“`What is Hereditary Angioedema (HAE)?
Hereditary angioedema is a disorder that occurs due to malfunctioned or depleted C1-INH i.e. C1 esterase Inhibitor gene. It is an uncommon Autosomal Dominant disorder. It is a subset of non-allergic angioedema.
Mechanism of HAE
The pathogenic mechanism of HAE is regulated by bradykinin. C1-INH is a moderator of the complement and contact mechanisms. The contact system gets triggered if C1-INH is malfunctioned or suboptimal. This results in uninterrupted production of kallikrein, an enzyme that can cleave peptide bonds into proteins. As a consequence, unregulated proteolysis of bradykinin and kininogen occurs, ultimately resulting in enhanced vascular permeability causing edema.
Types of HAE
Hereditary Angioedema is categorized into three types:
1. Type I HAE
2. Type II HAE
3. Type III HAE
Type I HAE
- Inadequacy of C1-INH gene.
- 80-85% of total cases are of Type I.
- Mutation of SERPING 1 gene which transcribes the C1-inhibitor protein.
- A range of mutations takes place in the gene encoding region.
- Aberrant or curtailed C1-inhibitor protein is present, thus reduced circulating levels.
Type II HAE
- Malfunctioned C1-INH gene is produced. Patient reflects normal levels.
- 15-20% of total cases are of Type II.
- Mutation of SERPING 1 gene, predominantly a missense mutation in exon 8.
Type III HAE
- Identified as Estrogen-dependent HAE as it is highly correlated with elevated estrogen levels.
- Prevalent in female patients and worsened in case of pregnancy or use of hormonal contraceptives.
- High levels of estrogen align with elevated levels of factor XIIa, which further raises bradykinin levels.
Clinical Judgement:
- Periodic cutaneous or submucosal angioedema coexisted with abdominal discomfort.
- The cutaneous angioedema is patchy and irregular.
- Visceral angioedema, involving visceral organs, is a primary factor in identifying the disease.
- Laryngeal edema is a fatal visceral complication that patients with HAE may encounter.
- Children are often non-symptomatic, but symptoms are reported before the age of 20 years.
- HAE attacks may be triggered by trauma, medical procedures, stress, hormonal contraceptives, and ACE inhibitors.
- During diagnosis, the patient should not have high body temperature or fever, nor should they have urticaria or hives.
Laboratory Tests
- Insufficiency/deficiency of C1 esterase inhibitor, which may result in high levels of bradykinin.
- Low levels of C1-INH due to deficient SERPING 1 gene.
- Monitoring C4 level and D-dimer level in case of an acute attack.
- Genetic testing.
Treatment and Management
Acute Treatment
- Swelling diminishes in 3-5 days in the absence of treatment.
- In case of laryngeal edema, prompt action is required.
- The primary objective of acute treatment is to restrain rapid progression.
- Treatment should begin as early as within 6 hours for more favorable outcomes.
- Acute treatment offers plasma-derived C1-INH (pdC1-INH), recombinant human C1-INH (rhC1-INH), ecallantide, and icatibant.
- These drugs are impactful within 60 minutes, and comfort is seen within 2 hours.
- In case of unavailability of the above drugs, FFP (Fresh Frozen Plasma) containing C1-INH is used (although NOT RECOMMENDED, as the level of evidence is low).
- Intravenous (IV) options include pdC1-INH and rhC1-INH.
- Histamines, antihistamines, epinephrine, and glucocorticoids are ineffective.
Short-term Prophylaxis
- Trauma and stress due to some medical procedures (such as oral surgery, endoscopy, or endotracheal intubation) may stimulate acute attacks.
- IV or SC dose immediately before the procedure or a 5-day course of androgens before and followed by 2-3 days may work.
- Tranexamic acid (TXA), an antifibrinolytic medication, is primarily used during surgeries to prevent blood loss. A case report demonstrates that it may treat ACE inhibitor-induced angioedema.
Long-term Prophylaxis
- Prevalence and criticality of attacks, its consequences, healthcare availability, and coexisting conditions are considered before deciding whether it is long-term prophylaxis or not.
- Monoclonal plasma kallikrein inhibitors are primary treatment options.
- Antifibrinolytics or anabolic agents are considered alternative treatments or secondary therapies.
- Androgens should be avoided in pregnant patients as well as in pre-adult teens.
- In case of pregnant women and children, tranexamic acid is considered as an alternative agent.
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