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Hereditary Angioedema (HAE)

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Histology

Hereditary angioedema (HAE), a disorder with autosomal-dominant inheritance, is caused by deficiency (type1) or dysfunction (type2) of the complement component C1-esterase inhibitor. In a rare type of HAE (type 3), the levels and function of C1-esterase inhibitor are normal. The symptoms of HAE are related to edema of the upper airways, skin, and/or gastrointestinal system. The most severe manifestation is swelling of the upper airways, which can lead to asphyxiation.1-3 Complement activation has been thought to be a major factor in the pathophysiology of episodic, localized, subcutaneous and/or submucosal symptoms of angioedema.4 

Few studies of the histology of HAE have been conducted. Gross anatomical and microscopic changes have been identified in the skin and the respiratory and gastrointestinal tracts of patients with HAE.5,6 Biopsy specimens show dilatation of capillaries and venules, extensive edema, mast cell degranulation, and minor diapedesis of inflammatory cells.6 

Skin 

Urticaria, which is widespread in angioedema with other causes, affects the epidermis and upper dermis; in contrast, the cutaneous manifestations of HAE affect the deeper layers of the skin, including the inner dermal layers and subcutaneous tissue.7 

On histological examination, angioedema in HAE is similar to angioedema with other causes. The typical findings include a perivascular mononuclear cell infiltrate and dermal edema resembling that of chronic urticaria or other types of angioedema. Edema is identified in the reticular dermis, subcutaneously, or in a submucosal location in the absence of infiltrating inflammatory cells. Capillary and venular dilatation can be seen. Subcutaneous edema is one of the most obvious histological findings, evidenced by separation of the collagen bundles. Significant venular dilatation and a perivascular accumulation of mononuclear cells are clearly seen. During attacks of angioneurotic edema, mast cells as seen under light and electron microscopy appear considerably degranulated. In biopsy specimens taken before attacks begin or between attacks, edema is not observed.5,6 

Gastrointestinal System

Up to 85% of patients with HAE experience abdominal symptoms as a result of gastrointestinal edema. The attacks are excruciatingly painful and usually resemble those of other conditions, such as inflammatory bowel disease, appendicitis, small-bowel obstruction, and diverticulitis.8 Involvement of the gastrointestinal system is segmental and transitory, and the gastrointestinal tract usually returns to a normal state many days after the attack.9 

Histologic examination of lesions in the stomach reveals mild, nonspecific inflammatory cell infiltration and edema of the lamina propria. The foveolar epithelium may show mild hyperplasia.7,9

In biopsy specimens from the jejunum, histological studies have shown clearly defined edema involving the entire jejunum. Edema of the superficial portion of the villi along with widening of the lamina propria has been documented. The edematous villi appear club-shaped. The jejunal submucosa and subserosa also show marked edema.6  

The size of the spleen is reduced by the smaller vascular volume. Depletion of the Malpighian follicles (germinal) and the absence of secondary centers with depleted red pulp are characteristic histological findings in the spleens of patients with HAE. Infiltration by eosinophils has not been observed.6 

Respiratory Tract

Even though laryngeal attacks with edema of the glottis are uncommon, a minimum of 50% of patients with HAE experience at least one laryngeal attack at some point in their lifetime.8 When the upper respiratory tract is involved, laryngeal swelling is due to non-inflammatory submucosal edema. The histological alterations seen in the lungs of people who die of upper airway obstruction or another cause cannot be differentiated from the severe pulmonary edema seen in patients with HAE who have died of laryngeal edema. Histopathologic examination of the epithelial cells that line the mucosal membrane show extensive spongiosis along with cytoplasmic vacuoles. The fibrous laryngeal structures are obliterated by marked submucosal edema.6 

References

  1. Abdulkarim A, Craig TJ. Hereditary angioedema. StatPearls [Internet]. Updated May 4, 2022. Accessed June 29, 2022.
  2. Hereditary angioedema. National Organization for Rare Disorders (NORD). Accessed June 29, 2022. 
  3. 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
  4. Caccia S, Suffritti C, Cicardi M. Pathophysiology of hereditary angioedema. Pediatr Allergy Immunol Pulmonol. 2014;27(4):159-163. doi:10.1089/ped.2014.0425
  5. Frank MM. Hereditary angioedema workup. Medscape. Updated August 30, 2018. Accessed June 29, 2022.
  6. Sheffer AL, Craig JM, Willms-Kretschmer K, Austen KF, Rosen FS. Histopathological and ultrastructural observations on tissues from patients with hereditary angioneurotic edema. J Allergy. 1971;47(5):292-297. doi:10.1016/s0091-6749(71)80007-6
  7. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001;161(20):2417-2429. doi:10.1001/archinte.161.20.2417
  8. Grumach AS, Ferraroni N, Olivares MM, López-Serrano MC, Bygum A. An ABC of the warning signs of hereditary angioedema. Int Arch Allergy Immunol. 2017;174(1):1-6. doi:10.1159/000479839
  9. ​​Hara T, Shiotani A, Matsunaka H, et al. Hereditary angioedema with gastrointestinal involvement: endoscopic appearance. Endoscopy. 1999;31(4):322-324. doi:10.1055/s-1999-14

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

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