Pathophysiology of Hypercalcemia and Hypocalcemia
Calcium homeostasis is maintained through the coordinated actions of parathyroid hormone (PTH), vitamin D, and fibroblast growth factor 23 (FGF23) acting on bone, kidney, intestine, and parathyroid glands—disruption of these mechanisms leads to hypercalcemia or hypocalcemia through distinct pathophysiologic pathways. 1
Normal Calcium Regulation
The body maintains serum calcium through three key hormonal systems 1:
PTH response to hypocalcemia: The calcium-sensing receptor on parathyroid glands detects low calcium and triggers PTH release, which increases calcium through three mechanisms: (1) stimulating 1-α-hydroxylase (CYP27B1) to convert 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D for intestinal calcium absorption, (2) increasing renal tubular calcium reabsorption while decreasing phosphate reabsorption, and (3) mobilizing calcium and phosphate from bone via PTH1R receptor activation 1
Vitamin D metabolism: 1,25-dihydroxyvitamin D increases intestinal calcium absorption through vitamin D receptor binding, completing the calcium-raising response 1
FGF23 counterregulation: Released by osteocytes in response to high phosphate, PTH, and 1,25-dihydroxyvitamin D, FGF23 increases renal phosphate excretion and inhibits CYP27B1, thereby decreasing 1,25-dihydroxyvitamin D production 1
Pathophysiology of Hypercalcemia
PTH-Mediated Hypercalcemia
Primary hyperparathyroidism is characterized by inappropriately elevated or normal PTH levels despite hypercalcemia 2:
Mechanism: Autonomous PTH secretion from parathyroid adenoma or hyperplasia leads to excessive bone resorption, increased renal calcium reabsorption, and enhanced intestinal calcium absorption via increased 1,25-dihydroxyvitamin D production 2, 3
Laboratory pattern: Elevated intact PTH with elevated calcitriol (1,25-dihydroxyvitamin D) levels 2
Normocalcemic variant: Some patients present with elevated PTH but normal calcium values, yet remain at risk for complications—accurate PTH measurement is essential for this diagnosis 1
Malignancy-Associated Hypercalcemia
This occurs in 10-25% of lung cancer patients, most commonly squamous cell carcinoma, with median survival approximately 1 month 2:
PTHrP-mediated: Tumors secrete parathyroid hormone-related protein (PTHrP), which mimics PTH actions on bone and kidney but suppresses endogenous PTH production 2, 3
Laboratory pattern: Decreased PTH with elevated PTHrP; 25-hydroxyvitamin D is decreased because hypercalcemia suppresses PTH, which normally stimulates 1,25-dihydroxyvitamin D production 2
Osteolytic metastases: Direct bone destruction releases calcium, particularly in breast cancer and multiple myeloma 3
Vitamin D-Mediated Hypercalcemia
Granulomatous diseases (sarcoidosis, lymphomas): Extrarenal 1-α-hydroxylase activity in granulomas or lymphoma cells produces excessive 1,25-dihydroxyvitamin D, causing increased intestinal calcium absorption 2, 4
Laboratory pattern: Low 25-hydroxyvitamin D but elevated 1,25-dihydroxyvitamin D due to increased 1-α-hydroxylase activity in granulomas 2
Vitamin D intoxication: Excessive hepatic production of 25-hydroxyvitamin D leads to increased calcium absorption 4
Secondary Hyperparathyroidism in Chronic Kidney Disease
Declining kidney function triggers compensatory PTH elevation through multiple pathways 1:
Mechanisms: Hyperphosphatemia, hypocalcemia, decreased 1,25-dihydroxyvitamin D production, and elevated FGF23 all stimulate PTH secretion 1
C-terminal PTH fragment accumulation: These fragments accumulate with kidney disease (half-life 5-10 times longer than full-length PTH), complicating PTH measurement and potentially contributing to mineral bone disease 1
Progression to tertiary hyperparathyroidism: Prolonged stimulation can lead to autonomous PTH secretion and hypercalcemia 2
Pathophysiology of Hypocalcemia
Hypoparathyroidism
Decreased or absent PTH production is the most common cause 1, 5:
Surgical hypoparathyroidism (75% of cases): Parathyroid gland removal or damage during thyroid/parathyroid surgery eliminates PTH production 6
Primary hypoparathyroidism (25% of cases): Autoimmune destruction or genetic disorders (including 22q11.2 deletion syndrome where 80% develop hypocalcemia) 1
Pathophysiologic consequences: Loss of PTH eliminates renal calcium reabsorption, decreases 1,25-dihydroxyvitamin D production (reducing intestinal absorption), and prevents bone calcium mobilization 1, 5
Vitamin D Deficiency
Impaired 1,25-dihydroxyvitamin D production: Whether from inadequate substrate (25-hydroxyvitamin D deficiency), impaired renal 1-α-hydroxylase activity (chronic kidney disease), or genetic defects (vitamin D-dependent rickets type I), the result is decreased intestinal calcium absorption 4
Secondary hyperparathyroidism: PTH rises appropriately in response to hypocalcemia, distinguishing this from primary hypoparathyroidism 2, 5
Pseudohypoparathyroidism
- End-organ resistance: Normal or elevated PTH levels with hypocalcemia due to PTH1R resistance—the hormone is present but tissues cannot respond 4
Hypomagnesemia
- Dual mechanism: Magnesium deficiency both impairs PTH secretion and causes PTH resistance at target tissues, creating functional hypoparathyroidism 1
Critical Illness and Precipitating Factors
Hypocalcemia can be triggered or worsened by 1:
- Fever, ischemia, hypoxia, surgery (particularly thyroid/parathyroid procedures)
- Medications including antipsychotics
- Hyperprolinemia
- Biological stress (infection, childbirth)
- Alcohol or carbonated beverages (particularly colas)
Clinical Consequences and Complications
Hypercalcemia Manifestations
Moderate hypercalcemia: Polyuria, polydipsia, nausea, vomiting, abdominal pain, myalgia, confusion 2
Severe hypercalcemia (>14 mg/dL): Mental status changes, bradycardia, hypotension, severe dehydration, acute renal failure 2
Hypocalcemia Manifestations
Symptoms relate to neuromuscular excitability 1:
- Seizures (can occur at any age, even without prior history, due to underlying parathyroid dysfunction)
- Fatigue, emotional irritability
- Abnormal involuntary movements
- Cardiac arrhythmias with QT interval prolongation
- Long-term: osteopenia/osteoporosis
Important Clinical Pitfalls
PTH measurement variability: PTH assays differ by up to 47% between generations due to varying antibody recognition of PTH fragments and post-translational modifications—use assay-specific reference values and trend monitoring within the same laboratory 1, 2
Vitamin D status affects PTH interpretation: PTH reference values are 20% lower in vitamin D-replete individuals; vitamin D deficiency must be excluded before diagnosing primary hyperparathyroidism as it causes appropriate secondary PTH elevation 2
22q11.2 deletion syndrome: Hypocalcemia can emerge at any age despite no prior history, requiring lifelong vigilance and calcium/vitamin D supplementation for all affected adults 1
Post-bariatric surgery: Secondary hyperparathyroidism develops in up to 63% of patients at 5 years due to malabsorption of calcium and vitamin D 1