Transcript Cutaneous Manifestations of Internal Disease

Cutaneous Manifestations
of Internal Disease
Residents’ Conference
Hallie McDonald, MD
August 16, 2005
Diabetes Mellitus
According to Perez et al (3) ,approximately
30% of patients with DM develop skin
lesions at some point
 Overall prevalence of cutaneous disorders
does not differ between type I and type II
diabetics

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
Type I patients get more autoimmune-type
lesions
Type II patients get more cutaneous infections
Diabetes Mellitus


Cutaneous lesions usually appear after
the development of DM, but may be the
first presenting sign
Four major groups of skin findings
1.
2.
3.
4.
Skin diseases associated with DM (necrobiosis
lipoidica and diabetic bullae)
Cutaneous infections
Cutaneous manifestions of diabetic
complications (neuropathic ulcers)
Skin reactions to diabetic treatment
Necrobiosis Lipoidica (NL)
NL appears in 0.3-1.6% of diabetics (2,4)
 Anywhere from 11-65% of patients with
NL have DM at the time of skin dx (2,7,8)
 If they do not have DM at time of dx,
about 90% will develop diabetes, have
abnormal glucose tolerance, or report
parents with DM (2, 4)
 Diabetic control has no effect on the
course of NL.

Necrobiosis Lipoidica (NL)
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NL is 3x more common in women.
According to Jelinek, (9) NL appears earlier (mean
age 22) in Type I diabetics than Type II (mean
age 49.)
Appearance
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Begins as an oval, violaceous patch and expands slowly.
Advancing border is red.
Central area turns yellowish brown.
Central area atrophies and telangiectasia become
evident.
13% of cases progress to ulceration
Necrobiosis Lipoidica (NL)
Classically, NL occurs bilaterally on the
pretibial or medial malleolar areas.
 Not painful.
 Spontaneous resolution occurs in 13-19%
with residual scarring.
 Treatment: potent topical steroids,
intralesional steroids at the active border,
or rarely systemic steroids

Necrobiosis Lipoidica (NL)
Necrobiosis Lipoidica (NL)
Necrobiosis Lipoidica (NL)
Necrobiosis Lipoidica (NL)
Necrobiosis Lipoidica (NL)
Granuloma Annulare (GA)
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Controversy surrounds the association between
GA and DM.
A case-control study by Nebesio et al. (5) failed
to reveal a statistically significant correlation
between the two.
A retrospective study by Studer et al. (6)
suggested that up to 12% of patients presenting
with GA had DM.
Despite conflicting studies, it is reasonable to
screen patients presenting with GA for DM.
Granuloma Annulare (GA)

Appearance
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Histology
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Ring of small, firm, flesh-colored or red papules
If localized, most frequently found on lateral and dorsal
surfaces of hands and feet
Disease begins with an asymptomatic, flesh-colored
papule that undergoes central involution
Over months, a ring of papules grows
Can spontaneously regress without scarring
Focal degeneration of collagen in the upper and middermis, palisaded histiocytes around collagen bundles,
and abundant dermal mucin
Pathogenesis unknown
Granuloma Annulare (GA)
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Treatment
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If localized, best left untreated.
Can treat with intralesional steroids, if needed
If generalized, can also use dapsone,
isotretinoin, freezing, cyclosporin, or PUVA.
Granuloma Annulare (GA)
Granuloma Annulare (GA)
Granuloma Annulare (GA)
Granuloma Annulare (GA)
Granuloma Annulare (GA)
Granuloma Annulare (GA)
Granuloma Annulare (GA)
Histology showing focal
degeneration of
collagen in the upper
and mid-dermis,
palisaded histiocytes
around collagen
bundles, and abundant
dermal mucin
Diabetic Bullae
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Approximately 0.5% of diabetics (2)
More common in men with long-standing DM and neuropathy
Two types have been described
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Pathogenesis not well-understood
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More frequent, non-scarring lesions with a histologic intraepidermal
split without acantholysis
Less common, occasionally hemorrhagic bullae that heal with scarring,
slight atrophy, and have a histologic subepidermal split
Could be related to trauma with reduced threshold for blister formation
Other theories include immunologic factors, disturbed catabolism of
calcium, magnesium, or carbohydrates, microangiopathy, and vascular
insufficiency
Appearance
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Painless bullae on non-inflamed base that appear suddenly
Most common on the dorsa and sides of lower legs and feet,
sometimes with similar lesions on the hands and forearms
Bullae contain clear, sterile fluid
Diabetic Bullae
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Bullae tend to heal spontaneously in 2-5 weeks
Bullosis diabeticorum remains a diagnosis of
exclusion with negative immunofluorescence
studies, porphyrin levels, and cultures
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DDx: bullous pemphigoid, epidermolysis bullosa
acquisita, porphyria cutanea tarda, bullous impetigo,
erythema multiforme, and coma blisters
May recur in the same or new locations
If large and symptomatic, can aspirate the fluid
leaving an intact blister roof as a wound covering
Diabetic Bullae
Diabetic Bullae
Diabetic Bullae

