RESUMEN
Objective: To examine the effects of peripheral blood eosinophil (EOS) count and its dynamic alterations on the treatment efficacy and prognosis of patients with advanced hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) receiving camrelizumab combined with lenvatinib (C + L) therapy. Methods: A retrospective analysis was performed on 200 patients with advanced HBV-HCC who were admitted to two centers from January 2018 to August 2023 and treated with C + L. EOS, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were determined before C + L treatment (EOS0, NLR0, and PLR0) and after three cycles of treatment (EOS3, NLR3, and PLR3). The area under the curve was calculated using the receiver operating characteristic (ROC) curve. NLR and PLR served as references to analyze the effect of differences in EOS in predicting the survival efficacy of patients with HBV-HCC treated using C + L. The independent risk factors affecting progression-free survival (PFS) and overall survival (OS) were analyzed using univariate and multivariate Cox proportional risk models. Results: The ROC curve revealed that the predictive value of EOS3 was better than those of NLR3 and PLR3 for the long-term treatment efficacy of patients with intermediate and advanced HBV-HCC receiving C + L. Statistically significant differences were observed between groups with different levels of EOS0 and EOS3 and the evaluation of treatment efficacy after 3 weeks (P < 0.05). The median PFS of the high-EOS0 group was higher than that of the low-EOS0 group (P = 0.027); median PFS of the high EOS3 group was higher than that of the low EOS3 group (P = 0.018); median OS of the high EOS0 group was higher than that of the low EOS0 group (P = 0.032); median OS of the high EOS3 group was higher than that of the low EOS3 group (P < 0.0001). Multifactorial Cox analysis revealed that EOS3 was an independent predictor of PFS and that EOS0 was an independent predictor of OS (P < 0.05). Conclusion: EOS may be an ideal indicator for predicting the treatment efficacy and prognosis of patients with advanced HBV-HCC receiving C + L.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular , Eosinófilos , Hepatitis B , Neoplasias Hepáticas , Compuestos de Fenilurea , Quinolinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/sangre , Femenino , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/sangre , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Pronóstico , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Hepatitis B/complicaciones , Hepatitis B/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Curva ROC , Anciano , Recuento de Leucocitos , Adulto , Virus de la Hepatitis B/aislamiento & purificación , Resultado del TratamientoRESUMEN
Hepatitis C virus (HCV) is a hepatotropic virus that can be transmitted through unsafe medical procedures, such as injections, transfusions, and dental treatment. The infection may be self-limiting or manifest as a chronic form that induces liver fibrosis, cirrhosis, or progression into hepatocellular carcinoma (HCC). Epigenetic mechanisms are major regulators of gene expression. These mechanisms involve DNA methylation, histone modifications, and the activity of non-coding RNAs, which can enhance or suppress gene expression. Abnormal activity or the dysregulated expression of epigenetic molecules plays an important role in the pathogenesis of various pathological disorders, including inflammatory diseases and malignancies. In this review, we summarise the current evidence on epigenetic mechanisms involved in HCV infection and progression to HCC.
Asunto(s)
Metilación de ADN , Epigénesis Genética , Hepacivirus , Hepatitis C , Humanos , Hepacivirus/genética , Hepacivirus/patogenicidad , Hepatitis C/genética , Hepatitis C/virología , Metilación de ADN/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/etiología , AnimalesRESUMEN
Both maternal obesity and postnatal consumption of obesogenic diets contribute to the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). However, there is no consensus as to whether diets that are high in fat or carbohydrates/sugars differentially influence the development of HCC. Moreover, the long-term effects of prenatal HF exposure on HCC and whether this is influenced by postnatal diet has not yet been evaluated. C57BL/6 dams were fed either a low-fat, high-carbohydrate control (C) or low-carbohydrate, high-fat (HF) diet. At weaning, male and female offspring were fed the C or HF diet, generating four diet groups: C/C, C/HF, HF/C and HF/HF. Tissues were collected at 16 months of age and livers were assessed for MASLD and HCC. Glucose regulation and pancreatic morphology were also evaluated. Liver tissues were assessed for markers of glycolysis and fatty acid metabolism and validated using a human HCC bioinformatic database. Both C/HF and HF/HF mice developed obesity, hyperinsulinemia and a greater degree of MASLD than C/C and HF/C offspring. However, despite significant liver and pancreas pathology, C/HF mice had the lowest incidence of HCC while tumour burden was highest in HF/C male offspring. The molecular profile of HCC mouse samples suggested an upregulation of the pentose phosphate pathway and a downregulation of fatty acid synthesis and oxidation, which was largely validated in the human dataset. Both pre-weaning HF diet exposure and post-weaning consumption of a high-carbohydrate diet increased the risk of developing spontaneous HCC in aged mice. However, the influence of pre-weaning HF feeding on HCC development appeared to be stronger in the context of post-weaning obesity. As rates of maternal obesity continue to rise, this has implications for the future incidence of HCC and possible dietary manipulation of offspring carbohydrate intake to counteract this risk.
Asunto(s)
Carcinoma Hepatocelular , Dieta Alta en Grasa , Neoplasias Hepáticas , Ratones Endogámicos C57BL , Destete , Animales , Femenino , Dieta Alta en Grasa/efectos adversos , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/metabolismo , Embarazo , Masculino , Ratones , Efectos Tardíos de la Exposición Prenatal , Fenómenos Fisiologicos Nutricionales Maternos , Hígado/metabolismo , Hígado/patología , Obesidad , Hígado Graso/etiología , Carbohidratos de la Dieta/efectos adversos , Carbohidratos de la Dieta/administración & dosificaciónRESUMEN
BACKGROUND: CD74 is ectopically expressed in many tumors and can regulate tumor immunity. However, there are many gaps in the study of the prognostic value of CD74 expression and immune infiltration in hepatocellular carcinoma (HCC). METHODS: An online tumor database was searched to obtain data on gene/protein expression. Immune infiltration analysis was performed using the Tumor Immune Estimation Resource and Comprehensive Analysis on Multi-Omics of Immunotherapy in Pan-cancer databases. Single-cell data were obtained from the Tissue-specific Gene Expression and Regulation, Single-cell Transcriptomes of Tumor Immune Microenvironment and Tumor Immune Single-cell Hub 2 databases. RESULTS: CD74 was highly expressed in HCC patients. HCC patients with high CD74 expression who consumed alcohol or were negative for hepatitis virus had a better prognosis than patients with low CD74 expression. CD74 was mainly enriched in immune response regulation pathways. Both copy number variations in CD74 and CD74 expression patterns affected the infiltration levels of immune cells. Interestingly, CD74 regulated the differentiation of myeloid cells. CD74 in macrophages and dendritic cells (DCs) forms complex networks with malignant cells and hepatic progenitor cell (HPC)-like cells, respectively. High CD74 expression in HPC-like cells and malignant cells significantly decreased the fraction of C-type lectin domain family 9 A (CLEC9A)-cDC1+ DCs and IL-1B+ macrophages, respectively. Their crosstalk subsequently shaped the tumor microenvironment of HCC, possibly through the CD74-MIF axis. Importantly, patients with high CD74 expression presented higher immune scores and achieved good outcomes after receiving immunotherapy. CONCLUSION: High CD74 expression is associated with the abundance of a variety of immune cell types, mediating interactions among tumor and immune cells and shaping the malignant behavior of HCC. In summary, CD74 may be a hallmark for determining the prognosis and immune cell infiltration levels of HCC patients.
Asunto(s)
Antígenos de Diferenciación de Linfocitos B , Carcinoma Hepatocelular , Antígenos de Histocompatibilidad Clase II , Inmunoterapia , Neoplasias Hepáticas , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/etiología , Microambiente Tumoral/inmunología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/etiología , Antígenos de Diferenciación de Linfocitos B/metabolismo , Antígenos de Diferenciación de Linfocitos B/genética , Inmunoterapia/métodos , Antígenos de Histocompatibilidad Clase II/metabolismo , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Pronóstico , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor , Biología Computacional/métodosRESUMEN
Metabolic-dysfunction associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a growing global health concern with significant implications for oncogenesis. This review synthesizes current evidence on the association between MASLD and cancer risk, highlighting its role as a risk factor for both intrahepatic and extrahepatic malignancies. MASLD is increasingly recognized as a major cause of hepatocellular carcinoma (HCC), with its incidence rising in parallel with the prevalence of metabolic dysfunction. Furthermore, MASLD is associated with an elevated risk of various gastrointestinal cancers, including colorectal, esophageal, stomach, and pancreatic cancers. Beyond the digestive tract, evidence suggests that MASLD may also contribute to an increased risk of other cancers such as breast, prostate, thyroid, gynecological, renal and lung cancers. Understanding the mechanisms underlying these associations and the impact of MASLD on cancer risk is crucial for developing targeted screening and prevention strategies.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Factores de Riesgo , Neoplasias/metabolismo , Neoplasias/complicaciones , Neoplasias/epidemiología , Neoplasias/etiología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/etiología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/epidemiología , Enfermedades Metabólicas/complicaciones , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/etiologíaRESUMEN
Hepatitis C virus (HCV) infection is a major health problem worldwide. It can cause liver cirrhosis and hepatocellular carcinoma (HCC), making it a cause of morbidity from liver disease. Thus, there is an urgent need for a prophylactic HCV vaccine. Fortunately, modern medicine has transformed the therapy for HCV infection through development of direct-acting antiviral agents (DAAs), achieving high rates of sustained virologic response and giving significant relief from HCC and associated mortality, but unfortunately it fails to eradicate the risk of HCC, especially in HCV-cleared patients with already advanced liver disease. Additionally, DAA-cured patients do not develop sufficient antiviral immunity and are susceptible to reinfection. A comprehensive strategy to control HCV infection must include a vaccine development approach in which the host can develop humoral and cellular immunity to eradicate HCV successfully; however, this remains a challenge as HCV has developed systems to evade immune attacks from its host. This review highlights the current understanding of HCV's effect on liver disease and cancer progression, the nature of immune responses from cell populations interacting with HCV, and the current strategies for vaccine development. The information in this review will advance prophylactic intervention strategies for HCV infection, with the end goal being to prevent chronicity and subsequent liver disease leading to HCC.
Asunto(s)
Hepacivirus , Hepatitis C Crónica , Desarrollo de Vacunas , Humanos , Hepacivirus/inmunología , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/virología , Hepatitis C Crónica/prevención & control , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/etiología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/prevención & control , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/etiología , Vacunas contra Hepatitis Viral/inmunología , Vacunas contra Hepatitis Viral/uso terapéutico , Animales , Antivirales/uso terapéuticoRESUMEN
Hepatocellular carcinoma (HCC) has become the fourth leading cause of cancer-related deaths worldwide; annually, approximately 830,000 deaths related to liver cancer are diagnosed globally. Since early-stage HCC is clinically asymptomatic, traditional treatment modalities, including surgical ablation, are usually not applicable or result in recurrence. Immunotherapy, particularly immune checkpoint blockade (ICB), provides new hope for cancer therapy; however, immune evasion mechanisms counteract its efficiency. In addition to viral exposure and alcohol addiction, nonalcoholic steatohepatitis (NASH) has become a major cause of HCC. Owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance, NASH-associated HCC patients respond much less efficiently to ICB treatment than do patients with other etiologies. In addition, abnormal inflammation contributes to NASH progression and NASH-HCC transition, as well as to HCC immune evasion. Therefore, uncovering the detailed mechanism governing how NASH-associated immune cells contribute to NASH progression would benefit HCC prevention and improve HCC immunotherapy efficiency. In the following review, we focused our attention on summarizing the current knowledge of the role of CD4+T cells in NASH and HCC progression, and discuss potential therapeutic strategies involving the targeting of CD4+T cells for the treatment of NASH and HCC.
Asunto(s)
Linfocitos T CD4-Positivos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/terapia , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Animales , Inmunoterapia/métodos , Progresión de la EnfermedadRESUMEN
Dysbiosis of gut microbiota may account for pathobiology in simple fatty liver (SFL), metabolic dysfunction-associated steatohepatitis (MASH), fibrotic progression, and transformation to MASH-associated hepatocellular carcinoma (MASH-HCC). The aim of the present study is to investigate gut dysbiosis in this progression. Fecal microbial rRNA-16S sequencing, absolute quantification, histopathologic, and biochemical tests were performed in mice fed high fat/calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) or control diet (CD) for 2, 16 weeks, or 14 months. Histopathologic examination verified an early stage of SFL, MASH, fibrotic, or MASH-HCC progression with disturbance of lipid metabolism, liver injury, and impaired gut mucosal barrier as indicated by loss of occludin in ileum mucosa. Gut dysbiosis occurred as early as 2 weeks with reduced α diversity, expansion of Kineothrix, Lactococcus, Akkermansia; and shrinkage in Bifidobacterium, Lactobacillus, etc., at a genus level. Dysbiosis was found as early as MAHS initiation, and was much more profound through the MASH-fibrotic and oncogenic progression. Moreover, the expansion of specific species, such as Lactobacillus johnsonii and Kineothrix alysoides, was confirmed by an optimized method for absolute quantification. Dynamic alterations of gut microbiota were characterized in three stages of early SFL, MASH, and its HCC transformation. The findings suggest that the extent of dysbiosis was accompanied with MASH progression and its transformation to HCC, and the shrinking or emerging of specific microbial species may account at least in part for pathologic, metabolic, and immunologic alterations in fibrogenic progression and malignant transition in the liver.
Asunto(s)
Carcinoma Hepatocelular , Disbiosis , Microbioma Gastrointestinal , Neoplasias Hepáticas , Ratones Endogámicos C57BL , Animales , Ratones , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/microbiología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/microbiología , Neoplasias Hepáticas/etiología , Disbiosis/microbiología , Masculino , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/microbiología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Metabolismo de los Lípidos , Hígado/metabolismo , Hígado/patologíaRESUMEN
BACKGROUND: The outcome of hepatocellular carcinoma (HCC) is limited by its complex molecular characteristics and changeable tumor microenvironment (TME). Here we focused on elucidating the functional consequences of Maternal embryonic leucine zipper kinase (MELK) in the tumorigenesis, progression and metastasis of HCC, and exploring the effect of MELK on immune cell regulation in the TME, meanwhile clarifying the corresponding signaling networks. METHODS: Bioinformatic analysis was used to validate the prognostic value of MELK for HCC. Murine xenograft assays and HCC lung metastasis mouse model confirmed the role of MELK in tumorigenesis and metastasis in HCC. Luciferase assays, RNA sequencing, immunopurification-mass spectrometry (IP-MS) and coimmunoprecipitation (CoIP) were applied to explore the upstream regulators, downstream essential molecules and corresponding mechanisms of MELK in HCC. RESULTS: We confirmed MELK to be a reliable prognostic factor of HCC and identified MELK as an effective candidate in facilitating the tumorigenesis, progression, and metastasis of HCC; the effects of MELK depended on the targeted regulation of the upstream factor miR-505-3p and interaction with STAT3, which induced STAT3 phosphorylation and increased the expression of its target gene CCL2 in HCC. In addition, we confirmed that tumor cell-intrinsic MELK inhibition is beneficial in stimulating M1 macrophage polarization, hindering M2 macrophage polarization and inducing CD8 + T-cell recruitment, which are dependent on the alteration of CCL2 expression. Importantly, MELK inhibition amplified RT-related immune effects, thereby synergizing with RT to exert substantial antitumor effects. OTS167, an inhibitor of MELK, was also proven to effectively impair the growth and progression of HCC and exert a superior antitumor effect in combination with radiotherapy (RT). CONCLUSIONS: Altogether, our findings highlight the functional role of MELK as a promising target in molecular therapy and in the combination of RT therapy to improve antitumor effect for HCC.
Asunto(s)
Carcinoma Hepatocelular , Quimiocina CCL2 , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Proteínas Serina-Treonina Quinasas , Microambiente Tumoral , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/radioterapia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/radioterapia , Humanos , Animales , Ratones , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Quimiocina CCL2/metabolismo , Línea Celular Tumoral , Tolerancia a Radiación , Pronóstico , Factor de Transcripción STAT3/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , MicroARNs/genéticaRESUMEN
The increased risk of liver malignancies was found in workers of the first Russian nuclear production facility, Mayak Production Association, who had been chronically exposed to gamma rays externally and to alpha particles internally due to plutonium inhalation. In the present study, we updated the radiogenic risk estimates of the hepatobiliary malignancies using the extended follow-up period (1948-2018) of the Mayak worker cohort and the improved «Mayak worker dosimetry system-2013¼. The cohort comprised 22,377 workers hired at the Mayak PA between 1948 and 1982. The analysis considered 62 liver malignancies (32 hepatocellular carcinomas, 13 intrahepatic cholangiocarcinomas, 16 angiosarcomas, and 1 anaplastic cancer) and 33 gallbladder adenocarcinomas. The analysis proved the positive significant association of the liver malignancy risk (the total of histological types, hepatocellular carcinoma) with the liver absorbed alpha dose from internal exposure. The excess relative risk per Gy (95% confidence interval) of alpha dose (the linear model) was 7.56 (3.44; 17.63) for the total of histological types and 3.85 (0.95; 13.30) for hepatocellular carcinoma. Indications of non-linearity were observed in the dose-response for internal exposure to alpha radiation. No impact of external gamma-ray exposure on the liver malignancy incidence was found. In the study cohort, the number of angiosarcomas among various types of liver malignancies was very high (25.8%), and most of these tumors (73.3%) were registered in individuals internally exposed to alpha radiation at doses ranging between 6.0 and 21.0 Gy. No association with chronic occupational radiation exposure was observed for the incidence of gallbladder malignancies.
