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First_Aid_Step2. Steroid-sparing agents include mycophenolate mofetil and azathioprine. Recently, rituximab and IVIG have been successfully used for recalcitrant disease. An acquired blistering disease that leads to separation at the epidermal basement membrane. It is most commonly seen in patients 60–80 years of age. Its pathogenesis involves antibodies that are developed against the bullous pemphigoid antigen, which lies superficially in the basement membrane zone (BMZ). Antigen-antibody complexes activate complement and eosinophil degranulation that provoke an inﬂammatory reaction and lead to F IGU R E 2.2-7. Bullous pemphigoid. Multiple tense serous and partially hemorrhagic bullae can be seen. (Reproduced, with permission, from Fitzpatrick TB. Color Atlas & Synopsis of Clinical Dermatology, 4th ed. New York: McGraw-Hill, 2001: 100.) separation at the BMZ. The blisters are stable because their roof consists of nearly normal epidermis.


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First_Aid_Step2. Presents with firm, stable blisters that arise on erythematous skin, often preceded by urticarial lesions. Nikolsky’s sign is . The blisters form crusts and erosions (see Figure 2.2-7). Mucous membranes are less commonly involved than is the case in pemphigus. Diagnosed according to the clinical picture. Skin biopsy shows a subepidermal blister, often with an eosinophil-rich infiltrate. Immunoﬂ uorescence demonstrates linear IgG and C3 immunoglobulin and complement at the dermal-epidermal junction. Systemic corticosteroids. Topical corticosteroids can help prevent blister formation when applied to early lesions. A painful, recurrent vesicular eruption of the mucocutaneous surfaces due to infection with HSV. HSV-1 usually produces oral-labial lesions, whereas HSV-2 usually causes genital lesions. The virus spreads through epidermal cells, causing them to fuse into giant cells. The local host inﬂ ammatory response leads to erythema and swelling.


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First_Aid_Step2. The initial infection is passed by direct contact, after which the herpesvirus remains dormant in local nerve ganglia. 1° episodes are generally longer and more severe than recurrences. Onset is preceded by prodromal tingling, burning, or pain but can also present with lymphadenopathy, fever, discomfort, malaise, and edema of involved tissue. Recurrences are limited to mucocutaneous areas innervated by the involved nerve. Recurrent oral herpes (HSV-1): Typically consists of the common “cold sore,” which presents as a cluster of crusted vesicles on an erythematous base (see Figure 2.2-8A). It is often triggered by sun and fever. Recurrent genital herpes (HSV-2): Unilateral and characterized by a cluster of blisters on an erythematous base, but with less pain and systemic involvement than the 1° infection. Diagnosed primarily by the clinical picture. Multinucleated giant cells on Tzanck smear (see Figure 2.2-8B) yield a presumptive diagnosis.


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First_Aid_Step2. Diagnosed primarily by the clinical picture. Multinucleated giant cells on Tzanck smear (see Figure 2.2-8B) yield a presumptive diagnosis. VZV has the same appearance on Tzanck, so culture or direct ﬂ uorescent antibody staining is needed for definitive diagnosis. Dermatitis herpetiformis differs from HSV, consisting of pruritic papules and vesicles on the elbows, knees, buttocks, neck, and scalp. Granular IgA is seen on dermal papillae. The condition is associated with celiac disease (15–25% of celiac patients may have it). Treat with dapsone and a gluten-free diet. AB FIGURE 2.2-8. Herpes simplex. (A) 1° infection. Grouped vesicles on an erythematous base on the patient’s lips and oral mucosa may progress to pustules before resolving. (B) Tzanck smear. The multinucleated giant cells from vesicular ﬂuid provide a presumptive diagnosis of HSV infec tion. The Tzanck smear cannot distinguish between HSV and VZV infection. (Reproduced, with permission, from Hurwitz


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First_Aid_Step2. RM. Pathology of the Skin: Atlas of Clinical-Pathological Correlation, 2nd ed. Stamford, CT: Appleton & Lange, 1998: 145.) Oral or IV acyclovir (IV for severe cases or for immunocompromised patients) ↓ both the frequency and the severity of recurrences. Daily acyclovir, valacyclovir, or famciclovir suppressive therapy may be used in patients with > 6 outbreaks per year or for those with erythema multiforme. Acyclovir ointment is somewhat effective in reducing the duration of viral shedding but does not prevent recurrence. In AIDS patients, HSV can persist, with ulcers remaining resistant to antiviral therapy. Symptomatic HSV infection lasting > 1 month can be considered an AIDS-defining illness. VZV causes two different diseases, varicella and herpes zoster—with transmission occurring via respiratory droplet or by direct contact. VZV has an incubation period of 10–20 days, with contagion beginning 24 hours before the eruption appears and lasting until lesions have crusted.


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First_Aid_Step2. ■Varicella: A prodrome consisting of malaise, fever, headache, and myalgia occurs 24 hours before the onset of the rash. Pruritic lesions appear in crops over a period of 2–3 days, evolving from red macules to grouped central vesicles (“dewdrop on a rose petal”) and then crusting over. At any given time, patients have all stages of lesions over their entire body. The trunk, face, scalp, and mucous membranes are involved, but the palms and soles are spared. In adults, chickenpox is often more severe, with systemic complications such as pneumonia and encephalitis. Zoster: Herpes zoster represents the recurrence of VZV in a specific nerve, with lesions cropping up along the nerve’s dermatomal distribution. Outbreaks are usually preceded by intense local pain and then arise as grouped blisters on an erythematous base (see Figure 2.2-9).


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First_Aid_Step2. In immunocompromised patients, zoster can lead to severe local disease, disseminated cutaneous disease, and systemic diseases that mimic varicella. Older patients with severe zoster may develop postherpetic neuralgia. Diagnosed by the clinical picture. Varicella is self-limited in healthy children. A vaccine is available for infants, children, and adults and is routinely used for disease prevention. Adults should be treated with systemic acyclovir. Although acyclovir may speed the cutaneous course of zoster, pain control is most important for patients with this disease. A poxvirus infection that is most common in young children and in AIDS patients. It is spread by physical contact. ■The rash is composed of tiny waxy papules, frequently with central umbilication. In children, lesions are found on the trunk, extremities, or face If you see giant molluscum (see Figure 2.2-10). In adults, they are commonly found on the genitalia contagiosum, think HIV. and in the perineal region.


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First_Aid_Step2. and in the perineal region. FIGURE 2.2-9. Varicella zoster. The unilateral dermatomal distribution of the grouped vesicles on an erythematous base is characteristic. FIGURE 2.2-10. Molluscum contagiosum. The dome-shaped, ﬂeshy, umbilicated papule on the child’s eyelid is characteristic. (Repro duced, with permission, from Hurwitz RM. Pathology of the Skin: Atlas of Clinical-Pathological Correlation, 2nd ed. Stamford, CT: Appleton & Lange, 1998: 149.) In AIDS patients, lesions often appear on the face and can become quite large. Lesions are asymptomatic unless they become inﬂamed or irritated. Diagnosed by the clinical picture, and confirmed by expressing and staining the contents of the papules. Giemsa or Wright’s stain allows for the identification of large inclusion or molluscum bodies.


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First_Aid_Step2. Any local destructive method is effective, including curetting, freezing, or applying trichloroacetic acid to the lesions. Lesions resolve spontaneously over months to years and are often left untreated in children. Warts are caused by many different types of HPV and can occur on skin, mucous membranes, and other epithelia. Although usually benign, some subtypes of HPV (especially 16 and 18) lead to squamous malignancies. Spread is by direct contact. HPV leads to hyperproliferation of infected cells. Common warts are the most prevalent HPV infection. Although most often seen on the hands, they can occur anywhere. On plantar and palmar surfaces, warts tend to grow downward into the skin rather than outward, giving them a ﬂ atter appearance.


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First_Aid_Step2. The classic genital wart is a cauliﬂower-like papule or nodule appearing on the glans penis, the vulva, or the perianal region. Warts on mucous membranes are generally velvety and white, appearing on oral, genital, and even laryngeal mucosa. Laryngeal warts are transmitted to infants by mothers with genital HPV. Diagnosed by the clinical picture. Acetowhitening can be helpful in visualizing mucosal lesions. There is a long latency period, with children sometimes acquiring HPV at birth and not manifesting any lesions until years later. Treatment centers on destruction of the tissue by curettage, cryotherapy, or acid keratolytics. Genital warts are treated locally with podophyllin, trichloroacetic acid, imiquimod, or 5-FU. HPV lesions on the cervix must be monitored cytologically and histologically for evidence of malignancy.


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First_Aid_Step2. A superficial, weeping local infection that primarily occurs in children and is caused by both group A streptococcal and staphylococcal organisms. It is transmitted by direct contact. There are two types: Common type: Characterized by pustules and honey-colored crusts on an erythematous base; generally appears on the face (see Figure 2.211). Bullous type: Usually acral; characterized by large stable blisters. Bullous impetigo is almost always caused by S. aureus and can evolve into SSSS. Streptococcal impetigo can be complicated by acute streptococcal glomerulonephritis. FIGURE 2.2-11. Impetigo. What is another skin condition caused by group A strep? Erysipelas, which presents as a small red patch on the cheek that turns into a painful raised, shiny red plaque. Patients often have a history of trauma or pharyngitis. Treat with penicillin.


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First_Aid_Step2. Dried pustules with a superficial golden-brown crust are most commonly found around the nose and mouth. (Reproduced, with permission, from Hurwitz RM. Pathology of the Skin: Atlas of Clinical-Pathological Correlation, 2nd ed. Stamford, CT: Appleton & Lange, 1998: 165.) Scarlet fever: “Sunburn with goosebumps” appearance; strawberry tongue. Caused by S. pyogenes. Treatment: Penicillin. Salmonella typhi: Small pink papules on the trunk (“rose spots”) in groups of 10–20 plus gallbladder disease. Treatment: Cholecystectomy for chronic carrier state. Ludwig’s angina is a bilateral cellulitis of the submaxillary/ sublingual spaces that usually results from an infected tooth. It presents with dysphagia, drooling, fever, and a red, warm mouth and can lead to death from asphyxiation. Diagnosed by the clinical picture.


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First_Aid_Step2. Diagnosed by the clinical picture. Treat with antibiotics with antistaphylococcal activity. Topical antibiotics are often sufficient, but systemic agents can hasten recovery and prevent spread to other patients. An infection caused by Corynebacterium, presenting as brownish-red patches with fine scales that characteristically appear along major skin folds. It is more common among diabetics. Wood’s light exam reveals coral-red ﬂ uorescence of lesions. Gram staining reveals gram-, filamentous rods. Treat with erythromycin. (Remember: erythrasma is treated with erythromycin.) A deep, local infection involving the connective tissue, subcutaneous tissue, or muscle in addition to the skin. It is commonly caused by staphylococci or group A streptococci originating from an area of damaged skin or from a systemic source of infection. Community-acquired MRSA is an increasingly common cause. Risk factors include diabetes, IV drug use, venous stasis, and immune compromise.


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First_Aid_Step2. Presents with red, hot, swollen, tender skin. Fever and chills are also common. Diagnosed by the clinical picture; wound culture may aid in diagnosis and help determine antibiotic sensitivities for treatment. Blood cultures should be obtained when bacteremia is suspected. Culture and sensitivities are important in case of MRSA. Rule out abscess, urticaria, contact dermatitis, osteomyelitis, and necrotizing fasciitis. Treat with 7–10 days of oral antibiotics for mild cases or with IV antibiotics if there is evidence of systemic toxicity, comorbid conditions, DM, extremes of age, hand or orbital involvement, or other concerns. Deep infection along a fascial plane causing severe pain followed by anesthesia. Infection is caused by S. pyogenes or Clostridium perfringens. A history of trauma or a recent surgery to the affected area is often but not always elicited.


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First_Aid_Step2. Presents with sudden onset of pain and swelling at the site of trauma or recent surgery. Pain often progresses to anesthesia. An area of erythema quickly spreads over the course of hours to days. Margins move out into normal skin, and skin becomes dusky or purplish near the site of insult, ultimately leading to necrosis. Necrosis can initially have the appearance of undermining of the skin and subcutaneous layer; if the skin is open, gloved fingers can easily pass between the two layers to reveal yellow-green necrotic fascia (infection spreads quickly in deep fascia). The most important signs are tissue necrosis, a putrid discharge, bullae, severe pain, gas production, rapid burrowing through fascial planes, lack of classical tissue inﬂammatory signs, and intravascular volume loss. Local radiographs or CT scans show air in tissue. Biopsy from the edge of the lesion can be diagnostic. A surgical emergency. Early and aggressive surgical debridement is critical.


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First_Aid_Step2. Local radiographs or CT scans show air in tissue. Biopsy from the edge of the lesion can be diagnostic. A surgical emergency. Early and aggressive surgical debridement is critical. If Streptococcus is the principal organism involved, penicillin G is the drug of choice. Clindamycin is second line. For anaerobic coverage, give metronidazole or a third-generation cephalosporin. Inﬂammation of the hair follicle. Although typically caused by infection with Staphylococcus, Streptococcus, and gram-bacteria, folliculitis may occasionally be caused by yeast such as Candida albicans or Pityrosporum ovale. It may also be mechanical, arising from ingrown hairs (most common in patients with curly hair). Presents as a tiny pustule that appears at the opening of a hair follicle and usually has a hair penetrating it. When the infection is deeper, a furuncle, or hair follicle abscess, develops.


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First_Aid_Step2. Presents as a tiny pustule that appears at the opening of a hair follicle and usually has a hair penetrating it. When the infection is deeper, a furuncle, or hair follicle abscess, develops. Furuncles are larger and more painful than folliculitic lesions and may disseminate to adjacent follicles to form a carbuncle. Patients with diabetes or immunosuppression are at ↑ risk. Folliculitis can be a critical problem in AIDS patients, in whom the disease is intensely pruritic and resistant to therapy. Diagnosed by the clinical picture. Fournier gangrene is a form of necrotizing fasciitis that is localized to the scrotum and perineal area. leads to “hot tub folliculitis.” Ironically, erythromycin does not cause erythema with sun exposure. It is tetracycline and doxycycline that can cause serious photosensitivity!


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First_Aid_Step2. leads to “hot tub folliculitis.” Ironically, erythromycin does not cause erythema with sun exposure. It is tetracycline and doxycycline that can cause serious photosensitivity! Topical antibiotics can be used to treat mild disease, but severe cases require systemic antibiotics. Large lesions must be incised, drained, and cultured to rule out MRSA. Patients who are prone to ingrown hairs should be advised not to shave. An endogenous skin disease that is common among adolescents. The pathogenesis involves hormonal activation of sebaceous glands, the development of the comedo or plugged sebaceous follicle, and involvement of Propionibacterium acnes in the follicle, causing inﬂammation. Comedones may be caused by medications (e.g., lithium, corticosteroids) or by topical occlusion (e.g., cosmetics). There are three stages of acne lesions: Comedo: May be open (“blackheads”) or closed (“whiteheads”); present in large quantities but with little inﬂ ammation.


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First_Aid_Step2. There are three stages of acne lesions: Comedo: May be open (“blackheads”) or closed (“whiteheads”); present in large quantities but with little inﬂ ammation. Inﬂ ammatory: The comedo ruptures, creating a pustule that can be large and nodular. Scar: As the inﬂ ammation heals, scars may develop. Picking at papules exacerbates scarring. Two types of cysts can occur in acne: inﬂammatory cysts, which are large, ﬂuctuant pustules, and epidermoid cysts, which develop along the eyebrows and behind the ears. Acne first develops at puberty and typically persists for several years. Males are more likely to have severe, cystic acne than are females. Women in their 20s tend to have a variant that ﬂares cyclically with menstruation, featuring fewer comedones and more painful lesions on the chin. Androgenic stimulation may contribute to these lesions. Diagnosed by the clinical picture. Treat comedones with topical tretinoin (Retin-A) and benzoyl peroxide.


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First_Aid_Step2. Diagnosed by the clinical picture. Treat comedones with topical tretinoin (Retin-A) and benzoyl peroxide. Inﬂammatory lesions should be treated with topical antibiotics (e.g., erythromycin, clindamycin) or systemic agents (e.g., tetracycline, erythromycin). Isotretinoin (Accutane) leads to marked improvement in > 90% of acne patients and has greatly improved the treatment of severe acne. Isotretinoin is, however, a teratogen and may cause transient elevations in cholesterol, triglycerides, and LFTs, and it may also be associated with depression. Patients on isotretinoin are thus carefully monitored and are required to get monthly blood tests to check quantitative serum β-hCG (to rule out pregnancy), LFTs, cholesterol, and triglycerides. Monthly refills are contingent on completion of blood testing and evaluation by a dermatologist.


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First_Aid_Step2. Abscesses in the sacrococcygeal region that usually occur near the top of the natal cleft. Their name may not be appropriate, as not all such cysts contain hair, and not all are true cysts. Repetitive trauma to the region plays a role. The condition is thought to start as a folliculitis that becomes an abscess complicated by perineal microbes, especially Bacteroides. It most commonly occurs between the ages of 20 and 40, affecting men more often than women. Patients present with an abscess at the natal cleft that can be tender, ﬂ uctuant, warm, and indurated and is sometimes associated with purulent drainage or cellulitis. Systemic symptoms are uncommon, but cysts may develop into perianal fistulas. Risk factors include deep and hairy natal clefts, obesity, and a sedentary lifestyle. Diagnosed by the clinical picture. Rule out perirectal and anal abscess.


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First_Aid_Step2. Risk factors include deep and hairy natal clefts, obesity, and a sedentary lifestyle. Diagnosed by the clinical picture. Rule out perirectal and anal abscess. Treatment consists of incision and drainage of the abscess under local anesthesia followed by sterile packing of the wound. Abscesses should be allowed to heal by 2° intention. Antibiotics are not needed unless cellulitis is present; if they are prescribed, both aerobic and anaerobic coverage is required. Good local hygiene and shaving of the sacrococcygeal skin can help prevent recurrence. Patients should follow up with a surgeon. Caused by Malassezia furfur, a yeast that is part of the normal skin ﬂ ora (morphologic variants are Pityrosporum ovale and Pityrosporum orbiculare). It is unclear what leads the organism to overgrow on the skin surface and become a pathogen, but humid and sweaty conditions as well as host factors such as oily skin can contribute. Cushing’s syndrome and immunosuppression are also risk factors.


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First_Aid_Step2. Patients present with small, scaly patches of varying color, usually on the chest or back. Lesions may be hypopigmented as a result of interference with melanin production, or they may be hyperpigmented by virtue of thickened scale. Diagnosed by clinical impression, and confirmed by potassium hydroxide (KOH) preparation of scale that reveals a “spaghetti and meatballs” pattern of hyphae and spores. Treat lesions with topical selenium sulfide daily for one week, followed by application once weekly for prophylaxis. Commonly called “yeast infection” or “thrush,” candidiasis can be caused by any Candida species but is most commonly caused by C. albicans. In immune-competent patients, it typically presents as a superficial infection of the skin or mucous membranes in moist areas such as skin folds, armpits, the vagina, and below the breasts. Oral thrush is not uncommon among children, but in adults it is often a sign of a weakened immune system.


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First_Aid_Step2. Patients often have a history of antibiotic use, steroid use, or diabetes. Symptoms vary according to the site affected: Oral candidiasis: Presents with painless white plaques that cannot easily be scraped off. Candidiasis of the skin: Presents as pink, circular, erythematous macules that converge, with smaller satellite lesions seen nearby, often in skin folds. In infants, infection can often be seen in the diaper area and along the inguinal folds. Diagnosed by the clinical picture. Confirmed by KOH preparation of a scraping or swab of the affected area. KOH dissolves the skin cells but leaves the Candida untouched such that candidal hyphae and pseudospores become visible. Oral candidiasis: Oral ﬂuconazole; nystatin swish and swallow. Superficial (skin) candidiasis: Topical antifungals; keep skin clean and dry. Diaper rash: Topical nystatin.


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First_Aid_Step2. Oral candidiasis: Oral ﬂuconazole; nystatin swish and swallow. Superficial (skin) candidiasis: Topical antifungals; keep skin clean and dry. Diaper rash: Topical nystatin. Dermatophytes live only in tissues with keratin (i.e., the skin, nails, and hair) and are a common cause of infection. Causative organisms include Microsporum, Trichophyton, and Epidermophyton. The immune response to the dermatophyte, rather than the organism itself, is responsible for many of the symptoms. Pets are a reservoir for Microsporum. Other risk factors include diabetes, ↓ peripheral circulation, immune compromise, and chronic maceration of skin (e.g., from athletic activities). Presentation varies according to subtype: ■ Tinea corporis: Presents as a scaly, pruritic eruption with a sharp, irregular border, often with central clearing. May be seen in immunocompromised patients or in children following contact with infected pets.


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First_Aid_Step2. Tinea pedis/manuum: Presents as chronic interdigital scaling with erosions between the toes (“athlete’s foot”) or as a thickened, scaly skin on the soles. Asymmetric involvement of the hands is typical. Tinea cruris (“jock itch”): A chronic infection of the groin (typically sparing the scrotum) that is usually associated with tinea pedis. Tinea capitis (“ringworm”): A diffuse, scaly scalp eruption similar to seborrheic dermatitis. Diagnosed by the clinical picture; confirmed by scales prepared in KOH showing hyphae. Patients can be treated with topical or systemic antifungals. Tinea capitis must be treated with systemic drugs.


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First_Aid_Step2. Patients can be treated with topical or systemic antifungals. Tinea capitis must be treated with systemic drugs. Lice live off blood and on specific parts of the body, depending on their species. The head louse lives on the scalp and lays its eggs as nits attached to hair; the body louse lives in clothing and bites only the body. The pubic louse lives on pubic hair. Lice are spread through body contact or by the sharing of bedclothes and other garments. They secrete local toxins that lead to pruritus. Patients with lice often experience severe pruritus, and 2° bacterial infection of the excoriations is a risk. Classroom epidemics of head lice are common. Body lice are seen in people with inadequate hygiene or in those with crowded living conditions. Pubic lice (called “crabs” because of their squat, crablike body shape) contain anticoagulant in their saliva, so their bites often turn blue. Lice can be seen on hairs or in clothes.


