Systemic factors associated with Glaucoma 가톨릭 대학교 인천성모병원 이 나 영

녹내장은 어떻게 발생하는가? 정의 : Not a single disease process, but a large group of disorders : A characteristic optic neuropathy, which derives from various risk factors including increased IOP

시신경 유두함몰의 병인론 기계적 이론 (Mechanical theory) : 높은 안압에 의해 사상판이 뒤로 밀리면서 사상판 열공의 뒤틀림이 오고 이로 인해 axoplasmic flow 가 차단되어 시신경이 손상을 받는다. (2) 허혈성 이론 (Ischemic theory) : 정상안압 또는 높은 안압에서 perfusion pressure가 감소하여 시신경 유두에 허혈이 초래되고 결과적으로 축삭이 손상받는다.

안 압 우리가 할 수 있는 치료 : IOP is critical to our understanding of glaucoma, not only because they are the most common and best understood of the causative risk factors for glaucoma, but alse because they are presently the only factors that can be controlled to prevent progressive optic neuropathy.

안 압 왜 안압이 높은 많은 수의 사람들이 녹내장성 시신경변화를 보이지 않을까? 왜 안압이 높은 많은 수의 사람들이 녹내장성 시신경변화를 보이지 않을까? 정상안압에서 녹내장성 시신경변화가 생기는 이유가 무엇일까? 안압을 낮추어도 모든 환자의 녹내장이 진행을 멈추지 않는 이유는 무엇일까?

안압 이외의 연구들 안압 이외의 인자를 찾아서… 전신질환 및 전신인자

Systemic risk factors Diabetes mellitus : The prevalence of COAG higher in majority of population-based surveys vs no association in others (∵ selection bias, limitations) : The association of DM and glaucoma persisted after adjustment for IOP (The blue mountains eye study) : IOP is important confounder between DM and glaucoma, appear to have a slightly higher IOP : Not yet been shown to increase the incidence of glaucoma, : Probably a risk factor, however, not been a consistent finding

Systemic risk factors Blood pressure : The most meaningful BP -> Diastolic perfusion pressure (brachial sitting blood pressure-IOP) fell below 55 mmHg -> an important risk factor for glaucoma (RR of 3.2) : Between systolic BP or diastolic BP and glaucoma -> confusing, contradictory literature : IOP is associated with systolic BP and diastolic BP (but no clinical significance) : Episodic decreases in BP, particularly in NTG : Role of routine measurement of BP has not been established

Systemic risk factors Migraine : Significant association between a history of typical migraine head aches and NTG but not COAG with elevated IOP : CNTGS -> increased the risk of progression by 2.6 : Migraine/vasospasm -> evidence linking NTG, not for all COAG in the general population

Systemic risk factors Other systemic risk factors (1) Thyroid hormone : Hypothyroidism-> 녹내장환자에서 많음, 치료후 outflow 증가, 안압감소한다 vs 관련없다. : Graves disease-> 고안압증, 녹내장많음, episcleral venous pressure 증가에 의함. (2) Endocrine disorders-> IOP 상승으로 인한 녹내장 : Elevated IOP ->Cushing syndrome, testosterone. : Decreased IOP -> progesterone, estrogen. (3) Sleep apnea -> COAG and NTG 에서 high prevalence (4) Infectious and autoimmune risk factors (5) Elevated cholecterol or HDL, obesity : not appear to be associated with COAG

연구 개요 Surv Ophthalmol 52, 2007

NO in glaucoma -An important mediator of the homeostatic functions of the eye : Regulating aqueous humor dynamics, modulating local ocular blood flow, and controlling retinal ganglion cell death by apoptosis. -In POAG : Decreased aqueous humor and plasma NO levels : Higher NO levels in patients with glaucoma -In PXA and PXG : Lower aqueous humor NO levels : Increased aqueous humor NO levels, no difference plasma levels - confusing 12

VEGF in glaucoma -Stimulates growth of vascular endothelial cells and increases vascular permeability -VEGF is present in aqueous humor and vitreous -Increased concentration in the eye : proliferative diabetic retinopathy, neovascular glaucoma, PXG and POAG, RRD, uveitis, and AMD. -In PXA and PXG : Increased aqueous humor and plasma VEGF levels : The lack of correlation between VEGF and NO levels may indicate impaired downregulation. 13

ET-1 in glaucoma -Reduces optic nerve head blood flow -Impairs anterograde and retrograde axoplasmatic transport -Activates astrocytes 14

ET-1 plasma levels : determined by a specific radioimmunoassay

MCP-1 in glaucoma -Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that stimulates monocyte migration into the intima of arterial walls and organs. -Ischemia/reperfusion injury-stimulated MCP-1 gene expression may be responsible for enhanced monocyte infiltration and subsequent graft damage in kidney transplantation. -In glaucoma, the repeated I/R injury to the ONH might usually be and the resulting inflammatory response may remain clinically undetectable. 16

MMP-9 in glaucoma -Enzymes that digest extracellular matrix -MMP-2 and MMP-9 are upregulated in the astrocytes of the ONH of glaucoma patients and MMP-9 in produced by lymphocytes of glaucoma patients -Involved in tissue remodeling of the ONH and contributes to the change of the shape of the laminar cribrosa -In MMP-9 knock-out mice, the retinal ganglion cells do not die by apoptosis 18

Minerva Ofralmo 2002;44:79-89. 6명의 환자군과 대조군에서 leukocytes 내의 MMP-9과 MMP-14 gene의 upregulation을 RT-PCR과 Western-blot analysis를 이용하여 확인함.

MMP-2에 비해 TIMP-2가 증가한 결과로 degradation 보다는 ECM의 accumulation이 POAG와 PXG에서의 pathogenesis 와 관련됨.

Expression imbalance between MMPs and their endogenous tissue inhibitors in tissue samples from patients with POAG and ExG.

ET-1 and MMP, TIMP In human optic nerve head astrocytes, ET-1 increased the expression and activity of MMP-2 and TIMP-1 and -2. ET-1’s effects on MMPs/TIMPs may be important, not only in regulating the expression of MMPs and TIMPs, but also in influencing ECM remodeling.

NO and MMP MMP-9 is activated on RGCs after exposure to NMDA and glycine. The inhibitor studies coupled with in situ localization suggest that MMP-9contributes to NMDA-induced RGC death after NO generated from nNOS activates the MMP via S-nitrosylation.

이외의 factors ? VEGF ? TIMP ? ? ? Surv Ophthalmol 52, 2007

혈액점도와 안과질환 Retinal venous occlusive disease is due to an increased blood viscosity. Bilateral central retinal vein occlusion Intraretinal hemorrhages, cotton wool spots, and macular edema 60-yr-old women Secondary to Eisenmenger syndrome Hct = 56-62% Increased blood viscosity. Visual acuity: 20/100 Subsequent phlebotomy reduced Hct to 38% Visual stabilized Rodriguez and Eliott, AJO 2001;132: 268-9. 25

Mechanism of Retinal hemorrhages 전단응력에 의한 Autoregulatory vasodilation mechanism . 혈액점도 증가할 때 전단응력증가 소동맥 혈관확장 Retinal hemorrhages Flow direction Normal blood pressure Elevated BP; More gradual BP decrease with autoregulatory vasodilation with HVS Menke et al., Arch Ophthalmol 2006;124:1601-6 26

녹내장과 시신경 유두의 출혈 시신경 유두 출혈 : 만성 개방각녹내장군이나 녹내장 의증 환자에 비하여 정상안압녹내장군에서 빈번하게 발견. : 시야손상의 진행과도 연관되어 있어 중요한 임상적 의의. 27

연구 방법 연구대상 : 개방각 녹내장으로 확진된 80명의 환자군 혈액검사 : 혈색소, 헤마토크리트, 적혈구 수, 백혈구 수, 혈소판 수, 공복시 혈당, 당화 헤모글로빈, 총 콜레스테롤, 트리글리세리드, 저밀도와 고밀도 지단백 콜레스테롤, hs CRP, ET-1, MMP-9, MCP-1 등 Blood viscosity 측정 28

혈액의 점도 측정 Scanning capillary 점도계 광범한 전단율(1 - 300 s-1)에서 3분안에 혈액점도측정 완료 일회용 측정튜브 작동자에게 감염위험 최소화 함 Glass capillary viscometer – KFDA Class I m = 혈액의 점도 29

아직은 녹내장은 여러가지 복합적인 원인에 기인 대부분의 녹내장 환자에서 한가지로 원인을 단정하기 어려움 소금농도재기 하지만 우리가 조절할 수 있는 부분을 더 찾아야 하지 않을까 The most important 는 아니어도 고령화를 고려하면 충분한 가치가 있는 연구들

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