The Value of Neutrophil-to-Lymphocyte Ratio to Identify Bacterial Infection and Predict Short-Term Mortality in Patients with Acutely Decompensated Cirrhosis.

Liver cirrhosis patients are highly susceptible to infections, affecting survival, but current parameters for detecting infection are not reliable enough in this population. We investigated the ability of white blood cell (WBC), ∆WBC, neutrophil and ∆neutrophil counts, neutrophil-to-lymphocyte (NLR) and ∆NLR ratios and C-reactive protein (CRP) and procalcitonin (PCT) levels to identify infection and predict short-term mortality in liver cirrhosis patients. We recruited 233 patients with liver cirrhosis hospitalized with acute decompensation (AD) who had an outpatient visit within 1 month (baseline laboratory data) and followed them for 90 days. Difference between laboratory values at baseline and the AD episode was defined as delta (∆) values of the parameters. Delta values did not increase the diagnostic and predictive ability of investigated parameters. The CRP level was found to be the best diagnostic marker for infection in patients with cirrhosis. However, NLR seems to be superior for short-term mortality prediction, better than the WBC count. Distinguishing inflammations of different origin is a remaining clinical challenge in acutely decompensated cirrhosis. Based on our results, NLR might be more suitable for predicting short-term mortality in patients with AD than the WBC count currently included in the CLIF-C AD score.

EASY-APP: An artificial intelligence model and application for early and easy prediction of severity in acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a potentially severe or even fatal inflammation of the pancreas. Early identification of patients at high risk for developing a severe course of the disease is crucial for preventing organ failure and death. Most of the former predictive scores require many parameters or at least 24 h to predict the severity; therefore, the early therapeutic window is often missed. METHODS: The early achievable severity index (EASY) is a multicentre, multinational, prospective and observational study (ISRCTN10525246). The predictions were made using machine learning models. We used the scikit-learn, xgboost and catboost Python packages for modelling. We evaluated our models using fourfold cross-validation, and the receiver operating characteristic (ROC) curve, the area under the ROC curve (AUC), and accuracy metrics were calculated on the union of the test sets of the cross-validation. The most critical factors and their contribution to the prediction were identified using a modern tool of explainable artificial intelligence called SHapley Additive exPlanations (SHAP). RESULTS: The prediction model was based on an international cohort of 1184 patients and a validation cohort of 3543 patients. The best performing model was an XGBoost classifier with an average AUC score of 0.81 ± 0.033 and an accuracy of 89.1%, and the model improved with experience. The six most influential features were the respiratory rate, body temperature, abdominal muscular reflex, gender, age and glucose level. Using the XGBoost machine learning algorithm for prediction, the SHAP values for the explanation and the bootstrapping method to estimate confidence, we developed a free and easy-to-use web application in the Streamlit Python-based framework (http://easy-app.org/). CONCLUSIONS: The EASY prediction score is a practical tool for identifying patients at high risk for severe AP within hours of hospital admission. The web application is available for clinicians and contributes to the improvement of the model.

In-Hospital Patient Education Markedly Reduces Alcohol Consumption after Alcohol-Induced Acute Pancreatitis.

Although excessive alcohol consumption is by far the most frequent cause of recurrent acute pancreatitis (AP) cases, specific therapy is still not well established to prevent recurrence. Generally, psychological therapy (e.g., brief intervention (BI)) is the cornerstone of cessation programs; however, it is not yet widely used in everyday practice. We conducted a post-hoc analysis of a prospectively collected database. Patients suffering from alcohol-induced AP between 2016 and 2021 received 30 min BI by a physician. Patient-reported alcohol consumption, serum gamma-glutamyl-transferase (GGT) level, and mean corpuscular volume (MCV) of red blood cells were collected on admission and at the 1-month follow-up visit to monitor patients' drinking habits. Ninety-nine patients with alcohol-induced AP were enrolled in the study (mean age: 50 ± 11, 89% male). A significant decrease was detected both in mean GGT value (294 ± 251 U/L vs. 103 ± 113 U/L, p < 0.001) and in MCV level (93.7 ± 5.3 U/L vs. 92.1 ± 5.1 U/L, p < 0.001) in patients with elevated on-admission GGT levels. Notably, 79% of the patients (78/99) reported alcohol abstinence at the 1-month control visit. Brief intervention is an effective tool to reduce alcohol consumption and to prevent recurrent AP. Longitudinal randomized clinical studies are needed to identify the adequate structure and frequency of BIs in alcohol-induced AP.

