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Open Access 17.02.2023 | IM - REVIEW

NAFLD, MAFLD, and beyond: one or several acronyms for better comprehension and patient care

verfasst von: Piero Portincasa

Erschienen in: Internal and Emergency Medicine | Ausgabe 4/2023

Abstract

The term non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common type of chronic liver disease. NAFLD points to excessive hepatic fat storage and no evidence of secondary hepatic fat accumulation in patients with “no or little alcohol consumption”. Both the etiology and pathogenesis of NAFLD are largely unknown, and a definitive therapy is lacking. Since NAFLD is very often and closely associated with metabolic dysfunctions, a consensus process is ongoing to shift the acronym NAFLD to MAFLD, i.e., metabolic-associated fatty liver disease. The change in terminology is likely to improve the classification of affected individuals, the disease awareness, the comprehension of the terminology and pathophysiological aspects involved, and the choice of more personalized therapeutic approaches while avoiding the intrinsic stigmatization due to the term “non-alcoholic”. Even more recently, other sub-classifications have been proposed to concentrate the heterogeneous causes of fatty liver disease under one umbrella. While awaiting additional validation studies in this field, we discuss the main reasons underlying this important shift of paradigm.

Supplementary file1 (DOCX 33 KB)

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s11739-023-03203-0.

The original online version of this article was revised: In this article the word painless was changed as painful under the section NAFLD and metabolic dysfunctions. also, a grammatical change in text under Conclusions and future perspectives section has been amended.

A correction to this article is available online at https://doi.org/10.1007/s11739-023-03252-5.

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Introduction

The acronyms NASH (non-alcoholic steatohepatitis) and NAFLD (non-alcoholic fatty liver disease) were originally coined by Ludwig et al. in 1980 [1] and Shaffner and Thaler in 1986 [2], respectively. NAFLD is a clinico-histopathologic entity defining excessive hepatic fat storage without evidence of secondary hepatic fat accumulation [3‐7] in patients with “no or little alcohol consumption”. Hepatic fat content must be greater than 5% at liver histology [8] or 5.6% at magnetic resonance [9].

Since 2020, a debate is taking place worldwide to redefine NAFLD as metabolic (dysfunction)-associated fatty liver disease (MAFLD), according to the most prevalent causes of liver steatosis [10‐12]. Meantime, further terminologies are being proposed instead of NAFLD. While awaiting additional validation studies, the main reasons underlying this important shift of paradigm are discussed in the following paragraphs.

NAFLD and the burden of disease: prevalence, natural history, etiology and pathogenesis

Globally, NAFLD has reached epidemic levels, with pooled prevalence of 14% (Africa), 24% (North America) [13], 24–27% (range 18–40%, Europe) [14], 27% (Asia), 31% (South America), and 32% (Middle East) [13]. NAFLD is more frequent in men than in women (33 vs. 20%), and also affects 10–20% of the pediatric population [15]. Evidence indicates the prevalence of NAFLD is on the rise worldwide together with that of obesity and associated complications [11, 16, 17].

In this scenario, we can expect a time-dependent increase of the incidence of liver fibrosis, decompensated liver cirrhosis, hepatocellular carcinoma, and liver-related mortality due to the progressive deterioration of initial NAFLD in the affected population [17].

The natural history of NAFLD can vary, with most patients developing a benign or slowly progressive form, which is usually asymptomatic in the early stages. The spectrum ranges from simple steatosis (non-alcoholic fatty liver, NAFL) to the progressive non-alcoholic steatohepatitis (NASH) in about 20% of cases [18]. NASH has the potential to progress to compensated and decompensated liver cirrhosis and, with more than a tenfold increase in risk, to hepatocellular carcinoma (HCC) (Fig. 1) [9, 19]. Of note, NAFLD is also a risk factor for several extrahepatic, especially metabolic manifestations [20] and is linked with increased cardiovascular risk [21].

Excessive liver fat storage has a series of well-known causes (Supplementary Table 1) and originates from a dynamic balance between causal and protective factors (Fig. 1) [22, 23].

In this scenario, individual lifestyle changes and environmental factors can promote epigenetic mechanisms such as histone methylation, abnormal DNA methylation, miRNA profiles, able to affect gene expression and to influence the progression of disease. Examples are the consequences of metabolic disturbances in pregnancy on NAFLD offspring [24], and the pro-inflammatory liver response and weight gain in germ-free mice colonized with stool microbes from 2-week-old infants born to obese mothers [25]. These mechanisms interact with inherited risk factors and modulate individual susceptibility to NAFLD [26].

Lifestyle and dietary habits [27, 28] play a key role, and NAFLD is commonly associated with metabolic abnormalities [9] such as obesity, type 2 diabetes, dyslipidemia, hypertension, hypopituitarism, and sedentary life [20]. On the other hand, alcohol, air pollution [29, 30], food contaminants [31], and gut dysbiosis, e.g., higher proportion of Proteobacteria and E. coli, with a lower proportion of Firmicutes, especially F. prausnitzii [32] likely contribute to the onset and progression of NAFLD [20, 33, 34].

In the context of metabolic abnormalities, several pathogenic pathways are involved in lipotoxicity and can contribute to the onset and progression of NAFLD, according to the nomenclature in use. The “lean” healthy visceral adipose tissue expresses anti-inflammatory cytokines (i.e., adiponectin, interleukin IL-4, IL-10, IL-13, transforming growth factor (TGF)-β, and nitric oxide (NO)) which control M2 macrophagic response and inhibit the neutrophil-mediated inflammation. By contrast, during expansion of hypertrophic (and apoptotic) visceral adipose tissue, secretion of pro-inflammatory molecules such as leptin, resistin, IL-6 and tumor necrosis factor (TNF)-α occurs. This step activates a M1 macrophage response [35], and results in insulin resistance, a chronic “metabolic” inflammatory status, and increased lipolysis of triglycerides with abundant flux of blood long-chain free fatty acids (FFA) to the liver. In addition, FFA in blood increases because of fat-enriched dietary habits and from dietary sugars driving the de novo lipogenesis (DNL) in the liver. Altogether, these factors contribute to the expansion of the hepatocyte FFA pool which can stress the mitochondrial β-oxidation capacity, lead to defective secretion/export of very-low density lipoproteins (VLDL) to blood. Accumulation of lipotoxic species such as lysophosphatidylcholine, diacylglycerol, and ceramides mediates the endoplasmic reticulum (ER) stress, the cellular oxidative stress, and the activation of the inflammasome. This is a component of the innate immunity response consisting of a multiprotein cytoplasmic complex activated by several damage-associated molecular patterns (DAMPs). Additional abnormalities consist of dysregulation of adipocytokines, depleted mitochondrial ATP, production of toxic uric acid, periodic hypoxia (i.e., during sleep apnea in extremely obese patients), and toxic products from gut microbiome which include tumor necrosis factor (TNF)-α, endogenous ethanol, and endotoxins like lipopolysaccharides (LPS). Studies in pure fatty liver models without fibrosis suggest that lipid accumulation developing with obesity can induce a distortion of liver architecture manifesting with reduced sinusoidal space and increased intrahepatic vascular resistance. Such changes can pave the way to portal hypertension observed in obesity, and progression to hemodynamically decompensated liver cirrhosis [36‐39].

Conditions can promote the NASH phenotype which manifests with hepatocellular injury, inflammation, stellate cell activation and progressive accumulation of excess extracellular matrix. Additional targets of the ongoing cellular damage include intracellular organelles, the nucleus, receptors and signaling pathways [40‐44].

NAFLD and metabolic dysfunctions

As mentioned earlier, the diagnosis of NAFLD is based on hepatic steatosis at imaging techniques or histology, and “exclusion” of competing causes of liver disease including “significant” alcohol intake. Such strict definition has some limitations. Despite the NAFLD prognosis depends on the presence of fibrotic NASH, the ultimate utility of liver biopsy becomes questionable [45]. In fact, liver biopsy is invasive, painful, risky, prone to misclassification due to sampling errors, not easily performed in large groups of patients who still lack targeted therapies for NAFLD. The issue of alcohol intake in NAFLD deserves additional observations. A standard drink contains about 14 g of pure alcohol (Rethinking Drinking Homepage—NIAAA (nih.gov)) and the current definition for NAFLD must exclude a weekly intake of ≥ 21 and ≥ 14 drinks in males and females, respectively. Above this cutoff value, the risk of alcoholic fatty liver disease (ALD) increases [46, 47], but it is difficult to exactly calculate the intake of alcoholic units or the duration of alcohol abstinence. Phosphatidylethanol can become a potential biomarker of alcohol consumption [48]. Yet, the effect of modest alcohol intake at lower cutoff values is still controversial in NAFLD individuals [49, 50].

In addition, the diagnosis of NAFLD requires the exclusion of several other causes of liver steatosis such as viral hepatitis [51‐54], hepatotoxic drugs [55], Wilson’s disease [56], total parenteral nutrition, prolonged fasting [57], and several other less common conditions (Supplementary Table 1). Both NAFLD and ALD rank as the most frequent conditions [58]. On one hand, the diagnosis of NAFLD relies on exclusion criteria and does not require the presence of metabolic dysfunction. But NAFLD is no longer an isolated condition, since NAFLD is associated with morbid obesity in about 90% of the cases [59, 60], with obesity and dyslipidemia in over 80% of the cases [61, 62], with hypertension in 70% of cases and with type 2 diabetes (T2DM) in about 50% of the cases [63‐65]. Such close associations strongly suggests that NAFLD is a systemic disease [10, 11, 15, 66] increasing with poor lifestyles, and in parallel with the epidemiological raise of overweight, obesity, insulin resistance, and metabolic syndrome [4, 12, 67‐70]. Younossi et al. [71] studied the prevalence of NAFLD and NASH in a metanalysis including 80 studies from 20 countries worldwide and 49,419 patients with T2DM. The prevalence of NAFLD was more than twofold higher than in the general population, i.e., 56%. In the same group, the prevalence of NASH was 37%. In patients with NAFLD and T2DM undergoing liver biopsy, 17% had advanced (F3–F4) liver fibrosis [71]. The close association of NAFLD with systemic metabolic conditions also explains why cardiovascular complications are frequent in NAFLD patients [65, 72], including atrial fibrillation [73, 74], diabetes, chronic kidney disease and extrahepatic neoplasms [75‐77]. It is worth noting that 10–30% of non-obese individuals can have NAFLD [4, 78].

Another close link between NAFLD and metabolic dysfunction is that the metabolic syndrome is often associated with NAFLD and with increased cardiovascular disease. NAFLD per se, however, is independently associated with cardiovascular disease [65, 72, 79, 80].

The ultimate knowledge of complex mechanisms governing the onset and progression of NAFLD is poorly known. The term “steatosis” is intrinsically characterized by the interplay of multifactorial factors [34, 40, 81, 82]. The coexistence of such factors makes the diagnosis of NAFLD and the design of clinical trials often difficult, since several confounding factors can be present [9].

MAFLD: debate about nomenclature

The acronym NAFLD was originally established as a diagnosis of exclusion based on the use of the stigmatizing term “alcoholic” and on a poor pathophysiological knowledge. In the past years, this term has generated confusion or uncertainty with regard to knowledge and allocation in clinical trials [83, 84]. Studies show that up to 96% of subjects with NAFLD can be unaware they have liver disease [85].

Following the current directions, there is a need for adopting a better term for liver steatosis to emphasize what the disease “is”, rather than what “it is not” when considering the burden of contributing metabolic abnormalities, pathophysiological mechanisms, diagnostic, and therapeutic strategies [84]. Since 2020 experts from 134 countries have proposed the transition of terminology from NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) [10] which points to the close association between fatty liver, metabolic disorders and target organ dysfunction (i.e., diabetes, chronic kidney disease, atherosclerosis, lung dysfunction, colon cancer, and both intrahepatic and extrahepatic events) [86], rather than on exclusion criteria [12]. The new terminology is not yet endorsed by international societies, including European Association for the Study of Liver Disease (EASL) and the American Association for the Study of Liver Disease AASLD) [87]. MAFLD is based on the presence of fatty liver at imaging, or by the combination of serum biomarkers or liver biopsy (Table 1) in individuals with overweight/obesity (different in Caucasians or Asians), T2DM (i.e., HbA1c ≥ 6.5% or specific drug treatment). In lean/normal weight individuals, the diagnosis is based on the presence of metabolic dysregulation with at least two out of seven abnormalities which include increased waist circumference, blood pressure, hypertriglyceridemia, low plasma high-density lipoprotein cholesterol, impaired fasting plasma glucose, insulin resistance with impaired Homeostatic Model Assessment of Insulin Resistance, and subclinical inflammation by plasma high‐sensitivity C‐reactive protein level [10, 83, 88‐92] (Fig. 2A).

Table 1

Diagnosis of liver steatosis/fibrosis/inflammation/progression

Outcome	Methods		Notes
Steatosis	Serum biomarkers	AST, ALT, GGT	Not specific, can fluctuate or remain normal during progression of disease
	Algorithms	Hepatic Steatosis index Fatty Liver Index	Combined serum tests and metabolic information [110, 129]
	Imaging	Abdominal ultrasound	Easily available, noninvasive Low sensitivity for steatosis degree < 30%
		ATI	To be validated [130]
		MRI-PDFF	Expensive, limited availability
	CAP	Software (component of transient elastography)	Quantitative measurement of liver steatosis [131]
Fibrosis	Serum biomarkers	FIB-4, NFS, ELF	Combined anthropometric data and serum tests. Can exclude advanced fibrosis [132]
	Imaging	TE	Validated, accurate, associated with measurement of liver stiffness and steatosis (CAP). Decreased sensitivity in obese patients [133]
		2D-SWE	Liver stiffness
		MRI-MRE	Expensive, limited availability
Steatohepatitis	Imaging	SWDS	To be validated [130]
Progression of disease	Liver biopsy	Steatosis, fibrosis, inflammation	Invasive, limitations (see paragraph)

ALT alanine aminotransferase, AST aspartate aminotransferase, ATI attenuation imaging, CAP controlled attenuation parameter, 2D-SWE two-dimensional shear wave elastography, ELF enhanced liver fibrosis test, GGT γ-glutamyl transferase, MRE magnetic resonance elastography, MRI magnetic resonance imaging, NFS NAFLD fibrosis score, PDFF proton density fat fraction, SWDS shear wave dispersion slope (SWDS), TE transient elastography

According to this perspective, the adoption of MAFLD definition provides a better classification of patients at higher risk of cardiovascular and kidney diseases [21, 93‐95], and hepatic fibrosis [96‐98], independently of other causes of liver damage. For example, MAFLD terminology becomes independent of alcohol intake, a situation which appears to worsen hepatic fibrosis and increase mortality in liver steatosis [99‐103]. On the other hand, one could argue that liver disease in general is often associated with alcohol abuse in the perception of the general public, and that adding “non-alcoholic” would be beneficial since it is now explicitly stated that the liver disease is not related to alcohol.

The presence of viral hepatitis is not an “a priori” exclusion criterium for MAFLD. In addition, MAFLD represents a further risk factor for HCC in hepatitis C virus (HCV) and hepatitis B virus (HBV) patients [104, 105]. Vice versa, the 10-year risk of cardiovascular disease is higher in patients with MAFLD and concomitant viral infection by hepatitis B or C virus, than in patients with only MAFLD [106]. With MAFLD, moreover, the role of metabolic abnormalities on liver damage will be elaborated together with other causes of liver steatosis, such as drugs, pregnancy and gut surgery [107‐109]. This possibility will be labeled as “MAFLD plus additional cause ….” [11, 96].

The diagnosis of MAFLD can include the presence of positive biomarkers independently from imaging and histology. This is not the case in NAFLD (see above). Thus, the possibility exists that a patient referred with a high-score for a specific algorithm such as the fatty liver index [110]) will be classified as MAFLD in the presence of metabolic dysfunction.

By contrast, the criteria designed for MAFLD do not extend to individuals with liver steatosis without metabolic dysfunction.

In a recent metanalysis and systematic review involving a pool of over 3 million individuals, the prevalence of MAFLD was 39%, 30%, and 5% in obese, non-obese, and normal weight individuals, respectively. Although not all cases of NAFLD are MAFLD [93, 111], by adopting the MAFLD terminology, the clinicians can better understand the pathophysiological mechanisms of disease. In terms of risk assessment, although evidence is limited, MAFLD (but not pure NAFLD) can be directly related with all-cause mortality [112, 113]. NAFLD has been linked with the development of cardiovascular diseases [114], although this association seems mainly linked with the metabolic components. In fact, NAFLD subjects not classifiable as MAFLD are at lower risk [21, 115]. Therapeutic approaches will improve since MAFLD points to the interaction of several pathophysiological factors and the multidisciplinary collaboration between internists, cardiologists, endocrinologists, nutritionists, hepatologists, and family medicine [10, 11, 83, 91, 94, 115‐122]. In addition, the target populations will gain a better comprehension of terminology [88, 123] without feeling stigmatized because of the word “alcoholic” [12, 119, 121, 124].

The change in terminology, along with either exclusion or inclusion criteria for NAFLD and MAFLD, respectively, creates three groups partially overlapping (Fig. 2B):

“Pure” NAFLD (non-MAFLD) where metabolic dysfunction is absent, and significant alcohol intake is excluded.
“Overlapping” N(M)AFLD where metabolic dysfunction is present and significant alcohol intake is excluded.
“Pure” MAFLD (non-NAFLD) where metabolic dysfunction is present and alcohol consumption can be significant.

Furthermore, in terms of risk assessment related to metabolic phenotypes (all-cause mortality risk, cardiovascular risk, histological progression of liver disease), subjects with overlapping or pure MAFLD represent a heterogeneous group. We speculate that further studies should assess the suitability of a more detailed risk stratification of MAFLD based on specific metabolic phenotypes (Table 2). Recent evidence in a large Korean cohort reported a higher cardiovascular disease risk in lean MAFLD or MAFLD associated with diabetes mellitus, than in overweigh MAFLD subjects, irrespective of metabolic abnormalities or comorbidities. In this cohort, the cardiovascular risk was linked with advanced liver fibrosis irrespective of MAFLD subtype [125].

Table 2

Possible sub-classification of subjects with MAFLD according to metabolic phenotype

1. Normal weight, metabolic unhealthy, without type 2 diabetes

2. Normal weight, metabolic unhealthy, with type 2 diabetes

3. Overweight, metabolic unhealthy, without type 2 diabetes

4. Overweight, metabolic unhealthy, with type 2 diabetes

5. Obese, without type 2 diabetes

6. Obese, with type 2 diabetes

It is evident that further studies are required to better focus on risk-specific sub-profiles (adjusted for confounders) and natural history of MAFLD/NAFLD association between MAFLD and hypertension and diabetes in the last two groups [126]. Despite few studies have dealt with the comparison between NAFLD and MAFLD, we still need caution due to the nature of the studies (retrospective), selection of groups, statistical issues and conclusions of the studies [96, 127].

