension Arrhythmia Cardiac arrest

Associated Co-morbidities

Hypercalcemia can lead to many other complications such as:

• Osteoporosis: if the bones continue to release calcium into the blood, it could lead to this disease. 
• Kidney stones: this could be caused by too much calcium accumulation in the urine, leading to crystal formation in the kidneys.
• Kidney failure: Severe hypercalcemia can lead to damage in the kidneys and possibly cause permanent loss of kidney function.
• Nervous system deficits: Severe hypercalcemia can lead to dementia and confusion.
• Arrythmias: Hypercalcemia can affect the electrical impulses of cardiac muscle, causing irregular heartbeats.
• Primary Hyperparathyroidism: This is often associated with hypercalcemia because it causes an increased release of parathyroid hormone (PTH) which raises serum calcium levels.

Medications

Medication	Treatment Effect	Side Effects
Loop Diuretics (ex; furosemide)	Flushes out excess calcium from system	Frequent urination, arrythmias, electrolyte imbalances, dizziness, muscle cramps/weakness, extreme fatigue, blurred vision, confusion, headache, dehydration, fever, sore throat, cough, skin rash, loss of appetite, nausea, vomiting
Intravenous Biphosphonates	Prevent bone breakdown, reduce bone pain, reduce the number of pathologic fractures	Heartburn, headache, constipation, diarrhea, muscle and joint pain
Calcitonin	Reduce bone reabsorption and slow bone loss	Warmth/redness of the skin, itching of the skin, nausea, loss of appetite, stomach pain, vomiting, skin rash, increased urination, eye pain, swelling in the feet, swelling or irritation at injection site (if injection was given)
Glucocorticoids	Help to counter the effect of excess Vitamin D	Elevated pressure in the eyes, fluid retention that may cause swelling in the legs, increased blood pressure, mood swings, weight gain
Hemodialysis	Remove excess waste and calcium from the bloodstream	Hypotension, muscle cramps, itching, difficulty sleeping, anemia, pericarditis, hyperkalemia, infection, depression

Diagnostic Tests/Lab Tests/Lab Values

Hypercalcemia is diagnosed by blood tests revealing increased serum calcium levels. However, other tests may need to be done in order to determine the underlying cause of hypercalcemia. These may include: 

• Chest X-Ray
• CT Scan
• MRI
• Mammogram

These tests may help determine whether you have lung cancer, breast cancer, other malignancies, or sarcoidosis (a granulomatous disease of the lungs). 

http://www.the-hospitalist.org/SpringboardWebApp/userfiles/hosp/image

Etiology/Causes

Common causes of hypercalcemia include: 

• Overactivity of parathyroid glands
• Cancer-specifically lung and breast cancer as well as multiple myeloma can increase the risk of hypercalcemia. This is considered to be due to the fact that some malignant tumors can produce a protein that acts similar to the parathyroid hormone which stimulates the release of calcium from the bones into the bloodstream. 
• Other disease effects-some people with cancer that causes them to spend increased time lying down or in bed may cause bones to release calcium into the blood due to the lack of weight-bearing.
• Medications-Lithium, a drug used to treat bipolar disorder, may increase the release of parathyroid hormone and cause hypercalcemia. Also, Thiazie diuretics can cause elevated calcium levels by decreasing the amount of calcium excreted in the urine. 
• Supplements-eating or drinking too much calcium or Vitamin D
• Dehydration-less fluid in your blood causes the calcium levels to increase

Systemic Involvement

As stated in the chart above, hypercalcemia can present with symptoms in multiple systems. Usually, the first signs and symptoms are noticed in the nervous/musculoskeletal system causing some kind of muscle pain, weakness, and/or dysfunction. However, each patient will present differently depending on the severity and organ system involved.  

The primary systems effects and the mechanisms of involvement are described below:

Neurological

• Increased calcium levels decrease neuromuscular excitability, which leads to hypotonicity in smooth and striated muscle.
• Neuromuscular symptoms include weakness and diminished deep-tendon reflexes.
• Muscle strength is impaired, and respiratory muscular capacity may be decreased.
• Central nervous system impairment may portray as delirium, personality change, cognitive dysfunction, disorientation, hallucinations and delusions.
• Has been documented to increase cerebrospinal fluid protein, which may be associated with headache

Cardiovascular

• Associated with increased myocardial contractility and irritability.
• Electrocardiographic changes are characterized by slowed conduction, including prolonged P-R interval, widened QRS complex, shortened Q-T interval, shortened or absent S-T segments.
• Incomplete or complete atrioventricular block may develop and progress to complete heart block, a systole, and/or cardiac arrest.

