Differential Diagnosis for Hypercalcemia with Normal PTH
Single Most Likely Diagnosis
- Malignancy-associated hypercalcemia: This is often due to the production of parathyroid hormone-related protein (PTHrP) by tumor cells, leading to hypercalcemia without an elevation in PTH levels. The most common malignancies associated with this condition are squamous cell lung cancer, breast cancer, and multiple myeloma.
Other Likely Diagnoses
- Vitamin D intoxication: Excessive intake of vitamin D can lead to increased absorption of calcium from the gut, resulting in hypercalcemia. This condition can occur with normal PTH levels because the primary driver of the hypercalcemia is the increased calcium absorption rather than PTH-mediated bone resorption.
- Familial hypocalciuric hypercalcemia (FHH): Although PTH levels are typically elevated in FHH, there can be cases where PTH levels are within the normal range, especially if the assay used does not accurately measure the biologically active form of PTH. FHH is characterized by an inactivating mutation in the calcium-sensing receptor, leading to inappropriate secretion of PTH for the level of serum calcium.
- Hyperthyroidism: Thyrotoxicosis can cause hypercalcemia due to increased bone resorption. While the mechanism is not fully understood, it is thought that thyroid hormones can directly stimulate osteoclast activity. PTH levels are often normal or even low in the context of hyperthyroidism-induced hypercalcemia.
Do Not Miss Diagnoses
- Primary adrenal insufficiency: Although less common, primary adrenal insufficiency (Addison's disease) can present with hypercalcemia. The mechanism is not entirely clear but may involve increased renal reabsorption of calcium and decreased excretion. Missing this diagnosis can be fatal due to the risk of adrenal crisis.
- Pheochromocytoma: Rarely, pheochromocytomas can produce PTHrP, leading to hypercalcemia. More commonly, they can cause hypercalcemia through other mechanisms, such as increased renal calcium reabsorption due to catecholamine excess.
Rare Diagnoses
- Sarcoidosis and other granulomatous diseases: These conditions can lead to hypercalcemia due to the increased production of 1,25-dihydroxyvitamin D by activated macrophages within granulomas. While PTH levels are typically normal, the diagnosis might be suggested by other clinical features such as pulmonary symptoms, skin lesions, or eye involvement.
- Williams syndrome: A rare genetic disorder characterized by hypercalcemia due to sensitivity to vitamin D, leading to increased intestinal absorption of calcium. PTH levels are usually normal.
- Immobilization hypercalcemia: Typically seen in young individuals with high bone turnover (e.g., those with spinal cord injuries), immobilization can lead to hypercalcemia due to increased bone resorption. PTH levels are usually normal or low.