Angioedema hereditary D84.1

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 20.12.2021

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angioedema hereditary; Angioedema hereditary type I; Angioedema hereditary type II; Angioedema hereditary type III; edema hereditary angioedema; hereditary angioedema; Hereditary angioedema; Quincke's edema hereditary

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Osler, 1888

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Rare, hereditary disease with edema or swelling of the skin, larynx and intestinal organs, usually characterized by disturbances in C1-esterase inhibitor concentration/function (see below complement system; see below anaphylatoxins). In HAE type III, normal C1 esterase inhibitor concentration/function (C1-INH) is characterised by point mutations in the factor XII gene, which lead to factor XII deficiency.

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  • Type I (common form): One normal and one zero allele of the structural gene present. Phenotype 1: Most common form (85% of cases). Synthesis of theC1 esterase inhibitor decreased, turnover increased.
  • Type II (variant form): One normal and 1 mutant allele of the structural gene present:
    • Phenotype 2: Occurs in about 15% of cases. Functionally inactiveC1-INH at normal plasma concentration; functionally activeC1-INH at lower concentration.
    • Phenotype 3: Functionally inactiveC1-INH in increased plasma concentration; functionally activeC1-INH in decreased concentration.
  • Type III (estrogen-dependent hereditary angioedema): NormalC1-INH concentration and function. This type is caused by point mutations of the factor XII gene(gene localized on chromosome 5, coding for the Hagemann factor).

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Incidence: 2-4/100,000 inhabitants/year.

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C1-INH belongs to the serpin family of serine esterases and regulates various signal transduction pathways of the complement system, intravascular coagulation and the contact system of blood coagulation. In the case of HAE, a C1-INH deficiency can lead to edema in both systems. However, the peptide bradykinin appears to play the central role in the contact system of blood coagulation. Bradykinin causes an increase in nitric oxide, epoprostenol and endothelial-derived hyperpolarizing factor via its B2 receptor. This results in vasodilatation with increased fluid leakage from the vessels and edema formation. At the same time, contractions of the smooth muscles are triggered (cramps and pain). Normally, the release of bradykinin is limited by the effect of C1-INH. The C1-INH deficiency leads to increased bradykinin release.

  • Type I and II: Described is autosomal dominant inheritance with incomplete penetration of mutations of the C1 inhibitor gene (C1-INH) located at gene locus 11q12-q13.1. In about 80% of the cases there is an inherited C1-esterase inhibitor deficiency, in 20% of the patients have a defective C1-esterase inhibitor.
  • Type III: The X-linked dominant inheritance of a form of hereditary angioedema with normal C1 inhibitor concentration and function is discussed. The genetic basis are 2 point mutations in the factor XII gene, which codes for the Hageman factor (factor XII). Not all carriers of this mutation develop symptoms. Leading symptoms are angioedema of the skin and colicky abdominal discomfort. In addition to the usual trigger factors, oral contraceptives, ACE inhibitors, AT1 blockers can also trigger symptoms.
  • Angioedema can be due to antibody formation against C1-INH; this is an autoimmune disease. This acquired angioedema is associated with the development of lymphoma.
  • For all types, relapses can be triggered by surgery (e.g. dental treatment), infections or stress.

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Usually first appearing in childhood, often up to the 5th or later around the age of 15. A third peak of frequency is found in the 3rd decade of life (21-30 years). Rarely beyond the age of 50. No gender preference.

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Face, extremities (especially arms, more rarely legs), genitals; also lips, tongue, abdomen Life threatening: swelling of the larynx.

Clinical features
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Triggered mostly by minor trauma, infectious diseases involving the oropharynx or menses/pregnancy by reduction of functionalC1-INH activity.

  • Prodromes: Fatigue, headache, malaise, vomiting.
  • Integument: Slowly (over hours) developing, localized, skin-colored to markedly pale, nonpruritic, body-warm to cool skin and mucosal edema of variable size and doughy to coarse consistency.
  • Regression after hours to 2 days.
  • No accompanying urticaria!
  • Extracutaneous manifestations: Abdominal colic is characteristic. Misrecognition of the clinical symptoms may lead to misdiagnosis or even surgical intervention.
  • The development of laryngeal edema is less common than allergy-induced angioedema, but can lead to life-threatening obstruction.
  • Direct triggers may be: stress, infections, minor trauma, dental treatment, menstruation, oral contraceptives (progesterone-only preparations seem to have a beneficial effect on HAE).

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  • Type I: ReducedC1 inactivator in blood serum (below 30% of the norm), Inh-function reduced, reduction of total complement orC4.
  • Type II: High levels of a dysfunctionalC1-esterase inhibitor. C1-INH-Fect decreased (with commercial test systems the substrate conversion can be observed by colour change due to lack ofC1-esterase inhibition). C1-INH concentration normal, C4 decreased,
  • Type III: StandardC1 andC4. C1-IHF-Fect normal, C1-INH-concentration normal/mildly elevated; detection of the F-XII mutation.

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Edema in the subcutis. Non-specific pattern.

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Laboratory, molecular genetic analysis in patients with a blanched family history.

Hereditary angioedema is suspected when:

Main symptoms

  • episodes of swelling developing (slowly) over hours
  • C1 inhibitor function/concentration decreased
  • no concomitant urticaria
  • painful abdominal colic (pain, nausea, vomiting - CT/ sonography: wall-thickened sections of GI tract, ascites)
  • positive family history
  • first manifestation between 1-20 years (rarely 20-30 years)

Secondary symptoms

  • Prodromal symptoms (fatigue, malaise, muscle pain)
  • antihistamines are ineffective
  • Laryngeal edema (>50% of HAE patients)
  • Triggering factors (previous infections, ACE inhibitors, dental treatment, hormonal contraceptives)

Differential diagnosis
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Differential diagnostic distinction between "hereditary angioedema" and mast cell mediator-mediated angioedema (as a partial symptom of urticaria).
Angioedema (mast cell mediator induced) hereditary angioedema
Pathogenesis Partial symptom or equivalent of urticaria Kinin-mediated; by C1-INH deficiency
Medical history No familial clustering; begins in adulthood; often urticaria in the medical history Mostly familial, usually begins in the 1st or 2nd decade of life; no urticaria in the medical history
Trigger Usually no known triggers, occasionally medication (e.g. aspirin); pressure; vibration Often spontaneous occurrence; triggering by trauma or psychological stress possible
Symptoms Angioedema mostly periorbital and on the lips; rare or absent gastrointestinal symptoms Angioedema of the face or extremities; abdominal pain attacks; rarely laryngeal edema; no urticaria
Laboratory tests In general no pathological findings C1-INH concentration and activity (type 1) as well as C1-INH activity (type II) in plasma reduced
Therapy antihistamines; corticosteroids if necessary C1-INH concentrate; androgen derivatives, tranexamic acid, Icatibant

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Frequently recurrent laryngeal edema.

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Acute therapy (adults and children):

  • C1-INH concentrate: Inject highly purifiedC1-INH concentrate(e.g. Berinert P) 500 IU (10 ml) slowly i.v., in severe cases 1000 IU (20 ml) to max. 10,000 IU. Clinical improvement 20-30 min. after short infusion; check the C4 concentration in the blood as a therapy progress control (increasing). If i.v. therapy is not possible for technical reasons, the preparation can also be effectively administered s.c..
  • Icatibant (Firazyr®) is a synthetically produced decapeptide (protein fragment) approved by the EMA for the symptomatic treatment of acute attacks of hereditary angioedema in adults with C1 esterase inhibitor deficiency. This peptide is the most potent antagonist of the bradykinin B2 receptor to date and is available as a pre-filled syringe for subcutaneous injection (recommended dose: 30 mg s.c.). Caution. Inflammatory reactions at the injection site should be noted (redness, swelling, itching, pain).

Alternative therapy

  • Fresh plasma infusions, frozen plasma (500 ml), and lyophilized, clotting-active human plasma.
  • Antifibrinolytics: Antifibrinolytics are the second choice (therapeutic success presumably through inhibition of plasmin activation): tranexamic acid (e.g. Ugurol) 1.5-2.0 g/day i.v. or epsilon-aminocaproic acid (e.g. Amicar) 8-10 g/day i.v. under close coagulation control. Complications of these drugs are thromboembolism, myositis and peliosis hepatis.

Drugs not yet approved in Europe:

  • Ecallantide: A genetically engineered biopharmaceutical consisting of 60 amino acids, effective as an inhibitor of the enzyme kallikrein. In a clinical trial (EDEMA3) of 36 patients with hereditary angioedema, ecallantide performed better than placebo. Another study of 255 patients is available.
  • Rhucin (recombinant C1-INH) is a C1 inhibitor derived from transgenic rabbits by recombinant DNA technology to compensate for C1-INH deficiency (analogous mechanism of action to Berinert). Not approved to date.
  • Ecallantide (trade name Kalbitor; highly specific kallikrein inhibitor). Orphan drug designation in Europe.

Long-term therapy (> 1 episode/month; therapy of acute attacks not sufficiently effective/available):

  • Lanadelumab (Takhzyro®) is a subcutaneous (every 14 days) recombinant human monoclonal antibody (IgG1-kappa light chain antibody) directed against active kallikrein in blood plasma. The drug has been approved for prophylaxis in patients aged twelve years and older in the EU since 2019.
  • Androgens (no approval): In severe course, long-term prophylaxis with stanazol or danazol (e.g. Danadrol; available via international pharmacy) 3 times/day 100 mg (increase up to 600 mg/day possible), after 6 months reduction to 2 times/day 100 mg, after another 6 months alternating 100 and 200 mg/day. Aim for the lowest effective maintenance dose (Milan protocol). Alternatively, start with a low dosage, increase dosage until effective dose is reached (Budapest Protocol). Androgen derivatives promote the expression of male sexual characteristics and lead to masculinization (virilization) of the female organism. There is also a risk of kidney and liver dysfunction. Therefore, close monitoring of the course parameters is necessary. In rare cases, long-term hormone therapy can lead to liver carcinoma. In this respect, this therapy option should be reconsidered. Patients could benefit from a dose reduction or discontinuation of androgen prophylaxis if attacks that occur are controlled with an acute therapy (which can be controlled by the patient) with C1-INH or Icatibant.
  • Progestogens: In type III, prophylaxis with progesterone may be successful.

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Berotralstat, Orladeyo®: Oral prophylaxis of HAE for adolescents 12 years and older and adults. 1 time daily 150 mg

Anabolic steroids with androgenic residual potency show good results, e.g. Danazol (e.g. Danazol-ratiopharm Kps.) in an initial dose of 1-3 times/day 1 Kps. à 200 mg p.o. Continuous medication is usually 200 mg/day, possibly further reduction to 2 times/week 50 mg p.o. Caution! Virilisation in women! Long-term prophylaxis is also possible with stanazol. Glucocorticoids and antihistamines usually show no therapeutic efficacy, but are frequently used in the acute phase due to the differential diagnostic difficulties.

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In the case of severe seizures during pregnancy, there is good experience with the administration of a C1 esterase inhibitor. For seizure prophylaxis, androgen derivatives (e.g. danazol) must not be given during pregnancy.

Case report(s)
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Casuistry 1:

  • EA: 31-year-old woman with HAE III. first irregular swelling of face and extremities in the 17th year of life with cramping abdominal pain and vomiting. Attacks last about 1-3 days and do not respond to corticosteroids or antihistamines.
  • FA: Mother and maternal cousin also suffer from recurrent facial and limb swelling without response to corticosteroids and antihistamines. 3 years ago severe attack with laryngeal edema. In recent years, recurrences at shorter intervals and with increasing severity.
  • Diagnosis: Exclusion of all possible diseases (porphyrins, cryoglobulins, ANA, RF, ACE, histamine in plasma, routine laboratory or others, no evidence of sensitization to drugs or external agents). NormalC1-esterase inhibitor; normal function.
  • Therapy attempt with Danazol 600 mg/day p.o., no further attacks after that. Dose reduction in 2-week intervals to 50 mg p.o. twice a week as maintenance dose. Pat. has been free of symptoms for 2 years!
  • Side effects of the therapy: weight gain, mild acne papulopustulosa, amenorrhea after termination of oral contraception, low hyperandrogenemia.

Case history 2:

  • In one patient the following laboratory findings were found:
  • C1-Inhibitor Protein: 5,6 mg/dL (normal value: 15-35 mg/dL)
  • C1 inhibitor function: 1% (standard value 70-130%)
  • C4 protein: 10.0 mg/dL (standard value 20-50 mg/dL)
  • in addition: leukocytosis and increased CK
  • Diagnosis: C1-inhibitor deficiency, presence of hereditary angioedema (type I).

Casuistry 3:

  • A 35-year-old patient comes from a large family in which 10 other members suffer from hereditary angioedema. The first clinical symptoms appeared at the age of 27 years. Since then the angioedema has occurred 25 times on the skin, 2 times on the scrotum and 12 times in the gastrointestinal tract. The gastrointestinal symptoms manifested themselves in the form of colicky pain. The diagnosis was made in 1993. Danazol therapy was refused by the patient. Since 1994 the patient has been treated as an outpatient. Because of severe upper abdominal pain with repeated vomiting, he was admitted to hospital. C1-INH activity: 6%; C1-INH protein: normal, C4: 2mg/dl. Administration of 30 mg Icatibant s.c..30 min. later complete pain relief. 3 hours later, slight fatigue and some dizziness. After 1 month acute angioedema of the lips and chin region. 2 hours later, after renewed administration of Icatibant (dosage as above), the swelling was largely reduced.

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  1. Banerji A et al (2017) Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis. N Engl J Med 376:717-728.
  2. Bork K et al (2003) Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Arch Internal Med 163: 1229-1235
  3. Bork K et al (2009) Hereditary angioedema caused by missense mutations in the factor XII gene: Clinical features, trigger factors and therapy. J Allergy Clin Immunol 124: 129-134
  4. Giardino F et al (2015) Use of subcutaneous C1-INH for acute theapy and prophylaxis of a child with HAE. Ped All Immunol 26: 296-297
  5. Krause K et al (2010) Successful treatment of hereditary angioedema with the bradykinin B2 receptor anatagonist Icatibant. JDDG 8: 272-274
  6. Magerl M et al (2012) Diagnosis and exclusion of hereditary angioedema. Dermatologist 63: 567-572
  7. Maurer M et al (2011) Long-term prevention of hereditary angioedema with androgen derivatives: critical evaluation and possible alternatives. JDDG ):99-108
  8. Nzeako UC et al (2001) Hereditary angioedema a broad review for clinicians. Arch Internal Med 161: 2417-2429
  9. Nzeako UC et al (2002) Hereditary angioedema as a cause of transient abdominal pain. J Clin Gastroenterol 34: 57-61
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  11. Treudler R (2010) Allergic diseases in pregnant women. dermatologist 61: 1027-1033
  12. Weiler JM et al (2002) Does heparin prophylaxis prevent exacerbations of hereditary angioedema? J Allergy Clin Immunol 109: 995-1000


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Last updated on: 20.12.2021