RESUMO
Nonalcoholic fatty liver disease (NAFLD) and impaired glycemic control are closely linked; however, the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. The high secretory capacity of the liver and impairments in protein secretion in NAFLD suggest that endocrine changes in the liver are likely to contribute to glycemic defects. We identify hexosaminidase A (HEXA) as an NAFLD-induced hepatokine in both mice and humans. HEXA regulates sphingolipid metabolism, converting GM2 to GM3 gangliosides-sphingolipids that are primarily localized to cell-surface lipid rafts. Using recombinant murine HEXA protein, an enzymatically inactive HEXA(R178H) mutant, or adeno-associated virus vectors to induce hepatocyte-specific overexpression of HEXA, we show that HEXA improves blood glucose control by increasing skeletal muscle glucose uptake in mouse models of insulin resistance and type 2 diabetes, with these effects being dependent on HEXA's enzymatic action. Mechanistically, HEXA remodels muscle lipid raft ganglioside composition, thereby increasing IGF-1 signaling and GLUT4 localization to the cell surface. Disrupting lipid rafts reverses these HEXA-mediated effects. In this study, we identify a pathway for intertissue communication between liver and skeletal muscle in the regulation of systemic glycemic control.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Somatomedinas , Humanos , Animais , Camundongos , Hexosaminidase A , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Recombinantes , Glucose , Músculo Esquelético/metabolismoRESUMO
OBJECTIVE: Liver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies. DESIGN: Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations. RESULTS: Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (<1.3; ≥2.67) followed by LSM-VCTE cut-offs (<8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63-68) and 86% (84-87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (<1.3; ≥3.48) followed by LSM cut-offs (<8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37-39) and specificity of 90% (89-91) with 19% needing biopsy. CONCLUSION: Sequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies.
Assuntos
Diabetes Mellitus Tipo 2 , Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica , Biomarcadores , Biópsia , Feminino , Fibrose , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
BACKGROUNDS & AIMS: Obesity often leads to non-alcoholic fatty liver disease (NAFLD), which can progress from simple steatosis (non-alcoholic fatty liver (NAFL)) to non-alcoholic steatohepatitis (NASH). The accumulation of certain lipid subtypes is linked with worsening metabolic and liver disease, however, specific changes during progression from No-NAFL to NAFL then NASH are unresolved. Herein, we characterise the liver, adipose tissue and plasma lipidome of worsening NAFLD in obesity, and evaluate the utility of plasma lipids as biomarkers of NAFLD. METHODS: Venous blood, liver, visceral and subcutaneous adipose tissue samples were obtained from 181 patients undergoing bariatric surgery. NAFLD severity was assessed histologically. Lipidomic analysis was performed using liquid chromatography-tandem mass spectrometry. RESULTS: The liver lipidome showed substantial changes with increasing steatosis, with increased triacylglycerols, diacylglycerols and sphingolipids including ceramide, dihydroceramide, hexosyl-ceramide and GM3 ganglioside species. These lipid species were also increased in plasma with increasing hepatic steatosis and showed strong correlations with liver lipids. Adipose tissue lipidomes showed no correlation with NAFLD. There were no significant changes in liver lipids with NASH compared to NAFL. The addition of plasma lipid variables to routine markers yielded significant improvements in diagnostic accuracy for NASH (AUROC 0.667 vs. 0.785, p = 0.025). CONCLUSION: Overall, these data provide a detailed description of the lipidomic changes with worsening NAFLD, showing significant changes with steatosis but no additional changes with NASH. Alterations in the liver lipidome are paralleled by similar changes in plasma. Further investigation is warranted into the potential utility of plasma lipids as non-invasive biomarkers of NAFLD in obesity. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is characterised by distinct changes in the liver lipidome with steatosis. The development of non-alcoholic steatohepatitis (NASH) does not result in further changes in the lipidome. Lipids within body fat do not appear to influence the lipid profile of the liver or blood. Changes in liver lipids are paralleled by changes in blood lipids. This has potential to be developed into a non-invasive biomarker for NAFLD. CLINICAL TRIAL NUMBER: ACTRN12615000875505.
