of partial

and trans

of trans fatty acids13
Walter C Willett




are formed

during Concern

the process




verted that are

to margarine this process fatty

and may are

vegetable adverse destroyed to saturated

shortening. consequences and fats, acid. concentrations

has existed
natural isomers meta5 y a Seenzymatic

contain bacterial isomerases capable of converting the double bonds of polyunsaturated fats in plants to a trans configuration. At the turn of the century a dramatic change in the fatty acid
composition of the food supply of industrialized countries


because artificial the


acids similar
of the


new lack




of linoleic


linolenic plasma

In the


occurred when a process was into solid or semisolid fats (I). hydrogenation, oils are heated metal catalysts and exposed
causes some double bonds to

discovered to convert liquid oils In this process, known as partial in the presence of nickel or other to hydrogen gas. This process
be saturated while others are

of metabolic
fatty acids


has provided


of low-densityof high-densitynatural fat. ratio


lipoprotein lipoprotein

changed shifted
In of isomerism). cally these

to a trans to a new
The fatty contain artificial > 20

configuration (geometric position in the aliphatic
end products new acids isomers may make of partial of oleic

isomerism) or are chain (positional
hydrogenation and linoleic or more typiacids; of the

Downloaded from by on April 12, 2010

(HDL) studies,

cholesterol trans fatty

relative acids

to the parent increased



the plasma

compared with saturated fats. On the basis of these metabolic effects and the known relation of blood lipid concentrations to risk of coronary artery disease, we
estimate United conservatively States are attributable although that 30 000 premature of deaths/y trans on their fatty own, in the to consumption not conclusive acids. are

total to HDL




up to 40%



total fat (2). Altering the conditions of partial hydrogenation allows the creation of different fats that are used in the manufacture of margarine, fats for deep frying, or shortenings for baking. During the course of this century, the production of partially
hydrogenated vegetable oils increased steadily because of their

consistent Because

with there



of this

magnitude benefits

or even of trans


are no known

their consumption

and clear
policy information consumers.

dictate on the

that trans

acid content

of foods

fatty acids prudent public
and that

be minimized

low cost, By about vegetable
Various replaced


be available 1006S-1OS.


long shelf life, and suitability for commercial frying. 1910, the per capita production of margarine and shortening in the United States was already > 4 kg/y. forms of partially hydrogenated vegetable oils have
beef tallow, butter, and lard in homes economic Despite and in many and perceived the continuing


J Clin trans



KEY artery







commercial applications, largely for (but undocumented) health benefits.


Naturally occurring unsaturated fats contain double bonds

that are nearly all in the cis configuration, and these occur most commonly in certain positions in the aliphatic chain. Enzymes involved in fatty acids synthesis have evolved to recognize these natural fatty acids with a high degree of specificity.
Changes in the fatty acid composition of the diet can have

displacement of animal fats by partially hydrogenated fats in the United States, per capita consumption of trans fatty acids from vegetable sources declined slightly from a peak of ‘‘2.2% of energy in the l960s to ‘‘2. 1% in the mid-l980s. This resulted largely from a reduction in the degree of hydrogenation to retain more of the original polyunsaturated fats. Thus, polyunsaturated fat increased greatly over this period. Data on consumption of trans fatty acids in other countries are sparse. In the United Kingdom, consumption was ‘‘6% of total fat
(‘2.3% of energy) in the l980s, and similar values have been

reported from Sweden and Germany (3). Consumption fatty acids has increased in the Indian subcontinent,

of trans where

major effects on several critical physiologic processes because the number and position of double bonds influence the function and metabolism of fatty acids, including their incorporation into phospholipids and their transformation into prostaglandins and other eicosanoids. Through human evolution, oleic acid,
linoleic acid, supply. linolenic The only acid, and the long-chain sources of n-3 trans fatty acids

From the Departments
of Public Health, Medical of Health. reprint School requests the School Harvard

of Nutrition
Channing and by research to Health. WC 665 Brigham

and Epidemiology,
Department Women’s CA and grant

Harvard of from the of Hospital,

School Medicine, Boston. National Nutrition, MA



in part




fish oils constituted dairy fat and the


all of the unsaturated of ruminants,
Am J C/in

fat in the

Willett, Huntington

Harvard 02115.

of Public



were I0065





in USA.

© 1997



for Clinical


2010 concentrations conducted acids at lipoprotein lipoprotein relative in Holland 10% of energy (LDL) (HDL) to the natural oil. difference Direct tions in CAD associations concentra- In another metabolic in the above summary.001. trans low-densityhigh-densityfor oleic The concentrations this is highly by and mainly reducing with saturated because trans cholesterol. Change from unsaturated = in the ratio trans P < to HDL and 3 isomers the and of of oleic desaturated adverse acid.029. evidence fatty new that acids the metabolic partial that adversely studies hydrogenation affect have provided of vegetalipid trial fatty A common terol ever. fatty a longiacids in two investigation. When the were effects colleagues.03). but be of in the of energy saturated Downloaded from www.028. Katan Intake (%) cholesterol 0. 9). containing Similar have fats on 7. was about twice that of saturated fats. trans by 6% to a 12% trans fat reduces blood choles- plasma a rigorous (7). factors that This limita- tion tudinal women was addressed study in the of highest in the Nurses’ 90 000 US quintile of Health women. indicate the need for further research (2). and from P < Mensink reference by percent0. in the others (8. intake of trans fatty plasma concentrations of lipoprotein(a). (7).ans partially and relying dependent hydrogenated ghee the on on consumption subsistence a commercial of developing vegetable (clarified these oils butter). Also. assessed food sample. 6). 0. but did (7). worse of total adverse effect of trans fatty acids was that of saturated fat (7-9) as assessed cholesterol. cluded the individual studies in which (16). A comprehensive evidence in 1985 did not trans fat.0001. fatty and acids 3% on (9) LDL the average in trials of of energy and as HDL of cis and trans isomers similar to that of commercially able margarine. with elongated metabolism compounds to eicosanoids saturated fat. acids blood the being lipid in each percentage dose-response nearly concentrations of these the than of twice energy relation. In contrast. not inat 7% of energy markedly oleic adverse increased tative acid increased and LDL and fat reduced In HDL addition relative to having to both clear acids puof of trans isomers in adipose tissue and risk of death from myocardial infarction ( 18) and between plasma concentrations of trans fatty acids and the presence of atherosclerosis (19). significant adverse LDL. Katan 11. marily assertion is that compared misleading HDL effect. L ‘ .02). analysis average of replicate intake of trans fatty acids. intake Study In that of trans (20). with of saturated 1 are the slope fats shown there for (the in these The prediction. fatty cholesterol cholesterolemia saturated reported in men with mild hyperthe effect of trans fatty acids and of total to HDL cholesterol are EPIDEMIOLOGIC STUDIES plotted appears trans absolute Table against fatty 1). Intake rise in CAD of partially hydrogenated mortality in the United fats has paralleled the States and other countries Moreover. and have lack existed the inhibit and of the report effects decades adverse that trans they fatty are acids structurally activity desaturation may of FIGURE age with Data of energy natural are from < effects because essential the to saturated metabolic enzymatic Percentage of energy of total () trans and Figure fat. in HDL cholesterol. 0. . elaidic acid (9t-l8:l. partially ease has hydrogenated been based supported on the metabolic fats by increases several the studies. was strongly associated ratio to HDL effects summawere of fatty acids separately. adverse cholesto HDL Although it seems likely that the effects on blood cholesterol there are no In two of a mixture availthe trans cholesterol of trans compared oleic of total fractions are not the same data on the relative potency the above experiments (7.059. For fat at compared reduction example. fatty fat = acids (for saturated = fat (#{149}) compared in slopes. 10). Howfat does so pricannot study reduced fat. = on LDL and HDL cholesterol as in Figure 1 .t. In the unequivocal ble oil past creates decade.39 = mmol 0. More detailed investigations that allow for the control of individual risk factors are desirable because many other variables besides dietary fat composition (for 0. have may been account reported for at least between some of the P ‘. parent to the of linoleic interfere may be and linolenic cis acid (4). 0. effects on HDL cholesterol. the (8).ajcn. 0. Much less attention linoleic parent issued of has been which of also and unusual 1. for HDL. of been When ratio trans intakes well above were later confirmed 6% (9). In by Mensink and Katan in the when diet and increased decreased substituted cholesterol which construed Mensink total serum was this as a desirable Katan due cholesterol cholesterol acid. compounds. risk that intake investiga- to be a linear of coronary of dis- epidemiologic tions. -0.015.050. for both CI . structure find clear (5. P and for 0. In the may saturated (13). at trans fatty acid in most populations.012 = L’ % of energy 95% study trans -0. 10. 14). however. -0. trans isomer of oleic acid) contributed most of the total acids. adapted Judd et al (9). that for Figure contributed.7% effects also (10). f3 0. above affect by on April 12. FATTY (vanaspathi) It is likely are being populations ACIDS are AND replacing CORONARY ARTERY DISEASE 1 007S the traditional throughout that production widely move from 0 increasing urban societies C C U 0 METABOLIC For have similar the paid EFFECTS concerns physiologic fats. of individual compounds. among the seven countries studied by Keys and his by with compared. * p ** 0. another risk factor for coronary artery disease (CAD). These results.005. test for differences Zock (8). fats were significantly by trans rized seen 95% mmol 0. conducted fatty acids in Asia. products world agriculture food as to supply. three randomized trials (10. j3 = regional incidence of CAD (17). 10% with fat ( 1 5). HDL effect saturated when fatty fats acids increased on the ratio LDL with but did not decrease acid. the trans diet contained terol obtained intake diets trans. CI = .009. the risk of CAD were not other dietary considered. for all the trans isomers. .001. % of energy 3 = differ P among countries and incidence.

