Uloga oksidativnog stresa pri fotokoagulaciji retine kod neproliferacijske dijabetičke retinopatije

Galetović, Davor (2008) Uloga oksidativnog stresa pri fotokoagulaciji retine kod neproliferacijske dijabetičke retinopatije. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Diabetes mellitus (DM) is a complex multifactorial disease, often accompanied by progressive retinopathy and vision loss. With the development of social conditions and improvement of the living standard DM has become the main growing health problem in Europe, a problem of all ages in all countries that puts in danger at least ten milion European citizens. Diabetic retinopathy (DR), as one of the worst DM complications, is leading cause of blindness in fit for work adults of the developed western world. Applying retinal laser photocoagulation (LP) it is posible to prevent blindness, which has been proved, beyond doubt, by several multicentered randomized studies. A favourable impact of retinal lp in dm has been known for approximately 30 years. However, along with this favourable impact, retinal LP involves a number of side-effects complications. One of the most significant of them is development, or deterioration of the existing macular oedema, leading to temporary or permanent impairment of visual acuity. The role of the oxidant stress in the mementioned complications is quite certain. This study aims at determining the state of antioxidant defense in diabetic patients, as well as assesing the oxidant stress role in the macular oedema development after "scatter" LP. This prospective clinical study ivolves 90 subjects dividet into three groups: - 7 male and 23 female healthy subjects aged between 40 and 60 ( control group C1), - 15 men and 15 women suffering from DM type 1 and type 2, aged bettween 40 and 60, with no DR clinical symptoms, having HbA1c to 8% (control group C2), - 16 men and 14 women suffering from typ1 15 (50%) and type 2 15 (50%), with average DM duration of 12,7±2,05 years, aged between 40 and 60. All subjcts had clinical picture of severe nonproliferative diabetic retinopathy (NPDR), and are scheduled for "scatter" LP. "Full-scatter" retinal LP was applied with the number of burns N= 600-700, using 200-500μm size, with the power of 200-300 mW for 0,2 second duration. Widw-angle Mainster's WF panfundoscope was used. Visual acuity was tested just prior to, one day after, 7 days after and 30 days after retinal LP, using international tables at 5m. Optic fundus examination in mydriasis was carried out by Wide-angle Mainster's panfundoscope: just prior to, one day after, 7 days after and 30 days after retinal LP. Fluorescein angiography was applide, when needed, as supporting diagnostic test. Intraocular pressure (IOP) was taken prior to and one day after retinal LP using the applanation method. Venous blood was taken from the subjects suffering from DM with DR treated by LP, just before and 2 hours after standard LP. Venous blood was taken from subjects belonging to the control groups C1 and C2. The following antioxidans from plasma samples and erythrocyte lisate samples were tested: superoxide dismutase (SOD), glutation peroxidase (GPOD), total antioxidant status (TAS), catalase, transferrin, ceruloplasmin, hemopexin and haptoglobin. After applying the "scatter" retinal LP, 13 or 43,3% of the subjects either developed macular oedema or suffered from deterioration of the existing macular oedema; the differnce is significant (χ2=21,8; p=0,001). Immediately one day after LP tretment the mean value of the subjects' visula acuity worsened (0,40), as compared to the visual acuity prior to LP (0,47), the diferenc being significant (p=0,001). Seven days after LP the subjects' visual acuity mean value is firter worsened (0,41) as compared to the visual acuity prior to LP, with significant diference (p=0,002), that represents a direct consequence of a developed, or deterioration of the existing macular oedema. 