Unilateral Leg Swelling: Differential Diagnosis and Clinical Approach
Immediate Priority: Rule Out Deep Vein Thrombosis First
Deep vein thrombosis (DVT) must be excluded immediately in any patient presenting with unilateral leg swelling, as 70% of pulmonary embolism cases originate from lower extremity DVT, carrying significant risk of death if untreated. 1, 2
Primary Causes by Pathophysiologic Mechanism
Venous Pathology (Most Common and Most Dangerous)
- Deep vein thrombosis presents with unilateral extremity swelling (80% of cases), pain (75%), erythema (26%), heaviness distal to the thrombus, and unexplained persistent calf cramping 1, 2
- Chronic venous insufficiency causes valvular incompetence leading to venous hypertension, presenting with aching, heaviness, cramping, throbbing, and swelling that worsens at day's end and improves with leg elevation 3, 1
- Iliac vein obstruction (nonthrombotic) increases venous hypertension, particularly when edema extends to the thigh 1
- Superficial thrombophlebitis causes local pain, induration, and palpable cord but rarely causes diffuse leg swelling 2
- Extrinsic venous compression from masses (ganglion cysts, bladder enlargement, retroperitoneal lesions) can compress the femoral or iliac veins 4, 5, 6
Lymphatic Pathology
- Lymphedema (primary or secondary) causes excessive accumulation of protein-rich fluid that surpasses lymphatic transport capacity, resulting in chronic buildup in interstitial and fibro-adipose tissues 1, 7
Infectious/Inflammatory Causes
- Cellulitis presents with erythema, warmth, tenderness, and must be differentiated from DVT as both present with unilateral red, warm, swollen leg 2
- Charcot neuro-osteoarthropathy in diabetic patients with neuropathy presents with unilateral red, warm, swollen foot with intact skin—this is a critical pitfall as it mimics infection and DVT 1, 2
Systemic Causes
- Heart failure causes increased capillary hydrostatic pressure leading to leg swelling 2, 7
- Hypoproteinemia from liver or renal failure causes decreased oncotic pressure 2, 7
- Drug-induced edema from calcium channel blockers, NSAIDs, or other medications 7
Musculoskeletal/Traumatic Causes
- Soft tissue infection with effacement of fat planes, gas, or foreign bodies 3
- Arteriovenous fistula or vascular malformation after surgery or trauma 8
Critical Risk Factors for DVT (Prioritize These Patients)
- Indwelling venous devices (catheters, pacemakers, defibrillators) represent the highest risk 1, 2
- Active malignancy creates a hypercoagulable state 1, 2
- Recent surgery or trauma promotes clot formation through immobilization and endothelial injury 1, 2
- Advanced age increases baseline thrombotic risk 1
- Heart failure promotes venous stasis 1
Key Clinical Distinguishing Features
- Unilateral swelling indicates obstruction at the level of major veins 2
- Temperature asymmetry >2°C between limbs suggests active inflammatory process (DVT, infection, or Charcot arthropathy) requiring urgent evaluation 1, 2
- Swelling extending to the thigh suggests iliac vein involvement 1
- Varicose veins with aching, heaviness, cramping that worsens with prolonged standing and improves with elevation suggests chronic venous insufficiency 3
- Skin changes including pigmentation, eczema, lipodermatosclerosis, or ulceration indicate advanced venous insufficiency 3
- Palpable cord suggests superficial thrombophlebitis 2
Critical Pitfalls to Avoid
- Never delay anticoagulation in high-risk patients while awaiting imaging—this increases morbidity and mortality from thromboembolic complications 1, 9
- 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 1, 2
- Do not assume bilateral presentation excludes venous pathology, as some conditions present variably 1
- Acute hypoechoic thrombi may be missed on grayscale ultrasound alone—Doppler flow assessment is essential for accurate diagnosis 1, 9
- After pelvic surgery, consider complex arteriovenous vascular pathology or extrinsic compression in addition to DVT 8, 5
- In elderly patients with massive bladder enlargement from urinary retention, consider iliac vein compression simulating DVT 5
Initial Diagnostic Approach
For High Suspicion of DVT
- Proceed directly to proximal compression ultrasound or whole-leg ultrasound without D-dimer testing 2, 9
- Duplex Doppler ultrasound has sensitivity and specificity above 80% and can directly identify thrombus through visualization of echogenic material and lack of vein compression 9
- Initiate parenteral anticoagulation immediately while awaiting diagnostic results in high-risk patients 9
For Other Suspected Causes
- Plain radiography provides excellent anatomic overview and excludes fractures, tumors, and can show soft tissue swelling, joint effusion, or gas 3
- Consider CT or MRI for suspected masses causing extrinsic compression 4, 6
- Clinical examination focusing on skin changes, temperature asymmetry, presence of varicosities, and palpable cords guides diagnosis in most cases 3, 7