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Lutein, zeaxanthine, and AMD: Authors' response.
Submit responseDear Editor
Regarding the comments by Beaumont and Kang to our letter "Does dietary lutein and zeaxanthin increase the risk of age-related macular degeneration?" (Vu et al., BJO 2006;90:389), we feel that a dual standard is used in this letter to accept or reject data. How many of the case-control studies or cohort studies (that rely on self reported data on both exposure and outcome) that are used to support the notion of a protective effect of lutein and zeaxanthin come close to meeting any of the criteria set out in the letter?
The reanalysis of our data is invalid because of the "J" shaped distribution of data. With such a distribution, one could pick different cut points, and be able to rationalize their selection, and use these data to show either a positive or a negative association. A binary analysis is too simplistic for a quadratic function. This is one of the key points of this presentation. Another is that this is a true population-based cohort, examined before the promotion and advertising of diet and supplements for treating or preventing AMD.
Beaumont and Kang make a good point about confusion undermining confidence in public health messages. Many have taken early encouraging reports from methodologically variable case control and cohort studies as a basis to actively promote dietary intake and supplementation of lutein and zeaxanthin. Our study does have limitations and no observation study will ever be definitive. What is required is a careful, prospective trial in a study cohort that closely mirrors the general population.
Answering the specific questions:
Calculations of carotenoid and fatty acid intake were based on data from the USDA and Australian data, respectively. Because intakes of fruit and vegetables may be over-estimated by FFQs [1, 2], global questions on fruit and vegetable intake were used to scale the intakes of individual items to match the reported total intakes of fruit and vegetables.
Plasma biomarkers were used in another Cancer Council study to evaluate FFQ estimates of fatty acids [3] and carotenoids (unpublished). The crude correlation coefficient for plasma phospholipid vs FFQ linoleic acid (as percentage of total fatty acids) in 4439 people was 0.20 (0.17- 0.23), after adjusting for the reliability of each measurement the correlation coefficient was 0.58 (0.38-0.73). For lutein/zeaxanthin (n=3044), the correlation coefficient for plasma versus dietary levels was 0.29 (0.26-0.33), very similar to the results for ß-carotene and lycopene. The reliability coefficient for dietary lutein/zeaxanthin over 12 months was 0.34 (n=242) and for plasma 0.47 (n=73). Adjustment for this intra- person variation gave a correlation coefficient of 0.72. Although these correlations are not very high they are similar or better than in the other studies [4, 5]. Errors in the estimates due to random misclassification of intake usually attenuate true associations, rather than create spurious positive associations.
The intake of lutein/zeaxanthin reported for the population-based Melbourne VIP study is low compared with the self-reported volunteer Nurse's Health Study and Health Professional's Follow-Up Study. However the mean of around 800 microgram/day was similar to that observed using a different FFQ in an older Australian population, the BMES, of around 900 microgram/day. It shows the healthy participant bias possible in cohort and case-control studies. The mean intake is equivalent to around 7 g of raw spinach; the average serve of spinach in Australia is around 90 g.
People with AMD could have increased their consumption of fruit and vegetables. However, this is unlikely in this sample, as the association between eye health and carotenoids was probably not so well known in the 1990s when the FFQs were completed.
References
1. Michels KB, Welch AA, Luben R, Bingham SA, Day NE: Measurement of fruit and vegetable consumption with diet questionnaires and implications for analyses and interpretation. Am J Epidemiol 161:987-994, 2005
2. Salvini S, Hunter DJ, Sampson L, Stampfer MJ, Colditz GA, Rosner B, Willett WC: Food-based validation of a dietary questionnaire: the effects of a week-to-week variation in food consumption. Int J Epidemiol 18:858- 867, 1989
3. Hodge AM, Simpson JA, Gibson RA, Sinclair AJ, Makrides M, O'Dea K, English DR, Giles GG: Plasma phospholipid fatty acid composition as a biomarker of habitual dietary fat intake in an ethnically diverse cohort. Nutrition, Metabolism and Cardiovascular Diseases in press, 2006
4. Ma J, Folsom A, Shahar E, Eckfeldt J: Plasma fatty acid composition as an indicator of habitual dietary fat intake in middle-aged adults. Am J Clin Nutr 62:564-571, 1995
5. Michaud DS, Giovannucci EL, Ascherio A, Rimm EB, Forman MR, Sampson L, Willett WC: Associations of plasma carotenoid concentrations and dietary intake of specific carotenoids in samples of two prospective cohort studies using a new carotenoid database. Cancer Epidemiology, Biomarkers & Prevention 7:283-290, 1998
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Re: Dietary lutein and zeaxanthin (LZ) and the risk of age related macular degeneration?
