Index
What is Hereditary Angioedema?
Hereditary angioedema is a rare genetic condition that causes swelling under the skin. It can happen in different parts of your body.
Angioedema is a subcutaneous extension of the Urticaria, producing deep swelling in the subcutaneous sites. In contrast, Urticaria results from transient extravasation of plasma in the dermis, which causes a wheal characterized by tense edema with or without redness.
Angioedema can occur with generalized Urticaria if the swelling of the tissue has indistinct borders around the eyelids and lips. In addition, when the swelling of the Urticaria extends to the face, hands, feet, and genitals, the clinical manifestation may be termed angioedema. Up to 50% of children who have Urticaria have angioedema, with swelling of the hands and feet.
Classification of Angioedema
Based on the current clinical understanding of angioedema, it is helpful to divide the cases into the following types:
- Hereditary angioedema type 1 (HAE1).
- Hereditary angioedema type 2 (HAE2).
- Hereditary angioedema type 3 (HAE3).
- Acquired angioedema type 1 (AAE1) (very rare, only a few cases reported).
- Acquired angioedema type 2 (AAE2) (very rare, only a few cases reported).
- Non-histaminergic angioedema (INAE) (may occur in approximately 1 of 20 cases of angioedema).
- Idiopathic angioedema.
- Allergic angioedema (most common form).
- Angioedema induced by ACE inhibitor (4-8% of cases).
Hereditary angioedema (HAE) represents only 0.4% of cases of angioedema; however, specific diagnostic tests and the high mortality rate associated with hereditary angioedema deserve special attention.
In 1876, Milton described the first case of hereditary angioedema. Six years later, Quincke introduced the term angioneurotic edema to describe this disease.
Later, Osler described the disease as episodic episodes of subepithelial edema without holes, well-circumscribed, affecting mainly the extremities, larynx, face, and abdomen.
Hereditary angioedema is an autosomal dominant disease generally associated with a positive family history of angioedema. However, numerous cases are due to a new mutation of the gene.
In approximately 80-85% of the cases of hereditary angioedema, the serum levels of C1 inhibitor (C1INH) are reduced to approximately 30% of the reference range values.
In contrast, approximately 15% of patients with hereditary angioedema have reference range levels of antigenic C1INH but are primarily non-functional.
Missing or non-functional C1INH leads to a failure to control the C1 enzyme activity, resulting in lower levels of the early-acting complement components C4 and C2 due to excessive consumption.
A close relationship between plasma C1INH levels and the severity of attacks has not been observed.
Some patients with deficient levels of C1INH have few attacks, while others with much higher levels of C1INH have much more severe diseases.
HAE1 (low levels of functional C1INH) may be due to a wide range of genetic mutations.
In HAE2 (reference range or even increased levels of antigenic but non-functional C1INH), different point mutations have been described in or near the reactive center of the C1INH gene (SERPING1).
It has been found that structural abnormalities in SERPING1 genes in patients with hereditary angioedema are very heterogeneous. More than 150 mutations have been reported in unrelated patients. Agostino et al. have reported on the details of the genetic analysis.
HAE3 is the most recently described type of hereditary angioedema. In HAE3, the C1INH function and complement components are standard. Mutations have been found in the gene encoding coagulation factor XII (Hageman factor) in some patients with HAE3.
The essential features of HAE3 include the following:
- A long history of recurrent skin swelling, abdominal pain attacks, or episodes of upper airway obstruction.
- Family events, exclusively for women members of the family.
- No history of Urticaria in the patient or other family members.
- Average concentrations of C1INH and C4 in the plasma.
- Lack of response to antihistamines, corticosteroids or C1INH concentrate.
AAE1 is usually related to an underlying lymphoproliferative disorder. Complement-activating factors, idiotype / anti-idiotype antibodies, or other immune complexes associated with the underlying disorder destroy the function of C1INH.
The onset of angioedema may precede other symptoms of a lymphoproliferative disease; therefore, exploring the possibility of underlying malignancy in AAE1 cases is vital.
AAE2 is associated with autoantibodies that directly inhibit C1INH function. No underlying disorder is evident. AAE1 and AAE2 are very rare in the pediatric population.
INAE angioedema is angioedema without urticaria. Patients usually do not respond to H1 blockers (antihistamines). Parasites, infections, and autoimmune diseases are not present.
The idiopathic form of angioedema may be associated with swelling, Urticaria that persists for more than six weeks, or both. Thyroid dysfunction should be considered.
Swelling, Urticaria, or both characterize allergic angioedema in reaction to environmental factors such as food, insect bites or stings, cold, heat, latex, or a medication.
In general, these environmental factors cause histamine release, leading to swelling, hives, or both.
ACE inhibitors can also cause angioedema (e.g., Captopril, enalapril, genzapril, quinapril, ramipril) used to treat high blood pressure.
