(Circulation. 1998;97:2580-2583.)
© 1998 American Heart Association, Inc.
Diagnosing Essential Fatty Acid Deficiency
Edward Siguel, MD, PhD
Nutrek, Inc.,
Brookline, Mass
To the Editor:
Dr Gould and colleagues reported the effects of an intensive
cholesterol-lowering program using mostly low-fat
diets.1 To monitor essential fatty acid (EFA) status, they
measured the ratio 20:3
9/20:46 (triene/tetraene or T/T
ratio). The authors stated that a ratio >0.4 in serum phospholipids
indicates EFA deficiency (p 1532). In 1987, Siguel et
al2 3 showed that measures of T/T currently in use were in
error by a factor 
10. The use of old technology, which had inadequate
peak separation and erroneous peak integration, led to huge errors in
measuring 20:39. When 20:39 was properly measured, T/T ratios
>0.02 (in whole plasma) indicated EFA deficiency. For healthy people,
T/T ratios in red blood cells (RBCs), RBC phospholipids, and serum
phospholipids, which reflect the subject's plasma levels, give
reference values that are >10 times below the values reported by Dr
Gould (Siguel, unpublished data, 1997). The T/T reference values used
by Gould et al appear to be too high and would account for the
statement that "no patient showed evidence of EFA deficiency." If
we seek to detect abnormal cholesterol using a method that
can only measure cholesterol >1000 mg/dL, most patients
would be found to have normal cholesterol, and saturated
fat and obesity would be found not to increase cholesterol.
Patients are unlikely to develop the severe EFA deficiencies that would
have dramatic symptoms, such as substantial hair loss, overt clinical
dermatitis, and T/T ratios >0.4; this would require severe depletion
of EFAs over a period of many years. However, biochemical evidence of
EFA deficiency can be detected in patients after several months on a
low-fat diet when appropriate technology is used. Insufficient levels
of EFAs, a condition I characterized as EFA insufficiency
(EFAI),4 and imbalance of the 3/6 ratios is
associated with abnormal lipid levels,5 hypertension,
coronary artery disease, and a higher-than-average probability
of premature death as a result of heart disease.6 Patients
who routinely follow low-fat diets deprived of EFAs are likely to
develop EFAI and ought to be warned about the long-term consequences of
EFA deficiency. Researchers can now monitor EFA status quite accurately
and measure the biochemical onset of EFA deficiency over the duration
of a study.
These issues have far greater implications for public health than a
mere technical discussion on reference levels. The existence of EFA
abnormalities affects both medical and food policy in the United
States. Failure to diagnose EFA abnormalities may lead to expensive
treatments for preventable chronic diseases followed by unnecessary
premature death. Billions of dollars are now spent on drug treatments
and surgical procedures for conditions like high blood pressure,
abnormal cholesterol ratios, and coronary artery
disease, which respond quite well to correction of polyunsaturated
fatty acid (PUFA) abnormalities.4
Corporations are now developing a wide range of fat substitutes and fat
replacements. Replacing fat with fat substitutes (or substances that
inhibit fat absorption) obviously reduces the amount of fat in the
diet, which may help some patients, but also significantly reduces the
amount of EFAs in the body, which can have disastrous consequences.
One obvious concern about the safety of these new products has been
the likelihood that these food substitutes cause substantive EFA
deficiency in the population. Companies engaged in the development and
marketing of food substitutes would like to prove that their fat
substitute (or related product) is healthful and does not lead to
EFA deficiency. It is quite simple to prove that EFA deficiency does
not exist by measuring EFA deficiency with a technology that can only
detect severe EFA deficiency. By publishing articles, journals must be
careful that they do not endorse, unintentionally, use of a technology
that cannot detect EFA deficiency except in very rare and exceptional
cases. Corporations could use this published information to state that
subjects using their new products did not experience EFA depletion
and that they used the same methods of measurement reported in the
peer-reviewed journal. This is not a merely hypothetical issue; I have
been told of at least one company that plans to show that its
product does not cause EFA deficiency because the T/T ratios of
subjects remained <0.4, citing articles that rely on outdated
technology to support their contention.
