What is the differential diagnosis for intense lower extremity itching?

Differential Diagnosis for Intense Lower Extremity Itching

The differential diagnosis for intense lower extremity itching should be systematically approached by first determining whether a rash is present, then pursuing targeted investigations based on clinical context including age, medication history, systemic symptoms, and risk factors for underlying disease. 1

Primary Categorization: With or Without Rash

Pruritus WITH Rash (Primary Dermatologic Causes)

If a rash is present, consider primary dermatologic conditions first:

• Atopic dermatitis/eczema - typically involves popliteal fossae (back of knees) with eczematous changes 1
• Contact dermatitis - localized to areas of exposure 1
• Stasis dermatitis - associated with venous insufficiency and lower leg involvement 1
• Fungal infections - particularly between toes or on feet 1

Pruritus WITHOUT Rash (Systemic/Neuropathic Causes)

When intense itching occurs without a primary rash (though excoriations from scratching may be present), pursue systemic and neuropathic etiologies aggressively. 1

Systemic Causes of Lower Extremity Pruritus Without Rash

Hematologic Disorders

• Iron deficiency anemia - accounts for 25% of pruritus cases with systemic disease 1
• Polycythemia vera - may present with aquagenic pruritus (triggered by water contact) 1
• Hodgkin lymphoma - associated with nighttime itching, weight loss, fevers, and night sweats 1
• Non-Hodgkin lymphoma - less commonly causes pruritus 1

Renal Disease

• Chronic kidney disease/uremic pruritus - a significant cause requiring urea and electrolytes assessment 1

Hepatobiliary Disease

• Cholestatic liver disease - though typically causes generalized pruritus, can be prominent in lower extremities 1
• Primary biliary cholangitis - check antimitochondrial antibodies if suspected 1

Endocrine/Metabolic Disorders

• Diabetes mellitus - through neuropathic mechanisms 1
• Thyroid dysfunction (hypo- or hyperthyroidism) - only investigate if clinical features suggest thyroid disease 1

Infectious Causes

• HIV - particularly with relevant risk factors 1
• Hepatitis A, B, C - especially with risk factors or travel history 2
• Parasitosis or helminthosis - consider with travel history 1

Malignancy

• Paraneoplastic pruritus from solid tumors 1
• Heightened concern in patients >60 years with diffuse itch <12 months duration and liver disease history 3

Medication-Induced

• Opioids - common culprit 1
• Hydrochlorothiazide and other diuretics 1
• Requires thorough medication review rather than specific laboratory tests 2

Neuropathic Causes (Localized Lower Extremity)

When itching is strictly localized to lower extremities without systemic symptoms, neuropathic causes become more likely: 4, 5

• Lumbar radiculopathy - nerve root compression from spinal pathology 5
• Small fiber neuropathy - from diabetes, vitamin deficiencies, or idiopathic 5
• Peripheral neuropathy - multiple etiologies including metabolic and toxic 5
• Multiple sclerosis - central nervous system demyelination 1

Psychiatric/Functional Causes

• Anxiety, depression, obsessive-compulsive disorder - diagnoses of exclusion after organic causes ruled out 1, 6

Essential Initial Workup

The British Association of Dermatologists provides the most comprehensive evidence-based initial laboratory panel: 1, 2

Mandatory First-Line Tests

• Complete blood count with differential - screens for anemia, polycythemia, eosinophilia, leukemia 1, 2
• Ferritin level - iron deficiency is the most common treatable cause; check in ALL patients with chronic pruritus 1, 2
• Liver function tests - evaluates hepatobiliary disease 1, 2
• Urea and electrolytes - assesses renal function 1, 2

Second-Line Tests (Based on Clinical Suspicion)

• Blood film, lactate dehydrogenase, ESR - if hematological involvement suspected 1, 2
• JAK2 V617F mutation - if polycythemia vera suspected (raised hemoglobin/hematocrit) 1, 2
• HIV and hepatitis serology - with relevant risk factors 2
• Fasting glucose or HbA1c - if diabetes suspected 3
• Serum iron and total iron binding capacity - if ferritin "normal" but iron deficiency still suspected 1, 2

Critical Pitfalls to Avoid

• Do NOT order routine thyroid function tests unless clinical features suggest thyroid disease 1, 2
• Do NOT fail to check ferritin - this is recommended in ALL cases of chronic generalized pruritus 1, 2
• Do NOT order extensive malignancy workups without specific clinical indicators 1, 2
• Do NOT forget medication review - drug-induced pruritus requires medication history, not laboratory tests 2
• Do NOT mistake excoriations for primary rash - intense itching causes secondary skin changes that can mislead diagnosis 1

Special Populations

Pregnancy

If the patient is pregnant with lower extremity itching:

• Intrahepatic cholestasis of pregnancy (ICP) - predominantly affects palms and soles, worse at night, no rash 1
• Polymorphic eruption of pregnancy - urticarial papules/plaques on abdomen and proximal thighs 1
• Check bile acid levels if ICP suspected 1

Elderly Patients

• Higher risk for underlying malignancy - particularly >60 years with recent-onset diffuse pruritus 3
• Increased burden of chronic itch affecting quality of life 3