Fatty liver disease: more acronyms on the way

Notably, a further classification of liver steatosis is being proposed under the general umbrella of fatty liver disease (FLD). Sub-classifications include almost all possible combinations of genetic, lipodystrophy, metabolic, alcoholic, combined, and yet-to-be-defined causes. This schematic classification will stimulate a further discussion with the aim to improve both comprehension and diagnostic/therapeutic approaches for FLD populations (Table 3) (Fig. 3) [84]. The discussion has gone further with a novel taxonomic classification of NAFLD based on hepatic, pathogenic and systemic features of disease in the individual patient [86, 128]. The liver-determinant-extrahepatic (LDE) system applies to NAFLD and MAFLD and combines information on liver status independently of histology (L), determinants which include sex and reproductive status, genetic, and endocrine assessment (D), and extrahepatic manifestations at a metabolic, cardiovascular, and tumor level (E).

Table 3

Recently proposed sub-classifications of fatty liver disease (FLD) [84]

Acronym	Condition	Notes
MAFLD	Metabolic-associated fatty liver disease	Fatty liver because of the overarching metabolic syndrome. Can occur in lean individuals, in overweight/obese individuals, and in T2DM individuals [10‐12, 134]
O-MAFLD	Obesity-linked MAFLD	Subclassification of MAFLD. Defines the altered gluco-lipid metabolism and pro-inflammatory metabolic changes which link obesity to NAFLD [23, 40, 84, 135, 136]
SMAFLD	Sarcopenia-linked MAFLD	Subclassification of MAFLD. Fatty liver occurring during age-related, chronic progressive muscle mass loss, with or without obesity [137]. Sarcopenia can induce insulin resistance, steatosis and histological fibrosis grades [22]. Role for decreased skeletal muscle myokines involved in FFA metabolism [138]. Potential therapeutic target via the myostatin and/or activin/follistatin axis [139]. Can occur alone or combined with O-MAFLD, requiring double therapeutic approach
GAFLD	Genetics-associated fatty liver disease	Genetic variants either monogenic or polygenic not necessarily causing metabolic abnormalities [140]
LAFLD	Lipodystrophy-associated fatty liver disease	Fat or muscle mass abnormalities with partial or complete loss of adipose tissue and predisposition to develop fatty liver without obesity. Classified as congenital, familial partial or acquired disorders [84, 141]
AAFLD	Alcoholic-associated fatty liver disease	Occurs with significant chronic alcohol consumption. Similar potential progression as for NAFLD and risk of associated metabolic/cardiovascular complications [50, 84, 142]
CAFLD	Combined causes of FLD	Overlap of different entities of FLD, e.g., obesity and sarcopenia or genetic causes, or lipodystrophy
XAFLD	Yet-to-be-defined subgroups	Conditions of FLD where etiology remains (temporarily or constantly) undefined (e.g., autoimmune hepatitis [143]; viral hepatitis [144]), or plays an emerging role (e.g., thyroid subclinical dysfunction [145], mitochondrial dysfunction [40, 82, 146, 147]

As for MAFLD, however, any sub-classification linked to liver steatosis needs validation studies with terminology to be agreed upon [84]. While searching for better classification of liver steatosis, both researchers, clinicians, scientific societies, patients’ associations, and other stakeholders must be aware that change in terminology requires a better understanding of the molecular basis of the disease entity. Benefits of patients must be balanced along with novel risk stratification and characteristics of disease [87].

Conclusions and future perspectives

The rapid epidemiological increment and the global diffusion of NAFLD is a matter of major concern in terms of healthcare and social burden of disease. Both etiology and pathogenesis of NAFLD are largely unknown, and a multidisciplinary approach is required to handle a frequent liver disease still missing a definitive therapy, beside lifestyle, and maintenance or achievement of ideal body weight. The ongoing discussion urges to revise the terminology [11, 12] since the acronym NAFLD has several limitations: it suggests ignorance about true etiology, it remains an exclusion criterium, it can be ambiguous and misleading, and appears to stigmatize the affected individuals because of the word “alcoholic”. Since NAFLD is very often and closely associated with metabolic dysfunctions, the current view is to shift the acronym NAFLD to MAFLD, i.e., metabolic-associated fatty liver disease. MAFLD becomes an “active” diagnosis based on the presence of overweight/obesity or, in the lean subject, on the combination of metabolic dysfunctions which act as high‐risk factors for events. MAFLD is independent of alcohol intake and the co‐existing causes of liver disease. The change in terminology is likely to improve the classification of affected individuals, the disease awareness, the comprehension of terminology and pathophysiological aspects involved, the choice of more personalized therapeutic approaches, while avoiding the intrinsic stigmatization due to the term “non-alcoholic” (Table 4).

Table 4

Principal differences between NAFLD and MAFLD

Major features	NAFLD	MAFLD
Initial diagnosis of liver steatosis	Imaging Histology	Imaging Histology Biomarkers
Terminology criteria	Based on “negative” assumptions	Based on “positive” assumptions
Terminology comprehension/disease awareness	Poor	Clear
Terminology stigma	Yes (“alcoholic”)	No
Alcohol intake criterium	Dependent	Not dependent
Metabolic dysfunction	Not required	Required
Combination with other liver diseases	No (excluded)	Possible, if present
Liver biopsy	Essential for diagnosis of NASH	Not required
Chance for multidisciplinary interactions	Medium	Maximum
Therapeutic reflections	Few	Several
Possibility to identify groups at increased risk	Moderate	Likely high for hepatic/extrahepatic complications (metabolic, cardiovascular, genetic risk) Limited data in pediatric populations

Even more recently, other sub-classification have been proposed, e.g., the LDE terminology [128], and a detailed nomenclature has been proposed to concentrate the heterogeneous causes of fatty liver disease under one umbrella [84] (Table 3). We must take note of such shifts of paradigm and contribute to advance the discussion further. Several partners must agree upon a novel terminology, including clinicians, researchers, pharmaceutical industries, patients and their associations, and scientific societies. In this multidisciplinary field, we need motivated and dedicated researchers with holistic views, to bring tangible pathophysiological, diagnostic, and therapeutic benefits for the populations worldwide suffering from fatty liver disease and related burden of disease. Along with this shift of paradigm, i.e., NAFLD vs. MAFLD, the role of internal medicine and internists is undoubtedly gaining even more trust.

Acknowledgements

The author is indebted to Leonilde Bonfrate, Giuseppe Calamita, Agostino Di Ciaula, Domenica Di Palo, Dan Dumitrascu, Karel van Erpecum, Mohamad Khalil, Marcin Krawczyk, Paulo Oliveira, Harshita Shanmugam, and David Q.-H. Wang for helpful scientific discussion and longstanding collaborations.

Declarations

Conflict of interest

The author has no conflict of interest.

Human and animal rights statement and Informed consent

The article is a review analysis. Human Participants and/or Animals have not been involved in the present study.

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Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 33 KB)

Ludwig J, Viggiano TR, McGill DB, Oh BJ (1980) Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clinic proceedings. Mayo Clinic 55(7):434–438

Schaffner F, Thaler H (1986) Nonalcoholic fatty liver disease. Prog Liver Dis 8:283–298PubMed

Portincasa P, Krawczyk M, Smyk W, Lammert F, Di Ciaula A (2020) COVID-19 and non-alcoholic fatty liver disease: two intersecting pandemics. Eur J Clin Invest 50(10):e13338. https://doi.org/10.1111/eci.13338CrossRefPubMedPubMedCentral

Molina-Molina E, Krawczyk M, Stachowska E, Lammert F, Portincasa P (2019) Non-alcoholic fatty liver disease in non-obese individuals: prevalence, pathogenesis and treatment. Clin Res Hepatol Gastroenterol 43(6):638–645. https://doi.org/10.1016/j.clinre.2019.04.005CrossRefPubMed

Krawczyk M, Portincasa P, Lammert F (2013) PNPLA3-associated steatohepatitis: toward a gene-based classification of fatty liver disease. Semin Liver Dis 33(4):369–379. https://doi.org/10.1055/s-0033-1358525CrossRefPubMed

Krawczyk M, Bonfrate L, Portincasa P (2010) Nonalcoholic fatty liver disease. Best practice & research. Clin Gastroenterol 24(5):695–708. https://doi.org/10.1016/j.bpg.2010.08.005CrossRef

Targher G, Tilg H, Byrne CD (2021) Non-alcoholic fatty liver disease: a multisystem disease requiring a multidisciplinary and holistic approach. Lancet Gastroenterol Hepatol 6(7):578–588. https://doi.org/10.1016/S2468-1253(21)00020-0CrossRefPubMed

European Association for the Study of the L, European Association for the Study of D, and European Association for the Study of O (2016) EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 64(6):1388–1402. https://doi.org/10.1016/j.jhep.2015.11.004CrossRef

Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ (2018) The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67(1):328–357. https://doi.org/10.1002/hep.29367CrossRefPubMed

10.

Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, Zelber-Sagi S, Wong VW-S, Dufour J-F, Schattenberg JM (2020) A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol 73(1):202–209CrossRefPubMed

11.

Eslam M, Sanyal AJ, George J, International Consensus P (2020) MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 158(7):1999-2014 e1991. https://doi.org/10.1053/j.gastro.2019.11.312CrossRefPubMed

12.

Mendez-Sanchez N, Bugianesi E, Gish RG, Lammert F, Tilg H, Nguyen MH, Sarin SK, Fabrellas N, Zelber-Sagi S, Fan JG, Shiha G, Targher G, Zheng MH, Chan WK, Vinker S, Kawaguchi T, Castera L, Yilmaz Y, Korenjak M, Spearman CW, Ungan M, Palmer M, El-Shabrawi M, Gruss HJ, Dufour JF, Dhawan A, Wedemeyer H, George J, Valenti L, Fouad Y, Romero-Gomez M, Eslam M, Global multi-stakeholder consensus on the redefinition of fatty liver d (2022) Global multi-stakeholder endorsement of the MAFLD definition. Lancet Gastroenterol Hepatol 7(5):388–390. https://doi.org/10.1016/S2468-1253(22)00062-0CrossRefPubMed

13.

