多指标联合无创诊断代偿性乙肝肝硬化临床研究
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摘要
1.研究背景:
慢性乙肝病毒(Hepatitis B virus,HBV)感染可引起各种类型的肝脏病变,最终可逐渐进展为终末期肝病:失代偿性肝病和肝细胞癌。代偿性肝硬化与失代偿性肝硬化预后有明显差别,前者5年病死率近20%,10年累积生存率70%,而失代偿性肝硬化5年生存率仅约半数,有报道甚至只有35%。核营(酸)类似药物在用于乙肝相关的慢性肝病抗病毒治疗使乙肝肝硬化逆转成为可能,及时发现代偿性肝硬化并采取有效抗病毒治疗,对提高慢性肝炎病人生存质量有重要的现实意义。
肝活检能准确反映慢性肝炎组织病变和纤维化程度,迄今仍被视为诊断代偿性肝硬化的“金标准”,但肝活检为有创性检查,同时肝活检诊断肝硬化不可避免存在因取样误差而导致一定程度假阴性率。此外,病理学诊断存在不尽一致的现象。近年,随着核苷类药物抗病毒治疗对肝纤维化的逆转作用日益显著,迫切需要寻求具有可重复性、适应临床需要的无创性肝硬化诊断方法,以减少肝活检操作。
迄今已有肝纤维化指标透明质酸及其它多指标联合诊断模型研究用于代偿性肝硬化诊断,这些模型包括PAG指数、Forns指数、APRI指数、FibroTest以及DS评分等系统。然而,上述模型的提出多数基于诊断慢性丙型肝炎(ChronicHepatitis C,CHC)或酒精性肝病肝纤维化而提出,较少涉及CHB应用。CHB发病机制及病理学特点与CHC有本质区别,对肝纤维化的诊断以区别显著肝纤维化或肝硬化为主要研究目标,基于CHC、酒精性肝病而提出的诊断模型是否适用于CHB仍有待进一步研究确认。此外,近年欧洲、日本兴起的FibroScan在肝纤维化中的应用研究为CHB肝纤维化诊断提供了另一选择。
本研究目的在于结合现有研究成果,充分利用研究者所在单位大量肝活检病例优势,基于CHB治疗需要而构建无创诊断代偿性肝硬化模型,应用这些无创诊断模型可使大多数慢性乙肝病人明确是否存在肝硬化状态而避免不必要肝活检,而少数未能明确肝硬化状态的病人仍需肝活检检查。
2.病人与方法:
表1纳入研究的1051例慢性乙型肝炎病人检验、检查情况
1051例来自本院传染病科1998年8月至今的CHB病人纳入研究,所有病人均接受肝活检,按Child-Turcotte-Pugh评分系统确定为肝功能A级,血清乙肝表面抗原阳性6个月以上,并排除其它肝炎病毒感染、酒精性肝病、药物性肝损害、自身免疫性肝病、代谢性肝病及血液系统和胆道疾病。检验、检查指标包括:1)肝炎常规血液指标:白细胞、血小板、血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、AST/ALT比值、白蛋白、球蛋白、蛋白A/G比值、总胆红素、直接胆红素、胆汁酸、碱性磷酸酶、γ-谷氨酰转肽酶、胆碱酯酶、凝血酶原时间和甲胎蛋白;2)肝纤维化血清指标(放射免疫法测定):透明质酸、层粘蛋白、Ⅳ型胶原及Ⅲ型前胶原;3)空腹超声波检查指标:肝脏包膜光滑度、肝实质回声均匀度、肝内血管走行、胆囊壁状态、脾脏厚度及肋下长度、门静脉主干内径;4)瞬时弹性波(FibroScan(R))扫描。具体检验、检查指标实施时间段见表1.
肝活检采用经皮肝脏穿刺活组织检查术(1秒法),要求组织长度1cm以上,包含5个或以上完整汇管区,炎症分级参照2000年《病毒性肝炎防治方案》,按“METAVIR评分系统”确定肝组织纤维化分期诊断。
肝纤维化指标与肝纤维化分期相关性应用Spearman等级相关分析及偏相关分析;计量资料以均数±标准差表示,计量资料均数比较采用t检验或方差分析(两两比较采用LSD或Dunnett T3法);等级资料或符号资料比较采用非参数统计H检验(Kruskal-Wallis Test)或U检验(Mann-Whitney Test);多指标模型采用Logistic逐步回归分析;统计学显著性确定为双侧检验、P值低于0.05为差异显著性;所有统计分析采用SPSS15.0软件。
3.研究结果:
3.1肝纤维化血清指标透明质酸与肝炎常规血液指标
肝纤维化分期与透明质酸、Ⅲ型前胶原、层粘蛋白等级相关系数分别为0.596、0.357及0.264(P值均为0.000),与Ⅳ型胶原相关性无统计学意义,偏相关分析控制炎症、纤维化影响后,透明质酸与纤维化分期相关(r=0.298,P=0.000),Ⅲ型前胶原与炎症分级有关(r=0.212,P=0.000)。方差分析提示肝硬化病人透明质酸水平高于纤维化分期F3(P=0.000),其他指标均无统计学意义。上述指标的ROC曲线下面积(AUC)分别为0.846、0.646、0.513(P=0.793)及0.705。Logistic回归分析只有透明质酸参与模型组成,临界值120ug/L诊断肝硬化的灵敏度83.3%,特异度71%;临界值94ug/L的阴性预测值(NPV)93.7%,220ug/L的阳性预测值(PPV)77.8%,轻度纤维化病人8.3%,联合应用排除、确定临界值,透明质酸可望使68%病人免于肝活检。
肝硬化及非肝硬化病人有统计学差异的常规血液指标包括年龄、血小板、血清AST/ALT、血清蛋白、直接胆红素、凝血酶原时间,Logistic回归分析提出血小板与透明质酸联合诊断肝硬化,AUC 0.888,模型指数-1.76的肝硬化NPV 98%,-0.12的肝硬化PPV 74.4%,轻度纤维化5.1%,联合应用上述两个指数临界值可使约73%病人免除肝活检。
3.2肝炎常规血液指标与超声波评分
偏相关分析控制炎症影响后,血小板、AST/ALT比值、白蛋白、胆红素、胆汁酸、凝血酶原时间、白细胞等指标与肝纤维化分期相关性有统计学意义,其偏相关系数依次降低(r值0.292-0.109);除碱性磷酸酶外,肝硬化及非肝硬化病人常见血液指标均有统计学差异,单一指标诊断肝硬化的AUC均超过0.5,淘汰缺失资料超过20%的胆汁酸、胆碱酯酶、甲胎蛋白,Logistic回归分析提出血小板、胆红素、蛋白A/G参与诊断模型组合,模型拟合度检验P值0.921,诊断AUC 0.876,模型指数-1.83的肝硬化NPV 97.0%;0.40的肝硬化PPV 76%,轻度纤维化仅2%,联合应用上述两个指数临界值,模型可使超过60%病人免除肝活检。
在超声波检查中,不同肝纤维化分期的肝实质、肝内血管形态、脾脏大小、胆囊壁形态超声波评分均有统计学差异,上述四项指标的积分与肝纤维化分期的等级相关系数达到0.461,而肝包膜表现及门静脉主干内径则无差异。应用超声波积分诊断肝硬化的AUC 0.793。正常超声波表现的肝硬化NPV 93.7%,评分9分的肝硬化PPV 76%,轻度纤维化仅13.6%,联合应用排除、诊断临界值,50%病人可免除肝活检。
联合血液指标与超声波诊断肝硬化,提示病人年龄、PLT、超声波评分、胆红素、白蛋白参与诊断模型组合,模型拟合度检验P值0.854,模型指数与肝纤维化等级相关系数达到0.637,诊断肝硬化AUC 0.907,模型指数-2.18肝硬化NPV 97.4%,0.24的肝硬化PPV84.3%,轻度纤维化仅2.9%,联合应用排除、诊断临界值,70%病人免除肝活检。验证组具有类似排除诊断能力,但确定诊断能力下降。
3.3 FibroScan(FS)与肝炎常规血液指标、超声波评分
FS弹性值与肝组织炎症的等级相关系数及偏相关系数分别为0.689(P=0.000)及0.127(P=0.080),与纤维化分期的等级相关系数及偏相关系数分别为0.702(P=0.000)及0.374(P=0.000),表明FS弹性值主要与肝纤维化分期有关。不同肝纤维化分期之间的FS弹性值均有统计学差异,应用FS诊断肝硬化的AUC达到0.911,弹性值13.5KPa可取得最大诊断灵敏度与特异度之和,且NPV达到97.1%,非肝硬化检出率84.2%,弹性值21.8KPa诊断肝硬化PPV66.7%,误诊病例轻度纤维化病人接近0;两者可使85%病人免除肝活检,并可使78%病人得到正确诊断。
Logistic回归分析表明肝炎常规检验指标中只有血小板联合FS弹性值诊断肝硬化,模型拟合度检验P值0.756,诊断肝硬化AUC 0.912,对应FS诊断AUC0.913,其肝活检免除率80%,正确诊断率72.8%,均低于单一FS弹性值诊断;当加入肝纤维化指标血清透明质酸参与Logistic回归分析后,诊断模型只有FS单一指标。
4.讨论与结论:
目前慢性乙型肝炎临床常见辅助检查指标中大多数指标与肝纤维化分期有一定程度相关性。这些指标包括:1.病人年龄;2.血清透明质酸、Ⅲ型前胶原和Ⅳ型胶原;3.血液白细胞、血小板、AST、AST/ALT比值、白蛋白、球蛋白、蛋白A/G比值、胆红素、直接胆红素、胆汁酸、凝血酶原时间;4.超声波检查指标及FS弹性值。
上述指标中最终参与模型构建的指标包括病人年龄、血小板、透明质酸、胆红素、白蛋白、蛋白A/G、肝胆脾超声波指标(包括肝包膜、肝实质回声、肝内血管形态、胆囊炎症及脾脏大小)及FS弹性值,而血小板更是参与所有多指标模型构建。这些指标参与代偿性乙肝肝硬化诊断模型的构建有其合理性:1.病人年龄体现慢性肝病病程积累,是肝炎活动导致肝纤维化进展的时间体现;2.血小板减少反映了慢性肝脏破坏、纤维化形成造成门脉系统压力的升高,从而促进脾脏肿大,同时也源于乙肝病毒慢性感染对骨髓造血功能的抑制作用;3.血清白蛋白及胆红素均为肝功能Child-Turcotte-Pugh等级评价指标,前者反映肝脏合成功能,其减少提示肝功能状态下降,后者升高反映肝脏合成、排泄功能受损,都是肝脏受损、纤维化进展的体现;而蛋白A/G降低所体现的白蛋白相对减少与球蛋白升高更直接反映肝脏合成功能下降、炎症活跃程度增加;4.肝胆脾超声波检查改变是肝纤维化发展的直接后果;5.透明质酸作为肝纤维化血清指标应用由来已久;6.超声瞬时弹性(FS)扫描通过测定组织弹性而推测肝纤维化的存在,FS弹性值越高,肝纤维化程度越重。
Logistic回归分析最终构建以下诊断代偿性乙肝肝硬化模型:血液指标组合(包括血小板、胆红素及蛋白A/G比值)、血液多指标联合超声波系统(包括年龄、超声波评分、血小板、胆红素、白蛋白)、血小板联合透明质酸、血小板联合FS弹性值。构建这些诊断模型的临床意义在于:应用排除、确定诊断临界值明确大多数病人有无肝硬化存在而避免不必要肝活检,少数未能明确肝硬化状态的病人仍需借助肝活检诊断。
表2不同诊断模犁诊断代偿性乙肝肝硬化诊断价值比较
血液指标、透明质酸联合血小板、血液指标联合超声波评分及FS弹性值、FS弹性值联合血小板五种模型排除肝硬化的阴性预测值等于或高于97%,确定肝硬化诊断的病人中轻度纤维化比例低于5%,误诊病人主要为纤维化F3期病人,具有肝硬化发展趋势,因而可忽略(表2)。此外,FS弹性值联合血小板模型误诊病人中无轻度纤维化病例,其准确性更高。联合应用排除诊断及确定诊断临界值,五种模型的肝活检免除率分别为61.3%、73%、71.5%、84.4%、79.3%,提示FS弹性值单指标或联合血小板模型在代偿性乙肝肝硬化无创诊断中具有最好的应用前景;在缺乏FibroScan~(R)情况下,透明质酸联合血小板、血液指标联合超声波仍将发挥重要作用。
Background:
In patients with chronic hepatitis B(CHB),cirrhosis is the late stage in the long course of liver fibrosis,which is directly related to the chronic liver damage.The disease prognosis was significantly different between patients with compensated and decompensated cirrhosis.While patients with compensated cirrhosis owned a ten-year accumulated survival rate of 70%,with nearly 20%five-year mortality,patients' five-year survival rate in decompensated cirrhosis were only about one half,and even low to 35%.Anti-viral therapy of nucleot(s)ide analogues such as lamivudine, entecavir and telbivudine made it possible for us to reverse hepatitis B related fibrosis/cirrhosis.Being of great importance for improving patients' survival rate and quality of life,we should detect compensated cirrhosis as early as possible and take effective anti-virus therapy.Accurately determining the hepatic histological damages, liver biopsy is still considered as gold standard for assessing grade and stage of liver diseases.However,liver biopsy is an invasive method,and also yield false-negative results in nearly one-third of cases.Furthermore,liver biopsy is also limited by sampling error and inter-observer variability.As the role of reversing hepatic fibrosis of nucleot(s)ide analogue therapy becoming more and more obvious,it is necessary to explore non-invasive and reproducible alternative methods for detecting cirrhosis and evaluating anti-virus effect.
