Chapter 1.5 AMYLOIDOSIS

Question 1

What is an amyloid?

Answer 1

Any type of misfolded protein that deposits in the EXTRACELLULAR SPACE, thereby damaging tissues

Also deposits characteristically around BLOOD VESSELS

Question 2

What types or groups of proteins can deposit as amyloid?

Answer 2

Multiple proteins e.g-

1. AL amyloid derived from Immunoglobulin light chain protein
2. AA amyloid derived from SAA ( Serum amyloid associated protein)

Question 3

What are the GENERAL FEATURES of amyloid proteins?

Answer 3

1. Beta-pleated sheet configuration
2. Congo-red staining
3. Apple-green birefringence when viewed microscopically under polarized light

Question 4

What are the 2 patterns of deposition of amyloidosis?

Answer 4

1. Systemic

2. Localized

Question 5

What are the types under Systemic amyloidosis?

Answer 5

1. Primary systemic amyloidosis

2. Secondary systemic amyloidosis

Question 6

What is primary systemic amyloidosis?

Answer 6

Systemic deposition of AL amyloid

AL amyloid is derived from light chain Ig.

Cause of 80% of systemic amyloidosis

Question 7

Which disease is Primary Systemic Amyloidosis associated with?

Answer 7

Plasma cell dycrasias (i.e multiple myeloma)

Where there is disproportionate overproduction of light chain Ig—leaks into the blood—becomes misfolded—deposits in tissues.

Question 8

What is secondary systemic amyloidosis?

Answer 8

Systemic deposition of AA amyloid

AA amyloid is derived from SAA (Serum associated Amyloid)

Question 9

What is SSA? (Serum Associated Amyloid)

Answer 9

An acute phase reactant that is increased in:

1. chronic inflammatory states (lupus, RA, crohn’s, ulcerative colitis, chronic osteomyelitis)
2. Malignancy (ass with low grade chronic inflammatory state)
3. Familial Mediterranean Fever

Chronic inflammation triggers and converts SAA—AA which is deposited in tissues.

Question 10

What is Familial Mediterranean Fever?

Answer 10

Autosomal recessive
People of Mediterranean origin

Neutrophil dysfunction (incites inflammation even in absence of infection)

FEVER + acute SEROSAL INFLAMMATION (can mimic: APPENDICITIS, ARTHRITIS or MI)

During attacks, High SAA production—AA deposition in tissues

Question 11

What are the clinical findings of systemic amyloidosis?

Answer 11

1. Nephrotic syndrome (Kidneys-most common organ involved)
2. Restrictive cardiomyopathy or arrhythmia
3. Tongue enlargement(macroglossia), Gut enlargement (malabsorption), hepatosplenomegaly.
4. Lung involvement—Cough and dyspnea
5. Hematologic—Factor X def. (AL amyloid only absorbs factor X)

Question 12

How can you diagnose Systemic amyloidosis?

Answer 12

1. Tissue biopsy!

Abdominal fat pads (adipose tissue) and rectum- easy accessible biopsy targets

2. Immunoelectrophoresis (SPEP- serum protein electrophoresis)

To detect light chains in AL amyloidosis

Question 13

What is the definitive management of amyloidosis?

Answer 13

Organ transplantation.

Amyloid cannot be removed.

Question 14

What is localized amyloidosis?

Answer 14

Amyloid deposition usually localized to a single organ.

Question 15

Give examples of localized amyloidosis

Answer 15

1. Senile cardiac amyloidosis
2. Familial amyloid cardiomyopathy
3. Non insulin dependent DM-type II (Amylin deposition)
4. Alzheimer’s diseases (A-beta amyloid deposition)
5. Dialysis associated amyloidosis (beta-2 microglobulin dep.)
6. Medullary carcinoma of the thyroid (Calcitonin dep.)

Question 16

What is senile cardiac amyloidosis?

Answer 16

Deposition of NON-MUTATED serum transthyretin in the cardiac ventricles of the elderly.

Usually asymptomatic (25% >80 years) but may result in:

• HF due to massive ventricular deposition
• Atrial fibrillation due to atrial deposition.

Transthyretin- 2nd most common protein in blood.

Question 17

What is Familial Amyloid Cardiomyopathy?

Answer 17

Deposition of MUTATED serum transthyretin in the heart leading to restrictive cardiomyopathy.

5% of African Americans carry the mutated gene.

Autosomal dominant condition.

Question 18

What is the association between Type II DM and localized amyloidosis?

Answer 18

AMYLIN (derived from excess insulin produced in type II DM to which tissues are resistant to) deposits in the ISLETS OF THE PANCREAS.

Question 19

What is the association between Alzheimer’s disease and localized amyloidosis?

Answer 19

Deposition of A-BETA amyloid in the brain forming amyloid plaques.

A-BETA amyloid is derived from beta amyloid precursor protein.

Question 20

Why are most people with Down syndrome prone to develop early onset Alzheimer’s? (40 years)

Answer 20

The gene for BETA-Amyloid precursor protein (BAPP) is found in chromosome 21.

A-Beta amyloid is derived from BAPP.
A-Beta amyloid deposits in the brain causing amyloid plaques

Question 21

What is the association between dialysis and localized amyloidosis?

Answer 21

Chronic dialysis fails to filter off Beta-2 micro-globulin effectively—accumulation—deposition in JOINTS.

Beta-2 micro-globulin normally provides structural support for MHC-I on cells.

About 50% of dialysis related amyloidosis develop CARPAL TUNNEL SYNDROME due to a buildup of Beta-2 micro-globulin in the wrist

Question 22

How is medullary carcinoma of the thyroid associated with localized amyloidosis?

Answer 22

Medullary carcinoma of thyroid (MCT) is derived from C cells

Tumor of C cells— overproduction of calcitonin

Overproduced calcitonin deposits within the tumor as amyloids

TUMOR CELLS IN AN AMYLOID BACKGROUND- MCT

Question 23

How are amyloids characterized histologically?

Answer 23

Acellular eosinophilic deposits on traditional H&E staining

Question 24

What is cerebral amyloid angiopathy?

Answer 24

Condition in which Beta-amyloid deposits in the walls of the CNS blood vessels—increased vascular fragility and hemorrhagic stroke