Baseline characteristics of the patients
The baseline characteristics of the patients are presented in Table 1. One-hundred patients [71 men, 29 women, median age, 70.5 (range, 20-87) years] were enrolled in this study. Their liver diseases were induced by the hepatitis B virus (HBV) (n=19), hepatitis C virus (HCV) (n=21), alcohol (n=33), primary biliary cholangitis (PBC) (n=3), autoimmune hepatitis (AIH) (n=4), and others (e.g. Budd-Chiari syndrome and cryptogenic) (n=20). The status of the underlying liver disease was chronic hepatitis in 26 patients and cirrhosis in 74 patients. Cirrhotic patients were classified into Child-Pugh class A (n=37), B (n=25), and C (n=12), respectively. Esophageal varices were detected in 57 of the 100 patients examined and classified into F1 (n=26), F2 (n=29), and F3 (n=2), respectively. Gastric varices were detected in 24 patients, and the form was classified into F1 (n=14), F2 (n=7), F3 (n=3), respectively. Thirty patients were treated for GOV before enrollment in the study by endoscopic variceal ligation (EVL, n=21), endoscopic injection sclerotherapy (EIS, n=6), balloon retrograde transvenous obliteration (B-RTO, n=2), and Hassab's operation (n=1), respectively. Therefore, GOV had been disappeared in three patients at enrollment. Among the 60 patients with GOV at enrollment, 33 patients had never been treated previously (non-treated group). Portal hypertensive gastropathy (PHG) was identified in 27 patients. Thirty-two patients had ascites. Fifty-nine patients had hepatocellular carcinoma (TNM stage I: II: III: IV = 14: 28: 19: 5). Encephalopathy was diagnosed in only four patients. Splenomegaly and ascites were found in 32 and 53 patients, respectively.
Table 1. Characteristics of patients
Patients
|
n=100
|
Sex (Male:Female)
|
71 : 29
|
Age (years)
|
70.5 (20-87)
|
Etiology of liver disease
|
|
HBV infection
|
19
|
HCV infection
|
21
|
Alcoholism
|
33
|
PBC
|
3
|
AIH
|
4
|
Others†
|
20
|
The status of the underlying liver disease
|
|
Chronic hepatitis
|
26
|
Cirrhosis
|
74
|
Child-Pugh classification
|
|
A : B : C
|
37 : 25 : 12
|
esophageal varices‡
|
57
|
Location (Li : Lm : Ls)
|
10 : 34 : 13
|
Form (F1 : F2 : F3)
|
26 : 29 : 2
|
Color (Cw : Cb)
|
56 : 1
|
RC0 : RC1: RC2 : RC3
|
30 : 18 : 6 : 1
|
gastric varices†
|
24
|
Location (Lg-c : Lg-f : Lg-cf)
|
13 : 10 : 1
|
Form (F1 : F2 : F3)
|
14 : 7 : 3
|
Color (Cw : Cb)
|
14 : 10
|
RC0 : RC1: RC2 : RC3
|
24 : 0 : 0 : 0
|
Past treatment of GOV
|
30
|
EVL : EIS : B-RTO : Hassab
|
21 : 6 : 2 : 1
|
Past rupture history
|
12
|
Portal hypertensive gastropathy
|
27
|
Encephalopathy
|
4
|
Ascites
|
32
|
Splenomegaly
|
53
|
†including Budd-Chiari syndrome and cryptogenic, ‡ including treated patients
AIH, autoimmune hepatitis; Cw, white varices; Cb, blue varices; F1, straight, small-caliber varices; F2, moderately enlarged, beady varices; F3, markedly enlarged, nodular or tumor-shaped varices; GOV, gastroesophageal varices; HBV, hepatitis B virus; HCV, hepatitis C virus; Ls, locus superior; Lm, locus medialis; Li. locus inferior; Lg-c, adjacent to the cardiac orifice; Lg-cf, extension from the cardiac orifice to the fornix; PBC, primary biliary cholangitis; RC, red color sign; Data are expressed as median (range).
