Introduction
Metabolic associated fatty liver disease (MAFLD) is a common medical condition while visceral obesity is its most frequent underlying reason. MAFLD promotes the occurrence of other components of metabolic syndrome [1–3]. Patients with MAFLD are more prone to cardiovascular conditions, including atherosclerotic cardiovascular disease (ASCVD) than persons with normal liver function [4, 5].
The fairly high prevalence of non-alcoholic steatohepatitis (NASH) is a significant observation, as this condition precedes the development of serious hepatological consequences in patients with MAFLD. The incidence of NASH is rather difficult to estimate. Since NASH has to be confirmed by a histopathological evaluation, its exact diagnosis, in terms of proper methodology, can be obtained only in some patients. Following current estimates, NASH affects 2.5%–5% of the adult population. Progressive fibrosis will develop in about 40% of patients with NASH [6]. Regarding patients with MAFLD, but without NASH, disease progression is also observed but at a much slower rate [7]. NASH and its consequences are estimated to occur much more frequently than any other liver disease.
This expert opinion aims to outline principles of MAFLD diagnosis, methods of identification of the groups of patients in whom MAFLD should be diagnosed, and management procedures to reduce cardiovascular risks in patients with MAFLD.
The diagnosis of MAFLD
The overall prevalence of MAFLD is estimated at 25% of the general population in developed countries. According to the definition proposed in 2020, MAFLD affects the following subjects: overweight/obese individuals with type 2 diabetes mellitus (T2DM) and normal weight persons fulfilling at least 2 criteria, mainly metabolic ones. The diagnosis of hepatic steatosis in normal weight individuals, referred to by the English term “lean NAFLD”, may be an issue in clinical practice. The risk factors for its occurrence are still insufficiently recognized or understood. Some patients present metabolic disorders and specific genetic mutations in mitochondrial enzymes [8, 9]. The current division of fatty liver disease into alcoholic and non-alcoholic has been raising many controversies. Indeed, alcohol consumption may induce steatosis of the liver. However, it is increasingly suggested that, especially in these cases, metabolic effects are likely to outweigh toxic effects of alcohol.
The clinical diagnosis is obtained via assessment of risk factors for MAFLD [8, 9]. The diagnostic criteria for MAFLD include:
- Obesity or overweight, defined as a body mass index (BMI) ≥25 kg/m2;
- T2DM;
- The occurrence of at least 2 of the following factors, irrespective of BMI:
- abdominal obesity waist circumference ≥102/88 cm in men/women;
- pre-diabetes, defined as fasting glucose level: 100–125 mg/dl (5.6–6.9 mmol/l) or in 2 hours after glucose load: 140–199 mg/dl (7.8–11 mmol/l) or glycated hemoglobin level: 5.7%–6.4% (39–47 mmol/mol);
- arterial blood pressure ≥130/85 mm Hg or antihypertensive treatment;
- serum triglyceride level ≥150 mg/dl (1.7 mmol/l) or lipid-lowering treatment;
- high-density lipoprotein cholesterol (HDL-C) level <40 mg/dl (1.0 mmol/l) for men and <50 mg/dl (1.3 mmol/l) for women;
- Homeostatic Model Assessment — Insulin Resistance (HOMA-IR) ≥2.5;
- high-sensitivity C-reactive protein (hs-CRP) level >2 mg/l.
The diagnosis of MAFLD requires demonstration of hepatic steatosis by diagnostic imaging (non-invasive methods) and/or histopathology (liver biopsy) and ruling out any other cause of steatosis/liver disease. The other most common reasons for hepatic steatosis include alcohol abuse, hepatitis C virus infection, drugs, parenteral nutrition, Wilson’s disease, and malnutrition. In addition, differential diagnosis should take into account hemochromatosis, autoimmune liver disease, or alpha-1-antitrypsin deficiency [8]. MAFLD may be concomitant with other diseases. Detailed differential diagnostics is particularly important when advanced liver fibrosis and/or NASH is present.
MAFLD and cardiovascular prognosis
The 2021 guidelines of the European Society of Cardiology (ESC) for the prevention of cardiovascular conditions identify MAFLD as a condition to be considered in cardiovascular risk assessment. It was emphasized that MAFLD was associated with increased risk of myocardial infarction and stroke [10]. Also, a document on MAFLD and cardiovascular risk, issued by the American Society of Cardiology, emphasized that MAFLD was a common condition with a multidirectional relationship with cardiovascular diseases [11]. The consequences of MAFLD include, of course, hepatitis, hepatic fibrosis, and finally cirrhotic remodeling of the liver with increased risk of primary liver cancer. Regarding patients with advanced cirrhosis, liver failure and cancer are the most common reasons for death. Notably, the majority of patients with MAFLD may present a benign clinical course of liver disease/condition, whereas cardiovascular diseases become the main reason for premature death [12] (Figure 1).