The characteristics and prognostic role of acute abdominal on-admission pain in acute pancreatitis: A prospective cohort analysis of 1432 cases.

INTRODUCTION: Pain is the most common symptom in acute pancreatitis (AP) and is among the diagnostic criteria. Therefore, we aimed to characterize acute abdominal pain in AP. METHODS: The Hungarian Pancreatic Study Group prospectively collected multicentre clinical data on 1435 adult AP patients between 2012 and 2017. Pain was characterized by its intensity (mild or intense), duration prior to admission (hours), localization (nine regions of the abdomen) and type (sharp, dull or cramping). RESULTS: 97.3% of patients (n = 1394) had pain on admission. Of the initial population with acute abdominal pain, 727 patients answered questions about pain intensity, 1148 about pain type, 1134 about pain localization and 1202 about pain duration. Pain was mostly intense (70%, n = 511/727), characterized by cramping (61%, n = 705/1148), mostly starting less than 24 h prior to admission (56.7%, n = 682/1202). Interestingly, 50.9% of the patients (n = 577/1134) had atypical pain, which means pain other than epigastric or belt-like upper abdominal pain. We observed a higher proportion of peripancreatic fluid collection (19.5% vs. 11.0%; p = 0.009) and oedematous pancreas (8.4% vs. 3.1%; p = 0.016) with intense pain. Sharp pain was associated with AP severity (OR = 2.481 95% CI: 1.550-3.969) and increased mortality (OR = 2.263, 95% CI: 1.199-4.059) compared to other types. Longstanding pain (>72 h) on admission was not associated with outcomes. Pain characteristics showed little association with the patient's baseline characteristics. CONCLUSION: A comprehensive patient interview should include questions about pain characteristics, including pain type. Patients with sharp and intense pain might need special monitoring and tailored pain management. SIGNIFICANCE: Acute abdominal pain is the leading presenting symptom in acute pancreatitis; however, we currently lack specific guidelines for pain assessment and management. In our cohort analysis, intense and sharp pain on admission was associated with higher odds for severe AP and several systemic and local complications. Therefore, a comprehensive patient interview should include questions about pain characteristics and patients with intense and sharp pain might need closer monitoring.

Abnormal ferritin levels predict development of poor outcomes in cirrhotic outpatients: a cohort study.

BACKGROUND: Both iron overload and iron deficient anemia can associate with cirrhosis. At the same time, inflammation might be continuously present in cirrhotic patients due to bacterial translocation and patients' susceptibility to infections. Ferritin is a sensitive and widely available marker of iron homeostasis, in addition it acts as an acute phase protein. Therefore, we evaluated the prognostic potential of serum ferritin in the long-term follow-up of cirrhotic outpatients. METHODS: A cohort of 244 cirrhotic outpatients was recruited and followed for 2 years. We measured their serum ferritin levels in our routine laboratory unit at enrolment and investigated its association with clinical outcomes. RESULTS: Ferritin serum level was higher in males and older patients than in females (median: 152.6 vs. 75 µg/L, p < 0.001) or younger individuals (median: 142.9 vs. 67.9 µg/L, p = 0.002). Patients who previously survived variceal bleeding had lower ferritin levels (median: 43.1 vs. 146.6 µg/L, p < 0.001). In multivariate regression models, including laboratory and clinical factors, lower (< 40 µg/L) ferritin concentration was associated with the development of decompensated clinical stage in patients with previously compensated cirrhosis (sHR: 3.762, CI 1.616-8.760, p = 0.002), while higher (> 310 µg/L) circulating ferritin levels were associated with increased risks of bacterial infections in decompensated patients (sHR: 2.335, CI 1.193-4.568, p = 0.013) and mortality in the whole population (HR: 2.143, CI 1.174-3.910, p = 0.013). CONCLUSION: We demonstrated usefulness of serum ferritin as a prognostic biomarker in cirrhosis, pointing out that both low and high concentrations need attention in these patients.

Increased sTREM-1 levels identify cirrhotic patients with bacterial infection and predict their 90-day mortality.

