What are the causes and treatment options for generalized pruritus in a 40-year-old?

Causes of Generalized Itching in a 40-Year-Old

In a 40-year-old with generalized itching, the most common causes are iron deficiency (25% of cases with systemic disease), followed by chronic kidney disease, liver disease (especially cholestasis), thyroid disorders, hematological malignancies, and drug reactions. 1, 2

Classification Framework

Generalized pruritus without visible rash falls into two main categories 1:

• Secondary pruritus due to underlying systemic disorder
• Generalized pruritus of unknown origin (GPUO) when no cause is identified despite thorough workup

Most Important Systemic Causes to Consider

Iron Metabolism Disorders (Most Common)

• Iron deficiency is the single most common systemic cause, accounting for 25% of all cases with underlying disease 1
• Iron replacement can lead to complete cessation of pruritus shortly after starting therapy 1
• Iron overload (haemochromatosis or hyperferritinaemia) can also cause generalized itching 1

Chronic Kidney Disease

• Uraemic pruritus occurs in patients with renal impairment 1, 2
• Often associated with xerosis (dry skin) 3

Liver Disease

• Cholestatic liver disease is a key cause 1, 2, 4
• Pruritus may precede other symptoms of liver dysfunction 2

Hematological Disorders

• Polycythaemia vera: Characteristic aquagenic pruritus (triggered by water contact) 1
• Hodgkin lymphoma: Up to 30% of patients experience pruritus, often with night sweats, fever, and weight loss 1, 5
• Non-Hodgkin lymphoma less commonly causes pruritus 1
• Account for approximately 2% of generalized pruritus cases 1

Endocrine/Metabolic Diseases

• Thyroid disorders (both hyper- and hypothyroidism) 2, 4, 5
• Diabetes mellitus 5

Malignancy

• Solid tumors can cause paraneoplastic pruritus 1, 2
• Pruritus may be the first presenting symptom 6

Infections

• HIV, hepatitis B and C 1, 7
• Parasitic infections (malaria, strongyloidiasis, schistosomiasis) in patients with travel history 1, 7

Drug-Induced Pruritus

• Common culprit, especially with opiates 1
• Requires detailed medication history 1

Neurological Disorders

• Neuropathic pruritus from small fiber neuropathy 1

Psychological Factors

• Functional itch disorder (psychogenic pruritus) 2

Essential Diagnostic Workup

Mandatory Initial Investigations

All patients with chronic generalized pruritus require 1:

• Full blood count (to detect anemia, polycythemia, eosinophilia)
• Ferritin levels (acute-phase protein, may need serum iron and total iron binding capacity if suspicion high despite normal ferritin) 1
• Liver function tests (consider bile acids and antimitochondrial antibodies) 1
• Urea and electrolytes (renal function) 1
• Thyroid-stimulating hormone 5

Additional Investigations Based on Clinical Suspicion

• Blood film, lactate dehydrogenase, ESR if hematological disorder suspected 1
• JAK2 V617F mutation if polycythemia vera suspected (present in 97% of cases) 1
• HIV and hepatitis serology (A, B, C) 1
• Chest X-ray if lymphoma suspected 4, 5
• Tissue transglutaminase antibodies if unexplained iron deficiency (celiac disease) 1
• Fasting glucose for diabetes screening 5

Important Diagnostic Pitfalls

• Ferritin is an acute-phase protein and may appear falsely normal in iron deficiency with concurrent inflammation 1
• IgA deficiency can cause falsely negative TTG readings 1
• Consider trial of iron replacement if ferritin is below 15-25 µg/L or if unexplained anemia/microcytosis present 1

Treatment Approach

First-Line Management

Start with emollients and self-care advice before investigating 1:

• Keep nails short to minimize excoriation 1
• Apply emollients liberally and frequently 1
• Short trial of non-sedating antihistamine (fexofenadine 180 mg or loratadine 10 mg) 1, 8

Cause-Specific Treatment

• Iron deficiency: Iron replacement therapy (Strength of recommendation C) 1
• Iron overload: Venesection or desferrioxamine 1
• Uraemic pruritus: Ensure adequate dialysis, normalize calcium-phosphate, control PTH, correct anemia with erythropoietin; consider gabapentin, capsaicin cream, or topical calcipotriol 1
• Lymphoma-associated: Cimetidine, carbamazepine, gabapentin, or mirtazapine; oral corticosteroids for incurable disease 1
• Polycythemia vera: Cytoreductive therapy, aspirin, interferon-α, SSRIs, or phototherapy 1
• Drug-induced: Trial cessation if risk-benefit acceptable 1

When to Refer to Secondary Care

Refer when 1:

• Diagnostic doubt exists
• Patient is distressed despite primary care management
• Symptoms persist after appropriate initial treatment

Key Clinical Pearls

• In a 40-year-old, always check iron studies first as iron deficiency is the most treatable and common systemic cause 1
• Aquagenic pruritus (itching after water contact) strongly suggests polycythemia vera 1
• Night itching with B symptoms (fever, night sweats, weight loss) suggests lymphoma 1
• Never use sedating antihistamines long-term as they may predispose to dementia 1
• GPs should maintain regular follow-up as the underlying cause may not be evident initially 1