Summary
Evidence Report/Technology Assessment: Number 117
Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
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Introduction / Key Questions / Methods / Results / Discussion / Availability of Full Report / References
Authors: Hodge W, Barnes D, Schachter HM, Pan Y, Lowcock EC, Zhang L,
Sampson M, Morrison A, Tran K, Miguelez M, Lewin G.
Introduction
The purpose of this study was to conduct a
systematic review of the scientific-medical literature to identify, appraise,
and synthesize the human evidence for the effects of omega-3 fatty acids
on eye health. The review was requested and funded by the Office
of Dietary Supplements, National Institutes of Health. It was
undertaken as part of a consortium involving three Evidence-based Practice
Centers (EPCs), which investigated the value of omega-3 fatty acid supplementation
across eleven health/disease areas. The three EPCs are Southern
California-RAND, Tufts-New England Medical Center, and the University of
Ottawa. To ensure consistency of approach, the three
EPCs collaborated on selected methodologic elements, including literature
search strategies, rating of evidence, and data table design.
Visual health is a broad topic, yet we focused on eye health conditions that have a large public health
impact in North America. Impact was defined in various ways, which encompassed
conditions demonstrating a high prevalence (e.g.., diabetic retinopathy,
age-related macular degeneration [ARMD], retinal vascular occlusions),
producing many potential years of vision loss in that they affect the young
(e.g., retinitis pigmentosa [RP]), or constituting a challenge to health services
in no small part because they are costly to treat (e.g., cataracts).
The brain and eye are highly enriched with
omega-3 fatty acids, which accumulate in these tissues during late fetal
and early neonatal life.1 Very high levels of DHA
are present in the retina, specifically in the disk membranes of the outer
segments of photoreceptor cells. DHA accounts for over half
the total fatty acyl groups present in the phospholipids
of rod outer segment membranes, a proportion higher than is found in any
other tissues.2 Its specific role, however, is not
well understood. The role of DHA may be related to its biophysical
effects on the cell membrane. DHA influences the biophysical
properties of membranes via its high polyunsaturation,
and may help to create a membrane that accommodates the dynamic behavior
of rhodopsin during the photoreceptive process.3-5 In
addition, DHA may modulate the activity of membrane bound enzymes and receptors,
and the kinetics of membrane transport systems, as well as being a precursor
for the synthesis of other biologically active molecules.
A number of studies in preterm and term human
infants have suggested that a dietary supply of omega-3 fatty acids may be
essential for optimal visual development.6-8 Finally, animal data suggest that retinal degeneration
in rats might be prevented by dietary intake of DHA,9 and DHA
administered before ischemia may reduce pressure-induced retinal damage in
monkeys.10 It is against
this backdrop that various questions were investigated. Our
project's overarching goal was to systematically review
the human evidence to help develop a research agenda.
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Key Questions
The key questions are organized by type of eye disease or
visual impairment.
Degenerative Diseases of the Retina—Macular
Degeneration
- What is the evidence for efficacy of omega-3 fatty acids in preventing ARMD and slowing the progression of ARMD?
- What is the evidence that omega-3 fatty acids decrease the rate of progression to advanced forms of macular degeneration in all patients, diabetics, and patients with cataracts?
- What is the evidence that omega-3 fatty acids decrease the rate of progression of advanced forms of macular degeneration in all patients, diabetics, and patients with cataracts?
Degenerative Diseases of the Retina—Retinitis Pigmentosa (RP)
- What
is the evidence for efficacy of omega-3 fatty acids in slowing the progression
of RP (i.e., an inherited retinal dystrophy)?
Vascular
Diseases of the Retina—Retinal
Vein or Retinal Artery Occlusions
- What is the evidence for efficacy of omega-3 fatty acids in preventing retinal vein occlusion and retinal artery occlusion?
- What is the evidence for efficacy of omega-3 fatty acids in slowing the progression of retinal vein occlusion and retinal artery occlusion?
Vascular
Diseases of the Retina in Diabetics
- What
is the evidence for efficacy of omega-3 fatty acids in preventing proliferative retinopathy
in diabetics?
- What
is the evidence for efficacy of omega-3 fatty acids in slowing the progression
of proliferative retinopathy in diabetics?
- What
is the evidence for efficacy of omega-3 fatty acids in preventing clinically
significant macular edema in patients with diabetic retinopathy?
- What
is the evidence for efficacy of omega-3 fatty acids in slowing the progression
of clinically significant macular edema in patients with diabetic retinopathy?
Cataracts
- What
is the evidence for efficacy of omega-3 fatty acids in preventing age-related
cataracts?
- What is the evidence for efficacy of omega-3 fatty acids in
slowing the rate of progression of age-related cataracts in
all patients, diabetics, and patients with ARMD?
- What
is the evidence that omega-3 fatty acids decrease the rate of cataract surgery
in ageing populations?
Adverse Events:
- What
is the evidence for the risk of short- and long-term adverse events related
to the intake of omega-3 fatty acids?
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Methods
A Technical Expert Panel (TEP) was convened
to provide advisory support to the project, including refining the questions
and highlighting key variables requiring consideration in the evidence synthesis.
Study Identification
Several electronic databases were searched:
MEDLINE® (1966—November Week 2 2003 and updated to February Week 1 2004), PreMEDLINE® (May 4 2004), Embase® (1980
to 2003 Week 48 and updated to 2004 Week 7), the Cochrane Library including
the Cochrane Central Register of Controlled Trials (3rd Quarter 2003), and
CAB Health (1973-Dec 2003). Searches were not restricted by
language of publication, publication type, or study design, except with respect
to the MeSH term "dietary fats," which was limited
by study design to increase its specificity. Search elements
included: scientific terms, with acronyms, as well as generic and trade names
relating to the exposure and its sources (e.g., eicosapentaenoic acid (EPA);
omega-3 fatty acids; MaxEPA®); and, relevant population
terms (e.g., macular degeneration). Additional published or
unpublished literature was sought through manual searches of reference lists
of included studies and key review articles, and from the files of content
experts. A final set of 507 unique references was identified
and posted to an internet-based software system for review.
Studies were considered relevant if they described
live human populations of any age, investigated the use of any source, type,
dose or method to deliver omega-3 fatty acids as primary or secondary prevention
for any of the above-noted eye health conditions in any of the populations
or subpopulations of interest (e.g., diabetics), and investigated at least
one pertinent clinical outcome (e.g., prevalence, incidence; change in clinical
status; need for cataract surgery). No restrictions were placed
on the requisite levels of evidence (i.e., study designs) given the expected
dearth of studies. As markers of omega-3 fatty acid metabolism,
the following fatty acid compositions or concentrations, from any source
(e.g., red blood cell [RBC] membranes, plasma phospholipids), were considered
relevant: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid
(AA)/EPA, AA/DHA, and AA/EPA+DHA.
Two initial levels of screening for relevance,
and two reviewers per level, were employed (directed at bibliographic records,
then full articles). Calibration exercises preceded each step
of the screening process. Excluded studies were noted as to
the reason for their ineligibility using a modified QUOROM format.11 Disagreements
were resolved by forced consensus and, if necessary, third party intervention.
Data Abstraction
Following a calibration exercise, two reviewers
independently abstracted the contents of included studies using an electronic
Data Abstraction form developed especially for this review. A third reviewer
then verified those data. Data abstracted included the characteristics
of the:
- Report
(e.g., publication status, language of publication, year of publication).
- Study
(e.g., sample size; research design; number of study arms/groups).
- Population
(e.g., age; diagnosis, including severity, duration, and comorbidity).
- Intervention/exposure
(e.g., omega-3 fatty acid types, sources, doses, and intervention/exposure
length), and comparator(s).
- Cointerventions (e.g.,
concurrent treatments/medications, omega-6 fatty acid use).
- Withdrawals
and dropouts, including reasons.
- Clinical
outcomes.
- Fatty
acid content of biomarkers.
- Adverse events
(e.g., side effects).
Data Synthesis
A summary table provided a question-specific
overview of included studies' relevant data presented in greater detail in
evidence tables. A question-specific summary matrix situated
each study in terms of its quality (i.e., internal validity) and applicability
ratings (i.e., generalizability to the North American population). Question-specific
qualitative syntheses of the evidence were derived. While no
restrictions were placed on study designs, greater interpretative weight
was given to prospective and controlled designs. Given the
paucity of relevant studies addressing any given question, as well as the
variability in the research designs, definitions of the study populations,
exposures/interventions or clinical outcomes employed to investigate it,
meta-analysis was deemed impossible or inappropriate with respect to each
of the questions.
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Results
Sixteen unique studies were identified, which
addressed nine of the 23 questions posed by our project. Only
two studies were randomized clinical trials (RCTs).12,13 The
vast majority of investigations employed either a before-after or observational
study design. The paucity of interventional studies involving
omega-3 fatty acids delivered as supplementation made it difficult to ascertain
the rates or types of harm. The single, placebo-controlled
RCT systematically reporting harm data revealed few minor, mainly gastrointestinal,
effects associated with low-dose DHA supplementation.13
The most-frequently investigated question concerned
the primary prevention of ARMD.14-19 Designs
included a single prospective cohort study,16 two case-control
studies,14,15 one retrospective population-based
cohort study,19 and two single population cross-sectional studies.17,18
There
are sufficient between and within study conflicts (e.g., results of univariate vs multivariate analyses) in the results to preclude drawing
any inference that is conclusive with respect to the value of the intake
of omega-3 fatty acids to prevent ARMD. If it can be assumed
that the study designs likely best suited to address this question should
be both controlled and prospective, none of the included studies would qualify.
The
only prospective study included a large sample and appropriately conducted
multivariate analysis, and controlled for key confounders.14 These
investigators observed that the consumption of canned tuna fish or more than
four fish servings per week each played a protective role against ARMD. However,
their results also indicated that several types of oily fish well known to
have high concentrations of DHA and EPA (i.e., sardines, mackerel) failed
to show a similar, protective effect. These discordant observations
will require an explanation before anything conclusive can be asserted based
on this study alone. Moreover, their study design did not a
priori employ a separate, unexposed cohort as a control.
The
remaining studies cannot resolve the divergent primary prevention results
described by this study, even though each of the former failed to demonstrate
a statistically significant association between exposure and outcome.14,15,17-19 Foremost
among reasons is the use of research designs that constitute less than ideal
strategies to investigate this question. These studies also
varied in their definitions of the exposure, clinical outcome and/or confounders,
which together make it impossible to draw a definitive conclusion regarding
the potential of the intake of omega-3 fatty acids to prevent the onset of
either early or late ARMD.
The nature of the RCT design and the "cocktail-like"
exposure employed by Scorolli et al. made it impossible
to isolate the specific impact of omega-3 fatty acids on slowing the progression
of ARMD.12 A small sample size, the uncommonness
and dubious clinical relevance of the visual recovery outcome, low study
quality, and little or no applicability to the North American population
suggest that there are, at present, no data with which to meaningfully address
this research question.
Seddon et al.'s single
prospective cohort study found that fish intake did not affect the progression
to advanced ARMD overall, or in a high LA consumption group, but did
protect against the progression to advanced ARMD in the low (below median
consumption) LA consumption group.20 This parallels
what was observed exclusively via a significant test for trend in the Seddon et
al. study described earlier with reference to its investigation of the influence
of the intake of omega-3 fatty acids on preventing the onset of advanced
ARMD.15 However, the results from neither study
can be used as yet to provide a conclusive answer to their respective research
questions. Both require replication and a plausible explanation.
The four studies examining whether the intake
of omega-3 fatty acids slows the progression of RP do not provide
a conclusive answer to this question.13,21,22 Hoffman
et al.'s good quality RCT constituted the most rigorous test and revealed
conflicting results.13 That said, rod and cone functional
loss showed effect modification by age, with rod loss significantly reduced
in the prepuberty group supplemented with DHA compared with placebo,
and cone loss significantly reduced in the post-puberty group supplemented
with DHA compared with placebo. The observation that certain
analyses failed to reveal statistically significant between-group differences
could be explained by this having been an underpowered trial.13
By virtue of its research design, which did
not permit the isolation of the specific impact of omega-3 fatty acids on
slowing the progression of RP, results from Dagnelie et
al.'s internet-based comparative before-after study cannot be used to meaningfully
address this question.21 In Hoffman et al.'s two
very small noncomparative before-after studies of short duration, ERG
results did not reveal statistically significant changes following supplementation.22 Thus,
until Hoffman et al.'s RCT13 is replicated with a much larger
sample size, little that is conclusive can be said about the potential value
of the intake of omega-3 fatty acids in slowing the progression of RP.
Sorokin, et al.'s noncomparative before-after study received a low study quality
score and failed to resolve the questions of whether the intake of omega-3
fatty acids can slow the progression of either proliferative retinopathy
or clinically significant macular edema in patients with diabetic retinopathy.23 This
study did not constitute the best test of either of these possibilities,
however. The most relevant clinical outcome by North American
standards entailed fundus assessments, yet few details were reported. Covariates
were not measured, and the univariate analysis of the data was flawed. Thus,
the results of this study are inconclusive with respect to these two possible
benefits of the intake of omega-3 fatty acids in diabetic retinopathy.
Although both the Arnarsson, et
al.24 and Cumming, et al.25 studies are well known population-based
risk factor studies, in neither of them was the association between the intake
of foods or oils containing omega-3 fatty acids and age-related cataract
prevalence the primary question. That said, no statistically
significant associations were observed. Cross-sectional designs
constitute very limited evaluations of this question.
Suzuki et al.'s noncomparative before-after
study did not assess cataract status as its clinical outcome, preferring
instead to examine visual acuity.26 Thus, with improvements
in visual acuity unlikely to have been produced by reduced cataract formation,
this study does not directly address the question of whether the intake of
omega-3 fatty acids can slow the rate of progression of age-related cataracts.
A paucity of data prevented us from examining
the possible influence on efficacy, association, or safety evidence of various
covariates, which included both population (e.g., age at onset or diagnosis;
smoking; alcohol consumption) and intervention/exposure factors (e.g., source,
type, dose, and method to deliver omega-3 fatty acids; intake of omega-6
fatty acids).
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Discussion
Based on the studies identified by this review,
it is apparent that clinical research has only scratched the surface with
respect to understanding the possible utility of the intake of omega-3 fatty
acids as a primary or secondary prevention in eye health. Moreover,
seen from the point of view of clinical research's typical, linear arc—which
moves from basic science to observational research to RCTs, and culminating
in the systematic review/meta-analysis of the observations obtained by these
primary studies—there is a paucity of solid observational
research with which to construct an experimental framework affording the
meaningful conduct of RCTs. For example, there is little understanding
of the exact sources, types and doses of omega-3 fatty acids, or even the
possible duration of their use, which might usefully serve as definitions
of a prevention-centered "intervention" for any of the eye diseases/visual
impairments examined in our review. Moreover, a single study
reporting adverse event data likely does not permit laying to rest all possible
concerns regarding the short- or long-term safety of such an intervention.
It is therefore our view that much more research
will need to be conducted before anything conclusive can be asserted with
respect to the effects of omega-3 fatty acids on eye health. It
is also our understanding that sorting out the possible benefits of the intake
of omega-3 fatty acids in eye health might profit from taking into consideration
the impact of the concurrent intake of omega-6 fatty acids and, by definition,
the omega-6/omega-3 fatty acid intake ratio. Finally, any notable
causal or correlational relationships observed between the omega-6/omega-3
fatty acid intake ratio and the development or progression of eye disease/visual
impairment may then be "explained" by future studies, which focus on observing
patterns of omega-6/omega-3 fatty acid content in peripheral, or even brain,
biomarkers.
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Availability of Full Report
The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality (AHRQ) by the University of Ottawa Evidence-based
Practice Center under Contract No. 290-02-0021. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment No. 117, Effects of Omega-3 Fatty Acids on Eye
Health.
The Evidence Report is also online on the National Library of Medicine Bookshelf, or can be downloaded as a PDF File (1.5 MB). PDF Help.
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References
1. Innis SM.
Perinatal biochemistry and physiology of long-chain polyunsaturated fatty
acids. J Pediatr 2003; 143(4 Suppl):S1-S8.
2. Stone WL, Farnsworth
CC, Dratz EA. A reinvestigation of the fatty
acid content of bovine, rat and frog retinal rod outer segments. Exp Eye Res 1979;
28(4):387-97.
3. Gibson NJ, Brown
MF. Lipid headgroup and acyl chain composition
modulate the MI-MII equilibrium of rhodopsin in
recombinant membranes. Biochemistry 1993; 32(9):2438-54.
4. Brown MF. Modulation
of rhodopsin function by properties of the membrane bilayer. Chem Phys Lipids 1994; 73(1-2):159-80.
5. Litman BJ, Niu SL, Polozova A et al. The role
of docosahexaenoic acid containing phospholipids
in modulating G protein-coupled signaling pathways: visual transduction.
J Mol Neurosci 2001; 16(2-3):237-42.
6. Birch E, Birch D,
Hoffman D, et al. Breast-feeding and optimal visual development. J Pediatr Ophthalmol Strabismus
1993; 30(1):33-8.
