Primary Hyper­parathyroidism: Diagnosis and Surgical Criteria

Use an albumin-adjusted total calcium, confirmed on at least two occasions, because calcium in mild PHPT can drift into the normal range. When albumin is below 4.0 g/dL, adjusted Ca = measured Ca + 0.8 × (4.0 − albumin), rounded to 0.1 mg/dL; at 4.0 g/dL or higher, the measured total calcium is used. The formula over-corrects when albumin is below 3.0 g/dL or kidney function is impaired.

Ionized calcium is the gold standard and becomes essential when total calcium is equivocal, albumin is low, or normocalcemic PHPT is suspected; up to 10% of patients with PHPT have a normal total but elevated ionized calcium. When it is entered, it decides whether calcium is high. Values below 2.5 are read as mmol/L.

Draw an intact (second-generation) PTH at the same time as the calcium, given PTH's minutes-long half-life. This pairing is the central branch point.

Secondary (physiologic) PTH elevation is distinguished chiefly by normal or low calcium. Common causes are vitamin D deficiency, chronic kidney disease, malabsorption, hypercalciuria and drugs. If an elevated PTH normalizes after vitamin D repletion, the diagnosis is secondary hyperparathyroidism, not PHPT.

Present in this patient?

If an interfering medication can safely be stopped, it is usually stopped and the calcium and PTH are rechecked.

Hypercalciuria (renal calcium leak) criteria. Check the box only if both apply: (1) 24-h urine calcium above 250 mg/day in women or 300 mg/day in men on the usual diet, collected after holding thiazides for at least 1 week, with normal total and ionized calcium and an elevated PTH; and (2) the PTH rise is shown to be secondary to urinary calcium loss: on a thiazide challenge (hydrochlorothiazide 25 mg twice daily for 2 weeks, only if eGFR is 60 or more, then recheck calcium, PTH and potassium), PTH normalizes while calcium stays normal. Calcium that rises above normal with a persistently high PTH favors normocalcemic PHPT, and a PTH that falls but does not normalize is indeterminate. A high urine calcium alone does not qualify, because normocalcemic PHPT can also cause hypercalciuria. The challenge is only modestly accurate (about 82% sensitivity and 78% specificity in one small series).

Helpful 1,25-dihydroxyvitamin D is high or high-normal in PHPT, low in secondary hyperparathyroidism, and useful when granulomatous disease is suspected.

When PTH is suppressed (guided by history and examination): SPEP/UPEP for myeloma; PTHrP, which is high in adenocarcinoma and squamous cancers; 1,25-dihydroxyvitamin D, which is high in granulomatous disease and lymphoma; bone-specific alkaline phosphatase for lytic bone lesions; skeletal, chest, abdominal and pelvic imaging for malignancy; and TSH, cortisol and IGF-1 for other endocrine causes.

Familial hypocalciuric hypercalcemia (FHH) is separated from PHPT with the calcium/creatinine clearance ratio (CCCR). Note that parathyroidectomy cures PHPT but not FHH, which does not need treatment, so FHH is excluded before surgery whenever hypercalcemia is longstanding, mild or familial. Vitamin D deficiency and renal insufficiency both falsely lower the ratio into the FHH range, so vitamin D is repleted first.

If the lab reports only a ratio, enter it here. When the 24-h urine calcium, urine creatinine and serum creatinine are all entered, the CCCR is calculated from them instead.

CCCR = (24-h urine Ca × serum Cr) / (serum Ca × 24-h urine Cr)

Before a patient is considered asymptomatic, renal imaging for silent stones or nephrocalcinosis and vertebral imaging for subclinical fractures reclassify a substantial fraction of patients as surgical.

Any one of these, attributable to PHPT, makes surgery indicated, with unanimous guideline agreement.

Any one is sufficient. In normocalcemic PHPT, all criteria apply except the serum calcium threshold.

Symptoms the patient reports that are plausibly attributable to PHPT. AAES 2016 and the Australian and New Zealand 2024 guideline support parathyroidectomy for neurocognitive and neuropsychiatric symptoms attributable to PHPT (strong recommendation, low-quality evidence). The Fifth International Workshop does not accept these as formal criteria.