Omega 3:
Implications in Human Health and Disease

Published: August 1, 2001
ACPE Lesson Expires: August 1, 2003

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Provided through an educational grant from

The study of omega 3 fatty acids is one of the fastest growing research areas in nutritional and medical science today. As research interest in the topic has increased, so has consumer and patient awareness. Ten years ago, less than 10% of people polled recognized the term “omega 3,” but in 1999 an independent survey reported that consumer awareness had grown to over 50%.¹ Awareness and interest among scientists and physicians have also grown, as evidenced by the broad diversity of research projects currently examining the effects of omega 3 fatty acids. Many reports appearing in the scientific literature suggest that simple modification of the diet with certain fatty acids can have a positive impact on a broad range of diseases. These diseases include heart disease, hypertension, cancer, diabetes, cystic fibrosis, asthma, arthritis, dysmenorrhea, depression, schizophrenia, and attention deficit disorder.

INTRODUCTION

Fat is a hot topic! It is difficult to go anywhere without being reminded of it. From media and health advisories related to dietary fat intake to the wide availability of low-fat foods, fat has become a conscious part of our daily living. People discuss their diet and cholesterol levels in the same casual way they discuss weather and sports. For the most part, fat is regarded in a negative fashion. Typically, it is considered in relation to excess energy balance, obesity, and as a dietary factor in the development of cardiovascular disease. However, the term fat is broad by definition; in contrast to popular opinion that all fat is bad, there are “good” and “bad” fats, and fatty acid nutrition must be considered in an educated context.

Under certain conditions, dietary fat may play a role in disease development. What has not been emphasized is that certain types of fatty acids are essential; that is, they must be obtained from the diet, are necessary for health, and their absence from the diet can be detrimental.² The “good” fats are the essential fatty acids (EFAs) from the omega 3 and omega 6 fatty acid families. Their significance in the diet is not based simply on the presence or absence of one or the other, but rather their balance and the inclusion of short- and long-chain EFAs. As such, both classes of fatty acids are recognized as playing a significant role in health. Surprisingly, recommendations to eat more polyunsaturated fat have typically considered only omega 6 while ignoring omega 3. This pattern has resulted in an American population that consumes excessive amounts of omega 6 and very low levels of omega 3.

As far back as can be estimated, humans have relied on fat as a source of calories and EFAs.³ Yet, only in the past two decades have we learned about the life-giving role of fatty acids. This understanding began with the discovery of the essential nature of dietary fat by George and Mildred Burr at the University of Minnesota in 1929.^4,5 The Burrs detailed the consequences of an essential fatty acid deficiency in growing and developing animals. Clearly, the Burrs' early work in the field defined the significance of EFAs, but science has greatly expanded our knowledge of the relationship between fat and human health over the past 70 years. Research has highlighted the significance of particular types of fatty acids in the success or failure of our health. We are beginning to understand what types of fat to feed people, as well as the consequences of eating too much, not enough, or the wrong kind of fats. The message that is beginning to unfold is not as simple as a consideration of “total dietary fat intake,” but rather the composition of the diet with respect to specific fatty acids and the relative balance between omega 6 and omega 3.^6,7 For example, we know that long-chain omega 3 polyunsaturated fatty acids (PUFAs) are important for neural and visual development and the prevention of diseases such as coronary artery disease.² Indeed, just as it is becoming increasingly obvious that the fatty acid composition of dietary fat will affect clinical outcomes, omega 3 supplementation has shown potential value in the treatment of heart disease, hypertension, cancer, diabetes, depression, schizophrenia, cystic fibrosis, and arthritis.^8-13

FATTY ACIDS AND LIPIDS: THE BASICS

Fatty Acids

Historically in Western societies, the term fat described a type of material that was extracted from animals and plants and was equivalent to the terms lard, tallow, or suet. This term was replaced with a broader one, lipid, to more accurately identify a group of compounds with similar characteristics. By definition, the term lipid collectively refers to a group of substances that are insoluble in water and soluble in organic or nonpolar solvents such as hexane, benzene, chloroform, and ether.¹⁴ Lipids are divided into three main classes, simple (neutral), complex, and derived. Simple lipids are compounds in which the fatty acids are esterified to a glycerol backbone like mono-, di-, and triglycerides. Complex lipids, such as phospholipids, contain multiple functional groups, such as a phosphate group, nitrogenous base, or sugar moieties in addition to fatty acids and glycerol (Figure 1).

Fatty acids are derived from the hydrolysis of simple and complex lipids and are broadly classified into saturated (containing no carbon-carbon double bonds) and unsaturated (having one or more carbon-carbon double bonds). Unsaturated fatty acids can be further classified into:

• Monounsaturated—one carbon-carbon double bond;

• Polyunsaturated (PUFA)—two or more carbon-carbon double bonds; and

• Highly unsaturated fatty acids (HUFA)—three or more carbon-carbon double bonds.

NOTE: Fatty acids designated as HUFA are also PUFA but separate themselves from PUFA in that they contain three or more carbon double bonds.

Structurally, fatty acids are made up of a straight chain of carbons that end in a carboxylic acid terminus. In vertebrates, predominant chain lengths range from 2 to 26 carbons with as many as 6 carbon-carbon double bonds; however, longer highly unsaturated acids have been described in relatively small amounts in spermatozoa, retina, and brain cells.¹⁵ Common fatty acids are listed in Table 1.

The double bond structure of naturally occurring fatty acids assumes the cis configuration, where the two hydrogens of the double bond are on the same side of the double bond. Trans fatty acids have hydrogen molecules on opposite sides of the double bond and are produced when PUFA are heated or hydrogenated, which is the common process used to make margarine spreads from liquid vegetable oils. Dietary trans fatty acids are absorbed and metabolized in a similar fashion to the naturally occurring cis-configured fatty acids.¹⁶ Evidence suggests that trans fatty acids may be associated with an increased health risk. Consumption of diets high in trans fatty acids may be a significant risk factor in the development of cardiovascular disease in a similar manner to diets high in saturated fat.¹⁷

Fatty Acid Nomenclature

The nomenclature originally used to describe fatty acids was the “delta” system. This system counted the position of double bonds in the fatty acid chain starting from the carboxyl terminus. While accounting for every double bond, this system proved cumbersome in light of the fact that the entire sequence would change after elongation of the fatty acid. The “omega” () nomenclature (synonymous with the “n” system) was introduced in the 1960s by Dr. Ralph Holman to simplify the identification of polyunsaturated fatty acids.¹⁸ The general scheme is detailed in Figure 2. In this system, a string of numbers and symbols represents the fatty acid, whereby the first number of the sequence refers to the total number of carbons in the fatty acid chain, the second refers to the number of carbon-carbon double bonds, and the last or “omega” number refers to the position of the first carbon-carbon double bond that occurs with respect to the methyl end of the molecule. For example, -linolenic acid (18:33 or LNA) has 18 carbons, three carbon-carbon double bonds, and is an omega 3 fatty acid with the first carbon-carbon double bond occurring three carbons from the methyl terminus of the fatty acid, between the third and fourth carbons. As all modifications of unsaturation and/or chain length in humans occur at the carboxyl terminus or within nine carbons of the terminus, the “omega” nomenclature classifies fatty acids into families whose terminal structure never changes. Thus, the tail structure remains omega 3, omega 6, or omega 9 irrespective of chemical changes to the first nine carbons of the carboxyl functional group. In addition, mammals, unlike plants, cannot interchange. Thus mammals cannot change an omega 3 fatty acid into an omega 6 fatty acid and vice versa.

Food Sources of Lipids

Predominant sources of lipid in the diet are triglycerides in vegetable oils and meats.^19,20 Structural lipids like phospholipid also provide a significant source of fatty acid in animal-based food such as meat, poultry, fish, and eggs. The most commonly occurring polyunsaturated fatty acids in nature are linoleic acid (18:26 or LA) and -linolenic (18:33 or LNA) acids, which are predominantly found in vegetable oils. Plants possess the necessary enzymatic machinery to synthesize double bonds beyond the delta-9 carbon. Thus they can synthesize omega 3 and -6 essential fatty acids. Long-chain PUFA, including tri-, tetra-, penta-, and hexaenoic acids, are mainly found in marine and land animals. Commonly occurring vegetable and plant oil omega 3 and omega 6 fatty acid profiles are listed in Table 2. Significant dietary sources of LNA include flaxseed, walnuts, perilla (Perilla species), purslane (Portulaca species), canola, and soybean oils. Significant sources of LA include corn, sunflower, cottonseed, safflower, canola, and soybean oils.

Among the long-chain omega 3 fatty acids, those predominantly found in food sources include eicosapentaenoic (20:53 or EPA), docosapentaenoic (22:53 or DPA), and docosahexaenoic (22:63 or DHA). Perhaps the most well known sources of these fatty acids are cold-water fatty fish such as salmon.

Predominant dietary long-chain omega 6 fatty acids include dihomo-gamma-linolenic acid (20:36 or DGLA) and arachidonic acid (20:46 or AA). Long-chain omega 6 fatty acids are found in eggs, dairy products, and meats.

In the typical American diet, approximately 98% to 99% of dietary PUFA intake is obtained from 18 carbon EFAs with long-chain omega 3 intake comprising about 150 mg per day out of 60 g to 100 g of daily fat intake. Long-chain omega 6 intake, mainly as arachidonic acid, tends to vary but is estimated to be around 500 mg per day.³

HISTORICAL PERSPECTIVES OF ESSENTIAL FATTY ACIDS

Essentiality of Fatty Acids

As stated earlier, the essential nature of fat was discovered by the Burrs.⁵ Their experiments documented that when young rats were fed an EFA-deficient diet, they ceased to develop normally. The animals also developed dermatitis, scaly tails, dry skin, thickened and brittle hair, kidney malfunction, and they failed to reproduce. This condition was reversed when corn or flaxseed oil was added to the diet. The main components of these oils, linoleic acid (18:26) and a-linolenic acids (18:33), were determined to be the fatty acids responsible for this recovery and thus were termed “essential.”

Subsequent studies have documented the unique requirements of PUFA in human and animal nutrition.²¹ However, because flaxseed oil contains a small amount of linoleic acid (6), the essential nature of omega 3 fatty acids was contested until a classic case of -linolenic acid (3) deficiency was reported by Holman in 1982.²² LNA deficiency was described in a young girl injured by a gunshot. The girl was maintained on a parenteral nutrition formula that included LA as the sole EFA. Symptoms of an EFA deficiency (EFAD) developed that were related to neurological function and included episodic paralysis, blurred vision, weakness, and the inability to walk. Analysis of the patient's plasma lipid fatty acid profile revealed near normal levels of omega 6 fatty acids and very low levels of omega 3 fatty acids. The addition of LNA to the parenteral emulsion resolved many of the patient's neurological symptoms.

A lack of EFA in the diet can result in EFAD. There is a correlation between the extent and duration of EFA deprivation and the severity of symptoms. Extreme deficits result in symptomatology similar to that originally described by the Burrs; however, smaller deficits may not result in acute and overt symptomatology, but rather may culminate in disease over a period of several years or decades. In EFAD, the body deficient in PUFA attempts to replenish and restore unsaturation by utilizing endogenous synthesis pathways (the omega 9 pathway) as a source of PUFA. This pathway terminates in the formation of a triene, Mead's acid (20:39)—the body's best attempt at achieving unsaturation. Mead's acid is produced in excess during EFAD. In 1960, Holman identified a decrease of arachidonic acid and an increase of Mead's acid as a marker of EFAD and referred to it as the triene:tetraene ratio.²³ Today, however, more revealing and detailed analyses of blood lipid profiles are available, and these have facilitated more precise descriptions of the roles that omega 3 and omega 6 EFAs play in health (Table 3).¹⁴⁶

By classical definition, true omega 3 deficiency is relatively rare, but a relative insufficiency of omega 3 that may approach deficiency status is considered prevalent.^24,25 Experimentally, omega 3 deficiency has been studied largely in rat and monkey models.²⁶ In omega 3 deficient animals, brain and tissue DHA (3) is replaced by DPA (6), the closest structural substitute for DHA. In primates, this omega 3 deficiency resulted in visual as well as neurological abnormalities that could be attenuated by the reintroduction of omega 3 to the diet. Dietary DHA is very important for humans in the development of brain and retinal tissue. Children who were breast fed or received long-chain PUFA-supplemented formula reportedly perform better on visual and problem-solving testing and intelligence quotients testing, compared to those fed formula without long-chain PUFA. ²⁷

METABOLISM OF OMEGA 3 AND OMEGA 6

Fatty Acid Metabolism

If LNA and LA are supplied by the diet, they can be desaturated and elongated to long-chain highly unsaturated fatty acids, but the efficiency of this conversion is reported to be low.²⁸ Thus, it is recommended that long-chain PUFA also be included in the diet.

