[Show abstract][Hide abstract] ABSTRACT: Abstract
BACKGROUND & AIMS:
Acute-on Chronic Liver Failure (ACLF) is a frequent syndrome (30% prevalence) characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality. This study develops and validates a specific prognostic score for ACLF patients.
Data from 1,349 patients included in the CANONIC study were used. First, a simplified organ function scoring system (CLIF-Consortium Organ Failure score, CLIF-C OFs) to diagnose ACLF was developed using data from all patients. Subsequently, in 275 patients with ACLF, CLIF-C OFs and two other independent predictors of mortality (age and white-cell count) were combined to develop a specific prognostic score for ACLF (CLIF CONSORTIUM score for ACLF, CLIF-C ACLFs). Concordance index (C-index) was used to compare the discrimination abilities of CLIF-C ACLFs, MELD (MELDs), MELD-Sodium (MELD-Nas) and Child-Pugh (CPs) scores. CLIF-C ACLFs was validated in an external cohort and assessed for sequential use.
CLIF-C ACLFs showed a significantly higher predictive accuracy than MELDs, MELD-Nas and CPs, reducing (19-28%) the corresponding prediction error rates at all the main time-points after ACLF diagnosis (28, 90, 180 and 365 days) in both the CANONIC and the external validation cohort. CLIF-C ACLFs computed at 48 hours, 3-7 days and 8-15 days after ACLF diagnosis predicted 28-day mortality significantly better than at diagnosis.
CLIF-C ACLFs at ACLF diagnosis is superior to MELDs and MELD-Nas in predicting mortality. CLIF-C ACLFs is a clinically relevant, validated scoring system that can be used sequentially to stratify the risk of mortality in ACLF patients.
Journal of Hepatology 06/2014; · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Probiotics can prevent pathological bacterial translocation in cirrhosis by modulating intestinal microbiota and improving gut barrier and immune disturbances.AimTo evaluate the effect of probiotic VSL#3 on bacterial translocation, intestinal microbiota, gut barrier and inflammatory response in rats with experimental cirrhosis.Methods
Forty-six Sprague-Dawley rats with CCl4-induced cirrhosis were randomized into two groups: VSL#3 group (n=22) that received VSL#3 in drinking water, and water group (n=24) that received water only. Treatment began at week 6 of cirrhosis induction and continued until laparotomy, performed one week after development of ascites or at week 20. A control group included 11 healthy rats. At the study end we evaluated bacterial translocation, intestinal flora, intestinal barrier (ileal claudin-2 and 4, β-defensin-1, occludin and malondialdehyde as index of oxidative damage) and serum cytokines.ResultsMortality during the study was similar in the VSL#3 group (10/22, 45%) and the water group (10/24, 42%) (p=1). The incidence of bacterial translocation was 1/12 (8%) in the VSL#3 group, 7/14 (50%) in the water group 2 (p=0.03 vs VSL#3 group) and 0/11 in the control group (p=0.008 vs water group). The concentration of ileal and cecal enterobacteria and enterococci was similar in the two groups of cirrhotic rats. The ileal occludin concentration was higher and ileal malondialdehyde and serum levels of TNF-α were lower in the VSL#3 group than in the water group (p<0.05).ConclusionsVSL#3 decreases bacterial translocation, the proinflammatory state and ileal oxidative damage and increases ileal occludin expression in rats with experimental cirrhosis.This article is protected by copyright. All rights reserved.
Liver international: official journal of the International Association for the Study of the Liver 04/2014; · 3.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Polycystic liver in the adult (PLA) is a rare disease characterized by chronic liver enlargement.Objective: To analyse gastroenterologists´ involvement in, experience with, and attitude toward diagnosing, monitoring, andtreating patients with PLA in Spain.Methods: Each of seven study coordinators contacted 15 specialists in their geographic area about participating in the study via an online structured survey.Results: Of the 105 clinics contacted, 88 completed the questionnaire, with a mean of 3 patients being followed per practice, although 6 clinics were following more than 20 patients with PLA. Patients were being followed mainly by the Department of Hepatology (81 %) and/or the Department of Gastroenterology (33 %). The majority of patients were diagnosed (98 %) and monitored (97 %) using liver ultrasound. When diagnosed, 76 % of patients were under 50 years of age, females predominating.The primary treatment objective for the patients was symptomatic management. Pharmacotherapy was prescribed by 28 % of physicians: Somatostatin analogues, primarily, followed by mTOR inhibitors. One-third of the clinics indicated that they had patients who had undergone liver transplant and/or surgery.Conclusions: Ultrasound is the diagnosing and monitoring method of choice. Among the clinics using pharmacotherapy for symptomatic management, somatostatin analogues were the drugs of choice. These clinics´ infrequent use of invasive procedures suggests that they perceive the various invasive techniques as not very effective.
