T h e In t e r a c t i o n s o f N o n a l c o h o l i c Fatty Liver Disease and C a rd i o v a s c u l a r Di s e a s e s Hugo Perazzo, MDa,b, Thierry Poynard, Jean-François Dufour, MDd,e,*
MD, PhD
a,b,c
,
KEYWORDS Nonalcoholic fatty liver disease Liver fibrosis Cardiovascular disease Atherosclerosis Insulin resistance KEY POINTS Patients with nonalcoholic fatty liver disease present higher overall mortality, and cardiovascular disease is one of the leading causes of death. Individuals with fatty liver presented higher carotid and coronary plaques measured by surrogate markers of atherosclerosis. NAFLD is associated with new onset of cardiovascular events independently of confounding factors. A complex interaction among metabolic factors, adipose tissue lipolysis, insulin resistance, and excessive free fatty acids results in an inflammatory state, hypercoagulability, and endothelial dysfunction, which might explain the association between NAFLD and cardiovascular disease.
Funding Source: This study was supported by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n Health-F2-2009-241762, for the project FLIP; the Institute of Cardiometabolism and Nutrition (ICAN) funded by MESR 2011-2016 and the Association pour la Recherche sur les Maladies He´patiques Virales (ARMHV). These sponsors played no role in the interpretation of data. Conflict of Interest Statement: The authors have nothing to disclose related to this topic. a Hepatology Department, Liver Center, Groupe Hospitalier Pitie´-Salpeˆtrie`re (GHPS), Assistance Publique Hoˆpitaux de Paris (APHP), 47-83, Boulevard de l’Hoˆpital, Paris 75013, France; b Pierre et Marie Curie University (Paris 6), Inserm UMR_S 938, Paris, France; c Institute of Cardiometabolism and Nutrition (ICAN), Paris, France; d University Clinic for Visceral Surgery and Medicine, University of Bern, Inselspital, Freiburgstrasse, Bern 3010, Switzerland; e Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland * Corresponding author. University Clinic for Visceral Surgery and Medicine, University of Bern, Inselspital, Freiburgstrasse, Bern 3010, Switzerland. E-mail address: [email protected] Clin Liver Dis 18 (2014) 233–248 http://dx.doi.org/10.1016/j.cld.2013.09.014 1089-3261/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
liver.theclinics.com
234
Perazzo et al
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide.1 This liver disease is characterized by presence of fat accumulation in at least 5% of hepatocytes without others causes of chronic liver disease, including alcohol-induced and drug-induced liver disease, autoimmune or viral hepatitis, and cholestatic or genetic liver disease.2 NAFLD presents a large clinical spectrum, ranging from simple steatosis to coexistent hepatocyte injury, nonalcoholic steatohepatitis (NASH), associated with fibrosis and cirrhosis and its complications.3,4 Simple steatosis usually presents a benign course; however, patients who progress to NASH may develop cirrhosis and suffer from liver-related mortality.5,6 Patients with NAFLD usually present metabolic syndrome and its components, common risk factors for cardiovascular disease (CVD).7 More recently, some studies have reported a close relationship between NAFLD and increased atherosclerosis.8 This review focuses on the association between NAFLD and CVD, discussing the data linking these major diseases and the likely mechanisms underlying this interaction. NAFLD AND SURROGATE MARKERS OF ATHEROSCLEROSIS
NAFLD might play an important role in the atherosclerosis complex process, reinforcing the relationship between fatty liver and CVD.9 Several studies have reported the association of NAFLD with surrogate markers of atherosclerosis as presence of carotid and coronary plaques and cardiac dysfunction. Cardiac multislice computed tomography accurately assesses coronary plaques.10 This method calculates the coronary artery calcium (CAC) score, which reflects the underlying total plaque burden that accurately correlates to increased risk of coronary events.11,12 Individuals with NAFLD presented higher calcified and noncalcified plaques compared with matched controls. In addition, the presence of fatty liver was predictive of coronary artery disease (CAD) after adjustment for confounding factors.13 Studies have reported a strong relationship between NAFLD and CAC score.14,15 Increased CAC score was significantly associated with NAFLD independently of metabolic factors, including visceral adiposity.14 Furthermore, a study reported a strong association between NAFLD and presence of vulnerable plaques, increasing the risk of severe CV