Dermatology is a specialty in which visual inspection allows for rapid diagnosis. A brief physical examination prior to a lengthy history is valuable because some of the classic skin diseases with obvious morphologies allow a “doorway diagnosis” to be established. The tools the physician needs are readily available: magnifying glass, glass slide (for diascopy to determine if a lesion is blanchable), adequate lighting, a flashlight, alcohol pad to remove scale or makeup, scalpel, and at times a Wood lamp. Universal precautions should always be used.
The ability to describe lesions accurately is an important skill, as is the ability to recognize specific patterns. These abilities aid clinicians in their approach to the patient with a cutaneous eruption both in developing a differential diagnosis and while communicating with other physicians. The classic dermatologic lesions are defined in Table 17–1.
TABLE 17–1Dermatologic Diagnostic Descriptions of Lesions of the Skin ||Download (.pdf) TABLE 17–1 Dermatologic Diagnostic Descriptions of Lesions of the Skin
|Primary Cutaneous Lesions ||Secondary Cutaneous Lesions |
Comedone: open and closed dilated pores (blackheads and whiteheads, respectively)
Macule: a circumscribed flat variation of color that is brown, blue, yellow, red, or hyper- or hypopigmented, <1 cm
Patch: a circumscribed flat variation of color that is brown, blue, yellow, red, or hyper- or hypopigmented, >1 cm
Papule: a circumscribed elevation of <1 cm in diameter
Plaque: a circumscribed elevation of >1 cm in diameter
Nodule: a circumscribed elevation often >2 cm in diameter, involves the dermis and at times subcutis
Pustule: a circumscribed collection of purulent fluid that varies in size
Tumor: an elevation of >0.5 cm in diameter
Vesicle: a circumscribed collection of clear fluid <1 cm in diameter
Bulla: a circumscribed collection of clear fluid >1 cm in diameter
Wheal: a firm edematous plaque resulting from infiltration of the dermis with fluid
Erosion: a loss of the epidermis up to the full thickness of the epidermis but not through the basement membrane
Ulcer: a loss of full-thickness epidermis and papillary dermis, reticular dermis, or subcutis
Lichenification: thickening of the epidermis and accentuation of natural skin lines
Atrophy: thinning of the epidermis
Scale: flaking caused by accumulation of stratum corneum (hyperkeratosis) or delayed desquamation
Scar: a thickened, often discolored surface
The skin shields the internal organs from harmful xenobiotics in the environment and maintains internal organ integrity. The adult skin covers an average surface area of 2 m2. Despite its outwardly simple structure and function, the skin is extraordinarily complex. The skin is affected by xenobiotic exposures that occur through many routes. Dermal exposures themselves are important as they account for approximately 7% of all human exposures reported to the American Association of Poison Control Centers (Chap. 130). The clinician must obtain essential information as to the dose, timing, route, and location of exposure. Knowledge of the physical and chemical properties of the xenobiotic can be used to make relevant predictions of adverse cutaneous reactions and whether the response will be local or systemic. The location of xenobiotic exposure determines the histologic morphology, the severity of the reaction pattern, and the overall clinical findings. It should be noted, however, that different xenobiotics produce clinically similar skin changes and conversely that an individual xenobiotic produces diverse cutaneous lesions.
SKIN ANATOMY AND PHYSIOLOGY
The skin has 3 main components that interconnect anatomically and interact functionally: the epidermis, the dermis, and the subcutis or hypodermis (Fig. 17–1). Some experts further categorize the components of the skin into 3 reactive units: The superficial reactive unit, which is composed of the epidermis, the dermal–epidermal junction, and the superficial or papillary dermis with its vascular system; the dermal reactive unit, which is composed of the reticular layer of the dermis and the dermal microvascular plexus; and the subcutaneous reactive unit, which consists of fat lobules and septae.38 The primary physiologic role of the epidermis, the outermost layer of the skin, is to serve as a barrier, maintain fluid balance, and prevent infection. The degree of barrier function of the epidermis varies with the thickness of the epidermis, which ranges from 1.5 mm on the palms and soles to 0.1 mm on the eyelids. The epidermis is composed of 4 layers: the horny layer (stratum corneum), the granular layer (stratum granulosum), the spinous layer (stratum spinosum), and the basal layer (stratum germinativum), which overlies the basement membrane zone (Fig. 17–1). The keratinocyte, or squamous cell, which is an ectodermal derivative, comprises the majority of cells in the epidermis.
Skin histology and pathology. Intraepidermal cleavage sites in various xenobiotic-induced blistering diseases. In pemphigus foliaceus, the cleavage is below or within the granular layer, whereas in pemphigus vulgaris, it is suprabasilar. This accounts for the differing types of blisters found in the 2 diseases. HF = hair follicle.
The stratum corneum, a semipermeable surface composed of differentiated keratinocytes, is predominantly responsible for the physical barrier function of the skin. Disruption or abnormal formation of the stratum corneum leads to inadequate function of this barrier, whether by disorders of proliferation or desquamation. For example, accelerated cornification leads to retained nuclei in the stratum corneum (parakeratosis) causing gaps in the stratum corneum, as in psoriasis, which impedes barrier function.38 Alternatively, in some forms of ichthyosis there is decreased desquamation leading to epidermal retention that influences the barrier function of the stratum corneum.4 Barrier function is also partly maintained by the upper spinous and granular layers. In this layer, there are Odland bodies, also known as membrane-coating granules, lamellar granules, and keratinosomes. The contents of these organelles provide a barrier to water loss while mediating stratum corneum cell cohesion.19 The stratum corneum is covered by a surface film composed of sebum emulsified with sweat and breakdown products of keratinocytes.33 This surface film functions as an external barrier to protect from the entry of bacteria, viruses, and fungi. The role of the surface film, however, is limited with regard to percutaneous absorption. The major barrier molecules to percutaneous absorption in the skin are lipids called ceramides.33 Diseases characterized by dry skin, such as atopic dermatitis and psoriasis, are in part caused by decreased concentrations of ceramide in the stratum corneum, which allows increased xenobiotic penetration because of barrier degradation.33 Similarly, hydrocarbon solvents, including alcohols, or detergents, commonly produce a “defatting dermatitis” by keratolysis or the dissolution of these surface lipids.
The cells of the basal layer control the renewal of the epidermis. The basal layer contains stem cells and transient amplifying cells, which are the proliferative cells resulting in new epidermal formation that occurs approximately every 28 days.38 As the basal cells migrate toward the skin surface they flatten, lose their nuclei, develop keratohyalin granules, and eventually develop into keratinocytes of the stratum corneum. The basal layer of the epidermis is just above the basement membrane zone and is also populated by melanocytes and Langerhans cells in addition to basal keratinocytes. Melanocytes contain melanin, which is the major chromophore in the skin that protects the skin from ultraviolet radiation. Melanocytes are primarily responsible for producing skin pigmentation. Langerhans cells are bone marrow–derived dendritic cells with a primary role in immunosurveillance. These cells function in the recognition, uptake, processing, and presentation of antigens to previously sensitized T lymphocytes. In addition, Langerhans cells also carry antigens via dermal lymphatics to regional lymph nodes.
The basement membrane zone (BMZ) consists of 3 layers—the lamina lucida, the lamina densa, and the sublamina densa (which is composed of anchoring fibrils) — and separates the epidermis from the dermis (Fig. 17–1). It provides a site of attachment for basal keratinocytes and permits epidermal–dermal interaction. The BMZ is also of clinical significance as it is the target of genetic defects and autoimmune attack, leading to a variety of inherited and acquired cutaneous diseases.
The dermal–epidermal junction (DEJ) provides resistance against trauma, gives support to the overlying structures, organizes the cytoskeleton in the basal cells, and serves as a semipermeable barrier. The dermis, below the DEJ, contains the adnexal structures, blood vessels, and nerves. It is arranged into 2 major regions, the upper papillary dermis and the deeper reticular dermis. The dermis provides structural integrity and contains many important appendageal structures. The structural support is provided by both collagen and elastin fibers embedded in glycosaminoglycans, such as chondroitin A and hyaluronic acid. Collagen accounts for 70% of the dry weight of the skin, whereas elastic fibers comprise 1% to 2% of the skin’s dry weight. Several important cells, including fibroblasts, macrophages, and mast cells, are residents of the dermis, each with their own unique function. Traversing the dermis are venules, capillaries, arterioles, nerves, and glandular structures.
