Hyperparathyroidism: A High-Yield USMLE Review

Hyperparathyroidism is the state of inappropriate parathyroid hormone (PTH) secretion, and it sits at the center of the calcium-metabolism differential. Primary hyperparathyroidism is the most common cause of hypercalcemia in outpatients and classically shows high calcium, high PTH, and low phosphorus. Because PTH is the first branch point in evaluating hypercalcemia, recognizing an inappropriately elevated PTH is the single most tested concept.

Presentation

• Most patients with primary hyperparathyroidism are asymptomatic, discovered on routine labs showing elevated calcium.
• When present, hypercalcemia is usually mild (calcium ~10.5–12 mg/dL) and chronic, in contrast to the severe, acute presentation of hypercalcemia of malignancy.
• Severe hypercalcemia can produce symptoms such as fatigue, confusion/altered mental status, and cardiac arrhythmias.
• Secondary hyperparathyroidism from CKD may present with hyperphosphatemia and markers of renal osteodystrophy; osteomalacia-related secondary hyperparathyroidism causes bone pain and proximal muscle weakness.

Diagnosis

• Serum calcium with simultaneous PTH is the first branch point: high calcium with high or inappropriately normal PTH indicates a parathyroid problem (primary hyperparathyroidism), whereas suppressed PTH points to malignancy, vitamin D toxicity, or granulomatous disease.
• Serum phosphorus: low in primary hyperparathyroidism due to PTH-driven renal phosphate wasting; high in secondary hyperparathyroidism from CKD.
• 24-hour urine calcium distinguishes primary hyperparathyroidism (normal to high urine calcium) from familial hypocalciuric hypercalcemia (low urine calcium); a calcium clearance/creatinine clearance ratio <0.01 suggests FHH.
• 25-OH vitamin D helps exclude vitamin D deficiency as a cause of secondary hyperparathyroidism.

Management

• Primary hyperparathyroidism: surgery (parathyroidectomy) is the definitive treatment and is indicated for specific criteria; many asymptomatic patients can be monitored.
• Acute severe hypercalcemia (calcium >14 mg/dL or symptomatic): IV normal saline for volume expansion to enhance renal calcium excretion, followed by IV bisphosphonate (zoledronic acid or pamidronate) to inhibit osteoclasts, with calcitonin as a rapid but transient bridge; treat the underlying cause.
• Secondary hyperparathyroidism from CKD: control hyperphosphatemia with phosphate binders (e.g., sevelamer) and give active vitamin D (calcitriol), since the kidney cannot activate 25-OH vitamin D.
• Tertiary hyperparathyroidism: parathyroidectomy for autonomous PTH secretion after prolonged secondary disease.

High-yield

• Primary hyperparathyroidism = HIGH calcium, HIGH PTH, LOW phosphorus; it is the most common cause of hypercalcemia in outpatients.
• PTH is the first branch point: high PTH means a parathyroid problem; low/suppressed PTH means malignancy (PTHrP), vitamin D toxicity, or granulomatous disease.
• FHH mimics primary hyperparathyroidism but has LOW urine calcium (Ca clearance/Cr clearance ratio <0.01) and does NOT require surgery — caused by an inactivating CaSR mutation.
• Secondary hyperparathyroidism (CKD or vitamin D deficiency) has HIGH PTH but LOW or normal calcium.
• Lithium raises the PTH set point and is a PTH-dependent cause of hypercalcemia.

Pitfalls

• Do not confuse primary (high calcium) with secondary hyperparathyroidism (low/normal calcium) — both have elevated PTH but opposite calcium levels and different treatments.
• Failing to check urine calcium can misdiagnose FHH as primary hyperparathyroidism and lead to unnecessary parathyroidectomy.
• Avoid loop diuretics (furosemide) in hypercalcemia unless the patient is volume overloaded — they worsen dehydration and electrolyte abnormalities; oral bisphosphonates and calcitonin alone are inadequate for acute severe hypercalcemia.
• In CKD, plain vitamin D3 won't work because the kidney cannot activate it — active vitamin D (calcitriol) is required; surgery is reserved for tertiary, not secondary, disease.