编者按：近期，在2025第九届药物性肝损伤国际论坛上，英国诺丁汉大学Guruprasad P. Aithal教授针对两个高度相关的临床领域——长期存在争议的甲氨蝶呤肝毒性风险以及免疫检查点抑制剂（ICI）相关肝损伤的复杂管理，提出了关键性见解。本刊特邀Guruprasad P. Aithal教授围绕这两个问题进行专访。Guruprasad P. Aithal教授基于多中心队列研究等证据，挑战了甲氨蝶呤诱导肝纤维化的传统认知，指出代谢风险因素的关键作用，并探讨了肝毒性监测策略。同时，他就ICI相关肝损伤的激素使用原则、肝损伤亚型管理及多组学预测模型的未来方向等内容进行了分享，为临床实践提供了新的思路。

《国际肝病》

您本次会上的报告主题为“Methotrexate and Liver: Half-life of truth”（甲氨蝶呤与肝脏：真相的半衰期），如何理解这一报告主题？

Guruprasad P. Aithal教授：我报告的核心主题是对长期以来关于甲氨蝶呤诱导肝纤维化的担忧提出挑战。数十年来，临床医生一直依赖丙氨酸氨基转移酶（ALT）等生物标志物来监测肝毒性。然而，ALT并非慢性肝损伤（尤其是肝纤维化）的理想标志物。随后，虽引入了Ⅲ型前胶原氨基末端肽（P3NP）等标志物，但这些标志物主要反映炎症（并非肝脏特异性），而非真正的纤维化改变。

我们开展的多中心队列研究覆盖了众多研究点的999例患者，并采用巢式病例对照设计。研究表明，甲氨蝶呤，尤其是在低剂量使用时，并非慢性肝病发生或进展的病因。相反，在这些患者中观察到的肝纤维化主要由潜在的代谢风险因素驱动，如体重指数（BMI）升高和2型糖尿病。这些发现强调，有必要将监测重点转向脂肪变性肝病（SLD）易感性增加的患者，而瞬时弹性成像目前是最准确的无创评估工具之一。

Q1: Your presentation at this conference is titled “Methotrexate and Liver: Half-life of truth.” How should we interpret this theme?

Prof. Guruprasad P. Aithal: The central theme of my presentation challenges long-standing concerns regarding methotrexate-induced liver fibrosis. For decades, clinicians have relied on biomarkers such as alanine aminotransferase (ALT) to monitor hepatotoxicity. However, ALT is a poor marker for chronic liver injury, particularly fibrosis. Subsequently, markers like procollagen type III amino-terminal peptide (P3NP) were introduced, but these too primarily reflect inflammation, not specific to the liver, rather than true fibrotic changes.

Our multicenter cohort study, encompassing 999 patients across numerous sites and utilizing a nested case-control design, demonstrated that methotrexate, particularly at low doses, is not a causal factor in the development or progression of chronic liver disease. Instead, hepatic fibrosis observed in these patients is predominantly driven by underlying metabolic risk factors, such as elevated body mass index (BMI) and type 2 diabetes mellitus. These findings underscore the necessity of shifting our monitoring focus toward patients with increased susceptibility to steatotic liver disease (SLD), for which transient elastography currently represents one of the most accurate and non-invasive assessment tools.

《国际肝病》

当前研究显示，尽管甲氨蝶呤累积剂量与肝纤维化无直接关联，但代谢综合征或代谢相关脂肪性肝病患者肝毒性风险显著增加。在临床实践中，如何界定这类高危人群的用药阈值？是否应调整监测频率或采用更敏感的肝纤维化评估工具？

Guruprasad P. Aithal教授：区分甲氨蝶呤相关肝毒性的两种不同类型很重要：慢性纤维化和急性肝损伤。

在我们队列研究中所涉及的低剂量甲氨蝶呤治疗情况下，我们观察到甲氨蝶呤本身并未增加纤维化风险。这些患者中出现的任何肝损伤通常反映的是已存在的代谢性肝病负担，而非甲氨蝶呤暴露所致。因此，关于是否继续使用甲氨蝶呤的临床决策，应主要以治疗效果为指导，而非对纤维化的假设性担忧。

急性肝损伤仍是一个值得关注的问题，尤其是在治疗开始后的第一年内。我们的数据显示，在此期间，肝酶升高超过正常上限五倍的发生率约为每1000患者年40例（约4%）。若采用更严格的标准，发生率降至约每1000患者年20例（2%）。一年后，显著肝损伤的发生率进一步降至每1000患者年2例（0.2%），这支持在初始治疗一年后大幅降低监测强度。

为优化监测，我们开发了一种计算机预测模型，该模型纳入了早期标志物，如前六个月内的转氨酶升高、早期血细胞减少、肌酐升高以及是否存在糖尿病。该模型可实现个性化风险分层：约60%的患者属于极低风险类别（五年风险＜5%），10%为中度风险（5%-10%），25%被确定为需要更强化的监测。对于大多数患者，成功度过治疗第一年之后，每年进行一次肝功能检测即可。

Q2: Current research suggests that although the cumulative dose of methotrexate is not directly associated with hepatic fibrosis, patients with metabolic syndrome or metabolic-associated fatty liver disease (MAFLD) exhibit a significantly increased risk of hepatotoxicity. In clinical practice, how should we define the therapeutic threshold for this high-risk population? Should the monitoring frequency be adjusted, or should more sensitive tools for liver fibrosis assessment be employed?

Prof. Guruprasad P. Aithal: It is important to distinguish between two distinct categories of methotrexate-associated liver toxicity: chronic fibrosis and acute liver injury.

In the setting of low-dose methotrexate, as studied in our cohort, we observed no excess risk of fibrosis attributable to methotrexate itself. Any liver injury in these patients typically reflects the burden of pre-existing metabolic liver disease rather than methotrexate exposure. Thus, clinical decisions regarding methotrexate continuation should be guided primarily by therapeutic efficacy rather than hypothetical concerns over fibrosis.

Acute liver injury remains a valid concern, particularly within the first year of therapy initiation. Our data indicate that during this period, elevations of liver enzymes exceeding five times the upper limit of normal occur at approximately 40 per 1,000 patient-years (roughly 4%). Applying more stringent criteria, the incidence falls to approximately 20 per 1,000 patient-years (2%). Beyond the first year, the incidence of significant liver injury drops further to 2 per 1,000 patient-years (0.2%), supporting a substantial reduction in monitoring intensity after the initial treatment year.

To optimize monitoring, we have developed a computerized predictive model incorporating early markers such as transaminase elevations within the first six months, early cytopenias, rise in creatinine and the presence of diabetes. This model enables personalized risk stratification: approximately 60% of patients fall into a very low-risk category (＜5% five-year risk), 10% are classified as moderate risk (5%-10%), and 25% are identified as requiring more intensive monitoring. For the majority of patients, annual liver function testing is sufficient once the first year of therapy has been successfully navigated.

《国际肝病》

对于肿瘤负荷高、需快速重启ICIs治疗的患者，如何平衡激素剂量与肿瘤预后风险？是否应基于肝损伤亚型调整激素方案？

Guruprasad P. Aithal教授：这是肿瘤学与肝病学交叉领域中一个关键且日益常见的临床难题。管理方法必须根据肝损伤的组织学和生化模式进行调整。

对于表现为胆汁淤积型或混合型肝损伤的患者，通常应避免免疫抑制治疗。在这种情况下，可考虑使用熊去氧胆酸，尽管高质量证据仍然有限。重要的是，糖皮质激素在胆管病（包括ICI诱导的胆管病）中已被证明无临床获益。

