Hereditary angioneurotic edema
Hereditary angioneurotic edema (HANE) is a nonsex-linked (autosomal) dominant disease that results from mutations in a gene responsible for producing one of the proteins responsible for human immunity. This disease is also known as hereditary angioedema (HAE) or hereditary C1 inhibitor deficiency because it is a deficiency of the protein (C1-INH) that inhibits the action of the enzyme known as C1 which causes this disease.
There are two recognized forms of HANE. Type I represents approximately 80-85% of the cases of hereditary angioneurotic edema. In this type, the protein C1-INH is not produced in sufficient quantities. Type II HANE represents the remaining 15-20% of cases. In this type, C1-INH concentrations are normal, but the C1-INH protein produced is defective.
Related to the two types of hereditary angioneurotic edema are acquired types of this disease (AANE or AAE) that are not based on a defective gene. Type I AAE is caused by a disorder that causes over-growth (proliferation) of the lymph tissues and destroys C1-INH. Type II AAE is caused by the presence of autoantibodies (antibodies that attack the host organism that produced them) that destroy C1-INH. Both of these acquired forms of angioedema can generally be differentiated from the two types of HANE by the age of onset. Symptoms of the acquired diseases usually do not occur until the fourth decade of life, while those of the hereditary forms are generally present prior to puberty.
The human body has two distinct immune systems: the humoral immune system and the cell-mediated immune system. The complement system is a part of the humoral immune system. Humoral means within the humor, or fluids, of the body. Blood, lymph, and bile compose the fluids of the humor. The complement system uses at least 30 different proteins to "mark" any foreign cells in the body that do not have certain protective proteins on their cell membranes which identify them as belonging in the body. These complement proteins are designated C1, C2, C3, et cetera. Once the foreign cells have been "marked," a particular form of white blood cell, called a phagocyte, is dispatched to the area with the marked cells and destroys them.
Phagocytes will eventually destroy any cell that is marked by complement; therefore, it is important to make sure that the complement proteins are not marking non-foreign cells. When cells are improperly marked, these cells will also be destroyed, causing what is called an autoimmune response. In effect, this autoimmune response means that the body is recognizing itself as foreign and attempting to destroy healthy cells. Inhibitors of the various complement proteins are necessary to prevent these proteins from marking the wrong cells or from continuing to mark cells after the foreign cells have been destroyed.
C1 inhibitor (C1-INH) is a chemical that is involved in the regulation of the complement system by inhibiting the action of the first complement protein (C1). C1-INH acts by binding free C1 molecules in the humor, preventing them from being able to function. It also limits the activation of other complement proteins.
Because C1-INH is diminished or defective in people affected with HANE, C1 is not inhibited and this inappropriately initiates the complement reaction which causes the swelling (acute inflammatory response) characteristic of HANE.
C1-INH also binds to the chemicals kallikrein and plasmin that are involved in blood clotting. Kallikrein is
With the absence or dysfunction of the C1-INH protein, the functions of blood flow, blood clotting, and immune response are impaired in individuals affected by hereditary angioneurotic edema, leading to swelling of the bodily tissues.
The central Pyncheon family in Nathaniel Hawthorne's The House of the Seven Gables carries an ancestral curse of dying from choking on their own blood. Hawthorne describes members of the family who made odd sounds in the throat and chest when agitated, and sometimes died from choking: "This mode of death has been an idiosyncrasy with his family, for generations past....[the] prophecy was probably founded on a knowledge of this physical predisposition in the Pyncheon race." It seems possible that Hawthorne was not only describing the symptoms of HANE but also acknowledging it to be an inherited genetic disorder.
All hereditary forms of HANE are caused by mutations in the gene responsible for the production of C1-INH. This gene is located on the long arm (q) of chromosome 11, at the specific location q11.2-q13. There are at least 13 different mutations of the C1-INH gene that cause the symptoms of HANE. Six of these are known to cause type I HANE, while another six are known to cause type II HANE. The final mutation has only been found in one individual. In this case, an acquired form of angioedema was determined to be caused by a mutation in a different region of the C1-INH gene than those mutations causing type I or type II cases of HANE.
HANE affects approximately 50,000 people in the United States and Europe. It is estimated to occur in approximately one in every 50,000 to 150,000 live births. HANE appears to affect males and females equally and does not have a racial preference.
As an autosomal dominant trait, only one copy of an abnormal gene needs to be inherited for an individual to be affected. Therefore, if one child is affected with HANE, the likelihood that a second child will be affected with HANE is 50%. In cases of parents related by blood (consanguineous parents) the likelihood of HANE is increased.
Signs and symptoms
Individuals affected with either form of HANE have episodes of swelling of the hands, feet, trunk, face, digestive tract, and airways (angioneurotic edema or angioedema). These attacks of angioedema are often accompanied by attacks of nausea, vomiting, and abdominal pain. The frequency and severity of these attacks is not predictable and varies from individual to individual. These attacks may occur without cause, or they may be triggered by anxiety, stress, or minor traumas, such as dental procedures. If these symptoms are accompanied by hives (urticaria) a diagnosis other than HANE is indicated.
