慢性乙型肝炎肝纤维化无创性诊断模型的研究进展

早期诊断慢性乙型肝炎肝纤维化并给予及时抗病毒治疗是减少肝硬化、肝癌等并发症发生的关键。肝活组织检查虽然是诊断肝纤维化的"金标准",但存在操作较复杂、有创和容易产生并发症等缺点,因此无创性诊断模型越来越受到临床重视。回顾了目前国内外已有的慢性乙型肝炎肝纤维化无创性诊断模型,发现虽然研究的模型较多,且有一定诊断价值,但是缺乏统一的认识。未来还需要更多的研究来开发更好的模型,使其能够代替肝活组织检查来评估慢性乙型肝炎肝纤维化并指导抗病毒治疗。     

非创伤性诊断肝纤维化临床研究进展

正确评估肝纤维化程度有利于临床治疗和随访慢性肝病。笔者就非创伤性诊断肝纤维化的不同方法、适应证和步骤的最新进展进行讨论。瞬间弹性超声检查与多项血清标志物组合的诊断模型,符合非创伤性肝纤维化诊断技术的多项要求,能有效诊断严重肝纤维化（S≥3期）,但区分轻、中度肝纤维化（S≤2期）欠佳。目前,非创伤性诊断肝纤维化方法仍不成熟,还不能完全取代肝脏活体组织检查。     

GGT与PLT比值指数对慢性乙型肝炎肝纤维化的诊断价值

早期、准确地诊断肝纤维化并给予抗病毒治疗是改善慢性乙型肝炎预后的关键。肝活组织检查及瞬时弹性成像技术诊断肝纤维化难以在临床普遍使用,因而血清学诊断模型成为近年的研究热点。介绍了一种新的肝纤维化血清学诊断模型GGT与PLT比值指数(GPR),其对慢性乙型肝炎肝纤维化的诊断价值较高,但GPR在不同人群、不同地区诊断的准确性存在差异。GPR也是慢性乙型肝炎相关肝细胞癌预后的良好预测指标。认为GPR用于慢性乙型肝炎肝纤维化的诊断有良好前景,但因GPR临床研究数据较少,故在我国推广应用尚需进一步的研究证实。     

慢性乙型肝炎相关肝纤维化中医诊疗进展与思考

肝纤维化是慢性乙型肝炎发展至肝硬化、肝癌的必经中间过程。近年来，中医药防治慢性乙型肝炎肝纤维化的研究取得突破性进展。以提高临床疗效为目的，多学科联合开展产学研研究，阐释慢性乙型肝炎肝纤维化中医证候生物学基础、建立与研发中医特色无创诊断模型，优化中医/中西医结合治疗方案并阐释中医治疗的科学内涵能够帮助中医药防治肝纤维化走向国际。     

慢性乙型肝炎肝纤维化非创伤性诊断评分表模型的建立

目的 从慢性乙型肝炎患者的临床、生物化学及影像学等临床常用的非创伤性指标中,构建诊断肝纤维化的评分表模型。方法 374例临床诊断为慢性乙型肝炎患者,行肝组织活检术,常规检查血常规、生物化学、病毒载量、血清透明质酸（HA）、超声检查肝脏及脾脏厚径、年龄等,根据各临床指标在肝组织病理分期的相对比值,制定各变量的分值,构建诊断肝纤维化的评分表模型,用受试者工作特征曲线（ROC曲线）评价评分表模型的诊断预测能力。结果 建模组314例慢性乙型肝炎患者中,由血小板计数、白蛋白/球蛋白（A/G）、脾厚、透明质酸（HA）、年龄5项指标构成判断肝纤维化的评分表模型（SZFibroS模型）。ROC曲线分析显示,SZFibroS ≥ 5.4,诊断≥ S2的敏感性为78.2%,特异性为67.7%,受试者工作特征曲线下面积（AUC）为0.8153。60例验证组验证该模型的准确度为76.7%。结论 运用该非创伤性评分表模型评价慢性乙型肝炎的肝纤维化程度,简单易记、可重复性好,具有较高的敏感性及准确性,可在一定程度上替代肝组织活检来监测慢性乙型肝炎肝纤维化的动态变化。     

