Mise à jour le : 31-07-2010
Les derniers abstracts de la revue Journal of Hepatology : |
Date de mise en ligne : Dimanche 01 août 2010
Editorial Board
Editorial Board
http://www.jhep-elsevier.com/article/PIIS0168827810003910/abstract?rss=yes
Date de mise en ligne : Dimanche 01 août 2010
Mono Istanbul Delta (Colour)
Mono Istanbul Delta (Colour)
http://www.jhep-elsevier.com/article/PIIS0168827810003922/abstract?rss=yes
Date de mise en ligne : Dimanche 01 août 2010
EASL History Book (b/w)
EASL History Book (b/w)
http://www.jhep-elsevier.com/article/PIIS0168827810003934/abstract?rss=yes
Date de mise en ligne : Dimanche 01 août 2010
Fellowship (b/w)
Fellowship (b/w)
http://www.jhep-elsevier.com/article/PIIS0168827810003946/abstract?rss=yes
Date de mise en ligne : Dimanche 01 août 2010
Clinical School of Hepatology (b/w)
Clinical School of Hepatology (b/w)
http://www.jhep-elsevier.com/article/PIIS0168827810003958/abstract?rss=yes
Date de mise en ligne : Dimanche 01 août 2010
Contents
Contents
http://www.jhep-elsevier.com/article/PIIS0168827810003971/abstract?rss=yes
Date de mise en ligne : Mardi 11 mai 2010
Daniel Shouval
Focus
During the last decade, the development of several potentially potent anti-viral agents against hepatitis B virus (HBV) infection was discontinued for a variety of reasons. Among them was Clevudine, a drug which interferes in a number of steps in the HBV replication cycle. Clevudine distinguished itself due to several attractive properties including its sustained suppression of circulating HBV-DNA observed after 24weeks of treatment discontinuation as well as a reduction in intrahepatic cccDNA. Despite these properties, phase III studies came to a halt in most countries due to initially anecdotal reports of Clevudine associated myopathy and fear of mitochondrial toxicity as well as early selection of an rt181T mutation also observed in resistance to lamivudine and adefovir. Yet, following the successful completion of a 24week placebo controlled trial in HBeAg positive and negative HBV patients, Korea, remained the only country in which Clevudine was licensed for chronic HBV infection (CHB). Since 2009, more than 10 reports from Korea appeared in the literature describing various aspects of Clevudine associated myopathy.
Date de mise en ligne : Mardi 20 avril 2010
Heiner Wedemeyer, Mark Thursz
The role of different EASL-papers: Clinical practice guidelines vs. position papers vs. conference summaries
In this month’s issue of the Journal of Hepatology, you will find a paper entitled “A Position Statement on NAFLD/NASH based on the EASL 2009 Special Conferenceâ€. The EASL Governing Board acknowledges the outstanding and timely work of the authors Vlad Ratziu, Stefano Bellentani, Helena Cortez-Pinto, Chris Day, and Giulio Marchesini. We are convinced that this is a very important paper that not only summarizes the current knowledge on fatty liver disease but also defines key areas for future research.
Date de mise en ligne : Mardi 11 mai 2010
Vlad Ratziu
Serum fibrosis markers: Death by validation or a leap of faith?
Before the year 2000, serum fibrosis markers were in an embryonic state of development . Then along came an era of rapid therapeutic advances in viral hepatitis, prompting the clinical need for diagnosing liver fibrosis simply, safely, and in the largest number of candidates for therapy. As a consequence, the past 10 years have witnessed a flurry of publications on newly identified non-invasive fibrosis markers. All of them have reported the area under the receiver operating characteristic curves (AUROC) for significant fibrosis, calculated sensitivity, specificity, and positive and negative predictive values in cross-sectional studies, and as a result, have claimed to be validated. Left with no choice in the past, the clinician is now facing a bewildering situation each time news about a new fibrosis marker is published: what do we call validation, how much validation is needed, and which test can we trust in clinical practice?
Date de mise en ligne : Vendredi 07 mai 2010
Francesco Salerno, Massimo Cazzaniga, Silvia Accordino
May vaptans contribute to the treatment of refractory ascites?
Ascites is one of the most frequent complications of cirrhosis. Indeed, ascites develops in about 50% of cirrhotic patients and in many of them it will become refractory ascites, which is defined as an ascites that cannot be mobilized by the standard therapy with dietary salt restriction and with diuretic medications at doses of up to 160mg/day of furosemide and 400mg/day of spironolactone .
Date de mise en ligne : Jeudi 06 mai 2010
O. Chazouillères
MARS: The ultimate warrior against pruritus of cholestasis?
Pruritus is the most prevalent symptom of cholestasis. Although it is often under-appreciated by physicians, pruritus is more than just an annoyance for patients with cholestasis. It reduces quality of life and can lead to significant disability. When very severe, it may sometimes cause the patient to even contemplate suicide. The pruritus of cholestasis is a difficult clinical problem to manage and current medical treatments accepted as conventional are unsatisfactory in a considerable proportion of cases, causing distress and exasperation to the patient as well as to the doctor . Progress in the study of pruritus has been hampered by two major problems. One is the subjective and multi-dimensional nature of pruritus, which makes objective assessment difficult. The dimensions include: (1) a sensory signal (itch), (2) an emotional reaction (discomfort, stress) and (3) a behavioural response (scratching); the latter two components appear to be susceptible to great individual variability and the former cannot yet be measured. The other major problem is the poorly defined pathogenesis of pruritus in cholestasis. Peripherally acting pruritogens and altered central neurotransmission have been implicated as causing pruritus in cholestasis. Unfortunately, the pruritogen(s) are not yet identified although bile salts, progesterone metabolites, histamine, and endogenous opioids have been proposed to induce pruritus . A new potential player in this field has recently emerged, namely lysophosphatidic acid (LPA) which is a potent neuronal activator and is formed from lysophosphatidylcholine by the enzyme autotoxin (ATX) . Nevertheless, and as a consequence, current anti-pruritic treatments are mostly empirical and not consistently effective.
