If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Hepatology, University Clinic for Visceral Surgery and Medicine (UVCM), Inselspital, University Hospital of Bern, Freiburgstrasse, 3010 Bern, SwitzerlandDepartment of Biomedical Research, University of Bern, Switzerland
Hepatology, University Clinic for Visceral Surgery and Medicine (UVCM), Inselspital, University Hospital of Bern, Freiburgstrasse, 3010 Bern, SwitzerlandDepartment of Biomedical Research, University of Bern, Switzerland
Hepatology, University Clinic for Visceral Surgery and Medicine (UVCM), Inselspital, University Hospital of Bern, Freiburgstrasse, 3010 Bern, SwitzerlandDepartment of Biomedical Research, University of Bern, Switzerland
Clinically significant portal hypertension can be identified noninvasively (liver stiffness >21 kPa; portosystemic collaterals on imaging), but cannot be ruled out with confidence.
•
Endoscopic screening of varices can be safely avoided if liver stiffness is less than 20 kPa and platelet count is greater than 150 g/L, because varices needing treatment are rare in these patients.
•
Spleen stiffness is a novel promising parameter for the noninvasive assessment of portal hypertension.
Introduction
The natural history of chronic liver disease is characterized by a long asymptomatic or compensated phase. During this long phase, fibrosis progresses eventually leading to cirrhosis, which is histologically defined by marked anatomic changes encompassing septae formation, hepatocyte extinction and regeneration, and angiogenesis. Portal pressure increases progressively as well, and in patients with bridging fibrosis and cirrhosis the hepatic venous pressure gradient (HVPG; the best method to assess portal hypertension in cirrhosis) is over the normal threshold of 5 mm Hg.
Once the HVPG doubles its normal values, namely, once it exceeds 10 mm Hg, portosystemic collateralization becomes relevant, gastroesophageal varices can develop, and patients are prone to experience clinical decompensation, including ascites, bleeding from portal hypertensive sources, and hepatic encephalopathy. This is why an HVPG of 10 mm Hg or higher is as defined clinically significant portal hypertension (CSPH). As discussed, liver fibrosis progression is a slow, dynamic process, often not completely homogenous within the liver, and distinguishing between severe fibrosis and cirrhosis in a compensated patients is not trivial. This led to propose the term compensated advanced chronic liver disease (cACLD).
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
The HVPG measurement remains the reference standard to identify CSPH and to further stratify the risk of complications in cACLD, but is relatively expensive, not point of care, is available only in specialized centers with personnel with adequate training, and can be (rarely) associated with complications.
Given the strong prognostic value of CSPH and owing to its therapeutic implications, noninvasive tests to detect this hemodynamic threshold in a simple and accurate manner have been object of an increasing number of studies in the last 20 years. Ideally, noninvasive tests should reflect exactly the HVPG, or should at least correctly classify patients as having or not CSPH, and as having or not varices needing treatment.
From a logical point of view, noninvasive tests should be used stepwise to identify CSPH first, and then to identify patients who require endoscopy owing to a negligible risk of varices needing treatment. Within the compensated stage, the presence of gastroesophageal varices identify patients at further risk of complications
Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
(Fig. 1). It is very important to underline that the field of action of noninvasive tests for the detection of CSPH and varices is restricted to patients with compensated ACLD, who can have or not have these conditions and are object of the present review. In patients with decompensated cirrhosis, portal hypertension is per definition present,
Fig. 1Stages of cACLD according to D’Amico (D'Amico, 2014 #62). As shown, noninvasive tests (NITs) play a role in the compensated stage of the disease, when the patient is asymptomatic but at risk of carrying CSPH and varices. HE, hepatic encephalopathy; HRS, hepatorenal syndrome; OLT, orthotopic liver transplantation.
Noninvasive tests investigated in this field include laboratory tests, imaging tests, and elastography. These modalities complement the clinical history and physical examination of patients, and have different costs and complexities.
Laboratory tests and physical signs
The physical examination can reveal signs of CSPH, including ascites (sometimes associated with abdominal hernias), splenomegaly, spider nevi, visible abdominal portosystemic collaterals, pleural effusions, and lower limb edema. However, their absence cannot rule out CSPH. Of note, the presence of subclinical ascites (ascites sole detected by ultrasound examination) has been shown to be associated with similar HVPG values than clinical ascites, and to an intermediary survival compared with patients without ascites and with clinical ascites,
In terms of laboratory data, serum biomarkers have initially been introduced to detect liver fibrosis and cirrhosis noninvasively and are classified as direct when reflecting matrix deposition and as indirect when reflecting liver dysfunction. A subset of them has been correlated to portal hypertension and its complications.
The advantages of using laboratory tests to noninvasively assess portal hypertension include their high applicability, good interlaboratory reproducibility, and availability.
European Association for Study of LiverAsociacion Latinoamericana para el Estudio del H EASL-ALEH clinical practice guidelines: non-invasive tests for evaluation of liver disease severity and prognosis.
However, serum biomarkers need to be interpreted critically because some of their individual components can be affected by a variety of comorbidities. Overall, their diagnostic accuracy to detect CSPH and gastroesophageal varices, when used alone, remains modest. Moreover, none of them has been validated to monitor portal pressure and HVPG changes with or without treatment, limiting further their clinical usefulness.
and a platelet count of less than 100 × 109/L strongly suggests CSPH. Von Willebrand factor antigen, produced by activated endothelial cells, also correlates with HVPG and was shown to be an independent predictor of CSPH (area under the receiver operating characteristic curve [AUROC] 0.85 using a cut-off value of ≥241%).
The VITRO Score (Von Willebrand Factor Antigen/Thrombocyte Ratio) as a new marker for clinically significant portal hypertension in comparison to other non-invasive parameters of fibrosis including ELF test.
A variety of biomarkers based on a combination of routine liver blood tests including aspartate aminotransferase (AST)-to-alanine aminotransferase ratio, AST to platelet ratio index, Fibrosis index, Fibrosis 4 index, Forns index, King's score, and the Lok index (Table 1) have shown a moderate diagnostic accuracy in predicting CSPH. A recent study showed that King's score, AST to platelet ratio index, and the Lok index had the best diagnostic accuracy, but that the latter was modest, with AUROCs of 0.755 and 0.742, 0.740 and 0.742, and 0.722 and 0.717, for CSPH, and severe portal hypertension, respectively.
Some scores combining direct and indirect biomarkers with the use of patented formulas were also shown to be able to detect CSPH. For instance, the FibroTest (Biopredictive, Paris, France) had in 1 study an AUROC of 0.79 for severe portal hypertension; however, it correlated weakly with the HVPG in patients with cirrhosis.
Numerous other individual biomarkers have shown a correlation with CSPH, such as the prothrombin index (Pearson correlation coefficient, −0.72; AUROC 0.89 with a cut-off value of 82.5%),
The macrophage activation marker sCD163 combined with markers of the Enhanced Liver Fibrosis (ELF) score predicts clinically significant portal hypertension in patients with cirrhosis.
Despite some interesting data, the evidence is currently not strong enough to recommend the use of these markers in clinical practice.
Looking specifically at the diagnosis of gastroesophageal varices, the platelet count is usually lower in patients with gastroesophageal varices, but no absolute cut-off value used alone has a satisfactory performance to detect them, with AUROCs in the 0.60 to 0.75 range.
A systematic review and meta-analysis concluded that AST to platelet ratio index, AST-to-alanine aminotransferase ratio, Fibrosis 4 index, and Lok and Forns scores had low to moderate diagnostic accuracy in predicting the presence of varices and large varices in cirrhosis, with AUROCs of 0.65 to 0.79 overall and summary sensitivities and specificities of 0.60 to 0.78 and 0.56 to 0.68, respectively.
Diagnostic accuracy of APRI, AAR, FIB-4, FI, King, Lok, Forns, and FibroIndex scores in predicting the presence of esophageal varices in liver cirrhosis: a systematic review and meta-analysis.
The FibroTest was shown to be a good predictor of large esophageal varices (AUROC, 0.77) and had an 86% negative predictive value at a cut-off of 0.80.
have also been showed to predict the presence of gastroesophageal varices, contrary to hyaluronic acid, laminin, amino-terminal propeptide of type III procollagen, and collagen IV.
Despite data showing that individual laboratory tests have a moderate performance in detecting CSPH and gastroesophageal varices, their use alone cannot currently be recommended. Nevertheless, their combination with other noninvasive methods has shown promising results.
Imaging
Imaging methods used for portal hypertension include ultrasound (complemented by color, power, and pulsed Doppler, and contrast-enhanced techniques), computed tomography (CT) scan and magnetic resonance (MR). All these methods are able to depict the macroscopic changes occurring in the liver, spleen, and vessels of the portal venous system as a consequence of the progression of liver disease and portal hypertension. Some recent studies reported that the nodularity of the liver surface (as quantified by using a specific software) by ultrasound examination
is able to detect the presence of cirrhosis confidently and correlates with the HVPG, so allowing the identification of patients with likely CSPH (AUROC, 0.88; cut-off, 2.8; positive predictive value, 88%). The advantage of this simple method is that it could be implemented automatically in CT scans.
The portal vein, splenic vein, and superior mesenteric vein progressively dilate, splenomegaly often appears, and portosystemic collaterals (Fig. 2) can be evident. Particular attention should be paid to portosystemic collaterals, because they are pathognomonic signs of portal hypertension in cACLD,
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
Fig. 2Imaging signs of portal hypertension. (Upper left panel) Dilatation of the splenic vein by ultrasound examination. (Upper right panel) Large splenomegaly and numerous large splenorenal collaterals. (Lower panel) Large splenorenal collaterals on conventional ultrasound examination (left) and color Doppler ultrasound examination (right).
Doppler measurements are not sufficiently accurate for CSPH; however, a very low velocity of flow in the portal vein (<12 cm/s) has been associated consistently to the presence of gastroesophageal varices, and is a risk factor for developing portal vein thrombosis.
Several new MR techniques are being tested in patients with portal hypertension and include diffusion-weighted imaging, hepatocellular contrast-enhanced MRI, T1 relaxometry, T1ρ imaging, textural analysis, susceptibility-weighted imaging, and perfusion imaging.
They are highly promising, but need further evaluation and clinical validation.
Among the emerging methods, contrast-enhanced ultrasound examination, taking advantage of the physical properties of the inert gas contained in the microbubbles, has been shown to provide information on portal hypertension. In particular, it has been observed that the amplitude of the subharmonic ultrasound waves decreases in parallel (linearly) to the pressure of the liquid surrounding the microbubbles. Hence, by measuring the subharmonic signal amplitude in the liver veins and in the hepatic veins by contrast-enhanced ultrasound examination, a subharmonic gradient reflecting the HVPG can be measured through adequate mathematical modeling. This approach subharmonic aided pressure estimation (SHAPE) has proven successful and allowed an excellent correlation between the SHAPE HVPG and the HVPG measured invasively (R2 = 0.82); the proposed cut-off was greater than 90% accurate for CSPH.
Imaging methods, and ultrasound examination in particular, are routinely used to follow-up patients with cACLD. Signs suggesting worsening of portal hypertension in compensated patients include enlargement of the portal venous system, further enlargement of spleen size,
Liver elastography for the assessment of clinically significant portal hypertension
Transient Elastography
Liver stiffness measurement (LSM) by transient elastography (TE) has been demonstrated to detect CSPH in patients with cACLD owing to different causes, although the majority of data is linked to viral hepatitis (Table 2). LSM obtained by TE correlates significantly with the HVPG in patients with cACLD, showing a correlation coefficient ranging between 0.55 to 0.86.
As mentioned elsewhere in this article, the correlation between the HVPG and LSM is excellent below the threshold of 10 mm Hg, although it decreases in patients with an HVPG above the threshold for CSPH, likely owing to a flow-dependent increase in portal pressure, not reflected in LSM.
A meta-analysis confirmed the diagnostic capability of this method, reporting an AUROC of 0.93 with a sensitivity of 87.5% (95% confidence interval [CI], 75.8%–93.9%) and a specificity of 85.3% (95% CI, 76.9%–90.9%). The summary correlation coefficient was 0.783 (95% CI, 0.737–0.823).
The VITRO Score (Von Willebrand Factor Antigen/Thrombocyte Ratio) as a new marker for clinically significant portal hypertension in comparison to other non-invasive parameters of fibrosis including ELF test.
Correlation of transient elastography with hepatic venous pressure gradient in patients with cirrhotic portal hypertension: a study of 326 patients from India.
Evaluation of portal hypertension and varices by acoustic radiation force impulse imaging of the liver compared to transient elastography and AST to platelet ratio index.
Evaluation of liver and spleen stiffness with acoustic radiation force impulse quantification elastography for diagnosing clinically significant portal hypertension.
Non-invasive evaluation of portal hypertension using shear-wave elastography: analysis of two algorithms combining liver and spleen stiffness in 191 patients with cirrhosis.
Based on these data, the Baveno VI consensus stated that an LSM greater than 20 to 25 kPa can be used to identify the presence of CSPH (varices) in patients with untreated hepatitis C virus (HCV) or hepatitis B virus cACLD.
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
Comparison of three cut-offs to diagnose clinically significant portal hypertension by liver stiffness in chronic viral liver diseases: a meta-analysis.
performed exclusively in patients with chronic viral hepatitis, it was suggested that 2 cut-offs can be used, namely, less than 13.6 kPa to rule out CSPH (pooled sensitivity 96%; CI 95% 93%–97%), and greater than 22 kPa to rule in CSPH (pooled specificity, 94%; 95% CI, 86%–97%), thus confirming Baveno VI consensus recommendations.
Comparison of three cut-offs to diagnose clinically significant portal hypertension by liver stiffness in chronic viral liver diseases: a meta-analysis.
Consequently, the 13.6 kPa cut-off to rule out CSPH performed poorly after achieving a SVR, because almost one-half of patients with an LSM less than 13.6 kPa still showed an HVPG of 10 mm Hg or greater. In contrast, an LSM of greater than 21 kPa showed to accurately rule in CSPH even after achieving a SVR.
Nevertheless, current evidence does indicate an LSM cut-off that could be used to safely rule out persistence of CSPH, in patients with SVR after HCV therapy.
Because the etiology of the underlying liver disease influences LSM, the application of previous described cut-offs, it has been postulated that LSM accuracy may be limited in patients with nonviral cACLD.
LSM correlated well with the HVPG in patients with alcohol-related liver disease (ArLD) in a recent retrospective study (correlation coefficient, 0.753; AUROC, 0.925).
Reliability of transient elastography-based liver stiffness for diagnosing portal hypertension in patients with alcoholic liver disease: a diagnostic meta-analysis with specific cut-off values.
Despite a good pooled sensitivity (0.89; 95% CI, 0.83–0.93), both the specificity (0.71; 95% CI, 0.64–0.78) and positive likelihood ratio (3.1; 95% CI, 2.4–4 were modest.
Reliability of transient elastography-based liver stiffness for diagnosing portal hypertension in patients with alcoholic liver disease: a diagnostic meta-analysis with specific cut-off values.
Therefore, the cut-off value of 21.8 kPa has a good performance in ruling out CSPH, but it is not satisfactory in ruling in CSPH (similarly to what described for the 13.6 kPa cut-off in viral ACLD).
Comparison of three cut-offs to diagnose clinically significant portal hypertension by liver stiffness in chronic viral liver diseases: a meta-analysis.
Reliability of transient elastography-based liver stiffness for diagnosing portal hypertension in patients with alcoholic liver disease: a diagnostic meta-analysis with specific cut-off values.
According to these data, the cut-off value to be used to rule in CSPH in ArLD seems to be higher than that for viral ACLD. In a recent meeting, a multicenter study with 786 patients showed that LSM was accurate in diagnosing CSPH in most etiologies, including nonalcoholic steatohepatitis, but not in obese patients with nonalcoholic steatohepatitis.
Data on the accuracy of LSM for CSPH in cholestatic liver disease (in which a presinusoidal component of portal hypertension is invariably present) and autoimmune hepatitis are lacking and require targeted studies.
Point Shear Wave Elastography
Similar to TE, point shear wave elastography (pSWE) (acoustic radiation force impulse imaging; Acuson Siemens 2000, Germany) based LSM showed a significant correlation with HVPG (r = 0.609–0.650) and a good diagnostic accuracy for CSPH (AUROC, 0.83–0.93).
Evaluation of portal hypertension and varices by acoustic radiation force impulse imaging of the liver compared to transient elastography and AST to platelet ratio index.
