blistering bullous disease

1. Blistering Bullous Disease

2. Bullae occurs in several unrelated conditions;
1. Herpes virus infection
2. Spongiotic dermatitis
3. Erythema nodusum
4. Thermal burns
• There exist a group of disorders in which blisters are the primary
and most distinctive factors.
• Bullous disorders produce dramatic lesions and in some instances
fatal if untreated .
• Histologic assessment is essential for accurate diagnosis and
provides insight into pathogenic mechanism.
• Knowledge of desmosome and hemi desmosome provide skin with
mechanical stability is helpful in understanding these diseases.

3. Inflammatory Blistering Disorders
Pemphigus:
It is blistering disorder caused by auto-antibodies that result in
dissolution of inter cellular attachments within epidermis.
Age – majority are in 4th to 6th decade of life.
Gender – man and woman equally effected.
Variants of Pemphigus:
1. Pemphigus vulgaris
2. Pemphigus vegitans
3. Pemphigus foliaceus
4. Pemphigus erythematosus
5. Pemphigus Para neoplastic

4. • These disorders are usually benign but in extreme
cases fatal without treatment.
Pemphigus Vulgaris:
• The most common type (accounting 80% cases
worldwide).
• Involves mucosa and skin on the scalp, face, axilla,
groin, trunk and points of pressure.
• It may possibly present as oral ulcers that may persist
for months before skin involvement appears.
• Primary lesions are superficial vesicles and bullae and
that rupture easily leaving shallow crosin covered with
dried serum and crust.

6. Pemphigus Vegitans:
Rare form usually present not with blister but with large moist
verricous (wart like) vegetating plagues studded with pustules
on groin, axillae and flexural surfaces.
Pemphigus Foliaceus:
• More benign
• Endemic in Brazil
• Lesions are most common on scalp, face, chest and back.
• Bullae are so superficial that they mainly present as area of
erythema and crusting.
• They represent superficial erosion at .site of blister
ruptures.

7. • Pemphigus Erythematosus:
• It is localized, less severe form of pemphigus
foliaceus.
• That may selectively involve malar area of the
face in a lupus erythamatosus like fashion.
Pemphigus Para neoplastic :
occurs in association with various malignancies .
Most commonly in Hodgkin lymphoma.

8. Pathogenesis
• All forms of bullous are auto immune disease caused by IgG
antibodies against desmoglein- that disrupt intracellular adhesion
and results in the formation of blister.
• By direct immunofluorescence – lesions shows characteristic net
like pattern of intercellular IgG deposits.
• IgG deposits usually seen at all levels of epithelium in pemphigus
vulgaris.
• But more superficial in pemphigus foliaceus .
• The antibodies cause the lesion primarily by disrupting the
intercellular adhesive function of desmosomes.
• They may also act by activating the intercellular proteases.
• Para neoplastic pemphigus in the setting of lymphoid neoplasm is
also caused by auto antibodies that recognize desmoglein or other
proteins involved in inter cellular adhesion.

9. Morphology
• The common histological feature of all form of pemphigus
is acantholysis –dissolution of intercellular bridge that
connect squamous epithelial cells.
• Acantholytic cells dissociate from each other and loss their
polyhedral shape and become rounded.
• Blisters – in pemphigus vulgaris and pemphigus vegetans –
acantholysis selectively involve the cells immediately above
basal layers producing superficial blisters.
• In vegetans--there is also overlying epidermal hyperplasia.
• The single layer of intact basal cells that form the blister
base in pemphigus vulgaris has been thickened to row of
tomb stone.

10. • In Pemphigus foliaceus – blister from by similar
mechanism but found in superficial epidermis at
the level of stratum granulosum.
• Infiltration of superficial dermis  by
lymphocyte, macrophages and eosinophil
accompying each type of vulgaris.
Treatment :
• In all form of pemphigus -- is immunosuppressive
agents –which decrease the titers of pathogenic
antibodies.

11. Bullous Pemphigoid
• Affecting elderly individuals.
• Show wide range of clinical presentation.
• Sites of involvement include inner aspect of
thigh , surfaces of forearm , axillae, groin and
lower abdomen.
• Oral lesion in 10 to 15 % affected individual
appearing after cutaneous lesions.
• Some patients present with urticaria and
severe pruritus.

13. Morphology
• Lesions are tense bullae filled with clear fluid—involving erythematous or
normal appearing skin.
• Size—bullae’s are less than 2cm.
• Do not rupture easily unlikely blister of pemphigus .
• Heal without scarring unless secondarily infected.
• Differ from pemphigus that this is in non acantholytic sub epidermal
blisters.
• Early lesion show superficial and deep perivascular infiltrate of
lymphocytes and variable number of eosinophil occasional neutrophils.
• Dermal edema and basal cell layer vacuolization.
• Eosinophil are typically present directly beneath the epidermal basal cell
layer.
• Vacuolated basal layer eventually lifts away allowing space for fluid filled
blister.

14. Pathogenesis
• Caused by auto antibodies that binds to proteins that are
required for adherence of basal keratinocytes to basal
membrane.
• Antibody deposition occurs in continuous linear pattern at
dermo - epidermal junction ,which hemi desmosome link
basal keratinocytes to underlying basement membrane.
• Bullae pemphigoid antigen(BPAGs) are component of hemi
desmosomes.
• Antibodies against one such component called bpag2 are
present proven to cause blistering.
• antibodies also activate compliment leading to recruit
neutrophils , eosinophil inflammation and disruption of
epidermal attachment.

15. Dermatitis Herpetoformis
• Rare disorder.
• Characterized by urticaria and grouped vesicles.
• Disease affects predominantly in 3rd and 4th decade of life.
• In some cases it occurs in association with coeliac disease.
• Plaques and vesicles are extremely pruritic.
Pathogenesis:
• Association with coeliac disease provide clue to its pathogenesis .
• Genetically predisposed individuals develop IgA antibodies to dietary
gluten (derived from the wheat gliadin)
• Antibodies cross react with reticulin and components of anchoring fibrils
that tether the epidermal basement membrane to superficial dermis.
• The resultant injury and inflammation produce a sub epidermal blister.
• In some people with dermatitis herpetiformis and gluten sensitive
enteropathy-both disorder respond to gluten free diet.

17. Morphology
• Lesions are bilateral and symmetric, site involving
predominantly the extensor surfaces- elbows, knees, upper
back and buttocks.
• Histologically – fibrin and neutrophils accumulate
selectively to the tips of dermal papillae forming small
micro abscesses.
• Basal cells overlying these microabceses show vacuolization
and focal dermo epidermal separation that ultimately
coalesce to form a free sub epidermal blister.
• By direct immunofluorescence dermatitis herpetiforms
shows discontinuous granular deposits of IgA that
selectively localize in the tips of dermal papillae.

18. Non Inflammatory Blistering
Disorders
Epedermolysis Bullosa And Porphyria:
• Characterized by vesicle and bullae are mediated by inherited or in
some cases acquired defects involving structural proteins that
maintain the integrity of skin.
• Two such disorders:
1. Epedermolysis bullosa.
2. Porphyria
Epidermolysis Bullosa:- They are growth disorders caused by
inherited defects in structural proteins that lend the mechanical
stability to skin.
• The common feature is proclivity to form blister at this site of
pressure, rubbing or trauma at or soon after birth.
• Histological changes are so subtle that electron microscopy may be
required to differentiate among various type.

19. I Simplex Type:
• Defects of basal cell layer of epidermis.
• Always result from mutation in gene encoding
keratin 14 or keratin 5, the two protein pairs to
make functional keratin fiber so similar
phenotype resulting forms mutation. the
mutated protein have dominant negative activity.
• As a result the disorder show an autosomal
dominant mode of inheritance.
• This is most common type of epidermolysis
bullosa 75-85% of cases.

20. II Junction Type
• Blisters occurs in otherwise histologically
normal skin at the level of lamina Lucida.
• Most cases are caused by autosomal recessive
defect in one of the sub units of laminin (a
multicomponent) protein located in lamina
Lucida that binds to both hemi desmosomes
and anchoring filament.

21. • Remaining cases caused by mutation in BPAG2 same
protein that is targeted by auto antibodies in bullous
pemphigoid.
Scarring Dystrophic Type:
• Blisters develop beneath the lamina Dura .
• Associated with rudimentary or defective anchoring fibrils.
• Dystrophic epidermolysis bullosa results from mutation in
COL7A1 gene which encode type vii collagen, major
component of basement membrane anchoring fibrils.
• Disorders may follow an autosomal dominant or autosomal
recessive inheritance.
Mixed type : marked by defects at several levels.

22. Porphyria
• An uncommon inborn or acquired disturbance of
porphyria metabolism.
• Porphyria are pigment normally present in hemoglobin
,myoglobin and cytochromes.
• Classification of porphyria based on clinical and
biochemical features:
1. Congenital erythropoietic porphyria
2. Erythropoietic porphyria
3. Acute intermittent porphyria
4. Porphyria cutanae tarda
5. Mixed porphyria

23. • Cutaneous manifestation consist of:
1. Urticaria and vesicles associated with scaring
which are exacerbated by exposure to
sunlight.
2. Vesicles are sub epidermal in location and
adjunct dermis contains vessels with wall
that are thickened by glassy deposits of
serum proteins including immunoglobulin.
• Pathogenesis not understood.