Working Memory in Patients with Varying Degree of Hepatic Encephalopathy (HE): A Pilot EEG-fNIRS Study.

It is known that patients with covert hepatic encephalopathy (CHE) exhibit working memory abnormalities, but to date there is no study comparing patients with cirrhosis with/without CHE and controls with both electrophysiological and hemodynamic data collected at the same time.Here we collected behavioral [accuracy and reaction times (RTs), electrophysiological (evoked potentials) and hemodynamic (oxygenated and deoxygenated haemoglobin) correlates of an n-back task [formed by a control (0-back) condition, a low (1-back) and a high (2-back) working memory load conditions] in patients with cirrhosis with/without CHE: (1) at baseline (n = 21, males = 15, 58±8 yrs), and by comparison with controls (n = 21, males = 15, 57±11 yrs) and (2) after a 3-month course of rifaximin (n = 18, males = 12, 61±11 yrs), and by comparison to baseline.All patients showed slower RTs (p < 0.0001) and lower P2 amplitude compared with controls (p = 0.018); moreover, patients with CHE showed reduced accuracy (p < 0.0001) compared with controls, and patients without CHE showed higher oxygenated haemoglobin in the central dorsolateral prefrontal cortex in the 2-back compared with patients with CHE. Post-rifaximin, oxygenated haemoglobin increased in the central frontopolar cortex. In addition, in patients without CHE the RTs of the 2-back became comparable to those of the 0-back and P3 showed higher amplitude.In conclusion, the presence of cirrhosis seemed to have more effects than CHE on working memory at baseline. A course of treatment with rifaximin was more beneficial to patients without CHE, who probably had more room for improvement in this complex task.

Studies on the Role of Compartmentalized Profiles of Cytokines in the Risk of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), the most common form of liver cancer, is frequently diagnosed late due to the absence of symptoms during early disease, thus heavily affecting the overall survival of these patients. Soluble immunological factors persistently produced during cirrhosis have been recognized as promoters of chronic inflammation and neoplastic transformation. The aim of this pilot study was to evaluate the predictive value of the cytokine profiles for HCC development. A Luminex xMAP approach was used for the quantification of 45 proteins in plasma and ascitic fluids of 44 cirrhotic patients without or with HCC of different etiologies. The association with patient survival was also evaluated. Univariate analyses revealed that very low levels of interleukin 5 (IL-5) (<15.86 pg/mL) in ascites and IL-15 (<12.40 pg/mL) in plasma were able to predict HCC onset with an accuracy of 81.8% and a sensitivity of 95.2%. Univariate analyses also showed that HCC, hepatitis B virus/hepatitis C virus infections, low levels of IL-5 and granulocyte-macrophage colony-stimulating factor in ascitic fluids, and high levels of eotaxin-1, hepatocyte growth factor and stromal-cell-derived factor 1α in plasma samples were factors potentially associated with a poor prognosis and decreased survival. Our results suggest a potential protective role of some immune modulators that may act in the peritoneal cavity to counteract disease progression leading to HCC development.

Investigation of the Interaction between Human Serum Albumin and Branched Short-Chain Perfluoroalkyl Compounds.

The current trend dealing with the production of per- and polyfluoroalkyl substances (PFASs) involves the shifting toward branched short-chain fluorinated compounds known as new-generation PFASs. A key aspect to be clarified, to address the adverse health effects associated with the exposure to PFASs, is their binding mode to human serum albumin (hSA), the most abundant protein in plasma. In this study, we investigated the interaction between hSA and two representative branched short-chain PFASs, namely, HPFO-DA and C6O4. In-solution studies revealed that both compounds bind hSA with affinities and stoichiometries lower than that of the legacy long-chain perfluoroalkyl compound PFOA. Competition experiments using hSA-binding drugs with known site-selectivity revealed that both HPFO-DA and C6O4 bound to pockets located in subdomain IIIA. The crystal structure of hSA in complex with HPFO-DA unveiled the presence of two binding sites. The characterization and direct comparison of hSA interactions with new-generation PFASs may be key elements for the understanding of the toxicological impact of these compounds.

Endoscopic diode laser therapy for gastric hyperplastic polyps in cirrhotic patients.

Purpose Endoscopic polypectomy to remove gastric hyperplastic polyps in cirrhotic patients is associated to a high risk of postprocedural bleeding. The current study set out to examine the effect of diode laser therapy used to treat this type of polyps in cirrhotic patients. Methods This single-center study retrospectively examined the data of cirrhotic patients with macroscopic bleeding or anemia who underwent diode laser therapy (940 nm wave length, 30-W power setting in continuous mode) to remove histology-confirmed hyperplastic gastric polyps. Results A total of 222 polyps (mean diameter 10 ± 8 mm) were treated in 55 patients who were included in the study. No complications such as bleeding or perforations were reported. After a mean of 5 ± 4 sessions, 31 patients (56%) were completely healed. In 16 patients (29%), there was only a partial response (mean polyp reduction diameter of 64 ± 15%), while 8 (15%) patients did not respond to treatment. Statistically significant better results were noted in the patients who underwent ≥ 2 laser sessions. Hemoglobin levels and number of blood transfusions required were not statistically different after treatment. After a mean study period of 21 ± 17 months, polyp recurrences were noted in 11 patients (20%), but none of the polyps had degenerated. Conclusion Diode laser therapy was found to be a safe treatment for hyperplastic polyps in cirrhotic patients. Due to the presence of others bleeding lesions in cirrhotic patients, this treatment did not have an impact on anemia and transfusion requirements.

Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites.

BACKGROUND & AIMS: In patients with cirrhosis, the clinical benefit of the treatment with human albumin for ascites is debated, and no data are available regarding refractory ascites. In this study, in patients with cirrhosis and refractory ascites, we assessed the effect of long-term albumin administration on emergent hospitalization and mortality. METHODS: Seventy patients with cirrhosis and refractory ascites, followed at the Unit of Internal Medicine and Hepatology, University and General Hospital of Padova, Italy, were included into the study. Forty-five patients were non-randomly assigned to receive long-term administration of human albumin at the doses of 20 g twice per week (n = 45), in addition to standard medical of care (SOC), and compared to those followed according to SOC. Patients were followed up to the end of the study, liver transplantation or death. RESULTS: The cumulative incidence of 24-month mortality was significantly lower in patients treated with albumin than in the group of patients treated with SOC (41.6% vs 65.5%; P = 0.032). The period free of emergent hospitalization was significantly longer in patients treated with long-term administration of albumin (P = 0.008). Analysing separately the causes of inpatient admission, patients treated with albumin showed a reduction in the incidence of overt hepatic encephalopathy, ascites, spontaneous bacterial peritonitis (SBP) and non-SBP infections. In addition, a non-significant trend towards a reduced probability of hepatorenal syndrome was observed. CONCLUSION: In patients with cirrhosis and refractory ascites, long-term treatment with albumin improves survival and reduces the probability of emergent hospitalizations.

Incidence, predictors and outcomes of acute-on-chronic liver failure in outpatients with cirrhosis.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is the most life-threatening complication of cirrhosis. Prevalence and outcomes of ACLF have recently been described in hospitalized patients with cirrhosis. However, no data is currently available on the prevalence and the risk factors of ACLF in outpatients with cirrhosis. The aim of this study was to evaluate incidence, predictors and outcomes of ACLF in a large cohort of outpatients with cirrhosis. METHODS: A total of 466 patients with cirrhosis consecutively evaluated in the outpatient clinic of a tertiary hospital were included and followed up until death and/or liver transplantation for a mean of 45±44months. Data on development of hepatic and extrahepatic organ failures were collected during this period. ACLF was defined and graded according to the EASL-CLIF Consortium definition. RESULTS: During the follow-up, 118 patients (25%) developed ACLF: 57 grade-1, 33 grade-2 and 28 grade-3. The probability of developing ACLF was 14%, 29%, and 41% at 1year, 5years, and 10years, respectively. In the multivariate analysis, baseline mean arterial pressure (hazard ratio [HR] 0.96; p=0.012), ascites (HR 2.53; p=0.019), model of end-stage liver disease score (HR 1.26; p<0.001) and baseline hemoglobin (HR 0.07; p=0.012) were found to be independent predictors of the development of ACLF at one year. As expected, ACLF was associated with a poor prognosis, with a 3-month probability of transplant-free survival of 56%. CONCLUSIONS: Outpatients with cirrhosis have a high risk of developing ACLF. The degree of liver failure and circulatory dysfunction are associated with the development of ACLF, as well as low values of hemoglobin. These simple variables may help to identify patients at a high risk of developing ACLF and to plan a program of close surveillance and prevention in these patients. LAY SUMMARY: There is a need to identify predictors of acute-on-chronic liver failure (ACLF) in patients with cirrhosis in order to identify patients at high risk of developing ACLF and to plan strategies of prevention. In this study, we identified four simple predictors of ACLF: model of end-stage liver disease (MELD) score, ascites, mean arterial pressure and hemoglobin. These variables may help to identify patients with cirrhosis, at a high risk of developing ACLF, that are candidates for new strategies of surveillance and prevention. Anemia is a potential new target for treating these patients.

Validation of a Staging System for Acute Kidney Injury in Patients With Cirrhosis and Association With Acute-on-Chronic Liver Failure.

BACKGROUND & AIMS: In patients with cirrhosis of the liver, acute kidney injury (AKI) is classified into 3 stages. Recent studies indicate that there are 2 subgroups of stage 1 disease, associated with different outcomes and serum levels of creatinine (SCr): stage 1A (SCr <1.5 mg/dL) and stage 1B (SCr ≥1.5 mg/dL). We performed a prospective study to validate, in a large series of patients with cirrhosis, the association between this new description and patient outcomes, and assess the relationship between AKI stage and the presence of acute-on-chronic liver failure. METHODS: We collected data from 547 consecutive patients admitted for cirrhosis with acute decompensation to 2 tertiary hospitals (Italy and Spain), from February 2011 through June 2015. A total of 290 patients had AKI (53%; 197 had stage 1 disease); AKI stages were determined based on levels of SCr at diagnosis. Patients were followed up until death, liver transplantation, or for 90 days. The primary outcome was 90-day survival; secondary outcomes were progression and resolution of AKI and association with acute-on-chronic liver failure. RESULTS: Based on level of sCr at diagnosis, 58 patients had stage 1A disease and 139 had stage 1B disease. Of patients with stage 1A disease, 82% survived for 90 days; of patients with stage 1B disease, 55% survived for 90 days (P = .001). Hepatorenal syndrome and acute tubular necrosis were the most common causes of stage 1B AKI, and hypovolemia was the most common cause of stage 1A AKI. AKI progressed in a higher proportion of patients with 1B than 1A AKI (31% vs 15%; P = .017) and resolved in a higher proportion of patients with 1A disease (90% vs 52% of patients with stage 1B; P < .001). Stage 1B disease, but not 1A, was an independent predictor of AKI progression and mortality. ACLF developed in a significantly greater proportion of patients with stage 1B disease (76%) than stage 1A disease (22%; P < .001), which could account for the poor outcomes of patients with stage 1B disease. CONCLUSIONS: In a large group of patients with decompensated cirrhosis, we validated the association between AKI stages IA and IB (based on level of sCR) with survival times and AKI progression. We also associated these subgroups of AKI with development of acute-on-chronic liver failure. These findings are important for management of patients with decompensated cirrhosis.

Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study.

UNLABELLED: In patients with cirrhosis and hepatorenal syndrome (HRS), terlipressin has been used either as continuous intravenous infusion or as intravenous boluses. To date, these two approaches have never been compared. The goal of this study was to compare the administration of terlipressin as continuous intravenous infusion versus intravenous boluses in the treatment of type 1 HRS. Seventy-eight patients were randomly assigned to receive either continuous intravenous infusion (TERLI-INF group) at the initial dose of 2 mg/day or intravenous boluses of terlipressin (TERLI-BOL group) at the initial dose of 0.5 mg every 4 hours. In case of no response, the dose was progressively increased to a final dose of 12 mg/day in both groups. Albumin was given at the same dose in both groups (1 g/kg of body weight at the first day followed by 20-40 g/day). Complete response was defined by decrease of serum creatinine (sCr) from baseline to a final value ≤133 µmol/L, partial response by a decrease ≥50% of sCr from baseline to a final value >133 µmol/L. The rate of adverse events was lower in the TERLI-INF group (35.29%) than in the TERLI-BOL group (62.16%, P < 0.025). The rate of response to treatment, including both complete and partial response, was not significantly different between the two groups (76.47% versus 64.85%; P value not significant). The mean daily effective dose of terlipressin was lower in the TERLI-INF group than in the TERLI-BOL group (2.23 ± 0.65 versus 3.51 ± 1.77 mg/day; P < 0.05). CONCLUSION: Terlipressin given by continuous intravenous infusion is better tolerated than intravenous boluses in the treatment of type 1 HRS. Moreover, it is effective at doses lower than those required for intravenous bolus administration.

The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: Results of a randomized, controlled clinical trial.

UNLABELLED: Spontaneous bacterial peritonitis (SBP) is a common, life-threatening complication of liver cirrhosis. Third-generation cephalosporins have been considered the first-line treatment of SBP. In 2014, a panel of experts suggested a broader spectrum antibiotic regimen for nosocomial SBP, according to the high rate of bacteria resistant to third-generation cephalosporins found in these patients. However, a broader-spectrum antibiotic regimen has never been compared to third-generation cephalosporins in the treatment of nosocomial SBP. The aim of our study was to compare meropenem plus daptomycin versus ceftazidime in the treatment of nosocomial SBP. Patients with cirrhosis and nosocomial SBP were randomized to receive meropenem (1 g/8 hours) plus daptomycin (6 mg/kg/day) or ceftazidime (2 g/8 hours). A paracentesis was performed after 48 hours of treatment. A reduction in ascitic fluid neutrophil count <25% of pretreatment value was considered a treatment failure. The primary outcome was the efficacy of treatment defined by the resolution of SBP after 7 days of treatment. Thirty-two patients were randomized and 31 were analyzed. The combination of meropenem plus daptomycin was significantly more effective than ceftazidime in the treatment of nosocomial SBP (86.7 vs. 25%; P < 0.001). Ninety-day transplant-free survival (TFS) was not significantly different between the two groups. In the multivariate analysis, ineffective response to first-line treatment (hazard ratio [HR]: 20.6; P = 0.01), development of acute kidney injury during hospitalization (HR: 23.2; P = 0.01), and baseline mean arterial pressure (HR: 0.92; P = 0.01) were found to be independent predictors of 90-day TFS. CONCLUSION: The combination of meropenem plus daptomycin is more effective than ceftazidime as empirical antibiotic treatment of nosocomial SBP. Efficacy of the empirical antibiotic treatment is a strong predictor of 90-day survival in patients with nosocomial SBP.

Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial.

UNLABELLED: Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the reversal of HRS. Where terlipressin is not available, as in the United States, midodrine and octreotide with albumin are used as an alternative treatment of HRS. The aim was to compare the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in a randomized controlled trial. Twenty-seven patients were randomized to receive terlipressin with albumin (TERLI group) and 22 to receive midodrine and octreotide plus albumin (MID/OCT group). The TERLI group received terlipressin by intravenous infusion, initially 3 mg/24 hours, progressively increased to 12 mg/24 hours if there was no response. The MID/OCT group received midodrine orally at an initial dose of 7.5 mg thrice daily, with the dose increased to a maximum of 12.5 mg thrice daily, together with octreotide subcutaneously: initial dose 100 µg thrice daily and up to 200 µg thrice daily. Both groups received albumin intravenously 1 g/kg of body weight on day 1 and 20-40 g/day thereafter. There was a significantly higher rate of recovery of renal function in the TERLI group (19/27, 70.4%) compared to the MID/OCT group (6/21, 28.6%), P = 0.01. Improvement in renal function and lower baseline Model for End-Stage Liver Disease score were associated with better survival. CONCLUSION: Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS.

Ternary Hybrid γ-Fe2 O3 /Cr(VI) /Amine Oxidase Nanostructure for Electrochemical Sensing: Application for Polyamine Detection in Tumor Tissue.

Dichromate binds to surface-active maghemite nanoparticles (SAMNs) to form a stable core-shell nanostructures (SAMN@Cr(VI) ). The hybrid was characterized by Mössbauer spectroscopy, high-angle annular dark-field imaging, electron energy-loss spectroscopy, and electrochemical techniques, which revealed a strong interaction of dichromate with the nanoparticle surface. Electrochemical characterization showed lower charge-transfer resistance, better electrochemical performance, and more reversible electrochemical behavior with respect to naked SAMNs. Moreover, SAMN@Cr(VI) is an excellent electrocatalyst for hydrogen peroxide reduction. Furthermore, an enzyme, namely, bovine serum amine oxidase (BSAO: EC 1.4.3.6), was immobilized on SAMN@Cr(VI) by self-assembly to give a ternary hybrid nanostructured catalyst for polyamine oxidation (SAMN@Cr(VI) -BSAO). SAMN@Cr(VI) -BSAO was applied for the development of a reagentless, fast, inexpensive, and interference-free polyamine biosensor, which was successfully exploited for the discrimination of tumorous tissue from healthy tissue in human crude liver extracts.

New ICA criteria for the diagnosis of acute kidney injury in cirrhotic patients: can we use an imputed value of serum creatinine?

BACKGROUND & AIMS: The new International Club of Ascites diagnostic criteria to diagnose acute kidney injury at hospital admission suggests the possibility of using a presumed baseline serum creatinine, defined as the last of at least two stable creatinine values during the last 3 months. Nevertheless, the possibility of the lack of such a value still remains. In these patients, the KDIGO criteria suggest to use an inverse application of MDRD equation assuming that baseline glomerular filtration rate is 75 ml/min per 1.73 m(2) (imputed baseline creatinine). We tested the accuracy of this approach to detect acute kidney injury at admission in patients with decompensated cirrhosis and creatinine <1.5 mg/dl. METHODS: We analysed 213 patients hospitalized for acute decompensation of cirrhosis. At admission, glomerular filtration rate was estimated using creatinine-based equations and measured by inulin clearance. A diagnosis of acute kidney injury was made using an imputed value of serum creatinine as baseline. RESULTS: The diagnosis of AKI based on an imputed baseline creatinine identified only 20.1% of patients with measured glomerular filtration rate ≤60 ml/min/1.73 m(2) without any predictive value on 90-day survival. CONCLUSIONS: In patients with cirrhosis and ascites with a creatinine <1.5 mg/dl without a baseline value on their records, the diagnosis of acute kidney injury at admission based on an imputed baseline creatinine is not accurate.

Adherence to a moderate sodium restriction diet in outpatients with cirrhosis and ascites: a real-life cross-sectional study.

BACKGROUND & AIMS: A moderate sodium restriction diet should be indicated in patients with cirrhosis and ascites. Nevertheless, there is a lack of specific investigation on its correct application. To evaluate the adherence of patients with cirrhosis and ascites to a moderately low-salt diet and the impact on intake of total calories and serum sodium concentration. METHODS: A total of 120 outpatients with cirrhosis and ascites were interviewed with a pre-established questionnaire. A quantitative assessment of nutrient and salt intake was performed. RESULT: A moderately low-salt diet was followed by 37 patients (Group A). Of the 83 patients who did not follow the diet (Group B), 54 thought that they were following it. The mean daily sodium intake was 79.5 ± 5.5 mmol/day (Group A) and 205.9 ± 14.1 mmol/day (Group B), P < 0.0001. The adherence to diet was related to the severity of cirrhosis, and was higher among candidates for liver transplantation and in patients followed through the Care Management Program. Patients of Group A had reduced the mean daily calorie intake by 20% compared with Group B patients (P < 0.0005), while there was no difference on the occurrence of hyponatraemia. CONCLUSIONS: This study shows a poor adherence of patients with cirrhosis and ascites to a moderate dietary sodium restriction. Adherence to a diet seems to increase with the worsening of liver disease, probably because of the reduction of alternative therapeutic options. In addition, a deficiency in the educational process can lead the patient to follow a sodium-reduced diet by means of dangerous tools, such as reducing the overall daily food intake.

The Treatment of Hepatorenal Syndrome.

Hepatorenal syndrome (HRS) is a severe complication that often occurs in patients with cirrhosis and ascites. HRS is a functional renal failure that develops mainly as a consequence of a severe cardiovascular dysfunction which is characterized by an extreme splanchnic arterial vasodilation and a reduction of cardiac output. HRS may develop in two clinical types: as an acute and rapidly progressive renal failure (AKI-HRS) or as chronic and not progressive renal failure (CKD-HRS). Several small studies and some randomized control studies have been published on the use of terlipressin plus albumin in the treatment of HRS, mainly on AKI-HRS. Terlipressin plus albumin was shown to improve renal function in almost 35-45% of patients with AKI-HRS, as well as to improve short-term survival in these patients. Terlipressin was most commonly used by intravenous boluses moving from an initial dose of 0.5-1 mg every 4 h to 3 mg every 4 h in the case of a nonresponse. In other studies, terlipressin was also given by continuous intravenous infusion. Thus, the best way to administer terlipressin in the treatment of HRS has not yet been defined. α-Adrenergic drugs, such as intravenous norepinephrine or oral midodrine plus subcutaneous octreotide, administered with albumin have also been used in the treatment of AKI-HRS, with promising results. However, we need further studies in order to define whether they can represent a real therapeutic alternative. In conclusion, available data are sufficient to state that the use of terlipressin plus albumin has really changed the management of HRS. Nevertheless, some crucial unsolved issues still exist, in particular: (a) how to predict nonresponse to treatment, (b) how to manage nonresponse to treatment and (c) how to consider the response in those patients who are candidates for liver transplant in the priority allocation process.

Assessment of alcohol consumption in liver transplant candidates and recipients: the best combination of the tools available.

The detection of alcohol consumption in liver transplant candidates (LTCs) and liver transplant recipients (LTRs) is required to enable a proper assessment of transplant eligibility and early management of alcohol relapse, respectively. In this clinical setting, urinary ethyl glucuronide (uEtG), the Alcohol Use Disorders Identification Test for Alcohol Consumption (AUDIT-c), serum ethanol, urinary ethanol, carbohydrate-deficient transferrin (CDT), and other indirect markers of alcohol consumption were evaluated and compared prospectively in 121 LTCs and LTRs. Alcohol consumption was diagnosed when AUDIT-c results were positive or it was confirmed by a patient's history in response to abnormal results. Alcohol consumption was found in 30.6% of the patients. uEtG was found to be the strongest marker of alcohol consumption (odds ratio = 414.5, P < 0.001) and provided a more accurate prediction rate of alcohol consumption [area under receiving operating characteristic (ROC) curve = 0.94] than CDT (area under ROC curve = 0.63, P < 0.001) and AUDIT-c (area under ROC curve = 0.73, P < 0.001). The combination of uEtG and AUDIT-c showed higher accuracy in detecting alcohol consumption in comparison with the combination of CDT and AUDIT-c (area under ROC curve = 0.98 versus 0.80, P < 0.001). Furthermore, uEtG was the most useful marker for detecting alcohol consumption in patients with negative AUDIT-c results. In conclusion, the combination of AUDIT-c and uEtG improves the detection of alcohol consumption in LTCs and LTRs. Therefore, they should be used routinely for these patients.

Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms.

UNLABELLED: The aim of this study was to evaluate the effect and molecular mechanism of albumin infusion on cardiac contractility in experimental cirrhosis with ascites. Cardiac contractility was recorded ex vivo in rats with cirrhosis and ascites and in control rats after the injection in the caudal vein of albumin, saline, or hydroxyethyl starch (HES). Gene and protein expression of ß-receptors and pathways involved in their intracellular signaling such as Gα(i2) protein (Gα(i2)), adenylate cyclase 3 (Adcy3), protein expression of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS), were evaluated in cardiac tissue in both groups. Phosphorylation and membrane-translocation of the cytosolic components of nicotinamide adenine dinucleotide phosphate (NAD(P)H)-oxidase and translocation of nuclear factor kappa B (NF-κB) were also evaluated. After saline intravenous injection, cardiac contractility was significantly reduced in rats with cirrhosis as compared to control rats (P < 0.01). This was associated with: (1) increased expression of protein Gα(i2) (P < 0.05), TNF-α (P < 0.05), iNOS (P < 0.05); (2) increased NAD(P)H-oxidase activity (P < 0.05); (3) increased nuclear translocation of NF-κB (P < 0.05); and (4) lower expression of Adcy 3 (P < 0.05) in cardiac tissue of rats with cirrhosis. After albumin injection cardiac contractility (P < 0.01), protein expression of TNF-α, iNOS, Gα(i2), and Adcy3, NAD(P)H-oxidase activity and nuclear translocation of NF-κB in cardiac tissue of rats with cirrhosis were reversed to control levels (P < 0.05). HES injection did not modify cardiac contractility and nuclear translocation of NF-κB in cardiac tissue of rats with cirrhosis. CONCLUSION: Albumin exerts a positive cardiac inotropic effect in rats with cirrhosis and ascites counteracting the negative effects of oxidative stress- and TNF-α-induced activation of NF-κB-iNOS pathway and oxidative stress-induced alteration of ß-receptor signaling.

Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites.

BACKGROUND & AIMS: For several years hepatologists have defined acute renal failure in patients with cirrhosis as an increase in serum creatinine (sCr) ≥ 50% to a final value of sCr>1.5mg/dl (conventional criterion). Recently, the Acute Kidney Injury Network (AKIN) defined acute renal failure as acute kidney injury (AKI) on the basis of an absolute increase in sCr of 0.3mg/dl or a percentage increase in sCr ≥ 50% providing also a staging from 1 to 3. AKIN stage 1 was defined as an increase in sCr ≥ 0.3mg/dl or increase in sCr ≥ 1.5-fold to 2-fold from baseline. AKI diagnosed with the two different criteria was evaluated for the prediction of in-hospital mortality. METHODS: Consecutive hospitalized patients with cirrhosis and ascites were included in the study and evaluated for the development of AKI. RESULTS: Conventional criterion was found to be more accurate than AKIN criteria in improving the prediction of in-hospital mortality in a model including age and Child-Turcotte-Pugh score. The addition of either progression of AKIN stage or a threshold value for sCr of 1.5mg/dl further improves the value of AKIN criteria in this model. More in detail, patients with AKIN stage 1 and sCr<1.5mg/dl had a lower mortality rate (p=0.03), a lower progression rate (p=0.01), and a higher improvement rate (p=0.025) than patients with AKIN stage 1 and sCr ≥ 1.5mg/dl. CONCLUSIONS: Conventional criterion is more accurate than AKIN criteria in the prediction of in-hospital mortality in patients with cirrhosis and ascites. The addition of either the progression of AKIN stage or the cut-off of sCr ≥ 1.5mg/dl to the AKIN criteria improves their prognostic accuracy.

How to improve care in outpatients with cirrhosis and ascites: a new model of care coordination by consultant hepatologists.

BACKGROUND & AIMS: The development of ascites in patients with cirrhosis is associated with a high rate of health care utilization. New models of specialized caregiving support are necessary to optimize its management. The aim of the study was to evaluate the efficacy and financial sustainability of the "Care management check-up" as a new model of specialized caregiving support based on a series of diagnostic facilities performed in real time and on the integrated activity of consultant hepatologists at the hospital unit for outpatients, dedicated nurses, physicians in training and primary physicians, compared to standard care in outpatients with cirrhosis and ascites. METHODS: 100 cirrhotic patients admitted to our hospital were allocated, after discharge, to the "Care management check-up" group (group 1), or to the "Standard outpatient care" group (group 2), and followed prospectively as outpatients up to death or for at least 12 months. Patients of the two groups could also access to a "Day hospital" when an invasive procedure was required. In group 1, the "Care management check-up" and the "Day hospital" taken together defined the "Care management program". RESULTS: Twelve-month mortality was higher in group 2 than in group 1 (45.7% vs. 23.1%, p<0.025). The rate of 30-day readmission was also higher in group 2 (42.4% vs. 15.4%, p<0.01). The global cost attributable to the management per patient-month of life was lower (1479.19 ± 2184.43 €) in group 1 than (2816.13 ± 3893.03 €) in group 2 (p<0.05). CONCLUSIONS: The study suggests that this new model of specialized caregiving reduces 12-month mortality in patients with cirrhosis and ascites as well as the global health care costs for their management.

Severe acute hepatitis B in a treatment-naïve patient with antiviral drug resistant mutations in the polymerase gene.

This is a case of 62 years old Caucasian treatment-naïve patient who developed a severe acute hepatitis B infection soon after a trip to Thailand. The infection was due to genotype C HBV which was found to be resistant to lamivudine and telbivudine. The patient was treated with tenofovir resulting in complete suppression of viral replication and complete clinical and laboratory remission of acute hepatitis. Later the patient also developed seroconversion of HBeAg to anti-HBe and of HBsAg to anti-HBs. This case demonstrates that mutations of HBV polymerase associated with lamivudine, telbivudine, and adefovir resistance can be present also in untreated patients with severe acute hepatitis B. This suggests that in the clinical context, which represents a life threatening condition, a baseline resistance-testing should be an additional marker in the diagnostic evaluation process. Finally, this case report seems to support the use of tenofovir for the immediate treatment of severe acute hepatitis B.

SerpinB3 Upregulates Low-Density Lipoprotein Receptor-Related Protein (LRP) Family Members, Leading to Wnt Signaling Activation and Increased Cell Survival and Invasiveness.

Abnormal activation of the Wnt-ß-catenin signaling cascade is involved in tumor growth and dissemination. SerpinB3 has been shown to induce ß-catenin, and both molecules are overexpressed in tumors, particularly in those with poor prognoses. The aim of this study was to evaluate the ability of SerpinB3 to modulate the Wnt pathway in liver cancer and in monocytic cells, the main type of inflammatory cells in the tumor microenvironment. The Wnt cascade, Wnt co-receptors, and low-density lipoprotein receptor-related protein (LRP) members were analyzed in different cell lines and human monocytes in the presence or absence of SerpinB3. The Wnt-ß-catenin axis was also evaluated in liver tumors induced in mice with different extents of SeprinB3 expression. In monocytic cells, SerpinB3 induced a significant upregulation of Wnt-1/7, nuclear ß-catenin, and c-Myc, which are associated with increased cell lifespan and proliferation. In liver tumors in mice, the expression of ß-catenin was significantly correlated with the presence of SerpinB3. In hepatoma cells, Wnt co-receptors LRP-5/6 and LRP-1, implicated in cell survival and invasiveness, were upregulated by SerpinB3. The LRP pan-inhibitor RAP not only induced a decrease in LRP expression, but also a dose-dependent reduction in SerpinB3-induced invasiveness. In conclusion, SerpinB3 determines the activation of the Wnt canonical pathway and cell invasiveness through the upregulation of LRP family members.