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1.
Liver Transpl ; 30(2): 192-199, 2024 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-37146168

RESUMEN

Metabolic flexibility is the ability to match biofuel availability to utilization and is inversely associated with increased metabolic burden among liver transplant (LT) recipients. The present study evaluated the impact of metabolic flexibility on weight gain following LT. LT recipients were enrolled prospectively (n = 47) and followed for 6 months. Metabolic flexibility was measured using whole-room calorimetry and is expressed as a respiratory quotient (RQ). Peak RQ represents maximal carbohydrate metabolism and occurs in the post-prandial state, while trough RQ represents maximal fatty acid metabolism occurring in the fasted state. The clinical, metabolic, and laboratory characteristics of the study cohort of lost weight (n = 14) and gained weight (n = 33) were similar at baseline. Patients who lost weight were more likely to reach maximal RQ (maximal carbohydrate oxidation) early and rapidly transitioned to trough RQ (maximal fatty acid oxidation). In contrast, patients who gained weight had delayed time to peak RQ and trough RQ. In multivariate modeling, time to peak RQ (ß-coefficient 0.509, p = 0.01), time from peak RQ to trough RQ (ß-coefficient 0.634, p = 0.006), and interaction between time to peak RQ to trough RQ and fasting RQ (ß-coefficient 0.447, p = 0.02) directly correlated with the severity of weight gain. No statistically significant relationship between peak RQ, trough RQ, and weight change was demonstrated. Inefficient transition between biofuels (carbohydrates and fatty acids) is associated with weight gain in LT recipients that is independent of clinical metabolic risk. These data offer novel insight into the physiology of obesity after LT with the potential to develop new diagnostics and therapeutics.


Asunto(s)
Metabolismo Energético , Trasplante de Hígado , Humanos , Trasplante de Hígado/efectos adversos , Aumento de Peso , Obesidad , Ácidos Grasos
2.
Liver Transpl ; 29(9): 979-986, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-36847136

RESUMEN

NAFLD is common after liver transplantation (LT) and is associated with an increased metabolic burden. Currently, there is a paucity of investigations into the treatment of post-LT NAFLD. In the present study, we evaluated the safety and efficacy of saroglitazar, a novel dual peroxisome proliferator-associated receptor α/γ agonist, on the treatment of post-LT NAFLD and metabolic burden. This is a phase 2A, single-center, open-label, single-arm study in which patients with post-LT NAFLD received saroglitazar magnesium 4 mg daily for 24 weeks. NAFLD was defined by a controlled attenuation parameter ≥264 dB/m. The primary endpoint was the reduction in liver fat as measured by MRI proton density fat fraction (MRI-PDFF). Secondary MRI-based metabolic endpoints included visceral adipose tissue, abdominal subcutaneous adipose tissue volumes, muscle fat infiltration, and fat-free muscle volume. Saroglitazar treatment led to a reduction in MRI-PDFF from 10.3±10.5% at baseline to 8.1±7.6%. A relative 30% reduction from baseline MRI-PDFF value was noted in 47% of all patients and 63% of patients with baseline MRI-PDFF >5%. Reduction in serum alkaline phosphatase was an independent predictor of MRI-PDFF response. Saroglitazar did not decrease fat-free muscle volume nor increase muscle fat infiltration, but did lead to a mild increase in visceral adipose tissue and abdominal subcutaneous adipose tissue. The study drug was well tolerated and a mild nonsignificant increase in serum creatinine was noted. Saroglitazar did not affect the weight. The study provides preliminary data demonstrating the safety and metabolic benefits of saroglitazar in LT recipients and underscores the importance of future studies to establish its efficacy after LT.