Abdominal wall varices visualization and classification
In UI, AWV was classified by two doctors into grade 0 (n=72, 59), grade 1 (n=25, 33), and grade 2 (n=3, 7), respectively. The kappa was 0.5. In VWI, AWV was classified by two doctors into grade 0 (n=16, 25), grade 1 (n=43, 30), and grade 2 (n=41, 45), respectively. Comparing UI and VWI, the AWV-positive cases (grade1 and 2) were significantly higher in VWI than UI (24% vs 72%, p = 0.0005) (Table 2). In VWI, Grade 0 was decreased, and grade 2 was increased significantly in both doctors compared to the UI grading (p <0.01) (Fig 2). In VWI, the kappa was 0.55 for all grades; however, it was 0.72 for grade 2 classification.
Table 2. Comparison between UI and VWI for depicting AWV
|
VWI-negative
|
VWI-positive†
|
total
|
UI-negative
|
28
|
48
|
76
|
UI-positive†
|
0
|
24
|
24
|
total
|
28
|
72
|
100
|
UI, unmanipulated image; VWI, vein-weighed image; AWV, abdominal wall varices; UI-positive and VWI-positive cases are classified as grade1 and 2 by two doctors.
Comparing factors between negative and positive GOV
The comparison factors between negative and positive GOV demonstrated that the presence of cirrhosis was higher in the positive GOV group (42.5% vs 95%, p < 0.001). The presence of GOV was significantly higher in patients classified as VWI-AWV grade 2 by both doctors (22.5% vs. 43.3%, p = 0.032). For non-treated GOV (n = 70), the presence of GOV was also significantly higher in the patients classified as VWI-AWV grade 2 by both doctors (27.1% vs. 53.3%, p = 0.012). VWI could also detect grade 2 AWV in eight patients with no varices on their abdomen in UI (Fig. 3). In these eight patients, five patients (63%) had F2 esophageal varices and RC1 in two. Splenomegaly (35% vs 65%, p = 0.003), VWI-AWV grade 2 (22.5% vs 43.3%, p = 0.032), FIB-4 index (3.8 ± 2.5 vs. 6.1 ± 4.2, p = 0.003), APRI (1.0 ± 1.0 vs. 1.6 ± 1.2, p = 0.010), and liver stiffness (17.0 ± 16.7 vs. 28.0 ± 17.5 kPa, p = 0.011) were significantly higher in the positive group. In contrast, platelet count (151.7 ± 58.5 × 103 vs. 107.7 ± 49.7 × 103/mm3, p < 0.001), albumin (3.9 ± 0.7 vs. 3.6 ± 0.6 g/dL, p = 0.037), and PT (84.7 ± 23.0 vs.73.3 ± 22.2 %, p = 0.017) were significantly lower in the positive group (Table 3).
Table 3. Comparison of factors for prediction between patients with or without gastroesophageal varices.
|
Gastroesophageal varices †
|
|
negative
(n = 40)
|
positive
(n = 60)
|
p value
|
Gender (male/female)
|
27 / 13
|
44 / 16
|
0.529
|
Age (years)
|
72 (50-87)
|
69 (20-87)
|
0.050
|
Child-Pugh scores
|
7.2 ± 2.3
|
7.1 ± 2.2
|
0.885
|
Splenomegaly ( yes / no )
|
14 / 26
|
39 / 21
|
0.003
|
UI-AWV (grade0 / grade ≥ 1‡)
|
33 / 7
|
43 / 17
|
0.214
|
UI-AWV (grade0-1 / grade 2‡)
|
40 / 0
|
57 / 3
|
0.273
|
VWI-AWV (grade0 / grade ≥1‡)
|
14 / 26
|
14 / 46
|
0.203
|
VWI-AWV (grade0-1 / grade 2‡)
|
31 / 9
|
34 / 26
|
0.032
|
Platelet count
|
(103/mm3)
|
151.7 ± 58.5
|
107.7 ± 49.7
|
<0.001
|
FIB4 index
|
|
3.8 ± 2.5
|
6.1 ± 4.2
|
0.003
|
APRI
|
|
1.0 ± 1.0
|
1.6 ± 1.2
|
0.010
|
Liver stiffness§
|
(kPa)
|
17.0± 16.7
|
28.0± 17.5
|
0.011
|
APRI, aspartate aminotransferase to platelet ratio; AWI, abdominal wall varices; FIB-4, fibrosis index based on the four factors; UI, unmanipulated image; VWI, vein-weighed image; PT, Percent prothrombin time; Data are expressed as median (range) or mean ± SD. †including treated patients, ‡Classified by two doctors, § Liver stiffness was evaluated in 68 patients without ascites.
Comparing factors between grade 2 AWV and the others of VWI.
