Digestive and Liver Disease 55 (2023) 75–80

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Digestive and Liver Disease

journal homepage: www.elsevier.com/locate/dld

Liver, Pancreas and Biliary Tract

Splenic-hepatic elastography index is useful in differentiating between

porto-sinusoidal vascular disease and cirrhosis in patients with portal
hypertension ✩,✩✩,★
Joel Ferreira-Silva a,b,∗, Rui Gaspar a,b, Rodrigo Liberal a,b, Hélder Cardoso a,b,
Guilherme Macedo a,b
a
Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal
b
Faculty of Medicine of the University of Porto, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: In patients with portal hypertension (PH), the differential diagnosis between porto-
Received 12 July 2022 sinusoidal vascular disease (PSVD) and cirrhosis is challenging. This study aims to evaluate the diagnostic
Accepted 30 September 2022
accuracy of the SSM/LSM index in the diagnosis of PSVD.
Available online 22 October 2022
Methods: Prospective study of patients with PH and PSVD or cirrhosis. Transient liver and spleen elas-
Keywords: tography were performed and the ratio between spleen stiffness measurement (SSM) and liver stiffness
Portal hypertension measurement (LSM) was calculated. The relation of SSM/LSM with the diagnosis of PSVD was evaluated.
Spleen elastography Results: Forty-four patients with PSVD and 44 patients with cirrhosis were evaluated. Median age was
Liver elastography, porto-sinusoidal vascular 57.5 (IQR 49.0–64.5) years, 66.3% were males. In patients with PSVD, median SSM was 59.4 (33.5–77.7)
disease kPa, median LSM was 6.2 (5.2–10.2) kPa and median SSM/LSM was 5.62 (3.15–9.68). In patients with cir-
rhosis, median SSM was 47.3 (24.3–60.3) kPa, median LSM was 27.8 (17.7–53.9) kPa and median SSM/LSM
was 1.55 (1.06–3.24). The SSM/LSM AUROC was 0.940 (p<0.001). Using 2 as a cut-off, we obtained good
sensitivity (86.5%), specificity (92.7%), and accuracy (89.7%) for the diagnosis of PSVD.
Conclusion: The SSM/LSM index is useful in the differential diagnosis between liver cirrhosis and PSVD.
Using the cut-off of 2 we achieved a good sensitivity and specificity for diagnosing PSVD.
© 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

1. Introduction 80% of patients, at diagnosis [5]. Furthermore, in comparison with

cirrhotic patients, patients with PSVD have a greater prevalence of
Porto-sinusoidal vascular disease (PSVD) was recently proposed high-risk esophageal varices (HRV) at diagnosis and a greater inci-
by Vascular Liver Disease Interest Group (VALDIG) as a term to de- dence of variceal bleeding [5,6].
scribe a group of rare vascular liver entities previously known as A liver biopsy is mandatory for the diagnosis of PSVD. However,
idiopathic non-cirrhotic portal hypertension [1]. This diagnosis is as a consequence of its limitations and risks, liver biopsy is being
characterized by the combination of the absence of liver cirrho- replaced by noninvasive alternatives in the first-line investigation
sis and the presence of microvascular histological lesions or find- of patients with PH [7].
ings of portal hypertension (PH) [1]. As a consequence of its rarity, Liver stiffness measurement (LSM) using transient elastogra-
PSVD is still frequently overlooked and misdiagnosed as cirrhosis phy (FibroscanTM ) is routinely used for the diagnosis of advanced
[2–4]. However, the management of PSVD is different from cirrho- chronic liver disease (ACLD). In addition, in combination with
sis. In patients with PSVD, esophageal varices can be found in up to platelet count, it is routinely used for the assessment of PH in
ACLD [8–10]. Indeed, this combination (LSM <20 kPa and platelet
count >150 × 109 /L) accurately selects patients that can safely
avoid endoscopic screening for gastroesophageal varices [7]. In
✩
Financial disclosure: None to report. contrast with ACLD, data on LSM in patients with PSVD is lim-
✩✩
Conflicts of interest from all authors: None to report. ited [11–15]. Recently the cut-off values of <10 kPa and >20 kPa
★
Financial relationships relevant to this publication: None to report. were described as strongly suggestive of PSVD and cirrhosis, re-
∗
Corresponding author at: Gastroenterology Department, Centro Hospitalar Uni-
spectively [15]. However, this cut-off only presented a sensitivity
versitário de São João, Porto. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto,
Portugal. of 65% for the diagnosis of PSVD and a significant percentage of
E-mail address: [email protected] (J. Ferreira-Silva). patients (25%) were in the “gray area” of 10–20 kPa.

