Hypercalcemia: Symptoms, Types, Causes and Treatment

Hypercalcemia—a condition defined by elevated calcium levels in the blood—can be a subtle disruptor of health or a dramatic medical emergency. It is a common electrolyte imbalance, most frequently encountered in adults, but also affects children and adolescents. Understanding hypercalcemia means recognizing its diverse symptoms, knowing its various types, identifying the underlying causes, and tailoring the treatment approach accordingly. This article provides a comprehensive, evidence-based overview of hypercalcemia, referencing up-to-date clinical research and expert consensus.

Symptoms of Hypercalcemia

Hypercalcemia often creeps in quietly, with symptoms that are easily mistaken for other conditions or even overlooked. However, when calcium levels rise significantly, the effects can be profound—ranging from vague fatigue to life-threatening crises.

Symptom	System	Severity Range	Source(s)
Weakness	Neuromuscular	Mild to severe	1 3 5
Nausea/Vomiting	Gastrointestinal	Mild to crisis	1 2 5
Polyuria/Thirst	Renal	Mild to severe	1 2 4 10
Confusion/Disorientation	Neuropsychiatric	Moderate to severe	3 4 5 10
Constipation	Gastrointestinal	Mild to moderate	1 10
Depression/Emotional instability	Neuropsychiatric	Mild to moderate	4 5 10
Renal stones	Renal	Chronic	1 8 10
Coma/Death	Multi-system	Hypercalcemic crisis	1 2 5

Table 1: Key Symptoms

Understanding Hypercalcemia Symptoms

Hypercalcemia can present with a wide spectrum of clinical symptoms, often affecting multiple organ systems at once:

Neuromuscular and Neuropsychiatric Manifestations

• Weakness and Fatigue: The most common presenting symptoms, often mistaken for general malaise or aging 1 3 5.
• Confusion & Disorientation: Especially in severe cases or in elderly patients, mental status changes can range from mild confusion to stupor and coma 3 4 5 10.
• Depression, Apathy, and Emotional Instability: Patients may exhibit mood changes, depression, or emotional lability 4 5 10.
• Rare Focal Neurological Signs: In some cases, neurological symptoms such as transient ischemic attacks or sensory disturbances may occur, likely due to vascular effects of elevated calcium 4.

Gastrointestinal Symptoms

• Nausea and Vomiting: Common in moderate to severe hypercalcemia; intractable vomiting can signal a hypercalcemic crisis 1 2 5.
• Constipation and Dyspepsia: These nonspecific symptoms are frequently reported by patients and may precede more severe manifestations 1 10.

Renal and Fluid Balance Disturbances

• Polyuria and Thirst: Increased urination and thirst are highly characteristic and should raise suspicion for hypercalcemia, particularly in patients with malignancy 2 4 10.
• Nephrolithiasis and Nephrocalcinosis: Chronic hypercalcemia can lead to kidney stones and calcium deposition in the kidneys 1 8 10.

Severe and Life-Threatening Presentations

• Hypercalcemic Crisis: Marked by intractable vomiting, severe dehydration, stupor, coma, and often leads to multi-organ failure if not promptly addressed 1 2 5.
• Death: Untreated severe hypercalcemia can be rapidly fatal, particularly in malignancy-associated cases 2 5.

Types of Hypercalcemia

Hypercalcemia is not a one-size-fits-all diagnosis. It can be classified by severity, chronicity, and underlying pathophysiology—each influencing the clinical approach.

Type	Characteristic Feature	Typical Context	Source(s)
Mild/Asymptomatic	Slightly elevated calcium	Routine labs, PHPT	9 11 13
Moderate	Symptoms present	PHPT, early malignancy	5 9 13
Severe/Crisis	Life-threatening symptoms	Malignancy, late PHPT	1 2 5 13
Acute	Rapid onset, severe	Malignancy, intoxication	2 5 13
Chronic	Long duration, subtle	PHPT, FHH	7 13
PTH-dependent	High/normal PTH	PHPT, FHH	7 10 13
PTH-independent	Suppressed PTH	Malignancy, vitamin D	8 10 13

Table 2: Types of Hypercalcemia

Exploring Hypercalcemia Types

By Severity

• Mild Hypercalcemia: Often discovered incidentally; patients may be asymptomatic or have vague symptoms. Frequently associated with primary hyperparathyroidism (PHPT) 9 11 13.
• Moderate Hypercalcemia: Symptoms are more apparent, such as fatigue, GI discomfort, and mild confusion 5 9 13.
• Severe Hypercalcemia (Hypercalcemic Crisis): Defined by serum calcium typically ≥2.8 mmol/L (11.2 mg/dL), with neuropsychiatric, GI, and renal symptoms progressing to coma or death if untreated 1 2 5 13.

By Time Course

• Acute Hypercalcemia: Develops rapidly, often due to malignancy, vitamin D intoxication, or certain medications. Symptoms tend to be more pronounced 2 5 13.
• Chronic Hypercalcemia: Evolves over months or years, seen in conditions like PHPT or familial hypocalciuric hypercalcemia (FHH); symptoms may be subtle or absent 7 13.

By Pathophysiology

• PTH-dependent Hypercalcemia: Driven by elevated or inappropriately normal parathyroid hormone levels, as in PHPT or FHH 7 10 13.
• PTH-independent Hypercalcemia: Characterized by suppressed PTH; seen in malignancy, vitamin D intoxication, granulomatous diseases, or rare genetic syndromes 8 10 13.

Causes of Hypercalcemia

Understanding what drives hypercalcemia is key to effective management. While a few causes account for the majority of cases, many rarer conditions can also be culprits.

Cause	Mechanism	Prevalence/Context	Source(s)
Primary hyperparathyroidism (PHPT)	↑ PTH → ↑ bone resorption	Most common in outpatients	3 7 9 11 13
Malignancy (MAHC/HHM)	↑ bone resorption (PTHrP, local osteolysis)	Most common in hospitalized patients	2 3 5 11 13 16
Vitamin D intoxication	↑ GI absorption	Supplements, granulomatous disease	8 10 13
Familial hypocalciuric hypercalcemia (FHH)	Genetic, altered calcium sensing	Lifelong, benign course	7 10 13
Medications	Thiazides, lithium	Variable	13
Granulomatous diseases	↑ 1,25(OH)₂D production	Sarcoidosis, TB, lymphoma	8 10 13
Milk-alkali syndrome	Excess Ca + alkali intake	Rare, supplement overuse	12 13
Endocrinopathies	Thyrotoxicosis, adrenal insufficiency	Rare	6 10 13
Immobilization	Bone resorption	Children, immobilized adults	10 13
Renal failure	↓ renal excretion	Secondary hyperparathyroidism	17

Table 3: Causes of Hypercalcemia

Unpacking the Causes

Common Causes

• Primary Hyperparathyroidism (PHPT)

  • The leading cause in the outpatient setting, especially in middle-aged women.
  • Characterized by inappropriately high PTH levels, leading to increased bone resorption and renal calcium reabsorption 3 7 9 11 13.
  • Often mild and chronic, but can progress to symptomatic or severe disease.

• Malignancy-Associated Hypercalcemia (MAHC)

  • Most common cause among hospitalized and acutely ill patients.
  • Includes humoral hypercalcemia of malignancy (HHM), where tumors secrete PTH-related peptide (PTHrP), and local osteolytic hypercalcemia from bone metastases 2 3 5 11 13 16.
  • Fast onset and often severe, requiring urgent intervention.

Less Common and Rare Causes

• Vitamin D–Related Hypercalcemia

  • Can result from overdose of vitamin D supplements, granulomatous diseases (like sarcoidosis or tuberculosis), or genetic defects in vitamin D metabolism 8 10 13.
  • Causes increased intestinal calcium absorption.

• Familial Hypocalciuric Hypercalcemia (FHH)

  • A benign, lifelong genetic disorder affecting calcium-sensing receptors.
  • Characterized by mild hypercalcemia, low urinary calcium, and usually no need for intervention 7 10 13.

• Medications

  • Thiazide diuretics, lithium, and excessive intake of calcium or vitamin D can elevate calcium levels 13.

• Other Endocrinopathies and Syndromes

  • Thyrotoxicosis, adrenal insufficiency, milk-alkali syndrome, and immobilization can also lead to hypercalcemia, though these are rare 6 10 12 13.

• Renal Failure

  • Chronic kidney disease can cause secondary or tertiary hyperparathyroidism, resulting in elevated calcium 17.

Pediatric Considerations

• In children, causes are grouped as PTH-dependent or PTH-independent, with congenital syndromes and acquired conditions both possible. Symptoms may include hypotonia, poor feeding, and even seizures 10.

Treatment of Hypercalcemia

The treatment of hypercalcemia is tailored to its severity, underlying cause, and the presence or absence of symptoms. Prompt recognition and intervention can be lifesaving in severe cases.

Therapy	Mechanism	Indication/Context	Source(s)
IV fluids	Volume expansion	First-line for all, esp. crisis	5 13 15
Bisphosphonates	Inhibit bone resorption	Malignancy, severe cases	5 14 15
Calcitonin	Rapid Ca lowering	Emergency, adjunct	13 15
Glucocorticoids	↓ GI absorption, bone resorption	Vitamin D excess, malignancy	8 14 15
Cinacalcet	Calcimimetic, ↓ PTH	PHPT, renal failure, post-transplant	17
Parathyroidectomy	Remove source	PHPT (surgical candidates)	7 11 13
Dialysis	Remove Ca, correct fluid	Severe/refractory, renal failure	13

Table 4: Summary of Treatments

Approaches to Treatment

General Principles

• Assess Severity and Symptoms
  • Immediate treatment is warranted for severe or symptomatic hypercalcemia, regardless of underlying cause 5 9 13.

Acute Management

• Intravenous Fluids

  • Isotonic saline is the cornerstone, correcting dehydration and promoting renal calcium excretion 5 13 15.
  • Furosemide was previously used to enhance calciuresis, but evidence does not support routine use; only consider if volume overload is a concern 15.

• Bisphosphonates

  • Highly effective agents that inhibit bone resorption; first-line for malignancy-associated hypercalcemia 5 14 15.
  • Examples include pamidronate and zoledronic acid. Onset of action is within 48-72 hours.

• Calcitonin

  • Provides rapid but short-lived reduction in serum calcium; useful as a bridge while awaiting bisphosphonate effect 13 15.

• Glucocorticoids

  • Useful in vitamin D–mediated hypercalcemia (e.g., sarcoidosis, lymphoma) and some malignancies 8 14 15.

• Dialysis

  • Reserved for patients with renal failure or refractory/severe cases, especially if fluid overload limits IV therapy 13.

Chronic and Specific Therapies

• Cinacalcet

  • A calcimimetic agent that suppresses PTH secretion, useful in PHPT, secondary hyperparathyroidism, and after renal transplantation 17.
  • Particularly helpful in patients who are not surgical candidates.

• Parathyroidectomy

  • Definitive treatment for PHPT in patients meeting surgical criteria 7 11 13.
  • Not indicated for FHH, which does not respond to surgery.

• Management of Underlying Cause

  • Discontinuation of offending medications (e.g., thiazides, lithium).
  • Treatment of malignancy, granulomatous disease, or correction of endocrine disorders as appropriate 13.

Special Considerations

• Children and Adolescents

  • Approach based on distinguishing PTH-dependent from PTH-independent causes, with supportive care and targeted therapy as indicated 10.

• Long-term Monitoring

  • Regular follow-up is necessary to prevent recurrence and manage complications, especially in chronic or relapsing cases 11 13.

Conclusion

Hypercalcemia is a multifaceted disorder with a wide range of symptoms, causes, and treatment strategies. Early detection and targeted intervention are essential to prevent serious complications.

Main Points Covered:

• Hypercalcemia symptoms often affect multiple organ systems and can range from mild to life-threatening 1 2 3 4 5 10.
• Primary hyperparathyroidism and malignancy are the most common causes; other etiologies include vitamin D intoxication, medications, genetic syndromes, and rare endocrine disorders 3 5 7 8 10 11 12 13 16.
• Classification by severity, chronicity, and underlying mechanism guides clinical decision-making 5 7 9 10 13.
• Treatment is determined by severity and underlying cause, with IV fluids, bisphosphonates, and calcitonin forming the backbone of acute management; surgery or specific medical therapy addresses chronic forms 5 11 13 14 15 17.
• Vigilance is crucial, especially in populations at risk (e.g., cancer patients, those with known PHPT), to ensure timely diagnosis and effective therapy 2 5.

By understanding the nuances of hypercalcemia, clinicians and patients alike can better navigate its challenges—preventing complications and improving outcomes.