What is the differential diagnosis for cold extremities?

Differential Diagnosis for Cold Extremities

Acute Life-Threatening Causes (Evaluate First)

Acute limb ischemia is the most critical diagnosis to exclude immediately, as irreversible tissue damage occurs within 4-6 hours of arterial occlusion. 1, 2

Acute Arterial Occlusion

• Assess for the "6 P's": Pain, Pallor, Pulselessness, Poikilothermia (coldness), Paresthesias, and Paralysis 2, 3
• Sudden onset of symptoms distinguishes acute from chronic ischemia 2
• Risk factors include atrial fibrillation (embolic source), known peripheral arterial disease, age ≥65 years or ≥50 years with smoking/diabetes 2, 4
• If suspected, initiate anticoagulation immediately and obtain CT angiography within hours—do not delay for other testing 2, 3

Acute Deep Vein Thrombosis with Phlegmasia Cerulea Dolens

• Total venous outflow occlusion causes cold, painful, dusky extremity with preserved distal arterial pulses (key differentiating feature from arterial occlusion) 1
• Presents with severe swelling, pain, and cyanosis 1

Cold Exposure Injuries

Frostbite

• Freezing of skin and underlying tissues from exposure to temperatures below 32°F (0°C) 1
• Symptoms include numbness, tingling, pain, skin color changes from pale to hardened and dark 1
• Extremities (fingers, toes, nose, ears) are most susceptible 1
• Do not rewarm until definitive care is available to avoid freeze-thaw cycles 1, 5
• Associated with alcohol use, smoking, altitude, wind speed, and duration of exposure 5

Non-Freezing Cold Injury (Trench Foot)

• Results from prolonged cold exposure above freezing point with sufficient severity and duration 6
• Presents as a painful vaso-neuropathy with persistent sensory symptoms, cold hypersensitivity, and vascular abnormalities 6
• 90% of patients show decreased intraepidermal nerve fiber density on skin biopsy 6
• Symptoms may persist for months to years after initial exposure 6

Chilblain (Pernio)

• Non-freezing cold injury affecting superficial tissues 5
• Presents with localized erythema, swelling, and burning sensation 5

Chronic Vascular Causes

Peripheral Arterial Disease (Chronic)

• Atherosclerotic burden causing progressive stenosis or occlusion, typically multifocal 1
• Risk factors: smoking, hypertension, diabetes, hyperlipidemia, obesity, family history 1
• Presents with intermittent claudication, rest pain, or critical limb-threatening ischemia 1
• Ankle-brachial index <0.9 indicates disease; <0.3 represents severe ischemia 2

Buerger Disease (Thromboangiitis Obliterans)

• Non-atherosclerotic inflammatory vasculitis of small- and medium-sized distal arteries 1
• Almost always associated with heavy tobacco smoking 1
• Predominantly affects patients 25-45 years old with incidence of 12.6 per 100,000 in North America 1
• Classic imaging shows "corkscrew" collateral vessels 1
• Presents with progressive superficial thrombophlebitis, intermittent claudication, paresthesias, rest pain, ulceration 1

Popliteal Artery Entrapment Syndrome (PAES)

• Most common cause of surgically correctable lower-extremity vascular insufficiency in young adults 1
• Presents with calf claudication, paresthesias, and swelling during exercise 1
• Anatomic types (I, II, III, V) involve compression by extravascular structures; functional type (IV) occurs despite normal anatomy 1

External Iliac Artery Endofibrosis (EIAE)

• Rare cause of performance-limiting claudication primarily in endurance athletes (especially cyclists) 1
• Symptoms include lower-extremity weakness, thigh pain, resolution after exercise cessation 1
• Ankle-brachial pressure indexes decrease following exercise 1

Cystic Adventitial Disease

• Non-atherosclerotic arterial disease causing intermittent claudication 1
• Typically affects popliteal artery 1

Fibromuscular Dysplasia

• Non-atherosclerotic arterial disease that can affect lower extremity vessels 1

Vasospastic and Functional Disorders

Raynaud's Phenomenon (Primary or Secondary)

• Episodic vasospasm triggered by cold or stress causing color changes (white-blue-red sequence)
• Primary vasospastic syndrome causes thermal discomfort from cold extremities (TDCE) in otherwise healthy subjects 7
• Prevalence: 31.1% in women, 6.9% in men aged 20-40 years 7
• Secondary forms associated with connective tissue diseases, particularly systemic sclerosis

