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Renaming NAFLD to MAFLD: Advantages and Potential Changes in Diagnosis, Pathophysiology, Treatment, and Management

Rui, Fajuan1; Yang, Hongli2; Hu, Xinyu2; Xue, Qi3; Xu, Yayun2; Shi, Junping4; Li, Jie1,5,6

Editor(s): Chen, Zhi

Author Information
Infectious Microbes & Diseases: June 2022 - Volume 4 - Issue 2 - p 49-55
doi: 10.1097/IM9.0000000000000089
  • Open

Abstract

Introduction

In 1980, “nonalcoholic steatohepatitis (NASH)” was first used to describe fatty liver disease of unknown cause without a history of excessive alcohol consumption.1,2 However, over the last few decades, there have been many criticisms on the nomenclature and definition of non-alcoholic fatty liver disease (NAFLD),3 not only due to the prominent role of alcohol in the definition, but also due to the adverse effects of the nomenclature, including stigmatization, trivialization and lack of consideration of the disease in health policy.3 Recently, an international panel of experts recommended changing the name from NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD), which might be a more appropriate and inclusive definition.2,4

NAFLD is a heterogeneous disease, and its pathogenesis involves different genetic and metabolic factors.5 The inter-individual heterogeneity observed in the severity and clinical course of fatty liver disease has seriously hampered the development of a single noninvasive test to accurately diagnose or stage the disease.5,6 Similarly, treatment options face significant challenges. The unique feature of MAFLD is the inclusion of metabolic dysfunctions, which are high-risk factors.7 Furthermore, patients with MAFLD and other liver diseases are defined as having dual (or multiple) etiologies of fatty liver disease (such as MAFLD with alcohol, or hepatitis C with MAFLD), which will help to exclude more heterogeneous patients.8–10 This new concept of MAFLD has been widely accepted by the Middle East and North Africa consensus panels, the Latin American Association for the Study of the Liver, the Chinese Society of Hepatology and the Asian Pacific Association for the Study of the Liver.11–14

The diagnosis of NAFLD and MAFLD

There is a certain degree of concordance between MAFLD and NAFLD. However, not all NAFLD patients have MAFLD and vice versa.15 Data from population-based research showed that most patients with fatty liver disease meet the definition of both MAFLD and NAFLD, but as many as 10%–25% may meet the criteria of only one of these conditions.16

NAFLD is a clinical entity characterized by abnormal lipid deposition in the liver. It is diagnosed when liver biopsy reveals steatosis in >5% of hepatocytes, without secondary cause of liver injury or excessive alcohol intake.2,4,17 The definition of NAFLD is an exclusion diagnosis. This lack of “objective proof” brings heterogeneity and impedes the development of rational, evidence-based therapies.18 This leads to an increase in medical expenses, a waste of time, and an obstacle to effective nursing.18 The diagnosis criteria for MAFLD are: evidence of hepatic steatosis by liver histology, imaging, or blood biomarkers, and association with any one or more of the following factors: type 2 diabetes mellitus (T2DM), overweight/obesity, or evidence of metabolic disorders.2,7,17,19 In contrast to NAFLD, MAFLD is a diagnosis relying on a simple and relevant set of “positive” criteria, which is likely the first pivotal step toward precision medicine for fatty liver disease.18

The diagnosis of MAFLD is based on metabolic dysfunction with a fatty liver, identifying a significant population with more comorbidities and worse outcomes than NAFLD alone.7,20 MAFLD is more valuable for identifying fatty liver patients who are at high risk of disease progression.21 In addition, studies have consistently concluded that the diagnostic criteria for MAFLD are simple, practical, and are superior to existing diagnostic criteria for NAFLD in distinguishing patients with significant hepatic fibrosis, chronic kidney diseases, and in predicting progression of cardiovascular risk for atherosclerosis.8,22,23 Renaming to MAFLD will help deconvolute disease heterogeneity and simplify the diagnosis in virtually all healthcare settings, including in the most resource-limited regions in the world.24

Pathophysiology of NAFLD/MAFLD

The pathophysiology of MAFLD is multifactorial, complex, and incompletely understood. Several gene variants have been discovered as genetic susceptibility genes for MAFLD.2,25 Lipotoxicity plays an essential role in the pathogenesis of MAFLD.4,26 Increased insulin resistance (IR) in skeletal muscle/adipose tissue and pathological alterations in the gut microbiota affect hepatic lipid metabolism, which further promotes hepatic inflammation and fat accumulation (Figure 1).2

F1
Figure 1:
Summary of the pathogenesis and treatment of MAFLD. FFAs: free fatty acids; MBOAT7: membrane bound O-acyltransferase domain-containing 7; PNPLA3: patatin-like phospholipase domain containing protein 3; TM6SF2: transmembrane 6 superfamily 2.