In the group of patients with MAFLD, cardiovascular deaths were recorded in 43% of patients during a 33-year follow-up [13]. An observational study (the mean follow-up period of 19 years) of patients with a liver biopsy-confirmed diagnosis of MAFLD showed that cardiovascular events had occurred in 28% of the subjects with MAFLD and 21% of the subjects with normal liver function [14]. In turn, a population-based evaluation from the Framingham study reported that hepatic steatosis had been associated with coronary artery and abdominal aortic calcifications, regardless of the presence of other conditions that had been enhancing the cardiovascular risk [15]. Lee et al. [16] obtained computed tomography scans of the coronary artery in asymptomatic patients without a history of cardiovascular events and showed that MAFLD had predisposed to non-calcified atherosclerotic plaques while the degree of fibrosis and hepatic steatosis had correlated with their prevalence. In a meta-analysis, involving 12 620 736 patients, MAFLD had increased the risk of total, all-cause, and cardiovascular mortality compared to patients without MAFLD. Patients with MAFLD demonstrated an increased risk of cardiovascular events, stroke, and chronic kidney disease [17]. In another meta-analysis, including 10 576 383 patients with MAFLD and normal weight, after excluding obesity as a significant factor for a cardiovascular prognosis, cardiovascular events had been common in patients with MAFLD (18.7/1000 person-years) [18].
The high prevalence of cardiovascular conditions in patients with MAFLD is a result of the complex correlation between hepatic steatosis and classical and non-classical cardiovascular risk factors, commonly observed in this particular population (Figure 2) [19]. The majority of patients with MAFLD demonstrate insulin resistance, hypertension, dyslipidemia, overweight, or obesity [20, 21]. In addition, MAFLD is associated with a high prevalence of non-classic cardiovascular risk factors, i.e. chronic kidney disease, hyperuricemia, low vitamin D levels, and low adiponectin levels [22–24].
The mechanisms of ASCVD development in patients with MAFLD are multidirectional. MAFLD induces insulin resistance, increases hepatic glucose synthesis, and significantly affects the lipid profile. These mechanisms coexist with enhanced oxidative stress, impaired fibrinolysis, and increased blood clotting. In addition, in patients with MAFLD, excess of visceral adipose tissue and its hormonal dysfunction is observed, with increased leptin and decreased adiponectin levels. Given the imbalance between anti-inflammatory factors and increased production of pro-inflammatory cytokines and of increased pro-coagulant activity and dyslipidemia in patients with MAFLD, atherosclerotic mechanisms begin to be activated [25–27].
It has been shown that cardiovascular conditions, other than ASCVD, are more common in patients with MAFLD than in the population without liver disease. A meta-analysis of nine studies involving 364 919 patients showed that MAFLD was a predisposing factor to atrial fibrillation [28]. Ventricular arrhythmias were also shown to be more frequent in patients with MAFLD [29]. A meta-analysis of 12 studies, involving 280 000 patients, demonstrated that heart failure with preserved left ventricular systolic function in patients with well-controlled T2DM and MAFLD occurred independently of other risk factors [30].
Practical diagnostic tips
Taking into account the frequent concomitance of MAFLD, cardiovascular and metabolic conditions, MAFLD should actively be screened in patients with cardiovascular and metabolic diseases. We propose to carry out diagnostic examinations for MAFLD in patients with:
- T2DM/pre-diabetes;
- dyslipidemia;
- hypertension;
- overweight/obesity;
- ASCVD;
- increased activity of hepatic enzymes.
On the other hand, given that cardiovascular complications including ASCVD are more likely to develop in patients with MAFLD than in patients with a healthy liver, we recommend performing the following examinations in patients with MAFLD:
- BMI and waist circumference measurements;
- blood pressure measurements at home and in a surgery;
- glucose and uric acid level and lipid profile tests;
- electrocardiographic examination;
- ultrasonography imaging of the carotid arteries.
