MAFLD enhances clinical practice for liver disease in the Asia-Pacific region

Article information

Clin Mol Hepatol. 2022;28(2):150-163

Publication date (electronic) : 2021 November 10

doi : https://doi.org/10.3350/cmh.2021.0310

, Tsubasa Tsutsumi ¹, Dan Nakano ¹, Mohammed Eslam ², Jacob George ², Takuji Torimura ¹

¹Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan

²Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, New South Wales, Australia

Corresponding author : Takumi Kawaguchi Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan Tel: +81-942-31-7627, Fax: +81-942-31-2623 E-mail: takumi@med.kurume-u.ac.jp

Editor: Dae Won Jun, Hanyang University College of Medicine, Korea

Received 2021 September 30; Revised 2021 November 4; Accepted 2021 November 7.

Abstract

Fatty liver is now a major cause of liver disease in the Asia-Pacific region. Liver diseases in this region have distinctive characteristics. First, fatty liver is frequently observed in lean/normal-weight individuals. However, there is no standard definition of this unique phenotype. Second, fatty liver is often observed in patients with concomitant viral hepatitis. The exclusion of viral hepatitis from non-alcoholic fatty liver disease limits its value and detracts from the investigation and holistic management of coexisting fatty liver in patients with viral hepatitis. Third, fatty liver-associated hepatocellular carcinoma (HCC) is generally categorized as non-B non-C HCC. Fourth, the population is aging rapidly, and it is imperative to develop a practicable, low-intensity exercise program for elderly patients. Fifth, most patients and non-specialized healthcare professionals still lack an awareness of the significance of fatty liver both in terms of intrahepatic and extrahepatic disease and cancer. Recently, an international expert panel proposed a new definition of fatty liver: metabolic dysfunction-associated fatty liver disease (MAFLD). One feature of MAFLD is that metabolic dysfunction is a prerequisite for diagnosis. Pertinent to regional issues, MAFLD also provides its diagnostic criteria in lean/normal-weight individuals. Furthermore, MAFLD is independent of any concomitant liver disease, including viral hepatitis. Therefore, MAFLD may be a more suitable definition for fatty liver in the Asia-Pacific region. In this review, we introduce the regional characteristics of fatty liver and discuss the advantages of MAFLD for improving clinical practice for liver disease in the region.

Keywords: Fatty liver; Leanness; Hepatitis viruses; Liver cancer; Awareness

INTRODUCTION

Liver disease is highly prevalent in the Asia-Pacific region, accounting for over 60% of global liver-related deaths [1,2]. The main causes of liver-related mortality are liver cirrhosis and liver cancer. The Asia-Pacific region accounts for approximately half of deaths due to cirrhosis and three-quarters of deaths due to liver cancer globally [1]. Thus, treatment of liver disease should be a focus for improving health in the Asia-Pacific region [3-5].

During the past four decades, great progress has been made in the prevention and treatment of viral hepatitis [6]. Universal infant hepatitis B virus (HBV) vaccination has significantly reduced the prevalence of hepatitis B virus surface antigen (HBsAg) [7]. Nucleos(t)ide analogs suppress HBV replication and increase the rate of HBsAg seroclearance with favorable clinical outcomes, including a reduction in the incidence of hepatocellular carcinoma (HCC) [8]. Likewise, the nucleic acid test for hepatitis C virus (HCV) has contributed tremendously to the prevention of transfusion transmission [9], while all-oral direct-acting antivirals (DAAs) for HCV have resulted in high cure rates in Asia-Pacific patients in general clinical practice settings, including elderly patients and those with decompensated cirrhosis [10]. The World Health Organization published the Global Health Sector Strategy on viral hepatitis and aims to eliminate viral hepatitis by 2030 by reducing new viral hepatitis infections and reducing deaths due to viral hepatitis [11]. As a result, the prevalence of viral hepatitis is expected to rapidly decrease in the Asia-Pacific region.

Concomitantly, a rapid increase has been observed in the prevalence of fatty liver disease, estimated at approximately 30% of the Asia-Pacific population [12-17]. Consequently, fatty liver is both a major etiology of chronic liver disease and will be an increasing cause of liver-related death in the future [13,18]. As in Western countries, obesity and type 2 diabetes mellitus are the dominant risk factors for clinical progression and adverse outcomes in patients with fatty liver disease in the Asia-Pacific region [19-22].

Fatty liver in this region also has distinctive features. First, non-obese fatty liver accounts for approximately 40% of cases of fatty liver [23]. While metabolic dysfunction is associated with the development of fatty liver in non-obese individuals [24,25], there are no standardized diagnostic criteria. Second, fatty liver is often seen in patients with viral hepatitis [26,27]. However, the exclusion of viral hepatitis from non-alcoholic fatty liver disease (NAFLD) limits the investigation of any coexisting fatty liver, while also reducing awareness both at the patient and clinician levels. Third, with regard to HCC, fatty liver disease is generally categorized as non-B non-C or non-viral HCC [28-31]. Therefore, precise information and therapeutic strategies are still lacking for this entity. Fourth, rapid population aging is seen in the Asia-Pacific region [32,33], and it is important to develop a practical, low-intensity exercise program that is suitable even for elderly patients with poor cardiorespiratory fitness. Fifth, most patients and non-specialized healthcare professionals remain unaware of the significance of fatty liver disease [34,35]. This lack of awareness has significant negative impacts on lifestyle intervention, patient-reported outcomes, and the economic burden on patients and healthcare systems. We contend that the diagnostic term used for fatty liver should be based on these regional characteristics.

METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASE (MAFLD)

Recently, an international expert panel proposed a new definition of fatty liver disease, MAFLD [36]. MAFLD is not simply a renaming of NAFLD but represents a new concept for understanding liver disease related to metabolic dysregulation [37]. A diagnosis of MAFLD is made based on evidence of fatty liver in patients who are overweight/obese or have type 2 diabetes mellitus. In addition, MAFLD can be diagnosed in lean/normal-weight people with the criteria requiring evidence of fatty liver and at least two metabolic abnormalities [36]. The prevalence of MAFLD is approximately 80% in patients with fatty liver and 30% to 40% of the general population in Asia [38-41].

According to the new criteria, the MAFLD definition excludes patients with fatty liver and no metabolic abnormalities, with the corollary result of its predictive ability for clinical events being higher for MAFLD than for NAFLD. In fact, in contrast to NAFLD, MAFLD better identifies patients with hepatic fibrosis, a high risk of atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease, colorectal polyps, and all-cause mortality [40-48]. Another important distinction is that MAFLD is independent of alcoholic intake or other liver diseases, including viral hepatitis. Therefore, patients with dual (or more) etiologies of liver disease can be diagnosed with “MAFLD and alcoholic liver disease” or “MAFLD and chronic hepatitis B (CH-B).” [49,50] Therefore, MAFLD allows us to investigate the impact of coexisting fatty liver in patients with viral hepatitis. Such assessments will also impact studies of viral hepatitis and MAFLD in their contribution to HCC development.

VALIDITY OF THE MAFLD DEFINITION FOR PEOPLE WHO ARE LEAN/NORMAL WEIGHT

Patients with fatty liver who are a healthy weight are often metabolically unhealthy. Several studies have reported that the incidence of advanced fibrosis and liver-related events in these patients is similar to or worse than that in patients with fatty liver who are overweight/obese [51-53]. In addition, a higher risk for ASCVD and higher all-cause mortality has been reported in patients with fatty liver in the context of normal weight than that in patients who are overweight/obese [53-55].

Patients with lean/normal weight fatty liver have been reported to progress to advanced liver disease, ASCVD, and liver-related mortality, independent of PNPLA3 genotype [56]. No significant difference has been reported in the prevalence of visceral adiposity, hypertension, and dyslipidemia between patients with lean/normal weight and those with overweight/obese fatty liver [57,58]. Metabolic syndrome has been reported to be associated with the development of advanced hepatic fibrosis in patients with lean/normal weight fatty liver [24,25]. Recently, Francque and Wong [59] noted that metabolic dysfunction may be the main risk factor that is associated with an increased risk of hepatic fibrosis among lean patients with MAFLD. Park et al. [60] also reported that diabetes mellitus is the strongest risk factor for hepatic fibrosis in lean patients. Furthermore, lifestyle intervention is effective for these patients [61,62]. These previous findings suggest that various metabolic abnormalities may be involved in the development and progression of fatty liver in lean/normal-weight individuals.

The international expert panel proposed a definition of lean/normal weight MAFLD in Asian patients (body mass index [BMI] <23 kg/m²), which requires the presence of fatty liver with a combination of at least two of the following metabolic abnormalities: visceral adiposity, hypertension, dyslipidemia, pre-diabetes, insulin resistance, or an elevation of serum high-sensitivity C-reactive protein level (Fig. 1) [36]. The prevalence of lean/normal weight MAFLD has been reported to be 16% to 18% of patients with MAFLD in the Asia-Pacific region [40,63].

Figure 1.

Definition of lean/normal weight MAFLD in the Asia-Pacific region. The definition requires ① the presence of fatty liver, ② BMI <23, and ③ at least two of the metabolic abnormalities. BMI, body mass index; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; CRP, C-reactive protein; MAFLD, metabolic dysfunction-associated fatty liver disease.

Several studies have used the lean/normal-weight MAFLD definition. Ciardullo et al. [64] demonstrated that a high prevalence of significant fibrosis is seen in patients with lean/normal-weight MAFLD. Sohn et al. [65] investigated the difference in hepatic fibrosis among subgroups of MAFLD and showed that the prevalence of significant fibrosis in lean/normal-weight MAFLD was similar to that in obese (BMI >25.0) MAFLD and was higher than that in overweight (BMI 23.0–24.9) MAFLD. Liu et al. [66] investigated the impact of MAFLD on liver-related events using a large-scale UK Biobank database (n=160,979). They reported that lean/normal weight MAFLD was associated with an increased risk of liver-related events independent of the five genetic variants (PNPLA3 rs738409 C/G, TM6SF2 rs58542926 C/T, GCKR rs1260326 T/C, MBOAT7 rs641738 C/T, and HSD17B13 rs72613567 T/TA) [66]. Lin et al. [67] evaluated the impact of MAFLD on the recurrence of HBV-related HCC after curative resection and found that lean/normal weight MAFLD was a risk factor for tumor recurrence among patients with MAFLD (hazard ratio [HR], 2.030; 95% confidence interval [CI], 1.117–3.690; P=0.020) (Table 1). Fukunaga et al. [42] investigated the impact of MAFLD on the prevalence of colorectal adenoma in health check-up examinees. The authors demonstrated that lean/normal-weight MAFLD was the sole independent factor associated with the presence of colorectal adenoma (odds ratio [OR], 3.351; 95% CI, 1.589–7.262; P≤0.001). Lean/normal weight MAFLD was also the most important classifier for the presence of colorectal adenoma in data-mining analysis [42]. Semmler et al. [68] investigated the relevance of MAFLD for mortality and demonstrated that lean/normal-weight MAFLD had the worst survival rates. Although the number of studies in lean/normal-weight MAFLD is limited, this avalanche of publications in such a short time supports the validity of the lean/normal-weight MAFLD definition.

Table 1.

The interaction between MAFLD and HBV infection

IMPORTANCE OF MULTIPLE ETIOLOGIES OF LIVER DISEASE: MAFLD, VIRAL HEPATITIS, AND ALCOHOLIC INTAKE

HBV and HCV infection rates are high in the Asia-Pacific region. In patients with viral hepatitis, fatty liver is observed in 30% to 40% [26,27], and co-existing fatty liver has been reported to be associated with a higher risk of HCC in patients with HBV infection [69]. The presence of fatty liver has also been reported to increase the risk of HCC even in patients with HCV infection who achieve a cure with DAA therapy [70]. In addition, alcoholic liver disease is a common cause of chronic liver disease in the Asia-Pacific region [71]. Co-existing alcoholic liver disease and hyperalimentation-associated fatty liver shows synergistic interaction, resulting in the progression of liver disease [72]. These findings imply that assessment of fatty liver is important for the clinical management of patients with viral hepatitis and alcohol intake, especially in the Asia-Pacific region (Fig. 2).

Figure 2.

MAFLD accelerates the progression of liver disease in patients with HBV/HCV infection. Co-existing MAFLD is a higher risk for liver cirrhosis and HCC in patients with HBV and HCV infection. HBV, hepatitis B virus; HCV, hepatitis C virus; MAFLD, metabolic dysfunction-associated fatty liver disease; HCC, hepatocellular carcinoma.

A unique feature of the MAFLD definition is that a diagnosis of MAFLD can be made irrespective of the diagnosis of any other liver disease, including viral hepatitis. This allows clinicians to investigate the interaction between viral hepatitis and MAFLD. Mak et al. [73] investigated the impact of MAFLD in patients with HBV infection (Table 1). They found that 45.7% of patients (1,083/2,370) fulfilled the criteria of both CH-B and MAFLD. Patients with CH-B plus MAFLD had a higher prevalence of advanced fibrosis/cirrhosis compared to patients with CH-B alone (22.6% vs. 11.8%) [73]. Likewise, van Kleef et al. [74] investigated the impact of MAFLD on adverse clinical outcomes in patients with HBV infection (Table 1). MAFLD was independently associated with poor event-free (adjusted HR, 2.00; 95% CI, 1.26–3.19), HCC-free (adjusted HR, 1.93; 95% CI, 1.17–3.21), and transplant-free (adjusted HR, 1.80; 95% CI, 0.98–3.29) survival rates [74]. In other studies, Wang et al. [75] demonstrated that HBV infections were associated with a significantly lower grade of hepatic steatosis in patients with MAFLD (OR, -0.088; 95% CI, -0.027 to 0.291), but higher inflammation (OR, -4.059; 95% CI, -1.403 to 11.742), and fibrosis (OR, -3.016; 95% CI, -1.087 to 8.370) rates after adjusting for age, gender, and other metabolic parameters. Huang et al. [76] also showed that advanced hepatic fibrosis was associated with the presence of both HBV infections and metabolic disease. Therefore, there is a clinically meaningful interaction between MAFLD and HBV infection.

Similar data are available for patients with HCV infection. In patients with HCV infection, DAAs are currently the standard of care and achieve high cure rates in real-world settings [10]. Treatment with DAAs reduces liver stiffness; however, this is negatively associated with an increase in the severity of fatty liver [77,78]. Co-existing fatty liver is also a risk factor for HCC after cure in patients with HCV infection [79,80]. Furthermore, Peleg et al. [81] demonstrated that fatty liver is a major predictor of all-cause mortality in patients who achieve a sustained virological response following DAA treatment, regardless of fibrosis stage. Thus, MAFLD should be treated and managed on its own merits, even in patients with cured HCV infection. Fouad et al. [82] proposed the importance of a holistic and multidisciplinary approach for the management of the growing number of patients with treated HCV who achieved cure, since the global prevalence of previous/current infection is likely well in excess of 150 million. To date, no study employed MAFLD to examine the impact of fatty liver with metabolic dysfunction on clinical outcomes in patients with HCV infection after cure. However, previous studies have indicated that MAFLD is useful for assessing the morbidity and mortality of patients with HCV infection who have achieved this endpoint.

Alcoholic liver disease is also a common cause of liver disease in the Asia-Pacific region [71]. In this population, heterozygosity for the aldehyde dehydrogenase 2×2 allele, which results in lower enzymatic activity, is highly prevalent, with the incidence reaching 45% in East Asia [71,83]. Whereas, in India, 96.3% of patients with alcoholic liver disease have at least one component of metabolic syndrome and 53.0% has three or more components of metabolic syndrome, suggesting the high prevalence of co-existence of alcoholic liver disease and hyperalimentation-associated fatty liver [84,85]. Patients with both alcoholic and NAFLD have higher serum levels of aminotransferases and a high prevalence of advanced fibrosis than in patients with NAFLD [86]. Harmful effect of mild-to-moderate alcohol intake on hepatic fibrosis was seen in patients with metabolic syndrome, but not in patients with no metabolic syndrome [87]. In patients with MAFLD, even modest alcohol intake has been reported to be associated with significant hepatic fibrosis in Asia [40]. Thus, previous studies suggest that alcohol intake exacerbates the progression of liver disease in patients with MAFLD. Future research may be focused on the effects of MAFLD on life-threatening events and prognosis in patients with alcoholic liver disease, and vice versa.

MAFLD-RELATED HCC: A PROPOSED NEW CLASSIFICATION FOR THE ETIOLOGY OF HCC

Fatty liver causes lipotoxicity and oxidative stress in the liver; both are well-established drivers of hepatocarcinogenesis, while hepatic steatosis is recognized as an independent risk factor [88-92]. Fatty liver has been frequently categorized in the Asia-Pacific region as non-B non-C or non-viral HCC, probably because fatty liver represents a minor etiological cause of HCC in the region [28-31]. Non-B non-C HCC includes not only fatty liver but also other liver diseases, such as alcoholic liver disease, autoimmune liver diseases, and genetic liver diseases. Moreover, non-B non-C HCC is separate from HBV/HCV-related HCC, and co-existing fatty liver is not considered in the current etiological classification of HCC (Fig. 3).

Figure 3.

MAFLD renovates the etiological classification of HCC. The clinical features of HCC differ depending on its etiology. MAFLD should be categorized as an independent single etiology for HCC rather than mixing up as non-B non-C. MAFLD also allows for mixed etiology of HCC, which is frequent in the Asia-Pacific region. HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; MAFLD, metabolic dysfunction-associated fatty liver disease; AIH, autoimmune hepatitis; PBC, primary biliary cholangitis.

Non-B non-C HCC is now becoming the leading cause of HCC in many countries of the Asia-Pacific region following the control and treatment of viral hepatitis [30,53,93-96]. Eighty-five percent of patients with non-B non-C HCC have at least one risk factor for MAFLD, suggesting that it is the dominant etiology for non-B non-C HCC [97]. The prevalence of fatty liver-related HCC is estimated to increase by 47% in Japan and 86% in China by 2030 [98]. In addition, HCC often occurs in patients with fatty liver who do not have cirrhosis [99,100] and tends to be diagnosed at an advanced stage [28,101]. Therefore, these patients require a different screening strategy.

No cohort studies have demonstrated that MAFLD is associated with a higher HCC risk. Furthermore, it remains unclear whether MAFLD-related HCC cells have specific pathological features including a steatohepatitic phenotype. In addition, there is insufficient evidence to modify the treatment of HCC patients according to the HCC etiology. However, accumulated evidence demonstrates that obesity, type 2 diabetes, and metabolic syndrome are risk factors for HCC in patients with fatty liver, all embodied in the MAFLD definition [19-22,102-106]. Moreover, co-existing fatty liver is a risk factor for HCC in patients with HBV/HCV infection [69,70,79,107,108]. Recently, Pfister et al. [109] performed a meta-analysis and demonstrated that non-viral HCC is less responsive to immunotherapy. Non-viral HCC does not equal MAFLD-related HCC. However, there was an increase in the number of CD8⁺ PD1⁺ T cells in the liver of a NASH-related HCC mouse model [109]. Additionally, the CD8⁺ PD1⁺ T cells showed high thymocyte selection-associated high mobility group box protein expression levels [109], which reduced the degradation of PD-1 and promoted its translocation to the surface of the T cells, leading to an impairment of the immune surveillance [109,110]. Therefore, the efficacy of immunotherapy for MAFLD-related HCC may be limited compared to the other HCC etiologies. Although robust evidence is lacking, MAFLD could be categorized as an independent etiological cause of HCC, especially in the immunotherapy era (Fig. 3). This new classification will promote the development of novel context-specific strategies for the prevention and treatment of HCC in the Asia-Pacific region.

SARCOPENIA AND A LOW-INTENSITY EXERCISE PROGRAM FOR MAFLD

Physical inactivity causes loss of skeletal muscle, a major organ that determines resting energy expenditure [111,112]. In patients with MAFLD, Chun et al. [113] investigated the impact of sarcopenia on hepatic fibrosis and ASCVD risk using a large, population-based cohort. They found that sarcopenia was associated with significant hepatic fibrosis and risk of ASCVD in patients with MAFLD. Whereas, O’Gorman et al. [114] performed a non-randomized controlled trial and found that 12 weeks of moderate-to-vigorous intensity aerobic exercise reduced fibrosis and hepatocyte ballooning by one stage in 58% and 67% of patients, respectively, in the absence of clinically significant weight loss. Thus, exercise is an important treatment for patients with MAFLD.

A reduction in physical activity is seen in approximately 50% of patients with fatty liver in Asia [115]. In addition, patients with MAFLD are at high risk for ASCVD. Therefore, moderate-to-vigorous intensity exercise may be impracticable in many patients. Recently, a low-intensity resistance exercise program was developed based on the results of a meta-analysis of exercise for patients with fatty liver (Fig. 4) [116]. This low-intensity resistance exercise program was feasible even for subjects with no exercise habits. The program altered the expression of microRNA (miR)-630, miR-5703, and fractalkine, which are associated with the inhibition of cancer cell proliferation [117-119]. Therefore, even low-intensity exercise may exert beneficial effects through alterations in miR and fractalkine expression in humans. A practicable exercise program is an unmet medical need for patients with MAFLD in the Asia-Pacific region. Future research should be focused on better low-intensity exercise for patients with MAFLD.

Figure 4.

Scheme for a low-intensity resistance exercise program based on a meta-analysis. The exercise consists of six types of exercises such as (A) stepping, (B) good-morning exercises, (C) towel lat pulldowns, (D) squats, (E) calf raises, and (F) triceps surae stretching. The figure is adopted from an article by Hashida et al. [116] with permission from John Wiley and Sons.

MAFLD IMPROVES DISEASE AWARENESS

NAFLD is diagnosed based on the amount of alcohol intake and the exclusion of other causes of hepatic steatosis. In these patients, lifestyle intervention is one of the cornerstones of current management [12,120,121]. However, the effect of mild-to-moderate alcohol intake differs based on individual characteristics, including body weight, sex, and genetic polymorphisms in enzymes of alcohol metabolism [122-124]. In addition, patient understanding is the first step toward improving their lifestyle, and most patients are unable to understand the meaning of “non-alcoholic.” [34] Similarly, most non-specialist physicians lack awareness of the importance of fatty liver [35] and are unfamiliar with the difference between NAFLD and non-alcoholic steatohepatitis [125]. Furthermore, Muslims are widely distributed in the Asia-Pacific region, in particular West Asia. Islam prohibits alcohol consumption, and there is still a stigma associated with the term “non-alcoholic.” [126]

MAFLD is independent of alcohol intake and clearly indicates the etiology of fatty liver to be “metabolic dysfunction.” Fouad et al. [35] recently performed a survey in Egypt showing that 73.3% of physicians reported that they became more familiar with fatty liver disease after the name changed from NAFLD to MAFLD. Moreover, Méndez-Sánchez et al. [127] from Mexico reported that 65.7% of participants became more familiar with fatty liver disease following the redefinition to MAFLD. Furthermore, MAFLD has had a positive impact on nurses and allied health personnel’s ability to motivate patients to undertake lifestyle changes [128]. In addition, an international expert panel recently proposed a definition of MAFLD for children [129]. Accordingly, MAFLD may help improve disease awareness of patients, doctors, medical staff, and various stakeholders. This improvement will contribute to the development of prevention and treatment strategies, including pharmacotherapies, resulting in an improvement in patient-reported outcomes and a reduction in healthcare costs [130]. Several associations and expert panels have published consensus/position statements to endorse “MAFLD” as the official term [126,131-134].

ISSUES TO BE RESOLVED

One of the issues with the MAFLD definition is the exclusion of fatty livers in the absence of metabolic dysfunction. Therefore, future studies should focus on the impact of the new criteria on intra- and extra-hepatic outcomes and prognoses by comparing the NAFLD criteria. Caution should also be used when managing patients who have fatty livers but not metabolic dysfunction, as they may be consuming alcohol surreptitiously, they may have an undiscovered cause of the excess liver fat or another disease that has not been tested for (e.g., lysosomal acid lipase deficiency), or they may develop MAFLD over time. Additionally, there is no requirement to exclude other contributing liver disease etiologies when diagnosing a patient with MAFLD. In clinical practice, however, it is important to test for other diseases, as they may exist concomitantly with MAFLD and thus should be managed appropriately.

CONCLUSION

In this review, we described the distinctive characteristics of fatty liver in the Asia-Pacific region. We also summarized the many advantages of using the definition of MAFLD in this regional context (Fig. 5). Although studies using the MAFLD criteria are in their infancy, a more precise definition of MAFLD in lean/normal-weight people will help standardize and promote the clinical and translational investigation of this unique phenotype. The concept of MAFLD is also particularly useful to disentangle the impact of concomitant fatty liver in patients with viral hepatitis, which is prevalent in the Asia-Pacific region. MAFLD will likewise reconstruct the etiological classification of and therapeutic strategies for HCC. The term MAFLD highlights the impact of metabolic dysfunction on pathogenesis and the importance of lifestyle interventions, including exercise. Last but not least, the term “MAFLD” itself may increase disease awareness, leading to improvements in natural history and clinical outcomes, patient-reported outcomes, and the economic burden to patients and national healthcare systems.

Figure 5.

Scheme for MAFLD enhances clinical practice for liver disease in the Asia-Pacific region. HBV, hepatitis B virus; HCV, hepatitis C virus; MAFLD, metabolic dysfunction-associated fatty liver disease; HCC, hepatocellular carcinoma.

Notes

Authors’ contribution

All authors were responsible for drafting and critical revision of the manuscript for important intellectual content.

Conflicts of Interest: Takumi Kawaguchi received lecture fees from Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and Otsuka Pharmaceutical Co., Ltd. The other authors have no conflicts of interest.

Acknowledgements

This work was supported by AMED under Grant Number JP21fk0210090. ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; National Health and Medical Research Council of Australia (NHMRC) Program and Investigator Grants (APP1053206, APP1196492) and Project and Ideas grants (APP2001692, APP1107178, and APP1108422).

Abbreviations

ASCVD

atherosclerotic cardiovascular disease

BMI

body mass index

CH-B

chronic hepatitis B

confidence interval

DAAs

direct-acting antivirals

HBsAg

hepatitis B virus surface antigen

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

hazard ratio

MAFLD

metabolic dysfunction-associated fatty liver disease

miR

micro RNA

NAFLD

non-alcoholic fatty liver disease

odds ratio

References

1. Sarin SK, Kumar M, Eslam M, George J, Al Mahtab M, Akbar SMF, et al. Liver diseases in the Asia-Pacific region: a Lancet Gastroenterology & Hepatology Commission. Lancet Gastroenterol Hepatol 2020;5:167–228.

2. Kang SH, Lee HW, Yoo JJ, Cho Y, Kim SU, Lee TH, et al. KASL clinical practice guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2021;27:363–401.

3. Tampi RP, Wong VW, Wong GL, Shu SS, Chan HL, Fung J, et al. Modelling the economic and clinical burden of non-alcoholic steatohepatitis in East Asia: data from Hong Kong. Hepatol Res 2020;50:1024–1031.

4. Terai S, Buchanan-Hughes A, Ng A, Lee IH, Hasegawa K. Comorbidities and healthcare costs and resource use of patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) in the Japan medical data vision database. J Gastroenterol 2021;56:274–284.

5. Golabi P, Paik JM, AlQahtani S, Younossi Y, Tuncer G, Younossi ZM. Burden of non-alcoholic fatty liver disease in Asia, the Middle East and North Africa: data from global burden of disease 2009-2019. J Hepatol 2021;75:795–809.

6. Wong MCS, Huang JLW, George J, Huang J, Leung C, Eslam M, et al. The changing epidemiology of liver diseases in the Asia-Pacific region. Nat Rev Gastroenterol Hepatol 2019;16:57–73.

7. Chang KC, Chang MH, Chen HL, Wu JF, Chang CH, Hsu HY, et al. Universal infant hepatitis B virus (HBV) vaccination for 35 years: moving toward the eradication of HBV. J Infect Dis 2022;225:431–435.

8. Kim GA, Lim YS, An J, Lee D, Shim JH, Kim KM, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut 2014;63:1325–1332.

9. Busch MP, Bloch EM, Kleinman S. Prevention of transfusion-transmitted infections. Blood 2019;133:1854–1864.

10. Ji F, Wei B, Yeo YH, Ogawa E, Zou B, Stave CD, et al. Systematic review with meta-analysis: effectiveness and tolerability of interferon-free direct-acting antiviral regimens for chronic hepatitis C genotype 1 in routine clinical practice in Asia. Aliment Pharmacol Ther 2018;47:550–562.

11. World Health Organization (WHO). Hepatitis C. WHO web site, <https://www.who.int/news-room/fact-sheets/detail/hepatitis-c>. Accessed 25 Feb 2022.

12. Powell EE, Wong VW, Rinella M. Non-alcoholic fatty liver disease. Lancet 2021;397:2212–2224.

13. Estes C, Chan HLY, Chien RN, Chuang WL, Fung J, Goh GB, et al. Modelling NAFLD disease burden in four Asian regions-2019-2030. Aliment Pharmacol Ther 2020;51:801–811.

