PubMed Health⌕ Search

Biomedical subjects

Dominique Larrey

Publications and source records attributed to Dominique Larrey.

At least 19 recordsLinked to original sources
PubMed2006

The low-density lipoprotein receptor plays a role in the infection of primary human hepatocytes by hepatitis C virus.

BACKGROUND/AIMS: The direct implication of low-density lipoprotein receptor (LDLR) in hepatitis C virus (HCV) infection of human hepatocyte has not been demonstrated. Normal primary human hepatocytes infected by serum HCV were used to document this point. METHODS: Expression and activity of LDLR were assessed by RT-PCR and LDL entry, in the absence or presence of squalestatin or 25-hydroxycholesterol that up- or down-regulates LDLR expression, respectively. Infection was performed in the absence or presence of LDL, HDL, recombinant soluble LDLR peptides encompassing full-length (r-shLDLR4-292) or truncated (r-shLDLR4-166) LDL-binding domain, monoclonal antibodies against r-shLDLR4-292, squalestatin or 25-hydroxycholesterol. Intracellular amounts of replicative and genomic HCV RNA strands used as end point of infection were assessed by RT-PCR. RESULTS: r-shLDLR4-292, antibodies against r-shLDLR4-292 and LDL inhibited viral RNA accumulation, irrespective of genotype, viral load or liver donor. Inhibition was greatest when r-shLDLR4-292 was present at the time of inoculation and gradually decreased as the delay between inoculation and r-shLDLR4-292 treatment increased. In hepatocytes pre-treated with squalestatin or 25-hydroxycholesterol before infection, viral RNA accumulation increased or decreased in parallel with LDLR mRNA expression and LDL entry. CONCLUSIONS: LDLR is involved at an early stage in infection of normal human hepatocytes by serum-derived HCV virions.

Adolescent↗
PubMed2006

Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation.

UNLABELLED: The purpose of the study was to introduce mycophenolate mofetil (MMF) in liver transplant recipients with renal dysfunction to decrease calcineurin inhibitor (CNI) dosages without increasing rejection risk. In this prospective, multicenter, randomized study, chronic CNI-related renal dysfunction was defined by an increase in serum creatinine with values >140 micromol/L and <300 micromol/L. Patients were randomized in 2 groups. STUDY GROUP: combination of MMF (2 to 3 g/day) and reduced dose of CNI >or=50% of initial dose; control group: no MMF, but with the ability to reduce CNI doses, but not below 75% of initial dose. Fifty-six patients were included, 27 in the study group and 29 in the control group. In the study group, there was a significant decrease in serum creatinine values, from 171.7 +/- 24.2 micromol/L at day 0 to 143.4 +/- 19 micromol/L at month 12 and a significant increase in creatinine clearance, from 42.6 +/- 10.9 mL/min to 51.7 +/- 13.8 mL/min. No rejection episode was observed in the study group. In the control group, there was no improvement of renal function, assessed by the changes in serum creatinine values, from 175.4 +/- 23.4 micromol/L at day 0 to 181.6 +/- 63 micromol/L at month 12, and in creatinine clearance, from 42.8 +/- 12.8 mL/min to 44.8 +/- 19.7 mL/min. The differences between the 2 groups were significant: P = 0.001 for serum creatinine, and P = 0.04 for creatinine clearance. In conclusion, the introduction of MMF combined with the reduction of at least 50% of CNI dose allowed the renal function of liver transplant recipients to significantly improve at 1 year, without any rejection episode and without significant secondary effects.

Aged↗
PubMed2005

Drug-induced acute liver failure.

Acute liver failure is the most severe expression and represents the first cause of fatalities related to drugs. As a consequence, it is also the first cause of drug withdrawal from the pharmaceutical market. The incidence of drug-induced hepatotoxicity in the general population has been recently estimated to be around 14/100,000 inhabitants in a Western country. Drugs appear to be responsible for 10-52% of all causes of acute liver failure. In Western countries, paracetamol (acetaminophen) represents the first cause of all liver failures. The contribution of non-paracetamol drugs given at normal doses is equivalent to that of combined viral hepatitis A and B. The natural prognosis varies between drugs. The spontaneous mortality rate ranges from 32% to 50% for paracetamol intoxication and more than 75% for other drugs. The preventive occurrence of drug hepatotoxicity and the course to acute liver failure is rather limited. It is recommended to stop the administration of a suspected drug when alanine aminotransferase levels increase to more than 3-5 times the upper limit of normal. In paracetamol intoxication, the rapid administration of N-acetylcysteine is a classical antidote. At the stage of liver failure, treatment is mostly supportive. Since irreversible damage is unpredictable, early transfer to a transplantation centre should be considered.

Acetaminophen↗
PubMed2005

Are preoperative patterns of alcohol consumption predictive of relapse after liver transplantation for alcoholic liver disease?

Predictive factors for alcoholic relapse after liver transplantation (LT) performed for alcoholic liver disease (ALD) have been assessed in numerous studies, often with contradictory results. The aim of the study was to assess pretransplantation alcohol consumption characteristics on alcoholic relapse after LT. Patients transplanted for ALD for at least 6 months were included. An anonymous questionnaire assessed socio-demographic characteristics, medical history, and alcohol consumption before and after LT. Relapse was defined as any alcohol use after LT. Severe relapse was defined by heavy drinking: more than 21 units/week for males and 14 units/week for females. A total of 61 patients were studied. The mean follow up after LT was 49 +/- 34 months. Alcoholic relapse occurred in 32 of 61 patients (52%) and severe relapse in eight of 61 patients (13%). Risk factors for severe relapse were: length of abstinence before LT (P = 0.0001), more than one alcohol withdrawal before LT (P = 0.001), alcohol dependence (P = 0.05), alcohol abuse in first relatives (P = 0.05), and younger age (P = 0.05). Information on previous alcohol consumption (dependence, number of withdrawals, family history) helps to predict severe relapse after LT in patients with ALD, allowing early awareness and specific postoperative care.

Alcohol Drinking↗
PubMed2005

Hepatic findings in long-term clinical trials of ximelagatran.

OBJECTIVE: In clinical trials, the efficacy and safety of the oral direct thrombin inhibitor ximelagatran have been evaluated in the prevention or treatment of thromboembolic conditions known to have high morbidity and mortality. In these studies, raised aminotransferase levels were observed during long-term use (>35 days). The aim of this analysis is to review the data regarding these hepatic findings in the long-term trials of ximelagatran. PATIENTS AND METHODS: The prospective analysis included 6948 patients randomised to ximelagatran and 6230 patients randomised to comparator (warfarin, low-molecular weight heparin followed by warfarin or placebo). Of these, 6931 patients received ximelagatran for a mean of 357 days and 6216 patients received comparator for a mean of 389 days. An algorithm was developed for frequent testing of hepatic enzyme levels. A panel of four hepatologists analysed all cases of potential concern with regard to causal relation to ximelagatran treatment using an established evaluation tool (Roussel Uclaf Causality Assessment Method [RUCAM]). RESULTS: An elevated alanine aminotransferase (ALT) level of >3 x the upper limit of normal (ULN) was found in 7.9% of patients in the ximelagatran group versus 1.2% in the comparator group. The increase in ALT level occurred 1-6 months after initiation of therapy and data were available to confirm recovery of the ALT level to <2 x ULN in 96% of patients, whether they continued to receive ximelagatran or not. There was some variability in the incidence of ALT level elevation between indications, those with simultaneous acute illnesses (acute myocardial infarction or venous thromboembolism) having higher incidences. Combined elevations of ALT level of >3 x ULN and total bilirubin level of >2 x ULN (within 1 month of the ALT elevation), regardless of aetiology, were infrequent, occurring in 37 patients (0.5%) treated with ximelagatran, of whom one sustained a severe hepatic illness that appeared to be resolving when the patient died from a gastrointestinal haemorrhage. No death was observed directly related to hepatic failure caused by ximelagatran. CONCLUSION: Treatment with ximelagatran has been associated with mainly asymptomatic elevation of ALT levels in a mean of 7.9% of patients in the long-term clinical trial programme and nearly all of the cases occurred within the first 6 months of therapy. Rare symptomatic cases have been observed. An algorithm has been developed for testing ALT to ensure appropriate management of patients with elevated ALT levels. Regular ALT testing should allow the clinical benefits of ximelagatran to reach the widest population of patients while minimising the risk of hepatic adverse effects.

Adult↗
PubMed2004

Risk factors for hepatic decompensation in patients with HIV/HCV coinfection and liver cirrhosis during interferon-based therapy.

