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Page 2 of 13 Oliveira et al. Hepatoma Res 2020;6:xx I http://dx.doi.org/10.20517/2394-5079.2020.73

Brazil were mostly insulin-resistant. For each weight category, subjects from India were more insulin-sensitive than
those from other regions. Disease activity increased from lean to overweight to obese in France but was similar
across weight categories in other regions.

Conclusion: The phenotype of NAFLD in lean subjects varies by region. Some obese subjects with NAFLD
are insulin-sensitive. We hypothesize that genetics and region-specific disease modifiers account for these
differences.

Keywords: Non-alcoholic fatty liver disease, phenotype, epidemiology, demographics

INTRODUCTION
[1]
Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and mortality .
Nonalcoholic steatohepatitis (NASH), the more aggressive form of NAFLD, can progress to cirrhosis
[2]
and end-stage liver disease more frequently than non-alcoholic fatty liver (NAFL) . The principal risk
factors for NAFLD include obesity and insulin resistance (IR) and its associated conditions such as type 2
[3-5]
diabetes .

Numerous reports from Asia and other parts of the developing world have identified NAFLD, including
[6,7]
NASH, in lean subjects without biochemically obvious IR . NAFLD has also been described in lean
subjects in western countries [8-10] . There is however only limited information on the clinical, laboratory,
and histological profile of lean versus obese subjects with NAFLD in the West. It is also not known if
the histological spectrum of NAFLD and its relationship to IR is similar from one continent to another
when subjects of identical body mass index (BMI) are considered. Similarly, when considering afflicted
individuals with similar degree of IR, the distribution of histological findings from one continent to another
is not known. These are likely to be relevant for either continuing a “one set of risk factors fits all” paradigm
globally or informing development of “region-specific” risk stratification approaches.

In this study, we report data from four cohorts of subjects from the USA, Brazil, France and India to
address the trans-continental drifts in disease phenotype across the spectrum of BMI and IR. The specific
aims were to: (1) define the similarities and differences in disease expression between lean vs. obese
subjects with NAFLD in the countries represented in this study; and (2) to compare the disease phenotype
within specific weight and IR strata from one country to the next.

METHODS
The current study is a retrospective cross-sectional analysis of a cohort of subjects with NAFLD at the
participating centers. The participating centers were in Virginia, USA (PI: AJS), Brazil (PI: CPO), France (PI:
LS) and India (PI: AC). The data sheets were developed at EUA: (2008-2013); France: (1999-2014); Brazil:
(2009-2014); India (2008-2014); and analyzed by the investigators. The study involved an anonymized data
set from an existing larger data set and was therefore considered exempt from IRB review.

Patient population
Subjects with biopsy proven NAFLD with a full set of histological and laboratory data were included in
this analysis from each site. Exclusion criteria included age < 18 years, absence of full data set including
measures of IR, liver injury and function, anthropometric data, lipid profile and liver histology. Subjects
with concomitant presence of alternate causes of liver disease, e.g., hepatitis C were also excluded to
avoid their confounding effects. Finally, those with drug-induced NAFLD, TPN-associated NAFLD,
and bariatric surgery within last 5 years or known infectious, e.g., HIV or known genetic disorders, e.g.,
abetalipoproteinemia associated with NAFLD, were excluded to keep the analysis focused on “garden-
variety” NAFLD.