What are the causes and treatments of hypocalcemia (low calcium levels)?

Causes of Hypocalcemia

Primary Etiologic Categories

Hypocalcemia results from either PTH-mediated or non-PTH-mediated mechanisms, with hypoparathyroidism (most commonly post-surgical) being the single most frequent cause, followed by vitamin D deficiency and disorders of vitamin D metabolism. 1, 2, 3, 4

PTH-Mediated Causes

Hypoparathyroidism is the predominant PTH-mediated cause and accounts for the majority of chronic hypocalcemia cases:

• Post-surgical hypoparathyroidism represents 75% of all hypoparathyroidism cases, occurring after anterior neck surgery including thyroidectomy or parathyroidectomy 1, 2, 5, 4, 6
• Primary (non-surgical) hypoparathyroidism accounts for 25% of cases and includes autoimmune destruction, genetic abnormalities (including 22q11.2 deletion syndrome with 80% lifetime prevalence of hypocalcemia), and infiltrative disorders of the parathyroids 1, 2, 6
• Impaired PTH secretion due to hypomagnesemia or hypermagnesemia, which disrupts normal parathyroid function 2, 6

Non-PTH-Mediated Causes

Vitamin D deficiency and disorders of vitamin D metabolism represent the second major category:

• Vitamin D deficiency from inadequate intake, malabsorption, or lack of sunlight exposure 2, 3, 5, 4
• Impaired 1α,25-dihydroxyvitamin D production in chronic kidney disease, where decreased renal conversion of 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D reduces intestinal calcium absorption 1, 7
• Vitamin D-dependent rickets type I due to genetic defects in 1α-hydroxylase 7
• Resistance to 1,25-dihydroxyvitamin D (pseudohypoparathyroidism), characterized by elevated PTH with hypocalcemia due to end-organ resistance 6, 7

Chronic Kidney Disease-Related Mechanisms

In CKD, hypocalcemia develops through multiple interconnected pathways:

• Phosphate retention leads to decreased ionized calcium, which stimulates compensatory PTH release (secondary hyperparathyroidism) 1, 2
• Reduced vitamin D activation in diseased kidneys decreases duodenal and jejunal calcium absorption 1
• Impaired passive intestinal calcium absorption can be partially compensated by increasing calcium intake 1

Hypomagnesemia

Hypomagnesemia causes hypocalcemia through dual mechanisms: impaired PTH secretion and end-organ resistance to PTH, explaining why calcium supplementation alone fails without concurrent magnesium correction 1, 2, 8, 6

Iatrogenic and Medication-Related Causes

• Calcium-chelating agents: Citrate in blood products during massive transfusion binds calcium, with citrate metabolism further impaired by hypoperfusion, hypothermia, and hepatic insufficiency 2, 8
• Loop diuretics increase urinary calcium excretion 2
• Bisphosphonates and denosumab can cause severe hypocalcemia, particularly in patients with vitamin D deficiency or renal impairment 1, 2
• Calcimimetics cause hypocalcemia in 7-9% of dialysis patients, likely underreported 8
• Post-parathyroidectomy hungry bone syndrome: Rapid bone remineralization after correction of hyperparathyroid bone disease 1, 8

Genetic Syndromes

22q11.2 deletion syndrome deserves special mention due to its high prevalence of hypocalcemia:

• 80% lifetime history of hypocalcemia due to underlying parathyroid dysfunction 1, 2, 8
• Hypocalcemia may arise or recur at any age, even in patients with apparent childhood resolution 1, 2, 8
• Risk increases during biological stress (surgery, childbirth, infection, puberty, pregnancy) 1, 2

Precipitating Factors and Exacerbating Conditions

Even in patients with underlying parathyroid dysfunction, specific triggers can unmask or worsen hypocalcemia:

• Biological stressors: Surgery, fractures, injuries, childbirth, acute illness, fever 1, 2, 8
• Dietary factors: Decreased oral calcium intake, alcohol consumption, carbonated beverages (especially colas) 1, 2, 8
• Associated endocrine disorders: Hypothyroidism may be a contributory condition 1, 2

Tumor Lysis Syndrome

Rapid cell breakdown releases intracellular phosphate, which binds calcium and precipitates hypocalcemia, particularly when phosphate levels are markedly elevated 8

Critical Clinical Pearls

• Hypocalcemia can trigger seizures at any age in patients with underlying parathyroid dysfunction, even without prior history of hypocalcemia or seizures 1
• Hypomagnesemia is present in 28% of hypocalcemic patients and must be corrected concurrently, as hypocalcemia cannot be adequately treated without addressing magnesium deficiency first 8
• Measure pH-corrected ionized calcium rather than total calcium for most accurate diagnosis, as acid-base status significantly affects ionized calcium (0.1 unit pH increase decreases ionized calcium by approximately 0.05 mmol/L) 2
• Check PTH levels to distinguish between PTH-mediated (low/inappropriately normal PTH) and non-PTH-mediated causes (elevated PTH in vitamin D deficiency or pseudohypoparathyroidism) 2, 4, 6