Primary Biliary Cholangitis

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterized by progressive destruction of the small intrahepatic bile ducts. This results in cholestasis, fibrosis, and potentially, cirrhosis and liver failure. PBC predominantly affects middle-aged women and has a higher prevalence in those with other autoimmune diseases.

Pathophysiology

The exact cause of PBC remains unclear, but it is thought to involve a combination of genetic, environmental, and immunological factors. Key mechanisms include:

1. Autoimmune Mechanism:
   • The immune system mistakenly targets the small bile ducts, leading to inflammation and destruction of the epithelial cells lining the ducts.
   • Antimitochondrial antibodies (AMA), present in about 90-95% of PBC patients, target the pyruvate dehydrogenase complex (PDC-E2) on the mitochondrial membrane of biliary epithelial cells.
2. Genetic Predisposition:
   • Genetic factors increase susceptibility to PBC, as indicated by familial clustering and associations with certain human leukocyte antigen (HLA) alleles (e.g., HLA-DRB1).
3. Environmental Factors:
   • Infections (e.g., urinary tract infections), chemicals, and smoking may trigger the autoimmune response in genetically susceptible individuals.

Epidemiology

• Prevalence: PBC is more common in women, with a female-to-male ratio of about 9:1.
• Age: Most commonly diagnosed in individuals aged 40-60 years.
• Geography: Higher prevalence in North America and Northern Europe.

Clinical Features

The presentation of PBC can range from asymptomatic to symptomatic, with symptoms typically developing over years.

1. Asymptomatic Stage:
   • Approximately 25-50% of patients are asymptomatic at diagnosis, often identified through elevated liver enzymes during routine testing.
   • Even in asymptomatic patients, liver biopsy may reveal significant histological changes.
2. Symptomatic Stage:
   • Fatigue: One of the most common symptoms, often debilitating and disproportionate to the degree of liver damage.
   • Pruritus (Itching): Often precedes jaundice and can be severe. The mechanism is thought to involve accumulation of bile acids, endogenous opioids, and pruritogens.
   • Jaundice: Late manifestation due to elevated serum bilirubin levels.
   • Right Upper Quadrant Pain: Due to liver capsule stretching.
3. Complications Associated with Advanced Disease:
   • Cirrhosis and Portal Hypertension: Leading to ascites, variceal bleeding, and hepatic encephalopathy.
   • Osteoporosis and Osteomalacia: Due to malabsorption of fat-soluble vitamins.
   • Hyperlipidemia: Elevated cholesterol levels are common but do not appear to increase the risk of cardiovascular disease in PBC patients.
   • Fat-Soluble Vitamin Deficiencies (A, D, E, K): Due to impaired bile flow and fat absorption.

Diagnostic Approach

The diagnosis of PBC is based on clinical, serological, and histological criteria.

1. Laboratory Findings:
   • Liver Function Tests:
     • Elevated alkaline phosphatase (ALP) is a hallmark of cholestasis.
     • Mildly elevated alanine transaminase (ALT) and aspartate transaminase (AST).
   • Antimitochondrial Antibodies (AMA): Present in 90-95% of cases and highly specific for PBC.
   • Antinuclear Antibodies (ANA): Present in 30-50% of cases.
   • Elevated Immunoglobulin M (IgM): Common in PBC patients.
2. Imaging:
   • Ultrasound, CT, or MRI: Used to rule out extrahepatic cholestasis and other liver pathologies.
   • Magnetic Resonance Cholangiopancreatography (MRCP): Can help differentiate PBC from primary sclerosing cholangitis (PSC), another cholestatic liver disease.
3. Liver Biopsy:
   • Reserved for cases where the diagnosis is unclear or to stage liver fibrosis.
   • Histological findings include lymphocytic infiltration and granulomas around bile ducts, bile duct loss, and periportal fibrosis.

Staging

PBC is staged histologically from I to IV:

• Stage I: Portal inflammation.
• Stage II: Periportal inflammation with bile duct damage.
• Stage III: Bridging fibrosis.
• Stage IV: Cirrhosis.

Management

The treatment of PBC aims to slow disease progression, alleviate symptoms, and manage complications.

1. First-Line Therapy:
   • Ursodeoxycholic Acid (UDCA):
     • The cornerstone of PBC treatment. It works by improving bile flow and reducing liver enzyme levels.
     • Dosage: 13-15 mg/kg body weight per day.
     • Response to UDCA is defined by a reduction in ALP levels. A favorable response is associated with improved outcomes.
2. Second-Line Therapy (for UDCA Non-responders or Intolerance):
   • Obeticholic Acid (OCA):
     • A synthetic bile acid derivative that activates the farnesoid X receptor, which reduces bile acid synthesis.
     • Dosage: 5-10 mg once daily, adjusted based on response and tolerance.
   • Fibrates (e.g., Bezafibrate): Show promise in reducing liver enzymes and pruritus.
3. Symptom Management:
   • Pruritus:
     • Cholestyramine: A bile acid sequestrant, dosed at 4 g once or twice daily, is first-line therapy.
     • Rifampicin, Naltrexone, or Sertraline: Considered for refractory cases.
   • Fatigue:
     • Difficult to manage, but sleep hygiene and physical activity may help.
   • Bone Health:
     • Vitamin D and Calcium Supplementation: For osteoporosis prevention.
     • Bisphosphonates or Denosumab: In patients with established osteoporosis.
4. Advanced Disease Management:
   • Management of Cirrhosis and Its Complications:
     • Monitoring for varices, ascites, and hepatic encephalopathy.
   • Liver Transplantation: Indicated for end-stage liver disease or severe, refractory symptoms. PBC has an excellent post-transplant prognosis, though disease recurrence can occur.

Prognosis

• The prognosis of PBC has significantly improved with UDCA treatment. Patients with a good biochemical response to UDCA have a near-normal life expectancy.
• Without treatment, or in patients with poor response, the disease can progress to cirrhosis and liver failure over 10-20 years.

Monitoring

• Regular Liver Function Tests: To monitor disease progression.
• Assessment for Varices and Hepatocellular Carcinoma (HCC): In patients with cirrhosis.