Chapter 151. Diabetes Mellitus and Other Endocrine Diseases

Epidemiology

Diabetes mellitus (DM) is a major cause of morbidity and mortality in the United States. More than 24 million Americans have the disease1, and approximately 11% ($92 billion) of all health care expenditures in the United States were directly attributable to the medical care of diabetes in 2002.2 Men and women diagnosed with diabetes at age 40 years are expected to lose 12 and 14 life-years, respectively.3 Major studies have shown that tight glycemic control decreases microvascular disease, i.e., retinopathy, neuropathy, nephropathy, however, coronary vascular disease, the major contributor to morbidity and mortality in patients with diabetes, showed no benefit from intensive glycemic control for patients with a known 10-year duration of diabetes. In one large randomized controlled trial with about a third of patients with known coronary artery disease, intensive glycemic control was, in fact, associated with an increase in mortality. Newly diagnosed type 2 diabetes appears to have long-term benefit from similar degrees of tight control.4 New guidelines for glycemic control (HbA1c <7%) attempt to balance this body of evidence. The data and guidelines have been recently reviewed.5 Tight glycemic control may have a beneficial effect on a subset of skin-related, diabetes-associated disorders, but evidence is generally lacking.

Diabetes is characterized by a state of relative or complete insulin deficiency, leading to gross defects in glucose, fat, and protein metabolism. In type 1 diabetes (formerly insulin-dependent DM), an insufficiency of insulin occurs through a gradual, immune mediated destruction of β islet cells in the pancreas, marked by autoantibodies. In type 2 diabetes (formerly noninsulin-dependent DM), chronic hyperglycemia occurs mainly through end-organ insulin resistance followed by a progressive decrease in pancreatic insulin release associated with aging. A fasting blood glucose level of ≥126 mg/dL or a random value of ≥200 mg/dL on two separate occasions confirms the diagnosis of diabetes. Diabetes may also now be diagnosed with an HbA1c level ≥6.5%. A genetic predisposition and a strong association with obesity exist in type 2 diabetes. In both types of diabetes, abnormalities of insulin and elevated blood glucose levels lead to metabolic, vascular, neuropathic, and immunologic abnormalities. Affected organs include the cardiovascular, renal, and nervous systems, the eyes, and the skin.

Etiology and Pathogenesis

Nearly all patients with diabetes have cutaneous findings related to their condition, including those listed in Box 151-1. Some diabetes-associated skin conditions are a direct result of the related metabolic changes such as hyperglycemia and hyperlipidemia. Progressive damage to the vascular, neurologic, or immune systems also contributes significantly to skin manifestations. The mechanisms for other diabetes-associated skin conditions remain unknown.

Hyperglycemia leads to nonenzymatic glycosylation (NEG) of various structural and regulatory proteins, including collagen. Although NEG occurs normally with aging, the process is greatly accelerated in diabetes.6,7 NEG leads to the formation of advanced glycation end products (AGEs) that are responsible for decreases in both acid solubility and enzymatic digestion of cutaneous collagen. Disorders such as diabetic thick skin and limited joint mobility (LJM) are thought to result directly from accumulation of AGEs.8 Studies show that the degree of cutaneous AGEs correlates strongly with retinopathy, nephropathy, and other microvascular complications of diabetes.9

Derangements of immunoregulatory mechanisms also occur in diabetes. Hyperglycemia and ketoacidosis diminish chemotaxis, phagocytosis, and bactericidal ability of white blood cells.10 Historically, infections were a major cause of death in the diabetic patient. This has changed dramatically with improved glucose control and antibiotic use. Despite these improvements, certain infections, such as malignant external otitis, necrotizing soft tissue infections, and the devastating disease of mucormycosis, occur more frequently in patients with diabetes.11

Metabolic abnormalities, including hyperinsulinemia, as is seen in early insulin-resistant type 2 diabetes, can contribute to cutaneous manifestations as well. The action of insulin on the insulin-like growth factor-1 (IGF1) receptor appears to mediate the abnormal epidermal proliferation and resulting phenotype of acanthosis nigricans.12 Dysregulated lipid metabolism occurs with diabetes-associated insulin deficiency. The activity of lipoprotein lipase (LPL) is directly dependent on insulin,13 making insulin central to the processing of triglyceride-rich chylomicrons and very-low-density lipoproteins. In insulin-deficient diabetic patients, defective lipid processing can lead to massive hypertriglyceridemia, manifesting in the skin as eruptive xanthomas. Naturally, disorders of lipid processing also play an integral role in the vasculopathies of diabetes.

Macro- and microangiopathy contribute significantly to the cutaneous complications of diabetes. In patients with diabetes, there is increased “leakiness” or vessel wall permeability, decreased vascular responsiveness to sympathetic innervation, and less ability to respond to thermal and hypoxemic stress.10 In combination with arteriosclerosis of large vessels, these microvascular abnormalities contribute to the formation of diabetic ulcers. In addition, a loss of cutaneous sensory innervation occurs with diabetes, predisposing patients to infection and injury. The loss of neuroinflammatory cell signaling plays a causal role in nonhealing, lower extremity ulcers.14 Patients with diabetes who lack lower extremity vibratory perception have a 15.5-fold increased probability of leg amputation.15

The cutaneous disorders associated with DM are characterized in the following section by disorders with evidence for metabolic, vascular, neurologic, or immunologic pathogenesis induced by glucose and insulin abnormalities and by disorders associated with diabetes, but without a clear pathogenesis (see below).

Acanthosis Nigricans

Epidemiology

Acanthosis nigricans is probably the most readily recognized skin manifestation of diabetes. Acanthosis nigricans is common in the general population, and most cases are linked to obesity and insulin resistance. In some cases, increased androgen production is also identified.16,17 Drug-related and idiopathic acanthosis nigricans or familial acanthosis nigricans have been reported.18 In general, though, acanthosis nigricans should be considered a prognostic indicator for developing type 2 diabetes.19 The prevalence of acanthosis nigricans varies among different ethnic groups. In one study, despite similar obesity rates, the prevalence was lower in whites (0.5%) and Hispanics (5%) than in African-American children (13%).17 This finding suggests a possible genetic predisposition or increased sensitivity of the skin to hyperinsulinemia among certain populations.19 Although historical data have emphasized the relationship between acanthosis nigricans and malignancy, a true association is rare. Only when the onset is particularly rapid, the clinical findings are florid, or in the nonobese or nondiabetic adult with acanthosis nigricans is an evaluation for malignancy beyond routine age appropriate screening warranted. In one author's experience with seeing more than 12,000 patients with cancer, only two developed acanthosis nigricans.20

Etiology and Pathogenesis

Advances are taking place in understanding the pathogenesis of acanthosis nigricans. Insulin clearly plays a central role in the presentation of acanthosis nigricans. In a subset of women with hyperandrogenism and insulin resistance with acanthosis nigricans, loss of function mutations in the insulin receptor or anti-insulin receptor antibodies can be found (type A and type B syndrome).21 It is postulated that excess growth factor stimulation in the skin causes the aberrant proliferation of keratinocytes and fibroblasts that results in the phenotype of acanthosis nigricans.16 In states of insulin resistance and hyperinsulinemia, acanthosis nigricans may result from excess insulin binding to IGF1 receptors on keratinocytes and fibroblasts.12 IGF1 receptors are expressed on basal keratinocytes and are upregulated in proliferative conditions.22 Studies show that high concentrations of insulin stimulate fibroblast proliferation through IGF1 receptors in vitro.23 Other members of the tyrosine kinase receptor family, including the epidermal growth factor receptor and the fibroblast growth factor receptor, have been implicated in acanthosis nigricans. Several genetic syndromes [Crouzon and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans)] with mutations in fibroblast growth factor receptor 3 result in acanthosis nigricans in the absence of hyperinsulinemia or obesity, implicating this growth factor receptor in the pathogenesis of acanthosis nigricans.22 In several reports of acanthosis nigricans associated with malignancy, evidence suggests that transforming growth factor-β released from the tumor cells may stimulate keratinocyte proliferation via the epidermal growth factor receptors.24,25 Support for the role of different growth factors in the pathogenesis of acanthosis nigricans continues to accrue.

In addition to the direct effects of hyperinsulinemia on keratinocytes, insulin also appears to augment androgen levels in women. High insulin levels stimulate the production of ovarian androgens and ovarian hypertrophy with cystic changes.21 Although associated with elevated androgen levels, the acanthosis nigricans in women with polycystic ovarian syndrome (PCOS) does not respond reliably to antiandrogen therapy, implicating the relative importance of hyperinsulinemia over hyperandrogenism in acanthosis nigricans. Several drugs have also been reported to cause acanthosis nigricans, including systemic glucocorticoids, nicotinic acid, and estrogens such as diethylstilbestrol.16

Clinical Findings: Cutaneous Lesions

Clinically, acanthosis nigricans presents as brown to gray-black papillomatous cutaneous thickening in the flexural areas, including the posterolateral neck, axillae, groin, and abdominal folds. The distribution is usually symmetric. The affected skin has a dirty, velvety texture. In some cases, oral, esophageal, pharyngeal, laryngeal, conjunctival, and anogenital mucosal surfaces may be involved. In general, however, the back of the neck is the most consistently and severely affected area19 (Fig. 151-1). The development of superimposed acrochordons in involved areas is well described (Fig. 151-2). In particularly florid cases, involvement on the back of the hands over the knuckles and even on the palms can be seen. When the palms are involved, the rugated appearance of the palmar surface has been called tripe palms and is usually associated with acanthosis nigricans seen in the setting of malignancy. In the majority of cases, the most important factor in diagnosing acanthosis nigricans is recognizing the usually associated hyperinsulinemia, which is a known risk factor for type 2 diabetes and the metabolic syndrome.

The histopathology of clinical lesions demonstrates papillomatosis and hyperkeratosis but minimal acanthosis. Hyperpigmentation of the basal layer has been variably demonstrated and the brown color of the lesions is attributed to the hyperkeratosis by most.26,27

Treatment

Treatment of acanthosis nigricans is generally ineffective. Topical treatment with calcipotriol,28 salicylic acid, urea, systemic, and topical retinoids have all been used with anecdotal success.29 When identifiable, treatment of the underlying cause may be beneficial. Improvement or resolution does occur with weight loss in some obese patients.12,16 Medications that improve insulin sensitivity, such as metformin, have a theoretic benefit. Removal of an offending medication generally results in clearance of the skin.30 In patients with acanthosis nigricans in association with malignancy, there is usually improvement following treatment of the underlying malignancy. The skin finding may present before or after the diagnosis of malignancy is made. When it is associated with malignancy, a tumor of intraabdominal origin, usually gastric, is seen in the majority of cases.31 It has been repeatedly described that patients’ skin improves with chemotherapy and remits with recurrences.

Diabetic Thick Skin

Several specific syndromes are associated with localized thickening of the skin in diabetes. The common underlying pathogenesis involves biochemical alterations in dermal collagen and mucopolysaccharides. The clinical syndromes are a result of increased deposition and improper degradation of these constituents, likely related to the formation of AGEs.

Limited Joint Mobility and Scleroderma-Like Syndrome

Diabetic LJM, or cheiroarthropathy, presents as tightness and thickening of the skin and periarticular connective tissue of the fingers, resulting in a painless loss of joint mobility. Initial involvement of the distal interphalangeal joints of the fifth digit usually progresses proximally to involve all fingers. Larger joints of the elbow, knee, and foot may be affected. The actual joint space, however, remains uninvolved, so that LJM is not a true arthropathy. This disorder is characterized by the “prayer sign,” which is an inability to approximate the palmar surfaces and interphalangeal joint spaces with the hands pressed together and fingers separated (Fig. 151-3). In addition to joint contractures, the skin may appear thickened, waxy, and smooth with apparent loss of adnexa, resembling skin changes in scleroderma.

Thirty to fifty percent of adult patients with type 1 diabetes have LJM, and it is common in type 2 diabetes as well. LJM is associated with increased duration of diabetes and poor glucose control.32,33 One longitudinal prospective study showed a 2.5-fold increase in the risk of LJM for every unit increase in the glycosylated hemoglobin.33 In addition, it appears that LJM may be correlated with the presence of microvascular disease.34

Most important, the evidence indicates that intensive insulin therapy is central in prevention and, possibly, treatment of LJM and scleroderma-like syndrome. Long-term tight glycemic control leads to decreased skin AGEs,9 and tight glycemic control is associated with delayed onset and severity of LJM.33 On the basis of improvements in diabetes management, a fourfold reduction in the frequency of LJM over the last 20 years was reported.35 Treatment for LJM is difficult and should focus on tight control of blood sugar as well as physical therapy to preserve active range of motion.

Although the scleroderma-like skin changes can occur independently, they often occur together with LJM in patients with diabetes. The scleroderma-like syndrome is not associated with systemic sclerosis but does correlate with the duration of diabetes, the severity of joint contractures, and retinopathy.36 It seems likely that the historical description of “diabetic hand syndrome” represents a combination of LJM and the scleroderma-like syndrome.

Scleredema Diabeticorum

(See Chapter 158)

Recognized in 1970 as a syndrome,37,38 scleredema of diabetes (scleredema diabeticorum) presents with the insidious onset of painless, symmetric induration and thickening of the skin on the upper back and neck. Spreading to the face, shoulders, and anterior torso may occur. The skin retains a nonpitting, woody, peau d'orange quality. Identical changes occur with postinfectious scleredema, usually associated with streptococcal pharyngitis. In scleredema associated with infection, however, the onset is often sudden, and the symptoms usually remit over time. Scleredema diabeticorum affects 2.5%–14% of patients with diabetes.39,40 Scleredema diabeticorum is a disease of long-standing diabetes associated with obesity. Most patients have type 2 diabetes. This disorder has not been reported in children.

The pathogenesis of scleredema diabeticorum is postulated to be unregulated production of extracellular matrix molecules by fibroblasts, leading to thickened collagen bundles and increased deposition of glycosaminoglycans (GAGs, mainly hyaluronic acid). Studies using in vitro fibroblast analysis from involved skin have variably demonstrated increased synthesis of GAGs and type I collagen.41 However, most of these reports involved nondiabetic patients with paraproteinemia and are based on small numbers of cases.

Patients with scleredema diabeticorum may experience decreased sensation to pain and light touch over the affected areas and difficulties with upper extremity and neck range of motion. Extreme cases may result in full loss of range of motion. Unlike in LJM and scleroderma-like syndrome, the presence of scleredema does not correlate with retinopathy, nephropathy, neuropathy, or principal vascular disease.39 However, no large-scale prospective studies have been done. Most patients with scleredema diabeticorum become insulin dependent are difficult to treat, and have multiple complications of diabetes.41 Treatment for scleredema diabeticorum is usually unsuccessful. Case reports describe treatment with radiotherapy, low-dose methotrexate, bath psoralen and ultraviolet A light (PUVA), extracorporeal photopheresis, factor XIII, and prostaglandin E1.38,42,43 Weight reduction and physical therapy to preserve range of motion may be useful.

Eruptive Xanthomas

(See Chapter 135)

Eruptive xanthomas present clinically as 1- to 4-mm, reddish-yellow papules on the buttocks and extensor surfaces of the extremities (Fig. 151-4). The lesions occur in crops and may coalesce into plaques over time. Although eruptive xanthomas are generally asymptomatic, there is often underlying severe hypertriglyceridemia (>1,000 mg/dL) and potentially undiagnosed diabetes. Histologic and biochemical studies show that lipoproteins (mainly chylomicrons) in the blood permeate cutaneous vessel walls and accumulate in macrophages in the dermis.44 Initially, triglycerides predominate in the skin lesions but, because triglycerides are mobilized more easily than cholesterol, the lesions contain progressively more cholesterol as they resolve.44 Whether this mechanism plays a role in the atherosclerosis of large arteries is unknown.

Insulin is an important regulator of LPL activity. The degree of enzymatic dysfunction and subsequent clearing of serum triglycerides is proportionate to the amount of insulin deficiency and hyperglycemia.13 Clearance of plasma lipoproteins depends on adequate insulin.45 In uncontrolled diabetes, this inability to metabolize and clear triglyceride-rich chylomicrons and very-low-density lipoproteins can lead to plasma triglyceride levels in the thousands. Uncontrolled diabetes is a common cause of massive hypertriglyceridemia.

In addition to eruptive xanthomas, triglyceride levels above 4,000 may cause lipemia retinalis. On funduscopic examination, lipemia retinalis appears as pale pink to white retinal arterioles and venules. The fundus may have a milky hue. Untreated, severe hypertriglyceridemia may also present clinically with abdominal pain, hepatosplenomegaly, pancreatitis, or dyspnea from decreased pulmonary diffusing capacity and abnormal hemoglobin oxygen affinity.46 Treatment of hypertriglyceridemia involves strict dietary fat restrictions and control of the underlying diabetes. LPL activity returns to normal after treatment with long-term insulin or oral glucose-lowering agents.13 The eruptive xanthomas respond rapidly and usually resolve completely in 6–8 weeks.47

Cutaneous Infections

In diabetic patients, there is not strong evidence for an increased susceptibility to infections in general, but several skin infections do occur more commonly, with greater severity, or with a greater risk for complications in patients with DM. Joshi et al have reviewed this subject.11

There is extensive research on the pathogenesis of immune dysfunction in diabetes. Although some studies could not detect defects at the cellular level,48 other studies show that leukocyte chemotaxis, adherence, and phagocytosis are impaired in patients with diabetes, especially during hyperglycemia and diabetic acidosis.49 Further studies show that cutaneous T-cell function and response to antigen challenge are also decreased in diabetes.11 Some of the skin infections which occur more commonly or more severely in diabetic patients are shown in Table 151-1.

Diabetic Ulcers

Epidemiology

Foot ulcers are a significant problem for patients with diabetes, occurring in 15%–25% of diabetic patients.50 Patients with diabetes have an estimated increased risk of lower extremity amputation that is 10–30 times greater than the general population. Lower extremity ulcers were the proximal cause of amputation in 67 of 80 patients (84%) in a study by Pecoraro et al.51 In diabetic patients with foot ulcers, 14%–24% will eventually undergo amputation.52 The attributable cost of treating a diabetic foot ulcer, excluding the cost of amputation, was estimated to be $28,000 in a 1999 US study.53

Etiology and Pathogenesis

Many of the factors previously described in this chapter contribute to the pathogenesis of diabetic ulcers. Peripheral neuropathy, pressure, and trauma are felt to play prominent roles in the development of diabetic ulcers. Neuropathy (associated with uncontrolled hyperglycemia) is one of the major predictors of diabetic ulcers.15 Patients with diabetes also suffer the loss of cutaneous sensory nerves.54 The subsequent diminished neuroinflammatory signaling via neuropeptides to keratinocytes, fibroblasts, endothelial cells, and inflammatory cells may adversely affect wound healing.55 Excessive plantar pressure develops from foot deformities (Charcot arthropathy), as a result of LJM related to NEG, and from callus formation. Ill-fitting shoes and socks were the most common reasons for foot ulcers in a study of 314 diabetic patients with ulcers.56 By wearing running shoes, patients with diabetes had a measurable reduction of calluses in one study.57 Callus formation is a sign of excess friction and often precedes foot ulcers. Once an ulcer develops, peripheral vascular disease and intrinsic wound healing disturbances contribute to adverse outcomes. Known factors associated with foot ulceration in the setting of diabetes include previous foot ulceration, prior lower extremity amputation, long duration of diabetes (>10 years), impaired visual acuity, onychomycosis, and poor glycemic control. Boyko and colleagues have recently published a prediction model for foot ulceration based on the relative contributions of these factors.58

Clinical Findings

Callus formation precedes necrosis and breakdown of tissue over bony prominences of feet, usually on great toe and sole, over first and/or second metacarpophalangeal joints. Ulcers are surrounded by a ring of callus and may extend to underlying joint and bone (Fig. 151-5). Complications are soft tissue infection and osteomyelitis.

Treatment

Treatment of diabetic ulcers requires modification of factors that contribute to ulcer formation, for example, stasis dermatitis, leg edema, and skin infection. Standard therapy for neuropathic diabetic ulcers includes debridement, off-loading (often nonweight bearing), moist wound care, and protective dressings (Fig. 151-6).

There has been substantial interest in developing adjunctive therapies for diabetic ulcers, including growth factors and skin-replacement products, but data have not supported their use as a replacement for standard wound care. Recombinant platelet-derived growth factor for the topical treatment of diabetic foot ulcers demonstrates a modest benefit if used with adequate off-loading, debridement, and control of infection.59 A large multicenter, clinical trial of a bilayered living skin equivalent60 showed 56% healing at 12 weeks as compared with 38% healing for standard care. The most favorable published results for a monolayered living skin equivalent and platelet-derived growth factor show roughly comparable improvement in healing to that reported for bilayered living skin equivalents when each is compared with standard care or placebo.60 These technologies await definitive analysis of cost effectiveness compared with standard older approaches. While studies available do not support the routine use of these biologic approaches they may have a role in the treatment of large ulcers (>2 cm) or ulcers poorly responsive to standard therapy. A recent meta-analysis makes the points that typically a higher percentage of ulcers heal during a 12-week study period with biologic products, but analysis of cost effectiveness is made difficult by differences in study designs, short duration of studies, different cost structures, the absence of quality of life measures and pharmaceutical funding of the primary studies and analysis.61

Prevention

Ulcer prevention is the most important intervention physicians and other health care professionals can provide for diabetic patients. An excellent review of ulcer prevention was published by Singh et al.50 Optimizing glycemic control is well supported to prevent the neuropathy that is so intimately associated with foot ulceration. In a recent study, the risk of a foot ulcer increased in nearly direct proportion to every 1% increase in hemoglobin A1C.58 Foot examination should be part of every patient visit if diabetes is on the problem list. Failure to perceive touch by a Semmes-Weinstein 10-g monofilament means a patient lacks protective sensation in the foot tested. If tinea pedis is present, it should be treated to prevent the associated skin barrier disruption. Smoking cessation should be encouraged. Patients should be counseled about the importance of daily foot care (Box 151-2).

Specialized ulcer care teams have published impressive results on the prevention and healing of ulcers.62 This multidisciplinary team approach is becoming more important in the treatment of diabetic ulcers in large population centers. Patients with a history of ulceration are at high risk for reulceration (34% at 1 year, 61% at 3 years, and 70% at 5 years).56 Intensifying education (formal foot care classes) and prevention efforts in this group along with lifelong surveillance is required.

Necrobiosis Lipoidica

Epidemiology and Pathogenesis

Coined by Urbach in 1932 as necrobiosis lipoidica diabeticorum, this disorder was named after characteristic histologic findings and was first described in patients with diabetes. Because not all patients have concurrent diabetes, the shortened term, necrobiosis lipoidica (NL) is preferred. Epidemiologic data show that the mean age of onset is around 30 years, with women representing three times more cases than men.63 The most often quoted statistics concerning the association of NL with diabetes are from a 1966 retrospective study at the Mayo Clinic. Of 171 patients with NL, two-thirds had diabetes at diagnosis, and another 5%–10% had glucose tolerance abnormalities.63 However, in a 1999 study of 65 patients with NL, only 11% had diabetes after 15 years of follow-up.64 Conversely, the prevalence of NL has been found to be only 0.3%–3.0% in patients with diabetes.63 Although lacking full concordance, NL definitely has a strong association with diabetes and remains a valid marker of the disease. The pathogenesis of this skin disease is unclear. Many etiologic mechanisms have been proposed and reviewed.65 Evidence suggests that the degree of hyperglycemia and diabetic control does not correlate with the presence of NL.66

Clinical Findings: Cutaneous Lesions

Classically, NL presents with one to several sharply demarcated yellow–brown plaques on the anterior pretibial region (Fig. 151-7). The lesions have a violaceous, irregular border that may be raised and indurated. Initially, NL often presents as red–brown papules and nodules that may mimic sarcoid or granuloma annulare (GA). Over time, the lesions flatten, and a central yellow or orange area becomes atrophic, and commonly telangiectasias are visible, taking on the characteristic “glazed-porcelain” sheen. Aside from the shins, other sites of predilection include ankles, calves, thighs, and feet. Fifteen percent of patients develop lesions on the upper extremities and trunk that tend to be more papulonodular. Although pain and pruritus have been reported, most lesions are asymptomatic. Anesthesia of the plaques does occur.67

The clinical course is often indolent, with spontaneous remission in less than 20% of cases.10 Over time, the plaques tend to stabilize, and formation of new lesions tapers off. However, the possibility of ulceration, a poor spontaneous remission rate, and cosmetic concerns lead patients to seek treatment. Ulceration, the most serious complication, occurs in approximately 13%–35% of cases on the legs.63,65 A few cases of squamous cell carcinoma arising in chronic ulcerative lesions of NL have been reported.68 Multiple reports document the association of NL with GA and sarcoidosis.69

Treatment

Treatment for NL is disappointing. At this time, only case reports and small, uncontrolled trials provide the basis for treatment decisions. Early application of potent topical glucocorticoids might slow progression.65 Although some authors63 report improvement with intralesional injection of glucocorticoids to the active border, the risk of ulceration with this treatment modality should be considered. A few case reports and one series of six patients70 showed benefit with short-term systemic glucocorticoids. Aspirin and dipyridamole have produced variable results.65 Anecdotal reports exist that support the use of topical retinoids and topical PUVA. Treatment with fumaric acid esters in 18 patients was reported to improve lesions clinically and histologically.71

Given the generally benign nature of the lesions, physicians should consider the adage “do no harm.” Focus should be on prevention of ulcers. When ulceration occurs in patients with NL, the same wound care principles apply as for all diabetic ulcers. Healing of ulcerated lesions with cyclosporine has been demonstrated in several patients.72 Surgical excision down to fascia and split-thickness skin grafting remain as the last resort for very recalcitrant ulcers in NL.73

Granuloma Annulare

(See Chapter 44)

Epidemiology and Pathogenesis

The association of GA with diabetes is weaker than that of NL. Although most patients with GA are in good health, without underlying systemic illness, an association with diabetes is supported in the literature. Dabski and Winkelmann74 found diabetes in 10% of 1,353 patients with localized GA and 21% of 100 patients with generalized GA. An additional small retrospective case-control study showed an increased prevalence of diabetes among patients with GA (18%) as compared with the prevalence in age-matched controls (8%).75 Furthermore, there is an impression that diabetes is found more frequently in patients with adult onset GA and in those with generalized or perforating GA, and that these patients tend to experience a more chronic, relapsing course of GA. The pathogenesis is unclear.

Clinical Findings and Treatment

Clinical findings and treatment of GA are discussed in Chapter 44.

Diabetic Dermopathy

Etiology and Pathogenesis

Atrophic skin lesions of the lower extremity, or shin spots, were first characterized and proposed as a cutaneous marker for diabetes in 1964.76 Shortly after, Binkley coined the term diabetic “dermopathy” to correlate the pathologic changes with those of retinopathy, nephropathy, and neuropathy77 Since that time, controversy has existed about the disorder's etiology, specificity for diabetes, and association with other microangiopathic complications of diabetes.

The prevalence of shin spots in ambulatory patients with diabetes varies. In a population-based study from Sweden, diabetic dermopathy was found in 33% of patients with type 1 diabetes and in 39% of patients with type 2 diabetes, compared with 2% of controls.78 In other studies, the prevalence rate for individuals without diabetes ranges from 1.5% for healthy medical students to 20% for a group of nondiabetic endocrine patients.79 Diabetic dermopathy occurs more often in patients with an increased duration of diabetes and is more frequent in men.79

It is likely that the lesions are related to antecedent trauma. Lithner80 induced diabetic dermopathy on the legs of diabetic patients with heat and cold injury, whereas nondiabetic control subjects healed without residual change. When questioned, most patients think that the changes are caused by injury, but they are often unable to detail preceding trauma.

Clinical Findings, Diagnosis, and Treatment

Diabetic dermopathy presents as small (<1 cm), atrophic, pink to brown, scar-like macules on the pretibial areas (Fig. 151-8). The lesions are asymptomatic and clear within 1–2 years with slight residual atrophy or hypopigmentation.77 The appearance of new lesions gives the sense that the pigmentation and atrophy are persistent.

An association seems to exist between diabetic dermopathy and the more serious complications of diabetes. In a study of 173 patients with diabetes, the incidence of shin spots correlated with the duration of diabetes and the presence of retinopathy, nephropathy, and neuropathy.81 Diabetic dermopathy does not, however, correlate with obesity or hypertension in patients with diabetes.79 No treatment is necessary for the individual atrophic tibial lesions. They are asymptomatic and are not directly associated with an increase in morbidity.

Acquired Perforating Disorders

(See Chapter 69)

The acquired perforating disorders comprise an overlapping group of disorders characterized by transepidermal elimination or “spitting” of altered dermal constituents. Included in this group are Kyrle disease, reactive perforating collagenosis, perforating folliculitis, and elastosis perforans serpiginosa.82 These disorders and their treatment83 are fully described in Chapter 69.

Clinically, these lesions appear as pruritic, keratotic papules mainly on the extensor surfaces of the extremities. Papules and nodules with a perforating component may also occur on the trunk and face. Many are follicular and contain a prominent central keratotic plug. The papules may be grouped, or coalesce to form verrucous plaques. Treatment for the perforating disorders is usually unsuccessful. Retinoic acid, topical glucocorticoids, and PUVA are partially successful.83

Bullosis Diabeticorum

Etiology and Pathogenesis

The abrupt, spontaneous development of blisters on the lower extremities without other demonstrable cause is a rare characteristic skin manifestation of diabetes. The pathogenesis of diabetic bullae is unknown. Patients with bullosis diabeticorum (BD) do not have a history of antecedent trauma or infection. One study found a decreased threshold to suction-induced blister formation in patients with diabetes.84 Reduced suction blister time is also observed with increasing age in nondiabetic subjects.85 Although a history of antecedent trauma is not elicited, this finding suggests a role of increased skin fragility in diabetic bullae. Perhaps the formation of AGEs leads to increased fragility.

Clinical Findings, Diagnosis, and Treatment

BD is characterized by the abrupt onset of bullae on the lower extremities, usually the toes, feet, and shins, arising in normal skin. Occasionally, the distal upper extremities are involved. The blisters are usually painless and not pruritic. Healing occurs within 2–5 weeks and rarely leaves scarring. The condition may recur as successive crops of bullae over many years. Studies of affected individuals excluded other blistering skin disorders, and revealed no abnormalities of porphyrin metabolism.84 Histopathologic examination of the bullae shows an inconsistent level of separation varying from intraepidermal to subepidermal.85 No immunopathologic features are consistently observed (Box 151-3).

BD runs a benign course without involvement of large body surface areas. The only serious complication is that of secondary infection, which should be managed with culture and appropriate antibiotics if suspected. Otherwise, therapy is supportive. The real importance of this disorder is that of correct diagnosis because several of the blistering skin diseases have a high rate of morbidity and require potentially toxic systemic treatments. Even a negative workup is important. The patient should be educated, reassured, and good wound care implemented.

Obesity and the Metabolic Syndrome

Epidemiology

Obesity is characterized by excess fat mass and defined according to the body mass index (BMI, kg/m2), a calculation based on weight and height [BMI = body weight (in kg) ÷ square of stature (height in meters)]. BMI is correlated with body fat and the WHO defines overweight as a BMI of >25 and obesity as >30 kg/m2. For Americans the risk of becoming overweight or obese in adulthood is high. As part of the National Health and Nutrition Examination Survey (NHANES) in 2003–2004, 17.1% of children and adolescents were overweight and 32.2% of adults were obese. Approximately 30% of nonhispanic white adults were obese as were 45.0% of nonhispanic black adults and 36.8% of Mexican American. It was also noted that obesity increased in the adult population with age.86

Etiology and Pathogenesis

Contributing factors to obesity are nutritional choices, activity and exercise, medications, and rarely one of several endocrine disorders. In the setting of nutrient excess and weight gain, numerous comorbid factors occur that may contribute to further weight gain by increasing energy intake or decreasing energy expenditure. These include, inflammation and insulin resistance, depression and emotional eating, degenerative joint disease, obstructive sleep apnea, gonadal dysfunction, vitamin D deficiency, among others. Familial studies suggest a strong genetic basis for human obesity. The genetics of obesity are complex, though most human obesity is likely polygenic, multiple single genes have been identified as key regulators of body adiposity. Three of these genes [(1) leptin, (2) pro-opiomelanocortin (POMC), and (3) agouti-related protein (AgRP)] with dermatologic relevance are discussed in detail below.

The hormone leptin is secreted by adipose tissue in proportion to total body fat. Leptin regulates energy homeostasis, neuroendocrine function, and metabolism.87 Rare cases in humans have shown that leptin deficiency causes extreme obesity, hyperphagia, diabetes, neuroendocrine abnormalities, and infertility, all of which can be reversed by administration of exogenous leptin. However, most obese humans are leptin resistant, have high circulating levels of leptin and pharmacological leptin administration has not proven to be a successful weight-loss strategy. Leptin resistance appears to be at the hypothalamic leptin receptor or downstream.87 Congenital and acquired forms of lipoatrophy (HIV or HAART associated) are characterized by low leptin levels and metabolic abnormalities including insulin resistance, hyperlipidemia, and fatty liver. Leptin treatment in these patients can improve insulin resistance, lipid abnormalities, and fat distribution.88,89

Leptin stimulates the hypothalamic melanocortin pathway including hypothalamic neurons expressing POMC. Cleavage of POMC results in peptide agonists for all five homologous melanocortin receptors. The melanocortin 1 receptor (MC1R) is expressed on melanocytes and mutations in MC1R are known to cause red hair and fair skin.90 Inactivating mutations in MC4R and to a lesser degree MC3R are associated with obesity. Studies estimate that inactivating mutations in MCR4 account for up to 6% of all severe cases of early onset obesity. Further emphasizing the importance of the POMC pathway is the finding that homozygous loss of function of POMC (complete POMC deficiency) produces obesity, pale skin, and red hair.91

AgRP is an endogenous hypothalamic melanocortin receptor antagonist, which causes obesity when overexpressed. Though studies have found high serum AgRP levels in obese men,92 the role of AgRP in common obesity is unclear. The gene is closely related to agouti, a skin pigmentation gene, which causes yellow coat color and obesity when overexpressed in mice.

The hormonal regulation of obesity is similarly complex and several gut hormones are likely involved in the regulation of food intake. The gastric derived, appetite stimulating hormone ghrelin impacts obesity and diabetes by modulating body weight, insulin secretion, and gastric motility.93 Serum ghrelin levels rise before meals and are thought to promote food intake. Sharp rises are seen in states of starvation and after weight loss in obesity. This likely contributes to weight regain. Interestingly, postgastric bypass surgery patients have altered ghrelin secretion and this may be one of the reasons for the long-term success of this surgical treatment for obesity.94 Ghrelin receptors are located in the pituitary and hypothalamus and stimulate growth hormone (GH1) release and regulate energy expenditure93 (see Fig. 151-15). Several ghrelin antagonists are in development for the treatment of obesity, metabolic syndrome, and diabetes.

Clinical Findings

Physiologic changes in the skin related to obesity include alterations in epidermal barrier function,95,96 increased sweating along with larger skin folds, increased skin surface pH in intertriginous areas,97 poor lymphatic drainage (eFig. 151-8.1), impaired wound healing in animal models,98 and impaired responsiveness of the microvasculature.99 Several reviews regarding obesity and dermatology have been published.100,101 The cutaneous disorders seen in obesity are listed in Box 151-4. Detailed discussion of findings and treatments for these disorders are found in the appropriate sections of the text.

It is now well recognized that the presence of abdominal—central rather than subcutaneous—obesity (more than just increased BMI) is associated with insulin resistance, hyperlipidemia, hypertension, and vascular inflammation (Box 151-5). The coexistence of these disorders increases the risk for diabetes and cardiovascular disease and has been called the metabolic syndrome. It is not clear that the metabolic syndrome confers risk beyond that of the individual components but because the traits co-occur, those with one trait are likely to have others. The most important therapy is weight reduction and exercise along with adequate control of cardiac risk factors.

The cornerstones of treatment for overweight and obesity are dietary changes, increased physical activity, and behavioral modification. In high-risk patients with comorbid conditions, pharmacologic therapy (sibutramine or orlistat) can be considered as an additional intervention. In clinically severe obesity, surgical therapies may be appropriate. All successful patients will require long-term nutritional adjustments that reduce caloric intake. The role of liposuction in weight loss has been studied and despite the removal of a large volume of subcutaneous adipose tissue there was no improvement seen in the metabolic risk factors associated with obesity.102,103

Thyroid Disease

Epidemiology

Worldwide estimates of the prevalence of goiter (enlargement of the thyroid gland) range from 200 to 800 million affected people. The majority of these worldwide cases are secondary to iodine deficiency. However, in industrialized countries where salt is routinely iodized, the main causes of goiter are autoimmune thyroiditis and nodular thyroid disease. The overall incidence of hyperthyroidism in the US population is estimated at approximately 1%, but may be four to five times higher in older women.104 Graves disease accounts for 60%–80% of all cases of hyperthyroidism and was first described by Caleb Parry in 1825 (and later by Robert Graves in 1835) as an association between goiter, palpitations, and exophthalmos.105 Although the incidence of Graves disease is similar between whites and Asians, it appears to be lower in blacks.105 Toxic adenoma and toxic multinodular goiter refer to the hyperplastic growth of thyroid tissue that is functioning independent of TSH regulation, resulting in increased levels of thyroid hormone. Toxic multinodular goiter has been reported to be more common in areas of low iodine intake, particularly in patients older than the age of 50 years.106 Population-based screening with laboratory testing found hypothyroidism in 4.6% of the US population, although >90% of individuals with tests consistent with hypothyroidism were normal clinically.104

The majority of thyroid disease is acquired, but thyroid disease can also be congenital. Congenital hypothyroidism is the most common treatable cause of mental retardation, and occurs in up to 1 in 3,000 neonates worldwide due to either an absent or anatomically defective gland, inborn errors of thyroid metabolism, or iodine deficiency.107 Congenital hyperthyroidism is much less common, and although 0.2% of pregnant women have Graves disease, only about 1% of the resultant neonates will have hyperthyroidism, with most cases resulting from the transfer of maternal thyroid-activating autoantibodies.108

Etiology and Pathogenesis

The metabolic regulation of every cell in the body relies on thyroid hormones, which is synthesized primarily in the thyroid gland. Hyperthyroidism (also known as thyrotoxicosis) results from the excess levels of thyroid hormones with resultant hypermetabolism, whereas hypothyroidism (or myxedema) is characterized by hypometabolism secondary to diminished levels of thyroid hormone. Thyroid hormones act on target tissues by activating cytoplasmic receptors that subsequently translocate to the nucleus and activate specific thyroid-responsive genes.109 Thyroid hormone synthesis is heavily dependent on iodine and, consequently, changes in iodine intake can result in both hyperthyroidism and hypothyroidism.

Synthesis of thyroid hormone is regulated by the pituitary via release of TSH in response to hypothalamic release of thyrotropin-releasing hormone (TRH). TSH acts on the thyroid gland by binding a G-protein-coupled receptor (TSHR) to trigger thyroid hormone synthesis and release. Aberrant activation of TSHR is thought to underlie the hyperthyroidism seen in Graves disease, where almost all patients have long-acting thyroid-stimulator autoantibodies that bind and activate TSHR.110 Release of TSH is, in turn, stimulated by TRH, which also acts via a G-protein-coupled receptor. Administration of recombinant TRH followed by measurement of the response in TSH levels provides a useful test for distinguishing whether hypothyroid disease results from dysfunction of the hypothalamic–pituitary axis or the thyroid gland. Levels of TSH and TRH are both tightly controlled by circulating levels of thyroxine (T4) and triiodothyronine (T3), which provide feedback regulation (eFig. 151-8.2). Persistent stimulation of the thyroid leads to the hypertrophy of the gland, known as goiter.

The great majority of thyroid hormone in the blood is bound by plasma proteins, including thyroid-binding globulin, which is the major determinant of protein binding, and to a lesser extent transthyretin (formerly called prealbumin) and albumin. A variety of medical conditions (Box 151-6) and medications can alter levels of thyroid hormone-binding proteins or peripheral conversion of T4 to T3 (which is responsible for most of thyroid hormone's effects), and subsequently alter the tissue availability of thyroid hormone independent of changes in thyroid hormone synthesis. Thyroid hormone levels can be affected by a variety of medications, including several that are prescribed by dermatologists (Box 151-7).111

Hyperthyroidism can be broadly classified into two categories: (1) high radioiodine (radioactive iodine) uptake and (2) low radioiodine uptake. The presence of high radioiodine uptake indicates increased synthesis of thyroid hormone, while diminished or absent radioiodine uptake suggests either an extrathyroidal source of thyroid hormone or the destruction of thyroid tissue with concomitant release of preformed thyroid hormone into the circulation. Evidence suggests that genetic predisposition as well as environmental factors, including infection, may play a role in the pathogenesis of autoimmune thyroid disease.112 In the case of toxic adenoma, molecular studies have identified a high prevalence of TSHR mutations, resulting in a receptor that triggers thyroid hormone synthesis in the absence of bound TSH.113

Although some of the cutaneous findings seen in hyperthyroidism are indirect consequences of thyroid hormone's actions on other tissues, most of the skin manifestations of thyroid disease result from the direct effects of thyroid hormones on the keratinized epithelium of the epidermis, hair, and nails as well as effects on stromal cells in the dermis. Thyroid hormones are essential for optimal epidermal proliferation both in vitro and in vivo.114 Thyroid hormones regulate genes involved in keratinocyte proliferation and also stimulate the expression of certain keratins.114

Approximately 95% of cases of hypothyroidism are thought to arise from defects in the thyroid gland itself, whereas the remaining cases result from defects in the hypothalamic–pituitary axis. Ironically, the most common cause of hypothyroidism without a goiter is the surgical or radioiodine-induced ablation of the thyroid gland for the treatment of Graves thyrotoxicosis. Cretinism occurs with untreated congenital hypothyroidism and does not have a goiter. The most common cause of hypothyroidism with a goiter in North America is Hashimoto thyroiditis. Less common causes of hypothyroidism include inherited defects in hormone synthesis or the ingestion of drugs that inhibit hormone synthesis, such as lithium or aspirin. Bexarotene, a retinoid-X-receptor agonist (see Chapter 228) used to treat cutaneous T-cell lymphoma, causes a central hypothyroidism with a decrease in TSH, followed by low levels of T3 and T4.115 In rare cases, hypothyroidism can occur from decreased secretion of TSH, such as with pituitary failure, a tumor of the pituitary region, or postpartum pituitary necrosis (Sheehan syndrome). Inadequate secretion of TRH by the hypothalamus is another very rare cause of hypothyroidism.

