Increased cytokine levels induced by high phenylalanine concentrations in late diagnosis PKU patients compared to early diagnosis: Anti‐inflammatory effect of L‐carnitine

Abstract

Phenylketonuria (PKU) was the first genetic disease to have an effective therapy, which consists of phenylalanine intake restriction. However, there are patients who do not adhere to treatment and/or are not submitted to neonatal screening. PKU patients present L‐carnitine (L‐car) deficiency, compound that has demonstrated an antioxidant and anti‐inflammatory role in metabolic diseases. This study evaluated the effect caused by exposure time to high Phe levels in PKU patients at early and late diagnosis, through pro‐ and anti‐inflammatory cytokines, as well as the L‐car effect in patients under treatment. It was observed that there was a decrease in phenylalanine levels in treated patients compared to patients at diagnosis, and an increase in L‐car levels in the patients under treatment. Inverse correlation between Phe versus L‐car and nitrate plus nitrite versus L‐car in PKU patients was also showed. We found increased proinflammatory cytokines levels: interleukin (IL)‐1β, interferons (IFN)‐gamma, IL‐2, tumor necrosis factor (TNF)‐alpha, IL‐8 and IL‐6 in the patients at late diagnosis compared to controls, and IL‐8 in the patients at early diagnosis and treatment compared to controls. Increased IL‐2, TNF‐alpha, IL‐6 levels in the patients at late diagnosis compared to early diagnosis were shown, and reduced IL‐6 levels in the treated patients compared to patients at late diagnosis. Moreover, it verified a negative correlation between IFN‐gamma and L‐car in treated patients. Otherwise, it was observed that there were increased IL‐4 levels in the patients at late diagnosis compared to early diagnosis, and reduction in treated patients compared to late diagnosed patients. In urine, there was an increase in 8‐isoprostane levels in the patients at diagnosis compared to controls and a decrease in oxidized guanine species in the treated patients compared to the diagnosed patients. Our results demonstrate for the first time in literature that time exposure to high Phe concentrations generates a proinflammatory status, especially in PKU patients with late diagnosis. A pro‐oxidant status was verified in not treated PKU patients. Our results demonstrate the importance of early diagnosis and prompt start of treatment, in addition to the importance of L‐car supplementation, which can improve cellular defense against inflammation and oxidative damage in PKU patients.