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First_Aid_Step2. Lice can be seen on hairs or in clothes. Head lice: Treat with OTC pyrethrin (RID) and mechanical removal of nits. Body lice: Wash body, clothes, and bedding thoroughly. Treating the body with topical permethrin or pyrethrin may also be required. Pubic lice: Treat with RID. Caused by Sarcoptes scabiei, a tiny arthropod that mates on the skin surface, after which the female digs a passage into the stratum corneum and lays her eggs. The burrowing leads to pruritus that ↑ in intensity once an allergy to Other ulcers (all can be treated with specialized wound dressings): ■Venous stasis ulcers: Found near the lateral or medial malleolus, often in association with lower extremity edema. Treat with compression (Unna boots or compression stockings) and elevation. ■Arterial insufficiency ulcers: Found on the heel and tips of toes. Typically very painful. ■Neuropathic ulcers: Found on the underside of the foot and toes, usually at pressure points. Typically painless.


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First_Aid_Step2. ■Neuropathic ulcers: Found on the underside of the foot and toes, usually at pressure points. Typically painless. the mite or its products develops. Scabies mites are spread through close contact. Patients present with intense pruritus, especially at night and after hot showers. The most commonly affected sites are the hands, axillae, and genitals. On exam, the mite’s track can sometimes be seen along with erythematous, excoriated papules. 2° bacterial infection is common. A history of pruritus in several family members is suggestive. The mite may be identifiable by scraping an intact tunnel and looking under the microscope, but this is often difficult. Patients should be treated overnight with 1–2 applications of 5% permethrin from the neck down, and their contacts should be treated as well. Oral ivermectin is also effective. Pruritus may persist for two weeks after treatment, so symptomatic treatment should be provided.


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First_Aid_Step2. Result from ischemic necrosis following continuous pressure on an area of skin that restricts microcirculation to the area. Ulcers are most commonly seen in bedridden patients who lie in one spot for too long. An underlying bony prominence or lack of fat ↑ the likelihood of ulcer formation. Patients who lack mobility or cutaneous sensation are also at ↑ risk. Incontinence of urine or stool may macerate the skin, facilitating ulceration. Ulcers are graded by degree of damage: Grade I: Characterized by persistent redness. Grade II: Marked by ulceration. Grade III: Involves destruction of structures beneath the skin such as muscle or fat. Diagnosed by the history and clinical appearance. Prevention is key and involves routinely moving bedridden patients and using special beds that distribute pressure. Once an ulcer has developed, low-grade lesions can be treated with routine wound care, including hydrocolloid dressings. High-grade lesions require surgical debridement.


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First_Aid_Step2. Defined as necrosis of body tissue. There are three subtypes: dry, wet, and gas. The presence of one subtype does not exclude the others. Etiologies are as follows: Dry gangrene: Due to insufficient blood ﬂow to tissue, typically from atherosclerosis. Wet gangrene: Involves bacterial infection, usually with skin ﬂ ora. Gas gangrene: Due to Clostridium perfringens infection. Dry gangrene: Early signs are a dull ache, cold, and pallor of the ﬂ esh. As necrosis sets in, the tissue (usually a toe) becomes bluish-black, dry, and shriveled. Diabetes, vasculopathy, and smoking are risk factors. Wet gangrene: The tissue appears bruised, swollen, or blistered with pus. Gas gangrene: Typically occurs at a site of recent injury or surgery, presenting with swelling around the injury and with skin that turns pale and then dark red. Bacteria are rapidly destructive of tissue, producing gas that separates healthy tissue and exposes it to infection. A medical emergency.


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First_Aid_Step2. Diagnosed by clinical impression. Surgical debridement, with amputation if necessary, is the mainstay of treatment. Antibiotics alone do not suffice by virtue of inadequate blood ﬂow, but they should be given as an adjuvant to surgery. Gas gangrene can be treated with hyperbaric oxygen, which is toxic to the anaerobic C. perfringens. Susceptible patients should maintain careful foot care and should avoid trauma. A condition in which the skin in the intertriginous zones (genital and axillary regions and especially the nape of the neck) is hyperkeratotic and hyperpigmented with a velvety appearance (see Figure 2.2-12). Associated with DM, Cushing’s disease, HAIR-AN syndrome, and obesity. May also be a paraneoplastic sign of underlying adenocarcinoma (usually GI). Dx: Clinical appearance. Tx: May be treated with topical retinoids, but typically not treated. Patients should be encouraged to lose weight.


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First_Aid_Step2. Dx: Clinical appearance. Tx: May be treated with topical retinoids, but typically not treated. Patients should be encouraged to lose weight. A chronic inﬂammatory dermatosis involving the skin and mucous membranes. The condition is intensely pruritic, can be induced by drugs, and can be associated with HCV infection. Hx/PE: Presents with violaceous, ﬂat-topped, polygonal papules. Lesions may have Wickham’s striae (white stripes), especially on the mucous mem- Lichen planus is the “P” disease: Planar, Purple, Pruritic, Persistent, Polygonal, Penile, Perioral, Puzzling, and Koebner’s Phenomenon. FIGURE 2.2-12. Acanthosis nigricans. Velvety, dark brown epidermal thickening of the armpit is seen with prominent skin fold and feathered edges. (Reproduced, with permission, from Wolff K et al. Fitzpatrick’s Color Atlas &


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First_Aid_Step2. Velvety, dark brown epidermal thickening of the armpit is seen with prominent skin fold and feathered edges. (Reproduced, with permission, from Wolff K et al. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York: McGraw-Hill, 2005: 87.) branes (see Figure 2.2-13), as well as prominent Koebner’s phenomena (lesions that appear at the site of trauma). The initial lesions often appear on the genitalia, where they are ulcerated. ■Although most cases resolve spontaneously over 6–18 months, those with oral involvement have a more chronic course. Dx: Histology reveals a “lichenoid pattern”—i.e., a band of T lymphocytes at the epidermal-dermal junction with damage to the basal layer. Tx: Mild cases can be treated with topical corticosteroids. For severe disease, systemic corticosteroids may be used. Tretinoin gel may be helpful on oral mucosa.


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First_Aid_Step2. Tx: Mild cases can be treated with topical corticosteroids. For severe disease, systemic corticosteroids may be used. Tretinoin gel may be helpful on oral mucosa. A chronic disorder of pilosebaceous units. The disorder has a female predominance and is more common among those with fair skin. Its etiology is unclear. Patients are generally middle-aged and often have an abnormal ﬂ ushing response to various substances. Early in the disease, central facial erythema is seen with telangiectasias. Later, papules and pustules may develop. Associated findings include ocular keratitis and rhinophyma (sebaceous gland hyperplasia of the nose). FIGURE 2.2-13. Lichen planus. Flat-topped, polygonal, sharply defined papules of violaceous color are grouped and conﬂ uent. The surface is shiny and reveals fine white lines (Wickham’s striae). (Reproduced, with permis sion, from Wolff K et al. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 5th ed.


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First_Aid_Step2. The surface is shiny and reveals fine white lines (Wickham’s striae). (Reproduced, with permis sion, from Wolff K et al. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York: McGraw-Hill, 2005: 125.) Diagnosed by the clinical picture. Rosacea can be confused with acne but is not follicular in origin and involves an older age group. In a high percentage of patients, ↑ numbers of Demodex mites (which normally live harmlessly in hair follicles, especially in the facial area) are found on the facial skin and can be seen by microscopic examination of skin scrapings. Treat with low-potency topical corticosteroids or topical metronidazole. In more severe disease, systemic antibiotics may be used. Extremely severe cases can be treated with short-term oral metronidazole.


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First_Aid_Step2. An acute dermatitis that is pink and scaly. Its etiology is unknown, but it has been hypothesized to represent a reaction to a viral infection with human herpesvirus (HHV) 6 or 7 because it tends to occur in mini-epidemics among young adults. ■The initial lesion is a herald patch that is several centimeters in diameter and erythematous with a peripheral scale. Days to weeks later, a 2° exanthem appears, presenting with multiple tiny, symmetric papules with a fine “cigarette paper” scale (see Figure 2.2-14). Papules are arranged along skin lines, giving a classic “Christmas tree pattern” on the patient’s back. Patients are generally asymptomatic, although the disease may be more extensive, pruritic, and chronic among African-Americans. Diagnosed by clinical impression and confirmed by KOH exam to rule out fungus (the herald patch may be mistaken for tinea corporis). The differential also includes 2° syphilis (RPR should be ordered), guttate psoriasis, and drug eruptions.


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First_Aid_Step2. Patients usually heal without treatment in 2–3 weeks, but skin lubrication, topical antipruritics, and systemic antihistamines may occasionally be necessary. Severe cases can be treated with a short course of systemic corticosteroids. A disease of depigmentation whose pathogenesis is unknown. The mechanism may be autoimmune, neurologic, or both. ■ Patients develop small, sharply demarcated, depigmented macules or patches on otherwise normal skin, often on the hands, face, or genitalia. FIGURE 2.2-14. Pityriasis rosea. The round to oval erythematous plaques are often covered with a fine white scale (“cigarette paper”) and are often found on the trunk and proximal extremities. Plaques are often preceded by a larger herald patch (arrow). (Reproduced, with permission, from Hurwitz RM. Pathology of the Skin: Atlas of Clinical-Pathological Correlation, 2nd ed. Stamford, CT: Appleton & Lange, 1998: 13.)


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First_Aid_Step2. These spots then expand, sometimes in dermatomal patterns, to include large segments of skin. The disease is usually chronic and progressive, with some patients becoming completely depigmented. Many patients have serologic markers of autoimmune disease (e.g., antithyroid antibodies, DM, pernicious anemia) but seldom present with these diseases. Patients with malignant melanoma may develop an antimelanocyte immune response that leads to vitiligo. Diagnosed by the history and clinical picture, with histology demonstrating total absence of melanocytes. Conditions to rule out include postinﬂ ammatory hypopigmentation, scleroderma, piebaldism, and toxic exposure (pheno-lated cleansers are toxic to melanocytes).


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First_Aid_Step2. Topical or systemic psoralens and exposure to sunlight or PUVA may be helpful. Patients must wear sunscreen because depigmented skin lacks inherent sun protection. Dyes and makeup may be used to color the skin, or the skin may be chemically bleached to produce a uniformly white color. A very common skin tumor, appearing in almost all patients after age 40. The etiology is unknown. When many seborrheic keratoses erupt suddenly, they may be part of a paraneoplastic syndrome due to tumor production of epidermal growth factors. Lesions have no malignant potential but may be a cosmetic problem. Present as exophytic, waxy brown papules and plaques with prominent follicle openings (see Figure 2.2-15). Lesions often appear in great numbers and have a “stuck-on” appearance. Lesions may become irritated either spontaneously or by external trauma, “Seborrheic keratoses, or especially in the groin, breast, or axillae. Irritated lesions are smoother and SKs, look StucK on.” redder.


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First_Aid_Step2. Diagnosed by the clinical picture; can be confirmed by histology showing hyperplasia of benign, basaloid epidermal cells with horn pseudocysts (prominent follicular openings). Rule out actinic keratosis, lentigo (focal ↑ in melanocytes), squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). Cryotherapy or curettage is curative. A precursor of SCC in situ. Lesions are caused by exposure to sunlight. FIGURE 2.2-15. Seborrheic keratoses. Multiple brown, warty papules and nodules are seen on the back, characterized by a “stuck-on” appearance. (Reproduced, with permission, from Fitzpatrick TB. Color Atlas & Synopsis of Clinical Dermatology, 4th ed. New York: McGraw-Hill, 2001: 195.)


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First_Aid_Step2. Clinical Dermatology, 4th ed. New York: McGraw-Hill, 2001: 195.) Lesions appear on sun-exposed areas (especially the face and arms) and primarily affect older patients, who rarely have a solitary lesion. They are erythematous with a light scale that can become thick and crusted (see Figure 2.2-16). Early lesions may be difficult to visualize and may be easier to find by palpation. Diagnosed by clinical impression. Biopsy is seldom necessary but shows intraepidermal atypia over a sun-damaged dermis. The differential includes Bowen’s disease, a form of squamous cell carcinoma in situ. Cryosurgery, topical 5-FU, or topical imiquimod can be used to destroy the lesion. If carcinoma is suspected, biopsy followed by excision or curettage is appropriate. Patients should be advised to use sun protection. FIGURE 2.2-16. Actinic keratosis.


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First_Aid_Step2. FIGURE 2.2-16. Actinic keratosis. The discrete patch above has an erythematous base and a rough white scale. (Reproduced, with permission, from Hurwitz RM. Pathology of the Skin: Atlas of Clinical-Pathological Correlation, 2nd ed. Stamford, CT: Appleton & Lange, 1998: 359.) The second most common skin tumor, with locally destructive effects as well as the potential for metastasis and death. UV light is the most common causative factor, but exposure to chemical carcinogens, prior radiation therapy, and the presence of chronically draining infectious sinuses (as in osteomyelitis) also predispose patients to developing SCC. Most SCCs occur in older adults with sun-damaged skin, arising from actinic keratoses. ■SCCs have a variety of forms, and a single patient will often have multiple variants (see Figure 2.2-17). FIGURE 2.2-17. Squamous cell carcinoma.


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First_Aid_Step2. ■SCCs have a variety of forms, and a single patient will often have multiple variants (see Figure 2.2-17). FIGURE 2.2-17. Squamous cell carcinoma. Note the crusting and ulceration of this erythematous plaque. Most lesions are exophytic nodules with erosion or ulceration. (Reproduced, with permission, from Hurwitz RM. Pathology of the Skin: Atlas of Clinical-Pathological Correlation, 2nd ed. Stamford, CT: Appleton & Lange, 1998: 360.) Keratoacanthoma, a benign epithelial tumor, can look like SCC but develops more rapidly and may regress spontaneously. Treatment is usually similar to that of SCCs. ■SCCs that arise from actinic keratoses rarely metastasize, but those that arise on the lips and on ulcers are more likely to do so. SCC occurs on the lip far more commonly than does BCC. Diagnosed by clinical suspicion and confirmed by biopsy, which is necessary for accurate diagnosis and appropriate therapeutic planning.


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First_Aid_Step2. Diagnosed by clinical suspicion and confirmed by biopsy, which is necessary for accurate diagnosis and appropriate therapeutic planning. Histology shows intraepidermal atypical keratinocytes, with penetration of the basement membrane by malignant epidermal cells growing into the dermis. SCCs are graded histologically. Surgical excision. Lesions with high metastatic potential may require additional radiation or chemotherapy. The most common malignant skin tumor, BCC is slow growing and locally destructive but has virtually no metastatic potential. Chronic UV light exposure is the main risk factor. Multiple lesions on non-sun-exposed areas are suggestive of arsenic exposure or inherited basal cell nevus syndrome. Most lesions appear on the face and on other sun-exposed areas. There are many types of BCC with varying degrees of pigmentation, ulceration, and depth of growth (see Figure 2.2-18). FIGURE 2.2-18. Basal cell carcinoma.


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First_Aid_Step2. There are many types of BCC with varying degrees of pigmentation, ulceration, and depth of growth (see Figure 2.2-18). FIGURE 2.2-18. Basal cell carcinoma. Seen above is an erythematous, ﬂeshy, telangiectatic nodule with a translucent surface. (Reproduced, with permission, from Hurwitz RM. Pathology of the Skin: Atlas of Clinical-Pathological Correlation, 2nd ed. Stamford, CT: Appleton & Lange, 1998: 362.) Diagnosed by clinical impression; confirmed by biopsy showing islands of proliferating epithelium resembling the basal layer of the epidermis. The differential includes benign tumors, hypopigmented melanocytic nevi, melanoma, dermatitis, psoriasis, and Paget’s disease. Options include excision, curettage and electrodesiccation/cautery, deep cryotherapy, superficial radiation therapy, and Mohs’ surgery. Cure rates are > 95%.


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First_Aid_Step2. Options include excision, curettage and electrodesiccation/cautery, deep cryotherapy, superficial radiation therapy, and Mohs’ surgery. Cure rates are > 95%. The most common life-threatening dermatologic disease; incidence has been increasing throughout the world. Risk factors include short, intense bursts of sun exposure (especially in childhood and with intermittent exposure) and the presence of congenital melanocytic nevi, an ↑ number of nevi, or dysplastic nevi. Immunosuppression also ↑ risk. Some patients inherit a predisposition to melanoma with the familial atypical mole and melanoma (FAM-M) syndrome. There are several subtypes (see Table 2.2-4). Malignant melanomas usually begin in the epidermal basal layer, where melanocytes are normally found. The first growth phase is horizontal-intraepidermal, presenting with a lesion that is ﬂat but increasing in diameter (typical of lentigo maligna or melanoma in situ). Later, there is a vertical growth phase with dermal invasion.


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First_Aid_Step2. Lesion characteristics that are suggestive of melanoma include irregular pigment, irregular contour and border, nodule and ulcer formation, and changes in size/shape/color/contour/surface noted by the patient (see Figure 2.2-19). TABLE 2.2-4. Types of Melanoma Lentigo maligna Arises in a lentigo. Usually found on sun-damaged skin of the face. Superfcial spreading Typically affects younger adults, presenting on the trunk in men and on the legs in women. A relatively prolonged horizontal growth phase helps identify the disease early, when it is still conf ned to the epidermis. Nodular Lesions have a rapid vertical growth phase and appear as a rapidly growing reddish-brown nodule with ulceration or hemorrhage. Acral lentiginous Begins on the hands and feet as a slowly spreading, pigmented patch. Type most commonly seen in Asians and African-Americans. Amelanotic Presents as a lesion without clinical pigmentation. Extremely diffcult to identify. FIGURE 2.2-19. Melanoma.


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First_Aid_Step2. FIGURE 2.2-19. Melanoma. Note the asymmetry, border irregularity, color variation, and large diameter of this plaque. (Reproduced, with permission, from Hurwitz RM. Pathology of the Skin: Atlas of Clinical- Pathological Correlation, 2nd ed. Stamford, CT: Appleton & Lange, 1998: 432.) ■Malignant melanoma may metastasize, and 10% of patients with metastatic melanoma have no known 1° lesion. Metastasis may be local (to nearby skin), regional (between the original lesion and its regional lymph nodes), or distant (via lymphatic or hematogenous spread to almost every organ in the body). Early recognition and treatment are essential. All adults should be examined for lesions that are suspicious for melanoma according to the ABCDE criteria, which identify dysplastic nevi and superficial spreading melanoma (see mnemonic).


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First_Aid_Step2. The onset of pruritus is also an early sign of malignant change. An excisional biopsy should be performed on any suspicious lesion. Malignancy is determined histologically. Malignant melanomas are staged by Breslow’s thickness (depth of invasion measured in millimeters) and by tumor-node-metastasis (TNM) staging (see Table 2.2-5). Clark’s level is another classification system linking melanoma depth to prognosis (see Table 2.2-6). TABLE 2.2-5. TNM Staging of Melanoma T AB LE 2.2-6. Characterization of Melanoma by Clark’s Level Lesions confined to the skin are treated by excision with margins. Lymph node dissection is useful for staging but does not ↑ survival. Chemotherapy and radiation therapy may be used but are not likely to be successful. Malignant melanoma has the potential to relapse after several years; patients with early melanoma are at low risk for relapse but are at high risk for the development of subsequent melanomas. Patient surveillance is thus essential.


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First_Aid_Step2. A vascular proliferative disease that has been attributed to a herpesvirus, HHV8, which is also called Kaposi’s sarcoma–associated herpesvirus (KSHV). There are several types of KS: The classic variant is characterized by multicentric vascular macules and coalescent papules and plaques on the lower extremities. It usually occurs in the elderly, with a preponderance of cases in patients of Ashkenazi Jewish or Mediterranean descent. More disseminated cases occur in African KS (endemic KS) and in immunocompromised patients. Epidemic HIV-associated KS is an aggressive form of the disease, and although less common since the advent of HAART, it remains the most common HIV-associated malignancy. Diagnosed by history and clinical impression, which are confirmed by biopsy showing spindle cells (elongated tumor cells) with HHV-8 staining. The presence of the viral protein LANA in tumor cells can also be detected for diagnostic confirmation.


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First_Aid_Step2. Treatment is technically palliative. Local lesions may be treated with radiation or cryotherapy; surgery is not recommended. Widespread or internal disease is treated with systemic chemotherapy (anthracyclines, paclitaxil, or IFN-α). Not a fungus, but rather a slow, progressive neoplastic proliferation of T cells. Its pathogenesis is thought to be related to chronic immunostimulation that leads helper T cells to gather in the epidermis. Industrial exposure to irritating chemicals appears to ↑ risk. The disease is chronic and is more common in men than in women. The early lesion is a nonspecific, psoriatic-appearing plaque that is palpable and often pruritic. Stage I involves limited plaques, papules, and patches affecting < 10% BSA with no nodal involvement.


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First_Aid_Step2. Stage I involves limited plaques, papules, and patches affecting < 10% BSA with no nodal involvement. Stage II is characterized by limited or generalized skin involvement with palpable lymph nodes or one or more skin tumors with multicentric, often conﬂuent reddish-brown nodules (see Figure 2.2-20). Rarely, patients skip the plaque stage and present directly with tumors. Stage III is characterized by generalized erythroderma. FIGURE 2.2-20. Mycosis fungoides. Massive nodular infiltration of the face leads to a leonine facies. (Reproduced, with permission, from Fitzpatrick TB. Color Atlas & Synopsis of Clinical Dermatology, 4th ed. New York: McGraw-Hill, 2001: 541.) Stage IV is characterized by biopsy-lymph nodes or internal organ spread. Patients may have dermatopathic lymphadenopathy without actual tumor involvement of the node. However, the internal organs can be involved, including the nodes, liver, and spleen.


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First_Aid_Step2. Patients may have dermatopathic lymphadenopathy without actual tumor involvement of the node. However, the internal organs can be involved, including the nodes, liver, and spleen. Sézary’s syndrome is the leukemic phase of cutaneous T-cell lymphoma and is characterized by circulating Sézary cells in the peripheral blood, erythroderma, and lymphadenopathy. Diagnosed by clinical features and histology, with immunologic characterization and electron microscopy showing the typical Sézary or Lutzner cells (cerebriform lymphocytes). The early lesion is clinically indistinguishable from dermatitis, so histologic diagnosis is indicated for any dermatitis that is chronic and resistant to treatment. Once clinical tumors have evolved, histology is useful for showing the type of cells present. Stage I disease: Treat topically with steroids, retinoids, chemotherapy, or PUVA. Stage II disease: Treat systemically with retinoids, interferon, monoclonal antibodies, or chemotherapy.


