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Omega-3 Fatty Acids EPA and DHA: Health Benefits Throughout Life1,2 - 3The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY - 4Department of Community and Preventive Medicine, and Division of Cardiology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY - 5College of Medicine, King Saud University, Riyadh, Saudi Arabia - ↵*To whom correspondence should be addressed: E-mail: shaker.mosua{at}acphs.edu. Abstract Omega-3 [(n-3)] fatty acids have been linked to healthy aging throughout life. Recently, fish-derived omega-3 fatty acids EPA and DHA have been associated with fetal development, cardiovascular function, and Alzheimer’s disease. However, because our bodies do not efficiently produce some omega-3 fatty acids from marine sources, it is necessary to obtain adequate amounts through fish and fish-oil products. Studies have shown that EPA and DHA are important for proper fetal development, including neuronal, retinal, and immune function. EPA and DHA may affect many aspects of cardiovascular function including inflammation, peripheral artery disease, major coronary events, and anticoagulation. EPA and DHA have been linked to promising results in prevention, weight management, and cognitive function in those with very mild Alzheimer’s disease. Introduction Omega-3 [(n-3)] long-chain PUFA, including EPA and DHA, are dietary fats with an array of health benefits (1). They are incorporated in many parts of the body including cell membranes (2) and play a role in antiinflammatory processes and in the viscosity of cell membranes (3, 4). EPA and DHA are essential for proper fetal development and healthy aging (5). DHA is a key component of all cell membranes and is found in abundance in the brain and retina (6). EPA and DHA are also the precursors of several metabolites that are potent lipid mediators, considered by many investigators to be beneficial in the prevention or treatment of several diseases (7). It can be challenging to get the appropriate intake of EPA and DHA through diet alone, even though EPA and DHA are produced by water plants such as algae and are prevalent in marine animals. A shorter chain omega-3 fatty acid, a-linolenic acid (ALA),6 is a prominent component of our diet as it is found in many land plants that are commonly eaten, but it does not provide the health benefits seen with EPA and DHA. Although it is possible for the body to convert ALA to EPA and DHA by enlongase and desaturase enzymes, research suggests that only a small amount can be synthesized in the body from this process (8). For example, 1 study suggested that only ∼2 to 10% of ALA is converted to EPA or DHA (9), and other studies found even less: Goyens et al. (10) found an ALA conversion of ∼7% for EPA, but only 0.013% for DHA; Hussein et al. (11) found an ALA conversion of only 0.3% for EPA and <0.01% for DHA. The current American diet has changed over time to be high in SFA and low in omega-3 fatty acids (12). This change in eating habits is centered on fast food containing high amounts of saturated fat, which has small amounts of essential omega-3 PUFA compared with food prepared in the home (13). Seafood sources such as fish and fish-oil supplements are the primary contributors of the 2 biologically important dietary omega-3 fatty acids, EPA and DHA (14–16). This low intake of dietary EPA and DHA is thought to be associated with increased inflammatory processes as well as poor fetal development, general cardiovascular health, and risk of the development of Alzheimer’s disease (AD). This review focuses on the many benefits of EPA and DHA supplementation throughout life, including use during pregnancy for proper fetal development and full-term gestation, to reduce many cardiovascular issues, and potential uses in AD. Omega-3 fatty acids and fetal development Maternal nutrition guidelines have always stressed a diet including sufficient caloric and protein requirements, but recently fatty acids have also been deemed important (17). This is partially due to the fact that EPA and DHA supplementation during pregnancy has been associated with multiple benefits for the infant (Table 1). During pregnancy, the placenta transfers nutrients, including DHA, from the mother to the fetus (18). The amount of omega-3 fatty acid in the fetus is correlated with the amount ingested by the mother, so it is essential that the mother has adequate nutrition (19). The 2010 U.S. Department of Health and Human Services dietary guidelines recommend that women who are pregnant or breastfeeding should “consume 8 to 12 ounces of seafood per week from a variety of seafood types” (12). Ingesting 8–12 oz of seafood per week, depending on the type of fish, is equivalent to ∼300–900 mg EPA+DHA per day. Unfortunately, this amount is not being met by most mothers in the United States and Canada, which means that infants many not be receiving adequate amounts of these vital nutrients in the womb (20). Several studies confirmed the benefit of omega-3 supplementation during pregnancy in terms of proper development of the brain and retina. Of the 2 most important long-chain omega-3 fatty acids, EPA and DHA, DHA is the more important for proper cell membrane function and is vital to the development of the fetal brain and retina (17). During the third trimester, vast amounts of DHA accumulate in fetal tissue (20). The 2 most infiltrated fetal areas include the retina and brain, which may correlate with normal eyesight and brain function (19). A study by Judge et al. (20) found that children whose mothers had taken DHA supplementation during pregnancy (n = 29) had significantly better problem-solving skills at 9 mo old (P = 0.017) than those whose mothers had not taken DHA supplementation during pregnancy (n = 15). Another study provided a cognitive assessment of children 2.5 y after maternal EPA+DHA supplementation during pregnancy from 20 wk of gestation until delivery (n = 33) compared with children in a placebo group (n = 39). Children in the EPA + DHA–supplemented group attained significantly higher scores for eye and hand coordination [mean score, 114 (SD 10.2] than those in the placebo group [mean score, 108 (SD 11.3)] (P = 0.021, adjusted P = 0.008) (19). Of great clinical importance, EPA and DHA supplementation during pregnancy has been associated with longer gestation and increased concentrations of EPA and DHA in fetal tissues (21). In 2005, preterm births accounted for 12.7% of all births in the United States, increasing the likelihood of health complications (22). Carrying a baby to term is very important because prematurity is the cause of various infant diseases and can lead to death; preterm delivery is an underlying factor for 85% of the deaths of normally formed infants (23). One mechanism by which EPA and DHA may decrease the incidence of preterm birth is by decreasing prostaglandin E2 and prostaglandin F2a production, therefore reducing inflammation within the uterus, which could be associated with preterm labor (21, 24). Several studies investigated EPA and DHA intake during pregnancy and its correlation with longer gestation. Conclusions were that EPA+DHA supplementation during pregnancy delayed the onset of delivery to term or closer to term; however, supplementation did not delay delivery to the point of being post-term (20, 23, 25). This supports the evidence that EPA+DHA ingestion leads to optimal pregnancy length. EPA+DHA supplementation reduced the HR of preterm delivery by 44% (95% CI: 14–64%) in those who consumed relatively low amounts of fish and 39% (95% CI: 16–56%) in those who consumed medium amounts of fish; however, a level of statistical significance was not met (P = 0.10) (23). The Judge et al. (20) study found that women who had DHA supplementation from gestation week 24 until full-term delivery carried their infants significantly (P = 0.019) longer than did the women in the placebo group. One study found that DHA supplementation after gestation week 21 led to fewer preterm births (<34 wk of gestation) in the DHA group compared with the control group (1.09% vs. 2.25%; adjusted RR, 0.49; 95% CI: 0.25–0.94; P = 0.03). Also, mean birth weight was 68 g heavier (95% CI: 23–114 g; P = 0.003) and fewer infants were of low birth weight in the DHA group compared with the control group (3.41% vs. 5.27%; adjusted RR, 0.65; 95% CI: 0.44–0.96; P = 0.03) (25). There is also evidence that mothers who use EPA and DHA supplementation during pregnancy and breastfeeding may protect their children against allergies. This may be due to the fact that fish-oil supplementation has been associated with decreased levels of body cells associated with inflammation and immune response (26). In a study about food allergy and IgE-associated eczema, the period prevalence of food allergy was lower in the maternal EPA+DHA supplementation group compared to placebo (P < 0.05), and the incidence of IgE-associated eczema was also lower in the maternal EPA+DHA supplementation group compared to placebo (P < 0.05) (27). Omega-3 fatty acids and cardiovascular disease Cardiovascular disease is the cause of 38% of all deaths in the United States, many of which are preventable (28). Chronic inflammation is thought to be the cause of many chronic diseases, including cardiovascular disease (29). EPA and DHA are thought to have antiinflammatory effects and a role in oxidative stress (30) and to improve cellular function through changes in gene expression (31). In a study that used human blood samples, EPA+DHA intake changed the expression of 1040 genes and resulted in a decreased expression of genes involved in inflammatory and atherogenesis-related pathways, such as nuclear transcription factor kB signaling, eicosanoid synthesis, scavenger receptor activity, adipogenesis, and hypoxia signaling (31). Circulating markers of inflammation, such as C-reactive protein (CRP), TNF a, and some ILs (IL-6, IL-1), correlate with an increased probability of experiencing a cardiovascular event (32). Inflammatory markers such as IL-6 trigger CRP to be synthesized by the liver, and elevated levels of CRP are associated with an increased risk of the development of cardiovascular disease (33). A study of 89 patients showed that those treated with EPA+DHA had a significant reduction in high-sensitivity CRP (66.7%, P < 0.01) (33). The same study also showed a significant reduction in heat shock protein 27 antibody titers (57.69%, P < 0.05), which have been shown to be overexpressed in heart muscle cells after a return of blood flow after a period of ischemia (ischemia-reperfusion injury) and may potentially have a cardioprotective effect (33). There have been conflicting results reported about EPA and DHA and their use with regard to major coronary events and their use after myocardial infarction. EPA+DHA has been associated with a reduced risk of recurrent coronary artery events and sudden cardiac death after an acute myocardial infarction (RR, 0.47; 95% CI: 0.219–0.995) and a reduction in heart failure events (adjusted HR: 0.92; 99% CI: 0.849–0.999) (34–36). A study using EPA supplementation in combination with a statin, compared with statin therapy alone, found that, after 5 y, the patients in the EPA group (n = 262) who had a history of coronary artery disease had a 19% relative reduction in major coronary events (P = 0.011). However, in patients with no history of coronary artery disease (n = 104), major coronary events were reduced by 18%, but this finding was not significant (37). This Japanese population already has a high relative intake of fish compared with other nations, and, thus, these data suggest that supplementation has cardiovascular benefits in those who already have sufficient baseline EPA+DHA levels. Another study compared patients with impaired glucose metabolism (n = 4565) with normoglycemic patients (n = 14,080). Impaired glucose metabolism patients had a significantly higher coronary artery disease HR (1.71 in the non-EPA group and 1.63 in the EPA group). The primary endpoint was any major coronary event including sudden cardiac death, myocardial infarction, and other nonfatal events. Treatment of impaired glucose metabolism patients with EPA showed a significantly lower major coronary event HR of 0.78 compared with the non–EPA-treated impaired glucose metabolism patients (95% CI: 0.60–0.998; P = 0.048), which demonstrates that EPA significantly suppresses major coronary events (38). When looking at the use of EPA+DHA and cardiovascular events after myocardial infarction, of 4837 patients, a major cardiovascular event occurred in 671 patients (13.9%) (39). A post hoc analysis of the data from these diabetic patients showed that rates of fatal coronary heart disease and arrhythmia-related events were lower among patients in the EPA+DHA group than among the placebo group (HR for fatal coronary heart disease: 0.51; 95% CI: 0.27–0.97; HR for arrhythmia-related events: 0.51; 95% CI: 0.24–1.11, not statistically significant) (39). Another study found that there was no significant difference in sudden cardiac death or total mortality between an EPA+DHA supplementation group and a control group in those patients treated after myocardial infarction (40). Although these last 2 studies appear to be negative in their results, it is possible that the more aggressive treatment with medications in these more recent studies could attribute to this. Omega-3 fatty acids have been found to play a role in atherosclerosis and peripheral arterial disease (PAD). It is thought that both EPA and DHA improve plaque stability, decrease endothelial activation, and improve vascular permeability, thereby decreasing the chance of experiencing a cardiovascular event (41). It was found that EPA supplementation is associated with significantly higher amounts of EPA in the carotid plaque than placebo (P < 0.0001), which may lead to decreased plaque inflammation and increased stability (42). PAD, a manifestation of atherosclerosis, is characterized by buildup of plaque in the arteries of the leg and can eventually lead to complete blockage of the arteries. EPA+DHA supplementation has been shown to improve endothelial function in patients with PAD by decreasing plasma levels of soluble thrombomodulin from a median value of 33.0 ug/L to 17.0 ug/L (P = 0.04) and improve brachial artery flow–mediated dilation from 6.7% to 10.0% (P = 0.02) (43). Patients who had PAD and were supplemented with EPA experienced a significantly lower major coronary event HR than those who did not take EPA (HR: 0.44; 95% CI: 0.19–0.97; P = 0.041) (44). Omega-3 fatty acids have been shown to increase platelet responsiveness to subtherapeutic anticoagulation therapies, including aspirin. Recently, it was noted that patient response to aspirin for anticoagulation therapy is widely variable (45), and, thus, the number of patients with a low response to aspirin or aspirin resistance is estimated to range from <1% to 45%, depending on many variables. However, in patients with stable coronary artery disease taking low-dose aspirin, EPA+DHA supplementation has been proven to be as effective as aspirin dose escalation to 325 mg/d for anticoagulation benefits (45). The antiplatelet drug clopidogrel has also been associated with hyporesponsiveness in some patients. This could be attributed to poor patient compliance, differences in genes and platelet reactivity, variability of drug metabolism, and drug interactions. More importantly, in 1 study, patients receiving standard dual antiplatelet therapy (aspirin 75 mg/d and clopidogrel 600-mg loading dose followed by 75 mg/d) were assigned to either EPA+DHA supplementation or placebo. After 1 mo of treatment, the P2Y12 receptor reactivity index (an indicator of clopidogrel resistance) was significantly lower, by 22%, for patients taking EPA+DHA compared with patients taking placebo (P = 0.020) (46). Omega-3 fatty acids and AD AD is a devastating disease for which there are limited treatment options and no cure. Memory loss is an early indicator of the disease, which is progressive, and leads to the inability of the patient to care for him- or herself and eventually to death (47). Currently, the number of individuals with AD is estimated to be 26.6 million and is expected to increase to 106.2 million by 2050 (48). There have been many studies conducted regarding the use of omega-3 fatty acid supplementation and AD (Table 2). DHA is present in large amounts in neuron membrane phospholipids, where it is involved in proper function of the nervous system, which is why it is thought to play a role in AD (49). A case-control study consisting of 148 patients with cognitive impairment [Mini-Mental State Examination (MMSE) score <24] and 45 control patients (MMSE score ≥24) showed that serum cholesteryl ester-EPA and -DHA levels were significantly lower (P < 0.05 and P < 0.001, respectively) in all MMSE score quartiles of patients with AD compared with control values (49). Another study found that a diet characterized by higher intakes of foods high in omega-3 fatty acids (salad dressing, nuts, fish, tomatoes, poultry, cruciferous vegetables, fruits, dark and green leafy vegetables), and a lower intake of foods low in omega-3 fatty acids (high-fat dairy products, red meat, organ meat, butter) was strongly associated with a lower AD risk (50). Image analysis of brain sections of an aged AD mouse model showed that overall plaque burden was significantly reduced by 40.3% in mice with a diet enriched with DHA (P < 0.05) compared with placebo. The largest reductions (40–50%) were seen in brain regions that are thought to be involved with AD, the hippocampus and parietal cortex (51). A central event in AD is thought to be the activation of multiple inflammatory cells in the brain. Release of IL-1B, IL-6, and TNF a from microglia cells may lead to dysfunction of the neurons in the brain (52). In 1 study, AD patients treated with EPA+DHA supplementation increased their plasma concentrations of EPA and DHA, which were associated with reduced release of inflammatory factors IL-1B, IL-6, and granulocyte colony–stimulating factor from peripheral blood mononuclear cells (53). Unintended weight loss is a problem that many patients with AD may face, and EPA+DHA supplementation has had a positive effect on weight gain in patients with AD. In a study using EPA+DHA supplementation, patients’ weight significantly increased by 0.7 kg in the EPA+DHA treatment group at 6 mo (P = 0.02) and by 1.4 kg at 12 mo (P < 0.001) and was observed mainly in patients with a BMI <23 at the study start (54). This means that those patients with a lower BMI preferentially gained weight compared with those patients already with a higher BMI. Although results from studies regarding the disease processes of AD seem to be promising, there are conflicting data regarding the use of omega-3 fatty acids in terms of cognitive function. Neuropsychiatric symptoms accompany AD from early stages and tend to increase with the progression of the disease (55). An analysis of 174 patients randomized to a placebo group or to a group with mild to moderate AD (MMSE score ≥15) treated with daily DHA (1.7 g) and EPA (0.6 g) found that at 6 mo, the decline in cognitive function did not differ between the groups. Yet, in a subgroup with very mild cognitive dysfunction (n = 32, MMSE score >27), they observed a significant reduction in the MMSE decline rate in the DHA+EPA-supplemented group compared with the placebo group (47). Another study that looked at DHA supplementation in individuals with mild to moderate AD used the Alzheimer’s Disease Assessment Scale–Cognitive subscale, which evaluates cognitive function on a 70-point scale in terms of memory, attention, language, orientation, and praxis. This study found that DHA supplementation had no beneficial effect on cognition during the 18-mo trial period for the DHA group vs. placebo (56). Conclusion The omega-3 PUFA EPA and DHA are important throughout life and are a dietary necessity found predominantly in fish and fish-oil supplements. The omega-3 fatty acids EPA and DHA are essential for proper fetal development, and supplementation during pregnancy has also been linked to decreased immune responses in infants including decreased incidence of allergies in infants. Omega-3 fatty acid consumption has been associated with improved cardiovascular function in terms of antiinflammatory properties, PAD, reduced major coronary events, and improved antiplatelet effects in the face of aspirin resistance or clopidogrel hyporesponsiveness. Patients with AD have been shown to be deficient in DHA, and supplementing them with EPA+DHA not only reverses this deficiency, but may also improve cognitive functioning in patients with very mild AD. With increasing rates of pediatric allergies, cardiovascular disease, and AD in the United States, EPA and DHA may be a safe and inexpensive link to a healthier life. Further research should be conducted in humans to assess a variety of clinical outcomes including quality of life and mental status. In addition, because potent lipid mediator metabolites of EPA and DHA are of great interest currently, their influence on these important outcomes should be assessed because current evidence suggests that their antiinflammatory and tissue-protective effects are nearly 1000 times greater than those of EPA and DHA (7). Acknowledgments Thanks to Dr. Kelly A. Keating (Pharmaceutical Research Institute at Albany College of Pharmacy and Health Sciences) for her outstanding editorial support. All authors have read and approved the final version of this manuscript. Footnotes ↵1 Supported by the Pharmaceutical Research Institute and in part by grant 10-NAN1034-02 from the Long-Term Comprehensive National Plan for Science, Technology and Innovation, King Saud University, Kingdom of Saudi Arabia. ↵2 Author disclosures: D. Swanson, R. Block, and S.A. Mousa, no conflicts of interest. 6 Abbreviations used: AD, Alzheimer’s disease; ALA, a-linolenic acid; CRP, C-reactive protein; MMSE, Mini-Mental State Examination; PAD, peripheral arterial disease. - © 2012 American Society for Nutrition
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10 istina i zabluda Omega-3 masne kiseline Za koje indikacije i u kojim slučajevima ih treba preporučiti, u kojoj količini i s kakvim omjerom EPA i DHA, iz kojih izvora, pročišćene ili ne, da li u kombinaciji s drugim masnim kiselinama – iako su dugo prisutne na tržištu i imaju velik broj poklonika među zdravstvenim radnicima i pacijentima – još uvijek su u javnosti prisutne brojne zablude. Omega-3 iz biljnih izvora dovoljan je izvor omega-3 masnih kiselina, te je podjednako dobro ako se uzima iz biljnih i animalnih izvora. - NETOČNO Alfa-linolenska kiselina (18:3 n-3) – (alpha-linoleic acid - ALA) koja se smatra esencijalnom masnom kiselinom, glavna je omega-3 masna kiselina u prehrani suvremenog čovjeka. Termin „esencijalnosti“ podrazumijeva nemogućnost organizma da ju sam sintetizira, nego je treba unositi prehranom. ALA je bila jedna od prvih makronutrijenata za koju se pokazalo da je važna pri strukturi i funkciji membrana moždanih stanica te diferencijaciji stanica. Prehrambeni izvori alfa-linolenske kiseline su lan, orasi, chia sjemenke, lisnato povrće, zrno soje i neka biljna ulja. No, važno je naglasiti da se procjenjuje da je kod zdravih osoba stupanj metaboličke konverzije ALA u EPA 5-10%, a ALA u DHA svega 2-5%, dok se u nekim studijama ta procjena kreće od 4-6%. International Society for the Study of Fatty Acids and Lipids izdalo je mišljenje o spomenutoj konverziji ALA u EPA i DHA, prema kojem je konverzija ALA u DHA kod dojenčadi svega 1%, a još je manja kod odraslih. Naime, metabolizacija alfa-linolenske masne kiseline do omega-3 dugolančanih masnih kiselina EPA (20:5 n-3) i DHA(22:6 n-3) koje su duže za 2, odnosno za 4 ugljikova atoma, odvija se nizom biokemijskih reakcija posredovanih enzimima koji kataliziraju desaturaciju i elongaciju. Dakle, ALA može biti endogeno konvertirana u EPA i DHA, no takav proces nije biokemijski učinkovit, pa je uz takve neučinkovite procese elongacije i desaturacije najopravdanije EPA i DHA unijeti iz životinjskih izvora, a to su morske namirnice (riba, račići, alge). Za primjer, neke su studije pokazale da je ingestija 10,7 g ALA iz lanenog ulja tijekom 4 tjedna rezultirala niskom koncentracijom DHA u majčinom mlijeku. Čimbenik slabe konverzije jedan je od glavnih kriterija po kojem se smatra da je isključiv unos ALA, uz izostavljanje EPA i DHA - nepoželjan. Stoga je spomenuta preferencija unosa EPA i DHA u odnosu na ALA nedvojbena. Navedene preporuke posebno su važne kod vegetarijanaca koji ne jedu ribu, a ponajviše kod vegana. U tom je pogledu važna i podrška ciljanom suplementacijom. Dovoljno je jesti ribu 1-2 puta tjedno i time postići željeni učinak na zdravlje. - TOČNO i NETOČNO Preporuka Američkog Udruženja za srce kao i Europskog društva za kardiologiju i ostalih društava za prevenciju kardiovaskularnih bolesti u kliničkoj praksi glasi da ribu treba jesti barem dva puta tjedno, od čega barem jedno serviranje treba biti masna riba (plava riba, tuna, losos, ne i riječna riba poput šarana). No, pritom valja imati na umu da se radi o prehrambenim preporukama koje nemaju za cilj provođenje terapije prema određenoj indikaciji, nego im je svrha informirati opću populaciju o prevenciji kardiovaskularnih bolesti. Stoga je tvrdnja o profilaktičnim učincima omega-3 masnih kiselina za zdravu populaciju kroz prehrambeno ponašanje u tom smislu - točna. No, u realnim okolnostima prehrambenog ponašanja mnogih ljudi, prehrana ribom je varijabilna i nekod nzistentna. Nadalje, prehrambeni unos, a time i status omega-3 kiselina, neposredno ovisi o vrsti ribe koja se konzumira. Naime, koncentracija omega-3 masnih kiselina u tkivu ribe znatno se razlikuje zmeđu pojedinih vrsta. Budući da ishrana direktno utječe na sadržaj i profil lipida u masnim tkivima ribe, važno je kakva je bila ishrana ribe, te je li ona iz slobodnog ili ekstenzivnog uzgoja. Terapijski učinak omega-3 višestruko nezasićenih masnih kiselina EPA i DHA nije jednostavno postići količinom tipičnom za isključivo prehrambeni unos ribe. Stoga je mnogo praktičnije ciljanu dozu odrediti kvalitetnom suplementacijom omega-3 masnih kiselina iz koncentriranih oblika, te takvom standardiziranom dozom omogućiti njihov . Pritom se ne valja odreći konzumacije svježe i kvalitetne ribe, ali u vidu treba imati važnost sinergije prehrane i kvalitetnih dodataka prehrani. Stručna radna skupina Europske akademije znanosti o prehrani dala je preporuku da osobe koje ne jedu ribu trebaju razmisliti o unosu 200 mg EPA+DHA iz drugih izvora. Tijekom trudnoće i dojenja nije potrebno posebnu važnost davati suplementaciji omega-3 masnim kiselinama. - NETOČNO DHA se smatra fiziološki esencijalnom masnom kiselinom u retini oka i mozgu, u čijim je stanicama ona predominantna. Uz ostale mnogobrojne učinke ona posjeduje esencijalni značaj za neurološko zdravlje zbog specifičnih strukturalnih i fizikalno-kemijskih uloga, te posredovanja u prijenosu živčanih informacija. Posljednje tromjesečje posebno je ključno u postizanju kritične koncentracije tih dugolančanih masnih kiselina, pri čemu se DHA akumulira u neuralnim i ostalim tkivima. Ta činjenica posebno dobiva na važnosti ako se uzme u obzir da je posljednje tromjesečje naročito važno razdoblje za neurološki razvoj i opće intenzivno razdoblje razvoja djeteta. Tijekom razdoblja laktacije, koncentracija DHA u mozgu se nastavlja povećavati, pa je od 24. tjedna gestacijske dobi, pa sve do 2. godine života i za 30 puta viša. PERiLIP i EARNEST projekti Europske komisije, preporučuju trudnicama unos 200 mg DHA na dan. Iako se čini da omega-3 masne kiseline ipak ne smanjuju sklonost nastanku postporođajne depresije, ista nasumična studija s visoko koncentriranom dozom DHA od 800 mg i EPA od 100 mg, pokazala je da je učestalost prijevremenog poroda manja za čak 52%. Prema recentnim studijama i uglednim autorima, smatra se da je suplementacija DHA omega-3 masnom kiselinom od kliničke važnosti u trudnoći i tijekom razdoblja ranog djetinjstva. Omega-3 višestruko nezasićene masne kiseline mogu poboljšati razvoj djeteta ako trudnica ima adekvatan status tih masnih kiselina. Akumulacija DHA u tkivu fetusa počinje već in utero, a prijenos se odvija dominantno kroz posteljicu. Preporuka za prehranu trudnica je unos ribe bogate omega-3 masnim kiselinama, no uz ograničenje koje je usvojio i American College of Gynacaelogist and Obstetritians i američka FDA još 2004. - da treba ograničiti unos morske hrane na 340 grama tjedno, zbog mogućeg izlaganja fetusa tragovima neurotoksičnih tvari. Pritom treba posebno izbjegavati kritične velike ribe: sabljarku, kraljevsku skušu, morskog psa i tunu, jer žive u morskim područjima u kojima su mogući potencijalni hazardi teških metala (metil-živa) i organskih polutanata (PCB, dioksini). Upravo iz straha od potencijalnog unosa neurotoksičnih tvari za fetus i zbog mjera predostrožnosti, mnoge trudnice izbjegavaju konzumirati preporučenu količinu ribe. Zbog toga nastaje veliki potencijal za deficit tih važnih nutrijenata kojima su uskraćena djeca, a to je samo razlog više za preporuku ciljane i provjereno sigurne suplementacija za trudnice. Nakon 30 mjeseci starosti, dojenčad dojilja koje su svakodnevno uzimale 200 mg DHA tijekom 4 mjeseca, iskazala su značajno bolje rezultate na specifičnom testu indeksa psihomotoričkog razvoja, u usporedbi s djecom žena koje su uzimale biljno ulje. Uz to, neke su studije potvrdile da suplementacija ribljim uljem tijekom trudnoće rezultira smanjenim rizikom od alergija u dojenačkoj dobi. Omega-3 masne kiseline korisne su isključivo pri očuvanju i poboljšanju kardiovaskularnog zdravstvenog statusa. - NETOČNO Činjenica je da se omega-3 masne kiseline najviše propisuju upravo zbog pozitivnih učinaka na kardiovaskularno zdravlje. No, prema raspoloživim dokazima, deficit omega-3 masnih kiselina ima važnu ulogu ne samo pri etiologiji kardiovaskularnih bolesti i pri njihovoj prevenciji i terapiji, već je njihova primjena korisna i kod mnogih drugih poremećaja i bolesti: karcinoma, inzulinske rezistencije, reumatoidnog artritisa i neuroloških bolesti. Za neke indikacije iskazana je veća dokazivost, a za druge manja pri korištenju omega-3 masnih kiselina. Dobri klinički dokazi istaknuti su kod smanjenja smrtnosti od srčanih bolesti i kod primarne i sekundarne prevencije. Takav se učinak ponajprije povezuje s hipotrigliceridemijskim, antihipertenzijskim, antiaritmijskim i protuupalnim učinkom omega-3 masnih kiselina. Trenutno predloženi osnovni mehanizmi učinka omega-3 masnih kiselina uključuju: promjenu ekspresije gena, regulaciju upale, modifikaciju strukture membrana i njihove funkcije. Također, iz navedenih činjenica pod točkom 3. razvidna je izuzetna važnost EPA i naročito DHA pri neurološkom razvoju fetusa i djeteta. Rezultati nekih kliničkih studija daju naslutiti da se povećana koncentracija omega-3 dugolančanih masnih kiselina povezuje s povećanom koncentracijom IgA i nekih citokina u majčinom mlijeku, što može imati implikacije na očuvanje zdravlja djeteta. Omega-3 masne kiseline na kardiovaskularno zdravlje djeluju i terapeutski, a ne samo samo blagotvorno. - TOČNO Jedine službene i konkretne preporuke o pozologiji kod bolesti, koje su dosad dale Europska komisija i EFSA, odnose se upravo na kardiovaskularno zdravlje - preporuke o održavanju normalne koncentracije triglicerida i krvnog tlaka, odnosno kod terapije trigliceridemije i hipertenzije. EPA i DHA smatraju se snažnim antitrigliceridemijskim agensima. Službene preporuke EFSA-e i Europske komisije navode da unos od 2.000 mg DHA u kombinaciji s EPA pridonose održavanju normalnih vrijednosti triglicerida, dok unos od 3.000 mg EPA+DHA iskazuje učinak na održavanje normalnih vrijednosti krvnog tlaka. Analiza 36 crossover studija zaključila je da terapija od 3-4 grama EPA+DHA na dan rezultira s čak 24%-tnim smanjenjem vrijednosti triglicerida kod osoba s normalnim vrijednostima triglicerida, te 35%-tnim smanjenjem kod osoba s povišenim vrijednostima triglicerida. Nadalje, protuupalno i antiaritmijsko djelovanje omega-3 masnih kiselina ima potencijalno pozitivan učinak kod kardiovaskularnih bolesti povezanih s proupalnom i aritmijskom prirodom ranih poremećaja tog sustava. Peta radna skupina za akutni infarkt miokarda pri Europskom društvu za kardiologiju predlaže suplementaciju od jednog grama ribljeg ulja za pacijenate s niskim prehrambenim unosom masne ribe. Također, preporuka iste skupine je da pacijenti koji ne toleriraju dobro farmakoterapiju i kod kojih je koncentracija triglicerida iznad 1,7 mmol/L, trebaju razmisliti o uvođenju suplementacije omega-3 masnih kiselina. Omega-3 masne kiseline ne mogu biti lijek nego su samo koncentrirani sastojak hrane. -NETOČNO U mnogim studijama u proteklih 40-ak godina ispitivan je terapijski učinak omega-3 masnih kiselina na mnoge bolesti. Te studije su raznolikog dizajna, no mnoge od njih su i kliničke, nasumične i dvostruko slijepe. Sama činjenica da se EPA i DHA omega-3 masne kiseline nalaze u supstratu hrane (riba, račići), a priori je bila otegotna okolnost u ranim shvaćanjima mogućeg konkretnog farmakološkog djelovanja omega-3 masnih kiselina. Primjerice, prve usporedne studije u 1950-im godinama proučavale su antidislipidemijski učinak ulja kukuruza i sardina, pri čemu su slični pozitivni rezultati posve u drugi plan stavili djelovanje ulja iz sardina u odnosu na ulje kukuruza. Dugolančane masne kiseline DHA, EPA, ali i ALA, preferencijalno se ugrađuju u fosfolipide staničnih membrana. U staničnim membranama utječu na njihovu fluidnost, prijenos signala i gensku ekspresiju, no još je bitnije - služe kao supstrat za sintezu potentnih parakrinih hormona: eikosanoida, proupalnih i protuupalnih biokemijskih medijatora, pa time utječu na ekspresiju imunološkog odgovora. Omega-3 masne kiseline EPA i DHA pokazuju moguće interakcije s antikoagulantnim lijekovima i nesteroidnim protuupalnim lijekovima (kroz metabolički put sinteze eikosanoida) te tako utječu na produljenje protrombinskog vremena. Stoga se uglavnom ne preporučuje istovremena primjena omega-3 EPA i DHA tijekom terapije tim lijekovima. Naime, takve interakcije lijekova s tako potentnom farmakološki aktivnom tvari mogla bi implicirati da su omega-3 masne kiseline EPA i DHA u određenim dozama mnogo više od hrane i dodataka prehrani. No ipak, uz sve navedeno, osim prehrambenih izvora, većina koncentriranih oblika EPA i DHA omega-3 masnih kiselina nalazi se na tržištu registrirana kao dodaci prehrani s odgovarajućim zdravstvenim tvrdnjama. Omega-3 masne kiseline nalaze se u trigliceridnoj kemijskoj strukturi (riba) ili pak u obliku fosfolipida (krill račići). Farmaceutskim postupcima purificirani i koncentrirani, te tako modificirani oblici ribljeg ulja u obliku etilnih estera, odobreni su kao lijekovi kod indikacije hipertrigliceridemije. Taj primjer najbolje pokazuje da prehrambeni i koncentrirani izvori zookemikalija mogu biti izvor farmakološki aktivnih tvari koje mogu biti registrirane i kao lijekovi, ako prođu rigorozne postupke provjere sigurnosti i djelotvornosti. Svi dodaci prehrani s omega-3 masnim kiselinama su podjednaki i ne treba posebno obraćati pozornost na detalje specifikacija proizvoda. - NETOČNO Masna riba može biti jedan od najvećih potencijalnih izvora teških metala u prehrani. Od posebne su važnosti mjere predostrožnosti unosa potencijalnih kontaminata za trudnice i djecu te neurološke pacijente. Prilikom suplementacije omega-3 masnih kiselina, od velike je važnosti kriterij farmaceutske čistoće proizvoda. Ona se provodi složenim postupcima purifikacije, superkritične ekstrakcije i molekulske predestilacije. Tim se postupcima značajno uklanjaju dioksini, živa i poliklorirani bifenilni spojevi (PCB). Iako anorganska živa ima slabiju sposobnost prolaska kroz tkivne barijere, metilirana živa je vrlo potentan neurotoksin koji se pritom bioakumulira u tkivima. S obzirom da prelazi barijeru posteljice, kritični je čimbenik onemogućiti ingestiju žive iz prehrambenih izvora, a još više - njezinu kontinuiranu bioakumulaciju. Osim već spomenutih većih riba koje mogu biti izvor žive, skriveniji i katkad manje očekivani izvori žive u tragovima mogu biti dodaci prehrani s ribljim uljem, koji nisu prošli procese uklanjanja žive i ostalih toksičnih organskih tvari. Zbog toga, te manje mogućnosti kontaminacijom žive, prikladan izvor EPA i DHA omega-3 masnih kiselina iz ribjeg ulja može biti ulje antarktičkih krill račića. Važno je u kojoj se koncentraciji suplementiraju omega-3 masne kiseline. - TOČNO Različite institucije i profesionalna udruženja daju razne preporuke koje se razlikuju prema ciljevima, a većina njih odnosi se na primarnu prevenciju nastanka bolesti i održavanje zdravlja optimalnim. No, isto tako, mnoga udruženja i institucije daju konkretne preporuke s ciljem postizanja terapijskog učinka. Američki Food and Nutrition Board i International society for the study of fatty acids and lipids preporučuju unos EPA i DHA zajedno, i to u količini od minimalno 500 mg na dan, s ciljem održavanja i postizanja optimalnog zdravlja srca i krvnih žila. No, kako su ciljevi sve bliže terapijskom učinku, tako se mijenjaju i preporučene