Soft technique, hard end-points

Soft technique, hard end-points

Editorial Soft technique, hard end-points Jaume Bosch⇑ Hepatic Hemodynamic Laboratory, Hospital Clínic-IDIBAPS, University of Barcelona and CIBERehd,...

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Editorial

Soft technique, hard end-points Jaume Bosch⇑ Hepatic Hemodynamic Laboratory, Hospital Clínic-IDIBAPS, University of Barcelona and CIBERehd, Barcelona, Spain See Article, pages 1017–1024

Increased portal pressure is the major factor driving the clinical course of cirrhosis [1]. 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]. 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 [3,4], its reversion by effective portal pressure reduction by medical treatment [5,6]. 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 [1,3,4]. In this issue of the Journal of Hepatology, Rotic and his coworkers from Toulouse [7] 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 [3,4]), (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 rais-

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DOI of original article: 10.1016/j.jhep.2011.01.051. Address: Hepatic Hemodynamic Lab, Hospital Clínic, C.Villarroel 170, 08036, Barcelona, Spain. Tel.: +34 932 275 5790; fax: +34 932 275 9348. E-mail address: [email protected]

ing the cut off value of TE to detect a HVPG P10 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 P10 mmHg) has not been confirmed by other investigators using the same equipment. Thus, Vizzutti et al. [8] 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] something that was also found by Vizzutti et al. [8]. 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]. 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 [8,11,12]. 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]. 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

Journal of Hepatology 2011 vol. 55 j 955–956

Editorial 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] and hepatitis B [14], which is also correlated with the degree of HVPG elevation [15]. 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] 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 [17,18]. 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], or in assessing the response to the medical treatment of portal hypertension [20] 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.

Conflict of interest The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References [1] Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010;362:823–832. [2] Bosch J. Vascular deterioration in cirrhosis. The big picture. J Clin Gastroenterol 2007;41:S247–S253. [3] Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005;353:2254–2261. [4] Ripoll 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– 488.

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[5] Feu F, Garcia-Pagan JC, 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;346:1056–1059. [6] Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodes J, Bosch J. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology 2003;37:902–908. [7] Ronic MA, Procopet B, Metivier S, Peron JM, Selves J, Vinel JP, et al. Liver stiffness accurately predicts portal hypertension related complications in patients with chronic liver disease: a prospective study. J Hepatol 2011;55:1017–1024. [8] Vizzutti F, Arena U, Romanelli RG, Rega L, Foschi M, Colagrande S, et al. Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis. Hepatology 2007;45:1290–1297. [9] Kazemi F, Kettaneh A, N’kontchou G, Pinto E, Ganne-Carrie N, Trinchet JC, et al. Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices. J Hepatol 2006;45:230–235. [10] Bosch J. Predictions from a hard liver. J Hepatol 2006;45:174–177. [11] Blasco A, Forns X, Carrion JA, Garcia-Pagan JC, Gilabert R, Rimola A, et al. Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation. Hepatology 2006;43:492–499. [12] Bureau C, Metivier S, Peron JM, Selves J, Robic MA, Gourraud PA, et al. Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease. Aliment Pharmacol Ther 2008;27:1261–1268. [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;49:1954–1961. [14] Jung KS, Kim SU, Ahn SH, Park YN, Kim DY, Park JY, et al. Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using liver stiffness measurement [FibroScan]. Hepatology 2011;53:885–894. [15] Ripoll C, Groszmann RJ, 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;50:923–928. [16] Talwalkar JA, Yin M, Fidler JL, Sanderson SO, Kamath PS, Ehman RL. Magnetic resonance imaging of hepatic fibrosis: emerging clinical applications. Hepatology 2008;47:332–342. [17] Friedrich-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;30:478–484. [18] Piscaglia 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]. [19] Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020–1022. [20] D’Amico G, Garcia-Pagan JC, Luca A, Bosch J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology 2006;131:1611–1624.

Journal of Hepatology 2011 vol. 55 j 955–956