outcomes.16 Measurement of carotid intima-media thickness (CIMT) and plaque by ultrasonography is a validated method for diagnosing early atherosclerosis and prediction of CVD.17,18 Several studies have associated carotid with NAFLD independently of components of the metabolic syndrome.19–22 A systematic review involving 3497 individuals (7 studies) strongly correlated CIMT with fatty liver, showing an increase of up to 13% of CIMT and higher prevalence of plaques in patient with NAFLD.23 Furthermore, a study reported that severity of histologic features seems to correlates with CIMT, agreeing with the hypothesis that patients with NASH carry a higher risk of CVD than individuals with simple steatosis.24 A few studies have reported the relationship between NAFLD and cardiac dysfunction. Increased cardiac left ventricular (LV) mass index and diastolic dysfunction were associated with NAFLD.25,26 Hallsworth and colleagues27 described significant changes in cardiac structure and function in NAFLD patients with NAFLD compared with an age-matched, sex-matched, and body mass index (BMI)-matched healthy population. In this study, patients with NAFLD presented thicker LV walls at systole and diastole as well as higher peak whole wall and peak endocardial circumferential strain. Fallo and colleagues28 also reported a positive correlation between diastolic cardiac dysfunction and severity of fatty liver disease. Yilmaz and colleagues29 reported a reduced coronary flow reserve, measured by echocardiography, in patients
Interactions of NAFLD and Cardiovascular Diseases
with NAFLD compared with matched controls independently of common metabolic factors. In this study, histologic liver fibrosis was predictive of impaired coronary flow reserve. Furthermore, NAFLD was also associated with increased risk of cardiac arrhythmia. Targher and colleagues30,31 reported an increased incidence of atrial fibrillation in type 2 diabetic patients with NAFLD defined by ultrasonography followed for a long-term. NAFLD AND MORTALITY
Published data have shown that presence of NAFLD seems to be associated with higher mortality than in the general population, mainly as a result of CVD. In a community-based cohort, Adams and colleagues32 reported that NAFLD increased in 34% of the cohort the risk of overall mortality compared with the general population. Ong and colleagues33 reported that NAFLD was independently associated with overall and liver-related mortality in a representative sample of the US population. Dunn and colleagues34 confirmed previous results and showed that presence of NAFLD was associated with cardiovascular (CV)-related death in a subgroup of patients aged from 45 to 54 years. So¨derberg and colleagues35 reported an increase between 70% and 86% on the risk of overall mortality in presence of NAFLD or NASH compared with the general population in a long-term follow-up. In type 2 diabetic patients, Adams and colleagues36 described NAFLD as a factor independent of overall mortality but not related to specific CV death. However, a recent US, adult population-based prospective cohort study reported no relationship between NAFLD and overall or specific death.37 Stepenova and Younossi38 described higher CVrelated death in patients with NAFLD compared with patients who did not have NAFLD. However, the presence of NAFLD was not predictive of CV death. The role of noninvasive markers was also evaluated in the prediction of mortality in patients with NAFLD. Fatty liver index (FLI) is a validated surrogate marker of steatosis that uses triglyceride level, BMI, waist circumference, and g-glutamyltransferase (GGT) to estimate liver steatosis.39 Despite borderline hazard ratios, NAFLD defined as per the FLI was independently associated with overall, liver-related, and CV-related death.40 In NAFLD defined by ultrasonography, Kim and colleagues41 reported no association between NAFLD and overall mortality. However, in this cohort, patients with NAFLD with advanced fibrosis presumed by noninvasive methods, such as NAFLD fibrosis score (NFS),42 aspartate aminotransferase to platelet ratio index (APRI),43 and FIB-444 score presented higher risk of overall and CV-related death. More recently, Angulo and colleagues45 confirmed these results in 320 patients with NAFLD proved by biopsy in a multicenter international trial. In this study, patients with advanced fibrosis, estimated by the same noninvasive markers, presented an increased risk for liver-related complications and death. These results confirm that presence of fibrosis should be implicated in increased overall and specific