What are the potential causes of burning skin sensations in multiple areas without rashes or lesions, considering possible underlying conditions such as neuropathic pain, paresthesia, diabetes, vitamin deficiencies, or autoimmune disorders?

Burning Skin Sensations Without Rash: Causes and Diagnostic Approach

Burning skin sensations in multiple areas without visible rashes or lesions most commonly result from neuropathic pruritus, small fiber neuropathy, iron deficiency, or systemic diseases including diabetes, uremia, hepatic disease, and malignancy. 1

Primary Diagnostic Categories

The British Association of Dermatologists classifies this presentation as "generalized pruritus without underlying dermatosis," which encompasses secondary pruritus from systemic disorders and generalized pruritus of unknown origin (GPUO). 1

Neuropathic Causes (Most Common for Burning Sensations)

Neuropathic pruritus is caused by pathology anywhere along the afferent sensory pathway and characteristically presents with burning, paraesthesia, stinging, and tingling sensations. 1

Key neuropathic etiologies include:

• Small fiber neuropathy - Can cause localized or generalized burning sensations and occurs in diabetes mellitus, Guillain-Barré syndrome, sarcoidosis, neurofibromatosis type 1, and HIV. 1 This may be too subtle to produce clinical or electrophysiological changes, with skin biopsy being the only diagnostic test. 1

• Diabetic neuropathy - Leads to regional burning affecting the trunk and is present in 15-20% of people with diabetes. 1, 2 Peripheral neuropathy affects approximately 1% of adults worldwide, with diabetes being the most common cause. 3

• Peripheral nerve compression - Causes burning in corresponding dermatomes, including conditions like brachioradial pruritus, notalgia paresthetica, and postherpetic neuropathy. 1, 4

• Central nervous system lesions - Spinal cord tumors, multiple sclerosis, and neurofibromatosis type 1 can produce burning sensations. 1

Systemic Disease Causes

The British Association of Dermatologists identifies multiple systemic causes of burning sensations without rash: 1

• Iron deficiency - Generalized pruritus with burning is associated with iron deficiency, and iron replacement can lead to complete cessation of symptoms shortly after starting therapy. 1 Iron deficiency anemia is the most common cause of generalized pruritus in patients with underlying systemic disease (25% of cases). 1

• Uremia - Chronic kidney disease and dialysis patients commonly experience burning sensations. 1

• Hepatic disease - Especially cholestasis produces burning and pruritus. 1

• Malignancy - Hematological disorders and solid tumors can present with burning skin sensations. 1

• Endocrine diseases - Thyroid disorders and other hormonal imbalances. 1

• Polycythemia vera - Presents with generalized pruritus in approximately 48% of patients, often with burning sensations exacerbated by hot water. 5

Metabolic and Nutritional Causes

• Vitamin B12 deficiency - Can cause peripheral neuropathy with burning sensations. 3

• Impaired glucose tolerance - Even pre-diabetes can cause neuropathic burning through metabolic disturbances, oxidative stress, and microvascular insufficiency. 2

Psychological and Functional Causes

Psychogenic or "functional itch disorder" can present with burning sensations, particularly when symptoms worsen with stress, predominate during rest, and vary in intensity with psychological factors. 1 However, all physical causes must be excluded before this diagnosis. 1

Drug-Induced Causes

Medications can cause burning sensations without visible lesions, including chemotherapies (cisplatin, paclitaxel, vincristine), amiodarone, HIV medications (stavudine, zalcitabine), and opioids. 1, 3

Essential Initial Workup

For all patients with burning skin sensations without rash, obtain: complete blood count with differential, comprehensive metabolic panel (including renal and liver function), ferritin level, and thyroid-stimulating hormone. 6, 5

Additional targeted investigations based on clinical suspicion:

• Blood glucose and hemoglobin A1c - Screen for diabetes and impaired glucose tolerance. 6, 3

• Vitamin B12 with metabolites (methylmalonic acid ± homocysteine) - Evaluate for B12 deficiency neuropathy. 3

• Serum protein electrophoresis with immunofixation - Screen for monoclonal gammopathies. 3

• JAK2 mutation and erythropoietin level - If polycythemia vera suspected. 5

• Skin biopsy - Consider for small fiber neuropathy confirmation when clinical suspicion is high. 1, 7

Critical Clinical Pitfalls

Review all current medications thoroughly, as 20-30% of generalized pruritus cases have drug-induced causes. 6 This is frequently overlooked but essential.

Ferritin is an acute-phase protein and may be falsely elevated in inflammatory conditions despite true iron deficiency. 1 Consider checking serum iron levels and transferrin saturation if ferritin is borderline.

Do not dismiss burning sensations as purely psychological without completing a thorough systemic workup. 1 Up to 27% of adults with neuropathy have no identifiable cause after testing, but this is a diagnosis of exclusion. 3

Examine for subtle dermatoses including finger webs, anogenital region, nails, and scalp - conditions like scabies or early dermatitis may not be immediately obvious. 6

Rare but Important Considerations

• Preeruptive herpes zoster - Can present with burning sensations in a dermatomal distribution before visible lesions appear. 8

• Aquagenic pruritus - Burning triggered by water contact, associated with polycythemia vera and myeloproliferative disorders. 5, 8

• Sensitive skin syndrome - Hyperreactivity of the cutaneous nervous system causing burning, stinging, and tingling without visible lesions, affecting approximately 50% of the population to varying degrees. 9