Hereditary angioedema (HAE) is a rare genetic disorder caused due to recurrent episodes of severe swelling.
This condition affects various parts of the body including extremities, face, and airways. It is an autosomal dominant disease that causes low levels of the plasma protein C1 inhibitor.
Types of HAE are:
Type I: It is most common form, where C1-INH levels are reduced
Type II: Normal levels of C1-INH are present, but the protein is dysfunctional
Type III: It is rare and not linked to C1-INH deficiency
Estrogen-dependent angioedema in women is caused due to HAE with normal C1 inhibitor levels and function.
C1-INH dysfunction causes excessive complement and contact system activation to disrupt bradykinin production. Bradykinin promotes blood vessel dilation and swelling through increased permeability.
Epidemiology
Hereditary angioedema is rare disorder affects nearly 20% population.
HAE affect individuals of all races with no ethnic bias. Both men and women are equally affected, but women may experience more severe attacks.
C1-INH deficiency present from birth in HAE with perinatal angioedema rare their symptoms arise in first or second decade.
Childhood swelling may go unnoticed and worsens in puberty for patients. HAE with normal C1 inhibitor levels rare before puberty.
Anatomy
Pathophysiology
C1-INH, alpha-antitrypsin, antithrombin III, and angiotensinogen are serpin family protease inhibitors to inactivate target proteases.
Regulation of production not fully understood, but patients respond to androgens and show increased levels.
The C1 inhibitor binds to and inactivates proteins to cause low C1 inhibitor levels and removal from circulation.
Etiology
Causes of HAE are:
Autosomal Dominant Inheritance
Types of HAE
Bradykinin Overproduction
Trauma and Surgery
Stress and Hormones
Genetics
Prognostic Factors
Abdominal attacks can cause unnecessary surgery, diagnosis delays, and narcotic dependence.
Worse prognosis for HAE patients with early attacks compared to late attacks.
Mortality rate was 20% to 30% before effective therapy. Prognosis improved with prophylactic therapy for HAE.
Patients with HAE do not require C1-INH for immune function or infection risk.
Clinical History
Detailed information including initial episodes and family history of patient should be gathered.
Physical Examination
Facial and Periorbital swelling assessment
Abdominal Examination
Airway Assessment
Age group
Associated comorbidity
Associated activity
Acuity of presentation
Life-Threatening Acute symptoms are:
Throat tightness, difficulty swallowing, and voice changes
Severe symptoms are:
Crampy abdominal pain, nausea, and vomiting
Differential Diagnoses
Contact Urticaria Syndrome
Cholinergic Urticaria
Urticarial Vasculitis
Pressure Urticaria
Dermographism Urticaria
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
Hypotensive patients with fluid sequestration may need extensive IV fluids for hemodynamic stability.
For HAE types I and II, treat acute attacks with C1 inhibitor concentrates or kallikrein inhibitor.
Ecallantide is a recombinant, selective, and reversible kallikrein inhibitor that increases the effectiveness of C1-INH concentrate.
Use danazol doses to treat without normalizing C1-INH levels and long-term use may cause arterial hypertension.
Antifibrinolytic agents like epsilon-aminocaproic acid or tranexamic acid can be used for prophylaxis but less effective.
Treatment started with weakened androgens for prevention before adjusting for severity and side effects.
The procedure should be performed to minimize trauma. Gentle atraumatic techniques should be indicated in dental work or surgeries.
use-of-phases-in-hereditary-angioedema
In initial treatment phase use of acute and preventive management therapies to resolve symptoms during an acute HAE attack.
Pharmacologic therapy is effective in the treatment phase as it includes use of androgens, C1-inhibitor concentrates, and bradykinin receptor antagonists.
In supportive care and management phase, patients should receive required attention such as lifestyle modification and intervention therapies.
The regular follow-up visits with the physician are scheduled to check the improvement of patients along with treatment response.
