Pub Date: Thursday, Apr 14, 2022
Author: Raul D. Santos MD, PhD, MSc
Affiliation: Heart Institute (InCor) University of Sao Paulo Medical School Hospital and Hospital Israelita Albert Einstein, Sao Paulo, Brazil
Excess body adiposity is ubiquitous and is associated with several other ailments like type 2 diabetes mellitus, dyslipidemia, hypertension, sleep apnea, cancer, orthopedic problems, and cardiovascular diseases (CVD) among others(1). One important component of excessive adiposity is accumulation of fat in the liver or steatosis. The latter defined as an accumulation of fat (triglycerides) in > 5% of liver cells is usually part of a common syndrome called non-alcoholic fatty liver disease (NAFLD)(2). NAFLD is associated with a greater risk of liver disease (e.g., cirrhosis and liver cancer), CVD as well as total mortality(2, 3).
NAFLD is a silent and progressive and may evolve from simple liver fat accumulation to liver inflammation i.e., non-alcoholic steatohepatitis or NASH, liver fibrosis, cirrhosis and hepatocarcinoma(2). Indeed, due to its elevated prevalence NAFLD (25-30% of adults and almost in 50% of people with type 2 diabetes mellitus) is the main cause of liver disease in the US and elsewhere(4). In most situations NALFD is associated and worsens the metabolic derangements of the metabolic syndrome (elevation in blood pressure, atherogenic dyslipidemia, insulin resistance and dysglycemia and low-grade inflammation). Despite the important role played by excess adiposity on its origin and pathophysiology, NAFLD is multifactorial and genetic (variations in genes like the patatin-like phospholipase domain containing protein 3- PNLAP3, or the membrane bound O-acyltransferase domain containing 7 -MBOAT7 among others), dietary (e.g., diets rich in fructose), lifestyle (sedentarism) and microbiota components may all be operative(2).
Considering that NAFLD has a strong association with obesity, that the metabolic derangements may contribute to progression of liver disease, and that it can also occur in people who drink alcohol and may also have viral liver disease, hepatologists have suggested to change the term NAFLD to Metabolic (dysfunctional) Associated Fatty Liver Disease or MAFLD(5). This term is more inclusive since considers NALFD in the context of excess body weight and the metabolic syndrome as common links to either liver or cardiovascular problems. At any rate, changing names will not change the characteristics and magnitude of the problem. Considering this the recent American Heart Association (AHA) scientific statement on NAFLD and Cardiovascular Risk brings important and practical information for health care providers and lay people with focus on CVD prevention and management in those with NAFLD/MAFLD(6).
It is of extreme importance that non-liver disease specialists be aware of the hepatic aspects of the disease since one may have NASH and fibrosis (more severe forms of the disease that may affect up in 10-25% of those with NAFLD) be totally symptomless and have normal liver enzymes(6). These people may evolve to liver fibrosis and more severe liver disease. The strong association of more severe disease with type 2 diabetes is important for non-liver specialists must have a low threshold to refer these individuals to an hepatologist.
Unfortunately, the only certain way of diagnosing NASH and fibrosis is by liver biopsy however this procedure may bring very important prognostic information for physicians and patients. On the other hand, liver specialists, must be aware that NASH and fibrosis stages are associated with higher CVD risks when compared to those with steatosis only. The document emphasizes the need for a good CVD and liver disease risk stratification that can be done with use of risk scores like the pooled risk equation and the NAFLD fibrosis or the Fibrosis-4 (FIB-4) score respectively. Of importance the AHA document considers NAFLD as an aggravating factor for CVD. Imaging techniques for detection of both liver (ultrasound, computed tomography or elastography) and CVD (i.e., coronary calcium scores) may also be useful in risk stratification. It is also important to consider that NAFLD/NASH is associated with a greater risk of chronic kidney disease(7), a situation that predisposes to CVD per se and that is common in people with hypertension and type 2 diabetes that are frequent companions to NAFLD. Therefore, it is of great relevance to check renal function in those individuals.
