Hereditary angioedema is a rare disease

What is hereditary angioedema?

Hereditary angioedema (HAE) is a rare genetic disorder that causes sudden and severe episodes of swelling in various parts of the body, including the skin, gastrointestinal tract, and airways. The symptoms start in childhood and get worse in adolescence. Inflammation of the lips, face, feet, and hands is a symptom that some HAE patients report.   Constipation, queasiness, and an upset stomach are typical signs of gastrointestinal side effects. Despite its lifetime nature, HAE is manageable with medication. Here's a breakdown to help you understand it better.

Hereditary angioedema

What are the causes of hereditary angioedema?

One parent with the gene has a 50% probability of passing it on. A protein called C1 esterase inhibitor (C1-INH) that regulates inflammation and fluid balance is deficient or dysfunctional.

Prevalence

• Worldwide prevalence is estimated as 1 in 50,000, ranging from 1:10,000 to 1:150,000.
• A systematic review showed 1.22 incidences per 100,000, lower in Asia and Africa than in Europe and North America.

Challenges in diagnosing

• Patients often wait 3.9 to 26 years for diagnosis.
• Only 38% of patients are diagnosed correctly within 1–3 years.

Demographics

• Both men and women are affected, but women may have more severe bouts with Type III HAE.
• Without ethnic bias, it occurs across all races and ethnicities.
• Beginning in childhood or adolescence, symptoms develop around puberty.

Pathophysiology and cause

Genetic abnormalities that affect vascular permeability cause episodic swelling in hereditary angioedema (HAE). The aetiology and pathophysiology are organized here.

Cause, origin

• Autosomal dominant inheritance: Mutated parents pass it on in most cases.
• Over 90% of patients have SERPING1 gene mutations, which alter C1 esterase inhibitor synthesis or action.
• Additional gene alterations in Type III HAE:
• Factor XII
• Plasminogen (PLG), Angiopoietin-1 (ANGPT1), Kininogen-1 (KNG1), and Myoferlin exist.
• Mutations cause C1-INH deficiency or KKS regulatory changes.

Mechanisms of pathophysiology

• C1-INH deficiency/dysfunction compromises control over the complement system (classical and lectin pathways).
• Key in inflammation and vascular permeability. KKS
• The fibrinolytic and coagulation pathways
• This causes excessive bradykinin, a powerful vasodilator that raises vascular permeability.
• Fluid leaks into tissues
• Swells without itching or hives

HAE kinds

Based on C1 esterase inhibitor (C1-INH) protein levels and function, hereditary angioedema (HAE) has three primary types:

The most prevalent form of HAE is Type I (≈85% of cases).

• Low C1-INH levels cause
• Unregulated bradykinin production causes edema.

Type II HAE accounts for around 15% of cases.

• Normal or high C1-INH levels, but protein dysfunction
• Similar symptoms to Type I

HAE type III (normal C1-INH)

• Rare and unclear
• Normal C1-INH levels and function
• Associated with F12 gene mutations
• It mainly affects natal females and may be estrogen-dependent.

Presenting hereditary angioedema symptoms

Hereditary angioedema (HAE) causes unpredictable, recurring swelling in different body systems. Its clinical presentation is organized here:

Common Swelling Sites

• The skin and soft tissues: Hands, feet, face, genitalia
• GI tract: Intestines, abdominal wall
• Upper airway: Tongue, throat, larynx (life-threatening)

 Key symptoms

• Skin swelling without itching or bleeding: HAE edema doesn't itch or have an allergic reaction.

Attacks on the abdomen

• Painful cramps
• Vomiting, diarrhoea
• Can resemble appendicitis or bowel blockage

Airway issue:

• Tight throat, hoarseness
• Trouble breathing or swallowing
• Untreated asphyxiation risk

Early Warning Signs

• Fatigue/irritability
• Skin tingling or tightness, Mood or anxiety changes
• Marginal erythema

Attack Duration/Frequency

• 2–5-day episodes are typical.
• Periods range from weekly to annual.
• One attack may cause swelling and migration.

Triggers and Onset

• Children and adolescents often develop symptoms.
• Common causes:
• Trauma or stress
• Menstruation-related hormonal alterations
• Surgery or infections
• Drugs like ACE inhibitors

Pattern of assaults

Clinical research and patient surveys have found trends and triggers for hereditary angioedema (HAE) attacks, which vary. The overview is structured as follows:

• The frequency and duration
• Attack frequency varies greatly:
• Some have monthly or weekly episodes.
• Some have attacks months or years apart.
• Average duration: 12–72 hours, occasionally up to 5 days.

Repeat and Progress

• Many attacks start in childhood or adolescence.
• Age, especially puberty, might worsen symptoms.
• During one episode, swelling might move from hands to face.

Common Triggers

• Mental tension (most common)
• Tasks like typing, pounding, and mowing
• Menstruation, hormonal changes
• Flu, colds, infections
• Minor surgery or injuries
• Fatigue and weather change

Early Signs

• Tingling, weariness, and mood changes may precede an attack.
• Some experience erythema marginatum, a light rash preceding swelling.

Also read https://www.worldallergyorganizationjournal.org/article/S1939-4551(19)30453-3/fulltext.

Investigations for hereditary angioedema  

Clinical suspicion, laboratory tests, and genetic analysis are used to diagnose hereditary angioedema (HAE). A structured review of major investigations:

Initial Lab Tests

• These distinguish HAE from other angioedemas:
• Screening marker C4 levels are generally low, even between assaults.
• Low C1-INH-antigenic levels in Type I and normal/high in Type II indicate protein levels.
• C1-INH functional assay—Low Type I and II. Measures protein activity at the C1q level. -Normal in HAE, low in acquired angioedema to distinguish hereditary from acquired forms
• Note that acute attack testing improves the C4 and C1-INH diagnoses.

Genetic Testing

• Normal C1-INH levels and function, but symptoms remain (suspected Type III HAE).
• Finds F12, PLG, ANGPT1, and KNG1 mutations.
• Helpful for family screening, especially asymptomatic relatives.

Clinical Indications for Testing

• Repeated angioedema without urticaria
• Unknown abdominal ache
• Laryngeal swelling or unclear respiratory symptoms
• Poor antihistamine, corticosteroid, or epinephrine response
• Similar symptoms in family or HAE3 diagnosis

Managing hereditary angioedema

The video about the treatment of hereditary angioedema

A tailored, multi-tiered approach to managing hereditary angioedema (HAE) includes acute therapy, long-term prevention strategies, and lifestyle interventions. A structured guide:

On-demand acute treatment

• Reduces the severity and duration of current attacks:
• Berinert and Cinryze offer C1-INH substitution.
• Icatibant (Firazyr) blocks Bradykinin.
• Ecallantide (Kalbitor) inhibits kallikrein
• Sebetralstat, the newly reviewed oral option, offers quick, non-injectable relief.

Two on-demand pharmaceutical doses should always be available for patients.

• Prevention Treatment
• Lowers attack frequency and severity:
• Long-term options:
• Lanadelumab (Takhzyro): Anti-kallikrein monoclonal antibody
• Preventing C1-INH with IV or subcutaneous infusions
• Temporary prevention:
• Before surgery or dentistry
• C1-INH or decreased androgens (danazol)

Special Populations

• In women, estrogen can exacerbate symptoms; hormonal treatment may be needed.
• For children, the dosing and safety of medications vary, so I prefer using C1-INH.
• C1-INH is safest during pregnancy; other medications are contraindicated.

The prognosis and complications

Hereditary angioedema (HAE) can be life-threatening if it is not diagnosed and treated early. Here is an organized outline of the complications and prognosis associated with hereditary angioedema:

Common complication

• Airway blockage:
• Misdiagnosis:
• Chronic pain:
• Disability and disfigurement:
• Drug dependence:
• Before contemporary therapies, airway-related deaths accounted for 20–30% of mortality rates.
• Since on-demand and preventative treatments are available, life expectancy is now comparable to the general population.
• Early-onset HAE is characterized by more frequent and severe episodes, which indicate a worse prognosis.

Upcoming treatments

Here are some novel hereditary angioedema (HAE) treatments that are changing care:

New and Approved Therapies

1. Sebetralstat Type:

• Oral on-demand therapy
• It decreases the production of bradykinin by blocking plasma kallikrein.
• Highlights: Faster attack alleviation; no injections

2. Dondalorsen

• Subcutaneous prophylactic injection
• Pre-kallikrein's expression is reduced by antisense oligonucleotides.

Clinical Trials:

OASIS-HAE: 81% monthly attack decrease with 4-week dosing of OASISplus: Open-label extension reduced attacks by 93%.

3. Garadacimab (Andembry)

• The monthly subcutaneous monoclonal antibody
• The mechanism involves blocking Factor XIIa, which is a trigger in the kallikrein-kinin cascade.
• FDA Approval: Newly approved prophylactic

Efficacy:

• 62% of patients avoided attacks.
• Median attack reduction >99%

Future Paths

• We use oral kallikrein inhibitors to replace both acute and preventive injectable treatments.
• Factor XIIa inhibitors: Improve control by targeting upstream triggers
• Blockers of Bradykinin B2: Maintain vascular permeability suppression

Gene therapy:

Gene therapy aims to correct underlying mutations over time. These advancements promise HAE patients convenience, fewer side effects, and a better quality of life.

Conclusion

With an adequate treatment plan and emergency medication, HAE patients should expect a near-normal life expectancy and a dramatically reduced disease burden due to increased awareness, an earlier diagnosis, and novel therapies.