Insights into Nonalcoholic Fatty-Liver Disease Heterogeneity

Abstract

The acronym nonalcoholic fatty-liver disease (NAFLD) groups a heterogeneous patient population. Although in many patients the primary driver is metabolic dysfunction, a complex and dynamic interaction of different factors (i.e., sex, presence of one or more genetic variants, coexistence of different comorbidities, diverse microbiota composition, and various degrees of alcohol consumption among others) takes place to determine disease subphenotypes with distinct natural history and prognosis and, eventually, different response to therapy. This review aims to address this topic through the analysis of existing data on the differential contribution of known factors to the pathogenesis and clinical expression of NAFLD, thus determining the different clinical subphenotypes observed in practice. To improve our understanding of NAFLD heterogeneity and the dominant drivers of disease in patient subgroups would predictably impact on the development of more precision-targeted therapies for NAFLD.

Fig. 1

The acronym nonalcoholic fatty-liver disease (NAFLD) groups a heterogeneous patient population. The different phenotypes observed in clinical practice stem from a complex and dynamic interaction of different factors (age, sex, reproductive status, presence of one or more genetic variants and epigenetic factors, a diverse microbiota composition, coexistence of different comorbidities, the degree of alcohol consumption, and muscle mass and physical activity among other). These variables critically influence NAFLD development and progression. Disease heterogeneity imply that pathophysiological mechanisms underlying NAFLD may have different hierarchy or trajectory in different patients defining different subphenotypes which may be relevant to molecular pathway-based therapies. NAFLD heterogeneity may also influence natural history and prognosis and, eventually, response to therapy.

Fig. 2

The differential contribution of genetic/epigenetic, environmental and metabolic factors deters a significant interpatient variation regarding the major driver of disease. Circles depict three hypothetical patients that exhibit a different predominance of the three above-mentioned factors. While patient 1 has environmental factors (e.g., poor diet and/or physical activity) as main driver of disease, patients 2 and 3 has a mixed predominance of genetic factors and metabolic derangement as determinants of their phenotypes. Better distinction of main drivers in each patient may help to implementation of individualized or precision medicine approaches in nonalcoholic fatty-liver disease (NAFLD) management (adapted from Eslam et al).