18: Dermatologic Principles

Dermatology is a specialty in which visual inspection may allow for rapid diagnosis. Some authors suggest a brief examination before a lengthy history 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 and include a magnifying glass, glass slide (for diascopy), flashlight, alcohol pad to remove scale or makeup, scalpel, and at times a Wood’s 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 18–1.

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 can be affected by xenobiotic exposures that occur through many routes. Dermal exposures themselves are important because they account for approximately 1% of the fatalities reported to the American Association of Poison Control Centers (AAPCC) (Chap. 136). 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 reaction and whether the response will be local or systemic. The location of xenobiotic injury determines the histologic morphology, the severity of the reaction pattern, and the overall clinical findings. It should be noted, however, that different xenobiotics may produce clinically similar skin changes and conversely that an individual xenobiotic may produce diverse cutaneous lesions.

The skin has three main components that interconnect anatomically and interact functionally: the epidermis, the dermis, and the subcutis or hypodermis (Fig. 18–1). Some experts further categorize the components of the skin into three reactive units: The superficial reactive unit, which is composed of the epidermis, the dermal–epidermal junction (DEJ), 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.³⁶ The primary physiologic roles of the epidermis, the outermost layer of the skin, are 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 four layers: the horny layer (stratum corneum); granular layer (stratum granulosum); spinous layer (stratum spinosum); and basal layer (stratum germinativum), which overlies the basement membrane zone (BMZ) (Fig. 18–1). The keratinocyte, or squamous cell, which is an ectodermal derivative, comprises the majority of cells in the epidermis.

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.³⁶ Alternately, in some forms of ichthyosis, there may be decreased desquamation, leading to epidermal retention, which 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.¹⁸ The stratum corneum is covered by a surface film composed of sebum emulsified with sweat and breakdown products of keratinocytes.³² This surface film functions as an external barrier as protection 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.³² 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.³² Similarly, hydrocarbon solvents, such as gasoline or methanol, and 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.³⁶ 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 BMZ and is populated by melanocytes and Langerhans cells in addition to basal keratinocytes. Melanocytes contain melanin, which is the major chromophore in the skin that is responsible for absorbing ultraviolet (UV) and other light energies. 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 may carry antigens via dermal lymphatics to regional lymph nodes.

The BMZ consists of three layers—the lamina lucida, the lamina densa, and the sublamina densa—and separates the epidermis from the ­dermis (Fig. 18–1). It provides a site of attachment for basal keratinocytes and permits epidermal–dermal interaction. The BMZ is also of clinical significance because it is the target of genetic defects and autoimmune attack leading to a variety of inherited and acquired cutaneous diseases.

The 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 two 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. Whereas collagen accounts for 70% of the dry weight of the skin, elastic fibers comprise only 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 its 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. 18–1). 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.²¹

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.²¹ Apocrine glands, which are concentrated in select areas of the body such as the axilla, 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. Xenobiotics can be concentrated in the sweat and increase the intensity of the local skin reactions. Certain antineoplastics, such as cytarabine and bleomycin, directly damage the eccrine sweat glands, resulting in anhidrosis.

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 a syndrome, chloracne, that appears clinically similar to 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. 18–2). Similar syndromes result from exposure to brominated and iodinated compounds and are known as bromoderma and ioderma, respectively.⁶⁶

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 long-term feedback of appetite and satiety signaling, is synthesized and regulates fat mass (adiposity) in this layer.

The hair follicle is divided into three portions, the hair bulb, infundibulum, and isthmus.⁵⁵ 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 three 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 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/d.³⁶ Understanding the phases of hair growth is important because hair growth can be used to identify clues regarding the timing and mechanism of action of a xenobiotic.

The nail plate, which is often considered analogous to the hair, is also a continuously growing structure. Fingernails grow at average of 0.1 mm/d, and toenails grow at about one-third that rate. The mitotically active cells of the nail matrix that produce the nail plate are subject to both traumatic and xenobiotic injury, which in turn affect the appearance and growth of the nail plate. Because nail growth is consistent, location of an abnormality in the plate, such as Mees lines (transverse white lines), can predict the timing of exposure.

Transdermal Xenobiotic Absorption

Although there is no active uptake mechanism for xenobiotics by the skin, many undergo percutaneous absorption by passive diffusion. Lipid solubility, concentration gradient, molecular weight, and certain specific skin characteristics are important determinants of dermal absorption.^22,23,48,52 Absorption is determined to a great extent by the lipid solubility of the specific xenobiotic.^15,37 The pharmacokinetic profile of transdermally administered xenobiotics is markedly different than by the enteral or other parenteral routes.¹⁷ As with any route of administration, adverse effects and toxicity caused by excessive absorption after patch application may occur after therapeutic use and misuse. For example, adverse effects and toxicity are reported with nicotine, fentanyl, nonsteroidal antiinflammatory drugs (NSAIDs), and lidocaine transdermal delivery devices. Other xenobiotics, topically applied without a specific delivery device, including podophyllin, camphor, phenol, organic phosphorus compounds, ethanol, organochlorines, nitrates, and hexachlorophene, may be associated with systemic toxicity and mortality (Special ­Considerations: SC1).

Direct Dermal Toxicity

Exposure to any one of a myriad of industrial and environmental xenobiotics can result 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 may act as oxidizing or reducing agents, corrosives, protoplasmic poisons, desiccants, or vesicants. Often an injury may initially appear to be mild or superficial with minimal erythema, blanching, or discoloration of the skin. Over the subsequent 24 to 36 hours, there may be progression 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 that limits the spread of the xenobiotic. The histopathologic finding after acid injury is termed coagulative necrosis.¹⁰ Inorganic acids that are frequently used in industry include hydrochloric and sulfuric acids, but the weakly acidic hydrofluoric (HF) acid that is used for the etching of glass, metal, and stone leads to the severe injury. HF acid, because of its limited dissociation constant, is able to penetrate intact skin with subsequent penetration into deeper tissues. The fluoride ion is an extremely cytotoxic agent, causing severe tissue damage, including bone destruction, by interfering with a variety of cellular enzyme systems. Severe pain is caused by the capacity of fluoride ions to bind tissue calcium, thus affecting nerve conduction.⁵⁸ In the dermis, the proton (H⁺) and fluoride ions (F⁻) may ionize and cause both acid-induced tissue necrosis and f­luoride-induced toxicity (Chap. 107).⁵

Alkali exposures characteristically produce a liquefactive necrosis, which allows continued penetration of the corrosive xenobiotic. Consequently, cutaneous and subcutaneous injury after alkali exposure is typically more severe than after an acid exposure, with the exception of HF acid. With alkali burns, there are generally no vesicles but rather necrotic skin caused by the disruption of barrier lipids and 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, drain openers, and soaps and detergents. Alkali burns from wet cement result from the liberation of calcium hydroxide, which has an initial pH of 10 to 12 that rises to 12 to 14 as the cement sets.³⁵

Thermal damage can also be the result of a xenobiotic exposure. For example, the exothermic reaction generated by the wetting of elemental phosphorus or sodium may result in a thermal burn. In these circumstances, the products of reactivity, phosphoric acid, and sodium hydroxide, respectively, may 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), can produce a freezing injury, or frostbite.

Hydrocarbon-based solvents are typically liquids that are capable of dissolving non–water-soluble solutes.¹⁰ Although the most prominent effect is a dermatitis caused by loss of ceramides from the stratum corneum of the epidermis, prolonged exposure can result in deeper dermal irritation and pressure and hydrocarbon skin exposure.

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. After 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 may be 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. After 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 after 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.³⁸ Calcium oxide (quicklime) thickens and forms Ca(OH)₂ after exposure to water, which releases heat and causes cutaneous ulcerations, suggesting that mechanical removal as above is advised.

Cyanosis

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. 127). The presence of the more deeply colored hemoglobin moiety within the dermal plexus results in cyanosis that is most pronounced on areas of thin skin such as the mucous membranes or underneath fingernails. Also, in the differential diagnosis for a patient with discoloration of the skin is pseudochromhidrosis, also termed extrinsic apocrine chromhidrosis. This results from staining of the sweat by chromogenic bacteria, including Corynebacterium, Malassezia furfur, and Bacillus species; the latter two species have been known to cause blue discoloration of the skin. Several cases of blue pseudochromhidrosis caused by topiramate use are reported in the literature; the diagnosis can be made by the ability of the clinician to wipe off the discoloration with a damp cotton swab.¹¹

