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Background and Aims: Bacterial infections are associated with high mortality rates in patients with decompensated cirrhosis. Early diagnosis with the available diagnostic tools is challenging. Metabolomics is a novel technique with a widespread application in hepatology. The aims of our study were to find new biomarkers for decompensated cirrhosis and for those with overlapping bacterial infections., Methods: 43 patients with compensated and 54 patients with decompensated cirrhosis were enrolled in the study. In patients with decompensation, a complete infectious workup was performed at admission. Blood and ascitic fluid were collected and stored at -80° C until performing the metabolomic analysis. Statistical analysis was performed using the Metaboanalyst 4.0 software., Results: 36 patients (66%) in the decompensated group were infected. Among them, 15 had multiple infections; thus, finally, 52 infections were diagnosed. The main metabolic pathways affected in patients with decompensated cirrhosis were those related to lipid metabolism, involving acylcarnitines, stearic acid derivatives, and 12/15 HETE-GABA. N-oleoyl ethanolamine was the most promising biomarker for bacterial infection diagnosis. Moreover, prostaglandin E2/D2/H2 and N-oleoyl alanine levels were higher in Gram- positive infections and ceramides (d16:2/18:0), in Gram-negative infections, respectively. L-phenylalanine (m/z=166.09) and lysophosphatidylethanolamine (18:3/0:0) were the two most relevant identified ascitic biomarkers for spontaneous bacterial peritonitis diagnosis., Conclusions: The lipid and energetic metabolic pathways were the most affected in patients with decompensated cirrhosis and those with overlapping infections.

Background and Aims: Health-related quality of life is an essential part of managing chronically ill patients, including patients with chronic liver disease. Various methods are used to try to assess the quality of life ranging from generic to disease-specific questionnaires. Some of the results may reveal a novel connection to the disease's evolution, which is observed directly by the patient. This study aimed to validate and assess the chronic liver disease questionnaire (CLDQ-RO) performance in the Romanian population., Methods: A two-phase study was designed. The first phase consisted of linguistic validation of CLDQ-RO (translation and piloting), while in the second phase, the questionnaire was applied to patients with various chronic liver diseases. Statistical validation (reliability, structural, and construct validity) was performed using SPSS v20.0, and statistical significance was considered p<0.05., Results: The CLDQ-RO was applied to 231 patients with chronic liver disease (14.3% with chronic hepatitis, 35.5% with compensated cirrhosis, and 50.2% with decompensated cirrhosis). The questionnaire showed excellent overall reliability (Cronbach's alpha=0.93) and good structural and construct validity, with most of the items in CLDQ-RO fitting in the domains of the original version of the questionnaire. There was a significant decrease in the overall score of the CLDQ-RO with the progression of disease (p<0.001), indicating a substantial impact of the decompensation event on health-related quality of life. Regarding the type of decompensation, ascites accurately predicted a lower quality of life (p=0.004)., Conclusions: The CLDQ-RO is a valid and disease-specific method for assessing patients' health-related quality of life with liver disease. Among the decompensation events, it seems that ascites seriously impacts the quality of life.

This report describes the use of local thrombolysis using a tissue plasminogen activator in a case of a patient with refractory ascites referred for transjugular intrahepatic portosystemic shunt (TIPS) insertion. After successful TIPS insertion, the patient developed acute extended portal vein and TIPS thrombosis, which were treated with local thrombolysis using a tissue plasminogen activator, followed by the complete resolution of ascites. Although there are only limited published data of local thrombolysis for acute splanchnic vein thrombosis, we also review the relevance of the problem in the context of advanced liver disease.

Background and Aims: Current management of alcoholic liver disease (ALD), especially for alcoholic hepatitis (AH) is still driven by liver biopsy. Therefore, the identification of novel and accurate noninvasive biomarkers for the diagnosis and assessment of severity is important. Metabolomics, because it unravels changes closest to the phenotype, may represent the key for novel biomarkers. The aim of this study was to identify and characterize potential metabolomic biomarkers for diagnosis, staging and severity assessment of ALD., Methods: 30 consecutive ALD patients and 10 healthy controls were included in this proof-of-concept cross-sectional study. Baseline assessment consisted in evaluation of Maddrey's Discriminant Function, Model for End-Stage Liver Disease (MELD) and ABIC scores as well as ASH-Test (Fibromax) as a surrogate for the confirmatory diagnosis of AH in suggestive clinical and biologic settings. Additionally, SOP metabolomics and lipidomics were performed from serum samples by liquid chromatography mass-spectrometry analysis., Results: From the 127 and 135 serum/urine candidate metabolites initially identified, only 11/5 metabolites were characteristic for ALD patients. None of them correlated with alcohol intake, and only 5/1 metabolites could differentiate cirrhotic from non-cirrhotic patients. Of those, N-Lauroglycine (NLG) was the best for identifying cirrhosis (100% sensitivity and 90% negative predictive value, NPV) and decatrienoic acid (DTEA) was the best for assessing disease severity (evaluated by ABIC score) with 100% sensitivity and 100% NPV., Conclusion: Due to their high NPV, NLG and DTEA could be used in conjunction in ALD patients to exclude cirrhosis or a severe disease. If further validated, they could become biomarkers for better management and risk assessment in ALD.

