Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study,The Lancet Gastroenterology & Hepatology

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Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study
The Lancet Gastroenterology & Hepatology ( IF 35.7 ) Pub Date : 2023-03-21 , DOI: 10.1016/s2468-1253(23)00017-1
Yasaman Vali ₁ , Jenny Lee ₁ , Jerome Boursier ₂ , Salvatore Petta ₃ , Kristy Wonders ₄ , Dina Tiniakos ₅ , Pierre Bedossa ₄ , Andreas Geier ₆ , Sven Francque ₇ , Mike Allison ₈ , Georgios Papatheodoridis ₉ , Helena Cortez-Pinto ₁₀ , Raluca Pais ₁₁ , Jean-Francois Dufour ₁₂ , Diana Julie Leeming ₁₃ , Stephen A Harrison ₁₄ , Yu Chen ₁₅ , Jeremy F Cobbold ₁₆ , Michael Pavlides ₁₇ , Adriaan G Holleboom ₁₈ , Hannele Yki-Jarvinen ₁₉ , Javier Crespo ₂₀ , Morten Karsdal ₁₃ , Rachel Ostroff ₂₁ , Mohammad Hadi Zafarmand ₁ , Richard Torstenson ₂₂ , Kevin Duffin ₁₅ , Carla Yunis ₂₃ , Clifford Brass ₂₄ , Mattias Ekstedt ₂₅ , Guruprasad P Aithal ₂₆ , Jörn M Schattenberg ₂₇ , Elisabetta Bugianesi ₂₈ , Manuel Romero-Gomez ₂₉ , Vlad Ratziu ₁₁ , Quentin M Anstee ₃₀ , Patrick M Bossuyt ₁ ,

Affiliation

Epidemiology and Data Science, Amsterdam Public Health, University of Amsterdam, Amsterdam, Netherlands.
Laboratoire Hémodynamique, Interaction Fibrose et Invasivité Tumorales Hépatiques, University Paris Research, Structure Fédérative de Recherche, Interactions Cellulaires et Applications Thérapeutiques 4208, University of Angers, Angers, France; Department of Hepato-Gastroenterology and Digestive Oncology, University Hospital of Angers, Angers, France.
Section of Gastroenterology and Hepatology, Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza, Department, University of Palermo, Palermo, Italy.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Department of Pathology, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Division of Hepatology, Department of Medicine II, Wurzburg University Hospital, Wurzburg, Germany.
Department of Gastroenterology Hepatology, Antwerp University Hospital, Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium.
Liver Unit, Department of Medicine, Cambridge National Institute for Health and Care Research Biomedical Research Centre, Cambridge University National Health Service Foundation Trust, Cambridge, UK.
Gastroenterology Department, National and Kapodistrian University of Athens, Athens, Greece.
University Clinic of Gastroenterology, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
Public Assistance Hospital of Paris, Pitié Salpêtrière Hospital, Institute of Cardiometabolism and Nutrition, Sorbonne University, Paris, France.
Hepatology, Department of Biomedical Research, University of Bern, Bern, Switzerland.
Nordic Bioscience, Herlev, Denmark.
The Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Lilly Research Laboratories, Eli Lilly, Indianapolis, IN, USA.
Department of Gastroenterology and Hepatology, Oxford National Institute for Health and Care Research Biomedical Research Centre, Oxford University Hospitals, Oxford, UK.
Department of Medicine, Oxford National Institute for Health and Care Research Biomedical Research Centre, Oxford, UK.
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Gastroenterology and Hepatology Department, Valdecilla Health Research Institute, Marqués de Valdecilla University Hospital, Santander, Spain.
SomaLogic, Boulder, CO, USA.
Cardiovascular, Renal or Metabolism Regulatory Affairs, AstraZeneca, Mölndal, Sweden.
Clinical Development and Operations, Pfizer, Lake Mary, FL, USA.
Novartis Pharmaceuticals, East Hanover, NJ, USA.
Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
Nottingham Digestive Diseases Centre, School of Medicine, National Institute for Health and Care Research Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, The University of Nottingham, Nottingham, UK.
Metabolic Liver Research Program, Department of Medicine, University Medical Center Mainz, Mainz, Germany.
Department of Medical Sciences, Division of Gastro-Hepatology, City of Health and Science of Turin, University of Turin, Turin, Italy.
Digestive Diseases, Virgen of Rocio University Hospital, Institute of Biomedicine of Seville, Department of Medicine, University of Seville, Seville, Spain.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Newcastle National Institute for Health and Care Research Biomedical Research Centre, Newcastle upon Tyne Hospitals National Health Service Trust, Newcastle upon Tyne, UK.

Background

The reference standard for detecting non-alcoholic steatohepatitis (NASH) and staging fibrosis—liver biopsy—is invasive and resource intensive. Non-invasive biomarkers are urgently needed, but few studies have compared these biomarkers in a single cohort. As part of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) project, we aimed to evaluate the diagnostic accuracy of 17 biomarkers and multimarker scores in detecting NASH and clinically significant fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) and identify their optimal cutoffs as screening tests in clinical trial recruitment.

Methods

This was a comparative diagnostic accuracy study in people with biopsy-confirmed NAFLD from 13 countries across Europe, recruited between Jan 6, 2010, and Dec 29, 2017, from the LITMUS metacohort of the prospective European NAFLD Registry. Adults (aged ≥18 years) with paired liver biopsy and serum samples were eligible; those with excessive alcohol consumption or evidence of other chronic liver diseases were excluded. The diagnostic accuracy of the biomarkers was expressed as the area under the receiver operating characteristic curve (AUC) with liver histology as the reference standard and compared with the Fibrosis-4 index for liver fibrosis (FIB-4) in the same subgroup. Target conditions were the presence of NASH with clinically significant fibrosis (ie, at-risk NASH; NAFLD Activity Score ≥4 and F≥2) or the presence of advanced fibrosis (F≥3), analysed in all participants with complete data. We identified thres holds for each biomarker for reducing the number of biopsy-based screen failures when recruiting people with both NASH and clinically significant fibrosis for future trials.

Findings

Of 1430 participants with NAFLD in the LITMUS metacohort with serum samples, 966 (403 women and 563 men) were included after all exclusion criteria had been applied. 335 (35%) of 966 participants had biopsy-confirmed NASH and clinically significant fibrosis and 271 (28%) had advanced fibrosis. For people with NASH and clinically significant fibrosis, no single biomarker or multimarker score significantly reached the predefined AUC 0·80 acceptability threshold (AUCs ranging from 0·61 [95% CI 0·54–0·67] for FibroScan controlled attenuation parameter to 0·81 [0·75–0·86] for SomaSignal), with accuracy mostly similar to FIB-4. Regarding detection of advanced fibrosis, SomaSignal (AUC 0·90 [95% CI 0·86–0·94]), ADAPT (0·85 [0·81–0·89]), and FibroScan liver stiffness measurement (0·83 [0·80–0·86]) reached acceptable accuracy. With 11 of 17 markers, histological screen failure rates could be reduced to 33% in trials if only people who were marker positive had a biopsy for evaluating eligibility. The best screening performance for NASH and clinically significant fibrosis was observed for SomaSignal (number needed to test [NNT] to find one true positive was four [95% CI 4–5]), then ADAPT (six [5–7]), MACK-3 (seven [6–8]), and PRO-C3 (nine [7–11]).

Interpretation

None of the single markers or multimarker scores achieved the predefined acceptable AUC for replacing biopsy in detecting people with both NASH and clinically significant fibrosis. However, several biomarkers could be applied in a prescreening strategy in clinical trial recruitment. The performance of promising markers will be further evaluated in the ongoing prospective LITMUS study cohort.

Funding

The Innovative Medicines Initiative 2 Joint Undertaking.

中文翻译：

非酒精性脂肪肝病中纤维化和非酒精性脂肪性肝炎分期的生物标志物（LITMUS 项目）：比较诊断准确性研究

背景

检测非酒精性脂肪性肝炎 (NASH) 和纤维化分期的参考标准（肝活检）是侵入性的且需要大量资源。迫切需要非侵入性生物标志物，但很少有研究在单个队列中比较这些生物标志物。作为肝脏调查：测试脂肪性肝炎标记物效用 (LITMUS) 项目的一部分，我们旨在评估 17 种生物标记物和多标记物评分在检测非酒精性脂肪性肝病 (NAFLD) 和临床显着纤维化方面的诊断准确性。确定其最佳截止点作为临床试验招募中的筛选测试。

方法

这是一项针对来自欧洲 13 个国家的活检确诊 NAFLD 患者的诊断准确性比较研究，研究对象于 2010 年 1 月 6 日至 2017 年 12 月 29 日期间从欧洲 NAFLD 前瞻性登记处的 LITMUS 荟萃队列中招募。具有配对肝活检和血清样本的成年人（年龄≥18岁）符合资格；那些过度饮酒或有其他慢性肝病证据的人被排除在外。生物标志物的诊断准确性以肝组织学为参考标准的受试者工作特征曲线下面积（AUC）表示，并与同一亚组的肝纤维化Fibrosis-4指数（FIB-4）进行比较。目标条件是存在具有临床显着纤维化的NASH（即，有风险的NASH；NAFLD活动评分≥4且F≥2）或存在晚期纤维化（F≥3），在所有具有完整数据的参与者中进行分析。当招募患有 NASH 和临床显着纤维化的患者进行未来试验时，我们确定了每种生物标志物的阈值，以减少基于活检的筛查失败的数量。

发现

在 LITMUS 荟萃队列中，有 1430 名患有 NAFLD 的血清样本参与者，在应用所有排除标准后，纳入了 966 名（403 名女性和 563 名男性）。966 名参与者中有 335 名 (35%) 患有经活检证实的 NASH 和临床显着的纤维化，271 名 (28%) 患有晚期纤维化。对于患有 NASH 和临床显着纤维化的患者，没有单一生物标志物或多标志物评分显着达到预定义的 AUC 0·80 可接受阈值（FibroScan 控制的衰减参数的 AUC 范围为 0·61 [95% CI 0·54–0·67] SomaSignal 为 0·81 [0·75–0·86]），精度与 FIB-4 基本相似。关于晚期纤维化的检测，SomaSignal (AUC 0·90 [95% CI 0·86–0·94])、ADAPT (0·85 [0·81–0·89]) 和 FibroScan 肝脏硬度测量 (0· 83 [0·80–0·86]）达到了可接受的精度。对于 17 种标记物中的 11 种，如果只有标记物呈阳性的人进行活检来评估资格，则试验中的组织学筛查失败率可降低至 33%。SomaSignal 观察到 NASH 和临床显着纤维化的最佳筛查性能（检测 [NNT] 发现 1 个真阳性所需的数量为 4 个 [95% CI 4-5]），然后是 ADAPT（6 个 [5-7]）， MACK-3（七个 [6–8]）和 PRO-C3（九个 [7–11]）。