Carotenoids and Age-Related Macular Degeneration: The Impossible Clinical Trial?
Randomized, double-blind, controlled clinical trials are seen as the gold standard for biomedical research for proving that a given intervention causes a certain result. However, there are a few issues with testing interventions for chronic diseases that begin to develop decades before the clinical disease. One example of this is age-related macular degeneration (AMD).
AMD is a disease that normally only begins to appear in people aged over 50 years (see studies by Klein in the USA and Tamura in Japan). The disease is caused by the breakdown of center vision cells located in the macula of the eye. It is thought that carotenoids from the diet (lutein and zeaxanthin) protect against AMD because they accumulate specifically in front of the macula where they can shield the vision cells from damage from bright light, and mop up free-radicals that can also damage the vision cells (see review from Hammond, Johnson and George). The trouble is, although lutein and zeaxanthin start to accumulate in utero (see landmark study from Bone and Landrum), the amount that accumulates in the eye depends on dietary intake and the resulting serum levels of the carotenoids (Olmedilla-Alonso et al). In a controlled feeding study of macaques (Malinow), animals fed a diet free of lutein and zeaxanthin had changes in the eye that were consistent with AMD compared to the standard diet. Presumably, risk of AMD develops over the entire lifespan, therefore lifetime lutein and zeaxanthin intake is important for determining risk of AMD.
How can we adequately prove this association? Ideally, we would supplement pregnant women with lutein and zeaxanthin and continue to provide it to them if they decide to breastfeed, as breast milk contains lutein and zeaxanthin, at concentrations related to maternal intakes (Lipkie). Infants consuming infant formula should also be supplemented. Children should be then supplemented and followed for decades until AMD develops. We should include a control group, and various doses would be a good idea, and it would also be interesting to see whether there is a “window of opportunity” for supplementation: the quantity of macular pigment in the eye tends to stabilize after around 3 years of age, therefore baby- and toddlerhood may be a critical period of development in terms of protecting the macula. In any case, as AMD normally only begins to be found in people older than 50, and adequate lutein and zeaxanthin intake is suggested to prevent (not cure) AMD, supplementation before the age of 50 with lutein and zeaxanthin is essential. While not all these factors need to be tested in the one study, the thought of supplementing and follow-up people for decades is daunting. The cost and effort involved in a long-term supplementation study is enormous.
An alternative option for AMD is presented in a publication by Wu and colleagues. They used data from two large epidemiological studies, the Nurses’ Health Study and the Health Professionals Follow-up Study, that started in 1976 and 1986, respectively, and are both currently still ongoing. The authors predicted plasma carotenoid values based on the results from food frequency questionnaires conducted every two years. The predicted carotenoid score was based on knowledge of variable bioavailability of carotenoids from the diet and it was validated within a sub-study within the Nurses’ Health Study.
Among over 100,000 participants, there were almost 2500 cases of AMD over the follow-up period until January 2010. The risk of advanced AMD in the highest quintile of predicted lutein/zeaxanthin plasma concentration was 40% lower than the lowest quintile. Risk of advanced AMD was also reduced in the highest quintiles of intake for the other carotenoids, but not to the same extent.
This study is unique in that carotenoid bioavailability was taken into account, and carotenoid plasma concentrations over the long term were estimated. While this study does not prove causation, it is highly unlikely that we will see a clinical trial performed that will show that lutein and zeaxanthin can prevent AMD due to the length of time likely needed for supplementation. The type of analysis presented by Wu and co-workers is the next best form of evidence.
Wu J, Cho E, Willett WC, Sastry SM, Schaumberg DA. Intakes of Lutein, Zeaxanthin, and Other Carotenoids and Age-Related Macular Degeneration During 2 Decades of Prospective Follow-up. JAMA Ophthalmol. Published online October 08, 2015. doi:10.1001/jamaophthalmol.2015.3590.
Bone RA, Landrum JT, Fernandez L, Tarsis SL. Analysis of the macular pigment by HPLC: retinal distribution and age study. Invest Ophthalmol Vis Sci. 1988 Jun;29(6):843-9. http://www.ncbi.nlm.nih.gov/pubmed/3372161
Hammond BR, Johnson BA, George ER. Oxidative photodegradation of ocular tissues: beneficial effects of filtering and exogenous antioxidants. Exp Eye Res. 2014 Dec;129:135-50. doi: 10.1016/j.exer.2014.09.005. Epub 2014 Sep 16. http://www.ncbi.nlm.nih.gov/pubmed/25236792
Klein R, Knudtson MD, Lee KE, Gangnon RE, Klein BE. Age-period-cohort effect on the incidence of age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology. 2008 Sep;115(9):1460-7. doi: 10.1016/j.ophtha.2008.01.026. http://www.ncbi.nlm.nih.gov/pubmed/18762073
Lipkie TE, Morrow AL, Jouni ZE, McMahon RJ, Ferruzzi MG. Longitudinal Survey of Carotenoids in Human Milk from Urban Cohorts in China, Mexico, and the USA. PLoS One. 2015 Jun 10;10(6):e0127729. doi: 10.1371/journal.pone.0127729. eCollection 2015. http://www.ncbi.nlm.nih.gov/pubmed/26061885
Malinow MR, Feeney-Burns L, Peterson LH, Klein ML, Neuringer M. Diet-related macular anomalies in monkeys. Invest Ophthalmol Vis Sci. 1980 Aug;19(8):857-63. http://www.ncbi.nlm.nih.gov/pubmed/7409981
Olmedilla-Alonso B, Beltrán-de-Miguel B, Estévez-Santiago R, Cuadrado-Vives C. Markers of lutein and zeaxanthin status in two age groups of men and women: dietary intake, serum concentrations, lipid profile and macular pigment optical density. Nutr J. 2014 Jun 3;13:52. doi: 10.1186/1475-2891-13-52. http://www.ncbi.nlm.nih.gov/pubmed/24889185