Younossi Z, Tacke F, Arrese M, Chander Sharma B, Mostafa I, Bugianesi E, Wai-Sun Wong V, Yilmaz Y, George J, Fan J, Vos MB (2019) Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 69(6):2672–2682. https://doi.org/10.1002/hep.30251CrossRefPubMed

14.

Cholongitas E, Pavlopoulou I, Papatheodoridi M, Markakis GE, Bouras E, Haidich AB, Papatheodoridis G (2021) Epidemiology of nonalcoholic fatty liver disease in Europe: a systematic review and meta-analysis. Ann Gastroenterol 34(3):404–414. https://doi.org/10.20524/aog.2021.0604CrossRefPubMedPubMedCentral

15.

Rojano A, Sena E, Manzano-Nunez R, Pericas JM, Ciudin A (2022) NAFLD as the metabolic hallmark of obesity. Intern Emerg Med. https://doi.org/10.1007/s11739-022-03139-xCrossRefPubMed

16.

Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ (2018) Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 67(1):123–133. https://doi.org/10.1002/hep.29466CrossRefPubMed

17.

Estes C, Anstee QM, Arias-Loste MT, Bantel H, Bellentani S, Caballeria J, Colombo M, Craxi A, Crespo J, Day CP, Eguchi Y, Geier A, Kondili LA, Kroy DC, Lazarus JV, Loomba R, Manns MP, Marchesini G, Nakajima A, Negro F, Petta S, Ratziu V, Romero-Gomez M, Sanyal A, Schattenberg JM, Tacke F, Tanaka J, Trautwein C, Wei L, Zeuzem S, Razavi H (2018) Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J Hepatol 69(4):896–904. https://doi.org/10.1016/j.jhep.2018.05.036CrossRefPubMed

18.

Loomba R, Adams LA (2019) The 20% rule of NASH progression: the natural history of advanced fibrosis and cirrhosis caused by NASH. Hepatology 70(6):1885–1888. https://doi.org/10.1002/hep.30946CrossRefPubMed

19.

Wong T, Dang K, Ladhani S, Singal AK, Wong RJ (2019) Prevalence of alcoholic fatty liver disease among adults in the United States, 2001–2016. JAMA 321(17):1723–1725. https://doi.org/10.1001/jama.2019.2276CrossRefPubMedPubMedCentral

20.

Powell EE, Wong VW, Rinella M (2021) Non-alcoholic fatty liver disease. Lancet 397(10290):2212–2224. https://doi.org/10.1016/S0140-6736(20)32511-3CrossRefPubMed

21.

Lee H, Lee YH, Kim SU, Kim HC (2021) Metabolic dysfunction-associated fatty liver disease and incident cardiovascular disease risk: a nationwide cohort study. Clin Gastroenterol Hepatol 19(10):2138-2147 e2110. https://doi.org/10.1016/j.cgh.2020.12.022CrossRefPubMed

22.

Li AA, Kim D, Ahmed A (2020) Association of sarcopenia and NAFLD: an overview. Clin Liver Dis (Hoboken) 16(2):73–76. https://doi.org/10.1002/cld.900CrossRefPubMed

23.

Polyzos SA, and Mantzoros CS (2020). Making progress in nonalcoholic fatty liver disease (NAFLD) as we are transitioning from the era of NAFLD to dys-metabolism associated fatty liver disease (DAFLD). Metab-Clin Exp 111

24.

Hagstrom H, Simon TG, Roelstraete B, Stephansson O, Soderling J, Ludvigsson JF (2021) Maternal obesity increases the risk and severity of NAFLD in offspring. J Hepatol 75(5):1042–1048. https://doi.org/10.1016/j.jhep.2021.06.045CrossRefPubMed

25.

Soderborg TK, Clark SE, Mulligan CE, Janssen RC, Babcock L, Ir D, Young B, Krebs N, Lemas DJ, Johnson LK, Weir T, Lenz LL, Frank DN, Hernandez TL, Kuhn KA, D’Alessandro A, Barbour LA, El Kasmi KC, Friedman JE (2018) The gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD. Nat Commun 9(1):4462. https://doi.org/10.1038/s41467-018-06929-0CrossRefPubMedPubMedCentral

26.

Arrese M, Arab JP, Barrera F, Kaufmann B, Valenti L, Feldstein AE (2021) Insights into nonalcoholic fatty-liver disease heterogeneity. Semin Liver Dis 41(4):421–434. https://doi.org/10.1055/s-0041-1730927CrossRefPubMedPubMedCentral

27.

Semmler G, Datz C, Reiberger T, Trauner M (2021) Diet and exercise in NAFLD/NASH: beyond the obvious. Liver Int 41(10):2249–2268. https://doi.org/10.1111/liv.15024CrossRefPubMedPubMedCentral

28.

Angelidi AM, Papadaki A, Nolen-Doerr E, Boutari C, Mantzoros CS (2022) The effect of dietary patterns on non-alcoholic fatty liver disease diagnosed by biopsy or magnetic resonance in adults: a systematic review of randomised controlled trials. Metab Clin Exp 129:155136. https://doi.org/10.1016/j.metabol.2022.155136CrossRefPubMed

29.

Li FR, Liao J, Zhu B, Li X, Cheng Z, Jin C, Mo C, Wu X, Li Q, Liang F (2022) Long-term exposure to air pollution and incident non-alcoholic fatty liver disease and cirrhosis: a cohort study. Liver Int. https://doi.org/10.1111/liv.15416CrossRefPubMedPubMedCentral

30.

Guo B, Guo Y, Nima Q, Feng Y, Wang Z, Lu R, Baimayangji MY, Zhou J, Xu H, Chen L, Chen G, Li S, Tong H, Ding X, Zhao X, Cohort CM-E, collaborative g (2022) Exposure to air pollution is associated with an increased risk of metabolic dysfunction-associated fatty liver disease. J Hepatol 76(3):518–525. https://doi.org/10.1016/j.jhep.2021.10.016CrossRefPubMed

31.

Di Ciaula A, Portincasa P (2019) Diet and contaminants: driving the rise to obesity epidemics? Curr Med Chem 26(19):3471–3482. https://doi.org/10.2174/0929867324666170518095736CrossRefPubMed

32.

Alferink LJM, Radjabzadeh D, Erler NS, Vojinovic D, Medina-Gomez C, Uitterlinden AG, de Knegt RJ, Amin N, Ikram MA, Janssen HLA, Kiefte-de Jong JC, Metselaar HJ, van Duijn CM, Kraaij R, Darwish Murad S (2021) Microbiomics, metabolomics, predicted metagenomics, and hepatic steatosis in a population-based study of 1,355 adults. Hepatology 73(3):968–982. https://doi.org/10.1002/hep.31417CrossRefPubMed

33.

Smyk W, Janik MK, Portincasa P, Milkiewicz P, Lammert F, Krawczyk M (2020) COVID-19: focus on the lungs but do not forget the gastrointestinal tract. Eur J Clin Investig 50(9):e13276CrossRef

34.

Di Ciaula A, Bonfrate L, Portincasa P (2022) The role of microbiota in nonalcoholic fatty liver disease. Eur J Clin Invest 52(7):e13768. https://doi.org/10.1111/eci.13768CrossRefPubMed

35.

Vecchie A, Dallegri F, Carbone F, Bonaventura A, Liberale L, Portincasa P, Fruhbeck G, Montecucco F (2018) Obesity phenotypes and their paradoxical association with cardiovascular diseases. Eur J Intern Med 48:6–17. https://doi.org/10.1016/j.ejim.2017.10.020CrossRefPubMed

36.

Francque S, Verrijken A, Mertens I, Hubens G, Van Marck E, Pelckmans P, Van Gaal L, Michielsen P (2010) Noncirrhotic human nonalcoholic fatty liver disease induces portal hypertension in relation to the histological degree of steatosis. Eur J Gastroenterol Hepatol 22(12):1449–1457. https://doi.org/10.1097/MEG.0b013e32833f14a1CrossRefPubMed

37.

Di Ciaula A, Carbone F, Shanmugham H, Molina-Molina E, Bonfrate L, Ministrini S, Montecucco F, Portincasa P (2021) Adiponectin involved in portal flow hepatic extraction of 13C-methacetin in obesity and non-alcoholic fatty liver. Eur J Intern Med 89:56–64. https://doi.org/10.1016/j.ejim.2021.03.036CrossRefPubMed

38.

Pasarin M, La Mura V, Gracia-Sancho J, Garcia-Caldero H, Rodriguez-Vilarrupla A, Garcia-Pagan JC, Bosch J, Abraldes JG (2012) Sinusoidal endothelial dysfunction precedes inflammation and fibrosis in a model of NAFLD. PLoS ONE 7(4):e32785. https://doi.org/10.1371/journal.pone.0032785CrossRefPubMedPubMedCentral

39.

Ryou M, Stylopoulos N, Baffy G (2020) Nonalcoholic fatty liver disease and portal hypertension. Explor Med 1:149–169. https://doi.org/10.37349/emed.2020.00011CrossRefPubMedPubMedCentral

40.

Di Ciaula A, Passarella S, Shanmugam H, Noviello M, Bonfrate L, Wang DQ-H, Portincasa P (2021) Nonalcoholic fatty liver disease (NAFLD). Mitochondria as players and targets of therapies? Int J Mol Sci 22(10):5375CrossRefPubMedPubMedCentral

41.