Assuntos
Fígado Gorduroso/etiologia , Lipidômica/métodos , Obesidade Mórbida/complicações , Adulto , Fígado Gorduroso/fisiopatologia , Feminino , Humanos , Lipidômica/estatística & dados numéricos , Lipídeos/análise , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/fisiopatologiaRESUMO
Ectodysplasin A (EDA) was recently identified as a liver-secreted protein that is increased in the liver and plasma of obese mice and causes skeletal muscle insulin resistance. We assessed if liver and plasma EDA is associated with worsening non-alcoholic fatty liver disease (NAFLD) in obese patients and evaluated plasma EDA as a biomarker for NAFLD. Using a cross-sectional study in a public hospital, patients with a body mass index >30 kg/m2 (n=152) underwent liver biopsy for histopathology assessment and fasting liver EDA mRNA. Fasting plasma EDA levels were also assessed. Non-alcoholic fatty liver (NAFL) was defined as >5% hepatic steatosis and nonalcoholic steatohepatitis (NASH) as NAFLD activity score ≥3. Patients were divided into three groups: No NAFLD (n=45); NAFL (n=65); and NASH (n=42). Liver EDA mRNA was increased in patients with NASH compared with No NAFLD (P=0.05), but not NAFL. Plasma EDA levels were increased in NAFL and NASH compared with No NAFLD (P=0.03). Plasma EDA was related to worsening steatosis (P=0.02) and fibrosis (P=0.04), but not inflammation or hepatocellular ballooning. ROC analysis indicates that plasma EDA is not a reliable biomarker for NAFL or NASH. Plasma EDA was not increased in patients with type 2 diabetes and did not correlate with insulin resistance. Together, we show that plasma EDA is increased in NAFL and NASH, is related to worsening steatosis and fibrosis but is not a reliable biomarker for NASH. Circulating EDA is not associated with insulin resistance in human obesity. Clinical Trial Registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12615000875505, identifier ACTRN12615000875505.
Assuntos
Citocinas/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Ectodisplasinas/sangue , Ectodisplasinas/metabolismo , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Adulto , Biomarcadores/metabolismo , Biópsia , Índice de Massa Corporal , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Inflamação , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Obesidade/sangue , Obesidade/complicações , Obesidade/metabolismo , RNA Mensageiro/metabolismo , Curva ROC , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Liver biopsy remains the gold standard for characterizing and evaluating treatment response in nonalcoholic fatty liver disease (NAFLD). Liver heterogeneity and sampling variability can affect the reliability of results. This study aimed to compare histological variability of intraoperative wedge and core liver biopsies from different lobes in bariatric patients, to better inform surgeons on biopsy method and guide interpretation of results. METHODS: We prospectively recruited bariatric surgical patients. Intraoperative core biopsies were taken from the left and right lobe, with a wedge biopsy taken from the left. All biopsies were graded by a specialist liver pathologist, blinded to clinical details and biopsy site. Concordance of histological findings between sites was evaluated. RESULTS: There were 91 participants (72.2% female), mean age 46.8 ± 12.0 years, body mass index 45.9 ± 9.4 kg/m2. There was no significant pattern for up- or down-grading disease dependent on biopsy technique. Moderate to strong agreement was seen in the presence of NAFLD and nonalcoholic steatohepatitis (NASH, κ = 0.609-0.865, p < 0.001) between biopsy sites. Individual components (steatosis, inflammation, ballooning) showed weaker agreement (κ = 0.386-0.656, p < 0.01). Fibrosis showed particularly poor agreement (κ = 0.223-0.496, p < 0.01). Detection of pathology improved with a combination of biopsy techniques, compared to a single biopsy method. CONCLUSION: Overall diagnosis of NAFLD or NASH shows good agreement between biopsy sites, but individual components, particularly fibrosis stage, vary significantly. Clinicians should consider biopsies from varied sites, to better assess liver disease severity. These data have important implications in fibrosis assessment of NAFLD and are relevant in the interpretation of histological efficacy of investigational pharmacotherapies. TRIAL REGISTRATION: ACTRN12615000875505 (Australian Clinical Trials Register).
