Non-alcoholic Fatty Liver Disease and Cardiovascular Disease Risk

doi:10.1007/S12170-009-0070-3

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Non-alcoholic Fatty Liver Disease and Cardiovascular Disease Risk

Journal Article•DOI•

Non-alcoholic Fatty Liver Disease and Cardiovascular Disease Risk

Giovanni Targher¹•Institutions (1)

University of Verona¹

06 Jan 2010-Current Cardiovascular Risk Reports (Current Science Inc.)-Vol. 4, Iss: 1, pp 32-39

TL;DR: NAFLD/NASH is not merely a marker of CVD, but may also be actively involved in its pathogenesis, possibly through the systemic release of proinflammatory/proatherogenic factors from the inflamed/steatotic liver as well as the contribution of NAFLD per se to whole-body insulin resistance and atherogenic dyslipidemia.

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Abstract: Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized cause of liver disease in the United States and worldwide. Increasing recognition of the importance of NAFLD and its strong relationship with the metabolic syndrome has stimulated an interest in the possible role of NAFLD in the development and progression of cardiovascular disease (CVD). Recent prospective studies demonstrated that NAFLD, especially in its necroinflammatory form (NASH), is linked to an increased risk of CVD, independently of obesity and other shared cardiometabolic risk factors. This suggests that NAFLD/NASH is not merely a marker of CVD, but may also be actively involved in its pathogenesis, possibly through the systemic release of proinflammatory/proatherogenic factors from the inflamed/steatotic liver as well as the contribution of NAFLD per se to whole-body insulin resistance and atherogenic dyslipidemia. Health care providers managing NAFLD patients should recognize this increased CVD risk and undertake early, aggressive risk factor modification.

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Journal Article•DOI•

Vitamin D deficiency in chronic liver disease

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Paula Iruzubieta, A Terán, Javier Crespo, Emilio Fábrega

27 Dec 2014-World Journal of Hepatology

TL;DR: It seems that the involvement of vitamin D in the activation and regulation of both innate and adaptive immune systems and its antiproliferative effect may explain its importance in these liver diseases.

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Abstract: Vitamin D is an important secosteroid hormone with known effect on calcium homeostasis, but recently there is increasing recognition that vitamin D also is involved in cell proliferation and differentiation, has immunomodulatory and anti-inflammatory properties. Vitamin D deficiency has been frequently reported in many causes of chronic liver disease and has been associated with the development and evolution of non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) virus infection. The role of vitamin D in the pathogenesis of NAFLD and CHC is not completely known, but it seems that the involvement of vitamin D in the activation and regulation of both innate and adaptive immune systems and its antiproliferative effect may explain its importance in these liver diseases. Published studies provide evidence for routine screening for hypovitaminosis D in patients with liver disease. Further prospectives studies demonstrating the impact of vitamin D replacement in NAFLD and CHC are required.

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86 citations

Journal Article•DOI•

Mechanisms Linking Nonalcoholic Fatty Liver Disease with Coronary Artery Disease

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W. Nseir¹, W. Nseir², A. Shalata, A. Marmor, Nimer Assy¹ - Show less +1 more•Institutions (2)

Technion – Israel Institute of Technology¹, Holy Family Hospital²

08 Jun 2011-Digestive Diseases and Sciences

TL;DR: Patients with NAFLD are at higher risk of cardiovascular risk and should undergo periodic cardiovascular risk assessment including the Framingham score, cardiac effort test, and measurement of intimae-media thickening of the carotids arteries, which may improve risk stratification for CAD.

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Abstract: The most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD) is coronary artery disease (CAD), not chronic liver disease. Fatty liver increases cardiovascular risk by classical (dyslipidemia, hypertension, diabetes) and by less conventional mechanisms. Common pathways involved in the pathogenesis of fatty liver and CAD includes hepatic insulin resistance and sub clinical inflammation. The hepatic insulin resistance state of fatty liver infiltration is characterized by increased FFA, which causes lipotoxicity and impairs endothelium-dependent vasodilatation, increases oxidative stress, and has a cardio toxic effect. Additional metabolic risk factors include leptin, adiponectin, pro inflammatory cytokines [such as IL-6, C-reactive protein and plasminogen activator inhibitor-1 (PAI-1)], which together lead to increased oxidative stress and endothelial dysfunction, finally promoting coronary artery disease (CAD). When classical risk factors are superimposed on fatty liver accumulation, they may further increase the new metabolic risk factors, exacerbating CAD. The clinical implication is that patients with NAFLD are at higher risk (steatohepatitis, diabetes, obesity, atherogenic dyslipidemia) and should undergo periodic cardiovascular risk assessment including the Framingham score, cardiac effort test, and measurement of intimae-media thickening of the carotids arteries. This may improve risk stratification for CAD.

