Hemodynamic Evaluation of Nonselective \u3b2-Blockers in Patients with Cirrhosis and Refractory Ascites

BACKGROUND:Nonselective \u3b2-blockers (NSBB) have been associated with increased incidence of paracentesis-induced circulatory dysfunction (PICD) and reduced survival in patients with cirrhosis and refractory ascites. AIM:To prospectively evaluate a hemodynamic response to NSBB in cirrhotics listed for liver transplantation with refractory ascites undergoing large volume paracentesis (LVP). METHODS:Patients with cirrhosis and refractory ascites, with an indication to start NSBB in primary prophylaxis for variceal bleeding, were enrolled. During two consecutive LVP, while being, respectively, off and on NSBB, cardiac output (CO), systemic vascular resistances (SVR), peripheral vascular resistances (PVR), and plasma renin activity (PRA) were noninvasively assessed. RESULTS:Seventeen patients were enrolled, and 10 completed the study. Before NSBB introduction, SVR (1896 to 1348\u2009dyn\ub7s\ub7cm-5; p = 0.028) and PVR (47 to 30\u2009mmHg\ub7min\ub7dl\ub7ml-1; p = 0.04) significantly decreased after LVP, while CO showed an increasing trend (3.9 to 4.5\u2009l/m; p = 0.06). After NSBB introduction, LVP was not associated with a significant increase in CO (3.4 to 3.8\u2009l/m; p = 0.13) nor with a significant decrease in SVR (2002 versus 1798\u2009dyn\ub7s\ub7cm-5; p = 0.1). Incidence of PICD was not increased after NSBB introduction. CONCLUSION:The negative inotropic effect of NSBB was counterbalanced by a smaller decrease of vascular resistances after LVP, probably due to splanchnic \u3b22-blockade. This pilot study showed that NSBB introduction may be void of detrimental hemodynamic effects after LVP in cirrhotics with refractory ascites

Reply to: "A cut-off serum creatinine value of 1.5mg/dl for AKI – To be or not to be"

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Continuous recurrence of type 1 hepatorenal syndrome and long-term treatment with terlipressin and albumin: A new exception to MELD score in the allocation system to liver transplantation?

Background & Aims The recurrence of type 1 hepatorenal syndrome has been described in up to 20% of responders to terlipressin and albumin after the discontinuation of the treatment. Subsequent recurrence of type 1 hepatorenal syndrome may require long-term treatment with terlipressin and albumin. Methods We describe our experience of long-term administration of terlipressin as a bridge to LT in three patients with cirrhosis and recurrent type 1 hepatorenal syndrome. For all three patients we requested an "early transplant" which is an option recognized in our country to reduce waiting times for liver transplantation. Results All three patients were transplanted within 2months of onset of hepatorenal syndrome. All patients are still alive and none of them have developed chronic kidney disease. Conclusions The outcomes of these patients suggest that long-term treatment with terlipressin and albumin is effective and well tolerated in patients with continuous recurrence of type 1 hepatorenal syndrome and, therefore, should be considered an absolute priority criterion in the allocation system for liver transplantation

SerpinB3 and Yap Interplay Increases Myc Oncogenic Activity

SerpinB3 has been recently described as an early marker of liver carcinogenesis, but the potential mechanistic role of this serpin in tumor development is still poorly understood. Overexpression of Myc often correlates with more aggressive tumour forms, supporting its involvement in carcinogenesis. Yes-associated protein (Yap), the main effector of the Hippo pathway, is a central regulator of proliferation and it has been found up-regulated in hepatocellular carcinomas. The study has been designed to investigate and characterize the interplay and functional modulation of Myc by SerpinB3 in liver cancer. Results from this study indicate that Myc was up-regulated by SerpinB3 through calpain and Hippo-dependent molecular mechanisms in transgenic mice and hepatoma cells overexpressing human SerpinB3, and also in human hepatocellular carcinomas. Human recombinant SerpinB3 was capable to inhibit the activity of Calpain in vitro, likely reducing its ability to cleave Myc in its non oncogenic Myc-nick cytoplasmic form. SerpinB3 indirectly increased the transcription of Myc through the induction of Yap pathway. These findings provide for the first time evidence that SerpinB3 can improve the production of Myc through direct and indirect mechanisms that include the inhibition of generation of its cytoplasmic form and the activation of Yap pathway

Low P66shc with High SerpinB3 Levels Favors Necroptosis and Better Survival in Hepatocellular Carcinoma.

Cell proliferation and escape from apoptosis are important pathological features of hepatocellular carcinoma (HCC), one of the tumors with the highest mortality rate worldwide. The aim of the study was to evaluate the expression of the pro-apoptotic p66shc and the anti-apoptotic SerpinB3 in HCCs in relation to clinical outcome, cell fate and tumor growth. p66shc and SerpinB3 were evaluated in 67 HCC specimens and the results were correlated with overall survival. Proliferation and cell death markers were analyzed in hepatoma cells overexpressing SerpinB3, under different stress conditions. p66shc-/- mice and xenograft models were also used to assess the effects of p66shc and SerpinB3 on tumor growth. In patients with HCC, the best survival was observed in the subgroup with p66shc levels below median values and SerpinB3 levels above median values. Mice p66shc-/- showed high levels of SerpinB3, while in HepG2 cells overexpressing SerpinB3, p66shc expression was trivial. HepG2 overexpressing SerpinB3 cells were more prone to die after oxidizing treatments, such as diamide or high concentration H2O2. These cells injected in nude mice developed tumors five times smaller than those from control HepG2 cells. Tumors originating from HepG2 overexpressing SerpinB3 cells showed decreased activated Caspase-8, with concomitant increase of RIP3K and decreased levels of cleaved RIP3K, typical features of necroptosis. In conclusion, in patients affected by HCC, the pattern characterized by p66shc downregulation and elevated SerpinB3 levels was associated with markedly better survival. This pattern favored necroptosis in experimental high-stress conditions

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Terapia diuretica combinata "Ab Initio" versus terapia diuretica sequenziale nel trattamento dell'ascite moderata in pazienti con cirrosi epatica senza insufficienza renale

Sequential versus "ab initio" combined diuretic treatment of moderate ascites in cirrhotic patients: preliminary results of a randomized controlled multicenter clinical study. Background: the most rational treatment of cirrhotic patients with moderate ascites is a stepwise sequential therapy with increasing oral doses of an aldosterone antagonist. If no response occurs at the maximum dosage of the aldosterone antagonist (400mg/day), furosemide is added at increasing oral doses in a stewise way up to 160 mg/day (sequential diuretic treatment). Nevetheless, the onset of response following a sequential diuretic trreatment of ascites may requires to much time. Aim of the study: as a consequence, the aim of the study was to compare sequential diuretic therapy with a schedule combining "ab initio" aldosterone antagonist and furosemide in the treatment of moderate ascites in nonazotemic cirrhotic patients. Material and method: sixty-eight nonazotemic cirrhotic patients with moderate ascites wererandomly assigned to be treated by sequential diuretic treatment (Group A, n°=37) or by "ab initio" combined diuretic treatment (Group B, n°=31). In patients of Group A, potassium kanrenoate was used at the initial dosage of 200 mg/day (1st step) and if no response was obtained, it was peaked to 400 mg/day (2nd step). In nonresponders to 400 mg/day of potassium kanrenoate, furosemide was added at the initial dosage of 50 mg b.i.d. (3rd step) eventually inceasing to 100 mg/day b.i.d. (4th step) and then up to 150 mg/day b.i.d. (common step). Patients of Group B received 200 mg/day of potassium kanrenoate and 50 mg b.i.d. of furosemide as 1st step. If no response was observed the dosages of potassium kanrenoate and furosemide were increased to 400 mg/day and 100 mg b.i.d. (2nd step) and then up to 400 mg/day and 150 mg b.i.d., respectively (3rd step).No response was defined as a three-day weight loss lower than 600 gr. Outcome: the response rate was similar in both groups (88 % in Group A vs 96 % in Group B, p= N.S.). The patients's rate that need to change the effective diuretic step for diureticinduced complications was significantly lower in Group B (20%) than in Group A (38%) (p 10.2 ug/ml. Conclusions. "ab initio" combined diuretic treatment by means of potassium kanrenoate and furosemide makes it possible to shorten the time to mobilize moderate ascites in nonazotemic cirrhotic patients if comared to a sequential diuretic treatment. Thus, it appears the more suitable and cost-effective diuretic treatment schedule in these patients. Moreover, the probability to develop diuretic-induced adverse effects is correlated with basal value of plasma renin activity (PRA)

Cardiac dysfunction in patients with cirrhosis: is the systolic component its main feature? PMID: 25923940

To investigate the subclinical cardiac morphological and functional modifications in cirrhotic patients according to the stage of liver disease. PATIENTS AND METHODS: One hundred and thirteen cirrhotic patients underwent standard Doppler echocardiography and were compared with healthy individuals. Left ventricular (LV) geometry, systolic/diastolic function, and the main hemodynamic parameters were assessed according to current guidelines. RESULTS: Cirrhotic patients showed a reduction in the peripheral vascular resistance (PVR), a compensatory hyperdynamic syndrome, and a significant increase in cardiac index (CI), cardiac output (CO), and cardiac work, with a consequent increase in the prevalence of LV hypertrophy and associated diastolic dysfunction (DD). Age (P=0.005) and LV mass index (P=0.03) were the strongest predictors of DD. Even though all the systolic parameters assessed were similar between patients and controls, in patients with refractory ascites, the reduction of the PVR and mean blood pressure was not balanced by a further increase in cardiac work and therefore the CI and CO were supported only by the increase in heart rate. CONCLUSION: In cirrhotic patients, DD is strongly related to the increase in LV mass, not related to the stage of the liver disease, and can be correctly detectable only by the use of tissue Doppler imaging. For systolic dysfunction, along with the development and worsening of ascites, CO and CI do not increase further to compensate the continuous reduction of PVR and mean blood pressure, and their maintenance becomes critically dependent on the heart rate, thus suggesting a possible detrimental effect of \u3b2-blockers in these patients

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