Initially 200 mg orally 2-3 times daily
After a better initial response, try decreasing the dose by half or less
Keep 1-3 months of an interval between this dose titration
Increase the daily dose by 200 mg if an attack occurs
Administer 300 milligrams subcutaneously every two weeks
If the patient has been free from attacks for more than six months and is well-controlled
considering a dosing interval of 300 mg subcutaneously every four weeks can be an effective option
Indicated for Acute Treatment for Hereditary Angioedema
Berinert: 20 units/Kg intravenously infused slowly; it should not exceed 4 ml/min
It can be self-administered by patients after completing education for intravenous administration
Prophylaxis for Hereditary Angioedema
Haegarda: 60 IU/Kg subcutaneous two times a week (i.e.,3-4 days)
Cinryze: 1000 units intravenously every three-four days, infuse for about 10 min (1 ml/min)
Kidney Transplant Rejection as Orphan
Cinryze: After kidney transplantation, it is an orphan designed for therapy of acute antibody-mediated rejections
Delayed Graft Function as Orphan
After solid organ transplantation, prevention, and therapy of delayed graft functions
Indicated as prophylaxis of HAE (hereditary angioedema attacks)
150 mg orally each day
Dose Modifications Hepatic impairment
For severe or moderate Child-Pugh B/C, reduce the dose to 110 mg orally each day
P-gp or BCRP inhibitors
When these are administered for long, like cyclosporine, reduce the dose to 110 mg orally each day
Persistent GI reactions
Reduce the dose to 110 mg orally each day
Indicated for the prevention of hereditary angioedema (HAE) attacks
The suggested dose is 80 mg subcutaneously every four weeks
Administration every eight weeks may be considered
Take 2 tablets (600 mg) at the first sign of an HAE attack.
If symptoms do not improve or return, a second dose of 2 tablets can be taken at least 3 hours later.
Do not exceed 4 tablets (1,200 mg) in a 24-hour period. Dosage modification
Dosage adjustments when EKTERLY is used with CYP3A4 inhibitors:
Strong CYP3A4 inhibitors: Do not use EKTERLY at the same time.
Moderate CYP3A4 inhibitors: Lower the EKTERLY dose to 300 mg (1 tablet) at the first sign of an acute HAE attack. If symptoms do not improve, get worse, or come back, a second 300 mg dose may be taken at least 3 hours later.
Weak CYP3A4 inhibitors: No change to the EKTERLY dose is needed. Dosage adjustments when EKTERLY is used with CYP3A4 inducers:
Strong or moderate CYP3A4 inducers: Do not use EKTERLY together with these medicines.
Weak CYP3A4 inducers: No change to the EKTERLY dose is needed.
Administer initial dose of 400 mg (two 200-mg injections) through subcutaneous route, followed by maintenance dose 1 month later
Administered dose of 200 mg through subcutaneous route monthly
Indicated for acute heart attacks caused due to hereditary angioedema
For more than 12 years-
30 mg injected subcutaneously as 3 separate injections of 10 mg/ml
Age 2 to <6 years- Administer a subcutaneous dose of 150 mg every four weeks
Age 6 to <12 years-The recommended dosage for subcutaneous administration is 150 mg every two weeks
In cases where the patient has achieved good control of symptoms, such as being free from attacks, for a period of more than six months, the dosing interval can be considered as 150 mg every four weeks
Age ≥12 years-The recommended dosage is 300 mg subcutaneously every two weeks
Indicated for Acute Treatment for Hereditary Angioedema
Berinert: 20 units/Kg intravenously infused slowly; it should not exceed 4 ml/min
Prophylaxis for Hereditary Angioedema
Haegarda: 60 IU/Kg subcutaneous two times a week (i.e.,3-4 days)
Cinryze
Age >12 years
1000 units intravenously every three-four days, infuse for about 10 min (1 ml/min)
The dose may enhance to 2500 units intravenously every three-four days, depending on the patient’s response; it should not exceed 100 U/Kg
Age 6-11 years
500 units intravenously every three-four days, infuse for about 5 min (5 ml/min)
The dose may enhance to 1000 units intravenously every three-four days, depending on the patient’s response
Age <6 years
Safety and efficacy not established
Indicated as prophylaxis of HAE (hereditary angioedema attacks) in adolescents over 12 years of age
150 mg orally each day
Dose Modifications Hepatic impairment
For severe or moderate Child-Pugh B/C, reduce the dose to 110 mg orally each day
P-gp or BCRP inhibitors
When these are administered for long, like cyclosporine, reduce the dose to 110 mg orally each day
Persistent GI reactions
Reduce the dose to 110 mg orally each day
Adolescents Below 84 kg: 50 IU/kg intravenous infusion for 5 minutes; should not exceed more than 4200 IU/dose Above 84 kg: 4200 IU intravenous infusion for 5 minutes If symptoms of attack persist, can be administered with a second dosage at a recommended dosage level (should not exceed more than 4200 IU/dose) Should not exceed more than 2 doses/24 hours
Approved for treatment of acute hereditary angioedema (HAE) attacks in patients 12 years and older.
