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 capac-
ity and abnormal hemoglobin oxygen affinity.46 Treat-
ment 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 complica-
tions 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 stud-
ies could not detect defects at the cellular level,48 other
studies show that leukocyte chemotaxis, adherence,
and phagocytosis are impaired in patients with dia-
betes, 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 dia-
betic patients are shown in Table 151-1.
DIABETIC ULCERS
EPIDEMIOLOGY. Foot ulcers are a significant prob-
lem for patients with diabetes, occurring in 15%–25% of
diabetic patients.50 Patients with diabetes have an
estimated increased risk of lower extremity amputa-
tion that is 10–30 times greater than the general popu-
lation. 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 con-
tribute to the pathogenesis of diabetic ulcers. Periph-
TABLE 151-1
Infections More Common or Severe in Diabetes
Bacteria Fungal and Yeast
Invasive Group B Strep Candida
Invasive Group A Strep Dermatophyte
Malignant external otitis Rhinocerebral
Necrotizing fasciitis Mucormycosis
eral neuropathy, pressure, and trauma are felt to play
prominent roles in the development of diabetic ulcers.
26
Neuropathy (associated with uncontrolled hyperglyce-
mia) 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 neuroin-
flammatory signaling via neuropeptides to keratino-
cytes, fibroblasts, endothelial cells, and inflammatory
cells may adversely affect wound healing.55 Excessive
plantar pressure develops from foot deformities (Char-
cot 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 reduc-
Chapter 151
tion 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 previ-
::
ous foot ulceration, prior lower extremity amputation,
Diabetes Mellitus and Other Endocrine Diseases
long duration of diabetes (>10 years), impaired visual
acuity, onychomycosis, and poor glycemic control.
Boyko and colleagues have recently published a pre-
diction 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 promi-
nences 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.
Figure 151-5 “Diabetic foot.” Two larger ulcers overlying
the first right and second left metacarpophalangeal joints
in a 56-year-old man with diabetes of 20 years’ duration.
There is significant sensory neuropathy and peripheral
vascular disease. 1845
26 Approach to care for the diabetic foot and diabetic ulcers

Risk factors for diabetic ulcers

Elevated A1C
Vision poorer than 20/40
History of foot ulcer Address modifiable
risk factors
History of amputation
Monofilament insensitivity
Onychomycosis

Ulcer present NO
Section 26 ::

YES

YES Palpable foot pulses NO

Clinical signs of cellulitis Non-invasive vascular assessment

Skin Manifestations of Internal Organ Disorders

or osteomyeltis NO
demonstrates clinically significant arterial
obstruction (ankle-brachial index ? 0.8)
YES NO (TcPO2 20)

Sharp debridement
Eliminate pressure
Consider osteomyelitis
evaluation and begin
appropriate antibiotics
YES
Perform sharp
débridement
Eliminate pressure Referral for vascular care
Eliminate pressure
with removable device
Treat any infection

Moist wound healing

Reduction of edema with compression

YES Improvement by 4 weeks NO

Regular follow-up Education Check compliance

about foot care Address Reassess for infection
modifiable risk factors Consider adjuvant care

Figure 151-6 Approach to the care of the diabetic foot and diabetic ulcers. A1C = hemoglobin A1C; TcPO2 = transcutane-
ous oxygen tension.178

TREATMENT. Treatment of diabetic ulcers requires
modification of factors that contribute to ulcer forma-
tion, for example, stasis dermatitis, leg edema, and skin
infection. Standard therapy for neuropathic dia- betic
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 stan-
dard 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
1846 A large multicenter, clinical trial of a bilayered liv-
ing skin equivalent60 showed 56% healing at 12 weeks
as compared with 38% healing for standard care. The
most favorable published results for a monolayered liv-
ing 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 effective-
ness 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 treat-
ment 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 impor-
tant 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 sup-
ported 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 exami-
nation 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 impres-
sive results on the prevention and healing of ulcers.62
This multidisciplinary team approach is becoming
BOX 151-2 GENERAL FOOT CARE
GUIDELINES FOR PATIENTS WITH
DIABETES
Examine feet every day, including areas between
the toes.
Regular washing of feet with careful drying, espe-
cially between the toes.
Water temperature should always be less than 37°C
(98.6°F) and checked first with the hand rather than
the foot.
Barefoot walking in- or outdoors and wearing of
shoes without socks is discouraged.
Daily inspection and palpation of the inside of the
shoes for irregular surfaces or foreign objects.
If vision is impaired, patients should not try to treat
their feet (e.g., nails) by themselves.
Emollients should be used for dry skin but not be-
tween the toes.
Change stockings daily.
Wearing of stockings with seams inside out or pref-
erably without any seams at all.
Nails should be cut straight across.
Corns and calluses should not be cut by patients but
by a health care provider.
The patient must ensure that the feet are examined
regularly by a health care provider.
The patient should seek early health care attention
for any blister, cut, scratch, sore, ingrown toenail, or
dermatitis.
more important in the treatment of diabetic ulcers in
large population centers. Patients with a history of
26
ulceration are at high risk for reulceration (34% at 1
year, 61% at 3 years, and 70% at 5 years).56 Intensify-
ing education (formal foot care classes) and prevention
efforts in this group along with lifelong surveillance is
required.
DISORDERS ASSOCIATED WITH
DIABETES MELLITUS BUT OF
UNKNOWN PATHOGENESIS
Chapter 151
NECROBIOSIS LIPOIDICA
EPIDEMIOLOGY AND PATHOGENESIS.
Coined by Urbach in 1932 as necrobiosis lipoidica dia-
beticorum, this disorder was named after characteristic
::
histologic findings and was first described in patients
with diabetes. Because not all patients have concurrent
Diabetes Mellitus and Other Endocrine Diseases
diabetes, the shortened term, necrobiosis lipoidica (NL)
is preferred. Epidemiologic data show that the mean
age of onset is around 30 years, with women repre-
senting 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 preva-
lence of NL has been found to be only 0.3%–3.0% in
patients with diabetes.63 Although lacking full concor-
dance, NL definitely has a strong association with dia-
betes and remains a valid marker of the disease. The
pathogenesis of this skin disease is unclear. Many etio-
logic mechanisms have been proposed and reviewed.65
Evidence suggests that the degree of hyperglycemia
and diabetic control does not correlate with the pres-
ence of NL.66
CLINICAL FINDINGS: CUTANEOUS LESIONS.
Classically, NL presents with one to several sharply
demarcated yellow–brown plaques on the anterior pre-
tibial 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 annu-
lare (GA). Over time, the lesions flatten, and a central
yellow or orange area becomes atrophic, and com-
monly telangiectasias are visible, taking on the charac-
teristic “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 spon-
taneous remission in less than 20% of cases.10 Over
time, the plaques tend to stabilize, and formation of
1847
26
Section 26 ::

A B

Figure 151-7 Necrobiosis lipoidica. A. A single orange plaque with atrophy of the overlying epidermis and arborizing
Skin Manifestations of Internal Organ Disorders

