What are the etiologies, clinical presentation, laboratory findings, and management strategies for primary hyperparathyroidism compared with secondary hyperparathyroidism?

Primary vs Secondary Hyperparathyroidism

Distinguishing Feature: Serum Calcium

Primary hyperparathyroidism is defined by hypercalcemia with elevated or inappropriately normal PTH, whereas secondary hyperparathyroidism presents with normal or low serum calcium despite elevated PTH. 1, 2

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Etiology

Primary Hyperparathyroidism

• Parathyroid adenoma accounts for 80–90% of cases, representing autonomous hypersecretion of PTH by a single gland. 3, 4
• Multigland hyperplasia causes a smaller percentage of cases. 5
• Parathyroid carcinoma is rare, occurring in only 1–5% of patients with primary hyperparathyroidism. 6

Secondary Hyperparathyroidism

• Chronic kidney disease (CKD) is the most common cause; reduced 1,25(OH)₂D production leads to decreased intestinal calcium absorption and impaired PTH suppression. 1
• Vitamin D deficiency (25-hydroxyvitamin D <30 ng/mL) is present in 47–76% of CKD stage 3–4 patients and aggravates secondary hyperparathyroidism even in those with normal kidney function. 1
• Dietary calcium deficiency can trigger compensatory PTH elevation. 2

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Clinical Presentation

Primary Hyperparathyroidism

• Most patients are now asymptomatic, discovered incidentally on routine serum chemistry showing hypercalcemia. 4, 5
• Moderate hypercalcemia (10.2–14 mg/dL) causes polyuria, polydipsia, nausea, vomiting, abdominal pain, myalgia, and confusion. 2
• Severe hypercalcemia (>14 mg/dL) produces mental status changes, bradycardia, hypotension, severe dehydration, and acute renal failure. 2
• Neuropsychiatric manifestations include refractory depression, emotional lability, impaired cognition, "brain fog," and memory loss—these are recognized target-organ manifestations justifying surgical intervention when disabling. 2
• Bone disease and kidney stones were the classic presentation but are now less common at diagnosis. 4

Secondary Hyperparathyroidism

• Symptoms relate to the underlying cause (CKD, vitamin D deficiency) rather than hypercalcemia. 1
• Bone pain, fractures, and skeletal deformities occur with prolonged, untreated disease due to high bone turnover. 1
• Vascular calcification develops when hyperphosphatemia is uncontrolled, particularly if vitamin D therapy is initiated prematurely. 1
• Patients are typically normocalcemic or hypocalcemic, distinguishing them from primary hyperparathyroidism. 2, 7

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Laboratory Findings

Primary Hyperparathyroidism

• Serum calcium: Elevated (>10.2 mg/dL); corrected calcium >1 mg/dL above upper limit of normal indicates more severe disease. 2, 8
• Intact PTH: Elevated or inappropriately normal (fails to suppress below 20 pg/mL despite hypercalcemia). 2, 8
• Serum phosphorus: Low or low-normal. 8, 3
• 24-hour urine calcium: Most patients have hypercalciuria (>250–300 mg/day); levels >400 mg/day signal increased risk for kidney stones and bone complications and constitute a surgical indication. 2, 8
• 25-hydroxyvitamin D: Should be measured to exclude vitamin D deficiency as a secondary cause of PTH elevation; target >20 ng/mL. 2, 8
• Alkaline phosphatase: May be elevated, suggesting high bone turnover. 1

Secondary Hyperparathyroidism

• Serum calcium: Normal or low. 2, 7
• Intact PTH: Elevated; begins to rise when eGFR falls below 60 mL/min/1.73 m². 1, 8
• Serum phosphorus: Elevated as renal function declines, driving PTH secretion. 1
• 25-hydroxyvitamin D: Often low (<30 ng/mL), aggravating hyperparathyroidism. 1
• 1,25-dihydroxyvitamin D: Low in CKD (reduced renal conversion); elevated in granulomatous disease despite low 25-OH vitamin D. 1, 2
• Alkaline phosphatase: Elevated, suggesting high bone turnover; adds predictive value when interpreting PTH levels. 1
• Serum creatinine and eGFR: Abnormal, reflecting underlying CKD. 1

Critical Laboratory Considerations

• PTH assays vary by up to 47% between different generations; always use assay-specific reference values. 2, 8
• PTH is most stable in EDTA plasma at 4°C, not serum. 2, 8
• Biotin supplementation interferes with PTH immunoassays, causing under- or overestimation. 2
• Biological variation of PTH is substantial (~20% in healthy individuals); changes must exceed 54% to be clinically meaningful. 2

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Management Strategies

Primary Hyperparathyroidism

Surgical Management (Definitive Therapy)

• Parathyroidectomy is the only curative treatment and is indicated for: 2, 8

  • Corrected calcium >1 mg/dL above upper limit of normal
  • Age <50 years
  • Impaired kidney function (eGFR <60 mL/min/1.73 m²)
  • Osteoporosis (T-score ≤−2.5 at any site)
  • History of nephrolithiasis or nephrocalcinosis
  • 24-hour urine calcium >400 mg/day
  • Disabling neuropsychiatric symptoms
  • Symptomatic hypercalcemia

• Preoperative localization imaging (ultrasound and/or ⁹⁹ᵐTc-sestamibi SPECT/CT) is performed only after biochemical diagnosis is confirmed and surgery is planned—imaging does not diagnose hyperparathyroidism. 2, 8

• Refer to high-volume, experienced parathyroid surgeons; outcomes (cure rates, complication profiles) are significantly better with specialized expertise. 2

• Minimally invasive parathyroidectomy is feasible when a single adenoma is localized preoperatively, offering shorter operative time and faster recovery. 2

Post-Parathyroidectomy Care

• Monitor ionized calcium every 4–6 hours for the first 48–72 hours to detect "hungry bone syndrome"—rapid calcium decline after removal of hyperfunctioning tissue. 1, 2
• If ionized calcium drops below 0.9 mmol/L (≈3.6 mg/dL), start IV calcium gluconate infusion at 1–2 mg elemental calcium/kg/hour. 2
• Begin oral calcium carbonate 1–2 g three times daily plus calcitriol up to 2 µg/day once oral intake is tolerated. 2

Medical Management (Non-Surgical Candidates)

• Maintain normal calcium intake (1000–1200 mg/day); avoid high or low calcium diets. 2
• Ensure 25-hydroxyvitamin D >20 ng/mL with ergocalciferol or cholecalciferol supplementation. 2
• Avoid calcitriol or active vitamin D analogs, as they increase intestinal calcium absorption and exacerbate hypercalcemia. 2
• Monitor serum calcium every 3 months for patients with eGFR <60 mL/min/1.73 m² who are not surgical candidates. 2

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Secondary Hyperparathyroidism

Immediate Priority: Control Hyperphosphatemia

• Target serum phosphorus 3.5–5.5 mg/dL for stage 5 CKD patients. 1
• Initiate dietary phosphorus restriction to 800–1,000 mg/day, adjusted for protein needs (1.0–1.2 g/kg/day for dialysis patients). 1
• Add phosphate binders (calcium-based or non-calcium-based) if dietary restriction is insufficient. 1
• Monitor serum phosphorus monthly after initiating therapy. 1

Address Hypocalcemia

• Provide supplemental calcium carbonate 1–2 g three times daily with meals, serving dual purpose as phosphate binder and calcium supplement. 1
• Measure calcium within 1 week of initiating therapy. 1

