Page 846 - Read Online

Page 10 of 13 Oliveira et al. Hepatoma Res 2020;6:xx I http://dx.doi.org/10.20517/2394-5079.2020.73

European countries like France [20-23] . In Brazil, the prevalence of arterial hypertension found was 21.4%
(95%CI: 20.8-22.0) using the self-reported criterion, 22.8% (95%CI: 22.1-23.4) for measured arterial
hypertension, and 32.3% (95%CI: 31.7-33.0) for hypertension arterial pressure and / or report of medication
[24]
use . Furthermore, according IDF Atlas, in Brazil and USA, the prevalence of T2DM in 2019 was 8.5%
and 11.1% respectively, while in Europe was 6.3%. USA is the third-highest country with patients with
[20]
T2DM in the world, and Brazil the fifth . Also, caloric consumption in American countries is higher than
[25]
in some countries and in Europe . In addition, patients in Brazil and the USA come from large tertiary-
level university hospitals, where patients of greater severity are referred to them.

An important observation in this study is the remarkable range of laboratory-histological findings when
comparing lean subjects with overweight and obese subjects in the different countries where this study
was conducted. In France, a clear stepwise worsening of IR and severity of liver histology was noted with
increasing BMI. In contrast, lean subjects in Brazil were more insulin-resistant and like overweight and
obese subjects with respect to both the severity of their IR and liver histology. Subjects from the United
States and India had an intermediate relationship with Indian subjects tending to demonstrate generally
lower insulin levels than those from the other cohorts at all weight strata. These corroborate the concept
that the severity of NAFLD is not a simple function of increasing body mass and that these relationships
can be variable from one region to another.

The current study further demonstrates that the spectrum of IR and liver histology is variable from one
country to another even when the body mass is accounted for. Lean subjects in the Brazilian cohort
were more insulin-resistant and had greater steatosis than subjects from other regions. However, the
severity of cytological ballooning was similar in the US, Brazil, and India and higher than that seen in
the French subjects. These data are in line with the concept that development of liver injury is more than
a simple function of IR and that additional factors are likely to play a role. While theoretically possible,
we believe it is unlikely that these data purely represent differences in how the histology was read by the
local pathologists since all of the pathologists involved are senior and experienced pathologists who have
previously published in the field.

Another noteworthy finding in this study is that even in Western countries, a subset of overweight and even
obese subjects with NAFLD were relatively insulin sensitive, i.e., with a fasting insulin < 12 µU/mL and
[glucose] < 100 mg/dL. The lower blood glucose could not be attributed to the use of anti-diabetic therapy
alone although it may have played a role in a few subjects. The only potential exception was the obese
Indian cohort where all subjects were known to have diabetes and many also had a fasting plasma glucose <
[26]
100 mg/dL. While the presence of insulin sensitive obese individuals is well established , there is a general
perception that these so called “fit-fat” subjects do not develop end organ diseases typically associated with
IR. The current study further demonstrates that the distribution of liver histology in these subjects includes
the full spectrum of NAFLD. The mechanisms underlying the liver disease in these subjects are not well
understood. Unfortunately, due to the retrospective nature of this current analysis, the subjects were not
genotyped and their PNPLA3 and TM6SF2 and other SNPs associated with the metabolic syndrome were
not available. This is now a logical future direction of research in the field.

It is also not known if obese insulin-sensitive subjects respond to insulin sensitizers and improve their
liver histology in the same manner as obese insulin resistant subjects. In the PIVENS trial, baseline
HOMA scores did not predict histological response to pioglitazone [27,28] . This study however did not
evaluate assess the insulin sensitivity status by HOMA alone but by graphical analysis of the relationship of
glucose and insulin. It is also recognized that an euglycemic hyperinsulinemic clamp is the gold standard
[29]
for measurement of insulin sensitivity . In this retrospective analysis, this was not possible. However,
it will be valuable to perform these in obese subjects with NAFLD who have a low fasting glucose and