What is the treatment for primary biliary cholangitis?

Treatment of Primary Biliary Cholangitis

All patients with PBC should be offered ursodeoxycholic acid (UDCA) at 13-15 mg/kg/day as first-line therapy, which significantly reduces disease progression and the need for liver transplantation. 1, 2

First-Line Treatment: UDCA

• Start UDCA at 13-15 mg/kg/day immediately upon diagnosis in all patients without decompensated cirrhosis or portal hypertension 1, 2
• UDCA significantly decreases serum bilirubin, alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), cholesterol, and immunoglobulin M levels compared to placebo 2, 3
• Long-term UDCA treatment delays histological progression when started at early stages and reduces the likelihood of liver transplantation or death in patients with moderate to severe disease 2
• Never use high-dose UDCA (>20 mg/kg/day) as this has been associated with worse outcomes 2

UDCA Administration Details

• Take UDCA with or without food 1
• If the patient is taking bile acid binding resins (cholestyramine, colestipol), administer UDCA at least 4 hours before or 4 hours after the resin to avoid absorption interference 1
• Continue UDCA during pregnancy and breastfeeding as it is safe in these settings 1

Response Assessment After 1 Year

• Perform biochemical response assessment after 12 months of UDCA therapy using validated risk stratification tools such as GLOBE or UK-PBC Risk Scores 1, 2
• Document response status in 80% of patients receiving UDCA therapy, including the criteria used 1
• Approximately 40% of patients show incomplete response to UDCA and require second-line treatment 4

Second-Line Treatment Options

For Inadequate Responders to UDCA

Obeticholic Acid (OCA):

• Start OCA at 5 mg once daily for the first 3 months in patients without cirrhosis or with compensated cirrhosis who lack evidence of portal hypertension 5
• After 3 months, if ALP and/or total bilirubin have not adequately reduced and the patient tolerates OCA, increase to maximum 10 mg once daily 5
• OCA is absolutely contraindicated in patients with decompensated cirrhosis (Child-Pugh Class B or C), prior decompensation events, or compensated cirrhosis with evidence of portal hypertension (ascites, varices, persistent thrombocytopenia) 5
• Permanently discontinue OCA if patients develop laboratory or clinical evidence of hepatic decompensation, develop portal hypertension, or experience complete biliary obstruction 5
• OCA increases the risk of new-onset pruritus (RR: 1.43-1.79) and serious adverse events (RR: 2.67-3.82) compared to placebo 4

Fibrates (Fenofibrate, Bezafibrate, Elafibranor):

• Fibrates combined with UDCA significantly improve biochemical markers in UDCA inadequate responders 6, 7
• At 12 months, fenofibrate 200 mg/day plus UDCA normalized ALP in 54.2% of patients versus 4.2% with UDCA alone 6
• Elafibranor showed slightly superior biochemical response compared to seladelpar in network meta-analysis 4
• Monitor serum creatinine and transaminases as reversible elevations can occur with fibrate therapy 6
• Fibrates may be used after the first trimester in pregnancy if benefits outweigh risks 1

Seladelpar:

• Seladelpar is the only second-line agent associated with decreased pruritus risk (RR: 0.30) compared to placebo 4
• Consider seladelpar preferentially in patients with significant baseline pruritus 4

Monitoring Requirements During Treatment

Routine Monitoring

• Monitor liver biochemistry regularly to assess treatment response and disease progression 1, 2
• Closely monitor patients with compensated cirrhosis for new evidence of portal hypertension (ascites, varices, persistent thrombocytopenia) or increases in total bilirubin, direct bilirubin, or prothrombin time 5

Symptom Assessment

• Evaluate all patients for fatigue and pruritus with documentation in 90% of patients annually 1
• UDCA does not significantly improve pruritus or fatigue 2, 3

Transplant Referral Criteria

• Refer all patients with bilirubin >50 μmol/L or evidence of decompensated liver disease to a hepatologist linked to a transplant center 1

Management of Pruritus

For Intolerable Pruritus on Treatment

Step 1: Add adjunctive therapy

• Add bile acid binding resins: cholestyramine 4-8 g/day or colestipol 5-10 g/day (given at least 4 hours after UDCA) 1
• Add antihistamines 5
• Consider rifampicin 300-600 mg daily 1

Step 2: Reduce medication dosage

• For patients on OCA 5 mg daily: reduce to 5 mg every other day 5
• For patients on OCA 10 mg daily: reduce to 5 mg once daily 5

Step 3: Temporary interruption

• Temporarily interrupt dosing for up to 2 weeks, then restart at reduced dosage 5

Step 4: Consider discontinuation

• Discontinue treatment if persistent, intolerable pruritus continues despite management strategies 5

Additional Essential Management

Osteoporosis Screening

• Perform osteoporosis risk assessment within 5 years in 80% of patients as PBC increases fracture risk 1, 2
• Treat and follow according to national osteoporosis guidelines 1

Baseline Assessment

• Obtain abdominal ultrasound in 90% of patients at baseline to exclude alternative causes of cholestasis 1

Overlap Syndromes

• Overlap with autoimmune hepatitis (AIH) is rare 1
• When suspected, perform liver biopsy with expert clinicopathological assessment in 90% of cases to confirm diagnosis 1

Psychosocial Support

• Offer patient support groups to all patients, as fatigue and social isolation significantly impact quality of life 1
• Refer patients with profound psychological distress associated with fatigue to appropriate psychological services for assessment 1

Post-Transplant Management

• Give UDCA lifelong at 10-15 mg/kg/day post-transplant to prevent PBC recurrence and improve graft survival 2

Critical Pitfalls to Avoid

• Never start OCA without first confirming absence of decompensated cirrhosis and portal hypertension as this can lead to fatal hepatic decompensation 5
• Never use UDCA doses exceeding 20 mg/kg/day as higher doses worsen outcomes 2
• Never administer UDCA within 4 hours of bile acid binding resins as this reduces UDCA absorption 1
• Never assume normal drug metabolism in cholestatic liver disease even if transaminases are normal, as cholestasis affects drug clearance differently than hepatocellular disease 8
• Never delay transplant referral in patients with bilirubin >50 μmol/L or decompensation signs 1