C1 inhibitor deficiency Flashcards
C1 inhibitor deficiency
Also known as hereditary angioedema (HAE)
Recurrent attacks of cutaneous and submucosal swelling
Prevalence between 1:25 000 and 1:100 000
Angioedema
Most angioedema is not HAE
Variety of other causes
Spontaneous, autoimmune, drug-induced, physical, allergy
Often associated with urticaria
General features of C1 inhibitor deficiency
AD inheritance, but 20% of cases sporadic
Onset of symptoms may be delayed – infants and children often asymptomatic or mildly affected
Conversely, some people asymptomatic lifelong
Episodes/ attacks
Episodic symptoms – patients well between
Attacks are usually paroxysmal
Trauma (often dental work) and infection may precipitate attacks
Diagnosis, mortality
Delayed diagnosis very common
Historically around 10% mortality; 30% have family member who has died
Complement pathway
Globular heads of C1q bind to antibody constant regions
This activates C1r which then activates C1s
C1s cleaves c4 and c2, c4b and c2a form the c3 convertase which cleaves c3 into c3b
Problems with complement system
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
Various control mechanisms in place to prevent inappropriate activation
C1 inhibitor is the major negative regulator of classical complement
C1 inhibitor
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
HAE mechanism
Inflammation due to bradykinin
Bradykinin production pathway is inhibited by C1 inhibitor
Bradykinin leads to edema, fluid loss, pain
Kinases inhibit bradykinin. These kinases are inhibited by ACE-inhibitors
Genetics of HAE
C1 inhibitor protein encoded in 8 exons on C11
- Now 283 mutations described*
Span all exons and exon-intron boundaries
Type 1 HAE
- Deletions/ missense mutations in C1 inhibitor gene
- Low C1 inhibitor protein levels
Type 2 HAE
- Point mutations at active site
- Normal/ high levels dysfunctional protein
Type 1 HAE
- Deletions/ missense mutations in C1 inhibitor gene
- Low C1 inhibitor protein levels
Type 2 HAE
- Point mutations at active site
- Normal/ high levels dysfunctional protein
Making a diagnosis
Clinical history of attacks of swelling and/ or abdominal pain without urticaria
- Check serum C4 levels
- If very normal, HAE excluded
- If low, proceed to test for C1 inhibitor protein levels (type 1 HAE) and functional activity (type 1 and 2 HAE)
Tests perform poorly in infants<1yr old
Acquired C1 inhibitor deficiency
Very rare non-genetic cause of C1 inhibitor deficiency
Occurs in two settings:
Systemic lupus erythematosis
?Auto-antibodies against C1 inhibitor
Monoclonal B cell disorders with paraproteins
Mechanism unknown
Prophylaxis
Consider if attacks frequent, severe or very disruptive
Tranexamic acid
Believed to act locally at tissues to prevent activation of the kinin system
Attenuated androgens
Danazol/ stanozolol
Stimulate the hepatic production of C1 inhibitor
Very effective, but…….
Side-effects in some, especially at high doses (weight gain, hirsuitism, hypertension, hyperlipidemia, acne etc)
Not suitable for children/ in pregnancy
Regular C1 inhibitor injections
Effective, but requires venous access twice a week
Cost >£100 000/ year
Main indication is pregnancy, when disease may worsen and androgens cannot be used
