Non-alcoholic fatty liver disease and cardiovascular risk

Table 1 Recent epidemiological studies evaluating cardiovascular risk in non-alcoholic fatty liver disease

Ref.	Study characteristics	Years of follow-up	Diagnosis of NAFLD	Study outcomes	Main findings
Ekstedt et al[30] (2015)	Retrospective cohort study n = 229 Swedish patients with NAFLD and elevated liver enzymes (49% NASH); mean age 49 yr, 66% men	26.4 (mean)	Histology	n = 96 total deaths, 41 CVD related deaths	Increased rates of all-cause, liver-related and CVD mortality with NAFLD compared with general control population. Fibrosis stage on histology significantly predicted the risk of all-cause, liver-related and CVD mortality
Ekstedt et al[31] (2006)	Cohort study 129 consecutively enrolled patients diagnosed with biopsy-proven NAFLD were reevaluated. Survival and causes of death were compared with a matched reference population. Living NAFLD patients were offered repeat liver biopsy and clinical and biochemical investigation	13.7 (mean)	Histology	Mortality was not increased in patients with steatosis. Survival of patients with nonalcoholic steatohepatitis (NASH) was reduced. These subjects more often died from cardiovascular and liver-related causes. At follow-up, 69 of 88 patients had diabetes or impaired glucose tolerance. Progression of liver fibrosis occurred in 41%. These subjects more often had a weight gain exceeding 5 kg, they were more insulin resistant, and they exhibited more pronounced hepatic fatty infiltration at follow-up	Increased total mortality which was primarily CV related (only in NASH patients but not in simple steatosis) compared with matched reference population
Soderberg et al[11] (2010)	Retrospective cohort study 256 subjects (61% men, mean age of 45 ± 12 yr) This study was undertaken to determine the frequency of NAFLD in a cohort of subjects who underwent liver biopsy from 1980 to 1984 because of elevated liver enzymes, and to assess mortality among subjects with NAFLD in comparison with the general Swedish population. Liver biopsies were blindly scored for NAFLD and NASH	24 yr (mean)	Histology	During the follow-up period, 113 (44%) of the total population and 47 (40%) of the 118 subjects diagnosed with NAFLD died. Of the 113 deaths, 37 were of cardiovascular disease and 16 of liver diseases. NAFLD exhibited a 69% increased mortality, subjects with bland steatosis, a 55% increase, and subjects with NASH, 86%	Increased total mortality in NAFLD was predominantly CV related, compared with matched reference population
Pickhardt et al[32] (2014)	Retrospective cohort study United States adults undergoing abdominal CT selected among 4412 consecutive adults scanned with CT for clinical reasons over a 12-mo period: 282 NAFLD patients and 786 non-steatotic controls after exclusion of those with known liver diseases or < 1 yr of follow-up; mean 51 yr, 46% men	7.5 (mean)	Unenhanced CT	Non-fatal CVD events (myocardial infarction, stroke, TIA or coronary bypass or stent); n = 73 CVD events	NAFLD was not independently associated with non-fatal CVD events
Zeb et al[12] (2016)	Prospective cohort study n = 4119 United States participants aged 45-84 yr (mean 62 yr, 45% men) who were free of CVD and known liver diseases at baseline	7.6 (mean)	Unenhanced CT	All-cause mortality and no-fatal CVD events (myocardial infarction, resuscitated cardiac arrest, angina, or coronary revascularization procedures), n = 253 deaths and 209 non-fatal CVD events	NAFLD was independently associated with a composite endpoint inclusive of all-cause death and non-fatal CVD events
Kim et al[33] (2013)	Population-based cohort n = 11154 Unites States adults; mean age 43 yr, 48% men	14.5 (median)	Ultrasound	All-cause and CVD mortality n = 1795 total deaths (673 CVD deaths)	NAFLD was not associated with increased all-cause and CVD mortality in the whole cohort however NAFLD with advanced fibrosis (defined by the NAFLD fibrosis score) was independently associated with increased all-cause and CVD mortality
Emre et al[34] (2015)	Retrospective cohort study n = 186 Turkish, non-diabetic patients undergoing PCI for ST-elevation MI; patients with known liver disease were excluded; mean age 58 yr, 78% men	In-hospital cardiac events	Ultrasound	In-hospital CVD events (MI, acute heart failure, cardiac arrest), n = 32 CVD events and n = 8 CVD deaths	Moderate-severe NAFLD was independently associated with increased in-hospital CVD events but not with increased CVD death

NAFLD: Non-alcoholic fatty liver disease; CT: Computed tomography; CAC: Coronary artery calcification; CIMT: Carotid intima-media thickness; CP: Carotid plaque; DM: Diabetes mellitus; NASH: Nonalcoholic steatohepatitis.