30 days after LP there is a slight improvement of the subjects' visual acuity mean value (0,48), as compared to the visual acuity prior to LP, the difference not being significant (p>0,448). IOP mean values prior to and after LP show substantial differences (p=0,003) but not exceeding the limits. Concentrations of the tested antioxidans from plasma samples and erythrocytes lisate samples are significantly lowered in C2 subjects as compared to C1 subjects: SOD (p<0,001), GPOD (p=0,030), TAS (p<0,001), catalase (p=0,001), transferrin (p<0,001), ceruloplasmin (p<0.001), hemopexin (p=0,003), haptoglobin (p=0,173). Values in subjects with DR are also significantly lowered as compared to C1 subjects: SOD (p<0,001), GPOD (p=0,001), TAS (p<0,001), catalase (p<0,001), transferrin (p<0,001), ceruloplasmin (p<0,001), hempexin (p=0,002), haptoglobin (p=0,019). Values in subjects with DR were no significantly lowered when compared to C2 subjects. The difference in antioxidant values from plasma samples and erthrocyte lisate samples in subjects with severe DR was tested prior and after the "scatter" LP. Values of all tested antioxidants were lowered after LP in: ceruloplasmin (p=0.458), hemopexin (p=0.075) and haptoglobin (p=0470), and were significantly lowered in SOD (p=0,001), GPOD (p=0,001), TAS (p=0,001), catalase (p=0,001) and transferrin (p=0,001). Antioxidants values in C2 subjects, as well ac in diabetic patients with DR as a complication, were significantly lowered as compared to C1 subjects, indicating weakened antioxidant defence in patients with DM. Values in diabetic patients with DR as a complication, were not significantly lowered as compared to C2 subjects. Macular oedema represents a significant complication of "scatter" LP. Subjects' mean visual acuity on the first and seventh day after LP were significantly lowered as compared to the visula acuity prior to LP, as a direst result of aa developed, or deterioration of the existing macular oedema, with a slight improvement after 30 days. Antioxidant values in diabetic patients with DR were significantly lowered after "scatter" LP, as a direct consequence of the retinal oxidant stress caused by thermal treatment. Oxidant stress caused by produstion of free radicals (FR) and reactive oxidant species (ROS), most often by lipd peroxidation, directly or idirectly damages microvascular endote. Endotel damages necessarily lad to increased vascular permeability, finally resulting in macular oedema development. Assessing antioxidant reserves of the patient scheduled for "scatter" LP, it is possible to predict LP tretment inefficiency or risk factor, regarding macular oedema developments as a complication, possible therapeutic intervention with simple and safe antioxidants, such as vitamins C and E, would enable these susceptible patients to undergo to scheduled laser photocoagulation more effectively, simultaneosly suggested manifold LF procedure to these susceptible patients, but with less numbers of spots and decrease of power.

Abstract in Croatian

Dijabetes melitus (DM) je kompleksna multifaktorijelna bolest, često udružena s progresivnom retinopatijom i gubitkom vida. Razvojem društvenih uvjeta i poboljšanjem životnog standarda DM postaje glavni rastući zdravstveni problem u Europi, problem svih dobi u svim državama, a ugrožava najmanje deset milijuna stanovnika Europe. Dijabetička retinopatija (DR), kao jedna od najtežih komplikacija DM, vodeći je uzrok sljepoće kod odraslih, radno sposobnih ljudi razvijenog zapadnog svijeta. Laserskom fotokoagulacijom (LF) retine moguće je spriječiti sljepoću, što nedvojbeno potvrđuje nekoliko velikih, multicentričnih randomiziranih studija. Povoljan efekt LF retine kod DR poznat je približno 30 godina. Međutim, uz povoljan efekt, LF retine uključuje i mnoge popratne komplikacije. Jedna od najznačajnijih je nastanak ili pogoršanje postojećeg edema makule, što dovodi do prolaznog ili trajnog oštećenja vidne oštrine. Uloga oksidativnog stresa u navedenim zbivanjima je vrlo izvjesna, a cilj ove studije je utvrđivanje stanja antioksidativne obrane dijabetičkih bolesnika i ocjena uloge oksidativnog stresa u nastajanju edema makule nakon "rastresite" (engl. scatter) LF. U ovu prospektivnu kliničku studiju uključeno je 90 ispitanika. Ispitanici su podijeljeni u tri skupine: - 7 muških i 23 ženska zdrava ispitanika, u dobi od 40-60 godina ( kontolna skupina K1); - 15 muškaraca i 15 žena oboljelih od tip 1 i tip 2 DM, u dobi od 40-60 godina, bez kliničkih znakova DR, s vrijednostima HbA1c do 8% ( kontrolna skupina K2). - 16 muškaraca i 14 žena, oboljelih od tip 1 15 (50%) i tip 2 15(50%) DM, s prosječnim trajanjem DM od 12,7±2,05 godina, u dobi od 40-60 godina. Svi ispitanici imali su kliničku sliku teške neproliferativne dijabetičke retinopatije (NPDR), i predviđeni su za "rastresitu" LF. Provedena je "puna-rastresita" (engl. full-scatter) LF retine, s brojem pečata N=600-700, veličine 200-500 μm, snage 200-300 mW, s