We found a strong inverse association between vitamin C and cataract. The results confirm those from our previous feasibility study.6
The present study was 5 times larger, included participants from both north and south India, and added dietary measures of vitamin C. To our knowledge, this is the first large population-based study to provide evidence from a low- or middle-income country on vitamin C and cataract.
Plasma vitamin C levels in our study were low. We think it unlikely that the low values were due to degradation of the samples. Considerable care was taken in the collection, processing, and transport of the samples, and our assay was carefully standardized. Moreover, the results show typical patterns observed in other studies, such as lower levels in men and tobacco users.14
It is unlikely that these patterns would be preserved if the blood samples had degraded. The few studies that have measured plasma vitamin C levels in India, including our feasibility study, also reported low levels.6,15,16
In a population aged 20–50 years, the mean plasma vitamin C was 18 μmol/L and 74% had values <22.7 μmol/L. In a case-control study of cataract in an older age group (50–70 years), the mean plasma vitamin C levels were ~13 μmol/L in controls.
Epidemiologic studies have examined associations with cataract and vitamin C, but there is limited evidence from India.16,17
The US-India case-control study conducted in the northern part of India found an unexpected positive association between plasma vitamin C and the combination of nuclear with PSC cataract; however, an antioxidant index estimated from glutathione peroxidase, ascorbic acid, vitamin E, and glucose-6-phosphate dehydrogenase was strongly inversely associated.17
In a case-control study from western India, plasma ascorbic acid was lower in low-income cataract cases compared with low-income controls; it was unclear which, if any, potential confounders were included in the analysis.16
In other epidemiologic studies, predominantly conducted in high-income countries, plasma vitamin C levels were substantially higher than in our study. For example, in 3 studies that reported a significant inverse association with plasma vitamin C and cataract (2 from southern Europe and 1 from the United States), the lowest quintile of plasma vitamin C was <50 μmol/L18,19
or <30 μmol/L,20
and the highest quintile was approximately 70 μmol/L19,20
or >86 μmol/L in the Nutrition and Vision project18
(possibly reflecting that the study was conducted only in women). By comparison in the India Age-Related Eye Disease Study, the lowest and highest quintile cut points were <2 and >21 μmol/L. In the National Health and Nutrition Examination Survey, a 1 mg/dL increase in serum vitamin C (equivalent to a 58 μmol/L increase) was associated with a 26% reduction in self-reported cataract.21
The average vitamin C levels were 62 μmol/L (standard deviation = 28). In our study, the association of vitamin C with cataract was across the range of vitamin C levels in our population and not found only for those with clinical deficiency (<11 μmol/L). The finding of gradients of risk across different levels of plasma vitamin C suggests that, at least within the range of vitamin C levels in the studies, there is no clear threshold above which there is no additional benefit or indeed adverse effect. These comments are tentative because of the relative paucity of studies that have investigated plasma vitamin C and cataract and the inconsistent findings in results from high-income countries. No association between plasma vitamin C and cataract was found in the Pathologies Oculaires Liées à l'Age (POLA) study in southern France (mean vitamin C ~35 μmol/L)22
or in an older age group in the United Kingdom (OR for nuclear cataract = 1.0 [95% CI, 0.5–1.9] for levels <24 μmol/L compared with >57 μmol/L).23
In the Baltimore Longitudinal Study on Aging in the United States, no association was found with nuclear (OR 1.31; 95% CI, 0.65–2.60) or cortical cataract with plasma vitamin C (<60 μmol/L) compared with high levels (>82 μmol/L).24
In a study in a Hong Kong fishing community, no significant association was found between plasma vitamin C <40 μmol/L compared with >80 μmol/L and either early (OR 0.7; 95% CI, 0.3–1.6) or late cataract (OR 0.8; 95% CI, 0.2–3.2).25
Many of these studies were small, for example with less than 500 participants,18,23–25
and low powered to detect other than large effects.
The associations with plasma vitamin C and cataract were attenuated slightly when other blood antioxidants were included in the model. Inverse associations with cataract remained for lutein, zeaxanthin, and retinol, but not for β-carotene or α-tocopherol. Evidence from other studies on these blood antioxidants is relatively sparse, especially from studies that included also vitamin C. Of the studies that investigated β-carotene,19,20,23,24
found an inverse association, but this study did not adjust for other antioxidants. Two studies investigated plasma lutein and zeaxanthin.23,26
Only one, the POLA study, found a significant inverse association with zeaxanthin and no association for lutein, although the OR for nuclear cataract was in the direction of benefit (OR 0.6).26
The POLA study was also the only study to report a significant inverse association with retinol, whereas 3 other studies found no association.19,20,24
Lutein and zeaxanthin levels in the POLA study were comparable to those in our study, but retinol levels were higher. Of the studies that have investigated α-tocopherol,19,20,23,24,27
only one reported an inverse association with nuclear cataract,24
whereas higher ORs between 2 and 3 were associated with high levels of α-tocopherol and cortical and PSC opacities in the Italian American Study.20
In all these studies, the levels of α-tocopherol were higher than in our participants. Other studies have also investigated associations with blood carotenoids or tocopherols, with some studies reporting inverse associations for lutein and zeaxanthin28
or all tocopherols.32
However, none of these studies measured blood vitamin C and could not evaluate the independent association with these other antioxidants.
