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InternalMed_Harrison. Other blistering eruptions with mucositis associated with infections may be confused with SJS/TEN. Erythema multiforme (EM) associated with herpes simplex virus is characterized by mucosal involvement and target lesions often more acrally distributed and with limited skin detachment. Mycoplasma infection in children causes a clinically distinct presentation with prominent mucositis and limited blistering lesions; some believe that this clinical entity is the syndrome originally described by Stevens and Johnson. FIguRE 74-9 Toxic epidermal necrolysis. (Photo credit: Lindy Peta Fox, MD, and Jubin Ryu, MD, PhD.)


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InternalMed_Harrison. Patients with SJS, SJS/TEN, or TEN initially present with acute onset of painful skin lesions, fever >39°C (102.2°F), sore throat, and conjunctivitis resulting from mucosal lesions. Intestinal and pulmonary involvement is associated with a poor prognosis, as are a greater extent of epidermal detachment and older age. About 10% and 30% of SJSand TEN-affected persons die from their disease, respectively. Drugs that most commonly cause SJS or TEN are sulfonamides, nevirapine (1 in 1000 risk of SJS or TEN), allopurinol, lamotrigine, aromatic anticonvulsants, and NSAIDs, specifically oxicam. Frozen-section skin biopsy may aid in rapid diagnosis. At this time, SJS and TEN have no proven effective treatment. The best results come from early diagnosis, immediate discontinuation of any suspected drug, supportive therapy, and paying close attention to ocular complications and infection. Systemic glucocorticoid therapy (prednisone 1–2 mg/kg) may be useful early in the evolution of the disease,


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InternalMed_Harrison. drug, supportive therapy, and paying close attention to ocular complications and infection. Systemic glucocorticoid therapy (prednisone 1–2 mg/kg) may be useful early in the evolution of the disease, but long-term systemic glucocorticoid use has been associated with higher mortality. Cyclosporine may be a possible therapy for SJS/TEN. After initial enthusiasm for the use of intravenous immunoglobulin (IVIG) in the treatment of SJS/TEN, some recent data questions whether IVIG benefits these patients. Randomized studies to more definitively assess the potential benefit of systemic glucocorticoids and IVIG are lacking and difficult to perform but are necessary.


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InternalMed_Harrison. Overlap Hypersensitivity Syndromes An important emerging concept in the clinical approach to severe drug eruptions is the presence of overlap syndromes, most notably DIHS with TEN-like features, DIHS with pustular eruption (AGEP-like), and AGEP with TEN-like features. In several case series of AGEP, 50% of cases had TEN-like or DRESS-like features, and 20% of cases had mucosal involvement resembling SJS/ TEN. In one study, up to 20% of all severe drug eruptions had overlap features, suggesting that AGEP, DIHS, and SJS/TEN represent a clinical spectrum with common pathophysiologic mechanisms. Designation of a single diagnosis based on cutaneous and extracutaneous involvement may not always be possible in cases of hypersensitivity. There are four main questions to answer regarding an eruption: 1. Is it a drug reaction? 2. Is it a severe eruption or the onset of a form that may become severe? 3. Which drug(s) is (are) suspected, and which drug(s) should be withdrawn? 4.


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InternalMed_Harrison. Is it a drug reaction? 2. Is it a severe eruption or the onset of a form that may become severe? 3. Which drug(s) is (are) suspected, and which drug(s) should be withdrawn? 4. What is recommended for future use of drugs? Generalized erythema Facial edema Skin pain Palpable purpura Target lesions Skin necrosis Blisters or epidermal detachment Positive Nikolsky's sign Mucous membrane erosions Urticaria Swelling of tongue High fever (temperature >40°C [>104°F]) Enlarged lymph nodes Arthralgias or arthritis Shortness of breath, wheezing, hypotension Lymphocytosis with atypical lymphocytes Source: Adapted from JC Roujeau, RS Stern: N Engl J Med 331:1272, 1994.


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InternalMed_Harrison. Lymphocytosis with atypical lymphocytes Source: Adapted from JC Roujeau, RS Stern: N Engl J Med 331:1272, 1994. Rapid recognition of adverse drug reactions that may become serious or life threatening is paramount. Table 74-2 lists clinical and laboratory features that, if present, suggest that the reaction may be serious. Table 74-3 provides key features of the most serious adverse cutaneous reactions. Intensity of symptoms and rapid progression of signs should raise the suspicion of a severe eruption. Any doubt should lead to prompt consultation with a dermatologist and/or referral of the patient to a specialized center.


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InternalMed_Harrison. The probability of drug etiology varies with the pattern of the reaction. Only fixed drug eruptions are always drug-induced. Morbilliform eruptions are usually viral in children and drug-induced in adults. Among severe reactions, drugs account for 10–20% of anaphylaxis and vasculitis and between 70–90% of AGEP, DIHS, SJS, or TEN. Skin biopsy helps in characterizing the reaction but does not indicate drug causality. Blood counts and liver and renal function tests are important for evaluating organ involvement. The association of mild elevation of liver enzymes and high eosinophil count is frequent but not specific for a drug reaction. Blood tests that could identify an alternative cause, antihistone antibody tests (to rule out drug-induced lupus), and serology or polymerase chain reaction for infections may be of great importance to determine a cause.


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InternalMed_Harrison. Most cases of drug eruptions occur during the first course of treatment with a new medication. A notable exception is IgE-mediated urticaria and anaphylaxis that need presensitization and develop a few minutes to a few hours after rechallenge. Characteristic times of onset to drug reaction are as follows: 4–14 days for morbilliform eruptions, 2–4 days for AGEP, 5–28 days for SJS/TEN, and 14–48 days for DIHS. A drug chart, compiling information of all current and past medications/ supplements and the timing of administration relative to the rash, is a key diagnostic tool to identifying the inciting drug. Medications introduced for the first time in the relevant time frame are prime suspects. Two other important elements to suspect causality at this stage are (1) previous experience with the drug in the population and (2) alternative etiologic candidates.


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases aOverlap of Stevens-Johnson syndrome and toxic epidermal necrolysis have features of both and attachment of 10–30% of body surface area may occur. Source: Adapted from JC Roujeau, RS Stern: N Engl J Med 331:1272, 1994.


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InternalMed_Harrison. The decision to continue or discontinue any medication will depend The usefulness of laboratory tests to determine causality is still on the severity of the reaction, the severity of the primary disease, the debated. Many in vitro immunologic assays have been developed, but degree of suspicion of causality, and the feasibility of an alternative the predictive value of these tests has not been validated in any large safer treatment. In any potentially fatal drug reaction, elimination series of affected patients; these tests exist primarily for research and of all possible suspect drugs or unnecessary medications should be not clinical purposes. attempted. Some rashes may resolve when “treating through” a benign In some cases, diagnostic rechallenge may be appropriate, even for drug-related eruption. The decision to treat through an eruption drugs with high rates of adverse reactions. Desensitization is often should, however, remain the exception and withdrawal of every sus-successful


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InternalMed_Harrison. eruption. The decision to treat through an eruption drugs with high rates of adverse reactions. Desensitization is often should, however, remain the exception and withdrawal of every sus-successful in HIV-infected patients with morbilliform eruptions to pect drug the general rule. On the other hand, drugs that are not sus-sulfonamides but is not recommended in HIV-infected patients who pected and are important for the patient (e.g., antihypertensive agents) manifested erythroderma or a bullous reaction in response to their generally should not be quickly withdrawn. This approach prevents earlier sulfonamide exposure. reluctance to future use of these agents. In patients with history suggesting immediate IgE-mediated reac tions to penicillin, skin-prick testing with penicillins or cephalosporins has proved useful for identifying patients at risk of anaphylactic reac-The aims are (1) to prevent the recurrence of the drug eruption and (2) tions to these agents. However, skin tests


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InternalMed_Harrison. has proved useful for identifying patients at risk of anaphylactic reac-The aims are (1) to prevent the recurrence of the drug eruption and (2) tions to these agents. However, skin tests themselves carry a small risknot to compromise future treatments by contraindicating otherwise of anaphylaxis. Negative skin tests do not totally rule out IgE-mediateduseful medications.


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InternalMed_Harrison. reactivity, but the risk of anaphylaxis in response to penicillin admin-Begin with thorough assessment of drug causality. Drug causality istration in patients with negative skin tests is about 1%. In contrast, is evaluated based on timing of the reaction, evaluation of other postwo-thirds of patients with a positive skin test experience an allergicsible causes, effect of drug withdrawal or continuation, and knowledge response upon rechallenge. of medications that have been associated with the observed reaction.


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InternalMed_Harrison. of medications that have been associated with the observed reaction. For patients with delayed-type hypersensitivity, the clinical utilityCombination of these criteria leads to considering the causality as of skin tests is more questionable. At least one of a combination ofdefinite, probable, possible, or unlikely. The RegiSCAR group has several tests (prick, patch, and intradermal) is positive in 50–70% ofproposed a useful algorithm called Algorithm of Drug Causality for patients with a reaction “definitely” attributed to a single medication. Epidermal Necrolysis (ALDEN) to determine drug causality in SJS/ This low sensitivity corresponds to the observation that readministra-TEN. A drug with a “definite” or “probable” causality should be tion of drugs with negative skin testing resulted in eruptions in 17%contraindicated, a warning card or medical alert tag (e.g., wristband) of cases.


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InternalMed_Harrison. should be given to the patient, and the drugs should be listed in the patient’s medical chart as an allergy. A drug with a “possible” causality may be submitted to further CROSS-SENSITIVITY investigations depending on the expected need for future treatment. Because of the possibility of cross-sensitivity among chemically related A drug with “unlikely” causality or that has been continued when drugs, many physicians recommend avoidance of not only the medicathe reaction improved or was reintroduced without a reaction can be tion that induced the reaction but also all drugs of the same pharmaadministered safely. cologic class.


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InternalMed_Harrison. There are two types of cross-sensitivity. Reactions that depend on a pharmacologic interaction may occur with all drugs that target the same pathway, whether they are structurally similar or not. This is the case with angioedema caused by NSAIDs and ACE inhibitors. In this situation, the risk of recurrence varies from drug to drug in a particular class; however, avoidance of all drugs in the class is usually recommended. Immune recognition of structurally related drugs is the second mechanism by which cross-sensitivity occurs. A classic example is hypersensitivity to aromatic antiepileptics (barbiturates, phenytoin, carbamazepine) with up to 50% reaction to a second drug in patients who reacted to one. For other drugs, in vitro as well as in vivo data have suggested that cross-reactivity existed only between compounds with very similar chemical structures. Sulfamethoxazolespecific lymphocytes may be activated by other antibacterial sulfonamides but not diuretics, antidiabetic drugs,


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InternalMed_Harrison. existed only between compounds with very similar chemical structures. Sulfamethoxazolespecific lymphocytes may be activated by other antibacterial sulfonamides but not diuretics, antidiabetic drugs, or anti-COX2 NSAIDs with a sulfonamide group. Approximately 10% of patients with penicillin allergies will also develop allergic reactions to cephalosporin class antibiotics.


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InternalMed_Harrison. Recent data suggest that although the risk of a drug eruption to another drug was increased in persons with a prior reaction, “crosssensitivity” was probably not the explanation. As an example, persons with a history of an allergic-like reaction to penicillin were at higher risk to develop a reaction to antibacterial sulfonamides than to cephalosporins. These data suggest that the list of drugs to avoid after a drug reaction should be limited to the causative one(s) and to a few very similar medications. Because of growing evidence that some severe cutaneous reactions to drugs are associated with HLA genes, it is recommended that first-degree family members of patients with severe cutaneous reactions also should avoid these causative medications. This may be most relevant to sulfonamides and antiseizure medications.


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InternalMed_Harrison. Desensitization can be considered in those with a history of reaction to a medication that must be used again. Efficacy of such procedures has been demonstrated in cases of immediate reaction to penicillin and positive skin tests, anaphylactic reactions to platinum chemotherapy, and delayed reactions to sulfonamides in patients with AIDS. Various protocols are available, including oral and parenteral approaches. Oral desensitization appears to have a lower risk of serious anaphylactic reactions. However, desensitization carries the risk of anaphylaxis regardless of how it is performed and should be performed in monitored clinical settings such as an intensive care unit. After desensitization, many patients experience non-life-threatening reactions during therapy with the culprit drug.


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InternalMed_Harrison. Any severe reaction to drugs should be reported to a regulatory agency or to pharmaceutical companies (e.g., MedWatch, http://www.fda.gov/ Safety/MedWatch/default.htm). Because severe reactions are too rare to be detected in premarketing clinical trials, spontaneous reports are of critical importance for early detection of unexpected life-threatening events. To be useful, the report should contain enough details to permit ascertainment of severity and drug causality. This enables recognition of similar cases that may be reported from several different sources. We acknowledge the contribution of Dr. Jean-Claude Roujeau to this chapter in the 17th edition. Photosensitivity and other 75 Reactions to Light Alexander G. Marneros, David R. Bickers


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InternalMed_Harrison. We acknowledge the contribution of Dr. Jean-Claude Roujeau to this chapter in the 17th edition. Photosensitivity and other 75 Reactions to Light Alexander G. Marneros, David R. Bickers Sunlight is the most visible and obvious source of comfort in the environment. The sun provides the beneficial effects of warmth and vitamin D synthesis. However, acute and chronic sun exposure also has pathologic consequences. Few effects of sun exposure beyond those affecting the skin have been identified, but cutaneous exposure to sunlight is the major cause of human skin cancer and can have immunosuppressive effects as well.


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InternalMed_Harrison. The sun’s energy reaching the earth’s surface is limited to components of the ultraviolet (UV) spectrum, the visible spectrum, and portions of the infrared spectrum. The cutoff at the short end of the UV spectrum at ~290 nm is due primarily to stratospheric ozone—formed by highly energetic ionizing radiation—that prevents penetration to the earth’s surface of the shorter, more energetic, potentially more harmful wavelengths of solar radiation. Indeed, concern about destruction of the ozone layer by chlorofluorocarbons released into the atmosphere has led to international agreements to reduce production of those chemicals.


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InternalMed_Harrison. Measurements of solar flux showed a twentyfold regional variation in the amount of energy at 300 nm that reaches the earth’s surface. This variability relates to seasonal effects, the path that sunlight traverses through ozone and air, the altitude (a 4% increase for each 300 m of elevation), the latitude (increasing intensity with decreasing latitude), and the amount of cloud cover, fog, and pollution. The major components of the photobiologic action spectrum that are capable of affecting human skin include the UV and visible wavelengths between 290 and 700 nm. In addition, the wavelengths beyond 700 nm in the infrared spectrum primarily emit heat and in certain circumstances may exacerbate the pathologic effects of energy in the UV and visible spectra.


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InternalMed_Harrison. The UV spectrum reaching the earth represents <10% of total incident solar energy and is arbitrarily divided into two major segments, UV-B and UV-A, which constitute the wavelengths from 290 to 400 nm. UV-B consists of wavelengths between 290 and 320 nm. This portion of the photobiologic action spectrum is the most efficient in producing redness or erythema in human skin and thus is sometimes known as the “sunburn spectrum.” UV-A includes wavelengths between 320 and 400 nm and is ~1000-fold less efficient in producing skin redness than is UV-B.


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InternalMed_Harrison. The wavelengths between 400 and 700 nm are visible to the human eye. The photon energy in the visible spectrum is not capable of damaging human skin in the absence of a photosensitizing chemical. Without the absorption of energy by a molecule, there can be no photosensitivity. Thus, the absorption spectrum of a molecule is defined as the range of wavelengths it absorbs, whereas the action spectrum for an effect of incident radiation is defined as the range of wavelengths that evoke the response. Photosensitivity occurs when a photon-absorbing chemical (chromophore) present in the skin absorbs incident energy, becomes excited, and transfers the absorbed energy to various structures or to molecular oxygen.


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InternalMed_Harrison. Human skin consists of two major compartments: the outer epidermis, which is a stratified squamous epithelium, and the underlying dermis, which is rich in matrix proteins such as collagens and elastin. Both compartments are susceptible to damage from sun exposure. The epidermis and the dermis contain several chromophores capable of absorbing incident solar energy, including nucleic acids, proteins, and lipids. The outermost epidermal layer, the stratum corneum, is a major absorber of UV-B, and <10% of incident UV-B wavelengths penetrate through the epidermis to the dermis. Approximately 3% of radiation


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InternalMed_Harrison. CHAPTER 75 Photosensitivity and Other Reactions to Light 386 below 300 nm, 20% of radiation below 360 nm, and 33% of short visible radiation reach the basal cell layer in untanned human skin. In contrast, UV-A readily penetrates to the dermis and is capable of altering structural and matrix proteins that contribute to photoaging of chronically sun-exposed skin, particularly in individuals of light complexion. Thus, longer wavelengths can penetrate more deeply into the skin.


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InternalMed_Harrison. Molecular Targets for uVR-Induced Skin Effects Epidermal DNA— predominantly in keratinocytes and in Langerhans cells, which are dendritic antigen-presenting cells—absorbs UV-B and undergoes structural changes between adjacent pyrimidine bases (thymine or cytosine), including the formation of cyclobutane dimers and 6,4-photoproducts. These structural changes are potentially mutagenic and are found in most basal cell and squamous cell carcinomas (BCCs and SCCs, respectively). They can be repaired by cellular mechanisms that result in their recognition and excision and the restoration of normal base sequences. The efficient repair of these structural aberrations is crucial, since individuals with defective DNA repair are at high risk for the development of cutaneous cancer. For example, patients with xeroderma pigmentosum, an autosomal recessive disorder, have a variably deficient repair of UV-induced photoproducts. The skin of these patients often shows the dry, leathery appearance of


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InternalMed_Harrison. with xeroderma pigmentosum, an autosomal recessive disorder, have a variably deficient repair of UV-induced photoproducts. The skin of these patients often shows the dry, leathery appearance of prematurely photoaged skin, and these patients have an increased frequency of skin cancer already in the first two decades of life. Studies in transgenic mice have verified the importance of functional genes that regulate these repair pathways in preventing the development of UV-induced skin cancer. DNA damage in Langerhans cells may also contribute to the known immunosuppressive effects of UV-B (see “Photoimmunology,” below).


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InternalMed_Harrison. In addition to DNA, molecular oxygen is a target for incident solar UVR, leading to the generation of reactive oxygen species (ROS). These ROS can damage skin components, such as epidermal lipids— either free lipids in the stratum corneum or cell membrane lipids. UVR also can target proteins, leading to increased cross-linking and degradation of matrix proteins in the dermis and accumulation of abnormal dermal elastin leading to photoaging changes known as solar elastosis.


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InternalMed_Harrison. Cutaneous Optics and Chromophores Chromophores are endogenous or exogenous chemical components that can absorb physical energy. Endogenous chromophores are of two types: (1) normal components of skin, including nucleic acids, proteins, lipids, and 7-dehydrocholesterol (the precursor of vitamin D); and (2) components that are synthesized elsewhere in the body and that circulate in the bloodstream and diffuse into the skin, such as porphyrins. Normally, only trace amounts of porphyrins are present in the skin, but, in selected diseases known as the porphyrias (Chap. 430), porphyrins are released into the circulation in increased amounts from the bone marrow and the liver and are transported to the skin, where they absorb incident energy both in the Soret band (around 400 nm; short visible) and, to a lesser extent, in the red portion of the visible spectrum (580–660 nm). This energy absorption results in the generation of ROS that can mediate structural damage to the skin, manifested as


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InternalMed_Harrison. and, to a lesser extent, in the red portion of the visible spectrum (580–660 nm). This energy absorption results in the generation of ROS that can mediate structural damage to the skin, manifested as erythema, edema, urticaria, or blister formation. It is of interest that photoexcited porphyrins are currently used in the treatment of nonmelanoma skin cancers and their precursor lesions, actinic keratoses. Known as photodynamic therapy, this modality generates ROS in the skin, leading to cell death. Topical photosensitizers used in photodynamic therapy are the porphyrin precursors 5-aminolevulinic acid and methyl aminolevulinate, which are converted to porphyrins in the skin. It is believed that photodynamic therapy targets tumor cells for destruction more selectively than it targets adjacent nonneoplastic cells. The efficacy of such therapy requires appropriate timing of the application of methyl aminolevulinate or 5-aminolevulinic acid to the affected skin followed by exposure to


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InternalMed_Harrison. nonneoplastic cells. The efficacy of such therapy requires appropriate timing of the application of methyl aminolevulinate or 5-aminolevulinic acid to the affected skin followed by exposure to artificial sources of visible light. High-intensity blue light has been used successfully for the treatment of thin actinic keratoses. Red light has a longer wavelength, penetrates more deeply into the skin, and is more beneficial in the treatment of superficial BCCs.


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InternalMed_Harrison. Acute Effects of Sun Exposure The acute effects of skin exposure to sunlight include sunburn and vitamin D synthesis. PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. SUNBURN This painful skin condition is an acute inflammatory response of the skin, predominantly to UV-B. Generally, an individual’s ability to tolerate sunlight is inversely proportional to that individual’s degree of melanin pigmentation. Melanin, a complex polymer of tyrosine derivatives, is synthesized in specialized epidermal dendritic cells known as melanocytes and is packaged into melanosomes that are transferred via dendritic processes into keratinocytes, thereby providing photoprotection and simultaneously darkening the skin. Sun-induced melanogenesis is a consequence of increased tyrosinase activity in melanocytes. Central to the suntan response is the melanocortin-1 receptor (MC1R), and mutations in this gene contribute to the wide variation in human skin and hair color; individuals with red hair and fair skin typically have low MC1R activity. Genetic studies have revealed additional genes that influence skin color variation in humans, such as the gene for tyrosinase (TYR)


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InternalMed_Harrison. with red hair and fair skin typically have low MC1R activity. Genetic studies have revealed additional genes that influence skin color variation in humans, such as the gene for tyrosinase (TYR) and the genes APBA2[OCA2], SLC45A2, and SLC24A5. The human MC1R gene encodes a G protein–coupled receptor that binds α-melanocyte-stimulating hormone, which is secreted in the skin mainly by keratinocytes in response to UVR. The UV-induced expression of this hormone is controlled by the tumor suppressor p53, and absence of functional p53 attenuates the tanning response. Activation of the melanocortin receptor leads to increased intracellular cyclic adenosine 5′-monophosphate (cAMP) and protein kinase A activation, resulting in an increased transcription of the microphthalmia-associated transcription factor (MITF), which stimulates melanogenesis. Since the precursor of α-melanocytestimulating hormone, proopiomelanocortin, is also the precursor of β-endorphins, UVR may result in not only


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InternalMed_Harrison. factor (MITF), which stimulates melanogenesis. Since the precursor of α-melanocytestimulating hormone, proopiomelanocortin, is also the precursor of β-endorphins, UVR may result in not only increased pigmentation but also in increased β-endorphin production, an effect that has been hypothesized to promote sun-seeking behaviors.


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InternalMed_Harrison. The Fitzpatrick classification of human skin phototypes is based on the efficiency of the epidermal-melanin unit, which usually can be ascertained by asking an individual two questions: (1) Do you burn after sun exposure? (2) Do you tan after sun exposure? The answers to these questions permit division of the population into six skin types, varying from type I (always burn, never tan) to type VI (never burn, always tan) (Table 75-1).


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InternalMed_Harrison. Sunburn erythema is due to vasodilation of dermal blood vessels. There is a lag time (usually 4–12 h) between skin exposure to sunlight and the development of visible redness. The action spectrum for sunburn erythema includes UV-B and UV-A, although UV-B is much more efficient than UV-A in evoking the response. However, UV-A may contribute to sunburn erythema at midday, when much more UV-A than UV-B is present in the solar spectrum. The erythema that accompanies the inflammatory response induced by UVR results from the orchestrated release of cytokines along with growth factors and the generation of ROS. Furthermore, UV-induced activation of nuclear factor κB–dependent gene transcription can augment release of several pro-inflammatory cytokines and vasoactive mediators. These cytokines and mediators accumulate locally in sunburned skin, providing chemotactic factors that attract neutrophils, macrophages, and T lymphocytes, which promote the inflammatory response. UVR also stimulates


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InternalMed_Harrison. mediators accumulate locally in sunburned skin, providing chemotactic factors that attract neutrophils, macrophages, and T lymphocytes, which promote the inflammatory response. UVR also stimulates infiltration of inflammatory cells through induced expression of adhesion molecules such as E-selectin and intercellular adhesion molecule 1 on endothelial cells and keratinocytes. UVR also has been shown to activate phospholipase A2, resulting in increases in eicosanoids such as prostaglandin E2, which is known to be a potent inducer of sunburn erythema. The role of eicosanoids in this reaction has been verified by studies showing that nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce it.


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InternalMed_Harrison. Epidermal changes in sunburn include the induction of “sunburn cells,” which are keratinocytes undergoing p53-dependent apoptosis as a defense, with elimination of cells that harbor UV-B-induced structural DNA damage.


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InternalMed_Harrison. VITAMIN d SYNTHESIS ANd PHOTOCHEMISTRY Cutaneous exposure to UV-B causes photolysis of epidermal 7-dehydrocholesterol, converting it to pre–vitamin D3, which then undergoes temperature-dependent isomerization to form the stable hormone vitamin D3. This compound diffuses to the dermal vasculature and circulates to the liver and kidney, where it is converted to the dihydroxylated functional hormone 1,25-dihydroxyvitamin D3. Vitamin D metabolites from the circulation and those produced in the skin itself can augment epidermal differentiation signaling and inhibit keratinocyte proliferation. These effects are exploited therapeutically in psoriasis with the topical application of synthetic vitamin D analogues. In addition, vitamin D is increasingly thought to have beneficial effects in several other inflammatory conditions, and some evidence suggests that—besides its classic physiologic effects on calcium metabolism and bone homeostasis—it is associated with a reduced risk of various


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InternalMed_Harrison. other inflammatory conditions, and some evidence suggests that—besides its classic physiologic effects on calcium metabolism and bone homeostasis—it is associated with a reduced risk of various internal malignancies. There is controversy regarding the risk-to-benefit ratio of sun exposure in vitamin D homeostasis. At present, it is important to emphasize that no clear-cut evidence suggests that the use of sunscreens substantially diminishes vitamin D levels. Since aging also substantially decreases the ability of human skin to photocatalytically produce vitamin D3, the widespread use of sunscreens that filter out UV-B has led to concerns that the elderly might be unduly susceptible to vitamin D deficiency. However, the amount of sunlight needed to produce sufficient vitamin D is small and does not justify the risks of skin cancer and other types of photodamage linked to increased sun exposure or tanning behavior. Nutritional supplementation of vitamin D is a preferable strategy for


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InternalMed_Harrison. does not justify the risks of skin cancer and other types of photodamage linked to increased sun exposure or tanning behavior. Nutritional supplementation of vitamin D is a preferable strategy for patients with vitamin D deficiency.


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InternalMed_Harrison. Chronic Effects of Sun Exposure: Nonmalignant The clinical features of photoaging (dermatoheliosis) consist of wrinkling, blotchiness, and telangiectasia as well as a roughened, irregular, “weather-beaten” leathery appearance.


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InternalMed_Harrison. UVR is important in the pathogenesis of photoaging in human skin, and ROS are likely involved. The dermis and its connective tissue matrix are major targets for sun-associated chronic damage that manifests as solar elastosis, a massive increase in thickened irregular masses of abnormal-appearing elastic fibers. Collagen fibers are also abnormally clumped in the deeper dermis of sun-damaged skin. The chromophore(s), the action spectra, and the specific biochemical events orchestrating these changes are only partially understood, although more deeply penetrating UV-A seems to be primarily involved. Chronologically aged sun-protected skin and photoaged skin share important molecular features, including connective tissue damage and elevated levels of matrix metalloproteinases (MMPs). MMPs are enzymes involved in the degradation of the extracellular matrix. UV-A induces expression of some MMPs, including MMP-1 and MMP-3, leading to increased collagen breakdown. In addition, UV-A reduces


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InternalMed_Harrison. enzymes involved in the degradation of the extracellular matrix. UV-A induces expression of some MMPs, including MMP-1 and MMP-3, leading to increased collagen breakdown. In addition, UV-A reduces type I procollagen mRNA expression. Thus, chronic UVR alters the structure and function of dermal collagen. On the basis of these observations, it is not surprising that high-dose UV-A phototherapy may have beneficial effects in some patients with localized fibrotic diseases of the skin, such as localized scleroderma.


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InternalMed_Harrison. Chronic Effects of Sun Exposure: Malignant One of the major known consequences of chronic excessive skin exposure to sunlight is non-melanoma skin cancer. The two most common types of nonmelanoma skin cancer are BCC and SCC (Chap. 105). A model for skin cancer induction involves three major steps: initiation, promotion, and progression. Exposure of human skin to sunlight results in initiation, a step by which structural (mutagenic) changes in DNA evoke an irreversible alteration in the target cell (keratinocyte) that begins the tumorigenic process. Exposure to a tumor initiator such as UV-B is believed to be a necessary but not a sufficient step in the malignant process, since initiated skin cells not exposed to tumor promoters 387 generally do not develop tumors. The second stage in tumor development is promotion, a multistep process by which chronic exposure to sunlight evokes further changes that culminate in the clonal expansion of initiated cells and cause the development, over


InternalMed_Harrison

InternalMed_Harrison. development is promotion, a multistep process by which chronic exposure to sunlight evokes further changes that culminate in the clonal expansion of initiated cells and cause the development, over many years, of premalignant growths known as actinic keratoses, a minority of which may progress to form SCCs. As a result of extensive studies, it seems clear that UV-B is a complete carcinogen, meaning that it can act as both a tumor initiator and a tumor promoter. The third and final step in the malignant process is malignant conversion of benign precursors into malignant lesions, a process thought to require additional genetic alterations.


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InternalMed_Harrison. On a molecular level, skin carcinogenesis results from the accumulation of gene mutations that cause inactivation of tumor suppressors, activation of oncogenes, or reactivation of cellular signaling pathways that normally are expressed only during epidermal embryologic development. Accumulation of mutations in the tumor-suppressor gene p53 secondary to UV-induced DNA damage occurs in both SCCs and BCCs and is important in promoting skin carcinogenesis. Indeed, the majority of both human and murine UV-induced skin cancers have characteristic p53 mutations (C → T and CC → TT transitions). Studies in mice have shown that sunscreens can substantially reduce the frequency of these signature mutations in p53 and inhibit the induction of tumors.


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InternalMed_Harrison. BCCs also harbor inactivating mutations in the tumor-suppressor gene patched, which result in activation of the sonic hedgehog signaling pathway and increased cell proliferation. Thus, these tumors can manifest mutations in tumor suppressors (p53 and patched) or oncogenes (smoothened). New evidence links alterations in the Wnt/βcatenin signaling pathway, which is known to be critical for hair follicle development, to skin cancer as well. Thus interactions between this pathway and the hedgehog signaling pathway appear to be involved in both skin carcinogenesis and embryologic development of the skin and hair follicles.


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InternalMed_Harrison. Clonal analysis in mouse models of BCC revealed that tumor cells arise from long-term resident progenitor cells of the interfollicular epidermis and the upper infundibulum of the hair follicle. These BCC-initiating cells are reprogrammed to resemble embryonic hair follicle progenitors, whose tumor-initiating ability depends on activation of the Wnt/β-catenin signaling pathway. SCC initiation occurs both in the interfollicular epidermis and in the hair follicle bulge stem cell populations. In mouse models, the combination of mutant K-Ras and p53 is sufficient to induce invasive SCCs from these cell populations. The transcription factor Myc is important for stem cell maintenance in the skin, and oncogenic activation of Myc has been implicated in the development of BCCs and SCCs. Thus, nonmelanoma skin cancer involves mutations and alterations in multiple genes and pathways that occur as a result of their chronic accumulation driven by exposure to environmental factors such as UVR.