Genetics

MAFLD is a heterogeneous multifactorial disease, and genetic factors play an important role in its development and progression.10 In recent years, increasing numbers of MAFLD susceptibility genes have been reported, such as patatin-like phospholipase domain containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), and membrane bound O-acyltransferase domain-containing 7 (MBOAT7).10,27 NAFLD-related variants in PNPLA3, TM6SF2, and MBOAT7 have been identified as alcoholic cirrhosis-associated risk loci.4 In addition, PNPLA3 and MBOAT7 are implicated in hepatic steatosis in patients with viral hepatitis.4

The PNPLA3 gene encodes an endoplasmic reticulum membrane protein located on the surface of lipid droplets.28 This protein has hydrolase activity and is highly expressed in hepatic stellate cells and human hepatocytes.28 A single nucleotide polymorphism (SNP, I148M variant) in PNPLA3 is closely associated with elevated liver fat levels and hepatic inflammation.2,10

TM6SF2, which is essentially an endoplasmic reticulum membranous protein, may participate in neutral lipid transfer across lipid bilayers.29 The TM6SF2 protein is involved in regulating hepatic triglyceride secretion, and it is associated with an increased risk for progressive metabolic-associated steatohepatitis and a reduced risk of cardiovascular disease.2,30,31

The MBOAT7 gene encodes an enzyme that is a member of the Lands cycle of membrane phospholipid acyl-chain remodeling.25 The MBOAT7 rs641738 polymorphism is associated with lower expression of the MBOAT7 protein in the liver, increased hepatic fat content, and changes of plasma phosphatidylinositol species.2 The rs641738 polymorphism has been identified as a risk factor for NAFLD and is also associated with severity of fibrosis in hepatitis C virus infection and alcoholic liver diseases.32

Lipotoxicity

In general, there is an equilibrium between lipid disposal (β-oxidation or metabolism, and elimination as very low-density lipoproteins) and lipid uptake [free fatty acids (FFAs), esterification, and “de novo lipogenesis”].33 In obese patients, 59% of the liver triglyceride composition comes from non-esterified fatty acids, 15% from the diet, and 26% from de novo lipogenesis.2,4,10 The main proximal event in MAFLD is the accumulation of FFAs in the liver.10

Lipotoxicity is projected to be one of the major triggers of liver injury in a multiple-hit model during the different stages of the MAFLD spectrum. Overconsumption of nutrients leads to increased visceral adipose tissue and increased mobilization rates of fatty acids to the liver, along with a decrease in adiponectin release and an increase in the release of pro-inflammatory cytokines.26 The decrease of serum adiponectin may lead to accumulation of fat in the liver, liver inflammation and IR.34 High levels of fatty acids cause over-stimulation of fatty acid oxidation and reactive oxygen species generation pathways, and increase the effects of oxidative stress on endoplasmic reticulum and mitochondrial physiology.

Gut microbiota

Over the past decade, tremendous progress has been made in understanding the complex cross-talking network among the gut, the microbiome, and the liver through the portal circulation, thereby illuminating one of its major roles in the pathogenesis of NAFLD.2,35 The blood supply from the intestinal portal circulation accounts for 75% of the blood supply to the liver, which provides the first line of metabolism for the gastrointestinal luminal contents. These include dietary nutrients, as well as xenobiotics and toxins that migrate through the intestinal epithelium.35,36 Alterations in the gut-liver axis play a key role in the pathogenesis of various liver diseases, including MAFLD.36

