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1.
Med Sci Monit ; 26: e927444, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33320844

RESUMO

BACKGROUND Alpha-fetoprotein (AFP) is widely used to screen for hepatocellular carcinoma (HCC). However, the use of this biomarker has been challenged due to its low sensitivity and high rate of false negatives. In this study, we evaluated the diagnostic capability of cyclin D2 (CCND2) promoter methylation in patients with HCC related to hepatitis B virus (HBV). MATERIAL AND METHODS Using methylation-specific PCR and quantitative real-time PCR, we measured methylation status and mRNA levels of CCND2 in plasma and peripheral blood mononuclear cells (PBMCs) from 275 subjects: 75 patients with chronic hepatitis B (CHB), 47 with liver cirrhosis (LC), 118 with HCC, and 35 healthy controls (HCs). RESULTS The methylation rate of the CCND2 promoter was significantly higher in HCC patients than in patients without HCC (P<0.001). Furthermore, advanced HCC (TNM III/IV) was associated with a significantly higher frequency of CCND2 methylation and lower CCND2 mRNA levels than early-stage disease (TNM I/II; P<0.05). Combined measurement of CCND2 methylation and AFP yielded significantly higher sensitivity and area under the curve (AUC) than AFP alone in distinguishing patients with HCC from subjects with LC and CHB (P<0.001). CONCLUSIONS CCND2 methylation may be useful for predicting HCC progression. In addition, combined measurement of CCND2 methylation and AFP could serve as a non-invasive diagnostic marker for patients with HBV-related HCC.


Assuntos
Carcinoma Hepatocelular , Ciclina D2/genética , Metilação de DNA , Hepatite B Crônica , Cirrose Hepática , Neoplasias Hepáticas , alfa-Fetoproteínas/análise , Área Sob a Curva , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Diagnóstico Diferencial , Progressão da Doença , Feminino , Hepatite B Crônica/sangue , Hepatite B Crônica/diagnóstico , Humanos , Leucócitos Mononucleares/patologia , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , RNA Mensageiro/análise , Sensibilidade e Especificidade
2.
PLoS One ; 15(11): e0242101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33206696

RESUMO

BACKGROUND AND AIMS: Prison-based HCV treatment rates remain low due to multiple barriers, including accessing transient elastography for cirrhosis determination. The AST-to-platelet ratio index (APRI) and FIB-4 scores have excellent negative predictive value (NPV) in hospital cohorts to exclude cirrhosis. We investigated their performance in a large cohort of prisoners with HCV infection. METHODS: This was a retrospective cohort study of participants assessed by a prison-based hepatitis program. The sensitivity, specificity, NPV and positive predictive value (PPV) of APRI and FIB-4 for cirrhosis were then analysed, with transient elastography as the reference standard. The utility of age thresholds as a trigger for transient elastography was also explored. RESULTS: Data from 1007 prisoners were included. The median age was 41, 89% were male, and 12% had cirrhosis. An APRI cut-off of 1.0 and FIB-4 cut-off of 1.45 had NPVs for cirrhosis of 96.1% and 96.6%, respectively, and if used to triage prisoners for transient elastography, could reduce the need for this investigation by 71%. The PPVs of APRI and FIB-4 for cirrhosis at these cut-offs were low. Age ≤35 years alone had a NPV for cirrhosis of 96.5%. In those >35 years, the APRI cut-off of 1.0 alone had a high NPV >95%. CONCLUSION: APRI and FIB-4 scores can reliably exclude cirrhosis in prisoners and reduce requirement for transient elastography. This finding will simplify the cascade of care for prisoners living with hepatitis C.


Assuntos
Hepatite C/complicações , Cirrose Hepática/diagnóstico , Prisioneiros , Índice de Gravidade de Doença , Adulto , Algoritmos , Aspartato Aminotransferases/sangue , Técnicas de Imagem por Elasticidade/normas , Feminino , Humanos , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas/normas
3.
Am Fam Physician ; 102(10): 603-612, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-33179890

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease in the United States, affecting up to 30% of adults. There are two forms of NAFLD: nonalcoholic fatty liver (NAFL), defined as 5% or greater hepatic steatosis without hepatocellular injury or fibrosis, and nonalcoholic steatohepatitis (NASH), defined as 5% or greater hepatic steatosis plus hepatocellular injury and inflammation, with or without fibrosis. Individuals with obesity are at highest risk of NAFLD. Other established risk factors include metabolic syndrome and type 2 diabetes mellitus. Although NAFLD is common and typically asymptomatic, screening is not currently recommended, even in high-risk patients. NAFLD should be suspected in patients with elevated liver enzymes or hepatic steatosis on abdominal imaging that are found incidentally. Once other causes, such as excessive alcohol use and hepatotoxic medications, are excluded in these patients, risk scores or elastography tests can be used to identify those who are likely to have fibrosis that will progress to cirrhosis. Liver biopsy should be considered for patients at increased risk of fibrosis and when other liver disorders cannot be excluded with noninvasive tests. Weight loss through diet and exercise is the primary treatment for NAFLD. Other treatments, such as bariatric surgery, vitamin E supplements, and pharmacologic therapy with thiazolidinediones or glucagon-like peptide-1 analogues, have shown potential benefit; however, data are limited, and these therapies are not considered routine treatments. NAFL typically follows an indolent course, whereas patients with NASH are at higher risk of death from cardiovascular disease, cancer, and end-stage liver disease.


Assuntos
Dieta Redutora , Exercício Físico , Hepatopatia Gordurosa não Alcoólica/terapia , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Cirurgia Bariátrica , Biópsia , Técnicas de Imagem por Elasticidade , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Hipoglicemiantes/uso terapêutico , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico por imagem , Imagem por Ressonância Magnética , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Encaminhamento e Consulta , Medição de Risco , Albumina Sérica/metabolismo , Índice de Gravidade de Doença , Tiazolidinedionas/uso terapêutico , Vitamina E/uso terapêutico , Vitaminas/uso terapêutico
4.
Z Gastroenterol ; 58(11): 1099-1106, 2020 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-33197951

RESUMO

In emergency medicine and intensive care the key to control active bleeding - besides definitive therapy (endoscopy, therapeutic angiography or operation) - often is to improve the patients clotting and thrombus formation. Knowledge about routine laboratory testing, their strength and weaknesses as well as indications and dosing of pro-coagulants and blood products remains pivotal in these situations. Achieving hemostasis can be especially challenging in patients with liver cirrhosis, innate or acquired coagulation disorders. This review summarizes the principles of hemostasis diagnostics and management in acute bleeding for gastroenterologists and hepatologists including novel available antidotes and innovative tools for patients with advanced liver disease such as thromboelastometry.


Assuntos
Gastroenterologia , Cirrose Hepática/complicações , Trombose/etiologia , Cuidados Críticos , Hemostasia , Humanos , Cirrose Hepática/sangue , Trombose/prevenção & controle
5.
Nat Commun ; 11(1): 5807, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199780

RESUMO

Chronic nonalcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to liver fibrosis, a condition with limited therapy options. Adiponectin is an adipocytokine that regulates glucose and lipid metabolism via binding to its receptors AdipoR1 and AdipoR2, and AdipoRs signaling is reported to enhance fatty acid oxidation and glucose uptake. Here, we synthesize and report an adiponectin-based agonist JT003, which potently improves insulin resistance in high fat diet induced NASH mice and suppresses hepatic stellate cells (HSCs) activation in CCl4 induced liver fibrosis. Mechanistic studies indicate that JT003 simultaneously stimulates AdipoR1- and AdipoR2- mediated signaling pathways as well as the PI3K-Akt pathway. Moreover, JT003 treatment significantly improves ER-mitochondrial axis function, which contributes to the reduced HSCs activation. Thus, the AdipoR1/AdipoR2 dual agonist improves both NASH and fibrosis in mice models, which provides the pharmacological and biological foundation for developing AdipoRs-based therapeutic agents on liver fibrosis.


Assuntos
Retículo Endoplasmático/metabolismo , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores de Adiponectina/agonistas , Adenilato Quinase/metabolismo , Alanina Transaminase/sangue , Animais , Tetracloreto de Carbono , Dieta Hiperlipídica , Modelos Animais de Doenças , Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fibrose , Células Hep G2 , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Resistência à Insulina , Cirrose Hepática/sangue , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/sangue , Obesidade/sangue , Obesidade/complicações , Obesidade/tratamento farmacológico , PPAR alfa/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Domínios Proteicos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Adiponectina/metabolismo , Transdução de Sinais , Ganho de Peso/efeitos dos fármacos
6.
Medicine (Baltimore) ; 99(48): e23428, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33235124

RESUMO

BACKGROUND: Human epididymis protein 4 (HE4) has been identified as marker for renal fibrosis. Present study aimed to investigate the clinical significance of serum HE4 in liver fibrosis. METHODS: Serum from 65 liver fibrosis patients, 68 hepatic patients without fibrosis, and 50 controls was collected respectively. Serum HE4 levels were measured by chemiluminescence immunoassay and compared among the groups. The relationships between serum HE4 levels and the clinical characteristics of liver fibrosis were also analyzed. A receiver operator characteristic curve was plotted to investigate the diagnostic efficacy of serum HE4 for liver fibrosis. Child-Pugh (C-P) score and liver fibrosis score were also evaluated. Data were analyzed by statistical software 13.0. RESULTS: Serum HE4 levels were significantly higher in liver fibrosis than that of controls [105.35 (82.64, 164.18) vs 46.2 (39.9, 58.9) pmol L, P = .00] and hepatic patients without liver fibrosis [105.35 (82.64, 164.18) vs 51.00 (44.02, 65.65) pmol L, P < .01]; Serum HE4 levels in liver fibrosis patients with C-P class C were significantly higher than those with C-P class A [143.75 (106.50, 186.08) vs 81.42 (69.73, 99.26) pmol L, P = .005] and C-P class B [143.75 (106.50, 186.08) vs 113.10 (88.92, 169.50) pmol L, P = .01]; the diagnostic sensitivity and specificity of serum HE4 levels for liver fibrosis detection were 87.5% and 81.1%, at a cutoff value of 69 pmol L; Serum HE4 levels in alcoholic liver fibrosis were higher than that of liver fibrosis with hepatitis B virus infection [131.30 (100.67, 228.35) vs 89.46 (73.74, 116.45) pmol L, P < .01]. CONCLUSION: Serum HE4 was closely correlated with C-P class and might be a potential marker for liver fibrosis.


Assuntos
Cirrose Hepática/sangue , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/análise , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Hepatite B Crônica/sangue , Hepatite C Crônica/sangue , Humanos , Cirrose Hepática/classificação , Cirrose Hepática/diagnóstico , Hepatopatias Alcoólicas/sangue , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade
7.
Sci Rep ; 10(1): 16093, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999391

RESUMO

Sarcopenia is an independent predictor of mortality in patients with liver cirrhosis. However, evidence has emerged that skeletal muscles mediate their protective effect against sarcopenia by secreting myokines. Therefore, we investigated whether irisin was associated with sarcopenia in patients with liver cirrhosis. This was an observational cross-sectional study of data collected from 187 cirrhotic patients. Sarcopenia was defined by computed tomography (CT) scans using specific cutoffs of the 3rd lumbar vertebra skeletal muscle index (L3 SMI). Morning irisin levels were obtained in all patients. Of the 187 patients, sarcopenia was noted in 73 (39%). Irisin concentrations were lower in sarcopenic patients (32.40 pg/ml [interquartile range (IQR): 18.70, 121.26], p < 0.001) than in nonsarcopenic patients. There was a weak correlation between L3 SMI and irisin levels (r = 0.516, p < 0.001). Multivariable regression analysis including L3 SMI, body mass index (BMI), very-low-density lipoprotein (VLDL)-cholesterol, aspartate aminotransferase (AST), adiponectin, and irisin levels showed that L3 SMI (odds ratio [OR] = 0.915, p = 0.023), adiponectin levels (OR = 1.074, p = 0.014), irisin levels (OR = 0.993, p < 0.001) and BMI (OR = 0.456, p = 0.004) were independently associated with sarcopenia. Irisin levels are associated with sarcopenia in patients with liver cirrhosis. This paper addresses a gap in the literature and facilitates the future transition into clinical treatment.


Assuntos
Fibronectinas/sangue , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Sarcopenia/sangue , Sarcopenia/complicações , Adiponectina/sangue , Idoso , Estudos Transversais , Feminino , Humanos , Vértebras Lombares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Músculo Esquelético/diagnóstico por imagem , Estudos Retrospectivos , Fatores de Risco , Sarcopenia/diagnóstico por imagem , Tomografia Computadorizada por Raios X
8.
BMC Infect Dis ; 20(1): 758, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33059627

RESUMO

BACKGROUND: HIV infection exacerbates the prognosis of HCV infection, with a faster progression of hepatitis. Hepatic fibrosis is the major disruption of the hepatic tissue architecture characterized by anarchic deposition and excess of the extracellular matrix. The objective of this study was to evaluate hepatic fibrosis in HIV/HCV co-infected individuals as compared to HCV mono-infected. METHODS: A total of 97 participants (mean age 60.2 ± 14.3 years and 0.76 male/female sex ratio) was enrolled in a study conducted in Yaoundé, Cameroon from November 2018 to January 2019. Liver fibrosis was assessed by the APRI score (Aspartate Aminotransferase or AST/Platelet Ratio Index) which identifies the stage of fibrosis as classified by the Metavir system (F0 to F4). CD4 counts and plasmatic HIV viral load of HIV/HCV co-infected individuals were determined and the correlation between hepatic fibrosis and immuno-virological status established. Statistical analysis was done using Microsoft Excel 2016 and EpiInfo7 software. RESULTS: A high proportion (63.6%) of HIV/HCV co-infected participants had an abnormal AST level: 73.6 ± 45.8 IU/L as compared to 58.5 ± 39.3 IU/L (59.3%) among HCV mono-infected participants. The frequency of thrombocytopenia was 63.6% with a mean platelet count of 137 ± 50 ×  103 IU/L in HIV/HCV co-infected participants as compared to 176 ± 67 × 103 IU/L in HCV mono-infected participants (38.4%). The progression of hepatic fibrosis in participants with clinically significant fibrosis: F2, F3 and F4 was higher among HIV/HCV co-infected and the mean APRI score was 1.7 ± 1.4 versus 1 ± 0.8 among HCV mono-infected (26.7%). All participants (100%) with detectable HIV viral load had clinically significant fibrosis compared to 33.4% in those with undetectable HIV viral load (p = 0.55). Only 42.9% participants with CD4 >  500 cells/µL had clinically significant fibrosis (p = 0.72) while 100% participants with CD4 <  200 cells/µL had clinically significant fibrosis (p = 0.58). CONCLUSIONS: A high level of AST combined with thrombocytopenia (APRI score > 1.5) is an indicator of hepatic fibrosis in HIV/HCV co-infected individuals. Because of its non-invasive and less costly nature, the APRI score can be a suitable biomarker to monitor hepatic fibrosis in HIV/HCV co-infected individuals in resource constrained settings.


Assuntos
Aspartato Aminotransferases/sangue , Coinfecção/virologia , Infecções por HIV/sangue , Hepatite C/sangue , Cirrose Hepática/virologia , Contagem de Plaquetas , Idoso , Biomarcadores/sangue , Contagem de Linfócito CD4 , Camarões , Estudos Transversais , Feminino , Fibrose , Infecções por HIV/virologia , Hepatite C/virologia , Humanos , Cirrose Hepática/sangue , Masculino , Pessoa de Meia-Idade , Trombocitopenia/virologia , Carga Viral , Viremia/complicações , Viremia/patologia
9.
PLoS One ; 15(10): e0240195, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33095789

RESUMO

This study aimed to investigate the relationship between serum zinc level and hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). A cross-sectional study was conducted using nationally representative samples from the Korea National Health and Nutrition Examination Survey 2010. Significant hepatic fibrosis was defined as Fibrosis-4 (FIB-4) index>1.3. Zinc level was measured using inductively coupled plasma mass spectrometry. Univariable and multivariable logistic regression analyses were performed to assess risk factors for significant hepatic fibrosis in patients with NAFLD. A total of 300 patients with NAFLD were analyzed in this study. The mean serum zinc level was 139.8±29.9 µg/dL. FIB-4 index was significantly increased as the serum zinc level decreased (Adjusted correlation coefficient = -0.177, p = 0.003). Significant liver fibrosis was observed in 62 patients (21%). The multivariable analysis showed that significant liver fibrosis in NAFLD was associated with diabetes mellitus (odds ratio [OR], 3.25; 95% confidence interval [CI], 1.71-6.19; p<0.001), male (OR, 2.59; 95% CI, 1.31-5.12; p = 0.006), and zinc level <140 µg/dL (OR, 2.14; 95% CI, 1.16-3.94; p = 0.015). There was an inverse relationship between serum zinc level and FIB-4 index in NAFLD. Low levels of serum zinc were an independent risk factor for significant hepatic fibrosis in NAFLD.


Assuntos
Cirrose Hepática/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Zinco/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia
10.
Sci Rep ; 10(1): 15558, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968110

RESUMO

Advanced fibrosis and portal hypertension influence short-term mortality. Lipocalin 2 (LCN2) regulates infection response and increases in liver injury. We explored the role of intrahepatic LCN2 in human alcoholic hepatitis (AH) with advanced fibrosis and portal hypertension and in experimental mouse fibrosis. We found hepatic LCN2 expression and serum LCN2 level markedly increased and correlated with disease severity and portal hypertension in patients with AH. In control human livers, LCN2 expressed exclusively in mononuclear cells, while its expression was markedly induced in AH livers, not only in mononuclear cells but also notably in hepatocytes. Lcn2-/- mice were protected from liver fibrosis caused by either ethanol or CCl4 exposure. Microarray analysis revealed downregulation of matrisome, cell cycle and immune related gene sets in Lcn2-/- mice exposed to CCl4, along with decrease in Timp1 and Edn1 expression. Hepatic expression of COL1A1, TIMP1 and key EDN1 system components were elevated in AH patients and correlated with hepatic LCN2 expression. In vitro, recombinant LCN2 induced COL1A1 expression. Overexpression of LCN2 increased HIF1A that in turn mediated EDN1 upregulation. LCN2 contributes to liver fibrosis and portal hypertension in AH and could represent a new therapeutic target.


Assuntos
Colágeno Tipo I/genética , Hepatite Alcoólica/genética , Lipocalina-2/genética , Cirrose Hepática/genética , Animais , Tetracloreto de Carbono/toxicidade , Modelos Animais de Doenças , Etanol/toxicidade , Feminino , Regulação da Expressão Gênica/genética , Hepatite Alcoólica/sangue , Hepatite Alcoólica/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Hipertensão Portal/sangue , Hipertensão Portal/genética , Hipertensão Portal/patologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Knockout , Análise em Microsséries/métodos , Inibidor Tecidual de Metaloproteinase-1/genética
11.
Clinics (Sao Paulo) ; 75: e1670, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32935822

RESUMO

OBJECTIVES: Acoustic radiation force impulse (ARFI) elastography, the aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), and the fibrosis-4 (FIB-4) index are widely used to assess liver fibrosis. However, efficacies of these methods in the evaluation of hepatic functional reserve remain unclear. In this study, we investigated the relationship between ARFI elastography combined with either AAR, APRI, or FIB-4 index and Child-Pugh (CP) class for the evaluation of hepatic functional reserve in patients with chronic hepatitis B (CHB)-related cirrhosis. METHODS: The shear wave velocities of 104 patients with clinically confirmed CHB-related cirrhosis were determined using the ARFI; and clinical serum markers (e.g. ALT, AST, PLT) were used to calculate the AAR, APRI, and FIB-4 index. Cirrhosis patients were scored according to their CP class. The ARFI, AAR, APRI, and FIB-4 index were compared with the CP class. The efficacy of each indicator in diagnosis was analyzed using the receiver operating characteristic (ROC) curve and the ARFI combined with either the AAR, APRI, or FIB-4 index, which is used to predict decompensated cirrhosis. RESULTS: No significant differences were observed in gender and age among CP classes A, B, and C patients (p>0.05). The ARFI values and the AAR, APRI, and FIB-4 index of patients with CP classes A, B, and C were significantly different (p<0.05). With an increasing CP class, the ARFI, AAR, APRI, and FIB-4 values increased. The correlation between the ARFI and the CP class was stronger than that between the AAR, APRI, and FIB-4 index and the CP class. The area under the ROC curve for the diagnosis of decompensated cirrhosis using the ARFI was 0.841, which was higher than that for the AAR, APRI, and FIB-4 index. According to the area under the curve results, no significant differences were found when the ARFI was combined with either the AAR, APRI, or FIB-4 index and when the ARFI alone was used. CONCLUSIONS: The ARFI value has a strong correlation with the CP class. Therefore, ARFI elastography complements CP class in the assessment of the hepatic functional reserve in patients with CHB-related cirrhosis.


Assuntos
Acústica , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Técnicas de Imagem por Elasticidade , Cirrose Hepática/patologia , Biomarcadores/sangue , Biópsia , Criança , Técnicas de Imagem por Elasticidade/métodos , Feminino , Humanos , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico por imagem , Masculino , Valor Preditivo dos Testes , Curva ROC , Sensibilidade e Especificidade , Índice de Gravidade de Doença
12.
Sci Rep ; 10(1): 15308, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943694

RESUMO

Non-alcoholic steatohepatitis (NASH) is major health burden lacking effective pharmacological therapies. Clinical trials enrol patients with histologically-defined NAFLD (non-alcoholic fatty liver disease) activity score (NAS) ≥ 4 and Kleiner-Brunt fibrosis stage (F) ≥ 2; however, screen failure rates are often high following biopsy. This study evaluated a non-invasive MRI biomarker, iron-corrected T1 mapping (cT1), as a diagnostic pre-screening biomarker for NASH. In a retrospective analysis of 86 biopsy confirmed NAFLD patients we explored the potential of blood and imaging biomarkers, both in isolation and in combination, to discriminate those who have NAS ≥ 4 and F ≥ 2 from those without. Stepwise logistic regression was performed to select the optimal combination of biomarkers, diagnostic accuracy was determined using area under the receiver operator curve and model validated confirmed with and fivefold cross-validation. Results showed that levels of cT1, AST, GGT and fasting glucose were all good predictors of NAS ≥ 4 and F ≥ 2, and the model identified the combination of cT1-AST-fasting glucose (cTAG) as far superior to any individual biomarker (AUC 0.90 [0.84-0.97]). This highlights the potential utility of the composite cTAG score for screening patients prior to biopsy to identify those suitable for NASH clinical trial enrolment.


Assuntos
Biomarcadores/sangue , Fibrose/sangue , Fibrose/patologia , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , Biópsia , Estudos Transversais , Técnicas de Imagem por Elasticidade/métodos , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética Multiparamétrica/métodos , Estudos Prospectivos , Curva ROC , Estudos Retrospectivos
13.
Nat Commun ; 11(1): 4489, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895384

RESUMO

We report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific extracellular vesicle (EV) purification system for early detection of HCC by performing digital scoring on the purified EVs. Earlier detection of HCC creates more opportunities for curative therapeutic interventions. EVs are present in circulation at relatively early stages of disease, providing potential opportunities for HCC early detection. We develop an HCC EV purification system (i.e., EV Click Chips) by synergistically integrating covalent chemistry-mediated EV capture/release, multimarker antibody cocktails, nanostructured substrates, and microfluidic chaotic mixers. We then explore the translational potential of EV Click Chips using 158 plasma samples of HCC patients and control cohorts. The purified HCC EVs are subjected to reverse-transcription droplet digital PCR for quantification of 10 HCC-specific mRNA markers and computation of digital scoring. The HCC EV-derived molecular signatures exhibit great potential for noninvasive early detection of HCC from at-risk cirrhotic patients with an area under receiver operator characteristic curve of 0.93 (95% CI, 0.86 to 1.00; sensitivity = 94.4%, specificity = 88.5%).


Assuntos
Biomarcadores Tumorais/isolamento & purificação , Carcinoma Hepatocelular/diagnóstico , Detecção Precoce de Câncer/métodos , Vesículas Extracelulares/genética , Neoplasias Hepáticas/diagnóstico , Idoso , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Química Click/instrumentação , Química Click/métodos , Química Computacional , Simulação por Computador , Diagnóstico Diferencial , Dimetilpolisiloxanos/química , Progressão da Doença , Detecção Precoce de Câncer/instrumentação , Feminino , Células Hep G2 , Humanos , Dispositivos Lab-On-A-Chip , Biópsia Líquida/instrumentação , Biópsia Líquida/métodos , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Técnicas Analíticas Microfluídicas/instrumentação , Técnicas Analíticas Microfluídicas/métodos , Pessoa de Meia-Idade , Nanoestruturas/química , Nanofios/química , Estadiamento de Neoplasias , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa/instrumentação , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
14.
Clin Sci (Lond) ; 134(16): 2117-2135, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32820802

RESUMO

End-stage chronic liver diseases are often associated with insulin resistance (IR) and diabetes mellitus (DM). Indeed, to quantify insulin sensitivity the euglycemic clamp technique was utilized, allowing the following to be stated: in small groups of patients, an IR in almost all cirrhotic patients can be observed, compared with a control group. Additionally, it has been demonstrated that IR in cirrhosis is linked to a decreased peripheral (muscle) glucose uptake rather than an increased liver glucose production. The homoeostasis model of IR (HOMA-IR) technique, devised only later, was then exploited to assess this same phenomenon in a larger sample population. The research established that even in patients with preserved liver function, cirrhosis is associated with significant alterations in glucose homoeostasis levels. The purpose of the present paper is to present the current research around the affiliation of cirrhosis and IR, discuss potential mechanisms explaining the association between cirrhosis and IR (i.e. endocrine perturbation, liver inflammation, altered muscle mass and composition, altered gut microbiota and permeability), complications that can arise as well as treatment options, through a critical review of the literature surrounding this subject. This research will also be investigating the beneficial impact, if there is any, of identifying and curing IR in patients with cirrhosis.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Homeostase , Resistência à Insulina , Cirrose Hepática/complicações , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/uso terapêutico , Inflamação/sangue , Inflamação/fisiopatologia , Insulina/sangue , Insulina/uso terapêutico , Fígado/patologia , Fígado/fisiopatologia , Cirrose Hepática/sangue
15.
Medicine (Baltimore) ; 99(32): e21551, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769895

RESUMO

To explore the association between serum cystatin C (Cys-C) and renal damage in patients with chronic hepatitis B.We retrospectively analyzed the clinical data of 425 patients with chronic hepatitis B virus (HBV) infection. Liver stiffness measured by FibroScan was used to diagnosis liver fibrosis. Cys-C levels were detected via latex-enhanced immunoturbidimetric assay.A total of 425 patients were enrolled. Among them, 217 were patients with CHB with an eGFR > 90 mL/min/1.73 m and 208 with an eGFR ≤90 mL/min/1.73 m. Cys-C levels significantly differed in patients with eGFR > 90 mL/min/1.73 m compared with patients with eGFR ≤90 mL/min/1.73 m (0.81 ±â€Š0.05 vs 1.05 ±â€Š0.06 mg/L, P < .001). Moreover, the Cys-C levels were 0.82 ±â€Š0.04 mg/L in patients without liver fibrosis, 0.98 ±â€Š0.05 mg/L in patients with mild liver fibrosis, 1.05 ±â€Š0.08 mg/L in patients with advanced liver fibrosis, and 1.12 ±â€Š0.07 mg/L in patients with liver cirrhosis (P < .001). Multivariate analyses were conducted to explore the independent factors associated with a decreased eGFR. Multivariate analysis suggested that T2DM (P = .032), liver fibrosis (P = .013), and Cys-C level (P = .035) were the independent factors associated with the decreased eGFR in patients with CHB. While age (P = .020) and Cys-C level (P = .001) were the independent factors associated with the decreased eGFR in patients with CHB-related fibrosis.The fibrosis group had significantly higher Cys-C levels than those without fibrosis. Routine monitoring of Cys-C levels is of positive significance in preventing the development of renal impairment of CHB patients.


Assuntos
Cistatina C/sangue , Vírus da Hepatite B , Hepatite B Crônica/sangue , Insuficiência Renal/sangue , Adulto , Feminino , Taxa de Filtração Glomerular , Hepatite B Crônica/complicações , Hepatite B Crônica/virologia , Humanos , Rim/virologia , Cirrose Hepática/sangue , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/virologia , Estudos Retrospectivos
16.
Medicine (Baltimore) ; 99(34): e21408, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846758