相反，对于肝细胞损伤型（前提是胆红素水平保持在正常范围内），在1-2周内进行密切的生化监测通常会发现病情自发改善，因此无需使用糖皮质激素。我在报告中提及的《美国医学会杂志》（JAMA）研究显示，在ICI治疗前两个月内接受糖皮质激素治疗的患者，其肿瘤治疗结局比未接受激素治疗的患者更差，这进一步支持了这种保守方法。

当认为必须使用糖皮质激素治疗时，理想情况下应通过肝活检进行组织学确认，以确保存在显著的炎症浸润。在无法进行活检但存在高胆红素血症的情况下，可谨慎启动低剂量糖皮质激素治疗。然而，不建议使用大剂量糖皮质激素，因为现有证据不支持其在加速药物性肝损伤恢复方面的疗效。

Q3: In patients with a high tumor burden who require rapid re-initiation of immune checkpoint inhibitor (ICI) therapy, how can clinicians balance corticosteroid dosing with the potential risk to oncologic outcomes? Should steroid regimens be tailored according to the subtype of liver injury?

Prof. Guruprasad P. Aithal: This is a crucial and increasingly encountered clinical dilemma in oncology-hepatology interface. The management approach must be tailored to the histologic and biochemical pattern of liver injury.

For patients exhibiting cholestatic or mixed-patternliver injury, immunosuppression should generally be avoided. In such cases, ursodeoxycholic acid may be considered, although high-quality evidence remains limited. Importantly, corticosteroids have demonstrated no clinical benefit in cholangiopathies, including those induced by ICIs.

Conversely, in hepatocellular injury patterns—provided bilirubin levels remain within normal limits—close biochemical monitoring over one to two weeks often reveals spontaneous improvement, negating the need for corticosteroids. The JAMA study I presented demonstrated that patients who received corticosteroids within the first two months of ICI therapy experienced inferior oncological outcomes compared to those who did not receive steroids, further supporting this conservative approach.

When corticosteroid therapy is considered unavoidable, histological confirmation via liver biopsy is ideal to ensure the presence of significant inflammatory infiltrates. In scenarios where biopsy is not feasible but hyperbilirubinemia is present, cautious initiation of low-dose corticosteroids may be warranted. High-dose corticosteroids, however, are not recommended, as current evidence does not support their efficacy in expediting recovery from drug-induced liver injury.

《国际肝病》

未来能否通过多组学整合建立预测模型，实现ICIs治疗前的肝毒性风险分层？

Guruprasad P. Aithal教授：的确，这是肝毒性研究中最有前景的方向之一。尽管我在本次会议上未展示这些数据，但我们最近在一本肿瘤学杂志上发表了研究结果，描述了一种与ICI诱导的肝损伤相关的新型循环生物标志物。同时，我们正在推进遗传生物标志物的研究，并且已成功开发出一种基于细胞的检测方法，可准确诊断ICI相关肝毒性。

尽管这些工具仍在评估中，但我们的目标是在未来1-2年内将这些多组学平台整合到全面的预测算法中。这种个性化风险分层模型有望优化患者选择，最大限度地发挥治疗效益，并将接受免疫检查点抑制剂治疗患者的肝毒性风险降至最低。

Q4: Looking ahead, is it possible to develop predictive models through multi-omics integration to enable pre-treatment risk stratification of hepatotoxicity associated with ICI therapy?

Prof. Guruprasad P. Aithal: Indeed, this represents one of the most promising frontiers in hepatotoxicity research. While I did not present these data during this conference, we have recently published findings in an oncology journal describing a novel circulating biomarker associated with ICI-induced liver injury. Simultaneously, we are advancing research into genetic biomarkers, and we have successfully developed a cell-based assay that accurately diagnoses ICI hepatotoxicity.

Although these tools remain under evaluation, our goal is to integrate these multi-omics platforms into comprehensive predictive algorithms within the next one to two years. Such personalized risk stratification models hold great promise for optimizing patient selection, maximizing therapeutic benefit, and minimizing the risk of hepatotoxicity in patients receiving immune checkpoint inhibitors.

（来源：《国际肝病》编辑部）

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