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OBJECTIVE: The biological heterogeneity of hepatocellular carcinoma (HCC) makes prognosis difficult. We translate the results of a genome-wide high-throughput analysis into a tool that accurately predicts at presentation tumour growth and survival of patients with HCC. DESIGN: Ultrasound surveillance identified HCC in 78 (training set) and 54 (validation set) consecutive patients with cirrhosis. Patients underwent two CT scans 6â weeks apart (no treatment in-between) to determine tumour volumes (V0 and V1) and calculate HCC doubling time. Baseline-paired HCC and surrounding tissue biopsies for microarray study (Agilent Whole Human Genome Oligo Microarrays) were also obtained. Predictors of survival were assessed by multivariate Cox model. RESULTS: Calculated tumour doubling times ranged from 30 to 621â days (mean, 107±91â days; median, 83â days) and were divided into quartiles: ≤53â days (n=19), 54-82â days (n=20), 83-110â days (n=20) and ≥111â days (n=19). Median survival according to doubling time was significantly lower for the first quartile versus the others (11 vs 41â months, 42, and 47â months, respectively) (p<0.0001). A five-gene transcriptomic hepatic signature including angiopoietin-2 (ANGPT2), delta-like ligand 4 (DLL4), neuropilin (NRP)/tolloid (TLL)-like 2 (NETO2), endothelial cell-specific molecule-1 (ESM1), and nuclear receptor subfamily 4, group A, member 1 (NR4A1) was found to accurately identify rapidly growing HCCs of the first quartile (ROC AUC: 0.961; 95% CI 0.919 to 1.000; p<0.0001) and to be an independent factor for mortality (HR: 3.987; 95% CI 1.941 to 8.193, p<0.0001). CONCLUSIONS: The hepatic five-gene signature was able to predict HCC growth in individual patient and the consequent risk of death. This implies a role of this molecular tool in the future therapeutic management of patients with HCC. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01657695.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/mortalidad , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Neovascularización Patológica/genética , Estudios Prospectivos , Tasa de Supervivencia , Factores de Tiempo , Carga TumoralRESUMEN
Given the worldwide increase in obesity and diabetes, non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. NAFLD is associated with increased hepatic and extrahepatic morbidity and mortality, mainly related to non-alcoholic steatohepatitis with fibrosis. An early diagnosis in the high-risk population with features of insulin resistance and a proper identification of those patients with progressive liver disease are needed. Practicing physicians dealing with NAFLD should be aware of and should carefully evaluate the extended spectrum of NAFLD-related extrahepatic diseases, which significantly affects liver- and non-liver-related prognosis. This clinical practice-oriented article reviews the diagnostic methods and staging strategies for NAFLD and proposes an investigational algorithm for a global evaluation of NAFLD patients.
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Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Comorbilidad , Humanos , Hígado/patología , Cirrosis Hepática/patología , Tamizaje Masivo , Enfermedad del Hígado Graso no Alcohólico/patologíaRESUMEN
This review of the literature consists of three sections. First, papers concerning non-alcoholic fatty liver disease (NAFLD) awareness among the general population, general practitioners, and liver and non-liver specialists were retrieved and analyzed to highlight the perception of disease, verify knowledge of current recommendations, and identify the main difficulties experienced in clinical practice. Next, position papers and clinical practice guidelines issued by International and National Hepatological Scientific Societies were identified and critically assessed in order to pinpoint the areas of convergence/difference. Finally, practical suggestions on NAFLD diagnosis and management in daily practice are provided and the open questions highlighted.
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Hígado Graso/diagnóstico , Hígado Graso/terapia , Biopsia , Gastroenterología , Humanos , Enfermedad del Hígado Graso no Alcohólico , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en MedicinaRESUMEN
The complex and bi-directional relationship linking the liver and diabetes has recently gained intense new interest. This critical review of the published work aims to highlight the most recent basic and clinical data underlying the development of type 2 diabetes, in those with non-alcoholic fatty liver disease. Moreover, the potentially detrimental effects of type 2 diabetes in liver injury are also discussed in each of the two sections of the present paper. Fatty liver and diabetes share insulin resistance as their chief pathogenic determinant. The roles of the hypothalamus, the intestinal microbiome, white adipose tissue and inflammation are discussed in detail. Molecular insights into hepatocyte insulin resistance as the initiator of systemic insulin resistance are also presented with full coverage of the danger of fatty acids. Lipotoxicity, apoptosis, lipoautophagy, endoplasmic reticular stress response and recent developments in genetics are discussed. Closing the circle, special emphasis is given to biochemical pathways and clinical evidence supporting the role of type 2 diabetes as a risk factor for the development of progressive liver disease, including non-alcoholic steatohepatitis, cirrhosis and primary liver cancer. In conclusion, data support non-alcoholic fatty liver disease as a risk factor for the development of type 2 diabetes which is, in turn, a major contributor to progressive liver disease. This pathway leading from fatty liver to type 2 diabetes and back from the latter to the progressive liver disease is a vicious circle.
