RESUMO
The prediction of liver-related events (LRE) after sustained virological response (SVR) in HCV-advanced chronic liver disease (ACLD) patients is crucial. We aimed to evaluate incidence and risk factors of LRE in HCV-cirrhotic patients after SVR and to assess dynamic changes of liver stiffness in participants without LRE at the end of follow-up. We enrolled 575 consecutive patients with HCV-ACLD treated with DAAs and followed up for 5 years after SVR12. Overall, 98 (17%) patients developed any type of event, and HCC was the most frequent LRE. The incidence rate was 1.6 per 100 person-years (p/y) for both HCC and hepatic decompensation. Baseline LSM ≥ 20 kPa was the only independent predictor of hepatic decompensation, while LSM ≥ 20 kPa and male sex were independent predictors of HCC development. Among the 341 participants without LRE and with paired LSM, any LSM reduction was observed in 314 (92.1%), and half of them showed a decrease of LSM ≥ 20%. Among patients without LRE, 27.3% of participants without ≥20% LSM decrease at 2 years achieved the 5-year goal; in contrast, 31.6% of participants with ≥20% LSM decrease at 2 years lost it at 5 years. These findings provide evidence that baseline LSM is a tool to stratify patients at risk of developing LRE; the dynamic changes of LSM value suggest the need for monitoring this parameter over time.
Assuntos
Antivirais , Hepatite C Crônica , Cirrose Hepática , Resposta Viral Sustentada , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Estudos Prospectivos , Antivirais/uso terapêutico , Fatores de Risco , Cirrose Hepática/virologia , Fígado/patologia , Fígado/virologia , Idoso , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/etiologia , Hepacivirus , Técnicas de Imagem por Elasticidade , Carcinoma Hepatocelular/virologia , Incidência , AdultoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) remains a significant concern for patients with chronic hepatitis C (HCV), even after achieving a sustained virological response (SVR) with direct-acting antivirals (DAAs) or interferon (IFN)-based therapies. This study compared the risk of HCC in patients with HCV who achieved SVR through the DAA versus IFN regimens. METHODS: A retrospective analysis was conducted on 4806 HCV patients, without coinfection nor prior HCC history, treated at the Chang Gung Memorial Hospital, Taiwan (DAA: 2825, IFN: 1981). Kaplan-Meier and Cox regression analyses with propensity score matching (PSM) were used to adjust for baseline differences. RESULTS: DAA-treated patients exhibited a higher incidence of HCC than IFN-treated patients before and after PSM (after PSM: annual: 1% vs. 0.5%; 6-year: 6% vs. 3%, p = 0.01). Both DAA and IFN patients had a decreased HCC incidence during follow-up (>3 vs. <3 years from the end of treatment: DAA: 1.43% vs. 1.00% per year; IFN: 0.47% vs. 0.36% per year, both p < 0.05). HCC incidence was higher in the first three years post-SVR in DAA-treated ACLD patients and then decreased (3.26% vs. 1.39% per year, p < 0.01). In contrast, HCC incidence remained constant in the non-ACLD and IFN-treated groups. Multivariate Cox regression identified age ≥ 60, male sex, BMI, AFP ≥ 6 ng/mL, FIB-4, and ACLD status as independent risk factors for HCC, but antiviral regimens were not an independent factor for HCC. CONCLUSION: DAA treatment significantly affects HCC risk primarily within three years post-treatment, especially in younger HCV patients with ACLD. HCC incidence was reduced after three years in ACLD patients treated by DAA, but continued surveillance was still necessary. However, patients under 60 without advanced liver disease may require less intensive follow-up.
