Abstract
Non-alcoholic fatty liver disease (NAFLD) is common and strongly associated with the metabolic syndrome. Though NAFLD may progress to end-stage liver disease, the top cause of mortality in NAFLD is cardiovascular disease (CVD). Most of the data on liver-related mortality in NAFLD derives from specialist liver centres. It is not clear if the higher reported mortality rates in individuals with non-cirrhotic NAFLD are entirely accounted for by complications of atherosclerosis and diabetes. Therefore, we aimed to describe the CVD burden and mortality in NAFLD when adjusting for metabolic risk factors using a 'real world' cohort. We performed a retrospective study of patients followed-up after an admission to non-specialist hospitals with a NAFLD-spectrum diagnosis. Non-cirrhotic NAFLD and NAFLD-cirrhosis patients were defined by ICD-10 codes. Cases were age-/sex-matched with non-NAFLD hospitalised patients. All-cause mortality over 14-years follow-up after discharge was compared between groups using Cox proportional hazard models adjusted for demographics, CVD, and metabolic syndrome components. We identified 1,802 patients with NAFLD-diagnoses: 1,091 with non-cirrhotic NAFLD and 711 with NAFLD-cirrhosis, matched to 24,737 controls. There was an increasing burden of CVD with progression of NAFLD: for congestive heart failure 3.5% control, 4.2% non-cirrhotic NAFLD, 6.6% NAFLD-cirrhosis; and for atrial fibrillation 4.7% control, 5.9% non-cirrhotic NAFLD, 12.1% NAFLD-cirrhosis. Over 14-years follow-up, crude mortality rates were 14.7% control, 13.7% non-cirrhotic NAFLD, and 40.5% NAFLD-cirrhosis. However, after adjusting for demographics, non-cirrhotic NAFLD (HR 1.3 (95% CI 1.1-1.5)) as well as NAFLD-cirrhosis (HR 3.7 (95% CI 3.0-4.5)) patients had higher mortality compared to controls. These differences remained after adjusting for CVD and metabolic syndrome components: non-cirrhotic NAFLD (HR 1.2 (95% CI 1.0-1.4)) and NAFLD-cirrhosis (HR 3.4 (95% CI 2.8-4.2)). In conclusion, from a large non-specialist registry of hospitalised patients, those with non-cirrhotic NAFLD had increased overall mortality compared to controls even after adjusting for CVD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in Europe [1] and is strongly associated with all features of the metabolic syndrome [2]
After adjustment for cardiovascular factors, allcause mortality was still elevated compared to the control group: non-cirrhotic NAFLD hazard ratio (HR) 1.2 and NAFLD-cirrhosis HR 3.4
After removing patients who had experienced liver-related events (S4 Table), there was no difference in hazard ratio of mortality for patients with non-cirrhotic NAFLD compared to control when adjusting for demographics (HR 1.2, q = 0.08)
Summary
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in Europe [1] and is strongly associated with all features of the metabolic syndrome [2]. It has been established that fibrosis is the main predictor of long-term liver-related morbidity in NAFLD [3, 7,8,9] and that patients with NASH but no fibrosis have a similar outcome to those with NAFL and no fibrosis. These studies included biopsy-proven patients in specialist clinics and there is likely significant ascertainment bias in estimating rates of hepatic complications. The natural history of NAFLD and its impact upon clinical services is an important topic that divides expert opinion [11, 12]
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