A similar concern arises with regard to drug treatment for heart
disease, particularly when combined with a diet high in
monounsaturated fatty acids (MUFAs), as proposed by
many public health organizations and popular books such as The
Zone.7 For example, the Heart Owner's
Handbook states that MUFAs are better than PUFAs (p
33).8 However, MUFAs obviously cannot replace the PUFAs
missing in low-fat foods. These matters are critical now that many new
food products are either under government review or already
approved for consumer use. Failure to use a sensitive blood test would
obscure EFA deficiency caused by the extensive use of low-fat foods or
foods high in MUFAs. Failure to diagnose and treat PUFA abnormalities
can cause unnecessary premature death.9
Editors who publish articles involving the analysis of fatty
acids should insist that authors provide the following information and
reviewers be qualified to understand it: column used (ID, phase,
length, etc), gas-liquid chromatograph (GLC) (brand model),
injection method (split, splitless, etc), amount of injection, how
fatty acid methyl esters were prepared, GLC method (eg, temperature
run, duration, gases used, flows), how samples were integrated,
software used (model, version, etc), quality control for peak
integration, how the area of each peak was evaluated for integration
errors, and how peaks were identified. Articles should include (for
review, if not for publication) at least 2
representative chromatograms for subjects in each group
showing peaks and integration: 1 that shows all peaks and 1 enlarged
enough to see the baseline and noise levels. This is needed to evaluate
the accuracy of the integration and the presence of artifacts or extra
peaks that would affect the results. These data are simple to produce
and readily available to the authors.
(Dr Siguel has a patent on a blood test to diagnose
fatty acid abnormalities.)
References
1.
Gould KL, Martucci JP, Goldberg DI, Hess MJ, Edens
RP, Latifi R, Dudrick SJ. Short-term cholesterol
lowering decreases size and severity of perfusion abnormalities by
positron emission tomography after dipyridamole in
patients with coronary artery disease: a potential noninvasive
marker of healing coronary endothelium.
Circulation.. 1994;89:1530–1538.[Abstract/Free Full Text]
2.
Siguel EN, Maclure M. Relative enzyme activity of
unsaturated fatty acid metabolic pathways in
humans. Metabolism.. 1987;36:664–669.[Medline]
[Order article via Infotrieve]
3.
Siguel EN, Chee KM, Gong J, Schaefer EJ. Criteria
for essential fatty acid deficiency in plasma as assessed by capillary
column gas-liquid chromatography. Clin
Chem.. 1987;33:1869–1873.[Abstract/Free Full Text]
4.
Siguel EN, Lerman RH. Fatty acid patterns in
patients with angiographically documented coronary artery
disease. Metabolism.. 1994;43:982–993.[Medline]
[Order article via Infotrieve]
5.
Siguel E. A new relationship between
polyunsaturated fatty acids and total/HDL
cholesterol. Lipids.. 1996;31:S51–S56.
6.
Siscovick DS, Raghunathan TE, King I, Weinmann S,
Wicklund KG, Albright J, Bovbjerg V, Arbogast P, Smith H, Kushi LH,
Cobb LA, Copass MK, Psaty BM, Lemaitre R, Retzlaff B, Childs M, Knopp
RH. Dietary intake and cell membrane levels of long-chain n-3
polyunsaturated fatty acids and the risk of primary cardiac
arrest. JAMA.. 1995;274:1363–1367.[Abstract/Free Full Text]
7.
Sears B. The Zone. New York,
NY: Harper Collings Publishers, Inc; 1996.
8.
Texas Heart Institute. The Heart
Owner's Handbook. New York, NY: John Wiley & Sons; 1996.
9.
Siguel E, Lerman RH, MacBeath B. Low-fat diets
for coronary heart disease: perhaps, but which one?