ekspozicijom od 0.20 sec. U radu se koristio širokokutni Mainsterov WF panfundoskop. Oštrina vida se ispitivala neposredno prije, 1 dan poslije, 7 dana poslije i 30 dana poslije LF retine internacionalnim tablicama na 5 m. Pregled fundusa u midrijazi uradio se širokokutnim Mainsterovim WF panfundoskopom: neposredno prije, 1 dan poslije, 7 dana poslije i 30 dana poslije LF retine. Fluoresceinska angiografija (FA) se koristila po potrebi kao pomoćna dijagnostička pretraga. Intraokularni tlak (IOT) se mjerio prije i 1 dan poslije LF retine metodom aplanacije. Ispitanicima oboljelima od DM s DR tretiranih LF, venozna se krv vadila neposredno prije i 2 sata poslije standardne LF. Kontrolnim skupinama K1 i K2 venozna se krv vadila jednokratno. U uzorcima plazma i lizata eritrocita ispitivali su se sljedeći antioksidansi: superoksid dismutaza (SOD), glutation peroksidaza (GPOD), totalni antioksidatvni status (TAS), katalaza, transferin, ceruloplazmin, hemopeksin i haptoglobin. Nakon izvršene "rastresite" LF retine, kod 13 ili 43,3% ispitanika došlo je do pojave ili pogoršanja već postojećeg edema makule, razlika je značajna (χ2=21,8 ; p=0.001). Neposredno 1 dan nakon tretmana LF, srednja vrijednost vidne oštrine ispitanika je pogoršana ( 0,40) u odnosu na vidnu oštrinu prije LF (0.47), a razlika je značajna (p=0.001). Srednja vrijednost vidne oštrine ispitanika 7 dana nakon LF i dalje je pogoršana (0.41) u odnosu na vidnu oštrinu prije LF, sa značajnom razlikom (p=0,002), što predstavlja izravnu posljedicu nastalog ili pogoršanja postojećeg EM. Nakon 30 dana dolazi do poboljšanja srednje vrijednosti vidne oštrine ispitanika (0,48) u odnosu na vidnu oštrinu prije LF, ali razlika nije značajna (p>0.448). Srednje vrijednosti IOT prije i nakon LF pokazuju značajne razlike (p=0,003), ali unutar gornje granice normale. Koncentracije ispitivanih antioksidansa u lizatu eritrocita i plazmi značajno su snižene kod ispitanika K2, u odnosu na ispitanike K1: SOD (p<0,001), GPOD (p=0,030), TAS (p<0,001), katalaza (p=0,001), transferin (p<0,001), ceruloplazmin (p<0,001), hemopeksin (p=0,003), haptoglobin (p=0,173), a također su značajno snižene i vrijednosti ispitanika s DR u odnosu na ispitanike K1: SOD (p<0.001), GPOD (p=0,005), TAS (p<0,001), katalaza (p<0,001), transferin (p<0,001), ceruloplazmin (p<0,001), hemopeksin (p=0,002), haptoglobin (p=0,191). Vrijednosti ispitanika s DR nisu bile značajno snižene u odnosu na ispitanike K2. Ispitivana je razlika vrijednosti antioksidansa u lizatu eritrocita i plazmi kod ispitanika s teškom DR prije i nakon "rastresite" LF. Vrijednosti ispitivanih antioksidansa bile su snižene nakon LF: ceruloplazmin (p=0.458), haptoglobin (p=0.470) i hemopeksin (p=0.075), a značajno smanjenje bile su vrijednosti SOD (p=0,001), GPOD (p=0,001), TAS (p=0,001), katalaza (p=0,001), transferin (p=0,001),. Vrijednosti antioksidansa ispitanika K2, kao i dijabetičkih bolesnika s DR kao komplikcijom, značajno su snižene u odnosu na ispitanike K1, što govori za oslabljenu antioksidativnu obranu bolesnika s DM. Vrijednosti kod dijabetičkih bolesnika s DR kao komplikacijom, nisu značajno snižene u odnosu na ispitanike K2. Edem makule predstavlja značajnu komplikaciju "rastresite" LF. Srednja vidna oštrina ispitanika 1. i 7. dan nakon LF značajno je snižena u odnosu na vidnu oštrinu prije LF, kao izravni rezultat pojave ili pogoršanja postojećeg edema makule, da bi se nakon 30 dana neznatno poboljšala. Vrijednosti antioksidansa dijabetičkih bolesnika s DR značajno su sniženi nakon "rastresite" LF, kao izravna posljedica oksidativnog stresa retine izazvanog termičkim djelovanjem LF. Oksidativni stres potaknut stvaranjem SR i RKS, najčešće putem lipidne peroksidacije, izravno ili neizravno oštećuje mikrožilni endotel. Oštećenja endotela nužno vode povećanoj vaskularnoj propustljivosti, koja se u konačnici manifestira kao edem makule. Procjenom antioksidativne rezerve bolesnika predviđenih za "rastresite" LF moglo bi se predvidjeti neučinkovitost ili rizičnost LF tretmana u smislu pojave edema makule kao komplikacije. Mogućom terapeutskom intervencijom jednostavnim i sigurnim antioksidansima, kao što su vitamini C i E, omogućili bi tako osjetljivim bolesnicima da djelotvornije podnesu planiranu laser fotokoagulaciju, ujedno sugerirajući da se kod takvih bolesnika primjeni višekratni LF tretman, ali sa manjim brojem spotova, i smanjenog intenziteta.

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