FIGURE 34–1. Urticaria.
FIGURE 34–2. Angioedema involving the tongue obstructing the airway.
• Inflammation occurs in the mucosa and deeper dermis.
• Extravasation involves deep dermal vessels.
• Histamine plays some role, mainly when urticaria is also present.
• Bradykinin appears to have a more important role in isolated angioedema.
• The diagnosis for angioedema alone is very different from that of angioedema with urticarial (Table 34–1)
• For otolaryngolgists, determining the presence or absence of urticaria is one of the first steps in the evaluation of any patient with angioedema.
• For allergists who usually see patients with urticaria, the duration of the urticaria is the first step in evaluation.
• This chapter is organized based on the presence or absence of urticaria in patients with angioedema.
Pathophysiology—Primarily Bradykinin-mediated
• Control of bradykinin by C1-esterase inhibitor (C1-INH) and Factor XII (Figure 34–3)
1. Factor XII is the starting point of the intrinsic pathway of the coagulation system.
2. It is activated to Factor XIIa, which in turn converts pre-kallikrein to kallikrein, which then converts HMW-kininogen into bradykinin.
3. The C1-esterase inhibitor, a member of the SERPIN protein family, is the most important regulator of the kallikrein-kinin system; it inhibits both plasma kallikrein as well as factor XIIa, thus preventing bradykinin formation.
4. C1-esterase inhibitor also prevents auto-activation of the classical pathway of the complement system.
• ACE-I and bradykinin levels
1. The angiotensin-converting enzyme, also known as kininase II, inactivates bradykinin.
2. Use of an ACE-I decreases kininase function, allowing for increase in circulating bradykinin.
Classification
• See Table 34–2
C1-INH Deficiency HAE
• Inheritance
1. AD, due to mutations on SERPING1 (C1-inhibitor) gene on chromosome 11
2. De novo mutations may occur.
FIGURE 34–3. Roles of Factor XII and C1-INH in the bradykinin production pathway.
1. It is often first seen in the second decade of life, which is significantly earlier than what is seen with acquired C1-INH deficiency.
2. Episodes may be triggered by trauma, pressure, stress, menstruation, or infection.
3. Presence of ACE-I decreases the threshold for having an attack.
• Subtypes
1. Type 1 (85% of cases): quantitative deficiency of C1-INH
2. Type 2 (15% of cases): functional deficiency of C1-INH
Factor XII Mutation HAE
• Normal C4
• Autosomal dominant transmission with very low penetrance, thus frequently “negative” family history
• Significantly higher prevalence in females—90% of male carriers are asymptomatic, 40% of females are asymptomatic
• Hormonal factors may trigger the angioedema
Unknown HAE
• Normal complements
• Positive family history
C1-INH Deficiency
• Presentation
1. Age of onset >40 years
2. No family history of angioedema
• Etiology
1. More than 50% either have or will have a hematologic disorder or autoimmune disease
– Examples: MGUS, B-cell malignancy, systemic lupus erythematosus (SLE)
– Disorders either consume C1-INH or form anti-C1-INH autoantibodies
2. Possible that 25% of C1-INH deficiency without family history due to de novo mutations in SERPING1 gene in patients with negative FMH
• Epidemiology
1. Seen in 0.1% to 2.2% of patients treated with ACE-I
2. Highest rates seen in African American women >65 years of age
• Onset
1. Variable timing: although most cases present shortly after initiation of medication, some do not present until years later; some will occur even after discontinuation of the medication
2. Variable location: but oral cavity and throat most often affected
Idiopathic Cases (normal C4)
• These patients lack family history, have normal C4, and have no clear triggers for their angioedema.
• Clinician needs to rule out FXII-HAE with low penetrance.
Work-Up for Angioedema Without Urticaria
History and Physical Exam Is Critical
• Is there a family history?
• Are there any triggers?
• Was the patient on ACE-I?
• Were urticaria present?
Lab Testing (Figure 34–4)
• Screening test
1. C4 is the first test for suspected C1-INH deficiency: low at all times, even between attacks of angioedema.
• If C4 is low, clinician follow-up with tests of C1q and C1-INH levels and function
1. Low C1q: acquired angioedema
– Look for lymphoproliferative or immunomodulatory diseases.
– Test for auto-antibodies against C1-INH.
1. Normal C1q: genetic angioedema
– Positive FMHx: suspect HAE (type 1 vs type 2) – Negative FMHx: suspect de novo SERPING1 mutation
• If C4 is normal (and no ACE-I)
2. Check for FXII mutation and FMHx
3. Positive FMHx and mutation present: FXII-HAE
FIGURE 34–4. Lab work-up for angioedema without wheals.
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