Soft technique, hard end-points
Authors: Jaume Bosch
Journal: Journal of Hepatology (2011)

Increased portal pressure is the major factor driving the clinical course of cirrhosis [[1]Garcia-Tsao G. Bosch J. Management of varices and variceal hemorrhage in cirrhosis.N Engl J Med. 2010; 362: 823-832Crossref PubMed Scopus (593) Google Scholar]. This concept seems obvious as most (severe) clinical consequences of chronic liver disease are related to portal hypertension – including varices, bleeding from varices or from portal hypertensive gastropathy/colopathy, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy, hepatopulmonary syndrome, and porto-pulmonary hypertension [[2]Bosch J. Vascular deterioration in cirrhosis. The big picture.J Clin Gastroenterol. 2007; 41: S247-S253Crossref PubMed Scopus (104) Google Scholar]. However, it has not been until very recently demonstrated by longitudinal studies assessing the natural history of portal hypertension in patients with cirrhosis and more important [3Groszmann R.J. Garcia-Tsao G. Bosch J. Grace N.D. Burroughs A.K. Planas R. et al.Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.N Engl J Med. 2005; 353: 2254-2261Crossref PubMed Scopus (671) Google Scholar, 4Ripoll C. Groszmann R. Garcia-Tsao G. Grace N. Burroughs A. Planas R. 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 (676) Google Scholar], its reversion by effective portal pressure reduction by medical treatment [5Feu F. Garcia-Pagan J.C. Bosch J. Luca A. Teres J. Escorsell A. et al.Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis.Lancet. 1995; 346: 1056-1059Abstract Full Text PDF PubMed Scopus (490) Google Scholar, 6Abraldes J.G. Tarantino I. Turnes J. Garcia-Pagan J.C. Rodes J. Bosch J. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis.Hepatology. 2003; 37: 902-908Crossref PubMed Scopus (382) Google Scholar]. The best predictor of development of these complications (or clinical “decompensation”) so far detected is an increase of the hepatic venous pressure gradient (HVPG) of at least 10 mmHg, which represents the threshold value for the complications of portal hypertension to occur [1Garcia-Tsao G. Bosch J. Management of varices and variceal hemorrhage in cirrhosis.N Engl J Med. 2010; 362: 823-832Crossref PubMed Scopus (593) Google Scholar, 3Groszmann R.J. Garcia-Tsao G. Bosch J. Grace N.D. Burroughs A.K. Planas R. et al.Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.N Engl J Med. 2005; 353: 2254-2261Crossref PubMed Scopus (671) Google Scholar, 4Ripoll C. Groszmann R. Garcia-Tsao G. Grace N. Burroughs A. Planas R. 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 (676) Google Scholar]. In this issue of the Journal of Hepatology, Rotic and his co-workers from Toulouse [[7]Ronic M.A. Procopet B. Metivier S. Peron J.M. Selves J. Vinel J.P. et al.Liver stiffness accurately predicts portal hypertension related complications in patients with chronic liver disease: a prospective study.J Hepatol. 2011; 55: 1017-1024Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar] go a step further by showing that one can detect these patients with poor prognosis – who therefore are candidates to portal hypotensive therapy – just by looking at something so simple and “clean” as transient elastography (TE), that had the same predictive value as HVPG, which is a much more invasive, sophisticated, and expensive measurement. Bravo! Certainly the study has limitations. These include: (a) a small number of patients (100, and only 65 of them had cirrhosis, which is the relevant population as only three non-cirrhotic had any event during follow-up), (b) it is likely to have some selection bias, as suggested by the high percentage of patients who already had varices (72% of the compensated cirrhotics) and their unusually high risk of decompensation (55% at 2 year; as compared with the 40% prevalence of varices and 29% incidence of decompensation in a larger study in totally compensated cirrhotics with an 8-year follow-up [3Groszmann R.J. Garcia-Tsao G. Bosch J. Grace N.D. Burroughs A.K. Planas R. et al.Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.N Engl J Med. 2005; 353: 2254-2261Crossref PubMed Scopus (671) Google Scholar, 4Ripoll C. Groszmann R. Garcia-Tsao G. Grace N. Burroughs A. Planas R. 