InternalMed_Harrison

InternalMed_Harrison. Epidemiologic studies have linked excessive sun exposure to an increased risk of nonmelanoma cancers and melanoma of the skin; the evidence is far more direct for nonmelanoma skin cancers (BCCs and SCCs) than for melanoma. Approximately 80% of nonmelanoma skin cancers develop on sun-exposed body areas, including the face, neck, and hands. Major risk factors include male sex, childhood sun exposures, older age, fair skin, and residence at latitudes relatively close to the equator. Individuals with darker-pigmented skin have a lower risk of skin cancer than do fair-skinned individuals. More than 2 million individuals in the United States develop nonmelanoma skin cancer annually, and the lifetime risk that a fair-skinned individual will develop such a neoplasm is estimated at ~15%. The incidence of non-melanoma skin cancer in the population is increasing at a rate of 2–3% per year. One potential explanation is the widespread use of indoor tanning. It is estimated that 30 million people


InternalMed_Harrison

InternalMed_Harrison. of non-melanoma skin cancer in the population is increasing at a rate of 2–3% per year. One potential explanation is the widespread use of indoor tanning. It is estimated that 30 million people tan indoors in the United States annually, including >2 million adolescents.


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InternalMed_Harrison. The relationship of sun exposure to melanoma development is less direct, but strong evidence supports an association. Clear-cut risk


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InternalMed_Harrison. CHAPTER 75 Photosensitivity and Other Reactions to Light 388 factors include a positive family or personal history of melanoma and multiple dysplastic nevi. Melanomas can occur during adolescence; the implication is that the latent period for tumor growth is shorter than that for nonmelanoma skin cancer. For reasons that are only partially understood, melanomas are among the most rapidly increasing human malignancies (Chap. 105). Epidemiologic studies indicate that indoor tanning is a risk factor for melanoma, which may contribute to the increasing incidence of melanoma formation. Furthermore, epidemiologic studies suggest that life in a sunny climate from birth or early childhood may increase the risk of melanoma development. In general, risk does not correlate with cumulative sun exposure but may be related to the duration and extent of exposure in childhood. However, in contrast to nonmelanoma skin cancers, melanoma frequently develops in sun-protected skin, and oncogenic mutations


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InternalMed_Harrison. but may be related to the duration and extent of exposure in childhood. However, in contrast to nonmelanoma skin cancers, melanoma frequently develops in sun-protected skin, and oncogenic mutations in melanoma may also not be UVR-signature mutations; these observations suggest that UVR-independent factors contribute to melanomagenesis. Low MC1R activity leads to production of the red/yellow pheomelanin pigment in individuals with red hair and fair skin, while high MC1R activity results in increased production of the black/brown eumelanin. Experiments in mice suggest that high pheomelanin content in skin (as in individuals with red hair and fair skin) leads to a UVR-independent increase in the risk of melanoma through a mechanism that involves oxidative damage. Thus, both UVR-dependent and UVR-independent factors are likely to contribute to melanoma formation.


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InternalMed_Harrison. Photoimmunology Exposure to solar radiation causes both local immunosuppression (through inhibition of immune responses to antigens applied at the irradiated site) and systemic immunosuppression (through inhibition of immune responses to antigens applied at remote, unirradiated sites). For example, human skin exposure to modest doses of UV-B can deplete the epidermal antigen-presenting cells known as Langerhans cells, thereby reducing the degree of allergic sensitization to application of the potent contact allergen dinitrochlorobenzene at the irradiated skin site.


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InternalMed_Harrison. An example of the systemic immunosuppressive effects of higher doses of UVR is the diminished immunologic response to antigens introduced either epicutaneously or intracutaneously at sites distant from the irradiated site. Various immunomodulatory factors and immune cells have been implicated in UVR-induced systemic immunosuppression, including tumor necrosis factor α, interleukin 4, interleukin 10, cis-urocanic acid, and eicosanoids. Experimental evidence suggests that prostaglandin E2 signaling through prostaglandin E receptor subtype 4 mediates UVR-induced systemic immunosuppression by elevating the number of regulatory T cells, and this effect can be inhibited with NSAIDs.


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InternalMed_Harrison. The major chromophores in the upper epidermis that are known to initiate UV-mediated immunosuppression include DNA, transurocanic acid, and membrane components. The action spectrum for UV-induced immunosuppression closely mimics the absorption spectrum of DNA. Pyrimidine dimers in Langerhans cells may inhibit antigen presentation. The absorption spectrum of epidermal urocanic acid closely mimics the action spectrum for UV-B-induced immunosuppression. Urocanic acid is a metabolic product of the essential amino acid histidine and accumulates in the upper epidermis through breakdown of the histidine-rich protein filaggrin due to the absence of its catabolizing enzyme in keratinocytes. Urocanic acid is synthesized as a trans-isomer, and UV-induced trans-cis isomerization of urocanic acid in the stratum corneum drives immunosuppression. Cis-urocanic acid may exert its immunosuppressive effects through a variety of mechanisms, including inhibition of antigen presentation by Langerhans


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InternalMed_Harrison. in the stratum corneum drives immunosuppression. Cis-urocanic acid may exert its immunosuppressive effects through a variety of mechanisms, including inhibition of antigen presentation by Langerhans cells.


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InternalMed_Harrison. One important consequence of chronic sun exposure and associated immunosuppression is an enhanced risk of skin cancer. In part, UV-B activates regulatory T cells that suppress antitumor immune responses via interleukin 10 expression, whereas, in the absence of high UV-B exposure, epidermal Langerhans cells present tumor-associated antigens and induce protective immunity, thereby inhibiting skin tumorigenesis. UV-induced DNA damage is a major molecular trigger of this immunosuppressive effect. PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. Perhaps the most graphic demonstration of the role of immunosuppression in enhancing the risk of nonmelanoma skin cancer comes from studies of organ transplant recipients who require lifelong immunosuppressive/antirejection drug regimens. More than 50% of organ transplant recipients develop BCCs and SCCs, and these cancers are the most common types of malignancies arising in these patients. Rates of BCC and SCC increase with the duration and degree of immunosuppression. These patients ideally should be screened prior to organ transplantation, be monitored closely thereafter, and adhere to rigorous photoprotection measures, including the use of sunscreens and protective clothing as well as sun avoidance. Notably, immunosuppressive drugs that target the mTOR pathway, such as sirolimus and everolimus, may reduce the risk of nonmelanoma skin cancer in organ transplant recipients from that associated with the use of calcineurin inhibitors (cyclosporine and tacrolimus), which may contribute


InternalMed_Harrison

InternalMed_Harrison. may reduce the risk of nonmelanoma skin cancer in organ transplant recipients from that associated with the use of calcineurin inhibitors (cyclosporine and tacrolimus), which may contribute to nonmelanoma skin cancer formation not only through their immunosuppressive effects but also through suppression of p53-dependent cancer cell senescence pathways independent of host immunity.


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InternalMed_Harrison. The diagnosis of photosensitivity requires elicitation of a careful history in order to define the duration of signs and symptoms, the length of time between exposure to sunlight and the development of subjective symptoms, and visible changes in the skin. The age of onset can also be a helpful diagnostic clue; for example, the acute photosensitivity of erythropoietic protoporphyria almost always begins in childhood, whereas the chronic photosensitivity of porphyria cutanea tarda (PCT) typically begins in the fourth and fifth decades of life. A patient’s history of exposure to topical and systemic drugs and chemicals may provide important diagnostic clues. Many classes of drugs can cause photosensitivity on the basis of either phototoxicity or photoallergy. Fragrances such as musk ambrette that were previously present in numerous cosmetic products are also potent photosensitizers.


InternalMed_Harrison

InternalMed_Harrison. Examination of the skin may offer important clues. Anatomic areas that are naturally protected from direct sunlight, such as the hairy scalp, the upper eyelids, the retroauricular areas, and the infranasal and submental regions, may be spared, whereas exposed areas show characteristic features of the pathologic process. These anatomic localization patterns are often helpful, but not infallible, in making the diagnosis. For example, airborne contact sensitizers that are blown onto the skin may produce dermatitis that can be difficult to distinguish from photosensitivity despite the fact that such material may trigger skin reactivity in areas shielded from direct sunlight.


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InternalMed_Harrison. Many dermatologic conditions may be caused or aggravated by sunlight (Table 75-2). The role of light in evoking these responses may be dependent on genetic abnormalities ranging from well-described defects in DNA repair that occur in xeroderma pigmentosum to the inherited abnormalities in heme synthesis that characterize the porphyrias. The chromophore has been identified in certain photosensitivity diseases, but the energy-absorbing agent remains unknown in the majority.


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InternalMed_Harrison. Polymorphous Light Eruption A common type of photosensitivity disease is polymorphous light eruption (PMLE). Many affected individuals never seek medical attention because the condition is often transient, becoming manifest in the spring with initial sun exposure but then subsiding spontaneously with continuing exposure, a phenomenon known as “hardening.” The major manifestations of PMLE include (often intensely) pruritic erythematous papules that may coalesce into plaques in a patchy distribution on exposed areas of the trunk and forearms. The face is usually less seriously involved. Whereas the morphologic skin findings remain similar for each patient with subsequent recurrences, significant interindividual variations in skin findings are characteristic (hence the term “polymorphous”).


InternalMed_Harrison

InternalMed_Harrison. A skin biopsy and phototest procedures in which skin is exposed to multiple erythemal doses of UV-A and UV-B may aid in the diagnosis. The action spectrum for PMLE is usually within these portions of the solar spectrum. Whereas the treatment of an acute flare of PMLE may require topical or systemic glucocorticoids, approaches to preventing PMLE are External Drugs, plants, food important and include the use of high-SPF and high UVA-protection broad-spectrum sunscreens as well as the induction of “hardening” by the cautious administration of artificial UV-B (broad-band or narrow-band) and/or UV-A radiation or the use of psoralen plus UV-A (PUVA) photochemotherapy for 2–4 weeks before initial sun exposure. Such prophylactic phototherapy or photochemotherapy at the beginning of spring may prevent the occurrence of PMLE throughout the summer.


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InternalMed_Harrison. Phototoxicity and Photoallergy These photosensitivity disorders are related to the topical or systemic administration of drugs and other chemicals. Both reactions require the absorption of energy by a drug or chemical with consequent production of an excited-state photosensitizer that can transfer its absorbed energy to a bystander molecule or to molecular oxygen, thereby generating tissue-destructive chemical species, including ROS. Phototoxicity is a nonimmunologic reaction that can be caused by drugs and chemicals, a few of which are listed in Table 75-3. The usual clinical manifestations include erythema resembling a sunburn reaction that quickly desquamates, or “peels,” within several days. In addition, edema, vesicles, and bullae may occur.


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InternalMed_Harrison. Photoallergy is much less common and is distinct in that it is an immunopathologic process. The excited-state photosensitizer may create highly unstable haptenic free radicals that bind covalently to macromolecules to form a functional antigen capable of evoking a delayed-type hypersensitivity response. Some drugs and chemicals that can produce photoallergy are listed in Table 75-4. The clinical manifestations typically differ from those of phototoxicity in that an intensely pruritic eczematous dermatitis tends to predominate and evolves into lichenified, thickened, “leathery” changes in sun-exposed areas. A small subset (perhaps 5–10%) of patients with photoallergy may develop a persistent exquisite hypersensitivity to light even when the offending drug or chemical is identified and eliminated, a condition known as persistent light reaction.


InternalMed_Harrison

InternalMed_Harrison. A very uncommon type of persistent photosensitivity is known as chronic actinic dermatitis. The affected patients are typically elderly men with a long history of preexisting allergic contact dermatitis or photosensitivity. These individuals are usually exquisitely sensitive to UV-B, UV-A, and visible wavelengths.


InternalMed_Harrison

InternalMed_Harrison. Phototoxicity and photoallergy often can be diagnostically confirmed by phototest procedures. In patients with suspected photo-toxicity, determining the minimal erythemal dose (MED) while the patient is exposed to a suspected agent and then repeating the MED after discontinuation of the agent may provide a clue to the causative drug or chemical. Photopatch testing can be performed to confirm the diagnosis of photoallergy. In this simple variant of ordinary patch testing, a series of known photoallergens is applied to the skin in duplicate, and one set is irradiated with a suberythemal dose of UV-A. The development of eczematous changes at sites exposed to sensitizer and light is a positive result. The characteristic abnormality in patients with persistent light reaction is a diminished threshold to erythema evoked + Halogenated salicylanilides + Hypericin (St. John’s wort) + + Musk ambrette + Piroxicam


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InternalMed_Harrison. CHAPTER 75 Photosensitivity and Other Reactions to Light 390 by UV-B. Patients with chronic actinic dermatitis usually manifest a broad spectrum of UV hyperresponsiveness and require meticulous photoprotection, including avoidance of sun exposure, use of high-SPF (>30) sunscreens, and, in severe cases, systemic immunosuppression, such as with azathioprine. The management of drug photosensitivity involves first and foremost the elimination of exposure to the chemical agents responsible for the reaction and the minimization of sun exposure. The acute symptoms of phototoxicity may be ameliorated by cool moist compresses, topical glucocorticoids, and systemically administered NSAIDs. In severely affected individuals, a rapidly tapered course of systemic glucocorticoids may be useful. Judicious use of analgesics may be necessary. Photoallergic reactions require a similar management approach. Furthermore, patients with persistent light reaction and chronic actinic dermatitis must be


InternalMed_Harrison

InternalMed_Harrison. use of analgesics may be necessary. Photoallergic reactions require a similar management approach. Furthermore, patients with persistent light reaction and chronic actinic dermatitis must be meticulously protected against light exposure. In selected patients to whom chronic systemic high-dose glucocorticoids pose unacceptable risks, it may be necessary to employ an immunosuppressive drug such as azathioprine, cyclophosphamide, cyclosporine, or mycophenolate mofetil.


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InternalMed_Harrison. Porphyria The porphyrias (Chap. 430) are a group of diseases that have in common inherited or acquired derangements in the synthesis of heme. Heme is an iron-chelated tetrapyrrole or porphyrin, and the nonmetal chelated porphyrins are potent photosensitizers that absorb light intensely in both the short (400–410 nm) and the long (580–650 nm) portions of the visible spectrum.


InternalMed_Harrison

InternalMed_Harrison. Heme cannot be reutilized and must be synthesized continuously. The two body compartments with the largest capacity for its production are the bone marrow and the liver. Accordingly, the porphyrias originate in one or the other of these organs, with an end result of excessive endogenous production of potent photosensitizing porphyrins. The porphyrins circulate in the bloodstream and diffuse into the skin, where they absorb solar energy, become photoexcited, generate ROS, and evoke cutaneous photosensitivity. The mechanism of porphyrin photosensitization is known to be photodynamic, or oxygen-dependent, and is mediated by ROS such as singlet oxygen and superoxide anions.


InternalMed_Harrison

InternalMed_Harrison. Porphyria cutanea tarda is the most common type of porphyria and is associated with decreased activity of the enzyme uroporphyrinogen decarboxylase. There are two basic types of PCT: (1) the sporadic or acquired type, generally seen in individuals ingesting ethanol or receiving estrogens; and (2) the inherited type, in which there is autosomal dominant transmission of deficient enzyme activity. Both forms are associated with increased hepatic iron stores.


InternalMed_Harrison

InternalMed_Harrison. In both types of PCT, the predominant feature is chronic photo-sensitivity characterized by increased fragility of sun-exposed skin, particularly areas subject to repeated trauma such as the dorsa of the hands, the forearms, the face, and the ears. The predominant skin lesions are vesicles and bullae that rupture, producing moist erosions (often with a hemorrhagic base) that heal slowly, with crusting and purplish discoloration of the affected skin. Hypertrichosis, mottled pigmentary change, and scleroderma-like induration are associated features. The diagnosis can be confirmed biochemically by measurement of urinary porphyrin excretion, plasma porphyrin assay, and assay of erythrocyte and/or hepatic uroporphyrinogen decarboxylase. Multiple mutations of the uroporphyrinogen decarboxylase gene have been identified in human populations. Some patients with PCT have associated mutations in the HFE gene, which is linked to hemochromatosis; these mutations could contribute to the iron


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InternalMed_Harrison. gene have been identified in human populations. Some patients with PCT have associated mutations in the HFE gene, which is linked to hemochromatosis; these mutations could contribute to the iron overload seen in PCT, although iron status as measured by serum ferritin, iron levels, and transferrin saturation is no different from that in PCT patients without HFE mutations. Prior hepatitis C virus infection appears to be an independent risk factor for PCT.


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InternalMed_Harrison. Treatment of PCT consists of repeated phlebotomies to diminish the excessive hepatic iron stores and/or intermittent low doses of chloroquine and hydroxychloroquine. Long-term remission of the disease can be achieved if the patient eliminates exposure to porphyrinogenic agents and prolonged exposure to sunlight. PART 2 Cardinal Manifestations and Presentation of Diseases Erythropoietic protoporphyria originates in the bone marrow and is due to a decrease in the mitochondrial enzyme ferrochelatase secondary to numerous gene mutations. The major clinical features include acute photosensitivity characterized by subjective burning and stinging of exposed skin that often develops during or just after sun exposure. There may be associated skin swelling and, after repeated episodes, a waxlike scarring.


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InternalMed_Harrison. The diagnosis is confirmed by demonstration of elevated levels of free erythrocyte protoporphyrin. Detection of increased plasma protoporphyrin helps distinguish erythropoietic protoporphyria from lead poisoning and iron-deficiency anemia, in both of which erythrocyte protoporphyrin levels are elevated in the absence of cutaneous photo-sensitivity and elevated plasma protoporphyrin levels. Treatment includes reduction of sun exposure and oral administration of the carotenoid β-carotene, which is an effective scavenger of free radicals. This drug increases tolerance to sun exposure in some affected individuals, although it has no effect on deficient ferrochelatase. An algorithm for managing patients with photosensitivity is presented in Fig. 75-1.


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InternalMed_Harrison. An algorithm for managing patients with photosensitivity is presented in Fig. 75-1. Laboratory screen Delayed Photosensitivity Phototesting Photo Patch Test Discontinue drug Rash persists History of exposure to photosensitizing drug History of association of rash to exposure UV-A Immediate Drug photosensitivity Unrelated Drug photosensitivity Photoallergic contact dermatitis Plasma porphyrin ANA Ro/La Rash disappears Solar urticaria UV-B (± UV-A) Lupus erythematosus dermatomyositis Porphyria Polymorphous light eruption Lupus erythematosus Atopic dermatitis with photoaggravation Chronic actinic dermatitis + – Phototest with UV-B, UV-A, and visible; read MED at 30 min Phototest with UV-B, UV-A, and visible; read MED at 24 h + + – – + – + + + – – FIguRE 75-1 Algorithm for the diagnosis of a patient with photo-sensitivity. ANA, antinuclear antibody; MED, minimal erythemal dose; UV-A and UV-B, ultraviolet spectrum segments including wavelengths of 320–400 nm and 290–320 nm, respectively.


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InternalMed_Harrison. Since photosensitivity of the skin results from exposure to sunlight, it follows that absolute avoidance of sunlight will eliminate these disorders. However, contemporary lifestyles make this approach impractical for most individuals. Thus better approaches to photoprotection have been sought. Natural photoprotection is provided by structural proteins in the epidermis, particularly keratins and melanin. The amount of melanin and its distribution in cells are genetically regulated, and individuals of darker complexion (skin types IV–VI) are at decreased risk for the development of acute sunburn and cutaneous malignancy. Other forms of photoprotection include clothing and sunscreens. Clothing constructed of tightly woven sun-protective fabrics, irrespective of color, affords substantial protection. Wide-brimmed hats, long sleeves, and trousers all reduce direct exposure. Sunscreens are now considered over-the-counter drugs, and a monograph from the


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InternalMed_Harrison. U.S. Food and Drug Administration (FDA) has recognized category I ingredients as safe and effective. Those ingredients are listed in Table 75-5. Sunscreens are rated for their photoprotective effect by their sun protection factor (SPF). The SPF is simply a ratio of the time required to produce sunburn erythema with and without sunscreen application. The SPF of most sunscreens reflects protection from UV-B but not from UV-A. The FDA monograph stipulates that sunscreens must be rated on a scale ranging from minimal (SPF ffi2 and <12) to moderate (SPF ffi12 and <30) to high (SPF ffi30, labeled as 30+). Broad-spectrum sunscreens contain both UV-B-absorbing and UV-A-absorbing chemicals, the latter including avobenzone and ecamsule (terephthalylidene dicamphor sulfonic acid). These chemicals absorb UVR and transfer the absorbed energy to surrounding cells. In contrast, physical UV blockers (zinc oxide and titanium dioxide) scatter or reflect UVR.


InternalMed_Harrison

InternalMed_Harrison. In addition to light absorption, a critical determinant of the sustained photoprotective effect of sunscreens is their water resistance. The FDA monograph has defined strict testing criteria for sunscreens that claim to possess a high degree of water resistance. Some degree of photoprotection can be achieved by limiting the time of sun exposure during the day. Since a large part of an individual’s total lifetime sun exposure may occur by age 18, it is important to educate parents and young children about the hazards of sunlight. Simply eliminating exposure at midday will substantially reduce lifetime UVR exposure.


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InternalMed_Harrison. UVR can be used therapeutically. The administration of UV-B alone or in combination with topically applied agents can induce remissions of many dermatologic diseases, including psoriasis and atopic dermatitis. In particular, narrow-band UV-B treatments (with fluorescent bulbs emitting radiation at ~311 nm) have enhanced efficacy over that obtained with broad-band UV-B in the treatment of psoriasis.


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InternalMed_Harrison. Photochemotherapy in which topically applied or systemically administered psoralens are combined with UV-A (PUVA) is effective in treating psoriasis and the early stages of cutaneous T cell lymphoma and vitiligo. Psoralens are tricyclic furocoumarins that, when intercalated into DNA and exposed to UV-A, form adducts with pyrimidine bases and eventually form DNA cross-links. These structural changes are thought to decrease DNA synthesis and to be related to the amelioration of psoriasis. Why PUVA photochemotherapy is effective in cutaneous T cell lymphoma is only partially understood, but it has been shown to induce apoptosis of atypical T lymphocyte populations in the skin. Consequently, direct treatment of circulating atypical lymphocytes by extracorporeal photochemotherapy (photopheresis) has been used in Sézary syndrome as well as in other severe systemic diseases with circulating atypical lymphocytes, such as graft-versus-host disease.


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InternalMed_Harrison. In addition to its effects on DNA, PUVA photochemotherapy stimulates epidermal thickening and melanin synthesis; the latter property, together with its anti-inflammatory effects, provides the rationale for use of PUVA in the depigmenting disease vitiligo. Oral 8-methoxypsoralen and UV-A appear to be most effective in this regard, but as many as 100 treatments extending over 12–18 months may be required for satisfactory repigmentation.


InternalMed_Harrison

InternalMed_Harrison. Not surprisingly, the major side effects of long-term UV-B photo-therapy and PUVA photochemotherapy mimic those seen in individuals with chronic sun exposure and include skin dryness, actinic keratoses, and an increased risk of skin cancer. Despite these risks, the therapeutic index of these modalities continues to be excellent. It is important to choose the most appropriate phototherapeutic approach for a specific dermatologic disease. For example, narrow-band UV-B has been reported in several studies to be as effective as PUVA photo-chemotherapy in the treatment of psoriasis but to pose a lower risk of skin cancer development than PUVA. CHAPTER 75 Photosensitivity and Other Reactions to Light


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InternalMed_Harrison. Atlas of Skin Manifestations of Internal Disease Thomas J. Lawley, Calvin McCall, Robert A. Swerlick In the practice of medicine, virtually every clinician encounters patients with skin disease. Physicians of all specialties face the daily 76e task of determining the nature and clinical implication of dermatologic disease. In patients with skin disease, the physician must confront the question of whether the cutaneous process is confined to the skin, representing a purely dermatologic event, or whether it is a manifestation of internal disease related to the patient’s overall medical condition. Evaluation and accurate diagnosis of skin lesions are particularly critical given the marked rise in both melanoma and nonmelanoma skin cancer. Dermatologic conditions can be classified and categorized in many ways. In this atlas, a selected group of inflammatory skin eruptions and neoplastic conditions are grouped in the following manner: common skin diseases and lesions, (2) nonmelanoma skin


InternalMed_Harrison

InternalMed_Harrison. in many ways. In this atlas, a selected group of inflammatory skin eruptions and neoplastic conditions are grouped in the following manner: common skin diseases and lesions, (2) nonmelanoma skin cancer, melanoma and benign pigmented lesions, (4) infectious disease and the skin, (5) immunologically mediated skin disease, and (6) skin manifestations of internal disease.


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InternalMed_Harrison. (Figs. 76e-1 to 76e-19) While most of these common inflammatory skin diseases and benign neoplastic and reactive lesions usually present as a predominantly dermatologic process, underlying systemic associations may be found in some settings. Atopic dermatitis is often present in patients with an atopic diathesis, including asthma or sinusitis. Psoriasis ranges from limited patches on the elbows and knees to severe erythrodermic and pustular involvement and associated psoriatic arthritis. Some patients with alopecia areata may have an underlying thyroid abnormality requiring screening. Finally, even acne vulgaris, one of the most common inflammatory dermatoses, can be associated with a systemic process such as polycystic ovarian syndrome.


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InternalMed_Harrison. (Figs. 76e-20 to 76e-27) In fair-skinned ethnic populations, rates of nonmelanoma skin cancer are increasing at an alarming rate. Basal cell carcinoma is the most common cancer in humans and is strongly linked to ultraviolet radiation. Squamous cell carcinoma, including keratoacanthoma, is the second most common skin cancer in most ethnic groups and is also most commonly linked to ultraviolet radiation. Less common cutaneous malignancies include cutaneous T cell lymphoma (mycosis fungoides) and carcinoma and lymphoma metastatic to skin. FIguRE 76e-1 Acne vulgaris, with inflammatory papules, pustules, and comedones. (Courtesy of Kalman Watsky, MD; with permission.) FIguRE 76e-2 Acne rosacea, with prominent facial erythema, telangiectasias, scattered papules, and small pustules. (Courtesy of Robert Swerlick, MD; with permission.)


InternalMed_Harrison

InternalMed_Harrison. FIguRE 76e-2 Acne rosacea, with prominent facial erythema, telangiectasias, scattered papules, and small pustules. (Courtesy of Robert Swerlick, MD; with permission.) FIguRE 76e-3 Psoriasis. A. Typical psoriasis is characterized by small and large erythematous plaques with adherent silvery scale. B. Acute inflammatory variants of psoriasis may present with widespread superficial pustules. CHAPTER 76e Atlas of Skin Manifestations of Internal Disease PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 76e-4 Atopic dermatitis, with hyperpigmentation, licheni-fication, and scaling in the antecubital fossae. (Courtesy of Robert Swerlick, MD; with permission.) FIguRE 76e-5 Dyshidrotic eczema, characterized by deep-seated vesicles and scaling on palms and lateral fingers, is often associated with an atopic diathesis. FIguRE 76e-6 Seborrheic dermatitis, with erythema and scale in the nasolabial fold. (Courtesy of Robert A. Swerlick, MD; with permission.)


InternalMed_Harrison

InternalMed_Harrison. FIguRE 76e-6 Seborrheic dermatitis, with erythema and scale in the nasolabial fold. (Courtesy of Robert A. Swerlick, MD; with permission.) FIguRE 76e-7 Stasis dermatitis, with erythematous, scaly, and oozing patches over the lower leg. Several stasis ulcers are also seen in this patient. FIguRE 76e-8 Allergic contact dermatitis. A. Acute phase, with sharply demarcated, weeping, eczematous plaques in a perioral distribution. B. Allergic contact reaction to nickel, chronic phase, with an erythematous, lichenified, weeping plaque on skin chronically exposed to a metal snap. (B: Courtesy of Robert Swerlick, MD; with permission.) FIguRE 76e-9 Lichen planus, with multiple flat-topped, violaceous papules and plaques. Nail dystrophy, as seen in this patient’s thumb-nail, may also be a feature. (Courtesy of Robert Swerlick, MD; with per-mission.) FIguRE 76e-11 Vitiligo in a typical acral distribution, with striking cutaneous depigmentation as a result of melanocyte loss.


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InternalMed_Harrison. FIguRE 76e-11 Vitiligo in a typical acral distribution, with striking cutaneous depigmentation as a result of melanocyte loss. CHAPTER 76e Atlas of Skin Manifestations of Internal Disease FIguRE 76e-10 Seborrheic keratoses are “stuck on,” waxy, verrucous papules and plaques with a variety of colors ranging from light tan to black. FIguRE 76e-12 Alopecia areata, characterized by a sharply demar-cated circular patch of scalp completely devoid of hairs. Preservation of follicular orifices is indicative of nonscarring alopecia. (Courtesy of Robert Swerlick, MD; with permission.) FIguRE 76e-13 Pityriasis rosea. Multiple round or oval erythematous patches with fine central scale are distributed along the skin tension lines on the trunk. FIguRE 76e-16 Keloids resulting from ear piercing, with firm exo-phytic flesh-colored to erythematous nodules of scar tissue. PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. FIguRE 76e-16 Keloids resulting from ear piercing, with firm exo-phytic flesh-colored to erythematous nodules of scar tissue. PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 76e-14 A. Urticaria, with characteristic discrete and confluent, edematous, erythematous papules and plaques. B. Dermatographism. Erythema and whealing developed after firm stroking of the skin. (B: Courtesy of Robert Swerlick, MD; with permission.) FIguRE 76e-15 Epidermoid cysts. Several inflamed and noninflamed firm cystic nodules are seen in this patient. Often a patulous follicular punctum is observed on the overlying epidermal surface. FIguRE 76e-17 Cherry hemangiomas—multiple erythematous to dark-purple papules, usually located on the trunk—are very common and arise in middle-aged to older adults. FIguRE 76e-18 Frostbite of the hand, with vesiculation surrounded by edema and erythema. (Courtesy of Daniel F. Danzl, MD; with permission.)


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InternalMed_Harrison. FIguRE 76e-18 Frostbite of the hand, with vesiculation surrounded by edema and erythema. (Courtesy of Daniel F. Danzl, MD; with permission.) FIguRE 76e-22 Basal cell carcinoma, with central ulceration and a pearly, rolled, telangiectatic tumor border. FIguRE 76e-21 Non-Hodgkin’s lymphoma involving the skin, with typical violaceous, “plum-colored” nodules. (Courtesy of Jean Bolognia, MD; with permission.) FIguRE 76e-19 Frostbite of the foot, with vesiculation surrounded by edema and erythema. (Courtesy of Daniel F. Danzl, MD; with permission.) FIguRE 76e-20 Kaposi’s sarcoma in a patient with AIDS. Patch, plaque, and tumor stages are shown. CHAPTER 76e Atlas of Skin Manifestations of Internal Disease FIguRE 76e-23 Mycosis fungoides is a cutaneous T cell lymphoma. Plaque-stage lesions are seen in this patient.


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InternalMed_Harrison. (Figs. 76e-28 to 76e-33) As the prognosis of melanoma is related primarily to the microscopic depth of invasion, and as early detection with surgical treatment can be curative in a high percentage of patients, it is essential that all clinicians acquire some facility in evaluating pigmented lesions. Three clinicopathologic subtypes of melanoma—superficial spreading, lentigo maligna, and acral lentiginous melanoma—typically display features noted in the “ABCD rule”: asymmetry (one half of the lesion varies from the other half); border irregularity (the circumferential border exhibits an irregular, sometimes jagged appearance); color (there is uneven coloration and tone to the pigmented lesion, with various shades of brown, black, red, and white in different areas); and diameter (the diameter is typically >6 mm). The more uncommon subtype, nodular melanoma, may not manifest all these features but rather may present as a more symmetric, evenly pigmented, or amelanotic lesion. Dysplastic


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InternalMed_Harrison. is typically >6 mm). The more uncommon subtype, nodular melanoma, may not manifest all these features but rather may present as a more symmetric, evenly pigmented, or amelanotic lesion. Dysplastic (atypical) melanocytic nevi may occur as solitary or multiple lesions as well as in the setting of familial melanoma. These nevi display some degree of asymmetry, border irregularity, and color variation. Ordinary nevi may be acquired or congenital and are quite common.


