A. KESH HEBBAR, MD, Assistant Professor, Department of Family Medicine, Medical University of South Carolina, Charleston.
MARIA V. GIBSON, MD, PhD, Medical Director, University Family Medicine, Charleston, SC; and Assistant Professor, Department of Family Medicine, Medical
University of South Carolina, Charleston.
Table 1 What causes hypercalcemia?
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An elevated calcium level is often an incidental laboratory finding, or it may be detected in the laboratory workup for complaints
of fatigue, abdominal or bone pain, nausea, constipation, polydipsia, polyuria, or altered mentation. Serial elevated calcium
levels in an otherwise healthy and asymptomatic adult are usually caused by primary hyperparathyroidism (PHP), although certain
endocrine disorders and drugs can also elevate the calcium level. Together, hyperparathyroidism and malignancy account for
80% to 90% of cases of hypercalcemia (see Table 1).1,2 An initial finding of an elevated calcium level is often followed by a normal level and must be confirmed with a repeat elevated
level. Because tumors associated with hypercalcemia of malignancy are usually clinically obvious, a thorough physical examination
should be performed to rule out clinical clues to malignancy.3
Sorting through the causes of excess calcium
Commonly used drugs that can induce hypercalcemia are thiazide diuretics, which reduce urinary calcium excretion; lithium,
which enhances parathyroid hormone (PTH) secretion; and calcium supplements containing antacids and vitamins A and D.4 Endocrine disorders associated with elevated calcium levels include thyrotoxicosis, Addison's disease, and pheochromocytoma.
Patients who have familial hypocalciuric hypercalcemia (FHH) have mild or moderate hypercalcemia from a young age and usually
remain asymptomatic. In this condition urine calcium is low, and the urinary calcium-creatinine clearance ratio is less than
0.01. This ratio is usually greater than 0.02 in PHP.5 Serum PTH values are normal in 85% of patients with FHH. Serum calcium, bone density, and PTH measurements usually do not
change over decades, and patients should be counseled regarding the benign nature of the disease. Multiple endocrine neoplasia
type 1 and type 2A are associated with hyperparathyroidism and combinations of other tumors.6
Table 2 Diagnostic tools for evaluating hypercalcemia
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A confirmed repeat finding of an elevated calcium level is followed with an evaluation to determine the patient's history
of endocrinopathies such as hyperthyroidism, Addison's disease, pheochromocytoma, nephrogenic diabetes insipidus, and other
problems such as arthritis, renal insufficiency, nephrolithiasis, osteoporosis, pancreatitis, and peptic ulcer disease (see
Table 2). Calcium levels greater than 13 mg/dL are unusual in PHP, while significant elevations are found in malignancy. A
family history of endocrine disease may be a clue to the rare multiple endocrine neoplasias.
Table 3 Causes of elevated PTH levels
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An elevated serum PTH concentration usually indicates PHP but may also be caused by the entities listed in Table 3. Increasing
use of assay testing has revealed a new clinical form of the disease—normocalcemic PHP—in which patients who have an elevated
PTH level also have normal serum calcium levels.7,8 This condition may be an early stage of PHP.
Serum phosphate levels are low in hyperparathyroidism. Curiously, the phosphate level is low in nonmetastatic hypercalcemia
of malignancy in which hypercalcemia is due to parathyroid hormone-related protein (PTHrP). In comparison, the serum phosphate
level is normal or elevated in metastatic bone disease, granulomatous disease, thyrotoxicosis, and vitamin D intoxication.
Serum creatinine and creatinine clearance measurements are recommended at baseline and for monitoring hypercalcemia in hyperparathyroidism.
Urinary calcium excretion is the high end of normal or greater in PHP. Although urinary calcium varies depending on age, race,
gender and other factors, a 24-hour level of 4 mg/kg body weight or greater is well above the upper limit of normal.9 Twenty-four-hour urinary calcium levels greater than 400 mg are an indication for parathyroid surgery because of the increased
risk for renal calculi. Indications for surgery for patients with hyperparathyroidism are
- Age less than 50 years
- Serum calcium level 1 mg above upper limit of normal
- 24-hour urinary calcium levels greater than 400 mg
- Reduction in creatinine clearance greater than 30%
- Bone mineral density T score of less than 2.5 at any site
- Nephrolithiasis.
Bone mineral density should be measured at the spine, hip, and distal third of the forearm. PHP typically causes an increased
reduction in bone density in the forearm and preserves the lumbar spine. Intermediate bone loss is seen in the hip. This preferential
bone loss is typical of hyperparathyroidism, unlike that seen in cancer.10
Other tests for hypercalcemia are indicated only if there is a clinical suspicion of cancer or if the PTH value is low in
the presence of hypercalcemia. Testing for PTHrP secreted by cancer cells is usually not needed because the tumors associated
with humeral hypercalcemia of malignancy are usually clinically obvious.3 A CBC, ESR, thyrotropin level, serum protein electrophoresis, plasma 1,25-dihydroxy-vitamin D level, and dual-energy x-ray
absorptiometry (DEXA) scan can be obtained if the diagnosis of PHP is not obvious.
