Intraperitoneal Activation of Coagulation and Fibrinolysis in Patients with Cirrhosis and Ascites

Development of ascites is the most common form of decompensation of cirrhosis. We aimed to investigate the coagulation system in ascitic fluid and plasma of patients with cirrhosis. We determined coagulation parameters and performed clotting and fibrinolysis experiments in ascitic fluid and plasma of thoroughly characterized patients with cirrhosis and ascites ( n  = 25) and in plasma of patients with cirrhosis but without ascites ( n  = 25), matched for severity of portal hypertension. We also investigated plasma D-dimer levels in an independent cohort of patients ( n  = 317) with clinically significant portal hypertension (HVPG ≥ 10 mmHg), grouped according to ascites severity. Ascitic fluid was procoagulant in a clotting assay. The procoagulant potential of ascitic fluid was abolished by depletion of extracellular vesicles from ascitic fluid by filtration or by addition of a tissue factor-neutralizing antibody. Compared with plasma, extracellular vesicle-associated tissue factor activity was high in ascitic fluid, while activities of other coagulation factors were low. The extracellular vesicle-depleted fraction of ascitic fluid induced fibrinolysis, which was prevented by aprotinin, indicating the presence of plasmin in ascitic fluid. Plasma peak thrombin generation and parameters reflecting fibrinolysis were independently associated with the presence of ascites. Finally, plasma D-dimer levels were independently linked to ascites severity in our second cohort comprising 317 patients. In conclusion, coagulation and fibrinolysis become activated in ascites of patients with cirrhosis. While tissue factor-exposing extracellular vesicles in ascitic fluid seem unable to pass the peritoneal membrane, fibrinolytic enzymes get activated in ascitic fluid and may re-enter the systemic circulation and induce systemic fibrinolysis

Dynamics in Liver Stiffness Measurements Predict Outcomes in Advanced Chronic Liver Disease

Background &amp; Aims:Liver stiffness measurements (LSMs) provide an opportunity to monitor liver disease progression and regression noninvasively. We aimed to determine the prognostic relevance of LSM dynamics over time for liver-related events and death in patients with chronic liver disease. Methods:Patients with chronic liver disease undergoing 2 or more reliable LSMs at least 180 days apart were included in this retrospective cohort study and stratified at baseline (BL) as nonadvanced chronic liver disease (non-ACLD, BL-LSM &lt; 10 kPa), compensated ACLD (cACLD; BL-LSM ≥ 10 kPa), and decompensated ACLD. Data on all consecutive LSMs and clinical outcomes were collected. Results: There were 2508 patients with 8561 reliable LSMs (3 per patient; interquartile range, 2–4) included: 1647 (65.7%) with non-ACLD, 757 (30.2%) with cACLD, and 104 (4.1%) with decompensated ACLD. Seven non-ACLD patients (0.4%) and 83 patients with cACLD (10.9%) developed hepatic decompensation (median follow-up, 71 months). A 20% increase in LSM at any time was associated with an approximately 50% increased risk of hepatic decompensation (hazard ratio, 1.58; 95% CI, 1.41–1.79; P &lt;.001) and liver-related death (hazard ratio, 1.45; 95% CI, 1.28–1.68; P &lt;.001) in patients with cACLD. LSM dynamics yielded a high accuracy to predict hepatic decompensation in the following 12 months (area under the receiver operating characteristics curve = 0.933). The performance of LSM dynamics was numerically better than dynamics in Fibrosis-4 score (0.873), Model for End-Stage Liver Disease (0.835), and single time-point LSM (BL-LSM: 0.846; second LSM: 0.880). Any LSM decrease to &lt;20 kPa identified patients with cACLD with a substantially lower risk of hepatic decompensation (hazard ratio, 0.13; 95% CI, 0.07–0.24). If reliable, LSM also confers prognostic information in decompensated ACLD. Conclusions: Repeating LSM enables an individual and updated risk assessment for decompensation and liver-related mortality in ACLD.</p

Gastroenterology Report / Renal dysfunction in cirrhosis : acute kidney injury and the hepatorenal syndrome