Cutaneous Manifestations of Hyperthyroidism

(Box 151-8) Signs and symptoms of hyperthyroidism and hypothyroidism are variably present and summarized in Table 151-2. The skin changes of hyperthyroidism have been likened to infant's skin and described as soft, warm, and velvety in texture. Pruritus can be a manifestation of thyroid disease, and laboratory screening for thyroid disease is often included in working up patients experiencing diffuse pruritus with no obvious rash. Scalp hair in hyperthyroid patients is described as soft and fine, and in certain cases may be accompanied by a diffuse nonscarring alopecia analogous to telogen effluvium. Patients with hyperthyroidism frequently have nail changes that are commonly described as soft, shiny, and brittle nails with an increased rate of growth. A small percentage of patients with hyperthyroidism will have Plummer's nails, which exhibit a concave shape with distal onycholysis (see Chapter 89). Plummer's nails can also be found in a variety of other conditions and are not pathognomonic for hyperthyroidism. Vitiligo appears to be overrepresented in patients with Graves disease, but not in patients with other forms of hyperthyroidism. Vitiligo may often predate the diagnosis of thyroid disease and does not improve with the treatment of the hyperthyroidism (see Chapter 74).

Thyroid dermopathy is most commonly seen with Graves disease but has been reported in hypothyroid patients as well. Pretibial thyroid dermopathy (in the past referred to as pretibial myxedema) is a classic manifestation of hyperthyroidism and Graves disease (Fig. 151-11). The term thyroid dermopathy is used in this chapter because the lesions can occur at any site on the body, are not limited to the pretibial region, and the name does not suggest myxedema as a cause.116 Although there are reports of hyperthyroid patients who have presented with thyroid dermopathy as their initial finding, thyroid dermopathy is usually a later manifestation of thyroid disease. Almost all patients with thyroid dermopathy also have thyroid ophthalmopathy, another late manifestation of hyperthyroidism.117 The clinical appearance of thyroid dermopathy can be quite varied. Classically, thyroid dermopathy occurs bilaterally as painless nonpitting nodules and plaques with variable coloring and a waxy, indurated texture (Fig. 151-9). The distribution can range from very circumscribed to diffuse, but by far the most common location is on the extensor surfaces of the legs.117 Some cases can exhibit a peau d'orange appearance as well. An extreme form of diffuse thyroid dermopathy has been termed the elephantiasic variant, which occurs in less than 1% of patients with Graves disease and is characterized by progressive thickening and gray-black hyperpigmentation of the pretibial skin accompanied by a woody, firm edema with nodule formation. The exact pathophysiology underlying thyroid dermopathy is still unclear.116 Biopsies of thyroid dermopathy reveal a thickened dermis with splayed collagen fibrils and abundant mucin, usually hyaluronic acid, in the interstitial space.

The increased amounts of hyaluronic acid in the dermis and the subcutis have led the hypothesis that fibroblasts or other cells in the dermis may be synthesizing increased levels of GAGs secondary to stimulation by activating autoantibodies. However, antibodies that bind TSHR on fibroblasts can be seen in patients with and without thyroid dermopathy, indicating that other determinants are likely involved. The presence of dependent edema in the lower extremities may also contribute somehow to either the fibroblast stimulation or hyaluronic acid accumulation, and thus account for the tendency of thyroid dermopathy to occur in this anatomic site.

Thyroid acropachy refers to digital clubbing, soft-tissue swelling of the hands and feet, and the presence of characteristic periosteal reactions.116 This very rare clinical finding is also associated with thyroid dermopathy and exophthalmos, and almost always presents after the diagnosis and treatment of hyperthyroidism (eFig. 151-9.1). Like thyroid dermopathy, thyroid acropachy has also been reported in hypothyroid conditions. Clubbing occurs most frequently on the first, second, and fifth metacarpals, the proximal phalanges of the hand, and the first metatarsal and proximal phalanges of the feet.116 The radiologic findings are characterized by a lamellar periosteal reaction of the hands or wrists, with long bones only rarely involved. Because increased osteoblastic activity has been observed in the diaphyseal parts of small bones, the use of bone scan has been suggested as a sensitive way to aid in diagnosis.118 The mechanisms underlying thyroid acropachy remain unknown, although interestingly, a large case series identified a disproportionately high percentage of smokers (80%) in patients with thyroid acropachy.119

The effects of thyroid hormone excess on other organ systems can also result in cutaneous findings. Hyperpigmentation similar to Addison disease has been seen with hyperthyroid disease, with resultant pigment in the palmar creases, gingiva, and buccal mucosa that is usually more prominent in individuals with darker skin. It has been postulated that the hyperpigmentation may be the result of increased corticotropin (ACTH) resulting from accelerated cortisol metabolism.116 The cardiovascular effects of thyroid hormone excess include atrial fibrillation, increased cardiac output, and decreased peripheral vascular resistance, resulting in increased blood flow to the skin along with facial flushing and palmar erythema. The overall increased metabolism, along with changes in peripheral blood flow and temperature dysregulation, can also result in a generalized hyperhidrosis as well as high-output cardiac failure similar to that seen with Paget disease of bone.

There is extensive literature regarding the association between thyroid disease and urticaria120 (see Chapter 38). Several studies have found a much higher incidence of thyroid disease in patients with chronic urticaria compared with control populations, although the mechanism behind this association remains unclear. Other dermatologic conditions have been reported in association with Graves disease, including dermatitis herpetiformis, Sweet syndrome, pemphigoid gestationis, vitiligo, pemphigus vulgaris, anetoderma, and middermal elastolysis.116

Cutaneous Manifestations of Hypothyroidism

(Box 151-9). In hypothyroidism, decreased core temperature and increased peripheral vasoconstriction cause the skin to be cool and pale. The skin is also xerotic, and the stratum corneum is poorly hydrated. Histologically, the epidermis is thin, and there is hyperkeratosis with follicular plugging. The generalized distribution of these findings can help distinguish these changes from those of atopic dermatitis and keratosis pilaris, which tend to be more prominent on the extremities. A fine wrinkling can also be seen. A yellow–orange discoloration of the skin can be seen secondary to the accumulation of β-carotene in the stratum corneum, possibly secondary to increased circulating carotene from diminished hepatic conversion of β-carotene to vitamin A.

Myxedema is the most classic finding associated with hypothyroidism and is distinct from the thyroid dermopathy seen with Graves disease. Myxedema occurs as a result of dermal accumulation of mucopolysaccharides, namely, hyaluronic acid and chondroitin sulfate, and tends to resolve with treatment of the hypothyroidism. The myxedema tends to be generalized but can appear more striking in the extremities. Characteristic facial changes can be seen, including a broadened nose, thickened lips, puffy eyelids, and macroglossia with a smooth and clumsy tongue (eFig. 151-9.2). The skin can be doughy, swollen, and waxy, but without pitting. Wound healing is impaired in hypothyroidism.

The hair in hypothyroidism is coarse, dry, and brittle with slowed growth. Hair loss in the scalp can be either diffuse or patchy. Hypothyroidism can result in increased numbers of hair follicles in telogen, as well as telogen effluvium when the onset of hypothyroidism is abrupt. There can be loss of eyebrow hair in a characteristic pattern involving the outer third (see eFig. 151-9.2). Although body hair can be diminished, hypothyroidism can also result in increased lanugo hair on the back, shoulders, and extremities. The nails in hypothyroidism grow slowly and can be thickened and brittle with longitudinal and transverse striations. In patients with a goiter, hoarseness can result secondary to compression of the recurrent laryngeal nerve. With large goiters, tracheal or esophageal displacement can be seen. In extreme cases, large retrosternal goiters can cause Pemberton's sign, characterized by facial plethora suggestive of compression when patients raise their arms above their head.

Hashimoto thyroiditis has been associated with several other dermatologic disorders, including alopecia areata, connective tissue disease (including lupus and dermatomyositis), bullous pemphigoid, dermatitis herpetiformis, and chronic mucocutaneous candidiasis (CMC).121–125

Laboratory Tests

The diagnosis of thyroid-related cutaneous disease is often suspected clinically, although in certain instances a skin biopsy may prove helpful in confirming the diagnosis. The clinical diagnosis of thyroid disease is confirmed by thyroid function tests. Serum levels of TSH are recommended as an initial screen, and any abnormalities in TSH should be followed up with measurements of serum T4 and free T3 to confirm whether the abnormal TSH truly reflects a thyroid disorder. Other tests that can be useful include in vitro T3 resin uptake and measurements of antithyroid antibodies. This combination of tests will diagnose the vast majority of patients with suspected thyroid disease.

Treatment

The mainstay of treatment for the cutaneous findings of thyroid disease is normalization of thyroid function, either through replacement of thyroid hormone for hypothyroidism or through ablation of thyroid function for hyperthyroidism. Thyroid dermopathy and thyroid acropachy can be a chronic problem even in patients who are treated effectively for their thyroid disease, and the current treatment options can be classified as either experimental or palliative at best. Complete or partial remission of cutaneous findings can be seen even in the absence of any localized topical treatment.126 Reported treatments of thyroid dermopathy include topical corticosteroids, systemic corticosteroids, intralesional corticosteroids, intralesional octreotide, intravenous (IV) immunoglobulin, plasmapheresis, compression therapy, and even surgical excision.126,127 The success of these therapies is still controversial and based on small uncontrolled case series or anecdotal reports.

Parathyroid Disease

Epidemiology

The annual incidence of primary hyperparathyroidism has decreased in the past two decades to about 20 cases per 100,000, potentially reflecting a decrease in the use of ionizing radiation to the neck, which is a known risk factor for developing primary hyperparathyroidism.128 The majority of cases occur in individuals older than 45 years of age, with an approximate 2:1 female–male predominance. In the outpatient setting, parathyroid disease accounts for almost all cases of hypercalcemia. In hospitalized patients, parathyroid disease accounts for approximately one-third of all cases of hyperparathyroidism, while the majority of other cases are accounted for by malignancy. Together, hyperparathyroidism and malignancy account for greater than 90% of all cases of hypercalcemia.

Etiology and Pathogenesis

Parathyroid hormone (PTH) is secreted by the parathyroid gland in response to low levels of serum calcium and acts as one of the main regulators of calcium levels in the body. Elevations of PTH (hyperparathyroidism) are associated with hypercalcemia, whereas decreased levels of PTH (hypoparathyroidism) are associated with hypocalcemia. PTH acts through varying mechanisms that include the stimulation of vitamin D production, stimulation of calcium absorption in the gastrointestinal tract, regulation of renal absorption of calcium and phosphate, and direct regulation of calcium mobilization from bone. Circulating free calcium acts on the parathyroids via a G-protein-coupled receptor to control the release of PTH. Released PTH then acts in target tissues by binding another G-protein-coupled receptor, the PTH receptor, resulting in changes in calcium metabolism. Because problems with PTH result primarily in alterations of circulating calcium, it is not surprising that the skin manifestations of parathyroid disease are primarily changes resulting from calcium dysregulation. The skin is likely a site of PTH action, although the exact effects of PTH on skin are not understood. Keratinocytes express a PTH-related peptide (PTHLH) that has been implicated in regulating keratinocyte growth and differentiation and utilizes the same receptors as PTH.129–132 Although PTHLH has been associated with normal wound healing, elevated PTHLH can also be seen in the setting of certain squamous cell carcinomas.131,133,134 The elevated PTHLH with squamous cell carcinoma can result in malignancy-related hypercalcemia in these patients.

Primary hyperparathyroidism results from abnormal function of the parathyroid gland, resulting in increased levels of PTH. In 80% of diagnosed cases, the cause of hyperparathyroidism is a result of either parathyroid hyperplasia, parathyroid carcinoma, or parathyroid adenoma. Pseudohyperparathyroidism occurs when PTH or a PTH-like molecule (for instance, PTHLH) is secreted from a nonparathyroid tissue such as occurs in malignancy.

Secondary hyperparathyroidism occurs most commonly in the setting of renal disease. Resistance of end organs to PTH results in hypersecretion of PTH and consequent hypocalcemia and hyperphosphatemia. Secondary hyperparathyroidism is found in almost all patients with chronic renal failure requiring dialysis. Secondary hyperparathyroidism can also be associated with idiopathic hypercalciuria as well as with certain medications, including oral contraceptives and long-term furosemide therapy. In renal patients with long-term secondary hyperparathyroidism, hyperplastic parathyroid tissue can become autoactivated, resulting in tertiary hyperparathyroidism. This condition is characterized by persistent hypersecretion of PTH and resultant osteomalacia despite hypercalcemia.

Primary hypoparathyroidism occurs primarily from iatrogenic causes such as the removal of the parathyroid glands during a thyroidectomy. There are also several genetic and nongenetic congenital causes of primary hypoparathyroidism, although these are much less common. Secondary hypoparathyroidism refers to decreased PTH secretion secondary to a primary process that causes hypercalcemia.

Clinical Findings

Parathyroid disease most often presents in the setting of altered calcium metabolism. The physical findings and symptoms associated with hyper- and hypocalcemia are shown in Box 151-10. As for hypercalcemia and hyperparathyroidism, skin manifestations are rarely seen but can be impressive and dramatic. An approach to a patient with suspected hyperparathyroidism is outlined in Box 151-11. Cutaneous calcinosis (sometimes referred to as calcinosis cutis or metastatic calcinosis) is thought to be related to elevated calcium and phosphate135 (see Chapter 138). Subcutaneous calcifications can be found in a symmetric distribution, often overlying large joints or in linear arrayed papules and plaques that are normally of skin color and hard on palpation (Fig. 151-10). These lesions can be pruritic. Chronic urticaria has been associated with hyperparathyroidism as well.136 Signs of hyperparathyroidism in association with cutaneous skin tumors, such as angiofibromas, collagenomas, and lipomas, should engender a workup for multiple endocrine neoplasia type 1 (MEN1), which is caused by mutations in the MEN1 gene and characterized by tumors of the anterior pituitary, the pancreas, and the parathyroid. The finding of somatic (nongermline) mutations and loss of heterozygosity of the MEN1 gene in 20%–30% of spontaneous parathyroid tumors further supports a role for this gene in parathyroid oncogenesis.137 The differential diagnosis is of hypercalcemia is shown in Box 151-12.

Calciphylaxis (also called calcific uremic arteriolopathy or CUA) is a rare but life-threatening cutaneous condition associated with hyperparathyroidism. Calciphylaxis occurs most often in the setting of chronic renal failure and secondary hyperparathyroidism, although there are reports of calciphylaxis associated with primary hyperparathyroidism and normal renal function. Although the name may falsely imply an immune etiology, calciphylaxis actually results from calcium deposition in the walls of small- to medium-sized vessels, resulting in vascular occlusion and skin necrosis. Clinically, patients present initially with violaceous patches that may exhibit a mottled or reticular pattern. Subsequently, involved areas can become indurated and painful, with eventual ulceration and eschar formation that proceeds to tissue gangrene (Fig. 151-11). Both the trunk and extremities can be involved. A calcium-phosphate product (serum calcium × serum phosphate) of greater than 70 mg/dL has often been cited as a predisposing risk factor. The histologic finding of calcium deposits in vessel walls coupled with compatible clinical findings is diagnostic. Calciphylaxis has a very poor prognosis, with reported mortality rates up to 80%, usually from infection. Parathyroidectomy and aggressive management of wounds and infections has been successful in treating some cases. There is not compelling evidence to support the use of hyperbaric oxygen, but there are small case series reporting successful treatment of calciphylaxis using hyperbaric oxygen, suggesting use for this often life-threatening condition.138,139 An accumulating number of case reports using the calcium-sequestering compound sodium thiosulfate have demonstrated considerable efficacy, particularly in patients with renal disease.140 While large clinical trials are lacking, the lack of any serious short-term side effects reported with sodium thiosulfate suggests serious consideration of this therapy for patients with calciphylaxis.

Hypoparathyroidism is associated with scaly, hyperkeratotic, and edematous puffy skin (Box 151-13). Paresthesias secondary to hypocalcemia can be seen. Patchy alopecia and generalized thinning of the hair have been reported. Nails can be brittle with transverse ridging. Hypoparathyroidism has been associated with psoriatic flares, which is interesting in light of the response of psoriasis to calcipotriene.141 These skin abnormalities often resolve with normalization of serum calcium levels, suggesting that they are due to changes in calcium homeostasis rather than deficiency of PTH.

Hypoparathyroidism in the setting of familial autoimmune polyglandular syndrome type 1 has been associated with CMC and adrenal failure.142 The CMC can precede the diagnosis of hypoparathyroidism, although the CMC does not improve significantly with treatment of the hypoparathyroidism with calcium and vitamin D. Other findings in these patients include dental enamel hypoplasia, vitiligo, and the cutaneous manifestations of adrenal failure (see under Section “Addison Disease”).

Hypoparathyroidism in the setting of elevated serum PTH is known as pseudohypoparathyroidism or PTH-resistant hypoparathyroidism. Although several variants of pseudohypoparathyroidism have been described, perhaps the best characterized is Albright's hereditary osteodystrophy.143 These patients present with a constellation of findings that include short stature, obesity, rounded facies, dental hypoplasia, and shortened bones of the hands and feet. Characteristic shortening of the fourth metacarpal leads to a dimpling of the fourth knuckle, known as Albright's sign. These patients can also have subcutaneous ossifications and calcifications.

Laboratory Tests

The diagnosis of parathyroid disease can be made with measurements of serum calcium levels and serum levels of PTH. In the case of hypercalcemia related to malignancy, measurement of PTHLH may also be useful in the workup.

Treatment

The main treatment for hyperparathyroidism is partial or total parathyroidectomy (see Box 151-11). For hypoparathyroidism, treatment focuses on correction of serum calcium and phosphate (see Box 151-13). In the setting of acute hypercalcemia, aggressive fluid and electrolyte management are essential, because cardiorespiratory failure may result from dehydration.

Cushing Syndrome

Excessive production of endogenous cortisol manifests clinically as Cushing syndrome. Similar findings are seen from chronic exogenous administration of glucocorticoids (see Chapter 224). In the normal physiology of the hypothalamic–pituitary–adrenal axis, corticotropin-releasing hormone is secreted from the hypothalamus and stimulates the production of corticotropin, also known as ACTH, by the anterior pituitary. ACTH is synthesized as part of a larger precursor molecule, POMC. This relationship of POMC to ACTH is important in diseases of the adrenal gland and the resulting skin manifestations. POMC is processed into several peptides, including melanocyte-stimulating hormone (MSH) and ACTH, which stimulates the production of cortisol from the adrenal cortex. In a classic negative feedback manner, cortisol inhibits corticotropin-releasing hormone and ACTH production.

Epidemiology, Etiology, and Pathogenesis

The overall incidence of Cushing syndrome is about 10 persons per million per year, with a female predominance.144 Cushing syndrome is divided into two categories. The first is caused by inappropriately high secretion of ACTH, usually from a pituitary microadenoma. It is given the unique name of Cushing disease. The excess ACTH drives glucocorticoid production in the adrenals. Rarely ectopic, or nonpituitary, production of ACTH results in Cushing syndrome. This clinical presentation is most often associated with a pulmonary carcinoid tumor, although numerous other tumor types have been reported.145 The second category of Cushing syndrome results from excess cortisol produced by the adrenal cortex independent of regulation by the pituitary or hypothalamus. This is usually due to an adrenal adenoma, which may be benign or malignant, or is the result of generalized hyperplasia of the adrenal gland. Cushing syndrome can be seen in the McCune–Albright syndrome146 and in association with primary pigmented nodular adrenocortical disease in the Carney complex.147

Clinical Findings

The clinical presentation of Cushing syndrome may be subtle (Box 151-14). Skin findings may be present, and if careful attention is paid to the relationship of skin findings and systemic complaints, one may consider the diagnosis early in the clinical course. Common skin complaints are easy bruisability and skin thinning. Mild hypertrichosis often of the lanugo type and acne may occur. Frank hirsutism and severe acne raise the possibility of a concurrent androgen-secreting tumor. The development of multiple violaceous striae wider than 1 cm on the abdomen or proximal extremities is highly suggestive of Cushing syndrome (eFig. 151-11.1). The width and color of these striae differentiate them from the commonly seen striae in pregnancy or with weight gain. Relatively dramatic changes in fat distribution often occur along with a generalized gain in weight. There is an increase in central obesity and concurrent thinning of the arms and legs with loss of muscle mass. Increased facial fat results in a rounded appearance of the face, often with increased redness and telangiectasias. This appearance has been referred to as a moon facies. In addition to truncal obesity, there is an increase in the size of the dorsocervical fat pad, known as a buffalo hump and increased fat in the supraclavicular fossae. Men may experience gynecomastia.

Although unusual, hyperpigmentation can occur in cases of Cushing syndrome caused by massive increased ACTH production either from the pituitary or, more commonly, an ectopic source.148 ACTH itself, in addition to MSH derived from POMC, contributes to increased melanin synthesis. This is similar to the hyperpigmentation more commonly associated with Addison disease. Acanthosis nigricans may be seen because Cushing syndrome contributes to insulin resistance, and, often, patients develop diabetes. The immunosuppressive effects of glucocorticoids result in increased dermatophyte and candidal nail and skin infections. Women may experience irregular menses or amenorrhea. Additional extracutaneous signs and symptoms of Cushing syndrome include hypertension, osteoporosis, and decreased muscle mass and strength.149

Laboratory Tests

Diagnostic confirmation of Cushing syndrome requires demonstration of excess cortisol production. Cortisol production varies throughout the day and, as a rule, should be examined in the early morning when it is usually at its highest value. The average daily cortisol level can be measured using a 24-hour urine collection. Any abnormal test should be repeated two or three times for confirmation. If the urine or serum levels are elevated, failure to suppress the 8:00 a.m. serum cortisol level or 24-hour urine cortisol with a low-dose dexamethasone suppression test is confirmatory. Additional testing, including a high-dose dexamethasone suppression test, can be useful to determine if the source of the excess cortisol production is from the pituitary or elsewhere. Hypercortisolism may be present in patients without true Cushing syndrome. This is known as pseudo-Cushing syndrome and can be caused by obesity, major depressive disorders, and chronic alcohol abuse. With further testing, these patients can usually be identified.

Treatment

The primary treatment of Cushing disease is surgical removal of the ectopic focus of ACTH production or adenoma in the pituitary or adrenal gland. Cure is achieved in the majority of patients, but resistant disease requires radiation in the case of pituitary disease or medical therapy with adrenal enzyme inhibitors.148 Historically, Cushing syndrome was treated with bilateral adrenalectomy. This frequently resulted in Nelson syndrome, which is characterized by unchecked ACTH production from an enlarging pituitary adenoma with resulting hyperpigmentation. Pituitary radiation can be helpful in these cases.150

Addison Disease

Epidemiology, Etiology, and Pathogenesis

Destruction of the adrenal glands and the resulting life-threatening deficiency of glucocorticoids, mineralocorticoids, and adrenal androgens is known as Addison disease. It occurs at an estimated prevalence rate of 120 per million in Western countries.151 It is suspected that many more cases remain undiagnosed. Historically, the most common cause was tuberculosis infection, but now autoimmune destruction as part of the autoimmune polyglandular syndromes 1 and 2 is the most common etiology. In autoimmune cases, enzymes of the adrenal cortex, including 21-hydroxylase and 17-hydroxylase, are target autoantigens, and circulating autoantibodies can be detected. Subsequent lymphocytic infiltration of the adrenal gland with damage and scarring results.

Infectious causes of adrenal insufficiency remain the next most common etiology. Tuberculosis is still a major problem in many areas of the world. Atypical mycobacterial infection can also cause adrenal insufficiency. This is seen more commonly in immunosuppressed patients. Addison disease is increasingly recognized in patients with acquired immunodeficiency syndrome and, in these patients, infection with cytomegalovirus is the most recognized cause. Fungal infections have also been associated with Addison disease, including histoplasmosis, blastomycosis, paracoccidioidomycosis, coccidioidomycosis, and cryptococcosis. In the setting of an acute bacterial infection, bilateral adrenal infarction due to adrenal hemorrhage is known as the Waterhouse–Friderichsen syndrome. Classically this is due to meningococcal infection, although other infections have been reported (see Chapters 180 and 181).152 Other rare causes of Addison disease include drugs, congenital adrenal hypoplasia, and infiltrative disorders, including amyloidosis, sarcoidosis, and metastatic carcinomas. The surgical treatment of Cushing syndrome can be an additional cause of adrenal insufficiency.

Clinical Findings

(Box 151-15). The clinical and cutaneous manifestations of adrenal insufficiency are not usually present until 90% of the gland function is destroyed.151 The most recognized cutaneous manifestation is the hyperpigmentation of skin and mucous membranes. This occurs after long-standing adrenal insufficiency and would not be present in an acute presentation of adrenal crisis unless it is superimposed on a history of chronic adrenal insufficiency. The skin pigmentation is accentuated in sun-exposed areas, flexural folds, and skin creases, including the creases on the palms (Fig. 151-12). Pigment may develop in scars and longitudinal pigmented bands may appear in the nails. These pigment changes are a consequence of low cortisol levels and the resulting loss of negative regulatory feedback on the hypothalamus and pituitary. This results in unchecked production of POMC, ACTH, and MSH, which increase melanogenesis. In contrast, vitiligo can be seen in 10%–20% of patients.153 Axillary and pubic hair may be sparse in women, due to the loss of adrenal androgens. This does not occur in men because adequate androgen levels are maintained by the testes. Unique to men is the reported calcification of the auricular cartilages.154 Extracutaneous symptoms include weakness, anorexia, weight loss, abdominal pain, and postural hypotension due to electrolyte abnormalities.

Laboratory Tests

Acute adrenal crisis can occur in the setting of chronic adrenal insufficiency and can be life threatening. The primary treatment is glucocorticoid replacement and, in an acute crisis, a blood sample should be obtained for measurement of cortisol, but therapy with 100 mg IV hydrocortisone should be instituted immediately. In chronic adrenal insufficiency, the diagnosis is confirmed using the cosyntropin stimulation test. This involves the IV administration of synthetic corticotropin (ACTH) and the measurement of stimulated cortisol in the blood 30 minutes later. Inability to produce adequate cortisol is diagnostic. Chronic replacement therapy is necessary and may require adjustments for illness or severe stress. With treatment, there is a gradual improvement in the skin changes.

Estrogen and Progesterone

Epidemiology

The most commonly encountered cause of estrogen excess is the pharmacologic use of estrogens for birth control, treatment of dysfunctional uterine bleeding, and as postmenopausal hormone replacement. Up to one-third of child-bearing age women in the United States use oral contraceptives.155 Ovarian, testicular, or hypothalamic tumors can also cause estrogen excess. Estrogen deficiency occurs most commonly as a result of menopause, which occurs on average at about 50 years of age. Other less common causes of estrogen deficiency include pituitary or gonadal failure. Exercise-induced amenorrhea is also associated with a concomitant estrogen deficiency.

Etiology and Pathogenesis

Estrogen receptors are found throughout the skin, including on keratinocytes, sebaceous glands, eccrine and apocrine glands, in hair follicles, in dermal fibroblasts, and in melanocytes. In women of reproductive age, reported variations in dermatological responses seen throughout the menstrual cycle suggest that estrogens and progesterones have important effects on the clinical presentation of numerous disease states and allergic conditions of the skin.156 Estrogens bind to cytosolic receptors that subsequently translocate to the nucleus and activate gene transcription. Estrogen receptors are found in greater numbers in women compared with men. The main observations regarding the effects of estrogen on skin come from studies of postmenopausal women, in whom estrogen deprivation leads to skin wrinkling, xerosis, and atrophy. Increased epidermal and dermal thickness, increased water-holding capacity, changes in lipid composition of the stratum corneum, and improvement in skin laxity all occur with estrogen replacement, highlighting the important effects of this hormone throughout the skin.157 Estrogen deprivation has also been reported to hinder wound healing, which subsequently improves with estrogen replacement. Estrogens have also been reported to suppress sebaceous gland function and also tend to inhibit hair growth.

The most potent naturally occurring estrogen is estradiol, which is the principal estrogen secreted by the ovary. Estrone, another estrogen secreted by the ovaries, is synthesized primarily in peripheral tissues from the conversion of androstenedione. In the menstrual cycle, estradiol levels peak at midcycle immediately preceding ovulation, and then again near the end of the cycle around day 24 before falling to baseline before menses. During pregnancy, the main estrogen is estriol, which is synthesized by the placenta. Progesterone is the main hormone secreted by the corpus luteum, and peak levels are seen after ovulation, remaining elevated until just before menses. Gonadal hormones are not entirely specific, and progesterone is able to crossreact by binding to androgen receptors to exert androgenic or antiandrogenic effects.

Clinical Findings and Diagnosis: Cutaneous Manifestations of Estrogen Excess and Deficiency

Estrogen can have both beneficial and undesired effects. Estrogen replacement therapy in postmenopausal women can reverse epidermal atrophy and restore cutaneous collagen. The inhibitory actions of estrogen on sebum production can lead to improvement of acne with oral contraceptive therapy, particularly with the use of estrogen-dominant preparations. Despite circulating estriol during pregnancy, the relative androgen excess due to elevated progesterone can actually exacerbate acne in some patients. Telogen effluvium characterized by diffuse loss of scalp or body hair can occur after delivery or discontinuation of oral contraceptives. Both pregnant women and patients taking synthetic estrogen can be more prone to certain side effects of estrogen, including telangiectasias, palmar erythema, spider angiomas, and pigmentary changes.

Melanocytic lesions, including preexisting nevi and malignant melanoma, can darken during pregnancy. Hyperpigmentation of the nipples, linea nigra, and genitalia can be seen. Melasma, sometimes referred to as the mask of pregnancy, presents as irregularly shaped, hyperpigmented patches on the forehead, cheeks, nose, upper lip, chin, and neck (Fig. 151-13). Although melasma may improve after delivery, it can persist or reoccur with subsequent pregnancies. When caused by oral contraceptives, melasma can still persist even after discontinuation of the medication. In the very rare cases of men with melasma, the suspected etiology is thought to be sun exposure or familial susceptibility rather than estrogen excess, but the clinicopathological features are similar to that seen in female patients.158

Acanthosis nigricans can be associated with estrogen excess. In clinical states characterized by elevated estrogen levels, including pregnancy and the use of oral contraceptives, increased hair growth over the face, breasts, and extremities can be seen. This phenomenon may be a result of the complex interplay of estrogens and androgenic hormones rather than a direct effect of increased estrogen levels on the hair follicles themselves. Estrogen and progesterone dermatitis has been described in the literature and is characterized by a polymorphous eruption marked by cyclical premenstrual flares that may include pruritus. The diagnosis may be made by separate subcutaneous injection of both estrogen and progesterone in the skin of the forearm, checking within 15–60 minutes for reactions ranging from erythema to a wheal.159 Oral contraceptives have been implicated as a cause of erythema nodosum.

Estrogen deficiency from either menopause or pituitary failure can result in hot flashes, epithelial atrophy of the genitalia, and decreased breast size. Certain medications, such as danazol, leuprolide, and clomiphene citrate, can induce a pharmacologic menopause that presents with flushing. Flushing episodes accompanied by uncomfortable heat lasting several minutes can occur in younger women immediately before or during their period when estrogen levels are at their lowest.

Treatment

The Pigmentary Disorders Academy generated a consensus statement on the treatment of melasma and recommended the use of fixed “triple-ingredient” combinations as first-line therapy.160 Topical retinoids, corticosteroids, azelaic acid, and hydroquinone-based bleaching creams have been used in various combinations to treat melasma. Kligman's formula, first developed in 1975, is the classic triple-ingredient melasma preparation consisting of 5% hydroquinone, 0.1% tretinoin, and 0.1% dexamethasone in a hydrophilic ointment. Dual ingredient combinations or single agents are reasonable alternatives. For refractory cases, chemical peels (i.e., glycolic acid or trichloroacetic acid) in combination with topical therapy can be tried. Lasers can also be considered but seem to be of limited usefulness. Given the exacerbation of hyperpigmentation with sun exposure, the consistent use of broad-spectrum sunscreens is also important for melasma treatment.