Xanthoderma

Xanthoderma is a yellow to yellow-orange macular discoloration of the skin.²⁵ Xanthoderma can be caused by xenobiotics such as carotenoids, which deposit in the stratum corneum, and cause carotenoderma. Carotenoids are lipid soluble and consist of α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin and serve as precursors of vitamin A ­(retinol). The carotenoids are excreted via sweat, sebum, urine, and gastrointestinal (GI) secretions. Jaundice is typically a sign of hepatocellular failure or hemolysis and is caused by hyperbilirubinemia, either conjugated or unconjugated, a condition in which the yellow bilirubin deposits in the subcutaneous fat, leading to a common cause of xanthoderma. Jaundice caused by hyperbilirubinemia from liver failure may be accompanied by other cutaneous stigmata, including spider angiomas, telangiectasias, palmar erythema, and dilated superficial abdominal veins (caput medusa). True hyperbilirubinemia is differentiated from hypercarotenemia by the presence of scleral icterus in patients with the former, which is absent in patients with the latter. In addition, the cutaneous discoloration seen in hypercarotenemia can be removed by wiping the skin with an alcohol swab. Lycopenemia, an entity similar to carotenemia, is caused by the excessive consumption of tomatoes. Additionally, topical exposure to dinitrophenol or picric acid or stains from cigarette use produces localized yellow discoloration of the skin.

Pruritus

Pruritus is the poorly localized, unpleasant sensation that elicits a desire to scratch. The biologic purpose of pruritus is to provoke scratching in order to remove a pruritogen, a response likely to have originated when most pruritogens were parasites. Pruritus is a common manifestation of urticarial reactions, but it may also be of nonimmunologic origin. Pruritus is the most common dermatologic symptom and can arise from a primary dermatologic condition or may be a symptom of an underlying systemic disease in an estimated 10% to 50% of patients.²⁸ Patients with hepatocellular disease frequently have pruritus, which is mediated by the release of bile acids. In addition, in patients with chronic liver disease and obstructive jaundice, pruritus can be caused by central mechanisms, as suggested by elevated central nervous system (CNS) endogenous opioid concentrations. Pruritus can also be caused by topical exposure to the urticating hairs of Tarantula spiders, spines of the stinging nettle plant (Urtica species), or via stimulation of substance P by certain xenobiotics such as capsaicin.²⁴ 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.²⁸

Flushing

Vasodilation of the dermal arterioles leads to flushing, or transient reddening of the skin commonly of the face, neck, and chest. Flushing can occur after autonomically mediated vasodilation, as occurs with stress, anger, or exposure to heat, or it can be chemically 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 and saurine poisoning can result from the consumption of scombrotoxic fish and can produce flushing. Flushing after the consumption of ethanol is common in patients of Asian and Inuit descent and is similar to the reaction after ethanol consumption in patients exposed to disulfiram or similar xenobiotics (Chap. 79). The increased production of and 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.^7,62 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 can be managed with nonselective β-adrenergic antagonists (nadolol, propranolol) or clonidine, and anxiolytics may have benefit if emotional distress or anxiety is evident. Other nontoxicologic causes of flushing, including carcinoid syndrome, pheochromocytoma, mastocytosis, anaphylaxis, medullary carcinoma of the thyroid, pancreatic cancer, menopausal flushing, and renal carcinoma, must be considered as etiologies in a flushed patient.²⁷

Sweating

Xenobiotic-induced diaphoresis may be part of a physiologic response to heat generation or may be pharmacologically mediated after parasympathetic or sympathomimetic xenobiotic use. Because the postsynaptic receptor on the eccrine glands is muscarinic, most muscarinic agonists stimulate sweat production. Sweating occurs after exposure to cholinesterase inhibitors, such as organic phosphorus compounds, but it may also occur with direct-acting muscarinic agonists such as pilocarpine. Alternatively, antimuscarinics, such as belladonna alkaloids and antihistamines, reduce sweating and produce dry skin. Certain xenobiotics, including the anticholinergics glycopyrrolate, propantheline bromide, and botulinum toxin, have proven useful for the treatment of hyperhidrosis. Botulinum toxin A derived from Clostridium botulinum temporarily chemodenervates eccrine sweat glands at the neuromuscular junction via inhibition of presynaptic acetylcholine release and is approved by the Food and Drug Administration for the treatment of primary focal axillary hyperhidrosis.²

