ShapeShapeauthorShapecrossShapeShapeShapeGrouphamburgerhomeGroupmagnifyShapeShapeShapeShape

Fatty acids and the skin

by
01 March 2013, at 12:00am

Dr STEPHEN SHAW reviews the role and usefulness of essential fatty acids and explains how lipids in the skin are crucial to the interpretation and treatment of dermatological disease.

IT is about 20 years since essential fatty acids were first widely advocated in veterinary dermatology and their introduction was consolidated in the veterinary literature by a whole issue of Veterinary Dermatology dedicated to understanding their role and usefulness in dogs and cats.1

Since then our knowledge of the structure and function of the skin has increased, indicating that the role of lipids in the skin is crucial to our interpretation and treatment of dermatological disease.

Sources of essential fatty acids 

There are two families of polyunsaturated fatty acids (pFAs). The n-6 fatty acids are derived from linoleic acid (18:2n-6) and are widely found in vegetables and seed oils such as sunflower or evening primrose.

The n-3 fatty acids are derived from alpha-linolenic acid (18:3n-3), which are found in green leafy vegetables. An important metabolite of alpha-linolenic acid, eicosapentaenoic acid (20:5n-3) is found in fish oils.

Both families of pFAs are metabolised by the same pathway of enzymes, which act to desaturate and elongate fatty acid molecules. However, animals cannot convert n-3 to n-6 fatty acids. The epidermis is not equipped with 5-desaturase or 6- desaturase enzymes and most metabolism occurs in the liver.

Linoleic and α-linolenic acids are considered essential in dogs and cats with dietary arachidonic acid also being essential in the cat (see Figure 1).

The functions of epidermal lipids 

Epidermal lipids are important in four main functions of the skin.2 The most important is barrier function, but after this comes moisturisation of the stratum corneum, cohesion and desquamation of keratinocytes and influences upon epidermal proliferation and differentiation.

The skin is present to act as a barrier and the combination of keratin proteins, tight intercellular junctions and the terminal differentiation of the keratinocyte to form the corneocyte is the foundation for this protection. However, without the lipid that fills the spaces between cells, this protection fails.

Lipid is not squeezed between the corneocytes in a random fashion, but the combination of fatty acids, cholesterol, and ceramides is highly organised to form sheets (lipid lamellae) with a defined structure3 and it is the quality of these lipids that determine the permeability of the epidermis.4

The water holding capacity of the skin, measured by transepidermal water loss (TEWL), has been described by several authors.5-8

In disease, skin water is lost from the skin at an increased rate and TEWL is increased. In healthy skin, this is prevented by lipids in the stratum corneum facilitated by amino acids formed by the breakdown of filaggrin (e.g. histadine).

In atopic dermatitis the lipid lamellae are seen to be disrupted9 and TEWL is also increased.6,7,10 However, whereas in man where TEWL is a useful marker of disease severity, this is not so in dogs.11

Desquamation is an essential part of skin defence. Corneocytes are shed into the environment carrying away bacteria, yeasts and other contaminants. Cutaneous lipid abnormalities usually result in scale building up on the skin surface, called retention hyperkeratosis.12

The control of epidermal proliferation and differentiation is highly complex and reflects local environmental effectors and systemic effectors such as hormones. Locally, an inadequate lipid barrier may directly, or indirectly through secondary infection, change the rate of turnover of skin cells and the maturation process.

Eisconanoids produced through the metabolism of fatty acids often cause epidermal hyperplasia and an increased epidermal turnover2, but may cause a reduction in barrier function through reduced development of corneocytes.13

Eicosanoids are derived from fatty acid precursors and have pro- inflammatory and anti-inflammatory actions. The 1-series prostaglandins and thromboxanes are derived from di-homo-γ-linolenic acid, the 5-series leukotrienes and 3-series prostaglandins and thromboxanes are derived from eicosapentanoic acid and a vast array of eicosanoids including the 2-series prostaglandins (e.g. PGD2, PGE2) and thromboxane via cyclo-oxygenase, leukotrienes such as LTB4 (via 5 lipoxygenase) as well as products of 12- and 15- lipoxygenase such as 12-HETE and 15-HETE.

When arachidonic acid is released from the cell wall it is converted immediately into various eicosanoids, the nature of which is determined by the nature of the stimulus, the cell type and the maturation/differentiation of the cell.

As there are long pathways involved in the conversion of essential fatty acids into their active metabolites, there is potential to reduce the production of pro-inflammatory eicosanoids in favour of anti-inflammatory metabolites through supplementation with fatty acids, particularly di-homo-γ-linolenic acid (GLA) and eicosapentaenoic acid (EPA).

EFAs in canine dermatology

Good quality dog foods should contain sufficient levels of linoleic acid for normal dogs and cats. However, even in these normal animals, EFA supplementation will often result in an improvement in coat quality and gloss with an associated reduction of transepidermal water loss (TEWL).14

Where there is seborrhoea sicca, the cutaneous levels of linoleic acid are low and supplementation will restore the levels.15 Excessive cooking may reduce linoleic acid in foods that would otherwise have acceptable levels. Many dogs with scaling skin disease will benefit from EFA supplementation, and EFAs are widely used in idiopathic scaling and sebaceous adenitis.

EFA supplementation is considered to be useful in ichthyosis of the golden retriever by this author16, and is used in combination with baths.

Many clients report an improvement in this scaling condition caused by a mutation in the PNPLA1 gene that has a key role in the lipid organisation and metabolism of the epidermal barrier.17 However, others have reported poor results with EFA supplementation in a small number of cases.18

The use of EFA supplementation for atopic dermatitis and other inflammatory skin diseases in the dog and cat has been the focus of research attention for some time19,20; however, there is still considerable confusion regarding their use. Although widely used, questions that remain to be answered include the optimum dose, optimum ratio of n- 3:n-6 fatty acids and their efficacy.

A number of studies suggest that EFAs are helpful in reducing pruritus or erythema, without undue adverse effects19-22, and in one study the treatment combining shampoo and EFA supplementation was compared favourably to the use of prednisolone23, which is a higher level of efficacy than generally reported.

However, many studies suffer from the lack of a standardisation. Importantly, a standardised diet was not used during many of the trials. This may lead to the wide variation in the EFAs being fed and have a great influence on the results.

Other trials, some as short as two weeks in duration, are too short to allow this food supplement to have maximum effect. Also, a wide variety of products containing EFAs have been tested, including evening primrose oil or borage oil, with or without additional constituents, such as fish oils.

This has resulted in a lack of consensus as to the correct ratio of n-6:n-3 fatty acids and a clear indication of the efficacy of these apparently useful products.

A recent trial addressed the issue of consistency of the diet24 and suggested that dogs with early atopic disease might be more successfully managed using EFA supplementation, but did not continue the trial for the three months recommended by Olivry and colleagues.25

A more recent review26 looked critically at the body of work available and considered two studies to be well-designed and clear evidence for a steroid-sparing effect when using EFAs.27

EFAs in feline dermatology

EFA supplements have been recommended for use in allergic, pruritic disorders in the cat. There are marked differences in the biochemistry of the lipids in the cat as they have no 6-desaturase activity.

This means that di-homo-γ- linolenic acid or arachidonic acid as well as linolenic acid are needed for n-6 fatty acid metabolism. An alternative pathway circumventing the 6-desaturase pathway is suspected, but a diet of 18:2n6 fatty acid will not ameliorate all the cutaneous signs of fatty acid deficiency.

EFAs have been recommended for papulocrusting dermatoses (flea bite hypersensitivity, atopic dermatitis and idiopathic disease).28 A reduced efficacy was noted when n-3 fatty acids were used alone compared to either n-6 fatty acids or a mixture of n-6 and n-3 fatty acids.29 In light of this, tuna and other fish oils may not be beneficial to cats with skin disease.

Adverse effects

Adverse effects of EFA administration have been rarely reported. Perhaps the most serious potential side effect is pancreatitis. Soft stool and contribution to obesity are more common.

Concern that n-3 EFAs may contribute to bleeding disorders and platelet abnormalities have not been supported30 and similarly a recent trial, albeit rather short in duration, does not suggest that EFAs lower the threshold for seizures in epilepsy.31

Recommendations

The role of fatty acids in a healthy skin is clear, but there is still considerable work to be done to hone our knowledge to use these agents effectively. Dogs and cats given EFA supplementation will show beneficial coat changes and may show reduced need for more potent medications to control their inflammatory skin disease.

The low rate of adverse effects makes EFA supplements an ideal treatment for milder cases of atopic dermatitis and as an adjuvant treatment in more severe cases.

1. Lloyd, D. H. (1993) Veterinary Uses of Essential Fatty Acids. Vet Dermatol 4 (4): iii. 2. Kwochka, K. W. (1993) The structure and function of epidermal lipids. Vet Dermatol 4 (4): 151-159.

3. Elias, P. M. (1983) Epidermal Lipids, Barrier Function, and Desquamation. J Invest Dermatol 80 (6 Supplement): 44s- 49s.

4. Elias, P. M. et al (1981) Percutaneous transport in relation to stratum corneum structure and lipid composition. J Invest Dermatol 76 (4): 297-301.

5. Lau-Gillard, P. J. et al. (2010) Evaluation of a hand-held evaporimeter (VapoMeter) for the measurement of transepidermal water loss in healthy dogs. Vet Dermatol 21 (2): 136-145. 

 6. Hightower, K., Marsella, R. and Flynn- Lurie, A. (2010) Effects of age and allergen exposure on transepidermal water loss in a house dust mite-sensitized beagle model of atopic dermatitis. Vet Dermatol 21 (1): 88-95. 

