Linoleic essential fatty acid deficiency

The essential fatty acids in humans are linoleic acid (C-18 2 N-6) and a-linolenic acid (C18 3 N-3). Arachidonic acid (C20 4 N-6) is also essential but can be synthesized from linoleic acid. Administration of 2% to 4% of total daily calories as linoleic acid should be adequate to prevent essential fatty acid deficiency in adults (e.g., infusion of 500 mL of 20% intravenous lipid emulsion once weekly).7 Biochemical evidence of essential fatty acid deficiency can develop in about 2 to 4 weeks in adult patients receiving lipid-free PN, and clinical manifestations generally appear after an additional... 

Essential fatty acid deficiency Deficiency of linoleic acid, linolenic acid, and/or arachidonic acid, characterized by hair loss, thinning of skin, and skin desquamation. Long-chain fatty acids include trienes (containing three double-bonds [e.g., 5,8,11-eicosatrienoic acid, or Mead acid trienoic acids) and tetraenes (containing four doublebonds [e.g., arachidonic acid]). Biochemical evidence of essential fatty acid deficiency includes a trieneitetraene ratio greater than 0.4 and low linoleic or arachidonic acid plasma concentrations. 

FIGURE 3-7 Pathways for the interconversion of brain fatty acids. Palmitic acid (16 0) is the main end product of brain fatty acid synthesis. It may then be elongated, desaturated, and/or P-oxidized to form different long chain fatty acids. The monoenes (18 1 A7, 18 1 A9, 24 1 A15) are the main unsaturated fatty acids formed de novo by A9 desaturation and chain elongation. As shown, the very long chain fatty acids are a-oxidized to form a-hydroxy and odd numbered fatty acids. The polyunsaturated fatty acids are formed mainly from exogenous dietary fatty acids, such as linoleic (18 2, n-6) and a-linoleic (18 2, n-3) acids by chain elongation and desaturation at A5 and A6, as shown. A A4 desaturase has also been proposed, but its existence has been questioned. Instead, it has been shown that unsaturation at the A4 position is effected by retroconversion i.e. A6 unsaturation in the endoplasmic reticulum, followed by one cycle of P-oxidation (-C2) in peroxisomes [11], This is illustrated in the biosynthesis of DHA (22 6, n-3) above. In severe essential fatty acid deficiency, the abnormal polyenes, such as 20 3, n-9 are also synthesized de novo to substitute for the normal polyunsaturated acids. 

Essential fatty acid deficiency is rare but can occur with prolonged lipid-free parenteral nutrition, very low fat enteral formulas, severe fat malabsorption, or severe malnutrition. The body can synthesize all fatty acids except for linoleic and linolenic acid, which should constitute approximately 2% to 4% of total calorie intake. 

Diets. Three basic diets were utilized (Table I), a 2% low fat diet (2% linoleic acid methyl esters), a 20% polyunsaturated fat diet containing 20% stripped corn oil, and a high saturated fat diet containing 18% coconut oil and 2% linoleic acid methyl esters to prevent an essential fatty acid deficiency (6 ). All diets were prepared to our specifications by ICN Life Sciences (Cleveland, OH) and analyzed both by ICN and our laboratory for fatty acids, antioxidants and some trace minerals. They are routinely stored in sealed plastic containers at 4°. Antioxidants when added (see Figure 2) were supplemented just prior to feeding and at 0.2% or 0.3% of the diet by weight as specified in each experiment. 

Linoleic acid normally is converted to arachidonic acid (a tetraene fatty acid). If linoleic acid is unavailable, oleic acid will be substituted, which results in production of eicosatrienoic acid (atriene fatty acid) as the metabolic end product. Therefore essential fatty acid deficiency can be detected on the basis of decreased tetraene production and increased triene production. Normally, the ratio of trienes to tetraenes is less than 0.4 when this ratio becomes greater than 0.4, the diagnosis of essential fatty acid deficiency is established. Analysis of plasma fatty acids, however, is expensive and not widely available. 

Requirements for PUFA cannot be met by de novo metabolic processes in mammalian tissues. Animals are absolutely dependent on plants (or insects) for providing double bonds in the A12 and A15 positions of the two major precursors of the n-6 and n-3 fatty acids, linoleic and a-linolenic acids (Fig. 5). These two fatty acids therefore are called essential fatty acids. Classical studies of essential fatty acid deficiency in rodents demonstrated that the main symptoms are dry skin, dermatitis, and massive water... 

Physiological Function of n-6 DPA Reported to Date. Not only is the occurrence of n-6 DPA rare in the biosphere it is also a minor fatty acid in mammals. Of the n-6 essential fatty acids (EFA) for primates or humans, linoleic acid (LA, 18 2n-6) and arachidonic acid (AA, 20 4n-6) are the most prominent and important. Among the docosapolyenoic acids (22-carbon chain), which can cross the blood-brain barrier more than the eicosapolyenoic acids (20-carbon), DHA (an n-3 EFA) is the most important. In mammals, the levels of n-6 DPA in brain and retina increase in accordance with n-3 essential fatty acid deficiency (EFAD). Is the increase only compensatory for DHA or does n-6 DPA have any positive physiologic functions ... 

Fig. 3. Essential fatty acid deficiency-induced epidermal hyperproliferation and protein kinase C (PKC)-P activity are suppressed by dietary linoleic acid. Membrane-associated epidermal PKC isozyme (a and p) activities were determined in the epidermal extracts from control, essential fatty acid-deficient (EFAD) and reversed guinea pigs (EFAD guinea pigs restored to normal). Specifically, epidermal high-speed particulate membrane fractions were prepared and PKC isozyme activities from each dietary group were assayed as described previously (16). The upper portion of the figure represents PKC-p and PKC-a activities of the three dietary groups values are means SD (n = 12) from three separate experiments. The lower portion of the figure represents the expression of the 2 PKC isozymes. To determine PKC-P and PKC-a expression, 30 mg protein of solubilized epidermal membrane preparation from each dietary group was subjected to gel electrophoresis (SDS-PACE, 10 % gel) followed by Western blot assay with specific PKC-a and PKC-p. The gel electrophoresis data were reproducible in three separate experiments.

Ten Hoor and co-workers (1973) measured heart function In rats during maximum lipidosis, i.e., 3 days after feeding a HEAR oil containing diet. Heart function was measured two ways, one, in isolated left ventricular papillary muscle and the other with a heart-lung preparation in which the work load put on the heart could be adjusted as desired. With all measured parameters (i.e., maximal isometric contractile force, maximal developed tension and rate of tension development, and left ventricular stroke work), the hearts from rats that were put on a 50 calorie % HEAR oil diet had poorer contractile properties than did the hearts from the control group that received sunflower oil. Similarly, when rats were reared on an essential fatty acid deficient diet, the contractile force of isolated papillary muscle from heart was weaker than that from the control group that received linoleic acid, I.e., sunflower oil supplement. These authors suggest that in both instances the decreased contractile force of heart muscle may be related to an Impaired mitochondrial function and a decreased rate of ATP synthesis. 

Very soon after the discovery of essential fatty acid phenomena in rats, medical researchers at the University of Minnesota began investigations on humans. The first medical phenomenon related to essential fatty acids was a dermatitis associated with intractable eczema. Hansen and his co-workers chose cases which did not respond to the usual treatments for eczema and gave these patients supplements of lard which contains approximately 10% of linoleic acid and a few percent of arachidonic acid (Hansen, 1937). They found that in the cases of intractable eczema the serum iodine number was low, and that when the diets were supplemented with lard, the iodine value rose to normal and the skin cleared up in 75% of the cases. An example of this disease which responded to essential fatty acids is shown in Figure 4 (Azerad Crupper, 1949). A study of the histological features of normal and essential fatty acid deficient human skin shown in Figure 5 indicates that in the deficient condition... 

Studies in the mid 20th century identified the effects, in rats, of essential fatty acid deficiency (Table 5). Biochemically, the disease is characterized by changes in the fatty acid compositions of many ceU membranes whose functions are impaired (see British Nutrition Foundation, 1992 Gurr et al., 2002 for further details). One of the striking features of essential fatty acid deficiency in rats is skin dermatitis and water loss (see Mead, 1984). Epidermal lipids are rich in ceramides. The fatty acyl substituent in these is linoleic acid linked via its carboxylic acid group to the terminal methyl carbon of another fatty acid (34 1 n-9) to generate an extremely long-chain (52 carbons) stmcture. 

In animals, certain unsaturated fatty acids, such as linolenic or linoleic acids, are essential dietary components. Whether these compounds can be synthesized by man has not been determined, but since they are widely present in fats ordinarily consumed, deficiency seems an unlikely possibility. In dogs, there is evidence for a need of fat above that necessary to relieve specific effects of essential fatty acid deficiency (Chapter 7). This may be true in other species, including man. 

In the body, linoleic acid is converted to longer-chain fatty acids with three, four, and five double bonds, which are essential components of membranes. In infants fed formulas, the primary symptom noted in essential fatty acid deficiency is drying and flaking of the skin. A fatty acid deficiency in adult humans was unknown until recently. In the past several years, there have been numerous reports of such deficiency being produced inadvertently in hospitalized patients, both infants and adults, fed exclusively by intravenous fluids not containing fat. 

The measurements of the total amount of various essential fatty acids as co-3 fatty acids in plasma, serum, or erythrocyte membrane phospholipids have been indicated as useful markers of essential polyunsaturated fatty adds. Essential fatty acid deficiency is a clinical condition that derives from inadequate status of co-3 and co-6 fatty acids however, the symptoms are nonspecific and may not present prior to marginal essential fatty acid status. Widely used biomarkers for bicx hemi( essai-tial fatty acid deficiency are mead acid and the triene/tetraene ratio. Howcvct, the total plasma triene/tetraene ratio has been considered the gold standard for essential fatty acid deficiency. Mead acid, or 5,8,11-eicosatrienoic acid (5,8,11-20 3 co-9) is synthesized from endogenous oleic acid and is increased when there is insufficient concentrations of linoleic and a-linolenic acid to meet the needs of polyunsaturated fatty acids. Under normal conditions only trace amounts of mead acid are found in plasma. EPA and DHA inhibit mead acid synthesis. Mead acid measurement is an indicator of essential fatty acid deficiency state, while essential fatty add depletion is associated with a decrease in plasma hnoleate and arachidonate percentages. Assessment of long-term essential fatty acid intake is measured in adipose tissue, and it is considered the best indicator because of its slow tumover. - Cutoff values for the assessment of essential fatty adds and to-3 fatty acid status in erythrocytes have been reported. Proposed cutoff values for children older than 0.2 years are 0.46 mol% 20 3 co-9 (mead acid) for early suspicion of essential fatty acid defidency, 0.068 mol/mol docosapentaenoic/arachidonic acid... 

From experiments mainly with laboratory animals, it has been demonstrated that relatively high intakes of trans fatty acids in the diet in conjunction with marginal intakes of essential fatty acids (less than 2% dietary energy from linoleic acid) can lead to the presence of Mead acid (cis-5,8,11-20 3) in tissue lipids and an increase in the ratio of 20 3 n-9 to 20 4 n-6. This has been interpreted to suggest early signs of essential fatty acid deficiency, with potentially increased requirements for essential fatty acids. Mead acid can accumulate in the presence of linoleic acid, if large amounts of nonessential fatty acids are also present. Two mechanisms have been suggested to explain these observations in relation to intake of trans fatty acids ... 

When the absolute amount of linoleic acid in the diet is low. This can happen, for example, when hospital patients are on enteral or parenteral feeds low in fat, or when babies are fed artificial formulas that contain little or no linoleic acid, or in malnutrition. Thus, attention has often focused on protein-energy malnutrition in third world countries, but essential fatty acid deficiency should also be considered when chronic malnutrition results in a low fat intake. As illustrated in Figure 5.3, the serum lipids of malnourished children are often deficient in linoleic and related acids. 

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