mortality. CVD was described as one of the leading causes of death in most population-based studies.32–34,46 Targher and colleagues47 showed that NAFLD was associated with CV-related death in an Italian population after adjustment for metabolic confounding factors. Rafiq and colleagues4 reported CVD as the most frequent cause of death in 173 patients with NAFLD proved by biopsy followed for 13 years. In addition, these investigators described higher overall mortality in patients with NASH and those with NAFLD associated with type 2 diabetes mellitus. Despite a similar overall survival of patients with NAFLD compared with an age-matched and gender-matched control group, Ekstedt and colleagues48 reported a 2-fold higher 14-year risk of CV-related death in patients with NASH. More recently, Stepanova and colleagues49 described
235
236
Perazzo et al
that CVD remains as the leading cause of death among biopsy-proven NAFLD. However, they have not found significant difference in mortality between patients with NASH and those who do not have NASH, suggesting that the presence of hepatic steatosis, rather than the necroinflammatory features, might be the main risk factor of CV death.49 Table 1 summarizes the main prospective studies that reported NAFLD and mortality. Published data on long-term mortality suggest that NAFLD is significantly associated with a higher risk of overall mortality. In addition, CVD is one of the main causes of death in this population. The specific mortality risks attributable to CVD events and to liver-related events are unknown. Further prospective studies should be conducted to establish the real relationship between CV-related death and presence of liver injury features. In NAFLD, the 3 main features are fibrosis, the main cause of liver-related mortality, but also steatosis and necroinflammatory activity. NAFLD AND CV EVENTS
Type 2 diabetes, insulin resistance (IR), dyslipidemia, and obesity are common risk factors for NAFLD and CVD. Several studies have evaluated whether NAFLD is associated with CVD as a consequence of shared risk factors or whether this disease can actively contribute to CV events independently of these factors (Table 2). A second point is whether CVD represents a risk in simple steatosis or whether necroinflammatory liver injury (ie, NASH) must be present to trigger the atherosclerosis process. The impact of the metabolic syndrome components as confounding factors on ischemic heart disease remains unclear.50 However, some studies have associated NAFLD and CVD independently of metabolic risk factors.51,52 Several studies reported an association between NAFLD and CVD using liver enzymes as fatty liver markers. In a cohort of 163944 Austrian adults, increased GGT levels were associated with CVD mortality. This study also showed a clear doseresponse relationship between this liver enzyme and severe CV outcome: CVD death was increased by 66% and 64% per log unit of GGT in men and women, respectively.53 Lee and colleagues54,55 reported similar results in the association of high GGT levels with fatal and nonfatal CVD independently of metabolic risk factors and alcohol consumption. A meta-analysis pooling 10 studies56 confirmed these previous results regarding GGT and CVD. A few studies also reported the association of increased alanine aminotransferase (ALT) levels and CVD.34,57,58 The major limits of these studies are that GGT and ALT are not specific biomarkers of steatosis, necroinflammatory injury, or fibrosis. In a community-based cohort of healthy adults,59 the presence of NAFLD, as per imaging methods, was significantly associated with an increased risk of CV-related events such as myocardial infarction, unstable angina, and ischemic stroke. The presence of NAFLD was also associated with new CV events in type 2 diabetic patients independently of confounding factors.47 CAD prevalence was higher in patients with NAFLD undergoing coronary angiography compared with the general population, independently of components of the metabolic syndrome.60 In addition, CAD was more prevalent in NASH-cirrhotic patients compared with patients with cirrhosis from other causes.61 Wong and colleagues62 confirmed the relationship between NAFLD and CAD independently of common metabolic factors. However, in this study, fatty liver was not predictive of new CV events in patients with established CVD. More recently Stepanova and Younossi38 studied a US sample population and showed that CVD was significantly more prevalent in individuals with fatty liver and NAFLD was associated with CV events independently of metabolic risk factors.
Table 1 Main studies that have reported relationship between NAFLD and mortality n
Study Population
NAFLD Criteria
CVD Criteria
Design
Main Results (95% Confidence Interval)
Adams et al,32 2005
480
Population-based cohort (United States)
Imaging or liver biopsy
Death certificates
Prospective (FU 7.6 y)
CVD second death cause; higher overall mortality (SMR 1.34 [1.003–1.76]; P 5 .03) in patients with NAFLD compared with general population
Adams et al,36 2010
337
T2DM population (United States)
Ultrasonography or liver biopsy
Death certificates
Prospective (FU 11 y)
NAFLD increased the risk of overall mortality (HR 2.2 [1.1–4.2]; P 5 .03), but not the CV death (HR 0.9 [0.3–2.4]; P 5 .81)
Ekstedt et al,48 2006
129
Patients with NAFLD with ELF (Sweden)
Liver biopsy
Registry of death
Prospective (FU 13.7 y)
Survival similar to a matched population. Mortality was not increased in simple steatosis. Patients with NASH died most from CV and liver
Rafiq et al,4 2009
173
Patients with NAFLD (United States)
Liver biopsy
Registry of death
Prospective (FU 13 y)
CVD leading death cause. Similar overall mortality for NASH and non-NASH; liver death was higher in NASH; overall and liver death was higher in patients with NAFLD with T2DM
Soderberg et al,35 2010
256
Patients with ELF (Sweden)
Liver biopsy
Registry of death
Prospective (FU 24 y)
CVD leading death cause; NAFLD (SMR 1.69 [1.24–2.25]) and NASH (SMR 1.86 [1.19–2.76]) higher overall mortality compared with matched controls
Lazo et al,37 2011
11,371
Population-based cohort (United States)
Ultrasonography
Registry of death
Prospective (FU 14.5 y)
NAFLD was not related to overall (HR 0.92 [(0.67–1.09]), CV (HR 0.86 [0.67–1.12]), or liver mortality (HR 0.64 [0.12–3.59])
Dunn et al,34 2008
7574
Population-based cohort (United States)
ELF, imaging, or liver biopsy
Registry of death
Prospective (FU 8.7 y)
NAFLD higher overall mortality (HR 1.37 [0.98–1.91]; P 5 .067); in ages 45–54 y NAFLD related to CV death (HR 8.43 [2.43–22.72]) (continued on next page)
Interactions of NAFLD and Cardiovascular Diseases
Reference
237
238
Reference
n
Study Population
NAFLD Criteria
CVD Criteria
Design
Main Results (95% Confidence Interval)
Ong et al,33 2008
11,285
Population-based cohort (United States)
Ultrasonography
Registry of death
Prospective (FU 8.7 y)
NAFLD: higher risk of overall (HR 1.038 [1.036–1.041]); P
MD, PhD
a,b,c
,
KEYWORDS Nonalcoholic fatty liver disease Liver fibrosis Cardiovascular disease Atherosclerosis Insulin resistance KEY POINTS Patients with nonalcoholic fatty liver disease present higher overall mortality, and cardiovascular disease is one of the leading causes of death. Individuals with fatty liver presented higher carotid and coronary plaques measured by surrogate markers of atherosclerosis. NAFLD is associated with new onset of cardiovascular events independently of confounding factors. A complex interaction among metabolic factors, adipose tissue lipolysis, insulin resistance, and excessive free fatty acids results in an inflammatory state, hypercoagulability, and endothelial dysfunction, which might explain the association between NAFLD and cardiovascular disease.
