In the ‘50s Hugh Sinclair suggested that many chronic diseases, particularly those in the Western civilization (cardiovascular, inflammatory and neoplastic), were to be correlated to a relative deficiency in essential fatty acids.
The Sinclair hypothesis has proved to be fundamentally correct.
In the last two decades the essential fatty acids (EFA), for their importance in many body functions, have been the subject of great attention both from doctors, researchers, and the general public.
In fact the use of the EFA in medicine dates back to the ’30s, when they were used for the first time in the treatment of infant atopic eczema (1).
Despite their use were promising, they were quickly ignored with the advent of the topical corticosteroids.
Sinclair suggested that Western affluent populations, feeding diets with a high content of polyunsaturated fatty acids EFA, went to meet him to a decrease in the composition in EFA of their body such as to prevent the structural and physiological functions related to these fatty acids. Sinclair hypothesis, at that time considered ridiculous and without fundaments, in light of subsequent research has proved to be fundamentally correct (3.4).
What are EFAs?
They are polyunsaturated fatty acids (PUFAs) or organic compounds to long chain formed from carbon atoms containing double bonds, a carboxyl group at one end and a methyl group at the other. The PUFA (and thus EFA) are classified according to their first double bond from the terminal methyl group. Thus, a formula capable of identifying both the total number of carbon atoms of which they are composed, as well as the number of double bonds present that the first double bond, was prepared.
For example: 18:2n-6 indicates be a polyunsaturated fatty acid consisting of a chain of 18 carbon atoms where there are two double bonds, the first of which is positioned between the 6th and the 7th carbon atom.
EFA of greater importance are grouped into two large families: the n-6 or Omega 6, derived by the cis-linoleic acid (18: 2n-6) and n-3 or omega 3, derived from alpha-linolenic (18: 3n-3).
EFA cover both structural features (components of cell membranes with barrier function) and physiological (eicosanoid production) vital for the organism (5, 6).
Those are referred to as “vitamin F” and considered essential nutrients because like vitamins cannot be synthesized ex-novo by the body and must be taken regularly with food.
Be noted that some EFAs are found in high concentrations in some districts where are particularly important for the performance of normal biological functions: for example the acids arachidonic, eicosapentaenoic and docosahexaenoic acid are found in the CNS and retina, while the adrenic acid (22: 4n -6) and docosapentaenoic acid (22: 5n-6) are particularly present in the adrenal glands and gonads.
Currently we consider only the cis-linoleic acid in the dog as essential, the only one not be directly synthesized in the body.
The other polyunsaturated fatty acids are produced, in particular at the hepatic level, from precursors in the diet by the action of two enzymatic chains: the delta-desaturase that insert, for removal of two hydrogen atoms, a new double bond between two carbon atoms and the elongase that add two carbon atoms to the chain.
So, by the acid cis-linoleic acid (18: 2n-6) is synthesized the gamma-linolenic acid (18: 3n-6), the diomogammalinolenic acid (20: 3n-6) and arachidonic acid (20: 4n- 6) of great importance for mammals while from alpha-linolenic (18: 3n-3) is synthesized eicosapentaenoic acid (20: 5n-3) and docosahexaenoic acid (22: 6n-3).
In cats it was found decreased activity of the enzyme delta-6-desaturase (required for the synthesis of arachidonic acid) thus making it essential in this species the intake of arachidonic acid in the diet (7).
THE DELTA-6-DESATURASE IS THE FUNDAMENTAL AND LIMITING ENZYME FOR THE SYNTHESIS OF ARACHIDONIC ACID IS (BY THE ACID CIS-LINOLEIC) AND EICOSAPENTAENOIC ACID (FROM ALPHA-LINOLENIC ACID). IN DOGS IT WAS REPORTED LESS ACTIVITY OF THE DELTA-6-DESATURASE IN ATOPIC INDIVIDUALS AS WELL AS IN HYPOTHYROID SUBJECTS. REMEMBER THAT FOODS POORLY PRESERVED OR CONTAINING SMALL QUANTITIES OF ANTI OXIDANT SUBSTANCES OR FOODS SUBJECTED TO PROLONGED COOKING INVOLVE A FAILURE IN EFA INTAKE.
Metabolic synthesis of EFA
The polyunsaturated fatty acids in the diet and transported to the liver are metabolized competitively by the same chain elongase and desaturase enzymes to produce their derivatives. In particular, the delta-6-desaturase is the essential and limiting enzyme for the synthesis of arachidonic acid is (by acid cis-linoleic) and eicosapentaenoic acid (from alpha-linolenic). In humans it has been demonstrated less activity of the delta-6-desaturase in atopic individuals as well as in subjects with severe liver disease or suffers from hyperadrenocorticism, hyperglycemia, hypoproteinemia, malnutrition and other anomalies (8.9).
Even in dogs was reported less activity of the delta-6-desaturase in atopic individuals as well as in subjects with hypothyroidism (10, 11). In mammals, it is also not possible to convert PUFA of a family in another (e.g. the n-6 to n-3 or vice versa) so the presence in excess in the diet of a family of PUFA results in a lower synthesis and availability of the other. For this reason it is important that both the EFA families are present in the diet in a right relationship with each other and with other fatty acids.
Dietary sources of PUFAs
The cis-linoleic acid is present in seed oils, sunflower and maize in particular (but not in olive oil), whereas the alpha-linolenic acid is found in the oil of primrose, black currant, flax, soybean, canola and marine fish.
Remember that poorly preserved foods or containing scarce amounts of anti-oxidants substances (such as vitamin E or ascorbic acid), or subjected to prolonged cooking foods involve a failure in EFA intake.
Even chronic digestive diseases such as intestinal malabsorption, liver disease and / or chronic pancreatitis or restrictive diets (for treating obesity or pancreatic diseases) with low content of fat fee, if prolonged, deficiency problems in EFA.
Commercial food for dog must contain at least 3% in fats while the dry food at least 7-8%; Also recommended levels of cis-linoleic acid should be at least greater than or equal to 1% of the dry matter, and greater than or equal to 2% of the caloric intake.
In cats usually 35-40% of calories should come from fat and any rancidity leads to the loss of both the fatty acids of both vitamins E and D present.
Finally the recommended optimum ratio between polyunsaturated fatty acids n-6 and n-3 present in the diets ranges from 5: 1 to 10: 1.
What functions do the EFA?
STRUCTURAL FUNCTION: EFAS ARE NECESSARY FOR MAINTAINING MEMBRANE FLUIDITY
BARRIER FUNCTION: THE LACK OF EFAS DETERMINES A DISPERSION OF WATER FROM THE EPIDERMIS MAKING THE DRY SCALP AND SEBORRHEIC
CHOLESTEROL TRANSPORT FUNCTION: CHOLESTEROL, IF ESTERIFIED WITH THE EFA, POTENTIALLY LESS HARMFUL FORM COMPLEXES
PRECURSOR OF EICOSANOIDS FUNCTION: MORE THAN 270 ARE KNOWN AND ARE DIVIDED INTO PROSTAGLANDINS, THROMBOXANES, LEUKOTRIENES AND PROSTACYCLINS
In humans (and probably also in animals) are attributed schematically four main functions to EFA:
- Structural function: each cell membrane, cytoplasmic, nuclear, myth-condriale contains EFAs (especially n-6 as the cis-linoleic acid and arachidonic acid) incorporated as phospholipids.
EFAs are necessary for maintaining membrane fluidity thus modulating the activity of protein molecules linked to them; in particular of membrane receptors, ion channels and ATPase enzymes (12).
- At the level of epidermal barrier function: intercellular lipids (derived from lamellar bodies and rich in EFAs) present in the granular layer and lower areas of the stratum corneum, avoid the dispersion of water and of other intracellular molecules from the upper layers of the epidermis.
The presence of cis-linoleic acid is essential for the provision of appropriate layers geometric lamellar epidermal lipid molecules.
The lack of EFAs determines a dispersion of water from the epidermis making the dry skin and seborrheic (13).
- Cholesterol Transport function: cholesterol is transported in the organism under esterified form.
When is esterified with saturated fatty acids form insoluble complexes which tend to deposit in the vessel walls while, if esterified with the SSF, are formed potentially less harmful complex because more easily mobilizable.
- precursor of eicosanoids feature: the eicosanoids are important substances for the maintenance of homeostasis, with properties autacoids (hormone-like locally-acting).
More than 270 are known and are divided into prostaglandins, thromboxane, leukotrienes and prostacyclins.
These have specific physiological activities (control of epithelial cell proliferation, in inflammation and immune modulators, platelet aggregating activity), of varying intensity, depending on the set of belonging.
THERE ARE TWO ENZYMATIC PATHWAYS LEADING TO THE SYNTHESIS OF EICOSANOIDS: THE WAY OF THE CYCLOOXYGENASE AND LIPOXYGENASE OF THE WAY (5-12 AND 15-LIPOXYGENASE)
THE WAY OF THE CYCLOOXYGENASE IS PREFERRED FOR THE FATTY ACIDS OF THE OMEGA 6 SERIES
THE WAY OF THE LIPOXYGENASE IS PREFERRED FOR THE FATTY ACIDS OF THE OMEGA 3 SERIES
Metabolism and mechanism of action of eicosanoids
The eicosanoids are of cellular mediators to quick action produced locally in response to receptor stimulation or as a result of cell damage.
They are produced to departure of polyunsaturated fatty acids to 20 carbon atoms [arachidonic acid (AA), eicosapentaenoic acid (EPA) and diomogammalinolenic acid (DGLA)] in the cell membranes.
There are two enzymatic pathways leading to the synthesis of eicosanoids: the path of cyclooxygenase, leading to the formation of prostaglandins (PG) and thromboxane (TX), and the way of lipoxygenase (5-12 and 15-lipoxygenase) that lead to formation of leukotrienes (LT) and their precursors, the acids idroperossieicosatetraenoic (HPETE) and idrossieicosatetraenoic acids (HETE).
When the cell receives a stimulus receptor (for example for the presence of an allergen), or suffers damage, the phospholipase A2 is activated, calcium dependent, present in the cytosol Cell.
The activated phospholipase acts on the cell membrane releasing and making available the arachidonic acid as substrate to the two enzymatic pathways: the cyclooxygenase, present in all cells, and that of the lipoxygenase present only in neutrophils, eosinophils, mast cells, monocytes, macrophages, basophils and epithelial / endothelial cells.
The way of the cyclooxygenase is preferred for the fatty acids of the series Omega 6 and leads to the formation of prostaglandins of the series 2 (PGG2, PGH2, PGD2, PGE2, PGF2a) pro-inflammatory and pro thrombotic thromboxane TXA2.
The way of the lipoxygenase is preferred for the fatty acids of the Omega 3 series but acting on Food on arachidonic acid involves the formation of leukotrienes Series 4 (LTA4, LTB 4, LTC 4, LTD 4 and LTE 4) pro inflammatory and 12-HETE (acid 12 -idros-sieicosatetraenoico) and 15-HETE (15-idrossieicosatetraenoico acid).
STUDIES CONDUCTED BY KIETZMANN HAVE SHOWN AN INCREASE IN THE SKIN OF PGE2 IN DOGS SUFFERING FROM PYODERMA AND AN INCREASE OF LTB4 IN DOGS SUFFERING FROM SEBORRHEA AND PYODERMA
CORTICOSTEROIDS ACT BY BLOCKING THE RELEASE OF FATTY ACIDS FROM CELL MEMBRANES (BY INHIBITING THE PRODUCTION OF EICOSANOIDS IN ITS ENTIRETY) WHILE NSAIDS ACT BY BLOCKING ONLY THE CYCLOOXYGENASE (THEREBY INHIBITING THE PRODUCTION OF PROSTAGLANDINS / PROSTACYCLINS AND THROMBOXANES BUT NOT LEUKOTRIENE)
OMEGA-6 EICOSANOIDS DERIVED BY DIOMOGAMMALINOLENICO ACID (DGLA) (20: 3N-6) HAVE ANTI-INFLAMMATORY ACTION (PRODUCTION OF PGE1 ACTION INHIBITING THE RELEASE OF AA FROM CELL MEMBRANES AND 15-HETE THAT WORKS BY BLOCKING COMPETITIVELY LTB4)
OMEGA 3 DERIVED EICOSANOIDS BY THE ACID EICOSAPENTAENOIC ACID (EPA) HAVE ANTI-INFLAMMATORY, IMMUNOMODULATORY AND ANTIPLATELET (PRODUCTION LTB5, TX3 AND PGE3)
Anti-inflammatory activity of the EFA
Several factors interfere with the metabolic pathways used during the inflammatory response: for example the composition in fatty acids in cell membranes, the presence of adequate amounts of cyclooxygenase and lipoxygenase and the presence or absence of substances with anti-inflammatory action.
