Calcium/Creatinine Clearance Ratio for Diagnosing FHH
The calcium/creatinine clearance ratio (CCCR) cutoff of <0.01 is traditionally used to diagnose FHH, though a more sensitive screening threshold of <0.02 should be employed to capture most FHH cases, followed by calcium-sensing receptor (CASR) gene analysis for definitive diagnosis. 1, 2
Diagnostic Thresholds and Performance
Primary CCCR Cutoffs
The optimal CCCR cutoff for diagnosing FHH is <0.0115, which provides a diagnostic specificity of 88% and sensitivity of 80% when using CASR gene analysis as the gold standard 1
A CCCR cutoff of <0.02 captures 98% of FHH patients but includes 35% of primary hyperparathyroidism (PHPT) patients, making it an appropriate screening threshold rather than a definitive diagnostic criterion 1, 2
The traditional cutoff of <0.01 (or 1%) suggested by the American Association of Endocrine Surgeons misses a substantial proportion of FHH cases, with sensitivity as low as 42.9-64.3% in recent studies 3, 4
Alternative Biochemical Markers
**24-hour urine calcium excretion <100 mg** is commonly used for FHH screening, but 38% of genetically confirmed FHH patients have urine calcium >100 mg, and 24% have levels >200 mg 3
The CCCR performs only marginally better than 24-hour calcium/creatinine excretion ratio (area under curve 0.923 vs 0.903) or 24-hour calcium excretion alone (area under curve 0.876), though it includes fewer PHPT patients at various cutoff points 1
Recommended Two-Step Diagnostic Approach
Step 1: Initial Biochemical Screening
Calculate CCCR from 24-hour urine collection using the formula: (Urine calcium × Serum creatinine) / (Serum calcium × Urine creatinine) 1, 2
Use CCCR <0.02 as the screening threshold to identify patients requiring genetic testing, accepting that this will include some PHPT patients 1, 2
Step 2: Genetic Confirmation
Perform CASR gene mutation analysis in all patients with CCCR ≤0.02 to definitively distinguish FHH from PHPT 1, 2, 5
Consider genetic testing even when CCCR is >0.02 if clinical suspicion remains high (family history of hypercalcemia, young age, mild hypercalcemia with normal PTH, absence of complications) 3
Critical Limitations and Pitfalls
Biochemical Overlap
Substantial biochemical overlap exists between FHH and PHPT, with neither urine calcium excretion nor CCCR providing adequate discrimination as standalone tests (receiver operating characteristic area under curve 0.55-0.63) 3, 4
57% of genetically confirmed FHH patients have normal or increased 24-hour urine calcium, and similar proportions have CCCR values in the PHPT range 3, 4
Clinical Context Matters
FHH patients typically present younger and leaner than PHPT patients, with comparable serum calcium but lower PTH, 1,25-dihydroxyvitamin D, alkaline phosphatase, and urinary NTx levels 5
Imaging studies are typically nonlocalizing in FHH, with sestamibi scans showing inconclusive results in 57% of cases and ultrasound nonlocalizing in 85% of tested FHH patients 3
Why This Matters Clinically
FHH requires no treatment and parathyroidectomy is ineffective, whereas PHPT benefits from surgical intervention, making accurate differentiation essential to avoid unnecessary surgery 2, 5. The benign nature of FHH, with normal bone mineral density despite lifelong hypercalcemia, contrasts sharply with the skeletal and renal complications of untreated PHPT 5.