Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 150
Filtrar
1.
J Hepatol ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34656649

RESUMO

BACKGROUND & AIMS: Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. METHODS: Three cohorts (GenomALC-1: n=1690, GenomALC-2: n=3037, UK Biobank: relevant n=6898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to eight genetic loci identified previously as associated with alcohol-related cirrhosis and three clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC). RESULTS: A combination of three single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated for cirrhosis risk. The odds ratio (OR) and 95% confidence intervals (CI) for the extreme score quintiles (Q1-Q5) of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18;8.60) (GenomALC-1); 2.81 (2.03;3.89) (GenomALC-2); and 3.10 (2.32;4.14) (UK Biobank). Patients with diabetes and high-risk score, compared to those without diabetes and a low-risk score, had ORs increased to 14.7 (7.69;28.1) (GenomALC-1) and 17.1 (11.3;25.7) (UK Biobank). Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76±0.06 versus 0.61±0.02, p=0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption. CONCLUSIONS: A risk score based on three genetic risk variants and diabetes status can provide meaningful risk stratification for cirrhosis in excess drinkers, allowing earlier prevention planning including intensive intervention. LAY SUMMARY: Excessive chronic drinking leads to liver cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. Our study has developed a genetic risk score (GRS) test that can identify patients at high risk and shows that the risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and high GRS. Risk assessment using this test has potential for early and personalised management of this disease in high-risk patients.

2.
Am J Gastroenterol ; 116(9): 1896-1904, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465693

RESUMO

INTRODUCTION: Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment. METHODS: Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1-6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis). RESULTS: Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0-4: 100%; weeks 5-8: 98.3%; and weeks 9-12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (<90%: 94.4%-100%; <80%: 83.3%-100%). Psychiatric disorders were associated with <80% adherence, and shorter treatment duration was associated with ≥80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of ≥1 day, with an SVR12 rate of 93.9% (31/33). No virologic failures occurred. DISCUSSION: These findings support the impact of treatment duration on adherence rates and further reinforce the concept of "treatment forgiveness" with direct-acting antivirals.


Assuntos
Ácidos Aminoisobutíricos/uso terapêutico , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Ciclopropanos/uso terapêutico , Hepatite C/tratamento farmacológico , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Adesão à Medicação , Prolina/análogos & derivados , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Feminino , Humanos , Leucina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prolina/uso terapêutico , Resposta Viral Sustentada , Resultado do Tratamento
3.
Am J Gastroenterol ; 116(9): 1924-1928, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465694

RESUMO

INTRODUCTION: We evaluated 8, 12, or 24 weeks of ledipasvir/sofosbuvir in patients with hepatitis C virus and end-stage renal disease undergoing dialysis. METHODS: Primary efficacy end point was sustained virologic response 12 weeks after treatment. Primary safety end point was treatment discontinuation because of adverse events (AEs). RESULTS: Ninety-four percent (89/95) achieved sustained virologic response 12 weeks after treatment. Six patients died during treatment (n = 4) or before study completion (n = 2); no deaths were related to treatment. No patients discontinued treatment because of AEs. Thirteen percent had serious AEs; none were related to treatment. DISCUSSION: Treatment with ledipasvir/sofosbuvir was safe and effective in patients with end-stage renal disease undergoing dialysis.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C/tratamento farmacológico , Falência Renal Crônica/terapia , Sofosbuvir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Esquema de Medicação , Feminino , Fluorenos/administração & dosagem , Hepatite C/complicações , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Sofosbuvir/administração & dosagem , Resposta Viral Sustentada , Resultado do Tratamento
4.
Hepatology ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34260763
5.
J Hepatol ; 75(4): 810-819, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34126105

RESUMO

BACKGROUND & AIMS: The SALVE Histopathology Group (SHG) developed and validated a grading and staging system for the clinical and full histological spectrum of alcohol-related liver disease (ALD) and evaluated its prognostic utility in a multinational cohort of 445 patients. METHODS: SALVE grade was described by semiquantitative scores for steatosis, activity (hepatocellular injury and lobular neutrophils) and cholestasis. The histological diagnosis of steatohepatitis due to ALD (histological ASH, hASH) was based on the presence of hepatocellular ballooning and lobular neutrophils. Fibrosis staging was adapted from the Clinical Research Network staging system for non-alcoholic fatty liver disease and the Laennec staging system and reflects the pattern and extent of ALD fibrosis. There are 7 SALVE fibrosis stages (SFS) ranging from no fibrosis to severe cirrhosis. RESULTS: Interobserver κ-value for each grading and staging parameter was >0.6. In the whole study cohort, long-term outcome was associated with activity grade and cholestasis, as well as cirrhosis with very broad septa (severe cirrhosis) (p <0.001 for all parameters). In decompensated ALD, adverse short-term outcome was associated with activity grade, hASH and cholestasis (p = 0.038, 0.012 and 0.001, respectively), whereas in compensated ALD, hASH and severe fibrosis/cirrhosis were associated with decompensation-free survival (p = 0.011 and 0.001, respectively). On multivariable analysis, severe cirrhosis emerged as an independent histological predictor of long-term survival in the whole study cohort. Severe cirrhosis and hASH were identified as independent predictors of short-term survival in decompensated ALD, and also as independent predictors of decompensation-free survival in compensated ALD. CONCLUSION: The SALVE grading and staging system is a reproducible and prognostically relevant method for the histological assessment of disease activity and fibrosis in ALD. LAY SUMMARY: Patients with alcohol-related liver disease (ALD) may undergo liver biopsy to assess disease severity. We developed a system to classify ALD under the microscope by grading ALD activity and staging the extent of liver scarring. We validated the prognostic performance of this system in 445 patients from 4 European centers.

6.
Hepatology ; 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34046927

RESUMO

BACKGROUND AND AIMS: Infection is a major driver of mortality in patients with advanced alcohol-associated liver disease (ALD). The epidemiology and clinical course of patients infected with life-threatening forms of ALD, including severe alcohol-associated hepatitis (sAH) and decompensated alcohol-associated cirrhosis (DAC), and specific risk factors for infection remain mostly unknown. APPROACH AND RESULTS: In this observational study, we assessed all infectious episodes occurring within a 90-day period from diagnosis in all consecutive patients with biopsy-proven sAH (modified Maddrey's discriminant function ≥ 32, Model for End-Stage Liver Disease [MELD] ≥ 18) and DAC (MELD ≥ 18) without alcohol-associated hepatitis in our tertiary hospital between 2003 and 2016. A total of 207 patients were included: 139 with sAH and 68 with DAC. One hundred seventeen (84%) patients with sAH and 41 (60%) patients with DAC experienced at least one infection episode at 90 days (P < 0.001). In multivariable analysis, factors associated with the development of infection were the presence of sAH and baseline MELD score. Bacterial infections represented the most common infection in the two groups, and only the MELD score was independently associated with the occurrence of bacterial infection. In both groups, pneumonia was the most prevalent bacterial infection, and gram-negative bacilli were the main pathogens. Invasive fungal infections (IFI) occurred in 20 (14.5%) patients with sAH and 3 (4.5%) with patients with DAC (P < 0.05). Multivariable regression showed that younger age, higher MELD, and corticosteroid therapy were independently associated with IFI. The 90-day cumulative incidence of death in patients infected with sAH and patients infected with DAC was 46% and 41.5%, respectively (P = 0.43). CONCLUSIONS: Patients with sAH are more susceptible to develop infection than those with DAC. In life-threatening forms of ALD, patients who were infected share a similar mortality rate. Corticosteroid treatment, not sAH, seems to be the main risk factor triggering IFI.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33667676

