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1.
J Clin Invest ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34597274

RESUMO

BACKGROUND: There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. METHODS: We combined individual level data from 13,888 COVID-19 patients (N=7,185 hospitalized) from 17 cohorts in nine countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications and laboratory values. We next performed meta-analyses using FinnGen and the Columbia University COVID-19 Biobank. RESULTS: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR 1.4, 95%CI 1.2-1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR 2.1, 95%CI 1.6-2.6), venous thromboembolism (OR 1.7, 95%CI 1.2-2.4), and hepatic injury (OR 1.5, 95%CI 1.2-2.0). Risk allele carriers ≤60 years had higher odds of death or severe respiratory failure (OR 2.7, 95%CI 1.8-3.9) compared to those >60 years (OR 1.5, 95%CI 1.2-1.8, interaction-p=0.038). Amongst individuals ≤60 years who died or experienced severe respiratory failure, 32.3% were risk variant carriers, compared to 13.9% of those not experiencing these outcomes. The genetic risk improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors. CONCLUSIONS: The major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced amongst individuals ≤60 years. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.

2.
Transfusion ; 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34647620

RESUMO

BACKGROUND: A large proportion of SARS-CoV-2-infected individuals does not develop severe symptoms. Serological tests help in evaluating the spread of infection and disease immunization. The aim of this study was to prospectively examine the trends and risk factors of SARS-CoV-2 infection in blood donors. STUDY DESIGN AND METHODS: We screened 8798 asymptomatic donors presenting in Milan from July 2020 to February 2021 (10,680 presentations) before the vaccination campaign for anti-nucleoprotein (NP) antibodies, and for anti-spike receptor-binding domain (RBD) antibodies and nasopharyngeal swab PCR in those who tested positive. RESULTS: The prevalence of anti-NP+/RBD+ tests increased progressively with time up to ~15% (p < .0001), preceded by a peak of PCR+ tests. Anti-RBD titers were higher in anti-NP IgG+/IgM+ than in IgG+/IgM- individuals and in those with a history of infection (p < .0001); of these 197/630 (31.2%) displayed high titers (>80 AU/ml). Anti-RBD titers declined during follow-up, depending on baseline titers (p < .0001) and time (p = .025). Risk factors for seroconversion were a later presentation date and non-O ABO blood group (p < .001). A positive PCR was detected in 0.7% of participants in the absence of SARS-CoV-2 viremia. CONCLUSIONS: During the second wave of SARS-CoV-2 infection in Northern Italy, we detected an increase in seroprevalence in healthy blood donors from ~4% to ~15%, with a trend paralleling that observed in the general population. Seroconversion was more frequent in carriers of non-O blood groups. The persistence of anti-RBD antibodies was short-lived.

3.
Hepatol Commun ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34520121

RESUMO

The changing epidemiology of liver disease, and modifications in the recommended analytical methodology call for a re-evaluation of the upper reference limits (URLs) of alanine aminotransferase (ALT) levels. Using the same approach consolidated 20 years ago to define the healthy population, we defined the URL for the newly recommended International Federation of Clinical Chemistry (IFCC) standardized test. In a cross-sectional study, we examined 21,296 apparently healthy blood donors (age 18-65 years) and calculated the sex-specific URL by the 95th percentile in individuals without risk factors for liver disease. These were tested for the ability to predict liver damage in a subset of 745 participants with dysmetabolism, in an independent cohort of 977 unselected donors, and in 899 patients with chronic liver disease. ALT levels were measured by the IFCC test. Male sex, body mass index, glucose, lipids, ferritin, hypertension, and younger age were independent ALT predictors (P < 0.001). Updated URLs were identified at 42/30 U/L in males/females, approximately 30% lower than those currently recommended by the IFCC. Due to improved sensitivity, they conferred the ability to detect steatosis and significant fibrosis in individuals with dysmetabolism (odds ratio [OR] = 2.31, range 1.40-3.80, P = 0.001; and OR = 3.35, range 1.19-9.42, P = 0.021; respectively), although with a limited accuracy, and significant fibrosis in unselected donors (OR = 2.32, 1.02-5.31, P = 0.045). Updated URLs had a moderate to high accuracy to discriminate liver conditions (area under the receiver operating characteristic curve = 0.81, range 0.78-0.91). Conclusion: Updated URLs by the IFCC method were lower than those calculated in initial studies, but higher than those in use with the recommended old, nonstandardized method, and were able to better predict liver disease. The limited awareness that different techniques are still in use should be regarded as a possible source of medical errors.