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BACKGROUND: Differentiating steatosis from NASH is key in deciding treatment and follow-up schedules. We hypothesized that sonographic grading of steatosis will correlate with metabolic and pathologic changes of NASH. METHODS: Fifty-three non-consecutive patients had a semi-quantitative evaluation of hepatic steatosis through ultrasonographic Fatty Liver Indicator (US-FLI) just prior to liver biopsy. All biopsies demonstrated NAFLD. US-FLI is a new scoring system ranging 2-8 based on the intensity of liver/kidney contrast, posterior attenuation of ultrasound beam, vessel blurring, difficult visualization of gallbladder wall, difficult visualization of the diaphragm and areas of focal sparing. NAFLD is diagnosed by the minimum score ≥2. Ultrasonographic findings were correlated with metabolic and histological data. Inter-observer US-FLI score agreement, evaluated by three different operators in 31 consecutive patients with steatosis, showed "almost perfect/substantial" agreement (P < 0.001). RESULTS: US-FLI showed a positive correlation with HOMA, insulin, uric acid, ferritin, ALT and bilirubin and was associated with steatosis extent assessed histologically and histological features of NASH, except for fibrosis. US-FLI was an independent predictor of NASH (OR 2.236; P = 0.007) and a US-FLI < 4 had a high negative predictive value (94%) in ruling out the diagnosis of severe NASH according to Kleiner's criteria. CONCLUSION: Data confirm the hypothesis that US-FLI significantly correlates with metabolic derangements and individual pathologic criteria for NASH and may better select patients for liver biopsy.
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Hígado Graso/diagnóstico por imagen , Hígado Graso/metabolismo , Ultrasonografía/normas , Adulto , Biopsia , Diagnóstico Diferencial , Hígado Graso/patología , Femenino , Humanos , Hígado/metabolismo , Hígado/patología , Hígado/ultraestructura , Masculino , Persona de Mediana Edad , Análisis Multivariante , Enfermedad del Hígado Graso no Alcohólico , Variaciones Dependientes del Observador , Selección de Paciente , Valor Predictivo de las Pruebas , Ultrasonografía/estadística & datos numéricosRESUMEN
Hepatocellular carcinoma (HCC) is a common, treatment-resistant malignancy with a complex molecular pathogenesis. Statins are a widely used class of cholesterol-lowering drugs with potential anticancer activity. We reviewed the evidence for a role of statins in primary and secondary chemoprevention of HCC and slowing the course of otherwise incurable primary or recurrent disease. A literature search (key words: Statins, hepatocellular carcinoma) conducted to this end, retrieved 119 references. Here we summarize the history, mechanism of action and cardiovascular use of statins and highlight that statins can affect several pathways implicated in the development of HCC. In vitro and animal studies provide strong evidence for a favorable effect of statins on HCC. However, evidence in humans is conflicting. We discuss in full detail the methodological strengths and pitfalls of published data including three cohort studies suggesting that the use of statins may protect from the development of HCC and of a single trial reporting increased survival in those with advanced HCC randomized to receive statins. A remarkably hepato-safe class of drugs acting on both hepatocyte and endothelial cells, statins also have potentially beneficial effects in lowering portal hypertension. In conclusion, there is strong experimental evidence that statins are beneficial in chemopreventing and slowing the growth of HCC. However, randomized controlled trials are necessary in order to investigate the role of statins in the chemoprevention of HCC and in slowing the course of otherwise incurable disease in humans.