Revista espanola de enfermedades digestivas: organo oficial de la Sociedad Espanola de Patologia Digestiva 04/2014; 106(4):263-275. · 1.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Physical exercise could improve functional limitations, muscle mass, and health-related quality of life (HRQoL) in patients with cirrhosis.
The purpose of this study was to evaluate the efficacy and safety of an exercise programme and leucine supplementation to increase exercise capacity, muscle mass, and HRQoL in patients with cirrhosis.
Seventeen outpatients with cirrhosis were randomized to an exercise group (n = 8) or a control group (n = 9) in a pilot study. The programme of moderate exercise was performed for 12 weeks under supervision of a physiotherapist. All patients received oral leucine (10 g/day) during the study. At baseline and at the end of the study, we determined exercise capacity (6-min walk and 2-min step tests), anthropometric measurements, and HRQoL by Short Form-36 (SF-36) questionnaire. We also analyzed safety regarding complications of cirrhosis, liver and renal function, inflammatory response and oxidative stress.
In the exercise group, exercise capacity improved, as shown by the increase in the 6-min walk test from 365 (160-420) to 445 m (250-500) (p = 0.01), and in the 2-min step test (p = 0.02). Lower thigh circumference also increased, from 41 (34-53) to 46 cm (36-56) (p = 0.02), and the domains of SF-36 general health (p = 0.03), vitality (p = 0.01) and social function (p = 0.04) improved significantly. In the control group, no statistically significant changes were observed in any of the parameters. We did not observe complications of cirrhosis in either group during the study.
A programme of moderate physical exercise together with leucine supplements in patients with cirrhosis is safe and improves exercise capacity, leg muscle mass and HRQoL.
Digestive Diseases and Sciences 03/2014; · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Terlipressin and albumin is the standard of care for classical type-1 Hepatorenal syndrome (HRS) not associated with active infections. However, there is no information on efficacy and safety of this treatment in patients with type-1 HRS associated with sepsis. Study aim was to investigate the effects of early treatment with terlipressin and albumin on circulatory and kidney function in patients with type-1 HRS and sepsis and assess factors predictive of response to therapy.
Prospective study in 18 consecutive patients with type-1 HRS associated with sepsis.
Treatment was associated with marked improvement in arterial pressure and suppression of the high levels of plasma renin activity and norepinephrine. Response to therapy (serum creatinine<1.5 mg/dL) was achieved in 12/18 patients (67%) and was associated with improved 3-month survival compared to patients without response. Non-responders had significantly lower baseline heart rate, poor liver function tests, slightly higher serum creatinine, and higher Child-Pugh and MELD scores compared to responders. Interestingly, non-responders had higher values of CLIF-SOFA score compared to responders (14±3 vs 8±01,respectively p<0.001), indicating greater severity of acute-on-chronic liver failure (ACLF). A CLIF-SOFA score ⩾11 had 92% sensitivity and 100% specificity in predicting no response to therapy. No significant differences were observed between responders and non-responders in baseline urinary kidney biomarkers. Treatment was safe and no patient required withdrawal of terlipressin.
Early treatment with terlipressin and albumin in patients with type-1 HRS associated with sepsis is effective and safe. Patients with associated severe ACLF are unlikely to respond to treatment.
Journal of Hepatology 01/2014; · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort.
A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (-1774G>del, -1549A>G, -24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5' allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed.
None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 -1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 -1774G/-1549A/-24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI.
Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 -1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility.
PLoS ONE 01/2014; 9(4):e94675. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Episodic hepatic encephalopathy is frequently precipitated by factors that induce circulatory dysfunction, cause oxidative stress-mediated damage or enhance astrocyte swelling. The administration of albumin could modify these factors and improve the outcome of hepatic encephalopathy. The aim of this study is to assess the efficacy of albumin in a multicenter, prospective, double-blind, controlled trial (ClinicalTrials.gov number, NCT00886925).
Cirrhotic patients with an acute episode of hepatic encephalopathy (grade II-IV) were randomized to receive albumin (1.5 g/Kg on day 1 and 1.0 g/Kg on day 3) or isotonic saline, in addition to the usual treatment (laxatives, rifaximin 1200 mg per day). The primary end point was the proportion of patients in which encephalopathy was resolved on day 4. The secondary end points included survival, length of hospital stay and biochemical parameters.