Histology showing a
noninflammatory
blister with a
subepidermal and
focally intraepidermal
separation
Acanthosis Nigricans
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Seen in situations of insulin resistance
Besides in DM, also seen in the following:
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Carcinomas, especially of the stomach
Secondary to meds (nicotinic acid, estrogen, or
corticosteroids)
Pineal tumors
Other endocrine syndromes (PCOS, acromegaly,
Cushing’s disease, hypothyroidism)
Obesity
Pathogenesis

According to Cruz (12) , it may be related to insulin
binding insulin-like growth factor receptors on
keratinocytes and dermal fibroblasts, thus stimulating
growth.
Acanthosis Nigricans

Appearance
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Hyperpigmented, velvety plaques in body
folds, mostly axillae and neck
Can also present on groin, umbilicus, areolae,
submammary areas, and on the hands (tripe
hands)
Treatment- usually asymptomatic
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Weight loss
Retinoic acid and salicylic acid
Acanthosis Nigricans
Acanthosis Nigricans
Acanthosis Nigricans
Skin Infections in DM
Occur in 20-50% of poorly controlled
diabetics (2, 4)
 More common in Type II
 May be related to abnormal
microcirculation, hypohidrosis, PVD,
neuropathy, decreased phagocytosis and
killing activity, impaired leukocyte
adherence, and delayed chemotaxis all
seen in diabetics (2, 9, 10, 11)

Skin Infections in DM
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Fungal infections- most common
Candida
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Candidal paronychia
Inframammary candida
Genital candida
Psedudohyphae and spores on KOH prep support dx of
Candida
Purulent drainage may indicate secondary bacterial
infection
Because maceration and skin breaks can serve as portals of
infection, tinea pedis should be treated aggressively in
diabetics
Treatment includes drainage of any abscesses, keeping the
digits dry, and topical antifungals (clotrimazole)
Candidiasis in Diabetics

White, curdlike
material adherent to
erythematous,
fissured oral
commisure; angular
stomatitis
Candidiasis in Diabetics
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Initial pustules
on erythematous
base that
become eroded
and confluent
Candidiasis in Diabetics
Candidiasis in Diabetics
Candidiasis in Diabetics
Candidiasis in Diabetics
KOH prep showing pseudohyphae and budding
yeast forms
Skin Infections in DM
Bacterial Infections- can be more severe
and widespread in diabetics
 Malignant otitis externa
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Pseudomonas aeruginosa
Fatal in over 50% patients (13)
Can progress to chondritis, osteomyelitis, and
bacterial meningitis
Treat up to 3 months with oral quinolones but
may need IV antibiotics
Malignant Otitis Externa in Diabetics
Skin Infections in DM
Bacterial infections in DM
 Erythrasma
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Reddish tan scaling patches of the upper inner
thighs, axillae, toe web spaces, and
inframammary creases
Gram positive Corynebacterium minutissimum
Identified with Wood’s light coral fluorescence
Treat with oral erythromycin for 5 days
Erythrasma in Diabetics
Reddish
tan scaling patches of the upper
inner thighs, axillae, toe web spaces, and
inframammary creases
Erythrasma in Diabetics
Erythrasma in Diabetics
Wood’s Lamp in the Diagnosis of
Erythrasma
Cutaneous Manifestations of Diabetic
Complications: Foot Ulcers
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Responsible for 70% of annual lower limb
amputations in the U.S.(2)
Large economic impact from medical and surgical
therapy, rehab, loss of work, and mortality
Prevention is key
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Daily foot inspections, appropriate footwear
Causes for ulcer formation:
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Peripheral neuropathy (60-70%)
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Vascular disease (15-20%)
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Treatment: aggressive debridement and offloading or with
a contact cast
Treatment: surgical re-vascularization
Combination of peripheral neuropathy and vascular
disease (15-20%)
Cutaneous Reactions to Diabetic
Treatment

