Aminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors

doi:10.1016/S0140-6736(02)08914-6

The Lancet

Volume 359, Issue 9323, 15 June 2002, Pages 2088-2089

https://doi.org/10.1016/S0140-6736(02)08914-6 Get rights and content

Summary

Angio-oedema is a rare but potentially life threatening side-effect of angiotensin-converting-enzyme (ACE) inhibitor treatment. Identification of individuals at risk of this adverse effect is not possible. Angio-oedema is associated with raised concentrations of bradykinin, which is mainly inactivated by ACE. We assessed the plasma activity of two other enzymes that catabolise bradykinin (aminopeptidase P and carboxypeptidase N) in 39 hypertensive patients with a history of angio-oedema during ACE inhibitor treatment and in 39 hypertensive patients who had never had ACE inhibitor associated side-effects. Patients with previous angio-oedema had a lower plasma activity of aminopeptidase P than did those who never presented with angio-oedema (p=0·003). Our data suggest that low plasma concentrations of aminopeptidase P could be a predisposing factor for development of angio-oedema in patients treated with ACE inhibitors.

References (5)

J Nussberger et al.
Plasma bradykinin in angio-oedema
Lancet
(1998)
A Agostoni et al.
Drug-induced angioedema without urticaria
Drug Saf
(2001)

There are more references available in the full text version of this article.

Cited by (163)

The Importance of Complement Testing in Acquired Angioedema Related to Angiotensin-Converting Enzyme Inhibitors
2021, Journal of Allergy and Clinical Immunology: In Practice
Angiotensin-converting enzyme inhibitors may cause angioedema. Currently, no laboratory method is available for identifying acquired angioedema related to angiotensin-converting enzyme inhibitors. However, establishing the diagnosis is possible from the medical history and the preexisting angiotensin-converting enzyme inhibitor therapy, as well as by excluding other angioedema types.
To evaluate the results of complement testing in patients experiencing angioedema while taking angiotensin-converting enzyme inhibitors.
Between 2005 and 2019, a total of 149 patients taking angiotensin-converting enzyme inhibitors were referred to our Angioedema Center for the diagnostic evaluation of recurrent angioedema episodes. Complement measurement was performed on these patients.
The mean age of the 149 patients treated with angiotensin-converting enzyme inhibitors at the onset of the index angioedema episode was 55.8 years. The mean interval between the introduction of angiotensin-converting enzyme inhibitor therapy and the occurrence of the initial symptoms of angioedema was 43 months. The most commonly used angiotensin-converting enzyme inhibitor was perindopril (32.9% of the patients). The initial angioedema episode involved the face in 50.3%, the lips in 40.9%, and the tongue in 33.5% of the patients. Angiotensin-converting enzyme inhibitors were discontinued in all 149 patients, and at the same time, a complement test was performed. The complement tests confirmed hereditary angioedema with C1-inhibitor deficiency in 2 patients and an additional 12 family members. Acquired angioedema with C1-inhibitor deficiency was found in 3 patients.
Excluding hereditary angioedema and acquired angioedema with C1-inhibitor deficiency is indispensable for establishing the diagnosis of acquired angioedema related to angiotensin-converting enzyme inhibitors.
ACE inhibitor-mediated angioedema
2020, International Immunopharmacology
Angioedema (AE) occurring during ACE inhibitor therapy (ACEi-AE) is a rare complication involving between 0.1 and 0.7% of treated patients. AE can also complicate other therapeutic regimens that block the renin-angiotensin aldosterone system. Other drugs, such as immune suppressors, some type of antidiabetics or calcium antagonists, can increase the likelihood of ACEi-AE when associated to ACEi. There is a clear ethnic predisposition, since African-Americans or Hispanics show a higher prevalence of this condition compared to Caucasians. At least in African-Americans the genetic predisposition accounts for a general higher prevalence of AE, independently from the cause. People that experience ACEi-AE may have some recurrence when they are switched to an angiotensin-receptor blocker (ARB); however, epidemiological studies on large cohorts have shown that angiotensin receptor blockers (ARB) do not increase the likelihood of AE compared to other antihypertensives. Clinical manifestations consist of edema of face, lips, tongue, uvula and upper airways, requiring intubation or tracheotomy in severe cases. Attacks last for 48–72 h and require hospital admission in most cases. Intestinal involvement with sub-occlusive symptoms has also been reported.
The pathogenesis of ACEi-AE depends mainly on a reduced catabolism and accumulation of bradykinin, which is normally metabolized by ACE. Genetic studies have shown that some single nucleotide polymorphisms at genes encoding relevant molecules for bradykinin metabolism and action may be involved in ACEi-AE, giving a basis for the ethnic predisposition. Treatment of ACEi-AE is still a matter of debate. Corticosteroids and antihistamines do not show efficacy. Some therapeutic attempts have shown some efficacy for fresh frozen plasma or C1 inhibitor concentrate infusion. Interventional studies with the specific bradykinin receptor antagonist icatibant have shown conflicting results; there might be a different ethnic predisposition to icatibant efficacy which has been proven in caucasian but not in black patients.
Biological diagnosis of bradykinin mediated angioedema: CREAK recommendations
2019, Presse Medicale
Les angioedèmes (AE) bradykiniques sont soit associés à un déficit héréditaire ou acquis en C1Inhibiteur (C1Inh) soit associés à un C1Inh normal dans certaines formes héréditaires et en cas d’iatrogénie (AE secondaire aux inhibiteurs de l’enzyme de conversion de l’angiotensine). Quand il existe une forte suspicion clinique d’angioedème bradykinique, une exploration de C1Inh doit être réalisée. Cette exploration doit toujours comporter un dosage fonctionnel et pondéral de C1Inh ainsi qu’un dosage du C4. Un déficit pathologique en C1Inh peut être affirmé lorsque les taux sont inférieurs à 50 % des valeurs normales sur 2 prélèvements distincts. Si le déficit en C1Inh se confirme, des examens plus approfondis doivent être réalisés afin de déterminer le caractère héréditaire ou acquis du déficit. Le dosage du C1q et la recherche d’un anticorps anti-C1Inh peuvent alors être proposés. La recherche d’une mutation sur le gène SERPING1 s’impose, même en l’absence d’antécédents familiaux. L’absence de déficit en C1Inh n’exclut pas un angioedème héréditaire. Dans ce cas-là, après validation du tableau clinique par un expert du CREAK, la recherche de mutation sur les gènes F12 et PLG sera proposée.
Bradykinin mediated angioedema (BK-AE) can be associated either with C1Inhibitor deficiency (hereditary and acquired forms), either with normal C1Inh (hereditary form and drug induced AE as angiotensin converting enzyme inhibitors…). In case of high clinical suspicion of BK-AE, C1Inh exploration must be done at first: C1Inh function and antigenemy as well as C4 concentration. C1Inh deficiency is significant if the tests are below 50 % of the normal values and controlled a second time. In case of C1Inh deficiency, you have to identify hereditary from acquired forms. C1q and anti-C1Inh antibody tests are useful for acquired BK-AE. SERPING1 gene screening must be done if a hereditary angioedema is suspected, even if there is no family context (de novo mutation 15 %). If a hereditary BK-AE with normal C1Inh is suspected, F12 and PLG gene screening is suitable.
Cardiovascular and Diabetic Medications That Cause Bradykinin-Mediated Angioedema
2017, Journal of Allergy and Clinical Immunology: In Practice
Citation Excerpt :
When ACE is inhibited, as in the use of ACEi, the other degrading enzymes play a larger role in the breakdown of bradykinin. Therefore, individuals who have decreased activity in one or more of these enzymes (ie, APP, dipeptidyl peptidase IV) have a higher risk for ACEi-induced angioedema.14 Genetic polymorphisms in these degradation enzymes may explain why Americans of African heritage are at increased risk for angioedema.15
Medication-induced angioedema is a bradykinin-mediated process that results from increased production or decreased degradation of bradykinin. These reactions are documented for several cardiac medications including blockers of the renin-angiotensin-aldosterone system (RAAS). Other cardiovascular and diabetes medications further increase the risk of medication-induced angioedema, particularly with concomitant use of RAAS inhibitors. Dipeptidyl peptidase IV inhibitors are a class of oral diabetic agents that affect bradykinin and substance P degradation and therefore can lead to angioedema. Neprilysin inhibitors are a separate class of cardiac medications, which includes sacubitril, and can lead to drug-induced angioedema especially when used in combination with RAAS inhibitors. This article discusses the proposed mechanisms by which these medications cause angioedema and how medication-induced angioedema differs from mast cell-mediated angioedema. It also details how to recognize medication-induced angioedema and the treatment options available.
The Angiotensin-Converting-Enzyme-Induced Angioedema
2017, Immunology and Allergy Clinics of North America
PGX: Pharmacogenomics During Generation X
2016, Advances in Chronic Kidney Disease

View all citing articles on Scopus

View full text

Research LettersAminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors

Summary

Lancet

Drug-induced angioedema without urticaria

Drug Saf

Research Letters
Aminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors