EFA supplementation and dietary manipulation of EFA metabolism appear to have some efficacy in the treatment of certain skin disorders that are not the result of a dietary EFA deficiency. The PUFAs are divided into several series based on the position of the first double bond in the carbon chain. Of greatest interest are the omega-3 and omega-6 series of fatty acids. The omega-3 (or n-3) fatty acids have the first double bond located at the third carbon atom from the terminal methyl group. The omega-6 fatty acids have the first double bond at the sixth carbon atom (see Section 1, p. 19). The effects of both types of fatty acids upon cell membrane fluidity and permeability, and their availability for synthesis of new compounds, are affected by the molecule’s chain length, the degree of saturation, and the position of the first double bond.

Algae synthesize large amounts of omega-3 fatty acids. As a result, most marine animal tissues contain high concentrations of the omega-3 PUFAs. Sources of omega-3 fatty acids in pet foods include cold-water fish oils as well as whole-fat flax (flax oil is an enriched source of ALA). Land animals, in contrast, have higher concentrations of the omega-6 fatty acids in their tissues because most plants consumed by these animals contain greater amounts of omega-6 than omega-3 fatty acids. ³⁹ Enriched sources of omega-6 fatty acids in pet foods include corn, safflower, sunflower, and cottonseed oils. Soy and canola oils contain high levels of omega-6 fatty acids, as well as some ALA. Another omega-6 fatty acid, gamma-linolenic acid (18:3n-6) (GLA), is found in borage, black currant, and evening primrose oil. ⁴⁰ Oils containing a large proportion of monounsaturated fatty acids, such as olive oil, and saturated animal fats are not considered enriched in either omega-3 or omega-6 fatty acids (Table 31-2).

In addition to providing structural integrity and fluidity to cell membranes, membrane fatty acids also have specific roles in the regulation of cell functions. The PUFAs AA, GLA, EPA, and DHA are all precursors for the synthesis of eicosanoids. Eicosanoids are immunoregulatory molecules that have local and short-lived hormonelike effects. The four primary types of eicosanoids are prostaglandins, leukotrienes, prostacyclins, and thromboxanes. Eicosanoids are involved in inflammatory reactions, immunoregulation, and epidermal cell proliferation. When cellular injury occurs, membranes release their component fatty acids, which are then metabolized to eicosanoids. The amount and type of eicosanoid synthesized is determined by the availability and type of fatty acid precursor from the cell membrane and by the activities of the two metabolic enzyme systems, cyclooxygenase and lipoxygenase. The omega-3 and omega-6 fatty acids produce different families of eicosanoids and also compete for these two metabolic pathways. ⁴¹

During an inflammatory response, the release and metabolism of omega-6 fatty acids produces the 2-series prostaglandins, the 4-series leukotrienes, hydroxyeicosatetraenoic acid, and thromboxane A ₂ (Figure 31-3). These agents are immunosuppressive at high levels, are proinflammatory, promote platelet aggregation, and act as potent mediators of inflammation in type-I hypersensitivity reactions. ^{42. and 43.} In contrast, the release and metabolism of omega-3 fatty acids (specifically, EPA) produces mediators with much less inflammatory activity. Those compounds are antiaggregatory, not immunosuppressive at levels normally found in the body, and vasodilatory. They include the 3-series prostaglandins, the 5-series leukotrienes, hydroxyeicosapentaenoic acid, and thromboxane A ₃. For example leukotriene B ₅ (LTB ₅), produced from EPA, is approximately 10-fold less potent as a neutrophil chemoattractant than leukotriene B ₄ (LTB ₄), which is produced from AA. ⁴⁴ In addition to being less biologically active than LTB ₄, there is evidence that LTB ₅ may inhibit the action of LTB ₄, possibly via competition for cell membrane receptors. ^{45. and 46.} These data suggest that the ratio of leukotrienes produced from AA to leukotrienes produced from EPA may be more important than absolute amounts of these compounds.

Research studies with humans, laboratory animals, and companion animals have shown that levels of omega-6 and omega-3 fatty acids present in tissue cell membranes can be manipulated by diet, and that these manipulations influence the inflammatory response. Increasing the amount of omega-3 fatty acids in skin and other tissues leads to decreased production and activity of the proinflammatory eicosanoids and increased synthesis of the less-inflammatory metabolites. ⁴⁷ Several factors are responsible for this effect. First, as discussed previously, omega-6 and omega-3 fatty acids compete directly for the same enzyme systems. Therefore increasing the amount of available omega-3 fatty acids competitively inhibits the metabolism of omega-6 fatty acids when fatty acids are released from membranes during an inflammatory reaction. Second, the compounds produced from the metabolism of omega-3 fatty acids are less inflammatory than those produced from AA. ⁴⁸ Finally, two of the end products of EPA metabolism are LTB ₅ and 15-hydroxyeicosapentaenoic acid. There is evidence that these compounds inhibit the potent proinflammatory action of omega-6–derived leukotrienes.

The amount and type of omega-3 and omega-6 fatty acids and the ratio of these two classes of fatty acids in the diet must be considered when determining effects on plasma and tissue levels and consequent eicosanoid synthesis. ^{49.50. and 51.} For example, an early study with healthy dogs showed that feeding a diet containing an omega-6 to omega-3 ratio between 5:1 and 10:1 resulted in the production of significantly lower levels of LTB ₄ and significantly higher levels of the less inflammatory metabolite LTB ₅ in the skin, when compared with levels that were produced when the dogs were fed a diet with ratios of 28:1 or higher. ⁵² Similarly, the neutrophils of dogs fed diets containing the lowest omega-6 to omega-3 ratios (5:1 and 10:1) had decreased LTB ₄ and increased LTB ₅ concentrations (Figure 31-4). Cells from lipopolysaccharide-stimulated (LPS) skin biopsy samples synthesized 48% to 62% less LTB ₄ and 48% to 79% more LTB ₅ when compared with samples obtained prior to feeding the experimental diets. Similar changes were observed in neutrophils. These responses were considered to be clinically significant because decreases in tissue LTB ₄ concentrations of 50% or more are typically large enough to attenuate an inflammatory response.

Additional research corroborated these results and further refined understanding of the specific types and amounts of omega-3 fatty acids that can modulate the inflammatory response. Healthy elderly Beagles fed diets that were supplemented with fish oil to achieve an omega-6 to omega-3 fatty acid ratio of 1.4:1 had altered plasma fatty acids (increased DHA and EPA and decreased AA) and had reduced prostaglandin E ₂ (PGE ₂) production by peripheral blood mononuclear cells. ⁵³ Fish oil–supplemented dogs also showed a reduction in response to a delayed-type hypersensitivity (DTH) skin test and a blunted response to immunization with a novel protein. ⁵⁴ A follow-up study was conducted to examine the relationship between plasma fatty acid concentrations and leukotriene production by peripheral blood neutrophils in dogs fed these diets for 36 weeks. ⁵⁵ Plasma concentrations of EPA and AA reflected dietary intake, and a strong and significant correlation was found between the plasma ratio of EPA:AA and the ratio of LTB ₅ to LTB ₄ produced by stimulated neutrophils. Specifically, plasma EPA increased, plasma AA decreased, and LTB ₅ produced by stimulated neutrophils increased in dogs fed fish oil–supplemented diets. The same researchers demonstrated an interaction between dietary vitamin E intake and intake of omega-3 fatty acids, suggesting that the benefits of vitamin E on DTH response are reduced when the intake of omega-3 fatty acids is very high. ⁵⁶ Together, these studies suggest that there is an optimal level of omega-3 fatty acid intake and an omega-6 to omega-3 ratio that can modify the production of proinflammatory compounds but that is not high enough to negatively impact other immune system functions or vitamin E status.

In a study, a group of 15 healthy adult dogs were fed a base diet supplemented with either sunflower oil (source of LA), fish oil (source of EPA and DHA), or fish oil plus vitamin E. ⁵⁷ The fish oil–enriched diets provided 1.75 grams (g) EPA/kg diet and 2.2-g DHA/kg diet, resulting in an omega-6 to omega-3 ratio of 3.4:1. After 12 weeks of feeding the test diets, in vivo measurement of the serum of dogs fed fish oil–enriched foods showed a blunted inflammatory response to LPS when compared with the response observed in dogs fed the sunflower oil–enriched diet. These results are especially significant because this was the first report that used an in vivo assay to examine LPS-stimulated cytokine response after feeding omega-3 fatty acid enriched diets. Additional studies of the same dogs showed that increasing omega-3 fatty acids in the diet did not significantly increase plasma concentrations of lipid peroxides or cause a reduction in serum vitamin E concentrations. ⁵⁸ These results indicate that the dogs did not experience increased oxidative stress in response to the altered fatty acid ratios and increased intake of EPA and DHA.

Although changing the ratio of omega-6 to omega-3 fatty acids is an effective approach to modifying the production of proinflammatory and less inflammatory compounds, there is also evidence that when an equal ratio is fed and kept constant, increasing the omega-3 dose alone influences the plasma fatty acid profile. ⁵⁹ Healthy dogs were fed diets containing an omega-6 to omega-3 ratio of 1:1, with varying concentrations of each class of fatty acid, supplied by corn oil and fish oil, respectively. Plasma concentrations of omega-3 fatty acids increased with increasing total intake of omega-3 fatty acids, up to a certain level of intake, regardless of the fact that omega-6 fatty acids were also increasing. These results suggest a dose-dependent response to omega-3 intake that was independent of the ratio of the two classes of fatty acids. However, it is important to note that the diets that were fed in this study already contained an “adjusted” fatty acid ratio (1:1). It is unknown (and questionable) whether a similar response would have occurred if the ratio was more similar to that seen in many commercial foods (i.e., 15:1 or greater). Second, the omega-3 fatty acids in this study were supplied as EPA and DHA (fish oil), while the omega-6 fatty acid was supplied as primarily LA (corn oil). Therefore the dose response may reflect a selective favoring of highly unsaturated fatty acids for esterification into phospholipids when compared with their precursors. It is not known if these effects would have been observed if increased omega-6 fatty acids had been supplied as AA instead of as LA. Regardless, these results suggest that when a favorable ratio is included in the diet, increasing the source of EPA and DHA while maintaining a constant omega-6 to omega-3 ratio positively affects plasma fatty acid profiles and, presumably (although not yet reported), the production of less inflammatory eicosanoids.

Dogs and cats are susceptible to a wide range of inflammatory skin diseases. In dogs, these include allergic disorders, parasitic infestations, bacterial infections, and adverse reactions to food. Cats show the same disorders with the addition of miliary dermatitis and eosinophilic granuloma complex. Inflammatory skin disorders that are associated with immunoglobulin E (IgE)-mediated type-1 hypersensitivity (allergic) responses are most likely to respond favorably to modifications of dietary fatty acid concentrations. In dogs, these include atopic dermatitis (atopy), flea-bite hypersensitivity, and food hypersensitivity (discussed below). In cats, allergic skin disease also manifests as miliary dermatitis. ⁶⁰ Because flea-bite hypersensitivity is best treated via stringent flea-control programs, current research studies have focused on the use of fatty acid therapy to control atopic disease in dogs and cats.

In dogs, atopic dermatitis is considered to be the most frequently diagnosed form of allergic skin disease. ⁶¹ Many animals with atopy are sensitized to multiple environmental allergens, which may include house dust mites or dust, molds, weeds, grasses, and trees. In addition, a substantial proportion of dogs with atopic dermatitis are simultaneously affected by an adverse food reaction. ⁶² Recent studies suggest that dogs with atopic disease have almost four times greater risk of developing concurrent food allergy than dogs without atopy. For these reasons, differential diagnosis of allergic skin disorders must always include consideration of the presence of both atopy and adverse food reaction and the role that multiple allergens and the pruritic threshold plays in the development of clinical signs.

Atopy is characterized by pruritus, self-trauma to the skin, and secondary bacterial or yeast infection. ^{63. and 64.} Chronic otitis externa is also a common finding. Diagnosis of atopic dermatitis in dogs typically uses the criteria of Willemse, which includes case history information and clinical signs. ⁶⁵ Observations of breed and family predilections, along with results of limited breeding trials, indicate that some dogs are genetically predisposed to develop atopy. ⁶⁶ Breeds identified as being at increased risk include Chinese Shar-Peis, Dalmatians, Irish Setters, Golden Retrievers, Boxers, Labrador Retrievers, Belgian Tervurens, and several Terrier and toy breeds. Cats with atopic disease often develop military dermatitis, which is characterized by small papules and crusts found most frequently on the head and neck.

Clinical signs develop when the animal is exposed to the offending antigen(s) and IgE-sensitized mast cells in the skin degranulate and release a host of inflammatory mediators. These compounds include histamine, heparin, proteolytic enzymes, chemotactic factors, and various types of eicosanoids. As discussed previously, the type and proportions of fatty acids present in the cell membranes and activity of the cyclooxygenase and lipoxygenase enzyme systems determine the specific type of eicosanoids that will be produced during an inflammatory response. In pets with atopy, the immediate-type hypersensitivity response (IgE-mediated) is followed by a late-phase response that develops 6 to 12 hours following mast cell activation. ⁶⁷ In addition, some of the released cytokines function to recruit inflammatory cells to the local area, which can persist for several days and are responsible for the chronic inflammatory skin changes seen in atopic animals.

Although IgE-mediated immediate-type and delayed (late-phase) hypersensitivities are responsible for the cascade of inflammatory agents after exposure to offending allergens in most patients, it appears that other factors are also involved. ⁶⁸ The most important of these is epidermal barrier function. Human subjects with atopic dermatitis have irregularities in the lipid and ceramide components of their stratus corneum (the uppermost protecting layer of the epidermis). ⁶⁹ A defect in this layer can affect the skin’s function as a protective barrier, leading to increased transepidermal water loss and increased risk of penetration by allergens and infectious agents. Although these changes have not been definitely demonstrated in dogs, there is evidence that the stratum corneum of atopic dogs has structural differences when compared with normal canine skin and that these differences may involve the lipid-containing ceramides. ⁷⁰ It is theorized that a stratum corneum with an impaired lipid barrier predisposes an animal to the development of hypersensitive response to contact allergens because foreign agents are able to penetrate further into the skin. Another potentially influencing factor is the presence of a defect in fatty acid metabolism. There is evidence that dogs with atopy may have compromised ability to metabolize omega-6 fatty acids due to reduced activity of delta-5 and/or delta-6 desaturase enzymes. ^{71. and 72.}

Increased understanding of the role of an optimally functioning skin barrier has implications for both the prevention and treatment of atopic disease. While it was previously believed that inhalant allergens were the most common cause of atopy, new evidence suggests that contact allergens are most important. Avoidance of known allergens and frequent bathing to reduce time of exposure and penetration into the skin are now routinely recommended for pets with atopic disease. ⁷³ Because secondary staphylococcal infections may be responsible for many of the clinical signs of atopy, antimicrobial treatment is also an important component of management. Glucocorticoid or cyclosporine therapies are typically prescribed to control inflammation. Fatty acid therapy that helps to restore defects in the intercellular ceramides of the stratum corneum may also be helpful and may allow reduction or discontinuation of the use of these antiinflammatory medications. In recent years, fatty acid therapy for atopic disease has focused both on modulating the inflammatory response by altering the types of eicosanoids produced by the mast cells and other skin cells involved in the inflammatory response (keratinocytes and cutaneous antigen-presenting cells), and providing nutrients that support a healthier skin barrier. ⁷⁴

A second, less common omega-6 fatty acid that has been studied for its antiinflammatory effects is GLA. Once consumed, GLA is readily converted to dihomo-gamma-linolenic acid in the liver, where it is then further metabolized to either the monoenoic prostaglandins and thromboxanes or to AA (Figure 31-5). The more active pathway is toward the production of the monoenoic prostaglandins (PGE ₁) because the rate-limiting delta-5-desaturase step for AA production is quite slow in animals. ⁴¹ Like the eicosanoids that are produced from EPA, PGE ₁ is less inflammatory than the dienoic prostaglandins that are produced from AA. Therefore it is expected that providing supplemental GLA will promote the formation of dihomo-gamma-linolenic acid and the monoenoic prostaglandins, rather than the formation of AA and its more inflammatory metabolites.

When dogs’ diets are supplemented with GLA, plasma levels of dihomo-gamma-linolenic acid increase. ⁷⁵ Similarly, when dogs with atopy that had been controlled by feeding a supplement containing omega-3 fatty acids and GLA were switched to a supplement containing only olive oil (a poor source of both omega-3 and omega-6 fatty acids), plasma levels of dihomo-gamma-linolenic acid subsequently decreased. ⁷⁶ A return of clinical signs in these dogs paralleled the reduction in dihomo-gamma-linolenic acid. As stated previously, it has been theorized that one factor that may contribute to atopic disease in some dogs is low activity of the enzyme delta-6-desaturase, the rate-limiting step for conversion of LA to GLA. ⁷⁷ Providing GLA to this subpopulation of dogs would be expected to bypass this step of fatty acid metabolism and provide substrate for the production of the monoenoic prostaglandins. However, not all studies have shown a benefit of providing GLA to pruritic dogs. A study comparing pruritic and healthy dogs found that the unmedicated dogs with signs of atopy naturally had higher concentrations of dihomo-gamma-linolenic acid in subcutaneous fat when compared with levels in the dogs with healthy skin. ⁷⁸ These results suggest that some dogs with atopy may have an abnormality in dihomo-gamma-linolenic metabolism caused by a deficiency in delta-5-desaturase. Together these studies suggest that there may be several underlying causes and influencing factors that contribute to atopy in dogs. While some atopic animals show abnormal fat absorption and clearance, others may have deficiencies of delta-6- and/or delta-5-desaturase activities, and/or, as examined more recently, impairments that affect the epidermal barrier.

Using supplementation of pets’ regular diets with omega-3 and omega-6 fatty acids to manage the pruritus and inflammatory responses associated with atopy has met with variable success. A review of five separate clinical tests of a commercial supplement (DVM Derm Caps) shows that fatty acid supplementation was effective in controlling pruritus in 11% to 27% of dogs with inflammatory skin disease. ^{79.80.81.82. and 83.} This supplement contains EPA, DHA, LA, and GLA. In one study, 93 dogs with a diagnosis of atopic dermatitis were supplemented at a dose that provided 15 mg EPA per 9 kg (20 pounds [lb]) of BW. ⁷⁹ One third of the dogs showed a good or excellent response to the supplement, and 17 dogs (18%) required no additional therapy. A second study using the same supplement reported that 11% of dogs with atopy, food allergy, or flea-bite allergy were adequately controlled by the supplement alone with no other treatment necessary. ⁸⁰ Because these studies did not control dogs’ regular diets, variability of the background fatty acid intake among dogs fed different commercial foods may have significantly influenced response rate. A more recent study fed 22 atopic dogs the same balanced homemade food and administered a daily supplement containing 17 mg/kg BW EPA, 5 mg/kg BW DHA, and 35 mg/kg BW GLA. ⁸⁴ Supplementation resulted in an overall omega-6 to omega-3 ratio of 5.5:1. The dogs in this study were also divided into two groups: early stage (preimmunotherapy) and late-stage (nonresponsive to immunotherapy). More than half (53%) of the early-stage dogs responded positively to fatty acid supplementation, compared with only one dog from the group of seven dogs that had chronic and refractory atopy. Interestingly, plasma fatty acid profiles also differed between the two categories of atopic dogs, even though they were fed the same diets and supplements. This difference supports the theory that subpopulations of atopic dogs exist, whose disease is influenced by different factors, which in turn could affect clinical response to supplementation.