Hereditary Angioedema
Disease Details
Family Health Simplified
- Description
- Hereditary angioedema is a rare genetic disorder characterized by recurrent episodes of severe swelling in various body parts, including the extremities, face, airway, and intestinal tract.
- Type
- Hereditary angioedema (HAE) is typically transmitted in an autosomal dominant manner. This means that an affected individual has a 50% chance of passing the mutated gene on to their offspring.
- Signs And Symptoms
- People diagnosed with Hereditary Angioedema have recurrent swelling in the extremities, genitals, face, lips, larynx or GI tract. 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.Some people may experience prodromal symptoms, including tingling, fatigue or weakness at the site of impending edema with one third of people experiencing an erythematous rash (erythema marginatum) as the prodromal symptom. Urticaria is usually not seen in hereditary angioedema, as compared to other causes of angioedema such as histamine induced symptoms.
- Prognosis
- About 25% of those affected die in the first two decades of life, mainly due to lack of treatment.
- Onset
- Hereditary angioedema typically has an onset in late childhood or adolescence, though symptoms can appear earlier. The onset age can vary widely among individuals, and it often becomes apparent around puberty. It is characterized by recurrent episodes of severe swelling in various body parts, including the limbs, face, intestinal tract, and airway.
- Prevalence
- Hereditary angioedema (HAE) is a rare genetic disorder. Its prevalence is estimated to be approximately 1 in 50,000 to 1 in 150,000 people worldwide.
- Epidemiology
- Data regarding the epidemiology 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.
- Intractability
-
Hereditary angioedema (HAE) is a genetic disorder characterized by recurrent episodes of severe swelling in various parts of the body, including the extremities, face, gastrointestinal tract, and airway. While it is a chronic condition, it is not intractable.
Effective management and treatment options are available. These include preventive medications to reduce the frequency of attacks and acute treatments to manage symptoms during an episode. Early diagnosis and appropriate treatment can significantly improve quality of life and reduce the impact of the disease. - Disease Severity
- Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of severe swelling (angioedema). The severity of the disease can vary widely among individuals. Some may experience frequent and severe attacks leading to significant morbidity, while others might have milder and less frequent symptoms. Triggers can include stress, trauma, hormonal changes, and certain medications. Severity is also influenced by whether the affected individual receives proper management and treatment.
- Healthcare Professionals
- Disease Ontology ID - DOID:14735
- Pathophysiology
- The pathophysiologic mechanisms contributing to bradykinin mediated angioedema in hereditary angioedema have been described. C1 inhibitor usually acts as an inhibitor of the plasma contact system. However in hereditary angioedema with C1 inhibitor deficiency, C1 inhibitor is either reduced in quantity and function (type 1) or dysfunctional (type 2), this leads to bradykinin disinhibition and bradykinin mediated activation of bradykinin B1 receptor and bradykinin B2 receptor on endothelial cells (cells lining blood vessels). This activation leads to vascular endothelial cadherin (a type of cell adhesion molecule) phosphorylation, internalization and degradation. Cadherin degradation leads to actin cytoskeleton contraction and increased pore size of the vascular endothelial cells. Adherens junctions are also reduced due to bradykinin B1 and B2 receptor activation and vascular endothelial growth factor (VEGF) is also activated. The degradation of these endothelial intercellular barrier junctions mediated by histamine leads to increased vascular permeability, leading to vascular leakage into surrounding tissues and thus causing the characteristic swelling seen in hereditary angioedema. The bradykinin B1 receptor (unlike the B2 receptor) is slowly and only partially desensitized after binding the bradykinin agonist, thus remaining consitutively active long after initial bradykinin exposure which can explain the protracted swelling seen in hereditary angioedema as compared to other causes of angioedema.
- Carrier Status
- Hereditary angioedema (HAE) is an inherited disorder characterized by recurrent episodes of severe swelling (angioedema). It is typically passed down in an autosomal dominant manner, meaning one copy of the altered gene in each cell is sufficient to cause the disorder. Carriers of one mutated gene typically show symptoms, so in the context of HAE, carriers are usually affected individuals. There is no concept of 'silent carriers' as in recessive diseases because carrying the mutation usually results in the manifestation of symptoms.
