Background/purpose: Noninvasive assessment of esophageal varices (EVs), their size and bleeding stigmata may reduce endoscopic burden, cost and drawbacks. We aimed to evaluate the diagnostic performance of noninvasive fibrosis scores (AAR, APRI, FIB-4, King and VITRO scores) in predicting the presence of EVs and high risk varices needing treatment (VNT) in HCV-related cirrhosis of Egyptian patients. Methods: This prospective study included 154 HCV-related advanced compensated cirrhotic patients with no history of bleeding who underwent screening endoscopy for EVs. AAR, APRI, FIB-4, King and VITRO scores were assessed. Results: Esophageal varices were found in 120 patients (77.9%) and VNT in 92 patients (59.7%). Apart from AAR, all scores demonstrated statistically significant correlations with the presence and the size of EVs. Using area under receiver operating characteristic curve (AUC), these scores were good predictors for the presence of EVs and VNT, where VITRO score had the highest AUC (0.920 and 0.900) and accuracy (97.1% and 87%), sensitivity (75, 82.6%), specificity (100, 93.5%), PPV (100, 95%) and NPV (53.2, 78.4%) with cutoffs >1.3 and >1.8 respectively. Conclusion: Noninvasive fibrosis scores can predict the presence of EVs and VNT. VITRO score was the best predictor with higher accuracy for clinical applicability than studied scores.
Esophageal varices (EVs) contribute to cirrhosis-related morbidity and mortality which are found in 60% - 80% of cirrhotic patients and correlated with the severity of liver disease [
In order to avoid the endoscopic burden, cost, drawbacks, unpleasant and repeated examinations to the patients, several non-invasive parameters have been investigated for prediction of the presence and the size of EVs [
In this study, we aimed to investigate the ability of five noninvasive fibrosis scores (AAR, APRI, FIB-4, King and VITRO scores) to predict the presence and the size of EVs in hepatitis C virus (HCV)-related cirrhosis of Egyptian patients in comparison to upper endoscopy.
This prospective study was carried out at Al-Rajhi Liver Center, Assiut University Hospital, Assiut Egypt, from May 2016 to February 2017. The study protocol was approved by the local ethics committee of the Assiut University Hospital and was in accordance with the previsions of the Declaration of Helsinki. Informed consent was obtained from all the participants before enrollment in the study.
This study included 154 adult patients with liver cirrhosis selected consecutively from inpatient wards of the departments of Tropical Medicine and Gastroenterology and Internal medicine, Al-Rajhi Liver Center, Assiut University Hospital.
Cirrhotic patients had diagnostic criteria of liver cirrhosis (LC) by clinical, biochemical and ultrasonographic findings. The cause of liver dysfunction was hepatitis C. The severity of liver cirrhosis was assessed according to Child-Pugh classification [
At the study entry, detailed clinical history and examination were taken and abdominal ultrasonography was undertaken. Blood samples were collected from stable patients for laboratory investigations included complete blood count, liver, kidney function tests, and serum von-Willebrand factor Antigen (vWF-Ag) levels that were measured by using a fully automated STA analyser and vWF6 Liatest (Diagnostic Stargo, Paris, France) according to the instructions of the manufacturer.
By data collection, non-invasive fibrosis scores were calculated as following:
- AAR = AST (U/L)/ALT (U/L) [
- APRI = (AST (U/L)/upper limit of normal)/platelet (109/L) × 100 [
- FIB-4 = [age (years) × AST (U/L)]/[platelet (109/L) × ALT (U/L)1/2] [
- King score = age (years) × AST (U/L) × INR/platelets (109/L) [
- VITRO = vWF-Ag/platelets (109/L) [
Upper gastrointestinal endoscopy was done for evaluation of the presence, grade of EVs and stigmata of bleeding by an experienced endoscopist who was blinded to the outcomes of the study. Esophageal varices were graded as following: no varices, small varices without stigmata of bleeding and varices with stigmata of bleeding that need treatment that were large varices and small varices with red signs and known as high risk varices needing treatment (VNT) [
All statistical analyses were conducted using Statistical Package for the Social Sciences (SPSS) for Windows version 16 (SPSS Inc., Chicago, IL, USA) and MedCalc program. The quantitative data were expressed as mean ± standard deviation (SD) and qualitative data were expressed as percentage. Spearman’s rank correlation coefficient (r) was used to find correlations. The receiver operating characteristic curves (ROC) were plotted to measure and compare the performance of different noninvasive models for predicting EVs and VNT. Using ROC, The value with the best sensitivity and specificity was chosen as the best cutoff value, in addition, calculation of positive (PPV) and negative (NPV) predictive value, positive and negative likelihood ratio (+LR, −LR) for prediction or exclusion of varices. Logistic regression analysis was used to establish the best model for prediction of high risk esophageal varices needing treatment. All tests were two-tailed and statistical significance was assessed <0.05.
