Glukokortikoidna senzitivnost, funkcionalni polimorfizmi gena za gltokortikoidni receptor i ekspresija glukokortikoidnog receptora u tumorskom tkivu kod pacijenata sa slučajno otkrivenim tumorima kore nadbubrežne žlezde

Abstract

Uvod: Adrenalni incidentalomi su tumori otkriveni različitim vizualizacionim metodama učinjenim bez sumnje na adrenalnu patologiju. Većina ovih tumora su nefunkcijski adrenokortikalni adenomi. Izvestan broj AI se prezentuje subkliničkim hiperkorticizmom (SH), stanjem biohemijskog kortizolskog ekscesa, u odsustvu klasičnih znakova i simptoma hiperkorticizma. Prevalencija SH kod pacijenata sa AI se procenjuje između 5 i 24%. Polimorfizam gena za glukokortikoidni receptor (GR) menja glukokortikoidnu (GC) senzitivnost, što dovodi do promena u metaboličkom profilu. Cilj studije: je bio da se ispita prevalenca subkliničkog hiperkorticizma (SH) i pridruženih bolesti kod pacijenata sa unilateralnim (UAI) i bilateralnim AI (BAI). Ispitivali smo učestalost četiri polimorfizma gena za GR (BclI, ER22/23EK, N363S i 9β) i predispoziciju za nastanak AI. Analizirali smo ekspresiju GR u tumorskom, peritumorskom i normalnom adrenalnom tkivu. Materijal i metode: Ispitivanje je obuhvatilo 152 pacijenta, 105 (69.1%) sa UAI i 47 (30.9%) sa BAI. SH je definisan na osnovu serumskog kortizola >50nmol/L nakon prekonoćnog deksametazon supresivnog testa (DST) sa 1mg ili nakon dvodnevnog niskodoznog DST (LDDST) sa 2mg deksametazona, uz još jedan navedeni parametar (ponoćni serumski kortizol >208nmol/L, 24-h urinarni slobodni kortizol >245nmol/L ili ACTH<10ng/L). Telesni sastav i koštana gustina su mereni dual-energy X-ray absorptiometry metodom na nivou lumbalnog dela kičme, vrata femura i celog skeleta. DNK je dobijena iz leukocita periferne krvi. Prisustvo polimorfizama je detektovano metodama PCR, RFLP i sekvenciranjem DNK. Uzorci tkiva su analizirani Western blot metodom. Rezultati: Pacijenti sa BAI se nisu razlikovali u odnosu na pacijente sa UAI po starosti, BMI, obimu struka, učestalosti dijabetesa, hipertenzije i dislipidemije. Prevalencija SH u celoj grupi iznosila je 20.5% (prekonoćni DST), odnosno 20.0% (LDDST) i bila je značajno veća kod pacijenata sa BAI u odnosu na pacijente sa UAI (31.1% vs 15.2%, p=0.026). Nezavisni prediktor SH je bila veličina adrenalnog adenoma (odds ratio [OR]=1.055, 95% confidence interval [CI] 1.017-1.094, p=0.004), nakon korekcije za godine, obim struka, indeks telesne mase i prisustvo BAI. Kostna gustina na nivou kičme je bila značajno niža kod pacijenata sa BAI u odnosu na UAI (0.96±0.14 vs 0.87±0.15, p=0.002). Nije nađena razlika u kostnoj gustini na nivou vrata femura...

Background: Adrenal incidentalomas (AIs) are clinically silent adrenal masses that are detected incidentally during imaging procedures performed for unrelated diseases. The vast majority of these lesions are non-hypersecreting cortical adenoma. However, some of them present with subclinical hypercortisolism (SH), the condition of biochemical cortisol excess without the classical signs or symptoms of overt hypercortisolism. The prevalence of SH in patients with AIs varies between 5 and 24%. Glucocorticoid receptor (GR) polymorphisms alter glucocorticoid (GC) sensitivity and have been associated with altered metabolic profiles. Objective: The aim of this study was to investigate the prevalence of SH and associated co-morbidities in patients with unilateral AIs (UAIs) and bilateral AIs (BAIs). We also evaluated the prevalence of the four GR polymorphism genes (BclI, ER22/23EK, N363S and 9β) and investigated whether they influence susceptibility for AIs. We analyzed GR expression in tumorous, peritumorous and normal adrenocortical tissue samples. Material and Methods: We enrolled 152 patients, 105 (69.1%) with UAIs and 47 (30.9%) with BAIs. SH was diagnosed in the presence of serum cortisol levels after 1mg dexamethasone suppression test (DST) or after 2-day low-dose DST (LDDST) >50nmol/l with at least one of the following parameter (midnight serum cortisol >208nmol/L, 24-h urinary free cortisol >245nmol/24h, or ACTH <10ng/L). Body composition and bone mineral density (BMD) were measured with dual-energy X-ray absorptiometry at lumbar spine (LS), femoral neck (FN), and total skeleton. DNA was obtained from peripheral blood leucocytes. The polymorphisms were detected using PCR, RFLP and DNA sequencing. Tissue samples were studied by Western blot. Results: Age, body mass index (BMI), and waist circumference (WC) were comparable, and diabetes, hypertension and dyslipidemia occurred with a similar frequency in BAI and UAI patients. The overall prevalence of SH was 20.5% based on post-1mg DST, and 20.0% based on post-LDDST cortisol levels, and was more prevalent in BAIs than UAIs patients (31.1% vs 15.2%, respectively, p=0.026). Factor related to SH was adrenal mass size (odds ratio [OR]=1.055, 95% confidence interval [CI] 1.017-1.094, p=0.004), after adjustment for age, WC, BMI, and presence of BAIs. LS BMD was lower in BAI than in UAIs patients (0.96±0.14 vs 0.87±0.15, p=0.002). There were no differences in FN BMD...