https://doi.org/10.1016/j.dld.2022.09.018
1590-8658/© 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
J. Ferreira-Silva, R. Gaspar, R. Liberal et al. Digestive and Liver Disease 55 (2023) 75–80

Spleen stiffness measurement (SSM) using transient elastogra- tal hypertensive bleeding, and other porto-systemic collaterals at
phy (FibroscanTM ) with a 100 Hz specific probe, was recently pro- imaging. Nonspecific signs of PH included: a history of ascites,
posed as a useful tool in the evaluation of clinically significant PH platelet count <150 × 109/L, and splenomegaly. Platelet count was
in patients with ACLD [7]. In PSVD, SSM’s usefulness as a diag- collected within one month before or after elastography measure-
nostic tool has limited evidence. SSM using point shear wave elas- ment in all patients. Imaging data were obtained from liver ul-
tography was described as useful in the diagnosis of PSVD in pa- trasonography, computed tomography scan, or magnetic resonance
tients with human immunodeficiency virus [16]. Recently, SSM by imaging performed within 6 months before or after elastography
transient elastography was proposed as able to diagnose high-risk measurement in all patients. Splenomegaly was defined as spleen
varices in patients with PSVD [17]. size ≥13 cm in the largest axis. Ascites was defined as either radi-
The present study aimed to assess the accuracy of SSM, LSM, ological ascites or ascites controlled with diuretic therapy.
and SSM/LSM index using transient elastography, for discriminat-
ing PSVD from cirrhosis in patients with signs of PH. 2.5. Endoscopic evaluation

