Hypercalcemia and Differential Diagnosis
The severity of hypercalcemia may be classified based on total serum and ionized calcium levels, as indicated in Table 1. The differential diagnosis for hypercalcemia includes an extensive group of disorders. The most common disorders include PHPT, malignancy, granulomatous diseases, and medications. Hypercalcemia may be distinguished in parathyroid-hypercalcemia and nonparathyroid hypercalcemia. The PTH-dependent family of hypercalcemic disorders includes primary and tertiary hyperparathyroidism, their inherited variants, and familiar hypocalciuric hypercalcemia [7]. These disorders are described in the Primary Hyperparathyroidism section below.
Malignancy-associated hypercalcemia represents approximately 90% of cases of hypercalcemia among hospitalized patients. About 20–30% of patients with cancer have hypercalcemia during the course of the disease, and its occurrence may signify an unfavorable prognosis [8]. Of the cases that result from malignancy, approximately 80% are due to the effects of PTH-related peptide (PTHrP), while the other 20% are due to bone metastases. Hypercalcemia secondary to malignancy may be classified into the following 4 types, based on the mechanism involved:
1. Humoral Hypercalcemia of Malignancy from an Increased Secretion of PTHrP
Whereas almost any kind of tumor may cause humoral hypercalcemia of malignancy (HHM), the most common types are squamous carcinoma of any origin (lung, esophagus, skin, and cervix are common sites) and breast and renal carcinomas. The continuous secretion of PTHrP by tumors leads to a dramatic uncoupling of bone resorption from formation, by activating osteoclastic bone resorption and suppressing bone formation. As a result, large net amounts of calcium of up to 700–1,000 mg/day leave the skeleton, causing hypercalcemia. In addition, the anticalciuric effect of PTHrP restricts effective renal calcium clearance. Finally, HHM is associated with a reduction of 1,25 dihydroxyvitamin D [1,25(OH)2D3] levels, which in turn limit intestinal calcium absorption but enhance skeletal resorption. HHM is also associated with a reduction in the renal phosphorous threshold with hyperphosphaturia and hypophosphatemia [7–9]. In very rare instances, benign neoplastic lesions may also lead to hypercalcemia by systemic overproduction of PTHrP [7].
2. Local Osteolytic Hypercalcemia from Osteoclastic Activity and Bone Resorption Surrounding the Tumor Tissue
This is the second most common mechanism, accounting for about 20% of cases. Breast cancer and hematological neoplasms (myeloma, lymphoma, leukemia) are the most important. Patients with local osteolytic hypercalcemia are characterized by extensive bone metastases or marrow infiltration and the bone scintigraphic scan is generally widely positive.
3. Secretion of Active Vitamin D by Some Lymphomas
All types of lymphomas have been reported to cause this syndrome. The malignant cells overexpress the enzyme 1-alpha-hydroxylase, which converts normal circulating 25(OH) vitamin D to the abnormally elevated circulating concentration of the active form of vitamin D, 1,25(OH)2D3. This increase induces an increase of intestinal calcium absorption and decrease of renal clearance [10]. In addition, 1,25(OH)2D3 may increase osteoclast activity by increasing the levels of RANK-L [7].
4. Ectopic PTH Secretion – Very Rare
The remaining 10% of cases of nonparathyroid hypercalcemia are caused by many different conditions.
Causes related to vitamin D include the following:
– Vitamin D toxicity.
– Granulomatous disease (especially sarcoidosis) due to an inappropriate production of 1,25(OH)2D3 by the granulomas. Hypercalcemia occurs in approximately 10% of patients with active pulmonary sarcoidosis. These patients have high levels of serum 1,25(OH)2D3 and normal PTH. The hypercalcemia reverses with the eradication of granulomas (e.g., using glucocorticoid) and by intravenous hydration. In addition, the reduction of sun exposure, avoidance of excessive exogenous vitamin D intake, and control of dietary calcium intake are efficacious in the control of hypercalcemia and hypercalciuria [11].
Causes related to endocrine disorders include the following:
– Hyperthyroidism: hypercalcemia is reported in tirotoxicosis and acute thyroiditis, and the mechanism appears to be thyroid hormone-mediated increased osteoclastic bone resorption.
– Pheochromocytoma: hypercalcemia is due to catecholamine-induced volume concentration, epinephrine-induced PTH secretion, and, in some cases of malignant tumors, secretion of PTHrP.
– Adrenal insufficiency (Addison crisis): factors that induce hypercalcemia include volume depletion with hemoconcentration and a reduction in the glomerular filtration rate, GFR, which facilitates increased tubular resorption of calcium and increased skeletal release of calcium.
– Pancreatic islet cell tumors: hypercalcemia can occur as the results of severe different abnormalities. These tumors may be of multiple endocrine neoplasia type 1 (MEN1) syndrome and occur in association with PHPT. However, the occurrence of hypercalcemia is particularly high in patients with tumor-secreted vasoactive intestinal polypeptide (VIPomas) via an unknown mechanism.
Causes related to high bone turnover include the following:
– Hyperthyroidism (see above).
– Immobilization: suppresses osteoblastic activity and increases osteocalastic bone resorption, leading to complete uncoupling of these 2 normally coupled processes. The result is a massive loss of calcium from bone, hypercalcemia, and low bone mineral density (BMD). It is suggested that the process may be mediated by sclerostin that is high in serum of immobilized patients and inhibits bone formation [12]. The process is most effectively reversed by the restoration of normal weight bearing. Alternate options are bisphosphonates.
– Thiazide diuretic use: due to increased renal tubular reabsorption of calcium. The finding of more severe hypercalcemia is a sign of an underlying disorder of calcium metabolism (e.g., PHPT).
– Vitamin A intoxication: treatment with a high dose of vitamin A analogs (more than 50,000 IU/day) can result in hypercalcemia due to an increase of osteoclastic activity.
– Milk-alkali syndrome: due to the ingestion of large amounts of milk or calcium supplements and soluble alkali (antacid). Two types are described: (a) chronic milk-alkali syndrome (Burnett syndrome),