BACKGROUND AND AIMS: Patients with cirrhosis are susceptible to bacterial infections (BIs) that are major causes of specific complications and mortality. However, the diagnosis of BIs can often be difficult in advanced disease stage since their symptoms may overlap with the ones of acute decompensation (AD). Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is released from monocytes/macrophages and neutrophils during activation and has been reported to correlate with activity of various inflammatory processes. We investigated its diagnostic and prognostic performance in patients with cirrhosis and BI. METHODS: Sera of 269 patients were assayed for sTREM-1 by ELISA (172 outpatients and 97 patients with AD of whom 56 had BI). We investigated capacity of sTREM-1 to identify patients with BI and conducted a 90-day follow-up observational study to assess its possible association with short-term mortality. RESULTS: sTREM-1 levels were significantly higher in patients with more severe liver disease, BI, and acute-on-chronic liver failure than in patients without these conditions. sTREM-1 had similar accuracy to CRP identifying BI [sTREM-1: AUROC (95%CI) 0.804 (0.711-0.897), p < 0.0001; CRP: 0.791 (0.702-0.881), p < 0.0001)] among AD patients. The combination of these two molecules and the presence of ascites into a composite score significantly increased their discriminative power (AUROC: 0.878, 95%CI: 0.812-0.944, p < 0.0001). High sTREM-1 level (>660 pg/mL) was an independent predictor of 90-day mortality in patients with BI [HR: 2.941, (95%CI: 1.009-8.573), p = 0.048] in our multivariate model. CONCLUSIONS: Use of sTREM-1 could increase the recognition of BIs in cirrhosis and help clinicians in mortality risk assessment of these patients.

Management of acute gastrointestinal bleeding. Multidisciplinary guideline proposal. / Heveny gastrointestinalis vérzések ellátása. Multidiszciplináris útmutató javaslat.

Gastrointestinal bleeding has a profound impact on public health due to its high prevalence and severity. With the elderly population taking more anticoagulants/antiaggregants/non-steroid anti-inflammatory drugs, the digestive bleeding will certainly raise more and more challenges in quantity as well as in severity for the public healthcare system. The emergency medicine specialists and gastroenterologists have a central role in the management of patients presenting with gastrointestinal bleeding. In certain cases, radiologists, invasive radiologists, intensive care specialists and surgeons should also be involved in the decision making process and management of patients. Therefore, Hungarian experts felt the need to elaborate a comprehensive, multidisciplinary, practical local guideline reflecting the frequently arisen aspects based on current international guidelines. This guideline proposal covers topics of basic requirements, initial assessment of patients, risk evaluation, laboratory tests, hemodynamic resuscitation in the case of gastrointestinal bleeding followed by its consecutive steps of diagnosis and therapy sorted by location of the source of the hemorrhage. The authors give practical instructions for unsuccessful hemostasis or rebleeding. Finally, the role of surgery is also summarized in the management of gastrointestinal bleeding. Orv Hetil. 2020; 161(30): 1231-1242.

Development of disturbance of consciousness is associated with increased severity in acute pancreatitis.

BACKGROUND: Disturbance of consciousness (DOC) may develop in acute pancreatitis (AP). In clinical practice, it is known that DOC may worsen the patient's condition, but we have no exact data on how DOC affects the outcome of AP. METHODS: From the Hungarian Pancreatic Study Groups' AP registry, 1220 prospectively collected cases were analyzed, which contained exact data on DOC, included patients with confusion, delirium, convulsion, and alcohol withdrawal, answering a post hoc defined research question. Patients were separated to Non-DOC and DOC, whereas DOC was further divided into non-alcohol related DOC (Non-ALC DOC) and ALC DOC groups. For statistical analysis, independent sample t-test, Mann-Whitney, Chi-squared, or Fisher exact test were used. RESULTS: From the 1220 patients, 47 (3.9%) developed DOC, 23 (48.9%) cases were ALC DOC vs. 24 (51.1%) Non-ALC DOC. Analysis between the DOC and Non-DOC groups showed a higher incidence of severe AP (19.2% vs. 5.3%, p < 0.001), higher mortality (14.9% vs. 1.7%, p < 0.001), and a longer length of hospitalization (LOH) (Me = 11; IQR: 8-17 days vs. Me = 9; IQR: 6-13 days, p = 0.049) respectively. Patients with ALC DOC developed more frequently moderate AP vs. Non-ALC DOC (43.5% vs. 12.5%), while the incidence of severe AP was higher in Non-ALC vs. ALC DOC group (33.3% vs. 4.4%) (p < 0.001). LOH showed a tendency to be longer in Non-ALC DOC compared to ALC DOC, respectively (Me:13; IQR:7-20 days vs. Me:9.5; IQR:8-15.5 days, p = 0.119). CONCLUSION: DOC during AP is associated with a higher rate of moderate and severe AP and increases the risk of mortality.