Date de mise en ligne : Mercredi 05 mai 2010
Patrice Cacoub, Philippe Halfon, Eric Rosenthal, François Bailly, Firouze Bani Sadr, Yves Benhamou, Stéphane Chevaliez, Jean Michel Pawlotsky, Lionel Piroth, Yazdan Yazdanpanah, Stanislas Pol
Care of hepatitis C virus infection in human immunodeficiency virus-infected patients: Modifications in three consecutive large surveys between 2004 and 2009
Background & Aims: To analyze the care of HCV infection in HIV–HCV coinfected patients and its progression between 2004 and 2009.Methods: Three hundred eighty HIV–HCV coinfected patients were prospectively included from November 22 to 29, 2004 (2004 survey), 416 patients from April 3 to 10, 2006 (2006 survey), and 419 patients from June 15 to 22, 2009 (2009 survey).Results: The rate of liver biopsy decreased (14% vs. 38% vs. 56%), while the use of non-invasive liver damage tests increased (47% vs. 24% vs. ND) in the 2009, 2006, and 2004 surveys, respectively. The rate of patients that had never been treated for HCV infection progressively decreased in the 2009, 2006, and 2004 surveys (37%, 42%, and 54%). The main reasons for HCV non-treatment changed as HCV treatment was deemed less questionable and the lack of liver biopsy became a very rare reason (6%, 18%, and 34%). Among patients treated for HCV infection, the rate of sustained virological response increased (49%, 29%, and 29%). The main factors independently associated with HCV treatment were a liver fibrosis score ⩾F2 (odds ratio=3.5; 95% CI 2.1–5.7), a liver biopsy activity grade ⩾A2 (2.7; 1.4–5.3), a CD4 cell count ⩾350ml (2.7; 1.6–4.4), European origin (2.1; 1.3–3.4), daily alcohol consumption<30g (2.1; 1.2–3.8), and male gender (2.0; 1.2–3.3).Conclusion: Compared to the 2004 and 2006 surveys, the 2009 coinfected patients had liver damage assessment more frequently, more patients had received HCV treatment and more patients had achieved a sustained virological response.
Date de mise en ligne : Lundi 26 avril 2010
Paul Calès, Philippe Halfon, Dominique Batisse, Fabrice Carrat, Philippe Perré, Guillaume Penaranda, Dominique Guyader, Louis d’Alteroche, Isabelle Fouchard-Hubert, Christian Michelet, Pascal Veillon, Jérôme Lambert, Laurence Weiss, Dominique Salmon, Patrice Cacoub
Comparison of liver fibrosis blood tests developed for HCV with new specific tests in HIV/HCV co-infection
Background & Aims: We compared 5 non-specific and 2 specific blood tests for liver fibrosis in HCV/HIV co-infection.Methods: Four hundred and sixty-seven patients were included into derivation (n=183) or validation (n=284) populations. Within these populations, the diagnostic target, significant fibrosis (Metavir F ⩾2), was found in 66% and 72% of the patients, respectively. Two new fibrosis tests, FibroMeter HICV and HICV test, were constructed in the derivation population.Results: Unadjusted AUROCs in the derivation population were: APRI: 0.716, Fib-4: 0.722, Fibrotest: 0.778, Hepascore: 0.779, FibroMeter: 0.783, HICV test: 0.822, FibroMeter HICV: 0.828. AUROCs adjusted on classification and distribution of fibrosis stages in a reference population showed similar values in both populations. FibroMeter, FibroMeter HICV and HICV test had the highest correct classification rates in F0/1 and F3/4 (which account for high predictive values): 77–79% vs. 70–72% in the other tests (p=0.002). Reliable individual diagnosis based on predictive values ⩾90% distinguished three test categories: poorly reliable: Fib-4 (2.4% of patients), APRI (8.9%); moderately reliable: Fibrotest (25.4%), FibroMeter (26.6%), Hepascore (30.2%); acceptably reliable: HICV test (40.2%), FibroMeter HICV (45.6%) (p<10−3 between tests). FibroMeter HICV classified all patients into four reliable diagnosis intervals (⩽F1, F1±1, ⩾F1, ⩾F2) with an overall accuracy of 93% vs. 79% (p<10−3) for a binary diagnosis of significant fibrosis.Conclusions: Tests designed for HCV infections are less effective in HIV/HCV infections. A specific test, like FibroMeter HICV, was the most interesting test for diagnostic accuracy, correct classification profile, and a reliable diagnosis. With reliable diagnosis intervals, liver biopsy can therefore be avoided in all patients.
Date de mise en ligne : Mardi 11 mai 2010
Ava John-Baptiste, Murray Krahn, Jenny Heathcote, Audery Laporte, George Tomlinson
The natural history of hepatitis C infection acquired through injection drug use: Meta-analysis and meta-regression
Background & Aims: Our aim was to estimate the rate of progression to cirrhosis for those infected with hepatitis C virus (HCV) through injection drug use.Methods: We searched the published literature for articles assessing cirrhosis in this population and abstracted data on cirrhosis prevalence, mean duration of infection, mean age, mean alanine aminotransferase (ALT) enzyme levels, proportion of males, proportion HIV co-infected, proportion consuming excessive alcohol, and study setting. Summary progression rates were estimated using weighted averages and random effects Poisson meta-regression. The impact of co-variates was assessed by estimating the posterior probability that the relative risk (RR) of progression exceeded 1.0.Results: A total of 47 published articles were identified. After adjusting for covariates in 44 studies representing 6457 patients, the estimated rate of progression to cirrhosis, was 8.1 per 1000 person-years (95% credible region (CR), 3.9–14.7). This corresponds to a 20-year cirrhosis prevalence of 14.8% (95% CR, 7.5–25.5). A 5% increase in the proportion of male participants and a 5% increase in the proportion consuming excessive alcohol were associated with faster progression (probability RR>1=0.97 and 0.92, respectively). A 5% increase in the proportion of HIV co-infected, an increase in ALT of 5IU/L and studies in settings with a high risk of referral bias were not associated with faster progression (probability RR>1=0.42, 0.65, and 0.43, respectively).Conclusions: Analysis of aggregate level data suggests that for patients who contracted HCV through injection drug use prognosis is poor in populations with many male patients and high levels of alcohol consumption.
