Letter: The association between liver biochemistry, biliary and fibrosis in primary biliary cholangitis

We read with great interest the recent article by Kowdley et al., which highlights treatment persistence and alkaline phosphatase (ALP) normalisation as key determinants of long-term outcomes in primary biliary cholangitis (PBC). While biochemical response assessed at fixed time points has well-established prognostic value, whether ALP improvement reliably reflects histological disease activity remains uncertain [1]. We evaluated the concordance between biochemical and histological responses using paired liver biopsies in PBC patients treated at the Second Hospital of Nanjing between 1 January 2016 and 31 December 2023. (Figure S1) This study was approved by the Ethics Committee of the Second Hospital of Nanjing (Approval No. 2024-LS-ky-067) and conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all the patients. Biochemical response was defined as ALP ≤ 1.67 × the upper limit of normal at the time of the second biopsy. Histological response was defined as stage/grade ≤ 1 or an improvement of ≥ 1 grade/stage across inflammatory activity (G), fibrosis stage (S), Ludwig stage, Nakanuma stage, cholangitis activity (CA) or hepatitis activity (HA) (Table S1) [2]. Agreement was assessed using Cohen's Kappa [3]. Among 37 patients with paired biopsies, 26 (70.27%) achieved biochemical response (Tables S2–S4 and Figures S2, S3). Concordance was strongest for bile duct injury: CA response occurred in 69.23% (18/26) of biochemical responders versus 27.27% (3/11) of non-responders (kappa = 0.371, p = 0.019; Figure 1 and Table S5). In contrast, agreement was limited for hepatic inflammatory activity and absent for fibrosis-related endpoints. HA response showed fair but non-significant agreement (kappa = 0.220, p = 0.173), while fibrosis stage demonstrated poor concordance (kappa = −0.127, p = 0.367). Agreement for G grade, Ludwig stage and Nakanuma stage was slight to very low (all p > 0.05). These paired-biopsy data indicate that ALP-based biochemical response aligns more consistently with improvement in bile duct injury than with broader histological remission or fibrosis regression. As ALP primarily reflects cholestasis and cholangiocyte-related injury, biochemical improvement may underestimate persistent portal inflammation and ongoing fibrogenesis in a subset of patients. While routine repeat biopsy is not feasible, targeted histological reassessment may be informative when clinical features suggest discordant disease activity despite biochemical response. In conclusion, biochemical response in PBC appears necessary but insufficient to define true histological remission, underscoring the need for integrated assessment beyond ALP alone. Hong-Li Liu: conceptualization, methodology, software, data curation, investigation, validation, formal analysis, visualization, project administration, writing – original draft, writing – review and editing. Yi-Fan Hu: conceptualization, methodology, software, data curation, investigation, validation, formal analysis, visualization, project administration, writing – original draft, writing – review and editing. Miao-Yang Chen: conceptualization, methodology, software, data curation, investigation, validation, formal analysis, visualization, project administration, writing – original draft, writing – review and editing. Sha-Sha Li: methodology, data curation, investigation, validation, formal analysis, visualization, writing – review and editing. Xi-Xuan Wang: methodology, data curation, investigation, visualization, formal analysis, validation, writing – review and editing. Yi-Jun Bao: methodology, data curation, investigation, validation, formal analysis, visualization, writing – review and editing. Yu Zhang: methodology, data curation, investigation, validation, formal analysis, visualization, writing – review and editing. Li Wang: methodology, data curation, investigation, validation, formal analysis, visualization, writing – review and editing. Rui-Qi Li: methodology, data curation, validation, formal analysis, visualization, writing – review and editing. Shu-Ling Chen: methodology, data curation, investigation, validation, formal analysis, visualization, writing – review and editing. Qing-Fang Xiong: investigation, formal analysis, supervision, project administration, resources, writing – review and editing. Yan-Dan Zhong: investigation, formal analysis, supervision, project administration, resources, writing – review and editing. Du-Xian Liu: conceptualization, formal analysis, supervision, resources, writing – review and editing. Cai-Yun Zhang: investigation, formal analysis, supervision, project administration, resources, writing – review and editing. Kai Zhang: supervision, funding acquisition, project administration, writing – review and editing. Xing Liu: data curation, investigation, formal analysis, supervision, project administration, writing – review and editing. Yong-Feng Yang: conceptualization, methodology, investigation, visualization, project administration, writing – review and editing, supervision, funding acquisition, resources. Thank you for all the help from the Second Hospital of Nanjing. Thank you for the funding of Construction Project of Jiangsu Provincial Medical Innovation Center (CXZX202232); National Natural Science Foundation of China (No. 32200428); Natural Science Foundation of Jiangsu Province (BK20220778). A large language model (ChatGPT, OpenAI) was used solely for language polishing. No content, data interpretation or scientific conclusions were generated by the AI tool. This work is supported by Funding of Construction Project of Jiangsu Provincial Medical Innovation Center (Grant no. CXZX202232), National Natural Science Foundation of China (No. 32200428), and Natural Science Foundation of Jiangsu Province (Grant no. BK20220778). The authors declare no conflicts of interest. This article is linked to Kowdley et al. paper. To view this article, visit https://doi.org/10.1111/apt.70391. The data that support the findings of this study are available from the corresponding author upon reasonable request. Figure S1: Flow chart of PBC patients undergoing repeat liver biopsy. PBC, Primary Biliary Cholangitis; Untreated group: Ursodeoxycholic Acid (UDCA) Untreated group; Treatment group: UDCA treatment group. Figure S2: Comparison of liver function parameters between biochemical response and non-biochemical response groups in PBC patients undergoing repeat liver biopsy. PBC, Primary Biliary Cholangitis; ALT, Alanine Aminotransferase; AST, Aspartate Aminotransferase; TB, Total Bilirubin; DB, Direct Bilirubin; ALP, Alkaline Phosphatase; GGT, Gamma-Glutamyl Transferase; First, First biopsy; Second, Second Biopsy. p < 0.05 indicates statistical significance(*); p < 0.01(**); p < 0.001(***); ns, not significant. Figure S3: Comparison of globulin and immunoglobulin levels between biochemical response and non-biochemical response groups in PBC patients undergoing repeat liver biopsy. PBC, Primary Biliary Cholangitis; GLO, Globulin; IgA, Immunoglobulin A; IgG, Immunoglobulin G; IgM, Immunoglobulin M; First, First biopsy; Second, Second biopsy. p < 0.05 indicates statistical significance (*); p < 0.01(**); p < 0.001(***); ns, not significant. Table S1: Pathological scores of PBC patients. Table S2: Baseline characteristics of PBC patients undergoing repeat liver biopsy. Table S3: Comparison of laboratory parameters between biochemical response and non-biochemical response groups in PBC patients undergoing repeat liver biopsy. Table S4: Comparison of histological features between biochemical response and non-biochemical response groups in PBC patients. Table S5: Comparison of histological improvement between biochemical response and non-biochemical response groups. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.