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Should we routinely measure portal pressure in patients with cirrhosis, using hepatic venous pressure gradient (HVPG) as a guide for prophylaxis and therapy of bleeding and rebleeding? No
European Journal of Internal Medicine 22 (2011) 5–7
Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Debate
Should we routinely measure portal pressure in patients with cirrhosis, using hepatic venous pressure gradient (HVPG) as a guide for prophylaxis and therapy of bleeding and rebleeding? No Ulrich Thalheimer a, Lia Bellis b, Claudio Puoti b, Andrew K. Burroughs a,⁎ a b
The Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK Department of Internal Medicine and Liver Unit, Marino Hospital, 00043 Marino, Rome, Italy
a r t i c l e
i n f o
Available online 31 December 2010 Keywords: Portal hypertension Oesophageal varices HVPG
a b s t r a c t Portal hypertension (PH) is a severe complication of liver cirrhosis. Measurement of the degree of portal hypertension is usually performed by measuring the hepatic venous pressure gradient (HVPG) which is the difference between the free hepatic venous pressure (FHVP) and the wedged hepatic venous pressure (WHPG). The HVPG accurately reflects the degree of PH in the majority of liver diseases. PH is defined by an increase of HVPG values above the normal upper limit of 5 mm Hg, while clinically significant PH is defined by an HVPG to ≥ 10 mm Hg. Although measurement of HVPG potentially has several applications, in clinical practice its major use has been related to the assessment of hemodynamic response to pharmacological therapy, in order to evaluate the efficacy of treatment and to predict the risk of rebleeding from esophageal varices. When properly performed, HVPG is a reliable, safe and good predictive tool in the management of portal hypertension. However, the need for appropriate equipment, sufficient and reliable operators and costs, have discouraged its use outside Liver Units specifically devoted to the clinical management of portal hypertension. This has diminished its applicability. Combining its use with transjugular liver biopsy and using the prognostic value of HVPG may help encourage its use. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Portal hypertension is a severe complication of liver cirrhosis. Patients with portal hypertension are at risk of developing gastro-esophageal varices and related bleeding, ascites, hepatorenal syndrome, and hepatic encephalopathy [1]. Thus, the diagnosis of portal hypertension and measurement of portal pressure has relevant prognostic and therapeutic implications [2,3]. The portal pressure gradient is the difference between portal pressure and the pressure at the hepatic veins. It reflects the hepatic perfusion pressure. In patients with cirrhosis, portal pressure increases because of increased intrahepatic vascular resistance and increased portal blood flow. The relationship between portal blood flow and the vascular resistance that opposes that flow is defined by the Ohm's law (ΔP = Q × R), where ΔP is the portal pressure gradient, Q is portal blood flow and R is the vascular resistance. Increased resistance is due to: (1) liver architectural disturbance, with distortion of vascular architecture by fibrosis, scarring, regenerative nodules, throm-
⁎ Corresponding author. The Sheila Sherlock Liver Centre, Royal Free Hospital, NW3 2QG London, UK. Tel.: + 44 20 7472 6229; fax: + 44 7472 6226. E-mail address: [email protected] (A.K. Burroughs).
bosis (mechanical or fixed component, not modifiable by pharmacological treatment), and (2) functional hepatic microcirculation alterations (active contraction of portal/septal myofibroblasts, activated stellate cells, portal venules — the so-called dynamic component, modifiable by drugs). This active intrahepatic vascular contraction is a consequence of an inbalance between vasoconstrictor substances (endothelin, angiotensin II, vasopressin, tromboxane A2, leukotrienes, etc) and vasodilators (nitric oxide-NO, CO, prostacyclin etc.) [1]. Portal blood flow in its turn increases because of enhanced production of vasodilators, increased eNOS activity and NO release, systemic and splanchnic vasodilatation, hyperkinetic circulation and hyposensitivity to vasoconstrictors [1]. Portal pressure measurement may be performed directly through portal vein puncture, although it is usually determined indirectly, by subtracting the free hepatic venous pressure (FHVP) from the wedged hepatic venous pressure (WHVP). In cirrhosis, WHVP equals portal (sinusoidal) pressure, as the catheter in the occluded position forms a continuous column of fluid between the catheter itself and the blood in the hepatic vein, the sinusoids and the portal vein. This gradient is the hepatic venous pressure gradient (HVPG), which accurately
0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.12.006
6
U. Thalheimer et al. / European Journal of Internal Medicine 22 (2011) 5–7
reflects the degree of PH in all forms of sinusoidal and post-sinusoidal causes of portal hypertension [4]. The technique of hepatic vein catheterization with measurement of the HVPG is safe and reproducible, and its coefficient of variation has been calculated at 2.6 ± 2.6% [5]. The advent of portal hypertension worsens prognosis as the related complications are a major cause of death and their presence signals the need for liver transplantation in appropriate candidates. For many years, the degree of portal hypertension has been recognized as an independent factor for survival in patients with cirrhosis [6]. Conversely, improvement of liver function in abstinent subjects with cirrhosis has been associated with a reduction in portal pressure [7]. Importantly, reduction in portal pressure has been shown to result in a reduction of the complications of cirrhosis together with improved survival. It is unclear if this was linked to an improvement in liver function [8,9]. Clinically significant portal hypertension is defined by a portal pressure gradient of≥ 10 mm Hg, as the development of ascites and variceal bleeding usually occur above this threshold. Monitoring of HVPG has been increasingly used to assess target reductions of portal pressure during secondary, and less commonly, primary pharmacological prophylaxis of variceal bleeding. A decrease of HVPG of ≥20% from baseline or to ≤12 mm Hg is considered a haemodynamic response to treatment [10–12]. Several studies have assessed the haemodynamic response with respect to the risk of variceal haemorrhage, mostly in the setting of secondary prophylaxis [10–14], but also in primary prophylaxis [15–17] or in cohorts with patients undergoing both primary and secondary prophylaxis [18,19]. A systematic review of these studies [20] demonstrates that achieving a haemodynamic response reduces the risk of bleeding and mortality. It has been recommended that patients undergoing pharmacological prophylaxis for variceal rebleeding should undergo monitoring of HVPG to assess their haemodynamic response [21]. However, close evaluation of the 5 studies and the single smaller case series assessing haemodynamic response in patients undergoing secondary pharmacological prophylaxis for variceal bleeding raises some issues [22,23]. The studies vary with regard to treatment used (only beta-blockers in 1 or combination therapy with nitrates in the remaining 4), percentage of patients with alcoholic liver disease (from 50% to 70%), time of follow-up (from 8 to 28 months), percentage of patients in Child class C (from 6% to 47%) and especially in the interval of time after which the second HVPG measurement was performed (which varied as widely as a mean of 57 days to 5.3 months). Furthermore, there are several specific issues which complicate the interpretation of the haemodynamic data. In a percentage ranging from 17% to 65%, the responder/non responder status could not be assessed as the HVPG was not measured and/or remeasured. The rebleeding rate in these patients varies widely, from 17% to 64%, representing an important source of bias. Also, a number of patients rebleed before their HVPG was remeasured. This rate varied between the studies, suggesting a difference in the baseline risk of rebleeding between them. One of the main concerns arising from the current data, however, is that not all haemodynamic responders will stay free of bleeding/ rebleeding unless HVPG is below 12 mm Hg (but only a median of 14% achieve this response) [23] and conversely, not all non-responders will eventually bleed or rebleed. Overall, 22–67% (median, 47%) of non-responders rebleed [23], which is lower and at least not worse than historical controls with a 63% bleeding rate at 2 years without treatment [21]. In trials of primary prophylaxis, the bleeding rate in non-responders was 37% during follow-up for up to 5 years (excluding patients with small varices without red signs) [16], while a more recent study [17] (recruiting all patients with varices) had a bleeding rate of 30% in the non-responder group during a follow-up period of up to 8 years. This compares favourably to a historical risk of 26.5% at one year without treatment (and thus comprising both potential responders and nonresponders) [24]. Indeed the positive predictive value of haemody-