- Mechanism
-
Hereditary angioedema (HAE) is primarily caused by a deficiency or dysfunction of C1 inhibitor (C1-INH), an important regulatory protein in the complement system, coagulation, and kinin pathways.
**Mechanism:** The lack or malfunction of C1-INH leads to unregulated activation of these pathways, particularly the kallikrein-kinin system. This results in excessive production of bradykinin, a potent vasoactive peptide.
**Molecular Mechanisms:**
1. **C1-INH Deficiency (Type I HAE):** The most common form, where there is a reduced quantity of C1-INH protein due to mutations in the SERPING1 gene.
2. **C1-INH Dysfunction (Type II HAE):** Involves normal levels of C1-INH protein, but it is functionally defective, also associated with mutations in SERPING1.
3. **Normal C1-INH Levels (Type III HAE):** Also known as HAE with normal C1-INH, often linked to mutations in the F12 gene, which codes for coagulation factor XII, leading to increased bradykinin production.
This bradykinin-induced increased vascular permeability manifests clinically as recurrent episodes of severe, localized edema. - Treatment
-
Hereditary angioedema (HAE) is a rare genetic disorder that causes severe swelling in various parts of the body. Treatment options include:
1. **Prophylactic Treatments**:
- **C1 Esterase Inhibitor (C1-INH) Concentrates**: Can be administered intravenously.
- **Lanadelumab**: A monoclonal antibody given via subcutaneous injection.
2. **On-Demand Treatments** (for acute attacks):
- **C1 Esterase Inhibitor (C1-INH) Concentrates**: Administered intravenously to manage acute swelling.
- **Icatibant**: A bradykinin receptor antagonist given via subcutaneous injection.
- **Ecallantide**: A kallikrein inhibitor administered subcutaneously.
3. **Supportive Care**:
- Avoiding known triggers and managing stress.
- Emergency care for severe attacks that involve the airway.
4. **Androgens** (used less frequently):
- **Danazol or Stanozolol**: To increase the production of C1-INH, although these are less commonly used due to side effects.
Regular monitoring and a personalized treatment plan are essential for managing HAE effectively. - Compassionate Use Treatment
-
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of severe swelling. While there are specific treatments approved for HAE, sometimes physicians may consider off-label or compassionate use treatments for patients who do not respond well to standard therapies.
1. **Compassionate Use Treatments**: These are experimental drugs provided to patients who have exhausted all other treatment options. Access to such treatments typically requires approval from regulatory authorities. An example might include the investigational use of new C1-inhibitors before they receive formal approval.
2. **Off-Label Treatments**: These involve the use of approved medications for an unapproved indication. Some options might include:
- **Icatibant**: Originally approved for acute HAE attacks, it may be used off-label for different patient profiles.
- **Ecallantide**: Another drug approved for acute attacks but might be considered in a different dosing regimen or for prophylactic use in certain cases.
- **Tranexamic Acid**: Often used as an antifibrinolytic agent, it can have a role in managing HAE although it is not as effective as other agents specifically approved for HAE.
These treatments should only be considered under strict medical supervision by healthcare professionals experienced in managing HAE. - Lifestyle Recommendations
-
Lifestyle recommendations for managing hereditary angioedema (HAE) include:
1. **Avoid Triggers**: Identify and avoid known triggers such as stress, physical trauma, certain medications (e.g., ACE inhibitors), and hormonal changes.
2. **Medication Management**: Adhere to prescribed prophylactic treatments to prevent attacks and keep on-demand medications accessible for acute episodes.
3. **Stress Management**: Practice stress-reduction techniques like yoga, meditation, and deep-breathing exercises to help manage emotional triggers.
4. **Medical Alert**: Wear medical alert identification to inform healthcare providers of your condition in case of an emergency.
5. **Regular Monitoring**: Schedule regular check-ups with your healthcare provider to monitor your condition and update treatment plans as necessary.