Although estrogen therapy can reverse some of the epithelial atrophy seen during menopause, the risks and benefits of hormone replacement therapy must be weighed on an individual basis. Low-dose clonidine has been reported as an effective treatment for menopause-related flushing. There has been controversy regarding the use of estrogen therapies in patients with systemic lupus erythematosus, although two recent, well-designed trials suggest that these therapies can be used safely in most patients with systemic lupus erythematosus whose disease is stable.161,162

Androgenic Hormones

Epidemiology

In males, cutaneous manifestations of androgen excess occur most commonly with either the onset of sexual maturation or with androgen replacement therapy. Androgen-secreting tumors are a less common cause of androgen excess. In women, androgen excess can occur due to congenital adrenal hyperplasia (CAH) secondary to deficiency of enzymes in adrenal enzymes such as 21-hydroxylase (encoded by the gene CYP21A2), which accounts for almost 90 percent of CAH in the United States.163 Deficiency of CYP21 is inherited as an autosomal recessive trait and results in accumulation of 17-hydroxyprogesterone. Although progestins in oral contraceptives are listed as potential causes of hirsutism due to their chemical similarity to testosterone, they likely do not cause androgenic effects at clinically used doses based on data from animal studies. Polycystic ovary syndrome (PCOS) occurs in about 5% of premenopausal women in the United States and is characterized by insulin resistance, polycystic ovaries, and the presence of androgenic cutaneous findings, including acne, hirsutism, and androgenic alopecia. PCOS is also associated with the metabolic syndrome, which is characterized by lipid abnormalities, diabetic predisposition, and heart disease. Androgenic alopecia affects approximately one-half of men older than age 40 years, and potentially as many women as well, with most patients showing signs of alopecia by age 30 (see Chapter 88).

Etiology and Pathogenesis

Like estrogen receptors, androgen receptors are also present throughout the skin. In men, androgens are synthesized in the testis and adrenals, whereas in women androgens are secreted by the ovaries and adrenals. In addition to testosterone, progesterone, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEA-S) are all natural androgens that can lead to cutaneous findings when they are present in excess.164 Testosterone is subsequently converted in peripheral target tissues to the active metabolite 5 α-dihydrotestosterone (5α-DHT) by the enzyme 5α-reductase. Unlike testosterone, which can be aromatized to form estrogen, 5α-DHT cannot be aromatized and thus retains purely androgenic properties. In addition, 5α-DHT binds the androgen receptor with greater affinity than testosterone.

Androgens are significant regulators of hair growth and sebaceous gland function. Androgens have also been implicated in wound healing, epidermal differentiation, and the regulation of dermal fibroblasts. Androgen receptors have a trophic distribution throughout the body that is most evident with the appearance of “male pattern” hair growth on the face, chest, and back, as well as areas of hair loss on the scalp. Both estrogens and androgens can be bound by sex hormone-binding globulin (SHBG). SHBG levels are decreased by synthetic progestins found in oral contraceptives (i.e., norgestrel, norethindrone, norgestimate, and desogestrel), as well as in obesity, acromegaly, hypothyroidism, and hyperinsulinemia. The decreased SHBG results in higher levels of circulating androgens and accounts, in part, for why androgenic findings can be associated with these conditions.

Clinical Findings and Diagnosis: Cutaneous Manifestations of Androgen Excess

Androgen-related skin conditions are commonly seen in dermatology practice. Although our knowledge regarding acne pathogenesis is still incomplete, at least part of acne's pathophysiology involves the response of sebaceous glands to androgens. In most males and females, acne tends to subside after adolescence (see Chapter 80). Cases of persistent acne should elicit a differential diagnosis that includes causes of persistent androgen excess, including CAH, PCOS in women, or an androgen-secreting tumor (Fig. 151-14), in addition to rosacea and chemically induced acne. In the appropriate clinical setting, laboratory studies may be helpful in determining the source of androgen excess (Box 151-16). Performance-enhancing anabolic steroids are derivatives of testosterone, and the resulting androgen excess can manifest as acne.

There is some genetic variation underlying the response of hair follicles to androgens as evidenced by the varying degrees of hirsutism seen among women with different ethnic backgrounds but similar serum androgen levels. Hirsutism secondary to androgen excess occurs in a characteristic distribution involving the beard region of the face, the chest, the upper back, and the suprapubic area.

Ironically, although androgens can cause hair excess, they are also responsible for male-pattern alopecia as well. Scalp hairs are eventually converted first to indeterminate hairs and then to vellus hairs. Clinically, scalp hairs become thinner until they are replaced by nonpigmented vellus hairs. In men, the pattern is characteristic and consists of symmetric recession of the hairline and the temples along with hair loss on the vertex. In women, the frontal hairline is usually preserved, and the pattern is mostly diffuse thinning without an area of frank baldness. Although androgenetic alopecia can be acquired in patients with androgen excess, it is most commonly an incompletely characterized genetic disorder that appears to be inherited in an autosomal dominant manner (see Chapter 88).

Treatment

In women whose acne appears to be hormonally related, the use of antiandrogens, including the diuretic spironolactone or the oral contraceptive drospirenone, may prove more effective than conventional topical and oral acne medications. These drugs act as competitive inhibitors of DHT binding to androgen receptors. Specific 5α-reductase inhibitors, such as finasteride, can be used to treat androgenetic alopecia, although this medication is contraindicated in women of child-bearing age due to possible effects on development of genitalia and gonads in the male fetus. The use of finasteride has been linked to an increased risk of high-grade prostate cancer but without an increase in the absolute risk of prostate cancer in men with benign prostatic hypertrophy, although similar data on men using finasteride for hair loss has not been reported.165 In postmenopausal women finasteride treatment has not demonstrated significant benefit in a large placebo-controlled trial.166

When patients have an excess of adrenal androgens such as DHEA-S, the use of low-dose glucocorticosteroids (such as prednisone, 2.5–5.0 mg/day) can be used for suppressive therapy, and the efficacy of therapy can be monitored by measuring serum DHEA-S levels. Cyproterone acetate is an antiandrogen that is not available in the United States, although it has shown promise in the treatment of acne when used in other countries in oral contraceptive preparations. Flutamide is a nonsteroidal androgen receptor antagonist that is rarely used due to the risk of fatal hepatitis as well as concerns about effects on fetal development in women of child-bearing age.167

Acromegaly

GH is secreted by the pituitary in a pulsatile fashion and reaches its maximum rate during puberty and then declines over time. The pulsatile pattern of secretion is equally important to the amount of hormone for normal function. Secretion of GH is primarily regulated by GH-releasing hormone (GHRH) and somatostatin.168 The natural GH secretagogue ghrelin, produced in the stomach, has been discovered to have potent GH-releasing properties and may be involved in a separate pathway of GH regulation.168,169 GHRH stimulates the release of GH, whereas somatostatin has an inhibitory effect. The target of these regulatory factors is the GHRH receptor in the pituitary. The peripheral effects of GH are largely indirectly mediated through production of IGF1 in the liver and stimulation of the IGF1 receptor. GH contributes significantly to linear growth in children, increases protein synthesis, mobilizes stored triglycerides, and antagonizes the action of insulin (Fig. 151-15).

Etiology and Pathogenesis

Excessive production of GH is almost always due to a pituitary adenoma. In children, this results in pituitary gigantism, whereas in adults, excessive GH manifests as the clinical syndrome acromegaly. This syndrome is diagnosed in about 3 to 4 people per million every year.170 Very rarely, acromegaly is caused by a GH-producing tumor in the hypothalamus or by an ectopic nonendocrine tumor such as small cell lung cancer or carcinoid tumor.171 GH-producing adenomas are present in 8% of patients with Carney complex, an inherited disorder with multiple lentigines and multiple endocrine abnormalities.172

Clinical Findings

(Box 151-17). The clinical manifestations of acromegaly include the overgrowth of bone and connective tissue, metabolic effects, and localized tumor mass effects. The onset is insidious, and the average age at the time of diagnosis is 40–45 years, but often the condition has been present for many years before the diagnosis.173 The metabolic effects include diabetes, hypertension, and hyperlipidemia. There is a gradual coarsening of the features and increased head, hand, and foot size. This acral pattern of overgrowth may be noticed as increasing shoe, ring, glove, or hat size (Fig. 151-16A). Macroglossia can be seen. The skin becomes thickened, almost doughy, with deep grooves prominent on the forehead and around the nasolabial folds (Fig. 151-16B). On the scalp, cutis verticis gyrata may develop. Heel pads and the pads of the digits become thickened. Nails are thickened and brittle, and some patients develop hirsutism. Hyperhidrosis and malodor are common complaints. Many patients develop acanthosis nigricans and multiple acrochordons with or without frank diabetes. Retinal angioid streaks can be seen in acromegaly (as well as in osteogenesis imperfecta and pseudoxanthoma elasticum) (see Chapter 137). Histologically, there is a dense deposition of GAGs in the papillary and superficial reticular dermis. Often, coarse collagen bundles with normal elastin and increased numbers of fibroblasts are seen in the dermis.

Laboratory Tests

Measurement of the serum GH level is highly variable and unreliable diagnostically because of the pulsatile pattern of secretion. Plasma IGF1 levels are very much dependent on GH and fairly stable during any 24-hour period. Serum IGF1 can be used as a surrogate measurement of GH. As a screening test for acromegaly, IGF1 levels will be elevated. Further workup with assistance from a consulting endocrinologist may include an oral glucose tolerance test. In the proper clinical setting failure to suppress the GH level to <1 ng/mL within 1–2 hours after 75–100 g of oral glucose is diagnostic for acromegaly.174

Treatment

Because most cases of GH excess are due to a pituitary adenoma, surgical removal is the primary therapy. This is most commonly accomplished through a selective transsphenoidal resection.175 Residual disease after surgery is more common in larger adenomas and may be higher than 30% for tumors larger than 1 cm. The inhibitory effect of somatostatin on GH secretion is harnessed for therapy. Somatostatin analogues, including octreotide, are used for the medical treatment of residual disease after surgery and are increasingly being considered as potential primary therapy. The somatostatin analogues alone have demonstrated the ability to reduce the size of tumors and to control IGF1 levels in select patients. In resistant cases, radiation therapy can be considered.

Growth Hormone Deficiencyand Panhypopituitarism

GH deficiency can occur in children or adults and be inherited or acquired. The primary clinical manifestation of this deficiency occurs in children as abnormal short stature. This can be corrected by the administration of GH. The clinical presentation of GH deficiency in adults includes decreased lean body mass, decreased strength and exercise capacity in part due to decreased sweating, and a loss of general vitality. Replacement therapy in adults is a complex discussion and beyond the scope of this chapter. Recently, practice guidelines have been established by the Endocrine Society for the assessment and treatment of GH deficiency in adults.176 In the setting of panhypopituitarism, there is total loss of all pituitary function, including GH (Box 151-18). These patients usually present with a combination of symptoms either due to a space-occupying lesion in the pituitary or to hormone dysregulation. These symptoms may be a manifestation of any number of endocrine systems that are regulated at the level of the pituitary including features of hypothyroidism. Skin findings that have been described in these patients include fine wrinkling of the skin, decreased pigmentation, and decreased to absent pubic and axillary hair (Fig. 151-17).