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BACKGROUND & AIMS: Homozygous ZZ alpha-1 antitrypsin (AAT) deficiency produces mutant AAT (Z-AAT) proteins in hepatocytes, leading to progressive liver fibrosis. We evaluated the safety and efficacy of an investigational RNA interference therapeutic, fazirsiran, that degrades Z-AAT messenger RNA, reducing deleterious protein synthesis. METHODS: This ongoing, phase 2 study randomized 40 patients to subcutaneous placebo or fazirsiran 25, 100, or 200 mg. The primary endpoint was percent change in serum Z-AAT concentration from baseline to week 16. Patients with fibrosis on baseline liver biopsy received treatment on day 1, at week 4, and then every 12 weeks and had a second liver biopsy at or after weeks 48, 72, or 96. Patients without fibrosis received 2 doses on day 1 and at week 4. RESULTS: At week 16, least-squares mean percent declines in serum Z-AAT concentration were -61%, -83%, and -94% with fazirsiran 25, 100, and 200 mg, respectively, vs placebo (all P < .0001). Efficacy was sustained through week 52. At postdose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo. All fazirsiran-treated patients had histologic reduction from baseline in hepatic globule burden. Portal inflammation improved in 5 of 12 and 0 of 8 patients with a baseline score of >0 in the fazirsiran and placebo groups, respectively. Histologic meta-analysis of histologic data in viral hepatitis score improved by >1 point in 7 of 14 and 3 of 8 patients with fibrosis of >F0 at baseline in the fazirsiran and placebo groups, respectively. No adverse events led to discontinuation, and pulmonary function tests remained stable. CONCLUSIONS: Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose-dependent manner and reduced hepatic globule burden. (ClinicalTrials.gov, Number NCT03945292).
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OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. DESIGN: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. RESULTS: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. CONCLUSION: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.
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Colelitiasis/epidemiología , Cirrosis Hepática/epidemiología , Neoplasias Hepáticas/epidemiología , Deficiencia de alfa 1-Antitripsina/complicaciones , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Prevalencia , Reino UnidoRESUMEN
BACKGROUND & AIMS: Corticosteroids are the only effective therapy for severe alcohol-associated hepatitis (AH), defined by a model for end-stage liver disease (MELD) score >20. However, there are patients who may be too sick to benefit from therapy. Herein, we aimed to identify the range of MELD scores within which steroids are effective for AH. METHODS: We performed a retrospective, international multicenter cohort study across 4 continents, including 3,380 adults with a clinical and/or histological diagnosis of AH. The main outcome was mortality at 30 days. We used a discrete-time survival analysis model, and MELD cut-offs were established using the transform-the-endpoints method. RESULTS: In our cohort, median age was 49 (40-56) years, 76.5% were male, and 79% had underlying cirrhosis. Median MELD at admission was 24 (19-29). Survival was 88% (87-89) at 30 days, 77% (76-78) at 90 days, and 72% (72-74) at 180 days. A total of 1,225 patients received corticosteroids. In an adjusted-survival-model, corticosteroid use decreased 30-day mortality by 41% (hazard ratio [HR] 0.59; 0.47-0.74; p <0.001). Steroids only improved survival in patients with MELD scores between 21 (HR 0.61; 0.39-0.95; p = 0.027) and 51 (HR 0.72; 0.52-0.99; p = 0.041). The maximum effect of corticosteroid treatment (21-30% survival benefit) was observed with MELD scores between 25 (HR 0.58; 0.42-0.77; p <0.001) and 39 (HR 0.57; 0.41-0.79; p <0.001). No corticosteroid benefit was seen in patients with MELD >51. The type of corticosteroids used (prednisone, prednisolone, or methylprednisolone) was not associated with survival benefit (p = 0.247). CONCLUSION: Corticosteroids improve 30-day survival only among patients with severe AH, especially with MELD scores between 25 and 39. LAY SUMMARY: Alcohol-associated hepatitis is a condition where the liver is severely inflamed as a result of excess alcohol use. It is associated with high mortality and it is not clear whether the most commonly used treatments (corticosteroids) are effective, particularly in patients with very severe liver disease. In this worldwide study, the use of corticosteroids was associated with increased 30-day, but not 90- or 180-day, survival. The maximal benefit was observed in patients with an MELD score (a marker of severity of liver disease; higher scores signify worse disease) between 25-39. However, this benefit was lost in patients with the most severe liver disease (MELD score higher than 51).
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Consumo de Bebidas Alcohólicas/efectos adversos , Hepatitis/tratamiento farmacológico , Esteroides/administración & dosificación , Factores de Tiempo , Adulto , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Consumo de Bebidas Alcohólicas/fisiopatología , Estudios de Cohortes , Femenino , Hepatitis/etiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Esteroides/uso terapéuticoRESUMEN
Alpha-1 antitrypsin deficiency (AATD) liver disease is characterized by marked heterogeneity in presentation and progression, despite a common underlying gene mutation, strongly suggesting the involvement of other genetic and/or epigenetic modifiers. Variation in clinical phenotype has added to the challenge of detection, diagnosis, and testing of new therapies in patients with AATD. We examined the contribution of DNA methylation (5-methylcytosine [5mC]) to AATD liver disease heterogeneity because 5mC responds to environmental and genetic cues and its deregulation is a major driver of liver disease. Using liver biopsies from adults with early-stage AATD and the ZZ genotype, genome-wide 5mC patterns were interrogated. We compared DNA methylation among patients with early AATD, and among patients with normal liver, cirrhosis, and hepatocellular carcinoma derived from multiple etiologic exposures, and linked patient clinical/demographic features. Global analysis revealed significant genomic hypomethylation in AATD liver-impacting genes related to liver cancer, cell cycle, and fibrosis, as well as key regulatory molecules influencing growth, migration, and immune function. Further analysis indicated that 5mC changes are localized, with hypermethylation occurring within a background of genome-wide 5mC loss and with patients with AATD manifesting distinct epigenetic landscapes despite their mutational homogeneity. By integrating clinical data with 5mC landscapes, we observed that CpGs differentially methylated among patients with AATD disease are linked to hallmark clinical features of AATD (e.g., hepatocyte degeneration and polymer accumulation) and further reveal links to well-known sex-specific effects of liver disease progression. Conclusion: Our data reveal molecular epigenetic signatures within this mutationally homogeneous group that point to ways to stratify patients for liver disease risk.
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Metilación de ADN , Hepatopatías/etiología , Obesidad/complicaciones , Deficiencia de alfa 1-Antitripsina/complicaciones , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Alpha-1 antitrypsin deficiency (AATD)-mediated liver disease is a toxic "gain-of-function" inflammation in the liver associated with intracellular retention of mutant alpha-1 antitrypsin. The clinical presentation of the disease includes fibrosis, cirrhosis and liver failure. However, the pathogenic mechanism of AATD-mediated liver disease is not well understood. Here, we investigated the role of plasma extracellular vesicles (EVs) in progression of AATD-mediated liver disease. METHODS: EVs were isolated from plasma of AATD individuals with liver disease and healthy controls. Their cytokines and miRNA content were examined by multiplex assay and small RNA sequencing. The bioactivity of EVs was assessed by qPCR, western blot analysis and immunofluorescent experiments using human hepatic stellate cells (HSCs) treated with EVs isolated from control or AATD plasma samples. RESULTS: We have found that AATD individuals have a distinct population of EVs with pathological cytokine and miRNA contents. When HSCs were cultured with AATD plasma derived-EVs, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with healthy control plasma EVs. CONCLUSION: AATD individuals have a distinct population of EVs with abnormal cytokine and miRNA contents and the capacity to activate HSCs and mediate fibrosis. Better understanding of the components which cause liver inflammation and fibrogenesis, leading to further liver injury, has the potential to lead to the development of new treatments or preventive strategies to prevent AATD-mediated liver disease. Video abstract.
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Vesículas Extracelulares/patología , Cirrosis Hepática/patología , Hígado/patología , Deficiencia de alfa 1-Antitripsina/patología , Adulto , Anciano , Citocinas/análisis , Vesículas Extracelulares/genética , Femenino , Regulación de la Expresión Génica , Humanos , Hígado/metabolismo , Cirrosis Hepática/sangre , Cirrosis Hepática/complicaciones , Cirrosis Hepática/genética , Masculino , MicroARNs/análisis , MicroARNs/genética , Persona de Mediana Edad , Deficiencia de alfa 1-Antitripsina/sangre , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/genéticaRESUMEN
BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is an uncommonly recognized cause of liver disease in adults, with descriptions of its natural history limited to case series and patient-reported data from disease registries. Liver pathology is limited to selected patients or unavailable. Therefore, we aimed to determine the prevalence and severity of liver fibrosis in an adult AATD population who were not known to have cirrhosis, while defining risk factors for fibrosis and testing non-invasive markers of disease. METHODS: A total of 94 adults with classic genotype 'PI*ZZ' AATD were recruited from North America and prospectively enrolled in the study. Liver aminotransferases and markers of synthetic function, transient elastography, and liver biopsy were performed. RESULTS: The prevalence of clinically significant liver fibrosis (Fâ¯≥â¯2) was 35.1%. Alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase values were higher in the Fâ¯≥â¯2 group. Metabolic syndrome was associated with the presence of clinically significant fibrosis (OR 14.2; 95% CI 3.7-55; p <0.001). Additionally, the presence of accumulated abnormal AAT in hepatocytes, portal inflammation, and hepatocellular degeneration were associated with clinically significant fibrosis. The accuracy of transient elastography to detect Fâ¯≥â¯2 fibrosis was fair, with an AUC of 0.70 (95% CI 0.58-0.82). CONCLUSIONS: Over one-third of asymptomatic and lung affected adults with 'PI*ZZ' AATD have significant underlying liver fibrosis. Liver biopsies demonstrated variable amounts of accumulated Z AAT. The risk of liver fibrosis increases in the presence of metabolic syndrome, accumulation of AAT in hepatocytes, and portal inflammation on baseline biopsy. The results support the hypothesis that liver disease in this genetic condition may be related to a "toxic gain of function" from accumulation of AAT in hepatocytes. LAY SUMMARY: Individuals diagnosed with classic alpha-1 antitrypsin deficiency (ZZ) are at risk of liver injury and scarring, because of the accumulation of abnormal alpha-1 antitrypsin in the liver. A liver biopsy in ZZ individuals can demonstrate the accumulation of alpha-1 antitrypsin within the liver and identify if any associated liver scarring is present. Indviduals with large amounts of alpha-1 antitrypsin on biopsy may be at risk of liver injury and fibrosis. Additional common medical conditions of diabetes, obesity, high cholesterol, and hypertension (known as metabolic syndrome) are associated with a greater degree of liver injury. CLINICAL TRIAL NUMBER: clinicaltrials.gov NCT01810458.
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Cirrosis Hepática/epidemiología , Cirrosis Hepática/etiología , Síndrome Metabólico/complicaciones , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/patología , alfa 1-Antitripsina/metabolismo , Adulto , Anciano , Biopsia , Canadá/epidemiología , Comorbilidad , Estudios Transversales , Diagnóstico por Imagen de Elasticidad , Femenino , Hepatocitos/metabolismo , Humanos , Hígado/patología , Enfermedades Pulmonares Obstructivas/epidemiología , Masculino , Persona de Mediana Edad , Fenotipo , Prevalencia , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Estados Unidos/epidemiología , alfa 1-Antitripsina/genéticaRESUMEN
BACKGROUND & AIMS: Pioglitazone is effective for long-term treatment of patients with nonalcoholic steatohepatitis (NASH) with prediabetes or type 2 diabetes. However, it is not clear how the presence of type 2 diabetes affects the drug's efficacy. We compared metabolic and histologic responses to pioglitazone in patients with NASH and prediabetes vs type 2 diabetes. METHODS: We performed a prospective study of adults with biopsy-proven NASH (52 with type 2 diabetes and 49 with prediabetes), enrolled from the general population of San Antonio, Texas, from 2008 through 2014. After a run-in period of approximately 4 weeks, when all baseline measurements were made (liver magnetic resonance proton spectroscopy, euglycemic insulin clamp with glucose turnover measurements, dual-energy absorptiometry, and liver biopsy), subjects were randomly assigned to groups given pioglitazone or placebo (45 mg/d) for 18 months; all procedures performed at baseline were then repeated. The primary outcome was a reduction in nonalcoholic fatty liver disease activity score of 2 points or more (for at least 2 components) without worsening of fibrosis (and expressed as difference vs placebo). Secondary outcomes included NASH resolution, individual histologic components, intrahepatic triglyceride content (measured by 1H magnetic resonance spectroscopy), and insulin sensitivity (measured by euglycemic insulin clamp). RESULTS: The primary outcome was met by 48% of patients with type 2 diabetes vs 46% without diabetes. Resolution of NASH was achieved in 44% of patients with type 2 diabetes vs 26% without diabetes. A significant reduction in fibrosis, from baseline, was observed only in patients with type 2 diabetes (P = .035). Intrahepatic triglyceride content was reduced by 11% ± 2% in patients with diabetes vs a reduction of 9% ± 2% in patients without diabetes (P = .62); the plasma level of alanine aminotransferase was reduced by 50 ± 10 U/L in patients with diabetes vs a reduction of 36 ± 5 U/L in patients without diabetes (P = .22). Pioglitazone was associated with a significantly greater insulin sensitivity in adipose tissue of patients with diabetes vs without diabetes (P < .001), but nonsignificant differences in responses in hepatic (P = .49) and skeletal muscle (P = .32) insulin sensitivity. CONCLUSIONS: In a prospective study, we found pioglitazone to be effective in patients with and without type 2 diabetes. However, pioglitazone reduced liver fibrosis and increased adipose tissue insulin sensitivity at significantly greater levels in patients with type 2 diabetes than in patients with prediabetes. Further studies are needed to determine the mechanisms by which pioglitazone reduces liver disease in patients with type 2 diabetes. ClinicalTrials.gov: NCT00994682.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Pioglitazona/administración & dosificación , Sustancias Protectoras/administración & dosificación , Adolescente , Adulto , Anciano , Biopsia , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Histocitoquímica , Humanos , Hígado/patología , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Placebos/administración & dosificación , Estudios Prospectivos , Texas , Resultado del Tratamiento , Adulto JovenAsunto(s)
Deficiencia de alfa 1-Antitripsina , Adulto , Estudios de Cohortes , Genotipo , Humanos , FenotipoRESUMEN
BACKGROUND AND AIMS: Patients with alcohol use disorder (AUD) can develop alcohol-associated fatty liver disease (AFLD). However, the impact of AFLD on outcomes remains unclear. We studied the impact of AFLD on readmission, 30-day mortality, and overall mortality in patients admitted with AUD. METHODS: Hospitalized patients with AUD between 2011 and 2019 at a tertiary medical center were retrospectively evaluated. Our population included patients with AUD with AFLD: AST and ALT elevation and serum bilirubin <3â mg/dl. Patients with AUD without evidence of liver disease served as control and were labeled as no ALD. Patients with alcohol-associated cirrhosis (AC) and alcohol-associated hepatitis (AH) were included for comparison. Kaplan-Meier survival analysis and multivariable regression for predictors of mortality and survival were performed. RESULTS: There were 7522 patients of which 32.44% were female with mean age of 51.86â ±â 14.41 years. Patient distribution included no ALD (nâ =â 3775), AFLD (nâ =â 2192), AC (nâ =â 1017) and AH (nâ =â 538) groups. Compared to no ALD group, AFLD group was associated with significantly higher 30-day mortality [4.43% vs. 1.56%, hazard ratio (HR): 2.84; P â <â 0.001], overall mortality [15.97% vs. 12.69%, HR 1.40, P â <â 0.001], and 30-day readmission [21.85% vs. 18.49%, odds ratio: 1.21; P â <â 0.01]. CONCLUSION: We demonstrated that AFLD is not a benign entity and poses significant mortality risk. Our results suggest that AFLD may be under-recognized and highlight the need for focused management and close follow-up after discharge.
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Alcoholismo , Hígado Graso Alcohólico , Hepatitis Alcohólica , Hepatopatías Alcohólicas , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Masculino , Readmisión del Paciente , Estudios Retrospectivos , Hepatopatías Alcohólicas/complicaciones , Hígado Graso Alcohólico/complicaciones , Cirrosis Hepática Alcohólica/diagnóstico , Cirrosis Hepática Alcohólica/complicaciones , Alcoholismo/complicaciones , Alcoholismo/epidemiología , Hepatitis Alcohólica/complicacionesRESUMEN
BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by misfolding and accumulation of mutant alpha-1 antitrypsin (ZAAT) in the endoplasmic reticulum of hepatocytes. Hepatic ZAAT aggregates acquire a toxic gain-of-function that impacts the endoplasmic reticulum which is theorized to cause liver disease in individuals with AATD who present asymptomatic until late-stage cirrhosis. Currently, there is no treatment for AATD-mediated liver disease except liver transplantation. In our study of mitochondrial RNA, we identified that Sirtuin3 (SIRT3) plays a role in the hepatic phenotype of AATD. METHODS: Utilizing RNA and protein analysis in an in vitro AATD model, we investigated the role of SIRT3 in the pathophysiology of AATD-mediated liver disease while also characterizing our novel, transgenic AATD mouse model. RESULTS: We show lower expression of SIRT3 in ZAAT-expressing hepatocytes. In contrast, the overexpression of SIRT3 increases hepatic ZAAT degradation. ZAAT degradation mediated by SIRT3 appeared independent of proteasomal degradation and regular autophagy pathways. We observed that ZAAT-expressing hepatocytes have aberrant accumulation of lipid droplets, with ZAAT polymers localizing on the lipid droplet surface in a direct interaction with Perilipin2, which coats intracellular lipid droplets. SIRT3 overexpression also induced the degradation of lipid droplets in ZAAT-expressing hepatocytes. We observed that SIRT3 overexpression induces lipophagy by enhancing the interaction of Perilipin2 with HSC70. ZAAT polymers then degrade as a consequence of the mobilization of lipids through this process. CONCLUSIONS: In this context, SIRT3 activation may eliminate the hepatic toxic gain-of-function associated with the polymerization of ZAAT, providing a rationale for a potential novel therapeutic approach to the treatment of AATD-mediated liver disease.
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Sirtuina 3 , Deficiencia de alfa 1-Antitripsina , alfa 1-Antitripsina , Animales , Ratones , Deficiencia de alfa 1-Antitripsina/genética , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/metabolismo , Autofagia/genética , Ratones Transgénicos , Polímeros , Sirtuina 3/genética , Humanos , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismoRESUMEN
Telaprevir and boceprevir are the first direct-acting antiviral agents approved for use in HCV treatment and represent a significant advance in HCV therapy. However, these first-generation drugs also have significant limitations related to thrice-daily dosing, clinically challenging side-effect profiles, low barriers to resistance and a lack of pan-genotype activity. A second wave of protease inhibitors are in phase II and III trials and promise to provide a drug regimen with a better dosing schedule and improved tolerance. These second-wave protease inhibitors will probably be approved in combination with PEG-IFN and Ribavirin (RBV), as well as future all-oral regimens. The true second-generation protease inhibitors are in earlier stages of development and efficacy data are anxiously awaited as they may provide pan-genotypic antiviral activity and a high genetic barrier to resistance.
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Antivirales/uso terapéutico , Proteínas Portadoras/antagonistas & inhibidores , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Inhibidores de Serina Proteinasa/uso terapéutico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/efectos adversos , Antivirales/química , Proteínas Portadoras/metabolismo , Diseño de Fármacos , Farmacorresistencia Viral , Quimioterapia Combinada , Hepacivirus/enzimología , Hepacivirus/genética , Hepatitis C/diagnóstico , Humanos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Ribavirina/uso terapéutico , Inhibidores de Serina Proteinasa/efectos adversos , Inhibidores de Serina Proteinasa/química , Resultado del Tratamiento , Proteínas no Estructurales Virales/metabolismoRESUMEN
BACKGROUND/AIMS: Interleukin-28B (IL-28B) polymorphism is the strongest pretreatment predictor of viral clearance in the hepatitis C (HCV) population. Donor and recipient IL-28B genomic background may play an important role in post-transplant HCV recurrence. We sought to examine the role of IL-28B polymorphisms of donor and recipients in liver transplant patients with recurrent HCV and its impact on the response to interferon-based therapy. METHODS: The cohort study consisted of 135 adult liver transplant patients who received interferon-based therapy for recurrent HCV between 1996 and 2005 at the University of Florida. IL-28B single nucleotide polymorphism (rs. 12979860) was characterized using liver tissue from all donors and recipients. RESULTS: The CC genotype was observed in approximately 30% of donors and recipients. Sustained viral response (SVR) to HCV therapy was 100% if both recipient and donor were CC genotype, while the SVR was only 25% if neither donor nor recipient had a CC genotype. (Recipient, P = 0.025, Donor, P < 0.001). Recipients and donors with CC genotype had less fibrosis than recipients with genotypes CT and TT, but the difference was not statistically significant. IL-28B genotype did not seem to play a role in the overall survival in these patients. CONCLUSION: In conclusion, recipient and donor CC genotype is associated with a better treatment response to interferon-based therapy after liver transplant. Our study suggests that using CC genotype donor livers for HCV patients may improve the overall clinical outcome after liver transplantation.
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Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Interleucinas/genética , Cirrosis Hepática/cirugía , Trasplante de Hígado , Polimorfismo de Nucleótido Simple , Donantes de Tejidos , Anciano , Biopsia , Femenino , Florida , Genotipo , Hepatitis C/complicaciones , Hepatitis C/diagnóstico , Hepatitis C/genética , Hepatitis C/inmunología , Hepatitis C/mortalidad , Humanos , Interferones , Estimación de Kaplan-Meier , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/mortalidad , Cirrosis Hepática/virología , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIM: The goal of this study is to evaluate whether an elevated neutrophil-lymphocyte ratio (NLR) at the time of diagnosis predicts survival of patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). We hypothesize that the NLR is predictive of overall survival (OS) and recurrence-free survival (RFS) in patients with HCC who undergo LT. METHODS: This is a retrospective analysis of adult patients undergoing LT for HCC between 2000 and 2008 at our institution. We define an elevated NLR as a ratio of 5 or greater. RESULTS: We included 160 patients who underwent LT for HCC in the time period, of whom 28 had an elevated NLR. Seventeen subjects experienced recurrent HCC during the study period. The cumulative survival among subjects with an elevated NLR was significantly lower than among subjects with a normal NLR. On univariate analysis, several factors (including an elevated NLR) predicted decreased OS and RFS. However, after multivariate analysis, only three factors (including elevated NLR) remained significant as predictors of OS. Additionally, multivariate analysis revealed that an elevated NLR was the only significant independent predictor of RFS. CONCLUSION: Preoperative NLR is a powerful independent predictor of OS and RFS in patients undergoing LT for HCC. Measurement of NLR could serve as a useful and easily obtained adjunct to the Model for End-Stage Liver Disease score and Milan criteria when evaluating this patient population and determining which patients will gain the most survival benefit from transplantation.
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BACKGROUND: Preservation injury in the HCV liver transplant population has been reported to correlate with poorer survival outcomes compared to preservation injury in the non-HCV liver transplant population. However, determinants of progression to cirrhosis in HCV infection remain poorly defined in this population. AIM: This study aimed to determine if the presence and severity of preservation injury impact the acceleration of HCV recurrence and survival after liver transplant. METHODS: We retrospectively reviewed liver transplant HCV patients over a 10-year period. Biopsies from postoperative day 7 were assessed for preservation injury and 4- and 12-month biopsies were assessed for fibrosis. Patients with Ishak fibrosis >0.8 Units/year were considered rapid fibrosers. RESULTS: Our study group consisted of 255 patients. The mean age was 49.3 years old, 180 (70.6 %) were male, and 221 (86.7 %) were Caucasian. The incidence of preservation injury on the 7-day biopsy was 69.0 %. A strong correlation between postoperative peak AST within the first week and preservation injury was found. The overall prevalence of rapid fibrosers at 4 months, 1 and 2 years was 47.4, 75.2, and 58.9 %, respectively. The prevalence of rapid fibrosers at 4 months, 1 and 2 years between patients with or without preservation injury was not statistically significant (p = 0.39, p = 0.46, and p = 0.53, respectively). No differences were seen between patients with and without PI in terms of patient and graft survival. CONCLUSION: In this study, the presence and severity of preservation injury were not associated with development of rapid HCV recurrence or worsening in survival.
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Hepatitis C/etiología , Trasplante de Hígado/mortalidad , Preservación de Órganos/efectos adversos , Adolescente , Adulto , Anciano , Femenino , Florida/epidemiología , Hepatitis C/mortalidad , Humanos , Cirrosis Hepática/epidemiología , Cirrosis Hepática/etiología , Masculino , Persona de Mediana Edad , Preservación de Órganos/mortalidad , Recurrencia , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: The American Association for the Study of Liver Disease recommends screening patients with cirrhosis for hepatocellular carcinoma (HCC) using imaging with or without alpha-fetoprotein every six months. Unfortunately, screening rates remain inadequate. AIM: To assess root causes of screening failure in a subspecialty hepatology clinic. METHODS: The authors identified patients with cirrhosis seen in a subspecialty hepatology clinic and determined whether they underwent appropriate screening, defined as two cross-sectional images between five and seven months apart. The authors characterized the primary driver of screening failure. Finally, other hepatologists were surveyed to determine provider perceptions of screening failure causes. RESULTS: 1034 patients were identified with an average age of 61 years and a mean MELD of 8.1 ± 3.8. Hepatitis C virus was the most common cirrhosis etiology. 489 (47%) underwent appropriate screening. No demographic or clinical differences were detected between those who underwent appropriate screening and those who did not. The most common etiologies of screening failure, in descending order, were: radiology unable to schedule timely imaging, provider did not order imaging, patient canceled follow up appointment, appointments scheduled too far apart, lost to follow up, no-show to radiology appointment, and provider canceled appointment. Hepatologists surveyed believed the most common cause of screening failure was no-show to radiology. CONCLUSION: Rates of screening were poor even in a subspecialty hepatology clinic. Screening failure was mostly due to systemic factors such as radiology availability and time between hepatology appointments rather than individual error.
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BACKGROUND: The prevalence of liver fibrosis detected by non-invasive imaging in alpha-1-antitrypsin (AAT) deficiency has not been systematically assessed. AIMS: We conducted a systematic review and meta-analysis to determine the prevalence of significant fibrosis and advanced fibrosis in AAT deficiency based on non-invasive imaging. METHODS: Medline and Embase electronic databases were searched for studies from inception to 13 November 2022 that provided data for the prevalence of fibrosis in adults with AAT deficiency. A generalised linear mixed model with Clopper-Pearson intervals was used to pool single-arm outcomes. RESULTS: Of the 214 records identified, 8 studies were included. Five studies assessed fibrosis using vibration-controlled transient elastography. The prevalence of significant fibrosis (defined as ≥7.1 kPA) in Z homozygosity, Z heterozygosity and non-carrier status was 22.10% (five studies, 95% CI: 17.07-28.12), 9.24% (three studies, 95% CI: 4.68-17.45) and 5.38% (one study, 95% CI: 3.27-8.73), respectively, p < 0.0001, and the prevalence of advanced fibrosis (defined as ≥9.5 kPa) was 8.13% (five studies, 95% CI: 4.60-13.96), 2.96% (three studies, 95% CI: 1.49-5.81) and 1.08% (one study, 95% CI: 0.35-3.28), respectively, p = 0.003. There were limited data regarding the use of magnetic resonance elastography or acoustic radiation force impulse to assess for fibrosis. CONCLUSION: More than one in five adult individuals with AAT deficiency and Z homozygosity harbour significant fibrosis, and nearly 1 in 10 harbours advanced fibrosis. The risk of fibrosis increases incrementally with the frequency of Pi*Z mutations.
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Deficiencia de alfa 1-Antitripsina , Adulto , Humanos , Prevalencia , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/epidemiología , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/epidemiología , Cirrosis Hepática/etiologíaRESUMEN
Transcriptome analysis of the facultative anaerobe, Neisseria gonorrhoeae, revealed that many genes of unknown function were induced under anaerobic conditions. Mutation of one such gene, NGO1024, encoding a protein belonging to the 2-nitropropane dioxygenase-like superfamily of proteins, was found to result in an inability of gonococci to grow anaerobically. Anaerobic growth of an NG1024 mutant was restored upon supplementation with unsaturated fatty acids (UFA), but not with the saturated fatty acid palmitate. Gonococcal fatty acid profiles confirmed that NGO1024 was involved in UFA synthesis anaerobically, but not aerobically, demonstrating that gonococci contain two distinct pathways for the production of UFAs, with a yet unidentified aerobic mechanism, and an anaerobic mechanism involving NGO1024. Expression of genes involved in classical anaerobic UFA synthesis, fabA, fabM and fabB, was toxic in gonococci and unable to complement a NGO1024 mutation, suggesting that the chemistry involved in gonococcal anaerobic UFA synthesis is distinct from that of the classical pathway. NGO1024 homologues, which we suggest naming UfaA, form a distinct lineage within the 2-nitropropane dioxygenase-like superfamily, and are found in many facultative and obligate anaerobes that produce UFAs but lack fabA, suggesting that UfaA is part of a widespread pathway involved in UFA synthesis.
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Proteínas Bacterianas/metabolismo , Dioxigenasas/metabolismo , Ácidos Grasos Insaturados/biosíntesis , Hidroliasas/metabolismo , Neisseria gonorrhoeae/enzimología , Anaerobiosis , Proteínas Bacterianas/genética , Dioxigenasas/genética , Evolución Molecular , Hidroliasas/genética , Mutación , Neisseria gonorrhoeae/clasificación , Neisseria gonorrhoeae/genética , Neisseria gonorrhoeae/metabolismo , FilogeniaRESUMEN
BACKGROUND & AIMS: Liver disease is a significant cause of death among adults with α(1)-antitrypsin (A-AT) deficiency. Age and male sex are reported risk factors for liver disease. In the absence of adequate risk stratification, current recommendations are to intermittently test A-AT-deficient adults for liver function. We evaluated this recommendation in a large group of adults with A-AT deficiency to determine the prevalence of increased levels of alanine aminotransferase (ALT) and identify risk factors for liver disease. METHODS: We used the Alpha-1 Foundation DNA and Tissue Bank to identify a cross section of A-AT-deficient adults (n = 647) with and without liver disease; individuals without A-AT deficiency were used as controls (n = 152). Results from ALT tests were compared between groups. RESULTS: The prevalence of liver disease among individuals with A-AT deficiency was 7.9%; an increased level of ALT was observed in 7.8% of A-AT-deficient individuals, which did not differ significantly from controls. Mean levels of ALT fell within normal range for all groups. An increased level of ALT identified patients with liver disease with 11.9% sensitivity. The level of only γ-glutamyl transpeptidase was significantly higher in the A-AT-deficient group than in controls (43 vs 30 IU/mL; P < .003). A childhood history of liver disease and male sex were risk factors for adult liver disease in the multivariate analysis. CONCLUSIONS: An increased level of ALT does not identify adults with A-AT deficiency who have liver disease. Male sex and liver disease during childhood might help identify those at risk.
