Angioedema Types

TYPE	DESCRIPTION
Hereditary Type I (HAE-I)	Description Represents approximately 80 to 85% of HAE cases. C1 inhibitor is considerably below normal due to a defective gene on chromosome 11. There is usually a family history of angioedema, but a number of cases are due to a spontaneous mutation of the gene. Common Symptoms ¹ Swelling can occur in the extremities, abdomen, throat and other organs. Swelling of the airway can be fatal. Abdominal swelling usually involves pain, vomiting and diarrhea. Symptoms usually appear early in life, most often by age 13 and may increase in severity after puberty. Episodes may be spontaneous or triggered by physical trauma or emotional stress. Complement System Low levels of C1 inhibitor. C4 is almost always low. C1, C3 and C1q are normal. Abnormal complement (above) is the same whether the condition is hereditary or spontaneous. Possible Treatment Anabolic steroids (also known as androgens) such as danazol, oxandrolone and stanozolol have, historically, been the most commonly prescribed HAE therapies. While anabolic steroids have been shown to be useful, they are not well-tolerated by many women, directly linked to liver toxicity and cause an increase in cholesterol levels. In addition, these drugs should not be used to treat children, some of whom, tragically, are severely affected and suffer frequent attacks. Research indicates that patients treated with anabolic steroids can experience breakthrough laryngeal or abdominal attacks that require hospitalization. Three new treatments are now FDA approved for treating HAE, including 2 C1 inhibitor products and a Kalikrein inhibitor. Patients and their physicians now have options for developing a non-steroidal HAE treatment plan tailored to meet each patient’s unique needs. Cinryze ™ brand of C1-inhibitor The Cinryze ™ brand of C1-inhibitor concentrate has been FDA-approved for preventing HAE attacks. The product is delivered intravenously and is approved for home infusion. Contact your HAEA regional Patient Services Representative (see list below) for more information. Berinert^® brand of C1-inhibitor The Berinert^® brand of C1-inhibitor concentrate was FDA approved on October 9, 2009. for treating facial and abdominal HAE attacks . The product label states that Berinert is indicated for facial and abdominal HAE attacks. Berinert^® is delivered intravenously and will be available in the United States in December 2009. Contact your HAEA regional Patient Services Representative (see list below) for more information. Kalbitor^®, from Dyax Corp., was approved in December 2009 to treat acute HAE attacks in patients 16 years of age and older. The product is delivered through subcutaneous injections and is estimated to be available in the US in early 2010.
Hereditary Type II (HAE-II)	Description Represents approximately 15 to 20% of HAE cases. Similar description to Type I, but C1 inhibitor does not function properly. Common Symptoms ¹ Same as HAE-I. Complement System C1 inhibitor level may be normal or elevated, but it is dysfunctional. C1, C3 and C1q are normal, but C4 is almost always low. Possible Treatments Same as HAE-1
Hereditary (experienced by more than one family member) swelling not caused by C1-inhibitor deficiency. Sometimes referred to as “HAE III.”	Description In women, swellings have been correlated with pregnancy or the use of oral contraceptives; however, affected male family members have also been identified. Some scientists believe that a mutation in the gene for human coagulation Factor XII may be a potential cause of swelling in these patients. Common Symptoms ¹ Same as HAE-I. Complement System Normal. Possible Treatments None yet specifically identified, however, some clinicians have treated patients with androgens and C1-inhibitor with varying degrees of success.
Acquired Type I (AAE-I) AAE-I & II are considered very rare; there are few reported cases.	Description Immune complexes that are usually linked to an underlying lymphoproliferative disorder destroy the function of C1 inhibitor. Angioedema can be an indicator that a lymphoproliferative disease is developing, so early detection needs to be emphasized. Common Symptoms ¹ Similar to HAE. The symptoms typically appear in the fourth decade of life or later. Because acquired angioedema is not related to a genetic defect there is an absence of a family history of symptoms. Complement System Low level of C1 inhibitor and C4. C1q is usually reduced, but not always. Treatments Diagnosis and treatment of underlying lymphoproliferative disease often eliminates the root cause. Antifibrinolytics such as tranexamic acid and epsilon-aminocaproic acid for possible prevention of episodes. Androgen therapy may help.
Acquired Type II (AAE-II) AAE-I & II are considered very rare; there are few reported cases.	Description Autoantibodies are present and destroy C1 inhibitor function. There is no apparent underlying disorder. Common Symptoms ¹ Same as AAE-I. Complement System Same as AAE-I. A lab test for autoantibodies may be appropriate. Possible Treatments Antifibrinolytics such as tranexamic acid and epsilon-aminocaproic acid for possible prevention. It is possible that immunosuppressive therapy might be successful.
Acquired Type I (AAE-I) AAE-I & II are considered very rare; there are few reported cases.	Description Immune complexes that are usually linked to an underlying lymphoproliferative disorder destroy the function of C1 inhibitor. Angioedema can be an indicator that a lymphoproliferative disease is developing, so early detection needs to be emphasized. Common Symptoms ¹ Similar to HAE. The symptoms typically appear in the fourth decade of life or later. Because acquired angioedema is not related to a genetic defect there is an absence of a family history of symptoms. Complement System Low level of C1 inhibitor and C4. C1q is usually reduced, but not always. Treatments Diagnosis and treatment of underlying lymphoproliferative disease often eliminates the root cause. Antifibrinolytics such as tranexamic acid and epsilon-aminocaproic acid for possible prevention of episodes. Androgen therapy may help.
Acquired Type II (AAE-II) AAE-I & II are considered very rare; there are few reported cases.	Description Autoantibodies are present and destroy C1 inhibitor function. There is no apparent underlying disorder. Common Symptoms ¹ Same as AAE-I. Complement System Same as AAE-I. A lab test for autoantibodies may be appropriate. Possible Treatments Antifibrinolytics such as tranexamic acid and epsilon-aminocaproic acid for possible prevention. It is possible that immunosuppressive therapy might be successful.
Idiopathic	Description Swelling and/or hives persist beyond 6 weeks. Thyroid dysfunction should be considered. Common Symptoms ¹ Swelling may occur just about anywhere and may be accompanied by urticaria (hives). Complement System Normal Possible Treatment Primarily antihistamines. DHEA. 1-thyroxine for thyroid dysfunction. Prednisone therapy.
Nonhistaminergic (INAE) May occur in about 1 out of 20 cases of angioedema	Description Angioedema without urticaria (usually not responsive to H1 antihistamine blockers). Parasites, infections and autoimmune diseases are not present. Common Symptoms ¹ Swelling may occur anywhere: face, arms, legs, genitalia, throat, abdomen (but abdomen is less frequent than those with HAE). Symptoms do not change due to menstrual period or pregnancy. Complement System Normal Possible Treatment Antifibrinolytics such as tranexamic acid and epsilon-aminocaproic acid.
Allergic This is the most common form of angioedema.	Description Swelling and/or hives are a reaction to an outside influence such as food, bee sting, cold, heat, latex or drug. The outside influence provokes a histamine reaction, which leads to swelling and/or the hives. Common Symptoms ¹ Swelling occurs most often in the face and throat area. Urticaria (hives) may be present. If condition persists beyond 6 weeks it is considered chronic idiopathic and not an allergic reaction. Complement System Normal Possible Treatment Avoid the substance or behavior that causes the allergic reaction. Antihistamines. Adrenaline (epinephrine) possibly as self-injecting Epi pens for emergencies.
ACE-Inhibitor (Angiotensin-Converting Enzyme Inhibition) Possible cause for 4 to 8% of people with angioedema.	Description Caused by ACE-Inhibitors for high blood pressure (captopril, enalapril, genzapril, quinapril, ramipril). Swelling may commence anywhere from a few hours to years after first starting medication. Common Symptoms ¹ Swelling may occur just about anywhere: throat, face, lips, tongue, hands, feet, genitals, intestines. If urticaria is present it reduces the probability of a link to ACE-Inhibitors. Complement System Normal Possible Treatment Suspension or change of medication.

Revised 10/2/09

*Patients with the slightest hint of throat swelling should seek immediate treatment to ensure that their airway is not compromised. The medical literature and practitioner experience confirms that corticosteriods (Prednisone), antihistamines, and epinephrine are not effective in treating angioedema created by C1-inhibitor deficiency. However, a recent study noted success using inhaled epinephrine to prevent complete airway closure.

NOTES:

The presence of urticaria associated with angioedema usually suggests a diagnosis other than HAE or AAE.

A Brief Description of the Complement System: The Complement is part of our immune system. It involves a series of complex proteins (C1 thru C9 in addition to C1 inhibitor) that act in "concert" to clear foreign organisms from our bodies. C1 inhibitor essentially monitors the complement system and prevents it from having a "runaway" reaction. When C1 inhibitor is not present at an adequate level, or is dysfunctional, the system "overreacts" resulting in abnormal swelling.

Angioedema Types was compiled based upon current research and medical knowledge. The emphasis has been on presenting the information in language that is not technical and is primarily for those that are trying to understand the different types of angioedema.

DISCLAIMER: The information, including opinions and recommendations, contained in this document is for educational purposes only. It is not intended to be a substitute for professional medical advice, diagnosis or treatment. No one should act upon any information provided in this document without first seeking medical advice from a qualified, licensed medical doctor. Information derived from the internet, no matter how accurate or relevant is no substitute for competent medical care.