Case report: Primary hyperparathyroidism
A 47-year-old woman presents for a routine physical examination. Her only complaints are fatigue and hot flushes; the medical
history is unremarkable, and she uses no medications. The family history is significant for hypertension and diabetes.
Table 4 A spectrum of clues to hyperparathyroidism
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Laboratory tests show the following values: serum sodium, 137 mEq/L; potassium, 3.5 mEq/L; chloride, 105 mEq/L; bicarbonate,
22 mEq/L; serum urea nitrogen, 8 mg/dL; and creatinine, 0.9 mg/dL. The total serum calcium level is 10.9 mg /dL; the phosphorus
is 3.5 mg /dL; and the albumin is 4 g/dL. (The reference ranges for serum calcium and phosphorus are 8.5-10.2 mg/dL and 2.4-4.1
mg/dL, respectively.)
Clinical questions
How should this patient be followed, and what are the indications for parathyroidectomy?
Although patients with PHP typically have no or nonspecific symptoms, those of fatigue, nausea, constipation, polydipsia,
polyuria, and bone pain are more common when total serum calcium levels are greater than 12 mg/dL. Eighty percent of cases
of PHP are caused by a solitary adenoma, and 10% to 15% are caused by diffuse hyperplasia.10 The clinical spectrum of hyperparathyroidism is summarized in Table 4.
Discussion
The definition of asymptomatic hyperparathyroidism remains controversial, but the condition is usually diagnosed in patients
with asymptomatic hypercalcemia no greater than 1 mg/dL above the upper limit of normal and with 24-hour urinary calcium levels
in the reference range. Serum phosphate and chloride levels are usually normal, but PTH is usually less than twice the upper
limit of normal. DEXA scan reveals no osteopenia in the hip and spine.
Mild asymptomatic hyperparathyroidism usually does not progress—no changes in average serum calcium and PTH levels occur over
20 years, and bone density and urinary calcium levels typically remain stable. Although younger patients appear to have a
higher risk for disease progression, no biochemical or bone densitometric indices can predict progression.11,12 Patient monitoring follows National Institutes of Health guidelines of serum calcium screening every 6 months and annual
serum creatinine measurement and DEXA scans. Twenty-four-hour measurements of urinary calcium and creatinine clearance are
not recommended.13 Parathyroidectomy remains the only cure for PHP.
Case resolution
Because the patient had 2 indications for surgery—age younger than 50 and 24-hour urinary calcium level greater than
400 mg/dL—parathyroidectomy was recommended. The patient's serum calcium, 24-hour urinary calcium, and serum PTH levels have
been normal in the 4 years since parathyroidectomy.
Case report: Hypercalcemia associated with cancer
A 53-year-old man with colon cancer presents in the emergency department with confusion and frequent falls. He is dehydrated,
has orthostatic hypotension, drowsiness, and no focal neurologic signs. The total serum calcium is 15 mg/dL; serum phosphorus,
5 mg/dL; serum urea nitrogen, 100 mg/dL; and creatinine, 2.4 mg/dL. The albumin level is 3 mg/dL.
Clinical questions
Given this patient's cancer, what does the elevated calcium level suggest, and how should treatment proceed? How should
hypercalcemia of malignancy be managed?
Hypercalcemia has been reported to occur in as many as 30% of cancer patients and portends a very poor prognosis: mortality
is approximately 50% within 30 days of the finding.3,4 Osteolytic metastatic disease and PTHrP are the 2 main causes of hypercalcemia of malignancy. (Lymphomas secrete vitamin
D, a rare mechanism of hypercalcemia.) The major goals of treatment are to increase urinary secretion of calcium, inhibit
the bone resorption, and reduce intestinal absorption.