LIFEStyle, Prevention and Risk of Acute PaNcreatitis (LIFESPAN): protocol of a multicentre and multinational observational case-control study.

INTRODUCTION: Acute pancreatitis (AP) is a life-threatening inflammatory disease of the exocrine pancreas which needs acute hospitalisation. Despite its importance, we have significant lack of knowledge whether the lifestyle factors elevate or decrease the risk of AP or influence the disease outcome. So far, no synthetising study has been carried out examining associations between socioeconomic factors, dietary habits, physical activity, chronic stress, sleep quality and AP. Accordingly, LIFESPAN identifies risk factors of acute pancreatitis and helps to prepare preventive recommendations for lifestyle elements. METHODS AND ANALYSIS: LIFESPAN is an observational, multicentre international case-control study. Participating subjects will create case and control groups. The study protocol was designed according to the SPIRIT guideline. Patients in the case group (n=1700) have suffered from AP (alcohol-induced, n=500; biliary, n=500; hypertriglyceridemiainduced, n=200; other, n=500); the control group subjects have no AP in their medical history. Our study will have three major control groups (n=2200): hospital-based (n=500), population-based (n=500) and aetiology-based (alcohol, n=500; biliary, n=500 and hypertriglyceridemia, n=200). All of them will be matched to the case group individually by gender, age and location of residence. Aggregately, 3900 subjects will be enrolled into the study. The study participants will complete a complex questionnaire with the help of a clinical research administrator/study nurse. Analysis methods include analysis of the continuous and categorical values. ETHICS AND DISSEMINATION: The study has obtained the relevant ethical approval (54175-2/2018/EKU) and also internationally registered (ISRCTN25940508). After obtaining the final conclusions, we will publish the data to the medical community and will also disseminate our results via open access. TRIAL REGISTRATION NUMBER: ISRCTN25940508; Pre-results.

Deleterious effect of proton pump inhibitors on the disease course of cirrhosis.

OBJECTIVES: Proton pump inhibitors(PPIs) are widely prescribed to patients with liver cirrhosis. We hypothesized that long-standing PPI use is associated with spontaneous bacterial peritonitis(SBP) and accelerated development of disease-specific complications and liver-related death. METHODS: A 5-year follow-up observational cohort study assessed the impact of long-standing PPI use on the clinical course of cirrhosis in a large referral patient cohort. Three hundred fifty patients with cirrhosis (alcohol:69.1%, Child-Pugh stage A/B/C:206/108/36) were assigned to two groups: regular PPI users (n=196) and nonusers (n=154). Occurrence of SBP, decompensation events (ascites, hepatic encephalopathy and variceal bleeding), and liver-related death were assessed. RESULTS: Regular PPI use was associated with an increased cumulative probability of SBP compared to nonusers [55% vs. 24.8%, hazard ratio(HR):4.25; P=0.05], in patients without previous SBP episode (n=84). A similar association was found between regular PPI use and decompensation events. The risk of the development of a first decompensation was higher in regular PPI users compared with nonusers, in patients with compensated clinical stage at enrollment (HR: 2.81, P= 0.008, n=146). The risk of liver-related death was also significantly increased among regular PPI users (P<0.001). In multivariate Cox-regression analysis, regular PPI use (HR:2.81, P=0.003) and MELD score (HR:1.21, P<0.001) was an independent predictor of mortality. CONCLUSION: In the present follow-up cohort study, long-term PPI use was associated with the development of SBP and a progressive disease course in patients with cirrhosis that may have been caused by enhanced pathologic bacterial translocation, accelerated development of bacterial translocation-dependent disease-specific complications, and liver-related death.

Functional polymorphisms of innate immunity receptors are not risk factors for the non-SBP type bacterial infections in cirrhosis.