RESUMO

BACKGROUND & AIMS: Severe alcoholic hepatitis (AH) is a highly lethal condition and it is still a challenge to predict the outcome. We previously identified and validated a composite score of hepatic 123-gene prognostic signature and the model for end-stage liver disease (MELD) score: gene signature-MELD. However, the need for liver biopsy limits its clinical application. Therefore, we aimed to identify a plasma protein-based surrogate of the gene signature and independently validate its prognostic capability. METHODS: All patients were diagnosed with severe AH at Cliniques universitaires de Bruxelles Hôpital Erasme (Brussels, Belgium), and the plasma samples were collected at admission before any treatment. The primary outcome was death or liver transplantation within 90 days. Using our computational pipeline, named translation of tissue expression to secretome (TexSEC), a hepatic-transcriptome-based prognostic signature was converted to a plasma-based secretome signature, which was optimized in 50 patients by comparing their hepatic molecular dysregulation status and combining it with the MELD score. The composite score was validated independently in 57 patients. RESULTS: The TexSEC and optimization process identified a 6-plasma-protein panel as a surrogate for the 123-gene signature. A composite score with the MELD score, the plasma-signature (ps)-MELD score, was created by using the coefficients of the gene signature-MELD equation. In the validation cohort, the high-risk ps-MELD (n = 23; 40%) was associated significantly with death or liver transplantation within 90 days (adjusted hazard ratio, 4.57; 95% CI, 2.15-9.30; P < .001). The ps-MELD score showed a stable, high prognostic association (time-dependent area under receiver operating characteristics curve, >0.80) and was well calibrated over time; it consistently outperformed existing clinical scores as indicated by various model performance indices. CONCLUSIONS: The high-risk ps-MELD score was associated with short-term survival in patients with severe AH.

9.
J Gastroenterol Hepatol ; 36(5): 1366-1377, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33150992

RESUMO

BACKGROUND AND AIM: The aim of this study is to describe the cholangiographic features and endoscopic management of biliary cast syndrome (BCS), a rare specific ischemic cholangiopathy following liver transplantation. METHODS: Patients with biliary complications were identified from prospectively collected database records of patients who underwent liver transplantation at the Erasme Hospital from January 2005 to December 2014. After excluding patients with hepatico-jejunostomy or no suspicion of stricture, cholangiograms obtained during endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance imaging were systematically reviewed. Biliary complications were categorized as anastomotic (AS) and non-AS strictures, and patients with BCS were identified. Clinical, radiological, and endoscopic data were reviewed. RESULTS: Out of 311 liver transplantations, 14 cases were identified with BCS (4.5%) and treated with ERCP. Intraductal hyperintense signal on T1-weighted magnetic resonance and a "duct-in-a-duct" image were the most frequent features of BCS on magnetic resonance imaging. On initial ERCP, 57% of patients had no stricture. Complete cast extraction was achieved in 12/14, and one of these had cast recurrence. On follow-up, 85% of the patients developed biliary strictures that were treated with multiple plastic stents reaching 60% complete stricture resolution, but 40% of them had recurrence. After a median follow-up of 58 months, BCS patients had lower overall and graft survival (42.9% and 42.9%) compared with non-AS (68.8% and 56.3%) and AS (83.3% and 80.6%), respectively. CONCLUSIONS: Particular magnetic resonance-cholangiographic and ERCP-cholangiographic features of BCS have been identified. Outcomes for BCS are characterized by high complete cast extraction rates, high incidence of secondary strictures, and poorer prognosis.

