VALUTAZIONE DELL ’ATTIVITÀ DELLA PARAOXONASI -1 (PON -1) E SUA ASSOCIAZIONE CON I PRODOTTI FINALI DELLA GLICAZIONE AVANZATA (AGES) COME MARCATORI DI STRESS OSSIDATIVO NEI PAZIENTI CON TIROIDITE DI HASHIMOTO

Objective. Advanced glycation end products (AGEs), compounds derived from non-enzymatic transformation of macromolecules, are able to increase oxidative stress and promote inflammation and are deemed to play a role in the pathogenesis of several diseases related to oxidative stress, including cardiovascular and metabolic disorders (coronary artery disease, atherosclerosis, obesity insulin resistance and hypercholesterolemia). In the same diseases, the activity of paraoxonase-1 (PON-1), an anti-oxidant enzyme protecting against the oxidation of LDL and cell membranes, is decreased and it often negatively correlates with serum levels of AGEs. Recently, increased levels of AGEs, as a specific marker of oxidative stress, have been reported in adult individuals suffering from Hashimoto’s thyroiditis (Ruggeri et al. Thyroid 2016). No data are available on the relationship and potential clinical relevance of such oxidative stress parameters (AGEs and PON-1 activity) in HT patients. Materials and Methods. We enrolled 38 HT patients (females aged ) and 38 age- and sex-matched healthy controls. None was on LT-4 therapy. Exclusion criteria: autoimmune, inflammatory and infection comorbidities. Patients did not differ significantly from controls with regard to lipid and glucidic profile neither for anthropometric parameters. Serum levels of AGEs and PON-1 acivity were simultaneously assayed in sera from each subject. For AGE determination, fluorescence intensity of diluted serum was recorded at emission maximum (∼440 nm) upon excitation at 350 nm; results were expressed in arbitrary units per gram of protein (AU/g protein). Serum PON-1 activity was quantified by UV spectrophotometry. The method is based on the conversion of the substrate paraoxon to p-nitrophenol by the serum PON-1. The increase in absorbance of the resulting p-nitrophenol was measured spectrophotometrically at a wavelength of 412 nm, PON1 activity was expressed in U/l; 1 unit is equivalent to 1 mmol/min of p-nitrophenol. Results. Serum AGEs were significantly higher in HT patients (mean value 401 + 90 AU/g protein; median 378) compared to controls (295 + 60 AU/g protein; median 290 AU/g protein; P<0.001), while PON-1 activity was significantly lower in HT subjects (mean value 198 + 98 U/L; median 174 U/L) than in controls (mean value 256 + 131 U/L, median 192 U/L; P<0.05), clearly indicating an imbalance between endogenous production of oxidants and antioxidant defense systems in HT patients. PON-1 activity was inversely correlated to AGEs levels (P<0.01) irrespective of TSH values and thyroid functional status (all subjects being euthyroid). However, in age- and sex-adjusted analysis, PON-1 activity was inversely related to free thyroxine levels, even within normal range (P<0.05). In regression models age and HDL cholesterol were independent predictors for PON-1 activity, and LDL cholesterol for AGEs levels (P<0.05). Conclusion. Serum AGEs are increased and PON-1 activity reduced in euthyroid HT patients and the two parameters are inversely correlated, indicating redox homoeostasis dysregulation, irrespective of any functional alteration. Serum PON‐1 activity is inversely associated with free T4 in euthyroid subjects, suggesting that low‐normal thyroid function may affect PON‐1 regulation. This may contribute to atherosclerosis susceptibility since PON-1 may protect against atherosclerotic disease development by attenuating oxidative stress.