Acrocyanosis

• Persistent blue discoloration of hands and feet due to vasospasm of small vessels
• Typically painless, worsens with cold exposure

Connective Tissue and Systemic Diseases

Systemic Sclerosis (Scleroderma)

• Raynaud's phenomenon often the presenting symptom
• Associated with digital ulcers, calcinosis, telangiectasias

Mixed Cryoglobulinemia

• HCV-related extrahepatic manifestation causing vasculitis 1
• Presents with purpura, weakness, arthralgias, low complement C4, cutaneous leukocytoclastic vasculitis 1
• Serum cryoglobulins may be temporarily negative, requiring repeated testing 1

Systemic Lupus Erythematosus

• Can present with Raynaud's phenomenon and vasculitis
• Associated with other systemic manifestations

Marfan Syndrome, Loeys-Dietz Syndrome, Vascular Ehlers-Danlos Syndrome

• Connective tissue disorders with vascular system involvement 1
• Can cause arterial complications including dissection and aneurysm formation 1

Sarcoidosis

• Granulomatous disease that can involve peripheral vasculature 1
• Extrapulmonary involvement may include vascular manifestations 1

Neurological Causes

Peripheral Neuropathy

• Diabetic, alcoholic, or other causes producing dysesthesia and burning sensations 8
• Key differentiator: redness and local warmth are absent 8
• Patients often experience symptoms when legs are under covers at bedtime 8

Complex Regional Pain Syndrome (Algodystrophy)

• During inflammatory phase can mimic other conditions with intense pain and local modifications 8
• Unilateral presentation and post-traumatic situation direct diagnosis 8

Trench Foot Sequelae

• Late effects include altered vasomotor function, neuropathies, joint changes 5
• In children, growth defects from epiphyseal plate damage 5

Metabolic and Toxic Causes

Hypothyroidism

• Causes cold intolerance and peripheral vasoconstriction
• Associated with other systemic symptoms (fatigue, weight gain, bradycardia)

Acrodynia (Mercury Poisoning)

• Rare disease from excessive mercury intake, mainly in children 8
• Red color of hands and feet with intense paroxysmal burn-type pain 8
• Diagnosis confirmed by high mercury levels in urine 8

Fabry's Disease

• Hereditary sphingolipidosis, X-linked, predominantly in men 8
• Starts early in childhood with burning sensation in limbs 8
• Diagnosis confirmed by chromatographic search for abnormal sphingolipids in urine 8

Venous Causes

Chronic Venous Insufficiency

• Produces sensations of warm feet (not typically cold), often at bedtime 8
• Associated with edema and increased local heat 8
• Presence of warmth distinguishes from arterial causes 8

Hematologic Causes

Polycythemia Vera

• Increased blood viscosity can cause acrocyanosis and cold extremities
• Associated with erythromelalgia (paradoxically, burning pain)

Cryoglobulinemia (Type I Monoclonal)

• Most frequently caused by hematological malignancies 1
• Must exclude infectious or neoplastic disorders when cryoglobulins detected 1

Infectious Causes

HCV-Related Vasculitis

• Particularly frequent in Southern Europe 1
• Virus-driven B-cell lymphoproliferation produces circulating immune complexes responsible for vasculitic manifestations 1

Critical Pitfalls to Avoid

• Never apply compression therapy, elevate the leg above heart level, or apply ice to a cold extremity with suspected arterial insufficiency—these interventions worsen ischemia and can cause tissue necrosis 4, 3
• Do not delay revascularization for additional testing if acute limb ischemia is suspected—the 4-6 hour window is absolute 2, 3
• Ankle-brachial index alone is insufficient for acute presentations—it confirms occlusion but provides no anatomic information for treatment planning 2
• Repeated cryoglobulin testing may be necessary as levels vary and can be temporarily negative 1
• In frostbite, do not begin rewarming until definitive care is available to avoid freeze-thaw cycles, which cause additional tissue necrosis 1, 5
• Distinguish between warm and cold leg edema—cold indicates arterial compromise requiring urgent evaluation, while warm suggests venous or other causes 4