ELIMINATE: a PCR record-based macroelimination project for systematic recall of HCV-RNA-positive persons in Austria.

BACKGROUND AND AIMS: Micro-elimination projects targeted to specific hepatitis C virus (HCV) risk populations have been successful. Systematic identification of persons with HCV viremia, regardless of risk group, based on already available laboratory records may represent an effective macroelimination approach to achieve global HCV elimination. METHODS: Persons with a last positive HCV-RNA PCR result between 2008-2020 in the reference virology laboratories in eastern Austria were identified. First, (i) we described their demographic characteristics, (ii) we systematically recalled persons to the respective centers and (iii) started antiviral treatment if HCV-RNA viremia was confirmed, and (iv) recorded sustained virologic response (SVR). This interim report includes the preliminary results from 8 participating centers. RESULTS: During the study period 22,682 persons underwent HCV-RNA PCR testing, 11,216 (49.4%) were positive at any point in time, and 6006 (26.5%) showed detectable HCV-RNA at the last PCR test, suggesting ongoing HCV viremia. At the time of this interim report, 2546/6006 HCV-RNA PCR(+) persons were evaluated: 443/2546 (17.4%) had died, 852/2546 (33.5%) had invalid contact data, and 547/2546 (21.5%) had achieved SVR between data retrieval and recall. Contact could be established in 236/704 (33.5%) of the remaining target population with 97/236 (41.1%) presenting at the clinic for treatment evaluation. Ultimately, 71/236 (30.1%) started antiviral treatment and SVR was documented in 47/71 (66.2%). CONCLUSION: This ELIMINATE project based on systematic assessment of HCV-RNA PCR-records, identified 6006 persons with potential persisting HCV viremia. Invalid contact data and missed visits for treatment evaluation were the main barriers towards HCV elimination within this project. Importantly, many subjects with HCV viremia lost to follow-up were successfully linked to care and started antiviral treatment.

Adherence to guidelines in patients with non-variceal upper gastrointestinal bleeding (UGIB) - results from a retrospective single tertiary center registry.

BACKGROUND: Guidelines for the management of upper gastrointestinal bleeding (UGIB) are regularly published, yet little is known concerning adherence to recommendations in practice. OBJECTIVES: We aimed to assess adherence to European Society of Gastrointestinal Endoscopy (ESGE) recommendations in patients with non-variceal UGIB. MATERIALS AND METHODS: All hospitalized patients with an esophagogastroduodenoscopy (EGD) performed due to suspected non-variceal UGIB at our department were included in a prospective registry. Data between 2018-2020 from this registry were retrospectively analyzed. Adherence to the 2015 ESGE bleeding and propofol sedation guidelines was assessed. Adherence to recommendations concerning preendoscopic (risk) evaluation, preendoscopic PPI, transfusion management, and endoscopic management of peptic ulcers was analyzed. RESULTS: Among 1005 patients (mean age 70.4 years, 42.1% women) the most common bleeding etiologies were gastric or duodenal ulcers (16.8%), esophagitis/GERD (11.1%), and angiodysplasia (9.9%); mortality was 7.6%. Adherence to preendosopic risk evaluation was low, in 0% a Mallampati classification and in 37.5% an ASA scoring was documented. Preendoscopic PPI was started at 58.6%, and adherence to recommended transfusion management was >98%. Peptic ulcers were Forrest-graded in 72.8%. High-risk ulcers were treated appropriately in 77.9% and low-risk ulcers were not treated in 73.6%. Especially Forrest Ib ulcers were undertreated, with an adherence of 59.6%. Only 22/179 (12.3%) patients with peptic ulcers and early endoscopy were consistently managed according to ESGE recommendations. CONCLUSIONS: Adherence to ESGE guidelines in patients with non-variceal UGIB is moderate to low, even at a tertiary university hospital. Strategies must be devised for guidelines to reach patients in everyday practice.

Splenectomy ameliorates portal pressure and anemia in animal models of cirrhotic and non-cirrhotic portal hypertension.

