When the Spleen Gets Tough, the Varices Get Going

Abstract

See“Measurements of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices,” by Takuma Y, Nouso K, Morimoto Y, et al, on page 92; and “Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis,” by Berzigotti A, Seijo S, Arena U, et al, on page 102. See“Measurements of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices,” by Takuma Y, Nouso K, Morimoto Y, et al, on page 92; and “Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis,” by Berzigotti A, Seijo S, Arena U, et al, on page 102. In this era of personalized medicine, it is necessary to stratify different risk groups among patients with cirrhosis. As recently proposed, a revised staging of cirrhosis should start with its main classification of compensated and decompensated cirrhosis, 2 separate entities with different prognostic significance.1Garcia-Tsao G. Friedman S. Iredale J. et al.Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis.Hepatology. 2010; 51: 1445-1449Crossref PubMed Scopus (369) Google Scholar Decompensated cirrhosis is defined by the presence of complications that are mostly secondary to portal hypertension: Ascites, variceal hemorrhage, and/or hepatic encephalopathy. Compensated cirrhosis would in turn be composed of 2 substages: Without varices or with varices. These 2 substages of compensated cirrhosis also have different prognostic significance; patients without varices have a significantly better survival than those with varices.2D'Amico G. Garcia-Tsao G. Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.J Hepatol. 2006; 44: 217-231Abstract Full Text Full Text PDF PubMed Scopus (1836) Google Scholar, 3Zipprich A. Garcia-Tsao G. Rogowski S. et al.Prognostic indicators of survival in patients with compensated and decompensated cirrhosis.Liver Int. 2012; 32: 1407-1414Crossref PubMed Scopus (145) Google Scholar In compensated patients without varices, the degree of portal hypertension predicts the development of both varices4Groszmann R.J. Garcia-Tsao G. Bosch J. et al.Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.N Engl J Med. 2005; 353: 2254-2261Crossref PubMed Scopus (699) Google Scholar and decompensation.5Ripoll C. Groszmann R. Garcia-Tsao G. et al.Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.Gastroenterology. 2007; 133: 481-488Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar Therefore, staging in compensated cirrhosis could be further refined into patients without portal hypertension or portal hypertension that is not clinically significant (hepatic venous pressure gradient [HVPG] < 10 mmHg) and those with clinically significant portal hypertension (CSPH; HVPG > 10 mmHg). Although the diagnosis of decompensated cirrhosis is made clinically, substaging of the compensated patient requires esophagogastroduodenoscopy for the diagnosis of varices and measurement of HVPG for the determination of portal pressure. However, both investigations are invasive and HVPG measurement is only routinely available and/or adequately performed in expert centers. There is thus a need for noninvasive methods able to predict, with acceptable diagnostic accuracy, the presence and size of esophageal varices and the presence of CSPH. Although several simple noninvasive methods, such as serum fibrosis biomarkers and platelet count/spleen diameter ratio have been proposed,6Thabut D. Moreau R. Lebrec D. Noninvasive assessment of portal hypertension in patients with cirrhosis.Hepatology. 2011; 53: 683-694Crossref PubMed Scopus (109) Google Scholar emphasis has been recently placed on liver stiffness measurements (LSM) using transient elastography (TE).7Castera L. Pinzani M. Bosch J. Non invasive evaluation of portal hypertension using transient elastography.J Hepatol. 2012; 56: 696-703Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar Evidence of this is the fact that in the past few months, 3 papers have been or will be published in Gastroenterology that deal with the accuracy of LSM in the diagnosis of varices and/or CSPH.8Berzigotti A. Seijo S. Arena U. et al.Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis.Gastroenterology. 2013; 144: 102-111Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar, 9Colecchia 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.Gastroenterology. 2012; 143: 646-654Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 10Takuma Y. Nouso K. Morimoto Y. et al.Measurements of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices.Gastroenterology. 2013; 144: 92-101Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar However, LSM alone cannot be considered equivalent to CSPH or HVPG in terms of overall accuracy.7Castera L. Pinzani M. Bosch J. Non invasive evaluation of portal hypertension using transient elastography.J Hepatol. 2012; 56: 696-703Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 11Castera L. Le Bail B. Roudot-Thoraval F. et al.Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores.J Hepatol. 2009; 50: 59-68Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar Splenomegaly is a common finding in patients with cirrhosis and portal hypertension and it is therefore reasonable to consider spleen parameters in the diagnosis of varices/CSPH. The most recent study by Berzigotti et al8Berzigotti A. Seijo S. Arena U. et al.Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis.Gastroenterology. 2013; 144: 102-111Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar published in Gastroenterology shows that LSM, when associated with spleen diameter/platelet count ratio, has a higher diagnostic accuracy for both varices and CSPH than LSM alone, as previously suggested for varices in Asian patients with hepatitis B virus cirrhosis.12Kim B.K. Han K.H. Park J.Y. et al.A liver stiffness measurement-based, noninvasive prediction model for high-risk esophageal varices in B-viral liver cirrhosis.Am J Gastroenterol. 2010; 105: 1382-1390Crossref PubMed Scopus (164) Google Scholar Going further, and based on a previous study using magnetic resonance to assess spleen stiffness,13Talwalkar J.A. Yin M. Venkatesh S. et al.Feasibility of in vivo MR elastographic splenic stiffness measurements in the assessment of portal hypertension.AJR Am J Roentgenol. 2009; 193: 122-1227Crossref PubMed Scopus (151) Google Scholar 2 other studies analyze spleen stiffness measurements (SSM) using ultrasound-based techniques in predicting the presence of CSPH and/or varices.9Colecchia 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.Gastroenterology. 2012; 143: 646-654Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 10Takuma Y. Nouso K. Morimoto Y. et al.Measurements of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices.Gastroenterology. 2013; 144: 92-101Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar A study by Colecchia et al9Colecchia 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.Gastroenterology. 2012; 143: 646-654Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar published in a recent issue of Gastroenterology had shown that SSM accurately predicted both the presence of varices and the degree of portal hypertension as evaluated by HVPG.9Colecchia 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.Gastroenterology. 2012; 143: 646-654Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar In this issue of Gastroenterology, Takuma et al10Takuma Y. Nouso K. Morimoto Y. et al.Measurements of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices.Gastroenterology. 2013; 144: 92-101Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar provide evidence supporting the usefulness of SSM in the diagnosis of varices. Whereas the study by Colecchia et al used TE to measure spleen stiffness, the study by Takuma et al used acoustic radiation force impulse (ARFI) imaging. In the study by Takuma et al,10Takuma Y. Nouso K. Morimoto Y. et al.Measurements of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices.Gastroenterology. 2013; 144: 92-101Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar 359 patients who met clinical and radiologic or histologic criteria of cirrhosis, were not receiving therapy for portal hypertension, and did not have portal vein thrombosis or active alcohol ingestion were included in the study. They also excluded 36 patients with prior gastrointestinal hemorrhage and this is inexplicable because the authors included a wide spectrum of disease, with one third of the patients classified as Child B/C and 23% having ascites. They report the results of SSM and LSM in 340 patients, after excluding unsuccessful SSM in 16 patients (4.5%) and LSM in 3 patients. They found that patients with varices had higher SSM compared with patients without varices with highest values in those with high-risk varices (medium/large or small with red wale marks or occurring in a Child C patient). However, a large overlap of SSM could be observed among these groups (Figure 2 in Takuma et al's paper10Takuma Y. Nouso K. Morimoto Y. et al.Measurements of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices.Gastroenterology. 