Date de mise en ligne : Jeudi 22 avril 2010
Matthew Hoare, William T.H. Gelson, Abhi Das, Jean M. Fletcher, Susan E. Davies, Martin D. Curran, Sarah L. Vowler, Mala K. Maini, Arne N. Akbar, Graeme J.M. Alexander
CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection
Background & Aims: Increasing age is associated with impaired immune function and in chronic HCV infection specifically, with progressive fibrosis, liver failure, HCC and impaired responses to antiviral therapy. T-lymphocyte telomere length declines with age. We hypothesised that shorter T-lymphocyte telomere length would be associated with poor clinical outcome in HCV infection.Methods: Circulating T-lymphocyte telomere length, an objective measure of immune senescence, was measured by flow-FISH in 135 HCV-RNA-positive, treatment-naïve patients and 41 healthy controls in relation to clinical outcome.Results: Shorter CD4+CD45RO+ T-lymphocyte telomeres were associated with severe fibrosis (p=0.003), independent of male sex (p=0.04), CMV positivity (p=0.003), previous HBV infection (p=0.007), and age (p=ns) in viraemic patients compared to controls. There were inverse correlations between CD4+CD45RO+ telomere length and fibrosis stage (p<0.001), portal tract inflammatory grade (p=0.035), prothrombin time (p<0.001) and bilirubin (p=0.001). One hundred and twenty-four viraemic individuals were followed prospectively to a composite endpoint of death, hepatic decompensation or HCC. Independent of age, those with shorter CD4+CD45RO+ telomeres were less likely to be complication free after 2-years than those with longer telomeres (86% versus 96%, p=0.009) with an age-adjusted hazard ratio of 0.93 (0.90–0.96). In addition, CD4+CD45RO+ telomere length predicted successful antiviral therapy (p=0.001) independent of other factors.Conclusions: CD4+ T-lymphocyte telomere length, independent of age, was related to inflammatory grade, fibrosis stage, laboratory indices of severity, subsequent hepatic decompensation and treatment outcome in patients with chronic HCV infection.
Date de mise en ligne : Lundi 26 avril 2010
Won Young Tak, Soo Young Park, Chang Min Cho, Min Kyu Jung, Seong Woo Jeon, Young Oh Kweon, Ji Young Park, Yoon Kyung Sohn
Clinical, biochemical, and pathological characteristics of clevudine-associated myopathy
Background & Aims: The aim of this study was to define the clinical, biochemical, and pathological characteristics of myopathy developed during clevudine therapy.Methods: We prospectively enrolled 36 consecutive myopathy patients who were receiving clevudine therapy for the treatment of chronic hepatitis B (CHB). We evaluated patients with a complete medical history, neurologic examination with a questionnaire on neuromuscular diseases, laboratory tests, electrophysiology studies, and muscle biopsies.Results: The median duration of clevudine therapy was 18.0months (ranging from 9 to 24months). The chief complaint was weakness of the lower extremities in 30 patients (83.3%) and asthenia in five patients (13.9%). One patient (2.8%) had only persistently elevated serum muscle enzyme without any symptoms. Weakness of the lower extremity mainly involved proximal muscle group of the lower extremity, characterized by difficulty in climbing stairs (83.3%), a decrease in exercise capacity (75.0%) and difficulty in walking (55.6%). All patients showed an elevation of more than two of serum creatine kinase, lactate dehydrogenase, and lactate levels. Muscle biopsies performed in 23 patients revealed myopathic features with abnormal mitochondria in 21 patients, and nonspecific myositis in two patients. Motor weakness gradually improved after discontinuation of clevudine.Conclusions: Myopathy associated with clevudine is characterized by a weakness in proximal muscles of the lower extremities with elevated muscle enzymes and presumably caused by mitochondrial toxicities. Careful medical and serologic examinations are essential for the early detection and management of this potential adverse reaction in CHB patients under clevudine therapy.
Date de mise en ligne : Mercredi 05 mai 2010
Oliviero Riggio, Lorenzo Ridola, Stefania Angeloni, Federica Cerini, Chiara Pasquale, Adolfo Francesco Attili, Fabrizio Fanelli, Manuela Merli, Filippo Maria Salvatori
Clinical efficacy of transjugular intrahepatic portosystemic shunt created with covered stents with different diameters: Results of a randomized controlled trial
Background & Aims: The incidence of post-TIPS hepatic encephalopathy (HE) could be reduced by using stents with a small diameter. The aim of this study was to compare the incidence of HE and the clinical efficacy of TIPS created with 8- or 10-mm PTFE-covered stents.Methods: Consecutive cirrhotics submitted to TIPS for variceal bleeding or refractory ascites were randomized to receive a 8- or 10-mm covered stent. As recommended by our Ethical Committee, the trial was stopped after the inclusion of 45 patients.Results: The two groups were comparable for age, sex, etiology, and psychometric performance. After TIPS, the portosystemic pressure gradient was significantly higher in the 8-mm stent group (8.9±2.7 versus 6.5±2.7mmHg; p=0.007). Consequently, the probability of remaining free of complications due to portal hypertension was significantly higher in the 10-mm than in the 8-mm stent group: 82.9% versus 41.9% at one year; log-rank test, p=0.002. In particular, the persistence of ascites with the need for repeated paracentesis was significantly more frequent in the patients treated with 8-mm stent diameter for refractory ascites (log-rank test, p=0.008). The probability of remaining free of HE was similar in both groups. Cumulative survival rate was similar in both groups.Conclusions: The use of 8-mm diameter stents for TIPS leads to a significantly less efficient control of complications of portal hypertension. HE remains an unsolved major problem after TIPS.
