OTU-09 Use of early-TIPSS in patients with oesophageal variceal bleeding, a UK dual-centre randomised control trial

Abstract

transplantation. Murine models of acute liver injury are characterised by changes in the hepatic macrophage compartment, with an initial accumulation of pro-inflammatory Ly6C hi monocytes and loss of Kupffer cells, followed by the dominance of recruited pro-reparative Ly6C lo macrophages. Current experimental immunomodulatory therapeutics like MC21 and Cenicriviroc inhibit Ly6C hi monocyte recruitment. In non-hepatic sterile injury models IL-4 is known to promote pro-reparative macrophage functions and IL-4 administered prior to injury with carbon tetrachloride (CCl 4 ) has been shown to be hepatoprotective by directly promoting hepatocyte proliferation. We therefore aimed to assess the potential pro-reparative and immunomodulatory effects of therapeutic IL-4 administered following acute liver injury with CCl 4 . Methods Male C57Bl/6 mice were given CCl 4 intraperitoneally to induce an acute liver injury. IL-4 was administered in the form of an immune complex subcutaneously. To investigate the role of IL-4Ra signalling in bone marrow derived cells, whole-body and tissue-protected chimeras were generated with wild type or IL-4Ra -/donor bone marrow. Results were analysed using immunohistochemistry of tissue sections, serum biochemistry and flow cytometric analysis of leukocytes. Results Therapeutic administration of IL-4 following CCl 4 reduced markers of hepatic injury (ALT and necrotic area) and enhanced hepatic regeneration as measured by hepatocyte proliferation. This was paralleled by profound alterations to the monocyte/macrophage pool, with increases in the number of pro-reparative Ly6C lo macrophages but also a significant reduction in the number of pro-inflammatory hepatic Ly6C hi monocytes. Using chimeras, we have shown that Ly6C lo macrophage accumulation required cell-intrinsic, IL-4Ra-dependent proliferation and the loss of hepatic Ly6C hi monocytes was dependent on cell-intrinsic, IL-4Ra signalling. Importantly, analysis of kidney, spleen and blood revealed that the loss of Ly6C hi monocytes secondary to IL-4 treatment was not limited to the liver and occurred systemically. In vitro and ex vivo assays showed that the reduction in Ly6C hi monocytes in response to administration of IL-4 was due to IL-4Ra-dependent apoptosis of circulating monocytes rather than decreased output from the bone marrow. Conclusion This novel role of IL-4 offers potential therapeutic benefits over monocyte inhibitors by not only reducing proinflammatory Ly6C hi monocyte numbers through apoptosis but also increasing the number of pro-reparative Ly6C lo macrophages.

Transjugular intrahepatic portosystemic stent-shunt in the management of portal hypertension

“…Furthermore, endoscopic sclerotherapy was used in more than 5% of patients, which is not in keeping with current international guidelines where VBL is recommended 31 32. A RCT from the UK of early TIPSS in 58 patients with Child-Pugh score ≥8, published in abstract form, showed no difference in survival (HR 1.154 (95%CI 0.3289 to 3.422); P 0.79) nor rebleeding regardless of severity of liver disease or active bleeding 33. The 1-year transplant-free survival in the control arm was significantly better than in the 2010 study (76% vs 61%),28 suggesting improvements in overall care of patients with acute variceal bleeding in the past decade, and extrapolation of results from the 2010 study to the present time needs careful consideration.…”

“…However, the authors concluded that further study was required to identify factors associated with poor prognosis after early TIPSS. Moreover, the recent RCTs by Lv et al and Dunne et al were not included 30 33…”

Risk Stratification Based on Chronic Liver Failure Consortium Acute Decompensation Score in Patients With Child‐Pugh B Cirrhosis and Acute Variceal Bleeding

“…(1)(2)(3) The early preemptive placement of transjugular intrahepatic portosystemic shunt (TIPS) has emerged as a very effective strategy to improve outcomes in selected populations. (4)(5)(6)(7)(8)(9)(10)(11) Until now, it has been clear that the application of early TIPS is justified in patients with Child-Pugh C (<14 points) cirrhosis and not necessary in those with Child-Pugh A class. (5,7,12,13) Nevertheless, the optimal candidates for early TIPS in Child-Pugh B cirrhosis remain under debate.…”

Twitter debate: controversies in the management of portal hypertension

“…Unusually, this occurred without a statistically significant increase in hepatic encephalopathy in the TIPSS group. A recent publication from China identified a survival benefit,10 but a Scottish randomised controlled trial did not 11. As these findings are controversial, more studies are required to convincingly demonstrate a survival benefit of early TIPSS.…”