It was not until 20 years after the discovery of EFAs that their metabolism was elucidated.^29-31 In 1950, Holman and Widmer reported that when LA was fed to rats, a tetraene [arachidonic acid (20:46)] increased, and when LNA was fed, a pentaene [eicosapentaenoic acid (20:53) or EPA] and a hexaene [docosahexaenoic acid (22:63) or DHA] increased significantly in rat liver lipids.²⁹ As more definitive analytical techniques became available, Holman, Klenk and associates found that the metabolism of LA resulted in the formation of omega 6 PUFA, and the metabolism of LNA resulted in the formation of omega 3 PUFA.^31,32 This discovery led to the identification of the elongation and desaturation products of the EFAs illustrated in Figure 3.

The preferred anabolic pathway for PUFA follows steps starting with 6 desaturation, elongation to 20 carbons, 5 desaturation, elongation to 22 carbons, 4 desaturation by and finally elongation to 24 carbons. The one exception, docosahexaenoic acid (22:63), is now known to be formed by an alternative pathway, referred to as the “Sprecher shunt,” which involves 6 desaturase instead of 4 desaturase.³³

The three main fatty acid families, omega 3, omega 6, and omega 9, compete with each other for the desaturase and elongase enzymes that regulate the conversion of short-chain PUFAs into long-chain PUFAs based on 3>6>9. The competitive nature of LNA and LA for these enzymes was established by Holman and Mohrhauer and modeled mathematically by Lands and coworkers.^34,35 Experimentally, when rats were fed a constant amount of LNA (1% of energy) and increasing amounts of LA (from 1% to 9% of energy), liver lipid content of omega 3 fatty acids decreased significantly. Likewise, when LA was fed at a constant amount (0.6% energy) and dietary LNA was increased, liver lipid composition of omega 6 fatty acids decreased. From these early models, we know that diets high in the omega 6 LA—the typical American diet—suppress the metabolism and accretion of blood and tissue omega 3 fatty acids.^2,36,37

OMEGA 3 FATTY ACIDS IN HEALTH AND DISEASE

Eicosanoids

In 1930, two gynecologists reported that extracts of seminal fluid caused uterine tissue to contract.³⁸ Soon after this report, von Euler attributed the uterine-stimulating characteristic of seminal fluid to lipid-like substances originating in the prostate and collectively referred to these compounds as “prostaglandins”.³⁹

Prostaglandins (and leukotrienes) are eicosanoids, biologically active substances that are produced by the direct enzymatic oxidation of 20- and 22-carbon PUFA, including AA, DGLA, EPA, and DHA, by the cyclooxygenase (prostaglandin H synthase) and lipoxygenase (5-lipoxygenase) enzymes (Figure 4).⁴⁰ Almost all cells in the human body are capable of producing eicosanoids and, so far, over 100 eicosanoids have been identified.⁴¹ Eicosanoids are essential for normal physiology and contribute to disease pathology, supporting a wide variety of processes such as cardiovascular function, intestinal motility and acid secretion, inflammation, and ischemia/reperfusion injury. During the inflammatory cascade, eicosanoids influence the immune response by causing vascular changes and edema, stimulating neutrophil chemotaxis, and stimulating the production of cytokines. In this way, PUFA play an integral role in the inflammatory process.^42,43

AA, DGLA, EPA, and DHA predominate as substrate for the cyclooxygenase and lipoxygenase enzyme systems. However, their eicosanoid products differ in physiological potency or effect.

Eicosanoids can be arranged into three groups or series depending on their fatty acid origin. Group 1 eicosanoids are derived from DGLA (6). Group 2 are derived from AA (6) and are potent mediators of inflammation. Group 3 eicosanoids are derived from EPA (3) and are of considerably lower potency as inflammatory mediators than group 2 eicosanoids.^41,44 For example, leukotriene B₄ derived from AA (Group 2) is 30 times more potent a chemotactic agent than EPA-derived leukotriene B₅. In addition, prostaglandin E₂ (Group 2) elicits marked vasoconstriction and edema, while prostaglandin E₃ (Group 3) stimulates little vasoactive activity (Figure 4).

Group 1 eicosanoids, such as prostaglandin E₁ derived from DGLA, also possess some anti-inflammatory properties, and thus dietary sources of gamma-linolenic acid (18:36 or GLA) such as primrose and borage oil have also been investigated in models of experimental and clinical inflammation.⁴⁵

Anti-inflammatory Nature of Omega 3

Omega 3 fatty acids have a well-documented anti-inflammatory effect, the basis of which relates to eicosanoid production.^2,46 The inflammatory response relies on dietary AA (6) and the subsequent production of group 2 eicosanoids; however, dietary sources rich in omega 3 increase the cell membrane content of both EPA and DHA.^47,48 Increased proportions of membranous omega 3 at the expense of arachidonic acid results in the competitive inhibition of pro-inflammatory group 2 eicosanoid production and increased production of anti-inflammatory group 3 eicosanoids.⁴⁹

Experimentally, the competitive inhibition of group 2 synthesis by EPA and DHA omega 3 fatty acids has been reported to have a rate constant similar to that of ibuprofen.⁵⁰ Lands et al were the first to identify that omega 3 fatty acids could inhibit the formation of the highly inflammatory omega 6-derived eicosanoids.⁵⁰ It was noted that omega 3-derived analogs antagonized metabolism of arachidonic acid by cyclooxygenase. Experimental models subsequently examined the hypothesis that omega 3 fatty acids could attenuate injury by reducing the inflammatory response.^51,52 Fish oil supplementation reportedly decreased injury severity in a feline model of cerebral ischemic injury as well as decreased injury in experimentally-induced myocardial infarction in dogs. Other studies have investigated the anti-inflammatory nature of fish oil for the treatment of diseases including arthritis, cystic fibrosis, IgA nephropathy, diabetes, ulcerative colitis, Crohn's disease, asthma, and sepsis, with apparent success at improving outcomes.^2,13,53-57 For example, in cystic fibrosis patients with lung dysfunction, leukotriene B₄ (LTB₄) levels in bronchial lavage fluids were reported to be significantly higher compared to unaffected controls.¹² Fish oil supplementation in this patient population resulted in reduced LTB₄ production and improved lung function, including increased tidal volume and sputum generation. In inflammatory bowel disorders, fish oil supplementation resulted in significant improvements in remission time and histological findings for ulcerative colitis and Crohn's disease patients.^57,58

Improvements in joint tenderness and morning stiffness have also been reported in arthritic patients whose diets were supplemented with fish oil.¹³ In septic patients, enteral formulas enriched with fish oil reduced infectious complications by 70% and mean hospital stay length up to 29% compared to patients on traditional formulas without long-chain omega 3.⁵⁴

Experimentally, improved outcomes with supplemental omega 3 are attributed not only to eicosanoid effects but also to eicosanoid-related events, including cytokine production and second messenger cell signaling.⁵⁹ Omega 3 fatty acids have been reported to down-regulate the inflammatory response by decreasing the production of inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor- (TNF). In humans, 300 g/day of fish or 18 g/day of fish oil for 3 months reportedly diminished production of IL-1 and TNF by up to 30% to 50% in stimulated peripheral blood monocytes.^61,62 In a septic rat model, fish oil treatment reduced PgE₂ production, calcium flux, inositol triphosphate signaling, and mortality compared to corn oil treated animals.^47,60

SUPPLEMENTAL FORMS OF OMEGA 3

Essential Fatty Acid Supplements

Several different types of EFA supplements exist in the marketplace today. The vast majority are related to omega 3 fatty acids. Predominant sources of supplemental omega 3 fatty acids include flaxseed, fish oil, and single cell oils derived from algae. Flaxseed is rich in the short-chain omega 3, -linolenic acid (LNA or 18:33), whereas fish oils are rich in long-chain omega 3 fatty acids, EPA and DHA. The typical fatty acid profile of common fish oil is listed in Table 4. Fish oil or fish body oils are a rich source of long-chain omega 3, with typical concentrations of omega 3 in fish oil being around 30% or about 300 mg of EPA and DHA (180 mg EPA/120 mg DHA) per 1 g capsule.

Flax

Flaxseed and flaxseed oil products also comprise an abundance of the supplemental fatty acid market. Flaxseed and its derived oil provide a rich source of -linolenic acid, the parent omega 3 essential fatty acid. By weight, flaxseed contains 40% to 45% oil, which on average contains ~55% LNA. Thus, the overall weight percentage of LNA is ~22% of the whole flaxseed weight. Flaxseed also has additional nutritional attributes including its high content of soluble and insoluble fiber and lignans or phytosterols, both of which are thought to be chemopreventive for certain types of cancers in animal studies.⁶³ Flaxseed oil (triglyceride) is derived by pressing seeds to expel their oil content and is typically sold in liquid or capsular form. In supplemental form, whole flaxseed is typically milled or ground to afford better digestion and integration into physical mixtures. It is often the mainstay of many derived nutritional products that manufacturers claim as omega 3 nutritional supplements.

It should be noted, however, that flaxseed or flaxseed oil does not contain EPA or DHA. Thus flaxseed and fish oil are not interchangeable sources of omega 3 fatty acids per se. Before making a recommendation to consume “omega 3” fatty acids, diligent care should be taken to discern the actual omega 3 constituents of a product, and a survey of the literature conducted to define the actual components (LNA, EPA, or DHA) used in clinical trials.

Purslane

Purslane (Portulaca oleracea) is one of the most highly undervalued food-plants, partly because it is also one of the world's most common weeds. In England, it was once cultivated in kitchen gardens and in the 17th century in Massachusetts served as a salad vegetable. The protein content of purslane has been measured at 19.9%. Purslane is also rich in antioxidants such as ascorbic acid, -tocopherol, and glutathione. What few know is that this weed contains more LNA than any other green leafy vegetable plant tested (4 mg/g fresh weight). Purslane is grown in Europe as a pot herb and could be cultivated commercially if there was enough demand.^64-66

Fish Oil

Fish oil supplements have been around for decades. Cod liver oil has been used for the promotion of health for many years as a source of vitamins A and D, but it is now well known that this oil also contains significant amounts of omega 3 fatty acids. The classical publications by Bang and Dyerberg, and Dyerberg, Bang, and Hjorne in the 1970s that ascribed the low incidence of heart disease in Eskimos to dietary consumption of marine-related omega 3 were the initial impetus for much of the supplemental fish oil industry development.^67,68 Fish oil is generally derived from oily or fatty fish rich in EPA and DHA. To produce food-grade fish oil, a fairly complex process of extraction and purification is performed. The process is designed to eliminate impurities such as free fatty acids, protein residues, and oxidation products.⁶⁹ The omega 3 fatty acid content may also be concentrated by additional techniques such as molecular distillation and urea precipitation, which separate long-chain polyunsaturates rich in omega 3 from other fatty acids present in the oil. Highly concentrated omega 3 preparations are also available as ethyl esters, but tend to be directed toward more pharmaceutical type applications. Fish oil capsules typically contain vitamin E, which is added to prevent oxidation.

Fish Oil Delivery Systems

Traditionally, fish oil delivery systems have either been simply liquid triglycerides, like cod liver oil, or encapsulated products such as fish oil capsules. Liquid fish oil, for obvious reasons of palatability, has for the most part been abandoned. Fish oil capsules are still the predominant supplemental form of omega 3, but while protecting from initial fishy flavors, side effects from capsule consumption often include fish oil “burps” or reflux of fishy flavors. This potential side effect raises compliance concerns in studies examining supplementation. Newer products have attempted to eliminate fishy reflux by integrating fish oil into more food-like matrices. Flavored fish oil emulsions are emerging as a new delivery system that not only offer fish oil in a palatable state but also may increase bioavailability or absorption of the fish oil fatty acids, even when taken without food and on an empty stomach.⁷⁰ Emulsion technology claims to eliminate gastric reflux or burping of fishy flavors and improve bioavailability by reducing gastric and esophageal emptying times and improving absorption based on its pre-emulsified state. Ease of use, compliance, and the ability to consume fairly large dosages of fish oil conveniently—as sometimes is required in clinical studies or as a part of a therapeutic regimen—are all potentially positive characteristics of food-type fish oil emulsions. Daily 10 g to 20 g doses of emulsified fish oil can be consumed easily with a few spoonfuls, whereas ingesting 20 to 40 fish oil 500 mg capsules requires a considerably greater effort, especially for children or patients averse to or incapable of taking capsules.