The comparison of factors between VWI-AWV grade 2 and the other grade groups demonstrated that the presence of cirrhosis (CH vs LC = 3 / 32, p = 0.004), GOV (52.3% vs 74.3%, p = 0.032), ascites (24.6% vs 47.1%, p = 0.023), and PHG (20% vs 40%, p = 0.023) were significantly higher in the VWI-AWV grade 2 group. In contrast, platelet count (133.7 ± 60.2 × 103 vs 109.7 ± 48.9 × 103/mm3, p = 0.046) was significantly lower in the VWI-AWV grade 2 group (Table 4).
Table 4. Comparison of factors between patients with VWI-AEV grade 2 and the others
|
VWI-AWV
|
p value
|
Grade 0-1
(n = 65)
|
Grade 2†
(n = 35)
|
|
Gender (male/female)
|
45 / 20
|
26 / 9
|
0.595
|
Age (years)
|
71 (46-87)
|
69 (20-87)
|
0.290
|
chronic hepatitis /cirrhosis
|
23 / 42
|
3 / 32
|
0.004
|
Child-Pugh scores
|
6.25 ± 21.7
|
7.5 ± 2.4
|
0.020
|
Ascites (yes / no)
|
16 / 49
|
17 /18
|
0.015
|
Splenomegaly (yes / no)
|
32/ 33‡
|
21/14
|
0.303
|
GOV (yes / no)
|
34 / 31
|
26/ 9
|
0.032
|
GOV > F2 (yes / no)
|
19 /46
|
14 / 21
|
0.170
|
GOV > RC1 (yes / no)
|
13 / 52
|
12 / 23
|
0.116
|
Past treatment of GOV (yes / no)
|
17 /48
|
13 / 22
|
0.253
|
Past rupture history (yes / no)
|
5 / 60
|
7 / 28
|
0.071
|
PHG (yes / no)
|
13 / 52
|
14 / 21
|
0.036
|
Platelet count
|
(103/mm3)
|
133.7 ± 60.2
|
109.7 ± 48.9
|
0.046
|
AST
|
(U/L)
|
35.2 ± 17.6
|
46.0 ± 27.6
|
0.019
|
ALT
|
(U/L)
|
27.9 ± 14.5
|
33.2 ± 18.4
|
0.118
|
Albumin
|
(g/dL)
|
3.8 ± 0.7
|
3.5 ± 0.6
|
0.053
|
Total bilirubin
|
(mg/dL)
|
1.1 ± 0.7
|
2.2 ± 4.5
|
0.050
|
PT
|
(%)
|
80.0 ± 21.0
|
73.4 ± 26.1
|
0.180
|
FIB4 index
|
|
4.9 ± 4.1
|
5.7 ± 3.2
|
0.302
|
APRI
|
|
1.3 ± 1.2
|
1.6 ± 1.0
|
0.129
|
Liver stiffness§
|
(kPa)
|
23.1± 18.1
|
24.0± 18.0
|
0.849
|
AST, aspartate aminotransferase; ALT, alanine aminotransferase; APRI, aspartate aminotransferase to platelet ratio; F2, moderately enlarged, beady varices; FIB4, fibrosis index based on the four factors; GOVs, Gastroesophageal varices; PHG, portal hypertensive gastropathy; PT, Percent prothrombin time; RC, red color sign; Data are expressed as median (range) or mean ± SD. † Classified by two doctors, ‡ Two patients had been undergone splenectomy, § Liver stiffness was evaluated in 68 patients without ascites.
Multivariate analysis of predicting factors for GOV.
Multivariate analysis was applied for the factors related to GOV in Table 3. Liver stiffness was obtained in only 68 patients because of ascites. Therefore, multivariate analysis was applied to groups with (n=68) and without (n=32) liver stiffness data. In the group with liver stiffness, age ≥71 years [OR = 0.28 (0.08 - 0.97), p = 0.045] and VWI-AWV grade2 [OR=3.92 (1.00 – 15.34), p = 0.049] were independent factors. In the group without liver stiffness, only age ≥71 years [OR = 0.29 (0.12 - 0.77), p = 0.012] was an independent factor. In this study, liver cirrhosis was lower in patients ≥71 years old (64% vs. 84%, p = 0.023). Therefore, age was negatively related to GOV (Table 5).
Table 5. Multivariate analysis of predicting factors for GOV with and without liver stiffness.
Factors
|
Multivariate analysis
|
Odds ratio
|
95%CI
|
p-value
|
with liver stiffness
|
|
|
|
Age
|
≥71 years†
|
0.28
|
0.08 – 0.97
|
0.045
|
Splenomegaly
|
|
2.21
|
0.49 – 9.81
|
0.296
|
Platelet count
|
<80,000/mm3 ‡
|
6.72
|
0.85 – 53.17
|
0.071
|
APRI
|
≥1.3 §
|
0.11
|
0.02 – 1.57
|
0.114
|
FIB-4 index
|
≥3.23¶
|
2.27
|
0.44 – 11.78
|
0.331
|
Liver stiffness
|
≥20kPa*
|
1.77
|
0.40 – 7.76
|
0.450
|
VWI-AWV
|
grade 2**
|
3.92
|
1.00 – 15.34
|
0.049
|
without liver stiffness
|
|
|
|
Age
|
≥ 71 years†
|
0.29
|
0.12 - 0.77
|
0.012
|
Splenomegaly
|
|
2.19
|
0.79 - 6.08
|
0.133
|
Platelet count
|
<80,000/mm3‡
|
3.03
|
0.62 – 14.70
|
0.170
|
APRI
|
≥1.3§
|
0.45
|
0.09 – 2.17
|
0.316
|
FIB-4 index
|
≥ 3.23¶
|
2.44
|
0.73 – 8.11
|
0.145
|
VWI-AWV
|
grade 2*
|
2.45
|
0.89 – 6.78
|
0.084
|
APRI, aspartate aminotransferase to platelet ratio; AWI, abdominal wall varices; FIB-4, fibrosis index based on the four factors; GOV, Gastroesophageal varices; VWI, vein-weighed image.†according to the median age of all the patients, ‡according to the report by Burton et al21, § according to the report by Castéra et al22 ¶ according to the report by Kraja et al 23 * according to the updated Baveno VI guidelines16,**Classified by two doctors.
Multivariate analysis of factors for non-treated GOV.
Multivariate analysis was also applied for non-treated GOV. It was also applied both with and without liver stiffness. Only VWI-AWV grade2 was an independent factor related to non-treated GOV in both individuals with [OR = 3.43 (1.03 – 11.44), p = 0.045] and without [OR = 2.97 (1.17 – 7.53), p = 0.022] liver stiffness data (Table 6).
Table 6. Multivariate analysis of predicting factors for non-treated GOV with liver stiffness.
Factors
|
Multivariate analysis
|
Odds ratio
|
95%CI
|
p-value
|
with liver stiffness
|
|
|
|
Age
|
≥71 years†
|
0.49
|
0.14 – 1.77
|
0.276
|
Splenomegaly
|
|
1.30
|
0.30 – 5.69
|
0.729
|
Platelet count
|
<80,000/mm3 ‡
|
3.15
|
0.53 – 18.82
|
0.208
|
APRI
|
≥1.3 §
|
0.85
|
0.11 – 6.58
|
0.874
|
FIB-4 index
|
≥3.23¶
|
0.62
|
0.11 – 3.57
|
0.593
|
Liver stiffness
|
≥20kPa*
|
0.78
|
0.18 – 3.44
|
0.744
|
VWI-AWV
|
grade 2**
|
3.43
|
1.03 – 11.44
|
0.045
|
without liver stiffness
|
|
|
|
Age
|
≥ 71 years†
|
0.66
|
0.26 – 1.67
|
0.380
|
Splenomegaly
|
|
0.79
|
0.26 – 2.37
|
0.675
|
Platelet count
|
<80,000/mm3‡
|
1.59
|
0.42 – 6.05
|
0.497
|
APRI
|
≥1.3§
|
1.49
|
0.36 – 6.15
|
0.578
|
FIB-4 index
|
≥ 3.23¶
|
0.79
|
0.21 – 2.94
|
0.729
|
VWI-AWV
|
grade 2*
|
2.97
|
1.17 – 7.53
|
0.022
|
APRI, aspartate aminotransferase to platelet ratio; AWI, abdominal wall varices; FIB-4, fibrosis index based on the four factors; GOV, Gastroesophageal varices; VWI, vein-weighed image. †according to the median age of all the patients, ‡according to the report by Burton et al21, § according to the report by Castéra et al22 ¶ according to the report by Kraja et al 23 * according to the updated Baveno VI guidelines16,**Classified by two doctors.