Which action would the nurse perform to differentiate between cutaneous jaundice and normal skin color?

Skin color.

Skin color is one of the most important risk factors for skin aging and skin cancer. In Caucasians, the incidence rates of skin cancers and the severity of wrinkles are greater than in blacks. The brown skin of Asians seems to lie in between white and black skins. The increase of facultative skin color above the constitutive level, which we define as the Sun Exposure Index (SEI), might be an indicator of individual sun exposure throughout life [15]. In Korean skin, the SEI is also correlated significantly with sun exposure in both sexes [44].

It has been demonstrated that facultative skin color, but not constitutive skin color, increases with age in the brown skin of Asians (Table 1). After controlling for age and gender, it has been found that facultative skin color and SEI have a positive correlation with the severity of wrinkling in the brown skin of Asians [44].

c Limitation of skin color studies: measurement difficulties and the confounding effect

Skin color is usually measured in scientific studies using a reflectometer, which measures how much light of a particular wavelength is reflected from the skin. Specific skin areas are usually favored, especially those with little sun exposure (eg, under arm, inner wrist), in order to get the most natural and “unacclimated” phenotype. Pigmentation is, however, a continuous trait and a rather unstable character, modifiable by time (age) and external parameters, such as sun exposure, UV machines, hair lotions, and dyes. Consequently, the link between phenotype and genotype is difficult to determine, since the exact and natural pigmentation needs be assessed without these confounding parameters. Depending when and under which circumstances skin color is measured, the phenotypic trait observed might not be representative, introducing bias into biological studies. This highlights the need for scientific studies to establish the most reliable protocol to limit background noise of this kind.

Skin Color/Condition

Skin color varies considerably from individual to individual and is generally determined by the presence of melanocytes, carotene, oxygenated hemoglobin, and local blood flow. Melanocytes, found in the deep basal layer of the epidermis, contain brown granules called melanin. Besides contributing to skin color, melanin provides protection during episodes of sun exposure. Carotene found in subcutaneous fat tissue contributes to the yellowish color of the skin. This substance is especially concentrated in the palms of the hands and soles of the feet. Lastly, the normal reddish color of skin is attributed to the presence of oxygenated blood being transported through the arteries and capillaries.

Certain skin colors may represent serious disease, including pallor (pale), cyanosis (blue), jaundice or icterus (yellow), gray, and hyperpigmentation (brown). Table 8-1 summarizes these abnormal states, including the underlying physiological features and associated causes of the color. The physiological events may result in observable changes other than those noted in the skin. For example, there are two forms of cyanosis, central and peripheral. Central cyanosis results from low arterial oxygen levels and is best identified by color changes in the lips, tongue, and oral mucosa. Peripheral cyanosis results from a decrease or slowing of cutaneous blood flow, which allows for tissues to extract increased levels of oxygen from the circulating blood. The bluish hue noted in the hands, feet, or nails can be of central or peripheral origin.2 Another example is excessive bilirubin, associated with the yellowish hue of the skin, which can result in the sclera of the eyes or mucous membranes assuming a similar hue. Lastly, severely jaundiced individuals may have a greenish hue to the skin resulting from the oxidation of bilirubin to biliverdin.19,22

In addition to general skin color changes, local alterations can also indicate a condition that should be reported to a physician. Local redness accompanied by local heat, edema, and tenderness that develops within a few days may be a manifestation of cellulitis, a bacterial infection. This infection may be accompanied by red streaks extending proximally, which are associated with secondary lymphangitis.24 Local skin changes could also be a result of chronic arterial insufficiency. Ischemic ulcers, thin and shiny skin, hair loss, paleness of an elevated extremity, and intense rubor when the limb assumes a dependent position are all possible manifestations of this condition. Although cuts and bruises are fairly common, their presence on the head, face, and neck may be an indication of physical abuse. Also, similar findings on the forearms may be indicative of defensive injuries sustained while trying protect oneself.6,16 Additional information regarding screening for domestic abuse can be found in Chapter 5.

Limb ischemia

Skin color and temperature can provide information about severity of limb arterial perfusion. The feet, hands, fingers and toes should be examined for temperature and skin color, and the nails for evidence of fragility and pitting. Limb temperature can best be appreciated using the back of the examiner's hand. Temperature changes of adjacent segments on the ipsilateral limb and comparisons with the contralateral limb can be made. Presence of foot pallor while the leg is horizontal is indicative of poor perfusion and may be a sign of ischemia. Foot pallor may be precipitated in patients with PAD (who do not have CLI) by elevating the patient's leg to 60 degrees for 1 minute. Repetitive dorsiflexion and plantar flexion of the foot may also precipitate pallor on the sole of the foot when PAD is present. To qualitatively assess collateral blood flow, the leg is then lowered as the patient moves to the seated position. This is done to elicit rubor, indicative of reactive hyperemia, and determine pedal vein refill time. The time to development of dependent rubor is indicative of the severity of PAD. Severe PAD and poor collateral blood flow may prolong reactive hyperemia by more than 30 seconds. Normally, pedal venous refill occurs in less than 15 seconds. Moderate PAD subserved by collateral vessels is suspected if venous refill is 30 to 45 seconds; severe disease with poor collateral development is likely when venous filling time is longer than 1 minute.

Color

Skin color provides important clues about the nature of a disease process. For example, many skin lesions appear erythematous (red). However, it is important to ascertain whether the erythema is blanching, which disappears with pressure, because this suggests that the erythema is due to vasodilation, or whether it is nonblanching erythema (purpura), which implies hemorrhage into the skin. Other causes of pigment in the skin include hypoxia, topical medications, oral drugs, other ingestants, or even infections.

Fitzpatrick Skin Types

Also, there is variation in normal skin tones, even in the general population. These variations in skin color are due to differences in the amount and distribution of melanin in the epidermis. Sometimes, the term skin of color is used to describe any skin tone darker than white skin, but dermatologists more often use the Fitzpatrick scale (see “Fitzpatrick Skin Types” box), which describes skin color based on a response to sun exposure.

Baseline pigmentation also affects cutaneous findings in skin disorders. For example, erythema may be difficult to appreciate in darker skin. Keloids (aberrant scarring) are more common in those with darker skin types. Even after a disease process has resolved, postinflammatory hypopigmentation and postinflammatory hyperpigmentation are more marked (or more evident) in those with darker skin types.

Cyanosis is also more difficult to appreciate when the skin is more darkly pigmented.

Genetic Determinants of Pigmentation

Skin, eye, and hair colors are determined by the type of melanin. Racial differences in skin pigmentation are not due to differences in the density of melanocytes but rather to how melanin is synthesized and packaged (10). In white skin, fewer and smaller melanosomes are produced in melanocytes, whereas in black skin, melanocytes produce larger and more numerous melanosomes, which in keratinocytes are distributed singly leading to greater absorption of photons. In the United States, blacks and Latinos have a more than five- to tenfold reduced incidence of melanoma compared with whites.

In the context of melanoma, the most important genetic determinant of pigmentation is the receptor for melanocyte stimulate hormone (MSH), called MC1R. This is a transmembrane G protein–coupled receptor expressed by epidermal melanocytes that generates a cAMP second messenger through adenylate cyclase to regulate gene expression, including MITF(Figure 36-2; 11). MC1R is polymorphic in humans, and different allelic variants determine distinct skin phenotypes (12). MC1R variants that strongly transduce MSH signals lead to synthesis of darker pigment (eumelanin); in contrast, deficient MC1R signals are associated with synthesis of pheomelanin and red and other fair complexions.

One relevant group of loss-of-function MC1R alleles determines the Red Hair Color phenotype, characterized by red hair, fair complexion, difficulty in tanning, and the tendency to freckle, which are phenotypic characteristics of individuals with an approximate 1.2 to twofold increased risk of melanoma. Inheritance of Red Hair Color MC1R alleles is associated with increased risk of melanoma, even in individuals with darker skin. These observations implicate factors in addition to skin color and UV absorbance, such as generation of mutagenic molecules during inflammation and/or pigment synthesis following sun exposure. Even inheritance of a single Red Hair Color MC1R allele is associated with decreased capacity to respond to cutaneous damage by UV radiation, potentially contributing to melanoma risk.

Where We are Influences What We are

Skin color is an obvious example, if a divisive one, of people in different environments differing anatomically, indeed physiologically, because individuals with certain traits do better in certain environment than do individuals without those traits. Oddly enough, even Darwin was wrong on skin color. He could not see how it matched the environment (Darwin, 1871, p. 174). But it does. People from the tropics tend to be darker than people whose ancestors came from outside the tropics.

The reason is that tropical peoples’ skin has in its surface layers more melanocytes. By blocking and scattering the passage of light, the melanocytes help prevent sunburn, in other words, damage to the surface layer of skin cells. More crucially, the melanocytes filter out ultraviolet light by both absorbing and scattering it. That prevents the rays from penetrating deeper into the skin, and so prevents the ultraviolet from destroying vitamin B9 in any blood circulating near the skin (Jablonski and Chaplin, 2002). Vitamin B9, also known as folate or folic acid, has a variety of vital jobs in the human body. One is in the production of red blood cells. Another crucial part it plays is in the development of the fetus’ spinal cord and brain.

