What are the differential diagnoses for a patient with deep itching without a present rash?

Differential Diagnoses for Deep Itching Without Rash

For a patient presenting with deep itching without a visible rash, the most critical differentials to consider are systemic diseases including iron deficiency, chronic kidney disease, cholestatic liver disease, hematological malignancies (particularly Hodgkin lymphoma and polycythemia vera), thyroid disorders, drug-induced pruritus, HIV infection, and parasitic infections. 1, 2

Primary Systemic Causes

Hematological and Iron Disorders

• Iron deficiency is a frequently overlooked but treatable cause, with iron replacement leading to complete cessation of pruritus shortly after treatment begins 2
• Polycythemia vera characteristically presents with aquagenic pruritus (itching triggered by water contact) and should prompt JAK2 V617F mutation testing 2
• Hodgkin lymphoma is the malignancy most strongly associated with pruritus, affecting up to 30% of patients with this disease 3

Renal and Hepatic Disease

• Chronic kidney disease and uremia are well-established causes requiring assessment of urea and electrolytes 2
• Cholestatic liver disease is a major cause, with pruritus predominantly affecting palms and soles, worsening at night, and requiring bile acid measurement for diagnosis 2, 4
• Cholestatic pruritus occurs without a primary rash, though excoriations from scratching may be present 4

Endocrine and Metabolic Disorders

• Thyroid disorders (both hypo- and hyperthyroidism) can cause generalized pruritus 2, 3
• Diabetes mellitus should be screened for in all patients with unexplained pruritus 5, 3

Drug-Induced Pruritus

• Opioid-induced pruritus affects 2-10% of patients on oral opioids, 10-50% on intravenous, and 20-100% on epidural/intrathecal opioids 1
• Drug reactions account for 12.5% of cutaneous drug reactions presenting with pruritus without rash 2
• Statins (particularly rosuvastatin) can cause cholestatic hepatitis with pruritus as a cardinal symptom 2
• A complete medication history including over-the-counter pharmaceuticals and herbal remedies is essential 1

Infectious Causes

• HIV infection correlates with viral load and can present with severe pruritus and minimal skin signs 1
• Scabies should always be considered, particularly in immunocompromised patients, as it can present with severe pruritus and minimal visible signs 1
• Parasitic infections, notably helminths such as Strongyloides stercoralis, and schistosomes causing swimmer's itch 1
• Hepatitis A, B, and C can cause generalized pruritus and should be considered with appropriate travel or risk history 2

Neurological and Dermatological Causes

Neuropathic Pruritus

• Localized cutaneous pruritus is indicative of a neuropathic cause 6
• Small fiber neuropathy should be evaluated via skin biopsy for persistent unexplained pruritus 2
• Postherpetic pruritus may occur following varicella zoster infection 1

Cutaneous Lymphoma

• Cutaneous T-cell lymphoma should be considered for persistent unexplained pruritus, requiring skin biopsy evaluation 2

Psychogenic and Unknown Origin

Functional Itch Disorder

• Psychogenic pruritus can be triggered or worsened by stress, emotional excitation, and cognitive factors 2
• Psychological factors should be considered when organic causes are excluded 7

Chronic Pruritus of Unknown Origin (CPUO)

• CPUO describes chronic itch that is often generalized and for which no underlying cause can be identified despite comprehensive diagnostic workup 6
• This diagnosis should only be made after thorough exclusion of systemic causes 2

Essential Diagnostic Workup

The British Association of Dermatologists recommends the following initial panel for all patients with chronic generalized pruritus without rash: 2

• Complete blood count with differential to assess for anemia, eosinophilia, or lymphocytosis 2, 5
• Ferritin levels (with serum iron and TIBC if abnormal, as ferritin may be falsely elevated as an acute-phase protein) 2, 4
• Liver function tests, total bilirubin, and serum bile acids to evaluate for cholestatic disease 2, 4
• Urea and electrolytes to assess renal function 2
• Thyroid-stimulating hormone if clinical features suggest thyroid disease 2, 3
• Fasting glucose for diabetes screening 5, 3

Additional Testing Based on Clinical Suspicion

• JAK2 V617F mutation analysis if polycythemia vera is suspected 2
• HIV and hepatitis serology with appropriate risk history 2
• Chest radiography when lymphoma is suspected 3
• Antimitochondrial antibodies if primary biliary cholangitis is considered 2
• Skin biopsy for persistent unexplained pruritus to evaluate for cutaneous lymphoma or small fiber neuropathy 2

Critical Clinical Pitfalls

• Do not dismiss the absence of rash as excluding serious systemic disease; 14-24% of patients with generalized pruritus have a systemic etiology 3
• Always obtain a complete medication history including over-the-counter and herbal remedies, as drug-induced pruritus is common 1
• Consider scabies even with minimal skin signs, especially in immunocompromised or HIV-positive patients 1
• Do not delay bile acid testing if cholestatic disease is suspected, as this is the definitive diagnostic test 4
• Increased blood eosinophils may serve as a biomarker of T helper cell type 2 polarization and response to immunomodulator therapies in chronic pruritus of unknown origin 5
• Heightened concern for underlying malignancy is warranted in individuals older than 60 years with diffuse itch of less than 12 months duration 5