We examined associations by type of cataract. Associations with vitamin C remained strong for all types of cataract irrespective of whether other antioxidants were included in the models. The associations were stronger for vitamin C and PSC cataract, but the large number of people with mixed cataracts, especially nuclear cataracts, limits the interpretation of these results. In analyses of vitamin C alone, there was some evidence that the association was stronger in north India compared with south India (P for interaction ~0.1 for nuclear and PSC cataract). The interaction was weaker when other antioxidants were included.
There is strong biological plausibility for the importance of vitamin C in the lens. Vitamin C is found at concentrations in lens or aqueous of approximately 20- to 30-fold that of the plasma33
and even higher in the vitreous.34
Early studies in India were among the first to report that vitamin C concentrations measured in the aqueous of patients undergoing cataract extraction were higher in those with normal lenses compared with those with mature cataracts.35
The authors also noted that aqueous vitamin C levels in the Indian studies were considerably lower than those reported for equivalent studies on vitamin C in aqueous in western populations. Vitamin C is a powerful reducing agent and protects the lens from oxidative stress. Lutein, zeaxanthin, and α-tocopherol have been detected in human lenses but at similar levels to plasma, whereas α-carotene, β-carotene, lycopene, and β-cryptoxanthin have not been detected.36
Vitamin C acts synergistically with vitamin E, and both vitamins C and E maintain the antioxidant activity of glutathione.37
Randomized controlled trials (RCTs) of antioxidant supplementation have shown largely negative results on cataract.38
Single vitamin supplementation trials found no benefit from vitamin E alone39,40
or from β-carotene alone.41,42
Two placebo-controlled factorial trials found no effect of either vitamin E and vitamin C43
or α-tocopherol and β-carotene.44
There was no benefit from high-dose multivitamin supplement (vitamins C and E, and β-carotene) in the Age-Related Eye Disease Study.45
An RCT in Italy with a longer follow-up than most trials found a reduced rate of progression of nuclear opacities after an average 9 years of a broad multivitamin/mineral supplement use;46
that trial also found an increase in PSC opacities. One RCT has been undertaken in India and reported no benefit in the rate of progression of opacities over a 5-year period from supplementation with high-dose vitamins A, C, and E.47
The trial was small (n=798), and although it was powered to detect a small change in nuclear opacity, the use of clinical grading at the slit lamp may have led to random errors in grading. The study duration also may have been too short.
In our study, dietary intakes of vitamin C also showed an inverse association with cataract. In high-income countries, associations with dietary vitamin C and cataract have been reported in some studies18,19,48,49
but not in others.50,51
There are no comparable data on associations with cataract and dietary vitamin C in India or other low- or middle-income countries. Caution is required in comparing dietary intake levels across studies because of the variations in dietary assessment methods and food composition tables. We used the ICMR food composition tables, which provide values of vitamin C from food items common to the Indian population.
In our study, measurement of diet and blood antioxidants were made at the same time as determination of lens status, making it more difficult to establish the temporal relationship between vitamin C and cataract. There is no evidence that cataract can lead to a change in blood antioxidant level for biological reasons, nor is it likely that plasma vitamin C status was influenced by supplementation because use of any nutritional supplement was rare in our participants. We cannot exclude the possibility that reduced household income due to a family member with cataract may have influenced diet. Other limitations in our study include a single measurement of vitamin C and dietary intake increasing the possibility of measurement error diluting the associations. We attempted to minimize recall error by using a method that made little demand on participants because they were only asked to describe the meals in the previous 24 hours. Other dietary methods such as 3- or 5-day weighed intakes are preferable measures of usual intakes but are more resource intensive, whereas food-frequency questionnaires are relatively novel in the Indian setting. We had no information from the ICMR tables of dietary intakes of lutein and zeaxanthin or retinol and could not assess the association of dietary intakes of these nutrients. The strengths of our study include the large sample size and precision of our results, the high response rates, the recruitment of participants from 2 different geographic areas of India, the collection of information on a wide range of potential confounders, the accurate measurement of cataract through lens photography, and the quality assurance in grading.
In conclusion, the strong association with vitamin C and cataract in our vitamin C–depleted population may, in part, explain the high levels of cataract in India. Studies are needed on vitamin C and cataract in other vitamin C–depleted populations.