So why do we not all have dark skin and why do females not have darker skin than do males? The answer is that UV light stimulates the production in our skin of vitamin D, crucial for healthy bones via its effect on the body’s metabolism of calcium, among other elements. Too little sun, and a diet without vitamin D supplements, and children develop rickets. Strictly dressed Moslem women in northern latitudes can also suffer.

Yet the palest people are not those the farthest north. Arctic people are darker than western Europeans. It turns out that the Arctic peoples’ traditional diet, heavy in fish and meat, is high in vitamin D. Until recently that was not true of western Europeans. Their diet was largely cereals, and cereals are unusually low in vitamin D (Khan, 2010). A main reason we do not see rickets in western European populations nowadays is that the major producers of bread and cereals add large amounts of supplemental vitamin D.

Many other aspects of our physiology and anatomy differ between regions (Harcourt, 2012, 2015). The lengths of our limbs and the shape of our bodies differ. For instance, Africans tend to be longer and thinner than Europeans and certainly Arctic people. A likely reason is that long, thin bodies lose heat more easily than do short, squat ones. Africans are better than Europeans at retaining salt when they sweat. Why? Probably because salt is in shorter supply in Africa than it is in Europe, so weathered are the rocks and soils of Africa.

But all these anatomical and physiological differences between people from different regions are in many textbooks of biological anthropology. A topic rarely found in any of the textbooks is the question of why in biogeographical terms, the tropics are more culturally diverse than are higher latitudes.

5.4 Mechanisms of Toxicity: Pigmentation

Skin and hair color may be influenced by the presence of hemoglobin and carotenoids, but is primarily attributed to the presence of melanocytes that synthesize melanin pigments. There are two primary types of melanin that influence skin color: eumelanin, which is brown-black, and phaeomelanin, which confers red-yellow pigmentation. Melanocytes export melanin in melanosomes (melanin-containing granules) to adjacent keratinocytes for distribution to the upper layers of the skin, or from the hair bulb to the hair shaft. The number, size, composition, density, and distribution of melanosomes are primarily responsible for variations in pigmentation, whereas the number of melanocytes remains relatively constant. Numerous intrinsic factors may also influence skin pigmentation by acting on melanocytes. These include genetic factors and epigenetic factors derived from keratinocytes (e.g., bFGF, α-MSH, PAR2), dermal fibroblasts (e.g., DKK1, TGF-β1, bFGF, HGF, SCF), endocrine and neural factors (e.g., nitric oxide, α-MSH), and systemic inflammation (e.g., prostaglandins, leukotrienes, thromboxanes, IL1, IL6).

Studies on mouse coat color mutants have identified more than 300 genes that may influence skin and hair color. Melanocortin-1 receptor (MC1R) is considered the major determinant of pigment phenotype. Alpha-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH) are the principle agonists of MC1R that act to increase eumelanin via elevation of cAMP levels. Melanin synthesis is controlled by tyrosinase (TYR) enzymes that initiate melanin synthesis by catalyzing oxidation of L-tyrosine. TYR activity is mediated principally by TYR-related protein 1 (TRP1) and dopachrome tautomerase (TRP2).

Skin pigmentation may also be influenced by extrinsic factors such as ultraviolet radiation (UVR). The skin is the main barrier to environmental stresses and noxious stimuli, and the melanocytes ability to absorb UVR provides a significant contribution to the protective mechanisms of skin. UVA (320–400 nm) and particularly UVB (280–320 nm) are able to penetrate skin and stimulate melanin pigmentation. Hence, the degree of pigmentation, which is a reflection of degree of photoprotection afforded, is termed skin “photoype” and may be used as a predictor of photoaging and photocarcinogenesis where lighter-skinned individuals are at higher risk.

Disorders of pigmentation may be classified as hyperpigmentation or hypopigmentation, which may or may not involve alterations in melanocyte numbers. In the extreme, complete lack of pigmentation, termed albinism, is the result of genetic mutations. More often, however, pigmentation changes are associated with variations in the amount of melanin in skin or hair (i.e., described clinically as normochromia, hyperchromia, and hypochromia), although drug or metal deposits may occasionally be involved.

Drug-induced cutaneous pigmentation disorders that may account for 10–20% of acquired cases of hyperpigmentation in humans are of particular interest to the toxicologic pathologists. Numerous drugs have been implicated in pigmentation disorders, including non-steroidal anti-inflammatory drugs (NSAIDS), antimalarial agents (e.g., chloroquine, quinine), antipsychotic drugs (e.g., chlorpromazine, phenothiazine), anticonvulsants (e.g., phenytoin), amiodarone, tetracyclines, cytotoxic drugs (e.g., cyclophosphamide, busulfan, bleomycin, adriamycin), and heavy metals. The mechanisms involved in pigmentation disorders vary with the type of agent involved. For example, some drugs may react with melanin to form drug–pigment complexes, which may be exacerbated by sunlight stimulation of melanin synthesis. Other types of drugs may either accumulate in the skin or bind to skin components other than melanin. Acute or chronic inflammatory processes may result in non-specific post-inflammatory hypopigmentation or hyperpigmentation through the release of numerous mediators, including cytokines and growth factors, which may cause aberrant melanogenesis.

The exact mechanisms involved in post-inflammatory hypopigmentation are not clearly understood but are thought to be the result of inhibition of melanogenesis rather than overt destruction of melanocytes (although in some instances severe inflammation may result in destruction and loss of melanocytes with permanent pigment change). Heavy metals, on the other hand, may be deposited in the dermis, contributing to a pigmentation change by a mechanism other than one involving melanin (see Heavy Metals, Chapter 41).

Non-clinical toxicity studies are conducted to determine the toxicologic potential of drug candidates prior to administration to humans in order to assess and mitigate potential adverse clinical effects. Observance of pigmentation disorders may manifest fortuitously in routine toxicity studies or from development of specific animal models. For example, chloroquine has demonstrated a distinct affinity for ocular melanin involving reversible hydrophobic or electrostatic interactions based on studies in pigmented and non-pigmented (albino) rats. Administration of an experimental platelet aggregation inhibitor, PD-89454, caused an unintended a loss of color in normally pigmented areas of the nose, lips, eyelids, and oral mucosa of Beagle dogs. Decreased melanin was demonstrated in melanocytes and keratinocytes by Fontana-Masson staining, and, ultrastructurally, melanocytes appeared round or globoid, with fewer and smaller dendritic processes, and fewer, incompletely pigmented melanosomes.

In addition to unintended adverse effects of systemic drugs, many drug development efforts have purposefully pursued hypopigmentation for cosmetic skin lightening. Numerous mechanisms have been targeted for decreasing pigmentation, including tyrosinase, TRP1, and TRP2 inhibition (via microphthalmia-associated transcription factor downregulation), increased tyrosinase ubiquitination, decrease of MC1R activity, cAMP inhibition (anti-inflammatory agents), interference with melanosome transfer or maturation, and liberation of toxic melanin synthesis intermediates.

Methimazole (MMI) is an antithyroid agent that is an inhibitor of tyrosinase and may serve to inhibit melanogenesis. Topical application of MMI to the ear skin of brown guinea pigs resulted in depigmentation characterized morphologically by altered shape and larger size of melanocytes, loss of dendrites, increased thickness of remaining dendrites, and, in some areas, a reduction in the number of melanocytes. Similarly, 4-n-butylresorcinol (BR; Rucinol®) has been shown to be a reversible inhibitor of melanin production in B16 mouse melanoma cells without producing cytotoxicity, through potent inhibition of TYR and TRP1, and shows promise as a whitening agent in the clinical treatment of liver spots. Administration of 4-S-cysteaminyl phenol to C57BL/6J black mice or black guinea pigs caused depigmentation through a mechanism of selective cytotoxicity involving a reduction in the number of functioning melanocytes, a decrease in the number of melanosomes produced and transferred to keratinocytes, and destruction of membranous organelles of melanocytes.

Periwound Skin Color.

Periwound skin color can provide information about the type of wound and the status of the surrounding tissue. Any change in skin color and the extent of the change should be documented because reduction or increase in the degree and size of color changes are indicators of improvement or decline in wound status. Skin color is presented here as it relates to PUs.

Erythema is redness of the skin that may result from an inflammatory response (reactive hyperemia), from underlying infection, or from unrelieved pressure. In darker-skinned patients, erythema may be more difficult to see; however, accompanying changes in warmth or texture may be detected. Erythema may be blanchable or unblanchable, meaning it does or does not pale with pressure. Normal skin will pale when the blood is pushed out of the capillaries (refer to capillary refill time). Unblanchable erythema in the periwound area is a sign of the inflammatory response to healing or a sign of infection. Unblanchable redness or prolonged refill time in the foot indicates microvascular or small vessel disease. Dark-red discoloration, a result of repeated shear forces, may also be referred to as pre-ulcer or a purple ulcer. Blanched, white periwound skin is typical of maceration that occurs when moisture is inadequately managed. Darker skin tones around the periphery of an open PU are often an indication of extensive undermining.