Publications > Journals > Journal of Clinical and Translational Hepatology > Article Full Text

  • OPEN ACCESS

Nonalcoholic Fatty Liver Disease (NAFLD) Name Change: Requiem or Reveille?

  • Shivaram P. Singh1,* ,
  • Prajna Anirvan1 ,
  • Reshu Khandelwal1  and
  • Sanjaya K. Satapathy2 
 Author information
Journal of Clinical and Translational Hepatology 2021;():-

doi: 10.14218/JCTH.2021.00174

Abstract

Nonalcoholic fatty liver disease (NAFLD) affects about a quarter of the world’s population and poses a major health and economic burden globally. Recently, there have been hasty attempts to rename NAFLD to metabolic-associated fatty liver disease (MAFLD) despite the fact that there is no scientific rationale for this. Quest for a “positive criterion” to diagnose the disease and destigmatizing the disease have been the main reasons put forth for the name change. A close scrutiny of the pathogenesis of NAFLD would make it clear that NAFLD is a heterogeneous disorder, involving different pathogenic mechanisms of which metabolic dysfunction-driven hepatic steatosis is only one. Replacing NAFLD with MAFLD would neither enhance the legitimacy of clinical practice and clinical trials, nor improve clinical care or move NAFLD research forward. Rather than changing the nomenclature without a strong scientific backing to support such a change, efforts should be directed at understanding NAFLD pathogenesis across diverse populations and ethnicities which could potentially help develop newer therapeutic options.

Graphical Abstract

Keywords

Heterogeneity, MAFLD, Metabolic, NAFLD, NASH, Nomenclature, Steatohepatitis

Introduction

Of late, there have been a plethora of articles supporting the change of nomenclature of nonalcoholic fatty liver disease (NAFLD) to metabolic-associated fatty liver disease (MAFLD). In the face of such a vociferous campaign and the emanating din of MAFLD, one may very easily be led to think that this name change is a positive step in NAFLD research. There have been ‘consensus’ statements as well as a number of articles which have tried to emphasize upon the urgent requirement of this change of nomenclature.13 However, this proposed change of nomenclature is faulty and does not take into account several factors in NAFLD pathophysiology and also ignores the gamut of evidence garnered in NAFLD research to date. Besides, it is equally important to recognize the implications of a name change and its effects on both physicians and patients.46 In this review, we have tried to critically analyze the historical perspective of NAFLD, the origin of the term and the pathophysiological mechanisms involved, and deliberate whether a change in nomenclature is warranted.

History of NAFLD

‘Fatty liver’ is not a new term. Thomas Addison had described the presence of fatty liver in individuals who consumed alcohol in 1845.7 Fatty infiltration of the liver and the development of cirrhosis in diabetes and chronic alcoholism had been described by Connor in 1930.8 However, the histological features of NAFLD were first described in the late 1950s by Wastewater and Fainer,9 in persons who had no history of alcohol intake but had hepatic steatosis. In 1979, Klatskin, Miller and Ishimaru presented their landmark study at the plenary session of American Association for the Study of Liver Diseases (AASLD) Annual Meeting, where they described the hepatic histological findings in 27 patients with typical features of alcoholic liver disease but with no history of alcohol intake, and labelled it as ‘non-alcoholic liver disease’.7 Perhaps, this was the point in time when the term ‘NAFLD’ had its humble beginnings. Similar findings were reported almost simultaneously by Adler and Schaffner,10 who categorized the patients on the basis of histopathological findings into ‘fatty liver, fatty hepatitis, fatty fibrosis and fatty cirrhosis’. Eight months later, Ludwig and his colleagues11 at Mayo clinic reported similar findings in a cohort of patients, which they named ‘non-alcoholic steatohepatitis’. Surprisingly, the MAFLD consensus statement makes no mention of these facts and states that the “….term non-alcoholic fatty liver disease (NAFLD) was coined by Ludwig and colleagues in 1980…”1 Ludwig et al.11 coined the term nonalcoholic steatohepatitis (NASH) in their 1980 article and never used the term NAFLD.

Not much was known about the pathophysiology of the entity at that point of time. In the course of time, it was evident that NAFLD encompasses a spectrum of disorders, ranging from simple steatosis to cirrhosis of the liver12 and a strong association between obesity, metabolic syndrome (MS) and NAFLD was established.1315 However, it soon became obvious that this was an oversimplification and multiple factors were involved in NAFLD pathogenesis.16 Despite all the advances in our understanding of the causes of hepatic steatosis, the exact pathophysiologic mechanisms driving NAFLD have not been clearly defined and the search for the Holy Grail continues. With each passing day, a new player emerges and the adjective ‘key’ is thrust upon it!

Pathophysiology of NAFLD - The Six Blind Men of Indostan

The pathophysiology of NAFLD is similar to the story of the six blind men and the elephant (Fig. 1). There have been numerous attempts to ascribe hepatic steatosis to a multitude of factors. It is generally accepted that NAFLD/NASH is commonly associated with insulin resistance (IR) or metabolic diseases such as diabetes, obesity and dyslipidemia and has even been termed as the hepatic manifestation of the MS.17 However, given the complexity of the pathogenesis of NAFLD, it is difficult to explain the entire range of its manifestations by any single mechanism. We have explained in the following sections why it would be unscientific and illogical to ascribe the entire pathophysiology of NAFLD to MS. This attempt to change the nomenclature betrays a lack of complete understanding of the processes that go into the pathogenesis of NAFLD. Changing the name may neither reflect nor improve our understanding of ‘what causes' or ‘what leads to’ or ‘what happens to’ this entity.

The different etiologies of NAFLD-described by different experts: No single factor can explain the whole spectrum of disease.
Fig. 1  The different etiologies of NAFLD-described by different experts: No single factor can explain the whole spectrum of disease.

NAFLD, nonalcoholic fatty liver disease.

Is NAFLD merely an extension of the MS?