Background and Aims: Obesity proved to favor clinical decompensation in patients with cirrhosis. Our aim was to investigate if metabolic syndrome (MS) in cirrhotic patients represents a risk factor for decompensation., Methods: 704 cirrhotics, included in a MS prevalence study were considered for evaluation; 121 patients were excluded because they did not complete the follow-up and 303 because they were decompensated at the start of the study. The remaining 280 were followed-up for a median period of 28.1+/-18 months. Patients were censored at the end of follow-up or at occurrence of a liver related event (LRE). Liver related events were considered the following: decompensation (ascites, variceal bleeding, hepatorenal syndrome, jaundice, encephalopathy), hepatocellular carcinoma, portal vein thrombosis and infections., Results: All MS criteria except the abdominal circumference were significantly different between decompensated and compensated patients. HDL-cholesterol levels were lower in decompensated patients. Among the 280 patients who completed the follow-up, 85 (30%) presented LREs. Ascites was the most frequent event. In the univariate analysis of the MS criteria we found a trend to significance of an inverse correlation between MS and LREs. There was no significant difference between patients with or without MS regarding survival free of LREs, 76.7% and 66.5%, respectively. None of the MS criteria reached the level of significance in discriminating patients with and without LREs., Conclusions: In short term, presence of MS was not a risk factor for LREs. In short term, liver function and lower nutritional status influenced the prognosis. In decompensated patients, the MS defining criteria are not applicable.

Background & Aims: Liver stiffness (LS) is increased in liver cirrhosis, higher values being associated with complications, among them the development of hepatocellular carcinoma (HCC). However, LS values alone cannot accurately differentiate patients with HCC. Therefore, our aim was to study the performance of LS measurement data and common biomarkers for the detection of HCC in HCV related liver cirrhosis., Methods: We performed a case matching study comparing HCV cirrhotic patients with and without HCC (72 in each group) that were identical in terms of sex, age, BMI and duration of HCV infection. All patients underwent LS measurement, endoscopy, liver imaging and liver function tests. A multiple regression analysis was performed and a HCC detection model was calculated, which was further validated in another group of 40 HCV infected cirrhotics, of whom 52% had HCC., Results: In the HCC group, LS was significantly higher (42 vs 27 kPa, p<0.0001). In the multivariate analysis higher values of LS, alanine-aminotransferase (ALAT), alpha-fetoprotein (AFP) and interquartile range (IQR) of LS measurements were independently associated with the presence of HCC (p<0.0001 for all parameters; Odds Ratios of 8.27, 1.01, 1.04 and 1.16, respectively). The detection model combining the four variables showed a good diagnostic performance in both training and validation groups, with AUROCs of 0.86 and 0.8, respectively. All variables were also positively correlated with tumor size., Conclusion: In HCV related cirrhosis, HCC is associated with increased LS and IQR values and high ALAT and AFP levels. By combining these four parameters into a regression model, liver cancer may be noninvasively predicted with good accuracy.

Background & Aims: The current study aimed to establish the liver stiffness (LS) cut-off values and their performance in the prediction of the fibrosis stage in chronic hepatitis C (CHC) patients, to find the anthropometric and biochemical factors leading to overestimation of the fibrosis stage and to analyze the factors leading to the technique failure., Methods: 1,202 consecutive CHC patients were prospectively included in the study. All of them underwent percutaneous liver biopsy for grading and staging the disease (METAVIR) and were referred to LS measurement 1 day prior to biopsy., Results: LS values varied between 2.8-75 kPa. Transient elastography success rate (SR) ranged between 0-100% (84.82 +/- 24.46%). In 27 patients (2.2%), no valid measurement was obtained; high BMI influenced independently the measurement failure. In 11.2% of cases, the SR was <60%, but 10 valid measurements were nevertheless recorded; the female sex and high BMI were the only factors independently leading to a SR<60%. AUROCs for the diagnosis of fibrosis F≥1, F≥2, F≥3, and F=4 were 0.879, 0.889, 0.941 and 0.970, for the cut-off values of 5.3 kPa, 7.4 kPa, 9.1 kPa and 13.2 kPa respectively, and they did not significantly differ from the adjusted AUROC values. The patients with false positive results were younger and had significantly higher serum aminotransferase (ALT, AST) and gamma glutamyl-transpeptidase levels than the patients with concordant results. The multivariate analysis showed that only high ALT levels influenced independently the occurrence of false positive results., Conclusion: Transient elastography is a useful non-invasive method for the assessment of fibrosis in CHC patients. However, it must be interpreted in the clinical and biochemical context, in order to insure high-quality results.

