Hypercalcemia - ICUNOTES

Hypercalcemia

Normal total serum calcium:

Approximately 8.5–10.5 mg/dL (2.1–2.6 mmol/L)
Ionized calcium >1.32 mmol/L
This severity Classification values are different in Different sources(ionized calcium does not have a universally accepted equivalent 3-tier classification.)

Severity	Total serum calcium	Ionized calcium
Normal	8.5–10.5 mg/dL	1.12–1.32 mmol/L
Mild	10.5–11.9 mg/dL	~1.33–1.50 mmol/L
Moderate	12.0–13.9 mg/dL	~1.51–1.75 mmol/L
Severe	≥14 mg/dL	≥1.76 mmol/L

Table of Contents

Calcium Physiology

About 99% of body calcium is stored in bone.

Serum calcium exists in 3 forms:

Ionized (free) calcium (~50%)—Physiologically active form
Protein-bound calcium (~40%)—Mainly albumin-bound

Complexed calcium (~10%)—Bound to phosphate/citrate

Corrected Calcium Formula

Low albumin lowers measured total calcium.

Corrected Calcium (mg/dL)=Measured Calcium+0.8×(4−Albumin)

Regulation of Calcium Homeostasis

Organ	PTH	Calcitriol	Calcitonin
Bone	↑ Bone resorption → ↑ Ca²⁺ release	Promotes mineralization; with PTH can facilitate resorption when needed	↓ Osteoclast activity
Kidney	↑ Ca²⁺ reabsorption, ↓ phosphate reabsorption, ↑ calcitriol synthesis(1,25 vitamin D -activated)	Mild ↑ Ca²⁺ reabsorption	Mild ↑ Ca²⁺ excretion
Gastrointestinal Tract	Indirect effect via calcitriol	↑ Calcium and phosphate absorption	No significant effect

Causes of Hypercalcemia

Major Causes(90% cases)

Primary hyperparathyroidism → most common outpatient cause
Malignancy → most common inpatient cause

Classification by PTH Level

PTH-Dependent Hypercalcemia

PTH elevated or inappropriately normal.

Primary hyperparathyroidism(Single parathyroid adenoma)
Tertiary hyperparathyroidism
Familial hypocalciuric hypercalcemia (FHH)
Lithium therapy

PTH-Independent Hypercalcemia(PTH suppressed)

A. Malignancy-Associated Hypercalcemia

PTHrP-mediated humoral hypercalcemia
Osteolytic metastases
Hematologic malignancies
Lymphoma (↑ calcitriol)

Common malignancies

Squamous cell carcinoma lung
Renal cell carcinoma
Breast cancer
Multiple myeloma

B. Vitamin D-Mediated

Vitamin D intoxication
Granulomatous diseases(Sarcoidosis,Tuberculosis)
Lymphoma

C. Endocrine Causes

Thyrotoxicosis
Adrenal insufficiency
Pheochromocytoma
Acromegaly

D. Drug-Induced

Thiazides
Lithium
Vitamin A excess
Calcium antacids

E. Miscellaneous

Immobilization
Milk-alkali syndrome
Paget disease
Recovery phase rhabdomyolysis

Clinical Features

“Stones, Bones, Groans, Thrones, Psychiatric Overtones”

Renal (“Stones”)

Polyuria
Polydipsia
Nephrolithiasis
Nephrocalcinosis
Acute kidney injury

Mechanism:

Nephrogenic diabetes insipidus
Renal vasoconstriction
Volume depletion

Skeletal (“Bones”)

Bone pain
Osteoporosis
Osteitis fibrosa cystica
Pathological fractures

Gastrointestinal (“Groans”)

Constipation
Nausea
Vomiting
Abdominal pain
Pancreatitis
Peptic ulcer disease

Neurologic/Psychiatric

Fatigue, Muscle Weakness,hyporeflexia,paresthesia
Confusion,Depression
Cognitive dysfunction
Delirium
Coma

Cardiovascular

Hypertension(if patient is hypovolemic)
Arrhythmias
Bradycardia
Shortened QT interval
Heart block

ECG Findings

Characteristic finding:Short QT interval

Other findings:

PR prolongation
Widened QRS
Bundle branch block
AV block with bradyasystolic arrest

Hypercalcemic Crisis

Severe symptomatic hypercalcemia
Usually calcium >14 mg/dL

Features:

Severe dehydration
AKI
Altered mental status
Arrhythmias

This is a medical emergency.