Symptoms of HANE generally first occur prior to puberty and episodes generally increase in severity after puberty.
A diagnosis of HANE is suspected in individuals who have recurrent attacks of swollen tissues (angioedema). Diagnosis of type I HANE is confirmed by blood tests showing abnormally low levels of C1-INH, C2, and C4. Diagnosis of type II HANE is confirmed by blood tests showing normal levels of C1-INH and C2, but abnormally low levels of C4. Abnormally low levels of C1-INH and C4 without the presence of autoantibodies suggest a diagnosis of type I acquired angioedema, while abnormally low levels of C1-INH and C4 and the presence of autoantibodies suggest a diagnosis of type II acquired angioedema.
Hives (urticaria) are not generally associated with HANE. If hives are present with tissue swelling, this may suggest an allergic reaction, not a case of HANE. Occasionally, individuals affected with HANE also develop hives, but they are usually secondary to the angioedema. In a severe allergic reaction, hives are generally prominent as the major symptom.
Treatment and management
The treatment of both hereditary forms of angioedema is the same. Androgens (male sex hormones) such as winstrol, danazol, and oxandrolone have been shown to be effective in preventing chronic recurrences of swelling. These drugs are seldom used to treat acute attacks. In instances of abdominal attacks, fluid replacement therapy via intravenous injection may be required. Demerol and Compazine suppositories are often prescribed to relieve abdominal pain and vomiting.
Edema (swelling) of the airways is the most life-threatening feature of HANE. Without prompt medical attention, individuals affected with HANE can die from an obstruction of the airway caused by this swelling. Unfortunately, if the attending physician does not recognize HANE, attempts at tracheal intubation (formation of an airway directly in the neck) may aggravate the swelling rather than produce a functioning airway.
Treatment with vapor-heated C1-INH concentrate has proven to be an effective treatment both as a prophylactic (preventative) and a treatment for acute attacks of angioedema in all individuals affected with HANE. The C1-INH concentrate is derived from human blood plasma; therefore it may possibly be contaminated. It is vapor-heated to inactivate possible hepatitis and HIV viruses. However, because HANE is a disease of the immune system, many doctors are reluctant to use C1-INH from other people and many patients are unwilling to accept such a treatment. The use of human recombinant C1-INH should alleviate any concerns arising from possible contamination of the blood supply.
Androgens are still the preventative treatment of choice because they are more cost-effective than treatments with C1-INH. However, androgens should not be given to women who are pregnant, or who might become pregnant. In these cases, C1-INH treatment is required.
In 1999, the U.S. Food and Drug Administration granted Orphan Drug Designations to human recombinant C1-INH for both preventative and acute treatment of HANE. On March 21, 2000, Baxter Healthcare's Hyland Immuno division and Europe's Pharming Group announced an agreement to jointly develop recombinant human C1-INH. As of the March 2000 press release by these two companies, pre-clinical (animal) studies were expected to be completed in late 2000 and phase I human trials were slated to begin in late 2000 or early 2001. Because of the Orphan Drug Designations from the USFDA, this possible treatment for HANE is automatically "fast-tracked," which means that it could potentially be approved for human use by 2004.
The key to successful management of HANE is a proper medical diagnosis. With proper medical treatment, HANE is completely controllable and individuals affected with HANE suffer no diminishment in quality of life.
Hawthorne, Nathaniel. The House of the Seven Gables. New York, New York: Signet Classics Penguin Books Ltd., 1961.
Asghar, S., and M. Pasch. "Therapeutic inhibition of the complement system." Frontiers in Bioscience (September 2000): E63-81.
Cicardi, M., et al. "Pathogenetic and clinical aspects of C1 inhibitor deficiency." Immunobiology (August 1998): 366-376.
Markovic, S., D. Inwards, A. Evangelos, and R. Phyliky. "Acquired C1 esterase inhibitor deficiency." Annals of Internal Medicine (January 2000): 144-150.
Waytes, A., F. Rosen, and M. Frank. "Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate." New England Journal of Medicine (June 1996): 1630-1634.
Hereditary Angioedema Association. PO Box 492, Live Oak, FL 32064. <http://www.hereditaryangioedema.com>.
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
"Angioedema (Hereditary)." eMedicine. <http://www.emedicine.com/derm/topic24.htm> (February 23, 2001).
"Angioedema, Hereditary; HAE." Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?106100> (February 23, 2001).
The Complement Laboratory at the University of Iowa. <http://ictg.uiowa.edu/clab/what.htm> (February 23, 2001).
"Pharming and Baxter to co-develop human C1 inhibitor to treat hereditary angioedema." Pharming Group N.V. Press Release (March 21, 2000).
Paul A. Johnson