namic non-response for variceal rebleeding is as low as 52.1% when pooling the data from the trials [25]. A further problem is whether knowing if a patient has responded or not to treatment actually results in a change in management. There is so far no clear data that adding nitrates to increase haemodynamic response rates actually improves outcome. At the same time, a non randomised study proposing “à la carte” treatment for portal hypertension [18], in which patients not achieving a haemodynamic response with propranolol alone or in combination to ISMN had their beta blockers discontinued and were switched to endoscopic banding ligation, showed a very high rebleeding rate of 87% – more than twice the median of the other studies. Indeed, increasing evidence points to a subgroup of patients who are protected from rebleeding by non selective beta blockade without achieving a haemodynamic response [25], possibly by an effect of propranolol on bacterial translocation and bacterial infections [26–28]. Two recent trials are of great importance in considering the role of haemodynamic monitoring in patients on prophylaxis for variceal bleeding. Villanueva et al. [29] assessed the specific issue of how to manage haemodynamic non-responders to secondary prophylaxis. Their study randomized 59 patients with cirrhosis and variceal bleeding to either HVPG guided therapy with nadolol + prazosin in non-responders to nadolol + isosorbide mononitrate or to the combination of nadolol and endoscopic banding ligation. While the addition of prazosin increased the response rate and the risk of rebleeding was lower in haemodynamic responders in the guided therapy group, no difference was observed in bleeding rates between haemodynamic responders and non-responders in those patients undergoing both pharmacological and endoscopic prophylaxis. Given that the latest Baveno consensus [30] states that the combination of beta blockers and banding ligation is the preferred approach to secondary prophylaxis, the assessment of a haemodynamic response loses much of its rationale and evidence in terms of bleeding due to portal hypertension. Garcia-Pagan et al. [31] randomly assigned a total of 63 patients with cirrhosis and acute variceal bleeding (who had been treated with vasoactive drugs and endoscopic therapy) at high risk of rebleeding (as defined by Child class C or Child class B with active bleeding at endoscopy) to either standard treatment with vascoactive drugs followed by banding ligation and non selective beta blockade or early TIPS within 72 h. Not only was the rate of rebleeding or failure to control bleeding decreased in the early TIPS group, but also mortality. Apart from its obvious implications for the management of acute variceal bleeding, this trial might well influence the future of primary and secondary prophylaxis of variceal bleeding [32]. The availability of a highly effective treatment for acute variceal bleeding with a low bleeding associated mortality might well call in question the need for primary prophylaxis and the associated endoscopic procedures or lengthy drug treatment. In a similar fashion, patients with cirrhosis in Child class C or in Child class B with active bleeding at endoscopy would undergo TIPS as definitive treatment, again resulting in no need for secondary prophylaxis. This might eventually be restricted to patients at low risk of rebleeding (Child class A and Child class B without bleeding at endoscopy). In conclusion, while haemodynamic response status has some prognostic significance in patients undergoing prophylaxis for variceal bleeding and rebleeding, it cannot currently be recommended as standard clinical practice. In primary prophylaxis the low incidence of bleeding in haemodynamic non-responders does not justify the invasiveness and cost of HVPG monitoring. In secondary prophylaxis, the current evidence does currently not support any rescue treatment for patients who fail to achieve a haemodynamic response, and many of these patient might indeed not need any further treatment as they will not rebleed, mainly due to the beneficial effects of beta blockade on bacterial translocation and bacterial infections. The use of haemodynamic monitoring will however remain important in the setting of clinical trials of prophylaxis for variceal bleeding, as it will allow for a better
U. Thalheimer et al. / European Journal of Internal Medicine 22 (2011) 5–7