BACKGROUND & AIMS: Pattern recognition receptors (PRRs) have a key role in the innate host defense. Functional polymorphisms of various PRRs have been established to contribute to an increased susceptibility to spontaneous bacterial peritonitis (SBP). Their role in the development of cirrhosis-associated bacterial infections (BI), beyond SBP or progressive disease course related to pathological bacterial translocation (BT) remains unknown. METHODS: Three hundred and forty-nine patients with cirrhosis were genotyped for common NOD2 (R702W, G908R and L1007PfsinsC), TLR2 (-16934T>A), and TLR4 (D299G) variants. Incidence of BIs, decompensating events and liver-related death were assessed in a 5-year follow-up observational study. Pathological BT was assessed based on the presence of antimicrobial antibodies or lipopolysaccharide-binding protein (LBP) level. RESULTS: In patients with ascites (n = 88) only NOD2 gene variants were associated with an increased cumulative probability of SBP (76.9% ± 19.9%) compared to wild-type (30.9% ± 6.9%, PLogRank  = .047). Individual or combined PRR genetic profiles were associated with the risk of non-SBP type BI. Advanced disease stage (HR [95% CI]: 2.11 [1.38-3.25]) and prior history of a BI episode (HR: 2.42 [1.58-3.72]) were the major clinical risk factors of a subsequent BI. The risk of a non-SBP type BI in patients with advanced disease and a prior BI was even higher (HR: 4.74 [2.68-8.39]). The frequency of antimicrobial antibodies and LBP levels did not differ between various PRR genotypes. Correspondingly, PRR genetic profile was not able to predict the long-term disease course. CONCLUSIONS: In cirrhosis, functional polymorphisms of PRRs did not improve the identification of patients with high risk of BI beyond SBP or progressive diseases course.

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 anti-microbial 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 anti-microbial 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 posvsneg: 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.

Lectin-complement pathway molecules are decreased in patients with cirrhosis and constitute the risk of bacterial infections.

BACKGROUND & AIMS: Lectin pathway molecules of the complement system are synthesized by hepatocytes and have pivotal role in innate host defence against infectious organisms. Ficolins (FCNs) act as soluble pattern recognition molecules, while mannan-binding lectin serine proteases(MASPs) do as effector molecules in elimination of pathogens. We aimed to study the significance of low level of these molecules in the development of cirrhosis-associated bacterial infections, which has not been elucidated so far. METHODS: Sera of 266 stable outpatients with cirrhosis and 160 healthy subjects were assayed for a panel of lectin molecules (FCN-2, FCN-3 and MASP-2) by ELISA. In cirrhosis, a 5-year follow-up observational study was conducted to assess a possible association between lectin levels and development of clinically significant bacterial infections(CSI). RESULTS: FCN-2, FCN-3 and MASP-2 levels were significantly lower in cirrhosis compared to healthy subjects and decreased according to disease severity (P<.001 for all molecules). In Kaplan-Meier analysis, development of CSI was associated with low level of FCN-2 (<427 ng/mL, pLogRank=0.047) and FCN-3 (<4857 ng/mL, pLogRank=0.029), but not with MASP-2 deficiency (<100 ng/mL, pLogRank=0.306). Combined FCN deficiency was associated with increased risk of development of bacterial infections in a step-wise manner. Patients with low level of both FCNs had higher cumulative probability of CSI (63.8%) compared to those with low level of one or normal FCN (52.7% and 45.7%, pLogRank=0.016). Neither FCN serum profile, nor MASP-2 deficiency were associated with infection-related mortality. CONCLUSIONS: Low level of FCNs associated with hepatic insufficiency might be considered as an additional constituent of cirrhosis-associated immune dysfunction.

[Spontaneous bacterial peritonitis]. / Spontán bakteriális peritonitis.

Spontaneous bacterial peritonitis occurs most commonly in cirrhotic patients with ascites. Pathogens get into the circulation by intestinal translocation and colonize in peritoneal fluid. Diagnosis of spontaneous bacterial peritonitis is based on elevated polymorphonuclear leukocyte count in the ascites (>0,25 G/L). Ascites culture is often negative but aids to get information about antibiotic sensitivity in positive cases. Treatment in stable patient can be intravenous then orally administrated ciprofloxacin or amoxicillin/clavulanic acid, while in severe cases intravenous III. generation cephalosporin. Nosocomial spontaneous bacterial peritonitis often caused by Gram-positive bacteria and multi-resistant pathogens can also be expected thus carbapenem should be the choice of the empiric treatment. Antibiotic prophylaxis should be considered. Norfloxacin is used most commonly, but changes are expected due to increase in quinolone resistance. As a primary prophylaxis, a short-term antibiotic treatment is recommended after gastrointestinal bleeding for 5 days, while long-term prophylaxis is for patients with low ascites protein, and advanced disease (400 mg/day). Secondary prophylaxis is recommended for all patients recovered from spontaneous bacterial peritonitis. Due to increasing antibiotic use of antibiotics prophylaxis is debated to some degree. Orv. Hetil., 2017, 158(2), 50-57.