Two questions are of paramount importance while analyzing the multiple factors involved in NAFLD pathogenesis. First, is MS ubiquitous in NAFLD and second, is the pathogenesis of NAFLD/NASH so linear? A careful look at the various factors causing NAFLD and the complex interplay therein, far from allaying our doubts and making things easier, raise crucial points to ponder upon.

Fatty liver disease - different avatars

It is well known that lipid deposition in the liver is not exclusively hyperinsulinemia-mediated and can be caused by a range of conditions, like lipodystrophies, hepatitis C virus infection, adverse effects of drugs like tetracyclines, defects in metabolism like Reye’s syndrome, chronic inflammation, and in states of malnutrition.1823 This lends credence to the hypothesis that NAFLD can exist in the absence of MS and IR and involve hitherto unexplored pathophysiological mechanisms. The different conditions that can cause fatty liver are illustrated in Figure 2.

Different conditions that can cause hepatic steatosis.
Fig. 2  Different conditions that can cause hepatic steatosis.

AIH, Autoimmune Hepatitis; HCV, Hepatitis C Virus.

NAFLD without metabolic syndrome – peculiarities

Studies have revealed that underweight subjects and those with normal BMI also develop NAFLD.24 In a study by Singh et al.,25 nearly half of the NAFLD subjects did not have IR and a significantly higher proportion of patients in non-IR group were non-obese. Similar findings were also observed in a study on NAFLD subjects in Bangladesh.26 Thus, the universality of association of MS with NAFLD is being increasingly disputed. Furthermore, although NAFLD with MS has been shown to have considerable risk for cardiovascular diseases, diabetes and increase of left ventricular mass index in comparison to NAFLD without MS,27 other studies have also shown that NAFLD patients without MS displayed preclinical cardiologic abnormalities which were independent of diabetes mellitus and hypertension.28 Classical features of MS-IR, hyperglycemia and dyslipidemia have not been observed in NAFLD associated with the patatin like phospholipase domain-containing protein 3 (PNPLA3) Ile148Met variant, in which fatty liver occurs independent of presence of MS.29 Thus, two things are clear: neither is MS ubiquitous in NAFLD, nor does the association of MS and NAFLD follow the cause-effect equation, clearly indicating that there is much more to NAFLD pathogenesis than IR and MS.

Can hepatic steatosis give rise to IR?

The chicken-egg conundrum concerning the primacy of MS over NAFLD has persisted for a long time. While IR leading to hepatic steatosis has always held center stage, there is increasing evidence to indicate that hepatic triglyceride accumulation is also responsible for causing IR in the liver.30 This implies that the suppressive effects of insulin on hepatic glucose and very low-density lipoprotein (VLDL) and triglyceride production are hampered.31 This contributes to postprandial hyperglycemia and hyperlipidemia, major components of the MS. From an evolutionary viewpoint, IR is an adaptive mechanism of the body to preserve glucose for various cellular processes, especially in states of starvation and immune activation.32 However, multiple factors can lead to this process of adaption to go awry with deleterious consequences.33 IR is associated with release of inflammatory mediators at the cellular level.34 Production of adipokines, IL-1, IL-6, resistin, leptin and free fatty acids mediate the release of kinases, like JNK, IKK-β and protein kinase C (PKC), which further impair insulin signalling.34 IR acts at two levels: hepatic and peripheral sites. However, hepatic IR can occur independent of changes in circulating adipokines.35 Hepatic steatosis and hepatic IR have also been found to occur in experimental models prior to the development of obesity, and increases in adipokine levels imply that hepatic steatosis may have an independent genesis.36

The diacylglycerol (DAG)-PKC hypothesis and the associated controversies might possibly partly explain this conundrum. Increased hepatic DAG activates the PKC-ϵ isoform, which causes phosphorylation of the insulin receptor and drives hepatic IR.36 Knockdown of PKC-ϵ has been shown to protect rats from high-fat diet-induced hepatic IR.37 Intrahepatic DAG accumulation can be from free fatty acid-derived lipolysis, chylomicron-mediated uptake, or hepatic de novo lipogenesis.38 The DAG-PKC-ϵ pathway successfully explains that NAFLD can definitely act as a precursor to MS.

Do all patients with hepatic steatosis develop MS?

This hypothesis, however, contradicts the findings of Monetti et al.,39 who have reported that mice overexpressing acylCoA:DAG acyltransferase 2, which converts DAG to triacylglycerol (TAG) in the liver, do not demonstrate hepatic IR, even with elevated hepatic TAG and DAG content. This has brought to the fore the idea of compartmentalization of DAG in the hepatocyte.40 Cytoplasmic compartmentalization of DAG in the hepatocyte, in the form of lipid droplet, strongly correlated with PKC-ϵ activation and IR, whereas other lipid metabolites had no correlation with IR.41 The dissociation of hepatic steatosis from IR has also been seen in murine models.40 The sequestration of DAGs in specific compartments, which might include membrane-bound cellular vesicles that do not lead to PKC-ϵ activation and consequent IR, is an idea upon which much work is being focused.42 The idea that PKCs might have different affinities for different species of DAGs has also gained prominence.43 This might partly explain why in a proportion of subjects, the relationship between hepatic steatosis and IR seems dichotomous.44 However, despite advances in lipidomics and molecular biology, these are grey zones and much remains to be done to understand the exact mechanisms better.

NAFLD multifactorial pathogenesis

In addition to genetic and environmental factors as well as bile acid metabolism, gut microbiota and a host of other players work in tandem and play important roles in the pathophysiological processes. The various mediators of hepatocyte injury and the pathophysiological processes involved in the development of NAFLD/NASH are discussed below.

Genetic factors

Epidemiological, familial and twin studies have provided ample evidence in favor of heritability of NAFLD.45,46 Genetic modifications occur at multiple steps of NAFLD pathogenesis, including insulin sensitivity, fatty acid influx, oxidative stress, cytokine activity and fibrogenesis.47 Genome-wide association studies have identified a single nucleotide polymorphism (SNP) in the PNPLA3 gene, rs738409 C>G SNP, which conferred a more than 2-fold risk for higher hepatic fat content.48 PNPLA3 is induced in the liver after feeding and during IR by fatty acids and sterol regulatory element-binding protein-1c (SREBP-1c), the master regulator of lipogenesis.49 The function of PNPLA3 is to catalyze DAG and TAG hydrolysis.50 Quite interestingly, steatosis was found to be independent of IR and serum lipid levels in individuals with PNPLA3 polymorphism.48 The presence of this SNP prevents ubiquitination of PNPLA3 and its proteasomal degradation, resulting in decreased TAG mobilization from lipid droplets in the liver.51 In addition, several other SNPs have been identified in other genes. These include neurocan (SNP rs2228603), protein phosphatase 1, regulatory (inhibitor) subunit 3B (SNP rs4240624), glucokinase regulator (SNP rs780094), lysophospholipase-like 1 (SNP rs12137855), peroxisome proliferator activator-alpha (PPAR-α SNP Val227Ala), lipin1 (SNP rs13412852 T) and transmembrane 6 superfamily member 2 (TM6SF2, SNP rs58542926 c.449 C>T).5255

Bile acid metabolism

Elevation in total bile acids has been observed in NAFLD patients.56 Increased serum levels of glychochendeoxycholate, glycholate, and taurocholate have been observed in patients with NASH compared to healthy controls.57 Bile acids regulate multiple pathways through activation of nuclear receptors, like farnesoid X receptor (FXR), pregnane X receptor, and vitamin D receptor.58,59 FXR functions to protect hepatocytes from the harmful effects of increased bile acid levels by FGF-19-mediated inhibition of endogenous bile acid synthesis and upregulation of bile acid biotransformation.60,61 The role of FXR in ameliorating hepatic inflammation through the nuclear factor kappa B (NF-κB) pathway has also been established.62 Recent studies seem to suggest that elevated serum bile acid levels have an independent association with NASH in individuals who are non-diabetic.63

Gut microbiota

The involvement of gut microbiota in NAFLD pathogenesis has not been fully elucidated. Increased intestinal permeability subsequent to small intestinal bacterial overgrowth has been observed in NASH patients.64 Inflammation ensues with hepatic expression of toll like receptor 4 and release of interleukin-8.64 Conversion of choline to trimethylamine and trimethylamine oxide (TMAO) by gut microflora has also been linked to hepatic inflammation and damage.65 Gut dysbiosis leads to decreased synthesis of secondary bile acids, which in turn decreases activation of nuclear receptors.66 FXR and TGR5 downregulation affect bile acid metabolism and promote hepatocyte injury.67,68 Ethanol production by gut microbiota leading to NAFLD is another example of the role of gut dysbiosis in the complex pathophysiologic mechanisms underlying NAFLD.69 Further, NAFLD patients have been found to have lower abundance of Ruminococcus, Faecalibacterium prausnitzii and Coprococcus independent of body mass index and IR, implying that NAFLD is associated with dysbiosis independent of body mass index and IR.70

Epigenetic modifications

The rapidly growing field of epigenetics has shed new light on NAFLD pathogenesis by explaining the effect of several environmental factors, like over nutrition and physical inactivity, upon gene expression.71 5-Hydroxymethylcytosine, an epigenetic modification, is likely to be involved in the pathogenesis of NAFLD by regulating liver mitochondrial biogenesis and peroxisome proliferator activated receptor γ coactivator 1 α expression.72 DNA methylation at certain CpG islands in genes mediating fibrogenesis has been found to differentiate between patients with mild and severe fibrosis in NAFLD.73 However, these studies are in their infancy, and before attributing disease processes in NAFLD to epigenetic modifications, meticulous follow-up studies are required to understand the effects of DNA methylation on fibrosis progression.74 An emerging concept is the interplay between genetic and epigenetic variants in determining gene expression and NAFLD disease progression. Methylation in the PNPLA3 promoter region has been studied and it has been seen that it was significantly hypermethylated in patients with severe (F3–4) fibrosis.75 The role of histone deacetylation has also gained importance in view of the observation that histone deacetylase 3 has been implicated in the diversion of metabolites from hepatic gluconeogenesis to lipogenesis and storage.76 Thus, a growing body of evidence is accumulating in favor of the role of epigenetics in NAFLD pathogenesis.

Role of circadian rhythm

The workings of the circadian clock have been greatly explored in the pathogenesis of multiple disorders and the close interactions of circadian rhythm with endocrine functions and energy homoeostasis have been discovered.7780 Circadian clock is modulated by a core oscillator in the suprachiasmatic nucleus of the hypothalamus in conjunction with multiple peripheral clocks in other organs, including the liver.81 There is an increasing body of evidence to suggest that the pathways of energy homeostasis in the liver involves complex mechanisms of transcriptional and post-translational regulation of circadian clock gene expression.81 Evidence suggests that transcription factors, such as PARbZIP and Nfil3, which regulate the process of hepatic xenobiotic transformation are under the control of circadian clock proteins, such as Per1, Per2, Rev-erbα, Rev-erbβ, Rorα, Rorβ, and Rorγ.82 One particular SNP, 3111T>C in Clock (rs1801260), has been found to be associated with overweight status and an increased risk of hepatic steatosis in women.83 This is compatible with experiments in murine models where mutations in clock genes produce more severe hepatic steatosis under both regular and high-fat chow feeding conditions compared to wild-type mice.84 An intricate network operates between circadian rhythm, epigenetic changes, gene expression and nuclear receptor working.84 Nuclear receptors sense nutrient levels and control cellular metabolism.85 Recruitment of nuclear receptor co-repressors induce histone deacetylase activity.86 This, in turn, influences chromatin conformation and modelling.87 Normal hepatic lipid homoeostasis requires recruitment of HDAC3 by Rev-erbα, a circadian nuclear receptor.88 Bile acid homoeostasis works under circadian control, evidenced by disturbed bile acid metabolism in mice with Per1 and Per 2 knockouts.89 Therefore, it is amply clear that circadian misalignment can cause dysregulation of cellular metabolism leading to hepatic steatosis.84

