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1.
Liver Transpl ; 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34109723

RESUMO

BACKGROUND AND AIMS: AUDIT-10 and its shorter form, AUDIT-C, are questionnaires used to characterize severity of drinking. We hypothesized that liver injury and short-term outcomes of alcohol-associated hepatitis (AH) would correlate with a patient's recent alcohol consumption as determined by AUDIT-10 and -C. METHODS: We analyzed a prospective international database of patients with AH diagnosed based on the NIAAA standard definitions. All subjects were interviewed using AUDIT-10. Primary outcomes included the discriminatory ability of the AUDIT-10 and AUDIT-C scores for predicting survival status at 28 and 90 days and severity of liver injury, as measured by MELD-Na. The relationship between AUDIT scores and survival status was quantified by calculating the area under the curve (AUC) of the receiver operating characteristics (ROC) analysis. The relationship between AUDIT scores and MELD-Na was examined using correlation coefficients. RESULTS: In 245 subjects (age range: 25-75 years) (35% female), we found no correlation between AUDIT-10 or AUDIT-C scores and either 28-day or 90-day mortality. Similarly, there was no correlation between AUDIT-10 and AUDIT-C and MELD-Na scores. There was a strong positive correlation between MELD-Na and 28-day and 90-day mortality. Additional measures of severity of alcohol use (average grams of alcohol consumed per day, years of drinking, convictions for driving under the influence and rehab attempts) and psychosocial factors (marriage, paid employment and level of social support) had no influence on MELD-Na. CONCLUSIONS: In patients presenting with AH, AUDIT-10 and AUDIT-C were not predictors of clinical severity of liver disease nor of short-term mortality, suggesting that level of alcohol consumption in the prior year is not key to the presenting features or outcome of AH.

2.
J Hepatol ; 2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34129887

RESUMO

BACKGROUND & AIMS: Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, because understanding of the molecular drivers leading to death are not well understood. This study evaluates the Hippo/Yes-associated protein (YAP) pathway which has been shown to play a role in liver regeneration. METHOD: The Hippo/YAP pathway was dissected in explants of patients transplanted for AH or alcoholic cirrhosis and in control livers, using RNA-Seq, real-time PCR, Western blot, immunohistochemistry (IHC) and transcriptome analysis after laser microdissection. We transfected primary human hepatocytes with constitutively active YAP (YAPS127A) and treated HepaRG cells and primary hepatocytes isolated from AH livers with a YAP inhibitor. We also used mouse models of ethanol exposure (Lieber de Carli) and liver regeneration (CCl4) after hepatocyte transduction of YAPS127A. RESULTS: In AH samples RNA-Seq analysis and IHC of total liver and microdissected hepatocytes revealed marked down-regulation of Hippo shown by lower MST1 kinase and abnormal activation of YAP in hepatocytes. Overactivation of YAP in hepatocytes in vitro and in vivo led to biliary differentiation and loss of key biological functions such as regeneration capacity. Conversely, treatment of abnormal hepatocytes from AH patients with a YAP inhibitor restored the mature hepatocyte phenotype. In ethanol-fed mice, YAP activation using YAPS127A resulted in a loss of hepatocyte differentiation. Hepatocyte proliferation was hampered using YAPS127A after CCl4 intoxication. CONCLUSION: Aberrant activation of YAP plays an important role in hepatocyte transdifferentiation in AH, through a loss of hepatocyte identity and impaired regeneration. Thus, targeting YAP is a promising strategy for the treatment of patients with AH. LAY SUMMARY: Alcoholic hepatitis (AH) is characterized by inflammation and a life-threatening alteration of liver regeneration by mechanisms that have not been identified. We show that AH livers are characterized by profound deregulation of the Hippo/YAP pathway with uncontrolled activation of the transcription co-factor YAP in hepatocytes. YAP activation in hepatocytes leads to their transdifferentiation towards a biliary phenotype associated with inflammation as well as a regeneration defect. YAP inhibition reverts this hepatocyte defect and appears to be an original therapeutic strategy of regenerative treatment for AH.

