Friend or Foe? Spontaneous Portosystemic Shunts in Cirrhosis—Current Understanding and Future Prospects

Portal hypertension (PHT) in cirrhosis results from increased resistance to splanchnic blood flow secondary to parenchymal and vascular changes within the liver. In an attempt to counteract the increased portal pressure, two mechanisms simultaneously occur: splanchnic vasodilatation and formation of spontaneous portosystemic shunts (SPSS). Long considered to be a compensatory mechanism to decompress the portal venous system, it is now well established that SPSS are not only inefficient in decreasing the portal pressure but also contribute to reduced hepatocyte perfusion and increased splanchnic blood flow and resistance, associated with worsening PHT. Recent studies have described a high prevalence of SPSS in cirrhosis patients, increasing with liver dysfunction, and observed an association between the presence of SPSS and worse clinical outcomes. In cirrhosis patients with preserved liver functions, the presence of SPSS independently increases the risk of hepatic encephalopathy, variceal bleeding, and ascites, and reduces transplant-free survival. Moreover, the presence of SPSS in patients undergoing transjugular intrahepatic portosystemic shunting and liver transplant has been shown to variably affect the postprocedural outcome. This article provides an overview of the current understanding of the role of SPSS in the natural history of liver cirrhosis and their status as a therapeutic target and an imaging biomarker to identify patients at higher risk of developing complications of PHT.

THE INFLUENCE OF POSTOPERATIVE ANALGESIA TECHNIQUES ON SPLANCHIC BLOOD FLOW IN CHILDREN WITH INTRAABDOMINAL HYPERTENSION

Introduction. Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) often develop in critically ill patients and can lead to affected splanchnic blood flow, intestinal mucosal ischemia, bacterial translocation, sepsis, and multiorgan dys-function. There is limited literature data on the effect of analgesic methods on splanchnic blood flow in IAG / AСS. The aim of the study was to define the effect of different postoperative analgesia techniques on splanchnic blood flow in children with appendicular peritonitis with IAH. Materials and methods. The study included 115 children who underwent surgery for appendicular peritonitis. Children were randomized into three groups depending on the method of postoperative analgesia: “Opioids” (n = 36; intravenous infusion of morphine 10 μg/kg/h); “Lidocaine” (n = 40; intravenous infusion of lidocaine 1.5 mg/kg/h); “EDA” (n = 39; epidural infusion 0.25% bupivacaine 0.4 mg/kg/h). Postoperatively intraabdominal pressure (IAP) was measured 4 times a day using the standard in-direct method through a Foley catheter in the bladder. According to the IAP level and presence of organ dysfunction patients in each group were divided in subgroups: “Without IAH”, “IAH” and “ACS”. The diameters and linear velocities of blood flow in the superior mesenteric artery (SMA) and portal vein (PV) were detected using US. The blood flow indices in SMA and PV (BFISMA, BFIPV, ml/min/m2) were calculated. Results. BFISMA and BFIPV were significantly higher in children without IAH than in children with IAH (p <0.0001) and ACS (p <0.0001). Among patients in all subgroups, BFISMA was significantly higher in the groups “Lidocaine” (p <0.05) and “EDA” (p <0.0001) compared with the group “Opioids”. BFIPV was higher in the group “EDA” (p <0.05) in children with IAH and in the groups “Lidocaine” (p <0.0001) and “EDA” (p <0.0001) in children with ACS compared with children of all subgroups in the group “Opioids”. Among the children without IAH a statistically significant negative correlation between IAP and BFISMA was observed only in the group “Opioids” (rs = -0.5; p <0.001). Among the children with IAH and ACS, a statistically significant negative correlation between IAP and BFISMA was observed in all analgesia groups, but it was weakest in the group “EDA” (rs = -0.24; p <0.04 and rs = -0.39; p <0.05, respectively). In the group “Opioids” a statistically significant negative correlation between IAP and BFIPV was observed only in the children with IAH (rs=-0.31; p<0.01) and ACS (rs=-0.4; p<0.0001). Conclusions. Epidural analgesia is the most optimal method of analgesia for the effect on impaired splanchnic blood flow in children with peritonitis complicated with intra-abdominal hypertension. Intravenous analgesia with lidocaine may be an alternative to epidural anesthesia.

The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model

Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. Results: Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of −41% (10 mg/kg) and −69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (−41%), expression of col1a1 (−37%) and pdgfr-β (−36%), as well as desmin area (−42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (−28%) but also mean arterial pressure (−25%) and heart rate (−37%). Conclusion: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion.