Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease

Table 2 Main prospective studies relating non-alcoholic fatty liver disease to increased risk of incident coronary heart disease or cardiovascular events, ordered by methodology used for the diagnosis of non-alcoholic fatty liver disease

Ref.	Study characteristics	Years of follow-up	NAFLD diagnosis	Study outcomes	Main findings
Fraser et al[47], 2007	Meta-analysis of 10 population-based cohort studies	7.3	Liver enzymes	Fatal and non-fatal CVD events	Elevated serum GGT level was associated with increased incidence of CVD events, independently of alcohol intake and traditional CVD risk factors
Schindhelm et al[48], 2007	Population-based cohort, n = 1439 subjects (Hoorn Study)	10.0	Liver enzymes	Fatal and non-fatal CHD events	Elevated serum ALT level was associated with CHD events, independently of the MetS and traditional CVD risk factors
Goessling et al[49], 2008	Community-based cohort, n = 2812 (Framingham Offspring Heart Study)	20.0	Liver enzymes	Fatal and non-fatal CVD events	Elevated serum ALT level was not associated with CVD events at multivariate analyses
Dunn et al[50], 2008	Population-based cohort, n = 7574 (NHANES-III)	8.7	Liver enzymes	All-cause and cause- specific mortality	Increased all-cause and CVD mortality rates in NAFLD but only in 45-54 year age group, independently of conventional CVD risk factors and C-reactive protein
Ong et al[51], 2008	Population-based cohort, n = 11285 subjects (NHANES-III)	8.7	Liver enzymes	All-cause and cause- specific mortality	Increased rates of all-cause, CVD and liver-related mortality in NAFLD. Liver disease was the third leading cause of death among persons with NAFLD after CVD and cancer-related mortality
Ruhl et al[52], 2009	Population-based cohort, n = 14950 (NHANES-III)	8.8	Liver enzymes	All-cause and cause- specific mortality	Elevated serum GGT level was associated with mortality from all causes, liver disease but not from CVD causes. Serum ALT level was associated only with liver disease mortality
Yun et al[53], 2009	Community-based cohort, n = 37085 (Health Promotion Center)	5.0	Liver enzymes	CVD or diabetes-related mortality	Elevated serum ALT level was independently associated with increased CVD or diabetes-related mortality
Calori et al[54], 2011	Community based-cohort, n = 2074 (Cremona study)	15.0	FLI index	All-cause and cause- specific mortality	FLI was independently associated with all-cause, hepatic, cancer and CVD mortality. When HOMA-insulin resistance was included in multivariate analyses, FLI retained its statistical association with hepatic-related mortality but not with all-cause, CVD and cancer-related mortality
Lerchbaum et al[55], 2013	Consecutive sample of patients, n = 3270 subjects routinely referred to coronary angiography	7.7	FLI index	All-cause and cause- specific mortality	High FLI was independently associated with increased all-cause, CVD, non-cardiovascular and cancer mortality
Jepsen et al[56], 2003	Population-based cohort, n = 1804 with hospital diagnosis of NAFLD (Danish national registry of patients)	16.0	US	All-cause and cause- specific mortality	Increased rates of all-cause, CVD and liver-related mortality in NAFLD, independently of sex, diabetes, and cirrhosis at baseline
Targher et al[57], 2007	Outpatient cohort, n = 2103 type 2 diabetic subjects (Valpolicella Heart Diabetes Study)	6.5	US	Fatal and non-fatal CVD	Increased rates of fatal and non-fatal CVD events in NAFLD, independently of age, sex, body mass index, smoking, diabetes duration, hemoglobin A1c, LDL-cholesterol, MetS features, medication use
Soler Rodriguez et al[58], 2007	Community-based cohort, n = 1637 healthy Japanese	5.0	US	Non-fatal CVD events	Increased rates of non-fatal CVD events in NAFLD, independently of age, sex, body mass index, alcohol intake, smoking, LDL-cholesterol, MetS features
Lazo et al[59], 2011	Population-based cohort, n = 11371 (NHANES-III)	14.5	US	All-cause and cause-specific mortality	NAFLD was not associated with increased all-cause and cause-specific (CVD, cancer and liver) mortality
