section name header

Information

Editors

HannaJarva
SeppoMeri

Hereditary Angioedema (HAE) and ACE Inhibitor-Induced Angioedema

Essentials

  • Consider the possibility of hereditary angioedema (HAE) in the differential diagnosis of anaphylactic reaction if the patient has, or has had
    • episodes of mucocutaneous oedema or
    • bouts of abdominal pain or
    • bouts of headache or
    • a family history of HAE.
  • Remember that angioedema is a possible adverse effect of ACE inhibitors.

HAE

Definition

  • Hereditary angioedema (HAE) is a rare illness transmitted as an autosomal dominant trait. It causes angioedema as a result of a deficiency or dysfunction of the C1-inhibitor (C1-INH) of the complement system.
  • The principal cause of the symptoms is bradykinin whose formation is normally prevented by C1-INH.
  • Used to be called HANE (hereditary angioneurotic oedema).

Symptoms

  • The patient typically presents with episodes of mucocutaneous oedema lasting for 1-5 days (pictures 1 2). The oedema may be accompanied by erythematous rash, whereas urticaria, pruritus and pain are not typical manifestations.
  • Oedema of the intestines causes attacks of abdominal pain which may be the only symptom. Vomiting and diarrhoea may occur.
  • If surgery is carried out for the abdominal pain, the operative findings will include oedematous intestines and copious amounts of ascites.
  • Laryngeal oedema may occur in up to 50% of the patients, and it might be the first sign of the illness. Laryngeal oedema may be life-threatening.
  • Urinary retention
  • Headache
  • Attacks may be triggered by trauma, injury to the skin, mental or physical stress, menstruation, ovulation or pharyngitis. ACE inhibitors and oestrogen may also trigger an attack (progestogen-only contraceptive pills may be used). Dental procedures and surgery around the head may induce laryngeal oedema. Often no triggering factors can be identified.
  • Symptoms may manifest themselves in childhood, youth or adulthood. Symptoms emerging in late adulthood or old age are suggestive of acquired angioedema (AAE) or angioedema associated with ACE inhibitors.

Diagnosis

  • History
    • Has the patient had similar episodes in the past?
    • Is there a family history of similar symptoms?
      • A third of the patients are the first ones in their family to be afflicted. A negative family history does therefore not exclude the possibility of HAE.
  • Laboratory investigations
    • C1-inhibitor concentration, biochemical C1-inhibitor function as well as C3 and C4. The measurement of C1-inhibitor concentration alone is not sufficient for the diagnosis or exclusion of the condition.
    • In Type I HAE (about 85% of HAE patients) the antigen levels and biochemical function of C1-INH as well as the concentration of C4 are decreased. The concentration of C3 is normal.
    • In Type II HAE (about 15% of HAE patients) the antigen levels of C1-INH are normal or higher than normal, but the biochemical function is markedly decreased. The concentration of C4 is decreased, but the concentration of C3 is normal.
    • HAE disease in which the concentration and activity of C1-INH is normal was earlier called type III HAE. The symptoms are typical for HAE, but C1-INH results are repeatedly normal. A mutation of factor FXII has been described in a small share of patients, in which case the condition is referred to as FXII-HAE . If the mutation is not found, but diagnostic criteria are fulfilled, the condition is referred to as U-HAE (HAE of unknown origin).
      • Recommended diagnostic criteria of U-HAE
        • Typical symptoms of HAE
        • One or more relatives with similar symptoms
        • Repeatedly normal results of C1-INH (including activity)
        • Other aetiologies of angio-oedema have been excluded
        • If additionally FXII mutation is present, the diagnosis is FXII-HAE.
  • In acquired C1-inhibitor deficiency (acquired angioedema, AAE), the symptoms generally first appear in midlife or later. Some patients suffer from B-cell lymphoma, cancer or an autoimmune disease which is associated with increased consumption of C1-INH. In others, the disease may be caused by C1-INH antibodies. C1-INH and C4 concentrations are decreased. In contrast to HAE, the concentration of C1q is decreased.
  • Since the condition is so rare, all patients with suspected HAE are referred to a specialist in internal medicine or in dermatology after the initial investigations.

Differential diagnosis: anaphylaxis or HAE?

