In a patient with elevated intact parathyroid hormone, hypercalcemia, and normal vitamin D, what is the most likely diagnosis and the appropriate work‑up and management?

Primary Hyperparathyroidism: Diagnosis and Management

Most Likely Diagnosis

In a patient with elevated intact PTH, hypercalcemia, and normal vitamin D, the diagnosis is primary hyperparathyroidism (PHPT). 1 The combination of hypercalcemia with elevated or inappropriately normal PTH levels is the biochemical hallmark of PHPT, where autonomous parathyroid glands continue secreting PTH despite elevated calcium. 1, 2

Understanding the Biochemistry

• In normal physiology, elevated calcium should suppress PTH to very low levels (<20 pg/mL), but in PHPT the parathyroid glands autonomously secrete PTH despite hypercalcemia, resulting in elevated or "inappropriately normal" PTH levels (typically >65 pg/mL when calcium is elevated). 3

• The "normal" vitamin D in this scenario is actually a critical diagnostic clue. In severe PHPT with extreme hypercalcemia, 1,25-dihydroxyvitamin D (active vitamin D) may paradoxically be low or normal rather than elevated, because severe hypercalcemia suppresses renal 1-alpha-hydroxylase activity. 4, 5 This distinguishes PHPT from vitamin D-mediated hypercalcemia (granulomatous disease, lymphoma) where 1,25-dihydroxyvitamin D would be elevated. 2

• Serum phosphate is typically low or low-normal in PHPT, which helps confirm the diagnosis. 1, 3

Essential Diagnostic Work-Up

Immediate Laboratory Tests

• Measure 25-hydroxyvitamin D level to exclude vitamin D deficiency, which can complicate PTH interpretation and must be ruled out before confirming PHPT. 1, 3 Vitamin D deficiency causes secondary hyperparathyroidism and can mask the true severity of hypercalcemia. 6

• Check serum creatinine and calculate eGFR to assess kidney function, as this determines surgical candidacy and prognosis. 1, 3 Impaired kidney function (eGFR <60 mL/min/1.73 m²) is itself a surgical indication. 2, 3

• Obtain ionized calcium for definitive assessment if albumin is abnormal, as total calcium can be misleading. 2, 3

• Measure serum phosphate, which should be low or low-normal in PHPT. 1, 3

Critical PTH Measurement Considerations

• Use assay-specific reference values for PTH interpretation, as different PTH assay generations can vary by up to 47% and measure different PTH fragments. 1, 2 This lack of standardization between laboratories can significantly affect clinical interpretation. 1

• Collect blood samples in EDTA tubes for PTH measurement, as PTH is most stable in EDTA plasma stored at 4°C. 1, 2

Additional Diagnostic Studies

• Order a 24-hour urine collection for calcium, creatinine, sodium, and other metabolites to evaluate complications and assess surgical candidacy. 1 Hypercalciuria >400 mg/day identifies patients at increased risk for kidney stones and bone complications and is a surgical indication. 1

• Obtain renal ultrasonography to assess for nephrocalcinosis or kidney stones. 2

• Order a DEXA scan to evaluate for osteoporosis (T-score ≤-2.5 at any site), which is a surgical indication. 3

Differential Diagnosis to Exclude

Secondary Hyperparathyroidism

• Secondary hyperparathyroidism presents with normal or LOW serum calcium (not elevated) with elevated PTH, commonly seen in chronic kidney disease or vitamin D deficiency. 1, 2 This is biochemically distinct from your patient's presentation.

Tertiary Hyperparathyroidism

• Tertiary hyperparathyroidism occurs in end-stage renal disease patients with hypercalcemia and elevated PTH after prolonged secondary hyperparathyroidism. 1 Check the patient's renal history to exclude this.

Familial Hypocalciuric Hypercalcemia (FHH)

• Measure 24-hour urine calcium to calculate calcium-to-creatinine clearance ratio; FHH shows low urinary calcium excretion (<100 mg/24hr or calcium/creatinine clearance ratio <0.01), whereas PHPT typically shows hypercalciuria. 1

Management Algorithm

Step 1: Determine Surgical Candidacy

All patients with confirmed PHPT should be evaluated for parathyroidectomy, as this is the only curative treatment. 3, 7 Surgical indications include:

• Corrected calcium >1 mg/dL above the upper limit of normal (approximately >11.2 mg/dL if upper limit is 10.2 mg/dL) 2, 3
• Age <50 years 2, 3
• eGFR <60 mL/min/1.73 m² 2, 3
• Osteoporosis on DEXA scan (T-score ≤-2.5 at any site) 3
• History of kidney stones or nephrocalcinosis 3
• 24-hour urine calcium >400 mg/day 1
• Symptomatic disease (fatigue, constipation, bone pain, cognitive symptoms) 7
• Patient preference for definitive treatment 2

Step 2: Pre-Operative Localization Imaging (Only After Biochemical Diagnosis)

Never order parathyroid imaging before confirming the biochemical diagnosis, as imaging is for surgical planning, not diagnosis. 2

• Obtain neck ultrasound as the first-line localization study. 1, 3
• Add dual-phase 99mTc-sestamibi scintigraphy with SPECT/CT as second-line imaging. 1, 3
• The combination of ultrasound plus sestamibi offers the highest sensitivity for localization. 1
• Consider 4D-CT or MRI if initial imaging is negative or for reoperative cases. 1

Step 3: Specialist Referral

Refer all patients meeting surgical criteria to both an endocrinologist for medical optimization and a high-volume parathyroid surgeon, as outcomes are significantly better with specialized expertise. 2, 3