慢性乙型肝炎病毒感染患者肝纤维化非创伤性诊断模型的应用评价

目的在慢性乙型肝炎病毒（HBV）感染患者中评价肝纤维化非创伤性诊断模型的诊断价值，为其在临床诊疗上的应用提供参考。方法对131例慢性HBV感染患者进行肝活检的病理学分级、分期，并检测血清指标以计算S指数、SI，FG模型、Hepascore、Forns指数和APRI指数等诊断模型。用受试者工作曲线（ROC）等方法验证和比较各模型的诊断价值。结果各指标组合模型对肝纤维化程度都具有一定诊断价值。其中由γ-谷氨酰转肽酶（GGT）、血小板（PI。T）和白蛋白（Alb）三个常规指标组成的s指数在验证组中表现最佳[S指数：1000×GGT／（PLT×Alb^2）]。其判断有无明显肝纤维化、有无重度肝纤维化和有无早期肝硬化时的ROC曲线下面积（AUC）分别达0．797、0．880和0．881。以S指数〈0．1预测无明显肝纤维化，S指数≥0．5预测存在明显肝纤维化，验证组中40．5％病例可被正确预测。以S指数〈0．3预测无早期肝硬化，S指数≥1．5预测存在早期肝硬化，验证组中68．7％病例可被正确预测。结论肝纤维化非创伤性诊断模型能较好地区分存在明显肝纤维化或早期肝硬化的慢性HBV感染患者，其中以S指数最为简便有效，它的应用可以减少一部分慢性HBV感染患者肝活检的需要。     

肝纤维化血清学诊断研究进展

肝纤维化是由各种慢性肝病引起细胞外基质在肝脏过度沉积所致,可进展为肝硬化并导致肝功能衰竭和门静脉高压等。肝纤维化具有可逆性已成为共识。因此,准确诊断和评估肝纤维化程度对肝纤维化的防治及其预后评估具有非常重要的意义。肝纤维化诊断的金标准是肝脏活检,但由于其具有创伤性、费用昂贵而难以被患者接受。血清学检查是诊断肝纤维化较为理想的检测方法,可对肝纤维化进行早期诊断,并可进行动态观察。由多个血清学指标组成的非创伤性诊断模型,提高了肝纤维化的诊断准确性。本文就肝纤维化的血清学诊断研究进展进行综述。     

重视肝纤维化的诊断和评估

肝纤维化是各种慢性肝病向肝硬化发展过程中的关键步骤和影响慢性肝病患者预后的重要环节。尽管目前对肝纤维化尚无确切的有效干预手段,但无论是临床医师还是患者仍急切需求对其进行早期诊断和评估。因此,需要加强肝纤维化早期诊断和评估的研究,为临床诊治和预后判断提供更好的依据[1]。尽管这些年很多学者对肝纤维化的诊断和评估做了大量的研究工作,尤其是在非创伤性诊断和评估方面,包括一些无创血清诊断模型和影像学检查等非创伤性检测方法,对肝纤维化有较高的诊断价值,但由于各存缺陷和准确性差强人意,目前肝活检仍然是诊断肝纤维化的“金标准”。     