Dietary and environmental factors

Dietary habits and intake of certain food products have been implicated in the pathogenesis of NAFLD.90,91 Foods rich in animal protein and less in fiber, soft drinks and snacks have been associated with presence of fatty liver.90 Consumption of soft drinks has been associated with NAFLD independent of the traditional risk factors like obesity, diabetes, and hyperlipidemia.92,93 Cigarette smoking has been linked to exacerbation of liver injury in a rat model of obese-NAFLD through oxidative stress and hepatocellular apoptosis.94 In a large cohort study of 199,468 young and middle aged persons who did not have NAFLD at baseline and were followed up for 1,070,991 person-years, 45,409 persons developed NAFLD.95 Cigarette smoking, pack-years of cigarettes smoked, and urinary cotinine levels were found to be positively associated with NAFLD incidence, and smoking was observed be an independent risk factor for NAFLD progression.95 Therefore, the prevalent view that dietary factors lead to obesity, diabetes, MS and thereby impact NAFLD pathogenesis96 has been increasingly questioned, and emerging evidence suggests that environmental stressors can cause liver injury independent of traditional risk factors.

The spectrum of the pathophysiological pathways in NAFLD, a maze in itself, is illustrated in Figure 3.

The maze of NAFLD-interactions and cross-talk among multiple factors leading to hepatic steatosis. Hepatic steatosis itself can give rise to IR.
Fig. 3  The maze of NAFLD-interactions and cross-talk among multiple factors leading to hepatic steatosis. Hepatic steatosis itself can give rise to IR.

NAFLD, nonalcoholic fatty liver disease; SREBP 1C, Sterol Regulatory Element Binding Protein 1C; PNPLA 3, Patatin Like Phospholipase Domain Containing Protein-3; TM6SF2, Transmembrane 6 Superfamily Member 2; SNP, Single Nucleotide Polymorphism; DAG, Diacyl Glycerol; TAG, Triacyl Glycerol; VLDL, Very Low-Density Lipoprotein; FXR, Farnesoid X Receptor; TGR5, Takeda G-Protein Receptor 5; NF-ĸB, Nuclear Factor Kappa B; SBA, Secondary Bile Acids; TMAO, Trimethylamine Oxide; PKCє, Protein Kinase C-epsilon isoform.

Philosophy behind medical nomenclature

Naming of a disease or an entity, although seemingly simple, has far-reaching consequences. There have been several attempts to systematize the nomenclature of diseases.97 Best practice recommendations have also been issued by the World Health Organization in this regard for infectious diseases.6 The idea behind these is to impress upon members of the medical fraternity as well as the general populace about the significance of the disease entity. The term ‘non-alcoholic fatty liver disease (acronym-NAFLD)’ encompasses those individuals who have fatty liver without history of significant alcohol intake and other conditions that could cause fatty liver. Importantly, not all patients in Ludwig’s study were overweight/obese. Further research has only consolidated the point that NAFLD is a disease of multifactorial and competing etiologies and can not be ascribed to any single factor.

It has not been possible as of yet to ascribe hepatic steatosis to any single cause and the unitary treatment targeting has not yielded successful treatment options. The general idea is that NAFLD is a spectrum of disorders, with MS occupying a predominant part of that spectrum. Despite years of research, we have not been able to add much to the treatment arsenal of NAFLD. Changing the nomenclature could put an exaggerated emphasis on MS, which ultimately may not turn out to be the only target. While the pathophysiology is still a puzzle, how would a mere change in name help?

MAFLD: Is the new terminology justified?

There have been several arguments put forward by the proponents of MAFLD in favor of a name change. The objections to NAFLD are that NAFLD should be defined by inclusion rather than by exclusion, the heterogeneity of NAFLD implies that it is difficult to manage it as a single entity, and the effects of non-significant amounts of alcohol consumed by NAFLD patients on hepatic steatosis have not yet been clearly defined.2 The diagnosis of MAFLD requires radiological evidence of hepatic steatosis and the presence of any one of the following three conditions: overweight/obesity, presence of diabetes mellitus, or evidence of metabolic dysregulation.2 In fact, in their algorithm, the diagnosis of MAFLD is essentially identical to the diagnosis of NAFLD.

There are several problems with this approach. First, putting ‘non’ in the nomenclature of a disease and approaching it through exclusion has been a time-tested, simple and very effective approach in medical science. Non-Hodgkin’s lymphoma and non-small cell carcinoma are prime examples of this approach.98100 It is indeed peculiar the way the change in name is sought to be justified. The proponents of MAFLD have surprisingly split “nonalcoholic” into two words: ‘non’ and ‘alcoholic’, followed by the assertion that the word “non” trivializes their problem, while the word alcoholic demeans the patient and blames the patient for the disease. This rationale for change in terminology, however, trivializes the seriousness of changing a term which has stood the test of time for almost half a century. Quite to the contrary, the term ‘nonalcoholic’ destigmatizes the patient. The term “metabolic” in MAFLD as a reference to MS itself trivializes the gamut of evidence garnered in NAFLD research to date.

To put things in perspective, the Rome Foundation has been frequently changing the names of functional bowel disorders, many of which are not so functional after all. For example, in a validation study of 1,452 patients with gastrointestinal symptoms, the Rome III criteria performed only modestly in identifying those with functional dyspepsia and were not significantly superior to previous definitions.101 Despite one of the rationales for the revision being to allow separation of functional dyspepsia and gastroesophageal reflux disease more clearly, almost identical proportions of patients meeting criteria for each of the different definitions of FD were found to have erosive esophagitis.101

Second, merely replacing the term NAFLD with MAFLD would not make the entity any less heterogeneous. At the moment, their exists considerable uncertainty regarding the pathogenesis of NAFLD, and a change in name cannot be justified.

