#GUT Blog: Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach?

Professor El-Omar has chosen Dr Ramy Younes and Dr Angelo Armandi on behalf of Professor Bugianesi to do the next #GUTBlog. Dr Younes MD PhD is affiliated to Boehringer Ingelheim International GmbH, Ingelheim, Germany and Dr Armandi MD is affiliated to Department of Medical Sciences, Division of Gastroenterology and Hepatology, A.O. Città della Salute e della Scienza di Torino, Università degli Studi di Torino, Torino, Italy.  The #GUTBlog focusses on the latest paper “Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach?” which was published in paper copy in GUT in February 2022.  Dr Younes is the first author on this paper and Dr Armandi is a co-author.

Dr Ramy Younes (L) and Dr Angelo Armandi (R)


Dr Younes and Dr Armandi write:

“Non-Alcoholic Fatty Liver Disease (NAFLD) is addressed as the hepatic expression of the metabolic syndrome. In this perspective, obesity represents, together with type 2 diabetes, a major risk factor for disease progression. Hence, obese individuals are considered a high-risk population where investigation of NAFLD is highly recommended. Nonetheless, in clinical practice it is not uncommon to meet lean patients with NAFLD. The multidimensional pathophysiology and the balance between environmental harms and genetic susceptibility are responsible for the heterogeneous phenotype of NAFLD.

Giving the absence of obesity, we asked ourselves whether the lean population affected by NAFLD would share the same prognosis of obese patients. This question has driven our study, which was conducted on a large multicenter cohort of more than one thousand Caucasian individuals. Both obese and non-obese patients with biopsy-proven NAFLD were enrolled in different high-specialised hospitals and followed up over time to assess the incidence of clinical events. We found that obese patients share the same prognosis of non-obese patients, and that the latter are diagnosed with NAFLD at a younger age. Potentially, NAFLD may represent either an earlier diagnosis in lean individuals or one specific expression of the NAFLD spectrum. In fact, other independent mechanisms may underlie the onset of liver disease, including genetics, the gut-liver axis and insulin resistance. In particular, insulin resistance is the main pathophysiologic ground where NAFLD develops and progresses towards more severe stages of liver disease.

What are the main implications of our findings? First, NAFLD should not only be suspected and investigated in well-established high-risk populations, giving the absence of a fully comprehensive picture of disease drivers. In addition, lean individuals with NAFLD would require the same follow up suggested for obese subjects since they share same prognostic outcomes. Finally, the younger age at diagnosis of lean patients with NAFLD does not imply a milder disease. On the contrary, the development of a liver disease in the absence of the most impacting factors would suggest a more aggressive phenotype of NAFLD.

What would be the key message for clinicians? Current guidelines suggest investigating NAFLD in individuals with typical features of the metabolic syndrome. The title of our paper, written in a provocative way, suggests an alternative and more comprehensive management of this complex disease: it is time for a reappraisal of the BMI-driven approach. The more we progress with the understanding of NAFLD, the more we realize how unpredictable the crosstalk between the harmful factors and the individual’s responses can be. The intermittent injuries and the lifestyle responses differently shape the course of NAFLD and determine the transition from “simple” fat accumulation to features of progressive inflammatory disease.

We think that our contribution to this complex picture would consist of suggesting a deeper investigation in different clusters of patients. Ethnicity is one relevant aspect in NAFLD, linked to specific gene expressions and behavioral habits. Our findings refer to Caucasian individuals from Europe and Australia, with stronger evidence in the results. The natural history of “lean NAFLD” deserves more elucidations, in particular across different ethnicities. Furthermore, an outstanding challenge in this population is certainly the lack of specific treatments. Currently, lifestyle interventions aiming at weight loss are the first-line recommendations in the clinical management of NAFLD patients, but the assessment of response may be more challenging in subjects who are already lean. This aspect would also encourage a broader choice of target population for clinical studies with investigational products that are currently being undertaken in NAFLD.”

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Dr Ramy Younes @RamyYounes9

Dr Angela Armandi @AngeloArmandi

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