C1 Inhibitor Deficiency

Question 1

Describe the general features of C1 inhibitor deficiency?

Answer 1

• 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

Question 2

Describe the general features of C1 inhibitor deficiency?

Answer 2

• Episodic symptoms-patients well betwen
• Attacks are usually paroxymal
• Trauma (often dental work) and infection may precepitate attacks
• Delayed diagnosis very common
• Historically around 10% mortality, 30% have family member who has died

Question 3

Describe the classical complement pathway?

Answer 3

-Globular heads of C1q bind to antibody constant regions
-This activates C1r which when activates C1s
C1s+C4–>C4b
C1s+C2–>C2a
-C4b and C2a –>C4b2a =C3 convertase which converts C3 to C3b

Question 4

What are the problems with the complement system?

Answer 4

• Antigen+antibody complexes are produced all the time during immune processes before removal in the spleen
• It is not always appropriate or desirable to activate inflammatory pathway in this setting
• Various control mechanism in place to prevent inappropriate activation
• C1 Inhibitor is the major negative regulator of classical complement

Question 5

What is the role of C1 inhibitor in this complement process?

Answer 5

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 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 6

Describe the genetics of HAE?

Answer 6

-C1 inhibitor protein encoded in 8 exons on C11
-span all exons and exon-introns boundaries
-

Question 7

Describe the two types of HAE?

Answer 7

1) Type 1 HAE:
- Deletions/missense mutations in C1 inhibitor gene
- Low C1 inhibitor protein levels
2) Type 2 HAE:
- Point mutations at active site
- Normal/high levels dysfunctional protein

Question 8

Describe the process of making diagnosis?

Answer 8

• 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 type 2 HAE)
• Test perform poorly in infant <1yr old

Question 9

Describe the situation where acquired C1 inhibitor deficiency is acquired?

Answer 9

• Very rare non-genetic cause of C1 inhibitor deficiency
• Occurs in two settings:
  1) Systemic lupus erythematosis: ?auto-antibodies against C1 inhibitor
  2) Monoclonal B cell disorders with paraproteins: mechanism unknown

Question 10

When should you consider C1 inhibitor deficiency?

Answer 10

-Consider if attacks are frequent, severe or very disruptive

Question 11

What are the treatment options for C1 inhibitor deficiency?

Answer 11

1) Tranexamic acid: believed to act locally at tissues to prevent the activation of kinin system
2) Attenuated androgens: Danazol/stanozolol
- Stimulate the hepatic production of C1 inhibitor
- Very effective but has SE: especially at high doses (weight gain, hirstuitism, hypertension, hyperlipidaemia and acne
- Not suitable for children or pregnancy
3) 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 can not be used

Question 12

What are the treatment of acute attacks?

Answer 12

C1 inhibitor concentrate: purified from plasma donor pools or produced by recombinant technology

• Licensed in children and pregnancy
• Extremely effective but:
• Expensive
• Must be given IV
• Human blood product