Fish oils - an update
The Pharmaceutical Journal Vol 265 No 7122 p720-724
November 11, 2000 Continuing Education
Fish oils - an update
By Pamela Mason
Sold by pharmacists since the early years of the 20th century, cod liver oil is one of the oldest and most well-known food supplements. The oil first gained its reputation as an effective preventative against rickets because of its high vitamin D content and it was taken by generations of children, decreasing in popularity only when, in the 1960s, the British government decided to phase it out as a welfare food.
For several years this old-fashioned image, together with the taste, resulted in cod liver oil being ignored, until a series of papers published in the 1970s reported that the Inuit people of Greenland, who ate a traditional diet high in seal meat, whale meat and fish, had rates of coronary heart disease 10 times lower than their nearest neighbours, the Danes.1,2 This low rate of heart disease occurred despite the fact that the Inuit diet contained a similar proportion of fat to the Danish diet and most of it was derived from animal sources. As a result, there was renewed scientific interest in the potential benefits of fish oils, and fish oil supplements again began to increase in popularity. Figures from Seven Seas, a manufacturer of supplements indicate that fish oils represent 21 per cent of the total dietary supplement market in the UK.
Fish oil is a rich source of the n-3 (also known as omega-3) fatty acids, eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA).
The n-3 fatty acids belong to one of two families of polyunsaturated fatty acids (PUFAs), the other being the n-6 (omega-6) family. The n-3 family is derived from the essential fatty acid, alpha-linolenic acid, and the n-6 family from the essential fatty acid, linoleic acid.
Both these parent fatty acids are essential because the body cannot make them, so they have to be provided by the diet. The richest sources of alpha-linolenic acid include vegetable oils (eg, linseed, rapeseed and soya), nuts (including walnuts and peanuts), green leafy vegetables and meat from grass-fed animals (eg, beef). The richest sources of very long chain n-3 fatty acids are oily fish and fish oil (see Panel 1). However, a few so-called "functional foods", such as eggs, margarine and bread are now being fortified with EPA/DHA. Good sources of linoleic acid include oils, such as sunflower and safflower.
Alpha-linolenic and linoleic acids use the same enzyme systems to undergo a process of desaturation and chain elongation, which forms very long chain fatty acids. This conversion occurs sparingly and slowly and it has been suggested that some individuals (eg, premature infants and possibly patients with insulin-dependent diabetes mellitus or schizophrenia) may have a limited ability to make EPA and DHA from the parent alpha-linolenic acid. In addition, there is competition between alpha-linolenic and linoleic acids for the enzymes involved in the conversion process and high levels of linoleic acid can inhibit the conversion of alpha-linolenic acid to its longer chain derivatives. This is important because the longer chain fatty acids in both families are precursors of eicosanoids, which include prostaglandins, leukotrienes and thromboxanes.
Eicosanoids have a wide range of functions, including the ability to influence inflammation, atherogenesis, blood pressure, blood clotting, platelet aggregation and reproduction. In general, eicosanoids derived from the n-3 fatty acid EPA are less potent in their ability to cause inflammation and platelet aggregation than those produced from the n-6 fatty acids arachidonic acid and dihomo-g-linolenic acid. This is the mechanism by which n-3 fatty acids are thought to reduce the symptoms of inflammatory conditions, such as rheumatoid arthritis, and to decrease the likelihood of atherosclerosis and thrombosis. Moreover, both n-3 and n-6 fatty acids are components of cell membranes and they compete with each other for incorporation into the cell membrane. This element of competition between the two families suggests that balance in the intake of the n-3 and n-6 fatty acids is important.
Over the past 30 years, increased consumption of vegetable oils and margarines has led to relatively high intakes of n-6 fatty acids in comparison with n-3 fatty acids and the suggestion has been made that the typical western diet may not supply the appropriate balance of n-3 and n-6 fatty acids. The increased availability of rapeseed oil may be helping to redress this balance but fish consumption remains low. Only about one-third of the UK population consume oily fish on a regular basis and the average intake among those who eat it is only one small portion (135g) a week. The average intake of oily fish in the whole UK population is about 47g a week.3
Importance of n-3 fatty acids
There is little doubt that n-3 fatty acids have an important role in nutrition. They are significant structural components of the phospholipid membranes of tissues throughout the body, particularly in the brain and retina.
Because of their role in cell membranes, n-3 fatty acids are essential for the formation of new tissue and are therefore important for development and growth (eg, during foetal and infant development). During the last three months of pregnancy, n-3 fatty acids rapidly accumulate in the brain and nervous system of the foetus. Babies born pre-term may miss some of this period and could have a suboptimal ability to synthesise long chain fatty acids. Thus, they may require these to be provided pre-formed. Long chain n-3 fatty acids (and other fatty acids) are present in breast milk and European Union regulations now allow their addition to infant formulas.
