SUMMARY ARTICLE

A Primer on Pigmentation David G. Greenhalgh, MD, FACS

There is at least a temporary loss of skin pigmentation with all but first-degree burns. Commonly, pigment changes persist for months, and sometimes, permanent changes in skin color add to the ultimate change in appearance that commonly affects burn patients. There are many different treatment modalities for the treatment of pigment changes, but most of them have little scientific basis and often lead to disappointing results. The purpose of this review is to discuss the molecular and cellular mechanisms of skin pigmentation, mechanisms of repigmentation after burns, treatment options for dealing with pigmentation changes, and advice for dealing with the sun after burn injury. (J Burn Care Res 2015;36:247–257)

There are significant pigmentation changes that occur after a burn injury. Anyone who suffers from a seconddegree (partial-thickness) burn loses the outer most layer of skin—the epidermis. Because the epidermis contains our pigment, second-degree or deeper burns that heal spontaneously are initially pink and unpigmented. The purpose of this review is to discuss what determines the color of skin and how wounds regain pigmentation. Treatment options for pigmentary changes are also discussed. Another confusing issue is how a burn survivor should deal with sun exposure. Some burn patients have been told to totally avoid the sun for a year or even for their lifetimes. Others are told that sun exposure is acceptable if they use some type of protection. What is the right approach? This review will provide the reader with some of the concepts behind managing repigmentation after burn injury.

PIGMENTATION The color of our skin is determined by four pigments: melanin (brown/black), carotene (yellow), oxygenated hemoglobin (red), and reduced hemoglobin (blue).1 The main pigment, melanin, is found in the bottom of the epidermis.2–6 Melanin gives skin the From the Shriners Hospitals for Children Northern California, Sacramento; Firefighters Regional Burn Center at University of California, Davis; and Department of Surgery, University of California, Davis. Address correspondence to David G. Greenhalgh, MD, FACS, 2425 Stockton Blvd., Sacramento, California 95817. Email: david. [email protected] Copyright © 2014 by the American Burn Association 1559-047X/2015 DOI: 10.1097/BCR.0000000000000224

brown or black pigment that defines our skin color— ranging from white to black. There are two types of melanin produced—eumelanin (black-brown) and pheomelanin (yellow-red), which explains the varied colors of people. The other pigments play a lesser role in skin color. Carotene, a byproduct of vitamin A, is found in the dermis and epidermis and provides yellow coloring. Eating too many carrots can lead to an accentuation of the yellow color. Carotene is the main pigment of feathers, whereas melanin dominates skin and hair pigment.6 Although the process is influenced by skin perfusion, hemoglobin appears either red if it is oxygenated (such as with blushing) or blue when not oxygenated or reduced (such as when people are cold). Pathologic processes may also affect the color of skin. Because of shifts in dermal blood supply, people often appear gray or green after syncope. Yellow skin may be the result of too much bilirubin (icterus) that occurs with biliary obstruction or cirrhosis. Hemosiderin and other products of excess iron that are deposited in the tissues in chronic venous stasis also lead to hyperpigmentation.5 The predominant pigment of skin and hair is melanin. The biochemistry of melanin production is well described but relatively complicated.2–4,6–8 The ultimate precursor is tyrosine, which undergoes hydroxylation by a copper-dependent enzyme called tyrosinase (TYR) to produce β-3,4dihydroxyphenylalanine (DOPA), which then leads to DOPAquinone. From DOPAquinone, the pathway splits to synthesize either eumelanin or pheomelanin. For the eumelanin pathway, DOPAchrome is created by spontaneous oxidation and then two key enzymes DOPAchrome tautomerase (DCT, 247



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also known as tyrosine-related protein-2 [TYRP2]) and tyrosine-related protein-1 (TYRP1), which ultimately lead to the synthesis of eumelanin (­ Figure 1). If DOPAquinone acquires cysteines through a

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separate pathway, pheomelanin is produced. The first reaction using tyrosinase is the rate-limiting step for all melanogenesis. TYR, TYRP1, and TYRP2 are essential for melanin production. A related pigment

Figure 1.  The biochemical and cellular pathways of melanosome production in response to UV light. Ultraviolet (UV) light exposure to a keratinocyte that overcomes the protection of melanosomes (brown/black ovals) leads to DNA stress. Sunscreen and protective clothing inhibit this reaction. DNA stress leads to proteins, such as p53, that assist with DNA repair and, at the same time, lead to production of proopiomelanocortin (POMC). POMC is the precursor of α-MSH, which is secreted from the keratinocyte and binds to its receptor (MC1R). MC1R activation increases adenyl cyclase to produce cAMP. Epinephrine binding to the β-adrenergic receptor (betaAR) also increases adenyl cyclase activity, whereas UV light activates bone matrix protein receptors to inhibit the activation. Many other cytokines (described in the text) influence the activity of melanin synthesis. cAMP activity is prolonged by inhibiting its breakdown through phosphodiesterase 4D3 inhibitors (PDEI4). cAMP then activates protein kinase A (PKA) to phosphorylate CREB, which then binds to the CREB responsive element (CRE) to produce the main activator or melanin production (MITF). Signaling through steel factor which binds to the receptor cKIT produces MAP kinases that in turn phosphorylate MITF to produce tyrosinase (TYR), TYRP1 (or DCT), and TYRP2. Tyrosinase is the rate-limiting enzyme for converting tyrosine to DOPA and DOPAquinone. Dopaquinone can either take on cysteines to lead to the red pigment pheomelanin or with the use of TYRP2 and TYRP1 produce the brown/black pigment eumelanin. Melanosomes start off as empty lysosome-like structures (stage 1) that pick up either pigment at stage 2. The pigments are then concentrated into stage 3 and stage 4 melanosomes as they travel up actin filaments with the assistance of kinesin/myosin motors to the tip of dendrites. The keratinocyte has special receptors called protease-activated receptor-2 (PAR2) that accept the melanosomes. The melanosomes are then transferred to the keratinocyte by processes resembling phagocytosis. Once in the keratinocyte, the melanosomes are transferred to above the nucleus to provide more protection from UV light—leading to a tan.

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“neuromelanin” is produced by dopaminergic neurons in the substantia nigra of the brain. These central nervous system cells are similar in origin to the cells (melanocytes) producing pigment in the epidermis. Slight variations (polymorphisms) in the structure of all of these proteins and enzymes lead to the various colors of skin. Various defects in the same molecules or their biochemical pathways lead to all sorts of congenital pigment abnormalities, such as albinism, that are well described in other reviews (and will not be covered here).2–4,6–8 Specialized cells called “melanocytes” synthesize melanin. These cells are derived from “melanoblasts” that form in the second month of embryonic life.2,3 Melanocytes are derived from the neural crest of the dorsal most point of the developing neural tube. Melanoblasts then migrate to the dermis by 10 to 12 weeks and to the epidermis around 12 to 14 weeks of gestation. Melanoblasts are directed by specific receptors (especially the cKIT receptor) that recognize specific target ligands—“steel factor” to migrate to their ultimate resting site in the skin. Once the melanoblasts arrive at the skin (as early as 50 days gestation), they differentiate into melanocytes. The dermal melanocytes gradually decline in numbers, whereas the epidermal melanocytes proliferate and become established at the epidermal–dermal junction and start producing melanin by 4 months and are well established by 6 months gestation. As people age, their melanocyte numbers remain constant until the fourth to fifth decades when their numbers gradually decrease.9 Melanin is stored in special cell organelles called “melanosomes” that have a lysosome-like structure. Melanosomes are included in a family of cell-specific organelles “lysosome-related organelles” that contain acid-dependent hydrolases and lysosomalassociated membrane proteins.4 Included in the family of lysosome-related organelles are lytic granules of cytotoxic T lymphocytes and natural killer cells, major histocompatibility complex class II compartments seen in antigen-presenting cells, platelet-dense granules, basophil granules, azurophil granules of neutrophils and Weibel-Palade bodies of endothelial cells.4 Melanosomes undergo four stages of development2–8 (Figure 1). They are assembled in the perinuclear region near Golgi stacks where they receive all of the enzymes and structural proteins required to make melanin. In Stage I, they are essentially empty vacuoles that start to form intraluminal fibrils. In Stage II, the intraluminal fibrils develop a meshwork and they pick up tyrosinase and an essential structural protein—Pmell7. In Stage III, melanin is synthesized and deposited on the intraluminal fibrils.

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Stage IV melanosomes are full of melanin and have minimal tyrosinase activity. The structure and size of melanosomes vary depending on whether they have eumelanin (elliptical) or pheomelanin (round). The melanocytes are then ready to distribute their melanosomes packages to the keratinocytes. Melanocyte viability and melanin production are regulated through several factors.2–4 Signals produced in response to inflammation have profound effects on pigmentation, which may explain some of the hyperpigmentation we see in burn patients.3,10 Endothelin-1, steel factor (also known as stem cell factor), inflammatory mediators (prostaglandins [PGE2, PGF2α] and leukotrienes), neurotrophins, fibroblast growth factor-2 (basic fibroblast growth factor), hepatic growth factor, granulocyte-macrophage colony stimulating factor, leukemia inhibitory factor, nitric oxide and catecholamines have all been shown to influence melanocyte viability and function. Melanin production is regulated through the melanocortin-1 receptor (MC1R) (Figure 1). There are seven melanocortin receptors but only MC1R is involved in pigmentation. A related receptor, MC4R, is found in the hypothalamus and is involved in energy metabolism.2 MC1R is found in many species of animals and thus has an evolutionary role in the pigmentation of skin, hair, feathers, and other ectodermal structures. MC1R is a seventransmembrane G-protein-coupled receptor that, when bound, leads to activation of adenylyl cyclase leading to cyclic adenosine monophosphate (cAMP) production (Figure 1). cAMP then leads to phosphorylation of cAMP responsive-element-binding protein transcription factor family members. cAMP responsive-element-binding protein then binds on to its response element (CRE) to produce microphthalmia transcription factor (MITF), which is pivotal to the production of the many pigment enzymes and differentiation factors. There are many (at least 30) allelic variations in the structure of MITF that have a profound influence on the variability in pigmentation in people.2–4 The two major agonists for MC1R are α-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH)2–8 (Figure 1). Both α-MSH and ACTH are derived from proopiomelanocortin (POMC), which is produced in the pituitary and also in the skin and especially the hair follicles. As a side effect, adrenal insufficiency, which leads to increased ACTH, can lead to increased pigmentation. POMC also is a precursor for β-endorphin; therefore, conceptually there could be a link between pain signaling and pigmentation.11 α-MSH, however, is the main regulator



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of pigmentation. α-MSH has also been reported to increase melanin production independently of MC1R by blocking the inhibitor of tyrosinase [6(R)l-erythro-5,6,7,8-tetrahydrobiopterin (6BH4)]. There is an inhibitor of MC1R transduced through the Agouti (ASIP) gene, which produces “agouti signal protein” that reduces the color of hair in mice and pigmentation in people.2,4 Melanocytes reside in the bottom-most cell layer of the epidermis (the basal layer) where they spread out cellular “arms,” called “dendrites,” that distribute melanosomes to keratinocytes of the bottom two layers of the epidermis2–8 (Figure 2). There are several parallels for neurons and melanocytes. Both cells, which are derived from the neural crest, have the ability to create multiple dendrites to “communicate” to other cells. Neuron dendrites communicate to other neurons in the periphery and central nervous center and melanocytes communicate to their target cell, the keratinocyte. Each melanocyte is associated with an “epidermal melanin unit” with one melanocyte linking to roughly 40 keratinocytes in the basal and suprabasal epidermal layers. The mechanism of transfer of melanin to the keratinocytes has been extensively studied and again resembles protein transit in neurons.2–8 Melanosomes are

transferred on microtubules that are associated with two microtubule-associated “motor proteins”— kinesin and dynein. Kinesins attach melanosomes to the microtubules and transfer them centrifugally to the tips of the dendrites. Dyneins carry the empty organelles centripetally back to the center of the cell. Myosin-Va “captures” the melanosome on to the actin of the microtubule and is required for delivery to the distal end of the dendrite. Other proteins Rab27a and melanophilin participate in the transport process.2–4,12 The melanocyte transfer process depends on a keratinocyte seven-transmembrane G-protein coupled receptor called “protease-activated receptor-2” (PAR-2).2,12,13 PAR-2 increases phagocytosis of melanosomes and ultraviolet (UV) light increases its activity. The transfer occurs by several mechanisms: exocytosis, cytophagocytosis, and fusion.7 Exocytosis involves fusion of melanosomes with the melanocyte cell membrane with ultimate release of melanosomes into the intracellular space and phagocytosis by the keratinocyte. Cytophagocytosis involves phagocytosis of the tip of the melanosome dendrite followed by fusion to a lysosome, which releases melanosomes. Fusion occurs when the melanocyte dendrite fuses with the keratinocyte cell membrane to transfer

David Greenhalgh

Figure 2.  Melanocytes (yellow) exist in the basal (bottom) layer of the epidermis and have multiple dendrites that transfer melanosomes to sites above the nucleus of keratinocytes (grey) to protect their DNA from UV light.

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melanosomes. Finally, recent evidence demonstrates that filopodia are used during the transfer of melanin.14 Melanin is then distributed in “caps” above the nucleus of the keratinocytes, which protects the nuclear DNA from UV light. All people have a similar number of melanocytes but pigmentation varies based on the number and size of melanosomes distributed to the keratinocytes. Highly pigmented people have larger melanosomes that are filled with more melanin and are found in higher density than those of lighter pigmentation. Darker pigmented people also have increased activity of PAR-2, leading to more rapid transfer of melanosomes. The type of melanosomes, along with their density, is determined genetically. As will be described later, melanin production is also increased in response to sun exposure. It is also interesting to consider evolutionary theories of the development of different degrees of pigmentation in people. One concept is that pigmentation is a compromise between the need for sun exposure to complete the final step in vitamin D synthesis and the need to protect the skin from the harmful effects of UV light.15,16 People who are chronically exposed to sun such as at the equator have plenty of exposure for vitamin D production but need more protection from UV light—thus they have darkly pigmented skin. Those people who have little sun exposure, especially those people in the more northern or southern latitudes, have evolved to produce less pigment to allow for the limited sun exposure to produce vitamin D. Thus, these people have pale skin that is at greater risk for sun-related damage.

REPIGMENTATION BURN INJURY Any burn that is partial-thickness or deeper destroys the epidermis of the skin. Because melanin exists in the lower levels of the epidermis, the pigment is lost. Surprisingly, very little is written about the repigmentation process after injury.5,17–19 Much more is published related to the repigmentation of vitiligo. Partial-thickness burns heal by having the bottom layer of keratinocytes in the epidermis (called the basal cell layer) migrate over the surface of the wound. Migration from the wound edge can only occur for about 1 inch, which explains why fullthickness wounds heal more by contraction and scar formation than by re-epithelialization. In partialthickness wounds, however, the remaining dermis contains hair follicles, oil, and sebaceous glands, which contain the same epithelial cells (called keratinocytes) that migrate out of the follicle (or gland) and spread over the dermis to resurface the area.

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These “epithelial buds” spread over the wound to create a new but unpigmented skin. The re-epithelialized skin has a new epithelial layer that protects against water loss and thus is dry but pink due to the loss of pigment and increased vascularity of freshly “healed” skin. There has been a debate about how melanocytes migrate from the wound edge.5 Some have said that melanocytes migrate along with the leading edge of keratinocyte and then later synthesize melanin. Others say that there is a lag in melanocyte migration that occurs after re-epithelialization. Chadwick et al performed histologic studies of the healing of differing depth wounds (incisions, partial-thickness, and full-thickness wounds) and followed melanocytes with special stains. They found that at 35 days there was complete repopulation of melanocytes in the basal layers of the epithelium of the partial-thickness wounds but not in the full-thickness wounds. They concluded that there were different types of repigmentation that occur in wounds—from migration from the wound edge and from skin adnexa. In addition to the epidermis, melanocytes also exist in hair follicles but their main role in uninjured skin is to pigment hair.19 Melanocyte stem cells reside in the “bulge” of the hair follicle, whereas mature melanocytes (but not stem cells) exist in the “bulb” or bottom. The bulge is near the area of the sebaceous gland and erector pili muscle of the hair follicle. Just as for keratinocytes, melanocytes migrate from hair follicles and other skin adnexa to repopulate the new epithelium. Melanocyte migration to the lower levels of the new epithelium or, at least, melanocyte distribution of melanosomes to keratinocytes always lags after re-epithelialization by weeks to months. One will initially observe brown dots at the hair follicles that enlarge and gradually coalesce to form new pigment (Figure 3). The reason for the delay in pigmentation is not known. One could speculate, however, that melanocytes first need to repopulate the new skin, then synthesize melanin, and then distribute melanosomes to neighboring keratinocytes. It is also conceivable that the first priority of new keratinocytes is to set up a “barrier” before accepting melanosomes. Later, after differentiation has started, they will accept melanosomes to repigment freshly healed skin. The regulation of hair growth, type (straight or curly), and color is highly regulated and influenced by genetics.20,21 At least 150 genes influence the type and color of hair. If one considers the multitude of hair colors and patterns of various animals such as zebras and leopards, then it is clear that the regulation of hair color is extremely important.



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Figure 3.  Serial pictures of a thick split-thickness skin graft donor site that has re-epithelialized and shows the stages of repigmentation. (A) At 20 days after harvest, the donor sites have clear islands of pigmentation that correlate with hair follicles. (B) At day 41, the donor site has various stages of repigmentation with some dark areas and pinker areas with clear pigmentation islands. There is an area of pigment loss that resulted from a sheer injury on the medial side of the donor site. (C) At 62 days after harvest, the donor site reveals marked hyperpigmentation that is associated with some hypertrophic scarring on the lower edge. Delayed healing and possible excessive inflammation may have contributed to the hyperpigmentation. The series of pictures demonstrate that there is little control in the extent of return of pigmentation.

Melanocytes give hair its color, but the melanocytes of hair follicles are different than in skin. Hair follicle melanocytes are larger and have longer dendrites than in epidermis.20 They also produce larger melanosomes—thus explaining why skin pigment is often lighter than hair color (such as a Caucasian person with black hair). This fact also explains why hair turns gray, although skin pigment does not change color. In addition, “hair” melanocytes only synthesize melanin during the anagen phase of hair follicle life cycle. Delayed skin repigmentation could be related to these cellular differences. It is conceivable that melanocytes need to “reprogram” from a “hair pigmenting” to “skin pigmenting” phenotype during the re-epithelialization and repigmentation of wounds. Another possibility is that the hair follicle involved in resurfacing the wound must enter anagen before initiating melanin synthesis. Anagen could be delayed because of the hair follicle’s re-epithelialization activities. The deeper the wound, the slower the repigmentation process and very deep wounds may never regain pigment. The entire repigmentation process often takes over a year to be completed. During this time, sun exposure may alter the extent of pigmentation— this is why burn patients are advised to be careful with sun exposure during the repigmentation phase. Too much exposure may lead to darker skin than the surrounding areas. Although most people advocate being careful with sun exposure, one burn group suggested that sun exposure might improve outcomes.22

Unfortunately, we do not have much control over the extent of repigmentation; therefore, there is often a color difference in the healed burn wound. The deeper the burn, the more difficult it is to get a good color match. Influencing the extent of the final pigmentation is difficult. Some patients have lighter areas while others have darker areas. For obvious reasons, light-colored people have fewer problems with color differences than darker-pigmented people. Because the re-epithelialized wound has no pigment, those patients with little pigment have less contrast in color difference. Darkly pigmented people have marked contrasts between normally pigmented skin and the unpigmented wound. Therefore, a darkly pigmented person with minimal hypertrophic scarring still has a very noticeable color contrast which can lead to significant quality of life issues. Inflammation influences pigmentation, therefore infection or delayed healing, which increases cytokine expression, can lead to excessive pigmentation. One way to reduce hyperpigmentation is to limit the extent of sun exposure until repigmentation is complete. Unfortunately, his concept is often carried to the extreme. Patients may be told that they should never go out in the sun during repigmentation, and some have reported to me that they were told never to go in the sun for the rest of their lives. Such extremes are counter to our major goal in burn care, which is to have a burn survivor return to as normal activity as possible. Patients and caregivers should use common sense when dealing with the sun. More caution

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should be used during the early stages of healing— such as keeping areas covered or using adequate sun block. Patients should avoid prolonged exposure and minimize going outside during peak sun hours (10:00 to 4:00). Eventually, they should return to normal activities, and like all people (burn or not), they should be careful with sun exposure. Questions arise as to whether burn patients are at increased risk for sun-related skin cancers than uninjured people? This question has not really been investigated, but currently, there is no evidence of increased risk for skin cancer from sun exposure. The risk for developing Marjolin’s ulcers is related to chronic nonhealing wounds, not sun exposure.