Evaluation of liver and spleen stiffness with acoustic radiation force impulse quantification elastography for diagnosing clinically significant portal hypertension.
Nevertheless, the data are lacking to establish an accurate cut-off value to rule in and rule out CSPH. The current cut-offs are highly variable (ranging from 2.17 to 2.58 m/s), likely owing to the population. Owing to these limitations, pSWE is not recommended for the diagnosis of CSPH.
Two-dimensional shear wave elastography (2D-SWE) demonstrated a good discriminative capacity (AUROC, 0.80–0.87), with sensitivity and specificity ranging between 80% and 90% in most of the studies. In a meta-analysis, Suh and colleagues
confirmed a good diagnostic performance (AUROC, 0.88; 95% CI, 0.85–0.91). The summary sensitivity and summary specificity were 85% (95% CI 75%–91%) and 85% (95% CI, 77%–90%), respectively. The correlation between LSM by 2D-SWE and HVPG was high with a summary correlation coefficient of 0.741 (95% CI, 0.658–0.825).
In a recent study, 2D-SWE correlated with HVPG (r = 0.704; P<.0001), especially if the HVPG was less than 10 mm Hg and was significantly higher in patients with CSPH (15.52 vs 8.14 kPa; P<.0001) and not inferior to LSM-TE (0.92; P = .79). Furthermore, in the subgroup of compensated patients with ArLD, 2D-SWE classified CSPH better than TE (93.33% vs 85.71%; P = .039).
A recent individual patient meta-analysis including 328 patients, 27% with cACLD, showed that LSM using a 2D-SWE of less than 14 kPa may be used to rule out CSPH in patients with cirrhosis.
In the context of hepatitis B virus–related cACLD, a cut-off of less than 13.2 kPa ruled out CSPH with a sensitivity of greater than 90%, and a cut-off greater than 24.9 kPa ruled in CSPH with a specificity of greater than 90%.
Algorithm to rule out clinically significant portal hypertension combining Shear-wave elastography of liver and spleen: a prospective multicentre study.
developed 2 algorithms to noninvasively rule in and rule out CSPH using 2D-SWE using LSM followed by spleen stiffness measurement (SSM). An LSM of less than 16 kPa and an SSM of less than 26.6 were able to rule out CSPH with a sensitivity of 98.6%.
Algorithm to rule out clinically significant portal hypertension combining Shear-wave elastography of liver and spleen: a prospective multicentre study.
An LSM of greater than 38 kPa correctly ruled in CSPH in all patients. In patients with an LSM of less than 38 kPa, an SSM of greater than 27.9 kPa was able to rule in CSPH with a specificity of 91.4%. Combining both algorithms, patients were correctly classified as having or not CSPH in 91.6% of cases with a sensitivity of 98.3% and a specificity of 96.3%.
Non-invasive evaluation of portal hypertension using shear-wave elastography: analysis of two algorithms combining liver and spleen stiffness in 191 patients with cirrhosis.
However, the heterogeneity of cut-offs (2D-SWE, 16–38 kPa), possibly underlines a lack of standardization. Although currently not implemented in clinical practice, the method seems promising and further data are awaited.
Fig. 3 summarizes the advantages and disadvantages of LSM and SSM using the different available ultrasound elastography techniques.
Fig. 3Advantages and disadvantages of LSM and spleen stiffness measurement (SSM) for portal hypertension using the different available ultrasound elastography techniques. 2D-SWE, 2-dimensional shear wave elastography; ACLD, advanced chronic liver disease; PH, portal hypertension; US, ultrasound examination.
Liver elastography for the assessment of gastroesophageal varices
Screening endoscopy for esophageal varices in patients with a diagnosis of ACLD is a crucial part of the management, because it can precisely identify varices needing treatment aimed at decreasing the risk of bleeding.
European Association for the Study of the LiverElectronic address eee, European Association for the Study of the L EASL Clinical practice guidelines for the management of patients with decompensated cirrhosis.
LSM has been proven extensively to predict varices needing treatment. This section includes more recent studies in this field published after the Baveno VI workshop (Table 3).
Table 3Accuracy of LSM using ultrasound elastography techniques (TE, pSWE, and 2D-SWE) for the diagnosis of gastroesophageal varices in the post-Baveno VI era
Study, Year
Design
Type of Ultrasound Elastography Method ± Other Combined
Patient Population; Number of Esophageal Varices, Number Varices Needing Treatment
TE-Cut-offs and AUC Esophageal Varices/Varices Needing Treatment
Baveno criteria 26% (US) and 16% (Italy) spared. SENS. and NPV were 100%. PLT >150 G/L and MELD = 6, increased the number of endoscopies avoided to 54% (US) while maintaining a SENS. and NPV of 100%.
Accuracy of liver stiffness, spleen stiffness, and LS-spleen diameter to platelet ratio score in detection of esophageal varices: systemic review and meta-analysis.
For esophageal varices detection: SSM and LSPS vs LSM (0.90 and 0.91 vs 0.85), specificity (0.73 and 0.76 vs 0.64) For varices needing treatment: SSM (0.87) > LSM (0.85) > LSPS (0.82); LSM, SSM, and LSPS cannot be recommended for detection of varices needing treatment
LSM (20 kPa) and PLT >150 G/L LSM (25 kPa) and PLT >110 G/L
Expanded Baveno VI criteria spare more (51.7%) than (27.6%). expanded missed varices needing treatment (6.8%) than the original criteria (3.8%), Baveno VI: NPV HBV: 0.92, HCV: 1.00, ARLD: 1.00, NAFLD:1.00
Baveno-VI criteria 0% False negative rate in PBC and PSC, saving 39% and 30% of endoscopies. In PBC the other LSM-TE: FNRs >5%. In PSC the expanded Baveno: adequate performance. In both conditions.
