What are the common metabolic or inflammatory causes of neuropathy to consider in patients?

Metabolic and Inflammatory Neuropathy: Key Differential Diagnoses

When evaluating neuropathy, you must systematically exclude metabolic and inflammatory causes before attributing symptoms to diabetes alone, as these conditions are often treatable and may significantly improve patient outcomes.

Metabolic Causes to Consider

Diabetes and Prediabetes

• Diabetes mellitus is the most common metabolic cause of peripheral neuropathy, accounting for approximately half of all neuropathy cases 1
• Impaired glucose tolerance (IGT/prediabetes) is found in approximately 40% of patients with idiopathic neuropathy and causes clinically similar small fiber neuropathy with pain and autonomic dysfunction 2
• Up to 50% of diabetic peripheral neuropathy may be asymptomatic, yet still increases risk for ulceration and amputation 3, 4
• The metabolic syndrome (beyond glucose alone) includes multiple risk factors that drive nerve injury through fatty deposition, oxidative stress, and chronic metabolic inflammation 5

Thyroid Dysfunction

• Hypothyroidism is one of the most common treatable metabolic causes and should be screened with thyroid-stimulating hormone (TSH) levels in all neuropathy patients 3, 1

Nutritional Deficiencies

• Vitamin B12 deficiency must be excluded in all diabetic neuropathy patients, as it is a common and reversible cause 3
• Vitamin E, thiamine, nicotinamide, and red-cell folate deficiencies should be assessed, particularly in patients with malabsorption or inflammatory bowel disease 4
• Copper deficiency can cause peripheral neuropathy and warrants consideration in the appropriate clinical context 4

Renal Disease

• Uremia from renal disease is a metabolic cause that should be evaluated with comprehensive metabolic profile 3, 1

Inflammatory Causes to Consider

Autoimmune/Inflammatory Neuropathies

• Chronic inflammatory demyelinating polyneuropathy (CIDP) is a treatable inflammatory condition that must be distinguished from diabetic neuropathy 3
• Vasculitis can cause neuropathy through inflammatory vascular injury and requires specific evaluation 3
• Autoimmune mechanisms associated with inflammatory bowel disease can cause peripheral neuropathy 4

Paraprotein-Related Neuropathies

• Monoclonal gammopathies and plasma cell dyscrasias (particularly POEMS syndrome) cause neuropathy through direct inflammatory effects 4
• Light chain amyloidosis leads to neuropathy through nerve infiltration and should be screened with serum protein electrophoresis 4
• Cryoglobulinemia (often associated with hepatitis C infection) causes inflammatory neuropathy 4

Infection-Related Inflammatory Neuropathy

• HIV infection can cause inflammatory neuropathy and should be screened in appropriate risk populations 3
• Hepatitis C with cryoglobulins causes peripheral neuropathy through inflammatory mechanisms 4

Toxic/Drug-Induced Causes (Metabolic Impact)

Alcohol

• Alcohol toxicity is a common and treatable metabolic/toxic cause that should be assessed in all patients 3

Neurotoxic Medications

• Chemotherapy agents including vincristine (10% motor neuropathy rate), bortezomib (10% motor impairment), taxanes, platinum compounds, and thalidomide cause neuropathy through metabolic disruption 6, 4
• Metronidazole is a common antimicrobial cause requiring temporal association assessment and discontinuation 4
• Anti-TNF agents can cause peripheral neuropathy through inflammatory mechanisms 4

Malignancy-Associated Causes

• Multiple myeloma and bronchogenic carcinoma can cause neuropathy through metabolic and inflammatory mechanisms 3

Critical Diagnostic Approach

Initial laboratory screening should include: 1

• Complete blood count
• Comprehensive metabolic profile (including renal function)
• Fasting blood glucose and hemoglobin A1c
• Thyroid-stimulating hormone (TSH)
• Vitamin B12 level
• Erythrocyte sedimentation rate

Specialized testing when clinically indicated: 4, 1

• Serum protein electrophoresis with immunofixation (for paraproteins)
• Cryoglobulins
• HIV and hepatitis C serology
• Copper level
• Vitamin E, thiamine, folate levels (if malabsorption suspected)

Common Pitfall to Avoid

The most critical error is assuming all neuropathy in a diabetic patient is diabetic neuropathy. Diabetic neuropathy is a diagnosis of exclusion—nondiabetic neuropathies may be present in patients with diabetes and are often treatable 3. Always systematically evaluate for the metabolic and inflammatory causes listed above, as identifying these can dramatically alter management and improve patient outcomes.