TREATMENT OF HYPOPIGMENTATION The options for treating pigmentation changes are limited.23,24 Currently, the main way to repigment areas that lack color is to create a new wound— usually with dermabrasion—and then place a new graft at the site.23,24 Skin grafts carry pigments to the new site. One can even completely excise the hypopigmented area and place a new graft, but that is an extreme treatment. Some surgeons have reported applying epithelial autografts after dermabrasion with improved pigmentation.25 The application of noncultured epithelial cells has had mixed results by other surgeons.26 People will also tattoo hypopigmented areas, but it is hard to get a good color match and tattoos tend to fade with time. One can also use sun tan lotions that “create instant tans,” but they are obviously temporary. A novel approach that is in its infancy is to use agonists that augment the UV signaling pathway but avoid the risks of UV exposure.27 The concept is to use activators of the α-MSH receptor (MC1R) (Figure 2). These “analogs” of α-MSH have been developed and are often more potent than α-MSH itself. Other strategies target other sites in the UV signaling pathway.27 Drugs that increase cAMP (adenylate cyclase activators or phosphodiesterase inhibitors) are being tested as agents that increase pigmentation. One must wonder, however, whether manipulating such universal signaling agent is worth the potential side effects. Finally, investigation into the pharmacologic manipulation of the key pigmentation transcription factor (MITF) is underway.27 Studies of these novel pharmacologic agents are in their infancy. One should also know that there is no melanin in the palms or soles of the feet; therefore, skin grafts harvested from all areas except for the palm or sole will leave a pigmented graft in those areas. Some

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surgeons advocate that palm grafts be harvested from the sole of the foot to avoid pigmentation, but the quality of that skin is poor. Other sources of full-thickness, while leaving pigment, have much better qualities in texture and flexibility. Another interesting finding is that autologous composite skins that are placed on patients do not have melanocytes and thus usually have no pigment or islands of pigments that are probably the result of isolated melanocytes remaining in the wounds.28 Even 4:1 meshed autografts carry melanocytes that lead to a relatively uniform color. It is also important to know that when grafting the face, skin harvested from below the clavicle is yellower than skin from above the clavicles. Skin harvested from below leads to obviously darker and yellower grafts that persist for life. Skin harvested from above, the scalp, for instance, matches the color of the rest of the face well.

TREATMENT OF HYPERPIGMENTATION For an unknown reason, skin grafts often become darker than the surrounding skin. Studies in mice suggest skin grafts have increased melanocyte numbers and increased melanocyte activity.29 The treatment of hyperpigmentation has received more investigation than for hypopigmentation. The main strategy is to inhibit the enzymes of melanogenesis.30 The most well-known therapy is to inhibit tyrosinase activity with hydroquinone creams. Dark skin can be lightened using creams containing hydroquinone creams, but the extent and uniformity of lightening is not controlled and the results are often disappointing. There are other inhibitors of tyrosinase that are well described in an excellent review.30 These targets for hyperpigmentation treatment include other key enzymes such as TYRP-1 and TYRP-2. MITF activity may also be manipulated to reduce pigmentation (as opposed to increasing pigmentation as described above).30 Finally, lasers are increasingly being used to reduce pigmentation in burn patients.31 Research into the control of pigmentation after burns would significantly benefit burn survivors.

TANNING It is well known that sun exposure increases pigmentation, a process called “tanning.” Skin can be damaged by all wavelengths of light, from infrared to UV. Of the light striking the surface of the earth, 56% is infrared light (wavelength 780–5000 nm), 39% visible light (wavelength 400–780 nm) and 5% UV light.32 The greatest concern for skin damage,



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however, comes from UV light. How UV light affects tissues is complicated.27,32–34 There are three types of UV wavelength that reach the ground. UV C light (UVC: wavelength 190–280 nm) is filtered by the ozone layer in the stratosphere and is usually not a major problem. UV B light (UVB: wavelength 280–320 nm) is the main source of concern in the skin. UV A (UVA: wavelength 320–400 nm) is the third type to reach the surface and it also injures skin. The ratio of UVA to UVB light is 20:1. Because UVA light has a longer wavelength, it is not affected as much by altitude, latitude, or atmospheric conditions as UVB light. UVA light is also not filtered by regular glass and penetrates farther into the skin. UV light will lead to erythema that is well known as “sunburn.” UVA light has 1000-fold less erythema-inducing effects compared with UVB light. Within seconds of exposure, UVA and visible light will lead to “immediate pigment darkening” that is caused by photo-oxidation of existing melanin stores. At higher UVA levels, “persistent pigment darkening” will be found within 2 to 24 hr, which is also caused by photo-oxidation of melanin. UVB light will produce erythema (redness), “sunburn,” as early as 4 hr and peaks after 8 to 24 hr of exposure. It also causes photochemical damage to DNA and is thus involved in “photoaging” (thinning, wrinkling, sagging, and other changes due to sun exposure). All forms of light (especially UVB light) cause “delayed tanning” by increasing melanocyte numbers, enhancing tyrosinase activity, and stimulating melanin production. This “delayed tanning” starts 2 to 3 days after exposure, peaks at 3 weeks and does not return to the original color until 8 to 10 months later. No tanning occurs unless there is erythema in the skin. In addition to tanning, UVB light exposure increases skin mitotic activity to cause a doubling of thickness of the dermis and epidermis. UVA light does contribute to photoaging, and it is a likely contributor to the development of skin cancers. UVB light is also tied to the formation of skin cancers, although the relationship is not clear because it seems that UVB light increases the chances of one type of skin cancer (squamous cell) and may not be as great a factor in inducing other types (basal cell and melanoma). Evidence now indicates that visible light along with infrared light also injures the skin.35 UVB light does have a beneficial effect—it stimulates vitamin D synthesis in the epidermis. Only a small area needs to be exposed, and only 5% of the light needed to produce redness is needed for Vitamin D production. Melanosomes are placed above the cell nucleus and act as barriers to harmful UV light. It makes