The arteriovenous framework of the skin is derived from a deep plexus of perforating vessels within the skeletal muscle and subcutaneous fat. From this deep plexus, smaller arterioles transverse upward to the junction of the reticular and papillary dermis, where they form the superficial plexus. Capillary venules form superficial vascular loops that ascend into and descend from the dermal papillae (Fig. 17–1). The communicating blood vessels provide channels through which xenobiotics exposed on the skin surface can be transported internally. This circulatory network provides nutrition for the tissue and is involved in temperature and blood pressure regulation, wound repair, and numerous immunologic events.12 Parallel to the vasculature are cutaneous nerves, which serve the dual function of receiving sensory input and carrying sympathetically mediated autonomic stimuli that induce piloerection and sweating.22
The apocrine glands consist of secretory coils and intradermal ducts ending in the follicular canal. The secretory coil is located in the subcutis and consists of a large lumen surrounded by columnar to cuboidal cells with eosinophilic cytoplasm.22 Apocrine glands, which are concentrated in select areas of the body such as the axillae, eyelids, external auditory meatus, areolae, and anogenital region, produce secretions that are rendered odoriferous by cutaneous bacterial flora.
The eccrine glands, in contrast, produce an isotonic to hypotonic secretion that is modified by the ducts and emerges on the skin surface as sweat. The eccrine unit consists of a secretory gland as well as intradermal and intraepidermal ducts. The coiled secretory gland is located in the area of the deep dermis and subcutis. These glands are innervated by postganglionic sympathetic fibers that use acetylcholine neurotransmission, explaining the clinical effects of anticholinergic xenobiotics. Xenobiotics that are concentrated in the sweat increase the intensity of the local skin reactions. Certain chemotherapeutics, such as cytarabine or bleomycin, directly damage the eccrine sweat glands, resulting in neutrophilic eccrine hidradenitis.65
Sebaceous glands also reside in the dermis. They produce an oily, lipid-rich secretion that functions as an emollient for the hair and skin, and can be a reservoir of noxious environmental xenobiotics. Pilosebaceous follicles, which are present all over the body, consist of a hair shaft, hair follicle, sebaceous gland, sensory end organ, and erector pili. Certain halogenated aromatic chemicals, such as polychlorinated biphenyls (PCBs), dioxin, and 2,4-dichlorophenoxyacetic acid, are excreted in the sebum and cause hyperkeratosis of the follicular canal. This produces the syndrome, chloracne, which appears clinically like severe acne vulgaris but predominates in the malar, retroauricular, and mandibular regions of the head and neck and typically develops after several weeks of exposure (Fig. 17–2). Similar syndromes result from exposure to brominated and iodinated compounds, and are known as bromoderma and ioderma, respectively.70
Chloracne due to dioxin intoxication. Comedones and papulopustular lesions, nodules, and cyst have led to a gross deformity of the nose. (Used with permission from Dr. Alexandra Geusau.)
The subcutis serves to insulate, cushion, and allow for mobility of the overlying skin structures. Adipocytes represent the majority of cells found in this layer. Leptin, an adipose-derived hormone responsible for feedback of appetite and satiety signaling, is synthesized and regulates fat mass (adiposity) in this layer.
The hair follicle is divided into 3 portions, the hair bulb, infundibulum, and isthmus.57 The deepest portion of the hair follicle contains the bulb with matrix cells. The matrix cells are highly mitotically active and often are the target of cytotoxic xenobiotics. The rate of growth and the type of hair are unique for different body sites. Hair growth proceeds through 3 distinct phases: the active prolonged growth phase (anagen phase) during which matrix cell mitotic activity is high; a short involutional phase (catagen phase), and a resting phase (telogen phase). The length of the anagen phase determines the final length of the hair and varies depending on site of the body. For example, hair on the scalp has the longest anagen phase ranging from 2 to 8 years with hair growth at a rate of 0.37 to 0.44 mm/day.38 Understanding the phases of hair growth is important because hair growth can be used to identify clues regarding the timing of exposure and the mechanism of action of a particular xenobiotic.
The nail plate, which is often considered analogous to the hair, is also a continuously growing structure. Fingernails grow at average of 2 to 3 mm per month and toenails grow approximately 1 mm per month. The mitotically active cells of the nail matrix that produce the nail plate are subject to both traumatic and xenobiotic injury, which in turn affects the appearance and growth of the nail plate. Because nail growth is relatively stable, location of an abnormality in the plate can predict the timing of exposure, such as Mees lines (transverse white lines).
Transdermal Xenobiotic Absorption
Although there is no active cutaneous uptake mechanism for xenobiotics, many undergo percutaneous absorption by passive diffusion. Lipid solubility, concentration gradient, molecular weight, and certain specific skin characteristics are important determinants of dermal absorption.23,24,50,54 Absorption is determined to a great extent by the lipid solubility of the specific xenobiotic.15,39 The pharmacokinetic profile of transdermally administered xenobiotics is markedly different than by the enteral or other parenteral routes.17 As with any other routes of administration, adverse effects are caused by excessive absorption following application or even with therapeutic use of a transdermal patch. Other xenobiotics, topically applied without a specific delivery device, including podophyllin, camphor, phenol, organic phosphorus compounds, ethanol, organochlorines, nitrates, and hexachlorophene, can lead to systemic morbidity and mortality (Special Considerations: SC3).
Exposure to any of a myriad of industrial and environmental xenobiotics results in dermal “burns.” Although the majority of these xenobiotics injure the skin through chemical reactivity rather than thermal damage, the clinical appearances of the two are often identical. Injurious xenobiotics act as oxidizing or reducing agents, corrosives, protoplasmic poisons, desiccants, or vesicants. Often an injury initially appears to be mild or superficial with minimal erythema, blanching, or discoloration of the skin. Over the subsequent 24 to 36 hours, the injury progresses to extensive necrosis of the skin and subcutaneous tissue.
Both inorganic and organic acids are capable of penetrating and damaging the epidermis via protein denaturation and cytotoxicity; however, organic acids tend to be less irritating. The damaged tissue coagulates and forms a thick eschar, which limits the spread of the xenobiotic. The histopathologic finding following acid injury is termed coagulative necrosis.10 Inorganic acids that are frequently used in industry include hydrochloric and sulfuric acids which lead to the severe injury. The weakly acidic hydrofluoric (HF) acid, is used for the etching of glass, metal and stone. Hydrofluoric acid, because of its limited dissociation constant, is able to penetrate intact skin with subsequent penetration into deeper tissues. The fluoride ion is extremely cytotoxic, causing severe tissue damage, including bone destruction, by interfering with cellular enzymes. Severe pain is due to the capacity of fluoride ions to bind tissue calcium, thus affecting nerve conduction.61 Once in the dermis, the proton (H+) and fluoride ions (F–) cause both acid-induced tissue necrosis and fluoride-induced toxicity (Chap. 104).5
Alkali exposures characteristically produce a liquefactive necrosis, which allows continued penetration of the corrosive. Consequently, cutaneous and subcutaneous injury following alkali exposure is typically more severe than after an acid exposure, with the exception of hydrofluoric acid. With alkali burns there are generally no vesicles, but rather necrotic skin due to the disruption of barrier lipids, including denaturation of proteins with subsequent fatty acid saponification. Common strong alkalis include sodium, ammonium, and potassium hydroxide; sodium and potassium carbonate; and calcium oxide. These are used primarily in the manufacture of bleaches, dyes, vitamins, pulp, paper, plastics, and soaps, and detergents. Alkali burns from wet cement, which has an initial pH of 10 to 12 that rises to 12 to 14 as the cement sets,37 result from the liberation of calcium hydroxide.
Thermal damage also results from xenobiotic exposure. For example, the exothermic reaction generated by the wetting of elemental phosphorus or sodium results in a thermal burn.18 In these circumstances, the products of reactivity, phosphoric acid and sodium hydroxide, respectively, produce secondary chemical injury. Alternatively, skin exposure to a rapidly expanding gas, such as nitrous oxide from a whipped cream cartridge or compressed liquefied nitrogen, or to frozen substances, such as dry ice (CO2), produce a freezing injury, or frostbite. Dermatologists routinely use liquid nitrogen to induce a cold injury that destroys precancerous lesions such as actinic keratoses.
Hydrocarbon-based solvents are liquids that are capable of dissolving non–water-soluble solutes.10 Although the most prominent effect is dermatitis due to loss of ceramides from the stratum corneum of the epidermis, prolonged exposure results in deeper dermal injury.
PRINCIPLES OF DERMAL DECONTAMINATION
On contact with xenobiotics, the skin should be thoroughly cleansed to prevent direct effects and systemic absorption. In general, water in copious amounts is the decontaminant of choice for skin irrigation. Soap should be used when adherent xenobiotics are involved. Following exposures to airborne xenobiotics, the mouth, nasal cavities, eyes, and ear canals should be irrigated with appropriate solutions such as water or a 0.9% NaCl solution. For nonambulatory patients, the decontamination process is conducted using special collection stretchers if available.9
There are a few situations in which water should not be used for skin decontamination. These situations include contamination with the reactive metallic forms of the alkali metals, sodium, potassium, lithium, cesium, and rubidium, which react with water to form strong bases. The dusts of pure magnesium, sulfur, strontium, titanium, uranium, yttrium, zinc, and zirconium will ignite or explode on contact with water. Following exposure to these metals, any residual metal should be removed mechanically with forceps, gauze, or towels and stored in mineral oil. Phenol, a colorless xenobiotic used in the manufacturing of plastics, paints, rubber, adhesives, and soap, has a tendency to thicken and become difficult to remove following exposure to water. Suggestions for phenol decontamination include alternating washing with water and polyethylene glycol (PEG 400) or 70% isopropanol for 1 minute each for a total of 15 minutes.40 Our conclusions are that inexpensive readily available tepid water should be utilized (Special Considerations: SC2). Calcium oxide (quicklime) thickens and forms Ca(OH)2 following exposure to water, which releases heat and causes cutaneous ulcerations, suggesting that mechanical removal as above is advised.
DERMATOLOGIC SIGNS OF SYSTEMIC DISEASES
Normal cutaneous and mucosal pigmentation is caused by several factors, one of which is the visualization of the capillary beds through the translucent epidermis and dermis. Cyanosis manifests as a blue or violaceous appearance of the skin, mucous membranes, and nailbeds. It occurs when excessive concentrations of reduced hemoglobin (>5 g/dL) are present, as in hypoxia or polycythemia, or when oxidation of the iron moiety of heme to the ferric state (Fe3+) forms methemoglobin, which is deeply pigmented (Chap. 124). The presence of the more deeply colored hemoglobin moiety within the dermis results in cyanosis that is most pronounced on areas of thin skin such as the mucous membranes or underneath fingernails. In the differential diagnosis of skin discoloration is pseudochromhidrosis, also termed extrinsic apocrine chromhidrosis. The discoloration is a product of staining of the sweat by chromogenic bacteria including Corynebacterium, Malassezia furfur, and Bacillus spp; the latter 2 species have been known to cause blue discoloration of the skin. Several cases of blue pseudochromhidrosis due to topiramate are reported in the literature, and diagnosis is established by the ability of the clinician to wipe off the discoloration with a damp cotton swab (Fig. 17–3).11
Pseudochromhidrosis. Blue discoloration on the elbow in a 28-year-old woman as a result of topiramate treatment for epilepsy. This entity is postulated to be a result of a decrease in sweat gland activity and a change in the skin’s pH induced by topiramate, leading to the growth of chromogenic bacteria. (Reproduced with permission from Castela E, Thomas P, Bronsard V, et al. Blue pseudochromhidrosis secondary to topiramate treatment. Acta Derm Venereol. 2009;89(5):538-539.)
Xanthoderma is a yellow to yellow-orange macular discoloration of skin.26 Xanthoderma is caused by xenobiotics such as carotenoids, which deposit in the stratum corneum, and causes carotenoderma. Carotenoids are lipid soluble and consist of α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthan, and serve as precursors of vitamin A (retinol). The carotenoids are excreted via sweat, sebum, urine, and GI secretions. Jaundice is typically a sign of hepatocellular failure or hemolysis and is caused by hyperbilirubinemia, either conjugated or unconjugated, deposits in the subcutaneous fat. Jaundice due to hyperbilirubinemia is often accompanied by other cutaneous stigmata including spider angiomas, telangiectasias, palmar erythema, and dilated superficial abdominal veins (caput medusae). True hyperbilirubinemia is differentiated from hypercarotenemia by the presence of scleral icterus in patients with hyperbilirubinemia. In addition, the cutaneous discoloration seen in hypercarotenemia can be removed by wiping the skin with an alcohol swab. Hypercarotenemia is reported among people who take carotene nutrient supplements (Fig. 17–4).59 Lycopenemia, an entity similar to carotenemia, is caused by the excessive consumption of tomatoes, which contain lycopene. Additionally, topical exposure to dinitrophenol, picric acid, or stains from cigarette use produces localized yellow discoloration of the skin.
Carotenemia. Yellow-orange discoloration on the palm (left) as compared with that of a normal control (right). In the presence of excessive blood carotene concentrations, this yellow component is increased, and is most conspicuously accentuated where the skin is thick on the palms and soles. (Reproduced with permission from Takita Y, Ichimiya M, Hamamoto Y, et al. A case of carotenemia associated with ingestion of nutrient supplements. J Dermatol. 2006 Feb;33(2):132-134.)
Pruritus is the poorly localized, unpleasant sensation that elicits a desire to scratch. The biologic purpose of pruritus is to provoke the removal of a pruritogen, a response likely to have originated when most pruritogens were parasites. Pruritus is a common manifestation of urticarial reactions, but at times it is of nonimmunologic origin. Pruritus is the most common dermatologic symptom and can arise from a primary dermatologic condition or is a symptom of an underlying systemic disease in an estimated 10% to 50% of patients.29 Pruritus is also caused by topical exposure to the urticating hairs of Tarantula spiders, spines of the stinging nettle plant (Urtica spp), or via stimulation of substance P by capsaicin.25 Virtually any xenobiotic can cause a cutaneous reaction that can be associated with pruritus, whether by inducing hepatotoxicity, cholestasis, phototoxicity, or histamine release (ie, neurologically mediated). Xenobiotics commonly implicated in neurally mediated itch include tramadol, codeine, cocaine, morphine, butorphanol, and methamphetamine.29
Vasodilation of the dermal arterioles leads to flushing, or transient reddening of the skin, commonly of the face, neck, and chest. Flushing occurs following autonomically mediated vasodilation, as occurs with stress, anger, or exposure to heat, or it can be induced by vasoactive xenobiotics. Xenobiotics that cause histamine release through a type I hypersensitivity reaction are the most frequent cause of xenobiotic-induced flush. Histamine poisoning produces flushing from the consumption of scombrotoxic fish (Chap. 39). Flushing after the consumption of ethanol is common in patients of Asian and Inuit descent and is similar to the reaction following ethanol consumption in patients exposed to disulfiram or similar xenobiotics (Chap. 78). The inability to efficiently metabolize acetaldehyde, the initial metabolite of ethanol, results in the characteristic syndrome of vomiting, headache, and flushing. Niacin causes flushing through an arachidonic acid–mediated pathway that is generally prevented by aspirin.7,66 Vancomycin, if too rapidly infused, causes a transient bright red flushing, mediated by histamine and at times can be accompanied by hypotension. This reaction typically occurs during and immediately after the infusion, and is termed “red man syndrome.” Idiopathic flushing is managed with nonselective beta-adrenergic antagonists (nadolol, propranolol) or clonidine, while anxiolytics are beneficial if emotional distress or anxiety is determined to be causative. Other nontoxicologic causes of flushing including carcinoid syndrome, pheochromocytoma, mastocytosis, anaphylaxis, medullary carcinoma of the thyroid, pancreatic cancer, menopausal flushing, and renal carcinoma, are in the differential diagnosis of the flushed patient.28