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Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/prevención & control , Carcinoma Hepatocelular/complicaciones , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/prevención & control , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipertensión Portal/complicaciones , Neoplasias Hepáticas/complicacionesRESUMEN
Five nontruncating missense APOB mutations, namely A31P, G275S, L324M, G912D, and G945S, were identified in heterozygous carriers of familial hypobetalipoproteinemia (FHBL) in the Italian population. To test that the FHBL phenotype was a result of impaired hepatic secretion of mutant apoB proteins, we performed transfection studies using McA-RH7777 cells stably expressing wild type or mutant forms of human apolipoprotein B-48 (apoB-48). All mutant proteins displayed varied impairment in secretion, with G912D the least affected and A31P barely secreted. Although some A31P was degraded by proteasomes, a significant proportion of it (although inappropriately glycosylated) escaped endoplasmic reticulum (ER) quality control and presented in the Golgi compartment. Degradation of the post-ER A31P was achieved by autophagy. Expression of A31P also decreased secretion of endogenous apoB and triglycerides, yet the impaired lipoprotein secretion did not lead to lipid accumulation in the cells or ER stress. Rather, expression of genes involved in lipogenesis was down-regulated, including liver X receptor alpha, sterol regulator element-binding protein 1c, fatty acid synthase, acetyl-CoA carboxylase 1, stearoyl-CoA desaturase 1, and lipin-1. These results suggest that feedback inhibition of hepatic lipogenesis in conjunction with post-ER degradation of misfolded apoB proteins can contribute to reduce fat accumulation in the FHBL liver.
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Apolipoproteínas B/genética , Hipobetalipoproteinemia Familiar por Apolipoproteína B/metabolismo , Lipogénesis/genética , Mutación Missense , Apolipoproteínas B/metabolismo , Autofagia , Regulación hacia Abajo , Retículo Endoplásmico , Retroalimentación Fisiológica , Aparato de Golgi , Heterocigoto , Humanos , Hipobetalipoproteinemia Familiar por Apolipoproteína B/genética , Italia , Hígado/metabolismo , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Pliegue de ProteínaRESUMEN
BACKGROUND AND AIMS: The knowledge of natural history is essential for disease management. We evaluated the natural history (e.g. frequency and characteristics of symptoms and clinical outcome) of gallstones (GS) in a population-based cohort study. METHODS: A total of 11 229 subjects (6610 men, 4619 women, age-range: 29-69 years, mean age: 48 years) were studied. At ultrasonography, GS were present in 856 subjects (338 men, 455 women) (7.1%). GS were followed by means of a questionnaire inquiring about the characteristics of specific biliary symptoms. RESULTS: At enrollment, 580 (73.1%) patients were asymptomatic, 94 (11.8%) had mild symptoms and 119 (15.1%) had severe symptoms. GS patients were followed up for a mean period of 8.7 years; 63 subjects (7.3%) were lost to follow up. At the end of the follow up, of the asymptomatic subjects, 453 (78.1%) remained asymptomatic; 61 (10.5%) developed mild symptoms and 66 (11.4%) developed severe symptoms. In subjects with mild symptoms, the symptoms disappeared in 55 (58.5%), became severe in 23 (24.5%), remained stable in 16 (17%); in subjects with severe symptoms, the symptoms disappeared in 62 (52.1%), became mild in 20 (16.8%) and remained stable in 37 (31.1%). A total of 189 cholecystectomies were performed: 41.3% on asymptomatic patients, 17.4% on patients with mild symptoms and 41.3% on patients with severe symptoms. CONCLUSIONS: This study indicates that: (i) asymptomatic and symptomatic GS patients have a benign natural history; (ii) the majority of GS patients with severe or mild symptoms will no longer experience biliary pain; and (iii) a significant proportion of cholecystectomies are performed in asymptomatic patients. Expectant management still represents a valid therapeutic approach in the majority of patients.