telangiectasias is seen on the lower leg of a juvenile with diabetes mellitus; the crust marks an area of early ulceration.
B. Older lesions with striking central atrophy involving both the dermis and epidermis.
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
63,65
approximately 13%–35% of cases on the legs.
cases of squamous cell carcinoma arising in chronic
ulcerative lesions of NL have been reported. Mul- 68
tiple reports document the association of NL with GA
and sarcoidosis.69
TREATMENT. Treatment for NL is disappointing. diabetes among patients with GA (18%) as compared
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 glucocor-
ticoids 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. Aspi-
rin 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 ulcer-
ation occurs in patients with NL, the same wound care
principles apply as for all diabetic ulcers. Healing of
ulcerated lesions with cyclosporine has been demon-
strated 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)
1848
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 associ-
A few
ation with diabetes is supported in the literature. Dab-
ski 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
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 compli-
cations 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 with-
out 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 mac-
ules 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 appear-
ance of new lesions gives the sense that the pigmenta-
tion and atrophy are persistent.
An association seems to exist between diabetic der-
mopathy 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 neuropa-
thy.81 Diabetic dermopathy does not, however, correlate
with obesity or hypertension in patients with diabetes.79
No treatment is necessary for the individual atrophic tib-
ial 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 tran-
sepidermal elimination or “spitting” of altered dermal
constituents. Included in this group are Kyrle disease,
reactive perforating collagenosis, perforating fol-
liculitis, and elastosis perforans serpiginosa.82 These
disorders and their treatment83 are fully described in
Chapter 69.
Figure 151-8 Diabetic dermopathy with hyperpigment-
ed macules on the anterior lower legs.
Clinically, these lesions appear as pruritic, keratotic
papules mainly on the extensor surfaces of the extrem-
26
ities. Papules and nodules with a perforating compo-
nent 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 dis-
orders 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
Chapter 151
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 for-
::
mation in patients with diabetes.84 Reduced suction
Diabetes Mellitus and Other Endocrine Diseases
blister time is also observed with increasing age in
nondiabetic subjects.85 Although a history of anteced-
ent 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 dis-
tal upper extremities are involved. The blisters are usu-
ally 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. Stud-
ies 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 immunopatho-
logic features are consistently observed (Box 151-3).
BOX 151-3 DIFFERENTIAL DIAGNOSIS
AND EVALUATION OF BULLOSIS
DIABETICORUM
DIFFERENTIAL DIAGNOSIS
Bullous impetigo Bullous
pemphigoid Epidermolysis
bullosa acquisita Porphyria
cutanea tarda
Bullous erythema multiforme
Insect bite reaction
LABORATORY TESTS
Skin biopsy for histology and immunofluorescence
Bacterial cultures
Screening for porphyrins
1849
26 BD runs a benign course without involvement of
large body surface areas. The only serious complica-
tion 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 diagno-
sis because several of the blistering skin diseases have
a high rate of morbidity and require potentially toxic
systemic treatments. Even a negative workup is impor-
tant. The patient should be educated, reassured, and
good wound care implemented.
OBESITY AND THE METABOLIC
SYNDROME
Section 26 ::
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
Skin Manifestations of Internal Organ Disorders
the WHO defines overweight as a BMI of >25 and obe-
sity 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 Sur-
vey (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 endo-
crine 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, depres-
sion 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 genet-
ics 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 metabo-
lism.87 Rare cases in humans have shown that leptin
deficiency causes extreme obesity, hyperphagia, dia-
betes, 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
1850
forms of lipoatrophy (HIV or HAART associated)
are characterized by low leptin levels and metabolic
abnormalities including insulin resistance, hyper-
lipidemia, and fatty liver. Leptin treatment in these
patients can improve insulin resistance, lipid abnor-
malities, and fat distribution.88,89
Leptin stimulates the hypothalamic melanocortin
pathway including hypothalamic neurons expressing
POMC. Cleavage of POMC results in peptide ago-
nists 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 over-
expressed. Though studies have found high serum
AGRP levels in obese men,92 the role of AGRP in com-
mon 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 com-
plex and several gut hormones are likely involved
in the regulation of food intake. The gastric derived,
appetite stimulating hormone ghrelin impacts obe-
sity 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 sur-
gery 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 recep-
tors 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 epider-
mal 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 in online
edition), 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 discus-
sion 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
 BOX 151-4 CUTANEOUS DISORDERS
weight reduction and exercise along with adequate
control of cardiac risk factors.
26
The cornerstones of treatment for overweight and
ASSOCIATED WITH OBESITY obesity are dietary changes, increased physical activ-
METABOLIC ity, and behavioral modification. In high-risk patients
Acanthosis nigricans with comorbid conditions, pharmacologic therapy
(sibutramine or orlistat) can be considered as an addi-
Acrochordons tional intervention. In clinically severe obesity, surgical
Keratosis Pilaris therapies may be appropriate. All successful patients
Hyperandrogenism will require long-term nutritional adjustments that
Hirsutism reduce caloric intake. The role of liposuction in weight
Tophaceous gout 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
INFECTIOUS
associated with obesity.102,103
Candidiasis

Chapter 151
Dermatophytosis
Intertrigo THYROID DISEASE
Cellulitis
Erysipelas
Necrotizing fasciitis THYROID DISEASE AT A GLANCE

::
The most common cause of hyperthyroidism

Diabetes Mellitus and Other Endocrine Diseases

MECHANICAL
is Graves disease, characterized by the
Plantar hyperkeratosis triad of autoimmune thyroid disease, eye
Striae distensae disease, and thyroid dermopathy (pretibial
Lymphedema myxedema).
Elephantiasis nostras verrucosa
Venous stasis Toxic multinodular goiter is another cause of
hyperthyroidism that should be considered,
Cellulite
particularly in elderly individuals.
MISCELLANEOUS
Serious signs of thyrotoxicosis include atrial
Hidradenitis supprativa fibrillation and fever.
Adiposis dolorosa
Psoriasis

Hashimoto thyroiditis and thyroid ablation

these disorders increases the risk for diabetes and car-
diovascular 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
for treatment of hyperthyroidism are the two
most common causes of hypothyroidism.
The best screening test for thyroid disease is
thyrotropin (TSH), which is elevated in
hypothyroidism and depressed or absent in
hyperthyroidism.

BOX 151-5 DEFINITION OF THE

METABOLIC SYNDROME (ANY THREE
OF FIVE TRAITS)
1. Abdominal Obesity
2. Serum triglycerides ≥150 mg/dl (or drug treatment
for elevated triglycerides)
3. Serum HDL cholesterol <40 mg/dl in men and
<50 mg/dl in women (or drug treatment for low
HDL-C)
4. Blood pressure ≥130/85 (or drug treatment for
elevated blood pressure)
5. Fasting plasma glucose ≥100 mg/dl (or drug treat-
ment for elevated blood glucose)
EPIDEMIOLOGY. Worldwide estimates of the prev-
alence 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 goi-
ter 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 exoph-
thalmos.105 Although the incidence of Graves disease
is similar between whites and Asians, it appears to be 1851
26 lower in blacks.105 Toxic adenoma and toxic multinodular
goiter refer to the hyperplastic growth of thyroid tis- sue
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 hypo-
thyroidism in 4.6% of the US population, although
>90% of individuals with tests consistent with hypo-
thyroidism 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
Section 26 ::
neonates worldwide due to either an absent or ana-
tomically defective gland, inborn errors of thyroid
metabolism, or iodine deficiency.107 Congenital hyper-
thyroidism is much less common, and although 0.2% of
pregnant women have Graves disease, only about
1% of the resultant neonates will have hyperthyroid-
Skin Manifestations of Internal Organ Disorders
ism, with most cases resulting from the transfer of
maternal thyroid-activating autoantibodies.108
ETIOLOGY AND PATHOGENESIS. The meta-
bolic 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 tis-
sues by activating cytoplasmic receptors that subse-
quently translocate to the nucleus and activate specific
thyroid-responsive genes.109 Thyroid hormone synthe-
sis is heavily dependent on iodine and, consequently,
changes in iodine intake can result in both hyperthy-
roidism and hypothyroidism.
Synthesis of thyroid hormone is regulated by the
pituitary via release of TSH in response to hypotha-
lamic 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 recep-
tor. 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 pro-
vide feedback regulation (eFig. 151-8.2 in online edi-
tion). 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-bind-
ing globulin, which is the major determinant of protein
1852
BOX 151-6 MEDICAL CONDITIONS
THAT CAN AFFECT THYROID
HORMONE LEVELS
Increased thyroid-binding globulin
Pregnancy
Infectious/chronic active hepatitis
Biliary cirrhosis
Acute intermittent porphyria
Decreased thyroid-binding globulin
Chronic liver disease
Severe systemic illness
Active acromegaly
Nephrosis
Decreased peripheral conversion of thyroxine to
triiodothyronine
Fasting/malnutrition
Systemic illness
Physical trauma
Postoperative state
binding, and to a lesser extent transthyretin (formerly
called prealbumin) and albumin. A variety of medical
conditions (Box 151-6) and medications can alter lev- els
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 medica-
tions, including several that are prescribed by derma-
tologists (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 synthe- sis
of thyroid hormone, while diminished or absent
radioiodine uptake suggests either an extrathyroidal
source of thyroid hormone or the destruction of thy-
roid tissue with concomitant release of preformed thy-
roid 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 identi-
fied 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 epithe-
lium 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
 BOX 151-7 MEDICATIONS AFFECTING
with pituitary failure, a tumor of the pituitary region,
or postpartum pituitary necrosis (Sheehan syndrome).
26
THYROID HORMONE LEVELS Inadequate secretion of TRH by the hypothalamus is
another very rare cause of hypothyroidism.
Drugs that affect thyroid hormone secretion
Lithium (decreases secretion)
Iodide (can increase or decrease secretion)
CLINICAL FINDINGS
Amiodarone (can increase or decrease secretion)
Drugs that increase serum thyroid-binding globulin CUTANEOUS MANIFESTATIONS OF
concentrations HYPERTHYROIDISM
Estrogens/tamoxifen
(Box 151-8) Signs and symptoms of hyperthyroidism
Heroin/methadone
and hypothyroidism are variably present and summa-
Fluorouracil rized in Table 151-2. The skin changes of hyperthyroid-

