Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of
severe swelling.
The swelling most commonly affects the arms, legs, face, intestinal tract, and airway.
[ If the intestinal tract is affected, ]abdominal pain
Abdominal pain, also known as a stomach ache, is a symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than ...
and vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose.
Vomiting can be the result of ailments like Food-poisoning, foo ...
may occur. Swelling of the airway can result in its obstruction and trouble breathing.[ Without preventive treatment, attacks typically occur every two weeks and last for a few days.][
There are three main types of HAE.][ Types I and II are caused by a mutation in the '' SERPING1'' gene, which makes the C1 inhibitor protein, while type III is often due to a mutation in the '' F12'' (factor XII) gene.][ The result is increased levels of ]bradykinin
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and ...
, which promotes swelling.[ The condition may be inherited in an ]autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
manner or occur as a new mutation.[ Triggers for an attack may include minor trauma or stress, but attacks often occur without any obvious preceding event.][ Diagnosis of types I and II is based on measurement of C4 and C1-inhibitor levels.]
Management of HAE involves efforts to prevent attacks and the treatment of attacks if they occur.[ During an attack, ]supportive care
Symptomatic treatment, supportive care, supportive therapy, or palliative treatment is any medical therapy of a disease that only affects its symptoms, not the underlying cause. It is usually aimed at reducing the signs and symptoms for the comfor ...
such as intravenous fluids and airway support may be required.[ C1 inhibitor medications can be used for both prevention and treatment, while ]ecallantide
Ecallantide (trade name Kalbitor) is a drug used for the treatment of hereditary angioedema (HAE) and in the prevention of blood loss in cardiothoracic surgery. It is an inhibitor of the protein kallikrein and a 60-amino acid polypeptide which wa ...
and icatibant
Icatibant, sold under the brand name Firazyr, is a medication for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults with C1-esterase-inhibitor deficiency. It is not effective in angioedema caused by medication f ...
can be used to treat acute attacks.[
HAE affects approximately 1 in 50,000 people.][ The condition is typically first noticed in childhood.][ Type I and II affected females and males equally,] while type III affects females more often than males.[ When the airway is involved, without treatment, the risk of death is about 25%.][ With treatment, outcomes are generally good.][ The condition was first described in 1888 by Canadian physician ]William Osler
Sir William Osler, 1st Baronet, (; July 12, 1849 – December 29, 1919) was a Canadian physician and one of the "Big Four" founding professors of Johns Hopkins Hospital. Osler created the first Residency (medicine), residency program for spec ...
.
Signs and symptoms
People diagnosed with Hereditary Angioedema have recurrent swelling in the extremities, genitals
A sex organ (or reproductive organ) is any part of an animal or plant that is involved in sexual reproduction. The reproductive organs together constitute the reproductive system. In animals, the testis in the male, and the ovary in the female, a ...
, face
The face is the front of an animal's head that features the eyes, nose and mouth, and through which animals express many of their emotions. The face is crucial for human identity, and damage such as scarring or developmental deformities may aff ...
, lip
The lips are the visible body part at the mouth of many animals, including humans. Lips are soft, movable, and serve as the opening for food intake and in the articulation of sound and speech. Human lips are a tactile sensory organ, and can be ...
s, larynx
The larynx (), commonly called the voice box, is an organ in the top of the neck involved in breathing, producing sound and protecting the trachea against food aspiration. The opening of larynx into pharynx known as the laryngeal inlet is about ...
or GI tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...
. Some patients describe a sensation of fullness but not pain or itching in the affected area except for those with abdominal swellings who often experience acute abdominal pain. Others experience an intense amount of pain, described as radiating from the bone outward along with intense itching just beneath the skin and intense heat, regardless of the area targeted.
Swelling involving the respiratory and gastrointestinal systems can cause significant risk and distress. Involvement of respiratory structures, such as the throat or larynx, can cause difficulties in breathing and life-threatening airway obstruction. Episodes that attack the gastrointestinal tract can cause a number of complications including vomiting, crampy abdominal pain, diarrhea, and dehydration.
Some people with HAE experience 'wandering' attacks. These attacks will center around an extremity. For example: Should the affected person's hand swell up, it will go through the normal swelling cycle before 'transferring' to either the connection limb (In this case wrist to forearm) or move to the opposite hand. People with this symptom may find their episodes last longer and may find their triggers more difficult to track.
Genetics
Because HAE is an autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
disease, there is no sex difference in transmission and both sexes are equally likely to receive the mutated gene from their parents. In an example, a father (individual A) with a mutated gene for HAE, has the disease while his wife (individual B) with 2 non-mutated copies of the C1 inhibitor gene and does not have the disease. The possibility of a cross between them gives the possibilities as shown: two of their offspring will have the disease (HAE) while the others would not.
The affected father who has HAE has a mutation on one of his genes (C1-INH). Each one of his children, regardless of sex, will have a 50% chance to inherit the mutated C1-INH gene from him. HAE is generally referred to as a "dominant" condition because it only takes a mutation in one of the two C1-INH genes in a carrier to cause the disease.
The prevalence of HAE is relatively low – between 1 in every 10,000 to 1 in every 50,000 persons. Most persons with HAE acquire a C1 esterase inhibitor (C1-INH) mutation from one of their parents. A parent with HAE usually has a 50% probability of transmitting this condition on to one of his/her children of either sex as shown in the figure (HEA Inheritance). People with no previous history of can acquire HAE by spontaneous changes in the sperm or egg cell. In a review of patients who do not have a history of HAE in their family, but who have relatively low levels of mutated C1-INH with persistent angioedema, 25% of new patients who had HAE had C1-INH changes that do not show signs of inheritance.
Diagnosis
Recognizing HAE is often difficult due to the wide variability in disease expression. The course of the disease is diverse and unpredictable, even within a single patient over their lifetime. This disease may be similar in its presentation to other forms of angioedema resulting from allergies or other medical conditions, but it is significantly different in cause and treatment. When HAE is misdiagnosed as an allergy it is most commonly treated with steroids and epinephrine, drugs that are usually ineffective in treating a HAE episode. Other misdiagnoses have resulted in unnecessary exploratory surgery for patients with abdominal swelling and other HAE patients report that their abdominal pain was wrongly diagnosed as psychosomatic.
HAE accounts for only a small fraction of all cases of angioedema. To avoid potentially fatal consequences such as upper airway obstruction and unnecessary abdominal surgery, the importance of a correct diagnosis cannot be overemphasized.
HAE should be considered if a patient presents with:
* Recurrent angioedema (without urticaria)
* Recurrent episodes of abdominal pain and vomiting
* Laryngeal edema
* Positive family history of angioedema
A blood test, ideally taken during an episode, can be used to diagnose the condition. Measure: serum complement factor 4 (C4),
C1 inhibitor (C1-INH) antigenic protein, C1 inhibitor (C1-INH) functional level if available. Analysis of complement C1 inhibitor levels may play a role in diagnosis. C4 and C2 are complementary components.
Types
There are three types of C1 inhibitor deficiency:
HAE type I is primarily caused by a deficiency in blood proteins ( C1 esterase inhibitors) which normally suppress activation of the complement system
The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...
. The resultant overstimulation of this system leads to the production of inflammatory anaphylatoxins
Anaphylatoxins, or complement peptides, are fragments ( C3a, C4a and C5a) that are produced as part of the activation of the complement system. Complement components C3, C4 and C5 are large glycoproteins that have important functions in the imm ...
, which affects the flow of body fluids between the vascular system and body tissues. This deficiency is responsible for approximately 80–85% of cases.
HAE type II is a less frequently encountered form of this disorder and accounts for 15–20% of cases. In this type, atypical C1-inhibitor proteins are produced which are less capable of suppressing activation of the complement system. Like HAE type I, this results in overstimulation of this system.
HAE type III is rare and has only been documented recently. Unlike types I and II, this form does not appear to be connected with C1-inhibitor deficiency. This type mainly affects females and appears to be influenced by contact with estrogens and also by hormone replacement therapy (e.g. oral contraceptives). Its pathogenesis is credited to increased activity of the enzyme kininogenase, which leads to rise in the levels of bradykinin
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and ...
. Other patients with type III HAE have alterations in gene F12, which encodes a protein which participates in blood coagulation
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
. Some patients with type III HAE have a mutation in the F12 gene which produces a protein involved in blood clotting.[ ype III hereditary angioedema: defined, but not understood. Kaplan A. Ann Allergy Asthma Immunol. 2012 Sep;109(3):153-4. doi: 10.1016/j.anai.2012.07.007. No abstract available./ref> Due to the results of a genetic test on 4 affected German families, it is believed that this type of the condition is caused by a disease-causing gene in chromosome 5q.35.2-q35.3.
]
Prevention
Treatment with ACE inhibitors
Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease in blood volum ...
is contraindicated in this condition, as these drugs can lead to bradykinin accumulation, which can precipitate disease episodes.
Long-term
People in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prevention. There are several phase III clinical trials addressing HAE prophylaxis and therapy. These have led to the licensing of pdC1INH in many parts of the world; bradykinin receptor antagonists (icatibant
Icatibant, sold under the brand name Firazyr, is a medication for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults with C1-esterase-inhibitor deficiency. It is not effective in angioedema caused by medication f ...
) in Europe; kallikrein
Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (encoded by ''KLKB1 gene'') has no known paralogue, while tissue kallikrein-related peptidases (''KLKs'') encode a f ...
inhibitors (ecallantide
Ecallantide (trade name Kalbitor) is a drug used for the treatment of hereditary angioedema (HAE) and in the prevention of blood loss in cardiothoracic surgery. It is an inhibitor of the protein kallikrein and a 60-amino acid polypeptide which wa ...
and lanadelumab
Lanadelumab, sold under the brand name Takhzyro, is a human monoclonal antibody (class IgG1 kappa) that targets plasma kallikrein (pKal) in order to promote prevention of angioedema in people with hereditary angioedema. Lanadelumab, was approved ...
) in the United States; and recombinant C1-INH replacement therapy (rhC1INH; conestat alfa) in Europe. Tranexamic acid
Tranexamic acid (TXA) is a medication used to treat or prevent excessive blood loss from major trauma, postpartum bleeding, surgery, tooth removal, nosebleeds, and heavy menstruation. It is also used for hereditary angioedema. It is taken eith ...
has been shown to be relatively ineffective therapy. Danazol
Danazol, sold as Danocrine and other brand names, is a medication used in the treatment of endometriosis, fibrocystic breast disease, hereditary angioedema and other conditions. It is taken by mouth.
The use of danazol is limited by masculini ...
prophylaxis remains an option but therapeutic agents are now being used more for prophylaxis because of danazol's adverse events. For people requiring long-term prophylaxis, home therapy which allows people to self-administer the product, is considered an integral part of allowing patients a normal quality of life.
In 2018, the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
approved lanadelumab
Lanadelumab, sold under the brand name Takhzyro, is a human monoclonal antibody (class IgG1 kappa) that targets plasma kallikrein (pKal) in order to promote prevention of angioedema in people with hereditary angioedema. Lanadelumab, was approved ...
, an injectable monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ca ...
, to prevent attacks of HAE types I and II in patients over age 12. Lanadelumab inhibits the plasma enzyme kallikrein
Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (encoded by ''KLKB1 gene'') has no known paralogue, while tissue kallikrein-related peptidases (''KLKs'') encode a f ...
, which liberates the kinin A kinin is any of various structurally related polypeptides, such as bradykinin and kallidin. They are members of the autacoid family. Kinins are peptides that are cleaved from kininogens by the process of kallikreins. Kallikreins activate kinins ...
s bradykinin
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and ...
and kallidin
Kallidin is a bioactive kinin formed in response to injury from kininogen precursors through the action of kallikreins.
Kallidin is a decapeptide whose sequence is H-Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH. It can be converted to bradykinin b ...
from their kininogen Kininogens are precursor proteins for kinins, biologically active polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, inflammatory regulation, and the regulation of the cardiovascular and renal systems.
Types o ...
precursors and is produced in excess in individuals with HAE types I and II.
Berotralstat
Berotralstat, sold under the brand name Orladeyo, is a medication used to prevent attacks of hereditary angioedema (HAE) in people aged twelve years and older.
The most common side effects include abdominal pain, vomiting, diarrhea, back pain, ...
was approved in the United States in December 2020, for the prevention of attacks of hereditary angioedema in people over twelve years of age.[ ]
Short-term
Short-term prevention is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1–1.5 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal edema), high-dose androgen treatment is administered for 5–7 days.
Management
The aim of acute treatment is to halt progression of the edema
Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...
as quickly as possible, which can be life-saving, particularly if the swelling is in the larynx
The larynx (), commonly called the voice box, is an organ in the top of the neck involved in breathing, producing sound and protecting the trachea against food aspiration. The opening of larynx into pharynx known as the laryngeal inlet is about ...
. In Germany, most acute treatment consists of C1 inhibitor concentrate from donor blood, which must be administered intravenously; however, in most European countries, C1 inhibitor concentrate is only available to patients who are participating in special programs. In emergency situations where C1 inhibitor concentrate is not available, fresh frozen plasma
Fresh frozen plasma (FFP) is a blood product made from the liquid portion of whole blood. It is used to treat conditions in which there are low blood clotting factors (INR > 1.5) or low levels of other blood proteins. It may also be used as the re ...
(FFP) can be used as an alternative, as it also contains C1 inhibitor.