PURPOSE: Portal hypertension (PH)-associated splenomegaly is caused by portal venous congestion and splanchnic hyperemia. This can trigger hypersplenism, which favors the development of cytopenia. We investigated the time-dependent impact of splenectomy on portal pressure and blood cell counts in animal models of non-cirrhotic and cirrhotic PH. MATERIALS AND METHODS: Ninety-six rats underwent either partial portal vein ligation (PPVL), bile duct ligation (BDL), or sham operation (SO), with subgroups undergoing additional splenectomy. Portal pressure, mean arterial pressure, heart rate, blood cell counts and hemoglobin concentrations were evaluated throughout 5 weeks following surgery. RESULTS: Following PPVL or BDL surgery, the animals presented a progressive rise in portal pressure, paralleled by decreased mean arterial pressure and accelerated heart rate. Splenectomy curbed the development of PH in both models (PPVL: 16.25 vs. 17.93 â€‹mmHg, p â€‹= â€‹0.083; BDL: 13.55 vs. 15.23 â€‹mmHg, p â€‹= â€‹0.028), increased mean arterial pressure (PPVL: +7%; BDL: +9%), and reduced heart rate (PPVL: -10%; BDL: -13%). Accordingly, splenectomized rats had lower von Willebrand factor plasma levels (PPVL: -22%; BDL: -25%). Splenectomy resulted in higher hemoglobin levels in PPVL (14.15 vs. 13.08 â€‹g/dL, p â€‹< â€‹0.001) and BDL (13.20 vs. 12.39 â€‹g/dL, p â€‹= â€‹0.097) animals, and significantly increased mean corpuscular hemoglobin concentrations (PPVL: +9%; BDL: +15%). Thrombocytopenia only developed in the PPVL model and was alleviated in the splenectomized subgroup. Conversely, BDL rats presented with thrombocytosis, which was not affected by splenectomy. CONCLUSIONS: Splenectomy improves both cirrhotic and non-cirrhotic PH, and ameliorates the hyperdynamic circulation. Hypersplenism related anemia and thrombocytopenia were only significantly improved in the non-cirrhotic PH model.

Perceptions on the management of varices and on the use of albumin in patients with cirrhosis among GI specialists in Austria.

BACKGROUND: Portal hypertension (PH) causes severe complications in patients with liver cirrhosis, such as variceal bleeding and ascites; however, data on the knowledge and perceptions on guideline recommendations for the management of varices and the use of albumin is scarce. METHODS: We designed two structured surveys on (i) the management of varices and (ii) the use of albumin for Austrian physicians of specialized Gastro-Intestinal (GI) centers. The interviewed physicians were confronted spontaneously and provided ad hoc responses to the questionnaire. RESULTS: In total, 158 surveys were completed. Interestingly, many specialists (30%) would recommend a follow-up gastroscopy after 1 year in patients with compensated cirrhosis without varices (i.e., overtreatment). For small varices, 81.5% would use non-selective beta blockers (NSBB) for primary prophylaxis (PP). For PP in patients with large varices, endoscopic band ligation (EBL) plus NSBB was preferred by 51.4% (i.e., overtreatment). Knowledge on the indication criteria for early TIPS (transjugular intrahepatic portosystemic shunt) was reported by 54.3%, but only 20% could report these criteria correctly. The majority (87.1%) correctly indicated a preference to use NSBB and EBL for secondary prophylaxis (SP). The majority of participating gastroenterologists reported no restrictions on the use of albumin (89.8%) in their hospitals. Of the interviewed specialists, 63.6% would use albumin in patients with SBP; however, only 11.4% would use the doses recommended by guidelines. The majority of specialists indicated using albumin at the recommended doses for hepatorenal syndrome (HRS-AKI, 86.4%) and for large volume paracentesis (LVP, 73.3%). The individual responses regarding albumin use for infections/sepsis, hyponatremia, renal impairment, and encephalopathy were heterogeneous. CONCLUSION: The reported management of PH and varices is mostly adherent to guidelines, but endoscopic surveillance in patients without varices is too intense and EBL is overused in the setting of PP. Knowledge on the correct use of early TIPS must be improved among Austrian specialists. Albumin use is widely unrestricted in Austria; however, albumin is often underdosed in established indications.

