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Essential Fatty Acids (EFAs) and dry eye

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  • Essential Fatty Acids (EFAs) and dry eye

    Following is an excerpt from the TFOS DEWS II Management and Therapy report, relating to essential fatty acids and their role in dry eye, both in terms of risk and potential to help treat/manage dry eye. I've taken the liberty of highlight some parts that I found of most interest.

    I have found the whole Omega 3 area a little frustrating over the years - there is so much noise, and so many studies, and more than anything, so much marketing going on, that it always feels difficult to separate the wheat from the chaff. So I was extremely appreciative of this compact summary of "what we know, really" about dry eye and EFAs.

    Here are some of my takehomes from the excerpt. At the end of the day it just reinforced what I've always felt - that getting more Omega 3 into our diets is a good thing, especially if it can be in the form of food, but beware marketing hype for one specific product or another due to poor quality scientific evidence, and bear in mind that any benefits you get may or may not actually make you feel any better (note highlight in red about unchanged OSDI score even when clinical signs improved).
    • That EFAs matter to dry eye, and specifically because we tend to get far too little Omega 3 in relation to Omega 6.
    • That while there's a ton of studies done on supplements, it's really hard to come to any conclusions from them via meta-analysis because of factors like:
      • overall quality of the studies is not that great
      • the studies don't have very many participants
      • on many (especially Omega 3 alone) the evaluation period is very short
      • masking, especially double masking, just isn't used near enough
      • different dosage
      • different endpoint measures
      • failure to measure compliance
      • the study results frequently contradict each other
    • There are distinct safety issues to be aware of with EFA supplementation
    • Medical advice will probably vary a lot as regards supplement because of the inconsistency in study results.
    • Supplement sources and quality varies a lot.
    • We should really probably be trying for dietary improvement and not just rely on supplements, given the relatively poor evidence base for whether & in what form, dosage, etc, they'll actually help.
    Keep an eye out for the DREAM STUDY results (scroll to bottom)!

    6. Dietary modifications

    6.2 Essential fatty acids

    Essential fatty acids (EFAs) are termed ‘essential’ as they are necessary for healthy metabolic processes to occur [822]. Humans are unable to form EFAs in vivo and must ingest them from dietary sources. Two key EFAs are the 18-carbon omega-3 (ω-3) and omega-6 (ω-6) fatty acids. The ω-3 EFAs exist as both short (alpha-linolenic acid, ALA) and long-chain (eicosapentaenoic acid, EPA and docosahexaenoic acid, DHA) sub-types. Both subtypes can be consumed from food, with long-chain forms also capable of being produced from short-chain forms within the body, through the desaturation/elongation of short-chain EFAs. Common food sources for ALA include flaxseeds, walnuts, chia seeds and soybean oil. The long-chain ω-3 polyunsaturated fatty acids (PUFAs), EPA and DHA, are present in high concentrations in oily fish (such as tuna, salmon, trout, sardines and mackerel) and to a lesser extent in shellfish (such as prawns, oysters and mussels). The ω-6 EFAs are commonly derived from vegetable oils, such as safflower oil and corn oil, in the form of linolenic acid (LA), which, once ingested, is desaturated and elongated to gamma-linoleic acid (GLA) and arachidonic acid (AA) [823].

    Within the body, ω-3 and ω-6 EFAs compete for the enzymes that regulate their metabolism, to produce eicosanoids that modulate systemic inflammation. Eicosanoids derived from the ω-6, AA-dependent pathway, including prostaglandin-E2 (PGE2), thromboxane-A2 and leukotriene-B4, are pro-inflammatory. While most ω-6 eicosanoids promote inflammation [824], metabolism of GLA can result in the production of prostaglandin-E1 (PGE1) and thromboxane-A1, which are anti-inflammatory mediators [824]. The potential effect(s) of ω-6 EFAs on inflammation is therefore complex. Long-chain ω-3 EFAs bias prostaglandin metabolism towards the production of anti-inflammatory eicosanoids, including resolvins and protectins, which are essential for limiting and resolving inflammation [825]. As such, the relative ratio of consumed ω-3 to ω-6 EFAs influences the overall inflammatory status of the body [824].

    In modern times, the balance of ω-3 to ω-6 essential fatty acids (EFA) dietary intake has shifted, thereby altering the balance of inflammatory cytokines [826]. In current Western diets, the ratio of ω-6:ω-3 intake is typically 15:1, whereas an ideal ratio is generally considered to be 4:1 [827]. As a result, there has been scientific interest in understanding whether increasing systemic ω-3 EFA levels through nutritional intervention, to lower the ω-6:ω-3 ratio, can yield systemic anti-inflammatory effects that are beneficial for conditions with an inflammatory overlay, including DED.

    6.2.1 Basic science studies

    Omega-3 EFAs are recognized to have a broad range of systemic anti-inflammatory effects, including inhibiting the production of several key pro-inflammatory cytokines (such as IL-1, IL-2 and TNF-α) [828–830] and preventing T-lymphocyte proliferation [831,832], processes that have been implicated in the pathogenesis of DED.

    Several laboratory studies have shown that fatty acid enrichment can impart lacrimal gland changes and alter the ocular surface response to pharmacologic-induced models of DED [833–838]. Two recent laboratory-based studies have evaluated the impact of EFAs on the function of human meibomian gland epithelial cells [833,834]. The study by Liu et al. showed that EFAs influence the quality and quantity of intracellular lipids, resulting in a 2.4- to 3.7-fold increase in the cellular content of triglycerides after ω-3 and ω-6 treatment, respectively. In rats, dietary supplementation with ω-3 (EPA + DHA) for three months was associated with their incorporation into lacrimal gland tissues [835]. Two-month dietary enrichment with combined ω-3 (EPA + DHA) and ω-6 (GLA) PUFAs, reduced corneal keratitis, minimized the overexpression of conjunctival major histocompatibility complex (MHC) II and inhibited upregulation of prostaglandin (PG) E1 and PGE2 in the lacrimal gland, after 28 days of scopolamine intervention [836]. In murine DED models, topical formulations of ω-3 EFAs have been shown to reduce levels of corneal fluorescein staining [837,838], and decrease both CD11b (+) cell numbers and conjunctival expression of IL-1α and TNF-α [837]. Topical ω-3 EFAs, with and without added 0.1% HA, have also been found to improve corneal irregularity and reduce epithelial barrier disruption [838].

    Experimental evidence supports the therapeutic potential of a class of endogenous lipid-derived immunomodulators, resolvins, derived from EPA (resolvin E1) and DHA (resolvin D1), as an anti-inflammatory treatment for DED [14,839,840]. Resolvins E1 and D1 promote the resolution of inflammation in cultured conjunctival goblet cells by reducing cysteinyl leukotrienes [839,840]. In murine DED models, resolvin E1 has been reported to increase tear production, improve corneal regularity and decrease macrophage infiltration [841], and to reduce corneal epithelial barrier disruption and attenuate conjunctival goblet cell loss [842]. Topical application of a prodrug of resolvin E1, RX-10045 (0.1%), which is rapidly hydrolyzed to its active form in biological matrices, can reduce corneal stromal haze after rabbit corneal injury [843]. In a recent clinical study RX-10045 failed to meet a primary endpoint related to corneal staining [329]. While investigations involving resolvin D1 are less prevalent, it should be noted that these agents have a role in corneal health. For example, a derivative of DHA, NPD1, is important in nerve regeneration and corneal sensitivity [844,845].

    6.2.2 Human observational data

    The Women's Health Study, involving over 32,000 women, described an association between a low dietary intake of ω-3 EFAs and DED in women [846]. This study reported a 30% reduction in the risk of DED with each additional gram of ω-3 EFAs consumed per day. A higher ratio of dietary ω-6:ω-3s was also associated with an elevated risk of DED (for ≥15:1 versus <4:1, odds ratio: 2.51; 95% CI: 1.13, 5.58, p = 0.01). Furthermore, it has been recently shown that the ratio of ω-6:ω-3 tear lipids is elevated in people with DED and that this occurs in proportion to the degree of tear film dysfunction and corneal staining [847]. The level of dietary ω-3 EFA intake is also associated with differences in the polar lipid pattern of meibomian gland secretions in women with Sjögren syndrome [848].

    6.2.3 Clinical trials of EFA supplements

    Clinical trials have been undertaken to assess the potential benefit of oral ω-3 and ω-6 EFA supplementation, both alone and in combination, for treating DED. Most of these intervention trials have been performed at single sites and with relatively small participant numbers (sample size <70). The clinical trials have had varying degrees of masking, of both participants and outcome assessors, with few being double-masked.

    All of the clinical trials evaluating ω-3 EFAs alone (Table 13) [849–,859] have been undertaken for three months or less,
    with the exception of one pilot study that investigated the efficacy of short-chain ω-3 EFAs (ALA) for treating MGD and blepharitis over 12 months [849]. The ω-3 EFA interventions have varied both in terms of subtype (short- and/or long-chain formulations) and dose. To date, only one study has evaluated the relative efficacy of different forms of long-chain ω-3 EFAs for treating DED, comparing krill oil, in primarily phospholipid form, to fish oil, in triacylglyceride form [858]. This randomized, placebo-controlled clinical trial suggested that ω-3 EFAs in phospholipid form (krill oil) might confer additional therapeutic benefit in DED, with further clinical investigations needed to assess this potential. A variety of outcome measures have been examined, primarily involving quantifying changes to patient symptomatology and objective clinical measures relating to tear stability and/or production. More recently, beneficial effects with oral ω-3 EFA supplements in DED have also been demonstrated, with the specification of tear osmolarity as a primary outcome measure [858,859]. A recent pilot study has further demonstrated central corneal neuroprotective effects with a three-month supplementation of a moderate dose of ω-3s (1000 mg/day EPA + 500 mg/day DHA) in DED [860]. Attempting to summarize the best available evidence, a meta-analysis concluded that ω-3 EFA supplementation improves TBUT and Schirmer scores in individuals with DED, without significantly altering OSDI scores [861].

    Although many patients self-medicate with ω-3 EFA supplements on the premise of their well-publicized health benefits, use of these supplements requires some precautions. There are several important systemic contra-indications, including liver disease, atrial fibrillation and bleeding disorders; in these cases, medical advice should be sought prior to commencing supplementation. There may be potential risks to health with high-dose ω-3 EFA intake (>2000 mg/day combined EPA + DHA), in terms of a heightened risk of bleeding [862], and people with hematological disorders should seek medical advice before consuming ω-3 EFA supplements [863]. The possibility that males with high serum concentrations of long-chain ω-3 PUFAs have a heightened risk of prostate cancer has also been raised [864], but remains contentious [865,866]. Both the FDA and the National Health and Medical Research Council (NHMRC) in Australia recommend an upper daily limit for omega-3 fatty acid consumption of 3 g (3000 mg); this includes omega-3 fatty acids derived both from food and supplements. It is important to note that this dosage relates to the amount of omega-3 fatty acid content, rather than the size of the supplement capsule per se. For example, many 1 g (1000 mg) fish oil capsules contain 180 mg EPA + 120 mg DHA; thus only about 30% of the content of the fish oil supplement capsule will be long-chain omega-3 fatty acids.

    Interventional clinical trials that have evaluated ω-6 EFA formulations for treating DED have been performed at single-sites, ranging in duration from three weeks to six months, and with considerable variations in daily dose (Table 14) [867–,871]. Most studies targeted study populations with Sjögren syndrome, with variable outcomes reported in relation to changes in dry eye symptoms, ocular inflammatory markers and other clinical signs (such as ocular surface staining, TBUT, Schirmer score).

    Clinical trials that investigated supplementation with combined ω-3 and ω-6 EFAs have ranged in duration from three to six months and include both single-site and multi-center studies (Table 15) [872–877]. A 2014 meta-analysis that considered the overall efficacy of PUFA supplementation for treating DED concluded that, compared with placebo, these interventions resulted in a significant reduction in both symptom score (quantified using the OSDI) and in the rate of cells positive for HLA-DR [878]. A Cochrane systematic review protocol on this topic was also published in 2014 and is currently in progress [879].

