Systemic Manifestation of

disease

By: Lawrence Foo

Meighalah
Chua Yoong Ern
Nicholas Tan
 Learning objectives
Recognise that systemic diseases are often associated or present
with cutaneous signs
Discuss the cutaneous manifestations seen in the following
systemic disorders
endocrine disorders
connective tissue diseases and vasculitides
chronic renal failure
chronic liver failure and gastrointestinal diseases
HIV and other common infections
haematological diseases
Systemic malignant diseases
Discuss how to evaluate a patient with vasculitic skin lesions using
history , physical examination and lab investigations
Discuss how to evaluate a patient with erythema nodosum using
history , physical examination and lab investigations.
LO 1: Recognise that systemic
diseases are often associated or
present with cutaneous signs
 LO2: Discuss the cutaneous
manifestation seen the following
disorders
Endocrine disorders
Connective tissue diseases and vasculitides
Chronic renal failure
Chronic liver failure and gastrointestinal
diseases
HIV and other common infections
Haematological diseases
Systemic malignant diseases
 Endocrine disorder
A) Diabetes mellitus
1. Cutaneous infection
Poor control Mucocutaneous candidiasis
Tinea pedis, a particular problem because of their
peripheral vascular disease
Staphylococci cause folliculitis and furuncles; streptococci
cause impetigo and ecthyma but also necrotizing fasciitis
and gangrene
Ketosis are at risk for mucormycosis
Postmortem
photograph of a
woman with
diabetes and left
rhinocerebral
Mucocutaneous candidiasis mucormycosis
complicating
ketoacidosis.
Note the orbital
Tinea pedis and facial cellulitis
and the black
nasal discharge
 Folliculitis Impetigo

Furuncle Necrotizing fasciitis

Ecthyma
2. Diabetes-associated dermatoses

Acanthosis nigricans Velvety hyperpigmentation usually on

the skin folds in obese and diabetic
patient
Aurantiasis Yellow discoloration of thickened skin
of the palms of the hands and soles of
the feet caused by abnormal hepatic
metabolism of carotenoids.
Diabetic dermopathy Small atrophic hyperpigmented
patches on the shins reflect vessel
damage and leakage
Perforating folliculitis DM patients with renal disease often
have marked pruritus, scratch and rub
their skin, and develop a severe form
of prurigo nodularis (perforating
folliculitis )
Eruptive xanthomas Poorly controlled DM and secondary
increase in triglyceride levels may have
sudden onset of small yellow papules.
Necrobiosis lipoidica Yellow telangiectatic scar-like plaques
on the shins
 Pruritus associated with unexplained
dermatitis or prurigo.
Rubeosis faciei Persistent facial flushing may be
diabeticorum seen in adults with poorly
controlled DM.
Vitiligo Patients with DM of either type
are more likely to have vitiligo

3. Diabetic neurovascular disease

Muscle atrophy, bone damage, and abnormal
biomechanics combined with lack of sensation
(neuropathy) and poor vascular supply lead to infarcts
and painless ulcers (malum perforans)

4. Complications of therapy
Injections of insulin may cause urticaria, although this
is much less common with humanized insulin.
Eruptive xanthomas perforating folliculitis

Rubeosis faciei diabeticorum

Vitiligo
B) Pituitary gland
Direct effects on the skin
Melanocyte-stimulating hormone influences pigmentation, so patients
with panhypopituitarism tend to be pale

C) Thyroid gland
Hyperthyroidism
Warm, moist skin, sweaty palms, onycholysis
(Plummer nail), and diffuse alopecia
Graves disease orbital disease with
exophthalmos. acropachy, and pretibial
myxedema.

