What are the differential diagnosis and next steps for a 51-year-old female with hypercalcemia and elevated phosphate levels?

Hypercalcemia with Elevated Phosphate: Differential Diagnosis and Workup

Initial Assessment

This patient's presentation of hypercalcemia (11.0 mg/dL) with elevated phosphate (149 mg/dL, assuming this is 4.9 mmol/L or approximately 14.9 mg/dL) is highly unusual and immediately narrows the differential diagnosis, as most causes of hypercalcemia present with low or normal phosphate levels. 1

The combination of hypercalcemia with hyperphosphatemia is distinctly uncommon and suggests specific etiologies that must be systematically evaluated.

Differential Diagnosis

Most Likely Causes

Primary hyperparathyroidism with concurrent renal insufficiency is the most common scenario where both calcium and phosphate are elevated, as declining GFR prevents phosphate excretion despite PTH-mediated phosphaturia 1, 2. Key features to assess:

• Measure serum creatinine and calculate eGFR to evaluate renal function 1
• In primary hyperparathyroidism, phosphate is typically low (<3 mg/100 mL) unless renal impairment is present 2
• The chloride/phosphate ratio can help distinguish hyperparathyroidism (ratio >33 in 94% of cases) from other causes (ratio <33 in 96% of cases) 2

Malignancy-associated hypercalcemia with renal failure should be strongly considered, particularly given the patient's age 1, 3. This typically presents with:

• Markedly elevated calcium levels and severe symptoms 3
• Suppressed PTH (<20 pg/mL) 1
• Evidence of malignancy on history, examination, or imaging 3

Vitamin D intoxication can cause both hypercalcemia and hyperphosphatemia through increased intestinal absorption of both minerals 1, 3. Look for:

• History of excessive vitamin D or calcium supplementation 1
• Elevated 25-OH vitamin D levels (>150 ng/mL suggests toxicity) 1
• Suppressed PTH 1

Less Common Causes

Tertiary hyperparathyroidism in chronic kidney disease can present with hypercalcemia and hyperphosphatemia, though this typically occurs in dialysis patients 4, 5.

Milk-alkali syndrome from excessive calcium carbonate intake can cause hypercalcemia with elevated phosphate, particularly with concurrent renal impairment 1.

Next Steps for Workup

Immediate Laboratory Tests (Priority Order)

1. Serum intact PTH - This is the single most important test to guide diagnosis 1:

   • Elevated or normal PTH (>20 pg/mL): Suggests primary hyperparathyroidism 1
   • Suppressed PTH (<20 pg/mL): Indicates PTH-independent cause 1

2. Serum creatinine and eGFR - Essential to explain the hyperphosphatemia 1, 2

3. 25-OH vitamin D and 1,25-dihydroxyvitamin D - To evaluate for vitamin D intoxication or granulomatous disease 1, 3

4. Serum albumin - To confirm the corrected calcium is truly elevated 1

5. Calculate chloride/phosphate ratio - If >33, strongly suggests hyperparathyroidism; if <33, suggests non-parathyroid cause 2

Secondary Laboratory Tests

• PTH-related peptide (PTHrP) if PTH is suppressed and malignancy suspected 3
• Serum protein electrophoresis and free light chains to evaluate for multiple myeloma 6, 3
• Thyroid function tests (TSH, free T4) to exclude hyperthyroidism 1

Imaging Studies

• Chest X-ray - To evaluate for malignancy or granulomatous disease (sarcoidosis) 1, 3
• Parathyroid imaging (ultrasound and/or sestamibi scan with SPECT/CT) if PTH is elevated, to localize adenoma before potential surgery 4
• Skeletal survey or bone scan if malignancy suspected with suppressed PTH 3

Clinical Assessment Priorities

Symptom Evaluation

Assess for symptoms of hypercalcemia 1, 6:

• Mild symptoms (calcium <12 mg/dL): Fatigue, constipation, muscle weakness 1
• Severe symptoms (calcium ≥14 mg/dL): Nausea, vomiting, confusion, somnolence, coma 1, 6
• This patient at 11.0 mg/dL may be asymptomatic or have mild constitutional symptoms 1

Medication and Supplement Review

• Thiazide diuretics (can cause hypercalcemia) 1
• Calcium supplements, vitamin D, vitamin A 1
• Lithium (can cause hyperparathyroidism) 1
• Recent denosumab discontinuation 1

Common Pitfalls to Avoid

Do not assume typical primary hyperparathyroidism when phosphate is elevated - this combination mandates evaluation of renal function 2. Standard hyperparathyroidism presents with low phosphate (<3 mg/100 mL) 2.

Do not delay PTH measurement - this single test immediately divides the differential into PTH-dependent versus PTH-independent causes and guides all subsequent workup 1.

Do not overlook malignancy in a 51-year-old with hypercalcemia, especially if PTH is suppressed - this represents a medical urgency requiring rapid diagnosis 1, 3.

Do not forget to correct calcium for albumin - apparent hypercalcemia may be spurious if albumin is elevated 1.

Do not initiate treatment before establishing the diagnosis unless the patient is severely symptomatic (calcium ≥14 mg/dL or acute symptoms), as treatment may obscure the underlying cause 1, 6.