What are the causes of neuropathy in a patient with small fiber neuropathy, likely with a history of diabetes?

Causes of Small Fiber Neuropathy

Small fiber neuropathy results from a broad spectrum of etiologies, with diabetes mellitus being the most common identifiable cause, though nearly half of cases remain idiopathic despite thorough evaluation. 1, 2

Primary Etiologic Categories

Metabolic and Endocrine Disorders

• Diabetes mellitus is the leading metabolic cause, affecting small unmyelinated C-fibers and thinly myelinated Aδ-fibers earliest in the disease process, often before large fiber involvement becomes detectable on conventional nerve conduction studies 3, 4
• Hypothyroidism represents the second most common endocrine cause after diabetes, accounting for approximately 9.4% of secondary small fiber neuropathy cases 2
• Impaired glucose tolerance can cause small fiber damage even before overt diabetes develops, highlighting the importance of screening for prediabetic states 5

Nutritional Deficiencies

• Vitamin B12 deficiency causes both symptomatic and asymptomatic small fiber loss similar to diabetes mellitus, with histopathological confirmation of reduced intraepidermal nerve fiber density 5, 6
• Vitamin E, thiamine, nicotinamide, and red-cell folate deficiencies should be excluded, particularly in patients with malabsorption or inflammatory bowel disease 1
• Copper deficiency warrants consideration in the differential diagnosis 1

Autoimmune and Inflammatory Conditions

• Sjögren's syndrome accounts for approximately 3% of secondary cases and represents an important treatable autoimmune cause 2, 7
• Cryoglobulinemia (often associated with hepatitis C infection) causes approximately 7% of secondary small fiber neuropathy cases 2
• Vasculitis and other autoimmune disorders can selectively damage small nerve fibers 5, 7

Hematologic and Oncologic Disorders

• Monoclonal gammopathy of undetermined significance (MGUS) accounts for 4.7% of cases and requires screening with serum protein electrophoresis 2
• Multiple myeloma and other plasma cell dyscrasias cause neuropathy through direct effects and light chain deposition 1
• Paraneoplastic neuropathy represents 3% of cases, necessitating malignancy screening in appropriate clinical contexts 2

Toxic and Drug-Induced Causes

• Alcohol is a common neurotoxin that must be assessed in all patients 5
• Chemotherapeutic agents including bortezomib, thalidomide, vincristine, taxanes, and platinum compounds cause treatment-related small fiber neuropathy 1
• Metronidazole and other antimicrobials require temporal association assessment and discontinuation when suspected 1
• Anti-TNF agents can cause peripheral neuropathy and may worsen demyelinating diseases 1

Infectious Causes

• HIV infection should be screened in at-risk populations 5
• Hepatitis C (particularly with associated cryoglobulinemia) causes small fiber damage 1

Genetic and Hereditary Causes

• Sodium channel mutations (SCN9A, SCN10A, SCN11A genes encoding Nav1.7, Nav1.8, and Nav1.9) and TRPA1 gene variants have been identified in small fiber neuropathy patients, expanding the spectrum of channelopathies 4
• Hereditary neuropathies including Charcot-Marie-Tooth disease should be considered, especially with family history 1

Iatrogenic Causes

• Treatment-induced neuropathy of diabetes (insulin neuritis) occurs with rapid glycemic improvement, with absolute risk exceeding 80% when HbA1c decreases >4% points over 3 months 8
• This acute small fiber neuropathy develops within 8 weeks of abrupt glycemic correction in the setting of chronic hyperglycemia 8

Renal Disease

• Chronic kidney disease and dialysis-related complications contribute to small fiber neuropathy development 5, 1

Idiopathic Cases

• Nearly half (41-48%) of small fiber neuropathy cases remain idiopathic despite comprehensive evaluation, representing a diagnosis of exclusion after thorough workup 5, 2

Critical Clinical Considerations

Diabetic neuropathy is a diagnosis of exclusion—even in patients with diabetes, alternative or coexisting causes must be systematically evaluated, as nondiabetic neuropathies may be present and potentially treatable 5

The American Diabetes Association emphasizes that up to 50% of diabetic peripheral neuropathy may be asymptomatic, yet these patients remain at high risk for complications including foot ulceration 5, 9

Small fibers constitute 70-90% of peripheral nerve fibers and are damaged earliest in diabetic neuropathy, often before conventional electrophysiology shows abnormalities—relying solely on nerve conduction studies will miss early small fiber-predominant disease 5, 3