amyloid Flashcards
— is a pathologic proteinaceous
substance deposited between cells in various tissues and organs of the body in a wide variety of clinical settings –> Proteins — & form – aggregates of fibrils (deposits). –> The deposition of the various types of amyloid in tissues
( — ) leads to —
amyloid
polymerise
insoluble
amyloidosis
organ malfunction
amyloidosis and abnormal protein:
1- * — of protein
– Core issue in amyloidosis
– — abnormal protein cannot be cleared
– prevents the normal – of cells/tissues
2- * A specific precursor protein pathologically – from its
physiologic – structure into a more— shape dominated by —
– Resistant to —
– Misfolded protein aggregates into — , eventually forming — amyloid fibrils
– deposit — in tissues
3- * Organ dysfunction occurs because
– circulating oligomers are —
– Fibrils lead to distortion of the tissue –
4-* >35 different proteins implicated in various amyloid diseases
– — or –
– — or —
– with different organ – and —
misfolding
structurally
normal function
misfiles
territory
linear
bear pleated sheets
proteolysis
oligomers
insoluble
extracellular
cytotoxic
architecture
heredity or non heredity
localised or systemic
involvement n prognosis
- Amyloidosis should not be considered a — disease - it is a — of diseases having in common the deposition of –
- On H&E, appears as – ,—
extracellular substance
– Characteristic appearance under —
single
group
amyloid protein
amorphous eosinophilic hyaline
polarised light
amyloid composition:
Physical Nature:
* Three components
1. — fibrils in a — conformation.
Varies depending on underlying— .
2. —-
(Amyloid P component)
Derived from a circulating —
protein called — (SAP).
3. —
non branching fibrils
beta pleated sheet
disease
nonfibrilliar pentagonal glycoprotein
serum
serum amyloid P
protegylcan
diagnosis of amyloid:
* Depends on — identification of amyloid deposits in appropriate biopsy specimens ( — diagnosis).
* With the – microscope and
standard — (– ),
amyloid:
– — , — extracellular substance that, with progressive accumulation,
encroaches on and produces — of adjacent cells.
* May be done — on the
affected organ, on an
abdominal – pad biopsy
* Congo red/Sirius red stain (under ordinary light) imparts a – or– colour to amyloid deposits. It binds to amyloid by —
* – birefringence of the stained amyloid when observed by —
* — can be used for certain proteins
morphologic
histological
light
standard tissue stain
h&e
amorphous estiniphilic
pressure atrophy
directly
fat
pink or red
hydrogen bonds
green
olarizig microscopy
immunochimestry
additional investigation that maybe required:
FBC, LFTs
* Renal function tests – creatinine, eGFR, 24hr proteinuria
* Cardiac tests: Troponin, ECG, ECHO, MRI
* SPEP, light chain quantification
* Bone marrow biopsy
* Skeletal imaging
* Genetic sequencing
* Variably presentation – diagnosis may take time to reach
amyloid classification:
- clinical method of classification
* Historically, divided into – or — :
1- —: – generalized, involving several organ systems
– — amyloidosis – associated with some immunocyte dyscrasia
– — amyloidosis – complication of an underlying chronic inflammatory or destructive tissue process
2- — – deposits in a single organ, eg heart
— or — amyloidosis – separate yet distinctive pattern of organ involvement, that is usually –
systemic or localised
systemic
primary
secondary
loclaised
heredity or familial
systemic
( info: Current classification systems are based on the protein that produces the majority of the deposits; usually abbreviated, starting with the letter ‘A’.
Some of these are biochemically distinct proteins (egTransthyretin (TTR), or β2
macroglobulin (TTR)))
other classifications of amyloidisis;
* Other forms are due to different diseases causing — or abnormal —
- Most common types of amyloidosis:
– — (amyloid — ) is due to an overproduction of immunoglobulin
— derived from plasma cells
– – (amyloid- — ) is due to continuous overproduction of — in — inflammation
– Aβ amyloid is found in the – lesions of — disease
– — - transthyretin – heart, lung, tenosynovium, ligaments
overabundant
abdormal protein production
AL amyloid light chain
light chain
AA amyloid associated
acute phase proteins
chronic
cerebral lesions
alzhermiers
ATTR
AL amyloid:
* Overall, a – disease (minimum incidence of 8/million*)
* Precursor protein is immunoglobulin — derived from – cells
(or other — ).
* Many patients have some form of a monoclonal B cell proliferation, which – abnormal amounts of immunoglobulin.
* Seen in approx. 5-15% of patients with multiple myeloma.
* The increased amounts of immunoglobulin will produce an —
on serum electrophoresis.
