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Hepatocellular carcinoma (HCC) is the most common primary liver cancer and presents a continuously growing incidence and high mortality rates worldwide. Besides advances in diagnosis and promising results of pre-clinical studies, established curative therapeutic options for HCC are not currently available. Recent progress in understanding the tumor microenvironment (TME) interactions has turned the scientific interest to immunotherapy, revolutionizing the treatment of patients with advanced HCC. However, the limited number of HCC patients who benefit from current immunotherapeutic options creates the need to explore novel targets associated with improved patient response rates and potentially establish them as a part of novel combinatorial treatment options. Glucocorticoid-induced TNFR-related protein (GITR) belongs to the TNFR superfamily (TNFRSF) and promotes CD8+ and CD4+ effector T-cell function with simultaneous inhibition of Tregs function, when activated by its ligand, GITRL. GITR is currently considered a potential immunotherapy target in various kinds of neoplasms, especially with the concomitant use of programmed cell-death protein-1 (PD-1) blockade. Regarding liver disease, a high GITR expression in liver progenitor cells has been observed, associated with impaired hepatocyte differentiation, and decreased progenitor cell-mediated liver regeneration. Considering real-world data proving its anti-tumor effect and recently published evidence in pre-clinical models proving its involvement in pre-cancerous liver disease, the idea of its inclusion in HCC therapeutic options theoretically arises. In this review, we aim to summarize the current evidence supporting targeting GITR/GITRL signaling as a potential treatment strategy for advanced HCC.
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One of the World Health Organization's targets for the 2030 viral hepatitis elimination strategy is to reduce new hepatitis C (HCV) infections. In Athens, Greece, people who inject drugs (PWID) have a high HCV prevalence, with increasing trends since the 2000s. This analysis aims to assess primary HCV incidence among PWID during 2012-2020. Two community-based interventions were implemented in 2012-2013 and 2018-2020 with repeated sero-behavioural surveys in each period. Participants enrolled in multiple surveys were identified through linkage. To assess trends in HCV transmission, three indicators were estimated: (i) anti-HCV prevalence among 'new' injectors (those injecting ≤2 years), (ii) indirect HCV incidence among 'new' injectors, assuming infection occurred at the midpoint between initiating injection and the first positive test, and (iii) HCV incidence from repeat participants. There were 431 and 125 'new' injectors, respectively, in 2012-2013 and 2018-2020. Αnti-HCV prevalence [95% CI] declined from 53.6% [48.8%, 58.3%] in 2012-2013 to 40.0% [31.3, 49.1%] in 2018-2020 (25.4% reduction, p = .007). The indirect estimate [95% CI] of HCV incidence among 'new' injectors decreased from 56.1 [49.3, 63.8] to 39.0/100 person-years (PYs) [29.6, 51.5] (30.5% reduction, p = .020). HCV incidence [95% CI] based on seroconversions in repeat participants (16/63 in 2012-2013 and 9/55 in 2018-2020) declined from 64.6 [39.6105.4] to 13.8/100 PYs [7.2, 26.5], respectively (78.6% reduction, p < .001). Primary HCV incidence remains high among PWID in Athens. Consistent implementation of combined interventions, including high-coverage harm reduction programs and initiatives tailored to increase access to HCV treatment, is essential to sustain the declining trends documented during 2012-2020.
