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. This condition can occur with normal intact PTH levels because vitamin D itself can suppress PTH secretion.
• Familial hypocalciuric hypercalcemia (FHH): Although PTH levels are typically elevated in FHH, some cases may present with normal intact PTH levels due to the variability in PTH secretion and the specific mutation involved. FHH is characterized by hypercalcemia, hypocalciuria, and often a family history of hypercalcemia.
• Hyperthyroidism: Thyrotoxicosis can cause hypercalcemia due to increased bone resorption. Intact PTH levels may be normal or slightly decreased as a result of the feedback inhibition by elevated calcium levels.

Do Not Miss Diagnoses

• Primary hyperparathyroidism with PTH assay variability: Although the intact PTH level is reported as normal, there could be assay variability or the sample might have been drawn during a period of relatively normal PTH secretion in a patient with primary hyperparathyroidism. This diagnosis is critical to consider because it requires a different management approach.
• Vitamin A intoxication: Similar to vitamin D, excessive intake of vitamin A can lead to hypercalcemia. This condition is less common but can have serious consequences if not recognized and treated promptly.

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. Intact PTH levels are typically suppressed in response to the hypercalcemia.
• Williams syndrome: A rare genetic disorder that can cause hypercalcemia due to sensitivity to vitamin D. It is characterized by distinctive facial features, intellectual disability, and congenital heart defects.
• Jansen's metaphyseal chondrodysplasia: A rare genetic disorder caused by constitutive activation of the PTH/PTHrP receptor, leading to hypercalcemia and skeletal abnormalities. Intact PTH levels are typically normal or low.