Assuntos
Bariatria/métodos , Biópsia/métodos , Fígado/cirurgia , Hepatopatia Gordurosa não Alcoólica/cirurgia , Austrália , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
Obesity is a strong risk factor for Barrett's esophagus (BE), the only proven precursor lesion to esophageal adenocarcinoma (EAC). Bariatric surgery is currently the only reliable treatment that achieves long-term sustained weight loss; however, it can markedly affect the development of de novo BE, and the progression or regression of existing BE. Bariatric procedures may also have implications on future surgical management of any consequent EAC. In this review, we examine the current evidence and published guidelines for BE in bariatric surgery. Current screening practices before bariatric surgery vary substantially, with conflicting recommendations from bariatric societies. If diagnosed, the presence of BE may alter the type of bariatric procedure. A selective screening approach prevents unnecessary endoscopy; however, there is poor symptom correlation with disease. Studies suggest that sleeve gastrectomy predisposes patients to gastroesophageal reflux and de novo BE. Conversely, Roux-en-Y gastric bypass is associated with decreased reflux and potential improvement or resolution of BE. There are currently no guidelines addressing the surveillance for BE following bariatric surgery. BE is an important consideration in the management of bariatric surgical patients. Evidence-based recommendations are required to guide procedure selection and postoperative surveillance.
Assuntos
Adenocarcinoma , Esôfago de Barrett , Neoplasias Esofágicas , Derivação Gástrica , Obesidade , Adenocarcinoma/diagnóstico , Adenocarcinoma/fisiopatologia , Adenocarcinoma/cirurgia , Esôfago de Barrett/diagnóstico , Esôfago de Barrett/fisiopatologia , Esôfago de Barrett/cirurgia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/fisiopatologia , Neoplasias Esofágicas/cirurgia , Humanos , Obesidade/diagnóstico , Obesidade/fisiopatologia , Obesidade/cirurgiaRESUMO
In the original article the name of author Alexandra Klejn was misspelled.
RESUMO
INTRODUCTION: Preoperative very low energy diets (VLEDs) improve access during bariatric surgery. Compliance with traditional VLED is variable, mainly due to gastrointestinal side effects. Formulite™ is a new formulation of VLED, with higher protein, soluble fibre and probiotics. AIMS: To compare traditional VLED (Optifast™) with the new VLED (Formulite™) and assess compliance, weight loss, satisfaction, side effects and surgical access. METHODS: This was a randomised double-blinded study involving patients scheduled for bariatric surgery. The primary outcome was compliance, assessed by urinary ketone concentration and proportion of patients in ketosis at 2 weeks. Secondary outcomes were weight loss, satisfaction and patient reported outcomes, gastrointestinal side effects and operative conditions. RESULTS: There were 69 participants: 35 in the Formulite™ group and 34 in the Optifast™ group. Ketosis at 2 weeks was achieved in both groups (88.5% vs 83.3%, Formulite™ vs. Optifast™, p = 0.602). Urinary ketones were higher with Formulite™ (1.5 vs 15 mmol/L, p = 0.030). Total body weight loss percentage, hunger and operative conditions were similar in both groups. Formulite™ produced less flatulence (score 3 vs 2, p = 0.010) and emotional eating (score 2 vs 1, p = 0.037); however, Optifast™ ranked higher in terms of taste (score 4 vs 3, p = 0.001) and overall satisfaction (score 5 vs 7, p = 0.011). CONCLUSIONS: Compliance over 2 weeks was high in both VLEDs with most subjects achieving ketosis. Overall satisfaction was moderately high, although variable. Whilst Formulite™ is a viable alternative to Optifast™, better formulations of VLED that addresses key adverse effects, whilst achieving ketosis, would be of significant value.
Assuntos
Cirurgia Bariátrica , Dieta Redutora , Alimentos Formulados , Cooperação do Paciente/estatística & dados numéricos , Dieta Redutora/efeitos adversos , Dieta Redutora/métodos , Dieta Redutora/estatística & dados numéricos , Método Duplo-Cego , Humanos , Obesidade Mórbida/dietoterapia , Obesidade Mórbida/cirurgia , Período Pré-Operatório , Redução de PesoRESUMO
Hepatocellular carcinoma (HCC) is one of the most fatal and fastest-growing cancers. Recently, non-alcoholic steatohepatitis (NASH) has been recognized as a major HCC catalyst. However, it is difficult to decipher the molecular mechanisms underlying the pathogenesis of NASH and understand how it progresses to HCC by studying humans. Progress in this field depends on the availability of reliable preclinical models amenable to genetic and functional analyses and exhibiting robust NASH-to-HCC progression. Although numerous mouse models of NASH have been described, many do not faithfully mimic the human disease and few reliably progress to HCC. Here, we review current literature on the molecular etiology of NASH-related HCC and critically evaluate existing mouse models and their suitability for studying this malignancy. We also compare human transcriptomic and histopathological profiles with data from MUP-uPA mice, a reliable model of NASH-driven HCC that has been useful for evaluation of HCC-targeting immunotherapies.
