Increased intestinal permeability in patients with acute-on chronic liver failure (ACLF): an update on the pathogenesis of ACLF
Creators: name: Kumar, Dinesh
name: Gaurav Pandey
name: Kumar, Umesh
name: Kumar, Amit
name: VP, Krishna
name: Guleria, Anupam
name: Kumar, Kamlesh
name: Sharma, Prabhat N.
name: Manjunath Hatti
name: Kumar, Alok
name: Mohindra, Samir
name: Saraswat, Vivek Anand
Publisher: name: F1000Research
Year: 2017

description: Acute-on-chronic liver failure (ACLF) is a syndrome characterized by acute deterioration of liver function resulting from different types of precipitants (e.g. bacterial infections, active alcoholism) in patients with underlying liver cirrhosis.<sup>1-7</sup> It differs from acute liver failure (ALF), which occurs in the absence of any preexisting liver disease, and also results in new onset ascites, hepatic encephalopathy, gastrointestinal hemorrhage and extrahepatic organ failure (kidney, brain, coagulation, circulation and/or respiration) or any combination of these.<sup>5-7</sup> Current management of ACLF is rather poor, due to deprived understating of the pathogenesis and limited therapeutic options resulting in high incidence of short/medium term mortality (&gt;50%).<sup>5-9</sup> Bacterial infection has been a frequent trigger of ACLF<sup>9</sup> rendering a state of systemic inflammatory response syndrome (SIRS, due to initial cytokine burst), progression to compensatory anti-inflammatory response syndrome (CARS) and associated immune-paralysis which altogether leads to sepsis and multi-organ failure.<sup>6</sup> Bio-artificial liver support systems, hepatic regeneration (through bone marrow derived stem cells), immunotherapy, and gut microbiota modulation are on the horizon of medical care for this patient population; however, data are too premature to implement them as standard of care.<sup>2,6,10</sup> Liver transplantation remains the only option for these patients; however, limited availability of donor organs, cost, complications and side effects associated with immunosuppression limit its application in routine clinical management. Therefore, there is an urgent need (i) first to identify reliable clinical biomarkers for predicting prognosis in ACLF patients and second (ii) to understand the pathogenesis of liver failure so that the treatment and/or support systems can be tailored for rapid and efficient recovery of these patients. Currently, the Department of Gastroenterology, SGPGIMS Lucknow, in collaboration with CBMR Scientists is making efforts to achieve both these objectives.<br><br>As a part of this long-term project, recently, intestinal permeability (IP) in ACLF patients has been investigated to underscore the role of mucosal barrier function in the pathogenesis of ACLF, which, in turn, may help to guide clinical management in critical care. The intestinal mucosa functions as a digestive-cum-absorptive organ for nutrients and allows passage of digested nutrients into the bloodstream. It also functions as a powerful immune-mechanical barrier against excessive absorption of bacteria, food antigens, and other undigested food macromolecules. Increased intestinal permeability (IP), increased bacterial translocation (BT), small intestinal bacterial overgrowth (SIBO) and gut dysbiosis are well known in liver cirrhosis (LC).<sup>11-13</sup> The increased intestinal permeability (IIP) in patients with liver cirrhosis has been demonstrated previously.<sup>14</sup> In ACLF, marked increase in IP and BT may occur due to a surge in portal hypertension. The intent of this study was to establish this experimentally by comparing IP in patients with decompensated liver cirrhosis and in patients with ACLF before and after standard medical treatment supplemented by a novel approach to near complete gut decongestion by diuretic therapy (Slow Albumin Furosemide Infusion with or without Terlipressin, SAFI (T)].<sup>15</sup> Probiotics are known to stabilize gut microbiota and improve functioning of intestinal barrier;<sup>16,17</sup> therefore the treatment was further supplemented with dietary probiotics to facilitate the recovery of altered mucosal barrier function. The experimental details and results are presented within the poster.<br><br>References<br>(1)     Laleman, W.; Verbeke, L.; Meersseman, P.; Wauters, J.; Van Pelt, J.; Cassiman, D.; Wilmer, A.; Verslype, C.; Nevens, F. Acute-on-chronic liver failure: current concepts on definition, pathogenesis, clinical manifestations and potential therapeutic interventions. <i>Expert review of gastroenterology &amp; hepatology</i> 2014,<br>(2)     Asrani, S. K.; O'Leary, J. G. Acute-on-chronic liver failure. <i>Clinics in liver disease</i> 2014, 18, 561.<br>(3)     Blasco-Algora, S.; Masegosa-Ataz, J.; Gutierrez-Garcia, M. L.; onso-Lopez, S.; Fernandez-Rodriguez, C. M. Acute-on-chronic liver failure: Pathogenesis, prognostic factors and management. <i>World journal of gastroenterology</i> 2015, 21, 12125.<br>(4)     Sarin, S. K.; Choudhury, A. Acute-on-chronic liver failure: terminology, mechanisms and management. <i>Nature Reviews Gastroenterology &amp; Hepatology</i> 2016,<br>(5)     Ampuero, J. Acute-on-chronic liver failure: A time to step forward. <i>Revista espanola de enfermedades digestivas: organo oficial de la Sociedad Espanola de Patologia Digestiva</i> 2017, 109<br>(6)     Hernaez, R.; Solá, E.; Moreau, R.; Ginès, P. Acute-on-chronic liver failure: an update. <i>Gut</i> 2017,  gutjnl-2016.<br>(7)     Jalan, R.; Gines, P.; Olson, J. C.; Mookerjee, R. P.; Moreau, R.; Garcia-Tsao, G.; Arroyo, V.; Kamath, P. S. Acute-on chronic liver failure. <i>Journal of hepatology</i> 2012, 57, 1336-1348.<br>(8)     Moreau, R. Acute-on-chronic liver failure: a new syndrome in cirrhosis. <i>Clinical and molecular hepatology</i> 2016, 22, 1.<br>(9)     Fernandez, J.; Acevedo, J.; Weist, R.; Gustot, T.; Amoros, A.; Deulofeu, C.; Reverter, E.; Martinez, J.; Saliba, F.; Jalan, R. Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis. <i>Gut</i> 2017,  gutjnl-2017.<br>(10)    Maiwall, R.; Maras, J. S.; Nayak, S. L.; Sarin, S. K. Liver dialysis in acute-on-chronic liver failure: current and future perspectives. <i>Hepatology international</i> 2014, 8, 505-513.<br>(11)    Wiest, R.; Garcia-Tsao, G. Bacterial translocation (BT) in cirrhosis. <i>Hepatology</i> 2005, 41, 422-433.<br>(12)    Qin, N.; Yang, F.; Li, A.; Prifti, E.; Chen, Y.; Shao, L.; Guo, J.; Le Chatelier, E.; Yao, J.; Wu, L. Alterations of the human gut microbiome in liver cirrhosis. <i>Nature</i> 2014, 513, 59.<br>(13)    Jiang, W.; Wu, N.; Wang, X.; Chi, Y.; Zhang, Y.; Qiu, X.; Hu, Y.; Li, J.; Liu, Y. Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. <i>Scientific reports</i> 2015, 5<br>(14)    Pijls, K. E.; Koek, G. H.; Elamin, E. E.; de Vries, H.; Masclee, A. A.; Jonkers, D. M. Large intestine permeability is increased in patients with compensated liver cirrhosis. <i>American Journal of Physiology-Gastrointestinal and Liver Physiology</i> 2014, 306, G147-G153.<br>(15)    Runyon, B. A. Management of adult patients with ascites due to cirrhosis. <i>Hepatology</i> 2004, 39, 841-856.<br>(16)    Isolauri, E.; Kirjavainen, P. V.; Salminen, S. Probiotics: a role in the treatment of intestinal infection and inflammation? <i>Gut</i> 2002, 50, iii54-iii59.<br>(17)    Madsen, K.; Cornish, A.; Soper, P.; McKaigney, C.; Jijon, H.; Yachimec, C.; Doyle, J.; Jewell, L.; De Simone, C. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. <i>Gastroenterology</i> 2001, 121, 580-591.