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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



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



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


New drugs




Small molecule inhibitor of pre-kallikrein
Approximately 50% reduction in attacks in early study



Subcutaneous C1 inhibitor prophylaxis
Twice weekly subcutaneous injections
95% reduction in attacks
Licensed in North America, awaiting EU



Monoclonal antibody against Kallikrein
Monthly subcutaneous injection
Not yet licensed; in Phase 3 reduced attacks by 95%


Treatment of acute attacks: C1 inhibitor concentrate

Purified from plasma donor pools , or produced by recombinant technology
Licensed for children and in pregnancy
Extremely effective, but:
Expensive (usually £800+ per attack)
Must be given iv
Human blood product
Guidelines previously suggest treatment for severe attacks (facial, airway, abdominal)
New guidelines suggest treating any disabling attack
Self-treatment (home therapy) preferred


Targeting bradykinin system

Ecallantide (kallakrein inhibitor)
Icatibant (bradykinin B2 antagonist)



(N America only)
Kallikrein inhibitor
Subcut injectionx3
Effective for acute attacks
1-2% anaphylactoid reactions



Bradykinin B2 antagonist
Subcut injection – very suited to self-treatment
Safe and effective for acute attacks