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INTRODUCTION AND OBJECTIVES: Prevalence and mortality of chronic liver disease have risen significantly. In end stage liver disease, the survival of patients is approximately two years. Despite the poor prognosis and high symptom burden of these patients, integration of palliative care is limited. We aim to assess associated factors and trends in palliative care use in recent years. MATERIALS AND METHODS: A Multicenter retrospective cohort of patients with end stage liver disease who suffered in-hospital mortality between 2017 and 2019. Information regarding patient demographics, hospital characteristics, comorbidities, etiology, decompensations, and interventions was collected. Two-sided tests and logistic regression analysis were used to identify factors associated with palliative care use. RESULTS: A total of 201 patients were analyzed, with a yearly increase in palliative care consultation: 26.7 % in 2017 to 38.3 % in 2019. Patients in palliative care were older (65.72 ± 11.70 vs. 62.10 ± 11.44; p = 0.003), had a lower Karnofsky functionality scale (χ=18.104; p = 0.000) and had higher rates of hepatic encephalopathy (32.1 % vs. 17.4 %, p = 0.007) and hepatocarcinoma (61.7 % vs. 26.2 %; p = 0.000). No differences were found for Model for End-stage Liver Disease (19.28 ± 6.60 vs. 19,90 ± 5.78; p = 0.507) or Child-Pugh scores (p = 0.739). None of the patients who die in the intensive care unit receive palliative care (0 % vs 31.6 %; p = 0.000). Half of the palliative care consultations occurred 6,5 days before death. CONCLUSIONS: Palliative care use differs based on demographics, disease complications, and severity. Despite its increasing implementation, palliative care intervention occurs late. Future investigations should identify approaches to achieve an earlier and concurrent care model.
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Doença Hepática Terminal , Cuidados Paliativos , Encaminhamento e Consulta , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Doença Hepática Terminal/terapia , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/diagnóstico , Encaminhamento e Consulta/estatística & dados numéricos , Idoso , Estudos Retrospectivos , Mortalidade Hospitalar , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/epidemiologiaRESUMO
Chronic liver disease is a global health issue. Patients with chronic liver disease require a fresh approach that focuses on the genetic and environmental factors that contribute to disease initiation and progression. Emerging knowledge in the fields of Genomic Medicine and Genomic Nutrition demonstrates differences between countries in terms of genetics and lifestyle risk factors such as diet, physical activity, and mental health in chronic liver disease, which serves as the foundation for the implementation of Personalized Medicine and Nutrition (PerMed-Nut) strategies. Most of the world's populations have descended from various ethnic groupings. Mexico's population has a tripartite ancestral background, consisting of Amerindian, European, and African lineages, which is common across Latin America's regional countries. The purpose of this review is to discuss the genetic and environmental components that could be incorporated into a PerMed-Nut model for metabolic-associated liver disease, viral hepatitis B and C, and hepatocellular carcinoma in Mexico. Additionally, the implementation of the PerMed-Nut approach will require updated medicine and nutrition education curricula. Training and equipping future health professionals and researchers with new clinical and investigative abilities focused on preventing liver illnesses in the field of genomic hepatology globally is a vision that clinicians and nutritionists should be concerned about.
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INTRODUCTION AND OBJECTIVES: Liver transplant (LT) is a recent option available in the United States (US) to treat those with severe, refractory alcoholic hepatitis (AH). We examined changes in clinical characteristics of patients admitted with AH and tracked hospital outcomes as practice changes involving LT have shifted. MATERIALS AND METHODS: Using the National Inpatient Sample, we performed a cross-sectional analysis of patients admitted with AH during the years 2016-2020 in the US. Differences in clinical characteristics over time were assessed. To compare outcomes between 2016-2017 (when LT was less common) and 2018-2020 (when LT was more common), we conducted linear and logistic regression. Propensity-score matching was used to compare outcomes between patients with and without LT. RESULTS: From 2016-2017 to 2018-2020, patients admitted with AH tended to have a higher frequency of infection (p = 0.006), hepatorenal syndrome (<0.001), and ascites (<0.001). Hospital costs and length of stay (LOS) were highest in transplant hospitals, and costs rose over time in both non-transplant (NT) teaching and non-teaching hospitals (p < 0.001). Mortality decreased in NT teaching hospitals [aOR 0.7 (95% CI: 0.6-0.8)] and slightly decreased in NT non-teaching hospitals [aOR 0.7 (95% CI: 0.5-1.0)]. In the propensity-matched cohort involving LT versus non-LT patients, there was a 10% absolute reduction in-hospital mortality, but this came at a higher cost (p < 0.001) and length of stay (p < 0.001). CONCLUSIONS: The severity of AH has been increasing over time, yet mortality has declined after adjusting for severity of disease. Patients who underwent LT survived; however, the healthcare burden of LT is substantial.
