Hereditary Angioedema

Etiology

Type I hereditary angioedema (HAE) (HAE with deficient C1-inhibitor) is due to a deficiency in C1 inhibitor. C1 inhibitor is a broad-spectrum serine protease inhibitor that's a member of the serpin superfamily. It inhibits several complement proteases (C1r, C1s, MASP-1, and MASP-2) and contact system proteases (plasma kallikrein and activated Hageman factor [coagulation factors XIIa and XIIf], fibrinolytic protease plasmin, and the coagulation protease factor XIa). C1 inhibitor deficiency is due to mutations in the SERPING1 gene. More than 150 different mutations have been identified in patients with HAE. In type I HAE, the different SERPING1 mutations identified were missense, nonsense, frameshift, deletion, and insertion. This results in truncated or misfolded proteins that eventually cannot be secreted; hence a deficiency in C1 INH levels characterizes type 1. While in type 2 (HAE with dysfunctional C1-inhibitor), SERPING1 mutations associated with it include residues at or near the active site on the reactive mobile loop that result in a mutant C1 inhibitor protein secreted but dysfunctional. For this reason, in type II HAE, the C1 INH antigen level in plasma is normal or even elevated while the protein function is decreased.[1]

Epidemiology

The estimated prevalence is 1 in 50,000.[2][3] The presentation is usually during the first two decades of life, which varies from acquired angioedema with deficient C1-inhibitor that often presents after the fourth decade of life.  A family history of angioedema helps in the diagnosis, but 25% of cases are new spontaneous mutations. Genetic testing is usually not essential since the biologic tests are relatively accurate after the age of 1 year.

History and Physical

The symptoms vary in severity, location, and duration, but the organs involved include the upper airway, skin, and gastrointestinal tract. In the latter, bowel obstruction creates the symptoms. The skin swelling is deforming but not pruritic; however, if extreme can be painful. The main fear is upper airway swelling that can proceed to asphyxiation. Fortunately, upper airway involvement accounts for only 1 to 3% of attacks.

The attacks last 2 to 5 days, usually slowly increasing and then resolving even without therapy.  Triggers, such as trauma, infections, stress, or procedures, are identified in 40% of attacks. Prodromal symptoms, including a rash, referred to as erythema marginatum, occur before the majority of attacks, but the sensitivity and especially specificity are questionable. Other triggers include ACE inhibitors and estrogens.[4][3]

Evaluation

The tests that are used include C4, which is commonly the initial screening test.[5][6] The confirmatory tests include C1-inhibitor protein and function, which are both low in type 1 HAE. Type 2 HAE has a low function, but normal or excessive quantity of C1-inhibitor that is defective. Type 3 HAE has all normal tests and at this time appears to be composed of patients with a gain of function of Factor 12 of the coagulation pathway and other poorly defined groups of patients that appear to have angioedema from bradykinin but of unknown mechanism. C1q is usually reserved for those with the late-onset disease to exclude acquired angioedema since it is low in most cases of acquired angioedema with deficient C1-inhibitor but normal in HAE. In all the diseases described above, the cause of the swelling is secondary to overproduction of bradykinin. Angiotensin-converting enzyme inhibitors (ACE-I) also cause angioedema, but in this case, secondary to the lack of catabolism of bradykinin.

Treatment / Management

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. [7][8]Most experts divide therapy into 3 types: treatment of attacks, short-term prevention of attacks, and long-term prevention of attacks. The drugs used for treating attacks include ecallantide, icatibant, C1-inhibitor derived from human plasma, or recombinant C1-inhibitor. In addition, fresh frozen plasma can be used but is avoided due to allosensitization unless one of the previous drugs is not available. Because of the short half-life of icatibant and ecallantide, neither are effective in preventing attacks. C1-inhibitor obviously works by replacing the dysfunctional or deficit C1-inhibitor, and it has a long half-life and can be used for the treatment of attacks, short-term prophylaxis, such as before a procedure, and long-term prophylaxis to prevent attacks when indicated. Similarly, recent data demonstrate that recombinant C1-inhibitor can be used for attacks and long-term prophylaxis, and most experts suspect it is also effective for short-term prophylaxis.[1]

Two other therapies, which have recently fallen out of favor, include antifibrinolytics and androgens. Androgens induce the production of C1-inhibitor and are very effective in preventing attacks but have no benefit in treating an attack. Short-term prophylaxis is tolerated well and is effective for pre-procedure of other short-term events; however, the toxicity of androgens limits their use for long-term prophylaxis. Most experts recommend not exceeding 200 mg of danocrine a day. Adverse effects include hyperlipidemia, obesity, androgenic effects in females, and disposition problems.[9][10]

Antifibrinolytics include tranexamic acid and aminocaproic acid, and both have minimal effectiveness in the prevention and treatment of attacks. 

Medications available for long term prophylaxis include lanadelumab (a kallakrein inhibitor), subcutaneous and inrtravenous C1-inhibitor, berotralstat (a kallakrein inhibitor), androgens (limited use due to toxicity) and tranexamic acid (limited use secondary to lack of efficacy).  

Non-medicinal Therapy Used for Treatment of HAE

In addition to medications, management includes avoidance of triggers, estrogens, and ACE-inhibitors and a management plan. The management plan should include long-term prophylaxis if indicated, therapy to use before dental and surgical procedures, how to treat attacks and a backup plan for treatment of attacks. Most patients should be taught self-treatment to enhance freedom and quality of life. Serial assessment is essential to ensure that morbidity is minimal and therapy is effective.

Differential Diagnosis

While hereditary angioedema is bradykinin-mediated, other types of angioedema can be mediated by histamine or other mechanisms; hence they have different methods of management, and differentiating them is crucial for it. Unfortunately, there isn't a single valid diagnostic test to differentiate between histamine-mediated and bradykinin-mediated angioedemas; however, there are some features of each one that can guide the diagnosis and, consequently, the treatment.Histamine-Mediated Angioedema

Angioedema secondary to histamine often is associated with urticaria and pruritus. Triggers may include viruses, drugs, food; however, in most chronic cases, an external trigger cannot be identified and is often autoimmune mediated. Histamine can be released from mast cells by IgE hypersensitivity or non-IgE mediated mechanisms such as opiates, contrast, vancomycin, and physical causes such as cold, heat, vibration, pressure, water, or sun. Significant abdominal pain is not usual. Most cases are rapid in onset and respond quickly to antihistamines, epinephrine, and or steroids. In some cases, the angioedema is refractory, and more aggressive therapy such as omalizumab or cyclosporine is necessary.  The main distinctions from bradykinin disease are the minimal abdominal complaints, the presence of urticaria, response to antihistamines, rapid onset and resolution, and sometimes, accompanying symptoms and signs of anaphylaxis.

Bradykinin-Mediated Angioedema

Bradykinin-mediated angioedema includes hereditary angioedema, acquired angioedema, and angiotensin-converting enzyme-induced angioedema. It is not commonly associated with itching, and urticaria does not occur. It progressives at a slower rate than histamine-mediated angioedema, usually over several hours. If untreated, attacks tend to be more persistent and severe than histamine-mediated attacks, with abdominal involvement in approximately 50% of cases. Although not a proper method for diagnosis, lack of response to treatment with epinephrine, antihistaminics, and corticosteroids can give an important clue for follow-up.[11]