4.
Microbiol Spectr ; : e0054921, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34468185

RESUMO

In one year of the coronavirus disease 2019 (COVID-19) pandemic, many studies have described the different metabolic changes occurring in COVID-19 patients, linking these alterations to the disease severity. However, a complete metabolic signature of the most severe cases, especially those with a fatal outcome, is still missing. Our study retrospectively analyzes the metabolome profiles of 75 COVID-19 patients with moderate and severe symptoms admitted to Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Lombardy Region, Italy) following SARS-CoV-2 infection between March and April 2020. Italy was the first Western country to experience COVID-19, and the Lombardy Region was the epicenter of the Italian COVID-19 pandemic. This cohort shows a higher mortality rate compared to others; therefore, it represents a unique opportunity to investigate the underlying metabolic profiles of the first COVID-19 patients in Italy and to identify the potential biomarkers related to the disease prognosis and fatal outcome. IMPORTANCE Understanding the metabolic alterations occurring during an infection is a key element for identifying potential indicators of the disease prognosis, which are fundamental for developing efficient diagnostic tools and offering the best therapeutic treatment to the patient. Here, exploiting high-throughput metabolomics data, we identified the first metabolic profile associated with a fatal outcome, not correlated with preexisting clinical conditions or the oxygen demand at the moment of diagnosis. Overall, our results contribute to a better understanding of COVID-19-related metabolic disruption and may represent a useful starting point for the identification of independent prognostic factors to be employed in therapeutic practice.

5.
Curr Opin Pharmacol ; 61: 6-11, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34537584

RESUMO

Nonalcoholic fatty liver disease is the leading cause of chronic liver disease. Genetic predisposition, lifestyle, and metabolic comorbidities concur to nonalcoholic fatty liver disease development and progression to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Improvement in risk stratification and development of effective therapies for nonalcoholic steatohepatitis are key unmet clinical needs. Knowledge emerging from genomics could meet this need. A polygenic risk score (PRS) is calculated by summing the number of trait-associated alleles carried by an individual, which can be weighted by their effect size on the trait and captures the individual's genetic risk to develop a disease. In this review, we focalize on the potential use of PRSs for disease detection at an early stage and stratification of the risk of progression to severe forms. PRSs may represent robust instruments to implement targeted prevention programs, hepatocellular carcinoma surveillance in at-risk individuals, and to develop precision medicine therapeutic approaches.

6.
J Autoimmun ; 124: 102728, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34592707

RESUMO

Extremely rare reactions characterized by thrombosis and thrombocytopenia have been described in subjects that received ChAdOx1 nCoV-19 vaccination 5-16 days earlier. Although patients with vaccine-induced thrombotic thrombocytopenia (VITT) have high levels of antibodies to platelet factor 4 (PF4)-polyanion complexes, the exact mechanism of the development of thrombosis is still unknown. Here we reported serum studies as well as proteomics and genomics analyses demonstrating a massive complement activation potentially linked to the presence of anti-PF4 antibodies in a patient with severe VITT. At admission, complement activity of the classical and lectin pathways were absent (0% for both) with normal levels of the alternative pathway (73%) in association with elevated levels of the complement activation marker sC5b-9 (630 ng/mL [n.v. 139-462 ng/mL]) and anti-PF4 IgG (1.918 OD [n.v. 0.136-0.300 OD]). The immunoblotting analysis of C2 showed the complete disappearance of its normal band at 110 kDa. Intravenous immunoglobulin treatment allowed to recover complement activity of the classical pathway (91%) and lectin pathway (115%), to reduce levels of sC5b-9 (135 ng/mL) and anti-PF4 IgG (0.681 OD) and to normalize the C2 pattern at immunoblotting. Proteomics and genomics analyses in addition to serum studies showed that the absence of complement activity during VITT was not linked to alterations of the C2 gene but rather to a strong complement activation leading to C2 consumption. Our data in a single patient suggest monitoring complement parameters in other VITT patients considering also the possibility to target complement activation with specific drugs.

7.
Nat Commun ; 12(1): 4878, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385447

RESUMO

A postprandial increase of translation mediated by eukaryotic Initiation Factor 6 (eIF6) occurs in the liver. Its contribution to steatosis and disease is unknown. In this study we address whether eIF6-driven translation contributes to disease progression. eIF6 levels increase throughout the progression from Non-Alcoholic Fatty Liver Disease (NAFLD) to hepatocellular carcinoma. Reduction of eIF6 levels protects the liver from disease progression. eIF6 depletion blunts lipid accumulation, increases fatty acid oxidation (FAO) and reduces oncogenic transformation in vitro. In addition, eIF6 depletion delays the progression from NAFLD to hepatocellular carcinoma, in vivo. Mechanistically, eIF6 depletion reduces the translation of transcription factor C/EBPß, leading to a drop in biomarkers associated with NAFLD progression to hepatocellular carcinoma and preserves mitochondrial respiration due to the maintenance of an alternative mTORC1-eIF4F translational branch that increases the expression of transcription factor YY1. We provide proof-of-concept that in vitro pharmacological inhibition of eIF6 activity recapitulates the protective effects of eIF6 depletion. We hypothesize the existence of a targetable, evolutionarily conserved translation circuit optimized for lipid accumulation and tumor progression.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Hepatopatia Gordurosa não Alcoólica/genética , Fatores de Iniciação de Peptídeos/genética , Biossíntese de Proteínas/genética , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Clofazimina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Progressão da Doença , Inativação Gênica , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Fatores de Iniciação de Peptídeos/antagonistas & inibidores , Fatores de Iniciação de Peptídeos/metabolismo
9.
Eur J Clin Invest ; : e13659, 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34309833

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic that encompasses three distinct clinical phenotypes: uncomplicated fatty liver, nonalcoholic steatohepatitis (NASH) and NASH-related cirrhosis with its complications, including hepatocellular carcinoma. To date, no pharmacological treatments have been approved and lifestyle modifications including reduced caloric intake targeting a 7%-10% weight loss from baseline assessment represent the standard approach. Mediterranean diet has been recommended as the best dietary pattern since it is easy to follow and, independently of caloric intake its nutritional components have beneficial metabolic effects that not only improve steatosis but also risk factors for cardiovascular events, the leading cause of morbidity/mortality in individuals with NAFLD. Other dietary patterns such as ketogenic diet and Dietary Approach to Stop Hypertension (DASH) diet can be used in patients with NAFLD. Recently, intermittent fasting diets have gained popularity among healthy individuals and have been proposed as a safe and effective treatment for the metabolic syndrome in experimental and in a few human studies. In this narrative review, we aim to summarize the evidence for the available dietary approaches for patients with NAFLD.

10.
Dig Liver Dis ; 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34294580

RESUMO

Hepatocellular carcinoma (HCC) is on the rise globally, causing more than 800 thousand deaths annually, with an estimated annual percent change of 0.51 for causes other than viral hepatitis, including nonalcoholic fatty liver disease (NAFLD). The incidence of NAFLD-related HCC is peaking in several Far East regions (6-12% vs. 2-3% in Western Europe and USA), HCC risk being mainly driven by the epidemic of obesity and diabetes, both favored by an unhealthy diet and sedentary lifestyle. Under inherited susceptibility outlined by such genetic markers as variants in PNPLA3, TM6SF2 and MBOAT7, neoplastic transformation of NAFLD is driven by sublethal lipotoxicity consequent to hepatocyte lipid overload, whereas a myriad of factors spanning from subverted circadian homeostasis and gut dysbiosis to alcohol abuse and tobacco may interact as risk modifiers. At variance with viral HCC, NAFLD-HCC shows a frequent association with cardiovascular co-morbidities, absence of cirrhosis in up to half of patients and an association with persistently normal transaminase values. All these misleading features of NAFLD-related HCC account for the low uptake of surveillance and linkage to curative treatments that has been reported in patients with this cancer, a downside that could be attenuated when scores for cost-effective risk stratification become available.