Hypothyroidism. The most common cause in

adults is Hashimoto thyroiditis.
Dry puffy skin, alopecia, and loss of the
lateral one-third of the eyebrows (Hertoghes Pretibial myxedema
sign) - Sharply demarcated
plaques on the shins,
The skin is yellow from carotinemia which
often with "orange-peel"
associate with hypothyroidism surface
D) Adrenal gland
Cushing syndrome
hypersortisolism
moon facies, lipodystrophy with truncal obesity and
buffalo hump, hirsutism, acne and excessive striae
Addison disease
Adrenal insufficiency
Main cutaneous feature diffuse hyperpigmentation of
sun-exposed skin, the nipples, scars, palmoplantar
creases, and mucosal surfaces. (ACTH and MSH share
the same precursor Proopiomelanocortic, POMC)
Hyperandrogenism
Acne, hirsutism, and even virilization
Pheochromocytoma
Flushing but often lead to hypertension, palpitations,
and panic attacks
Cutaneous feature neurofibromatosis
 Connective tissue diseases
A) Ehlers-Danlos Syndrome
A group of disorders with skin, joint,
and in some instances skeletal and
cardiovascular defects
Underlying collagen abnormality is
different for each type
Classical type
Autosomal dominant (Mutations in
type V collagen, type I collagen, and
tenascin)
hyperextensible joints and easily
stretched skin
Typical finding is gaping scars
(molluscoid pseudotumors), marked
striae and frequent extensive
bruises.
B) Marfan Syndrome
defect in fibrillin, inherited in an
autosomal dominant pattern
Patients are often tall with an
elongated face and
disproportionately long limbs
Elastosis perforans serpiginosa
(arachnodactly), hypermobility and
Small papules erupt and are
are at considerable risk for aortic grouped in a confined area,
and visceral rupture eventually becoming serpiginous.
Cutaneous findings - prominent The central core of each papule
striae, elastosis perforans contains a compressed aggregate
serpiginosa, and hyperextensibility. of fibrous material and cellular
debris that eventually disgorged
to the surface
C) Pseudoxanthoma Elasticum
Rare defect in the MRP6 protein
(autosomal recessive)
Main problems are with
abnormal calcification of elastic
fibers in the eyes, vessels, and
skin
Classic cutaneous finding is
chicken skin with subtle yellow
plaques in the flexures.
Skin biopsy shows disrupted
elastin fibers, which are
strikingly positive for calcium
with von Kossa stain.
 Cutaneous Signs of Chronic
Renal Failure/Dialysis
Pruritus
Half and half nails/ Lindsays
nails
Perforating disease
Calciphylaxis
Nephrogenic systemic
fibrosis
Pseudoporphyria
 Cutaneous Signs of Chronic Renal
Failure/Dialysis

Half and half nails/ Lindsays

Terrys nail
nails
Fingernails or toenails appear white with
Proximal portion of the nail
a characteristic "ground glass"
white and the distal half red,
appearance without any lunula due to a
pink, or brown, with a sharp line
decrease in vascularity and an increase
of demarcation between the two
in connective tissue within the nail bed
halves.
Cutaneous Signs of Chronic Renal
Failure/Dialysis

Perforating disease
Especially in diabetes
mellitus
Histology
Lesions centered on
hair follicles
May show epidermal
perforation with
discharge of dermal
components.
Cutaneous Signs of Chronic Renal
Failure/Dialysis
Calciphylaxis
Calcification of the blood
vessels, blood clots and skin
necrosis.
More commonly in end stage
renal disease
(GFR<15ml/min/1.73m^2) and
hypercalcemic states
(Hyperparathyroidism)
Develop sudden vessel
calcification
Irregular erythema
necrosis with black eschar
painful ulcerations
 Cutaneous Signs of Chronic Renal
Failure/Dialysis
Nephrogenic systemic
fibrosis
Caused by exposure to
contrast material
containing gadolinium
in a patient with renal
insufficiency.
Localised thickening
and tightness of the
skin of the
fingers/toes.
Internal organs are
involved
-Gadolinium and iodinated contrast are widely employed as a contrast agent for
magnetic resonance imaging-
Cutaneous Signs of Chronic Renal
Failure/Dialysis

Pseudoporphy
ria
Subepiderm
al blister
Mimic
porphyria
cutanea
tarda
 Chronic liver failure
Palmar erythema
-Increased estrogen l/t increased vascularity
Spider nevi/spider angioma
-slightly raised, small, reddish spots from which fine lines radiate
outward
(a spider-like appearance)
- occur with elevated estrogen levels
Caput Medusae
- distended and engorged superficial epigastric veins
- d/t dilation of the paraumbilical veinsbecoming re-canalised due to
portal hypertension caused by liver failure
- commonly seen in patients with alcoholic cirrhosis
Paper-money skin
-upper trunk is covered with many randomly scattered, needle-thin
superficial capillaries
 Bier spots
-small, irregularly shaped, hypopigmented patches on the arms and legs
- blanches with pressure

Prurigo nodularis
- Pruritic papules and scattered nodules
- a/w viral infections (eg, hepatitis C, human immunodeficiency virus)
and bacterial infections
Jaundice
Ecchymosis
Puritus(stracth mark around abdomen)
Nail :
a) Clubbing
b) Koilynychia
c) Terrys nails (ground glass" appearance without any lunula due to a
decrease in vascularity and an increase in connective tissue within the
nail bed)
 Gastroenterology
Crohn disease and Ulcerative colitis
a) pyoderma gangrenosum
- painful red nodules which rapidly break down to become ulcers with a marked
bluish undermined overhanging edge which fail to heal
- usually begins at therapeutic marks
- also a/w associated AML, CML and multiple myeloma

b) erythema nodosum
- reddish, painful, tender lumps most commonly located in the front of the legs
- inflammation of the fat cells under the skin causing in tender red nodules or
lumps that are usually seen on both shins

c) Sweet syndrome/acute febrile neutrophilic dermatosis

- sudden onset of fever, an elevated white blood cell count, and tender, red, well-
demarcated papules and plaques
- dense infiltrates by neutrophil granulocytes on histologic examination
 HIV and other common infections
Karposi Sarcoma
- infection with HHV8
- violaceous plaques (flat-topped, polygonal papules that can coalesce
into plaques)
- involve skin breakdown with resulting fungating lesions
Bacterial
-Staphylococcus aureus (paronychia, abscess)
- Streptococcus pyrogenes (causes erysepelas)
- Pseudomonas aeriginosa
causes ecthyma gangrenosum(single or multiple ulcerative lesions with a
necrotic centre and surrounding induration common at the perineum,
axillae and submammary areas )
Viral(VZ, HPV-warts)
Fungal primary(Pityriasis versicolor), secondary(candida)
Hematological disease
IDA- Koilynychia, angular chelitis
Sickle cell anemia cutaneous ulceration d/t reduction in blood
supply to the skin (infarction being the primary cause), local edema
and minor trauma
Fanconi anemia - caf au lait spots ( hypopigmented macules)
AML Sweet syndrome
Lymphoma- pyoderma gangrenosum
Pernicious Anemia- Late onset- vitiligo
Plasma cell disease- cutaneous plasmacytoma(monoclonal
proliferation of mature plasma cells in the skin)
Metastatic multiple myeloma
Polycythemia Rubra Vera- Raynauds phenomenon
 Malignancy related
Acanthosis nigricans (gastrointestinal cancer)
-flexures and neck typically show epidermal thickening
-skin is velvety or papillomatous, darkly pigmented
-warty lesions are seen around the mouth, the palms and soles

Erythema gyratum repens(ca lung)

- concentric scaly rings of erythema that shift visibly from day to day
- wood grain pattern seen

Necrolytic migratory erythema (glucanoma tumour/ hyperplasia of glucagon

secreting alpha cells of pancreas)
- eruption of serpiginous erythematous plaques, with a migratory erode
edge
- starts in the perineum
- ass/w weight loss, anaemia,mild diabetes, diarrhoea and glossitis
 Paget's disease of the nipple and extramammary Pagets disease
(represents the intraepidermal spread of an intraductal breast ca)
- unilateral eczema like plaque of the nipple areola
- eczema like eruption around the perineum or axilla
- skin biopsy confirms the diagnosis prior to surgical excision

Skin secondaries (Breast cancer)

1) carcinoma en cuirasse (atrophic, hard, pigmented, studded with nodules)
2) Peau d'orange (skin dimpling d/t lymphadenopathy)
3) Carcinoma erysipeloides
-fixed erythematous patch, well demarcated red patch

Peau d orange Carcinoma erysipeloides

Carcinoma en cuirasse
 Acquired ichthyosis (Hodgkin lymphoma)
- inherited and starts in infancy
- may be acquired by drug therapy with nicotinic add, allopurinol and clofazimine

Dermatomyositis (lung, breast, stomach ca)

- a skin rash and worsening muscle weakness over time
- associated with weight loss, fever, lung inflammation, light sensitivity
- Prodromic symptoms: Gottrons papules, Periungual telangiectasia, Heliotrope rash,
Poikilodermatomyositis

Generalized puritus (Hodgkin's disease and polycythemia rubra vera)

- Treatment: Sedative antihistamines, calamine lotion and topical antipruritics (e.g. 0.5% menthol in
aqueous cream)
Pyoderma gangrenosum (Leukemia- bulluous form)
- starts as a pustule or inflamed nodule, which breaks down to produce an ulcer with an undermined
purplish margin and a surrounding erythema( occurs on the trunk or lower limbs)
- Also seen in: ulcerative colitis, Crohn's disease, chronic autoimmune liver disease, RA, Behcet's
syndrome, multiple myeloma and monoclonal gammopathy
superficial thrombophlebitis (Ca lung or pancreas)

tylosis (keratoderma) (esophageal carcinoma)

- Maybe hereditary
L0 4: Discuss how to evaluate a patient with
erythema nodusum using history , physical
examination and lab investigations
 Erythema nodusum
An inflammation of the subcutaneous fat (panniculitis).
Usually presents as painful red nodules on the lower
legs result from circulating immune complex
deposition in vessels of the subcutaneous tissue
Commonly viewed as a type IV delayed
hypersensitivity reaction
Most common in young adults(especially females)
May be associated with arthralgia, malaise and fever
 History
Chief concern (CC)
sudden onset of painful, warm, erythematous, subcutaneous nodules
usually appear symmetrically on pretibial surfaces
size may range from 1 to 10 cm in diameter
may also be present on forearms, trunk, neck, and head
prodromal symptoms may occur 1-3 weeks prior to skin eruption, including
fever
weight loss
malaise
fatigue
cough
arthritis
arthralgia
systemic symptoms during eruptive phase may include
fever
headache
abdominal pain
vomiting
diarrhea
 History
History of present illness (HOPI)
lesions appear suddenly, last about 2 weeks, then fade over 1-2 months
(shorter duration in children)
lesions typically erythematous initially, then may change color to resemble
bruising
lesions fade without ulceration or scarring by 3-6 weeks, but may last longer
new crops of lesions may arise for up to 6 weeks
prodrome of systemic symptoms may begin 1-3 weeks before appearance of
nodules
Medication history
ask about history of medications that can cause erythema nodosum, such as
oral contraceptives
antibiotics (especially sulfonamides)
proton pump inhibitors
leukotriene modifiers
 History

Past medical history

(PMH)
ask about history of
causes of erythema
nodosum

Social history (SH)

ask about foreign
travel, pets, hobbies,
risk for tuberculosis, or
familial cases which
may suggest cause
 Physical
General physical
lymphadenopathy ( uncommon)
Skin
tender, warm, erythematous, subcutaneous nodules 1-10
cm in diameter (characteristic)
typically appear symmetrically on pretibial surfaces
may also be present on ankles, knees, forearms, trunk, neck, and head
nodules change appearance as they heal
first appear as bright red, raised lesions that are poorly demarcated
within days, appear flat with livid red or purple color
fade to become yellow or green, appearing as deep bruise
heal without ulceration or scarring
HEENT
episcleral lesions and phlyctenular conjunctivitis
Abdomen
hepatomegaly and splenomegaly ( uncommon )
 Investigations
Name
Complete blood count Leukocytosis(> 10,000 per mm3)
Erythrocyte May be elevated, normalizes when lesions fade
sedimentation rate (ESR)
Throat culture for group A To detect streptococcal infection
streptococci
Antistreptolysin O titer -to measure antibodies against streptolysin O, a substance
(ASOT) produced by group A streptococcus bacteria.
-taken at diagnosis and again within 4 weeks
Tuberculin skin test -to exclude tuberculosis
Urine pregnancy test To exclude pregnancy
Chest x-ray to detect pulmonary disease (especially tuberculosis or sarcoidosis)

Stool culture To detect ova ,parasites and inflammatory bowel syndrome in

patients with diarrheal symptoms
Blood cultures To detect bacteria or fungus if clinical symptoms warrant
Name
Biopsy histology shows stereotypical septal panniculitis without vasculitis,
(deep septa of subcutaneous fat tissue appears thickened and infiltrated by
incisional or inflammatory cells
excisional ) overlying dermis contains perivascular inflammatory infiltrate rich in
lymphocytes
neutrophils may be prolific in early lesionstissue damage
granulomatous features may range from Miescher radial granuloma to
widened, fibrotic subcutaneous septa