RESUMEN
Previous studies suggested that osteocyte lacunar network disruption could play a role in the complex pathophysiology of bone changes in aging and disease. Considering that particular research interest is lacking, we aimed to assess alcoholic liver cirrhosis (ALC)-induced changes in osteocyte lacunar network and bone marrow adiposity. Immunohistochemistry was conducted to assess changes in the micro-morphology of osteocyte lacunar network and bone marrow adiposity, and expression of connexin 43 and sclerostin in vertebral and femoral samples collected from 40 cadaveric men (age range between 44 and 70 years) divided into ALC group (n = 20) and control group (n = 20). Furthermore, the assessment of the potential association between bone changes and the severity of the hepatic disorder (given by Knodell's pathohistologic scoring) was conducted. Our data revealed fewer connexin 43-positive osteocytes per vertebral and femoral bone area (p < 0.01), suggesting defective signal transduction among osteocytes in ALC individuals. Moreover, we found an ALC-induced increase in the number of adipocytes in the vertebral bone marrow (p = 0.038). Considering significant associations between the severity of liver tissue disturbances and impaired functionality of osteocyte lacunar network (Pearson's correlation analyses, p < 0.05), we may assume that timely treatment of the liver disease may delay bone impairment. ALC induced an increase in osteocytic sclerostin expression (p < 0.001), suggesting its role in mediating low bone formation among ALC individuals. Hence, medicaments targeting low bone formation may be beneficial to attenuate the bone changes among ALC patients. However, future clinical studies are required to verify the therapeutic utility of these findings.
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Proteínas Adaptadoras Transductoras de Señales , Conexina 43 , Cirrosis Hepática Alcohólica , Osteocitos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Cadáver , Conexina 43/metabolismo , Humanos , Cirrosis Hepática Alcohólica/metabolismo , Cirrosis Hepática Alcohólica/patología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND AND AIMS: To systematically summarize the prevalence of alcohol-related liver disease (ALD) and the alcohol-attributable proportions of liver cirrhosis and hepatocellular carcinoma (HCC) cases in Asia. METHODS: The Embase, PubMed, Web of Science, Cochrane, CINAHL, WanfangMed and China National Knowledge Infrastructure databases were searched from 01 January 2000 to 01 December 2021 for reports of ALD prevalence and alcohol-attributable proportions of liver cirrhosis/HCC in Asian populations. Study characteristics were extracted, and meta-analyses were conducted. RESULTS: Our literature search identified 13 studies reporting the ALD prevalence, 62 studies reporting the alcohol-attributable proportion of liver cirrhosis and 34 studies reporting the alcohol-attributable proportion of HCC. The overall prevalence of ALD was 4.81% (95% confidence interval [CI] 3.67%, 6.09%). The ALD prevalence was higher in men (7.80% [95% CI 5.70%, 10.19%]) than in women (0.88% [95% CI 0.35%, 1.64%]) and increased significantly over time from 3.82% (95% CI 2.74%, 5.07%) between 2000 and 2010 to 6.62% (95% CI 4.97%, 8.50%) between 2011 and 2020. Among 469 640 cases of liver cirrhosis, the pooled alcohol-attributable proportion was 12.57% (95% CI 10.20%, 15.16%). Among 82 615 HCC cases, the pooled alcohol-attributable proportion was 8.30% (95% CI 6.10%,11.21%). Significant regional differences were observed in alcohol-attributable proportions of liver cirrhosis and HCC. CONCLUSIONS: The prevalence of ALD and the proportions of alcohol-related liver cirrhosis and HCC in Asia are lower than those in western populations. However, a gradual increasing trend was observed over the last 21 years. ALD is likely to emerge as a leading cause of chronic liver disease in Asia.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/epidemiología , Femenino , Humanos , Cirrosis Hepática/epidemiología , Cirrosis Hepática/etiología , Cirrosis Hepática Alcohólica/patología , Neoplasias Hepáticas/epidemiología , Masculino , PrevalenciaRESUMEN
(1) Background: Fibrosis in early-stage alcohol-associated liver disease (ALD) is commonly under-diagnosed in routine clinical practice. This study characterized the liver-injury and cell death response in alcohol use disorder (AUD) patients with ALD who also exhibited fibrosis and assessed the efficacy of standard of care (SOC) treatment in the improvement in liver injury. (2) Methods: Forty-eight heavy-drinking AUD patients aged 21−65 yrs. without clinical manifestations of liver injury were grouped by Fibrosis-4 (FIB-4) score, as negative (Gr.1 < 1.45, n = 21) or positive (Gr.2 ≥ 1.45, n = 27). Patients received 2-weeks (2 w) inpatient SOC. Data on demographics, drinking patterns, liver-injury, immune markers, and liver cell death (K18s) markers were analyzed at baseline (BL) and after 2 w SOC. (3) Results: Lifetime drinking (LTDH, yrs.) and acute heavy drinking (Heavy Drinking Days Past 90 Days [HDD90]) markers were significantly higher in Gr.2 vs. Gr.1. BL ALT, AST, AST:ALT and K18M65 were considerably higher in Gr.2. Dysregulated gut dysfunction and elevated immune activity were evident in Gr.2 characterized by TNF-α, IL-8 and LPS levels. After SOC, Gr.2 showed improvement in AST, ALT, AST/ALT ratio; and in the K18M65, K18M30 and K18M65/M30 ratio vs. Gr.1. The true positivity of BL IL-8 response to predict the improvement in K18M65 to normal levels among Gr.2 patients against those who did not have improvement after 2 w SOC was very high (AUROC = 0.830, p = 0.042). (4) Conclusions: Gut dysfunction, elevated cytokine response and necrotic liver cell death were elevated in AUD patients with early-stage ALD. K18 showed promise as a predictive theragnostic factor to differentiate among the AUD patients with early-stage ALD and baseline fibrosis who had improvement in liver injury against those who did not, by the levels of baseline IL-8.
