Hereditary angioedema

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Classification according to ICD-10
D84.1 Defects in the complement system, including C1 esterase inhibitor [C1-INH] deficiency
ICD-10 online (WHO version 2019)

The hereditary angioedema ( English hereditary angioedema , HAE; outdated "hereditary angioneurotic edema" HANE) is a rare genetic disease , but in which about 20% of spontaneous mutations (de novo mutations) to accept and are in it (to recurring swelling angioedema ) the skin, mucous membranes and internal organs, which under certain circumstances can be life-threatening. It is estimated that around one in 50,000 people is affected, but the number of unreported cases is probably much higher. The symptoms usually show up in the first two decades of life, with men and women falling ill about the same frequency. This bradykinin-mediated clinical picture must be distinguished from histamine-mediated angioedema .

Clinical picture

The angioedema of the skin is usually little or not reddened and typically does not itch. They mostly appear on the skin or the mucous membranes of the face, especially in the lip area, extremities or genitals, and can be disfiguring or restrictive in function. Swelling in the gastrointestinal tract often manifests itself as painful, colicky cramps. Since HAE is a rare disease, doctors often confuse these symptoms with those of colic or appendicitis. Swelling in the upper respiratory tract (larynx, nose, tongue) is particularly dangerous and can be life-threatening if left untreated. Every third person affected suffers at least one such attack in their life.

The symptoms occur repeatedly and are interrupted by symptom-free intervals of different lengths. It is not possible to predict where and when the next edema will occur. Most patients have an occasional attack, but there are also cases when it happens weekly or only once or twice a year. The triggers can be of various types, such as infection, minor injuries, mechanical irritation, surgery, or stress, but the majority of swellings are spontaneous. Angioedema usually develops within a few hours and then subsides over the course of 2–5 days.

causes

Hereditary angioedema is caused by a genetic defect that leads to a deficiency of C1 inhibitor (C1-INH). More than 500 mutations are known. The body either produces too little of this protein (type 1 HAE, 85% dF) or it is not functional (type 2 HAE, 15% dF). C1-INH has a regulating function in two vital systems of the body: in the contact system and in the complement system of the immune system. In the case of HAE, the lack of regulation of kallikrein and factor XIIa by C1-INH leads to excessive formation of the peptide bradykinin . Via the bradykinin receptor 2 on the endothelium, the peptide increases the permeability of the blood vessels, which leads to the escape of fluid from the vessels into the tissue. At the same time, it expands the vessels and triggers contractions in the smooth muscles .

Autoimmune processes can also lead to a C1-INH deficiency. In contrast to the hereditary, this is called an acquired angioedema ( acquired angioedema , AAE). Also ACE inhibitors to lower blood pressure can cause severe of edema, as they bradykinin degradation influence.

A very rare form of HAE associated with normal C1-INH levels and function was first reported in 2001. In the meantime, various mutations have been identified as the cause (factor XII, plasminogen, angiopoietin, kininogen). It is assumed that these mutations contribute in various ways to an increased formation of bradykinin or increase the effectiveness of bradykinin at the receptor.

diagnosis

The disease is often not recognized for a long time because the symptoms are similar to more common diseases such as allergy or intestinal colic. Important indications of the possible presence of HAE are: Failure to respond to acute angioedema to antihistamines or cortisone preparations , first occurrence of the symptoms in childhood or adolescence, recurring painful abdominal complaints, other affected persons in the family (positive family history). The diagnosis is ultimately made through a laboratory analysis. Typical for the presence of a HAE is a significantly reduced value for the function of C1-INH, and in type 1 also the concentration of C1-INH. Due to the lack of regulation by C1-INH, the complement factor C4 is constantly overactively consumed and is therefore often measured at a lower level.

Forms of therapy

Acute therapy

The aim of acute therapy is to stop the development of angioedges as quickly as possible, which can be life-saving, especially in the case of attacks in the larynx. Various C1-INH concentrates are available (trade names: Berinert, Cinryze from donor plasma or Ruconest, produced recombinantly) that are administered intravenously. Alternatively, Icatibant, a subcutaneously administered bradykinin antagonist, is available. Freshly frozen blood plasma , which also contains C-1-INH, can also be used in an emergency . The kallikrein inhibitor Ecallantide is only approved in the USA. In many countries, only a limited range of therapies are available to patients.

A tracheotomy should be considered if life is threatened and no specific drug therapy is available .

Long-term prophylaxis

Long-term prophylaxis should be considered in patients with frequent attacks, impaired quality of life, or lack of disease control due to reliever therapy. C1-INH concentrates (iv and sc) and the kallikrein antibody lanadelumab are approved for this in Germany. In the past, male sex hormones ( androgens ) were often used, which increase the production of C1-INH in the liver via a previously unexplained mechanism. The use of androgens is contraindicated in children, as well as during pregnancy and in women who wish to have children. The multiple occurrence of liver tumors under the androgen danazol led to the substance being withdrawn from the market in Germany at the beginning of 2005. ACE inhibitors should be replaced with antihypertensive drugs that do not raise bradykinin.

Short-term prophylaxis

Short-term prophylaxis is usually done before surgery or dental work. In Germany, C1-INH concentrate is given 1-1½ hours before the procedure. In countries where no C1 inhibitor concentrate is available for prophylaxis, high-dose treatment with androgens is carried out for five to seven days.

New therapeutic developments

There are currently several new active ingredients in clinical development that intervene in the disease process in various ways. These include various oral kallikrein inhibitors or an antibody against factor XIIa. Initial research has been carried out on oligonucleotides (inhibition of prekallikrein translation by antisense RNA) and gene therapy.

literature

Individual evidence

  1. ↑ H. Longhurst, M. Cicardi: Hereditary angio-edema. In: Lancet , 2012 Feb 4, 379 (9814), pp. 474-481.
  2. ↑ Emel Aygören-Pürsün, Konrad Bork: Hereditary angioedema . In: The internist . tape 60 , no. 9 , September 2019, ISSN  0020-9554 , p. 987-995 , doi : 10.1007 / s00108-019-0644-1 ( springer.com [accessed February 12, 2020]).
  3. ↑ Markus Magerl, Anastasios E. Germenis, Coen Maas, Marcus Maurer: Hereditary Angioedema with Normal C1 Inhibitor . In: Immunology and Allergy Clinics of North America . tape 37 , no. 3 , August 2017, p. 571-584 , doi : 10.1016 / j.iac.2017.04.004 ( elsevier.com [accessed February 12, 2020]).
  4. ↑ M. Maurer, M. Magerl, I. Ansotegui, E. Aygören-Pürsün, S. Betschel: The international WAO / EAACI guideline for the management of hereditary angioedema-The 2017 revision and update . In: Allergy . tape 73 , no. 8 , August 2018, p. 1575–1596 , doi : 10.1111 / all.13384 ( wiley.com [accessed February 12, 2020]).
  5. ↑ Jonathan A. Bernstein: On-demand Therapy for Hereditary Angioedema . In: Immunology and Allergy Clinics of North America . tape 33 , no. 4 , November 2013, p. 487–494 , doi : 10.1016 / j.iac.2013.07.004 ( elsevier.com [accessed February 12, 2020]).
  6. ↑ Timothy Craig, Bruce Zuraw, Hilary Longhurst, Marco Cicardi, Konrad Bork: Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks . In: The Journal of Allergy and Clinical Immunology: In Practice . tape 7 , no. 6 , July 2019, p. 1793–1802.e2 , doi : 10.1016 / j.jaip.2019.01.054 ( elsevier.com [accessed February 12, 2020]).
  7. ↑ Aleena Banerji, Marc A. Riedl, Jonathan A. Bernstein, Marco Cicardi, Hilary J. Longhurst: Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial . In: JAMA . tape 320 , no. 20 , November 27, 2018, ISSN  0098-7484 , p. 2108 , doi : 10.1001 / jama.2018.16773 , PMID 30480729 , PMC 6583584 (free full text) - ( jamanetwork.com [accessed February 12, 2020]).
  8. ↑ V. Zampeli, M. Magerl: prophylaxis of angioedema . In: The dermatologist . tape 70 , no. 2 , February 2019, ISSN  0017-8470 , p. 107–115 , doi : 10.1007 / s00105-018-4345-9 ( springer.com [accessed February 12, 2020]).
  9. ↑ Francesca Perego, Maddalena A. Wu, Anna Valerieva, Sonia Caccia, Chiara Suffritti: Current and emerging biologics for the treatment of hereditary angioedema . In: Expert Opinion on Biological Therapy . tape 19 , no. 6 , June 3, 2019, ISSN  1471-2598 , p. 517-526 , doi : 10.1080 / 14712598.2019.1595581 ( tandfonline.com [accessed February 12, 2020]).