3.
Swiss Med Wkly ; 151: w20502, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-34000056

RESUMO

BACKGROUND AND AIM: Acute decompensation and death have been observed in patients with acute hepatitis E virus (HEV) infection and preexisting liver cirrhosis. However, the clinical, laboratory and histological features need to be fully characterised. METHODS: Some of us recently described the histological presentation of hepatitis E in a large panel of liver tissue specimens. Here, we conducted a case-control study to investigate the clinical and laboratory features of the subset of patients with HEV-related acute-on-chronic liver failure (ACLF) and death. Each patient was matched to three control patients with histologically confirmed severe alcoholic hepatitis based on sex, age, total bilirubin, INR, serum creatinine and MELD score on admission. RESULTS: Of 5 patients who died in a context of HEV-related ACLF, 3 (60%) were male and the median age was 66 years (range 51–76). Median alanine aminotransferase (ALT) at presentation was 2610 U/l (range 705–3134) and aspartate aminotransferase (AST) 2818 U/l (range 1176–8611). Liver function was heavily altered in all patients. Histological analyses revealed steatohepatitis on a background of cirrhosis, suggestive of an alcoholic or nonalcoholic origin. Based on histopathology, alcoholic hepatitis was initially suspected in two patients and corticosteroid treatment was initiated. Ribavirin was started in four patients. Median time from hospitalisation to death was 17 days (range 6–25 days). AST levels in patients with HEV-related ACLF were significantly higher as compared to the matched patients with severe alcoholic hepatitis. CONCLUSION: Typical histopathological features of viral hepatitis may be absent in ACLF caused by HEV infection. HEV infection should be sought in acute decompensation of cirrhosis and ACLF even in the absence of histological changes suggesting viral infection.

4.
J Hepatol ; 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34058297

RESUMO

In patients with severe alcoholic hepatitis who are not responding to medical therapy, it is detrimental to postpone the decision to list a patient as there are no therapeutic alternatives. Early transplantation of patients with severe alcoholic hepatitis, using a restrictive selection process, has increasingly been used in the last decade with acceptable relapse rates. Indeed, early transplantation has gained the support of a growing number of experts from different countries, as shown by the European, American and Latin American recommendations. However, there is still great heterogeneity in its application between countries and even between centres within the same country.

5.
Dig Dis Sci ; 2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031802

RESUMO

BACKGROUND: The relationship between the severity of NAFLD and extra-hepatic events such as cardiovascular disease (CVD), extra-hepatic cancer (EHC) or chronic kidney diseases (CKD) has not been clearly investigated in the general population. AIMS: The aim of this study was to assess whether the severity of fibrosis in NAFLD subjects was associated with extra-hepatic diseases based on noninvasive markers in a large population-based cohort. METHODS: The study population included a cohort of 118,664 participants from the nationwide CONSTANCES cohort. After excluding individuals with excessive alcohol consumption and other causes of liver disease, 102,344 were included. The noninvasive diagnosis of NAFLD and fibrosis was performed using a combination of the Fatty Liver Index (FLI) and the Forns Index. The history of CVD or EHC was recorded by a physician, and CKD was defined by a glomerular filtration rate < 60 ml/mn. RESULTS: The prevalence of NAFLD (FLI > 60) was 18.2%, 10% with mild fibrosis (Forns Index < 4.2), 7.7% with intermediate fibrosis (Forns Index 4.2-6.9), and 0.4% with advanced fibrosis (Forns Index > 6.9). The prevalence of CVD, EHC, or CKD increased significantly with the severity of fibrosis (p < 0.0001). When adjusted for demographic, metabolic risk factors, and smoking, NAFLD with intermediate or advanced fibrosis remained associated with CVD (OR 1.36, p < 0.0001 and OR 3.07, p < 0.0001, respectively), EHC (OR 1.24, p = 0.001 and OR 1.64, p = 0.004, respectively), and CKD (OR 1.18, p = 0.03 and OR 2.09, p < 0.0001, respectively). CONCLUSIONS: In a large adult population-based cohort, there is a dose-dependent relationship between the severity of fibrosis and CVD, EHC, or CKD in NAFLD subjects.

