Seronegative Primary Biliary Cholangitis: Epidemiological, Clinical, Therapeutic, and Prognostic Characteristics

Abstract

Background: Seronegative primary biliary cholangitis (snPBC) is an uncommon variant of PBC in which characteristic antimitochondrial antibodies are absent despite clinical, biochemical, and histological features consistent with the disease. The lack of serological markers may delay diagnosis and raises questions regarding its epidemiological profile, therapeutic response, and long-term prognosis compared with seropositive PBC. Aims: To describe the epidemiological, clinical, biological, histological, therapeutic, and prognostic characteristics of strictly seronegative primary biliary cholangitis (PBC) and compare them with seropositive PBC. Study Design: Retrospective observational single-center descriptive comparative study. Place and Duration of Study: The study was conducted in the Department of Functional Digestive Explorations at Ibn Sina University Hospital, Mohammed V University, Rabat, Morocco. Patients followed for PBC between January 2010 and February 2026 were included. Methodology: Adult patients diagnosed with PBC according to international criteria were retrospectively identified from hospitalization registries, outpatient databases, and archived medical records. Patients were classified into two groups: seropositive PBC (positive AMA and/or anti-gp210/sp100 antibodies) and strictly seronegative PBC (negative AMA, anti-gp210, and anti-sp100 with compatible histology). Baseline demographic, clinical, biochemical, immunological, imaging, histological, therapeutic, and prognostic data were collected. Biochemical response to ursodeoxycholic acid (UDCA) at 12 months was assessed using Paris II criteria. Prognostic evaluation included GLOBE and UK-PBC scores. Data were analyzed descriptively due to the limited sample size.  Results: Among 40 patients with PBC, 22 had seropositive PBC, 8 had strictly seronegative PBC, 9 had PBC-autoimmune hepatitis overlap syndrome, and 1 had PBC-primary sclerosing cholangitis association. Strictly seronegative PBC represented 20% of the overall cohort and 26.7% of pure PBC forms. Compared with seropositive PBC, seronegative patients had a longer diagnostic delay (36 vs 14 months), more frequent advanced fibrosis (Metavir F3–F4: 75% vs 25%), and higher rates of portal hypertension (62.5% vs 31.8%) and advanced liver disease at diagnosis. Complete biochemical response to UDCA according to Paris II criteria was less frequent in the seronegative group (28.6% vs 57.1%). Histology was essential for diagnosis in all strictly seronegative cases.  Conclusion: Strictly seronegative PBC is an uncommon but clinically important phenotype of PBC. Although its clinical and biochemical presentation is broadly similar to seropositive PBC, delayed diagnosis is associated with more advanced fibrosis and liver disease at presentation. Liver biopsy remains indispensable for diagnosis in the absence of specific autoantibodies. Early recognition and timely management are essential to improve outcomes. Larger multicenter studies are needed to better define the prognosis and therapeutic response of this rare phenotype.