Xenobiotic-induced diaphoresis is either part of a physiologic response to heat generation or is pharmacologically mediated following parasympathetic or sympathomimetic xenobiotic use. Because the postsynaptic receptor on the eccrine glands is muscarinic, most muscarinic agonists stimulate sweat production. Sweating occurs following exposure to cholinesterase inhibitors, such as organic phosphorus compounds, but also occurs with direct-acting muscarinic agonists such as pilocarpine. Alternatively, antimuscarinics, such as belladonna alkaloids or antihistamines, reduce sweating and produce dry skin. Certain xenobiotics have proven useful for the treatment of hyperhidrosis including the anticholinergics glycopyrrolate, propantheline bromide, and botulinum toxin. Botulinum toxin-A derived from Clostridium botulinum, which is FDA approved for the treatment of primary focal axillary hyperhidrosis, temporarily chemodenervates eccrine sweat glands at the neuroglandular junction via inhibition of presynaptic acetylcholine release.1
Cutaneous pigmentary changes can result from the deposition of xenobiotics that are ingested and carried to the skin by the blood or that permeate the skin from topical applications. Many heavy metals are associated with dyspigmentation. Argyria, a slate-colored discoloration of the skin resulting from the systemic deposition of silver particles in the skin after excessive ingestion of colloidal silver, can be localized or widespread. The discoloration tends to be most prominent in areas exposed to sunlight, probably because silver stimulates melanocyte proliferation. Histologically, fine black granules are found in the basement membrane zone of the sweat glands, blood vessel walls, the dermoepidermal junction, and along the erector pili muscles (Chap. 98). Gold, which was historically used parenterally in the treatment of rheumatoid arthritis, caused a blue or slate-gray pigmentation, often periorbitally, known as chrysiasis. The pigmentation is also accentuated in sun-exposed areas but, unlike argyria, sun-protected areas do not histologically demonstrate gold. Also, melanin is not increased in the areas of hyperpigmentation. The hyperpigmentation is probably caused by the gold itself, but the cause of its distribution pattern remains unknown. Histologically, the gold is found within lysosomes of dermal macrophages and distributed in a perivascular and perieccrine pattern in the dermis. Bismuth produces a characteristic oral finding of the metallic deposition in the gums and tongue known as bismuth lines, as well as a blue-gray discoloration of the face, neck, and dorsal hands. Chronic arsenic exposure occurs following exposure to pesticides or contaminated well-water, which can cause cutaneous hyperpigmentation with a bronze hue, with areas of scattered hypopigmentation occurring between 1 and 20 years following exposure. Lead also deposits in the gums, causing the characteristic “lead lines,” which are the result of subepithelial deposition of lead granules. Intramuscular injection of iron stains the skin, resulting in pigmentation similar to that seen in tattoos, and iron storage disorders, known as hemochromatosis, and results in a bronze appearance of the skin.21
Medications are also often implicated in dyspigmentation. The tetracycline-class antibiotic minocycline is a highly lipid-soluble, yellow crystalline xenobiotic that turns black with oxidation. Minocycline-induced discoloration of the skin is at times accompanied by darkening of the nails, sclerae, oral mucosa, thyroid, bones, and teeth. Hyperpigmentation from minocycline is divided into 3 types depending on the color, anatomic distribution, and whether iron- or melanin-containing granules are found within the skin. Other medications associated with hyperpigmentation include amiodarone, zidovudine, bleomycin, and other chemotherapeutics, antimalarials, and psychotropics (chlorpromazine, thioridazine, imipramine, desipramine, amitriptyline).30 Although not true dyspigmentation, as noted above topiramate is linked to blue pseudochromhidrosis.11
XENOBIOTIC-INDUCED CUTANEOUS REACTIONS (DRUG REACTIONS)
The skin is one of the most common targets for adverse drug reactions.3 Drug eruptions occur in approximately 2% to 5% of inpatients and in greater than 1% of outpatients. Several cutaneous reaction patterns account for the majority of clinical presentations of xenobiotic-induced dermatotoxicity (Table 17–2). The following drug reactions will be discussed in detail: urticaria, erythema multiforme, Steven-Johnson syndrome and toxic epidermal necrolysis, fixed eruptions, and drug-induced hypersensitivity syndrome (formerly called “DRESS” syndrome).
TABLE 17–2Xenobiotics Commonly Associated with Various Cutaneous Reaction Patterns ||Download (.pdf) TABLE 17–2 Xenobiotics Commonly Associated with Various Cutaneous Reaction Patterns
Allergic Contact Dermatitis
Balsam of Peru
Methylchloroisothiazolinone or methylisothiazolinone
p-tert-Butylphenol formaldehyde resin
Antiepileptics (phenytoin, carbamazepine)
Antimicrobial (sulfonamides, aminopenicillins)
Antimicrobials (aminopenicillins, sulfonamides, vancomycin)
Calcium channel blockers
Fixed Drug Eruptions
β-Adrenergic antagonists (eg, timolol, propranolol)
Anticoagulants (heparin, warfarin)
Antiepileptics (phenytoin, valproic acid, carbamazepine)
Antithyroid (propylthiouracil, methimazole)
Oral contraceptives (discontinuation)
Vitamin A excess
Alkylating agents: cyclophosphamide, ifosfamide, mechlorethamine
Anthracyclines: daunorubicin, doxorubicin, idarubicin
Chemotherapeutics (taxanes: paclitaxel, docetaxel, topoisomerase-1 inhibitors: topotecan, irinotecan, etoposide, vincristine, vinblastine, busulfan, actinomycin D, gemcitabine)
Maculopapular or Exanthematous Drug Eruptions
Antimicrobials (cephalosporins, sulfonamides and aminopenicillins)
Dispense blue 35
Toxic Epidermal Necrolysis
Cephalosporins (commonly cefaclor)
Serum (antithymocyte globulin)
Canthaxanthin (tanning pills)
Dipyridamole (yellow compound)
Hepatic jaundice (acetaminophen, isoniazid)
Dihydroxyacetone (spray tanning)
Nail Changes: Beau Lines and Mees Lines (Leukonychia)
Urticarial Drug Reactions
Urticarial drug reactions are characterized by transient, pruritic, edematous, pink papules, or wheals that arise in the dermis, which blanch on palpation and are frequently associated with central clearing. At times, the urticarial lesions are targetoid and mimic erythema multiforme. Approximately 40% of patients with urticaria experience angioedema and anaphylactoid reactions as well.2 The reaction pattern is representative of a type I, or IgE-dependent, immune reaction and commonly occurs as part of clinical anaphylaxis or anaphylactoid (non–IgE-mediated) reactions. Widespread urticaria occurs following systemic absorption of an allergen or following a minimal localized exposure in patients highly sensitized to the allergen. Regardless of whether the eruption is localized or widespread, it occurs as a result of immunologic recognition of a putative antigen by IgE antibodies, thus triggering the immediate degranulation of mast cells, which are distributed along the dermal blood vessels and nerves. The release of histamine, complements C3a and C5a, and other vasoactive mediators results in extravasation of fluid from dermal capillaries as their endothelial cells contract. This produces the characteristic urticarial lesions described above. Activation of the nearby sensory neurons produces pruritus. Nonimmunologically mediated mast cell degranulation producing an identical urticarial syndrome also occurs following exposure to any xenobiotic.14
Historically, it was believed that erythema multiforme existed on a spectrum with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) given overlapping clinical features and morphology. However, these entities were reclassified on the basis that most cases of erythema multiforme are believed to be triggered by viral infection (herpes simplex virus most commonly) and most cases of SJS/TEN are triggered by xenobiotics.51 Erythema multiforme is an acute self-limited disease characterized by target-shaped, erythematous macules and patches on the palms and soles, as well as the trunk and extremities (Fig. 17–5). The Nikolsky sign, defined as sloughing of the epidermis when direct pressure is exerted on the skin, is absent. Mucosal involvement is absent or mild in erythema multiforme minor and severe in erythema multiforme major. While less common than viral-induced erythema multiforme, xenobiotics such as sulfonamides, phenytoin, antihistamines, many antibiotics, rosewood, and urushiol also elicit erythema multiforme. Differentiating erythema multiforme from SJS/TEN, which can also present with targetoid lesions, can be difficult, especially in the case of bullous erythema multiforme. A skin biopsy revealing partial or full-thickness epidermal necrosis would favor a diagnosis of SJS/TEN rather than erythema multiforme.
Erythema multiforme. Typical targetoid macules on the palm. (Reproduced with permission from Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York, NY: McGraw-Hill; 2008.)
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (Fig. 17–6) are considered to be related disorders that belong to a spectrum of increasingly severe skin eruptions.45 Stevens-Johnson syndrome is defined by lesser than 10% body surface area epidermal detachment, SJS-TEN overlap 10% to 30% involvement, and TEN greater than 30% epidermal sloughing. Although on a spectrum, SJS has a mortality rate of 5%, which is far lower than the approximate 25% to 50% mortality rate for patients with TEN.49,52 However, a more recent series of 40 patients with TEN cared for at academic burn units revealed a 10% mortality rate.35 Toxic epidermal necrolysis is a rare, life-threatening dermatologic emergency whose incidence is estimated at 0.4 to 1.2 cases per 1 million persons. More than 220 xenobiotics are causally implicated in 80% to 95% of the TEN cases. The largest study examining medication triggers of TEN divided these medications into long-term (used for months to years) and short-term. Short-term xenobiotics most commonly implicated in the development of TEN included trimethoprim-sulfamethoxazole and other sulfonamide antibiotics, followed by cephalosporins, quinolones, and aminopenicillins.53 With chronic medication use, the increased risk largely occurred during the first 2 months of treatment and was greatest for carbamazepine, phenobarbital, phenytoin, valproic acid, the oxicam NSAIDs, allopurinol, and corticosteroids.
Toxic epidermal necrolysis. (A) Early eruption. Erythematous dusky red macules (flat atypical target lesions) that progressively coalesce and show epidermal detachment. (B) Advanced eruption. Blisters and epidermal detachment have led to large confluent erosions. (C) Full-blown epidermal necrolysis characterized by large erosive areas reminiscent of scalding. (Reproduced with permission from Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York, NY: McGraw-Hill, 2008.)
Classically, the eruption of TEN is painful and occurs within 1 to 3 weeks after the exposure to the implicated xenobiotic(s). The eruption is preceded by malaise, headache, abrupt onset of fever, myalgia, arthralgia, nausea, vomiting, diarrhea, chest pain, or cough. One to 3 days later, signs begin in the mucous membranes including the eyes, mouth, nose, and genitals in 90% of cases.49 A macular erythema then develops that subsequently becomes raised and morbilliform on the face, neck, and central trunk and finally the extremities. Individual lesions can appear targetoid because of their dusky centers and progress to bullae in the following 3 to 5 days involving the entire thickness of the epidermis. This necrosis and sloughing can also lead to loss of the fingernails. A Nikolsky sign, or sloughing of the epidermis with gentle manual pressure, is suggestive of TEN but not pathognomonic. A Nikolsky sign occurs in a variety of other dermatoses, including pemphigus vulgaris. If the diagnosis is suspected, a punch biopsy should be performed for immediate frozen section and the suspected triggering xenobiotic discontinued immediately. The histopathology typically shows partial- or full-thickness epidermal necrosis, with subepidermal bullae with a sparse infiltrate, and vacuolization with numerous dyskeratotic keratinocytes along the dermoepidermal junction adjacent to the necrotic epidermis.
The incidence of TEN is higher in patients with advanced HIV disease.45,62 There is general agreement that the keratinocyte cell death in TEN is the result of apoptosis, which is suggested based on electronic microscopic studies with DNA fragmentation analysis.45 Cytotoxic T lymphocytes are the main effector cells and experimental evidence points to involvement of the Fas-ligand (FasL) and perforin/granzyme pathways. There are several theories as to the pathogenesis of SJS/TEN. These include that a xenobiotic could induce upregulation of Fas Ligand leading to a death receptor–mediated apoptotic pathway. A xenobiotic might interact with MHC class I–expressing cells and cause drug-specific CD8+ cytotoxic T lymphocytes to accumulate within epidermal blisters, releasing perforin and granzyme B that kills keratinocytes. Finally it has been proposed that the xenobiotic triggers the activation of CD8+ T lymphocytes, NK cells and NKT cells to secrete granulysin, with keratinocyte death not requiring cell contact.44 Serum Fas ligand concentrations are elevated up to 4 days prior to mucosal involvement in patients with SJS/TEN and have the potential to be useful clinically as an early predictor of these severe dermatologic diseases.43 Serum granulysin, a proinflammatory cytolytic enzyme released by CD8+ T lymphocytes found in the blisters of TEN was demonstrated to be a potential early predictive marker of SJS/TEN.20 A rapid immunochromatographic test that detects elevated serum granulysin (>10 ng/mL) in 15 minutes demonstrates promise in a small study in which its sensitivity was noted to be 80% and specificity 95.8% for differentiating SJS/TEN from ordinary exanthematous drug eruptions.20 However, this test is not yet commercially available.
Because immediate removal of the inciting xenobiotic is critical to survival, patients with TEN related to a xenobiotic with a long half-life have a poorer prognosis, and these patients should be transferred to a burn or other specialized center for sterile wound care. Risk factors for mortality include older patient age, higher total surface area of involvement, and more pre-existing comorbidities.35 In a recent study, only serum bicarbonate less than 20 mmol/L was found to portend hospital mortality in patients with TEN.68 Porcine xenografts or human skin allografts including amniotic membrane transplantation are used and are widely accepted therapy.48 A meta-analysis of 17 studies revealed a trend toward improved mortality with high-dose IVIG in adults and good prognosis in children; however, there is insufficient evidence to support a clinical benefit.27 Patients with TEN develop metabolic abnormalities, sepsis, multiorgan failure, pulmonary emboli, and gastrointestinal hemorrhages and should be closely monitored. The major microbes leading to sepsis are Staphylococcus aureus and Pseudomonas aeruginosa. In a patient with SJS/TEN with ophthalmic involvement, early ophthalmologic consultation is necessary because blindness is a potential complication.
Mimickers of TEN include SJS, staphylococcal scalded skin syndrome, severe exanthematous drug eruptions, erythema multiforme-major, linear IgA dermatosis, paraneoplastic pemphigus, acute graft versus host disease, drug-induced pemphigoid and pemphigus vulgaris, and acute generalized exanthematous pustulosis. Discussion of some of these entities is beyond the scope of this chapter (Table 17–3).
TABLE 17–3Differential Diagnosis of Xenobiotic-Induced Blistering (Vesiculobullous) Disorders ||Download (.pdf) TABLE 17–3 Differential Diagnosis of Xenobiotic-Induced Blistering (Vesiculobullous) Disorders
|Disease ||Fever ||Mucositis ||Morphology ||Onset ||Miscellaneous |
|Acute graft-versus-host disease ||Yes ||Present ||Morbilliform rash, bullae and erosions ||Acute ||Closely resembles toxic epidermal necrolysis |
|Acute generalized exanthematous pustulosis ||Yes ||Rare ||Superficial pustules ||Acute ||Self-limiting on discontinuation of drug |
|Linear IgA bullous dermatosis ||No ||Rare ||Tense, subepidermal bullae ||Acute ||Vancomycin is most commonly implicated |
|Pemphigus ||No ||Usually absent ||Erosions, crusts, patchy erythema (resembles pemphigus foliaceous) ||Gradual ||Commonly caused by penicillamine and other “thiol” drugs; often resolves after the inciting xenobiotic is discontinued |
|Pemphigoid ||No ||Rare ||Tense bullae (sometimes hemorrhagic) ||Acute ||Diuretics a common cause, especially furosemide, spironolactone; often pruritic |
|Paraneoplastic pemphigus ||No ||Present (usually severe) ||Polymorphous skin lesions, flaccid bullae ||Gradual ||Resistant to treatment; associated with malignancy, especially lymphoma |
|Staphylococcal scalded skin syndrome ||Yes ||Absent ||Erythema, skin tenderness, periorificial crusting ||Acute ||Affects children younger than 5 years, adults on dialysis, and those on immunosuppressive therapy |
|Xenobiotic-triggered Pemphigus ||No ||Present ||Mucosal erosions, flaccid bullae ||Gradual ||Caused by “nonthiol” xenobiotics which are more likely to persist after discontinuation of xenobiotic; may require long-term immunosuppressive therapy |
Bullous Reactions (Blistering Reactions)
In addition to SJS and TEN, other bullous cutaneous reactions include drug-induced pseudoporphyria, fixed drug eruption, acute generalized exanthematous pustulosis, phototoxic drug eruptions, and drug-induced autoimmune blistering diseases. Xenobiotic-related cutaneous blistering reactions are clinically indistinguishable from autoimmune blistering diseases such as pemphigus vulgaris or bullous pemphigoid (Fig. 17–7). Certain topically applied xenobiotics such as the vesicant cantharidin derived from “blister beetles” in the Coleoptera order and Meloidae family are used in the treatment of molluscum and viral warts. In high concentrations, xenobiotics lead to necrosis of both skin and mucous membranes. Other systemic xenobiotics cause a similar reaction pattern mediated by the production of antibody directed against the cells at the dermal–epidermal junction (Table 17–3).
