Clinical background
A cataract is any opacification of the lens. Visually significant cataracts may be present at birth or may occur at any time thereafter, but incidence increases exponentially after 50 years of age. Age-related cataracts are responsible for nearly half of all blindness worldwide. As longevity increases, the impact of cataracts on society is expected to increase. At present, surgical removal of the lens opacity with implantation of an intraocular lens (IOL) is the standard of care throughout most of the world where cataract surgery is available. Although this is usually a safe and effective treatment, intraocular surgery is an expensive and technically challenging solution for such a widespread problem. Rare but serious surgical complications include intraocular infection and inflammation and swelling of the retina (cystoid macular edema). Secondary opacification of the lens tissue remaining after surgery may occur (secondary cataract or posterior capsular opacification), the frequency of which depends on the age of the patient, the experience of the surgeon, and the type of IOL. Secondary cataract is treated by laser-mediated disruption of the posterior capsule of the lens, a procedure that requires expensive equipment and may incite further complications. There is no recognized medical treatment for age-related cataracts. For these reasons, identifying interventions to prevent or delay lens opacities represents an exceptional opportunity to reduce morbidity, increase productivity, and reduce health care costs.
The lens comprises an anterior layer of epithelial cells covering a mass of elongated fiber cells ( Figure 30.1 ). Fiber cells are responsible for the transparency and refractive properties of the lens. The entire lens is surrounded by a thick, acellular capsule that provides structural support to the lens cells and a site of attachment for the zonular fibers that anchor the lens to the ciliary body. The lens grows linearly throughout life by the proliferation of epithelial cells near the equator and the differentiation of their progeny into fiber cells. Fiber cells are laid down in concentric shells over pre-existing layers of fiber cells ( Figure 30.1 ). As part of their differentiation, fiber cells degrade their nuclei, mitochondria, and other membrane-bound organelles, preventing the synthesis of new proteins. Enzyme systems in mature fiber cells soon become nonfunctional. To maintain homeostasis (and transparency), most fiber cells depend on the metabolic activities of the epithelium and a thin layer of metabolically competent superficial fiber cells.
This chapter outlines the major risk factors for age-related cataract, identifies areas where more knowledge is needed, and highlights promising opportunities for prevention. The information provided is not meant as a complete review of the biochemical mechanisms that may contribute to cataract formation, which would be a much larger undertaking. Instead, it explores the results of epidemiologic studies, biochemical and biophysical analyses of human lenses, and selected animal studies, to suggest the likely causes and potential treatment of clinically significant cataracts in humans.
Pathology
“Age-related cataract” encompasses at least three distinct diseases ( Box 30.1 ). Although each involves opacification of lens fiber cells, these opacities occur in different regions of the lens, have different risk factors, and involve different pathologic mechanisms. Interventions to delay or prevent age-related cataracts must take into account these different pathologies. The three types are nuclear, cortical, and posterior subcapsular cataracts.
The three types of age-related cataract (cortical, nuclear, posterior subcapsular) occur in different regions of the lens, cause opacity by different mechanisms, and have different environmental, societal, and genetic risk factors. Studies that consider “cataract” as a single entity are likely to miss important relationships
In most western populations, nuclear cataracts are the commonest reason for cataract surgery. Opacities occur in the central region of the lens, the lens nucleus, in fiber cells that were produced before birth ( Figure 30.2 ). Opacification of the nucleus is associated with increased light scattering, caused by the aggregation or condensation of lens proteins, and increased coloration. Nuclear cataracts are associated with relatively minor effects on cell structure. In some populations, nuclear color may be responsible for most of the opacity, resulting in “brunescent” nuclear cataracts.
Cortical cataracts are the commonest reason for cataract surgery in many Asian populations and are frequently seen in western countries. They begin in the outer third of the lens, in cells that were generated postnatally. Cortical opacities are associated with gross disruption of the structure of fiber cells, local proteolysis, and protein precipitation. Opacities usually begin in small foci near the lens equator, then spread along the length of the fiber cells toward the optic axis and circumferentially to adjacent fiber cells ( Figures 30.1 and 30.2 ). Cortical cataracts may progress for years before they impinge on the optic axis and become visually significant.
Posterior subcapsular cataracts typically account for less than 10% of age-related cataracts. They arise from epithelial cells that fail to differentiate properly into fiber cells. These cells migrate or are carried by their neighbors to the posterior pole of the lens, where they swell and form a plaque that scatters light ( Figure 30.2 ). Because these plaques are in the optic axis, they significantly degrade vision, even when quite small.
Etiology
Other than age, lower socioeconomic status and poorer nutrition are often associated with increased risk of all types of age-related cataract. However, the specific components of these societal risks have been difficult to identify. Attempts to prevent or slow the progression of age-related cataracts by dietary supplementation have had modest success, at best.
Many studies have shown that women are at greater risk of age-related cataracts, although this has not been a universal finding. Protective effects of hormone replacement therapy have been small or inconclusive. Given the natural, long-term exposure of women to estrogenic steroids, it is difficult to argue that these hormones offer significant protection against age-related cataract. It seems more likely that, if there is a role of female sex steroids in cataract, the decline in estrogen levels at menopause may increase risk. The possibility that male sex hormones protect against cataract seems plausible, but has been little explored.
Beyond these more general risks, each type of age-related cataract is associated with a distinct spectrum of environmental risk factors. The most consistent positive association with lifestyle and nuclear cataracts is smoking. Since smoking is preventable, it represent an important, though challenging, opportunity for intervention. Nuclear cataracts are more prevalent in warmer climates. Whether this is due to ambient temperature or to other nutritional or societal risks has not been established. Cortical cataracts are associated with greater sunlight exposure and diabetes. Although a contribution of sunlight exposure to cortical cataracts is well established, greater sunlight exposure accounts for only a small increase in the risk of cortical cataracts in a typical population. Numerous studies have shown that even the highest level of sunlight exposure represents no detectable increased risk for the development of nuclear or posterior subcapsular opacities. Posterior subcapsular cataracts are most often associated with diabetes and therapeutic treatment with steroids or ionizing radiation. When diabetes is reasonably well controlled, it presents only a modest increase in the risk of age-related cataracts. Most of the increase in cataract surgery in diabetics is due to posterior subcapsular opacities. Steroid-induced posterior subcapsular cataracts have typically been associated with long-term systemic administration, but are becoming more prevalent due to the increasing popularity of high-dose intraocular steroids to treat retinal inflammation and neovascularization. Because the biology of these cataracts is less well understood than other types, studying cataracts induced by steroids during retina therapy or in animal models may offer an opportunity for understanding better the pathobiology of this disease.
Environmental risk factors provide clues to the etiology of age-related cataracts ( Box 30.2 ). Unfortunately, we know little about the biochemical mechanisms by which smoking contributes to nuclear cataracts or sunlight promotes cortical cataracts. Therefore, these risk factors have, so far, told us little about the pathogenic mechanisms underlying these diseases. Equally important, environmental factors that do not increase the risk of cataracts tend to rule out certain pathways in the cause of that type of cataracts. For example, the biochemical effects of sunlight exposure do not contribute significantly to the risk of nuclear or posterior subcapsular opacities. Therefore, it is reasonable to conclude that light-generated free radicals, for example, are not central to the etiology of these diseases.
Epidemiologic studies in populations around the world have identified recurring risk factors for the different types of age-related cataracts. Nuclear cataracts are often associated with smoking, poorer nutrition, and living in a warmer climate. Common risk factors for cortical cataracts include higher sunlight exposure and diabetes. Posterior subcapsular cataracts are associated with diabetes, use of immunosuppressive and intraocular steroids, and therapeutic radiation to the head. Anatomic factors, like lens thickness and the stability of the vitreous gel, also seem to contribute to the risk of nuclear and cortical cataracts. Surprisingly, the biochemical links that connect these risk factors to age-related cataracts are generally not known
As important as they may eventually be for understanding cataract etiology, environmental factors appear to account for a relatively small percentage of age-related cataracts. Other variables, many of which are less easily modified, are more significant contributors to the burden of disease. Among the most significant is genetic variation ( Box 30.3 ).
