What is the workup and management for a middle-aged female patient with a history of autoimmune diseases diagnosed with Primary Biliary Cholangitis (PBC)?

Workup and Management of Primary Biliary Cholangitis

Diagnostic Workup

The diagnosis of PBC is established by demonstrating cholestatic liver biochemistry (elevated alkaline phosphatase and GGT) combined with positive antimitochondrial antibodies (AMA), without requiring liver biopsy in most cases. 1

Laboratory Evaluation

• Cholestatic pattern: Parallel elevation of alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT) is characteristic 1
• Aminotransferases: AST and ALT are often mildly elevated but do not necessarily indicate autoimmune hepatitis overlap 1
• Bilirubin: Elevated serum bilirubin indicates more advanced disease and portends poor prognosis 1
• Autoantibodies: AMA is positive in approximately 95% of patients 2
  • AMA-negative patients (5%) are often positive for PBC-specific nuclear antibodies (ANA), which are equivalent to AMA in diagnostic accuracy 2
  • AMA-negative, ANA-positive patients do not require biopsy for diagnostic confirmation 2
  • True autoantibody-negative PBC cannot be diagnosed without biopsy 2

When to Perform Liver Biopsy

• Autoantibody-negative disease with cholestatic biochemistry requires biopsy for diagnosis 2
• Suspected AIH-PBC overlap syndrome: Biopsy is required for cholestasis patients with negative AMAs or PBC patients who respond inadequately to UDCA, especially those with elevated ALT and IgG 3
• Concurrent metabolic liver disease: AMA-positive patients with clinical features suggesting NAFLD may need biopsy to identify the dominant liver injury 2

Screening for Associated Conditions

Given the autoimmune nature of PBC, screen for associated autoimmune diseases that contribute to fatigue and quality of life impairment 2:

• Thyroid disease (hypothyroidism)
• Celiac disease
• Pernicious anemia and autoimmune hemolytic anemia
• Addison's disease
• Sjögren's syndrome (sicca complex is common)

Osteoporosis Risk Assessment

• All patients with PBC should have risk assessment for osteoporosis using FRAX or similar tools 2
• Treatment and follow-up should be according to national guidelines 2

First-Line Management

Ursodeoxycholic acid (UDCA) at 13-15 mg/kg/day is the standard of care for all patients with PBC and should be initiated immediately upon diagnosis. 1

UDCA Administration

• Dosing: 13-15 mg/kg/day is the established therapeutic dose 2, 1
• Timing with bile acid resins: If cholestyramine is used for pruritus, UDCA must be taken at least 4 hours before or after to avoid interaction 2, 4
• Efficacy: UDCA dramatically improves prognosis by delaying disease progression and improving survival 1

Response Assessment at 12 Months

Assess biochemical response after 1 year of UDCA therapy at 13-15 mg/kg/day to identify high-risk patients requiring second-line therapy. 2

• Patients not meeting UDCA response criteria (various criteria exist, but generally include failure to normalize or significantly reduce ALP) have significantly worse clinical outcomes 2
• ALP normalization is considered the improved therapeutic goal for high-risk patients 3
• Age and sex are independent indicators of non-responsiveness to UDCA 5

Second-Line Therapies

For patients with inadequate response to UDCA or UDCA intolerance, add second-line therapy targeting patients not meeting response criteria at 1 year. 2

Obeticholic Acid (OCA)

OCA is FDA and EMA approved as second-line therapy for PBC patients with inadequate response to UDCA or UDCA intolerance. 2, 4

Dosing and Administration

• Starting dose: 5 mg once daily 4
• Titration: May increase to 10 mg once daily after 3-6 months based on tolerability and biochemical response 4
• Take with or without food 4
• Separate from bile acid resins by at least 4 hours 4

Critical Contraindications

OCA is absolutely contraindicated in: 4

• Decompensated cirrhosis (Child-Pugh Class B or C) or prior decompensation event
• Compensated cirrhosis with evidence of portal hypertension (ascites, gastroesophageal varices, persistent thrombocytopenia)
• Complete biliary obstruction

Monitoring Requirements

• Routinely monitor for progression of PBC with laboratory and clinical assessments 4
• Closely monitor patients with compensated cirrhosis for new evidence of portal hypertension or increases in total bilirubin, direct bilirubin, or prothrombin time 4
• Permanently discontinue OCA if patients develop hepatic decompensation, portal hypertension evidence, or clinically significant hepatic adverse reactions 4

Major Adverse Effect: Pruritus

• Severe pruritus occurs in 23% of patients on OCA 10 mg versus 7% on placebo 4
• Management includes bile acid binding resins, antihistamines, dose reduction, or temporary interruption 4
• Consider discontinuing OCA in patients with persistent, intolerable pruritus despite management strategies 4