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Hepatite C , Abuso de Substâncias por Via Intravenosa , Humanos , Grécia/epidemiologia , Incidência , Hepatite C/epidemiologia , Masculino , Abuso de Substâncias por Via Intravenosa/epidemiologia , Abuso de Substâncias por Via Intravenosa/complicações , Feminino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Prevalência , AdolescenteRESUMO
BACKGROUND: Preventing disease progression and viral suppression are the main goals of antiviral therapy in chronic hepatitis B (CHB). Liver stiffness measurement (LSM) by transient elastography is a reliable non-invasive method to assess liver fibrosis in patients with CHB. Our aim was to explore factors that may affect changes in LSMs during long term tenofovir (TDF) monotherapy in a well characterized cohort of patients with compensated CHB. METHODS: We analyzed serial LSMs in 103 adult patients with CHB who were on TDF monotherapy and had at least three LSMs over a period of 90 months. RESULTS: Twenty-five (24%) patients had advanced fibrosis at baseline. A significant decline in mean LSM between baseline and last visit (8.7 ± 6.2 kPa vs. 6.7 ± 3.3, p = 10- 3) was observed. Twenty-four (23%) patients had progression of liver fibrosis with mean increase in liver stiffness of 2.8 kPa (range: 0.2-10.2 kPa). Multivariate analysis showed that BMI ≥ 25 (OR, 0.014; 95% CI, 0.001-0.157; p = 0.001) and advanced fibrosis (OR, 5.169; 95% CI, 1.240-21.540; p = 0.024) were independently associated with a fibrosis regression of > 30% of liver stiffness compared to baseline value. CONCLUSIONS: In CHB patients TDF monotherapy resulted in liver fibrosis regression, especially in patients with advanced fibrosis. Despite the successful antiviral effect of TDF, 1 out of 4 patients had liver fibrosis progression. Obesity and advanced fibrosis at baseline were independently associated with significant liver fibrosis regression.
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Técnicas de Imagem por Elasticidade , Hepatite B Crônica , Adulto , Humanos , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Cirrose Hepática/diagnóstico por imagem , Tenofovir/uso terapêuticoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies worldwide, while it persists as the fourth most prevalent cause of cancer-related death in the United States of America. Although there are several novel therapeutic strategies for the approach of this intensely aggressive tumor, it remains a clinical challenge, as it is hard to identify in early stages, due to its asymptomatic course. A diagnosis is usually established when the disease is already in its late stages, while its chemoresistance constitutes an obstacle to the optimal management of this malignancy. The discovery of novel diagnostic and therapeutic tools is considered a necessity for this tumor, due to its low survival rates and treatment failures. One of the most extensively investigated potential diagnostic and therapeutic modalities is extracellular vesicles (EVs). These vesicles constitute nanosized double-lipid membraned particles that are characterized by a high heterogeneity that emerges from their distinct biogenesis route, their multi-variable sizes, and the particular cargoes that are embedded into these particles. Their pivotal role in cell-to-cell communication via their cargo and their implication in the pathophysiology of several diseases, including pancreatic cancer, opens new horizons in the management of this malignancy. Meanwhile, the interplay between pancreatic carcinogenesis and short non-coding RNA molecules (micro-RNAs or miRs) is in the spotlight of current studies, as they can have either a role as tumor suppressors or promoters. The deregulation of both of the aforementioned molecules leads to several aberrations in the function of pancreatic cells, leading to carcinogenesis. In this review, we will explore the role of extracellular vesicles and miRNAs in pancreatic cancer, as well as their potent utilization as diagnostic and therapeutic tools.
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Carcinoma Ductal Pancreático , Vesículas Extracelulares , MicroRNAs , Neoplasias Pancreáticas , Humanos , MicroRNAs/genética , Vesículas Extracelulares/genética , Vesículas Extracelulares/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/terapia , Carcinogênese/patologiaRESUMO
BACKGROUND: Mortality among people who inject drugs (PWID) is high, with overdose and HIV infection being the main causes of death. In Greece, there have been no data on mortality, and two HIV outbreaks have been recorded in this population in the past decade. In this study, we aim to estimate the all-cause crude mortality rate and the standardised mortality ratio in this population during 2018-2022. METHODS: PWID recruited from two community-based programs in Athens and Thessaloniki during 2018-2021 were interviewed and tested for HIV/HCV. Data on vital status (deceased/alive) and date of death were obtained from death registries through December 31, 2022. All-cause crude mortality rates (CMR) and standardised mortality ratios (SMR) were estimated. Determinants of mortality were assessed using Cox proportional-hazards model. RESULTS: Of 2,530 participants, 301 died over 8,543 person-years (PYs) of follow-up. The CMR (95 % CI) was 3.52 (3.15-3.94) deaths per 100 PYs; 3.10 per 100 PYs (2.68-3.58) in Athens and 4.48 per 100 PYs (3.74-5.37) in Thessaloniki. An increasing trend in CMR was identified over 2018-2022 in Athens (from 2.90 to 4.11 per 100 PYs, 41.5 % increase, p = 0.018). The pooled SMR (95 % CI) was 15.86 (14.17-17.76) for both cities and was particularly increased in younger individuals, females, those injecting daily, not enrolled to opioid agonist treatment and HIV-infected individuals. Older age, living in Thessaloniki, Greek origin, homelessness, history of injection in the past 12 months, and HIV infection were independently associated with higher risk of death. CONCLUSION: Mortality among PWID in the two largest cities (Athens and Thessaloniki) in Greece in 2018-2022 was high, with the population in Thessaloniki being particularly affected. The increasing trend in mortality in Athens may reflect the long-term impact of the COVID-19 pandemic. Preventive programs such as take-home naloxone, screening and treatment for HIV, are urgently needed.
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Overdose de Drogas , Infecções por HIV , Abuso de Substâncias por Via Intravenosa , Humanos , Abuso de Substâncias por Via Intravenosa/mortalidade , Abuso de Substâncias por Via Intravenosa/epidemiologia , Feminino , Masculino , Adulto , Grécia/epidemiologia , Pessoa de Meia-Idade , Infecções por HIV/mortalidade , Overdose de Drogas/mortalidade , Causas de Morte , Adulto Jovem , Fatores de RiscoRESUMO
Cholangiocarcinomas (CCAs) constitute a heterogeneous group of highly malignant epithelial tumors arising from the biliary tree. This cluster of malignant tumors includes three distinct entities, the intrahepatic, perihilar, and distal CCAs, which are characterized by different epidemiological and molecular backgrounds, as well as prognosis and therapeutic approaches. The higher incidence of CCA over the last decades, the late diagnostic time that contributes to a high mortality and poor prognosis, as well as its chemoresistance, intensified the efforts of the scientific community for the development of novel diagnostic tools and therapeutic approaches. Extracellular vesicles (EVs) comprise highly heterogenic, multi-sized, membrane-enclosed nanostructures that are secreted by a large variety of cells via different routes of biogenesis. Their role in intercellular communication via their cargo that potentially contributes to disease development and progression, as well as their prospect as diagnostic biomarkers and therapeutic tools, has become the focus of interest of several current studies for several diseases, including CCA. The aim of this review is to give a rundown of the current knowledge regarding the emerging role of EVs in cholangiocarcinogenesis and their future perspectives as diagnostic and therapeutic tools.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Vesículas Extracelulares , Humanos , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/terapia , Colangiocarcinoma/etiologia , Comunicação Celular , Ductos Biliares Intra-Hepáticos , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/terapia , Neoplasias dos Ductos Biliares/etiologiaRESUMO
BACKGROUND AND AIMS: Hepatitis D virus (HDV) underdiagnosis remains common. We assessed the HDV screening and prevalence rates in HBsAg-positive patients seen at tertiary liver centres throughout Greece as well as factors affecting HDV diagnosis. METHODS: All adult HBsAg-positive patients seen within the last 5 years were included. Non-screened patients who visited or could be recalled to the clinics over a 6-month period were prospectively tested for anti-HDV. RESULTS: Of 5079 HBsAg-positive patients, 53% had anti-HDV screening (41% before and 12% after study initiation). Pre-study (8%-88%) and total screening rates (14%-100%) varied widely among centres. Screening rates were associated with older age, known risk group, elevated ALT, centre location and size and period of first visit. Anti-HDV prevalence was 5.8% without significant difference in patients screened before (6.1%) or after study initiation (4.7%, p = 0.240). Anti-HDV positivity was associated with younger age, parenteral drug use, born abroad, advanced liver disease and centre location. Overall, HDV RNA detectability rate was 71.6% being more frequent in anti-HDV-positive patients with elevated ALT, advanced liver disease and hepatitis B therapy. CONCLUSIONS: Anti-HDV screening rates and recall capabilities vary widely among Greek liver clinics being higher in HBsAg-positive patients of known risk group with active/advanced liver disease seen at smaller centres, while non-medical factors are also important. Anti-HDV prevalence varies throughout Greece being higher in patients born abroad with younger age, parenteral drug use and advanced liver disease. Viremia is more frequently but not exclusively detected in anti-HDV-positive patients with elevated ALT and advanced liver disease.