12.
Liver Int ; 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34268860

RESUMO

BACKGROUND AND AIMS: Farnesoid X receptor (FXR) plays a key role in bile acid and lipid homeostasis. Experimental evidence suggests that it can modulate liver damage related to nonalcoholic fatty liver disease (NAFLD). We examined the impact of the NR1H4 rs35724 G>C, encoding for FXR, on liver damage in a large cohort of patients at risk of steatohepatitis. METHODS: We considered 2,660 consecutive individuals at risk of steatohepatitis with liver histology. The rs35724 G>C polymorphisms were genotyped by TaqMan assays. Gene expression was evaluated by RNASeq in a subset of patients (n = 124). RESULTS: The NR1H4 rs35724 CC genotype, after adjusting for clinic-metabolic and genetic confounders and for enrolling centre, was protective against severity of steatosis (GG vs CC OR 0.77, 95% CI 0.62-0.95; P = .01), steatohepatitis (GG vs CC OR 0.62, 95% CI 0.47-0.83; P = .001) and severity of fibrosis (GG vs CC OR 0.83, 95% CI 0.67-0.98; P = .04). The C allele was associated with higher total circulating cholesterol (P = .01). Patients carrying the NR1H4 rs35724 C allele had significantly higher hepatic mRNA levels of FXR and were associated with higher hepatic FGFR4 and Cyp39A1 that are in turn involved in bile acid synthesis. CONCLUSIONS: Increased hepatic FXR expression due to the NR1H4 rs35724 C allele is linked to higher serum cholesterol but protects against steatosis, steatohepatitis and liver fibrosis. The translational relevance of these results for patient risk stratification and FXR-targeted therapy warrants further investigation.

13.
Semin Liver Dis ; 41(4): 421-434, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34233370

RESUMO

The acronym nonalcoholic fatty-liver disease (NAFLD) groups a heterogeneous patient population. Although in many patients the primary driver is metabolic dysfunction, a complex and dynamic interaction of different factors (i.e., sex, presence of one or more genetic variants, coexistence of different comorbidities, diverse microbiota composition, and various degrees of alcohol consumption among others) takes place to determine disease subphenotypes with distinct natural history and prognosis and, eventually, different response to therapy. This review aims to address this topic through the analysis of existing data on the differential contribution of known factors to the pathogenesis and clinical expression of NAFLD, thus determining the different clinical subphenotypes observed in practice. To improve our understanding of NAFLD heterogeneity and the dominant drivers of disease in patient subgroups would predictably impact on the development of more precision-targeted therapies for NAFLD.

14.
Mol Metab ; 53: 101275, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34153521

RESUMO

OBJECTIVE: Neddylation is a druggable and reversible ubiquitin-like post-translational modification upregulated in many diseases, including liver fibrosis, hepatocellular carcinoma, and more recently, non-alcoholic fatty liver disease (NAFLD). Herein, we propose to address the effects of neddylation inhibition and the underlying mechanisms in pre-clinical models of NAFLD. METHODS: Hepatic neddylation measured by immunohistochemical analysis and NEDD8 serum levels measured by ELISA assay were evaluated in NAFLD clinical and pre-clinical samples. The effects of neddylation inhibition by using a pharmacological small inhibitor, MLN4924, or molecular approaches were assessed in isolated mouse hepatocytes and pre-clinical mouse models of diet-induced NAFLD, male adult C57BL/6 mice, and the AlfpCre transgenic mice infected with AAV-DIO-shNedd8. RESULTS: Neddylation inhibition reduced lipid accumulation in oleic acid-stimulated mouse primary hepatocytes and ameliorated liver steatosis, preventing lipid peroxidation and inflammation in the mouse models of diet-induced NAFLD. Under these conditions, increased Deptor levels and the concomitant repression of mTOR signaling were associated with augmented fatty acid oxidation and reduced lipid content. Moreover, Deptor silencing in isolated mouse hepatocytes abolished the anti-steatotic effects mediated by neddylation inhibition. Finally, serum NEDD8 levels correlated with hepatic neddylation during the disease progression in the clinical and pre-clinical models CONCLUSIONS: Overall, the upregulation of Deptor, driven by neddylation inhibition, is proposed as a novel effective target and therapeutic approach to tackle NAFLD.

