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.     

Comparative evaluation of GPR versus APRI and FIB‐4 in predicting different levels of liver fibrosis of chronic hepatitis B

It is of great significance to develop and evaluate noninvasive indexes predicting the level of liver fibrosis. The aim of this study was to comparatively evaluate gamma‐glutamyl transpeptidase‐to‐platelet ratio (GPR) versus aspartate aminotransferase‐to‐platelet ratio index (APRI) and fibrosis index based on 4 factors (FIB‐4) in predicting different levels of liver fibrosis of chronic hepatitis B (CHB) within the framework of HBeAg‐positive and HBeAg‐negative patients. A total of 1157 HBeAg‐positive and 859 HBeAg‐negative CHB patients were enrolled, among whom the pathological stage ≥S2, ≥S3, ≥S4 were defined as significant fibrosis, extensive fibrosis and cirrhosis, respectively. Receiver operating characteristic (ROC) curves were used to evaluate the performance of GPR, APRI and FIB‐4 in predicting different levels of liver fibrosis. In HBeAg‐positive patients, the area under ROC curves (AUROCs) of GPR in predicting extensive fibrosis and cirrhosis were both significantly larger than those of APRI (P = .0001 and P < .0001). In HBeAg‐negative patients, the AUROCs of GPR in predicting significant fibrosis and cirrhosis were significantly larger than those of FIB‐4 (P = .0006 and P = .0041). The AUROC of GPR in predicting extensive fibrosis was significantly larger than that of APRI and FIB‐4 (P = .0320 and P = .0018). Using a cut‐off of GPR > 0.500 as standard, the sensitivities and specificities of GPR in predicting significant fibrosis in HBeAg‐positive patients were 59.6% and 81.2%, and for cirrhosis 80.9% and 63.8%, respectively; and those of HBeAg‐negative patients were 60.3% and 78.3%, 84.5% and 66.1%, respectively. Regardless of HBeAg‐positive or HBeAg‐negative status, GPR had the best performance in predicting different levels of liver fibrosis.     

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.     

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。     

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.     

Performance of Enhanced Liver Fibrosis test and comparison with transient elastography in the identification of liver fibrosis in patients with chronic hepatitis B infection

Assessment of liver fibrosis is important in determining prognosis, disease progression and need for treatment in patients with chronic hepatitis B (CHB). Limitations to the use of liver biopsy in assessing fibrosis are well recognized, and noninvasive tests are being increasingly evaluated including transient elastography (TE) and serum markers such as the Enhanced Liver Fibrosis (ELF) test. We assessed performance of ELF and TE in detecting liver fibrosis with reference to liver histology in a cohort of patients with CHB (n = 182), and compared the performance of these modalities. Median age was 46 and mean AST 70 IU/L. Cirrhosis was reported in 20% of liver biopsies. Both modalities performed well in assessing fibrosis at all stages. Area under receiver operator characteristic (AUROC) curves for detecting METAVIR fibrosis stages F ≥ 1, F ≥ 2, F ≥ 3 and F4 were 0.77, 0.82, 0.80 and 0.83 for ELF and 0.86, 0.86, 0.90 and 0.95 for TE. TE performed significantly better in the assessment of severe fibrosis (AUROC 0.80 for ELF and 0.90 for TE, P < 0.01) and cirrhosis (0.83 for ELF and 0.95 for TE, P < 0.01). This study demonstrates that ELF has good performance in detection of liver fibrosis in patients with CHB, and when compared, TE performs better in detection of severe fibrosis/cirrhosis.     

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。     

Non‐invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B

Background: The need for new non‐invasive tools to assess liver fibrosis in chronic liver diseases has been largely advocated. Liver stiffness measurement (LSM) using transient elastography (FibroScan^®, Echosens^?) has been shown to be correlated to liver fibrosis in various chronic liver diseases. This study aims to assess its diagnosis accuracy in patients with chronic hepatitis B. Patients and methods: We prospectively enrolled 202 patients with chronic hepatitis B in a multicentre study. Patients underwent liver biopsy (LB) and LSM. METAVIR and Ishak liver fibrosis stages were assessed by two pathologists. Results: LSM or LB was considered unreliable in 29 patients. Statistical analysis was conducted in 173 patients. LSM was significantly (P<0.001) correlated with METAVIR (r=0.65) and Ishak fibrosis stage (0.65). The area under receiver‐operating characteristic curves were 0.81 (95% confidence intervals, 0.73–0.86) for F≥2, 0.93 (0.88–0.96) for F≥3 and 0.93 (0.82–0.98) for F=4. Optimal LSM cut‐off values were 7.2 and 11.0 kPa for F≥2 and F=4, respectively, by maximizing the sum D of sensitivity and specificity, and 7.2 and 18.2 kPa by maximizing the diagnosis accuracy. Conclusion: In conclusion, LSM appears to be reliable for detection of significant fibrosis or cirrhosis in HBV patients and cut‐off values are only slightly different from those observed in HCV patients.     

Noninvasive assessment of liver fibrosis with combined serum aminotransferase/platelet ratio index and hyaluronic acid in patients with chronic hepatitis B

AIM： To construct a noninvasive assessment model consisting of routine laboratory data to predict significant fibrosis and cirrhosis in patients with chronic hepatitis B （CHB）. METHODS： A total of 137 consecutive patients with CriB who underwent percutaneous liver biopsy were retrospectively analyzed. These patients were divided into two groups according to their aminotransferase （ALT） level. The sensitivity, specificity, positive predictive value （PPV）, negative predictive value （NPV）, the likelihood ratio （LR） of aminotransferase/platelet ratio index （APRI） ≥ 1.5 or 〈 1.5 in combination with different hyaluronic acid （HA） cut-off points were calculated for the presence of moderate to severe fibrosis/cirrhosis （fibrosis stages 2 and 4） and no to mild fibrosis/cirrhosis （fibrosis stages 0 and 1）. RESULTS： The APRI correlated with fibrosis stage in CriB patients. The APRI ≥1.5 in combination with a cut-off HA cut-off point 〉 300 ng/mL could detect moderate to severe fibrosis （stages 2-4） in Crib patients. The PPV was 93.7%, the specificity was 98.9%. The APRI 〈 1.5 in combination with different HA cut-off points could not detect no to mild fibrosis in CHB patients. CONCLUSION： The APRI ≥ 1.5 in combination with a HA cut-off point 〉 300 ng/mL can detect moderate to severe fibrosis （stages 2-4） in Crib patients.     

Transient elastography and simple blood markers in the diagnosis of esophageal varices for compensated patients with hepatitis B virus-related cirrhosis

Background and Aim: Transient elastography (TE) has been useful in esophageal varices (EV) diagnosis for chronic hepatitis C patients. In the present study, we evaluate the usefulness of TE and simple blood markers in the EV diagnosis of patients with hepatitis B virus (HBV)‐related cirrhosis, prospectively. Methods: Consecutive patients with compensated cirrhosis and positive HBV surface antigen were enrolled, prospectively. At enrollment, the aspartate aminotransferase (AST) to alanine aminotransferase ratio (AAR) and the AST to platelet ratio index (APRI) were recorded, and TE was performed. Two experienced endoscopists assessed EV independently. High‐risk EV was defined as small size with a red color sign, and medium or large in size. The diagnostic performances, optimal cut‐offs, and the validities of TE, APRI, platelet count (PLT), and AAR in EV diagnosis were assessed. Results: A total of 126 patients (male/female: 93/33; mean age: 54.5 years) with reliable TE results were analyzed. There was good agreement between two endoscopists in assessing the presence of EV and high‐risk EV (kappa value: 0.82 and 0.96). Forty‐eight (38.1%) patients had EV (small: 35; high risk: 13). There was correlation between TE result and EV size (r = 0.515, P < 0.001). TE, APRI, and PLT were similar; however, superior to AAR in the diagnostic accuracies for EV and high‐risk EV. In high‐risk EV prediction, the negative predictive value (NPV) was 97%, 98%, and 98%, with cut‐offs of 21 kPa, 1.24, and 110 (× 10⁹/L) for TE, APRI, and PLT, respectively. Conclusions: For compensated patients with HBV‐related cirrhosis, TE, APRI, and PLT are useful in excluding high‐risk EV with high NPV.     

慢性乙肝患者肝组织纤维化程度与细胞因子相关性

探讨慢性乙肝患苦血清细胞因子(TGF-β1、TNF-α、IFN-γ)在肝纤维化中的作用机制。采用ELISA和 RIA方法检测95例慢性乙肝患者血清TGF-β1、TNF-α、IFN-γ、HA、PCⅢ、C-Ⅳ的水平,并与肝组织病理学变化进 行对照研究。结果显示慢性乙肝患者血清TGF-β1、TNF-α、IFN-γ、HA、PCⅢ、C-Ⅳ的含量均不同程度高于对照 组,且随肝损害程度的加重而升高,与肝损害程度呈正相关;并且其水平与肝纤维化程度具有明显的相关性(P< 0．05)。血清TGF-β1水平与血清HA、PCⅢ、C-Ⅳ水平具有直线相关性,而IFN-γ与血清HA、PCⅢ、C-Ⅳ水平呈 负相关。慢性乙肝患者血清TCF-β1、TNF-α、IFN-γ水平可以作为诊断肝纤维化的血清学指标。     

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.     

瞬时弹性成像在慢性乙型肝炎肝纤维化诊断中的应用

目的：探讨瞬时弹性成像（ FS）在慢性乙型肝炎（乙肝）肝纤维化诊断中的应用价值。方法选取慢性乙肝患者165例,其中轻度肝纤维化者77例,中度肝纤维化者47例,重度肝纤维化及肝硬化者41例;另选同期健康体检者50例。采用FS扫描仪检测所有受试者肝脏硬度值;采用常规及临床生化检查检测血小板、AST、谷氨酰转肽酶及胆固醇,计算APRI指数、Forns指数。采用受试者工作特征（ ROC）曲线分析FS、APRI、Forns单独及联合诊断慢性乙肝肝纤维化的准确性。结果在诊断中度肝纤维化时,FS、Forns、APRI的ROC曲线下面积（ AUC）值分别为0．807、0．786、0．767,诊断界值分别为8．5 kPa及8．1、11．7,敏感度分别为83．3％、60．0％、73．3％,特异度分别为81．6％、92．1％、76．3％;在诊断重度肝纤维化及肝硬化时,FS、Forns、APRI的AUC值分别为0．896、0．886、0．829,诊断界值分别为16．3 kPa及8．4、9．3,敏感度分别为73．3％、80．0％、73．3％,特异度分别为90．6％、83．0％、88．7％。在诊断中度肝纤维化时,FS＋APRI ＋Frons、FS＋Frons、FS＋APRI、FS 的AUC 值分别为0．851、0．832、0．826、0．807,敏感度分别为66．7％、76．7％、70．0％、83．3％,特异度分别为97．4％、81．6％、89．5％、81．6％;在诊断重度肝纤维化及肝硬化时,FS＋APRI＋Frons、FS＋Frons、FS＋APRI、FS的AUC值分别为0．922、0．904、0．907、0．896,敏感度分别为86．7％、86．7％、80．0％、73．3％,特异度分别为88．7％、83．0％、88．7％、90．6％。结论 FS对慢性乙肝肝纤维化诊断准确性高,联合血清学检测诊断效能增高,具有良好的临床应用价值。