Diagnosing a disorder with few symptoms

Hypercalcemia can have absent, few or nondifferential symptoms, but the condition can indicate the presence of major diseases such as breast cancer. Experts review how to quickly apply a high index of suspicion to make a diagnosis.

Internists are often the first physicians to diagnose outpatient cases of hypercalcemia, a condition that may have few or no symptoms in the primary care setting if mild. When more advanced, it can be accompanied by a wide-ranging list of complaints and, when severe, it can be the first sign of cancer.

“I had a patient who presented with calcium of 20. She had not known that she had breast cancer until she had that calcium level,” said Susan B. LeGrand, MD, FACP, an oncologist and palliative medicine specialist at the Cleveland Clinic. “Some patients don't experience the symptoms of severe hypercalcemia if the increase occurs slowly, but a quick increase in calcium is more likely to cause symptoms.”

Susan B LeGrand MD FACP seated and Rafael Espinal Bloise MD ACP Associate Member collaborate on patient care at the Cleveland Clinic Incidental findings are sometimes the first signs of hype
Susan B. LeGrand, MD, FACP, (seated) and Rafael Espinal Bloise, MD, ACP Associate Member, collaborate on patient care at the Cleveland Clinic. Incidental findings are sometimes the first signs of hypercalcemia, Dr. LeGrand says. Photo courtesy of Cleveland Clinic Center for Medical Art and Photography

Because symptoms may be absent or nonspecific in many patients, an incidental finding of elevated serum calcium on a periodic multichannel blood test may be the first sign of hypercalcemia. Management of the condition requires understanding the differences between hyperparathyroidism and other causes of hypercalcemia, knowing which patients should be referred to an endocrinologist or surgeon, and understanding how to manage patients in the primary care setting.

Parathyroid hormone (PTH)-dependent hypercalcemia occurs in about 1% to 4% of the general population. It can be diagnosed in men and women of any age but is far more common in postmenopausal women, according to the National Library of Medicine. Patients will have elevated serum calcium (higher than about 10.5 mg/dL), and a subsequent PTH measurement will also be elevated (above 20 pg/mL).

According to a May 2003 article in American Family Physician, primary hyperparathyroidism is the most common cause of hypercalcemia, and about one in every 500 patients treated by primary care physicians has undiagnosed primary hyperparathyroidism.

PTH-independent hypercalcemia is diagnosed when the serum calcium is elevated and the PTH is low or suppressed. This type of hypercalcemia can indicate a malignancy and is a secondary effect of cancer or of a paraneoplastic syndrome that develops in 10% to 20% of patients with certain types of cancer.

PTH-independent hypercalcemia is most often associated with breast, lung, and renal cancers; myeloma; and squamous cell cancer of any site, according to a November 2011 article in the American Journal of Hospice and Palliative Care.

In addition to elevated PTH and malignancy, several other factors may cause hypercalcemia:

  • vitamin D-related causes, such as vitamin D intoxication (more cases may be identified because of increasing use of high-dose vitamin D supplements), granulomatous disease sarcoidosis, tuberculosis, and Hodgkin's lymphoma;
  • medications, such as thiazide diuretics, lithium, and calcium antacids;
  • endocrine disorders, such as adrenal insufficiency, acromegaly, and pheochromocytoma;
  • inactivity, such as being bedbound for long periods; and
  • genetic disorders, such as familial hypocalciuric hypercalcemia.

Index of suspicion

Diagnosing hypercalcemia requires a high index of suspicion, particularly since the symptoms can be nonspecific or subtle. Recognition of the condition often occurs with an incidental finding of elevated calcium on a blood test, said Michael Whitaker, MD, chair of the division of endocrinology at the Mayo Clinic in Scottsdale, Ariz.

When an abnormal calcium level is detected, Dr. Whitaker and other experts recommend calculating a corrected calcium level by using the values for both calcium and albumin. A high albumin level, above 4, can artificially elevate the measured calcium; a low albumin level, below 4, can artificially lower the measure of calcium. Without correcting for albumin, hypercalcemia may be misdiagnosed or not diagnosed at all.

For every gram of albumin above or below 4, the serum calcium is corrected, down or up, respectively, by 0.8 mg/dL.

For example, if the albumin level is 5, the measured calcium should be reduced by 0.8 mg/dL to arrive at the corrected level. If the albumin level is 3, the measured calcium should be increased by 0.8 mg/dL. A corrected level between 10.5 mg/dL and 12 mg/dL indicates mild hypercalcemia, and generally there are no symptoms.

Michael Kleerekoper, MD, FACP, a clinical professor of internal medicine at Wayne State University in Detroit, recommends repeating the blood test in two to three months if the serum calcium is 0.1 mg/dL above the normal range. No correction for albumin is needed for this very mild elevation, he said.

“Sometimes doctors see a calcium level of 10.1 and then start looking for parathyroid disease, whereas if the level was 9.9 they would ignore it even though that is about the same as 10.1,” said Dr. Kleerekoper, who is also a coauthor of the American College of Physicians' PIER module on hypercalcemia. “Instead, they should watch it over a period of time and repeat the test. A level of 10.1 is very mild. Just because the level is outside the reference range, you don't need to go track down really small changes in serum calcium.”

