Systemic inflammation - C1 inhibitor deficiency COPY

Question 1

INTRO

i) what is it aka?
ii) how is it characterised? (2)
iii) which areas can it affect?
iv) what can laryngeal swelling lead to?
v) is all angioedema c1 inhib defic?

Answer 1

i) hereditary angioedema
ii) charac by recurrent attacks of cutaneous and sub mucosal swelling
iii) can affect anywhere in the skin or sub mucosa
iv) laryngeal swelling can lead to death by suffocation
v) not all AE is HAE

Question 2

ANGIOEDEMA

i) is it likely to be HAE?
ii) name four other causes of AE
iii) what is it often associated with? which molecule mediates this?
iv) what is not seen in HAE that is seen in AE?

Answer 2

i) no
ii) spontaneous eg mast cells release histamine, auto immune, drug related, physical, allergy
iii) often associated with urticaria (red itchy rash) - mediated by histamine
iv) dont see urticaria in HAE

Question 3

GENERAL FEATURES OF HAE

i) what is the inheritance pattern? what % of cases are sporadic?
ii) when may symptoms present?
iii) can people be asymptomatic life long?
iv) what is the general pattern of symptoms? do attacks usually have a trigger?
v) name two possible triggers of an attack
vi) what is the estimated mortality?

Answer 3

i) auto dominant but 20% cases are sporadic
ii) often have delayed presentation > infants and children are often asymptomatic
iii) can be asymp lifelong

iv) episodic symptoms > patients are well in between
- attacks dont usually have a trigger

v) trauma and infection can be trigger
vi) approx mortality is 10%

Question 4

CLASSICAL COMPLEMENT

i) which complement component binds antibody constant region? what does this activate? (2)
ii) which organ removes antigen-antibody complexes?
iii) what is the major negative regulator of classical complement? what will absence of this inhibitor lead to?

Answer 4

i) C1q binds to antibody and activates C1r and C1s
ii) antigen antibody complexes are removed by the spleen

iii) major neg regulator is C1 inhibitor
- absence > excessive activation of classical complement pway and low levels of C3 and C4

Question 5

MECHANISMS OF HAE

i) what does absence of C1 inhibitor cause?
ii) what central molecule mediates HAE?
iii) how is this molecule activated? (3 steps) which of these molecules is inhibited by C1 inhibtor?
iv) why can ACE inhibitors bring on HAE?

Answer 5

i) absence of C1 inhibitor causes uncontrolled activation of classical complement
ii) bradykinin is the central molecule

iii) factor 12a > activates kallikrein > activates kinases to bradykinin = swelling
- c1 inhibitor inhibits factor 12 (therefore defic = more factor 12 to activate more bradykinin)

iv) ACE inhibitors can inhibit the kinases that break down bradykinin therefore causing it to accumulate

Question 6

GENETICS OF HAE

i) where is the mutation hotspot in C1 inhibitor protein?
ii) what type of mutations are found in type I HAE?
iii) what type of mutations are found in type 2 HAE?

Answer 6

i) mutation in 8 exons on Chr 11
ii) large muts in type I
iii) smaller muts in type II

Question 7

MAKING A DIAGNOSIS OF HAE

i) what may there be clinical history of? (2) what will there be absence of?
ii) what should be checked for in the serum to exclude HAE?
iii) if HAE is suspected - what further two further tests should be done? which type of HAE does each test for?
iv) which group of patients will tests perform poorly on? why?

Answer 7

i) clin history of attacks of swelling and/or abdo pain
- without urticaria

ii) check for serum C4 levels - if normal = exclude HAE
iii) if C4 is low then test for c1 inhibitor protein levels (type I) and functional activity (type I and II)
iv) infants will perform poorly on test as they have high levels of C1 inhib protein and normal ranges dont apply

Question 8

ACQUIRED C1 INHIBITOR DEFICIENCY

i) is this common? what may be happening
ii) which two setting does it occur in?

Answer 8

i) rare non genetic cause > may have antibodies against C1 inhibitor protein
ii) occ in SLE and monoclonal B cell disorders with paraproteins

Question 9

PROPHYLAXIS

i) when should this be considered?
ii) what can be given to act locally and prevent activation of kinin system?
iii) name two attenuated androgens that may be given? what do these do? give three side effects? which group are they not suitable for?
iv) what can be injected? how many times a week is needed? when would this most commonly be used?

Answer 9

i) consider if attacks are frequent, severe or disruptive
ii) tranexamic acid can act local and prev kinin activ

iii) danazol and stanozolol (anabolic steroids)
- stimulate hepatic production of C1 inhibitor
- SEs > weight gain, hirtuism, hypertension
- not suitable for children or pregnancy

iv) regular C1 inhibitor infections
- need venous access twice a week
- used in pregnancy when androgens cant be used

Question 10

TREATMENT OF ACUTE ATTACKS - C1 INHIB CONCENTRATE

i) name two ways it can be purified/produced?
ii) which two groups is it also licensed for?
iii) how effective is it? give three down sides to use
iv) when do guidelines suggest to use it?
v) can it be used for self treatment?

Answer 10

i) purified from plasma donor pools or produced by recombinant technology
ii) licensed for children and pregnany women

iii) very effective
- expensive, must be given IV and human blood product

iv) guidelines say use it in any disabling attack
v) can be used for self treatment at home