Vitamin D Therapy

• Do not initiate active vitamin D therapy until serum phosphorus falls below 4.6 mg/dL—starting vitamin D with uncontrolled hyperphosphatemia worsens vascular calcification and increases calcium-phosphate product. 1
• Replete nutritional vitamin D first: ergocalciferol 50,000 IU monthly if 25(OH)D <30 ng/mL; recheck annually once replete. 1
• For hemodialysis patients, intermittent IV calcitriol or paricalcitol is more effective than oral administration in suppressing PTH. 1
• Target PTH 150–300 pg/mL for stage 5 CKD/dialysis patients—do not target normal range (<65 pg/mL), as this causes adynamic bone disease with increased fracture risk. 1
• Monitor calcium and phosphorus monthly for the first 3 months, then every 3 months; monitor PTH every 3 months. 1
• Discontinue or reduce vitamin D therapy if serum calcium rises above 10.2 mg/dL. 1

Dose Escalation for Persistent Hyperparathyroidism

• For PTH >800 pg/mL on hemodialysis, increase vitamin D dose to 10–15 mcg three times weekly; doses below 0.75–1.0 mcg per treatment are often ineffective. 1
• Measure PTH 4 weeks after dose adjustment; continue escalating every 2–4 weeks until PTH reaches 150–300 pg/mL. 1
• Severe hyperparathyroidism requires 12–24 weeks of treatment due to downregulated vitamin D receptors in nodular parathyroid glands. 1

Calcimimetics

• Consider adding calcimimetics (cinacalcet, etelcalcetide, evocalcet, or upacicalcet) if PTH remains elevated despite optimized vitamin D therapy. 1
• In X-linked hypophosphatemia, cinacalcet has been linked to severe hypocalcemia and prolonged QT interval—use with caution. 1

Surgical Management

• Parathyroidectomy is indicated if PTH remains persistently >800 pg/mL with hypercalcemia and/or hyperphosphatemia refractory to medical therapy after 3–6 months of optimized treatment. 1
• Total parathyroidectomy (TPTX) may be superior to TPTX with autotransplantation (TPTX+AT) in terms of lower recurrence rates (OR 0.17,95% CI 0.06–0.54) and shorter operative time, though TPTX carries higher risk of hypoparathyroidism (OR 2.97,95% CI 1.09–8.08). 1
• Parathyroidectomy is associated with lower mortality than calcimimetics in observational data and shows more substantial increase in bone mineral density. 1

Monitoring Schedule

• CKD Stage 3: Measure calcium, phosphorus, and PTH every 12 months. 1
• CKD Stage 4: Measure every 3 months. 1
• CKD Stage 5 (dialysis): Measure every 3 months; increase to monthly calcium/phosphorus monitoring when on active vitamin D or phosphate binders. 1

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Common Pitfalls to Avoid

Primary Hyperparathyroidism

• Do not order parathyroid imaging before confirming biochemical diagnosis—imaging is for surgical planning, not diagnosis. 2
• Do not supplement with vitamin D until hypercalcemia is resolved; discontinue all vitamin D therapy if calcium exceeds 10.2 mg/dL. 2
• Do not use calcitriol or active vitamin D analogs in primary hyperparathyroidism, as they worsen hypercalcemia. 2
• Do not ignore vitamin D deficiency when interpreting PTH levels—vitamin D deficiency causes secondary hyperparathyroidism and must be excluded before diagnosing primary hyperparathyroidism. 2, 8

Secondary Hyperparathyroidism

• Never start active vitamin D therapy with uncontrolled hyperphosphatemia (>4.6 mg/dL)—this markedly worsens vascular calcification and increases calcium-phosphate product, which should never exceed 70 mg²/dL². 1
• Never target normal PTH levels (<65 pg/mL) in dialysis patients—this causes adynamic bone disease with increased fracture risk and reduced bone capacity to buffer calcium-phosphate loads. 1
• Do not increase vitamin D doses more frequently than every 2–4 weeks—PTH suppression is delayed, and premature escalation causes hypercalcemia. 1
• Do not ignore alkaline phosphatase—rising alkaline phosphatase with elevated PTH suggests progressive bone disease and adds predictive value when interpreting PTH levels. 1