Investigations in Hypercalcemia

Step	Investigation	Why
1	Confirm calcium + albumin	Ensure true hypercalcemia
2	Ionized calcium	Confirm physiologic hypercalcemia
3	PTH	Most important categorization test
4	If PTH high/normal → urinary calcium + CCCR	Differentiate PHPT vs FHH
5	If PTH suppressed → PTHrP, vitamin D metabolites, SPEP/UPEP	Search for malignancy/vitamin D causes
6	Imaging guided by suspicion	Identify source disease

Investigation	When to Investigate	Reason / What It Helps Diagnose
Repeat serum total calcium	Immediately after first elevated calcium	Confirms true hypercalcemia and excludes lab error
Ionized calcium	Hypoalbuminemia, paraproteinemia, critically ill patients, acid-base disorders	Measures biologically active calcium; confirms true hypercalcemia when total calcium unreliable
Serum albumin	In all patients with hypercalcemia	Needed to calculate corrected calcium
Corrected calcium calculation	When albumin abnormal	Determines actual calcium status in hypoalbuminemia
ECG	Moderate/severe hypercalcemia or symptomatic patients	Detects short QT interval, arrhythmias, AV block
Serum phosphate	Initial evaluation in all patients	Low phosphate suggests primary hyperparathyroidism; high phosphate may suggest CKD/tertiary HPT or vitamin D excess
Serum magnesium	Initial workup	Magnesium disorders affect PTH secretion and calcium metabolism
Serum creatinine/eGFR	Initial evaluation in all	Assesses renal impairment from hypercalcemia or CKD-related hyperparathyroidism
Electrolytes (Na, K, HCO₃)	Initial evaluation	Evaluates dehydration, metabolic alkalosis, milk-alkali syndrome
Intact PTH	After confirming hypercalcemia	Most important test; differentiates PTH-mediated vs non-PTH-mediated hypercalcemia
Tests Below Are additional tests which can be done based on history
24-hour urinary calcium	Elevated/inappropriately normal PTH	Differentiates primary hyperparathyroidism from FHH
Calcium-creatinine clearance ratio (CCCR)	Suspected FHH vs PHPT	CCCR <0.01 suggests FHH; >0.02 suggests PHPT
25-OH vitamin D	All patients or suspected vitamin D disorder	Detects vitamin D deficiency or intoxication
1,25-(OH)₂ vitamin D	Low PTH with suspected granulomatous disease or lymphoma	Elevated in sarcoidosis, TB, lymphoma due to extrarenal vitamin D activation
PTH-related peptide (PTHrP)	Suppressed PTH with suspected malignancy	Diagnoses humoral hypercalcemia of malignancy
Serum alkaline phosphatase (ALP)	Bone pain, malignancy, high bone turnover	Elevated in osteolytic metastases, Paget disease, hyperparathyroidism
SPEP (serum protein electrophoresis)	Bone pain, anemia, renal dysfunction, elderly patients	Detects multiple myeloma
UPEP (urine protein electrophoresis)	Suspected myeloma	Detects Bence Jones proteins/light chains
Serum free light chains	Suspected plasma cell dyscrasia	Improves detection of multiple myeloma
CBC	Initial evaluation or malignancy suspicion	Detects anemia, leukocytosis, hematologic malignancy
ESR/CRP	Suspected inflammatory disease or myeloma	Elevated in infection, malignancy, inflammatory disorders
TSH and thyroid profile	Symptoms/signs of hyperthyroidism	Hyperthyroidism can cause mild hypercalcemia via increased bone turnover
Morning cortisol / ACTH stimulation test	Suspected adrenal insufficiency	Addison disease may cause mild hypercalcemia
Serum ACE level	Suspected sarcoidosis	May support diagnosis of sarcoidosis
Chest X-ray	Smokers, malignancy suspicion, granulomatous disease	Detects lung cancer, TB, sarcoidosis
CT chest/abdomen/pelvis	Suspected occult malignancy	Identifies hidden cancers causing hypercalcemia
PET-CT	Unexplained malignancy-associated hypercalcemia	Detects occult metastatic disease
Skeletal survey	Suspected multiple myeloma	Detects lytic bone lesions
Bone scan	Suspected metastatic bone disease	Identifies osteolytic metastases
DEXA scan	Primary hyperparathyroidism	Evaluates osteoporosis and fracture risk
Parathyroid ultrasound	Confirmed primary hyperparathyroidism before surgery	Localizes parathyroid adenoma
Sestamibi scan	Preoperative localization in PHPT	Identifies hyperfunctioning parathyroid tissue
Genetic testing for CaSR mutation	Strong suspicion of FHH	Confirms familial hypocalciuric hypercalcemia
Serum vitamin A level	Excess supplement use suspected	Hypervitaminosis A can cause hypercalcemia
Serum cortisol and catecholamines	MEN syndrome suspicion	Evaluates endocrine neoplasia syndromes
TB testing (IGRA/AFB studies)	Suspected tuberculosis	TB can cause calcitriol-mediated hypercalcemia
Medication review	In every patient	Identifies thiazides, lithium, vitamin D, calcium supplements, vitamin A, teriparatide, antacids
Arterial blood gas	Critically ill or alkalosis suspected	Evaluates acid-base status affecting calcium binding

Pattern Recognition

Finding	Likely Cause
High PTH + low phosphate	Primary hyperparathyroidism
High PTH + CKD	Tertiary HPT
Low PTH + high PTHrP	Malignancy
Low PTH + high 25-OH D	Vitamin D intoxication
Low PTH + high 1,25-OH₂ D	Sarcoidosis/lymphoma
Low urine calcium	FHH
Hypercalcemia + lytic lesions	Myeloma/metastases
Hypercalcemia + alkalosis + AKI	Milk-alkali syndrome

Management of Hypercalcemia

Indications for Immediate Treatment

Serum calcium ≥14 mg/dL
Symptomatic hypercalcemia
ECG changes
Acute kidney injury
Severe dehydration
Pancreatitis
Hypercalcemic crisis
Rapidly rising calcium

Treatment Based on Severity

Severity	Treatment
Mild asymptomatic	Treat cause, hydration
Symptomatic	hydration + calcitonin
Severe (>14 mg/dL)	hydration + calcitonin + bisphosphonate
Refractory	Denosumab/dialysis

1. Volume Resuscitation

Most important initial therapy.

Fluid—Plasmalyte>Ringer Lactate>Isotonic saline

Mechanism:Corrects dehydration,Enhances calciuresis

Typical Regimen

Initial bolus:1–2 L over first 1–2 hours if hypovolemic
Maintenance:100–150 mL/hr( give only if Patient is not retaining fluid and pouring out urine or else patient will land up in volume overload)
Adjust to:Urine output: 100–150 mL/hr and Clinical status

Special Situations

Heart Failure

Slower infusion
Hemodynamic monitoring
May require loop diuretic

CKD

Careful hydration
Frequent reassessment

Loop Diuretics

Not routinely recommended initially.

Use ONLY:

After adequate hydration
If fluid overload develops

Example:Furosemide -20–40 mg IV

Pharmacologic Therapy

1. Calcitonin

Mechanism—Inhibits osteoclasts,Increases renal calcium excretion
Dose—4 IU/kg SC/IM every 12 hours,Can increase to:8 IU/kg every 8 hours
Onset—4–6 hours
Duration—Tachyphylaxis after 48 hours -so it must be given simultaneously with a bisphosphonate.Used as bridge therapy

2. Bisphosphonates

Mainstay for malignancy-associated hypercalcemia.
Mechanism—Inhibit osteoclast-mediated bone resorption

Contraindication-GFR <30 ml/min(relative contraindication),hypercalcemia due to increased calcium intake (milk-alkali syndrome)

Zoledronic Acid(Preffered)

Dose	4 mg IV Over ≥60 min
Onset	24–48 hr
Peak effect	4–7 days
Duration	Can be repeated after 7 days if required and every 3-4 weeks subsequently.

Pamidronate

Parameter	Details
Dose	60–90 mg IV
Infusion	Over 2–4 hr
Onset	24–48 hr

3. Denosumab

Useful in:

Refractory hypercalcemia
Severe renal failure
Bisphosphonate-resistant disease

Mechanism:RANKL inhibitor

onset within ~3-10 days

Dose:120 mg SC

Typically:after 1, 2, and 4 weeks and monthly thereafter

4. Glucocorticoids

Best for:

Vitamin D-mediated hypercalcemia
Sarcoidosis
Lymphoma

Drug	Dose
Prednisone	60 mg/day
Hydrocortisone	200–400 mg/day IV

Mechanism:Reduce calcitriol production,Inhibition of GI calcium absorption,Increased urinary calcium excretion

5.Cinacalcet

Cinacalcet is a calcimimetic that activates the calcium-sensing receptor (CaSR) on parathyroid cells, thereby suppressing PTH secretion and reducing serum calcium.
It is primarily used for PTH-mediated hypercalcemia, particularly primary/secondary hyperparathyroidism.
It has also been used off-label in refractory hypercalcemia of malignancy, particularly when hypercalcemia is PTH-independent and resistant to standard therapy, but evidence is limited to case reports/series.
Dose: Start 30 mg PO twice daily; titrate according to serum calcium and PTH. Doses up to 90 mg four times daily have been reported in refractory hypercalcemia.
Adverse effects: Nausea, vomiting, diarrhea, headache, and hypocalcemia.
Key limitation: GI intolerance, particularly nausea and vomiting, commonly limits dose escalation.

6. Dialysis

Indications:

Severe refractory hypercalcemia
Renal failure
Heart failure
Life-threatening arrhythmias
Unable to tolerate fluids

Use:Low-calcium dialysate