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Cutaneous Manifestations of Internal Disease

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Title: Cutaneous Manifestations of Internal Disease


1
Cutaneous Manifestations of Internal Disease
  • Residents Conference
  • Hallie McDonald, MD
  • August 16, 2005

2
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
  • Type I patients get more autoimmune-type lesions
  • Type II patients get more cutaneous infections

3
Diabetes Mellitus
  • Cutaneous lesions usually appear after the
    development of DM, but may be the first
    presenting sign
  • Four major groups of skin findings
  • Skin diseases associated with DM (necrobiosis
    lipoidica and diabetic bullae)
  • Cutaneous infections
  • Cutaneous manifestions of diabetic complications
    (neuropathic ulcers)
  • Skin reactions to diabetic treatment

4
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.

5
Necrobiosis Lipoidica (NL)
  • 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
  • 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

6
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

7
Necrobiosis Lipoidica (NL)
8
Necrobiosis Lipoidica (NL)
9
Necrobiosis Lipoidica (NL)
10
Necrobiosis Lipoidica (NL)
11
Necrobiosis Lipoidica (NL)
12
Granuloma Annulare (GA)
  • 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.

13
Granuloma Annulare (GA)
  • Appearance
  • 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
  • Histology
  • Focal degeneration of collagen in the upper and
    mid-dermis, palisaded histiocytes around collagen
    bundles, and abundant dermal mucin
  • Pathogenesis unknown

14
Granuloma Annulare (GA)
  • Treatment
  • If localized, best left untreated.
  • Can treat with intralesional steroids, if needed
  • If generalized, can also use dapsone,
    isotretinoin, freezing, cyclosporin, or PUVA.

15
Granuloma Annulare (GA)
16
Granuloma Annulare (GA)
17
Granuloma Annulare (GA)
18
Granuloma Annulare (GA)
19
Granuloma Annulare (GA)
20
Granuloma Annulare (GA)
21
Granuloma Annulare (GA)
Histology showing focal degeneration of collagen
in the upper and mid-dermis, palisaded
histiocytes around collagen bundles, and abundant
dermal mucin
22
Diabetic Bullae
  • Approximately 0.5 of diabetics (2)
  • More common in men with long-standing DM and
    neuropathy
  • Two types have been described
  • 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
  • Pathogenesis not well-understood
  • 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
  • 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

23
Diabetic Bullae
  • Bullae tend to heal spontaneously in 2-5 weeks
  • Bullosis diabeticorum remains a diagnosis of
    exclusion with negative immunofluorescence
    studies, porphyrin levels, and cultures
  • 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

24
Diabetic Bullae
25
Diabetic Bullae
26
Diabetic Bullae
  • Histology showing a noninflammatory blister with
    a subepidermal and focally intraepidermal
    separation

27
Acanthosis Nigricans
  • Seen in situations of insulin resistance
  • Besides in DM, also seen in the following
  • Carcinomas, especially of the stomach
  • Secondary to meds (nicotinic acid, estrogen, or
    corticosteroids)
  • Pineal tumors
  • Other endocrine syndromes (PCOS, acromegaly,
    Cushings 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.

28
Acanthosis Nigricans
  • Appearance
  • 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
  • Weight loss
  • Retinoic acid and salicylic acid

29
Acanthosis Nigricans
30
Acanthosis Nigricans
31
Acanthosis Nigricans
32
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)

33
Skin Infections in DM
  • Fungal infections- most common
  • Candida
  • 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)

34
Candidiasis in Diabetics
  • White, curdlike material adherent to
    erythematous, fissured oral commisure angular
    stomatitis

35
Candidiasis in Diabetics
  • Initial pustules on erythematous base that become
    eroded and confluent

36
Candidiasis in Diabetics
37
Candidiasis in Diabetics
38
Candidiasis in Diabetics
39
Candidiasis in Diabetics
KOH prep showing pseudohyphae and budding yeast
forms
40
Skin Infections in DM
  • Bacterial Infections- can be more severe and
    widespread in diabetics
  • Malignant otitis externa
  • 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

41
Malignant Otitis Externa in Diabetics
42
Skin Infections in DM
  • Bacterial infections in DM
  • Erythrasma
  • Reddish tan scaling patches of the upper inner
    thighs, axillae, toe web spaces, and inframammary
    creases
  • Gram positive Corynebacterium minutissimum
  • Identified with Woods light coral fluorescence
  • Treat with oral erythromycin for 5 days

43
Erythrasma in Diabetics
  • Reddish tan scaling patches of the upper inner
    thighs, axillae, toe web spaces, and inframammary
    creases

44
Erythrasma in Diabetics
45
Erythrasma in Diabetics
46
Woods Lamp in the Diagnosis of Erythrasma
47
Cutaneous Manifestations of Diabetic
Complications Foot Ulcers
  • 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
  • Daily foot inspections, appropriate footwear
  • Causes for ulcer formation
  • Peripheral neuropathy (60-70)
  • Treatment aggressive debridement and offloading
    or with a contact cast
  • Vascular disease (15-20)
  • Treatment surgical re-vascularization
  • Combination of peripheral neuropathy and vascular
    disease (15-20)

48
Cutaneous Reactions to Diabetic Treatment
  • Insulin
  • Allergy may be local or systemic and usually
    occurs within the first month of therapy
  • Erythematous or urticarial pruritic nodules at
    the site of injection
  • Lipoatrophy can also occur
  • 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
  • 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

49
Cutaneous Reactions to Diabetic Treatment
Lipoatrophy
50
Cutaneous Reactions to Diabetic Treatment- Insulin
  • Highly purified or recombinant insulins have a
    reduced allergy prevalence (0.1-0.2) (4)
  • Observe the patients technique to make sure it
    isnt intradermal
  • Treatment includes substitution of a more
    purified insulin, discontinuation or
    desensitization for severe systemic rxns

51
Cutaneous Reactions to Diabetic Treatment-Oral
Hypoglycemics
  • 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.

52
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.

53
Hyperthyroidism and the Skin
  • 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)

54
Plummers Nail in Hyperthyroidism
Plummers nail concave contour and distal
onycholysis, esp. the ring finger (not specific-
also seen in hypothyroidism, psoriasis, after
trauma, or in allergic contact dermatitis)
55
Scleromyxedema in Hyperthyroidism
  • Numerous firm white, yellow, or pink papules on
    face, trunk, axillae, and extremities
  • 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, Raynauds phenomenon,
    monoclonal gammopathy, neurologic manifestations,
    joint dz, and myopathy (14)
  • Treatment of hyperthyroid state with radioactive
    iodine does not improve skin findings (14, 16)

56
Scleromyxedema in Hyperthyroidism
  • Firm white, yellow, or pink papules on face,
    trunk, axillae, and extremities

57
Scleromyxedema in Hyperthyroidism
58
Graves Disease
  • 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)
  • Presentation varies from peau dorange
    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.

59
Pretibial Myxedema in Graves Disease
  • Bilateral, asymmetric, raised, firm plaques or
    nodules varying from pink to brown, sometimes
    with woody induration

60
Pretibial Myxedema in Graves Disease
61
Pretibial Myxedema in Graves Disease
62
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
63
Graves Disease and Thyroid Acropachy
  • AP radiograph of the hand demonstrates feathery
    periosteal bone proliferation of the diaphyses of
    the metacarpals and proximal phalanges

64
Hypothyroidism and the Skin
  • 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.
  • 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

65
Hypothyroidism Facies with Generalized Myxedema
  • Generalized myxedema
  • 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

66
Thyroid Disease and Other Cutaneous Disease
Associations
  • Autoimmune thyroid disease has been associated
    with other cutaneous diseases
  • Alopecia areata (18)
  • Bullous disorders
  • Pemphigus foliaceus
  • Pemphigus vulgaris (19)
  • Vitiligo (20)
  • Derived from the Greek vitelius, signifying a
    calf's white patches
  • Fairly symmetric pattern of white macules with
    well-defined borders
  • Connective tissue diseases
  • Dermatomyositis (21) , SLE (22) , scleroderma(23)

67
Alopecia Areata Associated with Autoimmune
Thyroid Disease
  • 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

68
Pemphigus foliaceus Associated with Autoimmune
Thyroid Disease
  • Pemphigus foliaceus recurrent shallow erosions,
    erythema, scaling, and crusting

69
Pemphigus vulgaris Associated with Autoimmune
Thyroid Disease
  • Painful oral erosions usually precede the onset
    of skin blisters by weeks or months

70
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

71
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)
  • 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) .

72
Cutaneous Paraneoplastic Syndromes
  • May be initial clue to underlying neoplasm
  • Can herald the recurrence of a malignancy
  • Examples
  • Necrolytic migratory erythema
  • Sign of Leser-Trelat
  • Hypertichosis lanuginosa acquisita
  • Bazexs syndrome
  • Dermatomyositis
  • Erythroderma

73
Necrolytic Migratory Erythema
  • 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
  • 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
  • Pathophysiology is not known, but it is probably
    related to catabolism from increased levels of
    glucagon
  • When physician suspects this, be aggressive
  • 75 glucagonomas are metastatic at time of
    diagnosis(27)
  • Gold standard for treatment is surgery

74
Necrolytic migratory erythema
  • Erythematous macules and papules, often annular
    or arciform than can progress to erosions

75
Sign of Leser-Trelat
  • 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)

76
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 SKs in about ½ of cases
    (24,31)

77
Hypertrichosis lanuginosa acquisita
  • 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)

78
Bazexs Syndrome
  • 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 Bazexs
    syndrome (35)

79
Bazexs Syndrome
  • 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

80
Dermatomyositis
  • Proximal muscle weakness, elevated CK and
    aldolase
  • Heliotrope rash, Gottrons papules, and others
  • Poikiloderma, periungual telangiectasia, scalp
    pruritis and erythema
  • Some factors associated with higher incidence of
    paraneoplastic dermatomyositis
  • 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
  • Genital neoplasms in women (24, 36)
  • Respiratory tract neoplasms in men (24, 36)

81
Heliotrope Rash in Dermatomyositis
  • Heliotrope rash (violaceous erythema) of
    periorbital skin

82
Gottrons papules in Dermatomyositis
  • Flat-topped, violaceous or erythematous papules
    on extensor surfaces

83
Erythroderma
  • 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.
  • 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, Hodgkins, 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)

84
Erythroderma
  • May begin as scattered erythematous pruritic
    patches that generalize with time
  • Palms and soles usually spared
  • Treat the underlying malignancy and use topical
    steroids.

85
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