Assuntos
Carcinoma Hepatocelular/etiologia , Modelos Animais de Doenças , Neoplasias Hepáticas/etiologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Animais , Progressão da Doença , Humanos , CamundongosRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), driven by the obesity epidemic, has become the most common form of liver disease. Despite this, there is controversy regarding the prevalence and severity of NAFLD in obesity. Obesity-related factors, such as increasing adiposity, metabolic disease and inflammation, may influence prevalence. We therefore prospectively measured NAFLD prevalence in obesity and studied factors associated with NAFLD. MATERIALS AND METHODS: We recruited consecutive bariatric patients. Intraoperative liver biopsies were taken. The liver, adipose tissue and serum were collected to measure inflammation. Adipocyte cell size was measured. NAFLD severity was correlated to body mass index (BMI), metabolic health and adipose characteristics. RESULTS: There were 216 participants; BMI 45.9 ± 8.9 kg/m2, age 44.4 ± 12.1 years, 75.5% female. Overall NAFLD prevalence was 74.1%, with 17.1% having non-alcoholic steatohepatitis (NASH) and/or steatofibrosis. Odds of NASH/steatofibrosis increased independently with BMI category (odds ratio (OR) 2.28-3.46, all p < 0.05) and metabolic disease (OR 3.79, p = 0.003). These odds markedly increased when both super obesity (BMI > 50) and metabolic disease were present (OR 9.71, p < 0.001). NASH/steatofibrosis prevalence was significantly greater with diabetes, hypertension and dyslipidemia. Although greater visceral adipocyte hypertrophy was evident in NASH/steatofibrosis, there was no significant association between adipose inflammation and NASH/steatofibrosis. CONCLUSION: NAFLD remains endemic in obesity; however, NASH/steatofibrosis are less common than previously reported. Worsening obesity and metabolic disease increase odds of NAFLD independently, with substantially compounded effect with both. These observations may help with risk stratification in obese populations. We were unable to delineate clear associations between adipose inflammation and NASH/steatofibrosis in this obese population. TRIAL REGISTRATION: Australian Clinical Trials Registry ( ACTRN12615000875505 ).
Assuntos
Tecido Adiposo/fisiopatologia , Índice de Massa Corporal , Inflamação , Hepatopatia Gordurosa não Alcoólica , Obesidade Mórbida , Adulto , Cirurgia Bariátrica , Feminino , Humanos , Inflamação/complicações , Inflamação/epidemiologia , Inflamação/fisiopatologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Obesidade Mórbida/complicações , Obesidade Mórbida/epidemiologia , Obesidade Mórbida/cirurgia , Estudos ProspectivosRESUMO
Obesity is a major driver of cancer, especially hepatocellular carcinoma (HCC). The prevailing view is that non-alcoholic steatohepatitis (NASH) and fibrosis or cirrhosis are required for HCC in obesity. Here, we report that NASH and fibrosis and HCC in obesity can be dissociated. We show that the oxidative hepatic environment in obesity inactivates the STAT-1 and STAT-3 phosphatase T cell protein tyrosine phosphatase (TCPTP) and increases STAT-1 and STAT-3 signaling. TCPTP deletion in hepatocytes promoted T cell recruitment and ensuing NASH and fibrosis as well as HCC in obese C57BL/6 mice that normally do not develop NASH and fibrosis or HCC. Attenuating the enhanced STAT-1 signaling prevented T cell recruitment and NASH and fibrosis but did not prevent HCC. By contrast, correcting STAT-3 signaling prevented HCC without affecting NASH and fibrosis. TCPTP-deletion in hepatocytes also markedly accelerated HCC in mice treated with a chemical carcinogen that promotes HCC without NASH and fibrosis. Our studies reveal how obesity-associated hepatic oxidative stress can independently contribute to the pathogenesis of NASH, fibrosis, and HCC.
Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/patologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Hepatocelular/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Estresse Oxidativo , Proteína Tirosina Fosfatase não Receptora Tipo 2/deficiência , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Transdução de SinaisRESUMO
INTRODUCTION: In obese individuals, nonalcoholic fatty liver disease (NAFLD) is common but often goes undiagnosed, and therefore untreated. The presence of significant fibrosis is a key determinant of NAFLD progression, and liver steatosis has substantial cardiovascular implications. We aimed to determine the diagnostic accuracy of common noninvasive diagnostic tests for steatosis and fibrosis in the obese. METHODS: We recruited 182 severely and morbidly obese individuals undergoing bariatric surgery (age 44 ± 12 years, body mass index 45.1 ± 8.3 kg/m2). Medical history, blood tests and liver biopsy were taken on the day of surgery. Serum steatosis and fibrosis scores were calculated. In a subgroup of patients, transient elastography with controlled attenuation parameter (TE/CAP) (n = 82) and proton magnetic resonance spectroscopy (1H-MRS) (n = 49) were performed. RESULTS: 1H-MRS had excellent diagnostic accuracy for steatosis, with strong correlation to steatosis (r = 0.647, p < 0.001), good AUROC (0.852, p = 0.001), sensitivity (81.3%) and specificity (87.5%). However, due to low feasibility in this cohort (65.3% success), this was substantially decreased with intention-to-diagnose analysis (sensitivity 50.0%, specificity 60.9%). CAP had good feasibility (80.5%), and performed better in intention-to-diagnose analysis (AUROC 0.688, sensitivity 84.8%, specificity 47.2%). Serum steatosis scores performed poorly, with comparable accuracy to ALT. For significant fibrosis, TE had the best accuracy (AUROC 0.903, p = 0.007), which remained reasonable after intention-to-diagnose analysis (sensitivity 100%, specificity 59.0%). A combination approach using CAP with ALT for steatosis and TE with Forn index for fibrosis yielded reasonable overall accuracy. CONCLUSIONS: 1H-MRS and TE/CAP had greatest accuracy for NAFLD-related steatosis and fibrosis. Failure rates in obesity significantly diminished diagnostic ability. Use of a combination of serum and imaging tests improved overall feasibility of assessment and diagnostic accuracy in obese individuals.
Assuntos
Técnicas de Imagem por Elasticidade , Cirrose Hepática/patologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade Mórbida/patologia , Adulto , Cirurgia Bariátrica , Biópsia , Feminino , Humanos , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Obesidade Mórbida/fisiopatologia , Obesidade Mórbida/cirurgia , Estudos Prospectivos , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: Dyslipidemia affects up to 75% of morbidly obese individuals and is a key driver of cardiovascular disease. Weight loss is an established strategy to improve metabolic risk, including dyslipidemia. We aimed to determine weight loss goals for resolution of serum lipid abnormalities, by measuring improvements during progressive weight loss in obese individuals. METHODS: We performed a prospective cohort study of obese individuals with the metabolic syndrome undergoing adjustable gastric banding. Lipid levels were monitored monthly for 9 months, then three monthly until 24 months. RESULTS: There were 101 participants included, age 47.4 ± 10.9 years with body mass index 42.6 ± 5.9 kg/m2. At 24 months, total body weight loss (TBWL) was 18.3 ± 7.9%. This was associated with significant improvements in high-density lipoprotein (HDL) (1.18 vs 1.47, p < 0.001), triglyceride (2.0 vs 1.4, p < 0.001), and total cholesterol to HDL ratio (TC:HDL) (4.6 vs 3.6, p < 0.001). Over this time, progressive and linear improvements in HDL, triglycerides, and TC:HDL were seen with incremental weight loss (observed at 2.5% TBWL intervals). Significant improvements occurred after a threshold weight loss of 7.5-12.5% TBWL was achieved, with odds ratio (OR) 1.48-2.50 for normalization. These odds improved significantly with increasing weight loss (OR 18.2-30.4 with > 25% TBWL). Despite significant weight loss, there was no significant change in low-density lipoprotein (LDL). CONCLUSION: Significant improvements in triglycerides, HDL, and TC:HDL occur after 7.5-12.5% TBWL, with ongoing benefit after greater weight loss. LDL needs to be addressed independently, as this was not observed to respond to weight loss alone. TRIAL REGISTRATION NUMBER: Australian Clinical Trials Registry (ACTRN12610000049077).