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Hepatite B , Hepatite D , Hepatopatias , Transtornos Relacionados ao Uso de Substâncias , Adulto , Humanos , Vírus Delta da Hepatite/genética , Antígenos de Superfície da Hepatite B , Prevalência , Hepatite D/diagnóstico , Hepatite D/epidemiologia , Hepatite D/complicações , Hepatite B/diagnóstico , Hepatite B/epidemiologia , Hepatite B/complicações , Hepatopatias/complicações , Transtornos Relacionados ao Uso de Substâncias/complicaçõesRESUMO
BACKGROUND: The Inflammatory Bowel Disease-Disk (IBD-Disk) is a physician-administered tool that evaluates the functional status of patients with Inflammatory Bowel Disease (IBD). The aim of our study was to validate the content of the IBD-Disk in a Greek cohort of IBD patients. METHODS: Two questionnaires [the IBD Disk and the IBD-Disability Index (IBD-DI)] were translated into Greek and administered to IBD patients at baseline visit, after 4 weeks and 6 months. Validation of the IBD Disk included measuring of concurrent validity, reproducibility, and internal consistency. RESULTS: A total of 300 patients were included at baseline and 269 at follow-up. There was a good correlation between the total scores of the IBD-Disk and IBD-DI at baseline (Pearson correlation 0.87, p < 0.001). Reproducibility of the total IBD-Disk score was very good [intra-class correlation coefficient (ICC), 95% confidence interval (CI) 0.89 (0.86-0.91)]. Cronbach's coefficient alpha for all items achieved 0.90 (95%CI 0.88-0.92), demonstrating a very good homogeneity of the IBD-Disk items. Female gender and extraintestinal manifestations were significantly associated with a higher IBD-Disk total score. CONCLUSIONS: The Greek version of the IBD-Disk proved to be a reliable and valid tool in detecting and assessing IBD-related disability in a Greek cohort of IBD patients.
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Non-alcoholic fatty liver disease (NAFLD) is considered the most frequent chronic hepatic disease in the general population, while it is the first cause of liver transplantation in the US. NAFLD patients will subsequently develop non-alcoholic steatohepatitis (NASH), which is characterized by aberrant hepatocellular inflammation with or without the presence of fibrosis. The lack of specific biomarkers and therapeutic strategies makes non-alcoholic steatohepatitis (NASH) management a difficult task for clinicians. Extracellular vesicles (EVs) constitute a heterogenic population of vesicles produced by inward or outward plasma-membrane budding. There is an emerging connection between autophagy EVs production, via an unconventional non-degradative procedure. Alterations in the amount of the secreted EVs and the cargo they carry are also involved in the disease progression and development of NASH. Autophagy constitutes a multistep lysosomal degradative pathway that reassures cell homeostasis and survival under stressful conditions, such as oxygen and energy deprivation. It prevents cellular damage by eliminating defected proteins or nοn-functional intracellular organelles. At the same time, it reassures the optimal conditions for the cells via a different mechanism that includes the removal of cargo via the secretion of EVs. Similarly, autophagy machinery is also associated with the pathogenetic mechanism of NAFLD, while it has a significant implication for the progression of the disease and the development of NASH. In this review, we will shed light on the interplay between autophagy and EVs in NASH, the emerging connection of EVs production with the autophagy pathway, and their possible manipulation for developing future therapeutic strategies for NASH.
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Vesículas Extracelulares , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fígado/metabolismo , Vesículas Extracelulares/metabolismo , Autofagia , Biomarcadores/metabolismo , Oxigênio/metabolismoRESUMO
Nonalcoholic fatty liver disease (NAFLD) is dramatically increasing in parallel with the pandemic of type 2 diabetes. Here, the authors aimed to assess the performance of the most commonly used noninvasive, blood-based biomarkers for liver fibrosis (FibroTest, NAFLD fibrosis score, BARD score, and FIB-4 Index) in subjects with type 2 diabetes. Liver stiffness measurement was estimated by two-dimensional shear wave elastography. Finally, the authors assessed the diagnostic role of ActiTest and NashTest 2 in liver fibrosis in the examined population.