Several models for significant fibrosis or cirrhosis had been introduced for hepatitis C,such as fibrosis marker of hyaluronic acid and other multiple variables models, including PGA,Forns,APRI,FibroTest and DS score.Among them,the application of Fibro Test had been reported in several validating study.However,these models were established mainly for hepatic fibrosis of hepatitis C and alcoholic liver diseases, but seldom for hepatitis B.As the pathogenesis and pathology of CHB were virtually different from hepatitis C,which study emphasis should be severe fibrosis and cirrhosis,model for hepatitis C may not be suitable for CHB.In recent years, FibroScan study was popular in Europe and Japan,which was another alternative method for detecting hepatic fibrosis in patients with chronic liver diseases.
Relying on reported studies about non-invasive diagnosis for hepatic fibrosis or cirrhosis,and also large cohort of liver biopsied patients in our Hepatology Unit,our objective of present study was to construct a non-invasive model for detecting compensated cirrhosis in patients with CHB.With this model,most of the CHB patients would be determined as absence or presence of cirrhosis and then be free from liver biopsy.Of course,minority of patients still can not be accurately identified, which still need biopsy to determine the state of cirrhosis.
Patients and Methods: Table 1 Total of 1051 patients with chronic hepatitis B included in study
Total of 1051 patients with CHB of in Department of Infectious Disease of our hospital from AUG 1998 were analyzed(Table 1).All patients had been undergone percutaneous liver biopsies,and positive for serum HBsAg more than 6 months,these patients were compensated for liver function,characterized as Child-Turcotte-Pugh A grade.Exclusion criteria included autoimmune liver disease,evidence of alcoholic or fatty liver disease;drug induced hepatic injury,metabolic disease,combined positive for other hepatitis virus markers and other spleen,and gallbladder related diseases.
Blood tests were performed within one week of liver biopsy,which including hematology,10 serum biochemical indexes,coagulations index and serum alpha fetoproteins(AFP).Patients' age were also recorded.Patients between AUG 1998 and DEC 2001 and patients after OCT 2007 were also detected fibrosis serum markers of hyaluronic acid(HA),laminin,typeⅣof collagen and typeⅢof precollagen(detected by radio-immunity assay).
Ultrasound(US) examination was performed in patients after JAN 2003.The ultrasonic assessment of liver surface,liver parenchyma,gallbladder,hepatic vessel, splenomegaly and diameter of main portal vein were recorded.
Patients after JUN 2007 were received FibroScan scanning in 191 patients.
Blood tests and Imageological Examination analyzed in different periods were listed in Table 1 in detail.
Liver biopsy specimens were obtained using a 16 gauge Menghini biopsy needle, and at least 1.0 centimeter long,each containing at least 5 portal tracts.The fibrosis score of portal tract was graded by METAVIR scoring system.
Spearman's rho rank correlation and partial correlation analysis were used to evaluate correlation between liver inflammation and fibrosis.Continuous variables were expressed as mean±SD and compared using one-way ANOVA or student's t test.Ranked or symbol data were compared with Kruskal-Wallis' H test or Mann-Whitney U Test.For the formulation of predictive model,Logistic stepwise regression analysis was performed.The diagnostic value of formula was assessed by AUC.A two-sided P value of less than 0.05 was considered statistically significant. Statistical analysis was performed by SPSS software version 15.0.
Results:
1.Fibrosis Serum markers and routine blood test indexes.
The rank correlation coefficient between hepatic fibrosis and serum HA,typeⅢprecollagen and laminin was 0.596、0.357 and 0.264,respectively(P=0.000).The correlation between fibrosis and typeⅣof collagen was not statistically significant. While controlling of liver inflammation and fibrosis,serum HA was correlated with hepatic fibrosis stages(r=0.298,P=0.000),and typeⅢprecollagen was correlated with inflammation grades(r=0.212,P=0.000).Among fibrosis markers in patients with cirrhosis,only serum level of HA was significantly higher than other fibrosis stages.AUC of HA for diagnosing cirrhosis was 0.846,which was higher than other fibrosis markers(0.646,0.513,0.705 for typeⅢofprecollagen,laminin and typeⅣof collagen in the same order).Diagnostic sensitivity and specificity of HA 120μg for determining cirrhosis was 83.3%and 71%.HA 94μg for excluding cirrhosis owned a negative predictive value(NPV) 93.7%and 220μg for determining cirrhosis with positive predictive value(PPV) 77.8%,and only 8.3%patients with mild fibrosis were found in cirrhosis determined patients.With excluding and determining cut-off value,serum HA would free 68%patients from biopsy.
Patients' ages,platelet,ratio of AST/ALT,serum protein,serum direct bilirubin and prothrombin time were different between patients with and without cirrhosis.While incorporated with routine blood tests,hyaluronic acid and platelet were included to identify cirrhosis,with AUC of 0.888.With excluding model index of-1.76,NPV for cirrhosis was 98%,and PPV 74.4%for determining index -0.12,with mild fibrosis rate of 5.1%.With these two cut-off values,model consisting of hyaluronic acid and platelet would free 78%patients from biopsy.
2.Routine blood tests for hepatitis and US score system.
While inflammation controlled by partial correlation analysis,blood indexes of platelet,ratio of AST/ALT,albumin,bilirubin,bile acid,prothrombin time and white blood were correlated with fibrosis stages with descending order(r varied between 0.292 and 0.109).Apart from alkaline phosphatase,routine blood indexes in patients with cirrhosis were significantly different from other fibrosis stages.As more than 20%of data missed,indexes of bile acid,cholinesterase and AFP were excluded from logistic analysis.Model for cirrhosis diagnosis consists of platelet,bilirubin and protein ratio of albumin and globulin,with AUC 0.876.P value of Hosmer and Lemeshow test for model was 0.921.With model index-1.83,NPV for cirrhosis was 97.0%,and PPV 76%for determining index 0.4,with mild fibrosis rate of 2%.Used with these two cut-off values,model would free about 60%patient from biopsy.
In US score system,there were significantly differences between fibrosis stages and ultrasonic indexes of liver parenchyma,gallbladder,hepatic vessel and splenomegaly.Ultrasonic scores were significantly different between F4 and other fibrosis,and significantly correlated with fibrosis stages(rho=0.461).Used with excluding and determining value,US score would free 50%patient from biopsy,with AUC 0.793.NPV of cirrhosis for normal ultrasound images of liver,spleen and gallbladder was 93.6%.Score of 9 determined cirrhosis with PPV 76%,with mild fibrosis rate 13.6%.
If routine blood tests and US score combined used for identifying cirrhosis,model for cirrhosis consists of patients' age,blood platelet,US score,serum albumin and bilirubin,with AUC of 0.907.P value of Hosmer and Lemeshow test for model was 0.854.The cirrhosis index was correlated with fibrosis stages with coefficient of 0.637.Model would free 70%patients from biopsy,with NPV 97.4%for excuding index-2.18 and PPV 84.3%for diagnosing index 0.24,and mild fibrosis in cirrhosis diagnosed patients was only 2.9%.Model in validation set showed similar excluding but lower determining ability.
3.FibroScan scanning and blood test,ultrasounds score system.
The rank correlation and partial correlation coefficient between inflammation and liver stiffness were 0.689(P=0.000) and 0.127(P=0.080),respectively.The same coefficient of hepatic fibrosis and liver stiffness were 0.702(P=0.000) and 0.374 (P=0.000),respectively.These coefficients showed that liver stiffness was correlated mainly with hepatic fibrosis.Liver stiffness was significantly different between fibrosis stages,with AUC 0.911 for identifying compensated cirrhosis.Liver stiffness 13.5KPa owned a maximal cumulant of sensitivity and specificity,with NPV 97.1%. With this cut-off value,84.2%of non-cirrhosis patients were detected.While liver stiffness up to 21.8KPa,PPV for cirrhosis was 66.7%,with nearly 0 of mild fibrosis. With absence and presence of cirrhosis cut-off value,FibroScan would free 85% patients from biopsy,and 78%patients were identified correctly.
Multi-variable Logistic regression analysis showed that compensated cirrhosis diagnosed model consisted of platelet and FibroScan liver stiffness,with AUC 0.912, and corresponding FibroScan AUC for cirrhosis was 0.913.With this model,the biopsy free rate was 80%and 72.8%patients would be correctly determined. Forthermore,mild fibrosis was 0 in the cirrhosis diagnosed patients.In 70 patients' FibroScan,routine serum tests and serum hyaluronic acid,FibroScan was the only variable for diagnosing cirrhosis.
Discussion and Conclusion:
In present study for patients with CHB,majority of routine blood tests for hepatitis were correlated with hepatic fibrosis stages.These variables included four type of indexes:demography of age,fibrosis markers of serum hyaluronic acid,typeⅢof precollagen and typeⅣof collagen,routine blood tests of white blood cell,platelet, AST,ALT,AST/ALT ratio,albumin,globulin,protein A/G ratio,bilirubin,direct bilirubin,bile acid and prothrombin time,and imageology of ultrasound and FibroScan liver stiffness.
Patients' age,blood platelet,serum hyaluronic acid,albumin,protein A/G ratio, bilirubin,US indexes of liver,spleen and gallbladder and FibroScan liver stiffness were involved in cirrhosis diagnosis model construction.Furthermore,platelet was invoved in all multi-indexes models.Patients' age suggested the history of hepatitis activity,which would result in liver fibrosis progress.Thrombocytopenia in liver cirrhosis may be partially due to the accumulation and destruction of platelet in the portal hypertensive-enlarged spleen resulting from progressive liver fibrosis,and partially due to the impaired production of thrombopoietin in the cirrhotic liver. Serum albumin and bilirubin were the indexes in Child-Turcotte-Pugh score for liver function evaluation.Hypoalbuminemia and hyperbilirubinemia were both indication of impaired liver function resulted from continuous fibrosis.They were acceptable and diagnostic biochemical features of liver cirrhosis.Serum hyaluronic acid used as fibrosis marker was a custom practice in clinical work for years.US was also a common examination for detecting cirrhosis.Ultimately,FibroScan detected hepatic fibrosis by determining live stiffness,which was positively correlated with fibrosis stages.
