Is AMA M2 a useful serologic test for screening high-risk patients for PBC?: Editorial on “Prediction of primary biliary cholangitis among health check-up population with anti-mitochondrial M2 antibody positive”

Article information

Clin Mol Hepatol. 2025;31(2):640-641

Publication date (electronic) : 2025 February 13

doi : https://doi.org/10.3350/cmh.2025.0117

Nae-Yun Heo

Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea

Corresponding author : Nae-Yun Heo Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, 875 Haeun-daero, Haeundae-gu, Busan 48108, Korea Tel: +82-51-797-2436, Fax: +82-51-797-1291, E-mail: nyheo@hanmail.net

Editor: Han Ah Lee, Chung-Ang University College of Medicine, Korea

Received 2025 February 3; Accepted 2025 February 11.

Primary biliary cholangitis (PBC) is a relatively rare condition in the general population, yet it remains an essential differential diagnosis when physicians encounter abnormal liver function tests with a cholestatic pattern, such as elevated alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT). The presence of anti-mitochondrial antibodies (AMA), a highly specific serologic marker for PBC, has significantly reduced the need for invasive liver biopsy in diagnosing the disease.

AMA is a non-organ-specific autoantibody that targets internal and external mitochondrial membrane structures. It consists of several subtypes (M1 to M9), with AMA M2 being directed against the E2 component of the pyruvate dehydrogenase complex (PDC-E2), a key mitochondrial enzyme complex. AMA M2 is particularly relevant in PBC, as it constitutes the major component of AMA in affected patients, making it a more specific marker compared to total AMA.

The study by Li et al. [1] provides valuable insights into the natural course of AMA M2-positive individuals within a health check-up population. The prevalence of AMA M2 in this study was 3.23%, notably higher than in previous reports (<1%) except for one study that reported 9.67% [2]. The authors suggest that the relatively high proportion of older individuals and those with abnormal liver function tests in their cohort may have contributed to this finding. Additionally, regional, environmental, and methodological variations, including differences in diagnostic cut-off values across ELISA tests, could influence prevalence rates. Further studies in diverse geographic populations are needed to clarify these discrepancies.

The study also reports a 5-year cumulative incidence of PBC among AMA M2-positive but non-established PBC subjects of 0.5%, significantly lower than previous estimates (>4%) [3-5]. This difference may stem from the fact that earlier studies focused on hospital-based cohorts and examined AMA rather than the specific M2 subtype. The findings of Li et al. represent the first report on the incidence of PBC among asymptomatic, AMA M2-positive individuals without a prior or current diagnosis of PBC.

Furthermore, the study proposes a predictive model for PBC onset based on seven baseline variables: ALP, GGT, eosinophil percentage, IgM, gamma-globulin percentage, hemoglobin, and sex. This model demonstrated high diagnostic accuracy and may prove to be a valuable tool for identifying high-risk individuals in clinical practice. Current clinical guidelines recommend annual biochemical reassessment for AMA-positive individuals with normal liver function tests to monitor for the development of liver disease [6].

Despite the important contributions of this study, several unresolved issues remain regarding the role of AMA M2 in PBC screening. First, should AMA M2 testing be incorporated into routine health check-ups to identify individuals at risk for PBC? Given the low prevalence and incidence of PBC in the general population, routine screening with AMA or AMA M2 may not be cost-effective. However, AMA M2 testing could be useful in patients presenting with cholestatic liver dysfunction or when screening for autoimmune diseases is warranted.

Second, is AMA M2 superior to total AMA for detecting PBC? While AMA can be negative in the early stages of PBC and is less specific to the disease, AMA M2 theoretically offers improved diagnostic precision. However, meta-analyses have shown that AMA and AMA M2 exhibit similarly high diagnostic accuracy [7,8]. Additionally, in clinical practice, AMA is more widely available and cost-effective than AMA M2, leading to its more frequent use. Future studies should aim to validate the diagnostic capacity of AMA M2 across diverse populations worldwide to determine its optimal role in PBC diagnosis and screening.

In conclusion, AMA M2 represents a promising biomarker for PBC, but further research is needed to establish its utility in routine screening and its advantages over total AMA. While not currently recommended for general population screening, AMA M2 testing remains a valuable tool for identifying at-risk individuals, particularly those with abnormal liver function profiles suggestive of cholestasis.