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Hepatite Alcoólica , Transplante de Fígado , Humanos , Estados Unidos/epidemiologia , Transplante de Fígado/efeitos adversos , Hepatite Alcoólica/diagnóstico , Hepatite Alcoólica/cirurgia , Pacientes Internados , Estudos Transversais , HospitalizaçãoRESUMO
Este año la revista Hepatología inicia su cuarto año de publicación y continuamos esta-bleciendo cambios que serán de beneficio para mejorar la calidad y visibilidad de la revista. Entre ellos, está la implementación de la plataforma OJS (Open Journal Systems), la cual es un sistema para la edición de revistas que facilita la gestión y publicación de los artículos en línea. Se caracteriza por su capacidad de interacción con las diferentes ba-ses de datos e índices, su sistema de notificaciones y comunicación permanente entre el equipo editorial, los autores y los pares evaluadores, además de su integración con otros servicios académicos como son CrossRef y ORCID. Por lo tanto, hemos migrado todo el contenido del sitio web previo de la revista Hepatología hacia la plataforma OJS, y es-peramos comenzar a recibir los artículos por este medio (www.revistahepatologia.com)
This year the Hepatology journal begins its fourth year of publication and we continue to establish changes that will be of benefit to improve the quality and visibility of the journal. Among them is the implementation of the OJS (Open Journal Systems) platform, which is a system for publishing journals that facilitates the management and publication of articles online. It is characterized by its ability to interact with the different databases and indexes, its notification system and permanent communication between the editorial team, authors and peer reviewers, as well as its integration with other academic services such as CrossRef and ORCID. . Therefore, we have migrated all the content from the previous Hepatology journal website to the OJS platform, and we hope to start receiving articles through this means (www.revistahepatologia.com).
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Humanos , Organização e Administração , Publicações , GastroenterologiaRESUMO
Resumen Objetivo: describir un caso de trasplante hepático en un paciente con resultado positivo en la prueba del coronavirus del síndrome respiratorio agudo grave de tipo 2 (SARS-CoV-2) con éxito en el postrasplante temprano, pero que desarrolló complicaciones asociadas a la inmunosupresión y trombosis portal sin una trombofilia identificada en un centro de alta complejidad de un país latinoamericano. Descripción del caso: paciente de 48 años con diagnóstico de cirrosis hepática secundaria a esteatohepatitis no alcohólica (NASH) complicada por varios episodios de ascitis portal hipertensiva y encefalopatía hepática, ingresada para trasplante hepático ortóptico. En los exámenes iniciales tuvo una prueba positiva para SARS-CoV-2 y era asintomático respiratorio. El trasplante se realizó con éxito luego de la autorización del comité de infección. Después del primer mes posoperatorio presentó diarrea, ascitis y daño renal agudo. Los niveles de tacrolimus en el reingreso fueron superiores a 10 ng/mL y hubo una mejoría clínica significativa con la suspensión del fármaco. Finalmente, el paciente requirió retrasplante por trombosis de la vena porta y de las venas suprahepáticas, aunque no se identificó la etiología. Conclusión: se describe uno de los primeros informes de trasplante de hígado en un paciente con recuperación reciente de COVID-19 y pruebas persistentemente positivas. En el postrasplante temprano hubo una buena respuesta; sin embargo, luego del primer mes presentó complicaciones relacionadas con la inmunosupresión. Este caso también plantea la posible asociación entre el SARS-CoV-2 y el desarrollo de trombosis en la circulación portal hepática.