Recommended dose: 600 mg by mouth at the first sign of an acute HAE attack.
If symptoms do not improve, worsen, or return, a second 600 mg dose can be taken at least 3 hours after the first.
Do not take more than 1,200 mg in a 24-hour period. Dosage modifications When given with CYP3A4 inhibitors or inducers:
Strong CYP3A4 inhibitors or strong/moderate inducers: Do not use together.
Moderate CYP3A4 inhibitors: Lower the starting and possible second dose to 300 mg.
Weak CYP3A4 inhibitors or inducers: No dose change needed.
For kidney function:
Mild impairment (eGFR 60–89): No meaningful difference in how the drug works.
Moderate to severe impairment (eGFR below 60): Effects are unknown.
For liver function:
Mild impairment (Child-Pugh A): No dose change needed.
Moderate impairment (Child-Pugh B): Reduce the initial and possible second dose to 300 mg.
Severe impairment (Child-Pugh C): Do not use.
<12 years: Safety and efficacy not established
For ≥12 years old:
Administer initial dose of 400 mg (two 200-mg injections) through subcutaneous route, followed by maintenance dose 1 month later
Administered dose of 200 mg through subcutaneous route monthly
Hereditary angioedema (HAE) is a rare genetic disorder caused due to recurrent episodes of severe swelling.
This condition affects various parts of the body including extremities, face, and airways. It is an autosomal dominant disease that causes low levels of the plasma protein C1 inhibitor.
Types of HAE are:
Type I: It is most common form, where C1-INH levels are reduced
Type II: Normal levels of C1-INH are present, but the protein is dysfunctional
Type III: It is rare and not linked to C1-INH deficiency
Estrogen-dependent angioedema in women is caused due to HAE with normal C1 inhibitor levels and function.
C1-INH dysfunction causes excessive complement and contact system activation to disrupt bradykinin production. Bradykinin promotes blood vessel dilation and swelling through increased permeability.
Hereditary angioedema is rare disorder affects nearly 20% population.
HAE affect individuals of all races with no ethnic bias. Both men and women are equally affected, but women may experience more severe attacks.
C1-INH deficiency present from birth in HAE with perinatal angioedema rare their symptoms arise in first or second decade.
Childhood swelling may go unnoticed and worsens in puberty for patients. HAE with normal C1 inhibitor levels rare before puberty.
C1-INH, alpha-antitrypsin, antithrombin III, and angiotensinogen are serpin family protease inhibitors to inactivate target proteases.
Regulation of production not fully understood, but patients respond to androgens and show increased levels.
The C1 inhibitor binds to and inactivates proteins to cause low C1 inhibitor levels and removal from circulation.
Causes of HAE are:
Autosomal Dominant Inheritance
Types of HAE
Bradykinin Overproduction
Trauma and Surgery
Stress and Hormones
Abdominal attacks can cause unnecessary surgery, diagnosis delays, and narcotic dependence.
