We thank Dr. Nae-Yun Heo for his interest in our recent publication, “Prediction of primary biliary cholangitis among health check-up population with anti-mitochondrial M2 antibody positive” [1], and for his thoughtful editorial [2]. We sincerely appreciate his meaningful comments and have responded to him in detail in the following discussion.

Primary biliary cholangitis (PBC) is a chronic progressive cholestatic liver disease, characterized by non-suppurative inflammation of the small and medium-sized bile ducts in the liver. This condition can further develop into hepatic fibrosis and cirrhosis. However, PBC is often insidious, and patients may exhibit no symptoms in the early stages [3]. Many cases of PBC are discovered by chance through abnormal elevations in alkaline phosphatase and gamma-glutamyl transpeptidase levels. Therefore, early identification of individuals at potential risk of PBC is crucial, as it can help improve the prognosis of the disease and reduce the risk of liver failure and the need for liver transplantation [4]. The prevalence and incidence of PBC are relatively low, and the time from AMA-M2 positivity to a confirmed diagnosis of PBC is usually lengthy. These factors can make the AMA-M2 test appear less cost-effective from an epidemiological perspective. However, early detection of PBC remains a significant challenge. Our study has shown that individuals who are AMA-M2 positive but do not yet have PBC have a higher risk of developing the disease compared to the general population. Although the progression of PBC is typically slow, it is highly susceptible to severe complications, including liver cirrhosis and liver failure. However, early treatment can significantly improve the prognosis for PBC patients. If AMA-M2 testing is cost-effective and blood collection causes minimal harm, then performing the AMA-M2 test for early risk identification is highly beneficial. This is especially true for known high-risk groups, including middle-aged females, individuals with abnormal liver function, and those with a family history of autoimmune diseases.

Meanwhile, previous studies have observed that some autoantibodies, such as rheumatoid factor [5], anti-citrullinated cyclic peptides antibody [6], anti-double-stranded DNA antibody [7], anti-SSA antibody [8], and others, can be detected before the onset of autoimmune diseases. This suggests that autoantibodies have predictive value for the development of autoimmune diseases. Compared to common chronic diseases such as hypertension, diabetes, and chronic obstructive pulmonary disease, the awareness rate of autoimmune diseases is lower, while the disability rate is higher [9]. In China, many hospitals now include autoantibody tests as part of routine health check-ups. This helps raise awareness of the risks associated with autoimmune diseases and facilitates early diagnosis for individuals with positive autoantibody results. To some extent, performing autoantibody tests in health check-up populations is significant for identifying individuals at risk of autoimmune diseases and reducing the incidence of severe adverse events.

Some guidelines indicate that both AMA and AMA-M2 can be used to diagnose PBC [10,11]. AMA-M2 is one of the more specific subtypes of total AMA for PBC. AMA and AMA-M2 show similar diagnostic performance for PBC, as Dr. Nae-Yun Heo has mentioned. In our experience, the results of AMA and AMA-M2 for diagnosing PBC are usually consistent, with both AMA and AMA-M2 being positive at the same time. However, inconsistent results can also arise.

One situation is AMA positive but AMA-M2 negative. This result may be related to PBC patients who do not have the M2 subtype in their serum. Instead, they may have other subtypes of AMA, such as M4 and M9. Another situation is AMA negative but AMA-M2 positive. This result may be associated with the different detection methods and the quality of the reagents used [12]. AMA is usually detected by indirect immunofluorescence assay (IFA), while AMA-M2 is usually detected by enzyme-linked immunosorbent assay (ELISA) or chemiluminescence immunoassay (CLIA) in our clinical testing. Compared to ELISA and CLIA, IFA has higher requirements for technicians, making it difficult to achieve standardized testing. The interpretation of results is also somewhat subjective. In addition, IFA itself has the disadvantage of low detection sensitivity, which can lead to false negatives in AMA detection. Therefore, it is advisable to combine AMA and AMA-M2 detection for diagnosing PBC. This approach can enhance the sensitivity of PBC diagnosis and minimize false-negative results that may arise from limitations in detection method [12]. Although both AMA and AMA-M2 have high specificity for PBC, they can also be detected in other diseases besides PBC, such as systemic sclerosis [13], idiopathic inflammatory myositis [14], systemic lupus erythematosus [15], and others. Therefore, it should be noted that AMA and AMA-M2 cannot be used as the only criteria for PBC diagnosis. Diagnosing PBC requires an integrated assessment by physicians based on the diagnostic criteria for PBC.

In conclusion, we would like to once again express our sincere gratitude to the experts for their insightful comments. Our study has shown that AMA-M2 can be positive in the health check-up population. For those AMA-M2–positive individuals who do not currently have PBC, they have a higher risk of developing PBC in the future compared to the general population. This indicates that AMA-M2 has predictive value for PBC. We anticipate that future studies will investigate the screening role of AMA-M2 for PBC in other populations.