JAMA.. 1996;275:1402–1403.[Abstract/Free Full Text]
Response
K. Lance Gould, , MD
Professor of Medicine,
University of Texas Medical School,
Houston, Tex
In his letter about our study published in
Circulation 3 years ago,1 Dr Siguel raises
essentially two concerns: (1) how to assay blood for essential fatty
acid deficiency and (2) whether low-fat diets cause essential fatty
acid deficiency. Both are addressed separately below.
There are two essential fatty acids, linoleic acid and
alpha-linolenic acid, required for synthesis for arachinoids,
eicosanoids, prostaglandins, thromboxanes, and
leukotrienes that are important for cell membrane
function.2 3 4 With essential fatty acid deficiencies, an
"abnormal" intermediate, eicosatrienoic acid (20:39),
accumulates and the "normal" intermediate metabolite,
arachidonic or an eicosatetranoic acid (20:46),
decreases such that the triene to tetraene ratio (20:39/20:46) or
the T/T ratio increases.2 3 4
Current texts of nutrition indicate that a T/T ratio of 0.4 is
associated with clinical linoleic acid deficiency,3 4 a
criterion used in our 1993 study. Table 3 (page 666) of Dr Siguel's
1987 study in the journal Metabolism shows an
average T/T ratio of 0.45 in six patients with clinical essential fatty
acid deficiency as the result of malabsorption syndromes or prolonged
fat-free parenteral alimentation.5 A normal reference
group had a T/T ratio of 0.008, and a subset of subjects from the
Framingham Study had values of 0.014. A patient with essential fatty
acid deficiency corrected to a T/T ratio of 0.02, in the normal range,
after intravenous infusion of adequate essential fatty
acids.
In his second 1987 study,6 Dr Siguel reports a T/T ratio
in a normal reference group as 0.013±0.006. In 10 patients with
clinical malabsorption syndromes, the T/T ratio was 0.30±0.61, with a
value of P=.06 for the difference, not statistically
significant at the .05 level. The normal T/T ratio in older literature
is reported as 0.1±0.07.6 On the basis of these data, Dr
Siguel claims in his letter that "measures of T/T currently in use
were in error by a factor 10." With his average value of the T/T
ratio of 0.455 and 0.36 in patients with
essential fatty acid deficiency by new technology5
compared with 0.4 used traditionally,3 4 his basis for
this claim is questionable, particularly since his own value of 0.3 was
not significantly different from his reference group at the
P=.05 level of probability.6 His normal
reference values for the T/T ratio of 0.013 compared with older
literature of 0.16 do not redefine the criteria for
clinical fatty deficiency, which are 0.3 to 0.45 by his own numbers,
the same as traditionally used. Therefore, the criteria for our 1993
article in Circulation are the same as those traditionally
used3 4 and consistent with Dr Siguel's own
data.5 6
In a publication of 1994,7 Dr Siguel proposed a new
intermediate stage of essential fatty acid insufficiency (as opposed to
deficiency) with a number of other end point measures proposed as being
more sensitive than the T/T ratio as indicators of essential fatty acid
insufficiency. On the basis of fatty acid analyses in 47
patients with documented coronary artery disease, he reasoned
that excessive dietary levels of saturated fatty acids saturate or
disturb the transport of essential fatty acids, thereby producing a
possible abnormal T/T ratio or other proposed biochemical markers of
possible essential fatty acid deficiency despite apparently relatively
normal diets in these patients. In this study,7 the T/T
ratio in the normal reference population was 0.013±0.001 and in the
coronary artery disease patients was 0.016±0.001, a
statistically significant difference of unclear biological importance,
particularly in view of a T/T ratio of 0.3±0.61 in patients with
clinical essential fatty acid deficiency that was not significantly
different from normal at the P=.05 level in his previous
study.6 By his T/T ratio criteria in the 1994
study,7 5 of 47 patients were claimed to have deficiency
of essential fatty acids without reference to the type of diet the
patients were on. Dr Siguel then extrapolated this point of view to the
more extended hypothesis that a low-fat diet causing essential fatty