Asunto(s)
Trasplante de Hígado , Enfermedad del Hígado Graso no Alcohólico , Fenilpropionatos , Humanos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Trasplante de Hígado/efectos adversos , Hígado/diagnóstico por imagen , Fenilpropionatos/uso terapéutico , Imagen por Resonancia Magnética
3.
Hepatology ; 76(6): 1811-1824, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35561146

RESUMEN

BACKGROUND AND AIMS: Bile acids are hepatic metabolites and have many properties considered to be relevant to the pathophysiology of NAFLD. Circulating levels of the intestinal microbiome-modified bile acid deoxycholate are increased in cirrhosis. APPROACH AND RESULTS: To further elucidate the role of bile acids and intestinal microbiota linked to bile acids in progressively severe NAFLD, a multiomic study of feces including 16S rRNA sequencing, microbial transcriptomics and metabolomics was performed in a cohort with varying phenotypes of NAFLD. Several bile acids of microbial origin derived from deoxycholic acid (DCA) (glycodeoxycholate, 7-ketodeoxycholic acid, dehydrocholic acid) increased with disease activity and fibrosis stage. These were linked to increased expression of microbial bile salt hydrolase, bile acid operon (BaiCD) and hydroxysteroid dehydrogenases (hdhA) required for DCA and downstream metabolite synthesis providing a mechanistic basis for altered bile acid profiles with disease progression. Bacteroidetes and several genera of Lachnospiraceae family containing DCA generating genes increased with increasing disease severity, whereas several potentially beneficial microbes sensitive to antibacterial effects of DCA e.g., Ruminococcaceae were decreased. The clinical relevance of these data was confirmed in an independent cohort enrolled in a clinical trial for NASH where at entry DCA and its conjugates were associated with advanced fibrosis. In patients treated with placebo, DCA declined in those with fibrosis regression and increased in those with fibrosis progression. DCA rose further in those with compensated cirrhosis when they experienced decompensation. CONCLUSIONS: These findings demonstrate a role for bile acids and the bile acid dependent microbiome in the development and progression of NAFLD and set the stage to leverage these findings for NASH biomarker development and for therapeutics.


Asunto(s)
Microbioma Gastrointestinal , Enfermedad del Hígado Graso no Alcohólico , Humanos , Ácidos y Sales Biliares/farmacología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , ARN Ribosómico 16S , Cirrosis Hepática
4.
Liver Int ; 42(6): 1401-1409, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35129295

RESUMEN

Metabolic flexibility is the ability to match biofuel availability to utilization. Reduced metabolic flexibility, or lower fatty acid (FA) oxidation in the fasted state, is associated with obesity. The present study evaluated metabolic flexibility after liver transplantation (LT). METHODS: Patients receiving LT for non-alcoholic steatohepatitis (NASH) (n = 35) and non-NASH (n = 10) were enrolled. NASH was chosen as these patients are at the highest risk of metabolic complications. Metabolic flexibility was measured using whole-body calorimetry and expressed as respiratory quotient (RQ), which ranges from 0.7 (pure FA oxidation) to 1.0 is (carbohydrate oxidation). RESULTS: The two cohorts were similar except for a higher prevalence of obesity and diabetes in the NASH cohort. Post-prandially, RQ increased in both cohorts (i.e. greater carbohydrate utilization) but peak RQ and time at peak RQ was higher in the NASH cohort. Fasting RQ in NASH was significantly higher (0.845 vs. 0.772, p < .001), indicative of impaired FA utilization. In subgroup analysis of the NASH cohort, body mass index but not liver fat content (MRI-PDFF) was an independent predictor of fasting RQ. In NASH, fasting RQ inversely correlated with fat-free muscle volume and directly with visceral adipose tissue. CONCLUSION: Reduced metabolic flexibility in patients transplanted for NASH cirrhosis may precede the development of non-alcoholic fatty liver disease after LT.


Asunto(s)
Trasplante de Hígado , Enfermedad del Hígado Graso no Alcohólico , Carbohidratos , Humanos , Cirrosis Hepática/complicaciones , Trasplante de Hígado/efectos adversos , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Obesidad/complicaciones
5.
Dig Dis Sci ; 66(1): 263-272, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32189102

RESUMEN

INTRODUCTION: The prevalence of coronary artery disease (CAD) is high among patients with cirrhosis; however, the impact of it on cardiovascular disease (CVD) is not known. The aim of the current study was to evaluate CVD events in patients with cirrhosis and impact of cirrhosis on biomarkers of atherogenesis. METHODS: The study included 682 patients with decompensated cirrhosis referred for liver transplantation (LT) evaluation between 2010 and 2017. All patients were followed until they experienced a CVD event, non-cardiac death, liver transplantation or last follow-up. To evaluate mechanistic link, patients with NASH cirrhosis were propensity matched 1:2 to non-cirrhosis NASH patients and biomarkers of atherogenic risk were compared. RESULTS: The composite CVD outcome occurred in 23(3.4%) patients after a median follow-up period of 585 days (IQR 139, 747). A strong association between presence of any CAD and CVD event was noted (HR = 6.8, 95% CI 2.9, 15.9) that was independent of age, gender, BMI, and MELD score. In competing risk model, the combined rate of LT and non-cardiac was significantly higher when compared to the rate of CVD events. Marker of insulin resistance and inflammation-related markers were similar in patients with and without cirrhosis. Patients with cirrhosis were more likely to have reduced VLDL, sdLDL-C, LDL-C, and triglycerides. Interestingly, patients with cirrhosis had an increase in serum HDL-2, the anti-atherogenic lipoprotein, and adiponectin, a protective serum adipokine. CONCLUSION: The risk of CVD events in patients with cirrhosis is low and may potentially be due to improvement in markers of atherogenic risk.


Asunto(s)
Enfermedades Cardiovasculares/sangre , Progresión de la Enfermedad , Mediadores de Inflamación/sangre , Trasplante de Hígado/tendencias , Enfermedad del Hígado Graso no Alcohólico/sangre , Aterosclerosis/sangre , Aterosclerosis/diagnóstico , Enfermedades Cardiovasculares/diagnóstico , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/cirugía , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/cirugía , Estudios Retrospectivos
6.
Clin Gastroenterol Hepatol ; 19(10): 2202-2204, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33007508

RESUMEN

Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease,1 is independently associated with increased risk of cardiovascular disease (CVD), which is the leading cause of mortality in patients with NAFLD.2 This is likely caused by the centrality of the liver in lipid homeostasis. Prior cross-sectional studies have shown that NAFLD is associated with perturbations in lipid profile and atherogenic lipoprotein subparticles.3 Although statins improve lipid profile and CVD-associated mortality, residual CVD risk has been demonstrated in major statin trials.4,5 A key contributor to this residual risk is the limited ability of the standard lipid profile to precisely quantify atherogenic lipoprotein subparticles, such as small dense low-density lipoprotein (sdLDL), which might confer higher atherogenic risk. There are currently no studies evaluating the longitudinal impact of sdLDL on atherosclerotic events in NAFLD. Thus, we conducted a prospective study in patients with histologically confirmed NAFLD to better define the relationship among NAFLD, residual CVD risk, and sdLDL.


Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Enfermedad del Hígado Graso no Alcohólico , Aterosclerosis/epidemiología , Estudios Transversales , Humanos , Lipoproteínas , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Estudios Prospectivos , Factores de Riesgo
7.
Hepatology ; 72(1): 271-286, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32056227

RESUMEN

BACKGROUND AND AIMS: The role of the intestinal microbiome in alcoholic hepatitis is not established. The aims of this study were to (1) characterize the fecal microbial ecology associated with alcoholic hepatitis, (2) relate microbiome changes to disease severity, and (3) infer the functional relevance of shifts in microbial ecology. APPROACH AND RESULTS: The fecal microbiome in patients with moderate alcoholic hepatitis (MAH) or severe alcoholic hepatitis (SAH) was compared with healthy controls (HCs) and heavy drinking controls (HDCs). Microbial taxa were identified by 16S pyrosequencing. Functional metagenomics was performed using PICRUSt. Fecal short chain fatty acids (SCFAs) were measured using a liquid chromatography-mass spectrometry platform. A total of 78 participants (HC, n = 24; HDC, n = 20; MAH, n = 10; SAH, n = 24) were studied. HDC had a distinct signature compared with HC with depletion of Bacteroidetes (46% vs. 26%; P = 0.01). Alcoholic hepatitis was associated with a distinct microbiome signature compared with HDC (area under the curve = 0.826); differential abundance of Ruminococcaceae, Veillonellaceae, Lachnospiraceae, Porphyromonadaceae, and Rikenellaceae families were the key contributors to these differences. The beta diversity was significantly different among the groups (permutational multivariate analysis of variance [PERMANOVA] P < 0.001). SAH was associated with increased Proteobacteria (SAH 14% vs. HDC 7% and SAH vs. HC 2%, P = 0.20 and 0.01, respectively). Firmicutes abundance declined from HDC to MAH to SAH (63% vs. 53% vs. 48%, respectively; P = 0.09, HDC vs. SAH). Microbial taxa did not distinguish between MAH and SAH (PERMANOVA P = 0.785). SCFAs producing bacteria (Lachnospiraceae and Ruminococcaceae) were decreased in alcoholic hepatitis, and a similar decrease was observed in fecal SCFAs among alcoholic hepatitis patients. CONCLUSIONS: There are distinct changes in fecal microbiome associated with the development, but not severity, of alcoholic hepatitis.