Third, the impact of nonsignificant intake of alcohol on hepatic metabolism is itself very unclear; some studies have shown a decreased progression to NASH with moderate alcohol consumption, as acknowledged in the consensus paper. Moreover, metabolic complications in alcoholic fatty liver disease have been demonstrated too.102 Besides, lipid metabolism abnormalities,103 disturbances in sirtuin104 and PPAR-γ105 pathways have also been shown to occur in alcoholic liver disease. Can the change in terminology to MAFLD provide adequate answers to these perplexing questions? Thus, it is clear that the reasons stated for such a sudden change are very flimsy and have no rational basis.

Interestingly, in a review concerning the challenges of the diagnosis and classification of NAFLD by Hashimoto, Tokushige and Ludwig in 2015, it was argued that recommendations to change the nomenclature of NAFLD to metabolic fatty liver or metabolic steatohepatitis would be of little help, and since patients with NAFLD/NASH were also being treated by cardiologists and diabetologists in addition to hepatologists, such changes in nomenclature would create confusion and should be avoided.106

It will be worthwhile to mention here that as regards the change in nomenclature, European Liver Patients Association (ELPA) had expressed its concerns to the European Commission in 2018, arguing for a change in nomenclature.1 We tried to elicit an answer from ELPA in this regard - if this was true and if so, the reasons for such a suggestion. We also sought to know how this was decided, the percentage of patients who feel uncomfortable with such terminology and importantly, if the heterogeneity in NAFLD pathogenesis—especially in non-Caucasians—was taken into account. However, despite repeated queries, unfortunately, we did not receive any reply from ELPA.

Most of the emerging literature on the NAFLD versus MAFLD debate have pooled patients of NAFLD with other patients of fatty liver due to dual etiology and then compared these patients with NAFLD patients.107 This has obviously resulted in increased prevalence of hepatic fibrosis in this cohort108 and it needs no rocket science to understand this, since fatty liver patients with dual etiology including alcohol (up to 60 gram/day) have been compared to patients with NAFLD! Instead of achieving ‘homogeneity’ which the proponents of MAFLD harp on, this has paradoxically made the entity more heterogenous. Besides, another offshoot of this change would be that this will push the field back, since all study protocols to date have been based on NAFLD. It would not be possible to reconcile previous data on NAFLD with new data on MAFLD.

Conclusion

NAFLD cannot be kept confined to the precincts of MS, nor is NAFLD just another ‘manifestation’ of MS. It is clear that rather than changing the nomenclature without a strong scientific backing to support such a change, there should be more efforts directed at understanding NAFLD pathogenesis across diverse populations and ethnicities. This would definitely lead to newer therapeutic approaches. We hope in the near future, there will be sufficient advances in our understanding of NAFLD pathogenesis to enable translation into clinical practice.

Abbreviations

AASLD: 

American Association for the Study of Liver Diseases

DAG: 

diacylglycerol

ELPA: 

European Liver Patients Association

FXR: 

farnesoid X receptor

IR: 

insulin resistance

MAFLD: 

metabolic-associated fatty liver disease

MS: 

metabolic syndrome

NAFLD: 

nonalcoholic fatty liver disease

NASH: 

nonalcoholic steatohepatitis

NF-ĸB: 

nuclear factor kappa B

PKC: 

protein kinase C

PNPLA3: 

patatin like phospholipase domain-containing protein 3

SBA: 

secondary bile acid

SNP: 

single nucleotide polymorphism

SREBP 1C: 

sterol regulatory element binding protein 1C

TAG: 

triacylglycerol

TGR5: 

Takeda G-protein receptor 5

TM6SF2: 

transmembrane 6 superfamily member 2

TMAO: 

trimethylamine oxide

VLDL: 

very low-density lipoprotein

Declarations

Funding

None to declare.

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Study concept and design (SPS), analysis and interpretation of data (SPS, PA, RK, SKS), drafting of the manuscript (SPS, PA), critical revision of the manuscript for important intellectual content (SPS, SKS), administrative, technical, or material support, study supervision (SPS, SKS, RK).

