Hereditary Angioedema (HAE)


Hereditary angioedema (HAE), a genetic disorder inherited in an autosomal-dominant pattern, is characterized by severe swelling in the limbs, face, intestinal tract, and airways.1 

In retrospective studies, researchers tracked down in church records from the 17th century what they believed to be the first documented cases of hereditary angioedema, describing “hereditary periodic edema” in a family.2,3

In 1843, Robert James Graves—after whom Graves disease, a type of hyperthyroidism, is named—published a case study in Clinical Lectures on the Practice of Medicine in which he detailed episodic edema.2

In 1876, John Laws Milton described the case of a woman with significant swelling covering both of her eyes, which he called giant urticaria.2,4

Heinrich Irenaeus Quincke (1842-1922) was a German internist and surgeon renowned for introducing lumbar puncture to the field of medicine.5 In 1882, Eugen Dinkelacker, one of Quincke’s students, defended a doctoral thesis in which he analyzed 14 patients with acute-onset angioedema. Quincke later summarized Dinkelacker’s findings without referencing any of his previously cited sources.2 

Quincke accurately characterized the clinical features of HAE, differentiated familial from sporadic inheritance, and correctly hypothesized that increased vascular permeability is the cause of HAE. However, he incorrectly thought that the increased vascular permeability was due to neurogenic rather than humoral factors.5 As a result of his clinical observations and descriptions, the disease was referred to as Quincke’s edema.2 

In 1885, Paul Strübing suggested using the name angioneurotic edema, following Quincke’s train of thought that the disease was associated with neurogenic effects.2

In 1888, Sir William Osler, a Canadian physician and co-founder of Johns Hopkins University Hospital,6 published an article, “Hereditary Angioneurotic Edema,” in which he detailed the case of a 24-year-old woman with a family history of recurrent episodes of swelling of the extremities, hips, genitals, and pharynx. Over 5 generations, 28 of her family members had similar symptoms, and 2 of them died of suffocation due to swollen airways.2

Osler described 3 important disease characteristics: a strong familial pattern of inheritance, localized swelling of multiple body regions, and frequent gastrointestinal symptoms.2 Osler’s 1888 work is often cited as the first comprehensive clinical and genetic description of HAE.7,8  

In 1917, Joseph R. Crowder and Thomas R. Crowder, 2 American physicians, studied 5 generations of a family with HAE symptoms and determined that the pattern of HAE inheritance is autosomal dominant.2,9

Insights into the pathophysiology of HAE were acquired after World War II, when advancements in the fields of hematology and immunology made it possible to explain the relationship of enzymes to the complement cascade, coagulation, and serum permeability factors.2 

In 1961, Irwin H. Lepow and colleagues discovered C1-esterase inhibitor, an enzyme that inhibits the first component of the complement cascade.2,10 In 1963, Donaldson and Evans proved that C1-esterase inhibitor is absent in patients with HAE, indicating that this enzyme plays a key role in regulating vascular permeability.2,11

At about the same time, Nathaniel Landerman, Virginia Donaldson, and Oscar Ratnoff identified a failure to inhibit kallikrein, an enzyme in the contact system, in patients with HAE; if left unregulated, the contact system releases excessive amounts of bradykinin, increasing vasodilation and vascular permeability.2,12 However, it wasn’t until 1998 that Nussburger and colleagues showed that bradykinin was the culprit causing increased vascular permeability following contact system activation.2,13

In 1965, Rosen and colleagues identified 2 types of HAE: 

  • Type 1, in which little to no C1-esterase is produced, so that enzymatic inhibition is deficient or absent;
  • Type 2, in which serum levels of C1-esterase are normal but the enzyme does not function properly.

In their research, they described members of a family with HAE who had normal serum C1-esterase levels but impaired inhibition, a pattern that differed from the frequently observed pattern characterized by the absence of C1-esterase.2,14

Research has continued to elucidate the complicated pathways and relationships underlying the pathophysiology of HAE, and a pivotal discovery was made when Bock and colleagues sequenced the C1-esterase molecule and identified it as a member of the serine protease inhibitor (SERPING1) family.2,15 

Bock, Theriault, Janson, and colleagues each independently mapped the gene responsible for encoding the enzyme to chromosome 11 at the q11-q13.1 position, now known as the SERPING1 gene.2,15,16 These scientists discovered the root cause of HAE: genetic variations within SERPING1.

References

  1. Hereditary angioedema. MedlinePlus. Accessed June 4, 2022.
  2. Gülbahar O, Germenis AE. Rediscovery of a forgotten disease: hereditary angioedema. Balkan Med J. 2021;38(2):68-72. doi:10.5152/balkanmedj.2021.20030
  3. Arnoldsson H, Belin L, Hallberg L, Helander E, Lindholm B, Westling H. Hereditary periodic oedema. Acta Med Scand. 1967;181(1):115-124. doi:10.1111/j.0954-6820.1967.tb07235.x
  4. Milton JL. On giant urticaria. Edinb Med J. 1876;22(6):513-526. 
  5. van Gijn J, Gijselhart JP. [Quincke and his oedema.] [Article in Dutch.] Ned Tijdschr Geneeskd. 2012;156(39):A5238.
  6. William Osler. Biographical overview. National Library of Medicine. Profiles in Science. Accessed June 4, 2022.
  7. Khan DA. Hereditary angioedema: historical aspects, classification, pathophysiology, clinical presentation, and laboratory diagnosis. Allergy Asthma Proc. 2011;32(1):1-10. doi:10.2500/aap.2011.32.3411
  8. Horiuchi T. Hereditary angioedema from 1888 to 2018 – progress and problems. Intern Med. 2018;57(21):3065-3066. doi:10.2169/internalmedicine.1818-18
  9. Crowder JR, Crowder TR. Five generations of angioneurotic edema. Arch Intern Med (Chic). 1917;XX(6):840-852. doi:10.1001/archinte.1917.00090060014002
  10. Pensky J, Levy LR, Lepow IH. Partial purification of a serum inhibitor of C’1-esterase. J Biol Chem. 1961;236:1674-1679. 
  11. Donaldson VH, Evans RR. A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C’ 1-esterase. Am J Med. 1963;35:37-44. doi:10.1016/0002-9343(63)90162-1
  12. Pirahanchi Y, Sharma S. Physiology, Bradykinin. StatPearls [Internet]. Updated July 26, 2021. Accessed June 4, 2022.
  13. Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angio-oedema. Lancet. 1998;351(9117):1693-1697. doi:10.1016/S0140-6736(97)09137-X
  14. Rosen FS, Pensky J, Donaldson V, Charache P. Hereditary angioneurotic edema: two genetic variants. Science. 1965;148(3672):957-958. doi:10.1126/science.148.3672.957
  15. Bock SC, Skriver K, Nielsen E, et al. Human C1 inhibitor: primary structure, cDNA cloning, and chromosomal localization. Biochemistry. 1986;25(15):4292-4301. doi:10.1021/bi00363a018
  16. Theriault A, Whaley K, McPhaden AR, Boyd E, Connor JM. Regional assignment of the human C1-inhibitor gene to 11q11-q13.1. Hum Genet. 1990;84(5):477-479. doi:10.1007/BF00195824

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

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