Fatty Acid Metabolism in Health and Disease
Essential Fats (EFs), Secrets to Living Long and Well

Key Definitions

Recent research indicates that the prevalence of Essential Fatty Acid (EFA) abnormalities is far greater than suspected.

The U.S. Surgeon General's Report on Nutrition and Health identified the type of fat that people eat as one of the most significant factors in health and disease. Insufficient intake of EFAs has been proposed as a cause of atherosclerotic disease and thrombosis. Using modern gas-liquid chromatography, abnormal levels of EFAs have been associated with chronic conditions such as diabetes, coronary artery disease (CAD), and hypertension.

EFAs are of special importance in nutrition because humans cannot synthesize them. Thus, they must be obtained from the diet in a manner similar to vitamins, but in far greater quantities. Fatty acid analysis is needed to diagnose EFA abnormalities and to plan an optimal diet, because it is impossible to predict the cumulative effects (on EFA levels) of diet, food processing, oxidation, utilization and exercise.

Fatty acid analysis is cost effective because it identifies both the problem and the means to correct it. Optimal nutritional treatment is cheaper and often more effective than lifetime treatment with drugs.

Genetic traits, addictive behaviors such as smoking, and entrenched cultural preferences such as physical inactivity are difficult to change. In contrast, modifications to the balance of EFAs can be accomplished by supplementing the diet with oil or oil capsules.

Description and Names

Fatty acids are named according to chain length, number of double bonds, and characteristic end methyl carbon known as the "w" or "omega" or "n-" carbon.

Saturated fatty acids have no double bonds; 16:0 (palmitic, 16 carbons) and 18:0 (stearic, 18 carbons) are the most abundant in blood and tissues. Monounsaturated fatty acids have one double bond; polyunsaturated (PUFA) have 2 or more double bonds. The monounsaturated family w9 derives from oleic (18:1w9, the most abundant), and the w7 derives from palmitoleic (18:1w7). Excess calories from carbohydrates and protein are stored by the body as saturated or monounsaturated fatty acids.

The major PUFA families are the w6, derived from linoleic (18:2w6), and the w3, derived from linolenic (18:3w3). Linoleic and linolenic are EFAs because humans must obtain them from the diet. The w6 derivatives of linoleic are abbreviated as DFA6 (i.e., 20:4w6, arachidonic acid), and the w3 derivatives of linolenic as DFA3 (i.e., eicosapentaenoic, EPA, 20:5w3, docosahexaenoic, DHA, 22:6w3). The most abundant PUFAs are linoleic, arachidonic, and DHA.

Biochemical characteristics

The 4 precursor fatty acids are linolenic (w3), linoleic (w6), oleic (w9), and palmitoleic (w7), abbreviated PFAi (i=3,6,9,7, for the w3, w6, w9 and w7).

Their elongation and desaturation products are referred to as derivatives, abbreviated DFAi (i=3,6,9,7).

Fatty acids undergo desaturation and elongation in the body using enzymes apparently shared among fatty acid families.

The affinity for these enzymes follows this order: w3 > w6 > w9 > w7.

enzymes/cofactors
PFAi ---------------------------> DFAi
Precursor Derivatives
i = 3, 6, 7, 9 are the w3, w6, w7, w9 families of fatty acids.

 PUFA family members are not interchangeable; members of one family (w6 or w3) cannot be made from the other family.

 Monounsaturated can be made from saturated fatty acids.

 Grouping the fatty acids into precursors and derivatives helps to diagnose abnormal conditions and treat them with either precursors (such as vegetable oil) or derivatives (such as fish oil).

Relative excesses or deficiencies of one fatty acid alter the metabolism of the others. This property constitutes the basis for treatment of diseases where one wants to avoid accumulation of specific fatty acids. Humans have the elongation and desaturation enzymes required to make derivatives from precursors. However, some individuals have decreased enzyme activity or increased need for EFA derivatives either due to age, disease or a deficiency of vitamins or minerals that act as cofactors. The fatty acid profile EFA Status Report (EFA-SRÔ ) can identify deficient elongation or desaturation (to prescribe a diet with derivatives).

Natural unsaturated fatty acids are cis (hydrogen molecules on same side of molecule); processes such as hydrogenation and cooking transform some molecules to the trans form and other isomers. Trans fatty acids have hydrogens on opposite sides and resemble a straight saturated molecule. They have no known desirable function and may interfere with cis fatty acid metabolism. Trans fatty acids increase the risk of CAD.

Functions

Fatty acids are critical participants in all cell functions and body systems. PUFA have at least three main functions: (1) they regulate membrane fluidity and membrane function; (2) they are precursors to eicosanoids (prostanglandins, thromboxanes and leukotrienes, relative eicosanoid production depends on EFA metabolism); and (3) they may have enzyme-like activities or be cofactors in enzymes. The availability of EFAs may be the limiting factor in lipid synthesis because glucose, amino acids and other nutrients are rarely deficient in the American diet.

Fatty acids are absorbed through the small intestine and are stored in adipose tissue as saturated, monounsaturated and EFAs (rarely as EFA derivatives). Fatty acids are oxidized for energy or metabolized to other compounds. They are protected from oxidation by vitamins E, C, selenium and other vitamins or minerals. Changes in fatty acid metabolism can dramatically impair body function. Platelet aggregation decreases and bleeding time increases in proportion to the w3/w6 ratio (specifically, 20:5w3/20:4w6).

Fatty Acid Abnormalities

Requirements for EFAs are increased in processes characterized by increased cell turnover (burns, pregnancy, GI disease, inflammation). EFA abnormalities may be caused by genetic disorders, or by deficiencies or excesses of dietary fatty acids. Severe EFA deficiency (EFAD), found mostly in animals fed EFAD diets, causes dermatitis, hair loss, and abnormal cell histology.

EFA insufficiency (EFAI) is characterized by an abnormal fatty acid profile EFA-SRÔ without the clinical signs noted in experimental animals made severely EFAD. EFAI may lead to abnormal eye and neurological function, hyperlipidemia, hypertension, abnormal eicosanoid activity, reduced cell survival, impaired wound healing and cell growth, and is a significant factor in cardiovascular disease and complications caused by diabetes. EFAI is diagnosed by low PUFA or high levels of markers of EFAD.

Low absolute (whole body) levels of the EFAs produce Absolute EFAD or Absolute EFAI, depending on the severity of the abnormality. Absolute deficiencies are seen in gastrointestinal disease with fat malabsorption, anorexia nervosa, bulimia, diets very low in PUFAs, and may also be found in newborns and premature infants.

Relative EFAI is characterized by normal to high plasma levels of EFAs, elevated markers of EFAD (see below), and high levels of plasma saturated or monounsaturated fatty acids. Usually, adipose tissue levels of EFAs are adequate. This pattern is found in cardiovascular disease, hypertension, and hyperlipidemia.

Relative vs. Absolute abnormalities are diagnosed using a plot of lipid or fatty acid concentration (Y-axis) vs. EFA or PUFA % (X-axis).

EFA Abnormalities

The fatty acid profile EFA-SRÔ characterizes deficiencies, metabolic blocks or abnormalities. It quantifies major saturated, w3, w6, w7 and w9, trans and odd fatty acids. Decreased plasma EFAs cause shifts in fatty acid metabolism leading to increased ratios of Derivatives/ Precursors (DFAi/PFAi) and increased w7 and w9 monounsaturated fatty acids. The trienoic/tetraenoic or 20:3w9/20:4w6 (Mead/Arachidonic acid), or "T/T" ratio, increases, and values above 0.02 are indicative of insufficient EFA levels. To diagnose abnormalities, one must concurrently compare the values of several fatty acids and ratios as described in US Patent No. 5075101.

Sequential measurements are needed to evaluate intravenous lipid requirements, nutritional needs, deficiencies, imbalances, and the ability of individuals to absorb EFAs and convert them to active derivatives (pathway activity).

Several metabolic disorders cause the appearance of specific fatty acids that serve as markers of such disorders. Nervous system injury may alter plasma levels of w3 fatty acids and very long chain fatty acids, found in abundance in neurological tissue.

Analytical methods

Lipids extracted from samples are hydrolyzed. The fatty acids are converted to fatty acid methyl esters (FAME) and separated with high resolution Capillary Gas Liquid Chromatography using long columns (preferably 100 m). Peaks are identified by comparison with known standards. Using computers, we calculate peak areas, ratios, concentrations, and percentages of individual compounds and groups of selected compounds. Each peak is individually reviewed on a monitor to verify that it is properly integrated and identified. Our patented methods are used to analyze fatty acids in the Framingham Heart Study1; NIH reviewers described them as "state-of-the-art GLC methodology".

Adipose tissue aspiration, similar to a SQ injection, provides almost painless fat cell samples useful to estimate total body fatty acid stores that reflect long-term (months to years) dietary intake.

The optimal mixture of w3 and w6 fatty acids may be established using the plasma fatty acid profile EFA-SRÔ.

Treatment & management

In general, the diet that works best for prevention or treatment of cardiovascular disease may also help to prevent other diseases, including cancer. The treatment diet is designed to correct deficiencies identified by the fatty acid profile EFA-SRÔ using foods and oil supplements. Increased dietary intake of PUFAs (eg, oil or oil extracts) should be accompanied by increased amounts of antioxidants such as Vitamin E and Se to match body requirements.

A low fat diet, if deficient in EFAs, may increase the risk of cardiovascular disease.

Diets should specify PUFA content as percent of calories and in absolute terms, as grams of PUFA/kg of body weight. Many diets describe EFA content as PUFA/Saturated Fat (P/S ratio) without distinguishing EFA from EFA derivatives, or w3 from w6 fatty acids. The P/S ratio is misleading because a high P/S ratio can be achieved with a diet low in both PUFA and saturated fat but high in monounsaturates, carbohydrates and/or proteins. Because excess calories are stored by the body as saturated or monounsaturated fatty acids, the relevant factors are total EFAs and total calories.

Recommended Daily Allowances are not established for EFAs. Some researchers proposed 2% of calories as linoleic and 0.5%-1% as linolenic acid. Data on healthy humans suggest 5%-10% of calories as PUFA, with w6:w3 between 10:1 to 2:1. Public health groups recommend a diet with less than 30% of calories as fat, 10%-10%-10% as saturated-monounsaturated-PUFA. However, EFA requirements are better expressed as minimum daily requirements of 0.30 g/Kg body weight (approximately). For a 70 Kg person this represents about 21 gr. of PUFA per day, or about 2 tablespoons of soybean oil per day.

Optimal mixtures of EFA and EFA derivatives may improve medical conditions such as cardiovascular disease, hypertension, diabetes, & immuno-inflammatory processes.

Fish and vegetable oils which contain w3 and w6 fatty acids help to prevent cardiovascular disease, aid to lower cholesterol and triglycerides, and make blood less likely to form clots. They may normalize blood pressure and prevent the complications of diabetes mellitus, improve arthritis and poor blood circulation, and increase the effectiveness of the immune system.

The fatty acid profile EFA Status Report (EFA-SRä) aids in the prevention or treatment of:

 Cardiovascular disease, stroke, atherosclerosis; poor blood circulation (EFAs reduce while trans and saturated fatty acids increase the risk of CAD);

 Hyperlipidemia & hypertension;

 Complications of diabetes;

 Complications of pregnancy and pre-eclampsia due to EFAI;

 Inflammatory bowel disease; celiac disease; cystic fibrosis;

 Seborrheic dermatitis;

 Kidney disease (dialysis patients have EFA deficiencies);

 Deficiencies in children fed diets low in EFAs, particularly w3s (i.e., milk and formulas without EFAs) and infants (blood testing identifies need for IV lipids to correct EFAI);

 Malnutrition; wasting states; patients on elemental diets or parenteral alimentation;

 Measurements of EFAs in women contribute to better therapeutic intervention on lipid parameters to reduce atherogenic risk. Other conditions include neurologic dysfunction; arthritis, coagulation disorders; abnormal red cells; immune deficiencies, obesity. EFAI occurs when the body can not meet its demand for EFAs.