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Cálculos Biliares/epidemiología , Adulto , Anciano , Distribución de Chi-Cuadrado , Colecistectomía/efectos adversos , Estudios Transversales , Progresión de la Enfermedad , Femenino , Cálculos Biliares/complicaciones , Cálculos Biliares/diagnóstico por imagen , Cálculos Biliares/cirugía , Humanos , Italia/epidemiología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Selección de Paciente , Vigilancia de la Población , Recurrencia , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento , UltrasonografíaRESUMEN
A growing number of chronic liver disease patients, especially those with metabolic syndrome-associated nonalcoholic fatty liver disease or hepatitis C virus-associated dysmetabolic syndrome, will take statins to prevent cardiovascular disease. As a result, clinicians will weigh complex issues raised by the interaction of statins with liver metabolism in these disorders. In this article, we critically review data concerning statins and liver pathophysiology with an emphasis on nonalcoholic fatty liver disease and hepatitis C virus, while also touching on other chronic liver diseases. Basic research interests include statins' mechanism of action and their effects on cholesterol-related cell signaling pathways and angiogenesis. From the clinical standpoint, many chronic liver diseases increase cardiovascular risk and would undeniably benefit from sustained statin use. The false alarms and security accompanying aminotransferase monitoring, however, are disturbing in light of the scarcity of data on statins' long-term effects on liver histology. Although some actions of statins might eventually prove to be particularly useful in nonalcoholic steatohepatitis, hepatitis C virus, or hepatocellular carcinoma, others may prove harmful. The lack of definitive data makes a fully informed decision impossible. Research using histological endpoints is urgently needed to determine the indications and contraindications of this extraordinary class of agents in patients with chronic liver disease.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hepatopatías/tratamiento farmacológico , Hígado/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/fisiopatología , Enfermedades Cardiovasculares/prevención & control , Colesterol/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/fisiopatología , Hepatitis C/tratamiento farmacológico , Hepatitis C/fisiopatología , Humanos , Hígado/fisiopatología , Hepatopatías/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/fisiopatología , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND AND AIM: Studies have shown monounsaturated oleic acid to be less toxic than palmitic acid and to prevent/attenuate palmitic acid hepatocites toxicity in steatosis models in vitro. However, to what degree these effects are mediated by steatosis extent is unknown. METHODS: We evaluated whether steatosis per se is associated with hepatocytes apoptosis and determined the role of oleic and palmitic acid, the most abundant fatty acids in western diets, on triglyceride accumulation and apoptosis in an in vitro model of steatosis induced in three hepatocytic cell lines (HepG2, HuH7, WRL68). The impact of incubation for 24 h with oleic (0.66 and 1.32 mM) and palmitic acid (0.33 and 0.66 mM), alone or combined (molar ratio 2 : 1) on steatosis, apoptosis, and insulin signalling, was evaluated. RESULTS: Concurrent with PPARgamma and SREBP-1 gene activation, steatosis extent was larger when cells were treated with oleic than with palmitic acid; the latter fatty acid was associated with increased PPARalpha expression. Cell apoptosis was inversely proportional to steatosis deposition. Moreover, palmitic, but not oleic acid, impaired insulin signalling. Despite the higher amount of fat resulting from incubation of the two fatty acids combined, the apoptosis rate and impaired insulin signalling were lower than in cells treated with palmitic acid alone, indicating a protective effect of oleic acid. CONCLUSIONS: Oleic acid is more steatogenic but less apoptotic than palmitic acid in hepatocityc cell cultures. These data may provide a biological basis for clinical findings on dietary patterns and pathogenetic models of nonalcoholic fatty liver disease.
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Apoptosis/efectos de los fármacos , Hígado Graso/inducido químicamente , Hepatocitos/efectos de los fármacos , Ácido Oléico/toxicidad , Ácido Palmítico/toxicidad , Triglicéridos/metabolismo , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Hígado Graso/genética , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/prevención & control , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Insulina/metabolismo , Ácido Oléico/metabolismo , PPAR alfa/genética , PPAR gamma/genética , Ácido Palmítico/metabolismo , ARN Mensajero/metabolismo , Receptor de Insulina/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genéticaRESUMEN
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C feature steatosis and insulin resistance (IR), conditions associated with the metabolic syndrome (MS). OBJECTIVES: To assess the prevalence of MS and determinants of IR in patients with NAFLD and chronic hepatitis C. METHODS: Ninety-three consecutive patients with NAFLD, 97 with chronic hepatitis C virus (HCV) genotypes 1 and 2, and 182 'healthy' controls without steatosis were enrolled in the present study. The prevalence of MS was assessed by modified Adult Treatment Panel III criteria and IR by the homeostasis model assessment of insulin resistance (HOMA-IR). IR was defined as the 75th percentile of the HOMA-IR of control subjects. RESULTS: While the prevalence of IR was similar in NAFLD and HCV-infected subjects (70.0% and 78.7%, respectively), the prevalence of MS was significantly higher in NAFLD patients than in HCV-infected patients (27.9% versus 4.1%) and in controls (5.6%). With multivariate analysis, IR was predicted by body mass index (OR 1.263; 95% CI 1.078 to 1.480) and triglyceridemia (OR 1.011; 95% CI 1.002 to 1.020) in NAFLD and by sex (OR for female sex 0.297; 95% CI 0.094 to 0.940) and fibrosis stage (OR 2.751; 95% CI 1.417 to 5.340) in chronic hepatitis C. CONCLUSIONS: IR is independently associated with body mass index and triglyceridemia in NAFLD, sex and fibrosis in chronic HCV infection, and has a higher prevalence in NAFLD and chronic hepatitis C than in controls. However, the frequency of MS in HCVinfected patients, similar to that of controls, is significantly lower than that seen in NAFLD patients. The current diagnostic criteria of MS are more likely to 'capture' patients with NAFLD than with chronic hepatitis C, although both groups are insulin resistant.