    6.2.4 Summary of essential fatty acids

    The role of ω-3 and/or ω-6 EFA supplementation for treating DED is not yet completely understood. Although a sizeable number of clinical trials have been conducted (Tables 13–15), most have been of short duration and show contrasting findings. There are few high-quality, randomized controlled clinical trials to inform practice. As a result, there is currently a lack of consensus in relation to the optimal protocol, in particular to the dose, composition or duration of treatment. Furthermore, most clinical studies have not measured compliance to the study interventions with blood serum fatty acid assays. This is considered essential to precisely assess the health effects of supplementation, particularly as common sources of ω-3 EFAs (such as fish oil supplements) have potential gastro-intestinal side effects that include fishy after-taste and diarrhoea, which can negatively impact compliance [880]. A large-scale, multi-center, randomized, placebo-controlled trial (DREAM study) assessing the efficacy and safety of ω-3 PUFAs (dosed at 2000 mg EPA + 1000 mg DHA/day) over 24 months, funded by the , is currently underway (https://clinicaltrials.gov/ct2/show/NCT02128763). This study is predicted to inform treatment recommendations for using high-dose ω-3 PUFAs for treating DED.
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    Rebecca Petris
    The Dry Eye Zone

  • #2
    Update: The DREAM study results were released today. Omega 3 supplements did not provide any improvement superior to an olive oil placebo.

    This was a HUGE study, involving hundreds of patients, and using fish oil in triglyceride form for maximal absorption. After a long history of small studies with varying results and too many differences to compare them apples to apples, this is a disappointing outcome but a very welcome confidence level.
    Rebecca Petris
    The Dry Eye Zone

    Comment


    • #3
      We might be reduced to... you know... eating better or something.
      Rebecca Petris
      The Dry Eye Zone

      Comment


      • #4
        I just read this study today... was happy to see the full text published FREE on the New England Journal of Medicine website (https://www.nejm.org/doi/full/10.1056/NEJMoa1709691#)

        I'm not firmly in the "omg fish oil is the holy grail" camp, nor am I in the "fish oil is pointless" camp. But I don't think we can draw too many conclusions from this study because it has some flaws... In other words, I don't think we need to be toooo disappointed in these results because there are many issues still not addressed in this study.

        ...For anyone interested, also see more info on the study in the supplementary appendix here: https://www.nejm.org/doi/suppl/10.10...1_appendix.pdf
        ...And study protocol here: https://www.nejm.org/doi/suppl/10.10...1_protocol.pdf

        After reading it through, I'm left with more questions than answers... there are several issues:

        1. It wasn't as large as I'd like to see, and that makes the results less likely to be as good as we'd like... 186 people in the placebo group, 349 in the active supplement group. Sure, that's better than studies with only a few dozen participants, but compared to massive studies like the Women's Health Study (following over 39k participants, and granted, not specifically about dry eye, but only mentioning it as example of a very large study), the AREDS study (4757 participants... not dry eye specific, but again, an example of the type of truly large study I'd like to see for dry eye), and even Restasis where the prescribing info alone references a study of 1200 people.

        2. It doesn't differentiate between results for those with mild, moderate, and severe dry eye. It doesn't differentiate between causes of dry eye and the study results. They left out LASIK patients (so the results don't necessarily apply to them... ie. maybe they do, maybe they don't... but we don't know) Perhaps supplementation works for one group, and not for another. My suspicion is that that couldn't differentiate between all these groups because the sample sizes would have ended up too small to draw any conclusions from.

        3. There were lots of factors not controlled for...ex. participants diets and other lifestyle factors (ex. hours of computer use, exposure to windy environments, etc.)

        They used an intake of 3g omega-3's per day. This is convenient because doses up to 3g per day do not require physician supervision, whereas such supervision would be required with doses GREATER THAN 3g per day due to the theoretical increased risk for bleeding. But... was 3g a day high enough to make a difference in this study population? It appears not... but perhaps the results of the study would have been different if higher omega-3 doses were used... or perhaps not... the point is, we don't know.

        I think the study authors did a decent job overall. And I suspect the effects of fish oil on dry eye - if any - are small to medium... but I don't think this study alone is enough to draw definitive conclusions that fish oil is of no use at all. I'd like to see more, larger studies address this question... if they all get the same result, that would lend more confidence to the idea that fish oil providing 3g a day of omega-3's doesn't help dry eye.
        Last edited by SAAG; 26-Nov-2018, 07:54.
        Yet another post-Lasik (2005)...
        Anyone have a time machine so I can go back and undo this mess?

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