AMYLOIDOSIS
AMYLOIDOSIS
a group of diseases - disorder of protein misfolding
extracellular deposition of insoluble abnormal fibrillar proteinaceous substance (amyloid)
that alters the normal function of tissues
about 36 different types of amyloidosis, each due to a specific protein misfolding
a combined estimated prevalence of 30 per 100,000 persons (three most common forms
are AL, ATTR, and AA) - median age at diagnosis is 64
more than 30 different proteins can aggregate and form fibrils with the appearance of
amyloid
deposited between cells in many tissues and organs; the most commonly involved are kidney
and heart
HE: intercellular pink translucent material
causes: idiopathic or associated with a variety of inherited conditions and acquired
inflammatory disorders
AMYLOIDOSIS
1/3 of amyloidosis cases is hereditary - an early age of onset
1/2 of amyloid-related diseases are sporadic and have a late age of onset – in
these cases, the protein aggregation may be associated with aging-related decline in
protein regulation
amyloid-forming proteins aggregate into distinctive fibrillar forms with a beta-
sheet structure - proteolysis-resistant -> buildup of amyloid deposits in the
extracellular space
AMYLOIDOSIS
amyloidoses are referred to with a capital A (for amyloid) followed by an
abbreviation for the fibril protein
in most cases called primary amyloidosis, the fibril protein is an immunoglobulin light
chain or light chain fragment (abbreviated L) = light chain amyloidosis (AL)
AA amyloidosis occurs with continuous overproduction of acute phase
proteins in chronic inflammation
in most cases termed senile systemic (cardiac) amyloidosis and in many cases termed
familial amyloid polyneuropathy (FAP), the fibrils consist of the transport protein
transthyretin synthesized in the liver (TTR) = collectively termed ATTR
STAINING OF AMYLOID
Gross reactions
Virchow I. - staining by Lugol's solution
Virchow II. - reaction with H2SO4
Microscopy
metachromasia (cresyl violet, gentian violet)
Congo red – red in light microscope, green birefringence under polarized light
monoclonal antibodies against different types of amyloid - more precise classification
- immunohistochemistry
AMYLOIDOSIS - PATHOGENESIS
CLASSIFICATION
several different biochemical forms of amyloid
combined biochemical-clinical classification
SYSTEMIC (GENERALIZED) – several organ systems involved
Primary – idiopathic/plasma cell dyscrasias (e.g. plasma cell myeloma)
Secondary (Reactive) - associated with chronic infections and non-infectious chronic inflammatory conditions
(AA)
Hemodialysis-associated – in chronic renal failure
Heredofamilial
LOCALIZED – deposits limited to single organ
Senile cerebral
Endocrine
Tumor-forming
CHEMICAL STRUCTURE OF AMYLOID
Fibrillar proteins – major component (95%)
AL protein
AA protein
Others – transthyretin, Abeta2-microglobulin, immunoglobulin heavy chain amyloid, amyloid of prion
protein…
Non-fibrillar components
Amyloid P
Apolipoprotein E
Protein X
Etc.
