Hereditary angioedema Flashcards
Genetics
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
Presentation
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
Classical complement biology
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
Biological role of C1 inhibitor
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
Kallikrein pathway
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
Bradykinin
Inflammatory mediator
- Made via kvllikrein system
Causes blood vessel dilation
- Oedema
- Fluid loss
- Pain in HAE
Type 1 and Type 2 HAE
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
Acquired C1 inhibitor deficiency
Non genetic cause due to:
- SLE (possible auto Ab against C1 inhibitor)
Monoclinal B cells disorders with paraproteins
Prophylaxis for attacks
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
C1 inhibitor concentrate
Best for acute attacks
- BUT v. expensive
- Must be given i.v
Obtained via recombinant or purified donor plasma
Indications for tests
Clinical history of swelling and or abdominal pain attacks
- Without urticaria
Diagnosis
Low serum C4 levels
Low C1 inhibitor levels or dysfunction C1 inhibitor levels