acid insufficiency may increase the risk of coronary artery
disease.7
In a 1996 study8 and in his letter, this point of view is
still further extrapolated to the more extended hypothesis that low-fat
diets cause essential fatty acid deficiency and heart disease and that
"billions of dollars are now spent on drug treatments and surgical
procedures for conditions like high blood pressure, abnormal
cholesterol ratios, and coronary artery disease,
which respond quite well to correction of PUFA abnormalities." His
letter goes on to indict the low-fat food industry and "public
health organizations" and concludes that "failure to diagnose and
treat PUFA abnormalities can cause unnecessary premature death,"
where "correcting PUFA abnormalities" apparently does not mean
low-fat food or cholesterol-lowering drugs. The data
documenting these extended hypotheses are not reported, to my
knowledge. In fact, high intake of linoleic acid of >12% of calories
reportedly decreases HDL cholesterol that is associated
with higher risk of atherosclerosis.3 9 10
Reading the 19875 6 and 19947 articles of Dr
Siguel suggests that he knows a great deal about measuring fatty acids
and about their possible interactions, with thoughtful,
provocative hypotheses about their potential biological
importance. However, his own data do not support the claim of an error
by a factor of 10 in the criteria of the T/T ratio indicating clinical
essential fatty acid deficiency. His data actually support the current
traditional criteria. The reader and Dr Siguel need to clearly separate
documented criteria and conditions for clinical essential fatty acid
deficiency supported by Dr Siguel's own data5 6 from a
hypothesized, intermediate stage of essential fatty acid insufficiency
in free-living people on undefined diets, on the basis of changes in
fatty acid ratios of unknown significance, without defined clinical
abnormalities, due to a hypothesized adverse effect on lipid profiles,
by an undefined level of dietary polyunsaturated fatty
acids.7 8 These latter provocative hypotheses
are just that—unconfirmed hypotheses. Furthermore, these hypotheses
involve the effects of substantial amounts of dietary polyunsaturated
fatty acids, particularly linoleic acid and alpha-linolenic
acid, on lipid metabolism, not clinical deficiency of these
essential fatty acids in the diet of well individuals without
malabsorption syndromes or parenteral alimentation.
As to the second issue, do low fat-diets cause essential fatty acid
deficiency? The Recommended Dietary Allowances (RDA) published by the
National Research Council do not make recommendations on minimum daily
requirements of essential fatty acids. The reason is a lack of data and
the difficulty of identifying essential fatty acid deficiency in a
free-living population other than patients with malabsorption syndromes
or total parenteral alimentation. The United Kingdom Reference Nutrient
Intakes suggest minimum consumption of 1% of calories from linoleic
acid and 0.2% from alpha-linolenic acid.3 4 For a
1500-calorie diet commonly needed to achieve lean body habitus, 
1.67
g of linoleic acid and 0.33 g of alpha-linolenic acid
would be minimum requirements on the basis of these criteria. For an
1800-calorie diet, 2 g of linoleic acid and 0.4 g of
alpha-linolenic acid would be the minimal requirements by these
criteria.
Soybean oil, walnut oil, corn oil, grapeseed, sunflower, and cottonseed
oil contain >50% linoleic acid. Soybean oil, walnut oil, canola, and
rapeseed oil contain 7% to 11%, and linseed oil contains 53%
alpha-linoleic acid.11 12 13 14 15 Only soybean and walnut oils
have significant balanced amounts of both linoleic acid and
alpha-linolenic acid in proportion to their essential
requirements. Alternatively, the compounds synthesized from
alpha-linolenic acid, docosahexanoic (DHA) and eicosapentenoic
(EPA), can be acquired from seafood, specifically omega-3 fish oil. In
view of the ubiquity of the two essential fatty acids in Western diets,
essential fatty acid deficiency is considered rare in free-living
adults if it occurs at all,3 4 being seen only and
uncommonly in severe malnutrition, untreated malabsorption syndromes or
prolonged incomplete fat-free intravenous alimentation.
