What is the diagnosis and management for a patient with pruritus (itching) without a rash, elevated liver function tests (LFTs), and proteinuria (excess protein in the urine)?

Diagnosis: Intrahepatic Cholestasis of Pregnancy (ICP) or Cholestatic Liver Disease

In a patient presenting with pruritus without rash, elevated liver function tests, and proteinuria, the most likely diagnosis is intrahepatic cholestasis of pregnancy (if pregnant) or cholestatic liver disease, and immediate measurement of serum bile acids is essential to confirm the diagnosis and guide management. 1

Clinical Presentation and Diagnostic Approach

Key Clinical Features

• Pruritus characteristics in cholestatic disease: Itching is typically generalized but predominantly affects the palms and soles, worsens at night, and occurs without a primary rash (though excoriations from scratching may be present) 1
• Absence of rash is critical: True cholestatic pruritus does not present with a primary dermatologic rash; any skin changes are secondary to scratching 1, 2
• Proteinuria adds complexity: While not typical of isolated cholestatic disease, proteinuria suggests either concurrent renal involvement or a systemic process affecting both liver and kidneys 1

Essential Diagnostic Workup

Immediate laboratory investigations should include:

• Serum bile acids (total): This is the single most important diagnostic test for cholestatic liver disease; levels >10 μmol/L are diagnostic of ICP in pregnancy, though pregnancy-specific reference ranges should be used when available 1
• Comprehensive liver function tests: Transaminases (ALT, AST) are often elevated in cholestasis, though elevation is not required for diagnosis 1
• Complete blood count with ferritin: Iron deficiency is the most common systemic cause of pruritus (25% of cases) and must be ruled out; however, ferritin is an acute-phase protein and may be falsely elevated, so check serum iron and total iron binding capacity if suspicion remains 2, 3
• Renal function (urea, creatinine, electrolytes): Essential given the proteinuria, as uremia and chronic kidney disease are well-established causes of generalized pruritus 2, 3
• Urinalysis with quantification of proteinuria: To assess severity and rule out primary renal disease 1

Secondary Investigations Based on Initial Results

If bile acids and liver tests do not fully explain the presentation:

• Thyroid function tests: Only if clinical features suggest thyroid disease; routine endocrine testing is not recommended 2, 3
• HIV and hepatitis serology: If appropriate risk factors or travel history exist 2
• JAK2 V617F mutation: If polycythemia vera is suspected (aquagenic pruritus, elevated hemoglobin/hematocrit) 1, 2
• Lactate dehydrogenase and ESR: If hematological malignancy (particularly Hodgkin lymphoma) is suspected based on constitutional symptoms 1

Management Algorithm

If Intrahepatic Cholestasis of Pregnancy is Confirmed

First-line therapy:

• Ursodeoxycholic acid (UDCA): This is the primary treatment for ICP, though specific dosing should follow obstetric guidelines 1
• Close fetal monitoring: ICP carries significant fetal risks including stillbirth, requiring intensive surveillance 1
• Delivery timing: Consider early delivery based on bile acid levels and institutional protocols 1

If Non-Pregnancy Cholestatic Liver Disease

First-line therapy:

• Cholestyramine: Generally well-tolerated and effective as first-line therapy for cholestatic pruritus 4, 5
• Treat underlying liver disease: Essential for resolution of symptoms 2, 4

Second-line options if cholestyramine fails:

• Rifampicin: Alternative drug for refractory cases 4
• μ-opioid receptor antagonists: Evidence supports opioid-mediated mechanisms in cholestatic pruritus 4, 5

Experimental therapies for severe refractory cases:

• Albumin dialysis, photopheresis, plasmapheresis, or biliary diversion may be considered when medical therapy fails and pruritus significantly impairs quality of life 4

If Iron Deficiency is Identified

• Iron replacement therapy: Often leads to complete cessation of pruritus shortly after starting treatment 2, 3
• Monitor ferritin and iron studies: Ensure adequate repletion 2

If Uremia/Chronic Kidney Disease is the Cause

• Nephrology referral: For management of underlying renal disease 2, 3
• Symptomatic management: May include antihistamines, though efficacy is limited in uremic pruritus 6

Critical Pitfalls to Avoid

• Do not rely solely on ferritin: It may be falsely elevated as an acute-phase protein; always check serum iron and total iron binding capacity if iron deficiency is suspected despite normal ferritin 3
• Do not delay bile acid testing: This is the definitive diagnostic test for cholestatic disease and should be ordered immediately, though turnaround time may be 4-14 days depending on the assay 1
• Do not assume proteinuria rules out cholestasis: While not typical, concurrent renal and hepatic involvement can occur, particularly in systemic diseases 1
• Do not use long-term sedating antihistamines: These have limited efficacy in cholestatic pruritus and carry dementia risk; reserve for palliative care only 3
• Do not miss pregnancy: Always confirm pregnancy status in women of childbearing age, as ICP has specific maternal-fetal implications requiring urgent obstetric management 1

When to Escalate Care

• Immediate obstetric referral: If patient is pregnant with confirmed or suspected ICP 1
• Hepatology referral: For persistent cholestatic disease, abnormal bile acids, or significantly elevated liver enzymes 4
• Nephrology referral: For significant proteinuria or elevated creatinine suggesting primary renal disease 2
• Dermatology referral: If diagnosis remains uncertain after 2 weeks or if skin biopsy is needed to rule out cutaneous lymphoma 2, 7