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

BACKGROUND: 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. METHODS: Cirrhotic patients receiving SEMS for VB at four tertiary care centres were included in this retrospective multicentre study. Rates of failure-to-control bleeding (within 5 days) and bleeding-related mortality (6 weeks) were assessed. RESULTS: SEMS controlled VB in 79.4% (27/34) of patients. In the rest of patients, other rescue treatments including endoscopic band ligation (EBL, n = 3), SEMS renewed (n = 2) or Linton (n = 2) were applied; however, VB was only controlled in one patient. Early rebleeding within six weeks occurred in 17.6% (6/34) patients. Median SEMS dwell time was three (IQR:6) days. Overall n = 13/34 (38.2%) patients died with SEMS in situ. After SEMS removal, rebleeding and bleeding-related death occurred in n = 7 (35%) and n = 5 (14.7%) patients respectively. Only 32.4% (10/34) patients did not experience any rebleeding within six weeks after SEMS removal. Bleeding-related mortality was 47.1% (n = 16/34) and the median survival after SEMS placement was 2.1 months. Notably, no patient received an early transjugular intrahepatic portosystemic shunt (TIPS). The most common adverse events were stent dislocations (n = 13; 38.2%), while ulcers/necrosis of the oesophageal mucosa was seen in only four (11.8%) patients. CONCLUSION: SEMS controlled refractory VB in most patients. However, bleeding-related mortality remained high. While SEMS dislocations were frequent, ulcers/necrosis of the oesophagus was rare. Further studies should investigate whether the wider use of early TIPS reduces bleeding-related mortality after SEMS placement.

Small Esophageal Varices in Patients with Cirrhosis-Should We Treat Them?

PURPOSE OF REVIEW: The natural history and classification systems of small varices (≤ 5 mm in diameter) in cirrhotic patients with portal hypertension are summarized. Studies that assessed the course of and therapeutic intervention for small varices are discussed. RECENT FINDINGS: Current non-invasive methods show suboptimal sensitivity to detect small varices in patients with cirrhosis. Next to etiological therapy, hepatic venous pressure gradient (HVPG)-guided non-selective betablocker or carvedilol treatment has shown to impact on natural history of small varices. SUMMARY: The main therapeutic focus in cirrhotic patients with small varices is the cure of the underlying etiology. The optimal management of small varices should include measurement of HVPG. A pharmacological decrease in HVPG by non-selective betablocker therapy of ≥ 10% reduces the risk of progression to large varices, first variceal bleeding, and hepatic decompensation. If HVPG is not available, we would recommend carvedilol 12.5 mg q.d. for treatment of small varices in compensated patients without severe ascites. Only if small esophageal varices (EV) are not treated or in hemodynamic non-responders, follow-up endoscopies should be performed in 1-2 years of intervals considering the activity of liver disease or if hepatic decompensation occurs.

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.

Re-bleeding rates and survival after early transjugular intrahepatic portosystemic shunt (TIPS) in clinical practice.

BACKGROUND: Early implantation (<72h) of a transjugular intrahepatic portosystemic shunt (TIPS) after acute variceal bleeding (AVB) improves survival in highly selected patients. METHODS: We retrospectively assessed bleeding control and survival of unselected cirrhotic patients undergoing early TIPS implantation within 72h. We compared the outcomes to patients meeting early TIPS criteria but receiving late TIPS within 3-28days after AVB and endoscopic/medical treatment. RESULTS: Forty-nine patients were included. Mean MELD was 14.4 (±4.4). Thirteen patients (26.5%) presented characteristics that were exclusion criteria in previous early TIPS trials (age>75, CPS>13, HCC>Milan, previous beta-blocker/band-ligation, renal insufficiency). Bare metal and PTFE-covered stents were used in n=32 (65.3%) and n=17 (34.7%) patients, respectively, and showed similar early re-bleeding rates (9.9% vs. 7.1%; p=0.6905) and bleeding-related mortality (25.0% vs. 23.5%; p=0.9906). However, overall re-bleeding rate was lower with PTFE-TIPS (7.7% vs. 64.2%; p=0.0044) over a median follow-up of 18.5 months with a tendency towards improved survival (median 70.5 vs. 13.8 months; p=0.204). Additional 68 patients meeting stringent criteria but receiving late TIPS also showed a favorable bleeding-related mortality (8.8%), which was not achieved in similar n=34 patients by a medical/endoscopic strategy with bleeding-related mortality of 35.7%. CONCLUSIONS: An early TIPS strategy using covered stents and implementation of 'stringent criteria' results in a favorable outcome in patients with acute variceal bleeding.

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

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 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 ß). 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.