编者按：随着草药与膳食补充剂（HDS）的广泛应用，肝病领域学者发现HDS相关肝损伤（HDS-DILI）病例呈持续增长趋势。在2025第九届药物性肝损伤国际论坛上，本刊特邀美国宾夕法尼亚州立大学医学院Victor Navarro教授探讨了HDS相关肝毒性在流行病学、诊断、治疗及监管层面的挑战，并概述了改善预防与管理的潜在策略。

《国际肝病》

在美国，HDS-DILI的发病率显著上升，尤其是与膳食补充剂相关的病例，但产品成分标注缺失和患者报告偏差显著影响监测准确性。在流行病学监测中，如何界定HDS-DILI的真实发生率？是否应建立更主动的监测系统？

Victor Navarro教授：这是一个非常重要的问题。在美国，我们通过“药物性肝损伤网络（DILIN）”开展的研究并非基于人群，这使得准确估算HDS-DILI的真实发病率颇具挑战。计算发病率需要分子（肝损伤病例数）和分母（使用这些补充剂的人群数）。我们目前虽能识别肝损伤患者，却缺乏全国范围内补充剂使用人数的全面数据。

因此，确定真实发生率仍然极其困难。但我们可以肯定的是，膳食补充剂确实会导致肝损伤，这凸显了建立强有力监测系统的必要性。一旦发现病例，监管机构可调查类似报告，并在必要时迅速采取行动，将有害产品下架。在这一过程中，政府的主动监测对保护公众健康起着关键作用。

Q1: The incidence of HDS-induced liver injury has risen significantly in the United States, particularly related to dietary supplements. However, reporting bias and lack of accurate usage data limit the precision of current epidemiological estimates. How can we define the true incidence of HDS-induced liver injury? Should a more proactive surveillance system be established?

Prof. Victor Navarro: This is a very important question. In the U.S., our research through the Drug-Induced Liver Injury Network (DILIN) is not population-based, which makes it challenging to accurately estimate the true incidence of HDS-induced liver injury. To calculate incidence, we need both the numerator (number of liver injury cases) and the denominator (number of individuals using these supplements). While we can identify patients with liver injury, we currently lack comprehensive data on how many people are using these products nationwide.

Thus, determining true incidence remains extremely difficult. Nevertheless, we know with certainty that dietary supplements do cause liver injury, which underscores the need for robust surveillance systems. Once a case is identified, regulatory authorities can investigate similar reports and take prompt action to remove harmful products from the market if necessary. In this context, proactive government surveillance plays a critical role in protecting public health.

《国际肝病》

HDS-DILI的致病机制涉及直接肝毒性、免疫介导损伤及代谢紊乱等多种因素。在临床实践中，如何整合基因检测、代谢组学及临床表型分析，建立精准的诊断模型？

Victor Navarro教授：膳食补充剂种类繁多，不同产品导致肝损伤的机制各异。例如，许多用于健身或提升运动表现的补充剂常与胆汁淤积性肝损伤相关，这为临床诊断提供了有用线索。但迄今为止，我们尚未发现这类补充剂导致肝损伤的一致性遗传易感性因素。

相反，对于某些富含多酚的补充剂（如绿茶提取物、姜黄），有证据表明其与基因相关。携带HLA-B*35:01等位基因的个体似乎更容易因这些产品发生肝损伤。但局限性在于，美国约30%的人口携带该等位基因，这令在常规实践中出于预防目的进行基因筛查并不现实。

在我看来，目前临床表型分析的价值远高于基因检测。当患者出现特定特征（如服用健身补充剂后明显黄疸）时，结合临床背景能更可靠地建立因果关系。尽管基因和代谢数据可能深化我们的理解，但诊断的核心仍依赖于临床表型分析。

Q2: The pathogenesis of HDS-induced liver injury is multifactorial, involving direct hepatotoxicity, immune-mediated mechanisms, and metabolic disturbances. How can we integrate genetic testing, metabolic profiling, and clinical phenotyping to construct a more precise diagnostic approach?

Prof. Victor Navarro: Dietary supplements are highly diverse, encompassing a wide array of products with distinct mechanisms of liver injury. For instance, many supplements used for bodybuilding or performance enhancement are associated with cholestatic liver injury, which provides a useful clinical clue. However, to date, we have not identified consistent genetic predispositions for this category.

Conversely, for certain polyphenol-rich supplements—such as green tea extract, turmeric, there is evidence suggesting a genetic association. Individuals who carry the HLA-B*35:01 allele appear to have an increased susceptibility to liver injury from these products. The limitation, however, is that approximately 30% of the U.S. population carries this allele, making genetic screening impractical for preventive purposes in routine practice.

