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Nonalcoholic Fatty Liver Disease and Cardiovascular Risk: A Scientific Statement From the American Heart Association
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One reason for heart disease being a leading cause of death among PLWH in NYC is that NASH, fatty liver can contribute to heart disease. In fact, CVD is a principal cause of death in patients with NAFLD. And among PLWH their providers do not screen or pay much attention to fatty liver disease nor do PLWH have much awareness around this problem. Jules
14 Apr 2022
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition that is believed to affect >25% of adults worldwide. Unless specific testing is done to identify NAFLD, the condition is typically silent until advanced and potentially irreversible liver impairment occurs. For this reason, the majority of patients with NAFLD are unaware of having this serious condition. Hepatic complications from NAFLD include nonalcoholic steatohepatitis, hepatic cirrhosis, and hepatocellular carcinoma. In addition to these serious complications, NAFLD is a risk factor for atherosclerotic cardiovascular disease, which is the principal cause of death in patients with NAFLD. Accordingly, the purpose of this scientific statement is to review the underlying risk factors and pathophysiology of NAFLD, the associations with atherosclerotic cardiovascular disease, diagnostic and screening strategies, and potential interventions.
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on January 13, 2022, and the American Heart Association Executive Committee on February 21, 2022. A copy of the document is available at https://professional.heart.org/statements by using either "Search for Guidelines & Statements" or the "Browse by Topic" area. To purchase additional reprints, call 215-356-2721 or email Meredith.Edelman@wolterskluwer.com.
The American Heart Association requests that this document be cited as follows: 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. Arterioscler Thromb Vasc Biol. 2022;42: doi: 10.1161/ATV.0000000000000153
The expert peer review of AHA-commissioned documents (eg, scientific statements, clinical practice guidelines, systematic reviews) is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit https://professional.heart.org/statements. Select the "Guidelines & Statements" drop-down menu, then click "Publication Development."
Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at https://www.heart.org/permissions. A link to the "Copyright Permissions Request Form" appears in the second paragraph
(https://www.heart.org/en/about-us/statements-and-policies/copyright-request-form).
TERMINOLOGY
Although there are some differences in definitions between organizations, it is important to define the ter-minology for NAFLD. Hepatic steatosis refers to ectopic deposition of triglycerides in the liver. Alcohol-associated liver disease is associated with liver injury and character-ized by hepatic steatosis that is attributable to excess alcohol intake. Many patients with NAFLD consume modest amounts of alcohol, which may contribute to the development of hepatic steatosis in this scenario, simple sugars, can aggravate hypertriglyceridemia and hyperglycemia in many patients, but there are impor-tant exceptions. Dietary fructose intake is associated with reduced glycemic index compared with glucose, but it is more likely to aggravate insulin resistance and hypertriglyceridemia. In addition, among patients with severe hypertriglyceridemia (plasma triglycerides >500 mg/dL), weight reduction is likely to reduce triglyceride levels. Reduced dietary fat intake may reduce triglycer-ide levels, especially if very severely elevated. However, increased carbohydrate intake may also increase tri-glyceride levels in some individuals in the 500- to 1000-mg/dL range. Weight gain is a multifactorial condition that aggravates multiple risk factors for NAFLD, includ-ing increased triglyceride production, insulin resistance, hyperglycemia, and hypertriglyceridemia. Although obesity is common among patients with NAFLD, ≈10% to 20% of Americans and Europeans with NAFLD are lean by BMI criteria.2 Physical inactivity favors weight gain and insulin resistance, which contribute to devel-opment of NAFLD.
PATHOGENESIS OF NAFLD
The initial stages of hepatic steatosis involve ectopic accumulation of triglycerides in the liver. Several sources of fatty acids are used for hepatic synthesis of ectopi-cally deposited triglycerides, but the majority are typically derived from increased flux of free fatty acids resulting from excess hydrolysis of adipose tissue triglycerides attributable to unsuppressed hormone-sensitive lipase in the setting of insulin resistance. There also are con-tributions from increased intrahepatic de novo fatty acid synthesis from excess carbohydrates, as well as uptake from plasma of dietary derived chylomicrons and hepati-cally synthesized VLDL. Hepatic triglyceride assembly is generally coordinated with VLDL synthesis and secre-tion, with intrahepatic triglycerides stored in intracellular lipid droplets. Hepatic steatosis occurs when there is an imbalance between hepatic lipid storage and lipid clear-ance, thereby favoring excessive triglyceride storage in hepatocyte lipid droplets. Factors that may contribute to this imbalance include (1) deviations in the relative size of the intrahepatic pool of fatty acids, (2) rates of triglyc-eride and apolipoprotein B (apoB) synthesis, (3) rates of lipolysis of lipid droplet triglycerides, and (4) rates of fatty acid β-oxidation. The formation of microvesicular (small) and macrovesicular (large) lipid droplets is a bidirectional process that can be diminished or reversed by interven-tions that reduce fatty acid uptake and de novo synthe-sis, decrease triglyceride synthesis, increase lipolysis, increase fatty acid oxidation, or increase VLDL produc-tion and secretion.
