Amyloidosis

Question 1

Define amyloidosis

Answer 1

Amyloidosis is a conditions where there is a deposition of abnormally folded proteins in the body.

normally proteins are folded in a specific a manner for their function .

If the protein is misfolded ,it will not function and they will aggregate to form fibrils which are insoluble and they becomes deposited in the tissue

Question 2

Describe the properties of amyloid proteins including physical and chemical properties

Answer 2

• Amyloidosis are a group of diseases rather than a single disease .
• More than 20 proteins have been identified that contribute amyloidosis
• These proteins are morphologically similar due to uniform physical organization of amyloid protein

*The proteins are structurally similar

• They form continuous non-branching fibrils
• They are arranged in a doughnut -shaped structure

Chemical properties
*95% fibril proteins ,5% P components and other glycoproteins

There are 3 main groups
=AL : Amyloid light chain
=AA : Amyloid Associated chain
=A bets amyloid

Amyloid light chain

• made of complete light chains , light chain amino terminal fragments or both
• Usually lembda but sometimes kapper
• Produced from free Ig light chain secreted by monoclonal plasma cells

Associated Amyloid chain

• Derived from proteolysis from a larger precursors protein (Serum Amyloid associated protein )
• Synthesized in the liver and circulates in association with HDL (high density lipoprotein )
• Increased production in inflammatory states as part of the acute phase response

*associated with chronic inflammation > secondary amyloidosis

Beta amyloid proteins
*Center of plaques and desposited in vessel walls in AD
*

Others Transthyretin
*Derived from a normal serum protein that binds and transports thyroxin and retinol
Familial amyloid polyneuropathies – mutant forms
Heart of elderly individuals – senile systemic amyloidosis
Β2-microglobulin – long term haemodialysis
Prion proteins – aggregate in extracellular space in CNS in prion diseases

Question 3

Discuss the pathogenesis of amyloidosis

Answer 3

• Abnormal folding of proteins = deposited in extracellular space = disrupt cell function
• Diverse conditions which all result in excessive production of proteins prone to misfolding

There are 2 groups
-Normal proteins which have a tendency to misfold ,self associate and produce fibrils in increased amounts

-Mutant proteins prone to misfoldings

Normally misfolded proteins are degraded internally by proteasomes or extracellularly by macrophages

*In amyloidosis these mechanisms fail therefore these proteins accumulate

In plasma cells ,disorder result from increased Ig light chain produced In inflammation ,ther is an uncrease in SAA protein

Derived from a normal serum protein that binds and transports thyroxin and retinol
Familial amyloid polyneuropathies – mutant forms
Heart of elderly individuals – senile systemic amyloidosis
Β2-microglobulin – long term haemodialysis
Prion proteins – aggregate in extracellular space in CNS in prion diseases

Question 4

Discuss the classification of amyloidosis

Answer 4

1. Primary amyloidsis (Immunocyte dyscrasia with amyloidosis )
   * Most common group
   * Usually systemic
   * AL type
   * Malignant cells produce an abnormal amount of Ig and light chains
   * Majority of patients have monoclonal immunoglobins or light free chain can be foind in their urine

Reactive systemic amyloidosis
*Systemic
AA type
*Secondary amyloidosis is secondary to chronic inflammation
*seen in TB ,osteomyelitis ,rheumatoid arthritis

Haemodialysis associated amyloid

• Beta2 microglobulin
• Increased in renal failure
• Not filtered in dialysis
• Deposited in joints and tendon shaeth

Heredofamilial amyloidosis

• Several types
• Abnormally production of cytokines IL1
• Mostly seen in mediterranean fever
• Clinically attacks of fever with inflammation of seronal surfaces

Localised amyloidosis

• Single organ or tissue
• AL protein
• gross nodular masses or microscopic deposits
• Seen in the lungs ,urinary bladder ,skin and around the eyes

Endocrine Amyloid

• localised deposits in endocrine organs
• endocrine tumours eg medullary carcinoma of the thyroid
• beta cells islets in diabetes
• Amyloid derived from polypeptide hormones or unique proteins

Amyloid aging

• Senie systemic amyloidosis
• Systemic deposition in 8 and 9 decades
• Dominan involvement of the heart = restictive cardiomyopathy
• Forms with normal and mutant TTR protein

Question 5

Describe the gross and microscopic features of amyloidosis

Answer 5

• Amyloid may or may not be present ,macroscopically
• if large amounts > enlarge the organ with a firm ,grey ,waxy appearance

*Histologically ,begins with extracellularly between cells and can later encroach on cells ,surround them and destroy them

With plasma cell disorders it is often perivascular or vascular

Congo red stain

• pinky with light microscopy
• apple green with polarised light

Question 6

Discuss the clinical effects ,diagnosis and prognosis of amyloidosis

Answer 6

Kidneys

• Most common affected
• Normal /shrunken in advanced disease(ischaemia)
• Deposited in glomeruli but also in tubular basement membrane ,interstitial tissue ,arteries and arterioles

*In glomeruli ,starts thickening of mesangium and basement membranes of the glomerular capillary .

Causes proteinuria ,nerphrotic syndrome

Later capillary narrowing and obstructionn of glomerular tuft > uraemia

SPLEEN

• Enlarged
• there are 2 patterns of deposition
• small nodules in follicles
• walls of splenic sinuses and connective tissue in red pulp .DEPOSISTS OF enlarged and fuse > lardaceous spleen

Liver

• Enlarged liver
• Space of disse then encroach on hepatocytes and sinusoids
• Normally liver function usually preserved

Heart

• Grossly normal
• Histologically ,subendocardial deposits and between muscle fibers of myocardium
• Pressure atrophy of mayocardial fibers
• Subendocardial deposites can disrupt conduction > arrhythmias
• Congestive cardiac failure ,

*Congestive cardiac failure ,restrictive cardiomyopathy

Other organs
*Tongue: macroglossia. Abnormal speech, swallowing.
Stomach and intestine: malabsorption, disturbances in digestion and diarrhoea.
Brain: Alzheimer’s disease – vascular deposits and deposits in neuritic plaques.
Nerves: peripheral and autonomic in severe familial amyloidotic neuropathies.
Carpal ligament: Long term dialysis. Carpal tunnel syndrome.
Vascular deposits: fragility of vessels and abnormal A.