In my view, clinical phenotyping remains far more valuable at present. When a patient presents with specific features—such as marked jaundice following consumption of bodybuilding supplements—the clinical context allows us to more confidently establish a causal relationship. Ultimately, while genetic and metabolic data may enhance our understanding, clinical pattern recognition remains central to diagnosis.

《国际肝病》

对于HDS相关急性肝衰竭，是否应制定特定的治疗干预措施（如早期使用N-乙酰半胱氨酸、糖皮质激素）？

Victor Navarro教授：目前，针对药物性肝损伤的特异性治疗手段甚少，HDS-DILI的治疗选择则更少。对于某些非药物毒素，如含鹅膏毒素的蘑菇，水飞蓟宾或青霉素等解毒剂可能有效。但在大多数HDS-DILI相关病例中，停用致病物质仍是主要干预措施。

对于HDS导致的急性肝衰竭，N-乙酰半胱氨酸（NAC）现已广泛应用并有证据支持。在非对乙酰氨基酚所致急性肝衰竭中，早期使用NAC已被证实有明确益处，并成为许多中心的标准支持治疗手段。

关于糖皮质激素的应用则更具选择性。如果存在自身免疫成分的迹象（如IgG水平升高或自身抗体标志物阳性），则可能适合使用糖皮质激素。由于大多数补充剂导致肝损伤的具体机制尚未完全明确，一旦患者出现自身免疫特征时，我们会毫不犹豫地使用糖皮质激素。

Q3: In cases of HDS-induced acute liver failure, should specific therapeutic interventions—such as early use of N-acetylcysteine (NAC) or corticosteroids—be established?

Prof. Victor Navarro: Currently, there are very few specific treatments for drug-induced liver injury, and even fewer for HDS-induced liver injury. For certain non-pharmaceutical toxins, such as amanitin-containing mushrooms, antidotes like silibinin or penicillin may be beneficial. However, in most HDS-related cases, withdrawal of the offending agent remains the primary intervention.

In cases of acute liver failure due to HDS, N-acetylcysteine (NAC) is now widely used and supported by evidence. Early administration of NAC in non-acetaminophen-induced acute liver failure has demonstrated clear benefit and has become a standard supportive therapy in many centers.

Regarding corticosteroids, their role is more selective. If there is any suggestion of an autoimmune component—such as elevated IgG levels or positive autoimmune markers—then corticosteroids may be appropriate. Since the precise mechanisms of liver injury for most supplements remain incompletely understood, we do not hesitate to use corticosteroids in cases where autoimmune features are present.

《国际肝病》

鉴于HDS是急性肝衰竭的重要诱因，您认为应如何平衡公众教育与政策干预？例如，是否应强制要求HDS产品在标签上明确标注肝毒性风险？在公众教育中，如何有效传达“天然≠安全”的理念，同时避免引发不必要的恐慌？

Victor Navarro教授：这是一个很好的问题。在我看来，政府监管是最有效的方法。在美国，我们对膳食补充剂的监管框架仍相对宽松，允许产品在上市前无需进行强制性的临床前安全性验证。

一旦发现某产品可能有害，我认为监管机构应迅速采取行动限制其销售或全面下架。虽然公众教育非常重要，但很难有效覆盖所有潜在消费者。因此，强有力的监管控制对公众保护至关重要。

此外，持续研究应聚焦于确定特定成分的安全剂量阈值，这些数据可用于指导生产规范，确保产品不超过既定的安全范围。归根结底，尽管公众教育有其独特价值，但政府的主动监管才是防范 HDS-DILI更可靠的保障。

Q4: Given that HDS has become a leading cause of acute liver failure, how should public education and regulatory policy be balanced? Should there be mandatory hepatotoxicity warnings on supplement labels or restrictions on high-risk ingredients? How can we effectively communicate that "natural" does not equal "safe" without causing undue alarm?

Prof. Victor Navarro: This is an excellent question, and in my view, governmental regulation is the most effective approach. In the United States, our regulatory framework for dietary supplements remains relatively relaxed, allowing products to enter the market without mandatory preclinical safety testing.

Once a product is identified as potentially harmful, I believe regulatory agencies should act promptly to restrict its sale or remove it from the market entirely. While public education remains important, it is difficult to reach all potential consumers effectively. Thus, strong regulatory control is essential for public protection.

Additionally, ongoing research should focus on determining safe dosage thresholds for specific ingredients. This data can then inform manufacturing guidelines to ensure products do not exceed these established safety margins. Ultimately, while education is valuable, proactive government oversight provides a more reliable safeguard against HDS-related liver injury.

（来源：《国际肝病》编辑部）

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