What are the differential diagnoses for a patient with hypercalcemia and suppressed parathyroid hormone (PTH)?

Differential Diagnoses for Hypercalcemia with Suppressed PTH

In a patient with hypercalcemia and suppressed parathyroid hormone (PTH), the primary differential diagnoses include malignancy-associated hypercalcemia, granulomatous diseases (particularly sarcoidosis), vitamin D intoxication, hyperthyroidism, and medication-induced hypercalcemia. 1, 2

Diagnostic Framework

The key principle is that PTH should be suppressed to undetectable or very low levels (<20 pg/mL) in hypercalcemia unless the parathyroid glands are the source of the problem 2, 3. When PTH is appropriately suppressed, this confirms PTH-independent hypercalcemia and narrows the differential significantly 4.

Major Differential Diagnoses

Malignancy-Associated Hypercalcemia

• Accounts for 10-25% of patients with certain cancers, particularly squamous cell lung carcinoma, with a poor prognosis (median survival approximately 1 month) 1
• Characterized by suppressed PTH with elevated PTHrP (parathyroid hormone-related peptide) 1
• The 25-hydroxyvitamin D is typically decreased because hypercalcemia suppresses PTH, which normally stimulates 1,25-dihydroxyvitamin D production 1
• Approximately 90% of hypercalcemia cases are due to either primary hyperparathyroidism or malignancy 3

Granulomatous Diseases (Sarcoidosis, Tuberculosis, Fungal Infections)

• Characterized by elevated 1,25-dihydroxyvitamin D with LOW or normal 25-hydroxyvitamin D 2
• This unique pattern occurs due to increased 1α-hydroxylase activity in granulomas, which converts 25-OH vitamin D to the active 1,25-(OH)₂ form 1
• Measuring both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels together is essential to distinguish this from vitamin D intoxication 1
• Glucocorticoids are effective treatment for vitamin D-mediated hypercalcemia in these conditions 1

Vitamin D Intoxication

• Characterized by markedly elevated 25-hydroxyvitamin D levels (typically >150 ng/mL) 2
• In contrast to granulomatous disease, 25-OH vitamin D is HIGH while 1,25-(OH)₂ vitamin D may be normal or elevated 1
• Common with excessive supplementation; all vitamin D therapy should be discontinued when serum calcium exceeds 10.2 mg/dL 1
• Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption 3

Hyperthyroidism (Graves' Disease)

• A rare but important cause of PTH-independent hypercalcemia 5, 6
• The reported prevalence varies depending on the method used to measure serum calcium 5
• Treatment of the underlying hyperthyroidism with normalization of thyroid function tests is followed by improvement of calcium and PTH levels 6
• Should be considered in patients with suggestive clinical features (weight loss, tachycardia, tremor) 6

Medication-Induced Hypercalcemia

• Thiazide diuretics, calcium supplements, and vitamin D supplements are common culprits 1, 3
• Newer associations include sodium-glucose cotransporter 2 inhibitors, immune checkpoint inhibitors, and denosumab discontinuation, though these account for <1% of cases 3
• Immediate discontinuation of offending agents is essential 2

Other Endocrine Disorders

• Adrenal insufficiency, pheochromocytoma, and VIPomas are associated with hypercalcemia 5
• These should be considered when common causes have been excluded 5

Genetic Disorders

• Consider in young patients, those with family history of hypercalcemia, or those with endocrine tumors 7
• Familial hypocalciuric hypercalcemia (FHH) presents with moderate hypercalcemia, normal PTH, and relative hypocalciuria 7
• Very rare causes include hypophosphatasia (low alkaline phosphatase) and renal phosphate wasting 7

Essential Diagnostic Workup

The following tests should be obtained to differentiate these causes:

• Measure 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together before any supplementation 1
• PTHrP level to evaluate for malignancy-associated hypercalcemia 1
• Thyroid function tests (TSH, free T4) to exclude hyperthyroidism 5, 6
• 24-hour urine calcium or spot urine calcium/creatinine ratio to assess for hypercalciuria versus hypocalciuria 1
• Comprehensive medication review, particularly for thiazides, calcium, and vitamin D supplements 1, 3
• Imaging for malignancy if clinically indicated (chest X-ray, CT chest for lung cancer) 1

Critical Pitfalls to Avoid

Do not order parathyroid imaging before confirming the biochemical diagnosis 1. Imaging is for surgical planning in confirmed primary hyperparathyroidism, not for diagnosis of hypercalcemia.

Always use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma at 4°C 1, 2.

Correct calcium for albumin if albumin is abnormal, or measure ionized calcium directly (normal: 4.65-5.28 mg/dL) to avoid misleading total calcium measurements 1.

The relationship between 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D provides critical diagnostic information: in granulomatous disease, 25-OH is LOW but 1,25-(OH)₂ is HIGH, whereas in vitamin D intoxication, 25-OH is markedly ELEVATED 1, 2.