Date de mise en ligne : Vendredi 21 mai 2010
Puneeta Tandon, Juan G. Abraldes, Annalisa Berzigotti, Juan Carlos Garcia-Pagan, Jaime Bosch
Renin–angiotensin–aldosterone inhibitors in the reduction of portal pressure: A systematic review and meta-analysis
Background & Aims: Renin–angiotensin–aldosterone antagonists [ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), aldosterone antagonists (AA)] are potential therapies for portal hypertension. We evaluated the efficacy and safety of RAAS inhibitors in hepatic venous pressure gradient (HVPG) reduction.Methods: We included full-text controlled trials in patients with cirrhosis and portal hypertension. The primary outcome was mean change in HVPG between treatment and control. Two independent reviewers performed trial selection and quality assessment. An individual patient meta-analysis based on the data of three studies was performed.Results: From 193 citations, 19 controlled trials (n=678) were included. When compared to placebo, ARB/ACEi resulted in significant HVPG reduction. The best quality trials compared ARB/ACEi to beta-blockers (BB). Pooled individual patient data for three of four of these trials showed that BB decreased the HVPG more than ARB/ACEi. In patients with Child Pugh A cirrhosis, the HVPG reduction with ARB/ACEi (−17%; 95% CI: −28 to −6), was similar to that of BB (−21%; 95% CI: −32 to −9). Significant variation in the comparison groups of AA trials precluded pooling. There was no difference in adverse events in any group but selected studies noted adverse hemodynamic effects in decompensated patients on ARB/ACEi.Conclusions: ARB/ACEi reduce portal pressure in patients with Child Pugh A cirrhosis without adverse events. The efficacy and safety in this group may be secondary to a targeted effect on the local hepatic RAAS system, as compared to decompensated patients who risk hypotension and renal insufficiency due to activation of the systemic RAAS. Further studies should determine the potential of these drugs as an alternative or adjunct to BB.
Date de mise en ligne : Lundi 31 mai 2010
Florence Wong, Pere Gines, Hugh Watson, Yves Horsmans, Paolo Angeli, Paul Gow, Pascal Minini, Mauro Bernardi
Effects of a selective vasopressin V2 receptor antagonist, satavaptan, on ascites recurrence after paracentesis in patients with cirrhosis
Background & Aims: Cirrhotic patients with recurrent ascites frequently require paracentesis despite diuretic therapy. Vasopressin receptor antagonists, by increasing free water clearance, may reduce the recurrence of ascites. To investigate the effects of the addition of a vasopressin V2 receptor antagonist, satavaptan, to 100mg spironolactone on ascites recurrence after a large volume paracentesis in patients with liver cirrhosis irrespective of the presence of hyponatraemia.Methods: One hundred and fifty one cirrhotic patients with recurrent ascites with or without hyponatraemia, and normal to mildly abnormal renal function were randomised in a double-blind study to receive either 5mg (n=39), 12.5mg (n=36), 25mg (n=40) of satavaptan or placebo (n=36) for 12weeks. Their Child–Pugh scores were 9.2±1.3, 8.7±1.7, 8.8±1.3, and 9.0±1.5, respectively.Results: Median time to first paracentesis was 23, 26, and 17days with satavaptan 5, 12.5, and 25mg, respectively, versus 14days with placebo (ns for all doses). The frequency of paracenteses was decreased significantly (p<0.05) in all satavaptan groups versus placebo. Mean increase in ascites was 2.82±0.48L/week for placebo versus 2.12±0.40, 2.14±0.33, and 2.06±0.40L/week for the 5, 12.5, and 25mg of satavaptan, respectively (ns for all doses). Similar numbers of patients experienced major adverse events in all groups. Increases in serum creatinine, orthostatic changes in systolic pressure and thirst were more common with satavaptan.Conclusions: Satavaptan has the potential to reduce recurrence of ascites after a large volume paracentesis at doses from 5 to 25mg in cirrhotic patients with ascites.
Date de mise en ligne : Mercredi 05 mai 2010
Valentina Santi, Franco Trevisani, Annagiulia Gramenzi, Alice Grignaschi, Federica Mirici-Cappa, Paolo Del Poggio, Maria Anna Di Nolfo, Luisa Benvegnù, Fabio Farinati, Marco Zoli, Edoardo Giovanni Giannini, Franco Borzio, Eugenio Caturelli, Maria Chiaramonte, Mauro Bernardi, for the Italian Liver Cancer (ITA.LI.CA) Group
Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival
Background & Aims: The current guidelines recommend the surveillance of cirrhotic patients for early diagnosis of hepatocellular carcinoma (HCC), based on liver ultrasonography repetition at either 6 or 12month intervals, since there is no compelling evidence of superiority of the more stringent program. This study aimed at comparing cancer stage, treatment applicability, and survival between patients on semiannual or annual surveillance.Methods: We analyzed the clinical records of 649 HCC patients in Child-Pugh class A or B, observed in ITA.LI.CA centers. HCC was detected in 510 patients submitted to semiannual surveillance (Group 1) and in 139 submitted to annual surveillance (Group 2). In Group 1 the survival was presented as observed and corrected for the lead time.Results: The cancer stage was less severe in Group 1 than in Group 2 (p<0.001), with more single tiny (⩽2cm) and less advanced tumors. Treatment applicability was improved by the semiannual program (p=0.020). The median observed survival was 45months (95% CI 40.0–50.0) in Group 1 and 30months (95% CI 24.0–36.0) in Group 2 (p=0.001). The median corrected survival of Group 1 was 40.3months (95% CI 34.9–45.7) (p=0.028 with respect to the observed survival of Group 2). Age, platelet count, α-fetoprotein, Child-Pugh class, cancer stage, and hepatocellular carcinoma treatment were independent prognostic factors.Conclusions: Semiannual surveillance increases the detection rate of very early hepatocellular carcinomas and reduces the number of advanced tumors as compared to the annual program. This translates into a greater applicability of effective treatments and into a better prognosis.
