How do peripheral arterial disease (PAD) and lymphadenopathy differ regarding pathophysiology, clinical presentation, diagnostic work‑up, and management?

Peripheral Arterial Disease vs. Lymphadenopathy: Key Distinctions

Peripheral arterial disease (PAD) and lymphadenopathy are fundamentally different conditions—PAD is a vascular disorder caused by atherosclerotic occlusion of arteries resulting in reduced blood flow to the limbs, while lymphadenopathy refers to enlarged lymph nodes typically indicating infection, inflammation, or malignancy. These conditions differ completely in their pathophysiology, clinical presentation, diagnostic approach, and management strategies.

Pathophysiology

PAD

• Atherosclerosis is the primary pathologic process, causing stenosis or occlusion of noncoronary arteries, particularly affecting the abdominal aorta, renal, mesenteric, and lower extremity arteries 1
• The disease results from altered arterial structure and function, leading to reduced perfusion and ischemia 1
• Risk factors mirror those of systemic atherosclerosis: smoking, diabetes, hypertension, hyperlipidemia, and family history 2, 3
• Less common causes include thromboangiitis obliterans (Buerger's disease) in young smokers and degenerative disorders affecting arterial wall integrity 2

Lymphadenopathy

• Represents lymph node enlargement from diverse etiologies including infection (bacterial, viral, fungal), inflammatory conditions, or malignancy (lymphoma, metastatic disease)
• Involves immune system activation and lymphoid tissue proliferation
• Pathophysiology varies dramatically based on underlying cause

Clinical Presentation

PAD Clinical Subsets

The 2024 ACC/AHA guidelines categorize PAD into four distinct clinical presentations 1:

Asymptomatic PAD (20-59% of cases):

• Patients report no leg symptoms but may self-limit activity to avoid ischemic threshold 1
• Functional impairment comparable to symptomatic patients despite absence of reported symptoms 1
• Detection requires objective testing (abnormal ankle-brachial index) 1

Chronic Symptomatic PAD:

• Intermittent claudication: reproducible leg pain with exertion that resolves with rest 1
• Atypical leg symptoms: heaviness, discomfort, or fatigue that may delay diagnosis 1

Chronic Limb-Threatening Ischemia (CLTI):

• Ischemic rest pain requiring analgesia 1
• Non-healing wounds or ulcerations 1
• Gangrene and tissue loss 1
• Worst prognosis for both limb and life 1

Acute Limb Ischemia:

• Sudden onset of limb-threatening ischemia requiring urgent intervention 1

Physical Examination Findings in PAD

• Diminished or absent peripheral pulses (dorsalis pedis, posterior tibial) 4
• Cool skin temperature in affected extremity 4
• Trophic changes: hair loss, shiny skin, nail thickening 4
• Pallor on leg elevation 4
• Notably, edema is ABSENT in pure PAD—its presence suggests alternative or coexisting diagnoses 4

Lymphadenopathy Presentation

• Palpable, enlarged lymph nodes (>1 cm generally considered abnormal)
• May be localized (suggesting regional process) or generalized (suggesting systemic disease)
• Associated symptoms depend on etiology: fever, night sweats, weight loss (malignancy), localized infection signs
• Node characteristics matter: tender nodes suggest infection/inflammation; hard, fixed nodes suggest malignancy

Diagnostic Work-Up

PAD Diagnostic Algorithm

Initial Non-Invasive Testing:

• Ankle-Brachial Index (ABI) is the primary diagnostic test 1
  • ABI ≤0.90 confirms PAD diagnosis 1
  • ABI >1.4 suggests non-compressible vessels (often in diabetes) 1
  • Post-exercise ABI (>20% decrease) confirms PAD when resting ABI is normal but clinical suspicion remains 1
• Toe-Brachial Index (TBI) for patients with non-compressible vessels 1
• Transcutaneous oxygen pressure (TcPO2) for tissue perfusion assessment in CLTI 1

Advanced Imaging (when revascularization considered):

• Duplex ultrasound for anatomic detail 5
• CT angiography or MR angiography for surgical/endovascular planning 5, 6
• These are unnecessary for diagnosis alone 5

Functional Assessment:

• 6-minute walk test (6MWT) to quantify functional impairment 1
• Treadmill testing with post-exercise ABI 1

Lymphadenopathy Diagnostic Approach

• History focusing on infectious exposures, systemic symptoms, risk factors for malignancy
• Physical examination: node size, consistency, mobility, tenderness, distribution
• Laboratory testing: CBC, inflammatory markers, specific serologies based on suspected etiology
• Imaging: ultrasound, CT, or PET-CT for extent and characteristics
• Tissue diagnosis (fine needle aspiration or excisional biopsy) often required for persistent or suspicious nodes

Management

PAD Management Strategy

Medical Management (Guideline-Directed Management and Therapy):

Antiplatelet Therapy:

• Aspirin or clopidogrel to reduce major adverse cardiovascular events (MACE) 3, 7

Lipid Management:

• High-intensity statins regardless of baseline LDL-C 3, 7

Blood Pressure Control:

• Antihypertensive therapy targeting systemic cardiovascular risk 3

Diabetes Management:

• SGLT2 inhibitors or GLP-1 receptor agonists with proven cardiovascular benefit 1
• Individualized HbA1c targets, avoiding hypoglycemia 1

Symptom-Specific Therapy:

• Cilostazol improves pain-free and peak walking distances in intermittent claudication 7, 6
• Supervised exercise therapy (SET) as first-line for claudication 1

Lifestyle Modification:

• Smoking cessation is paramount 5, 6
• Structured exercise programs 3

Pain Management:

• Multimodal approach incorporating biopsychosocial model 1
• Avoid opioid dependence; address psychological factors (depression, anxiety) 1
• Cognitive behavioral approaches for chronic pain 1

Revascularization:

• Reserved for lifestyle-limiting claudication unresponsive to medical therapy or CLTI 6
• Options include endovascular (angioplasty, stenting) or surgical (bypass) procedures 1

Lymphadenopathy Management

• Treatment directed at underlying cause:
  • Antibiotics for bacterial infection
  • Observation for viral etiologies
  • Chemotherapy/radiation for malignancy
• Symptomatic relief with analgesics
• Serial examination to monitor response

Critical Distinctions Summary

PAD is a chronic arterial occlusive disease requiring lifelong cardiovascular risk modification and symptom management, while lymphadenopathy is a sign requiring identification and treatment of its underlying cause. 1

Key Clinical Pitfall: The presence of peripheral edema should prompt evaluation for conditions OTHER than PAD, including venous disease, heart failure, lymphedema, or infection 4. Pure PAD does not cause edema 4.

Cardiovascular Risk: PAD patients have 4-5 times increased risk of major adverse cardiovascular events (myocardial infarction, stroke, death) compared to those without PAD 1. This systemic risk necessitates aggressive medical management even in asymptomatic patients 1.