Membranes are high in EFAs. Linoleic acid is found in safflower, sunflower, and corn oil. Linolenic acid is found in linseed (flax) oil. Soybean, walnut and canola oil have mixtures of linoleic and linolenic acid. Derivatives of linolenic are found in fish oil; derivatives of linoleic are found in Evening Primrose Oil, Borage Oil, some uncommon vegetables, and animal organs.

Intake of PUFA above 15% of calories may be toxic for a person eating a high calorie diet, particularly without adequate amounts of antioxidants. Intake below 5% may contribute to hyperlipidemia, cardiovascular disease and other disorders.

Due to frequent use of processed foods low in EFAs (such as cereals, breads & pasta), most individuals have a dietary history of reduced intake of w6 and w3 and increased intake of saturated fat which can be characterized by the fatty acid profile EFA-SRÔ.

CASE REPORTS (composites)

Crohn's disease with EFAI.

45 y.o. female with Crohn's disease for over 10 years, partial intestinal resection. She has elevated 20:3w9/20:4w6, decreased levels of EFAs and derivatives. She had been taking oral supplements deficient in EFAs. Recommended treatment: oral soybean oil supplements (15-30 ml/day) plus 100 I.U. Vit E/day (plus Questran to minimize diarrhea). Repeat the fatty acid profile EFA-SRÔ to see if EFAs are absorbed. "Load" EFAs with intravenous lipids, and periodic intravenous supplement if needed to normalize EFAs. Repeat the fatty acid profile EFA-SRÔ after three months to determine whether EFA levels have increased significantly and whether derivatives were formed. Repeated analyses showed significant normalization of the fatty acid profile EFA-SRÔ. The w3s returned to normal but w6s were still deficient. Changed to 1/2 safflower, 1/2 soybean mixture to increase w6/w3 ratio. Monitor with periodic fatty acid profiles EFA-SRÔ. A normal fatty acid profile EFA-SRÔ may minimize complications and increase bowel healing.

Coronary Artery Disease with hyperlipidemia and high trans plasma levels: Relative EFAI

42 y.o. male with elevated cholesterol, angina, 15% overweight, elevated 20:3w9/20:4w6 and 16:1w7, increased trans, reduced w3/w6. Recommended weight reduction, avoid processed food, beef, hydrogenated oils. Take 10 ml/day soybean oil plus 100 I.U. Vit E/day. This plan aims to decrease TC/HDLC, lower total chol. and triglycerides, normalize platelet aggregation, and reduce the risk of a heart attack.

Patients who need lipid supplements because of chronic fat malabsorption require higher doses to correct absolute EFAD. Most commercial IV lipid solutions are made from soybean or safflower oil and contain only EFAs (very little derivatives). The optimal mixture of safflower (w6) vs soybean (mixture of w3 and w6) can be determined by fatty acid analyses.

Your physician may order a fatty acid profile EFA-SRÔ with an interpretative report to assist in the diagnosis of EFA abnormalities.

Warning/disclaimer. This is only a brief brochure. It is not intended to provide diagnosis or treatment advice. No representations, either express or implied, are made or given regarding the medical consequences of opinions herein presented. Please consult a physician and nutritionist who can interpret test results and provide the appropriate treatment for you in accordance with the entire clinical evaluation and other test results. Do not self-diagnose or treat.

Essential Fatty Acid Insufficiency... a risk factor
We have more than 10 years experience in its diagnosis.

