What are the causes of hypocalcemia?

Causes of Hypocalcemia

Hypocalcemia results from either PTH-mediated disorders (primarily hypoparathyroidism) or non-PTH-mediated mechanisms including vitamin D deficiency, chronic kidney disease, magnesium depletion, and medication effects. 1, 2

PTH-Mediated Causes

Hypoparathyroidism

• Postsurgical hypoparathyroidism is the most common cause of chronic hypocalcemia, accounting for approximately 75% of hypoparathyroidism cases. 2, 3
• Primary (non-surgical) hypoparathyroidism accounts for the remaining 25% of cases. 2
• Genetic disorders, particularly 22q11.2 deletion syndrome, carry an 80% lifetime prevalence of hypocalcemia due to underlying parathyroid dysfunction and can manifest at any age, even without prior neonatal hypocalcemia. 1, 2, 4

Non-PTH-Mediated Causes

Vitamin D Disorders

• Vitamin D deficiency is one of the two most common causes of hypocalcemia (along with hypoparathyroidism), as vitamin D is essential for intestinal calcium absorption. 5, 3
• Impaired production of 1,25-dihydroxyvitamin D reduces intestinal calcium absorption and can lead to chronic hypocalcemia. 2
• Disorders disrupting vitamin D metabolism include impaired hepatic 25-hydroxylation, decreased renal 1-alpha-hydroxylation (as in chronic kidney disease), and end-organ resistance. 6

Chronic Kidney Disease

• In CKD, three interrelated mechanisms cause hypocalcemia: (a) phosphate retention, (b) skeletal resistance to PTH, and (c) altered vitamin D metabolism. 7
• Phosphate retention leads to decreased ionized calcium, which directly stimulates PTH release and causes secondary hyperparathyroidism. 7, 2
• Decreased vitamin D activation in kidney disease compounds the problem by reducing intestinal calcium absorption. 7, 2
• Progressive loss of kidney function decreases vitamin D receptors (VDR) and calcium-sensing receptors (CaR) in parathyroid glands, rendering them resistant to vitamin D and calcium. 7

Magnesium Disorders

• Magnesium deficiency impairs PTH secretion and creates PTH resistance—hypocalcemia will not resolve until magnesium levels are corrected. 2, 4
• Always check magnesium levels in all hypocalcemic patients, as hypomagnesemia must be corrected first before calcium normalization can occur. 1, 2

Medication-Induced Hypocalcemia

• Loop diuretics induce hypocalcemia through increased urinary calcium excretion. 2
• Calcium channel blockers may reduce calcium levels by affecting calcium homeostasis. 2
• Bisphosphonates can cause severe hypocalcemia, particularly in patients with unrecognized hypoparathyroidism, impaired renal function, or vitamin D deficiency, with risk related to bisphosphonate potency. 8
• Antipsychotic medications can precipitate hypocalcemia, particularly in vulnerable patients. 2
• Citrate in blood transfusions can cause acute hypocalcemia during massive transfusion protocols. 1, 2

Neonatal-Specific Causes

Early-Onset (First 24-48 Hours)

• Interruption of placental calcium transfer at birth combined with relative immaturity of hormonal control (delayed PTH surge) causes early hypocalcemia. 4
• This early hypocalcemia is common, generally asymptomatic, and not associated with obvious clinical problems such as tetany. 4

Late-Onset (After 72 Hours)

• Excessive phosphate intake from high-phosphate formulas is a primary cause of late-onset neonatal hypocalcemia. 4
• Maternal vitamin D deficiency can manifest as neonatal hypocalcemia after 72 hours of life. 4
• Hypomagnesemia and primary hypoparathyroidism can present in the neonatal period. 4

Precipitating Factors and High-Risk Situations

Biological Stress

• Surgery, fractures, injuries, childbirth, and infection significantly increase hypocalcemia risk, particularly in patients with underlying parathyroid dysfunction. 1, 2
• Perioperative periods represent particularly vulnerable times for calcium decompensation. 1, 2
• Fever, ischemia, and hypoxia can trigger hypocalcemic episodes. 2
• Acute illness of any type increases vulnerability to symptomatic hypocalcemia. 1, 2

Life Stage Vulnerabilities

• Puberty and pregnancy are high-risk periods for hypocalcemia manifestation in susceptible individuals. 1, 2
• Maternal hypocalcemia can result in increased rates of spontaneous abortion, premature and dysfunctional labor, and possibly preeclampsia. 9

Dietary and Lifestyle Factors

• Decreased oral calcium intake contributes to hypocalcemia development. 1, 2
• Alcohol consumption worsens hypocalcemia. 1, 2
• Carbonated beverages, especially colas, may exacerbate hypocalcemia. 1, 2

Critical Diagnostic Pitfalls

• Always measure pH-corrected ionized calcium (most accurate) rather than total calcium alone, as ionized calcium is the physiologically active fraction. 1, 2, 4
• Symptoms may be subtle and confused with psychiatric conditions such as anxiety or depression, delaying appropriate diagnosis. 1, 2
• Hypocalcemia can occur at any age in patients with underlying parathyroid dysfunction, even without prior history of calcium disorders. 2
• In patients receiving bisphosphonate therapy, assess for vitamin D deficiency and renal function before administration to prevent severe hypocalcemia. 8