Asunto(s)
Neoplasias Hepáticas , Neoplasias Inducidas por Radiación , Exposición Profesional , Humanos , Exposición Profesional/efectos adversos , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Masculino , Neoplasias Inducidas por Radiación/epidemiología , Neoplasias Inducidas por Radiación/etiología , Incidencia , Persona de Mediana Edad , Femenino , Radiación Ionizante , Estudios de Cohortes , Adulto , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Federación de Rusia/epidemiología , Anciano , Partículas alfa/efectos adversos , Rayos gamma/efectos adversos , Exposición a la Radiación/efectos adversosRESUMEN
Hepatocellular carcinoma (HCC) is the most frequent among primary liver tumors (90%) and one of the main causes of cancer-related death. It develops usually in a chronically inflamed environment, ranging from compensatory parenchymal regeneration to fibrosis and cirrhosis: carcinogenesis can potentially happen in each of these stages. Inflammation determined by chronic viral infection (hepatitis B, hepatitis C, and hepatitis delta viruses) represents an important risk factor for HCC etiology through both viral direct damage and immune-related mechanisms. The deregulation of the physiological liver immunological network determined by viral infection can lead to carcinogenesis. The recent introduction of immunotherapy as the gold-standard first-line treatment for HCC highlights the role of the immune system and inflammation as a double-edged weapon in both HCC carcinogenesis and treatment. In this review we highlight how the inflammation is the key for the hepatocarcinogenesis in viral, alcohol and metabolic liver diseases.
Asunto(s)
Carcinoma Hepatocelular , Inflamación , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/virología , Inflamación/patología , Animales , Inmunoterapia/métodosRESUMEN
Stearoyl-CoA desaturase-1 (SCD1) is a pivotal enzyme in lipogenesis, which catalyzes the synthesis of monounsaturated fatty acids (MUFA) from saturated fatty acids, whose ablation downregulates lipid synthesis, preventing steatosis and obesity. Yet deletion of SCD1 promotes hepatic inflammation and endoplasmic reticulum stress, raising the question of whether hepatic SCD1 deficiency promotes further liver damage, including fibrosis. To delineate whether SCD1 deficiency predisposes the liver to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), we employed in vivo SCD1 deficient global and liver-specific mouse models fed a high carbohydrate low-fat diet and in vitro established AML12 mouse cells. The absence of liver SCD1 remarkably increased the saturation of liver lipid species, as indicated by lipidomic analysis, and led to hepatic fibrosis. Consistently, SCD1 deficiency promoted hepatic gene expression related to fibrosis, cirrhosis, and HCC. Deletion of SCD1 increased the circulating levels of Osteopontin, known to be increased in fibrosis, and alpha-fetoprotein, often used as an early marker and a prognostic marker for patients with HCC. De novo lipogenesis or dietary supplementation of oleate, an SCD1-generated MUFA, restored the gene expression related to fibrosis, cirrhosis, and HCC. Although SCD1 deficient mice are protected against obesity and fatty liver, our results show that MUFA deprivation results in liver injury, including fibrosis, thus providing novel insights between MUFA insufficiency and pathways leading to fibrosis, cirrhosis, and HCC under lean non-steatotic conditions.
Asunto(s)
Carcinoma Hepatocelular , Cirrosis Hepática , Neoplasias Hepáticas , Estearoil-CoA Desaturasa , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Estearoil-CoA Desaturasa/deficiencia , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/etiología , Ratones , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/etiología , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/etiología , Hígado/metabolismo , Hígado/patología , Lipogénesis/genética , Osteopontina/genética , Osteopontina/metabolismo , Osteopontina/deficiencia , Ratones Noqueados , Masculino , Ratones Endogámicos C57BL , Carbohidratos de la Dieta/administración & dosificación , Carbohidratos de la Dieta/efectos adversos , HumanosRESUMEN
BACKGROUND: Patients treated with direct-acting antivirals for hepatitis C exhibit high cure rates and improved survival. However, there is limited knowledge on their long-term clinical evolution. AIMS: In this study, we aimed to analyse the risk of hepatocarcinoma and hepatic decompensation in patients treated with direct-acting antivirals. METHODS: We conducted a retrospective single-centre study of Portuguese patients with advanced fibrosis treated with direct-acting antiviral agents between 2015 and 2022 at a tertiary hospital. RESULTS: Out of 460 patients, 50 (10.9 %) developed hepatocarcinoma and 36 (7.8 %) experienced hepatic decompensation. The risk for hepatocarcinoma was higher in patients aged over 55 (HR 4.87, 95 % CI 2.34-10.13, p < 0.001), with signs of portal hypertension (HR 3.83, 95 % CI 2.05-7.13, p < 0.001) and arterial hypertension (HR 1.98, 95 % CI 1.09-3.58, p = 0.024). Alcohol consumption (HR 3.30, 95 % CI 1.22-8.94, p = 0.019), signs of portal hypertension (HR 4.56, 95 % CI 2.19-9.48, p < 0.001) and hepatocarcinoma (HR 3.47, 95 % CI 1.69-7.10, p < 0.001) increased the risk of hepatic decompensation. CONCLUSION: Our study found a high incidence of hepatocarcinoma and hepatic decompensation, along with high mortality, in patients with advanced fibrosis treated with direct-acting antivirals. We identified risk factors such as arterial hypertension, alcohol consumption, and signs of portal hypertension, highlighting their role in clinical management and patient monitoring.
