Novel Score for Prediction of Esophageal Varices in HCV- Related ‎Chronic Liver Disease Patients ‎

INTROODUCTION

Portal hypertension (PHT) commonly accompanies the presence of liver cirrhosis; therefore, the ‎development of esophageal varices (EV) is one of the most serious consequences of (PHT). The ‎prevalence of esophageal varices varies according to the severity of liver disease in cirrhotic ‎people, ranging from 24% to 69% [1]. The incidence of EV formation is 5% per year in individuals ‎with cirrhosis, and progression from small to large varices occurs in 10% to 20% of cases after one ‎year [1]. In Egypt, 77 % of patients with portal hypertension were found to have EV [3]. Between 25% ‎and 40% of patients with cirrhosis and varices experience variceal bleeding [4]. Large variceal ‎bleeding accounts for 30% to 53% of all variceal bleeding, while small variceal bleeding accounts ‎for 5% to 18% of all variceal bleeding [2].‎

In Egypt, bleeding esophageal varices account for 53.3 percent of all bleeding cases [5]. Each ‎variceal hemorrhage event is expected to have a mortality rate of 17–57% [6].  Within the first two ‎years after varices are discovered, the incidence of the initial bleeding incident ranges between ‎‎20% and 40% of all cases. As a result, preventing esophageal variceal bleeding is crucial for long-‎term care of liver cirrhosis [7]‎.

When liver cirrhosis is confirmed, the American Association for the Study of Liver Disease ‎‎(AASLD) and the Baveno V Consensus Conference on portal hypertension urge that cirrhotic‎‎ patient be evaluated for the presence of EV using esophago-gastro-duodenoscopy (EGD) [8,9]. 

Additionally, EGD should be repeated at 3-year intervals in patients without varices and ‎compensated cirrhosis, and at 2-year intervals in patients with minor varices to assess the ‎development or advancement of this characteristic. EGD should also be done annually if there is ‎indication of hepatic decompensation [10]. These recommendations imply a significant burden on ‎endoscopies and related costs because they require patients to undergo an unpleasant invasive ‎procedure repeatedly, even though the majority of subjects undergoing screening EGD either do ‎not have varices or have varices that do not require prophylactic therapy [11‎].

Many patients, on the other hand, avoid repeated endoscopies due to discomfort and worry of ‎infection transfer or contribution due to disturbance of the natural barriers [12]. Additionally, sedated ‎endoscopy in a cirrhotic patient can be harmful [13]. As a result, there is considerable interest in ‎creating non-endoscopic models for predicting the presence of esophageal varices, particularly ‎those associated with increased risk. Numerous models for predicting fibrosis and varices, such as ‎the AST/platelet radio index (APRI) and the FIB-4 index, have been established on patients with ‎chronic hepatitis C [14].‎

Seto and colleagues developed a new model to predict significant liver fibrosis (i.e., Ishak ‎fibrosis score 3) using the formula Log (index+1) = 0.0255+ 0.0031 age (years) + 0.1483 log ALP ‎‎(U/L) + 0.004 log AST (U/L) + 0.0908 log AFP (ng/L +1 -0.028log platelet count (109/L) [15]. ‎According to Ozelet and colleagues, the PAPAS index was also beneficial for discriminating ‎cirrhosis in persons with CHC, with a negative predictive value (NPV of 83.85%) [16]. The purpose ‎of this study was to determine whether the PAPAS index (Platelet/ Age/ Phosphatase/ AFP/ AST) ‎could be used to predict the presence of EV in patients with HCV-related cirrhosis.‎

PATIENTS AND METHODS

Study design and participants

This study was conducted in a cross-sectional manner. 100 cirrhotic patients at any stage were ‎recruited from the Tropical Medicine department, Tropical outpatient clinic, and endoscopy unit to ‎help us achieve our goal. Cirrhosis was diagnosed using a combination of clinical, biochemical, ‎imaging, and histological data, as well as a fibroscan where necessary.‎

Exclusion criteria

(1) Patients with current gastrointestinal bleeding, (2) Patients who had previously undergone ‎band ligation or variceal sclerotherapy, (3) Patients who had previously undergone Trans jugular ‎intrahepatic Porto systemic shunt, or surgery for portal hypertension were all excluded. (4) Portal ‎vein thrombosis, (5) Hepatocellular carcinoma, (6) advanced other organ malignancy (7) Patients ‎taking drugs for the primary prophylaxis  of variceal hemorrhage (8) Patients with ongoing alcohol ‎usage (less than 6 months without alcohol,‎  ‎ Patients with other causes of splenomegaly or ‎thrombocytopenia (hematological illness), (9) Other severe  medical condition (end stage renal ‎disease, congestive heart failure or severe respiratory  syndrome) (10) Patients with bilharziasis or a ‎history of canal water exposure.

Study tools

All participants were subjected to the following at the outset: ‎

‎(1)‎ Written informed consent, (2) full history taking, (3) complete clinical examination, (4) ‎biochemical examination (complete blood count, liver profile tests (ALT, AST, Albumin, PT, ‎alkaline phosphatase, total bilirubin, INR), antibilharzial Ab, HBsAg, HCV-Ab, and serum ‎creatinine), and (5) Abdominal ultrasonography was performed using a Toshiba "Just vision" ‎real-time scanner instrument with a 3.5 MHz convex transducer (after an overnight fast) with a ‎focus on Liver size, Liver echogenicity, Presence of periportal thickening, Portal vein diameter ‎and patency, Splenic size, Splenic vein diameter and patency. Ascites condition (6) Upper GI ‎endoscopy to assess the presence and severity of varices, as well as any other pertinent upper ‎GIT abnormalities. The videoscope system was a Pentax EG-3440. To avoid interobserver ‎variability, each patient's endoscopic examination was performed by the same examiner. ‎According to Garcia et al. [8], esophageal varices (EV) were categorized into small and large ‎varices (small; the varices can be depressed by endoscope, large; the varices cannot be ‎depressed by endoscope and/or confluent around the circumferential)‎ [7]. Varices with ‎red spots were considered to qualify as HRVs.‎

All of the patients were categorized using Child-Pugh classification16 of the severity of liver ‎disease according to the degree of ascites, the serum concentrations of bilirubin and albumin, ‎the prothrombin time, and the degree of encephalopathy. Encephalopathy: None = 1 point, ‎Grade 1 and 2 = 2 points, Grade 3 and 4 = 3 points. Ascites:  None = 1 point, slight = 2 ‎points, moderate = 3 points Bilirubin: under 2 mg/ml = 1 point, 2 to 3 mg/ml = 2 points, over 3 ‎mg/ml = 3 points. Albumin: greater than 3.5mg/ml = 1 point, 2.8 to 3.5mg/ml = 2 points, less ‎than 2.8mg/ml = 3 points. Prothrombin Time (sec prolonged): less than 4 sec = 1 point, 4 to 6 ‎sec = 2 points, over 6 sec = 3 points. Frequently INR will be used as a substitute for PT, with ‎INR under 1.7 = 1 point, INR 1.7 to 2.2 = 2 points, INR above 2.2 = 3 points. A total Child-‎Turcotte-Pugh score of 5 to 6 is considered Child-Pugh class A (well-compensated disease), 7 ‎to 9 is class B (significant functional compromise), and 10 to 15 is class C (decompensated ‎disease). These classes correlate with one- and two-year patient survival: class A: 100 and ‎‎85%; class B: 80 and 60%; and class C: 45 and 35%. ‎

All patients had their PAPAS Index and other known accessible prediction scores calculated, ‎PAPAS index:  Log =0.0255 + 0.0031 × age + 0.1483 × log[ALP] + 0.004 × log[AST] + ‎‎0.0908 × log[AFP + 1]− 0.028 × log [platelet count)] [15]. (APRI) AST to platelets ratio ‎index: [(AST/ULN) X100)]/platelets [17]. Fibrosis 4 index: (AgeXAST)/(PLTXALT½) [18]. Lok ‎Score: -5.56–0.0089 X PLT+ 1.26 X AST/ALT+5.27 X INR [19].‎

Table (1): The simple noninvasive models being evaluated as a predictor of EV.

PAPAS index: Platelet/Age/Phosphatase/AFP/AST [15]

APRI:  AST to platelets ratio index: [17]

FIB4:  Fibrosis 4 index [18] Lok Score [19]

Table (1). ‎ Within two weeks, the initial clinical evaluation, biochemical study, endoscopic ‎evaluation, and spleen measurement were completed.‎

Statistical methods

Data descriptive statistics: Continuous data were presented in a variety of mean± SD formats ‎‎(median; range). Numbers and percentages were used to present categorical data. ‎

Data analytic statistics include: Student t-test (t value) for normally distributed parameters and ‎Mann Whitney U test for non-parametric data distribution (z value), both tests were used to ‎compare continuous data parameters between groups. The chi square test or Fisher exact test were ‎used to compare groups and find relationships between categorical data characteristics (x² value).‎