OBJECTIVE: Hepatic decompensation was reported from two recent trials (APRICOT and RIBAVIC) assessing interferon (IFN)-based treatment of hepatitis C virus (HCV) in HIV/HCV-coinfected patients. This paper identifies risk factors associated with hepatic decompensation in APRICOT. METHODS: APRICOT is a randomized, partially-blinded, controlled trial comparing treatment with peg-IFN alpha-2a 180 microg once weekly plus ribavirin/placebo 400 mg twice daily with IFN alpha-2a 3 million units three times weekly plus ribavirin 400 mg twice daily for 48 weeks in a total of 859 patients. Multiple logistic regression analysis was performed comparing the baseline characteristics of those cirrhotic patients who experienced decompensation with those of the other cirrhotic patients enrolled. RESULTS: Fourteen patients, all cirrhotic, experienced hepatic decompensation during the study. The incidence in the cirrhotic subgroup of the study was 10.4% (14/134). Six of the 14 patients died as a result of hepatic decompensation. The risk factors associated with hepatic decompensation were increased bilirubin, decreased haemoglobin, increased alkaline phosphatase or decreased platelets, and treatment with didanosine. Markers of viral replication, histological activity, cellular immune status or HCV-therapy, treatment with ribavirin and pegylated versus non-pegylated IFN were not associated with hepatic decompensation. CONCLUSIONS: The results from APRICOT indicate that the overall risk of hepatic decompensation in HIV/HCV-coinfected patients without cirrhosis receiving IFN-based treatment is low. In contrast, patients with markers of advanced cirrhosis, despite the absence of a history of hepatic decompensation, should be monitored closely during IFN-based therapy, because they are at risk of hepatic decompensation. Treatment with antiretrovirals such as didanosine may increase the risk further.

Antiviral Agents↗
PubMed2004

Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance.

During the inflammatory response, intrahepatic cholestasis and decreased drug metabolism are frequently observed. At the hepatic level, the orphan nuclear constitutive androstane receptor (CAR) (NR1I3) controls phase I (cytochrome P450 [CYP] 2B and CYP3A), phase II (UGT1A1), and transporter (SLC21A6, MRP2) genes involved in drug metabolism and bilirubin clearance in response to xenobiotics such as phenobarbital or endobiotics such as bilirubin. We investigated the negative regulation of CAR, a glucocorticoid-responsive gene, via proinflammatory cytokine interleukin 1beta (IL-1beta) and lipopolysaccharides (LPSs) in human hepatocytes. We show that IL-1beta decreases CAR expression and decreases phenobarbital- or bilirubin-mediated induction of CYP2B6, CYP2C9, CYP3A4, UGT1A1, GSTA1, GSTA2, and SLC21A6 messenger RNA. This occurs via nuclear factor kappaB (NF-kappaB) p65 activation, which interferes with the enhancer function of the distal glucocorticoid response element that we have identified recently in the CAR promoter. We demonstrate that: (1) LPSs, IL-1beta, or overexpression of p65RelA inhibit glucocorticoid receptor (GR)-mediated CAR transactivation; (2) these suppressive effects can be blocked both by pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB activation, or by overexpression of SRIkBalpha, a NF-kappaB repressor; and (3) the GR agonist dexamethasone induces histone H4 acetylation at the proximal CAR promoter region, whereas LPSs and IL-1beta inhibit this acetylation as assessed via chromatin immunoprecipitation assay. In conclusion, GR/NF-kappaB interaction affects CAR gene transcription through chromatin remodeling and provide a mechanistic explanation for the long-standing observation that inflammation and sepsis inhibit drug metabolism while inducing intrahepatic cholestasis or hyperbilirubinemia.

Acetylation↗
PubMed2003

[From hepatic steatosis due to obesity to cirrhosis, in the absence of alcoholic intoxication].

