Amyloidosis Flashcards
What is amyloidosis❓
What is the general pathophysiology behind it’s generation❓
- Amyloidosis is deposition of fibrillar proteins in the ECF which causes tissue damage
2. Inherited disorder/inflammation ⬇️ Abnormal misfolding of proteins ⬇️ 🚫degradation by proteasomes/macrophages ⬇️ Aggregation of insoluble abnormal fibrils ⬇️ Fibrillar deposits bind to proteoglycans, glycosaminoglycans (heparan and dermatan sulfate) and plasma proteins
How would you identify an amyloid❓
1. Light microscopy (H and E stain): Amorphous Eosinophilia Hyaline, extracellular substance
2.
Congo Red stain:
Pink/red tissue deposits
- Polarizing microscopy:
Green birefringence - Waxy, firm enlarged organ
Describe the:
- Physical
- Chemical structure
of an amyloid
- Election microscopy:
Presence of continuous, non-branching fibrils
Diameter- 7.5-10nm
X-ray crystallography/Infrared Spectoscopy:
Cross-b-pleated sheet conformation
- Fibril proteins (95%)
P component and glycoproteins (5%)
What are the forms of an amyloid fibril❓
1.
AL (Amyloid light chain) protein:
•made of complete immunoglobulin light chains or a.a terminal fragments
•produced by monoclonal population of plasma cells
•deposition is associated w plasma cell tumors
2. AA (Amyloid Associated Type): •derived from non-Ig protein made by liver SAA (serum amyloid associated) protein •circulates bound to HDLs •produced in inflammatory states •associated w chronic inflammation •secondary amyloidosis
3.
Beta-amyloid protein:
•constitutes the core of cerebral plaques in Alzheimer’s dx
•deposited in walls of cerebral blood vessels
- TTR, Transthyretin:
•serum protein that binds and transports thyroxine and retinol
•mutant forms are deposited in some disorders (familial amyloid polyneuropathies)
•and in the heart of the aged (senile systemic amyloidosis) - Beta-microglobulin:
•component of MHC class I, Normal serum protein
•found in amyloidosis in pt with long-term hemodialysis - Prion
The amyloid protein, TTR, Transthyretin, is seen in which conditions❓
Familial amyloid polyneuropathies
Senile systemic amyloidosis
The amyloid protein, b-microglobin, is seen in which condition❓
long-term hemodialysis
The amyloid protein, Beta-amyloid protein, is seen in which condition❓
Alzheimer’s dx
What other minor components are present in amyloids❓
Serum amyloid P component
Proteoglycans
Sulfate glucosaminoglycans
Primary amyloidosis…
- Caused by❓
- Systemic/local in distribution❓
- Is of which type❓
- Associates with which dx❓
- Clonal proliferation of plasma cells that synthesize an Ig
- Systemic in distribution
- AL-type and most common
- Multiple myeloma
Reactive Systemic amyloidosis…
- Caused by❓
- Systemic/local in distribution❓
- Is of which type❓
- Associates with which dx❓
- Secondary to chronic inflammation
- Systemic
- AA protein
4. Rheumatoid arthritis (3%) IV heroin abusers Renal cell and Hodgkin lymphoma Ankylosing spondylitis Crohn dx Ulcerative colitis
What is the mechanism of amyloid formation in reactive systemic amyloidosis❓
Chronic inflammation ⬇️ IL-6 and IL-1 stimulate sustained SAA synthesis by hepatocytes ⬇️ 🚫breakdown of SAA ⬇️ Insoluble AA molecules
Heredofamilial amyloidosis…
- Caused by❓
- Systemic/local in distribution❓
- Is of which type❓
- Associates with which dx❓
In Familial Mediterranean Fever: ⬇️ Encoding of pyrin protein ⬇️ Generation of pro-inflammatory cytokines ⬇️ Inflammation ⬇️ Excessive production of IL-1
OR
Familial amyloidotic polyneuropathies ⬇️ Alteration of structure of TTRs ⬇️ Misfolding and aggregation of mutant TTRs ⬇️ 🚫proteolysis
- a. What is the mode of inheritance of Familial Mediterranean Fever❓
b. What is it characterized by❓
2. What is the mode of inheritance of Familial amyloidotic polyneuropathies❓
1.
a. Autosomal recessive
b. Bouts of fever
Inflammation of serosal surfaces
2.
Autosomal dominant
Endocrine amyloids can be found in which endocrine disorders❓
Medullary carcinoma of the thyroid
Islet tumors of the pancreas
Pheochromocytomas
Undifferentiated carcinomas of the stomach
Type 2 DM
Amyloid of aging…
- Systemic/local in distribution❓
- Associates with which dx❓
- Is of which type❓
- Systemic
- Restrictive cardiomyopathy
Arrhythmias - Normal TTR
Mutant TTR
What morphological changes are observed in a kidney with amyloids❓
Grossly:
Normal/Shrunken (advances cases)
Histologically: •Mainly glomerular deposition •Widened basement membrane of glomerular capillaries •Capillary narrowing (obliteration) •Distortion of glomerular vascular tuft •Thickened mesengial matrix
What morphological changes are observed in a spleen with amyloids❓
Gross:
Splenomegaly (800g)
Tapioca-like granules/sago spleen (deposits in splenic follicles)
OR
Deposition in walls of splenic sinuses and connective tissue framework of red pulp
Fusion give rise to large, maplike areas (lardaceous spleen)
What morphological changes are observed in a liver with amyloids❓
Moderate to marked hepatomegaly
First appears in space of Disse
Encroaches on parenchymal cells and sinusoid
Disappearance of hepatocytes and total replacement
Normal function is preserved
What morphological changes are observed in a heart with amyloids❓
Most occurs in systemic amyloidosis
Main organ involved in senile systemic amyloidosis
No significance changes OR
Enlarged, firm
What is the main organ involved in senile systemic amyloidosis❓
The heart
What other organs can be involved amyloidosis❓
Tongue (Macroglossia)
Joint deposition
Brain deposition (Alzheimer’s)
Respiratory tract (larynx to bronchioles)
Amyloidosis of peripheral and autonomic nerves
What are the clinical features associated w amyloidosis❓
Asymptomatic
Non specific weakness, weight loss, syncope
Nephrotic/Renal failure/Uraemia
Congestive heart failure/Restrictive cardiomyopathy
Macroglossia/Malabsorption/Diarrhea
Bleeding
How would you make a confirmatory diagnosis of amyloidosis❓
What is the prognosis❓
1.
Biopsy (mostly kidney)
Bone marrow aspirates (plasma cell neoplasm)
2.
Poor in generalized amyloidosis
