Pathology

Age-Related Macular Degeneration

The choroidal vasculature is at the heart of age-related macular degeneration. There are many forms of AMD, but the two major types are exudative or wet and nonexudative or dry AMD. In nonexudative AMD eyes, there are macular drusen and sharply defined focal areas of RPE atrophy, which are associated with varying degrees of loss of the choriocapillaris. Drusen is a form of deposit on Bruch's membrane, which is believed to be incompletely digested material from the RPE that cannot traverse Bruch's membrane for removal by the choriocapillaris. One hypothesis states that the deposit of the debris on Bruch's membrane is a result of choriocapillaris insufficiency. Alternatively, debris may accumulate on Bruch's membrane and choriocapillaris atrophy results since it is not needed any more. Drusen appear as refractile structures when viewing the ocular fundus, and the ophthalmologist refers to them as hard drusen when they are sharply demarcated and highly refrac-tile. We have found that hard drusen are present almost always over intercapillary septa and not over choriocapil-laris lumens, suggesting that this material accumulates on Bruch's membrane where transport is least likely.

There is considerable controversy over the role of the choroidal vasculature in AMD. Our recent study on geographic atrophy, a form of dry AMD, demonstrated that the RPE cells degenerated first and then the choriocapillaris atrophied. Interestingly, even in areas with complete RPE atrophy, some choriocapillaris segments remained viable (alkaline phosphatase positive) but severely constricted [7].

Exudative AMD is characterized by fluid and hemorrhage beneath the RPE or sensory retina due to choroidal neovascularization (CNV). In exudative AMD, we have observed areas with choriocapillaris atrophy in advance of the growing choroidal neovascularization. Every example of CNV in our study had surviving RPE associated with it. It is tempting to speculate that choriocapillaris loss results in ischemic RPE, and the RPE cells in turn produce angiogenic factors such as vascular endothelial cell growth factor, which stimulated growth of CNV. CNV grows through Bruch's membrane and spreads under the retinal pigment epithelium in most cases (Figure 4).

Whether choriocapillaris is responsible in part for AMD and which forms it initiates remains to be determined. However, there can be no question that there is a dynamic symbiosis between choriocapillaris and RPE and this synergy is disrupted in AMD.

Systemic Diseases

Hypertension

Stenosis, focal narrowing, and occlusion of choroidal arteries accompanied by hypertrophy of smooth muscle cells, endothelial cell proliferation, and reduplication of basement membrane occurs frequently in benign hyperten-

Retinal Venous Reduplication

Figure 4 (A) Alkaline phosphatase incubated choroid from a diabetic subject. Choroidal neovascularization (CNV) is apparent (asterisk) adjacent to an area with severe choriocapillaris dropout (lack of viable, APase-positive capillary lumens). The yellow areas are drusen. (B) Section through the CNV formation in (A) shows that the new blood vessels (asterisk) are between a basal laminar deposit (arrow), which is characteristically positive for PAS, and Bruch's membrane (arrowhead). The origin of the new vessels appears to be choriocapillaris. (Blue APase reaction product, PAS, and hematoxylin stain.) (see color insert)

Figure 4 (A) Alkaline phosphatase incubated choroid from a diabetic subject. Choroidal neovascularization (CNV) is apparent (asterisk) adjacent to an area with severe choriocapillaris dropout (lack of viable, APase-positive capillary lumens). The yellow areas are drusen. (B) Section through the CNV formation in (A) shows that the new blood vessels (asterisk) are between a basal laminar deposit (arrow), which is characteristically positive for PAS, and Bruch's membrane (arrowhead). The origin of the new vessels appears to be choriocapillaris. (Blue APase reaction product, PAS, and hematoxylin stain.) (see color insert)

sion. These findings led to the assumption that arterial occlusion may precede rarefaction of the choriocapillaris. Long-standing hypertension leads to severe arteriosclerosis, with marked thickening and hyalinization of choroidal arterioles, irregular thickened basement membrane, and reduction in caliber of the lumen. In addition, necrosis and fibrinoid deposition occurs in the choroidal vessel wall. Based on morphologic study of vascular casts on spontaneously hypertensive rats, the early changes in the choroidal vasculature were a decrease in number of draining venules, especially in the peripapillary choroid. As the systolic blood pressure increased progressively, the choroidal vessels were often sparse and tortuous. Some of the venules showed localized aneurismal dilatation and irregular calibers. In long-term hypertension, severe tortuosity, caliber irregularity, and generalized narrowing of the choroidal arteries; considerably decreased number of the draining venules converging from all directions into the vortex veins; narrow ampullae of the vortex veins; and elongated and engorged choriocapillaris were the most extensive morphological changes in the choroid [8].

Diabetic Choroidopathy

In both hypertensive and diabetic choroids, we have observed intrachoroidal neovascularization lying deep in choroids near the interface with sclera. These structures, which we termed intrachoroidal microangiopathy or ICMA, were the only sites where we found microaneurysms in human choroids. They were present in 20 percent of the diabetic choroids we have analyzed.

Using the alkaline phosphatase flat-embedding technique, we have observed a fivefold greater loss in choroidal capillaries in diabetic subjects compared to older nondia-betic subjects. This capillary dropout is a hallmark of diabetic retinopathy but had never been quantified in diabetic choroid before [9]. The cause of the choriocapillaris loss may be related to neutrophil-initiated occlusions in chorio-capillaris. We documented a twofold greater number of PMNs in diabetic choriocapillaris, compared to normal subjects, and there was a significant increase in PMNs in areas of diabetic choroid with capillary loss as compared to normal-appearing areas of choriocapillaris. The retention of PMNs may be due to increased expression of both ICAM-1 and P-selectin in diabetic choroid. ICAM-1 is constitutively made in normal choriocapillaris, but levels were increased in diabetic choriocapillaris and immunoreactivity was also observed in other choroidal vessels. P-selectin, responsible for leukocyte rolling, was also observed in diabetic chorio-capillaris and platelet aggregates in choroid, whereas in normal subjects it was confined to postcapillary venules [10].

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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