Nicholas W. S. Chew
Shankar Kannan1†
Bryan Chong
Yiphan Chin
Mark Muthiah- 1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- 2Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
- 3Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- 4National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
Editorial on the Research Topic
The heart of NAFLD
The silent obesity epidemic has led to the rising global prevalence of non-alcoholic fatty liver disease (NAFLD). This metabolic burden is a growing public health concern as forecast analysis has shown that NAFLD-related disability-adjusted life years will impose a large metabolic burden on the young adult population (1), which will have long-term global implications for the coming decades (1–3). Individuals with NAFLD have a 45% higher risk of fatal and non-fatal cardiovascular events, with cardiovascular-related mortality demonstrated to be the leading cause of death in NAFLD. Those with NAFLD are also at higher risk of incident coronary artery disease, aortic stenosis, heart failure, carotid atherosclerosis, stroke, and atrial fibrillation (4, 5).
The metabolic sequelae of NAFLD, namely insulin resistance, intrahepatic lipid accumulation, inflammation and oxidative stress, increased adiponectin, atherogenic dyslipidemia, the influence on hemostatic-fibrinolytic factors, intestinal microbiome, altered bile acid metabolism, predispose these individuals to atherosclerosis and structural changes to the myocardium. Expectedly, NAFLD is more prevalent in a population with overweight/obesity, although there are geographical variations in its prevalence with the highest amongst those with obesity in America and Europe, but lowest in Southeast Asia (6–11). On the contrary, the prevalence of lean NAFLD in the Asian population is almost doubled that of the Western population (6). Moreover, concomitant metabolic disorders such as hypertension and diabetes mellitus are more common in those with NAFLD, as they share common underlying pathomechanistic pathways and often exist in tandem (12, 13). Concomitant hypertension and diabetes mellitus in individuals with NAFLD exacerbates the cardiovascular risk profile and prognosis (9, 14). In fact, there has been increasing evidence of the genetic cross-talks between NAFLD and cardiovascular diseases (15).
With the increased metabolic milieu in individuals with NAFLD, the global prevalence of coronary heart disease (CHD) has been shown to be 44%. NAFLD patients are at an increased risk of incident CHD compared to those without NAFLD (16), with a step-wise incremental risk of CHD from those with mild hepatic steatosis to those with moderate-severe steatosis. Even in the absence of hypertension, hyperlipidemia and diabetes mellitus, hepatic steatosis and advanced fibrosis were independent predictors of mortality in patients with acute myocardial infarction (17–22). NAFLD is also associated with adverse cardiac remodeling that can lead to impaired systolic and diastolic dysfunction (23, 24). Concomitant metabolic factors and liver disease severity further increase the individual's risk of incident heart failure (25).
The shift from NAFLD to metabolic (26) associated fatty liver disease [MAFLD (Perdomo et al.) (19, 27)] nomenclature also redefines the cardiovascular risk profile of the individual. Carolina et el described that the MAFLD definition accounted for 81% of all NAFLD diagnoses, with MAFLD significantly associated with higher body mass index, hypertension, diabetes mellitus, hyperlipidemia compared to NAFLD (6, 19, 28–30). The use of the MAFLD definition places greater emphasis on the screening and management of concomitant metabolic diseases, and a collaborative effort between cardiologists and hepatologists in the treatment of the chronic liver diseases and cardiovascular risk factors.
There is a need for increased awareness amongst non-hepatologists in the screening of NAFLD in addition to the traditional cardiovascular risk factor testing. A growing body of evidence reveal that readily available non-invasive tests such as the Fibrosis-4 index (FIB-4) have good predictive utility in detecting incident major adverse cardiac events (MACE). Chew et al. reported that a FIB-4 score of ≥2.67 increases the odds of MACE, and is independently associated with 40% increase risk in cardiovascular mortality (27). As traditional cardiovascular risk scoring measures may be inaccurate in NAFLD patients, with alterations in hepatic architecture alterations that can affect the circulatory lipid profile, the integration of hepatic fibrosis screening using the FIB-4 score in traditional CVD risk stratification appears promising (26, 31) although this warrants further validation studies.
