Hypercalcemia Workup and Differential Diagnosis
When approaching a patient with hypercalcemia, it's crucial to consider a broad range of potential causes to ensure accurate diagnosis and appropriate management. The differential diagnosis can be organized into the following categories:
Single Most Likely Diagnosis
- Primary hyperparathyroidism: This condition is the most common cause of hypercalcemia in outpatient settings, resulting from excessive parathyroid hormone (PTH) secretion, often due to a parathyroid adenoma or hyperplasia. It leads to increased calcium levels in the blood by enhancing calcium release from bones, increasing calcium absorption from the intestine, and reducing calcium excretion by the kidneys.
Other Likely Diagnoses
- Malignancy-associated hypercalcemia: Various cancers, such as squamous cell lung cancer, breast cancer, and multiple myeloma, can cause hypercalcemia through different mechanisms, including the production of parathyroid hormone-related protein (PTHrP), osteolytic metastases, or the secretion of other cytokines that stimulate osteoclast activity.
- Vitamin D intoxication: Excessive intake of vitamin D can lead to hypercalcemia by increasing intestinal absorption of calcium and mobilizing calcium from bone.
- Familial hypocalciuric hypercalcemia (FHH): A genetic disorder characterized by mild hypercalcemia, which is often asymptomatic and discovered incidentally. It's caused by mutations in the calcium-sensing receptor gene, leading to inappropriate secretion of PTH.
Do Not Miss Diagnoses
- Hypercalcemia of malignancy with parathyroid hormone-related protein (PTHrP): Although included under malignancy-associated hypercalcemia, it's crucial to identify this specific cause due to its implications for cancer diagnosis and management.
- Multiple endocrine neoplasia (MEN) syndromes: These are hereditary conditions that can involve multiple endocrine glands, including the parathyroids, and can lead to hyperparathyroidism and hypercalcemia.
- Vitamin A intoxication: While less common, vitamin A toxicity can cause hypercalcemia and has significant clinical implications, including potential for severe liver damage and other systemic effects.
Rare Diagnoses
- Sarcoidosis: A systemic granulomatous disease that can lead to hypercalcemia through the increased production of 1,25-dihydroxyvitamin D by activated macrophages within granulomas.
- Thyrotoxicosis: Hyperthyroidism can cause hypercalcemia, although this is less common, by increasing bone turnover.
- Pheochromocytoma: Rarely, pheochromocytomas can produce PTHrP, leading to hypercalcemia.
- Adrenal insufficiency: Although more commonly associated with hypocalcemia, certain cases of adrenal insufficiency can present with hypercalcemia, particularly if there's associated dehydration or other complicating factors.
Each of these diagnoses has distinct clinical and biochemical features that can guide further investigation and management. A thorough history, physical examination, and laboratory evaluation, including serum calcium, PTH, and vitamin D levels, are essential for determining the underlying cause of hypercalcemia.