Step 4: Medical Management (For Non-Surgical Candidates or While Awaiting Surgery)

Calcium and Vitamin D Management

• Maintain normal dietary calcium intake (1,000-1,200 mg/day) and avoid both high and low calcium diets. 2, 3 Total elemental calcium intake should not exceed 2,000 mg/day. 2, 3

• DO NOT supplement with vitamin D until hypercalcemia is resolved, and discontinue all forms of vitamin D therapy if serum calcium exceeds 10.2 mg/dL. 2 Vitamin D supplementation can unmask severe hypercalcemia in PHPT patients with vitamin D deficiency. 6

• Once calcium normalizes and if 25-hydroxyvitamin D is <30 ng/mL, cautiously supplement with ergocalciferol or cholecalciferol at low doses (800-1,000 IU daily) with monthly calcium monitoring for the first 3 months. 2

Medication Review

• Discontinue thiazide diuretics immediately, as they reduce urinary calcium excretion and worsen hypercalcemia. 3, 7

• Discontinue calcium-based phosphate binders if the patient is on them. 2

• Ensure adequate oral hydration to prevent worsening hypercalcemia. 3

Monitoring During Medical Management

• Monitor serum calcium and ionized calcium every 1-2 weeks until stable. 3
• Check PTH levels every 3 months. 3
• Monitor serum creatinine to assess kidney function. 3
• Measure serum calcium and phosphorus at least every 3 months. 2

Step 5: Management of Severe Hypercalcemia (If Present)

If the patient has severe hypercalcemia (total calcium ≥14 mg/dL or ionized calcium ≥10 mg/dL) or symptomatic hypercalcemia (nausea, vomiting, confusion, altered mental status), initiate urgent treatment: 7

• Aggressive intravenous hydration with isotonic normal saline to restore intravascular volume and promote calciuresis is the cornerstone of acute therapy. 2, 7

• Administer intravenous bisphosphonates (zoledronic acid 4 mg or pamidronate 60-90 mg) as first-line pharmacologic agents; they inhibit osteoclast-mediated bone resorption and typically achieve calcium reduction within 2-4 days. 2, 7

• Monitor ionized calcium every 4-6 hours during acute treatment. 2

• In patients with kidney failure, consider denosumab and dialysis. 7

Post-Operative Management (After Parathyroidectomy)

Monitoring for Hungry Bone Syndrome

Anticipate "hungry bone syndrome," a rapid fall in serum calcium that occurs after removal of hyperfunctioning parathyroid tissue, especially in patients with severe PHPT and osteitis fibrosa cystica. 2, 4

• Measure ionized calcium every 4-6 hours during the first 48-72 hours after surgery to detect rapid declines. 2

• If ionized calcium drops below 0.9 mmol/L (approximately 3.6 mg/dL), start an intravenous calcium gluconate infusion at 1-2 mg elemental calcium per kilogram per hour. 2

Calcium and Vitamin D Supplementation

• Begin oral calcium carbonate at a total dose of 1-2 g three times daily once the patient can tolerate oral intake. 2

• Add calcitriol, titrating up to 2 µg per day, to support calcium absorption and mitigate hypocalcemia. 2

• Vitamin D supplementation following parathyroidectomy reduces the incidence of postoperative normocalcemic PTH elevation. 8 Consider routine calcitriol and calcium carbonate postoperatively to prevent this phenomenon. 8

Common Pitfalls and How to Avoid Them

Pitfall 1: Not Assessing Vitamin D Status

Failing to measure 25-hydroxyvitamin D when interpreting PTH levels can lead to misdiagnosis, as vitamin D deficiency causes secondary hyperparathyroidism and can mask the severity of PHPT. 1, 2 Always check vitamin D status before confirming PHPT.

Pitfall 2: Supplementing Vitamin D Before Resolving Hypercalcemia

Vitamin D supplementation in PHPT patients with vitamin D deficiency can unmask severe, life-threatening hypercalcemia. 6 Never supplement vitamin D until calcium normalizes, and when you do, use low doses with frequent calcium monitoring. 2

Pitfall 3: Ordering Imaging Before Biochemical Diagnosis

Imaging has no utility in confirming or excluding the diagnosis of hyperparathyroidism; it is used only for localization after biochemical diagnosis is established. 2 Confirm PHPT biochemically first, then order imaging only when surgery is planned.

Pitfall 4: Using Different PTH Assays Without Considering Variability

PTH assays differ markedly between generations—differences of up to 47% have been reported—and measure different PTH fragments. 1, 2 Always use assay-specific reference values and avoid comparing PTH values from different laboratories or assay platforms.

Pitfall 5: Underestimating Post-Operative Hypocalcemia Risk

Patients with severe PHPT, high PTH levels, elevated alkaline phosphatase, or radiological evidence of osteitis fibrosa cystica are at high risk for hungry bone syndrome and severe post-operative hypocalcemia. 2, 4, 5 Anticipate this complication with aggressive calcium and calcitriol supplementation and frequent ionized calcium monitoring.

Pitfall 6: Assuming Normal PTH Excludes PHPT

Patients with hypercalcemia and PTH in the "normal" range can still have PHPT, as the PTH is inappropriately normal for the elevated calcium level. 2 In normal physiology, hypercalcemia should suppress PTH to <20 pg/mL; any PTH >20 pg/mL in the setting of hypercalcemia is inappropriate and suggests PHPT. 3, 7