从常规指标中建立肝纤维化非创伤性诊断模型

目的在慢性乙型肝炎病毒（HBV）感染患者中建立基于常规实验室指标的肝纤维化非创伤性诊断模型,为传统的肝穿刺活检提供简便的非创伤性替代手段。方法采用Logistic回归等方法分析386例慢性HBV感染患者的常规实验室指标与肝纤维化分期的关系,建立诊断模型。用受试者工作曲线（ROC）等方法验证和比较该模型与Forns指数、APRI指数、Hepascore及SLFG模型的诊断价值。结果各指标组合模型对肝纤维化分期的诊断价值优于单项常规实验室指标,其中SLFG模型、S指数和Hepascore均具有较好的表现。由γ-谷氨酰转肽酶（GGT）、血小板（PLT）和白蛋白（Alb）三个常规指标组成的S指数（S指数=1000×GGT/（PLT×Alb2））判断有无明显肝纤维化和有无早期肝硬化时的受试者工作曲线下面积（AUC）分别达到0.686和0.762。使用以下推荐界值,S指数〈0.1预测无明显肝纤维化的灵敏度为90.4%,S指数≥0.5预测存在明显肝纤维化的特异度为86.2%;S指数〈0.3预测无早期肝硬化的灵敏度为84.8%,S指数≥1.5预测存在早期肝硬化的特异度为97.7%。结论由常规实验室指标建立的简单组合S指数,能较准确而方便地区分存在明显肝纤维化或早期肝硬化的慢性HBV感染患者。     

血清“肝纤四项”联合检测诊断模型的建立

目的构建以"肝纤四项"为变量的诊断模型,并探讨该诊断模型对明显肝纤维化的诊断效能。方法选取485例乙型病毒性肝炎患者,随机分为建模组324例和验证组161例,采用放射免疫分析法检测建模组和验证组患者血清中HA、LN、PⅢNP、CⅣ的含量;采用二元Logistic回归分析法,以肝组织活检作为"金标准",构建以"肝纤四项"为变量的诊断模型;采用受试者工作特征(ROC)曲线,评价该诊断模型的诊断效能;用独立的验证组检验该模型的诊断效率。结果在二元Logistic回归分析中,确定了3项与研究终点相关的独立预测指标(HA、PⅢNP和CIV),由这3个指标建立了诊断模型FSM,FSM=1.56 ln(HA)+0.92 ln(PⅢNP)+1.90 ln(CⅣ)-8.18。FSM用于预测明显肝纤维化具有较高的诊断价值,ROC曲线下面积(AUC)为0.85。该模型应用于验证组,其诊断明显肝纤维化的AUC同样为0.85。根据ROC曲线,用于预测明显肝纤维化时,FSM取10.8为排除界值,敏感性和阴性预测值分别为88.31%和69%;取12.6为诊断界值,特异性和阳性预测值分别为93.55%和95.3%。比较FSM模型与HA的诊断效能,FSM模型的约登指数、阳性似然比、敏感性、特异性和准确率均高于HA,两者的AUC差异有统计学意义(Z=2.06,P0.05)。结论本研究所建立的"肝纤四项"联合检测FSM模型,一定程度上提高了诊断效能。将该模型应用于预测明显肝纤维化,可使65%~70%无或轻度肝纤维化乙型肝炎患者避免"肝组织活检"。作为一种非创伤性检查手段,该模型可用于动态监测乙型肝炎患者肝纤维化进程。     

Evaluation and comparison of thirty noninvasive models for diagnosing liver fibrosis in chinese hepatitis B patients

The limitations of liver biopsy have led to the development of indirect noninvasive models for liver fibrosis assessment. We aimed to evaluate and compare the performance of 30 noninvasive models to predict fibrosis stage in treatment‐naïve and treated chronic hepatitis B (CHB) patients. A total of 576 Chinese treatment‐naïve CHB patients and 236 treated CHB patients who had undergone percutaneous liver biopsy were included in the analysis. Histological grading and staging was assessed by the Ishak scoring system. The diagnostic accuracies of 30 noninvasive models were assessed by area under the receiver operating characteristic curves (AUROCs). In treatment‐naïve CHB patients, the AUROCs of the 30 noninvasive models for discriminating significant fibrosis (SF) were less than 0.800, and only the AUROC of the PP score for diagnosing advanced fibrosis (AF) was more than 0.800, while the AUROCs of FIB‐4, FibroQ, HB‐F, Lok index, PHP score and PP score for predicting cirrhosis were greater than 0.800. In treated CHB patients, only the AUROCs of APRI, GUCI, King's score and Wang I for identifying cirrhosis were more than 0.800. The Spearman correlation analysis identified that only the changes in FCI and Virahep‐C model values were weakly correlated with changes in Ishak fibrosis scores before and after treatment (r = 0.206, p = 0.008; r = 0.187, p = 0.016, respectively). In conclusion, in Chinese CHB patients, the 30 existing noninvasive models were not suitable for assessing each stage of fibrosis except cirrhosis before and after antiviral therapy, especially in gauging progression and regression of liver fibrosis following therapy.     

