Hepatic fibrosis developing in morbid obesity independent of steatohepatitis: new mechanism or the Rube Goldberg machine?

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Obesity represents a major health burden. Nonalcoholic fatty liver disease (NAFLD) is strongly associated with visceral obesity. NAFLD encompasses a broad spectrum of pathology from steatosis alone, to nonalcoholic steatohepatitis (NASH), with or without fibrosis. As the prevalence of steatosis and NASH was recently estimated to be 46 and 12 % [1], respectively, understanding the mechanism of fibrosis that leads to hepatic complications is crucial. In the current issue of Hepatology International, Ciupinska-Kajor et al. [2] present data suggesting the mechanism of fibrosis in NAFLD might differ based on the degree of adiposity, and that early angiogenesis could be the distinguishing feature. Prognosis in NAFLD is variable, dependent on histologic findings. Bland steatosis alone has a benign prognosis, whereas NASH leads to increased fibrosis and mortality. A recent review of natural history data spanning a mean follow-up of 15 years found a 0.7 % prevalence of cirrhosis in cohorts with steatosis alone, compared to a 10.8 % prevalence of cirrhosis in cohorts with NASH [3]. Steatohepatitis was also shown to be associated with increased mortality. When 118 persons with NAFLD were followed up for a mean period of over 20 years, persons with NASH had a significant increase in mortality, whereas those with steatosis alone did not [4]. With different prognostic ramifications, it is important to understand the pathophysiologic mechanisms that distinguish bland steatosis from NASH. Unfortunately, events that differentiate NASH from steatosis are not well defined. Theories do exist. The ‘‘two-hit’’ hypothesis involves a sequential process where first steatosis develops and a second hit is caused by oxidative stress resulting in lipid peroxidation and steatohepatitis [5]. A second theory involves ‘‘multiple parallel hits’’ [6]. These multiple hits include gut-derived signals such as endotoxin, adiposederived signals such as adipocytokines, innate immunity, endoplasmic reticulum stress, and genetic differences. Important to this hypothesis is the potential for inflammation to precede steatosis in some cases. Different theories highlight the concept that NAFLD and NASH represent a heterogenous group of disorders where a histologic endpoint can be represented by numerous contributing pathogenic mechanisms. One pathophysiologic mechanism of progressive liver disease in NAFLD is angiogenesis. Angiogenesis is associated with hepatic inflammation [7], hepatic fibrosis [8], the formation of portosystemic collateral vessels [9], and hepatic carcinogenesis [10]. In animal models of steatohepatitis, the expression of vascular endothelial growth factor (VEGF) and angiogenesis occurred in parallel to fibrosis and carcinogenesis [11]. In human tissue, angiogenesis, measured by CD 34-positive staining cells, occurred in NASH, but not normal liver or bland steatosis [12, 13]. Angiogenesis in NASH was associated with both hepatocellular apoptosis and insulin resistance [13]. The association between hepatic inflammation and angiogenesis is not unique to NAFLD. In persons with chronic hepatitis C, serum levels of proangiogenic markers, VEGF and angiopoietin-2, were elevated at baseline and decreased after interferon-based therapy [14]. The study by Ciupinska-Kajor et al. [2] mirrors the potential heterogeneity seen in the pathogenesis of NAFLD. The authors examined angiogenic markers, including VEGF A and CD 34 staining, in a population of morbidly E. R. Kallwitz (&) Section of Hepatology, University of Illinois, 840 S Wood Street MC 787, Chicago, IL 60612, USA e-mail: Kallwitz@uic.edu