Hereditary Angioedema with C1 Esterase Inhibitor Deficiency

Hereditary angioedema with C1 esterase inhibitor deficiency is a rare genetic disorder that causes sudden, unpredictable episodes of severe swelling in different parts of the body, including the face, hands, feet, digestive system, and airways—where it can become life-threatening.

Table of contents

• What Is Hereditary Angioedema with C1 Esterase Inhibitor Deficiency?
• Types of the Disease
• What Causes This Condition
• How Common Is This Condition
• Signs and Symptoms
• What Can Trigger Attacks
• How This Condition Is Inherited
• Diagnosing the Condition
• Treatment Options

What Is Hereditary Angioedema with C1 Esterase Inhibitor Deficiency?

Hereditary angioedema with C1 esterase inhibitor deficiency is a disorder characterized by repeated episodes of severe swelling, called angioedema. The condition affects various parts of the body, most often the limbs, face, intestinal tract, and airway^[1]. Unlike allergic reactions, this swelling does not cause itching, hives, or redness^[2].

The swelling episodes occur because the body either does not have enough of a protein called C1 esterase inhibitor (also called C1 inhibitor or C1-INH), or the protein does not work properly^[3]. This protein normally helps control inflammation and swelling in the body by blocking certain other proteins that promote inflammation^[4].

Without enough functioning C1 inhibitor, the body produces too much of a substance called bradykinin. Bradykinin increases the amount of fluid that leaks through blood vessel walls into body tissues, causing the swelling seen in people with this condition^[5].

Types of the Disease

There are two main types of hereditary angioedema caused by problems with C1 esterase inhibitor^[6]:

Type I accounts for approximately 85% of cases. In this type, there is not enough C1 inhibitor protein in the blood. Blood levels are typically 5-30% of normal^[7]. The genetic changes cause the body to produce less of the protein than it should^[8].

Type II makes up about 15% of cases. In this type, the amount of C1 inhibitor protein in the blood is normal or even elevated, but the protein does not function correctly^[9]. The genetic changes result in a defective protein that cannot do its job properly^[10].

Both types cause similar symptoms and are treated in similar ways^[3].

What Causes This Condition

Hereditary angioedema with C1 inhibitor deficiency is caused by changes (also called mutations or variants) in the SERPING1 gene. This gene provides instructions for making the C1 inhibitor protein^[3]. More than 150 different genetic changes in this gene have been identified in patients with the condition^[5].

In type I, the genetic changes lead to reduced production of C1 inhibitor. The changed gene produces proteins that are misfolded or shortened and cannot be released from cells properly^[5].

In type II, the genetic changes cause the production of a C1 inhibitor protein that is released normally but does not work correctly. These changes often affect a specific area of the protein that is critical for its function^[5].

When C1 inhibitor is deficient or dysfunctional, the body cannot properly control several important systems that regulate inflammation. This leads to excessive production of bradykinin, which causes fluid to leak from blood vessels into surrounding tissues, resulting in swelling^[6].

How Common Is This Condition

Hereditary angioedema with C1 esterase inhibitor deficiency is estimated to affect approximately 1 in 50,000 people worldwide^[3]. Some sources estimate the prevalence at 1 in 10,000 to 50,000 people^[7]. The condition affects all ethnic groups and occurs equally in males and females^[10].

Symptoms typically begin during childhood or adolescence. In about 75% of patients with type I, the first episode occurs by age 15^[4]. Studies show that symptoms typically first appear between ages 5 and 11, with 40% of people experiencing their first episode by age 5^[2].

Signs and Symptoms

The main symptom of hereditary angioedema is episodes of swelling that can occur in different parts of the body^[3]. The swelling is non-pitting (does not leave an indentation when pressed), non-itchy, and not associated with hives or redness^[2].

Skin swelling is the most common symptom. More than 90% of people develop swelling that affects the face, limbs (especially hands and feet), and genitals. This swelling is often temporarily deforming and can be painful and disabling^[7].

Abdominal attacks involve swelling of the intestinal lining. These episodes cause severe abdominal pain, nausea, vomiting, and diarrhea. The pain can be intense enough to require bed rest and may lead to dehydration^[2][7].

Airway swelling is the most dangerous symptom. It can affect the tongue, soft palate, or voice box (larynx). Symptoms include difficulty breathing, stridor (a high-pitched breathing sound), hoarseness, drooling, and changes in voice. About 50% of patients experience at least one episode of airway swelling during their lifetime^[7]. In the past, untreated airway attacks resulted in death by suffocation in up to 30% of cases^[7].

About one-third of people develop a non-itchy rash called erythema marginatum either before or during an attack. This rash can serve as a warning sign^[2][3].

