What is the appropriate work‑up and initial management for a patient with facial and hand pruritus and pale stools suggestive of cholestasis?

Work-Up and Management of Facial and Hand Pruritus with Pale Stools

Immediate Diagnostic Work-Up

Begin with abdominal ultrasound to differentiate intrahepatic from extrahepatic cholestasis—this is the mandatory first imaging step. 1

Essential Laboratory Tests

• Serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) – Elevated levels confirm cholestasis and guide further work-up 1
• Antimitochondrial antibodies (AMA) – Testing is mandatory in all adults with chronic intrahepatic cholestasis; positive AMA at titer ≥1:40 establishes primary biliary cholangitis (PBC) diagnosis with >95% specificity 1
• Serum bilirubin (conjugated), ALT, AST – Assess severity and pattern of liver injury 1
• Prothrombin time and serum albumin – Evaluate for advanced disease 1

Advanced Imaging When Ultrasound is Non-Diagnostic

• Magnetic resonance cholangiopancreatography (MRCP) is the next step for patients with unexplained cholestasis after negative ultrasound 1
• Endoscopic ultrasound (EUS) serves as an alternative to MRCP specifically for evaluating distal biliary tract obstruction 1
• Avoid diagnostic ERCP unless therapeutic intervention is anticipated, given the 3-5% pancreatitis risk, 2% bleeding risk with sphincterotomy, and 0.4% procedure-related mortality 1

Liver Biopsy Indications

• Perform liver biopsy when AMA is negative and diagnosis remains unclear after imaging studies 1
• The biopsy must contain ≥10 portal fields due to high sampling variability in small bile duct diseases 1

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First-Line Pharmacologic Treatment of Pruritus

Start rifampicin 150 mg orally twice daily as first-line therapy for moderate-to-severe cholestatic pruritus, titrating up to 600 mg twice daily based on response. 2, 3

Rifampicin: Evidence and Monitoring

• Strongest evidence base – Two meta-analyses of randomized controlled trials demonstrate superior efficacy (Strength A, Level 1+ evidence), achieving meaningful relief in >90% of patients with chronic cholestasis and severe refractory itching 2, 3
• Hepatotoxicity monitoring – Check liver function tests every 2-4 weeks; approximately 7.3% develop significant hepatitis, typically after 4-12 weeks of therapy 2, 3
• Patient counseling – Warn that rifampicin causes harmless orange-red discoloration of urine, tears, and sweat 2, 3

Important Exception: PSC and PBC

• For primary sclerosing cholangitis (PSC) or primary biliary cholangitis (PBC), bezafibrate is now recommended as first-line based on the 2022 EASL guidelines and the FITCH trial, which showed clear benefit for moderate-to-severe pruritus 1, 3
• Rifampicin remains the alternative when bezafibrate is unavailable or contraindicated 1

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Second-Line Treatment Options

Cholestyramine (When Rifampicin Fails or Causes Hepatotoxicity)

• Dose: 4 g daily, titrating up to maximum 16 g daily 2
• Critical administration rule – Give cholestyramine 2-4 hours before or after all other medications to prevent binding interactions and loss of efficacy 2, 3
• Limited efficacy – Meta-analyses show heterogeneous results, particularly weak evidence in sclerosing cholangitis compared to PBC 1, 2
• Not recommended as first-line despite historical use, due to inferior evidence compared to rifampicin 3

Sertraline

• Dose: 75-100 mg orally once daily 2, 3
• Small randomized controlled trials demonstrate significant itch reduction with fewer side effects than opioid antagonists 2, 3

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Third-Line Treatment for Refractory Cases

Naltrexone

• Initiate at 12.5 mg daily and titrate slowly to maximum 50 mg daily 2, 3
• Mandatory gradual titration – Rapid dose escalation precipitates severe opioid-withdrawal-like symptoms including pain and confusion 2, 3
• Higher adverse event rates limit routine use 2, 3

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Treatments to Avoid

• Gabapentin has no proven efficacy for hepatic pruritus in controlled trials and should not be used 2, 3
• Antihistamines do not relieve cholestatic pruritus – they provide only non-specific sedative effects and may increase dementia risk with long-term use in elderly patients 2, 3
• Ondansetron is not recommended due to lack of efficacy in recent randomized controlled trials 2, 3

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Common Pitfalls to Avoid

• Do not skip ultrasound – Mechanical biliary obstruction must be excluded before starting pharmacotherapy, as relieving obstruction often resolves pruritus promptly 3
• Do not use cholestyramine as first-line – Rifampicin has superior evidence and should be prioritized 3
• Remember the 4-hour separation rule for cholestyramine to prevent drug-binding interactions 3
• Do not assume bile acids cause pruritus – Current evidence indicates lysophospholipids and sulfated progesterone metabolites are more likely pruritogens than bile acids themselves 4

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Supportive Non-Pharmacologic Measures

• Apply emollients to prevent skin dryness 1
• Avoid hot baths or showers 1
• Use cooling menthol gels on affected areas 1
• Keep fingernails trimmed to reduce scratching-related skin damage 1

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Refractory Pruritus

• Liver transplantation is highly effective, with pruritus frequently resolving within 24 hours, but should only be considered when all available medical interventions have failed 2
• Experimental options include extracorporeal albumin dialysis, plasmapheresis, nasobiliary drainage, or ultraviolet phototherapy 3, 5