One of the greatest challenges in clinical practice is how to prevent progression of NAFLD as well as CVD. Weight loss, low calory diets, avoidance of sucrose sweetened beverages and alcohol, and exercise are extremely important considering the role played by excess adiposity in NAFLD. Weight losses of 5-10% may induce robust reductions in hepatic fat. Indeed, medications approved for weight loss like the Glucagon-like 1 peptide receptor agonists liraglutide(8) and semaglutide(9) may reduce not only steatosis but also liver inflammation. Interesting these medications have anti-atherosclerotic effects in people with type 2 diabetes and it is tempting to speculate if effects on the liver may have influenced on the results(10). However, we don’t know how these medications will affect liver disease in the long-term since there is no evidence that they may reduce liver fibrosis(8, 9) . Some other medications for type 2 diabetes like pioglitazone(11) and metformin(12) may be useful but with modest effects. Another important aspect is to control atherogenic dyslipidema with statins since this may change the course of both liver and CVD(13). Unfortunately, there are no specific approved medications to treat NAFLD, but many drugs are being investigated.
In conclusion NAFLD is common disease associated with increased visceral adiposity. It is associated with a higher risk of either liver or CVD disease and should be seen in the context of an additional and important component of the metabolic syndrome(6). Whether if liver fat alone causes atherosclerosis is irrelevant since it is usually encountered in the context of the metabolic syndrome, and one must identify it and control de concomitant risk factors for CVD(2).
Duell PB, Welty FK, Miller M, Chait A, Hammond G, Ahmad Z, Cohen DE, Horton JD, Pressman GS, Toth PP; on behalf of the American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Hypertension; Council on the Kidney in Cardiovascular Disease; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease. Nonalcoholic fatty liver disease and cardiovascular risk: a scientific statement from the American Heart Association. [published online ahead of print April 14, 2022]. Arterioscler Thromb Vasc Biol. doi: 10.1161/ATV.0000000000000153
- Neeland IJ, Ross R, Despres JP, Matsuzawa Y, Yamashita S, Shai I, et al. Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement. Lancet Diabetes Endocrinol. 2019;7(9):715-25.
- Santos RD, Valenti L, Romeo S. Does nonalcoholic fatty liver disease cause cardiovascular disease? Current knowledge and gaps. Atherosclerosis. 2019;282:110-20.
- Sanyal AJ, Van Natta ML, Clark J, Neuschwander-Tetri BA, Diehl A, Dasarathy S, et al. Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease. The New England journal of medicine. 2021;385(17):1559-69.
- 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(1):73-84.
- Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020;73(1):202-9.
- Duell PB Welty F, Miller M , Chait A, Hammond G, Ahmad Z, Cohen DE, Horton JD, Pressman GS, Toth PP Nonalcoholic Fatty Liver Disease and Cardiovascular Risk: A Scientific Statement from the American Heart Association. Circulation 2022.
- Byrne CD, Targher G. NAFLD as a driver of chronic kidney disease. J Hepatol. 2020;72(4):785-801.
- Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679-90.
- Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. The New England journal of medicine. 2021;384(12):1113-24.
- Ferrari F, Scheffel RS, Martins VM, Santos RD, Stein R. Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus and Cardiovascular Disease: The Past, Present, and Future. Am J Cardiovasc Drugs. 2021. Dec 27. pii: 10.1007/s40256-021-00515-4. doi: 10.1007/s40256-021-00515-4.
- Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med. 2016;165(5):305-15.
- Li Y, Liu L, Wang B, Wang J, Chen D. Metformin in non-alcoholic fatty liver disease: A systematic review and meta-analysis. Biomed Rep. 2013;1(1):57-64.
- Sigler MA, Congdon L, Edwards KL. An Evidence-Based Review of Statin Use in Patients With Nonalcoholic Fatty Liver Disease. Clin Med Insights Gastroenterol. 2018;11:1179552218787502.
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