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Hígado Graso/epidemiología , Hepatitis C Crónica/epidemiología , Resistencia a la Insulina , Síndrome Metabólico/epidemiología , Adulto , Índice de Masa Corporal , Estudios de Casos y Controles , Comorbilidad , Hígado Graso/sangre , Femenino , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/sangre , Hepatitis C Crónica/virología , Humanos , Italia/epidemiología , Masculino , Síndrome Metabólico/sangre , Persona de Mediana Edad , Prevalencia , Factores Sexuales , Triglicéridos/sangreRESUMEN
BACKGROUND: The prevalence and predictors of nonalcoholic fatty liver disease (NAFLD) in human immunodeficiency virus (HIV)-infected highly active antiretroviral therapy-experienced patients and the association of NAFLD with risk of cardiovascular disease and subclinical atherosclerosis are unknown. METHODS: We performed a cross-sectional observational study. NAFLD was defined by liver-spleen attenuation values of <1.1 on computed tomography in persons who had neither evidence of chronic viral hepatitis nor a significant history of alcohol consumption. RESULTS: We enrolled 225 patients; 163 (72.4%) were men. Mean (+/-SD) HIV infection duration was 145 +/- 60 months, and mean (+/-SD) body mass index (calculated as weight in kilograms divided by the square of height in meters) was 23.75 +/- 3.59. NAFLD was diagnosed in 83 patients (36.9% of the total cohort). The following variables were significantly associated with NAFLD in univariate analyses: sex, waist circumference, body mass index, cumulative exposure to nucleoside reverse-transcriptase inhibitors, visceral adipose tissue, homeostasis model assessment of insulin resistance index, serum alanine and aspartate aminotransferase levels, and ratios of total serum cholesterol to high-density lipoprotein cholesterol. Coronary artery calcium scores and a diagnosis of diabetes were not associated with NAFLD. In multivariable logistic regression analyses, factors associated (P<0.001) with NAFLD were higher serum alanine to aspartate ratio (odds ratio, 4.59; 95% confidence interval, 2.09-10.08), male sex (odds ratio, 2.49; 95% confidence interval, 1.07-5.81), greater waist circumference (odds ratio, 1.07; 95% confidence interval, 1.03-1.11), and longer nucleoside reverse-transcriptase inhibitor exposure (odds ratio, 1.12 per year of exposure; 95% confidence interval, 1.03-1.22). CONCLUSIONS: NAFLD is common among HIV-infected persons who have the traditional risk factors for NAFLD (elevations in serum alanine level, male sex, and increased waist circumference) apparent. Exposure to nucleoside reverse-transcriptase inhibitors was an independent risk factor for NAFLD, with an 11% increase in the odds ratio for each year of use.