Asunto(s)
Consumo de Bebidas Alcohólicas , Heces/microbiología , Microbioma Gastrointestinal , Hepatitis Alcohólica/diagnóstico , Hepatitis Alcohólica/microbiología , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad
8.
Artículo en Inglés | MEDLINE | ID: mdl-36419503

RESUMEN

Aim: To compare the phenotype of lean versus overweight (OW) and obese (OB) subjects with non-alcoholic fatty liver disease (NAFLD) across multiple continents. Methods: A retrospective study of histologically defined subjects from a single center each in France (Fr), Brazil (Br), India (In) and United States (US) was performed. Results: A total of 70 lean [body mass index (BMI) < 25 kg/m2] subjects (Fr:Br:In:US: 16:19:22:13) with NAFLD were compared to 136 OW (BMI > 25 kg/m2, BMI < 29 kg/m2) (n = 28:33:52:23) and 224 OB subjects (BMI > 29 kg/m2) (n = 81:11:22:103). Lean French subjects had the lowest incidence of type 2 diabetes while those from Brazil (P < 0.01) had the highest. Lean subjects had similar low-density lipoprotein-cholesterol, but higher high-density lipoprotein-cholesterol compared to obese subjects in all regions. In both lean and obese subjects, there were both insulin-sensitive and insulin-resistant subjects. Lean French subjects were most insulin-sensitive while those from Brazil were mostly insulin-resistant. For each weight category, subjects from India were more insulin-sensitive than those from other regions. Disease activity increased from lean to overweight to obese in France but was similar across weight categories in other regions. Conclusion: The phenotype of NAFLD in lean subjects varies by region. Some obese subjects with NAFLD are insulin-sensitive. We hypothesize that genetics and region-specific disease modifiers account for these differences.

9.
Hepatology ; 67(2): 534-548, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28696585

RESUMEN

The histologic spectrum of nonalcoholic fatty liver disease (NAFLD) includes fatty liver (NAFL) and steatohepatitis (NASH), which can progress to cirrhosis in up to 20% of NASH patients. Bile acids (BA) are linked to the pathogenesis and therapy of NASH. We (1) characterized the plasma BA profile in biopsy-proven NAFL and NASH and compared to controls and (2) related the plasma BA profile to liver histologic features, disease activity, and fibrosis. Liquid chromatography/mass spectrometry quantified BAs. Descriptive statistics, paired and multiple group comparisons, and regression analyses were performed. Of 86 patients (24 controls, 25 NAFL, and 37 NASH; mean age 51.8 years and body mass index 31.9 kg/m2 ), 66% were women. Increased total primary BAs and decreased secondary BAs (both P < 0.05) characterized NASH. Total conjugated primary BAs were significantly higher in NASH versus NAFL (P = 0.047) and versus controls (P < 0.0001). NASH had higher conjugated to unconjugated chenodeoxycholate (P = 0.04), cholate (P = 0.0004), and total primary BAs (P < 0.0001). The total cholate to chenodeoxycholate ratio was significantly higher in NAFLD without (P = 0.005) and with (P = 0.02) diabetes. Increased key BAs were associated with higher grades of steatosis (taurocholate), lobular (glycocholate) and portal inflammation (taurolithocholate), and hepatocyte ballooning (taurocholate). Conjugated cholate and taurocholate directly and secondary to primary BA ratio inversely correlated to NAFLD activity score. A higher ratio of total secondary to primary BA decreased (odds ratio, 0.57; P = 0.004) and higher conjugated cholate increased the likelihood of significant fibrosis (F≥2) (P = 0.007). Conclusion: NAFLD is associated with significantly altered circulating BA composition, likely unaffected by type 2 diabetes, and correlated with histological features of NASH; these observations provide the foundation for future hypothesis-driven studies of specific effects of BAs on specific aspects of NASH. (Hepatology 2018;67:534-548).