To determine the variables independently linked with the existence of EV, a ranked ‎Spearman's Correlation Test was performed on all the characteristics that were substantially ‎different in a univariate analysis between patients with EV and those without EV. The optimal ‎sensitivity and specificity cut off values were determined using receiver operating characteristic ‎curves (ROC curves). The area under the curve was used to determine the model's validity (AUC). ‎PAPAS, FIB4, ABRI, and Lok scores were used to calculate sensitivity, specificity, positive ‎predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy (DA) as a non-‎invasive measure in the identification of esophageal varices. When the area under the curve (AUC) ‎is greater than 0.7, the diagnostic accuracy of ROC is considered useful, and when the AUC is ‎between 0.8 and 0.9, it is considered outstanding [31].‎

RESULTS

This Patients were divided into two groups based on the results of upper GIT endoscopy (Figure 1): ‎There were 67 individuals (67.0%) in Group I who had esophageal varices (EV). This group was ‎further divided into the following categories: Group Ia consisted of 28 patients (28.0%) with a ‎small EV. Group Ib consisted of 39 patients (39.0%) with a large EV. Group II consisted of 33 ‎individuals (33.0%), none of whom had esophageal varices. There were 58 males and 42 females ‎with a mean age of 46.24± 7.05 years. 67% of patients in our study had EV, and 40% had HREV. ‎We found that the Child-Pugh classification among our patients was 41 (41 percent), 33 (33 ‎percent), and 26 (26 percent) in Child A, B, and C, respectively. Endoscopic studies revealed EV ‎in around 67 % of cases, with large EV accounting for 39%. In 56 % of the cases, the portal ‎hypertensive gastropathy (PHG) was found. The prevalence of EV was 29.3%, 87.9 percent, and ‎‎100% in child A, B, and C‎, respectively (Table 2). The level of serum albumin in ‎patients with EV was found to be considerably lower than in those without EV (P value 0.001). ‎  In our study, patients with varices had a significantly lower platelet count than those ‎without (p0.001). Patients with HREV had a lower platelet count than those without HREV ‎‎(104.20± 26.96 vs 115.37± 26.96; P value =0.101), although this was not statistically significant in ‎predicting HREV  ‎ (Table 2). Ultrasonography revealed that patients with EV had a ‎substantially greater average portal vein width (PVD) than patients without EV (p0.000) (13.73 ‎‎1.81 vs 10.79 2.12 mm). PVD was also observed to be substantially greater in HREV patients than ‎in non-HREV patients (p0.000) (14.35± 1.93 vs 12.81± 1.11mm). In terms of spleen diameter, this ‎study found that patients with EV had a significantly larger spleen diameter (P0.001) than those ‎without EV (Table 2). With a p value of 0.001, EV was substantially more prevalent in Child B ‎and Child C patients compared to Child A patients (87.9%, 100%, and 29.3%, respectively) in the ‎current study. These data indicate that patients with Child B and C cirrhosis have a greater risk of ‎having varices and bleeding (Table 2).‎

Our research found that an APRI score of >1.46 (AUC of 0.753) can predict the existence of ‎EV with a sensitivity of 68 % and specificity of 80%. Despite the fact that the APRI score was ‎much higher in large EV than in small EV (2.14 VS 1.76; Table 3 and Figure 2&3), the APRI ‎score had no effect in predicting large varices in our study.‎

The Cutoff values for FIB-4 in the diagnosis of EVs and Large EVs are >2.78 and >4.06, ‎respectively, with 84%, 69.23 % sensitivity and 86.67 %, 67.86 % specificity respectively (Table ‎‎3).‎

LOK score was proposed to have a cutoff value of >0.69 for the diagnosis of EV. At this ‎cutoff, the sensitivity was 80%, the specificity was 66.67%, the PPV was 80%, and the NPV was ‎‎66.7 percent (AUROC was 0.784). Additionally, we established a diagnostic criterion of >0.87 for ‎Large EV, with a sensitivity of 61.54 percent and specificity of 82.14 percent. AUROC was 0.787. ‎‎(See Table 3)‎

Patients with EV showed a significantly higher PAPAS index than those without EV in our ‎study (Table 2). The PAPAS index exhibited a much higher diagnostic accuracy than the other ‎tests assessed for detecting EV and large EV (APRI, FIB-4, and Lok Score). PAPAS index AUCs ‎were 0.939 for diagnosis of EVs with 86 % sensitivity, 93.33 % specificity, 95.2 % PPV, 73.7 % ‎NPV, and AUC 0.746 for detecting Large EVs with 94.87 % sensitivity, 86.43 %specificity, 71.2 ‎‎% PPV, 86.7 % NPV, indicating its usefulness in identifying patients with large varices who ‎require endoscopy, (Table 3) & (figure 2). ‎

PAPAS index was the most significant independent predictor of the development of EV and ‎large EV using the logistic regression model (Table 4).‎ ‎