Thus corticosteroids act by blocking the activation of phospholipase A, and then the release of fatty acids from cell membranes (by inhibiting the production of eicosanoids in its entirety) while NSAIDs act by blocking only the cyclooxygenase (thereby inhibiting the production of prostaglandins / prostacyclins and thromboxane but not leukotriene).
It is known that the eicosanoids series produced depends on the type of more present at the cell membrane level polyunsaturated fatty acid: in fact the Omega 6 fatty acids and omega 3 to 20 carbon atoms are in competition with each other, because they use the same cyclooxygenase and lipoxygenase to produce eicosanoids.
So from these enzymatic pathways you can get:
- Omega-6 eicosanoids derived from arachidonic acid (AA) to pro inflammatory, immunosuppressive, pistrinic aggregator and thrombotic.
Are potent mediators of inflammation in hypersensitivity-type reactions I.
Omega-6 eicosanoids derived by diomogammalinolenic acid (DGLA) (20: 3n-6) anti-inflammatory action (production of PGE1 action inhibiting the release of AA from cell membranes and 15-HETE that works by blocking competitively LTB4).
- Omega 3 derived eicosanoids by the acid eicosapentaenoic acid (EPA) with anti-inflammatory, immunomodulatory and antiplatelet (production LTB5, TX3 and PGE3).
In particular LTB5 is 30-100 times less active LTB4 in stimulating the membrane receptors for leukotrienes places on neutrophils, also the presence of LTB5 inhibits for the competition to the same receptor the neutrophilic activation induced by LTB4 thus decreasing the production of further LTB4 and decreasing the inflammatory response or allergic.
Note also that the eicosapentaenoic acid is metabolized in LTB5 by the action of the same enzyme (leukotriene A hydrolase) required for the synthesis of LTB4, so high amounts of EPA in a competitive manner inhibit the production of LTB4.
From what described it appears evident that by varying the relative amounts of Omega 3 fatty acids or omega-6 bound to the cell membrane can also vary the entity of the products mediators.
The manipulation of the amount of fatty acids present in the diet can allow you to alter the composition of fatty acids in membrane phospholipids.
The increase in Omega 3 fatty acids causes a decrease in production of pro-inflammatory eicosanoids and increased production of metabolites to less inflammatory action.
Also the increase of Omega 6 fatty acids other than arachidonic, like gamma-linolenic acid (GLA) or the Diomo-gamma-linolenic (DGLA) means less use of arachidonic acid (for the competition to the same enzymatic pathways) with a lower production of pro-inflammatory metabolites, instead favoring the synthesis of anti-inflammatory action products (PGE1, 15-HETE).
THE GAMMA-LINOLENIC ACID (GLA) OR THE DIOMOGAMMALINOLENICO (DGLA) MEANS LESS USE OF ARACHIDONIC ACID WITH A LOWER PRODUCTION OF PRO-INFLAMMATORY METABOLITES, FAVORING INSTEAD THE SYNTHESIS OF ANTI-INFLAMMATORY ACTION PRODUCTS (PGE1, 15-HETE)
DOGS FED DIETS DEFICIENT IN EFA HAVE DANDRUFF, DRY COAT (FOR INCREASED TRANS-EPIDERMAL WATER LOSS), EPIDERMAL HYPERPLASIA AND HYPERKERATOSIS
THE ERYTHEMA, ITCHING AND INFLAMMATION ASSOCIATED WITH ATOPIC DERMATITIS DECREASED FOLLOWING ADMINISTRATION OF EPA AND / OR GLA
DO NOT OVERLOOK THE POSSIBILITY OF USING THE EFA IN CONJUNCTION WITH ANTIHISTAMINES AND CORTICOSTEROIDS
IN CATS IT IS REPORTED THE USE OF EFA IN ATOPIC THERAPY AND ALLERGIC TO FLEAS THAT PRESENT CLINICAL PICTURES RELATED TO MILIARY DERMATITIS, SYMMETRICAL ALOPECIA AND EXTENSIVE EOSINOPHILIC GRANULOMA COMPLEX
Therapeutic utility of EFA in dermatology Veterinary
SEBORRHEA The epidermal cell turnover dog happens quickly (22 days) and is related to a correct dermal intake of fatty acids.
The cis-linoleic acid is essential for the maintenance of the barrier function against the leakage of water in the skin, while the arachidonic acid is important for the control of epidermal proliferation.
Thus, dogs fed diets deficient in EFA have dandruff, dry coat (for greater trans-epidermal water loss), epidermal hyperplasia and hyperkeratosis.
In the cell membranes of these dogs, the cis-linoleic acid is to be replaced by the acid oleic (unable to prevent trans-epidermal water loss).
In literature there are reported cases of dogs suffering from primary idiopathic seborrhea that have high concentrations of oleic acid at the cutaneous level while are not present alterations of their serum fatty acid composition; this observation would suggest the presence of a defect in these individuals, the metabolism epidermal cis-linoleic acid.
Administration of sunflower oil (1.5 ml / kg dog / day) for a month in seborrheic dogs diet has been reported as effective in promoting an improvement in clinical condition in the treated subjects (17).
ATOPIC DERMATITIS During the reaction of type I hypersensitivity, are derived eicosanoids produced by the metabolism of arachidonic acid.
PGD2 is released from mast cells, and keratinocytes from damaged it has production of LTB4 and PGE2.
The administration of diets enriched in EPA and GLA has proved useful in modulating the inflammatory response induced by the reaction of type I hypersensitivity (18).
Thus the erythema, itching and inflammation associated with atopic dermatitis decrease following the administration of EPA and / or GLA (19).
Many other studies have been published on the use of fatty acids Omega 3 and Omega 6 in the treatment of atopic dermatitis and itchy dog.
Although it is impossible a comparison between them (for the presence of protocols and different pharmacological preparations), from the various studies performed it is clear that the atopic dogs are susceptible to the administration of the EFA (20).
Studies performed using high doses of EFA (preparations containing 80% of primrose oil and 20% of sea fish oil) indicate greater effectiveness of treatment and greater success rate in dogs.
These data suggest that the effect of therapy is dose dependent.
Other studies indicate the possibility of keeping the treatment for long periods (even years) without excessive side effects (described rare gastrointestinal disorders, pancreatitis rare and sometimes halitosis).
Other publications report the successful use of balanced diets enriched in fatty acids with an optimal ratio omega-3 / omega-6 to 5: 1 to 10: 1 as the sole therapeutic approach in dogs with pruritic dermatoses (21).
Although these data are comforting it must be recalled as well not even let it be known that fatty acid, which combination of fatty acids, which report Omega 3 / Omega 6 and what dosage is needed to achieve the best results.
The observation of dogs treated without success with a product based EFA presenting clinical response when subjected to therapy with other EFA-based products is likely to indicate that there are individual responses to the various types of fatty acids.
Do not overlook the possibility of using the EFA in conjunction with antihistamines and corticosteroids, there is more work to document a synergistic action between these substances (22, 23).
The assessment of clinical response to therapy requires a minimum of 9-12 week period.
In cats it is reported the use of EFA in atopic therapy and allergic to fleas that present clinical pictures related to miliary dermatitis, symmetrical alopecia and extensive eosinophilic granuloma complex (24, 25).
Bibliography
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NBF-Lanes thank Dr. Fabrizio Fabbrini for his cooperation.
