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Splenic-hepatic elastography index is useful in differentiating between porto-sinusoidal vascular disease and cirrhosis in patients with portal hypertension

  • Joel Ferreira-Silva
    Correspondence
    Corresponding author at: Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal.
    Affiliations
    Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal

    Faculty of Medicine of the University of Porto, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal
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  • Rui Gaspar
    Affiliations
    Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal

    Faculty of Medicine of the University of Porto, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal
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  • Rodrigo Liberal
    Affiliations
    Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal

    Faculty of Medicine of the University of Porto, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal
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  • Hélder Cardoso
    Affiliations
    Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal

    Faculty of Medicine of the University of Porto, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal
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  • Guilherme Macedo
    Affiliations
    Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal

    Faculty of Medicine of the University of Porto, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal
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Published:October 21, 2022DOI:https://doi.org/10.1016/j.dld.2022.09.018

      Abstract

      Introduction

      In patients with portal hypertension (PH), the differential diagnosis between porto-sinusoidal vascular disease (PSVD) and cirrhosis is challenging. This study aims to evaluate the diagnostic accuracy of the SSM/LSM index in the diagnosis of PSVD.

      Methods

      Prospective study of patients with PH and PSVD or cirrhosis. Transient liver and spleen elastography were performed and the ratio between spleen stiffness measurement (SSM) and liver stiffness measurement (LSM) was calculated. The relation of SSM/LSM with the diagnosis of PSVD was evaluated.

      Results

      Forty-four patients with PSVD and 44 patients with cirrhosis were evaluated. Median age was 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) 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 cirrhosis, 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.

