AMYLOIDOSIS

Definition

A medical condition resulting from

aggregation of extracellularly
deposited abnormal proteins called
amyloid fibrils that cause damage to
organs and tissues.
In 1854 Rudolph Virchow named it
amyloid based on color after staining
these proteins with iodine and sulfuric
acid.
Amyl=starch, oid=resembling

Classification:
Historical vs Modern

Historical (Clinical): Primary, Secondary,

multiple myeloma associated, Familial.
Modern (Biochemical): Since 1960s based
on ability to solubilize fibrils and
immunostain for protein subtypes.
23 different human subtypes named based
on A for amyloid followed the precursor
protein e.g AL, AH.

Table was adapted from Harrison's principles of internal medicine 16th edition vol II, chapter 310-Amyloidosis

Classification:

a) Organ-limited

b) systemic

Organ limited amyloidosis:

Not assosiated with systemic diseses
occur in variety of organs
Rarely occurs in oral soft tissues
amyloid nodule-appears as a solitory,asymptomatic,
submucosal deposit
Consists of immunoglobulin light chains

Systemic Amyloidosis: several forms

Primary
Myloma associated
Secondary
Hemodyalisis associated
Heredofamilial

Primary & Myloma- Associated Amyloidosis:

Age: older -65yrs
Sex: male
Cause: due to deposition of light chain molicules
idiopathic
15 20% associated with multiple myloma
Signs & symptoms: fatigue
weight loss
1stindications
parasthesia
of
hoarseness
disease
edema
process
orthostatic hypotension

Mucocutaneous lessions
Hepatomegaly
Macroglossia- diffuse, nodular enlargement of
tongue.
Skin lessions-smooth surfaced firm,waxy papules&
plaqus
-affects eyelids, retro auricular region,
neck, lips.
some times oral lesions show ulcerations
pt c/o dry eyes & mouth becoz of lacrimal & salivary
gland destruction

Secondary amyloidosis:

Charecteristically develops as a result of

chronic inflamatory process Tb,osteomylitis.

Cause- clevage fragment of circulating acute

phase reactant protein

Organs affected: Liver, kidney, spleen,

adrenal involvement

Becoz of advent treament became less

common.

Hemodyalysis- Associated Amyloidosis:

Affected pts- long term renal dialysis pts

Cause- accumulation of 2-microglobulin

in plasma.

Deposit in bones & joints

Affects cervical spine-pain & dysfunction

Affects toung

Heredofamilial Amyloidosi

Seen in Sweedish,Portugeese,Japanese
population
Inherited as autosomal dominent traits
As amyloid deposits developspolyneuropathies, cardiomyopathy,
congestive heart failure, renal failure

Procedures used to examine:

Biopsy of rectal mucosa- classically
used - confirm the diagnosis of
primary/myloma associated
amyloidosisa
Aspiration of abdominal mucosa
or
From gingiva, labial salivary glands

H/P of affected gingival tissue shows-

Extra cellular deposition of amorphous

eosinophilic material in submucosal C.T
arranged perivascularly or throughout
tissue.

In labial salivary gland- perivascularly/

periductal

Characteristics common to all

amyloid subtypes

Hematoxylin and Eosin (HE) staining

results in amorphous eosinophilic
appearance when viewed on light
microscopy.

Standerd stains:
Congo red- have affinity for abnormal
protein
normal-stains red colour
Polarized light- birefringe apple green
color
Cristal violet- reveal metachromasia
Purple dye- more reddish wn react with
amyloid
Thioflavin-T shows +vity

Congo red staining of a cardiac biopsy specimen containing

amyloid, viewed under polarized light

Electron microscopy collection of

7.5- 10nm diameter, nonbranching,
linear fibrils.

CARDIAC AMYLOID

Adapted from K. Shah et al, Archives of internal medicine 2006.

Treatment
Treatment of this medical disorder is limited and
research is still in progress.
Treatment differs depending on subtype.
AL and AH
-High dose mephalan plus
dexamethasone/prednisone
-In selected candidates autologous stem cell
transplant is an option.
- The goal with treatment is to get rid of clonal
plasma cells that lead to immunoglobulin protein

AA: Treat the infection or chronic

inflammatory condition causing apo serum
A protein elevation.
Familial Mediterranean fever: Colchicine
Other conditions are treated
conservatively or require organ transplant
Prognosis is poor with this medical
disorder.

TAKE HOME MESSAGE

Can affect any organ system

Hematoxylin and Eosin (HE) and Congo
stain only tells you these are amyloid
fibrils
Need to immunostain to determine
subtype
Different subtypes are treated differently.
A lot still have to be known about the
therapy as prognosis is poor for this
disease.

LANGERHANS CELL HISTIOCYTOSIS

Langerhans cell histiocytosis (LCH) (formerly

histiocytosis-X) is characterized by intense and
abnormal proliferation of bone marrow-derived
histiocytes (Langerhans cells), together with a
variable number of leucocytes, eosinophils,
neutrophils, lymphocytes,plasma cells and
giant multi-nucleated cells causing tissue
destruction.
This tissue destruction-cellular infiltration that
replaces bone and invades skin, mucosa and
internal organs

CLASSIFICATION:
Lichtenstein- depending on the age
of the patient when the lesions first
appear and their distribution.
classified LCH into three clinical forms

1. Chronic focal LCH (eosinophilic granuloma)

2. Chronic diffuse LCH (Hand-Schller-Christian
disease)
3. Acute disseminated LCH (Letterer-Siwe disease)
4. Congenital reticulohistiocytosis (HashimotoPritzker syndrome)

Chronic focal LCH (eosinophilic granuloma):

Most frequent and benign of the clinical

forms.
It appears as a uni- or multifocal lesion in a
single,or occasionally various bones, with or
without soft tissue involvement, without
systemic involvement
Presenting at any age

Chronic diffuse LCH (Hand-Schller-Christian

disease):
usually appears in children or young adults
manifests with the characteristic triad of
exophthalmos,
osteolytic lesions of the cranium
diabetes insipidus.
Other manifestations: petechiae, purpura,
ulcerations

Acute disseminated LCH (Letterer-Siwe

disease):
Patients generally children under 3yrs
Due to the aggressive behavior of the disease
follow a fatal course in a short time.
Affected organs- liver, lung, lymph nodes,
skin, bone marrow and bone
Manifestations- eczema, otitis media,
hepatosplenomegaly, anemia, hemorrhages,
lymphadenopathies and osteolytic lesions

Congenital reticulohistiocytosis
(Hashimoto-Pritzker syndrome):
Believed to be a purely cutaneous form
characterized by the appearance of dark
nodules on the trunk, face and scalp.
The mucosae are always involved,
No involvement of other organs

C/F:
Age- wide age range
peak incidence bt 1st& 3rd decade
15% younger than 15yrs
Sex- m> f
Oral manifestations- 1st signs of LHS
70% shows oral manifestations
Shows manifestations in bone , mucosa,
periodontium

Bone lesions:
along with cranium max & mand
most commonly affected
Man>max
Site :man-post distal to canine &
ramus
Lessions are described according to
radiologic appearence

Solitary intra-bony lesions:

localized outside the alveolar process

Most frequent in the initial phases.
The images are circular or elliptical, solitary
or unifocal
Found principally in the body and ramus of
mandible.
They may be obvious and painful, causing
facial swelling, or they may be asymptomatic
being an incidental radiographic finding.

Multiple alveolar lesions:

37.7% of alveolar lesions may have poorlydefined or invasive margins.
Scooped-out alveolar lesions:
formed by bone destruction beginning below
the alveolar crest, either at furcal level or at
half the tooth root height

Mucosal lesions:

These are ulcerated, ovoid or round

lesions, with erythematous, inflamed borders
painful on palpation
localized principally in the buccal mucosa and at
the back of the vestibule.
associated with cutaneous lesions

Periodontal lesions:

Alveolar bone lesions form the basis for all the

associated periodontal involvement
Alveolar bone loss-pts manifest gingival
inflammation, ulceration, destruction of the
keratinized gingiva, gingival recession,
periodontal pockets and bleeding of the oral soft
tissues,associated with pain and even swelling
loss of bone support- characteristic floating teeth
Excessive mobility-inevitable
premature loss of teeth

H/P:

H&E- areas of fibrous tissue related with a mixed

inflammatory infiltrate. Non-malignant histiocytic

proliferation is seen together with the Langerhans
cells
These are large mononuclear histiocytic cellsround or oval in shape, with a vesicular nucleus,
eosinophilic cytoplasm
Abundant eosinophils & other inflammatory cells
such as lymphocytes and mononuclear phagocytes
may be found accompanying these cells.

IHC- positive to markers S-100 and/or CD1A

Electron microscopy:

Birbeck granules in the lesional cells- organelles

with rod-shaped or tennis-racket morphology that
could represent structural changes of the membrane
following contact with an antigen.

Pathogenesis: unknown
various hypotheses have been proposed
about its possible etiology.
Dysfunction of the immune system,
representing a hypersensitive reaction to
an unknown antigen, with stimulation of
the histiocytesmacrophage System
Deficiency of suppressor lymphocytes(T8),
altered immunoglobins
Autoantibodies
Chronic inflamation

Prognosis:

important factors that may worsen the prognosis

are1.visceral involvement (liver, lung, bone marrow)
2. Age less than two years since mortality rises
to 50%.
3. when the disease spreads to various bones or
soft tissues.

treatment:
Depend on the location and extent of the lesionsAntibiotic therapy, chemotherapy, radiotherapy,
surgery, Adrenocorticotropic hormone (ACTH)

Lipid reticuloendotheliasis

inherited disorders
Pts lack certain enzymes necessary for processing
specific enzymes-accumulation of specific lipids with
in cells
Gaucher disease
Niemann-pick disease
in Ashkenazi Jewish ppl
Tay-sachs disease

Gaucher,s disease

rare inherited disease

deficiency or lack of an enzyme called
Glucocerebrosidase
Results in an accumulation of
glucocerebroside within cells in various
body tissues ( spleen, liver, bone marrow,
and skeleton)
Severity of the disease can vary

Classification:
Presence /absence of neurological
involvement
Type-1:chronic non-neuropathic form:

Most common and can begin at any age

1 in 10,000
Patients are bruised very easily
Fatigue due to anemia
Lung and kidney injuries
Weakening of the skeleton
Victims have a shortened life-span
Usually die from clots and pneumonia

Type-ii: infantile/acute neuropathic form:

Rarest of all the types

Appears during the first few months of life
in a baby
Great brain damage mental retardation
Loss of muscle control
Enlargement of liver and spleen
Nervous system fails to function well
Patients usually die by age 2

Type-iii/juvenile form:

Begins in childhood
Liver and spleen enlargement
Causes bone marrow and damages the
central nervous system
Mental retardation is quite common
Usually die around the ages 15-30
Intermediate bet type1& type2

Jaws: mandible affected commonly

Does,t devitalize the teeth/loss of
laminadura
r/f- illdefined radiolucency
Decreased salivary flow

H/P:
Wn bone involved- bone marrow shows
diffuse changes.
Numerous large foamy,slightly granular
cells with picnotic eccentric nucleigoucher,s cells group together & replase
the normal marrow structure.

Prevention:

No real prevention
Genetic Counseling is recommended for
parents with a family history of the
disease

Treatment

No CURE
Enzyme replacement therapy-injections of
the enzyme
Result: decrease liver and spleen size
reduce skeletal abnormalities
restores normal growth &
development
restores well being of the patient

Niemann-Pick disease

Disease results from lysosomal

occumulation of sphingomylin due to
inherited def of sphingomylinase
Classification:
Type-A
Type-B
Type-C

Type-A: Acute infantile

severe with extensive neurologic

involvement
Progressive wasting
Early death before 3yers
Type-B: Non neurological form
Early symptoms seen in childhood
but parsons may stay up to adulthood
Type-c:neurological form
intracellular cholesterol esterification

H/P:

Affected cells extremely enlarged due to

accumulation of sphingomylin& cholesterol
Cells show foamy cytoplasm due to
numerous vacuoles
IHC: show +vity for cholesterol

Tay-sachs disease
Due to lack of -hexosaminidase A
-accumulation of gangloside with in the
lysosomes of neurons
C/F:

mild forms- survive till adulthood

Severe forms-infantile form- proressive neuronal
degeneration develops shrotly aft birth
Signs& symptoms: blindness,
developmental retardation
Death before 3-5yrs