Pemphigus vulgaris. (A) Flaccid blisters. (B) Oral erosions. (Part A, Used with permission from Lawrence Lieblich, MD. Part B, Reproduced with permission from Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York, NY: McGraw-Hill; 2008.)
A number of medications, many of which contain a “thiol group” such as penicillamine and captopril, induce either pemphigus resembling pemphigus foliaceus, a superficial blistering disorder in which the blister is at the level of the stratum granulosum, or pemphigus vulgaris, in which blistering occurs above the basal layer of the epidermis (Fig. 17–1). Other xenobiotics, such as furosemide, penicillin, and sulfasalazine produce tense bullae that resemble bullous pemphigoid. Direct immunofluorescence studies demonstrate epidermal intracellular immunoglobulin deposits at the dermal–epidermal junction. The offending xenobiotic should be discontinued and the patient should be referred to a dermatologist to determine treatment. The reaction may persist for up to 6 months after the offending xenobiotic is withdrawn.
Fixed drug eruption is another bullous drug eruption and is characterized by well-circumscribed erythematous to dusky violaceous patches which with central bullae or erosions and develops 1 to 2 weeks after first exposure to the drug. This reaction pattern is so named because re-exposures to the xenobiotic cause lesions in the same area, typically within 24 hours of exposure (Fig. 17–8). Typical locations include acral extremities, genitals, and intertriginous sites, and this process is confused with TEN if widely confluent as in a “generalized fixed drug eruption.” This reaction pattern is generally not life threatening and heals with residual postinflammatory hyperpigmentation. Bullous fixed-drug reactions result from exposure to diverse xenobiotics such as angiotensin-converting enzyme inhibitors and a multitude of antibiotics. As mentioned above, EM can have a bullous variant that can also be confused with SJS/TEN.
Fixed drug eruption due to tetracycline. A well-defined plaque on the knee, merging with 3 satellite lesions. The large plaque exhibits epidermal wrinkling, a sign of incipient blister formation. This was the second such episode after ingestion of a tetracycline. No other lesions were present. (Reproduced with permission from Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York, NY: McGraw-Hill; 2008.)
“Coma bullae” are tense bullae on normal-appearing skin that occur within 48 to 72 hours in comatose patients with sedative–hypnotic overdoses, particularly phenobarbital, or carbon monoxide, poisoning. They also occur in patients in coma from infectious, neurologic, or metabolic causes. Although these blisters are thought to result predominantly from pressure-induced epidermal necrosis, they occasionally occur in non–pressure-dependent areas, suggesting a systemic mechanism. Histologically, an intraepidermal or subepidermal blister is observed. There is accompanying eccrine duct and gland necrosis.
Drug-Induced Hypersensitivity Syndrome
The skin is linked with systemic immunologic diseases such that an alteration in the metabolism of certain xenobiotics leads to a hypersensitivity syndrome. The drug-induced hypersensitivity syndrome, formerly called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), can be severe and potentially life threatening. The hypersensitivity syndrome is characterized by the triad of fever, skin eruption, and internal organ involvement.32 The frequency is estimated between 1 in 1,000 to 1 in 10,000 with antiepileptic or sulfonamide antibiotic exposures and usually presents within 2 to 6 weeks of the initial exposure. For antiepileptics, the inability to detoxify arene oxide metabolites is suggested to be a key factor; once a patient has a documented drug-induced hypersensitivity syndrome to one antiepileptic, it is important to note that cross-reactivity between phenytoin, carbamazepine, and phenobarbital is well documented, both in vivo and in vitro.47 In the case of sulfonamides, acetylator phenotype and lymphocytes’ susceptibility to the metabolite hydroxylamine are risk factors for developing drug hypersensitivity syndrome. Further support for the role of genetic predisposition comes from data in Northern European populations in which the presence of the HLA-A*3101 allele significantly increases the risk of developing carbamazepine-induced hypersensitivity syndrome.34 Fever and a cutaneous eruption are the most common symptoms. Accompanying malaise, pharyngitis, and cervical lymphadenopathy are frequently present. Atypical lymphocytes and eosinophilia occur initially. The exanthem is initially generalized and morbilliform, and conjunctivitis and angioedema occur (Fig. 17–9). Later the eruption becomes edematous, and facial edema, which is often present, is a hallmark of this syndrome. One-half of patients with drug induced hypersensitivity syndrome will have hepatitis, interstitial nephritis, vasculitis, CNS manifestations (including encephalitis, aseptic meningitis), interstitial pneumonitis, acute respiratory distress syndrome, and autoimmune hypothyroidism. Hepatic involvement can be fulminant and is the most common cause of deaths associated with this syndrome. Colitis with bloody diarrhea and abdominal pain are associated. In addition to the aromatic antiepileptics (phenobarbital, carbamazepine, and phenytoin), lamotrigine, allopurinol, sulfonamide antibiotics, dapsone and the protease inhibitor abacavir are implicated. Early withdrawal of the offending xenobiotic is crucial and treatment is generally supportive.42,67 If cardiac or pulmonary involvement is present, systemic corticosteroids should be initiated. However, their benefit on outcome has not been demonstrated, and relapse may occur during tapering, necessitating long-term (several month) courses of therapy. The authors recommend that patients with drug-induced hypersensitivity syndrome be managed in conjunction with a dermatologist and that adequate follow-up is ensured.
A patient with a hypersensitivity syndrome associated with phenytoin. He has a symmetric, bright red, and exanthematous eruption, confluent in some sites. The patient had associated lymphadenopathy. (Reproduced with permission from Wolff K, Johnson RA. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, NY: McGraw-Hill; 2009.)
Erythroderma, also known as exfoliative dermatitis, is defined as a generalized redness and scaling of the skin. However, it does not represent one disease entity, but rather it is a severe clinical presentation of a variety of skin diseases including psoriasis, atopic dermatitis, drug reactions, or cutaneous T-cell lymphoma (CTCL). At times, the underlying etiology of erythroderma is never discovered and this is termed “idiopathic erythroderma.” The importance of this presentation is its association with systemic complications such as hypothermia, peripheral edema, and loss of fluid, electrolytes and albumin with subsequent tachycardia and cardiac failure. Many xenobiotics produce erythroderma (Table 17–2). Boric acid, when ingested, can cause systemic toxicity in addition to a bright red eruption (“lobster skin”), followed usually within 1 to 3 days by a generalized exfoliation.55
Xenobiotic-induced vasculitis (Fig. 17–10) comprises 10% to 15% of secondary cutaneous vasculitis. It generally occurs from 7 to 21 days after initial exposure to the xenobiotic or 3 days after rechallenge and is considered to be a secondary cause of cutaneous small vessel vasculitis (typically involving dermal postcapillary venules). Many xenobiotics are implicated as triggers of cutaneous vasculitis (Table 17–2).60 Cutaneous vasculitis is characterized by purpuric, nonblanching macules that usually become raised and palpable. The purpura tends to occur predominantly on gravity-dependent areas, including the lower extremities, particularly the feet, ankles, and buttocks (Fig. 17–11). Sometimes the reaction pattern has edematous purpuric wheals (urticarial vasculitis), hemorrhagic bullae, or ulcerations. Histologic examination of affected skin shows a leukocytoclastic vasculitis, which is characterized by fibrin deposition in the vessel walls. There is a perivascular infiltrate with intact and fragmented neutrophils that appear as black dots, known as “nuclear dust” and extravasated red blood cells. Vasculitis can be limited to the skin, or can involve other organ systems, particularly the kidneys, joints, liver, lungs, and brain. The purpura results from the deposition of circulating immune complexes, which form as a result of hypersensitivity to a xenobiotic. Treatment consists of withdrawing the putative xenobiotic and initiating systemic corticosteroid therapy if systemic involvement is present. A syndrome of vasculitis, neutropenia, and retiform purpura occurs as a result of levamisole-adulterated cocaine (Fig. 17–12).13 The earlobe is a common site of purpuric lesions from levamisole, and it was estimated that up to 70% of the cocaine sold in some areas during an epidemic in the United States contained levamisole.6,63,64
Leukocytoclastic vasculitis in a patient with mixed cryoglobulinemia manifested as palpable purpura and acrocyanosis. Patient with tuberculosis, positive antinuclear antibody, and hepatitis. (Reproduced with permission from Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York, NY: McGraw-Hill; 2008.)