      Keywords

      1. Introduction

      Porto-sinusoidal vascular disease (PSVD) was recently proposed by Vascular Liver Disease Interest Group (VALDIG) as a term to describe a group of rare vascular liver entities previously known as idiopathic non-cirrhotic portal hypertension [
      • De Gottardi A.
      • Rautou P.E.
      • Schouten J.
      • et al.
      Porto-sinusoidal vascular disease: proposal and description of a novel entity.
      ]. This diagnosis is characterized by the combination of the absence of liver cirrhosis and the presence of microvascular histological lesions or findings of portal hypertension (PH) [
      • De Gottardi A.
      • Rautou P.E.
      • Schouten J.
      • et al.
      Porto-sinusoidal vascular disease: proposal and description of a novel entity.
      ]. As a consequence of its rarity, PSVD is still frequently overlooked and misdiagnosed as cirrhosis [
      • Hillaire S.
      • Cazals-Hatem D.
      • Bruno O.
      • et al.
      Liver transplantation in adult cystic fibrosis: clinical, imaging, and pathological evidence of obliterative portal venopathy.
      ,
      • Meijer B.
      • Simsek M.
      • Blokzijl H.
      • et al.
      Nodular regenerative hyperplasia rarely leads to liver transplantation: a 20-year cohort study in all Dutch liver transplant units.
      ,
      • Krasinskas A.M.
      • Goldsmith J.D.
      • Burke A.
      • Furth E.E.
      Abnormal intrahepatic portal vasculature in native and allograft liver biopsies: a comparative analysis.
      ]. However, the management of PSVD is different from cirrhosis. In patients with PSVD, esophageal varices can be found in up to 80% of patients, at diagnosis [
      • Khanna R.
      • Sarin S.K.
      Non-cirrhotic portal hypertension–diagnosis and management.
      ]. Furthermore, in comparison with cirrhotic patients, patients with PSVD have a greater prevalence of high-risk esophageal varices (HRV) at diagnosis and a greater incidence of variceal bleeding [
      • Khanna R.
      • Sarin S.K.
      Non-cirrhotic portal hypertension–diagnosis and management.
      ,
      • Gioia S.
      • Nardelli S.
      • Pasquale C.
      • et al.
      Natural history of patients with non cirrhotic portal hypertension: comparison with patients with compensated cirrhosis.
      .
      A liver biopsy is mandatory for the diagnosis of PSVD. However, as a consequence of its limitations and risks, liver biopsy is being replaced by noninvasive alternatives in the first-line investigation of patients with PH [
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      Baveno VII - renewing consensus in portal hypertension.
      ].
      Liver stiffness measurement (LSM) using transient elastography (Fibroscan™) is routinely used for the diagnosis of advanced chronic liver disease (ACLD). In addition, in combination with platelet count, it is routinely used for the assessment of PH in ACLD [
      • Thabut D.
      • Bureau C.
      • Layese R.
      • et al.
      Validation of baveno vi criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy.
      ,
      • Augustin S.
      • Pons M.
      • Maurice J.B.
      • et al.
      Expanding the Baveno VI criteria for the screening of varices in patients with compensated advanced chronic liver disease.
      ,
      • Abraldes J.G.
      • Bureau C.
      • Stefanescu H.
      • et al.
      Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: the "Anticipate" study.
      ]. Indeed, this combination (LSM <20 kPa and platelet count >150 × 109/L) accurately selects patients that can safely avoid endoscopic screening for gastroesophageal varices [
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      Baveno VII - renewing consensus in portal hypertension.
      ]. In contrast with ACLD, data on LSM in patients with PSVD is limited [
      • Chougule A.
      • Rastogi A.
      • Maiwall R.
      • Bihari C.
      • Sood V.
      • Sarin S.K.
      Spectrum of histopathological changes in patients with non-cirrhotic portal fibrosis.
      ,
      • Seijo S.
      • Reverter E.
      • Miquel R.
      • et al.
      Role of hepatic vein catheterisation and transient elastography in the diagnosis of idiopathic portal hypertension.
      ,
      • Sharma P.
      • Agarwal R.
      • Dhawan S.
      • et al.
      Transient elastography (fibroscan) in patients with non-cirrhotic portal fibrosis.
      ,
      • Laharie D.
      • Vergniol J.
      • Bioulac-Sage P.
      • et al.
      Usefulness of noninvasive tests in nodular regenerative hyperplasia of the liver.
      ,
      • Elkrief L.
      • Lazareth M.
      • Chevret S.
      • et al.
      Liver stiffness by transient elastography to detect porto-sinusoidal vascular liver disease with portal hypertension.
      ]. Recently the cut-off values of <10 kPa and >20 kPa were described as strongly suggestive of PSVD and cirrhosis, respectively [
      • Elkrief L.
      • Lazareth M.
      • Chevret S.
      • et al.
      Liver stiffness by transient elastography to detect porto-sinusoidal vascular liver disease with portal hypertension.
      ]. However, this cut-off only presented a sensitivity of 65% for the diagnosis of PSVD and a significant percentage of patients (25%) were in the “gray area” of 10–20 kPa.
      Spleen stiffness measurement (SSM) using transient elastography (Fibroscan™) with a 100 Hz specific probe, was recently proposed as a useful tool in the evaluation of clinically significant PH in patients with ACLD [
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      Baveno VII - renewing consensus in portal hypertension.
      ]. In PSVD, SSM's usefulness as a diagnostic tool has limited evidence. SSM using point shear wave elastography was described as useful in the diagnosis of PSVD in patients with human immunodeficiency virus [
      • Ahmad A.K.
      • Atzori S.
      • Taylor-Robinson S.D.
      • Maurice J.B.
      • Cooke G.S.
      • Garvey L.
      Spleen stiffness measurements using point shear wave elastography detects noncirrhotic portal hypertension in human immunodeficiency virus.
      ]. Recently, SSM by transient elastography was proposed as able to diagnose high-risk varices in patients with PSVD [
      • Ferreira-Silva J.
      • Gaspar R.
      • Liberal R.
      • Cardoso H.
      • Macedo G
      Transient splenic elastography predicts high-risk esophageal varices in patients with non-cirrhotic portal hypertension.
      ].
      The present study aimed to assess the accuracy of SSM, LSM, and SSM/LSM index using transient elastography, for discriminating PSVD from cirrhosis in patients with signs of PH.

      2. Material and methods

      2.1 Study design

      We performed a prospective study that included patients with PSVD or liver cirrhosis, signs of PH, and a liver biopsy performed at least 3 years prior. The study was conducted in the gastroenterology department at a tertiary hospital center. All patients were selected from our population of patients under esophageal varices screening. Patients were enrolled between January 2020 and December 2021. The exclusion criteria were: previous splenectomy, high volume ascites at the day of study inclusion, oncologic disease, transjugular intrahepatic porto-systemic shunt, and current treatment with beta blockers. The choice to exclude patients under beta blockers was made in line with recent finds that show that the use of betablockers may decrease elastography measurements, especially SSM measurements that can be lowered by up to 10% [
      • Marasco G.
      • Dajti E.
      • Ravaioli F.
      • et al.
      Spleen stiffness measurement for assessing the response to β-blockers therapy for high-risk esophageal varices patients.
      ]. We performed a study protocol with clinical exam, laboratory tests (hemogram, hepatic panel, renal biochemistry, and albumin), abdominal ultrasound, and liver and spleen transient elastography. Informed consent forms were signed by the participants. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki (6th revision, 2008) as reflected in a priori approval by our institution's human research committee.

      2.2 Patients with PSVD

      PSVD was defined, in accordance with vascular liver disease group (VALDIG) criteria, as liver biopsy with a fragment of at least 20 mm excluding cirrhosis and presence of PH or presence of liver biopsy findings specific to PSVD (obliterative venopathy, nodular regenerative hyperplasia or incomplete septal fibrosis) [
      • De Gottardi A.
      • Rautou P.E.
      • Schouten J.
      • et al.
      Porto-sinusoidal vascular disease: proposal and description of a novel entity.
      ]. We selected patients with at least one specific sign of PH, and liver biopsy was performed within 3 years previous to elastography measurements in all patients. Extra-hepatic conditions associated with PSVD were classified following VALDIG criteria [
      • De Gottardi A.
      • Rautou P.E.
      • Schouten J.
      • et al.
      Porto-sinusoidal vascular disease: proposal and description of a novel entity.
      ].

      2.3 Patients with cirrhosis

      Patients with alcohol-related cirrhosis from our institution were included. All patients had histologically proven cirrhosis with a history of excessive alcohol consumption, without associated liver diseases, including previous virus-related cirrhosis. All patients included were abstinent at enrollment. All had Child-Pugh class A cirrhosis and were included while in the outpatient clinic at enrollment. Patients with a previous history of decompensated cirrhosis before enrollment were also included. We selected patients with at least one specific sign of PH. Liver biopsy was performed within 3 years previous to elastography measurements in all patients.

      2.4 Portal hypertension

      We defined signs of PH as proposed by VALDIG [
      • De Gottardi A.
      • Rautou P.E.
      • Schouten J.
      • et al.
      Porto-sinusoidal vascular disease: proposal and description of a novel entity.
      ]. Specific signs of PH included: varices (gastric, esophageal, or ectopic), portal hypertensive bleeding, and other porto-systemic collaterals at imaging. Nonspecific signs of PH included: a history of ascites, platelet count <150 × 109/L, and splenomegaly. Platelet count was collected within one month before or after elastography measurement in all patients. Imaging data were obtained from liver ultrasonography, computed tomography scan, or magnetic resonance imaging performed within 6 months before or after elastography measurement in all patients. Splenomegaly was defined as spleen size ≥13 cm in the largest axis. Ascites was defined as either radiological ascites or ascites controlled with diuretic therapy.

      2.5 Endoscopic evaluation

      Upper endoscopy was performed within 1 year of elastography measurement. Esophageal varices were evaluated using upper gastrointestinal endoscopy and were classified into low-risk esophageal varices (varices that had a thickness of less than 5 mm) or HRV (varices that had a thickness of more than 5 mm or varices of any size that display red wales or cherry red spots) in accordance with Baveno VII guidelines [
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      Baveno VII - renewing consensus in portal hypertension.
      ]. Patients with elastic band ligation (EBL) in previous gastroscopies, for treatment of HRV, were classified as high-risk. Patients were under conscious sedation with midazolam during the procedure.

      2.6 Elastography measures

      SSM and LSM were performed on the same day with patients in the supine position, with at least 6 h of fasting, using FibroScan 360 (Echosens®) device. Spleen marking was performed with an ultrasound probe before SSM. LSM was performed with M or XL probes in accordance with the thickness of subcutaneous fat and SSM was performed with a 100 Hz M probe alone. Two separate sets of 10 measures each were performed for SSM and LSM and the average value was recorded. Quality criteria applied for SSM measurement were similar to LSM (≥60% success rate; interquartile range <30% of median). We calculated the SSM/LSM index by dividing the median SSM value by the median LSM value in each patient.