Date de mise en ligne : Vendredi 14 mai 2010
Ying-Ying Yang, Hongqun Liu, Soon Woo Nam, George Kunos, Samuel S. Lee
Mechanisms of TNFα-induced cardiac dysfunction in cholestatic bile duct-ligated mice: Interaction between TNFα and endocannabinoids
Background & Aims: Chronic liver disease is associated with endotoxemia, oxidative stress, increased endocannabinoids and decreased cardiac responsiveness. Endocannabinoids activate the tumor necrosis factor-alpha (TNFα)–nuclear factor κB (NFκB) pathway. However, how they interact with each other remains obscure. We therefore aimed to clarify the relationship between the TNFα–NFκB pathway and endocannabinoids in the pathogenesis of cardiodepression of cholestatic bile duct ligated (BDL) mice.Methods: BDL mice with TNFα knockout (TNFα−/−) and infusion of anti-TNFα antibody were used. Cardiac mRNA and protein expression of NFκBp65, c-Jun-N-terminal kinases (JNK), p38 mitogen-activated protein kinase (p38MAPK), extracelullar-signal-regulated kinase (ERK), inducible nitric oxide synthase (iNOS), Copper/Zinc and Magnesium-superoxide dismutase (Cu/Zn- and Mn-SOD), cardiac anandamide, 2-arachidonoylglycerol (2-AG), nitric oxide (NOx) and glutathione, and plasma TNFα were measured. The effects of TNFα, cannabinoid receptor (CB1) antagonist AM251 and the endocannabinoid reuptake inhibitor UCM707, on the contractility of isolated cardiomyocytes, were assessed.Results: In BDL mice, cardiac mRNA and protein expression of NFκBp65, p38MAPK, iNOS, NOx, anandamide, and plasma TNFα were increased, whereas glutathione, Cu/Zn-SOD, and Mn-SOD were decreased. Cardiac contractility was blunted in BDL mice. Anti-TNFα treatment in BDL mice decreased cardiac anandamide and NOx, reduced expression of NFκBp65, p38MAPK, and iNOS, enhanced expression of Cu/Zn-SOD and Mn-SOD, increased reductive glutathione and restored cardiomyocyte contractility. TNFα-depressed contractility was worsened by UCM707, whereas AM251 improved contractility.Conclusions: Increased TNFα, acting via NFκB–iNOS and p38MAPK signaling pathways, plays an important role in the pathogenesis of cardiodepression in BDL mice. TNFα also suppressed contractility by increasing oxidative stress and endocannabinoid activity.
Date de mise en ligne : Vendredi 07 mai 2010
Albert Parés, Manuel Herrera, Juan Avilés, Miquel Sanz, Antoni Mas
Treatment of resistant pruritus from cholestasis with albumin dialysis: Combined analysis of patients from three centers
Background & Aims: Albumin dialysis using molecular adsorbent recirculating system (MARS) is a new procedure for treating resistant pruritus from cholestasis, but it is usually published as a case report or a short series. Therefore, we analyzed patients with resistant pruritus treated with MARS from three centers, to assess the changes on pruritus and the indices of cholestasis.Methods: Twenty patients (12 female, mean age: 51±3.4years) with chronic cholestatic liver disease or chronic liver-graft rejection were evaluated. The severity of pruritus was assessed using a visual analogue scale (VAS) before and after treatment, and 30days thereafter. Liver tests, including total bilirubin, alkaline phosphatase, gamma-glutamyl-transferase, cholesterol, triglycerides, and total bile acid were also determined, as well as the number of sessions and the coupled procedure (dialysis or perfusion).Results: Albumin dialysis resulted in a decrease of pruritus (VAS: from 70.2±4.8 to 20.1±4.2, p<0.001), which partially resumed after 30days (38.7±6.6). VAS decreased by 72% immediately after treatment and by 51% after 1month. Pruritus decreased in all but one patient. MARS resulted in a significant bile acid decrease of 41% after treatment and by 37% after 1month. The effect of MARS on pruritus and markers of cholestasis was similar in patients with different diseases and was independent of the coupled procedure. The improvement of pruritus in individuals was positive in 75% of patients. No major adverse effects were observed.Conclusions: Albumin dialysis using MARS is an effective procedure for managing resistant pruritus in most patients with chronic cholestasis and graft rejection.
Date de mise en ligne : Mardi 04 mai 2010
Gerda Rudolph, Daniel Gotthardt, Petra Kloeters-Plachky, Daniel Rost, Hasan Kulaksiz, Adolf Stiehl
In PSC with dominant bile duct stenosis, IBD is associated with an increase of carcinomas and reduced survival
Background & Aims: In patients with primary sclerosing cholangitis (PSC) treated with ursodeoxycholic acid (UDCA), dominant stenoses are associated with reduced survival free of liver transplantation and the role of inflammatory bowel disease (IBD) in such patients is unclear. In the present study the influence of IBD on the outcome in patients with and without dominant stenosis has been evaluated.Methods: In a prospective study, 171 patients were followed for up to 20years. All patients were treated with ursodeoxycholic acid; patients with dominant stenosis in addition were treated endoscopically.Results: A total of 97 out of 171 patients had or developed dominant bile duct stenoses and 96 out of 97 were treated endoscopically. In patients with dominant stenosis without IBD, no carcinoma was found whereas all six bile duct and two gallbladder carcinomas and 6/7 colo-rectal carcinomas were found in patients with dominant stenosis with IBD (p=0.012). In patients without dominant stenosis but with IBD, 1 out of 7 had colo-rectal carcinoma. In patients with dominant stenosis without IBD (n=30), actuarial survival free of liver transplantation at 18years was 77.8% and in those with dominant stenosis and inflammatory bowel disease (n=67) it was 23.0% (p=0.045). In PSC patients without dominant stenosis and without IBD (n=21), actuarial survival free of liver transplantation at 18years was 68.2% and in those with inflammatory bowel disease (n=53) it was 78.4% (n.s.).Conclusions: In patients without dominant stenosis, IBD had no effect on the incidence of carcinomas and survival. Only patients with dominant stenosis with additional IBD had an increased carcinoma rate. This may contribute to the reduced survival free of liver transplantation in such patients.