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 portal hypertension and varices by acoustic radiation force impulse imaging of the liver compared to transient elastography and AST to platelet ratio index.
Evaluation of liver and spleen stiffness with acoustic radiation force impulse quantification elastography for diagnosing clinically significant portal hypertension.
Evaluation of liver stiffness by 2D-SWE in combination with non-invasive parameters as predictors for esophageal varices in patients with advanced chronic liver disease.
A recent meta-analysis with a total of 3644 patients reported a correct diagnosis of esophageal varices or varices needing treatment after a positive measurement of LSM (with variable cut-offs) did not exceed 70%.
The majority of studies including LSM by TE after the publication of the Baveno VI consensus report have been focused on combination tests (see Table 3).
Point Shear Wave Elastography
pSWE has been widely evaluated for the prediction of esophageal varices, with varied results. A 2014 cohort study reported an AUROC of 0.743 for the prediction of esophageal varices using pSWE (vs TE with an AUROC of 0.802).
Evaluation of portal hypertension and varices by acoustic radiation force impulse imaging of the liver compared to transient elastography and AST to platelet ratio index.
Real-time two-dimensional shear wave ultrasound elastography of the liver is a reliable predictor of clinical outcomes and the presence of esophageal varices in patients with compensated liver cirrhosis.
which was not confirmed in another study including 79 patients revealing no difference between LSM and SSM values (L-2D-SWE and by TE) between patients for varices needing treatment.
demonstrated that, with a stepwise approach combining LSM at a cut-off less than 19 kPa with a cut-off of PLT greater than 100 G/L, esophageal varices were ruled out with 83% accuracy. Another cohort study of patients with cACLD supported these data.
More recently, diagnostic performance of 2D-SWE was shown to be similar to that of TE for predicting the presence of esophageal varices. The AUROCs for predicting varices needing treatment for 2D-SWE and a modified Liver Stiffness-Spleen Size-To-Platelet Ratio Risk Score were 0.712 (95% CI, 0.621–0.738) and 0.834 (95% CI, 0.785–0.875), respectively.
The diagnostic performance of 2D-SWE is similar to that of TE for predicting the presence of esophageal varices.
Overall, larger scale studies are needed to overcome significant discrepancies between among reported cut-offs for both pSWE and 2D-SWE–based LSM. There is solid evidence to support the use of LSM and platelet count, but the future implementation of SSM and other tests to further enhance esophageal varices screening strategies in cACLD is promising.
Liver Stiffness Measurement for the Follow-up of Portal Hypertension
CSPH is a key predictor of risk of clinical decompensation in patients with cACLD.
showed that LSM and HVPG were similarly accurate in predicting a first episode of decompensation in patients with cACLD. All of the clinical events occurred in patients with an LSM of 21.1 kPa or higher.
have shown that in patients with cACLD, LSM holds prognostic value for liver-related events and death. Recently, this finding was confirmed in a systematic review and meta-analysis
Liver stiffness is associated with risk of decompensation, liver cancer, and death in patients with chronic liver diseases: a systematic review and meta-analysis.
of 17 prospective studies, including 7058 patients. In 1 study, an increase of more than 1.5 kPa per year in LSM seemed to add prognostic value to baseline LSM in both primary biliary sclerosis
Baseline values and changes in liver stiffness measured by transient elastography are associated with severity of fibrosis and outcomes of patients with primary sclerosing cholangitis.
As for the combination of LSM with other noninvasive tests, the liver stiffness to spleen/platelet score predicted first decompensation in an hepatitis B virus cohort better than LSM alone cACLD.
Our group recently reported that the liver stiffness to spleen/platelet score was superior to LSM (using an XL probe) and portal hypertension risk score to predict the first clinical decompensation in obese/overweight patients with nonalcoholic steatohepatitis.
Mendoza Y, CS, Murgia G, et al. Simple non-invasive surrogates of portal hypertension predict clinical decompensation in overweight/obese patients with cACLD. 2019;70:e664.
followed 548 patients with cACLD for 3 years and showed that an LSM/SSM–guided screening strategy for varices had a similar low risk of variceal hemorrhage as compared with universal screening endoscopy.
As far as prediction of hepatocellular carcinoma is concerned, a number of prospective studies have identified that LSM in patients with viral cirrhosis is associated with the risk of incidence of hepatocellular carcinoma.
Liver stiffness measurement as an alternative to fibrotic stage in risk assessment of hepatocellular carcinoma incidence for chronic hepatitis C patients.
Transient elastography-based risk estimation of hepatitis B virus-related occurrence of hepatocellular carcinoma: development and validation of a predictive model.
Regarding nonselective beta-blockers (NSBB) response, LSM changes in patients with portal hypertension undergoing therapy do not correlate with changes in HVPG.
As for patients with cACLD who did not undergo variceal screening being within the Baveno criteria, LSM should be repeated yearly, and an increase of LSM or more than 10 kPa indicates the need of starting variceal screening.
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
Validation of Baveno VI criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy.
In patients with portal hypertension, the elevated portal pressure is transmitted to the splenic vein and leads to passive congestion in the spleen. Combined with an increased arterial inflow from splanchnic vasodilation, hyperactivation of splenic lymphoid tissue, fibrogenesis and angiogenesis, this causes an increase in spleen stiffness.
The advantages of SSM in comparison with LSM to assess portal hypertension are multiple (see Fig. 3). First, SSM is devoid of some of the confounding factors that may affect LSM reliability, such as liver congestion, inflammation, infiltration or cholestasis, although a recent study suggested that liver inflammation could potentially increase SSM.
Moreover, SSM takes into account the dynamic component of portal hypertension that is not reflected by LSM and hence correlates better with portal pressure in later stages of liver disease.
SSM can also be useful to differentiate between cirrhotic and noncirrhotic (prehepatic, idiopathic, and presinusoidal) portal hypertension, where there is a mismatch between the LSM and the SSM.
However, 2 main disadvantages have made SSM difficult to implement in clinical practice to date. The first is the high failure rate (≤15%–30%) that has been observed with SSM, mostly with TE and 2D-SWE (supersonic imaging) compared with pSWE, which is feasible most of the time (Table 4). The absence of splenomegaly, ascites, and obesity, as well as movements caused by the heart beating in the case of 2D-SWE, negatively affect the success rate.
and with a novel, spleen-dedicated TE examination (SSM at 100 Hz, where the shear wave frequency is set at 100 Hz instead of 50 Hz) (6%–13% and 7.5% failure rate, respectively).
Liver and spleen stiffness measurements by point shear wave elastography via acoustic radiation force impulse: intraobserver and interobserver variability and predictors of variability in a US population.
Modified spleen stiffness measurement by transient elastography is associated with presence of large oesophageal varices in patients with compensated hepatitis C virus cirrhosis.
Liver and spleen stiffness measured by acoustic radiation force impulse elastography for noninvasive assessment of liver fibrosis and esophageal varices in patients with chronic hepatitis B.
A new sampling method for spleen stiffness measurement based on quantitative acoustic radiation force impulse elastography for noninvasive assessment of esophageal varices in newly diagnosed HCV-related cirrhosis.
Evaluation of liver and spleen stiffness with acoustic radiation force impulse quantification elastography for diagnosing clinically significant portal hypertension.
Is the spleen stiffness value acquired using acoustic radiation force impulse (ARFI) technology predictive of the presence of esophageal varices in patients with cirrhosis of various etiologies?.
Acoustic radiation forced impulse-based splenic prediction model using data mining for the noninvasive prediction of esophageal varices in hepatitis C virus advanced fibrosis.
Real-time two-dimensional shear wave ultrasound elastography of the liver is a reliable predictor of clinical outcomes and the presence of esophageal varices in patients with compensated liver cirrhosis.
The second disadvantage of SSM is the ceiling effect at 75 kPa, specific to TE. The spleen is a stiffer organ than the liver, even in normal subjects, and the use of the same probes and software than for LSM may not be appropriate. To overcome this effect, some authors have proposed to use a modified software, where the SSM can be reflected up to 150 kPa
Modified spleen stiffness measurement by transient elastography is associated with presence of large oesophageal varices in patients with compensated hepatitis C virus cirrhosis.
Spleen Elastography for the Assessment of Portal Hypertension
A number of studies have evaluated the ability of SSM to predict portal hypertension (see Table 4). A recent meta-analysis of 9 studies concluded that SSM strongly correlates with HVPG (summary R = 0.72; 95% CI, 0.63–0.80) and has a good accuracy for predicting CSPH (AUROC, summary sensitivity and specificity of 0.92 [95% CI, 0.89–0.94], 0.88 [95% CI, 0.70–0.96], and 0.84 [95% CI, 0.72–0.92], respectively),
although the heterogeneity of studies included limits the interpretation of these results. Another recent meta-analysis including only studies evaluating 2D-SWE (supersonic imaging) showed a moderate diagnostic accuracy for CSPH.
As for the prediction of severe portal hypertension, a recent study confirms that the correlation between SSM and HVPG decreases with increasing HVPG, especially greater than 16 mm Hg,
where SS is more dependent on the chronic spleen parenchymal remodeling rather than reflecting passive congestion. Thus, SSM is likely not a good tool to identify patients with severe portal hypertension.
Determining the optimal SSM cut-off values to predict CSPH is challenging, as highlighted by the multiple cut-off values proposed in various studies, which depend on the population included (the etiology of liver disease and compensated or decompensated stage) (see Table 4). The use of a single cut-off value is usually associated with suboptimal sensitivity and specificity, whereas the use of 2 values (one rule out with high sensitivity and one rule in with high specificity) has the disadvantage of leading to a large number of unclassified patients. As with LSM, the use of specific cut-offs for each etiology of CLD has been proposed,
Reliability of transient elastography-based liver stiffness for diagnosing portal hypertension in patients with alcoholic liver disease: a diagnostic meta-analysis with specific cut-off values.
Measurement of spleen stiffness with acoustic radiation force impulse imaging predicts mortality and hepatic decompensation in patients with liver cirrhosis.
Real-time two-dimensional shear wave ultrasound elastography of the liver is a reliable predictor of clinical outcomes and the presence of esophageal varices in patients with compensated liver cirrhosis.
Predicting the risk of postoperative liver failure and overall survival using liver and spleen stiffness measurements in patients with hepatocellular carcinoma.
MR elastography (MRE) of the spleen has recently emerged as a potential tool to evaluate portal hypertension. A recent systematic review and meta-analysis of 14 studies (8 studies including spleen MRE) concluded that MRE had a good diagnostic accuracy in detecting portal hypertension with a summary AUROC, sensitivity, and specificity of 0.92 (95% CI, 0.89–0.94), 0.79 (95% CI, 0.61–0.90), and 0.90 (95% CI, 0.80–0.95), respectively.
The major inconvenient of MRE remains its limited availability and cost.