Gastrointestinal

• Symptoms related to the depressive action of hypercalcemia on the autonomic nervous system, resulting smooth-muscle hypotonicity.
• Increased gastric acid secretion often accompanies hypercalcemia.
• Anorexia, nausea, and vomiting are made worse by increased gastric residual volume.
• Constipation is worse due to dehydration associated with hypercalcemia.
• Abdominal pain may progress to obstipation (can be confused with acute abdominal obstruction).

Renal

• Loss of urinary concentrating ability and polyuria due to tubular defect in the kidney.
• Decreased fluid intake and polyuria lead to symptoms associated with dehydration.
• Decreased reabsorption of sodium, magnesium, and potassium occur as a result of salt and water depletion
• Renal insufficiency may occur as a result of diminished glomerular filtration.

Musculoskeletal

• Hypercalcemia of malignancy (multiple myeloma) can result from osteolytic metastases or humerally mediated bone resorption.
• Secondary fractures, skeletal deformities, and/or pain may be symptoms present.

Medical Management (current best evidence)

Mild Hypercalcemia (defined as corrected total serum calcium level lower than 12 mg/dL (<6 mEq/L or 3.0 mmol/L)

• Hydration (IV fluids) followed by observation; this option should be considered for asymptomatic patients who are about to be treated for tumors that are likely to respond to antineoplastic treatment (ex: lymphoma, breast cancer, ovarian cancer, head and neck carcinoma, and multiple myeloma).
• Additional interventions should be directed toward controlling nausea and vomiting, encouraging mobility, noting febrile episodes. 
• Minimal use of sedating medications.

Moderate to Severe Hypercalcemia (defined as corrected total serum calcium equal to 12 to 14 mg/dL (6–7 mEq/L or 3.0–3.5 mmol/L)

• Rehydration is the essential first step replenishing extracellular fluid, restoring intravascular volume, and saline diuresis
• Hypocalcemic agents 
  
• Moderate doses of furosemide (20–40 mg every 12 hours) increase saline-induced urinary calcium excretion and are useful in preventing or managing fluid overload in adequately rehydrated patients. 
• Surgery; resulting from primary hyperparathyroidism, urgent parathyroidectomey.

Prevention

Preventive measures include:

• Ensuring adequate fluid intake of 3 to 4 L (100–140 fl oz per day if not contraindicated)
• Salt intake
• Nausea and vomiting control
• Encouraging patient mobility
• Attention to febrile episodes
• Cautious use or elimination of drugs that may complicate management ( ex: drugs that inhibit urinary calcium excretion or decrease renal blood flow, contain calcium, vitamin D, vitamin A, or other retinoids)
  

Physical Therapy Management (current best evidence)

• Weightbearing exercises to prevent osteoporosis and immobility
• Prevention of fractures 
• Ensure adequate hydration
• Quality of life measures
• Strength/ROM
• Patient and Family Education

Alternative/Holistic Management (current best evidence)

• Increase fluid intake
• Substitute with sea salt in diet
• Decease consumption of dietary calcium and Vitamin D 
• Avoid pasteurized dairy products, low-fat dairy products, and processed foods high in polyunsaturated fats and low in saturated fats
• Probiotics

Differential Diagnosis

Evaluation of a patient should include: history, physical examination focusing on clinical manifestations of hypercalcemia, risk factors for malignancy, causative medications, and a family history of hypercalcemia-associated conditions to help clinically determine effectively and accurately a differential diagnosis. 

• Hyperparathyroidism
• Malignancy
• Sarcoidosis
• Lithium, Salicylate, Theophylline Toxicity
• Thyroid Toxicity
• Vitamin Toxicity
• Tuberculosis

Prognosis:

The prognosis of patients with hypercalcemia depends upon the etiology of the elevation:

• Prognosis is very poor with malignancy that has progressed into development of hypercalcemia.
• Prognosis is excellent when the underlying cause is treatable and treatment is initiated promptly.
  

Case Reports/ Case Studies

Hypercalcemia Case Study

http://www.aapsus.org/articles/6.pdf

http://annonc.oxfordjournals.org/content/11/1/97.full.pdf

Resources

National Cancer Institute

MayoClinic

WebMD

American Academy of Family Physicians