Omega 3 Fatty Acid Enriched Products

Food products supplemented with omega 3 fatty acids include an experimental spread,⁷¹ omega 3-enriched eggs from flaxseed-fed hens,^72,73 and an omega 3-enriched partially-skimmed cow milk product.⁷⁴ Research on these products is still at the early stage, but the main clinical studies are briefly reviewed below.^75,76

Healthy male subjects (ages 25-44) maintaining a typical Western diet used a spread rich in LNA and substituted flaxseed oil for cooking oil. After 4 weeks, the regimen caused a 2.5-fold increase in plasma lipid concentrations of EPA compared to controls (n=15) who maintained a diet low in LNA and high in LA. The authors concluded that using LNA-rich vegetable oil products (the intake of LNA amounted to 9 g/day) as part of a Western diet low in LA could help increase levels of EPA.⁷¹

Male subjects consuming four omega 3-enriched eggs per day for 2 weeks showed a significant decrease in the ratio of omega 6 to omega 3 in platelet phospholipids, though without any significant change in their total cholesterol, plasma triglycerides, or HDL-cholesterol.⁷² In hypercholesterolemic patients on a low-fat (Step-1) diet, 12 omega 3-enriched eggs per week for 6 weeks resulted in a 16% decrease in serum triglycerides; however, a subset of patients also showed a significant increase in serum total cholesterol and LDL cholesterol. (Three eggs provide about the same quantity of omega 3 fatty acids as 3 oz of fish.⁷³)

The development of an omega 3-enriched partially-skimmed milk product was based on the fact that milk is the most efficient medium for fat absorption. In a preliminary study, healthy, normolipidemic volunteers ingested the product for 6 weeks while maintaining their usual diet and not eating fish. The subjects developed greatly increased plasma lipid levels of EPA (31%) and DHA (31%), increased HDL-cholesterol levels (19%), and decreased triglyceride levels (19%) compared to control subjects. The test product supplied 400 mg/day of omega 3 fatty acids (including 180 mg DHA and 120 mg/day EPA).⁷⁴

A lipid-rich extract of the New Zealand green-lipped mussel (Perna canaliculus) has been studied in the treatment of osteoarthritis and rheumatoid arthritis, uses learned from folk medicine.⁷⁷ Recent controlled clinical trials of stabilized extract powders of the green-lipped mussel have resulted in significant improvements in patients with either type of arthritis in morning stiffness, joint tenderness, night pain, and the functional index.⁷⁸ The benefits of the extract are attributed to EPA, DHA, and other long-chain PUFAs.^77,78

Beware of Charlatans and Misinformation

Consumer and patient confusion regarding fatty acids abounds, often a direct result of “ambiguous” marketing practices. Contributing to this confusion is the trading off of studies by using the general term “omega 3” without specifying LNA, EPA, or DHA content or application. For example, a sales ad or product literature for a flaxseed or flaxseed oil product may cite that a study confirmed treatment efficacy with “omega 3,” when in fact the study referenced was conducted with a high dose of fish oil containing EPA and DHA. Whenever a product makes a claim regarding composition and function, scientific principles should be applied to discern fact from fiction.

SAFETY PROFILES OF OMEGA 3 FATTY ACIDS

Adverse Effects

A recent review on the safety of omega 3 fatty acids by the US Food and Drug Administration concluded that a daily intake of EPA and DHA of up to 3 g is “generally recognized as safe.”⁷⁹ The safety profiles of supplemental fish oil and flaxseed are also good. Dosages as high as 3 g to 8 g of omega 3 fatty acids per day (10 g to 27 g fish oil) show virtually no significant adverse effects.⁸⁰ The most common side effects observed with fish oil capsule consumption are complaints of a fishy taste and belching of fish flavors. At relatively higher doses, as with any oil, gastrointestinal complaints including loose stools have been reported.

Bleeding

Increased bleeding times that are within the normal range have been reported with very high intake of omega 3 fatty acids (ie, 7 g to 10 g omega 3 per day in Greenland Eskimos), but this side effect is regarded as posing little threat with supplemental doses under 5 g of omega 3 as EPA and DHA per day or the equivalent of ~15 g of fish oil.^2,81 However, owing to a lack of data and because some individuals may be at potential risk of increased bleeding from dosages of EPA and DHA of greater than 3 g/day, the FDA concluded that only intake levels limited to 3 g/day are “generally recognized as safe.”⁷⁹

Although there has never been a reported case of clinical bleeding attributed to fish oil consumption even during surgery,⁸² obvious consideration should be given to patients with bleeding disorders and patients taking blood thinners or anticoagulants. In a prospective, randomized, controlled trial of a fish oil concentrate (32% DHA, 51% EPA, and 3.7 mg vitamin E/g) in 511 patients undergoing coronary bypass surgery, a dosage of 4 g/day for 9 months failed to cause any episodes of excess bleeding compared to the control group not receiving the fish oil, whether or not patients received 300 mg/day aspirin or warfarin sufficient to maintain an INR of 2.5-4.2.⁸³

Drug Interactions

Drug interactions of fish oil and digitalis require further research. In male rats, a diet supplemented with fish oil concentrate (DHA 129 mg/g, EPA 180 mg/g) at a dosage of 500 mg/kg/day for 60 days caused the response to digitalis to increase twofold. The rats also showed a delayed response to a toxic dose of digitalis. While this study suggests that fish oil might improve the efficacy of digitalis,⁸⁴ it also emphasizes the need to closely monitor patients taking digitalis who are supplementing their diet with fish oil products.

Dosage

Therapeutic doses of 15 g fish oil per day (~5g EPA and DHA) or greater should be administered under the supervision of a healthcare professional. In addition, the type (short- or long-chain) and concentration (mg omega 3/supplement unit) should be considered to accurately determine daily dosages.

NUTRITIONAL ATTRIBUTES OF OMEGA 3

Dietary Recommendations

Currently, no formal governmental recommendations exist for dietary omega 3 fatty acid intake in the United States, unlike other developed countries such as Canada.¹⁹ Present US recommendations are to consume from 7% to 10% of energy as PUFA and for LA, a minimum of 1% to 2% energy. Despite the lack of governmental recommendations, a group of leading US physicians, biochemists, and nutritionists have released guidelines for adequate intake of omega 3 fatty acids (Table 5).⁸⁵ The proposed adequate intake for EPA and DHA is 650 mg per day (combined) with an LNA intake of 2.2 g per day. It has also been recommended that the intake of LA be limited to 6.7 g per day from the present average intake of 10-20 g per day. This recommendation, in effect, serves to reduce the average dietary LA to LNA ratio from the present 10:1 to 2.3:1. This would support greater conversion of LNA into long-chain omega 3, which is inhibited by elevated intakes of LA and high ratios of LA to LNA.

Reduced dietary ratios of omega 6 to omega 3 have also been proposed by countries like Sweden (5:1) and Japan (2 to 4:1) and by the World Health Organization (5 to 10:1). However, these recommendations have been made under the assumption that adequate intake levels of EPA and DHA could be met. Without appreciable dietary amounts of EPA and DHA, the ratio of LA to LNA that supports adequate conversion of LNA into EPA and DHA is estimated to be 1:1 to 4:1.^25,35

Other countries, including Canada and the United Kingdom, have established recommended daily intakes for omega 3 fatty acids.¹⁹ Canada recommends consumption of 1.2 g to 1.6 g omega 3 per day, although the guidelines do not specify which omega 3 should be consumed. The United Kingdom recommends LNA consumption be 1% of energy and EPA and DHA should comprise 0.5% energy which, based on a 2000 calorie diet, equates to 2.2 g of LNA and 1.1 g of EPA and DHA per day.

The American Heart Association (AHA) has recently recommended increasing the consumption of long-chain omega 3 for the prevention of primary and secondary heart disease.⁸⁶ For primary prevention, AHA recommends eating at least two fatty fish meals per week, a dosage approximately equivalent to 300 mg EPA and DHA per day. For secondary prevention, “consumption of one fatty fish meal per day (or alternatively, a fish oil supplement) could result in an omega 3 fatty acid intake (ie, EPA and DHA) of ~900 mg/d, an amount shown to beneficially affect coronary heart disease mortality rates in patients with coronary artery disease.”^86,87 The consensus of this report recognizes that while some positive data regarding consumption of dietary sources of LNA exist, primary benefit is achieved from dietary sources of the long-chain omega 3 fatty acids EPA and DHA in the prevention of primary and secondary heart disease.

Essential Fatty Acids in Pregnancy and Neonatal Nutrition

During pregnancy, EFAs play an important role in maternal health as well as the health and development of the fetus and of the newborn infant.^88,89 The mother serves as a supply of EFAs for her developing fetus. Neurological tissues, including the brain and retina, contain high concentrations of DHA. The human brain is approximately 30% lipid with a gray matter DHA content of around 40%. Brain DHA content increases three to five times during the last trimester of pregnancy and again during the first 12 weeks of postnatal life. Coupled with the observation that 70% of all brain cell division occurs prior to birth and that a newborn's brain triples in size in the first year of life, the supply of dietary DHA through the placenta, breast milk, or formula is paramount. It is believed that humans cannot produce adequate amounts of DHA from LNA to meet the requirements of brain growth and development, as breast-fed babies have considerably higher amounts of brain DHA than infants fed formula containing only LNA. Breast milk also differs in DHA composition depending on diet. In general, populations consuming greater amounts of dietary omega 3 and lower amounts of LA have higher levels of DHA in their breast milk. Dietary intake of DHA in American women is around 35 mg to 50 mg per day, while Japanese women consume nearly 600 mg of DHA. Thus Japanese women typically have considerably higher levels of DHA in their breast milk compared to that of American mothers.

Crawford noted that human breast milk contained significant amounts of arachidonic acid (20:46) as well as DHA, and so it was recommended that artificial infant formula be fortified with long-chain omega 3 and 6 PUFA.⁹⁰ However, American infant formulas, unlike most formulas in developed countries, still do not contain long-chain omega 6 and omega 3 fatty acids. Recently, however, the FDA has approved the use of AA and DHA in infant formulas.

Pregnancy is also a known stress on maternal stores of long-chain omega 3. Significant decreases in omega 3 have been reported in pregnant women at 36 weeks gestation.⁹¹ When studied throughout pregnancy, maternal deficits of omega 3 corresponded to late-stage pregnancy, when fetal brain development is greatest (Table 6). Deficits of omega 3 reportedly persisted 6 weeks postpartum and were more pronounced in breastfeeding mothers than in non-breastfeeding mothers. Omega 3 may also play a role in postpartum depression, as elevated fish consumption correlates with a lower incidence of postpartum depression.⁹²

Breastfeeding mothers whose diets were supplemented with DHA from high-DHA eggs, low-EPA/high-DHA fish oil, or an algae-derived high-DHA triglyceride supplement, all showed increased breast milk and plasma concentrations of DHA with the result that their infants showed higher postpartum levels of DHA.⁹³ While no adverse effects have been found,^94,95 there is debate over whether an increased intake of DHA or omega 3 fatty acids will result in functional benefits to either the mother or infant. Apart from the need for further investigations on the mechanisms of long-chain PUFAs on the nervous system,^96,97 proof of functional benefits still require well-designed, randomized, controlled trials.^27,98,99

Studies on the potential benefits of omega 3 fatty acid supplementation in mothers and infants have largely centered on neurological and visual functions. Benefits to visual function of the newborn are predicated upon the high concentration of omega 3 fatty acids in the human macula retinae and retina and on research indicating that DHA plays an important role in retinal functions.^100,101 A systematic review of 12 empirical studies on PUFA intake and visual acuity resolution in healthy full-term infants found that among randomized studies, DHA-supplemented formula-fed infants at the age of 2 months showed a significantly higher acuity compared to non-DHA-supplemented formula-fed infants (P=0.0003). Among nonrandomized studies, the difference between DHA-free formula-fed infants and human milk-fed infants was also significant in favor of DHA supplementation at 2 months (P=0.000001), as well as at 4 months (P=0.04). Beyond those ages, the lasting benefits of omega 3 fatty acid supplementation to visual functions is as yet unknown,^102,103 but Birch et al showed benefit until 18 months.¹⁰⁴

Based on the data available to date, authorities on the subject of omega 3 fatty acids in infant development conclude that AA should be fed along with DHA in infant formulas in order to achieve the rate of DHA accumulated in breast-fed infants; that it appears likely that DHA should be provided to infants for the first 6 months; and that further research is needed to determine whether the amount of DHA provided in breast milk (60 mg/day) will be sufficient for infant formulas.¹⁰⁵ As for a dietary amount of DHA for mothers, an expert panel recently recommended that during lactation and pregnancy women should ensure that they receive a minimum of 300 mg/day.⁸⁵

Normal Health and the American Diet

It is well recognized that omega 3 fatty acids are essential for normal growth and development.² It has also become increasingly apparent that adequate intakes of omega 3 are required to prevent common diseases and that consuming diets rich in omega 6 at the expense of omega 3 may actually promote the development of disease. The diet of modern day people in Western cultures has changed significantly over the past century. Changes in agriculture, food processing practices, and consumer food preferences have not only resulted in increased fat and saturated fat consumption but have also significantly altered the EFA profile of the modern day diet, which is now high in LA and low in long-chain omega 3.^2,19,53 On average, our society consumes around 35% of its caloric intake from fat, mainly as vegetable oil. The omega 6 LA comprises 7% to 9% of our daily caloric intake, while the omega 3 LNA makes up about 0.7% of energy. It is therefore estimated that the dietary ratio of LA to LNA ranges from 10 to 20:1, at which level the metabolism of LNA is strongly suppressed.^2,25 Again, this is far more than the recommended ratio of 2.3:1.

