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Splenic-hepatic elastography index is useful in differentiating between porto-sinusoidal vascular disease and cirrhosis in patients with portal hypertension
Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, PortugalFaculty of Medicine of the University of Porto, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal
Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, PortugalFaculty of Medicine of the University of Porto, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal
Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, PortugalFaculty of Medicine of the University of Porto, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal
Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, PortugalFaculty of Medicine of the University of Porto, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal
Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, PortugalFaculty of Medicine of the University of Porto, Porto, Portugal. Alameda Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal
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.
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 [
]. 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) [
]. 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 [
]. 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 [
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 [
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 [
Validation of baveno vi criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy.
]. 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 [
]. 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 [
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% [
]. 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) [
]. 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 [
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.
]. 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 [
]. 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 [
], 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).
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.
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.
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 [
]. 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 [
. 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 [
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 [
Diagnostic accuracy of spleen stiffness to evaluate portal hypertension and esophageal varices in chronic liver disease: a systematic review and meta-analysis.
]. 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.
References
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Porto-sinusoidal vascular disease: proposal and description of a novel entity.
Validation of baveno vi criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy.
Evaluation of splenic stiffness in patients of extrahepatic portal vein obstruction using 2D shear wave elastography: comparison with intra-operative portal pressure.
Diagnostic accuracy of spleen stiffness to evaluate portal hypertension and esophageal varices in chronic liver disease: a systematic review and meta-analysis.
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