MAFLD and lipid disorders
Patients with MAFLD demonstrate proatherogenic lipid profiles, characterized by high triglyceride levels, low-density lipoprotein cholesterol (LDL-C), reduced HDL-C, and high apolipoprotein B (apoB) levels. MAFLD sometimes coexists with hypobetalipoproteinemia, which is a rare pathology characterized by low LDL-C <50 mg/dl resulting from mutations in the apoB encoding gene. In the course of hypobetalipoproteinemia, there is an increased synthesis of cholesterol of the very low-density lipoprotein cholesterol (VLDL) fraction, apoB, and triglycerides. There are no conclusive data on the prognosis of patients with MAFLD and hypobetalipoproteinemia [31].
Cardiovascular risk assessment should be performed in patients with MAFLD and dyslipidemia, according to general principles. As in the majority of patients with MAFLD, this liver disease coexists with metabolic syndrome, and these patients are characterized by high triglyceride and low LDL-C levels, it is worth paying attention to non-HDL-C levels in this group. It reflects the concentration of total cholesterol, transferred by atherogenic apoB-containing lipoproteins, including triglyceride-rich particles and their remnants present in VLDL. According to the 2019 ESC guidelines on dyslipidemia in patients with metabolic disorders, the apoB assay may be an alternative to LDL-C and preferred to non-HDL-C level assays [32].
Following qualification into a specific risk group, lipids targets should be set for patients with dyslipidemia and MAFLD. The main therapeutic target is LDL-C level, while non-HDL-C and apoB levels are additional therapeutic targets [32, 33].
Due to the common prevalence of cardiovascular conditions in patients with MAFLD, they usually present with high cardiovascular risk and require lipid-lowering agents. In patients with MAFLD, statin therapy is very effective in reducing the risk of cardiovascular morbidity and mortality, compared to patients not using statins (68% vs. 39%; P = 0.007) [34]. Statins are safe and well-tolerated agents. In rare cases, they can induce side effects, myalgia, and elevated liver enzymes [35]. A transient, asymptomatic increase in liver enzymes occurs in 0.1%–3% of patients while liver failure, due to statin effects, is an extremely rare condition (2 per 100 000 patients) [36]. However, in the vast majority of cases, the elevations of liver enzymes, observed in statin users, do not correlate with the presence of morphological changes in histological evaluations and cannot be thus regarded as indicators of actual liver damage. Despite that, there is a fairly high proportion of patients (1.85%–12%) in whom statin therapy is discontinued due to an increase in liver enzymes [37, 38]. The discontinuation of lipid-lowering therapy in patients with MAFLD, who present an increase in liver enzymes, which is part of the clinical picture of fatty liver diseases, is undoubtedly an important factor accelerating the development of cardiovascular complications in this particular group of patients. Discontinuation of statin therapy in patients with MAFLD results from concerns that these drugs may exacerbate hepatic steatosis. However, this hypothesis has not been confirmed by the results of clinical trials. On the contrary, chronic statin use in patients with MAFLD has been shown to regress steatotic lesions, reduce inflammatory activity, and even reduce the degree of fibrosis [39]. In a post hoc analysis of the GREACE study, including patients with MAFLD and with moderately elevated liver enzymes, a reduction in cardiovascular mortality was observed in the statin-treated patients while no significant statin-related increase in liver enzymes was observed in these patients [40]. A meta-analysis of 22 studies, involving patients with MAFLD, showed that aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGTP) activities decreased, on average, by one-third of the baseline values during statin therapy [41].
Data also support the safety of ezetimibe use in patients with MAFLD. In the MOZART study, ezetimibe in a dose of 10 mg had no effect on the course of hepatic steatosis [42]. Furthermore, the ESSENTIAL study showed that ezetimibe, in a dose of 10 mg, combined with rosuvastatin in a dose of 5 mg, was safe and reduced fibrosis in patients with MAFLD, compared to those treated with rosuvastatin alone [43].
The selection of a lipid-lowering drug and its dose in patients with dyslipidemia and MAFLD should be guided by its efficacy in achieving the LDL-C target values, as defined for a given cardiovascular risk group [32, 33]. According to an expert opinion, rosuvastatin is the preferred statin in patients with liver disease due to its pharmacokinetic profile [44]. The treatment of both dyslipidemia and MAFLD should start with non-pharmacological management, which will be discussed later. Lipid-lowering therapy should be launched in patients with MAFLD, starting with a potent statin at the highest recommended/tolerated dose and, if the main therapeutic goal is not achieved, ezetimibe should be added, and if this scheme is still ineffective, a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9) should be added [32, 33]. According to the currently valid guidelines, liver function monitoring (ALT activity determination) should be performed before the onset of lipid-lowering treatment; it should be then repeated after 4–6 weeks from the therapy starting point [32, 33]. Figure 3 presents a lipid-lowering treatment initiation scheme in patients with dyslipidemia and MAFLD.
MAFLD and obesity
MAFLD usually accompanies abdominal obesity. Hepatic steatosis rarely occurs in patients with normal body weight and normal glucose tolerance. Insulin resistance and impaired fat tissue distribution with an increased waist circumference are usually observed in such cases. Steatosis of the liver occurs in 70%–80% of obese people [45]. A 1% increase in visceral fat deposition increases hepatic lipid accumulation by 40%, and a 1% increase in subcutaneous fat deposition increases hepatic lipid accumulation by 20% [46]. Abdominal ultrasound is recommended in patients with excessive body weight to assess hepatic steatosis [47].
Patients with MAFLD and a BMI ≥25 kg/m2 are recommended to reduce their body weight by reducing the energy component in the diet and increasing physical activity. BMI reduction by at least 5% is recommended, which significantly decreases hepatic steatosis. A gradual weight reduction is advisable; body weight reduction must not exceed 0.5 kg per week. The objective of diet modification should be the reduction of its energy content by 30% vs. total energy demand, which can be achieved by cutting calories, namely by 750–1000 kcal per day [48]. Diets that are too low in energy, causing rapid weight loss, may contribute to progression of liver lesions. It is recommended to limit simple sugars and saturated fats in the diet in favor of mono- and polyunsaturated fats. Restricting carbohydrate intake, including fructose, is important in the management of obesity in patients with MAFLD. The recommended physical efforts should be of moderate intensity and adapted to the patient’s physical capabilities. The weight reduction process in patients with BMI ≥35 kg/m2, besides dietary recommendations, may require pharmacotherapy and/or bariatric surgery [49].
MAFLD and T2DM
The development of T2DM in patients with MAFLD is promoted by the following two primary mechanisms: reduced tissue sensitivity to insulin and impaired insulin secretion/generation by pancreatic beta cells. A meta-analysis, including 20 clinical studies and 117 020 patients with an average 5-year follow-up, showed that patients with MAFLD had a twofold increased risk of T2DM, compared to those without fatty liver disease [50]. MAFLD is diagnosed in 70% of patients with T2DM [51]. MAFLD is strongly associated with insulin resistance; patients with MAFLD tend to demonstrate worse glycemic control than those with T2DM and normal liver function. Therapy strategies, aimed at reducing intrahepatic triglyceride levels and improving insulin sensitivity, may result in better glycemic control in patients with T2DM and MAFLD [23]. On the other hand, proper glycemic control is known to limit liver exposure to harmful metabolic factors, so the selection and setup of an optimal treatment regimen for T2DM and MAFLD are the key issues.
The choice of glucose-lowering treatment in patients with T2DM and MAFLD should be based on the efficacy of a given agent to achieve glycemic targets and ensure a potential impact of the drug on body weight reduction. Patients with T2DM and MAFLD are at high risk of cardiovascular events, so the prescribed glucose-lowering drugs should ensure a reduction of their incidence rate. In the Polish 2019 expert opinion on the management of patients with MAFLD, two drugs: pioglitazone and incretin are recommended for patients with concomitant T2DM [49]. Similarly, in the 2022 American Association for the Study of Liver Diseases guidelines, the preferred glucose-lowering drugs in patients with T2DM and MAFLD include pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors [47]. The profile of the patient with T2DM and MAFLD should determine the choice of a glucose-lowering drug. In patients with coexisting heart failure and/or chronic kidney disease, SGLT2 inhibitors should be preferred while GLP-1 agonists should be favored in patients with obesity and/or coronary artery disease.
Treatment of MAFLD in patients with cardiovascular conditions
As MAFLD is rarely isolated and most often occurs with cardiometabolic conditions, and the multidirectional relationship between hepatic steatosis and cardiovascular conditions worsens the prognosis of these patients, a parallel treatment of cardiovascular conditions should be adopted to achieve therapeutic goals. An optimal strategy should include cardiac drugs as well as drugs to improve liver function (Figure 4) [50].