References

  1. Eslam M, Sanyal AJ, George J, International Consensus Panel. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 2020;158(7):1999-2014.e1 View Article
  2. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol 2020;73(1):202-209 View Article
  3. Eslam M, Ratziu V, George J. Yet more evidence that MAFLD is more than name change. J Hepatol 2021;74(4):977-979 View Article
  4. Young ME, Norman GR, Humphreys KR. The role of medical language in changing public perceptions of illness. PLoS One 2008;3(12):e3875 View Article
  5. Janda JM. Proposed nomenclature or classification changes for bacteria of medical importance: taxonomic update 5. Diagn Microbiol Infect Dis 2020;97(3):115047 View Article
  6. WHO | WHO issues best practices for naming new human infectious diseases. WHO. Available from: https://www.who.int/mediacentre/news/notes/2015/naming-new-diseases/en/
  7. Reuben A. Leave gourmandising. Hepatology 2002;36(5):1303-1306 View Article
  8. Connor CL. Fatty infiltration of the liver and the development of cirrhosis in diabetes and chronic alcoholism. Am J Pathol 1938;14(3):347-364.9
  9. Westwater JO, Fainer D. Liver impairment in the obese. Gastroenterology 1958;34(4):686-693
  10. Adler M, Schaffner F. Fatty liver hepatitis and cirrhosis in obese patients. Am J Med 1979;67(5):811-816 View Article
  11. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55(7):434-438
  12. Kopec KL, Burns D. Nonalcoholic fatty liver disease: a review of the spectrum of disease, diagnosis, and therapy. Nutr Clin Pract 2011;26(5):565-576 View Article
  13. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatol Baltim Md 1990;12(5):1106-1110 View Article
  14. Eriksson S, Eriksson KF, Bondesson L. Nonalcoholic steatohepatitis in obesity: a reversible condition. Acta Med Scand 1986;220(1):83-88 View Article
  15. Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994;107(4):1103-1109 View Article
  16. Medina J, Fernández-Salazar LI, García-Buey L, Moreno-Otero R. Approach to the pathogenesis and treatment of nonalcoholic steatohepatitis. Diabetes Care 2004;27(8):2057-2066 View Article
  17. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatol Baltim Md 2018;67(1):328-357 View Article
  18. Polyzos SA, Perakakis N, Mantzoros CS. Fatty liver in lipodystrophy: a review with a focus on therapeutic perspectives of adiponectin and/or leptin replacement. Metabolism 2019;96:66-82 View Article
  19. Noureddin M, Wong MM, Todo T, Lu SC, Sanyal AJ, Mena EA. Fatty liver in hepatitis C patients post-sustained virological response with direct-acting antivirals. World J Gastroenterol 2018;24(11):1269-1277 View Article
  20. Tetracycline. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Available from: http://www.ncbi.nlm.nih.gov/books/NBK547920/
  21. Partin JC. Reye’s syndrome (encephalopathy and fatty liver). Diagnosis and treatment. Gastroenterology 1975;69(2):511-518
  22. Zhao L, Zhong S, Qu H, Xie Y, Cao Z, Li Q, et al. Chronic inflammation aggravates metabolic disorders of hepatic fatty acids in high-fat diet-induced obese mice. Sci Rep 2015;5(1):10222 View Article
  23. van Zutphen T, Ciapaite J, Bloks VW, Ackereley C, Gerding A, Jurdzinski A, et al. Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction. J Hepatol 2016;65(6):1198-1208 View Article
  24. Alam S, Fahim SM, Chowdhury MAB, Hassan MZ, Azam G, Mustafa G, et al. Prevalence and risk factors of non-alcoholic fatty liver disease in Bangladesh. JGH Open 2018;2(2):39-46 View Article
  25. Singh SP, Misra B, Kar SK, Panigrahi MK, Misra D, Bhuyan P, et al. Nonalcoholic fatty liver disease (NAFLD) without insulin resistance: is it different?. Clin Res Hepatol Gastroenterol 2015;39(4):482-488 View Article
  26. Azam G, Alam S, Hasan SN, Alam SMNE, Kabir J, Alam AK. Insulin resistance in nonalcoholic fatty liver disease: experience from Bangladesh. Bangladesh Crit Care J 2016;4(2):86-91 View Article
  27. Käräjämäki AJ, Bloigu R, Kauma H, Kesäniemi YA, Koivurova OP, Perkiömäki J, et al. Non-alcoholic fatty liver disease with and without metabolic syndrome: different long-term outcomes. Metabolism 2017;66:55-63 View Article
  28. Makker J, Tariq H, Bella JN, Kumar K, Chime C, Patel H, et al. Preclinical cardiac disease in nonalcoholic fatty liver disease with and without metabolic syndrome. Am J Cardiovasc Dis 2019;9(5):65-77
  29. Lallukka S, Sevastianova K, Perttilä J, Hakkarainen A, Orho-Melander M, Lundbom N, et al. Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3. Diabetologia 2013;56(4):886-892 View Article
  30. den Boer M, Voshol PJ, Kuipers F, Havekes LM, Romijn JA. Hepatic steatosis: a mediator of the metabolic syndrome. lessons from animal models. Arterioscler Thromb Vasc Biol 2004;24(4):644-649 View Article
  31. Lee RG. Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol 1989;20(6):594-598 View Article
  32. Soeters MR, Soeters PB. The evolutionary benefit of insulin resistance. Clin Nutr Edinb Scotl 2012;31(6):1002-1007 View Article
  33. Tsatsoulis A, Mantzaris MD, Bellou S, Andrikoula M. Insulin resistance: an adaptive mechanism becomes maladaptive in the current environment—an evolutionary perspective. Metab - Clin Exp 2013;62(5):622-633 View Article
  34. Meshkani R, Adeli K. Hepatic insulin resistance, metabolic syndrome and cardiovascular disease. Clin Biochem 2009;42(13):1331-1346 View Article
  35. Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A 2001;98(13):7522-7527 View Article
  36. Samuel VT, Liu Z-X, Qu X, Elder BD, Bilz S, Befroy D, et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 2004;279(31):32345-32353 View Article
  37. Gassaway BM, Petersen MC, Surovtseva YV, Barber KW, Sheetz JB, Aerni HR, et al. PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling. Proc Natl Acad Sci 2018;115(38):E8996-E9005 View Article
  38. Jornayvaz FR, Shulman GI. Diacylglycerol activation of protein kinase Cε and hepatic insulin resistance. Cell Metab 2012;15(5):574-584 View Article
  39. Monetti M, Levin MC, Watt MJ, Sajan MP, Marmor S, Hubbard BK, et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 2007;6(1):69-78 View Article