Disturbance of the normal gut microbiota is also known as dysbiosis.37 Gut dysbiosis promotes the production of bacteria that can regulate the inflammatory activation of Kupffer cells, promotes the production of short-chain fatty acids, and alters the enterohepatic circulation of bile acids, leading to inflammation and ultimately hepatic steatosis.33 Hepatic steatosis is associated with reduced diversity of the microbiota inhabiting the gut.35 In recent years, data sets related to microbiome changes after bariatric surgery have been accumulating. Several potentially beneficial anaerobic commensal bacteria, such as Faecalibacterium prausnitzii, Akkermansia muciniphila, and Rosburia intestinalis, have been found to be enriched after bariatric surgery.38 Family members share similar microbial signatures, and it is thought that the composition of the gut microbiota is at least partly influenced by genetics.37 Furthermore, small intestinal bacterial overgrowth, increased gut permeability, and gut-derived metabolites are related to the development of NAFLD/MAFLD.2,39

Insulin resistance

The term “insulin resistance” is commonly used to describe insulin-mediated glucose uptake.33 A number of studies have shown that NAFLD is associated with IR, resulting in resistance to the antilipolytic effects of insulin in adipose tissue with increased FFAs.40 Insulin mediates glucose metabolism not only by promoting glucose uptake in adipose and hepatic tissues, but also by inhibiting glucose production in the liver.33

IR patients with NAFLD/MAFLD show reduced insulin sensitivity at the liver, adipose tissue, and muscle levels.2,40 Adipocyte-derived exosome MiR-27a induces skeletal muscle IR by repression of peroxisome proliferator-activated receptor γ (PPARγ).41 In addition, skeletal muscle IR is the major defect in T2DM.2 T2DM patients are characterized by high levels of circulating FFAs, which lead to IR by reducing insulin-stimulated glucose uptake.42 Furthermore, liver insulin clearance is inhibited in patients with T2DM and correlates with the severity of metabolic syndrome (MetS).33 Epidemiological studies have shown that T2DM patients have a two-fold increase in the odds of developing NAFLD.33 Renaming NAFLD to MAFLD brings the disease back to reality, making it not only closer to its pathophysiology, but also closer to T2DM.43

In conclusion, MAFLD is associated with genetic susceptibility genes, lipotoxicity, IR, and gut microbiota. Including specific etiological information related to metabolic dysfunction in the new definition of MAFLD and defining metabolic dysfunction as a disease subject with these variable drivers, is more conducive to the study of MAFLD mechanisms and sharing pathological information with a multidisciplinary team.4,7

Clinical manifestations, complications, and outcomes of MAFLD

The unique feature of MAFLD is metabolic dysfunction. Hepatologists should be aware that metabolic risk factors include blood pressure, waist circumference, plasma triglycerides, high-density lipoprotein cholesterol, plasma high-sensitive C-reactive protein levels, and prediabetes homeostasis model assessment of insulin resistance (HOMA-IR) score. Studies have confirmed that MAFLD patients generally have a higher systolic blood pressure, waist circumference, triglycerides, C-reactive protein, and HOMA-IR score compared to NAFLD patients.21,23 In addition, compared with NAFLD, MAFLD patients have a higher age, body mass index, and liver enzyme levels, and a higher incidence of metabolic diseases such as hypertension and diabetes.21

MAFLD can also arise in multisystem diseases with extrahepatic complications, including cardiovascular diseases, polycystic ovary syndrome, chronic kidney diseases, obstructive sleep apnea, and osteoporosis.13 At present, some conclusions have been drawn on the clinical manifestations and extrahepatic complications of MAFLD (Table 1).8,21–23,44–46 Huang et al.47 confirmed that there is no difference in steatosis, hepatitis, and fibrosis between MAFLD and NAFLD. The MAFLD definition better identifies a group with fatty liver and significant fibrosis evaluated by non-invasive tests.23 Liu et al.48 demonstrated that MAFLD is an independent risk factor for both intrahepatic and extrahepatic events. Compared with participants without MAFLD, MAFLD cases had a multivariate adjusted hazard ratio of 2.77 for cirrhosis [95% confident interval (CI) 2.29, 3.36], 1.59 for liver cancer (95% CI 1.28, 1.98), 1.39 for cardiovascular diseases (95% CI 1.34, 1.44), and 1.56 for renal diseases (95% CI 1.48, 1.65).48 A study by Nguyen et al.20 also confirmed that the MAFLD definition identified a significant population with more comorbidities and worse outcomes than NAFLD alone. However, clinicians need to pay more attention to patients with severe hepatic steatosis who are not diagnosed with MAFLD, and this group of patients may have significant liver injury and fibrosis.49

