编者按：脓毒症相关肝损伤（SRLI）和药物性肝损伤（DILI）是住院患者，尤其是重症监护环境中急性肝功能不全的两个最复杂且表现易重叠的病因。在2025第九届药物性肝损伤国际论坛上，冰岛雷克雅未克国立大学医院Einar S. Björnsson教授围绕英夫利昔单抗（infliximab）诱导的肝损伤进行了专题报告。本刊特邀Einar S. Björnsson教授分享了他对DILI和SRLI在诊断挑战、炎症标志物、表型差异及临床管理策略方面的见解。

《国际肝病》

脓毒症肝损伤中血清脂多糖结合蛋白和可溶性CD14亚型会特异性升高，而DILI患者常出现胆汁酸代谢紊乱。能否通过多标志物联合检测提升鉴别诊断准确性？

Einar S. Björnsson教授：这是一个非常重要且高度相关的问题，同时也颇具难度。遗憾的是，目前在临床实践中，我们尚未建立一套可靠的生物标志物组合来有效区分DILI和SRLI。将脓毒症中常见的如血清脂多糖结合蛋白（LBP）和可溶性CD14（sCD14）等标志物与DILI中的胆汁酸谱相结合的想法，是一个绝佳的研究假设。然而，要使这些标志物具有临床实用性，它们就必须在诊断窗口期内快速可得，理想情况下是在症状出现后的几天内。目前，这仍是一个未满足的需求，也是未来研究的一个潜在方向。

Q1: Serum lipopolysaccharide-binding protein and soluble CD14 subtype specifically increase in sepsis liver injury, while DILI patients often show bile acid dysregulation. Can combined multi-marker testing improve diagnostic accuracy?

Prof. Einar S. Björnsson: This is a very important and highly relevant question, but also a difficult one. Unfortunately, we currently do not have an established biomarker panel that can reliably differentiate between DILI and SRLI in clinical practice. The idea of combining markers like LBP and soluble CD14—common in sepsis—with bile acid profiles in DILI is an excellent research hypothesis. However, for such markers to be clinically useful, they must be rapidly available within the diagnostic window, ideally within a few days of symptom onset. At present, this remains an unmet need and a potential direction for future research.

《国际肝病》

SRLI和DILI最初都可能表现为转氨酶升高或黄疸，但所需的治疗策略截然不同。对于缺乏肝活检条件的基层医院，是否可通过特定时间点的炎症因子阈值辅助诊断SRLI？

Einar S. Björnsson教授：这也是一个非常好的问题。我首先要澄清的是，由于脓毒症的急性和全身性特点，它通常是在重症监护病房（ICU）而非基层医院进行管理。

在我们自己的研究中，我们主要关注的是肝酶模式，而非C反应蛋白（CRP）、白细胞介素-6（IL-6）或降钙素原（PCT）等炎症标志物。尽管如此，这一问题突出了未来研究的一个非常有前景的领域——研究特定时间点的炎症标志物阈值是否能支持SRLI和DILI的早期区分。据推测，与免疫介导的DILI相比，脓毒症会导致更明显的全身性炎症，但我们尚未正式对此进行验证。

Q2: Sepsis-related liver injury (SRLI) and drug-induced liver injury (DILI) may both initially present with elevated transaminases or jaundice, yet they require markedly different treatment strategies. In primary care settings where liver biopsy is not feasible, is it possible to aid in the diagnosis of SRLI through threshold values of specific inflammatory markers at defined time points?

Prof. Einar S. Björnsson: Thank you—this is another excellent question. I would first clarify that sepsis is typically managed in intensive care units rather than primary care, due to its acute and systemic nature. In our own research, we have looked primarily at liver enzyme patterns rather than inflammatory markers like CRP, IL-6, or procalcitonin. That said, your question highlights a very promising area for future research—investigating whether inflammatory marker thresholds at specific time points could support early differentiation between SRLI and DILI. It is hypothesized that sepsis would result in more pronounced systemic inflammation compared to immune-mediated DILI, but we have not yet formally tested this.

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在ICU中，脓毒症患者通常会接受多种药物治疗，临床医生如何快速区分以缺血性损伤为主的SRLI和免疫介导为主的DILI？

Einar S. Björnsson教授：这种区分具有重要的临床意义。对于缺血性或缺氧性肝损伤，诊断往往更容易。其生化模式非常独特——患者的天冬氨酸氨基转移酶（AST）会迅速急剧升高，随后丙氨酸氨基转移酶（ALT）升高。当血流动力学状态改善后，肝酶往往会在几天到两周内恢复正常。在我们的研究中，60%的脓毒症合并缺血性肝损伤患者在两周内肝肾功能检测恢复正常。相比之下，只有1例DILI患者表现出如此快速的改善。

当面对胆汁淤积表型时，区分就变得更加困难。然而，我们观察到碱性磷酸酶（ALP）在DILI中通常升高得更明显。此外，文献和我们的数据表明，脓毒症相关的胆汁淤积往往发生得非常早——在最初的24-48小时内，而药物性胆汁淤积通常发展得更缓慢。这些时间依赖性模式可以帮助指导鉴别诊断。

Q3: In the intensive care unit (ICU), where septic patients are often treated with multiple medications, how can clinicians rapidly distinguish SRLI dominated by ischemic injury from DILI with an immune-mediated basis?

Prof. Einar S. Björnsson: This distinction is clinically significant, and in cases of ischemic or hypoxic liver injury, the diagnosis is often easier. The biochemical pattern is quite distinct—patients exhibit a rapid and dramatic increase in AST, often followed by ALT. When the hemodynamic status improves, liver enzymes tend to normalize within days or up to two weeks.

In our study, 60% of patients with sepsis and ischemic liver injury showed normalization of liver tests within two weeks. In contrast, only one DILI case showed such rapid improvement.

When dealing with cholestatic phenotypes, the distinction becomes more difficult. However, we observed that alkaline phosphatase (ALP) was generally more elevated in DILI. Moreover, literature and our data indicate that sepsis-related cholestasis tends to occur very early—within the first 24–48 hours—whereas drug-induced cholestasis typically develops more gradually. These time-dependent patterns can help guide differentiation.

《国际肝病》

英夫利昔单抗所致肝损伤可分为三类：无症状转氨酶升高、自身免疫性肝炎样综合征和乙肝病毒再激活。在您的临床实践中，是否发现特定HLA等位基因与某一类肝损伤表型存在强关联？对于携带高风险HLA基因型的患者，是否应提前进行肝活检或密切监测自身抗体以实现早期干预？

Einar S. Björnsson教授：DILI与HLA的关联已有研究，特别是在英夫利昔单抗诱导的肝损伤方面。一项小型研究提示其与HLA-B*35:01存在强关联，报告了非常高的比值比（OR）。然而，该研究样本量有限，仅16例病例和60例对照，且方法学存在缺陷。

在我们自己的队列中，我们对约30例患者进行了基因分型，未发现携带HLA-B*35:01的病例。不过，我们确实发现了其他与风险增加相关的基因型，尽管其比值比仅为2到3。其中一个HLA变异体甚至显示出保护性关联。

我认为对于轻中度病例进行肝活检通常没有必要。根据我的经验，50%的患者在未使用糖皮质激素的情况下康复。那些未改善的患者开始接受30-40毫克泼尼松治疗，且均反应良好，没有复发。因此，我们认为在这些病例中，肝活检并不会改变治疗方案。然而，对于伴有凝血功能障碍或急性肝衰竭的严重病例，肝活检可能有所帮助。

Q4: Infliximab-induced liver injury can be classified into three phenotypes: asymptomatic transaminase elevation, autoimmune hepatitis-like syndrome, and hepatitis B virus reactivation. In your clinical practice, have you observed strong associations between specific HLA alleles and particular liver injury phenotypes? For patients carrying high-risk HLA genotypes, should preemptive liver biopsy or close monitoring of autoantibodies (e.g., ANA, SMA) be considered for early intervention?

Prof. Einar S. Björnsson: Yes, HLA associations with DILI have been investigated, particularly in infliximab-induced liver injury. One small study suggested a strong link with HLA-B*35:01, reporting a very high odds ratio. However, that study was limited—only 16 cases and 60 controls—and the methodology had flaws.

In our own cohort, we genotyped around 30 patients and found no cases with HLA-B*35:01. However, we did identify similar genotypes associated with increased risk, although the odds ratio was only around 2 to 3. One HLA variant even showed a protective association.

Regarding liver biopsy, in my opinion, it is generally unnecessary in mild to moderate cases. In our experience, 50% of patients recovered without corticosteroids. Those who did not improve were started on 30–40 mg of prednisone, and they all responded well—with no relapses. Therefore, we felt that liver biopsy would not alter management in these cases. However, in severe cases with coagulopathy or acute liver failure, liver biopsy may be helpful.

《国际肝病》

激素治疗可加速英夫利昔单抗相关肝损伤患者的转氨酶恢复，但长期使用的安全性仍需权衡。在临床实践中，如何判断激素使用的最佳时机？对于激素依赖型患者，是否可尝试联合使用免疫抑制剂以减少激素剂量？

Einar S. Björnsson教授：这是最容易回答的问题。在英夫利昔单抗诱导的肝损伤中，不需要与其他免疫抑制剂联合治疗。这些患者即使在停用激素后也不会复发。文献中没有证据表明存在长期的激素依赖。

在我们的实践中，患者接受皮质类固醇治疗的中位持续时间约为80天（约8周）。如果ALT水平仅轻度升高，例如在200-500 U/L之间，且患者无症状，通常可以等待观察，无需立即进行类固醇治疗。然而，如果患者因其基础疾病需要继续使用生物制剂治疗，则可以考虑使用低剂量激素以加速肝酶恢复正常。但再次强调，在大多数情况下，激素并非绝对必需。

Q5: While corticosteroid therapy can accelerate transaminase normalization in patients with infliximab-induced liver injury, the long-term safety of steroid use remains a concern. In clinical practice, how do you determine the optimal timing for initiating corticosteroids? For steroid-dependent patients, is it advisable to consider combination therapy with immunosuppressants to reduce steroid exposure?

Prof. Einar S. Björnsson: This is the easiest question to answer. In infliximab-induced liver injury, combination therapy with other immunosuppressants is not necessary. These patients do not relapse, even after steroid withdrawal. There is no evidence in the literature suggesting long-term steroid dependence.

In our practice, patients were treated with corticosteroids for a median duration of around 80 days (approximately 8 weeks). If ALT levels are only mildly elevated—say, between 200–500 U/L—and the patient is asymptomatic, you can often wait without immediate steroid treatment. If, however, the patient requires further biological therapy for their underlying disease, you may consider low-dose steroids to accelerate liver enzyme normalization. But again, in most cases, steroids are not absolutely essential.

（来源：《国际肝病》编辑部）

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