Rinella ME, Sanyal AJ (2016) Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol 13(4):196–205. https://doi.org/10.1038/nrgastro.2016.3CrossRefPubMed

42.

Portincasa P, Wang DQH (2017) Nonalcoholic fatty liver and gallstone disease. In: Wang DQH, Portincasa P (eds) Gallstones. Recent advances in epidemiology, pathogenesis, diagnosis and management. Nova Science Publisher Inc, USA, pp 387–414

43.

Grattagliano I, De Bari O, Di Palo D, Montecucco F, Carbone F, Oliveira P, Wang DQH, Portincasa P (2018) Mitochondria in liver diseases. In: Oliveira P (ed) Mitochondrial biology and experimental therapeutics. Springer Nature, Berlin, pp 91–126CrossRef

44.

Chen Z, Yu Y, Cai J, Li H (2019) Emerging molecular targets for treatment of nonalcoholic fatty liver disease. Trends Endocrinol Metab: TEM 30(12):903–914. https://doi.org/10.1016/j.tem.2019.08.006CrossRefPubMed

45.

Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, Sebastiani G, Ekstedt M, Hagstrom H, Nasr P, Stal P, Wong VW, Kechagias S, Hultcrantz R, Loomba R (2017) Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 65(5):1557–1565. https://doi.org/10.1002/hep.29085CrossRefPubMed

46.

Di Ciaula A, Baj J, Garruti G, Celano G, De Angelis M, Wang HH, Di Palo DM, Bonfrate L, Wang DQ, Portincasa P (2020) Liver steatosis, gut-liver axis, microbiome and environmental factors. A never-ending bidirectional cross-talk. J Clin Med 9(8):2648. https://doi.org/10.3390/jcm9082648CrossRefPubMedPubMedCentral

47.

Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ, American Gastroenterological A, American Association for the Study of Liver D, and American College of G (2012) The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American gastroenterological association, American association for the study of liver diseases, and American college of gastroenterology. Gastroenterology 142(7):1592–1609. https://doi.org/10.1053/j.gastro.2012.04.001CrossRefPubMed

48.

Blomdahl J, Nasr P, Ekstedt M, Kechagias S (2021) Moderate alcohol consumption is associated with advanced fibrosis in non-alcoholic fatty liver disease and shows a synergistic effect with type 2 diabetes mellitus. Metab Clin Exp 115:154439CrossRefPubMed

49.

Patel PJ, Smith D, Connor JP, Horsfall LU, Hayward KL, Hossain F, Williams S, Johnson T, Stuart KA, Brown NN, Saad N, Clouston AD, Irvine KM, Russell AW, Valery PC, Powell EE (2017) Alcohol consumption in diabetic patients with nonalcoholic fatty liver disease. Can J Gastroenterol Hepatol 2017:7927685. https://doi.org/10.1155/2017/7927685CrossRefPubMedPubMedCentral

50.

Di Ciaula A, Bonfrate L, Krawczyk M, Fruhbeck G, Portincasa P (2022) Synergistic and detrimental effects of alcohol intake on progression of liver steatosis. Int J Mol Sci 23(5):2636. https://doi.org/10.3390/ijms23052636CrossRefPubMedPubMedCentral

51.

Li JF, Qu F, Zheng SJ, Wu HL, Liu M, Liu S, Ren Y, Ren F, Chen Y, Duan ZP, Zhang JL (2014) Elevated plasma sphingomyelin (d18:1/22:0) is closely related to hepatic steatosis in patients with chronic hepatitis C virus infection. Eur J Clin Microbiol Infect Dis 33(10):1725–1732. https://doi.org/10.1007/s10096-014-2123-xCrossRefPubMed

52.

Yasui K, Harano Y, Mitsuyoshi H, Tsuji K, Endo M, Nakajima T, Minami M, Itoh Y, Zen Y, Nakanuma Y, Yoshikawa T, Okanoue T (2010) Steatosis and hepatic expression of genes regulating lipid metabolism in Japanese patients infected with hepatitis C virus. J Gastroenterol 45(1):95–104. https://doi.org/10.1007/s00535-009-0133-8CrossRefPubMed

53.

Jian WY, Shu Chen L, Gui Qiang W (2006) Effects of fatty liver and related factors on the efficacy of combination antiviral therapy in patients with chronic hepatitis C. Liver Int 26(2):166–172. https://doi.org/10.1111/j.1478-3231.2005.01219.xCrossRef

54.

Hwang SJ, Luo JC, Chu CW, Lai CR, Lu CL, Tsay SH, Wu JC, Chang FY, Lee SD (2001) Hepatic steatosis in chronic hepatitis C virus infection: prevalence and clinical correlation. J Gastroenterol Hepatol 16(2):190–195. https://doi.org/10.1046/j.1440-1746.2001.02407.xCrossRefPubMed

55.

Satapathy SK, Kuwajima V, Nadelson J, Atiq O, Sanyal AJ (2015) Drug-induced fatty liver disease: an overview of pathogenesis and management. Ann Hepatol 14(6):789–806. https://doi.org/10.5604/16652681.1171749CrossRefPubMed

56.

Stattermayer AF, Traussnigg S, Dienes HP, Aigner E, Stauber R, Lackner K, Hofer H, Stift J, Wrba F, Stadlmayr A, Datz C, Strasser M, Maieron A, Trauner M, Ferenci P (2015) Hepatic steatosis in Wilson disease–role of copper and PNPLA3 mutations. J Hepatol 63(1):156–163. https://doi.org/10.1016/j.jhep.2015.01.034CrossRefPubMed

57.

Jordan T, Popovic P, Rotovnik Kozjek N (2020) Liver steatosis in adult patients on home parenteral nutrition. Eur J Clin Nutr 74(2):255–260. https://doi.org/10.1038/s41430-019-0455-4CrossRefPubMed

58.

Grattagliano I, Di Ciaula A, Baj J, Molina-Molina E, Shanmugam H, Garruti G, Wang DQ, Portincasa P (2021) Protocols for mitochondria as the target of pharmacological therapy in the context of nonalcoholic fatty liver disease (NAFLD). Methods Mol Biol 2310:201–246. https://doi.org/10.1007/978-1-0716-1433-4_12CrossRefPubMedPubMedCentral

59.

Angulo P (2007) Obesity and nonalcoholic fatty liver disease. Nutr Rev 65(6 Pt 2):S57-63. https://doi.org/10.1111/j.1753-4887.2007.tb00329.xCrossRefPubMed

60.

Liu CJ (2012) Prevalence and risk factors for non-alcoholic fatty liver disease in Asian people who are not obese. J Gastroenterol Hepatol 27(10):1555–1560. https://doi.org/10.1111/j.1440-1746.2012.07222.xCrossRefPubMed

61.

Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J, Bugianesi E (2018) Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 15(1):11–20. https://doi.org/10.1038/nrgastro.2017.109CrossRefPubMed

62.

Yarnoz-Esquiroz P, Olazaran L, Aguas-Ayesa M, Perdomo CM, Garcia-Goni M, Silva C, Fernandez-Formoso JA, Escalada J, Montecucco F, Portincasa P, Fruhbeck G (2022) “Obesities”: position statement on a complex disease entity with multifaceted drivers. Eur J Clin Investig 52(7):e13811. https://doi.org/10.1111/eci.13811CrossRef

63.

Vernon G, Baranova A, Younossi ZM (2011) Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 34(3):274–285. https://doi.org/10.1111/j.1365-2036.2011.04724.xCrossRefPubMed

64.

Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA (2011) Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140(1):124–131. https://doi.org/10.1053/j.gastro.2010.09.038CrossRefPubMed

65.

Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M (2016) Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64(1):73–84. https://doi.org/10.1002/hep.28431CrossRefPubMed

66.

Byrne CD, Targher G (2015) NAFLD: a multisystem disease. J Hepatol 62(1 Suppl):S47-64. https://doi.org/10.1016/j.jhep.2014.12.012CrossRefPubMed

67.

Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, Srishord M (2011) Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 9(6):524–530. https://doi.org/10.1016/j.cgh.2011.03.020CrossRefPubMed

68.

Molina-Molina E, Lunardi Baccetto R, Wang DQ, de Bari O, Krawczyk M, Portincasa P (2018) Exercising the hepatobiliary-gut axis. The impact of physical activity performance. Eur J Clin Investig 48(8):e12958. https://doi.org/10.1111/eci.12958CrossRef

69.

Zhou J, Zhou F, Wang W, Zhang XJ, Ji YX, Zhang P, She ZG, Zhu L, Cai J, Li H (2020) Epidemiological features of NAFLD from 1999 to 2018 in China. Hepatology 71(5):1851–1864. https://doi.org/10.1002/hep.31150CrossRefPubMed

70.

Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, Marczak L, Mokdad AH, Moradi-Lakeh M, Naghavi M, Salama JS, Vos T, Abate KH, Abbafati C, Ahmed MB, Al-Aly Z, Alkerwi A, Al-Raddadi R, Amare AT, Amberbir A, Amegah AK, Amini E, Amrock SM, Anjana RM, Arnlov J, Asayesh H, Banerjee A, Barac A, Baye E, Bennett DA, Beyene AS, Biadgilign S, Biryukov S, Bjertness E, Boneya DJ, Campos-Nonato I, Carrero JJ, Cecilio P, Cercy K, Ciobanu LG, Cornaby L, Damtew SA, Dandona L, Dandona R, Dharmaratne SD, Duncan BB, Eshrati B, Esteghamati A, Feigin VL, Fernandes JC, Furst T, Gebrehiwot TT, Gold A, Gona PN, Goto A, Habtewold TD, Hadush KT, Hafezi-Nejad N, Hay SI, Horino M, Islami F, Kamal R, Kasaeian A, Katikireddi SV, Kengne AP, Kesavachandran CN, Khader YS, Khang YH, Khubchandani J, Kim D, Kim YJ, Kinfu Y, Kosen S, Ku T, Defo BK, Kumar GA, Larson HJ, Leinsalu M, Liang X, Lim SS, Liu P, Lopez AD, Lozano R, Majeed A, Malekzadeh R, Malta DC, Mazidi M, McAlinden C, McGarvey ST, Mengistu DT, Mensah GA, Mensink GBM, Mezgebe HB, Mirrakhimov EM, Mueller UO, Noubiap JJ, Obermeyer CM, Ogbo FA, Owolabi MO, Patton GC, Pourmalek F, Qorbani M, Rafay A, Rai RK, Ranabhat CL, Reinig N, Safiri S, Salomon JA, Sanabria JR, Santos IS, Sartorius B, Sawhney M, Schmidhuber J, Schutte AE, Schmidt MI, Sepanlou SG, Shamsizadeh M, Sheikhbahaei S, Shin MJ, Shiri R, Shiue I, Roba HS, Silva DAS, Silverberg JI, Singh JA, Stranges S, Swaminathan S, Tabares-Seisdedos R, Tadese F, Tedla BA, Tegegne BS, Terkawi AS, Thakur JS, Tonelli M, Topor-Madry R, Tyrovolas S, Ukwaja KN, Uthman OA, Vaezghasemi M, Vasankari T, Vlassov VV, Vollset SE, Weiderpass E, Werdecker A, Wesana J, Westerman R, Yano Y, Yonemoto N, Yonga G, Zaidi Z, Zenebe ZM, Zipkin B, Murray CJL, GBD 215 Obesity Collaborators (2017) Health effects of overweight and obesity in 195 Countries over 25 years. New Engl J Med 377(1):13–27. https://doi.org/10.1056/NEJMoa1614362CrossRefPubMed

71.

Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, Qiu Y, Burns L, Afendy A, Nader F (2019) The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol 71(4):793–801. https://doi.org/10.1016/j.jhep.2019.06.021CrossRefPubMed

72.

Brouwers M, Simons N, Stehouwer CDA, Isaacs A (2020) Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality. Diabetologia 63(2):253–260. https://doi.org/10.1007/s00125-019-05024-3CrossRefPubMed

73.

Cai X, Zheng S, Liu Y, Zhang Y, Lu J, Huang Y (2020) Nonalcoholic fatty liver disease is associated with increased risk of atrial fibrillation. Liver Int 40(7):1594–1600. https://doi.org/10.1111/liv.14461CrossRefPubMed

74.

Anstee QM, Mantovani A, Tilg H, Targher G (2018) Risk of cardiomyopathy and cardiac arrhythmias in patients with nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 15(7):425–439. https://doi.org/10.1038/s41575-018-0010-0CrossRefPubMed

75.

Tsochatzis EA, Newsome PN (2018) Non-alcoholic fatty liver disease and the interface between primary and secondary care. Lancet Gastroenterol Hepatol 3(7):509–517. https://doi.org/10.1016/s2468-1253(18)30077-3CrossRefPubMed

76.

Younossi ZM, Blissett D, Blissett R, Henry L, Stepanova M, Younossi Y, Racila A, Hunt S, Beckerman R (2016) The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 64(5):1577–1586. https://doi.org/10.1002/hep.28785CrossRefPubMed

77.

Paik JM, Golabi P, Younossi Y, Mishra A, Younossi ZM (2020) Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of NAFLD. Hepatology 72(5):1605–1616. https://doi.org/10.1002/hep.31173CrossRefPubMed

78.

Kim D, Kim WR (2017) Nonobese fatty liver disease. Clin Gastroenterol Hepatol 15(4):474–485. https://doi.org/10.1016/j.cgh.2016.08.028CrossRefPubMed

79.

Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S (2020) Nonalcoholic steatohepatitis: a review. JAMA 323(12):1175–1183. https://doi.org/10.1001/jama.2020.2298CrossRefPubMed

80.

Stepanova M, Younossi ZM (2012) Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol 10(6):646–650. https://doi.org/10.1016/j.cgh.2011.12.039CrossRefPubMed

81.

Catalan V, Aviles-Olmos I, Rodriguez A, Becerril S, Fernandez-Formoso JA, Kiortsis D, Portincasa P, Gomez-Ambrosi J, Fruhbeck G (2022) Time to consider the “exposome hypothesis” in the development of the obesity pandemic. Nutrients. https://doi.org/10.3390/nu14081597CrossRefPubMedPubMedCentral

82.

Di Ciaula A, Calamita G, Shanmugam H, Khalil M, Bonfrate L, Wang DQ, Baffy G, Portincasa P (2021) Mitochondria matter: systemic aspects of nonalcoholic fatty liver disease (NAFLD) and diagnostic assessment of liver function by stable isotope dynamic breath tests. Int J Mol Sci 22(14):7702. https://doi.org/10.3390/ijms22147702CrossRefPubMedPubMedCentral

83.

Shiha G, Korenjak M, Eskridge W, Casanovas T, Velez-Moller P, Hogstrom S, Richardson B, Munoz C, Sigurethardottir S, Coulibaly A, Milan M, Bautista F, Leung NWY, Mooney V, Obekpa S, Bech E, Polavarapu N, Hamed AE, Radiani T, Purwanto E, Bright B, Ali M, Dovia CK, McColaugh L, Koulla Y, Dufour JF, Soliman R, Eslam M (2021) Redefining fatty liver disease: an international patient perspective. Lancet Gastroenterol Hepatol 6(1):73–79. https://doi.org/10.1016/S2468-1253(20)30294-6CrossRefPubMed

84.

Valenzuela-Vallejo L, Mantzoros CS (2022) Time to transition from a negative nomenclature describing what NAFLD is not, to a novel, pathophysiology-based, umbrella classification of fatty liver disease (FLD). Metab Clin Exp 134:155246. https://doi.org/10.1016/j.metabol.2022.155246CrossRefPubMed

85.

Alqahtani SA, Paik JM, Biswas R, Arshad T, Henry L, Younossi ZM (2021) Poor awareness of liver disease among adults with NAFLD in the United States. Hepatol Commun 5(11):1833–1847CrossRefPubMedPubMedCentral

86.

Lonardo A, Singal AK, Osna N, Kharbanda KK (2022) Effect of cofactors on NAFLD/NASH and MAFLD. A paradigm illustrating the pathomechanics of organ dysfunction. Metab Target Organ Damage. https://doi.org/10.2057/mtod.2022.14CrossRefPubMedPubMedCentral

87.

Younossi ZM, Rinella ME, Sanyal AJ, Harrison SA, Brunt EM, Goodman Z, Cohen DE, Loomba R (2021) From NAFLD to MAFLD: implications of a premature change in terminology. Hepatology 73(3):1194–1198. https://doi.org/10.1002/hep.31420CrossRefPubMed

88.

Mendez-Sanchez N, Diaz-Orozco L, Cordova-Gallardo J (2021) Redefinition of fatty liver disease from NAFLD to MAFLD raised disease awareness: Mexican experience. J Hepatol 75(1):221–222. https://doi.org/10.1016/j.jhep.2021.04.021CrossRefPubMed

89.

Nan Y, An J, Bao J, Chen H, Chen Y, Ding H, Dou X, Duan Z, Fan J, Gao Y, Han T, Han Y, Hu P, Huang Y, Huang Y, Jia J, Jiang J, Jiang Y, Li J, Li J, Li R, Li S, Li W, Li Y, Lin S, Liu J, Liu S, Lu L, Lu Q, Luo X, Ma X, Rao H, Ren H, Ren W, Shang J, Shi L, Su M, Wang B, Wang R, Wei L, Wen Z, Wu B, Wu J, Xin S, Xing H, Xu J, Yan M, Yang J, Yang J, Yang L, Yang Y, Yu Y, Zhang L, Zhang L, Zhang X, Zhang Y, Zhang Y, Zhao J, Zhao S, Zheng H, Zhou Y, Zhou Y, Zhuang H, Zuo W, Xu X, Qiao L (2021) The Chinese Society of Hepatology position statement on the redefinition of fatty liver disease. J Hepatol 75(2):454–461. https://doi.org/10.1016/j.jhep.2021.05.003CrossRefPubMed

90.

Eslam M, Sarin SK, Wong VW, Fan JG, Kawaguchi T, Ahn SH, Zheng MH, Shiha G, Yilmaz Y, Gani R, Alam S, Dan YY, Kao JH, Hamid S, Cua IH, Chan WK, Payawal D, Tan SS, Tanwandee T, Adams LA, Kumar M, Omata M, George J (2020) The Asian Pacific association for the study of the liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int 14(6):889–919. https://doi.org/10.1007/s12072-020-10094-2CrossRefPubMed

91.

Shiha G, Alswat K, Al Khatry M, Sharara AI, Ormeci N, Waked I, Benazzouz M, Al-Ali F, Hamed AE, Hamoudi W, Attia D, Derbala M, Sharaf-Eldin M, Al-Busafi SA, Zaky S, Bamakhrama K, Ibrahim N, Ajlouni Y, Sabbah M, Salama M, Anushiravani A, Afredj N, Barakat S, Hashim A, Fouad Y, Soliman R (2021) Nomenclature and definition of metabolic-associated fatty liver disease: a consensus from the Middle East and north Africa. Lancet Gastroenterol Hepatol 6(1):57–64. https://doi.org/10.1016/S2468-1253(20)30213-2CrossRefPubMed

92.

Tilg H, Effenberger M (2020) From NAFLD to MAFLD: when pathophysiology succeeds. Nat Rev Gastroenterol Hepatol 17(7):387–388. https://doi.org/10.1038/s41575-020-0316-6CrossRefPubMed

93.

Lin S, Huang J, Wang M, Kumar R, Liu Y, Liu S, Wu Y, Wang X, Zhu Y (2020) Comparison of MAFLD and NAFLD diagnostic criteria in real world. Liver Int 40(9):2082–2089. https://doi.org/10.1111/liv.14548CrossRefPubMed

94.

Yamamura S, Eslam M, Kawaguchi T, Tsutsumi T, Nakano D, Yoshinaga S, Takahashi H, Anzai K, George J, Torimura T (2020) MAFLD identifies patients with significant hepatic fibrosis better than NAFLD. Liver Int 40(12):3018–3030. https://doi.org/10.1111/liv.14675CrossRefPubMed

95.

The Lancet G Hepatology (2020) Redefining non-alcoholic fatty liver disease: what’s in a name? Lancet Gastroenterol Hepatol 5(5):419. https://doi.org/10.1016/s2468-1253(20)30091-1CrossRef

96.

Kawaguchi T, Tsutsumi T, Nakano D, Torimura T (2022) MAFLD: Renovation of clinical practice and disease awareness of fatty liver. Hepatol Res 52(5):422–432. https://doi.org/10.1111/hepr.13706CrossRefPubMed

97.

Park H, Yoon EL, Cho S, Jun DW, Nah E-H (2022) Diabetes is the strongest risk factor of hepatic fibrosis in lean patients with non-alcoholic fatty liver disease. Gut 71(5):1035–1036CrossRefPubMed

98.

Kawaguchi T, Torimura T (2020) Is metabolic syndrome responsible for the progression from NAFLD to NASH in non-obese patients? SpringerCrossRef

99.

Ochiai Y, Kawamura Y, Kobayashi M, Shindoh J, Kobayashi Y, Okubo S, Muraishi N, Kajiwara A, Iritani S, Fujiyama S, Hosaka T, Saitoh S, Sezaki H, Akuta N, Suzuki F, Suzuki Y, Ikeda K, Arase Y, Hashimoto M, Kumada H (2021) Effects of alcohol consumption on multiple hepatocarcinogenesis in patients with fatty liver disease. Hepatol Res 51(1):62–68. https://doi.org/10.1111/hepr.13572CrossRefPubMed

100.

Xu L, Xie J, Chen S, Chen Y, Yang H, Miao M, Zhu Z, Li Y, Yu C, Xu C (2020) Light-to-moderate alcohol consumption is associated with increased risk of type 2 diabetes in individuals with nonalcoholic fatty liver disease: a nine-year cohort study. Off J Am College Gastroenterol ACG 115(6):876–884CrossRef

101.

Hajifathalian K, Torabi Sagvand B, McCullough AJ (2019) Effect of alcohol consumption on survival in nonalcoholic fatty liver disease: a national prospective cohort study. Hepatology 70(2):511–521. https://doi.org/10.1002/hep.30226CrossRefPubMed

102.

Chang Y, Cho YK, Kim Y, Sung E, Ahn J, Jung HS, Yun KE, Shin H, Ryu S (2019) Nonheavy drinking and worsening of noninvasive fibrosis markers in nonalcoholic fatty liver disease: a cohort study. Hepatology 69(1):64–75. https://doi.org/10.1002/hep.30170CrossRefPubMed

103.

Fuster D, Samet JH (2018) Alcohol use in patients with chronic liver disease. New Engl J Med 379(13):1251–1261CrossRefPubMed

104.

Choi HS, Brouwer WP, Zanjir WM, de Man RA, Feld JJ, Hansen BE, Janssen HL, Patel K (2020) Nonalcoholic steatohepatitis is associated with liver-related outcomes and all-cause mortality in chronic hepatitis B. Hepatology 71(2):539–548CrossRefPubMed

105.

Tada T, Nishimura T, Matono T, Yoshida M, Yuri M, Fujiwara A, Yuri Y, Takashima T, Aizawa N, Ikeda N, Enomoto H, Kumada T, Iijima H (2021) 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 51(8):860–869. https://doi.org/10.1111/hepr.13677CrossRefPubMed

106.

Guerreiro GTS, Longo L, Fonseca MA, de Souza VEG, Alvares-da-Silva MR (2021) Does the risk of cardiovascular events differ between biopsy-proven NAFLD and MAFLD? Hepatol Int 15(2):380–391CrossRefPubMed

107.

Tanaka N, Horiuchi A, Yokoyama T, Kaneko G, Horigome N, Yamaura T, Nagaya T, Komatsu M, Sano K, Miyagawa S, Aoyama T, Tanaka E (2011) Clinical characteristics of de novo nonalcoholic fatty liver disease following pancreaticoduodenectomy. J Gastroenterol 46(6):758–768. https://doi.org/10.1007/s00535-011-0370-5CrossRefPubMed

108.

Pavlik L, Regev A, Ardayfio PA, Chalasani NP (2019) Drug-induced steatosis and steatohepatitis: the search for novel serum biomarkers among potential biomarkers for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Drug Saf 42(6):701–711CrossRefPubMed

109.

Sasamori Y, Tanaka A, Ayabe T (2020) Liver disease in pregnancy. Hepatol Res 50(9):1015–1023. https://doi.org/10.1111/hepr.13540CrossRefPubMed

110.

Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, Tiribelli C (2006) The fatty liver index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol 6:33. https://doi.org/10.1186/1471-230X-6-33CrossRefPubMedPubMedCentral

111.

Bianco C, Romeo S, Petta S, Long MT, Valenti L (2020) MAFLD vs NAFLD: let the contest begin! Liver Int 40(9):2079–2081. https://doi.org/10.1111/liv.14620CrossRefPubMedPubMedCentral

112.

Xie J, Lu L, Chen Y, Xu L, Xu C (2022) A simpler definition of MAFLD better predicts long-term all-cause mortality in American adults. J Hepatol 77(3):877–879. https://doi.org/10.1016/j.jhep.2022.01.015CrossRefPubMed

113.

Kim D, Konyn P, Sandhu KK, Dennis BB, Cheung AC, Ahmed A (2021) Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States. J Hepatol 75(6):1284–1291. https://doi.org/10.1016/j.jhep.2021.07.035CrossRefPubMed

114.

Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C (2016) Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J Hepatol 65(3):589–600. https://doi.org/10.1016/j.jhep.2016.05.013CrossRefPubMed

115.

Tsutsumi T, Eslam M, Kawaguchi T, Yamamura S, Kawaguchi A, Nakano D, Koseki M, Yoshinaga S, Takahashi H, Anzai K, George J, Torimura T (2021) MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: generalized estimating equation approach. Hepatol Res 51(11):1115–1128. https://doi.org/10.1111/hepr.13685CrossRefPubMed

116.

Eslam M, Ahmed A, Despres JP, Jha V, Halford JCG, Wei Chieh JT, Harris DCH, Nangaku M, Colagiuri S, Targher G, Joshi S, Byrne CD, Khunti K, Nguyen MH, Gish RG, George J (2021) Incorporating fatty liver disease in multidisciplinary care and novel clinical trial designs for patients with metabolic diseases. Lancet Gastroenterol Hepatol 6(9):743–753. https://doi.org/10.1016/S2468-1253(21)00132-1CrossRefPubMed

117.

Ayada I, van Kleef LA, Alferink LJM, Li P, de Knegt RJ, Pan Q (2022) Systematically comparing epidemiological and clinical features of MAFLD and NAFLD by meta-analysis: focusing on the non-overlap groups. Liver Int 42(2):277–287. https://doi.org/10.1111/liv.15139CrossRefPubMed

118.

van Kleef LA, Ayada I, Alferink LJM, Pan Q, de Knegt RJ (2022) Metabolic dysfunction-associated fatty liver disease improves detection of high liver stiffness: the rotterdam study. Hepatology 75(2):419–429. https://doi.org/10.1002/hep.32131CrossRefPubMed

119.

Mendez-Sanchez N, Arrese M, Gadano A, Oliveira CP, Fassio E, Arab JP, Chavez-Tapia NC, Dirchwolf M, Torre A, Ridruejo E, Pinchemel-Cotrim H, Castellanos Fernandez MI, Uribe M, Girala M, Diaz-Ferrer J, Restrepo JC, Padilla-Machaca M, Dagher L, Gatica M, Olaechea B, Pessoa MG, Silva M (2021) The Latin American association for the study of the liver (ALEH) position statement on the redefinition of fatty liver disease. Lancet Gastroenterol Hepatol 6(1):65–72. https://doi.org/10.1016/S2468-1253(20)30340-XCrossRefPubMed

120.

Eslam M, Alkhouri N, Vajro P, Baumann U, Weiss R, Socha P, Marcus C, Lee WS, Kelly D, Porta G, El-Guindi MA, Alisi A, Mann JP, Mouane N, Baur LA, Dhawan A, George J (2021) Defining paediatric metabolic (dysfunction)-associated fatty liver disease: an international expert consensus statement. Lancet Gastroenterol Hepatol 6(10):864–873. https://doi.org/10.1016/S2468-1253(21)00183-7CrossRefPubMed

121.

Shiha G, Korenjak M, Casanovas T, Mooney V, Sigurethardottir S, Koulla Y, Soliman R (2022) MAFLD 2022: an ELPA/ALPA/EASO-ECPO joint statement on disease stigma. J Hepatol. https://doi.org/10.1016/j.jhep.2022.08.027CrossRefPubMed

122.