doze. Upravo doza omega-3 masnih kiselina EPA i DHA čini razliku, jer je farmakološki učinak direktno uvjetovan konkretnom primijenjenom dozom. Često preporučivana doza od 1.000 mg omega-3 masnih kiselina sa 300 mg EPA-DHA neće značajno pridonijeti smanjenju povišenih koncentracija triglicerida, dok se primjenom terapijskih doza mijenja i učinak. Spomenute koncentracije EPA+DHA od 2.000 mg mogu sniziti povišene koncentracije triglicerida, no daljnjim povećanjem koncentracije postiže se naročito koristan učinak. Velika je količina dokaza o primjeni doze omega-3 masnih kiselina (DHA i EPA) pri povišenim koncentracijama triglicerida u krvi. Doze od 4 grama na dan mogle bi sniziti povišenu vrijednost triglicerida za čak 40%! Njemačko Društvo za prehranu u primarnoj prevenciji kardiovaskularnih bolesti preporučuje 250 mg EPA+DHA, dok se kod sekundarne prevencije tih bolesti koncentracija povećava za 4 puta, na preporučenih 1.000 mg EPA+DHA. EFSA priznaje antihipertenzijski učinak EPA i DHA koji direktno ovisi o vrijednostima povišenog krvnog tlaka i o primijenjenoj dozi EPA i DHA. U nižim vrijednostima od preporučene neće doći do primjetnog farmakološkog učinka. Masti, pa tako i omega-3 masne kiseline, nisu važne pri mršavljenju. - NETOČNO Rastući broj studija koje su proučavale ketogeni način prehrane, u posljednjih je nekoliko godina posve promijenio način razmišljanja o ulozi masti pri redukciji prekomjerne tjelesne mase i terapiji debljine. No, iako su masti tijekom desetljeća službenih preporuka bile znatno ograničavane u prehrani, istraživanja o ulozi određenih masnih kiselina pri redukciji tjelesne mase nisu bile nepoznate. Najbolji primjer je proučavanje učinka konjugirane linolne kiseline (CLA) pri redukciji tjelesne mase, ali i EPA i DHA. Tek je nekoliko intervencijskih ispitivanja na ljudima istraživalo učinak omega-3 masnih kiselina na debljinu. Mnoge su studije pokazale da primjena omega-3 masnih kiselina povećava osjetljivost na inzulin, lipolizu masti i bolju adaptaciju korištenja masti kao preferentnog izvora energije, iako su mnoge od njih uglavnom bile provedene na animalnom modelu. Takve mnogobrojne studije pokazale su da je uvrštavanje omega-3 masnih kiselina u prehranu glodavaca s visokim udjelom masti smanjilo akumulaciju masnog tkiva. Kod metaboličkog sindroma i debljine taj je biološki učinak od izuzetne važnosti kao i smanjenje upale te poboljšanje statusa kardiovaskularnog zdravlja. Mogući mehanizmi su višestruki, no neke in vivo studije pokazale su mogući mehanizam djelovanja ribljeg ulja na smanjenje akumulacije masti kroz pojačavanje ekspresije UCP1 proteina u smeđem masnom tkivu. Naime, smeđe adipozno tkivo ima središnju ulogu u regulaciji energetske homeostaze. In vivo studije pokazale su da su ispitni miševi koji su bili na ishrani koja je uključivala riblje ulje, pokazali bolje rezultate u smanjenju masnog tkiva kroz mehanizme povećanja funkcije smeđeg adipoznog tkiva. Uz to, zabilježena je smanjena proliferacija masnih stanica u bijelom tkivu, a kroz ostale mehanizme kod životinja na prehrani s ribljim uljem postignute su povoljnije vrijednosti glukoze u krvi natašte, inzulina, triglicerida i leptina. Omega-3 masne kiseline iz ribljeg ulja mogu stimulirati aktivnost enzima uključenih u oksidaciju masti, no taj je poželjan učinak prema do sada dostupnim istraživanjima moguć uz uključivanje redovite tjelesne aktivnosti. Velik broj longitudinalnih prospektivnih kohortnih studija pokazao je učinak suplementacije omega-3 masnih kiselina na kardiovaskularno zdravlje, no nijedna nije pokazala učinak na tjelesnu masu ili na masno tkivo. Jedna od rijetkih prospektivnih kohortnih studija, tzv. Health Professional Follow-Up Study, provedena na 43.671 muškaraca, praćenih tijekom čak 12 godina, pokazala je da su ispitanici koji su konzumirali veće količine ribe (unos veći od 5 puta tjedno) imali manju sklonost prekomjernoj tjelesnoj težini nego oni s niskim prehrambenim unosom ribe (jednom mjesečno). Najbolje je suplementirati sva tri osnovna tipa masnih kiselina: omegu 3-6-9 - NETOČNO Jedna od najvećih zabluda vezanih za suplementaciju omega-3 masnih kiselina je primjena predformuliranih dodataka prehrani koji u jednoj dozi sadrže masne kiseline iz sve tri skupine: omegu-3, omegu-6 i omegu-9 što se može kvalificirati i kao nepotrebno. Naime, budući da su omega-6 i omega-3 masne kiseline u znatno nepovoljnijem međusobnom omjeru, te da omega-6 i omega-9 imaju kompetitivan odnos kao supstrati za enzime (delta-6-desaturaza) povoljan učinak na metabolizam može se očekivati tek smanjivanjem učestalo vrlo visokog unosa omega-6 u prehrani, te usporednim povećanjem prehrambenog unosa omega-3 masnih kiselina, jer se time postiže biokemijska ravnoteža. Stoga se dodatno povećanje tih, u prehrani ionako previše prisutnih masnih kiselina, čini neracionalnim, uz mogući izuzetak gama-linolenske omega-6 masne kiseline. Omega-9 jednostruko nezasićene masne kiseline često su deficijentne u tipičnoj prehrani čovjeka Zapadnog svijeta, pa se u načelu mogu suplementirati. No, valja razmotriti mogući doista konkretan učinak tipično prisutnih doza tih masnih kiselina (oleinska kiselina) u primjerice jednoj kapsuli, ili ipak razmotriti prednosti oblika iz prehrane (ekstra djevičansko maslinovo ulje, avokado i sl.). 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