Hereditary Angioedema Flashcards
Hereditary Angioedema
Hereditary angioedema is an autosomal dominant condition associated with low plasma levels of the C1 inhibitor (C1-INH) protein. C1-INH is a multifunctional serine protease inhibitor - the probable mechanism behind attacks is uncontrolled release of bradykinin resulting in oedema of tissues.
Investigation
C1-INH level is low during an attack
low C2 and C4 levels are seen, even between attacks. Serum C4 is the most reliable and widely used screening tool
Symptoms
attacks may be proceeded by painful macular rash
painless, non-pruritic swelling of subcutaneous/submucosal tissues
may affect upper airways, skin or abdominal organs (can occasionally present as abdominal pain due to visceral oedema)
urticaria is not usually a feature
Management
acute: IV C1-inhibitor concentrate, fresh frozen plasma (FFP) if this is not available
prophylaxis: anabolic steroid Danazol may help
Hereditary Angioedema - Example Question
A 16-year-old female was admitted with new onset facial swelling. The facial swelling started 45 minutes ago and initially involved her lips. She complained of a sensation of choking and a feeling of being unable to speak with hoarseness of her voice. She had been investigated on multiple occasions for abdominal pain and was diagnosed with non-specific abdominal pain. She was not taking any medication and was otherwise healthy prior to the admission.
She was given prednisolone 40mg PO and chlorpheniramine 10mg PO and admitted for observation. Whilst in the department she developed profound shortness of breath with associated stridor. Her swelling around her lips worsened and involved the whole of her face. On examination, she was in respiratory distress with severe biphasic stridor. Her respiratory rate was 32/min with an oxygen saturation of 88% on air. Auscultation of her chest also revealed the presence of a widespread polyphonic wheeze. Examination of her cardiovascular system revealed the presence of flushed peripheries with a bounding peripheral pulse. Her pulse was 102bpm and her blood pressure was 92/68 mmHg. Her GCS was 15 and neurological and abdominal examinations were unremarkable. She was cannulated and commenced on stat intravenous colloid solution. She was given adrenaline 0.5mg IM on three separate occasions within 10 minutes with no improvement. She was transferred immediately to the Intensive Care Unit and an anaesthetist fast bleeped to secure her airway.
What is the best immediate management step pending definitive airway management?
Commence IV adrenaline infusion Commence danazol Commence IV dopamine Commence fresh frozen plasma infusion > Commence C1 esterase inhibitor concentrate infusion
This patient has hereditary angioedema. This condition is characterised by a lack of C1 esterase inhibitor and may present with laryngeal oedema, recurrent abdominal pain and localised subcutaneous swelling. Laryngeal oedema may be fatal, does not respond to glucocorticoids or antihistamines, and has an only modest response to adrenaline. The immediate management is to commence C1 esterase inhibitor concentrate infusion. Fresh frozen plasma infusion may be administered if the concentrate is not available. Danazol is more suitable for subcutaneous oedema or as prophylaxis in certain situations eg prior to surgery.
Hereditary Angioedema - Pathogenesis
Hereditary angioedema (HAE) is an autosomal dominantly inherited immune condition characterised by episodic swelling of the extremities, intra-abdominal viscera and mucous membranes. Often attacks are unprecipitated although sometimes exogenous oestrogens in the form of contraception can be traced, as well as exposure to angiotensin converting enzyme inhibitors. The primary pathophysiological defect is in the complement cascade and deficiencies in factors C4 and C1-esterase inhibitor are seen in type I. In type II HAE C1-esterase inhibitor levels are normal but the enzyme is dysfunctional and activity is low. An acquired form of HAE is described in which all complement levels are low. In type III HAE the clinical features of angioedema are present but immunological testing reveals normal levels and activity of complement factors. Ultimately, failure of C1-esterase inhibitor leads to upregulation of the rest of the complement system and membrane attack complex, but also it leads to activation of the signalling protein kallikrein which acts directly on the vascular wall to increase permeability, and it cleaves high molecular weight kininogen to release bradykinin, again a potent peripheral vasodilator giving rise to the symptoms of HAE.
Hereditary angioedema vs Anaphylaxis
HAE should be recognised as a separate entity from anaphylaxis since the clinical signs are different, as is the pathophysiology of the condition and its treatment. Anaphylaxis is an IgE mediated immune phenomenon related to a specific allergen causing massive mast cell degranulation and histamine release. HAE is driven by complement dysregulation and consequent release of the inflammatory cytokines bradykinin and kallikrein. Anaphylaxis is characterised by rapidly progressive, itchy, erythematous, oedematous rash, swelling of the lips, tongue and airways with accompanying hypovolaemic hypotension and cardiovascular collapse due to increased tissue permeability. Anaphylaxis is a medical emergency and death can ensue in minutes unless treated properly. HAE in comparison may present recurrently and often with no obvious precipitant. Usually its course is more insidious with evolution of symptoms over minutes to hours. Swelling will often only affect an isolated limb and it is not itchy or painful and minimally erythematous. Hypotension is rarely seen and cardiovascular instability is extremely unlikely. HAE can be fatal however if swelling of the upper airways causes obstruction, and in some cases prophylactic intubation and mechanical ventilation may be appropriate. Since the driving mechanism is not histamine in HAE, steroids and antihistamines are of no value. Where there is no haemodynamic compromise, adrenaline is not warranted and may even worsen the situation due to increased plasma glucose load and risk of capillary rupture.
Hereditary Angioedema - Mx
Knowledge of the cytokine cascade in HAE allows for knowledge of its management. Since the initiating pathophysiological hallmark is deficiency or reduced effectiveness of C1-esterase inhibitor, exogenous administration of synthetic or reconstituted inhibitor should be effective.
National guidelines released in 2013 recommend treatment of episodes of HAE with administration of reconstituted human C1-esterase inhibitor. In the UK two brands are available; either Cinryze which is dosed at 1000 unit administration or Berinert at 20 units/kg. Both are administered as slow intravenous infusions. Interestingly, good clinical response is often seen to these drugs even in HAE type III where C1-esterase levels are normal.
An alternative to exogenous C1-esterase inhibitor is icatibant which is a specific antagonist at B2 bradykinin receptors in vascular smooth muscle. The 30mg dose may be repeated up to three times in 24 hours but rapid resolution of symptoms is often seen. Many patients with HAE are supplied with their own icatibant autoinjectors for use in the pre-hospital setting at the onset of symptoms.
Ecallantide is a selective inactivator of the cytokine kallikrein. It is highly effective in the treatment of HAE in the United States but has no European licence at this current time.
Hereditary Angioedema - Pathogenesis: Example Question
A 27 year old woman presents to the Emergency Department with a sudden onset of swelling of the hands and face. She describes multiple similar episodes over the past few years, but this episode is the most severe. She cannot recall any obvious precipitant. On previous occasions the symptoms have subsided within thirty minutes but on this occasion they have worsened over the course of an hour. On examination, there is significant swelling of the lips which are dry and shiny. The tongue is not enlarged. There is no stridor and the chest is clear. Respiratory rate is 22 and oxygen saturations are 96% on air. The hands are swollen and slightly erythematous but there is no pain or itching and no lymphadenopathy. Heart rate is 106bpm and blood pressure is 118/79mmHg. Tympanic temperature is 36.7°C. A diagnosis of hereditary angioedema is suspected.
Which one of the following is not implicated in the pathogenesis of hereditary angioedema?
C1-esterase inhibitor Bradykinin > Histamine Kallikrein High molecular weight kininogen
Hereditary angioedema (HAE) is pathophysiologically separate from anaphylaxis and is treated differently. Therapeutic options are: intravenous infusion of human C1-esterase inhibitor or subcutaneous injection of the bradykinin receptor inhibitor icatibant
Hereditary Angioedema and Laryngeal swelling
This condition is characterised by a lack of C1 esterase inhibitor and may present with laryngeal oedema, recurrent abdominal pain and localised subcutaneous swelling.
TRIAD: Laryngeal oedema, Recurrent abdo pain + Localised subcut swelling
Laryngeal oedema may be fatal, does not respond to glucocorticoids or antihistamines, and has an only modest response to adrenaline.
The immediate management is to commence C1 esterase inhibitor concentrate infusion. Fresh frozen plasma infusion may be administered if the concentrate is not available. Danazol is more suitable for subcutaneous oedema or as prophylaxis in certain situations eg prior to surgery.