Renal dysfunction is a common complication of liver cirrhosis and of utmost clinical and prognostic relevance. Patients with cirrhosis are more prone to developing acute kidney injury (AKI) than the non-cirrhotic population. Pre-renal AKI, the hepatorenal syndrome type of AKI (HRS-AKI, formerly known as ‘type 1) and acute tubular necrosis represent the most common causes of AKI in cirrhosis. Correct differentiation is imperative, as treatment differs substantially. While pre-renal AKI usually responds well to plasma volume expansion, HRS-AKI and ATN require different specific approaches and are associated with substantial mortality. Several paradigms, such as the threshold of 2.5 mg/dL for diagnosis of HRS-AKI, have recently been abolished and novel urinary biomarkers are being investigated in order to facilitate early and correct diagnosis and treatment of HRS-AKI and other forms of AKI in patients with cirrhosis. This review summarizes the current diagnostic criteria, as well as pathophysiologic and therapeutic concepts for AKI and HRS-AKI in cirrhosis.(VLID)457099

Journal für Gastroenterologische und Hepatologische Erkrankungen / „Early TIPS“ bei Varizenblutungen : Ergebnisse aus der klinischen Routine

Hintergrund Die frühzeitige Implantation (innerhalb von 72 h) eines transjugulären intrahepatischen portosystemischen Shunts (TIPS) verbessert das Überleben nach einer akuten Varizenblutung bei selektionierten Patienten. Methodik Wir analysierten die effektive Blutungskontrolle sowie das Überleben von unselektierten Patienten, die innerhalb von 72 h nach einer Varizenblutung einen „early TIPS“ erhalten haben. Ergebnisse Es wurden n = 49 Patienten mit einem mittleren MELD(„model for end-stage liver disease“)-Score von 14,4 ( 4,4) inkludiert; n = 13 Patienten (26,5 %) zeigten eigentlich Ausschlusskriterien von früheren Early-TIPS-Studien. Diese „strikten Kriterien“ waren im Detail: Alter >75 Jahre: n = 3, Child-Pugh-Score >13 Punkte: n = 3; Hepatozelluläres Karzinom außerhalb von Milan: n = 1; Sekundärprophylaxe mit Blockern oder Varizenligatur: n = 5, Niereninsuffizienz: n = 1. Unbeschichtete und PTFE(Polytetrafluorethylen)-beschichtete Stents zeigten eine ähnliche frühe Reblutungsrate (10 % vs. 6,1 %, p = 0,627) sowie blutungsassoziierte Mortalität innerhalb von 6 Wochen (25,0 % vs. 11,8 %, p = 0,295). Die Gesamtreblutungsrate war beim beschichteten TIPS im Vergleich zu den unbeschichteten Stents jedoch deutlich niedriger (6,7 % vs. 61,1 % über einen medianen Zeitraum von 18,5 Monaten, p = 0,002). Das mediane Überleben war tendenziell bei Verwendung eines PTFE-beschichteten TIPS ebenso besser als bei unbeschichteten TIPS (70,5 vs. 13,8 Monate, p = 0,147). Das Überleben war bei Patienten, die die „strikten Early-TIPS-Kriterien“ erfüllten, deutlich besser (p > 0,001), insbesondere wenn PTFE-beschichtete TIPS verwendet wurden. Schlussfolgerung Ein „early PTFE-TIPS“ innerhalb von 72 h nach akuter Varizenblutung verbessert bei Child-Pugh C10 bis C13 und Child-Pugh-B-Patienten mit aktiver Blutung im Rahmen der Endoskopie das Outcome und das Überleben.Background Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) within 72h after acute variceal bleeding (AVB) has been shown to improve bleeding control and survival in highly selected patients. Methods We retrospectively assessed the outcomes after early TIPS implantation for AVB in unselected cirrhotic patients. Results Early TIPS was used in n=49 patients with a mean model for end-stage liver disease (MELD) of 14.4 (4.4), while N=13 patients (26.5%) actually would have not qualified as they did not meet inclusion criteria of the original early TIPS trials (“stringent criteria”: n=3 age >75, n=3 Child Pugh Score (CPS) >13, n=1 hepatocellular carcinoma beyond Milan criteria, n=5 previous blocker/band-ligation, n=1 renal insufficiency). We also included patients who had received bare metal stents (n=32, 65.3%) and not only patients receiving PTFE(polytetrafluoroethylene)-covered stents (n=17, 34.7%). Bare and PTFE-TIPS patients showed similar early re-bleeding rates (10.0% vs 6.1%, p=0.627) and bleeding-related mortality (25.0% vs 11.8%, p=0.295). However, overall re-bleeding rate was significantly lower with PTFE-TIPS than with bare stents (6.7% vs 61.1% during a median follow-up period of 18.5 months, p=0.002). Median survival tended to be longer with PTFE-TIPS (70.5 vs 13.8 months with bare metal stents, p=0.147). Survival was significantly better when “stringent criteria” were met (p<0.001), especially in patients receiving PTFE-TIPS. Conclusions The use of PTFE-covered stents for early TIPS resulted in a favorable outcome in patients with CPS C10C13 and in patients with CPS B with active bleeding at endoscopy.(VLID)357823