Staging of liver fibrosis in chronic hepatitis B patients with a composite predictive model:A comparative study

AIM:To evaluate the efficacy of 6 noninvasive liver fibrosis models and to identify the most valuable model for the prediction of liver fibrosis stage in chronic hepatitis B(CHB) patients.METHODS:Seventy-eight CHB patients were consecutively enrolled in this study.Liver biopsy was performed and blood serum was obtained at admission.Histological diagnosis was made according to the METAVIR system.Significant fibrosis was defined as stage score ≥ 2,severe fibrosis as stage score ≥ 3.The diagnostic accuracy of ...     

Noninvasive models to predict liver cirrhosis in patients with chronic hepatitis B.

Objectives: Few noninvasive models of chronic hepatitis B (CHB) to predict liver cirrhosis have been studied. The aim of the current study is to investigate the diagnostic accuracy of two simple novel models of spleen–platelet ratio index (SPRI) and age–spleen–platelet ratio index (ASPRI) in patients with CHB. Patients and methods: A total of 346 consecutive treatment‐naïve patients with CHB were retrospectively studied. The aspartate to alanine aminotransferase ratio (AAR), age–platelet index (API), aspartate aminotransferase to platelet ratio index (APRI), SPRI, and ASPRI were compared with liver histology. Results: AAR, APRI, SPRI, API, and ASPRI correlated significantly to fibrosis stage (all P<0.001). The diagnostic accuracy of ASPRI was the highest among five tests for prediction of cirrhosis (area under receiver operating characteristic curve, AUROC=0.893). Using a cutoff score of ASPRI>12, the presence of cirrhosis could be correctly identified with a high accuracy (96.3% positive predictive value) in 35 (10.1%) of 346 patients. Similarly, using a cutoff of <5, the presence of cirrhosis could be totally excluded with 100% of negative predictive value in 120 (34.7%) of 346 patients. Conclusion: ASPRI was accurate in predicting cirrhosis and screening with ASPRI has the potential to reduce the number of liver biopsies in CHB patients.     

Ceruloplasmin,a reliable marker of fibrosis in chronic hepatitis B virus patients with normal or minimally raised alanine aminotransferase

AIM To develop a non-invasive model to evaluate significant fibrosis and cirrhosis by investigating the association between serum ceruloplasmin(CP) levels and liver fibrosis in chronic hepatitis B(CHB) patients with normal or minimally raised alanine aminotransferase(ALT).METHODS Serum samples and liver biopsy were obtained from 193 CHB patients with minimally raised or normal ALT who were randomly divided into a training group(n = 97) and a validation group(n = 96). Liver histology was evaluated by the METAVIR scoring system. Receiver operator characteristic curves were applied to the diagnostic value of CP for measuring liver fibrosis in CHB patients. Spearman rank correlation analyzed the relationship between CP and liver fibrosis. A noninvasive model was set up through multivariate logistic regression analysis.RESULTS Serum CP levels individualized various fibrosis stages via area under the curve(AUC) values. Multivariate analysis revealed that CP levels were significantlyrelated to liver cirrhosis. Combining CP with serum GGT levels, a CG model was set up to predict significant fibrosis and liver cirrhosis in CHB patients with normal or minimally raised ALT. The AUC, sensitivity, specificity, positive predictive value, and negative predictive value were 0.84, 83.1%, 78.6%, 39.6%, and 96.5% to predict liver cirrhosis, and 0.789, 80.26%, 68.38%, 62.25%, and 84.21% to predict significant fibrosis. This model expressed a higher AUC than FIB-4(age, ALT, aspartate aminotransferase, platelets) and GP(globulin, platelets) models to predict significant fibrosis(P = 0.019 and 0.022 respectively) and revealed a dramatically greater AUC than FIB-4(P = 0.033) to predict liver cirrhosis.CONCLUSION The present study showed that CP was independently and negatively associated with liver fibrosis. Furthermore, we developed a novel promising model(CG), based on routine serum markers, for predicting liver fibrosis in CHB patients with normal or minimally raised ALT.     

A novel noninvasive index for the prediction of moderate to severe fibrosis in chronic hepatitis B patients

BackgroundsThe evaluation of liver fibrosis stages is essential for the clinical management of chronic hepatitis B (CHB).AimsTo develop and validate a novel noninvasive index for moderate to severe fibrosis (≥S2) in CHB patients.MethodsA total of 401 CHB patients who underwent liver biopsy were divided into the training (n = 300) and validation (n = 101) cohort. Histological severity was scored using a modified Scheuer system. Clinical and laboratory assessments were collected.ResultsIn the training cohort, PACG, a novel index combining the quantitative hepatitis B core antibody (qAnti-HBc), platelet count (PLT), and albumin globulin ratio (A/G), presented better diagnostic performance (AUROC = 0.814) than that of APRI (0.735, p = 0.007) and FIB-4 (0.749, p = 0.014). In the validation cohort, the AUROC of the PACG, APRI, FIB-4 and Fibroscan were 0.834, 0.806, 0.791 and 0.810, respectively. More importantly, a higher and lower cutoff of PACG for predicting ≥S2 fibrosis or not had a >90% sensitivity and specificity, with a diagnostic accuracy of 85.9%.ConclusionPACG is a promising noninvasive alternative to liver biopsy in CHB patients for the evaluation of moderate to severe fibrosis.     

Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B

Summary.  The aim of this study is to know the liver stiffness measurement (LSM) cutoffs for different stages of liver fibrosis in chronic hepatitis B (CHB) and to investigate the effect of alanine aminotransferase (ALT) on LSM. We prospectively studied consecutive CHB patients undergoing liver biopsy and transient elastography examinations. Diagnostic performance of LSM for different degrees of liver fibrosis was evaluated. One hundred and sixty-one CHB patients with adequate liver biopsy sample size were studied. Area under receiver operating characteristics curves of LSM for no fibrosis (F0 vs F1–4), bridging fibrosis (F0–2 vs F3–4) and liver cirrhosis (F0–3 vs F4) was 0.80 (95% CI: 0.68–0.92), 0.87 (95% CI: 0.82–0.93) and 0.93 (95% CI: 0.89–0.97) respectively. For liver cirrhosis, these optimal cutoff values were 8.4 kPa (98% sensitivity), 9.0 kPa (maximum sum of sensitivity and specificity), 13.4 kPa (94% specificity) and 13.4 kPa (maximum diagnostic accuracy, 85%) respectively. Patients with the same fibrosis staging but higher ALT levels tend to have higher LSM, and the diagnostic performance for low stage fibrosis was most seriously affected when ALT was elevated. Different LSM cutoff values and algorithms were derived for normal and elevated ALT levels. Based on these algorithms, liver biopsy can be avoided in 62% and 58% of patients with normal and elevated ALT respectively. In conclusion, transient elastography is a reasonable noninvasive tool to substitute liver biopsy among the lowest and highest risk patients for the assessment of liver fibrosis.     

Establishment and validation of a simple noninvasive model to predict significant liver fibrosis in patients with chronic hepatitis B

Background  

There have been still few valuable noninvasive models that can be used as indirect markers of liver fibrosis in chronic hepatitis B (CHB) infection.     

