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.
Biochemistry
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
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).
Rheumatoid arthritis
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 Crohn’s
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 Crohn’s 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 Crohn’s 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
Psoriasis
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.
Asthma
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.
Mental disorders
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 Alzheimer’s 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
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.
Cancers
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.
Diabetes
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
Safety
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 Health’s 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.
Recommended intakes
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 Foundation’s 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.
Summary
Dr Mason is a pharmacist with a postgraduate qualification in nutrition