2. Material and methods Upper endoscopy was performed within 1 year of elastogra-
phy measurement. Esophageal varices were evaluated using up-
2.1. Study design per gastrointestinal endoscopy and were classified into low-risk
esophageal varices (varices that had a thickness of less than 5 mm)
We performed a prospective study that included patients with or HRV (varices that had a thickness of more than 5 mm or varices
PSVD or liver cirrhosis, signs of PH, and a liver biopsy performed of any size that display red wales or cherry red spots) in accor-
at least 3 years prior. The study was conducted in the gastroen- dance with Baveno VII guidelines [7]. Patients with elastic band
terology department at a tertiary hospital center. All patients were ligation (EBL) in previous gastroscopies, for treatment of HRV, were
selected from our population of patients under esophageal varices classified as high-risk. Patients were under conscious sedation with
screening. Patients were enrolled between January 2020 and De- midazolam during the procedure.
cember 2021. The exclusion criteria were: previous splenectomy,
high volume ascites at the day of study inclusion, oncologic dis- 2.6. Elastography measures
ease, transjugular intrahepatic porto-systemic shunt, and current
treatment with beta blockers. The choice to exclude patients under SSM and LSM were performed on the same day with patients
beta blockers was made in line with recent finds that show that in the supine position, with at least 6 h of fasting, using FibroScan
the use of betablockers may decrease elastography measurements, 360 (Echosens®) device. Spleen marking was performed with an
especially SSM measurements that can be lowered by up to 10% ultrasound probe before SSM. LSM was performed with M or XL
[18]. We performed a study protocol with clinical exam, laboratory probes in accordance with the thickness of subcutaneous fat and
tests (hemogram, hepatic panel, renal biochemistry, and albumin), SSM was performed with a 100 Hz M probe alone. Two separate
abdominal ultrasound, and liver and spleen transient elastography. sets of 10 measures each were performed for SSM and LSM and
Informed consent forms were signed by the participants. The study the average value was recorded. Quality criteria applied for SSM
protocol conforms to the ethical guidelines of the 1975 Declaration measurement were similar to LSM (≥60% success rate; interquar-
of Helsinki (6th revision, 2008) as reflected in a priori approval by tile range <30% of median). We calculated the SSM/LSM index by
our institution’s human research committee. dividing the median SSM value by the median LSM value in each
patient.
2.2. Patients with PSVD
2.7. Sample size calculation
PSVD was defined, in accordance with vascular liver disease
group (VALDIG) criteria, as liver biopsy with a fragment of at
The sample size was based on the primary outcome measure of
least 20 mm excluding cirrhosis and presence of PH or presence
diagnostic accuracy. Assuming a diagnostic accuracy of 85% as pre-
of liver biopsy findings specific to PSVD (obliterative venopathy,
viously reported for LSM [15], with 80% power and α = 0.05, the
nodular regenerative hyperplasia or incomplete septal fibrosis) [1].
total sample size was estimated at 84 patients, with 42 patients
We selected patients with at least one specific sign of PH, and
per group. The final sample size was estimated at 44 patients in
liver biopsy was performed within 3 years previous to elastogra-
each group to account for a 5% dropout rate.
phy measurements in all patients. Extra-hepatic conditions associ-
ated with PSVD were classified following VALDIG criteria [1].
2.8. Statistical analysis
2.3. Patients with cirrhosis
The results were recorded and analyzed using SPSS Version 23
Patients with alcohol-related cirrhosis from our institution were (IBM Corporation). The variables’ normality was evaluated using
included. All patients had histologically proven cirrhosis with a histograms and Shapiro-Wilk test. Patients were divided in two
history of excessive alcohol consumption, without associated liver groups: Group 1 (Patients with PSVD) and Group 2 (Patients with
diseases, including previous virus-related cirrhosis. All patients in- cirrhosis). Univariable analysis were performed using independent
cluded were abstinent at enrollment. All had Child-Pugh class A samples T test or independent samples Mann-Whitney U test for
cirrhosis and were included while in the outpatient clinic at enroll- continuous variables and Qui-scare test for categorical variables.
ment. Patients with a previous history of decompensated cirrhosis For SSM, LSM, and SSM/LSM index values, we performed a receiver
before enrollment were also included. We selected patients with at operating characteristic (ROC) curve and calculated the area un-
least one specific sign of PH. Liver biopsy was performed within 3 der the curve (AUROC) using the presence of PSVD as the binary
years previous to elastography measurements in all patients. system classifier. The AUROC was interpreted based as insignifi-
cant for results between 0.50 0–0.60 0, poor predictors for 0.600–
2.4. Portal hypertension 0.700, fair predictors for 0.70 0–0.80 0, good predictors for 0.800–
0.900, and excellent predictors for >0.900. The ideal cut-off value
We defined signs of PH as proposed by VALDIG [1]. Specific for each ROC curve analysis was calculated using the Kolmogorov-
signs of PH included: varices (gastric, esophageal, or ectopic), por- Smirnov test. We performed an additional ROC curve analysis of

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J. Ferreira-Silva, R. Gaspar, R. Liberal et al. Digestive and Liver Disease 55 (2023) 75–80

Fig. 1. Flowchart regarding patients’ selection.

PSVD: Porto-sinusoidal vascular disease; TIPS: Transjugular intrahepatic porto-systemic shunt.

the SSM/LSM index restricted to patients with LSM values between Table 1
Extra-hepatic conditions and histologic findings associ-
10 and 20 kPa, patients without portal vein thrombosis (PVT), and
ated with PSVD.
patients without HRV, using the presence of PSVD as the binary
system classifier. Sensitivity, specificity, positive and negative pre- Extra-hepatic conditions
dictive values, positive and negative likelihood ratios, and diagnos- Immunologic 4 (9.1%)
tic accuracy were calculated based on the ROC curve. Diagnostic Blood diseases 6 (13.6%)
accuracy of LSM and SSM/LSM index was compared using the Mc- Drug-induced 7 (15.9%)
Prothrombotic 2 (4.5%)
Nemar test.
Genetic 3 (6.8%)

3. Results Histologic findings

Nodular regenerative hyperplasia 116 (36.3%)

3.1. Patients with PSDV Obliterative venopathy 10 (22.6%)
Incomplete septal fibrosis 33 (75.1%)

Forty-four patients with PSVD were included (Fig. 1). The me- Abbreviations: PSVD: porto-sinusoidal vascular disease.
dian (IQR) duration between liver biopsy and elastography mea-
surements was 18 (10–26) months. Most patients were male
(56.8%), the median age was 55 (46–62) years. Thirty-five (79.5%) including HRV (14%), gastric varices (6.8%), previous variceal bleed-
patients with PSVD presented at least one specific sign of pH, ing (6.8%), and portosystemic collaterals (40.9%). In the remainder
including HRV (40.9%), gastric varices (11.4%), previous variceal of patients (56.8%), signs of PH included splenomegaly (n = 24),
bleeding (20.5%), and portosystemic collaterals (61.3%). In the re- platelet count <150 × 109 /L (n = 23) and history of ascites (n = 4).
mainder of patients (20.5%), signs of pH included splenomegaly Seven (15.9%) patients with cirrhosis had a previous history of de-
(n = 9), platelet count <150 × 109 /L (n = 9) and history of ascites compensation of cirrhosis.
(n = 3). PVT was present in 7 (15.9%) patients. Twenty-two (50%)
patients presented at least one extra-hepatic condition associated 3.3. Diagnostic performance of elastography measurements for
with PSVD (Table 2). Specific histologic finds of PSVD included discriminating PSVD from cirrhosis
nodular regenerative hyperplasia (36.3%), obliterative venopathy
(22.6%), and incomplete septal fibrosis (75.1%) (Table 2). When The success rate of LSM was 97.8% in our population. Patients
compared with patients with cirrhosis, patients with PSVD pre- with PSVD had lower values of LSM [6.2 (5.2–10.2) kPa] than pa-
sented higher median levels of albumin and platelet count, lower tients with cirrhosis [27.8 (17.7–53.9) kPa] (p<0.001) (Table 3). AU-
levels of prothrombin time, and higher prevalence of specific signs ROC (95% confidence interval) of LSM for the diagnosis of PSVD
of pH (Table 1). was 0.843 (0.751–0.934). Using a cut-off value of 12.4 kPa, LSM
predicted the diagnosis of PSVD with a sensitivity of 91.7%, speci-
3.2. Patients with cirrhosis ficity of 65.9%, and diagnostic accuracy of 77.9% (Table 4). No sta-
tistically significant differences were found between patients with
Forty-four patients with PSVD were included (Fig. 1). The me- PSVD and different histologic finds regarding LSM.
dian (IQR) duration between liver biopsy and elastography mea- Regarding SSM, we obtained a success rate of 97.8%. Patients
surements was 19 (11–27) months. Most patients were male with PSVD presented higher values [59.4 (33–77.7) kPa] than pa-
(65.9%), the median age was 58 (49–65) years. Nineteen (43.2%) of tients with cirrhosis [47.3 (24.3–60.3) kPa] (p = 0.042) (Table 3).
patients with cirrhosis presented at least one specific sign of PH, AUROC (95% confidence interval) of SSM for the diagnosis of PSVD

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J. Ferreira-Silva, R. Gaspar, R. Liberal et al. Digestive and Liver Disease 55 (2023) 75–80

Table 2
Patients baseline characteristics.

Variables Cirrhosis (n = 44) PSVD (n = 44) p value

Sex (M/F) 29/15 25/19 0.863

Age, median (IQR), years 58 (49–65) 55 (46–62) 0.841
BMI, median (IQR) 21.1 (19.0–25.0) 23.5 (21.0–27.0) 0.264
Bilirubin, median (IQR), mg/dL 0.9 (0.8–1.3) 1.19 (0.9–1.4) 0.235
ALT, median (IQR), UI/L 62 (33–82) 49 (34–68) 0.065
Alkaline phosphatase, median (IQR), UI/L 108 (90–151) 93 (65–127) 0.096
GGT, median (IQR), UI/L 92 (57–174) 48 (28–99) 0.064
Albumin, median (IQR), g/L 37 (31–39) 41 (35–51) 0.021
Prothrombin time, median (IQR), s 19 (12–21) 13 (13–15) 0.034
Platelet count, median (IQR), ∗ 10^9 104 (67–167) 195 (80–249) 0.001
High-risk esophageal varices, n (%) 6 (14%) 18 (40.9%) 0.012
Gastric varices, n (%) 3 (6.8%) 5 (11.4%) 0.154
Previous variceal bleeding, n (%) 3 (6.8%) 9 (20.5%) 0.011
Porto-systemic collaterals, n (%) 18 (40.9%) 27 (61.3%) 0.039
Spleen size, median (IQR), mm 140 (124–152) 162 (126–185) 0.057
Ascites, n (%) 4 (9%) 3 (6.8%) 0.123
Portal thrombosis, n (%) 4 (9%) 7 (15.9%) 0.089

Abbreviations: PSVD: Porto-sinusoidal vascular disease; IQR: interquartile ratio; BMI: body mass in-
dex; ALT: alanine aminotransferase.

Table 3
Elastography measurements.

Elastography measurement PSVD (n = 44) Cirrhosis (n = 44) p value

LSM, median (IQR), kPa 6.2 (5.2–10.2) 27.8 (17.7–53.9) <0.001

SSM median (IQR), KPa 59.4 (33–77.7) 47.3 (24.3–60.3) 0.042
SSM/LSM median (IQR), kPa 5.62 (3.15–9.68) 1.55 (1.06–3.24) <0.001

Abbreviations: PSVD: porto-sinusoidal vascular disease, LSM: liver stiffness measure-

ment, SSM: spleen stiffness measurement.

Table 4
Diagnostic performance of elastography measurements.

Elastography measurement AUROC p value Cut-off value Se (%) Sp (%) PPV (%) NPV (%) -LR + LR Diagnostic accuracy (%)

LSM 0.843 ≤0.001 12.5 91.7 65.9 70.2 90 0.12 2,6 77.9
SSM 0.635 0.037 54.0 72.2 60.9 61.9 71.4 0.46 1.8 66.2
SSM/LSM 0.940 ≤0.001 2 86.5 92.7 91.4 88.4 0.14 11.8 89.7
SSM/LSM (patients with LSM 10–20 kPa) 0.859 ≤0.001 2 82.9 73.8 64.3 91.7 0.15 2.88 76.9
SSM/LSM (patients without PVT) 0.928 ≤0.001 2 88.5 88.4 82.1 92.7 0.13 7.63 88.4
SSM/LSM (patients without HRV) 0.891 ≤0.001 2 84.7 78.9 73.3 88.24 0.19 4.02 81.2

Abbreviations: AUROC: area under a receiver operating characteristic curve, Se: sensitivity, Sp: specificity, PPV: positive predictive value, NPV: negative predictive value, -LR:
negative likelihood ration, +LR: positive likelihood ratio, LSM: liver stiffness measurement, SSM: spleen stiffness measurement, PVT: portal vein thrombosis.