Abstract Objective: To describe a case of liver transplantation in a patient with a positive result in the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) test with success in the early post-transplantation, but who developed complications associated with immunosuppression and portal vein thrombosis without thrombophilia identified at a tertiary referral center in a Latin American country. Case: A 48-year-old patient diagnosed with liver cirrhosis secondary to non-alcoholic steatohepatitis (NASH) complicated by several episodes of portal hypertension ascites and hepatic encephalopathy was admitted for orthoptic liver transplantation. On initial examinations, he had a positive test for SARS-CoV-2 and was asymptomatic in the respiratory tract. The transplant was carried out successfully after the authorization of the infection committee. After the first postoperative month, he presented with diarrhea, ascites, and acute kidney injury. Tacrolimus levels at readmission were more significant than 10 ng/mL, and there was a significant clinical improvement with drug discontinuation. Finally, the patient required re-transplantation due to thrombosis of the portal vein and suprahepatic veins, although the etiology was not identified. Conclusion: One of the first reports of liver transplantation in a patient with recent recovery from COVID-19 and persistently positive tests is described. In the early post-transplant, there was a good response; however, after the first month, he had complications related to immunosuppression. This case also posits the possible association between SARS-CoV-2 and the development of thrombosis in the hepatic portal circulation.
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BACKGROUND: The Center for Disease Control and Prevention (CDC) reports that liver disease is a significant cause of morbidity and mortality in the US, afflicting 4.5 million people in 2018, or approximately 1.7% of the American adult population. OBJECTIVE: To determine the prevalence and risk factors associated with liver disease among older Mexican Americans over 18 years of follow-up. METHODS: Non-institutionalized Mexican Americans aged ≥67 years (N = 1938) from the Hispanic Established Population for the Epidemiologic Study of the Elderly (1995/96-2012/13) were studied. Measures included socio-demographic variables, self-reported liver disease, language of interview, medical conditions, hand-grip strength, physical and cognitive function, depressive symptoms, and body mass index. Generalized estimating equation models were used to estimate the odds ratio and 95% confidence interval (CI) of liver disease over time. RESULTS: The mean age at baseline was 74.9 ± 6.0 years and 58.4% were female. The prevalence of liver disease ranged from 2.4% to 8.4%. Over time, the odds ratio of reporting liver disease was 1.17 (CI = 1.12-1.22). Older age, Spanish interview, arthritis, diabetes, heart failure, cancer, and high scores on the Mini-Mental-State-Examination were factors associated with greater odds of reporting liver disease over time. Married participants reported lower odds of liver disease over time. CONCLUSIONS: The prevalence of liver disease in this population was high, ranging from 2.4% to 8.4%. Diabetes, heart failure, arthritis, and cancer were risk factors for liver disease. Screening for liver function among patients with these morbidities may help prevent liver disease in this population with high rates of diabetes and obesity.
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Artrite , Insuficiência Cardíaca , Hepatopatias , Idoso , Feminino , Força da Mão , Humanos , Hepatopatias/epidemiologia , Masculino , Americanos Mexicanos/psicologia , Fatores de RiscoRESUMO
The abundance of neutrophils in human circulation, their fast mobilization from blood to tissues, along with their alleged short life-span led to the image of neutrophils as a homogeneous cell type designed to fight infections and die in the process. Additionally, their granule content and capacity to produce molecules with considerable cytotoxic potential, lead to the general belief that neutrophil activation inexorably results in side effect of extensive tissue injury. Neutrophil activation in fact causes tissue injury as an adverse effect, but it seems that this is restricted to particular pathological situations and more of an "exception to the rule". Here we review evidences arising especially from intravital microscopy studies that demonstrate neutrophils as cells endowed with sophisticated mechanisms and able to engage in complex interactions as to minimize damage and optimize their effector functions. Moreover, neutrophil infiltration may even contribute to tissue healing and repair which may altogether demand a reexamination of current anti-inflammatory therapies that have neutrophil migration and activation as a target.
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Anti-Inflamatórios/farmacologia , Inflamação/patologia , Neutrófilos/metabolismo , Animais , Humanos , Inflamação/tratamento farmacológico , Ativação de Neutrófilo/fisiologia , Infiltração de Neutrófilos/fisiologiaRESUMO
Chemotherapy is a potential cause of focal and diffuse hepatobiliary lesions. Many of these lesions may be demonstrated on imaging, especially computed tomography and MRI. Some of these lesions, especially those of steatosis and sinusoidal obstruction syndrome, are associated with a worse prognosis and risk of hepatic failure in the context of surgical management. Notably, some chemotherapy-induced hepatic alterations, such as sinusoidal obstruction syndrome, pseudocirrhosis and focal hepatopathies, may be mistakenly interpreted as signs of cancer progression, misguiding the therapeutic planning for patients receiving chemotherapy.