Purpura. Nonblanching red erythematous papules and plaques (palpable purpura) on the legs, representing leukocytoclastic vasculitis. (Reproduced with permission from Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York, NY: McGraw-Hill; 2008.)
Levamisole-induced purpura: violaceous patches on the ear, neck, and thigh of 46-year-old woman exposed to levamisole-adulterated cocaine. (Reproduced with permission from Chung C, Tumeh PC, Birnbaum R, et al. Characteristic purpura of the ears, vasculitis, and neutropenia—a potential public health epidemic associated with levamisole-adulterated cocaine. J Am Acad Dermatol. 2011 Oct;65(4):722-725.)
Purpura is the multifocal extravasation of blood into the skin or mucous membranes (Fig. 17–12). Ecchymoses, therefore, are considered to be purpuric lesions. Chemotherapeutics that either diffusely suppress the bone marrow or specifically depress platelet counts below 30,000/mm3, predispose to purpuric macules. Xenobiotics that interfere with platelet aggregation, such as aspirin, clopidogrel, ticlopidine, valproic acid, and thrombolytics, cause purpura. Anticoagulants, such as heparin and warfarin, may also result in purpura (Chaps. 20 and 58).
Anticoagulant-Induced Skin Necrosis
Skin necrosis from warfarin, low-molecular-weight heparin, or unfractionated heparin usually begins 3 to 5 days after the initiation of treatment, which corresponds with the expected early decline of protein C function with warfarin (Fig. 17–13). The estimated risk is one in 10,000 persons. It is 4 times higher in women, especially if obese, with peaks in sixth to seventh decades of life. The necrosis is secondary to thrombus formation in vessels of the dermis and subcutaneous fat. Heparin-induced cutaneous necrosis results from antibodies that bind to complexes of heparin and platelet factor 4 and induce platelet aggregation and consumption. This causes bullae, ecchymosis, ulcers, and massive subcutaneous necrosis, usually in areas of abundant subcutaneous fat, such as the breasts, buttocks, abdomen, thighs, and calves. Heparin-induced necrosis is associated with protein C or S deficiency, anticardiolipin antibody syndrome, as well as factor V Leiden mutations.46
Skin necrosis in a patient after 4 days of warfarin therapy. (Reproduced with permission from Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York, NY: McGraw-Hill; 2008.)
When a xenobiotic comes in contact with the skin, it can result in either an allergic contact dermatitis (20% of cases) or more commonly an irritant contact dermatitis (80% of cases). Contact dermatitis is characterized by inflammation of the skin with spongiosis (intercellular edema) of the epidermis that results from the interaction of a xenobiotic with the skin. Well-demarcated erythematous vesicular or scaly patches or plaques, and at times bullae, are noted on areas in direct contact with the xenobiotic, whereas the remaining areas are spared.
Allergic contact dermatitis fits into the classic delayed hypersensitivity, or type IV, immunologic reaction. The development of this reaction requires prior sensitization to an allergen, which, in most cases, acts as a hapten by binding with an endogenous molecule that is then presented to an appropriate immunologic T cell. Upon reexposure, the hapten diffuses to the Langerhans cell, is chemically altered, bound to an HLA-DR, and the complex is expressed on the Langerhans cell surface. This complex interacts with primed T cells either in the skin or lymph nodes, causing the Langerhans cells to make interleukin-1 and the activated T cells to make interleukin-2 and interferon. This subsequently activates the keratinocytes to produce cytokines and eicosanoids that activate mast cells and macrophages, leading to an inflammatory response (Fig. 17–14).31
Contact dermatitis. (1) Causative xenobiotic, typically a hapten of <500 Da, diffuses through stratum corneum and binds to receptor on Langerhans cell (LC). (2) The antigen is processed with major histocompatibility complex II (MHC II) receptor site, presented to T-helper lymphocytes, and carried through the lymphatics to regional lymph nodes. (3) There it undergoes the sensitization phase by producing memory, effector, and suppressor T-lymphocytes. (4) On reexposure to the same, or to a cross-reactive antigen, the LC presents the antigen to T-lymphocytes (
), which are now sensitized. This initiates an inflammatory process that appears as indurated, scaly patches.
Many allergens are associated with contact dermatitis (Table 17–2). Among the most common plant-derived sensitizers are urushiol (Toxicodendron species), sesquiterpene lactone (ragweed), and tuliposide A (tulip bulbs). Metals, particularly nickel, are commonly implicated in contact dermatitis and should be considered in patients with erythematous, vesicular, or scaly patches or plaques around the umbilicus from nickel buttons on pants, and on the ear lobes from earrings. Several industrial chemicals, such as the thiurams (rubber) and urea formaldehyde resins (plastics), account for the majority of occupational contact dermatitis. Medications, particularly topical medications such as neomycin, commonly cause contact dermatitis. Another important allergen is paraphenylenediamine, a black dye in permanent and semipermanent hair coloring, leather, fur, textiles, industrial rubber products, and black henna tattoos. According to the North American Contact Dermatitis Group, the frequency of sensitization has been found to be 5%.69 The management of contact dermatitis varies based on the severity of the reaction, ranging from treatment with topical steroids to oral cyclosporine (Table 17–4). A thorough history in addition to patch testing (the gold standard) will often identify the culprit.
TABLE 17–4Overview of Treatment of Acute Contact Dermatitis ||Download (.pdf) TABLE 17–4 Overview of Treatment of Acute Contact Dermatitis
|Identification of contactant and future avoidance (consider patch testing to identify culprit) |
|Emollients for lichenified lesions |
|Topical or oral corticosteroids to treat dermatitis (may take 6 weeks of treatment) |
|Topical calcineurin inhibitors (tacrolimus or pimecrolimus) |
|Cyclosporine (oral) |
|Phototherapy: narrow-band UVB |
Irritant dermatitis, although clinically indistinguishable from allergic contact dermatitis, results from direct damage to the skin and does not require prior antigen sensitization. Still, the inflammatory response to the initial mild insult is the cause of the majority of the damage. Xenobiotics that cause an irritant dermatitis include acids, bases, solvents, and detergents, many of which, in their concentrated form or after prolonged exposure, can cause direct cellular injury. The specific site of damage varies with the chemical nature of the xenobiotic. Many xenobiotics affect the lipid membrane of the keratinocyte, whereas others diffuse through the membrane, injuring the lysosomes, mitochondria, or nuclear components. When the cell membrane is injured, phospholipases are activated and affect the release of arachidonic acid and the synthesis of eicosanoids. The second-messenger system is then activated, leading to the expression of genes and the synthesis of various cell surface molecules and cytokines. Interleukin-1 is secreted, which can activate T cells directly and indirectly by stimulation of granulocyte-macrophage colony–stimulating factor production. The treatment is similar to allergic contact dermatitis (Table 17–4).
Photosensitivity is caused by topical or systemic xenobiotics. Nonionizing radiation, particularly to ultraviolet A (UVA) (320–400 nm) and less often to ultraviolet B (UVB) (280–320 nm), are the wavelengths that commonly cause photosensitivity. There are generally 2 types of xenobiotic-related photosensitivity: phototoxic and photoallergic.41 Phototoxic reactions occur within 24 hours of the first exposure, usually within hours, and are dose-related. These reactions result from direct tissue injury caused by ultraviolet-induced activation of a phototoxic xenobiotic. The clinical findings include erythema, edema, and vesicles in a light-exposed distribution, and resemble a severe sunburn that lasts days to weeks, with patients complaining of burning and stinging (Fig. 17–15). A subtype of phototoxic reaction is phytophotodermatitis, in which linear streaks of erythema occur due to skin contact with furocoumarins from plants followed by exposure to sunlight (Table 17–2). Photoallergic reactions occur less commonly, occur following even small exposures, and resemble allergic contact dermatitis with lichenoid papules or an eczematous dermatitis on exposed areas and is often pruritic. These are type IV hypersensitivity reactions that develop in response to a xenobiotic that has been altered by absorption of nonionizing radiation, acting as a hapten and eliciting an immune response on first exposure. Only on recurrent exposure do the lesions develop. Studies indicate that benzophenone-3 (oxybenzone), often found in sunscreen, is the most common cause of photoallergic dermatitis.8,16 Other common photoallergens include xenobiotics such as promethazine, NSAIDs, fragrances, and antibiotics. Photoallergic reactions can be diagnosed by the use of photopatch tests. Both phototoxic and photoallergic reactions are managed with symptomatic treatment, including topical or, if needed, systemic corticosteroids. Identification and avoidance of the triggering xenobiotic are crucial in addition to avoidance of sun exposure and wearing a broad-spectrum sunscreen (SPF 30 or above) that blocks both UVA and UVB preferably without para-aminobenzoic acid (PABA) and oxybenzone. Para-amino benzoic acid is a sensitizer for many patients and is rarely included in current sunscreen products.
Phototoxicity associated with a cyclic antidepressant. Note erythema and edema on sun-exposed areas and sparing of sun-protected chest and shaded upper lip and neck. (Reproduced with permission from Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York, NY: McGraw-Hill; 2008. Photo contributor: Dr. Adrian Tanew.)
A number of environmental xenobiotics are associated with localized or diffuse scleroderma-like reactions. Scleroderma refers to a tightened indurated surface change of the skin that typically occurs on the face, hands, forearms, and trunk and is 3 times more common in women. This can be accompanied by facial telangiectasias and Raynaud syndrome. Raynaud syndrome consists of skin color changes of white, blue, and red accompanied by intense pain with exposure to cold, and can cause acral ulcerations, if untreated. The fibrotic process usually does not remit with removal of the external stimulus, and specific autoantibodies are absent. The association of scleroderma-like reactions with polyvinyl chloride manufacture is likely related to exposure to vinyl chloride monomers. Similar reports of this syndrome are associated with exposure to trichloroethylene and perchlorethylene, which are structurally similar to vinyl chloride. Epoxy resins, silica, and organic solvents are implicated as environmental causes. Bleomycin, carbidopa, pentazocine, and taxanes are also causative.
In Spain, patients exposed to imported rapeseed oil mixed with an aniline additive and colorant developed widespread cutaneous sclerosis. This became known as the “toxic oil syndrome.” A similar syndrome following ingestion of contaminated L-tryptophan as a dietary supplement used as a sleeping aid resulted in the eosinophilia myalgia syndrome, which is characterized by myalgia, edema, arthralgias, alopecia, urticaria, mucinous yellow papules, and erythematous plaques.56
Xenobiotics have the potential to cause distinctive patterns of hair loss (Table 17–2). Anagen effluvium, or hair loss during the anagen stage of the growth cycle, is caused by interruption of the rapidly dividing cells of the hair matrix, producing rapid hair loss within 2 to 4 weeks. Telogen effluvium, or toxicity during the resting stage of the cycle, typically produces hair loss 2 to 4 months later and occurs as a side effect of a xenobiotic or in the setting of systemic disease or altered physiologic states (eg, postpartum). Anagen toxicity is commonly associated with xenobiotic exposures such as doxorubicin, cyclophosphamide, vincristine, and thallium.58 Many chemotherapeutics reduce the mitotic activity of the rapidly dividing hair matrix cells, leading to the formation of a thin, easily breakable shaft. Thallium, classically associated with hair loss, causes alopecia by 2 mechanisms. Thallium distributes intracellularly, like potassium, altering potassium-mediated processes and thereby disrupting protein synthesis. By binding sulfhydryl groups, thallium also inhibits the normal incorporation of cysteine into keratin. Thallium toxicity results in alopecia 1 to 4 weeks after exposure. Within 4 days of exposure, a hair mount observed using light microscopy will demonstrate tapered or bayonet anagen hair with a characteristic bandlike black pigmentation at the base. Seeing this anagen effect can reveal the timing of exposure. Soluble barium salts, such as barium sulfide, are applied topically as a depilatory to produce localized hair loss. The mechanism of hair loss is undefined.
The nail consists of a horny layer: the “nail plate” and 4 specialized epithelia—proximal nail fold, nail matrix, nail bed, and hyponychium. The nail matrix consists of keratinocytes, melanocytes, Langerhans cells, and Merkel cells.
Nail hyperpigmentation occurs for unclear reasons, but can be caused by focal stimulation of melanocytes in the nail matrix leading to melanonychia. The pigment deposition can be longitudinal, diffuse, or perilunar in orientation and typically develops several weeks after chemotherapy.58 Dark-skinned patients are more commonly affected because of a higher concentration of melanocytes. Cyclophosphamide, doxorubicin, hydroxyurea, zidovudine, and bleomycin are among the most common xenobiotics that cause melanonychia, and the pigmentation generally resolves with cessation of therapy. When approaching a patient with a single streak of longitudinal melanonychia, it is crucial to include nail melanoma in the differential diagnosis, particularly if the band is greater than 3 mm in breadth and/or evolving.
Nail findings serve as important clues to xenobiotic exposures that occurred in the recent past. Matrix keratinization in a programmed and scheduled pattern leads to the formation of the nail plate. Certain changes in nails, such as Mees lines and Beau lines, result from a temporary arrest of the proximal nail matrix proliferation. These lines can be used to predict the timing of a toxic exposure because of the reliability of rate of growth of the fingernails at approximately 2 to 3 mm per month. Mees lines, first described in 1919 in the setting of arsenic poisoning, can be used to approximate the date of the insult by the position of growth of the Mees line a patterned leukonychia (not indentation) causing transverse white lines.36 Multiple Mees lines suggests multiple exposures over time. Arsenic, thallium, doxorubicin, vincristine, cyclophosphamide, methotrexate, and 5-fluorouracil cause Mees lines, but Mees lines can develop after any period of critical illness such as sepsis or trauma. Beau lines are transverse grooves or indentations more often in the central portion of the nail plate, most commonly caused by trauma (eg, manicures) or dermatologic disease affecting the proximal nail fold. Beau lines present on multiple digits, especially at the same level on each nail, indicate a systemic illness or xenobiotic exposure (Fig. 17–16).
Presence of proximal indented Beau line and distal band of leukonychia due to cyclophosphamide 3 months after bone marrow transplantation. (Reproduced with permission from Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York, NY: McGraw-Hill; 2008.)
The integument is constantly exposed to both topical and systemic xenobiotics, and these exposures result in reactive dermatoses.
Prompt examination of the entire skin, hair, and nails provide invaluable clues about the route and nature of the offending xenobiotic.
A careful history, clinical examination, and consultation with a dermatologist and biopsy when indicated can aid in identifying the etiology and nature of the reaction and lead to prompt treatment.
Medication or drug reactions range from ordinary exanthematous reactions to potentially life-threatening drug-induced hypersensitivity reactions and SJS/TEN; these entities can be distinguished with a careful history, physical examination, and precise drug-exposure timeline.
Dr. Dina Began contributed to this chapter in previous editions.
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