Esophageal variceal bleeding (EVB) is an important cause of mortality and morbidity in liver cirrhosis. In this study, we aimed to predict the possibility of EVB in patients with cirrhosis using a non-invasive score.
A total of 359 patients with cirrhosis were divided into two groups based on the presence or absence of EVB. ChildTurcotte-Pugh (CTP) score, a model for end-stage liver disease, aspartate aminotransferase to alanine aminotransferase ratio, aspartate aminotransferase to platelet ratio index (APRI), fibrosis-4-index (FIB-4), aspartate aminotransferase to alanine aminotransferase ratio/platelet ratio index (AARPRI), and S-index were measured for all participants. Receiver operating characteristic curves were obtained for all parameters, and the optimal cut-off value was determined in predicting EVB.
In patients with EVB, the number of platelets (PLT) were low (
FIB-4 and AARPRI, which are non-invasive markers of fibrosis, can be used to predict EVB. In addition, the 66.5 109/L cut-off value for PLT is important for EVB.
Liver cirrhosis (LC) occurs because of widespread hepatocyte necrosis, development of regenerative nodules, fibrous tissue hyperplasia, and increased intrahepatic vascular pressure due to long-term and recurrent damage of one or more factors. Portal hypertension (PH), which develops as a result of increased intrahepatic vascular resistance in cirrhosis, results from the combination of damage in hepatic sinusoids and disruption of the balance between vasodilator and vasoconstrictor agents [
Normal portal pressure gradient values range from 1 to 5 mmHg, and values greater than 5 mmHg indicate the presence of PH [
Evaluation of the hepatic venous pressure gradient (HVPG) is the gold standard for diagnosing and measuring the degree of PH [
Evaluating the severity of PH and EV is essential for the management and prognosis of the disease in patients with cirrhosis. There are some adversities with these methods. For example, HVPG measurement can only be performed in specialized centers and endoscopic examination to detect EV is not a risk-free procedure. However, since EV development results from liver fibrosis and is due to increased intrahepatic resistance, non-invasive fibrosis markers (NFM) can be useful in detecting EV. Regarding this, aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4-index (FIB-4) are recommended and validated by the World Health Organization guidelines for evaluating hepatic fibrosis [
In this study, we aimed to predict the possibility of EVB using non-invasive fibrosis indicators to reduce the complications associated with the number of endoscopic scans, increase the cost-effectiveness, and determine the best time for invasive procedures.
This study was conducted between 2015 and 2020 by scanning the files of patients followed-up for LC, online hospital data, and endoscopy records in the gastroenterology clinic of the institution. A total of 413 patients over the age of 18 years who had cirrhosis and detected EV in upper gastrointestinal endoscopy were included in the preliminary examination. Data on age, sex, cirrhosis etiology, MELD and Child-Turcotte-Pugh (CTP) classification scores, platelet (PLT) and biochemical results, endoscopically defined EV degrees, EVB history of the previous year were recorded. A total of 54 patients with portosystemic shunt, previous gastrointestinal surgery, liver metastasis, hepatocellular carcinoma, portal, hepatic and splenic vein thrombosis, myeloproliferative disease, pre-splenectomy, and those with a history of transjugular intrahepatic portosystemic shunt were excluded from the study.
Endoscopies were performed by a gastroenterologist using Fujinon EG-580RD (Fujifilm Europe, Düsseldorf, Germany) brand gastroscopy devices. Varices grading was defined as grade I, II, and III [
The following formulas were used to calculate the investigated non-invasive markers:
1) AAR = aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio
2) FIB-4 = (year of age × AST)/(PLT × the square root of ALT)
3) APRI = (AST/upper limit of normal) × 100/PLT (109/L)
5) S-index = 1000 × gamma glutamyl transferase/(PLT × albumin2)
6) aspartate aminotransferase to alanine aminotransferase ratio/platelet ratio index (AARPRI) = AAR/(PLT count (109/L)/150)
All data were analyzed using SPSS Statistics version 21 (IBM Co., Armonk, NY, USA). The consistency of continuous variables to normal distribution was evaluated using visual (histogram and probability plots) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests).
Categorical variables are reported as numbers, percentages, normally distributed data as arithmetic means and standard deviations, and skewed-distributed data as median (minimum-maximum) values. An independent sample t-test was used for the comparative analysis between two independent groups of normally distributed data, and the Mann-Whitney U test was used in the non-compliant data. In the comparative analysis for categorical variables between independent groups, the Pearson’s or Fisher’s test was chosen from the chi-square (
The study protocol was carried out with the approval of the Ethics Committee of the Ordu Training and Research Hospital, Ordu (Turkey) (No: 16/2018).
In the analysis based on the presence of bleeding, no significant difference was found between the groups in terms of age and sex (
In the group with EVB, grade I esophageal bleeding was not detected, while grade III esophageal varices were found in 84.1% (
There was no significant difference between the groups in terms of albumin, AST, ALT, CTP score, MELD, and AAR (
The predictive power of the CTP score, MELD, AAR, APRI, AARPRI, FIB-4, PLT, and S-index were evaluated by ROC analysis. AUC values and significance obtained from ROC analysis are presented in
EVB is a fatal complication of cirrhotic PH. However, there is no apparent clinical finding for EV in most patients with cirrhosis, even during the decompensation period.
Today, clinicians are concerned with identifying some non-invasive biochemical markers with high sensitivity and specificity that are cheaper and easier to obtain to reduce the number of upper gastrointestinal endoscopies for screening and treating EV in liver patients. These non-invasive biomarkers are applied using routine laboratory tests that do not require extra cost and special devices or additional biochemical tests [
While Iwata et al., reported that AAR was related to the severity of esophageal varices [
The APRI and FIB-4 index are two classic non-invasive scores with good diagnostic efficacy for cirrhosis [
In the study by Zhang et al., the FIB-4 index was an independent predictor of EV, and the AUROC value was determined to be 0.64 [
According to the Baveno VI consensus criteria, it was stated that endoscopic examination was not required in patients with transient elastography value less than 20 kPa and platelet value more than 150×109/L and annual PLT level monitoring was recommended [
In a study where the S-Index and FIB-4 score were evaluated by ROC analysis for the predictive power of EVB, the S-index was found to be stronger than the FIB-4 score (AUC, 0.695 and 0.673, respectively). However, it has been stated that EV is not an independent predictor (all
In a limited number of studies in which the AARPRI score was examined, a significant relationship was found between the liver fibrosis rate and the AARPRI score [
In addition, to predict the likelihood of EVB, AARPRI was found to have a 63.33% diagnostic accuracy rate with a 1.63 likelihood at a 3.02 cut-off value (70% sensitivity and 58% specificity).
There were some limitations in this study. First, due to the retrospective nature of the study, we could not investigate the predictive values of these markers for EVB in patients without a previous history of EVB. Second, since the treatment records of patients were not fully available, it was not possible to distinguish patients who received prophylactic treatment for EVB.
In conclusion, the current study showed that FIB-4, AARPRI, and PLT as non-invasive liver fibrosis markers will contribute to our clinical knowledge in predicting EVB. However, larger studies are needed to implement a routine use of these markers in clinical practice. We hope that this study will guide future studies on the use of non-invasive methods as a screening method to predict EVB.
None.
Conceptualization: Sami Cifci, Nergiz Ekmen
Data curation: SC, NE
Formal analysis: SC, NE
Investigation: SC, NE
Methodology: SC, NE
Project administration: SC, NE
Ono Supervision: SC, NE
Validation: SC, NE
Writing-original draft: SC, NE
Writing-review&editing: SC, NE
Receiver operating characteristic curves for the APRI, AAR, FIB4, AARPRI, and S-index. Larger results of APRI, AAR, FIB- 4, AARPRI, and S-index indicate more diagnostic positive tests for esophageal variceal bleeding. AAR, aspartate aminotransferase to alanine aminotransferase ratio; APRI, aspartate aminotransferase-to-platelet-ratio index; AARPRI, aspartate aminotransferase to alanine aminotransferase ratio/platelet ratio index; FIB-4, fibrosis-4 index.
Receiver operating characteristic curves for the platelet. A small number of platelets indicate a more diagnostic positive test for esophageal varices bleeding.
Comparison Clinicodemographic and Laboratory Parameters in Study Population
Parameters | No esophageal varices bleeding (n=189) | Esophageal varices bleeding (n=170) | |
---|---|---|---|
Age (years) | 53.83±9.75 | 51.92±9.61 | 0.063 |
Gender | 0.206 | ||
Male | 143 (75.7) | 138 (81.2) | |
Female | 46 (24.3) | 32 (18.8) | |
Etiology of cirrhosis | NA | ||
Alcoholic | 25 (13.2) | 23 (14.7) | |
Hepatitis B virus | 82 (43.4) | 77 (45.3) | |
Hepatitis C virus | 25 (13.2) | 24 (14.1) | |
Cryptogenic | 21 (11.1) | 27 (15.9) | |
NASH | 18 (9.5) | 12 (7.1) | |
Autoimmune hepatitis | 5 (2.6) | 1 (0.6) | |
Others | 13 (6.8) | 4 (2.4) | |
Varices degree | NA | ||
Grade I | 34 (18) | 0 (0.0) | |
Grade II | 97 (51.3) | 27 (15.9) | |
Grade III | 58 (30.7) | 143 (84.1) | |
Platelets (109/L) | 82 (24-348) | 56 (16-219) | <0.001 |
Serum albumin (g/dL) | 3 (1.5-4.8) | 2.9 (1.6-4.5) | 0.733 |
Alanine aminotransferase (U/L) | 41 (9-473) | 34.5 (7-354) | 0.062 |
Aspartate aminotransferase (U/L) | 59 (15-317) | 52.5 (10-463) | 0.076 |
CTP score | 9 (5-14) | 9 (5-15) | 0.393 |
MELD | 15 (6-33) | 16 (6-30) | 0.495 |
AAR | 1.53 (0.41-11.84) | 1.57 (0.54-4.84) | 0.208 |
APRI | 1.98 (0.13-1.33) | 2.41 (0.36-19.61) | 0.002 |
AARPRI | 2.81 (0.34-26.13) | 4.14 (0.91-16.5) | <0.001 |
FIB-4 | 6.29 (0.62-43.91) | 8.74 (2.17-42.45) | <0.001 |
S-index | 78.35 (8.80-3172) | 94.10 (4.38-2126) | 0.025 |
Data are expressed as mean±SD, number (%), or median (range).
AAR, aspartate aminotransferase to alanine aminotransferase ratio; AARPRI, aspartate aminotransferase to alanine aminotransferase ratio/platelet ratio index; APRI, aspartate aminotransferase-to-platelet-ratio index; CTP: Child-Turcotte-Pugh score; NASH, nonalcoholic steatohepatitis; FIB-4, fibrosis-4 index; MELD, model for end-stage liver disease; NA, not applicable.
Performance of Non-Invasive Markers for Prediction of Esophageal Variceal Bleeding
Variable | AUC (95% CI) | Cut-off value | Sensitivity (%) | Specificity (%) | PPV (%) | NPV (%) | Diagnostic accuracy (%) | LR + | LR - | OR (EV vs. NEV) | |
---|---|---|---|---|---|---|---|---|---|---|---|
0.52 (0.46-0.58) | 0.398 | ≥8.5 | 60.60 | 44.30 | 49.28 | 55.33 | 51.81 | 1.08 | 0.9 | 1.20 (0.79-1.83) | |
0.52 (0.46-0.58) | 0.496 | ≥14.5 | 57.10 | 49.10 | 50.00 | 55.76 | 52.65 | 1.11 | 0.88 | 1.26 (0.83-1.91) | |
0.53 (0.47-0.59) | 0.208 | ≥1.51 | 57.10 | 49.20 | 50.06 | 56.02 | 52.92 | 1.12 | 0.87 | 1.29 (0.85-1.95) | |
APRI | 0.59 (0.53-0.65) | 0.002 | ≥2.01 | 60.00 | 52.10 | 52.85 | 59.04 | 55.71 | 1.25 | 0.77 | 1.61 (1.06-2.45) |
AARPRI | 0.68 (0.63-0.74) | <0.001 | ≥3.02 | 70.00 | 58.10 | 59.50 | 67.92 | 63.23 | 1.63 | 0.53 | 3.11 (2.01-4.81) |
FIB-4 | 0.63 (0.57-0.69) | <0.001 | ≥6.70 | 65.20 | 57.40 | 57.22 | 64.24 | 60.45 | 1.49 | 0.62 | 2.40 (1.56-3.68) |
S-index | 0.56 (0.50-0.62) | 0.025 | ≥75.44 | 58.20 | 48.30 | 50.25 | 56.17 | 52.92 | 1.12 | 0.87 | 1.29 (0.85-1.96) |
PLT | 0.70 (0.65-0.75) | <0.001 | ≤66.50 | 62.40 | 70.30 | 64.63 | 67.18 | 66.02 | 2.03 | 0.54 | 3.74 (2.41-5.97) |
AAR, aspartate aminotransferase to alanine aminotransferase ratio; APRI, aspartate aminotransferase to platelet ratio index; AARPRI, aspartate aminotransferase to alanine aminotransferase ratio/platelet ratio index; AUC, area under the curve; CI: confidence interval; CTP: Child-Turcotte-Pugh score; EV, esophageal varices; FIB-4: fibrosis-4-index; LR, likelihood ratio; MELD: a model for end-stage liver disease; NEV, no esophageal varices; NPV, negative predictive value; OR, odds ratios, PLT, platelet; PPV, positive predictive value.
Statistically not significant AUC obtained from the receiver operating characteristic. 95% CI and