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Hepatocellular carcinoma (HCC) is the most prevalent primary liver malignancy and is a major cause of cancer-related mortality in the world. This study aimed to characterize glutamine amino acid transporter expression profiles in HCC compared to those of normal liver cells. In vitro and in vivo models of HCC were studied using qPCR, whereas the prognostic significance of glutamine transporter expression levels within patient tumors was analyzed through RNAseq. Solute carrier (SLC) 1A5 and SLC38A2 were targeted through siRNA or gamma-p-nitroanilide (GPNA). HCC cells depended on exogenous glutamine for optimal survival and growth. Murine HCC cells showed superior glutamine uptake rate than normal hepatocytes (p < 0.0001). HCC manifested a global reprogramming of glutamine transporters compared to normal liver: SLC38A3 levels decreased, whereas SLC38A1, SLC7A6, and SLC1A5 levels increased. Also, decreased SLC6A14 and SLC38A3 levels or increased SLC38A1, SLC7A6, and SLC1A5 levels predicted worse survival outcomes (all p < 0.05). Knockdown of SLC1A5 and/or SLC38A2 expression in human Huh7 and Hep3B HCC cells, as well as GPNA-mediated inhibition, significantly decreased the uptake of glutamine; combined SLC1A5 and SLC38A2 targeting had the most considerable impact (all p < 0.05). This study revealed glutamine transporter reprogramming as a novel hallmark of HCC and that such expression profiles are clinically significant.
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Carcinoma Hepatocelular , Regulação Neoplásica da Expressão Gênica , Glutamina , Neoplasias Hepáticas , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Humanos , Animais , Prognóstico , Camundongos , Linhagem Celular Tumoral , Glutamina/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Masculino , Feminino , Proteínas de Transporte , Sistema ASC de Transporte de AminoácidosRESUMO
The liver is a highly specialized organ involved in regulating systemic metabolism. Understanding metabolic reprogramming of liver disease is key in discovering clinical biomarkers, which relies on robust tissue biobanks. However, sample collection and storage procedures pose a threat to obtaining reliable results, as metabolic alterations may occur during sample handling. This study aimed to elucidate the impact of pre-analytical delay during liver resection surgery on liver tissue metabolomics. Patients were enrolled for liver resection during which normal tissue was collected and snap-frozen at three timepoints: before transection, after transection, and after analysis in Pathology. Metabolomics analyses were performed using 1H Nuclear Magnetic Resonance (NMR) and Liquid Chromatography-Mass Spectrometry (LC-MS). Time at cryopreservation was the principal variable contributing to differences between liver specimen metabolomes, which superseded even interindividual variability. NMR revealed global changes in the abundance of an array of metabolites, namely a decrease in most metabolites and an increase in ß-glucose and lactate. LC-MS revealed that succinate, alanine, glutamine, arginine, leucine, glycerol-3-phosphate, lactate, AMP, glutathione, and NADP were enhanced during cryopreservation delay (all p<0.05), whereas aspartate, iso(citrate), ADP, and ATP, decreased (all p<0.05). Cryopreservation delays occurring during liver tissue biobanking significantly alter an array of metabolites. Indeed, such alterations compromise the integrity of metabolomic data from liver specimens, underlining the importance of standardized protocols for tissue biobanking in hepatology.
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Bancos de Espécimes Biológicos , Criopreservação , Fígado , Metabolômica , Humanos , Criopreservação/métodos , Fígado/metabolismo , Metabolômica/métodos , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Idoso , Metaboloma , Fatores de Tempo , Cromatografia Líquida/métodos , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Bancos de TecidosRESUMO
Many people living with diabetes also have nonalcoholic fatty liver disease (NAFLD). Interleukin-6 (IL-6) is involved in both diseases, interacting with both membrane-bound (classical) and circulating (trans-signaling) soluble receptors. We investigated whether secretion of IL-6 trans-signaling coreceptors are altered in NAFLD by diabetes and whether this might associate with the severity of fatty liver disease. Secretion patterns were investigated with use of human hepatocyte, stellate, and monocyte cell lines. Associations with liver pathology were investigated in two patient cohorts: 1) biopsy-confirmed steatohepatitis and 2) class 3 obesity. We found that exposure of stellate cells to high glucose and palmitate increased IL-6 and soluble gp130 (sgp130) secretion. In line with this, plasma sgp130 in both patient cohorts positively correlated with HbA1c, and subjects with diabetes had higher circulating levels of IL-6 and trans-signaling coreceptors. Plasma sgp130 strongly correlated with liver stiffness and was significantly increased in subjects with F4 fibrosis stage. Monocyte activation was associated with reduced sIL-6R secretion. These data suggest that hyperglycemia and hyperlipidemia can directly impact IL-6 trans-signaling and that this may be linked to enhanced severity of NAFLD in patients with concomitant diabetes. ARTICLE HIGHLIGHTS: IL-6 and its circulating coreceptor sgp130 are increased in people with fatty liver disease and steatohepatitis. High glucose and lipids stimulated IL-6 and sgp130 secretion from hepatic stellate cells. sgp130 levels correlated with HbA1c, and diabetes concurrent with steatohepatitis further increased circulating levels of all IL-6 trans-signaling mediators. Circulating sgp130 positively correlated with liver stiffness and hepatic fibrosis. Metabolic stress to liver associated with fatty liver disease might shift the balance of IL-6 classical versus trans-signaling, promoting liver fibrosis that is accelerated by diabetes.
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Diabetes Mellitus , Hepatopatia Gordurosa não Alcoólica , Humanos , Receptor gp130 de Citocina/metabolismo , Receptores de Interleucina-6/metabolismo , Interleucina-6/metabolismo , Hemoglobinas Glicadas , Fibrose , GlucoseRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is a major contributor to cancer-related morbidity and mortality burdens globally. Given the fundamental metabolic activity of hepatocytes within the liver, hepatocarcinogenesis is bound to be characterized by alterations in metabolite profiles as a manifestation of metabolic reprogramming. METHODS: HCC and adjacent non-tumoral liver specimens were obtained from patients after HCC resection. Global patterns in tissue metabolites were identified using non-targeted 1H Nuclear Magnetic Resonance (1H-NMR) spectroscopy whereas specific metabolites were quantified using targeted liquid chromatography-mass spectrometry (LC/MS). RESULTS: Principal component analysis (PCA) within our 1H-NMR dataset identified a principal component (PC) one of 53.3%, along which the two sample groups were distinctively clustered. Univariate analysis of tissue specimens identified more than 150 metabolites significantly altered in HCC compared to non-tumoral liver. For LC/MS, PCA identified a PC1 of 45.2%, along which samples from HCC tissues and non-tumoral tissues were clearly separated. Supervised analysis (PLS-DA) identified decreases in tissue glutathione, succinate, glycerol-3-phosphate, alanine, malate, and AMP as the most important contributors to the metabolomic signature of HCC by LC/MS. CONCLUSIONS: Together, 1H-NMR and LC/MS metabolomics have the capacity to distinguish HCC from non-tumoral liver. The characterization of such distinct profiles of metabolite abundances underscores the major metabolic alterations that result from hepatocarcinogenesis.
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BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is a major health problem with complex pathogenesis. Although sex differences in NAFLD pathogenesis have been reported, the mechanisms underlying such differences remain understudied. Interleukin (IL)22 is a pleiotropic cytokine with both protective and/or pathogenic effects during liver injury. IL22 was shown to be hepatoprotective in NAFLD-related liver injury. However, these studies relied primarily on exogenous administration of IL22 and did not examine the sex-dependent effect of IL22. Here, we sought to characterize the role of endogenous IL22-receptor signaling during NAFLD-induced liver injury in males and females. METHODS: We used immunofluorescence, flow cytometry, histopathologic assessment, and gene expression analysis to examine IL22 production and characterize the intrahepatic immune landscape in human subjects with NAFLD (n = 20; 11 men and 9 women) and in an in vivo Western high-fat diet-induced NAFLD model in IL22RA knock out mice and their wild-type littermates. RESULTS: Examination of publicly available data sets from 2 cohorts with NAFLD showed increased hepatic IL22 gene expression in females compared with males. Furthermore, our immunofluorescence analysis of liver sections from NAFLD subjects (n = 20) showed increased infiltration of IL22-producing cells in females. Similarly, IL22-producing cells were increased in wild-type female mice with NAFLD and the hepatic IL22/IL22 binding protein messenger RNA ratio correlated with expression of anti-apoptosis genes. The lack of endogenous IL22-receptor signaling (IL22RA knockout) led to exacerbated liver damage, inflammation, apoptosis, and liver fibrosis in female, but not male, mice with NAFLD. CONCLUSIONS: Our data suggest a sex-dependent hepatoprotective antiapoptotic effect of IL22-receptor signaling during NAFLD-related liver injury in females.
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Hepatopatia Gordurosa não Alcoólica , Feminino , Humanos , Masculino , Camundongos , Animais , Receptores de Interleucina/genética , Transdução de Sinais , Cirrose Hepática , Camundongos KnockoutRESUMO
Immune checkpoint inhibitors (ICI) are being increasingly used to successfully treat several types of cancer. However, due to their mode of action, these treatments are associated with several immune-related adverse events (irAEs), including immune-mediated autoimmune-like hepatitis in 5 to 10% of cases. The specific immune mechanism responsible for the development of immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI) is currently unknown. This review summarizes the current knowledge on hepatic irAEs during cancer immunotherapy. It also addresses the clinical management of ILICI and how it is becoming an increasingly important clinical issue. Clinical, histological, and laboratory features of autoimmune hepatitis (AIH) and ILICI are compared, and their shared and distinctive traits are discussed in an effort to better understand the development of hepatic irAEs. Finally, based on the current knowledge of liver immunology and AIH pathogenesis, we propose a series of events that could trigger the observed liver injury in ICI-treated patients. This model could be useful in the design of future studies aiming to identify the specific immune mechanism(s) at play in ILICI and improve immune checkpoint inhibitor cancer immunotherapy.
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Hepatite Autoimune , Neoplasias , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/terapia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/efeitos adversos , Neoplasias/patologiaRESUMO
Most patients with hepatocellular carcinoma (HCC) are diagnosed at a late stage and have few therapeutic options and a poor prognosis. This is due to the lack of clearly defined underlying mechanisms or a dominant oncogene that can be targeted pharmacologically, unlike in other cancer types. Here, we report the identification of a previously uncharacterized oncogenic signaling pathway in HCC that is mediated by the tyrosine kinase Yes. Using genetic and pharmacological interventions in cellular and mouse models of HCC, we showed that Yes activity was necessary for HCC cell proliferation. Transgenic expression of activated Yes in mouse hepatocytes was sufficient to induce liver tumorigenesis. Yes phosphorylated the transcriptional coactivators YAP and TAZ (YAP/TAZ), promoting their nuclear accumulation and transcriptional activity in HCC cells and liver tumors. We also showed that YAP/TAZ were effectors of the Yes-dependent oncogenic transformation of hepatocytes. Src family kinase activation correlated with the tyrosine phosphorylation and nuclear localization of YAP in human HCC and was associated with increased tumor burden in mice. Specifically, high Yes activity predicted shorter overall survival in patients with HCC. Thus, our findings identify Yes as a potential therapeutic target in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Proteínas de Sinalização YAPRESUMO
Studies on pediatric patients with primary sclerosing cholangitis (PSC) have been limited by short follow-up and inconsistent classification of pediatric patients with autoimmune hepatitis-sclerosing cholangitis overlap (AIC). We conducted a retrospective study of patients diagnosed with AIC or PSC during childhood with extension of follow-up into adulthood. Methods: We reviewed records of patients followed for PSC or AIC between 1998 and 2019 at a pediatric referral center. Features at diagnosis, biochemical and liver-related outcomes (cholangitis, liver transplant, and cirrhosis) were compared. Results: Forty patients (27 PSC, 13 AIC) were followed for 92 months on average (standard deviation 79 months) with extension into adulthood in 52.5%; 70% had associated inflammatory bowel disease (IBD). The proportion of patients with significant fibrosis and abnormal baseline liver tests (serum bilirubin and transaminase levels) were similar in both groups. One year postdiagnosis, 55% (15/27) of PSC patients had normal liver tests versus only 15% (2/13) in the AIC group (P = 0.02). During follow-up, more liver-related events occurred in the AIC group (69% versus 27%, hazard ratio [HR] = 3.7 [95% confidence interval (CI): 1.4-10] P = 0.01). Baseline elevated serum bilirubin levels (HR = 5.3 [95% CI: 1.7-16.9] P = 0.005) and elevated transaminase levels at 1 year (HR = 9.09 [95% CI: 1.18-66.7) P = 0.03) were predictive of liver-related events, while having IBD was not (HR = 0.48 (95% CI: 0.15-1.5) P = 0.22). Conclusions: Pediatric patients with AIC and PSC presented at a similar fibrosis stage, however, with a more severe hepatitis in AIC. In this cohort, AIC was associated with more liver-related events, primarily driven by a higher rate of cirrhosis compared with PSC; transplant rates were similar.
