Pathophysiological and clinical approach to cirrhotic cardiomyopathy.

Hyperdynamic circulation, systolic and diastolic left ventricular dysfunction and certain electrophysiological abnormalities have been associated with cirrhosis and known for a long time. These clinical features have been introduced as cirrhotic cardiomyopathy (CCM), which is characterized by blunted myocardial contractile responsiveness to physical, physiological and pharmacological stress. Importantly, cardiac dysfunction can be reversible and can improve due to effective medical treatment and also after liver transplantation. Echocardiography and electrocardiography are essential tools for recognizing the characteristic changes in the myocardial function and also the alterations in the electrophysiological properties of the heart. Laboratory markers are auxiliary modalities further aiding the establishment of the correct diagnosis. In this review, we aimed to collect the pathophysiological background and clinical characteristics of CCM with the intention of summarizing the current possibilities for the diagnosis establishment and treatment of this cardio-hepatic disorder. Key words: liver cirrhosis – cardiomyopathy – heart failure – arrhythmias. Abbreviations : A: late diastolic transmitral peak flow velocity; ACE: angiotensin converting enzyme; ANP: atrial natriuretic peptide; ARB: angiotensin receptor blocker; BNP: brain natriuretic peptide; cAMP: cyclic adenosine monophosphate; CCM: cirrhotic cardiomyopathy; CGRP: calcitonin gene-related peptide; CO: carbon monoxide; DD: diastolic dysfunction; DT: deceleration time; E: early diastolic transmitral peak flow velocity; Ea: early diastolic velocity of the septal mitral annulus; EF: ejection fraction; MUGA: Multi Gated Acquisition Scan; NO: nitric oxide; NSBB: non-selective beta-blocker; pro-BNP: pro-brain natriuretic peptide; QTc: corrected QT interval; RAAS: renin-angiotensin aldosterone system; RALES: Randomized Aldactone Evaluation Study; suPAR: urokinase-type plasminogen activator receptor; TDI: Tissue Doppler Imaging; TIPS: transjugular intrahepatic portosystemic shunt; TNF-alpha: tumor necrosis factor-alpha

Bakteriális infekciók májátültetés után

INTRODUCTION: The authors reviewed the prevalence of postoperative infections, the results of bacterium cultures, and the incidence of multidrug resistance in their liver transplanted patients during a period between 2003 and 2012. AIM: The aim of this study was to analyse risk factors and colonisations of bacterial infections. METHOD: The files of 408 patients (281 bacterium cultures) were reviewed. RESULTS: Of the 408 patients 70 had a postoperative infection (17%); 58 patients (14.2%) had positive and 12 patients (2.9%) negative bacterial culture results. Cholangitis was found in 7 cases (12.1%), abdominal infection in 17 cases (29.3%), and pulmonal infection in 28 cases (48.3%). Postoperative infection was more frequent in patients with initial poor graft function, acute renal insufficiency, biliary complication, and in those with intraabdominal bleeding. The 1-, 3- and 5-year cumulative survival of patients who had infection was 70%, 56% and 56%, respectively, whereas the cumulative survival data of patients without infection was 94%, 87% and 85%, respectively (p<0.001). Multidrug resistance was found in 56% of the positive cultures, however, the one-year survival was not different in patients who had multidrug resistance positive and negative bacterial infection (both 70.2%). CONCLUSIONS: Infection control must target the management of multidrug resistance microbes through encouraging prevention, hygienic, and isolation rules, improving the operational, transfusion, and antimicrobial policy in a teamwork setting. Orv. Hetil., 2015, 156(34), 1366-1382

Presepsin teardown – pitfalls of biomarkers in the diagnosis and prognosis of bacterial infection in cirrhosis

