We read with interest the article by Charlton et al.1 The authors observe that levels of dehydroepiandrosterone (DHEA) are significantly lower in patients with histologically advanced nonalcoholic steatohepatitis (NASH), as compared with patients with simple, nonalcoholic fatty liver disease (NAFLD). DHEA levels exert a good sensitivity and specificity in discriminating patients with more advanced histological disease, as shown by the receiver operating characteristic analysis.
The strong rationale supporting this evidence is the fact that free fatty acids (FFAs) are the major source of DHEA, also known as the “hormone of youth”, and they can stimulate androgen secretion in vivo.2 We could speculate that in genetically prone individuals and in the presence of severe insulin resistance, increased circulating FFAs are not converted into DHEA, which could act as a reservoir. In this view, DHEA may play a protective role against morbidities related to insulin resistance: first contributing to blood FFA removal and sex hormone balance and then acting through a number of molecular pathways, which have been in part addressed by the authors.1 The inability to produce appropriate amounts of DHEA in response to FFAs may translate into a more rapid and worsening progression toward NASH.
Although the hypothesis is potentially interesting, we would suggest caution in evaluating the results and possible implications of the study by Charlton et al.1 Physiological roles for endogenous DHEA and therapeutic benefits of hormone supplementation for the treatment of aging, insulin resistance, and cardiovascular disease remain obscure and controversial, in spite of intensive studies for more than 50 years. With regard to results obtained from the logistic regression model, the authors intended to support the concept that the association between low levels of DHEA and worsening histology is independent of age, sex, and metabolic abnormalities, clustering into the metabolic syndrome. However, they consider neither body mass index nor hyperinsulinemia as key components of the syndrome, and do not mention that the effect of DHEA may be mediated by low expression of adiponectin in patients with NASH.3 With regard to insulin, the authors must be aware that insulin and DHEA are capable of reciprocal regulation, with hyperinsulinemia causing a decline in serum DHEA concentration.4 The body mass index is a rough index of adiposity and it associates with worsening histology with a statistical significance of 0.02.
Finally, we wonder how the model might change by entering total or visceral fat, adiponectin, and/or hyperinsulinemia as predictors, or by replacing continuous instead of dichotomous variables.
We believe that the study by Charlton et al. adds a significant contribution to our comprehension of the mechanisms regulating the progression from NAFLD to NASH, but we are still far from reaching the solution.