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.     

The gamma‐glutamyl transpeptidase‐to‐platelet ratio predicts liver fibrosis and cirrhosis in HBeAg‐positive chronic HBV infection patients with high HBV DNA and normal or mildly elevated alanine transaminase levels in China

The gamma‐glutamyl transpeptidase‐to‐platelet ratio (GPR) is a new serum diagnostic model, which is reported to be more accurate than aspartate transaminase‐to‐platelet ratio index (APRI) and fibrosis index based on the four factors (Fib‐4) for the diagnosis of significant fibrosis and cirrhosis in chronic HBV infection (CHBVI) patients in West Africa. To evaluate the performance of the GPR model for the diagnosis of liver fibrosis and cirrhosis in HBeAg‐positive CHBVI patients with high HBV DNA (≥5 log₁₀ copies/mL) and normal or mildly elevated alanine transaminase (ALT) (≤2 times upper limit of normal (ULN)) in China. A total of 1521 consecutive CHBVI patients who underwent liver biopsies and routine laboratory tests were retrospectively screened. Of these patients, 401 treatment naïve HBeAg‐positive patients with HBV DNA≥5 log₁₀ copies/mL and ALT≤2 ULN were included. The METAVIR scoring system was adopted as the pathological diagnosis standard of liver fibrosis. Using liver histology as a gold standard, the performances of GPR, APRI, and Fib‐4 for the diagnosis of liver fibrosis and cirrhosis were evaluated and compared by receiver operating characteristic (ROC) curves and the area under the ROC curves (AUROCs). Of 401 patients, 121 (30.2%), 49 (12.2%) and 17 (4.2%) were classified as having significant fibrosis (≥F2), severe fibrosis (≥F3) and cirrhosis (=F4), respectively. After estimating the AUROC to predict significant fibrosis, the performance of GPR (AUROC=0.66, 95% CI 0.60–0.72) was higher than APRI (AUROC=0.58, 95% CI 0.52–0.64, P=.002) and Fib‐4 scores (AUROC=0.54, 95% CI 0.47–0.60, P<.001). After estimating the AUROC to predict severe fibrosis, the performance of GPR (AUROC=0.71, 95% CI 0.63–0.80) was also higher than APRI (AUROC=0.65, 95% CI 0.56–0.73, P=.003) and Fib‐4 scores (AUROC=0.67, 95% CI 0.58–0.75, P=.001). After estimating the AUROC to predict cirrhosis, the performance of GPR (AUROC=0.73, 95% CI 0.56–0.88) was higher than APRI (AUROC=0.69, 95% CI 0.54–0.83, P=.041) and Fib‐4 scores (AUROC=0.69, 95% CI 0.55–0.82, P=.012) too. The GPR is a new serum model for the diagnosis of liver fibrosis and cirrhosis and shows obvious advantages in Chinese HBeAg‐positive patients with HBV DNA≥5 log₁₀ copies/mL and ALT≤2 ULN compared with APRI and Fib‐4, thus warranting its widespread use for this specific population.     

Serum markers for predicting advanced fibrosis in patients with chronic hepatitis B and nonalcoholic fatty liver disease

To compare the diagnostic utility of serum markers in nonalcoholic fatty liver disease (NAFLD) patients with chronic hepatitis B (CHB).This study enrolled 118 consecutive biopsy-proven NAFLD patients with or without CHB. Fibrosis scores of each marker were compared against histological fibrosis staging. Receiver operating characteristic curve (ROC) analysis helped assess the accuracy of each marker.In patients with both diseases, 12.96% (7/54) had advanced fibrosis on biopsy and aspartate aminotransferase (AST) to platelet ratio index was the best performing marker for predicting advanced fibrosis. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the ROC (95% confidence interval) for AST to platelet ratio index (APRI) were 0%, 93.62%, 0%, 86.27%, and 0.676 (0.524–0.828), respectively. The markers ranked as follows from highest to lowest with respect to their accuracy: APRI; BARD; fibrosis-4; and AST to ALT ratio. In patients without CHB, fibrosis-4 was the best performing marker for predicting advanced fibrosis. The sensitivity, specificity, PPV, NPV, and area under the ROC (95% confidence interval) for fibrosis-4 were 77.78%, 85.45%, 46.67%, 95.92%, and 0.862 (0.745–0.978), respectively.Serum markers are less reliable in predicting advanced fibrosis in NAFLD patients with CHB; APRI is the most accurate predictor of the absence of advanced fibrosis.     