Spleen Elastography for the Assessment of Gastroesophageal Varices
Because the development of gastroesophageal varices depends on CSPH, it is not surprising that SSM can predict their presence (see Table 4). A recent systematic review and meta-analysis of 45 studies (17 evaluating SS with various techniques) concluded that SSM was superior to LSM in predicting esophageal varices in CLD with AUROC, summary sensitivity, and summary specificity of 0.899, 0.90 (95% CI, 0.87–0.94), and 0.73 (95% CI, 0.65–0.80), respectively, compared with 0.817, 0.85 (95% CI, 0.81–0.89), and 0.64 (95% CI, 0.56–0.71) for LSM.
Accuracy of liver stiffness, spleen stiffness, and LS-spleen diameter to platelet ratio score in detection of esophageal varices: systemic review and meta-analysis.
This result is likely attributable to the better performance of SSM compared with LSM in more severe portal hypertension because it reflects better the hemodynamic component of portal hypertension. The diagnostic accuracy was not as good for high-risk esophageal varices (AUROC, 0.807). A study published after showed a slightly better performance for high-risk esophageal varices (AUROC, 0.847).
The results of this meta-analysis, however, need to be interpreted carefully given the heterogeneity of the population included, with both compensated and decompensated patients.
As discussed elsewhere in this article, some studies have evaluated new technologies to improve further the diagnostic capacity of SSM. In a recent study, prediction of large esophageal varices was improved with the use of a novel, spleen-dedicated TE with higher shear wave frequency (100 Hz, compared with the traditional 50 Hz).
In this study, the use of SSM at 100 Hz alone (with a cut-off of 41.3 kPa) could spare 37.8% esophagogastroduodenoscopy compared with Baveno VI alone (8.1%), with a 4.7% rate of missed high-risk esophageal varices (with the total number of high-risk esophageal varices as denominator). Colecchia and associates
As with CSPH, once again, determining optimal rule out and rule in cut-off values is challenging. For SSM by TE, a value of 46 kPa has been accepted as an adequate rule out cut-off, whereas for pSWE and 2D-SWE, no single values can currently be recommended, although they probably are in the range of 2.5 to 3.5 m/s and 21 to 33 kPa, respectively. The Spleen Stiffness Probability Index was recently proposed by Giuffrè and coworkers
to establish, instead of cut-offs, a probability of high-risk esophageal varices for each SSM value, supporting the clinician in deciding whom to screen or not and avoiding the issue of false negatives and false positives that occur with cut-offs.
SSM was also found to be a good predictor of esophageal variceal bleeding (cumulative incidence 7.4%), with an AUROC of 0.857 (0.911 in compensated patients) in a prospective study by Takuma and colleagues,
where patients were followed for a median duration of 32.7 months. In this study, the SSM with the maximal negative predictive value was 3.64 m/s (3.48 m/s in compensated cirrhosis). A retrospective study using TE showed similar results with a 100% negative predictive value at a cut-off SSM value of 42.6 kPa.
Spleen Elastography for the Follow-up of Portal Hypertension
Given the rationale behind SSM, it can be expected that the most efficient treatment for portal hypertension, liver transplantation, causes a net decline in SSM.
Whether SSM could be a useful tool to assess response to other treatments for portal hypertension is a topic of interest. A recent study showed a good performance (AUROC, 0.848) of a model based on dynamic changes in SSM (by pSWE) in predicting the hemodynamic response to NSBB prophylaxis in patients with high-risk esophageal varices.
SSM has also been repeatedly shown to decrease after transjugular intrahepatic portosystemic shunt and, therefore, could be a reliable tool to monitor transjugular intrahepatic portosystemic shunt function,
Modification of splenic stiffness on acoustic radiation force impulse parallels the variation of portal pressure induced by transjugular intrahepatic portosystemic shunt.
except when there is concurrent embolization or thrombosis of competitive shunts, where SSM may increase after transjugular intrahepatic portosystemic shunting.
Sonographic assessment of spleen stiffness before and after transjugular intrahepatic portosystemic shunt placement with or without concurrent embolization of portal systemic collateral veins in patients with cirrhosis and portal hypertension: a feasibility study.
Changes in liver and spleen stiffness by virtual touch quantification technique after balloon-occluded retrograde transvenous obliteration of gastric varices and exacerbation of esophageal varices: a preliminary study.
SSM by virtual touch quantification increased after balloon-occluded retrograde transvenous obliteration and was a predictor of exacerbation of esophageal varices. Studies done in the post-direct-acting antiviral era showed that SSM also decreases after HCV eradication
In conclusion, there are now enough solid data to include SSM in the list of standard, noninvasive tools available to assess CSPH. A number of studies have also proven its good performance in detecting the presence of esophageal varices, justifying its integration in algorithms to select patients for screening endoscopy for varices.
Combination tests
Strategies combining other noninvasive markers of portal hypertension have been implemented to improve diagnostic accuracy of LSM. In a recent meta-analysis, esophageal varices detection for the liver stiffness to spleen/platelet score and SSM was superior to LSM.
Accuracy of liver stiffness, spleen stiffness, and LS-spleen diameter to platelet ratio score in detection of esophageal varices: systemic review and meta-analysis.
Furthermore, in a prospective cohort of patients with cACLD, the liver stiffness to spleen/platelet score correctly classified esophageal varices in around 80% of patients.
Subsequently, the Baveno VI Consensus suggested that a platelet count of more than 150 g/L and a LSM of less than 20 kPa could identify patients with cACLD, with a very low risk (<5%) of varices needing treatment.
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
A meta-analysis concluded that varices needing treatment are found in no more than 4% of patients when the LSM is less than 20 kPa with a normal platelet count.
