Amyloidosis

Question 1

What is amyloidosis?

Answer 1

Heterogenous group of diseases characterised by extracellular deposition of amyloid fibrils.

Question 2

What is the pathophysiology of amyloidosis?

Answer 2

• Amyloid fibrils are aggregates of proteins comprising LMW subunit proteins with a predominantly insoluble, antiparallel beta-pleated sheet configuration. There are 37 known amyloid proteins. Amyloid deposits recruit various sugars including glycosaminoglycans and serum amyloid P-component (SAP), leading to formation of complex structures and progressive disruption of the structure and function of normal tissue.
• Amyloid fibrils can be deposited systemically or locally (for example, in the cerebral cortex leading to Alzheimer’s, pancreatic Islets of Langerhans leading to T2DM etc.)

Question 3

What are the main classifications of amyloidosis? (x3)

Answer 3

• Based on type of fibril subunit protein
• SERUM AMYLOID A (SAA) PROTEIN leading to AA amyloidosis, a type of secondary amyloidosis
• MONOCLONAL IMMUNOGLOBULIN LIGHT CHAINS leading to AL amyloidosis (aka primary systemic amyloidosis)
• Genetic-variant TRANSTHYRETIN leading to ATTR amyloidosis, a type of hereditary amyloidosis

Question 4

What is the aetiology of AA amyloidosis? (x3)

Answer 4

Chronic inflammatory diseases such as RA, seronegative arthritides, Crohn’s disease, Familial Mediterranean Fever. Chronic infections such as TB, bronchiectasis, osteomyelitis. Malignancy such as Hodgkin’s and renal cancer.

Question 5

What is the aetiology of AL amyloidosis? (x3)

Answer 5

Idiopathic. Associated with multiple myeloma, Waldenstrom’s macroglobulinemia, B-cell lymphoma.

Question 6

What is the aetiology of ATTR amyloidosis?

Answer 6

Autosomal dominantly inherited mutations in transthyretin (TTR).

Question 7

What is the epidemiology of amyloidosis: Most common type? AL Gender and Age? AA incidence?

Answer 7

Most common type is AL amyloidosis. AL: male, 60s. AA falling due to more effective treatment for aetiologies.

Question 8

!!! What are the signs and symptoms of amyloidosis? (x7) How do patients present?

Answer 8

• RENAL: deposition in glomerular basement membrane leading to proteinuria, nephrotic syndrome, and renal failure.
• CARDIAC: deposition in ECM, disrupting contractility and conductance, leading to restrictive cardiomyopathy, HF, arrythmia, angina (from accumulation in coronary arteries)
• GI: macroglossia (characteristic of AL), HEPATOMEGALY, splenomegaly, malabsorption, bleeding
• NEUROLOGICAL: neuropathy similar to ischaemia (motor and sensory), autonomic neuropathy (bowel and bladder dysfunction, postural hypotension), Carpal Tunnel Syndrome
• SKIN: waxy skin, easy bruising, purpura or petechiae AROUND EYES (characteristic of AL)
• JOINTS: painful asymmetrical large joints, ‘shoulder pad’ sign (enlargement of anterior shoulder)
• HAEMATOLOGICAL: bleeding diathesis (factor X deficiency from deposits in liver and spleen, and decreased synthesis of coagulation factors in patients with ALD)
• Patients present with unexplained weight loss, fatigue, and oedema (from nephrotic syndrome) resistant to diuretic therapy

Question 9

What are the investigations for amyloidosis? (x4)

Answer 9

• TISSUE BIOPSY: diagnostic and identified type; Congo red stain with green birefringence when viewed under polarised light is, by definition, an amyloid deposit
• URINE: proteinuria, immunofixation electrophoresis of urine confirms free monoclonal immunoglobulin light chains in AL (tissue biopsy is often a poor diagnostic technique for AL, so this method is better for this type)
• BLOOD: FBC (anaemia from blood loss and renal insufficiency – erythropoietin), CRP, ESR, RF, LFTs, U&Es, immunofixation of serum confirms Ig light chains in AL. SAA levels for monitoring treatment in AA
• 123 I-SAP SCAN (nuclear medicine scan): radiolabelled SAP localises deposits enabling imaging of affected organs throughout body