Once abundant, omega 3 and omega 6 HUFA currently make up only a very small amount of the American diet. Omega 3 HUFA intake per day is estimated to be below 200 mg while intake of omega 6 HUFA varies but in general is less than 600 mg per day.^3,19,106 This results from changes in both food consumption patterns and the composition of fatty acids in foods, mainly processed foods or foods that contain vegetable oils. Food-consumption patterns have changed with the increased intake of vegetable oil-containing foods such as processed foods, deep fried foods, salad dressings, and spreadable margarines.¹⁰⁷ Our reliance on vegetable oil as a primary ingredient in food has grown, replacing vegetables, fruits, fish, and lean meats—all potential sources of omega 3 fatty acids.

The fatty acid content of the animals that we raise for food—chickens, pigs, and cattle—has also changed as a result of common animal feeding practices. Animals once raised in a free-ranging environment, with a diet balanced in grasses and grains, are now raised on feed lots with corn-based diets that contain high ratios of omega 6 to omega 3, which suppress omega 3 metabolism. Reports as early as 1968 recognized that range-fed animals contained higher amounts of omega 3 fatty acids.^108-111 Range-fed African cattle, for example, had a polyunsaturated-to-saturated ratio of 0.7, compared to 0.1 for European domesticated cattle. Striated muscle from the African cattle contained significant amounts of HUFA, including DGLA (1%), AA (6%), EPA (3%), DPA-omega 3 (5%) and trace amounts of DHA, or 16% HUFA in tissue fatty acids. Today, the amounts of these fatty acids in commercial beef are almost undetectable. The difference between free-ranging and feed-lot animals is primarily due to the fact that range-fed animals consume a low ratio of LA to LNA (nearly 1:1) compared to corn-fed feed-lot animals, since corn has a very high LA to LNA ratio, typically greater than 50:1.

The omega 3 content of vegetable oils has also changed. There has been a substantial effort to reduce the LNA content of vegetable oils through plant breeding programs to improve stability and shelf life of food products incorporating vegetable oils.¹¹² Commercially available soy oils now contain LNA reduced to levels as low as 3%. The common “William's” variety that has been a main supply of food grade soy oil has an LNA composition of 8%.¹⁹

The change in the fat and fatty acid content of our diet has occurred primarily with the advent of industrialization. From an evolutionary perspective, a significant change in the diet has occurred in a very short time. The diet of our ancestors in the Paleolithic period (400,000 to 45,000 years ago) was lower in fat and balanced in omega 6 and omega 3—a ratio of 1:1, or 10- to 20-fold lower than today's standard.³ The Paleolithic diet was high in green leafy vegetables, fruits, roots, fish, and free-ranging animals. Fat in the Paleolithic diet came from wild animals and fish and from fruits and vegetables, which contain small amounts of relatively LNA-rich fat.¹¹³ Wild animals also contained appreciable amounts of long-chain omega 3, whereas domesticated animals contain virtually none.¹⁰⁸

Population studies confirm the consequence of a Western-type diet high in LA and low in LNA and long-chain omega 3 on omega 3 status, compared to populations that regularly consume fish. (Table 7, Figure 5).²⁵ Figure 5 shows the omega 3 status of various healthy populations and confirms the competitive nature of omega 6 and omega 3 fatty acids for the construction of phospholipid.²⁵ For example, populations with elevated levels of omega 6, like Americans, have low levels of omega 3, and populations with high levels of omega 3, like the Swedish, have low levels of omega 6. Additionally, this figure demonstrates that Minnesotans are near the bottom with respect to omega 3 status. However, fish-consuming populations, such as the Swedes and Kerala Indians, have high omega 3 status. Populations that do not eat as much fish, but consume diets with lower ratios of LA and LNA, such as Nigerians, also have a high omega 3 status compared to Minnesotans.

Furthermore, there is growing evidence that diets high in LA and low in LNA contribute to diseases including coronary artery disease and cancer (breast, lung, and colon).^114-116 For example, Israeli Jews, who have one of the highest intakes of LA in the world (12% of calories), also have an unusually high incidence of obesity, hypertension, diabetes, heart disease, and cancer. These disease patterns, however, are not observed in non-Jewish populations in the same region, who consume a traditional Mediterranean diet, rich in monounsaturated fat.

Similar observations have been made in Japan following the advent of industrialization and the influence of Western culture. Japan has gone from having one of the highest long-chain omega 3 fatty acid intakes in the world to a diet almost identical to that of the United States.¹¹⁴ During the past 40 years, the average intake of vegetable oil has increased nearly threefold in Japan. The previously low omega 6 to omega 3 ratio increased from 2.8:1 in 1955 to 7:1 in 1994 as a result of the food preferences of Japanese youth. Younger Japanese eat far higher quantities of food products containing vegetable oil and lower amounts of fish and vegetables. Increases in the incidence of cardiovascular disease, allergic hypersensitivities, and breast, lung, and colon cancer have mirrored the changes in the Japanese diet. In animal models, diets with a high ratio of omega 6 to omega 3 stimulate the formation of lung cancer.¹¹⁶ In regard to experimental cancer models, it is generally observed that diets high in LA promote carcinogenesis, while diets high in LNA, EPA, and DHA, as well as inhibitors of eicosanoid synthesis such as aspirin, suppress carcinogenesis.¹¹⁶ The incidence of other inflammatory diseases like Crohn's disease has also risen dramatically in the past 35 years in Japan. From 1966 to 1982, the incidence of Crohn's disease in Japan rose from 10 to 155 cases per 10,000 persons.¹¹⁷

In order to bring the US population closer to a healthier fatty acid profile, it has been recommended that DHA and EPA intake be increased from the present 100 to 200 mg/day to 650 mg/day. The recommended greater than fourfold increase in DHA and EPA would require approximately the same increase in fish consumption and a decrease in dietary LA from the current 11-16 g/day to 6.7 g/day. Even a threefold increase is not presently possible because the United States imports about 60% of its fish, and fish stocks, while recovering, are in many cases still depleted. Therefore, in order to achieve the recommended intake of these omega 3 fatty acids in the United States, the number of fish farms would have to greatly increase.¹⁹ Special consideration would need to be given to the source of fish in the diet. As a general rule, fish are a good source of omega 3 fatty acids because their diets are rich in omega 3 fatty acids. However, farm-raised fish may or may not be fed a omega 3 rich diet like their wild counterparts and thus there may be variations in the omega 3 fatty acid content of farm-raised fish.

Flaxseed oil has been proposed as a less expensive means of obtaining DHA and EPA than dietary fish or fish oil supplements.^71,118 LNA is the parent fatty acid of DHA and EPA and occurs in flaxseed oil in high amounts (45% to 50%). However, as a dietary source of EPA and DHA, LNA-rich vegetable oils such as flaxseed oil have not proven to be reliable and the conversion rate of LNA to long-chain omega 3 fatty acids remains to be established. The highest conversion rate reported to date is 15%, but was not confirmed by others.¹¹⁸ A dietary ratio of 4 to 1 of linoleic acid to -linolenic acid is needed to get a conversion of LNA to EPA of 10-11 to 1.¹¹⁹

SUPPLEMENTAL OMEGA 3 IN THE TREATMENT OF DISEASE

Cardiovascular Disease

Epidemiological studies have correlated increased dietary intake of omega 3 with reduced incidence in coronary heart disease and complications related to this disease.¹²⁰ Studies of Inuit populations of Greenland by Bang and Dyerberg, and Dyerberg, Bang, and Hjorne in the 1970s are accredited with establishing the cardioprotective effects of omega 3 from marine sources.^67,68 These studies found that the Inuit population had a very low incidence of cardiovascular disease despite consuming a high-fat diet, which was known at the time to cause heart disease. This seeming discrepancy between doctrine and experimental observation was ultimately attributed to the Inuits' consumption of omega 3-rich foods like whale blubber and fatty fish. Additional epidemiological studies have reported that increased omega 3 and LNA consumption from fish is cardioprotective.¹²⁰ Subsequent to the Inuit study, the Chicago Western Electric study found that fish consumption as low as 35+ grams per day, or about one serving per week, significantly reduced the risk of myocardial infarction (MI).¹²¹ Starting in 1958, this study followed over 1800 men ages 40 to 55 who were free of known cardiovascular disease for a period of 30 years. The study reported that fish consumption was significantly associated with a 30-year reduced risk of MI. Multivariate relative risk of death for men consuming 35+ grams of fish per day from coronary artery disease, MI, and nonsudden MI were 0.62, 0.56, and 0.33 respectively, compared to nonfish consumers. Similar findings were reported in the MRFIT and Honolulu Heart Program studies.¹²⁰

In addition to protecting against the development of cardiovascular disease, omega 3 fatty acids have also been shown to reduce the risk of dying from a secondary heart attack after an initial heart attack.^8,122 The GISSI heart study reported results from over 11,000 Italian patients followed for 3.5 years who were treated with fish oil and/or vitamin E shortly after an initial MI. Patients randomly received either 850 mg of eicosapentaenoic acid and docosahexaenoic acid/day at a ratio of 2:1 (equivalent to 100 g of fatty fish per day), 300 mg vitamin E/day, both treatments, or no supplements (control). Findings reported that treatment with 850 mg of long-chain omega 3 per day but not vitamin E resulted in a significantly lower risk (10% to 15%) of primary endpoints that included death, nonfatal MI, and stroke. Risk of death decreased by 20% by four-way analysis and myocardial infarction decreased by 45%, as did nonfatal stroke, nonfatal myocardial infarction, cardiovascular deaths, and sudden deaths.¹²³

Similar findings were reported in the DART study, which used dietary fish as a source of omega 3 fatty acids.¹²² The DART study followed over 2000 men with a previous history of MI. Men in the treatment group consumed two meals of fish (about 300 g) per week. This study reported no significant differences in myocardial infarction rate, but did find a 29% lower rate of sudden death in the group consuming fish in patients followed for 2 years, suggesting that the reduction in sudden death resulted from the anti-arrhythmic effect of omega 3.

The findings were similar in other observational studies, including the Health Professional Study and the US Physicians' Health Study.^120,124 This second study reported a 52% lower risk of sudden cardiac death for men (n=20551, ages 40-84) consuming one or more fish meals per week.

From the NHANES I Epidemiologic Follow-up Study, the Centers for Disease Control and Prevention in the United States reported that although white males (ages 25-74) who ate fish once weekly showed only about 75% of the risk of death compared to men who never ate fish, men who ate fish more frequently showed no further risk reduction. The study, a 22-year follow-up involving 8825 US Caucasian and African-American men and women, found no significant reduction in the risk of cardiovascular death in white men and no significant reduction in the risk of death from all causes in white women, black men or black women, after controlling for multiple risk factors. However, the CDC noted the need for further studies to confirm these results.¹²⁵

A systematic review of 11 prospective cohort studies from 1966 to 1998 on the association between congestive heart disease (CHD) and fish consumption concluded that while the biochemical basis for the effect remains unknown, 40-60 g of fish/day versus no fish intake is found in association with a marked reduction in CHD mortality of 40% to 60%, but only in those at higher risk of CHD. Subjects at low risk of CHD who also maintained healthy life-styles appeared to show no added reduction in the risk of CHD from the consumption of fish. These conclusions are based largely upon two high-quality studies involving a combined total of 2674 men compared to all other studies for the period.¹²³

Reducing relative ratios of LA to LNA has also demonstrated efficacy in preventing death after an initial MI.¹²⁶ The Lyon Diet Heart Study reported a 73% reduction in nonfatal MI for persons consuming a diet based on the diet of Crete, Greece versus an American Heart Association diet. Subjects in this cohort were advised to consume a diet rich in monounsaturated fat, while avoiding foods rich in LA. In this study, dietary counseling of subjects resulted in a significant decrease in their dietary ratio of LA to LNA—4.11 in treatment versus 19.6 in control. Lower ratios like this support greater conversion of LNA into long-chain omega 3, thus improving omega 3 status.

