Amyloidoses Flashcards
what is the stain commonly used to diagnose amyloidosis?
Congo red stain
what is the tertiary structure of amyloid protein?
beta pleated sheet
what type of amyloid is usually associated with monoclonal B-cell dyscrasias?
AL amyloid (these used to be called primary amyloidosis)
what amyloid producing disease is characterized by PMN leukocyte disfunction and recurrent episodes of serositis?
Familial Mediterranean Fever
what type of amyloid is featured in familial Mediterranean fever and renal cell carcinoma?
AA amyloid
what type of amyloid is seen in Alzheimer’s?
A beta amyloid
what protein is the precursor for amyloid deposit in Islets of Langerhans in type 2 diabetics?
amylin (AKA islet amyloid polypeptide) becomes AIAPP
what is the precursor protein for amyloid deposited in joints of chronic dialysis patients?
beta 2 microglobulin (invariant chain of MCH class I)
what is the precursor protein for amyloid assoc with Creutzfeldt-Jacob disease?
prion protein (PrPsc)
what is the amyloid precursor protein for familial amyloidotic polyneuropathy?
transthyretin (TTR)
- most common hereditary amyloidosis
what is a definitive form of treatment for familial amyloidotic polyneuropathy?
liver transplant
what cell type mediates amyloid turnover?
macrophages
what type of heart disease is generally associated with amyloidosos?
restrictive cardiomyopathy: diastolic dysfunction and preserved systolic function
what type of amyloid is assoc with Waldenstrom macroglobulinemia?
AH amyloid
what type of protein is found in the urine of pts with plasma cell dyscrasia and amyloidosis?
Bence-Jones proteins
How is clinical amyloidosis classified?
by the identity of the fibril protein accumulating
amyloid-forming proteins can exist in what stable structures?
1 - native form
2 - beta sheets
what form of amyloid-forming proteins can aggregate to form fibrils?
beta sheets
what biophysical properties do all amyloid fibrils share?
1 - insoluble in physiologic solutions
2 - fairly resistant to proteolysis
3 - binds congo red dye to create green birefringence
What is the risk of an abnormally high abundance of certain proteins that are present in low concentrations normally?
AMYLOID Deposition:
ex. serum amyloid A protein (chronic inflammation)
beta2 microglobulin (renal failure)
True or False: Normal concentrations of proteins with amyloidogenic potential will not produce amyloidosis
False, if proteins with amyloidogenic potential are present for a long period of time at normal concentrations they can aggregate as seen in senile amyloidosis (transthyretin) and Alzheimer’s (beta protein)
Can amyloidoses be acquired or inherited?
Yes, ex. monoclonal immunoglobulin light chains in AL amyloidosis and genetic amyloidogenic variants of transthyretin, lysozyme, apolipoprotein AI, and fibrinogen A alpha chain
True or False: amyloid deposits are made solely of amyloid
False: they contain minor constituents such as GAGs, serum amyloid protein, apoE, laminin, collagen IV
True or False: Females over 40 are most likely to have wild type transthyretin accumulate
FALSE: MEN OVER 60 make of 90% of the patient population for this disorder
True or False: the pathologic effects of amyloid are due to inflammatory responses?
FALSE! amyloid provokes little to no inflammatory reaction
they impair function by physically obstructing things (not just large deposits)
Does the amount of amyloid deposited indicate severity of dysfunction?
NO, it varies depending on person, organ and rate of deposition.
How can we treat amyloidoses?
reduce the supply of amyloid precursors!
What methods are used to detect amyloid?
1 - congo red stain
2 - immunohistochemistry (depends on fibril protein type)
all forms of amyloid consist of _________ ________ of ____________ arrays of fibrils.
all forms of amyloid consist of INTERLACING BUNDLES of PARALLEL arrays of fibrils
What is the most common acquired amyloidosis?
systemic AL amyloidosis
What type of amyloidosis may result from chronic infections or inflammatory diseases?
AA amyloidosis
why? long-term overproduction of acute phase reactant SAA
what part of SAA forms the amyloid fibrils?
N-terminal cleavage fragment = single non-glycosylated polypeptide chain
What infections may cause AA amyloidosis?
TB, leprosy
What types of cell convert SAA into AA?
macrophages cleave SAA into AA via several proteinases
What is the key to treating AA amyloidosis?
suppress the underlying inflammatory disorder
Why is a rectal biopsy used to diagnose AA amyloidosis?
the AA amyloid deposits are widely distributed
What are the transcriptional regulators of SAA?
IL-1, IL-6, TNF-alpha
Which of the following organs may be directly affected by AL amyloidosis?
Brain, Heart, Liver, Kidneys, Peripheral nerves
Virtually all organs EXCEPT the brain can be directly affected but those listed are most important clinically (except the brain)
Which amyloidosis involves immunoglobulins?
AL amyloidosis: consists of the variable region of Ig light chains derived from kappa or lambda polypeptides
ATTR amyloidosis almost always presents with ________ _________.
Restrictive cardiomyopathy (ATTR = transthyretin amyloidosis)
Medullary carcinoma of the thyroid is associated with amyloid precursor?
procalcitonin (becomes ACal)
Where in the brain are amyloid deposits never seen?
cerebral parenchyma (not seen in any form of acquired systemic visceral amyloidosis)
What protein is beta-protein derived from and where is the precursor found?
amyloid precursor protein (APP), transmembrane protein in neurons and glia
What is the link between Alzheimer’s and Down Syndrome?
APP (which makes beta amyloid, which causes Alzhiemer’s) is encoded on chromosome 21; some Down syndrome patients develop AD by 35
What hereditary amyloidosis presents as cerebral amyloid angiopathy with recurrent cerebral hemorrhage and silent systemic deposits?
cystatin C amyloidosis
- only reported in Icelandic families
most common hereditary renal amyloidosis
Hereditary fibrinogen A alpha-chain amyloid
A 50 year old man presents with proteinuria, and hypertension. Despite your best efforts to treat him, he develops end-stage renal failure within 5 years. What is the most likely amyloidosis in this patient? And what is the mechanism of disease?
Hereditary fibrinogen A alpha-chain amyloid.
Mech: amyloid deposits in kidneys, spleen, and perhaps liver
Because amyloid deposits accumulate along _______ __________, the deposits take on the architectural framework of the ________ ________.
because amyloid deposits accumulate along STROMAL NETWORKS, the deposits take on the architectural framework of the ORGANS INVOLVED
Amyloid deposition can cause: A- Increased size of organs affected B - Organ Atrophy C - All of the above D- none of the above
C: amyloid add material to th organs where they deposit but they may also occulde blood vessels and impair circulation leading to atrophy
Where do amyloid deposits tend to localize? and how does this affect cellular processes?
they localize between parenchymal cells and their blood supply interfering with normal nutrition and gas exchange
What are two methods through which amyloidosis damages/ kills cells?
1 - blocking blood supply
2 - direct toxic effect through protofibrils interacting with cell membranes
What classic symptoms of amyloidosis should instantly indicate the diagnosis?
TRICK QUESTION! There is no single set of sx that point to amyloidosis
- sx depend on underlying disease, type of amyloid and organ affects
Enlargement of the tongue is associated with what type of amyloidosis?
AL amyloidosis
What type of amyloid is associated with spongiform encephalopathies?
PrPsc (prion protein)
what type of amyloid protein is associated with multiple myeloma?
AL amyloid (immunoglobulin precursor)