However, I have seen 14 lean patients on self-imposed, well-documented
diets of <5% of calories as fat for 1 to 3 years (less than my
guidelines of 10% of calories as fat) who had clinical symptoms
consistent with essential fatty acid deficiency. These symptoms
included mild but definite temporary recent memory loss, difficulty
concentrating, episodic somnolence during the day, visual scotoma,
decreased visual acuity, and/or sexual dysfunction. One, several, or
all of these symptoms first appeared on very low-fat diets and reverted
to normal on increasing sources rich in essential fatty acids. In
addition to these symptoms, 4 of these 14 subjects had their first
episode of atrial fibrillation or tachyarrhythmia
without alcohol exposure or identifiable cause and without
recurrence after increasing essential fatty acid intake. Nine
of these subjects had their first episode of overt vasovagal syncope
preceded by symptoms of similar but less severe vasovagal reactions,
all of which disappeared on increasing sources of essential fatty acids
without other identifiable changes in food, weight, or medications. Two
individuals developed flaking, soft nails that became normal after
increased intake of essential fatty acid sources. None had the typical
fatigue, elevated triglycerides, and low HDL commonly
caused by excess carbohydrate and inadequate protein previously
discussed in "Letters to the Editor" of JAMA in
response to Dr Siguel.16 Therefore, clinically relevant
essential fatty acid deficiency may occur in otherwise well-nourished,
active, well individuals on very low-fat diets of <5% of calories as
fat. Any treatment powerful enough to heal is also powerful enough to
harm if misused or if its side effects are not understood. Very-low-fat
food also has similar beneficial or bad potential and must be
implemented properly with no less than 10% of calories as fat.
For individuals adherent to very-low-fat foods, I recommend specific
sources of essential fatty acids. Soybean oil contains 51% linoleic
acid and 6.8% alpha-linolenic acid.11 12 13 14 15 One
teaspoon of soybean oil containing 4.7 g of oil provides 2.4 g
of linoleic acid and 0.38 g of alpha-linolenic acid, the
minimum requirements to prevent clinical essential fatty acid
deficiency on the basis of the criteria of the United Kingdom Reference
Nutrient Intakes3 4 and consistent with discussion
of the recommended dietary allowances of the US National Research
Council.2 One form of soybean oil is soya
lecithin,15 containing 1.2 g of oil per capsule, so
that 4 capsules per day would provide this minimum requirement.
One teaspoon of walnut oil provides 2.4 g of linoleic acid and
0.25 g of alpha-linolenic acid. One to two teaspoons of
walnut oil ingested per day provide the minimal requirements for
essential fatty acids. It is the only oil besides soybean oil with
balanced equivalent amounts of both linoleic and alpha
linolenic acids in approximate proportion to their essential
requirements.
One teaspoon of corn oil, grapeseed, sunflower, or cottonseed oil
provides the same amount or more of linoleic acid, since all contain
>50% linoleic acid. However, these oils lack the
alpha-linolenic acid. Alpha-linolenic acid can be
obtained from a teaspoon of linseed oil, rapeseed oil, or canola oil,
containing 2.4, 0.5, and 0.5 g of alpha-linolenic acid,
respectively. Alternatively, instead of alpha-linolenic acid,
fish consumption or fish oil could be used as sources of EPA and DHA
instead of oils containing alpha-linolenic acid from which the
body synthesizes these compounds.
In the study by Siscovick et al,17 quoted by Dr Siguel,
one fish meal per week consisting of 5.5 g of N-3 fatty acids per
month was associated with a 50% decrease in risk of primary cardiac
arrest in patients without known heart disease after adjustment for
confounding other risk factors. This level of intake is the equivalent
of only 0.2 g of fish oil per day, not the "high intakes" of
PUFA that Dr Siguel recommends in his 1996 study8 and
implies in his letter. Although the Siscovick study17 has
limitations, it suggests that very small amounts of fatty acids may be
beneficial.
To keep this discussion with Dr Siguel in perspective, it is important
to emphasize that low-fat or very-low-fat food, with adequate essential
fatty acids, protein, and other nutrients and
cholesterol-lowering drugs have been documented to
stabilize or partially reverse coronary and cerebrovascular
atherosclerosis with a profound decrease in cardiac and
cerebrovascular events. Inadequate lowering of dietary fat or serum
cholesterol in the management of patients with
coronary artery disease because of extended, unvalidated
hypotheses about potential essential fatty acid deficiency could be
detrimental to optimal patient management.