Asunto(s)
Ácidos y Sales Biliares/sangre , Enfermedad del Hígado Graso no Alcohólico/sangre , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Cirrosis Hepática/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Receptores Citoplasmáticos y Nucleares/fisiología , Índice de Severidad de la Enfermedad
11.
J Vis Exp ; (113)2016 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-27501005

RESUMEN

Small non-coding RNAs (miRNAs) have been implicated in a variety of human diseases including metabolic syndromes. They may be utilized as biomarkers for diagnosis and prognosis or may serve as targets for drug development, respectively. Recently it has been shown that miRNAs are carried in lipoproteins, particularly high density lipoproteins (HDL) and are delivered to recipient cells for uptake. This raises the possibility that miRNAs play a critical and pivotal role in cellular and organ function via regulation of gene expression as well as messenger for cell-cell communications and crosstalk between organs. Current methods for miRNA isolation from purified HDL are impractical when utilizing small samples on a large scale. This is largely due to the time consuming and laborious methods used for lipoprotein isolation. We have developed a simplified approach to rapidly isolate purified HDL suitable for miRNA analysis from plasma samples. This method should facilitate investigations into the role of miRNAs in health and disease and in particular provide new insights into the variety of biological functions, outside of the reverse cholesterol transport, that have been ascribed to HDL. Also, the miRNA species which are present in HDL can provide valuable information of clinical biomarkers for diagnosis of various diseases.


Asunto(s)
Lipoproteínas HDL/química , MicroARNs/aislamiento & purificación , Transporte Biológico , Biomarcadores , Electroforesis en Gel de Agar , Humanos , Lipoproteínas HDL/aislamiento & purificación , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
12.
J Hepatol ; 65(5): 980-987, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27302378

RESUMEN

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of thrombosis. However, it remains unclear if hypercoagulability contributes to this risk. We, therefore, determined an in-depth hemostatic profile in a cohort of well-defined patients with NAFLD. METHODS: We drew blood samples from 68 patients with biopsy-proven NAFLD (simple steatosis n=24, NASH n=22, and NASH cirrhosis n=22), 30 lean controls, 30 overweight controls (body mass index (BMI) >25kg/m2), and 15 patients with alcoholic (ASH) cirrhosis, and performed in-depth hemostatic profiling. RESULTS: Basal and agonist-induced platelet activation, plasma levels of markers of platelet activation, and plasma levels of the platelet adhesion regulators von Willebrand factor and ADAMTS13 were comparable between patients with non-cirrhotic NAFLD and controls. Agonist-induced platelet activation was decreased in patients with cirrhosis. Thrombomodulin-modified thrombin generation was comparable between all patients and controls, although patients with cirrhosis had a reduced anticoagulant response to thrombomodulin. Thromboelastography test results were comparable between controls and non-cirrhotic NAFLD patients, but revealed moderate hypocoagulability in cirrhosis. Plasma fibrinolytic potential was decreased in overweight controls and non-cirrhotic NAFLD, but accelerated fibrinolysis was observed in ASH cirrhosis. Clot permeability was decreased in overweight controls and patients with NAFLD. CONCLUSIONS: The overall hemostatic profile is comparable between patients with non-cirrhotic NAFLD and controls. Additionally, pro-thrombotic features (hypofibrinolysis and a pro-thrombotic structure of fibrin clot) in patients with NAFLD are likely driven by obesity. Our study suggests a limited role for hyperactive hemostasis in the increased thrombotic risk in NAFLD. LAY SUMMARY: The combined results of this study show that the overall hemostatic status is comparable between healthy individuals and patients with a fatty liver disease.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Hemostasis , Hemostáticos , Humanos , Cirrosis Hepática , Sobrepeso
13.
Liver Int ; 36(4): 572-9, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26713759

RESUMEN

BACKGROUND & AIMS: In non-alcoholic fatty liver disease, presence of fibrosis is predictive of long-term liver-related complications. Currently, there are no reliable and non-invasive means of quantifying fibrosis in those with non-alcoholic fatty liver disease. Therefore, we aimed to evaluate the performance of a panel of non-invasive models in predicting fibrosis in non-alcoholic fatty liver disease. METHODS: The accuracy of FibroMeter non-alcoholic fatty liver disease, fibrosis 4 and four other non-invasive models in predicting fibrosis in those with biopsy proven non-alcoholic fatty liver disease was compared. These models were constructed post hoc in patients who had necessary clinical information collected within 2 months of a liver biopsy. The areas under receiver operating characteristics curves were compared for each model using Delong analysis. Optimum cut-off for each model and fibrosis stage were calculated using the Youden index. RESULTS: The area under receiver operating characteristics curves for F ≥ 1 fibrosis for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease was 0.821 and 0.801 respectively. For F ≥ 3, the area under receiver operating characteristics curves was 0.866 for fibrosis 4 and 0.862 for FibroMeter non-alcoholic fatty liver disease. Delong analysis showed the area under receiver operating characteristics curves was statistically different for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease compared with BARD, BAAT and aspartate aminotransferase:alanine aminotransferase ratio for F ≥ 1 and F ≥ 3. Area under receiver operating characteristics curves were significantly different for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease for F ≥ 3 compared with non-alcoholic fatty liver disease fibrosis score. At a fixed sensitivity of 90%, FibroMeter non-alcoholic fatty liver disease had the highest specificity for F ≥ 1 (52.4%) and F ≥ 3 (63.8%). In contrast, at a fixed specificity of 90%, fibrosis 4 outperformed other models with a sensitivity of 60.2% for F ≥ 1 and 70.6% for F ≥ 3 fibrosis. CONCLUSION: These non-invasive models of fibrosis can predict varying degrees of fibrosis from routinely collected clinical information in non-alcoholic fatty liver disease.


Asunto(s)
Técnicas de Apoyo para la Decisión , Cirrosis Hepática/etiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Adulto , Alanina Transaminasa/sangre , Área Bajo la Curva , Aspartato Aminotransferasas/sangre , Biomarcadores/sangre , Biopsia , Plaquetas , Índice de Masa Corporal , Pruebas Enzimáticas Clínicas , Femenino , Humanos , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Recuento de Plaquetas , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo
14.
Dig Dis Sci ; 60(8): 2529-37, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25784075

RESUMEN

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) represents a histological spectrum ranging from benign hepatic steatosis (NAFL) to nonalcoholic steatohepatitis (NASH). NAFLD is closely associated with insulin resistance (IR), and although the role of IR in NAFLD has been an area of intense investigation, there are limited data on pancreatic ß-cell function. AIM: To evaluate the pancreatic ß-cell function in NAFLD using the homeostatic model assessment-ß (HOMA-ß) and ß-cell index (BI). METHODS: HOMA-ß was measured in ninety-nine non-diabetic subjects with histologically confirmed NAFLD and compared to lean (age- and gender-matched) and obese (age-, gender-, and BMI-matched) controls. Using the values from an oral glucose tolerance test, BI was compared in 31 non-diabetic, non-cirrhotic subjects with NASH and gender- and BMI-matched controls. RESULTS: The subjects with NAFLD had higher HOMA-ß compared to both lean and obese controls (43.1 vs. 9 vs. 22.1 %, respectively, P < 0.05). HOMA-ß was directly related to serum alkaline phosphate, total bilirubin, and weight and inversely related to age. There was no difference in HOMA-ß between subjects with NAFL and NASH. Subjects with NASH had lower ß-cell function as measured by a lower BI (2.09 ± 1.64 vs. 7.74 ± 25.12; P = 0.04). In patients with NASH, BI was inversely associated with fibrosis independent of age, BMI, and serum ALT levels. In contrast, HOMA-ß was directly associated with fibrosis stage. CONCLUSION: NASH is associated with strained pancreatic ß-cell function in non-diabetic subjects. Future studies are necessary to evaluate the temporal relationship between ß-cell function and hepatic histology.


Asunto(s)
Células Secretoras de Insulina/fisiología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Adulto , Anciano , Femenino , Prueba de Tolerancia a la Glucosa , Homeostasis/fisiología , Humanos , Resistencia a la Insulina/fisiología , Masculino , Persona de Mediana Edad
15.
Clin Gastroenterol Hepatol ; 13(5): 1000-8.e3, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25311381

RESUMEN

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is associated independently with increased cardiovascular mortality. Although NAFLD is associated with dyslipidemia, it is not clear whether recently identified markers of cardiovascular risk indicate liver disease progression in patients with histologically confirmed NAFLD. We evaluated an extensive panel of serum markers of cardiovascular risk in nondiabetic patients with histologically proven NAFLD. METHODS: We performed a case-control study in which we compared serum levels of laboratory markers of cardiovascular risk among 81 nondiabetic subjects with histologically confirmed NAFLD vs lean (N = 81) and obese (N = 81) individuals without NAFLD (based on liver fat score, controls). For ex vivo studies, liver tissues were obtained from subjects undergoing elective cholecystectomy or from a tissue repository. RESULTS: Subjects with NAFLD had increased serum levels of insulin, triglycerides, and apolipoprotein B; increased size and concentration of very large density lipoprotein particles; increased concentrations of low-density lipoprotein (LDL) particles and small dense LDL (sdLDL) cholesterol, and an increased percentage of sdLDL, compared with controls. Although nonalcoholic steatohepatitis was associated with a worse profile of serum atherogenic markers than NAFLD, these differences did not reach statistical significance. Despite hyperinsulinemia, triglyceride and apolipoprotein B levels, concentrations of LDL particles and LDL cholesterol, and sdLDL-related parameters decreased significantly in patients with cirrhosis. Ex vivo studies showed that patients with NAFLD had increased sensitivity of hepatic triglyceride levels and cholesterol synthesis to insulin, and that sensitivity increased the development of cirrhosis. CONCLUSIONS: Atherogenic dyslipidemia is related to increased insulin-induced hepatic lipid synthesis in patients with NAFLD. Reduced dyslipidemia in patients with cirrhosis is associated with increased insulin resistance and possibly failed lipid synthesis.


Asunto(s)
Aterosclerosis/epidemiología , Aterosclerosis/patología , Biomarcadores/sangre , Fibrosis/patología , Lipoproteínas/sangre , Enfermedad del Hígado Graso no Alcohólico/patología , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Fibrosis/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones
16.
Clin Gastroenterol Hepatol ; 13(2): 402-5, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25004459

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is common among patients with human immunodeficiency virus (HIV) infection; a reliable noninvasive method of detection is needed. We aimed to validate noninvasive means of identifying steatosis in HIV-positive patients. We performed a single-center retrospective study to validate the abilities of the liver fat score (LFS) and the lipid accumulation product (LAP) to detect hepatic steatosis in HIV-positive patients, compared with HIV-negative individuals (controls); NAFLD was confirmed by histology, and findings were compared with those from ultrasonography. These models then were validated in HIV-positive patients with NAFLD vs patients co-infected with HIV and hepatitis C virus (HCV) infection, without hepatic steatosis. LFS identified hepatic steatosis in HIV-positive subjects, compared with controls, with an area under the receiver operating curve value of 0.971 ± 0.027 (95% confidence interval, 0.91-1.000). At a cut-off value of -0.945, the LFS identified patients with steatosis with 100% sensitivity and 84% specificity. At a cut-off of value of -0.234, the LFS differentiated between HIV-positive subjects with NAFLD and patients co-infected with HIV and HCV with 100% sensitivity and 74% specificity. LAP scores ≥38 identified HIV-positive patients with steatosis with 89% sensitivity and 83% specificity. LAP scores ≥42 differentiated between HIV-positive subjects with steatosis and patients co-infected with HIV and HCV with 89% specificity and 70% sensitivity. We validated the accuracy of LFS and LAP in detecting hepatic steatosis in HIV-positive patients.


Asunto(s)
Hígado Graso/diagnóstico , Infecciones por VIH/complicaciones , Producto de la Acumulación de Lípidos , Hígado/diagnóstico por imagen , Hígado/patología , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Estudios Retrospectivos , Sensibilidad y Especificidad , Ultrasonografía
17.
Gastroenterology ; 145(6): 1271-9.e1-3, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23973920

RESUMEN

BACKGROUND & AIMS: Liver disease has been associated with cardiovascular disorders, but little is known about the relationship between serum levels of alanine aminotransferase (ALT) and markers of atherogenesis. We investigated the relationship between low-normal and high-normal levels of ALT and an extended panel of cardiovascular risk factors among individuals with no known diseases in a primary care setting. METHODS: We performed a retrospective analysis of data collected from 6442 asymptomatic patients at wellness visits to a primary care setting in central Virginia from 2010 through 2011. Serum levels of ALT were compared with levels of lipids and lipoproteins, as well as metabolic, inflammatory, and coagulation-related factors associated with risk for cardiovascular disease. RESULTS: Serum levels of ALT were higher than 40 IU/L in 12% of subjects, and in the high-normal range (19-40 IU/L in women and 31-40 IU/L in men) in 25% of subjects. ALT level was associated with the apolipoprotein B level, concentration and particle size of very-low-density lipoproteins, concentration of low-density lipoprotein (LDL) particles (LDL-P), and percentages of small dense LDL (sdLDL) and sdLDL-cholesterol (sdLDL-C) (P < .0001 for all). A high-normal level of ALT was associated with higher levels of LDL-C, LDL-P, sdLDL-C, and sdLDL particles (P < .001 for all). These effects were independent of age, body mass index, and hyperinsulinemia. Increasing levels of ALT and fasting hyperinsulinemia (>12 µU/mL) synergized with increasing levels of triglycerides, very-low-density lipoprotein particles, LDL-P, sdLDL-C, and percentage of sdLDL-C. Levels of APOA1, high-density lipoprotein-cholesterol, and high-density lipoprotein-class 2 were associated inversely with serum level of ALT (P < .0001 for all). CONCLUSIONS: In an analysis of asymptomatic individuals, increased serum levels of ALT (even high-normal levels) are associated with markers of cardiovascular disease.


Asunto(s)
Alanina Transaminasa/sangre , Aterosclerosis/sangre , Aterosclerosis/epidemiología , Adulto , Anciano , Aterosclerosis/fisiopatología , Biomarcadores/sangre , Índice de Masa Corporal , Estudios de Cohortes , Femenino , Humanos , Resistencia a la Insulina/fisiología , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo
18.
Hepatology ; 50(4): 1175-83, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19670416

RESUMEN

UNLABELLED: Patients with minimal hepatic encephalopathy (MHE) have impaired driving skills, but association of MHE with motor vehicle crashes is unclear. Standard psychometric tests (SPT) or inhibitory control test (ICT) can be used to diagnose MHE. The aim was to determine the association of MHE with crashes and traffic violations over the preceding year and on 1-year follow-up. Patients with cirrhosis were diagnosed with MHE by ICT (MHEICT) and SPT (MHESPT). Self and department-of-transportation (DOT)-reports were used to determine crashes and violations over the preceding year. Agreement between self and DOT-reports was analyzed. Patients then underwent 1-year follow-up for crash/violation occurrence. Crashes in those with/without MHEICT and MHESPT were compared. 167 patients with cirrhosis had DOT-reports, of which 120 also had self-reports. A significantly higher proportion of MHEICT patients with cirrhosis experienced crashes in the preceding year compared to those without MHE by self-report (17% vs 0.0%, P = 0.0004) and DOT-reports (17% vs 3%, P = 0.004, relative risk: 5.77). SPT did not differentiate between those with/without crashes. A significantly higher proportion of patients with crashes had MHEICT compared to MHESPT, both self-reported (100% vs 50%, P = 0.03) and DOT-reported (89% vs 44%, P = 0.01). There was excellent agreement between self and DOT-reports for crashes and violations (Kappa 0.90 and 0.80). 109 patients were followed prospectively. MHEICT patients had a significantly higher future crashes/violations compared to those without (22% vs 7%, P = 0.03) but MHESPT did not. MHEICT (Odds ratio: 4.51) and prior year crash/violation (Odds ratio: 2.96) were significantly associated with future crash/violation occurrence. CONCLUSION: Patients with cirrhosis and MHEICT have a significantly higher crash rate over the preceding year and on prospective follow-up compared to patients without MHE. ICT, but not SPT performance is significantly associated with prior and future crashes and violations. There was an excellent agreement between self- and DOT-reports.


Asunto(s)
Accidentes de Tránsito/psicología , Conducción de Automóvil/psicología , Encefalopatía Hepática/fisiopatología , Adulto , Femenino , Estudios de Seguimiento , Encefalopatía Hepática/diagnóstico , Encefalopatía Hepática/psicología , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Psicometría , Trastornos Psicomotores/psicología , Autorrevelación
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