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80 citations

Cites background from "Non-alcoholic Fatty Liver Disease a..."

...It is evident that patients with NASH are more prone to develop CAD (increase mortality by 86%) than patients with simple steatosis (increase mortality by 55%, [117]); however, it has not been clear until now whether the treatment of NAFLD patients will prevent CAD development....
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Journal Article•DOI•

Low 25-hydroxyvitamin D level is independently associated with non-alcoholic fatty liver disease.

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Kristen L. Jablonski¹, Anna Jovanovich¹, John Holmen², Giovanni Targher, Kimberly K. McFann¹, Jessica Kendrick¹, Michel Chonchol¹ - Show less +3 more•Institutions (2)

University of Colorado Denver¹, Intermountain Healthcare²

01 Aug 2013-Nutrition Metabolism and Cardiovascular Diseases

TL;DR: Compared with matched controls, patients with NAFLD have significantly decreased serum 25( OH)D levels, suggesting that low 25(OH)D status might play a role in the development and progression ofNAFLD.

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Abstract: Background and aims We sought to explore associations between serum 25-hydroxyvitamin D [25(OH)D] levels and non-alcoholic fatty liver disease [NAFLD] in an integrated healthcare delivery system in the U.S. Methods and results Six hundred and seven NAFLD cases were randomly matched 1:1 with controls for age, sex, race and season of measurement. Conditional logistic regression was used to evaluate if serum 25(OH)D levels were associated with increased odds of NAFLD (diagnosed by ultrasound) after adjusting for body mass index and history of diabetes, renal, peripheral vascular and liver diseases (model 1) and also for hypertension (model 2). Mean (SD) serum 25(OH)D level was significantly lower in the group with NAFLD as compared with that in the matched control group (75±17 vs. 85±20nmol/L [30±7 vs. 34±8ng/mL], P 30ng/mL], reference group), insufficient (37–75nmol/L [15–30ng/mL]; adjusted odds ratio [OR]: 2.40, 95% confidence interval [CI]: 0.90–6.34) or deficient ( 10 25(OH)D was inversely associated with the risk of prevalent NAFLD (adjusted OR: 0.25, 95% CI: 0.064–0.96, P =0.02). Conclusion Compared with matched controls, patients with NAFLD have significantly decreased serum 25(OH)D levels, suggesting that low 25(OH)D status might play a role in the development and progression of NAFLD.

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60 citations

Cites background from "Non-alcoholic Fatty Liver Disease a..."

...As these frequencies are largely based upon diagnosis by liver ultrasound, which is not (totally) sensitive when liver fat infiltration is <30% [5], the actual prevalence of NAFLD is likely even greater....
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...Indeed, chronic inflammation is considered a key factor in NAFLD progression [22,24], with the severity of the hepatic disease relating to both circulating and intra-hepatic mRNA expression of several pro-inflammatory factors [5]....
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...Systemic, chronic inflammation appears also to be central in the pathogenesis ofNAFLD, as itmaypromote thedevelopment of intra-hepatic necro-inflammation [5]....
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...Non-alcoholic fatty liver disease [NAFLD] has reached epidemic proportions in Western societies such as the United States, affecting approximately 20e30% of adults [1e3], with frequency increasing to approximately 70e80% in type 2 diabetes [4] andw90% in severe obesity [5]....
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Journal Article•DOI•

The utility of noninvasive scores in assessing the prevalence of nonalcoholic fatty liver disease and advanced fibrosis in type 1 diabetic patients.

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Amandeep Singh¹, Phuc Le¹, Rocio Lopez¹, Naim Alkhouri•Institutions (1)

Cleveland Clinic¹

09 Jan 2018-Hepatology International

TL;DR: In this large cohort of patients with T1DM, a high prevalence of hepatic steatosis and advanced fibrosis was detected using noninvasive scores, indicating a high risk of developing cirrhosis and end-stage liver disease.