Some people experience warning signs before swelling begins, including fatigue, flu-like symptoms, tingling in the affected area, or the characteristic rash^[2].

Attacks typically peak at 24 hours and gradually resolve over 48 to 72 hours without treatment^[2]. On average, untreated individuals experience attacks every 1 to 2 weeks^[3], though the frequency and severity vary greatly among people, even within the same family^[3].

The frequency and severity of attacks often worsen during puberty and adolescence, and symptoms typically persist throughout life^[2].

What Can Trigger Attacks

Attacks can occur without any identifiable trigger, but they are often precipitated by certain factors^[3]:

• Physical trauma or injury, including minor injuries, dental procedures, tongue piercings, or surgery^[2][4]
• Infections, particularly viral illnesses^[2][4]
• Emotional stress and psychological stress^[2][4]
• Certain medications, especially those containing estrogen (such as birth control pills or hormone replacement therapy) and medications called ACE inhibitors used for high blood pressure^[2][4]
• Hormonal changes, including menstruation and pregnancy^[2][4]
• Vigorous exercise^[2]
• Certain foods^[2]
• Cold exposure^[4]

How This Condition Is Inherited

Hereditary angioedema with C1 esterase inhibitor deficiency is inherited in an autosomal dominant pattern. This means that having one copy of the altered gene in each cell is sufficient to cause the disorder^[3].

A family history of the condition is present in about 75% of cases^[2]. However, approximately 25% of cases occur as a spontaneous (new) genetic change, meaning the person has no family history of the condition^[10][7].

When a parent has the condition, each child has a 50% chance of inheriting the altered gene and developing the disorder^[3].

Diagnosing the Condition

Doctors may suspect hereditary angioedema when a person has repeated episodes of swelling without hives, itching, or redness, especially if there is a family history of similar symptoms^[2].

Diagnosis is confirmed through blood tests that measure levels of specific proteins. The key tests measure^[5]:

• C4 levels: This protein is typically low in people with hereditary angioedema, even between attacks^[2]
• C1 inhibitor protein level (antigen): This is low in type I and normal or high in type II^[7]
• C1 inhibitor function: This measures how well the protein works and is reduced in both type I and type II^[6]

In some cases, genetic testing may be performed to identify the specific change in the SERPING1 gene^[6].

It is important to distinguish hereditary angioedema from other conditions that cause swelling, including allergic reactions and anaphylaxis, drug-induced angioedema, and idiopathic (unknown cause) angioedema^[2].

Treatment Options

Treatment for hereditary angioedema consists of three main approaches: treating acute attacks when they occur, preventing attacks, and providing treatment before situations that might trigger attacks^[4].

Important note: Standard treatments for allergic reactions—including antihistamines, corticosteroids, and epinephrine (adrenaline)—do not work for hereditary angioedema attacks^[2].

Treatment of Acute Attacks

Early treatment of attacks is important to improve outcomes and reduce severity^[2]. Several medications are approved for treating acute attacks^[13]:

• C1 esterase inhibitor concentrates (such as Berinert or Cinryze) replace the missing or defective protein. These are given by injection into a vein^[12]
• Icatibant (Firazyr) blocks the action of bradykinin. It is given by injection under the skin and can be self-administered^[12][13]
• Ecallantide (Kalbitor) prevents excessive bradykinin production. It is given by injection under the skin^[12]

Response to these medications should occur within about 2 hours^[2]. If airway swelling is severe and causes difficulty breathing, emergency procedures such as intubation or tracheostomy may be necessary^[13].

Patients may need intravenous fluids if swelling in the digestive system causes dehydration. Pain is managed with appropriate pain medications^[13].

Prevention of Attacks

For people who have frequent or severe attacks, preventive treatment may be recommended^[4]. Options include:

• Attenuated androgens (such as danazol) increase production of C1 inhibitor. These are taken by mouth but have potential side effects and must be used carefully^[13][4]
• C1 inhibitor concentrates (such as Cinryze given intravenously or Haegarda given under the skin) are used regularly to prevent attacks^[12][15]
• Lanadelumab (Takhzyro) blocks a protein called plasma kallikrein. It is given by injection under the skin every 2-4 weeks^[12]
• Berotralstat (Orladeyo) is taken by mouth daily to prevent attacks^[12]
• Antifibrinolytic drugs may also be used for prevention in some cases^[10]

Before Procedures

People with hereditary angioedema should receive preventive treatment before dental work, surgery, or other medical procedures that might trigger an attack^[10][4].

Management Plans

Children and adults diagnosed with hereditary angioedema should have a personalized management plan that explains when and how to treat attacks. Many patients can be trained to self-administer medications at home^[2][15].

Patients should avoid known triggers when possible, including estrogen-containing medications and ACE inhibitors^[4][13].