1. Skin in Systemic Disease
Digital Lecture Series : Chapter 20
Dr. NIRMAL B.
Assistant Professor,
Christian Medical College, Vellore.

2. 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

3. 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.

4. 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

5. 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

6. 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.

7. 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.

8. Skin in metabolic disorders
Porphyrias
Amyloidosis
Xanthomatosis

9. 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

10. 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.

11. Amyloidosis Classification of systemic amyloidosis
Primary systemic amyloidosis
Secondary systemic amyloidosis
Dialysis related amyloidosis
Inherited systemic amyloidosis

12. 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.

13. 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.

14. 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.

15. Tuberous xanthoma Occur over extensor aspect of elbows & knees.
Seen in Type III hyperlipoproteinemia.

16. Xanthelasma palpebrarum
Occur over upper eyelids & around medial canthus.
Seen in normolipemics, Familial hypercholesterolemia (Type II), Type III hyperlipoproteinemia.
Xanthelasma

17. 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)

18. Skin in heritable diseases
Neurofibromatosis
Tuberous sclerosis
Multiple neurofibromas
Ash leaf macule in Tuberous sclerosis

19. 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…

20. 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.

21. 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.

22. Skin manifestations of blood disorders
Leukaemia cutis
Cutaneous Lymphoma
Mycosis Fungoides
Langerhans cell histiocytosis

23. 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.

24. 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.

25. 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.

26. 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.

27. 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

28. 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

29. Acanthosis nigricans Grey-black velvety plaques involving flexors.
Tripe palms : palmar acanthosis seen in malignancy.
Acanthosis Nigricans

30. 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

31. 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.

32. 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).

33. 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.

34. 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).

35. 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

36. 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.

37. 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.

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

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

40. Liver disorder Pruritus Icterus Pigmentary changes Spider angiomas
Palmar erythema
Dilated abdominal wall veins
Purpura
Loss of body hair
Gynaecomastia
Peripheral edema

41. 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)

42. 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.

43. Sarcoidosis

44. 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

45. 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

46. 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

47. 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

48. Lupus erythematosus
Haematological disorder - haemolytic anaemia or leukopenia (<4000/mm) or
lymphopenia (<1500/mm) or thrombocytopenia (< /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.

49. 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.

50. Malar Rash
Oral Erosion

51. 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.

52. 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.

53. 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.

54. 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.

55. 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

56. 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

57. 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.

58. Skin in vascular and inflammatory disorders
Cutaneous necrotizing vasculitis
Systemic necrotizing vasculitis
Wegener’s granulomatosis
Churg Strauss disease
Behcet’s disease

59. 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.

60. 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.

61. 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.

62. 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.

63. MCQ’s
Q.1) Pellagra is characterized by a triad of clinical symptoms including all except
Dermatitis
Dementia
Dysphagia
Diarrhoea
Q.2) Eruptive xanthomas are characteristically seen in which type of familial hyperlipidemia?
Type I
Type II
Type III
Type IV
Ans : Q. 1 – C, Q. 2 – A

64. MCQ’s
Q.3) ___________ or more café-au-lait macules of over 5 mm in greatest diameter in prepubertal individuals.
Two
Four
Six
Eight
Q.4) The sequence of events in Raynaud’s phenomenon are :
Pallor, Cyanosis, Rubor
Cyanosis, Pallor, Rubor
Rubor, Pallor, Cyanosis
Pallor, Rubor, Cyanosis
Ans : Q. 3 – C, Q. 4 – A

65. MCQ’s Q.5) The following amine is one of the mediators of itch -
Serotonin
Epinephrine
Norepinephrine
Bradykinin
Ans : Q. 5 – A

66. Q. Identify the clinical condition
Photo Quiz
Ans : Acanthosis nigricans
Q. Identify the clinical condition

67. Q. Identify the clinical condition
Photo Quiz
Ans : Malar rash in SLE
Q. Identify the clinical condition

68. Thank You!