15.
Eur J Clin Invest ; 51(9): e13629, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34184268

RESUMO

Background During COVID-19 outbreak, Italy was the first country in Europe to be heavily affected with an intensive care unit mortality of 26%. In order to reduce this percentage, physicians should establish clear and objective criteria to stratify COVID-19 patients at high risk of in-hospital death. Thus, the aim has been to test a large spectrum of variables ranging from clinical evaluation to laboratory biomarkers to identify which parameter would best predict all-cause in-hospital mortality in COVID-19 patients. Design observational study. Results Multivariate Cox regression analysis showed that each 5 years of increase in age corresponded to a hazard ratio (HR) of 1.28 (95% CI 1.00-1.65, P = .050); each increment of 803 ng/L of N-terminal pro-B-type natriuretic peptide (NT-proBNP) corresponded to a HR of 1.24 (95% CI 1.11-1.39, P < .001); each increment of 58 ng/L of interleukin (IL)-6 corresponded to a HR of 1.23 (95% CI 1.09-1.40, P < .001), and each increment of 250 U/L of lactate dehydrogenase (LDH) corresponded to a HR of 1.23 (95% CI 1.10-1.37, P < .001). According to the calculated cut-points for age (≥70 years), NT-proBNP (≥803 ng/L), IL-6 (≥58 ng/L) and LDH (≥371 U/L) when 2 out of these 4 were overcome, the HR was 2.96 (95% CI 1.97-4.45, P < .001). Conclusion In COVID-19 patients, besides age, the evaluation of three biochemical parameters, available in few hours after hospital admission can predict in-hospital mortality regardless of other comorbidities.


Assuntos
COVID-19/mortalidade , Mortalidade Hospitalar , Interleucina-6/sangue , L-Lactato Desidrogenase/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Fatores Etários , Idoso , Biomarcadores , COVID-19/sangue , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , SARS-CoV-2
16.
Liver Int ; 41(9): 1988-1998, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34152690

RESUMO

In December 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China and has since resulted in a global pandemic in excess of 165 million reported infections and 3.4 million attributable deaths. COVID-19 is primarily a respiratory illness, which may be complicated by pneumonia and acute respiratory distress syndrome. SARS-CoV-2 is also responsible for numerous extrapulmonary manifestations involving the haematologic, cardiovascular, renal, gastrointestinal and hepatobiliary, endocrinologic, neurologic, ophthalmologic and dermatologic systems. This review will discuss the pathophysiology of COVID-19; focusing on the mechanisms and outcomes of liver injury associated with COVID-19; its impact on chronic liver disease (CLD); management of CLD during the COVID-19 pandemic and the long-term impact of COVID-19 on CLD.


Assuntos
COVID-19 , Hepatopatias , Humanos , Hepatopatias/epidemiologia , Pandemias , SARS-CoV-2
17.
Artigo em Inglês | MEDLINE | ID: mdl-34091049

RESUMO

BACKGROUND & AIMS: A polygenic risk score based on well-known genetic variants in PNPLA3, TM6SF2, MBOAT7, and GCKR predicts hepatic fat content (polygenic risk score-hepatic fat content [PRS-HFC]). Here, we hypothesized that the addition of PRS-HFC to clinical fibrosis scores may improve risk stratification and prediction of severe liver disease (SLD). METHODS: We used data from 266,687 individuals in the UK Biobank, evaluating the incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation during a median follow-up period of 9 years. Nonalcoholic fatty liver disease fibrosis score, Fibrosis-4, aspartate aminotransferase-to-platelet ratio, BARD, and Forns scores, and PRS-HFC, were computed. All analyses were stratified according to the presence of diabetes, obesity, and a positive fatty liver index (≥60). RESULTS: Unfavorable genetics (PRS-HFC, ≥0.396) further stratified the risk of SLD in subjects in intermediate-/high-risk classes of fibrosis scores, with a higher effect in those with metabolic risk factors, and the prediction was improved by integrating PRS-HFC (areas under the receiver operating characteristic increased for all scores with a P value of approximately 10-2 to 10-4, except for the aspartate aminotransferase-to-platelet ratio in the overall population and in subjects with obesity). PRS-HFC improved diagnostic accuracies and positive predictive values for SLD in intermediate-high clinical score risk classes. Risk stratification and prediction were not affected or were poorly affected by unfavorable genetics in subjects without metabolic risk factors. CONCLUSIONS: Integration of genetics with clinical fibrosis scores refines individual risk and prediction for SLD, mainly in individuals at risk for nonalcoholic fatty liver disease. These data provide evidence from a prospective cohort that common genetic variants capture additional prognostic insights not conveyed by validated clinical/biochemical parameters.

18.
J Hepatol ; 75(4): 786-794, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34090928

RESUMO

BACKGROUND & AIMS: Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain. METHODS: The most common NSS (NFS, FIB-4, BARD, APRI) and the Hepamet fibrosis score (HFS) were assessed in 1,173 European patients with NAFLD from tertiary centres. Performance for fibrosis risk stratification and for the prediction of long-term hepatic/extrahepatic events, hepatocarcinoma (HCC) and overall mortality were evaluated in terms of AUC and Harrell's c-index. For longitudinal data, NSS-based Cox proportional hazard models were trained on the whole cohort with repeated 5-fold cross-validation, sampling for testing from the 607 patients with all NSS available. RESULTS: Cross-sectional analysis revealed HFS as the best performer for the identification of significant (F0-1 vs. F2-4, AUC = 0.758) and advanced (F0-2 vs. F3-4, AUC = 0.805) fibrosis, while NFS and FIB-4 showed the best performance for detecting histological cirrhosis (range AUCs 0.85-0.88). Considering longitudinal data (follow-up between 62 and 110 months), NFS and FIB-4 were the best at predicting liver-related events (c-indices>0.7), NFS for HCC (c-index = 0.9 on average), and FIB-4 and HFS for overall mortality (c-indices >0.8). All NSS showed limited performance (c-indices <0.7) for extrahepatic events. CONCLUSIONS: Overall, NFS, HFS and FIB-4 outperformed APRI and BARD for both cross-sectional identification of fibrosis and prediction of long-term outcomes, confirming that they are useful tools for the clinical management of patients with NAFLD at increased risk of fibrosis and liver-related complications or death. LAY SUMMARY: Non-invasive scoring systems are increasingly being used in patients with non-alcoholic fatty liver disease to identify those at risk of advanced fibrosis and hence clinical complications. Herein, we compared various non-invasive scoring systems and identified those that were best at identifying risk, as well as those that were best for the prediction of long-term outcomes, such as liver-related events, liver cancer and death.

20.
Sci Transl Med ; 13(599)2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162749

RESUMO

Aberrant hepatocyte Notch activity is critical to the development of nonalcoholic steatohepatitis (NASH)-induced liver fibrosis, but mechanisms underlying Notch reactivation in developed liver are unclear. Here, we identified that increased expression of the Notch ligand Jagged1 (JAG1) tracked with Notch activation and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in human liver biopsy specimens and mouse NASH models. The increase in Jag1 was mediated by hepatocyte Toll-like receptor 4 (TLR4)-nuclear factor κB (NF-κB) signaling in pericentral hepatocytes. Hepatocyte-specific Jag1 overexpression exacerbated fibrosis in mice fed a high-fat diet or a NASH-provoking diet rich in palmitate, cholesterol, and sucrose and reversed the protection afforded by hepatocyte-specific TLR4 deletion, whereas hepatocyte-specific Jag1 knockout mice were protected from NASH-induced liver fibrosis. To test therapeutic potential of this biology, we designed a Jag1-directed antisense oligonucleotide (ASO) and a hepatocyte-specific N-acetylgalactosamine (GalNAc)-modified siRNA, both of which reduced NASH diet-induced liver fibrosis in mice. Overall, these data demonstrate that increased hepatocyte Jagged1 is the proximal hit for Notch-induced liver fibrosis in mice and suggest translational potential of Jagged1 inhibitors in patients with NASH.


Assuntos
Proteína Jagged-1 , Hepatopatia Gordurosa não Alcoólica , Receptores Notch , Transdução de Sinais , Receptor 4 Toll-Like , Animais , Modelos Animais de Doenças , Hepatócitos/patologia , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/patologia , Receptor 4 Toll-Like/genética
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