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Internal Medicine

Angioedema

Localized and self‐limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s).

Introduction

Localized and self‐limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s).

  • Urticaria and/or angioedema has been reported in up to 20% of the general population. In addition, 40-50% of patients with chronic urticaria have angioedema.

History:

Although urticaria was first reported approximately 200 BC, angioedema itself was not described until the 1500’s. The term ‘angioedema’ was first coined in 1586. In the 19th century, a case of HAE was reported in a family where the common cause of death was ‘fatal suffocation’. Angioedema received further recognition in the 1960’s after cases were reported dating to the 17th century from Swedish church records, where it was common to register cause of death. In 1963, it was discovered that patients with HAE possessed low levels of C1 INH. First described in 1972, acquired angioedema was initially characterised by angioedema symptoms, C1-INH deficiency and hyperactivation of the complement pathway.


Aetiology

Angioedema is caused by a rapid increase in permeability of submucosal or subcutaneous capillaries and post-capillary venules with localized plasma extravasation. Most causes of angioedema are dependent upon the release of either histamine or bradykinin; other vasoactive substances may be contributory.

Classification of Angioedema | Institut FüR Medizinische Diagnostik Berlin-Potsdam. (2020) IMD Institut für medizinische Diagnostik, Labor: Diagnostics of Hereditary Angioedema. Retrieved February 07, 2020, from https://www.imd-berlin.de/en/subject-information/diagnostics-information/diagnostics-of-hereditary-angioedema.html
Epidemiology of angioedema, from left to right with decreasing frequency | ACE, angiotensin converting enzyme; HAE, hereditary angioedema | Hahn, J., Hoffmann, T. K., Bock, B., Nordmann-Kleiner, M., Trainotti, S., & Greve, J. (2017). Angioedema. Deutsches Arzteblatt international, 114(29-30), 489–496. https://doi.org/10.3238/arztebl.2017.0489

Histamine-mediated angioedema:

Mast-cell mediated angioedema results from IgE-mediated degranulation of mast cells. The majority of cases are associated with urticaria and/or pruritus. Anaphylaxis is a severe example of this type of angioedema, which is preceded by exposure to an allergen. Allergic reactions without anaphylaxis can also give rise to angioedema.
  • IgE-mediated allergic reactions (such as to food, drug, or environmental triggers)
  • Nonsteroidal anti-inflammatory drug (NSAID) use (including aspirin)
  • Chemically-induced histamine release (most commonly opiates, highly cationic antibiotics, and muscle relaxants)
Mechanism of mast cell versus bradykinIgE-mediated allergic reactions (such as to food, drug, or environmental triggers)
Nonsteroidal anti-inflammatory drug (NSAID) use (including aspirin)
Chemically-induced histamine release (most commonly opiates, highly cationic antibiotics, and muscle relaxants)in mediated angioedema. | The Mayo Foundation for Medical Education and Research | Misra, L., Khurmi, N., & Trentman, T. L. (2016). Angioedema: Classification, management and emerging therapies for the perioperative physician. Indian journal of anaesthesia, 60(8), 534–541. https://doi.org/10.4103/0019-5049.187776

Bradykinin-mediated angioedema:

Mechanistically, activated factor XII cleaves prekallikrein to produce kallikrein
Plasma kallikrein then cleaves kininogen to release bradykinin, which binds to B2 receptors on endothelial cells. To modulate bradykinin production, C1 INH inhibits plasma kallikrein and activated factor XII. If C1 INH is deficient in quantity or quality, an uninhibited contact system will produce excess bradykinin.
  • Hereditary angioedema (HAE): Rare genetic disorder caused by deficiency of C1 esterase inhibitor (C1-INH) and characterized by recurrent episodes of severe swelling that affect the limbs, face, intestinal tract and airway.
  • Acquired C1-inhibitor deficiency (AAE)
  • ACE inhibitor-associated angioedema (M/C cause)
C1 inhibitor plays essential regulatory functions in the contact (kallikrein-kinin) system and in the complement system. Biologic effects of bradykinin, a mediator of angioedema, are also depicted. Dotted lines represent inhibitory pathways. MASP, mannose-binding lectin–associated serine protease. | A Girl with Severe Hand Swelling and Abdominal Cramps – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/C1-inhibitor-plays-essential-regulatory-functions-in-the-contact-kallikrein-kinin_fig1_23289842 [accessed 7 Feb, 2020]

Clinical features

Angioedema has multiple subtypes, but at their core is a temporary increase in endothelial permeability which in turn leads to plasma extravasation in the deeper layers of the dermis and submucosa.