6. **Healthy Lifestyle**: Maintain a balanced diet, regular exercise, and adequate sleep to support overall health.
7. **Education**: Educate yourself and those close to you about HAE to improve response times during attacks and reduce anxiety associated with the condition.
These strategies may help reduce the frequency and severity of HAE episodes and improve overall quality of life. - Medication
-
Hereditary angioedema (HAE) is typically managed with several types of medications, including:
1. C1-Inhibitor (C1-INH) Concentrates: These replace the deficient or dysfunctional C1-inhibitor protein in patients and can be used for both treatment and prophylaxis of attacks.
2. Bradykinin B2 Receptor Antagonists: Icatibant is an example of this class. It blocks the bradykinin receptor, which helps relieve swelling during an attack.
3. Kallikrein Inhibitors: Ecallantide is a drug that inhibits kallikrein, an enzyme involved in producing bradykinin, thereby reducing the severity of an attack.
4. Androgens: Danazol or stanozolol may be used as prophylaxis to increase levels of C1-inhibitor, though they are less commonly used due to side effects.
5. Fresh Frozen Plasma: In certain cases, fresh frozen plasma can be used as it contains C1-inhibitor.
Management of HAE aims to prevent attacks, minimize symptoms, and improve the quality of life for patients. Regular consultations with a healthcare provider are essential to tailor the treatment to individual needs. - Repurposable Drugs
-
Hereditary angioedema (HAE) is a rare genetic disorder characterized by spontaneous episodes of severe swelling. While there are specific treatments approved for HAE such as C1-inhibitor concentrates, there are also drugs initially intended for other conditions that have shown some effectiveness for HAE. These repurposable drugs include:
1. **Icatibant (Firazyr)**: A bradykinin B2 receptor antagonist originally developed for other types of angioedema but found effective for HAE, particularly during acute attacks.
2. **Ecallantide (Kalbitor)**: A plasma kallikrein inhibitor initially designed for reducing bradykinin production.
3. **Danazol**: An attenuated androgen, originally used to treat endometriosis, has been found to help increase levels of C1-inhibitor.
4. **Tranexamic Acid**: An antifibrinolytic agent used to treat excess bleeding, which can help reduce the frequency of HAE attacks.
These drugs offer alternative or adjunctive options in the management of HAE, particularly when specific HAE therapies are not available or suitable. - Metabolites
-
Hereditary angioedema (HAE) is primarily associated with a deficiency or dysfunction of the C1-inhibitor (C1-INH) protein, which plays a critical role in regulating various biochemical pathways, including the complement, coagulation, and kallikrein-kinin systems. The dysregulation can lead to uncontrolled activation of these pathways. Key metabolites and biochemical markers involved include:
1. **Bradykinin:** One of the main effector molecules that cause the swelling seen in HAE. Overproduction of bradykinin leads to increased vascular permeability, resulting in angioedema.
2. **C1-inhibitor (C1-INH):** Deficiency or dysfunction of this protein is a hallmark of HAE. It is critical for the regulation of the complement system.
3. **C4 and C2 Levels:** Typically, patients with HAE have low levels of these complement components. C4 is usually more noticeably reduced.
4. **Kallikrein:** An enzyme that, when unregulated due to C1-INH deficiency, promotes the generation of bradykinin from high-molecular-weight kininogen (HMWK).
Managing and diagnosing HAE often involves monitoring these biochemical markers to better understand disease activity and guide treatment. - Nutraceuticals
- There is no established scientific evidence to support the effectiveness of nutraceuticals or nanotechnology-based treatments for hereditary angioedema. Management typically involves preventative measures and medications prescribed by healthcare professionals such as C1 inhibitor concentrates, bradykinin receptor antagonists, and androgens. Always consult a healthcare provider for treatment advice.
- Peptides
- Hereditary angioedema (HAE) is linked to issues in the regulation of peptide hormones, specifically bradykinin. Elevated bradykinin levels cause the sudden swelling episodes characteristic of HAE.