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 disorders, and medication effects. 1, 2

PTH-Mediated Causes

Hypoparathyroidism

• Postsurgical hypoparathyroidism is the most common cause of hypocalcemia, accounting for approximately 75% of hypoparathyroidism cases, typically following anterior neck surgery including thyroidectomy or parathyroidectomy. 3, 4, 5
• Genetic disorders, particularly 22q11.2 deletion syndrome, carry an 80% lifetime prevalence of hypocalcemia due to underlying parathyroid dysfunction and can emerge at any age. 1, 2
• Autoimmune hypoparathyroidism accounts for approximately 25% of primary hypoparathyroidism cases. 5
• Destruction or infiltrative disorders of the parathyroid glands (including hemochromatosis, Wilson's disease, metastatic disease) can cause impaired PTH secretion. 4

Pseudohypoparathyroidism

• PTH resistance leads to hypocalcemia despite elevated PTH levels, representing a distinct mechanism from true hypoparathyroidism. 4

Non-PTH-Mediated Causes

Vitamin D Disorders

• Vitamin D deficiency is a leading cause of hypocalcemia through impaired intestinal calcium absorption. 3, 5
• Impaired production of 1,25-dihydroxyvitamin D reduces intestinal calcium absorption independent of PTH status. 2
• In chronic kidney disease, decreased vitamin D activation compounds hypocalcemia by reducing intestinal calcium absorption. 6, 2

Chronic Kidney Disease

• Phosphate retention in CKD leads to decreased ionized calcium, which stimulates PTH release and causes secondary hyperparathyroidism. 6, 1
• The mechanism involves three interrelated pathways: phosphate retention, skeletal resistance to PTH's calcemic action, and altered vitamin D metabolism. 6
• Decreased number of vitamin D receptors (VDR) and calcium-sensing receptors (CaR) in parathyroid glands renders them resistant to vitamin D and calcium. 6

Magnesium Disorders

• Magnesium deficiency impairs PTH secretion and creates PTH resistance, and hypocalcemia will not resolve until magnesium levels are corrected. 2, 7
• Both hypomagnesemia and hypermagnesemia can impair PTH secretion. 4
• Less than 1% of total body magnesium is in extracellular fluids, so patients can have magnesium deficiency despite normal serum concentrations. 7

Medication-Induced Hypocalcemia

• Loop diuretics induce hypocalcemia through increased urinary calcium excretion. 1, 2
• Calcium channel blockers may reduce calcium levels by affecting calcium homeostasis. 1, 2
• Antipsychotic medications can precipitate hypocalcemia, particularly in vulnerable patients. 2
• Citrate in blood transfusions causes acute hypocalcemia during massive transfusion through calcium chelation. 1, 2
• Bisphosphonates can cause hypocalcemia, particularly in patients with multiple myeloma or malignancy. 1

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 Factors

• Puberty and pregnancy are high-risk periods for hypocalcemia manifestation. 1, 2

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 total calcium can be misleading in the presence of albumin abnormalities. 1, 2, 7
• Check magnesium levels in all hypocalcemic patients, as hypomagnesemia must be corrected first before calcium supplementation will be effective. 1, 2, 7
• Hypocalcemia can occur at any age in patients with underlying parathyroid dysfunction, even without prior history of calcium abnormalities. 2
• Symptoms may be subtle and confused with psychiatric conditions such as anxiety or depression, delaying appropriate diagnosis. 1, 2
• Check PTH levels to distinguish between PTH-mediated and non-PTH-mediated causes. 1
• Assess renal function (creatinine) to evaluate for CKD as an underlying cause. 1
• Monitor thyroid function, as hypothyroidism may be associated with hypocalcemia. 1