Inflammation can start some hours to years after you start taking the medication.
For other discussions about angioedema, see the general topics Acquired angioedema and hereditary angioedema.
Pathophysiology
The pathophysiology of angioedema associated with Urticaria is discussed in detail in Urticaria.
The cause of angioedema in patients with hereditary angioedema is still unknown. One hypothesis implies the persistent activation of C1, which results in a continuous segmentation of the following two components of the complement cascade, C4 and C2.
According to this hypothesis, cleaved C2 is acted by other proteolytic enzymes (possibly plasmin), generating a molecule similar to the kinin that causes angioedema. The participation of local mediators is practically uncertain.
A second hypothesis is that angioedema attacks are caused by the activation of the kinin generation system, which involves the cleavage of high molecular weight kininogen by activated kallikrein with the concomitant formation of bradykinin.
It is believed that bradykinin is responsible for episodes of angioedema.
In hereditary angioedema, two phenotypic variants have been described. HAE1 may be due to a wide range of genetic mutations, resulting in the lack of transcription of messenger RNA or in abnormal messenger RNAs that do not translate into a stable protein.
In HAE2, different point mutations have been described in or near the reactive center, which results in different dysfunctional proteins.
The AAE is due to malignant cells’ production of a factor that consumes C1INH. Most cases of deficient angioedema acquired with C1INH have been associated with the presence of lymphoid or other malignancy.
In rare cases, C1INH deficiency could be due to the consumption of the immune complex during autoimmune disease.
Another type of C1INH deficiency results from the monoclonal or oligoclonal production of antibodies that appear to recognize C1INH and destroy its functional activity.
Fluctuations in sex hormone levels at the beginning of adolescence, in the perimenopausal period, during pregnancy, or using oral contraceptives can precipitate edematous attacks in hereditary angioedema.
One study indicated that the number of attacks was significantly higher in women with high progesterone levels (≥4 nmol / L); A significantly lower attack frequency was observed in patients with a higher level (40 nmol / l) of sex hormone-binding globulin (SHBG).
Therefore, monitoring these two hormone levels may help predict attacks in patients with hereditary angioedema.
Studies on the role of C1INH have helped to understand the pathophysiology of angioedema better.
C1INH controls the activation of the complement system by inhibiting the esterase activity of C1r and C1s in the classical pathway and the esterase activity of mannose-binding lectin serine peptidase 2 (MASP2) in the mannose-binding lectin pathway.
The second significant physiological role of C1INH is now believed to be the regulation of the contact system, where activated coagulation factor XII and kallikrein intervene and inhibit.
In addition to these two main functions, C1INH inhibits factor XI, plasmin, and tissue plasminogen activator (tPA). The relevance of these activities live continues to be controversial.
However, convincing evidence in vivo supports the activation of plasminogen in humans by factor XIIa.
HAE3 has been observed exclusively in women, which seems to correlate with high levels of estrogen (e.g., pregnancy, use of oral contraceptives).
One report proposed two nonsense mutations (i.e., c.1032C → A and c.1032C → G) in F12, the gene encoding human coagulation factor XII (Hageman factor), as a possible cause of HAE3.
The transcription of F12 is regulated positively by estrogen, which may explain why only women are affected by HAE3.
Another extensive family study of HAE3 was reported. In this family, a Thr309Lys nonsense mutation was identified in the factor XII gene with a heterozygous pattern. This mutation was also identified in the patient’s mother, daughter, and son.
Along with the 5 German and French families reported for HAE3, a large Italian family was also reported from Canada.
A nonsense mutation in F12 was present in the three affected women of this family with hereditary estrogen-dependent angioedema.
In addition, these affected women have polymorphisms associated with lower levels of the enzyme converting both aminopeptidase and angiotensin-1, the main enzymes responsible for the degradation of bradykinin.
Therefore, multiple genes may contribute to angioedema associated with estrogen or estrogen, leading to clinical features’ observed heterogeneity.
You were born with hereditary angioedema (AEH); although you will always have it, the treatment helps you control it. There have been significant improvements in treatment, and researchers continue to look for new solutions.
Symptoms usually appear in childhood and get worse during adolescence. Many people do not know that hereditary angioedema is causing their swelling until they are adults.
With this disease, a specific protein in your body is not balanced. This causes small blood vessels to push the fluid to nearby areas of your body. That leads to a sudden swelling.
Where you have it in your body, how often fights occur, and how strong they are different for everyone. The attacks can come and go and move to different points during the same fight.
Your throat can swell. That can cut your airways and could be deadly. So, if you know you have hereditary angioedema and you feel a change like that, call emergency immediately.
Without treatment, it can have attacks every 1 to 2 weeks and be challenging to control.