Regression analysis ultimately constructed several models for diagnosing compensated cirrhosis,including blood indexes(platelet,bilirubin and protein A/G ratio),combination of blood indexes and ultrasound(including patients' age, ultrasound score,platelet,bilirubin and albumin),platelet incorporated with hyaluronic acid and platelet plus FibroScan.The clinical significance of these diagnosing models was that most of patients with CHB would free from biopsies due to being identified as absence or presence of cirrhosis by excluding and determining cut-off value,while others were still needed biopsies to confirm the state of cirrhosis.
Model of blood indexes,hyaluronic acid plus platelet,combination of blood indexes and US,FibroScan,FibroScan plus platelet were of more applicable value, with NPV more than 97.0%in cirrhosis excluded and mild fibrosis rate less than 5% in cirrhosis determined patients.By these model,the misdiagnosis patients were majority sever fibrosis(which would progressed to cirrhosis without anti-virus treatment),and thus can be ignored(table 2).Furthermore,there was no mild fibrosis in misdiagnosis patients identified by model consisted of platelet and FibroScan.The biopsy free rate of these model diagnosing compensated cirrhosis were 61.3%,73%, 71.5%,84.4%and 79.3%in the same order.
Table 2 Evaluation of diagnostic value for compensated cirrhosis diagnosis by several model
Present study indicated that model consisted by FibroScan single index or combined with platelet be of more applicable value in the non-invasive diagnosis of compensated hepatitis B related cirrhosis.Without FibroScan,hyaluronic acid plus platelet,blood indexes combined with US score would still play important role in non-invasive identification of compensated cirrhosis resulted from HBV infection.
慢性乙肝病毒(Hepatitis B virus,HBV)感染可引起各种类型的肝脏病变,最终可逐渐进展为终末期肝病:失代偿性肝病和肝细胞癌。代偿性肝硬化与失代偿性肝硬化预后有明显差别,前者5年病死率近20%,10年累积生存率70%,而失代偿性肝硬化5年生存率仅约半数,有报道甚至只有35%。核营(酸)类似药物在用于乙肝相关的慢性肝病抗病毒治疗使乙肝肝硬化逆转成为可能,及时发现代偿性肝硬化并采取有效抗病毒治疗,对提高慢性肝炎病人生存质量有重要的现实意义。
肝活检能准确反映慢性肝炎组织病变和纤维化程度,迄今仍被视为诊断代偿性肝硬化的“金标准”,但肝活检为有创性检查,同时肝活检诊断肝硬化不可避免存在因取样误差而导致一定程度假阴性率。此外,病理学诊断存在不尽一致的现象。近年,随着核苷类药物抗病毒治疗对肝纤维化的逆转作用日益显著,迫切需要寻求具有可重复性、适应临床需要的无创性肝硬化诊断方法,以减少肝活检操作。
迄今已有肝纤维化指标透明质酸及其它多指标联合诊断模型研究用于代偿性肝硬化诊断,这些模型包括PAG指数、Forns指数、APRI指数、FibroTest以及DS评分等系统。然而,上述模型的提出多数基于诊断慢性丙型肝炎(ChronicHepatitis C,CHC)或酒精性肝病肝纤维化而提出,较少涉及CHB应用。CHB发病机制及病理学特点与CHC有本质区别,对肝纤维化的诊断以区别显著肝纤维化或肝硬化为主要研究目标,基于CHC、酒精性肝病而提出的诊断模型是否适用于CHB仍有待进一步研究确认。此外,近年欧洲、日本兴起的FibroScan在肝纤维化中的应用研究为CHB肝纤维化诊断提供了另一选择。
本研究目的在于结合现有研究成果,充分利用研究者所在单位大量肝活检病例优势,基于CHB治疗需要而构建无创诊断代偿性肝硬化模型,应用这些无创诊断模型可使大多数慢性乙肝病人明确是否存在肝硬化状态而避免不必要肝活检,而少数未能明确肝硬化状态的病人仍需肝活检检查。
2.病人与方法:
表1纳入研究的1051例慢性乙型肝炎病人检验、检查情况
1051例来自本院传染病科1998年8月至今的CHB病人纳入研究,所有病人均接受肝活检,按Child-Turcotte-Pugh评分系统确定为肝功能A级,血清乙肝表面抗原阳性6个月以上,并排除其它肝炎病毒感染、酒精性肝病、药物性肝损害、自身免疫性肝病、代谢性肝病及血液系统和胆道疾病。检验、检查指标包括:1)肝炎常规血液指标:白细胞、血小板、血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、AST/ALT比值、白蛋白、球蛋白、蛋白A/G比值、总胆红素、直接胆红素、胆汁酸、碱性磷酸酶、γ-谷氨酰转肽酶、胆碱酯酶、凝血酶原时间和甲胎蛋白;2)肝纤维化血清指标(放射免疫法测定):透明质酸、层粘蛋白、Ⅳ型胶原及Ⅲ型前胶原;3)空腹超声波检查指标:肝脏包膜光滑度、肝实质回声均匀度、肝内血管走行、胆囊壁状态、脾脏厚度及肋下长度、门静脉主干内径;4)瞬时弹性波(FibroScan(R))扫描。具体检验、检查指标实施时间段见表1.
肝活检采用经皮肝脏穿刺活组织检查术(1秒法),要求组织长度1cm以上,包含5个或以上完整汇管区,炎症分级参照2000年《病毒性肝炎防治方案》,按“METAVIR评分系统”确定肝组织纤维化分期诊断。
肝纤维化指标与肝纤维化分期相关性应用Spearman等级相关分析及偏相关分析;计量资料以均数±标准差表示,计量资料均数比较采用t检验或方差分析(两两比较采用LSD或Dunnett T3法);等级资料或符号资料比较采用非参数统计H检验(Kruskal-Wallis Test)或U检验(Mann-Whitney Test);多指标模型采用Logistic逐步回归分析;统计学显著性确定为双侧检验、P值低于0.05为差异显著性;所有统计分析采用SPSS15.0软件。
3.研究结果:
3.1肝纤维化血清指标透明质酸与肝炎常规血液指标
肝纤维化分期与透明质酸、Ⅲ型前胶原、层粘蛋白等级相关系数分别为0.596、0.357及0.264(P值均为0.000),与Ⅳ型胶原相关性无统计学意义,偏相关分析控制炎症、纤维化影响后,透明质酸与纤维化分期相关(r=0.298,P=0.000),Ⅲ型前胶原与炎症分级有关(r=0.212,P=0.000)。方差分析提示肝硬化病人透明质酸水平高于纤维化分期F3(P=0.000),其他指标均无统计学意义。上述指标的ROC曲线下面积(AUC)分别为0.846、0.646、0.513(P=0.793)及0.705。Logistic回归分析只有透明质酸参与模型组成,临界值120ug/L诊断肝硬化的灵敏度83.3%,特异度71%;临界值94ug/L的阴性预测值(NPV)93.7%,220ug/L的阳性预测值(PPV)77.8%,轻度纤维化病人8.3%,联合应用排除、确定临界值,透明质酸可望使68%病人免于肝活检。
肝硬化及非肝硬化病人有统计学差异的常规血液指标包括年龄、血小板、血清AST/ALT、血清蛋白、直接胆红素、凝血酶原时间,Logistic回归分析提出血小板与透明质酸联合诊断肝硬化,AUC 0.888,模型指数-1.76的肝硬化NPV 98%,-0.12的肝硬化PPV 74.4%,轻度纤维化5.1%,联合应用上述两个指数临界值可使约73%病人免除肝活检。
3.2肝炎常规血液指标与超声波评分
偏相关分析控制炎症影响后,血小板、AST/ALT比值、白蛋白、胆红素、胆汁酸、凝血酶原时间、白细胞等指标与肝纤维化分期相关性有统计学意义,其偏相关系数依次降低(r值0.292-0.109);除碱性磷酸酶外,肝硬化及非肝硬化病人常见血液指标均有统计学差异,单一指标诊断肝硬化的AUC均超过0.5,淘汰缺失资料超过20%的胆汁酸、胆碱酯酶、甲胎蛋白,Logistic回归分析提出血小板、胆红素、蛋白A/G参与诊断模型组合,模型拟合度检验P值0.921,诊断AUC 0.876,模型指数-1.83的肝硬化NPV 97.0%;0.40的肝硬化PPV 76%,轻度纤维化仅2%,联合应用上述两个指数临界值,模型可使超过60%病人免除肝活检。
在超声波检查中,不同肝纤维化分期的肝实质、肝内血管形态、脾脏大小、胆囊壁形态超声波评分均有统计学差异,上述四项指标的积分与肝纤维化分期的等级相关系数达到0.461,而肝包膜表现及门静脉主干内径则无差异。应用超声波积分诊断肝硬化的AUC 0.793。正常超声波表现的肝硬化NPV 93.7%,评分9分的肝硬化PPV 76%,轻度纤维化仅13.6%,联合应用排除、诊断临界值,50%病人可免除肝活检。
联合血液指标与超声波诊断肝硬化,提示病人年龄、PLT、超声波评分、胆红素、白蛋白参与诊断模型组合,模型拟合度检验P值0.854,模型指数与肝纤维化等级相关系数达到0.637,诊断肝硬化AUC 0.907,模型指数-2.18肝硬化NPV 97.4%,0.24的肝硬化PPV84.3%,轻度纤维化仅2.9%,联合应用排除、诊断临界值,70%病人免除肝活检。验证组具有类似排除诊断能力,但确定诊断能力下降。
3.3 FibroScan(FS)与肝炎常规血液指标、超声波评分
FS弹性值与肝组织炎症的等级相关系数及偏相关系数分别为0.689(P=0.000)及0.127(P=0.080),与纤维化分期的等级相关系数及偏相关系数分别为0.702(P=0.000)及0.374(P=0.000),表明FS弹性值主要与肝纤维化分期有关。不同肝纤维化分期之间的FS弹性值均有统计学差异,应用FS诊断肝硬化的AUC达到0.911,弹性值13.5KPa可取得最大诊断灵敏度与特异度之和,且NPV达到97.1%,非肝硬化检出率84.2%,弹性值21.8KPa诊断肝硬化PPV66.7%,误诊病例轻度纤维化病人接近0;两者可使85%病人免除肝活检,并可使78%病人得到正确诊断。
Logistic回归分析表明肝炎常规检验指标中只有血小板联合FS弹性值诊断肝硬化,模型拟合度检验P值0.756,诊断肝硬化AUC 0.912,对应FS诊断AUC0.913,其肝活检免除率80%,正确诊断率72.8%,均低于单一FS弹性值诊断;当加入肝纤维化指标血清透明质酸参与Logistic回归分析后,诊断模型只有FS单一指标。
4.讨论与结论:
目前慢性乙型肝炎临床常见辅助检查指标中大多数指标与肝纤维化分期有一定程度相关性。这些指标包括:1.病人年龄;2.血清透明质酸、Ⅲ型前胶原和Ⅳ型胶原;3.血液白细胞、血小板、AST、AST/ALT比值、白蛋白、球蛋白、蛋白A/G比值、胆红素、直接胆红素、胆汁酸、凝血酶原时间;4.超声波检查指标及FS弹性值。
上述指标中最终参与模型构建的指标包括病人年龄、血小板、透明质酸、胆红素、白蛋白、蛋白A/G、肝胆脾超声波指标(包括肝包膜、肝实质回声、肝内血管形态、胆囊炎症及脾脏大小)及FS弹性值,而血小板更是参与所有多指标模型构建。这些指标参与代偿性乙肝肝硬化诊断模型的构建有其合理性:1.病人年龄体现慢性肝病病程积累,是肝炎活动导致肝纤维化进展的时间体现;2.血小板减少反映了慢性肝脏破坏、纤维化形成造成门脉系统压力的升高,从而促进脾脏肿大,同时也源于乙肝病毒慢性感染对骨髓造血功能的抑制作用;3.血清白蛋白及胆红素均为肝功能Child-Turcotte-Pugh等级评价指标,前者反映肝脏合成功能,其减少提示肝功能状态下降,后者升高反映肝脏合成、排泄功能受损,都是肝脏受损、纤维化进展的体现;而蛋白A/G降低所体现的白蛋白相对减少与球蛋白升高更直接反映肝脏合成功能下降、炎症活跃程度增加;4.肝胆脾超声波检查改变是肝纤维化发展的直接后果;5.透明质酸作为肝纤维化血清指标应用由来已久;6.超声瞬时弹性(FS)扫描通过测定组织弹性而推测肝纤维化的存在,FS弹性值越高,肝纤维化程度越重。
Logistic回归分析最终构建以下诊断代偿性乙肝肝硬化模型:血液指标组合(包括血小板、胆红素及蛋白A/G比值)、血液多指标联合超声波系统(包括年龄、超声波评分、血小板、胆红素、白蛋白)、血小板联合透明质酸、血小板联合FS弹性值。构建这些诊断模型的临床意义在于:应用排除、确定诊断临界值明确大多数病人有无肝硬化存在而避免不必要肝活检,少数未能明确肝硬化状态的病人仍需借助肝活检诊断。
表2不同诊断模犁诊断代偿性乙肝肝硬化诊断价值比较
血液指标、透明质酸联合血小板、血液指标联合超声波评分及FS弹性值、FS弹性值联合血小板五种模型排除肝硬化的阴性预测值等于或高于97%,确定肝硬化诊断的病人中轻度纤维化比例低于5%,误诊病人主要为纤维化F3期病人,具有肝硬化发展趋势,因而可忽略(表2)。此外,FS弹性值联合血小板模型误诊病人中无轻度纤维化病例,其准确性更高。联合应用排除诊断及确定诊断临界值,五种模型的肝活检免除率分别为61.3%、73%、71.5%、84.4%、79.3%,提示FS弹性值单指标或联合血小板模型在代偿性乙肝肝硬化无创诊断中具有最好的应用前景;在缺乏FibroScan~(R)情况下,透明质酸联合血小板、血液指标联合超声波仍将发挥重要作用。
Background:
In patients with chronic hepatitis B(CHB),cirrhosis is the late stage in the long course of liver fibrosis,which is directly related to the chronic liver damage.The disease prognosis was significantly different between patients with compensated and decompensated cirrhosis.While patients with compensated cirrhosis owned a ten-year accumulated survival rate of 70%,with nearly 20%five-year mortality,patients' five-year survival rate in decompensated cirrhosis were only about one half,and even low to 35%.Anti-viral therapy of nucleot(s)ide analogues such as lamivudine, entecavir and telbivudine made it possible for us to reverse hepatitis B related fibrosis/cirrhosis.Being of great importance for improving patients' survival rate and quality of life,we should detect compensated cirrhosis as early as possible and take effective anti-virus therapy.Accurately determining the hepatic histological damages, liver biopsy is still considered as gold standard for assessing grade and stage of liver diseases.However,liver biopsy is an invasive method,and also yield false-negative results in nearly one-third of cases.Furthermore,liver biopsy is also limited by sampling error and inter-observer variability.As the role of reversing hepatic fibrosis of nucleot(s)ide analogue therapy becoming more and more obvious,it is necessary to explore non-invasive and reproducible alternative methods for detecting cirrhosis and evaluating anti-virus effect.