Stepanova et al[60], 2012	Population-based cohort, n = 11613 (NHANES-III)	14.2	US	All-cause and cause-specific mortality	NAFLD was associated with increased prevalence of CVD, after adjusting for established CVD risk factors, but not with increased CVD mortality
Zhou et al[61], 2012	Community-based cohort study, n = 3543 adult men and women	4.0	US	All-cause and CVD mortality	Increased rates of all-cause and CVD mortality in NAFLD
Younossi et al[62], 2013	Population-based cohort, n = 1448 with NAFLD (NHANES-III)	14.2	US	All-cause and cause- specific mortality	NAFLD was independently associated with increased all-cause, CVD and liver-related mortality only among NAFLD patients with the MetS
Haring et al[63], 2009	Population-based cohort, n = 4160 German subjects (Study of Health in Pomerania)	7.2	US and liver enzymes	All-cause and CVD mortality	Elevated serum GGT level was independently associated with increased all-cause and CVD mortality in men
Kim et al[64], 2013	Population-based cohort, n = 1154 (NHANES-III)	14.5	US and advanced fibrosis score systems	All-cause and cause- specific mortality	NAFLD was not associated with increased all-cause mortality. However, NAFLD with advanced hepatic fibrosis (defined by NAFLD fibrosis score, APRI index or Fib-4) was independently associated with risk of all-cause mortality, of which the majority of deaths were due to CVD
Treeprasertsuk et al[65], 2012	Community-based cohort, n = 309 patients with NAFLD	11.5	US and CT	Fatal and non-fatal CHD	NAFLD patients had a higher 10-year CHD risk by FRS than the general population of the same age and sex. Almost identical number of FRS-predicted and actual new CHD events
Matteoni et al[66], 1999	Patient-based cohort, n = 132 NAFLD	18.0	Histology	All-cause and cause-specific mortality	Increasing liver-related mortality with the severity of NAFLD histology (according to four different histological subtypes). All-cause mortality and other causes of mortality were not significantly different across histological subtypes
Dam-Larsen et al[67], 2004	Patient-based cohort (Danish national registry of patients), n = 109 subjects with non-alcoholic SS	16.7	Histology	All-cause and cause-specific mortality	All-cause and cause-specific mortality did not significantly differ between patients with non-alcoholic SS and the general population
Adams et al[68], 2005	Community-based cohort, n = 420 patients with NAFLD	7.6	US/CT and histology	All-cause and cause-specific mortality	Increased rate of age- and sex-adjusted all-cause mortality in NAFLD than in the general population with CHD being the second cause of death
Ekstedt et al[69], 2006	Patient-based cohort, n = 129 consecutive patients with NAFLD and elevated serum liver enzymes (55% NASH)	13.7	Histology	All-cause and cause-specific mortality	Increased rates of CVD and liver-related mortality in patients with NASH, but not in those with SS, compared with in the reference population
Rafiq et al[70], 2009	Patient-based cohort, n = 173 patients with NAFLD (41.6% NASH)	13.0	Histology	All-cause and cause-specific mortality	CHD was the first cause of death in NAFLD cohort with no difference between NASH and non-NASH. Liver-related mortality, but not all-cause mortality, was higher in NASH vs non-NASH. No comparison was provided with the general population
Söderberg et al[71], 2010	Patient-based cohort, n = 118 patients with NAFLD and elevated serum liver enzymes (43% NASH)	24.0	Histology	All-cause and cause-specific mortality	Increased mortality rates of CVD, malignancy and liver disease in patients with NASH, but not in those with SS, compared with the matched general population

AST: Alanine aminotransferase; CHD; Coronary heart disease; CT: Computed tomography; US: Ultrasonography; FLI: Fatty liver index; FRS: Framingham risk score; GGT: Gamma-glutamyltransferase; HOMA: Homeostasis model assessment; MetS: Metabolic syndrome; NASH: Non-alcoholic steatohepatitis; SS: Simple steatosis; CVD: Cardiovascular.