Assuntos
Antivirais , Carcinoma Hepatocelular , Hepatite C Crônica , Interferons , Neoplasias Hepáticas , Resposta Viral Sustentada , Humanos , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/etiologia , Masculino , Feminino , Antivirais/uso terapêutico , Pessoa de Meia-Idade , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/virologia , Incidência , Estudos Retrospectivos , Fatores de Risco , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/complicações , Interferons/uso terapêutico , Taiwan/epidemiologia , Idoso , Adulto , Hepacivirus/efeitos dos fármacosRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular , Eosinófilos , Hepatite B , Neoplasias Hepáticas , Compostos de Fenilureia , Quinolinas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/sangue , Feminino , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Prognóstico , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hepatite B/complicações , Hepatite B/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Curva ROC , Idoso , Contagem de Leucócitos , Adulto , Vírus da Hepatite B/isolamento & purificação , Resultado do TratamentoRESUMO
BACKGROUND: Although nucleos(t)ide analogues (NAs) are thought to reduce the risk of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), the effect of NA discontinuation on the prognosis of HBV-related HCC after hepatectomy is rarely reported. We aimed to investigate the potential for hepatitis B virus e antigen (HBeAg)-negative HBV-related HCC patients to discontinue NAs based on preoperative hepatitis B virus surface antigen (HBsAg) status. METHODS: This historical cohort study involved 1232 NA-treated HBeAg-negative patients who underwent curative hepatectomy for HBV-related HCC from 2014 to 2019. The recurrence-free survival (RFS) and overall survival (OS) of patients discontinuing NAs before surgery were compared with those continuing NAs. Propensity score matching (PSM) was used to balance baseline characteristics. RESULTS: Of all enrolled patients, 839 (68.1%) patients continued NAs, and 393 (31.9%) patients discontinued NAs. Continuation of NAs was identified as an independent risk factor for RFS (HR 2.047, 95% CI 1.348-3.109, p < 0.001 before PSM and HR 2.756, 95% CI 1.537-4.942, p < 0.001 after PSM) in HBsAg-negative patients. Similarly, subgroup survival analyses showed that NA discontinuation was associated with better RFS (p = 0.029 before PSM and p < 0.001 after PSM) and comparable OS (p = 0.935 before PSM and p = 0.115 after PSM) than NA continuation in HBsAg-negative patients. The interaction between HBsAg status and continuation or discontinuation of NAs was significant (p for interaction <0.001). CONCLUSIONS: These findings demonstrate the potential for HBeAg-negative HBV-related HCC patients who have achieved HBsAg seroclearance to discontinue NAs under strict monitoring.
Assuntos
Carcinoma Hepatocelular , Hepatectomia , Antígenos E da Hepatite B , Vírus da Hepatite B , Neoplasias Hepáticas , Pontuação de Propensão , Humanos , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/virologia , Masculino , Feminino , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/etiologia , Pessoa de Meia-Idade , Antígenos E da Hepatite B/sangue , Prognóstico , Antivirais/uso terapêutico , Antígenos de Superfície da Hepatite B/sangue , Nucleosídeos/uso terapêutico , Estudos Retrospectivos , Adulto , Idoso , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologiaRESUMO
The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) is a growing concern for the high incidence rate of hepatocellular carcinoma (HCC) globally. The progression of NAFLD to HCC is heterogeneous and non-linear, involving intermediate stages of non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. There is a high unmet clinical need for appropriate diagnostic, prognostic, and therapeutic options to tackle this emerging epidemic. Unfortunately, at present, there is no validated marker to identify the risk of developing HCC in patients suffering from NAFLD or NASH. Additionally, the current treatment protocols for HCC don't differentiate between viral infection or NAFLD-specific etiology of the HCC and have a limited success rate. The mammalian target of rapamycin complex 1 (mTORc1) is an important protein involved in many vital cellular processes like lipid metabolism, glucose homeostasis, and inflammation. These cellular processes are highly implicated in NAFLD and its progression to severe liver manifestations. Additionally, hyperactivation of mTORc1 is known to promote cell proliferation, which can contribute to the genesis and progression of tumors. Many mTORc1 inhibitors are being evaluated for different types of cancers under various phases of clinical trials. This paper deliberates on the strong pathological implication of the mTORc1 signaling pathway in NAFLD and its progression to NASH and HCC and advocates for a systematic investigation of known mTORc1 inhibitors in suitable pre-clinical models of HCC having NAFLD/NASH-specific etiology.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Alvo Mecanístico do Complexo 1 de Rapamicina , Hepatopatia Gordurosa não Alcoólica , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Animais , Reposicionamento de Medicamentos , Inibidores de MTOR/uso terapêutico , Inibidores de MTOR/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
AIMS: This review explores the mechanisms, diagnostic approaches, and management strategies for COVID-19-induced liver injury, with a focus on its impact on patients with pre-existing liver conditions, liver cancer, and those undergoing liver transplantation. MATERIALS AND METHODS: A comprehensive literature review included studies on clinical manifestations of liver injury due to COVID-19. Key areas examined were direct viral effects, drug-induced liver injury, cytokine storms, and impacts on individuals with chronic liver diseases, liver transplants, and the role of vaccination. Data were collected from clinical trials, observational studies, case reports, and review literature. KEY FINDINGS: COVID-19 can cause a spectrum of liver injuries, from mild enzyme elevations to severe hepatic dysfunction. Injury mechanisms include direct viral invasion, immune response alterations, drug toxicity, and hypoxia-reperfusion injury. Patients with chronic liver conditions (such as alcohol-related liver disease, nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma) face increased risks of severe outcomes. The pandemic has worsened pre-existing liver conditions, disrupted cancer treatments, and complicated liver transplantation. Vaccination remains crucial for reducing severe disease, particularly in chronic liver patients and transplant recipients. Telemedicine has been beneficial in managing patients and reducing cross-infection risks. SIGNIFICANCE: This review discusses the importance of improved diagnostic methods and management strategies for liver injury caused by COVID-19. It emphasizes the need for close monitoring and customized treatment for high-risk groups, advocating for future research to explore long-term effects, novel therapies, and evidence-based approaches to improve liver health during and after the pandemic.