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First_Aid_Step2. Stage I disease: Treat topically with steroids, retinoids, chemotherapy, or PUVA. Stage II disease: Treat systemically with retinoids, interferon, monoclonal antibodies, or chemotherapy. Photopheresis is the mainstay of treatment for many patients. For more extensive or advanced disease, radiation therapy is an effective option. Treatment modalities are often combined. Disorders of Glucose Metabolism 114 TYPE 1 DIABETES MELLITUS 114 TYPE 2 DIABETES MELLITUS 115 METABOLIC SYNDROME 117 Due to autoimmune pancreatic β-cell destruction leading to insulin deficiency and abnormal fuel metabolism. Classically presents with polyuria (especially nocturia), polydipsia, polyphagia, and rapid, unexplained weight loss. Patients may also present with ketoacidosis. Usually affects nonobese children or young adults. Associated with HLA-DR3 and -DR4. At least one of the following is required to make the diagnosis: A fasting (> 8-hour) plasma glucose of ≥ 126 mg/dL on two separate occasions.


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First_Aid_Step2. Associated with HLA-DR3 and -DR4. At least one of the following is required to make the diagnosis: A fasting (> 8-hour) plasma glucose of ≥ 126 mg/dL on two separate occasions. A random plasma glucose of ≥ 200 mg/dL plus symptoms. A two-hour postprandial glucose of ≥ 200 mg/dL after a glucose tolerance test on two separate occasions if the results of initial testing are equivocal. Insulin (see Table 2.3-1) and self-monitoring of blood glucose in the normal range (80–120 mg/dL). Higher blood glucose levels (≥ 200 mg/dL) can be tolerated, particularly in the very young, in light of the ↑ risk of hypoglycemia. Routine HbA1c testing (with a goal HbA1c < 8 in children), frequent BP checks, foot checks, annual dilated-eye exams, annual microalbuminuria screening, and a lipid profile every 2–5 years. TABLE 2.3-1. Types of Insulin


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First_Aid_Step2. TABLE 2.3-1. Types of Insulin Regular 30–60 minutes 2–4 hours 5–8 hours Humalog (lispro) 5–10 minutes 0.5–1.5 hours 6–8 hours NovoLog (aspart) 10–20 minutes 1–3 hours 3–5 hours Apidra (glulisine) 5–15 minutes 1.0–1.5 hours 1.0–2.5 hours NPH 2–4 hours 6–10 hours 18–28 hours Levemir (detemir) 2 hours No discernible peak 20 hours Lantus (glargine) 1–4 hours No discernible peak 20–24 hours a Combination preparations mix longer-acting and shorter-acting types of insulin together to provide immediate and extended coverage in the same injection (e.g., 70 NPH/30 regular = 70% NPH + 30% regular). Table 2.3-2 outlines the acute, chronic, and treatment-related complications of DM. A dysfunction in glucose metabolism that is best characterized as varying degrees of insulin resistance that may lead to β-cell burnout and insulin dependence. TABLE 2.3-2. Complications of DM


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First_Aid_Step2. Complications of treatment Dawn phenomenon Early-morning hyperglycemia caused by ↓ effectiveness of insulin and ↑ secretion of growth hormone (GH) and other hormones overnight. Move P.M. insulin closer to bedtime to treat. Acute complications Diabetic ketoacidosis (DKA) Hyperosmolar hyperglycemic state (HHS) Hyperglycemia-induced crisis that most commonly occurs in type 1 DM. Often precipitated by stress (including infections, MI, trauma, or alcohol) or by noncompliance with insulin therapy. May present with abdominal pain, vomiting, Kussmaul respirations, and a fruity, acetone breath odor. Patients are severely dehydrated with many electrolyte abnormalities and may also develop mental status changes. Treatment includes f uids, potassium, insulin, bicarbonate (if pH is < 7), and treatment of the initiating event or underlying disease process. Presents as profound dehydration, mental status changes, hyperosmolarity, and extremely high plasma glucose (> 600 mg/dL) without acidosis and


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First_Aid_Step2. of the initiating event or underlying disease process. Presents as profound dehydration, mental status changes, hyperosmolarity, and extremely high plasma glucose (> 600 mg/dL) without acidosis and with small or absent ketones. Occurs in type 2 DM; precipitated by acute stress (dehydration, infections) and often can be fatal. Treatment includes aggressive ﬂuid and electrolyte replacement and insulin. Treat the initiating event. Chronic complications Retinopathy (nonproliferative, proliferative) Diabetic nephropathy Neuropathy Macrovascular complications Appears when diabetes has been present for at least 3–5 years. Preventive measures include control of hyperglycemia and hypertension, annual eye exams, and laser photocoagulation therapy for retinal neovascularization. Characterized by glomerular hyperfltration followed by microalbuminuria. Preventive measures include ACEIs or ARBs and BP/glucose control. Peripheral, symmetric, sensorimotor neuropathy leading to burning pain, foot


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First_Aid_Step2. glomerular hyperfltration followed by microalbuminuria. Preventive measures include ACEIs or ARBs and BP/glucose control. Peripheral, symmetric, sensorimotor neuropathy leading to burning pain, foot trauma, infections, and diabetic ulcers. Treat with preventive foot care and analgesics. Late complications due to autonomic dysfunction include delayed gastric emptying, esophageal dysmotility, impotence, and orthostatic hypotension. Cardiovascular, cerebrovascular, and peripheral vascular disease. Cardiovascular disease is the most common cause of death in diabetic patients. The goal BP is < 130/< 75; ↓ LDL to < 100 mg/dL; ↓ triglycerides to < 150 mg/dL. Patients should also be started on low-dose ASA.


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First_Aid_Step2. ■Somogyi effect: Nocturnal hypoglycemia leading to a surge of counterregulatory hormones, leading in turn to hyperglycemia in the morning. ■Dawn phenomenon: Nocturnal secretion of GH leading to early-morning hyperglycemia. Patients typically present with symptoms of hyperglycemia. Onset is more insidious than that of type 1 DM, and patients often present with complications. Nonketotic hyperglycemia may be seen in the setting of poor glycemic control. Usually occurs in older adults with obesity (often truncal); has a strong genetic predisposition. Diagnostic criteria are the same as those for type 1 DM. Follow-up testing: Patients with no risk factors: Test at 45 years of age; retest every three years. Patients with impaired fasting glucose (> 110 mg/dL but < 126 mg/ dL): Follow up with frequent retesting. The goal of treatment is tight glucose control—i.e., blood glucose levels ranging from 80 to 120 mg/dL and HbA1c levels < 7. Treatment measures include the following:


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First_Aid_Step2. The goal of treatment is tight glucose control—i.e., blood glucose levels ranging from 80 to 120 mg/dL and HbA1c levels < 7. Treatment measures include the following: Diet, weight loss, and exercise. Oral agents (monotherapy or combination if uncontrolled): Sulfonylureas (glipizide, glyburide, and glimepiride): Insulin secretagogues. Hypoglycemia and weight gain are side effects. Meglitinides (repaglinide and nateglinide): Short-acting agents whose mechanism of action is similar to that of sulfonylureas. Metformin: Inhibits hepatic gluconeogenesis; ↑ peripheral sensitivity to insulin. Side effects include weight loss, GI upset, and, rarely, lactic acidosis. Contraindicated in the elderly (those > 80 years of age) and in patients with renal disease. Thiazolidinediones (the “glitazones”): ↑ insulin sensitivity. Side effects include weight gain, edema, and potential hepatotoxicity.


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First_Aid_Step2. Thiazolidinediones (the “glitazones”): ↑ insulin sensitivity. Side effects include weight gain, edema, and potential hepatotoxicity. α-glucosidase inhibitors: ↓ intestinal absorption of carbohydrates. Rarely used owing to the side effect of ﬂ atulence. DDP-4 inhibitors (sitagliptin): Inhibit the degradation of the endogenous enzyme that breaks down glucagon-like peptide 1 (GLP-1). Insulin (alone or in conjunction with oral agents). Incretins (exenatide): GLP-1 agonists. Injected subcutaneously. Delay absorption of food; ↑ insulin secretion and ↓ glucagon secretion. Side effects include nausea and (rarely) pancreatitis. Statins for hypercholesterolemia (goal LDL < 100); glucose control and fibric acid derivatives for hypertriglyceridemia. Strict BP control to < 130/80; ACEIs/ARBs are usually first-line agents. Antiplatelet agents (ASA) for patients at risk of cardiovascular disease or for those > 40 years of age.


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First_Aid_Step2. Strict BP control to < 130/80; ACEIs/ARBs are usually first-line agents. Antiplatelet agents (ASA) for patients at risk of cardiovascular disease or for those > 40 years of age. Regular screening for cardiovascular disease, nephropathy, retinopathy, neuropathy, and smoking cessation. See Table 2.3-2 for an outline of the complications of DM. Note that the presence of diabetes is equivalent to the highest risk for cardiovascular disease regardless of all other risk factors. Also known as insulin resistance syndrome or syndrome X. Associated with an ↑ risk of CAD and mortality from a cardiovascular event. Presents with abdominal obesity, high BP, impaired glycemic control, and dyslipidemia. Three out of five of the following criteria must be met: Abdominal obesity (↑ waist girth): > 40 inches in men and > 35 inches in women. Triglycerides ≥ 150 mg/dL. HDL < 40 mg/dL in men and < 50 mg/dL in women. BP ≥ 130/85 mmHg or administration of antihypertensive drugs.


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First_Aid_Step2. Triglycerides ≥ 150 mg/dL. HDL < 40 mg/dL in men and < 50 mg/dL in women. BP ≥ 130/85 mmHg or administration of antihypertensive drugs. Fasting glucose ≥ 100 mg/dL. Intensive weight loss, aggressive cholesterol lowering, and BP control. Metformin has been shown to slow the onset of diabetes in this high-risk population. Testing of Thyroid Function TFTs include the following (see also Table 2.3-3): ■TSH measurement: The single best test for assessing thyroid function. High TSH levels lead to 1° hypothyroidism; low TSH levels lead to thyrotoxicosis. ■Radioactive iodine uptake (RAIU) and scan: Determines the level of iodine uptake by the thyroid. Useful in differentiating thyrotoxic states, but has a limited role in determining malignancy. T AB LE 2.3-3. Common Thyroid Function Abnormalities In 1° endocrine disturbances, the gland itself is abnormal. In 2° endocrine disturbances, the HPA malfunctions.


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First_Aid_Step2. T AB LE 2.3-3. Common Thyroid Function Abnormalities In 1° endocrine disturbances, the gland itself is abnormal. In 2° endocrine disturbances, the HPA malfunctions. 1° hyperthyroidism ↓↑↑Graves’ disease, toxic multinodular goiter, toxic adenoma, amiodarone, molar pregnancy, postpartum thyrotoxicosis, postviral thyroiditis. 1° hypothyroidism ↑↓↓Hashimoto’s thyroiditis, hypothyroid phase of thyroiditis, iatrogenic factors (radioactive iodine thyroid ablation, excision with inadequate supplementation, external radiation, lithium, or amiodarone), iodine def ciency, inf ltrative disease. Thyroid storm is an acute, life-threatening form of thyrotoxicosis that may present with atrial f brillation, fever, and delirium. Admit to intensive care. TBG-elevating states that should not be treated include pregnancy, estrogen administration, infections, nephrotic syndrome, and anabolic steroid use.


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First_Aid_Step2. TBG-elevating states that should not be treated include pregnancy, estrogen administration, infections, nephrotic syndrome, and anabolic steroid use. Total T4 measurement: Not an adequate screening test. Ninety-nine percent of circulating T4 is bound to thyroxine-binding globulin (TBG). Total T4 levels can be altered by changes in levels of binding proteins. T3 resin uptake (T3RU): Used with total T4 or T3 to correct for changes in TBG levels (e.g., the free thyroxine index = total T4 × T3RU). Free T4 measurement: The preferred screening test for thyroid hormone levels; more useful for unstable thyroid states. Refers to causes of thyrotoxicosis (↑ levels of T3/T4 due to any cause) in which the thyroid overproduces thyroid hormone, including Graves’ disease, toxic multinodular goiter (also called Plummer’s disease), and toxic adenomas. Presents with weight loss, heat intolerance, nervousness, palpitations, ↑bowel frequency, insomnia, and menstrual abnormalities.


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First_Aid_Step2. Presents with weight loss, heat intolerance, nervousness, palpitations, ↑bowel frequency, insomnia, and menstrual abnormalities. Exam reveals warm, moist skin, goiter, sinus tachycardia or atrial f brillation, fine tremor, lid lag, and hyperactive reﬂ exes. Exophthalmos, pretibial myxedema, and thyroid bruits are seen only in Graves’ disease (see Figure 2.3-1). The initial test of choice is serum TSH level, followed by T4 levels and, rarely, T3 (unless TSH is low and free T4 is not elevated). See Table 2.3-3. AB F IGU R E 2.3-1. Physical signs of Graves’ disease. (A) Graves’ ophthalmopathy. (B) Pretibial myxedema. (Figure 2.3-1A reproduced, with permission, from the Pathology Education Instructional Resource [PEIR] digital library [ http://peir.


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First_Aid_Step2. (A) Graves’ ophthalmopathy. (B) Pretibial myxedema. (Figure 2.3-1A reproduced, with permission, from the Pathology Education Instructional Resource [PEIR] digital library [ http://peir. at the University of Alabama, Birmingham. Figure 2.3-1B reproduced, with permission, from Greenspan FS, Strewler GJ. Basic and Clinical Endocrinology, 5th ed. Stamford, CT: Appleton & Lange, 1997.) 1° therapy is radioactive 131I thyroid ablation; antithyroid drugs (methimazole or propylthiouracil) may also be used if radioactive iodine is not indicated. Thyroidectomy is rarely indicated. Give propranolol for adrenergic symptoms while awaiting the resolution of hyperthyroidism. Administer levothyroxine to prevent hypothyroidism in patients who have undergone ablation or surgery.


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First_Aid_Step2. Give propranolol for adrenergic symptoms while awaiting the resolution of hyperthyroidism. Administer levothyroxine to prevent hypothyroidism in patients who have undergone ablation or surgery. Hashimoto’s thyroiditis is the most common cause of hypothyroidism (see Table 2.3-3). Anti-TPO antibodies are . The second most common cause is iatrogenic. Myxedema coma refers to severe hypothyroidism with ↓ mental status, hypothermia, and other parasympathetic symptoms. Mortality is 30–60%. Presents with weakness, fatigue, cold intolerance, constipation, weight gain, depression, menstrual irregularities, and hoarseness. Exam may reveal dry, cold, puffy skin accompanied by edema, bradycardia, and delayed relaxation of DTRs. See Table 2.3-3. Uncomplicated hypothyroidism (e.g., Hashimoto’s disease): Administer levothyroxine. Myxedema coma: Treat with IV levothyroxine and IV hydrocortisone (if adrenal insufficiency has not been excluded).


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First_Aid_Step2. Myxedema coma: Treat with IV levothyroxine and IV hydrocortisone (if adrenal insufficiency has not been excluded). Inﬂammation of the thyroid gland. Common subtypes include subacute granulomatous, radiation-induced, autoimmune (lymphocytic, chronic, or Hashimoto’s), postpartum, and drug-induced (e.g., amiodarone) thyroiditis. The subacute form presents with a tender thyroid accompanied by malaise and URI symptoms. Other forms are associated with painless goiter. Thyroid dysfunction (typically thyrotoxicosis followed by hypothyroidism), with ↓ uptake on RAIU during the thyrotoxic phase. β-blockers for hyperthyroidism; levothyroxine for hypothyroidism. Subacute thyroiditis is usually self-limited; treat with NSAIDs or with oral corticosteroids for severe cases. TSH receptor antibodies are seen in patients with Graves’ disease. The most Popular is Papillary: Check calcitonin levels if medullary cancer is suspected.


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First_Aid_Step2. TSH receptor antibodies are seen in patients with Graves’ disease. The most Popular is Papillary: Check calcitonin levels if medullary cancer is suspected. Thyroid nodules are very common and show an ↑ incidence with age. Most are benign. Usually asymptomatic on initial presentation. Hyperfunctioning nodules present with hyperthyroidism and local symptoms (dysphagia, dyspnea, cough, choking sensation) and are associated with a family history (especially medullary thyroid cancer). An ↑ risk of malignancy is associated with a history of neck irradiation, “cold” nodules on radionuclide scan, male sex, age < 20 or > 70, firm and fixed solitary nodules, a family history (especially medullary thyroid cancer), and rapidly growing nodules with hoarseness. Check for anterior cervical lymphadenopathy. Carcinoma (see Table 2.3 4) may be frm and f xed. Medullary thyroid carcinoma is associated with multiple endocrine neoplasia (MEN) type 2 and familial medullary thyroid cancer.


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First_Aid_Step2. Medullary thyroid carcinoma is associated with multiple endocrine neoplasia (MEN) type 2 and familial medullary thyroid cancer. The best method of assessing a nodule for malignancy is f ne-needle aspiration (FNA), which has high sensitivity and moderate specificity. TFTs (TSH to exclude hyperfunction). Ultrasound determines if the nodule is solid or cystic; a radioactive scan determines whether it is hot or cold (cancers are usually cold and solid). Hot nodules are never cancerous and should not be biopsied. TABLE 2.3-4. Types of Thyroid Carcinoma


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First_Aid_Step2. TABLE 2.3-4. Types of Thyroid Carcinoma Papillary Represents 75–80% of thyroid cancers. The female-to-male ratio is 3:1. Slow growing; found in thyroid hormone–producing cells. Ninety percent of patients survive 10 years or more after diagnosis; the prognosis is worse in elderly patients or those with large tumors. Follicular Accounts for 17% of thyroid cancers; found in thyroid hormone– producing cells. Ninety percent of patients survive 10 years or longer after diagnosis; the prognosis is worse in elderly patients or those with large tumors. Medullary Responsible for 6–8% of thyroid cancers; found in calcitonin-producing C cells; the prognosis is related to degree of vascular invasion. Eighty percent of patients survive at least 10 years after surgery. Anaplastic Accounts for < 2% of thyroid cancers; rapidly enlarges and metastasizes. Ten percent of patients survive for > 3 years. a Tumors may contain mixed papillary and follicular pathologies.


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First_Aid_Step2. Benign FNA: Follow with physical exam/ultrasound or a trial of levothyroxine suppression treatment. Malignant FNA: Surgical resection is first-line treatment; adjunctive radioiodine ablation following excision is appropriate for follicular lesions. Indeterminate FNA: Remove the nodule by surgical excision and wait for final pathology. Medullary thyroid cancer has a poorer prognosis than papillary and follicular types. Anaplastic thyroid cancer has an extremely poor prognosis. Associated with autosomal-dominant inheritance. Subtypes are as follows: MEN type 1 (Wermer’s syndrome): Pancreatic islet cell tumors (e.g., Zollinger-Ellison syndrome, insulinomas, VIPomas), parathyroid hyperplasia, and pituitary adenomas. MEN type 2A (Sipple’s syndrome): Medullary carcinoma of the thyroid, pheochromocytoma or adrenal hyperplasia, parathyroid gland hyperplasia.


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First_Aid_Step2. MEN type 2A (Sipple’s syndrome): Medullary carcinoma of the thyroid, pheochromocytoma or adrenal hyperplasia, parathyroid gland hyperplasia. MEN type 2B: Medullary carcinoma of the thyroid, pheochromocytoma, oral and intestinal ganglioneuromatosis (mucosal neuromas), marfanoid habitus. A common metabolic bone disease characterized by low bone mass and microarchitectural disruption, with bone mineral density > 2.5 SDs below normal peak bone mass. Most often affects thin, postmenopausal women (17%), especially Caucasians and Asians, with risk doubling (30%) after age 65. Commonly asymptomatic even in the presence of a vertebral fracture. Exam may reveal hip fractures, vertebral compression fractures (loss of height and progressive thoracic kyphosis), and/or distal radius fractures following minimal trauma (see Figure 2.3-2). Bone pain unrelated to fracture is most likely osteomalacia rather than osteoporosis.


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First_Aid_Step2. Bone pain unrelated to fracture is most likely osteomalacia rather than osteoporosis. Smoking, excessive caffeine or alcohol intake, a history of estrogen-depleting conditions (e.g., amenorrhea, eating disorders), thyroid dysfunction, and steroid use are all associated with an ↑ risk. DEXA: The gold standard; reveals significant osteopenia (bone mineral density < 2.5 SDs from normal peak level), most commonly in the vertebral bodies, proximal femur, and distal radius. Labs: Markers of bone turnover (↑ urinary N-telopeptides and deoxypyridinoline) can facilitate diagnosis in equivocal cases but are not routinely used; rule out 2° causes with TFTs, CMP, serum 25-hydroxyvitamin D, CBC, and testosterone (in men). X-rays: Global demineralization is apparent only after > 30% of bone density is lost. Osteoporosis is the most common cause of pathologic fractures in elderly, thin women. F IGU R E 2.3-2. Radiographic findings in osteoporosis.


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First_Aid_Step2. Osteoporosis is the most common cause of pathologic fractures in elderly, thin women. F IGU R E 2.3-2. Radiographic findings in osteoporosis. compression). (Reproduced, with permission, from Kasper DL et al. Harrison’s Principles of Internal Medicine, 16th ed. New York: McGraw-Hill, 2005: 2269.) Prevention with calcium supplementation and vitamin D. Smoking cessation and weight-bearing exercises help maintain bone density. Bisphosphonates (e.g., alendronate, risedronate, ibandronate, zoledronic acid), selective estrogen receptor modulators (e.g., raloxifene), and intranasal calcitonin may be used to prevent resorption and stabilize bone mineral density. Estrogen replacement therapy may be indicated for short-term treatment in the symptomatic perimenopausal period. Recombinant PTH may be used in patients with the highest level of risk.


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First_Aid_Step2. Estrogen replacement therapy may be indicated for short-term treatment in the symptomatic perimenopausal period. Recombinant PTH may be used in patients with the highest level of risk. Characterized by an ↑ rate of bone turnover. Causes both excessive resorption and excessive formation of bone, leading to a “mosaic” lamellar bone pattern. Suspected to be due to latent viral infection in genetically susceptible individuals. Found in roughly 4% of men and women > 40 years of age, and associated with 1° hyperparathyroidism in up to one-fifth of patients. Usually asymptomatic, but may present with aching bone or joint pain, headaches, skull deformities, fractures, or nerve entrapment (leads to loss of hearing in 30–40% of cases). Based on clinical history, characteristic radiographic changes (see Figure 2.33), and lab findings. F IGU R E 2.3-3. Radiographic findings in Paget’s disease. Skull of a 58-year-old woman with Paget’s disease of bone. (Reproduced, with permission, from


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First_Aid_Step2. F IGU R E 2.3-3. Radiographic findings in Paget’s disease. Skull of a 58-year-old woman with Paget’s disease of bone. (Reproduced, with permission, from Kasper DL et al. Harrison’s Principles of Internal Medicine, 16th ed. New York: McGraw-Hill, 2005: 2280.) Imaging: Radionuclide bone scan is the most sensitive test. Labs: Abnormalities include ↑ serum alkaline phosphatase with normal calcium and phosphate levels; urinary pyridinolines may be helpful. Must be differentiated from metastatic bone disease. The majority of patients are asymptomatic and require no treatment. There is no cure for Paget’s disease. Bisphosphonates and calcitonin are used to slow osteoclastic bone resorption; NSAIDs and acetaminophen can be given for arthritis pain. Pathologic fractures, cardiac complications, osteosarcoma (up to 1%).


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First_Aid_Step2. Pathologic fractures, cardiac complications, osteosarcoma (up to 1%). Eighty percent of 1° cases are due to a single adenoma and 15% to parathyroid hyperplasia. The most common 2° cause is phosphate retention in chronic kidney disease, which leads to renal osteodystrophy. 3° hyperparathyroidism occurs when chronic 2° hyperparathyroidism progresses to an unregulated state, resulting in hypercalcemia. Most cases are asymptomatic, but signs and symptoms may be mild and include stones (nephrolithiasis), bones (bone pain, myalgias, arthralgias, fractures), abdominal groans (abdominal pain, nausea, vomiting, PUD, pancreatitis), and psychiatric overtones (fatigue, depression, anxiety, sleep disturbances). Chronic renal insufficiency and gout are also associated with 1° hyperparathyroidism.


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First_Aid_Step2. Chronic renal insufficiency and gout are also associated with 1° hyperparathyroidism. Relative surgical criteria for hyperparathyroidism include age < 50, markedly ↓ bone mass, nephrolithiasis/renal insuff ciency, profoundly elevated serum calcium or life-threatening hypercalcemia, and urine calcium > 400 mg in 24 hours. Labs reveal hypercalcemia, hypophosphatemia, and hypercalciuria. Intact PTH is inappropriately ↑ relative to ionized calcium (see Table 2.3-5). Vitamin D deficiency may obscure mild cases. A radionuclide parathyroid scan may help with localization of an adenoma, although localization is not always necessary. Cancer is the most likely alternative diagnosis and must be ruled out, but with carcinoma PTH is usually < 25 pg/mL unless hyperparathyroidism is also present. Lithium and thiazides may exacerbate hyperparathyroidism.


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First_Aid_Step2. Parathyroidectomy if the patient is symptomatic or if certain criteria are met. For acute hypercalcemia, give IV fuids (with a loop diuretic in the setting of renal or heart failure), IV bisphosphonate, and calcitonin. Oral phosphate binders (aluminum hydroxide, calcium salts, sevelamer hydrochloride, and lanthanum carbonate) and dietary phosphate restriction are used in patients with 2° hyperparathyroidism regardless of dialysis status. Cinacalcet ↓ PTH as well as calcium and phosphate and may be a helpful adjunct in end-stage renal disease. Hypercalcemia is the most severe complication, presenting acutely with coma or altered mental status, bone disease, nephrolithiasis, and abdominal pain with nausea and vomiting.


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First_Aid_Step2. Hypercalcemia is the most severe complication, presenting acutely with coma or altered mental status, bone disease, nephrolithiasis, and abdominal pain with nausea and vomiting. The most common endogenous cause of Cushing’s syndrome is hypersecretion of ACTH from a pituitary adenoma (known as Cushing’s disease, or central hypercortisolism). Other endogenous causes include ectopic ACTH secretion from neoplasia (e.g., carcinoid tumor, small cell lung cancer) and excess adrenal secretion of cortisol (e.g., bilateral adrenal hyperplasia, adenoma, adrenal cancer). The condition is most commonly iatrogenic, resulting from treatment with exogenous corticosteroids. T AB LE 2.3-5. Functions and Mechanisms of PTH


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First_Aid_Step2. T AB LE 2.3-5. Functions and Mechanisms of PTH Chief cells of parathyroid ↑ bone resorption of calcium and phosphate. ↑ kidney resorption of calcium in the distal convoluted tubule. ↓ kidney resorption of phosphate. ↑ 1,25-(OH)2 vitamin D (cholecalciferol) production by stimulating kidney 1α-hydroxylase. PTH ↑ serum Ca2+, ↓ serum (PO4)3–, and ↑urine (PO4)3–. PTH stimulates both osteoclasts and osteoblasts. ↓ in free serum Ca2+ ↑ PTH secretion. Presents with hypertension, central obesity, muscle wasting, thin skin with purple striae, psychological disturbances, hirsutism, moon facies, and “buffalo hump.” Exam reveals depression, oligomenorrhea, growth retardation, proximal weakness, acne, excessive hair growth, symptoms of diabetes (2° to glucose intolerance), and ↑ susceptibility to infection. Headache or cranial nerve deficits are also seen with increasing size of the pituitary mass. Diagnosis is as follows (see also Table 2.3-6):


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First_Aid_Step2. Diagnosis is as follows (see also Table 2.3-6): Begin with a screen: An elevated 24-hour free urine cortisol or evening salivary cortisol or a overnight low-dose dexamethasone suppression test is considered abnormal if A.M. cortisol is persistently elevated following overnight suppression. Distinguish ACTH-dependent from ACTH-independent causes: If late-afternoon ACTH levels are elevated, Cushing’s disease or ectopic ACTH is likely. Hyperglycemia, glycosuria, and hypokalemia may also be present. Surgical resection of the hypersecretory source (pituitary, adrenal). Pituitary radiotherapy may also be considered. Blockers of adrenal steroidogenesis (e.g., ketoconazole, aminoglutethimide) may be of benefit. Permanent hormone replacement therapy to correct deficiencies after treatment of the 1° lesion. An adult condition due to a benign pituitary GH adenoma. Children with excess GH production present with gigantism.


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First_Aid_Step2. An adult condition due to a benign pituitary GH adenoma. Children with excess GH production present with gigantism. ■ Presents with enlargement of the jaw, hands, and feet and coarsening of facial features. May lead to carpal tunnel syndrome, diastolic dysfunction, hypertension, and arthritis. T AB LE 2.3-6. Laboratory Findings in Cushing’s Syndrome For unknown reasons, patients with DI prefer ice-cold beverages. Bitemporal hemianopia may result from compression of the optic chiasm by a pituitary adenoma. Excess GH may also lead to glucose intolerance or diabetes. Imaging: MRI of the pituitary shows a sellar lesion. Labs: Screen by measuring insulin-like growth factor 1 (IGF-1) levels (↑with acromegaly); confirm the diagnosis with an oral glucose suppression test (GH levels will remain elevated despite glucose suppression; baseline GH is not a reliable test). Transsphenoidal surgical resection or external beam radiation of the tumor.


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First_Aid_Step2. Transsphenoidal surgical resection or external beam radiation of the tumor. Octreotide can be used to suppress GH secretion. Pegvisomant can be used to block GH receptors in refractory cases. Prolactinoma is the most common functioning pituitary tumor. Other pathologic causes include craniopharyngioma, irradiation, drugs (e.g., dopamine), and cirrhosis. Hx/PE: Hypogonadism is manifested by infertility, oligomenorrhea, or amenorrhea. Galactorrhea, gynecomastia, or bitemporal hemianopia may be prominent. Dx: The serum prolactin level is typically > 200 mg/mL. Tx: Dopamine agonists (f rst-line therapy): Cabergoline or bromocriptine. Surgery: Should be considered when medical treatment has failed, when the patient desires future pregnancies, or in the setting of visual field defects. Failure to concentrate urine as a result of central or nephrogenic ADH dysfunction. Subtypes are as follows:


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First_Aid_Step2. Failure to concentrate urine as a result of central or nephrogenic ADH dysfunction. Subtypes are as follows: Central DI: The posterior pituitary fails to secrete ADH. Causes include tumor, ischemia (Sheehan’s syndrome), traumatic cerebral injury, infection, and autoimmune disorders. Nephrogenic DI: The kidneys fail to respond to circulating ADH. Causes include renal diseases and drugs (e.g., lithium, demeclocycline). Presents with polydipsia, polyuria, and persistent thirst with dilute urine. Patients may present with hypernatremia and dehydration, but if given unlimited access to water, they are typically normonatremic. ■ During a water deprivation test, patients excrete a high volume of dilute urine. Desmopressin acetate (DDAVP), a synthetic analog of ADH, can be used to distinguish central from nephrogenic DI. Central DI: DDAVP challenge will ↓urine output and ↑urine osmolarity. Nephrogenic DI: DDAVP challenge will not significantly ↓ urine output.


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First_Aid_Step2. Central DI: DDAVP challenge will ↓urine output and ↑urine osmolarity. Nephrogenic DI: DDAVP challenge will not significantly ↓ urine output. MRI may show a pituitary or hypothalamic mass in central DI. Treat the underlying cause. Central DI: Administer DDAVP intranasally or orally. Nephrogenic DI: Salt restriction and water intake are the 1° treatment. Thiazide diuretics are used to promote mild volume depletion and to stimulate proximal reabsorption of salt and water. A common cause of euvolemic hyponatremia that results from stimulated ADH release independent of serum osmolality. Associated with CNS disease (e.g., head injury, tumor), pulmonary disease (e.g., sarcoid, pneumonia), ectopic tumor production/paraneoplastic syndrome (e.g., small cell carcinoma), drugs (e.g., antipsychotics, antidepressants), or surgery.


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First_Aid_Step2. Diagnose on the basis of a urine osmolality > 50–100 mOsm/kg with concurrent serum hyposmolarity in the absence of a physiologic reason for ↑ADH (e.g., CHF, cirrhosis, hypovolemia). Urinary sodium ≥ 20 mEq/L demonstrates that the patient is not hypo-Fluid restriction is the volemic. cornerstone of SIADH treatment. Restrict f uid and address the underlying cause. If hyponatremia is severe (< 110 mEq/L) or if the patient is significantly symptomatic (e.g., comatose, seizing), cautiously give hypertonic saline. Demeclocycline can help normalize serum sodium by antagonizing the action of ADH in the collecting duct. Chronic correction depends on treatment of the underlying disorder. Tolvaptan (a vasopressin agonist) can be used to treat refractory chronic cases.


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First_Aid_Step2. Chronic correction depends on treatment of the underlying disorder. Tolvaptan (a vasopressin agonist) can be used to treat refractory chronic cases. May be 1° or 2°. Etiologies are as follows: ■ 1°: ■Most commonly caused by autoimmune adrenal cortical destruction (Addison’s disease), leading to deficiencies of mineralocorticoids and glucocorticoids. Autoimmune destruction may occur as part of a The 4 S’s of adrenal crisis management: Salt: 0.9% saline Steroids: IV hydrocortisone 100 mg q 8 h Search for the underlying illness Do not delay in giving steroids when diagnosing a patient with AI. polyglandular autoimmune syndrome (hypothyroidism, type 1 DM, vitiligo, premature ovarian failure, testicular failure, pernicious anemia). ■Other causes of 1° AI include congenital enzyme deficiencies, adrenal hemorrhage, TB, and other infections. ■ 2°: Caused by ↓ ACTH production by the pituitary; most often due to cessation of long-term glucocorticoid treatment.


