With an elevated parathyroid hormone, normal serum calcium, and normal supplemented vitamin D, how would a high, normal, or low 24‑hour urine calcium result influence the diagnosis of primary hyperparathyroidism versus familial hypocalciuric hypercalcemia?

24-Hour Urine Calcium Interpretation in Suspected Primary Hyperparathyroidism

In your case—elevated PTH with normal calcium and normal vitamin D—a low 24-hour urine calcium (<100 mg/24h or calcium-to-creatinine clearance ratio ≤0.015) strongly suggests familial hypocalciuric hypercalcemia (FHH) and should prompt genetic testing, whereas normal or high urine calcium supports normocalcemic primary hyperparathyroidism. 1, 2

Diagnostic Framework: How Urine Calcium Distinguishes PHPT from FHH

Your clinical picture—elevated PTH with normal serum calcium and replete vitamin D—represents either normocalcemic primary hyperparathyroidism or familial hypocalciuric hypercalcemia, and the 24-hour urine calcium is the critical test to differentiate them. 1, 2

High Urine Calcium (>250–300 mg/24h or >400 mg/24h)

• Strongly supports normocalcemic primary hyperparathyroidism because PTH-driven hypercalcemia increases the filtered calcium load, leading to hypercalciuria despite PTH's calcium-retaining effects on the kidney. 2
• Urine calcium >400 mg/24h identifies patients at increased risk for kidney stones and bone complications and is an established surgical indication for parathyroidectomy. 2
• Most PHPT patients demonstrate hypercalciuria (>4 mg/kg/day or >250–300 mg/day) due to the increased filtered calcium load. 2

Normal Urine Calcium (100–250 mg/24h)

• Still consistent with normocalcemic primary hyperparathyroidism, particularly if vitamin D was recently deficient, because vitamin D deficiency can suppress urine calcium excretion even in PHPT patients. 2, 3
• Surgery may be considered based on other established criteria: age <50 years, osteoporosis (T-score ≤−2.5), impaired kidney function (eGFR <60 mL/min/1.73 m²), or kidney stones. 2
• Important caveat: Vitamin D deficiency can mask hypercalciuria in PHPT, so normal urine calcium in the setting of recently corrected vitamin D does not exclude PHPT. 2, 3

Low Urine Calcium (<100 mg/24h or <2.5 mmol/24h)

• Raises strong suspicion for familial hypocalciuric hypercalcemia, a benign inherited condition caused by inactivating mutations in the calcium-sensing receptor gene. 4, 5
• The calcium-to-creatinine clearance ratio (CCCR) is more reliable than absolute 24-hour urine calcium because it accounts for kidney function. 4
  • CCCR ≤0.015 has a positive predictive value of 3.28% for FHH and a negative predictive value of 100%, meaning values above 0.015 effectively rule out FHH. 4
  • CCCR ≤0.020 should prompt genetic testing for calcium-sensing receptor mutations. 4
• In FHH, the renal tubules exhibit increased calcium reabsorption independent of PTH, resulting in persistently low urine calcium despite elevated serum calcium. 5

Key Biochemical Differences Between PHPT and FHH

PTH Levels

• PHPT: PTH is elevated or inappropriately normal (fails to suppress below 20 pg/mL) in the setting of hypercalcemia or high-normal calcium. 2
• FHH: PTH is typically normal or only mildly elevated despite hypercalcemia. 6

1,25-Dihydroxyvitamin D (Calcitriol)

• PHPT: 1,25-(OH)₂ vitamin D is typically elevated because PTH stimulates renal 1α-hydroxylase activity. 7, 6
• FHH: 1,25-(OH)₂ vitamin D is normal or low, significantly lower than in PHPT patients with comparable calcium levels. 7, 6
• This difference is diagnostically useful: if your 1,25-(OH)₂ vitamin D is elevated, it strongly favors PHPT over FHH. 7, 6

Nephrogenic cAMP

• PHPT: Urinary nephrogenic cAMP is elevated (reflecting PTH action on the kidney). 5
• FHH: Urinary nephrogenic cAMP is normal despite elevated PTH, indicating the kidneys are not responding normally to PTH. 5

Practical Algorithm for Your Case

1. Measure 24-hour urine calcium AND calculate CCCR (urine calcium/serum calcium ÷ urine creatinine/serum creatinine). 4

2. Interpret the result:

   • CCCR >0.020 or urine calcium >250 mg/24h: Normocalcemic PHPT is confirmed; proceed to evaluate for surgical candidacy. 2, 4
   • CCCR ≤0.015 or urine calcium <100 mg/24h: FHH is likely; order genetic testing for calcium-sensing receptor mutations. 4
   • CCCR 0.015–0.020 or urine calcium 100–250 mg/24h: Consider measuring 1,25-(OH)₂ vitamin D (elevated in PHPT, normal/low in FHH) and nephrogenic cAMP (elevated in PHPT, normal in FHH). 5, 7, 6

3. If normocalcemic PHPT is confirmed, refer to endocrinology and a high-volume parathyroid surgeon for evaluation, as normocalcemic PHPT carries similar risks for osteoporosis, kidney stones, and fractures as hypercalcemic PHPT. 1, 2

Critical Pitfalls to Avoid

• Do not assume low urine calcium rules out PHPT if vitamin D was recently deficient, because vitamin D deficiency suppresses urine calcium excretion even in PHPT. 2, 3
• Do not rely on absolute 24-hour urine calcium alone—always calculate CCCR to account for kidney function. 4
• Do not order parathyroid imaging before biochemical diagnosis is established; imaging is for surgical localization only, not diagnosis. 2
• Do not dismiss normocalcemic PHPT as benign—it has similar complication rates to hypercalcemic PHPT and can progress over time. 1