Editor’s Note: With shifts in the global landscape of liver diseases, the incidence of primary biliary cholangitis (PBC) has been rising annually. In China, PBC’s prevalence has reached the highest level in the Asia-Pacific region. At the 10th “Silk Road Hepatology” Conference, Dr. Ying Han from The First Affiliated Hospital of Airforce Medical University presented an enlightening report titled “Early Diagnosis and Intervention Strategies for Refractory Primary Biliary Cholangitis.” The content has been compiled for readers’ reference.Diagnosis and Treatment of PBC
PBC is a chronic autoimmune intrahepatic cholestatic disease that predominantly affects middle-aged and older women, characterized by progressive intrahepatic bile duct injury and elevated anti-mitochondrial antibodies (AMA). The disease mechanism involves a loss of tolerance to the mitochondrial pyruvate dehydrogenase complex E2 subunit (PDC-E2) and autoimmune damage to biliary epithelial cells (BEC), which triggers an immune response that further causes mitochondrial PDC-E2 immune tolerance loss and small bile duct damage within the liver.
Diagnosis of PBC requires a comprehensive evaluation based on biochemical, immunological, imaging, and histological examinations. Meeting two of the following three criteria establishes a diagnosis:
- Evidence of cholestasis (primarily elevated ALP and GGT), with imaging ruling out extrahepatic or large intrahepatic bile duct obstruction.
- Positive AMA/AMA-M2, or other PBC-specific autoantibodies (anti-gp210, anti-sp100).
- Histological evidence of non-suppurative destructive cholangitis and small bile duct destruction.
Ursodeoxycholic acid (UDCA) is the only first-line treatment for PBC, shown to improve biochemical markers, slow disease progression, and extend transplant-free survival. However, studies indicate that 30–40% of patients show poor response to UDCA therapy. For UDCA non-responders, prognosis is worse, with a 10-year mortality rate as high as 91% and a 15-year mortality rate reaching 100%.
Refractory PBC
PBC patients should receive adequate long-term UDCA treatment, with dosages of 13–15 mg/kg/day. Patients who exhibit inadequate therapeutic response despite standard care are classified as true refractory PBC cases.
Dr. Ying Han highlighted that inadequate response to UDCA in PBC can also result from irregular treatment practices, including insufficient UDCA dosage, poor patient compliance, concurrent medications, environmental factors, and dietary habits. Co-existing chronic liver diseases such as viral hepatitis, metabolic-associated liver diseases, autoimmune hepatitis/primary sclerosing cholangitis, or drug-induced liver injury may also contribute to poor response in PBC patients.
Assessing response to UDCA is crucial as non-responders experience faster disease progression. Timely initiation of second-line therapy can halt disease progression, reduce decompensation events in cirrhosis, and delay liver transplant. International consensus guidelines provide slightly different standards for evaluating treatment response in PBC.
From 2004 to 2021, Dr. Han’s team conducted a longitudinal study over nearly two decades, enrolling 569 patients divided into a training group (n=397) and validation group (n=172), with a median follow-up of 53 months. The study assessed the predictive efficiency of various biochemical thresholds (TBIL, ALP, and AST) at 1, 3, 6, and 12 months post-UDCA initiation. Based on survival rates without adverse outcomes, they compared existing standards with a newly proposed standard. Endpoints included liver-related mortality, liver transplantation, and complications of cirrhosis.
The “Xi’an Criteria,” established from this study, evaluates response to UDCA at one month based on specific thresholds (ALP ≤ 2.5x ULN, AST ≤ 2x ULN, TBIL ≤ 1x ULN). Patients meeting this response criterion had a five-year adverse event-free survival rate of 97%, significantly higher than non-responders (64%). The “Xi’an Criteria” accurately identifies rapid progressors, allowing early initiation of second-line treatments.
Second-Line Drugs for PBC
For patients unresponsive to UDCA, early initiation of second-line treatments is recommended. Currently, PBC second-line drugs include FXR agonists and PPARs agonists.