14. Nakatsuka T, Tateishi R, Koike K. Changing clinical management of NAFLD in Asia. Liver Int 2021;Aug. 29. doi: 10.1111/liv.15046.

15. Zhang X, Wu M, Liu Z, Yuan H, Wu X, Shi T, et al. Increasing prevalence of NAFLD/NASH among children, adolescents and young adults from 1990 to 2017: a population-based observational study. BMJ Open 2021;11e042843.

16. Adams LA, Roberts SK, Strasser SI, Mahady SE, Powell E, Estes C, et al. Nonalcoholic fatty liver disease burden: Australia, 2019-2030. J Gastroenterol Hepatol 2020;35:1628–1635.

17. Roberts SK, Majeed A, Glenister K, Magliano D, Lubel JS, Bourke L, et al. Prevalence of non-alcoholic fatty liver disease in regional Victoria: a prospective population-based study. Med J Aust 2021;215:77–82.

18. Wong GL, Wong VW. How many deaths are caused by non-alcoholic fatty liver disease in the Asia-Pacific region? Lancet Gastroenterol Hepatol 2020;5:103–105.

19. Viganò L, Conci S, Cescon M, Fava C, Capelli P, D’Errico A, et al. Liver resection for hepatocellular carcinoma in patients with metabolic syndrome: a multicenter matched analysis with HCV-related HCC. J Hepatol 2015;63:93–101.

20. Pang Y, Kartsonaki C, Turnbull I, Guo Y, Clarke R, Chen Y, et al. Diabetes, plasma glucose, and incidence of fatty liver, cirrhosis, and liver cancer: a prospective study of 0.5 million people. Hepatology 2018;68:1308–1318.

21. Nderitu P, Bosco C, Garmo H, Holmberg L, Malmström H, Hammar N, et al. The association between individual metabolic syndrome components, primary liver cancer and cirrhosis: a study in the Swedish AMORIS cohort. Int J Cancer 2017;141:1148–1160.

22. Kim H, Lee DS, An TH, Park HJ, Kim WK, Bae KH, et al. Metabolic spectrum of liver failure in type 2 diabetes and obesity: from NAFLD to NASH to HCC. Int J Mol Sci 2021;22:4495.

23. Ye Q, Zou B, Yeo YH, Li J, Huang DQ, Wu Y, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2020;5:739–752.

24. Kim D, Kim W, Joo SK, Han J, Kim JH, Harrison SA, et al. Association between body size-metabolic phenotype and nonalcoholic steatohepatitis and significant fibrosis. J Gastroenterol 2020;55:330–341.

25. Kawaguchi T, Torimura T. Is metabolic syndrome responsible for the progression from NAFLD to NASH in non-obese patients? J Gastroenterol 2020;55:363–364.

26. Zheng Q, Zou B, Wu Y, Yeo Y, Wu H, Stave CD, et al. Systematic review with meta-analysis: prevalence of hepatic steatosis, fibrosis and associated factors in chronic hepatitis B. Aliment Pharmacol Ther 2021;54:1100–1109.

27. Fernandez-Fuertes M, Macías J, Corma-Gómez A, Rincón P, Merchante N, Gómez-Mateos J, et al. Similar prevalence of hepatic steatosis among patients with chronic hepatitis C with and without HIV coinfection. Sci Rep 2020;10:6736.

28. Yamada S, Kawaguchi A, Kawaguchi T, Fukushima N, Kuromatsu R, Sumie S, et al. Serum albumin level is a notable profiling factor for non-B, non-C hepatitis virus-related hepatocellular carcinoma: a data-mining analysis. Hepatol Res 2014;44:837–845.

29. Kudo M, Izumi N, Kokudo N, Sakamoto M, Shiina S, Takayama T, et al. Report of the 21st nationwide follow-up survey of primary liver cancer in Japan (2010-2011). Hepatol Res 2021;51:355–405.

30. Tateishi R, Uchino K, Fujiwara N, Takehara T, Okanoue T, Seike M, et al. A nationwide survey on non-B, non-C hepatocellular carcinoma in Japan: 2011-2015 update. J Gastroenterol 2019;54:367–376.

31. Siriwardana RC, Niriella MA, Dassanayake A, Ediriweera D, Gunetilleke B, Sivasundaram T, et al. Association of serum ferritin with diabetes and alcohol in patients with non-viral liver disease-related hepatocellular carcinoma. Liver Cancer 2017;6:307–312.

32. Barber SL, Rosenberg M. Aging and universal health coverage: implications for the Asia Pacific region. Health Syst Reform 2017;3:154–158.

33. McPake B, Mahal A. Addressing the needs of an aging population in the health system: the australian case. Health Syst Reform 2017;3:236–247.

34. Shiha G, Korenjak M, Eskridge W, Casanovas T, Velez-Moller P, Högström S, et al. Redefining fatty liver disease: an international patient perspective. Lancet Gastroenterol Hepatol 2021;6:73–79.

35. Fouad Y, Gomaa A, Semida N, Ghany WA, Attia D. Change from NAFLD to MAFLD increases the awareness of fatty liver disease in primary care physicians and specialists. J Hepatol 2021;74:1254–1256.

36. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, RomeroGomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol 2020;73:202–209.

37. Eslam M, Sanyal AJ, George J, ; International Consensus Panel. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 2020;158:1999–2014. e1.

38. Lee H, Lee YH, Kim SU, Kim HC. Metabolic dysfunction-associated fatty liver disease and incident cardiovascular disease risk: a nationwide cohort study. Clin Gastroenterol Hepatol 2021;19:2138–2147.e10.

39. Fan J, Luo S, Ye Y, Ju J, Zhang Z, Liu L, et al. Prevalence and risk factors of metabolic associated fatty liver disease in the contemporary South China population. Nutr Metab (Lond) 2021;18:82.

40. Yamamura S, Eslam M, Kawaguchi T, Tsutsumi T, Nakano D, Yoshinaga S, et al. MAFLD identifies patients with significant hepatic fibrosis better than NAFLD. Liver Int 2020;40:3018–3030.

41. Tsutsumi T, Eslam M, Kawaguchi T, Yamamura S, Kawaguchi A, Nakano D, et al. MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: generalized estimating equation approach. Hepatol Res 2021;51:1115–1128.

42. Fukunaga S, Nakano D, Kawaguchi T, Eslam M, Ouchi A, Nagata T, et al. Non-obese MAFLD is associated with colorectal adenoma in health check examinees: a multicenter retrospective study. Int J Mol Sci 2021;22:5462.

43. Sun DQ, Jin Y, Wang TY, Zheng KI, Rios RS, Zhang HY, et al. MAFLD and risk of CKD. Metabolism 2021;115:154433.

44. van Kleef LA, Ayada I, Alferink LJM, Pan Q, de Knegt RJ. Metabolic dysfunction-associated fatty liver disease improves detection of high liver stiffness: the Rotterdam study. Hepatology 2022;75:419–429.

45. Wang X, Wu S, Yuan X, Chen S, Fu Q, Sun Y, et al. Metabolic dysfunction-associated fatty liver disease and mortality among Chinese adults: a prospective cohort study. J Clin Endocrinol Metab 2022;107:e745–e755.

46. Wong VW, Lazarus JV. Prognosis of MAFLD vs. NAFLD and implications for a nomenclature change. J Hepatol 2021;75:1267–1270.

47. Huang Q, Zou X, Wen X, Zhou X, Ji L. NAFLD or MAFLD: which has closer association with all-cause and cause-specific mortality?-results from NHANES III. Front Med (Lausanne) 2021;8:693507.