  40. Cantley JL, Yoshimura T, Camporez JPG, Zhang D, Jornayvaz FR, Kumashiro N, et al. CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance. Proc Natl Acad Sci 2013;110(5):1869-1874 View Article
  41. Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, et al. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 2011;108(39):16381-16385 View Article
  42. Petersen MC, Shulman GI. Roles of diacylglycerols and ceramides in hepatic insulin resistance. Trends Pharmacol Sci 2017;38(7):649-665 View Article
  43. Kamiya Y, Mizuno S, Komenoi S, Sakai H, Sakane F. Activation of conventional and novel protein kinase C isozymes by different diacylglycerol molecular species. Biochem Biophys Rep 2016;7:361-366 View Article
  44. Kantartzis K, Peter A, Machicao F, Machann J, Wagner S, Königsrainer I, et al. Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes 2009;58(11):2616-2623 View Article
  45. Makkonen J, Pietiläinen KH, Rissanen A, Kaprio J, Yki-Järvinen H. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins. J Hepatol 2009;50(5):1035-1042 View Article
  46. Struben VM, Hespenheide EE, Caldwell SH. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am J Med 2000;108(1):9-13 View Article
  47. Rowell RJ, Anstee QM. An overview of the genetics, mechanisms and management of NAFLD and ALD. Clin Med Lond Engl 2015;15(Suppl 6):s77-82 View Article
  48. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40(12):1461-1465 View Article
  49. Huang Y, He S, Li JZ, Seo YK, Osborne TF, Cohen JC, et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A 2010;107(17):7892-7897 View Article
  50. He S, McPhaul C, Li JZ, Garuti R, Kinch L, Grishin NV, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 2010;285(9):6706-6715 View Article
  51. Bruschi FV, Tardelli M, Claudel T, Trauner M. PNPLA3 expression and its impact on the liver: current perspectives. Hepatic Med Evid Res 2017;9:55-66 View Article
  52. Dongiovanni P, Anstee QM, Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des 2013;19(29):5219 View Article
  53. Fawcett KA, Grimsey N, Loos RJF, Wheeler E, Daly A, Soos M, et al. Evaluating the role of LPIN1 variation in insulin resistance, body weight, and human lipodystrophy in U.K. Populations. Diabetes 2008;57(9):2527-2533 View Article
  54. Chen S, Li Y, Li S, Yu C. A Val227Ala substitution in the peroxisome proliferator activated receptor alpha (PPAR alpha) gene associated with non-alcoholic fatty liver disease and decreased waist circumference and waist-to-hip ratio. J Gastroenterol Hepatol 2008;23(9):1415-1418 View Article
  55. Liu Y-L, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JB, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun 2014;5(1):4309 View Article
  56. Bechmann LP, Kocabayoglu P, Sowa JP, Sydor S, Best J, Schlattjan M, Beilfuss A, et al. Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis. Hepatol Baltim Md 2013;57(4):1394-1406 View Article
  57. Kalhan SC, Guo L, Edmison J, Dasarathy S, McCullough AJ, Hanson RW, et al. Plasma metabolomic profile in nonalcoholic fatty liver disease. Metabolism 2011;60(3):404-413 View Article
  58. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, et al. Identification of a nuclear receptor for bile acids. Science 1999;284(5418):1362-1365 View Article
  59. Guo GL, Lambert G, Negishi M, Ward JM, Brewer HB, Kliewer SA, et al. Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity. J Biol Chem 2003;278(46):45062-45071 View Article
  60. Fuchs M. Non-alcoholic fatty liver disease: the bile acid-activated farnesoid X receptor as an emerging treatment target. J Lipids 2012;2012:934396 View Article
  61. Kir S, Kliewer SA, Mangelsdorf DJ. Roles of FGF19 in liver metabolism. Cold Spring Harb Symp Quant Biol 2011;76:139-144 View Article
  62. Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W. Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response. Hepatology 2008;48(5):1632-1643 View Article
  63. Li H, Ma J, Gu L, Jin L, Chen P, Zhang X, et al. Increased serum total bile acid is independently associated with non-alcoholic steatohepatitis in non-diabetes population. View Article
  64. Ferolla SM, Armiliato GNA, Couto CA, Ferrari TCA. The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease. Nutrients 2014;6(12):5583-5599 View Article
  65. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472(7341):57-63 View Article
  66. Chen J, Thomsen M, Vitetta L. Interaction of gut microbiota with dysregulation of bile acids in the pathogenesis of nonalcoholic fatty liver disease and potential therapeutic implications of probiotics. J Cell Biochem 2019;120(3):2713-2720 View Article
  67. Armstrong LE, Guo GL. Role of FXR in liver inflammation during nonalcoholic steatohepatitis. Curr Pharmacol Rep 2017;3(2):92-100 View Article
  68. Arab JP, Karpen SJ, Dawson PA, Arrese M, Trauner M. Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives. Hepatol Baltim Md 2017;65(1):350-362 View Article
  69. Zhu L, Baker RD, Zhu R, Baker SS. Gut microbiota produce alcohol and contribute to NAFLD. Gut 2016;65(7):1232 View Article
  70. Da Silva HE, Teterina A, Comelli EM, Taibi A, Arendt BM, Fischer SE, et al. Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance. Sci Rep 2018;8(1):1466 View Article
  71. Zhao F. Dysregulated epigenetic modifications in the pathogenesis of NAFLD-HCC. Adv Exp Med Biol 2018;1061:79-93 View Article
  72. Pirola CJ, Scian R, Gianotti TF, Dopazo H, Rohr C, Martino JS, et al. Epigenetic modifications in the biology of nonalcoholic fatty liver disease: the role of DNA hydroxymethylation and TET proteins. Medicine (Baltimore) 2015;94(36):e1480 View Article
  73. Zeybel M, Hardy T, Robinson SM, Fox C, Anstee QM, Ness T, et al. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease. Clin Epigenetics 2015;7:25 View Article
  74. Hardy T, Mann DA. Epigenetics in liver disease: from biology to therapeutics. Gut 2016;65(11):1895-1905 View Article
  75. Kitamoto T, Kitamoto A, Ogawa Y, Honda Y, Imajo K, Saito S, et al. Targeted-bisulfite sequence analysis of the methylation of CpG islands in genes encoding PNPLA3, SAMM50, and PARVB of patients with non-alcoholic fatty liver disease. J Hepatol 2015;63(2):494-502 View Article