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INTRODUCTION AND AIMS: Primary liver cancer is a public health problem in Mexico and the world. Liver transplantation (LT) is the ideal treatment for early hepatocellular carcinoma (HCC). Our aim was to evaluate the characteristics of patients with HCC and cholangiocarcinoma (CC) at two centers and identify transplantation candidates. MATERIALS AND METHODS: A retrospective observational study was conducted at the Hepatology Center (HC) and the University Center Against Cancer (UCAC), within the time frame of 2012-2018. HCC or intrahepatic CC was confirmed in 109 patients. Staging classifications, transplant selection models, and a predictive model for post-LT recurrence were applied to the HCC patients. RESULTS: Of the total population, 93% (n=102) presented with cirrhosis, 86% (n=94) had HCC (HC: 58%, UCAC: 42%), and 14% (n=15) had intrahepatic CC (HC: 40%, UCAC: 60%). Of the HC patients with HCC, Okuda I-II, BCLC A-B, and AFP levels <100ng/m predominated, whereas Okuda II-III, BCLC C-D, and AFP levels >1000ng/mL predominated in the UCAC patients. Half of the HC population with HCC met the criteria for LT, in contrast to 23% of the UCAC patients. Fifteen patients were evaluated for LT, and at present, six have undergone transplantation. CONCLUSIONS: The most frequent primary liver tumor was HCC. Patients from the HC presented with earlier-stage disease and a high number of them met the criteria for LT. Only patients from the HC underwent transplantation.
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Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Gastroenterologia , Neoplasias Hepáticas , Carcinoma Hepatocelular/terapia , Humanos , Neoplasias Hepáticas/terapia , Recidiva Local de Neoplasia , alfa-FetoproteínasRESUMO
Healthcare systems worldwide were challenged during the COVID-19 pandemic. In Mexico, the public hospitals that perform most transplants were adapted to provide care for COVID-19 patients. Using a nationwide database, we describe the first report of the impact of COVID-19 and related transplantation healthcare policies in a middle-income country by comparing statistics before and during the pandemic (pre-COVID: March 2019-February 2020 vs. COVID era: March 2020-February 2021) and by type of institution (public vs. private). The global reduction in transplantation was higher in public institutions compared with private institutions, 89% versus 62%, respectively, p < .001. When analyzing by organ, kidney transplantation decreased by 89% at public versus 57% at private, p < .001; cornea by 88% at public versus 64% at private, p < .001; liver by 88% at public versus 35% at private, p < .001; and heart by 88% in public versus 67% at private institutions, p = .4. The COVID-19 pandemic along with the implemented health policies were associated with a decrease in donations, waiting list additions, and a decrease in transplantation, particularly at public institutions, which care for the most vulnerable.
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COVID-19 , Pandemias , Setor de Assistência à Saúde , Disparidades em Assistência à Saúde , Humanos , México/epidemiologia , SARS-CoV-2Assuntos
Hepatite A , Hepatite B , Criança , Hepatite B/diagnóstico , Hepatite B/epidemiologia , Humanos , Responsabilidade SocialRESUMO
INTRODUCTION: Acute viral hepatitis is a disease of great clinical importance. This study proposes actions to better characterise cases of acute hepatitis in Brazil and to provide relevant information to institutionalised health policies within the Unified Health System. Available data on acute hepatitis in Brazil need to be re-evaluated regarding the different hepatotropic agent (hepatitis A to E virus) frequencies, as well as other agents that can cause similar clinical conditions, such as Herpes Simplex Virus 1 and 2(HSV1, HSV2), Varicella Zoster Virus (VZV), Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Human Herpes Virus 6 and 7 (HHV6, HHV7), arbovirus (yellow fever, dengue, chikungunya, Zika), parvovirus B19, adenovirus, parechovirus, enterovirus, HIV, leptospirosis, toxoplasmosis and syphilis, in addition to autoimmune hepatitis. In this context, the primary aim of this study is the clinical-epidemiological and molecular characterisation of acute viral hepatitis in Brazilian health services from all geographical regions of the country. The present article describes the study protocol. METHODS AND ANALYSIS: This study will evaluate 2280 patients with symptoms and/or signs suggestive of acute liver disease in Brazilian health institutions in all five geographic Brazilian regions. Demographic, epidemiological and clinical data will be collected, as well as blood samples to be analysed at Hospital Israelita Albert Einstein Clinical Laboratory. ETHICS AND DISSEMINATION: Ethics approval was obtained at the national research ethics committee (Conselho Nacional de Ética em Pesquisa- CONEP-CAAE 00952818.4.1001.0071) and at all participating sites. Results will be published in journals and presented at scientific meetings.
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Infecções por Vírus Epstein-Barr , Hepatite Viral Humana , Infecção por Zika virus , Zika virus , Brasil/epidemiologia , Serviços de Saúde , Hepatite Viral Humana/epidemiologia , Herpesvirus Humano 4 , HumanosRESUMO
INTRODUCTION AND AIMS: Primary liver cancer is a public health problem in Mexico and the world. Liver transplantation (LT) is the ideal treatment for early hepatocellular carcinoma (HCC). Our aim was to evaluate the characteristics of patients with HCC and cholangiocarcinoma (CC) at two centers and identify transplantation candidates. MATERIALS AND METHODS: A retrospective observational study was conducted at the Hepatology Center (HC) and the University Center Against Cancer (UCAC), within the time frame of 2012-2018. HCC or intrahepatic CC was confirmed in 109 patients. Staging classifications, transplant selection models, and a predictive model for post-LT recurrence were applied to the HCC patients. RESULTS: Of the total population, 93% (n = 102) presented with cirrhosis, 86% (n = 94) had HCC (HC: 58%, UCAC: 42%), and 14% (n = 15) had intrahepatic CC (HC: 40%, UCAC: 60%). Of the HC patients with HCC, Okuda I-II, BCLC A-B, and AFP levels < 100 ng/m predominated, whereas Okuda II-III, BCLC C-D, and AFP levels > 1,000 ng/mL predominated in the UCAC patients. Half of the HC population with HCC met the criteria for LT, in contrast to 23% of the UCAC patients. Fifteen patients were evaluated for LT, and at present, six have undergone transplantation. CONCLUSIONS: The most frequent primary liver tumor was HCC. Patients from the HC presented with earlier-stage disease and a high number of them met the criteria for LT. Only patients from the HC underwent transplantation.
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Exposure to the herbicides Paraquat and Roundup® may cause cell lesions due to an increase in oxidative stress levels in different biological systems, even in the liver. The aim of this study was to analyze the effect of melatonin on liver of rats exposed to herbicides. A total of 35 rats were randomly divided into seven equal-sized groups: control, Paraquat, Roundup®, Paraquat + Roundup®, Paraquat + melatonin, Roundup® + melatonin, and Paraquat + Roundup® + melatonin. Samples of blood and hepatic tissue were collected at the end of the seventh day of exposure and treatment with melatonin. Body weight, hematological parameters, and histopathological, biochemical analyses and determination of oxidative stress levels in liver were evaluated. Body weight was compromised (P < 0.01). Alterations of hematologic parameters were significant when compared to control (P < 0.001). Biochemically, serum levels of albumin decreased (P < 0.001), but serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase increased (P < 0.001). Histopathology revealed necrotic hepatocytes, portal and central-lobular inflammatory infiltrate, congestion of capillaries. Serum levels of thiobarbituric acid reactive substances were found to be significantly elevated (P < 0.05; P < 0.001), and serum level of reduced glutathione was significantly lower (P < 0.05; P < 0.001). The groups treated concomitantly with melatonin revealed results similar to those of the control. However, melatonin acted as a protective agent for the liver against experimentally induced hepatic toxicity, promoting prevention of body weight, oxidative stress, and normalization of hematological and biochemical parameters.
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OBJECTIVE: To evaluate risk factors for hepatic artery thrombosis (HAT) and examine the long-term outcomes of graft and patient survival after HAT in pediatric recipients of liver transplantation. STUDY DESIGN: Using multicenter data from the Society of Pediatric Liver Transplantation, Kaplan-Meier and Cox regression analyses were performed on first-time pediatric (aged <18 years) liver transplant recipients (n = 3801) in the US and Canada between 1995 and 2016. RESULTS: Of children undergoing their first liver transplantation, 7.4% developed HAT within the first 90 days of transplantation and, of those who were retransplanted, 20.7% developed recurrent HAT. Prolonged warm ischemia times increased the odds of developing HAT (OR, 1.11; P = .02). Adolescents aged 11-17 years (OR, 0.53; P = .03) and recipients with split, reduced, or living donor grafts had decreased odds of HAT (OR, 0.59; P < .001 compared with whole grafts). Fifty percent of children who developed HAT developed graft failure within the first 90 days of transplantation (adjusted hazard ratio, 11.87; 95% CI, 9.02-15.62) and had a significantly higher post-transplant mortality within the first 90 days after transplantation (adjusted hazard ratio, 6.18; 95% CI, 4.01-9.53). CONCLUSIONS: These data from an international registry demonstrate poorer long-term graft and patient survival in pediatric recipients whose post-transplant course is complicated by HAT. Notably, recipients of technical variant grafts had lower odds of HAT compared with whole liver grafts.