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.     

A novel index using routine clinical parameters for predicting significant liver inflammation in chronic hepatitis B

Identifying the degree of liver inflammation is critical for therapeutic judgement of patients with chronic hepatitis B (CHB). However, we lack indexes which can accurately predict significant liver inflammation in patients with CHB. This study aimed to develop a simple predictive index for liver inflammation in CHB using routine clinical parameters. A total of 519 patients with CHB who underwent liver biopsy were enrolled and randomly divided into training (n = 346) and validation cohorts (n = 173). Based on routine clinical parameters, gamma‐glutamyl transpeptidase (GGT; P = 0.031) and platelets (PLT; P < 0.001) were identified as independent predictors of significant inflammation by multivariable analysis in the training cohort. Accordingly, the GGT to PLT ratio (GPR) was developed to amplify the opposing effects for predicting liver inflammation. In the training cohort, the AUCs of GPR in predicting significant inflammation were 0.791 (95% CI: 0.742‐0.839), 0.783 (95% CI: 0.717‐0.849) and 0.791 (95% CI: 0.716‐0.867) in the entire patients with CHB, HBeAg‐positive CHB patients and HBeAg‐negative CHB patients, respectively. The diagnostic performance of GPR for significant inflammation was significantly superior to that of alanine aminotransferase (ALT), aspartate transaminase (AST) and GGT in all patients with CHB and HBeAg‐positive CHB patients, but was comparable with ALT, AST and GGT in HBeAg‐negative CHB patients. In the validation cohort, the diagnostic performance of GPR in assessing significant liver inflammation was also superior to other indexes in all patients with CHB and HBeAg‐positive CHB patients, but was comparable with GGT in HBeAg‐negative CHB patients. Thus, GPR can be a novel and simple index for predicting significant liver inflammation in CHB, especially for HBeAg‐positive CHB.     

APRI and FIB‐4 are good predictors of the stage of liver fibrosis in chronic hepatitis B: the Chronic Hepatitis Cohort Study (CHeCS)

We aim to determine the predictive ability of APRI, FIB‐4 and AST/ALT ratio for staging of liver fibrosis and to differentiate significant fibrosis (F2–F4) from none to minimal fibrosis (F0–F1) in chronic hepatitis B (CHB). Liver biopsy results were mapped to an F0–4 equivalent fibrosis stage. Mean APRI and FIB‐4 scores were significantly higher for each successive fibrosis level from F1 to F4 (P < 0.05). Based on optimized cut‐offs, the AUROCs in distinguishing F2–F4 from F0 to F1 were 0.81 (0.76–0.87) for APRI, 0.81 (0.75–0.86) for FIB‐4 and 0.56 (0.49–0.64) for AST/ALT ratio. APRI and FIB‐4 distinguished F2–F4 from F0 to F1 with good sensitivity and specificity and can be useful for treatment decisions and monitoring progression of fibrosis.     

血清HBeAg阴性慢性乙型肝炎患者APRI、FIB-4和血清TGF-β1水平变化*

目的 调查血清HBeAg阴性的慢性乙型肝炎(CHB)患者天门冬氨酸氨基转移酶与血小板比值(APRI)、基于4因子指数(FIB-4)和血清转化生长因子-β1(TGF-β1)的变化。方法 2018年1月～2019年5月我院诊治的血清HBeAg阴性的CHB患者78例和同期健康人78例,采用ELISA法测定血清TGF-β1水平,常规检测血生化指标,计算APRI和FIB-4评分。CHB患者接受肝活检,并行肝纤维化分期。结果 CHB患者APRI评分为(0.9±0.4),显著高于健康人【(0.3±0.1),P<0.05】;FIB-4评分为(1.4±0.4),显著高于健康人【(0.5±0.2),P<0.05】,血清TGF-β1水平为(14.5±5.3)ng/ml,显著高于健康人【(7.4±3.5)ng/ml,P<0.05】;33例CHB患者肝组织F0～1者APRI评分为(0.5±0.2),显著低于24例肝组织F2者【(1.0±0.3),P<0.05】,显著低于12例肝组织F3者【(1.3±0.5),P<0.05】,也显著低于9例肝组织F4者【(1.8±1.6),P<0.05】;F0～1患者FIB-4评分为(0.9±0.3),显著低于F2患者【(1.5±0.4),P<0.05】,显著低于F3患者【(1.9±0.4),P<0.05】,也显著低于F4患者【(3.2±0.6),P<0.05】;F0～1患者血清TGF-β1水平为(9.7±3.6)ng/ml,显著低于F2患者【(10.5±4.4)ng/ml,P<0.05】,显著低于F3患者【(15.8±5.9)ng/ml,P<0.05】,也显著低于F4患者【(19.5±6.2)ng/ml,P<0.05】。结论 血清HBeAg阴性的CHB患者APRI、FIB-4和血清TGF-β1水平发生了显著的变化,随着肝纤维化程度的加重,这些指标变化更明显,可能有助于提高对肝纤维化的诊断。     