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, the 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 pg/mL vs 477 pg/mL, P < 0.001), increasing with the severity of infection [organ failure (OF): Yes vs No, 2358 pg/mL vs 710 pg/mL, P < 0.001]. Diagnostic accuracy of presepsin for severe infections was similar to PCT and superior to CRP (AUC-ROC: 0.85, 0.85 and 0.66, respectively, P = NS for presepsin vs PCT and P < 0.01 for presepsin vs CRP). At the optimal cut-off value of presepsin > 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-d 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 nor CRP were independent risk factor for 28-d 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.

[Incidence of hepatocellular carcinoma and consequent lessons for its management in Northeastern Hungary]. / A hepatocellularis carcinoma elofordulása és kezelésének tanulságai az északkelet-magyarországi régióban.

INTRODUCTION: The increasing incidence and poor prognosis of hepatocellular carcinoma places huge burden on healthcare. AIM: After reviewing literature on epidemiological trends, risk factors, diagnosis and management options for hepatocellular carcinoma, the authors investigated results of treatment and survival data of patients in Northeastern Hungary. METHOD: In a retrospective study, the authors analyzed medical records of 187 patients with hepatocellular carcinoma (etiology, presence of cirrhosis, stage of the tumor, treatment and disease outcome). RESULTS: Seventy-one patients (38%) had known cirrhosis at the diagnosis of hepatocellular carcinoma, while in 52 patients (28%) the presence of cirrhosis was established at the time of the diagnosis of hepatocellular carcinoma. Fifteen patients (8%) had no cirrhosis and in 49 patients (26%) no data were available regarding cirrhosis. Etiological factors were alcohol consumption (52%), viral hepatitis (41%) and metabolic syndrome (44%). In cases of metabolic syndrome, hepatocellular carcinoma frequently occurred without cirrhosis. In 83% of the cases, the tumor was discovered in an advanced stage. Median survival time was significantly associated with tumor stage (Barcelona A stage vs. B/C vs. D: 829 vs. 387 vs. 137 days, respectively p<0.001) but not with disease etiology (virus 282 days, metabolic syndrome 335 days and alcohol 423 days, p = 0.65). CONCLUSIONS: High mortality of hepatocellular carcinoma was mainly attributed to the delayed diagnosis of the disease. Screening of patients with cirrhosis could only result in a partial improvement since in a great proportion cirrhosis was diagnosed simultaneously with the tumor. Screening of diabetic and obese patients by ultrasonography should be considered. Management of baseline liver disease is of importance in the care of hepatocellular carcinoma. Orv. Hetil., 2016, 157(45), 1793-1801.

Macrophage activation marker, soluble CD163, is an independent predictor of short-term mortality in patients with cirrhosis and bacterial infection.

BACKGROUND & AIMS: Innate immune system dysfunction is common in advanced cirrhosis, with a central role of the monocyte/macrophage system. Monocytes and macrophages express the scavenger receptor CD163, which is regulated by inflammatory mediators. Cleavage of the receptor leads to the formation of soluble (s)CD163 that represents an anti-inflammatory response. We aimed to study the clinical importance of sCD163 in cirrhosis. METHODS: Sera of 378 patients were assayed for sCD163 by ELISA [193 outpatients and 185 patients with acute decompensation (AD)]. A 5-year follow-up observational study was conducted to assess the possible association between sCD163 level and poor disease outcomes. RESULTS: sCD163 level was associated with disease severity, but not with the presence of varices or prior variceal bleeding. In outpatients, sCD163 level did not predict the development of disease-specific complications or the long-term mortality. In patients with AD episode, sCD163 level was significantly higher compared to outpatients but only in the presence of bacterial infection (INF) (AD-INF:4586, AD-NON-INF:3792 and outpatients: 3538 ng/ml, P < 0.015 and P = 0.001, respectively). sCD163 level gradually increased according to severity of infection. During bacterial infections, high sCD163 level (>7000 ng/ml) was associated with increased mortality rate (42% vs. 17%, P < 0.001) and was identified as an independent predictor of 28-day mortality (hazard ratio:2.96, 95% confidence intervals:1.27-6.95) in multivariate Cox-regression model comprising aetiology, co-morbidity, model for end-stage liver disease score and leucocyte count as covariates. CONCLUSIONS: High sCD163 level is useful to identify patients with high-risk of death during an AD episode complicated by bacterial infection. This finding serves as an additional hint towards the significance of anti-inflammatory response during bacterial infection.