was 0.635 (0.508–0.762). Using a cut-off value of 54 kPa, SSM pre- good when restricting the analysis to patients without HRV [0.891
dicted the diagnosis of PSVD with a sensitivity of 72.2%, specificity (0.793–0.989)] (Table 4).
of 60.9%, and diagnostic accuracy of 66.2% (Table 4). In our popu-
lation with PSVD, SSM values did not significantly differ between 4. Discussion
patients with PVT and those without PVT (48.9 kPa vs. 49.9 kPa,
p = 0.512). No statistically significant differences were found be- To our knowledge, this is the first study to evaluate the role
tween patients with PSVD and different histologic finds regarding of the combination of SSM and LSM in the differential diag-
SSM. nosis of PSVD and cirrhosis in patients with PH. We demon-
Applying the SSM/LSM index, patients with PSVD presented strated that, in patients with PH, SSM/LSM >2 accurately pre-
higher values [5.62 (3.15–9.68)] when compared with patients with dicts PSVD with greater accuracy when compared with LSM
cirrhosis [1.55 (1.06–3.24)] (p<0.001) (Table 3). AUROC (95% confi- alone.
dence interval) of SSM/LSM for the diagnosis of PSVD was 0.940 The diagnostic performance of LSM to discriminate PSVD from
(0.889–0.992). Using a cut-off value of 2, SSM/LSM predicted the cirrhosis was previously reported [11,13–15]. LSM <10 kPa was
diagnosis of PSVD with a sensitivity of 86.5%, specificity of 92.7%, proposed as a cut-off value with good diagnostic performance [15].
and diagnostic accuracy of 89.7% (Table 4). Comparing the diag- In our population, LSM was a good predictor of PSVD, confirming
nostic accuracy of LSM (77.9%) with SSM/LSM (89.7%), this differ- previous findings. The optimal cut-off value in our population was
ence was statistically significant (p = 0.0153) (Table 5). Restricting 12.5 kPa. We propose that low LSM values strongly suggest PSVD
the analysis to patients with LSM between the values of 10 and in patients with PH and should prompt the performance of a liver
20 kPa (n = 26), SSM/LSM remained a good predictor for the diag- biopsy.
nosis of PSVD [AUROC 0.859 (0.812–0.906)] (Table 4). In our popu- In patients with portal hypertension, hyperdynamic circulation
lation with PSVD, SSM/LSM values significantly differ between pa- in the spleen causes increased spleen size and stiffness [19]. Pre-
tients with PVT and those without PVT (8.92 vs. 5.18, p = 0.034). vious studies with cirrhotic and PSVD patients demonstrated that
AUROC of SSM/LSM remained excellent when restricting the anal- SSM can accurately predict HRV [17,20,21]. In our population, val-
ysis to patients without PVT [0.928 (0.865–0.991)] and continued ues of SSM were greater in patients with PSVD when compared
with patients with cirrhosis. Despite being statistically significant,

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J. Ferreira-Silva, R. Gaspar, R. Liberal et al. Digestive and Liver Disease 55 (2023) 75–80

Table 5
Accuracy comparison between liver stiffness measurement and SSM/LSM index using McNemar test.

LSM

Correct diagnosis Incorrect diagnosis Total P value

SSM/LSM
Correct diagnosis 65 (73.8%) 14 (15.9%) 79 (89.8%) 0.0153
Incorrect diagnosis 3 (3.4%) 6 (6.8%) 9 (10.2%)
Total 68 (77.3%) 20 (22.7%)

Abbreviations: LSM: liver stiffness measurement, SSM: spleen stiffness measurement.

this difference was smaller in absolute terms when compared with authors disclosed no financial relationships relevant to this publi-
LSM values. This might help explain the poorer diagnostic perfor- cation.
mance of SSM.
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