Letter: Metabolic Dysfunction-Associated Steatotic Liver Disease in Primary Biliary Cholangitis—Friend, Foe or Red Herring? Authors' Reply

Abstract

We thank Drs. Ergenc and Yilmaz for their thoughtful comments [1] regarding our recent study on the influence of metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with primary biliary cholangitis (PBC) [2]. The relationship between MASLD and other liver diseases is an emerging area of interest, which we believe will generate compelling information, along with inevitable discrepancies and debates, in the near future.

Firstly, the observation that 17.1% of our cohort was negative for antimitochondrial antibodies (AMA) is consistent with contemporary evidence. A recent meta-analysis [3] examining 28 studies reported an AMA sensitivity of 84%, indicating that 16% of PBC patients are expected to be AMA-negative. The 17.1% positivity in our cohort is therefore in line with these data and is further bolstered by the fact that our study utilised biopsy-proven diagnoses, ensuring accurate identification even in AMA-negative individuals. Thus, the suggestion that AMA negativity rate undermines the representativeness of our cohort is not currently supported [3]. Regarding our higher incidence of metabolic dysfunction-associated steatohepatitis (MASH), this has also been observed in other chronic inflammatory immune-mediated diseases [4].

The authors provide valuable insights into the association between PBC and MASLD. However, based on the information provided, we cannot ascertain the methodology used or how the diagnosis of steatosis was made. They reference another study [5] where 87 patients with both PBC and steatosis showed better responses with ursodeoxycholic acid than 129 patients with only PBC. Diagnosis in that study was made either non-invasively or via biopsy, though the proportion of each method was unspecified. Notably, in the patients reportedly without MASLD, the mean BMI was 29.6 ± 6.4 kg/m² and 17% were diabetic, which suggests a high probability of undiagnosed steatosis.

While the authors affirm that our study may overstate the impact of MASLD, we believe our multivariable analysis—which adjusted for various confounders—demonstrates a clear, independent association between MASLD and worse liver-related outcomes. Although our MASH subgroup was relatively small (13 out of 129), the robustness of our overall findings is supported by the consistency of MASLD's impact on treatment response and long-term prognosis in PBC patients, independently of the presence of MASH. Larger future studies may provide more granular insights into the contribution of MASH's, but our current data already emphasise the importance of addressing MASLD.

Liver biopsy, while not without drawbacks, remains the gold standard for diagnosing many liver diseases. In our study, despite its limitations, all patients were confidently diagnosed with PBC and classified for steatosis. As we mentioned in our Discussion [2], non-invasive methods for diagnosing steatosis, especially in the presence of other fibrosing liver diseases, are unreliable. For example, transient elastography cut-off points for various diseases were systematically established excluding concomitant conditions. Similarly, the performance of ultrasound in diagnosing steatosis in the presence of liver fibrosis is low [6, 7]. Therefore, we believe, and have sought to reflect in our study, that given the limited current information and uncertainties regarding the influence of MASLD on other concomitant liver diseases, studies should ideally be based on histological assessments at this time to ensure reliability.

Conrado Fernández: conceptualization, validation, writing – review and editing. Antonio Olveira: writing – original draft, writing – review and editing.

C.F.: speaker, consultant and advisory board member for Advanz Pharma and Intercept Pharmaceuticals. A.O.: speaker, consultant and advisory board member for Advanz Pharma and Intercept Pharmaceuticals and consultant for Ipsen.

This article is linked to Hernández-Pérez et al papers. To view these articles, visit https://doi.org/10.1111/apt.18134 and https://doi.org/10.1111/apt.18302.