Hereditary Angioedema (HAE)

Hereditary angioedema (HAE) is described as a disease with episodic nonpruritic, indurated swellings that are not accompanied by urticaria. All individuals who present with episodic swellings without urticaria should be suspected of having HAE. Swelling of the face, eyes, lips, hands, feet, and genitals, as well as abdominal pain and fatal laryngeal edema, are some of the clinical features.¹ The disease is a rare genetic disorder with a variable frequency estimated to be 1:50,000.² 

Hereditary angioedema is classified into 2 types: HAE with a deficiency in C1-esterase inhibitor protein (C1-INH HAE) and HAE with normal levels of C1-INH protein (nC1-INH HAE). C1-INH HAE is further subdivided into 2 variants. Type 1, which accounts for approximately 90% of cases, is characterized by low levels or the absence of C1-INH due to a failure to synthesize C1-INH. Type 2 HAE, which accounts for the remaining 10% of cases, is characterized by normal or increased levels of dysfunctional C1-INH. In this type, an abnormal, nonfunctional protein is synthesized. In nC1-INH-HAE, C1-INH is quantitatively and qualitatively normal; up to 25% to 30% of individuals with this rare variant have an alteration in the F12 gene (FXII HAE). The genetic basis for the remaining 70% to 75% of cases is unknown (unknown HAE).^3,4

A comprehensive clinical evaluation, a complete patient history, and blood tests that indicate low levels of complement proteins are used to diagnose HAE. Genetic testing is recommended in suspected cases with recurring episodic angioedema of unknown origin.⁵

Clinical Criteria for Diagnosis

A thorough physical examination combined with a complete family history is the key to establishing suspicion of HAE. The quintessential history includes recurrent attacks of angioedema (in absence of urticaria) (100%), abdominal pain (93%), family history of similar symptoms (75%), upper airway edema (50%), prodromal signs prior to episodes (87% to 95.7%), unresponsiveness to antihistamines, glucocorticoids, or epinephrine (100%), relation of attacks to menstruation or stress, and aggravation of attacks after the administration of estrogens or angiotensin-converting enzyme (ACE) inhibitors. ACE-inhibitor angioedema can lead to the development of angioedema as it is considered as the most common cause of angioedema compared to acquired or hereditary C1-INH deficiency. Hereditary angioedema must be distinguished from other types of angioedema, especially mast cell-mediated reactions, which are far more prevalent and respond to epinephrine, antihistamines, and glucocorticoids.⁶

Diagnostic Tests

Laboratory Tests

The tests performed in all patients with suspected HAE include measurements of serum complement component 4 (C4) level, serum complement component 1q (C1q) level, and

C1-esterase inhibitor (C1-INH) antigenic level (measured using nephelometry), as well as a

functional assay for C1-INH (measured using enzyme-linked immunosorbent assay [ELISA]). Low C1q levels can suggest acquired angioedema due to presence of autoantibodies against C1-INH protein. At present, there are not diagnostic biomarkers for nl-C1-INH-HAE.¹

All individuals suspected of having HAE should have their C1 level, C1-INH level, and C1-INH function tested. Patients with suspected autoimmune-mediated acquired angioedema (AAE) should have their C1q level checked as well.¹

In type 1 HAE, C4 and C1-INH levels are low and C1-INH function can be low or normal. In type 2 HAE, C4 and C1-INH functions are low but C1-INH levels are within the normal range. In the rare nC1-INH HAE, also referred to as type 3, C4 and C1-INH levels and C1-INH function are all normal.¹

Patients with late-onset (>40 years of age) symptoms and no family history should be considered for suspicion of AAE. Low C4 level, low or normal C1-INH level, low C1-INH function, and low C1q level are all noted in AAE and are caused by acquired C1-INH deficiency due to antibodies produced against C1-INH. Patients with ACE inhibitor-induced angioedema and those with idiopathic AAE (after ruling out all other causes) have normal C4 level and C1-INH level and function.¹

Genetic Testing

In patients with type 1 and type 2 HAE, the key methods for detecting genetic mutations are SERPING1 gene sequencing (using Sanger sequencing) and family screening. If the mutation is not found, more current techniques like next-generation sequencing (NGS) are needed. The role of genetic testing in the diagnosis of nC1-INH HAE is very significant. Patients with nC1-INH HAE have normal C4 and C1INH levels and C1-INH function, and the only way to diagnose nC1-INH HAE is to use NGS (either whole-exome sequencing or targeted NGS). Other genes that can be investigated include the F12, PLG, ANGPT1, and KNG1 genes. The increased demand for genetic tests that can identify a variety of diseases has resulted in lower costs and more widespread availability in large hospitals. Following the detection of a genetic mutation, genetic counseling is indicated to improve extended family screening.^1,2 

Imaging Studies

Imaging tests are not a reliable diagnostic tool and are only beneficial if performed during an acute episode; if performed too early or too late, these examinations provide false-negative results. Even in symptomatic individuals, subtle or mild intestinal edema can remain undetected on imaging. Negative findings on scans cannot rule out the possibility of HAE.⁶  

During attacks involving the airways, chest radiographs may show pleural effusion.⁷ The jejunum and duodenum are the most commonly affected intestinal segments in acute episodes, whereas the colon, ileum, and stomach are less commonly affected. Other causes of stomach pain may be ruled out via contrast-enhanced computed tomography. In pediatric patients, ultrasound may be performed instead to rule out other causes.⁶

 References

1. Jindal AK, Bishnoi A, Dogra S. Hereditary angioedema: diagnostic algorithm and current treatment concepts. Indian Dermatol Online J. 2021;12(6):796-804. doi:10.4103/idoj.idoj_398_21  
2. Campos RA, Valle SOR, Toledo EC. Hereditary angioedema: a disease seldom diagnosed by pediatricians. J Pediatr (Rio J). 2021;97(Suppl 1):S10-S16. doi:10.1016/j.jped.2020.10.011
3. Hereditary angioedema. MedlinePlus. Updated April 1, 2009. Accessed June 14, 2022.
4. Lai Y, Zhang G, Inhaber N, et al. A robust multiplexed assay to quantify C1-inhibitor, C1q, and C4 proteins for in vitro diagnosis of hereditary angioedema from dried blood spot. J Pharm Biomed Anal. 2021;195:113844. doi:10.1016/j.jpba.2020.113844
5. Hereditary angioedema. National Organization for Rare Disorders (NORD). Accessed June 14, 2022.
6. Henao MP, Kraschnewski JL, Kelbel T, Craig TJ. Diagnosis and screening of patients with hereditary angioedema in primary care. Ther Clin Risk Manag. 2016;12:701-711. doi:10.2147/TCRM.S86293
7. Frank MM. Hereditary angioedema workup: approach considerations. Medscape.

Updated August 30, 2018. Accessed June 14, 2022.

Reviewed by Debjyoti Talukdar, MD, on 6/26/2022.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.