Tissue advanced glycation endproducts in two populations associated with increased oxidative stress: Normal in cirrhosis but elevated in haemodialysis patients

Abstract

Introduction: Advanced glycation endproducts (AGE) result from non-enzymatic glycation between reducing sugars and proteins and are a measure of cumulative metabolic stress. Tissue and serum AGE are known to predict cardiovascular mortality in end stage renal disease. Serum AGE levels are elevated in euglycaemic cirrhotics and correlate with disease severity yet cirrhosis appears to be protective against coronary atherosclerosis. Tissue AGE has not been assessed in cirrhosis. Aims and Methods: We aimed to assess tissue AGE in two populations with increased oxidative stress: cirrhosis and haemodialysis (HD) and determine whether skin AF is a non-invasive marker of liver disease severity. We studied 56 patients (28 cirrhotics, 28 age and sex matched HD patients) and compared with a normal control database (NC). Tissue AGE was measured using UV autofluorescence (AF) (AGE Reader, DiagnOptics, The Netherlands). Three sequential readings were taken from the palmar aspect of the forearm, approximately 10 cm below the elbow, avoiding pigmentation or vascular structures. History of diabetes mellitus (DM) and ischaemic heart disease (IHD) was noted and Child–Pugh (CP) and Model for End Stage Liver Disease (MELD) scores calculated. Results: Mean age 56±15 years, 64% male. 71% alcoholic cirrhosis, median CP score 8, MELD 12. DM and IHD prevalence was similar in both groups; no cirrhotic patient had renal impairment. Compared with NC, mean AF was significantly higher in both HD (3.264 vs 2.218, CI 0.691 to 1.402, p = <0.0001) and cirrhosis (2.632 vs 2.218, CI 0.082 to 0.746, p = 0.016). When cirrhotic patients with DM and IHD were excluded, this became insignificant (2.352 vs 2.157, CI to 0.116 to 0.506, p = 0.209). Mean AF was significantly higher in HD compared with cirrhosis (3.264 vs 2.632, CI 0.180 to 1.084, p = 0.007). Conclusion: Despite high levels of cumulative metabolic stress in both HD and cirrhosis, tissue AGE is only increased in HD. Both conditions are associated with elevated serum AGE levels but the mechanism underlying the differential tissue deposition is unknown. One hypothesis that may explain the reduced cardiovascular risk in cirrhosis is that soluble RAGE acts as a decoy receptor preventing AGE-RAGE interaction and the resulting endothelial dysfunction. Skin AF measurement is unhelpful as a non-invasive tool to detect cirrhosis.