Selected observational studies exploring the risk of CVD in patients with NAFLD as diagnosed by histology or imaging (studies were ordered by methodology of NAFLD diagnosis and publication year)
| Authors, year (ref.) | Study population | Follow-up length | NAFLD diagnosis | Study outcomes | Main findings |
|---|---|---|---|---|---|
| Matteoni et al, 199961 | Retrospective cohort of 132 US patients with NAFLD and raised serum liver enzymes | 18 years | Histology | All-cause and cause-specific mortality | Patients with NASH had higher rates of all-cause and liver-related mortality than those without. CVD death rate did not differ between the groups |
| Dam-Larsen et al, 200462 | Retrospective cohort of 109 Danish patients with non-alcoholic simple steatosis (without NASH at baseline) | 16.7 years | Histology | All-cause and cause-specific mortality | No significant difference in death rates between patients with simple steatosis and the general population |
| Adams et al, 200564 | Retrospective community-based cohort of 420 US patients with NAFLD | 7.6 years | Histology and imaging | All-cause and cause-specific mortality | Patients with NAFLD (especially those with cirrhosis and NASH) had higher rates of all-cause, CVD and liver-related mortality than the matched general population |
| Ekstedt et al, 200650 | Retrospective cohort of 129 Swedish patients with NAFLD and raised serum liver enzymes | 13.7 years | Histology | All-cause and cause-specific mortality | Patients with NASH, but not those with simple steatosis, had higher rates of all-cause (∼2-fold), CVD (∼2-fold) and liver-related (∼10-fold) mortality than the reference population |
| Rafiq et al, 200963 | Retrospective cohort of 173 US patients with NAFLD and raised serum liver enzymes | 13 years | Histology | All-cause and cause-specific mortality | CVD, malignancy and liver-related complications were the most common causes of mortality |
| Söderberg et al, 201051 | Retrospective cohort of 118 Swedish patients with NAFLD and raised serum liver enzymes | 24 years | Histology | All-cause and cause-specific mortality | Patients with NASH, but not those with simple steatosis, had higher rates of all-cause (∼twofold), CVD (∼twofold) and liver-related mortality than the matched general population |
| Ekstedt et al, 20154 | Retrospective cohort of 229 Swedish patients with biopsy-proven NAFLD | 26.4±5.6 years | Histology | All-cause and disease-specific mortality | Patients with NAFLD have increased overall mortality (HR 1.29, 95% CI 1.04 to 1.59), with a high risk of death from CVD (HR 1.55, 95% CI 1.11 to 2.15) and liver-related disease. Stage of fibrosis rather than presence of NASH predicted both overall and disease-specific mortality |
| Fracanzani et al, 2016193 | Prospective case-control study of 125 Italian patients with NAFLD and 250 age-matched and sex-matched control individuals without known liver diseases | 10 years | Histology and ultrasound | Non-fatal CVD events (acute coronary syndrome, coronary revascularisation procedures, ischaemic stroke or transitory ischaemic attacks as combined end point) | NAFLD was independently associated with incident non-fatal CHD events (HR 1.99, 95% CI 1.01 to 3.91) |
| Jepsen et al, 200365 | Retrospective cohort of 1800 Danish patients discharged with a hospital diagnosis of NAFLD | 6.2 years | Ultrasound and liver enzymes | All-cause and cause-specific mortality | Patients with NAFLD had higher rates of all-cause (2.6-fold), CVD (2.1-fold) and liver-related (19.7-fold) mortality than the general population |
| Hamaguchi et al, 200759 | Community-based cohort of 1637 Japanese apparently healthy individuals | 5 years | Ultrasound | Non-fatal CHD and stroke | NAFLD was independently associated with increased risk of non-fatal CVD events (HR 4.10, 95% CI 1.6 to 10.7) |
| Targher et al, 200745 | Prospective cohort of 2103 Italian individuals with type 2 diabetes without baseline viral hepatitis and CVD | 6.5 years | Ultrasound | CVD mortality and non-fatal myocardial infarction, ischaemic stroke and revascularisation procedures (combined end point) | NAFLD was independently associated with increased risk of fatal and non-fatal CVD events (HR 1.87, 95% CI 1.2 to 2.6) |
| Haring et al, 200958 | Population-based cohort study of 4160 German adult men and women without baseline viral hepatitis or cirrhosis | 7.3 years | Ultrasound | All-cause and cause-specific mortality | NAFLD was independently associated with increased risk of all-cause and CVD mortality in men (HR 6.2, 95% CI 1.2 to 31.6) |
| Zhou et al, 201267 | Community-based cohort study of 3543 Chinese adult men and women | 4 years | Ultrasound | All-cause and cause-specific mortality | Patients with NAFLD had ∼threefold higher rates of all-cause and CVD mortality than those without NAFLD |
| Stepanova and Younossi, 201243; Lazo et al, 201144 | Nationally based cohort study of 11 371 US adult participants from the Third National Health and Nutrition Examination Survey, 1988–94 | 14.5 years | Ultrasound | All-cause and cause-specific mortality | No significant association between NAFLD and all-cause and cause-specific mortality |
| Pisto et al, 201460 | Population-based, randomly recruited cohort of 988 middle-aged Finnish participants | ∼18 years | Ultrasound | Fatal and non-fatal CVD events | Severe NAFLD did not significantly predict the risk of CVD events after adjustment for potential confounders, including insulin resistance |
| Wong et al, 201648 | 612 consecutive Chinese patients undergoing coronary angiograms without known liver diseases | 6 years | Ultrasound | Fatal and non-fatal CVD events, heart failure or secondary coronary interventions (combined end point) | Patients with NAFLD, compared with those without, were more likely to have >50% stenosis in one or more coronary arteries and therefore require percutaneous coronary intervention. NAFLD was not significantly associated with fatal and non-fatal CVD events |
| Mantovani et al, 2016194 | Retrospective cohort of 286 Italian adults with type 1 diabetes without known liver diseases | 5.3±2 years | Ultrasound | Non-fatal ischaemic heart disease, non-fatal ischaemic stroke or coronary/peripheral artery revascularisation procedures (combined end point) | NAFLD was independently associated with an increased risk of non-fatal CVD events (HR 6.73, 95% CI 1.2 to 38) |
| Treeprasertsuk et al, 201288 | Community-based cohort of 309 US patients with NAFLD | 11.5±4.1 years | Ultrasound and CT | New-onset CVD | Patients with NAFLD have a higher 10-year CHD risk than the general population of the same age and sex |
| Kim et al, 201357 | Nationally based cohort study of 11 154 US adult participants from the Third National Health and Nutrition Examination Survey, 1988–94 | 14.5 years | Ultrasound and non-invasive fibrosis markers (NFS/APRI/FIB4) | All-cause and cause-specific mortality | NAFLD not associated with increased mortality. However, advanced fibrosis, as determined by non-invasive fibrosis markers, is a significant predictor of mortality, mainly from CVD causes, independent of other known factors |
| Zeb et al, 2016195 | Prospective cohort study of 4119 US adult participants who were free of CVD and known liver diseases at baseline (The Multi-Ethnic Study of Atherosclerosis) | 7.6 years (median) | CT | All-cause mortality and CVD events (myocardial infarction, resuscitated cardiac arrest, angina or coronary revascularisation procedures) | NAFLD was independently associated with incident CHD events (HR 1.42, 95% CI 1.00 to 2.03) |
APRI, aspartate aminotransferase to platelet ratio index; CHD, coronary heart disease; CVD, cardiovascular disease; FIB-4, fibrosis-4; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NFS, NAFLD fibrosis score.