Chapter 151
Drugs that decrease serum thyroid-binding globulin ism have been likened to infant’s skin and described
concentrations as soft, warm, and velvety in texture. Pruritus can
Androgens be a manifestation of thyroid disease, and labora-
tory screening for thyroid disease is often included
Anabolic steroids
in working up patients experiencing diffuse pruri-
Slow-release nicotinic acid tus with no obvious rash. Scalp hair in hyperthyroid
Glucocorticoids patients is described as soft and fine, and in certain

::
Drugs that increase hepatic metabolism of thyroid

Diabetes Mellitus and Other Endocrine Diseases

hormone
Phenobarbital BOX 151-8 APPROACH TO PATIENT
Rifampin
WITH HYPERTHYROIDISM
Phenytoin
Carbamazepine CUTANEOUS FINDINGS IN HYpERTHYROIDISM
Drugs that decrease deiodination of thyroxine to Soft, velvety, infant-like skin
triiodothyronine Thyroid dermopathy
Propylthiouracil (used to treat hyperthyroidism) Soft, fine with diffuse nonscarring alopecia
Amiodarone Facial flushing
β Blockers Palmar erythema
Glucocorticoids Hyperpigmentation
Certain radiographic contrast dyes Plummer’s nails
Drugs that decrease thyrotropin Thyroid acropachy
Bexarotene Hyperpigmentation
Adapted from Surks MI, Sievert R: Drugs and thyroid function.
N Engl J Med 333:1688, 1995. RELATED FEATURES
Hyperhidrosis
Atrial fibrillation
Ophthalmopathy
involved in keratinocyte proliferation and also stimu-
Goiter
late the expression of certain keratins.114
Approximately 95% of cases of hypothyroidism are High-output cardiac failure
thought to arise from defects in the thyroid gland itself, “Thyroid storm”
whereas the remaining cases result from defects in the
hypothalamic–pituitary axis. Ironically, the most com- DIAGNOSIS
mon cause of hypothyroidism without a goiter is the Best initial test is serum thyrotropin
surgical or radioiodine-induced ablation of the thy- Other tests include serum free triiodothyronine,
roid gland for the treatment of Graves thyrotoxicosis.
Cretinism occurs with untreated congenital hypothy- thyroxine, and antithyroid antibodies
roidism and does not have a goiter. The most common Radioactive iodine uptake and imaging
cause of hypothyroidism with a goiter in North Amer-
ica is Hashimoto thyroiditis. Less common causes of MANAGEMENT
hypothyroidism include inherited defects in hormone Appropriate surgical and endocrine consultation
synthesis or the ingestion of drugs that inhibit hor- Propanolol for symptomatic treatment
mone synthesis, such as lithium or aspirin. Bexarotene,
Propylthiouracil to inhibit thyroid hormone
a retinoid-X-receptor agonist (see Chapter 228) used
to treat cutaneous T-cell lymphoma, causes a central metabolism
hypothyroidism with a decrease in TSH, followed by Methimazole to inhibit thyroid hormone synthesis
low levels of T3 and T4.115 In rare cases, hypothyroid- Radioiodine ablation of the thyroid gland
ism can occur from decreased secretion of TSH, such as
1853
26 TABLE 151-2
on the body, are not limited to the pretibial region, and
the name does not suggest myxedema as a cause.116
Symptoms, Clinical Findings, and Complications Although there are reports of hyperthyroid patients