Assuntos
COVID-19 , Hepatopatias , Transplante de Fígado , SARS-CoV-2 , Humanos , COVID-19/complicações , COVID-19/terapia , COVID-19/diagnóstico , Transplante de Fígado/efeitos adversos , Hepatopatias/etiologia , Hepatopatias/diagnóstico , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Neoplasias/complicações , Neoplasias/terapiaRESUMO
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.
Assuntos
Metilação de DNA , Epigênese Genética , Hepacivirus , Hepatite C , Humanos , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/genética , Hepatite C/virologia , Metilação de DNA/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/etiologia , AnimaisRESUMO
This JAMA Clinical Guidelines Synopsis summarizes the 2023 American Association for the Study of Liver Diseases practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Guias de Prática Clínica como Assunto , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/terapia , Prevenção Primária/normas , Hepatite B Crônica/complicações , Hepatite B Crônica/prevenção & controle , Hepatite C Crônica/complicações , Hepatite C Crônica/terapia , Incidência , Vacinas contra Hepatite B/administração & dosagem , Antivirais/uso terapêutico , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/terapia , Fígado Gorduroso Alcoólico/complicações , Fígado Gorduroso Alcoólico/terapia , Estadiamento de Neoplasias/normas , Fígado/diagnóstico por imagem , Fígado/patologia , Ultrassonografia/normas , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Fatores de Risco , Neoplasias/metabolismo , Neoplasias/complicações , Neoplasias/epidemiologia , Neoplasias/etiologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/etiologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/epidemiologia , Doenças Metabólicas/complicações , Doenças Metabólicas/metabolismo , Doenças Metabólicas/etiologiaRESUMO
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.
Assuntos
Hepacivirus , Hepatite C Crônica , Desenvolvimento de Vacinas , Humanos , Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Hepatite C Crônica/prevenção & controle , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/etiologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/prevenção & controle , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/etiologia , Vacinas contra Hepatite Viral/imunologia , Vacinas contra Hepatite Viral/uso terapêutico , Animais , Antivirais/uso terapêuticoRESUMO
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.
Assuntos
Antígenos de Diferenciação de Linfócitos B , Carcinoma Hepatocelular , Antígenos de Histocompatibilidade Classe II , Imunoterapia , Neoplasias Hepáticas , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/etiologia , Microambiente Tumoral/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/etiologia , Antígenos de Diferenciação de Linfócitos B/metabolismo , Antígenos de Diferenciação de Linfócitos B/genética , Imunoterapia/métodos , Antígenos de Histocompatibilidade Classe II/metabolismo , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Prognóstico , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais , Biologia Computacional/métodosRESUMO
Primary liver cancer is globally on the rise, partially due to poor diets and sedentary lifestyles. Shifting to more plant-based diets may lower the risk. We aimed to estimate the effect of replacing total red meat, unprocessed red meat and processed red meat with legumes on primary liver cancer in a free-living population. We analyzed data from 126,744 UK Biobank participants who completed ≥ two 24 h diet recalls. Baseline characteristics were collected from the initial assessment visit. Information on liver cancer diagnoses was collected via external linkage to inpatient hospital episodes or central cancer registries. Cox proportional hazards regression models were used to estimate the substitution of 15 g/day of legumes with 15 g/day of total red meat, unprocessed red meat or processed red meat on liver cancer risk, using the leave-one-out food substitution model. During a median follow-up time of 11.1 years, 173 participants developed liver cancer. In the fully adjusted models, no association was observed when substituting 15 g/day of legumes with total red meat (HR: 1.02 (95% CI 0.96-1.08)), unprocessed red meat (HR: 1.00 (95% CI 0.94-1.06)) or processed red meat (HR: 1.09 (95% CI 0.99-1.21)). Overall, little evidence of an association between replacing red meat with legumes and liver cancer was observed. Further research in other study populations with longer follow-up time is warranted.