This study included 154 patients with HCV-related liver cirrhosis who underwent upper digestive endoscopy; 94 were Child-Pugh class A (61%), and 60 were early Child-Pugh class B (40%). Baseline demographic and clinical characteristics of the studied patients were summarized in
Total (n = 154) | |
---|---|
Age (years, mean ± SD) | 50.5 ± 8.5 (40 - 80) |
Sex Male Female | 92 (59.7%) 62 (40.3%) |
Laboratory parameters (mean ± SD) | |
S. bilirubin (mg/dl) | 1.7 ± 0.6 |
S. albumin (g/dl) | 3.2 ± 0.8 |
AST (IU L−1) | 36.4 ± 10.7 |
ALT (IU L−1) | 52.2 ± 17.1 |
INR | 1.4 ± 0.2 |
Platelets (109 L−1) | 83 ± 29 |
vWF-Ag% | 123 ±27 |
Child-Pugh score (mean ± SD) | 8 ± 3 |
Non-invasive scores (mean ± SD) | |
AAR | 0.76 ± 0.4 |
APRI | 1.22 ± 0.54 |
FIB-4 | 3.8 ± 1.8 |
King | 37 ± 18.5 |
VITRO | 1.64 ± 0.62 |
Esophageal varices (%) No Small varices without red signs Small varices with red signs Large varices | 34 (22.1%) 28 (18.2%) 30 (19.5%) 62 (40.2%) |
SD: standard deviation; AST: aspartate aminotransferase; ALT: alanine aminotransferase; INR: international normalized ratio; AAR: aspartate aminotransferase-alanine aminotransferase ratio; APRI: AST-platelet ratio index; FIB-4: fibrosis-4 index.
that were large and small varices with red signs.
Apart from AAR, significant elevations in the mean values of noninvasive fibrosis scores (APRI, FIB-4, King and VITRO) were noted in patients with EVs compared to those without EVs (
In addition, these scores (APRI, FIB-4, King and VITRO) were significantly correlated with the grades of esophageal varices, where, VITRO score had the strongest correlation (r = 0.730, P < 0.001). On the other hand, no significant correlation was found between ARR and variceal grades (r = 0.129, P = 0.112) (
Noninvasive score | The presence of esophageal varices | ||
---|---|---|---|
Patients without EVs (n = 34) | Patients with EVs (n = 120) | P value | |
AAR | 0.66 ± 0.27 | 0.79 ± 0.42 | 0.101 |
APRI | 0.79 ± 0.35 | 1.35 ± 0.52 | <0.001 |
FIB-4 | 2.48 ± 1.32 | 4.15 ± 1.69 | <0.001 |
King | 23.27 ± 12.6 | 40.8 ± 18.1 | <0.001 |
VITRO | 0.94 ± 0.2 | 1.83 ± 0.56 | <0.001 |
The size of esophageal varices | |||
Patients with no or small EVs without red signs (n = 62) | Patients with high risk EVNT (n = 92) | P value | |
AAR | 0.69 ± 0.26 | 0.80 ± 0.47 | 0.07 |
APRI | 0.89 ± 0.38 | 1.45 ± 0.52 | <0.001 |
FIB-4 | 2.76 ±1.39 | 4.47 ± 1.64 | <0.001 |
King | 26.5 ±13.1 | 43.9 ± 18.4 | <0.001 |
VITRO | 1.13 ± 0.33 | 1.98 ± 0.54 | <0.001 |
P value < 0.05 = significant. EVs: esophageal varices; EVNT: esophageal varices needing treatment; AAR: aspartate aminotransferase-alanine aminotransferase ratio; APRI: AST-platelet ratio index; FIB-4: fibrosis-4 index.
r | P value | |
---|---|---|
AAR | 0.129 | 0.112 |
APRI | 0.546 | <0.001 |
FIB-4 | 0.511 | <0.001 |
King | 0.544 | <0.001 |
VITRO | 0.730 | <0.001 |
r: Spearman’s rank correlation coefficient; P value < 0.05 = significant. AAR: aspartate aminotransferase-alanine aminotransferase ratio; APRI: AST-platelet ratio index; FIB-4: fibrosis-4 index.