Insulin
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Allergy may be local or systemic and usually occurs within the
first month of therapy
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Lipoatrophy can also occur
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Erythematous or urticarial pruritic nodules at the site of injection
Circumscribed depressed areas of skin at the insulin injection site
6-24 months after starting insulin
More common in women and children
Pathogenesis unknown but may be related to lipolytic components
of the insulin preparation, an immune complex-mediated
inflammatory process with lysosomal enzyme release, cryotrauma
from refrigerated insulin, or mechanical trauma from injection
Lipohypertrophy can also occur
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Soft dermal nodules that resemble lipomas at sites of frequent
injection
May be a response to the lipogenic action of insulin
Treat and prevent by rotating sites of injection
Cutaneous Reactions to Diabetic
Treatment: Lipoatrophy
Cutaneous Reactions to Diabetic
Treatment- Insulin
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Highly purified or recombinant insulins have a
reduced allergy prevalence (0.1-0.2%) (4)
Observe the patient’s technique to make sure
it isn’t intradermal
Treatment includes substitution of a more
purified insulin, discontinuation or
desensitization for severe systemic rxns
Cutaneous Reactions to Diabetic
Treatment-Oral Hypoglycemics
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Most rxns are associated with the first-generation
sulfonylureas (chlorpropamide and tolbutamide)
1-5% of patients on these drugs will develop skin
rxns during the first 2 months of treatment (2,4)
Most commonly, they present with maculopapular
eruptions that resolve despite continuation of the
drug
For patients of chlorpropamide, 10-30% will
develop a disulfiram-like rxn of flushing,
headache, tachycardia, and shortness of break
after ingesting alcohol. This seems to be
autosomal dominant. (2,3)
Second-generation sulfonylureas can also be
associated with cutaneous rxns.
Hyperthyroidism and the Skin
Thyroid hormone plays a pivotal role in
the growth and formation of hair and
sebum production.
 Thyroid hormone stimulates epidermal
oxygen consumption, protein synthesis,
mitosis, and determination of epidermal
thickness.
 There is increased cutaneous blood flow
and peripheral vasodilation.

Hyperthyroidism and the Skin
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Skin is usually warm, moist, and smooth
Facial flushing
Palmar erythema
Hyperpigmentation, esp. creases of palms and
soles, gingiva, and buccal mucosa
Hyperhydrosis, particularly of palms and soles
Scalp hair can be soft, fine and sometimes
accompanied by non-scarring alopecia
5% of patients with hyperthyroidism have nail
findings (14)
Plummer’s Nail in Hyperthyroidism
“Plummer’s nail”: concave contour and distal
onycholysis, esp. the ring finger (not specific- also
seen in hypothyroidism, psoriasis, after trauma, or
in allergic contact dermatitis)
Scleromyxedema in Hyperthyroidism

Numerous firm white, yellow, or pink papules on
face, trunk, axillae, and extremities
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Lesions result from accumulation of hyaluronic acid in
the dermis, accompanied by large fibrocytes (14, 15)
Can be accompanied by weight loss, esophageal
dysmotility, vascular dz, Raynaud’s phenomenon,
monoclonal gammopathy, neurologic
manifestations, joint dz, and myopathy (14)
Treatment of hyperthyroid state with radioactive
iodine does not improve skin findings (14, 16)
Scleromyxedema in Hyperthyroidism
Firm
white, yellow, or pink papules on face, trunk,
axillae, and extremities
Scleromyxedema in Hyperthyroidism
Graves’ Disease
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These patients can have all of the other previously
mentioned cutaneous manifestations of hyperthyroidism in
addition to several unique entities
Pretibial myxedema (0.5-4% of patients)
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Presentation varies from “peau d’orange” appearance to
extensive infiltration that mimics elephantitis vurrucosa nostra
Most often, bilateral, asymmetric, raised, firm plaques or
nodules varying from pink to brown, sometimes with woody
induration
Can appear anywhere (arms, shoulders, head)
Can treat with topical steroids, intralesional steroids, IV pulse
steroids, or IVIG
Pathogenesis remains unknown, but one theory suggests
pretibial fibroblasts are the target for antithyroid antibodies(14)

In support of this theory, Wu et al. (16) reported the presence of
TSH and TSH receptor antibody binding in fibroblasts as well as
the presence of RNA encoding the extracellular domain of the TSH
receptor.
Pretibial Myxedema in Graves’ Disease