FROM STEATOSIS TO CIRRHOSIS: Obesity is frequently associated with steatosis. The latter may provoke inflammatory manifestations and steatohepatitis, the clinical biological and histological characteristics of which are identical to lesions of alcoholic origin. A fibrosis may appear after several years, particularly if the obesity is severe, the patient is elderly and suffering from diabetes and that the increase in transaminase exceeds twice the normal value. It is therefore justified to propose a hepatic biopsy in an obese patient when abnormalities in transaminase levels exceed twice the normal values and notably if other fibrosis risk factors exist. THERAPEUTIC ATTEMPTS: Treatment is aimed at correcting the metabolic disorders and the obesity. Other treatments are currently proposed (anti-oxidants, insulin-resistance modulators), but none of them have presently been completely validated. IN THE FUTURE: With the increase in obesity in industrialised countries, the prevalence of steatosis and steatohepatitis will also increase and there is a risk that they will become, within a few years, one of the principle causes of cirrhosis.

Diagnosis, Differential↗
PubMed2003

Are drugs a risk factor of post-ERCP pancreatitis?

BACKGROUND: Pancreatitis is the most severe complication of ERCP. The aim of this study was to assess whether the use of potentially pancreatotoxic drugs is a risk factor for post-ERCP pancreatitis. METHODS: Risk factors for post-ERCP pancreatitis and all drugs taken during the month before ERCP were recorded retrospectively in a database. Patients with other causes of acute pancreatitis or chronic pancreatitis were excluded from the analysis. Post-ERCP pancreatitis was defined as abdominal pain and/or vomiting associated with amylase/lipase plasma levels equal to or greater than twice the upper normal value. RESULTS: A total of 173 patients (95 men, 78 women; mean age, 68 [16] years) were included. Post-ERCP pancreatitis occurred in 31 patients (18%). Several risk factors were identified in a multivariate analysis: difficulty in cannulation (p<0.001), endoscopic sphincterotomy (p<0.005), and female gender (p=0.02). Having taken potent pancreatotoxic drugs increased the occurrence of post-ERCP pancreatitis: odds ratio 3.7: 95% confidence intervals [1.1,12.4], p=0.04. CONCLUSIONS: Use of pancreatotoxic drugs before or during ERCP significantly increased the risk of post-ERCP pancreatitis. Thus, discontinuation of the use of such drugs before ERCP seems justified whenever possible.

Adolescent↗
PubMed2003

Alcohol relapse after liver transplantation for alcoholic liver disease: does it matter?

BACKGROUND/AIMS: The aim of this study was to distinguish the types of alcohol consumption after liver transplantation (LT) for alcoholic cirrhosis and to assess the consequences of heavy drinking. METHODS: Patients transplanted for alcoholic cirrhosis were studied. Alcoholic relapse diagnosis was based upon patient's and family members' reports, liver enzyme tests, graft biopsy, and use of urine alcohol test. RESULTS: One hundred twenty-eight patients were studied, with a mean follow-up of 53.8 months. After LT, 69% of patients were abstinent, 10% were occasional drinkers, and 21% were heavy drinkers. Actuarial survival rates were not different, but three of the seven deaths observed among heavy drinkers were directly related to alcohol relapse. Although there was no difference between the three groups concerning the rejection rates, all rejection episodes observed in the group of heavy drinkers were related to poor compliance with immunosuppressive drugs. One heavy drinker developed alcoholic cirrhosis. CONCLUSIONS: The present study indicates that patients can resume heavy alcohol consumption after LT for alcoholic liver disease (ALD) and their grafts can be injured because of poor compliance with immunosuppressive drugs and alcohol-related liver injury. Although patient survival was not influenced by alcohol relapse, heavy alcohol consumption can be responsible for patients' death.

Adult↗
PubMed2002

Risk factors for lymphoproliferative disorders after liver transplantation in adults: an analysis of 480 patients.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a well-known complication of organ transplantation that leads to death in more than 50% of cases. The aim of this work was to identify specific risk factors for lymphoproliferative disorders after liver transplantation in adults. METHODS: A total of 480 consecutive patients who underwent transplantation between 1986 and 1997 were studied (323 men, 157 women; mean age: 49.8+/-10.4 years). Demographics, the indication for transplantation, the immunosuppressive regimens, the incidence of rejection episodes, and Epstein-Barr virus infection were analyzed. Univariate and multivariate analysis were used to identify factors predictive of PTLD. RESULTS: Sixteen cases of PTLD (3.3%) occurred at a median of 5.5 (range, 1-39) months after liver transplantation. All 16 cases occurred in patients with evidence of exposure to Epstein-Barr virus before transplantation. In multivariate analysis, the use of antilymphocyte antibodies (P=0.007, relative risk [RR]=4.2, 95% confidence interval [CI]=1.5-11.7), age older than 50 years (P=0.037, RR=3.5, 95% CI=0.95-13.0), liver transplantation for hepatitis C virus cirrhosis (P=0.015, RR=8.7, 95% CI=1-78.3), and liver transplantation for alcoholic cirrhosis (P=0.015, RR=9.6, 95% CI=1.2-77.2) were independently associated with the onset of PTLD. CONCLUSION: Liver transplantation for hepatitis C virus-related and alcoholic cirrhosis and age older than 50 years are three additional risk factors for lymphoproliferative disorder independent of the use of antilymphocyte antibodies. The use of antilymphocyte antibodies after liver transplantation should be avoided in these categories of patients, especially those older than 50 years.