In a report from the Framingham Heart Study (24). The study of Roberts et al (23). indicating that the association was not simply the result of healthier behavior by women association with a perceived between intake higher risk of CAD.52 4. we calculated that ‘‘7% of CAD deaths were attributable to trans fatty acid consumption.42 1. as well as a higher intake of margarine.98 1.96 4.30 5. We have also estimated the number of deaths due only to the effects of trans fatty acids on LDL cholesterol with the use of a summary of the metabolic studies shown in Figure 1 to estimate the change in LDL corresponding to 2% of energy from trans fatty acids. this was almost identical Study. saturated fatty acid.38 1. 2. from partially hydrogenated intake 3. Inasmuch as Spain also has very low CAD rates. unsaturated 2 Calculated as mean total cholesterol/mean 3 4 fatty acid. Unsaturated fat was cis polyunsaturated.47 1.47 1. and assumed .1008S TABLE Concentrations ASCHERIO 1 of serum total and HDL cholesterol and ratio of total AND WILLETF to HDL cholesterol with isoenergetic intakes of saturated.47 3. which is compatible with the suggestion that trans fatty acids may have other adverse physiologic effects perhaps mediated by lipoprotein(a) or a prothrombotic mechanism.82 3.74 4.14 Lichtenstein 3.25 1. in other studies.02 - Total-t Unsat Sat o-HDL trans cholesterol2 Unsat Percent of energy % 3. consumption of margarine was significantly associated with risk of future CAD. based on adipose fatty acid analysis of only 66 cases of sudden death and matched control subjects.84) easily included the relative risks seen in the Nurses’ Health Study. Two recent studies have been published that were interpreted by some as refuting an association between intake of trans fatty acids and risk of CAD (22. and trans fatty acids’ Total cholesterol trans Unsat Sat HDL cholesterol trans mmo/IL 5.7 4.44 (95% CI: 9. The positive association was limited to trans fatty acids from partially hydrogenated vegetable fat. 2010 consumption suggesting of margarine association during with the past 10 y were of preclinical intake excluded. Although not quite statistically significant.46 1. the relation between plasma total to HDL cholesterol and CAD risk is based on only one blood sample per subject. to a switch to margarine nary by women Also. indeed. after standard cardiovascular risk factors were adjusted for.46 5.41 1. unsaturated. this is certainly compatible with a causal relation.20) in the highest versus the lowest quartile of trans fat. saturated fat was a mixture cis monounsaturated.77 6.58 3.09 1. the adjusted relative risk of CAD was 1. 1. neither diabetes nor hypertension was significantly associated with outcome.00 3. In the EURAMIC study.18. which would lead no reasonable person to conclude that they were not causes of coronary disease. vitamins.3% disease than women in the lowest of total energy).04 4. In both studies the risk was quantitatively higher than predicted by the effect of trans fatty acids on blood LDL and HDL concentrations.90 4.26 5.89 5.26 4. the combined evidence from metabolic and epidemiologic studies strongly supports a causal interpretation. Saturated fat was stearic acid.90 4.98 1. a suspicion association coroof trans disease.47 seen these for the Nurses’ findings Health concluded.36 3.83) and 18:2 trans (0.2% of total = vegetable energy) had fats at baseline a 35% higher quintile (median risk of (median coronary 1 . The association remained significant after further adjustment for intake of other types of fat.78 3.ajcn. the dose-response findings suggested a possible J-shaped relation.70 3. and fiber.0 Sat mmoL/L - Judd Nestel et a! (9) et a! (l2) et al (10) 5.0 5.52 Judd et a! (9) Zock and Katan Mensink and 6. which is probably low.67 3.00 5.7 10.92 by on April 12.85. reasons: All they of these are only conservative 2% estimates for of energy from trans fatty acids for the population average. By this method. HDL cholesterol otherwise saturated because fat was not all studies primarily reported mean total-to-HDL cholesterol ratio.2 5. This estimation was based only on the effect of trans fatty acids on blood concentrations of total and HDL cholesterol from metabolic studies and on the relation of the blood total-to-HDL cholesterol ratio to risk of CAD repeatedly documented in many studies.84 5.42 1.56 5. the positive the possibility that trans fatty acids have a significant effect on risk of CAD. to the relative As the authors risk of 1. do not exclude Downloaded from www.1 1 0. which will substantially underestimate the magnitude of association.14 0.42 5. a case-control study of nonfatal myocardial infarction that also sampled adipose tissue for fatty acid analysis. This gives an estimate of 1 6 000 deaths several annually. of trans fatty acids A positive and risk of ESTIMATION FATTY ACIDS OF DEATHS ATTRIBUTABLE TO trans myocardial infarction was also observed in a case-control study among men and women (21).37 1.40 5. cholesterol. fatty acids was due to high consumption of cookies and white bread. We have elsewhere estimated that current intake of partially hydrogenated fats may account for > 30 000 deaths from CAD per year in the United States (25).61 4. although use of butter was not. the Spanish centers had by far the lowest concentra- Although possible confounding explanation of the by unmeasured of the factors epidemiologic remains inves- a results tigations.94. was simply too small to be informative.22 3. 23).0 (8) (7) 7.42 - 3. Unsat. the data tend to support such a relation. but a formal statistical test indicated that the data did not depart significantly from linearity. In this small study. The association was that stronger the when women was not who due had simply with changed their tions of trans fatty acids (22). of saturated fats considered to be cholesterolemic. 2. When the outlying Spanish data were appropriately excluded.72 Katan ‘ Sat. multiplying this by the “500 000 CAD deaths that occur annually in the United States yields > 30 000 deaths.40 1. This can be appreciated by the fact that the 95% CIs for the relative risks in highest quintiles of both 18: 1 trans (0.

