F Riedl

The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction

BACKGROUND & AIMS Steroidal farnesoid X receptor (FXR) agonists demonstrated potent anti-fibrotic activities and lowered portal hypertension in experimental models. The impact of the novel non-steroidal and selective FXR agonist PX20606 on portal hypertension and fibrosis was explored in this study. METHODS In experimental models of non-cirrhotic (partial portal vein ligation, PPVL, 7days) and cirrhotic (carbon tetrachloride, CCl4, 14weeks) portal hypertension, PX20606 (PX,10mg/kg) or the steroidal FXR agonist obeticholic acid (OCA,10mg/kg) were gavaged. We then measured portal pressure, intrahepatic vascular resistance, liver fibrosis and bacterial translocation. RESULTS PX decreased portal pressure in non-cirrhotic PPVL (12.6±1.7 vs. 10.4±1.1mmHg; p=0.020) and cirrhotic CCl4 (15.2±0.5 vs. 11.8±0.4mmHg; p=0.001) rats. In PPVL animals, we observed less bacterial translocation (-36%; p=0.041), a decrease in lipopolysaccharide binding protein (-30%; p=0.024) and splanchnic tumour necrosis factor α levels (-39%; p=0.044) after PX treatment. In CCl4 rats, PX decreased fibrotic Sirius Red area (-43%; p=0.005), hepatic hydroxyproline (-66%; p<0.001), and expression of profibrogenic proteins (Col1a1, α smooth muscle actin, transforming growth factor β). CCl4-PX rats had significantly lower transaminase levels and reduced hepatic macrophage infiltration. Moreover, PX induced sinusoidal vasodilation (upregulation of cystathionase, dimethylaminohydrolase (DDAH)1, endothelial nitric oxide synthase (eNOS), GTP-cyclohydrolase1) and reduced intrahepatic vasoconstriction (downregulation of endothelin-1, p-Moesin). In cirrhosis, PX improved endothelial dysfunction (decreased von-Willebrand factor) and normalized overexpression of vascular endothelial growth factor, platelet-derived growth factor and angiopoietins. While short-term 3-day PX treatment reduced portal pressure (-14%; p=0.041) by restoring endothelial function, 14week PX therapy additionally inhibited sinusoidal remodelling and decreased portal pressure to a greater extent (-22%; p=0.001). In human liver sinusoidal endothelial cells, PX increased eNOS and DDAH expression. CONCLUSIONS The non-steroidal FXR agonist PX20606 ameliorates portal hypertension by reducing liver fibrosis, vascular remodelling and sinusoidal dysfunction. LAY SUMMARY The novel drug PX20606 activates the bile acid receptor FXR and shows beneficial effects in experimental liver cirrhosis: In the liver, it reduces scarring and inflammation, and also widens blood vessels. Thus, PX20606 leads to an improved blood flow through the liver and decreases hypertension of the portal vein. Additionally, PX20606 improves the altered intestinal barrier and decreases bacterial migration from the gut.

Betablockers do not increase efficacy of band ligation in primary prophylaxis but they improve survival in secondary prophylaxis of variceal bleeding.

Endoscopic band ligation (EBL) is used for primary (PP) and secondary prophylaxis (SP) of variceal bleeding. Current guidelines recommend combined use of non‐selective beta‐blockers (NSBBs) and EBL for SP, while in PP either NSBB or EBL should be used.

Non-selective beta-blocker treatment does not impact on kidney function in cirrhotic patients with varices

Abstract Goals and background: Non-selective beta-blockers (NSBBs) are used for bleeding prophylaxis in cirrhotic patients with gastroesophageal varices (GEVs). Recent data suggested that NSBB treatment might increase the risk of renal dysfunction in patients with refractory ascites due to an impaired response to acute haemodynamic stress. Study: Retrospective longitudinal assessment of kidney function in a cohort of cirrhotic patients with GEVs with vs. without NSBB therapy. Serum creatinine (SCre), estimated glomerular filtration rate (eGFR), incidence of acute kidney injury (AKI), new onset of large volume ascites and TIPS-/transplant-free survival were compared. Results: Among 176 patients, 93 patients received NSBBs, while 83 did not. Most patients were male (77.8%), had alcoholic aetiology (52.3%) and compensated cirrhosis (51.1% Child-A, MELD: 12.1 ± 3.8). Over a 3-year follow-up, renal function was comparable between patients with and without NSBB treatment. Incidence of AKI was similar in NSBB vs. no-NSBB patients (p = .323). Even in potential risk groups (ascites, MAP <90 mmHg, baseline creatinine > ULN, hyponatraemia, MELD score ≥15 points, Child–Pugh B/C), there was no difference in SCre or eGFR with vs. without NSBBs (p = n.s. at 74/78 and 76/78 of analysed time points). However, multivariate analysis revealed that the presence of ascites (HR: 3.901, 95%CI: 1.352–11.251; p = .012) and pre-existing renal impairment (HR: 4.315, 95%CI: 1.054–17.672; p = .042) were independent risk factors for AKI. Importantly, NSBB use (HR: 0.319, 95%CI: 0.120–0.848; p = .022) was independently associated with improved TIPS-/transplant-free survival. Conclusions: In our cohort of unselected, mostly compensated cirrhotic patients with GEVs, NSBB treatment was neither associated with worsening of kidney function nor with increased incidence of AKI. On the contrary, NSBB treatment improved TIPS-/transplant-free survival.