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Hepatopatías Alcohólicas , Adulto , Anciano , Biomarcadores/análisis , Humanos , Interleucina-8/metabolismo , Cirrosis Hepática Alcohólica/diagnóstico , Cirrosis Hepática Alcohólica/metabolismo , Cirrosis Hepática Alcohólica/patología , Hepatopatías Alcohólicas/diagnóstico , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/patología , Persona de Mediana Edad , Adulto JovenRESUMEN
In hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infected patients, HIV enhances HCV replication and liver damage. Several microRNAs (miRNAs), active in pro-fibrotic and inflammatory pathways, have been implicated in the pathogenesis of this phenomenon. However, these miRNAs have been tested only in explanted cirrhotic livers, when the liver damage has become chronic and irreversible. No data are available on the early phase of viral infection, such as early after liver transplantation (LT). In the present study, the expression of miR-101, miR-122, miR-155, miR-192, miR-200c, miR-338, and miR-532 was determined by quantitative real-time polymerase chain reaction in liver biopsies of HCV (n = 19) and HCV/HIV-infected (n = 20) LT recipients, as well as in a control group (n = 18) of noninfected patients, transplanted for alcoholic cirrhosis. The timing of liver biopsy was 6 months post-LT. None of the patients was treated with direct-acting anti-HCV drugs. All co-infected recipients had suppressed HIV viral load. Grading and staging were assessed according to the Ishak Classification. HCV and HIV viral load were measured in the sera. miR-101 (p = .03), miR-122 (p = .012), and miR-192 (p = .038) were significantly downregulated in HCV/HIV co-infected and HCV mono-infected recipients when compared with noninfected recipients, and such downregulation was more pronounced in co-infected ones. Moreover, in co-infected recipients but not in mono-infected ones, miR-101 inversely correlated with the peripheral HCV-RNA levels (r = .41, p = .04) and miR-122 inversely correlated with peripheral HCV-RNA levels (r = .49, p = .03) and with the histological grading (r = .51, p = .02). In conclusion, as early as 6 months after LT, the presence of HIV-HCV co-infection enhanced a significant downregulation of certain miRNAs that showed a direct correlation with HCV viral load and liver inflammation.
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Coinfección/terapia , Infecciones por VIH/terapia , Hepatitis C/terapia , Trasplante de Hígado , Hígado/metabolismo , MicroARNs/metabolismo , Adulto , Aloinjertos/metabolismo , Aloinjertos/patología , Aloinjertos/virología , Coinfección/genética , Coinfección/patología , Coinfección/virología , Femenino , VIH/fisiología , Infecciones por VIH/genética , Infecciones por VIH/patología , Infecciones por VIH/virología , Hepacivirus/fisiología , Hepatitis C/genética , Hepatitis C/patología , Hepatitis C/virología , Humanos , Hígado/patología , Hígado/virología , Cirrosis Hepática Alcohólica/genética , Cirrosis Hepática Alcohólica/patología , Cirrosis Hepática Alcohólica/terapia , Masculino , MicroARNs/genética , Persona de Mediana Edad , ARN Viral/genética , ARN Viral/metabolismo , Carga ViralRESUMEN
ABSTRACT: Toxicological analysis is an important diagnostic component of a postmortem examination and may involve both antemortem and postmortem specimens. Here, we present a case in which an antemortem specimen, when reanalyzed in the forensic toxicology laboratory, resulted in values that contradicted the reported values from the medical record and required further investigation. This case involves a 51-year-old man decedent with a medical history of chronic alcohol abuse. His antemortem urine drug screen, performed upon admission to an emergency department, was negative. His serum blood alcohol level at presentation was reported as 0.960 g/dL and, repeated 4 hours later, was 0.500 g/dL with a comment indicating that there was significant lipemia interfering with the results. At autopsy, the antemortem blood sample collected from the hospital, postmortem blood, and vitreous humor samples were analyzed and all 3 samples were found to be negative for ethanol. The hospital laboratory used an enzymatic assay for ethanol detection, which is known to be impacted by lipemia, and the forensic laboratory used head-space gas chromatography, which is not impacted by lipemia. This highlights the need to critically analyze laboratory testing methodologies when interpreting conflicting results at autopsy.
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Depresores del Sistema Nervioso Central/análisis , Cromatografía de Gases/métodos , Pruebas de Enzimas , Etanol/análisis , Toxicología Forense/métodos , Hiperlipidemias/complicaciones , Alcoholismo/complicaciones , Autopsia , Humanos , Cirrosis Hepática Alcohólica/patología , Masculino , Persona de Mediana Edad , Pancreatitis Alcohólica/patología , Cuerpo Vítreo/químicaRESUMEN
We examined 74 patients with acute decompensation of alcoholic liver cirrhosis: 34 (45.9%) with bacterial infection (group 1) and 40 (54.1%) without bacterial infection (group 2). The degree and index of acute-on-chronic liver failure (ACLF) were determined using an on-line CLIF-C ACLF Calculator and the levels of cytokeratin-18 fragments, TNFα, IL-1ß, IL-4, IL-6, and IL-8. In group 1, AST, cytokeratin-18, TNFα, IL-1ß, IL-6, degree and score of ACLF were significantly higher than in group 2. ACLF developed in 18 (52.9%) patients in group 1 and in 11 (27.5%) (p<0.05) patients in group 2. Within 1 month, 10 (29.4%) patients of group 1 and 2 (5%) patients of group 2 died (p<0.05). Patients with bacterial infection showed a more severe course of alcoholic liver cirrhosis and ACLF than those without bacterial infection.
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Insuficiencia Hepática Crónica Agudizada/microbiología , Infecciones Bacterianas/microbiología , Cirrosis Hepática Alcohólica/microbiología , Insuficiencia Hepática Crónica Agudizada/sangre , Insuficiencia Hepática Crónica Agudizada/mortalidad , Insuficiencia Hepática Crónica Agudizada/patología , Adulto , Aspartato Aminotransferasas/sangre , Infecciones Bacterianas/sangre , Infecciones Bacterianas/mortalidad , Infecciones Bacterianas/patología , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Humanos , Interleucina-1beta/sangre , Interleucina-4/sangre , Interleucina-6/sangre , Interleucina-8/sangre , Queratina-18/sangre , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática Alcohólica/sangre , Cirrosis Hepática Alcohólica/mortalidad , Cirrosis Hepática Alcohólica/patología , Masculino , Persona de Mediana Edad , Pronóstico , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. The overlap between ALD and NAFLD suggests the existence of metabolic steatohepatitis. Development of in vivo models that reflect various aspects of human steatohepatitis is essential for drug discovery. We aimed to characterize several models of steatohepatitis (SH) and to investigate whether the pathology could be modulated. Sprague-Dawley rats were fed a high-fat diet (HFD) for 9 wk, followed by either a high-fat, high-cholesterol and cholate diet (HFC) or a HFC diet containing 13% trans fat (HFC-TF). A subset received 15% ethanol-water twice a week for 12 wk. Serum triglycerides, cholesterol, LDL, HDL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and rodent NH2-terminal propeptide of type III collagen (rPRO-C3) were assessed. The liver was weighed and evaluated using modified Nonalcoholic Steatohepatitis Clinical Research Network histological score system criteria. All diets induced hepatomegaly, but only HFC-TF increased the size of visceral adipose tissue. Trans fat augmented HFC-induced dyslipidemia, and cholesterol was higher and HDL was lower in the HFC-TF groups. Alcohol lowered triglycerides in both dietary groups. HFC elevated ALT and AST, which were lowered by trans fat. All diets induced histological SH, addition of trans fat induced more steatosis but less inflammation. Inclusion of alcohol augmented the HFC-induced inflammation. All diets induced mild fibrosis. Inclusion of trans fat and alcohol significantly increased rPRO-C3. The addition of trans fat reduced the HFC-induced inflammation but augmented steatosis and dyslipidemia. Inclusion of alcohol induced a more inflammatory and fibrogenic phenotype.NEW & NOTEWORTHY Alcoholic liver disease and nonalcoholic liver disease share significant overlap, which suggests the existence of metabolic steatohepatitis. Trans fat has been implicated in steatohepatitis development. Here, we show that the addition of trans fat to an atherogenic diet results in a more steatotic but less inflammatory phenotype, whereas the addition of alcohol to an atherogenic diet augments the inflammatory and fibrogenic properties of the diet.
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Consumo Excesivo de Bebidas Alcohólicas/complicaciones , Dieta Aterogénica , Hígado Graso Alcohólico/etiología , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/etiología , Ácidos Grasos trans , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Biomarcadores/sangre , Modelos Animales de Enfermedad , Dislipidemias/etiología , Dislipidemias/metabolismo , Dislipidemias/patología , Hígado Graso Alcohólico/metabolismo , Hígado Graso Alcohólico/patología , Hepatomegalia/etiología , Hepatomegalia/metabolismo , Hepatomegalia/patología , Metabolismo de los Lípidos , Hígado/metabolismo , Cirrosis Hepática Alcohólica/etiología , Cirrosis Hepática Alcohólica/metabolismo , Cirrosis Hepática Alcohólica/patología , Masculino , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/etiología , Obesidad/metabolismo , Obesidad/patología , Estrés Oxidativo , Fragmentos de Péptidos/metabolismo , Procolágeno/metabolismo , Ratas Sprague-DawleyRESUMEN
BACKGROUND & AIMS: Activation of TGFB (transforming growth factor ß) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers. METHODS: We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Δhep). ECM1 or soluble TGFBR2 (TGFB receptor 2) were expressed in livers of mice after injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy livers were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with αv integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4-induced liver fibrosis was accelerated in ECM1Δhep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice. CONCLUSIONS: ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.
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Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Proteínas de la Matriz Extracelular/metabolismo , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática Experimental/prevención & control , Hígado/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Tetracloruro de Carbono , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Proteínas de la Matriz Extracelular/deficiencia , Proteínas de la Matriz Extracelular/genética , Células Estrelladas Hepáticas/patología , Hepatitis Alcohólica/metabolismo , Hepatitis Alcohólica/patología , Hepatitis Viral Humana/metabolismo , Hepatitis Viral Humana/patología , Humanos , Hígado/patología , Cirrosis Hepática Alcohólica/metabolismo , Cirrosis Hepática Alcohólica/patología , Cirrosis Hepática Experimental/genética , Cirrosis Hepática Experimental/metabolismo , Cirrosis Hepática Experimental/patología , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal , Miembro 4 de la Subfamilia B de Casete de Unión a ATPAsunto(s)
Receptores X del Hígado , Humanos , Receptores X del Hígado/metabolismo , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Animales , Hepatopatías Alcohólicas/patología , Hepatopatías Alcohólicas/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática Alcohólica/patologíaRESUMEN
Although vertebral fracture is more common among alcoholic liver cirrhosis patients when compared to general population, current data on three-dimensional micro-architecture are scarce. Our study showed significant trabecular deterioration in lumbar vertebrae obtained from alcoholic liver cirrhosis donors, suggesting that they should be advised to undergo early-stage screening for osteoporosis. PURPOSE: Recent studies showed an increased incidence of vertebral fractures in alcoholic liver cirrhosis (ALC) patients, while data about vertebral micro-structure are still limited. The aim of this study was to compare trabecular and cortical micro-architecture of lumbar vertebrae between ALC patients and healthy age- and sex-matched controls. METHODS: Our study included lumbar vertebral samples of male cadaveric donors, divided into ALC (n = 20, age: 59 ± 6 years) and control group (n = 20, age: 59 ± 8 years). Following pathohistological verification of liver cirrhosis, trabecular and cortical bone micro-architecture was analyzed by micro-computed tomography (micro-CT). RESULTS: Micro-CT evaluation of the trabecular bone in lumbar vertebrae showed a significant decrease in bone volume fraction, trabecular thickness, trabecular number, and connectivity (p < 0.01). In contrast to trabecular deterioration, prominent alteration in cortical parameters was not observed in lumbar vertebrae of ALC patients (p > 0.05). CONCLUSIONS: Our data indicate that susceptibility to non-traumatic fractures in ALC patients could be explained by alterations in trabecular bone micro-architecture. Thus, we genuinely recommend osteological screening of the lumbar spine for all ALC patients in order to evaluate individual fracture risk. Graphical abstract.
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Cirrosis Hepática Alcohólica , Vértebras Lumbares , Fracturas de la Columna Vertebral , Anciano , Densidad Ósea , Humanos , Cirrosis Hepática Alcohólica/complicaciones , Cirrosis Hepática Alcohólica/patología , Vértebras Lumbares/patología , Masculino , Persona de Mediana Edad , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/etiología , Fracturas de la Columna Vertebral/patología , Microtomografía por Rayos XRESUMEN
BACKGROUND: Endothelial progenitor cells (EPCs) help in neovascularization and endothelial repair during injury. Patients with cirrhosis show increased number and function of EPCs in circulation. METHODS: Since natural killer (NK) cells regulate EPCs, we investigated the relationship between the 2 in alcoholic cirrhosis (AC, n = 50) and severe alcoholic hepatitis (SAH, n = 18) patients and compared with nonalcoholic cirrhosis (n = 15) and healthy controls (HC, n = 30). Levels of systemic inflammatory cytokines were measured, and coculture assays were performed between EPCs and NK cells in contact-dependent and contact-independent manner. NK cell-mediated killing of EPCs was evaluated, and expression of receptors including fractalkine (FKN) on EPCs and its cognate receptor CX3CR1 on NK cells was studied by RT-PCR assays. RESULTS: Patients with SAH had higher regulated on activation, normal T cell expressed and secreted (RANTES) (p = 0.01), vascular endothelial growth factor (VEGF) (p = 0.04), IL-1ß (p = 0.04), and IL-6 (p = 0.00) growth factors and proinflammatory cytokines as compared to AC and HC. Distinct populations of CD31+ CD34+ EPCs with low and high expression of CD45 were significantly lower in SAH than HC (CD45low , p = 0.03; CD45hi , p = 0.04) and AC (CD45low , p = 0.05; CD45hi , p = 0.02). SAH patients, however, showed increased functional capacity of EPCs including colony formation and LDL uptake. NK cells were reduced in SAH compared with AC (p = 0.002), however with higher granzyme ability (p < 0.001 and p = 0.04, respectively). In SAH, EPC-NK cell interaction assays showed that NK cells lysed the EPCs in both contact-dependent and contact-independent assays. Expression of interaction receptor CX3CR1 was significantly higher on NK cells (p = 0.0005), while its cognate receptor, FKN, was increased on EPCs in SAH patients as compared to HC (p = 0.0055). CONCLUSION: We conclude that in SAH, NK cells induce killing of EPCs via CX3CR1/FKN axis that may be one of the key events contributing to disease severity and proinflammatory responses in SAH.
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Células Progenitoras Endoteliales/patología , Hepatitis Alcohólica/patología , Células Asesinas Naturales/patología , Leucocitos Mononucleares/patología , Índice de Severidad de la Enfermedad , Adulto , Muerte Celular/fisiología , Movimiento Celular/fisiología , Técnicas de Cocultivo , Células Progenitoras Endoteliales/metabolismo , Femenino , Hepatitis Alcohólica/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Células Asesinas Naturales/metabolismo , Leucocitos Mononucleares/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática Alcohólica/metabolismo , Cirrosis Hepática Alcohólica/patología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. DESIGN: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. RESULTS: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). CONCLUSION: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.
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Predisposición Genética a la Enfermedad/epidemiología , Heterocigoto , Cirrosis Hepática Alcohólica/genética , alfa 1-Antitripsina/genética , Distribución por Edad , Austria , Biopsia con Aguja , Estudios de Casos y Controles , Intervalos de Confianza , Femenino , Tamización de Portadores Genéticos , Variación Genética , Alemania , Humanos , Inmunohistoquímica , Incidencia , Cirrosis Hepática Alcohólica/epidemiología , Cirrosis Hepática Alcohólica/patología , Masculino , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Pronóstico , Medición de Riesgo , Distribución por SexoRESUMEN
BACKGROUND & AIMS: To date, studies into the natural history of alcohol-related liver disease (ALD) have lacked long-term follow-up, large numbers of participants, or both. We performed a systematic review to summarise studies that describe the natural history of histologically proven ALD. METHODS: PubMed and Medline were searched for relevant studies according to pre-specified criteria. Data were extracted to describe the prevalence of ALD, histological progression of disease and mortality. Single-proportion meta-analysis was used to combine data from studies regarding rates of progression or mortality. RESULTS: Thirty-seven studies were included, reporting data from 7,528 participants. Amongst cohorts of hazardous drinkers, on average 15% had normal histological appearance, 27% had hepatic steatosis, 24% had steatohepatitis and 26% had cirrhosis. The annualised rates of progression of pre-cirrhotic disease to cirrhosis were 1% (0-8%) for patients with normal histology, 3% (2-4%) for hepatic steatosis, 10% (6-17%) for steatohepatitis and 8% (3-19%) for fibrosis. Annualised mortality was 6% (4-7%) in patients with steatosis and 8% (5-13%) in cirrhosis. In patients with steatohepatitis on biopsy a marked difference was seen between inpatient cohorts (annual mortality 15%, 8-26%) and mixed cohorts of inpatients and outpatients (annual mortality 5%, 2-10%). Only in steatosis did non-liver-related mortality exceed liver-specific causes of mortality (5% per year vs. 1% per year). CONCLUSIONS: These data confirm the observation that alcohol-related hepatic steatohepatitis requiring admission to hospital is the most dangerous subtype of ALD. Alcohol-related steatosis is not a benign condition as it is associated with significant risk of mortality. LAY SUMMARY: Knowledge of the natural history of a disease allows clinicians and patients to understand the risks that are associated with a medical condition. In this study we systematically gathered all the published data regarding the natural history of alcohol-related liver disease in people who had a liver biopsy. We used this data to define the prevalence of the disease, the annual risk of progression to cirrhosis and the annual risk of death at each stage of the disease.
Asunto(s)
Hígado Graso Alcohólico/epidemiología , Hígado Graso Alcohólico/patología , Cirrosis Hepática Alcohólica/epidemiología , Cirrosis Hepática Alcohólica/patología , Hígado/patología , Adulto , Biopsia , Progresión de la Enfermedad , Hígado Graso Alcohólico/mortalidad , Femenino , Humanos , Cirrosis Hepática Alcohólica/mortalidad , Masculino , Persona de Mediana Edad , Prevalencia , PronósticoRESUMEN
Histological fibrosis stage is one of the most important prognostic factors in compensated and decompensated alcohol-related liver disease (ALD). Morphological assessment of fibrosis is useful for patient stratification, enabling individualised management, and for evaluation of treatment effects in clinical studies. In contrast to most chronic liver diseases where fibrosis is portal-based, fatty liver disease (FLD) of alcoholic or non-alcoholic aetiology (NAFLD) is associated with a centrilobular pattern of injury which leads to perivenular fibrosis and/or pericellular fibrosis. Progression of FLD drives expansive pericellular fibrosis, linking vascular structures and paving the way for the development of cirrhosis. At the cirrhotic stage, ongoing tissue damage leads to increasing fibrosis severity due to parenchymal loss and proliferation of fibrous scars. Histologic fibrosis staging systems have been devised, based on topography and the extent of fibrosis, for most chronic liver diseases. The utility of histological staging is reflected in different risks associated with individual fibrosis stages which cannot be reliably distinguished by non-invasive fibrosis assessment. In contrast to NAFLD, ALD-specific staging systems that enable the standardised prognostication required for clinical management and trials are lacking. Although morphological similarities between NAFLD and ALD exist, differences in clinical and histological features may substantially limit the utility of established NAFLD-specific staging systems for prognostication in ALD. This review summarises morphological features of fibrosis in ALD and compares them to other chronic liver diseases, particularly NAFLD. ALD-related fibrosis is examined in the context of pathogenetic mechanisms of fibrosis progression, regression and clinical settings that need to be considered in future prognostically relevant ALD staging approaches.
