Editors,

We read with great interest the recent article regarding resmetirom—a promising treatment option for metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis.¹ In fact, another groundbreaking hallmark of resmetirom is that the US Food and Drug Administration (FDA) does not require a liver biopsy to determine a patient's eligibility for the medication.² Consequently, non-invasive tests (NITs) that can perfectly replace liver biopsies have come under the spotlight due to the approval of MASH drugs. However, the failure of existing techniques to completely replace liver biopsy has troubled physicians' clinical decision-making.

Although the FDA's decision provides opportunities for NITs, it also brings new challenges, when the burden of MASH disease is increasing.^{3, 4} First, although NITs offer numerous advantages, their implementation should be accompanied by rigorous validation and quality assurance measures to ensure accuracy and reliability.^{5, 6} Algorithms should be in place to clarify when to use liver biopsy as a second-line test. Second, non-invasive diagnostic technologies need to improve their accuracy and reliability further to better match or exceed the efficacy of traditional liver biopsies. In addition, these technologies must overcome the issues of simplicity of operation, ease of generalisation and cost-effectiveness before they can become the standard for clinical assessment. For example, resmetirom's clinical trial (NCT02912260) successfully met its primary endpoint, demonstrating that Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) results in the early studies helped to determine the efficacy of resmetirom.⁷ However, MRI-PDFF is not widely available for widespread use in primary care settings.⁸ Along with the gradual improvement of the technologies, clinical guidelines need to be updated to reflect the use of NITs in the treatment of MASH to ensure that the quality of healthcare services and patient outcomes are optimised. Moreover, in the general population, patients may have comorbid diseases; whether these comorbidities influence the results obtained from NITs is also not known.

In the face of these challenges, we need to delineate a systematic approach. Initially, to enhance the accuracy of NITs, we must develop new methodologies and improve existing protocols. Subsequently, there is an imperative need to establish standardised non-invasive assessment protocols to ensure the reliability and consistency of evaluation outcomes across various medical institutions. By implementing uniform standards, we can facilitate the widespread adoption and enhance trust in NITs results. Finally, we should adopt multimodal assessment strategies to formulate comprehensive assessment models.

The FDA's approval of resmetirom is of great significance, a pivotal event that has far-reaching implications in drug discovery and NIT development. However, NITs may not be ready to replace histological assessment as surrogate endpoints. The need for NITs that overcome existing challenges and meet clinical needs is clear, and these technological advances will not only complement but also have the potential to redefine the standard for MASH patient management and resmetirom's efficacy optimisation.

编辑们，

我们饶有兴趣地阅读了最近关于瑞美罗的文章——瑞美罗是治疗代谢功能障碍相关脂肪性肝炎 (MASH) 和肝纤维化的一种有前途的治疗选择。¹事实上，瑞美罗的另一个突破性特点是美国食品和药物管理局 (FDA) 不需要进行肝活检来确定患者是否有资格服用该药物。²因此，由于 MASH 药物的批准，可以完美替代肝活检的非侵入性检测 (NIT) 受到关注。然而，现有技术未能完全替代肝活检，困扰着医生的临床决策。

尽管 FDA 的决定为 NIT 提供了机遇，但随着 MASH 疾病负担的增加，它也带来了新的挑战。^{3, 4}首先，尽管 NIT 具有众多优势，但其实施应辅之以严格的验证和质量保证措施，以确保准确性和可靠性。^{5, 6}应制定算法来明确何时使用肝活检作为二线测试。其次，无创诊断技术需要进一步提高其准确性和可靠性，以更好地匹配或超过传统肝活检的功效。此外，这些技术必须克服操作简单、易于推广和成本效益的问题，才能成为临床评估的标准。例如，瑞美罗的临床试验（NCT02912260）成功达到了其主要终点，表明早期研究中的磁共振成像-质子密度脂肪分数（MRI-PDFF）结果有助于确定瑞美罗的疗效。⁷然而，MRI-PDFF 尚未广泛用于初级保健机构。⁸随着技术的逐步改进，临床指南需要更新，以反映 NIT 在 MASH 治疗中的使用，以确保医疗服务质量和患者治疗效果得到优化。此外，在一般人群中，患者可能患有合并症；这些合并症是否影响 NIT 获得的结果也不得而知。

面对这些挑战，我们需要制定系统的方法。首先，为了提高 NIT 的准确性，我们必须开发新的方法并改进现有协议。因此，迫切需要建立标准化的无创评估方案，以确保各个医疗机构评估结果的可靠性和一致性。通过实施统一标准，我们可以促进 NIT 结果的广泛采用并增强对 NIT 结果的信任。最后，应采用多模态评估策略，制定综合评估模型。

FDA对瑞美罗姆的批准意义重大，是对药物发现和NIT开发具有深远影响的关键事件。然而，NIT 可能还没有准备好取代组织学评估作为替代终点。显然，NIT 需要克服现有挑战并满足临床需求，这些技术进步不仅将补充，而且有可能重新定义 MASH 患者管理和瑞美罗疗效优化的标准。