RESUMO

Noninvasive tests for the assessment of liver fibrosis are highly needed for the management of patients with autoimmune hepatitis (AIH). We aimed to investigate the accuracy of red cell distribution width to platelet ratio (RPR) in predicting liver fibrosis in AIH patients. One hundred nineteen AIH patients who underwent liver biopsy were enrolled. Liver fibrosis stage was diagnosed using the Scheuer scoring system. The diagnostic accuracy was evaluated by the area under the receiver operating characteristic curve (AUROC). RPR values in AIH patients with S2-S4 (0.10, interquartile range [IQR] 0.08-0.15), S3-S4 (0.10, IQR 0.09-0.14), and S4 (0.14, IQR 0.09-0.19) were significantly higher than patients with S0-S1 (0.07, IQR 0.06-0.08, P < .001), S0-S2 (0.08, IQR 0.06-0.12, P = .025) and S0-S3 (0.09, IQR 0.07-0.13, P = .014), respectively. The RPR was positively correlated with fibrosis stages (r = 0.412, P < .001), while aspartate transaminase to platelet ratio index (APRI) and fibrosis-4 score (FIB-4) were not significantly associated with fibrosis stages in AIH patients. The AUROCs of RPR in identifying significant fibrosis (S2-S4), advanced fibrosis (S3-S4), and cirrhosis (S4) were 0.780 (95% confidence interval [CI] 0.696-0.865), 0.639 (95% CI 0.530-0.748), and 0.724 (95% CI 0.570-0.878), respectively. The AUROCs of RPR were significantly higher than APRI and FIB-4 in diagnosing significant fibrosis, advanced fibrosis, and cirrhosis. Our study demonstrates that the RPR is a simple predictor of liver fibrosis and is superior to APRI and FIB-4 in identifying liver fibrosis in AIH patients.


Assuntos
Hepatite Autoimune/complicações , Cirrose Hepática/sangue , Índices de Eritrócitos , Feminino , Hepatite Autoimune/sangue , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
17.
Lancet Gastroenterol Hepatol ; 5(11): 970-985, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32763196

RESUMO

BACKGROUND: Non-invasive tests that can identify patients with non-alcoholic steatohepatitis (NASH) at higher risk of disease progression are lacking. We report the development and validation of a blood-based diagnostic test to non-invasively rule in and rule out at-risk NASH (defined as non-alcoholic fatty liver disease [NAFLD] activity score [NAS] ≥4 and fibrosis stage ≥2). METHODS: In this prospective derivation and global validation study, blood samples, clinical data, and liver biopsy results from three independent cohorts with suspected NAFLD were used to develop and validate a non-invasive blood-based diagnostic test, called NIS4. Derivation was done in the discovery cohort, which comprised 239 prospectively recruited patients with biopsy-confirmed NASH (NAFLD NAS ≥3; fibrosis stage 0-3) from the international GOLDEN-505 phase 2b clinical trial. A complete matrix based on 23 variables selected for univariate association with the presence of at-risk NASH and avoiding high multi-collinearity was used to derive the model in a bootstrap-based process that minimised the Akaike information criterion. The overall diagnostic performance of NIS4 was externally validated in two independent cohorts: RESOLVE-IT diag and Angers. The RESOLVE-IT diag cohort comprised the first 475 patients screened for potential inclusion into the RESOLVE-IT phase 3 clinical trial. Angers was a retrospective cohort of 227 prospectively recruited patients with suspected NAFLD and clinical risk factors for NASH or fibrosis stage 2 or more according to abnormal elastography results or abnormal liver biochemistry. Both external validation cohorts were independently analysed and were combined into a pooled validation cohort (n=702) to assess clinical performance of NIS4 and other non-invasive tests. FINDINGS: The derived NIS4 algorithm comprised four independent NASH-associated biomarkers (miR-34a-5p, alpha-2 macroglobulin, YKL-40, and glycated haemoglobin; area under the receiver operating characteristics curve [AUROC] 0·80, 95% CI 0·73-0·85), and did not require adjustment for age, sex, body-mass index (BMI), or aminotransferase concentrations. Clinical cutoffs were established within the discovery cohort to optimise both rule out and rule in clinical performance while minimising indeterminate results. NIS4 was validated in the RESOLVE-IT diag cohort (AUROC 0·83, 95% CI 0·79-0·86) and the Angers cohort (0·76, 0·69-0·82). In the pooled validation cohort, patients with a NIS4 value less than 0·36 were classified as not having at-risk NASH (ruled out) with 81·5% (95% CI 76·9-85·3) sensitivity, 63·0% (57·8-68·0) specificity, and a negative predictive value of 77·9% (72·5-82·4), whereas those with a NIS4 value of more than 0·63 were classified as having at-risk NASH (ruled in) with 87·1% (83·1-90·3) specificity, 50·7% (45·3-56·1) sensitivity, and a positive predictive value of 79·2% (73·1-84·2). The diagnostic performance of NIS4 within the external validation cohorts was not influenced by age, sex, BMI, or aminotransferase concentrations. INTERPRETATION: NIS4 is a novel blood-based diagnostic that provides an effective way to non-invasively rule in or rule out at-risk NASH in patients with metabolic risk factors and suspected disease. Use of NIS4 in clinical trials or in the clinic has the potential to greatly reduce unnecessary liver biopsies in patients with lower risk of disease progression. FUNDING: Genfit.


Assuntos
Proteína 1 Semelhante à Quitinase-3/análise , Hemoglobina A Glicada/análise , Cirrose Hepática , Fígado , MicroRNAs/análise , Hepatopatia Gordurosa não Alcoólica , alfa-Macroglobulinas/análise , Área Sob a Curva , Biomarcadores/sangue , Biópsia/métodos , Testes de Química Clínica/métodos , Testes de Química Clínica/normas , Regras de Decisão Clínica , Progressão da Doença , Técnicas de Imagem por Elasticidade/métodos , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Gravidade do Paciente , Valor Preditivo dos Testes , Medição de Risco/métodos
18.
PLoS One ; 15(8): e0237840, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822420

RESUMO

BACKGROUND AND OBJECTIVES: The hydroxylation to 25-hydroxy vitamin D (25(OH)D) occurs in the liver and the impact of liver disease on vitamin D is unclear. This study evaluated the relationship between vitamin D concentrations and hepatic histopathology, seasonality and patient characteristics in well-characterized patients having undergone a liver biopsy. METHOD: 25(OH)D was measured post-hoc in pre-treatment serum from 331 North European patients with chronic HCV genotype 2 or 3 infection (NORDynamIC study). Liver biopsies were scored for fibrosis and inflammation according to the Ishak protocol, and graded for steatosis. Non-invasive markers of hepatic fibrosis as well as baseline viral and host characteristics, including genetic polymorphisms rs2228570, rs7975232, and rs10877012 were also evaluated. RESULTS: Mean 25(OH)D concentration was 59 ±23 nmol/L, with 41% having values <50 nmol/L and 6% were <30 nmol/L. 25(OH)D correlated with fibrosis (r = -0.10, p ≤0.05) in univariate but not in multivariate analyses. No association was observed between 25(OH)D and hepatic inflammation, but with steatosis in HCV genotype 2 infected patients. None of the genetic polymorphisms impacted on 25(OH)D levels or fibrosis. 25(OH)D levels were significantly inversely correlated to BMI (r = -0.19, p = 0.001), and was also associated with season and non-Caucasian ethnicity. CONCLUSION: Fibrosis was not independently associated with 25(OH)D concentration and no association was seen with hepatic inflammation, but HCV genotype 2 infected patients with moderate-to-severe steatosis had lower 25(OH)D levels compared to those without steatosis. A high percentage had potential risk of 25(OH)D deficiency, and BMI, seasonality and ethnicity were independently associated with 25(OH)D as previously reported.


Assuntos
Fígado Gorduroso/sangue , Hepatite C Crônica/sangue , Cirrose Hepática/sangue , Fígado/patologia , Vitamina D/análogos & derivados , Adulto , Biópsia , Índice de Massa Corporal , Dinamarca , Grupos Étnicos , Europa (Continente)/epidemiologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Fígado Gorduroso/virologia , Feminino , Finlândia , Genótipo , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatite C Crônica/genética , Hepatite C Crônica/patologia , Humanos , Fígado/citologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Noruega , Polimorfismo Genético , Análise de Regressão , Estações do Ano , Suécia , Vitamina D/sangue
20.
Sci Rep ; 10(1): 10926, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616821

RESUMO

Aberrant metabolisms have been hypothesized to precede the occurrence of hepatocellular carcinoma (HCC), therefore, we investigated biomarkers associated with subsequent HCC in peripheral bloods using metabolomic technologies. A cohort of 475 HCC-naïve liver cirrhotic patients were recruited and prospectively followed. A total of 39 patients developed HCC in the follow-up period. Baseline plasma metabolites were explored using untargeted nuclear magnetic resonance. Candidates were then quantified by ultra-performance liquid chromatography. A series of univairiate and multivariate analysis showed that Phenylalanine (Phe) and Glutamine (Gln) levels are associated with time to HCC, independent of viological etiologies and age. A HCC risk score R was then constructed using the polynomial combination of age, Phe and Gln in the units of micromolar (µM):[Formula: see text] R correlates with the time to HCC significantly (Hazard ratio [HR] = 2.368, 95% confidence interval [CI] 1.760-3.187, P < 0.001). An additional cross-sectional analysis showed that Phe and Gln concentrations both correlates with HCC occurrence in the next 3 years (area under the receiver operating characteristic curve [AUC] = 0.607 and 0.629, P = 0.033 and 0.010 respectively). In conclusion, phenylalanine and glutamine concentrations in the peripheral blood correlate with subsequent HCC.


Assuntos
Carcinoma Hepatocelular/etiologia , Glutamina/sangue , Cirrose Hepática/sangue , Fenilalanina/sangue , Fatores Etários , Idoso , Área Sob a Curva , Cromatografia Líquida , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Ressonância Magnética Nuclear Biomolecular , Sintomas Prodrômicos , Estudos Prospectivos , Curva ROC , Risco
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