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HBV RNA is considered as a promising predictor in patients who discontinue nucleos(t)ide analogues (NAs). We determined HBV RNA levels in non-cirrhotic HBeAg-negative patients who discontinued NAs and assessed their predictability for 12-month outcomes. Fifty-seven patients of DARING-B study were included. HBV RNA levels were determined in stored monthly serum samples drawn at 0-3 months after end of therapy (EOT). Other markers previously determined in the same cohort including hepatitis B core-related antigen (HBcrAg) were also assessed. HBV RNA at EOT was detectable in 7% of patients, who developed virological/clinical relapse and required retreatment at month 2; in patients with undetectable EOT HBV RNA, 12-month cumulative rates of virological relapse, clinical relapse and retreatment were 68%, 28% and 21%, respectively (p ≤ 0.008). HBV RNA at month-1 after EOT was detectable in 19% of patients being associated with higher probability only of virological relapse (p = 0.001). HBV RNA levels correlated significantly to HBV DNA, HBcrAg, ALT and interferon-induced protein-10, but not HBsAg levels. Combined EOT HBV RNA and HBcrAg detection and/or HBsAg >1000 IU/ml was associated only with higher probability of retreatment having higher sensitivity and lower specificity than HBV RNA alone. In conclusion, serum HBV RNA is detectable in a minority of non-cirrhotic HBeAg-negative patients under effective long-term NAs therapy offering low sensitivity but 100% specificity for early retreatment due to severe clinical relapses after NA discontinuation. The combinations of EOT HBV RNA with HBcrAg and/or high HBsAg levels increase sensitivity but decrease specificity for prediction of retreatment after NAs withdrawal.
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Hepatite B Crônica , Antivirais/uso terapêutico , DNA Viral , Antígenos do Núcleo do Vírus da Hepatite B , Antígenos de Superfície da Hepatite B , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Humanos , Interferons/uso terapêutico , RNA , RecidivaRESUMO
BACKGROUND: Tenofovir alafenamide (TAF) has exhibited a favourable safety profile on estimated glomerular filtration (eGFR) and bone mineral density (BMD), but has not been extensively studied in patients with renal impairment and/or BMD disorders. AIMS: To assess predictors of eGFR changes and other safety and efficacy outcomes during 24-month TAF therapy in patients with chronic hepatitis B with renal and/or BMD disorders/risks. METHODS: Adult patients who started TAF at 13 clinics throughout Greece were prospectively included. Main exclusion criteria were hepatitis D, active malignancy and bisphosphonates recent use. MDRD formula was used for eGFR estimation. RESULTS: TAF was initiated in 176 patients (91% switched from another agent). At 12 and 24 months, HBV DNA was undetectable in 97% and 100%, and ALT was normal in 96% and 95% of patients. Median ALT decreased from baseline to month 12/24 (p < 0.001). Mean eGFR decreased from previous treatment initiation to baseline (p < 0.001), increased at 12 months and remained stable at 24 months (p ≤ 0.001). An increase in eGFR of >3 ml/min at 12 month was observed in 50% of patients and was associated mainly with baseline eGFR 30-60 ml/min. In patients with baseline phosphate <2.5 mg/dl, mean serum phosphate increased at month-12/24 (p < 0.001). Median BMD did not change significantly from baseline to 12 months but improved at 24 months (p = 0.001). CONCLUSIONS: In mostly switched patients with renal and/or BMD disorders/risks, eGFR improved after 12-24 months of TAF treatment, especially in patients with baseline eGFR 30-60 ml/min. TAF may also improve low serum phosphate, BMD and ALT, whereas it maintains or induces virological suppression.
