What does hyperparathyroidism with elevated serum calcium indicate?

Hyperparathyroidism with Elevated Calcium: Primary Hyperparathyroidism

Hyperparathyroidism with elevated serum calcium indicates primary hyperparathyroidism (PHPT), a disorder in which the parathyroid glands autonomously secrete excessive PTH despite hypercalcemia, driving calcium release from bone, increased renal calcium reabsorption, and enhanced intestinal calcium absorption through stimulated 1,25-dihydroxyvitamin D production. 1

Diagnostic Confirmation

The biochemical hallmark is elevated or inappropriately normal PTH in the presence of hypercalcemia (corrected calcium >10.2 mg/dL, with normal range 8.6-10.3 mg/dL). 1 This combination confirms that the parathyroid glands are failing to suppress PTH secretion in response to elevated calcium—the defining feature of PHPT. 1

Essential Laboratory Panel

• Measure serum calcium (corrected for albumin), intact PTH, 25-hydroxyvitamin D, serum phosphorus, and serum creatinine/eGFR simultaneously. 1
• Use the correction formula: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)] to avoid pseudo-hypercalcemia when albumin is abnormal. 1, 2
• Measure ionized calcium (normal 4.65-5.28 mg/dL) for definitive assessment, as it is more sensitive than total calcium and correlates better with PTH levels and adenoma size. 1, 3
• Serum phosphorus is typically low-normal in PHPT due to PTH-mediated renal phosphate wasting, distinguishing it from CKD-related secondary hyperparathyroidism (which shows elevated phosphorus). 1, 4

PTH Measurement Considerations

• Use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma kept at 4°C. 1
• PTH assays vary by up to 47% between different generations; always use assay-specific reference ranges. 1
• Biological variation of PTH is substantial (~20% in healthy individuals), so changes must exceed 54% to be clinically meaningful. 1
• Biotin supplementation can interfere with PTH immunoassays, leading to falsely low or high results. 1

Pathophysiology: Why Calcium Is Elevated

The hypercalcemia in PHPT results from three PTH-mediated mechanisms operating simultaneously:

1. Increased Renal Calcium Reabsorption (Primary Driver)

• PTH directly stimulates calcium reabsorption in the distal renal tubules while promoting phosphate excretion, which appears to be the pivotal mechanism maintaining hypercalcemia. 5
• This renal tubular effect may play a more central role than skeletal calcium release in sustaining elevated calcium levels. 5

2. Enhanced Intestinal Calcium Absorption

• PTH stimulates renal 1-α-hydroxylase to convert 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D, which increases intestinal calcium absorption. 6, 7
• In patients with adequate vitamin D stores, intestinal hyperabsorption becomes the primary source of excess calcium, increasing the risk of nephrolithiasis. 7

3. Increased Bone Calcium Release

• PTH mobilizes calcium and phosphate from bone through increased osteoclastic resorption. 6
• In patients with vitamin D deficiency, bone resorption predominates, leading to osteoarticular symptoms and osteitis fibrosa cystica. 7

Differential Diagnosis: Excluding Secondary Causes

Before confirming PHPT, exclude secondary hyperparathyroidism, which presents with elevated PTH but hypocalcemia or normal calcium—never hypercalcemia. 1, 4

Critical Exclusions

• Measure 25-hydroxyvitamin D and ensure levels >20 ng/mL (>50 nmol/L), as vitamin D deficiency is the most common cause of secondary hyperparathyroidism and must be ruled out. 1
• Confirm adequate dietary calcium intake (1,000-1,200 mg/day for adults), as low intake can cause compensatory PTH elevation. 1
• Assess renal function (eGFR ≥60 mL/min/1.73 m²), because CKD causes secondary hyperparathyroidism with elevated PTH, low-normal calcium, and elevated phosphorus. 1, 4
• Measure 1,25-dihydroxyvitamin D alongside 25-hydroxyvitamin D to distinguish PHPT (both elevated) from granulomatous disease like sarcoidosis (25-OH low, 1,25-OH elevated) or vitamin D intoxication (25-OH markedly elevated). 1

Familial Hypocalciuric Hypercalcemia (FHH)

• FHH mimics PHPT with hypercalcemia and inappropriately normal PTH but is caused by calcium-sensing receptor mutations. 6
• Measure 24-hour urine calcium or spot urine calcium/creatinine ratio; FHH shows low urinary calcium (<100 mg/24hr or calcium/creatinine ratio <0.01), whereas PHPT typically shows normal or elevated urinary calcium. 1, 6

Clinical Significance and Severity Stratification

Mild Hypercalcemia (10.2-12 mg/dL)

• Symptoms include polyuria, polydipsia, nausea, vomiting, abdominal pain, myalgia, and confusion. 1
• Many patients are asymptomatic and discovered incidentally on routine laboratory testing. 8

Moderate Hypercalcemia (12-13.5 mg/dL)

• Symptoms intensify with anorexia, asthenia, persistent constipation, and progressive dehydration. 8

Severe Hypercalcemia (>14 mg/dL)

• Life-threatening manifestations include mental status changes, bradycardia, hypotension, severe dehydration, acute renal failure, and risk of cardiac arrest. 1, 8
• Requires emergency treatment with aggressive IV crystalloid hydration (normal saline), loop diuretics after volume restoration, and IV bisphosphonates (zoledronic acid or pamidronate). 1

Surgical Indications

Parathyroidectomy is the definitive treatment for PHPT and is indicated when:

• Corrected calcium >1 mg/dL above the upper limit of normal (>11.3 mg/dL) 1
• Age <50 years 1
• Impaired kidney function (eGFR <60 mL/min/1.73 m²) 1
• Osteoporosis (T-score ≤-2.5 at any site) 1
• History of nephrolithiasis or nephrocalcinosis 1
• 24-hour urinary calcium >300 mg 1
• Patient preference for definitive treatment 1

Preoperative Localization

• Do not order parathyroid imaging (ultrasound or 99mTc-sestamibi SPECT/CT) before confirming the biochemical diagnosis; imaging is for surgical planning only, not diagnosis. 1
• Refer to endocrinology and an experienced, high-volume parathyroid surgeon, as outcomes are significantly better with specialized expertise. 1

Medical Management for Non-Surgical Candidates

If surgery is declined or contraindicated:

• Maintain normal calcium intake (1,000-1,200 mg/day); avoid both high and low calcium diets. 1
• Total elemental calcium intake should not exceed 2,000 mg/day. 1
• Ensure 25-hydroxyvitamin D levels >20 ng/mL with ergocalciferol or cholecalciferol supplementation, but never use calcitriol or active vitamin D analogs, as they increase intestinal calcium absorption and worsen hypercalcemia. 1
• Ensure adequate oral hydration and discontinue thiazide diuretics, which reduce urinary calcium excretion. 1
• Monitor serum calcium every 3 months for patients with eGFR >30 mL/min/1.73 m². 1

Tertiary Hyperparathyroidism: The Autonomous Evolution

• Prolonged secondary hyperparathyroidism (e.g., from untreated CKD or vitamin D deficiency) can evolve into tertiary hyperparathyroidism, in which parathyroid glands become autonomously hyperplastic and secrete PTH despite hypercalcemia. 8, 6
• The biochemical profile shifts from low calcium (secondary) to high calcium (tertiary) with markedly elevated PTH (often >800 pg/mL) and concurrent hyperphosphatemia. 4, 6
• This represents autonomous nodular parathyroid hyperplasia with down-regulated vitamin D receptors, requiring parathyroidectomy if refractory to medical therapy. 4, 6

Critical Pitfalls to Avoid

• Never assume CKD itself causes hypercalcemia—CKD causes hypocalcemia through impaired 1,25-dihydroxyvitamin D production and phosphate retention. 2 Hypercalcemia in CKD patients indicates iatrogenic causes (calcium-based phosphate binders, vitamin D analogs) or tertiary hyperparathyroidism. 2
• Never rely on corrected calcium alone; measure ionized calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling. 2
• Never delay surgical referral for persistent hypercalcemia >12 mg/dL, as this leads to progressive renal damage, nephrocalcinosis, and bone disease. 4
• Never order parathyroid imaging before confirming the biochemical diagnosis; imaging is for surgical planning only. 1, 4