Obeticholic Acid (OCA) OCA, an FXR agonist, regulates metabolism, inflammation, and fibrosis by modulating bile acid synthesis. Clinical trials show that OCA significantly reduces biochemical markers in PBC patients who are UDCA-intolerant or non-responders. However, OCA is not recommended for decompensated cirrhosis patients due to the risk of severe liver decompensation events. The FDA advises against its use in patients with moderate to severe liver impairment (Child-Pugh B and C).
Fibrates (PPAR Agonists)
- Bezafibrate Multi-center trials have shown that combining bezafibrate with UDCA improves biochemical markers and liver stiffness in PBC patients with poor UDCA response. Large retrospective studies indicate that bezafibrate reduces all-cause and liver-related mortality or liver transplant requirements in non-responsive patients. It also helps alleviate pruritus symptoms associated with PBC.
- Fenofibrate Dr. Han introduced her team’s studies on fenofibrate. Retrospective cohort studies have shown that UDCA combined with fenofibrate improves long-term prognosis and reduces liver pathology in PBC patients. Clinical trials reveal that combining fenofibrate with UDCA improves biochemical response without increasing adverse events. Additionally, fenofibrate improves ALP and lipid levels in cirrhotic patients with poor UDCA response and reduces UK-PBC scores, maintaining stable levels of liver enzymes, bilirubin, and kidney function.
New PPAR Agonists Elafibranor, a dual PPARα/δ agonist, and Seladelpar, a selective PPARδ agonist, have shown promising results in clinical trials, improving cholestasis-related markers and alleviating pruritus in PBC patients.
Biological Therapies Mesenchymal stem cells (MSC) hold promise for refractory PBC by suppressing immune responses, combating fibrosis, and promoting hepatocyte differentiation. Clinical trials have demonstrated that MSC therapy is safe for PBC, reducing ALT, AST, ALP, and GGT levels.
The Impact of Hypercholesterolemia on Long-Term Prognosis of PBC
A study examining PBC patients hospitalized from 2008 to 2021 found baseline total cholesterol (TC) levels to be a high-risk factor for poor prognosis in PBC. High TC at baseline correlated with increased risk of adverse events, including cirrhosis complications, liver transplant, or death. Elevated baseline TC enhanced the predictive power of Globe scores and ALP 1.67 standards for long-term PBC prognosis.
Risk stratification based on TC ≥5.2 mmol/L and Globe score ≥0.3 identified patients with worse outcomes, demonstrating that high-risk PBC patients exhibit distinct lipid metabolism abnormalities and increased lipid markers associated with cholestasis.
Risk Assessment and Atypical PBC Diagnosis
FibroScan has significant value in diagnosing and predicting fibrosis in PBC. The Baveno VII consensus proposes liver stiffness measurement (TE values of 10-15-20-25 kPa) for assessing relative risk of decompensation and liver-related mortality.
Atypical PBC includes AMA-negative PBC and isolated AMA-positive PBC. AMA-negative PBC, comprising 5-10% of cases globally (15% in China), shows poorer prognosis than AMA-positive cases. For isolated AMA-positive individuals with normal cholestasis enzyme levels, criteria such as age >42 and IgM >0.773 ULN aid in diagnosing PBC. Long-term follow-up is needed, as some cases eventually progress to full PBC diagnosis.
Conclusion and Treatment Pathways
For diagnosed PBC patients, adequate, weight-adjusted, long-term UDCA treatment is essential. The “Xi’an Criteria” effectively guides response evaluation after one month of UDCA treatment, facilitating timely second-line interventions. Non-itchy, non-cirrhotic refractory PBC may benefit from combined OCA or fibrate therapy. Early fibrate use in PBC and non-invasive liver assessment help monitor treatment efficacy. For AMA-positive patients with normal ALP, IgM >0.773 ULN and age >42 can support diagnosis. Atypical PBC cases should be promptly diagnosed using IgM levels and liver pathology.
