Primary Biliary Cholangitis (PBC): From Ursodeoxycholic Acid to Advanced Therapies

Primary Biliary Cholangitis (PBC) is a rare autoimmune liver disease, formerly known as primary biliary cirrhosis, that predominantly affects women, usually diagnosed between the ages of 50 and 60. The disease is characterized by chronic inflammation and gradual destruction of the small intrahepatic bile ducts, leading to fibrosis and potentially cirrhosis. Diagnosing PBC is crucial for initiating appropriate treatment and managing the disease effectively. The diagnosis of PBC typically involves a combination of clinical evaluation, laboratory testing, and sometimes imaging or histological examination. Here’s a detailed overview of how PBC is diagnosed:

Clinical Presentation

Patients with PBC often present with symptoms that can be nonspecific, which makes the clinical diagnosis challenging. Common symptoms include:

Fatigue: One of the most common symptoms, affecting a significant portion of patients.
Pruritus: Itching is another frequent and sometimes severe symptom.
Jaundice: Yellowing of the skin and eyes may occur as the disease progresses.
Abdominal Pain: Occasionally reported, though less common.
Dry Eyes and Mouth: Part of associated sicca symptoms.

However, many patients, especially in the early stages of the disease, may be asymptomatic and diagnosed incidentally through abnormal liver function tests.

Biochemical Tests

The hallmark of PBC diagnosis is the presence of abnormal liver biochemistry, particularly cholestatic liver enzymes:

Elevated Alkaline Phosphatase (ALP): A significant increase in ALP is a key indicator of cholestasis and is often the first abnormality detected.
Gamma-glutamyl transferase (GGT): Often elevated along with ALP.
Bilirubin: May be elevated in more advanced disease.

Serological Markers

Serological tests play a critical role in confirming PBC:

Antimitochondrial Antibodies (AMA): Present in approximately 95% of patients with PBC, making it a highly specific marker for the disease. AMA targets the pyruvate dehydrogenase complex E2 subunit located in the mitochondria.
Antinuclear Antibodies (ANA): Specific ANA patterns such as those against gp210 and sp100 can aid in the diagnosis, especially in AMA-negative cases.

Imaging Techniques

While not primarily used for diagnosis, imaging studies can be helpful in excluding other hepatobiliary diseases:

Ultrasound: Useful for assessing the liver and biliary tract for alternative diagnoses such as gallstones or tumors.
MRI/MRCP (Magnetic Resonance Cholangiopancreatography): Can provide detailed images of the biliary tract and exclude other causes of biliary obstruction.

Liver Biopsy

Although not always necessary for diagnosis, a liver biopsy may be performed to:

Confirm the diagnosis when serological markers are negative and the clinical picture is unclear.
Assess the stage of liver fibrosis, which has implications for prognosis and management.

The biopsy typically shows non-suppurative destructive cholangitis and may also show granulomatous inflammation, both characteristic findings in PBC.

Histologic Staging

If a biopsy is performed, PBC can be staged histologically from stage 1 to stage 4:

Stage 1: Portal inflammation
Stage 2: Periportal fibrosis
Stage 3: Bridging fibrosis
Stage 4: Cirrhosis

Diagnostic Criteria

The diagnosis of PBC is generally confirmed based on a combination of:

Clinical features
Biochemical evidence of cholestasis
Seropositivity for AMA and/or specific ANA
Liver histology compatible with PBC (if available)

First-Line Therapy: Ursodeoxycholic Acid (UDCA)

UDCA remains the cornerstone of PBC management across all disease stages, recommended at a dose of 13–15 mg/kg/day. It enhances hepatobiliary secretion, suppresses apoptosis induced by bile acids, and protects cholangiocytes. Clinical trials in the early ’90s established the biochemical benefits of UDCA, including significant reductions in ALP, bilirubin, and transaminases, which manifest as early as three months and may continue improving for up to three years.

While initial studies did not show regression of fibrosis, they indicated a delay in its progression. Recent global studies further underscored the effectiveness of UDCA in reducing the risk of liver transplantation (LT) or death, highlighting a clear dose-response relationship and underscoring the benefits of even suboptimal biochemical responses.

Beyond UDCA: Advanced Therapeutic Options

Risk Stratification and Second-Line Therapies

For patients not normalizing cholestasis parameters on UDCA, second-line therapies become relevant. Criteria like the Paris II provide biochemical cutoffs used to identify patients needing additional treatment. These biochemical markers are crucial for long-term outcomes but are often not fully normalized by UDCA alone.

Nuclear Receptor Agonists

Advances in the treatment of PBC have introduced nuclear receptor agonists, such as obeticholic acid (OCA), a potent FXR agonist derived from bile acid. OCA reduces the hepatic bile acid pool, decreases apoptosis, and has immunomodulatory and antifibrotic effects. Despite its efficacy in reducing ALP levels and improving liver histology, pruritus remains a significant side effect leading to treatment discontinuation for some patients.

Fibrates

Fibrates, primarily PPAR agonists, have shown promise in reducing biliary enzyme levels and improving biochemical markers in PBC. Bezafibrate (BZF), in combination with UDCA, has demonstrated significant biochemical normalization and fibrosis regression in long-term studies. Notably, fibrates may also alleviate cholestatic pruritus, offering a dual benefit in symptom management.

Beyond Combination Therapy

Even with UDCA and second-line treatments, not all patients achieve satisfactory biochemical normalization. Triple therapy, incorporating a third drug, and alternative treatments like steroids are considered based on individual patient profiles and disease severity.

Conclusion

The treatment landscape for PBC has evolved significantly, moving from UDCA as the sole option to a more diversified approach involving old and new therapies. These developments allow for more personalized treatment plans, aiming to achieve complete normalization of biochemical markers. With ongoing research and the potential introduction of new therapies, the future holds promise for even better management of PBC, enhancing patient outcomes and quality of life.

This overview of PBC treatment highlights the importance of staying current with emerging therapies and adapting treatment strategies to individual patient needs, ensuring the best possible outcomes in this challenging chronic disease.