48. Kim D, Konyn P, Sandhu KK, Dennis BB, Cheung AC, Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States. J Hepatol 2021;75:1284–1291.

49. Kang SH, Cho Y, Jeong SW, Kim SU, Lee JW, ; Korean NAFLD Study Group. From nonalcoholic fatty liver disease to metabolic-associated fatty liver disease: big wave or ripple? Clin Mol Hepatol 2021;27:257–269.

50. Kawaguchi T, Tsutsumi T, Nakano D, Torimura T. MAFLD: renovation of clinical practice and disease awareness of fatty liver. Hepatol Res 2021;Sep. 2. doi: 10.1111/hepr.13706.

51. Hirose S, Matsumoto K, Tatemichi M, Tsuruya K, Anzai K, Arase Y, et al. Nineteen-year prognosis in Japanese patients with biopsyproven nonalcoholic fatty liver disease: lean versus overweight patients. PLoS One 2020;15e0241770.

52. Iritani S, Akuta N, Kawamura Y, Kajiwara A, Kasuya K, Fujiyama S, et al. Non-invasive predictors of prognosis of Asian patients with histopathologically-confirmed lean nonalcoholic fatty liver disease. BMC Gastroenterol 2020;20:368.

53. Ito T, Ishigami M, Zou B, Tanaka T, Takahashi H, Kurosaki M, et al. The epidemiology of NAFLD and lean NAFLD in Japan: a meta-analysis with individual and forecasting analysis, 1995-2040. Hepatol Int 2021;15:366–379.

54. Kim Y, Han E, Lee JS, Lee HW, Kim BK, Kim MK, et al. Cardiovascular risk is elevated in lean subjects with nonalcoholic fatty liver disease. Gut Liver 2022;16:290–299.

55. Ahmed OT, Gidener T, Mara KC, Larson JJ, Therneau TM, Allen AM. Natural history of nonalcoholic fatty liver disease with normal body mass index: a population-based study. Clin Gastroenterol Hepatol 2021;Jul. 13. doi: 10.1016/j.cgh.2021.07.016.

56. Younes R, Govaere O, Petta S, Miele L, Tiniakos D, Burt A, et al. Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach? Gut 2022;71:382–390.

57. Rahman MM, Kibria MG, Begum H, Haque M, Sultana N, Akhter M, et al. Prevalence, risk factors and metabolic profile of the non-obese and obese non-alcoholic fatty liver disease in a rural community of South Asia. BMJ Open Gastroenterol 2020;7e000535.

58. Semmler G, Wernly S, Bachmayer S, Wernly B, Schwenoha L, Huber-Schönauer U, et al. Nonalcoholic fatty liver disease in lean subjects: associations with metabolic dysregulation and cardiovascular risk-a single-center cross-sectional study. Clin Transl Gastroenterol 2021;12e00326.

59. Francque S, Wong VW. NAFLD in lean individuals: not a benign disease. Gut 2022;71:234–236.

60. Park H, Yoon EL, Cho S, Jun DW, Nah EH. Diabetes is the strongest risk factor of hepatic fibrosis in lean patients with non-alcoholic fatty liver disease. Gut 2021;Jun. 14. doi: 10.1136/gutjnl-2021-325102.

61. Wong VW, Wong GL, Chan RS, Shu SS, Cheung BH, Li LS, et al. Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease. J Hepatol 2018;69:1349–1356.

62. Hamurcu Varol P, Kaya E, Alphan E, Yilmaz Y. Role of intensive dietary and lifestyle interventions in the treatment of lean non-alcoholic fatty liver disease patients. Eur J Gastroenterol Hepatol 2020;32:1352–1357.

63. Cheng YM, Kao JH, Wang CC. The metabolic profiles and body composition of lean metabolic associated fatty liver disease. Hepatol Int 2021;15:405–412.

64. Ciardullo S, Monti T, Perseghin G. Prevalence of liver steatosis and fibrosis detected by transient elastography in adolescents in the 2017-2018 national health and nutrition examination survey. Clin Gastroenterol Hepatol 2021;19:384–390.e1.

65. Sohn W, Kwon HJ, Chang Y, Ryu S, Cho YK. Liver fibrosis in Asians with metabolic dysfunction-associated fatty liver disease. Clin Gastroenterol Hepatol 2021;Jul. 3. doi: 10.1016/j.cgh.2021.06.042.

66. Liu Z, Suo C, Shi O, Lin C, Zhao R, Yuan H, et al. The health impact of MAFLD, a novel disease cluster of NAFLD, is amplified by the integrated effect of fatty liver disease-related genetic variants. Clin Gastroenterol Hepatol 2022;20:e855–e875.

67. Lin YP, Lin SH, Wang CC, Lin CC, Chen DW, Chuang CH, et al. Impact of MAFLD on HBV-related stage 0/A hepatocellular carcinoma after curative resection. J Pers Med 2021;11:684.

68. Semmler G, Wernly S, Bachmayer S, Leitner I, Wernly B, Egger M, et al. Metabolic dysfunction-associated fatty liver disease (MAFLD)-rather a bystander than a driver of mortality. J Clin Endocrinol Metab 2021;106:2670–2677.

69. Lee YB, Ha Y, Chon YE, Kim MN, Lee JH, Park H, et al. Association between hepatic steatosis and the development of hepatocellular carcinoma in patients with chronic hepatitis B. Clin Mol Hepatol 2019;25:52–64.

70. Tada T, Nishimura T, Matono T, Yoshida M, Yuri M, Fujiwara A, et al. Association of liver stiffness and steatosis with hepatocellular carcinoma development in patients with hepatitis C virus infection who received direct-acting antiviral therapy and achieved sustained virological response. Hepatol Res 2021;51:860–869.

71. Ikejima K, Kon K, Yamashina S. Nonalcoholic fatty liver disease and alcohol-related liver disease: from clinical aspects to pathophysiological insights. Clin Mol Hepatol 2020;26:728–735.

72. Åberg F, Färkkilä M. Drinking and obesity: alcoholic liver disease/nonalcoholic fatty liver disease interactions. Semin Liver Dis 2020;40:154–162.

73. Mak LY, Yuen MF, Seto WK. Letter regarding “A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement”. J Hepatol 2020;73:1573–1574.

74. van Kleef LA, Choi HSJ, Brouwer WP, Hansen BE, Patel K, de Man RA, et al. Metabolic dysfunction-associated fatty liver disease increases risk of adverse outcomes in patients with chronic hepatitis B. JHEP Rep 2021;3:100350.

75. Wang MF, Wan B, Wu YL, Huang JF, Zhu YY, Li YB. Clinic-pathological features of metabolic associated fatty liver disease with hepatitis B virus infection. World J Gastroenterol 2021;27:336–344.

76. Huang SC, Su HJ, Kao JH, Tseng TC, Yang HC, Su TH, et al. Clinical and histologic features of patients with biopsy-proven metabolic dysfunction-associated fatty liver disease. Gut Liver 2021;15:451–458.

77. Rout G, Nayak B, Patel AH, Gunjan D, Singh V, Kedia S, et al. Therapy with oral directly acting agents in hepatitis C infection is associated with reduction in fibrosis and increase in hepatic steatosis on transient elastography. J Clin Exp Hepatol 2019;9:207–214.

78. Soliman H, Ziada D, Hamisa M, Badawi R, Hawash N, Salama M, et al. The effect of HCV eradication after direct acting antiviral agents on hepatic steatosis: a prospective observational study. Endocr Metab Immune Disord Drug Targets 2022;22:100–107.