It has been challenging to predict which patients will progress from NAFL to NASH and cirrhosis. Among those patients who develop progressive disease, there is additional heterogeneity in the tempo of the disease, with some patients experiencing rapid progression from ste-atohepatitis to fibrosis and cirrhosis and, in some cases, hepatocellular carcinoma. The rapidity of progress is best predicted by the extent of fibrosis observed on the initial liver biopsy. Other patients with NAFL may have an indo-lent course of progression over many years. It is important to emphasize that although lack of progression from NAFL to NASH is associated with the best prognosis for liver outcomes, uncomplicated NAFL is nonetheless associated with increased risk of CVD.
NAFLD AND ATHEROSCLEROTIC CVD RISK
NAFLD is an underappreciated and independent risk factor for atherosclerotic CVD (ASCVD) even after adjustment for ASCVD risk factor covariates in a large number of investigations (Table 2).34-55 Subclinical CVD and many other cardiovascular risk factors are increased among patients with NAFLD/NASH.56-58 Risk factors for ASCVD are also increased by NAFLD; severity of NAFLD is associated with a higher incidence of ASCVD risk factors such as diabetes and hyperten-sion.59 The underlying risk factors for NAFLD such as dyslipidemia and dysregulation of glucose homeostasis contribute to the increased ASCVD risk in NAFLD, but the predilection for ectopic fat deposition in the liver and other tissues seems to be associated with heightened risk of ASCVD beyond the risk attributable to traditional risk factors. In addition to the aforementioned factors, NAFLD is associated with endothelial dysfunction, heightened systemic inflammatory tone,60,61 and ectopic fat deposition in other organs (eg, pancreas, skeletal muscle, and epicardium). Increased epicardial fat pad volume correlates highly with heightened intramyocar-dial inflammation, endothelial dysfunction, and acceler-ated atherogenesis.62 Although the results of a previous meta-analysis suggested that NAFLD was associated with all-cause mortality and not CVD mortality63 and results of a recent analysis demonstrated that fibrosis stages F3 and F4 were associated with increased liver complications and total mortality,64 ASCVD is the princi-pal cause of death in patients with NAFLD.65
NAFLD is a consequence of profound systemic dis-turbances in lipid metabolism.66 In the setting of insulin resistance, there is metabolic dysregulation of visceral adipose tissue. Within adipocytes, hormone-sensitive lipase is no longer appropriately inhibited by insulin, resulting in increased lipolysis of adipocyte triglycerides and circulating levels of free fatty acids.67 As the flux of fatty acids to the liver increases, fatty acids can be disposed of through a variety of pathways: (1) Fatty acids can be transported into mitochondria and con-sumed via β-oxidation; (2) they can be reassimilated into triglycerides, packaged into VLDL particles, and secreted into the circulation; (3) glycerol and odd chain fatty acids arising from triglycerides can be diverted to gluconeogenesis; and (4) if these systems are over-whelmed, excess triglyceride can form cytosolic fat droplets, leading to the development of NAFLD. The propensity for increased liver fat deposition is exac-erbated by augmented de novo hepatic lipogenesis induced by insulin resistance.68
RISK FACTORS FOR NAFLD
There is overlap among risk factors for the metabolic syndrome and NAFLD, but patients can develop the metabolic syndrome without NAFLD and vice versa. Moreover, although a condition such as type 2 diabetes is associated with increased risk of NAFLD, the association is bidirectional, which means a diagnosis of NAFLD in a nondiabetic patient is associated with increased risk of incident type 2 diabetes. These interactions are related to the contribution of visceral adiposity and insulin resis-tance to the pathogenesis of NAFLD and type 2 diabe-tes. A summary of risk factors, including medications, is shown in Table 1.