Studies of the prevalence of age-related cataracts in families and cohorts of twins demonstrated the importance of hereditary factors. Identifying the underlying genes may be valuable for preventing all types of age-related cataracts. Gene products usually function in metabolic pathways. Knowing these pathways may permit the suppression or augmentation of the biochemical reactions that make the lens more susceptible to or protect it from cataracts, respectively
Studies that measured the incidence of specific types of cataract in families, or between monozygotic (identical) and dizygotic (fraternal) twins, showed that approximately half of the risk of cortical and at least one-third of the risk of nuclear cataracts can be attributed to heredity. Increased risk of nuclear or cortical cataract was genetically separable in these populations, underscoring the distinct nature of these diseases. Although the subject of ongoing studies, the genes associated with the increased risk of age-related cataracts have not been identified in published studies.
Genetic risk factors may seem to present intractable barriers to treatment, especially for a common disease. However, understanding the genetics of age-related cataract may hold significant promise for therapeutic intervention or prevention. It is not always necessary to correct a genetic alteration at the DNA level to treat a gene-based disease. It may be sufficient to understand the pathway in which the defective gene acts, then design therapies that compensate for that defect to restore the function of the pathway. Genetic studies can also identify genes and pathways that protect against age-related cataracts. Enhancing the function of the pathways that, when impaired, increase the risk of cataracts, or augmenting pathways that normally protect against cataract could provide effective means to delay cataract formation in all individuals. For these reasons, identifying the genes responsible for promoting cataract or protecting the lens from cataract represents one of the most promising areas for future advances.
Epidemiologic studies have also identified anatomic risks for cataract. In a cross-sectional analysis of participants in the Beaver Dam Eye Study, individuals with thinner lenses were at much increased risk of cortical cataract, while those with thicker lenses had significantly more nuclear cataracts. Five-year follow-up of this population showed that individuals were more likely to develop cortical cataracts if their lenses were initially smaller. Those with larger lenses were more likely to develop nuclear cataracts. Similar associations between lens size and cataract have been identified in cross-sectional and prospective studies in Japan and Singapore (K Nagai, K Sasaki, H Sasaki, personal communication). The reasons underlying the association between smaller (or thinner) lenses and cortical cataract have not been explored. Possible connections between larger lens size and nuclear cataract may involve the lens “diffusion barrier,” discussed below in the section on the natural history of nuclear opacification.
Like lens fiber cells and the proteins within them, the vitreous gel that lies between the lens and the retina is made early in life and is never regenerated or replenished. Gradual collapse (also called syneresis) of the vitreous body occurs to a greater extent in older individuals, presenting increased risk of retinal detachment, macular hole, and other retinal complications. The extent of vitreous liquefaction varies greatly in older individuals. Those with a more liquefied vitreous are at increased risk of nuclear cataracts. The increase in the length of the eye that occurs in high myopia (severe near-sightedness) is associated with early degeneration of the vitreous body and increased risk of nuclear cataract. The possible physiologic relationship between the structure of the vitreous body and nuclear cataract is discussed below in the section on oxygen and cataracts.
Pathophysiology of age-related cataract
Oxidative damage
All cataracts involve damage of lens cells and/or lens proteins, leading to increased light scattering and opacification. Much of this damage can be traced, directly or indirectly, to oxidative or free radical-mediated effects. However, it has been difficult to show that oxidative damage initiates human cataract formation, rather than being the final “executioner” of transparency. In fact, the lens appears to be remarkably well protected from oxidative stress. It is essential to discover how these protective mechanisms are broken down or overcome to understand cataract etiology. We discuss some of the likely causes for different types of age-related cataracts, linking them to oxidative or free radical damage when appropriate.