7. Birch EE, Hoffman DR, Uauy R, et al. Visual acuity
and the essentiality of docosahexaenoic acid
and arachidonic acid in the diet of term infants. Pediatr Res 1998; 44(2):201-9.
8. Hoffman DR, Birch
EE, Birch DG, et al. Impact of early dietary intake and blood lipid composition
of long-chain polyunsaturated fatty acids on later visual development.
J Pediatr Gastroenterol Nutr 2000;
31(5):540-53.
9. Moriguchi K, Yuri T, Yoshizawa K, et al. Dietary docosahexaenoic acid
protects against N-methyl-N-nitrosourea-induced
retinal degeneration in rats. Exp Eye Res 2003;
77(2):167-73.
10. Murayama K, Yoneya S, Miyauchi O, et al. Fish
oil (polyunsaturated fatty acid) prevents ischemic-induced injury in the
mammalian retina. Exp Eye Res 2002; 74(6):671-6.
11. Moher D, Cook DJ,
Eastwood S, et al. Improving the quality of reports of meta-analyses of randomised controlled
trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet
1999; 354(9193):1896-900.
12. Scorolli L, Scalinci SZ, Limoli PG, et al. [Photodynamic
therapy for age related macular degeneration with and without antioxidants].
[French]. Can J Ophthalmol 2002; 37(7):399-404.
13. Hoffman DR, Locke KG, Wheaton DH, et al. A randomized, placebo-controlled clinical
trial of docosahexaenoic acid supplementation
for X-linked retinitis pigmentosa. Am J Ophthalmol 2004; 137(4):704-18.
14. Ouchi M,
Ikeda T, Nakamura K, et al. A novel relation of fatty acid with age-related
macular degeneration. Ophthalmologica 2002; 216(5):363-7.
15. Seddon JM, Rosner B, Sperduto RD , et al. Dietary fat and risk for advanced age-related macular
degeneration. Arch Ophthalmol 2001; 119(8):1191-9.
16. Cho E,
Hung S, Willett WC, et al. Prospective study of dietary fat and the risk
of age-related macular degeneration. Am J Clin Nutr 2001;
73(2):209-18.
17. Smith W, Mitchell
P, Leeder SR. Dietary fat and fish intake and
age-related maculopathy. Arch Ophthalmol 2000;
118(3):401-4.
18. Heuberger RA, Mares-Perlman JA, Klein R et
al. Relationship of dietary fat to age-related maculopathy in the Third National Health and Nutrition Examination
Survey. Arch Ophthalmol 2001; 119(12):1833-8.
19. Mares-Perlman JA, Brady WE, Klein R, et al. Dietary fat and age-related maculopathy.
Arch Ophthalmol 1995; 113(6):743-8.
20. Seddon JM,
Cote J, Rosner B. Progression of age-related macular degeneration:
association with dietary fat, transunsaturated fat,
nuts, and fish intake. Arch Ophthalmol 2003;
121(12):1728-37.
21. Dagnelie G, Zorge IS, McDonald TM. Lutein improves
visual function in some patients with retinal degeneration: a pilot study
via the Internet. Optometry 2000; 71(3):147-64.
22. Hoffman DR, Uauy R, Birch DG. Metabolism
of omega-3 fatty acids in patients with autosomal dominant
retinitis pigmentosa. Exp Eye Res 1995; 60(3):279-89.
23. Sorokin EL, Smoliakova GP, Bachaldin IL. [Clinical
efficacy of eiconol in patients with diabetic
retinopathy]. [Russian]. Vestn Oftalmol 1997; 113(4):37-9.
24. Arnarsson A, Jonasson F, Sasaki H, et al. Risk factors for nuclear lens opacification: the Reykjavik Eye Study. Dev Ophthalmol 2002; 35:12-20.
25. Cumming RG, Mitchell
P, Smith W. Diet and cataract. The Blue Mountains Eye Study. Ophthalmology 2000; 107(3):450-6.
26. Suzuki H, Morikawa Y,
Takahashi H. Effect of DHA oil supplementation on intelligence and visual
acuity in the elderly. World Rev Nutr Diet 2001;
88:68-71.
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AHRQ Publication Number 05-E008-1
Current as of July 2005
Internet Citation:
Hodge W, Barnes D, Schachter HM, et al. Effects of Omega-3 Fatty Acids on Eye Health. Summary, Evidence Report/Technology Assessment: Number 117. AHRQ Publication No. 05-E008-1, July 2005. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/o3eyesum.htm