Some studies have shown an inverse relationship between n-3 fatty acid intake and cognitive ability or visual indices in infants and children. However, more research is required to determine the optimum levels of n-3 fatty acids in infants diets. In adults, the n-3 fatty acids may also have a role in the prevention and management of certain conditions. These include:
- Coronary heart disease and stroke, for which evidence is quite strong
- Inflammatory conditions, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and asthma
- Mental disorders such as depression, schizophrenia and Alzheimers disease
- Autoimmune disorders, such as nephro-pathy and lupus
- Diabetes mellitus
Coronary heart disease
The consumption of fish is associated with lower rates of coronary heart disease in many epidemiological studies. The seminal findings in the Inuit have been confirmed and extended in western populations and, in most studies, there is an inverse relationship between the intake of fish, or n-3 fatty acids, and both total mortality and cardiovascular mortality.4-8 However, some studies9,10 have not shown any benefit, possibly because fish intake was higher in the studied population as a whole.
Intervention studies, in which the intake of fish or fish oil was increased, have also shown beneficial effects. One classic study11 investigated 2,000 Welsh men who had just recovered from their first heart attack. The men were randomised to a fish advice group, in which they were asked to eat at least two portions of oily fish a week, or failing this fish oil in capsule form, or a no fish advice group. After two years, there was a 29 per cent reduction in mortality in the fish/fish oil group, which was attributable to a reduction in CHD deaths. However, although there were fewer fatal heart attacks in the fish group, the total number of heart attacks did not decrease.
More recently, an Italian trial12 investigated the effects of n-3 PUFAs (1g/day), vitamin E (300mg/day) or both as supplements on 11,324 patients who had survived a recent myocardial infarction. Treatment with n-3 PUFAs, but not vitamin E, reduced total deaths and cardiovascular deaths, and the effect of the combined treatment was similar to that for n-3 PUFAs alone.
In a double-blind, placebo-controlled study in India,13 360 patients with suspected myocardial infarction were randomised to receive fish oil (1.09g/day EPA/DHA), mustard oil (2.9g/day alpha-linolenic acid) or placebo for one year. Total cardiac events including cardiac arrhythmias, angina pectoris and left ventricular enlargement were significantly reduced in both the fish oil and mustard oil groups compared with placebo. Fish oil, but not mustard oil, was significantly correlated with fewer cardiac deaths than placebo. Support for the role of alpha-linolenic acid (the parent n-3 fatty acid) in heart disease prevention also came from the Lyon Diet Heart Study14 and a US trial,15 both of which showed that a higher intake of this fatty acid reduced fatal coronary events. Whether alpha-linolenic acid can fully reproduce the effects of EPA and DHA remains to be seen. The n-3 fatty acids may prevent heart disease through a variety of mechanisms, many of which involve their role as eicosanoid precursors (see Panel 2).
Fish oils appear to alleviate the symptoms of rheumatoid arthritis, which is, perhaps, unsurprising as n-3 fatty acids are thought to be involved in the suppression of the production of inflammatory eicosanoids.
Several studies have shown that very long chain n-3 fatty acids reduce pain and morning stiffness22 and decrease the need for non-steroidal anti-inflammatory drugs.23,24 Moreover, a meta-analysis of 10 double-blind, placebo-controlled, randomised trials in 395 patients showed that fish oil taken for three months was associated with a statistically significant reduction in joint tenderness and morning stiffness. There were no significant improvements in joint swelling, grip strength or erythrocyte sedimentation rate (a marker of inflammation).25
Inflammatory bowel disease
Fish oil has been found to have some benefits in patients with Crohns disease or ulcerative colitis but no real conclusions can be drawn.
A review of five studies26 investigating the effect of n-3 fatty acids in Crohns disease was inconclusive but a later study27 showed that an enteric-coated preparation of very long chain n-3 fatty acids significantly reduced the rate of relapse in patients with Crohns disease that was in remission.
In patients with ulcerative colitis, fish oil supplements have been found to reduce corticosteroid requirements,28 improve gastrointestinal histology29 and reduce disease activity index.30
Fish oils have been found to be beneficial in some individuals with psoriasis, leading to reduced itching and erythema. However, two double blind, placebo-controlled studies31,32 showed that fish oil did not produce any clinical benefit in the treatment of psoriasis.
Because asthma is an inflammatory condition, which appears to involve eicosanoids, it is theoretically plausible that fish oil could be of benefit. However, results of studies have been discouraging. There is also growing interest in the role of n-3 fatty acids in other conditions affecting respiration, including hay fever, chronic obstructive pulmonary disease and cystic fibrosis.
The potential role of fish oils in various mental disorders is an area of growing interest.
A limited number of studies have found low levels of n-3 fatty acids in cell membranes of patients with depression, schizophrenia and Alzheimers disease and it has been suggested that low dietary intakes of n-3 fatty acids or an imbalance in the n-6:n-3 ratio might be associated with these conditions. However, it remains to be seen whether the observed low levels of cell membrane n-3 fatty acids are a cause or an effect of the illnesses.