Date de mise en ligne : Mercredi 12 mai 2010
Motoko Sasaki, Masami Miyakoshi, Yasunori Sato, Yasuni Nakanuma
Modulation of the microenvironment by senescent biliary epithelial cells may be involved in the pathogenesis of primary biliary cirrhosis
Background & aims: Biliary epithelial cells (BECs) in damaged small bile ducts in primary biliary cirrhosis (PBC) show senescent features. Given that senescent cells modulate the microenvironment by expressing senescence-associated secretory phenotypes (SASP), including inflammatory cytokines and chemokines, we investigated the possible involvement of SASP in the pathogenesis of PBC.Methods: We examined the chemokine profiles and the induced migration of RAW264.7 cells in senescent BECs induced by oxidative stress, DNA damage, and serum deprivation. We also immunohistochemically examined the expression of CCL2 and CX3CX1 in livers taken from patients with PBC (n=37) and control livers (n=75).Results: Senescent BECs induced by oxidative stress, DNA damage, or serum deprivation expressed a significantly higher level of chemokines to various degrees, when compared with control BECs. Senescent BECs significantly facilitated the migration of RAW264.7 cells (p<0.01), and neutralizing antibodies against CCL2 and CX3CX1 partially blocked the migration induced by senescent BECs (p<0.01). The expression of CCL2 and CX3CL1 was significantly higher in BECs in inflamed and damaged small bile ducts in PBC, when compared with non-inflamed bile ducts and control livers (p<0.01). The expression of CCL2 and CX3CL1 was co-localized with the expression of senescent markers.Conclusions: Senescent BECs displayed an upregulated expression of various chemokines and chemotactic activities. The expression of CCL2 and CX3CL1 was increased in senescent BECs in PBC. These findings suggest that the senescent BECs may modulate the microenvironment around bile ducts by expressing SASP and contribute to the pathogenesis of bile duct lesions in PBC.
Date de mise en ligne : Jeudi 22 avril 2010
Noriyuki Obara, Koji Fukushima, Yoshiyuki Ueno, Yuta Wakui, Osamu Kimura, Keiichi Tamai, Eiji Kakazu, Jun Inoue, Yasuteru Kondo, Norihiko Ogawa, Kenta Sato, Tsuyoshi Tsuduki, Kazuyuki Ishida, Tooru Shimosegawa
Possible involvement and the mechanisms of excess trans-fatty acid consumption in severe NAFLD in mice
Background & Aims: Excessive trans-fatty acids (TFA) consumption has been thought to be a risk factor mainly for coronary artery diseases while less attention has been paid to liver disease. We aimed to clarify the impact of TFA-rich oil consumption on the hepatic pathophysiology compared to natural oil.Methods: Mice were fed either a low-fat (LF) or high-fat (HF) diet made of either natural oil as control (LF-C or HF-C) or partially hydrogenated oil, TFA-rich oil (LF-T or HF-T) for 24weeks. We evaluated the liver and body weight, serological features, liver lipid content and composition, liver histology and hepatic lipid metabolism-related gene expression profile. In addition, primary cultures of mice Kupffer cells (KCs) were evaluated for cytokine secretion and phagocytotic ability after incubation in cis- or trans-fatty acid-containing medium.Results: The HF-T-fed mice showed significant increases of the liver and body weights, plasma alanine-aminotransferase, free fatty acid and hepatic triglyceride content compared to the HF-C group, whereas the LF-T group did not differ from the LF-C group. HF-T-fed mice developed severe steatosis, along with increased lipogenic gene expression and hepatic TFA accumulation. KCs showed increased tumor necrosis factor secretion and attenuated phagocytotic ability in the TFA-containing medium compared to its cis-isomer.Conclusions: Excessive consumption of the TFA-rich oil up-regulated the lipogenic gene expression along with marked hepatic lipid accumulation. TFA might be pathogenic through causing severe steatosis and modulating the function of KCs. The quantity and composition of dietary lipids could be responsible for the pathogenesis of non-alcoholic steatohepatitis.
Date de mise en ligne : Mercredi 05 mai 2010
Stefano Romeo, Federica Sentinelli, Valentina M Cambuli, Michela Incani, Tiziana Congiu, Vanessa Matta, Sabrina Pilia, Isabel Huang-Doran, Efisio Cossu, Sandro Loche, Marco G Baroni
The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life
Background & aims: Childhood obesity is a growing problem worldwide. Non-alcoholic fatty liver disease (NAFLD) is frequently associated with obesity in children. Recently, the PNPLA3 gene I148M (rs738409) variant was demonstrated to be strongly associated with hepatic steatosis in obese adults. In this study we add further insight into the role of PNPLA3 by exploring whether this association begins early in life in obese children or becomes manifest only in adulthood.Methods: Four hundred and seventy-five obese/overweight children and adolescents were genotyped for the I148M allele. Clinical and biochemical parameters were collected for all participants, including indices of hepatic injury, glucose tolerance and insulin resistance. Ultrasound imaging of the liver was obtained to assess the degree of steatosis in a subset of children.Results: Carriers of two 148M alleles had a 52% increase in circulating ALT levels compared to carriers of two 148I alleles, with individuals with one 148M allele showing a 9.5% increase (p=0.001). AST concentration was also significantly higher in carriers of two and one M alleles (17.4% and 4%, respectively, p=0.022). A total of 36% of carries of two 148M alleles showed elevated ALT, defined as >30U/L, compared to only 10% of carriers of two 148I alleles (p<0.001). Liver steatosis was more prevalent in carriers of two 148M alleles. Glucose tolerance and insulin sensitivity were similar across all three genotypes.Conclusions: Our data show that the PNPLA3 gene I148M variant is associated with increased levels of ALT/AST in obese children and adolescents, suggesting that it confers genetic susceptibility to liver damage from a young age.
Date de mise en ligne : Mercredi 21 avril 2010
Ling Yang, Yixuan Zhang, Lingdi Wang, Fengjuan Fan, Lu Zhu, Zhigang Li, Xiangbo Ruan, Heng Huang, Zhenzhen Wang, Zhihua Huang, Yuliang Huang, Xiaoqiang Yan, Yan Chen
Amelioration of high fat diet induced liver lipogenesis and hepatic steatosis by interleukin-22
Background & Aims: Interleukin-22 (IL-22) is a Th17-related cytokine within the IL-10 family and plays an important role in host defense and inflammatory responses in orchestration with other Th17 cytokines. IL-22 exerts its functions in non-immune cells as its functional receptor IL-22R1 is restricted in peripheral tissues but not in immune cells. It was recently found that IL-22 serves as a protective molecule to counteract the destructive nature of the T cell-mediated immune response to liver damage. However, it is currently unknown whether IL-22 has an effect on lipid metabolism in the liver.Methods: In this study, we demonstrate that IL-22 alleviates hepatic steatosis induced by high fat diet (HFD).Results: Administration of recombinant murine IL-22 (rmIL-22) was able to stimulate STAT3 phosphorylation in HepG2 cells and mouse liver. The activation of STAT3 by rmIL-22 was reduced by the over-expression of a dominant negative IL-22R1. Within hours after rmIL-22 treatment, the expression of lipogenesis-related genes including critical transcription factors and enzymes for lipid synthesis in the liver was significantly down-regulated. The levels of triglyceride and cholesterol in the liver were significantly reduced by long-term treatment of rmIL-22 in C57BL/6 and ob/ob mice fed with HFD. The HFD-induced increases of ALT and AST in ob/ob mice were ameliorated by rmIL-22 treatment. In addition, the expression of fatty acid synthase and TNF-α in the liver was decreased by long-term rmIL-22 administration.Conclusions: Collectively, these data indicate that IL-22, in addition to its known functions in host defense and inflammation, has a protective role in HFD-induced hepatic steatosis via its regulation on lipid metabolism in the liver.
Date de mise en ligne : Mercredi 05 mai 2010
George V. Papatheodoridis, Pietro Lampertico, Spilios Manolakopoulos, Anna Lok
Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: A systematic review
Background & Aims: Chronic hepatitis B patients are at increased risk for hepatocellular carcinoma (HCC). The effect of medium-term nucleos(t)ide analogue therapy on HCC incidence is unclear; therefore, we systematically reviewed all the data on HCC incidence from studies in chronic hepatitis B patients treated with nucleos(t)ide analogues. Methods: We performed a literature search to identify studies with chronic hepatitis B patients treated with nucleos(t)ide analogues for ⩾24months. Results: Twenty-one studies including 3881 treated and 534 untreated patients met our inclusion criteria. HCC was diagnosed in 2.8% and 6.4% of treated and untreated patients, respectively, during a 46 (32–108) month period (p=0.003), in 10.8% and 0.5% of nucleos(t)ide naive patients with and without cirrhosis (p<0.001) and in 17.6% and 0% of lamivudine resistance patients with and without cirrhosis (p<0.001). HCC developed less frequently in nucleos(t)ide naive patients compared to those without virological remission (2.3% vs 7.5%, p<0.001), but there was no difference between lamivudine resistance patients with or without virological response to rescue therapy (5.9% vs 8.8%, p=0.466). Conclusions: Chronic hepatitis B patients receiving medium-term nucleos(t)ide analogue therapy had a significantly lower incidence of HCC compared to untreated patients but treatment does not completely eliminate the risk of HCC. Among the treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC.
Date de mise en ligne : Mardi 04 mai 2010
Dina G. Tiniakos, Apostolos Kandilis, Stephen A. Geller
Tityus: A forgotten myth of liver regeneration
Abstract: The ancient Greek myth of Tityus is related to liver regeneration in the same way as the well known myth of Prometheus is. Depictions of the punishment of Prometheus are frequently used by lecturers on liver regeneration; however, Tityus remains unknown despite the fact that he received the same punishment and his myth could also be used as a paradigm for the organ’s extraordinary ability to regenerate. Nevertheless, there is no convincing evidence that ancient Greeks had any specific knowledge about liver regeneration, a concept introduced in the early 19th century. We describe and analyze the myth of Tityus and compare it to the myth of Prometheus. We also explore artistic and literary links and summarize recent scientific data on the mechanisms of liver regeneration. Finally, we highlight links of the legend of Tityus with other sciences.
Date de mise en ligne : Mercredi 12 mai 2010
Ton Lisman, Stephen H. Caldwell, Andrew K. Burroughs, Patrick G. Northup, Marco Senzolo, R. Todd Stravitz, Armando Tripodi, James F. Trotter, Dominique-Charles Valla, Robert J. Porte, Coagulation in Liver Disease Study Group
Hemostasis and thrombosis in patients with liver disease: The ups and downs
Abstract: Patients with chronic or acute liver failure frequently show profound abnormalities in their hemostatic system. Whereas routine laboratory tests of hemostasis suggest these hemostatic alterations result in a bleeding diathesis, accumulating evidence from both clinical and laboratory studies suggest that the situation is more complex. The average patient with liver failure may be in hemostatic balance despite prolonged routine coagulation tests, since both pro- and antihemostatic factors are affected, the latter of which are not well reflected in routine coagulation testing. However, this balance may easily tip towards a hypo- or hypercoagulable situation. Indeed, patients with liver disease may encounter both hemostasis-related bleeding episodes as well as thrombotic events. During the 3rd International Symposium on Coagulopathy and Liver disease, held in Groningen, The Netherlands (18–19 September 2009), a multidisciplinary panel of experts critically reviewed the current data concerning pathophysiology and clinical consequences of hemostatic disorders in patients with liver disease. Highlights of this symposium are summarized in this review.