11.
JHEP Rep ; 2(5): 100139, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32775975

RESUMO

Background & Aims: Granulocyte colony-stimulating factor (G-CSF) treatment has been proposed as a therapeutic option for patients with severe alcoholic hepatitis (AH). The aim of this study was to synthesise available evidence on the efficacy of G-CSF in AH. Methods: This is a meta-analysis of randomised controlled trials evaluating the risk of death at 90 days and the risk of infection. Results: Seven studies were included. Of a total of 396 patients, 336 had AH, 197 patients were treated with G-CSF, and 199 received placebo or pentoxifylline. In overall meta-analysis, G-CSF therapy was associated with a reduced risk of death at 90 days (odds ratio [OR] 0.28; 95% CI 0.09-0.88; p = 0.03). There was high heterogeneity between studies (p <0.001; I 2 = 80%). Five studies were performed in Asia and 2 in Europe. In the subgroup analysis of studies performed in Asia, G-CSF was associated with a reduced risk of death (OR 0.15; 95% CI 0.08-0.28; p <0.001; heterogeneity: p = 0.5, I 2 = 0%). In European studies, G-CSF tended to increase mortality compared with controls, although the difference was not significant (OR 1.89; 95% CI 0.90-3.98; p = 0.09; heterogeneity: p = 0.8, I 2 = 0%). In Asian studies, occurrence of infection was less frequent in G-CSF patients than in controls (OR 0.12; 95% CI 0.06-0.23; p <0.001; heterogeneity: p = 0.7, I 2 = 0%), whilst in European studies, this occurrence was not statistically different (OR 0.92; 95% CI 0.50-1.68; p = 0.78; heterogeneity: p = 0.5, I 2 = 0%). In sensitivity analyses, excluding studies that included patients with acute-on-chronic liver failure (ACLF) other than AH, patients with less severe AH, or patients with non-response to corticosteroids, results were similar to those of overall analyses, both for mortality and occurrence of infection. Conclusions: Granulocyte colony-stimulating factor therapy may improve the prognosis of patients with severe AH. However, owing to the high heterogeneity observed in the overall analysis caused by conflicting results between the Asian and European studies, G-CSF cannot currently be recommended for AH, particularly in Europe. Whether these differences can be explained by ethnic differences or disparities in patient selection and disease severity remains unclear. Lay summary: The main finding of this meta-analysis is that the use of granulocyte colony-stimulating factor (G-CSF) is associated with a mortality reduction of more than 70% at 3 months amongst patients with alcoholic hepatitis (AH) compared with controls who did not receive this therapy. However, owing to the high heterogeneity observed in the overall analysis caused by conflicting results between the Asian and European studies, G-CSF cannot currently be recommended for patients with AH, particularly in Europe. Whether these differences can be explained by ethnic differences or disparities in patient selection and disease severity remains unclear.

12.
United European Gastroenterol J ; 8(9): 1003-1012, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32778003

RESUMO

BACKGROUND AND AIM: The alcoholic hepatitis histologic score has been proposed as a new prognostic tool to assess the risk of death in alcoholic hepatitis. We aimed to evaluate its prognostic value in patients with severe alcoholic hepatitis. METHODS: Liver biopsies were analysed independently by two pathologists according to the alcoholic hepatitis histologic score. The Laennec staging system was also used to evaluate fibrosis. RESULTS: One hundred and seven patients were included, and 89% of the patients received corticosteroids. The alcoholic hepatitis histologic score was available in 105 patients. Histologic scoring showed mild, moderate and severe scores in 10, 29 and 66 patients, respectively. Laennec staging was available for 53 patients, among whom 49 had cirrhosis, including 7 with Laennec 4A, 15 with 4B and 27 with 4C. Survival rates in mild, moderate and severe alcoholic hepatitis histologic score groups were 90%, 72% and 69% at 28 days (p = 0.6), 80%, 52% and 63% at 3 months (p = 0.3), and 70%, 41% and 58% at 6 months (p = 0.3), respectively. Within the alcoholic hepatitis histologic score, fibrosis demonstrated the best interobserver reproducibility (agreement = 100%, Κ = 1.00). Compared to patients with Laennec 4B or 4C cirrhosis, survival rates for patients without cirrhosis or with Laennec 4A cirrhosis were 100% vs 83% at 28 days (p = 0.16), 91% vs 68% at 3 months (p = 0.13), and 82% vs 64% at 6 months (p = 0.2), respectively. In multivariate analysis adjusted for age and for model for end-stage liver disease score, the alcoholic hepatitis histologic score and Laennec stage were not associated with 6-month mortality. CONCLUSIONS: The alcoholic hepatitis histologic score is not predictive of short-term survival in this cohort of patients with severe alcoholic hepatitis.

13.
United European Gastroenterol J ; 8(9): 995-1002, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32718222

RESUMO

Alcoholic hepatitis should be suspected in every patient with excessive chronic alcohol consumption and recent onset of jaundice. Diagnosis of alcoholic hepatitis is based on clinical and laboratory findings, and confirmed by a liver biopsy when available. Several scores are available to assess severity and prognosis of alcoholic hepatitis. The 1-month mortality of patients with severe alcoholic hepatitis, as defined by Maddrey's discriminant function, is 20-30%. Therefore, severe alcoholic hepatitis should be treated with a 28-day course of oral prednisolone after systematic screening for infection. In this review, we discuss diagnosis of alcoholic hepatitis, the different scores to assess severity of the disease, indications for corticosteroid therapy and alternative therapeutic options for non-responders to medical therapy.