In the first year after coronary artery bypass grafting in CHD patients, vein graft occlusion occurs in 15% to 30% of cases, largely due to atherosclerosis. The possible benefits of supplementation with fish oil versus no fish oil was studied in a randomized, controlled study of 610 subjects who received coronary artery bypass grafting and either warfarin or daily aspirin. The fish oil supplement was highly concentrated in DHA (32%) and EPA (51%) and contained 3.7 mg vitamin E/g as an antioxidant. In addition, patients were instructed to reduce their intake of meat products, hard margarine, and milk products (all sources of saturated fatty acids) and to avoid other fish oil products, including cod liver oil. One year after surgery, the results showed that the group taking the highly concentrated fish oil supplement developed significantly fewer vein graft occlusions (p=0.05) compared to the control group, and an inverse relationship was found between the frequency of occlusions and the serum phospholipid levels of omega 3 fatty acids. Significant trends were also seen in relation to increasing levels of DHA and EPA and decreasing numbers of vein graft occlusions. The authors concluded that dietary supplementation with omega 3 fatty acids was positively associated with vein graft patency, suggesting that patients undergoing coronary bypass surgery should be encouraged to maintain a high intake of these fatty acids.¹²⁷

Atherosclerosis—It is hypothesized that omega 3 fatty acid prevents atherosclerosis through several mechanisms, including its lowering effects on serum lipid levels and blood pressure, its anti-inflammatory and anti-thrombotic properties, and its ability to prevent cardiac arrhythmias, including ventricular tachycardia and fibrillation.¹²⁸

Fish oil has also been used successfully to treat elevated triglycerides in diseases such as diabetes. In a placebo controlled blinded trial in adult-onset diabetes, Connor and coworkers reported that 6 g of EPA and DHA per day resulted in a 43% reduction in fasting serum triglyceride levels with no significant adverse effects on fasting serum glucose levels.¹²⁹ In all of the above studies, omega 3 lowered the death rate from sudden death and overall mortality without lowering serum cholesterol levels, indicating the importance of anti-thrombotic, anti-inflammatory, and anti-arrhythmic effects of omega 3, with secondary prevention of CHD.

Hypertriglyceridemia—A substantial body of evidence supports the use of fish oil in the treatment of hypertriglyceridemia.¹³⁰ In normolipidemic subjects, daily dosages of 2-25 g of omega 3 fatty acids produced decreases in triglyceride concentrations of 20-60%. In patients with hypertriglyceridemia, decreases of up to 81% have been reported.^131-133 Recognizing the potential benefits of fish oil against hypertriglyceridemia, the latest guidelines for the treatment of dyslipidemia and prevention of atherogenesis from the American Association of Clinical Endocrinologists prudently recommends that diets for patients with dyslipidemia contain 2-4 g of fish oils/day.¹³⁴ A recent review of clinical studies on the effects of omega 3 fatty acids on lipoproteins by Harris found that 29 parallel and 36 crossover design studies arrived at the same conclusion: serum triglyceride levels are decreased by omega 3 fatty acids by 25-30% with dosages of omega 3 fatty acids from fish oil of 3-4 g/day. Looking at the three studies available on the effects of flaxseed oil on serum lipid concentrations, Harris found that only “very large amounts” reached effects equivalent to fish oil in lowering triglyceride concentrations.¹³⁰

Hyperlipidemia—The majority of clinical studies on the consumption of omega 3 fatty acids have concluded that HDL cholesterol concentrations increase by 1-3%, while LDL cholesterol concentrations increase by 5-10%.¹³⁰ Since it was demonstrated that omega 3 fatty acids reduce both the hepatic secretion and synthesis of VLDL,¹³² fish oil supplementation has also been shown to lower VLDL-cholesterol concentrations.^135,136 A recent preliminary study in Spanish women volunteers ages 24-34 who maintained a Mediterranean diet (high in monounsaturated fatty acids and fats and low in omega 6 fatty acids) and aerobic training 1-3 hours/week found evidence to suggest that this effect may occur with short-term administration of fish oil in low dosages (6 capsules of fish oil/day providing 252 mg DHA and 390 mg EPA); a significant decrease (p<0.05) in VLDL cholesterol was evident after only 10 days.¹³⁷

Fish Oil Plus HMG-CoA Reductase Inhibitors—Several studies suggest that omega 3 fatty acids may be beneficial to patients receiving HMG-CoA reductase inhibitors.^135,138,139 A placebo controlled, randomized study in 32 Australian patients with primary mixed (type IIB) hyperlipidemia compared the hypolipidemic effects of a fish oil supplement (3 g omega 3/day with EPA/DHA in a ratio of 2:1) and the fish oil supplement combined with pravastatin (40 mg/day) to a placebo. After a treatment period of 12 weeks, results were compared to a 6-week single-agent treatment period. Pravastatin alone failed to significantly change VLDL or intermediate density lipoprotein (IDL) concentrations. Fish oil alone failed to lower IDL concentrations, but significantly lowered the VLDL concentration by 37% or more (p<0.05). When the two treatments were combined, patients showed a significant (35% or more) reduction in concentrations of both IDL and VLDL (both p<0.01). The authors noted that the short-term combination of these agents appeared to be safe.¹³⁵

In 14 Japanese patients with hyperlipidemia previously treated with HMG-CoA reductase inhibitors (pravastatin or simvastatin) for 24-36 months, a combination of EPA (900-1800 mg/day) for 3 months resulted in significant reductions in serum concentrations of triglycerides and total cholesterol compared to HMG-CoA reductase inhibitors alone (p<0.05 and p<0.01, respectively), and serum HDL cholesterol concentrations showed a significant increase (p<0.05).¹³⁸

In a randomized, controlled, crossover design study, 10 patients with heterozygous familial hypercholesterolemia were randomized to a group receiving either lovastatin (20 mg twice daily) or a high dose of fish oil in capsules (27 g/day for 6 weeks). Patients followed a controlled-fat, low-cholesterol diet from beginning to end which was supplemented with olive oil in capsules (27 g/day for 4 weeks). This was followed with a washout period of 4 weeks before patients were crossed over and in the last period received fish oil (27 g/day) plus lovastatin (20 mg twice daily) for 6 weeks. The results showed that on fish oil alone there was a significant decrease in total cholesterol, no change in LDL cholesterol, a significant increase in HDL cholesterol (9%), and a significant decrease in triglyceride levels (43%). The combination of lovastatin and fish oil showed more beneficial results than either fish oil or lovastatin alone: total cholesterol decreased 39%, LDL cholesterol decreased 45%, triglyceride levels decreased 51% (each p<0.01), and HDL cholesterol remained the same. The authors concluded that lovastatin combined with fish oil had a favorable additive effect on triglyceride levels and LDL cholesterol in these patients.¹³⁹

Diabetes

The majority of clinical studies on omega 3 fatty acids in the treatment of patients with diabetes have been open trials of short duration (2-8 weeks) with less than 20 patients. Their aim has primarily been to determine effects on glucose tolerance and plasma lipoproteins, particularly triglyceride levels. According to a recent meta-analysis of studies on fish oil in the treatment of diabetes, triglyceride levels were lowered by close to 30%. The majority of studies in patients with type 1 diabetes (n=12) showed significant decreases in fasting glucose levels without significant adverse effects on glycemic control. Of 14 studies on fish oil in the treatment of patients with type 2 diabetes, the meta-analysis found that, although glycemic control was not adversely affected, there was a tendency for fasting blood glucose levels to increase.¹⁴⁰ Examples of findings from among the placebo controlled trials on fish oil in diabetes are reviewed in the following.

Type 1 Diabetes—A randomized, placebo controlled trial of fish oil (5 g three times/day for 6 weeks) in 41 Caucasian patients with type 1 diabetes (ages 30-59) examined changes in thromboxane A₂ levels produced by platelets, blood lipids, platelet function, and albuminuria. Fish oil was tested because DHA and EPA were shown to competitively inhibit the formation of thromboxane A₂, a mediator of platelet aggregation and vasoconstriction. Levels of thromboxane A₂ were produced in greater amounts in the platelets of patients with diabetes compared to those without the disease. The fish oil provided 1.9 g DHA plus 2.7 g EPA/day and a low dose of olive oil was used as the placebo. Patients were excluded if they had known coagulation disorders or hyperlipidemia, and all participants were instructed to eat a fat-free breakfast on those mornings when blood samples were taken. Significant changes evident at the end of 6 weeks were found in the fish oil group compared to placebo in a lowered production of thromboxane and an increase in total cholesterol, probably due to increased LDL cholesterol. Platelet aggregation showed no consistent change in rate or maximum amount, but the lag time prior to when platelets aggregated was prolonged in the fish oil group relative to the placebo group, which is consistent with a partially inhibited production of thromboxane and changes in the fatty acid composition of platelet membranes. No consistent change in the urinary excretion of albumin was evident, nor was it entirely expected; the fish oil used was much weaker than a specific thromboxane inhibitor and only a few of the patients had microalbuminuria.¹⁴¹

Since it was noted that red blood cell membranes of patients with type 1 diabetes show decreased levels of omega 3 fatty acids in an inverse relation to plasma glycosylated hemoglobin (HbA_1c) levels, Stiefel and coworkers conducted a prospective, randomized, controlled dietary intervention study on the effects of low-dose omega 3 fatty acids (330 mg DHA plus 630 mg EPA/day) on these parameters in 18 patients with type 1 diabetes. The control group maintained their usual diet while the treatment group supplemented their usual diet with omega 3 fatty acids. Those on the supplement showed a significant increase in the omega 3 fatty acid content of membrane lipids and a significant decrease in HbA_1c, yet without significant changes in insulin requirements. Neural conduction showed a slight but significant improvement. Stiefel and colleagues concluded that dietary supplementation with a low dose of omega 3 fatty acids in patients with type 1 diabetes appeared to change their cell membrane fatty acid composition while it improved metabolic control and slightly improved neural conduction.¹⁴²

Type 2 Diabetes—Hendra and coworkers conducted one of the largest studies to date on the effects of fish oil preparation on patients with type 2 diabetes (n=80). Along with effects on hemostatic function, they evaluated patients' fasting glucose and lipid levels. The prospective double blind, randomized, placebo controlled study found that after 10 g of fish oil per day was administered for 6 weeks, the EPA content of platelet membranes was significantly increased (p<0.001) compared to the placebo (olive oil) and total triglycerides were significantly decreased, yet no change in total cholesterol was evident. After 3 weeks, but not after 6 weeks of treatment, fasting plasma glucose levels were significantly increased (p<0.01). Whole blood platelet spontaneous aggregation decreased after 6 weeks (p<0.02), yet without evidence of changes in agonist-induced platelet aggregation, platelet factor IV levels, or plasma -thromboglobulin levels, and platelet-rich plasma showed no significant change in thromboxane generation. Hendra and colleagues concluded that despite the benefit of lower triglyceride levels from the fish oil preparation, a significant increase in clotting factor VII (p<0.02) and the increase in fasting plasma glucose at 3 weeks (p<0.01) were deleterious effects which suggested that the dosage used (10 g/day) was too high to be recommended as a dietary aid to reduce the risk of cardiovascular disease in type 2 patients.¹⁴³

The effects of a moderate intake of omega 3 fatty acids on glycemic control in hypertriglyceridemic patients with diabetes was recently investigated by Sirtori and colleagues in a large, multicenter, randomized, double blind placebo controlled study conducted in Italy.¹⁴⁴ The largest study of its kind, it enrolled patients of both sexes (n=935; ages 45-80; 62% male) and included hypertriglyceridemic patients without diabetes. Of the total, 55% were made up of subjects with either type 2 diabetes or impaired glucose tolerance, and 21% satisfied the criteria of syndrome X (arterial hypertension, impaired glucose tolerance, hypertriglyceridemia, and low HDL cholesterol).

After a washout and run-in period of 4 weeks, patients received either placebo (olive oil) or omega 3 fatty acids (1050 mg DHA plus 1530 mg EPA) three times per day for 2 months, equivalent to the amount of DHA plus EPA found in approximately 150 g of fresh salmon. This treatment period was followed by a further 4 months with a reduced dosage of omega 3 fatty acids (one capsule taken twice daily containing 700 mg DHA plus 1020 mg EPA). The supplements were taken before main meals and patients maintained their body weight with an isoenergetic diet along with instructions to reduce foods rich in AA (eggs, liver, heart, and lungs) or to eat them no more than once per week. If insulin was required, the patient was excluded from the study.