  • Cutaneous oedema caused by an anaphylactic reaction Anaphylaxis and one caused by HAE may be of similar type.
  • Urticaria is often seen in an anaphylactic reaction but not in HAE.
  • During the attack, or 1-2 days before it, some HAE patients develop pink, delicate non-itching ring-shaped patches (erythema marginatum).
  • Anaphylactic reaction is a systemic reaction, whereas in HAE the life-threatening symptoms are caused by pharyngeal and laryngeal oedema: hoarse voice is the first symptom, after which the patient is unable to speak and may suffocate.
  • Adrenaline is effective in anaphylactic reaction but its effect is weak in an HAE attack.

Treatment of an attack

  • Treatment should be initiated as soon as possible after the onset of symptoms.
  • A purified C1 inhibitor (Berinert® , Cinryze® ) has been used also during pregnancy.
  • Mild oedema; limb oedema in particular: tranexamic acid 250 mg-1.5 g 2-3 times a day (max. 75 mg/kg a day)
  • Severe oedema; around the head and neck in particular, or severe abdominal pain
    • C1 esterase inhibitor (C1-INH) concentrate (Berinert® , Cinryze® ) 500-2 000 units as an intravenous infusion or recombinant C1-INH protein (Ruconest® ) 50 units per kg intravenously (4 200 units if the patient weighs more than 84 kg).
    • Icatibant (Firazyr® ) 30 mg s.c. Icatibant is a bradykinin 2 receptor antagonist with rapid onset of action and better effectiveness than tranexamic acid.
    • The patient may be trained to use C1-INH concentrate infusions or icatibant injections independently for the initial symptoms of an attack. Early onset of effective medication may prevent the worsening of the attack, and hospital admission may thus be avoided.
    • If C1-INH or icatibant is not available fresh frozen plasma may be administered (2-6 units, according to response).
    • Methyl prednisolone (40-)80 mg intravenously because some patients are also atopic.
    • The patient should be admitted to a hospital, and the staff should prepare for possible tracheal intubation.

Prophylaxis

  • If the patient has recurring, severe attacks with laryngeal oedema, prophylactic medication should be commenced with anabolic steroids (stanozolol or danazol). Stanozolol is not available in all countries, and the use of danazol for this indication may require special license. The starting dose of danazol is 400 mg per day, and the dose is subsequently decreased down to 50-200 mg per day, based on the response. Danazol is not suitable for children or pregnant women.
  • Tranexamic acid (0.5-1 g t.d.s.) is another alternative for prophylactic use.
  • In severe cases, C1-INH concentrate infusions 500-1 000 units once or twice weekly may be used. Before the treatment is started, a consultation with a specialist in dermatology or internal medicine familiar with the C1-INH concentrate therapy is recommended.
  • Short-term prophylactic medication should be instigated before dental or other surgical procedures (concentrated to university or central hospitals). Tranexamic acid (dose as above) is administered for 2 days prior to the procedure or danazol (200 mg × 3/24 h) for 5 days prior to the procedure. The prophylactic medication should then continue for 2 days after the procedure. C1-INH concentrate may also be used for prophylaxis, 500-1 500 units intravenously 1 hour before the procedure.
  • Prophylaxis cannot completely prevent attacks.

Angioedema caused by ACE inhibitor medication

  • With the increased use of ACE inhibitors the incidence of angioedema as their adverse effect has also increased. 0.1-0.5% of the users of ACE inhibitors get angioedema, and it may appear even several years after the initiation of the medication. Angiotensin-II receptor blockers can cause a similar reaction.
  • Tissue oedema occurs most often in the face, pharynx and larynx. The aetiological mechanism is based on the ACE inhibitor-mediated accumulation of bradykinin in the body; C1-INH is also a potent regulator of the bradykinin system.
  • Pharyngeal oedema is managed with adrenaline and intravenous glucocorticoids (for dosage seeAnaphylaxis).
  • In life-threatening situations C1 esterase inhibitor concentrate (Berinert® , Cinryze® ) may also be administered (500-2 000 units as an infusion).

References

  • Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet 2012;379(9814):474-81. [PubMed]
  • Craig TJ, Bernstein JA, Farkas H et al. Diagnosis and treatment of bradykinin-mediated angioedema: outcomes from an angioedema expert consensus meeting. Int Arch Allergy Immunol 2014;165(2):119-27. [PubMed]
  • Riedl MA. Hereditary angioedema with normal C1-INH (HAE type III). J Allergy Clin Immunol Pract 2013;1(5):427-32. [PubMed]
  • Cicardi M, Aberer W, Banerji A et al. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy 2014;69(5):602-16. [PubMed]