Adult↗
PubMed2002

Epidemiology and individual susceptibility to adverse drug reactions affecting the liver.

Adverse drug reactions affecting the liver represent an important challenge for safety in drug development. Drugs can reproduce practically the whole spectrum of liver diseases, but acute hepatitis is the most common syndrome. Drug hepatotoxicity is one of the most common causes of fulminant hepatitis. Most hepatic drug reactions occur in only a small proportion of individuals, making them difficult to detect at the time of drug development. Liver injury is principally recognized on the basis of spontaneous reports within the first 2 years of marketing a new drug. The prevalence of drug hepatotoxicity is poorly documented by a small number of retrospective studies. Despite the development of international analytical methods to allow standardized evaluation, the diagnosis remains indeterminate in many cases. Acquired and genetic factors influence the individual susceptibility to drug hepatotoxicity. Important directions for the future include prospective studies of the incidence of hepatic adverse drug reactions, finding specific markers that augment or replace causality assessment, and further elucidating the role of the genetic and environmental factors that contribute to individual susceptibility.

Biomarkers↗
PubMed2002

Alpha interferon inhibits hepatitis C virus replication in primary human hepatocytes infected in vitro.

Chronic hepatitis C is a common cause of liver disease, the complications of which include cirrhosis and hepatocellular carcinoma. Treatment of chronic hepatitis C is based on the use of alpha interferon (IFN-alpha). Recently, indirect evidence based on mathematical modeling of hepatitis C virus (HCV) dynamics during human IFN-alpha therapy suggested that the major initial effect of IFN-alpha is to block HCV virion production or release. Here, we used primary cultures of healthy, uninfected human hepatocytes to show that: (i) healthy human hepatocytes can be infected in vitro and support HCV genome replication, (ii) hepatocyte treatment with IFN-alpha results in expression of IFN-alpha-induced genes, and (iii) IFN-alpha inhibits HCV replication in infected human hepatocytes. These results show that IFN-alpha acts primarily through its nonspecific antiviral effects and suggest that primary cultures of human hepatocytes may provide a good model to study intrinsic HCV resistance to IFN-alpha.

Antiviral Agents↗
PubMed2001

Liver transplantation for alcoholic liver disease.

Although increasing numbers of alcoholic patients are being referred to liver transplant centres, liver transplantation for alcoholic liver disease still remains controversial, essentially because we are in an era of organ shortage. In fact, the main issue is the likelihood of relapse and its influence on outcome, because it is the possibility of returning to alcohol use that separates patients with alcoholic liver disease from those with other forms of chronic liver disease. In all proposed clinical guidelines of indications for referral and assessment for liver transplantation for alcoholic liver disease, the authors emphasize the risk of alcoholism recurrence and, thus, a multidisciplinary approach is required to select patients who are likely to comply with follow-up and not return to a damaging pattern of alcohol consumption after transplantation. It emerges from all clinical studies that when we take into account the usual criteria of success for liver transplantation, i.e. patient and graft survival, rejection rate and infection rate, alcoholic liver disease is a good indication for liver transplantation. Predictive factors for alcoholic relapse after liver transplantation have been assessed in numerous studies, often with contradictory results making these difficult to analyse and compare. Several predictive factors for alcoholic relapse have been studied: length of abstinence before transplantation, associated psychiatric problems, social conditions, associated drug addiction, age. Abstinence after transplantation is the goal, but the necessary treatment for alcoholic disease can result in considerable improvement, even when complete abstinence is not achieved. Finally, the good results obtained with liver transplantation for alcoholic liver disease should help us to educate the general population about alcoholic disease.

Journal Article↗