Hereditary Angioedema (HAE)

Hereditary angioedema (HAE) is a rare, genetic, life-threatening condition characterized by episodes of cutaneous and submucosal swellings.^1,2 The disease most commonly derives from a deficiency in the C1-inhibitor (C1-INH) protein and affects the face, oropharynx, gastrointestinal tract, and extremities.² 

Episodes of HAE are usually unpredictable, with no clear trigger, and present with variable severity and duration. They can start in childhood, progress in puberty, and recur throughout a patient’s lifetime.² These nonpruritic, nonpitting, recurrent, and localized attacks may start by affecting one part of the body; however, other areas may become affected before the first swelling has resolved. Swelling progresses for 24 hours and typically resolves within the next 48 to 72 hours.² Acute HAE attacks can also lead to edema involving the upper airway, resulting in breathing difficulties. Although these episodes are less frequent, life-threatening laryngeal attacks are experienced by more than 50% of patients with HAE in the course of the disease.^2,3 Patients do not respond to treatment with corticosteroids, antihistamines, or adrenaline.³

The clinical features of HAE derive from the accumulation of different vasoactive peptides, such as bradykinin, histamine, prostaglandins, and interleukins, in different parts of the body.² The swelling observed is mainly caused by excessive bradykinin production, which is mediated through the contact system.³ Bradykinin levels in the blood are increased when there is a low amount of functional C1-INH, and these high levels of bradykinin are responsible for vasodilation, increased vascular permeability, and angioedema.³

There are different types of HAE that result from a deficiency in functional C1-INH. Type I HAE affects about 85% of patients and is characterized by a lack of C1-INH.^2,3 Type II HAE results from low functional activity of C1-INH, while the plasma levels of this protein remain normal. This is a less common form of HAE, representing about 15% of cases.^1,3 An acquired form of HAE characterized by C1-INH deficiency without any underlying associated genetic mutations has been also described.³ A different group of HAE patients, with normal C1-INH levels, has been reported.¹ The clinical manifestations of the different HAE forms are similar, however, patients with normal C1-INH blood levels are identified less frequently and present at a higher age when symptoms start.³

Hereditary Angioedema With C1-INH Deficiency

In type I and type II HAE, reductions in the quantity and functionality of C1-INH, respectively, are observed, driven by SERPING1 mutations.^1,3 The clinical manifestations in these forms of the disease typically start in the first or second decade of life, with a mean age at disease onset of 8 to 12 years, while in cases of acquired HAE, clinical manifestations are more common after the fourth decade of life.^1,4 Even though different triggers, including trauma and infection, can lead to an HAE episode, most of the reported attacks do not have a known direct cause.³ Symptoms of HAE are self-limited and typically resolve within 4 days. However, attacks may recur or progress to other parts of the body.² These episodes may occur weekly or only a few times each year.⁵

The most common HAE episodes include the abdominal and cutaneous forms, which can cause disfiguration.^1,2 Genitals, and rarely, bladder, muscle, 

joints, larynx can also be affected.¹ Swelling in the abdomen can resemble acute abdomen, leading patients to undergo surgery that is not required.¹ No urticaria or pruritus is observed, however, patients may report prodromal symptoms affecting the skin, such as erythema marginatum.^1,3,6 Other prodromal symptoms that have been described include tingling, nausea, rash, and fatigue.^1,2 HAE is characterized by significant morbidity, with patients experiencing pain syndromes deriving from the abdominal and urogenital areas or from the arms and legs.² When the upper airway is involved in an attack, asphyxiation may occur. This laryngeal edema may develop spontaneously but may also occur following dental procedures.³

Laboratory findings include low levels of the complement C4 protein in type I and type II HAE, low levels of C1-INH protein in type I HAE, and normal or slightly elevated levels of C1-INH with an impaired functional assay in type II HAE.²

Hereditary Angioedema With Normal C1-INH Levels

Several genetic defects can underlie HAE with normal C1-INH levels, such as mutations in genes encoding for coagulation factor XII, angiopoietin-1, and plasminogen.^2,3 The clinical features observed in these patients present a similar phenotype to those reported in type I and type II HAE, including skin swelling, the absence of urticaria, and pain syndromes.² Disease-free intervals during the disease course are more in comparison to other types.^1,7

References

1. Busse PJ, Christiansen SC. Hereditary angioedema. N Engl J Med. 2020;382(12):1136-1148. doi:10.1056/NEJMra1808012

2. Azmy V, Brooks JP, Hsu FI. Clinical presentation of hereditary angioedema. Allergy Asthma Proc. 2020;41(Suppl 1):S18-S21. doi:10.2500/aap.2020.41.200065

3. Longhurst HJ, Bork K. Hereditary angioedema: an update on causes, manifestations and treatment. Br J Hosp Med (Lond). 2019;80(7):391-398. doi:10.12968/hmed.2019.80.7.391

4. Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119(3):267-274. doi:10.1016/j.amjmed.2005.09.064

5. Patel N, Suarez LD, Kapur S, Bielory L. Hereditary angioedema and gastrointestinal complications: an extensive review of the literature. Case Reports Immunol. 2015;2015:925861. doi:10.1155/2015/925861

6. Yucelten D, Kus S. Chicken-wire erythema, but not urticaria, as the presenting sign of hereditary angioedema. Eur J Dermatol. 2006;16(2):197-198.

7. Bork K. Hereditary angioedema with normal C1 inhibitor. Immunol Allergy Clin North Am. 2013;33(4):457-470. doi:10.1016/j.iac.2013.07.002

Reviewed by Harshi Dhingra, MD, on 6/27/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.