Treatment with omega 3 fatty acids had no significant effect on oral glucose tolerance in either type 2 patients or those with impaired glucose tolerance, and major glycemic indices (fasting glucose, insulinemia, and HbA_1c) showed no alterations. LDL cholesterol concentrations showed a significant difference (p=0.048) between an increase of 3% in the placebo group and 6% in the group receiving the omega 3 supplement, as did the comparative decrease in triacylglycerol concentrations: -6.54% in the placebo group and -21.53% in the omega 3 group (p<0.0001). However, those with impaired glucose tolerance showed no significant difference in triacylglycerol concentrations compared to normoglycemic patients. Although all groups showed a slight increase in HDL concentrations (+5%) compared to their corresponding placebo group, those with type 2 diabetes or glucose intolerance showed a significantly greater increase (+8.31% versus 4.53% for placebo; p<0.05). The patients with traits conforming to syndrome X showed no improvement in symptoms, except for lipoprotein metabolism. The results indicated that omega 3 fatty acids, in a moderate daily dose, “can provide a suitable option for the management of the middle-aged population, including postmenopausal women, in whom hypertriglyceridemia may be a major risk for cardiovascular death.”

Inflammatory disorders

Omega 3 fatty acids from fish oils have been extensively studied in inflammatory diseases because of their anti-inflammatory properties. The inflammatory cascade plays a significant role in the proper functioning of the immune response; however, it is well recognized as a major cause of morbidity in inflammatory disorders and diseases.¹⁴⁵ Patients with inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disorder have elevated production of group 2 eicosanoids including PGE₂ and LTB₄, and inflammatory cytokines including IL-1 and TNF. Many pharmaceutical therapies are thus directed at inhibiting the production of these mediators.

The role that eicosanoids and cytokines play in the development of disease is multifactorial. Evidence presented herein suggests that diets elevated in omega 6 at the expense of omega 3 fatty acids result in eicosanoid precursor pools dominated by AA. This imbalance results in an inflammatory mediator production that favors group 2 eicosanoids and a pro-inflammatory state. Returning omega 3 fatty acids to the diet, either in the form of long-chain omega 3 (EPA and DHA) or short chain omega 3 (LNA), begins to restore balance between omega 6 and omega 3 fatty acids in the eicosanoid precursor pool. When a greater balance between AA and EPA and DHA exists in the eicosanoid precursor pool, inflammatory mediator production potential is reduced. Measuring fatty acid profiles of plasma phospholipids determines levels of omega 3 and omega 6 fatty acids and thus is a useful tool at estimating inflammatory potentials.¹⁴⁶ The underlying hypothesis is that an imbalance of dietary omega 6 and omega 3 fatty acids, and subsequently tissue omega 6 and omega 3 fatty acids, contributes to disease and disease morbidity, and that increasing the omega 3 fatty acid content of the diet while decreasing omega 6 fatty acids serves to balance the cellular eicosanoid precursor pool and subsequent inflammatory response.¹⁴⁷

Inflammatory Bowel Disorders—The plasma fatty acid profiles of 47 patients with chronic intestinal disorders, most of whom were diagnosed with Crohn's disease, showed an increased ratio of omega 6 fatty acid precursors compared to those of control and reference subjects (n=57), and over 25% showed evidence of EFA deficiency including deficits in omega 3 fatty acids. This “EFA insufficiency” is proposed to be a factor both contributing to the pathology of chronic intestinal disease and a consequence of it. It has therefore been recommended that in treating patients with chronic intestinal disease, imbalances and deficiencies of EFAs be evaluated and their treatment include dietary supplementation with fish oil and vegetable oils rich in EFAs, and, if necessary, lipids administered intravenously.¹⁴⁸

Lorenz and coworkers found no significant change in Crohn's disease patients and a moderate but insignificant improvement in patients with ulcerative colitis in a 7-month trial of fish oil in 39 men with inflammatory bowel disease. The fish oil supplement provided 3.2 g of omega 3 fatty acids/day.¹⁴⁹ However, in other trials, larger doses of omega 3 fatty acids are reported to be beneficial in both diseases.

Stenson reported significant improvements in disease activity in patients with ulcerative colitis who were supplemented with 4.5 g of EPA and DHA (15 g fish oil) after 8 weeks of treatment, and in a subsequent study he found similar results in a larger placebo controlled trial, feeding 5.4 g EPA and DHA (18 g fish oil) after 4 months.¹⁵⁰ Fish oil treatment in this study resulted in significant weight gain, reduced LTB₄ production, and improved endoscopy score.

Steroid-sparing effects (reduced dosage of anti-inflammatory agents or elimination of steroids) have also been reported in ulcerative colitis patients treated with fish oil.¹⁵¹ Seventy-two percent of patients reported a steroid-sparing effect after receiving 4.2 g of EPA and DHA for 3 months, and 56% of patients had a significantly improved disease activity score.¹⁵¹ In Crohn's disease patients, Belluzzi reported increased remission percentages after 1 year of 2.7 g of EPA and DHA (9 g of fish oil) versus placebo control.⁵⁷ After 1 year of treatment, only 10% of the placebo patients remained in remission, while 59% of the fish oil-treated patients remained in remission.

Arthritis—Fish oil supplementation has also demonstrated efficacy in the treatment of rheumatoid arthritis.^13,152 A preliminary investigation of the omega 3 fatty acid profile of synovial fluid in rheumatoid arthritis patients in Spain reported low levels compared to controls, significantly so for EPA and the precursor LNA.¹⁵³ Fish oil treatment reportedly resulted in decreased joint tenderness and morning stiffness and improved grip strength and joint activity indices for patients supplemented with 3 g to 6 g of EPA and DHA per day. Generally, improvements in symptomatology began to occur 12 to 22 weeks after initiation of fish oil treatment. Similar results were reported in a 12-week trial of fish oil in rheumatoid arthritis which provided 3.6 g PUFA/day.¹⁵⁴

It has also been reported that some arthritic patients administered a high dose of fish oil were able to reduce their dosage of nonsteroidal anti-inflammatory drugs (NSAIDs).¹⁵⁵ Thus, fish oil therapy may be desirable for persons with gastrointestinal complications related to chronic NSAID consumption.

The improvements seen in arthritic patients administered fish oil supplements have generally been modest,¹³ though significant. A meta-analysis of seven trials of fish oil in the treatment of rheumatoid arthritis (randomized, double blind, placebo controlled, and either crossover or parallel in design) demonstrated that 3 months of dietary supplementation with fish oil caused a significant reduction in tender joints (p<0.001) compared to controls. After re-analysis of a previous meta-analysis, improvements in morning stiffness were less than statistically significant.¹⁵⁶

Significant benefits from fish oil in the treatment of rheumatoid arthritis continue to be reported from more recent trials.^155,157 For example, Kremer and colleagues examined the drug-sparing, cytokine-modulating, and clinical efficacy of high-dose fish oil (130 mg/kg/day, eg, 9.75 g/75 kg/day) in 66 rheumatoid arthritis patients who were allowed to continue taking diclofenac (75 mg twice daily) and in 56 cases, various slow-acting antirheumatic agents. The 30-week, double blind, placebo controlled (corn oil), prospective study found significant improvements in the following: decreased IL-1 levels compared to baseline during weeks 18-22; decreased number of painful joints compared to placebo at 8 weeks (p=0.043); and no significant NSAID-sparing effect. It was noted that the benefits found were no greater than those of other studies using 3-6 g fish oil/day.

Geusens and colleagues conducted a 12-month, double blind, randomized study of fish oil in 90 rheumatoid arthritis patients. They compared the effects of fish oil in dosages of either 3 g/day (omega 3, 1.3 g/day) plus 3 g olive oil/day, 6 g fish oil/day (omega 3, 2.6 g/day), or olive oil at 6 g/day. Throughout the trial, patients continued to take disease-modifying antirheumatic drugs (DMARDs) and/or NSAIDs at stable dosages and received advice to eat fish once weekly. In approximate amounts, the diet prescribed contained 30% fat, 50-58% carbohydrate, and 12-15% protein. The amount of animal fat allowed was less than 100 g/day. Sixty patients completed the study. At 12 months, the only group showing significant overall improvement (20-25% from 3-12 months) was the highest dose fish oil group (6 g/day). Compared to placebo, the 6 g/day group showed a significant decrease in the use of NSAIDs and/or DMARDs (47% versus 15%, p<0.05), and a significant increase in grip strength at 6 and 9 months (p<0.05). The number of painful joints was significantly decreased in all treatment groups compared to baseline, but not compared to each other, and no significant changes in morning stiffness were found in any group. Gastric discomfort occurred in 6/30 patients on the 6 g/day dose of fish oil, 4/30 in the low dose group, and 2/30 on placebo.¹⁵⁷

IgA Nephropathy—Fish oil treatment has also been used successfully to treat patients with inflammatory disorders of the kidney. In 106 patients with IgA nephropathy, Donadio reported that 12 g of fish oil per day resulted in a significant reduction in death (p=0.006) and improved renal function compared to placebo.⁵⁵

Dysmenorrhea

PGE₂ is a metabolic product of AA which is metabolized to produce PGF₂. In dysmenorrheic women, elevated plasma levels of PGF₂ are associated with menstrual pain which is treated with prostaglandin synthetase inhibitors such as aspirin and indomethacin.^158,159 Omega 3 fatty acids also produce a class of prostaglandins (PGE₃), but these are believed to be less active (“aggressive”) than PGFs. Support for this hypothesis was found in an epidemiological study on Danish women (n=181, ages 20-45). Self-administered questionnaires from the subjects, none of who were pregnant or using oral contraceptives, revealed highly significant correlations with menstrual pain and low intakes of fish and vitamin B₁₂. Menstrual pain was significantly higher among those with a low intake of omega 3 fatty acids, which in turn significantly coincided with a low ratio of omega 3/omega 6.¹⁵⁹

Preliminary studies on the use of fish oil in the amelioration of symptoms of dysmenorrhea have shown promising results.^160,161 In a randomized, double blind, placebo controlled, crossover design study in 37 American adolescents ages 15-18 with dysmenorrhea, a 2 month treatment with fish oil (capsules providing 720 mg DHA, 1080 mg EPA plus 1.5 mg vitamin E/day) was reported to produce a significant reduction in the Cox Menstrual Symptom Scale in the fish oil group compared to the placebo group (p<0.004). Use of ibuprofen to control menstrual pain was significantly less during consumption of fish oil compared to placebo.¹⁶⁰

In Denmark, a double blind, placebo controlled study was conducted to test the hypothesis that menstrual cramps are mediated by prostaglandins. For 3 months or a minimum of three menstrual periods, Danish women (n=70, ages 16-39) received five capsules/day of placebo, fish oil, seal oil, or fish oil with vitamin B₁₂. Vitamin E (2.5 mg/capsule) was added to the marine oil preparations to inhibit peroxidation. Before the dietary intervention, the ratio of omega 3/omega 6 in the participants was low (0.096). When pain, interference with daily activities, and other symptoms of dysmenorrhea were taken together, all three of the marine oil preparations produced significant improvements; however, the best results were found in the fish oil with vitamin B₁₂ group. Unlike the others, they showed a significant reduction in the visual analog pain score that persisted during the washout period for a minimum of three menstrual periods. All groups receiving marine oil supplementation reported reduced symptoms of dysmenorrhea, but in the fish oil with B₁₂ group, symptom reduction was over 50% higher. The authors commented that the use of omega 3 fatty acids and B₁₂ as a dietary supplement in young women with dysmenorrhea might offer an alternative to treatment with NSAIDS.¹⁶¹

Asthma

Epidemiological studies in Australia have suggested that children who eat fish more often than once per week have a reduced risk of developing airway hyper-responsiveness. A study was undertaken to investigate the association of diet and asthma.¹⁶² Evidence was found suggesting that children who eat fresh, oily fish containing greater than 2% fat have a significantly reduced risk of both airway hyper-responsiveness and recent wheeze (current asthma). The evidence for a reduced risk of asthma in adults in association with increased fish consumption has largely been weak to negative.^163,164 However, a recent cross-sectional analysis of data in the United States derived from the National Health and Nutrition Examination Survey found an increase in the forced expiratory volume at 1 second (FEV₁) of approximately 80 mL in adults, including asthmatics, who consumed high amounts of fish compared to adults who consumed low amounts.¹⁶³

Clinical studies on the effects of fish oil in patients with asthma have been relatively few and small, involving less than 40 patients. In a review of eight randomized controlled trials (1986-1998) of fish oil in the treatment of asthma, reviewers found a lack of consistent effect on outcomes of asthma symptoms, FEV₁, bronchial hyper-reactivity, use of asthma medication, and peak flow rate. None of the studies reviewed reported exacerbation of asthma and no adverse events were reported in association with fish oil supplementation.¹⁶⁵