Sunlight, aging, and cortical cataracts
Although exposure to higher levels of sunlight over a lifetime is one of the best-validated environmental risks of cortical cataract, the mechanism by which light exposure contributes to cortical opacities in humans is not understood. We do not know if sunlight has its effect by damaging DNA, inhibiting enzyme activity, decreasing protein stability, increasing lipid oxidation, or some combination of these. We do not even know whether it is the direct interaction of light with the lens or another component of the anterior segment, the iris for instance, that increases cataract risk. Unlike the skin, which shows clear evidence of light-induced DNA damage in sun-exposed areas, no similar “signature” of light damage has been identified in cortical cataracts. Paradoxically, the equatorial region of the lens, where cortical cataracts originate, is better protected from light exposure than regions that show no apparent susceptibility to sunlight-induced cataract, like the nucleus. Dark iris color, which might be expected to protect the lens from light exposure, has been identified as a risk factor for cortical cataracts in some studies, although not in others. Lack of understanding of the causal chain between sunlight exposure and cortical cataract formation in humans makes it difficult to speculate whether there are biochemical similarities between the cause of sunlight-induced cortical cataracts and the cortical cataracts that are associated with smaller lens size, diabetes, or genetic variation. Each of these disparate risk factors may contribute separately to cortical cataract or may be connected through an, as yet, unidentified mechanism.
An alternative view of cortical cataract formation is based on the frequent occurrence of these cataracts at the onset of presbyopia. Shearing force between the soft cortex and stiffer nucleus, generated during attempted accommodation in the increasingly presbyopic eye, could cause local rupture of cortical fiber cells. This initially focal damage then spreads along damaged fiber cells and to nearby fiber cells, leading to the spoke-like pattern of damage that is often seen in cortical opacities. If this view is correct, it can be related to the epidemiologic risk factors for cortical cataracts. The increased glycation of lens proteins seen in diabetics might further stiffen nuclear fiber cells or weaken cortical fiber cells. Smaller lens size might be associated with higher strain on the lens during disaccommodation, as the zonules of smaller lenses could be more taut. High sunlight exposure could exacerbate the hardening of the lens nucleus, thereby indirectly contributing to cortical cataracts without exposing the cortical cells to light. Further tests of this view of cortical cataract formation seem warranted.
Diabetes and cataract
Diabetes is one of the most widely recognized risk factors for age-related cataracts, although other diabetic complications are more clinically significant. Rapid-onset, uniformly distributed cortical opacities are seen in patients or experimental animals with acute hyperglycemia. While this type of opacity is important because it may alert patients to the need for treatment, it is not the typical presentation for diabetic patients with reasonably well-controlled blood glucose. In general, diabetics have earlier-onset opacities than nondiabetics. These are usually cortical or posterior subcapsular cataracts. Although nuclear cataracts can occur in diabetics, epidemiologic studies suggest that diabetes may provide modest protection against nuclear opacification. Because they impair vision at an earlier stage, posterior subcapsular cataracts often account for a disproportionate percentage of cataract surgery in diabetics.
The natural history of nuclear opacification
With increasing age, the lens nucleus gradually increases in opacity and hardness in all individuals. When nuclear opacities become visually significant they are often called nuclear sclerotic cataracts. Thus, nuclear cataract formation can be thought of as an acceleration or exacerbation of changes that occur during aging. This is not the case for cortical and posterior subcapsular cataracts. Although more cortical and posterior subcapsular cataracts occur in older individuals, most older patients will never have even a trace of either type. In this way, nuclear cataracts are fundamentally different from cortical or posterior subcapsular cataracts.
Increasing nuclear opacification correlates with a decline in reduced glutathione and an increase in the oxidized form of this important intracellular antioxidant in the lens nucleus. Experimental depletion of glutathione causes rapid opacification of the lens. Glutathione is synthesized and converted to its protective, reduced form in the metabolically active cells near the lens surface. It then diffuses through abundant gap junctions in the fiber cell membranes to the center of the lens, where it can protect lens crystallins and membrane proteins from oxidation. Once glutathione is oxidized, it diffuses down its concentration gradient to the lens surface, where it can again be reduced ( Figure 30.3 ). This glutathione cycle slows with age, due to a decrease in the apparent viscosity of the lens cytoplasm, appearing as a diffusion barrier between cells at the lens surface and the nucleus The resulting decrease in access of reduced glutathione to the nucleus places the proteins there at greater risk of oxidative damage. It is likely that this decline in antioxidant capacity contributes to the age-related increase in opacification and hardening of the nucleus, seen in virtually all lenses. Other antioxidant systems may decline with aging, possibly contributing to increased risk of nuclear cataract.