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InternalMed_Harrison. FIguRE 76e-24 Metastatic carcinoma to the skin is characterized by inflammatory, often ulcerated dermal nodules. FIguRE 76e-27 Actinic keratoses consist of hyperkeratotic erythema-tous papules and patches on sun-exposed skin. They arise in middle-aged to older adults and have some potential for malignant transfor-mation. (Courtesy of Robert Swerlick, MD; with permission.) PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 76e-25 Keratoacanthoma is a low-grade squamous cell carci-noma that presents as an exophytic nodule with central keratinous debris. FIguRE 76e-26 Squamous cell carcinoma is seen here as a hyper-keratotic, crusted, and somewhat eroded plaque on the lower lip. Sun-exposed skin of the head, neck, hands, and arms are other typical sites of involvement. FIguRE 76e-28 Nevi are benign proliferations of nevomelanocytes characterized by regularly shaped hyperpigmented macules or pap-ules of a uniform color.


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InternalMed_Harrison. FIguRE 76e-28 Nevi are benign proliferations of nevomelanocytes characterized by regularly shaped hyperpigmented macules or pap-ules of a uniform color. FIguRE 76e-29 Dysplastic nevi are irregularly pigmented and shaped nevomelanocytic lesions that may be associated with familial melanoma. FIguRE 76e-32 Nodular melanoma most commonly manifests as a rapidly growing, often ulcerated or crusted black nodule. (Courtesy of S. Wright Caughman, MD; with permission.) CHAPTER 76e Atlas of Skin Manifestations of Internal Disease FIguRE 76e-30 Superficial spreading melanoma, the most com-mon type of malignant melanoma, is characterized by color variega-tion (black, blue, brown, pink, and white) and irregular borders.


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InternalMed_Harrison. FIguRE 76e-30 Superficial spreading melanoma, the most com-mon type of malignant melanoma, is characterized by color variega-tion (black, blue, brown, pink, and white) and irregular borders. (Figs. 76e-34 to 76e-58) One of the roles of the skin is to function as a barrier from the outside world. In this capacity, exposure to infectious agents occurs, and bacterial, viral, fungal, and parasitic infections may result. In addition, the skin may be secondarily involved and provides diagnostic clues to systemic infections such as meningococcemia, Rocky Mountain spotted fever, Lyme disease, and septic emboli. Most sexually transmitted bacterial and viral diseases exhibit cutaneous involvement; examples include primary and secondary syphilis, chancroid, genital herpes simplex, and condyloma acuminatum.


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InternalMed_Harrison. (Figs. 76e-59 to 76e-70) Immunologically mediated skin disease may be largely localized to skin and mucous membranes and manifest with blisters and erosions such as pemphigus, pemphigoid, and dermatitis herpetiformis. In diseases such as systemic lupus erythematosus, dermatomyositis, and vasculitis, skin manifestations are often only one element of a widespread process. FIguRE 76e-31 Lentigo maligna melanoma occurs on sun-exposed skin as a large, hyperpigmented macule or plaque with irregular bor-ders and variable pigmentation. (Courtesy of Alvin Solomon, MD; with permission.) FIguRE 76e-33 Acral lentiginous melanoma is more common among blacks, Asians, and Hispanics and occurs as an enlarging hyperpigmented macule or plaque on the palms or soles. Lateral pigment diffusion is present.


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InternalMed_Harrison. FIguRE 76e-37 Impetigo contagiosa is a superficial streptococcal or Staphylococcus aureus infection consisting of honey-colored crusts and erythematous weeping erosions. Bullous lesions are occasionally seen. PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 76e-34 Erysipelas is a streptococcal infection of the superficial dermis and consists of well-demarcated, erythematous, edematous, warm plaques. FIguRE 76e-38 Tender vesicles and erosions in the mouth of a patient with hand-foot-and-mouth disease. (Courtesy of Stephen D. Gellis, MD; with permission.) FIguRE 76e-35 Varicella, with numerous lesions in various stages of evolution: vesicles on an erythematous base, umbilicated vesicles, and crusts. (Courtesy of Robert Hartman, MD; with permission.) FIguRE 76e-39 Lacy reticular rash of erythema infectiosum (fifth disease).


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InternalMed_Harrison. FIguRE 76e-39 Lacy reticular rash of erythema infectiosum (fifth disease). FIguRE 76e-36 Herpes zoster is seen in this HIV-infected patient as hemorrhagic vesicles and pustules on an erythematous base in a dermatomal distribution. (Courtesy of Robert Swerlick, MD; with permission.) FIguRE 76e-40 Molluscum contagiosum is a cutaneous poxvirus infection characterized by multiple umbilicated flesh-colored or hypopigmented papules. (Courtesy of Yale Resident’s Slide Collection; with permission.) FIguRE 76e-43 Rocky Mountain spotted fever, with pinpoint pete-chial lesions on the palm and volar aspect of the wrist. (Courtesy of Robert Swerlick, MD; with permission.) CHAPTER 76e Atlas of Skin Manifestations of Internal Disease FIguRE 76e-44 Erythema migrans, the early cutaneous manifes-tation of Lyme disease, is characterized by erythematous annular patches, often with a central erythematous papule at the tick-bite site. (Courtesy of Yale Resident’s Slide Collection; with permission.)


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InternalMed_Harrison. (Courtesy of Yale Resident’s Slide Collection; with permission.) FIguRE 76e-41 Oral hairy leukoplakia often presents as white plaques on the lateral tongue and is associated with Epstein-Barr virus infection. (From K Wolff et al: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005. www .accessmedicine.com.) FIguRE 76e-42 Fulminant meningococcemia, with extensive angu-lar purpuric patches. (Courtesy of Stephen D. Gellis, MD; with permission.) FIguRE 76e-45 Primary syphilis, with a firm, nontender chancre. (Courtesy of Gregory Cox, MD; with permission.) PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 76e-46 Secondary syphilis commonly affects the palms and soles, with scaling, firm, red-brown papules. (Courtesy of Alvin Solomon, MD; with permission.)


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InternalMed_Harrison. FIguRE 76e-46 Secondary syphilis commonly affects the palms and soles, with scaling, firm, red-brown papules. (Courtesy of Alvin Solomon, MD; with permission.) FIguRE 76e-47 Condylomata lata are moist, somewhat verrucous inter-triginous plaques seen in secondary syphilis. (Courtesy of Yale Resident’s Slide Collection; with permission.) FIguRE 76e-49 A. Tinea corporis is a superficial fungal infection, seen here as an erythematous annular scaly plaque with central clearing. B. A common presentation of chronic dermatophyte infection involves the feet (tinea pedis), hands (tinea manum), and nails (tinea unguium). FIguRE 76e-48 Secondary syphilis, with the characteristic papulo-squamous truncal eruption. FIguRE 76e-50 Scabies, with typical scaling erythematous papules and few linear burrows. FIguRE 76e-51 Skin lesions caused by Chironex fleckeri sting. (Courtesy of V. Pranava Murthy, MD; with permission.)


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InternalMed_Harrison. FIguRE 76e-51 Skin lesions caused by Chironex fleckeri sting. (Courtesy of V. Pranava Murthy, MD; with permission.) FIguRE 76e-53 Condylomata acuminata are lesions induced by human papillomavirus and in this patient are seen as multiple verrucous papules coalescing into plaques. (Courtesy of S. Wright Caughman, MD; with permission.) CHAPTER 76e Atlas of Skin Manifestations of Internal Disease FIguRE 76e-54 A patient with features of polar lepromatous FIguRE 76e-52 Chancroid, with characteristic penile ulcers and leprosy: multiple nodular skin lesions, particularly of the forehead, associated left inguinal adenitis (bubo). and loss of eyebrows. (Courtesy of Robert Gelber, MD; with permission.) PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 76e-55 Skin lesions of neutropenic patients. A. Hemorrhagic papules on the foot of a patient undergoing treatment for multiple myeloma. Biopsy and culture demonstrated Aspergillosis species. B. Eroded nodule on the hard palate of a patient undergoing chemotherapy. Biopsy and culture demonstrated Mucor species. C. Ecthyma gangrenosum in a neutropenic patient with Pseudomonas aeruginosa bacteremia. FIguRE 76e-56 Septic emboli, with hemorrhage and infarction due to acute Staphylococcus aureus endocarditis. (Courtesy of L. Baden, MD; with permission.) FIguRE 76e-57 Vegetations (arrows) due to viridans streptococcal endocarditis involving the mitral valve. (Courtesy of AW Karchmer, MD; with permission.) FIguRE 76e-58 Disseminated gonococcemia in the skin is seen as hemorrhagic papules and pustules with purpuric centers in an acral distribution. (Courtesy of Daniel M. Musher, MD; with permission.)


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InternalMed_Harrison. FIguRE 76e-58 Disseminated gonococcemia in the skin is seen as hemorrhagic papules and pustules with purpuric centers in an acral distribution. (Courtesy of Daniel M. Musher, MD; with permission.) CHAPTER 76e Atlas of Skin Manifestations of Internal Disease FIguRE 76e-60 Discoid lupus erythematosus. Atrophic, depigmented plaques and patches surrounded by hyperpigmentation and erythema in association with scarring and alopecia are characteristic of this cutaneous form of lupus. FIguRE 76e-59 Lupus erythematosus. A. Systemic lupus erythematosus, with prominent, scaly malar erythema. Involvement of other sun-exposed sites is also common. B. Acute lupus erythematosus on the upper chest, with brightly erythematous and slightly edematous coalescence of papules and plaques. (B: Courtesy of Robert Swerlick, MD; with permission.) FIguRE 76e-61 Dermatomyositis. Periorbital violaceous erythema characterizes the classic heliotrope rash. (Courtesy of James Krell, MD; with permission.)


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InternalMed_Harrison. FIguRE 76e-61 Dermatomyositis. Periorbital violaceous erythema characterizes the classic heliotrope rash. (Courtesy of James Krell, MD; with permission.) FIguRE 76e-62 Scleroderma characterized by typical expressionless, mask-like facies. PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 76e-65 Erythema multiforme is characterized by multiple erythematous plaques with a target or iris morphology and usually represents a hypersensitivity reaction to drugs or infections (especially herpes simplex virus). (Courtesy of Yale Resident’s Slide Collection; with permission.) FIguRE 76e-63 Scleroderma, with acral sclerosis and focal digital ulcers. FIguRE 76e-64 Dermatomyositis often involves the hands as ery-thematous flat-topped papules over the knuckles (Gottron’s sign) and periungual telangiectasias.