Plateletcrit as a potential index for predicting liver fibrosis in chronic hepatitis B

Noninvasive tests (NITs) for liver fibrosis are highly needed for chronic hepatitis B (CHB) patients. We aimed to investigate whether plateletcrit (PCT) could be used as a NIT in predicting liver fibrosis for CHB patients. Five hundred and sixty‐seven treatment‐naïve CHB patients with available liver biopsies were included. Patients were randomly divided into a derivation cohort (n = 378) and a validation cohort (n = 189). The diagnostic accuracy of PCT was evaluated using receiver operating characteristic (ROC) curves. In the derivation cohort, PCT in CHB patients with S2‐S4 (0.14%), S3‐S4 (0.13%) and S4 (0.12%) was lower than patients with S0‐S1 (0.17%, P < .001), S0‐S2 (0.17%, P < .001) and S0‐S3 (0.16%, P < .001), respectively. PCT was an independent predictor of significant fibrosis (≥S2), advanced fibrosis (≥S3) and cirrhosis (S4). The area under the ROC curve (AUROC) of PCT in predicting significant fibrosis, advanced fibrosis and cirrhosis was 0.645, 0.709 and 0.714, respectively. The AUROC of PCT was higher than the aspartate transaminase to platelet ratio index (APRI) in identifying advanced fibrosis and cirrhosis, while this was comparable with APRI in identifying significant fibrosis. The diagnostic value of PCT was comparable with fibrosis‐4 score (FIB‐4) in predicting significant fibrosis, advanced fibrosis and cirrhosis. In the validation cohort, PCT could also identify significant fibrosis, advanced fibrosis and cirrhosis with similar diagnostic accuracy as in the derivation cohort. PCT represents a simple and inexpensive indictor for liver fibrosis in CHB patients. PCT is just as good or better than other more complex tools for staging liver fibrosis in CHB patients.     

Validation of FIB‐4 and comparison with other simple noninvasive indices for predicting liver fibrosis and cirrhosis in hepatitis B virus‐infected patients

Backgrounds: To optimize management and predict long‐term clinical courses in patients with chronic hepatitis B (CHB), noninvasive tests to determine the degree of hepatic fibrosis have been developed. Aims: This study aimed to validate a simple, noninvasive FIB‐4 index, which was first derived from an HCV–HIV‐co‐infected population, in patients with CHB and to compare it with other noninvasive tests for predicting cirrhosis. Methods: From 2006–2008, a total of 668 consecutive CHB patients who underwent liver biopsies were enrolled. The fibrosis stage was assessed according to the Batts and Ludwig system by a single pathologist blinded to patients' data. Results: For prediction of significant (F≥2) and severe (F≥3) fibrosis, and cirrhosis (F=4), the area under the receiver‐operating characteristic curves were 0.865, 0.910 and 0.926 respectively. In predicting cirrhosis, it demonstrated diagnostic values comparable to the age–spleen platelet ratio index (0.937, P=0.414) and age–platelet index (0.928, P=0.888), and better outcomes than spleen–platelet ratio index (0.882, P=0.007), aspartate aminotransferase (AST)–platelet ratio index (0.731, P<0.001) and AST–alanine aminotransferase ratio index (0.730, P<0.001). FIB‐4 cut‐offs of 1.6 and 3.6 provided 93.2% negative predictive value and 90.8% positive predictive value for detection of cirrhosis respectively. Based on these results, liver biopsy could be avoided in 70.5% of the study population. These cut‐offs were validated internally using bootstrap resampling methods, showing good agreement. Conclusions: FIB‐4 is a simple, accurate and inexpensive method of predicting cirrhosis, with outcomes comparable to other noninvasive tests and may reduce the need for liver biopsy in the majority of CHB patients.     

Combined use of aspartate aminotransferase,platelet count and matrix metalloproteinase 2 measurements to predict liver fibrosis in HIV/hepatitis C virus‐coinfected patients

Objective Noninvasive tests that can be used in place of liver biopsy to diagnose fibrosis have major limitations. They either leave a significant proportion of patients without a definitive diagnosis or produce inaccurate results. Moreover, the performance of these tests is lower in HIV/hepatitis C virus (HCV) coinfection. Against this background, we examined the utility of serum matrix metalloproteinase 2 (MMP‐2) and tissue inhibitor of metalloproteinase 1 (TIMP‐1) measurements in combination with routine clinical data to predict fibrosis in HIV/HCV‐coinfected patients. Methods Patients with a liver biopsy who had not received anti‐HCV therapy were included in the study. A model including variables independently associated with fibrosis was constructed. Diagnostic accuracy was determined by measuring the area under the receiver operating characteristic curve (AUROC). Positive (PPV) and negative (NPV) predictive values were calculated. Results Ninety patients were included in the study. Aspartate aminotransferase (AST), platelet count and MMP‐2 were predictors of significant fibrosis (F≥2) and cirrhosis (F4). A score constructed using these variables yielded an AUROC of 0.76 for F≥2 and 0.88 for F4. Score cut‐offs detected (value ≥3.5) and excluded (value ≤1.5) F≥2 with a PPV of 87% and an NPV of 88%. Thirty‐one patients (34%) were correctly diagnosed using these cut‐offs, with four (13%) incorrect classifications. Cirrhosis was excluded with a certainty of 98% and diagnosed with a probability of 83%. Two (17%) of 12 patients were misclassified as having cirrhosis. The AST to platelet count index and MMP‐2 levels were sequentially applied to detect F≥2. Forty‐one patients (46%) were identified with this approach, with six (15%) misclassifications. Conclusion MMP‐2 levels can be used in combination with AST and platelet count to aid the diagnosis of liver fibrosis in HIV/HCV‐coinfected patients.     

不同医院无创性肝纤维化指标预测慢性乙型肝炎患者肝纤维化效能差异分析*

目的 探讨应用谷草转氨酶/血小板比值（APRI）、基于4因子的纤维化指数（FIB-4）和瞬时弹性成像技术评判不同医院慢性HBV感染者肝纤维化的效能差异。方法 在2所大学附属医院收治的慢性HBV携带者或慢性乙型肝炎（CHB）行肝穿刺,并获得APRI、FIB-4和肝脏硬度检测（LSM）值,采用ROC曲线分析指标的诊断效能。结果 两组分别纳入327例（A组）和250例（B组）患者,两组患者肝组织病理学检查肝纤维化分期和LSM值存在极显著差异（P值均<0.001）,而APRI和FIB-4值无显著性统计学差异（P=0.547和0.578）;就区分S0-1和≥S2期肝纤维化而言,A组APRI分别为0.14和0.18,B组分别为0.15和0.24,A组FIB-4分别为0.98和1.26,B组分别为0.93和1.50,而A组LSM分别为5.2 kPa和6.8 kPa,B组分别为7.2 kPa和9.0 kPa（P<0.001）;A组和B组APRI诊断的截断点分别为0.105和0.145,FIB-4分别为0.675和0.775,而LSM分别为4.650和6.345,其诊断两家医院患者显著性肝纤维化的灵敏度在85%左右,而特异性在24%~46%之间。结论 可能由于一些不可控制的因素存在,导致临床数据的获得在不同医院间不可比,因此也需要经组织病理学检查,以确定APRI、FIB-4和LSM 诊断显著性肝纤维化的截断点,达到最佳诊断效果。     

超声弹性成像结合血清学指标诊断慢性乙型肝炎患者肝纤维化价值评价

目的 探讨应用超声弹性成像结合血清学指标诊断慢性乙型肝炎(CHB)患者肝纤维化的价值。方法 2015年1月～2018年6月我院诊治的CHB患者358例,接受肝穿刺和超声检查,记录肝组织剪切波速度(SWV),使用化学发光免疫分析仪测定血清透明质酸(HA)、Ⅳ型胶原(ⅣⅣ-Col)和Ⅲ型前胶原(PⅢNP),计算天冬氨酸氨基转移酶/血小板比值(APRI)和基于四因子指数(FIB-4),应用多因素Logistic回归分析影响肝纤维化发生的独立危险因素,应用受试者工作特征(ROC)曲线下面积(AUC)评估各项指标诊断肝纤维化的准确性。 结果 经肝组织病理学检查,发现F0期42例,F1期96例,F2期86例,F3期72例和F4期62例;220例≥F2期患者肝组织SWV为(3.12±0.65)m/s,显著大于138例≤F1期患者【(1.72±0.51)m/s,P<0.05】;≥F2期患者血清HA水平为(128.1±14.7)μg/L,显著高于≤F1期患者【(75.4±10.1)μg/L,P<0.05】,AST/ALT比值为(0.96±0.41),显著大于≤F1期患者【(0.80±0.27),P<0.05】,血清Ⅳ-Col水平为(36.7±14.3)μg/L,显著高于≤F1期患者【(24.9±9.2)μg/L,P<0.05】,APRI评分为(0.83±0.52)分,显著大于≤F1期患者【(0.61±0.49)分,P<0.05】,FIB-4指数为(1.70±0.98),显著大于≤F1期患者【(1.23±0.67),P<0.05】;多因素Logistic回归分析结果表明,SWV、AST/ALT比值、HA、Ⅳ-Col、APRI和FIB-4为影响肝纤维化发生的危险因素(P<0.05),SWV诊断肝纤维化的正确率为86.9%,血清HA为84.2%,APRI和FIB-4分别为82.5%和81.8%。结论 应用SWV联合血清学指标可提高CHB患者肝纤维化诊断的准确性,值得进一步研究。     

Noninvasive estimation of fibrosis progression overtime using the FIB‐4 index in chronic hepatitis C

Summary. The FIB‐4 index is a simple formula to predict liver fibrosis based on the standard biochemical values (AST, ALT and platelet count) and age. We here investigated the utility of the index for noninvasive prediction of progression in liver fibrosis. The time‐course alteration in the liver fibrosis stage between paired liver biopsies and the FIB‐4 index was examined in 314 patients with chronic hepatitis C. The average interval between liver biopsies was 4.9 years. The cases that showed a time‐course improvement in the fibrosis stage exhibited a decrease in the FIB‐4 index, and those that showed deterioration in the fibrosis stage exhibited an increase in the FIB‐4 index with a significant correlation (P < 0.001). Increase in the ΔFIB‐4 index per year was an independent predictive factor for the progression in liver fibrosis with an odds ratio of 3.90 (P = 0.03). The area under the receiver operating characteristic curve of the ΔFIB‐4 index/year for the prediction of advancement to cirrhosis was 0.910. Using a cut‐off value of the ΔFIB‐4 index/year <0.4 or ≥0.4, the cumulative incidence of fibrosis progression to cirrhosis at 5 and 10 years was 34% and 59%, respectively in patients with the ΔFIB‐4 index/year ≥0.4, whereas it was 0% and 3% in those with the ΔFIB‐4 index/year <0.4 (P < 0.001). In conclusion, measurement of the time‐course changes in the FIB‐4 index is useful for the noninvasive and real‐time estimation of the progression in liver fibrosis.     

瞬时弹性成像技术、APRI及FIB-4对儿童非酒精性脂肪性肝病肝纤维化诊断价值的研究

目的:评估肝脏瞬时弹性成像、天冬氨酸转氨酶与血小板比值指数（APRI）及基于4因子的肝纤维化指数（FIB-4）对儿童非酒精性脂肪性肝病（NAFLD）肝纤维化的诊断价值。方法:选取湖南省儿童医院2015年8月至2020年10月已行肝穿刺病理活检的非酒精性脂肪性肝病100例进行回顾性研究,收集肝脏病理组织和临床资料。采用受...     

应用瞬时弹性成像技术联合APRI和AAR指数评估慢性乙型肝炎患者肝纤维化临床价值研究

目的 探讨应用瞬时弹性成像技术联合天门冬氨酸氨基转移酶(AST)/血小板指数(APRI)和AST/丙氨酸氨基转移酶(ALT)比值(AAR)评估慢性乙型肝炎(CHB)患者肝纤维化的临床价值.方法 2017年5月 ～2018年5月我院收治的CHB患者118例,给予所有患者恩替卡韦治疗观察12个月,治疗前接受肝活检,使用法国...