6.
Clin Res Hepatol Gastroenterol ; : 101713, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33930591

RESUMO

BACKGROUND & AIMS: The factors predicting hepatocellular carcinoma (HCC) occurrence in chronic hepatitis B need to be precisely known to improve its detection. We identified pathways and individual predictive factors associated with HCC in the ANRS CO22 HEPATHER cohort. METHODS: The study analyzed HBV-infected patients recruited at 32 French expert hepatology centers from August 6, 2012, to December 31, 2015. We excluded patients with chronic HCV, HDV and a history of HCC, decompensated cirrhosis or liver transplantation. Structural equation models were developed to characterize the causal pathways leading to HCC occurrence. The association between clinical characteristics (age, gender, body-mass index, liver fibrosis, alcohol consumption, smoking status, diabetes, hypertension, dyslipidemia, alpha-fetoprotein, HBV DNA levels, antiviral therapy) and incident HCC was quantified. RESULTS: Among the 4,489 patients included, 33 patients reported incident HCC. The median follow-up was 45.2 months. Age (ß = 0.18 by decade, 95% CI 0.14-0.23), male gender (ß = 0.23, 95% CI 0.18-0.29), metabolic syndrome (ß = 0.28, 95% CI 0.22-0.33), alcohol consumption (ß = 0.09, 95% CI 0.05-0.14) and HBV DNA (ß = 0.25, 95% CI 0.17-0.34) had a significant and direct effect on the occurrence of advanced liver fibrosis. Liver fibrosis (ß = 0.71, 95% CI 0.55-0.87) predicted, in turn, the occurrence of HCC. CONCLUSIONS: Liver fibrosis mediates the effects of age, gender, alcohol, metabolic syndrome and HBV DNA on the occurrence of HCC. Elderly men with chronic hepatitis B, risky alcohol use, advanced liver fibrosis, metabolic syndrome and high HBV DNA levels should be monitored closely to detect the development of HCC.

8.
BMC Med ; 19(1): 39, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33593348

RESUMO

BACKGROUND: Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4α activity. METHODS: Factors regulating transferrin expression in alcoholic hepatitis (AH) were assessed via transcriptomic/methylomic analysis as well as chromatin immunoprecipitation coupled to DNA sequencing. The findings were corroborated in primary hepatocytes. Serum and liver samples from 40 patients with advanced liver disease of multiple etiologies were also studied. RESULTS: In patients with advanced liver disease, serum transferrin levels correlated with hepatic transferrin expression (r = 0.51, p = 0.01). Immunohistochemical and biochemical tests confirmed reduced HNF4α and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4α signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGFß1), tumor necrosis factor α (TNFα), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6) negatively associated with transferrin signature. A key regulatory region in transferrin promoter was hypermethylated in patients with AH. In primary hepatocytes, treatment with TGFß1 or the HNF4α inhibitor BI6015 suppressed transferrin production, while exposure to TNFα, IL-1ß, and IL-6 had no effect. The correlation between hepatic HNF4A and transferrin mRNA levels was also seen in advanced liver disease. CONCLUSIONS: Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4α signaling and liver failure.

9.
Hepatology ; 2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33638872
10.
J Hepatol ; 74(6): 1325-1334, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33503489

RESUMO

BACKGROUND & AIMS: In acute severe autoimmune hepatitis (AS-AIH), the optimal timing for liver transplantation (LT) remains controversial. The objectives of this study were to determine early predictive factors for a non-response to corticosteroids and to propose a score to identify patients in whom LT is urgently indicated. METHODS: This was a retrospective, multicenter study (2009-2016). A diagnosis of AS-AIH was based on: i) Definite or probable AIH based on the simplified IAIHG score; ii) international normalized ratio (INR) ≥1.5 and/or bilirubin >200 µmol/L; iii) No previous history of AIH; iv) Histologically proven AIH. A treatment response was defined as LT-free survival at 90 days. The evolution of variables from corticosteroid initiation (day-D0) to D3 was estimated from: Δ%3 = (D3-D0)/D0. RESULTS: A total of 128 patients were included, with a median age of 52 (39-62) years; 72% were female. Overall survival reached 88%. One hundred and fifteen (90%) patients received corticosteroids, with a LT-free survival rate of 66% at 90 days. Under multivariate analysis, D0-INR (odds ratio [OR] 6.85; 95% CI 2.23-21.06; p <0.001), Δ%3-INR ≥0.1% (OR 6.97; 95% CI 1.59-30.46; p <0.01) and Δ%3-bilirubin ≥-8% (OR 5.14; 95% CI 1.09-24.28; p <0.04) were predictive of a non-response. The SURFASA score: -6.80+1.92∗(D0-INR)+1.94∗(Δ%3-INR)+1.64∗(Δ%3-bilirubin), created by combining these variables, was highly predictive of LT or death (AUC = 0.93) (88% specificity; 84% sensitivity) with a cut-off point of <-0.9. Below this cut-off, the chance of responding was 75%. With a score higher than 1.75, the risk of dying or being transplanted was between 85% and 100%. CONCLUSION: In patients with AS-AIH, INR at the introduction of corticosteroids and the evolution of INR and bilirubin are predictive of LT or death. Within 3 days of initiating corticosteroids, the SURFASA score can identify non-responders who require a referral for LT. This score needs to be validated in a prospective cohort. LAY SUMMARY: The management of patients with acute severe autoimmune hepatitis is highly challenging, particularly regarding their early referral for liver transplantation. We found that international normalized ratio at the initiation of corticosteroid therapy and the evolution of international normalized ratio and bilirubin values after 3 days of therapy were highly predictive of liver transplantation or death. We are thus proposing a score that combines these variables and identifies patients in whom liver transplantation is urgently required.

12.
Hepatology ; 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33306215

RESUMO

INTRODUCTION: Because of the extensive use of this drug, further evaluation of acute liver injury with therapeutic doses of acetaminophen (≤6g/day) is required. AIMS: characterize the acute liver injury (ALI) with therapeutic doses (TD) of acetaminophen and determine the host factors associated with disease severity and the predictors of outcome. DESIGN: All patients admitted with severe acetaminophen-related acute liver injury in our center were included from 2002 to 2019, either due to therapeutic doses or overdose. ALITD was defined as acetaminophen intake <6g/day. RESULTS: 311/400 patients with acetaminophen-related ALI had overdose and 89 had taken therapeutic doses. The host factors associated with ALITD were fasting ≥1 day (47.5% of ALITD patients vs. 26% in overdose, p=0.001), excess drinking (93.3 vs. 48.5%, p<0.0001) and repeated acetaminophen use (4 vs. 1 day, p<0.0001). Patients with ALITD were older (44 vs. 30.7 years, p<0.0001) and had more severe liver injury. In the overall population, the independent predictors of disease severity were older age, longer duration of acetaminophen intake and excess drinking. 30-day survival was lower in ALITD than in overdose: 87.2±3.6 vs. 94.6±1.3%, p=0.02. Age and the presence of at least one of the King's College Hospital criteria were independent predictors of 30-day survival while the pattern of drug intoxication, excess drinking and bilirubin were not. CONCLUSION: Acute liver injury with therapeutic doses of acetaminophen is associated with more severe liver injury than overdose. It only occurs in patients with excess drinking and/or fasting. A warning should be issued about the repeated use of nontoxic doses of acetaminophen in patients with those risk factors.

13.
Aliment Pharmacol Ther ; 52(9): 1516-1526, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32931618

RESUMO

BACKGROUND: Body composition may be modified after improvement of portal hypertension (PHT) by transjugular intrahepatic portosystemic shunt (TIPSS) insertion. AIMS: To evaluate changes in body composition following TIPSS placement, their relationship with radiological TIPSS patency and function, and the predictive value of these parameters METHODS: We retrospectively included 179 patients with cirrhosis who underwent TIPSS placement in our centre for severe PHT from 2011 to 2017. CT scan-based surveillance was performed at baseline, 1-3 (M1-M3) and 6 months (M6). RESULTS: The median model for end-stage liver disease (MELD) score was 11.4 (8.8-15.1) and Child-Pugh score 8 (7-9). Only the MELD score (HR 1.14, 95% CI 1.08-1.20) and sarcopenia assessed by transversal right psoas muscle thickness at the umbilical level/height (TPMPT/height) (HR 0.86, 95% CI 0.79-0.96) were independently associated with 6-month mortality on multivariate analysis. After TIPSS insertion, TPMT/height increased from 19 mm/m (baseline) to 19.6 mm/m (M1-M3, P = 0.004) and 21.1 mm/m (M6, P < 0.0001). The improvement and its extent were dependent on the radiological patency and dysfunction of TIPSS. Subcutaneous fat surface (SCFS) increased from 183.4 to 193 cm2 (P < 0.0001) and 229.8 cm2 (P < 0.0001), respectively. We observed a decrease in visceral fat surface (VFS) between baseline and M1-M3 (163.5-140.5 cm2 [P < 0.0001]), but not between M1-M3 and M6 (140.5-141.2 cm2 [P = 0.9]). SCFS and VFS did not seem to be modified by radiological TIPSS patency and dysfunction. CONCLUSIONS: Sarcopenia is independently associated with 6-month outcome and improves after TIPSS placement, together with an inverse evolution of subcutaneous and visceral fat. TIPSS not only treats PHT but also improves body composition.