  76. Sun Z, Miller RA, Patel RT, Chen J, Dhir R, Wang H, Zhang D, et al. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat Med 2012;18(6):934-942 View Article
  77. Xie Y, Tang Q, Chen G, Xie M, Yu S, Zhao J, et al. New insights into the circadian rhythm and its related diseases. Front Physiol 2019;10:682 View Article
  78. Li X, Shaffer ML, Rodríguez-Colón SM, He F, Bixler EO, Vgontzas AN, et al. Systemic inflammation and circadian rhythm of cardiac autonomic modulation. Auton Neurosci Basic Clin 2011;162(1-2):72-76 View Article
  79. Inokawa H, Umemura Y, Shimba A, Kawakami E, Koike N, Tsuchiya Y, et al. Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice. Sci Rep 2020;10(1):2569 View Article
  80. Gnocchi D, Custodero C, Sabbà C, Mazzocca A. Circadian rhythms: a possible new player in non-alcoholic fatty liver disease pathophysiology. J Mol Med 2019;97(6):741-759 View Article
  81. Zhou D, Wang Y, Chen L, Jia L, Yuan J, Sun M, et al. Evolving roles of circadian rhythms in liver homeostasis and pathology. Oncotarget 2016;7(8):8625-8639 View Article
  82. Tahara Y, Shibata S. Circadian rhythms of liver physiology and disease: experimental and clinical evidence. Nat Rev Gastroenterol Hepatol 2016;13(4):217-226 View Article
  83. Bandín C, Martinez-Nicolas A, Ordovás JM, Ros Lucas JA, Castell P, Silvente T, et al. Differences in circadian rhythmicity in CLOCK 3111T/C genetic variants in moderate obese women as assessed by thermometry, actimetry and body position. Int J Obes (Lond) 2013;37(8):1044-1050 View Article
  84. Mazzoccoli G, Vinciguerra M, Oben J, Tarquini R, De Cosmo S. Non-alcoholic fatty liver disease: the role of nuclear receptors and circadian rhythmicity. Liver Int 2014;34(8):1133-1152 View Article
  85. Liu S, Downes M, Evans RM. Metabolic regulation by nuclear receptors. Innovative Medicine 2015:25-37 View Article
  86. You SH, Lim HW, Sun Z, Broache M, Won KJ, Lazar MA. Nuclear receptor corepressors are required for the histone deacetylase activity of HDAC3 in vivo. Nat Struct Mol Biol 2013;20(2):182-187 View Article
  87. Gallinari P, Marco SD, Jones P, Pallaoro M, Steinkühler C. HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics. Cell Res 2007;17(3):195-211 View Article
  88. Feng D, Liu T, Sun Z, Bugge A, Mullican SE, Alenghat T, et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 2011;331(6022):1315-1319 View Article
  89. Ma K, Xiao R, Tseng HT, Shan L, Fu L, Moore DD. Circadian dysregulation disrupts bile acid homeostasis. PLoS One 2009;4(8):e6843 View Article
  90. Rietman A, Sluik D, Feskens EJM, Kok FJ, Mensink M. Associations between dietary factors and markers of NAFLD in a general Dutch adult population. Eur J Clin Nutr 2018;72(1):117-123 View Article
  91. Tajima R, Kimura T, Enomoto A, Yanoshita K, Saito A, Kobayashi S, et al. Association between rice, bread, and noodle intake and the prevalence of non-alcoholic fatty liver disease in Japanese middle-aged men and women. Clin Nutr Edinb Scotl 2017;36(6):1601-1608 View Article
  92. Assy N, Nasser G, Kamayse I, Nseir W, Beniashvili Z, Djibre A, et al. Soft drink consumption linked with fatty liver in the absence of traditional risk factors. Can J Gastroenterol 2008;22(10):811 View Article
  93. Abid A, Taha O, Nseir W, Farah R, Grosovski M, Assy N. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J Hepatol 2009;51(5):918-924 View Article
  94. Azzalini L, Ferrer E, Ramalho LN, Moreno M, Domínguez M, Colmenero J, et al. Cigarette smoking exacerbates nonalcoholic fatty liver disease in obese rats. Hepatology 2010;51(5):1567-1576 View Article
  95. Jung HS, Chang Y, Kwon MJ, Sung E, Yun KE, Cho YK, et al. Smoking and the risk of non-alcoholic fatty liver disease: a cohort study. Am J Gastroenterol 2019;114(3):453-463 View Article
  96. Mirmiran P, Amirhamidi Z, Ejtahed H-S, Bahadoran Z, Azizi F. Relationship between diet and non-alcoholic fatty liver disease: a review article. Iran J Public Health 2017;46(8):1007-1017
  97. Chute CG. Clinical classification and terminology. J Am Med Inform Assoc 2000;7(3):298-303 View Article
  98. Armitage JO, Gascoyne RD, Lunning MA, Cavalli F. Non-Hodgkin lymphoma. Lancet 2017;390(10091):298-310 View Article
  99. Singh SP, Anirvan P, Reddy KR, Conjeevaram HS, Marchesini G, Rinella ME, et al. Non-alcoholic fatty liver disease: not time for an obituary just yet!. 2021;74(4):972-974 View Article
  100. Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res 2016;5(3):288-300 View Article
  101. Ford AC, Bercik P, Morgan DG, Bolino C, Pintos-Sanchez MI, Moayyedi P. The Rome III criteria for the diagnosis of functional dyspepsia in secondary care are not superior to previous definitions. Gastroenterology 2014;146(4):932-940 quiz e14-15 View Article
  102. Hamaguchi M, Obora A, Okamura T, Hashimoto Y, Kojima T, Fukui M. Changes in metabolic complications in patients with alcoholic fatty liver disease monitored over two decades: NAGALA study. BMJ Open Gastroenterol 2020;7(1):e000359 View Article
  103. Louvet A, Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol 2015;12(4):231-242 View Article
  104. Yin H, Hu M, Liang X, Ajmo JM, Li X, Bataller R, et al. Deletion of SIRT1 from hepatocytes in mice disrupts Lipin-1 signaling and aggravates alcoholic fatty liver. Gastroenterology 2014;146(3):801-811 View Article
  105. Tomita K, Azuma T, Kitamura N, Nishida J, Tamiya G, Oka A, et al. Pioglitazone prevents alcohol-induced fatty liver in rats through upregulation of c-Met. Gastroenterology 2004;126(3):873-885 View Article
  106. Hashimoto E, Tokushige K, Ludwig J. Diagnosis and classification of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: current concepts and remaining challenges. Hepatol Res 2015;45(1):20-28 View Article
  107. Fouad Y, Elwakil R, Elsahhar M, Said E, Bazeed S, Ali Gomaa A, et al. The NAFLD-MAFLD debate: eminence vs evidence. Liver Int 2021;41(2):255-260 View Article
  108. 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(12):3018-3030 View Article
  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

Nonalcoholic Fatty Liver Disease (NAFLD) Name Change: Requiem or Reveille?

Shivaram P. Singh, Prajna Anirvan, Reshu Khandelwal, Sanjaya K. Satapathy
  • Reset Zoom
  • Download TIFF