Prodromal symptoms (87–95% cases):

  • Tingling sensation in affected area 1-2 hours before episode
The serpiginous, nonpruritic rash of erythema marginatum, which precedes an attack of hereditary angiodema in one-third of patients. The rash is characterized by red rings that appear on the trunk and appendages as part of a prodrome that may also include a tingling sensation in the area where swelling will occur. | Zuraw BL. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-1036., US Hereditary Angioedema Association.

Hallmark manifestation:

  • Abrupt nonpitting swelling of the skin, mucous membranes, or both, including the upper respiratory and gastrointestinal tracts, which typically lasts from many hours to 3 days. The involved tissues then return to normal.
  • Sites of predilection: Face, hands, feet, and genitalia. Lip and eye (periorbital) swelling are the most common.
  • Swelling of the tongue, pharynx, and larynx is particularly problematic. Fatalities can occur because of laryngeal edema, but pharyngeal edema and tongue swelling can be similarly disastrous if they are massive.
m_28fig2
A young woman before (left) and during (right) an episode of facial hereditary angiodema. Such attacks cause disfigurement that can reduce a patient’s quality of life and social interaction. Patients are at risk of asphyxiation from laryngeal involvement during facial attacks. | US Hereditary Angioedema Association.

Other manifestations:

Clinical symptoms and diagnostic evaluation of bradykinin-mediated and mast cell–mediated angioedema | ACE, angiotensin converting enzyme; C1INH conc & act, esterase inhibitor concentration and activity; C4 comp, C4 complement; C1q comp, C1q complement; DPPIV, dipeptidyl peptidase IV; n-C1INH, hereditary angioedema (HAE) with normal C1 esterase inhibitor values; +/– FXII mut, with or without mutation of Factor XII; ?, lowered; ?, raised; =, constant; +, positive; = /?, constant or raised | Hahn, J., Hoffmann, T. K., Bock, B., Nordmann-Kleiner, M., Trainotti, S., & Greve, J. (2017). Angioedema. Deutsches Arzteblatt international, 114(29-30), 489–496. https://doi.org/10.3238/arztebl.2017.0489

Histamine vs bradykinin-mediated angioedema:

A distinguishing feature of histaminic/allergic angioedema is its ‘temporal’ relationship to a trigger. The onset of symptoms is typically rapid – minutes to a few hours after exposure. Typically, mast cells are not involved in bradykinin-induced angioedema thus, pruritus and urticaria are noticeably absent. Increased vascular permeability is caused by bradykinin, resulting in contraction of non-vascular smooth muscle, vasodilation and oedema formation. In addition to the typical locations of swelling, bradykinin-induced angioedema affects the gastrointestinal mucosa.
Distinguishing histamine- versus bradykinin-mediated angioedema | Bernstein, J. A., Cremonesi, P., Hoffmann, T. K., & Hollingsworth, J. (2017). Angioedema in the emergency department: a practical guide to differential diagnosis and management. International journal of emergency medicine, 10(1), 15. https://doi.org/10.1186/s12245-017-0141-z
Schematic representation of angioedema attack onset and duration. Histamine-mediated angioedema attacks tend to have rapid onset and resolution. Bradykinin-mediated angioedema usually develops more slowly and can persist for ≤5 days, although angiotensin-converting enzyme inhibitor (ACEi)–induced angioedema will usually resolve ≤48 h once the drug is discontinued | Bernstein, J. A., Cremonesi, P., Hoffmann, T. K., & Hollingsworth, J. (2017). Angioedema in the emergency department: a practical guide to differential diagnosis and management. International journal of emergency medicine, 10(1), 15. https://doi.org/10.1186/s12245-017-0141-z

Diagnosis

In order to determine the etiology of angioedema, a detailed medical history must be taken with particular attention to identifying possible triggers, as well as the medication history and family history.

Flow diagram of diagnosis of angioedema in the emergency department | ACEi angiotensin-converting enzyme inhibitor, HAE hereditary angioedema | Moellman JJ, Bernstein JA, Lindsell C, Banerji A, Busse PJ, Camargo CA, Jr., et al.; American College of Allergy Asthma & Immunology (ACAAI); Society for Academic Emergency Medicine (SAEM). A consensus parameter for the evaluation and management of angioedema in the emergency department. Acad Emerg Med. 2014;21:469–84 | Jaiganesh T, Wiese M, Hollingsworth J, Hughan C, Kamara M, Wood P, et al. Acute angioedema: recognition and management in the emergency department. Eur J Emerg Med. 2013;20:10–7. doi: 10.1097/MEJ.0b013e328356f76e.