As for hay fever, a long-term, parallel, double blind, placebo controlled trial of high-dose fish oil (providing DHA 2.2 g/day and EPA 3.2 g/day) found no prevention of asthma and seasonal hay fever in pollen-sensitive, nonsmoking asthmatics.¹²

Cystic Fibrosis

Leukotriene B₄ (LTB₄) has been proposed as a mediator of the inflammatory response in the lungs of cystic fibrosis (CF) patients. Furthermore, it was postulated that an overproduction of LTB₄, if sustained, could lead to a desensitization of neutrophils in the pulmonary circulation of CF patients resulting in a chemotactic defect of circulating neutrophils. In these patients, the chemotactic response of neutrophils to LTB₄ was found to be significantly less than that of healthy controls, suggesting that an increase in LTB₄-induced chemotaxis of neutrophils might be of benefit to cystic fibrosis patients.²⁴⁵

In a randomized, double blind, placebo controlled, crossover design trial, 16 cystic fibrosis patients (ages 12-26) with lung dysfunction received fish oil supplementation (2.7 g EPA/day for 6 weeks) while maintaining their normal diet and medications (antibiotics, pancreatic enzyme supplementation, and bronchodilator therapy). Fish oil supplementation resulted in significantly reduced LTB₄ production and improved lung function, including increased tidal volume and sputum generation. The chemotaxis of circulating neutrophils to LTB₄, which was significantly lower in all the subjects at baseline compared to healthy volunteers (p<0.0001), showed a highly significant improvement (p<0.001) with responses becoming nearly normal after the treatment with fish oil. No such change was found in patients on placebo (olive oil). Treatment was well tolerated and there were no reports of significant adverse effects. In order to prevent steatorrhea, supplementation with pancreatic enzymes was increased by the patients.¹²

Psychiatric Disorders

Depression—The investigation of the treatment of psychiatric disorders with omega 3 fatty acids is a relatively new but potentially promising field of research.^11,92,167 Major depression has been characterized by deficits of plasma and red blood cell omega 3 fatty acids, including EPA and DHA.^168,169 Adams reported that the severity of depression correlated clinically with the ratio of AA to EPA in plasma phospholipids. Similarly, Peet reported significant depletion of omega 3 fatty acids in red blood cells that was postulated to be related to oxidative stress and/or elevated activity of phospholipase A₂. Maes has also reported that the exaggerated production of pro-inflammatory cytokines and eicosanoids from external as well as internal stressors may be a contributing factor in major depression.¹⁷⁰

The level of fish consumption has also been noted to be predictive of major depression and suicide. Hibbeln reported that persons consuming relatively greater amounts of fish were less likely to suffer from major depression and postpartum depression, and less likely to commit suicide.⁹² He also demonstrated that plasma levels of PUFA essential fatty acids correlate with CNS metabolism of dopamine and serotonin.¹⁷⁵ It has been suggested that the remarkable increase in depression during the past 85 years may be attributable to the sharp rise in the ratio of omega 6 to omega 3 in the diet, which favors the production of pro-inflammatory eicosanoids and cytokines.

Supporting this theory, a recent study found that in patients with major depression, monosaturated fatty acids and omega 6 fatty acids in phospholipids appear to show a compensatory increase with a concomitant deficiency of omega 3 fatty acids. The effect of antidepressants on the fatty acid profile of patients was not significant. The results of the study suggested that in depression: omega 3 fatty acids undergo abnormal metabolism; that their alterations show a relation to inflammatory responses in depression; and that, regardless of a successful treatment using antidepressants, fatty acid disorders may persist.

Serum zinc levels were also significantly lower in those with major depression compared to those of healthy volunteers (p<0.0003). Compared to depressed patients with normal levels of zinc, those with lower levels also showed lower levels of DHA. Comparing the total omega 6 to total omega 3 fatty acid ratio and the total omega 3 fatty acid levels between the three groups revealed significant between-group differences. Patients with major depression who had lower levels of zinc showed the largest deviations from normal.¹⁷¹ Metabolism, utilization, and peroxidation of fatty acids depend on zinc and zinc plays a fundamental role in controlling 6-desaturase activity, which catalyses the conversion of LNA to EPA.¹⁷²

In a related study, patients with major depression showed significantly lower levels of omega 3 fatty acids in serum cholesteryl esters compared to patients with minor depression and healthy controls.¹⁷³ Bruinsma found that in healthy middle-aged women, dietary long-chain omega 3 fatty acid intake was inversely associated with depression. Significant associations were found with both the severity of depression and greater levels of body dissatisfaction.¹⁷⁴

Limited intervention data are available for the treatment of depression with omega 3 fatty acids.¹⁶⁷ In a pilot study, supplementation of long-chain omega 3 was reported to improve outcome in bipolar disorders. In 1999, Stoll, in a placebo controlled, double blinded study in 30 patients with bipolar depression, reported that 9.6 g/day of omega 3 as EPA (6.2 g) and DHA (3.4 g) resulted in significant improvements in remission and outcome compared to placebo (olive oil). The reductions in depressive and mania-related events in the omega 3 treatment group were so significant that the study was stopped after 4 months and a larger multicenter study is in progress.

Schizophrenia—Membrane and fatty acid abnormalities have also been reported in schizophrenic patients.¹⁷⁶ The so-called “phospholipid membrane hypothesis” of schizophrenia proposed by Horrobin suggests that schizophrenia may be a result of an excess and/or deficit of prostaglandins related to omega 6 and omega 3 polyunsaturated fatty acids.¹⁷⁷ Marked deficits of long-chain omega 3 and omega 6 have been reported in schizophrenic patients in several studies.¹¹ However, intervention with omega 6 fatty acids has yielded conflicting results, whereas trials with omega 3 fatty acids have reported positive findings. In 20 schizophrenic patients, a 6-week trial of 10 g of fish oil per day resulted in a 17% improvement in the Positive and Negative Symptom Scale (PANSS), and a 40% improvement in the Abnormal Involuntary Movement Scale (AIMS).¹⁷⁷

Similar findings were reported in patients treated with an EPA-enriched oil.¹⁷⁸ In a double blind placebo controlled trial, Peet reported that 45 schizophrenic patients supplemented with 2 g per day EPA had a 24% improvement in PANSS scoring after 3 months of treatment, but little effect was found in the DHA-treated group. Collectively, adjunctive therapy with omega 3 fatty acids in major depression and schizophrenia is a new but potentially promising area of research that highlights not only the significance of adequate dietary intake of omega 3 for normal health, but also its therapeutic potential.

Attention-Deficit Hyperactivity Disorder—Alterations in blood lipid EFAs have been reported in children with attention-deficit hyperactivity disorder (ADHD). In 53 ADHD patients, Burgess reported significant deficits of PUFA, including EPA and DHA, in plasma and red blood cell lipids.¹⁷⁹ Twenty-one of these patients exhibited symptoms of EFA deficiency, including dry skin and hair abnormalities, increased thirst and urination, and brittle nails. Subsets of the ADHD population with lower compositions of blood lipid omega 3 had significantly more behavioral problems (including temper tantrums) and learning, health, and sleep-related problems than subjects with higher levels of omega 3. Clinical trials are currently underway to determine the potential use of EFAs in the treatment of ADHD.

Psychological Stress—Mice fed a diet deficient in DHA showed significantly greater anxiety compared to mice fed a DHA-sufficient diet. Subsequently, a double blind, placebo controlled study on psychological stress in medical students was conducted prior to their undergoing exams. One group was given capsules containing 3-3.6 g/day of a DHA-rich fish oil (49.3% DHA) for 3 months, while the control group received capsules containing the same amount of soybean oil plus a small amount of the DHA-rich fish oil (0.5% DHA). Medical students receiving the DHA-rich supplement showed no change, whereas the control group exhibited a significant increase in external aggression. Plasma concentrations of DHA at baseline were 3% and rose to 6% after the supplementation period.¹⁸⁰ Typical plasma DHA concentrations in Americans are 1% or less.¹⁷⁵

Cancer

A growing body of in vitro, animal, epidemiological, and clinical studies is producing evidence which supports the use of omega 3 fatty acids in the prevention of colon and breast cancers and their use combined with chemotherapy.¹⁸¹ Prostate cancer has also responded to dietary lipids in animal models¹⁸² and is the subject of ongoing investigations.^183,184 The proposed chemopreventive mechanisms of omega 3 fatty acids in cancer of the breast and colon are multiple and include the suppression of eicosanoid production (produced by omega 6 fatty acid precursors), enhancement of apoptosis, increase in anti-angiogenic activity, and inhibition of tumor cell growth.¹⁸¹ Evidence from animal studies and more recent human studies suggests that a high intake of omega 6 fatty acids increases the amount of free estrogen available for hormonal catabolism and oxidative damage to DNA—mechanisms that can contribute to the development of cancer of the colon and breast at several stages. Research in animals and humans suggests that omega 3 fatty acids from fish oil can protect against both kinds of cancer.¹⁸⁵

Colon Cancer—In research on human large bowel cancer, particular attention is being paid to dysregulation of AA metabolism which leads to over-expression of cyclooxygenase-2 (COX-2), in turn resulting in an excess of prostaglandin production, both of which have been shown to allow tumor self-promotion. Similarly, NSAIDS have shown promise as chemopreventive agents with what appears to be a similar mechanism: they inhibit prostaglandin biosynthesis at the level of COX-2.¹⁸⁶ A high level of dietary omega 6 fatty acids is again implicated, with toxic effects on the epithelium of the colon, increased proliferation of colon crypt cell formation, increased levels of secondary bile acids in the colon, and increased levels of prostaglandin.

The deleterious effect of omega 6 fatty acids was recently demonstrated in a study of male rats which compared diets containing a high amount of a high-fat fish oil rich in omega 3 fatty acids and a diet containing high amounts of a high-fat corn oil rich in omega 6 fatty acids. Striking changes were discovered in the level of expression of ras-p21, a gene implicated in the development of human colon cancer. For the induction of colon carcinogenesis, the rats received a carcinogen (azoxymethane) subcutaneously. The corn oil-supplemented diet resulted in enhanced ras-p21 expression induced by the carcinogen and an increased incidence and multiplicity of visible colon tumors, whereas the fish oil-supplemented rats showed the opposite: a lower multiplicity of colon tumors, a decreased incidence of tumors, and interference with ras-p21, whereby the amount of membrane-bound ras-p21 was decreased while its level in cytoplasm was increased.¹⁸⁷

Breast Cancer—Animal studies have repeatedly shown that mammary tumor development is enhanced by dietary omega 6 fatty acids and inhibited by dietary omega 3 fatty acids.^188-190 Moreover, in one of the first studies to point this out, rats fed a diet high in saturated fat from butter, coconut oil, and tallow (20% w/w) showed close to half as many mammary tumors as rats fed diets high in omega 6 fatty acids from equivalent amounts of sunflower oil, cottonseed oil, or corn oil. A diet containing even a low amount of omega 6 fatty acid (0.5% corn oil) produced nearly as many tumors as one containing 20% saturated fats.¹⁹¹ Rose and coworkers have shown that the growth and metastasis of human breast cancer cells is stimulated in mice administered a diet rich in the omega 6, LA. Conversely, a diet supplemented with DHA and EPA suppressed the growth and metastasis of the tumors' cell line.¹⁸⁹ In a further study, they administered a high-fat diet to female mice which contained 8% LA and a week later implanted human breast cancer cells. After the tumors grew, the mice either continued the same diet or received diets containing 2%, 4%, or 8% DHA or EPA. After 8 weeks, the groups receiving either DHA or EPA showed significantly less lung metastases compared to mice fed the high-fat, 8% LA diet. In another experiment, mice administered the DHA- or EPA-supplemented diets 7 days prior to surgery showed dose-dependently and significantly less severe lung metastases at all three dosages. Post-surgical feeding of DHA (2% and 4%), but not EPA, caused a significant reduction in lung metastases.¹⁹²

One of the possible chemoprotective mechanisms of omega 3 fatty acids is the ability of unsaturated fatty acids to inhibit cancer cell adhesion, which is an essential requirement of cancer cells before they can metastasize; only by adhering to the subendothelial matrix are tumor cells able to invade secondary organs. In vitro studies have shown that levels of EPA (5-10 mg/mL) found in people who consume high amounts of fish oil can inhibit the adhesion of human breast cancer cells to the subendothelial matrix at the level of the basement membrane where metastasis occurs. The effect was also found from oleic acid (at 2.5 µg/mL).¹⁹²

In a 32-country analysis of dietary components and the risk of breast cancer, the caloric amount of fat in the diet showed the strongest association. Mortality from breast cancer was also most strongly associated with dietary fat. Of all the dietary components taken into account, only the percentage of calories from fish significantly improved the association of fat with breast cancer mortality and incidence. Supporting the assumption that fish oil may protect against breast cancer, a study of 73 female breast cancer patients found significantly lower dietary EPA and DHA compared to 55 women with benign breast disease. Compared to postmenopausal women with benign breast disease, phospholipids of breast adipose tissue from the postmenopausal breast cancer patients showed a significantly lower percentage of DHA.¹⁹³