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.

High prevalence of IgA class anti-neutrophil cytoplasmic antibodies (ANCA) is associated with increased risk of bacterial infection in patients with cirrhosis.

BACKGROUND & AIMS: Anti-neutrophil cytoplasmic antibodies (ANCA) are a non-uniform family of antibodies recognizing diverse components of neutrophil granulocytes. ANCA formation might be induced by protracted bacterial infections or probably reflect an abnormal immune response to commensal microorganisms. Bacterial infections are common complications in cirrhosis with high incidence of episodes caused by enteric organisms, therefore, we sought to study the presence and clinical importance of ANCA in cirrhosis. METHODS: Sera of 385 patients with cirrhosis of different etiologies were assayed for ANCA of IgG, IgA, IgA1, IgA2, and secretory IgA subtypes by indirect immunofluorescence and ELISAs. The control group comprised 202 patients with chronic liver diseases without cirrhosis and 100 healthy subjects. In cirrhosis, a 2-year follow-up, observational study was conducted to assess a possible association between the presence of ANCA and clinically significant bacterial infections. RESULTS: Prevalence of ANCA IgA was significantly higher in cirrhosis (52.2%) compared to chronic liver diseases (18.6%) or healthy controls (0%, p<0.001 for both). ANCA IgA subtyping assays revealed marked increase in the proportion of IgA2 subtype (46% of total ANCA IgA) and presence of the secretory component concurrently. Presence of ANCA IgA was associated with disease-specific clinical characteristics (Child-Pugh stage and presence of ascites, p<0.001). During a 2-year follow-up period, risk of infections was higher among patients with ANCA IgA compared to those without (41.8% vs. 23.4%, p<0.001). ANCA IgA positivity was associated with a shorter time to the first infectious complication (pLogRank <0.001) in Kaplan-Meier analysis and was identified as an independent predictor in multivariate Cox-regression analysis (HR:1.74, 95% CI: 1.18-2.56, p=0.006). CONCLUSIONS: Presence of IgA type ANCA is common in cirrhosis. Involvement of gut mucosal immune system is in center of their formation and probably reflects sustained exposure to bacterial constituents.

Acute phase proteins in the diagnosis and prediction of cirrhosis associated bacterial infections.

BACKGROUND: Bacterial infections are common cause of morbidity and mortality in patients with cirrhosis. The early diagnosis of these infections is rather difficult. AIMS: To assess the accuracy of acute phase proteins in the identification of bacterial infections. METHODS: Concentration of C-reactive protein (CRP), procalcitonin (PCT), lipopolysaccharide-binding protein (LBP), sCD14 and antimicrobial antibodies were measured in serum of 368 well-characterized patients with cirrhosis of whom 139 had documented infection. Clinical data was gathered by reviewing the patients' medical charts. RESULTS: Serum levels of CRP, PCT and LBP were significantly higher in patients with clinically overt infections. Among the markers, CRP - using a 10 mg/L cut-off value- proved to be the most accurate in identifying patients with infection (AUC: 0.93). The accuracy of CRP, however, decreased in advanced stage of the disease, most probably because of the significantly elevated CRP levels in non-infected patients. Combination of CRP and PCT increased the sensitivity and negative predictive value, compared with CRP on its own, by 10 and 5% respectively. During a 3-month follow-up period in patients without overt infections, Kaplan-Meier and proportional Cox-regression analyses showed that a CRP value of >10 mg/L (P = 0.035) was independently associated with a shorter duration to progress to clinically significant bacterial infections. There was no correlation between acute phase protein levels and antimicrobial seroreactivity. CONCLUSIONS: C-reactive protein on its own is a sensitive screening test for the presence of bacterial infections in cirrhosis and is also a useful marker to predict the likelihood of clinically significant bacterial infections in patients without overt infections.