What causes unilateral swelling of a leg?

Causes of Unilateral Leg Swelling

Most Critical Diagnosis to Exclude First

Deep vein thrombosis (DVT) must be ruled out immediately in any patient with unilateral leg swelling, as it carries significant risk of pulmonary embolism and death if untreated. 1, 2 In 70% of pulmonary embolism cases, the thrombus originates from lower extremity DVT. 2

Primary Pathophysiologic Mechanisms

Unilateral leg swelling results from five fundamental mechanisms that guide differential diagnosis:

Increased Venous Hydrostatic Pressure

• DVT/superficial vein thrombosis - Thrombus formation in deep or superficial veins causes increased venous hypertension and capillary permeability. 3 Classic presentation includes unilateral extremity swelling (80% of cases), pain (75%), and erythema (26%). 2
• Iliac vein obstruction (nonthrombotic iliac vein lesions) - Compression or stenosis of iliac veins increases venous hypertension, particularly when edema extends to the thigh. 3, 4
• Chronic venous insufficiency - Valvular incompetence leads to increased venous hypertension and capillary permeability. 3, 4
• Superior vena cava syndrome (for upper extremity) - Obstruction at the level of brachiocephalic, subclavian, or axillary veins causes unilateral swelling. 3

Lymphatic Obstruction

• Lymphedema - Excessive accumulation of protein-rich fluid that surpasses the lymphatic system's transport capacity. 3, 4 This chronic buildup occurs in interstitial and fibro-adipose tissues.
• Malignancy - Tumor compression or infiltration of lymphatic channels causes local venous hypertension. 3

Increased Capillary Permeability

• Cellulitis - Bacterial infection increases capillary permeability, presenting with erythema, warmth, and tenderness that must be differentiated from DVT. 3, 2
• Complex regional pain syndrome - Neurogenic and proinflammatory cytokines mediate increased capillary permeability. 3
• Allergic reactions - Histamine release increases vascular permeability. 3

Extravascular Fluid Accumulation

• Ruptured Baker's cyst - Synovial fluid leaks into calf tissues with associated inflammation-related increased capillary permeability. 3
• Ruptured calf muscle/intramuscular hematoma - Blood extravasation and inflammation increase capillary permeability. 3
• Compartment syndrome - Local venous hypertension results in increased capillary permeability. 3

Decreased Oncotic Pressure (Usually Bilateral, But Can Be Unilateral)

• Hypoproteinemia - Liver cirrhosis, nephrotic syndrome, or malnutrition decreases plasma oncotic pressure. 3, 5
• Heart failure - Increased plasma volume and capillary hydrostatic pressure. 3, 2

Less Common But Important Causes

Mechanical Compression

• External cystic lesions - Ganglion cysts compressing the femoral vein can cause progressive unilateral leg swelling. 6 Surgical removal or puncture with steroid instillation resolves symptoms.
• Bladder enlargement - Massive urinary retention can cause unilateral iliac vein compression simulating DVT, particularly in elderly patients. 7
• Pelvic mass/tumor - Direct compression increases local venous hypertension. 3

Adipose Tissue Disorders

• Lipedema - Subcutaneous adipose tissue deposition causes approximately one-fifth of lower extremity edema cases in specialized clinics, though rarely diagnosed in general practice. 8 This presents as bilateral symmetric fat deposition below the waist, sparing the feet.

Inflammatory/Autoimmune

• Superficial thrombophlebitis - Causes local pain, induration, and palpable cord but rarely causes diffuse limb swelling. 3, 2
• Reflex sympathetic dystrophy - Trauma-related increased capillary permeability. 3

Risk Factors That Increase DVT Probability

The following factors significantly elevate DVT risk and should prompt immediate evaluation:

• Indwelling venous devices - Catheters, pacemakers, defibrillators represent the highest risk. 3, 2
• Active malignancy - Hypercoagulable state increases thrombosis risk. 3, 2
• Recent surgery or trauma - Immobilization and endothelial injury promote clot formation. 3, 2
• Advanced age - Increased baseline thrombotic risk. 3, 2
• Heart failure - Venous stasis promotes thrombosis. 3, 2
• Hypercoagulable states - Inherited or acquired thrombophilias. 3, 2
• Postoperative state - Combination of immobilization and surgical trauma. 3, 2

Critical Clinical Pitfalls to Avoid

• Never delay anticoagulation in high-risk patients while awaiting imaging - This increases morbidity and mortality from thromboembolic complications. 1, 4
• Do not assume bilateral presentation excludes venous pathology - While unilateral swelling indicates obstruction at major vein level, some conditions present variably. 3
• Acute hypoechoic thrombi may be missed on grayscale ultrasound alone - Doppler flow assessment is essential for accurate diagnosis. 1
• In diabetic patients with neuropathy presenting with unilateral red, warm, swollen foot with intact skin - Always suspect active Charcot neuro-osteoarthropathy after excluding infection, gout, and DVT. 2
• Temperature asymmetry >2°C between limbs - Suggests active inflammatory process such as DVT, infection, or Charcot arthropathy requiring urgent evaluation. 2