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Artéria Hepática , Hepatopatias/cirurgia , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Trombose/epidemiologia , Adolescente , Fatores Etários , Canadá , Criança , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Humanos , Incidência , Lactente , Hepatopatias/etiologia , Hepatopatias/mortalidade , Masculino , Razão de Chances , Complicações Pós-Operatórias/diagnóstico , Fatores de Risco , Taxa de Sobrevida , Trombose/diagnóstico , Estados UnidosRESUMO
Neutrophils were classically described as powerful effectors of acute inflammation, and their main purpose was assumed to be restricted to pathogen killing through production of oxidants. As consequence, neutrophils also may lead to significant collateral damage to the healthy tissues, and after performing these tasks, these leukocytes are supposed to die within tissues. However, there is a growing body of evidence showing that neutrophils also play a pivotal role in the resolution phases of inflammation, because they can modulate tissue environment due to secretion of different kind of cytokines. Drug-induced liver injury (DILI) is a worldwide concern being one of the most prevalent causes of liver transplantation, and is well established that there is an intense neutrophil recruitment into necrotic liver during DILI. However, information if such abundant granulocyte infiltration is also linked to the tissue repairing phase of hepatic injury is still largely elusive. Here, we investigated the dynamics of neutrophil trafficking within blood, bone marrow, and liver during hepatic inflammation, and how changes in their gene expression profile could drive the resolution events during acetaminophen (APAP)-induced liver injury. We found that neutrophils remained viable during longer periods following liver damage, because they avidly patrolled necrotic areas and up-regulated pro-resolutive genes, including Tgfb, Il1r2, and Fpr2. Adoptive transference of "resolutive neutrophils" harvested from livers at 72 h after injury to mice at the initial phases of injury (6 h after APAP) significantly rescued organ injury. Thus, we provide novel insights on the role of neutrophils not only in the injury amplification, but also in the resolution phases of inflammation.
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Doença Hepática Induzida por Substâncias e Drogas/imunologia , Fígado/imunologia , Infiltração de Neutrófilos , Neutrófilos/imunologia , Acetaminofen/efeitos adversos , Acetaminofen/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Feminino , Fígado/patologia , Camundongos , Neutrófilos/patologia , Receptores de Formil Peptídeo/imunologia , Receptores Tipo II de Interleucina-1/imunologia , Fator de Crescimento Transformador beta/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated to intermittent hypoxia (IH) and is an aggravating factor of non-alcoholic fatty liver disease (NAFLD). We investigated the effects of hypoxia in both in vitro and in vivo models of NAFLD. METHODS: Primary rat hepatocytes treated with free fatty acids (FFA) were subjected to chemically induced hypoxia (CH) using the hypoxia-inducible factor-1 alpha (HIF-1α) stabilizer cobalt chloride (CoCl2). Triglyceride (TG) content, mitochondrial superoxide production, cell death rates, cytokine and inflammasome components gene expression and protein levels of cleaved caspase-1 were assessed. Also, Kupffer cells (KC) were treated with conditioned medium (CM) and extracellular vehicles (EVs) from hypoxic fat-laden hepatic cells. The choline deficient L-amino acid defined (CDAA)-feeding model used to assess the effects of IH on experimental NAFLD in vivo. RESULTS: Hypoxia induced HIF-1α in cells and animals. Hepatocytes exposed to FFA and CoCl2 exhibited increased TG content and higher cell death rates as well as increased mitochondrial superoxide production and mRNA levels of pro-inflammatory cytokines and of inflammasome-components interleukin-1ß, NLRP3 and ASC. Protein levels of cleaved caspase-1 increased in CH-exposed hepatocytes. CM and EVs from hypoxic fat-laden hepatic cells evoked a pro-inflammatory phenotype in KC. Livers from CDAA-fed mice exposed to IH exhibited increased mRNA levels of pro-inflammatory and inflammasome genes and increased levels of cleaved caspase-1. CONCLUSION: Hypoxia promotes inflammatory signals including inflammasome/caspase-1 activation in fat-laden hepatocytes and contributes to cellular crosstalk with KC by release of EVs. These mechanisms may underlie the aggravating effect of OSAS on NAFLD. [Abstract word count: 257].