Other treatment modalities can stimulate the synthesis of C1 inhibitor, or reduce C1 inhibitor consumption. Purified C1 inhibitor, derived from human blood, has been used in Europe since 1979. Several C1 inhibitor treatments are now available in the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
and two C1 inhibitor products are now available in Canada. Berinert P (CSL Behring), which is pasteurized, was approved by the F.D.A. in 2009 for acute attacks. Cinryze (ViroPharma), which is nanofiltered, was approved by the F.D.A. in 2008 for prophylaxis. Ruconest (Pharming) is a recombinant C1 inhibitor approved in the US and Europe that does not carry the risk of infectious disease transmission due to human blood-borne pathogens.[Morgan]
The medication ecallantide
Ecallantide (trade name Kalbitor) is a drug used for the treatment of hereditary angioedema (HAE) and in the prevention of blood loss in cardiothoracic surgery. It is an inhibitor of the protein kallikrein and a 60-amino acid polypeptide which wa ...
inhibits plasma kallikrein and was approved by the F.D.A. (but not in Europe) for acute attacks in 2009. Icatibant
Icatibant, sold under the brand name Firazyr, is a medication for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults with C1-esterase-inhibitor deficiency. It is not effective in angioedema caused by medication f ...
inhibits the bradykinin
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and ...
B2 receptor, and was approved in Europe and the USA.
In HAE, specific stimuli that have previously led to attacks may need to be avoided in the future. It does not respond to antihistamine
Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides re ...
s, corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
s, or epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
.
Prognosis
About 25% of those affected die in the first two decades of life, mainly due to lack of treatment.
Epidemiology
Data regarding the epidemiology
Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and determinants of health and disease conditions in a defined population.
It is a cornerstone of public health, and shapes policy decisions and evidenc ...
of angioedema is limited. The incidence of HAE is one in 10,000–50,000 people in the United States and Canada. Mortality rates are estimated at 15–33%, resulting primarily from laryngeal edema and asphyxiation. HAE leads to 15,000–30,000 emergency department visits per year.
Society and culture
There are national associations for HAE patients and their families in a number of countries around the world. These national associations are members of the global organization HAEi - International Patient Organization for C1-Inhibitor Deficiencies. HAEi is dedicated to raising awareness of C1 inhibitor deficiencies around the world. It is a non-profit international network established to promote co-operation, co-ordination and information sharing between HAE specialists and national HAE patient associations in order to help facilitate the availability of effective diagnosis and management of C1 inhibitor deficiencies throughout the world.
Each year on 16 May, HAEi and the HAE community raise awareness of HAE with the international hae day :-)
The Assistance Fund Inc. is an American nonprofit organization that offers co-pay assistance for medications that treat HAE and is open to any American Citizens or landed immigrants who have insurance.
A column on puzzling medical cases in The New York Times Magazine featured a 45-year-old woman with intestinal swelling who was ultimately diagnosed as having type III HAE. The patient’s HAE attack had been triggered by exposure to estrogen from her oral contraceptive.
Research
Clinical development of several new active substances, which intervene in the disease process in different ways, is currently ongoing.
Pharming Group NV announced on 24 June 2010 that the European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
has adopted a positive opinion on conestat alfa
C1-inhibitor (C1-inh, C1 esterase inhibitor) is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation but also as the major regulator of the con ...
(trade name Ruconest), a C1-inhibitor
C1-inhibitor (C1-inh, C1 esterase inhibitor) is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation but also as the major regulator of the cont ...
for the treatment of acute angioedema attacks.
Ecallantide
Ecallantide (trade name Kalbitor) is a drug used for the treatment of hereditary angioedema (HAE) and in the prevention of blood loss in cardiothoracic surgery. It is an inhibitor of the protein kallikrein and a 60-amino acid polypeptide which wa ...
, a peptide inhibitor of kallikrein
Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (encoded by ''KLKB1 gene'') has no known paralogue, while tissue kallikrein-related peptidases (''KLKs'') encode a f ...
, has received orphan status for HAE and has shown positive results in phase III trials.
Icatibant
Icatibant, sold under the brand name Firazyr, is a medication for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults with C1-esterase-inhibitor deficiency. It is not effective in angioedema caused by medication f ...
(marketed as Firazyr) is a selective bradykinin receptor
The bradykinin receptor family is a group of G-protein coupled receptors whose principal ligand is the protein bradykinin.
There are two Bradykinin receptors: the B1 receptor and the B2 receptor.
B1 receptor
Bradykinin receptor B1 (B1) is a ...
antagonist, which has been approved in Europe and was approved in the US by the FDA in Aug 2011. After initial borderline results this drug was shown to be effective in phase III trials. Cinryze has been approved by the FDA in October 2008.[Reuters]
UPDATE 1-US clears Lev Pharma drug for rare swelling disease
References
Further reading
*
External links
*
{{DEFAULTSORT:Hereditary Angioedema
Urticaria and angioedema
Serpinopathies
Complement deficiency
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