      2.7 Sample size calculation

      The sample size was based on the primary outcome measure of diagnostic accuracy. Assuming a diagnostic accuracy of 85% as previously reported for LSM [
      • Elkrief L.
      • Lazareth M.
      • Chevret S.
      • et al.
      Liver stiffness by transient elastography to detect porto-sinusoidal vascular liver disease with portal hypertension.
      ], with 80% power and α = 0.05, the total sample size was estimated at 84 patients, with 42 patients per group. The final sample size was estimated at 44 patients in each group to account for a 5% dropout rate.

      2.8 Statistical analysis

      The results were recorded and analyzed using SPSS Version 23 (IBM Corporation). The variables’ normality was evaluated using histograms and Shapiro-Wilk test. Patients were divided in two groups: Group 1 (Patients with PSVD) and Group 2 (Patients with cirrhosis). Univariable analysis were performed using independent samples T test or independent samples Mann-Whitney U test for continuous variables and Qui-scare test for categorical variables. For SSM, LSM, and SSM/LSM index values, we performed a receiver operating characteristic (ROC) curve and calculated the area under the curve (AUROC) using the presence of PSVD as the binary system classifier. The AUROC was interpreted based as insignificant for results between 0.500–0.600, poor predictors for 0.600–0.700, fair predictors for 0.700–0.800, good predictors for 0.800–0.900, and excellent predictors for >0.900. The ideal cut-off value for each ROC curve analysis was calculated using the Kolmogorov-Smirnov test. We performed an additional ROC curve analysis of the SSM/LSM index restricted to patients with LSM values between 10 and 20 kPa, patients without portal vein thrombosis (PVT), and patients without HRV, using the presence of PSVD as the binary system classifier. Sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and diagnostic accuracy were calculated based on the ROC curve. Diagnostic accuracy of LSM and SSM/LSM index was compared using the McNemar test.

      3. Results

      3.1 Patients with PSDV

      Forty-four patients with PSVD were included (Fig. 1). The median (IQR) duration between liver biopsy and elastography measurements was 18 (10–26) months. Most patients were male (56.8%), the median age was 55 (46–62) years. Thirty-five (79.5%) patients with PSVD presented at least one specific sign of pH, including HRV (40.9%), gastric varices (11.4%), previous variceal bleeding (20.5%), and portosystemic collaterals (61.3%). In the remainder of patients (20.5%), signs of pH included splenomegaly (n = 9), platelet count <150 × 109/L (n = 9) and history of ascites (n = 3). PVT was present in 7 (15.9%) patients. Twenty-two (50%) patients presented at least one extra-hepatic condition associated with PSVD (Table 2). Specific histologic finds of PSVD included nodular regenerative hyperplasia (36.3%), obliterative venopathy (22.6%), and incomplete septal fibrosis (75.1%) (Table 2). When compared with patients with cirrhosis, patients with PSVD presented higher median levels of albumin and platelet count, lower levels of prothrombin time, and higher prevalence of specific signs of pH (Table 1).
      Fig 1
      Fig. 1Flowchart regarding patients’ selection.
      PSVD: Porto-sinusoidal vascular disease; TIPS: Transjugular intrahepatic porto-systemic shunt.
      Table 1Extra-hepatic conditions and histologic findings associated with PSVD.
      Extra-hepatic conditions
       Immunologic4 (9.1%)
       Blood diseases6 (13.6%)
       Drug-induced7 (15.9%)
       Prothrombotic2 (4.5%)
       Genetic3 (6.8%)
      Histologic findings
       Nodular regenerative hyperplasia116 (36.3%)
       Obliterative venopathy10 (22.6%)
       Incomplete septal fibrosis33 (75.1%)
      Abbreviations: PSVD: porto-sinusoidal vascular disease.
      Table 2Patients baseline characteristics.
      VariablesCirrhosis (n = 44)PSVD (n = 44)p value
      Sex (M/F)29/1525/190.863
      Age, median (IQR), years58 (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/dL0.9 (0.8–1.3)1.19 (0.9–1.4)0.235
      ALT, median (IQR), UI/L62 (33–82)49 (34–68)0.065
      Alkaline phosphatase, median (IQR), UI/L108 (90–151)93 (65–127)0.096
      GGT, median (IQR), UI/L92 (57–174)48 (28–99)0.064
      Albumin, median (IQR), g/L37 (31–39)41 (35–51)0.021
      Prothrombin time, median (IQR), s19 (12–21)13 (13–15)0.034
      Platelet count, median (IQR), *10^9104 (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), mm140 (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 index; ALT: alanine aminotransferase.

