Amyloidosis
Epidemiology and
Etiology:
- Amyloid is not a chemically
distinct entity
- 3
major and several minor biochemical forms
- Amyloidosis is a group of diseases
having in common the deposition of similar-appearing proteins
- Systemic
or localized
- Primary
(immunocyte dyscrasia-associated)
or secondary (to some underlying inflammatory or tissue-destructive
process)
- Caused
by abnormal folding of proteins, which are deposited as fibrils in
extracellular tissues
- Some
proteins are prone to misfolding and may do so
when in increased quantity
- Failure
of degradation of misfolded proteins
- Intracellular
in proteasomes
- Extracellularly by macrophages
- Amyloid light chain (AL)
(primary amyloidosis)
- Immunoglobulin
light chains
- Most
are lambda, some are kappa
- Complete
or NH2-terminal fragments
- Derived
from plasma cells
- Monoclonal
B cell proliferation in some
- 5-15%
of patients with multiple myeloma have systemic amyloidosis
- Majority
of AL amyloid patients do not have an overt B
cell neoplasm
- Most
have a modest increase in plasma cells in the bone marrow
- many
have chromosomal translocations
- Almost
all have monoclonal immunoglobulins and/or
free light chains in the serum or urine
- Systemic
- Most
common form of amyloidosis
- Amyloid-associated (protein AA)
(secondary amyloidosis):
- Non-immunoglobulin
protein
- Synthesized
by the liver under the influence of cytokines such as IL-6 and IL-1 that
are produced during inflammation
- Cleavage
product of serum amyloid A (SAA)
- Associated
with protracted breakdown of cells
- Chronic
inflammatory conditions
- Rheumatoid
arthritis
- Ankylosing spondylitis
- Inflammatory
bowel disease (esp. Crohn)
- Heroine
abusers (chronic skin inflammation from needles)
- Infections
- Neoplasms
- Renal
cell carcinoma
- Hodgkin
disease
- Transthyretin (TTR)
- Senile
systemic amyloidosis
- familial
amyloid polyneuropathies
- Minor amyloid forms:
- Ab amyloid
(Beta-amyloid protein)
- Found
in Alzheimer disease
- Derived
from amyloid precursor protein
- Beta-2-microglobulin
- A
component of MHC class I molecules
- Complication
of renal failure
- Not
filtered out by hemodialysis membranes
- Prion disease
- Endocrine
amyloid
- Medullary carcinoma
- Islet
tumours of pancreas
- Islets
of Langerhans in DM II
- Pheochromocytomas
- Undifferentiated
carcinomas of the stomach
- Hereditary
amyloidosis:
- Mutations
in genes encoding transthyretin (TTR gene),
fibrinogen A alpha-chain (FGA gene), lysozyme
(LYZ gene), or apolipoprotein A-1 (APOA1 gene)
Common sites:
- Kidney
- Liver
- Spleen
- Lymph
nodes
- Adrenals
- Thyroid
- AL amyloid:
- Heart
- Kidney
- GI
tract
- Peripheral
nerves
- Skin
- tongue
- Amyloidomas:
- Lung
- Larynx
- Skin
- Urinary
bladder
- Tongue
- paraocular
Gross features:
- organ
enlargement
- firm
- waxy
- yellow
then blue violet with iodine followed by sulfuric acid
- spleen
- tapioca-like
granules (sago spleen) (splenic follicle
deposition)
- lardaceous
spleen
Histologic
features:
- Amyloid
- Extracellular
- Amorphous
- Hyaline
- Yellow-green
birefringence (specific)
- Kidney:
- Amyloid deposits:
- Glomeruli
- fibrillary eosinophilic
deposits within mesangium and capillary
walls
- Thickening
of mesangial matrix
- Uneven
widening of basement membranes of capillaries
- Capillary
lumens obliterated
- Confluent
masses or interlacing broad ribbons of amyloid
- eventually
obliterate the glomerulus
- Interstitium
- blood
vessel walls
- spleen
- one
of 2 patterns of deposition seen
- splenic follicle deposition
- follicle
sparing with involvement of walls of splenic
sinuses and connective tissue framework
- fusion
of areas gives rise to large, maplike areas
(lardaceous spleen)
- liver
- space
of Disse
- progressively
encroaches on adjacent hepatic parenchyma and sinusoids
- total
replacement of large areas of parenchyma
- vascular
involvement
- Kupffer cell deposits
- Heart:
- Subendocardial
- Between
muscle fibres
- Adrenals:
- Intercellular
adjacent to basement membranes of cortical cells
- Zona glomerulosa
Immunophenotype
and Special Stains:
Marker:
|
Sensitivity:
|
Specificity:
|
Congo Red
|
|
|
light chains
(AL)
|
|
|
AA?
|
|
|
TTR
|
|
|
Molecular features:
- Heredofamilial amyloidosis
(rare)
- Limited
geographic areas
- Familial
Mediterranean fever
- Armenian,
Sephardic Jewish, Arabic
- AA amyloid
- Pyrin mutation
- Familial
amyloidoti polyneuropathies
- ATTRs
– mutant transthyroidetins
Other features:
- EM
(identical for all types of amyloidosis):
- Nonbranching fibrils of indefinite
length
- Diameter
7.5-10nm
- X-ray
crystallography (identical for all types of amyloid)
- Characteristic
cross-beta-pleated sheet conformation
- Chronic
inflammatory conditions tend to yield the most severe systemic amyloidosis
- Renal
involvement is the most common cause of death
- Nephritic
syndrome
- Renal
failure
- Cardiac
involvement causes congestive heart failure and arrhythmias / death
- Abdominal
fat pat sampling (FNA)
- Scintigraphy with radiolabeled amyloid P
(SAP)
- Prognosis
is poor with generalized amyloidosis
- Hereditary
amyloidosis:
- To
test for mutations, the relevant exons of each
gene are amplified up by PCR, then sequenced using capillary
electrophoresis
References:
- Robbins
& Cotran Pathologic Basis of Disease (2005)