What are the physiological effects of hypercalcemia, particularly in older adults or individuals with underlying medical conditions?

Physiological Effects of Hypercalcemia

Hypercalcemia causes osmotic diuresis leading to hypovolemia, decreased glomerular filtration rate, and prerenal azotemia, while simultaneously impairing leukocyte function and creating a vicious cycle of worsening systemic calcium elevation through increased renal calcium resorption. 1, 2

Renal and Fluid Balance Effects

Osmotic diuresis and volume depletion represent the primary renal manifestations:

• Excessive calcium in the blood triggers polyuria and progressive dehydration as the kidneys attempt to excrete the excess calcium 2
• The resulting hypovolemia decreases glomerular filtration rate, which paradoxically increases renal resorption of calcium, creating a self-perpetuating cycle of worsening hypercalcemia 2, 3
• This leads to prerenal azotemia and can progress to acute kidney injury if untreated 1, 4
• Long-term hypercalcemia causes nephrocalcinosis (calcium deposition in kidney tissue) and relapsing nephrolithiasis (kidney stones), leading to progressive and potentially irreversible loss of renal function 5, 3

Cardiovascular Effects

Cardiac conduction abnormalities and vascular dysfunction occur through multiple mechanisms:

• Hypercalcemia causes prolongation of the QT interval on electrocardiogram, which can progress to life-threatening cardiac arrhythmias 5, 1
• In rare cases, severe untreated hypercalcemia can lead to cardiomyopathy 5
• Acute hypercalcemia impairs endothelial function by suppressing nitric oxide formation and impairing endothelium-dependent, flow-mediated dilation 5
• Increased vascular permeability occurs through activation of inflammatory pathways 5

Immune System and Wound Healing

Impaired leukocyte function creates increased susceptibility to infection:

• Hypercalcemia causes decreased phagocytosis, impaired bacterial killing, and reduced chemotaxis in white blood cells 5
• This leads to increased risk of hospital-acquired infections and poor wound healing 5
• The mechanism involves activation of nuclear factor κB (NF-κB) and production of proinflammatory cytokines 5

Neurological and Cognitive Effects

Central nervous system dysfunction varies with severity and rapidity of calcium elevation:

• Mild hypercalcemia (total calcium <12 mg/dL) causes constitutional symptoms including fatigue, irritability, and constipation in approximately 20% of patients 5, 6
• Moderate hypercalcemia produces confusion and somnolence 6, 7
• Severe hypercalcemia (total calcium ≥14 mg/dL or ionized calcium ≥10 mg/dL) causes nausea, vomiting, dehydration, profound confusion, somnolence, and can progress to coma 6, 7
• Hypercalcemia can trigger or worsen seizures, particularly when it develops acutely 5
• Movement disorders including dystonia, myoclonus, tremors, and parkinsonism may be induced or worsened by hypercalcemia 5

Musculoskeletal Effects

Bone and muscle manifestations depend on the underlying cause:

• In primary hyperparathyroidism, chronic hypercalcemia causes osteitis fibrosa cystica (a form of metabolic bone disease) 8
• Lower bone mineral density develops over time, increasing risk for osteopenia and osteoporosis 5
• Muscle weakness and hypotonia can occur, particularly in severe cases 7

Gastrointestinal Effects

Digestive system dysfunction includes:

• Nausea and vomiting, particularly in moderate to severe hypercalcemia 6, 7
• Constipation is common even in mild hypercalcemia 6
• Abdominal pain may occur 1
• These symptoms result from both direct effects on smooth muscle function and the systemic effects of dehydration 7

Metabolic and Cellular Effects

Oxidative stress and mitochondrial dysfunction occur at the cellular level:

• Acute hyperglycemia (which often coexists with hypercalcemia in critically ill patients) results in oxidative stress and mitochondrial dysfunction 5
• Production of proinflammatory cytokines contributes to systemic inflammation 5

Special Considerations in Older Adults

Elderly patients present with atypical manifestations:

• Older adults are LESS likely to experience typical symptoms such as polyuria and polydipsia because the renal threshold for glycosuria increases with age and thirst mechanisms become impaired 5, 4
• When elderly patients DO present with increased thirst and lethargy, this indicates MORE severe hypercalcemia than would be required to produce these symptoms in younger patients 4
• Elderly patients often present with nonspecific symptoms like weight loss, fatigue, and confusion that may be incorrectly attributed to aging or other conditions 5
• The interaction of age with duration of underlying disease (particularly in conditions like 22q11.2 deletion syndrome) increases risk of end-stage complications 5

Prognosis and Severity Correlation

Clinical outcomes depend on rapidity of onset and underlying cause:

• Hypercalcemia that develops rapidly over days to weeks causes more severe symptoms than chronic elevation 6
• Hypercalcemia of malignancy typically presents with rapid onset, higher calcium levels (often >12 mg/dL), severe symptoms, and marked anemia 8, 9
• Primary hyperparathyroidism tends to cause lower calcium levels (<12 mg/dL), longer duration (>6 months), fewer symptoms, and is associated with kidney stones and metabolic acidosis but not anemia 8
• Hypercalcemia of malignancy carries a poor prognosis with median survival of approximately 1 month if untreated 1