Funding Source: This study was supported by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n Health-F2-2009-241762, for the project FLIP; the Institute of Cardiometabolism and Nutrition (ICAN) funded by MESR 2011-2016 and the Association pour la Recherche sur les Maladies He´patiques Virales (ARMHV). These sponsors played no role in the interpretation of data. Conflict of Interest Statement: The authors have nothing to disclose related to this topic. a Hepatology Department, Liver Center, Groupe Hospitalier Pitie´-Salpeˆtrie`re (GHPS), Assistance Publique Hoˆpitaux de Paris (APHP), 47-83, Boulevard de l’Hoˆpital, Paris 75013, France; b Pierre et Marie Curie University (Paris 6), Inserm UMR_S 938, Paris, France; c Institute of Cardiometabolism and Nutrition (ICAN), Paris, France; d University Clinic for Visceral Surgery and Medicine, University of Bern, Inselspital, Freiburgstrasse, Bern 3010, Switzerland; e Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland * Corresponding author. University Clinic for Visceral Surgery and Medicine, University of Bern, Inselspital, Freiburgstrasse, Bern 3010, Switzerland. E-mail address: [email protected] Clin Liver Dis 18 (2014) 233–248 http://dx.doi.org/10.1016/j.cld.2013.09.014 1089-3261/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
liver.theclinics.com
234
Perazzo et al
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide.1 This liver disease is characterized by presence of fat accumulation in at least 5% of hepatocytes without others causes of chronic liver disease, including alcohol-induced and drug-induced liver disease, autoimmune or viral hepatitis, and cholestatic or genetic liver disease.2 NAFLD presents a large clinical spectrum, ranging from simple steatosis to coexistent hepatocyte injury, nonalcoholic steatohepatitis (NASH), associated with fibrosis and cirrhosis and its complications.3,4 Simple steatosis usually presents a benign course; however, patients who progress to NASH may develop cirrhosis and suffer from liver-related mortality.5,6 Patients with NAFLD usually present metabolic syndrome and its components, common risk factors for cardiovascular disease (CVD).7 More recently, some studies have reported a close relationship between NAFLD and increased atherosclerosis.8 This review focuses on the association between NAFLD and CVD, discussing the data linking these major diseases and the likely mechanisms underlying this interaction. NAFLD AND SURROGATE MARKERS OF ATHEROSCLEROSIS
NAFLD might play an important role in the atherosclerosis complex process, reinforcing the relationship between fatty liver and CVD.9 Several studies have reported the association of NAFLD with surrogate markers of atherosclerosis as presence of carotid and coronary plaques and cardiac dysfunction. Cardiac multislice computed tomography accurately assesses coronary plaques.10 This method calculates the coronary artery calcium (CAC) score, which reflects the underlying total plaque burden that accurately correlates to increased risk of coronary events.11,12 Individuals with NAFLD presented higher calcified and noncalcified plaques compared with matched controls. In addition, the presence of fatty liver was predictive of coronary artery disease (CAD) after adjustment for confounding factors.13 Studies have reported a strong relationship between NAFLD and CAC score.14,15 Increased CAC score was significantly associated with NAFLD independently of metabolic factors, including visceral adiposity.14 Furthermore, a study reported a strong association between NAFLD and presence of vulnerable plaques, increasing the risk of severe CV outcomes.16 Measurement of carotid intima-media thickness (CIMT) and plaque by ultrasonography is a validated method for diagnosing early atherosclerosis and prediction of CVD.17,18 Several studies have associated carotid with NAFLD independently of components of the metabolic syndrome.19–22 A systematic review involving 3497 individuals (7 studies) strongly correlated CIMT with fatty liver, showing an increase of up to 13% of CIMT and higher prevalence of plaques in patient with NAFLD.23 Furthermore, a study reported that severity of histologic features seems to correlates with CIMT, agreeing with the hypothesis that patients with NASH carry a higher risk of CVD than individuals with simple steatosis.24 A few studies have reported the relationship between NAFLD and cardiac dysfunction. Increased cardiac left ventricular (LV) mass index and diastolic dysfunction were associated with NAFLD.25,26 Hallsworth and colleagues27 described significant changes in cardiac structure and function in NAFLD patients with NAFLD compared with an age-matched, sex-matched, and body mass index (BMI)-matched healthy population. In this study, patients with NAFLD presented thicker LV walls at systole and diastole as well as higher peak whole wall and peak endocardial circumferential strain. Fallo and colleagues28 also reported a positive correlation between diastolic cardiac dysfunction and severity of fatty liver disease. Yilmaz and colleagues29 reported a reduced coronary flow reserve, measured by echocardiography, in patients
Interactions of NAFLD and Cardiovascular Diseases
with NAFLD compared with matched controls independently of common metabolic factors. In this study, histologic liver fibrosis was predictive of impaired coronary flow reserve. Furthermore, NAFLD was also associated with increased risk of cardiac arrhythmia. Targher and colleagues30,31 reported an increased incidence of atrial fibrillation in type 2 diabetic patients with NAFLD defined by ultrasonography followed for a long-term. NAFLD AND MORTALITY
Published data have shown that presence of NAFLD seems to be associated with higher mortality than in the general population, mainly as a result of CVD. In a community-based cohort, Adams and colleagues32 reported that NAFLD increased in 34% of the cohort the risk of overall mortality compared with the general population. Ong and colleagues33 reported that NAFLD was independently associated with overall and liver-related mortality in a representative sample of the US population. Dunn and colleagues34 confirmed previous results and showed that presence of NAFLD was associated with cardiovascular (CV)-related death in a subgroup of patients aged from 45 to 54 years. So¨derberg and colleagues35 reported an increase between 70% and 86% on the risk of overall mortality in presence of NAFLD or NASH compared with the general population in a long-term follow-up. In type 2 diabetic patients, Adams and colleagues36 described NAFLD as a factor independent of overall mortality but not related to specific CV death. However, a recent US, adult population-based prospective cohort study reported no relationship between NAFLD and overall or specific death.37 Stepenova and Younossi38 described higher CVrelated death in patients with NAFLD compared with patients who did not have NAFLD. However, the presence of NAFLD was not predictive of CV death. The role of noninvasive markers was also evaluated in the prediction of mortality in patients with NAFLD. Fatty liver index (FLI) is a validated surrogate marker of steatosis that uses triglyceride level, BMI, waist circumference, and g-glutamyltransferase (GGT) to estimate liver steatosis.39 Despite borderline hazard ratios, NAFLD defined as per the FLI was independently associated with overall, liver-related, and CV-related death.40 In NAFLD defined by ultrasonography, Kim and colleagues41 reported no association between NAFLD and overall mortality. However, in this cohort, patients with NAFLD with advanced fibrosis presumed by noninvasive methods, such as NAFLD fibrosis score (NFS),42 aspartate aminotransferase to platelet ratio index (APRI),43 and FIB-444 score presented higher risk of overall and CV-related death. More recently, Angulo and colleagues45 confirmed these results in 320 patients with NAFLD proved by biopsy in a multicenter international trial. In this study, patients with advanced fibrosis, estimated by the same noninvasive markers, presented an increased risk for liver-related complications and death. These results confirm that presence of fibrosis should be implicated in increased overall and specific mortality. CVD was described as one of the leading causes of death in most population-based studies.32–34,46 Targher and colleagues47 showed that NAFLD was associated with CV-related death in an Italian population after adjustment for metabolic confounding factors. Rafiq and colleagues4 reported CVD as the most frequent cause of death in 173 patients with NAFLD proved by biopsy followed for 13 years. In addition, these investigators described higher overall mortality in patients with NASH and those with NAFLD associated with type 2 diabetes mellitus. Despite a similar overall survival of patients with NAFLD compared with an age-matched and gender-matched control group, Ekstedt and colleagues48 reported a 2-fold higher 14-year risk of CV-related death in patients with NASH. More recently, Stepanova and colleagues49 described
235
236
Perazzo et al
that CVD remains as the leading cause of death among biopsy-proven NAFLD. However, they have not found significant difference in mortality between patients with NASH and those who do not have NASH, suggesting that the presence of hepatic steatosis, rather than the necroinflammatory features, might be the main risk factor of CV death.49 Table 1 summarizes the main prospective studies that reported NAFLD and mortality. Published data on long-term mortality suggest that NAFLD is significantly associated with a higher risk of overall mortality. In addition, CVD is one of the main causes of death in this population. The specific mortality risks attributable to CVD events and to liver-related events are unknown. Further prospective studies should be conducted to establish the real relationship between CV-related death and presence of liver injury features. In NAFLD, the 3 main features are fibrosis, the main cause of liver-related mortality, but also steatosis and necroinflammatory activity. NAFLD AND CV EVENTS
