Types of PTH-Dependent Hypercalcemia
PTH-dependent hypercalcemia comprises three distinct entities: primary hyperparathyroidism (most common), tertiary hyperparathyroidism, and familial hypocalciuric hypercalcemia (FHH).
Primary Hyperparathyroidism (PHPT)
Primary hyperparathyroidism is characterized by autonomous parathyroid gland overproduction of PTH, resulting in hypercalcemia with elevated or inappropriately normal PTH levels 1, 2.
Pathologic Causes
- Single parathyroid adenoma accounts for approximately 80% of cases 1
- Multigland disease (multiple adenomas or hyperplasia) affects 15-20% of patients 1
- Parathyroid carcinoma is rare, occurring in less than 1% of cases 1
Biochemical Profile
- Elevated or high-normal serum calcium with elevated or inappropriately normal iPTH 2
- Low or low-normal serum phosphate 2
- Most patients demonstrate hypercalciuria (>250-300 mg/day) due to increased filtered calcium load 2
Clinical Variants
PHPT presents in three distinct phenotypes 3:
- Symptomatic disease with target organ involvement (bone demineralization, fractures, nephrolithiasis, nephrocalcinosis) - predominates in countries without routine biochemical screening 1
- Asymptomatic mild hypercalcemia - most common presentation in countries with routine screening 1, 3
- Normocalcemic PHPT - high PTH with persistently normal albumin-corrected and ionized calcium, typically identified during evaluation of low bone density 3, 4
Tertiary Hyperparathyroidism (THPT)
Tertiary hyperparathyroidism is marked by hypercalcemia with elevated PTH, typically occurring in patients with end-stage renal disease or following kidney transplantation 2.
Pathophysiology
- Develops from long-standing secondary hyperparathyroidism where parathyroid glands become autonomous 1
- Characterized by lack of PTH suppression despite rising serum calcium levels 1
- Represents progression from compensatory PTH elevation to autonomous hypersecretion 1
Clinical Context
- Most commonly encountered following kidney transplantation in patients with chronic kidney disease 1
- Typically involves multigland disease (parathyroid hyperplasia) 1
Familial Hypocalciuric Hypercalcemia (FHH)
FHH is a PTH-dependent hypercalcemia caused by germline mutations in the calcium-sensing receptor gene, characterized by hypercalcemia with inappropriately normal PTH and low urinary calcium excretion 5, 6.
Distinguishing Features
- Low 24-hour urine calcium-to-creatinine clearance ratio is the hallmark finding 5
- PTH levels are typically normal or mildly elevated, but inappropriately so for the degree of hypercalcemia 7
- PTH is more effective at raising calcium and lowering phosphate in FHH compared to primary hyperparathyroidism, as evidenced by lower PTH levels achieving similar calcium elevations 7
Critical Diagnostic Pitfall
FHH can coexist with primary hyperparathyroidism, creating diagnostic and management challenges 5, 6. In such cases:
- Parathyroidectomy may reduce hypercalcemia but persistent mild hypercalcemia will remain due to underlying FHH 5
- Genetic testing for calcium-sensing receptor mutations should be performed when clinical suspicion exists 5, 6
- Surgery is indicated only for the coexistent PHPT component, not for FHH itself 6
Key Differential Diagnostic Algorithm
When evaluating PTH-dependent hypercalcemia:
Measure simultaneous serum calcium and iPTH - elevated calcium with elevated/inappropriately normal PTH confirms PTH-dependent mechanism 2
Assess 24-hour urine calcium excretion 2:
- High (>250-300 mg/day): suggests PHPT
- Low with low calcium-to-creatinine clearance ratio: suggests FHH 5
Evaluate kidney function and clinical history 2:
Check vitamin D status - deficiency can mask hypercalciuria in PHPT and complicate PTH interpretation 2
Consider genetic testing if FHH suspected (family history, low urine calcium, mild persistent hypercalcemia) 5, 6