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Abstract: The aim of our study is to assess the prevalence of nonalcoholic fatty liver disease (NAFLD) and advanced hepatic fibrosis in patients with type 1 diabetes (T1D) using simple noninvasive scores. There is paucity of data on the prevalence of NAFLD in T1D. Moreover, T1D could be a risk factor for advanced disease in NAFLD patients. Using ICD-9 codes, all patients with the diagnosis of T1D were reviewed and a retrospective chart analysis was carried out on 23,314 patients between the ages of 18 and 80. To predict the prevalence of NAFLD, we calculated the hepatic steatosis index (HSI). To estimate the prevalence of advanced fibrosis, NAFLD fibrosis score (NFS), FIB-4 index, AST to platelet ratio index (APRI), and AST/ALT ratio were calculated. Of the 4899 patients included in the analysis, 86.9% were Caucasian and 67% were above normal weight limit. NAFLD based on HSI > 36 was present in 71.3% of patients. Advanced fibrosis was present in 20.3% based on NFS > 0.676, 6.7% based on FIB-4 > 2.67, 2.1% based on APRI > 1.5, and 22.1% based on AST/ALT > 1.4%, indicating a high risk of developing cirrhosis and end-stage liver disease. In this large cohort of patients with T1DM, we detected a high prevalence of hepatic steatosis and advanced fibrosis using noninvasive scores. These scores are easy and inexpensive tools to screen for NAFLD and advanced fibrosis, although the significant variability of the percentage of advanced fibrosis using these scores indicates the need for further validation in diabetic populations. CCF-16-018.

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15 citations

Cites background from "Non-alcoholic Fatty Liver Disease a..."

...The clinicians who manage NAFLD should not only focus on liver disease but should also recognize the increased risk of extra-hepatic, especially CVD, complications [6, 11, 34]....
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Journal Article•DOI•

G004, a synthetic sulfonylurea compound, exerts anti-atherosclerosis effects by targeting SIRT1 in ApoE -/- mice

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Lifen Qian¹, Lingman Ma¹, Guanzhong Wu¹, Qian Yu¹, Huisheng Lin¹, Qidi Ying¹, Dan Wen¹, Cong Gao¹ - Show less +4 more•Institutions (1)

China Pharmaceutical University¹

01 Feb 2017-Vascular Pharmacology

TL;DR: The results indicated that G004 ameliorated the serum lipid accumulation, atherosclerotic lesions and liver steatosis and provided a strong rationale for G004 to be an efficient anti-atherosclerosis agent that improved vascular endothelial dysfunction by stimulating SIRT1/eNOS and promoted RCT by stimulated SIRT/LXRα/ABCA1/G1.

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12 citations

Cites background from "Non-alcoholic Fatty Liver Disease a..."

...A growing body of evidence shows that non-alcoholic fatty liver disease (NAFLD),manifested by various extents of TG accumulation in hepatocytes, is an important independent risk factor for developing atherosclerosis [31]....
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References

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Journal Article•DOI•

Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.

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Christi A. Matteoni, Zobair M. Younossi¹, Terry Gramlich¹, Navdeep Boparai¹, Yao Chang Liu¹, Arthur J. McCullough - Show less +2 more•Institutions (1)

Cleveland Clinic¹

01 Jun 1999-Gastroenterology

TL;DR: The outcome of cirrhosis and liver-related death is not uniform across the spectrum of nonalcoholic fatty liver, and poor outcomes are more frequent in patients in whom biopsies show ballooning degeneration and Mallory hyaline or fibrosis.

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3,167 citations

"Non-alcoholic Fatty Liver Disease a..." refers background in this paper

...In a community-based NAFLD cohort followed for 7.6 years, all-cause mortality, most commonly due to CVD and malignancy, was significantly higher than in the general population [24], and mortality rates from CVD were the second most common cause of death in 132 patients with biopsy-proven NAFLD followed up for 18 years, with rates equalling those of liver-related deaths [ 25 ]....
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Journal Article•DOI•

The Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study

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Leon A. Adams¹, James F. Lymp¹, Jenny St. Sauver¹, Schuyler O. Sanderson¹, Keith D. Lindor¹, Ariel E. Feldstein¹, Paul Angulo¹ - Show less +3 more•Institutions (1)

Mayo Clinic¹

01 Jul 2005-Gastroenterology

TL;DR: Mortality among community-diagnosed NAFLD patients is higher than the general population and is associated with older age, impaired fasting glucose, and cirrhosis, although the absolute risk is low.

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2,681 citations

"Non-alcoholic Fatty Liver Disease a..." refers background in this paper

...In a community-based NAFLD cohort followed for 7.6 years, all-cause mortality, most commonly due to CVD and malignancy, was significantly higher than in the general population [ 24 ], and mortality rates from CVD were the second most common cause of death in 132 patients with biopsy-proven NAFLD followed up for 18 years, with rates equalling those of liver-related deaths [25]....
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Journal Article•DOI•

Mechanisms linking obesity with cardiovascular disease

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Luc Van Gaal¹, Ilse Mertens¹, Christophe De Block¹•Institutions (1)

University of Antwerp¹

14 Dec 2006-Nature

TL;DR: The underlying mechanisms as well as the ways in which smoking and dyslipidaemia increase, and physical activity attenuates, the adverse effects of obesity on cardiovascular health are beginning to be understood.

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Abstract: Obesity increases the risk of cardiovascular disease and premature death. Adipose tissue releases a large number of bioactive mediators that influence not only body weight homeostasis but also insulin resistance - the core feature of type 2 diabetes - as well as alterations in lipids, blood pressure, coagulation, fibrinolysis and inflammation, leading to endothelial dysfunction and atherosclerosis. We are now beginning to understand the underlying mechanisms as well as the ways in which smoking and dyslipidaemia increase, and physical activity attenuates, the adverse effects of obesity on cardiovascular health.

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2,541 citations

"Non-alcoholic Fatty Liver Disease a..." refers background in this paper

...In fact, ectopic fat deposition is a source of multiple factors potentially involved in the atherogenesis, such as free fatty acids, hormones, proinflammatory cytokines, and adipocytokines [38]....
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...Interleukin (IL)-6 and tumour necrosis factor (TNF)-α are the major stimuli responsible for increased hepatic production of C-reactive protein (CRP), fibrinogen, and other acute-phase proteins [38]....
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Journal Article•DOI•

Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome

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Giulio Marchesini¹, Elisabetta Bugianesi², Gabriele Forlani¹, Fernanda Cerrelli¹, Marco Lenzi¹, R. Manini¹, S. Natale¹, Ester Vanni², Nicola Villanova¹, Nazario Melchionda¹, Mario Rizzetto² - Show less +7 more•Institutions (2)

University of Bologna¹, University of Turin²

01 Apr 2003-Hepatology

TL;DR: The presence of multiple metabolic disorders is associated with a potentially progressive, severe liver disease and the increasing prevalence of obesity, coupled with diabetes, dyslipidemia, hypertension, and ultimately the metabolic syndrome puts a very large population at risk of forthcoming liver failure in the next decades.

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2,538 citations

"Non-alcoholic Fatty Liver Disease a..." refers background in this paper

...Even in the absence of obesity and type 2 diabetes, NAFLD is strongly associated with other components of the metabolic syndrome [1–3•], with one study of nondiabetic patients with NAFLD reporting that approximately 20% of non-obese patients and approximately 70% of overweight patients fulfilled criteria for diagnosing the metabolic syndrome [5]....
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Journal Article•DOI•

Long-term follow-up of patients with NAFLD and elevated liver enzymes.

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Mattias Ekstedt¹, Lennart Franzén, Ulrik Mathiesen, Lars Thorelius, Marika Holmqvist, Göran Bodemar¹, Stergios Kechagias¹ - Show less +3 more•Institutions (1)

Linköping University¹

01 Oct 2006-Hepatology

TL;DR: It is concluded that nonalcoholic fatty liver disease with elevated liver enzymes is associated with a clinically significant risk of developing end‐stage liver disease and Survival is lower in patients with NASH, and most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term.

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2,149 citations

"Non-alcoholic Fatty Liver Disease a..." refers result in this paper

...[26] found that the 14-year risk of CVD mortality was doubled in 129 patients with biopsy-proven NASH, compared with that in the reference population....
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