understanding of the protective mechanism of different therapeutic interventions – in other words, to assess whether any reduction in the bleeding or rebleeding rate will be due to reduction in portal pressure or whether this will be unrelated to this. In the future, we feel that the main use of HVPG measurement and monitoring will lie in the prognostic assessment of patients with cirrhosis, as it has been well documented to be the single best prognostic factor in Hepatology [3,6]. Not only has HVPG a strong predictive association with the development of hepatocellular carcinoma [33] and progression of fibrosis in HCV related liver disease [34,35], but it should also help to subdivide cirrhosis into further stages [36]: a HVPG ≥ 10 mm Hg already defines clinically significant portal hypertension [37], when complications of cirrhosis are likely to occur. An added bonus of HVPG measurement is that a transjugular liver biopsy can be performed at the same time [38]. This is a safe procedure [38]; four cores provide optimal specimens even for staging chronic viral hepatitis [39], and the different cores reduce sampling variability found in the single core of standard percutaneous biopsies [40]. Thus the measurement of HVPG should continue to be standard practice in specialised Liver Centres, and if further data show benefit in staging cirrhosis and/or for prognosis, HVPG measurement should become more widespread. References [1] Bosch J, Abraldes JG, Groszmann R. Current management of portal hypertension. J Hepatol 2003;38(Suppl 1):S54–68. [2] Burroughs AK, Thalheimer U. Hepatic venous pressure gradient in 2010: optimal measurement is key. Hepatology 2010;51:1894–6. [3] Triantos CK, Nikolopoulou V, Burroughs AK. Review article: the therapeutic and prognostic benefit of portal pressure reduction in cirrhosis. Aliment Pharmacol Ther 2008;28:943–52. [4] Thalheimer U, Leandro G, Samonakis DN, Triantos CK, Patch D, Burroughs AK. Assessment of the agreement between wedge hepatic vein pressure and portal vein pressure in cirrhotic patients. Dig Liver Dis 2005;37:601–8. [5] Thalheimer U, Leandro G, Mela M, Patch D, Burroughs AK. Systematic review of HVPG measurement: statistics versus clinical applicability. Gastroenterology 2007;132:1201–2. [6] Armonis A, Patch D, Burroughs A. Hepatic venous pressure measurement: an old test as a new prognostic marker in cirrhosis? Hepatology 1997;25:245–8. [7] Vorobioff J, Groszmann RJ, Picabea E, Gamen M, Villavicencio R, Bordato J, et al. Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study. Gastroenterology 1996;111:701–9. [8] 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;37:902–8. [9] Villanueva C, Lopez-Balaguer JM, Aracil C, Kolle L, Gonzalez B, Minana J, et al. Maintenance of hemodynamic response to treatment for portal hypertension and influence on complications of cirrhosis. J Hepatol 2004;40:757–65. [10] 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;346:1056–9. [11] Villanueva C, Balanzo J, Novella MT, Soriano G, Sainz S, Torras X, et al. Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding. N Engl J Med 1996;334:1624–9. [12] Villanueva C, Minana J, Ortiz J, Gallego A, Soriano G, Torras X, et al. Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding. N Engl J Med 2001;345:647–55. [13] McCormick PA, Patch D, Greenslade L, Chin J, McIntyre N, Burroughs AK. Clinical vs haemodynamic response to drugs in portal hypertension. J Hepatol 1998;28:1015–9. [14] Patch D, Sabin CA, Goulis J, Gerunda G, Greenslade L, Merkel C, et al. A randomized, controlled trial of medical therapy versus endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis. Gastroenterology 2002;123:1013–9. [15] Groszmann RJ, Bosch J, Grace ND, HO CONN, Garcia-Tsao G, Navasa M, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990;99:1401–7.
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[16] Merkel C, Bolognesi M, Sacerdoti D, Bombonato G, Bellini B, Bighin R, et al. The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 2000;32:930–4. [17] Turnes J, Garcia-Pagan JC, Abraldes JG, Hernandez-Guerra M, Dell'Era A, Bosch J. Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis. Am J Gastroenterol 2006;101:506–12. [18] Bureau C, Peron JM, Alric L, Morales J, Sanchez J, Barange K, et al. "A La Carte" treatment of portal hypertension: Adapting medical therapy to hemodynamic response for the prevention of bleeding. Hepatology 2002;36:1361–6. [19] Escorsell A, Bordas JM, Castaneda B, Llach J, Garcia-Pagan JC, Rodes J, et al. Predictive value of the variceal pressure response to continued pharmacological therapy in patients with cirrhosis and portal hypertension. Hepatology 2000;31:1061–7. [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;131:1611–24. [21] Bosch J, Garcia-Pagan JC. Prevention of variceal rebleeding. Lancet 2003;361:952–4. [22] Thalheimer U, Mela M, Patch D, Burroughs AK. Targeting portal pressure measurements: a critical reappraisal. Hepatology 2004;39:286–90. [23] Thalheimer U, Mela M, Patch D, Burroughs AK. Monitoring target reduction in hepatic venous pressure gradient during pharmacological therapy of portal hypertension: a close look at the evidence. Gut 2004;53:143–8. [24] Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. N Engl J Med 1988;319:983–9. [25] Thalheimer U, Bosch J, Burroughs AK. How to prevent varices from bleeding: shades of grey–the case for nonselective beta blockers. Gastroenterology 2007;133:2029–36. [26] Senzolo M, Cholongitas E, Burra P, Leandro G, Thalheimer U, Patch D, et al. Betablockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. Liver Int 2009;29:1189–93. [27] Thalheimer U, De Iorio F, Capra F, del Mar LM, Zuliani V, Ghidini V, et al. Altered intestinal function precedes the appearance of bacterial DNA in serum and ascites in patients with cirrhosis: a pilot study. Eur J Gastroenterol Hepatol 2010;22: 1228–34. [28] Thalheimer U, Triantos CK, Samonakis DN, Patch D, Burroughs AK. Infection, coagulation, and variceal bleeding in cirrhosis. Gut 2005;54:556–63. [29] Villanueva C, Aracil C, Colomo A, Lopez-Balaguer JM, Piqueras M, Gonzalez B, et al. Clinical trial: a randomized controlled study on prevention of variceal rebleeding comparing nadolol + ligation vs. hepatic venous pressure gradient-guided pharmacological therapy. Aliment Pharmacol Ther 2009;29:397–408. [30] de Franchis R. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010;53:762–8. [31] Garcia-Pagan JC, Caca K, Bureau C, Laleman W, Appenrodt B, Luca A, et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med 2010;362:2370–9. [32] Rossle M, Grandt D. Early transjugular intrahepatic portosystemic shunt in patients with cirrhosis and variceal bleeding. Hepatology 2010;52:1847–50. [33] 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;50:923–8. [34] Burroughs AK, Groszmann R, Bosch J, Grace N, Garcia-Tsao G, Patch D, et al. Assessment of therapeutic benefit of antiviral therapy in chronic hepatitis C: is hepatic venous pressure gradient a better end point? Gut 2002;50:425–7. [35] Samonakis DN, Cholongitas E, Thalheimer U, Kalambokis G, Quaglia A, Triantos CK, et al. Hepatic venous pressure gradient to assess fibrosis and its progression after liver transplantation for HCV cirrhosis. Liver Transpl 2007;13:1305–11. [36] Garcia-Tsao G, Friedman S, Iredale J, Pinzani M. Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis. Hepatology 2010;51:1445–9. [37] 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;133:481–8. [38] Kalambokis G, Manousou P, Vibhakorn S, Marelli L, Cholongitas E, Senzolo M, et al. Transjugular liver biopsy–indications, adequacy, quality of specimens, and complications–a systematic review. J Hepatol 2007;47:284–94. [39] Vibhakorn S, Cholongitas E, Kalambokis G, Manousou P, Quaglia A, Marelli L, et al. A comparison of four- versus three-pass transjugular biopsy using a 19-G Tru-Cut needle and a randomized study using a cassette to prevent biopsy fragmentation. Cardiovasc Intervent Radiol 2009;32:508–13. [40] Cholongitas E, Senzolo M, Standish R, Marelli L, Quaglia A, Patch D, et al. A systematic review of the quality of liver biopsy specimens. Am J Clin Pathol 2006;125:710–21.
Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Debate
Should we routinely measure portal pressure in patients with cirrhosis, using hepatic venous pressure gradient (HVPG) as a guide for prophylaxis and therapy of bleeding and rebleeding? No Ulrich Thalheimer a, Lia Bellis b, Claudio Puoti b, Andrew K. Burroughs a,⁎ a b
The Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK Department of Internal Medicine and Liver Unit, Marino Hospital, 00043 Marino, Rome, Italy
a r t i c l e
i n f o
Available online 31 December 2010 Keywords: Portal hypertension Oesophageal varices HVPG
a b s t r a c t Portal hypertension (PH) is a severe complication of liver cirrhosis. Measurement of the degree of portal hypertension is usually performed by measuring the hepatic venous pressure gradient (HVPG) which is the difference between the free hepatic venous pressure (FHVP) and the wedged hepatic venous pressure (WHPG). The HVPG accurately reflects the degree of PH in the majority of liver diseases. PH is defined by an increase of HVPG values above the normal upper limit of 5 mm Hg, while clinically significant PH is defined by an HVPG to ≥ 10 mm Hg. Although measurement of HVPG potentially has several applications, in clinical practice its major use has been related to the assessment of hemodynamic response to pharmacological therapy, in order to evaluate the efficacy of treatment and to predict the risk of rebleeding from esophageal varices. When properly performed, HVPG is a reliable, safe and good predictive tool in the management of portal hypertension. However, the need for appropriate equipment, sufficient and reliable operators and costs, have discouraged its use outside Liver Units specifically devoted to the clinical management of portal hypertension. This has diminished its applicability. Combining its use with transjugular liver biopsy and using the prognostic value of HVPG may help encourage its use. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Portal hypertension is a severe complication of liver cirrhosis. Patients with portal hypertension are at risk of developing gastro-esophageal varices and related bleeding, ascites, hepatorenal syndrome, and hepatic encephalopathy [1]. Thus, the diagnosis of portal hypertension and measurement of portal pressure has relevant prognostic and therapeutic implications [2,3]. The portal pressure gradient is the difference between portal pressure and the pressure at the hepatic veins. It reflects the hepatic perfusion pressure. In patients with cirrhosis, portal pressure increases because of increased intrahepatic vascular resistance and increased portal blood flow. The relationship between portal blood flow and the vascular resistance that opposes that flow is defined by the Ohm's law (ΔP = Q × R), where ΔP is the portal pressure gradient, Q is portal blood flow and R is the vascular resistance. Increased resistance is due to: (1) liver architectural disturbance, with distortion of vascular architecture by fibrosis, scarring, regenerative nodules, throm-
⁎ Corresponding author. The Sheila Sherlock Liver Centre, Royal Free Hospital, NW3 2QG London, UK. Tel.: + 44 20 7472 6229; fax: + 44 7472 6226. E-mail address: [email protected] (A.K. Burroughs).
bosis (mechanical or fixed component, not modifiable by pharmacological treatment), and (2) functional hepatic microcirculation alterations (active contraction of portal/septal myofibroblasts, activated stellate cells, portal venules — the so-called dynamic component, modifiable by drugs). This active intrahepatic vascular contraction is a consequence of an inbalance between vasoconstrictor substances (endothelin, angiotensin II, vasopressin, tromboxane A2, leukotrienes, etc) and vasodilators (nitric oxide-NO, CO, prostacyclin etc.) [1]. Portal blood flow in its turn increases because of enhanced production of vasodilators, increased eNOS activity and NO release, systemic and splanchnic vasodilatation, hyperkinetic circulation and hyposensitivity to vasoconstrictors [1]. Portal pressure measurement may be performed directly through portal vein puncture, although it is usually determined indirectly, by subtracting the free hepatic venous pressure (FHVP) from the wedged hepatic venous pressure (WHVP). In cirrhosis, WHVP equals portal (sinusoidal) pressure, as the catheter in the occluded position forms a continuous column of fluid between the catheter itself and the blood in the hepatic vein, the sinusoids and the portal vein. This gradient is the hepatic venous pressure gradient (HVPG), which accurately
0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.12.006
6
U. Thalheimer et al. / European Journal of Internal Medicine 22 (2011) 5–7
reflects the degree of PH in all forms of sinusoidal and post-sinusoidal causes of portal hypertension [4]. The technique of hepatic vein catheterization with measurement of the HVPG is safe and reproducible, and its coefficient of variation has been calculated at 2.6 ± 2.6% [5]. The advent of portal hypertension worsens prognosis as the related complications are a major cause of death and their presence signals the need for liver transplantation in appropriate candidates. For many years, the degree of portal hypertension has been recognized as an independent factor for survival in patients with cirrhosis [6]. Conversely, improvement of liver function in abstinent subjects with cirrhosis has been associated with a reduction in portal pressure [7]. Importantly, reduction in portal pressure has been shown to result in a reduction of the complications of cirrhosis together with improved survival. It is unclear if this was linked to an improvement in liver function [8,9]. Clinically significant portal hypertension is defined by a portal pressure gradient of≥ 10 mm Hg, as the development of ascites and variceal bleeding usually occur above this threshold. Monitoring of HVPG has been increasingly used to assess target reductions of portal pressure during secondary, and less commonly, primary pharmacological prophylaxis of variceal bleeding. A decrease of HVPG of ≥20% from baseline or to ≤12 mm Hg is considered a haemodynamic response to treatment [10–12]. Several studies have assessed the haemodynamic response with respect to the risk of variceal haemorrhage, mostly in the setting of secondary prophylaxis [10–14], but also in primary prophylaxis [15–17] or in cohorts with patients undergoing both primary and secondary prophylaxis [18,19]. A systematic review of these studies [20] demonstrates that achieving a haemodynamic response reduces the risk of bleeding and mortality. It has been recommended that patients undergoing pharmacological prophylaxis for variceal rebleeding should undergo monitoring of HVPG to assess their haemodynamic response [21]. However, close evaluation of the 5 studies and the single smaller case series assessing haemodynamic response in patients undergoing secondary pharmacological prophylaxis for variceal bleeding raises some issues [22,23]. The studies vary with regard to treatment used (only beta-blockers in 1 or combination therapy with nitrates in the remaining 4), percentage of patients with alcoholic liver disease (from 50% to 70%), time of follow-up (from 8 to 28 months), percentage of patients in Child class C (from 6% to 47%) and especially in the interval of time after which the second HVPG measurement was performed (which varied as widely as a mean of 57 days to 5.3 months). Furthermore, there are several specific issues which complicate the interpretation of the haemodynamic data. In a percentage ranging from 17% to 65%, the responder/non responder status could not be assessed as the HVPG was not measured and/or remeasured. The rebleeding rate in these patients varies widely, from 17% to 64%, representing an important source of bias. Also, a number of patients rebleed before their HVPG was remeasured. This rate varied between the studies, suggesting a