      3.2 Patients with cirrhosis

      Forty-four patients with PSVD were included (Fig. 1). The median (IQR) duration between liver biopsy and elastography measurements was 19 (11–27) months. Most patients were male (65.9%), the median age was 58 (49–65) years. Nineteen (43.2%) of patients with cirrhosis presented at least one specific sign of PH, including HRV (14%), gastric varices (6.8%), previous variceal bleeding (6.8%), and portosystemic collaterals (40.9%). In the remainder of patients (56.8%), signs of PH included splenomegaly (n = 24), platelet count <150 × 109/L (n = 23) and history of ascites (n = 4). Seven (15.9%) patients with cirrhosis had a previous history of decompensation of cirrhosis.

      3.3 Diagnostic performance of elastography measurements for discriminating PSVD from cirrhosis

      The success rate of LSM was 97.8% in our population. Patients with PSVD had lower values of LSM [6.2 (5.2–10.2) kPa] than patients with cirrhosis [27.8 (17.7–53.9) kPa] (p<0.001) (Table 3). AUROC (95% confidence interval) of LSM for the diagnosis of PSVD 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%, specificity of 65.9%, and diagnostic accuracy of 77.9% (Table 4). No statistically significant differences were found between patients with PSVD and different histologic finds regarding LSM.
      Table 3Elastography measurements.
      Elastography measurementPSVD (n = 44)Cirrhosis (n = 44)p value
      LSM, median (IQR), kPa6.2 (5.2–10.2)27.8 (17.7–53.9)<0.001
      SSM median (IQR), KPa59.4 (33–77.7)47.3 (24.3–60.3)0.042
      SSM/LSM median (IQR), kPa5.62 (3.15–9.68)1.55 (1.06–3.24)<0.001
      Abbreviations: PSVD: porto-sinusoidal vascular disease, LSM: liver stiffness measurement, SSM: spleen stiffness measurement.
      Table 4Diagnostic performance of elastography measurements.
      Elastography measurementAUROCp valueCut-off valueSe (%)Sp (%)PPV (%)NPV (%)-LR+ LRDiagnostic accuracy (%)
      LSM0.8430.00112.591.765.970.2900.122,677.9
      SSM0.6350.03754.072.260.961.971.40.461.866.2
      SSM/LSM0.9400.001286.592.791.488.40.1411.889.7
      SSM/LSM (patients with LSM 10–20 kPa)0.8590.001282.973.864.391.70.152.8876.9
      SSM/LSM (patients without PVT)0.9280.001288.588.482.192.70.137.6388.4
      SSM/LSM (patients without HRV)0.8910.001284.778.973.388.240.194.0281.2
      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.
      Regarding SSM, we obtained a success rate of 97.8%. Patients with PSVD presented higher values [59.4 (33–77.7) kPa] than patients with cirrhosis [47.3 (24.3–60.3) kPa] (p = 0.042) (Table 3). AUROC (95% confidence interval) of SSM for the diagnosis of PSVD was 0.635 (0.508–0.762). Using a cut-off value of 54 kPa, SSM predicted the diagnosis of PSVD with a sensitivity of 72.2%, specificity of 60.9%, and diagnostic accuracy of 66.2% (Table 4). In our population with PSVD, SSM values did not significantly differ between patients with PVT and those without PVT (48.9 kPa vs. 49.9 kPa, p = 0.512). No statistically significant differences were found between patients with PSVD and different histologic finds regarding SSM.
      Applying the SSM/LSM index, patients with PSVD presented higher values [5.62 (3.15–9.68)] when compared with patients with cirrhosis [1.55 (1.06–3.24)] (p<0.001) (Table 3). AUROC (95% confidence interval) of SSM/LSM for the diagnosis of PSVD was 0.940 (0.889–0.992). Using a cut-off value of 2, SSM/LSM predicted the diagnosis of PSVD with a sensitivity of 86.5%, specificity of 92.7%, and diagnostic accuracy of 89.7% (Table 4). Comparing the diagnostic accuracy of LSM (77.9%) with SSM/LSM (89.7%), this difference was statistically significant (p = 0.0153) (Table 5). Restricting the analysis to patients with LSM between the values of 10 and 20 kPa (n = 26), SSM/LSM remained a good predictor for the diagnosis of PSVD [AUROC 0.859 (0.812–0.906)] (Table 4). In our population with PSVD, SSM/LSM values significantly differ between patients with PVT and those without PVT (8.92 vs. 5.18, p = 0.034). AUROC of SSM/LSM remained excellent when restricting the analysis to patients without PVT [0.928 (0.865–0.991)] and continued good when restricting the analysis to patients without HRV [0.891 (0.793–0.989)] (Table 4).
      Table 5Accuracy comparison between liver stiffness measurement and SSM/LSM index using McNemar test.
      LSM
      Correct diagnosisIncorrect diagnosisTotalP value
      SSM/LSM
      Correct diagnosis65 (73.8%)14 (15.9%)79 (89.8%)0.0153
      Incorrect diagnosis3 (3.4%)6 (6.8%)9 (10.2%)
      Total68 (77.3%)20 (22.7%)
      Abbreviations: LSM: liver stiffness measurement, SSM: spleen stiffness measurement.

      4. Discussion

      To our knowledge, this is the first study to evaluate the role of the combination of SSM and LSM in the differential diagnosis of PSVD and cirrhosis in patients with PH. We demonstrated that, in patients with PH, SSM/LSM >2 accurately predicts PSVD with greater accuracy when compared with LSM alone.
      The diagnostic performance of LSM to discriminate PSVD from cirrhosis was previously reported [
      • Chougule A.
      • Rastogi A.
      • Maiwall R.
      • Bihari C.
      • Sood V.
      • Sarin S.K.
      Spectrum of histopathological changes in patients with non-cirrhotic portal fibrosis.
      ,
      • Sharma P.
      • Agarwal R.
      • Dhawan S.
      • et al.
      Transient elastography (fibroscan) in patients with non-cirrhotic portal fibrosis.
      ,
      • Laharie D.
      • Vergniol J.
      • Bioulac-Sage P.
      • et al.
      Usefulness of noninvasive tests in nodular regenerative hyperplasia of the liver.
      ,
      • Elkrief L.
      • Lazareth M.
      • Chevret S.
      • et al.
      Liver stiffness by transient elastography to detect porto-sinusoidal vascular liver disease with portal hypertension.
      ]. LSM <10 kPa was proposed as a cut-off value with good diagnostic performance [
      • Elkrief L.
      • Lazareth M.
      • Chevret S.
      • et al.
      Liver stiffness by transient elastography to detect porto-sinusoidal vascular liver disease with portal hypertension.
      ]. In our population, LSM was a good predictor of PSVD, confirming previous findings. The optimal cut-off value in our population was 12.5 kPa. We propose that low LSM values strongly suggest PSVD in patients with PH and should prompt the performance of a liver biopsy.
      In patients with portal hypertension, hyperdynamic circulation in the spleen causes increased spleen size and stiffness [
      • Kim H.Y.
      • Jin E.H.
      • Kim W.
      • et al.
      The role of spleen stiffness in determining the severity and bleeding risk of esophageal varices in cirrhotic patients.
      ]. Previous studies with cirrhotic and PSVD patients demonstrated that SSM can accurately predict HRV [
      • Ferreira-Silva J.
      • Gaspar R.
      • Liberal R.
      • Cardoso H.
      • Macedo G
      Transient splenic elastography predicts high-risk esophageal varices in patients with non-cirrhotic portal hypertension.
      ,
      • Stefanescu H.
      • Grigorescu M.
      • Lupsor M.
      • Procopet B.
      • Maniu A.
      • Badea R.
      Spleen stiffness measurement using Fibroscan for the noninvasive assessment of esophageal varices in liver cirrhosis patients.
      ,
      • Colecchia A.
      • Montrone L.
      • Scaioli E.
      • et al.
      Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis.
      . In our population, values of SSM were greater in patients with PSVD when compared with patients with cirrhosis. Despite being statistically significant, this difference was smaller in absolute terms when compared with LSM values. This might help explain the poorer diagnostic performance of SSM.
      The creation of the SSM/LSM index was inspired by the finding of smaller values of LSM and greater levels of SSM in our population with PSVD when compared with patients with cirrhosis. The combination of these two diagnostic measurements in a single tool allowed us to achieve excellent diagnostic performance in our population, superior to LSM or SSM alone. Indeed, SSM/LSM index retained a good diagnostic performance even in patients previously in the “gray area” (LSM 10–20 kPa), allowing a correct diagnosis in 76.9% of patients in this subpopulation. Based on this finding we suggest that SSM/LSM index is especially useful in this subpopulation, where other diagnostic tools lack good diagnostic performance.
      PVT is known to induce a decrease in LSM values in animal models [
      • Chatelin S.
      • Pop R.
      • Giraudeau C.
      • et al.
      Influence of portal vein occlusion on portal flow and liver elasticity in an animal model.
      ]. Furthermore, SSM values are known to be associated with PVT [
      • Madhusudhan K.S.
      • Kilambi R.
      • Shalimar Pal S
      • Sharma R.
      • Srivastava D.N
      Evaluation of splenic stiffness in patients of extrahepatic portal vein obstruction using 2D shear wave elastography: comparison with intra-operative portal pressure.
      ]. To account for this, we restrained our analysis to patients without PVT. SSM/LSM index retained a good diagnostic performance in this subpopulation.
      Patients with PSVD had a higher prevalence of HRV and previous variceal bleeding, in our population. This finding allows us to suspect that our population with PSVD had more severe PH when compared to our population with cirrhosis. Previous studies correlated the severity of PH with both LSM and SSM in patients with cirrhosis [
      • Jansen C.
      • Bogs C.
      • Verlinden W.
      • et al.
      Shear-wave elastography of the liver and spleen identifies clinically significant portal hypertension: a prospective multicentre study.
      ,
      • Vizzutti F.
      • Arena U.
      • Romanelli R.G.
      • et al.
      Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis.
      ,
      • Hu X.
      • Huang X.
      • Hou J.
      • Ding L.
      • Su C.
      • Meng F.
      Diagnostic accuracy of spleen stiffness to evaluate portal hypertension and esophageal varices in chronic liver disease: a systematic review and meta-analysis.
      ,
      • Takuma Y.
      • Nouso K.
      • Morimoto Y.
      • et al.
      Portal hypertension in patients with liver cirrhosis: diagnostic accuracy of spleen stiffness.
      ]. We can speculate that having matched patients with PSVD and cirrhosis on the severity of PH would have increased the difference in LSM values between the groups, reinforcing our findings. However, the same speculation cannot be made for SSM values, which were greater in patients with PSVD. To overcome this potential limitation, we restricted the diagnostic performance of the SSM/LSM index to patients without HRV. Indeed, SSM/LSM retained a good AUROC for the diagnosis of PSVD, with a sensitivity of 84.7, specificity of 78.9, and accuracy of 81.2%.
      This study has some additional potential limitations. The small population used in this study might present a limitation and results should be interpreted with caution given the limited size of the cohorts. The lack of direct portal pressure measurement in our study did not allow us to evaluate the difference in portal pressure values between patients with PSVD and patients with cirrhosis and its potential influence on SSM and LSM.
      In conclusion, in a patient with signs of PH, LSM, SSM, and SSM/LSM index are useful in discriminating PSVD from cirrhosis. Given their noninvasive profile, they are most relevant in the initial assessment of these complex patients. SSM/LSM index presents a superior diagnostic performance, in our population, when compared with LSM and SSM alone. This diagnostic tool might be particularly useful in patients with LSM values between 10 and 20 kPa, namely in the absence of an established cause for cirrhosis, in whom clinical orientation remains doubtful.

      Conflict of Interest

      None of the authors acted as Reviewer or Editor of this article. There are no conflicts of interest or financial ties to disclose. All authors disclosed no financial relationships relevant to this publication.

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