Cataract EtiologyCHAPTER 1

Vision is one of the most valued senses. Proper vision is achieved by a series of eye tissues working harmoniously in concert. Most eye debilities involve dysfunction in the lens or retina, and hence this chapter will focus on and elucidate etiological factors which may affect the proper function of the lens as target organ.

The lens is an elegantly simple tissue. It is made up of only two types of cells.

Cataract is one of the major causes of visual impairment leading eventually to blindness. In the USA alone 1.35 million cataract extractions are performed annually. In developing countries, the magnitude of the problem is overwhelming.

Management of this age-old impairment of vision requires one of the three following approaches, or a combination of these approaches.

It is now well-established that cataract formation is a multifactorial disease. Several of the etiological factors are constitutional and hence difficult to manipulate. Others are environmental in nature and a little easier to control whilst a significant number are behavioral in nature and fall well within the individuals' own ability to control or modify.

The prevalence of infantile cataract has been reported to be between 1.2 and 6 cases per 10,000 births. Furthermore, it has been estimated that between 10% and 38.8% of all blindness in children is caused by congenital cataract (Figures 1.2 to 1.4) and that one out of every 250 newborns (0.4%) has some form of congenital cataract.

The etiology of infantile cataract (Table 1.1) can be established in up to one-half of children with bilateral cataract, but in a smaller proportion of infants with unilateral cataract. Infantile cataract most commonly occurs secondary to genetic or metabolic diseases, intrauterine infections or trauma. Less commonly they may occur as a side effect of treatment with certain medications or radiation therapy.

Galactokinase deficiency may cause cataract with few or no systemic abnormalities. The galactokinase gene is on chromosome 17 and has recently been cloned and found to harbor homozygous mutations in some patients with cataract. Heterozygotes for galactokinase deficiency have half normal values on blood tests. Conflicting results have been reported in the literature as to whether partial loss of enzyme activity leads to presenile cataract. Alpha mannosidosis can also be associated with early onset cataract.

Lamellar cataract may also develop in children with neonatal hypoglycemia or hypocalcemia. Neonatal hypoglycemia is more common in low birth weight infants.

Tavani et al studied 287 Italian women who had undergone cataract extraction and 1277 control subjects who were in the hospital for acute, nonneoplastic, nonophthalmologic, nonmetabolic, nongastroenterologic diseases in a case-control study in Northern Italy. The results of this study support the association in women between cataract extraction and diabetes, (OR 4.6 for those younger than 60 years and 1.7 for those age 60 and over) current overweight, (OR 2.2) history of clinically relevant obesity, (OR 1.5) hypertension(OR 1.5) and hyperlipidemia (OR 1.8). They suggest that these factors may have some biologically independent impact on the risk of cataract in women and therefore support the association in women between cataract extraction on the other hand and diabetes, current overweight, history of clinically relevant obesity, hypertension and hyperlipidemia on the other.

Experimental evidence also supports a possible protective effect of restriction of energy intake on the risk of cataract by protection against oxidative stress to the lens.

In developing countries, some studies have associated low BMI with cataract. A recent case control study in India, however, failed to confirm this association.

Hankinson et al in a prospective study examined the association of BMI with cataract extraction in a large cohort of women and found elevated rates of cataract in those with higher BMI. Women with BMI of 23 or above had significantly elevated rates of extraction, between 46% and 65% higher than those with BMI of less than 21. Glynn et al in a prospective cohort study of a total of 17,764 apparently healthy US male physicians aged 40 to 84 years who were free of cataract at baseline were followed for 5 years. In this group higher BMI was especially strongly related to risk of posterior subcapsular and nuclear sclerotic cataract and was also significantly related to risk of cataract 7extraction. Furthermore, BMI below 22 appeared especially protective against posterior subcapsular cataract, with reductions in risk of 50% or more relative to each of the groups with a higher BMI. They concluded that BMI appears to be a strong and independent risk factor for cataract in this well-nourished and socioeconomically homogeneous study population. Even modest elevations in weight were associated with increased risk.

In so far as BMI index is modifiable, cataract caused by overweight is therefore potentially preventable.

A private census of the population of Beaver Dam, Wisconsin, was performed from September 15, 1987 to May 4, 1988. Eligibility requirements for entry into the study included living in the city or township of Beaver Dam and being 43 to 84 years of age at the time of the census. A total of 5924 eligible people were identified. Of these, 4926 (83.1%) participated in the examination.

While controlling for age and sex in this study, less education was significantly (P< 0.05) related to higher frequency of nuclear sclerotic and cortical cataract. Lower reported total household income was significantly associated with higher frequen-cies of cortical and posterior subcapsular cataract. These relations between total household income and cataract were observed in both men and women.

Less education has been associated with higher frequencies of history of heavy drinking, cigarette smoking and less vitamin supplement intake, all of which have been found to be related to specific types of cataract. However, the association of education and income with cataract persisted, despite controlling these exposures in their population. It is possible that poorer nutrition occuring earlier in life, may be related to the development of age-related cataract. A second possible reason explaining the relation of education and income to cataract is that people with less education or lower income are less likely to see an ophthalmologist or have cataract surgery.

Marital status is a measure of social support which is postulated to be an important factor in developing and managing complications associated with disease. While controlling for age and sex, people who were never married had a higher frequency of impaired vision than those currently married. This may be due to the fact that married people may have more social pressure to seek health care and to maintain familial responsibilities, and they may have more transportation assistance than their unmarried/widowed counterparts.

In summary, less education and income are related to cataract and visual impairment, but not to age-related maculopathy. These data suggest that access to medical, surgical, and low vision care may be of benefit to people with low socioeconomic status.

Tobacco smoking is considered a major risk factor for 6 of the 15 leading causes of death. An individual who smokes has about twice the risk of premature death as a non-smoker, and the heavier the cigarette consumption, the higher the risk.

Of the 4,000 active substances in tobacco smoke, most are hazardous to human health. More than 40 of these chemicals are carcinogens and many others are deleterious to the cardiovascular and the pulmonary systems. They include nicotine, tars, nitrosamines, polycyclic aromatic hydrocarbons, hydrogen cyanide, formaldehyde, and carbon monoxide. Cigarette smoking is also a substantial source of intake of heavy metals and toxic mineral elements, such as cadmium, aluminum, lead, and mercury, all known to be poisonous in high concentrations.

Tobacco smoke also contains numerous compounds with oxidative properties; their existence is linked to the pathogenesis of several of the most common eye disorders, such as cataract and age-related macular degeneration.

Epidemiological data link cigarette smoking to several ophthalmologic disorders like ocular irritation, ocular ischemia, age-related macular degeneration (AMD), cataract, thyroid ophthalmopathy, tobacco-alcohol amblyopia, primary open-angle glaucoma, conjunctival intraepithelial neoplasia, uveal melanoma, Leber hereditary optic neuropathy, type II diabetes, ocular sarcoidosis and strabismus in the offspring of smoking mothers. The effects of smoking on ocular disorders show significant dose dependence; higher levels of smoking increase the risk of developing cataract. It is important to note, however, that the interpretation of results of different studies may be inherently biased, as smokers in these studies use cigarettes of different types, containing different concentrations of toxic substances. Moreover, some of the cigarettes have filters and others do not. Smoking habits may also be associated with other potentially noxious habits, such as excessive alcohol consumption, which may contribute a further bias to the results.

Table 1.2 summarizes five very thought-provoking studies all supporting the view that smoking is associated with the development of cataract.

Several authors have reported a significant link between tobacco smoking and an increased risk of cataract development.8

In the Beaver Dam Eye Study, the relationship between cigarette smoking and lens opacities was examined in 4926 adult subjects. A significant correlation was found between severe levels of nuclear sclerosis and the number of pack-years smoked. For both sexes, the odds ratio associated with 10 years was 1.09 (confidence interval, 1.04–1.16). The frequency of posterior subcapsular opacities was also increased (odds ratios, 1.05 [confidence interval, 1.00–1.11] for men and 1.06 [confidence interval, 0.98–1.14] for woman). Cortical opacities were not found to be linked to smoking. Leske et al studied, 1380 patients with cataract, aged 40 to 79 years, in an attempt to identify possible risk factors for the development of cataract, current smoking was correlated with the risk of developing nuclear cataract (odds ratio, 1.68; confidence interval, 0.96–1.94), but not other forms of cataract. The City Eye Study reported epidemiological data concerning 1029 volunteers, aged 54 to 65 years, from London, UK. The findings showed a significant relationship between nuclear lens opacities and moderate to heavy cigarette smoking. The relative risk for nuclear-type cataract ranged from 1.0 for past light smokers to 2.6 for past heavy smokers, and 2.9 for current heavy smokers.

Klein et al presented evidence that smoking has a detrimental effect on the development of cataract in the type II diabetic population.

Several prospective studies have investigated the relationship between cataract formation and cigarette smoking. In an 8-year prospective study, Hankinson et al examined the association between cigarette smoking and the risk of cataract extraction in 50,828 female nurses aged 45 to 67 years. The age-adjusted relative risk among female smokers of at least 65 pack-years was 1.63 (confidence interval, 1.18–2.26).

Smoking was also strongly associated with posterior subcapsular opacities for smokers of 65 or more pack-years (relative risk 2.59). In a 5-year prospective study of 22,071 men aged 40 to 84 years, current smokers of at least 20 cigarettes a day showed a significantly increased risk of developing cataract (relative risk 2.16; confidence interval, 1.46–3.20). When calculated for the different types, the relative risk was 2.24 for developing nuclear sclerosis and 3.17 for posterior subcapsular cataract. Past smokers were also at increased risk of developing posterior subcapsular opacities (relative risk 1.44), whereas current light smokers had the same chance of developing any type of cataract as subjects who had never smoked. In a study of 838 watermen from Chesapeake Bay, Maryland, West et al found a significantly increased risk of development of nuclear opacities associated with cigarette smoking (relative risk 2.40; confidence interval, 1.00–6.00).

A 5-year prospective study of this cohort of subjects reported an increase in the incidence and degree of nuclear opacities with increasing age. The risk of progression of nuclear opacities from less than grade 3 at baseline to grade 3 or worse was 2.4-fold higher among current smokers than among ex-smokers or non-smokers.

A significant increase (18%) in the risk of cataract progression was associated with each pack-year that a subject had smoked during the 5-year study period.

Smoking appears to further impair lenticular function by imposing an additional oxidative challenge as well as by contributing to the depletion of endogenous anti-oxidant pools. Tobacco smoke also contains large amounts of heavy metals, such as cadmium, lead and copper, which appear to accumulate in the lens and exert further toxicity.

The above data strongly support an association between tobacco smoking and cataract formation. Given the magnitude and seriousness of the cataract problem, an important preventive measure in fighting this disorder is to quit smoking. It is important to note that smoking is on the increase in the developing world, where cataract surgery is not always readily available.

As far back as 1973 Sabiston clinically observed in 40 patients over a 5-year period a definite correlation between alcohol intake, Dupuytren's contracture, and cataract. He stated that the mechanism of cataract formation was uncertain, but that an element of chronic dehydration was possible. In New Zealand, where he did his observations, heavy drinking often commenced with the ingestion of large quantities of beer. The national average consumption of beer there is 100 liters per head annually, with manual laborers ingesting a daily total of 4 liters of beer per person per day on average. These persons were almost invariably heavy cigarette smokers as well. He further noted that the cataract commenced in a posterior subcapsular position, and could progress to almost full maturity in six months. There was almost universally a history of heavy cigarette smoking as well. Malnutrition was only sometimes seen.

Drews in 1970 also drew attention to the association of ethanol and cataract. Two decades later he writes: “A patient in his or her 40s or 50s who appears with a posterior subcapsular cataract should be investigated for alcoholism… In the author's practice, about 25% of patients younger than age 65 years who present with cataract are found to be alcoholic on careful investigation. It has been his experience that if the opacities are incipient and if the consumption of alcohol is stopped completely, the posterior subcapsular changes may reverse and even disappear.”

Two decades later attention is once again drawn to the possible link between alcohol and cataract in the Archives of Ophthalmology by two different sets of authors. Munoz et al from the Wilmer Eye Institute, Baltimore, MD, USA conducted a follow-up study of surgical cases of posterior subcapsular cataract (PSC) and their controls to evaluate the possible association of alcohol intake and posterior subcapsular opacities. Two hundred thirty-eight cases and controls were interviewed. Current alcohol intake and usual and maximum weekly consumption ever were assessed. In this population, 57% of the cases and 56% of the controls were nondrinkers, 22% of the cases and 36% of the controls had an average of seven or fewer drinks per week, and 17% of the cases and 8% of the controls had more than seven drinks per week. Heavy drinkers were more likely to be cases than were nondrinkers (odds ratio, 4.6;P<0.05), and light drinkers were not at an increased risk. Light drinkers, defined as those who drink less than 91 g/wk (i.e. one drink or less per day), were at a lower risk than were nondrinkers, although this difference did not reach statistical significance. Moderate to heavy drinkers, that is, those drinking an average of more than one drink per day (more than 91 g/wk) were 2.7 times more likely to have PSC. This U-shaped relationship between alcohol and the risk of PSC was more pronounced in the logistic regression model when controlling for all the factors found to be related to PSC. Some studies have suggested that heavy drinking patterns are associated with lower socioeconomic status. In this study after adjustment for education level, the risk of PSC was still higher among drinkers. Smoking was also not related to PSC. Heavy alcohol use has been linked to poor nutritional status, so the presence of PSC may be related to poor nutrition rather than alcohol consumption per se. Dietary assessment however, was not performed in this study. In summary, this study concluded that moderate to heavy alcohol consumption is associated with a four-fold increase of PSC cataract whereas light drinkers, those consuming one drink per day or less, were not at an increased risk.

The second study reported in the same journal was on alcohol use and lens opacities in the Beaver Dam Eye Study group of patients. The relationship between alcohol use and lens opacities was examined in a large (N = 4926) population-based study of adults. Alcohol history was determined by a standardized questionnaire and the cataract severity was determined by masked grading of photographs obtained using a slit lamp camera and retroillumination. Several significant findings were made and conclusions drawn:

Alcohol has many metabolic effects, and modifies the absorption of drugs and dietary components. These effects may be important in the alcohol-cataract relationship. However, one cannot exclude the possibility that alcohol itself, especially when consumed in high volume, may be a direct toxin to the human phacos.

The rat sugar cataract model is an attractive model for juvenile diabetic cataract in terms of its acute development and other features. It is also relevant to human galactosemic cataract, in which the lens is exposed to high levels of aqueous galactose. The first visible indication of galactosemic cataract is the “oil-droplet” change on retroillumination, due to a change in refractive index between the inner and outer parts of the lens.

It has been noted that there are difficulties in accepting a role of aldose reductase in human cataract. Even though sorbitol is found in increased amount in the human diabetic lens, the amounts detected have been quite low, and insufficient on a lens mass basis to account for osmotic damage.

Data on a cell-to-cell basis, which would be appropriate, are not available.

Although Vadot and Guibal considered that there was sufficient sorbitol in young diabetic lenses to induce cataract, Lerman and Moran could not demonstrate the accumulation of significant amounts in sugar-incubated lenses over the age of 20 years. There is no information about levels in juvenile diabetic cataract itself. Jedziniak et al found a higher aldose reductase activity in the young lens than in the adult lens and calculated that it was sufficient to generate a significant osmotic stress. However, these calculations referred to the lens epithelium and assumed that sorbitol was not removed. Since polyol dehydrogenase is more active than aldose reductase in the human lens, the calculated levels would be expected to be lower. Lin et al demonstrated accumulation of dulcitol and loss of myoinositol in 72- hour cultures of infantile human lens epithelium in a 30 mlQI galactose medium, associated with vacuolar changes at ultrastructural level. Sorbinil and AL1576 reversed these changes. Similar changes have been produced in dog epithelial culture within 6 hours. Lin et al suggest that damage in the human lens may reflect compartmentalization of aldose reductase activity, for instance in the epithelium. If sorbitol accumulation in the epithelium (and not the fibers) were the basis of juvenile cataract, then a failure of epithelial permeability or pumping functions would be a more likely cause of lens swelling 11and cataract than an osmotic mechanism. There is no information available as to whether an oxidative mechanism, dependent on the polyol pathway or not, is operative in juvenile diabetic cataract.

Klein et al in a population study found cataract to be more prevalent in early and late onset diabetes with significant association with age, severity of retinopathy and diuretic usage. Diabetes duration and the level of glycosylated hemoglobin were also associations in early onset diabetics. In a second report, cataract was found to be the second most common cause of severe visual loss in adult onset diabetics. Various other reports have shown an association between cataract, and diabetes duration or retinopathy.

The frequency of cataract extraction is greater in diabetics than non-diabetics. The Framingham study showed a significant excess risk in the 50 to 64 years age group (relative risk 4.02), while the HANES study showed a relative risk of 2.97 in this age group and 1.63 in the 65 to 74 years age group. Both studies reported an excess prevalence of cataract in diabetics in 50 to 64 years age groups, which disappeared at an older age. This has been attributed to the higher mortality in diabetics with cataract. However, a case-control study in Oxford found an increased risk for cataract extraction in diabetics in the age group of 50 to 79 years, and a small increase in risk for women relative to men.

As has been noted, the morphology of cataract in the adult diabetic resembles that seen in age-related cataract in the absence of diabetes. Thus the major features are nuclear cataract (increased nuclear scattering and brunescence) and cortical spoke and posterior subcapsular cataract. In the Lens Opacity Case Control study, diabetes increased the risk of posterior subcapsular, cortical and mixed forms of cataract. Individual features may not have an identical etiology, but it is likely that those metabolic changes identified in experimental cataract are relevant for the human are in varying degrees. There is no relation between cataract type, and the level of either sorbitol or myoinositol in lens epithelium from patients with cataract and diabetes.

It has been suggested that the increased nuclear scattering and brunescence in diabetic lenses is likely to be the result of increased glycation and the formation of advanced glycation end products.

There is evidence for a fall in free lysine amino groups in the human diabetic lens. It is also possible to induce a change in tertiary structure in alpha-crystalline (bovine) incubated with glucose and glucose-6-phosphate.

A three-fold increase in glycation was measured in diabetics and controls by Vidal et al but there was no correlation with the degree of browning of the lenses measured spectrophotometrically, and they concluded that other chromophores were responsible for the browning at the relevant wavelengths.

Certainly a number of other factors have been proposed to contribute to nuclear brunescence of the non-diabetic lens, but since the diabetic state is not anticipated to increase their concentration, glycation products are still the most likely candidates responsible for diabetic cataract.

Cortical cataract can be caused experimentally by agents which interfere with membrane permeability, ion and water control. The non-diabetic, aging human lens, free of cataract, has an increased membrane permeability which parallels the increase in optical density which occurs from about the fifth decade. There is evidence of degradation of the lens protein MIP26 with age in non-diabetics, which could be responsible for a functional abnormality. This channel protein has until recently been regarded as the gap junctional protein, but may, in fact, serve as a volume regulating channel. Disturbance of either function could increase the risk of cataract. It would be of interest to examine these events in the diabetic lens. The greater thickness of the diabetic compared to the non-diabetic lens could be relevant to this point. The disturbance in Na’ K’-ATPase kinetics reported by Garner and Spector during exposure to glucose-6-phosphate is similar to the change noted in diabetic human lenses. Hydrogen peroxide is present in normal human aqueous, and present at raised levels in the aqueous of patients with cataract. Higher levels are found in the aqueous of diabetic patients with cataract. Simonelli et al have also shown an increase in malondialdehyde in cataractous compared with non-cataractous lenses which is greater in the cataract of diabetic patients. Malondialdehyde is a product of lipid peroxidation of cell membranes, and is regarded as an indicator of oxidative membrane damage. These are important findings, although the methods of measurement are not entirely specific.

The potential role of the sorbitol (polyol) pathway in juvenile cataract was discussed earlier. Recent studies of cultured lens epithelium from cataract patients have shown negligible or absent levels of sorbitol in the epithelium of non-diabetics. In diabetic epithelium sorbitol levels are higher than blood glucose levels, while there is an inverse relationship between blood glucose and myoinositol.

It has been noted that oxidative stress may cause lens membrane damage experimentally. It may also cause damage to DNA. Subcapsular cataract may be regarded as due to an aberration of lens mitosis and lens fiber differentiation, and could be the result of oxidative damage. There are no data, which link this to human subcapsular cataract.

Issues relating to drug safety and inherited defects in enzymes mediating cholesterol metabolism have brought renewed attention to a possible inter-relationship between lipid metabolism and cataract induction in humans. The lens is unique in that it contains a relative abundance of cholesterol in the fiber cell plasma membrane, (the highest of any cell group in the body) and furnishes its needs for cholesterol by onsite biosynthesis. It has been shown that inhibition of cholesterol synthesis in the lens leads to cataract formation in man.

Smith-Limli-Opitz syndrome, mevalonic aciduria and cerebrotendinous xanthomatosis are inherited disorders of cholesterol metabolism and affected patients may present with lens opacities. Triparanol, a hypolipidemic agent that inhibits cholesterol biosynthesis was withdrawn from clinical use because of its propensity to induce cataract formation in humans. The very widely used vastatin class of hypolipidemic medicines is potent inhibitors of cholesterol biosynthesis and is able to lower serum lipid concentration effectively. Although high ocular safety in older patients over periods of up to 5 years, has been reported, it is still not clear whether these agents have the potential to be cataractogenic, particularly in younger patients and over longer periods.

In order to assess the prevalence of lenticular opacities in patients with dyslipidemia (raised serum cholesterol and triglycerides) a group of 80 dyslipidemic patients were subjected to a general physical examination and an ophthalmic examination of the fully dilated eye at the Tygerberg Academic Hospital, University of Stellenbosch, South Africa (unpublished data).

Patients (n = 80) of both genders and irrespective of age were enrolled in the trial if they met the inclusion criteria for dyslipidemia. Patients were included if their fasting serum cholesterol and triglyceride concentrations were > 5.2 mmol/l and > 2.3 mmol/l, respectively when measured on three separate occasions over a one-month period (Figure 1.6). Patients were excluded if they suffered from any condition known to cause or predispose them to elevated lipid levels or lenticular opacification.

The prevalence of lenticular opacities divided the study group into two cohorts, i.e. those with normal lenses (62%) and those with opacities (39%) (Figure 1.7).

The prevalence of lenticular opacity in dyslipidemic patients in the age group of 30 to 40 years was 33%. This age group was not studied in the Barbados Eye Study (BES) or in The Beaver Dam Eye Study (BDES) and consequently data for comparison are not available (Table 1.3). In the 40 to 50 year age group, the prevalence of lenticular opacity in our patients was 50% compared to 4.7% in the BES and 8.3% in BDES. Differences in the older age groups were not prominent (Figure 1.8).

Modern medicine today aspires to early detection of disease processes with the aim of early intervention in an attempt either to halt the progression or to reverse the process.

Although the classic systemic signs of dyslipidemia are well-appreciated, i.e. xanthomata, xanthelasma, thickening of the Achilles tendon and corneal arcus, in our study the prevalence of one or more of the ocular signs was far greater than that of the systemic signs, 23.8% for the former as opposed to 47.3% for the latter.

The distribution of dyslipidemia-related signs in this study was:

It is noteworthy that the most frequent ocular sign—cortical lenticular opacity—occurred twice as frequently as the most frequent systemic sign—Achilles tendon thickening (Figure 1.9).

Jahn et al attempted to determine the role of glucose and lipid metabolism in the formation of cataract in elderly people undergoing cataract extraction. They found that patients with posterior subcapsular cataract had higher concentrations of fasting serum triglycerides and were significantly younger than patients with nuclear or cortical cataract. Their results furthermore suggest that the association of hypertriglyceridemia, hyperglycemia and obesity favors the formation of a specific morphologic type of lens opacity, posterior subcapsular cataract, occuring at an early age. Because these factors are potentially modifiable by lifestyle changes, these observations may prove important as the modification of these parameters could constitute an effective mode of prevention or retardation in a subgroup of patients developing cataract at an early age.

Several diseases have been linked to acetylator pheno- and/or genotype. The best documented are bladder cancer (slow), colorectal adenomas (rapid), Gilbert's syndrome (slow), allergic diseases Type I diabetes mellitus (fast), Type II diabetes mellitus (slow) and familial Parkinson's disease (slow).

Recent work (PhD level, unpublished) at the departments of Ophthalmology and Pharmacology at the University of Stellenbosch, South Africa, have also established an association between age-related cataract and acetylation status as determined both phenotypically and genotypically. Sixty adult patients of both sexes with classic age-related lens opacities presenting for cataract surgery were enrolled in a prospective controlled study. Patients were included in the trial if they perceived themselves to be colored and if this was verified by at least one independent observer. The South African population of mixed ancestry (including Malay, Khoisan, Negroid and Caucasoid stock) is referred to as “colored” and all patients were selected from this well studied subgroup of the population. Care was taken to exclude all patients with well-known etiological factors for cataract formation such as diabetes mellitus, previous ocular trauma, other metabolic and/or inherited diseases.

Figure 1.10 demonstrates that in the control group (representing the population at large) the distribution of the phenotypic acetylation status was 20% “rapid”, 50% “intermediate” and 30% “slow”. In the cataract group the distribution was 5% “rapid”, 42% “intermediate” and 53% “slow”. This clearly seems to suggest that cataract possibly occurs more frequently in slow acetylators than in the rest of the population. Could this finding perhaps suggest a possible etiologic role for chemical substances possessing a primary aromatic amine or hydrazine group in human lenticular opacification?

The addition of electrons to molecular oxygen leads to the formation of toxic free oxygen radicals or reactive oxygen species (ROS), e.g.

Iron is very important in this process according to the Haber-Weiss reaction:

These free radical species cause lipid peroxidation and other deleterious effects on cell structure. Recent studies have shown that lipid peroxidation, an event caused by imbalance between free radical production and antioxidant defense, may play a role in the genesis of cataract. Higher levels of malondialdehyde (MDA), a final product of the lipid peroxidation process, have been observed in diabetic and myopic cataract compared with senile cataract. Protection of the cell against damage by these free radicals takes place indirectly (enzymatically) by antioxidant enzymes—superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT). Direct protection is offered by mainly dietary antioxidants—ascorbate (Vit C), tocopherol (Vit E), carotenoids(Vit A) and glutathione (GSH).

Elevated levels of oxygen exposure perhaps show the clearest causal relationship between oxidative stress and cataract. Nuclear cataract was observed in patients treated with hyperbaric oxygen therapy, and markedly elevated levels of mature cataract were observed in mice that survived exposure to 100% oxygen twice weekly for 3 hours. A higher incidence of cataract was noted in lenses exposed to hyperbaric oxygen in vitro. Very early stages of cataract in guinea pigs exposed to hyperbaric oxygen was noted by Giblin.

The major aqueous antioxidants in the lens are ascorbate and GSH.

Ascorbate is probably the most effective, least toxic antioxidant identified in mammalian systems. The following has been observed:

With this basic science knowledge, several epidemiological, clinical and even interventional studies have been undertaken. Vitamin C was considered in approximately 9 published studies and observed to be inversely associated with at least one type of cataract in eight of these studies.

In the Nutrition and Vision Project, age-adjusted analyses bases on 165 women with high vitamin C intake (mean = 294 mg/day) and 136 women with low vitamin C intake (mean = 77 mg/day) indicated that the women who took vitamin C supplements for > 10 years had > 70% lower prevalence of early opacities (RR: 0.23; CI: 0.09-0.60) and > 80% lower risk of moderate opacities (RR: 0.17; CI: 0.03-0.87) at any site compared with women who did not use vitamin C supplements.

In comparison to the above data, Mares-Perlman et al report that past use of supplements containing vitamin C was associated with a reduced prevalence of nuclear cataract, but an increased prevalence of cortical cataract after controlling for age, sex, smoking, and history of heavy alcohol consumption.

Glutathione (GSH) levels in the lens are several fold the levels found in whole blood and plasma. GSH levels also diminish in the older and cataractous lenses. Pharmacological opportunities could be suggested by observations that incorporating the industrial 0.4% butylated hydroxytoluene in diets of galactose-fed (50% of diet) rats diminished prevalence of cataract. Clinical studies, however, have not yet been forthcoming.

Vitamin E, a natural lipid-soluble antioxidant, can inhibit lipid peroxidation and appears to stabilize lens cell membranes. Consumption of Vit E supplements was inversely correlated with cataract risk in two studies. Robertson et al found among age- and sex-matched cases and controls that the prevalence of advanced cataract was 56% lower (RR: 0.44; CI: 0.24–0.77) in persons who consumed vitamin E supplements (>400 IU/day) than in persons not consuming supplements. Jacques and Chylack (unpublished) observed a 67% (RR: 0.33; CI:0.12–0.96) reduction in prevalence of cataract for vitamin E supplement users after adjusting for age, sex, race and diabetes.

Two prospective studies demonstrated a reduced cataract progress among individuals with higher plasma vitamin E. Rouhianen et al found a 73% reduction in risk for cortical cataract progression (RR:027; CI: 0.08–0.83), whereas Leske et al reported a 42% reduction in risk for nuclear cataract progression (RR: 0.58; CI: 0.36–0.94). Vitamin E supplementation was related to a lower risk for progress of nuclear opacity (RR:0.43; CI: 0.19–0.99).

The carotenoids, like vitamine E, are also natural lipid-soluble antioxidants. Beta-carotene is the best known carotenoid because of its importance as a vitamin A precursor. However, it is only one of the 400 naturally occuring carotenoids, and other carotenoids may have similar or greater antioxidant potential. In addition to β-carotene, α-carotene, lutein and lycopene are important carotenoid components of the human diet.

Jacques and Chylack were the first to observe that persons with carotene intakes above 18,700 IU/day had the same prevalence of cataract as those with intakes below 5,677 IU/day (RR:0.91; CI:0.23–3.78). Hankinson et al followed this report with a study that reported that the multivariate-adjusted rate of cataract surgery was about 30% lower (RR: 0.73; CI: 0.55–0.97) for women with high carotene intakes (median = 14,558 IU/day) compared with women with low intakes of this nutrient (median = 2,935 IU/day). However, while cataract surgery was inversely associated with total carotene intake, it was not strongly associated with consumption of carotene-rich foods, such as carrots. Rather, cataract surgery was associated with lower intakes of foods such as spinach that are rich in lutein and xanthin carotenoids, rather than β-carotene. This would appear to be consistent with the observation that the human lens contains lutein and zeaxanthin but no β-carotene.

This observation would appear to be consistent with the observation that lutein and zeaxanthin are the most prevalent carotenoids in lens. However, Mares-Perlman did not detect a significantly altered risk for cataract among consumers of these nutrients.

Intervention studies To date only one intervention trial designed to assess the effect of vitamin supplements on cataract risk has been completed. Sperduto et al took advantage of two ongoing, randomized, double-blinded vitamin and cancer trials to assess the impact of vitamin supplements on cataract prevalence. The trials were conducted among almost 4,000 participants aged 45 to 74 years from rural communities in Linxian, China. Participants in one trial received either a multisupplement or placebo. In the second trial, a more complex factorial design was used to evaluate the effects of four different vitamin/mineral combinations:

At the end of the five to six years follow-up, the investigators conducted eye examinations to determine the prevalence of cataract. In the first trial there was a significant 43% reduction in the prevalence of nuclear cataract for persons aged 65 to 74 years receiving the multisupplement (RR: 0.57; CI: 0.36–0.90). The second trial demonstrated 17a significantly reduced prevalence of nuclear cataract in persons receiving the riboflavin/niacin supplement relative to those persons not receiving the supplement (RR: 0.59; CI: 0.45–0.79). The effect was strongest in those aged 65 to 74 years (RR: 0.45; CI: 0.31–0.64). However, the riboflavin/niacin supplement appeared to increase the risk of posterior subcapsular cataract (RR:2.64; CI: 1.31–5.35). The results further suggested a protective effect of the retinol/zinc supplement (RR: 0.77; CI: 0.58–1.02) and the vitamin C/molybdenum supplement (RR:0.78; CI: 0.50–1.04) on prevalence of nuclear cataract.

Conclusion Although light and oxygen are necessary for physiological function, when present in excess they seem to be causally related to cataractogenesis. Aging might diminish the bodies primary antioxidant reserves, antioxidant enzyme abilities, and diminished secondary defenses such as proteases.

The literature creates the strong impression that antioxidant intake might diminish the risk for cataract formation.

Longitudinal studies and more intervention studies are essential in order to establish the value of dietary antioxidants and to determine the extent to which cataract progress is affected by nutritional supplements. This fact becomes significant when one appreciates that poor education and lower socioeconomic status are directly related to poor nutrition. It is, therefore, not irrational to contemplate the value of intervention for populations at risk. The work available, albeit preliminary, indicates that nutrition may provide the least costly and most practicable means to attempt the objectives of delaying cataract.

Wensor et al demonstrated that a myopic shift is associated with nuclear cataract. In the population based study of 3,271 Australians an association between myopia of 1 Diopter or more and both nuclear and cortical cataract was observed. Between posterior subcapsular cataract and myopia such a relationship did not exist. It is not sure that a causal relationship exists between cortical cataract and myopia or rather that a myopic shift occurs after people develop cortical cataract. The temporality of this relationship should still be explored in future prospective analyses.

Besides formal filtering procedures like full thickness procedures, laser procedures for the management of different types of glaucomas are frequently performed such as argon laser trabeculoplasty, argon laser iridoplasty and Nd-Yag peripheral iridotomy. Each of these procedures carries the risk of inducing a cataract especially of the focal type. Zadok et al has described a previously unreported complication of a posterior chamber intraocular lens (IOL) implanted in a phakic eye.

Miotics, particularly long-acting cholinesterase inhibitors, if used for long term, may cause tiny anterior subcapsular vacuoles and, occasionally, more advanced opacities. Cessation of medication may stop, retard or occasionally reverse their progression.

Acute congestive angle-closure glaucoma is associated with the subsequent formation of glaukomflecken consisting of small, gray-white, anterior, subcapsular or capsular opacities in the pupillary zone.

