NAFLD or MAFLD: That is the conundrum

Giovanni Tarantino

Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Naples, Italy

Where do we stand and where are we going? This ques- tion is of paramount importance in the light of the necessity of shedding light on the novel, controversial issue that is chang- ing the acronym of nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD). The debate is deeply rooted in a multitude of unknown, or at the best scarcely understood, factors/phenomena involving various pieces of research and throwing up a range of different questions that need to be explored independently. Dealing with the NAFLD/MAFLD epi- demiology, Zeng et al. should be praised for approaching a com- plex topic concerning this multifaceted disease that bears a note- worthy impact on health care system. They carried out an intrigu- ing cross-sectional study published in this issue [1] . A large sam- ple size population consisting of 9927 Chinese individuals were included in that clinical investigation. The authors, interestingly, found that the prevalence of MAFLD was significantly higher than that of NAFLD (40.3% vs. 36.9%). MAFLD was highly represented in patients affected by glucose dysmetabolism, specifically in those with type 2 diabetes mellitus (53.8%) and pre-diabetes, the lat- ter including patients with impaired fasting glucose (35.7%) or im- paired glucose tolerance (40.9%). High risk of advanced fibrosis based on fibrosis-4 (FIB-4) determination (one of the most inter- esting tests that we will discuss further) was detected in 14.7% of lean (body mass index, BMI＜23 kg/m2, Asian criterion) MAFLD subjects with type 2 diabetes mellitus. Among the whole pop- ulation, 3481 (35.1%) subjects fulfilled the diagnostic criteria for MAFLD and NAFLD (MAFLD + NAFLD + ), 521 individuals (5.2%) were labelled as MAFLD + NAFLD-, and 181 patients (1.8%) were identi- fied as MAFLD-NAFLD + . The MAFLD + NAFLD- group showed more significant metabolic disorders than the MAFLD + NAFLD + group. Among MAFLD-NAFLD + subjects, 82.9% had metabolic disorders, emphasising that the NAFLD diagnosis, even though comprehend- ing some criteria of the metabolic syndrome, does not always over- lap the diagnosis of MAFLD. Anyway, these results clearly highlight the importance of tackling the metabolic syndrome presence in NAFLD patients, but with the clear evidence that a relatively few (nearly 2%) percentage of NAFLD patients does not fulfil the cri- teria of MAFLD. As pointed out by the authors of this study, over 82% of these previously mentioned patients (the so called MAFLD- NAFLD + ) had one metabolic disorder.

However, without casting any doubts on this new classifica- tion whether it correctly comprehends all causes of NAFLD or not, point of relatively scarce importance, who are these MAFLD- NAFLD + subjects? Patients with susceptibility gene polymorphism changes, or rare ignored causes, i.e., suffering from Wilson’s dis- ease, as rightly suggested by the authors. Actually, we do not know whether among this group were present patients with NAFLD linked to obstructive sleep apnea syndrome in the absence of coex- isting co-morbidities such as obesity or metabolic syndrome [2] or NAFLD related to polycystic ovary syndrome, in which hyperandro- genism is associated to NAFLD independently from obesity and in- sulin resistance [3] . Could patients diagnosed as MAFLD-NAFLD + have main risks for their disease environmental factors as pollution or endocrine disruptors such as bisphenol, one of the most widely used chemicals, or finally a smoking habit? Undoubtedly, the asso- ciation of NAFLD with these factors is not causation, but this is the type of close correspondence that should serve as starting point for establishing whether there could be a direct causal link. Thus, may this association explain the nearly 17% of MAFLD-NAFLD + having no metabolic disorders?

What about alcoholic fatty liver disease (AFLD)? This is a huge problem, splitting the scientific community between those who sustain that alcohol is a protective factor for NAFLD patients [4] and those who conclude that the policy of counseling NAFLD patients for alcohol abstinence should be maintained [5] . Accordingly, it is similarly worthy of speculation the finding that a little more than 10% of MAFLD patients were not diagnosed as having NAFLD (521 out of 4002 patients). Could it be due to the fact that the diagnosis of MAFLD comprehended also AFLD, as sug- gested by authors? This is a central point, considering the mostly extensive, especially among the young, alcohol use/abuse that can lead to liver cirrhosis, beyond permanent brain damage.