CLASSIFICATION
PRIMARY AMYLOIDOSIS (AL TYPE)
• most prevalent type of systemic amyloidosis
• idiopathic
or
• plasma cell dyscrasias (e.g. multiple myeloma, solitary plasmacytoma, B cell
lymphomas…) – clonal proliferation of plasma cells that synthesize Ig or light chains
• they can be detected in serum or urine
• an abnormal light chain in urine is known as Bence Jones protein
• most commonly kidneys; AL amyloidosis may also affect the heart, peripheral nervous
system, gastrointestinal tract, blood, lungs, skin, tongue
SECONDARY AMYLOIDOSIS (AA)
precursor protein = serum amyloid A protein, which is an acute phase reactant
produced in the liver in response to multiple cytokines
AA occurs in various chronic inflammatory disorders, chronic local or systemic
microbial infections:
Rheumatoid arthritis
Alzheimer disease
Psoriasis
Crohn disease (IBD)
Leprosy
Osteomyelitis
Tuberculosis
Chronic bronchiectasis
HEREDOFAMILIAL AMYLOIDOSIS
-> a familial form associated with a point mutation in the
transthyretin molecule (ATTR) - more than 100 variant
transthyretin proteins with single amino acid substitutions have
been described, most of which are amyloidogenic; clinical
presentation is usually polyneuropathy and/or
cardiomyopathy
SENILE SYSTEMIC (PREVIOUSLY SENILE
CARDIAC) AMYLOIDOSIS
in elderly patients, wild-type (non-mutated) transthyretin may become structurally
unstable, resulting in the development of misfolded intermediates that ultimately
aggregate and precipitate as amyloid
these fibrils form in many different organs, but they have a predilection for the
heart
LOCALIZED AMYLOIDOSIS
• detectable nodular masses
• lungs, larynx, skin, urinary bladder, tongue
INVOLVEMENT OF ORGANS
Affected organ is usually enlarged and pale
Cut surface shows waxy, firm parenchyma
Extracellular deposits of amyloid, in the interstitium and walls of blood
vessels -> pressure on adjacent cells (pressure atrophy) and narrowing of
the vascular lumen (decreased perfusion) -> organ failure
https://www.brown.edu/Courses/Digital_Path/systemic_path/cardio/amyloidosis1.html
INVOLVEMENT OF ORGANS
Kidneys
most common, most serious
most cases of secondary and 1/3 cases of primary
amyloidosis
amyloid in glomerular capillaries and mesangium,
vessels, interstitium
advanced cases – kidney shrunken because of
ischemia caused by vascular narrowing
kidney's ability to filter and excrete waste and
retain plasma protein is affected -> proteinuria and
nephrotic syndrome
cca 20% of people with AL and 40–60% with AA
amyloidosis progress to end-stage kidney
disease requiring dialysis
INVOLVEMENT OF ORGANS
Heart
amyloid deposition can cause both diastolic (heart filling with blood; restrictive
cardiomyopathy) and systolic heart failure (ability to pump blood) and arrhythmias
(conduction abnormalities)
amyloidosis of the heart can be part of AL amyloidosis or heredofamilial and senile
due to abnormal folding of transthyretin
AA amyloidosis usually spares the heart
symptoms of heart failure may be present, including shortness of breath, fatigue,
and edema
INVOLVEMENT OF ORGANS – AMYLOIDOSIS OF
SPLEEN
-> follicular involvement
-> diffuse involvement
INVOLVEMENT OF ORGANS
Liver
weight up to 9kg! (hepatomegaly)
atrophy of hepatocytes
jaundice, fatty stool, anorexia, ascites, and spleen enlargement
GIT - weight loss, diarrhea, abdominal pain, gastrointestinal reflux, GI bleeding
Lymph nodes
Nervous system - peripheral neuropathy
Thyroid and adrenal gland – hypothyroidism, low blood sodium levels, orthostatic hypotension
Musculoskeletal system – synovial tissue of the knee, joints of hands, wrists, elbow, hip, and ankle - joint pain
Oral cavity – 20% of people with AL amyloidosis have an enlarged tongue, that can lead to obstructive sleep
apnea, difficulty swallowing, and altered taste. Tongue enlargement does not occur in ATTR or AA amyloidosis.
CLINICAL SYMPTOMATOLOGY
variable clinical outcomes: incidental finding at autopsy or severe clinical symptoms - renal
malfunctions, hepatosplenomegaly, heart failure
often vague symptoms – fatigue, weight loss, shortness of breath, palpitations, and orthostatic
hypotension
in AL amyloidosis, symptoms can include enlargement of the tongue
Dg.: tissue biopsy of the lesion
the type of the amyloid protein can be determined in various ways; the detection of
abnormal proteins in the urine or bloodstream (protein electrophoresis or light chain
determination) or in tissue using IHC
prognosis in generalized amyloidosis is poor
most common causes of death = renal failure and cardiac arrythmias
