Acta Clinica Belgica International Journal of Clinical and Laboratory Medicine

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DECOMPENSATED CIRRHOSIS … ARE WE GAINING GROUND? J Henrion & P Deltenre To cite this article: J Henrion & P Deltenre (2013) DECOMPENSATED CIRRHOSIS … ARE WE GAINING GROUND?, Acta Clinica Belgica, 68:6, 411-415 To link to this article:

Published online: 30 May 2014.

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DECOMPENSATED CIRRHOSIS … ARE WE GAINING GROUND? Henrion J, Deltenre P Département de Médecine Interne, Unité d’hépato-gastroentérologie, Hôpital de Jolimont-Lobbes, 7100, Haine-Saint-Paul

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Correspondence and offprint requests to:  Jean Henrion, E-mail: [email protected]

INTRODUCTION From an elementary clinical point of view, cirrhosis is considered to be “compensated” or “decompensated”. Decompensated cirrhosis is cirrhosis with clinical manifestations. The “classical” clinical manifestations of cirrhosis are jaundice, ascites, oesophageal variceal bleeding and hepatic encephalopathy. All these complications of cirrhosis are totally or partially linked to the failure of liver function. Over the last 30 years, other complications of cirrhosis have aroused vivid interest, in particular renal failure (hepato-renal syndrome), respiratory failure (hepato-pulmonary syndrome), bacterial infections (spontaneous septicaemia and peritonitis), hepatocarcinoma and portal vein thrombosis. In this short review, we describe recent advances in the understanding and treatment of “decompensated cirrhosis”

ACUTE-ON-CHRONIC LIVER FAILURE (ACLF)… A NEW SYNDROME? The concept of acute-on-chronic liver failure (ACLF) was proposed by Jalan in 2002 (1), but went unnoticed until recently when it became the subject of several articles and reviews (2-4). Nevertheless, the true “raison d’être” of this new syndrome remains controversial. There is ongoing debate between “believers” and “non-believers” of this concept (5), and as yet, no agreement exists as to a clear definition. Moreover, the perception of the syndrome differs between the eastern and western hemispheres (4, 5). In our opinion, the best definition can be found in a review by Jalan et al published in 2012: “acute deterioration of liver function in patients with cirrhosis which is associated with a precipitating event and results in the failure of one or more organs and high short-term mortality” (4). In fact, two consensus definitions were proposed, the first by the Asian Pacific Association for Study of Liver Disease (APASLD) in 2009, and the second, in 2011, by a single topic conference of the EASL-AASLD (European ­Association for Study of the

doi: 10.2143/ACB.2210

Liver and American Association for Study of Liver Diseases) (4, 6). The two definitions differ and appeared incomplete. For eastern countries, ACLF encompasses not just cirrhosis but all chronic liver diseases. Moreover, the concept of acute insult also differs between east and west. For eastern countries, acute insult is directly of “hepatic” origin, for example acute reactivation of hepatitis B, hepatitis E and drug-induced injury. For the west, acute insult is rather indirectly of “hepatic” origin such as variceal bleeding or sepsis. Finally, the outcome of that syndrome is “liver failure” according to the eastern definition, while it is “multiple organ failure” according to the western definition. For these reasons, in order to arrive at an evidence-based definition and to better characterise this syndrome, a large multicentre prospective trial (CANONIC study) was conducted under the aegis of the EASL-CLIF consortium. That study included 1343 hospitalised cirrhotic patients in 12 European countries and the results were recently published (7). Similar studies are under way in the US and Asia as part of large consortia. From a clinical point of view, ACLF corresponds to a rapid deterioration of liver function in stable cirrhosis due to a precipitating event. This event may be either direct liver injury such as alcoholic hepatitis, superimposed viral hepatitis, druginduced injury, portal vein thrombosis or hypoxic hepatitis or an extrahepatic liver injury such as variceal bleeding, infection, trauma or surgery. It is noteworthy that in the EASL-CLIFF consortium study, in up to 40% of cases no precipitating event was observed (7). The deterioration in liver failure is rapid, but overall the syndrome is characterised by multiple organ failure (MOF) requiring multiple organ supports and resulting in a high incidence of short-term mortality. Nevertheless, the progression of liver and other organ failures is potentially reversible. This point is crucial for understanding the syndrome because it differentiates ACLF from “cirrhosis decompensation” also referred to as “end stage-liver disease”. Indeed, end-stage liver disease is a slow and irreversible condition which results in ineluctable death unless liver transplantation is performed. The exact physiopathology of ACLF remains to be elucidated. In brief, an exaggerated response of the innate immune system, and particularly of Kupffer cells, with an unregulated

Acta Clinica Belgica, 2013; 68-6


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systemic inflammatory response (SIRS), is ­considered the major contributing mechanism. Next, SIRS with or without bacterial infection, evolves to MOF (2, 3). The initial therapeutic intervention is directed toward the precipitating event; following this, management, usually in an intensive care unit, attempts to prevent death from MOF. Multiple organs supports are often required, sometimes including artificial non-biological liver support devices. Nevertheless, two large studies using the Prometheus liver device or the MARS system (RELIEF trial) did not show significant improvement in survival (4). Intense pharmacologic research is under way to control overexpression of the systemic inflammatory response (3). In some cases, liver transplantation has been performed. The mortality of ACLF is high, estimated at between 46 and 84% (3). In the large series of the EASL-CLIF consortium (CANONIC study), the mortality rate at day 28 was 33.9% (7). It was not the severity of liver failure, assessed using conventional clinical and biochemical data (MELD or Child Pugh stage) but rather, the number of organ failures that determined the outcome (4, 7). In conclusion, ACLF is not truly a “new disease”. It is merely an important element in the natural history of cirrhosis and a frequent cause of death in these patients. Accordingly, it is crucial to better characterise and understand this frequent syndrome in order to more efficiently treat it.

CARVEDILOL ... A NEW TREATMENT FOR PRIMARY PROPHYLAXIS OF VARICEAL BLEEDING? Thirty years ago, the liver unit at hôpital Beaujon, Clichy, reported the efficacy of propranolol in the prophylaxis of variceal bleeding in cirrhotic patients (8). Since then, nonselective beta-blockers are the standard of care for primary prophylaxis of variceal bleeding. However, the effectiveness of propranolol for decreasing portal pressure is limited. Indeed, about half of the patients will not exhibit a decrease in the hepatic vein pressure gradient (HVPG) below 12 mm Hg or of more than 20% of baseline pressure which is the agreed-upon appropriate response (9, 10). Carvedilol is a potent non-selective beta-blocker with moderate anti-alpha1 adrenergic activity. It is currently used for treatment of heart failure and arterial hypertension. Previous studies had shown that carvedilol was more effective than propranolol in decreasing portal pressure, and this could be explained by a decrease in intrahepatic vascular resistance (10, 11). A first randomised control trial (RCT) comparing carvedilol with propranolol was published in 2002 (11). In that study, 51 cirrhotic patients with oesophageal varices were randomised to receive carvedilol (26 patients) or propranolol (25 patients). The mean decrease in portal pressure was higher in the carvedilol group (19% of baseline value) than in the propranolol group (12%) (p 

Decompensated cirrhosis … are we gaining ground?

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