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Hereditary angioedema
Other Resources UpToDate PubMed

Hereditary angioedema

Contributors: Edward Li PhD, Christine Hunt MD, Sylvia Hsu MD, Susan Burgin MD
Other Resources UpToDate PubMed

Synopsis

Hereditary angioedema is a rare genetic condition characterized by sudden attacks of angioedema with associated complications. Angioedema is characterized by swelling of the deep dermis and subcutaneous / submucosal tissue. It is less well-defined than the superficial dermal swelling seen with the wheals of urticaria, and the affected areas are nonpruritic. Prodromal symptoms, including a tingling sensation, fatigue, or myalgia, may occur. Angioedema is often idiopathic but may also be a reaction to drugs or food, or it may be hereditary. This summary discusses hereditary angioedema.

Hereditary angioedema follows an autosomal dominant pattern of inheritance and occurs in approximately 1 in 50 000-150 000 individuals worldwide. The condition has been reported in all races and ethnicities and affects both sexes equally. Symptoms of hereditary angioedema typically first present in the second decade of life, although they may manifest in the first decade.

Angioedema can affect any part of the body and multiple sites at once. Areas of swelling can last for up to 48-72 hours. Commonly affected areas include the face, extremities, genitalia, trunk, upper respiratory tract, and gastrointestinal tract. Most attacks are brought on by trauma or stress. Acute attacks involving upper airway swelling can be life-threatening. The nonspecific gastrointestinal symptoms of hereditary angioedema can often be erroneously attributed to more common causes, particularly in pediatric patients, as abdominal pain is a common complaint in childhood. Severe attacks may be mistaken for acute abdomen. Because of these factors, hereditary angioedema with primarily abdominal symptoms can go undiagnosed or be misdiagnosed for years.

Hereditary angioedema is caused by a deficiency or diminished function of C1 esterase inhibitor. Inherited or spontaneous (approximately 25%) mutation in one copy of the SERPING gene for C1 esterase inhibitor results in decreased quantity of C1 esterase inhibitor (type I) in about 85% of cases, or reduced function of C1 esterase inhibitor (type II) in about 15% of cases. This allows for the unregulated activation of proteolytic pathways and the unchecked downstream production of vasoactive anaphylatoxins including bradykinin. The resulting excess bradykinin production increases vascular permeability and leads to localized tissue edema. C1 esterase inhibitor deficiency also causes activation of the C1 complement system, resulting in low serum C4, which is a diagnostic feature.

A more recently described type (type III) of hereditary angioedema has been recognized, which is associated with normal measurable quantities and function of C1 esterase inhibitor. It is seen primarily in women with a personal and family history of angioedema, but no demonstrable deficiency of C1 esterase inhibitor or other complement abnormalities. It is believed that attacks may be caused by defects in other pathways that result in bradykinin overproduction. It appears to be estrogen dependent, since affected women often reported disease onset or worsening of symptoms with the use of oral contraceptives containing estrogen.

For more information, see OMIM.

Codes

ICD10CM:
D84.1 – Defects in the complement system

SNOMEDCT:
82966003 – Hereditary angioedema

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Diagnostic Pearls

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Differential Diagnosis & Pitfalls

Angioedema secondary to acquired C1 esterase inhibitor deficiency is typically due to infectious disease or autoimmune or lymphoproliferative disorders. Acquired C1 esterase inhibitor deficiency may result from the formation of autoantibodies against C1 esterase inhibitor or persistent low-level activation of C1q by anti-idiotypic antibodies in patients with B-cell lymphoproliferative disorders. Symptoms of acquired angioedema closely resemble those of hereditary angioedema, but can be differentiated from it by 3 factors:
  1. Acquired angioedema first appears in middle age, whereas hereditary angioedema first manifests in childhood or adolescence.
  2. A family history of angioedema will be absent in acquired angioedema.
  3. Acquired angioedema typically has low levels of C1q, as opposed to hereditary angioedema which has normal levels of C1q.
Drug-induced angioedema without wheals is most commonly attributable to angiotensin-converting enzyme (ACE) inhibitors and NSAIDs. The most common sites of ACE inhibitor-induced angioedema are the lips, tongue, and face. Rarely, the bowel is also involved. It typically presents in the first 3 months of ACE inhibitor use, but it can present much later.

Allergic angioedema is typically accompanied by urticaria. It may be pruritic and may represent allergic anaphylaxis.

Gleich syndrome presents with episodic angioedema with eosinophilia, weight gain, and fever, all of which self-resolve without treatment.

Idiopathic angioedema refers to 3 or more episodes of recurrent angioedema with no apparent cause after a comprehensive medical evaluation.

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Management Pearls

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Therapy

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Drug Reaction Data

Below is a list of drugs with literature evidence indicating an adverse association with this diagnosis. The list is continually updated through ongoing research and new medication approvals. Click on Citations to sort by number of citations or click on Medication to sort the medications alphabetically.

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References

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Last Reviewed:03/19/2020
Last Updated:04/01/2021
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Hereditary angioedema
Hereditary angioedema (Prodome) : Fatigue, Myalgia
Clinical image of Hereditary angioedema
Numerous urticarial papules on the forehead.
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