Skin in Systemic Disease

Digital Lecture Series : Chapter 20

Dr. NIRMAL B.
Assistant Professor,
Christian Medical College, Vellore.
 CONTENTS

 Skin in nutritional disorders

 Skin in metabolic disorders
 Skin in heritable diseases
 Skin manifestations of blood disorders
 Skin manifestations of internal organ disorders
 Skin in connective tissue disorders
 Skin in vascular and inflammatory disorders
 MCQs
 Photo Quiz
 Cutaneous manifestations of systemic diseases

 Skin mirrors many internal diseases which are often first noticed due
to cutaneous manifestations. Skin involvement is an integral part of
many systemic illnesses.
 Few systemic diseases with classical cutaneous manifestations are
discussed.
 Skin in nutritional disorders

Physical signs of nutritional disease

 Alopecia
• Anorexia, Bulimia, Marasmus
• Biotin, Essential fatty acid, Iron deficiency
 Follicular hyperkeratosis
• Essential fatty acid deficiency
• Vitamin A, B, C, E deficiency
 Hyperpigmentation
• Kwashiorkar
• Vitamin B12 deficiency
• Iron overload
 Skin in nutritional disorders

 Hypopigmentation
• Kwashiorkar
• Biotin, Copper deficiency
 Seborrheic dermatitis
• Riboflavin, pyridoxine deficiency
 Periorificial dermatitis
• Biotin, Essential fatty acid, Zinc deficiency
 Acral dermatitis
• Zinc deficiency
 Photodistributed dermatitis
• Niacin deficiency
 Pellagra

 Cellular deficiency of niacin resulting

from inadequate dietary supply.
 Rare causes are carcinoid tumour,
Hartnup disease and isoniazid therapy.
 Classical triad of clinical features is
dermatitis, diarrhoea and dementia.
 Skin changes resemble sunburn and
there is often characteristic well -
marginated eruption on neck called
‘Casal’s necklace’.
 Treatment : Oral niacinamide 0.5 g/day.
 Acrodermatitis enteropathica

 Autosomal recessive disease due to

reduced zinc absorption.
 Typically starts after weaning or earlier if
the infant is not given breast milk.
 Acute eczematous erosive dermatitis
involving acral, perioral & anogenital
areas.
 Oral zinc dose of 2–3 mg/kg/day cures
all clinical manifestations apart from hair
and nail growth within a few days.
 Skin in metabolic disorders

 Porphyrias
 Amyloidosis
 Xanthomatosis
 Porphyrias

Cutaneous disease only

 Porphyria cutanea tarda
 Congenital erythropoietic porphyria
 Erythropoietic protoporphyria
Cutaneous disease & acute attacks
 Hereditary coproporphyria
 Variegate porphyria
Acute attacks only
 Acute intermittent porphyria
 Porphyria cutanea tarda

 Due to uroporphyrinogen decarboxylase deficiency.

 Age of onset : 3rd or 4th decade.
 Clinical features : vesicles, bullae in areas of repeated trauma
healing with milia & scarring, hypertrichosis, sclerodermoid plaques.
 Treatment : Photoprotection, Phlebotomy, low dose chloroquine 125
mg twice weekly.
 Amyloidosis

Classification of systemic amyloidosis

 Primary systemic amyloidosis
 Secondary systemic amyloidosis
 Dialysis related amyloidosis
 Inherited systemic amyloidosis
 Systemic amyloidosis

Primary systemic amyloidosis

 The fibrils compose of protein AL amyloid due to plasma cell
dyscrasia.
 Age of onset in 6th decade with slight male preponderance.
 Clinical features : Macroglossia, Carpal tunnel syndrome,
hepatomegaly, edema, leg claudication, weight loss.
 Cutaneous features : Post-proctoscopic palpable purpura, waxy
purpuric papules, scleroderma like infiltration, nail dystrophy.
 Systemic amyloidosis

Secondary systemic amyloidosis

 The fibrils are composed of AA protein.
 Causes : Rheumatoid arthritis, psoriasis, lepromatous leprosy,
venous ulcer, hidradenitis suppurativa, acne conglobata.
Dialysis related amyloidosis
 The fibrils are composed of β2 microglobulin.
Inherited systemic amyloidosis
 Muckle-Wells syndrome, Familial mediteranean fever,
Heredofamilial amyloid polyneuropathy.
 Xanthomatoses

 Term xanthoma derived from Greek word ‘xanthos’ meaning yellow.

 Types : Tendon, Tuberous, Xanthelasma, Palmar, Planar, Eruptive.

Tendon xanthoma
 Occur commonly over extensor tendons over knuckles &
tendoachilis.
 Seen in familial hypercholesterolemia, sitosterolaemia,
cerebrotendinous xanthoma.
 Tuberous xanthoma

 Occur over extensor aspect of elbows

& knees.
 Seen in Type III hyperlipoproteinemia.
 Xanthelasma palpebrarum

 Occur over upper eyelids & around

medial canthus.
 Seen in normolipemics, Familial
hypercholesterolemia (Type II), Type
III hyperlipoproteinemia.

Xanthelasma
Palmar xanthoma
 Occur over palmar creases
 Pathognomonic of Type III hyperlipoproteinemia
Planar xanthoma
 Wide based, flat & wide spread
 Seen in paraprotrinemias
Eruptive xanthoma
 Multiple small papules affecting the extensors predominantly
 Seen in hypertriglyceridemia (Type I)
 Skin in heritable diseases

 Neurofibromatosis
 Tuberous sclerosis

Multiple neurofibromas Ash leaf macule in

Tuberous sclerosis
 Neurofibromatoses (NF)

 Autosomal dominant inheritance with complete penetration.

 Gene for NF1 located in Chromosome 17.
 Criteria : Presence of two or more of the following
• Six or more café-au-lait macules of over 5 mm in greatest
diameter in pre-pubertal individuals and over 15 mm in greatest
diameter in post-pubertal individuals.
• Two or more neurofibromas of any type or one plexiform
neurofibroma.
• Freckling in the axillary or inguinal regions.
• Optic glioma.

Contd…
 Neurofibromatoses (NF)

• Two or more Lisch nodules.

• Sphenoid dysplasia or thinning of long bone cortex with or
without pseudoarthrosis.
• A first-degree relative with NF1.
 Tuberous sclerosis

 Autosomal dominant inheritance.

 Diagnostic clinical triad : Epilepsy, Low Intelligence, Adenoma
sebaceum (Epiloia).
Cutaneous features
 Angiofibroma : discrete red-bown papules around naso-labial
furrows.
 Koenen’s tumour : periungual fibroma.
 Shagreen patch : skin coloured plaque in lumbosacral region.
 Ash-leaf macules : white ovoid macules over trunk or limbs.
 Skin manifestations of blood disorders

 Leukaemia cutis
 Cutaneous Lymphoma
 Mycosis Fungoides
 Langerhans cell histiocytosis
 Leukemia cutis

 Localized or disseminated skin infiltration by leukemic cells.

 Sign of systemic disease or relapse of existing leukemia.
 Commonly occurs in acute monocytic leukemia M5 and acute
myelomonocytic leukemia M4.
 Clinical presentation is variable but usually presents with pink or
violaceous papules and plaques.
 Cutaneous lymphomas

 Skin is the second most common cause of extranodal lymphomas

after GIT.
 Classified as T-cell & NK cell and B-cell lymphomas.
 Mycosis fungoides is the most common cutaneous T-cell lymphoma
and represent 80% of all cutaneous lymphomas.
 Sezary syndrome is a leukemic variant of mycosis fungoides
characterized by a triad of erythroderma, lymphadenopathy and
circulating Sezary cells.
 Mycosis fungoides

 Commonly occurs in late adulthood

with male predominance.
 Clinical stages include : patch, plaque,
tumor stage.
 Distribution favours non-sun exposed
areas (bathing trunk distribution).
 Variants include folliculotropic,
hypopigmented, pagetoid reticulosis,
granulomatous slack skin.
 Langerhans cell histiocytosis

 Continuum of disorders considered reactive but have a broad

spectrum of severity.
 Cutaneous lesions vary from papules, vesicles, pustules, nodules,
ulcers involving head, trunk and skin folds.
 Associated with diabetes insipidus & exophthalmos.
 Systems involved include bones, lung and reticulo-endothelial
system.
 Skin manifestations of internal organ disorders

 Disorders of endocrine system

• Diabetes mellitus
• Disorder of thyroid gland
• Disorder of parathyroid gland
• Disorder of adrenal gland
• Disorder of sex hormones
 Disorder of renal system
 Disorder of gastrointestinal system
 Disorder of Liver
 Sarcoidosis
 Paraneoplastic dermatoses
 Diabetes mellitus

Cutaneous changes in diabetes include :

 Acanthosis nigricans
 Diabetic dermopathy
 Necrobiosis lipoidica
 Limited joint mobility
 Scleredema diabeticorum
 Eruptive xanthomas
 Granuloma annulare
 Perforating disorders
 Bullous diabeticorum
 Bacterial & fungal infections
 Acanthosis nigricans

 Grey-black velvety plaques involving

flexors.
 Tripe palms : palmar acanthosis
seen in malignancy.

Acanthosis Nigricans
Diabetic dermopathy
 Atrophic brown macules over
pretibial areas correlated with
duration and presence of end organ
complications of diabetes.

Necrobiosis lipoidica
 Yellow-brown plaque on anterior
pretibial region over time becomes
atrophic giving a glazed porcelain
sheen.
Diabetic Dermopathy
 Disorder of Thyroid

 Graves disease is the commonest cause of hyperthyroidism

characterized by exophthalmos, thyroid acropachy and pretibial
myxedema.
 Cutaneous findings of hypothyroidism include dry skin, absence of
hair in the lateral third of eyebrow, myxedema due to accumulation
of mucopolysaccharides in the dermis.
 Disorder of parathyroids

 Hypoparathyroidism :
• Skin : dry, scaly, eczematous eruptions or exfoliative dermatitis.
• Hair : thin, fragile, patchy alopecia.
• Nails : atrophic, brittle with horizontal ridging
 Hyperparathyroidism :
• Disabling pruritus in primary and secondary hyperparathyroidism
(due to chronic renal failure).
 Disorder of Adrenal Glands

 Cushing’s Syndrome :
• Skin : thin, fragile with purpura and
striae.
• Redistribution of body fat :
Truncal obesity, moon facies, buffalo
hump and thin limbs.
• Acne, hirsutism and acanthosis
nigricans.
 Addison’s Disease :
Generalised, diffuse brown-black pigmentation of skin and mucosae
 Accentuation of pigmentation on :
• Exposed areas (face, hands, forearms),
• Flexures (axillae, groins),
• Bony prominences (knuckles, knees, elbows),
• Normally pigmented areas (palmar creases, nipples, genitalia),
• Pre-existing melanocytic nevi,
• Frictional areas (e.g. beltline),
• Mucosae (blue black colour especially over oral mucosa).
 Disorder of sex hormones

 Excess :
• Polycystic ovary syndrome, ovarian tumours, congenital adrenal
hyperplasia, Cushing’s disease, prolactinoma, drugs like
androgens, anabolic steroids or progestagens.
 Defeminising and virilising syndromes :
• Hirsutism and male pattern alopecia
• Thick, oily, hyperhidrotic skin; acne, acanthosis nigricans
 Deficiency :
• Hypogonadism (Pituitary or non-pituitary)
• Features of hypopituitarism
• Absent or sparse axillary and pubic hair in males or female type
body hair distribution in males
 Renal Disorder

 Renal failure :
• Persistent generalised pruritus, dry, scaly skin.
• Tendency to develop purpura/ecchymoses on minor trauma.
• Half and half nails in chronic renal failure show brown red
discoloration of their distal half.
• Pale yellow skin : associated anemia and pitting edema due to
accumulation of urochrome or carotene pigments.
• Uremic frost : deposition of urea crystals on the nose and malar
area due to high urea levels.
• Calcinosis cutis, pseudoporphyria cutanea tarda, nephrogenic
fibrosing dermatopathy.
 Reno-cutaneous disease

 Systemic Lupus Erythematosus :

• Discoid lesions, butterfly erythema, palatal ulcer, alopecia,
photosensitivity.
 Systemic Sclerosis :
• Diffuse skin sclerosis, Raynaud’s phenomenon, telangiectasia,
pigmentation and calcinosis.
 Vasculitides (Henoch Schonlein, Wegener’s, Polyarteritis nodosa) :
• Palpable purpura, vesicles, skin infarcts, ulcers.
 Lepromatous Leprosy :
• Shiny papulonodules and diffuse infiltration of skin.
 Gastrointestinal disorder

 Dysphagia :  Bleeding :
Due to rashes that may extend • Hereditary haemorrhagic
to esophagus telangiectasia
• Infections • Blue rubber bleb nevi
• Congenital and acquired • Ehlers Danlos syndrome
blistering diseases • Pseudoxanthoma Elasticum
• Lichen planus • Kaposi’s sarcoma
• Behcet’s disease
• Stevens Johnson Syndrome
• Dermatomyositis
 Gastrointestinal disorder

 Abdominal pain :  Inflammatory Bowel Diseases :

• Herpes zoster • Pyoderma gangrenosum
• Angioedema • Aphthous ulcers
• Porphyria • Erythema Nodosum
• Anderson : Fabry disease • Malnutrition
• Vasculitis : Henoch Schonlein • Rashes at ileostomy and
purpura, Collagen vascular colostomy sites
diseases • Metastatic cutaneous Crohn’s
• Polyposis : Gardner’s disease
syndrome, Peutz-Jeghers
syndrome, ulcerative colitis,
neurofibromatosis
• Ulcerative Colitis and Crohn’s
disease
• Pancreatitis
 Liver disorder

 Pruritus
 Icterus
 Pigmentary changes
 Spider angiomas
 Palmar erythema
 Dilated abdominal wall veins
 Purpura
 Loss of body hair
 Gynaecomastia
 Peripheral edema
 Sarcoidosis

 Sarcoidosis is a systemic granulomatous disease primarily affects

lungs but skin manifestations are seen often.
 Specific cutaneous lesions include
• Translucent yellow-red papules,
• Lupus pernio,
• Angiolupoid lesions &
• Subcutaneous nodules (Darier-Roussy sarcoid)
 Sarcoidosis

 Lupus pernio are violaceous indurated plaques commonly involving

face and digits associated with upper respiratory tract disease.
 Erythema nodosum is the commonest non-specific finding and
heralds good prognosis.
 Histopathology is characterized by the presence of naked epitheloid
granuloma with paucity of surrounding lymphocytes.
Sarcoidosis
 Paraneoplastic dermatoses

 Tripe palms :
• Palmar ridges are accentuated mimicking mucosa of stomach.
• Association : Lung and gastric carcinoma.
 Bazex syndrome :
• Acral papulosquamous lesions with onychodystrophy.
• Association : SCC of upper aerodigestive tract.
 Paraneoplastic pemphigus :
• Severe refractory oral involvement.
• Association : Non-Hodgkin’s lymphoma, Chronic lymphocytic
leukemia
 Paraneoplastic dermatoses

 Erythema gyratum repens :

• Wood grain pattened erythema
• Association: Bronchial carcinoma
 Necrolytic migratory erythema :
• Painful eroded crusted intertriginous and facial eruption
• Association : Glucagonoma
 Hypertrichosis lanuginosa acquisita :
• Non-pigmented languo hair over face & ears
• Association : Lung, colon carcinoma
 Skin in connective tissue disorders

 SLE
 Dermatomyositis
 Scleroderma
 Systemic sclerosis
 Rheumatoid Arthritis
 Sjogren’s syndrome
 Raynaud’s phenomenon

 Detailed in chapter 19, few salient aspects discussed

 Lupus erythematosus

American Rheumatism Association criteria for diagnosis of systemic

lupus erythematosus
 Malar rash
 Discoid rash
 Photosensitivity
 Oral ulcers
 Non-erosive arthritis
 Serositis - pleurisy or pericarditis
 Renal disorder - persistent proteinuria (>0.5 g/day) or cellular casts
 Neurological disorder - seizures or psychosis
 Lupus erythematosus

 Haematological disorder - haemolytic anaemia or leukopenia

(<4000/mm) or
lymphopenia (<1500/mm) or thrombocytopenia (<100 000/mm).
 Immunological disorder - LE cells or anti-DNA antibody or anti-Sm
antibody or
false-positive serology for syphilis (longer than 6 months).
 Antinuclear antibodies
# A patient is diagnosed to have SLE if 4 or more criterias are
fulfilled.
 Cutaneous manifestations in LE

 Malar rash :
Fixed erythema over malar eminences
sparing nasolabial folds.
 Discoid rash :
Erythematous plaques with adherent
scaling and follicular plugging.
 Photosensitivity :
Skin rash as an unusual reaction to
sunlight.
 Oral ulcers :
Painless oral or nasopharyngeal
ulceration.
Malar Rash Oral Erosion
 Dermatomyositis

Disorder mainly affecting skin, muscle and

blood vessels
 Characteristic erythematous and
oedematous changes in the skin are
usually associated with muscle
weakness and inflammation.
 In childhood, diffuse calcinosis is
frequent.
 In adults, the disease is commonly
associated with underlying carcinoma or
lymphoma.
 Scleroderma

ARA criteria for scleroderma

 Major criteria : Scleroderma proximal to the digits, affecting limbs,
face, neck or trunk; or
 At least two minor criteria :
• Sclerodactyly
• Digital pitted scarring
• Bilateral basal pulmonary fibrosis.
 Diffuse cutaneous systemic sclerosis

 Short interval (<1 year) between the onset of Raynaud’s

phenomenon and development of skin changes.
 Truncal and peripheral skin involvement.
 Tendon friction rubs.
 Pulmonary fibrosis, renal failure, gastrointestinal disease, myocardial
involvement.
 Capillary drop-out visible in nail folds.
 Scl-70 antibody-positive.
 Limited cutaneous systemic sclerosis

 Long history of Raynaud’s phenomenon.

 Limited skin involvement at extremities only.
 Calcification, telangiectasia, late onset of pulmonary hypertension.
 Capillary dilatation visible in nail folds.
 Anticentromere antibody-positive.
 Rheumatoid arthritis

 Rheumatoid nodules
 Rheumatoid vasculitis (RV)
 Felty’s syndrome
 Pyoderma gangrenosum (PG)
 Interstitial granulomatous dermatitis with arthritis
 Palisaded neutrophilic and granulomatous dermatitis
 Rheumatoid neutrophilic dermatitis
 Juvenile rheumatoid arthritis (JRA)
 Adult-onset Still’s disease
 Sjogren syndrome

 Xeroderma
 SCLE-like rashes, annular erythema, Sweet’s-like lesions
 Raynaud’s syndrome
 Hyperglobulinaemic purpura
 Inflammatory vasculitis
 Vitiligo
 Abnormalities of sweating
 Amyloid
 Alopecia
 Raynaud’s phenomenon

 Refers to digital ischemia provoked by cold exposure or emotional

stress.
 Classical triad of colour change :
Pallor, cyanosis and hyperemia but most describe only blanching
followed by numbness.
 Classified as primary (idiopathic) and secondary.
 Secondary causes include connective tissue disorders, obstructive
arterial disease, neurological diseases, drugs and hypothyroidism.
 Skin in vascular and inflammatory disorders

 Cutaneous necrotizing vasculitis

 Systemic necrotizing vasculitis
 Wegener’s granulomatosis
 Churg Strauss disease
 Behcet’s disease
 Cutaneous necrotizing vasculitis

 Palpable purpura is the characteristic lesion commonly involving the

lower extremities.
 Henoch-Schonlein purpura is the most widely recognized subgroup
of this entity characterized by a triad of colicky abdominal pain,
arthralgia and hematuria.
 Histologic findings include fibrinoid necrosis of blood vessels,
neutrophilic infiltration of vessel wall, endothelial swelling and
extravasated erythrocytes.
 Systemic necrotizing vasculitis

Polyarteritis nodosa
 Characterized by necrotizing inflammation of medium-sized or small
arteries without glomerulonephritis.
Microscopic polyangiitis
 Systemic vasculitis affecting blood vessels ranging in size from
capillaries to medium-sized arteries.
 Symptoms include fever, weight loss, arthralgia several years before
onset of pulmonary and renal disease.
 Systemic necrotizing vasculitis

Wegener’s granulomatosis
 Characteristic triad of systemic small vessel vasculitis, necrotizing
granulomatous inflammation of upper & lower respiratory tracts and
glomerulonephritis.
Churg-Strauss syndrome
 Characterized by asthma, peripheral blood eosinophilia and
necrotizing vasculitis with extravascular granulomas.
 Behcet’s disease

International Study Group criteria for the diagnosis of Behçet’s disease

 Recurrent oral ulceration- at least 3 times in one 12-month period.
Plus two of the following :
 Recurrent genital ulceration.
 Eye lesions - anterior uveitis, posterior uveitis or retinal vasculitis.
 Skin lesions - Erythema nodosum, pseudofolliculitis, papulo-pustular
or acneiform nodules.
 Positive pathergy test.
 MCQ’S

Q.1) Pellagra is characterized by a triad of clinical symptoms including all

except
A. Dermatitis
B. Dementia
C. Dysphagia
D. Diarrhoea

Q.2) Eruptive xanthomas are characteristically seen in which type of

familial hyperlipidemia?
E. Type I
F. Type II
G. Type III
H. Type IV
 MCQ’S

Q.3) ___________ or more café-au-lait macules of over 5 mm in greatest

diameter in prepubertal individuals.
A. Two
B. Four
C. Six
D. Eight

Q.4) The sequence of events in Raynaud’s phenomenon are :

A. Pallor, Cyanosis, Rubor
B. Cyanosis, Pallor, Rubor
C. Rubor, Pallor, Cyanosis
D. Pallor, Rubor, Cyanosis
 MCQ’S

Q.5) The following amine is one of the mediators of itch -

A. Serotonin
B. Epinephrine
C. Norepinephrine
D. Bradykinin
 Photo Quiz

Q. Identify the clinical condition

 Photo Quiz

Q. Identify the clinical condition

Thank You!