7. Shimada, K. et al (2009) Increased transepidermal water loss and decreased ceramide content in lesional and non- lesional skin of dogs with atopic dermatitis. Vet Dermatol 20 (5-6): 541-546. 

8. Shimada, K. et al (2008) Transepidermal water loss (TEWL) reflects skin barrier function of dog. J Vet Med Sci 70 (8): 841-433. 

 9. Inman, A. O. et al (2001) Electron microscopic observations of stratum corneum intercellular lipids in normal and atopic dogs. Vet Pathol 38 (6): 720-723. 

 10. Cornegliani, L. et al (2012) Transepidermal water loss in healthy and atopic dogs, treated and untreated: a comparative preliminary study. Vet Dermatol 23 (1): 41-44, e9-10.

11. Marsella, R. (2012) Are transepidermal water loss and clinical signs correlated in canine atopic dermatitis? A compilation of studies. Vet Dermatol 23 (3): 238-e49.

12. Milstone, L. M. (2004) Epidermal desquamation. J Dermatol Sci 36 (3): 131-140. 

 13. Jensen, J.-M. et al (2004) Impaired Sphingomyelinase Activity and Epidermal Differentiation in Atopic Dermatitis. J Invest Dermatol 122: 1,423-1,431.

14. Marsh, K. A. et al (2000) Effects of zinc and linoleic acid supplementation on the skin and coat quality of dogs receiving a complete and balanced diet. Vet Dermatol 11: 277-284. 

 15. Campbell, K. L., Uhland, C. F. and Dorn, G. P. (1992) Effects of oral sunflower oil on serum and cutaneous fatty acid concentration profiles in seborrheic dogs. Vet Dermatol 3 (1): 29-35. 

16. Shaw, S. C. (2009) Systemic therapy and mode of action in treating keratinisation disorders. In: Proceedings of the British Veterinary Dermatology Study Group, Autumn Meeting, pp41-44. 

17. Grall, A. et al (2012) PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nat Genet 44 (2): 140- 147. 

 18. Cadiergues, M. C. et al (2008) Cornification defect in the golden retriever: clinical, histopathological, ultrastructural and genetic characterisation. Vet Dermatol 19 (3): 120- 129. 

19. Lloyd, D. H. and Thomsett, L. R. (1989) Essential fatty acid supplementation in the treatment of canine atopy. Vet Dermatol 1: 41-44. 

20. Lloyd, D. H. (1989) Essential fatty acids and skin disease. J Small Anim Pract 30: 207-212. 

21. Bond, R. and Lloyd, D. H. (1993) Double-blind Comparison of Three Concentrated Essential Fatty Acid Supplements in the Management of Canine Atopy. Vet Dermatol 4 (4). 

22. Bond, R. and Lloyd, D. H. (1992) Randomized Single-blind Comparison of an Evening Primrose Oil and Fish Oil Combination and Concentrates of these Oils in the Management of Canine Atopy. Vet Dermatol 3 (6): 215-216. 

23. Reme, C. A. et al (2005) Anti-allergic shampoo and oral essential fatty acid combination therapy to relieve signs of atopic dermatitis in dogs: a blinded, prednisolone-controlled trial (Abstract). Vet Dermatol 16: 355.

24. Abba, C. et al (2005) Essential fatty acids supplementation in different-stage atopic dogs fed on a controlled diet. J Anim Physiol Anim Nutr (Berl) 89: 203-207. 

25. Olivry, T., Marsella, R. and Hillier, A. (2001) The ACVD task force on canine atopic dermatitis (XXIII): are essential fatty acids effective? Vet Immunol Immunopathol 81: 347-362.

26. Olivry, T. et al (2010) Interventions for atopic dermatitis in dogs: a systematic review of randomized controlled trials. Vet Dermatol 21 (1): 4-22. 

27. Saevik, B. K. et al (2004) A randomized, controlled study to evaluate the steroid sparing effect of essential fatty acid supplementation in the treatment of canine atopic dermatitis. Vet Dermatol 15 (3): 137-145. 

28. Harvey, R. G. (1993) Essential fatty acids and the cat. Vet Dermatol 4 (4): 175- 179. 

29. Harvey, R. G. (1993) Effect of varying proportions of evening primrose oil and fish oil on cats with crusting dermatosis (“miliary dermatitis”). Vet Rec 133 (9): 208-211. 

30. Boudreaux, M. K. et al (1997) The effects of varying dietary n-6 to n-3 fatty acid ratios on platelet reactivity, coagulation screening assays, and antithrombin III activity in dogs. J Am Anim Hosp Assoc 33 (3): 235-243. 

31. Matthews, H. et al (2012) Effects of essential fatty acid supplementation in dogs with idiopathic epilepsy: a clinical