How do you differentiate between hyperparathyroidism and familial hypocalciuric hypercalcemia (FHH)?

Differentiating Hyperparathyroidism from Familial Hypocalciuric Hypercalcemia (FHH)

The calcium-to-creatinine clearance ratio (CCCR) is the most important biochemical test to differentiate between primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcemia (FHH), with genetic testing of the calcium-sensing receptor (CaSR) gene being definitive when clinical evaluation is inconclusive. 1

Key Diagnostic Criteria

Laboratory Findings

• Calcium levels:

  • Both conditions present with hypercalcemia
  • PHPT: Usually moderate to severe hypercalcemia
  • FHH: Typically mild to moderate hypercalcemia 2

• Parathyroid Hormone (PTH):

  • PHPT: Inappropriately normal or elevated PTH
  • FHH: Usually inappropriately normal or elevated PTH, but can occasionally be low 3

• Urinary Calcium Excretion (most discriminating test):

  • PHPT: Normal or elevated urinary calcium excretion
  • FHH: Relative hypocalciuria despite hypercalcemia 2

• Calcium-to-Creatinine Clearance Ratio (CCCR):

  • PHPT: Typically >0.02 (>2%)
  • FHH: Typically <0.01 (<1%) 1
  • Gray zone: 0.01-0.02 (1-2%) where overlap occurs 2

Family History

• PHPT: Usually sporadic, though can be part of genetic syndromes (MEN1, MEN2A)
• FHH: Autosomal dominant inheritance pattern with family history of asymptomatic hypercalcemia 4

Clinical Presentation

• PHPT: May present with symptoms (bone disease, kidney stones, neurocognitive disorders)
• FHH: Typically asymptomatic, benign lifelong condition 3

Diagnostic Algorithm

1. Initial Evaluation:

   • Measure serum calcium, PTH, phosphate, and vitamin D levels
   • Calculate CCCR using 24-hour urine collection: CCCR = (Urine Ca × Serum Cr) / (Serum Ca × Urine Cr)

2. Interpret CCCR:

   • CCCR <0.01: Strongly suggests FHH
   • CCCR >0.02: Strongly suggests PHPT
   • CCCR 0.01-0.02: Indeterminate zone requiring further evaluation 1

3. For Indeterminate Cases:

   • Evaluate family history of hypercalcemia
   • Consider genetic testing for CaSR mutations
   • Consider parathyroid imaging only if PHPT is still suspected

4. Confirmatory Testing:

   • Genetic testing of CaSR gene (and occasionally AP2S1 and GNA11 genes) for definitive diagnosis of FHH 2
   • Parathyroid imaging (sestamibi scan, 4D-CT, ultrasound) only if PHPT is suspected

Pitfalls and Caveats

1. Overlapping Values:

   • The CCCR has a considerable indeterminate range (0.01-0.02) where PHPT and FHH can overlap 1
   • Some FHH patients may have CCCR >0.01, especially with vitamin D deficiency or high bone turnover 2

2. False Positives in Imaging:

   • FHH patients can occasionally have positive parathyroid imaging that may falsely suggest PHPT 2
   • Imaging should not be the sole basis for diagnosis

3. Coexistence of Both Conditions:

   • Rare cases of FHH patients developing parathyroid adenomas have been reported 5
   • Persistent hypercalcemia after parathyroidectomy may suggest underlying FHH

4. Vitamin D Status:

   • Vitamin D deficiency can affect calcium excretion and PTH levels
   • Correct vitamin D deficiency before making final diagnosis 6

5. Atypical Presentations:

   • Some FHH patients may present with atypical biochemical profiles including low PTH or higher urinary calcium excretion than expected 3

Treatment Implications

• PHPT: Surgical excision of abnormal parathyroid tissue is the definitive treatment 4
• FHH: No treatment required as it's a benign condition; parathyroidectomy is ineffective and should be avoided 2

When to Pursue Genetic Testing

Genetic testing for CaSR mutations should be considered when:

• CCCR is in the indeterminate range (0.01-0.02)
• Family history suggests FHH
• Hypercalcemia persists after parathyroidectomy
• Young patient with asymptomatic hypercalcemia
• Multiple family members with hypercalcemia 2, 1

Correctly differentiating between PHPT and FHH is crucial to avoid unnecessary parathyroidectomy in FHH patients, as surgery will not correct the hypercalcemia in these cases and exposes patients to surgical risks without benefit.