Why are protein electrophoresis and thyroid function tests (TFTs) used in the diagnosis of peripheral neuropathy in patients with no clear history of diabetes, trauma, or toxin exposure?

Why Protein Electrophoresis and Thyroid Function Tests Are Essential in Peripheral Neuropathy Workup

Protein electrophoresis and thyroid function tests are critical screening tools in peripheral neuropathy because they identify two treatable causes—monoclonal gammopathies and hypothyroidism—that must be excluded before attributing neuropathy to diabetes or labeling it as idiopathic. 1, 2

Protein Electrophoresis: Detecting Monoclonal Gammopathies

Why It Matters for Morbidity and Mortality

• Monoclonal gammopathies cause peripheral neuropathy through direct nerve damage and can indicate serious underlying conditions like Waldenström macroglobulinemia, multiple myeloma, or POEMS syndrome that require specific treatment to prevent progression. 3

• Serum protein electrophoresis with immunofixation is recommended as part of initial laboratory evaluation for all patients with peripheral neuropathy of unclear etiology. 2, 4

• Up to 20% of patients with Waldenström macroglobulinemia develop peripheral neuropathy, often harboring antibodies against myelin-associated glycoprotein (MAG) that directly damage peripheral nerves. 3

Clinical Impact

• Detecting a monoclonal protein fundamentally changes management, as these patients may require hematologic treatment rather than symptomatic neuropathy management alone. 3

• Anti-MAG antibodies can be evaluated in patients with sensory peripheral neuropathies once a monoclonal protein is identified, helping confirm the pathophysiologic mechanism. 3

• Nerve conduction studies or electromyography may help determine if neuropathy is related to the monoclonal process versus other causes, guiding treatment decisions. 3

Thyroid Function Testing: Identifying Hypothyroidism

Why It Matters for Quality of Life

• Hypothyroidism is one of the most common treatable causes of peripheral neuropathy and must be excluded in the initial workup. 1, 2, 4

• Thyroid-stimulating hormone (TSH) measurement should be included in initial blood tests for all patients presenting with peripheral neuropathy. 1, 2

• Treating underlying hypothyroidism can prevent progression and potentially improve neuropathic symptoms, directly impacting patient quality of life. 1

Clinical Reasoning

• In patients with severe or atypical neuropathy, causes other than diabetes should always be considered, including hypothyroidism, before confirming a diagnosis of diabetic neuropathy. 3

• Diabetic neuropathy is a diagnosis of exclusion, making it essential to rule out thyroid dysfunction and other metabolic causes first. 3

The Systematic Diagnostic Approach

Initial Laboratory Panel

The recommended initial workup for unexplained peripheral neuropathy includes:

• Complete blood count and comprehensive metabolic profile 1, 2
• Fasting blood glucose and HbA1c (to exclude diabetes) 2, 4
• Vitamin B12 with metabolites (methylmalonic acid ± homocysteine) 2, 4
• Serum protein electrophoresis with immunofixation 2, 4
• Thyroid-stimulating hormone (TSH) 1, 2
• Erythrocyte sedimentation rate 1

Common Pitfalls to Avoid

• Do not assume diabetic neuropathy without excluding other causes, even in patients with known diabetes, as multiple etiologies can coexist. 3

• Standard nerve conduction studies may be completely normal in small fiber neuropathy, so normal electrodiagnostic studies do not exclude neuropathy. 5

• Up to 27% of adults with neuropathy have no identifiable etiology after diagnostic testing, but this diagnosis should only be made after comprehensive evaluation including protein electrophoresis and thyroid function. 4

When to Pursue Additional Testing

• If initial evaluation including protein electrophoresis and TSH is inconclusive, referral to a neurologist for electrodiagnostic studies, specific antibody assays, or nerve biopsy should be considered. 2

• In patients with monoclonal proteins and peripheral neuropathy, specialized testing for anti-MAG antibodies, cryoglobulins, and cold agglutinins may be warranted. 3

• Asymmetrical symptoms should prompt investigation for alternative etiologies such as vasculitis, entrapment syndromes, or mononeuropathy multiplex rather than typical length-dependent polyneuropathy. 5, 6

Impact on Treatment Decisions

• Identifying hypothyroidism or monoclonal gammopathy changes management from symptomatic treatment to disease-modifying therapy, potentially reversing or halting neuropathy progression. 1, 4

• Without these tests, treatable causes may be missed, leaving patients on symptomatic medications (gabapentin, pregabalin, duloxetine) when curative treatment exists. 2, 4

• Complete reversal of nerve damage is uncommon even with treatment, making early detection through appropriate screening critical for preventing irreversible damage. 4