Dermatologic Principles



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

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.



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.

FIGURE 17–1.

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

FIGURE 17–2.

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).

Direct Dermal Toxicity

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.



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.




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

FIGURE 17–3.

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.

FIGURE 17–4.

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

Xenobiotic-Induced Dyspigmentation

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



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).

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