Re: Non-alcoholic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million European adults
Alexander et al.  aimed at examining the association between non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) with risk of incident acute myocardial infarction and stroke using electronic records from four European primary care databases. Unfortunately, the investigators have fallen short from their stated goal. Clear evidence shows that cardiovascular disease is the leading cause of death among patients with NAFLD [2,3]. The European and American clinical practice guidelines for the management of NAFLD strongly recommended that all individuals with NAFLD (being at high risk of cardiovascular morbidity and mortality) should undergo careful cardiovascular surveillance [4,5]. Dr. Sattar was also a co-author on another paper he published in 2018, showing that NAFLD is an independent risk factor for incident cardiovascular events and mortality in a large cohort of patients with type 2 diabetes from the Scottish Diabetes database . The reported findings are, therefore, at odds with both clinical experience and current evidence.
Methodological issues include:
(1) Misclassification of NAFLD/NASH cases and controls. Use of an accurate case definition, both for NAFLD in general and to differentiate steatosis from NASH is crucial and appears to be an area where this study is inadequate. The prevalence of a recorded diagnosis of NAFLD in this electronic database is much lower than expected (ranging from 0.60% in 2007 to 1.85% in 2014) , highlighting the problem of under-diagnosis and under-recording. Indeed, the prevalence of recorded NAFLD diagnoses is ~15-20 fold lower than that usually reported in the European general population when the diagnosis of NAFLD is based on imaging methods .
(2) Misclassification of patients with a history of alcohol misuse.
(3) Extraction of data from electronic records regarding cardiovascular risk factors, such as total cholesterol levels, systolic blood pressure and smoking history was made, not only for two years before, but also for six months after the index date.
(4) Statin use in the Health Improvement Network (THIN) database was missing and, therefore, it was imputed in the database.
The lack of association of NAFLD/NASH with risk of incident acute myocardial infarction and stroke reported by Alexander et al.  is not likely because such an association does not exist, but is probably due to the important methodological flaws of the study design.
1. Alexander M, Loomis AK, van der Lei J, Duarte-Salles T, Prieto-Alhambra D, Ansell D, Pasqua A, Lapi F, Rijnbeek P, Mosseveld M, Avillach P, Egger P, Dhalwani NN, Kendrick S, Celis-Morales C, Waterworth DM, Alazawi W, Sattar N. Non-alcoholic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million European adults. BMJ. 2019;367:l5367.
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Competing interests: No competing interests