Natural Therapies for Ocular Disorders Part Two:
Cataracts and GlaucomaThis section is compiled by Frank M. Painter, D.C.
Send all comments or additions to: Frankp@chiro.org
FROM: Alternative Medicine Review 2001 (Apr); 6 (2): 141–166 ~ FULL TEXT
Kathleen A. Head, NDIntroduction
Part one of this article was published in the October 1999 issue of Alternative Medicine Review and discussed nutritional and botanical approaches to conditions of the retina. This second part covers alternative treatments for nonretinal disorders: senile cataracts, diabetic cataracts, and chronic open-angle glaucoma.
A large percentage of blindness in the world is nutritionally preventable. [1] The author of this comment was referring primarily to the use of vitamin A to prevent corneal degeneration associated with a vitamin A deficiency; however, there is considerable evidence that many other eye conditions, which are leading causes of vision impairment and blindness, also may be preventable with nutritional supplementation, botanical medicines, diet, and other lifestyle changes. In addition, a number of nutrients hold promise for the treatment of already existing cataracts and glaucoma.
Senile Cataracts
Senile cataracts are the leading cause of impaired vision in the United States, with a large percentage of the geriatric population exhibiting some signs of the lesion. Over one million cataract surgeries are performed yearly in this country alone. [2] Cataracts are developmental or degenerative opacities of the lens of the eye, generally characterized by a gradual painless loss of vision. The extent of the vision loss depends on the size and location of the cataract. Cataracts may be located in the center of the lens (nuclear), in the superficial cortex (cortical), or in the posterior subcapsular area. Cataracts are also classified according to their color, which is consistent with location and density of the cataract. Pale yellow cataracts are typically slight opacities of the cortex, subcapsular region, or both; yellow or light brown cataracts are consistent with moderate to intense opacities of the cortex, nucleus, or both; and brown cataracts are associated with dense nuclear cataracts. [3]
Diagnosis
Symptoms include near vision image blur, abnormal color perception, monocular diplopia, glare, and impaired visual acuity, and may vary depending on location of the cataract. For example, if the opacity is located in the center of the lens (nuclear cataract), myopia is often a symptom, whereas posterior subcapsular cataracts tend to be most noticeable in bright light. [4] Ophthalmoscopic examination is best conducted on a dilated pupil, holding the scope approximately one foot away. Small cataracts appear as dark defects against the red reflex, whereas a large cataract may completely obliterate the red reflex. Once a cataract has been established, a referral for slit-lamp examination, which provides more detail on location and extent of opacity, is recommended.
Etiological/Risk Factors
Factors contributing to cataract formation include aging, smoking, [5] exposure to UVB and ionizing radiation, [6] oxidative stress (secondary to other risk factors such as aging or smoking), [7] dietary factors, [8] increased body weight (above 22-percent body fat), central obesity, [9] and family history. Medications and environmental exposures which may contribute to cataract formation include steroids, gout medications, and heavy metal exposure. Cadmium, copper, lead,10 iron, and nickel11 have all been found in cataractous lenses. A high level of cadmium in the lens is associated with smoking and can contribute to accumulation of other heavy metals. [10] Conditions which predispose to cataracts include diabetes, galactosemia, neurofibromatosis, hypothyroidism, hyperparathyroidism, hypervitaminosis D, infectious diseases such as toxoplasmosis, and several syndromes caused by chromosomal disorders. [2]
Mechanisms Involved in the Pathophysiology of Cataracts
Cataracts are characterized by electrolyte disturbances resulting in osmotic imbalances. Derangements in the function of the membrane resulting in ion imbalance may be due to increased membrane permeability or to a depression of the Na+/K+ pump because of interference with the enzyme Na+/K+ ATPase. [12]
Cataracts are also characterized by aggregates of insoluble proteins. [12] Oxidative insult appears to be involved as a precipitating factor in all cataracts. Lens proteins typically remain in their reduced form. However, in cataractous lenses, the proteins are found in an insoluble, oxidized form. Oxidation may occur as a result of many factors (see Etiological Factors). Higher levels of hydrogen peroxide have been found in cataractous lenses when compared to normal controls. [13] Normally the lens contains significant levels of reduced glutathione (GSH), which keeps the proteins in their reduced form. However, there are significantly lower levels of GSH in cataractous lenses. Advanced glycation end products (AGE) appear to play a role in cataract formation. Researchers have tested the hypothesis that the major AGE formed in the lens has an EDTA-like structure, capable of binding to copper. They found copper binding was 20-30 percent greater in the older, cataractous lens protein fractions than in young, non-cataractous fractions. The prooxidant copper precipitates further oxidation, creating a vicious cycle. The researchers hypothesized that, “chelation therapy could be beneficial in delaying cataractogenesis.” [14] Other researchers have confirmed the involvement of transition metals, copper and iron, as instigators of ascorbyl and hydroxyl radical formation in cataracts. [15]
The Role of Glutathione in Lens Metabolism
In order to fully understand the mechanisms involved in cataract formation and the link to nutritional prevention, it is important to understand the role glutathione and its enzyme co-factors play in metabolism within the lens. In vitro studies of incubated lenses from animals as well as humans have helped elucidate the mechanisms involved.
The lens of the eye is avascular, depending entirely on passive diffusion, active transport, and intra-lens synthesis for nutrients and other substances important for metabolism. As a result, the content of the surrounding intraocular fluids (aqueous humor) is relevant. While levels of GSH are high in the lens, they are relatively low in the aqueous humor; thus, glutathione appears to be synthesized within the lens. Glutathione is composed of the amino acids cysteine, glutamic acid, and glycine, and its synthesis within the lens takes place in two steps (Figure 1). Cataractous lenses can demonstrate dramatic decreases in GSH, as much as 81 percent, when compared to normal lenses. [3] Researchers have examined this phenomenon in an attempt to determine whether low GSH is due to decreased synthesis or increased degradation. Decreases in the enzymes involved in both synthesis (?glutamyl transferase) and recycling (glutathione reductase) of GSH from oxidized glutathione (GSSG) lend credence to the theory that synthesis is diminished in cataractous lenses. [3]
These same researchers found a decrease in the activity of enzymes of GSH degradation (glutathione peroxidase and glutathione s-transferase) which should result in an increased rather than a decreased accumulation of GSH. They therefore concluded that the loss of activity of these enzymes was not enough to offset the losses associated with decreased synthesis. They also did not rule out the possible loss of GSH from the lens via membrane leakage.
There are several ways in which glutathione or its depletion can affect the opacity of the lens. A review by primary researchers on glutathione metabolism and its relationship to cataract formation outlines three possible mechanisms of cataract prevention by glutathione: [16] (1) maintaining sulfhydryl (SH) groups on proteins in their reduced form preventing disulfide cross-linkage; (2) protecting SH groups on proteins important for active transport and membrane permeability; and (3) preventing oxidative damage from hydrogen peroxide ( H2O2 ).
Considering the first mechanism by which GSH can protect lenses from opacities, there is an increase in high molecular weight (HMW) proteins in cataractous lenses. These protein aggregates contribute to lens opacity and are found particularly in dense cataracts. Reddy and Giblin examined x-ray-induced cataracts in rabbits and found increased levels of disulfide bonds, confirming their assertion that oxidation of SH groups resulted in disulfide bond formation and HMW proteins. They also found that SH groups on proteins only become oxidized when levels of GSH drop below some critical level. [16] Other researchers have found an increase in disulfide bonds in human cataractous lenses. [17]
Maintaining normal cell volume and transport of electrolytes are important factors in lens transparency. Glutathione may play a role in maintaining normal lens permeability and active cation transport by protecting sulfhydryl groups in the cell membrane from oxidation. Oxidation of SH groups on the surface of the cell membrane results in increased permeability, and oxidation of important SH groups of Na+/K+ ATPase impedes active transport. Reddy et al examined the effect of GSH depletion on rabbit lenses and found it directly led to increased membrane permeability. [18] While GSH depletion did not directly impair active transport, it resulted in increased susceptibility of the Na+/K+ pump to oxidative damage by H2O2 . Oxidation of GSH resulted in a 70-percent decrease in active transport and a two-fold increase in membrane permeability. Other experiments have found that lensepithelial-GSH needs to be depleted by about 60 percent for these changes to occur. The authors point out that, “the lens has a remarkable ability to regenerate reduced glutathione.” However, they found that, although the change in membrane permeability was reversible with the regeneration of GSH, the decrease in pump activity was irreversibly affected. [16]
H2O2 is found in the aqueous humor in humans as well as other species. GSH is involved in detoxifying this reactive oxygen species to water in a coupled reaction involving NADPH (Figure 2). Without detoxification the peroxide radicals would damage the lens membranes and susceptible protein groups. The researchers found both normal human and rabbit lenses with high GSH content were apidly able to detoxify H2O2 in culture medium. [16] Lenses pretreated with methyl mercury, which decreased the concentration of GSH by 75 percent, were less able to detoxify the peroxide radicals.
Other researchers have postulated a possible diffusion problem. Normally GSH is synthesized and regenerated in the lens cortex and then diffuses to other areas of the lens. Cataracts of the elderly are primarily in the nucleus. Researchers examined normal human lenses in vitro and found the older ones appeared to have a barrier to diffusion of GSH from the cortex to the nucleus. [19]
Specific Nutrients and Prevention of Cataracts
Oxidation of lens proteins is part of the pathophysiology of cataracts. Therefore, it is no surprise that antioxidants may help prevent the formation of cataracts.Carotenes and Vitamin A: Epidemiological Evidence Levels of nutrients, including carotenoids, have been examined in human cataractous lenses after extraction using high performance liquid chromatography. Vitamins A and E and the carotenoids lutein and zeaxanthin were found. The newer, epithelial/outer cortex layer had more carotenoids, tocopherol, and retinol (approximately 3-, 1.8-, and 1.3-fold higher, respectively) than the older, inner cortex/nuclear portion.20 Other studies have quantified significant levels of lutein, zeaxanthin, and alpha- and gamma-tocopherol in the lens. [21]
A prospective study of the effect of carotenes and vitamin A on the risk of cataract formation was conducted as part of the Nurses' Health Study. A total of 77,466 female nurses, ages 45-71 years, were included in the study, which involved food-frequency questionnaires over a 12-year period. After other risk factors were controlled for, including smoking and age, those in the highest quintile for consumption of lutein and zeaxanthin had a 22-percent decreased risk of cataract extraction compared with those in the lowest quintile. [22]
Another cohort of the Nurses' Health Study followed 50,823 women, ages 45-67, for eight years and found women in the highest quintile of vitamin A consumption had a 39-percent lower risk of developing cataracts compared to women in the lowest quintile. [23]
In a similar study of male health professionals in the United States, 36,644 participants, ages 45-75 years, were followed for eight years with periodic dietary questionnaires. Men in the highest quintile for lutein and zeaxanthin intake had a 19-percent decreased risk of cataract extraction when smoking, age, and other risk factors were controlled for. [24] Neither the women nor the men demonstrated a decreased risk of cataract with intakes of other carotenoids (a-carotene, b-carotene, lycopene, or beta-cryptoxanthin). It is hypothesized the protective effect of the carotenoids may be due to quenching reactive oxygen species generated by exposure to ultraviolet light. [25]
The Beaver Dam Eye Study examined risk for developing nuclear cataracts in 252 subjects who were followed over a five-year period. Only a trend toward an inverse relationship between serum lutein and cryptoxanthin and risk of cataract development was noted. [26]
Vitamin E: Animal, Epidemiological, and Clinical Studies As a fat-soluble antioxidant, it is reasonable to predict a positive role for vitamin E as a cataract preventive in the lens cell membrane. Animal, epidemiological, and clinical studies help confirm this hypothesis. A placebo-controlled animal study found 100 IU d-alpha-tocopherol injected subcutaneously prevented ionizing radiation damage to the lens, which did occur in rats not supplemented with vitamin E. [27] Two other animal studies using vitamin E instilled in the eyes as drops confirmed the preventive effect of vitamin E, at least when used topically. [28,29]