The impact of hepatic steatosis on portal hypertension.

Background and aimsStudies in animal models have suggested that hepatic steatosis impacts on portal pressure, potentially by inducing liver sinusoidal endothelial dysfunction and thereby increasing intrahepatic resistance. Thus, we aimed to evaluate the impact of hepatic steatosis on hepatic venous pressure gradient (HVPG) in patients with chronic liver disease.Method261 patients undergoing simultaneous HVPG measurements and controlled attenuation parameter (CAP)-based steatosis assessment were included in this retrospective study.ResultsThe majority of patients had cirrhosis (n = 205; 78.5%) and n = 191 (73.2%) had clinically significant portal hypertension (CSPH; HVPG≥10mmHg). Hepatic steatosis (S1/2/3; CAP ≥248dB/m) was present in n = 102 (39.1%). Overall, HVPG was comparable between patients with vs. without hepatic steatosis (15.5±7.5 vs. 14.8±7.7mmHg; p = 0.465). Neither in patients with HVPG (ConclusionHepatic steatosis, as assessed by CAP and liver histology, did not impact on HVPG in our cohort comprising a high proportion of patients with advanced chronic liver disease. However, high CAP values (i.e. pronounced hepatic steatosis) might lead to overestimation of liver fibrosis by 'artificially' increasing transient elastography-based liver stiffness measurements

Liver International / Controlled attenuation parameter does not predict hepatic decompensation in patients with advanced chronic liver disease

Background & Aims Assessment of hepatic steatosis by transient elastography (TE)based controlled attenuation parameter (CAP) might predict hepatic decompensation. Therefore, we aimed to evaluate the prognostic value of CAP in patients with compensated advanced chronic liver disease (cACLD) and decompensated cirrhosis (DC). Methods A total of 430 patients who underwent TE (liver stiffness 10 kPa) and CAP measurements were included in this retrospective analysis. Half of patients (n = 189) underwent simultaneous HVPG measurement. In cACLD patients, first hepatic decompensation was defined by new onset of ascites, hepatic encephalopathy or variceal bleeding. In patients with DC, the following events were considered as further hepatic decompensation: requirement of paracentesis, admission for/development of grade 3/4 hepatic encephalopathy, variceal (re)bleeding or liverrelated death. Results First hepatic decompensation occurred in 25 of 292 (9%) cACLD patients, while 46 of 138 (33%) DC patients developed further hepatic decompensation during a median followup of 22 and 12 months respectively. CAP was not predictive of first (cACLD; per 10 dB/m; hazard ratio [HR]: 0.97, 95% confidence interval [95% CI]: 0.911.03, P = 0.321) or further hepatic decompensation (DC; HR: 0.99, 95% CI: 0.941.03, P = 0.554) in adjusted analysis. Using the wellestablished CAP cutoff of 248 dB/m for hepatic steatosis, the incidence of first (cACLD; P = 0.065) and further hepatic decompensation (DC; P = 0.578) was similar in patients with hepatic steatosis or without. Serum albumin levels (per mg/dL; HR: 0.83, 95% CI: 0.770.89, P < 0.001) and MELDNa (per point; HR: 1.15, 95% CI: 1.041.28, P = 0.006) in cACLD and MELDNa (per point; HR: 1.12, 95% CI: 1.051.19, P < 0.0001) in DC patients were the only parameters independently associated with first and further hepatic decompensation, respectively. Conclusion Controlled attenuation parameter does not predict the development of first (cACLD)/further (DC) hepatic decompensation, while serum albumin levels and MELDNa are of prognostic value.(VLID)340097