By applying ROC curves, the diagnostic accuracies of AAR, APRI, FIB-4, King and VITRO scores as noninvasive predictors of EVs and VNT were studied to determine which score would have the most clinical utility for prediction (
The optimum cutoff values of the previously mentioned scores to predict the presence of EVs and VNT were illustrated in
By using these scores, we tried to construct a model for predicting the development of EVs and VNT by binary logistic regression analysis (forward: LR) (
Cut-off value | AUC 95% CI | SEN (%) | SPE (%) | PPV (%) | NPV (%) | +LR | −LR | Accuracy (%) | |
---|---|---|---|---|---|---|---|---|---|
AAR for EV diagnosis | >0.67 | 0.726 (0.613 - 0.822) | 63.3 | 82.4 | 92.7 | 38.9 | 3.59 | 0.45 | 67.5 |
AAR for EVNT diagnosis | >0.74 | 0.680 (0.563 - 0.781) | 52.2 | 83.9 | 82.8 | 54.2 | 3.23 | 0.57 | 65 |
APRI for EV diagnosis | >0.85 | 0.795 (0.687 - 0.878) | 78.3 | 82.4 | 94 | 51.9 | 4.44 | 0.26 | 79.2 |
APRI for EVNT diagnosis | >1.22 | 0.790 (0.682 - 0.874) | 73.9 | 83.9 | 87.2 | 68.4 | 4.58 | 0.31 | 77.9 |
FIB-4 for EV diagnosis | >2.8 | 0.800 (0.694 - 0.883) | 73.3 | 82.4 | 93.6 | 46.7 | 4.16 | 0.32 | 75.3 |
FIB-4 for EVNT diagnosis | >3.4 | 0.808 (0.702 - 0.889) | 78.3 | 74.2 | 81.8 | 69.7 | 3.03 | 0.29 | 76.6 |
King for EV diagnosis | >24.74 | 0.800 (0.693 - 0.882) | 80 | 76.5 | 92.3 | 52 | 3.4 | 0.26 | 79.2 |
King for EVNT diagnosis | >39.01 | 0.783 (0.674 - 0.869) | 69.6 | 87.1 | 88.9 | 65.9 | 5.39 | 0.35 | 76.7 |
VITRO for EV diagnosis | >1.3 | 0.920 (0.835 - 0.969) | 75 | 100 | 100 | 53.2 | - | 0.25 | 97.1 |
VITRO for EVNT diagnosis | >1.8 | 0.900 (0.811 - 0.957) | 82.6 | 93.5 | 95 | 78.4 | 12.8 | 0.19 | 87 |
EV: esophageal varices; EVNT: esophageal varices needing treatment; AAR: aspartate aminotransferase-alanine aminotransferase ratio; APRI: AST-platelet ratio index; FIB-4: fibrosis-4 index; AUC: area under the curve; SEN: sensitivity; SPE: specificity; PPV: positive predictive value; NPV: negative predictive value; +LR: positive likelihood ratio; -LR: negative likelihood ratio.
B | S.E. | Wald | df | Sig. | Exp(B) | 95% CI for EXP(B) | Percentage | |||
---|---|---|---|---|---|---|---|---|---|---|
Lower | Upper | |||||||||
Variables in the Equation (for prediction of esophageal varices) | ||||||||||
Step 1 | VITRO | 4.478 | 0.809 | 30.617 | 1 | <0.001 | 88.026 | 18.022 | 429.952 | 87% |
Constant | −4.536 | 0.931 | 23.742 | 1 | <0.001 | 0.011 | ||||
Step 2 | King | −0.074 | 0.034 | 4.929 | 1 | 0.026 | 0.928 | 0.869 | 0.991 | 85.7% |
VITRO | 6.811 | 1.556 | 19.161 | 1 | <0.001 | 907.624 | 43.001 | 19,157.1 | ||
Constant | −5.120 | 1.103 | 21.557 | 1 | <0.001 | 0.006 | ||||
Variables in the Equation (for prediction of esophageal varices needing treatment) | ||||||||||
Step 1 | VITRO Constant | 3.645 −5.165 | 0.555 0.845 | 43.101 37.362 | 1 1 | <0.001 <0.001 | 38.293 0.006 | 12.897 | 113.697 | 81.8% |
of this model was 77.9%. After removal of insignificant predictors (i.e., APRI and FIB-4), the accuracy of the model became 85.7%. If only VITRO was used, the accuracy of the model was 87% (odds ratio = 88.03, 95% CI = 18.02 - 430, P < 0.001) as shown in (
For prediction of VNT, dependent factors were either small or large varices while the independent factors were APRI, FIB-4 King and VITRO (significantly associated scores in univariate analysis). The accuracy of this model was about 59.7%. After removal of insignificant predictors (i.e., APRI, FIB-4 and King), the accuracy of the model becomes 81.8% where only VITRO was used (odds ratio= 38.3, 95% CI = 12.9 - 113.7, P < 0.001) (
In this study, we tried to approve the Baveno VI recommendation for prediction of EVs and VNT in compensated HCV-related cirrhosis with non-invasive parameters nearly different from that used in Baveno VI. As in many areas, Transient Elastography was not easily applicable or available. So, simple and easily applicable non invasive fibrosis tests were evaluated. Evaluation of hepatic fibrosis may provide information about the presence and severity of portal hypertension as increased hepatic vascular resistance in cirrhosis is influenced by the presence and the extent of fibrosis [