Table 1 - Comparison of hepatic and extra-hepatic complications between MAFLD and NAFLD
Hepatic complications
 Fibrosis 23 MAFLD identifies patients with significant hepatic fibrosis better than NAFLD.
 Fatty liver 21 MAFLD definition is more practical for identifying patients with fatty liver disease with high risk of disease progression.
 Cirrhosis 44 Liver stiffness values are higher in patients with MAFLD than NAFLD.
 Hepatocellular carcinoma 45 The burden of NAFLD- and MAFLD-associated HCCs increased significantly, driving an increase in HCC incidence, particularly in women.
Extra-hepatic complications
 Cardiovascular disease 22 MAFLD better identifies patients with worsening of atherosclerotic cardiovascular disease risk than NAFLD.
 Obstructive sleep apnea 46 MAFLD patients have higher prevalence and greater severity of obstructive sleep apnea and worse nocturnal desaturation parameters as compared to non-MAFLD patients.
 Chronic kidney disease 8 MAFLD identifies patients with chronic kidney disease better than NAFLD. MAFLD and MAFLD with increased liver fibrosis score are strongly and independently associated with chronic kidney disease and abnormal albuminuria.
HCC: hepatocellular carcinoma; MAFLD: metabolic dysfunction-associated fatty liver disease; NAFLD: non-alcoholic fatty liver disease.

Treatment options for MAFLD

Pharmacotherapy

The etiology of MAFLD is multifactorial and remains incompletely understood, but involves intrahepatic lipid accumulation, IR, alterations of energy metabolism, and inflammatory processes.1 Anti-obesity drugs and antidiabetic drugs may have a role in improving clinical outcomes and liver histology in MAFLD.4 Furthermore, MAFLD is a systemic disease, with cardiovascular diseases being the main cause of death.18 Medications that are beneficial for cardiovascular disease outcomes may decrease cardiovascular disease mortality in MAFLD patients.4

Anti-obesity drugs

The addition of anti-obesity drugs results in significantly more weight loss and maintenance than lifestyle modifications alone. However, anti-obesity drugs are expensive and may have side effects on some individuals. For instance, a clinical trial assessing drug safety showed lorcaserin caused an increased risk for cancer.50 Therefore, on February 13, 2020, the USA Food and Drug Administration ordered the withdrawal of lorcaserin from the market.50 Currently, four drugs (orlistat, naltrexone extended-release/bupropion extended-release, phentermine/topiramate controlled-release, and liraglutide) can be used long-term (>12 weeks) to promote weight loss by suppressing appetite or decreasing fat absorption.50,51 Development of safer and more economical new anti-obesity drugs is urgently needed.

Insulin sensitizers and new antidiabetic agents

MAFLD and T2DM share common pathophysiological features such as IR.1 Pioglitazone and metformin are effective insulin sensitizers used in T2DM.1,52 Pioglitazone is recommended for those confirmed to have metabolic-associated steatohepatitis.53 The effects of pioglitazone on the histology of metabolic-associated steatohepatitis with T2DM have been widely established, but several concerns exist, such as fluid retention, body weight gain, bone fracture, and elevated cancer incidence.54 There are concerns about the long-term safety of pioglitazone in higher doses.53 A meta-analysis reported that the use of metformin was critical in improving liver functions and body composition of non-diabetic patients with MAFLD.1

New antidiabetic agents, such as glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors, have been investigated to reverse liver steatosis and prevent progression to advanced fibrosis.1,4 GLP-1RAs both improve liver histology and reduce high cardiovascular risks in MAFLD patients.4,55 SGLT2 inhibitors appear to be able to reverse liver diseases and metabolic abnormalities in MAFLD.53,55 Among several SGLT2 inhibitors, dapagliflozin has already entered a phase 3 clinical trial.54 Diabetes subtype MAFLD patients should be preferentially treated with novel drugs licensed for diabetes treatment, such as GLP-1RAs and SGLT2 inhibitors.