Worse prognosis for HAE patients with early attacks compared to late attacks.
Mortality rate was 20% to 30% before effective therapy. Prognosis improved with prophylactic therapy for HAE.
Patients with HAE do not require C1-INH for immune function or infection risk.
Detailed information including initial episodes and family history of patient should be gathered.
Facial and Periorbital swelling assessment
Abdominal Examination
Airway Assessment
Life-Threatening Acute symptoms are:
Throat tightness, difficulty swallowing, and voice changes
Severe symptoms are:
Crampy abdominal pain, nausea, and vomiting
Contact Urticaria Syndrome
Cholinergic Urticaria
Urticarial Vasculitis
Pressure Urticaria
Dermographism Urticaria
Hypotensive patients with fluid sequestration may need extensive IV fluids for hemodynamic stability.
For HAE types I and II, treat acute attacks with C1 inhibitor concentrates or kallikrein inhibitor.
Ecallantide is a recombinant, selective, and reversible kallikrein inhibitor that increases the effectiveness of C1-INH concentrate.
Use danazol doses to treat without normalizing C1-INH levels and long-term use may cause arterial hypertension.
Antifibrinolytic agents like epsilon-aminocaproic acid or tranexamic acid can be used for prophylaxis but less effective.
Treatment started with weakened androgens for prevention before adjusting for severity and side effects.
Allergy and Immunology
Use of protective gear during activities that pose a risk of injury.
Minor trauma should be managed like bumping into objects, which can trigger an episode of swelling.
Create a calm environment at home and workplace to minimize stress.
HAE is not triggered by allergens and avoid environmental irritants to reduce stress on the body.
Proper awareness about HAE should be provided and its related causes with management strategies.
Appointments with a physician and preventing recurrence of disorder is an ongoing life-long effort.
Allergy and Immunology
Fresh frozen plasma:
Administer 2 units of FFP to sustain control that prevents development of angioedema.
Allergy and Immunology
Danazol:
It reduces the frequency of attacks in most patients involving the airway.
Allergy and Immunology
C1 inhibitor human:
It increases plasma concentration and activity of C1 inhibitors.
Allergy and Immunology
Ecallantide:
It reduces conversion of kininogen to bradykinin.
Lanadelumab:
It inhibits proteolytic activity to control excess bradykinin generated with HAE.
Allergy and Immunology
Icatibant:
It is indicated for acute attacks of hereditary angioedema.
It inhibits fibrinolysis through inhibition of plasminogen activator substances.
Allergy and Immunology
The procedure should be performed to minimize trauma. Gentle atraumatic techniques should be indicated in dental work or surgeries.
Allergy and Immunology
In initial treatment phase use of acute and preventive management therapies to resolve symptoms during an acute HAE attack.
Pharmacologic therapy is effective in the treatment phase as it includes use of androgens, C1-inhibitor concentrates, and bradykinin receptor antagonists.
In supportive care and management phase, patients should receive required attention such as lifestyle modification and intervention therapies.
The regular follow-up visits with the physician are scheduled to check the improvement of patients along with treatment response.
Hereditary angioedema (HAE) is a rare genetic disorder caused due to recurrent episodes of severe swelling.
This condition affects various parts of the body including extremities, face, and airways. It is an autosomal dominant disease that causes low levels of the plasma protein C1 inhibitor.
Types of HAE are:
Type I: It is most common form, where C1-INH levels are reduced
Type II: Normal levels of C1-INH are present, but the protein is dysfunctional
Type III: It is rare and not linked to C1-INH deficiency
Estrogen-dependent angioedema in women is caused due to HAE with normal C1 inhibitor levels and function.
C1-INH dysfunction causes excessive complement and contact system activation to disrupt bradykinin production. Bradykinin promotes blood vessel dilation and swelling through increased permeability.
Hereditary angioedema is rare disorder affects nearly 20% population.