In this study, we demonstrated the ability of noninvasive markers of liver fibrosis to predict the presence of EVs and their size in Egyptian patients with liver cirrhosis and compare them with upper endoscopy. Evaluation of hepatic fibrosis may provide information about the presence and severity of portal hypertension as increased hepatic vascular resistance in cirrhosis is influenced by the presence and the extent of fibrosis [
Identification of patients with EVs especially high risk varices by regular screening is fundamental as they candidates for prophylactic therapy [
In our work, AAR had the lowest performance in prediction of EVs (AUC = 0.726) and high risk EVs (AUC = 0.648), however these results were much better than that recorded by Deng et al. [
Previous studies investigating APRI as a predictor for EVs in LC patients showed that a low AUC in predicting EVs (0.62) and Large EVs (0.71) [
We used FIB-4 cutoff values > 2.8 and 3.4 for which AUCs were 0.8 and 0.808 for diagnosis of EVs and Large EVs with 73.3, 78.3% sensitivity and 82.4, 74.2% specificity respectively. Our findings were compatible with Hassan et al. [
King score had been considered a satisfactory predictor of EVs. In the current study, at a cutoff value of 24.7, the score had an AUC of 0.800, 80% sensitivity, 76.5% specificity, 92.3% PPV, 52% NPV and 79.2% accuracy for the diagnosis of EVs. While for a cut-off value of 39.01, the AUC was 0.783, sensitivity was 69.6%, specificity was 87.1%, PPV was 88.9%, NPV was 65.9% and the accuracy was 76.7% for the prediction of VNT. In the retrospective study of Deng et al. [
In our study, the VITRO score was significantly higher in patients with EVs than those without. The diagnostic accuracy of VITRO for detecting EVs was significantly better than the other studied tests with an AUC of 0.920 (95%CI 0.835 - 0.969) with 75% sensitivity, 100% specificity, 100% PPV, 53.2% NPV and the highest accuracy (97.1%) at a cut-off > 1.3. It showed the closest correlation with variceal size, and at cut-off > 1.8 it had AUC, 0.9 (95%CI 0.811 - 0.957), 82.6% sensitivity, 93.5% specificity, 95% PPV, 78.4% NPV and 87% accuracy in detecting Large EVs suggesting its usefulness in identifying patients with large varices who need endoscopy. Our results supported by Hametner et al. [
The increased diagnostic accuracy of VITRO score for prediction of EVs and its size may be attributed to incorporation of independent predictors of portal hypertension; platelets and vWF-Ag [
Elevated vWF-Ag levels in liver cirrhosis are partly due to increased synthesis by increased shear stress or bacterial infection associated with endothelial cell damage or reduced clearance by increased activity of ADAMTS13 (vWF cleaving protease) [
The limitations of this work are a single-centre study and lack of comparison between noninvasive fibrosis scores and measurement of HVPG; an accurate measurement of portal hypertension, as measuring HVPG is not routinely available in our area. These findings are needed to be confirmed by further multicentre prospective studies to validate the usefulness of VITRO score in clinical practice.
In conclusion, VITRO score had the best diagnostic performance to predict varices in liver cirrhosis in comparison to the other studied models that may aid in further improvement of the quality of noninvasive screening of EVs and high risk VNT and in further reduction of endoscopic requirement. Hence, it could offer a useful strategy to stratify high-risk patients who would benefit by intensive screening, and to recommend the prophylactic treatment.
Authors declared that no financial support from any agency.
The authors declare that they have no conflict of interest.
Hassan, E.A., Abd El-Rehim, A.S., Sayed, Z. A., Ashmawy, A.M., Kholef, E.F.M., Sabry, A. and Elsewify, W.A. (2017) Noninvasive Fibrosis Scores as Prognostic Markers for Varices Needing Treatment in Advanced Compensated Liver Cirrhosis. Open Journal of Gastroenterology, 7, 230-242. https://doi.org/10.4236/ojgas.2017.78025