Primary Biliary Cholangitis (PBC) is an autoimmune liver disease characterized by progressive cholestasis. Its diagnosis and management have historically centered on patients with overt biochemical abnormalities. However, a clinically significant subgroup presents with all routine liver function tests within normal limits, posing a diagnostic and therapeutic dilemma. The prevailing assumption that "normal" biochemistry equates to "quiescent" disease is increasingly challenged. This study aims to conduct a comprehensive, multidimensional comparison between PBC patients with normal and abnormal liver biochemistry to delineate the distinct clinical, serological, and histopathological features of the former group, thereby challenging the traditional paradigm and informing improved clinical management.

A single-center retrospective cohort study has been conducted. A total of 111 patients newly diagnosed with PBC at our institution between 2018 and 2023 were enrolled. Diagnosis adhered to international criteria. Patients were stratified into two groups: the Normal Liver Biochemistry Group (n=49), defined by having all the following parameters within laboratory reference ranges at diagnosis: Alanine Aminotransferase (ALT, 7-40 U/L), Aspartate Aminotransferase (AST, 13-35 U/L), Gamma-Glutamyl Transferase (GGT, 7-45 U/L), Alkaline Phosphatase (ALP, 35-100 U/L), and Total Bilirubin (TBIL, 3-22 μmol/L); and the Abnormal Liver Biochemistry Group (n=62), where any of these parameters was elevated. We systematically collected and compared baseline demographics, a comprehensive panel of liver biochemical indices (including transaminases, cholestatic markers, bilirubin, total bile acids, and immunoglobulins), autoantibody profiles (detected via immunofluorescence and immunoblotting, including ANA, AMA, AMA-M2, anti-gp210, anti-sp100, etc.), and liver histopathological findings. Histology was assessed using Ludwig staging for fibrosis and Scheuer systems for inflammatory activity (G0-G4) and fibrosis stage (S0-S4). Statistical analyses were performed to identify significant inter-group differences.

 Key differences emerged across all assessed dimensions. Demographically, patients in the normal biochemistry group were significantly younger (50.83 ± 13.55 vs. 58.24 ± 11.19 years, p=0.002). Biochemically, while all values in the normal group were within normal limits, their median levels for ALT, AST, GGT, ALP, TBIL, Direct Bilirubin, and Total Bile Acids were all significantly lower than those in the abnormal group (all p<0.05), suggesting a subclinical gradient of injury. Notably, serum IgM was significantly lower in the normal group (1.42 vs. 2.24 g/L, p<0.001). The most striking finding was in serology. The normal group had significantly lower positivity rates for ANA (51% vs. 94%, p<0.001) and the classic PBC antibody AMA-M2 (16% vs. 89%, p<0.001). Paradoxically, they exhibited a significantly higher positivity rate for anti-gp210 antibody (29% vs. 13%, p=0.026), a marker often associated with disease progression. Histopathological analysis provided definitive evidence of ongoing disease. Although fibrosis was markedly milder in the normal group (Ludwig stage I: 34 vs. 10 patients, p=0.008; Scheuer fibrosis stage S0: 48 vs. 17 patients, p<0.001), active interface hepatitis (Scheuer activity grades G1-G3) was present in 98% of these patients, and histological evidence of cholestasis was found in 51%.

This study conclusively demonstrates that PBC with normal liver biochemistry is not a benign or inactive condition, but rather represents a distinct disease subtype characterized by occult yet histologically-proven inflammatory activity, a unique serological signature (low AMA-M2/high anti-gp210), and an earlier fibrosis stage, often in younger patients. The dissociation between the high-risk serological marker (anti-gp210) and a seemingly bland biochemical profile presents a compelling "biological paradox." These findings fundamentally challenge the reliance on routine liver tests alone for assessing disease activity in PBC. They underscore the critical importance of a multimodal assessment strategy that integrates specific autoantibody testing (particularly for anti-gp210) and liver biopsy for accurate diagnosis, risk stratification, and to avoid underestimation of disease severity in this patient subgroup. Our data provide a strong rationale for reconsidering management paradigms, potentially advocating for earlier intervention and closer monitoring in normal-biochemistry PBC patients with adverse serological or histological features.