慢性肝病肝纤维化无创诊断的研究进展

肝活组织检查因其有创性和样本误差,使其临床应用受限,近年来无创诊断与评价肝纤维化成为研究热点之一。介绍了目前主要的血清学模型和FibroScan对肝纤维化诊断的价值,并简述了无创方法的联合应用。现阶段无创诊断方法尚不能完全取代肝活组织检查,不同肝纤维化无创诊断方法对不同病因肝纤维化的诊断价值是否存在差异尚须进一步研究。     

The gamma‐glutamyl transpeptidase‐to‐albumin ratio predicts significant fibrosis and cirrhosis in chronic hepatitis B patients

Background/Aim Simple, inexpensive and clinically available noninvasive liver fibrosis tests are highly needed. We aimed to develop a novel noninvasive index for predicting significant fibrosis and cirrhosis in chronic hepatitis B (CHB) patients. Methods Using liver histology as gold standard, we developed a novel index to predict significant fibrosis and cirrhosis in CHB patients and then compared the diagnostic accuracy of the novel index, aspartate transaminase‐to‐platelet ratio index (APRI), and fibrosis index based on four factors (FIB‐4) in a training set (606 patients) and a validation set (216 patients) from the same patient catchment area. Results Of 606 CHB patients in the training set, 33.2% had significant fibrosis and 11.4% had cirrhosis. In multivariable analysis, gamma‐glutamyl transpeptidase (GGT) (OR=1.032, p<0.001) and albumin (OR=0.953, p=0.048) were independent predictors of significant fibrosis. Consequently, a GGT‐to‐albumin ratio (GAR) was developed. In the training set, the area under the receiver operating characteristic curve (AUROC) of GAR was significantly higher than that of APRI and FIB‐4 to predict ≥F2 (0.82, 0.70, and 0.68, respectively), ≥F3 (0.86, 0.76, and 0.75, respectively), and F4 (0.88, 0.75, and 0.73, respectively), respectively. In the validation set, the AUROC of GAR was also better than APRI and FIB‐4 for predicting ≥F2 (0.81, 0.63 and 0.61, respectively), ≥F3 (0.88, 0.78, and 0.76, respectively) and F4 (0.92, 0.85, and 0.78, respectively), respectively. Conclusions GAR is a more accurate noninvasive index than APRI and FIB‐4 to stage significant fibrosis and cirrhosis in CHB patients and represents a novel noninvasive alternative to liver biopsy.     

Diagnostic potential of serum direct markers and non‐invasive fibrosis models in patients with chronic hepatitis B

Aim: Liver biopsy is recommended in the majority of patients with chronic viral hepatitis for fibrosis evaluation. Because of the disadvantages of liver biopsy, many studies related to non‐invasive biomarkers and scores have been performed. In this study, we aimed to assess the diagnostic value of serum direct markers and non‐invasive fibrosis models to predict liver fibrosis in the treatment‐naive chronic hepatitis B (CHB) patients and to compare their diagnostic performance. Methods: This study included 58 patients with a diagnosis of CHB virus infection and 30 healthy controls. Hyaluronic acid, tissue inhibitor of matrix metalloproteinase 1 and amino‐terminal propeptide of type III procollagen were measured by enzyme‐linked immunosorbent assay; and the Original European Liver Fibrosis panel, the Enhanced Liver Fibrosis (ELF) panel, PP score, aspartate aminotransferase to platelet ratio index (APRI) and FIB‐4 indexes were calculated using the formulas taken from previous publications. Fibrosis stage was determined using Ishak's scoring system. Results: The fibrosis stages identified upon liver biopsy was F0 in 12 patients (20.7%), F1–2 in 36 (62.1%) and F3–5 in 10 (17.2%). The diagnostic value of all the non‐invasive indices was low to detect mild fibrosis. We demonstrated that the diagnostic accuracy of HA is the best for predicting fibrosis of F3 or more (area under the receiver–operator curve, 0.902). In our study, the results from a combination of tests showed that ELF and APRI had the highest diagnostic value sensitivity of 90%, specificity of 100%, positive predictive value of 100% and negative predictive value of 96.4% for detection of fibrosis of F3 or more. Conclusion: In CHB patients, combination of ELF and APRI has a better diagnostic value in predicting fibrosis of F3 or more.