Several human studies have found low levels of vitamin E intake are associated with increased risk for cataract development. An epidemiological investigation examined self-reported supplementary vitamin consumption of 175 cataract patients compared to 175 matched individuals without cataracts. The cataract-free group used significantly more vitamin E (p=0.004) and vitamin C (p=0.01) than the cataract group, resulting in at least a 50-percent reduction in cataract risk in the supplemented group. [30] An Italian study compared 207 patients with cataracts to 706 control subjects in a hospital setting. Vitamin E, in addition to a number of other nutritional factors, was associated with a decreased risk for cataract. [8]
The Vitamin E and Cataract Prevention Study (VECAT) is a four-year, prospective, randomized, controlled trial of vitamin E versus placebo for cataract prevention in a population of healthy volunteers, ages 55-80 years. [31] Although results are still pending, data was collected on prior use of vitamin E and incidence of cataract in 1,111 participants. A statistically significant relationship was found between past vitamin E supplementation and prevention of cortical cataract but not nuclear cataract. [32]
The Lens Opacities Case-Control Study was designed to determine risk factors for cataracts in 1,380 participants, ages 40-79 years. Blood chemistry and levels of vitamin E and selenium were performed on all patients. The risk of developing cataracts was reduced to less than one-half (odds ratio 0.44 for nuclear cataracts) in subjects with higher levels of vitamin E. [33] Some of these same researchers examined the association between antioxidants and the risk of cataract in the Longitudinal Study of Cataract. Dietary intake, use of supplements, and plasma vitamin E levels were assessed on 764 participants. Lens opacities were examined on a yearly basis and the risk of development of cataract was 30-percent less in regular users of a multiple vitamin, 57-percent less in regular users of supplemental vitamin E, and 42-percent less is those with higher plasma levels of vitamin E. [34]
In a randomized trial of 50 patients with early cataracts, subjects were assigned to receive either 100 mg vitamin E twice daily or placebo for 30 days. There was a significantly smaller increase in the size of cortical cataracts in the vitamin E group compared to placebo. While increases of vitamin E were found in both nuclear and cortical lens homogenates after surgical removal, GSH levels were increased significantly only in those with cortical cataracts receiving vitamin E. In addition, the malondialdehyde (MDA) Ñ a measure of oxidative stress Ñ levels and glutathione peroxidase levels were higher in cortical cataract/vitamin E users than in the nuclear cataract/vitamin E group. [35] Some conclusions that can be drawn from this study are:(1) vitamin E decreases oxidative stress in cataractous lenses;
(2) part of vitamin E's protective effect is due to enhancement of GSH levels; and
(3) vitamin E seems to be more protective for cortical than nuclear cataracts, at least in this short-term study.Vitamin C and Risk of Cataracts Animal experimentation has shed some light on ascorbic acid and its role in cataract formation. Cataracts induced in chick embryos by the application of hydrocortisone were prevented by the introduction of vitamin C to the developing embryo. In addition, vitamin C slowed the decline in GSH levels, which occurred with the cortisone treatment. [36]
Ascorbic acid is normally found in high concentrations in the aqueous humor and lens in humans. A group of 44 subjects were supplemented with 2 g daily ascorbic acid. Significant increases in vitamin C in lens, aqueous humor, and plasma were noted. [37] In another study, lenses were exposed in vitro to light, which caused an increase in superoxide radicals and subsequent damage to the Na+/ K+ pump. The damage was prevented by addition of vitamin C in doses comparable to what would be found in the aqueous humor. [38]
In the Nurses’ Health Study supplemental vitamin C for a period of 10 years or greater was associated with a 77-percent lower incidence of early lens opacities and an 83- percent lower incidence of moderate lens opacities. In this study, no significant protection was noted from vitamin C supplementation of less than 10 years. [39]
Riboflavin Riboflavin is a precursor to flavin adenine dinucleotide (FAD), which is a coenzyme for glutathione reductase. In vitro evaluations of surgically removed cataracts have confirmed inactivity of glutathione reductase enzyme activity in a significant number of cataracts examined. Furthermore, the activity was restored by the addition of FAD. [40]
It is not surprising then that a deficiency of riboflavin has been implicated as a cause of cataract formation. A study of B vitamin nutritional status of cataract patients (n=37) compared to age-matched controls without cataract (n=16) found that 80 percent of those with cataracts and only 12.5 percent of control subjects had a riboflavin deficiency. [41] The same researcher tested for, but did not find, a deficiency of thiamin or pyridoxine in cataract patients. Other researchers have found a relationship between riboflavin deficiency and later-stage cataracts, but not in early cataract formation. [42] The Lens Opacities Case-Control Study found that lens opacities were associated with lower levels of riboflavin which were assessed by RBC enzyme assays and dietary intake reports.