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Metabolic reprogramming and deregulated cellular energetics are hallmarks of cancer. The aberrant metabolism of cancer cells is thought to be the product of differential oncogene activation and tumor suppressor gene inactivation. MYC is one of the most important oncogenic drivers, its activation being reported in a variety of cancer types and sub-types, among which are the most prevalent and aggressive of all malignancies. This review aims to offer a comprehensive overview and highlight the importance of the c-Myc transcription factor on the regulation of metabolic pathways, in particular that of glutamine and glutaminolysis. Glutamine can be extensively metabolized into a variety of substrates and be integrated in a complex metabolic network inside the cell, from energy metabolism to nucleotide and non-essential amino acid synthesis. Together, understanding metabolic reprogramming and its underlying genetic makeup, such as MYC activation, allows for a better understanding of the cancer cell phenotype and thus of the potential vulnerabilities of cancers from a metabolic standpoint.
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Disulfiram (DSF), a sulfur-containing compound, has been used to treat chronic alcoholism and cancer for decades by inactivating aldehyde dehydrogenase (ALDH). Hydrogen sulfide (H2S) is a new gasotransmitter and regulates various cellular functions by S-sulfhydrating cysteine in the target proteins. H2S exhibits similar properties to DSF in the sensitization of cancer cells. The interaction of DSF and H2S on ALDH activity and liver cancer cell survival are not clear. Here it was demonstrated that DSF facilitated H2S release from thiol-containing compounds, and DSF and H2S were both capable of regulating ALDH through inhibition of gene expression and enzymatic activity. The supplement of H2S sensitized human liver cancer cells (HepG2) to DSF-inhibited cell viability. The expression of cystathionine gamma-lyase (a major H2S-generating enzyme) was lower but ALDH was higher in mouse liver cancer stem cells (Dt81Hepa1-6) in comparison with their parental cells (Hepa1-6), and H2S was able to inhibit liver cancer stem cell adhesion. In conclusion, these data point to the potential of combining DSF and H2S for inhibition of cancer cell growth and tumor development by targeting ALDH.
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Inibidores de Acetaldeído Desidrogenases/farmacologia , Dissuasores de Álcool/farmacologia , Aldeído Desidrogenase/antagonistas & inibidores , Antineoplásicos/farmacologia , Dissulfiram/farmacologia , Sulfeto de Hidrogênio/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Aldeído Desidrogenase/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cobre/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Fígado/efeitos dos fármacos , Fígado/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , TemperaturaRESUMO
Importance: The COVID-19 pandemic is the greatest global test of health leadership of our generation. There is an urgent need to provide guidance for leaders at all levels during the unprecedented preresolution recovery stage. Objective: To create an evidence- and expertise-informed framework of leadership imperatives to serve as a resource to guide health and public health leaders during the postemergency stage of the pandemic. Evidence Review: A literature search in PubMed, MEDLINE, and Embase revealed 10â¯910 articles published between 2000 and 2021 that included the terms leadership and variations of emergency, crisis, disaster, pandemic, COVID-19, or public health. Using the Standards for Quality Improvement Reporting Excellence reporting guideline for consensus statement development, this assessment adopted a 6-round modified Delphi approach involving 32 expert coauthors from 17 countries who participated in creating and validating a framework outlining essential leadership imperatives. Findings: The 10 imperatives in the framework are: (1) acknowledge staff and celebrate successes; (2) provide support for staff well-being; (3) develop a clear understanding of the current local and global context, along with informed projections; (4) prepare for future emergencies (personnel, resources, protocols, contingency plans, coalitions, and training); (5) reassess priorities explicitly and regularly and provide purpose, meaning, and direction; (6) maximize team, organizational, and system performance and discuss enhancements; (7) manage the backlog of paused services and consider improvements while avoiding burnout and moral distress; (8) sustain learning, innovations, and collaborations, and imagine future possibilities; (9) provide regular communication and engender trust; and (10) in consultation with public health and fellow leaders, provide safety information and recommendations to government, other organizations, staff, and the community to improve equitable and integrated care and emergency preparedness systemwide. Conclusions and Relevance: Leaders who most effectively implement these imperatives are ideally positioned to address urgent needs and inequalities in health systems and to cocreate with their organizations a future that best serves stakeholders and communities.