Dr. Whitaker suggests several tips related to diagnosis of hypercalcemia:

  • Take the patient off lithium and/or thiazide diuretics at least two to three weeks before a blood or urine test;
  • Bring a low 25-hydroxyvitamin D level back up to normal before evaluating calcium; a low vitamin D level can mask hypercalcemia by lowering the calcium level;
  • Evaluate for hypercalcemia if a patient presents with a kidney stone; and
  • Take a complete history and do a physical exam to determine the etiology of hypercalcemia.

According to Dr. Whitaker, a 24-hour urine calcium test should be ordered for patients who have PTH-dependent hypercalcemia. A bone density test may also be considered in some. The most common cause is primary hyperparathyroidism, but other conditions such as lithium-induced hypercalcemia or familial hypocalciuric hypercalcemia (FHH) need to be considered in the differential diagnosis, He said.

“All patients with high calcium and high PTH should have their urine calcium measured,” he said. A measurement less than 100 mg/d on the urine calcium test suggests FHH, which does not require any treatment.

“You don't want to send people with FHH to surgery. FHH is benign and carries no consequences. Instead we will screen other family members and make sure their calcium is elevated. They just need to be made aware of it, but nothing needs to be done for it,” he said.

An elevated 24-hour urine calcium level can indicate hyperparathyroidism, which should prompt a referral to a surgeon or an endocrinologist. Most cases of primary hyperparathyroidism are caused by a single parathyroid adenoma. More uncommonly, two or more glands may be abnormal.

Surgical resolution

The best treatment may be a parathyroidectomy. The surgery can often cure the disease in most patients and can improve bone mineral density, according to Dr. Whitaker. The 1990 National Institutes of Health Consensus Development Conference statement on diagnosis and management of asymptomatic primary hyperparathyroidism lists the guidelines for surgery, and a few modifications were made in 2002. These updated recommendations include the following:

  • serum calcium level 1 mg/dL over the upper limits of normal,
  • creatinine clearance < 60 mL/min,
  • T score less than -2.5 at any site, and/or prior fragility fracture and
  • age younger than 50.

Some patients with primary hyperparathyroidism, however, have a benign course and do not need surgery. “The decision to operate depends on the severity of the disease and the overall health of the patient,” Dr. Kleerekoper said. The surgeon, rather than the internist, should order a sestamibi scan to evaluate the location of the enlarged parathyroid, he advised.

Patients with hypercalcemia should also be referred to an endocrinologist if the corrected serum calcium level indicates hypercalcemia but the PTH level is normal, if the etiology remains unclear, or if further diagnostic help is needed, he noted.

Patients with primary hyperparathyroidism who do not meet the guidelines for surgery will need to be monitored closely. Drug therapy for patients with chronic hypercalcemia will depend on the cause of the condition. The NIH's 2002 statement and Dr. Whitaker recommend several tips for management of patients who do not undergo surgery:

  • Drink plenty of water and avoid inactivity or prolonged immobilization;
  • Restrict calcium in diet to 1,000-1,200 mg daily;
  • Use loop or thiazide diuretics with caution;
  • Monitor bone density at three sites and serum creatinine yearly; and
  • Obtain corrected serum calcium level twice yearly.

Moderate to severe hypercalcemia

Moderate hypercalcemia may be diagnosed when the total serum calcium is between 12 mg/dL and 14 mg/dL; levels higher than 14 mg/dL can be life-threatening and generally indicate the presence of a malignancy. Patients with total calcium above 12 mg/dL may present with a constellation of symptoms that are commonly remembered as “stones, bones, abdominal moans, and psychic groans,” according to the May 2003 American Family Physician article:

  • renal “stones,” including polydipsia, polyuria, nephrolithiasis, and dehydration;
  • skeleton “bones,” including bone pain, arthritis, and osteoporosis, particularly of cortical bone, such as the wrist;
  • gastrointestinal “abdominal moans,” including nausea, vomiting, weight loss, constipation, and abdominal pain; and
  • neuromuscular “psychic groans,” which can present as impaired concentration, confusion, coma, lethargy, fatigue, and muscle weakness.

Other symptoms, such as hypertension, vascular calcification, itching, conjunctivitis, or keratitis, may also be present.

Implications in cancer

Hypercalcemia is much more common in patients with cancer than in the general population, according to Dr. LeGrand. Even though patients with cancer will most likely be treated by an oncologist, a primary care physician may first identify the malignancy through elevated calcium.

Myeloma can initially present with hypercalcemia, and the patient may also have some back pain, Dr. LeGrand said.

“This back pain may not be ordinary back pain. A primary care physician sees so much back pain every day, so picking up back pain that is not standard ordinary pain is more difficult. However, if you see a hypercalcemic patient who also has back pain, you would start to think cancer. Also any kind of bone pain can be a warning sign of cancer,” she said.

With more advanced hypercalcemia, the patient may present with some delirium, confusion, and deteriorating kidney function due to dehydration. Most patients with those symptoms will already be under the care of an oncologist, Dr. LeGrand said. Untreated, severe hypercalcemia will lead to coma and death.

In-hospital management of this type of hypercalcemia includes replacement of fluids and bisphosphonates. These medications can yield a 70% or greater response, but the hypercalcemia will recur. For patients with this condition, survival is poor and treatment will not prolong survival, Dr. LeGrand has noted.

Dr. LeGrand also advised that a primary care physician should do additional testing to identify the cause of the condition if a patient presents with hypercalcemia and a low PTH.

“Look for a breast mass, test the serum protein, get a CT scan of the chest to look for lung cancer,” she said. “If anything is found, refer the patient to an oncologist.”