The impact of thyroid hormones on patients with hepatocellular carcinoma

<div><p>Background & aims</p><p>Hypothyroidism has recently been proposed as predisposing factor for HCC development. However, the role of thyroid hormones (TH) in established HCC is largely unclear. We investigated the impact of TH on clinical characteristics and prognosis of HCC patients.</p><p>Methods</p><p>Of 838 patients diagnosed with nonsurgical HCC at the Division of Gastroenterology and Hepatology/Medical University of Vienna between 1992 and 2012, 667 patients fulfilled the inclusion criteria. The associations of thyroid function tests with patient, liver, and tumor characteristics as well as their impact on overall survival (OS) were investigated.</p><p>Results</p><p>Thyroid hormone substitution was more often observed in patients with low thyroid-stimulating hormone (TSH) concentration and in patients with elevated free tetraiodthyronine (fT4). Patients with high TSH (>3.77uU/ml) concentrations had larger tumors, while the opposite was true for patients with low TSH (<0.44uU/ml) concentrations. Subjects with elevated fT4 (>1.66ng/dl) were more likely to have elevated CRP. While TSH was only associated with OS in univariate analysis (≤1.7 vs. >1.7uU/ml, median OS (95%CI), 12.3 (8.9–15.7 months) vs. 7.3 months (5.4–9.2 months); p = 0.003), fT₄ (≤1.66 vs. >1.66ng/dl, median OS (95%CI), 10.6 (7.5–13.6 months) vs. 3.3 months (2.2–4.3 months); p = 0.007) remained an independent prognostic factor for OS (HR (95%CI) for fT₄>1.66ng/dl, 2.1 (1.3–3.3); p = 0.002) in multivariate analysis.</p><p>Conclusions</p><p>TSH and fT₄ were associated with prognostic factors of HCC (i.e., tumor size, CRP level). Elevated fT₄ concentrations were independently associated with poor prognosis in HCC. Further studies are needed to characterize the role of TH in HCC in detail.</p></div

Point Shear Wave Elastography by ElastPQ for Fibrosis Screening in Patients with NAFLD: A Prospective, Multicenter Comparison to Vibration-Controlled Elastography

Background: Since nonalcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in the Western world, clinicians need reliable noninvasive tools for the identification of NAFLD-associated fibrosis. Limited evidence on the performance of the novel shear wave elastography technique Elast-PQ (EPQ) in NAFLD is available. Method: In this prospective, European multinational study we assessed the diagnostic accuracy of EPQ using vibration-controlled transient elastography (VCTE) as a reference standard. Results: Among 353 NAFLD patients, 332 (94.1%) fulfilled reliability criteria of VCTE and EPQ (defined by IQR/median ≤0.3; 41.3% female, mean age: 59 [IQR: 16.5], mean BMI: 29.0 (7.1)). 4/353 (1.1%) and 17/353 (4.8%) had unreliable VCTE and EPQ measurements, respectively. VCTE-based NAFLD fibrosis stages were F0/F1: 222(66.9%), F2: 41 (12.3%), F3: 30 (9.1%), F4: 39 (11.7%). We found a strong correlation (Pearson R=0.87; p<0.0001) and concordance (Lin's concordance correlation coefficient =0.792) of EPQ with VCTE. EPQ was able to identify NAFLD-fibrosis risk with the following EPQ cutoffs: ≥6.5 kPa for significant fibrosis (≥F2) (≥1.47 m/s; sensitivity: 78%; specificity: 95%; AUROC: 0.94), ≥6.9 kPa for advanced fibrosis (≥F3) (≥1.52 m/s; sens.: 88%, spec.: 89%; AUROC: 0.949), and ≥10.4 kPa for cirrhosis (F4) (≥1.86 m/s; sens.: 87%; spec.: 94%; AUROC: 0.949). Conclusion: The point shear wave elastography technique EPQ shows excellent correlation to and concordance with VCTE. EPQ can reliably exclude NAFLD fibrosis <6.0 kPa (<1.41 m/s) and indicate a high risk of advanced fibrosis ≥10.4 kPa (≥1.86 m/s)

Multivariate analysis of prognostic factors.

<p>Multivariate analysis of prognostic factors.</p