14.
Expert Rev Gastroenterol Hepatol ; 14(7): 591-600, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32511039

RESUMO

INTRODUCTION: Current management of severe alcoholic hepatitis is based on corticosteroid therapy and abstinence from alcohol. As liver transplantation is lifesaving in alcoholic hepatitis patients at high risk of early death, refractory alcoholic hepatitis has become a new indication for liver transplantation in highly selected non-responders to corticosteroids. AREAS COVERED: This review summarizes the conditions under which liver transplantation may be considered, the available data on liver transplantation for refractory alcoholic hepatitis and explores the ethical considerations surrounding the use of liver transplantation in these patients. EXPERT OPINION: Selection of candidates should be made according to available scientific results on post-liver transplantation outcomes and the risk of alcohol relapse. Currently, a strict selection process based on a good psychosocial profile, including social stability, no previous treatments for alcohol dependence, no current drug use, and no co-existing severe mental disorder, seems to be the best way to manage these issues. Well-defined selection criteria for candidate selection and accurate tools to predict alcohol relapse after liver transplantation are still needed.


Assuntos
Hepatite Alcoólica/cirurgia , Transplante de Fígado , Glucocorticoides/uso terapêutico , Hepatite Alcoólica/tratamento farmacológico , Hepatite Alcoólica/etiologia , Humanos , Transplante de Fígado/ética , Seleção de Pacientes , Fatores de Risco
15.
J Viral Hepat ; 27(10): 974-986, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32396998

RESUMO

Data on the prevalence of resistance-associated substitutions (RASs) and their implications for treatment with direct-acting antivirals (DAAs) are sparse in European patients with HCV genotype 4. This study investigated RASs before and after DAA failure in different genotype 4 subtypes and evaluated retreatment efficacies. Samples of 195 genotype 4-infected patients were collected in the European Resistance Database and investigated for NS3, NS5A and NS5B RASs. Retreatment efficacies in DAA failure patients were analysed retrospectively. After NS5A inhibitor (NS5Ai) failure, subtype 4r was frequent (30%) compared to DAA-naïve patients (5%) and the number of NS5A RASs was significantly higher in subtype 4r compared to 4a or 4d (median three RASs vs no or one RAS, respectively, P < .0001). RASsL28V, L30R and M31L pre-existed in subtype 4r and were maintained after NS5Ai failure. Typical subtype 4r RASs were located in subdomain 1a of NS5A, close to membrane interaction and protein-protein interaction sites that are responsible for multimerization and hence viral replication. Retreatment of 37 DAA failure patients was highly effective with 100% SVR in prior SOF/RBV, PI/SOF and PI/NS5Ai failures. Secondary virologic failures were rare (n = 2; subtype 4d and 4r) and only observed in prior NS5Ai/SOF failures (SVR 90%). In conclusion, subtype 4r harboured considerably more RASs compared to other subtypes. A resistance-tailored retreatment using first- and second-generation DAAs was highly effective with SVR rates ≥90% across all subtypes and first-line treatment regimens.