Bilateral, asymmetric,
raised, firm plaques or
nodules varying from pink
to brown, sometimes with
woody induration
Pretibial Myxedema in Graves’ Disease
Pretibial Myxedema in Graves’ Disease
Thyroid Acropachy in Graves’ Disease
Thyroid acropachy (1% of Graves’ patients)
Triad of digital clubbing, soft tissue swelling of hands and
feet, and periosteal new bone formation
Graves’ Disease and Thyroid Acropachy
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AP radiograph of the hand demonstrates
feathery periosteal bone proliferation of
the diaphyses of the metacarpals and
proximal phalanges
Hypothyroidism and the Skin
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Skin changes in hypothyroidism reflect a hypometabolic
state and subsequent reduced core body temperature
results in cutaneous vasoconstriction. (14)
Skin is cool, dry, and pale.
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Pallor results from cutaneous vasoconstriction and increased
deposition of water and mucopolysaccharides in the dermis,
which alter the refraction of light
Hypohydrosis may lead to palmoplantar keratoderma
Carotenemia (from decreased hepatic conversion of beta
carotene to Vit A) gives skin yellowish hue (14, 17)
Hair: dry, brittle, coarse; partial alopecia
Loss of hair from lateral 1/3 of eyebrows
Hypothyroidism Facies with Generalized
Myxedema
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Generalized
myxedema
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Occurs as a result of
deposition of dermal
acid
mucopolysaccharides
(esp. hyaluronic acid
and chondroitin sulfate)
in the skin
Skin is non-pitting
Face: swollen lips,
broad nose,
macroglossia, and puffy
eyelids
Thyroid Disease and Other Cutaneous
Disease Associations
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Autoimmune thyroid disease has been associated
with other cutaneous diseases
Alopecia areata (18)
Bullous disorders
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Vitiligo
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Pemphigus foliaceus
Pemphigus vulgaris (19)
(20)
Derived from the Greek vitelius, signifying a “calf's white
patches”
Fairly symmetric pattern of white macules with welldefined borders
Connective tissue diseases
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Dermatomyositis
(21)
, SLE
(22)
, scleroderma(23)
Alopecia Areata Associated with
Autoimmune Thyroid Disease
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Rapid onset of total hair loss in a sharply
defined, usually round, area
Regrowth begins in 1 to 3 months and may be
followed by loss in the same or other areas
Pemphigus foliaceus Associated with
Autoimmune Thyroid Disease

Pemphigus foliaceus: recurrent shallow
erosions, erythema, scaling, and crusting
Pemphigus vulgaris Associated with
Autoimmune Thyroid Disease

Painful oral erosions
usually precede the onset
of skin blisters by weeks
or months
Pemphigus vulgaris Associated with
Autoimmune Thyroid Disease
Nonpruritic flaccid blisters varying in size from 1 to several
cm appear gradually on normal or erythematous skin
Invariably generalize if left untreated
Cutaneous Paraneoplastic Syndromes

In 1976, Helen Ollendorff Curth set criteria that
should be met before a skin disease can be called
a paraneoplastic dermatosis (24,25) :
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Both conditions start approximately the same time
Both conditions follow a parallel course
Neither the onset nor the course of either condition is
dependent on the other
A specific tumor occurs with a specific skin manifestation
The dermatosis is not common in the general population
A high percentage of association between the two
conditions is noted
Currently, only the first two criteria should be
met to call a skin disease a paraneoplastic
process (24, 25) .
Cutaneous Paraneoplastic Syndromes
May be initial clue to underlying neoplasm
 Can herald the recurrence of a malignancy
 Examples
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Necrolytic migratory erythema
Sign of Leser-Trelat
Hypertichosis lanuginosa acquisita
Bazex’s syndrome
Dermatomyositis
Erythroderma
Necrolytic Migratory Erythema

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Glucagonoma syndrome includes glucose intolerance,
weight loss, anemia, hair and nail changes,
hypoaminoaciduria, psychiatric disturbances, and
thromboembolic disease (24, 26)
Skin manifestation of the glucagonoma syndrome
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Pathophysiology is not known, but it is probably related to
catabolism from increased levels of glucagon
When physician suspects this, be aggressive
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Erythematous macules and papules, often annular or arciform,
on central face, lower abdomen, perineum, groin, buttocks,
and thighs
Progress to erosions secondary to epidermal necrosis
Skin disease has waxing and waning course that does not
seem to follow the course of the glucagonoma
75% glucagonomas are metastatic at time of diagnosis(27)
Gold standard for treatment is surgery
Necrolytic migratory erythema

