Hereditary Angioedema (HAE)

Several disorders have clinical features similar to those of hereditary angioedema (HAE). Cutaneous and/or upper airway edema without urticaria (wheals) can be seen in several diseases.

Anaphylaxis and Acute Hypersensitivity (Allergic) Reactions 

Anaphylaxis, classified as a type 1 hypersensitivity reaction, is a relatively common medical emergency. In type 1 hypersensitivity reactions, which are mediated by immunoglobulin E, the degranulation of sensitized basophils and mast cells leads to the release of numerous vascular mediators upon re-exposure to a specific antigen. The mediators include histamine, tryptase, carboxypeptidase A, and proteoglycans. Activation of phospholipase A, lipoxygenases, and cyclooxygenases results in the formation of arachidonic acid-derived metabolites such as leukotrienes, prostaglandins, and platelet-activating factors. The mechanism of action behind the swelling associated with HAE is distinct and does not involve histamine or any of the mediators previously listed. Rather, HAE attacks are mediated primarily by the release of bradykinin. Key features that distinguish anaphylaxis from HAE are the following:

1. Usually, a clear trigger can be associated with anaphylaxis (eg, bee sting, food allergen, medication). It is noteworthy that only one group of medications, the angiotensin receptor blockers, may precipitate an HAE attack.^1,2 
2. Urticaria (wheals), flushing, and itching are common in allergic reactions, whereas HAE attacks characteristically lack wheals and are not pruritic.^1,2
3. Usually, a patient with HAE has a clear family history of recurrent episodes of angioedema.^1,2
4. HAE does not respond to antihistamines, epinephrine, or corticosteroids.^1,2 

Non-hereditary (Acquired) Angioedema 

Acquired angioedema (C1-INH-AAE) is a deficiency of C1-esterase inhibitor (C1-INH) acquired through the consumption of C1-INH. Like HAE, it is not mediated by IgE and is characterized by recurrent episodes of asymmetric edema of the face, lips, tongue, limbs, genitals, upper airway, and gastrointestinal tract without urticaria. C1-INH-AAE is classified into 2 types.³ Type 1 C1-INH-AAE is usually associated with a lymphoproliferative malignancy causing the production of complement-activating factors, idiotype/anti-idiotype antibodies against C1-INH, or other destructive immune complexes that compromise C1-INH function. The most common associated malignancy is B-cell lymphoma, which produces anti-idiotype antibodies that cause C1-INH deficiency. In type 2 C1-INH-AAE, autoantibodies against C1-INH are produced for unknown reasons.^3,4 

In general, the onset of C1-INH-AAE is later (usually in individuals at least 40 years old) than that of HAE. Additionally, a clear family history of recurrent episodes of angioedema is usually lacking. The clinician should look for a history of lymphoproliferative disease in a patient with type 1 C1-INH-AAE. A determination of the C1 esterase and C4 levels makes it possible to differentiate HAE and AAE from angioedema with other causes.⁵ The serum C1q level is decreased in C1-INH-AAE, and measurement of this level is a useful laboratory study to differentiate between the 2 conditions.³ 

ACE Inhibitor-Induced Angioedema

Angiotensin-converting enzyme (ACE) inhibitors are drugs that act at the level of the renin-angiotensin-aldosterone system to reduce systemic blood pressure. In addition to inhibiting the conversion by ACE of angiotensin I to angiotensin II, ACE inhibitors prevent the catabolism of bradykinin and substance P by ACE. Patients with intrinsic defects in the degradation of bradykinin are prone to the development of ACE inhibitor-induced angioedema. The overall incidence of ACE inhibitor-induced angioedema is low, ranging from 1 to 7 events per 1000 patients, and ACE inhibitor-induced angioedema is most likely to occur during the first month of treatment with an ACE inhibitor. The condition is more frequent in African Americans, individuals who have a history of drug rash or seasonal allergies, persons older than 40 years, smokers, women, and those on immunosuppressive therapy. The risk for ACE inhibitor-induced angioedema is highest in patients taking enalapril.⁶  

Other HAE Differential Diagnoses

Thyroid disorders. Thyroid dysfunction may cause cutaneous manifestations resembling those of angioedema, including nonpitting, nonpruritic edema of the extremities without urticaria. The changes are gradual, occur over weeks to months, and are not episodic; in contrast, HAE attacks develop acutely over minutes.⁷

Allergic contact dermatitis. Pruritus is a hallmark feature of contact dermatitis and responds to corticosteroids and antihistamines, unlike HAE.^1,2 

Cheilitis granulomatosa (Miescher cheilitis) and Melkersson-Rosenthal syndrome. These are rare conditions characterized by persistent angioedema of the lips. Melkersson-Rosenthal syndrome is characterized by the triad of familial relapsing peripheral facial palsy, facial edema, and lingua plicata.⁸ Miescher cheilitis is considered to be a monosymptomatic form of Melkersson-Rosenthal syndrome; it is described as an association of recurrent labial and/or facial edema, relapsing facial paralysis, and fissured tongue.⁹ Complement studies are normal in both conditions. 

References

1. McLendon K, Sternard BT. Anaphylaxis. StatPearls [Internet]. Updated May 15, 2022. Accessed June 29, 2022. Available at: https://www.ncbi.nlm.nih.gov/books/NBK482124/

2. Abdulkarim A, Craig TJ. Hereditary angioedema. StatPearls [Internet]. Updated May 4, 2022. Accessed June 29, 2022. 

3. Li HH. Angioedema: practice essentials, background, pathophysiology. Medscape. Updated September 4, 2018. Accessed June 29, 2022. 

4. Moon AT. Acquired angioedema due to C1 inhibitor deficiency: background, pathophysiology, etiology. Medscape. Updated May 20, 2020. Accessed June 29, 2022. 

5. Swanson TJ, Patel BC. Acquired angioedema. StatPearls [Internet]. Updated May 1, 2022. Accessed June 29, 2022. 

6. Kostis WJ, Shetty M, Chowdhury YS, Kostis JB. ACE inhibitor-induced angioedema: a review. Curr Hypertens Rep. 2018;20(7):55. doi:10.1007/s11906-018-0859-x

7. Elshimy G, Chippa V, Correa R. Myxedema. StatPearls [Internet]. Updated May 5, 2022. Accessed June 29, 2022. 

8. Levenson MJ, Ingerman M, Grimes C, et al. Melkersson-Rosenthal syndrome. Arch Otolaryngol. 1984;110(8):540-542. doi:10.1001/archotol.1984.00800340052015

9. Camacho-Alonso F, Bermejo-Fenoll A, López-Jornet P. Miescher’s cheilitis granulomatosa. A presentation of five cases. Med Oral Patol Oral Cir Bucal. 2004;9(5):427-429, 425-427.

Reviewed by Hasan Avcu, MD, on 6/30/2022.

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Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.