Bagga et al demonstrated that breast adipose tissue levels of omega 3 fatty acids of breast cancer patients can be changed by adding fish oil to a low-fat diet. For 3 months, women with high-risk (stage II or III) localized breast cancer consumed a very low-fat (15%), high-fiber diet. A daily fish oil supplement (ten 1000 mg capsules/day) containing 12% DHA and 18% EPA was administered in order to achieve an intake of omega 3 fatty acids of 3 g/day. At the end of 3 months, omega 6 fatty acids in plasma were significantly reduced and omega 3 fatty acids increased 3-fold. Biopsies revealed that compared to baseline, breast fat showed a significant increase in omega 3 fatty acid deposits, a higher level of total omega 3 fatty acids, and higher ratio of omega 3/omega 6.¹⁹⁴

Shao and colleagues have shown that incorporating dietary fish oil may enhance breast cancer therapy. Twenty days prior to tumor implantation (MX-1 human mammary carcinoma), adult female athymic mice were fed either a diet high in fish oil (25% plus 5% corn oil) or a control diet containing 5% corn oil. Ten days later, half the mice in each group received chemotherapy with mitomycin C. Compared to the mice on the corn oil diet, mice receiving the diet high in fish oil showed significantly greater benefits from the chemotherapy, as evidenced by the mean weight of their tumors (p<0.01). Their response to chemotherapy was 10-fold better than the mice on the low corn oil diet. Based on extensive tests, researchers speculated that increased oxidative stress in the tumors (+300% versus +25% in the corn oil group) resulted in a better response to treatment. With chemotherapy, oxidative stress in the tumors increased 160% in the corn oil group and 600% in the fish oil group. Tumors from the chemotherapy-treated mice fed the diet high in fish oil showed a significant increase in xanthine oxidase and DT-diaphorase, enzymes with proposed involvement in the antitumor activity of mitomycin C. The authors of the study suggest that a dietary intervention using a high dosage of fish oil may increase the therapeutic response to pro-oxidant therapies for breast cancer.¹⁹⁵

Prostate Cancer—There are indications that omega 3 fatty acids perform functions in experimental prostate cancer progression similar to those described for breast cancer.¹⁹² Prostate cancer risk was examined in a population-based, case-control study involving 317 prostate cancer patients ages 40-80. Compared to 480 age-matched controls, a significantly reduced risk of prostate cancer was found in association with high levels of EPA and DHA in red blood cell phosphatidylcholine. However, the association was not significant when daily DHA and EPA from the diets of the patients were estimated. The results of this study support the association of a reduced risk of prostate cancer with higher levels of long-chain omega 3 fatty acids in red blood cells and the hypothesis that eicosanoid processes are involved in the progression or initiation of prostate cancer.¹⁸³

A much smaller study of prostate cancer patients reported results that warrant a considerably larger study. When the serum from 19 prostate cancer patients and 24 patients diagnosed with BPH (benign prostatic hyperplasia) were compared to age-matched controls, levels of omega 3 fatty acids showed a significant decrease in both groups of patients, while omega 6 fatty acid levels increased only in the prostate cancer patients. The ratio of omega 3/omega 6 also decreased in the prostate cancer patients, more so than those with BPH and less so compared to the controls in either group of patients. A significant decrease in omega 3 fatty acids in both types of patients and elevated levels of omega 6 fatty acids in the prostate cancer patients resulted in this decreased ratio. The researchers proposed that the ratio of omega 3/omega 6 may be related to both prostate cancer and BPH.¹⁸⁴

Lung Cancer—An association between fish consumption and lung cancer risk has been the subject of only a few studies with inconsistent results. The largest study to date examined fish consumption and rates of lung cancer mortality in 36 countries for 10 periods from 1961 to 1994. When smoking and other confounding factors were adjusted for, fish consumption was significantly associated with lower rates of lung cancer mortality; however, the inverse relation was only significant in those countries where smoking was above the median level of over 2437 cigarettes/year or where the population consumed a high level of animal fat versus fish fat, and then only in men. For reasons unknown, no significant relation between lung cancer mortality and fish consumption was evident in women.¹⁹⁶

Cancer Treatments—The use of omega-3 fatty acids in the treatment of cancer continues to be studied in animals¹⁹⁷ at the same time as progress is being shown in human clinical trials.¹⁹⁸ In the first veterinary investigation of its kind, a double blind randomized study set out to determine the benefits of diets supplemented with increasing levels of fish oil plus arginine on the survival and quality of life of 32 client-owned dogs diagnosed with stage IIIa (n=28) or stage IVa (n=4) lymphoma receiving chemotherapy with doxorubicin. Arginine was added because of reports from human studies of lower levels in patients with malignancies compared to healthy controls, and because elderly patients receiving supplementation with the amino acid showed immunological benefits and improved wound healing. No benefits were found in dogs with stage IV lymphoma, but, compared to controls receiving a standard diet with chemotherapy, the dogs with stage III lymphoma given the supplemented diet plus chemotherapy showed longer survival times and disease-free interval scores. These improvements showed a significant association with increasing serum levels of DHA. The cumulative survival time for the experimental group was about 300 days longer than the control group, which showed a cumulative survival time of only 410 days. Higher levels of EPA and DHA were significantly associated with lower plasma lactic acid levels. In turn, lower levels of lactic acid were associated with superior survival time and disease-free interval scores. The researcher noted that lactic acidosis is found in association with various kinds of cancer in humans and indicates a poor metabolic state.¹⁹⁷

Increased survival time was reported in a study on the possible benefits of omega-3 fatty acids (2.45 g EPA and DHA/day) plus an extract of milk thistle (Silybum marianum, 200 mg/day) in 405 patients with brain metastases receiving treatment with radiation. To avoid any interference with radiation treatment, patients received the supplement for up to 20 weeks after their course of radiotherapy. Patients treated with radiation alone showed a median survival of 54.1 weeks compared to 88.8 weeks for those receiving the supplement. The latter group also showed a significant decrease in radionecroses, a common side-effect of radiotherapy (14.1% versus 3.49% incidence, respectively).¹⁹⁸

In a prospective randomized control study conducted in Greece, 60 patients diagnosed with generalized solid tumors received either placebo or a fish oil supplement (18 g providing 1020 mg EPA and 690 mg DHA), daily for 40 days. In addition, the experimental group received 200 mg vitamin E daily to ameliorate the oxidative activity of the fish oil. Immunomodulating or chemotherapeutic treatments were not received by the patients during the 4 months preceding the trial and no therapy with any “efficient or established” tumor treatment would be available to them. Fifteen healthy subjects served as a control group and each group of cancer patients held two subgroups of patients in a well-nourished state and a malnourished state. The study set out to learn the effect of the nutritional state on survival and immune response of the patients, plus the effect of dietary supplementation with omega 3 fatty acids (fish oil) on survival and immunomodulation, with emphasis on a subgroup mostly comprised of severely malnourished, immunocompromised cancer patients.

Compared to the placebo group, the malnourished patients receiving omega 3 fatty acids plus vitamin E supplementation showed a restoration of previously low peripheral blood levels of the helper T/T cell ratio, significantly increased helper T cell numbers both in the absolute and as a percentage, and significantly decreased levels of suppressor T cells. The well-nourished group also showed an increase in the helper T/T cell ratio, but the change failed to reach a level of statistical significance. Serum cytokine production and levels showed a significant increase only in TNF production in the peripheral blood mononuclear cells of the malnourished subgroup of patients receiving omega 3 fatty acids plus vitamin E supplementation, which reached the same level as that of the well-nourished subgroup. The malnourished group also showed a significant increase in Karnofsky performance status. Compared to these patients, survival was only significantly prolonged in the well-nourished group receiving omega 3 fatty acid supplementation plus vitamin E (mean survival 213 versus 481 days; p<0.001). Nonetheless, when both groups of cancer patients were combined and compared to the placebo group, survival was significantly prolonged in the patients receiving omega 3 plus vitamin E (p<0.025).

Despite the high dosage of omega 3 plus vitamin E, no cases of serious toxicity were found, with the exceptions of transient diarrhea and “mild abdominal discomfort.” The authors concluded that omega 3 fatty acid supplementation combined with vitamin E may provide palliative support to patients with end-stage metastatic disease, especially to those in an undernourished state. They add that the addition of vitamin E appears to have diminished the immunosuppressive effect of fish oil on cell-mediated immunity and that the survival increase may be the result of antitumor and anticachectic activity through its immunomodulating and eicosanoid effects.¹⁹⁹

Cancer Cachexia—Experiments in mice have shown that, despite a cachexia-inducing tumor (MAC16), replacing part of the carbohydrate calories of the diet with fish oil will inhibit loss of body weight.^200,201 The effect was attributed to EPA which was shown to directly inhibit tumor-induced lipolysis and to inhibit protein degradation in skeletal muscles of the animals. This effect was due to interference with catabolic factors produced by tumors; in this case, EPA inhibited an increase in protein degradation by inhibiting the increased production of PGE₂ caused by a proteolytic factor produced by the tumor. EPA also inhibited tumor growth, an effect that LA was shown to suppress, although without affecting the anticachectic activity of EPA.²⁰¹

Clinical studies of fish oil in the treatment of cancer cachexia are proving fruitful ground for determining antitumor effects of omega 3 fatty acids in addition to elucidating their nutritional and anticachectic role in cancer patients. Recently, Burns et al conducted a phase I study to determine the dose-limiting toxicity of encapsulated fish oil in cancer and leukemia patients who had lost 2% of their body weight, thereby providing dosage information for future clinical studies of fish oil in cancer patients. The maximum daily tolerated dose was 300 mg/kg PO. Patients were able to tolerate up to 21 1000 mg capsules/day, a dosage totaling 13.1 g of DHA plus EPA. The main side effect from such a high dosage was diarrhea.²⁰²

Barber and colleagues, after two previous studies in pancreatic cancer patients administered fish oil against cachexia,^204,205 recently reported the results of a further pilot study in 20 patients with advanced pancreatic cancer using a canned fish oil-enriched supplement (providing 1.1 g EPA and 0.48 g DHA/can). Median consumption of the supplement was 1.9 cans/day. At both 3 and 7 weeks, most of the patients showed an increase in weight gain, a significant increase in Karnofsky status, and significantly improved appetite and caloric intake, whereas they had previously been losing weight at a median rate of 2.9 kg at least monthly. A randomized controlled trial is now underway to determine effects on survival and side effects, and to confirm the anticachectic effects of fish oil.²⁰⁵

Vision

In adults aged 49 and over (n=3654) who consumed fish frequently (more than once per week versus less than once monthly), an urban population-based study in Australia recently found a significantly reduced risk of late age-related maculopathy (ARM). However, it remains for future, larger studies to confirm whether low dietary omega 3 fatty acids are a risk factor for ARM—currently the most prevalent cause of blindness in the Western world.¹⁰⁰

FATTY ACID PROFILE ASSESSMENT

Analytical tests are available to assess EFA profiles of patients. While not prevalent in most clinical laboratories, many university and private laboratories offer fatty acid profiling of plasma and red blood cell lipids.¹⁴⁶ Analysis of plasma total phospholipid fatty acid profiles may provide an accurate assessment of dietary intake of EFAs and correlate well with tissue lipid composition. Similarly, red blood cell membrane fatty acid analysis provides an index of long-term intake (about 3 months) that is less sensitive to short-term changes in the diet since the red cell's life is 120 days. Baseline fatty acid profiles serve to identify potential aberrations in nutritional and physiological status, and analysis of nutritionally supplemented patients serves to identify compliance and the effects of supplementation on fatty acid profiles.

CONCLUSION

Omega 3 fatty acids play an important role in our health and well-being through their roles in membrane lipids, as eicosanoid precursors, and through their effects on gene expression. The American diet is clearly lacking in long-chain omega 3 fatty acids while it is high in omega 6 fatty acids, mainly from our reliance on vegetable oils, the absence of fish from our diet, and changes in animal feeds which have produced meat and dairy products devoid of omega 3. Consequences of this diet are multifactorial, but stem from relative imbalances between omega 6 and omega 3 fatty acids in tissue lipids that have a direct effect on normal cellular and immune system function. Restoring balance between omega 6 and omega 3 fatty acids by changing the diet via changing the oils or by supplementing it with fish oil has demonstrated promise in the treatment of several diseases and is a testament to the fundamental importance of omega 3 fatty acids in the human body and to the importance of a balanced 6:3 ratio.

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