Fifty-six patients were randomly assigned to albumin (n=26) or saline (n=30) stratified by the severity of HE. Both groups were comparable regarding to demographic data, liver function and precipitating factors. The percentage of patients without hepatic encephalopathy at day 4 did not differ between both groups (albumin: 57.7% vs. saline: 53.3%; p > 0.05). However significant differences in survival were found at day 90 (albumin: 69.2% vs. saline: 40.0%; P = 0.02).
Albumin does not improve the resolution of hepatic encephalopathy during hospitalization. However, differences in survival after hospitalization suggest that the development of encephalopathy may identify a subgroup of patients with advanced cirrhosis that may benefit from the administration of albumin.
Journal of Hepatology 07/2013; · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AIMS:: Confirm in patients with cirrhosis and gastrointestinal bleeding the safety of ornithine phenylacetate (OP) and assess the pharmacokinetic profile of OP and its effects on plasma ammonia. BACKGROUND:: OP is a drug that has shown experimentally to decrease hyperammonemia and improve hepatic encephalopathy. OP is safe in healthy subjects and in stable patients with cirrhosis, but there are no data in decompensated cirrhosis. METHODS:: We performed a study to assess safety and tolerance of OP in cirrhotic patients after an episode of upper gastrointestinal bleeding.Ten patients were included within 24 hours of an upper gastrointestinal bleeding. OP was administered as a continuous infusion up to a maximum of 10 g/24 h (0.42 g/h) for 5 days. The infusion was started at 33% of the target dose and increased at 12-hour intervals achieving target dose at 24 hours. Ammonia was also assessed in control group of 10 patients. RESULTS:: No severe adverse events were observed. Mild adverse events were reported in 4 patients. Plasma ammonia (baseline: 80±43 μmol/L) showed a progressive drop between baseline and 36 hours (42±15 μmol/L), 72 hours (44±15 μmol/L), 96 hours (40±24 μmol/L), and 120 hours (33±14 μmol/L). Plasma ammonia at 24 hours was significantly higher in the control group. Plasma glutamine showed a significant decrease (-37% at day 5) and its excretion in urine as phenylacetylglutamine, a progressive rise (52±35 mmol at day 5). CONCLUSIONS:: OP is a safe and well-tolerated drug in decompensated cirrhotics that may decrease plasma ammonia by inducing its appearance as phenylacetylglutamine in urine.
Journal of clinical gastroenterology 06/2013; · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Refractory hepatic encephalopathy (HE) remains a major cause of morbidity in cirrhotic patients. Large spontaneous portosystemic shunts (SPSSs) have been previously suggested to sustain HE in these patients. We aimed to retrospectively assess the efficacy and safety of patients treated with embolization of large SPSSs for the treatment of chronic therapy-refractory HE in a European multicentric working group and to identify patients that may benefit from this procedure. Between July 1998 and January 2012, 37 patients (Child A6-C13, MELD 5-28) with refractory HE were diagnosed with single large SPSSs which were considered eligible for embolization. On a short-term basis (i.e. within 100 days after embolization), 22 out of 37 patients (59.4%) were free of HE (P<0.001 vs before embolization) of which 18 (48.6% of patients overall) remained HE-free over a mean period of follow-up of 697 ± 157 days (P<0.001 vs before embolization). Overall, we noted improved autonomy, decreased number of hospitalizations or severity of the worst HE episode after embolization in three quarters of the patients. Logistic regression identified the MELD-score as strongest positive predictive factor of HE recurrence with a cut-off of 11 for patient selection. As to safety, we noted 1 major non-lethal procedure-related complication. There was no significant increase in de novo development or aggravation of preexisting varices, portal hypertensive gastropathy or ascites. (HEPATOLOGY 2013.).
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND AIMS: Refractory ascites (RA) affects 10% of patients with advanced cirrhosis and ascites. Usual therapy includes large volume paracentesis, and in selected patients, a transjugular portosystemic shunt (TIPS). These therapies may be associated with increased morbidity: paracentesis may induce circulatory dysfunction and impair quality of life and TIPS may induce encephalopathy and is associated with increased mortality in patients with severe liver dysfunction. We present the results of a multicenter, non-randomized trial to assess the safety and efficacy of a new automated pump system for treatment of RA. METHODS: Forty patients at 9 centers (February 2010 to June 2011) received an implanted pump for the automated removal of ascites from the peritoneal cavity into the bladder, from where it was eliminated through normal urination. Patients were followed-up for 6 months. The primary study outcome was safety. Secondary outcomes included recurrence of tense ascites and pump performance. RESULTS: Surgical complications occurred early in the study and became less frequent. The pump system removed 90% of the ascites and significantly reduced the median number of large volume paracentesis per month [3.4 (range 1-6) vs.0.2 (range 0-4); p<0.01]. Cirrhosis-related adverse events decreased along follow-up. CONCLUSIONS: The automated pump seems is an efficacious tool to move out ascites from the peritoeal cavity to the bladder. Its safety is still moderate, but a broad use in different countries will improve the surgical technique as well as the medical surveillance. A prospective randomized clinical trial vs. large volume paracentesis is underway to confirm these preliminary results.
Journal of Hepatology 01/2013; · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases.
High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls.
The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07).
HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.
PLoS ONE 01/2013; 8(7):e68111. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bacterial peritonitis is a severe complication in patients with cirrhosis and ascites and despite antibiotic treatment, the inflammatory response to infection may induce renal dysfunction leading to death. This investigation evaluated the effect of TNF-α blockade on the inflammatory response and mortality in cirrhotic rats with induced bacterial peritonitis treated or not with antibiotics. Sprague-Dawley rats with carbon-tetrachloride-induced cirrhosis were treated with an intraperitoneal injection of 10(9) CFU of Escherichia coli diluted in 20 mL of sterile water to induce bacterial peritonitis and randomized to receive subcutaneously-administered placebo, ceftriaxone, anti-TNF-α mAb and ceftriaxone, or anti-TNF-α mAb alone. No differences were observed between groups at baseline in respect to renal function, liver hepatic tests, serum levels of nitrite/nitrate and TNF-α. Treatment with ceftriaxone reduced mortality (73.3%) but differences did not reach statistical significance as compared to placebo. Mortality in rats treated with ceftriaxone and anti-TNF-α mAb was significantly lower than in animals receiving placebo (53% vs. 100%, p<0.01). Serum TNF-α decreased significantly in surviving rats treated with ceftriaxone plus anti-TNF-α mAb but not in treated with antibiotics alone. Additional studies including more animals are required to assess if the association of antibiotic therapy and TNF-α blockade might be a possible approach to reduce mortality in cirrhotic patients with bacterial peritonitis.
PLoS ONE 01/2013; 8(3):e59692. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Falls are frequent in patients with cirrhosis and cognitive dysfunction and can deteriorate health-related quality of life (HRQoL). OBJECTIVE: To evaluate the relationship between previous falls and HRQoL in patients with cirrhosis. METHODS: We measured HRQoL in 118 outpatients with cirrhosis using the Medical Outcomes Study Short Form (SF-36) questionnaire, grouping items into the Physical Component Score (PCS) and the Mental Component Score (MCS). The incidence of accidental falls in the 12 months before the study was assessed using a specific questionnaire. The Psychometric Hepatic Encephalopathy Score (PHES) was administered to assess cognitive dysfunction. We considered cognitive dysfunction if PHES was less than -4. HRQoL was compared between patients with falls and patients without falls. RESULTS: HRQoL was lower in patients with previous falls than in patients without falls (P<0.05 in all domains of SF-36). In the multivariate analysis, the only independent factors that affected the HRQoL in the PCS were (B coefficient, 95% confidence interval) cognitive dysfunction (6.5, 3.2-9.7, P<0.001), previous variceal bleeding (3.9, 0.4-7.3, P=0.02), anemia (3.2, 0.07-6.4, P=0.049), and hyponatremia (9.3, 1.07-17.5, P<0.02). Multivariate analysis for MCS showed the independent factors for worse HRQoL were female sex (12.2, 6.9-17.5, P<0.001) and previous falls (10.3, 4.0-16.5, P=0.001). CONCLUSION: Falls and cognitive dysfunction are independent factors associated with impaired HRQoL in patients with cirrhosis. Strategies addressed to improve HRQoL in these patients should consider the treatment of cognitive dysfunction and prevention of falls.
European journal of gastroenterology & hepatology 09/2012; · 1.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Entamoeba histolytica antigen assays on stool are widely used to diagnose amebiasis. We report a case of confirmed amebic colitis with a false-negative antigen detection that became positive after treatment. Our results indicate that these assays may underdiagnose acute amebic infection when used alone and should be used cautiously.