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Hígado Graso/etiología , Infecciones por VIH/complicaciones , Adulto , Anciano , Alanina Transaminasa/sangre , Antropometría , Fármacos Anti-VIH/efectos adversos , Aspartato Aminotransferasas/sangre , Pesos y Medidas Corporales , Enfermedades Cardiovasculares/epidemiología , Colesterol/sangre , Estudios Transversales , Hígado Graso/diagnóstico , Hígado Graso/epidemiología , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Humanos , Resistencia a la Insulina , Grasa Intraabdominal , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Prevalencia , Inhibidores de la Transcriptasa Inversa/efectos adversos , Factores de Riesgo , Factores SexualesRESUMEN
NAFLD (non-alcoholic fatty liver disease) encompasses the spectrum of fatty liver disease in insulin-resistant individuals who often display T2DM (Type 2 diabetes mellitus) and obesity. The present review highlights the pathophysiological basis and clinical evidence for a possible causal linkage between NAFLD and CVD (cardiovascular disease). The role of traditional and non-traditional CVD risk factors in the pathophysiology of NAFLD is considered in the first part of the review, with the basic science shared by atherogenesis and hepatic steatogenesis discussed in depth in the second part. In conclusion, NAFLD is not an innocent bystander, but a major player in the development and progression of CVD. NAFLD and CVD also share similar molecular mechanisms and targeted treatment strategies. On the research side, studies should focus on interventions aimed at restoring energy homoeostasis in lipotoxic tissues and at improving hepatic (micro)vascular blood supply.
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Aterosclerosis/etiología , Hígado Graso/etiología , Aterosclerosis/fisiopatología , Sistema Endocrino/fisiopatología , Hígado Graso/fisiopatología , Femenino , Humanos , Metabolismo de los Lípidos , Masculino , Síndrome Metabólico/etiología , Factores de RiesgoRESUMEN
BACKGROUND/AIM: Hepatic bile acid synthesis is the main mechanism whereby the organism can degrade cholesterol. Plasma levels of 7alpha-hydroxy-4-cholesten-3-one have been reported to reflect bile acid synthesis and the expression or activity of the limiting enzyme of the main biosynthetic pathway, cholesterol 7alpha-hydroxylase. Aim of this study was to correlate the levels of this metabolite with the rates of cholesterol 7alpha-hydroxylation in vivo, a direct measurement of bile acid synthesis, in hyperlipidemic patients. DESIGN: Concentrations of 7alpha-hydroxy-4-cholesten-3-one were assayed by gas-liquid chromatography: mass spectrometry in plasma samples obtained in 18 patients with primary hyperlipoproteinemia who previously underwent determination of cholesterol 7alpha-hydroxylation rates in vivo by tritium release analysis. Both determinations were performed in basal conditions and after treatment with hypolipidemic drugs (the fibric acid derivatives gemfibrozil and bezafibrate, cholestyramine alone or associated with simvastatin). RESULTS: Changes in plasma 7alpha-hydroxy-4-cholesten-3-one profile closely reflected in vivo cholesterol 7alpha-hydroxylation rates during treatment with fibrates, cholestyramine and cholestyramine plus simvastatin. When plotting determinations from all studies (n=40), a very strict correlation was disclosed between plasma 7alpha-hydroxy-4-cholesten-3-one and cholesterol 7alpha-hydroxylation rates (r=0.81, P<0.001). CONCLUSIONS: Plasma 7alpha-hydroxy-4-cholesten-3-one closely mirrors measurements of cholesterol 7alpha-hydroxylation rates in vivo in hyperlipidemic subjects and therefore stands as a reliable marker of global bile acid synthesis. In view of the correlation observed, these data may help to interpret changes of plasma levels of this metabolite in terms of cholesterol balance quantification.
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Colestenonas/metabolismo , Colesterol 7-alfa-Hidroxilasa/metabolismo , Hiperlipidemias/sangre , Hiperlipidemias/metabolismo , Anciano , Anticolesterolemiantes/administración & dosificación , Bezafibrato/administración & dosificación , Colesterol/metabolismo , Resina de Colestiramina/administración & dosificación , Complemento C4/metabolismo , Interpretación Estadística de Datos , Femenino , Gemfibrozilo/administración & dosificación , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/diagnóstico , Hiperlipidemias/diagnóstico , Hipolipemiantes/administración & dosificación , Cinética , Masculino , Persona de Mediana Edad , Estándares de Referencia , Simvastatina/administración & dosificaciónAsunto(s)
Hígado Graso/diagnóstico , Hígado Graso/patología , Índice de Severidad de la Enfermedad , Biopsia , Hígado Graso/clasificación , Hígado Graso/fisiopatología , Femenino , Humanos , Hígado/patología , Cirrosis Hepática/patología , Modelos Logísticos , Masculino , Enfermedad del Hígado Graso no Alcohólico , Sensibilidad y EspecificidadRESUMEN
AIM: To evaluate carotid intima-media thickening (IMT) and plaques, gallstone disease (GD) and fatty liver (FL) as a function of age. METHODS: In 449 subjects, FL and carotid disease were assessed ultrasonographically. In a subgroup of 65/449 patients with non-alcoholic fatty liver disease (NAFLD), carotid disease, GD and associated factors were determined. RESULTS: FL of unspecified etiology was more common in younger and GD in older individuals. FL subjects had an increased prevalence of IMT and a decreased prevalence of plaques and manifested carotid disease earlier. Plaques were more common in subjects with GD. Age was an independent predictor of carotid disease outcome and FL was a protective factor for plaques. In NAFLD, there was an inverse correlation between body weight and age and the latter independently predicted carotid findings. CONCLUSION: Cardiovascular risk in patients with FL and NAFLD needs to be assessed as a function of age and body weight.
