- deposition of extracellular fibrillar proteins with similar ultrastructural & staining characteristics

- stain positively with iodine (like starch)

- differing amino acid sequences but similar structural properties

Amyloidosis

- extra-cellular pink, glassy deposits (hyaline), subendothelial locations (around blood vessels)

- looks like "pick up sticks" on EM

- organs involved enlarged, hard, and waxy

Morphology of Amyloid

- Congo Red (brick red in regular light)

- Apple green birefringence (with polarized light)

- Thioflavin T (green glow in UV light)

- Specific antibodies to differend fibrillar proteins (light chains in AL type, transthretin in ATTR)

Special stains for Amyloidosis

- different for each amyloid (1 type per amyloidosis)

- all of these form secondary structures (IE-beta pleated sheets) which create similar staining patterns

- make up greater than 95% of amyloid deposits

Fibrillary protein pool

- pentagonal donut shaped protein found in normal BM & all types of amyloid

- derived from "serum amyloid P component" (SAP)

- solubilizes long chromatin

- prevents proteolytic cleavage of aggregates

Amyloid P Component

- laminin, collagen type IV, highly charged glycosaminoglycan (GAG)

- IE- perlecan or heparan sulfate proteglycan

Components of BM

- high density lipoprotein for cholesterol transport

- unclear contribution to amyloid

- Apolipoprotein E

ApoE

- Fibrillary protein pool

- Amyloid P component

- glycosaminoglycan, laminin, collagen type IV

- ApoE

Structural Components of Amyloid

- Amyloid protein is amyloid light chain (AL) made of immunoglobulin light chains (more lambda than kappa)

- NOT associated with overt B-call or plasma cell dyscrasias (myeloma)

- Most common type in US, mean age 60, men>women

- Widest spectrum of organ involvement

Primary Amyloidosis (AL type)

- type of amyloidosis associated with B-cell malignancy

- most often malignant plasma cells (Multiple Myeloma)

- Occasionally lymphoma (Waldenstrom's macroglobulinemia)

- Clinically the same as Primary AL type

Secondary Type of AL Amyloidosis

- Amyloidosis associated with chronic inflammatory dx's

- Ex: Rheumatoid arthritis, TB, leprosy, osteomyelitis, fibrile paraneoplastic syndromes (lymphoma, renal cell ca), IV drug abuse

- Primary amyloid protein is AA (amyloid associated)

- Precursor protein is acute phase reactant protein, SAA (serum amyloid associated)

- Less common now

- usually presents as renal disease, hepatomegaly or splenomegaly

AA Type or Secondary Amyloidosis

- deposition of mutated protein (ATTR, ApoE, lysozyme)

- Precursor protein is mutated transthyretin

- 2nd most common

- Mutated ATTR (Amyloid Trans-Thy-Retin), transport for thyroid hormone and retinol

- Midlife onset, most common familial type (Met 30)

- Primarily associated with neuropathy & cardiac arrhythmias

Hereditary or Familial Amyloidoses

- 4% of blacks have a gene mutation of this gene w/ substition of isoleucine at 122 (Ile 122)

- CAN cause cardiomyopathy, incidence unknown

ATTR

- this protein is not filtered with hemodialysis and can cause amyloidosis

- amyloid primarily deposited in soft tissue of joints & tendons

Beta-2 microglobulin

- Dx associated with Neuritic plaques and Neurofibrillary tangles resulting in dementia

- Leads to oxidative injury from B-amyloid protofibril

- inflammation from neurotoxic amyloid-beta or A-B peptide

- neurotransmitter deficits from intra-neuronal deposition of double helices (hyperphosphorylated tau protein)

Alzheimer disease

- core of amyloid surrounded by dystrophic neurites

- improperly cleaved surface amyloid precursor protein makes neurotoxic amyloid-beta

- amyloid angiopathy

Neuritic plaques

- intra-neuronal deposition of double helices of hyperphosphorylated tau protein

- Causes neurodegenerative changes and neurotransmitter deficits

Neurofibrillary tangles

- sudden accumulation of normal trnasthyretin in elderly heart

- leads to progressive heart failure

Senile cardiac amyloidosis

- Proteinuria (thickened BM) --> renal failure

- Cardiac dysfunction (arrhythmias more common than restrictive cardiomyopathy [stiff LV->RV failure->edema])

- Peripheral neuropathy (pain, paresthesia, sensation loss)

- GI tract problems, Macroglossia

- Ischemia due to vascular involvement

- Deficiency of Factor X (bleeding problem)

- Purpura or vascular skin involvement

Clinical manifestations of AL type of Amyloidosis

- presents primarily w/ renal disease, hepatomegaly, splenomegaly

Clinical manifestations of AA type of Amyloidosis

- presents with neuropathy w/ less renal involvement, cardiac arrhythmias from conduction infiltration (rather than restrictive dx)

Clinical manifestations of ATTR type of Amyloidosis

- presents mostly with soft tissue, joints and tendon deposition

Clinical manifestations of dialysis-associated amyloidosis

- Aspiration biopsy of abdominal fat (low sensitivity, easiest)

- Rectal or gingival biopsy (high yield)

- Scintigraphy w/ radiolabeled SAP (rapid & specific)

Diagnostic test for Amyloidosis

- progressive, median survival 2 yrs

- death comes w/ underlying dx, renal failure, or heart failure

- Renal failure most common

- AL and AA have better prognosis if underlying dx can be treated

Prognosis of amyloidosis