Background and Aim: Noninvasive serum liver fibrosis markers and liver stiffness could be used as predictors of esophageal varices in cirrhotic patients because portal hypertension is related to liver fibrosis. The aim of this study was to compare the performance of common serum fibrosis scores and transient elastography in diagnosing esophageal varices and to propose a new algorithm for predicting large varices., Methods: 231 consecutive cirrhotic patients (58.4% males, mean age 55.9 years) were enrolled. Routine biological tests were performed, so that APRI, FIB-4, Forns Index and Lok Score could be calculated. All patients underwent transient elastography and eso-gastroscopy. The diagnostic performance of the methods was assessed using sensitivity, specificity, positive predictive value, negative predictive value, accuracy, likelihood ratios and receiver operating characteristic curves., Results: The Lok Score was the best among all the serum scores for diagnosing the varices. For a value higher than 0.8, it had a 45.5% positive predictive value, 86.4% negative predictive value and 67.72% diagnostic accuracy for prediction of large varices. For liver stiffness higher than 30.8KPa, the positive predictive value was 47.3%, negative predictive value 81% and diagnostic accuracy 68.32%. Using both tests simultaneously, the presence of large varices was predicted with a diagnostic accuracy of 78.12%, obtaining an increment in NPV and -LR up to 93.67% and 0.21, respectively., Conclusion: The Lok Score is a good predictor for excluding the presence of large varices in cirrhotic patients, similarly with liver stiffness. The two methods can be successfully combined into a noninvasive algorithm for the assessment of esophageal varices in cirrhotic patients.

Background/aims: Transient elastography (TE) is a noninvasive method for predicting liver fibrosis, mainly validated in patients with viral hepatitis. Information is still limited concerning its performance in non-alcoholic steatohepatitis (NASH) patients. We aimed to assess the value of TE in the prediction of fibrosis stage in NASH as well as the factors determining the discordance between the TE-predicted and the biopsy-proven fibrosis stage in these patients., Methods: Liver biopsy and TE were performed on 72 consecutive NASH patients. Fibrosis, lobular inflammation, ballooning and steatosis were evaluated (Brunt system)., Results: Liver stiffness (LS) values ranged from 2.80 to 16.90 kPa. In the univariate analysis, LS was correlated with fibrosis (r=0.661; p<0.0001), steatosis (r=0.435, p<0.0001), ballooning (r=0.385; p=0.001) and lobular inflammation (r=0.364; p=0.002). In multivariate analysis, only fibrosis significantly correlated with LS (p<0.0001). The median (and range) LS values (kPa) according to the fibrosis stages were: 4.90 (2.80-7.30) for F0; 6.15 (4.80-12.50) for F1; 6.90 (3.30-16.90) for F2 and 14.00 (10.70-14.10) for F3, with significant difference between stages, except for F1-F2 (p=0.249). Cut off values were calculated for predicting each fibrosis stage: 5.3 kPa (AUROC=0.879) for F1; 6.8 kPa (AUROC=0.789) for F2; and 10.4 kPa (AUROC=0.978) for F3. Patients with false-positive results had a significantly higher ALT level than those with concordant results (p=0.039)., Conclusion: In NASH patients, TE allows a reliable assessment and prediction of liver fibrosis, especially in advanced stages. Steatosis, ballooning and inflammation do not influence liver stiffness.

Background and Aims: The current study aims to evaluate the performance of a new elastographic method (ARFI) in noninvasive fibrosis assessment and to compare it to another validated technology (transient elastography, TE)., Method: 112 consecutive chronic hepatitis C patients (histologically proven according to the Metavir scoring system: 12.5% F0, 26.6% F1, 16.1% F2, 7.1% F3, 37.5% F4) were prospectively included in this study. They were examined on the same day, using both ARFI (with shear wave velocity--SWV-quantification) and TE (with liver stiffness quantification)., Results: SWV is correlated only with fibrosis (r=0.717, p less than 0.0001) and necroinflammatory activity (r=0.328, p=0.014), but not with steatosis (r=0.122, p=0.321). There is a significant increase of SWV in parallel with the increase in the fibrosis stage: 1.079+/-0.150 (F0-F1), 1.504+/-0.895 (F2), 1.520+/-0.575 (F3), 2.552+/-0.782 (F4), p<0.0001, but there is a certain degree of overlap between the consecutive stages F1-F2 (p=0.072), F2-F3 (p=0.965). SWV cut-off values (m/s) that were predictive for each fibrosis stage were: 1.19 (F more or equal to 1), 1.34 (F>or=2), 1.61 (F more or equal to 3) and 2.00 (F4). AUROC for ARFI vs TE were: 0.709 vs 0.902, p=0.006 (F>or=1), 0.851 vs 0.941, p=0.022 (F>or=2), 0.869 vs 0.926, p=0.153 (F>or=3) and 0.911 vs 0.945, p=0.331 (F4)., Conclusions: ARFI allows SWV quantification, in strong correlation with the fibrosis stage. Steatosis does not influence SWV. The maximal performance of the method consists of the prediction in severe fibrosis and cirrhosis. The diagnostic accuracy is strongly comparable to TE only for the prediction of severe fibrosis and cirrhosis, whereas for earlier stages, TE performs better.