79. Ji D, Chen GF, Niu XX, Zhang M, Wang C, Shao Q, et al. Non-alcoholic fatty liver disease is a risk factor for occurrence of hepatocellular carcinoma after sustained virologic response in chronic hepatitis C patients: a prospective four-years follow-up study. Metabol Open 2021;10:100090.

80. Yen YH, Lin MT, Kuo FY, Chang KC, Tsai MC, Tseng PL, et al. The association between steatosis and diabetes with hepatocellular carcinoma in non-genotype 3 chronic hepatitis C patients. Liver Int 2018;38:1064–1073.

81. Peleg N, Issachar A, Sneh Arbib O, Cohen-Naftaly M, Harif Y, Oxtrud E, et al. Liver steatosis is a major predictor of poor outcomes in chronic hepatitis C patients with sustained virological response. J Viral Hepat 2019;26:1257–1265.

82. Fouad Y, Lazarus JV, Negro F, Peck-Radosavljevic M, Sarin SK, Ferenci P, et al. MAFLD considerations as a part of the global hepatitis C elimination effort: an international perspective. Aliment Pharmacol Ther 2021;53:1080–1089.

83. Wang Q, Chang B, Li X, Zou Z. Role of ALDH2 in hepatic disorders: gene polymorphism and disease pathogenesis. J Clin Transl Hepatol 2021;9:90–98.

84. Mehta M, Satsangi S, Duseja A, Taneja S, Dhiman RK, Chawla Y. Can alcoholic liver disease and nonalcoholic fatty liver disease coexist? J Clin Exp Hepatol 2017;7:121–126.

85. Senussi NH, McCarthy DM. Simultaneous metabolic and alcohol-associated fatty liver disease (SMAFLD) and simultaneous metabolic and alcohol-associated steatohepatitis (SMASH). Ann Hepatol 2021;24:100526.

86. Khoudari G, Singh A, Noureddin M, Fritze D, Lopez R, Asaad I, et al. Characterization of patients with both alcoholic and nonalcoholic fatty liver disease in a large United States cohort. World J Hepatol 2019;11:710–718.

87. Yamamura S, Kawaguchi T, Nakano D, Tomiyasu Y, Yoshinaga S, Doi Y, et al. Profiles of advanced hepatic fibrosis evaluated by FIB-4 index and shear wave elastography in health checkup examinees. Hepatol Res 2020;50:199–213.

88. Gentric G, Maillet V, Paradis V, Couton D, L’Hermitte A, Panasyuk G, et al. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J Clin Invest 2015;125:981–992.

89. Mirra S, Gavaldà-Navarro A, Manso Y, Higuera M, Serrat R, Salcedo MT, et al. ARMCX3 mediates susceptibility to hepatic tumorigenesis promoted by dietary lipotoxicity. Cancers (Basel) 2021;13:1110.

90. Ioannou GN. Epidemiology and risk-stratification of NAFLD-associated HCC. J Hepatol 2021;75:1476–1484.

91. Kim HY. Recent advances in nonalcoholic fatty liver disease metabolomics. Clin Mol Hepatol 2021;27:553–559.

92. Eguchi Y, Wong G, Lee IH, Akhtar O, Lopes R, Sumida Y. Hepatocellular carcinoma and other complications of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in Japan: a structured review of published works. Hepatol Res 2021;51:19–30.

93. Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol 2020;72:250–261.

94. Myers S, Neyroud-Caspar I, Spahr L, Gkouvatsos K, Fournier E, Giostra E, et al. NAFLD and MAFLD as emerging causes of HCC: a populational study. JHEP Rep 2021;3:100231.

95. Enomoto H, Ueno Y, Hiasa Y, Nishikawa H, Hige S, Takikawa Y, et al. The transition in the etiologies of hepatocellular carcinomacomplicated liver cirrhosis in a nationwide survey of Japan. J Gastroenterol 2021;56:158–167.

96. Nagaoki Y, Hyogo H, Ando Y, Kosaka Y, Uchikawa S, Nishida Y, et al. Increasing incidence of non-HBV- and non-HCV-related hepatocellular carcinoma: single-institution 20-year study. BMC Gastroenterol 2021;21:306.

97. David D, Raghavendran A, Goel A, Bharath Kumar C, Kodiatte TA, Burad D, et al. Risk factors for non-alcoholic fatty liver disease are common in patients with non-B non-C hepatocellular carcinoma in India. Indian J Gastroenterol 2017;36:373–379.

98. Estes C, Anstee QM, Arias-Loste MT, Bantel H, Bellentani S, Caballeria J, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J Hepatol 2018;69:896–904.

99. Mittal S, El-Serag HB, Sada YH, Kanwal F, Duan Z, Temple S, et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2016;14:124–131. e1.

100. Gawrieh S, Dakhoul L, Miller E, Scanga A, deLemos A, Kettler C, et al. Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: a United States multicentre study. Aliment Pharmacol Ther 2019;50:809–821.

101. Aby E, Phan J, Truong E, Grotts J, Saab S. Inadequate hepatocellular carcinoma screening in patients with nonalcoholic steatohepatitis cirrhosis. J Clin Gastroenterol 2019;53:142–146.

102. Tateishi R, Matsumura T, Okanoue T, Shima T, Uchino K, Fujiwara N, et al. Hepatocellular carcinoma development in diabetic patients: a nationwide survey in Japan. J Gastroenterol 2021;56:261–273.

103. Tokushige K, Ikejima K, Ono M, Eguchi Y, Kamada Y, Itoh Y, et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020. Hepatol Res 2021;51:1013–1025.

104. Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2021;18:223–238.

105. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology 2021;73 Suppl 1(Suppl 1):4–13.

106. Singal AG, El-Serag HB. Rational HCC screening approaches for patients with NAFLD. J Hepatol 2022;76:195–201.

107. Benhammou JN, Moon AM, Pisegna JR, Su F, Vutien P, Moylan CA, et al. Nonalcoholic fatty liver disease risk factors affect liver-related outcomes after direct-acting antiviral treatment for hepatitis C. Dig Dis Sci 2021;66:2394–2406.

108. Benhammou JN, Aby ES, Shirvanian G, Manansala K, Hussain SK, Tong MJ. Improved survival after treatments of patients with nonalcoholic fatty liver disease associated hepatocellular carcinoma. Sci Rep 2020;10:9902.

109. Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021;592:450–456.

110. Eso Y, Taura K, Seno H. Does immune checkpoint inhibitor exhibit limited efficacy against non-viral hepatocellular carcinoma?: a review of clinical trials. Hepatol Res 2022;52:67–74.

111. Zurlo F, Larson K, Bogardus C, Ravussin E. Skeletal muscle metabolism is a major determinant of resting energy expenditure. J Clin Invest 1990;86:1423–1427.

112. Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol 2017;67:862–873.

113. Chun HS, Kim MN, Lee JS, Lee HW, Kim BK, Park JY, et al. Risk stratification using sarcopenia status among subjects with metabolic dysfunction-associated fatty liver disease. J Cachexia Sarcopenia Muscle 2021;12:1168–1178.

114. O’Gorman P, Naimimohasses S, Monaghan A, Kennedy M, Melo AM, Ní Fhloinn D, et al. Improvement in histological endpoints of MAFLD following a 12-week aerobic exercise intervention. Aliment Pharmacol Ther 2020;52:1387–1398.