2013; 144: 92-101Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar) and, contrary to the authors' conclusion stating that ARFI provides excellent diagnostic performance for predicting varices and severity of varices, the real value of SSM in our view was in ruling out the presence of varices. In fact, the authors did select a cutoff value of 3.18 m/s with the highest sensitivity and the lowest negative likelihood ratio, the best cutoff to rule out the presence of varices. With this cutoff, 1 patient with high-risk varices (who would have required prophylactic therapy) would have been missed out of 132 patients with varices, although it is uncertain what criterion (endoscopic or Child C) was used to determine the “high risk” in this particular patient. Takuma10Takuma Y. Nouso K. Morimoto Y. et al.Measurements of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices.Gastroenterology. 2013; 144: 92-101Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar et al failed to select a cutoff value that would rule in varices. In contrast, the study by Colecchia et al9Colecchia 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.Gastroenterology. 2012; 143: 646-654Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar selected cutoff levels that could both rule out and rule in the presence of varices with about 25% of the population in the “grey zone.” The advantages of the study by Colecchia et al are that it included only patients with compensated cirrhosis and measured HVPG. The inclusion of patients with both compensated and decompensated cirrhosis in the study by Takuma et al could have affected the predictive value of the test and, in fact, when they analyze Child A patients versus Child B/C patients they find a different cutoff level to rule out varices. In this regard, determining the presence of varices and/or CSPH in patients with decompensated cirrhosis can be considered irrelevant because, by definition, these patients have CSPH and have a high prevalence of varices. In fact, it has been suggested that it would be cost-effective to not screen Child C patients and to start prophylactic β-blocker therapy.14Arguedas M.R. Heudebert G.R. Eloubeidi M.A. et al.Cost-effectiveness of screening, surveillance, and primary prophylaxis strategies for esophageal varices.Am J Gastroenterol. 2002; 97: 2441-2452Crossref PubMed Google Scholar This emphasizes the need to place all of these diagnostic tests in a clinical context. In what subpopulation of patients with cirrhosis do we want to rule out varices (or CSPH)? In what population do we want to rule in varices (or CSPH)? The use of multilevel cutoffs, depending on this clinical context, is more useful than single cutoff levels or than comparisons among AUROCs of different tests. In fact, a previous study had already analyzed SSM in predicting the presence of varices, using ARFI, but only compared mean values among study populations and did not establish any cutoff levels.15Bota S. Sporea I. Sirli R. et al.Spleen assessment by acoustic radiation force impulse elastography (ARFI) for prediction of liver cirrhosis and portal hypertension.Med Ultrason. 2010; 12: 213-217PubMed Google Scholar One technical advantage of ARFI over TE is that it can be performed using a regular ultrasound machine, allowing during a single procedure to choose the region of interest where the shear-wave velocity is measured under direct visualization of the spleen (or liver). In the study by Colecchia et al, ultrasound examination of the spleen was mandatory before performing TE to ensure that the ultrasound beam remained within the spleen parenchyma; SS could not be measured in patients with an anteroposterior spleen diameter measuring <4 cm. It should be stressed, however, that the units of measurement obtained by ARFI (m/s) are entirely different from those obtained by TE (kPa) and have a narrower range (0.5–4.4 m/s vs 2.5–75 kPa). This may limit the ability of SSM by ARFI to provide necessary granularity for clinically relevant cutoffs,16Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C.Gastroenterology. 2012; 142 (e4): 1293-1302Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar particularly given the findings by Colecchia et al that showed significantly higher kPa values (up to 70 kPa) with SSM compared with LSM at any given HVPG level (see Figure 2 from Colecchia et al9Colecchia 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.Gastroenterology. 2012; 143: 646-654Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar), suggesting that even an upper detection limit of 75 kPa could be too restrictive for a satisfactory SSM, and would need to be extended as proposed by some authors.17Calvaruso V. Di Marco V. Bronte F. et al.High spleen stiffness is related to presence of large esophageal varices in patients with HCV cirrhosis (abstract).J Hepatol. 