Several models for significant fibrosis or cirrhosis had been introduced for hepatitis C,such as fibrosis marker of hyaluronic acid and other multiple variables models, including PGA,Forns,APRI,FibroTest and DS score.Among them,the application of Fibro Test had been reported in several validating study.However,these models were established mainly for hepatic fibrosis of hepatitis C and alcoholic liver diseases, but seldom for hepatitis B.As the pathogenesis and pathology of CHB were virtually different from hepatitis C,which study emphasis should be severe fibrosis and cirrhosis,model for hepatitis C may not be suitable for CHB.In recent years, FibroScan study was popular in Europe and Japan,which was another alternative method for detecting hepatic fibrosis in patients with chronic liver diseases.
Relying on reported studies about non-invasive diagnosis for hepatic fibrosis or cirrhosis,and also large cohort of liver biopsied patients in our Hepatology Unit,our objective of present study was to construct a non-invasive model for detecting compensated cirrhosis in patients with CHB.With this model,most of the CHB patients would be determined as absence or presence of cirrhosis and then be free from liver biopsy.Of course,minority of patients still can not be accurately identified, which still need biopsy to determine the state of cirrhosis.
Patients and Methods: Table 1 Total of 1051 patients with chronic hepatitis B included in study
Total of 1051 patients with CHB of in Department of Infectious Disease of our hospital from AUG 1998 were analyzed(Table 1).All patients had been undergone percutaneous liver biopsies,and positive for serum HBsAg more than 6 months,these patients were compensated for liver function,characterized as Child-Turcotte-Pugh A grade.Exclusion criteria included autoimmune liver disease,evidence of alcoholic or fatty liver disease;drug induced hepatic injury,metabolic disease,combined positive for other hepatitis virus markers and other spleen,and gallbladder related diseases.
Blood tests were performed within one week of liver biopsy,which including hematology,10 serum biochemical indexes,coagulations index and serum alpha fetoproteins(AFP).Patients' age were also recorded.Patients between AUG 1998 and DEC 2001 and patients after OCT 2007 were also detected fibrosis serum markers of hyaluronic acid(HA),laminin,typeⅣof collagen and typeⅢof precollagen(detected by radio-immunity assay).
Ultrasound(US) examination was performed in patients after JAN 2003.The ultrasonic assessment of liver surface,liver parenchyma,gallbladder,hepatic vessel, splenomegaly and diameter of main portal vein were recorded.
Patients after JUN 2007 were received FibroScan scanning in 191 patients.
Blood tests and Imageological Examination analyzed in different periods were listed in Table 1 in detail.
Liver biopsy specimens were obtained using a 16 gauge Menghini biopsy needle, and at least 1.0 centimeter long,each containing at least 5 portal tracts.The fibrosis score of portal tract was graded by METAVIR scoring system.
Spearman's rho rank correlation and partial correlation analysis were used to evaluate correlation between liver inflammation and fibrosis.Continuous variables were expressed as mean±SD and compared using one-way ANOVA or student's t test.Ranked or symbol data were compared with Kruskal-Wallis' H test or Mann-Whitney U Test.For the formulation of predictive model,Logistic stepwise regression analysis was performed.The diagnostic value of formula was assessed by AUC.A two-sided P value of less than 0.05 was considered statistically significant. Statistical analysis was performed by SPSS software version 15.0.
Results:
1.Fibrosis Serum markers and routine blood test indexes.
The rank correlation coefficient between hepatic fibrosis and serum HA,typeⅢprecollagen and laminin was 0.596、0.357 and 0.264,respectively(P=0.000).The correlation between fibrosis and typeⅣof collagen was not statistically significant. While controlling of liver inflammation and fibrosis,serum HA was correlated with hepatic fibrosis stages(r=0.298,P=0.000),and typeⅢprecollagen was correlated with inflammation grades(r=0.212,P=0.000).Among fibrosis markers in patients with cirrhosis,only serum level of HA was significantly higher than other fibrosis stages.AUC of HA for diagnosing cirrhosis was 0.846,which was higher than other fibrosis markers(0.646,0.513,0.705 for typeⅢofprecollagen,laminin and typeⅣof collagen in the same order).Diagnostic sensitivity and specificity of HA 120μg for determining cirrhosis was 83.3%and 71%.HA 94μg for excluding cirrhosis owned a negative predictive value(NPV) 93.7%and 220μg for determining cirrhosis with positive predictive value(PPV) 77.8%,and only 8.3%patients with mild fibrosis were found in cirrhosis determined patients.With excluding and determining cut-off value,serum HA would free 68%patients from biopsy.
Patients' ages,platelet,ratio of AST/ALT,serum protein,serum direct bilirubin and prothrombin time were different between patients with and without cirrhosis.While incorporated with routine blood tests,hyaluronic acid and platelet were included to identify cirrhosis,with AUC of 0.888.With excluding model index of-1.76,NPV for cirrhosis was 98%,and PPV 74.4%for determining index -0.12,with mild fibrosis rate of 5.1%.With these two cut-off values,model consisting of hyaluronic acid and platelet would free 78%patients from biopsy.
2.Routine blood tests for hepatitis and US score system.
While inflammation controlled by partial correlation analysis,blood indexes of platelet,ratio of AST/ALT,albumin,bilirubin,bile acid,prothrombin time and white blood were correlated with fibrosis stages with descending order(r varied between 0.292 and 0.109).Apart from alkaline phosphatase,routine blood indexes in patients with cirrhosis were significantly different from other fibrosis stages.As more than 20%of data missed,indexes of bile acid,cholinesterase and AFP were excluded from logistic analysis.Model for cirrhosis diagnosis consists of platelet,bilirubin and protein ratio of albumin and globulin,with AUC 0.876.P value of Hosmer and Lemeshow test for model was 0.921.With model index-1.83,NPV for cirrhosis was 97.0%,and PPV 76%for determining index 0.4,with mild fibrosis rate of 2%.Used with these two cut-off values,model would free about 60%patient from biopsy.
In US score system,there were significantly differences between fibrosis stages and ultrasonic indexes of liver parenchyma,gallbladder,hepatic vessel and splenomegaly.Ultrasonic scores were significantly different between F4 and other fibrosis,and significantly correlated with fibrosis stages(rho=0.461).Used with excluding and determining value,US score would free 50%patient from biopsy,with AUC 0.793.NPV of cirrhosis for normal ultrasound images of liver,spleen and gallbladder was 93.6%.Score of 9 determined cirrhosis with PPV 76%,with mild fibrosis rate 13.6%.
If routine blood tests and US score combined used for identifying cirrhosis,model for cirrhosis consists of patients' age,blood platelet,US score,serum albumin and bilirubin,with AUC of 0.907.P value of Hosmer and Lemeshow test for model was 0.854.The cirrhosis index was correlated with fibrosis stages with coefficient of 0.637.Model would free 70%patients from biopsy,with NPV 97.4%for excuding index-2.18 and PPV 84.3%for diagnosing index 0.24,and mild fibrosis in cirrhosis diagnosed patients was only 2.9%.Model in validation set showed similar excluding but lower determining ability.
3.FibroScan scanning and blood test,ultrasounds score system.
The rank correlation and partial correlation coefficient between inflammation and liver stiffness were 0.689(P=0.000) and 0.127(P=0.080),respectively.The same coefficient of hepatic fibrosis and liver stiffness were 0.702(P=0.000) and 0.374 (P=0.000),respectively.These coefficients showed that liver stiffness was correlated mainly with hepatic fibrosis.Liver stiffness was significantly different between fibrosis stages,with AUC 0.911 for identifying compensated cirrhosis.Liver stiffness 13.5KPa owned a maximal cumulant of sensitivity and specificity,with NPV 97.1%. With this cut-off value,84.2%of non-cirrhosis patients were detected.While liver stiffness up to 21.8KPa,PPV for cirrhosis was 66.7%,with nearly 0 of mild fibrosis. With absence and presence of cirrhosis cut-off value,FibroScan would free 85% patients from biopsy,and 78%patients were identified correctly.
Multi-variable Logistic regression analysis showed that compensated cirrhosis diagnosed model consisted of platelet and FibroScan liver stiffness,with AUC 0.912, and corresponding FibroScan AUC for cirrhosis was 0.913.With this model,the biopsy free rate was 80%and 72.8%patients would be correctly determined. Forthermore,mild fibrosis was 0 in the cirrhosis diagnosed patients.In 70 patients' FibroScan,routine serum tests and serum hyaluronic acid,FibroScan was the only variable for diagnosing cirrhosis.