115. Hashida R, Nakano D, Yamamura S, Kawaguchi T, Tsutsumi T, Matsuse H, et al. Association between activity and brain-derived neurotrophic factor in patients with non-alcoholic fatty liver disease: a data-mining analysis. Life (Basel) 2021;11:799.

116. Hashida R, Matsuse H, Kawaguchi T, Yoshio S, Bekki M, Iwanaga S, et al. Effects of a low-intensity resistance exercise program on serum miR-630, miR-5703, and fractalkine/CX3CL1 expressions in subjects with no exercise habits: a preliminary study. Hepatol Res 2021;51:823–833.

117. Gong XF, Yu AL, Tang J, Wang CL, He JR, Chen GQ, et al. MicroRNA-630 inhibits breast cancer progression by directly targeting BMI1. Exp Cell Res 2018;362:378–385.

118. Sakurai MA, Ozaki Y, Okuzaki D, Naito Y, Sasakura T, Okamoto A, et al. Gefitinib and luteolin cause growth arrest of human prostate cancer PC-3 cells via inhibition of cyclin G-associated kinase and induction of miR-630. PLoS One 2014;9e100124.

119. Chen EB, Zhou ZJ, Xiao K, Zhu GQ, Yang Y, Wang B, et al. The miR-561-5p/CX3CL1 signaling axis regulates pulmonary metastasis in hepatocellular carcinoma involving CX3CR1+ natural killer cells infiltration. Theranostics 2019;9:4779–4794.

120. Yki-Järvinen H, Luukkonen PK, Hodson L, Moore JB. Dietary carbohydrates and fats in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2021;18:770–786.

121. Prenner S, Rinella ME. Moderate exercise for nonalcoholic fatty liver disease. JAMA Intern Med 2016;176:1083–1084.

122. Fuster D, Samet JH. Alcohol use in patients with chronic liver disease. N Engl J Med 2018;379:1251–1261.

123. Bosron WF, Lumeng L, Li TK. Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease. Mol Aspects Med 1988;10:147–158.

124. Choi JH, Sohn W, Cho YK. The effect of moderate alcohol drinking in nonalcoholic fatty liver disease. Clin Mol Hepatol 2020;26:662–669.

125. Younossi ZM, Ong JP, Takahashi H, Yilmaz Y, Eguc Hi Y, El Kassas M, et al. A global survey of physicians knowledge about nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2021;Jul. 3. doi: 10.1016/j.cgh.2021.06.048.

126. Shiha G, Alswat K, Al Khatry M, Sharara AI, Örmeci N, Waked I, et al. Nomenclature and definition of metabolic-associated fatty liver disease: a consensus from the Middle East and north Africa. Lancet Gastroenterol Hepatol 2021;6:57–64.

127. Méndez-Sánchez N, Díaz-Orozco L, Córdova-Gallardo J. Redefinition of fatty liver disease from NAFLD to MAFLD raised disease awareness: Mexican experience. J Hepatol 2021;75:221–222.

128. Clayton M, Fabrellas N, Luo J, Alghamdi MG, Hafez A, Qadiri TA, et al. From NAFLD to MAFLD: nurse and allied health perspective. Liver Int 2021;41:683–691.

129. Eslam M, Alkhouri N, Vajro P, Baumann U, Weiss R, Socha P, et al. Defining paediatric metabolic (dysfunction)-associated fatty liver disease: an international expert consensus statement. Lancet Gastroenterol Hepatol 2021;6:864–873.

130. Eslam M, Ahmed A, Després JP, Jha V, Halford JCG, Wei Chieh JT, et al. Incorporating fatty liver disease in multidisciplinary care and novel clinical trial designs for patients with metabolic diseases. Lancet Gastroenterol Hepatol 2021;6:743–753.

131. Mendez-Sanchez N, Arrese M, Gadano A, Oliveira CP, Fassio E, Arab JP, et al. The Latin American Association for the Study of the Liver (ALEH) position statement on the redefinition of fatty liver disease. Lancet Gastroenterol Hepatol 2021;6:65–72.

132. Spearman CW, Desalegn H, Ocama P, Awuku YA, Ojo O, Elsahhar M, et al. The sub-Saharan Africa position statement on the redefinition of fatty liver disease: from NAFLD to MAFLD. J Hepatol 2021;74:1256–1258.

133. Tan SS, Lee YY, Ali RAR, Mustapha F, Chan WK. Endorsing the redefinition of fatty liver disease. Lancet Gastroenterol Hepatol 2021;6:163.

134. Nan Y, An J, Bao J, Chen H, Chen Y, Ding H, et al. The Chinese society of hepatology position statement on the redefinition of fatty liver disease. J Hepatol 2021;75:454–461.

Article information Continued

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Study	Number	Study design	Prevalence of MAFLD	Mean age (years)	Main outcome
Lin et al. [67] (2021)	812	Retrospective cohort study	45.4% of the patients with chronic hepatitis B-related hepatocellular carcinoma (296/1,076)	MAFLD: -56.2	Lean MAFLD (BMI <23 kg/m²) was a relative risk factor for tumor recurrence (HR, 2.03) among patients with MAFLD
Lin et al. [67] (2021)	812	Retrospective cohort study		Non-MAFLD: -56.2
Mak et al. [73] (2020)	2,370	Retrospective cross-sectional study	45.7% of the patients with chronic hepatitis B (1,083/2,370)	MAFLD: -57.5	The patients with chronic hepatitis B plus MAFLD had a higher prevalence of severe steatosis compared to the patients with chronic hepatitis B plus NAFLD outside the MAFLD criteria (62.0% vs. 35.3%).
Mak et al. [73] (2020)	2,370	Retrospective cross-sectional study		Non-MAFLD: -51.5	The patients with chronic hepatitis B plus MAFLD had a higher prevalence of advanced fibrosis/cirrhosis compared to the patients with chronic hepatitis B plus NAFLD outside the MAFLD criteria (22.6% vs. 11.8%).
van Kleef et al. [74] (2021)	1,076	Retrospective cohort study	27.5% of the patients with chronic hepatitis B (296/1,076)	MAFLD: -43.6	MAFLD was independently associated with the poor event-free (adjusted HR, 2.00), hepatocellular carcinoma-free (adjusted HR, 1.93), and transplantfree (adjusted HR, 1.80) survival rates.
van Kleef et al. [74] (2021)	1,076	Retrospective cohort study	27.5% of the patients with chronic hepatitis B (296/1,076)	Non-MAFLD:-36.7	Among the patients with MAFLD, no significant difference was seen in the event-free survival between the patients with and without steatohepatitis or between the patients with an NAFLD activity score <3 and those with an NAFLD activity score ≥3.
Wang et al. [75] (2021)	417	Retrospective cross-sectional study	All the subjects had MAFLD	MAFLD: -41.5	Among the patients with MAFLD, hepatitis B virus infection was associated with a significantly lower grade of hepatic steatosis (OR, 0.088), but higher levels of inflammation (OR, 4.059), and fibrosis (OR, 3.016) after adjusting for age, gender, and other metabolic parameters
Huang et al. [76] (2021)	185	Retrospective cross-sectional study	84.9% of the patients with biopsy-proven fatty liver or cryptogenic cirrhosis (157/185)	MAFLD-only: -51.9	Advanced fibrosis was associated with the presence of hepatitis B virus infection and metabolic diseases
Huang et al. [76] (2021)	185	Retrospective cross-sectional study		NAFLD-only: -44.1