Acute-on-chronic failure is a syndrome that affects patients with cirrhosis and is characterized by intense systemic inflammation, single or multiple organ failure and 30% risk of mortality within 28 days of hospitalization. European Foundation for the Study of Chronic Liver Failure (EF CLIF) has performed a series of pioneering studies over the past 10 years that has led to the development of new criteria for the diagnosis and prognosis and defined the underlying mechanisms of this disease condition. About 30% of hospitalized cirrhosis patients have ACLF and about 30% will die within 28 days of admission to the hospital. In the most severe form, this mortality rises to over 85%. Only liver transplantation saves the lives of these patients but access to transplantation is limited by the lack of harmonization across Europe and the world. EF CLIF, in collaboration with ELITA, recently performed a study showing that there was a lack of equity of access across Europe.

Faced with this situation, EF CLIF, in collaboration with ELITA and ILTS, launched CHANCE – a multicenter and international three-year study, of a prospective and non-interventional observational nature”, in which over 2,000 patients from 95 hospitals located in 27 countries will be recruited. Of them, five are Spanish: Hospital Universitari i Politècnic La Fe (Valencia), Hospital Universitario Virgen del Rocío (Sevilla), Hospital Universitario de Cruces (Vizcaya), Hospital Clínic de Barcelona (Barcelona), and Hospital Universitario 12 de Octubre (Madrid).

“Every year around one million people with ACLF die in Europe. Several studies carried out so far have shown that liver transplantation is an option that clearly improves the survival of these patients. The results of the global CHANCE study will be important to better define criteria for selection, make transplantation even safer and allow harmonization across the world”, says Rajiv Jalan, Scientific Director of EF CLIF.

Among the objectives of CHANCE is to compare the survival rate of the patient 1-year after receiving a liver transplant and according to their degree of ACLF, as well as to confirm the impact it has on their quality of life. In addition, the results will allow the development of new prognostic models based on the ACLF classification to predict mortality on the waiting list, formalize drafting of new guidelines for patient selection and improve the criteria for organ allocation for patients with ACLF allowing harmonization across the world.

“Acute-on-chronic liver failure is a serious clinical condition for which transplantation is an effective therapeutic option. In Europe, referral and access to liver transplantation for ACLF patients varies by center and country. It must be harmonized to avoid inequalities”, explains Luca S. Belli, Head of the Department of Hepatology and Gastroenterology at Hospital Niguarda, Italy, and member of ELITA.

A study by EF CLIF and ELITA, published in the Journal of Hepatology1, showed these differences between European countries when performing a liver transplant in patients with ACLF grade 2-3. The percentage of liver transplants performed in these types of patients ranged from about 25% of all liver transplants for decompensated cirrhosis in France and Germany, to slightly less than 6% in the United Kingdom and Spain. In addition, this retrospective study showed that the survival of patients with ACLF in the first year after liver transplantation is more than 80%.

“Since transplantation is a limited therapeutic resource, Spain is the ideal country to prospectively evaluate this indication given the exceptional rate of organ donation compared to neighboring countries. With this study, we have seen that it is possible to achieve very good results if the indication for transplantation is done at the right time”, explains Constantino Fondevila, Head of General and Digestive Surgery of the Hospital Universitario La Paz, Spain.

In Spain and UK, patients with ACLF are a priority for liver transplantation

Spain, together with the United Kingdom, are two of the countries that have recently introduced new recommendations that allow list ACLF as a priority indication for liver transplantation. A proposal by the Spanish Society of Liver Transplantation was published in Transplantation, which concluded that liver transplantation dramatically improves the prognosis in patients with ACLF. They drew up a consensus document introducing the EFCLIF criteria for ACLF so that liver transplantation can be expanded homogeneously in Spain.

“With great joy and pride, on July 7, we included the first patient in the CHANCE study at the Italian Hospital in Buenos Aires, Argentina. The CHANCE study is a study of great global relevance since its objective is to be able to give answers to so many questions that we have every day about the management of patients with complications of cirrhosis who must undergo a liver transplant. We believe that it is very important for our region to participate in these studies, since Latin America has a very important potential to contribute in terms of research”, said Adrián Gadano and Sebastian Marciano of the Hepatology and Liver Transplantation Section at the Italian Hospital of Buenos Aires, Argentina.

About decompensated cirrhosis and ACLF syndrome

Acute on chronic liver failure (ACLF) represents the most serious phase of cirrhosis, characterized by intense systemic inflammation in which patients develop failure of different organs or systems. ACLF is the main cause of death in cirrhotic patients and has a great socioeconomic impact due to the high volume of healthcare resources that its treatment requires and because it incapacitates the patient from work. The diagnostic criteria for the syndrome were described for the first time in 2013 by the same authors of the PREDICT study. Decompensated cirrhosis, characterized by the appearance of complications such as ascites, digestive bleeding, and brain function disorders that can lead to hepatic coma can progress to ACLF, a syndrome associated with high mortality.
Recent research led by EF Clif has shown that ACLF is a highly complex disorder that appears in patients with liver cirrhosis in whom, in addition to the liver, cardiovascular, kidney, brain, lungs, gut, and immune system can fail. It is therefore a special form of multiorgan failure.
The probability of survival after the onset of ACLF is low since it is associated with high short-term morbidity (30% at 28 days) and its only treatment at present is liver transplantation.

Further reading

Arroyo, V.; Moreau, R.; Jalan, R. Acute-on-chronic liver failure. N. Engl. J. Med. 2020, 382 (22), 2137–2145. DOI: 10.1056/NEJMra1914900

Belli, L.S.; Duvoux, D.; Artzner, T.; Arroyo, V.; Jalan, R.; for the ELITA/EF-CLIF working group. Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: Results of the ELITA/EF-CLIF collaborative study (ECLIS). J. Hepatol. 2021, 75 (3), 610–620. DOI: 10.1016/j.jhep.2021.03.030

Moreau, R.; Jalan, R.; Gines, P.; Pavesi, M.; Angeli, P.; Cordoba, J.; Durand, F.; Gustot, T.; Saliba, F.; Domenicali, M.; Gerbes, A.; Wendon, J.; Alessandria, C.; Laleman, W.; Zeuzem, S.; Trebicka, J.; Bernardi, M.; Arroyo, V.; CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013, 144 (7), 1426–1437. DOI: 10.1053/j.gastro.2013.02.042

Rodríguez-Perálvarez, M.;Gómez-Bravo, M.A.; Sánchez-Antolín, G.; De la Rosa, G.; Bilbao, I.; Colmenero, J.; on behalf of the Spanish Society of Liver Transplantation (SETH) Consensus Panel. Expanding indications of liver transplantation in Spain: Consensus statement and recommendations by the Spanish Society of Liver Transplantation. Transplantation 2021, 105 (3), 602–607. DOI: 10.1097/TP.0000000000003281