What lab workup is recommended for an adult patient with no known medical history presenting with intermittent coldness of hands and feet?

Laboratory Workup for Intermittent Coldness of Hands and Feet

The initial laboratory workup should include a complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), antinuclear antibodies (ANA), thyroid-stimulating hormone (TSH), fasting glucose or HbA1c, and serum ferritin to distinguish between primary Raynaud's phenomenon and secondary causes including autoimmune connective tissue diseases, thyroid dysfunction, and hematologic disorders. 1, 2

Primary Diagnostic Considerations

The most critical distinction is between primary Raynaud's phenomenon (benign vasospasm) and secondary Raynaud's phenomenon (SRP), which can lead to permanent tissue destruction if untreated. 1 This differentiation drives the entire laboratory evaluation strategy.

Core Laboratory Panel

• CBC with differential to identify anemia, polycythemia, thrombocytosis, or hematologic malignancies that can cause acral coldness 3
• ESR and CRP to detect underlying inflammatory or autoimmune conditions, as elevated inflammatory markers suggest secondary causes 4
• Thyroid function tests (TSH and free T4) to exclude hypothyroidism, which commonly presents with cold extremities and can mimic or coexist with Raynaud's phenomenon 3, 5
• Fasting glucose or HbA1c to screen for diabetes mellitus, which causes peripheral neuropathy and vascular disease contributing to acral coldness 4, 3

Autoimmune and Rheumatologic Screening

• RF and ACPA testing to evaluate for rheumatoid arthritis, which can present with vasculitis and secondary Raynaud's phenomenon 4
• ANA (antinuclear antibodies) as the primary screening test for systemic lupus erythematosus, scleroderma, and mixed connective tissue disease—all major causes of SRP 1, 2
• If ANA is positive, proceed with specific antibody panels including anti-Scl-70 (scleroderma), anti-centromere (limited scleroderma/CREST syndrome), anti-dsDNA (lupus), and anti-Sm antibodies 1

Vascular and Metabolic Assessment

• Serum ferritin to assess iron status, as iron deficiency can contribute to cold intolerance and fatigue 3
• Lipid profile to evaluate cardiovascular risk factors and atherosclerotic disease that may cause peripheral arterial disease 4, 6
• Comprehensive metabolic panel including liver and kidney function, as these can affect vascular health and drug metabolism if treatment becomes necessary 3, 5

Additional Testing Based on Clinical Suspicion

When Peripheral Arterial Disease is Suspected

• Ankle-brachial index (ABI) measurement is simple, rapid, and reliable for confirming arterial occlusion as a cause of cold extremities 4
• Consider ABI screening in patients over 50 years or those with risk factors including smoking, hypertension, hyperlipidemia, or diabetes duration >10 years 4
• Handheld Doppler assessment of pedal pulses provides immediate bedside confirmation of vascular compromise 4

When Neuropathy is Considered

• Vitamin B12 and folate levels if peripheral neuropathy with vasomotor symptoms is suspected 3
• Clinical examination with 10-g monofilament testing and vibration assessment using 128-Hz tuning fork to identify loss of protective sensation 4

When Systemic Disease is Suspected

• Serum protein electrophoresis if cryoglobulinemia or paraproteinemia is considered (causes hyperviscosity and acral ischemia) 1
• Hepatitis B and C serologies as these infections are associated with cryoglobulinemia and vasculitis 1

Critical Diagnostic Pitfalls to Avoid

• Do not assume normal thyroid function based on TSH alone—if TSH is low with low free T4, consider central hypothyroidism from hypopituitarism, which presents with both cold extremities and fatigue 3
• Negative RF and ACPA do not exclude autoimmune disease—many connective tissue diseases causing SRP are seronegative 4
• Normal pedal pulses do not rule out forefoot ischemia—if clinical suspicion exists, obtain toe pressures and Doppler ankle pressures 4
• Laboratory abnormalities affect management in only 5% of cases, but missing treatable causes like hypothyroidism, anemia, or early connective tissue disease has significant consequences 3

Timing and Follow-Up Strategy

• Repeat inflammatory markers (ESR, CRP) when clinically relevant if initial values are borderline or symptoms progress 4
• Re-check autoantibodies in 3-6 months if initial screening is negative but clinical suspicion for evolving connective tissue disease remains high (particularly in young women with progressive symptoms) 1
• Annual screening for diabetes and thyroid dysfunction in patients with persistent symptoms and risk factors 4, 3

When to Escalate Beyond Basic Laboratory Testing

• Nailfold capillaroscopy (not a laboratory test but critical) should be performed if SRP is suspected, as abnormal capillary patterns predict development of systemic sclerosis 1, 2
• Vascular imaging with CTA or MRA if ABI is abnormal or severe symptoms suggest large vessel disease 4
• Specialized rheumatology referral if any autoantibodies are positive or if clinical features suggest evolving connective tissue disease 1