Discussion and Conclusion:
In present study for patients with CHB,majority of routine blood tests for hepatitis were correlated with hepatic fibrosis stages.These variables included four type of indexes:demography of age,fibrosis markers of serum hyaluronic acid,typeⅢof precollagen and typeⅣof collagen,routine blood tests of white blood cell,platelet, AST,ALT,AST/ALT ratio,albumin,globulin,protein A/G ratio,bilirubin,direct bilirubin,bile acid and prothrombin time,and imageology of ultrasound and FibroScan liver stiffness.
Patients' age,blood platelet,serum hyaluronic acid,albumin,protein A/G ratio, bilirubin,US indexes of liver,spleen and gallbladder and FibroScan liver stiffness were involved in cirrhosis diagnosis model construction.Furthermore,platelet was invoved in all multi-indexes models.Patients' age suggested the history of hepatitis activity,which would result in liver fibrosis progress.Thrombocytopenia in liver cirrhosis may be partially due to the accumulation and destruction of platelet in the portal hypertensive-enlarged spleen resulting from progressive liver fibrosis,and partially due to the impaired production of thrombopoietin in the cirrhotic liver. Serum albumin and bilirubin were the indexes in Child-Turcotte-Pugh score for liver function evaluation.Hypoalbuminemia and hyperbilirubinemia were both indication of impaired liver function resulted from continuous fibrosis.They were acceptable and diagnostic biochemical features of liver cirrhosis.Serum hyaluronic acid used as fibrosis marker was a custom practice in clinical work for years.US was also a common examination for detecting cirrhosis.Ultimately,FibroScan detected hepatic fibrosis by determining live stiffness,which was positively correlated with fibrosis stages.
Regression analysis ultimately constructed several models for diagnosing compensated cirrhosis,including blood indexes(platelet,bilirubin and protein A/G ratio),combination of blood indexes and ultrasound(including patients' age, ultrasound score,platelet,bilirubin and albumin),platelet incorporated with hyaluronic acid and platelet plus FibroScan.The clinical significance of these diagnosing models was that most of patients with CHB would free from biopsies due to being identified as absence or presence of cirrhosis by excluding and determining cut-off value,while others were still needed biopsies to confirm the state of cirrhosis.
Model of blood indexes,hyaluronic acid plus platelet,combination of blood indexes and US,FibroScan,FibroScan plus platelet were of more applicable value, with NPV more than 97.0%in cirrhosis excluded and mild fibrosis rate less than 5% in cirrhosis determined patients.By these model,the misdiagnosis patients were majority sever fibrosis(which would progressed to cirrhosis without anti-virus treatment),and thus can be ignored(table 2).Furthermore,there was no mild fibrosis in misdiagnosis patients identified by model consisted of platelet and FibroScan.The biopsy free rate of these model diagnosing compensated cirrhosis were 61.3%,73%, 71.5%,84.4%and 79.3%in the same order.
Table 2 Evaluation of diagnostic value for compensated cirrhosis diagnosis by several model
Present study indicated that model consisted by FibroScan single index or combined with platelet be of more applicable value in the non-invasive diagnosis of compensated hepatitis B related cirrhosis.Without FibroScan,hyaluronic acid plus platelet,blood indexes combined with US score would still play important role in non-invasive identification of compensated cirrhosis resulted from HBV infection.
引文
1. Benvegnu' L, Gios M, Boccato S, et al. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications [J]. Gut 2004; 53:744-749.
2. Bony C, Rayssiguier R, Ughetto S, et al. Medical practices and expectations of general practitioners in relation to hepatitis C virus infection in the Auvergne region [J]. Gastroenterol Clin Biol, 2003, 27: 1021-25
3. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserer variation in liver biopsy in patients with chronic HCV infection [J]. Am J Gastroenterol, 2002, 97:2614-8
4. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C [J]. Hepatology. 2003; 38:1449-1457.
5. Guechot J, Laudat A, Loria A, Serfaty L, Poupon R, Giboudeau J. Diagnostic accuracy of hyaluronan and type III procollagen amino-terminal peptide serum assays as markers of liver fibrosis in chronic viral hepatitis C evaluated by ROC curve analysis [J]. Clin Chem. 1996; 42:558-563.
6. McHutchison JG, Blatt LM, de Medina M, et al. Measurement of serum hyaluronic acid in patients with chronic hepatitis C and its relationship to liver histology. Consensus Interferon Study Group [J]. J Gastroenterol Hepatol. 2000; 15:945-951.
7. Halfon P, Bourliere M, Penaranda G, et al. Accuracy of hyaluronic acid level for predicting liver fibrosis stages in patients with hepatitis C virus [J]. Comp Hepatol. 2005; 4: 6.
8. Patel K, Lajoie A, Heaton S, et al. Clinical use of hyaluronic acid as a predictor of fibrosis change in hepatitis C [J]. J Gastroenterol Hepatol. 2003; 18(3): 253-7.
9. Suzuki A, Angulo P, Lymp J, et al. Hyaluronic acid, an accurate serum marker for severe hepatic fibrosis in patients with non-alcoholic fatty liver disease [J]. Liver Int. 2005; 25(4): 779-86.
10. Montazeri G, Estakhri A, Mohamadnejad M, et al. Serum hyaluronate as a non-invasive marker of hepatic fibrosis and inflammation in HBeAg-negative chronic hepatitis B [J]. BMC Gastroenterol. 2005; 5: 32.
11. Poynard T, Aubert A, Bedossa P, et al. A simple biological index for detection of alcoholic liver disease in drinkers [J]. Gastroenterology. 1991; 100(5 Pt 1): 1397-402.
12. Teare JP, Sherman D, Greenfield SM, et al. Comparison of serum procollagen III peptide concentrations and PGA index for assessment of hepatic fibrosis [J]. Lancet. 1993; 342(8876): 895-8.
13. Forns X, Ampurdanes S, Llovet JM, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model [J]. Hepatology. 2002; 36(4 Pt 1): 986-992.
14. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C [J]. Hepatology. 2003; 38: 518-526.
15. Chrysanthos NV, Papatheodoridis GV, Savvas S, et al. Aspartate aminotransferase to platelet ratio index for fibrosis evaluation in chronic viral hepatitis [J]. Eur J Gastroenterol Hepatol, 2006, 18(4): 389-96
16. Wai CT, Cheng CL, Wee A, et al. Non-invasive models for predicting histology in patients with chronic hepatitis B [J]. Liver Int, 2006, 26(6): 666-72
17. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: aprospective study [J]. Lancet. 2001; 357:1069-1075.
18. Poynard T, Imbert-Bismut F, Munteanu M, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C [J]. Comp Hepatol. 2004; 3(1):8.
19. Poynard T, Munteanu M, Imbert-Bismut F , et al. Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C [J]. Clin Chem. 2004; 50(8): 1344-55.
20. Myers RP, Tainturier MH, Ratziu V, et al. Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B [J]. J Hepatol. 2003; 39(2):222-30.
21. Poynard T, Zoulim F, Ratziu V, et al. Longitudinal assessment of histology surrogate markers (FibroTest-ActiTest) during lamivudine therapy in patients with chronic hepatitis B infection [J]. Am J Gastroenterol. 2005; 100(9): 1970-80.
22. Ratziu V, Massard J, Charlotte F, et al. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease [J]. BMC Gastroenterol. 2006; 6: 6.
23. Naveau S, Raynard B, Ratziu V, et al. Biomarkers for the prediction of liver fibrosis in patients with chronic alcoholic liver disease [J]. Clin Gastroenterol Hepatol. 2005;3(2): 167-74.
24. Myers RP, Benhamou Y, Imbert-Bismut F, et al. Serum biochemical markers accurately predict liver fibrosis in HIV and hepatitis C virus co-infected patients [J]. AIDS. 2003; 17(5):721-5.
25. Thabut D, Trabut JB, Massard J, et al. Non-invasive diagnosis of large oesophageal varices with FibroTest in patients with cirrhosis: a preliminary retrospective study [J]. Liver Int; 26(3):271-8.
26. Thabut D, Naveau S, Charlotte F, et al. The diagnostic value of biomarkers (AshTest) for the prediction of alcoholic steato-hepatitis in patients with chronic alcoholic liver disease [J]. J Hepatol. 2006;44(6): 1175-85.
27. Sene D, Limal N, Messous D, et al. Biological markers of liver fibrosis and activity as non-invasive alternatives to liver biopsy in patients with chronic hepatitis C and associated mixed cryoglobulinemia vasculitis [J]. Clin Biochem. 2006;39(7):715-21.
28. Rossi E, Adams L, Prins A, et al. Validation of the FibroTest biochemical markers scores in assessing liver fibrosis in hepatitis C patients [J]. Clin Chem. 2003;49:450-454.
29. Poynard T, Morra R, Halfon P, et al. Meta-analyses of Fibrotest diagnostic value in chronic liver disease [J]. BMC Gastroenterol. 2007;7(1):40
30. Varaut A, Fontaine H, Serpaggi J, et al. Diagnostic accuracy of the fibrotest in hemodialysis and renal transplant patients with chronic hepatitis C virus. [J] Transplantation. 2005; 80(11): 1550-5.
31. Munteanu M, Messous D, Thabut D, et al. Intra-individual fasting versus postprandial variation of biochemical markers of liver fibrosis (FibroTest) and activity (ActiTest) [J]. Comp Hepatol. 2004; 3(1): 3.
32. Imbert-Bismut F, Messous D, Thibault V, et al. Intra-laboratory analytical variability of biochemical markers of fibrosis (Fibrotest) and activity (Actitest) and reference ranges in healthy blood donors [J]. Clin Chem Lab Med. 2004; 42(3): 323-33.
33. Halfon P, Imbert-Bismut F, Messous D, et al. A prospective assessment of the inter-laboratory variability of biochemical markers of fibrosis (FibroTest) and activity (ActiTest) in patients with chronic liver disease [J]. Comp Hepatol. 2002;l:3.
34. Bonacini M, Hadi G, Govindarajan S, et al. Utility of a discriminant score for diagnosing advanced fibrosis or cirrhosis in patients with chronic hepatitis C virus infection [J]. Am J Gastroenterol. 1997; 92(8): 1302-4.
35. Gordon A, Bailey MJ, Gibson PR, et al. Comprehensive clinical assessment improves the accuracy of predicting cirrhosis in chronic hepatitis C [J]. J Gastroenterol Hepatol. 2005; 20(6): 825-32
36. Romagnuolo J, Andrews CN, Bain VG, et al. Simple clinical variables predict liver histology in hepatitis C: prospective validation of a clinical prediction model [J]. Scand J Gastroenterol. 2005; 40(11): 1365-71.
37. Murawaki Y, Ikuta Y, Idobe Y, et al. Serum matrix metalloproteinase-1 in patients with chronic viral hepatitis [J]. J Gastroenterol Hepatol. 1999; 14(2): 138-45.
38. Murawaki Y, Ikuta Y, Okamoto K, et al. Diagnostic value of serum markers of connective tissue turnover for predicting histological staging and grading in patients with chronic hepatitis C [J]. J Gastroenterol. 2001; 36(6): 399-406.
39. Boeker KH, Haberkorn CI, Michels D, et al. Diagnostic potential of circulating TIMP-1 and MMP-2 as markers of liver fibrosis in patients with chronic hepatitis C [J]. Clin Chim Acta. 2002; 316(1-2): 71-81.
40. El-Gindy I, El Rahman AT, El-Alim MA, et al. Diagnostic potential of serum matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as non-invasive markers of hepatic fibrosis in patients with HCV related chronic liver disease [J]. Egypt J Immunol. 2003; 10(1): 27-35.
41. Leroy V, Monier F, Bottari S, et al. Circulating matrix metalloproteinases 1, 2, 9 and their inhibitors TIMP-1 and TIMP-2 as serum markers of liver fibrosis in patients with chronic hepatitis C: comparison with PIIINP and hyaluronic acid [J]. Am J Gastroenterol. 2004; 99(2): 271-9.
42. Rosenberg WM, Voelker M, Thiel R, et al. Serum markers detect the presence of liver fibrosis: a cohort study [J]. Gastroenterology. 2004; 127: 1704-1713.
43. Cales P, Oberti F, Michalak S, et al. A novel panel of blood markers to assess the degree of liver fibrosis [J]. Hepatology. 2005; 42(6): 1373-81.
44. Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis [J]. Ultrasound in Med & Biol, 2003; 29(12): 1705-1713
45. Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C [J]. Hepatology 2005; 41:48-54.
46. Foucher J, Castera L, Bernard PH, et al. Prevalence and factors associated with failure of liver stiffness measurement using Fibroscan in a prospective study of 2114 examinations [J]. Eur J Gastroenterol Hepatol 2006, 18: 411-412
47. Saito H, Tada S, Nakamoto N, et al. Efficacy of non-invasive elastometry on staging of hepatic fibrosis [J]. Hepatol Res 2004; 29:97-103.
48. Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C [J]. Gastroenterology 2005; 128:343-350.
49. Colletta C, Smirne C, Fabris C, Toniutto P, Rapetti R, Minisini R, et al. Value of two noninvasive methods to detect progression of fibrosis among HCV carriers with normal aminotransferases [J]. Hepatology 2005; 42:838-845.
50. Ghany MG, Doo E. Assessment of liver fibrosis: palpate, poke or pulse? [J] Hepatology 2005;42:759-761.
51.Coco B,Oliveri F,Maina AM,et al.Transient elastography:a new surrogate marker of liver fibrosis influenced by major changes of transaminases[J].J Viral Hepatitis,2007,14:360-369
52.Ganne-Carrie N,Ziol M,de Ledinghen V,et al.Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases [J].Hepatology,2006;44:1511-1517
53.Sagir A,Erhardt A,Schmitt A,ET AL.Transient Elastography Is Unreliable for Detection of Cirrhosis in Patients with Acute Liver Damage[J].Hepatology,2008,47:592-595
54.Graudal N,Leth P,Marbjerg L,Galloe AM.Characteristics of cirrhosis undiagnosed during life:a comparative analysis of 73 undiagnosed cases and 149diagnosed cases of cirrhosis,detected in 4,229 consecutive autopsies[J].J Intern Med 1991;230:165-171.
55.Foucher J,Chanteloup E,Vergniol J,et al.Diagnosis of cirrhosis by transient elastography(Fibroscan):a prospective study[J].Gut 2006;55:403-408.
56.Kazemi F,Kettaneh A,N'kontchou G,et al.Liver stiffness measurement selects patients with cirrhosis at risk of beating large oesophageal varices[J].J Hepatol 2006;45:230-235.
57.Vizzutti F,Arena U,Romanelli RG,et al.Liver Stiffness Measurement Predicts Severe Portal Hypertension in Patients with HCV-Related Cirrhosis[J].Hepatology 2007,45:1290-1297.
58.蔡亚玲,陈汉诚,王海云,等.彩色多普勒超声综合评分与肝纤维化分期的关系[J].现代实用医学,2003;15(5):280-282.
59.Bernatik T,Strobel D,Hahn EG,et al.Doppler measurements:a surrogate marker of liver fibrosis?[J]Eur J Gastroenterol Hepatol.2002;14(4):383-7.
60.Albrecht T,Blomley MJ,Cosgrove DO,et al.Non-invasive diagnosis of hepatic cirrhosis by transit-time analysis of an ultrasound contrast agent[J].Lancet.1999;353(9164):1579-83.
61.Sugimoto H,Kaneko T,Hirota M,et al.Earlier hepatic vein transit-time measured by contrast ultrasonography reflects intrahepatic hemodynamic changes accompanying cirrhosis[J].J Hepatol.2002;37(5):578-83.
62.Blomley MJ,Lim AK,Harvey CJ,et al.Liver microbubble transit time compared with histology and Child-Turcotte-Pugh score in diffuse liver disease:a cross sectional study[J].Gut.2003;52(8):1188-93.
63.Lim AK,Taylor-Robinson SD,Patel N,et al.Hepatic vein transit times using a microbubble agent can predict disease severity non-invasively in patients with hepatitis C[J].Gut.2005;54(1):128-33.
64.Harbin WP,Robert NJ,Ferrucci JT Jr.Diagnosis of cirrhosis based on regional changes in hepatic morphology:a radiological and pathological analysis[J].Radiology.1980;135:273-283.
65.Eugene R.Schiff,Michael F.Sorrell,Willis Maddrey,主编,黄志强主译.希夫肝脏病学[M].第1版(原著第9版),北京:化学工业出版社,2006,263
66.陈永鹏,,戴琳,冯筱榕,等.超声波检查对肝脏纤维化分期的诊断价值[J].中华肝脏病杂志,2002,4:132-134
67.Gaiani S,Gramantieri L,Venturoli N,et al.What is the criterion for differentiating chronic hepatitis from compensated cirrhosis? A prospective study comparing ultrasonography and percutaneous liver biopsy[J].J Hepatol.1997;27:979-985.
68.Aube C,Oberti F,Korali N,et al.Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis[J].J Hepatol.1999;30:472-478.
69.Hirata M,Akbar SM,Horiike N,et al.Noninvasive diagnosis of the degree of hepatic fibrosis using ultrasonography in patients with chronic liver disease due to hepatitis C virus[J].Eur J Clin Invest.2001;31(6):528-535.
70.Lim AK,Patel N,Eckersley RJ,et al.Can Doppler sonography grade the severity of hepatitis C-related liver disease?[J]Am J Roentgenol.2005;184(6):1848-53.
71.Bernatik T,Strobel D,Hahn EG,Becker D.Doppler measurements:a surrogate marker of liver fibrosis?[J].Eur J Gastroenterol Hepatol.2002;14(4):383-387.
72.Liu CH,Hsu SJ,Lin JW,et al.Noninvasive diagnosis of hepatic fibrosis in patients with chronic hepatitis C by splenic Doppler impedance index[J].Clin Gastroenterol Hepatol.2007,5(10):1199-1206.
73.中华医学会传染病与寄生虫病学分会、肝病学分会.病毒性肝炎防治方案[J].中华肝脏病杂志,2000,8:342-32
74.Poynard T,Bedossa P,Opolon P.Natural history of liver fibrosis progression in patients with chronic hepatitis C.The OBSVIRC,METAVIR CLINIVIR,and DOSVIRC groups[J].Lancet,1997,349:825-832
75.骆抗先,编著.乙型肝炎:基础与临床[M].第3版.北京:人民卫生出版社,2006,578-579
76.Montalto G,Soresi M,Aragona F,et al.[Procollagen Ⅲ and laminin in chronic viral hepatopathies][J].Presse Med.1996;25:59-62.
77.Teare JP,Sherman D,Greenfield SM,et al.Comparison of serum procollagen Ⅲpeptide concentrations and PGA index for assessment of hepatic fibrosis[J].Lancet.1993;342:895-898.
78.Trinchet JC,Hartmann D J,Pateron D,et al.Serum type Ⅰ collagen and N-terminal peptide of type Ⅲ procollagen in chronic hepatitis.Relationship to liver histology and conventional liver tests[J].J Hepatol.1991;12:139-144.
79.王宝恩,张定凤,主编.现代肝脏病学[M].第1版.北京:科学出版社,2003,522
80.Hahn E,Wick G,Pencev D,Timpl R.Distribution of basement membrane proteins in normal and fibrotic human liver:collagen type Ⅳ,laminin,and fibronectin[J].Gut.1980;21:63-71.
81.George DK,Ramm GA,Walker NI,Powell LW,Crawford DH.Elevated serum type Ⅳ collagen:a sensitive indicator of the presence of cirrhosis in haemochromatosis[J].J Hepatol.1999;31:47-52.
82.Murawaki Y,Ikuta Y,Koda M,Kawasaki H.Serum type Ⅲ procollagen peptide,type Ⅳ collagen 7S domain,central triple-helix of type Ⅳ collagen and tissue inhibitor of metalloproteinases in patients with chronic viral liver disease:relationship to liver histology[J].Hepatology.1994;20(4 Pt 1):780-787.
83.Murawaki Y,Ikuta Y,Koda M,Yamada S,Kawasaki H.Comparison of serum 7S fragment of type Ⅳ collagen and serum central triple-helix of type Ⅳ collagen for assessment of liver fibrosis in patients with chronic viral liver disease [J]. J Hepatol. 1996;24:148-154.
84. Ninomiya T, Yoon S, Hayashi Y, et al. Clinical significance of serum hyaluronic acid as a fibrosis marker in chronic hepatitis C patients treated with interferon-alpha: histological evaluation by a modified histological activity index scoring system [J]. J Gastroenterol Hepatol. 1998;13:68-74.
85. Czaja AJ, Wolf AM, Baggenstoss AH. Clinical assessment of cirrhosis in severe chronic active liver disease [J]. Mayo Clin Proc. 1980, 55: 360-364
86. Aster RH. Pooling of platelets in the spleen: role in the pathogenesis of hypersplenic thrombocytopenia [J]. J Clin Invest. 1996, 45: 645-657
87. Martin III TG, Somberg KA, Meng YG, et al. Thrombopoietin levels in patients with cirrhosis before and after orthotopic liver transplanation [J]. Ann Intern Med. 1997,127: 285-288
88. Peck-Radosavljevic M, Zacherl J, Meng YG, et al. Is inadequate thrombopoietin production a major cause of thrombocytopenia in cirrhosis of the liver? [J] J Hepatol. 1997,27: 127-131
89. Kawasaki T, Takeshita A, Souda K, et al. Serum thrombopoietin levels in patients with chronic hepatitis and liver cirrhosis [J]. Am J Gastroenterol. 1999, 94: 1918-1922
90. Adinolfi LE, Giordano MG, Andreana A, et al. Hepatic fibrosis plays a central role in the pathogenesis of thrombocytopenia in patients with chronic viral hepatitis [J]. Br J Haematol. 2001, 113: 590-595
91. Sheth SG, Flamm SL, Gordon FD, Chopra S. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection [J]. Am J Gastroenterol. 1998;93:44-48.
92. Giannini E, Botta F, Borro P, et al. Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis [J]. Gut. 2003; 52: 1200-1205.
93. Croquet V, Vuillemin E, Ternisien C, et al. Prothrombin index is an indirect marker of severe liver fibrosis [J]. Eur J Gastroenterol Hepatol. 2002; 14:1133-1141.
94. Park GJ, Lin BP, Ngu MC, Jones DB, Katelaris PH. Aspartate aminotransferase: alanine aminotransferase ratio in chronic hepatitis C infection: is it a useful predictor of cirrhosis? [J] J Gastroenterol Hepatol. 2000; 15:386-390.
95. Assy N, Minuk GY. Serum aspartate but not alanine aminotransferase levels help to predict the histological features of chronic hepatitis C viral infections in adults [J]. Am J Gastroenterol. 2000;95:1545-1550.
96. Giannini E, Risso D, Botta F, et al. Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease [J]. Arch Intern Med. 2003; 163:218-224.
97. Ferral H, Male R, Cardiel M, et al. Cirrhosis: diagnosis by liver surface analysis with high-frequency ultrasound [J]. Gastrointest Radiol. 1992; 17(1):74-78.
98. Colli A, Fraquelli M, Andreoletti M, et al. Severe liver fibrosis or cirrhosis: accuracy of US for detection-analysis of 300 cases [J]. Radiology. 2003; 2279: 89-94
99. Ladenheim JA, Luba DG, Yao F, et al. Limitations of liver surface US in the diagnosis of cirrhosis [J]. Radiology, 1992;185(1):21-23
100.Colli A, Cocciolo M, Riva C, et al. Abnormalities of Doppler waveform of the hepatic veins in patients with chronic liver disease: correlation with histologic findings [J]. Am J Roentgenol. 1994; 162: 833-837.
101.Bolondi L, Li Bassi S, Gaiani S, et al. Liver cirrhosis: changes of Doppler waveform of hepatic veins [J]. Radiology. 1991; 178: 513-516.
102.O'Donohue J, Ng C, Catnach S, et al. Diagnostic value of Doppler assessment of the hepatic and portal vessels and ultrasound of the spleen in liver disease [J]. Eur J Gastroenterol Hepatol. 2004; 16: 147-155
103.Ong TZ, Tan HJ. Ultrasonography is not reliable in diagnosing liver cirrhosis in clinical practice [J]. Singapore Med J. 2003; 44: 293-295.
104.Xu Y, Wang B, Cao H. An ultrasound scoring system for the diagnosis of liver fibrosis and cirrhosis [J]. Chin Med J. 1999; 112: 1125-1128
105.Hung CH,Lu SN,Wang JH,et al.Correlation between ultrasonographic and pathologic diagnoses of hepatitis B and C virus-related cirrhosis[J].J Gastroenterol,2003;38(2):153-157.
106.Zeng MD,Lu LG,Mao YM,et al.Prediction of significant fibrosis in HBeAg-positive patients with phronic hepatitis B by a noninvasive model[J].Hepatology,2005,42(6):1437-1445.
107.张文胜,王宝恩,王泰龄,等.慢性乙型肝炎肝纤维化无创性诊断模型的建立[J].中华肝脏病杂志,2006,14(3):169-173
108.金丕焕.医学统计学[M].第二版.上海:复旦大学出版社,2003,439-440.
109.Afdhal NH,Nunes D.Evaluation of liver fibrosis:a concise review[J].Am J Gastroenterol.2004;99:1160-1174.
2. Bony C, Rayssiguier R, Ughetto S, et al. Medical practices and expectations of general practitioners in relation to hepatitis C virus infection in the Auvergne region [J]. Gastroenterol Clin Biol, 2003, 27: 1021-25
3. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserer variation in liver biopsy in patients with chronic HCV infection [J]. Am J Gastroenterol, 2002, 97:2614-8
4. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C [J]. Hepatology. 2003; 38:1449-1457.
5. Guechot J, Laudat A, Loria A, Serfaty L, Poupon R, Giboudeau J. Diagnostic accuracy of hyaluronan and type III procollagen amino-terminal peptide serum assays as markers of liver fibrosis in chronic viral hepatitis C evaluated by ROC curve analysis [J]. Clin Chem. 1996; 42:558-563.
6. McHutchison JG, Blatt LM, de Medina M, et al. Measurement of serum hyaluronic acid in patients with chronic hepatitis C and its relationship to liver histology. Consensus Interferon Study Group [J]. J Gastroenterol Hepatol. 2000; 15:945-951.
7. Halfon P, Bourliere M, Penaranda G, et al. Accuracy of hyaluronic acid level for predicting liver fibrosis stages in patients with hepatitis C virus [J]. Comp Hepatol. 2005; 4: 6.
8. Patel K, Lajoie A, Heaton S, et al. Clinical use of hyaluronic acid as a predictor of fibrosis change in hepatitis C [J]. J Gastroenterol Hepatol. 2003; 18(3): 253-7.
9. Suzuki A, Angulo P, Lymp J, et al. Hyaluronic acid, an accurate serum marker for severe hepatic fibrosis in patients with non-alcoholic fatty liver disease [J]. Liver Int. 2005; 25(4): 779-86.
10. Montazeri G, Estakhri A, Mohamadnejad M, et al. Serum hyaluronate as a non-invasive marker of hepatic fibrosis and inflammation in HBeAg-negative chronic hepatitis B [J]. BMC Gastroenterol. 2005; 5: 32.
11. Poynard T, Aubert A, Bedossa P, et al. A simple biological index for detection of alcoholic liver disease in drinkers [J]. Gastroenterology. 1991; 100(5 Pt 1): 1397-402.
12. Teare JP, Sherman D, Greenfield SM, et al. Comparison of serum procollagen III peptide concentrations and PGA index for assessment of hepatic fibrosis [J]. Lancet. 1993; 342(8876): 895-8.
13. Forns X, Ampurdanes S, Llovet JM, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model [J]. Hepatology. 2002; 36(4 Pt 1): 986-992.
14. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C [J]. Hepatology. 2003; 38: 518-526.
15. Chrysanthos NV, Papatheodoridis GV, Savvas S, et al. Aspartate aminotransferase to platelet ratio index for fibrosis evaluation in chronic viral hepatitis [J]. Eur J Gastroenterol Hepatol, 2006, 18(4): 389-96
16. Wai CT, Cheng CL, Wee A, et al. Non-invasive models for predicting histology in patients with chronic hepatitis B [J]. Liver Int, 2006, 26(6): 666-72
17. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: aprospective study [J]. Lancet. 2001; 357:1069-1075.
18. Poynard T, Imbert-Bismut F, Munteanu M, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C [J]. Comp Hepatol. 2004; 3(1):8.
19. Poynard T, Munteanu M, Imbert-Bismut F , et al. Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C [J]. Clin Chem. 2004; 50(8): 1344-55.
20. Myers RP, Tainturier MH, Ratziu V, et al. Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B [J]. J Hepatol. 2003; 39(2):222-30.
21. Poynard T, Zoulim F, Ratziu V, et al. Longitudinal assessment of histology surrogate markers (FibroTest-ActiTest) during lamivudine therapy in patients with chronic hepatitis B infection [J]. Am J Gastroenterol. 2005; 100(9): 1970-80.
22. Ratziu V, Massard J, Charlotte F, et al. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease [J]. BMC Gastroenterol. 2006; 6: 6.
23. Naveau S, Raynard B, Ratziu V, et al. Biomarkers for the prediction of liver fibrosis in patients with chronic alcoholic liver disease [J]. Clin Gastroenterol Hepatol. 2005;3(2): 167-74.
24. Myers RP, Benhamou Y, Imbert-Bismut F, et al. Serum biochemical markers accurately predict liver fibrosis in HIV and hepatitis C virus co-infected patients [J]. AIDS. 2003; 17(5):721-5.
25. Thabut D, Trabut JB, Massard J, et al. Non-invasive diagnosis of large oesophageal varices with FibroTest in patients with cirrhosis: a preliminary retrospective study [J]. Liver Int; 26(3):271-8.
26. Thabut D, Naveau S, Charlotte F, et al. The diagnostic value of biomarkers (AshTest) for the prediction of alcoholic steato-hepatitis in patients with chronic alcoholic liver disease [J]. J Hepatol. 2006;44(6): 1175-85.
27. Sene D, Limal N, Messous D, et al. Biological markers of liver fibrosis and activity as non-invasive alternatives to liver biopsy in patients with chronic hepatitis C and associated mixed cryoglobulinemia vasculitis [J]. Clin Biochem. 2006;39(7):715-21.
28. Rossi E, Adams L, Prins A, et al. Validation of the FibroTest biochemical markers scores in assessing liver fibrosis in hepatitis C patients [J]. Clin Chem. 2003;49:450-454.
29. Poynard T, Morra R, Halfon P, et al. Meta-analyses of Fibrotest diagnostic value in chronic liver disease [J]. BMC Gastroenterol. 2007;7(1):40
30. Varaut A, Fontaine H, Serpaggi J, et al. Diagnostic accuracy of the fibrotest in hemodialysis and renal transplant patients with chronic hepatitis C virus. [J] Transplantation. 2005; 80(11): 1550-5.
31. Munteanu M, Messous D, Thabut D, et al. Intra-individual fasting versus postprandial variation of biochemical markers of liver fibrosis (FibroTest) and activity (ActiTest) [J]. Comp Hepatol. 2004; 3(1): 3.
32. Imbert-Bismut F, Messous D, Thibault V, et al. Intra-laboratory analytical variability of biochemical markers of fibrosis (Fibrotest) and activity (Actitest) and reference ranges in healthy blood donors [J]. Clin Chem Lab Med. 2004; 42(3): 323-33.
33. Halfon P, Imbert-Bismut F, Messous D, et al. A prospective assessment of the inter-laboratory variability of biochemical markers of fibrosis (FibroTest) and activity (ActiTest) in patients with chronic liver disease [J]. Comp Hepatol. 2002;l:3.
34. Bonacini M, Hadi G, Govindarajan S, et al. Utility of a discriminant score for diagnosing advanced fibrosis or cirrhosis in patients with chronic hepatitis C virus infection [J]. Am J Gastroenterol. 1997; 92(8): 1302-4.
35. Gordon A, Bailey MJ, Gibson PR, et al. Comprehensive clinical assessment improves the accuracy of predicting cirrhosis in chronic hepatitis C [J]. J Gastroenterol Hepatol. 2005; 20(6): 825-32
36. Romagnuolo J, Andrews CN, Bain VG, et al. Simple clinical variables predict liver histology in hepatitis C: prospective validation of a clinical prediction model [J]. Scand J Gastroenterol. 2005; 40(11): 1365-71.
37. Murawaki Y, Ikuta Y, Idobe Y, et al. Serum matrix metalloproteinase-1 in patients with chronic viral hepatitis [J]. J Gastroenterol Hepatol. 1999; 14(2): 138-45.
38. Murawaki Y, Ikuta Y, Okamoto K, et al. Diagnostic value of serum markers of connective tissue turnover for predicting histological staging and grading in patients with chronic hepatitis C [J]. J Gastroenterol. 2001; 36(6): 399-406.
39. Boeker KH, Haberkorn CI, Michels D, et al. Diagnostic potential of circulating TIMP-1 and MMP-2 as markers of liver fibrosis in patients with chronic hepatitis C [J]. Clin Chim Acta. 2002; 316(1-2): 71-81.
40. El-Gindy I, El Rahman AT, El-Alim MA, et al. Diagnostic potential of serum matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as non-invasive markers of hepatic fibrosis in patients with HCV related chronic liver disease [J]. Egypt J Immunol. 2003; 10(1): 27-35.
41. Leroy V, Monier F, Bottari S, et al. Circulating matrix metalloproteinases 1, 2, 9 and their inhibitors TIMP-1 and TIMP-2 as serum markers of liver fibrosis in patients with chronic hepatitis C: comparison with PIIINP and hyaluronic acid [J]. Am J Gastroenterol. 2004; 99(2): 271-9.
42. Rosenberg WM, Voelker M, Thiel R, et al. Serum markers detect the presence of liver fibrosis: a cohort study [J]. Gastroenterology. 2004; 127: 1704-1713.
43. Cales P, Oberti F, Michalak S, et al. A novel panel of blood markers to assess the degree of liver fibrosis [J]. Hepatology. 2005; 42(6): 1373-81.
44. Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis [J]. Ultrasound in Med & Biol, 2003; 29(12): 1705-1713
45. Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C [J]. Hepatology 2005; 41:48-54.
46. Foucher J, Castera L, Bernard PH, et al. Prevalence and factors associated with failure of liver stiffness measurement using Fibroscan in a prospective study of 2114 examinations [J]. Eur J Gastroenterol Hepatol 2006, 18: 411-412
47. Saito H, Tada S, Nakamoto N, et al. Efficacy of non-invasive elastometry on staging of hepatic fibrosis [J]. Hepatol Res 2004; 29:97-103.
48. Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C [J]. Gastroenterology 2005; 128:343-350.
49. Colletta C, Smirne C, Fabris C, Toniutto P, Rapetti R, Minisini R, et al. Value of two noninvasive methods to detect progression of fibrosis among HCV carriers with normal aminotransferases [J]. Hepatology 2005; 42:838-845.
