What are the possible causes and recommended work‑up for a patient with generalized pruritus without rash, a sensation of feeling hot despite normal temperature, irritability, headache, and fatigue?

Generalized Pruritus Without Rash: Systematic Diagnostic and Management Approach

Your constellation of symptoms—generalized itching without rash, sensation of heat despite normal temperature, irritability, headache, and fatigue—most strongly suggests either iron deficiency (which accounts for approximately 25% of cases) or an early systemic disorder requiring immediate laboratory evaluation. 1, 2

Immediate Diagnostic Workup (Order Today)

The British Association of Dermatologists mandates the following initial panel for all patients with chronic generalized pruritus without visible rash 1, 2:

• Complete blood count with differential – screens for polycythemia vera, lymphoma, and anemia 1, 2
• Comprehensive iron studies (serum iron, ferritin, transferrin saturation) – ferritin alone is insufficient and may be falsely normal in inflammatory states 2, 3
• Liver function tests, total bilirubin, and serum bile acids – cholestatic liver disease causes generalized pruritus with palm/sole predominance and nocturnal worsening 1, 2
• Renal panel (urea, creatinine, electrolytes) – uremic pruritus correlates with chronic kidney disease severity 1, 2
• Thyroid-stimulating hormone – only if clinical features suggest thyroid dysfunction (your fatigue and irritability warrant this) 1, 2
• Fasting glucose and hemoglobin A1c – diabetic neuropathy can present with generalized pruritus 2

Critical Pitfall to Avoid

Do not accept "normal labs" without verifying that comprehensive iron studies were performed. Many patients with iron-deficiency pruritus are missed because only ferritin was checked, which appeared falsely normal in the setting of inflammation. 3

Most Likely Diagnoses Based on Your Symptom Pattern

Iron Deficiency (25% of Cases)

• Key features: Generalized pruritus, fatigue, irritability (from anemia), headache 2, 3
• Diagnostic confirmation: Low serum iron, low ferritin, low transferrin saturation 2, 3
• Treatment: Oral iron replacement (ferrous sulfate 325 mg daily or equivalent elemental iron 65 mg) leads to complete cessation of pruritus within days to weeks 2

Neuropathic Pruritus (25% of Cases)

• Key features: Burning or stinging quality to the itch, normal temperature sensation despite feeling hot (suggests small-fiber neuropathy affecting C-fibers that transmit both pain and temperature signals) 2
• Diagnostic confirmation: Skin biopsy with intra-epidermal nerve-fiber density quantification if routine labs unrevealing 2
• Treatment: Gabapentin 300 mg at bedtime, titrated to 300–1200 mg daily in divided doses 2

Thyroid Dysfunction

• Key features: Fatigue, irritability, sensation of heat (hyperthyroidism) or cold intolerance (hypothyroidism), pruritus 4, 5
• Diagnostic confirmation: Abnormal TSH 1, 2
• Treatment: Thyroid hormone replacement or antithyroid medication depending on diagnosis 4

Polycythemia Vera

• Key features: Aquagenic pruritus (triggered by water/bathing), headache, sensation of heat 1, 2
• Diagnostic confirmation: Elevated hemoglobin/hematocrit, positive JAK2 V617F mutation 1, 2
• Treatment: Cytoreductive therapy, low-dose aspirin, interferon-α 2

Immediate Symptomatic Management (While Awaiting Results)

Start these interventions today 1, 2:

• Emollients applied liberally at least twice daily – universal first-line therapy for all pruritus 1, 2
• Non-sedating antihistamines – fexofenadine 180 mg daily or loratadine 10 mg daily for symptomatic relief 1, 2
• Avoid sedating antihistamines (hydroxyzine, diphenhydramine) except for short-term use due to dementia risk 2
• Self-care measures: Keep nails short, avoid hot water (use lukewarm), wear loose cotton clothing, employ stress-reduction techniques 2

Cause-Specific Treatment Algorithms (Once Diagnosis Confirmed)

If Iron Deficiency Confirmed

• Oral iron 65 mg elemental iron daily → complete resolution within days to weeks 2

If Cholestatic Liver Disease Confirmed

• First-line: Rifampin 150 mg twice daily 1, 2
• Second-line: Cholestyramine 9 g daily 1, 2
• Third-line: Sertraline 75–100 mg daily 2

If Uremic Pruritus Confirmed

• First-line: Broadband UVB phototherapy (most effective, Level 1+ evidence) 2
• Optimize dialysis adequacy (Kt/V ≥1.6) 2
• Second-line: Gabapentin 300–1200 mg daily in divided doses 1, 2

If Neuropathic Pruritus Confirmed

• First-line: Gabapentin 300 mg at bedtime, titrated to 300–1200 mg daily 2
• Adjunctive: Topical menthol, pramoxine, or lidocaine 2

If Psychogenic Pruritus (Diagnosis of Exclusion)

Must meet all three criteria: chronic itch >6 weeks, no identifiable somatic cause after thorough investigation, generalized distribution 2

• Behavioral interventions: Patient education, trigger avoidance, relaxation techniques, cognitive restructuring, habit-reversal training 1, 2
• Pharmacologic: Narrow-band UVB phototherapy 1, 2
• Referral: Social workers, liaison psychiatry, psychologists 1, 2

When to Refer to Specialists

• Dermatology: Persistent pruritus >2–4 weeks despite first-line therapy or diagnostic uncertainty 2
• Hepatology: Significant hepatic impairment (transaminases >3× upper limit normal, elevated bilirubin or bile acids) 2
• Nephrology: Elevated creatinine requiring dialysis optimization 2
• Hematology: Suspected polycythemia vera (elevated hemoglobin/hematocrit with positive JAK2 mutation) 2
• Neurology: Refractory neuropathic pruritus or confirmed small-fiber neuropathy on biopsy 2

Red Flags Requiring Urgent Evaluation

Seek emergency care immediately if you develop 2:

• Severe abdominal pain with jaundice
• Altered mental status
• Rash with fever and mucosal involvement
• Hypotension, tachycardia, or respiratory distress

Additional History-Directed Testing (If Initial Workup Unrevealing)

• HIV and hepatitis A, B, C serologies – if risk factors present (travel, sexual history, IV drug use) 1, 2
• Skin biopsy – for persistent unexplained pruritus to evaluate cutaneous lymphoma or small-fiber neuropathy 1, 2
• Antimitochondrial antibodies – if cholestatic liver tests suggest primary biliary cholangitis 2

Key Clinical Pearls

• Iron replacement yields rapid symptom relief (days to weeks) when deficiency is the underlying driver, making it both diagnostic and therapeutic 2
• A burning quality of itch is a red flag for neuropathic mechanisms and should prompt gabapentin therapy rather than antihistamines 2
• Your sensation of feeling hot despite normal temperature may reflect small-fiber neuropathy affecting temperature-sensing C-fibers, not actual fever 2
• Irritability and headache are common in iron-deficiency anemia and should not be dismissed as purely psychological 2, 3