Nephropathy is a form of kidney disease that occurs particularly in older men with impaired kidney function and high blood pressure. In a placebo-controlled, multicentre trial, 106 patients were randomised to receive either 12g of fish oil/day or placebo over a period of two years.33 The rate of loss of kidney function was retarded in the supplemented group and the beneficial effect was suggested to be due to the impact of n-3 fatty acids on eicosanoid production and other factors. However, other studies have shown no such benefits and more work is needed.
In animal studies, fish oils have been shown to reduce cell proliferation and pre-cancerous cell changes, and some epidemiological studies in humans have suggested that fish oils could be protective against cancer. However, there is no consistent evidence that fish oil decreases cancer risk in humans.
Patients with diabetes mellitus are at increased risk of developing CHD and the potential effect of fish and fish oil in reducing this risk is likely to be of benefit to these patients. However, fish oil has been linked with deterioration in glucose and insulin control, although results from studies have been inconsistent. In one study, n-3 fatty acids led to a small increase in blood glucose levels in diabetes34 but not in another.35 However, a meta-analysis concluded that fish oil has no adverse effects on glucose or insulin metabolism in patients with diabetes and, importantly, that it lowers triacylglycerol levels effectively by 30 per cent.36
Fish oil supplements are generally safe and, in one prospective study involving 295 people aged 18-76 years,37 10-20ml of fish oil (providing 1.8-3.6g EPA/DHA) for seven years was not associated with any serious adverse effects.
The safety of n-3 fatty acids from fish oil (derived from menhaden, an oily fish used in the US as a source of fish oils) was reviewed by the US Food and Drug Administration (FDA) in 1997. After reviewing more than 2,600 articles, the FDA concluded that dietary intakes of up to 3g/day of EPA/DHA from menhaden oil were generally regarded as safe.38 The FDA came to this conclusion after considering three main issues related to the safety of fish oils the risk of deteriorating glycaemic control in type 2 diabetes, prolongation of bleeding times and the risk of increasing LDL levels in patients with hypertriglyceridaemia.
Many fish oil supplements (eg, cod liver oil and halibut liver oil) contain vitamin A and vitamin D, fat-soluble vitamins that can be toxic in excessive amounts. Some people may wish to take a multivitamin supplement and fish oils together. In this case, a fish oil rather than a fish liver oil should be taken to avoid excessive doses of vitamins A and D. However, provided the recommended dose of fish liver oil is not exceeded, it is unlikely to be harmful if taken with a multivitamin supplement. The Department of Healths warning for pregnant women not to take supplements containing vitamin A still stands.
Another safety concern expressed about fish oils is their potential to increase bleeding time (a beneficial effect in relation to prevention of CHD). However, it is unlikely that this will be a problem, particularly with intakes of less than 3g EPA/DHA daily. Nevertheless, patients taking anticoagulant medication or those with blood clotting disorders should be monitored while taking fish oils. People taking other dietary supplements that may prolong bleeding time, such as vitamin E, garlic and Ginkgo biloba, should be advised about a possible synergistic effect, although evidence that such effects occur is not available. It does not mean that such patients have to avoid fish oils just that their doctor should be aware of it. Concerns have also been expressed about the susceptibility of fish oil to peroxidation and vitamin E is commonly added to fish oil supplements to prevent this from occurring.
Various recommendations have been made, both in the UK and elsewhere, about the intake of very long chain n-3 fatty acids (see Panel 3).
As an illustration, in food terms, the British Nutrition Foundations recommendations equate to two to three medium portions of oily fish each week. The average intake of oily fish in the UK is 47g a week or about one-third of a medium portion. The Department of Health has advised the consumption of two portions of fish each week, one of which should be oil-rich.3 Some people do not enjoy oily fish, and may wish to take a fish oil supplement, particularly if they are at risk of CHD.
- Many people could benefit from an increased intake of n-3 fatty acids. The typical UK diet contains relatively low amounts of these.
- Over recent decades the balance between n-6 and n-3 fatty acids has changed in favour of n-6 fatty acids
- Fish oil appears to reduce the risk of CHD. It may help to reduce the risk of thrombosis (by increasing bleeding tendency), reduce blood levels of triacylglycerols, prevent atherosclerosis and arrhythmias and reduce blood pressure
- Fish oil could have beneficial effects in inflammatory conditions such as rheumatoid arthritis, Crohns disease and ulcerative colitis, but evidence of any benefit in asthma and psoriasis is poor.
- Fish oil may have a role in various mental disorders, such as depression, schizophrenia and Alzheimers disease, but research in this area is in its infancy
- Intake of n-3 fatty acids can be increased by consuming one to two portions of oily fish each week.
- People who could benefit from increased intake of n-3 fatty acids and who dislike oily fish may wish to consider a supplement.
- Fish oil supplements appear, in general, to be safe. However, patients on anticoagulants or with blood clotting disorders should be monitored.
Dr Mason is a pharmacist with a postgraduate qualification in nutrition
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