Causes of Hereditary Angioedema
A problem with a gene that controls a blood protein called a C1 inhibitor often causes hereditary angioedema. In most cases, you do not have enough of this protein. In others, you have normal levels, but it does not work well.
For the most common form of hereditary angioedema, if one of your parents has it, you have a 50% chance of having it too. However, sometimes the change of genes occurs for unknown reasons. If you have the broken gene, you can transmit it to your children.
Symptoms of Hereditary Angioedema
The main symptom is swelling. It will not have itching or hives that people usually have with allergic reactions. A fight can last 2 to 5 days.
It can happen in different parts of the body:
- Mouth or throat.
- Hands.
- Pies.
- Way.
- Genitals.
- Belly.
Swelling in the throat is the most dangerous symptom.
Swelling in the feet and hands can be painful and make daily life difficult.
The swelling in your belly can cause:
- Extreme pain.
- Nausea.
- Throwing up.
- Diarrhea.
You may notice warning signs before inflammation begins. These may include:
- Extreme fatigue
- Muscle pains.
- Shudder.
- Headache.
- Bellyache.
- Hoarseness
- Humor changes.
What Causes Hereditary Angioedema
Although you may not be able to tell what your triggers are, the most common include:
- Stress or anxiety
- Mild injury or surgery.
- Diseases such as colds or flu.
- Physical activities such as writing, hammering, or pushing a lawnmower.
- Medications, including some used for high blood pressure and congestive heart failure.
Women may notice a difference in the number or sharpness of attacks when:
- Have your period.
- They are pregnant. For some women, it does not occur as often when pregnant, but the attacks return after giving birth.
- Use contraceptives or hormone replacement therapy that contains estrogen. Women generally say they have more and worse attacks while taking these medications.
Obtain a Diagnosis of Hereditary Angioedema
If you have had symptoms of hereditary angioedema, your doctor may ask:
What changes have you noticed?
Where have you been bloating? How often?
Have you had any on your face, neck, tongue, or throat?
Did you notice any changes that occur before the inflammation begins?
Have you had a stomach problem or stomach surgery?
Does anyone in your family have a problem with the swelling?
Have you or anyone in your family been treated for allergies?
The correct diagnosis is critical. Sometimes people are treated for allergies when the hereditary angioedema causes their swelling. Antihistamines and corticosteroids that treat allergies do not work well for this disease.
You may have severe stomach cramps and, if misdiagnosed, can cause surgery that you do not need. Your doctor will do a physical exam. You will also need blood tests to confirm that it is hereditary angioedema.
If you have it, ask your doctor to refer you to a specialist familiar with the condition. You should also ask your doctor if you should be tested on other family members, even if no one has symptoms.
Questions for your Doctor
Do I need more evidence?
What can I expect from this condition?
What treatments do you recommend? What are the secondary effects?
What should I do if my throat swells? How likely is that?
How can I find out what triggers my attacks?
Will I pass this condition to my children?
Should my family have the hereditary angioedema test?
Will this affect my plans to have a family?
Treatment for Hereditary Angioedema
Doctors can use medications to treat the attacks:
- Berinert.
- Cinryze.
- Conestat alfa (Rhucin, Ruconest).
- Ecallantide (Kalbitor).
- Icatibant (Firazyr).
You may also need oxygen or fluids intravenously to relieve your symptoms. Your doctor will make recommendations for what you need.
Taking care of yourself
Learn as much as you can about hereditary angioedema to make informed decisions about your treatment.
If you can discover your triggers, you can avoid them better. It helps track your attacks and symptoms in a diary and look for patterns.
Talk to your doctor before doing any dental work. You may want to take medicine to avoid a flare. Also, talk to your doctor before taking any new prescription medication.
There is a possibility that they may trigger an attack. Take your medical information with you at all times.
If your child has hereditary angioedema, consider any changes in behavior that you see before an attack. You will have to learn your triggers and treatment needs as you grow.
Ensure all caregivers and family members know about the condition and what to do if an attack occurs.
Remember: any swelling in the throat is an emergency. Take your medicine to detect seizures, consult a doctor, or go to the hospital immediately.
Connect with other people who live with HAE. They can share their ideas and tips to help you manage your symptoms.
Patient Education
The following aspects of patient education should be considered:
- Patients should be monitored closely by specialists for lifelong care.
- Patients must be careful to avoid trauma.
- Patients must wear a MedicAlert bracelet or carry an identification card.
- Patients must keep up with prophylactic medication.
What to expect
There is no cure for hereditary angioedema, but new treatments have allowed people to control their symptoms and enjoy an active life.
Angioedema associated with Urticaria is usually self-limiting in pediatric patients. In patients with hereditary angioedema, the onset of symptoms frequently occurs during adolescence.
Morbidity varies from case to case. In some patients, acute attacks occur once every several years, while attacks in others occur several times a year. Morbidity changes after therapy begin.
