Amyloidosis

Question 1

Define

Answer 1

Heterogeneous group of disease characterised by extracellular deposition of amyloid fibrils (a protein in abnormal fibrillar form, resistant to degradation)

Note: Amyloid deposition is also a feature of Alzheimer’s disease, type 2 diabetes mellitus and haemodialysis-related amyloidosis

Question 2

Causes

Answer 2

Amyloid fibrils are polymers of low-molecular-weight subunit proteins

These are derived from proteins that undergo conformational changes to adopt an anti-parallel beta-pleated sheet configuration

Their deposition progressively disrupts the structure and function of normal tissue

Amyloidosis is classified according to the fibril subunit proteins

• Type AA - serum amyloid A protein
• Type AL - monoclonal immunoglobulin light chains
• Type ATTR (familial amyloid polyneuropathy) - genetic-variant transthyretin

Question 3

Epidemiology

Answer 3

• AA - incidence of 1-5% amongst patients with chronic inflammatory diseases
• AL - 300-600 cases in the UK per year
• Hereditary Amyloidosis - accounts for 5% of patients with amyloidosis

Question 4

Symptoms

Answer 4

AL amyloid (primary): proliferation of plasma cell clone → amyloidogenic monoclonal Igs → fibrillar light-chain protein deposition → organ failure → death
Multiple organs involved

Associations: myeloma (15%), Waldenström’s, lymphoma

↘ Kidneys: glomerular lesions—proteinuria and nephrotic syndrome

↘ Heart: restrictive cardiomyopathy (looks ‘sparkling’ on echo), arrhythmias, angina, HF

↘ Nerves: peripheral and autonomic neuropathy; carpal tunnel syndrome

↘ Gut: macroglossia (big tongue, characteristic of AL), malabsorption/↓weight, perforation, haemorrhage, obstruction, and hepatomegaly

↘ Vascular: purpura, especially periorbital purpura

Question 5

Signs

Answer 5

In addition:

 Waxy skin and east bruising

 Bowel or bladder dysfunction and postural hypotension due

to autonomic neuropathy

 Gut dysmotility

 Painful asymmetric large joints (‘shoulder pad’ sign,

enlargement of anterior shoulder)

 Bleeding diathesis (FX deficiency due to binding on amyloid

fibrils primarily in the liver/spleen, plus ↓coag factors due to advanced liver disease in some pts)

Question 6

Investigations

Answer 6

• Tissue Biopsy
• Urine - check for proteinuria, free immunoglobulin light chains (in AL)
• Bloods
  
  • CRP/ESR
  • Rheumatoid factor
  • Immunoglobulin levels
  • Serum protein electrophoresis
  • LFTs
  • U&Es
• SAP Scan - radiolabelled SAP will localise the deposits of amyloid