Submit responseDear Editor,
We are deeply concerned by the conclusion made by Vu et al that “there was a harmful effect of higher LZ intake on AMD among those with high level of linoleic acid intake. Based on these data LZ supplementation could not be recommended”.1 It is counterintuitive, and goes against the evidence currently available in the literature.2,3 The most likely explanation is that their results reflect the success of the public health messages put out to patients with AMD about eating foods high in antioxidants, such as green leafy vegetables and spinach. This important message is in danger of being undermined by such pronouncements.
It is our opinion that the letters section of a medical journal is not the place to publish contentious nutritional epidemiological data. It is too complex, and the limitation on the number of words does not allow an adequate disclosure of methods and results, or an appropriate depth of discussion. The readers, therefore, are not able to properly interpret the data. This type of article cannot be properly peer reviewed without the submission of much more data than was given in this case.
There are a number of problems with this study. The possibility of selection bias is a particular concern where the study is evaluating only 65 % of the original target population and is only examining crossectional data. The statistical method used to calculate the odds ratios was not given, although it could be assumed that a logistic regression model would have been applied. A close examination of the results indicates that there were only 4 cases of late AMD in the higher than median linoleic acid group (table 1). The odds ratio of 4.72 at a significance level of 0.005 for the effects of adjusted daily LZ intake on the prevalence of late AMD was based on these four cases. Regardless of the validity of the statistical methods, it needs to be borne in mind that a conclusion with major public health implications was based on such few cases. The food frequency questionnaire used in this study was not validated for the key variables, linoleic acid and LZ intake.4 The use of a single self-reported instrument for the estimation of lutein intake is subject to large biases and error, and has the lowest validity for lutein as opposed to the other carotenoids.5 These possible confounders are present in addition to the possibility of a dietary change towards higher LZ intake after the diagnosis of AMD.
Table1. The estimated numbers of subjects based on reported Odds Ratios
.
Group
Low linoleic
High linoleic
OR
Late AMD
32
4
0.11
Early AMD
102
45
0.44
Any AMD
134
49
0.35
Non AMD
852
937
total
986
986
Table legend: These estimates were based on the odds ratios (OR) reported for all participants graded using
Notwithstanding this, in order to better understand the significance of the results, we need to know (a) more details on how linoleic acid and LZ intake were calculated, and in particular, the chief food sources of these variables; (b) whether the separate food items confirm the trend; (c) what the demographics of the subset of patients with an above median linoleic acid and high LZ intake were; (d) how many of this subset were aware of their diagnosis; (e) whether more patients with AMD returned the food frequency questionnaire than those without; (f) and how the ophthalmologic diagnosis of AMD was validated.
Strong conclusions made in this article are not justified by the provided data. Their publication creates confusion and undermines professional, government and public confidence in the validity of other data with great potential public health benefits. It takes enormous time, effort and resources to educate the public on preventative lifestyle changes. We must ensure that the messages to the public remain clear and consistent, and that new findings are put through a process of rigorous examination to confirm their validity. It appears that, in this case, the process may have failed.
References
1. Vu, H. T.Robman, L.McCarty, C. A.Taylor, H. R.Hodge, A. Does dietary lutein and zeaxanthin increase the risk of age related macular degeneration? The
2. Seddon JM, Ajani AU, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. JAMA 1994;272:1413–1420.
3. Cho E, Seddon JM, Rosner B, et al. Prospective study of intake of fruits, vegetables, vitamins, and carotenoids and risk of age-related maculopathy. Arch Ophthalmol 2004;122:883–892.
4. Hodge A, Patterson AJ, Brown WJ, et al. The AntiCancer Council of
5. Natarajan L,Flatt WF,Xlaoying S, et al Validity and systematic error in measuring carotenoids consumption with dietary self reported instruments Am J Epidemiol March 2006 (in print)
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Authors' response
Submit responseDear Editor,
We were interested to see the letter by Mitchell et al, written in response to our earlier publication [1].
Mitchell and co-workers raise several points, the first of which is the way one handles missing data. AMD can be assessed either clinically or photographically. Rather than throw away data and run the potential of bias by excluding patients who did not have a retinal photograph, we chose to include in our analysis those people for whom we did not have a retinal photograph for one reason or another but for whom we had clinical macular grading. In separate analyses the data were not materially different if the analysis was confined to only those with photograding. In the data Mitchell et al report they excluded 15% of their sample as they lacked data and there is no evidence of what bias this may have induced.
We were very pleased to see the data from the Blue Mountains Study and recognise the advantage of incidence data over cross-sectional data. However, both cross sectional and longitudinal studies are susceptible to recall bias in the ascertainment of historical dietary intake. In nutritionally non-deficient populations people do alter their diets in response to the available commercial information. However, the bias caused by public awareness of hypothesized protective associations applies equally to both cross-sectional and longitudinal observational studies, as many know about either their disease or family predisposition to AMD before participation. However, our data were collected before the recent upsurge in publicity given to the use of nutritional supplement for macular degeneration.
The most striking thing from the data presented by Mitchell et al is that they show no evidence of a protective effect of dietary or supplement intake of Lutein and Zeaxanthin. The consistent finding of these two population-based studies must seriously challenge the association reported by previous case control studies. Case control studies are always strongly influenced by the possibility of bias in selection of controls and may frequently be influenced by the bias in the selection of. The fact that the dietary intakes in the two population-based studies is so much lower than the volunteer case control studies clearly indicates "healthy volunteer bias" as we point out in our paper (Vu et al).
The lack of effect modification by linoleic acid found in the BMES data is interesting and possibly not surprising. We found a complex U- shaped interaction between dietary intake and the risk of AMD and the decision as to where cut points are taken will strongly influence the outcome (Fig 1). It would be more informative if Mitchell et al presented their data either with the same cut points that we had used, or presented their data in a continuous form.
Nevertheless, these two studies confirm the lack of evidence to support recommendations for a specific increase in dietary intake of Lutein and Zeaxanthin to protect against macular degeneration. At the same time of course no one would encourage people to deviate from a normal healthy diet including fresh fruit and vegetables. (Vu et al, Br. J. Ophthalmol, Mar 2006; 90: 389 - 390)
Luba Robman
Allison Hodge
Catherine A McCarty
Hugh R TaylorReferences
1. Vu HTV, Robman L, McCarty CA, Taylor HR, and Hodge A. Does dietary lutein and zeaxanthin increase the risk of age related macular degeneration? The Melbourne Visual Impairment Project. Brit. J. Ophthalmol, 2006; 90: 389-390.
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Lutein and zeaxanthin dietary intake and age related macular degeneration
Submit responseLutein and Zeaxanthin dietary intake and age related macular degeneration
We read with interest the letter published by Vu et al (1) which investigated the risk of age related macular degeneration (AMD) and its association with the dietary carotenoids, lutein and zeaxanthin (LZ), stratified by linoleic acid intake. Vu et al reported a marked increase in the risk of both early and late AMD among people who consumed greater than the median intake of linoleic acid and higher dietary intakes of LZ.
We have a number of concerns in relation to the authors’ letter and their conclusions. The letter used cross-sectional data based on photographic macular assessments of 71.9% of their sample of 2448 persons, who attended follow-up examinations. The authors also included 212 persons who did not have photographic macular assessment (10.8% of those with dietary assessments). This is one area of concern. The dietary assessment method (food frequency questionnaire FFQ) was not conducted at baseline, which only allows measurements of association from the follow-up examination. Due to the cross-sectional nature of the data, it is plausible and even likely that participants with known signs of early macular degeneration or associated visual changes may have increased their dietary antioxidant intakes (indication bias); for example, after being told about their signs at the first examination, or at other times. This bias may have occurred in particular amongst those consuming higher linoleic acid diets as higher intakes of linoleic acid have been reported to increase the risk of AMD (2). An excellent example of this indication bias can be found in the finding of a significantly increased risk of poor night vision associated with increased consumption of carrots (3).
The letter also states that a possible protection existed with high LZ intake on AMD among those with low levels of linoleic acid intake. We could, however, not see any data in the results or tables to support this statement.
We thought that these findings needed to be confirmed in other study populations. Given our concerns about the cross-sectional data design we explored this association with the incidence of AMD in the Blue Mountains Eye Study cohort.Baseline data were collected in 1992-94 from 3654 residents of the
We found no association with energy adjusted LZ intake and the incidence of early, late or any AMD, whether or not this was stratified by linoleic acid intake (Table 1). Given that our median linoleic acid intake was less than the median used by Vu et al (1) (6.6g verses 7.2g) we also stratified the data by the highest tertile of linoleic acid intakes (cut-point 8.5g) and also found no association between LZ and incident AMD (data not shown).
While the examination of cross-sectional data to investigate associations with disease may be useful, conclusions drawn from such data need to be made with care, in the light of other known literature. Other data have demonstrated a potential protective effect from foods containing LZ (7) and foods and supplements rich in LZ are known to increase (protective) macular pigment density (8). In addition, Dietary Guidelines (9) include recommendations to increase vegetables and fruit that are rich in LZ (e.g. broccoli, green beans, silverbeet, brussel sprouts, oranges) (10). The authors conclusions, based on their very limited data, are non-intuitive and we are concerned that they are potentially misleading. Care needs to be taken to continue to encourage the vegetable and fruit intakes of populations.
Victoria Flood, Elena Rochtchina, Jie Jin Wang, Paul Mitchell
Centre for Vision Research,
Wayne Smith
Centre for Clinical Epidemiology and Biostatistics,
Correspondence to: Professor Paul Mitchell, Centre for Vision Research,
References:
- Vu
HTV, Robman L,
- Seddon JM, Cote J, Bernard R. Progression of age-related macular degeneration: association with dietary fat, transunsaturated fat, nuts, and fish intake. Arch Ophthalmol. 2003; 121: 1728-37.
- Smith W, Mitchell P, Lazarus R.Carrots, carotene and seeing in the dark.Australian & New Zealand Journal of Ophthalmology 1999; 27:200-203.
- Mitchell
P, Smith W, Attebo K, Wang JJ. Prevalence of
age-related maculopathy in
- Smith
W, Mitchell P, Reay EM, Webb K, Harvey PW.
Validity and reproducibility of a self-administered food frequency
questionnaire in older people. Australian
- Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Amer J Epidemiol. 1986; 124: 17-27.
- Seddon JM, Ajani UA, Sperduto RD, Hiller R, Blair N, Burton TC, Farber MD, Gragoudas ES, HallerJ, Miller DT et al. Dietary carotenoids, vitamins A, C and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. JAMA. 1994; 272: 1413-20.
- Hammond BR Jr, Johnson EJ, Russell RM, Krinsky NI, Yeum KJ, Edwards RB, Snodderly DM. Dietary modification of human macular pigment density. Invest OphthalmolVisSci. 1997; 38(9): 1795-1801.
- National Health and Medical Research Council. 2003. Dietary Guidelines for Australian Adults.
- Manzi F, Flood V, Webb K, Mitchell P. The intake of carotenoids in an older Australian population: The Blue Mountains Eye Study. Pub Health Nut. 2002; 5(2): 347-352.
Table 1: The odds ratio between baseline dietary lutein and zexanthin (LZ) intake, stratified by linoleic acid (LA) intake (less than and greater than median intake), and
10 year incident AMD in the Blue Mountains Eye Study
Any AMD
OR*
(95% CI)
P value
Early AMD
OR*
(95% CI)
n=220
P value
Late AMD
OR*
(95% CI)
n=59
P value
All participants
Daily energy adj LZ intake
0.94(0.71-1.24)
0.668
0.95 (0.71-1.28)
0.758
0.81 (0.45-1.50)
0.475
Energy adj LZ intake, < 6.6g LA
1.01 (0.71-1.45)
0.943
1.06 (0.73-1.53)
0.771
0.66 (0.3-1.46)
0.306
Energy adj LZ intake,> 6.6g LA
0.85 (0.54 -1.34)
0.487
0.82 (0.51-1.32)
0.820
1.18 (0.5-2.77)
0.698
Excluding those who took supplements
Daily energy adj LZ intake
1.1 (0.7-1.5)
0.749
1.1 (0.76-1.61)
0.596
0.85 (0.41-1.77)
0.666
Energy adj LZ intake, < 6.6g LA
1.1(0.7-1.7)
0.675
1.15 (0.7-1.83)
0.559
0.62 (0.23-1.68)
0.349
Energy adj LZ intake > 6.6g LA
0.98(0.54-1.79)
0.949
1.01 (0.54-1.89)
0.975
1.40 (0.49-3.96)
0.528
* adjusted for age, gender and smoking
- Vu
HTV, Robman L,
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