8c. which do not require manufacturers to reveal the trans content of their products and allow labeling of products as “low in saturated fatty replace products acid fat” saturated with these and “low This fats labels acids in cholesterol” policy with are. FDA of choosing low in saturated fat. Am acid J Clin for oleic Nutr acid 1994. health-conscious consumers products saturated vegetable these synthetic substances to the food supply.” acids. change ( 15). 1 1 C. essential Nutr the CSJ. Experimental biochemistry oils. Mai by JE.ajcn. the saturated fat content of ratio content of total of were to HDL margarines ratio similar choleswas and to butter. 6. In the United States. isomers FR. from ignore concon10. Annu of trans Rev MD: 1988. Podczasy JJ. Weber J Nutr of fatty 105:393-400. which include most fried fast of potato and tortilla chips.34:2517-20. with fatty choices. M. J Lipid P. provides partially in fact.4:339-76. I994. and at the fats and commercial products baked fats. cookies. 9. “cooked reduce acids. on the effects fatty 1981:34:2307-18. amount foods and contents of Downloaded from www. for Nutrition Health and aspects. fatty acid by consumption. are and no known to be nutritional fats appears well-documented no justification met- Without content particularly trans This greater availability mislead oil. other bakery items. of zrans. Belling of elaidic B. strongly margarines However.29:707-l4. Muesing RA. Dietary trans fatty acids: effects of plasma lipids and lipoproteins of healthy Nestel with men and women. Clevidence BA. 5. However. Plasma lipoprotein may be with a diet source g/d in the United Kingdom for mdiin fat. unhydrogenated table and avoiding animal or fried in hydrogenated by on April 12. with hydrogenated fish oils as A working group of WHOIFAO re- 1992. Fullmer amounts of trans fatty the effects of various Zock and Katan (29) margarines was unrelated In a meta-analysis margarines found that to the trans trans and butter on blood lipids. Akesson analyzed 4. (28). partially abolic representatives by randomized unfeasible Because hydrogenated effects. Kinsella acids with Am B. composition.59:861-8. that high 30). Emken acid 2. of Pelletier and other prostaglandins: Effects acid D. acid on WMN. Ockerman and normal technique. consumers which trans would fatty acids brands and form for frying. estimated Independent 8% of premature of our CAD calculation. in humans. that much trials other including on lipoprotein(a) undesirable Although the major European the greatly or or Grundy thrombotic (26) tendency. 2010 for fast minor reductions cesses the changes in trans be that and other products that are presently We thank with very high trans exempt from labeling for helpful requirements.trans FATtY possible effects ACIDS adverse AND effects of CORONARY viewed high ARTERY the health intakes of DISEASE effects trans of trans fatty acids fatty are 1009S acids and concluded and that their we have partially not taken hydrogenated into account fats. American no. regardless a strong hydrogenated those with the of their incentive fats. (on effects a per-unit on the basis) ratio than of total saturated fat. even moderate of foods rich in trans fatty acids may increase of energy. maintaining that a decrease in fat intake will also cause a decrease in saturated and trans fats consumption (12). of 27 high (31). Metabolism and El.) 3.33:399-4l0. Wittes J. From the changes that rates for CAD would were made by ‘25 in the 000/y. 8. Mensink high-density subjects. J Lipid l992. B-M. Sunkin ME. Ratnayake acids 7. Nuts Federation (Contract and positional of fatty cholesterol in metabolic studies. I 5t-eicosatetraenoic rats RPM. in vegetarian EA. Chen fed Katan J Med MB. reduce acid be 35% If such changes premature deaths (33). deaths in the fatty Oil consumption industry has rime effects and of oil should resisted trans fat be reduced (32). a substantial amounts of a reduction proportion fatty in 10% consumption of acids. and N Engl Katan stearic partially MB. Anderson linoleic 1975. comparing highest trans to and content.trans-octadecadienoate lipid view. and in Hollenbach metabolism linoleic G. and Lp[al changes Res in the diet. the have have and eliminated US food margaadverse reduced United acids. changing Also. Svensson portion J. and that causation surely can only be unethical never benefits adverse for adding be be of amounts in margarines alone. in vegetable fatty can specifically Prudent advice PUBLIC OF trans HEALTH FATTY APPROACH ACIDS TO REDUCING INTAKE the amount achieved in their Some have argued that dietary advice should still focus on lowering intake of total fat.33: 1029-36. Clin Nutr fatty on an overisomers rats. At present. United in margarine be reduced by this would fatty to and up to aim trans oils to fatty logistically States. the For of energy data population example. manufacturers acknowledged industry proven and conducted. Bethesda. crackers. reducing total fat intake is not likely to be the most effective way to reduce trans fatty acids consumption. of trans emphasis J Clin RL. fat intake has can and possibility During declined the past decade in the United States. This paradox is already a consequence of food labeling regulations in the United States and Canada. trans low-density 1990. acid terol. from 38% to 34% of energy. unusual polyunsaturated the total-to-HDL content cholesterol hydrogenated Effect lipoprotein of dietary cholesterol alternatives: acid on serum These described data provide in Figure consumption consumption independent confirmation of the relations 1 . N specific Meir Stampfer comments. Judd JT. baking. It is difficult to argue that should require and not that be that allowed food special to make labels labels indicate be created fatty acid informed the choices. be by of information claims as those of dietary of both by using “low on the trans are likely fat” contain should and saturated may of foods. canola trans of trans in Am P-A. Shimp acid. there there have argued (27). Johansson acid the Bruckner duplicate G. may individuals see their fatty of trans who efforts acids desire to reduce by their an blood foods cholesterol consumption hampered as a result increased in hydrogenated l984. . Occurrence oil. Biology. associated with the with high ZY. as suggested by the REFERENCES 1 . donuts. fat fat 5c. Finally. acids to HDL this may Much manufacturing contention have a worse achieved food trans total only greater proignores effect natural. 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