Liver fat accumulation as a barometer of insulin responsiveness again points to adipose tissue as the culprit
Authors: Fernando Bril, Kenneth Cusi
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We read with enthusiasm the editorial by Rotman and Neuschwander‐Tetri,1 who should be congratulated for putting our article2 into perspective. Our results suggest that dysfunctional (insulin‐resistant) adipose tissue plays a key role in the development of nonalcoholic fatty liver disease (NAFLD). In this context, NAFLD should be considered as a systemic disease, where the liver becomes the "barometer" of the lipotoxic state.3 Excessive rates of lipolysis from adipose tissue, in the setting of chronic hyperinsulinemia, lead to well‐defined metabolic consequences. These metabolic changes occur fairly rapidly in association with a relatively narrow threshold of intrahepatic tryglyceride (IHTG) (∼6% ± 2%). In their editorial, Rotman and Neuschwander‐Tetri addressed the potential impact of ethnicity on the metabolic threshold of IHTG. Our cohort was mainly composed of Hispanic (n = 151; 43%) or Caucasian (n = 148; 42%) patients, with only 15% from other ethnic backgrounds (excluded from this subanalysis due to small sample size). We observed no differences in the IHTG threshold associated with maximal impairment of clinical characteristics, such as plasma triglycerides and high‐density lipoprotein cholesterol between Caucasian and Hispanic patients. Linear relationships between IHTG content and fasting plasma aspartate aminotransferase/alanine aminotransferase, insulin, and homeostasis model assessment of insulin resistance (HOMA‐IR) were also similar between ethnicities. This lack of major ethnic differences is in line with our previous results showing that, when well‐matched for clinical characteristics, Caucasian and Hispanic patients have no significant differences in IHTG accumulation, insulin resistance (IR), or severity of liver histology.4 Sample size constraints precluded assessment of IR per ethnic group, as only ∼40% of patients had a euglycemic insulin clamp. Rotman and Neuschwander‐Tetri also expressed interest in whether our results were independent of the impact of obesity. In the original study, we decided not to adjust for obesity because total body fat as evaluated by dual energy X‐ray absorptiometry was similar among the 10 quantiles. However, we have since repeated all analyses with body mass index and total body fat as covariables, and all results remained the same after adjustment for them. The editorial successfully captures an important message of our article regarding the metabolic changes taking place in NAFLD. However, due to the lower slope of adipose tissue IR in their figure, readers unfamiliar with the pathogenesis of NAFLD may wrongly assume that adipose tissue IR occurs at a later stage of IHTG accumulation; in other words, they may assume that when hepatic and skeletal muscle IR are fully manifest (1.5% and 4.2% of IHTG, respectively), adipose tissue dysfunction is still mild. However, as discussed in our article, adipose tissue IR develops early on in the natural history of NAFLD. The main difference compared with IR in skeletal muscle and liver is that adipose tissue does not reach a plateau at any point along the spectrum of IHTG accumulation. In conclusion, our study suggests that the accepted 5.56% imaging cutoff point used for the diagnosis of NAFLD has a strong metabolic correlate and could be used as a "barometer" of metabolic health. Confirmation in longitudinal studies will be needed to determine if this threshold of liver fat content can also be pursued for lifestyle intervention or pharmacological therapy.