Differential Diagnosis for Hypercalcemia with Normal Intact 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 intact 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. Since vitamin D itself does not directly elevate PTH, intact PTH levels can remain normal.
- Familial hypocalciuric hypercalcemia (FHH): Although PTH levels might be slightly elevated in FHH, in some cases, they can be within the normal range, especially if the assay used does not accurately measure the biologically active PTH. This condition is characterized by an inborn error of calcium sensing, leading to hypercalcemia.
- Hyperthyroidism: Thyrotoxicosis can cause hypercalcemia due to increased bone resorption. Intact PTH levels can be normal or even slightly decreased as a compensatory response to the hypercalcemia.
Do Not Miss Diagnoses
- Primary hyperparathyroidism with PTH assay variability: Although the intact PTH level is reported as normal, there could be variability in the assay or the timing of the sample that misses a mildly elevated PTH level, especially in primary hyperparathyroidism.
- Lithium therapy: Lithium can increase PTH secretion, but in some cases, especially with chronic therapy, PTH levels might fluctuate and be reported as normal while still causing hypercalcemia.
- Hypercalcemia of immobilization: Prolonged immobilization, especially in young individuals with high bone turnover (e.g., those with spinal cord injuries), can lead to hypercalcemia. Intact PTH levels are usually normal or low in this condition.
Rare Diagnoses
- Sarcoidosis and other granulomatous diseases: These conditions can lead to an overproduction of 1,25-dihydroxyvitamin D by macrophages within granulomas, resulting in increased intestinal absorption of calcium and hypercalcemia. Intact PTH levels are typically suppressed in response to the hypercalcemia.
- Williams syndrome: A rare genetic disorder that can include hypercalcemia due to sensitivity to vitamin D, leading to increased calcium absorption. Intact PTH levels are usually normal or low.
- Jansen's metaphyseal chondrodysplasia: A rare genetic disorder characterized by hypercalcemia and skeletal abnormalities, with normal or low intact PTH levels due to constitutive activation of the PTH/PTHrP receptor.