Liver fat content, non-alcoholic fatty liver disease, and risk of ischaemic heart disease

Liver fat content, non-alcoholic fatty liver disease, and risk of ischaemic heart disease Downloaded from https://academic.oup.com/eurheartj/article-abstract/39/36/3398/4992185 by Ed 'DeepDyve' Gillespie user on 18 October 2018 DISCUSSION FORUM European Heart Journal (2018) 39, 3398 doi:10.1093/eurheartj/ehy237 Liver fat content, non-alcoholic fatty liver disease, and risk of ischaemic heart disease 1,2 3 Christopher D. Byrne , and Giovanni Targher * 1 2 Nutrition and Metabolism, Faculty of Medicine, University of Southampton, UK; Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK; and Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani 1, 37126 Verona, Italy Online publish-ahead-of-print 3 May 2018 association between PNPLA3 148 MM and IHD risk, again no infor- We congratulate the authors for attempting to address the question mation was available about NAFLD in the CARDIoGRAMplusC4D of whether hepatic fat content is a cardiovascular risk factor. Despite consortium. confirming the known association between hepatic fat content [and . non-alcoholic fatty liver disease (NAFLD)] and risk of ischaemic heart . . To date, it is supposed that there are at least two distinct forms disease (IHD), the authors suggested that fatty liver due to PNPLA3 . . of NAFLD, i.e. the obese/metabolic NAFLD and the PNPLA3- variant is not causally linked to IHD. However, certain caveats need . associated NAFLD, which can have different consequences for risk of to be considered when interpreting these results. 2 IHD. Less than 5–6% of northern European individuals with NAFLD carry the PNPLA3 148MM genotype and this genotype is neither suf- (1) Based on the International Classification of Diseases, 8th revision . ficient nor necessary to cause non-alcoholic steatohepatitis, cirrhosis, (ICD-8) codes, the prevalence of NAFLD was extraordinarily low (0.7%), and it is also likely there was contamination bias (with up to or hepatocellular carcinoma. The contribution of this genetic variant 25–30% of individuals in the reference group possibly having undiag- to inter-individual variation in NAFLD phenotype is relatively small, nosed NAFLD). . and the role of the PNPLA3 148M allele in the general population (2) The authors failed to show any increase in risk of prevalent IHD without NAFLD is far from clear. with the presence of the PNPLA3 148M allele among 1439 individu- . We consider that further studies are needed to test the effect of als in whom hepatic fat content was detected by computed tomog- PNPLA3 148 MM genotype on risk of incident IHD in large cohorts raphy. However, many of these individuals did not have NAFLD with proven NAFLD where it has also been shown that the reference (because liver fat percentage was <5.6%), and it is also noteworthy . population does not have NAFLD. that the mean liver fat percentage was low and similar in all three . PNPLA3 genotypes (II = 5.1%, IM = 6.0%, and MM = 6.5%). Conflict of interest: none declared. Moreover, these individuals were not well representative of the study (as shown in eTable 1 of the article by Lauridsen et al) . References (3) The authors also tested whether the PNPLA3 genotype was associ- 1. Lauridsen BK, Stender S, Kristensen TS, Kofoed KF, Køber L, Nordestgaard BG, ated with risk of IHD in the whole cohort, of whom nearly 99% did . Tybjærg-Hansen A. Liver fat content, non-alcoholic fatty liver disease, and ischae- mic heart disease: mendelian randomization and meta-analysis of 279013 individu- not have known NAFLD. Since PNPLA3 148 MM was associated . . als. Eur Heart J 2018;39:385–393. with a tiny increase in liver fat percentage in individuals with imaging- 2. Lonardo A, Sookoian S, Pirola CJ, Targher G. Non-alcoholic fatty liver disease and diagnosed NAFLD, it is unsurprising that in the general population risk of cardiovascular disease. Metabolism 2016;65:1136–1150. without NAFLD, PNPLA3 148 MM was not associated with . 3. Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepa- IHD. Although a subsequent meta-analysis confirmed the lack of an titis. N Engl J Med 2017;377:2063–2072. * Corresponding author. Tel: 0039-045-8123110, Fax: 0039-045-8027314, Email: giovanni.targher@univr.it Published on behalf of the European Society of Cardiology. All rights reserved. V The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

Liver fat content, non-alcoholic fatty liver disease, and risk of ischaemic heart disease

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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
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Abstract

Downloaded from https://academic.oup.com/eurheartj/article-abstract/39/36/3398/4992185 by Ed 'DeepDyve' Gillespie user on 18 October 2018 DISCUSSION FORUM European Heart Journal (2018) 39, 3398 doi:10.1093/eurheartj/ehy237 Liver fat content, non-alcoholic fatty liver disease, and risk of ischaemic heart disease 1,2 3 Christopher D. Byrne , and Giovanni Targher * 1 2 Nutrition and Metabolism, Faculty of Medicine, University of Southampton, UK; Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK; and Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani 1, 37126 Verona, Italy Online publish-ahead-of-print 3 May 2018 association between PNPLA3 148 MM and IHD risk, again no infor- We congratulate the authors for attempting to address the question mation was available about NAFLD in the CARDIoGRAMplusC4D of whether hepatic fat content is a cardiovascular risk factor. Despite consortium. confirming the known association between hepatic fat content [and . non-alcoholic fatty liver disease (NAFLD)] and risk of ischaemic heart . . To date, it is supposed that there are at least two distinct forms disease (IHD), the authors suggested that fatty liver due to PNPLA3 . . of NAFLD, i.e. the obese/metabolic NAFLD and the PNPLA3- variant is not causally linked to IHD. However, certain caveats need . associated NAFLD, which can have different consequences for risk of to be considered when interpreting these results. 2 IHD. Less than 5–6% of northern European individuals with NAFLD carry the PNPLA3 148MM genotype and this genotype is neither suf- (1) Based on the International Classification of Diseases, 8th revision . ficient nor necessary to cause non-alcoholic steatohepatitis, cirrhosis, (ICD-8) codes, the prevalence of NAFLD was extraordinarily low (0.7%), and it is also likely there was contamination bias (with up to or hepatocellular carcinoma. The contribution of this genetic variant 25–30% of individuals in the reference group possibly having undiag- to inter-individual variation in NAFLD phenotype is relatively small, nosed NAFLD). . and the role of the PNPLA3 148M allele in the general population (2) The authors failed to show any increase in risk of prevalent IHD without NAFLD is far from clear. with the presence of the PNPLA3 148M allele among 1439 individu- . We consider that further studies are needed to test the effect of als in whom hepatic fat content was detected by computed tomog- PNPLA3 148 MM genotype on risk of incident IHD in large cohorts raphy. However, many of these individuals did not have NAFLD with proven NAFLD where it has also been shown that the reference (because liver fat percentage was <5.6%), and it is also noteworthy . population does not have NAFLD. that the mean liver fat percentage was low and similar in all three . PNPLA3 genotypes (II = 5.1%, IM = 6.0%, and MM = 6.5%). Conflict of interest: none declared. Moreover, these individuals were not well representative of the study (as shown in eTable 1 of the article by Lauridsen et al) . References (3) The authors also tested whether the PNPLA3 genotype was associ- 1. Lauridsen BK, Stender S, Kristensen TS, Kofoed KF, Køber L, Nordestgaard BG, ated with risk of IHD in the whole cohort, of whom nearly 99% did . Tybjærg-Hansen A. Liver fat content, non-alcoholic fatty liver disease, and ischae- mic heart disease: mendelian randomization and meta-analysis of 279013 individu- not have known NAFLD. Since PNPLA3 148 MM was associated . . als. Eur Heart J 2018;39:385–393. with a tiny increase in liver fat percentage in individuals with imaging- 2. Lonardo A, Sookoian S, Pirola CJ, Targher G. Non-alcoholic fatty liver disease and diagnosed NAFLD, it is unsurprising that in the general population risk of cardiovascular disease. Metabolism 2016;65:1136–1150. without NAFLD, PNPLA3 148 MM was not associated with . 3. Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepa- IHD. Although a subsequent meta-analysis confirmed the lack of an titis. N Engl J Med 2017;377:2063–2072. * Corresponding author. Tel: 0039-045-8123110, Fax: 0039-045-8027314, Email: giovanni.targher@univr.it Published on behalf of the European Society of Cardiology. All rights reserved. V The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.

Journal

European Heart JournalOxford University Press

Published: Sep 21, 2018

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