sense that melanin is in the epidermis because this outer layer protects the underlying tissues from harmful light. Melanin, strategically located above the nucleus, absorbs the harmful UV light before it reaches the nucleus (and thus the DNA) to protect the skin. Exposure stimulates the melanocyte to produce hormones (in a simplified version— POMC a precursor of α-MSH) to stimulate melanocyte growth and melanin production (Figure 1). Melanin also neutralizes reactive oxygen species that cause damage to DNA. It absorbs, scatters, photo-oxidizes, and scavenges these reactive free radicals. It was once believed that darker pigmentation offered protection from light damage but darker skin is also damaged from UV light. Pheomelanin is a little more active as an antioxidant than eumelanin but they are both effective. Tanning does increase the “sun protection factor (SPF) of skin by 3.”32

SUN PROTECTION The main reason for sun protection is to reduce skin cancers. Skin cancer affects over two million people in the United States annually.36,37 Despite the high risk of skin cancer, a recent National Ambulatory Medical Care Survey revealed that using sunscreen was mentioned by primary care doctors to only 0.07% of patients during their visits.38 Dermatologists recorded the mention of sunblock in only 1.6% of their patient visits.39 The U.S. Preventive Services Task Force found that there was sufficient evidence to support sun protective counseling for fair-skinned patients between the ages of 10 and 24 yr, but failed to find evidence to support counseling in patients greater than 24 years of age.36 An editorial in response to these reports suggested that there is clear evidence to support sunblock use in Australia and that performing evidence-based studies to prove efficacy is an extremely difficult proposition.39 It is extremely difficult to perform any evidencebased studies for any treatment in burns; therefore, it would seem ludicrous to wait for evidence before suggesting the use of sunblock in burn patients. In my experience, however, the discussion of sunblock use with burn patients is prevalent in clinics managing burn patients. Sun protection strategies can be divided into environmental, physical, and chemical. The environmental protection strategies follow common sense.4,32–34 Approximately 50% of the total daily solar UV dose reaches the ground between noon and 3:00 pm. Therefore, it is recommended that people at risk (such as burn patients) avoid direct exposure during

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those hours or as the American Academy of Dermatology suggests—between 10:00 am and 4:00 pm.40 Ozone absorbs large amounts of UVB and UVC light but little or no UVA or visible light. The loss of the ozone layer is a major concern for increasing skin cancer risks. Elevation above sea level also influences the extent of UV exposure. For every 300 m in elevation, there is an increase in UV light exposure of 4% near sea level that increases to 8% to 10% in the higher elevations (such as for skiers). For every degree of change in latitude, there is a 3% increase in UV exposure so that the highest risk is at high elevations near the equator.41 Some other interesting facts are that fog, haze, or clouds can reduce UV exposure by 10% to 90% but sunburns still occur. Snow, sand, and metal can reflect up to 90% of UV light. Sea water can reflect up to 15% but pool water does not reflect much light. UV light will penetrate around 1 m into water so swimmers are at risk. Shade is an obvious environmental protector from sunlight, but there is less protection from a beach umbrella than dense foliage. The main physical sun protection is from photoprotective clothing. There is a large variation in the protective effects of clothing. A light-colored cotton shirt provides only a SPF of 10. It is reported that one third of summer clothing had an UV protection factor (UPF—a measure of total UVA and UVB light blocked) of 12 to 15.4,33 In Australia and New Zealand where skin cancers are very prevalent, there is a standard that clothing must have a UPF of at least 15. In Europe, there are also standards to keep clothing at a UPF of 40. There is no sun protection standard for clothing in the United States. The characteristics of the clothing influence the extent of sun protection.32,33 Loose fitting, dry clothing with tightly woven, thicker, darker, and unbleached fabrics offer more protection. Denim, wool, and synthetic fabrics or those treated with an UV absorber are also safer. Loosely woven, lighter colored (bleached), and thinner fabrics have less protection from the sun. There is less UV light protection from cotton, linen, acetate, and rayon clothing than other materials. Wet clothing provides less protection by allowing light to pass through the gaps in the threads. There are specially manufactured clothes designed to reduce sun exposure and laundry additives that absorb UV light. How much more effective they are than carefully chosen “regular” clothes is not known. Wide brim hats provide mild protection to the face and neck. A hat with a brim greater than 7.5 cm wide increases the SPF of the nose 7, cheeks 3, chin 2, and neck 5. The protection is less for smaller brimmed hats.32

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Chemical protection is offered by topical sunscreens which are divided into inorganic and organic forms. Inorganic sunscreens include zinc oxide and titanium dioxide. These agents both reflect and absorb UV and visible light. Zinc oxide has been found to be more effective than titanium dioxide. The inorganic sunscreens are effective but they are less cosmetically acceptable because they are obviously white on the skin. Organic sunscreens absorb UV radiation and are divided into UVB absorbers, UVA absorbers, and broadband absorbers (absorbing UVA and UVB light). UVB absorbers have been available for many years, but recent evidence suggests that UVA light is also involved in the development of skin cancers. Therefore, there are currently sunscreens that absorb both UVA and UVB light. The effectiveness of sunscreens is measured by the SPF.33 SPF is defined by the sun radiation dose (mainly UVB) required to produce the minimum erythemal dose (MED – the threshold dose that can produce sunburn) after application of 2 mg/cm2 of sunscreen divided by the dose producing 1 MED on unprotected skin. Therefore, an SPF of 2 absorbs 50% of UV radiation; SPF 8 absorbs 87.5%, SPF 16 absorbs 93.6%, and SPF 32 absorbs 96.9%. Note that after an SPF of 30, there is little increase in effectiveness in sunscreens at higher SPFs. There is no standard way to measure effectiveness of UVA radiation blockade. Australia and New Zealand do use standards to claim that a product provides “broad spectrum” protection. An 8-μm layer must not transmit more than 10% or a 20-μm layer must not transmit more than 1% of radiation between 320 and 360 nm (part of UVA light). Others test products as to whether they induce skin darkening or not. There are other forms of photoprotection that will not be covered in detail. There are topical antioxidants such as vitamin C, vitamin E, beta carotene, and many more. These agents have low SPFs so they tend to be added to sunscreens. There are also systemic antioxidants that have been described. There are excellent reviews that are available that describe the many agents.32–34 So what are the guidelines that should be given to patients recovering from their burns? I propose that burn patients follow the guidelines that all people should follow to protect themselves from photoaging and skin cancers (Table 1). In addition, patients should be extra cautious with exposing those burns that are regaining their pigment to improve the ultimate color match. Once pigment has stabilized, burn survivors should follow the recommendations of all people. The American Academy of Dermatology



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Table 1. Recommendations for sun exposure for burn patients •

• • • • •

• •

While outdoor activities are acceptable, extra caution with sun exposure should be used until repigmentation has stabilized (approximately 1 year after injury). Seek shade and avoid sun between 10:00 am and 4:00 pm. Wear protective clothing, including wide-brimmed hats. Beware of water, snow, and sand reflecting light. Avoid tanning beds. Everyone should use sunscreens irrespective of their skin color. °  Use SPF 30 or more. °  Use broad spectrum (covers UVA and UVB) sunscreens. °  Use water-resistant sunscreens. ° One ounce of sunscreen (a shot glass) is the amount needed to cover exposed areas in an adult. °  Wait 15 min for the sunscreen to absorb in the skin. °  Reapply sunscreen every 2 hr or after swimming or excessive sweating. All children younger than 6 months of age should not be exposed to sun. Because of loss of sweat glands, patients with extensive skin grafting should be careful with being exposed to excessive heat while in the sun.

recommends the following to reduce UV light exposure:40 •• Seek shade and avoid sun between 10:00 am and 4:00 pm. •• Wear protective clothing, including widebrimmed hats. •• Beware of water, snow, and sand reflecting light. •• Avoid tanning beds. •• Everyone should use sunscreens irrespective of their skin color. •• Use SPF 30 or more. •• Use broad spectrum (covers UVA and UVB) sunscreens. •• Use water-resistant sunscreens. •• One ounce of sunscreen (a shot glass) is the amount needed to cover exposed areas in an adult. •• Wait 15 min for the sunscreen to absorb in the skin. •• Reapply sunscreen every 2 hr or after swimming or excessive sweating. In addition, the American Academy of Pediatrics recommends that all children younger than 6 months should be kept out from the sun whenever possible.37 Children older than 6 months should

follow the same recommendations as those mentioned above for adults. They also remind us that 80% of the lifetime sun exposure takes place before the age of 18 years. The goal for any recovering burn survivor is to regain as much function and activity as possible. Going outside is important for all people. Burn survivors should not avoid such activities but, instead, use common sense when exposed to sun. The survivor should be extra cautious when the wounds are regaining pigment. Otherwise, using the guidelines that apply to all people for sensible exposure to the sun is the best recommendation. REFERENCES 1. Gilchrest BA, Goldwyn RM. Topical chemotherapy of pigment abnormalities in surgical patients. Plast Reconstr Surg 1981;67:435–9. 2. Lin JY, Fisher DE. Melanocyte biology and skin pigmentation. Nature 2007;445:843–50. 3. Costin GE, Hearing VJ. Human skin pigmentation: melanocytes modulate skin color in response to stress. FASEB J 2007;21:976–94. 4. Yamaguchi Y, Hearing VJ. Physiological factors that regulate skin pigmentation. Biofactors 2009;35:193–9. 5. Chadwick SL, Yip C, Ferguson MW, Shah M. Repigmentation of cutaneous scars depends on original wound type. J Anat 2013;223:74–82. 6. Hearing VJ, Tsukamoto K. Enzymatic control of pigmentation in mammals. FASEB J 1991;5:2902–9. 7. Park HY, Kosmadaki M, Yaar M, Gilchrest BA. Cellular mechanisms regulating human melanogenesis. Cell Mol Life Sci 2009;66:1493–506. 8. Dos Santos Videira I, Lima Moura DF, Magina S. Mechanisms regulating melanogenesis. An Bras Dermatol 2013;88:76–83. 9. Nordlund JJ. The lives of pigment cells. Clin Geriatr Med 1989;5:91–108. 10. Nordlund JJ. Postinflammatory hyperpigmentation. Dermatol Clin 1988;6:185–92. 11. β-endorphin: The forgotten hair follicle melanotropin. J Investig Dermatol Symp Proc 2005;10:212–6. 12. Scott G, Leopardi S, Parker L, Babiarz L, Seiberg M, Han R. The proteinase-activated receptor-2 mediates phagocytosis in a Rho-dependent manner in human keratinocytes. J Invest Dermatol 2003;121:529–41. 13. Boissy RE. Melanosome transfer to and translocation in the keratinocyte. Exp Dermatol 2003;12(Suppl 2):5–12. 14. Singh SK, Kurfurst R, Nizard C, Schnebert S, Perrier E, Tobin DJ. Melanin transfer in human skin cells is mediated by filopodia—a model for homotypic and heterotypic lysosome-related organelle transfer. FASEB J 2010;24:3756–69. 15. Jablonski NG, Chaplin G. Human skin pigmentation as an adaption to UV radiation. Proc Nat Acad Sci 2010;107(Suppl 2):8962–8. 16. Jablonski NG. The evolution of human skin colouration and its relevance to health in the modern world. J R Coll Physicians Edinb 2012;42:58–63. 17. Parsad D, Pandhi R, Dogra S, Kumar B. Clinical study of repigmentation patterns with different treatment modalities and their correlation with speed and stability of repigmentation in 352 vitiliginous patches. J Am Acad Dermatol 2004;50:63–7. 18. Heath RL, Thomlinson AM, Shah M. Melanocytes and wound healing. Burns 2009;35S:S44. 19. Chadwick S, Heath R, Shah M. Abnormal pigmentation within cutaneous scars: A complication of wound healing. Indian J Plast Surg 2012;45:403–11.

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20. Tobin DJ. The cell biology of human hair follicle pigmentation. Pigment Cell Melanoma Res 2011;24:75–88. 21. Westgate GE, Botchkareva NV, Tobin DJ. The biology of hair diversity. Int J Cosmet Sci 2013;35:329–36. 22. Rennekampff HO, Busche MN, Knobloch K, Tenenhaus M. Is UV radiation beneficial in postburn wound healing? Med Hypotheses 2010;75:436–8. 23. Dhanraj P, McCauley RL. Management of pigmenta tion changes in burn patients. In: McCauley RL, editor. Functional and aesthetic reconstruction of burned patients. Boca Raton, FL: Taylor & Francis; 2005. P. 157–72. 24. Grover R, Morgan BD. Management of hypopigmentation following burn injury. Burns 1996;22:627–30. 25. Stoner ML, Wood FM. The treatment of hypopigmented lesions with cultured epithelial autograft. J Burn Care Rehabil 2000;21(1 Pt 1):50–4. 26. Back C, Dearman B, Li A, Neild T, Greenwood JE. Noncultured keratinocyte/melanocyte cosuspension: effect on reepithelialization and repigmentation—a randomized, placebo-controlled study. J Burn Care Res 2009;30:408–16. 27. Chen H, Weng QY, Fisher DE. UV signaling pathways within the skin. J Invest Dermatol 2014;134:2080–5. 28. Harriger MD, Warden GD, Greenhalgh DG, Kagan RJ, Boyce ST. Pigmentation and microanatomy of skin regenerated from composite grafts of cultured cells and biopolymers applied to full-thickness burn wounds. Transplantation 1995;59:702–7. 29. Farooqui JZ, Auclair BW, Robb E, et al. Histological, biochemical, and ultrastructural studies on hyperpigmented human skin xenografts. Pigment Cell Res 1993;6(4 Pt 1):226–33. 30. Ebanks JP, Wickett RR, Boissy RE. Mechanisms regulating skin pigmentation: the rise and fall of complexion coloration. Int J Mol Sci 2009;10:4066–87.

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31. Raulin C, Schönermark MP, Greve B, Werner S. Q-switched ruby laser treatment of tattoos and benign pigmented skin lesions: a critical review. Ann Plast Surg 1998;41:555–65. 32. González S, Fernández-Lorente M, Gilaberte-Calzada Y. The latest on skin photoprotection. Clin Dermatol 2008;26:614–26. 33. Lautenschlager S, Wulf HC, Pittelkow MR. Photoprotection. Lancet 2007;370:528–37. 34. Kullavanijaya P, Lim HW. Photoprotection. J Am Acad Dermatol 2005;52:937–58; quiz 959–62. 35. Grether-Beck S, Marini A, Jaenicke T, Krutmann J. Photoprotection of human skin beyond ultraviolet radiation. Photodermatol Photoimmunol Photomed 2014;30:167–74. 36. Moyer VA; U.S. Preventive Services Task Force. Behavioral counseling to prevent skin cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;157:59–65. 37. Quatrano NA, Dinulos JG. Current principles of sunscreen use in children. Curr Opin Pediatr 2013;25:122–9. 38. Akamine KL, Gustafson CJ, Davis SA, Levender MM, Feldman SR. Trends in sunscreen recommendation among US physicians. JAMA Dermatol 2014;150:51–5. 39. Federman DG, Kirsner RS, Concato J. Sunscreen counseling by US physicians. JAMA 2014;312:87–8. 40. American Academy of Dermatology. Understanding skin cancer; available from www.aad.org/dermatology-a-to-z/ health-and-beauty/general-skin-care/sunprotection/ how-do-i-prevent-skin-cancer; accessed 15 Apr. 2014. 41. Rigel DS, Rigel EG, Rigel AC. Effects of altitude and latitude on ambient UVB radiation. J Am Acad Dermatol 1999;40:114–6.

A primer on pigmentation.

There is at least a temporary loss of skin pigmentation with all but first-degree burns. Commonly, pigment changes persist for months, and sometimes, ...
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