Assuntos
Cirurgia Bariátrica , Colesterol/sangue , Obesidade Mórbida/cirurgia , Redução de Peso , Adulto , Austrália , Índice de Massa Corporal , Dislipidemias/complicações , Feminino , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Obesidade Mórbida/sangue , Estudos Prospectivos , Triglicerídeos/sangueRESUMO
BACKGROUND: Radical surgical resection is the mainstay of curative treatment for oesophagogastric malignancy. However, survival and recurrence rates remain poor. Theoretical data suggests that the inflammatory response to surgery can promote tumour recurrence. The local and systemic inflammatory response to radical oesophagogastric cancer surgery has not been fully characterized. We aimed to measure this response, particularly factors associated with tumour implantation. METHODS: Consecutive patients undergoing radical junctional or gastric cancer resection over 12 months were recruited. Repeated serum and adipose tissue were collected intra-operatively. Adipose tissue was collected adjacent and remote to the tumour, and cytokine messenger RNA (mRNA) expression was measured. Post-operatively, daily serum was collected for 7 days, and analysed for inflammatory cell profile and cytokine concentration. RESULTS: There were nine patients recruited (67.1 ± 2.1 years). mRNA expression of interleukin-6 (IL-6), CC-chemokine ligand-2 and IL-1ß increased in adipose tissue intra-operatively (P < 0.05), equally both adjacent and remote from the tumour site. Serum IL-6 concentration increased from 23.3 pg/mL to 161.8 pg/mL intra-operatively (P < 0.05) before falling steadily to 35.7 pg/mL post-operatively (P < 0.05). Serum tumour necrosis factor-α was elevated throughout, and IL-1ß levels were unaffected. Leukocyte and neutrophil populations increased, while T-cell and dendritic cell populations decreased intra-operatively (P < 0.05). CONCLUSION: Radical surgery dramatically upregulates the expression of pro-tumourigenic cytokines in the peritoneum. There is also a marked systemic immune and inflammatory response to surgery, including downregulation of T-cell and dendritic cell populations. This offers two potential pathways that may facilitate tumour progression - local inflammation promoting peritoneal adherence and implantation, and secondary suppression of immunosurveillance due to circulating inflammatory response.
Assuntos
Quimiocina CCL2/metabolismo , Neoplasias Esofágicas/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Peritônio/metabolismo , Neoplasias Gástricas/metabolismo , Idoso , Quimiocina CCL2/genética , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Esofagectomia , Feminino , Gastrectomia , Humanos , Interleucina-1beta/genética , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), are endemic in obesity. We aimed to evaluate the diagnostic accuracy and reproducibility of a simple intraoperative visual liver score to stratify the risk of NASH and NAFLD in obesity and determine the need for liver biopsy. METHODS: This is a prospective cohort study of obese adults undergoing bariatric surgery. The surgical team used a visual liver score to evaluate liver colour, size and surface. This was compared to histology from an intraoperative liver biopsy. RESULTS: There were 152 participants, age 44.6 ± 12 years, BMI 45 ± 8.3 kg/m2. Prevalence of NAFLD was 70.4%, with 12.1% NASH and 26.4% borderline NASH. Single-visual components were less accurate than total composite score. Steatosis was most accurately identified (significant steatosis: AUROC 0.746, p < 0.05; severe steatosis: AUROC 0.855, p < 0.05). NASH was identified with moderate accuracy (AUROC 0.746, p = 0.001), with sensitivity 75% for a score ≥ 2. Stratification into low (≤ 1) and high-risk (≥ 4) scores accurately identified patients who should or should not have an intraoperative biopsy. Most patients with a normal-appearing liver did not have disease (94.4%). The structured visual assessment was quick and interobserver agreement was reasonable (κ = 0.53, p < 0.05). CONCLUSIONS: A simple, structured tool based on liver appearance can be a useful and reliable tool for NAFLD risk stratification and identification of patients who would most and least benefit from a biopsy. A normal liver appearance reliably excludes significant liver disease, avoiding the need for liver biopsy in patients otherwise at high clinical risk of NASH.
Assuntos
Cirurgia Bariátrica , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Obesidade/patologia , Obesidade/cirurgia , Adulto , Biópsia , Feminino , Humanos , Período Intraoperatório , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Obesidade/diagnóstico , Exame Físico/métodos , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Projetos de Pesquisa , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: Outcomes of oesophago-gastric cancer are poor and highly variable between centres. It is important that complex multimodal treatments are applied optimally. Low case volumes at Australian centres mean that the analysis of crude outcomes is an inadequate assessment of overall quality of care. Detailed analysis across a range of quality domains offers the opportunity to measure performance. METHODS: We compared data from the UK National Oesophago-gastric Cancer Audit 2010 with the prospective Alfred Hospital oesophago-gastric cancer database. RESULTS: There were 314 Alfred and 17 279 UK patients identified. The volume of patients assessed by the Alfred was equal to the second highest quartile in the UK trust (4-5 new cases per month). Case ascertainment was better, capturing 84% of all oesophago-gastric cancer within the Alfred prospective audit (P < 0.001). The use of staging CT and PET scans was more common among Alfred patients (99% versus 89%, P < 0.01 and 83.8% versus 17%, P < 0.01, respectively). More patients embarked on a curative pathway (P < 0.01), with greater use of neo-adjuvant therapies. Acceptable lymph node yields were less in oesophagectomies (88.2% versus 96.2%, P < 0.01) and similar in gastrectomies (77.4% versus 74.6%, P = 0.61). Higher overall complications were observed in Alfred patients (P < 0.01), predominantly due to respiratory complications. Perioperative mortality after resection and 1-year survival was similar. CONCLUSIONS: Comparing a range of quality domains as a means of identifying areas of deficiency is feasible. This allows for contemporaneous improvements in service quality and may be more appropriate in the Australian setting than focusing on volume.
Assuntos
Neoplasias Esofágicas/cirurgia , Esofagectomia/normas , Gastrectomia/normas , Qualidade da Assistência à Saúde , Neoplasias Gástricas/cirurgia , Idoso , Austrália/epidemiologia , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Qualidade de Vida , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Resultado do Tratamento , Reino Unido/epidemiologiaRESUMO
INTRODUCTION: The effect of the laparoscopic adjustable gastric band (LAGB) on esophageal acid exposure and reflux is poorly understood. Optimal technique and normative values for acid exposure have not been established in this group. METHODS: High-resolution manometry (HRM) and 24-h ambulatory esophageal pH monitoring were performed in three groups: asymptomatic LAGB, symptomatic LAGB, and pre-operative reflux patients. This technique utilized intraluminal pressure signatures during HRM to guide accurate pH sensor placement. RESULTS: The LAGB groups were well matched: age 48 vs 51 years (p = 0.249), weight loss 27.3 vs 26.7 kg (p = 0.911). The symptomatic group had a larger gastric pouch (5.2 vs 3.3 cm, p = 0.012), with higher esophageal acid exposure (10.8 vs 0.9%, p < 0.001). Two acidification patterns were observed: irritant and volume acidification, associated with substantial supine acidification. Symptomatic LAGB had altered esophageal motility, with poorer lower esophageal sphincter basal tone (8.0 vs 17.7 mmHg, p = 0.022) and impaired contractility of the lower esophageal segment (90 vs 40%, p = 0.009). Compared to pre-operative reflux patients, symptomatic LAGB patients demonstrated higher total and supine esophageal acid exposure (10.8 vs 7.0%, p = 0.010; 14.9 vs 5.1%, p < 0.001), less symptoms (2 vs 6, p = 0.001) and lower symptom index (0.7 vs 0.9, p = 0.010). CONCLUSIONS: Ambulatory pH monitoring is an effective technique if the pH sensor is positioned appropriately using HRM. The correctly positioned LAGB appears associated with low esophageal acidification. In contrast, patients with symptoms or pouch dilatation can have markedly elevated esophageal acidification, particularly when supine. This is a different pattern compared to pre-operative patients and importantly can be disproportionate to symptoms.