Asunto(s)
Progresión de la Enfermedad , Hígado Graso Alcohólico/patología , Cirrosis Hepática Alcohólica/patología , Enfermedad del Hígado Graso no Alcohólico/patología , Animales , Biopsia , Etanol/efectos adversos , Hígado Graso Alcohólico/etiología , Humanos , Hígado/patología , Cirrosis Hepática Alcohólica/etiología , PronósticoRESUMEN
BACKGROUND & AIMS: Alcohol is the leading cause of cirrhosis and liver-related mortality, but we lack serum markers to detect compensated disease. We compared the accuracy of the Enhanced Liver Fibrosis test (ELF), the FibroTest, liver stiffness measurements (made by transient elastography and 2-dimensional shear-wave elastography), and 6 indirect marker tests in detection of advanced liver fibrosis (Kleiner stage ≥F3). METHODS: We performed a prospective study of 10 liver fibrosis markers (patented and not), all performed on the same day. Patients were recruited from primary centers (municipal alcohol rehabilitation, n = 128; 6% with advanced fibrosis) and secondary health care centers (hospital outpatient clinics, n = 161; 36% with advanced fibrosis) in the Region of Southern Denmark from 2013 through 2016. Biopsy-verified fibrosis stage was used as the reference standard. The primary aim was to validate ELF in detection of advanced fibrosis in patients with alcoholic liver disease recruited from primary and secondary health care centers, using the literature-based cutoff value of 10.5. Secondary aims were to assess the diagnostic accuracy of ELF for significant fibrosis and cirrhosis and to determine whether combinations of fibrosis markers increase diagnostic yield. RESULTS: The ELF identified patients with advanced liver fibrosis with an area under the receiver operating characteristic curve (AUROC) of 0.92 (95% confidence interval 0.89-0.96); findings did not differ significantly between patients from primary vs secondary care (P = .917). ELF more accurately identified patients with advanced liver fibrosis than indirect marker tests, but ELF and FibroTest had comparable diagnostic accuracies (AUROC of FibroTest, 0.90) (P = .209 for comparison with ELF). Results from the ELF and FibroTest did not differ significantly from those of liver stiffness measurement in intention-to-diagnose analyses (AUROC for transient elastography, 0.90), but did differ in the per-protocol analysis (AUROC for transient elastography, 0.97) (P = .521 and .004 for comparison with ELF). Adding a serum marker to transient elastography analysis did not increase accuracy. For patients in primary care, ELF values below 10.5 and FibroTest values below 0.58 had negative predictive values for advanced liver fibrosis of 98% and 94%, respectively. CONCLUSION: In a prospective, direct comparison of tests, ELF and FibroTest identified advanced liver fibrosis in alcoholic patients from primary and secondary care with high diagnostic accuracy (AUROC values of 0.90 or higher using biopsy as reference). Advanced fibrosis can be ruled out in primary health care patients based on an ELF value below 10.5 or a FibroTest value below 0.58.
Asunto(s)
Técnicas de Apoyo para la Decisión , Diagnóstico por Imagen de Elasticidad , Cirrosis Hepática Alcohólica/sangre , Cirrosis Hepática Alcohólica/diagnóstico por imagen , Pruebas de Función Hepática , Hígado/diagnóstico por imagen , Hígado/metabolismo , Adolescente , Adulto , Anciano , Área Bajo la Curva , Biomarcadores/sangre , Biopsia , Toma de Decisiones Clínicas , Dinamarca , Femenino , Humanos , Hígado/patología , Cirrosis Hepática Alcohólica/patología , Cirrosis Hepática Alcohólica/terapia , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Valor Predictivo de las Pruebas , Atención Primaria de Salud , Pronóstico , Estudios Prospectivos , Curva ROC , Reproducibilidad de los Resultados , Atención Secundaria de Salud , Adulto JovenRESUMEN
The selection of liver transplantation (LT) candidates with alcohol-use disorder (AUD) is influenced by the risk of alcohol relapse (AR) after LT. We aimed to investigate the risk factors of AR after LT and its impact on graft and recipient outcomes. A retrospective study was conducted that included all consecutive patients with AUD undergoing LT from January 2004 to April 2016 (n = 309), excluding patients with alcoholic hepatitis. Odds ratios (ORs) and 95% confidence intervals (CIs) for AR were analyzed by multinomial logistic regression. Cox regression with time-dependent covariates was used to analyze patient survival and graft cirrhosis. There were 70 (23%) patients who presented AR (median follow-up, 68 months), most of them (n = 44, 63%) presenting heavy AR. The probability of heavy AR was 2.3%, 7.5%, 12%, and 29% at 1, 3, 5, and 10 years after LT, respectively. The independent risk factors for heavy AR included a High-Risk Alcoholism Relapse (HRAR) score ≥3 (OR, 2.39; 95% CI, 1.02-5.56; P = 0.04) and the duration of abstinence (months) before LT (OR, 0.81; 95% CI, 0.66-0.98; P = 0.03). In recipients with <6 months of abstinence before LT, the probability of heavy AR after LT was higher in patients with an HRAR score ≥3 than in those with an HRAR score <3 (20%, 36.7%, and 47% versus 6.8%, 12.4%, and 27% at 1, 3, and 5 years, respectively; log-rank 0.013). The risk of graft cirrhosis was increased in patients with heavy AR (hazard ratio, 3.44; 95% CI, 1.58-7.57; P = 0.002) compared with nonrelapsers, with no differences in patient survival. In conclusion, the HRAR score is helpful in identifying the risk of harmful AR after LT in candidates with <6 months of alcohol abstinence without alcoholic hepatitis. These patients could benefit from a longterm integrative patient-centered approach after LT until lifestyle changes are implemented.