* – are heart are most often involved
* Patients with myeloma and AL amyloidosis generally follow an unremitting and ultimately fatal course, either from malignancy or from —
complications of amyloid.
* Some treatment options are available including — or— with possible additional of —.
rare
light chais
plasma
other v cells
synthesises
m protein spike
kidneys
cardiac/renal
bone marrow transplantation
chemotherapy
steroids
AA amyloids;
* Deposits are composed of AA amyloid, derived from a – precursor synthesized in the – called — (serum amyloid-
associated) protein.
* Deposits are – in distribution.
* AA proteins are typically deposited in the setting of – inflammatory states.
* Sometimes known as— amyloidosis as it is associatedwith inflammatory conditions, eg RA, TB, osteomyelitis,
inflammatory bowel disease, ankylosing spondylitis.
*— is a normal plasma protein synthesised in the liver, under
influence of cytokines such as IL6 and IL1, as part of the physiologic – response.
* If untreated, it is associated with significant mortality due to end-
stage renal disease, infection, heart failure, bowel perforation, or
gastrointestinal bleeding
* Active management of the underlying inflammatory process is
critical in lowering the hepatic production of the — (eg
biologic agents in RA)
larger serum
liver
SSA
systemic
chronic
secondary
SSA
acute phase response
SSA
other amyloids:
* AL and AA amyloid tend to deposit – . Someforms of amyloid however are – .
* E.g. “Endocrine” amyloid is produced by certain tumours
– – cell tumours of the pancreas.
– — medullary carcinoma.
systemic
localised
islet
thyroid
( check slide 24 and the rest of pics pls)
clinical features:
* Presentation & signs
– Usually age—
– No single set of symptoms points unequivocally to amyloidosis as a diagnosis.
– Depends very much on the –
* The symptomatology is governed by the underlying – and the — and – (s) of deposits.
1- Kidneys
* commonly involved, especially in patients with — .
Signs include protein in the – , may develop – syndrome, —
2– Heart
* can present with — restrictive –
(especially with – or — types)
3– Liver
* raised LFTs (serum Alkaline Phosphatase and γ-glutamyl
transferase), hepatomegaly, later –
4– GIT
* — and altered GI – , non-specific presentation of diarrhoea/constipation, malnutrition, enlargement of the– in
— amyloidosis
5– Spleen
* dysfunction, abnormal–
nerves
6- peripheral nerves
* Familial polyneuropathic forms of amyloid may present with– , loss of – or – sensation
50-60
subtype
disease magnitude sites
multiple myeloma
urine
nerphotic syndrome n renal insufficiency
heart failure n restrictive cardiomyopathy
AL or TTR
jaundice
malsoprtion n altered GI motility
tongue
AL
enthrocyte
parathesias
temp
pain
clinical features morphology:
* Kidney
– Large, pale, grey, firm.
– Microscopic amyloid deposits principally in glomeruli and
interstitial peritubular tissue, as well as walls of blood vessels.
Eventual obliteration of the – .
* Spleen
– – enlargement, pale, grey, waxy
– Microscopically deposits in splenic follicles (sago spleen) or
involve the splenic sinuses in large sheet like deposits (lardaceous spleen)
* Liver
– – enlargement up to —
– Microscopic deposits in space of Disse, then hepatic parenchyma and sinusoids
– Trapped hepatocytes undergo — and get replaced by amyloid
* Heart
– — enlargement, grey pink subendocardial
elevations especially in the atria
– Microscopically, deposits throughout myocardium, first between myocardial fibres, then causing —
* Other organs / sites
– Generally encountered as part of – disease
– — : Adrenals, thyroid, pituitary, pancreas (diabetes)
– GIT – may be identified on a —
– — – macroglossia
– — tissue – carpal tunnel syndrome
glomerulus
moderate
massive
9000g
hepatocytes
compression atrophy
mild to moderate
pressure atrophy
systemic
endocrine
rectal biopsy
tongue
synovial
( check slide29,32 )
summary:
* Is an important diagnosis to consider with many differing clinical
presentations.
* Three most common forms are – , – (90%) and –
* A – followed by confirmation with — staining is the most important tool in the diagnosis.
– This is usually done in an organ suspected to be involved – e.g. kidney,
gingival, rectal, or abdominal ‘fat pad’ biopsy
– Immunohistochemistry may also be used
* For – , serum and urinary protein electrophoresis may be performed
* The outlook for patients presenting late with generalized amyloidosis is
poor with a mean survival time of – after diagnosis.
* In – amyloidosis, prognosis depends on controlling the underlying
condition
AA AL ATTR
biopsy followed by Congo red staining
Immunohistochemistry
AL
1-3 years
AA