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InternalMed_Harrison. FIguRE 76e-64 Dermatomyositis often involves the hands as ery-thematous flat-topped papules over the knuckles (Gottron’s sign) and periungual telangiectasias. FIguRE 76e-66 Dermatitis herpetiformis, manifested by pruritic, grouped vesicles in a typical location. The vesicles are often excori-ated and may also occur on the knees, buttocks, elbows, and poste-rior scalp. FIguRE 76e-67 Pemphigus vulgaris. A. Eroded bullae on the back. B. The oral mucosa is almost invariably involved, sometimes with erosions on the gingiva, buccal mucosa, palate, posterior pharynx, or tongue. (B: Courtesy of Robert Swerlick, MD; with permission.) FIguRE 76e-68 Erythema nodosum is a panniculitis characterized by tender deep-seated nodules and plaques, usually located on the lower extremities. (Courtesy of Robert Swerlick, MD; with permission.) FIguRe 76e-69 Vasculitis. Palpable purpuric papules on the lower legs are seen in this patient with cutaneous small-vessel vasculitis.


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InternalMed_Harrison. FIguRe 76e-69 Vasculitis. Palpable purpuric papules on the lower legs are seen in this patient with cutaneous small-vessel vasculitis. (Courtesy of Robert Swerlick, MD; with permission.) CHAPTER 76e Atlas of Skin Manifestations of Internal Disease


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InternalMed_Harrison. FIguRE 76e-70 Bullous pemphigoid, with tense vesicles and bullae on an erythematous, urticarial base. (Courtesy of Yale Resident’s Slide Collection; with permission.) (Figs. 76e-71 to 76e-78) While many systemic diseases also have cutaneous manifestations, there are well-recognized dermatologic markers of internal disease, some of which are shown in this section. Many of these dermatologic markers may precede, accompany, or follow diagnosis of systemic disease. Acanthosis nigricans is a prototypical dermatologic process that often occurs in association with underlying systemic abnormalities, most commonly obesity and insulin resistance. It may also be associated with other endocrine disorders and several rare genetic syndromes. Malignant acanthosis nigricans may occur in association with several malignancies, especially adenocarcinoma of the gastrointestinal tract, lung, and breast. Other markers of internal disease in this section include pretibial myxedema, which is associated with


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InternalMed_Harrison. several malignancies, especially adenocarcinoma of the gastrointestinal tract, lung, and breast. Other markers of internal disease in this section include pretibial myxedema, which is associated with thyroid disease, and Sweet syndrome, which may be associated with hematologic malignancies, solid tumors, infections, or inflammatory bowel disease. The skin is also involved in many systemic inflammatory diseases such as sarcoidosis, rheumatoid arthritis, and lupus erythematosus.


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InternalMed_Harrison. FIguRE 76e-71 Acanthosis nigricans, with typical hyperpigmented plaques on a velvet-like, verrucous surface on the neck. FIguRE 76e-74 Bilateral rheumatoid nodules of the upper extremi-ties. (Courtesy of Robert Swerlick, MD; with permission.) PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 76e-75 Neurofibromatosis, with numerous flesh-colored cutaneous neurofibromas. FIguRE 76e-72 Pretibial myxedema manifesting as waxy, infiltrated plaques in a patient with Graves’ disease. FIguRE 76e-73 Erythematous, indurated plaque of Sweet syn-drome, with a pseudovesicular border. (Courtesy of Robert Swerlick, MD, with permission.) FIguRE 76e-76 Coumarin necrosis. Shown is cutaneous and subcutaneous necrosis of a breast. Other fatty areas, such as buttocks and thighs, are also common sites of involvement. (Courtesy of Kim Yancey, MD; with permission.)


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InternalMed_Harrison. FIguRE 76e-77 Sarcoid. A. Infiltrated papules and plaques of variable color are seen in a typical paranasal and periorbital location. B. Infiltrated, hyperpigmented, and slightly erythematous coalescent papules and plaques on the upper arm. (B: Courtesy of Robert Swerlick, MD; with permission.) FIguRE 76e-78 Pyoderma gangrenosum on the dorsal aspect of both hands. Multiple necrotic ulcers are surrounded by a violaceous and undermined border. (Courtesy of Robert Swerlick, MD; with permission.) CHAPTER 76e Atlas of Skin Manifestations of Internal Disease


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InternalMed_Harrison. PART 2 Anemia and Polycythemia John W. Adamson, Dan L. Longo HEMATOPOIESIS AND THE PHYSIOLOgIC BASIS OF RED CELL PRODuCTION Hematopoiesis is the process by which the formed elements of blood are produced. The process is regulated through a series of steps begin-ning with the hematopoietic stem cell. Stem cells are capable of pro-red blood cells. The size of the red cell mass reflects the balance of red cell production and destruction. The physiologic basis of red cell pro-duction and destruction provides an understanding of the mechanisms that can lead to anemia. The physiologic regulator of red cell production, the glycoprotein hormone EPO, is produced and released by peritubular capillary lining cells within the kidney. These cells are highly specialized epithelial-like cells. A small amount of EPO is produced by hepatocytes. The funda-mental stimulus for EPO production is the availability of O2 for tissue metabolic needs. Key to EPO gene regulation is hypoxia-inducible factor


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InternalMed_Harrison. amount of EPO is produced by hepatocytes. The funda-mental stimulus for EPO production is the availability of O2 for tissue metabolic needs. Key to EPO gene regulation is hypoxia-inducible factor (HIF)-1α. In the presence of O2, HIF-1α is hydroxylated at a key 77 SECTion 10 HEMAToLogiC ALTERATionS proline, allowing HIF-1α to be ubiquitinated and degraded via the pro ducing red cells, all classes of granulocytes, monocytes, platelets, and the cells of the immune system. The precise molecular mechanism— either intrinsic to the stem cell itself or through the action of extrinsic factors—by which the stem cell becomes committed to a given lineage is not fully defined. However, experiments in mice suggest that ery tor that does not develop in the absence of expression of the GATA-1 teasome pathway. If O2 becomes limiting, this critical hydroxylation step does not occur, allowing HIF-1α to partner with other proteins, translocate to the nucleus, and upregulate the expression of the EPO


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InternalMed_Harrison. pathway. If O2 becomes limiting, this critical hydroxylation step does not occur, allowing HIF-1α to partner with other proteins, translocate to the nucleus, and upregulate the expression of the EPO gene, among others.


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InternalMed_Harrison. Impaired O2 delivery to the kidney can result from a decreased red cell mass (anemia), impaired O2 loading of the hemoglobin molecule or a high O2 affinity mutant hemoglobin (hypoxemia), or, rarely, impaired blood flow to the kidney (renal artery stenosis). EPO governs the day to-day production of red cells, and ambient levels of the hormone can be measured in the plasma by sensitive immunoassays—the normal level being 10–25 U/L. When the hemoglobin concentration falls below 100–120 g/L (10–12 g/dL), plasma EPO levels increase in proportion to the severity of the anemia (Fig. 77-2). In circulation, EPO has a half-clearance time of 6–9 h. EPO acts by binding to specific receptors on the surface of marrow erythroid precursors, inducing them to pro liferate and to mature. With EPO stimulation, red cell production can increase fourto fivefold within a 1to 2-week period, but only in the presence of adequate nutrients, especially iron. The functional capacity of the erythron, therefore,


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InternalMed_Harrison. red cell production can increase fourto fivefold within a 1to 2-week period, but only in the presence of adequate nutrients, especially iron. The functional capacity of the erythron, therefore, requires normal renal production of EPO, a functioning erythroid marrow, and an adequate supply of substrates for hemoglobin synthesis. A defect in any of these key components can lead to anemia. Generally, anemia is recognized in the laboratory when a patient’s hemoglobin level or hematocrit is reduced below an expected value (the normal range). The likelihood and severity of anemia are defined based on the deviation of the patient’s hemoglobin/hematocrit from values expected for ageand sex-matched normal subjects. The hemoglobin concentration in adults has a Gaussian distribution. The and FOG-1 (friend of GATA-1) transcription factors (Chap. 89e).


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InternalMed_Harrison. Following lineage commitment, hematopoietic progenitor and precur sor cells come increasingly under the regulatory influence of growth factors and hormones. For red cell production, erythropoietin (EPO) is the primary regulatory hormone. EPO is required for the maintenance of committed erythroid progenitor cells that, in the absence of the hormone, undergo programmed cell death (apoptosis). The regulated process of red cell production is erythropoiesis, and its key elements are illustrated in Fig. 77-1. In the bone marrow, the first morphologically recognizable ery throid precursor is the pronormoblast. This cell can undergo four to five cell divisions, which result in the production of 16–32 mature red cells. With increased EPO production, or the administration of EPO as a drug, early progenitor cell numbers are amplified and, in turn, give rise to increased numbers of erythrocytes. The regulation of EPO production itself is linked to tissue oxygenation.


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InternalMed_Harrison. In mammals, O2 is transported to tissues bound to the hemoglobin contained within circulating red cells. The mature red cell is 8 μm in diameter, anucleate, discoid in shape, and extremely pliable in order to traverse the microcirculation successfully; its membrane integrity is maintained by the intracellular generation of ATP. Normal red cell production results in the daily replacement of 0.8–1% of all circulating red cells in the body, since the average red cell lives 100–120 days. The organ responsible for red cell production is called the erythron. The erythron is a dynamic organ made up of a rapidly proliferating pool of marrow erythroid precursor cells and a large mass of mature circulating FIguRE 77-2 Erythropoietin (EPO) levels in response to anemia. When the hemoglobin level falls to 120 g/L (12 g/dL), plasma EPO levels increase logarithmically. In the presence of chronic kidney


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InternalMed_Harrison. FIguRE 77-2 Erythropoietin (EPO) levels in response to anemia. When the hemoglobin level falls to 120 g/L (12 g/dL), plasma EPO levels increase logarithmically. In the presence of chronic kidney Cardinal Manifestations and Presentation of Diseases disease or chronic inflammation, EPO levels are typically lower than expected for the degree of anemia. As individuals age, the level of EPO needed to sustain normal hemoglobin levels appears to increase.


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InternalMed_Harrison. EPO needed to sustain normal hemoglobin levels appears to increase. FIguRE 77-1 The physiologic regulation of red cell production by (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, tissue oxygen tension. Hb, hemoglobin. McGraw-Hill, 2010.) mean hematocrit value for adult males is 47% (standard deviation, ±7%) and that for adult females is 42% (±5%). Any single hematocrit or hemoglobin value carries with it a likelihood of associated anemia. Thus, a hematocrit of <39% in an adult male or <35% in an adult female has only about a 25% chance of being normal. Hematocrit levels are less useful than hemoglobin levels in assessing anemia because they are calculated rather than measured directly. Suspected low hemoglobin or hematocrit values are more easily interpreted if previous values for the same patient are known for comparison. The World Health Organization (WHO) defines anemia as a hemoglobin level <130 g/L (13 g/dL) in men and <120 g/L (12 g/dL) in women.


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InternalMed_Harrison. The critical elements of erythropoiesis—EPO production, iron availability, the proliferative capacity of the bone marrow, and effective maturation of red cell precursors—are used for the initial classification of anemia (see below).