With the concerted goal of improving both liver-related and cardiovascular-related outcomes, a multi-disciplinary approach in encouraging sustainable lifestyle measures is paramount. Lifestyle interventions are important to limit energy surplus and enhance weight loss. Antidiabetic medications such as glucagon-like peptide receptor agonists, sodium-glucose cotransporter-2 inhibitors, and pan-peroxisome proliferator-activated receptor-γ (PPAR) agonists (Yagai and Nakamura) have shown improvement in liver-related endpoints in terms of non-alcoholic steatohepatitis (NASH) resolution and fibrosis improvement, as well as concomitant improvement in blood pressure, glycaemic control, atherogenic lipid profile, weight loss, and cardiovascular prognostic endpoints. Yagai and Nakamura provided mechanistic insights into PPARα agonists that act as transcriptional suppressors, which represses target genes on hepatic lipid metabolism, fibrosis and carcinogenesis associated with NAFLD. In addition, bariatric surgery is an effective treatment modality for selected patients with obesity and metabolic syndrome, that can improve both histological characteristics of NASH as well as cardiovascular mortality (32). Lee and colleagues studied endoscopic bariatric and metabolic therapies on weight loss, suggesting promising benefits on weight reduction in intragastric balloon, endoscopic sleeve gastroplasty, and duodeno-jejunal bypass liner, compared to standard medical therapy (Lee et al.). The concerted approach to the reduction of the NAFLD and CVD burden was succinctly consolidated by the study, with the continued medical education program on NAFLD that encompass the best clinical practices tailored to primary care setting, that can improve confidence in the management of NAFLD-related conditions (Papadakis et al.). With the plethora of upcoming NASH therapeutic options (33–35) in the pipeline, treatment strategies in improving both liver-related outcomes and concomitant cardiometabolic profile are promising (32–43).
Whilst hepatology guidelines emphasize the importance of cardiovascular screening in NAFLD, the awareness of the association between NAFLD and CVD amongst cardiologists or in cardiology clinical practice guidelines appears to be lacking. This editorial aims to raise awareness (40) of the liver-heart interface, promoting research and treatment strategies, with both hepatologists and cardiologists working toward the unified goal in addressing the pertinent issues at the heart of NAFLD.
Author contributions
NC, SK, and MM contributed to conception and design of the study. NC, SK, BC, YC, and MM wrote the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
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References
1. Chong B, Kong G, Shankar K, Chew HSJ, Lin C, Goh R, et al. The global syndemic of metabolic diseases in the young adult population: a consortium of trends and projections from the Global Burden of Disease 2000-2019. Metab Clin Exp. (2023) 141:155402. doi: 10.1016/j.metabol.2023.155402
2. Kong G, Zhang A, Chong B, Lim J, Kannan S, Han Chin Y, et al. Long-term prognosis of patients with coexisting obesity and malnutrition after acute myocardial infarction: a cohort study. Circ Cardiovasc Qual Outcomes. (2023) 16:e009340. doi: 10.1161/CIRCOUTCOMES.122.009340
3. Chew NWS, Ng CH, Tan DJH, Kong G, Lin C, Chin YH, et al. The global burden of metabolic disease: data from 2000 to 2019. Cell Metab. (2023) 35:414–28.e413.