Peroxisome Proliferator-Activated Receptor (PPAR) Agonists

Elafibranor and seladelpar are recently approved PPAR agonists showing biochemical improvements and potential pruritus benefit. 6

Bezafibrate (Off-Label)

• Shows promise as prospective second-line therapy with the BEZURSO trial demonstrating efficacy and safety 5
• Caution: Associated with elevated serum creatinine 5
• May improve pruritus symptoms unlike OCA 6

Fenofibrate (Off-Label)

• Available as off-label therapy with biochemical improvements 6
• May improve pruritus symptoms 6

Combination Therapy Considerations

• Combined immunosuppressants are considered for patients with moderate-to-severe hepatitis, particularly in AIH-PBC overlap syndrome 3
• Patients with AIH-PBC overlap should be treated for the predominant disease first (UDCA at 13-15 mg/kg for PBC-predominant disease), then response assessed 2

Symptom Management

Pruritus Management Algorithm

Cholestyramine remains first-line therapy for pruritus given its safety profile, but must be taken separately from UDCA to avoid interaction. 2

Stepwise Approach:

1. First-line: Cholestyramine (bile acid resin) 2

   • Take separately from UDCA (at least 4 hours apart) 2

2. Second-line: Rifampicin 2

   • Safe and effective but requires evaluation of risks/benefits and appropriate monitoring for side effects 2

3. Emerging therapies: Bezafibrate, seladelpar, and IBAT inhibitors demonstrate significant therapeutic potential 3

4. Refractory cases: Plasmapheresis or albumin exchange for temporary relief 2

5. Liver transplantation: Highly effective for persistent and intractable pruritus after therapeutic trials, with rapid reduction within 24 hours 2

Fatigue Management

Fatigue in PBC is not related to liver disease severity, is not responsive to UDCA, and requires a structured parallel management approach. 2

Critical Pitfall

• Transplant for severe fatigue alone is not appropriate 2
• Post-transplant patients typically have ongoing fatigue 2

Structured Management Approach:

Step 1: Quantify and Assess

• Use tools such as PBC-40 QoL measure 2

Step 2: Treat Direct Contributors 2

• Pruritus: Particularly nocturnal pruritus causing sleep disturbance
• Associated autoimmune diseases: AIH overlap, thyroid disease, celiac disease, pernicious anemia, autoimmune hemolytic anemia, Addison's disease
• Age-related conditions: Diabetes, heart failure, renal failure

Step 3: Modify Exacerbating Processes 2

• Depression: Rarely primary but can exacerbate; consider antidepressants
• Autonomic dysfunction: Assess with 24-hour BP monitoring and tilt testing where appropriate; adjust inappropriate antihypertensive therapy
• Sleep disturbance: Assess and treat obstructive sleep apnea; case series support modafinil for severe daytime somnolence

Step 4: Lifestyle Adjustments 2

• Pacing strategies: Use available energy to best advantage
• Timing strategies: Arrange key tasks earlier in the day when fatigue is less severe

Step 5: Referral

• Patients with symptoms resistant to medical therapy should be referred for specialist management regardless of disease severity 2

Monitoring and Follow-Up

Variant Presentations Requiring Special Monitoring

AMA-positive with normal LFTs: 2

• Screen annually for biochemical abnormality development
• Follow-up can occur in primary care unless specific factors (associated autoimmune disease) warrant secondary care
• Treat as classical PBC if biochemical abnormality develops
• Long-term data show none developed cirrhosis, needed transplant, or died of PBC over 18 years 2

Disease Progression Monitoring

• Liver Stiffness Measurement is efficient for fibrotic monitoring 3
• OCA is useful for compensated fibrotic patients 3
• Fibrates are useful for decompensated fibrotic patients 3

Clinical Trial Consideration

Patients should be offered clinical trial participation if they fall into these categories 2:

1. High-risk/UDCA-unresponsive disease: Patients not meeting UDCA response criteria at 1 year
2. Pruritus resistant to current therapy: Significant residual pruritus after first and second-line therapy
3. Severe fatigue: After systematic exclusion of confounding causes

Key Clinical Pitfalls to Avoid

• Never use OCA in decompensated cirrhosis or compensated cirrhosis with portal hypertension - this is absolutely contraindicated and can cause fatal hepatic decompensation 4
• Never assume UDCA alone is sufficient - assess response at 12 months and add second-line therapy for inadequate responders 2
• Never separate cholestyramine and UDCA timing - they must be taken at least 4 hours apart to avoid interaction 2, 4
• Never pursue transplant for fatigue alone - fatigue persists post-transplant and is not an appropriate sole indication 2
• Never miss AIH-PBC overlap - perform liver biopsy in UDCA non-responders with elevated ALT and IgG 3