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Envejecimiento/patología , Enfermedades de las Arterias Carótidas/patología , Hígado Graso/patología , Cálculos Biliares/patología , Factores de Edad , Anciano , Anciano de 80 o más Años , Peso Corporal , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Interpretación Estadística de Datos , Hígado Graso/diagnóstico por imagen , Hígado Graso/etiología , Femenino , Cálculos Biliares/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prevalencia , Túnica Íntima/patología , Túnica Media/patología , UltrasonografíaRESUMEN
This study was performed to compare the effects of two hydrophilic bile acids, taurohyodeoxycholic acid (THDCA) and tauroursodeoxycholic acid (TUDCA), on HepG2 cells. Cytotoxicity was evaluated at different times of exposure by incubating cells with increasing concentrations (50-800 micromol/l) of either bile acid, while their cytoprotective effect was tested in comparison with deoxycholic acid (DCA) (350 micromol/l and 750 micromol/l)-induced cytotoxicity. Culture media, harvested at the end of each incubation period, were analyzed to evaluate aspartate transaminase (AST), alanine transaminase and gamma-glutamyltranspeptidase release. In addition, the hemolytic effect of THDCA and TUDCA on human red blood cells was also determined. At 24 h of incubation neither THDCA nor TUDCA was cytotoxic at concentrations up to 200 and 400 micromol/l. At 800 micromol/l both THDCA and TUDCA induced a slight increase in AST release. At this concentration and with time of exposure prolonged up to 72 h, THDCA and TUDCA induced a progressive increase of AST release significantly (P<0.05) higher than that of controls being AST values for THDCA (2.97+/-0.88 time control value (tcv) at 48 h and 4.50+/-1.13 tcv at 72 h) significantly greater than those of TUDCA (1.50+/-0.20 tcv at 48 h and 1.80+/-0.43 tcv at 72 h) (P<0.01). In cytoprotection experiments, the addition of 50 micromol/l THDCA decreased only slightly (-5%) AST release induced by 350 micromol/l DCA, while the addition of 50 micromol/l TUDCA was significantly effective (-23%; P<0.05). Higher doses of THDCA or TUDCA did not reduce toxicity induced by 350 micromol/l DCA, but were much less toxic than an equimolar dose of DCA alone. At the concentration used in this experimental model neither THDCA nor TUDCA was hemolytic; however at a very high concentration (6 mmol/l) both bile acids induced 5-8% hemolysis. We conclude that bile acid molecules with a similar degree of hydrophilicity may show different cytotoxic and cytoprotective properties.
