To cure occasionally, to relieve often, to comfort always. — Ancient Greek Epigraph Ichthyoses are a heterogeneous group of genetic dermatologic scaling skin disorders characterized by dry, thickened, scaling skin. The name is derived from the Greek word for fish — ichthy — and literally means fish disease, characterizing the scales and plaques formed by the abnormal turnover of the epidermis. Other organs also can be involved. More than 1 million Americans are affected by ichthyosis and its subsequent devastating disfiguring physical, social, and emotional sequalae.1,2 The result of a genetic mutation, ichthyosis has no cure. Treatment is symptom directed. An estimated 28 varieties of ichthyosis are recognized, with four major hereditary types3; lamellar ichthyosis, epidermolytic hyperkeratosis, ichthyosis vulgaris, and X-linked ichthyosis. Ichthyosis is classified on the basis of clinical presentation and inheritance pattern. Disease variations exhibit a wide range of severity and associated symptoms. The classification system depends on a handful of tools and tests to effectively diagnose, classify, and provide appropriate treatment for patients suffering from ichthyosis. The purpose of this case study was to evaluate the use of an over-the-counter product line containing olivamine® in the care of a patient with X-linked ichthyosis.Literature Review Topical treatments for ichthyosis found in the literature include moisturizers,4 emollients,5 humectants,6 water-in-oil emulsions, alpha-hydroxy acids,7 topical retinoids,8 topical steroids,9 topical tacrolimus,10 calcipotriol,11 N-acetylcysteine,12,13 and keratolytics.14 Systemic treatments include oral retinoids,15 the cytochrome P-450 inhibitor liarozole,16 and oral tacrolimus.10 Long- and short-term effectiveness varies with the type of ichthyosis and the kind of treatment. Summarizing the literature, Loden observes that a broad range of treatment side effects have been reported, including skin irritation, itching, burning, pain, abandonment of difficult and/or complicated skin care regimens, and cosmetic issues such as greasiness of different preparations.4 Clinical studies indicate that safety issues are infrequent with the majority of treatment options; oral retinoids produce untoward effects such as retinoid hyperostosis or bone changes in long-term therapy,17,18 hepatic toxicity,15,19 mucocutaneous system side effects such as chelitis and excessive dryness, muscle and joint pain, dry eyes and visual disturbances, and elevated blood lipids.9,20 Treatment success depends on the type of ichthyosis and the therapy. For most patients, it is generally agreed that moisturizers and keratolitics continue to be the mainstay of topical therapy.14 Dermatology researchers argue that endermic nutritionals are effective only when applied directly to the skin’s surface, not by mouth. Clinical studies and pre-clinical studies suggest that no matter how balanced the diet, the benefits of vitamins and other nutritionals are not guaranteed to reach the skin, especially the epidermis, as they could be utilized elsewhere in the body.21,22 According to Lupo,21,22 “The needs of our internal organs, especially those of the cardiovascular system, most likely trump the skin’s.” Applied topically, however, clinical studies have shown that properly formulated and stabilized vitamins can penetrate the top layer of skin so their benefits can be directed toward the complexion.21,22 Many cosmeceutical and biotech companies conduct research and development in the arena of aesthetics and anti-aging of the skin; however, few wound and skin care companies have marketed products with these characteristics with the intent to treat aged and compromised skin and prevent wounds and breaks in the skin’s integrity. Several studies describe nourishing the skin externally/endermically to increase integrity and health.23-28 Pre-clinical and clinical research has addressed the effects of endermic nutrition on various dermatologic conditions as well as its anti-aging capabilities. One of the most important skin treatment discoveries to date, the 500 Dalton Rule29 enhances understanding of topically treating and nourishing the skin using diffused ingredients and serves as the fundamental guide for the development of corneotheraputic products. The rule is based on the fact that molecules with a molecular weight of less that 500 Daltons can enter or exit the skin. All known topical drugs used in transcutaneous drug delivery systems are under 500 Daltons.29 The skin “allows” water (via diaphoresis or TEWL) and carbon dioxide to exit and amino acids, vitamins, water, and oxygen to enter. After transdermal penetration, the next goal is to increase bioavailability. Bioavailability is the percentage of an ingredient/drug that travels to the area of need (epidermis) in a form that can be recognized and used by the cells in that region.30 Antioxidants and free radicals. An antioxidant is generally defined as a chemical that prevents the oxidation of other chemicals, protecting the proper functioning of a system such as a cell.31 Antioxidants decrease cell damage by reducing the effect of oxidants before they can damage the cell,32 and create cellular homeostasis. Antioxidants are among the most important chemical combatants known to science and are fundamental in, among other effects on cells, the skin repair compendium. Antioxidants, especially hydroxytyrosol and L-taurine, repair the cell membranes and restore cells to a healthy state, making advanced skin repair possible. Hydroxytyrosol is a phenolic compound that scavenges radicals and inhibits neutrophil respiratory bursts.33 Clinical studies show that unlike other antioxidants, hydroxytyrosol is unaltered by the body’s reactive process and cellular metabolism.34 Clinical research has shown the broad antioxidant activity of hydroxytyrosol35,36 and olive oil phenolics.37 These and other polyphenols exhibit beneficial effects in vivo and/or in vitro against inflammation,38 atherosclerosis,39,40 antimicrobial activity,41 cancer,42 oxidative stress from passive cigarette smoke,34,43 and skin damage and photoprotection.44 Hydroxytyrosol, a substance in olives and virgin olive oil,45 has been found to be the most powerful antioxidant available today. Oxygen Radical Absorbance Capacity (ORAC) values, a standardized test adopted by the US Department of Agriculture to measure the total antioxidant potency of foods and nutritional supplements, provides a precise way of establishing the free-radical destroying or neutralizing power of a particular food supplement or compound. According to ORAC, hydroxytyrosol in olives and olive oil exceeds amounts in green tea and grape seed extract.46 A typical free radical is a molecule that has lost an electron and become positively charged. Because a free radical always will try to ensure its stability, it will bond with or attack another atom and steal an electron, creating a new free radical through the process of oxidation. Rusting metal, an apple turning brown, and meat going bad are examples of environmental oxidation. In the human body, oxidation is believed to be responsible for premature aging, wrinkling of the skin, and other diseases linked to chronic inflammation; in skin and wound repair, oxidative damage weakens cells, making the repair process arduous.47 Free radicals are generated largely during the production of adenosine triphosphate (ATP) in mitochondria. During this process, radicals leaking from the mitochondria form reactive oxygen species (eg, superoxide anion and hydroxyl radicals).47 These radicals have both beneficial and harmful actions in biologic tissues. As a potentially dangerous byproduct of cellular metabolism, they can directly influence cell growth, development, and survival and likely increase the pathogenesis of atherosclerosis, cancer, aging, and several other conditions, including inflammatory disease.47 Free radicals can cause oxidative damage to DNA, inducing a cascade effect that results in the disruption of all living cells by reducing the body’s defenses against free radicals. It has been suggested that the extent of damage caused by free radicals might be modified through several strategies, including supplementation of one or more dietary and topical antioxidants.26,47-49 Normally, the body can handle free radicals, but if its natural antioxidants are unavailable or if the free radical production becomes excessive, cellular damage can occur. Free radical damage, such as occurs in aging, is cumulative. Cell walls lose their structure and the cellular organelles are expelled, causing cell death. The skin’s protein — collagen — is particularly susceptible to free-radical damage, which causes the collagen protein molecules to break down and link back up again in a different way. It has been shown that this cross-linking causes normally mobile collagen to become stiff and less movable, potentially injuring the skin.50,51 Methylsulfonylmethane. Methylsulfonylmethane (MSM), a fundamental sulphur, is a naturally occurring anti-inflammatory agent52-56 that may inhibit or slow pain fiber conduction.57 These pain fibers (nerve endings) lack the protective myelin sheath and are responsible for the pain experienced by patients with low pain threshold (“stingers”). Reducing the pain and stinging (a complaint of many patients suffering from ichthyosis) associated with advanced skin care is an important hallmark of contemporary skin therapy. Additionally, MSM has been purported to have anti-cancer properties.58-60 Amino acids. In vitro clinical studies61 have demonstrated that the use of topical amino acids as nutritional supplements can cause an inflammatory response. Laser homogenization of these molecules has been shown to reduce the inflammatory response, increasing the bioavailability of the amino acid on a biochemical basis; untreated amino acids produce more than 11 times the inflammatory effect of treated amino acids. A patented laser optical technology used to alter the molecular configuration of amino acids employs holographic technology and light waves to generate wave forms, resonating to create more uniform molecular structures without degrading nutritional or treatment values.61 The amino acids in quatrapeptide olivamine have been treated with this laser to reduce the negative effect of topical amino acid application.61 The photo acoustic resonance method combines amino acids, antioxidants and their cofactors, and MSM to provide the nutrients to restore the skin without increasing inflammation. In addition, amino acids cannot work alone; they require cofactors — primarily vitamins A, C, D3, B6, and B3 (as niacinamide) — to increase their bioavailability and “activate” the amino acids. For example, in vitro studies have shown that vitamin C is essential for the creation of collagen.62 The properties of the aforementioned ingredients that differentiate the over-the-counter skin care line of products containing olivamine® from other topical treatments may be relevant to symptoms of ichthyosis.Case Study Mr. M is an African American who was diagnosed with ichthyosis at age 10 months. He has the X-linked type of ichthyosis, also known as steroid deficiency (of the enzyme, steroid sulfatase) or recessive X-linked ichthyosis. Female carriers are asymptomatic.3 The disease has been estimated to occur in 1:60,000 men and is usually apparent soon after birth. Key clinical observations include small, dark, firmly adherent scales, accentuated on the side of the neck and trunk, generally sparing the face, palms, soles, and antecubital and popliteal spaces. Mr. M is a classic example of X-linked ichthyosis, where epidermal turnover is normal and the accumulated scale is thought to be due to faulty shedding of the stratum corneum.3 At the time of treatment, Mr. M was 44-years-old with a history of hypertension and status post myocardial infarction unrelated to his ichthyosis. He recently lost 70 lb by dieting. His ichthyosis has been treated unsuccessfully with rock salt, scrubbing with a wire brush, motor oil soaks, Saran® wraps, bleach soaks, topical salicylates and poly hydroxy acid-containing lotions such as Lac-Hydrin® 12% (Bristol-Myers Squibb Company, Princeton, NJ), oil-in-water emulsions such as Eucerin® (Beiersdorf, Inc., Wilton, Conn), and hydrocarbon-based products such as Aquaphor® Ointment (Beiersdorf, Inc., Wilton, Conn); these approaches are noted in the literature.1-6,8,9 None provided him lasting physical or cosmetic relief. He described periods of intense itching, raw/bleeding skin, pain, and constant irritation. Despite some success with the poly hydroxy lotions, the condition always returned with a vengeance, his skin becoming increasingly thicker and itchier. In 1995, oral retinoids were prescribed and abandoned when his skin condition showed no improvement. Over time, Mr. M lost hope of overcoming his ichthyosis and became depressed and isolated. He also described frequent skin odor and tinea pedis in the interdigital web spaces. When he first visited the clinic, in January 2005, Mr. M was a quiet, reclusive gentleman who worked three jobs as a maintenance man to support his family. He was self-conscious about his appearance and had learned to cover his body with clothing to conceal his skin condition. His chief complaint was ichthyosis. When asked about his treatment goals, Mr. M said, “To be able to wear shorts and not itch or be in pain anymore.”Treatment Topical treatment with an over-the-counter (OTC) skin care line containing olivamine®, a quadrapeptide that combines amino acids, vitamins, antioxidants, MSM, and water-resistant silicones, and utilizes surfactant-free phospholipids cleansers that may help nourish the skin22 was initiated. This approach — administering bio-available amino acids and other nutrients — is a rather new concept in the literature and referred to as corneotherapy.24,25,63-67 Before his treatment with olivamine-containing skin care products, Mr. M’s left anterior arm showed substantial skin involvement (see Figures 1 and 2). The new therapy was implemented with the goal of nourishing his compromised skin.Protocol Mr. M was instructed by the clinician to cleanse the test area (left arm) with olivamine-containing, surfactant-free cleanser (Remedy® 4-in-1 Cleansing Lotion, Medline Industries, Inc., Mundelein, Ill); pat dry; and apply skin repair moisturizing cream (Remedy Skin Repair Cream, Medline Industries, Inc., Mundelein, Ill), daily. These measures were to be followed by application of a silicone-containing protectant cream (Remedy Nutrashield, Medline Industries, Inc., Mundelein, Ill), that has been found to reduce excessive transepidermal water loss (e-TEWL) in in vitro experiments.68 Additionally, Mr. M used an antimicrobial version of the surfactant-free cleaners (Remedy 4-in-1 Antimicrobial Cleanser, Medline Industries, Inc., Mundelein, Ill) for areas with odor and high risk for infection. For the frequent fungal infections of his feet, Mr. M was instructed to use a nutritive antifungal cream with 2% miconozole nitrate (Remedy Antifungal Cream, Medline Industries, Inc., Mundelein, Ill). Outcomes The fungal infection on his feet quickly resolved. During the first week of treatment, the test area on Mr. M’s arm began to exfoliate and he reported an immediate decrease in itching and discomfort. By week 2, some areas of skin on the left arm resumed a more normal appearance and by week 3, the entire test area was improving (see Figure 3). At week 4, the skin was totally clear of thickened scales and Mr. M reported no itching in the treated area (see Figure 4). At his final visit, Mr. M remarked, “People have noticed that my skin is getting better. I feel just great. I don’t itch or have any pain in this area. I feel like a new man!”Prognosis After successful treatment of his arm, Mr. M was anxious to continue treatment on the other affected areas of his body. He was eager for summer to arrive since he felt for the first time in decades he will be able to wear shorts and not feel embarrassed by his ichthyosis. The treatment area remained free of any build-up of skin scales and Mr. M experienced no further itching unlike with previous treatments. After complete clearing of his thickened sclerotic epidermis, good results are maintained by cleansing with the