Hereditary Angioedema (C1 Inhibitor deficiency)

Question 1

Presentation

Prevalence

Answer 1

• Recurrent attacks of cutaneous and submucosal swelling

- 1:25K-100K

Question 2

Characteristics of angioedema

Peripheral signs

Answer 2

• Featureless (not red and inflammed)
• Painless
• Resolves to leave perfectly normal skin
• Happens without warning
• Swelling of hands but not joints

Question 3

Why is it dangerous to the airway? Presentation

What is obstructive venous return?

Answer 3

• Laryngeal inflammation which causes whisteling sound

- Blocked venous return

Question 4

Abdominal signs

Answer 4

• Swelling in large bowel and thickened abdominal wall

- Often mistaken for appendicitis

Question 5

What is the commonest cause of angioedema

Answer 5

• Spontaneous urticaria
• extremely itchy due to histamine release
• Other causes: AI, drug induced, physical, allergy

Question 6

Describe the general features of the condition

• inheritance
• onset
• cause of attacks

Answer 6

• AD inheritance, but 20% of cases sporadic (index case)
• Onset of symptoms may be delayed – infants and children often asymptomatic or mildly affected
• trauma (often dental work) and infection

Question 7

Are patients ill all the time?

Answer 7

Episodic symptoms – patients well between

Attacks are usually paroxysmal

Question 8

What are the effects of delayed diagnosis?

Answer 8

• Attitudes of doctors, friends, family, employed
• Relationship with potential partners… its genetic. Do you want your children affected?
• Inconvenient swelling

Question 9

Why is inhibition of C1 important?

Answer 9

Antigen-antibody complexes are produced all the time during immune processes before removal in the spleen
It’s not always appropriate or desirable to activate inflammatory pathways in this setting

Question 10

How does C1 inhibitor work?

What happens in absence of this?

Answer 10

• C1 inhibitor protein binds to activated C1r and C1s and makes them dissociate from C1q
• Once free in solution, C1r and C1s are inactivated
• Only a really strong stimulus that generates lots of C1s leads to full activation

Absence of C1 inhibitor protein will lead to excessive activation of the classical complement pathway and low levels of C2 and C4

Question 11

Pathophysiology of HAE

Answer 11

Bradykinin produced by autoactivation of kalilkrein and fXIIIa under control of kinins

• When bradykinin reaches threshold you can have a swelling attack (edema, fluid loss,pain)

Question 12

Genetics of HAE

Answer 12

• 283 mutations of C1 inhibitor protein describes (on 8 exons on C11)
• Span all exons and exon-intron boundaries

Question 13

Outline the differences between type 1 and type 2 HAE

Answer 13

TYPE 1

• Deletions/missense mutations in C1 inhibitor gene
• Low C1 inhibitor protein levels

TYPE 2

• Point mutations at active site
• Normal/high levels of dysfunctional protein

Question 14

How do you make a diagnosis?

Answer 14

• Hx of attacks of swelling and/or abdominal pain without urticaria
• Check serum C4, if normal exclude HAE
• If low, test for C1 inhibitor protein levels (type 1) and functional activity (both types)

**Test poor in infants <1

Question 15

In what settings might you acquire C1 inhibitor deficiency?

Answer 15

• SLE: autoantibodies against C1 inhibitor

- Monoclonal B cell disorders with paraproteins

Question 16

Treatment involves the use of Icatibant

Describe it

Answer 16

• Bradykinin B2 anatagonist
• Subcutaneous injection (suited for self treatment)
• Safe and effective for acute attacks

Question 17

Treatment involves the use of Ecallantide (N america only)

Describe it

Answer 17

• Kallikrein inhibitor
• 3 Subcutaneous injection/ attack
• Effective for acute attacks
• 1/2% anaphylactic reactions

Question 18

When might you consider prophylaxis?

How is this induced?

Answer 18

• Frequent, severe or disruptive attacks

1. Tranexamic acid- local inhbitrion of kinin system
2. Attenuated androgens (danazol/stranozol) stimulate hepatic production of C1 inhibitor. Side effects at high doses= weight gain, hirsuitism, hypertension, hyperlipidaemia, acne, not suitable in pregnancy/kids)
3. Regular C1 inhibitor injections: costly, requires venous access twice a week, indicated in pregnancy

Question 19

C1 inhibitor concentrate is used for treatment of acute attacks

Where is it harvested from?
Indications
Disadvantages
Advantages

Answer 19

1. Purified from plasma donor pools/ recombinant technology
2. Children and pregnancy
3. Expensive, IV, Human blood product
4. Ability to self treat/home therapy