Letter: Lubiprostone Treatment for MASLD—Gender Imbalance and Blinding Considerations

Abstract

We read with great interest the studies by El-Kassas and their colleagues [1]. This study provides valuable insights, demonstrating that Lubiprostone is well tolerated and effectively reduces liver fat content in patients with MASLD. However, we wish to highlight a few key considerations to enhance the interpretation of the findings and propose avenues for future research.

Firstly, we would like to highlight the significant gender imbalance in the study's patient population. The patient group included a disproportionately high percentage of women, with 83% in the control group and 91% in the intervention group. Additionally, the mean age of the female patients in the intervention group (43.3 ± 9.1 years) was younger than that in the control group (47.0 ± 10.2 years). This age difference aligns with the menopausal transition, increasing oestrogen level variations between pre-menopausal and peri-menopausal women. Oestrogen plays a critical role in the progression of fatty liver disease [2]. Postmenopausal women often experience a worsened clinical course of fatty liver due to the decline in oestrogen levels [2, 3]. Given the age difference between the two groups of patients in this study, oestrogen levels may have differed significantly between the intervention and control groups, which may have exaggerated the actual effects of lubiprostone. A more refined approach might include monitoring oestrogen levels as part of a broader analysis of how these hormones influence the course of MASLD and treatment outcomes.

Secondly, while we commend the authors for employing a randomised, double-blind design, we note a potential limitation related to the drug's mechanism. Lubiprostone, as a laxative, is known to have a direct effect on bowel movements [4]. In clinical practice, patients receiving laxatives are often able to infer their treatment group based on changes in gastrointestinal function, which may affect their perceptions of the drug's efficacy. Although the study reports that both the participants and caregivers were blinded to treatment allocation, the physiological response to lubiprostone may introduce a psychological bias. Therefore, in similar study designs, a dummy laxative (a drug with no physiological effect) could be introduced as a control group in the study to ensure that participants are not able to judge their group by their physiological response.

Finally, it is important to acknowledge the limitations in the study's inclusion criteria. All trial participants had liver enzymes under 40, which suggests that the study focused on individuals with mild liver steatosis and without overt steatohepatitis. MASLD is a progressive, chronic disease, and its management requires a long-term approach. The safety and tolerability of lubiprostone over extended periods remain uncertain, particularly in patients with co-morbid metabolic conditions [5]. As such, we recommend that future research should consider a more diverse population with varying degrees of liver injury and metabolic dysfunction. Furthermore, extended follow-up periods are necessary to evaluate the long-term effects of lubiprostone, including potential adverse effects, drug resistance, and interactions with other therapies commonly used in the management of MASLD.