Hereditary angioedema (HAE) is an autosomal dominant disorder of C1 inhibitor (C1-INH) deficiency manifested by painless, nonpruritic, and nonpitting swelling of the skin. In hereditary angioedema, specific stimuli that have previously led to attacks may need to be avoided in the future. Individuals with hereditary angioedema may also have systemic lupus erythematosus or other autoimmune disorders.

Clinical types

• Type I HAE is defined by low plasma levels of a normal C1-INH protein.
• Type II HAE is characterized by the presence of normal or elevated levels of a dysfunctional C1-INH.
• Type III HAE has been recently identified as an estrogen-dependent inherited form of angioedema occurring mainly in women with normal functional and quantitative levels of C1-INH.

Causes

Precipitating factors

• Trauma (especially dental trauma)
• Anxiety
• Menstruation
• Infection
• Exercise
• Alcohol consumption
• Stress
• Medications (eg, estrogen, ACE inhibitors, and angiotensin II type 1 receptor antagonists) have also been shown to induce attacks

 

During pregnancy, symptoms may increase or decrease for HAE types I and II. In HAE type III, studies have reported first episodes or recurrences associated with estrogen-containing oral contraceptives, estrogen replacement therapy, or pregnancy.

As many as 2% of patients with HAE may have systemic lupus erythematosus. Less commonly, other autoimmune disorders, such as glomerulonephritis, rheumatoid arthritis, thyroiditis, Sjögren syndrome, and pernicious anemia, may be associated with HAE.

Those HAE patients infected with Helicobacter pylori have been found to be more symptomatic than those who are not infected.

Clinical history

A family history of HAE is typically obtained, although spontaneous mutations may occur.

Symptoms are referable to 3 prominent sites:

• Subcutaneous tissues (face, hands, arms, legs, genitals, and buttocks)
• Abdominal organs (stomach, intestines, bladder, and kidneys), which may manifest as vomiting, diarrhea, or paroxysmal colicky pain and mimic a surgical emergency
• Upper airway (larynx) and tongue, which may result in laryngeal edema and upper airway obstruction

other symptoms

• Mucosal edema of the bladder or urethra can result in urinary retention, stammering, pain, or anuria.
• Episodes of severe headaches, visual disturbances (eg, blurred vision, diplopia), and ataxia have been reported.
• Painful muscle swelling and unilateral hip or shoulder involvement have also been cited.
• Attacks may be preceded several hours in advance by sudden mood changes, anxiety, sensory changes, or exhaustion.
• Pediatric episodes are usually less frequent and commonly manifest as abdominal involvement.
• In approximately 25% of patients, erythematic may precede the occurrence of edema. An estimated 30-50% of patients with HAE reportedly have erythema marginatum preceding or accompanying the attacks.

Tests and diagnosis

• Diagnosis of type I HAE is confirmed by blood tests showing reduced  levels of C1-INH and low levels of C2 and C4. C1q levels are normal.
• Diagnosis of type II HAE is confirmed by blood tests showing normal or elevated levels of C1-INH and low levels of C2 and C4. C1q levels are normal.
• Type III the levels of C1-INH, C2, and C4 are normal.C1q levels are normal.
• Abdominal radiographs and ultrasound may show edematous thickening of the intestinal wall, a fluid layer around the bowel, and large amounts of free peritoneal fluid.
• Chest X-ray demonstrates pleural effusion

Treatment

Medical care in acute angioedema

In cases of serious laryngeal edema causing respiratory obstruction, intubation or tracheostomy should be performed.

In HAE types I and II, the treatment of choice in acute attacks consists of replacement with commercially available C1-INH concentrates or, if unavailable, fresh-frozen plasma. In HAE type III, infusion of C1-INH has proven to be ineffective.

Medicine usually used to treat swelling, such as corticosteroids (like prednisone), antihistamines, and epinephrine are not effective in treating hereditary angioedema attacks.

Prophylaxis

Long term prophylaxis

• Danazol or stanozolol (male sex hormone- androgens) may be used at doses that prevent attacks.
• The most significant complication of long-term use may be arterial hypertension.
• Regular monitoring of liver function test results, lipid levels, and liver ultrasonography findings is recommended.
• Although virilization may be an issue with women, keeping to the lowest possible dose usually obviates this concern.
• Contraindications to the use of androgens include prostate cancer, pregnancy, childhood, and breastfeeding.
• Antifibrinolytic agents such as epsilon-aminocaproic acid or tranexamic acid can also be used for prophylaxis, although they have not been found to be as effective as the androgenic agents. These agents are the option for pregnant women.

Short term prophylaxis

• Short-term prophylaxis for surgical procedures, especially dental work, is necessary.
• C1-INH infusions can be given 24 hours before the procedure or just prior to it.
• Alternatives, such as antifibrinolytics or androgens, can be used, and they should be started 5 days before the procedure and continued for 2 days afterwards.

 

Eradication of the underlying cause of the attack, such as H pylori or another infectious agent, may lead to resolution of symptoms.

Careful attention should be given to medications being taken by the patient that may have contributed to an attack, such as contraceptives, hormone replacement therapy, or ACE inhibitors.

New treatment options

• Recombinant human C1-INH- cinryze
• Ecallantide is a peptide inhibitor of kallikrein that has received orphan status for HAE
• Bradykinin-2 receptor antagonist (icatibant), may offer safer and more effective treatment options