Type 2 diabetes, insulin resistance (IR), dyslipidemia, and obesity are common risk factors for NAFLD and CVD. Several studies have evaluated whether NAFLD is associated with CVD as a consequence of shared risk factors or whether this disease can actively contribute to CV events independently of these factors (Table 2). A second point is whether CVD represents a risk in simple steatosis or whether necroinflammatory liver injury (ie, NASH) must be present to trigger the atherosclerosis process. The impact of the metabolic syndrome components as confounding factors on ischemic heart disease remains unclear.50 However, some studies have associated NAFLD and CVD independently of metabolic risk factors.51,52 Several studies reported an association between NAFLD and CVD using liver enzymes as fatty liver markers. In a cohort of 163944 Austrian adults, increased GGT levels were associated with CVD mortality. This study also showed a clear doseresponse relationship between this liver enzyme and severe CV outcome: CVD death was increased by 66% and 64% per log unit of GGT in men and women, respectively.53 Lee and colleagues54,55 reported similar results in the association of high GGT levels with fatal and nonfatal CVD independently of metabolic risk factors and alcohol consumption. A meta-analysis pooling 10 studies56 confirmed these previous results regarding GGT and CVD. A few studies also reported the association of increased alanine aminotransferase (ALT) levels and CVD.34,57,58 The major limits of these studies are that GGT and ALT are not specific biomarkers of steatosis, necroinflammatory injury, or fibrosis. In a community-based cohort of healthy adults,59 the presence of NAFLD, as per imaging methods, was significantly associated with an increased risk of CV-related events such as myocardial infarction, unstable angina, and ischemic stroke. The presence of NAFLD was also associated with new CV events in type 2 diabetic patients independently of confounding factors.47 CAD prevalence was higher in patients with NAFLD undergoing coronary angiography compared with the general population, independently of components of the metabolic syndrome.60 In addition, CAD was more prevalent in NASH-cirrhotic patients compared with patients with cirrhosis from other causes.61 Wong and colleagues62 confirmed the relationship between NAFLD and CAD independently of common metabolic factors. However, in this study, fatty liver was not predictive of new CV events in patients with established CVD. More recently Stepanova and Younossi38 studied a US sample population and showed that CVD was significantly more prevalent in individuals with fatty liver and NAFLD was associated with CV events independently of metabolic risk factors.
Table 1 Main studies that have reported relationship between NAFLD and mortality n
Study Population
NAFLD Criteria
CVD Criteria
Design
Main Results (95% Confidence Interval)
Adams et al,32 2005
480
Population-based cohort (United States)
Imaging or liver biopsy
Death certificates
Prospective (FU 7.6 y)
CVD second death cause; higher overall mortality (SMR 1.34 [1.003–1.76]; P 5 .03) in patients with NAFLD compared with general population
Adams et al,36 2010
337
T2DM population (United States)
Ultrasonography or liver biopsy
Death certificates
Prospective (FU 11 y)
NAFLD increased the risk of overall mortality (HR 2.2 [1.1–4.2]; P 5 .03), but not the CV death (HR 0.9 [0.3–2.4]; P 5 .81)
Ekstedt et al,48 2006
129
Patients with NAFLD with ELF (Sweden)
Liver biopsy
Registry of death
Prospective (FU 13.7 y)
Survival similar to a matched population. Mortality was not increased in simple steatosis. Patients with NASH died most from CV and liver
Rafiq et al,4 2009
173
Patients with NAFLD (United States)
Liver biopsy
Registry of death
Prospective (FU 13 y)
CVD leading death cause. Similar overall mortality for NASH and non-NASH; liver death was higher in NASH; overall and liver death was higher in patients with NAFLD with T2DM
Soderberg et al,35 2010
256
Patients with ELF (Sweden)
Liver biopsy
Registry of death
Prospective (FU 24 y)
CVD leading death cause; NAFLD (SMR 1.69 [1.24–2.25]) and NASH (SMR 1.86 [1.19–2.76]) higher overall mortality compared with matched controls
Lazo et al,37 2011
11,371
Population-based cohort (United States)
Ultrasonography
Registry of death
Prospective (FU 14.5 y)
NAFLD was not related to overall (HR 0.92 [(0.67–1.09]), CV (HR 0.86 [0.67–1.12]), or liver mortality (HR 0.64 [0.12–3.59])
Dunn et al,34 2008
7574
Population-based cohort (United States)
ELF, imaging, or liver biopsy
Registry of death
Prospective (FU 8.7 y)
NAFLD higher overall mortality (HR 1.37 [0.98–1.91]; P 5 .067); in ages 45–54 y NAFLD related to CV death (HR 8.43 [2.43–22.72]) (continued on next page)
Interactions of NAFLD and Cardiovascular Diseases
Reference
237
238
Reference
n
Study Population
NAFLD Criteria
CVD Criteria
Design
Main Results (95% Confidence Interval)
Ong et al,33 2008
11,285
Population-based cohort (United States)
Ultrasonography
Registry of death
Prospective (FU 8.7 y)
NAFLD: higher risk of overall (HR 1.038 [1.036–1.041]); P