Cutaneous pigmentary changes can result from the deposition of xenobiotics that can be ingested and carried to the skin by the blood or may 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, can be localized or widespread. The discoloration tends to be most prominent in areas exposed to sunlight, probably secondary to the fact that silver stimulates melanocyte proliferation. Histologically, fine black granules are found in the BMZ of the sweat glands, blood vessel walls, and DEJ and along the erector pili muscles (Chap. 101). 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 secondary to 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 may be the result of pesticides or contaminated well water, which can cause cutaneous hyperpigmentation with a bronze hue with areas of scattered hypopigmentation that develop from 1 and 20 years after 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 can cause staining of the skin, resulting in pigmentation similar to that seen in tattoos, and iron storage disorders, known as hemochromatosis, can result in a bronze appearance of the skin.²⁰

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 can be accompanied by darkening of the nails, sclerae, oral mucosa, thyroid, bones, and teeth. Hyperpigmentation from minocycline is divided into three types depending on the color, anatomic distribution, and whether iron- or melanin-containing granules are found within the skin. Other medications commonly associated with hyperpigmentation include amiodarone, zidovudine, bleomycin and other chemotherapeutics, antimalarials, and psychotropics (chlorpromazine, thioridazine, imipramine, desipramine, amitriptyline).²⁹ Although not true dyspigmentation, as noted earlier, topiramate has been 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 more than 1% of outpatients. Several cutaneous reaction patterns account for the majority of clinical presentations occurring in patients with xenobiotic-induced dermatotoxicity (Table 18–2). The following drug reactions will be discussed in detail: urticarial drug reactions, erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), fixed drug eruption, and drug-induced hypersensitivity syndrome.

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 can be targetoid and mimic EM. Approximately 40% of patients with urticaria experience angioedema and anaphylactoid reactions as well.¹ 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 may occur after systemic absorption of an allergen or after a minimal localized exposure in patients highly sensitized to the allergen. After limited exposure, a localized form of urticaria may occur. Regardless of the specific clinical presentation, the reaction 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 earlier. Activation of the nearby sensory neurons produces pruritus. Nonimmunologically mediated mast cell degranulation producing an identical urticarial syndrome may also occur after exposure to any xenobiotic.¹⁴

Erythema Multiforme

Historically, it was believed that EM existed on a spectrum with SJS and TEN given overlapping clinical features and morphology; however, these entities have been reclassified on the basis that most cases of EM are believed to be triggered by viral infection (herpes simplex virus most commonly) and most cases of SJS/TEN are triggered by xenobiotics.⁴⁹ EM 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. 18–3). 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 EM minor and severe in EM major. Although less common than viral-induced EM, xenobiotics such as sulfonamides, phenytoin, antihistamines, many antibiotics, rosewood, and urushiol can elicit EM. Differentiating EM from SJS/TEN, which can also present with targetoid lesions, can be difficult, especially in the case of bullous EM, and biopsy may be required.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Toxic epidermal necrolysis and SJS (Fig. 18–4) are considered to be related disorders that belong to a spectrum of increasingly severe skin eruptions.⁴³ SJS is defined by less than 10% body surface area epidermal detachment, SJS–TEN overlap is defined by 10% to 30% involvement, and TEN is defined by more than 30% epidermal sloughing. Although on a spectrum, SJS has a mortality rate of 5%, far lower than the approximately 25% to 50% mortality rate for TEN.^47,50 TEN is a rare, life-threatening dermatologic emergency whose incidence is estimated at 0.4 to 1.2 cases per 1 million persons, and xenobiotics are causally implicated in 80% to 95% of the cases. More than 220 xenobiotics are implicated in causing TEN. The largest study examining medication triggers of TEN divided these medications into long-term (used for months to years) and short-term ones. Short-term xenobiotics most commonly implicated in the development of TEN included trimethoprim–sulfamethoxazole and other sulfonamide antibiotics followed by cephalosporins, quinolones, and aminopenicillins.⁵¹ 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, oxicam NSAIDs, allopurinol, and corticosteroids.

Classically, the eruption of TEN is painful and occurs within 1 to 3 weeks of 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. About 1 to 3 days later, signs begin in the mucous membranes, including the eyes, mouth, nose, and genitals in 90% of cases.⁴⁷ Next a macular erythema develops that subsequently becomes raised and morbilliform on the face, neck, and central trunk, which then progresses to involve the extremities. Individual lesions may appear targetoid because of their dusky centers and progress to bullae in the next 3 to 5 days involving the entire thickness of the epidermis. The nails may be involved becoming necrotic and can slough off. A Nikolsky sign may occur, and although suggestive, is not pathognomonic of TEN because it 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 DEJ adjacent to the necrotic epidermis.

The incidence of TEN is higher in patients with advanced HIV ­disease.^43,59 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.⁴³ 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 might induce upregulation of FasL by keratinocytes constitutively expressing Fas, leading to a death receptor–mediated apoptotic pathway; the xenobiotic might interact with major histocompatibility class I–expressing cells, and then drug-specific CD8⁺ cytotoxic T lymphocytes accumulate within epidermal blisters, releasing perforin and granzyme B that kill keratinocytes; or that the xenobiotic may also trigger the activation of CD8⁺ T lymphocytes and natural killer (NK) cells, to secrete granulysin, with keratinocyte death not requiring cell contact.⁴² Serum FasL concentrations are elevated up to 4 days before mucosal involvement in patients with SJS/TEN and may become useful clinically because an early predictor of these severe dermatologic diseases.⁴¹ Serum granulysin, a proinflammatory cytolytic enzyme released by CD8+ T lymphocytes found in the blisters of TEN, has been investigated as a potential early predictive marker of SJS/TEN.¹⁹ A rapid immunochromatographic test that detects elevated serum granulysin (>10 ng/mL) in 15 minutes has shown 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.¹⁹ 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 should be transferred to a burn or other specialized center for sterile wound care. Risk factors for mortality, such as age, extent of epidermal detachment, and base deficit, have been proposed. In a recent study, only serum bicarbonate concentration less than 20 mEq/L was found to portend hospital death in patients with TEN.⁶⁴ P­orcine xenografts or human skin allografts, including amniotic membrane transplantation, are used and are widely accepted therapies.⁴⁶ Although corticosteroids are not generally recommended, there is emerging support for the use of intravenous immunoglobulin (IVIG), cyclophosphamide, and cyclosporine.⁴⁶ A large meta-analysis of 17 studies revealed a trend toward improved mortality with high-dose IVIG in adults and good prognosis in children; however, the authors concluded that there was no significant evidence to support a clinical benefit, so this treatment remains controversial.²⁶ Patients with TEN may develop metabolic abnormalities, sepsis, multiorgan failure, pulmonary emboli, and GI hemorrhages. 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, EM major, linear IgA dermatosis, paraneoplastic pemphigus, acute graft-versus-host disease, drug-induced pemphigoid, pemphigus vulgaris, and acute generalized exanthematous pustulosis; however, discussion of some of these entities is beyond the scope of this chapter (Table 18–3).

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 may be clinically indistinguishable from autoimmune blistering diseases such as pemphigus vulgaris or bullous pemphigoid (Fig. 18–5). 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 can 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 DEJ (Table 18–3).

A number of medications, many of which contain a “thiol group” such as penicillamine and captopril, can 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. 18–1). Other xenobiotics, such as furosemide, penicillin, and sulfasalazine, produce tense bullae that resemble bullous pemphigoid. Direct immunofluorescence studies might show epidermal intracellular immunoglobulin deposits at the DEJ. Treatment options include stopping the offending xenobiotic and at times treating with immunosuppressants used to treat bullous pemphigoid and pemphigus vulgaris. The reaction may persist for up to 6 months after the offending xenobiotic is withdrawn.

Fixed Drug Eruption.

Fixed drug eruption is another bullous drug eruption that is characterized by well-circumscribed erythematous to dusky violaceous patches that may have central bullae or erosions and develops 1 to 2 weeks after first exposure to the drug. This reaction pattern is so named because reexposure to the xenobiotic causes lesions in the same area but typically within 24 hours of exposures (Fig. 18–6). Typical locations include the acral extremities, genitals, and intertriginous sites, and this process may be confused with TEN if widely confluent as in “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 earlier, EM can have a bullous variant that can also be confused with SJS/TEN.