More recently with the advent of minus power phakic, IOL implantation surgery, several reports have appeared of cataract induction secondary to the implantation of these lenses into the ciliary sulcus. These cataracts have occurred both with silicone and collamer materials. Some have taken as short a time as 6 months, whilst others took 7 years to form. In another series of 38 consecutive eyes with high myopia implanted with a silicone posterior chamber plate-style intraocular lens (Chiron, Adatomed) over a period of 21 months and followed for between 3 and 24 months not a single cataract occurred. The lens style and design may play a significant role in the cataract pathogenesis, because in a recent study Brauweiler et al attempted to assess the effectiveness and safety of implantation of a silicone, posterior chamber IOL in the ciliary sulcus of phakic, highly myopic eyes in a noncomparative consecutive interventional series. Eighteen eyes of 10 patients underwent implantation of a Fyodorov 094M-1 IOL by the same surgeon and were evaluated for a 2-year postoperative period. Cataract formation of the anterior subcapsular (8 eyes) or nuclear (only 1 eye) type was observed in overall 9 (52.9%) of 17 eyes. When considering only the patients with a follow-up of 2 years, the incidence of cataract formation was 81.9% (9 of 11 eyes). Obviously this very high incidence of cataract formation should discourage the implantation of the type of IOL used in this study.

Ocular trauma is a major cause of monocular blindness in both the developed and developing world, but this is not seen as a significant cause of bilateral blindness. Trauma can, therefore, be considered as a major cause of blind eyes but not of blind people.

Crystalline lens subluxation, total dislocation, or localized cortical or diffuse opacities are often observed secondary to blunt ocular trauma. An unusual complication of blunt trauma is rupture of the posterior capsule with subsequent lens fiber hydration leading to rapidly progressive lens opacification. Posterior capsular breaks have been reported to develop thick, fibrous, opaque margins approximately 6 weeks after blunt trauma.

Wagner's vitreoretinal degeneration is characteristically associated with high myopia, glaucoma, choroidal atrophy, retinal detachment and presenile cataract.

Persistent hyperplastic primary vitreous (PHPV) is a congenital disorder that manifests a range of ocular anomalies including leukoria, microphthalmia, a retrolental fibrovascular membrane and cataract. In general the prognosis for visual acuity with PHPV is poor.

In the Italian-American Cataract Study, there was an increased, although not significant, risk of cortical cataract in people with brown irides. Dark iris color was not associated with cortical cataract in the Lens Opacities Case-Control Study. In the National Health and Nutrition Examination Survey, blacks, who have dark brown irides, were found to have significantly increased risk of cortical cataract. In both the above mentioned studies, dark iris color was also found to be a significant risk factor for nuclear cataract.

The relationship of nuclear cataract and iris color could result from genetic susceptibility associated with iris color or other factors not yet determined. This finding may partially explain the variation in the prevalence of nuclear cataract observed in different countries with different racial groups.

Six case-control studies have examined the relationship of severe diarrhea and increased risk of cataract, with discordant results. Two case-control, clinic-based studies done in Madhya Pradesh and Orissa, India have suggested a three- to four-fold increase in the risk for cataract for those with remembered episodes of life-threatening dehydration crises, severe enough to render the patient bedridden for at least three days. However, these findings were not replicated in two other epidemiologic investigations done in India. Using a less stringent definition of diarrhea (confinement to bed for one day), the India-US Case-Control Study found no associations with cataract. Also, a village-based case-control study in Southern India showed no association between severe diarrhea and risk of cataract. Furthermore, an observational study done in Matlab, Bangladesh, revealed that diarrhea from all causes was not significantly associated with cataract, although it was difficult to determine how cataract was defined in the study. The case-control study in Oxford found a marginally significant excess risk of cataract with reported severe diarrhea, but a significant risk in the subgroup aged 70 and older. Adjustments for the other possible confounding factors also found in the study were not done. Considering the potential public health importance of diarrhea as a risk factor, as well as the biologically plausible role of dehydration in cataractogenesis, further research to clarify this association is needed. Prospective studies involving closer follow-up of groups of patients who suffered from acute life-threatening diarrhea may provide more convincing evidence. Moreover, studies that examine the cumulative effect of milder, chronic dehydration episodes in cataractogenesis may also add to the current understanding of this issue.

Young suggests that sunlight is the primary causal factor in cataractogenesis, and strongly advocates the widespread distribution of sunglasses to prevent cataract. Harding on the other hand suggests that sunlight is not a major etiological factor in human cataract formation.

The lens is known to absorb UVB and UVA and change in lens clarity has been linked in animal experiments with short-term, high intensity exposure and chronic exposure to UVB.

Epidemiologic studies have demonstrated cataract to be more prevalent in sunny countries, such as Israel, than in cloudy countries, such as England. Moreover, in Romania and the United States, cataracts are more prevalent in dry hot areas with more sun exposure within each country than in areas with prolonged cloud cover. The Beaver Dam Eye Study found an association between ultraviolet B radiation exposure and cortical cataract in men only.

The Lens Opacity Case-Control Study did not find an association between sun exposure and any type of cataract development. However, this study investigated only urban populations, and this may explain why no association was found. In both the Italian-American Cataract Study and India-US Case-Control Study, sunlight exposure was associated with cataract formation. Taylor studied 797 watermen and went to great lengths to calculate an ultraviolet radiation exposure index on the basis of field variables such as outdoor hours worked, work location, and attenuation due to spectacle use and hat cover. He found a significant association between ultraviolet B radiation index and cortical cataract but found no association with other morphological cataract types.

Bochow et al studied the relationship between ultraviolet radiation exposure and posterior subcapsular cataract. He not only discovered a significant association but also a dose-response relationship.

