D Bauer

Von Willebrand factor indicates bacterial translocation, inflammation, and procoagulant imbalance and predicts complications independently of portal hypertension severity.

Elevated plasma von Willebrand factor antigen (vWF) has been shown to indicate the presence of clinically significant portal hypertension, and thus, predicts the development of clinical events in patients with cirrhosis.

Impact of patatin-like phospholipase domain containing 3 rs738409 G/G genotype on hepatic decompensation and mortality in patients with portal hypertension

The rs738409 C>G p.I148M variant in the patatin‐like phospholipase domain containing 3 (PNPLA3)‐gene promotes triglyceride accumulation in hepatocytes and hepatic stellate cell activation and has previously been linked to hepatic steatosis/liver fibrosis.

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.

Transjugular intrahepatic portosystemic shunts (TIPS) for the prevention of variceal re-bleeding – A two decades experience

Background and aims Transjugular intrahepatic portosystemic shunts (TIPS) are used in patients with cirrhosis for the prevention of variceal rebleeding. Methods We retrospectively evaluated re-bleeding rate, patency, mortality, and transplant-free survival (TFS) in cirrhotic patients receiving TIPS implantation for variceal bleeding between 1994–2014. Results 286 patients received TIPS (n = 119 bare metal stents, n = 167 polytetrafluorethylene (PTFE)-covered stents) for prevention of variceal re-bleeding. Mean age was 55.1 years, median MELD was 11.8, and the main etiology of cirrhosis was alcoholic liver disease (70%). Median follow-up was 821 days. 67 patients (23%) experienced at least one re-bleeding event. Patients with PTFE-TIPS were at significantly lower risk for variceal re-bleeding than patients with bare metal stents (14% vs. 37%, OR:0.259; p<0.001) and had less need for stent revision (21% vs. 37%; p = 0.024). Patients with PTFE stent grafts showed lower mortality than patients with bare stents after 1 year (19% vs. 31%, p = 0.020) and 2 years (29% vs. 40%; p = 0.041) after TIPS implantation. Occurrence of hepatic encephalopathy after TIPS was similar between groups (20% vs. 24%, p = 0.449). Conclusions PTFE-TIPS were more effective at preventing variceal re-bleeding than bare metal stents due to better patency. Since this tended to translate in improved survival, only covered stents should be implemented for bleeding prophylaxis when TIPS is indicated.

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.