Abstract: Background Liver fibrosis is a major risk factor for overall and liver-specific mortality of chronic Hepatitis B（CHB） combined with non-alcoholic fatty liver disease（NAFLD）. Combination of type 2 diabetes mellitus（T2DM） or hyperuricemia（HUA） accelerates the progression of liver fibrosis in CHB patients combined with NAFLD. Therefore，accurately assessing the stage of liver fibrosis using non-invasive diagnostic models is crucial for effective treatment and control of disease progression. Objective To compare the efficacy of five non-invasive diagnostic models［fibrosis-4（FIB-4），aspartate aminotransferase-to-platelet ratio index（APRI），aspartate-to-alanine aminotransferase ratio（AAR），S index，and gamma-glutamyl transpeptidase to platelet ratio index（GPRI）］ in diagnosing advanced liver fibrosis in CHB patients combined with NAFLD and T2DM/HUA，and to assess their feasibility for grassroots implementation. Methods CHB patients combined with NAFLD diagnosed by clinical evidence and liver pathology admitted in the Beijing Ditan Hospital，Capital Medical University from 2008 to 2021 were retrospectively recruited. They were divided into CHB&NAFLD（n=46），CHB&NAFLD&T2DM（n=80），and CHB&NAFLD&HUA groups（n=69） based on the comorbidities of T2DM or HUA. Using pathological results as the gold standard，DeLong's test was used to compare the area under the receiver operating characteristic curve（AUC）and diagnostic performance of five non-invasive indicators for the assessment of liver fibrosis progression in the three groups. Additionally，clinical utility of each model was evaluated using decision curve analysis（DCA）. Results In the CHB&NAFLD group，the AUC of FIB-4 in diagnosing liver fibrosis was 0.740，and that of AAR was 0.468，with an AUC difference of 0.272（△ AUC=0.272，P=0.05）. In the CHB&NAFLD&T2DM group，FIB-4 also exhibited the highest diagnostic performance（AUC=0.677），while the S index had the lowest AUC（0.588），with an AUC difference of 0.089（△ AUC=0.089，P=0.033）. In the CHB&NAFLD&HUA group，FIB-4 maintained the highest diagnostic performance（AUC=0.753），while AAR had the lowest AUC（0.609），with an AUC difference of 0.144（△ AUC=0.144，P=0.043）. Although FIB-4 performed the best in all three groups，its diagnostic performance was significantly lower in the CHB&NAFLD&T2DM group compared to the CHB&NAFLD group（ △ AUC=0.029，P<0.001） and CHB&NAFLD&HUA group（ △ AUC=0.029，P<0.001）. DCA showed that FIB-4 had a slightly higher clinical net benefit in the CHB&NAFLD and CHB&NAFLD&HUA groups. The optimal cutoff value for FIB-4 in the CHB&NAFLD&T2DM group was 1.425，which was higher than that in the CHB&NAFLD group（cutoff=1.117） and the CHB&NAFLD&HUA group（cutoff=1.305）. Conclusion The FIB-4 index is practical for assessing liver fibrosis in CHB patients combined with NAFLD and T2DM/HUA at the grassroots level. However，FIB-4 has a lower diagnostic efficacy and higher cutoff value in assessing liver fibrosis in CHB&NAFLD patients combined with T2DM than CHB&NAFLD and CHB&NAFLD&HUA patients. These results suggest that it is necessary to evaluate CHB&NAFLD patients with T2DM in combination with their specific characteristics and optimize the diagnostic strategy to improve accuracy.

Key words: Chronic hepatitis B, Nonalcoholic fatty liver disease, Type 2 diabetes mellitus, Hyperuricemia, Liver biopsy, Noninvasive diagnostic models

摘要： 背景 肝纤维化是慢性乙型肝炎（CHB）合并非酒精性脂肪性肝病（NAFLD）患者发生总体死亡及肝脏特异性死亡的主要危险因素。研究表明，合并2型糖尿病（T2DM）或高尿酸血症（HUA）会显著加速该类患者的肝纤维化进程。精准评估肝纤维化的阶段，对于制定有效治疗方案和控制疾病进展具有重要意义。目的 在伴有T2DM或HUA的CHB合并NAFLD患者中，比较5种无创诊断模型［纤维化4指数（FIB-4）、天冬氨酸氨基转移酶与血小板比率指数（APRI）、天冬氨酸氨基转移酶与丙氨酸氨基转移酶比值（AAR）、Sindex和γ-谷氨酰转肽酶与血小板比率指数（GPRI）］对进展期肝纤维化的诊断效能差异，并评估其在基层推广的可行性。方法 选取2008—2021年在首都医科大学附属北京地坛医院经临床及病理肝活检诊断为CHB合并NAFLD患者，按照是否合并T2DM或HUA将其分为3组：单纯CHB&NAFLD组（n=46）、CHB&NAFLD&T2DM组（n=80）和CHB&NAFLD&HUA组（n=69）。肝纤维化以病理结果为金标准，使用DeLong检验比较5种无创指标对3组患者进展期肝纤维化的受试者工作特征曲线下面积（AUC）及诊断性能，并通过临床决策曲线（DCA）评估各模型的临床实用性。结果 单纯CHB&NAFLD组中，FIB-4诊断肝纤维化的AUC为0.740，AAR的AUC为0.468，两者AUC差值为0.272（△AUC=0.272，P=0.05）；在CHB&NAFLD&T2DM组中，FIB-4同样表现出最高的诊断效能（AUC=0.677），而Sindex最低（AUC=0.588），两者AUC差值为0.089（△AUC=0.089，P=0.033）。在CHB&NAFLD&HUA组中，FIB-4的诊断效能仍为最高（AUC=0.753），而AAR最低（AUC=0.609），两者AUC差值为0.144（△AUC=0.144，P=0.043）。FIB-4在CHB&NAFLD&T2DM组的诊断效能低于CHB&NAFLD组（△AUC=0.029，P<0.001）和CHB&NAFLD&HUA组（△AUC=0.029，P<0.001）。DCA结果显示，FIB-4在CHB&NAFLD组和CHB&NAFLD&HUA组的临床净收益稍高。FIB-4的最佳截断值（cut-off）在CHB&NAFLD&T2DM组为1.425，高于单纯CHB&NAFLD组（cut-off=1.117）和CHB&NAFLD&HUA组（cut-off=1.305）。结论 FIB-4在基层医疗中评估合并T2DM或HUA的CHB合并NAFLD患者肝纤维化具有较高的实用价值。然而，与单纯CHB合并NAFLD患者或合并HUA的患者相比，FIB-4在合并T2DM患者中的诊断效能相对较低，且其最佳截断值更高。这些结果提示，在评估合并T2DM患者时需结合其特异性特征，优化诊断策略以提高准确性。

关键词: 慢性乙型肝炎, 非酒精性脂肪性肝病, 2 型糖尿病, 高尿酸血症, 肝活检, 无创诊断模型