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Treating Nonalcoholic Fatty Liver Disease From the Outside In?
Flynn CR
(2019) Cell Mol Gastroenterol Hepatol 7: 682-683
MeSH Terms: Animals, Hepatocytes, Intracellular Signaling Peptides and Proteins, Mice, Non-alcoholic Fatty Liver Disease, Oligonucleotides, Antisense, Protein-Serine-Threonine Kinases
Added April 15, 2019
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7 MeSH Terms
Alcohol Use and Cardiovascular Disease Risk in Patients With Nonalcoholic Fatty Liver Disease.
VanWagner LB, Ning H, Allen NB, Ajmera V, Lewis CE, Carr JJ, Lloyd-Jones DM, Terrault NA, Siddique J
(2017) Gastroenterology 153: 1260-1272.e3
MeSH Terms: Adolescent, Adult, Age Factors, Alcohol Drinking, Binge Drinking, Chi-Square Distribution, Coronary Artery Disease, Cross-Sectional Studies, Echocardiography, Doppler, Female, Humans, Linear Models, Logistic Models, Longitudinal Studies, Male, Middle Aged, Multidetector Computed Tomography, Multivariate Analysis, Non-alcoholic Fatty Liver Disease, Odds Ratio, Prognosis, Protective Factors, Risk Assessment, Risk Factors, Time Factors, Underage Drinking, United States, Young Adult
Show Abstract · Added September 11, 2017
BACKGROUND & AIMS - Cardiovascular disease (CVD) is the leading cause of death among patients with nonalcoholic fatty liver disease (NAFLD). Moderate drinking (vs abstinence) is associated with lower risk of CVD in the general population. We assessed whether alcohol use is associated with CVD risk in patients with NAFLD.
METHODS - We analyzed data from participants in the Coronary Artery Risk Development in Young Adults longitudinal cohort study of 5115 black and white young adults, 18-30 years old, recruited from 4 cities in the United States from 1985 through 1986. Participants self-reported alcohol use at study entry and then again after 15, 20, and 25 years. At year 25 (2010-2011), participants underwent computed tomography examination of the thorax and abdomen and tissue Doppler echocardiography with myocardial strain measured by speckle tracking. Coronary artery calcification was defined as an Agatston score above 0. NAFLD was defined as liver attenuation <51 Hounsfield Units after exclusions. Drinkers reported 1-21 (men) or 1-14 (women) standard drinks/week at years 15, 20, or 25. Nondrinkers reported no alcohol use at years 15, 20, and 25.
RESULTS - Of the 570 participants with NAFLD (mean age, 50 years; 54% black; 46% female), 332 (58%) were drinkers; significantly higher proportions of drinkers were white, male, and with higher levels of education compared with nondrinkers (P < .05 for all). Higher proportions of drinkers had obesity, diabetes, and metabolic syndrome compared with nondrinkers (P < .01). There was no difference in liver attenuation between groups (P = .12). After multivariable adjustment, there was no association between alcohol use and CVD risk factors (diabetes, hypertension, hyperlipidemia) or subclinical CVD measures (coronary artery calcification, early transmitral velocity/late (atrial) transmitral velocity (E/A) ratio, global longitudinal strain).
CONCLUSIONS - In a population-based sample of individuals with NAFLD in midlife, prospectively assessed alcohol use is not associated with significant differences in risk factors for CVD or markers of subclinical CVD. In contrast to general population findings, alcohol use may not reduce the risk of CVD in patients with NAFLD.
Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
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28 MeSH Terms
Testosterone Levels in Pre-Menopausal Women are Associated With Nonalcoholic Fatty Liver Disease in Midlife.
Sarkar M, Wellons M, Cedars MI, VanWagner L, Gunderson EP, Ajmera V, Torchen L, Siscovick D, Carr JJ, Terry JG, Rinella M, Lewis CE, Terrault N
(2017) Am J Gastroenterol 112: 755-762
MeSH Terms: Adult, Body Mass Index, Diabetes Mellitus, Follow-Up Studies, Humans, Insulin Resistance, Intra-Abdominal Fat, Lipoproteins, HDL, Middle Aged, Multidetector Computed Tomography, Non-alcoholic Fatty Liver Disease, Premenopause, Prevalence, Risk Factors, Testosterone, Triglycerides, Waist Circumference, Young Adult
Show Abstract · Added September 11, 2017
OBJECTIVES - Young women with hyperandrogenism have high risk of metabolic co-morbidities, including increased risk of nonalcoholic fatty liver disease (NAFLD). Whether testosterone (the predominant androgen) is associated with NAFLD independent of metabolic co-factors is unclear. Additionally, whether testosterone confers increased risk of NAFLD in women without hyperandrogenism is unknown.
METHODS - Among women in the prospective population-based multicenter Coronary Artery Risk Development in Young Adults (CARDIA) study, we assessed whether free testosterone levels measured at Year 2 (1987-1988) were associated with prevalent NAFLD at Year 25 (2010-2011) (n=1052). NAFLD was defined using noncontrast abdominal CT scan with liver attenuation≤40 Hounsfield units after excluding other causes of hepatic fat. The association of free testosterone with prevalent NAFLD was assessed by logistic regression.
RESULTS - Increasing quintiles of free testosterone were associated with prevalent NAFLD at Year 25 (adjusted odds ratio (AOR) 1.25, 95% confidence interval (CI) 1.04-1.50, P=0.015), independent of insulin resistance, body mass index, waist circumference, and serum lipids. Importantly, the association persisted among n=955 women without androgen excess (AOR 1.27, 95% CI 1.05-1.53, P=0.016). Visceral adipose tissue (VAT) volume partially mediated the association of free testosterone with NAFLD (mediating effect 41.0%, 95% CI 22-119%).
CONCLUSIONS - Increasing free testosterone is associated with prevalent NAFLD in middle age, even in women without androgen excess. Visceral adiposity appears to play an important role in the relationship between testosterone and NAFLD in women. Testosterone may provide a potential novel target for NAFLD therapeutics, and future studies in pre-menopausal women should consider the importance of testosterone as a risk factor for NAFLD.
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18 MeSH Terms
Nonalcoholic fatty liver disease and measures of early brain health in middle-aged adults: The CARDIA study.
VanWagner LB, Terry JG, Chow LS, Alman AC, Kang H, Ingram KH, Shay C, Lewis CE, Bryan RN, Launer LJ, Jeffrey Carr J
(2017) Obesity (Silver Spring) 25: 642-651
MeSH Terms: Brain, Female, Health Behavior, Humans, Intra-Abdominal Fat, Liver, Magnetic Resonance Spectroscopy, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Organ Size, Prevalence, Risk Factors, Tomography, X-Ray Computed
Show Abstract · Added April 6, 2017
OBJECTIVE - To assess associations between nonalcoholic fatty liver disease (NAFLD) and measures of brain health in a population-based sample of adults.
METHODS - Participants from the CARDIA study (Y25 exam; age 43-55 years) with concurrent computed tomography quantification of liver fat, visceral adipose tissue (VAT), and brain magnetic resonance (MR) images were included (n = 505). NAFLD was identified after exclusion of other causes of liver fat. Total tissue volume (TTV) and gray matter cerebral blood flow (GM-CBF) were estimated using 3T brain MR images.
RESULTS - NAFLD prevalence was 18%. NAFLD was associated with lower TTV and GM-CBF after adjusting for intracranial volume, demographics, and health behaviors (P < 0.04 for all). In models with additional adjustment for cardiovascular risk factors, the association of NAFLD with GM-CBF remained significant (P = 0.04) but was attenuated after adjustment for VAT (P = 0.06) and eliminated with BMI (P = 0.20). NAFLD was not associated with TTV after adjustment for cardiovascular risk factors (P = 0.10) or additional adjustment for VAT (P = 0.14) or BMI (P = 0.05).
CONCLUSIONS - NAFLD is negatively associated with early brain health as assessed by MR measures of structure (TTV) and perfusion (GM-CBF). BMI and VAT attenuated this relationship, providing insight into the potential metabolic role of liver fat in brain health and disease.
© 2017 The Obesity Society.
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14 MeSH Terms
Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans.
Liu W, Anstee QM, Wang X, Gawrieh S, Gamazon ER, Athinarayanan S, Liu YL, Darlay R, Cordell HJ, Daly AK, Day CP, Chalasani N
(2016) Aging (Albany NY) 9: 26-40
MeSH Terms: Adult, Alleles, Case-Control Studies, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Lipase, Liver, Male, Membrane Proteins, Middle Aged, Non-alcoholic Fatty Liver Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcription, Genetic
Show Abstract · Added April 13, 2017
The increased expression of leads to hepatosteatosis in mice. This study aims to investigate the genetic control of hepatic transcription and to explore its impact on NAFLD risk in humans. Through a locus-wide expression quantitative trait loci (eQTL) mapping in two human liver sample sets, a PNPLA3 intronic SNP, rs139051 A>G was identified as a significant eQTL ( = 6.6×10) influencing transcription, with the A allele significantly associated with increased PNPLA3 mRNA. An electrophoresis mobility shift assay further demonstrated that the A allele has enhanced affinity to nuclear proteins than the G allele. The impact of this eQTL on NAFLD risk was further tested in three independent populations. We found that rs139051 did not independently affect the NAFLD risk, whilst rs738409 did not significantly modulate transcription but was associated with NAFLD risk. The A-G haplotype associated with higher transcription of the disease-risk rs738409 G allele conferred similar risk for NAFLD compared to the G-G haplotype that possesses a lower transcription level. Our study suggests that the pathogenic role of in NAFLD is independent of the gene transcription in humans, which may be attributed to the high endogenous transcription level of gene in human livers.
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16 MeSH Terms
The Spectrum of Histologic Findings in Hepatic Outflow Obstruction.
Gonzalez RS, Gilger MA, Huh WJ, Washington MK
(2017) Arch Pathol Lab Med 141: 98-103
MeSH Terms: Adolescent, Adult, Aged, Budd-Chiari Syndrome, Capillaries, Child, Child, Preschool, Diagnosis, Differential, Female, Fibrosis, Heart Failure, Hepatic Veno-Occlusive Disease, Humans, Infant, Liver, Liver Diseases, Male, Middle Aged, Young Adult
Show Abstract · Added March 14, 2018
CONTEXT - -Cardiac hepatopathy and Budd-Chiari syndrome are 2 forms of hepatic venous outflow obstruction with different pathophysiology but overlapping histologic findings, including sinusoidal dilation and centrilobular necrosis.
OBJECTIVE - -To determine whether a constellation of morphologic findings could help distinguish between the 2 and could suggest the diagnoses in previously undiagnosed patients.
DESIGN - -We identified 26 specimens with a diagnosis of cardiac hepatopathy and 23 with a diagnosis of Budd-Chiari syndrome. Slides stained with hematoxylin and eosin and with trichrome were evaluated for several distinctive histologic findings.
RESULTS - -Features common to both forms of hepatic outflow obstruction included sinusoidal dilation and portal tract changes of fibrosis, chronic inflammation, and bile ductular reaction. Histologic findings significantly more common in cardiac hepatopathy included pericellular/sinusoidal fibrosis and fibrosis around the central vein. Only centrilobular hepatocyte dropout/necrosis was significantly more common in Budd-Chiari, regardless of duration.
CONCLUSIONS - -The finding of pericellular/sinusoidal fibrosis in cardiac hepatopathy compared with Budd-Chiari is not unexpected, given the chronic nature of most cardiac hepatopathy. Portal tract changes are common in both forms of hepatic outflow obstruction and should not deter one from making the diagnosis of hepatic outflow obstruction. Fibrosis along sinusoids and around the central vein may be suggestive of cardiac hepatopathy in biopsies from patients without a prior diagnosis.
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19 MeSH Terms
The effect of high intensity statin use on liver density: A post hoc analysis of the coronary artery calcification treatment with zocor [CATZ] study.
Sarkar S, Terry JG, Ikizler TA, Crouse JR, Carr JJ, Hung AM
(2016) Obes Res Clin Pract 10: 613-615
MeSH Terms: Adult, Aged, Coronary Artery Disease, Disease Progression, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Liver, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Plaque, Atherosclerotic, Radiography, Abdominal, Simvastatin, Tomography, X-Ray Computed, Treatment Outcome, Young Adult
Added September 29, 2016
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17 MeSH Terms
Nonalcoholic Fatty Liver Disease and Incident Cardiac Events: The Multi-Ethnic Study of Atherosclerosis.
Zeb I, Li D, Budoff MJ, Katz R, Lloyd-Jones D, Agatston A, Blumenthal RS, Blaha MJ, Blankstein R, Carr J, Nasir K
(2016) J Am Coll Cardiol 67: 1965-6
MeSH Terms: Age Distribution, Aged, Aged, 80 and over, Comorbidity, Coronary Artery Disease, Ethnic Groups, Female, Humans, Incidence, Kaplan-Meier Estimate, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Predictive Value of Tests, ROC Curve, Risk Assessment, Severity of Illness Index, Sex Distribution, United States
Added September 29, 2016
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19 MeSH Terms
Gestational Diabetes Mellitus Is Strongly Associated With Non-Alcoholic Fatty Liver Disease.
