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Caused by a deficiency of C1 inhibitor (C1-INH), hereditary angioedema (HAE) is characterized by repeated episodes of severe swelling. The inheritance pattern is autosomal dominant. The limbs, face, intestinal tract, and airway are the most commonly affected parts of the body. An attack may be triggered by minor trauma or stress, but swelling generally develops in the absence of any trigger.1,2

HAE is reported to affect approximately 1 in every 50,000 persons.3 The symptoms usually appear in the first 2 decades of life, whereas the symptoms of acquired angioedema (AAE) with defective C1-INH usually appear in the fourth decade of life. Although a family history of angioedema aids in successfully diagnosing patients, 25% of cases are caused by new, spontaneous mutations. After patients reach 1 year of age, biological tests are relatively reliable, and genetic testing is usually not required.4 

Types and Etiology

The 2 main types of HAE are inherited in an autosomal-dominant pattern. Type 1 HAE, which accounts for approximately 85% of cases, is caused by a quantitative deficiency of C1-INH. Type 2 HAE accounts for approximately 15% of cases and is caused by dysfunctional C1-INH protein.3

HAE with normal C1-INH has recently been identified as a third type. This form of the disease, originally classified as type 3 HAE, predominantly affects women with normal results on quantitative and functional C1-INH testing. Although it is suspected that elevated estrogen levels are linked to the illness, type 3 HAE is not found exclusively in women. Some cases can be linked to a gain-of-function mutation in the gene coding for factor XII, a protein involved in the coagulation cascade.3

HAE is caused by mutations in genes, including the SERPING1 gene, that code for C1-INH protease, which belongs to the serine superfamily of proteins.3 The SERPING1 mutations found in type I HAE include missense, nonsense, frameshift, deletion, and insertion mutations. Type 1 is characterized by a deficiency of C1-INH, in which shortened or misfolded proteins cannot be released. SERPING1 mutations associated with type 2 (HAE with dysfunctional C1 inhibitor) contain residues at or near the active site on the reactive mobile loop that result in the secretion of dysfunctional C1-INH protein. As a result, the C1-INH antigen level in plasma is normal or even raised in type 2 HAE, even though protein function is reduced.4

Clinical Features

The body parts most often affected by hereditary angioedema are the upper airway, skin, and gastrointestinal tract, with symptoms that vary in intensity, location, and duration.4  Skin swelling is most frequently observed on the face, hands, arms, legs, genitals, and buttocks. Although skin swelling can cause pain, dysfunction, and deformity, it usually is not hazardous and lasts only a few days. In the gastrointestinal tract, the stomach and intestines are affected. The bladder and urethra may also be affected. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal pain. If the larynx and tongue are involved, the upper airway may become obstructed. Majority of the attacks usually affect the upper airway and may involve one area of the body at a time or a combination of areas.5

The episodes last for approximately 2 to 5 days, gradually becoming more intense and then subsiding, even without treatment. In 40% of attacks, triggers such as trauma, infection, stress, and medical procedures are noted. Most attacks are preceded by a prodrome that includes a rash known as erythema marginatum, but the sensitivity and, more importantly, the specificity of this feature are debatable. Anticholinesterase inhibitors and estrogens are other triggers.4

Diagnosis and Differential Diagnosis

The tests most often used in the diagnosis of HAE are complement studies, usually of C4- and C1-esterase inhibitors. C1q testing can help distinguish HAE from AAE caused by C1-INH deficiency. Individuals with no family history of angioedema, who account for about half of those affected, as well as patients whose C1q level is borderline and cannot be used to distinguish between HAE and AAE, benefit from genetic testing.

Read more about hereditary angioedema testing

Fluorescence-assisted mismatch analysis, specific polymerase chain reaction (PCR) amplification and real-time PCR analysis, chemical cleavage of mismatches, denaturing high-performance liquid chromatography, gradient gel electrophoresis, and single-stranded conformational analysis are some of the specific genetic tests used to diagnose HAE. Autoantibodies against C1-INH may also be measured; however, the assay is available only in research laboratories. Simple complement assays can be use to screen patients and diagnose the condition.6 

Management of HAE

Long-term prophylaxis, short-term prophylaxis, and the treatment of acute attacks are all used to manage HAE.3 

Long-term prophylaxis

The aim of long-term treatment is to reduce the number and severity of angioedema events. Patients with HAE are thought to have an average of 1 to 2 attacks of swelling each month. Patients who have had life-threatening or major attacks more than once in 3 months should receive long-term prophylaxis.The various agents for long-term prophylaxis include synthetic 17-α-alkylated androgens such as danazol (Danocrine) and stanozolol (Winstrol) and antifibrinolytics such as epsilon aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron®). In 2008, the US Food and Drug Administration approved a human nanofiltered, pasteurized C1-INH concentrate (Cinryze®) for the prophylactic treatment of HAE. It offers maximum protection against viral, and prion disorders such as Creutzfeldt–Jakob disease through the Nanofiltration process that adds a step to purify plasma-derived products. A crossover trial showed treatment with this nano-filtered C1 inhibitor concentrate significantly reduced the number of attacks over the period of 12 weeks.3 

Short-term prophylaxis

Trauma and stress are the most common triggers of angioedema attacks. As a result, additional preoperative safety measures are required for individuals with HAE, particularly before dental treatments, to reduce the risk for oropharyngeal edema. C1-INH replacement, high-dose anabolic androgens, and fresh frozen plasma have all been beneficial in this regard.3

Acute attacks

Various agents for the management of acute attacks include plasma-derived purified C1-INH (Berinert®), the plasma kallikrein inhibitor ecallantide (Kalbitor®), the selective bradykinin type 2 receptor antagonist icatibant (Firazyr®), and recombinant C1 inhibitor (Ruconest®).3,7 Recently, the FDA approved berotralstat (Orladeyo®) to prevent attacks in patients with HAE who are 12 years of age or older.7

References

  1. ​​Bhivgade S, Melkote S, Ghate S, Jerajani HR. Hereditary angioedema: not an allergy. Indian J Dermatol. 2012;57(6):503. doi:10.4103/0019-5154.103081
  2. Hereditary angioedema. MedlinePlus. Accessed June 4, 2022. 
  3. Siles R. Hereditary angioedema. Cleveland Clinic Center for Continuing Education. Published April 2017. Last Reviewed December 2017. Accessed June 4, 2022.
  4. Abdulkarim A, Craig TJ. Hereditary angioedema. StatPearls [Internet]. Updated May 4, 2022. Accessed June 4, 2022.
  5. Hereditary angioedema. Genetic and Rare Diseases Information Center (GARD), ​​National Center for Advancing Translational Sciences. Accessed June 4, 2022.
  6. Nigam PK. Hereditary angioedema: an update. Indian J Dermatol Venereol Leprol 2011;77:621-624. doi:10.4103/0378-6323.84093
  7. Hereditary angioedema. National Organization for Rare Disorders (NORD). Accessed June 4, 2022.

Reviewed by Debjyoti Talukdar, MD, on 6/10/2022.

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