What are the non-dermatological causes of itching?

Non-Dermatological Causes of Itching

Generalized pruritus without a primary rash should prompt immediate investigation for systemic disease, with iron deficiency, cholestatic liver disease, chronic kidney disease, hematological malignancies, and endocrine disorders being the most common non-dermatological causes. 1, 2

Systemic Causes by Category

Hematological Disorders

• Iron deficiency is a common and highly treatable cause, with iron replacement leading to complete cessation of pruritus shortly after treatment begins 1, 2
• Polycythemia vera characteristically presents with aquagenic pruritus (water-induced itching), particularly after bathing or showering 1, 2
• Hodgkin lymphoma typically causes nocturnal pruritus, often accompanied by B symptoms (weight loss, fever, night sweats) 2, 3
• Other lymphomas and hematological malignancies can present with generalized itch as a paraneoplastic phenomenon 1, 2

Hepatobiliary Disease

• Cholestatic liver disease is a major cause, with pruritus predominantly affecting palms and soles, worsening at night 1, 2
• Primary biliary cholangitis should be suspected if antimitochondrial antibodies are positive 1, 2
• Intrahepatic cholestasis of pregnancy causes generalized itching in the second half of pregnancy without primary rash 4
• Serum bile acids are the definitive diagnostic test for cholestatic pruritus 1, 4

Renal Disease

• Uremic pruritus occurs in approximately 42% of patients on hemodialysis 3
• Chronic kidney disease causes pruritus through multiple mechanisms including xerosis, metabolic disturbances, and inadequate dialysis 1, 2
• Urea and electrolytes should be part of initial investigation for all unexplained pruritus 1

Endocrine and Metabolic Disorders

• Thyroid disease (both hyperthyroidism and hypothyroidism) can cause generalized pruritus 1, 2
• Diabetes mellitus may present with pruritus, though routine endocrine testing is only recommended if clinical features suggest endocrinopathy 2
• Thyroid function tests should be considered when clinical features suggest thyroid disease 2

Malignancy

• Solid tumors can cause paraneoplastic pruritus 1, 2
• Nocturnal pruritus with weight loss strongly suggests hematologic malignancy and mandates investigation 3
• Heightened concern for underlying malignancy is warranted in individuals older than 60 years with diffuse itch of less than 12 months duration 5

Infectious Diseases

• HIV infection can cause generalized pruritus 1, 2
• Hepatitis A, B, and C are established causes requiring serology with appropriate travel or risk history 1, 2
• Malaria, strongyloidiasis, and schistosomiasis should be considered with relevant travel history 1

Neurological Disorders

• Neuropathic pruritus may result from small fiber neuropathy or central nervous system pathology 1
• Detailed neurological history and examination are required, with skin biopsy considered if small fiber neuropathy is suspected 1, 2
• Localized pruritus is more indicative of neuropathic causes 6

Drug-Induced Pruritus

• Opioids are well-known to induce itching without skin lesions 7
• Antimalarials and hydroxyethyl starch commonly cause drug-induced itch 7
• Statins (particularly rosuvastatin) can cause cholestatic hepatitis with pruritus as a cardinal symptom 2
• Approximately 12.5% of drug reactions present with pruritus without rash 2
• A complete medication history is essential, with trial cessation if risk-benefit analysis is acceptable 1

Cardiovascular Disease

• Heart failure can cause pruritus, particularly when associated with fluid retention 1, 2
• Salt-sensitive pruritus that worsens with increased sodium intake strongly suggests fluid retention from cardiac, renal, or hepatic disease 2

Psychological and Functional Disorders

• Psychogenic pruritus (functional itch disorder) occurs when no organic cause is identified despite comprehensive workup 1, 6
• Stress, emotional excitation, and cognitive factors can trigger or worsen pruritus 2
• This remains a diagnosis of exclusion after thorough investigation 6

Essential Diagnostic Workup

Initial laboratory panel for all patients with generalized pruritus without rash should include: 1, 2

• Complete blood count with differential
• Ferritin levels (iron studies)
• Liver function tests, total bilirubin, and serum bile acids
• Urea and electrolytes (renal function)
• Consider thyroid function tests if clinically indicated

Additional testing based on clinical suspicion: 1, 2

• JAK2 V617F mutation if polycythemia vera suspected
• Antimitochondrial antibodies for primary biliary cholangitis
• HIV and hepatitis A, B, C serology with appropriate history
• Skin biopsy for persistent unexplained pruritus to evaluate cutaneous lymphoma or small fiber neuropathy

Critical Pitfalls to Avoid

• Never dismiss nocturnal pruritus without investigation, as it may herald hematologic malignancy 3
• Avoid long-term sedating antihistamines due to dementia risk, except in palliative care settings (Strength of recommendation B) 1, 3
• Do not delay bile acid testing when cholestatic disease is suspected, as this is the definitive diagnostic test 4
• Recognize that pruritus without rash is rarely an emergency unless accompanied by systemic signs of anaphylaxis, severe hepatic failure, or hemodynamic instability 2