Increased ratio of neutrophil elastase to α1‐antitrypsin is closely associated with liver inflammation in patients with nonalcoholic steatohepatitis

Abstract

An imbalance between neutrophil elastase (NE) and its inhibitor α1-antitrypsin (A1 AT) is known to contribute to the development of obesity-related inflammation. This study aimed to investigate the role of the NE-A1 AT system in the histological progression of non-alcoholic fatty liver disease (NAFLD), and to evaluate the ability of it to predict nonalcoholic steatohepatitis (NASH). A total of 252 adults (NAFLD group, n = 202; healthy group, n = 50) were recruited. Clinical biochemical characteristics, NE and A1 AT concentrations were measured in all subjects. Among the NAFLD group, 86 patients had previously undergone liver biopsy and information on histological characteristics was consequently available. The area under the receiver operating characteristic curve (AUC) was used to determine the predictive accuracy of the NE-A1 AT system for NASH. NAFLD patients had an elevated serum NE concentration and a reduced A1 AT level with consequent NE/A1 AT imbalance. NE increased in the early stage of steatosis, preceding the decline in A1 AT, dating from the onset of NASH (NAS 3-4), and subsequently NE/A1 AT increased in the presence of NASH. Nonetheless, this increase began to resolve as the disease state progressed to advanced fibrosis. A1 AT had a sensitivity (SEN) of 83.8% and a specificity (SP) of 83.3% with the optimal cut-off of -1459.43, NE/A1 AT had a SEN of 88.8% and a SP of 83.3% with cut-off of 0.363 to predict NASH. An increased NE: A1 AT ratio is closely associated with liver Inflammation in patients with NASH and could serve as a novel marker to predict NASH in humans.

Non-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications

“…Levels of metalloproteinases, as well serum elastase are correlated to arterial stiffness [42]. Interestingly, the latter was increased in NAFLD [43]. Others speculate a potential role of TGF-b [44].…”

“…Increased cIMT [30] Elevated serum elastase [43] elevated TGF-β [44] Arterial stiffening [28] Endothelium Endothelial dysfunction [27,28] Increased levels of ADMA [50,52] lower levels of HMGB1 [53] Endothelium disruption and repair [55] Reduced circulation EPCs [55] Redox status FGF21 ↑/FGF-resistance [124,125] CAD and NAFLD positively associated with FGF21 [126] SeP ↑ [127] Correlated with hsCRP and arterial stiffness [127] or cIMT [128] ANGPTL's ↑ [135] Associated with subclinical CVD [132][133][134] Paracrine cell signaling…”

Increasing Neutrophil Elastase and Decreasing Its Inhibitor, Alpha 1-Antitrypsin, in Patients with Non-Alcoholic Fatty Liver Disease

“…The systemic administration of AAT has shown to be a promising therapy for the treatment of acute liver failure (21). Similarly, the protective effects of A1AT in the prevention of atherosclerosis and aortic stiffness while maintaining elastic tissue have been attenuated in the common variants of A1AT (10,22,23).…”

“…The infiltration of neutrophils into the liver could predict fibrosis in patients with NAFLD, which is one of the impor-tant histological aspects of NASH (3,9). A high plasma neutrophil elastase concentration has been documented in patients with NAFLD (10). A significant increase in the elastase-mediated insulin resistance has been reported in overweight individuals (3).…”

Mice Deficient in the IL-1β Activation Genes Prtn3, Elane, and Casp1 Are Protected Against the Development of Obesity-Induced NAFLD

“…Consistent with these results, Zang and collaborators have shown an imbalance between NE and AAT serum concentrations in individuals with biopsy-diagnosed NAFLD when compared with healthy individuals. They calculated rather good sensitivity and specificity scores for the NE/AAT ratio in order to predict the advanced stages of the disease [17]. Our group has recently shown that, additionally to NE, also PR3 plays an important role in the development of obesity-induced NAFLD and insulin resistance in a mouse model for obesity-induced NAFLD [18].…”