Hereditary and acquired angioedema (acquired C1 inhibitor deficiency) is caused by a deficiency or dysfunction of C1 inhibitor, a protein that regulates the classical pathway of complement activation. The diagnosis is made through the measurement of complement concentrations. C1 inhibitor is used to treat acute attacks. Prophylaxis is performed with attenuated androgens, which increase C1 inhibitor levels. Deficiency or dysfunction of C1 inhibitor increases bradykinin concentrations because the C1 inhibitor inhibits activated kallikrein (necessary for the generation of bradykinin) in the kinin pathway.

Hereditary angioedema

Hereditary angioedema has 2 main types:

Type 1 (80 to 85%): Characterized by C1 inhibitor deficiency.

Type 2 (15-20%): Characterized by C1 inhibitor malfunction.

Inheritance is autosomal dominant. The clinical presentation is usually during childhood or adolescence.

A rare type of hereditary angioedema (hereditary angioedema type 3) is characterized by normal levels of C1 inhibitor. The prevalence of this type of hereditary edema is unknown; This type occurs mainly in women.

Acquired deficiency of C1 inhibitor.

C1 inhibitor deficiency can be acquired when

Autoantibodies against C1 inhibitors are produced in monoclonal gammopathies.

Rarely, an autoantibody against the C1 inhibitor is produced in autoimmune diseases (eg, systemic lupus erythematosus, dermatomyositis ).

The clinical presentation is usually in advanced age when patients have an associated disorder.

Triggers

In all forms of hereditary and acquired angioedema, attacks may be precipitated by

  • Mild trauma (eg, dental grooming, tongue piercing)
  • Viral disease
  • Exposure to cold
  • Pregnancy
  • Ingestion of certain foods
  • Angioedema can be aggravated by emotional stress.

Signs and symptoms

The symptoms and signs of hereditary and acquired angioedema are similar to those of other forms of bradykinin-mediated angioedema, with asymmetric and slightly painful inflammation that often involves the face, lips, and/or tongue. Inflammation can also occur on the backs of the hands or feet or the genitals. The gastrointestinal tract is usually involved, with manifestations suggesting intestinal obstruction, including nausea, vomiting, and colic.

No pruritus, urticaria, or bronchospasm develops, but laryngeal edema may be present, causing stridor (and sometimes death).

The inflammation resolves within about 1 to 3 days of onset. In hereditary angioedema, symptoms resolve when complement components are consumed.

Diagnosis

  • Detection of complement concentrations

· Concentrations of C4, C1 inhibitor, and C1q (a component of C1) are measured. 

· Decreased function of C1 inhibitor Other findings include

· Hereditary type 1 angioedema: low concentrations of C1 inhibitor and normal concentrations of C1q

· Hereditary type 2 angioedema: normal or elevated C1 inhibitor concentration and normal C1q concentration

· Acquired C1 inhibitor deficiency, low C1q concentrations.

· Hereditary angioedema type 3: normal levels of C1 and C4 inhibitor

If angioedema is not accompanied by urticaria and recurs without a clear cause, clinicians should suspect hereditary angioedema or acquired C1 inhibitor deficiency. If family members have the disease, doctors should suspect hereditary angioedema.

Treatment

· For the acute attack, C1 inhibitor, ecallantide 

· For attenuated androgen prophylaxis

Acute attacks are treated with purified human C1 inhibitor, ecallantide, or icatibant. If none of these medicines is available, fresh frozen plasma or tranexamic acid is used in the European Union. A recombinant form of C1 inhibitor (recombinant human C1 esterase inhibitor [rhC1INH], or alpha constant) is also available.

 However, the benefit may not be sufficient or it may be temporary; then endotracheal intubation may be required. Corticosteroids and antihistamines are not effective.

Pain relievers, antiemetics, and fluid replacement can be used to relieve symptoms.

Pearls and mistakes

   · Antihistamines and corticosteroids are not effective for inherited or acquired angioedema.

  For long-term prophylaxis, attenuated androgens (eg, stanozolol 2 mg three times a day vo, danazol 200 mg three times a day vo) are used to stimulate the hepatic synthesis of C1 inhibitor.  Short-term prophylaxis is indicated before high-risk procedures (eg, dental or airway procedures) if the C1 inhibitor is not available for the treatment of an acute attack. Patients generally receive attenuated androgens from 5 days before the procedure to 2 days after. If the C1 inhibitor is available, some experts suggest giving it 1 hour before high-risk procedures instead of attenuated androgens for short-term prophylaxis.

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