Alharthi J, Gastaldelli A, Cua IH, Ghazinian H, Eslam M (2022) Metabolic dysfunction-associated fatty liver disease: a year in review. Curr Opin Gastroenterol 38(3):251–260. https://doi.org/10.1097/MOG.0000000000000823CrossRefPubMed

123.

Fouad Y, Gomaa A, Semida N, Ghany WA, Attia D (2021) Change from NAFLD to MAFLD increases the awareness of fatty liver disease in primary care physicians and specialists. J Hepatol 74(5):1254–1256. https://doi.org/10.1016/j.jhep.2020.12.035CrossRefPubMed

124.

Karlsen TH, Sheron N, Zelber-Sagi S, Carrieri P, Dusheiko G, Bugianesi E, Pryke R, Hutchinson SJ, Sangro B, Martin NK, Cecchini M, Dirac MA, Belloni A, Serra-Burriel M, Ponsioen CY, Sheena B, Lerouge A, Devaux M, Scott N, Hellard M, Verkade HJ, Sturm E, Marchesini G, Yki-Jarvinen H, Byrne CD, Targher G, Tur-Sinai A, Barrett D, Ninburg M, Reic T, Taylor A, Rhodes T, Treloar C, Petersen C, Schramm C, Flisiak R, Simonova MY, Pares A, Johnson P, Cucchetti A, Graupera I, Lionis C, Pose E, Fabrellas N, Ma AT, Mendive JM, Mazzaferro V, Rutter H, Cortez-Pinto H, Kelly D, Burton R, Lazarus JV, Gines P, Buti M, Newsome PN, Burra P, Manns MP (2022) The EASL-lancet liver commission: protecting the next generation of Europeans against liver disease complications and premature mortality. Lancet 399(10319):61–116. https://doi.org/10.1016/S0140-6736(21)01701-3CrossRefPubMed

125.

Lee H, Lim TS, Kim SU, Kim HC (2022) Long-term cardiovascular outcomes differ across metabolic dysfunction-associated fatty liver disease subtypes among middle-aged population. Hepatol Int 16(6):1308–1317. https://doi.org/10.1007/s12072-022-10407-7CrossRefPubMed

126.

Chan KE, Koh TJL, Tang ASP, Quek J, Yong JN, Tay P, Tan DJH, Lim WH, Lin SY, Huang D, Chan M, Khoo CM, Chew NWS, Kaewdech A, Chamroonkul N, Dan YY, Noureddin M, Muthiah M, Eslam M, Ng CH (2022) Global prevalence and clinical characteristics of metabolic-associated fatty liver disease: a meta-analysis and systematic review of 10 739 607 individuals. J Clin EndocrinolMetab 107(9):2691–2700. https://doi.org/10.1210/clinem/dgac321CrossRef

127.

Mantovani A (2021) MAFLD vs NAFLD: where are we? Dig Liver Dis 53(10):1368–1372CrossRefPubMed

128.

Lonardo A, Ballestri S (2020) Perspectives of nonalcoholic fatty liver disease research: a personal point of view. Explor Med 1(3):85–107. https://doi.org/10.37349/emed.2020.00007CrossRef

129.

Lee JH, Kim D, Kim HJ, Lee CH, Yang JI, Kim W, Kim YJ, Yoon JH, Cho SH, Sung MW, Lee HS (2010) Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis 42(7):503–508. https://doi.org/10.1016/j.dld.2009.08.002CrossRefPubMed

130.

Lee DH, Cho EJ, Bae JS, Lee JY, Yu SJ, Kim H, Lee KB, Han JK, Choi BI (2021) Accuracy of two-dimensional shear wave elastography and attenuation imaging for evaluation of patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 19(4):797-805 e797. https://doi.org/10.1016/j.cgh.2020.05.034CrossRefPubMed

131.

Ferraioli G (2021) Quantitative assessment of liver steatosis using ultrasound controlled attenuation parameter (Echosens). J Med Ultrason 48(4):489–495. https://doi.org/10.1007/s10396-021-01106-1CrossRef

132.

Younossi ZM, Page S, Rafiq N, Birerdinc A, Stepanova M, Hossain N, Afendy A, Younoszai Z, Goodman Z, Baranova A (2011) A biomarker panel for non-alcoholic steatohepatitis (NASH) and NASH-related fibrosis. Obesity Surg 21(4):431–439. https://doi.org/10.1007/s11695-010-0204-1CrossRef

133.

Castera L, Friedrich-Rust M, Loomba R (2019) Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology 156(5):1264-1281 e1264. https://doi.org/10.1053/j.gastro.2018.12.036CrossRefPubMed

134.

Lonardo A (2021) Back to the future: from the history of NAFLD to MAFLD to heterogeneity of disease. Clin Transl Discov 1(1):e9. https://doi.org/10.1002/ctd2.9CrossRef

135.

Polyzos SA, Kountouras J, Zavos C (2009) Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines. Curr Mol Med 9(3):299–314. https://doi.org/10.2174/156652409787847191CrossRefPubMed

136.

Passarella S, Schurr A, Portincasa P (2021) Mitochondrial transport in glycolysis and gluconeogenesis: achievements and perspectives. Int J Mol Sci. https://doi.org/10.3390/ijms222312620CrossRefPubMedPubMedCentral

137.

Schmitz SM, Schooren L, Kroh A, Koch A, Stier C, Neumann UP, Ulmer TF, Alizai PH (2021) Association of body composition and sarcopenia with NASH in obese patients. J Clin Med 10(15):3445. https://doi.org/10.3390/jcm10153445CrossRefPubMedPubMedCentral

138.

Lee JH, Jun HS (2019) Role of myokines in regulating skeletal muscle mass and function. Front Physiol 10:42. https://doi.org/10.3389/fphys.2019.00042CrossRefPubMedPubMedCentral

139.

Perakakis N, Mougios V, Fatouros I, Siopi A, Draganidis D, Peradze N, Ghaly W, Mantzoros CS (2018) Physiology of activins/follistatins: associations with metabolic and anthropometric variables and response to exercise. J Clin Endocrinol Metab 103(10):3890–3899. https://doi.org/10.1210/jc.2018-01056CrossRefPubMedPubMedCentral

140.

Bril F (2021) What the new definition of metabolic dysfunction-associated fatty liver disease (MAFLD) left behind: genetically acquired fatty liver disease (GAFLD). EBioMedicine 72:103584. https://doi.org/10.1016/j.ebiom.2021.103584CrossRefPubMedPubMedCentral

141.

Fiorenza CG, Chou SH, Mantzoros CS (2011) Lipodystrophy: pathophysiology and advances in treatment. Nat Rev Endocrinol 7(3):137–150. https://doi.org/10.1038/nrendo.2010.199CrossRefPubMed

142.

Toshikuni N, Tsutsumi M, Arisawa T (2014) Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease. World J Gastroenterol: WJG 20(26):8393–8406. https://doi.org/10.3748/wjg.v20.i26.8393CrossRefPubMedPubMedCentral

143.

Chalasani S, Mathur K, Shammas N, Orman E, Vuppalanchi R, Lammert C (2020) Hepatic steatosis is highly prevalent but is not correlated with stiffness in autoimmune hepatitis. Medicine (Baltimore) 99(42):e22805. https://doi.org/10.1097/MD.0000000000022805CrossRefPubMed

144.

Haga Y, Kanda T, Sasaki R, Nakamura M, Nakamoto S, Yokosuka O (2015) Nonalcoholic fatty liver disease and hepatic cirrhosis: comparison with viral hepatitis-associated steatosis. World J Gastroenterol: WJG 21(46):12989–12995. https://doi.org/10.3748/wjg.v21.i46.12989CrossRefPubMedPubMedCentral

145.

Krause C, Grohs M, El Gammal AT, Wolter S, Lehnert H, Mann O, Mittag J, Kirchner H (2018) Reduced expression of thyroid hormone receptor beta in human nonalcoholic steatohepatitis. Endocr Connect 7(12):1448–1456. https://doi.org/10.1530/EC-18-0499CrossRefPubMedPubMedCentral

146.

Khalil M, Shanmugam H, Abdallah H, John Britto JS, Galerati I, Gomez-Ambrosi J, Fruhbeck G, Portincasa P (2022) The potential of the mediterranean diet to improve mitochondrial function in experimental models of obesity and metabolic syndrome. Nutrients 14(15):3112. https://doi.org/10.3390/nu14153112CrossRefPubMedPubMedCentral

147.

Longo M, Meroni M, Paolini E, Macchi C, Dongiovanni P (2021) Mitochondrial dynamics and nonalcoholic fatty liver disease (NAFLD): new perspectives for a fairy-tale ending? Metab Clin Exp 117:154708. https://doi.org/10.1016/j.metabol.2021.154708CrossRefPubMed

Titel: NAFLD, MAFLD, and beyond: one or several acronyms for better comprehension and patient care
verfasst von: Piero Portincasa
Publikationsdatum: 17.02.2023
Verlag: Springer International Publishing
Erschienen in: Internal and Emergency Medicine / Ausgabe 4/2023
Print ISSN: 1828-0447
Elektronische ISSN: 1970-9366
DOI: https://doi.org/10.1007/s11739-023-03203-0

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Abstract

Supplementary Information

Publisher's Note

Introduction

NAFLD and the burden of disease: prevalence, natural history, etiology and pathogenesis

NAFLD and metabolic dysfunctions

MAFLD: debate about nomenclature

Fatty liver disease: more acronyms on the way

Conclusions and future perspectives

Acknowledgements

Declarations

Conflict of interest

Human and animal rights statement and Informed consent

Publisher's Note

Unsere Produktempfehlungen

e.Med Interdisziplinär

e.Med Innere Medizin

e.Med Anästhesiologie

Supplementary Information

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