CHAPTER 11 Keratinization Defects

Keratinization defects are those that alter the surface appearance of the skin. The epidermis of animals is being replaced constantly by new cells. The epidermal cell renewal time in normal horses is approximately 17 days.¹ Despite this high turnover rate, the epidermis maintains its normal thickness, has a barely perceptible surface keratin layer, and loses its dead cells invisibly into the environment. If the delicate balance between cell death and renewal is altered, the epidermal thickness changes, the stratum corneum becomes noticeable, and the normally invisible sloughed cells of the stratum corneum become obvious. The causes of keratinization defects are numerous; they produce clinical signs by altering proliferation, differentiation, desquamation, or some combination of these.^6,^10,¹² Alterations in epidermal lipid formation and deposition can accompany these other changes.⁷

A characteristic of healthy skin is that the relationship between transepidermal water loss and hydration remains directly proportional.² Following skin damage or a decrease in efficiency of the water barrier, a dissociation between hydration (water-holding capacity) and transepidermal water loss occurs. In pathologic skin, the correlation between transepidermal water loss and stratum corneum water content shows an inverse relationship due to a damaged skin barrier or alterations in keratinization, or both. Hence, there is increased transepidermal water loss and decreased hydration.

Dryness (xerosis) of the skin is caused by decreased water content, which must be more than 10% in the stratum corneum for skin to appear and feel normal.³ Moisture loss occurs through evaporation to the environment under low humidity conditions and must be replenished by water from lower epidermal and dermal layers. In xerotic skin, the stratum corneum is thickened, disorganized, and fissured. An important part of the stratum corneum barrier is the presence of three intercellular lipids: sphingolipids, free sterols, and free fatty acids. Lamellar bodies are an essential part of this barrier both to trap and to prevent excess water loss. The optimal stratum corneum water concentration to promote softness and pliability is 20-35%.

Antiseborrheic treatments

Antiseborrheic agents are available as ointments, creams, gels, lotions, and shampoos. In veterinary medicine, seborrheic lesions are usually widespread in nature and occur in haired skin, thus making shampoo the most appropriate vehicle. For the most part, veterinary shampoo formulations are not patented, and “identical” products can be marketed by one or more generic manufacturers. The reader is advised to approach these products carefully. Although the active ingredients may be identical in name and concentration, the purity, stability, and irritability of the active and inert ingredients may be very different and the shampoo may perform poorly. If a change from one brand of the “same” shampoo to another is contemplated, it is best to give the new product to the clients who have been using the shampoo to be replaced. If they believe that the new product is equally as good as or better than the old one, the change can be made.

Antiseborrheics are commercially available in various combinations.^9,¹⁰ The clinician must decide which combination of drugs to use and needs to know each drug’s actions and concentrations. Ideal therapeutic response depends on the correct choice, but variations among individual patients do occur. For dry and scaly seborrhea (seborrhea sicca), a different preparation is needed than for oily and greasy seborrhea (seborrhea oleosa). Sulfur, for instance, is useful in dry seborrhea, but it is not a good degreaser. Benzoyl peroxide, on the other hand, degreases well but can be too keratolytic and drying for dry, brittle skin. The following discussion may help the clinician understand the differences and uses and help distinguish the correct medication from among the myriad of commercially available pharmaceuticals.

Antiseborrheic drugs include keratolytic and keratoplastic ingredients. Keratolytic agents facilitate decreased cohesion among corneocytes, desquamation, and shedding, resulting in a softening of the stratum corneum with easy removal of scale. They do not dissolve keratin. Keratoplastic agents attempt to renormalize the keratinization and abnormal epithelialization that is present in keratinization disorders. The complete mechanism of these effects is not known, although some keratoplastic agents (particularly tar) are believed to normalize epidermal proliferation by decreasing deoxyribonucleic acid (DNA) production with a resultant decrease in the mitotic index of the epidermal basal cells. Follicular flushing is a term used to describe agents that help remove follicular secretions, remove bacteria, and decrease follicular hyperkeratosis. The most common major ingredients in antiseborrheic shampoos include tars, sulfur, salicylic acid, benzoyl peroxide, and selenium sulfide. Other commonly included active agents are urea, glycerin, and lactic acid.

Sulfur is both keratoplastic and keratolytic, probably through the interaction of sulfur with cysteine in keratinocytes. It is a mild follicular flushing agent, but not a good degreaser. Sulfur is also antibacterial, antifungal, and antiparasitic, and these actions are attributed to the formation of pentathionic acid and hydrogen sulfide. The smaller the sulfur particles (colloidal are smaller than precipitated), the greater the efficacy. The best keratolytic action occurs when sulfur is incorporated in petrolatum. This is in sharp contrast to the findings with salicylic acid, which produces its effect faster when employed in an emulsion base. The keratolytic effect of sulfur results from its superficial effect on the horny layer and the formation of hydrogen sulfide. The keratoplastic effect is caused by the deeper action of the sulfur on the basal layer of the epidermis and by the formation of cystine.

In the shampoos marketed in North America by the well-recognized manufacturers of dermatologicals, a pure sulfur product cannot be purchased. Because of the synergistic activity between sulfur and salicylic acid, all “sulfur” shampoos contain both ingredients. Popular sulfur shampoos include SebaLyt (DVM Pharmaceuticals), SeboRx (DVM Pharmaceuticals), Micro Pearls Advantage Seba-Hex shampoo (Vétoquinol), and Sebolux (Virbac).

Salicylic acid (0.1-2%) is keratoplastic and exerts a favorable influence on the formation of the new keratinous layer. It is also mildly antipruritic and bacteriostatic. In stronger concentrations (3-6%), it solubilizes the intercellular “cement,” thus acting as a keratolytic agent, causing shedding and softening of the stratum corneum. When salicylic acid is combined with sulfur, it is believed that a synergistic effect occurs. A common combination is a 2-6% concentration of each drug. In human dermatologic practice, a 40% salicylic acid plaster is used to treat calluses and warts.

Tar preparations are derived from destructive distillation of bituminous coal or wood. Birch tar, juniper tar, and coal tar are crude products listed in order of increasing capacity to irritate. Coal tar solution (5%, 10%, or 20%) produces a milder, more readily managed effect. Coal tar solution contains only 20% of the coal tar present in coal tar extract or refined tar. Most pharmaceutical preparations for dermatologic use have been highly refined to decrease the staining effect and the strong odor. In this refining process, some of the beneficial effects of tar are lost, and its potential carcinogenic danger is also decreased. Unadulterated tar products have no place in equine practice because of their toxicity and tendency to cause local irritation. All tars are odiferous, potentially irritating and photosensitizing, and carcinogenic. Some tars may stain light-colored coats. In the authors’ experience, tars are the most irritating topical antiseborrheic medications in veterinary dermatology, and we do not use tar-containing topical preparations.

Tar shampoos are widely used, however, and seem to be helpful in managing seborrhea. They are keratolytic, keratoplastic, and mildly degreasing. As with sulfur shampoos, tar products usually contain other ingredients, usually sulfur and salicylic acid. Popular combination products include LyTar (DVM Pharmaceuticals), NuSal-T (DVM Pharmaceuticals), Allerseb-T (Virbac), and T-Lux (Virbac).

Benzoyl peroxide (2.5-5%) is keratolytic, antibacterial, degreasing, antipruritic, and follicular flushing. It is metabolized in the skin to benzoic acid, which lyses the intercellular substance in the horny layer to account for its keratolytic effect. It is not a stable ingredient and should not be repackaged, diluted, or mixed with other products. Benzoyl peroxide has a drying effect, can induce a contact dermatitis (in less than 10% of patients), and bleaches hair, clothing, and furniture. Skin tumor-promoting activity has been documented in laboratory rodents, but no such activity has been documented in any other species.

Benzoyl peroxide is available as a 5% gel (OxyDex, DVM Pharmaceuticals; Pyoben, Virbac) and as a 2.5-3% shampoo (OxyDex, DVM Pharmaceuticals; Micro Pearls Advantage Benzoyl-plus shampoo, Vétoquinol; Pyoben, Virbac). One product is available that also contains sulfur (Sulf OxyDex, DVM Pharmaceuticals). Only reputable benzoyl peroxide products should be used, because poor products have short shelf lives, little activity, or increased irritation potential. Because of its potent degreasing action, benzoyl peroxide dries out normal skin excessively with prolonged use, and it is generally contraindicated in the presence of dry skin or significant irritation, or both. Benzoyl peroxide combined with a liposome-based (Novasome microvesicles) humectant (Micro Pearls Advantage Benzoyl-Plus shampoo) eliminates or minimizes this drying effect.

Selenium sulfide alters the epidermal turnover rate and interferes with the hydrogen bond formation in keratin. It is keratolytic, keratoplastic, and very degreasing. At the time of writing this book, there are no selenium sulfide shampoos marketed specifically for veterinary use in North America. The human product that contains 1% selenium sulfide (Selsun Blue, Abbot Laboratories) is effective in horses and usually is not too irritating.

In human medicine, there are dozens of keratolytic and keratoplastic agents marketed in the cream, gel, or ointment formulation. Few are marketed in veterinary medicine, and most are generic products (e.g., 10% sulfur ointment, ichthammol ointment, zinc oxide, and thuja) or products marketed for other purposes (e.g., petroleum jelly, udder balm). KeraSolv Gel (DVM Pharmaceuticals) contains 6.6% salicylic acid, 5% sodium lactate, and 5% urea in a propylene glycol gel and is an effective local treatment for hyperkeratotic lesions, for example, cannon keratosis.

In the process of removing the excessive scale or grease, antiseborrheic products can damage the stratum corneum and alter the hydration of the epidermis.¹⁰ Excessively low humidity can cause similar alterations. Emollients and moisturizers are used to counteract these effects.

Emollients are agents that soften or soothe the skin, whereas moisturizers increase the water content of the stratum corneum. Both types of drugs are useful in hydrating and softening the skin. Many of the occlusive emollients are actually oils (safflower, sesame, and mineral oil) or contain lanolin. These emollients decrease transepidermal water loss and cause moisturization. These agents work best if they are applied immediately after saturation of the stratum corneum with water. For maximal softening, the skin should be hydrated in wet dressings, dried, and covered with an occlusive hydrophobic oil. The barrier to water loss can be further strengthened by covering the local lesion with plastic wrap under a bandage. Nonocclusive emollients are relatively ineffective in retaining moisture. Examples of emollients include vegetable oils (olive, cottonseed, corn, and peanut oil), animal oils (lard, whale oil, anhydrous lanolin, and lanolin with 25-30% water), silicones, hydrocarbons (paraffin and petrolatum [mineral oil]), and waxes (white wax [bleached beeswax], yellow wax [beeswax], and spermaceti). Hygroscopic (humectant) agents are moisturizers that work by being incorporated into the stratum corneum and attracting water. These agents draw water from the deep epidermis and dermis and from the environment if the relative humidity is greater than 70%.³ These agents, such as propylene glycol, glycerin, colloidal oatmeal, urea, sodium lactate, and lactic acid, may also be applied between baths. Both occlusive and hygroscopic agents are found in a variety of veterinary spray and cream rinse formulations, which are matched to a corresponding shampoo—for example, HyLyt* EFA cream rinse and shampoo (DVM Pharmaceuticals).

The addition of novasomes or spherulites to veterinary antiseborrheics has increased the efficacy of the products while decreasing the labor intensity of the treatments. As discussed in Chapter 3, these are tiny capsules incorporated into shampoos that adhere to the skin and hair and remain there after rinsing. In a time-dependent fashion, some of the capsules disintegrate and release either water and lipids (novasomes) or active ingredients with or without moisturizers (spherulites). The number of studies documenting their efficacy is limited.

Systemic antiseborrheic agents are used primarily in the treatment of the congenitohereditary seborrheic disorders (e.g., primary seborrhea, ichthyosis).^4,¹⁰ Because most of the generalized secondary seborrheas are due to altered environmental conditions, dietary deficiency, metabolic abnormalities, or other correctable disorders, systemic treatments are rarely considered and probably would be of little value. These agents might be useful in those idiopathic conditions in which the defect appears to be due to altered keratinization; for example, primary seborrhea and cannon keratosis.

Retinoids are the most commonly used systemic antiseborrheic agents in veterinary medicine. Retinoids refer to all the chemicals, natural or synthetic, that have vitamin A activity. Synthetic retinoids are primarily retinol, retinoic acid, or retinal derivatives or analogs. They have been developed with the intent of amplifying certain biologic effects while being less toxic than their natural precursors. More than 1500 synthetic retinoids have been developed and evaluated.^4,¹⁰ Different synthetic drugs, all classed as synthetic retinoids, may have profoundly different pharmacologic effects, side effects, and disease indications.

Naturally occurring vitamin A is an alcohol, all-trans

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