Assuntos
Fabaceae , Neoplasias Hepáticas , Carne Vermelha , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos de Coortes , Dieta/efeitos adversos , Dieta/estatística & dados numéricos , Dieta Vegetariana , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Modelos de Riscos Proporcionais , Carne Vermelha/efeitos adversos , Fatores de Risco , Biobanco do Reino Unido , Reino Unido/epidemiologiaRESUMO
More effective treatments for hepatitis viral infections have led to a reduction in the incidence of liver cirrhosis. A high-fat diet can lead to chronic hepatitis and liver fibrosis, but the effects of lipid intake on liver disease status, including hepatitis C virus and alcohol, after elimination of the cause are unclear. To investigate the effects, we used a rat cirrhosis model and a high-fat diet in this study. Male Wistar rats were administered carbon tetrachloride for 5 weeks. At 12 weeks of age, one group was sacrificed. The remaining rats were divided into four groups according to whether or not they were administered carbon tetrachloride for 5 weeks, and whether they were fed a high-fat diet or control diet. At 12 weeks of age, liver fibrosis became apparent and then improved in the groups where carbon tetrachloride was discontinued, while it worsened in the groups where carbon tetrachloride was continued. Liver fibrosis was notable in both the carbon tetrachloride discontinuation and continuation groups due to the administration of a high-fat diet. In addition, liver precancerous lesions were observed in all groups, and tumor size and multiplicity were higher in the high-fat diet-fed groups. The expression of genes related to inflammation and lipogenesis were upregulated in rats fed a high-fat diet compared to their controls. The results suggest that a high-fat diet worsens liver fibrosis and promotes liver carcinogenesis, presumably through enhanced inflammation and lipogenesis, even after eliminating the underlying cause of liver cirrhosis.
Assuntos
Tetracloreto de Carbono , Dieta Hiperlipídica , Modelos Animais de Doenças , Cirrose Hepática , Ratos Wistar , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Cirrose Hepática/etiologia , Ratos , Fígado/patologia , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/etiologia , Carcinogênese , LipogêneseRESUMO
Objectives: Smoking is a preventable risk factor for morbidity and mortality in patients with liver disease. This study aims to explore the additional risks of smoking in the development of alcoholic liver disease (ALD), cirrhosis, and hepatocellular carcinoma (HCC) in high-risk drinkers. Methods: Data from the National Health Insurance Service, including claims and health check-up information spanning 2011 to 2017, were used. The overall alcohol consumption was calculated, and ALD was defined based on ICD-10 codes. High-risk drinking was defined as 7 or more drinks for men and 5 or more for women, twice weekly. Half of the high-risk drinkers were smokers, decreasing in men but stable at 20% for women. Results: ALD prevalence was 0.97% in high-risk drinkers and 1.09% in high-risk drinkers who smoked, higher than 0.16% in social drinkers (p < 0.001). ALD incidence over 3-years was highest in high-risk drinkers who smoked (2.35%), followed by high-risk drinkers (2.03%) and social drinkers (0.35%) (p < 0.001). Cirrhosis and HCC followed similar patterns, with prevalence and incidence was highest in drinkers who smoked. 3-year mortality was 0.65% in high-risk drinkers who smoked, compared to 0.50% in high-risk drinkers and 0.24% in social drinkers (p < 0.001). Smoking increased the incidence of ALD, cirrhosis, and HCC by 1.32, 1.53, and 1.53 times, respectively (all p < 0.001). Gender-specific analysis revealed higher risk ratios (RR) for women in ALD, alcoholic cirrhosis, and HCC, particularly among high-risk drinkers who smoked. Women showed significantly increased RR in ALD (6.08 to 12.38) compared to men (4.18 to 4.40), and similar trends were observed for cirrhosis and HCC. Conclusion: Smoking significantly heightens the risk of ALD, cirrhosis, and HCC, especially in women, among high-risk drinkers. This emphasizes the importance of smoking cessation, particularly for female patients with ALD.