Lab studies:

  • Type I HAE (85% cases): Quantitative C1INH deficiency (which is functionally abnormal as well)
  • Type II HAE (15% cases): Functionally abnormal C1INH
  • Type III HAE (rare): Resembles Type I & Type II HAE but complement levels, including C1 inhibitor, are normal
  • Acquired C1 inhibitor deficiency (ACID): Low C1q levels. In contrast, patients with ACE-induced, idiopathic, and allergic AE have normal complement profiles.3,6
  • Type I & II HAE and ACID: C4 & C2 levels are low during and between attacks.
Clinical characteristics and laboratory markers that can be used to distinguish among hereditary angioedema (HAE) subtypes and other conditions with similar symptoms. Approved and off-label treatments are also shown. Abbreviations: | ACE, angiotensin-converting enzyme; AE, angioedema; C1-INH, C1 inhibitor; C1q, C3, and C4, complement proteolytic cascade proteins; FDA, Food and Drug Administration; IgM, immunoglobulin M. | Weis. Postgraduate Medicine is a registered trademark of JTE Multimedia LLC, 1235 Westlakes Dr, Suite 320, Berwyn, PA 19312, (630) 889-3730.

Differential diagnosis:

Diagnostic algorithm for patients presenting with wheals, angioedema, or both: a) Autoinflammatory diseases are the result of uncontrolled activation of the innate immune system including Schnitzler syndrome, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndromes, etc. | The EAACI/GA 2 LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update, ” by Zuberbier T, Aberer W, Asero R, Bindslev- Jensen C, Brzoza Z, Canonica GW, et al, 2014, Allergy, 69, p. 868e87. Copyright 2014. John Wiley & Sons A/S. Adapted with permission.
Location of extravasated fluid in hives versus angioedema. | The Mayo Foundation for Medical Education and Research
Common signs of hives versus angioedema. | The Mayo Foundation for Medical Education and Research

Management

Acute episodes of allergic angioedema are exquisitely responsive to therapy with anti-histamines, oral corticosteroids, and epinephrine; while other forms are refractory to this conventional therapy and may take hours to days to resolve. In all instances, particular attention must be paid to airway maintenance if the patient is experiencing tongue or laryngeal involvement. Supportive care should also include pain management and hydration if abdominal symptoms are predominant. Prompt removal of any suspected triggers is warranted.

Algorithm for angioedema management. | IV, intravenous; IM, intramuscular; ACEi, angiotensin converting enzyme inhibitor; FFP, fresh frozen plasma; ICU, intensive care unit. | Long, B. J., Koyfman, A., & Gottlieb, M. (2019). Evaluation and Management of Angioedema in the Emergency Department. The western journal of emergency medicine, 20(4), 587–600. https://doi.org/10.5811/westjem.2019.5.42650

Medication management focuses on three aspects: acute episode management, short-term prophylaxis, and long-term prophylaxis, with ED management focusing on the acute episode.

Histamine-mediated angioedema:

histamine-mediated angioedema i
  • Epinephrine
  • Steroids
  • Antihistamines
  • IV fluids

Bradykinin-mediated angioedema:

Treatment is unique from angioedema associated with histamine since antihistamines, corticosteroids, and epinephrine have little effect on the swelling. Instead, medications that either inhibitor production of bradykinin or compete with the receptor are utilized.
  • C1-INH concentrates: Provide plasma protein that regulates kallikrein and Factor XII activity, reducing bradykinin production.
    • Plasma-derived: Berinert, Cinryze
    • Recombinant: Ruconest
  • Kallikrein inhibitor: Ecallantide (Kalbitor), berotralstat
    • Reduces bradykinin synthesis by preventing the cleavage of kininogen
  • Bradykinin-2-receptor antagonist: Icatibant acetate (Firazyr)
    • Selective and competitive bradykinin B2 receptor antagonist
    • Fresh frozen plasma (FFP): Contains varying amounts of C1-INH.

Short-term prophylaxis of bradykinin-mediated angioedema:

Induce production of C1-inhibitor and are very effective in preventing attacks, but have no benefit in treating an attack.
  • Androgens: Danocrine
  • Antifibrinolytics: Tranexamic acid and aminocaproic acid

Summary:

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