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First_Aid_Step2. ■ 2°: Caused by ↓ ACTH production by the pituitary; most often due to cessation of long-term glucocorticoid treatment. Most symptoms are nonspecific. Weakness, fatigue, and anorexia with weight loss are common. GI manifestations, hypotension, and salt craving are also seen. Hyperpigmentation (due to ↑ ACTH secretion) is seen in Addison’s disease, especially in areas of sun exposure or friction. Labs show hyponatremia and eosinophilia (1° or 2°). Hyperkalemia is specific to 1° AI. Hypercalcemia is seen in up to one-third of cases. Diagnosis is confirmed with plasma cortisol levels: Low plasma cortisol levels (< 20 μg/dL) during a period of high physiologic stress is confirmatory. A random plasma cortisol level > 20 μg/dL excludes the diagnosis. Confrmatory test with synthetic ACTH stimulation test: A plasma cortisol level > 20 μg/dL excludes the diagnosis. Glucocorticoid replacement, with mineralocorticoid replacement if 1°.


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First_Aid_Step2. Confrmatory test with synthetic ACTH stimulation test: A plasma cortisol level > 20 μg/dL excludes the diagnosis. Glucocorticoid replacement, with mineralocorticoid replacement if 1°. In adrenal crisis, correct electrolyte abnormalities as needed; provide 50% dextrose to correct hypoglycemia; and initiate volume resuscitation. ■↑ steroids during periods of stress (e.g., major surgery, trauma, infection). Avoid 2° AI by tapering steroids slowly. A tumor of chromaffin tissue found either in the adrenal medulla or in extra-adrenal sites that secrete catecholamines. May be associated with von Hippel–Lindau syndrome, neurofibromatosis, or MEN 2 syndromes. Hx/PE: Presents with intermittent tachycardia, palpitations, chest pain, diaphoresis, hypertension, headache, tremor, and anxiety. Crises may be precipitated by anesthesia.


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First_Aid_Step2. Hx/PE: Presents with intermittent tachycardia, palpitations, chest pain, diaphoresis, hypertension, headache, tremor, and anxiety. Crises may be precipitated by anesthesia. Dx: CT or MRI often demonstrates a suprarenal mass. Screen with plasma-free metanephrines (metanephrine and normetanephrine) or 24hour urine metanephrines. MIBG scan is sometimes helpful. Tx: Surgical resection. Preoperatively, use α-adrenergic blockade f rst to control hypertension, followed by β-blockade to control tachycardia. Never give β-blockade first; otherwise, unopposed α-adrenergic stimulation will lead to refractory hypertension. Results from excessive secretion of aldosterone from the zona glomerulosa of the adrenal cortex. It is usually due to adrenocortical hyperplasia (70%) but can also result from unilateral adrenal adenoma (Conn’s syndrome). Presents with hypertension, headache, polyuria, and muscle weakness. Tetany, paresthesias, and peripheral edema are seen in severe cases.


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First_Aid_Step2. Presents with hypertension, headache, polyuria, and muscle weakness. Tetany, paresthesias, and peripheral edema are seen in severe cases. Patients have diastolic hypertension without edema. Labs show hypokalemia, mild hypernatremia, metabolic alkalosis, hypomagnesemia, and an ↑aldosterone/plasma renin activity ratio (from hyposecretion of renin that fails to ↑ appropriately with volume depletion as well as from hypersecretion that does not suppress with volume expansion). CT or MRI may reveal an adrenal mass. Laparoscopic or open adrenalectomy for adrenal tumors (after correcting BP and potassium). Treat bilateral hyperplasia with spironolactone, an aldosterone receptor antagonist.


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First_Aid_Step2. Laparoscopic or open adrenalectomy for adrenal tumors (after correcting BP and potassium). Treat bilateral hyperplasia with spironolactone, an aldosterone receptor antagonist. A family of inherited disorders that lead to cortisol def ciency. Most cases are due to 21-hydroxylase defciency (autosomal recessive) that leads to ↓ cortisol production with elevated cortisol precursors (e.g., 17-OH progesterone). In severe cases, mineralocorticoid deficiency with salt wasting may develop. Other causes include 11and 17-hydroxylase deficiencies. Cortisol deficiency stimulates ACTH synthesis, leading to overproduction of adrenal androgens. Presents with ambiguous genitalia in female infants and virilization when manifested later in life. Also characterized by macrogenitosomia in male infants; precocious puberty (if manifested later in life); and hypertension (with 11and 17-hydroxylase deficiencies). Diagnosed by high levels of cortisol precursors and androgens found in blood and urine.


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First_Aid_Step2. Diagnosed by high levels of cortisol precursors and androgens found in blood and urine. Medical: Immediate fuid resuscitation and salt repletion. Administer cortisol to ↓ ACTH and adrenal androgens. Fludrocortisone is appropriate for severe 21-hydroxylase deficiency. Surgical: May be required in the case of ambiguous genitalia in female infants. Refer to the Gynecology chapter for information on the diagnosis and treatment of late-onset congenital adrenal hyperplasia. Assessment of Disease Frequency 132 Assessment of Diagnostic Studies 132 Assessment of Risk 134 Measures of Effect 135 Survival Curves 136 Treatment 136 Screening Recommendations 141 Causes of Death 143 Reportable Diseases 144 The prevalence of a disease is the number of existing cases in the population at a specifc moment in time. The incidence of a disease is the number of new cases in the disease-free population that develop over a period of time.


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First_Aid_Step2. The incidence of a disease is the number of new cases in the disease-free population that develop over a period of time. Prevalent cases are incident cases that have persisted in a population for various reasons: Prevalence = Incidence × Average duration of disease A prevalence study is one in which people in a population are examined for the presence of a disease of interest at a given point in time. The advantages of prevalence studies are as follows: They provide an effcient means of examining a population, allowing cases and noncases to be assessed all at once. They can be used as a basis for diagnostic testing. They can be used to plan which health services to offer and where. Their disadvantages include the following: One cannot determine causal relationships because information is obtained only at a single point in time. The risk or incidence of disease cannot be directly measured.


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First_Aid_Step2. One cannot determine causal relationships because information is obtained only at a single point in time. The risk or incidence of disease cannot be directly measured. Physicians often use tests to try to ascertain a diagnosis, but because no test is perfect, a given result may be falsely or (see Figure 2.4-1). When deciding whether to administer a test, one should thus consider both its sensitivity and its specif city. ■Sensitivity is the probability that a patient with a disease will have a test result. A sensitive test will rarely miss people with the disease and is therefore good at ruling people out. Incidence is measured with a cohort study; prevalence is measured with a prevalence study. As the mortality of a disease decreases, the prevalence of that disease increases (e.g., HIV infection). Another name for a prevalence study is a cross-sectional study. F IGU R E 2.4-1. Sensitivity, specificity, PPV, and NPV.


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First_Aid_Step2. Another name for a prevalence study is a cross-sectional study. F IGU R E 2.4-1. Sensitivity, specificity, PPV, and NPV. ■Specificity is the probability that a patient without a disease will have a test result. A specific test will rarely determine that someone has the disease when in fact they do not and is therefore good at ruling people in. The ideal test is both sensitive and specifc, but a trade-off must often be made between sensitivity and specif city. High sensitivity is particularly desirable when there is a signif cant penalty for missing a disease. It is also desirable early in a diagnostic workup, when it is necessary to reduce a broad differential. Example: An initial ELISA test for HIV infection. High specificity is useful for confrming a likely diagnosis or for situations in which false-results may prove harmful. Example: A Western blot confrmatory HIV test. Example: You search for your physician, Mary Adel, MD, in the local phone book.


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First_Aid_Step2. Example: You search for your physician, Mary Adel, MD, in the local phone book. Identifying all individuals named “Mary” would be a sensitive test, as anyone named Mary Adel would likely be included in the results. However, it is not specif c, as numerous other physicians would also be included. Remember the mnemonic “Snout”: High SENsitivity would allow one to rule out physicians not listed with this f rst name. Identifying only individuals with the full name “Mary Lucy Adel IV” is very specifc, since individuals not named Mary Adel are especially likely to be declined. However, it is not sensitive, as she may be overlooked if she is not listed by her complete name. Remember the mnemonic “SPin”: High SPecifcity would allow one to rule in physicians listed with this full name. Once a test has been administered and a patient’s result has been made available, that result must be interpreted through use of predictive values (or post-test probabilities):


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First_Aid_Step2. Once a test has been administered and a patient’s result has been made available, that result must be interpreted through use of predictive values (or post-test probabilities): The positive predictive value (PPV) is the probability that a patient with a test result truly has the disease. The more specifc a test, the higher its PPV. The higher the disease prevalence, the higher the PPV of the test for that disease. The negative predictive value (NPV) is the probability that a patient with a test result truly does not have the disease. The more sensitive a test, the higher its NPV. The lower the disease prevalence, the higher the NPV of the test for that disease. Another way to describe the performance of a diagnostic test involves the use of likelihood ratios (LRs), which express how much more or less likely a given test result is in diseased as opposed to nondiseased people: Diseased people with a test result Sensitivity Nondiseased people with a test result 1 − specif city


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First_Aid_Step2. Diseased people with a test result Sensitivity Nondiseased people with a test result 1 − specif city SnOUT: Sensitive tests rule OUT disease. SpIN: Specific tests rule IN disease. Because the predictive value of a test is affected by disease prevalence, it is advantageous to apply diagnostic tests to patients with an ↑ likelihood of having the disease being sought (i.e., an at-risk population). If a test has an LR of 1, it does not change the pretest probability of disease. If the LR is 10, it makes disease 45% more likely. If the LR is 0.1, disease is 45% less likely. Diseased people with a test result 1 − sensitivity Nondiseased people with a test result Specif city If you see a set of COworkers being followed over time, think COhort study. Cohort studies are also known as longitudinal studies or incidence studies.


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First_Aid_Step2. If you see a set of COworkers being followed over time, think COhort study. Cohort studies are also known as longitudinal studies or incidence studies. Knowledge of risk factors may be used to predict future disease in a given patient. Risk factors may be causal (immediate or distant causes of disease) or disease markers (in which removing the risk factor does not necessarily ↓ the likelihood of disease). Risk factors can be diffcult to discover for a variety of reasons, including the following: A disease may have a long latency period, with risky exposures remote and forgotten. A risky exposure may be so common that its impact is hard to discern. Disease incidence may be low, and it is hard to draw conclusions from infrequent events. Risk associated with any individual exposure is small and hard to parse out. There is seldom a close, constant relationship between a risk factor and a disease.


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First_Aid_Step2. Risk associated with any individual exposure is small and hard to parse out. There is seldom a close, constant relationship between a risk factor and a disease. The best way to determine whether an exposure actually ↑ disease risk is with a prospective study. The ideal study for risk factor assessment would be an experiment in which the researcher controls risk exposure and then relates it to disease incidence. Doing so, however, may be unethical as well as prohibitively intrusive, time consuming, and expensive. Instead, observational studies such as cohort or case-control studies are used to determine risk.


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First_Aid_Step2. In a cohort study, a group of people is assembled, none of whom have the outcome of interest (i.e., the disease), but all of whom could potentially experience that outcome. For each possible risk factor, the members of the cohort are classifed as either exposed or unexposed. All the cohort members are then followed over time, and rates of outcome events are compared in the two exposure groups. Advantages of cohort studies are as follows: They follow the same logic as the clinical question (if people are exposed, will they get the disease?). They are the only way to directly determine incidence. They can be used to assess the relationship of a given exposure to many diseases. In prospective studies, exposure is elicited without bias from a known outcome. The disadvantages of such studies include the following: They can be time consuming and expensive. Studies assess only the relationship of the disease to the few exposure factors recorded at the start of the study.