difference in the baseline risk of rebleeding between them. One of the main concerns arising from the current data, however, is that not all haemodynamic responders will stay free of bleeding/ rebleeding unless HVPG is below 12 mm Hg (but only a median of 14% achieve this response) [23] and conversely, not all non-responders will eventually bleed or rebleed. Overall, 22–67% (median, 47%) of non-responders rebleed [23], which is lower and at least not worse than historical controls with a 63% bleeding rate at 2 years without treatment [21]. In trials of primary prophylaxis, the bleeding rate in non-responders was 37% during follow-up for up to 5 years (excluding patients with small varices without red signs) [16], while a more recent study [17] (recruiting all patients with varices) had a bleeding rate of 30% in the non-responder group during a follow-up period of up to 8 years. This compares favourably to a historical risk of 26.5% at one year without treatment (and thus comprising both potential responders and nonresponders) [24]. Indeed the positive predictive value of haemody-
namic non-response for variceal rebleeding is as low as 52.1% when pooling the data from the trials [25]. A further problem is whether knowing if a patient has responded or not to treatment actually results in a change in management. There is so far no clear data that adding nitrates to increase haemodynamic response rates actually improves outcome. At the same time, a non randomised study proposing “à la carte” treatment for portal hypertension [18], in which patients not achieving a haemodynamic response with propranolol alone or in combination to ISMN had their beta blockers discontinued and were switched to endoscopic banding ligation, showed a very high rebleeding rate of 87% – more than twice the median of the other studies. Indeed, increasing evidence points to a subgroup of patients who are protected from rebleeding by non selective beta blockade without achieving a haemodynamic response [25], possibly by an effect of propranolol on bacterial translocation and bacterial infections [26–28]. Two recent trials are of great importance in considering the role of haemodynamic monitoring in patients on prophylaxis for variceal bleeding. Villanueva et al. [29] assessed the specific issue of how to manage haemodynamic non-responders to secondary prophylaxis. Their study randomized 59 patients with cirrhosis and variceal bleeding to either HVPG guided therapy with nadolol + prazosin in non-responders to nadolol + isosorbide mononitrate or to the combination of nadolol and endoscopic banding ligation. While the addition of prazosin increased the response rate and the risk of rebleeding was lower in haemodynamic responders in the guided therapy group, no difference was observed in bleeding rates between haemodynamic responders and non-responders in those patients undergoing both pharmacological and endoscopic prophylaxis. Given that the latest Baveno consensus [30] states that the combination of beta blockers and banding ligation is the preferred approach to secondary prophylaxis, the assessment of a haemodynamic response loses much of its rationale and evidence in terms of bleeding due to portal hypertension. Garcia-Pagan et al. [31] randomly assigned a total of 63 patients with cirrhosis and acute variceal bleeding (who had been treated with vasoactive drugs and endoscopic therapy) at high risk of rebleeding (as defined by Child class C or Child class B with active bleeding at endoscopy) to either standard treatment with vascoactive drugs followed by banding ligation and non selective beta blockade or early TIPS within 72 h. Not only was the rate of rebleeding or failure to control bleeding decreased in the early TIPS group, but also mortality. Apart from its obvious implications for the management of acute variceal bleeding, this trial might well influence the future of primary and secondary prophylaxis of variceal bleeding [32]. The availability of a highly effective treatment for acute variceal bleeding with a low bleeding associated mortality might well call in question the need for primary prophylaxis and the associated endoscopic procedures or lengthy drug treatment. In a similar fashion, patients with cirrhosis in Child class C or in Child class B with active bleeding at endoscopy would undergo TIPS as definitive treatment, again resulting in no need for secondary prophylaxis. This might eventually be restricted to patients at low risk of rebleeding (Child class A and Child class B without bleeding at endoscopy). In conclusion, while haemodynamic response status has some prognostic significance in patients undergoing prophylaxis for variceal