Assuntos
Consumo de Bebidas Alcoólicas , Hepatopatias Alcoólicas , Fumar , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Hepatopatias Alcoólicas/epidemiologia , Hepatopatias Alcoólicas/mortalidade , Adulto , Fumar/epidemiologia , Prevalência , Fatores de Risco , Consumo de Bebidas Alcoólicas/epidemiologia , Estudos de Coortes , Idoso , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/mortalidade , Incidência , Taiwan/epidemiologiaRESUMO
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.
Assuntos
Carcinoma Hepatocelular , Dieta Hiperlipídica , Neoplasias Hepáticas , Camundongos Endogâmicos C57BL , Desmame , Animais , Feminino , Dieta Hiperlipídica/efeitos adversos , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Gravidez , Masculino , Camundongos , Efeitos Tardios da Exposição Pré-Natal , Fenômenos Fisiológicos da Nutrição Materna , Fígado/metabolismo , Fígado/patologia , Obesidade , Fígado Gorduroso/etiologia , Carboidratos da Dieta/efeitos adversos , Carboidratos da Dieta/administração & dosagemRESUMO
BACKGROUND: Higher magnesium intake was linked to a lower risk of hepatocellular carcinoma (HCC). However, the relationship between blood magnesium level and HCC has not been fully characterized, especially among patients with liver cirrhosis who are at a higher risk for HCC. METHODS: In the Mass General Brigham Biobank, we developed a new prospective cohort of 1,430 patients with liver cirrhosis without liver cancer history using the validated International Classification of Diseases codes. We used Cox proportional hazards models to generate hazard ratios (HRs) with 95% confidence intervals (CI) for incident HCC and used generalized estimating equations to compare changes in liver biomarkers according to baseline blood magnesium, adjusting for age, sex, race, lifestyles, body mass index, type 2 diabetes, model for end-stage liver disease score, and hepatitis infection. RESULTS: During a median follow-up period of 4.26 years, 109 patients developed HCC. Magnesium deficiency (<1.70 mg/dL; N = 158) was associated with a higher risk of HCC (HR = 1.93; 95% CI, 1.12-3.30) compared with magnesium sufficiency (≥1.70 mg/dL; N = 1282). This association remained robust in the 1-year lag analysis (HR = 2.18; 95% CI, 1.11-4.28) and in sensitivity analysis excluding patients with alcoholic liver disease (HR = 2.41; 95% CI, 1.23-4.74). Magnesium in the lowest quartile was associated with a faster increase in alanine transaminase (ß = 4.35; 95% CI, 1.06-7.63), aspartate aminotransferase (ß = 6.46; 95% CI, 0.28-12.6), direct bilirubin (ß = 0.18; 95% CI, 0.01-0.35), and total bilirubin (ß = 0.21; 95% CI, 0.03-0.39), compared with the highest quartile. CONCLUSIONS: Lower blood magnesium level is associated with higher HCC risk and unfavorable liver biomarker changes. IMPACT: If confirmed, our findings may potentially enable better identification of high-risk patients for HCC and inform better management strategies for liver cirrhosis.
Assuntos
Carcinoma Hepatocelular , Cirrose Hepática , Neoplasias Hepáticas , Magnésio , Humanos , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/epidemiologia , Feminino , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Masculino , Magnésio/sangue , Estudos Prospectivos , Pessoa de Meia-Idade , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Fatores de Risco , Idoso , AdultoRESUMO
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.
Assuntos
Linfócitos T CD4-Positivos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/terapia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Animais , Imunoterapia/métodos , Progressão da DoençaRESUMO
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.
Assuntos
Carcinoma Hepatocelular , Inflamação , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/virologia , Inflamação/patologia , Animais , Imunoterapia/métodosRESUMO
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.
Assuntos
Carcinoma Hepatocelular , Disbiose , Microbioma Gastrointestinal , Neoplasias Hepáticas , Camundongos Endogâmicos C57BL , Animais , Camundongos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/microbiologia , Neoplasias Hepáticas/etiologia , Disbiose/microbiologia , Masculino , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/microbiologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/patologiaRESUMO
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.