phospholipids product and applying the nutritional skin protectant containing silicones once daily to prevent the buildup of the epidermis. The skin remains clear and supple more than 2 months post treatment and Mr. M reports no pain or itching. Discussion The rationale for using the nutritional skin care products was based on the fact that Mr. M had tried and abandoned the usual accepted medical treatment for his condition. He was despondent, depressed, feeling hopeless, and increasingly reclusive. The products were easy to use and incorporate with his busy schedule and his symptoms improved rapidly. In addition to the potential effects of olivamine, the active ingredient in all products used by this patient,69 other ingredients such as the silicones in the protectant and antifungal creams may have facilitated the observed improvement. Silicones not only help deliver the active ingredients and nutrients in a prolonged time frame,68 but they also may help protect the skin and prevent transepidermal water loss.68,70 Most moisturizers (eg, petrolatum) provide an occlusive barrier over the skin’s surface that stops water loss and prevents dehydration; however, skin respiration is decreased.70 The use of cleansers that are soap- and surfactant-free, also may have helped reduce the symptoms of ichthyosis because they do not dehydrate or irritate skin. Cleansers can be described in terms of hierarchy.23 Ingredients with soaps (eg, sodium cocoyl and sodium talowate) are members of the first-generation, and most alkaline, cleansers. Liquid cleansers (eg, synthetic detergents or surfactants such as sodium lauryl sulfate) that contain surfactants are considered second-generation cleansers. Surfactants are generally classified by their ionic (electrical) charge — eg, soap is an anionic (negative electrical charge) surfactant with a high pH. Most cleansers are pH-balanced and less drying than soap but can still strip skin. Cleanser surfactants can bind to stratum corneum proteins, leading to transient swelling and hyper-hydration under wash conditions,71-73 usually followed by de-swelling (while the water evaporates) and leading to drying stress.70-72 Swelling also allows surfactants and other cleanser ingredients to penetrate into deeper layers, potentially causing a biochemical response which, in turn, can negatively affect skin hydration and viscoelasticity.71-73 Products with phospholipids are third-generation cleansers. Phospholipids mimic the body’s natural lipid requirements, cleaning without compromising, drying, or stripping the skin.24,25 Olivamine-containing skin cleansers contain phospholipids instead of surfactants. Because phospholipids are hygroscopic (attract water from the surrounding air) and hold water where an increased level of hydration is needed, they increase the hydration levels of the skin without being occlusive (forming a film to prevent water loss and preventing normal cellular function). A recent in vitro study74 demonstrated the value of topically applied phospholipids in skin care. It was shown that environmental factors (sun, wind, pollution) and the detergents and solvents found in most skin cleansers stripped the natural phospholipid content from the top layer of skin. This loss resulted in a rough feel and a pitted appearance under a microscope. Phospholipids in the uppermost skin layers cannot be replaced by natural cell function because the top layer cells no longer metabolize; they serve only as a protective barrier. Epidermal occlusion, defined for this review as occlusion from environmental oxygen, is not desirable for patients with ichthyosis. Approximately 2% of the body’s total need for oxygen is met via atmospheric oxygen through the skin.75 The upper skin layers to a depth of 0.2 mm to 0.40 mm are almost entirely supplied by atmospheric oxygen. Because the stratum corneum is 0.04 mm to 0.1 mm thick, 70% to 80% of the epidermis is supplied by atmospheric oxygen exclusively.76 The epidermis, unlike the dermis, has no vasculature (blood flow) — rather, it is exposed directly to the atmosphere. The effects of epidermal skin occlusion include increased vulnerability to chemicals and infection, prevention of normal TEWL and gland secretion, inhibition of barrier repair, suppression of barrier recovery, and reduction of epidermal proliferative response.76-79 Many skin care products used for the treatment of dry skin, xerosis, and ichthyosis contain occlusive agents. Petrolatum, frequently used for various types of ichthyosis and other dry skin conditions, is an occlusive agent that blocks the atmospheric oxygen supply to the epidermis.80 In addition, petrolatum blocks normal cellular respiration and traps toxins and moisture, increasing risk for infection. Since the olivamine-containing products contain no occlusive ingredients, it is hypothesized that the carrier as well as the nutritive qualities of the olivamine-containing products could have had a positive effect on this patient. Conclusion This case study suggests that use of an over-the-counter skin therapy product line can resolve symptoms of severe ichthyosis without some of the side effects reported following the use of other treatment modalities. Studies to ascertain the effect of these products on other dermatologic conditions are warranted. Acknowledgment The author thanks Joseph Leuchtmann for his assistance with photography, data collection, and patient communication for this case study.