How do primary hyperparathyroidism and secondary hyperparathyroidism differ in etiology, laboratory findings, and management?

Primary vs. Secondary Hyperparathyroidism

Primary hyperparathyroidism is characterized by autonomous parathyroid hormone (PTH) hypersecretion causing hypercalcemia, while secondary hyperparathyroidism represents a compensatory physiologic response with elevated PTH attempting to correct hypocalcemia or hyperphosphatemia due to underlying organ dysfunction—most commonly chronic kidney disease. 1

Etiology

Primary Hyperparathyroidism (PHPT)

• Single parathyroid adenoma accounts for approximately 80% of cases, making it the most common etiology 1
• Multigland disease (hyperplasia) affects 15-20% of patients 1
• Parathyroid carcinoma is rare, occurring in less than 1% of cases 1
• The pathophysiology involves autonomous PTH secretion independent of calcium feedback mechanisms 1

Secondary Hyperparathyroidism (SHPT)

• SHPT represents a compensatory physiologic response where increased PTH production attempts to correct calcium homeostasis but fails due to underlying organ dysfunction or reduced calcium availability 1
• Chronic kidney disease is the most common cause, as declining renal function leads to phosphate retention, decreased calcitriol production, and impaired calcium absorption 1
• The three primary drivers are: hyperphosphatemia, hypocalcemia, and vitamin D deficiency 1
• Other causes include malabsorption syndromes and vitamin D deficiency 2

Laboratory Findings

Diagnostic Distinctions Table

Feature	Primary HPT	Secondary HPT
Calcium	Elevated	Normal or low
PTH	Elevated or inappropriately normal	Elevated
Phosphorus	Low or low-normal	Elevated (in CKD)
Pathophysiology	Autonomous PTH secretion	Compensatory PTH response

1

Primary Hyperparathyroidism Laboratory Profile

• The combination of hypercalcemia with elevated or inappropriately normal PTH levels is diagnostic of primary hyperparathyroidism 1, 3
• Serum phosphate is typically low or low-normal 1
• Most patients demonstrate hypercalciuria (>250-300 mg/day) due to increased filtered calcium load from hypercalcemia 1
• Alkaline phosphatase may be elevated if bone disease is present 1

Secondary Hyperparathyroidism Laboratory Profile

• Normal or low serum calcium with elevated PTH is the hallmark finding 1
• Hyperphosphatemia is defined as serum phosphorus >4.6 mg/dL in CKD stages 3-4, or >5.5 mg/dL in stage 5 1
• Hypocalcemia is defined as corrected serum calcium <8.4 mg/dL 1
• Vitamin D deficiency is defined as 25(OH)D <30 ng/mL 1
• Alkaline phosphatase is often elevated, suggesting high bone turnover 1

Critical Diagnostic Pitfall

• Vitamin D deficiency can complicate interpretation of PTH levels in both conditions and must be assessed 1, 3
• Different PTH assay generations measure different PTH fragments and can yield significantly different values, requiring use of assay-specific reference ranges 1

Management Approaches

Primary Hyperparathyroidism Management

• Parathyroidectomy is the only curative therapy for PHPT 2, 4
• Most patients have a single adenoma, allowing for minimally invasive parathyroidectomy (MIP) with shorter operating times, faster recovery, and decreased perioperative costs 2
• Bilateral neck exploration (BNE) remains necessary in cases of discordant or nonlocalizing preoperative imaging or when there is high suspicion for multigland disease 2
• Imaging has no utility in confirming or excluding the diagnosis of PHPT—it is used only for localization after biochemical diagnosis is established 2
• Preoperative imaging is essential in the reoperative setting to localize target parathyroid lesions 2

Secondary Hyperparathyroidism Management Algorithm

Step 1: Control Hyperphosphatemia First

• Target serum phosphorus between 3.5-5.5 mg/dL for stage 5 CKD patients 5
• Initiate dietary phosphorus restriction to 800-1,000 mg/day, adjusted for protein needs (1.0-1.2 g/kg/day for dialysis patients) 5
• Provide supplemental calcium carbonate 1-2 g three times daily with meals, serving dual purpose as phosphate binder and calcium supplement 5
• Monitor serum phosphorus monthly after initiating therapy 5

Step 2: Address Vitamin D Deficiency

• Supplement with ergocalciferol (vitamin D2) 50,000 IU monthly if 25(OH)D levels are below 30 ng/mL 5
• Recheck 25(OH)D annually once replete 5

Step 3: Initiate Active Vitamin D Therapy

• Do not initiate active vitamin D therapy until serum phosphorus falls below 4.6 mg/dL, as this worsens vascular calcification and increases calcium-phosphate product 5
• Target PTH levels of 150-300 pg/mL for stage 5 CKD/dialysis patients, not normal range, as suppressing PTH to <65 pg/mL causes adynamic bone disease 5
• Vitamin D therapy with intermittent intravenous calcitriol or paricalcitol is more effective than oral administration in hemodialysis patients 5
• Monitor calcium and phosphorus monthly for the first 3 months, then every 3 months 5
• Monitor PTH every 3 months 5

Step 4: Add Calcimimetics if Needed

• If PTH remains elevated despite optimized vitamin D therapy, consider adding calcimimetics (cinacalcet, etelcalcetide, evocalcet, or upacicalcet) 5

Step 5: Consider Parathyroidectomy

• Parathyroidectomy should be considered if PTH remains persistently >800 pg/mL with hypercalcemia and/or hyperphosphatemia refractory to medical therapy 5
• Surgical excision is recommended for medically refractory cases of SHPT 2
• As SHPT typically involves multigland disease (parathyroid hyperplasia), the goal of imaging is to identify all eutopic and potential ectopic or supernumerary glands 2
• Total parathyroidectomy (TPTX) may be superior to total parathyroidectomy with autotransplantation (TPTX+AT) in terms of lower recurrence rates 5

Tertiary Hyperparathyroidism

• Tertiary hyperparathyroidism is marked by hypercalcemia with elevated PTH, representing autonomous PTH hypersecretion after longstanding secondary hyperparathyroidism 1
• Most commonly encountered following kidney transplantation in patients with long-standing chronic kidney disease 2, 1
• Unlike secondary hyperparathyroidism, PTH remains elevated despite rising serum calcium levels 2
• Typically involves multigland disease (parathyroid hyperplasia) 1
• Surgical excision is recommended for medically refractory cases 2

Critical Management Pitfalls to Avoid

• Never start vitamin D therapy with uncontrolled hyperphosphatemia in SHPT, as this worsens vascular calcification and increases calcium-phosphate product 5
• Never target normal PTH levels (<65 pg/mL) in dialysis patients, as this causes adynamic bone disease with increased fracture risk 5
• Never use imaging to confirm or exclude the diagnosis of hyperparathyroidism—diagnosis is purely biochemical 2
• Always assess vitamin D status when interpreting PTH levels, as deficiency can mask or complicate the diagnosis 1, 3