Amyloidosis - Baumgarten

Question 1

What is the criteria for definition of Amyloidosis (imagine)?

Answer 1

Homogenous, hyaline, eosinophilic material on H&E
stain

1. Stains with alkaline congo red: Apple green positive birefringence with polarized light
2. Yellow Green fluorescence by thioflavine T
3. Fibrillar structure on em-beta pleated: antiparallel and nonbranching
4. Fibril- forming protein is unique for each form of amyloid, composed of thousands of peptide subunit

• SAP – serum amyloid P-component.
• Pentraxin, non-fibrillar. Identical in all forms. (CRP family)
• Glycoseaminoglycans
• Apo E&J

6. Systemic / Organ deposition

Question 2

What diseases is light chain amyloidosis (AL) associated with?

What protein is deposited?

Who is the typical patient?

Answer 2

Primary amyloidosis, multiple myeloma (15-20%), Waldenstrom’s macroglobulinemia, NHL

Fragments of light chains (V1, Lambda > Kappa, 3:1)

Plasma clone is synthesizing light chain pathologically

Common in middle aged males

Question 3

What diseases is amyloid A amyloidosis (AA) associated with?

What is the pathological pathway of disease?

What population is most affected?

Answer 3

Secondary amyloidosis, reactive (in chronic rheumatic disease RA, AS, Behcet’s, IBD, FMF, TB, leprosy, osteomyelitis, neoplasms-rarely, renal cell carcinoma- if diseases controlled may decrease amyloidosis),

During normal infection the liver produces SAA, acute phase reactants, but here they are not degrades by macrophages and deposit on tissues

Thus the immune system is constantly triggered

Most common amyloidosis in the third world, where infectious disease most common

Question 4

What mutation causes heredofamilial amyloidosis?

Answer 4

ATTR-transthyretin overproduction leading to familial amyloid polyneuropathy

Autosomal dominant, onset 30+, but over 80 point mutation variations (but met –> val 30 most common)

Causes polyneuropathy, CMP, accumulates in nerves and myocardium

Fibrils are mutant proteins

Question 5

What is the pathogenesis of A-beta2-microglobulin formation?

Answer 5

Normally HLA1-Ag components shed and secreted in urine

In long term hemodyalysis, advanced glycation end product of AB2M in inable to filter through dialysis and can’t be filtered or excreted

Deposited in articular/periarticular space

Question 6

What is the manifestation of organ limited amyloidosis diseases?

Which type of protein creates each manifestation?

Answer 6

Brain: A-beta amyloid protein

• has direct cytotoxicity
• deposits in blood vessels to cause angiopathy and neuritic plaques
• Degeneration in Alzheimer’s disease, Downs’ syndrome, Hereditary Cerebral Hemorrhage and aging

Renal amyloidosis:

• From primary or secondary (AL or AA)
• Causes enlarged kidneys, glomerular disease (including renal failure) and rarely hypertension and tubular DI and RTA

Cardiac:

• From AL or AA or ATTR
• Replacement of myocardial fibrils with amyloid fibrils
• Causees low voltage, arrhythmias, CHF, hypotension, ANS dysfuction

GI:

• AL and AA
• Begins with macroglossia, then malabsorption, diarrhea, protein loss, dysmotility of esophagus or small bowel, pseudoobstruction, hemorrhage (ulcerations), hepatosplenomegaly
• Mucosa and submucosa infiltration or autonomic nerves

Musculoskeletal:

• AL, AA or A-beta-2M
• Summetrical Polyarthritis of small joints
• Cachexia with big shoulders
• From hemodialysis: CPS, bone cysts, spondyloarthropathy from pressure

Skin:

• From AL
• Causes papules and plaques, periorbital ecchymosis (raccoon eyes), factor X deficiency

Nervous System:

• AL, A-beta-2M, FAP, AA cause peripheral neuropathy (CPS) and autonomic dysfunction (orthostatic HTN and diarrhea)
• A-beta causes CNS neuropathy

Question 7

Which organ is involved in which mutation of amyloidosis?

Answer 7

Question 8

What is the treatment for amyloidosis?

Answer 8

For AL:
-reduce plasma cell: chemotherapy, autologous stem cell transplant, steroids, experimental like iodoxorubicin

For AA:

• For FMF- cholchicine
• For others, inflammatory treatment and colchicine, cytotoxic drugs

ATTR:
-Liver transplant (won’t recur in the new liver)

Supportive treatment for everyone

Eprodisate - no FDA approval, inhibits fibril polymerization & amyloid deposition, slows renal function deterioration