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In general, hypercalcemia is detected in 1 of 3 clinical circumstances. First, hypercalcemia may be discovered during routine laboratory work-ups in patients with no symptoms. These patients may or may not have a risk factor for hypercalcemia, such as malignancy. Most cases of hypercalcemia are diagnosed in these asymptomatic people. Second, hypercalcemia may be found during evaluation of patients with symptoms or findings that can be related to hypercalcemia, such as constipation, weakness, fatigue, depression, nephrolithiasis, or osteopenia. Third, severe hypercalcemia may present as altered mental status.
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Although most cases of hypercalcemia are due to only a handful of conditions (primary hyperparathyroidism, hypercalcemia of malignancy, chronic kidney disease (CKD), and the milk-alkali syndrome), the complete differential diagnosis is extensive. The most commonly used framework for the differential is organized by pathophysiology. What follows is a somewhat abbreviated list organized by etiology.
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Parathyroid hormone (PTH)–related
Primary hyperparathyroidism
Secondary hyperparathyroidism (with calcium supplementation)
Tertiary hyperparathyroidism
Lithium therapy (causes hypercalcemia in about 10% of patients)
Familial hypocalciuric hypercalcemia
Hypercalcemia of malignancy
Secretion of parathyroid hormone–related protein (PTHrP)
Squamous cell carcinomas
Adenocarcinoma of lung, pancreas, kidney, and others
Osteolytic metastasis
Breast cancer
Multiple myeloma
Production of calcitriol (Hodgkin disease)
Vitamin D–related
Hypervitaminosis D
Granulomatous diseases
Other relatively common causes of hypercalcemia
Milk-alkali syndrome (mainly seen in patients with CKD who are taking calcium carbonate)
Hyperthyroidism
Thiazide diuretics
Falsely elevated serum calcium (secondary to increased serum binding protein)
Hyperalbuminemia
Hypergammaglobulinemia
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Clinically, the differential diagnosis is most commonly organized by the pivotal findings of whether or not the PTH is elevated and whether the patient has a known malignancy. A useful clinical algorithm is presented in Figure 22-1.
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Before returning to the case, it is worthwhile to briefly review the basics of calcium metabolism. Calcium levels are dictated by the actions of PTH, calcitonin, and calcitriol (1,25-dihydroxyvitamin D). PTH levels rise and fall in response to serum calcium levels. High levels of PTH stimulate a rise in serum calcium by increasing both renal tubular calcium reabsorption and bone resorption. PTH also stimulates the conversion of calcidiol to calcitriol in the kidneys. Calcitriol leads to a further increase in serum calcium via increased absorption of calcium in the small intestine. Phosphate metabolism is also controlled by PTH and calcitriol; PTH generally lowers phosphate levels through its effects on the kidney, while calcitriol generally raises phosphate levels through its effects on the intestine and inhibitory effects on PTH levels. Calcitonin lowers calcium by suppressing calcium release from bones by inhibiting the function of osteoclasts.
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Mrs. D comes to your office for an initial visit. Her constipation has been long-standing and severe enough to lead to physician visits over the past 5 years. Evaluation with colonoscopy had been normal. Results of laboratory tests, drawn over the last few years by previous physicians, show normal results (including kidney function and TSH), with the exception of calcium levels in the range of 11 mg/dL. Despite use of stool softeners and high-fiber supplements, she often needs laxatives to move her bowels more than once a week.
In addition to constipation, the patient’s other medical problems are hypertension and tobacco use. She feels well. Her medications are atenolol and hydrochlorothiazide. Family history is notable only for hypertension in both parents. She is up-to-date on routine healthcare maintenance (mammography, colonoscopy, Pap smears) and her physical exam is unremarkable.
Following the laboratory results, she was told to stop taking the diuretic and return in 1 week to have her calcium level and BP rechecked.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?