HAE affect individuals of all races with no ethnic bias. Both men and women are equally affected, but women may experience more severe attacks.
C1-INH deficiency present from birth in HAE with perinatal angioedema rare their symptoms arise in first or second decade.
Childhood swelling may go unnoticed and worsens in puberty for patients. HAE with normal C1 inhibitor levels rare before puberty.
C1-INH, alpha-antitrypsin, antithrombin III, and angiotensinogen are serpin family protease inhibitors to inactivate target proteases.
Regulation of production not fully understood, but patients respond to androgens and show increased levels.
The C1 inhibitor binds to and inactivates proteins to cause low C1 inhibitor levels and removal from circulation.
Causes of HAE are:
Autosomal Dominant Inheritance
Types of HAE
Bradykinin Overproduction
Trauma and Surgery
Stress and Hormones
Abdominal attacks can cause unnecessary surgery, diagnosis delays, and narcotic dependence.
Worse prognosis for HAE patients with early attacks compared to late attacks.
Mortality rate was 20% to 30% before effective therapy. Prognosis improved with prophylactic therapy for HAE.
Patients with HAE do not require C1-INH for immune function or infection risk.
Detailed information including initial episodes and family history of patient should be gathered.
Facial and Periorbital swelling assessment
Abdominal Examination
Airway Assessment
Life-Threatening Acute symptoms are:
Throat tightness, difficulty swallowing, and voice changes
Severe symptoms are:
Crampy abdominal pain, nausea, and vomiting
Contact Urticaria Syndrome
Cholinergic Urticaria
Urticarial Vasculitis
Pressure Urticaria
Dermographism Urticaria
Hypotensive patients with fluid sequestration may need extensive IV fluids for hemodynamic stability.
For HAE types I and II, treat acute attacks with C1 inhibitor concentrates or kallikrein inhibitor.
Ecallantide is a recombinant, selective, and reversible kallikrein inhibitor that increases the effectiveness of C1-INH concentrate.
Use danazol doses to treat without normalizing C1-INH levels and long-term use may cause arterial hypertension.
Antifibrinolytic agents like epsilon-aminocaproic acid or tranexamic acid can be used for prophylaxis but less effective.
Treatment started with weakened androgens for prevention before adjusting for severity and side effects.
Allergy and Immunology
Use of protective gear during activities that pose a risk of injury.
Minor trauma should be managed like bumping into objects, which can trigger an episode of swelling.
Create a calm environment at home and workplace to minimize stress.
HAE is not triggered by allergens and avoid environmental irritants to reduce stress on the body.
Proper awareness about HAE should be provided and its related causes with management strategies.
Appointments with a physician and preventing recurrence of disorder is an ongoing life-long effort.
Allergy and Immunology
Fresh frozen plasma:
Administer 2 units of FFP to sustain control that prevents development of angioedema.
Allergy and Immunology
Danazol:
It reduces the frequency of attacks in most patients involving the airway.
Allergy and Immunology
C1 inhibitor human:
It increases plasma concentration and activity of C1 inhibitors.
Allergy and Immunology
Ecallantide:
It reduces conversion of kininogen to bradykinin.
Lanadelumab:
It inhibits proteolytic activity to control excess bradykinin generated with HAE.
Allergy and Immunology
Icatibant:
It is indicated for acute attacks of hereditary angioedema.
It inhibits fibrinolysis through inhibition of plasminogen activator substances.
Allergy and Immunology
The procedure should be performed to minimize trauma. Gentle atraumatic techniques should be indicated in dental work or surgeries.
Allergy and Immunology
In initial treatment phase use of acute and preventive management therapies to resolve symptoms during an acute HAE attack.
Pharmacologic therapy is effective in the treatment phase as it includes use of androgens, C1-inhibitor concentrates, and bradykinin receptor antagonists.
In supportive care and management phase, patients should receive required attention such as lifestyle modification and intervention therapies.
The regular follow-up visits with the physician are scheduled to check the improvement of patients along with treatment response.
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