of Thyroid Disease who have presented with thyroid dermopathy as their
initial finding, thyroid dermopathy is usually a later
manifestation of thyroid disease. Almost all patients
Symptoms, Clinical Symptoms, Clinical with thyroid dermopathy also have thyroid ophthal-
Findings, and Findings, and mopathy, another late manifestation of hyperthyroid-
Complications of Complications of ism.117 The clinical appearance of thyroid dermopathy
Hyperthyroidism Hypothyroidism can be quite varied. Classically, thyroid dermopathy
occurs bilaterally as painless nonpitting nodules and
Symptoms Symptoms plaques with variable coloring and a waxy, indurated
Unintentional weight loss Unexplained weight gain texture (Fig. 151-9). The distribution can range from
Heat intolerance/sweating Fatigue very circumscribed to diffuse, but by far the most com-
Palpitations Cold intolerance mon location is on the extensor surfaces of the legs.117
Agitation/emotional Constipation Some cases can exhibit a peau d’orange appearance as
Section 26 ::

lability Dry skin well. An extreme form of diffuse thyroid dermopathy

Multiple daily loose stools
Pruritus Weakness
Oligomenorrhea in
women
Clinical Findings and
Skin Manifestations of Internal Organ Disorders
Muscle weakness has been termed the elephantiasic variant, which occurs
Carpal tunnel syndrome in less than 1% of patients with Graves disease and is
Hoarseness characterized by progressive thickening and gray-black
Decreased body hyperpigmentation of the pretibial skin accompanied
temperature by a woody, firm edema with nodule formation. The
Facial swelling

Complications exact pathophysiology underlying thyroid dermopa-

Goiter Menorrhagia in women thy is still unclear.116 Biopsies of thyroid dermopathy
Tachycardia Clinical Findings and reveal a thickened dermis with splayed collagen fibrils
Atrial fibrillation Complications and abundant mucin, usually hyaluronic acid, in the
High-output cardiac Goiter interstitial space.
failure Cold, doughy skin The increased amounts of hyaluronic acid in the
Fine tremor Bradycardia dermis and the subcutis have led the hypothesis
Hot sweaty extremities Facial and finger swelling that fibroblasts or other cells in the dermis may be
Ophthalmopathy Slowed relaxation of deep
Agitation/confusion tendon reflexes
Muscle weakness/wasting Hair loss/lateral eyebrow
“Thyroid storm” with fever, loss
confusion, dehydration, Pericardial effusion
and eventual death, if Myocardial infarction or
untreated congestive heart failure
with aggressive thyroid
hormone replacement
Coma and death without
treatment
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 ony-
cholysis (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 hyperthyroid-
ism. Vitiligo may often predate the diagnosis of thy-
roid 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 Figure 151-9 Hyperthyroidism with thyroid dermopathy
(Fig. 151-11). The term thyroid dermopathy is used in in a classic location on the anterior shins. Note that infil-
this chapter because the lesions can occur at any site trated plaques extend to the calf and are partially hyper-
keratotic. An isolated nodule is also present on the dorsum
1854 of the foot.