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Infecções por HIV , Hepatite B Crônica , Adenina/efeitos adversos , Adulto , Alanina/efeitos adversos , Hepatite B Crônica/tratamento farmacológico , Humanos , Fosfatos , Estudos Prospectivos , Tenofovir/efeitos adversos , Tenofovir/análogos & derivadosRESUMO
Background: Bacterial infections are associated with the risk of variceal bleeding through complex pathophysiologic pathways. Objectives: The primary objective of the present case-control study was to investigate the role of bacterial translocation and intestinal barrier dysfunction in the pathogenesis of variceal bleeding. A secondary objective was to determine independent predictors of key outcomes in variceal bleeding, including bleeding-related mortality. Methods: Eighty-four (n = 84) consecutive patients participated in the study, 41 patients with acute variceal bleeding and 43 patients with stable cirrhosis, and were followed up for 6 weeks. Peripheral blood samples were collected at patient admission and before any therapeutic intervention. Results: Child-Pugh (CP) score (OR: 1.868; p = 0.044), IgM anti-endotoxin antibody levels (OR: 0.954; p = 0.016) and TGF-ß levels (OR: 0.377; p = 0.026) were found to be significant predictors of variceal bleeding. Regression analysis revealed that albumin (OR: 0.0311; p = 0.023), CRP (OR: 3.234; p = 0.034) and FABP2 levels (OR:1.000, p = 0.040), CP score (OR: 2.504; p = 0.016), CP creatinine score (OR: 2.366; p = 0.008), end-stage liver disease model (MELD), Na (OR: 1.283; p = 0.033), portal vein thrombosis (OR: 0.075; p = 0.008), hepatocellular carcinoma (OR: 0.060; p = 0.003) and encephalopathy (OR: 0.179; p = 0.045) were significantly associated with 6-week mortality. Conclusions: Bacterial translocation and gut barrier impairment are directly related to the risk of variceal bleeding. Microbiota-modulating interventions and anti-endotoxin agents may be promising strategies to prevent variceal bleeding.
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BACKGROUND AND AIMS: Scarce data exist on the effect of nucleos(t)ide analogue (NA) discontinuation on hepatocellular carcinoma (HCC) risk in HBeAg-negative chronic hepatitis B (CHBe-). Therefore, we assessed whether HCC risk is increased in non-cirrhotic CHBe- patients who discontinue compared to those remaining on NAs. METHODS: This cohort study included 650 consecutive non-cirrhotic Caucasian or Asian patients with CHBe- without a history of HCC who discontinued NAs after a median of 5 or 3 years (cases, n = 325; Caucasians: 143, Asians: 182) or remained on NA therapy beyond 5 or 3 years respectively (controls, n = 325; Caucasians: 223, Asians: 102). Propensity score (PS) 1:1 matching was applied to adjust for patients' origin, age and sex. RESULTS: During a median follow-up of 44 months, HCC developed in 7/325 cases and 9/325 controls or 7/245 PS-matched cases and 7/245 PS-matched controls with 5-year cumulative HCC incidence of 5.1% and 4.9% respectively (log-rank, P = .836). No difference in 5-year HCC risk was observed between cases and controls of Caucasian (3.0% vs 4.8%; log-rank, P = .510) or Asian origin (1.3% vs 2.2%; log-rank, P = .873). In both cases and controls, HCC incidence was independently associated with age and PAGE-B score. In cases alone, HCC development after NA discontinuation was associated only with pretreatment platelet counts and PAGE-B score, but not with any type of relapse or HBsAg loss. CONCLUSIONS: Our findings suggest that discontinuation of effective long-term NA therapy in non-cirrhotic CHBe- patients are not associated with increased HCC risk, which is not affected by post-NA relapses and/or HBsAg loss.