18.
J Hepatol ; 73(2): 303-314, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32145259

RESUMO

BACKGROUND & AIMS: Severe forms of alcohol-related liver disease are associated with increased susceptibility to infections which are associated with poor prognosis. The cellular and molecular mechanisms responsible for this altered host defense are incompletely understood. METHODS: We performed whole blood phenotypic analysis and ex vivo stimulation with various pathogen-associated molecular patterns (PAMPs). We included 34 patients with alcohol-related cirrhosis (18 of whom had biopsy-proven severe alcoholic hepatitis [sAH]), 12 healthy controls and 11 patients with chronic alcohol consumption without significant liver disease. We also evaluated the transcriptomic (RNA-seq) and chromatin accessibility (ATAC-seq) profiles of CD14+ monocytes from a subset of patients. RESULTS: Circulating monocytes and conventional dendritic cells (DCs) from patients with sAH displayed complex alterations characterized by increased expression of both activating and inhibitory surface markers and an impaired pro-inflammatory response upon stimulation with PAMPs representative of gram-negative bacteria (lipopolysaccharide, Pam3CSK4) or fungal pathogens (Zymosan). Their decreased ability to produce more than 1 cytokine (polyfunctionality) upon PAMP stimulation correlated with the risk of developing infection at 28 days or mortality at 90 days. The presence of acute-on-chronic liver failure in patients with sAH did not significantly modify the immune profile of monocytes and DCs. Moreover, CD14+ monocytes of patients with sAH displayed altered transcriptional and epigenomic profiles characterized by downregulation of key innate immune and metabolic pathways and upregulation of important immunomodulatory factors. CONCLUSIONS: In patients with sAH, the altered transcriptional program and functional properties of monocytes that contribute to patients' susceptibility to infection have strong epigenetic determinants. LAY SUMMARY: Patients with severe alcoholic hepatitis are at increased risk of infections, which contribute to the poor prognosis associated with the disease. Herein, we show that epigenetic determinants underly the immune cell dysfunction and inappropriate responses to pathogens that are associated with severe alcoholic hepatitis.

19.
Health Sci Rep ; 3(1): e146, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32166191

RESUMO

Background: Alcohol-related liver disease (ALD) represents a major cause of death worldwide, and unfortunately, most patients are diagnosed at an advanced stage of the disease, which is related to poorer outcomes. Liver biopsy has historically been the gold standard for identifying advanced hepatic fibrosis, but this approach has several limitations, including invasiveness, low applicability, sampling variability, and cost. Main Text: In order to detect earlier features of advanced liver fibrosis, surrogate biomarkers and techniques have been developed. While these were initially developed for chronic liver diseases such as viral hepatitis and nonalcoholic fatty liver disease (NAFLD), their performance in ALD has also been recently studied. Among the noninvasive surrogate markers and techniques used to detect liver fibrosis, the Enhanced Liver Fibrosis test, FibroTest, and Transient Elastography are the most accurate and validated techniques. In this review, we summarize the current status of the noninvasive assessment of liver disease in ALD and provide a synthesis of how these noninvasive tools can be used in clinical practice. Finally, we briefly outline novel biomarkers that are currently being investigated and discuss future directions and new opportunities in the noninvasive diagnosis of ALD.

20.
Alcohol Clin Exp Res ; 44(4): 856-865, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020641

RESUMO

BACKGROUND: Mitochondria play a fundamental role in the pathogenesis of alcoholic liver disease (ALD). The preservation of functional mitochondria during toxic alcohol insults is essential for cell survival and is maintained by key processes known as mitochondrial dynamics, including fragmentation and fusion, which are regulated by mitochondria-shaping proteins (MSP). We have shown mitochondrial dynamics to be distorted by alcohol in cellular and animal models, but the effect in humans remains unknown. METHODS: Hepatic gene expression of the main MSP involved in the mitochondrial fusion and fragmentation pathways was evaluated in patients with alcoholic hepatitis (AH) by DNA microarray (n = 15) and Reverse Transcription Polymerase Chain Reaction (n = 32). The activation of dynamin-1-like protein (Drp1) was also investigated in mitochondria isolated from liver biopsies of ALD patients (n = 8). The effects of alcohol on mitochondrial dynamics and on MSP protein expression were studied in human precision-cut liver slices (PCLS) exposed for 24 hours to increasing doses of ethanol (EtOH; 50 to 250 mM). RESULTS: A profound hyperactivation of the fragmentation pathway was observed in AH patients, with a significant increase in the expression of Drp1 and its adapters/receptors. The translocation of Drp1 to the mitochondria was also induced in patients with severe ALD and was affected in the PCLS with short-term exposure to EtOH but only mildly. The fusion pathway was not altered in ALD, and this was confirmed in the PCLS model. CONCLUSIONS: The present study reveals the role of mitochondrial dynamics in human ALD, confirming our previous observations in animal and cell culture models of ALD. Taken together, we show that alcohol has a significant impact on the fragmentation pathway, and we confirm Drp1 as a potential therapeutic target in severe ALD.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...