Hereditary angioedema

Question 1

Genetics

Answer 1

Autosomal dominant inheritance
- Children have 50% chance of getting it

20% of the cases are sporadic

C1 inhibitor protein mutated across 8 axons on chromosome 11

Question 2

Presentation

Answer 2

Symptoms often delayed. Can be asymptomatic lifelong.

Painless swelling of the skin and mucosa

• Abdomen: associated with vomiting, nausea
• Laryngeal
• Periphery

Swelling can be triggered by:

• Trauma
• Infection

Obstructive venous return
- Vascular compromise

Question 3

Classical complement biology

Answer 3

C1q binds to Constant region of Ab
- Activates C1r, which activates C1s

C1s cleaves C2, C4.

C2a and C4b forms C3 converts
- Cleaves C3 in C3b/a

Question 4

Biological role of C1 inhibitor

Answer 4

Major Negative regulator of classical complement pathway
- Inhibits the dissociation of C1s/r from C1q

Constant activation of Classical pathway = low levels of C2 and C4

In Kallikrien and coagulation
- Inhibits activation of Factor 11, and production of kallikrein, bradykinin

Question 5

Kallikrein pathway

Answer 5

Pathway that leads to the production of bradykinin.

Activated by contact with negative surface exposed by trauma/ other things.

Kallikrien is made from factor 12a
- Converts kinins into bradykinin

Question 6

Bradykinin

Answer 6

Inflammatory mediator
- Made via kvllikrein system

Causes blood vessel dilation

• Oedema
• Fluid loss
• Pain in HAE

Question 7

Type 1 and Type 2 HAE

Answer 7

Type 1
- Deletion/ missense of c1 inhibitor gene
= C1 inhibitor deficiency

Type 2

• Point mutation at active site of C1 inhibitor
• Normal/ high levels, but dysfunctional protein

Question 8

Acquired C1 inhibitor deficiency

Answer 8

Non genetic cause due to:
- SLE (possible auto Ab against C1 inhibitor)

Monoclinal B cells disorders with paraproteins

Question 9

Prophylaxis for attacks

Answer 9

Attenuated androgens

• Very effective but with side effects
• Not suitable in children and pregnancy

Regular c1 inhibitor injections

• Effect but v. expensive
• Venous access twice a week
• Can use in pregnancy

Question 10

C1 inhibitor concentrate

Answer 10

Best for acute attacks

• BUT v. expensive
• Must be given i.v

Obtained via recombinant or purified donor plasma

Question 11

Indications for tests

Answer 11

Clinical history of swelling and or abdominal pain attacks

- Without urticaria

Question 12

Diagnosis

Answer 12

Low serum C4 levels

Low C1 inhibitor levels or dysfunction C1 inhibitor levels