50. Ghany MG, Doo E. Assessment of liver fibrosis: palpate, poke or pulse? [J] Hepatology 2005;42:759-761.
51.Coco B,Oliveri F,Maina AM,et al.Transient elastography:a new surrogate marker of liver fibrosis influenced by major changes of transaminases[J].J Viral Hepatitis,2007,14:360-369
52.Ganne-Carrie N,Ziol M,de Ledinghen V,et al.Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases [J].Hepatology,2006;44:1511-1517
53.Sagir A,Erhardt A,Schmitt A,ET AL.Transient Elastography Is Unreliable for Detection of Cirrhosis in Patients with Acute Liver Damage[J].Hepatology,2008,47:592-595
54.Graudal N,Leth P,Marbjerg L,Galloe AM.Characteristics of cirrhosis undiagnosed during life:a comparative analysis of 73 undiagnosed cases and 149diagnosed cases of cirrhosis,detected in 4,229 consecutive autopsies[J].J Intern Med 1991;230:165-171.
55.Foucher J,Chanteloup E,Vergniol J,et al.Diagnosis of cirrhosis by transient elastography(Fibroscan):a prospective study[J].Gut 2006;55:403-408.
56.Kazemi F,Kettaneh A,N'kontchou G,et al.Liver stiffness measurement selects patients with cirrhosis at risk of beating large oesophageal varices[J].J Hepatol 2006;45:230-235.
57.Vizzutti F,Arena U,Romanelli RG,et al.Liver Stiffness Measurement Predicts Severe Portal Hypertension in Patients with HCV-Related Cirrhosis[J].Hepatology 2007,45:1290-1297.
58.蔡亚玲,陈汉诚,王海云,等.彩色多普勒超声综合评分与肝纤维化分期的关系[J].现代实用医学,2003;15(5):280-282.
59.Bernatik T,Strobel D,Hahn EG,et al.Doppler measurements:a surrogate marker of liver fibrosis?[J]Eur J Gastroenterol Hepatol.2002;14(4):383-7.
60.Albrecht T,Blomley MJ,Cosgrove DO,et al.Non-invasive diagnosis of hepatic cirrhosis by transit-time analysis of an ultrasound contrast agent[J].Lancet.1999;353(9164):1579-83.
61.Sugimoto H,Kaneko T,Hirota M,et al.Earlier hepatic vein transit-time measured by contrast ultrasonography reflects intrahepatic hemodynamic changes accompanying cirrhosis[J].J Hepatol.2002;37(5):578-83.
62.Blomley MJ,Lim AK,Harvey CJ,et al.Liver microbubble transit time compared with histology and Child-Turcotte-Pugh score in diffuse liver disease:a cross sectional study[J].Gut.2003;52(8):1188-93.
63.Lim AK,Taylor-Robinson SD,Patel N,et al.Hepatic vein transit times using a microbubble agent can predict disease severity non-invasively in patients with hepatitis C[J].Gut.2005;54(1):128-33.
64.Harbin WP,Robert NJ,Ferrucci JT Jr.Diagnosis of cirrhosis based on regional changes in hepatic morphology:a radiological and pathological analysis[J].Radiology.1980;135:273-283.
65.Eugene R.Schiff,Michael F.Sorrell,Willis Maddrey,主编,黄志强主译.希夫肝脏病学[M].第1版(原著第9版),北京:化学工业出版社,2006,263
66.陈永鹏,,戴琳,冯筱榕,等.超声波检查对肝脏纤维化分期的诊断价值[J].中华肝脏病杂志,2002,4:132-134
67.Gaiani S,Gramantieri L,Venturoli N,et al.What is the criterion for differentiating chronic hepatitis from compensated cirrhosis? A prospective study comparing ultrasonography and percutaneous liver biopsy[J].J Hepatol.1997;27:979-985.
68.Aube C,Oberti F,Korali N,et al.Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis[J].J Hepatol.1999;30:472-478.
69.Hirata M,Akbar SM,Horiike N,et al.Noninvasive diagnosis of the degree of hepatic fibrosis using ultrasonography in patients with chronic liver disease due to hepatitis C virus[J].Eur J Clin Invest.2001;31(6):528-535.
70.Lim AK,Patel N,Eckersley RJ,et al.Can Doppler sonography grade the severity of hepatitis C-related liver disease?[J]Am J Roentgenol.2005;184(6):1848-53.
71.Bernatik T,Strobel D,Hahn EG,Becker D.Doppler measurements:a surrogate marker of liver fibrosis?[J].Eur J Gastroenterol Hepatol.2002;14(4):383-387.
72.Liu CH,Hsu SJ,Lin JW,et al.Noninvasive diagnosis of hepatic fibrosis in patients with chronic hepatitis C by splenic Doppler impedance index[J].Clin Gastroenterol Hepatol.2007,5(10):1199-1206.
73.中华医学会传染病与寄生虫病学分会、肝病学分会.病毒性肝炎防治方案[J].中华肝脏病杂志,2000,8:342-32
74.Poynard T,Bedossa P,Opolon P.Natural history of liver fibrosis progression in patients with chronic hepatitis C.The OBSVIRC,METAVIR CLINIVIR,and DOSVIRC groups[J].Lancet,1997,349:825-832
75.骆抗先,编著.乙型肝炎:基础与临床[M].第3版.北京:人民卫生出版社,2006,578-579
76.Montalto G,Soresi M,Aragona F,et al.[Procollagen Ⅲ and laminin in chronic viral hepatopathies][J].Presse Med.1996;25:59-62.
77.Teare JP,Sherman D,Greenfield SM,et al.Comparison of serum procollagen Ⅲpeptide concentrations and PGA index for assessment of hepatic fibrosis[J].Lancet.1993;342:895-898.
78.Trinchet JC,Hartmann D J,Pateron D,et al.Serum type Ⅰ collagen and N-terminal peptide of type Ⅲ procollagen in chronic hepatitis.Relationship to liver histology and conventional liver tests[J].J Hepatol.1991;12:139-144.
79.王宝恩,张定凤,主编.现代肝脏病学[M].第1版.北京:科学出版社,2003,522
80.Hahn E,Wick G,Pencev D,Timpl R.Distribution of basement membrane proteins in normal and fibrotic human liver:collagen type Ⅳ,laminin,and fibronectin[J].Gut.1980;21:63-71.
81.George DK,Ramm GA,Walker NI,Powell LW,Crawford DH.Elevated serum type Ⅳ collagen:a sensitive indicator of the presence of cirrhosis in haemochromatosis[J].J Hepatol.1999;31:47-52.
82.Murawaki Y,Ikuta Y,Koda M,Kawasaki H.Serum type Ⅲ procollagen peptide,type Ⅳ collagen 7S domain,central triple-helix of type Ⅳ collagen and tissue inhibitor of metalloproteinases in patients with chronic viral liver disease:relationship to liver histology[J].Hepatology.1994;20(4 Pt 1):780-787.
83.Murawaki Y,Ikuta Y,Koda M,Yamada S,Kawasaki H.Comparison of serum 7S fragment of type Ⅳ collagen and serum central triple-helix of type Ⅳ collagen for assessment of liver fibrosis in patients with chronic viral liver disease [J]. J Hepatol. 1996;24:148-154.
84. Ninomiya T, Yoon S, Hayashi Y, et al. Clinical significance of serum hyaluronic acid as a fibrosis marker in chronic hepatitis C patients treated with interferon-alpha: histological evaluation by a modified histological activity index scoring system [J]. J Gastroenterol Hepatol. 1998;13:68-74.
85. Czaja AJ, Wolf AM, Baggenstoss AH. Clinical assessment of cirrhosis in severe chronic active liver disease [J]. Mayo Clin Proc. 1980, 55: 360-364
86. Aster RH. Pooling of platelets in the spleen: role in the pathogenesis of hypersplenic thrombocytopenia [J]. J Clin Invest. 1996, 45: 645-657
87. Martin III TG, Somberg KA, Meng YG, et al. Thrombopoietin levels in patients with cirrhosis before and after orthotopic liver transplanation [J]. Ann Intern Med. 1997,127: 285-288
88. Peck-Radosavljevic M, Zacherl J, Meng YG, et al. Is inadequate thrombopoietin production a major cause of thrombocytopenia in cirrhosis of the liver? [J] J Hepatol. 1997,27: 127-131
89. Kawasaki T, Takeshita A, Souda K, et al. Serum thrombopoietin levels in patients with chronic hepatitis and liver cirrhosis [J]. Am J Gastroenterol. 1999, 94: 1918-1922
90. Adinolfi LE, Giordano MG, Andreana A, et al. Hepatic fibrosis plays a central role in the pathogenesis of thrombocytopenia in patients with chronic viral hepatitis [J]. Br J Haematol. 2001, 113: 590-595
91. Sheth SG, Flamm SL, Gordon FD, Chopra S. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection [J]. Am J Gastroenterol. 1998;93:44-48.
92. Giannini E, Botta F, Borro P, et al. Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis [J]. Gut. 2003; 52: 1200-1205.
93. Croquet V, Vuillemin E, Ternisien C, et al. Prothrombin index is an indirect marker of severe liver fibrosis [J]. Eur J Gastroenterol Hepatol. 2002; 14:1133-1141.
94. Park GJ, Lin BP, Ngu MC, Jones DB, Katelaris PH. Aspartate aminotransferase: alanine aminotransferase ratio in chronic hepatitis C infection: is it a useful predictor of cirrhosis? [J] J Gastroenterol Hepatol. 2000; 15:386-390.
95. Assy N, Minuk GY. Serum aspartate but not alanine aminotransferase levels help to predict the histological features of chronic hepatitis C viral infections in adults [J]. Am J Gastroenterol. 2000;95:1545-1550.
96. Giannini E, Risso D, Botta F, et al. Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease [J]. Arch Intern Med. 2003; 163:218-224.
97. Ferral H, Male R, Cardiel M, et al. Cirrhosis: diagnosis by liver surface analysis with high-frequency ultrasound [J]. Gastrointest Radiol. 1992; 17(1):74-78.
98. Colli A, Fraquelli M, Andreoletti M, et al. Severe liver fibrosis or cirrhosis: accuracy of US for detection-analysis of 300 cases [J]. Radiology. 2003; 2279: 89-94
99. Ladenheim JA, Luba DG, Yao F, et al. Limitations of liver surface US in the diagnosis of cirrhosis [J]. Radiology, 1992;185(1):21-23
100.Colli A, Cocciolo M, Riva C, et al. Abnormalities of Doppler waveform of the hepatic veins in patients with chronic liver disease: correlation with histologic findings [J]. Am J Roentgenol. 1994; 162: 833-837.
101.Bolondi L, Li Bassi S, Gaiani S, et al. Liver cirrhosis: changes of Doppler waveform of hepatic veins [J]. Radiology. 1991; 178: 513-516.
102.O'Donohue J, Ng C, Catnach S, et al. Diagnostic value of Doppler assessment of the hepatic and portal vessels and ultrasound of the spleen in liver disease [J]. Eur J Gastroenterol Hepatol. 2004; 16: 147-155
103.Ong TZ, Tan HJ. Ultrasonography is not reliable in diagnosing liver cirrhosis in clinical practice [J]. Singapore Med J. 2003; 44: 293-295.
104.Xu Y, Wang B, Cao H. An ultrasound scoring system for the diagnosis of liver fibrosis and cirrhosis [J]. Chin Med J. 1999; 112: 1125-1128
105.Hung CH,Lu SN,Wang JH,et al.Correlation between ultrasonographic and pathologic diagnoses of hepatitis B and C virus-related cirrhosis[J].J Gastroenterol,2003;38(2):153-157.
106.Zeng MD,Lu LG,Mao YM,et al.Prediction of significant fibrosis in HBeAg-positive patients with phronic hepatitis B by a noninvasive model[J].Hepatology,2005,42(6):1437-1445.
107.张文胜,王宝恩,王泰龄,等.慢性乙型肝炎肝纤维化无创性诊断模型的建立[J].中华肝脏病杂志,2006,14(3):169-173
108.金丕焕.医学统计学[M].第二版.上海:复旦大学出版社,2003,439-440.
109.Afdhal NH,Nunes D.Evaluation of liver fibrosis:a concise review[J].Am J Gastroenterol.2004;99:1160-1174.
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