First Aid, Chapter 8, Immunologic Disorders, Hereditary and Acquired Angioedema

Question 1

What is the dominance of hereditary angioedema?

Answer 1

Autosomal dominant

Question 2

Where is the C1 inhibitor gene located?

Answer 2

chromosome 11

Question 3

What do C1 esterase inhibitor mutations cause?

Answer 3

C1esterase inhibitor mutations cause decreased protein (type I) or dysfunctional protein (type II).

Question 4

What does C1 inh deficiency cause an overproduction of?

Answer 4

Bradykinin is the major mediator of swelling, and the lack of C1-INH leads to bradykinin overproduction.

Question 5

What percentage of HAE have new mutations?

Answer 5

15%

Question 6

What type of rash might precede HAE swelling episodes?

Answer 6

Nonpruritic rash, erythema marginatum.

Question 7

What triggers HAE swelling episodes?

Answer 7

spontaneous or triggered by trauma or stress

Question 8

How long do HAE episodes last?

Answer 8

2-4 days

Question 9

What percentage of HAE type 1 patients experience laryngeal edema?

Answer 9

50%

Question 10

What does swelling of the GI system cause in HAE?

Answer 10

Severe abdominal pain and third spacing.

Question 11

What is HAE type 1 and what percentage of HAE patients does it constitute?

Answer 11

HAE type I: A mutation of one of the C1-INH gene alleles, leading to low or absent protein; 85% of patients present with HAE

Question 12

What is HAE type 2 and what percentage of HAE patients does it constitute?

Answer 12

HAE type II: A mutation of one of the two gene alleles, leading to normal or high levels of a nonfunctioning C1 inhibitor protein; 15% of patients with HAE

Question 13

What is HAE type 3? Who does it affect? What is it’s inheritance? What mutation might it be due to?

Answer 13

HAE type III: Normal C1-INH. Estrogen-dependent, seen primarily in women, and often triggered by pregnancy or exogenous estrogen administration. Inheritance is dominant, which may be due to a mutation in factor XII that augments its activity as an initiator of bradykinin formation.

Question 14

What lab tests are decreased in HAE type 1? What are normal?

Answer 14

Decreased: C4 (often undetectable during an attack), decreased C1-inh level and function, normal C1q, normal C3

C2 decreased during an attack, normal when asymptomatic

Question 15

What lab tests are decreased in HAE type 2? What are normal?

Answer 15

Increased: C1-inh normal or increased

C1 inh function: decreased
C4 level: decreased

Normal: C1q, C3

C2 decreased during an attack, normal when asymptomatic

Question 16

What lab tests are decreased in HAE type 3? What are normal?

Answer 16

All complements are normal: C1 inh level and function, C1q, C4, and C3.

Question 17

What lab tests are decreased in AAE type 1? What are normal?

Answer 17

decreased: c1 inh level and function, c1q, C4

Normal or decreased C3

Question 18

What lab tests are decreased in AAE type 2? What are normal?

Answer 18

Decreased: C1 inh level (or may be normal), C1 inh function, C1q (or may be normal), C4, C3 (or may be normal)

Question 19

What is the treatment for acute attacks in HAE?

Answer 19

• Airway management
• Hydration
• Pain control
• HAE-specific therapies: C1-INH concentrate, kallikrein inhibitor (ecallantide), bradykinin receptor antagonist (icatibant)
• Fresh frozen plasma has been historically used, but may lead to paradoxical worsening

Question 20

How do androgen derivatives work in HAE? What are adverse effects?

Answer 20

Attenuated androgens: Androgen derivatives, such as danazol and stanozolol, help prevent attacks by inducing hepatic synthesis of C1-INH. Common adverse effects of this type of long-term therapy include hepatotoxicity, dyslipidemia, masculinization, and headaches.

Question 21

What is the indication of Cinryze? What is it? What is the dose? What is the potential adverse effects?

Answer 21

Indication: long-term prophylaxis

Plasma-derived C1-inh

Dose: 1000 U IV q3-4 days

Adverse effect: Thrombotic events (rare)

Question 22

What is the indication of Berinert? What is it? What is the dose? What is the potential adverse effects?

Answer 22

Indication: acute attacks

Plasma-derived C1-inh

Dose: 20 units/kg IV

Adverse effect: Thrombotic events (rare)

Question 23

What is the indication of Kalbitor? What kind of drug is it? What is the dose? What is the potential adverse effects?

Answer 23

Indication: acute attacks

Kallikrein inhibitor ecallantide

Dose: 30 mg subq

Adverse effect: Anaphylaxis (~3-4% risk; black box warning)

Question 24

What is the indication of Firazyr? What kind of drug is it? What is the dose? What is the potential adverse effects?

Answer 24

Indication: acute attacks

Bradykinin receptor antagonist

Dose: 30 mg subq, may repeat q6h (max 3 doses/24 hours)

Adverse effect: Injection site reactions

Question 25

Which complement component is decreased in acquired, but not hereditary, angioedema?

Answer 25

c1q

Question 26

Which medication approved for treatment of acute attacks of HAE carries a black box warning for anaphylaxis?

Answer 26

Ecallantide (Kalbitor)

Question 27

What are the indications for short-term prophylaxis in HAE?

Answer 27

Indicated prior to oral or general surgical procedures. Angioedema episodes typically happen within 48 hours of trauma or surgery.

Question 28

What medications are used for short-term prophylaxis in HAE?

Answer 28

Androgens: High dose, 3–5 days prior to planned procedure

C1 esterase inhibitor, infused 1–2 hours prior to procedure

Question 29

What contraception should be used if it is used in HAE?

Answer 29

Estrogens should be avoided. Progestins can be used

Question 30

What is the treatment of HAE during pregnancy? What is contraindicated?

Answer 30

Pregnancy:
o Attenuated androgens are contraindicated
o Plasma-derived C1-INH is preferred for acute treatment, short-term and long-term prophylaxis

Question 31

Are HAE complications common for women during delivery? Is prophylaxis recommended?

Answer 31

o Complications during vaginal delivery are rare

o Plasma-derived C1-INH prophylaxis is advised before caesarian section, and forceps or vacuum extraction

Question 32

What are the two types of acquired angioedema? What conditions are they associated with? What are the C1-inh levels in each?

Answer 32

Classification
-Type I (paraneoplastic)
o Associated with B-cell lymphoproliferative diseases
o Monoclonal gammopathy of uncertain significance (MGUS)
o Consumption of C1-INH by neoplastic lymphatic tissue

-Type II (autoimmune)
o Autoantibody to C1-INH always present. Impairs enzyme function
o C1-INH levels are normal

Question 33

When does acquired angioedema present? What causes it? What complement level distingues it from hereditary? Why is the C1-inh level low?

Answer 33

• Late onset, after fourth decade
• Overproduction of bradykinin
• The low C1q level distinguishes this condition from the hereditary disorder
• C4, C2, and C3 may also be depleted
• Low C1-INH level caused by C1 activation.

Question 34

What are causes of recurrent angioedema? How often is urticaria and pruritus present?

Answer 34

Recurrent angioedema may be due to medications, allergen-induced, or physically induced. In about 50% of cases, urticaria and pruritus are associated.

Question 35

What is the most common cause of acute angioedema in the ED? What is the mechanism? What is being investigated as a potential treatment?

Answer 35

• ACE I use
• The mechanism is thought to involve impaired bradykinin degradation. Icatibant, which is a bradykinin receptor antagonist, is being investigated for potential use in ACEI-induced angioedema.