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 (676) Google Scholar]), (c) the potential impact of treatments for portal hypertension offered to these patients on the incidence of events, (d) the lack of explanation on the method of imputation of TE values in the patients where this measurement was not possible, and (e) the role of different etiologies raising the cut off value of TE to detect a HVPG ⩾10 mmHg. Indeed, a key issue is that the 21.1 kPa cut off value to detect patients with clinically significant portal hypertension (defined by an HVPG ⩾10 mmHg) has not been confirmed by other investigators using the same equipment. Thus, Vizzutti et al. [[8]Vizzutti F. Arena U. Romanelli R.G. Rega L. Foschi M. Colagrande S. et al.Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis.Hepatology. 2007; 45: 1290-1297Crossref PubMed Scopus (540) Google Scholar] showed this cut off to be much lower (13.6 kPa) in a study done in patients with chronic liver disease due to hepatitis C, and we do have very similar data at our institution (Berzigotti et al., unpublished data). Also, Kazemi et al. showed that French patients with hepatitis C related cirrhosis could have oesophageal varices (and therefore very significant portal hypertension) with TE values well below 21.1 kPa, [[9]Kazemi F. Kettaneh A. N’kontchou G. Pinto E. Ganne-Carrie N. Trinchet J.C. et al.Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices.J Hepatol. 2006; 45: 230-235Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar] something that was also found by Vizzutti et al. [[8]Vizzutti F. Arena U. Romanelli R.G. Rega L. Foschi M. Colagrande S. et al.Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis.Hepatology. 2007; 45: 1290-1297Crossref PubMed Scopus (540) Google Scholar]. Therefore, if we were to use the results of this study as a guide, we would classify as low risk some of the high risk patients with cirrhosis due to hepatitis C infection, which would diminish the predictive value of the test (and its clinical applicability). In summary, the results of the study that apparently are so clear-cut and robust – which in practice would overcome all its limitations – are not so rock hard as the livers from which the information was drawn [[10]Bosch J. Predictions from a hard liver.J Hepatol. 2006; 45: 174-177Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. This does not mean that the study is not useful. On the contrary, I think this study makes a lot of sense; actually I would be very surprised if such study would have yielded opposite results. This is because many studies have shown that TE correlates well with HVPG, especially when HVPG is <10–12 mm Hg [8Vizzutti F. Arena U. Romanelli R.G. Rega L. Foschi M. Colagrande S. et al.Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis.Hepatology. 2007; 45: 1290-1297Crossref PubMed Scopus (540) Google Scholar, 11Blasco A. Forns X. Carrion J.A. Garcia-Pagan J.C. Gilabert R. Rimola A. et al.Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation.Hepatology. 2006; 43: 492-499Crossref PubMed Scopus (232) Google Scholar, 12Bureau C. Metivier S. Peron J.M. Selves J. Robic M.A. Gourraud P.A. et al.Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease.Aliment Pharmacol Ther. 2008; 27: 1261-1268Crossref PubMed Scopus (281) Google Scholar]. Given this correlation, it is logical that TE can predict patients with HVPG above threshold, as already demonstrated by the same group back in 2008 [[12]Bureau C. Metivier S. Peron J.M. Selves J. Robic M.A. Gourraud P.A. et al.Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease.Aliment Pharmacol Ther. 2008; 27: 1261-1268Crossref PubMed Scopus (281) Google Scholar]. The only point in discussion is which the optimal cut off value is and to what extent it is disease specific or may be influenced by other factors. What is undeniable is the prognostic value of TE in cirrhosis. It is now clear that the harder your liver is, the harder your life will be… and the harder will be the task for the attending physician that shall face the problem of ameliorating this poor prognosis. On the other hand, the finding that TE predicts the occurrence of events during the follow up may appear obvious if TE can predict a marked HVPG elevation. It can further be argued that if something is obvious, then there is no need of demonstrating it. However, medicine is not (totally) an exact science and taking the pain of demonstrating what at first glance may seem obvious is wise and reassuring. The study under consideration has the merit of showing the right path for what would be a big step forward. Actually, two independent studies suggest that increased TE values (again with different cut off values) predict an increased risk of hepatocellular carcinoma during the follow-up of patients with chronic liver disease due to hepatitis C [[13]Masuzaki R. Tateishi R. Yoshida H. Goto E. Sato T. Ohki T. et al.Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography.Hepatology. 2009; 49: 1954-1961Crossref PubMed Scopus (308) Google Scholar] and hepatitis B [[14]Jung K.S. Kim S.U. Ahn S.H. Park Y.N. Kim D.Y. Park J.Y. et al.Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using liver stiffness measurement [FibroScan].Hepatology. 2011; 53: 885-894Crossref PubMed Scopus (293) Google Scholar], which is also correlated with the degree of HVPG elevation [[15]Ripoll C. Groszmann R.J. Garcia-Tsao G. Bosch J. Grace N. Burroughs A. et al.Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis.J Hepatol. 2009; 50: 923-928Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar]. It is debatable whether measurement of TE by Fibroscan will be the right technique to use. Fibroscan has been widely used in Europe, but there is large room for technological advances that can make elastography measurements more applicable and reliable. Actually, it has been shown that magnetic resonance elastography [[16]Talwalkar J.A. Yin M. Fidler J.L. Sanderson S.O. Kamath P.S. Ehman R.L. Magnetic resonance imaging of hepatic fibrosis: emerging clinical applications.Hepatology. 2008; 47: 332-342Crossref PubMed Scopus (261) Google Scholar] is more accurate and applicable than transient elastography by Fibroscan (but much more costly), and more recently, virtual touch elastography using acoustic radiation force impulse imaging (ARFI) is emerging as a reliable technique without the practical limitations inherent to MR elastography [17Friedrich-Rust M. Schwarz A. Ong M. Dries V. Schirmacher P. Herrmann E. et al.Real-time tissue elastography versus FibroScan for noninvasive assessment of liver fibrosis in chronic liver disease.Ultraschall Med. 2009; 30: 478-484Crossref PubMed Scopus (69) Google Scholar, 18Piscaglia F, Salvatore V, Di DR, D’Onofrio M, Gualandi S, Gallotti A, et al. Accuracy of virtual touch Acoustic Radiation Force Impulse [ARFI] imaging for the diagnosis of cirrhosis during liver ultrasonography. Ultraschall Med 2011 [Epub ahead of print Feb 14].Google Scholar]. Finally, whether measuring TE can substitute measurements of HVPG in other situations, for example in assessing the feasibility of liver resection surgery in patients with cirrhosis [[19]Bruix J. Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6252) Google Scholar], or in assessing the response to the medical treatment of portal hypertension [[20]D’Amico G. Garcia-Pagan J.C. Luca A. Bosch J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review.Gastroenterology. 2006; 131: 1611-1624Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar] would have to be specifically investigated, as essentially there is no solid data on these points. The same hold true for the question on whether new serum fibrosis markers may also be used to non-invasively detect when a patient with chronic liver disease is at risk of clinical complications aggravating his prognosis. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Liver stiffness accurately predicts portal hypertension related complications in patients with chronic liver disease: A prospective studyJournal of HepatologyVol. 55Issue 5PreviewThe prognosis of patients with chronic liver disease is to a great extent determined by the presence and degree of portal hypertension (PHT). Hepatic venous pressure gradient (HVPG) has been shown to be an accurate prognostic index in patients with cirrhosis. Transient elastography is a non-invasive procedure that assesses liver fibrosis through the measurement of liver stiffness (LS). In several reports, LS was found to be correlated with HVPG. LS could therefore be useful to identify patients with significant PHT. Full-Text PDF