AIM To evaluate the diagnostic and prognostic value of presepsin in cirrhosis associated bacterial infections. METHODS Two hundred and sixteen patients with cirrhosis were enrolled. At admission, presence of bacterial infections and level of plasma presepsin, serum C-reactive protein (CRP) and procalcitonin (PCT) were evaluated. Patients were followed for three months to assess the possible association between presepsin level and short-term mortality. RESULTS Present 34.7 of patients had bacterial infection. Presepsin levels were significantly higher in patients with infection than without (median, 1002 vs 477 pg/mL, P 1206 pg/mL sensitivity, specificity, positive predictive values and negative predictive values were as follows: 87.5%, 74.5%, 61.8% and 92.7%. The accuracy of presepsin, however, decreased in advanced stage of the disease or in the presence of renal failure, most probably because of the significantly elevated presepsin levels in non-infected patients. 28-day mortality rate was higher among patients with > 1277 pg/mL compared to those with ≤ 1277 pg/mL (46.9% vs 11.6%, P < 0.001). In a binary logistic regression analysis, however, only PCT (OR = 1.81, 95%CI: 1.09–3.01, P = 0.022) but neither presepsin and nor CRP were independent risk factor for 28-day mortality after adjusting with MELD score and leukocyte count. CONCLUSION Presepsin is a valuable new biomarker for defining severe infections in cirrhosis proving same efficacy as PCT. However, it is not a useful marker of short-term mortality

Presence of Anti-Microbial Antibodies in Liver Cirrhosis – A Tell-Tale Sign of Compromised Immunity?

Bacterial translocation plays important role in the complications of liver cirrhosis. Antibody formation against various microbial antigens is common in Crohn's disease and considered to be caused by sustained exposure to gut microflora constituents. We hypothesized that anti-microbial antibodies are present in patients with liver cirrhosis and may be associated with the development of bacterial infections.<0.001, OR:2.02) by Cox-regression analysis.The present study suggests that systemic reactivity to microbial components reflects compromised mucosal immunity in patients with liver cirrhosis, further supporting the possible role of bacterial translocation in the formation of anti-microbial antibodies

Gut barrier failure biomarkers are associated with poor disease outcome in patients with primary sclerosing cholangitis

AIM To assess the prevalence of a panel of serologic markers that reflect gut barrier dysfunction in a mixed cohort of pediatric and adult primary sclerosing cholangitis (PSC) patients. METHODS Sera of 67 PSC patients [median age (range): 32 (5-79) years, concomitant IBD: 67% and cirrhosis: 20%] were assayed for the presence of antibodies against to F-actin (AAA IgA/IgG) and gliadin (AGA IgA/IgG)] and for serum level of intestinal fatty acid-binding protein (I-FABP) by ELISA. Markers of lipopolysaccharide (LPS) exposure [LPS binding protein (LBP)] and various antimicrobial antibodies [anti-OMP Plus IgA and endotoxin core IgA antibody (EndoCAb)] were also determined. Poor disease outcome was defined as orthotopic liver transplantation and/or liver-related death during the follow-up [median: 99 (14-106) mo]. One hundred and fifty-three healthy subjects (HCONT) and 172 ulcerative colitis (UC) patients were the controls. RESULTS A total of 28.4%, 28.0%, 9% and 20.9% of PSC patients were positive for AAA IgA, AAA IgG, AGA IgA and AGA IgG, respectively. Frequencies of AAA IgA and AAA IgG ( P < 0.001, for both) and AGA IgG ( P = 0.01, for both) but not AGA IgA were significantly higher compared to both of the HCONT and the UC groups. In survival analysis, AAA IgA-positivity was revealed as an independent predictor of poor disease outcome after adjusting either for the presence of cirrhosis [HR = 5.15 (1.27-20.86), P = 0.022 or for the Mayo risk score (HR = 4.24 (0.99-18.21), P = 0.052]. AAA IgA-positivity was significantly associated with higher frequency of antimicrobial antibodies ( P < 0.001 for EndoCab IgA and P = 0.012 for anti-OMP Plus IgA) and higher level of the enterocyte damage marker (median I-FABPAAA IgA pos vs neg: 365 vs 166 pg/mL, P = 0.011), but not with serum LBP level. CONCLUSION Presence of IgA type AAA identified PSC patients with progressive disease. Moreover, it is associated with enhanced mucosal immune response to various microbial antigens and enterocyte damage further highlighting the importance of the gut-liver interaction in PSC

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis

Background & Aims: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (ADNo ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes. Methods: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. Results: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality. Conclusions: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis. Lay summary: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes. (c) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology

Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. ClinicalTrials.gov number: NCT03056612. Lay summary: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk