Lindvig Katrine P, Thorhauge Katrine H, Hansen Johanne K, Kjærgaard Maria, Hansen Camilla D, Johansen Stine, Lyngbeck Ellen, Israelsen Mads, Andersen Peter, Bech Katrine T, Torp Nikolaj, Schnefeld Helle L, Detlefsen Sönke, Möller Sören, Graupera Isabel, Trelle Morten B, Antonsen Steen, Harris Rebecca, Kårhus Line L, Bjørnsbo Kirsten S, Brøns Charlotte, Hansen Torben, Geier Andreas, Wedemeyer Heiner, Zeuzem Stefan, Schattenberg Jörn M, Ginès Pere, Guha Indra Neil, Krag Aleksander, Thiele Maja
Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.
Lancet Gastroenterol Hepatol. 2025 Jan;10(1):55-67. doi: 10.1016/S2468-1253(24)00274-7.
Clinically significant liver fibrosis is associated with future adverse events in patients with steatotic liver disease. We designed a software tool for detection of clinically significant liver fibrosis in primary care.
In this prospective cohort study, we developed and validated LiverPRO using six independent cohorts from Denmark, Germany, and England that included patients from primary and secondary care with steatotic liver disease related to alcohol or metabolic dysfunction. We used clinically significant fibrosis (histology stage ≥F2) and advanced fibrosis (≥F3) as outcomes for variable selection in the development cohort and built the model with fractional polynomial regression. In all cohorts, we independently validated the tool for prediction of elevated liver stiffness by transient elastography (≥8 kPa and ≥12 kPa) and for the 2-year and 5-year risk of liver-related events. Diagnostic performance was assessed using the area under the receiver operating curve (AUC), with clinical performance evaluated through sensitivity, specificity, and Harrell's C-statistic for prognostic purposes.
In the development cohort (n=462), we derived 466 multivariable models consisting of age in combination with three to nine variables from a list of nine blood tests (aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, international normalised ratio, albumin, sodium, bilirubin, platelet count, and cholesterol). In the development cohort, LiverPRO diagnosed clinically significant fibrosis with good accuracy (transient elastography ≥8 kPa area under the receiver operating characteristic curve [AUC] 0·86 [95% CI 0·83-0·90]). In the DECIDE validation cohort (n=6468), LiverPRO detected participants with a transient elastography of 8 kPa or higher with good accuracy (AUC 0·80 [95% CI 0·78-0·82]), comparable to enhanced liver fibrosis testing (0·78 [0·75-0·80]) and the LiverRisk score (0·81 [0·79-0·84]), but superior to the Fibrosis-4 index (0·69 [0·66-0·72]) and NAFLD Fibrosis Score (0·74 [0·72-0·77]). Findings were consistent in three other validation cohorts (n=2554), albeit accuracy was slightly lower. Using a rule-out cutoff of less than 25% (indicating no further examinations required), LiverPRO had a rule-out sensitivity of 80·6% (95% CI 76·4-84·3) and a rule-out negative predictive value of 98·0% (95% CI 97·5-98·4) in the DECIDE cohort. Similarly, with a rule-out cutoff of less than 1·3, FIB-4 had a rule-out sensitivity of 53·8% (48·5-58·9) and a rule-out negative predictive value of 95·8% (95·1-96·4). For rule-in thresholds, using a cutoff of more than 65% (indicating referral to a hepatologist required) LiverPRO had a rule-in specificity of 95·5% (95% CI 94·9-96·0) and a rule-in positive predictive value of 33·0% (95% CI 28·5-37·8) in the DECIDE cohort whereas FIB-4, with a rule-in threshold of 2·67, had a rule-in specificity of 98·7% (94·9-96·0) and a rule-in positive predictive value 35·6% (27·0-44·9). Using UK Biobank data, LiverPRO predicted liver-related events with a C-statistic of 0·80 (0·77-0·84) at 2 years.
LiverPRO reliably identifies clinically significant liver fibrosis and elevated liver stiffness, predicts the risk of liver-related events in primary care, and is adaptable to the availability of different liver blood test analytes. On the basis of these results LiverPRO was certified according to IVDR class b, obtaining European CE approval in 2024.
EU Horizon 2020 research and innovation programme and Novo Nordisk Foundation.
临床上显著的肝纤维化与脂肪性肝病患者未来的不良事件相关。我们设计了一种用于在初级保健中检测临床上显著肝纤维化的软件工具。
在这项前瞻性队列研究中，我们使用来自丹麦、德国和英国的六个独立队列开发并验证了LiverPRO，这些队列包括来自初级和二级保健机构的与酒精或代谢功能障碍相关的脂肪性肝病患者。我们将临床上显著的纤维化（组织学分期≥F2）和晚期纤维化（≥F3）作为开发队列中变量选择的结果，并使用分数多项式回归构建模型。在所有队列中，我们独立验证了该工具对通过瞬时弹性成像预测肝硬度升高（≥8 kPa和≥12 kPa）以及对2年和5年肝脏相关事件风险的预测能力。使用受试者工作特征曲线下面积（AUC）评估诊断性能，通过敏感性、特异性和用于预后目的的Harrell's C统计量评估临床性能。
在开发队列（n = 462）中，我们从九项血液检测（天冬氨酸转氨酶、碱性磷酸酶、γ-谷氨酰转移酶、国际标准化比值、白蛋白、钠、胆红素、血小板计数和胆固醇）列表中得出了466个多变量模型，这些模型由年龄与三到九个变量组合而成。在开发队列中，LiverPRO诊断临床上显著纤维化的准确性良好（瞬时弹性成像≥8 kPa时受试者工作特征曲线下面积[AUC]为0·86 [95% CI 0·83 - 0·90]）。在DECIDE验证队列（n = 6468）中，LiverPRO检测瞬时弹性成像为8 kPa或更高的参与者的准确性良好（AUC为0·80 [95% CI 0·78 - 0·82]）,与增强肝纤维化检测（0·78 [0·75 - 0·80]）和LiverRisk评分（0·81 [0·79 - 0·84]）相当，但优于纤维化-4指数（0·69 [0·66 - 0·72]）和非酒精性脂肪性肝病纤维化评分（0·74 [0·72 - 0·77]）。在其他三个验证队列（n = 2554）中的结果一致，尽管准确性略低。在DECIDE队列中，使用小于25%的排除临界值（表明无需进一步检查），LiverPRO的排除敏感性为80·6%（95% CI 76·4 - 84·3），排除阴性预测值为98·0%（95% CI 97·5 - 98·4）。同样，对于FIB-4，排除临界值小于1·3时，排除敏感性为53·8%（48·5 - 58·9），排除阴性预测值为95·8%（95·1 - 96·4）。对于纳入阈值，在DECIDE队列中，LiverPRO使用大于65%的临界值（表明需要转诊至肝病专家）时，纳入特异性为95·5%（95% CI 94·9 - 96·0），纳入阳性预测值为33·0%（95% CI 28·5 - 37·8），而FIB-4纳入阈值为2·67时，纳入特异性为98·7%（94·9 - 96·0），纳入阳性预测值为35·6%（27·0 - 44·9）。使用英国生物银行数据，LiverPRO在2年时预测肝脏相关事件的C统计量为0·80（0·77 - 0·84）。
LiverPRO能够可靠地识别临床上显著的肝纤维化和肝硬度升高，预测初级保健中肝脏相关事件的风险，并且能够适应不同肝脏血液检测分析物的可用性。基于这些结果，LiverPRO根据IVDR b类获得认证，并于2024年获得欧洲CE批准。
欧盟地平线2020研究与创新计划和诺和诺德基金会。