References

  1. Based on recent analyses of Framingham Heart Study subjects (1994) done using methods herein described. Dr. Ralph T. Holman, Prof of Biochemistry, Member of the National Academy of Sciences, also believes that "EFA deficiencies are widespread" and has published numerous articles describing EFAD in patients with a wide range of diseases.
  2. U.S. Department of Health and Human Services, PHS publication No. 88-50210, 1988.
  3. Sinclair HM. EFAs in perspective. Hum Nutr: Clin Nutr 38C:245-260, 1984.
  4. Siguel EN, Maclure M. Relative enzyme activity of unsaturated fatty acid metabolic pathways in humans,Metabolism,1987;36:664-9.
  5. This approach was popularized in the movie "Lorenzo's oil", although the treatment described may lead to EFA abnormalities.
  6. Siguel EN, Lerman RH. Trans fatty acid patterns in patients with angiographically documented coronary artery disease. Am. J. Cardiology 1993; 71:916-920.
  7. Anderson PA, Sprecher HW. Omega-3 Fatty Acids in Nutrition and Health. Dietetic Currents, Vol 14-No.2, 1987.
  8. Rivers JPW, Frankel TL. Essential fatty acid deficiency. Br Med Bull 37(1):59-64, 1981.
  9. Siguel EN. Nutrient Charts: Essential Fatty Acids. Nutr. Support Services. 8:24, Sept, 1988.
  10. Siguel, et al. Criteria for EFA Deficiency in Plasma. Clin Chem 33:1869-1873, 1987.
  11. Siguel, EN. Method and Apparatus for Diagnosis of Fatty Acid or Lipid Abnormalities. U.S. Patent No. 5075101.
  12. London SJ Sacks FM, Caesar J, Stampfer MJ, Siguel, EN, Willett, WC. Fatty Acid Composition of Subcutaneous Adipose Tissue and Diet among Postmenopausal US Women. Am.J.Clin.Nutr 1991; 54:340-5.
  13. Schaefer EJ, Rees DG, Siguel EN. Nutrition, Lipoproteins, and Atherosclerosis. Clin Nutrition, 5:99-111, 1986.
  14. Siguel EN. Cancerostatic effect of vegetable diets. Nutrition & Cancer, 983;4:285-9.
  15. Meydani SN, Siguel EN, Shapiro AC, Blumberg JB. Fish consumption and mortality from coronary heart disease. New Engl J Medicine, 313:822, 1985.
  16. Warren SE, Siguel EN, Gervino E, Salzman, EW, Smith, M, Silverman, KJ, Pasternak, RC. Effects of cod liver oil on plasma lipids, eicosanoids, platelet aggregation, and exercise in stable angina pectoris. J. Applied Cardiology, 3(4):227-236, 1988.
  17. Siguel EN, Schaefer EJ. Aging and Nutritional Requirements of Essential Fatty Acids. In: Beare J, ed. Dietary Fats, Champaign, IL. Am. Oil Chemists Society, Chapter 13. (1989).
  18. Miettinen TA, et al. Fatty-acid composition of serum lipids predicts myocardial infarction. Brit Med J 1982, 285:993-6.
  19. Siguel EN, Lerman RH. Fatty acid patterns in patients with angiographically documented coronary artery disease. In Press, Metabolism, 8/94. Includes citations to other articles, a discussion on the role of different types of fat in CAD, and dietary treatment.
  20. Horrobin DF. EFAs and the complications of diabetes mellitus. Wiener Klinische Wochenschrift, 1989; 101:289-93.
  21. LePage G et al. Direct transesterification of plasma fatty acids for the diagnosis of EFA deficiency in cystic fibrosis. J. Lipid Research, 1989; 30:1483-1490.
  22. Dasgupta A, Kenny MA, Ahmad S. Abnormal fatty acid profile in chronic hemodialysis patients: possible deficiency of EFAs. Clinical Physiol & Biochem, 1990; 8:238-43 (role of EFA abnormalities in pathogenesis of clinical conditions associated with uremia).
  23. Abstracts at Am. Oil Chem. Society Annual Meeting, Journal INFORM, 4 (3/1993).
  24. Simmer EJL, Gibson RA. EFA deficiency in parenterally fed preterm infants. J. Paediatr Child Health, 1993; 29:51-55. Many infants have EFAI which require IV lipids.
  25. Darioli R, Mailie M, Jacotot. Valeurs standard des acides gras esterifies du serum chez la femme adulte en bonne sante. Ann.Nutr.Metab 1987;31:282-291 (role of EFAs in women, diagnosis of EFAD with plasma).
  26. Rossner S, Walldisu G, Bjorvell H. Fatty acid composition in serum lipids and adipose tissue in severe obesity before and after six weeks of weight loss. Int. J of Obesity 1989; 13:603-612 (obese patients have low EFAs).
  27. Siguel, EN et al. Monitoring the Optimal Infusion of Intravenous Lipids: Detection of Essential Fatty Acid Deficiency. Arch.Path. and Lab.Med. 110: 792-797, 1986.

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