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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 doi: https://doi.org/10.1136/bmj.l5367 (Published 08 October 2019) Cite this as: BMJ 2019;367:l5367

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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. [1] 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 [6]. 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) [7], 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 [8].
(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. [1] is not likely because such an association does not exist, but is probably due to the important methodological flaws of the study design.

References
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.
2. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363:1341-1350.
3. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66:1138-1153.
4. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67:328-357.
5. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388-1402.
6. Wild SH, Walker JJ, Morling JR, McAllister DA, Colhoun HM, Farran B, McGurnaghan S, McCrimmon R, Read SH, Sattar N, Byrne CD; Scottish Diabetes Research Network Epidemiology Group. Cardiovascular disease, cancer, and mortality among people with type 2 diabetes and alcoholic or nonalcoholic fatty liver disease hospital admission. Diabetes Care. 2018; 41: 341-347.
7. Alexander M, Loomis AK, Fairburn-Beech J, van der Lei J, Duarte-Salles T, Prieto-Alhambra D, Ansell D, Pasqua A, Lapi F, Rijnbeek P, Mosseveld M, Avillach P, Egger P, Kendrick S, Waterworth DM, Sattar N, Alazawi W. Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease. BMC Med. 2018;16:130.
8. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease - Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73-84.

Competing interests: No competing interests

11 October 2019
Giovanni Targher
Associate professor of diabetes and endocrinology
University of Verona
Piazzale Stefani 1 - 37126 Verona, Italy