The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats

In cirrhotic patients, portal hypertension (PHT) deteriorates survival, yet treatment options are limited. A major contributor to increased intrahepatic vasoconstriction in PHT is dysfunctional nitric-oxide signaling. Soluble guanylate cyclase (sGC) is the receptor of nitric-oxide and can be stimulated by riociguat. Riociguat is approved for pulmonary hypertension but has not been studied in liver cirrhosis. In this study we assessed the effects of riociguat on PHT and liver fibrosis in cholestatic (bile duct ligation, BDL) and toxic (carbon-tetrachloride, CCl4) rat models. In cirrhotic livers sGC expression was upregulated. In BDL rats, riociguat reduced liver fibrosis and decreased portal pressure without affecting systemic hemodynamics. In an early BDL disease stage, riociguat decreased bile duct proliferation, improved sinusoidal vascular dysfunction and inhibited angiogenesis. In advanced BDL riociguat exhibited anti-inflammatory effects. In CCl4 rats the beneficial effects of riociguat treatment were less pronounced and confined to an early disease stage. Similarly, in patients with cholestatic cirrhosis and PHT nitrates (that induce sGC activity) decreased portal pressure more effectively than in patients with non-cholestatic etiology. We also found an improvement of transaminases in patients with pulmonary hypertension receiving riociguat. Our findings support the clinical development of sGC stimulators in patients with cirrhotic PHT.

Outcomes after placement of a SX-ELLA oesophageal stent for refractory variceal bleeding-A national multicentre study

Current guidelines favour the use of bleeding stents over balloon tamponade (BT) for refractory variceal bleeding (VB) from oesophageal varices. However, data on the efficacy and safety of self‐expandable metal SX‐ELLA Danis stents (SEMS) are limited.

Riociguat, ein Stimulator der Guanylat-Cyclase, reduziert Leberfibrose und portalvenösen Druck in Ratten mit bilärer Leberzirrhose.

Einleitung: Bei Leberzirrhose besteht ein Ungleichgewicht des Stickstoffmonoxid-Haushalts und eine Dysfunktion seines intrazellularen Rezeptors, der loslichen Guanylat-Cyklase (sGC). Riocyguat (RIO) ist ein Agonist der sGC und zur Behandlung pulmonaler Hypertension zugelassen. Neben vasodilatatorischer Eigenschaften wurden auch antifibrotische Effekte beschrieben. Wir untersuchten den Einfluss von RIO auf den Pfortaderdruck in einem Rattenmodel fur bilare Leberzirrhose. Materialen & Methoden: Zur Induktion einer Leberzirrhose wurden mannliche Sprague-Dawley-Ratten gallengangsligiert (BDL), wahrend eine Kontrollgruppe „schein“-operiert (SO) wurde. Die Ratten wurden taglich mit 1 mg/kg RIO oder Placebo (DMSO) gavagiert. In einem praventiven Setting erfolgte die Therapie vom postoperativem Tag 7 – 21, wahrend im therapeutischen Setting vom Tag 21 – 35 therapiert wurde. Nach Therapieende erfolgten Messungen der Herzfrequenz (HR), des mittleren arteriellen Blutdrucks (MAP), des Pfortaderdrucks (PP) und des Blutflusses in der A. mesenterica superior (SMABF). Das porto-systemische Shunting (PSS) wurde durch Injektion von Farb-Mikrospharen bestimmt. Die Quantifizierung der Leberfibrose erfolgte durch Chrom-Anilinblau (CAB) Farbung, beziehungsweise durch Messung des Hydroxyprolingehaltes (HP). Ergebnis: Im praventiven BDL-Setting entwickelte sich bei der Placebogruppe eine starker ausgepragte Leberfibrose (CAB: 23,7 ± 4,6 vs. 13,3 ± 2,1%, p < 0,001; HP: 286 ± 147 vs. 144 ± 74 µg/g, p = 0,039), verglichen zur RIO-Therapie. Weiters zeigte sich ein signifikanter Abfall des PP (13,2 ± 2,5 vs. 10,1 ± 2,4 mmHg, p = 0,048), wahrend MAP, HR, SMABF und PSS durch RIO nicht beeinflusst wurden. Im therapeutischen BDL-Setting zeigte sich in den BDL-Placebo Tieren eine deutliche Leberzirrhose, die durch RIO-Therapie deutlich weniger ausgepragt war (CAB: 29,9 ± 2,2 vs. 19,3 ± 5,7%, p < 0,001; HP: 354 ± 169 vs. 233 ± 45 µg/g, p = 0,044). Ebenso zeigte sich eine Reduktion des PP in BDL-RIO Tieren (15,5 ± 1,6 vs. 11,9 ± 2,1 mmHg, p = 0,002), ohne Beeinflussung des MAP, HR, SMABF oder PSS. Diskussion: Eine Riociguat-Therapie fuhrt in cholestatischen Ratten zu einer Reduktion des Leberschadens und des Pfortaderdrucks ohne den systemischen Druck negativ zu beeintrachtigen.