Ajmera VH, Gunderson EP, VanWagner LB, Lewis CE, Carr JJ, Terrault NA
(2016) Am J Gastroenterol 111: 658-64
MeSH Terms: Adult, Cohort Studies, Diabetes Complications, Diabetes, Gestational, Female, Humans, Middle Aged, Non-alcoholic Fatty Liver Disease, Pregnancy, Prevalence, Risk Factors, Time Factors, Young Adult
Show Abstract · Added September 29, 2016
OBJECTIVES - Insulin resistance is central to the development of non-alcoholic fatty liver disease (NAFLD), and gestational diabetes mellitus (GDM) is an early marker of insulin resistance. We hypothesized that a history of GDM would identify women at higher risk of NAFLD in middle age.
METHODS - Women from the multicenter Coronary Artery Risk Development in Young Adults (CARDIA) cohort study who delivered ≥1 birth, were free of diabetes prior to pregnancy(ies), and underwent CT quantification of hepatic steatosis 25 years following cohort entry (Y25: 2010-2011) were included (n=1,115). History of GDM by self-report, validated in a subsample by review of antenatal glucose testing, and metabolic risk factors were assessed prospectively. NAFLD was defined by liver attenuation (LA)≤40 Hounsfield Units on CT scan after exclusion of other causes of hepatic steatosis.
RESULTS - Of 1,115 women meeting selection criteria (57% black, 43% white, median age 25 years at baseline), 124 (11%) reported a history of GDM and 75 (7%) met the CT definition for NAFLD at year 25. The crude risk of NAFLD at the 25-year visit was significantly higher in women with GDM compared to those without (14 vs. 5.8%, OR: 2.56, 95% CI: 1.44-4.55, P<0.01). History of GDM remained associated with NAFLD (OR: 2.29, 95% CI: 1.23-4.27, P=0.01) after adjustment for covariates in multivariable logistic regression. Addition of incident diabetes mellitus (DM) into the final model attenuated the association between GDM and NAFLD (OR: 1.48, 95% CI: 0.73-3.02, P=0.28).
CONCLUSION - GDM is a risk marker for NAFLD and represents an opportunity to identify women at risk for NAFLD at a young age and may be mediated by the development of incident DM.
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13 MeSH Terms
A micro-RNA expression signature for human NAFLD progression.
Guo Y, Xiong Y, Sheng Q, Zhao S, Wattacheril J, Flynn CR
(2016) J Gastroenterol 51: 1022-30
MeSH Terms: Adult, Biomarkers, Carcinoma, Hepatocellular, Female, Gene Expression Profiling, Humans, Liver Neoplasms, Male, MicroRNAs, Middle Aged, Non-alcoholic Fatty Liver Disease, Obesity, RNA, Ribosomal, RNA, Small Nucleolar, RNA, Transfer, Severity of Illness Index
Show Abstract · Added February 15, 2016
BACKGROUND - The spectrum of nonalcoholic fatty liver disease (NAFLD) describes disease conditions deteriorating from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) to cirrhosis (CIR) to hepatocellular carcinoma (HCC). From a molecular and biochemical perspective, our understanding of the etiology of this disease is limited by the broad spectrum of disease presentations, the lack of a thorough understanding of the factors contributing to disease susceptibility, and ethical concerns related to repeat sampling of the liver. To better understand the factors associated with disease progression, we investigated by next-generation RNA sequencing the altered expression of microRNAs (miRNAs) in liver biopsies of class III obese subjects (body mass index ≥40 kg/m(2)) biopsied at the time of elective bariatric surgery.
METHODS - Clinical characteristics and unbiased RNA expression profiles for 233 miRs, 313 transfer RNAs (tRNAs), and 392 miscellaneous small RNAs (snoRNAs, snRNAs, rRNAs) were compared among 36 liver biopsy specimens stratified by disease severity.
RESULTS - The abundances of 3 miRNAs that were found to be differentially regulated (miR-301a-3p and miR-34a-5p increased and miR-375 decreased) with disease progression were validated by RT-PCR. No tRNAs or miscellaneous RNAs were found to be associated with disease severity. Similar patterns of increased miR-301a and decreased miR-375 expression were observed in 134 hepatocellular carcinoma (HCC) samples deposited in The Cancer Genome Atlas (TCGA).
CONCLUSIONS - Our analytical results suggest that NAFLD severity is associated with a specific pattern of altered hepatic microRNA expression that may drive the hallmark of this disorder: altered lipid and carbohydrate metabolism. The three identified miRNAs can potentially be used as biomarkers to access the severity of NAFLD. The persistence of this miRNA expression pattern in an external validation cohort of HCC samples suggests that specific microRNA expression patterns may permit and/or sustain NAFLD development to HCC.
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16 MeSH Terms