Asunto(s)
Abstinencia de Alcohol/psicología , Alcoholismo/diagnóstico , Hepatitis Alcohólica/cirugía , Cirrosis Hepática Alcohólica/epidemiología , Trasplante de Hígado/normas , Complicaciones Posoperatorias/epidemiología , Factores de Edad , Alcoholismo/complicaciones , Alcoholismo/psicología , Aloinjertos/patología , Enfermedad Crónica/psicología , Femenino , Estudios de Seguimiento , Hepatitis Alcohólica/diagnóstico , Humanos , Hígado/patología , Cirrosis Hepática Alcohólica/etiología , Cirrosis Hepática Alcohólica/patología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/patología , Pronóstico , Recurrencia , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores Sexuales , Factores de TiempoRESUMEN
Liver cirrhosis leads to bone loss. To date, information on bone quality (three-dimensional microarchitecture) and, thus, bone strength is scarce. We observed decreased bone quality at both assessed sites, independent of disease severity. Therefore, all patients should undergo early-stage screening for osteoporosis. INTRODUCTION: Recent studies found low bone mineral density in cirrhosis, but data on bone microstructure are scarce. This study assessed weight-bearing and non-weight-bearing bones in patients with cirrhosis and healthy controls. The primary objective was to evaluate trabecular and cortical microarchitecture. METHODS: This was a single-center study in patients with recently diagnosed hepatic cirrhosis. Thirty-two patients and 32 controls participated in this study. After determining the type of cirrhosis, the parameters of bone microarchitecture were assessed by high-resolution peripheral quantitative computed tomography. RESULTS: Both cortical and trabecular microarchitectures showed significant alterations. At the radius, trabecular bone volume fraction was 17% lower (corrected p = 0.028), and, at the tibia, differences were slightly more pronounced. Trabecular bone volume fraction was 19% lower (p = 0.024), cortical bone mineral density 7% (p = 0.007), and cortical thickness 28% (p = 0.001), while cortical porosity was 32% higher (p = 0.023), compared to controls. Areal bone mineral density was lower (lumbar spine - 13%, total hip - 11%, total body - 9%, radius - 17%, and calcaneus - 26%). There was no correlation between disease severity and microarchitecture. Areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) correlated well with parameters of cortical and trabecular microarchitecture. CONCLUSIONS: Hepatic cirrhosis deteriorates both trabecular and cortical microarchitecture, regardless of disease severity. Areal bone mineral density is diminished at all sites as a sign of generalized affection. In patients with hepatic cirrhosis, regardless of its origin or disease severity, aBMD measurements are an appropriate tool for osteologic screening.
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Remodelación Ósea/fisiología , Cirrosis Hepática/patología , Cirrosis Hepática/fisiopatología , Radio (Anatomía)/patología , Tibia/patología , Anciano , Biomarcadores/sangre , Densidad Ósea , Hueso Esponjoso/diagnóstico por imagen , Hueso Esponjoso/patología , Estudios de Casos y Controles , Hueso Cortical/diagnóstico por imagen , Hueso Cortical/patología , Femenino , Humanos , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática Alcohólica/diagnóstico por imagen , Cirrosis Hepática Alcohólica/patología , Cirrosis Hepática Alcohólica/fisiopatología , Masculino , Persona de Mediana Edad , Porosidad , Radio (Anatomía)/diagnóstico por imagen , Tibia/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Soporte de Peso/fisiologíaRESUMEN
BACKGROUND & AIMS: Familial aggregation of metabolic traits in NAFLD is well documented. However, relevance of these traits in alcoholic cirrhosis is not well studied. We aimed to explore the association of family history of metabolic traits with age at diagnosis, severity and complications of alcoholic cirrhosis. METHODS: In a cross-sectional study, all consecutive patients with alcoholic cirrhosis presenting to our tertiary care centre were included. Family and personal history, demographic characteristics, medical history, anthropometric measurements and laboratory data were recorded. The amount and duration of alcohol consumption were also carefully recorded. RESULTS: Out of 1084 alcoholic cirrhotics (age 48.5 ± 10.1 years, all males), family history for metabolic traits was documented in 688 (63.5%) patients. These patients had younger age at diagnosis, increased incidence of jaundice, ascites, variceal bleed and hepatic encephalopathy with consequently higher MELD and CTP score. These patients developed cirrhosis despite shorter median duration (13 years, IQR 7-20 vs 21, IQR 18-25) and lesser amount of alcohol consumption (74 g/d, IQR 24-96 vs 144, IQR 100-148). Patients with both family and personal history of metabolic traits had a higher risk by 3.3 times (95% CI 2.2-4.8) of an early age at diagnosis, 13.2 times (95% CI 8.7-20.1) of progression to cirrhosis with lesser amount of alcohol consumption and 4.6 times (95% CI 3.1-6.9) with lesser duration of alcohol consumption. CONCLUSIONS: Positive family and personal history of metabolic traits predispose to alcoholic cirrhosis with an earlier age at onset and more severity despite lesser exposure to alcohol.