References
1.
Gould KL, Martucci JP, Goldberg DI, Hess MJ, Edens RP,
Latifi R, Dudrick SJ. Short-term cholesterol lowering
decreases size and severity of perfusion abnormalities by positron
emission tomography after dipyridamole in patients with
coronary artery disease: a potential noninvasive marker of
healing coronary endothelium.
Circulation. 1994;89:1530–1538.
2.
Subcommittee on the 10th Edition of the RDAs, Food and
Nutrition Board Commission on Life Sciences National Research Council.
Recommended Dietary Allowances. 10th ed. Washington, DC:
National Academy Press; 1989.
3.
Sanders T. Essential fatty acids. In: Macrae R, Robinson RK,
Sadler MJ, eds. Encyclopaedia of Food Science, Food Technology,
and Nutrition. Academic Press; 1993:1651–1654.
4.
Bender DA, Bender AE. Nutrition. A Reference
Handbook. Oxford University Press; 1997:131–133.
5.
Siguel EN, Maclure M. Relative activity of unsaturated fatty
acid metabolic pathways in human.
Metabolism. 1987;36:664–669.
6.
Siguel EN, Chee KM, Gong J, Schaefer EJ. Criteria for
essential fatty acid deficiency in plasma as assessed by capillary
column gas-liquid chromatography. Clin Chem. 1987;33:1869–1873.
7.
Siguel EN, Lerman RH. Altered fatty acid
metabolism in patients with angiographically documented
coronary artery disease. Metabolism. 1994;43:982–993.
8.
Siguel E. A new relationship between total/high
density lipoprotein cholesterol and polyunsaturated fatty
acids. Lipids. 1996;31:S-51–S-56.
9.
Sacks FM. More chewing on the fat. N Engl J
Med. 1991;325:1740–1741.[Medline]
[Order article via Infotrieve]
10.
Mensink RP, Katan MB. Effect of dietary fatty acids on serum
lipids and lipoproteins. Arterioscler Thromb. 1992;12:911–919.[Abstract/Free Full Text]
11.
Dupont J. Vegetable oils. In: Macrae R, Robinson RK, Sadler
MJ, eds. Encyclopaedia of Food Science, Food Technology and
Nutrition. Academic Press; 1993:4711–4713.
12.
Snyder HE. Soya beans. In: Macrae R, Robinson RK, Sadler MJ,
eds. Encyclopaedia of Food Science, Food Technology and
Nutrition. Academic Press; 1993:4215–4218.
13.
Hammond EG, Johnson LA, Murphy PA. Soya beans: properties and
analysis. In: Macrae R, Robinson RK, Sadler MJ, eds.
Encyclopaedia of Food Science, Food Technology and
Nutrition. Academic Press; 1993:4223–4225.
14.
Prasad RBN. Walnuts and pecans. In: Macrae R, Robinson RK,
Sadler MJ, eds. Encyclopaedia of Food Science, Food Technology
and Nutrition. Academic Press; 1993:4828–4834.
15.
Szuhaj BF. Phospholipids. In: Macrae R, Robinson RK, Sadler
MJ, eds. Encyclopaedia of Food Science, Food Technology and
Nutrition. Academic Press; 1993:3553–3558.
16.
Gould KL. Letter to the editor. JAMA. 1996;275:1402–1403.
17.
Siscovick DS, Raghunathan TE, King I, Weinmann S, Wicklund KG,
Albright J, Bovbjerg V, Arbogast P, Smith H, Kushi LH, Cobb LA, Copass
MK, Psaty BM, Lemaitre R, Retzlaff B, Childs M, Knopp RH. Dietary
intake and cell membrane levels of long-chain n-3 polyunsaturated fatty
acids and the risk of primary cardiac arrest. JAMA. 1995;274:1363–1367.