bleeding and rebleeding, it cannot currently be recommended as standard clinical practice. In primary prophylaxis the low incidence of bleeding in haemodynamic non-responders does not justify the invasiveness and cost of HVPG monitoring. In secondary prophylaxis, the current evidence does currently not support any rescue treatment for patients who fail to achieve a haemodynamic response, and many of these patient might indeed not need any further treatment as they will not rebleed, mainly due to the beneficial effects of beta blockade on bacterial translocation and bacterial infections. The use of haemodynamic monitoring will however remain important in the setting of clinical trials of prophylaxis for variceal bleeding, as it will allow for a better
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understanding of the protective mechanism of different therapeutic interventions – in other words, to assess whether any reduction in the bleeding or rebleeding rate will be due to reduction in portal pressure or whether this will be unrelated to this. In the future, we feel that the main use of HVPG measurement and monitoring will lie in the prognostic assessment of patients with cirrhosis, as it has been well documented to be the single best prognostic factor in Hepatology [3,6]. Not only has HVPG a strong predictive association with the development of hepatocellular carcinoma [33] and progression of fibrosis in HCV related liver disease [34,35], but it should also help to subdivide cirrhosis into further stages [36]: a HVPG ≥ 10 mm Hg already defines clinically significant portal hypertension [37], when complications of cirrhosis are likely to occur. An added bonus of HVPG measurement is that a transjugular liver biopsy can be performed at the same time [38]. This is a safe procedure [38]; four cores provide optimal specimens even for staging chronic viral hepatitis [39], and the different cores reduce sampling variability found in the single core of standard percutaneous biopsies [40]. Thus the measurement of HVPG should continue to be standard practice in specialised Liver Centres, and if further data show benefit in staging cirrhosis and/or for prognosis, HVPG measurement should become more widespread. References [1] Bosch J, Abraldes JG, Groszmann R. Current management of portal hypertension. J Hepatol 2003;38(Suppl 1):S54–68. [2] Burroughs AK, Thalheimer U. Hepatic venous pressure gradient in 2010: optimal measurement is key. Hepatology 2010;51:1894–6. [3] Triantos CK, Nikolopoulou V, Burroughs AK. Review article: the therapeutic and prognostic benefit of portal pressure reduction in cirrhosis. Aliment Pharmacol Ther 2008;28:943–52. [4] Thalheimer U, Leandro G, Samonakis DN, Triantos CK, Patch D, Burroughs AK. Assessment of the agreement between wedge hepatic vein pressure and portal vein pressure in cirrhotic patients. Dig Liver Dis 2005;37:601–8. [5] Thalheimer U, Leandro G, Mela M, Patch D, Burroughs AK. Systematic review of HVPG measurement: statistics versus clinical applicability. Gastroenterology 2007;132:1201–2. [6] Armonis A, Patch D, Burroughs A. Hepatic venous pressure measurement: an old test as a new prognostic marker in cirrhosis? Hepatology 1997;25:245–8. [7] Vorobioff J, Groszmann RJ, Picabea E, Gamen M, Villavicencio R, Bordato J, et al. Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study. Gastroenterology 1996;111:701–9. [8] 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;37:902–8. [9] Villanueva C, Lopez-Balaguer JM, Aracil C, Kolle L, Gonzalez B, Minana J, et al. Maintenance of hemodynamic response to treatment for portal hypertension and influence on complications of cirrhosis. J Hepatol 2004;40:757–65. [10] 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;346:1056–9. [11] Villanueva C, Balanzo J, Novella MT, Soriano G, Sainz S, Torras X, et al. Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding. N Engl J Med 1996;334:1624–9. [12] Villanueva C, Minana J, Ortiz J, Gallego A, Soriano G, Torras X, et al. Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding. N Engl J Med 2001;345:647–55. [13] McCormick PA, Patch D, Greenslade L, Chin J, McIntyre N, Burroughs AK. Clinical vs haemodynamic response to drugs in portal hypertension. J Hepatol 1998;28:1015–9. [14] Patch D, Sabin CA, Goulis J, Gerunda G, Greenslade L, Merkel C, et al. A randomized, controlled trial of medical therapy versus endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis. Gastroenterology 2002;123:1013–9. [15] Groszmann RJ, Bosch J, Grace ND, HO CONN, Garcia-Tsao G, Navasa M, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990;99:1401–7.
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