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Alanina Transaminasa/sangre , Técnicas de Laboratorio Clínico/métodos , Pruebas Diagnósticas de Rutina/métodos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/etiología , Deficiencia de alfa 1-Antitripsina/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Adulto JovenRESUMEN
We have reported that Neisseria gonorrhoeae is extremely resistant to reactive nitrogen species (RNS) including peroxynitrite (PN). Recent literature suggests that catalase can provide protection against commercial preparations of PN. Though wild-type gonococci were shown to be highly resistant to 2 mM PN, Neisseria meningitidis and a gonococcal katA mutant were both shown to be extremely sensitive to 2 mM PN. Analysis of translational fusions to lacZ of the catalase promoters from N. gonorrhoeae and N. meningitidis demonstrated that basal katA expression from gonococci is 80-fold higher than in meningococci, though meningococcal katA retains a greater capacity to be activated by OxyR. This activation capacity was shown to be due to a single base pair difference in the -10 transcription element between the two kat promoters. PN resistance was initially shown to be associated with increasing catalase expression; however, commercial preparations of PN were later revealed to contain higher levels of contaminating hydrogen peroxide (H2O2) than expected. Removal of H2O2 from PN preparations with manganese dioxide markedly reduced PN toxicity in a gonococcal katA mutant. Simultaneous treatment with non-lethal concentrations of PN and H2O2 was highly lethal, indicating that these agents act synergistically. When treatment was separated by 5 min, high levels of bacterial killing occurred only when PN was added first. Our results suggest that killing of N. gonorrhoeae ΔkatA by commercial PN preparations is likely due to H2O2, that H2O2 is more toxic in the presence of PN, and that PN, on its own, may not be as toxic as previously believed.
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Proteínas Bacterianas/metabolismo , Catalasa/metabolismo , Farmacorresistencia Bacteriana , Gonorrea/microbiología , Neisseria gonorrhoeae/efectos de los fármacos , Neisseria gonorrhoeae/enzimología , Ácido Peroxinitroso/farmacología , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Catalasa/genética , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Humanos , Neisseria gonorrhoeae/genéticaRESUMEN
Despite years of clinical use and extensive research efforts, the mechanism of action of ribavirin (RBV) is not well understood. Although it has only a mild, transient antiviral effect on HCV replication when administered as monotherapy, when combined with interferon, RBV improves sustained virological response (SVR) rates by approximately 25-30%. Proposed mechanisms of action for RBV against HCV include (1) a direct effect against the HCV RNA dependent RNA polymerase; (2) induction of misincorporation of nucleotides leading to lethal mutagenesis; (3) depletion of intracellular pools via inhibition of inosine monophosphate dehydrogenase; (4) alteration in the cytokine balance between a Th2 profile (anti-inflammatory) to a Th1 profile (pro-inflammatory); and (5) potentiating the effect of interferon via up-regulation of genes involved in interferon signalling. Given the lack of a clear understanding of RBV mechanism of action, it has been challenging to confidently position this drug with new direct antiviral agents (DAA). However, early clinical studies provide strong evidence for a benefit of RBV in combination with DAAs for both IFN containing and sparing regimens. The addition of RBV reduces viral breakthroughs and/or relapses, at least when drugs with low to moderate genetic barriers to resistance are paired together. This is particularly true in patients harbouring HCV subtype 1a. Ongoing studies are now addressing the utility of RBV in nucleoside containing DAA regimens, which offer both potent antiviral activity as well as a high genetic barrier to resistance. It is remarkable that the age-old question of the role of RBV in the future of HCV therapy remains as real today as it was two decades ago.