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Oliveira et al. Hepatoma Res 2020;6:xx I http://dx.doi.org/10.20517/2394-5079.2020.73 Page 11 of 13

insulin level in the future to be certain that they are indeed insulin sensitive. Regardless, more information
about the pathophysiological mechanisms underlying disease development and progression in obese or
overweight insulin sensitive subjects will help future efforts to tailor specific therapies that are most likely
to engage the relevant therapeutic targets in these individuals.

There is a difference in the aggressiveness of NAFLD between American and European countries, mainly
Mediterranean countries. One interesting example is the number of liver transplantations in USA secondary
[30]
NASH compared with Europe countries . In Brazil there has also been an increase in the numbers of
liver transplantations secondary to NASH. Several hypotheses can be considered for the greater severity of
fibrosis in American countries, including lean NASH: (1) Higher caloric intake in the Americas, diet rich
[31]
in fructose and trans lipids low consumption of Mediterranean diet, including fiber and omega 3; (2)
[32]
greater sedentary lifestyle in American countries; (3) presence of genetic factors such as PNPLA3 ; and (4)
[33]
dysbiosis, even in Lean NASH patients . Furthermore, in the USA and Brazil, there is also admixture with
genes from non-caucasian Hispanic and native American genes. American Hispanics have more severe
NASH. The complex genetic background may be another potential explanation. Unfortunately given the
sample size of this initial assessment, it is not feasible to address the role of genetics. Similarly, there may be
differences in diet and also microbiome functionality that are not captured by current methods that could
play a role. NASH is a complex disorder driven by gene environment interactions.

There were also differences in the spectrum of other end organ diseases within lean subjects with NAFLD.
These corroborate the concept that the pathogenesis of each of these conditions is complex and there
are regional variations in the prevalence rates and severity. All of these data further attest to the trans-
continental drifts in phenotype development of this cluster of diseases.

There are several potential explanations for the observed variations in NAFLD phenotype and associated
conditions across the four cohorts studied. These include genetic differences in susceptibility, regional
variation in diet patterns, differences in the intestinal microbiome, exercise, environmental exposures etc.
While a detailed analysis of these is beyond the scope of this manuscript, such studies are now indicated to
better understand the variations in phenotype development in different regions.

Perhaps the most relevant implication of the current study is that it provides proof of concept that there are
differences in both the histological phenotype and associated clinical features in subjects with NAFLD in
different regions of the world and that region-specific data are now needed to provide optimal guidance for
clinical care on various regions. Also, it raises the possibility that therapeutic responses in one region may
or may not be similar from one region to another. A clearer understanding of variable disease mechanisms
underlying the differences in phenotype development should help targeting therapeutics towards the most
relevant targets in a given region and phenotype in the future.

The principal limitations of the current study are the relatively modest size of lean subjects with NAFLD in
various regions and the potential for ascertainment bias. The small numbers of lean subjects however reflect
the fact that they represent a small fraction of all subjects with NAFLD. Also, another limitation is that
we report the prevalence of fibrosis stage in patients with NAFLD who had a biopsy at the centers in this
study. Since this was done according to standard of care, the selection of patients for a biopsy was variable
across centers. Further, the distribution of fibrosis could also be impacted by ascertainment bias due to the
nature of the center. It was seen in the Indian cohort probably because increasing age is linked to higher
stages if fibrosis and is generally considered to be due to longer exposure to disease state. It is potentially
possible that the low fibrosis stage in India reflected the lower age of the population studied. It is noted
in the section about variations across centers and as a potential explanation for the differences in fibrosis
stage in India vs. other sites. However, most published studies of NAFLD also have the same ascertainment
bias associated with tertiary care academic medical centers. These limitations notwithstanding, the current
study demonstrates substantial variability in disease phenotype from one region to another.