Lipid-lowering agents

Statins are among the most widely prescribed lipid-lowering drugs and are commonly used to manage dyslipidemia.1,56 In various animal studies, statins were found to mitigate metabolic-associated steatohepatitis-related hepatic lipotoxicity, inflammatory responses, oxidative stress, and fibrosis through multiple pathways.57 A population-based study has also confirmed that a significant proportion of subjects with suspected MAFLD and/or fibrosis have an indication for lipid-lowering therapy due to increased cardiovascular risks and might benefit from statin therapy.58 Statins have potential antioxidant properties and favorable effects on adiponectin levels, and can reduce the risk of cardiovascular morbidity and mortality in metabolic-associated steatohepatitis and dyslipidemia patients.1,53,59 Unfortunately, no specific pharmacological treatment has been approved for MAFLD, and current trials for MAFLD or metabolic-associated steatohepatitis drugs are focusing on metabolic pathways to improve dyslipidemia or IR.60

Vitamin D and vitamin E

Vitamin D is a pleiotropic hormone with extensive anti-inflammatory, anti-fibrosis, and insulin sensitization properties, and is involved in mediating immune inflammation and metabolism.61 Vitamin D supplementation had a good effect on glycemic control and insulin sensitivity in MAFLD patients.62 A population-based study has shown that lower serum 25-hydroxy vitamin D levels are associated with a higher prevalence of MAFLD.63 However, as for the relationship between vitamin D and liver diseases, some clinical trials have attempted to answer the question whether vitamin D supplementation has a positive impact on MAFLD, and the results are controversial.

Vitamin E is a fat-soluble antioxidant that can prevent or repair liver damage and decrease steatosis. Its function is considered to be upstream of oxidative stress, but the exact mechanism remains unclear.64 A combination of vitamin E and curcumin treatment alleviates diet-induced steatosis in Hfe-/- mice.65 A meta-analysis confirmed that vitamin E, either alone or in combination with other drugs, can improve biochemical and histological outcomes in children and adult patients with MAFLD.66 Vitamin E can also prevent metabolic-associated steatohepatitis patients with advanced fibrosis from progressing to liver decompensation or liver transplantation, therefore is recommended for patients diagnosed with metabolic-associated steatohepatitis.53,54

Innovative clinical treatment of MAFLD

Hepatocyte death can trigger and aggravate liver fibrosis and chronic inflammation, which can further develop into chronic cirrhosis and hepatocyte cancer.67 Reducing sympathetic activation by pharmacological and device-based approaches has been demonstrated to improve the metabolic changes frequently present in patients with diabetes, MetS, and obesity.68 Targeting programmed cell death and sympathetic inhibition against MAFLD are promising new therapies. Furthermore, nanotechnology is an emerging approach addressing MAFLD.1 Macrophages also play a critical role in the development of MAFLD and in the progression of steatohepatitis and fibrosis.36 Macrophage-targeting therapy holds promise as a therapeutic option to improve MAFLD and steatohepatitis.36

MAFLD is a “hot” area for clinical trials, with >200 trials in various phases ongoing worldwide.69 To date, some phase IIb and phase III studies have either failed to meet the currently required histologic endpoints, or have reached modest margins.70 The heterogeneity in NAFLD population in terms of primary drivers and co-existing disease modifiers is an important barrier to the development of effective treatments.70 As MAFLD is a complex disease, phase II/III clinical trials should not be designed for all MAFLD patients.7 Within the term “metabolic dysfunction,” we can categorize this disease into detailed subtypes, which facilitates the development of precise medications based on systematic narratives.71