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COVID-19 , Pessoal de Saúde , Liderança , Pandemias , Consenso , Planejamento em Desastres , Pessoal de Saúde/legislação & jurisprudência , Pessoal de Saúde/organização & administração , Humanos , Modelos Organizacionais , SARS-CoV-2RESUMO
BACKGROUND: Patients with liver cirrhosis are generally considered ineligible for isolated cardiac transplantation or left ventricular assist device (LVAD) implantation. The aim of this retrospective study is to explore the diagnostic value of abdominal ultrasound, computed tomography scan (CT scan) and liver-spleen scintigraphy to detect the presence of cirrhosis in patients with advanced heart failure. METHODS: Among 567 consecutive patients who underwent pre-transplantation or LVAD evaluation, 54 had a liver biopsy to rule out cardiac cirrhosis; we compared the biopsy results with the imaging investigations. RESULTS: In about 26% (n = 14) of patients undergoing liver biopsy, histopathological evaluation identified cirrhosis. The respective sensitivity of abdominal ultrasound, CT scan and liver-spleen scintigraphy to detect cirrhosis was 57% [29-82], 50% [16-84], and 25% [3-65]. The specificity was 80% [64-91], 89% [72-98], and 44% [20-70], respectively. CONCLUSION: Ultrasonography has the best-combined sensitivity and specificity for the diagnosis of cirrhosis. However, more than a third of patients with cirrhosis will go undiagnosed by conventional imaging. As liver biopsy is associated with a low rate of complication, it should be considered in patients with a high-risk of cirrhosis or with evidence of portal hypertension to assess their eligibility for heart transplantation or LVAD implantation.
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Insuficiência Cardíaca , Coração Auxiliar , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Humanos , Cirrose Hepática/diagnóstico , Estudos Retrospectivos , UltrassonografiaRESUMO
BACKGROUND: Invasive aspergillosis (IA) is a rare but highly lethal complication after orthotopic liver transplantation (OLT). Targeted antifungal prophylaxis has been proposed as a strategy to prevent IA among orthotopic liver transplant recipient (OLTr), but limited data are available to support its efficacy. METHOD: We conducted a single-center, retrospective, before and after cohort study, comparing IA incidences among OLTr who did not receive antifungal prophylaxis after transplantation (cohort 1) to OLTr who received targeted antifungal prophylaxis after liver transplantation (cohort 2). Patients in cohort 2 received caspofungin prophylaxis if they presented one of the following risk factors: retransplantation, acute liver failure, dialysis, or Aspergillus colonization prior to transplantation. The primary outcome was IA at 90 days after transplantation. RESULTS: A total of 391 OLTr were included in the study; 181 patients in the cohort 1 (no prophylaxis) and 210 patients in the cohort 2 (targeted prophylaxis). Among patients in cohort 2, 19% (40/ 210) were considered at high risk for IA and 85% (34/40) of those received caspofungin prophylaxis. The incidence of IA at 90 days was 3.3% (6/ 181) and 0.5% (1/ 210), in cohort 1 and 2, respectively (OR 0.14; 95%CI 0.01-0.83; P = .03). Ninety-day mortality was similar among the two cohorts (3.9% (7/181) and 2.4% (5/210) in cohort 1 and 2, respectively (OR 0.61; 95% 0.18-1.93; P = .40)). The 90-day mortality among the OLTs with IA was 71% (5/7). CONCLUSION: Targeted caspofungin prophylaxis was associated with lower rate of IA.
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Aspergilose , Transplante de Fígado , Aspergilose/tratamento farmacológico , Aspergilose/epidemiologia , Aspergilose/prevenção & controle , Caspofungina , Estudos de Coortes , Humanos , Transplante de Fígado/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with chronic liver disease (CLD) and liver transplant (LT) recipients remains a concern. The aim of this study was to report the impact of coronavirus disease 2019 (COVID-19) infection among patients at the tertiary health care centre Centre hospitalier de l'Université de Montréal (CHUM) during the first wave of the SARS-CoV-2 pandemic. METHODS: This real-world, retrospective cohort included all patients admitted to our liver unit and/or seen as an outpatient with CLD with or without cirrhosis and/or LT recipients who tested positive to SARS-CoV-2 infection. Cases were considered positive as defined by the detection of SARS-CoV-2 by reverse-transcription polymerase chain reaction (RT-PCR) on nasopharyngeal swabs. RESULTS: Between April 1 and July 31, 2020, 5,637 were admitted to our liver unit and/or seen as outpatient. Among them, 42 were positive for SARS-CoV-2. Twenty-two patients had CLD without cirrhosis while 16 patients had cirrhosis at the time of the infection (13, 2, and 1 with Child-Pugh A, B, and C scores, respectively). Four were LT recipients. Overall, 15 of 42 patients (35.7%) were hospitalized; among them, 7 of 42 (16.7%) required respiratory support and 4 of 42 (9.5%) were transferred to the intensive care unit. Only 4 of 42 (9.5%) patients died: 2 with CLD without cirrhosis and 2 with CLD with cirrhosis. Overall survival was 90.5%. CONCLUSION: This real-world study demonstrates an unexpectedly low prevalence and low mortality in the context of SARS-CoV-2 infection among patients with CLD with or without cirrhosis and LT recipients.
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BACKGROUND: Intraoperative restrictive fluid management strategies might improve postoperative outcomes in liver transplantation. Effects of vasopressors within any hemodynamic management strategy are unclear. METHODS: We conducted an observational cohort study on adult liver transplant recipients between July 2008 and December 2017. We measured the effect of vasopressors infused at admission in the intensive care unit (ICU) and total intraoperative fluid balance. Our primary outcome was 48-hour acute kidney injury (AKI) and our secondary outcomes were 7-day AKI, need for postoperative renal replacement therapy (RRT), time to extubation in the ICU, time to ICU discharge and survival up to 1 year. We fitted models adjusted for confounders using generalized estimating equations or survival models using robust standard errors. We reported results with 95% confidence intervals. RESULTS: We included 532 patients. Vasopressors use was not associated with 48-hour or 7-day AKI but modified the effects of fluid balance on RRT and mortality. A higher fluid balance was associated with a higher need for RRT (OR = 1.52 [1.15, 2.01], p<0.001 for interaction) and lower survival (HR = 1.71 [1.26, 2.34], p<0.01 for interaction) only among patients without vasopressors. In patients with vasopressors, higher doses of vasopressors were associated with a higher mortality (HR = 1.29 [1.13, 1.49] per 10 µg/min of norepinephrine). CONCLUSION: The presence of any vasopressor at the end of surgery was not associated with AKI or RRT. The use of vasopressors might modify the harmful association between fluid balance and other postoperative outcomes. The liberal use of vasopressors to implement a restrictive fluid management strategy deserves further investigation.
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Injúria Renal Aguda , Hemodinâmica/fisiologia , Cuidados Intraoperatórios/métodos , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Adulto , Idoso , Estudos de Coortes , Feminino , Hidratação/métodos , Humanos , Transplante de Fígado/métodos , Transplante de Fígado/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Quebeque/epidemiologia , Terapia de Substituição Renal/estatística & dados numéricos , Fatores de Risco , Resultado do Tratamento , Equilíbrio Hidroeletrolítico/fisiologiaRESUMO
Type 2 diabetes, which is mainly linked to obesity, is associated with increased incidence of liver cancer. We have previously found that in various models of obesity/diabetes, hyperinsulinemia maintains heightened hepatic expression of cyclin D1, suggesting a plausible mechanism linking diabetes and liver cancer progression. Here we show that cyclin D1 is greatly elevated in human livers with diabetes and is among the most significantly upregulated genes in obese/diabetic liver tumors. Liver-specific cyclin D1 deficiency protected obese/diabetic mice against hepatic tumorigenesis, whereas lean/nondiabetic mice developed tumors irrespective of cyclin D1 status. Cyclin D1 dependency positively correlated with liver cancer sensitivity to palbociclib, an FDA-approved CDK4 inhibitor, which was effective in treating orthotopic liver tumors under obese/diabetic conditions. The antidiabetic drug metformin suppressed insulin-induced hepatic cyclin D1 expression and protected against obese/diabetic hepatocarcinogenesis. These results indicate that the cyclin D1-CDK4 complex represents a potential selective therapeutic vulnerability for liver tumors in obese/diabetic patients. SIGNIFICANCE: Obesity/diabetes-associated liver tumors are specifically vulnerable to cyclin D1 deficiency and CDK4 inhibition, suggesting that the obese/diabetic environment confers cancer-selective dependencies that can be therapeutically exploited.