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Ácido Tauroquenodesoxicólico/farmacología , Ácido Taurodesoxicólico/análogos & derivados , Ácido Taurodesoxicólico/farmacología , Alanina Transaminasa/análisis , Aspartato Aminotransferasas/análisis , Ácido Desoxicólico/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Eritrocitos/efectos de los fármacos , Hemólisis , Humanos , Ácido Tauroquenodesoxicólico/toxicidad , Ácido Taurodesoxicólico/toxicidad , Factores de Tiempo , Transglutaminasas/análisis , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
Hepatic steatosis is the hallmark of nonalcoholic fatty liver disease (NAFLD), which is the consequence of multiple metabolic derangements among which insulin resistance plays a pivotal role. Steatosis is, also, a feature of hepatitis C virus (HCV) infection. However, in chronic hepatitis C, the prevalence of steatosis is 2.5-fold more elevated than that expected by a chance concurrence with NAFLD, suggesting that HCV may be implied in the development of steatosis. As observed in NAFLD, in patients infected with HCV genotype 1 steatosis is associated with an increased body mass index. On the other hand, in patients infected with genotype 3 the extent of steatosis strictly correlates with the viral load indicating that steatosis is mainly "virus-related". Regardless of the "metabolic" or "viral" etiology, hepatic steatosis in HCV contributes to the progression of liver fibrosis, to the development of hepatocellular carcinoma and to an impaired response to interferon treatment. Features such as obesity, insulin resistance and type 2 diabetes mellitus are shared by NAFLD and HCV-associated steatosis. In addition, HCV infection, directly or through steatosis, favors the development of type 2 diabetes mellitus. Hyperlipidemia is an independent predictor of the development of NAFLD, but not of HCV-associated steatosis. Arterial hypertension is common in nonalcoholic steatohepatitis patients, and HCV infection has recently been acknowledged as an independent risk factor for atherosclerosis. The role of iron in the progression of both NAFLD and HCV-associated steatosis remains controversial while lipoperoxidation and oxidative stress are pathogenic mechanisms shared by both. Some metabolic risk factors may be shared by both HCV-associated steatosis and NAFLD although the disease progression and pathophysiological background may be different. Preliminary data suggest that the therapeutic options for NAFLD may also be useful to improve HCV-associated steatosis.
Asunto(s)
Hígado Graso/etiología , Hígado Graso/virología , Hepatitis C/complicaciones , Enfermedades Metabólicas/etiología , Hepacivirus , HumanosRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as an important cardiovascular risk (CVR) factor. This is a narrative clinical review aimed at answering how diagnosis and management of CVR should be conducted in the individual patient with NAFLD. To this end, the authors performed an extensive search of the existing literature on PubMed (1993-2014) using pertinent keywords. To date, CVR among patients with NAFLD might be assessed with the Framingham risk score equation or other risk calculators, to be adapted to the true CVR in the specific population being assessed; however, the use of these CVR calculators needs to be validated by future studies in larger cohorts of NAFLD patients of various ethnic backgrounds in order to substantiate their clinical relevance as a foundation for the primary prevention of cardiovascular diseases in this group of patients. Early and aggressive drug treatment of CVR should be started in NAFLD patients with a history of cardiovascular events, established diabetes or who are at high (calculated) CVR. Whether such an aggressive pharmacological approach is also justified in patients with NAFLD, who are at intermediate or low CVR, remains debatable. Currently, there are no clinical trials showing that the treatment of NAFLD per se (either associated or unassociated with traditional CVR factors) will result in decreased risk of cardiovascular events. Accordingly, drug treatment should be better individualized, aiming at correcting all the coexisting cardio-metabolic risk factors of the individual patient with NAFLD. To this end, an overview of the lifestyle interventions and the available drugs is offered, emphasis being conveyed to statins and metformin, which promise to cover worrying complications of NAFLD such as the risk of developing hepatocellular carcinoma.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/terapia , Terapia Combinada , Indicadores de Salud , Humanos , Enfermedad del Hígado Graso no Alcohólico/terapia , Medición de Riesgo , Factores de RiesgoRESUMEN
The conventional paradigm of nonalcoholic fatty liver disease representing the "hepatic manifestation of the metabolic syndrome" is outdated. We identified and summarized longitudinal studies that, supporting the association of nonalcoholic fatty liver disease with either type 2 diabetes mellitus or metabolic syndrome, suggest that nonalcoholic fatty liver disease precedes the development of both conditions. Online Medical databases were searched, relevant articles were identified, their references were further assessed and tabulated data were checked. Although several cross-sectional studies linked nonalcoholic fatty liver disease to either diabetes and other components of the metabolic syndrome, we focused on 28 longitudinal studies which provided evidence for nonalcoholic fatty liver disease as a risk factor for the future development of diabetes. Moreover, additional 19 longitudinal reported that nonalcoholic fatty liver disease precedes and is a risk factor for the future development of the metabolic syndrome. Finally, molecular and genetic studies are discussed supporting the view that aetiology of steatosis and lipid intra-hepatocytic compartmentation are a major determinant of whether fatty liver is/is not associated with insulin resistance and metabolic syndrome. Data support the novel paradigm of nonalcoholic fatty liver disease as a strong determinant for the development of the metabolic syndrome, which has potentially relevant clinical implications for diagnosing, preventing and treating metabolic syndrome.