Pruritus: Pathophysiology, Differential Diagnosis, and Stepwise Management
Pruritus (itch) is an unpleasant cutaneous sensation provoking the desire to scratch. It is a distinct sensory modality (not pain) mediated by dedicated pruriceptors (C-fibers) and central pathways.
Pathophysiology
- Mediators: Histamine (H₁/H₄), serotonin, tryptase, IL-31, TSLP, substance P, opioids (μ-agonist ↑ itch, κ-agonist ↓ itch), bile acids, bilirubin.
- Pathways: Histaminergic (acute urticaria) vs. non-histaminergic (chronic, uremic, cholestatic, neuropathic).
- Central: Spinal GRPR+ neurons → spinothalamic → thalamus → insula, cingulate, prefrontal cortex.
Etiologic Framework (Think "ITCH")
| Category | Key Causes |
|---|
| Inflammatory / Dermatologic | Atopic dermatitis, psoriasis, contact dermatitis, urticaria, lichen planus, bullous pemphigoid, scabies, fungal |
| Toxic / Systemic | CKD (uremic pruritus), cholestasis (PBC, PSC), thyroid (hypo/hyper), iron deficiency, malignancy (lymphoma, solid), HIV, polycythemia vera |
| Central / Neuropathic | Notalgia paresthetica, brachioradial pruritus, post-herpetic, MS, brain tumor, stroke |
| Harmacologic | Opioids, ACEi, statins, hydroxyurea, checkpoint inhibitors, contrast, niacin |
| Psychogenic / Psychosomatic | Delusional parasitosis, OCD, depression, anxiety, somatoform |
Clinical Assessment
- Primary vs. secondary (primary skin lesion vs. normal skin).
- Distribution: Generalized (systemic) vs. localized (dermatologic/neuropathic).
- Timing: Nocturnal (scabies, atopic), post-shower (aquagenic, polycythemia), chronic (>6 wks).
- Basic labs: CBC, CMP, TSH, Fe/TIBC, ESR/CRP, IgE, hepatitis panel, UA.
- Skin biopsy if primary lesion uncertain; imaging if neoplastic suspicion.
Stepwise Management
- Skin care: Emollients (ceramide-based), cool baths, humidifier, avoid irritants.
- Topical: Corticosteroids (inflammatory), calcineurin inhibitors, pramoxine (anesthetic), capsaicin (neuropathic), doxepin cream.
- Oral (non-sedating H₁): Cetirizine 10–40 mg, loratadine, fexofenadine — first line for histamine-mediated.
- Oral (sedating H₁): Hydroxyzine, doxepin (night) — if sleep disturbed.
- Gabapentinoids: Gabapentin/pregabalin — neuropathic, uremic, brachioradial.
- μ-Opioid antagonists / κ-agonists: Naltrexone, butorphanol, nalbuphine — cholestatic, opioid-induced.
- Biologics: Dupilumab (AD, PN), nemolizumab (PN, AD), omalizumab (CSU).
- Phototherapy: NB-UVB (uremic, AD, lymphomatous).
- Systemic immunosuppressants: Methotrexate, cyclosporine, azathioprine — refractory inflammatory.
Red Flags
- Generalized pruritus without rash + weight loss, night sweats, lymphadenopathy → malignancy workup (CT, LDH, SPEP).
- Cholestatic pattern (↑ ALP, GGT, bilirubin) → LFTs, US, MRCP.
- Uremic (CKD) → nephrology.
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