TO THE EDITOR
Liver diseases, including drug-induced liver injury (DILI) and metabolic dysfunction-associated steatotic liver disease (MASLD), represent a major global health burden. DILI is one of the leading causes of acute liver failure in developed countries, and its clinical spectrum ranges from mild elevations in liver enzymes to severe liver dysfunction and mortality[1]. MASLD, driven by the global epidemic of obesity and metabolic syndrome, is currently the most prevalent chronic liver disease worldwide[2]. Given this widespread prevalence, understanding how MASLD alters liver susceptibility to DILI and influences its clinical presentation is essential to improve diagnostic accuracy and patient outcomes. The overlapping burden of MASLD and DILI amplifies their individual clinical challenges, creating unique diagnostic and therapeutic complexities. MASLD profoundly alters the hepatic environment through mechanisms such as insulin resistance, lipotoxicity, oxidative stress, and chronic low-grade inflammation. The chronic inflammatory state that occurs in MASLD is driven by complex interactions between metabolic dysregulation and the immune system. One of the key mechanisms involved is pyroptosis, an inflammatory form of programmed cell death mediated by the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome. Pyroptosis is triggered by metabolic stressors such as lipotoxicity, oxidized lipids and gut-derived endotoxins, leading to the activation of caspase-1, which, in turn, promotes the release of interleukin-1β (IL-1β) and IL-18, amplifying hepatic inflammation and immune cell recruitment[2]. Additionally, excessive lipid accumulation in hepatocytes leads to mitochondrial stress, impaired β-oxidation, and increased production of reactive oxygen species, which further promote oxidative damage and inflammatory signaling. The mitochondrial permeability transition pore is also dysregulated in MASLD, making hepatocytes more prone to apoptosis or necrosis after exposure to hepatotoxic agents. In addition, the release of mitochondrial DNA in the cytoplasm is downregulated in MASLD[3]. These metabolic and immune changes may increase the vulnerability of the liver to DILI, modify the patterns of DILI presentation, and complicate its diagnosis by mimicking or masking hepatotoxic effects[4]. Zhao et al[5] explored the interaction between MASLD and DILI. Their findings highlight critical differences in the clinical presentation and prognosis of DILI between patients with MASLD and those without MASLD. Zhao et al[5] from Tianjin Second People’s Hospital in China are congratulated for their compelling report on the role of DILI in patients with MASLD. DILI is known for its two forms, idiosyncratic DILI (iDILI) and dose-dependent intrinsic DILI[6]. Traditionally, iDILI is associated with conventional chemical drugs, generally excluding herbal products such as traditional Chinese medicines and dietary supplements. The updated Roussel Uclaf Causality Assessment Method (RUCAM)[6], used in the reviewed study, is the method recommended by the Chinese Society of Hepatology and the Chinese Medical Association for the diagnosis of DILI[7].
The RUCAM is the preferred method for assessing drug causality in iDILI, either in its original 1993 version[8,9], or, preferably, in the updated 2016 version[4]. The RUCAM has benefited from early internal validation[9], as well as from subsequent external validation, and good interrater reliability has been reported in several studies. The RUCAM represents a structured, score-based diagnostic algorithm that uses key elements of iDILI, such as the time to onset and the course of liver tests after cessation of the drug, as well as risk factors, comedications, alternative causes, previous hepatotoxicity, and the response to unintentional re-exposure[7-11]. Each element receives an individual score, and summing these scores yields a total score that corresponds to a causality grade: ≤ 0, excluded; 1-2, unlikely; 3-5, possible; 6-8, probable; or ≥ 9, highly probable[8].
The use of the RUCAM as the most accurate diagnostic algorithm for diagnosing DILI in patients with MASLD has also been reported in other studies[6]. The study by Zhao et al[5] added to the 81856 cases of iDILI published worldwide, all of which have been assessed for causality via the RUCAM[12], which thus outperforms any other tool in terms of case numbers[10]. The diagnosis of DILI in patients with MASLD is made on the basis of the following criteria: Biochemical and histological indicators of hepatic impairment, time elapsed from exposure to the appearance of the first signs of hepatic impairment, and data on improvement in liver function after discontinuation of treatment[13]. Nevertheless, several limitations specific to MASLD patients should be considered. For example, baseline fluctuations in liver enzymes in MASLD patients due to underlying disease could interfere with the RUCAM time ratio score.