Coma Bullae.

“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 may also be seen 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 may be observed. There is accompanying eccrine duct and gland necrosis.

Drug-Induced Hypersensitivity Syndrome

The drug hypersensitivity syndrome, also called drug reaction with eosinophilia and systemic symptoms (DRESS), can be severe and potentially life threatening. The skin may be involved with systemic immunologic diseases such that an alteration in the metabolism of certain xenobiotics leads to a hypersensitivity syndrome. The hypersensitivity syndrome is characterized by the triad of fever, skin eruption, and internal organ involvement.³¹ The frequency has been estimated between one in 1000 to one in 10,000 with anticonvulsants or sulfonamide antibiotic exposures and usually begins within 2 to 6 weeks after the initial exposure. For anticonvulsants, the inability to detoxify arene oxide metabolites has been suggested to be a key factor; after a patient has a documented drug-induced hypersensitivity syndrome to one anticonvulsant, it is important to note that cross-reactivity between phenytoin, carbamazepine, and phenobarbital is well documented, both in vivo and in vitro.⁴⁵ In the case of sulfonamides, acetylator phenotype and lymphocyte 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.³³ Fever and a cutaneous eruption are the most common symptoms. Accompanying malaise, pharyngitis, and cervical lymphadenopathy may also be present. Atypical lymphocytes and eosinophilia occur initially. The exanthem is initially generalized and morbilliform, and conjunctivitis and angioedema may occur (Fig. 18–7). Later the eruption becomes edematous and facial edema, which is often present, is a hallmark of this syndrome. 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 death associated with this syndrome. Colitis with bloody diarrhea and abdominal pain may occur. In addition to the aromatic anticonvulsants (phenobarbital, carbamazepine, and phenytoin), lamotrigine, allopurinol, sulfonamide antibiotics, dapsone, and the protease inhibitor abacavir have been implicated. Early withdrawal of the offending xenobiotic is crucial, and treatment is generally supportive.^40,63 If cardiac or pulmonary involvement is present, systemic corticosteroids are often recommended; however, their benefit on outcome has not been demonstrated, and relapse may occur during tapering, necessitating long-term courses of therapy.

Erythroderma

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; 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 can lead to erythroderma (Table 18–2). When ingested, boric acid can cause systemic toxicity in addition to a bright red eruption (“lobster skin”) usually followed within 1 to 3 days by a generalized exfoliation.⁵³

Vasculitis

Xenobiotic-induced vasculitis (Fig. 18–8) 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 18–2).⁵⁷ 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. Sometimes the reaction pattern can have edematous purpuric wheals (urticarial vasculitis), hemorrhagic bullae, or ulcerations. The underlying histopathology 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. This reaction pattern may be limited to the skin or may be more serious and 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 a hypersensitivity to a xenobiotic. Treatment consists of withdrawing the putative xenobiotic and systemic corticosteroid therapy if systemic involvement is present. A syndrome of vasculitis, neutropenia, and retiform purpura has been reported as a result of levamisole-adulterated cocaine.¹³ The earlobe is a common site of purpuric lesions from levamisole, and it is estimated that up to 70% of the cocaine and less than 3% of the heroin supply in the United States contained levamisole.^6,60,61

Purpura.

Purpura is the multifocal extravasation of blood into the skin or mucous membranes (Fig. 18–9). Ecchymoses are therefore considered to be purpuric lesions. Cytotoxic medications 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, and valproic acid, may cause purpura, as may thrombolytics. Anticoagulants, such as heparin and warfarin, may also result in purpura (Chaps. 22 and 60).

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. 18–10). The estimated risk is one in 10,000 persons. It is four times higher in women, especially if they are obese, with peaks in the 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. There may be bullae, ecchymosis, ulcers, and massive subcutaneous necrosis, usually in areas of abundant subcutaneous fat, such as the breasts, buttocks, abdomen, thighs, and calves. It may be associated with protein C or S deficiency, anticardiolipin antibody syndrome, and factor V Leiden mutations.⁴⁴ Treatment involves discontinuing the medication; administration of vitamin K; and, if warfarin induced, switching to heparin. Treatment may include fresh-frozen plasma and protein C. Skin grafting may be necessary if full-thickness necrosis occurs.

Contact Dermatitis

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 may be noted on areas in direct contact with the xenobiotic while the remaining areas are spared. Bullae may be present.

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, and 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. 18–11).³⁰

Many allergens are associated with contact dermatitis; a complete list is beyond the scope of this chapter. However, some common xenobiotics are listed in Table 18–2. 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. An important allergen that is becoming more ­frequent is paraphenylenediamine (PPD), 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 to PPD has been found to be 5.0%.⁶⁵ Management strategies commonly used are outlined in Table 18–4. A thorough history in addition to patch testing (the gold standard) will often identify the culprit.

Irritant dermatitis, although clinically indistinguishable 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. Irritant xenobiotics 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 can affect the lipid membrane of the keratinocyte, but others can 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. Treatment is similar to allergic contact dermatitis.

Photosensitivity Reactions

Photosensitivity may be 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 two types of xenobiotic-related photosensitivies, phototoxic and photoallergic.³⁹ 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 UV-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 can last for days to weeks with patients complaining of burning and stinging (Fig. 18–12). A subtype of phototoxic reaction includes phytophotodermatitis in which linear streaks of erythema occur after skin contact with furocoumarins from plants plus exposure to sunlight (Table 18–2). Photoallergic reactions occur less commonly, may occur after 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 antibacterial agents. 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). PABA is a sensitizing agent to many patients and is rarely included in current sunscreen products.

Sclerodermalike Reactions

A number of environmental xenobiotics are associated with localized or diffuse sclerodermalike reactions. Sclerodermatous refers to a tightened, indurated surface change of the skin that typically occurs on the face, hands, forearms, and trunk and is three times more common in women. This may 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 left untreated. The fibrotic process usually does not remit with removal of the external stimulus, and specific autoantibodies are absent. The association of sclerodermalike reactions with polyvinyl chloride manufacture is likely related to exposure to vinyl chloride monomer. Similar reports of this syndrome are associated with exposure to trichloroethylene and perchloroethylene, which are structurally similar to vinyl chloride. Epoxy resins, silica, and organic solvents have been implicated as environmental causes. The xenobiotics bleomycin, carbidopa, pentazocine, and taxanes are causative.

In Spain, patients exposed to imported rapeseed oil mixed with an aniline denaturant developed widespread cutaneous sclerosis. This became known as the “toxic oil syndrome.” A similar syndrome, after 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, paralysis, edema, arthralgias, alopecia, urticaria, mucinous yellow papules, and erythematous plaques.⁵⁴

Hair Loss

Xenobiotics have the potential to cause distinctive patterns of hair loss (Table 18–2). 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 medication or in the setting of systemic disease or altered physiologic states (eg, postpartum). Anagen toxicity is commonly associated with xenobiotic exposures such as to doxorubicin, cyclophosphamide, vincristine, and thallium.⁵⁶ Many antineoplastics reduce the mitotic activity of the rapidly dividing hair matrix cells, leading to the formation of a thin, easily breakable shaft. Thallium, a toxin classically associated with hair loss, causes alopecia by two mechanisms. Thallium distributes intracellularly, similar to 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 (Chap. 102). 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.

Nails

The nail consists of a horny layer the “nail plate” and four specialized ­epithelia: proximal nail fold, nail matrix, nailbed, and hyponychium. The nail matrix consists of keratinocytes, melanocytes, Langerhans cells, and Merkel cells.

Nail hyperpigmentation occurs for unclear reasons but may 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.⁵⁶ Black 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.

Nail findings may serve as important clues to xenobiotic exposures that have 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 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 nails at approximately 0.1 mm/d. 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.³⁴ Multiple Mees lines suggest multiple exposures over time. Arsenic, thallium, doxorubicin, vincristine, cyclophosphamide, methotrexate, and 5-fluorouracil are examples of xenobiotics that cause Mees lines, but Mees lines may be noted 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 nailfold. Beau lines present on multiple digits, especially at the same level on each nail, indicate a systemic illness or xenobiotic exposure (Fig. 18–13).

• The integument is constantly exposed to both topical and systemic xenobiotics, and these exposures may result in reactive dermatoses.

• Prompt examination of the skin, hair, and nails can 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.

Acknowledgment

Dina Began, MD, contributed to this chapter in previous editions.

References