Reply
Authors: Eduardo Vilar‐Gomez, Luis Calzadilla‐Bertot, Scott L. Friedman, Manuel Romero‐Gomez
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. Reply: We thank Drs. Armstrong, Gaunt, and Newsome for analyzing the accuracy of the nonalcoholic steatohepatitis (NASH) resolution score1 in discriminating patients with histological resolution of steatohepatitis in the cohort of the recently published Liraglutide Safety and Efficacy in Patients with Nonalcoholic Steatohepatitis (LEAN) trial.2 We read with special interest their analyses and comments on the predictive capabilities of two well‐defined thresholds of our model for detecting/excluding subjects with NASH resolution. Interestingly, by applying the cutoff of <46.15, 32 (94%) of 34 patients were correctly classified as not having NASH resolution, denoting a higher specificity of the model. In contrast, only 4 (36%) of 11 were adequately classified as having NASH resolution when the threshold of >69.72 was applied. As noted by the authors, the practical applicability of using this model in the setting of pharmacological interventions may rely on identifying nonresponder patients to avoid prolongation of ineffective therapies and prevent drug‐related side effects. As these findings hold important practical implications, it is crucial to provide readers with a better understanding of results obtained with the NASH resolution score in the LEAN trial cohort. The NASH resolution score was developed and validated in a cohort of patients treated with lifestyle modifications, and weight loss (WL) was the most important factor associated with NASH resolution; it is unclear if the score would apply to patients treated for NASH with pharmacologic therapy rather than WL, and the data offered by Drs. Armstrong, Gaunt, and Newsome suggest that the score needs to be validated independently for such therapies. In fact, the area under the curve that included only WL for predicting NASH resolution was 0.87, denoting its crucial role in the model. Moreover, our data showed that significant WL (≥7%‐10%) was required for obtaining higher rates of NASH resolution, regardless of baseline factors. This finding may explain that higher WL may have a greater influence on positive predictive values of the model. Although WL and alanine aminotransferase (ALT) improvements were closely correlated in our study, normalization of ALT (≤30 U/L for men and ≤19 U/L for women) alone was unable to discriminate adequately subjects with NASH resolution. Thus, normalization of ALT levels during the course of other therapeutic interventions (i.e., liraglutide) should not significantly improve the accuracy of the model for detecting individuals with NASH resolution. In our study, type 2 diabetes negatively impacted NASH resolution. In contrast, data from the LEAN trial indicated that histological improvements were not proportional to extent of WL and that the presence of diabetes did not affect NASH resolution rates. These findings probably should explain the low accuracy of the model in detecting patients with NASH resolution. In terms of NASH resolution, the patient's response to therapeutic interventions depends partly on the patient's characteristics and the histologic severity of NASH. Patients with unfavorable prognostic factors (i.e., older age, diabetes, or nonalcoholic fatty liver disease activity score ≥5) and lack of efficacy of the intervention suspected by surrogate markers (i.e., absence of ALT normalization or lower rates of WL) may have lower probabilities of NASH resolution. In the presence of the above‐mentioned scenarios, the model should consistently identify patients without NASH resolution.