4. Xiao J, Ng CH, Chan KE, Fu C, Tay P, Yong JN, et al. Hepatic, extra-hepatic outcomes and causes of mortality in NAFLD – an umbrella overview of systematic review of meta-analysis. J Clin Exp Hepatol. (2022). doi: 10.1016/j.jceh.2022.11.006
5. Fu CE, Ng CH, Yong JN, Chan KE, Xiao J, Nah B, et al. A meta-analysis on associated risk of mortality in nonalcoholic fatty liver disease. Endocr Pract. (2023) 29:33–9. doi: 10.1016/j.eprac.2022.10.007
6. Tang A, Ng CH, Phang PH, Chan KE, Chin YH, Fu CE, et al. Comparative burden of metabolic dysfunction in lean NAFLD vs non-lean NAFLD - a systematic review and meta-analysis. Clin Gastroenterol Hepatol. (2022). doi: 10.1016/j.cgh.2022.06.029
7. Nah BKY, Ng CH, Chan KE, Tan C, Aggarwal M, Zeng RW, et al. Historical changes in weight classes and the influence of NAFLD prevalence: a population analysis of 34,486 individuals. Int J Environ Res Public Health. (2022) 19:9935. doi: 10.3390/ijerph19169935
8. Chin YH, Ng CH, Chew NW, Kong G, Lim WH, Tan DJH, et al. The placebo response rate and nocebo events in obesity pharmacological trials. A systematic review and meta-analysis. EClinicalMedicine. (2022) 54:101685. doi: 10.1016/j.eclinm.2022.101685
9. Anand VV, Zhe ELC, Chin YH, Lim WH, Goh RSJ, Lin C, et al. Barriers and facilitators to engagement with a weight management intervention in asian patients with overweight or obesity: a systematic review. Endocr Pract. (2022) 29:398–407. doi: 10.1016/j.eprac.2022.10.006
10. Chong B, Jayabaskaran J, Kong G, Chan YH, Chin YH, Goh R, et al. Trends and predictions of malnutrition and obesity in 204 countries and territories: an analysis of the Global Burden of Disease Study 2019. EClinicalMedicine. (2023) 57:101850. doi: 10.1016/j.eclinm.2023.101850
11. Llewellyn DC, Logan Ellis H, Aylwin SJB, Oštarijaš E, Green S, Sheridan W, et al. The efficacy of GLP-1RAs for the management of postprandial hypoglycemia following bariatric surgery: a systematic review. Obesity. (2023) 31:20–30. doi: 10.1002/oby.23600
12. Ng CH, Wong ZY, Chew NWS, Chan KE, Xiao J, Sayed N, et al. Hypertension is prevalent in non-alcoholic fatty liver disease and increases all-cause and cardiovascular mortality. Front Cardiovasc Med. (2022) 9:942753. doi: 10.3389/fcvm.2022.942753
13. Ng CH, Chan KE, Chin YH, Zeng RW, Tsai PC, Lim WH, et al. The effect of diabetes and prediabetes on the prevalence, complications and mortality in nonalcoholic fatty liver disease. Clin Mol Hepatol. (2022) 28:565–74. doi: 10.3350/cmh.2022.0096
14. Kong G, Chin YH, Lim J, Ng CH, Kannan S, Chong B, et al. A two-decade population-based study on the effect of hypertension in the general population with obesity in the United States. Obesity. (2023) 31:832–40. doi: 10.1002/oby.23658
15. Chew NWS, Chong B, Ng CH, Kong G, Chin YH, Xiao W, et al. The genetic interactions between non-alcoholic fatty liver disease and cardiovascular diseases. Front Genet. (2022) 13:971484. doi: 10.3389/fgene.2022.971484
16. Toh JZK, Pan XH, Tay PWL, Ng CH, Yong JN, Xiao J, et al. A meta-analysis on the global prevalence, risk factors and screening of coronary heart disease in nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. (2022) 20:2462–73.e2410. doi: 10.1016/j.cgh.2021.09.021
17. Kong G, Chin YH, Chong B, Goh RSJ, Lim OZH, Ng CH, et al. Higher mortality in acute coronary syndrome patients without standard modifiable risk factors: results from a global meta-analysis of 1,285,722 patients. Int J Cardiol. (2023) 371:432–40. doi: 10.1016/j.ijcard.2022.09.062