Erythematous macules and papules, often annular or arciform
than can progress to erosions
Sign of Leser-Trelat
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First described in 1890 as an increase in the
number of cherry angiomas in patients with
cancer (28)
Now refers to an increase in number or size of
seborrheic keratoses in patients with internal
malignancy (24)
Most often found in patients with adenocarcinoma
of the stomach or colon (28) , but also reported
with hematopoietic, breast, lung, ovarian, and
uterine cancers (24, 29, 30)
Can appear as early as 5 months before the dx of
cancer or as late as 9.8 months after (29)
Sign of Leser-Trelat

Pathogenesis could be
due to elevated levels
of growth factors,
disrupted epidermal
cell turnover
regulation, and
impeded
host defense
(30)

Treatment of the
underlying malignancy
results in involution of
the SK’s in about ½ of
cases (24,31)
Hypertrichosis lanuginosa acquisita
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Sudden appearance of downy, soft, nonpigmented hair on
the body
Most common associated malignancy is lung followed by
colorectal cancer (32)
Also has been associated with bladder, ovarian, uterine, and
pancreatic cancer (24, 33)
Typically occurs on face, but also on trunk, limbs, and ears
Palms, soles, and genitals are spared
Can be associated with other signs and symptoms,
including glossitis, glossodynia, diarrhea, adeopathy, and
acanthosis nigricans
In some cases, the hypertrichosis resolves with treatment
of the tumor (24)
Bazex’s Syndrome
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Violaceous, symmetric papulosquamous plaques
on the acral surfaces of ears, nose, hands, and
feet
75% have nail changes including longitudinal or
horizontal ridging, thickening, subungal debris,
and discoloration (24)
Mostly male (93% in one study) (34)
Associated with squamous cell carcinoma of the
oropharynx, larynx, lung, or esophagus
In one review, cutaneous changes preceded the
diagnosis of malignancy by an average of 11
months in over 60% of patients with Bazex’s
syndrome (35)
Bazex’s Syndrome
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Violaceous, symmetric papulosquamous plaques on the acral
surfaces of ears, nose, hands, and feet
The dermatosis improves with cancer treatment and worsens as
the cancer progresses (24)
Nail changes tend to persist after effective cancer treatment and
resolution of other skin manifestations
Dermatomyositis
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Proximal muscle weakness, elevated CK and aldolase
Heliotrope rash, Gottron’s papules, and others
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Some factors associated with higher incidence of
paraneoplastic dermatomyositis
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Poikiloderma, periungual telangiectasia, scalp pruritis and
erythema
Older age, male gender, patients that are difficult to control
Perform age-appropriate cancer screening for
dermatomyositis patients
25% will develop malignancy (24, 35) , most commonly
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Genital neoplasms in women (24, 36)
Respiratory tract neoplasms in men
(24, 36)
Heliotrope Rash in Dermatomyositis

Heliotrope rash (violaceous erythema) of
periorbital skin
Gottron’s papules in Dermatomyositis

Flat-topped, violaceous or erythematous
papules on extensor surfaces
Erythroderma
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Exfoliative dermatitis with a dramatic presentation characterized
by widespread erythema and scaling of skin
Often have lymphadenopathy, headaches, malaise,
photosensitivity, and chills
Pathogenesis is unknown, but may have to do with elevated
cytokines and adhesion molecules causing increased epidermal
turnover and exfoliation
Many potential causes, including pre-existing dermatoses, drug
rxns, and malignancy.
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Skin changes most commonly present before the diagnosis of
malignancy is made.
According to a study by Nicolis (37) , 20 out of 24 patients with
erythroderma and mycosis fungoides, Hodgkin’s, or other lymphomas
or leukemias had skin changes up to 25 years before the dx of cancer
was made.
Most often associated with lymphomas and leukemias (24, 37, 38, 39)
Also been reported with liver, lung, thyroid, and prostate cancer
(38)
Erythroderma
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May begin as scattered erythematous pruritic patches that
generalize with time
Palms and soles usually spared
Treat the underlying malignancy and use topical steroids.
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2.
3.
4.
5.
6.
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8.
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Perez MI, Kohn SR. Cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol 1994;
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Paron NB, Lambert PW. Cutaneous manifestations of diabetes mellitus. Prim Care 2000; 27:371-83.
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Studer E, Calza A, Saurat J: Precipitating factors and associated diseases in 84 patients with
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Stuart CA, Gilkison CR, Smith MM, et al. Acanthosis nigricans as a risk factor for non-insulin
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Lindhoudt V, Schumacher Jr HR, Algeo S, et al. Scleromyxedema with myopathy
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Heymann WR. Cutaneous manifestations of thyroid disease. JAAD 1992;25:885906.
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