Future studies of iDILI in patients with MASLD would benefit greatly from a prospective study design, as this approach allows for more comprehensive and standardized data collection than retrospective analyses, which may be limited by incomplete case data and lower RUCAM causality grades[6]. In addition, reporting causality grades for each drug and ensuring homogeneous cohorts—focused specifically on patients with iDILI due to chemical drugs—would improve the clarity and reliability of the results, as the inclusion of herbal products may introduce confounding factors. While the study by Zhao et al[5] offers valuable insights, addressing these aspects in future research could further strengthen the robustness and applicability of the findings[5]. A key limitation of Zhao et al’s study[5] is the lack of adjustment for metabolic confounders, such as diabetes, hypertension, and polypharmacy, which are highly prevalent in MASLD and could independently influence DILI risk and severity. As a result, these findings warrant further investigation and should be interpreted in the context of the study’s design limitations. In addition, many studies in this area lack robust and validated causality assessments, which requires careful consideration when conclusions are drawn from this research. A prospective, multicenter study design would mitigate selection bias, ensure more standardized diagnostic criteria for MASLD and DILI, and allow the collection of comprehensive metabolic and immunological data to better assess confounders such as obesity, diabetes, and polypharmacy.
In addition, the study by Zhao et al[5] explored the possible role of metabolic and immune alterations in the interaction between MASLD and DILI. Patients with MASLD and DILI were observed to have higher levels of triglycerides, cholesterol, low-density lipoprotein and insulin, which reflects the underlying metabolic dysregulation associated with MASLD. Elevated levels of IL-4 and complement C3 suggest immune involvement, which could indicate that an increased immune response contributes to liver injury. Nevertheless, the specificity of IL-4 in MASLD-related DILI remains unclear. Although IL-4 is a key cytokine involved in T helper 2 immune responses, its role in MASLD has been controversial. A recent meta-analysis of inflammatory cytokines in MASLD demonstrated that IL-4 was not significantly associated with the presence or progression of MASLD, unlike other proinflammatory cytokines such as IL-1β, IL-6, tumor necrosis factor α and intercellular adhesion molecule-1, which were significantly associated with MASLD and its progression to steatohepatitis and fibrosis[14]. In contrast, complement C3 is emerging as a more reliable immune marker in MASLD and liver injury. The complement system plays a crucial role in innate immunity and inflammation, and recent evidence suggests its involvement in the pathogenesis of MASLD. A meta-analysis evaluating complement components in non-alcoholic fatty liver disease revealed that C3, C5, complement factor B and acylation-stimulating protein were significantly elevated in patients with MASLD compared with controls and that C3 and C5 levels increased in proportion to MASLD severity[15]. These observations suggest the need for further investigation of how metabolic and immune factors may influence the severity and clinical presentation of DILI in MASLD patients, as well as their potential utility as biomarkers for risk assessment and therapeutic strategies.
The interaction between MASLD and DILI involves shared mechanisms such as metabolic dysregulation and immune activation, which complicate both diagnosis and treatment. A better understanding of these processes is essential to improve diagnostic accuracy and develop effective therapies. Future research should focus on identifying biomarkers that can distinguish DILI-induced liver injury from MASLD progression. The elevated levels of IL-4 and complement C3 observed in the study by Zhao et al[5] suggest an amplified immune response in MASLD-related DILI. However, more research is needed to determine whether these markers are specific to DILI susceptibility or simply reflect the underlying inflammation of MASLD. From a clinical standpoint, modification of the RUCAM or incorporation of MASLD-specific items could improve causality assessments of DILI in patients with metabolic dysfunction. In addition, personalized pharmacotherapy that takes into account altered CYP enzyme activity and drug metabolism in MASLD patients is essential to minimize hepatotoxic risk. Although the study by Zhao et al[5] underscores the importance of accurate causality assessment with tools such as the RUCAM, more research is needed to refine these methodologies, explore the underlying mechanisms, and develop strategies to mitigate.
