Hereditary Angioedema (C1 Inhibitor deficiency) Flashcards
Presentation
Prevalence
- Recurrent attacks of cutaneous and submucosal swelling
- 1:25K-100K
Characteristics of angioedema
Peripheral signs
- Featureless (not red and inflammed)
- Painless
- Resolves to leave perfectly normal skin
- Happens without warning
- Swelling of hands but not joints
Why is it dangerous to the airway? Presentation
What is obstructive venous return?
- Laryngeal inflammation which causes whisteling sound
- Blocked venous return
Abdominal signs
- Swelling in large bowel and thickened abdominal wall
- Often mistaken for appendicitis
What is the commonest cause of angioedema
- Spontaneous urticaria
- extremely itchy due to histamine release
- Other causes: AI, drug induced, physical, allergy
Describe the general features of the condition
- inheritance
- onset
- cause of attacks
- 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
Are patients ill all the time?
Episodic symptoms – patients well between
Attacks are usually paroxysmal
What are the effects of delayed diagnosis?
- Attitudes of doctors, friends, family, employed
- Relationship with potential partners… its genetic. Do you want your children affected?
- Inconvenient swelling
Why is inhibition of C1 important?
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
How does C1 inhibitor work?
What happens in absence of this?
- 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
Pathophysiology of HAE
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)
Genetics of HAE
- 283 mutations of C1 inhibitor protein describes (on 8 exons on C11)
- Span all exons and exon-intron boundaries
Outline the differences between type 1 and type 2 HAE
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
How do you make a diagnosis?
- 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
In what settings might you acquire C1 inhibitor deficiency?
- SLE: autoantibodies against C1 inhibitor
- Monoclonal B cell disorders with paraproteins