2012; 56: S409Abstract Full Text PDF Google Scholar Another advantage of ARFI may be its greater applicability as TE has been shown to be not applicable in around 1 in 5 European patients, particularly in the presence of obesity.18Castera L. Foucher J. Bernard P.H. et al.Pitfalls of liver stiffness measurement: A 5-year prospective study of 13,369 examinations.Hepatology. 2010; 51: 828-835PubMed Google Scholar In this regard, TE was not applicable in 13% of patients in the study by Colecchia et al, compared with 4.5% for ARFI, both findings consistent with previous reports.15Bota S. Sporea I. Sirli R. et al.Spleen assessment by acoustic radiation force impulse elastography (ARFI) for prediction of liver cirrhosis and portal hypertension.Med Ultrason. 2010; 12: 213-217PubMed Google Scholar, 19Stefanescu H. Grigorescu M. Lupsor M. et al.Spleen stiffness measurement using fibroscan for the noninvasive assessment of esophageal varices in liver cirrhosis patients.J Gastroenterol Hepatol. 2011; 26: 164-170Crossref PubMed Scopus (168) Google Scholar Mean body mass index in both studies was low (23.5 [Takuma et al10Takuma Y. Nouso K. Morimoto Y. et al.Measurements of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices.Gastroenterology. 2013; 144: 92-101Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar and 25 [Colecchia et al9Colecchia 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.Gastroenterology. 2012; 143: 646-654Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar), but with higher body mass indices in US compensated cirrhotic patients, this may be an additional issue. Although not clearly demonstrated in the study by Colecchia et al, the study by Takuma et al showed that SSM was better than LSM, particularly for ruling out the presence of varices. LSM reflect intrahepatic resistance owing to fibrous tissue (that makes the liver stiff) and this would explain how the correlation with HVPG is linear up to levels of 10 mmHg,20Vizzutti F. Arena U. Romanelli R.G. et al.Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis.Hepatology. 2007; 45: 1290-1297Crossref PubMed Scopus (556) Google Scholar, 21Lim J.K. Groszmann R.J. Transient elastography for diagnosis of portal hypertension in liver cirrhosis: is there still a role for hepatic venous pressure gradient measurement?.Hepatology. 2007; 45: 1087-1090Crossref PubMed Scopus (57) Google Scholar after which a hyperdynamic splanchnic circulation contributes to the portal hypertensive state. It seems that a stiff spleen reflects portal hypertension independent of the stage in its development, taking into account both the increased intrahepatic resistance and the increased portal venous inflow. A fascinating aspect of the paper that could provide some insight into the pathogenesis of portal hypertension and splenomegaly in cirrhosis is the fact that, although there is a clear correlation between spleen diameter and SSM (Figure 4 from Takuma et al), SSM was a better predictor of the presence of varices (and therefore the presence of CSPH) than spleen diameter. Notably, there were patients without splenomegaly (diameter <10 cm) who had elevated SSM and varices and there were patients with big spleens with low SSM, most of whom did not have varices. It has traditionally been considered that splenomegaly in cirrhosis is owing to passive congestion. However, a recent study in portal vein-ligated rats showed that splenomegaly is also owing to enlargement and hyperactivation of the splenic lymphoid tissue (white pulp), as well as increased angiogenesis and fibrogenesis.22Mejias M. Garcia-Pras E. Gallego J. et al.Relevance of the mTOR signaling pathway in the pathophysiology of splenomegaly in rats with chronic portal hypertension.J Hepatol. 2010; 52: 529-539Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar The latter were associated with an increase in vascular endothelial growth factor, which in turn has been shown to be implicated in the hyperdynamic circulatory state. Therefore, it is conceivable that angiogenesis and fibrogenesis are increased in small stiff, spleens and reflect the hyperdynamic circulatory state, whereas larger non-stiff spleens have an excess in lymphoid tissue that may reflect immune stimulation but not the hyperdynamic circulatory state. Unlike the paper by Berzigotti et al,9Colecchia 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.Gastroenterology. 