HYPERCALCEMIA 

1. DEFINITION & PHYSIOLOGY

Normal Calcium Physiology

  • Total serum calcium: 8.5–10.5 mg/dL (2.1–2.6 mmol/L)
  • Ionized calcium (physiologically active): 1.12–1.32 mmol/L
  • Distribution:
    • 45% ionized
    • 40% protein-bound (mainly albumin)
    • 15% complexed (citrate, phosphate)

Corrected Calcium Formula (for hypoalbuminemia)

Corrected Ca (mg/dL) = Measured Ca + 0.8 × (4 − albumin g/dL)

⚠️ ICU pearl: Use ionized calcium in:

  • Critical illness
  • Sepsis
  • Acid–base disorders
  • Massive transfusion


2. CLASSIFICATION BY SEVERITY

Severity

Total Calcium

Mild

10.5–12 mg/dL

Moderate

12–14 mg/dL

Severe / Hypercalcemic crisis

>14 mg/dL


3. ETIOLOGY 

A. PTH-DEPENDENT (↑ PTH)

Cause

Key Feature

Primary hyperparathyroidism

Most common outpatient cause

Tertiary hyperparathyroidism

CKD, post-transplant

Lithium therapy

Shifts Ca-PTH set point

Familial hypocalciuric hypercalcemia (FHH)

Low urine Ca

👉 Lab hallmark:

  • ↑ Ca, ↑/inappropriately normal PTH, ↓ phosphate


B. PTH-INDEPENDENT (↓ PTH)

1. Malignancy-related (Most common inpatient cause)

Mechanism

Examples

PTHrP secretion

Squamous cell carcinoma (lung, head & neck), renal, bladder

Osteolytic metastases

Breast cancer, multiple myeloma

↑ Calcitriol (1,25-OH₂D)

Lymphoma

Ectopic PTH

Rare

⚠️ Hypercalcemia of malignancy = poor prognosis


2. Vitamin D–Related

Cause

Mechanism

Vitamin D intoxication

↑ Intestinal absorption

Granulomatous disease (TB, sarcoidosis)

Macrophage ↑ 1α-hydroxylase

Lymphoma

↑ Calcitriol


3. Drugs

Drug

Mechanism

Thiazides

↓ Renal Ca excretion

Vitamin A

↑ Bone resorption

Calcium supplements

Milk-alkali syndrome

Theophylline toxicity

Bone resorption


4. Other Causes

Cause

Note

Immobilization

Especially high bone turnover

Thyrotoxicosis

↑ Bone resorption

Adrenal insufficiency

Volume contraction

Rhabdomyolysis (recovery phase)

Ca rebound

Milk-alkali syndrome

HyperCa + metabolic alkalosis + AKI


4. CLINICAL FEATURES – “STONES, BONES, GROANS, PSYCHIATRIC OVERTONES”

A. Neurological

  • Fatigue
  • Confusion
  • Delirium
  • Psychosis
  • Coma (severe)

B. Gastrointestinal

  • Anorexia
  • Nausea, vomiting
  • Constipation
  • Pancreatitis
  • Peptic ulcer disease

C. Renal

  • Polyuria (nephrogenic DI)
  • Dehydration
  • Nephrolithiasis
  • Nephrocalcinosis
  • AKI

D. Cardiovascular

  • Short QT interval
  • Bradycardia
  • AV block
  • Ventricular arrhythmias
  • Hypertension

E. Skeletal

  • Bone pain
  • Fractures
  • Osteitis fibrosa cystica (PTH excess)


5. INVESTIGATIONS – STEPWISE APPROACH 

Step 1: Confirm Hypercalcemia

  • Total Ca + albumin
  • Ionized Ca (preferred in ICU)


Step 2: Measure PTH

A. PTH ↑ / Normal

→ Primary hyperparathyroidism

  • Serum phosphate ↓
  • Urine Ca/Cr ratio:
    • <0.01 → FHH
    • 0.02 → PHPT

B. PTH ↓

→ PTH-independent causes


Step 3: Further Tests (Based on Context)

Test

Purpose

PTHrP

Malignancy

25-OH Vitamin D

Intoxication

1,25-OH₂ Vitamin D

Granulomatous disease

SPEP/UPEP

Myeloma

TSH

Thyrotoxicosis

Cortisol

Adrenal insufficiency

Imaging

Malignancy / parathyroid adenoma


6. ECG CHANGES (EXAM-CRITICAL)

Calcium Status

ECG Change

Hypercalcemia

Short QT

Severe

AV block, VT/VF


7. HYPERCALCEMIC CRISIS (ICU EMERGENCY)

Definition

  • Ca >14 mg/dL OR
  • Symptomatic hypercalcemia

Features

  • Severe dehydration
  • AKI
  • Encephalopathy
  • Life-threatening arrhythmias


8. MANAGEMENT – STEPWISE, GUIDELINE-BASED

PRINCIPLES

  1. Restore intravascular volume
  2. Promote calciuresis
  3. Inhibit bone resorption
  4. Treat underlying cause


9. ACUTE MANAGEMENT (SEVERE / ICU)

1️⃣ IV FLUIDS – FIRST & MOST IMPORTANT

  • 0.9% Normal Saline
  • Rate: 200–300 mL/hr
  • Target:
    • Urine output >100–150 mL/hr
    • Correct volume depletion

⚠️ Avoid fluid overload (elderly, CHF)


2️⃣ LOOP DIURETICS (ONLY AFTER EUVOLEMIA)

  • Purpose: ↑ Calciuresis
  • Never before adequate hydration


3️⃣ CALCITONIN – RAPID BUT SHORT-ACTING

  • Onset: 4–6 h
  • Effect lasts: 24–48 h
  • Tachyphylaxis common

👉 Used as bridging therapy


4️⃣ BISPHOSPHONATES – DEFINITIVE THERAPY

Drug

Dose

Onset

Duration

Zoledronic acid


48–72 h

Weeks

Pamidronate


48–72 h

Weeks

⚠️ Avoid in:

  • Severe renal failure
  • Hypocalcemia risk


5️⃣ DENOSUMAB (If Bisphosphonate Contraindicated)

  • Especially in:
    • CKD
    • Refractory malignancy-related hypercalcemia


6️⃣ GLUCOCORTICOIDS (SPECIFIC INDICATIONS)

  • Vitamin D–mediated hypercalcemia
  • Granulomatous disease
  • Lymphoma

Example:

  • Prednisolone 


7️⃣ DIALYSIS (LAST RESORT)

Indications:

  • Life-threatening hypercalcemia
  • Severe AKI
  • Fluid overload
  • Refractory to medical therapy

👉 Use low-calcium dialysate


10. CHRONIC MANAGEMENT

Primary Hyperparathyroidism

  • Parathyroidectomy if:
    • Symptomatic
    • Ca >1 mg/dL above normal
    • Age <50
    • Osteoporosis
    • Nephrolithiasis
    • eGFR <60

Malignancy

  • Treat underlying cancer
  • Repeated bisphosphonates / denosumab