Amyloidosis

Question 1

what is an amyloid deposit?

Answer 1

Any histological tissue specimen that:

• binds the cotton wool dye, Congo red
• demonstrates green birefringence (under polarised light)

Question 2

How is amyloidosis classified?

Answer 2

• acquired / inherited
• local / systemic
• named after the precursor plasma protein (20<)

Question 3

How do amyloid proteins tend to deposit? (process)

Answer 3

Process: locally (one organ) or systemically (>1 organ)

Question 4

What are the consequences of amyloid deposition?

Answer 4

progressive amyloid deposition in particular organ (extracellular space)

–> insoluble abnormal fibrils deposited (beta pleated sheets)

–> fibrils are resistant to proteolysis

–> disrupts function of the organ

–> dysfunction

Question 5

What the most common types of amyloidosis?

Answer 5

AL = light

• i.e. ~primary; lots of excess abnormal protein

​AA = serum amyloid A

• i.e. ~secondary; small proportiong of seruma amyloid A –> misfold

Question 6

When does [serum amyloid A protein] increase?

Answer 6

Acute phase protein, hence during inflammation

e.g rhematoid arthritis, IBD, cancers, famililal meditarrean fever

Question 7

What are the risk factors for amyloidosis?

Answer 7

• monoclonal gammopathy of undetermined significance (MGUS)
• inflammatory polyarthropathy
  
  • incl. rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, and ankylosing spondylitis.
• chronic infections
• IBD
• familial periodic fever syndromes
  
  • e.g. familial Mediterranean fever
  • TNFr-associated periodic fever syndromes

Question 8

Summarise the epidemiology of amyloidosis

Answer 8

• males > females
• black > (due to increased incidence of multiple myeloma + MGUS)
• incidence of AA is falling, only = 3% of systemic amyoidosis

Question 9

What are the presenting symptoms of amyloidosis?

Answer 9

clinical features depend on organ involved.

commonly:

• GI: Weight loss, steatorrhoea, faecal incontinence (alternating w 4 days constipation)
• CNS: paraesthesias, neuropathies, orthostatic hypotension
• lung: dyspnoea
• upper GI: pseudo-obstructive : nausea, vomiting, post-prandial cramping
• heart: fatigue & dyspnoea on exertion, (presyncope), angina <
• kidney: presyncope
• musculoskeletal: jaw, calf, limb claudication

Question 10

what are the signs of amyloidosis on physical examination?

Answer 10

commonly:

• (lower extremity) oedema
• increased JVP

specific pathognomic findings (only 15% of patients):

• Amyloid purpura
• Eyelid petechiae
• Macroglossia (AL)
• larger submandibular salivary glands (AL) —> sicca syndrome
• Palpable hepatomegaly < (AL)
• Splenomegaly << (AL)
• shoulder pad sign <<< (AL)
• Amyloid peripheral neuropathy (only AL) –> carpal tunnel syndrome

Question 11

What are the primary investigations for amyloidosis?

Answer 11

immunofixation of:

1. serum
2. urine
3. Ig free light chain assay

green bifringerence on Congo red stain essential - present in all forms (and systemic + local)

bloods:

• FBC
• serum alkaline phosphatase
• serum albumin
• serum creatinine
• urinary protein

Question 12

what are the secondary investigations required for diagnosis of amyloidosis?

Answer 12

• tissue biopsy - s.c. fat aspirate + bone marrow
  
  • (serum electropherisis of urine is not enough due to the high prevalenve of Bence Jones proteinurea –>hence no monoclonal spike seen)

Question 13

What is the gold standard for amyloid protein typing?

Answer 13

mass spectrometry

electron microscopy is limited to renal specimens to identify fibrillar nature of protein

Question 14

What are common sites of biopsy for amyloidosis diagnosis?

Answer 14

• s.c. fat aspirate
• bone marrow
• lip
• rectum
• temporal artery
• skin.

If these studies are negative, biopsy of an affected organ (heart, liver, kidney or nerve) should be performed

Question 15

Which investigations are required after a diagnosis of amyloidosis is made?

Answer 15

• ECG
  
  • (to find conduction abnbormalities)
• Imaging of affected organs
  
  • (end-organ damage + prognosis)
• Echocardiogram / cardiac MRI if echo difficult to diagnose cardiac involvment
  
  • (to find cardiac involvement)

Question 16

What is nephrotic syndrome?

Answer 16