2012; 143: 646-654Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar in which data were validated in a separate cohort, the main limitation of both studies on SSM is the lack of external validation; therefore, none of these techniques are ready for “prime time.” Also, it would be useful to determine whether SSM would be comparable with the combination of LSM and platelet count/spleen diameter ratio. Ultimately, any of these tests should demonstrate an ability to predict the development of clinical outcomes. Advantages and limitations of using TE versus ARFI in stiffness measurements are summarized in Table 1. We certainly hope that in the future we will be able to accurately predict the presence of varices (and those that require specific therapy) and the presence of CSPH (currently used to select patients in clinical studies that are high-risk for decompensation or patients with HCC who are candidates for resection) via noninvasive testing. One would foresee different levels of invasiveness, starting with simple laboratory tests, followed by measurements of spleen stiffness and, only in a minority of patients, would we need to perform an invasive test. The studies by Colecchia et al,10Takuma Y. Nouso K. Morimoto Y. et al.Measurements of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices.Gastroenterology. 2013; 144: 92-101Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar Takuma et al,11Castera L. Le Bail B. Roudot-Thoraval F. et al.Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores.J Hepatol. 2009; 50: 59-68Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar and Berzigotti et al9Colecchia 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.Gastroenterology. 2012; 143: 646-654Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar represent a positive step forward toward these goals.Table 1Respective Advantages and Limitations of Liver Stiffness Measurements (LSM) and Spleen Stiffness Measurements (SSM) Using Transient Elastography (TE) and Acoustic Radiation Force Impulse (ARFI) in CirrhosisTEARFIAdvantages User friendly (performed at bedside; rapid, short training)Can be implemented in a regular ultrasound machine Reproducible for LSMRegion of interest smaller than TE but chosen by the operator High range of values (2–75 kPa) for LSM that may be extended to 150 kPa criteria for SSMTheoretical higher applicability than TE Quality well-defined for LSMPerformance likely equivalent to that of TE for LSM Well-validated for LSM with high performance for cirrhosis (AUROC > 0.9)Limitations Requires a dedicated deviceUnits (m/sec) different from that of TE (kPa) Region of interest cannot be chosen by the operatorNarrow range of values (0.5–4.4 m/sec) with the risk of ceiling effect for SSM Ultrasound examination of the spleen mandatory before SSMReproducibility and validation for both LSM and SSM ongoing Low applicability for LSM 80% (obesity, ascites, limited operator experience)Quality criteria not well-defined Reproducibility, quality criteria, validation for SSM uncertainAUROC, area under the receiver operating characteristic curve. Open table in a new tab AUROC, area under the receiver operating characteristic curve. Elastography, Spleen Size, and Platelet Count Identify Portal Hypertension in Patients With Compensated CirrhosisGastroenterologyVol. 144Issue 1PreviewNoninvasive methods are needed to identify clinically significant portal hypertension (CSPH) and esophageal varices (EVs) in patients with compensated cirrhosis. We looked for markers of the presence of CSPH and EVs in patients with cirrhosis. Full-Text PDF Measurement of Spleen Stiffness by Acoustic Radiation Force Impulse Imaging Identifies Cirrhotic Patients With Esophageal VaricesGastroenterologyVol. 144Issue 1PreviewWe evaluated whether spleen stiffness (SS), measured by acoustic radiation force impulse imaging, can identify patients who have esophageal varices (EVs); those without EVs would not require endoscopic examination. Full-Text PDF Covering the CoverGastroenterologyVol. 144Issue 1PreviewUnderstanding of the hepatitis C virus (HCV) and the development of antiviral agents to treat chronic infection was hampered for many years by the inability to achieve viral replication in vitro. The significant advances that have occurred recently in the treatment of chronic hepatitis C infection are, in large part, the result of the development of HCV replicons, self-replicating HCV RNA sequences, for genotypes 1a, 1b, and 2a, and complete cell culture systems. However, no replication systems have been developed for other HCV genotypes, which may be more prevalent in certain areas of the world than HCV genotype 1. Full-Text PDF