Asunto(s)
Antivirales , Carcinoma Hepatocelular , Hepatitis C , Cirrosis Hepática , Neoplasias Hepáticas , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/mortalidad , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Estudios Retrospectivos , Antivirales/efectos adversos , Antivirales/uso terapéutico , Portugal/epidemiología , Factores de Riesgo , Incidencia , Humanos , Masculino , Femenino , Persona de Mediana Edad , Genotipo , Hepacivirus/genética , Adulto , Anciano , Anciano de 80 o más Años , Estimación de Kaplan-MeierRESUMEN
As a hepatotropic virus, hepatitis B virus (HBV) can establish a persistent chronic infection in the liver, termed, chronic hepatitis B (CHB), which causes a series of liver-related complications, including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCC with HBV infection has a significantly increased morbidity and mortality, whereas it could be preventable. The current goal of antiviral therapy for HBV infection is to decrease CHB-related morbidity and mortality, and achieve sustained suppression of virus replication, which is known as a functional or immunological cure. The natural history of chronic HBV infection includes four immune phases: the immune-tolerant phase, immune-active phase, inactive phase, and reactivation phase. However, many CHB patients do not fit into any of these defined phases and are regarded as indeterminate. A large proportion of indeterminate patients are only treated with dynamic monitoring rather than recommended antiviral therapy, mainly due to the lack of definite guidelines. However, many of these patients may gradually have significant liver histopathological changes during disease progression. Recent studies have focused on the prevalence, progression, and carcinogenicity of indeterminate CHB, and more attention has been given to the prevention, detection, and treatment for these patients. Herein, we discuss the latest understanding of the epidemiology, clinical characteristics, and therapeutic strategies of indeterminate CHB, to provide avenues for the management of these patients.
Asunto(s)
Antivirales , Virus de la Hepatitis B , Hepatitis B Crónica , Humanos , Hepatitis B Crónica/epidemiología , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/complicaciones , Antivirales/uso terapéutico , Virus de la Hepatitis B/patogenicidad , Virus de la Hepatitis B/fisiología , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/etiología , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/virología , Cirrosis Hepática/epidemiología , Cirrosis Hepática/virología , Progresión de la EnfermedadRESUMEN
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) constitutes the commonest cause of chronic liver disorder worldwide, whereby affecting around one third of the global population. This clinical condition may evolve into Metabolic Dysfunction-Associated Steatohepatitis (MASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC), in a predisposed subgroup of patients. The complex pathogenesis of MASLD is severely entangled with obesity, dyslipidemia and type 2 diabetes (T2D), so far so nutritional and lifestyle recommendations may be crucial in influencing the risk of HCC and modifying its prognosis. However, the causative association between HCC onset and the presence of metabolic comorbidities is not completely clarified. Therefore, the present review aimed to summarize the main literature findings that correlate the presence of inherited or acquired hyperlipidemia and metabolic risk factors with the increased predisposition towards liver cancer in MASLD patients. Here, we gathered the evidence underlining the relationship between circulating/hepatic lipids, cardiovascular events, metabolic comorbidities and hepatocarcinogenesis. In addition, we reported previous studies supporting the impact of triglyceride and/or cholesterol accumulation in generating aberrancies in the intracellular membranes of organelles, oxidative stress, ATP depletion and hepatocyte degeneration, influencing the risk of HCC and its response to therapeutic approaches. Finally, our pursuit was to emphasize the link between HCC and the presence of cardiometabolic abnormalities in our large cohort of histologically-characterized patients affected by MASLD (n=1538), of whom 86 had MASLD-HCC by including unpublished data.
