Reversing Advanced Hepatic Fibrosis in NASH: Clearly Possible, but Widely at Hand?

Nonalcoholic fatty liver disease (NAFLD) has become one of the most commonly diagnosed liver conditions, detectable in almost a third of adults in developed countries, with substantially higher prevalence figures if the study population is narrowed to adults with type 2 diabetes mellitus and/or obesity [1]. Depending on the population under study, 10–20 % of NAFLD patients have the potentially progressive form of NAFLD known as NASH or nonalcoholic steatohepatitis. It is the latter group that has been the target of numerous ongoing therapeutic studies in an effort to slow disease progression to cirrhosis, liver failure, and hepatocellular cancer. Therapeutic studies of NASH have been hindered by a number of factors, including a strong placebo effect, in part attributable to voluntary lifestyle changes, and limitations of noninvasive endpointswhich rely on surrogatemarkers of cell injury instead of liver biopsy [2]. In contrast, liver biopsy itself has had inherent limitations as an endpoint. Most problematic has been the assessment of a key histological finding in NASH—cellular ballooning. Although ballooning is likely an important marker related to disease pathogenesis [3], agreement among observers regarding this histological hallmark can be surprisingly infrequent, especially absent special staining techniques [4, 5]. Thus, a diagnosis of NAFLD solely based on isolated histological parameters or even composite scores such as the NAFLD Activity Score (NAS) is questionable. Alternatively, although perhaps still debatable, the absence ofNAFLDor the presenceof advancedfibrosis stages is arguably more easily agreed upon histological parameters [6]. Moreover, the fibrosis stage itself carries prognostic significance [7]. In this issue of Digestive Diseases and Sciences, Glass et al. [8] present their experience with the effects of weight loss on fibrosis stage in a well-defined cohort of NASH patients followed with serial biopsy over a mean of approximately 5 years. Of 45 patients studied with a mean initial fibrosis stage of 1.96, 12 underwent bariatric surgery with Roux-en-Y gastric bypass with the majority experiencing significant weight loss. The most salient findings are nicely encapsulated in Fig. 1 where regression of fibrosis stage based on blinded biopsy review is most evident with the loss of C10 % total body weight (TBW), variable with 0–10 % TBW loss, with progressive increases more apparent among those experiencing weight gain. Most striking is regression from stage 4 to stage 3 and from stage 3 to stage 2 or even to stage 1. On the basis of multivariate analysis, fibrosis regression was predicted only by weight loss and not influenced by age, gender, glucose tolerance, ferritin level, or heterozygosity for a-1-antitrypsin type. Although sampling error is a well-known problem with biopsy interpretation, taken in aggregate these results are convincing and support the emerging concept of the reversibility of even advanced stages of liver fibrosis [9]. Moreover, the results support the often challenging but fundamental tenets of NASH management to advise aggressive lifestyle changes with the encouragement of weight loss through dietary changes and exercise [10]. The broad application of bariatric surgery is more problematic due to concerns for costs, surgical eligibility, and perioperative risk with advanced fibrosis stages where postoperative complications can be substantial [11]. A recent study comparing the effects in NAFLD of Roux-en-Y gastric S. H. Caldwell (&) C. K. Argo (&) The Division of GI/Hepatology, University of Virginia Health System, JPA and Lee St., PO Box 800708, Charlottesville, VA 22908-0708, USA e-mail: shc5c@virginia.edu