Asunto(s)
Cirrosis Hepática Alcohólica/complicaciones , Anamnesis , Síndrome Metabólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Adulto , Consumo de Bebidas Alcohólicas/efectos adversos , Ascitis/etiología , Estudios Transversales , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Encefalopatía Hepática/complicaciones , Humanos , Cirrosis Hepática Alcohólica/diagnóstico , Cirrosis Hepática Alcohólica/patología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Índice de Severidad de la Enfermedad , Centros de Atención TerciariaRESUMEN
BACKGROUND: The multifactorial mechanisms driving negative health outcomes among risky drinkers with HIV may include immunosenescence. Immunosenescence, aging of the immune system, may be accentuated in HIV and leads to poor outcomes. The liver regulates innate immunity and adaptive immune tolerance. HIV-infected people have high prevalence of liver-related comorbidities. We hypothesize that advanced liver fibrosis/cirrhosis is associated with alterations in T-cell subsets consistent with immunosenescence. METHODS: ART-naïve people with HIV with a recent history of heavy drinking were recruited into a clinical trial of zinc supplementation. Flow cytometry was used to characterize T-cell subsets. The two primary dependent variables were CD8+ and CD4+ T-cells expressing CD28-CD57+ (senescent cell phenotype). Secondary dependent variables were CD8+ and CD4+ T-cells expressing CD45RO + CD45RA- (memory phenotype), CD45RO-CD45RA+ (naïve phenotype), and the naïve phenotype to memory phenotype T-cell ratio (lower ratios associated with immunosenescence). Advanced liver fibrosis/cirrhosis was defined as FIB-4 > 3.25, APRI≥1.5, or Fibroscan measurement ≥10.5 kPa. Analyses were conducted using multiple linear regression adjusted for potential confounders. RESULTS: Mean age was 34 years; 25% female; 88% hepatitis C. Those with advanced liver fibrosis/cirrhosis (N = 25) had higher HIV-1 RNA and more hepatitis C. Advanced liver fibrosis/cirrhosis was not significantly associated with primary or secondary outcomes in adjusted analyses. CONCLUSIONS: Advanced liver fibrosis/cirrhosis was not significantly associated with these senescent T-cell phenotypes in this exploratory study of recent drinkers with HIV. Future studies should assess whether liver fibrosis among those with HIV viral suppression and more advanced, longstanding liver disease is associated with changes in these and other potentially senescent T-cell subsets.
Asunto(s)
Alcoholismo/complicaciones , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Infecciones por VIH/inmunología , Inmunosenescencia , Cirrosis Hepática Alcohólica/inmunología , Adulto , Antígenos CD28/metabolismo , Linfocitos T CD4-Positivos/inmunología , Antígenos CD57/metabolismo , Linfocitos T CD8-positivos/inmunología , Estudios Transversales , Femenino , Infecciones por VIH/complicaciones , Hepatitis C/inmunología , Humanos , Memoria Inmunológica , Antígenos Comunes de Leucocito/metabolismo , Modelos Lineales , Cirrosis Hepática Alcohólica/diagnóstico por imagen , Cirrosis Hepática Alcohólica/enzimología , Cirrosis Hepática Alcohólica/patología , Masculino , Fenotipo , Ensayos Clínicos Controlados Aleatorios como Asunto , Federación de Rusia , Zinc/administración & dosificaciónRESUMEN
Alcoholic liver disease (ALD) is a highly prevalent spectrum of pathologies caused by alcohol overconsumption. Morbidity and mortality related to ALD are increasing worldwide, thereby demanding strategies for early diagnosis and detection of ALD predisposition. A potential candidate as a marker for ALD susceptibility is the transcription factor nuclear factor erythroid-related factor 2 (Nrf2), codified by the nuclear factor erythroid 2-related factor 2 gene (NFE2L2). Nrf2 regulates expression of proteins that protect against oxidative stress and inflammation caused by alcohol overconsumption. Here, we assessed genetic variants of NFE2L2 for association with ALD. Specimens from patients diagnosed with cirrhosis caused by ALD were genotyped for three NFE2L2 single nucleotide polymorphisms (SNP) (SNPs: rs35652124, rs4893819, and rs6721961). Hematoxylin & eosin and immunohistochemistry were performed to determine the inflammatory score and Nrf2 expression, respectively. SNPs rs4893819 and rs6721961 were not specifically associated with ALD, but analysis of SNP rs35652124 suggested that this polymorphism predisposes to ALD. Furthermore, SNP rs35652124 was associated with a lower level of Nrf2 expression. Moreover, liver samples from ALD patients with this polymorphism displayed more severe inflammatory activity. Together, these findings provide evidence that the SNP rs35652124 variation in the Nrf2-encoding gene NFE2L2 is a potential genetic marker for susceptibility to ALD.