18. Tang ASP, Chan KE, Quek J, Xiao J, Tay P, Teng M, et al. Non-alcoholic fatty liver disease increases risk of carotid atherosclerosis and ischemic stroke: an updated meta-analysis with 135,602 individuals. Clin Mol Hepatol. (2022) 28:483–96. doi: 10.3350/cmh.2021.0406
19. Quek J, Ng CH, Tang ASP, Chew N, Chan M, Khoo CM, et al. Metabolic associated fatty liver disease increases the risk of systemic complications and mortality. a meta-analysis and systematic review of 12 620 736 individuals. Endocr Pract. (2022) 28:667–72. doi: 10.1016/j.eprac.2022.03.016
20. Chew NWS, Kong G, Venisha S, Chin YH, Ng CH, Muthiah M, et al. Long-term prognosis of acute myocardial infarction associated with metabolic health and obesity status. Endocr Pract. (2022) 28:802–10. doi: 10.1016/j.eprac.2022.05.007
21. Kong G, Chew NWS, Ng CH, Chin YH, Zeng R, Foo R, et al. Long-term outcomes in acute coronary syndrome patients without standard modifiable risk factors: a multi-ethnic retrospective cohort study Of 5400 asian patients. J Thromb Thrombol. (2022) 54:569–78. doi: 10.1007/s11239-022-02704-7
22. Chin Y, Lim J, Kong G, Ng CH, Goh R, Muthiah M, et al. Hepatic steatosis and advanced hepatic fibrosis are independent predictors of long-term mortality in acute myocardial infarction. Diabetes Obes Metab. (2023) 25:1032–44. doi: 10.1111/dom.14950
23. Yong JN, Ng CH, Lee CW, Chan YY, Tang ASP, Teng M, et al. Non-alcoholic fatty liver disease association with structural heart, systolic and diastolic dysfunction: a meta-analysis. Hepatol Int. (2022) 16:269–81. doi: 10.1007/s12072-022-10319-6
24. Lim WH, Chew NW, Quek J, Ng CH, Tan DJH, Xiao J, al. Echocardiographic assessment of cardiovascular function and clinical outcomes in liver transplant recipients. Clin Transplant. (2022) 36:e14793. doi: 10.1111/ctr.14793
25. Chew NW, Figtree GA, Kong G, Vernon S, Muthiah M, Ng CH, et al. Hepatic steatosis and advanced fibrosis are independent predictors of mortality in acute myocardial infarction without standard modifiable risk factors. Diabetes Obes Metab. (2022) 24:2454–8. doi: 10.1111/dom.14820
26. Fu CE, Yong JN, Ng CH, Nah B, Chew NWS, Chin YH, et al. Original article: the prognostic value of including non-alcoholic fatty liver disease in the definition of metabolic syndrome. Aliment Pharmacol Ther. (2023) 57, 979–87. doi: 10.1111/apt.17397
27. Chew NWS, Ng CH, Chan KE, Chee D, Syn N, et al. FIB-4 Predicts MACE and cardiovascular mortality in patients with nonalcoholic fatty liver disease. Can J Cardiol. (2022) 38:1779–80. doi: 10.1016/j.cjca.2022.07.016
28. Lim GEH, Tang A, Ng CH, Chin YH, Lim WH, Tan DJH, et al. An observational data meta-analysis on the differences in prevalence and risk factors between MAFLD vs NAFLD. Clin Gastroenterol Hepatol. (2023) 21:619–29.e617. doi: 10.1016/j.cgh.2021.11.038
29. Chan KE, Koh TJL, Tang ASP, Quek J, Yong JN, Tay P, et al. Global prevalence and clinical characteristics of metabolic-associated fatty liver disease: a meta-analysis and systematic review of 10 739 607 individuals. J Clin Endocrinol Metab. (2022) 107:2691–700. doi: 10.1210/clinem/dgac321
30. Chan KE, Ng CH, Fu CE, Quek J, Kong G, Goh YJ, et al. The spectrum and impact of metabolic dysfunction in MAFLD: a longitudinal cohort analysis of 32,683 overweight and obese individuals. Clin Gastroenterol Hepatol. (2022). doi: 10.1016/j.cgh.2022.09.028
31. Ng CH, Chan KE, Muthiah M, Tan C, Tay P, Lim WH, et al. Examining the interim proposal for name change to steatotic liver disease in the US population. Hepatology. (2023) 77:1712–21. doi: 10.1097/HEP.0000000000000043
32. Lin C, Yeong TJJ, Lim WH, Ng CH, Yau CE, Chin YH, et al. Comparison of mechanistic pathways of bariatric surgery in patients with diabetes mellitus: a Bayesian network meta-analysis. Obesity. (2022) 30:1380–90. doi: 10.1002/oby.23453
33. Ng CH, Muthiah MD, Xiao J, Chin YH, Lim G, Lim WH, et al. Meta-analysis: analysis of mechanistic pathways in the treatment of non-alcoholic steatohepatitis. Evidence from a Bayesian network meta-analysis. Aliment Pharmacol Ther. (2022) 55:1076–87. doi: 10.1111/apt.16808
34. Chew NWS, Ng CH, Truong E, Noureddin M, Kowdley KV. Nonalcoholic steatohepatitis drug development pipeline: an update. Semin Liver Dis. (2022) 42:379–400. doi: 10.1055/a-1877-9656
35. Yeong T, Mai AS, Lim OZH, Ng CH, Chin YH, Tay P, et al. Can glucose-lowering medications improve outcomes in non-diabetic heart failure patients? A Bayesian network meta-analysis. ESC Heart Fail. (2022) 9:1338–50. doi: 10.1002/ehf2.13822
36. Ng CH, Lin SY, Chin YH, Lee MH, Syn N, Goh XL, et al. Antidiabetic medications for type 2 diabetics with nonalcoholic fatty liver disease: evidence from a network meta-analysis of randomized controlled trials. Endocr Pract. (2022) 28:223–30. doi: 10.1016/j.eprac.2021.09.013
37. Ng CH, Xiao J, Lim WH, Chin YH, Yong JN, Tan DJH, et al. Placebo effect on progression and regression in NASH: evidence from a meta-analysis. Hepatology. (2022) 75:1647–61. doi: 10.1002/hep.32315
38. Quek J, Lim G, Lim WH, Ng CH, So WZ, Toh J, et al. The association of plant-based diet with cardiovascular disease and mortality: a meta-analysis and systematic review of prospect cohort studies. Front Cardiovasc Med. (2021) 8:756810. doi: 10.3389/fcvm.2021.756810
39. Chew NWS, Ng CH, Muthiah MD, Sanyal AJ. comprehensive review and updates on holistic approach towards non-alcoholic fatty liver disease management with cardiovascular disease. Curr Atheroscler Rep. (2022) 24:515–32. doi: 10.1007/s11883-022-01027-5
40. Ng CH, Lim WH, Chin YH, Yong JN, Zeng RW, Chan KE, et al. Living in the non-alcoholic fatty liver disease silent epidemic: a qualitative systematic review of patients' perspectives. Aliment Pharmacol Ther. (2022) 56:570–9. doi: 10.1111/apt.17121
41. Chin YH, Lim O, Lin C, Chan YY, Kong G, Ng CH, et al. Meta-analysis of the placebo and nocebo effects associated with placebo treatment in randomized trials of lipid lowering therapy. Eur Heart J Qual Care Clin Outcomes. (2022). doi: 10.1093/ehjqcco/qcac060
42. Tay PWL, Ng CH, Lin SY, Chin YH, Xiao J, Lim WH, et al. Placebo adverse events in non-alcoholic steatohepatitis clinical trials: a pooled analysis of 2,944 participants. Am J Gastroenterol. (2022) 118:645–53. doi: 10.14309/ajg.0000000000002042
Keywords: non-alcoholic fatty liver disease, cardiovascular disease, coronary artery disease, heart failure, hyperlipidemia, diabetes, hypertension
Citation: Chew NWS, Kannan S, Chong B, Chin Y and Muthiah M (2023) Editorial: The heart of NAFLD. Front. Med. 10:1209625. doi: 10.3389/fmed.2023.1209625
Received: 21 April 2023; Accepted: 08 May 2023;
Published: 22 May 2023.
Edited and reviewed by: Angel Lanas, University of Zaragoza, Spain
Copyright © 2023 Chew, Kannan, Chong, Chin and Muthiah. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Nicholas W. S. Chew, bmljaG9sYXNfd3NfY2hldyYjeDAwMDQwO251aHMuZWR1LnNn
†These authors share first authorship
‡ORCID: Nicholas W. S. Chew orcid.org/0000-0002-0640-0430