Date de mise en ligne : Vendredi 07 mai 2010
Vlad Ratziu, Stefano Bellentani, Helena Cortez-Pinto, Chris Day, Giulio Marchesini
A position statement on NAFLD/NASH based on the EASL 2009 special conference
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are increasingly relevant public health issues owing to their close association with the worldwide epidemics of diabetes and obesity. NAFLD/NASH is one of the most common chronic liver diseases and increases the 5-year direct and indirect health care costs by an estimated 26% . Although evidence-based clinical practice guidelines for this condition are badly needed, currently not enough evidence is available to formulate guidelines in an unbiased, responsible, and unequivocal way. This position statement summarizes the proceedings of the 2009 EASL Special Conference on NAFLD/NASH and proposes expert opinion for different aspects of the clinical care of these patients.
Date de mise en ligne : Vendredi 07 mai 2010
Emmanuel Gonzales, Emmanuel Jacquemin
Mutation specific drug therapy for progressive familial or benign recurrent intrahepatic cholestasis: A new tool in a near future?
Abstract: Deficiency in P-type ATP8B1 is a severe and clinically highly variable hereditary disorder that is primarily characterized by intrahepatic cholestasis. It presents either as a progressive (progressive familial intrahepatic cholestasis type 1 [PFIC1]) or intermittent (benign recurrent intrahepatic cholestasis type 1 [BRIC1]) disease. ATP8B1 deficiency is caused by autosomal recessive mutations in the gene encoding ATP8B1, a putative aminophospholipid-translocating P-type adenosine triphosphatase. The exact pathogenesis of the disease is elusive, and no effective pharmacological therapy is currently available. Here, the molecular consequences of six distinct ATP8B1 missense mutations (p.L127P, p.G308V, p.D454G, p.D554N, p.I661T, and p.G1040R) and one nonsense mutation (p.R1164X) associated with PFIC1 and/or BRIC1 were systematically characterized. Except for the p.L127P mutation, all mutations resulted in markedly reduced ATP8B1 protein expression, whereas messenger RNA expression was unaffected. Five out of seven mutations resulted in (partial) retention of ATP8B1 in the endoplasmic reticulum. Reduced protein expression was partially restored by culturing the cells at 30°C and by treatment with proteasomal inhibitors, which indicates protein misfolding and subsequent proteosomal degradation. Protein misfolding was corroborated by predicting the consequences of most mutations onto a homology model of ATP8B1. Treatment with 4-phenylbutyrate, a clinically approved pharmacological chaperone, partially restored defects in expression and localization of ATP8B1 substitutions G308V, D454G, D554N, and in particular I661T, which is the most frequently identified mutation in BRIC1. Conclusion: A surprisingly large proportion of ATP8B1 mutations resulted in aberrant folding and decreased expression at the plasma membrane. These effects were partially restored by treatment with 4-phenylbutyrate. We propose that treatment with pharmacological chaperones may represent an effective therapeutic strategy to ameliorate the recurrent attacks of cholestasis in patients with intermittent (BRIC1) disease.
Date de mise en ligne : Vendredi 07 mai 2010
Mirjam B. Zeisel, Marine Turek, Thomas F. Baumert
Getting closer to the patient: Upgrade of hepatitis C virus infection in primary human hepatocytes
Abstract: Hepatitis C virus (HCV) remains a major public health problem, affecting approximately 130million people worldwide. HCV infection can lead to cirrhosis, hepatocellular carcinoma, and end-stage liver disease, as well as extrahepatic complications such as cryoglobulinemia and lymphoma. Preventative and therapeutic options are severely limited; there is no HCV vaccine available, and nonspecific, IFN-based treatments are frequently ineffective. Development of targeted antivirals has been hampered by the lack of robust HCV cell culture systems that reliably predict human responses. Here, we show the entire HCV life cycle recapitulated in micro-patterned co-cultures (MPCCs) of primary human hepatocytes and supportive stroma in a multiwell format. MPCCs form polarized cell layers expressing all known HCV entry factors and sustain viral replication for several weeks. When coupled with highly sensitive fluorescence- and luminescence-based reporter systems, MPCCs have potential as a high-throughput platform for the simultaneous assessment of in vitro efficacy and toxicity profiles of anti-HCV therapeutics.
Date de mise en ligne : Mardi 20 avril 2010
Erik Christensen
Glucocorticosteroids in acute alcoholic hepatitis: The evidence of a beneficial effect is getting even weaker
The effect of glucocorticosteroid therapy in acute alcoholic hepatitis has been debated for more than 40years . Although a large number of controlled clinical trials have been performed, there is still insufficient evidence to support glucocorticosteroids for patients with alcoholic hepatitis . Since autoimmunity is not a significant feature of this disease, the rationale behind the use of glucocorticosteroids, is to block cytotoxic and inflammatory pathways . However, the potential side-effects of glucocorticosteroids are numerous including anti-anabolism, muscle breakdown (proteolysis), immunosuppression, increased susceptibility to infection, and increased risk of GI bleeding.
Date de mise en ligne : Vendredi 07 mai 2010
Philippe Mathurin
The use of corticosteroids in severe alcohol hepatitis: We need to look beyond this controversy
The efficacy of corticosteroids in alcoholic hepatitis remains controversial for some authors. Three meta-analyses of the literature, from three different groups, concluded that the survival effect of corticosteroids was restricted to patients with severe disease. Conversely, two other meta-analyses of the literature from the same group questioned the efficacy of corticosteroids in alcoholic hepatitis, regardless of disease severity, although their latest meta-analysis observed that corticosteroids reduced mortality significantly in the subgroup of trials in patients with Maddrey discriminant function ⩾32 or hepatic encephalopathy . Unexpectedly, their latest meta-analysis included some inaccuracies: (i) the authors considered Richardet’s study to be a trial comparing corticosteroids with no treatment, whereas both arms were treated with corticosteroids (information provided by Dr. Richardet); (ii) mortality data in the short-term were mixed with long-term mortality data; and (iii) the authors included a study (Galambos) quoted by another author (Conn) that has never been published even in abstract form.