Lipodystrophy
Lipodystrophy can be congenital or acquired and is char-acterized by diminished adipose tissue, either total or partial. The inability to store fat in adipose tissue depots is associated with severe insulin resistance and ectopic triglyceride deposition, including in the liver, which fre-quently demonstrates features of NASH and NAFLD in both total and partial forms of lipodystrophy.22
Chronic Kidney Disease
A high prevalence of chronic kidney disease exists among patients with NASH. Both NASH and chronic kidney dis-ease are associated with visceral obesity, type 2 diabe-tes, metabolic syndrome, and insulin resistance.23 The severity of NASH histology is associated with decreased kidney function independently of insulin resistance and other components of the metabolic syndrome,24 although the presence of type 2 diabetes has been shown to pre-dict renal dysfunction in patients with NASH.25 Moreover, a meta-analysis showed that the presence and sever-ity of NAFLD were associated with increased risk and severity of chronic kidney disease.26 Mechanisms pro-posed to account for how NAFLD might potentiate renal injury include lipoprotein dysmetabolism and altered hepatic secretion of fibroblast growth factor-21, fetuin-A, insulin-like growth factor-1, and syndecan-1. Conversely, chronic kidney disease may mutually aggravate NAFLD and associated metabolic disturbances through altered intestinal barrier function and microbiota composition, accumulation of uremic toxic metabolites, and alterations in prereceptor glucocorticoid metabolism.27
Polycystic Ovarian Syndrome
Polycystic ovarian syndrome is characterized by chronic anovulation and hyperandrogenism and is strongly asso-ciated with obesity and insulin resistance, which are 2 key features of NASH. NAFLD and polycystic ovarian syndrome are direct manifestations of insulin resistance. About 25% to 40% of patients with polycystic ovarian syndrome have evidence of NASH.28,29 A systematic review and meta-analysis demonstrated that patients with polycystic ovarian syndrome have increased prev-alence of NAFLD with an odds ratio of 2.5 and that the presence of NAFLD is associated with high serum androgen levels, obesity, and insulin resistance.30
Lifestyle and Acquired Conditions
Lifestyle plays an important role in the development and treatment of NAFLD.19 Dietary factors that aggravate hypertriglyceridemia, hyperglycemia (fasting and post-prandial), insulin resistance, and weight gain are associ-ated with increased risk for the development of NAFLD. Increased carbohydrate intake, particularly in the form of obesity is common among patients with NAFLD, ≈10% to 20% of Americans and Europeans with NAFLD are lean by BMI criteria.2 Physical inactivity favors weight gain and insulin resistance, which contribute to devel-opment of NAFLD.
Type 2 Diabetes
Type 2 diabetes and impaired glucose tolerance are important risk factors for the development of NAFLD and NASH.20 Type 2 diabetes is associated with insu-lin resistance, hyperglycemia, hypertriglyceridemia, increased free fatty acid flux from adipose tissue to the liver, and increased visceral adiposity, all of which are associated with increased risk of NAFLD and NASH. Not all glucose-lowering interventions are associated with improvement in hepatic steatosis, whereas treat-ment with medications that augment insulin sensitivity is associated with improvement.
Dyslipidemia
Hypertriglyceridemia is associated with insulin resis-tance, impaired glucose tolerance, type 2 diabetes, vis-ceral adiposity, obesity, and the metabolic syndrome, all of which are associated with increased risk of NAFLD. As described in the section on pathophysiology, the plasma triglyceride concentration may be less important than the balance between rates of triglyceride synthe-sis, very-low-density lipoprotein (VLDL) secretion, free fatty acid flux, hydrolysis of triglycerides in hepatocyte lipid droplets, and intrahepatic fatty acid oxidation. If triglyceride production exceeds the rates of clearance/secretion, ectopic deposition of excess triglycerides in the liver will be favored.
Metabolic Syndrome
We do not yet have a universal consensus on defining the metabolic syndrome, but visceral adiposity and insu-lin resistance are key underlying features of the condition. In the United States, the diagnosis of the metabolic syndrome is based on the presence of 3 or more of the following: increased waist circumference (men >40 in, women >35 in), hyperglycemia (fasting plasma glucose ≥100 mg/dL), hypertriglyceridemia (fasting triglycerides ≥150 mg/dL), low high-density lipoprotein cholesterol (men <40 mg/dL, women <50 mg/dL), and elevated blood pressure (≥130/85 mm Hg). The association of the metabolic syndrome with insulin resistance, hyper-glycemia, visceral adiposity, and hypertriglyceridemia contributes to increased risk of NAFLD, but it is also possible that the presence of NAFLD negatively affects features of the metabolic syndrome. Metabolic syn-drome is also associated with increased risk of hepatic steatohepatitis and fibrosis.21
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