Asunto(s)
Carcinoma Hepatocelular , Factores de Riesgo Cardiometabólico , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Hígado Graso/complicaciones , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Factores de RiesgoRESUMEN
Background and aims: Liver hepatocellular carcinoma (LIHC) exhibits a multifactorial etiology, insidious onset, and a significantly low 5-year survival rate. We aimed to evaluate the causal impact of exposure factors (Alzheimer's disease, platelet count, ambidextrousness, cigarettes smoked per day, alcohol consumption, and endocarditis) on the risk of LIHC using a two-sample Mendelian randomization (MR) study. Methods: Independent single nucleotide polymorphisms (SNPs) strongly associated with Alzheimer's disease, platelet count, ambidextrousness, daily cigarette consumption, alcohol intake, and endocarditis were selected as instrumental variables (IVs) from the corresponding genome-wide association studies (GWAS). Genetic summary statistics for LIHC came from a GWAS that included 168 cases and 372,016 controls of European individuals. Multivariable MR analyses were performed to find the causal association between 6 exposure factors and LIHC risk. The inverse-variance weighted (IVW)-MR was employed as the primary analysis, and the MR-Egger regression, LASSO regression, and weighted Median approaches were performed as complementary analyses. Results: Multivariable MR analysis showed causal association between Alzheimer's disease [Odds ratio (OR) = 0.9999, 95% confidence intervals (CI) = 0.9998-0.9999, p = 0.0010], platelet count (OR = 0.9997, 95% CI = 0.9995-0.9999, p = 0.0066), alcohol consumption (OR = 0.9994, 95% CI = 0.9990-0.9999, p = 0.0098) and the LIHC outcome. After IVW-MR, MR-Egger and LASSO tests, the results are still significant. Next, we used different MR Methods to analyze platelet count, alcohol consumption, and Alzheimer's disease separately. Moreover, both funnel plots and MR-Egger intercepts provided compelling evidence to refute the presence of directional pleiotropy in the association between platelet count, alcohol consumption, Alzheimer's disease and the risk of LIHC. The IVW-MR analysis revealed a significant causal association between an elevated platelet count and a reduced risk of LIHC (OR = 0.9996, 95% CI= 0.9995-0.9998, p = 0.0005). Similarly, the analysis of weighted median revealed a negative correlation between platelet count and the risk of LIHC (OR = 0.9995, 95% CI = 0.9993-0.9999; p = 0.0160). Conversely, we observed a positive causal effect of alcohol consumption on the incidence of LIHC (OR = 1.0004, 95% CI = 0.9999-1.0009). However, no significant causal relationship was found between alcohol assumption, Alzheimer's disease, and LIHC susceptibility. Conclusions: A significant causal relationship exists between platelet count, alcohol consumption, Alzheimer's disease, and an increased risk of LIHC. The study presents compelling evidence for a genetically predicted decreased susceptibility to LIHC based on platelet count. The research implies that elevated platelet count may serve as a protective mechanism against LIHC. These findings may inform clinical strategies for LIHC prevention.
Asunto(s)
Consumo de Bebidas Alcohólicas , Carcinoma Hepatocelular , Estudio de Asociación del Genoma Completo , Neoplasias Hepáticas , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/etiología , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Consumo de Bebidas Alcohólicas/efectos adversos , Recuento de Plaquetas , Factores de RiesgoRESUMEN
BACKGROUND: Hepatocellular Carcinoma (HCC) can be classified as one of the most common malignancies worldwide. There is scarcity of the published data on the risk factors for HCC in the Gulf Cooperation Council countries specifically Kuwait. Therefore, this case-control study sought to examine the risk factors associated with HCC in Kuwait. METHODS: Fifty-three histopathologically confirmed HCC cases were recruited from the Kuwait Cancer Control Center Registry. One hundred ninety-six controls (1:4 ratio) were selected from medical and/ or surgical outpatient's clinics at all six public hospitals of Kuwait. A structured questionnaire was used to collect the data both from cases and controls through face-to-face interviews. A multivariable logistic regression model was fitted to the case-control data. Adjusted odds ratios (ORadj) and their 95% confidence intervals (CI) were computed using the parameters' estimates of the final model and used for interpretation of the model. RESULTS: The HCC cases compared with the controls were 41.6 times more likely to have had the history of non-alcoholic fatty liver disease (NAFLD) (ORadj = 41.6; 95% CI: 8.9-193.5; p < 0.001). The cases compared with the controls were more likely to have reported the history of heavy alcohol drinking (ORadj = 14.2; 95% CI: 1.2-173.4; p = 0.038). Furthermore, compared with the controls, the HCC cases tended to frequently consume milk and/or milk substitutes (≥ 3 glass/ week) (ORadj = 7.2; 95% CI: 1.2-43.4). Conversely however, there was a significant protective effect if the participants reportedly have had regularly used olive oil in their routine diet as a source of fat (ORadj = 0.17; 95% CI: 0.04-0.80) or regularly used non-steroid anti-inflammatory drugs (NSAIDs) (ORadj = 0.20; 95% CI: 0.05-0.71). CONCLUSIONS: This study showed that heavy alcohol consumption, NAFLD history, and excessive consumption of milk/ milk substitutes were associated with a significantly increased HCC risk. Conversely however, regular use of olive oil in the diet as a source of fat or regular use of NSAIDs had a significantly protective effect against HCC risk. Adapting healthy dietary habits and preventing/ treating NAFLD may minimize the HCC risk. Future research with a larger sample size may contemplate validating the results of this study and unraveling additional risk factors contributing to HCC risk. The resultant data may help design and implement evidence-based educational programs for the prevention of HCC in this and other similar settings.
Asunto(s)
Carcinoma Hepatocelular , Dieta , Estilo de Vida , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas/epidemiología , Femenino , Masculino , Estudios de Casos y Controles , Persona de Mediana Edad , Factores de Riesgo , Kuwait/epidemiología , Anciano , Comorbilidad , Adulto , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Enfermedad del Hígado Graso no Alcohólico/epidemiologíaRESUMEN
Following the advent of direct-acting antivirals (DAAs), hepatitis C virus (HCV) infection can be cured in almost all infected patients. This has led to a number of clinical questions regarding the optimal management of the millions of patients cured of HCV. This position statement provides specific guidance on the appropriate follow-up after a sustained virological response in patients without advanced fibrosis, those with compensated advanced chronic liver disease, and those with decompensated cirrhosis. Guidance on hepatocellular carcinoma risk assessment and the management of extrahepatic manifestations of HCV is also provided. Finally, guidance is provided on the monitoring and treatment of reinfection in at-risk patients. The recommendations are based on the best available evidence and are intended to help healthcare professionals involved in the management of patients after treatment for HCV.
Asunto(s)
Antivirales , Carcinoma Hepatocelular , Hepatitis C Crónica , Humanos , Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Hepatitis C Crónica/complicaciones , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/terapia , Respuesta Virológica Sostenida , Cirrosis Hepática/virología , Hepacivirus/efectos de los fármacosRESUMEN
BACKGROUND: Type 2 diabetes mellitus (T2DM) may be a risk factor for development of hepatocellular carcinoma (HCC). The association between risk of developing HCC and treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP4i) is currently unknown. This study aimed to compare the risk of new-onset HCC in patients treated with SGLT2i versus DPP4i. METHODS: This was a retrospective cohort study of patients with T2DM in Hong Kong receiving either SGLT2i or DPP4i between January 1, 2015, and December 31, 2020. Patients with concurrent DPP4i and SGLT2i use were excluded. Propensity score matching (1:1 ratio) was performed by using the nearest neighbor search. Multivariable Cox regression was applied to identify significant predictors. RESULTS: A total of 62,699 patients were included (SGLT2i, n=22,154; DPP4i, n=40,545). After matching (n=44,308), 166 patients (0.37%) developed HCC: 36 in the SGLT2i group and 130 in the DPP4i group over 240,269 person-years. Overall, SGLT2i use was associated with lower risks of HCC (hazard ratio [HR], 0.42; 95% CI, 0.28-0.79) compared with DPP4i after adjustments. The association between SGLT2i and HCC development remained significant in patients with cirrhosis or advanced fibrosis (HR, 0.12; 95% CI, 0.04-0.41), hepatitis B virus (HBV) infection (HR, 0.32; 95% CI, 0.17-0.59), or hepatitis C virus (HCV) infection (HR, 0.41; 95% CI, 0.22-0.80). The results were consistent in different risk models, propensity score approaches, and sensitivity analyses. CONCLUSIONS: SGLT2i use was associated with a lower risk of HCC compared with DPP4i use after adjustments, and in the context of cirrhosis, advanced fibrosis, HBV infection, and HCV infection.