Treatment to reduce the serum calcium level should be attempted if there is any neurologic or renal impairment or other symptoms
such as altered mentation or obtundation; levels greater than 13 mg/dL require urgent treatment, and levels 11.5 to 12.9 mg/dL
accompanied by symptoms also warrant initiation of treatment. In elderly hypercalcemic cancer patients, subtle neurologic
changes can occur even at levels below 11.5 mg/dL. Supportive therapy includes removal of calcium from the diet, discontinuing
calcium-containing medications, and encouraging physical activity. Severe hypophosphatemia (3 mg/dL or less) should be treated
with oral phosphorus (K-Phos Neutral Tablets, Uro-KP-Neutral Tablets).14
To promote renal excretion of calcium in cachectic and severely dehydrated patients, normal saline, 250 to 500 mL/h, should
be initiated and then replaced by loop diuretics such as furosemide (Lasix), 20 to 40 mg IV, after adequate hydration is achieved.15 Bisphosphonates IV are the most effective agents for blocking osteoclastic bone resorption and should be initiated as soon
as possible. (Bisphosphonates have largely replaced plicamycin [Mithracin], calcitonin, and gallium (Ganite) infusion in treating
hypercalcemia.) Calcium levels may normalize in 4 to 7 days and remain so for 3 weeks. Two IV bisphosphonates, zoledronic
acid (Zometa) and pamidronate (Aredia), are approved for use in hypercalcemia associated with cancer. Infusion with zoledronic
acid, 4 mg, is more rapid—15 minutes—while infusion with pamidronate, 60 to 90 mg, takes 2 hours. Oral or IV glucocorticoids
can be useful in managing hypercalcemia associated with lymphoma.
Clinical outcome
After 12 hours of treatment with parenteral fluids, furosemide, and zoledronic acid, the patient's mental status improved
and his serum calcium level dropped to 12 mg/dL. Despite intensive treatment of hypercalcemia, however, the patient died on
day 5 of the admission from the complications of metastatic colon cancer.
This article was contributed by Drs Hebbar and Gibson and edited by Julia M. Russell.
Drs Hebbar and Gibson disclose that they have no financial relationship with any manufacturer in this area of medicine.
REFERENCES
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3. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664.
4. Ralston SH, Gallagher SJ, Patel U, et al. Cancer-associated hypercalcemia: morbidity and mortality: clinical experience
in 126 treated patients. Ann Intern Med. 1990;112:499-504.
5. Fuleihan Gel-H. Familial benign hypocalciuric hypercalcemia. J Bone Miner Res. 2002;17(suppl 2):N51-N56.
6. Marx SJ, Spiegel AM, Skarulis MC, et al. Multiple endocrine neoplasia type 1; clinical and genetic topics. Ann Intern Med. 1998;129:484-494.
7. Silverberg SJ, Bilezikian JP. Evaluation and management of primary hyperparathyroidism. J Clin Endocrinol Metab. 1996;81:2036-2040.
8. Silverberg SJ, Bilezikian JP. "Incipient" primary hyperparathyroidism: a "forme fruste" of an old disease. J Clin Endocrinol Metab. 2003;88:5348-5352.
9. Lendel I, Horwith M. An update from the latest workshop on asymptomatic primary hyperparathyroidism. Otolaryngol Clin North Am. 2004;37:737-749.
10. Silverberg SJ, Bilezikian JP. Asymptomatic primary hyperparathyroidism: a medical perspective. Surg Clin North Am. 2004;84:787-801.
11. Silverberg SJ, Shane E, Jacobs T, et al. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid
surgery. N Engl J Med. 1999;341:1249-1255.
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a perspective for the 21st century. J Bone Miner Res. 2002;17(suppl 2):N2-N11.
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The science of calcium
Calcium is essential for homeostasis and is a highly regulated cation. A delicate interplay exists among parathyroid hormone
(PTH), vitamin D, and calcitonin. PTH promotes osteoclastic bone resorption, reduces renal clearance of calcium, and increases
the efficiency of calcium absorption in the intestine by activation of vitamin D. PTH production is closely regulated by the
parathyroid-sensing calcium receptor, which in turn is sensitive to levels of ionized calcium. Final hydroxylation of vitamin
D (1,25-dihydroxy-vitamin D) is facilitated by PTH and occurs in the proximal tubule of the kidney. Vitamin D increases calcium
and phosphate absorption in the small intestine. Calcitonin is a hypocalcemic peptide and inhibits osteoclast-mediated bone
resorption.
The total plasma calcium concentration consists of 3 fractions. Forty percent of plasma calcium is bound to albumin and 15%
to organic and inorganic anions such as sulfate, phosphate, and citrate. Approximately 45% of total plasma calcium is physiologically
active or ionized (free) calcium.
The ionized calcium concentration is tightly regulated by PTH and vitamin D. Measurement of total plasma calcium alone can
be misleading in conditions in which significant alterations in plasma proteins occur. In patients with hypoalbuminemia due
to renal or hepatic disease, for example, the total calcium level is low and the ionized calcium level is within the reference
range. In general, calcium concentration falls by 0.8 mg/dL for every 1 g/dL drop in the plasma albumin concentration.
Drugs mentioned in this article
Calcitonin
Furosemide (Lasix)
Gallium nitrate (Ganite)
Lithium
Pamidronate (Aredia)
Phosphorus (K-Phos Neutral Tablets, Uro-KP-Neutral Tablets)
Plicamycin (Mithracin)
Zoledronic acid (Zometa)
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