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Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Antivirais , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Antígenos E da Hepatite B , Vírus da Hepatite B , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Humanos , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia , Suspensão de TratamentoRESUMO
Objectives: Nonalcoholic fatty liver disease is dramatically increasing in parallel with the pandemic of type 2 diabetes mellitus. We investigated factors associated with hepatic steatosis (HS) in adult Greek individuals with established type 2 diabetes mellitus. Materials and Methods: We investigated 120 consecutive people with type 2 diabetes attending the Diabetic Outpatient Clinic at an Academic Hospital in Athens, Greece. All of them had demographic, clinical, and biochemical data recorded. HS was estimated by magnetic resonance imaging determined by proton density fat fraction software and defined as the percentage of total liver fat divided by the liver volume. HS of >5% was considered abnormal. The PNPLA3 (I148M) variant was evaluated as a genetic factor by standard molecular techniques. FibroMax™ was also calculated. Results: Of the 120 participants, median age was 61.7, 46% were females, diabetes duration was 10 years, and HbA1c (glycated hemoglobin) was 6.7%. The median value of HS was 7.8. The PNPLA3 rs738409 CC/CG/GG genotype frequencies were 54.2%, 35%, and 10.8%, respectively. In multivariate analysis, PNPLA3 rs738409 (ß = 0.425, P = 0.001), waist circumference (ß = 2.448, P = 0.001), and female sex (ß = 0.419, P = 0.002) had a direct association with HS, while duration of diabetes (ß = -0.179, P = 0.011) had an inverse association with HS. Conclusions: HS in type 2 diabetes is the sum of interplay of various factors exerting a direct or an inverse association, the most prominent among them being abdominal obesity and PNPLA3 molecular variability.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Adulto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença , Genótipo , Grécia/epidemiologia , Humanos , Lipase/genética , Fígado/diagnóstico por imagem , Fígado/patologia , Imageamento por Ressonância Magnética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , PrótonsAssuntos
COVID-19 , Hepatite Autoimune , Autoanticorpos , Humanos , RNA Mensageiro , SARS-CoV-2 , VacinaçãoRESUMO
BACKGROUND & AIMS: Several models have recently been developed to predict risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Our aims were to develop and validate an artificial intelligence-assisted prediction model of HCC risk. METHODS: Using a gradient-boosting machine (GBM) algorithm, a model was developed using 6,051 patients with CHB who received entecavir or tenofovir therapy from 4 hospitals in Korea. Two external validation cohorts were independently established: Korean (5,817 patients from 14 Korean centers) and Caucasian (1,640 from 11 Western centers) PAGE-B cohorts. The primary outcome was HCC development. RESULTS: In the derivation cohort and the 2 validation cohorts, cirrhosis was present in 26.9%-50.2% of patients at baseline. A model using 10 parameters at baseline was derived and showed good predictive performance (c-index 0.79). This model showed significantly better discrimination than previous models (PAGE-B, modified PAGE-B, REACH-B, and CU-HCC) in both the Korean (c-index 0.79 vs. 0.64-0.74; all p <0.001) and Caucasian validation cohorts (c-index 0.81 vs. 0.57-0.79; all p <0.05 except modified PAGE-B, p = 0.42). A calibration plot showed a satisfactory calibration function. When the patients were grouped into 4 risk groups, the minimal-risk group (11.2% of the Korean cohort and 8.8% of the Caucasian cohort) had a less than 0.5% risk of HCC during 8 years of follow-up. CONCLUSIONS: This GBM-based model provides the best predictive power for HCC risk in Korean and Caucasian patients with CHB treated with entecavir or tenofovir. LAY SUMMARY: Risk scores have been developed to predict the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. We developed and validated a new risk prediction model using machine learning algorithms in 13,508 antiviral-treated patients with chronic hepatitis B. Our new model, based on 10 common baseline characteristics, demonstrated superior performance in risk stratification compared with previous risk scores. This model also identified a group of patients at minimal risk of developing HCC, who could be indicated for less intensive HCC surveillance.
Assuntos
Inteligência Artificial/normas , Carcinoma Hepatocelular/fisiopatologia , Hepatite B Crônica/complicações , Adulto , Antivirais/farmacologia , Antivirais/uso terapêutico , Inteligência Artificial/estatística & dados numéricos , Povo Asiático/etnologia , Povo Asiático/estatística & dados numéricos , Carcinoma Hepatocelular/etiologia , Estudos de Coortes , Simulação por Computador/normas , Simulação por Computador/estatística & dados numéricos , Feminino , Seguimentos , Guanina/análogos & derivados , Guanina/farmacologia , Guanina/uso terapêutico , Hepatite B Crônica/fisiopatologia , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/fisiopatologia , Masculino , Pessoa de Meia-Idade , República da Coreia/etnologia , Tenofovir/farmacologia , Tenofovir/uso terapêutico , População Branca/etnologia , População Branca/estatística & dados numéricosRESUMO
BACKGROUND & AIMS: Antiviral treatment from hepatitis B envelope antigen (HBeAg)-positive status may attenuate the integration of hepatitis B virus DNA into the host genome causing hepatocellular carcinoma (HCC). We investigated the impact of HBeAg status at the onset of antiviral treatment on the risk of HCC. METHODS: The incidence of HCC was evaluated in Korean patients with chronic hepatitis B who started entecavir or tenofovir in either HBeAg-positive or HBeAg-negative phase. The results in the Korean cohort were validated in a Caucasian PAGE-B cohort. RESULTS: A total of 9143 Korean patients (mean age, 49.2 years) were included: 49.1% were HBeAg-positive and 49.2% had cirrhosis. During follow-up (median, 5.1 years), 916 patients (10.0%) developed HCC. Baseline HBeAg positivity was not associated with the risk of HCC in the entire cohort or cirrhotic subcohort. However, in the non-cirrhotic subcohort, HBeAg positivity was independently associated with a lower risk of HCC in multivariable (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.26-0.66), propensity score-matching (aHR, 0.46; 95% CI, 0.28-0.76), and inverse probability weighting analyses (aHR, 0.44; 95% CI, 0.28-0.70). In the Caucasian cohort (n = 719; mean age, 51.8 years; HBeAg-positive, 20.3%; cirrhosis, 34.8%), HBeAg-positivity was not associated with the risk of HCC either in the entire cohort or cirrhotic subcohort. In the non-cirrhotic subcohort, none of the HBeAg-positive group developed HCC, although the difference failed to reach statistical significance (aHR, 0.21; 95% CI, 0.00-1.67). CONCLUSIONS: This multinational cohort study implies that HBeAg positivity at the onset of antiviral treatment seems to be an independent factor associated with a lower risk of HCC in patients with chronic hepatitis B without cirrhosis, but not in those with cirrhosis.
Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Antivirais/uso terapêutico , Carcinoma Hepatocelular/etiologia , Estudos de Coortes , Antígenos da Hepatite B/uso terapêutico , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/complicações , Neoplasias Hepáticas/etiologia , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Increased gut permeability and bacterial translocation play an important role in liver cirrhosis. Zonulin is a recently recognized protein involved in the disintegration of the intestinal barrier. AIM: To investigate possible differences in serum zonulin levels among patients with different cirrhosis stages and their potential prognostic implications. METHODS: Consecutive cirrhotic patients who attended our liver clinic were included in the study. Serum zonulin levels, clinical, radiological and biochemical data were collected at baseline. Patients who accepted participation in a regular surveillance program were followed-up for at least 12 mo. RESULTS: We enrolled 116 cirrhotics [mean Child-Turcotte-Pugh (CTP) score: 6.2 ± 1.6; model for end-stage liver disease score: 11 ± 3.9]. The causes of cirrhosis were viral hepatitis (39%), alcohol (30%), non-alcoholic fatty liver disease (17%), and other (14%). At baseline, 53% had decompensated cirrhosis, 48% had ascites, and 32% had history of hepatic encephalopathy. Mean zonulin levels were significantly higher in patients with CTP-B class than CTP-A class (4.2 ± 2.4 ng/dL vs 3.5 ± 0.9 ng/dL, P = 0.038), with than without ascites (P = 0.006), and with than without history of encephalopathy (P = 0.011). Baseline serum zonulin levels were independently associated with the probability of decompensation at 1 year (P = 0.039), with an area under the receiving operating characteristic of 0.723 for predicting hepatic decompensation. Higher CTP score (P = 0.021) and portal vein diameter (P = 0.022) were independent predictors of mortality. CONCLUSION: Serum zonulin levels are higher in patients with more advanced chronic liver disease and have significant prognostic value in identifying patients who will develop decompensation.