What non‑arterial causes and work‑up should be considered for isolated ankle swelling in a healthy 29‑year‑old woman with a normal ankle‑brachial index and normal arterial Doppler ultrasound?

Differential Diagnosis and Work-Up for Bilateral Ankle Swelling in a Young Woman

In a 29-year-old woman with bilateral ankle swelling and normal arterial studies (ABI and Doppler), the most likely causes are venous insufficiency, lymphatic dysfunction, systemic conditions (cardiac, renal, hepatic, or endocrine), medication effects, or idiopathic edema—and the next steps should include venous duplex ultrasound to assess for venous insufficiency, basic laboratory work (CBC, comprehensive metabolic panel, TSH, urinalysis), and a focused history regarding medications, menstrual cycle patterns, and positional factors.

Understanding What Has Been Ruled Out

• The normal ABI (0.91-1.40) effectively excludes significant peripheral arterial disease as a cause of the swelling 1, 2
• Normal arterial Doppler confirms adequate arterial inflow and rules out arterial ischemia as a contributor 1
• These findings redirect the diagnostic focus entirely away from arterial pathology toward venous, lymphatic, or systemic causes 1

Most Likely Venous Causes

Venous insufficiency is the most common vascular cause of bilateral ankle swelling in young adults and should be evaluated first:

• Chronic venous insufficiency can occur even in young patients without obvious varicose veins, particularly in those with prolonged standing occupations or family history 1
• Venous duplex ultrasound is the diagnostic test of choice to assess for venous reflux and incompetent valves 1
• Look for associated findings: skin changes (hyperpigmentation, lipodermatosclerosis), varicose veins, or history of prior deep vein thrombosis 1

Deep venous thrombosis (DVT) is less likely given bilateral presentation but must be excluded:

• Bilateral DVT can occur with central venous obstruction (iliac or inferior vena cava level) or thrombophilia 1
• Risk factors include oral contraceptive use, recent travel, surgery, malignancy, or inherited thrombophilia 1
• Venous duplex ultrasound will identify acute or chronic thrombus 1

Lymphatic Causes

Primary or secondary lymphedema should be considered, especially if swelling is non-pitting or involves the dorsum of the foot:

• Primary lymphedema can present in young women (lymphedema praecox typically manifests before age 35) 1
• Secondary lymphedema may result from prior surgery, infection, or trauma—though less common in this age group without clear precipitant 1
• Clinical clues include non-pitting edema, positive Stemmer sign (inability to pinch dorsal foot skin), and "square toes" appearance 1

Systemic Causes Requiring Laboratory Evaluation

Cardiac causes:

• Right heart failure or cardiomyopathy can present with bilateral lower extremity edema, though unusual in a 29-year-old without known cardiac history 1
• Assess for dyspnea, orthopnea, jugular venous distension, and obtain BNP if clinically indicated 1

Renal causes:

• Nephrotic syndrome or chronic kidney disease can cause hypoalbuminemia and edema 1
• Order comprehensive metabolic panel, urinalysis with protein-to-creatinine ratio, and serum albumin 1
• Look for periorbital edema, foamy urine, or history of glomerulonephritis 1

Hepatic causes:

• Cirrhosis with portal hypertension leads to hypoalbuminemia and sodium retention 1
• Assess for ascites, spider angiomata, palmar erythema, and obtain liver function tests and albumin 1

Endocrine causes:

• Hypothyroidism causes myxedema with non-pitting edema 1
• Order TSH and free T4; look for weight gain, cold intolerance, constipation, and delayed deep tendon reflexes 1

Medication-Induced Edema

Common culprits in young women include:

• Calcium channel blockers (especially dihydropyridines like amlodipine) cause dose-dependent peripheral edema 1
• Oral contraceptives or hormone therapy can cause fluid retention 1
• NSAIDs promote sodium and water retention 1
• Corticosteroids cause sodium retention and edema 1

Idiopathic Edema (Diagnosis of Exclusion)

Idiopathic cyclic edema predominantly affects women of reproductive age:

• Characterized by fluctuating edema related to menstrual cycle, worse with prolonged standing 1
• Diagnosis requires exclusion of all other causes 1
• Often associated with diuretic abuse, which paradoxically worsens edema through secondary hyperaldosteronism 1

Recommended Diagnostic Algorithm

Immediate next steps:

1. Venous duplex ultrasound of bilateral lower extremities to assess for venous insufficiency or DVT 1
2. Basic laboratory panel:
   • Complete blood count (assess for anemia) 1
   • Comprehensive metabolic panel (creatinine, albumin, liver enzymes) 1
   • Thyroid-stimulating hormone (TSH) 1
   • Urinalysis with urine protein-to-creatinine ratio 1
3. Detailed medication history including over-the-counter NSAIDs, supplements, and hormonal contraceptives 1
4. Focused history:
   • Relationship to menstrual cycle 1
   • Positional factors (worse with standing, better with elevation) 1
   • Duration and progression of symptoms 1
   • Associated symptoms (dyspnea, orthopnea, abdominal distension, weight changes) 1

If initial work-up is unrevealing:

• Consider echocardiography if any cardiac symptoms or signs are present 1
• Consider lymphoscintigraphy if clinical features suggest lymphedema 1
• Reassess for occult malignancy if unexplained weight loss, constitutional symptoms, or progressive unilateral swelling develops 1

Common Pitfalls to Avoid

• Do not assume bilateral edema excludes DVT—central venous obstruction can cause bilateral swelling and requires imaging to the level of the inferior vena cava 1
• Do not overlook medication history—many young women take oral contraceptives or NSAIDs without considering them "real medications" 1
• Do not diagnose idiopathic edema without excluding systemic causes—this is a diagnosis of exclusion requiring comprehensive laboratory evaluation 1
• Do not forget to assess for lymphedema—it can be bilateral and is often misdiagnosed as venous insufficiency 1