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Ciclina D1/deficiência , Diabetes Mellitus Tipo 2/complicações , Neoplasias Hepáticas Experimentais/etiologia , Obesidade/complicações , Animais , Antineoplásicos/farmacologia , Ciclina D1/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Hiperinsulinismo/metabolismo , Hipoglicemiantes/farmacologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/prevenção & controle , Masculino , Metformina/farmacologia , Camundongos , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Regulação para CimaRESUMO
PURPOSE: Restrictive fluid management strategies have been proposed to reduce complications in liver transplant recipients. We conducted a systematic review to evaluate the effects of restrictive perioperative fluid management strategies, compared with liberal ones, on postoperative outcomes in adult liver transplant recipients. Our primary outcome was acute kidney injury (AKI). Our secondary outcomes were bleeding, mortality, and other postoperative complications. SOURCE: We searched major databases (CINAHL, EMB Reviews, EMBASE, MEDLINE, and the grey literature) from their inception to 10 July 2018 for randomized-controlled trials (RCTs) and observational studies comparing two fluid management strategies (or observational studies reporting two outcomes with available data on fluid volume received) in adult liver transplant recipients. Study selection, data abstraction, and risk of bias assessment were performed by at least two investigators. Data from RCTs were pooled using risk ratios (RR) and mean differences (MD) with random-effect models. PRINCIPAL FINDINGS: We found seven RCTs and 29 observational studies. Based on RCTs, fluid management strategies did not have any effect on AKI, mortality, or any other postoperative complications. Intraoperative RCTs suggested that a restrictive fluid management strategy reduced pulmonary complications (RR, 0.69; 95% confidence interval [CI], 0.47 to 0.99; n = 283; I2 = 27%), duration of mechanical ventilation (MD, -13.04 hr; 95% CI, -22.2 to -3.88; n = 130; I2 = 0%) and blood loss (MD, -1.14 L; 95% CI, -1.72 to -0.57; n = 151; I2 = 0%). CONCLUSION: Based on low or very low levels of evidence, we did not find any association between restrictive fluid management strategies and AKI, but we observed possible protective effects of intraoperative restrictive fluid management strategies on other outcomes. TRIAL REGISTRATION: PROSPERO (CRD42017054970); registered 18 May, 2017.
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Injúria Renal Aguda , Hidratação , Transplante de Fígado , Adulto , Humanos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controleRESUMO
BACKGROUND: Liver transplant recipients suffer many postoperative complications. Few studies evaluated the effects of fluid management on these complications. We conducted an observational cohort study to evaluate the association between intraoperative fluid balance and postoperative acute kidney injury (AKI) and other postoperative complications. METHODS: We included consecutive adult liver transplant recipients who had their surgery between July 2008 and December 2017. Our exposure was intraoperative fluid balance, and our primary outcome was the grade of AKI at 48 hours after surgery. Our secondary outcomes were the grade of AKI at 7 days, the need for postoperative renal replacement therapy, postoperative red blood cell transfusions, time to first extubation, time to discharge from the intensive care unit (ICU), and 1-year survival. Every analysis was adjusted for potential confounders. RESULTS: We included 532 transplantations in 492 patients. We observed no effect of fluid balance on either 48-hour AKI, 7-day AKI, or on the need for postoperative renal replacement therapy after adjustments for confounders. A higher fluid balance increased the time to ICU discharge, and increased the risk of dying (hazard ratio = 1.21 [1.04,1.40]). CONCLUSIONS: We observed no association between intraoperative fluid balance and postoperative AKI. Fluid balance was associated with longer time to ICU discharge and lower survival. This study provides insight that might inform the design of a clinical trial on fluid management strategies in this population.