Lifestyle modification and bariatric surgery

In the absence of approved pharmacological therapies, lifestyle changes, including dietary changes, weight loss, and organized exercise interventions, remain the cornerstone of MAFLD therapy.69,72 Dietary strategies, including ketogenic, paleolithic, Mediterranean, plant-based, high-protein, low-carbohydrate, and intermittent fasting diets, are gaining popularity.73 The Mediterranean diet is the most recommended dietary strategy, which encourages patients to increase the consumption of fruits and vegetables, whole grains, and olive oil.74,75 Its features are reduced carbohydrates intake, and increased intake of monounsaturated and omega-3 fatty acids.74 Physical movement or the lack of it plays an important role in the management of MAFLD. A 12-week aerobic exercise intervention was shown to have a potential benefit in improving histological endpoints in MAFLD.72 Meta-analysis confirmed that interval and continuous aerobic exercise may be more effective at improving alanine aminotransferase and benefit the management of MAFLD when intervention duration is less than 12 weeks.76

Weight loss of more than 10% overall body weight is beneficial for alleviating steatosis and reversing fibrosis.77 Bariatric surgery mitigates steatohepatitis, liver fibrosis, and IR.38 For obese patients, it is one of the most successful and effective methods to produce sustained weight loss.78 However, due to the aggressive invasiveness, bariatric surgery is not recommended.38 Not all bariatric surgeries are good for the liver. Surgery-induced malabsorption can lead to significant fibrosis and cirrhosis and even liver failure.79

NAFLD focuses on liver treatment, while MAFLD is a systemic disease. The transition to MAFLD will facilitate the use of existing drugs to treat other metabolic indications for MAFLD. Considering systemic metabolic inflammation and the effects of drugs on cardiovascular outcomes is necessary for the development of new therapies for MAFLD patients.18 In the absence of specific drugs, targeted metabolic therapies, along with lifestyle changes such as weight loss, dietary changes, and organized exercise interventions, are the first line and basic treatment (Figure 1).13

Disease awareness and management

Admittedly, the change from NAFLD to MAFLD has raised awareness among physicians. Results of a questionnaire survey of 161 physicians showed that 96% of them were not familiar with the difference between NASH and NAFLD. In addition, the majority of the physicians (73.3%) said that they became more familiar with fatty liver disease after NAFLD was renamed to MAFLD.80

A survey showed that 70% of investigated patients were unaware of having NAFLD and 100% said they did not know the difference between NASH and NAFLD, nor had they heard about it.81 A Mexican survey also showed that 28.6% of respondents did not consider NAFLD to be a potentially serious liver disease.82 Patients with fatty liver expressed high dissatisfaction with the word “NAFLD” and substantial support to “MAFLD.” Importantly, patient perspectives on quality of life, satisfaction, and adherence to lifestyle recommendations are critical to developing and evolving to a patient-centered approach to influence MAFLD outcomes.13 In addition, a multidisciplinary management approach is the key to ensured motivation and continued involvement of intervention programmers. The change to MAFLD is expected to help raise increased awareness of the disease and decrease its stigma.3

In addition, nurse specialists play an important role in educating patients with NAFLD, and every interaction between nurses and patients is an opportunity for information exchange and raising awareness.83 Renaming MAFLD has an impact on nurses and related health professions, improving patient-nurse communication and working partnership, motivating patients to undertake lifestyle changes, and promoting a variety of health behavioral changes.7 In addition, care for MAFLD cirrhosis patients is complex.84 With a clear diagnosis, there is great potential to improve the care for patients with liver cirrhosis MAFLD.80

Conclusion

International consensus guidelines recommended that NAFLD be renamed to MAFLD in 2020, supplemented by diagnostic criteria. According to the definition of MAFLD, fatty liver disease can be divided into three metabolic subtypes: obesity, T2DM, and lean/overweight with MetS.7 Individualized management is required for MAFLD with different subtypes.85 In addition, this transition is likely to increase clinical evidence and momentum at multiple levels, including disease diagnosis, pathophysiology, treatment, awareness, and management.

There is no doubt that the renaming of NAFLD to MAFLD is a defining moment and serves as a catalytic call to action. However, MAFLD overemphasizes metabolic dysfunctions, which may lead to an underestimation of the liver injury caused by steatosis itself, thus missing patients at risk of disease progression.49,86 Considering the heterogeneity and inclusion definition, further research is needed to subclassify the diseases of MAFLD, which will be of great importance for the precise intervention of MAFLD.87

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Keywords:

MAFLD; NAFLD; diagnosis; pathophysiology; treatment; management

Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.