Moreover, another study tested earlier noninvasive test-based algorithms and Baveno VI and found that esophageal varices misdiagnosed when using platelets in 3.1%, TE in 3.7%, the liver stiffness to spleen/platelet score in 10%, variceal risk index in 11.3%, Baveno VI in 1.8%, and Augustin algorithm in 3.7% of patients. The rate of unnecessary gastroscopies was 46% for platelet count, 25% for TE, 13% for the liver stiffness to spleen/platelet score, 6% for the variceal risk index, 53% for Baveno VI, and 39.1% for the Augustin algorithm.
Validation of noninvasive methods to predict the presence of gastroesophageal varices in a cohort of patients with compensated advanced chronic liver disease.
reported that a strategy using platelet count or more than 150 G/L and a Model for End-stage Liver Disease of 6 without LSM, substantially increased the number of endoscopies avoided to 54%, with a very low rate of missing varices needing treatment. These findings without LSM were not validated because of an unacceptable high rate of missed varices needing treatment.
The Expanded Baveno VI criteria used a platelet count or more than 110 G/L and a LSM of less than 25 kPa potentially spared 40% of endoscopies (21% with Baveno VI criteria) with a risk of missing varices needing treatment of 1.6%.
More recently, combined approaches have included SSM. The combination of SSM with Baveno VI criteria could spare 43.8% of endoscopies. The combined Baveno VI/SSM of 46 or less model would have safely spared 37.4% of endoscopies (0 high-risk esophageal varices missed), compared with 16.5% without SSM.
Fig. 4 summarizes the existing strategies combining noninvasive tests to optimize the selection of patients for endoscopy in the context of cACLD.
Fig. 4Existing strategies based on noninvasive tests to decrease the need of screening for varices treatment (VNT). EGD, esophagogastroduodenoscopy; PLT, platelet count; SSM, spleen stiffness measurement; TE, transient elastography.
Noninvasive tests, and in particular liver elastography, have represented a major advantage in the assessment of patients with cACLD in the last years. Although a perfect method to quantify noninvasively the HVPG is still lacking, novel techniques such as MR-based techniques and SHAPE by contrast-enhanced ultrasound examination have a large potential to become game-changers in this field within the next 5 years. The authors expect also radiomics to expand and become a novel strategy integrating the existing imaging data into robust algorithms allowing better identifying in a completely automated way the presence of CSPH and varices. Given the new data regarding a protective role of NSBB on the onset of decompensation (and not just variceal bleeding), a quick and accurate way of diagnosing CSPH noninvasively will become the standard of care. Awaiting for the validation of these methods, LSM and SSM used in combination, and combined to unrelated methods such as spleen size by imaging and platelet count, already allow to rule in CSPH with an accuracy exceeding 90%.
Recent data showing that the hemodynamic response to NSBB can be mirrored by changes in SSM by pSWE are awaiting validation and, if confirmed, would represent a major advantage in the management of patients with portal hypertension. The HVPG measurement remains the reference standard and it should be used whenever noninvasive tests provide inconsistent results or whenever the clinical decision based on the result implies possible risks for patients (eg, selection of candidates to liver resection for hepatocellular carcinoma; identification of patients nonresponding to medical therapy of portal hypertension after variceal bleeding, potential candidate to transjugular intrahepatic portosystemic shunt).
Clinics care points
•
CSPH can be diagnosed noninvasively in patients with cACLD by the following findings: portosystemic collaterals on imaging and a LSM of more than 20 to 25 kPa.
•
Splenomegaly, thrombocytopenia, and a SSM of more than 46 kPa further increase the likelihood of CSPH.
•
Patients presenting any of the signs discussed in this article while compensated should undergo endoscopy for screening of varices requiring treatment according to the existing guidelines.
•
In the future, patients with signs of CSPH on noninvasive tests might be started on carvedilol straight away to decrease the risk of a first clinical decompensation.
Disclosure
The authors have nothing to disclose.
References
Bosch J.
Abraldes J.G.
Berzigotti A.
et al.
The clinical use of HVPG measurements in chronic liver disease.
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
The VITRO Score (Von Willebrand Factor Antigen/Thrombocyte Ratio) as a new marker for clinically significant portal hypertension in comparison to other non-invasive parameters of fibrosis including ELF test.
The macrophage activation marker sCD163 combined with markers of the Enhanced Liver Fibrosis (ELF) score predicts clinically significant portal hypertension in patients with cirrhosis.
Diagnostic accuracy of APRI, AAR, FIB-4, FI, King, Lok, Forns, and FibroIndex scores in predicting the presence of esophageal varices in liver cirrhosis: a systematic review and meta-analysis.
Comparison of three cut-offs to diagnose clinically significant portal hypertension by liver stiffness in chronic viral liver diseases: a meta-analysis.
Reliability of transient elastography-based liver stiffness for diagnosing portal hypertension in patients with alcoholic liver disease: a diagnostic meta-analysis with specific cut-off values.
Evaluation of portal hypertension and varices by acoustic radiation force impulse imaging of the liver compared to transient elastography and AST to platelet ratio index.
Evaluation of liver and spleen stiffness with acoustic radiation force impulse quantification elastography for diagnosing clinically significant portal hypertension.
Algorithm to rule out clinically significant portal hypertension combining Shear-wave elastography of liver and spleen: a prospective multicentre study.
Non-invasive evaluation of portal hypertension using shear-wave elastography: analysis of two algorithms combining liver and spleen stiffness in 191 patients with cirrhosis.
00005-2&id=gr1.jpg){kind=link}
00005-2&id=gr2.jpg){kind=link}
00005-2&id=gr3.jpg){kind=link}
00005-2&id=gr4.jpg){kind=link}