Two unique studies, one prospective and one case-control, provide indirect evidence that ultraviolet light plays a role in cataract formation. Schein et al studied the distribution of cortical opacities by lens quadrant in a prospective study of Chesapeake Bay watermen. The prevalence of cortical lens opacities increased with age, with a high degree of concordance between eyes. The inferonasal 21lens quadrant was the most common location involved both for new cataract development and for progression of preexisting cataract. Cataract formation in this quadrant was presumed to be the most consistent with ultraviolet radiation damage on the basis of greater exposure in this area of the lens. Resnikoff et al studied the association of lens opacities with two other presumed ultraviolet radiation-associated ocular diseases, climatic droplet keratopathy and exfoliation syndrome. There was a strong correlation between the diseases in this case-control study.

Based on the available epidemiological evidence, the following conclusions can be drawn:

It is estimated that between 10 to 60% of patients using systemic corticosteroids develop cataract, especially of the posterior subcapsular (PSC) type. Glucocorticosteroids are lipophilic and therefore diffuse easily across the cell membrane after which they bind and activate a cytoplasmic glucocorticoid receptor. The resulting receptor steroid complex enters the cell nucleus, binds to the glucocorticoid response elements on the DNA and up- or downregulates the expression of corticosteroid-responsive genes with resultant effects on protein synthesis in target tissues.

Several ways have been identified in which corticosteroids may induce cataract formation including:

Posterior subcapsular cataract is the hallmark of steroid cataract. It starts as fine granular and vacuolated opacities at the posterior aspect of the lens. PSC opacities occur frequently with high doses (more than 15 mg prednisone or equivalent per day) and prolonged use (more than one year) of corticosteroids. Clinical trials have shown that PSC opacities secondary to oral corticosteroids may develop within as short a time as 4 months.

Recent studies have suggested that the use of inhaled corticosteroids may be a significant risk factor for the development of cataract, may be even more so than the use of oral corticosteroids. These studies have again pointed out the importance of the “first-order effect”. A drug absorbed through the nasal mucosa or conjunctiva “drains” to the right atrium and ventricle. The drug is then pumped in part, to the head (i.e. the eye as a target organ) before returning to the left atrium and ventricle. The second passage is then to the liver and kidneys, where the drug is metabolized and detoxified. With oral medication—the first pass includes absorption from the gut via the liver where, depending on the drug, more than 90% of the drug is detoxified before going to the right atrium. Therefore, oral medications are metabolized even before the first pass, while ocular or nasally administered drugs are not metabolized until the second pass. This, in part, may be a reason why more potent steroid inhalants have greater ocular exposure and some ocular medications cause significant systemic adverse effects.

Considering the widespread use of corticosteroids and their association with PSC cataract, clinicians should be aware of a patient's medication history and recognize the distinguishing features of PSC cataract.22

In 1982, Fraunfelder et al reported 30 cases of cortical and subcapsular cataract associated with long-term use of allopurinol reported to the National Registry of Drug-Induced Ocular Side Effects (Oregon Health Sciences University, Portland). The observed lens changes appeared to have the characteristics of early age-related cataract. At about the same time, Lerman et al used phosphorescence spectroscopy to demonstrate in vitro the probable presence of allopurinol in cataractous lenses that had been extracted from patients treated with allopurinol. The phosphorescence peaks characteristic of allopurinol could not be demonstrated in lenses from patients who had not ingested allopurinol. Evidence from epidemiologic studies on the possible cataractogenic effects of allopurinol is, however, inconclusive. Two separate epidemiologic studies did not show an increased risk. Another study reported an unusual morphologic thinning of the anterior clear zone of the lens in patients receiving long-term treatment with allopurinol. In the Lens Opacities Case Control Study, wherein gout medications were found to be associated with a 2.5-fold increased risk of mixed cataract, no distinction was made between allopurinol and other medications for gout. In a case control study conducted by Garbe et al using data from the Quebec universal health program for all elderly patients they established that a clear relationship exists between the long-term administration of allopurinol and an increased risk for cataract extraction.

Given the paucity and limitations of available epidemiologic data, more studies, such as those characterizing the specific types of senile cataract and phenothiazines, are needed to verify any association.

The calcium channel blocker nifedipine has been associated with increased risk of cataract extraction and angiotensin-converting enzyme inhibitors with decreased risk of nuclear cataract. Hypertension and other cardiovascular conditions is a potential confounding problem in studies of cataract and antihypertensive medications, including diuretics.

Because malaria is a disease most prevalent in regions of high light intensity, protective measures (clothing, sunblock, sunglasses or eye wraps) should be recommended whilst taking antimalarial drugs.

The clinical safety trials indicate that treatment with lovastatin for up to five years does not significantly increase the development of cataract or grossly alter visual function. The ocular safety in an older patient population (>50 years) appears high. This seems also to apply to simvastin, except that one clinical trial showed a significant increase in cortical opacities with the use of this drug (Figure 1.15).

An unpublished study conducted at the University of Stellenbosch Medical School found that the rate at which opacification occurs in dyslipidemic patients on Cerivastatin was 4.5% per year (Figure 1.15). Although this rate of opacification is not statistically noteworthy it would seem that if these data are projected over a period of 20 years and compared the normal rate of opacification reported by Boccuzzi and Leino et al, an alarming amount of opacities would be present in the group of patients on cerivistatin.

Hypolipidemic drugs are intended for life-long use and patients as young as 18 years can receive these drugs. Although the human lens grows throughout life, the rate of growth is slow after 10 years of age. About 40 years are required for the lens cortex to double in width. The size of the nucleus remains essentially constant after 10 years of age. Thus, the consequences of inhibiting lens growth due to block of cholesterol biosynthesis may be difficult to assess in only a 1 to 5 years period. A considerable body of evidence indicates that sustained alteration of lens sterol content and composition due to genetic mutations or exposure to drugs can lead to altered lens clarity. Long-term ocular safety of the vastatin drugs should perhaps be viewed in units of 10 to 20 years. Certainly a 20-year-old person required to have cataract surgery at age 40 because of some chronic treatment would constitute a medical crisis for this individual, particularly if a less toxic treatment had been available.