14.
Liver Int ; 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32881244

RESUMO

BACKGROUND&AIMS: Severely obese patients are a growing population at risk of non-alcoholic fatty liver disease (NAFLD). Considering the increasing burden, a predictive tool of NAFLD progression would be of interest. Our objective is to provide a tool allowing general practitioners to identify and refer the patients most at risk , and specialists to estimate disease progression and adapt the therapeutic strategy. METHODS: This predictive tool is based on a Markov model simulating steatosis, fibrosis and non-alcoholic steatohepatitis (NASH) evolution. This model was developped from data of 1,801 severely obese, bariatric surgery candidates, with histological assessment, integrating duration of exposure to risk factors. It is then able to predict current disease severity in the absence of assessment, and future cirrhosis risk based on current stage. RESULTS: The model quantifies the impact of sex, body-mass index at 20, diabetes, age of overweight onset, on progression. For example, for 40-year-old severely obese patients seen by the general practitioners: (A) non-diabetic woman overweight at 20, and (B) diabetic man overweight at 10, without disease assessment, the model predicts their current risk to have NASH or F3-F4: for (A) 5.7% and 0.6%, for (B) 16.1% and 10.0%, respectively. If those patients have been diagnosed F2 by the specialist, the model predicts the 5-year cirrhosis risk: 1.8% in the absence of NASH and 6.0% in its presence for (A), 10.3% and 26.7%, respectively, for (B). CONCLUSIONS: This model provides a decision-making tool to predict the risk of liver disease that could help manage severely obese patients.

15.
Am J Gastroenterol ; 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868629

RESUMO

INTRODUCTION: Sustained high alcohol intake is necessary but not sufficient to produce alcohol-related cirrhosis. Identification of risk factors, apart from lifetime alcohol exposure, would assist in discovery of mechanisms and prediction of risk. METHODS: We conducted a multicenter case-control study (GenomALC) comparing 1,293 cases (with alcohol-related cirrhosis, 75.6% male) and 754 controls (with equivalent alcohol exposure but no evidence of liver disease, 73.6% male). Information confirming or excluding cirrhosis, and on alcohol intake and other potential risk factors, was obtained from clinical records and by interview. Case-control differences in risk factors discovered in the GenomALC participants were validated using similar data from 407 cases and 6,573 controls from UK Biobank. RESULTS: The GenomALC case and control groups reported similar lifetime alcohol intake (1,374 vs 1,412 kg). Cases had a higher prevalence of diabetes (20.5% (262/1,288) vs 6.5% (48/734), P = 2.27 × 10) and higher premorbid body mass index (26.37 ± 0.16 kg/m) than controls (24.44 ± 0.18 kg/m, P = 5.77 × 10). Controls were significantly more likely to have been wine drinkers, coffee drinkers, smokers, and cannabis users than cases. Cases reported a higher proportion of parents who died of liver disease than controls (odds ratio 2.25 95% confidence interval 1.55-3.26). Data from UK Biobank confirmed these findings for diabetes, body mass index, proportion of alcohol as wine, and coffee consumption. DISCUSSION: If these relationships are causal, measures such as weight loss, intensive treatment of diabetes or prediabetic states, and coffee consumption should reduce the risk of alcohol-related cirrhosis.

16.
Hepatology ; 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32853455

RESUMO

Only a minority of heavy drinkers progress to alcohol-related cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy drinking subjects without known liver disease from Australia, the United States, the United Kingdom and three countries in Europe. Genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, BMI, diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in PNPLA3 (Odds Ratio (OR)=2.19 (G allele), p-value=4.93x10-17 ) and rs4607179 near HSD17B13 (OR=0.57 (C allele), p-value=1.09x10-10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a new protective association at rs374702773 in Fas Associated Factor family member 2 (FAF2) (OR=0.61 (del(T) allele), p-value=2.56x10-8 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR=0.79, p-value=0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the newly identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1, SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a new locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.

17.
Am J Gastroenterol ; 115(10): 1716-1718, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32858566

RESUMO

INTRODUCTION: We investigated the potential hepatotoxicity of lopinavir/ritonavir recently used in the treatment of Severe Acute Respiratory Syndrome Coronavirus. METHODS: This is a retrospective cohort of critical patients in a teaching hospital: 12 treated with lopinavir/ritonavir and 30 in the standard-of-care group. RESULTS: Elevation occurred more frequently in patients treated with lopinavir/ritonavir (33% vs 6.7%). DISCUSSION: Caution is advised regarding the use of lopinavir/ritonavir in the most severe cases of Severe Acute Respiratory Syndrome Coronavirus.


Assuntos
Antivirais/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Icterícia/induzido quimicamente , Lopinavir/efeitos adversos , Pneumonia Viral/tratamento farmacológico , Ritonavir/efeitos adversos , Idoso , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Icterícia/diagnóstico , Icterícia/epidemiologia , Lopinavir/administração & dosagem , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Estudos Prospectivos , Estudos Retrospectivos , Ritonavir/administração & dosagem , Índice de Gravidade de Doença , Padrão de Cuidado/estatística & dados numéricos
18.
Hepatology ; 2020 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-32654263

RESUMO

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD. APPROACH AND RESULTS: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality. CONCLUSIONS: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.

19.
J Hepatol ; 73(6): 1434-1445, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32615276

RESUMO

BACKGROUND & AIMS: Refining hepatocellular carcinoma (HCC) surveillance programs requires improved individual risk prediction. Thus, we aimed to develop algorithms based on machine learning approaches to predict the risk of HCC more accurately in patients with HCV-related cirrhosis, according to their virological status. METHODS: Patients with compensated biopsy-proven HCV-related cirrhosis from the French ANRS CO12 CirVir cohort were included in a semi-annual HCC surveillance program. Three prognostic models for HCC occurrence were built, using (i) Fine-Gray regression as a benchmark, (ii) single decision tree (DT), and (iii) random survival forest for competing risks survival (RSF). Model performance was evaluated from C-indexes validated externally in the ANRS CO22 Hepather cohort (n = 668 enrolled between 08/2012-01/2014). RESULTS: Out of 836 patients analyzed, 156 (19%) developed HCC and 434 (52%) achieved sustained virological response (SVR) (median follow-up 63 months). Fine-Gray regression models identified 6 independent predictors of HCC occurrence in patients before SVR (past excessive alcohol intake, genotype 1, elevated AFP and GGT, low platelet count and albuminemia) and 3 in patients after SVR (elevated AST, low platelet count and shorter prothrombin time). DT analysis confirmed these associations but revealed more complex interactions, yielding 8 patient groups with varying cancer risks and predictors depending on SVR achievement. On RSF analysis, the most important predictors of HCC varied by SVR status (non-SVR: platelet count, GGT, AFP and albuminemia; SVR: prothrombin time, ALT, age and platelet count). Externally validated C-indexes before/after SVR were 0.64/0.64 [Fine-Gray], 0.60/62 [DT] and 0.71/0.70 [RSF]. CONCLUSIONS: Risk factors for hepatocarcinogenesis differ according to SVR status. Machine learning algorithms can refine HCC risk assessment by revealing complex interactions between cancer predictors. Such approaches could be used to develop more cost-effective tailored surveillance programs. LAY SUMMARY: Patients with HCV-related cirrhosis must be included in liver cancer surveillance programs, which rely on ultrasound examination every 6 months. Hepatocellular carcinoma (HCC) screening is hampered by sensitivity issues, leading to late cancer diagnoses in a substantial number of patients. Refining surveillance periodicity and modality using more sophisticated imaging techniques such as MRI may only be cost-effective in patients with the highest HCC incidence. Herein, we demonstrate how machine learning algorithms (i.e. data-driven mathematical models to make predictions or decisions), can refine individualized risk prediction.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32536555

RESUMO

BACKGROUND: Mycophenolate mofetil (MMF) monotherapy following liver transplantation (LT) remains controversial due to a risk of acute rejection. The aim of this study was to report the largest multicenter experience of the use a MMF monotherapy guided by therapeutic drug monitoring using pharmacoslope modeling and Bayesian estimations of the MPA inter-dose AUC (BEAUCMPA) before withdrawing calcineurin inhibitors (CNI) and to evaluate the benefit of MMF monotherapy. METHODS: MMF daily doses were adjusted to reach the BEAUCMPA target of 45µg.h/mL. Then CNI were withdrawn and patients were followed on liver test and clinical outcomes. MAIN FINDINGS: From 2000-2014, in 2 transplantation centers, 94 liver transplant recipients received MMF monotherapy 6.5±4 years after LT. The mean BEAUCMPA was 45.5±16µg.h/mL. During follow-up, 4 patients experienced acute rejection (4%). During the first year, estimated glomerular filtration rate (eGFR) improved from 46.2±10.5 to 49.1±11.5mL/kg/min (P=0.025). Benefit persisted at year 5. In patients with metabolic syndrome, eGFR did not improve. CONCLUSION: MMF monotherapy regimen appears usually safe and beneficial, with low risk of acute rejection and eGFR improvement. Therapeutic drug monitoring strategy seemed useful by identifying 14% of patients with low MMF exposure.

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