At the end of their paper, Zeng et al., opportunely state that the individuals, who either had NAFLD or MAFLD but not both, had their own unique characteristics. The authors keep on suggesting that it would be necessary to closely follow the respective patients up and strengthen prevention and treatment as soon as possible. These, anyway, are the key points: prevention is linked to early diagnosis, while treatment is successive only to a complete under- standing of the inner mechanisms of NAFLD that are far from being clarified [6] .

Coming back to the old definition that has accompanied re- searchers and physicians for more than three decades, NAFLD pa- tients remain surprisingly quite under-diagnosed or are hugely overlooked as having all in all a not so dangerous or life- threatening disease to catch their attention and to alarm the physi- cians. Vice versa they, unfortunately, suffer from distant severe consequences and have a reduced life span due to the high like- lihood of mortality that increases with disease progression [7] . Therefore, an early identification of this very common disease and mainly effective management to halt the ongoing fibrosis, or better reverse it, are essential to prevent progression towards liver cirrho- sis, hepatic insufficiency/liver failure and hepatocarcinoma.

The first aim, i.e., precocious diagnosis when dealing with epidemiological surveys, mainly in population at high risk for NAFLD, i.e., obese and type 2 diabetic patients, has tentatively been achieved by the proposal of many diagnostic markers of NAFLD. However, it should be highlighted that no single marker is suffi- cient for diagnosis and staging (we successively will face this as- pect) of the disease, and applying a panel including different types of tests could be a more constructive approach [8] .

Between noninvasive methods presently and largely used for steatosis detection and quantification in NAFLD, we should men- tion the SteatoTest — obtained by the combination of FibroTest with alanine aminotransferase, BMI, blood glucose, serum triglyc- erides and cholesterol adjusted for age and sex — [9] , the Fatty Liver Index (FLI) [10] , regular abdominal ultrasound and the hep- atorenal ultrasound index [11] . FLI has a good agreement with SteatoTest and moderate agreements with abdominal ultrasound or hepatorenal ultrasound index [12] . Hepatic steatosis index, more- over, is a simple, reliable tool for screening NAFLD that may be utilized for selecting individuals for abdominal ultrasound and for determining the need for lifestyle modifications [13] , a central approach to alleviate NAFLD, waiting for more appropriate treat- ments. Another study combined triglycerides with fasting plasma glucose to create a formula, called triglyceride and glucose index (TyG), which is also effective to identify individuals at risk for NAFLD [14] .

The other noninvasive modalities of diagnosing hepatic steato- sis are images. Advanced magnetic resonance imaging can accu- rately diagnose and quantify steatosis, but is expensive and not easily available. Another imaging modality is quantitative ultra- sound, which provides high diagnostic accuracy for detection of hepatic steatosis [15] . However, in this specific field, future multi- centered trials are needed to determine reproducible and validate protocols well-accepted by every researcher.

Returning to the main subject of NAFLD progression, i.e., track- ing the entity of fibrosis, Enhanced Liver Fibrosis score (ELF), Fi- broMeter, FIB-4 and NAFLD fibrosis score (NFS) are among the most common. ELF and FibroMeterV2Ghave equal accuracy and perform better than the simple FIB-4 and NFS tests for the nonin- vasive diagnosis of advanced liver fibrosis in patients with NAFLD from tertiary care centers [16] . BARD score and NFS are capable of ruling out advanced fibrosis and markedly reducing the need for liver biopsies in patients with NAFLD [17] , but the BARD score is easier to estimate and does not have indeterminate results [18] .

The second aim is discovering an efficient therapy, not less im- portant at the light of the skyrocketing costs of the NAFLD seque- lae (cardiovascular diseases, hepatic and extrahepatic cancers [19] ). This aim is far from being completely fulfilled, even though the drugs on pipeline are many, all quite interesting and worthy to be carried forward in successive, confirmatory clinical trials [20] .

Conclusively, nobody can dispute that there is plenty of is- sues here and that we only have scratched the surface of this widespread, and in some respects obscure, chronic liver disease, but researchers involved in investigating NAFLD , such as those presenting this work, are to be commended for positioning us at the dawn of an exciting new era of participatory medicine, col- laborative and multidisciplinary thinking in human and scientific endeavor.

Acknowledgments

None.

CRediT authorship contribution statement

GiovanniTarantino:Conceptualization, Writing - original draft, Writing - review & editing.

Funding

None.

Ethical approval

Not needed.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the sub- ject of this article.