Data collected during cancer intervention trials in Linxian, China, were assessed for nutrient effects on other conditions, including cataracts. Two randomized, double-blind, controlled studies of cataract risk resulted from the Linxian study. In the first trial 12,141 participants, ages 45-74, were supplemented for five to six years with either a multiple vitamin- mineral or placebo. There was a statistically significant 36-percent reduction in incidence of nuclear cataract for subjects ages 65- 74 years given the multiple vitamin. In the second trial 23,249 participants were given one of four different vitamin/mineral combinations:(1) retinol/zinc,
(2) riboflavin/niacin,
(3) ascorbic acid/molybdenum, or
(4) selenium/alpha-tocopherol/beta carotene.Again, the most significant effect was noted in people age 65-74, with a 44-percent decrease in nuclear cataract risk in the group taking riboflavin/niacin (3 mg riboflavin/40 mg niacin). No significant protection was noted for the other nutrient combinations or for protection from cortical cataracts. [43]
A series of case reports from the University of Georgia treated 24 cataract patients (18 with lens opacities and six with fully-developed cataracts) with 15 mg riboflavin daily. Dramatic improvement was reported within 24-48 hours, and after nine months all lens opacities disappeared. [44] Larger, double-blind, placebo-controlled trials are needed to confirm these seemingly dramatic improvements.
Other B Vitamins Pantethine is the active coenzyme form of pantothenic acid (vitamin B5). Several animal studies have found pantethine can prevent chemically-induced cataracts if given within eight hours of exposure to lens insult. [45-47] The proposed mechanism of action was the prevention of the formation of insoluble proteins in the lens. [45]
Folic acid has been found to be low in those prone to cataracts. An Italian epidemiological survey found those in the highest quintile for folic acid consumption were only 40 percent as likely to develop cataracts than those in the lowest quintile. [8]
Selenium and Cataracts A decrease in glutathione peroxidase activity has been found in the lenses of selenium- deficient rats. Concomitantly, an increase in MDA and free radicals was also noted in both the selenium-deficient and vitamin-E deficient groups. [48] Evaluation of selenium levels in humans has found lower than normal levels of selenium in sera and aqueous humor in cataract patients. [49] The significance of low serum levels is unclear and the relationship between selenium and cataract risk demands further evaluation.
Dietary Factors in Cataract Risk Several epidemiological studies have found dietary links to increased or decreased risk of cataract. An Italian in-hospital study examined dietary patterns and incidence of cataract extraction. Significant inverse relationships were seen between meat, spinach, cheese, cruciferous vegetables, tomatoes, peppers, citrus fruits, and melon. An increased risk was found in those with the highest intakes of butter, total fat, salt, and oil (except olive oil). [8] The Nurses’ Health Study found regular consumption of spinach and kale was moderately protective for cataracts in women. [22] The Health Professionals Follow-up Study found spinach and broccoli decreased risk of cataract in men. [24]
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