The pharmacological treatment to improve liver function and correct the metabolic abnormalities caused by MAFLD should include drugs with antioxidant, anti-apoptotic, fibrosis-reducing, and hepatocyte metabolism normalizing effects. The drugs that potentially meet these criteria and are available in Poland include vitamin E and ursodeoxycholic acid (UDCA).
Vitamin E, used in high doses of 400–800 IU/day, reduces hepatic steatosis and inflammation but has no significant effect on the fibrosis process [51]. An increased risk of hemorrhagic stroke and the development of prostate cancer in men over 50 years of age are the limitations of this therapy. There are no data on the optimal duration of therapy and no data on the efficacy of vitamin E in patients with T2DM.
UDCA therapy reduces secretion of cholesterol into the bile, probably by reducing its absorption and increasing its conversion to bile acids. UDCA therapy has been shown to improve hepatocyte secretory function and inhibit pro-inflammatory cytokine activity at the cellular level. In a meta-analysis of 12 studies (1160 subjects), in which UDCA was used as monotherapy or in combination with other drugs at doses of 10–35 mg/kg, UDCA decreased ALT activity and reduced hepatic steatosis [52]. Ratziu et al. [53] showed that ALT activity was decreased by 41% and AST activity by 19% by the use of UDCA in patients with MAFLD. Significant improvements in hepatic parameters were noted after merely three months of taking the drug. What is more, in the patients with MAFLD and T2DM using UDCA, there was an additional improvement in carbohydrate management parameters (reduced glucose, insulin, glycated hemoglobin levels, and reduced HOMA-IR index) [53]. UDCA therapy is characterized by good tolerance and a high safety profile. No reports are known of any significant adverse effects during chronic UDCA use in MAFLD. UDCA may thus safely be used in long-term therapies. It is recommended to monitor the efficacy of the treatment after 3–6 months of its duration, and UDCA therapy should be maintained until a reduction in liver enzymes by at least one-third of their baseline value is achieved. No data are available on whether the listed drugs, used in the treatment of MAFLD, modify cardiovascular risks or affect the rate of cardiovascular complications.
Summary
MAFLD is a medical condition that significantly worsens prognosis and should therefore be actively sought in patients with predisposing factors. As the relationship between MAFLD and cardiovascular diseases is bidirectional, it is recommended to assess the ASCVD risk in patients with MAFLD. Non-pharmacological interventions, aimed at normalizing/maintaining body weight and correcting eating habits, are very important in MAFLD therapy. However, the most important factors for the prognosis of these patients include proper diagnosis and effective treatment of cardiovascular and metabolic conditions.
Article information
Conflict of interest: IGG — Bayer, Boehringer Ingelheim, KRKA, Novo Nordisk, Promed. MW — AstraZeneca, Egis, Novartis, Novo Nordisk, Polpharma, Pomed, Adamed, Apotex, Aurovitas, Bayer, Berlin Chemie, Boehringer Ingelheim, KRKA, Pfizer, Sandoz, Sanofi-Avensis, Servier, Teva. AM — Adamed, AstraZeneca, Aurovitas Pharma, Bayer, Berlin Chemie Menarini, Boehringer Ingelheim, Celon, Egis, Gedeon Richter, KRKA, Lilly, MSD, Novo Nordisk, Pfizer, Polpharma, Recordati, Sandoz, Sanofi, Servier, USP Zdrowie, Viatris, Zentiva. KJF — Adamed, AstraZeneca, Bausch Health, Bayer, Boehringer Ingelheim, Egis, KRKA, Mundipharma, Novartis, Pfizer, Sandoz, Servier, Viatris. BWK — Adamed, Bausch Health, Bayer, Biofarm, Boehringer Ingelheim, Egis, Gedeon Richter, KRKA, Pfizer, Sandoz, Servier, USP Zdrowie. MB — Adamed, Aurovitas Pharma, Bausch Health, Bayer, Biofarm, Bioton, Boehringer Ingelheim, Egis, Gedeon Richter, Krka, Merck, MSD, Pfizer, Polfarmex, Ranbaxy, Recordati, Sandoz, Sanofi, Servier, USP Zdrowie, Viatris, Zentiva. FS — Adamed Pharma, AstraZeneca, Boehringer Ingelheim, ProMed, KRKA, Viatris. JDK declares no conflict of interest. KT — AbbVie, Gilead, AstraZeneca, MSD, Pfizer, Promed, Roche.
Funding: None.
Open access: This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, which allows downloading and sharing articles with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially. For commercial use, please contact the journal office at kardiologiapolska@ptkardio.pl.
