What is hereditary angioedema? Hereditary angioedema (HAE) clinically presents with recurrent, self-limiting episodes of edema affecting the skin of the body, mucous membranes of the upper respiratory tract, gastrointestinal and urogenital systems. The edema is pale, firm, non-itchy, and painful, with a tendency for proximal spread and spontaneous resolution within 24-48 hours. These episodes can be disfiguring, disabling, or life-threatening in the case of laryngeal attacks.
Frequency of hereditary angioedema. Similar to other European countries, Bulgaria has a frequency of 1 in 50,000 to 1 in 100,000. There are no observed gender or ethnic differences. HAE rarely manifests before the age of 5 or after the age of 60. Asymptomatic adult patients have been observed in approximately 5% of cases.
The disease is due to a genetic defect in the synthesis of plasma C1-esterase inhibitor, a naturally occurring molecule known to inhibit kallikrein, bradykinin, and other serine proteases in the blood. It is transmitted in an autosomal dominant manner. If left untreated, HAE can lead to a mortality rate exceeding 40%, primarily due to upper respiratory tract edema.
Like other autosomal dominant disorders, patients with HAE usually inherit one normal gene and one defective gene. Thus, the child of an affected mother has a 50% chance of inheriting the defective gene.
What is the main cause of hereditary angioedema (HAE)? The main cause of HAE is the deficiency or consumption of C1-esterase inhibitor (C1-INH), which can occur in two main ways:
Pathophysiology of an HAE attack. Precipitating factors, such as trauma and infection, lead to activation of the complement system. Precipitating factors also lead to activation of the contact and fibrinolytic systems. In normal individuals, C1-INH regulates these systems by blocking these pathways, thereby preventing them from becoming overactive.
Patients with HAE have low levels of C1-INH, and once the enzyme reserves are further depleted, the systems are uncontrollably activated, resulting in the release of bradykinin, which is considered responsible for angioedema.
How does the condition manifest? Generally, it manifests after the age of 7, but there are many exceptions. The symptoms of an HAE attack typically present as swelling in one or more organs, most commonly affecting the skin, gastrointestinal tract, and/or respiratory airways.
The cutaneous form of hereditary angioedema (HAE) presents as recurrent, self-limiting swelling episodes on the skin of the body, extremities, head, neck, chest wall, often including the genital area and facial regions such as the lips, eyelids, and tongue. The swellings are localized, pale, firm, non-itchy, sometimes painful, with a tendency for proximal spread, and spontaneously resolve within 24-48 hours, with a maximum duration of up to 72 hours.
When the mucous membranes of the gastrointestinal tract are affected, patients experience severe abdominal pain mimicking acute surgical abdomen (often leading to unnecessary abdominal surgeries), accompanied or followed by vomiting and watery diarrhea.
The most severe manifestation is the involvement of the mucous membranes of the respiratory airways, particularly the larynx, leading to swelling with a potential risk of asphyxiation. Patients with no prior history of upper airway involvement are at risk of asphyxiation since there is no correlation between the anatomical location of previous attacks and the likely site of future attacks. In acute laryngeal attacks, death can occur within twenty minutes. Pregnant women with HAE are at risk of premature delivery. One study reports a 60% rate of premature birth.
What is the frequency of HAE attacks? HAE is an unpredictable condition with significant variations in the frequency and age of onset of attacks. Attacks can vary with age and may manifest at a single or multiple locations. Patients with symptomatic HAE usually experience at least one acute attack per month. Most HAE attacks last for 2-5 days, resulting in an annual impairment (absence from school/work) ranging from 20 to 100 days.
Risk factors triggering HAE attacks include trauma, surgical interventions, anesthesia, dental procedures, emotional stress, infections, menstruation, childbirth, menopause, ingestion of certain foods and medications (contraceptives, ACE inhibitors), insect bites or stings, and accidents. In the case of Type III, variations in hormone levels are also considered to have a potential influence.
There is limited correlation between the symptoms of attacks and the specific genetic defect, even within the same family. Additionally, age, gender, and previous episodes cannot predict the location, severity, or timing of future attacks.
How can HAE be accurately diagnosed? The diagnosis of HAE is complex and requires detailed clinical, laboratory, and genetic data. Specific laboratory tests used in diagnosing HAE include measuring C1 inhibitor – qualitative, C1 inhibitor – functional, and serum C4 levels. Serum C1q levels can be used to differentiate acquired angioedema from HAE. Importantly, the clinical symptoms should not be influenced by the use of routine anti-allergic therapy with antihistamines and corticosteroids.
Ancillary investigations can support the accurate diagnosis. Typically, the results of most laboratory tests are normal. If eosinophilia and/or an elevated erythrocyte sedimentation rate (ESR) are present, other conditions should be considered. During an attack, hemoconcentration and prerenal azotemia may be observed due to hypovolemia.
Determining the levels of C1 esterase inhibitor (qualitative and functional) and C4 have been established as the “gold standard” in the diagnosis of HAE. C4 levels are low and remain decreased in between attacks. During an attack, the C4 level may decrease to 0. There are variations in laboratory findings among different types of HAE.
What is the prognosis for patients with HAE? The mortality rate of undiagnosed HAE can exceed 40% and is primarily due to upper airway obstruction. Asphyxiation can occur within 20 minutes to 14 hours in patients of all ages and those without a prior history of respiratory symptoms. That is why early and accurate diagnosis of HAE is crucial in reducing the morbidity and mortality associated with HAE.
The goal of physicians treating patients with HAE is to provide active means for maintaining personal safety and achieving a normal quality of life. During each acute episode, the patient is at risk of the vicious cycle of bradykinin and C1-INH-mediated activation until appropriate treatment is administered (which raises serum C1-INH levels) or spontaneous remission occurs.
Treatment that effectively corrects the underlying cause of HAE would theoretically be more effective in reducing the severity and duration of acute HAE episodes. Treatment that restores physiological balance through C1-INH substitution has the potential to improve the patient’s quality of life with minimal interruption to daily activities.
Here are some links to clinical trials on Angioedema we are currently recruiting for: