编者按：随着药物性肝损伤（DILI）的临床谱系不断扩大，新的诊断难题应运而生，尤其是在合并代谢功能障碍相关脂肪性肝病（MASLD）或出现自身免疫样特征的患者中。在本次深度访谈中，西班牙马拉加大学Raúl J. Andrade教授探讨了如何区分药物诱导的自身免疫性肝炎（DIAIH）与自身免疫性肝炎（AIH）所面临的挑战、DILI与MASLD之间的复杂相互作用，以及在平衡代谢治疗与肝毒性风险时所需的临床判断。

《国际肝病》

DIAIH与经典AIH在免疫病理机制上有何区别？您认为哪些关键生物标志物或临床特征能更有效区分DIAIH与AIH？

Raúl J. Andrade教授：这是一个很有挑战性的问题。迄今为止，尚无明确的生物标志物能清晰地区分DIAIH和特发性或经典AIH。这两种疾病在临床表现、生化指标模式和组织学特征上往往存在显著重叠。

在实际临床中，肝病科医生会仔细评估药物暴露与肝损伤发作之间的时间关系。如果临床表型酷似AIH，但发生在特定药物暴露之后，就会考虑DIAIH的可能。当肝损伤在数日内未能自行缓解时，通常建议进行肝活检。然而，即使从组织学上看，界面性肝炎和浆细胞浸润等特征也并非某一种疾病所独有。晚期肝纤维化通常更提示经典AIH，但这并非绝对，因为经典AIH也可能急性起病且无明显肝纤维化。

鉴于缺乏具有鉴别意义的生物标志物，我们目前的方法是启动免疫抑制治疗（通常为糖皮质激素），并观察临床病程。如果患者能够耐受免疫抑制剂的减量和停药，并且在至少六个月的随访期内没有复发，那么诊断为DIAIH的可能性更大。相反，若出现复发，则更支持特发性AIH的诊断。这种基于纵向治疗反应的判断仍是当今临床肝病学中最实用的诊断方式。

Q1: What are the differences in the immunopathological mechanisms between “drug-induced AIH-like hepatitis” and classical AIH? What key biomarkers or clinical features do you propose to better differentiate DIAIH from idiopathic AIH, especially in cases with overlapping characteristics?

Prof. Raúl J. Andrade: This is a challenging question, and to date, no definitive biomarker exists to clearly distinguish between drug-induced autoimmune hepatitis (DIAIH) and idiopathic or classical autoimmune hepatitis (AIH). These two entities often display considerable overlap in clinical presentation, biochemical patterns, and histological features.

In practice, hepatologists carefully assess the temporal relationship between drug exposure and the onset of liver injury. If the clinical phenotype mimics AIH but occurs after a specific drug exposure, DIAIH is considered. When liver injury fails to resolve spontaneously within a few days, a liver biopsy is typically recommended. However, even histologically, features such as interface hepatitis and plasma cell infiltration are not exclusive to either condition. Advanced fibrosis is generally more suggestive of classical AIH, but this is not absolute, since classical AIH can also present acutely without significant fibrosis.

Given the lack of distinguishing biomarkers, our current approach involves initiating immunosuppression—usually corticosteroids—and observing the clinical course. If the patient tolerates tapering and withdrawal of immunosuppression without relapse over a follow-up period of at least six months, the diagnosis of DIAIH becomes more likely. In contrast, a relapse would favor a diagnosis of idiopathic AIH. This longitudinal therapeutic response remains the most practical diagnostic tool in clinical hepatology today.

《国际肝病》

MASLD患者合并DILI时，肝损伤模式是否因基础代谢紊乱而改变？

Raúl J. Andrade教授：这是另一种复杂的临床情况。对于合并DILI的MASLD患者，需要考虑两种主要的肝损伤途径。

首先，某些药物可加重已有的代谢功能障碍，导致脂肪变性加重、氧化应激增加或炎症加剧。从机制上讲，这可能涉及抑制脂噬作用、线粒体功能障碍或促炎信号传导。在这种情况下，肝损伤与代谢失调具有协同作用，会使MASLD的表型恶化。

其次，MASLD患者可能会出现与代谢功能障碍无关的独特肝损伤模式，例如由已知具有肝毒性的药物（如阿莫西林克拉维酸）引起的急性胆汁淤积性损伤。在这种情况下，DILI反映的是一种独立于代谢背景的机制。

因此，我们必须考虑两种可能性：药物诱导的潜在代谢性肝损伤加重，以及独立的药物诱导肝毒性反应。仔细的临床评估和识别对于区分这两种机制至关重要。

Q2: In MASLD patients who develop concomitant DILI, are the patterns of liver injury altered due to the underlying metabolic dysregulation?

Prof. Raúl J. Andrade: This is another complex scenario. In patients with MASLD who develop DILI, there are two principal pathways of injury to consider.

First, certain drugs can aggravate the pre-existing metabolic dysfunction—leading to worsened steatosis, increased oxidative stress, or enhanced inflammation. Mechanistically, this may occur via inhibition of lipophagy, mitochondrial dysfunction, or pro-inflammatory signaling. In such cases, the liver injury is synergistic with the metabolic dysregulation, exacerbating the MASLD phenotype.

Second, a MASLD patient may develop a distinct pattern of liver injury unrelated to metabolic dysfunction—such as acute cholestatic injury—from a drug with a known hepatotoxic profile, like amoxicillin-clavulanate. In this scenario, the DILI reflects a mechanism that is independent of the metabolic background.

Thus, we must consider both possibilities: drug-induced aggravation of underlying metabolic injury, and an independent drug-induced hepatotoxic reaction. Careful clinical assessment and pattern recognition are essential to distinguish between these two mechanisms.

《国际肝病》

MASLD患者常需长期服用降糖药或降脂药，这些药物本身可能引发DILI或加重肝损伤。在药物性肝损伤与代谢治疗需求冲突时，如何平衡停药风险与代谢控制目标？

Raúl J. Andrade教授：这是肝病学中常见的难题。幸运的是，目前尚无有力证据表明，用于管理代谢综合征的常用药物（如抗糖尿病药物、抗高血压药物或降脂药物）会带来显著的肝毒性风险，以至于需要在 MASLD 患者中常规停药。

关键在于进行合理的获益风险评估。例如，虽然已知他汀类药物偶尔会导致肝酶轻度升高，甚至罕见 DILI 病例，但其严重肝毒性的发生率极低。考虑到它们对心血管和代谢的益处，总体风险效益比非常支持继续使用。

即使存在对 DILI 的担忧，绝大多数患者也能良好耐受这些药物。只有当有明确的、基于证据的肝毒性怀疑时，才应考虑停药。否则，管理 MASLD 的治疗目标（尤其是血糖控制、血脂平衡和高血压）不应受到影响，因为这些因素直接影响肝脏和心血管的长期预后。

Q3: MASLD patients often require long-term use of hypoglycemic or lipid-lowering agents, which themselves can cause DILI or exacerbate liver injury. When facing the conflict between the risk of drug-induced liver injury and the need for metabolic therapy, how should the risks of drug discontinuation be balanced against the goals of metabolic control?

Prof. Raúl J. Andrade: This is a frequent dilemma in hepatology. Fortunately, we currently do not have strong evidence that commonly used medications for managing metabolic syndrome—such as antidiabetic agents, antihypertensives, or lipid-lowering drugs—pose a significant hepatotoxic risk that would justify routine discontinuation in MASLD patients.

The key is to apply a rational risk-benefit assessment. For example, statins, though known to occasionally cause mild elevations in liver enzymes or even rare cases of DILI, have an extremely low incidence of serious hepatotoxicity. Considering their cardiovascular and metabolic benefits, the overall benefit-risk ratio strongly favors their continued use.

Even in the case of DILI concerns, the vast majority of patients tolerate these medications well. Discontinuation should only be considered when there is a clear, evidence-based suspicion of hepatotoxicity. Otherwise, the therapeutic goals of managing MASLD—particularly glycemic control, lipid balance, and hypertension—should not be compromised, as these factors directly influence long-term liver and cardiovascular outcomes.

（来源：《国际肝病》编辑部）

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