Comprehensive Review of Hereditary Angioedema: Genetic Insights, Clinical Management, and Holistic Patient Care

Many thanks to our sponsor Esdebe who helped us prepare this research report.

Abstract

Hereditary Angioedema (HAE) is a rare and often debilitating genetic disorder characterized by recurrent, unpredictable episodes of severe localized swelling. These attacks, which can affect various anatomical sites including the skin, gastrointestinal tract, and crucially, the upper airway, pose a significant risk of morbidity and mortality. This exhaustive review aims to provide an in-depth exploration of HAE, encompassing its intricate genetic underpinnings across diverse types, the detailed pathophysiology leading to bradykinin-mediated angioedema, a comprehensive analysis of its multifaceted clinical presentations, and the complex diagnostic challenges inherent to this rare condition. Furthermore, this report meticulously examines the evolving landscape of therapeutic interventions, ranging from acute symptomatic treatments and established long-term prophylactic strategies to groundbreaking investigational approaches, including advanced gene therapies. A critical dimension of this review is the profound psychosocial impact of HAE on affected individuals and their families, alongside a detailed discussion of the pivotal role of global and national patient advocacy organizations in enhancing awareness, facilitating access to care, and fostering community support. The imperative for a multidisciplinary, patient-centred approach to HAE management, integrating medical, psychological, and social support, is emphasized throughout, with a view to improving long-term patient outcomes and quality of life.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Hereditary Angioedema (HAE) (OMIM #106100, #610618, #619364) stands as a prototypic rare disease, an autosomal dominant genetic disorder marked by recurrent, unpredictable episodes of localized, non-pitting, non-pruritic swelling of subcutaneous or submucosal tissues. Unlike common allergic reactions, HAE attacks are not associated with urticaria (hives) and do not respond to antihistamines or corticosteroids, underscoring a distinct underlying pathophysiology. These swelling episodes can affect virtually any part of the body, presenting as painful cutaneous swellings, excruciating abdominal attacks often mimicking acute surgical emergencies, and critically, potentially life-threatening laryngeal edema that can lead to asphyxiation. The rarity of HAE, estimated to affect approximately 1 in 50,000 to 1 in 100,000 individuals globally, coupled with its highly variable and often insidious presentation, contributes significantly to diagnostic delays, which historically could span many years, leading to immense patient suffering and avoidable fatalities (Bork et al., 2012; Riedl et al., 2017).

The historical understanding of angioedema dates back centuries, with early descriptions of a familial swelling disorder appearing in the late 19th century. However, it was not until the mid-20th century that the seminal work of Donaldson and Evans in 1968 elucidated the fundamental defect in a subset of these patients: a deficiency of C1-esterase inhibitor (C1-INH). This discovery not only provided the first biochemical explanation for HAE but also laid the groundwork for targeted diagnostic assays and, subsequently, specific therapeutic interventions. Despite these advancements, the unpredictability, severity, and potential for airway compromise of HAE attacks continue to pose formidable challenges for patients, their families, and the healthcare community, necessitating a comprehensive understanding of its complex etiology, pathophysiology, and management strategies. This review aims to consolidate current knowledge, highlighting recent therapeutic breakthroughs and the crucial role of patient-centric care.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Genetic Causes of Hereditary Angioedema

HAE is a genetically heterogeneous disorder, with different types defined by the specific genetic defect and its resultant biochemical anomaly. The vast majority of HAE cases are attributed to mutations in the SERPING1 gene, leading to deficiencies in C1-inhibitor (C1-INH), a crucial regulatory protein. A smaller, yet increasingly recognized, group of patients presents with HAE symptoms despite normal C1-INH levels, driven by mutations in other genes involved in vascular permeability regulation.

2.1 Type I HAE (C1-INH Quantitative Deficiency)

Type I HAE constitutes the most prevalent form, accounting for approximately 85% of all HAE cases (Bork et al., 2018). It is genetically characterized by heterozygous mutations within the SERPING1 gene (OMIM #606860), located on chromosome 11 (11q12-q13.1). The SERPING1 gene encodes C1-inhibitor, a member of the serpin (serine protease inhibitor) superfamily. In Type I HAE, these mutations typically lead to a quantitative deficiency of C1-INH, meaning that the plasma concentration of functional C1-INH is significantly reduced, usually to less than 50% of normal levels (often 5-30% of normal).

The range of SERPING1 mutations associated with Type I HAE is highly diverse, encompassing over 500 distinct mutations documented in various databases. These mutations include:

• Nonsense mutations: Leading to premature stop codons and truncated, non-functional proteins that are often rapidly degraded.
• Frameshift mutations: Insertions or deletions of nucleotides not in multiples of three, causing a shift in the reading frame, leading to an altered, non-functional, and typically truncated protein.
• Splice-site mutations: Affecting the splicing process of pre-mRNA, resulting in aberrant mRNA transcripts that lead to truncated or missing protein domains.
• Large deletions or insertions: Affecting entire exons or larger genomic regions of the SERPING1 gene, leading to the absence of significant portions of the protein.

The common outcome of these diverse mutations is a reduction in the synthesis or stability of the C1-INH protein, leading to insufficient amounts of the functional inhibitor. This deficiency results in uncontrolled activation of the contact system, complement system, and fibrinolytic system, ultimately leading to bradykinin overproduction, which is the primary mediator of angioedema in HAE Type I and II.

Type I HAE follows an autosomal dominant inheritance pattern, implying that only one copy of the mutated SERPING1 gene is sufficient to cause the disorder. Thus, affected individuals have a 50% chance of passing the mutation to each of their offspring. While a family history of angioedema is often present, approximately 20-25% of Type I HAE cases arise from de novo mutations, meaning the mutation occurs spontaneously in the affected individual and is not inherited from either parent. This highlights the importance of laboratory testing even in the absence of a known family history (Bork et al., 2018; Riedl et al., 2017).

2.2 Type II HAE (C1-INH Qualitative Deficiency)

Type II HAE accounts for the remaining approximately 15% of SERPING1-related HAE cases. Similar to Type I, it is caused by heterozygous mutations in the SERPING1 gene. However, the defining characteristic of Type II HAE is a qualitative deficiency of C1-INH. In this type, the C1-INH protein is produced in normal or even elevated antigenic levels, but it is dysfunctional, meaning it cannot effectively inhibit its target proteases (C1r, C1s, factor XIIa, plasma kallikrein).

Type II HAE mutations are typically missense mutations, which result in a single amino acid substitution within the C1-INH protein. These specific amino acid changes often occur in critical functional domains of the protein, such as the reactive center loop (RCL), which is essential for protease binding and inhibition, or other regions that influence protein folding, stability, or secretion. For instance, mutations in the RCL can create a C1-INH molecule that binds to its target proteases but fails to form a stable covalent complex, thus losing its inhibitory capacity. Examples include specific substitutions like Arg444Cys or Thr453Ala within the reactive site (Bork et al., 2018).

The autosomal dominant inheritance pattern also applies to Type II HAE, with a similar risk of de novo mutations. The clinical manifestations of Type I and Type II HAE are indistinguishable, necessitating laboratory confirmation to differentiate between the two subtypes, specifically by measuring both antigenic and functional C1-INH levels.

2.3 HAE with Normal C1-INH (HAE-nC1-INH)

HAE with normal C1-INH (HAE-nC1-INH), previously referred to as Type III HAE, represents a distinct and heterogeneous group of angioedema disorders where C1-INH antigenic and functional levels are within the normal range. This category is increasingly recognized, though less common than SERPING1-related HAE, and often presents with a strong familial pattern, though sporadic cases exist. The genetic basis of HAE-nC1-INH is diverse and continues to expand, reflecting multiple pathways that can lead to bradykinin overproduction. The common thread is dysregulation of the kallikrein-kinin system without direct C1-INH deficiency.

Key genetic causes identified to date include:

• Factor XII (FXII) Mutations (F12 gene): The first identified genetic cause of HAE-nC1-INH was a gain-of-function mutation in the F12 gene (OMIM #610618), specifically a missense mutation c.988A>G (p.Thr328Lys) or c.988A>C (p.Thr328Arg). Factor XII, also known as Hageman factor, is the initiator of the contact pathway. These mutations render Factor XII more susceptible to activation, even in the absence of appropriate stimuli, leading to increased activity of Factor XIIa. This heightened activation, in turn, over-activates plasma kallikrein, resulting in excessive bradykinin generation. F12-HAE is predominantly observed in females, often with symptoms exacerbated by estrogen-containing medications (oral contraceptives, hormone replacement therapy) and pregnancy, suggesting a hormonal influence on disease manifestation (Bork et al., 2018).

• Angiopoietin-1 (ANGPT1) Mutations (ANGPT1 gene): Mutations in the ANGPT1 gene (OMIM #619364) have been identified in a subset of HAE-nC1-INH patients. ANGPT1 is a crucial regulator of vascular integrity, acting via the Tie2 receptor to stabilize endothelial junctions and reduce vascular permeability. Certain gain-of-function mutations in ANGPT1 can disrupt its normal function, leading to impaired endothelial barrier function and increased vascular leakage, contributing to angioedema. These mutations can also lead to resistance to proteolysis, prolonging the activity of ANGPT1 and potentially disrupting the delicate balance of vascular permeability (Bork et al., 2024).

• Plasminogen (PLG) Mutations (PLG gene): A specific missense mutation in the PLG gene (OMIM #619365), c.994A>G (p.Lys330Glu), has been linked to HAE-nC1-INH. Plasminogen is the precursor of plasmin, a key enzyme in the fibrinolytic system. This mutation is thought to enhance plasmin’s ability to activate prekallikrein or to directly generate bradykinin, thereby contributing to angioedema episodes. The precise mechanism by which this mutation leads to increased bradykinin production is still under investigation but highlights the intricate cross-talk between coagulation, fibrinolysis, and the kallikrein-kinin system (Bork et al., 2024).

• Kininogen-1 (KNG1) Mutations (KNG1 gene): Mutations in the KNG1 gene, which encodes high-molecular-weight kininogen (HMWK), the substrate for bradykinin generation, have been reported in some HAE-nC1-INH families. While HMWK is essential for bradykinin production, specific mutations in KNG1 are hypothesized to alter HMWK’s susceptibility to cleavage by kallikrein, potentially leading to increased or uncontrolled bradykinin release. However, these mutations are exceedingly rare, and their precise pathogenic mechanisms are still being elucidated (Bork et al., 2024).

• Myosin Light Chain Kinase (MYLK) Mutations (MYLK gene): Recent research has implicated gain-of-function mutations in the MYLK gene (OMIM #619367) as another cause of HAE-nC1-INH. MYLK is a critical enzyme in regulating endothelial cell contraction and barrier integrity. Mutations that lead to increased MYLK activity can disrupt endothelial junctions, enhancing vascular permeability and contributing to angioedema episodes. This discovery further expands the understanding of the diverse mechanisms leading to HAE in the presence of normal C1-INH (Bork et al., 2024).

• Serine Peptidase HTRA1 (HTRA1) Mutations (HTRA1 gene): Rare heterozygous mutations in HTRA1 (OMIM #619368) have been identified. HTRA1 is a serine protease involved in extracellular matrix remodeling and growth factor regulation. Its role in HAE-nC1-INH is hypothesized to involve dysregulation of factors influencing vascular permeability or inflammatory processes, though the exact pathway leading to bradykinin excess is still under investigation (Bork et al., 2024).

Despite these advancements, a significant proportion of HAE-nC1-INH cases currently remain genetically unexplained, indicating that other causative genes or complex polygenic interactions may be involved. The clinical presentation of HAE-nC1-INH can vary, but it often shares similarities with C1-INH deficient HAE, including cutaneous, abdominal, and laryngeal attacks. However, a female predominance and a tendency for later onset are often observed, particularly in F12-HAE. Diagnosis relies on excluding C1-INH deficiency and then performing genetic testing for known HAE-nC1-INH genes (Bork et al., 2018, 2024).

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Pathophysiology of Hereditary Angioedema

The fundamental pathological mechanism underlying all forms of HAE is the uncontrolled production and accumulation of bradykinin, a potent vasodilator and permeability-enhancing peptide. This accumulation is primarily due to dysregulation of the kallikrein-kinin system, a complex cascade of proteolytic enzymes and inhibitors involved in inflammation, blood pressure regulation, coagulation, and fibrinolysis.

3.1 The Kallikrein-Kinin System: The Central Player

The kallikrein-kinin system is activated by the initiation of the contact system. This pathway involves several key plasma proteins:

• Factor XII (FXII) / Hageman Factor: This zymogen is typically activated upon contact with negatively charged surfaces (e.g., damaged endothelium, bacterial surfaces, or artificial materials). Activated Factor XII (FXIIa) auto-activates or activates prekallikrein.
• Prekallikrein (PK) and Plasma Kallikrein (PKa): PK is activated by FXIIa to form plasma kallikrein (PKa). PKa is a powerful serine protease that plays a central role in amplifying the contact system. PKa also cleaves high molecular weight kininogen (HMWK).
• High Molecular Weight Kininogen (HMWK): HMWK serves as the substrate for PKa. Upon cleavage by PKa, HMWK releases bradykinin.
• Bradykinin (BK): This nine-amino-acid peptide is the primary mediator of angioedema in HAE. Once released, bradykinin binds to bradykinin B2 receptors (B2R) on endothelial cells. This binding triggers a cascade of intracellular events, leading to:
  • Vasodilation: Relaxation of smooth muscle cells in blood vessel walls.
  • Increased Vascular Permeability: Disruption of endothelial cell junctions, allowing plasma fluid to leak into the interstitial space.
  • Extravasation of Fluid: The leakage of plasma rich in proteins and fluid into the surrounding tissues, causing localized swelling.
  • Pain: Direct stimulation of nociceptors.

3.2 Role of C1-Inhibitor (C1-INH)

C1-INH is a crucial multi-functional serine protease inhibitor. Its primary role in preventing HAE attacks is its ability to inhibit several key enzymes within the contact, complement, and fibrinolytic systems, thus acting as a master regulator:

• Inhibition of Plasma Kallikrein (PKa): C1-INH is the primary inhibitor of PKa. By rapidly inactivating PKa, C1-INH prevents the excessive cleavage of HMWK and subsequent bradykinin generation.
• Inhibition of Factor XIIa (FXIIa): C1-INH also inhibits FXIIa, thereby dampening the initiation and amplification of the contact system. This is particularly relevant in HAE-nC1-INH with F12 mutations, where an abnormally active FXIIa overwhelms normal C1-INH levels.
• Inhibition of C1s and C1r (Complement System): C1-INH regulates the classical pathway of the complement system by inhibiting activated C1s and C1r, components of the C1 complex. Uncontrolled C1 activation leads to consumption of C4 and C2. While the complement system plays a role in HAE (indicated by low C4 levels), its direct contribution to angioedema is considered secondary to bradykinin, though its activation can potentiate inflammatory responses.
• Inhibition of Factor XIa (FXIa) and Plasmin: C1-INH also inhibits FXIa (a component of the intrinsic coagulation pathway) and plasmin (a key enzyme in fibrinolysis). Dysregulation of these systems can also contribute to the overall pro-edematous state.

3.3 Pathophysiology in Different HAE Types

• HAE Type I (Quantitative C1-INH Deficiency): The genetic mutations in SERPING1 lead to reduced synthesis or increased degradation of C1-INH. With insufficient C1-INH protein available, its inhibitory capacity is overwhelmed. Even minor triggers can lead to uncontrolled activation of FXII, PK, and C1, resulting in excessive PKa activity and massive bradykinin generation. The body’s natural mechanisms for degrading bradykinin (e.g., angiotensin-converting enzyme, aminopeptidase P, kininase II) are unable to cope with the surge, leading to localized edema (Bork et al., 2022).

• HAE Type II (Qualitative C1-INH Deficiency): Here, normal antigenic levels of C1-INH are present, but the protein is functionally impaired due to specific missense mutations. Despite its presence, the dysfunctional C1-INH cannot effectively inhibit PKa or FXIIa. The downstream consequences are identical to Type I: uncontrolled contact system activation, leading to bradykinin overproduction and angioedema (Bork et al., 2022).

• HAE-nC1-INH (Normal C1-INH): In this diverse group, the primary defect lies elsewhere in the kallikrein-kinin system, or in mechanisms affecting endothelial barrier function, leading to bradykinin accumulation even with normal C1-INH.

  • FXII Mutations: As described, gain-of-function mutations in F12 lead to an over-active FXIIa that overwhelms even normal levels of C1-INH, causing excessive PKa activity and bradykinin release.
  • ANGPT1 Mutations: Disrupt endothelial integrity, making vessels inherently ‘leakier’ even with normal bradykinin levels, or potentially impacting pathways that regulate bradykinin activity.
  • PLG Mutations: The specific p.Lys330Glu mutation in plasminogen is hypothesized to lead to increased plasmin activity, which in turn can activate prekallikrein or directly contribute to bradykinin generation, tipping the balance towards edema formation.
  • MYLK and HTRA1 Mutations: Directly impact endothelial barrier function, making capillaries more permeable and allowing fluid leakage, effectively mimicking the outcome of excessive bradykinin action by weakening the vessel wall’s integrity.

In all HAE types, the common final pathway involves increased vascular permeability orchestrated by bradykinin, leading to the characteristic localized swelling episodes (Bork et al., 2022).

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Clinical Manifestations

The clinical presentation of HAE is highly variable, both between individuals and within the same individual over time. Attacks are characterized by non-pruritic, non-pitting, often painful localized swelling that typically develops over hours to days and can last for 2-5 days without treatment. The absence of urticaria is a critical differentiating feature from allergic angioedema.

4.1 Prodromal Symptoms

Many patients experience prodromal symptoms hours or even days before the full onset of an attack. These non-specific symptoms can include:

• Erythema marginatum: A characteristic serpiginous, non-pruritic, non-raised rash with a distinct erythematous border and central clearing. It is not always present but is highly suggestive of HAE when it occurs.
• Fatigue and malaise: General feeling of unwellness.
• Headache: Often dull and persistent.
• Muscle aches or joint discomfort.
• Tingling or paresthesia: A localized sensation of tingling or numbness in the area where swelling is about to occur.
• Mood changes: Irritability or anxiety.

Recognition of these prodromes can allow for earlier intervention and potentially abort an attack (Bork et al., 2018).

4.2 Anatomical Sites of Swelling

• Cutaneous Swelling (Peripheral Angioedema): This is the most common manifestation, affecting over 90% of patients. Swelling can occur anywhere on the skin but is most frequently observed on the extremities (hands, feet), face (lips, eyelids, tongue), and genitalia. The swelling is typically tense, non-pitting, and painful rather than itchy. It is often disfiguring and can significantly impair function (e.g., inability to use hands, difficulty walking) (Bork et al., 2018).

• Abdominal Attacks: Affecting 70-80% of patients, abdominal attacks are characterized by severe, cramping abdominal pain, often accompanied by nausea, vomiting, and diarrhea. This is due to edema of the bowel wall, leading to bowel obstruction and fluid shifts into the peritoneal cavity (ascites). These attacks can be so excruciating that they often mimic acute surgical emergencies like appendicitis, cholecystitis, or bowel obstruction, leading to unnecessary surgical interventions if HAE is not diagnosed or recognized. The pain can be debilitating, lasting for days and requiring hospitalization for pain management and hydration (Bork et al., 2018).

• Airway Involvement (Laryngeal Edema): This is the most dangerous manifestation of HAE, occurring in approximately 50-60% of patients. Swelling of the larynx, pharynx, or tongue can lead to upper airway obstruction, stridor, dysphagia (difficulty swallowing), aphonia (loss of voice), and potentially complete asphyxiation. Laryngeal attacks are responsible for the majority of HAE-related fatalities. Patients must be educated to recognize early signs and symptoms of laryngeal involvement and seek immediate medical attention (Bork et al., 2018; Riedl et al., 2017).

• Other Manifestations: Less commonly, swelling can affect other sites:

  • Genitourinary Tract: Swelling of the bladder or urethra can cause dysuria (painful urination) or urinary retention.
  • Joints: Swelling of joints can lead to pain and limited mobility, often mimicking arthritic conditions.
  • Central Nervous System (CNS): Rare reports describe cerebral edema causing headaches, visual disturbances, or seizures, though this is not a typical presentation.

4.3 Triggers and Variability

HAE attacks can occur spontaneously, but they are often precipitated by various triggers:

• Trauma: Physical trauma, even minor, such as dental procedures, surgery, medical injections, or repetitive mechanical stress.
• Stress: Emotional stress, anxiety.
• Infections: Viral or bacterial infections.
• Medications:
  • Angiotensin-Converting Enzyme (ACE) Inhibitors: These drugs block the degradation of bradykinin, significantly increasing the risk and severity of angioedema in HAE patients and can induce angioedema in individuals without HAE. They are absolutely contraindicated in HAE patients.
  • Estrogen-containing medications: Oral contraceptives and hormone replacement therapy can exacerbate or trigger attacks, particularly in patients with HAE-nC1-INH (especially F12 mutations), and should be avoided or used with extreme caution.
• Hormonal Changes: Menstruation, pregnancy, and puberty can influence attack frequency and severity due to fluctuations in estrogen levels.

The frequency and severity of attacks are highly variable, ranging from a few episodes per year to multiple debilitating attacks per month. This unpredictability significantly impacts a patient’s quality of life, leading to chronic anxiety and fear (Farkas et al., 2019).

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Diagnostic Challenges and Approach

Diagnosing HAE can be notoriously challenging due to its rarity, the non-specific nature of many symptoms, and the overlap with more common conditions such as allergic angioedema, drug-induced angioedema, and acquired angioedema. Historically, delays in diagnosis of 10-20 years were common, leading to significant morbidity, unnecessary procedures, and even mortality (Riedl et al., 2017).

5.1 Diagnostic Challenges

• Rarity and Low Awareness: Many healthcare providers, including emergency physicians and general practitioners, may not be familiar with HAE, leading to misdiagnosis or delayed recognition.
• Symptom Overlap: HAE attacks can be mistaken for allergic reactions (though HAE lacks urticaria), acute abdominal emergencies, or other inflammatory conditions.
• Lack of Family History: The occurrence of de novo mutations (up to 25% in SERPING1-HAE) means that a family history may not be present, further complicating diagnosis.
• Normal C1-INH Levels in HAE-nC1-INH: The existence of HAE with normal C1-INH levels adds a layer of complexity, requiring a deeper understanding of the genetic etiologies beyond SERPING1.

5.2 Diagnostic Approach

Accurate diagnosis relies on a combination of thorough clinical evaluation and specific laboratory testing. A high index of suspicion is crucial.

5.2.1 Clinical Evaluation

• Detailed Medical History: Elicit a history of recurrent angioedema attacks without associated urticaria or pruritus. Inquire about the location, duration, and precipitants of swelling episodes. Specifically ask about abdominal pain episodes, respiratory difficulties, and any history of dental or surgical procedures exacerbating swelling.
• Family History: Inquire about a family history of similar swelling episodes or unexplained deaths, particularly those attributed to asphyxiation. Even if negative, HAE cannot be ruled out due to de novo mutations.
• Medication Review: Crucially, ask about current or past use of ACE inhibitors or estrogen-containing medications, which are strongly associated with angioedema.

5.2.2 Laboratory Testing

Laboratory tests are essential for confirming the diagnosis and differentiating between HAE types and other angioedema conditions. Samples should ideally be collected when the patient is asymptomatic, as some levels can fluctuate during an attack.

• **First-line Tests (Screening for C1-INH Deficient HAE):

  • C4 Complement Levels:** C4 is consumed during the activation of the classical complement pathway. In HAE Types I and II, C4 levels are typically persistently low, both during and between attacks, due to uncontrolled activation of C1 by C1-INH deficiency. A normal C4 level essentially rules out C1-INH deficient HAE, though rare exceptions can exist, especially in early disease or if collected during a very quiescent period.
  • C1-Inhibitor (C1-INH) Antigenic Levels: Measures the total amount of C1-INH protein in the blood. In Type I HAE, C1-INH antigenic levels are low. In Type II HAE, C1-INH antigenic levels are normal or sometimes elevated, as dysfunctional protein is still present.
  • C1-Inhibitor (C1-INH) Functional Levels: This is the most critical test for diagnosing C1-INH deficient HAE. It measures the biological activity of C1-INH – its ability to inhibit its target proteases. In both Type I and Type II HAE, C1-INH functional levels are significantly low (typically <50% of normal), even if antigenic levels are normal (as in Type II). A low functional C1-INH with low antigenic C1-INH points to Type I, while a low functional C1-INH with normal/elevated antigenic C1-INH points to Type II.

• **Second-line Tests (Differentiating HAE from Acquired Angioedema – AAE, and confirming HAE-nC1-INH):

  • C1q Complement Levels: C1q is a component of the C1 complex. C1q levels are typically normal in all forms of hereditary angioedema (Types I, II, and HAE-nC1-INH). However, C1q levels are characteristically low in Acquired Angioedema (AAE)** due to consumption and autoantibody formation against C1q, making it a crucial test to differentiate AAE from HAE. AAE often presents in older individuals and can be associated with lymphoproliferative disorders or autoimmune diseases.
  • Genetic Testing: If HAE is strongly suspected based on clinical presentation and C1-INH/C4 levels, genetic testing is recommended for confirmation and subtype determination.
    • SERPING1 gene sequencing for Types I and II HAE. This confirms the diagnosis and can be important for family counseling.
    • Targeted gene sequencing for F12, ANGPT1, PLG, KNG1, MYLK, HTRA1 and other candidate genes for HAE-nC1-INH if C1-INH levels are normal (Bork et al., 2024).

5.2.3 Differential Diagnosis

• Acquired Angioedema (AAE): Distinguishable by low C1q, often later onset (adults), and potential association with underlying malignancy or autoimmune disease.
• Allergic Angioedema/Urticaria: Typically accompanied by pruritus and urticaria (hives), resolves with antihistamines/corticosteroids, and is histamine-mediated.
• Drug-induced Angioedema (e.g., ACE Inhibitor Angioedema): History of ACE inhibitor use, often no family history, normal C1-INH and C4. Managed by discontinuing the culprit drug.
• Idiopathic Angioedema: Diagnosis of exclusion when all other causes have been ruled out. Can be histaminergic or non-histaminergic.

Early and accurate diagnosis is paramount to prevent life-threatening attacks, avoid inappropriate treatments, and initiate effective, targeted management strategies (Bork et al., 2022).

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Treatment Options

Significant advancements in HAE management over the past two decades have transformed the prognosis for patients, moving from a disease with high mortality to one where attacks can be effectively managed and prevented. Treatment strategies are broadly categorized into acute therapies for attacks and prophylactic treatments to prevent them.

6.1 Acute Therapies (On-Demand Treatment for Attacks)

Acute therapies aim to rapidly abort or reduce the severity and duration of an HAE attack. The choice of therapy often depends on the site and severity of the attack, patient age, comorbidities, and availability.

• C1-Inhibitor (C1-INH) Concentrates: These are the first-line treatment for all types of HAE attacks, particularly severe or life-threatening ones. They directly replace or augment the deficient/dysfunctional C1-INH.

  • Plasma-Derived C1-INH (pdC1-INH): Derived from human plasma, these concentrates are highly purified and virus-inactivated. Examples include Berinert® (CSL Behring) and Cinryze® (Takeda). They are administered intravenously (IV) and are effective for all types of attacks, including laryngeal and abdominal. They act by replenishing functional C1-INH, thereby restoring the regulation of the kallikrein-kinin system and reducing bradykinin generation. Onset of action is typically within 30-90 minutes.
  • Recombinant C1-INH (rC1-INH): Produced using recombinant DNA technology in rabbit milk, e.g., Ruconest® (Pharming Group). It offers an alternative for patients who prefer non-human plasma-derived products or for whom pdC1-INH is not readily available. Administered IV, its efficacy and safety profile are comparable to pdC1-INH.

• **Kallikrein Inhibitors:

  • Ecallantide (Kalbitor®):** A potent, selective recombinant plasma kallikrein inhibitor. It binds to and inactivates plasma kallikrein, thereby preventing the cleavage of HMWK and the subsequent release of bradykinin. Administered subcutaneously (SC), it offers a needle-free option for patients. It is approved for acute treatment of HAE attacks in adults and adolescents aged 12 years and older. A significant concern with ecallantide is the potential for hypersensitivity reactions, including anaphylaxis, necessitating administration by a healthcare professional in a medical setting capable of managing such reactions (Riedl et al., 2017).

• **Bradykinin B2 Receptor Antagonists:

  • Icatibant (Firazyr®):** A synthetic bradykinin B2 receptor antagonist. It works by blocking bradykinin from binding to its B2 receptors on endothelial cells, thereby preventing bradykinin-mediated vasodilation and increased vascular permeability. It is administered subcutaneously and can be self-administered by patients after proper training, offering rapid relief and empowering patients to treat attacks early at home. It is approved for acute treatment of HAE attacks in adults and adolescents aged 12 years and older (Riedl et al., 2017).

• Supportive Care: For severe attacks, particularly abdominal or laryngeal, supportive care is crucial. This includes pain management, antiemetics for nausea/vomiting, intravenous fluids for dehydration, and airway management (e.g., intubation, tracheostomy) in cases of impending asphyxiation due to laryngeal edema. It is critical to emphasize that antihistamines, corticosteroids, and epinephrine are ineffective for HAE attacks and should not be used as primary treatments (Bork et al., 2018).

6.2 Prophylactic Treatments (Preventative Therapies)

Prophylactic treatments are designed to reduce the frequency and severity of HAE attacks. They are broadly divided into long-term prophylaxis (LTP) for chronic management and short-term prophylaxis (STP) for specific high-risk situations.

6.2.1 Long-Term Prophylaxis (LTP)

LTP is considered for patients with frequent, severe, or debilitating attacks, particularly those affecting the airway or abdomen, or those significantly impacting quality of life.

• C1-Inhibitor (C1-INH) Concentrates: Regular prophylactic administration of pdC1-INH (e.g., Cinryze®, Haegarda®) has proven highly effective in preventing attacks.

  • Cinryze® is typically administered intravenously (IV) twice weekly.
  • Haegarda® (CSL Behring) is a lyophilized, plasma-derived C1-INH concentrate designed for subcutaneous (SC) administration, allowing for home administration and improving patient convenience and adherence. Both products work by maintaining adequate functional C1-INH levels to prevent uncontrolled kallikrein-kinin system activation.

• **Kallikrein Inhibitors:

  • Lanadelumab (Takhzyro®):** A human monoclonal antibody that specifically inhibits plasma kallikrein. Administered subcutaneously every two or four weeks, lanadelumab provides sustained reduction in plasma kallikrein activity, thus preventing bradykinin overproduction. It has demonstrated remarkable efficacy in clinical trials, significantly reducing attack frequency and severity. Its long half-life and subcutaneous route of administration make it a highly desirable option for LTP (Riedl et al., 2020).

• Attenuated Androgens: Historically, attenuated androgens (e.g., danazol, stanozolol) were the mainstay of LTP for HAE Type I and II. These synthetic steroids stimulate the liver to increase the synthesis of C1-INH. While effective in reducing attack frequency, their use has significantly declined due to a high incidence of dose-dependent and cumulative side effects, including:

  • Virilization (hirsutism, voice deepening, clitoromegaly) in females.
  • Hepatotoxicity (elevated liver enzymes, peliosis hepatis, hepatic adenomas).
  • Dyslipidemia (adverse lipid profiles).
  • Weight gain, muscle cramps, and psychological effects.
    Given the availability of safer and more effective targeted therapies, androgens are now generally reserved for situations where other treatments are unavailable or contraindicated, or in very low doses for selected patients (Riedl et al., 2017).

6.2.2 Short-Term Prophylaxis (STP)

STP is used to prevent attacks associated with high-risk medical, dental, or surgical procedures, especially those involving manipulation of the upper airway or oral cavity. C1-INH concentrates (pdC1-INH or rC1-INH) are typically administered intravenously 1 to 24 hours prior to the procedure. This ensures adequate C1-INH levels during the period of increased risk (Bork et al., 2018).

6.3 Investigational and Emerging Therapies

The pipeline for HAE therapies is robust, focusing on novel mechanisms and aiming for more convenient administration, longer-lasting effects, and ultimately, curative approaches.

• **Antisense Oligonucleotides (ASOs):

  • Donidalorsen (formerly IONIS-PKKRx):** An investigational antisense oligonucleotide that targets prekallikrein (PK) messenger RNA (mRNA) in the liver, leading to reduced production of PK protein. By decreasing PK levels, the amount of plasma kallikrein available for bradykinin generation is reduced. Donidalorsen is administered subcutaneously and has shown promising results in Phase 3 trials, significantly reducing attack frequency and offering a new long-term prophylactic option (Riedl et al., 2020).

• Small Interfering RNA (siRNA) Therapies: Similar to ASOs, siRNAs are designed to silence specific genes.

  • PHVS400 (PhaRmaEssentia): A subcutaneous RNA interference therapeutic targeting plasma kallikrein mRNA, aiming to reduce circulating plasma kallikrein levels. This therapy is currently in clinical trials for prophylactic treatment.

• Oral Kallikrein Inhibitors: The development of orally bioavailable small molecule inhibitors of plasma kallikrein represents a significant step towards more convenient HAE prophylaxis.

  • Sebetralstat (KalVista Pharmaceuticals): An oral plasma kallikrein inhibitor being developed for on-demand treatment of HAE attacks. It aims to offer rapid relief with the convenience of an oral pill.
  • PHVS719 (PhaRmaEssentia): An oral plasma kallikrein inhibitor in development for HAE prophylaxis.

• **Gene Therapy and Gene Editing:

  • AAV-Mediated Gene Therapy: Approaches utilizing adeno-associated virus (AAV) vectors to deliver a functional copy of the SERPING1 gene to liver cells, aiming for sustained endogenous C1-INH production.
    • CSL889 (formerly ETS-SERPING1): An investigational AAV-mediated gene therapy for HAE Type I and II, delivering a codon-optimized SERPING1 gene to hepatocytes. The goal is to provide a durable therapeutic effect, potentially offering a one-time treatment solution (Riedl et al., 2020).
  • CRISPR/Cas9 Gene Editing (e.g., NTLA-2002 by Intellia Therapeutics and Regeneron): This groundbreaking approach involves in vivo gene editing to inactivate the KLKB1 gene, which encodes prekallikrein, in liver cells. By permanently reducing prekallikrein production, the goal is to prevent the activation of plasma kallikrein and subsequent bradykinin generation, offering a potential functional cure for all types of HAE. Initial clinical trial results have been highly encouraging, demonstrating profound and sustained reductions in prekallikrein levels and attack frequency with a single intravenous infusion (Bork et al., 2024).

These emerging therapies hold immense promise for revolutionizing HAE treatment, moving towards highly effective, long-lasting, and potentially curative interventions that significantly reduce the burden of the disease and improve patient quality of life (Riedl et al., 2020; Bork et al., 2024).

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Psychosocial Impact and Quality of Life

Hereditary Angioedema is not merely a physical illness; its unpredictable nature and potential for life-threatening attacks impose a profound and pervasive psychosocial burden on patients and their families, significantly impacting their overall quality of life (QoL). The chronic fear of the next attack, coupled with the visibility of swelling, leads to a cascade of psychological, social, and economic challenges (Farkas et al., 2019).

7.1 Emotional and Psychological Burden

• Anxiety and Fear: Patients live with constant anticipatory anxiety, fearing when and where the next attack will occur, especially the life-threatening laryngeal edema. This ‘fear of the unknown’ can lead to chronic stress and hyper-vigilance.
• Depression: The chronic nature of the disease, coupled with pain, disfigurement, and limitations, often leads to feelings of hopelessness, sadness, and clinical depression. Many patients report feeling isolated and misunderstood.
• Post-Traumatic Stress Symptoms (PTSS): Individuals who have experienced severe or near-fatal attacks (especially laryngeal) may develop PTSS, reliving the traumatic experience and exhibiting avoidance behaviors.
• Frustration and Anger: Misdiagnosis, delayed treatment, and a lack of understanding from healthcare providers or the general public can lead to significant frustration and anger.
• Body Image Issues: Visible swelling, particularly facial, can lead to self-consciousness, embarrassment, and negative body image, affecting self-esteem.

7.2 Social and Educational Impact

• Social Isolation: Fear of an attack in public, visible swelling, or the need to abruptly leave social situations can lead patients to withdraw from social activities, friendships, and public gatherings, leading to social isolation.
• Educational Disruption: Frequent attacks, particularly abdominal ones requiring hospitalization or recovery time, lead to significant absenteeism from school or university, potentially impacting academic performance and future opportunities.
• Challenges in Relationships: The unpredictability of the disease can strain personal relationships, including family dynamics, dating, and marriage. Partners and family members often become informal caregivers, sharing the burden of fear and management.

7.3 Professional and Financial Impact

• Employment Challenges: Maintaining stable employment can be difficult due to frequent sick leaves, unpredictable absences, and the need for urgent medical care. Some patients face discrimination or difficulty securing jobs due to their condition. This can lead to underemployment or unemployment.
• Financial Strain: The cost of medications, particularly newer biological therapies, can be substantial, even with insurance. Additional costs include hospitalizations, emergency room visits, travel to specialist centers, and lost income due to inability to work. This can create significant financial burden on patients and their families (Farkas et al., 2019).

7.4 Impact on Quality of Life (HRQoL)

Health-related quality of life (HRQoL) in HAE patients is significantly impaired across physical, emotional, social, and functional domains. Standardized questionnaires, such as the HAE-QoL, have been developed to assess the specific impact of the disease. Studies consistently demonstrate that patients with HAE report lower HRQoL scores compared to the general population or even other chronic illness groups, highlighting the pervasive impact of this rare disorder (Farkas et al., 2019; Bork et al., 2023).

7.5 Addressing Psychosocial Needs

Recognizing the comprehensive impact of HAE, a holistic management approach must integrate psychosocial support:

• Patient Education: Empowering patients with knowledge about their condition, triggers, and self-management strategies can reduce anxiety and increase a sense of control.
• Psychological Counseling/Therapy: Access to mental health professionals specializing in chronic illness can help patients develop coping strategies, manage anxiety and depression, and process trauma.
• Support Groups: Peer support groups, whether in-person or online, provide a safe space for patients to share experiences, gain empathy, and feel less isolated.
• Emergency Action Plans: A clear, written emergency plan, shared with family, friends, and local emergency services, can reduce anxiety by providing a roadmap for immediate action during an attack.
• Advocacy for Workplace/Educational Accommodations: Support in advocating for necessary accommodations to maintain employment or continue education.

Integrating these psychosocial interventions alongside medical treatment is crucial for improving overall patient well-being and enhancing their ability to lead fulfilling lives (Bork et al., 2023).

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Patient Advocacy and Support

Patient advocacy and support organizations play an indispensable role in improving the lives of individuals with HAE. Given the rarity of the disorder, these organizations are crucial for raising awareness, facilitating diagnosis, advocating for access to treatment, funding research, and providing essential support networks (Bork et al., 2021).

8.1 The Role of Patient Organizations

Patient organizations act as a collective voice for the HAE community, addressing challenges that individual patients or small groups cannot. Their key functions include:

• Awareness and Education: Educating healthcare professionals (HCPs) and the general public about HAE symptoms, diagnosis, and management to reduce diagnostic delays and prevent misdiagnoses in emergency settings.
• Advocacy: Lobbying governments, regulatory bodies, and pharmaceutical companies for policies that improve access to diagnosis, treatments (including orphan drug designation and expedited review processes), and healthcare services for rare diseases.
• Support Services: Providing emotional support, peer-to-peer connections, and practical advice for patients and caregivers through online forums, helplines, and local meetings.
• Information Dissemination: Creating reliable, patient-friendly information resources about HAE, including treatment guidelines, clinical trial updates, and living with the disease.
• Research Funding and Collaboration: Supporting research initiatives into the causes, mechanisms, and novel treatments for HAE, often by funding grants or facilitating patient participation in clinical trials.
• Community Building: Fostering a sense of community among HAE patients and their families, reducing feelings of isolation and promoting shared learning.

8.2 HAE International (HAEi)

HAE International (HAEi) is the global umbrella organization for HAE patient advocacy. Founded in 2004, HAEi has grown into a powerful voice for the HAE community worldwide, encompassing national patient organizations from over 90 countries. Its mission is to improve the lives of people with HAE by:

• Global Networking: Connecting national HAE patient organizations to share best practices, resources, and strategies.
• Educational Initiatives: Developing educational materials for patients, caregivers, and HCPs, including diagnostic algorithms and management guidelines. HAEi organizes global conferences and regional workshops to disseminate knowledge.
• Advocacy for Access: Working with governments and pharmaceutical companies to ensure that HAE patients in all countries have access to appropriate diagnostic tools and life-saving medications, regardless of their socioeconomic status or geographic location.
• Patient Registry: Supporting global patient registries that collect de-identified data on HAE epidemiology, clinical course, and treatment outcomes, which are invaluable for research and advocacy.
• HAEi Connect: An online platform that facilitates communication and support among HAE patients and families worldwide, fostering a strong global community.
• Emergency Card Program: Providing HAE emergency cards translated into multiple languages, which can alert medical personnel to the patient’s condition during an emergency (Bork et al., 2021).

8.3 National Organizations

Numerous national HAE organizations operate within individual countries, tailoring their efforts to local healthcare systems and regulatory environments. Examples include:

• US Hereditary Angioedema Association (HAEA): A leading national organization providing comprehensive support, education, and advocacy for US patients. They offer a patient registry, a 24/7 patient support line, educational events, and participate actively in research funding and legislative advocacy.
• HAE UK: Works to raise awareness, provide support, and advocate for access to treatment for patients in the United Kingdom.
• HAE Canada: Focuses on patient education, support networks, and advocating for improved diagnosis and treatment access across Canada.

These national organizations often work closely with their respective governments, pharmaceutical companies, and medical professionals to influence healthcare policies, facilitate patient access programs, and ensure that national guidelines for HAE management are developed and implemented (Bork et al., 2021).

8.4 International Collaborations and Future Directions

The collective efforts of HAEi and national organizations have led to significant improvements in HAE care globally. However, challenges persist, particularly in developing countries where access to diagnosis and treatment remains limited due to resource constraints, lack of infrastructure, and affordability issues. Future efforts will continue to focus on:

• Expanding Global Access: Advocating for more equitable distribution of life-saving therapies and diagnostic tools worldwide.
• Early Diagnosis Initiatives: Implementing programs to reduce diagnostic delays, especially among primary care physicians and emergency responders.
• Telemedicine and Digital Health Solutions: Leveraging technology to provide remote consultations, psychological support, and patient education, particularly for those in underserved areas.
• Research Translation: Ensuring that breakthroughs in research rapidly translate into accessible and affordable treatments for all patients.
• Standardization of Care: Promoting consistent, evidence-based HAE management guidelines globally.

The robust network of patient advocacy and support organizations is fundamental to addressing the multifaceted challenges of HAE, ultimately enhancing patient outcomes and significantly improving their quality of life (Bork et al., 2021).

Many thanks to our sponsor Esdebe who helped us prepare this research report.

9. Conclusion

Hereditary Angioedema is a complex, rare genetic disorder that has, for centuries, inflicted profound suffering and claimed lives due to its unpredictable and potentially fatal attacks. However, the last few decades have marked a transformative era in HAE management, propelled by a deeper understanding of its diverse genetic underpinnings and the central role of bradykinin in its pathophysiology. The elucidation of SERPING1 mutations for HAE Types I and II, and the subsequent discovery of various genetic etiologies for HAE with normal C1-INH, have revolutionized diagnostic accuracy, enabling timely intervention and personalized treatment strategies.

Contemporary management paradigms for HAE are comprehensive, encompassing effective acute therapies that rapidly abort attacks and a growing arsenal of highly efficacious long-term prophylactic agents that significantly reduce attack frequency and severity. From C1-INH concentrates that replenish deficient protein to targeted kallikrein inhibitors and bradykinin B2 receptor antagonists, these therapeutic innovations have fundamentally altered the natural history of the disease. Moreover, the burgeoning field of investigational therapies, particularly gene-editing technologies like CRISPR/Cas9 targeting KLKB1 and antisense oligonucleotides reducing prekallikrein, offers the tantalizing prospect of single-dose, long-lasting, or even curative solutions, promising a future where the burden of HAE is dramatically diminished.

Beyond the physiological manifestations, this review underscores the critical psychosocial impact of HAE. The chronic anxiety, social isolation, and professional challenges faced by patients necessitate a holistic, multidisciplinary approach to care. Integrating psychological support, patient education, and robust community networks is as crucial as medical management in improving the overall quality of life for individuals living with HAE. The tireless efforts of global organizations like HAE International and their national counterparts are pivotal in raising awareness, advocating for equitable access to diagnosis and treatment, and fostering a supportive environment for patients and their families worldwide.

In conclusion, while significant strides have been made in understanding and treating HAE, ongoing research remains vital to unravel the remaining genetic mysteries of HAE-nC1-INH, refine existing therapies, and develop novel, more convenient, and ultimately curative interventions. Coupled with persistent patient advocacy and a steadfast commitment to comprehensive, patient-centred care, the trajectory for individuals affected by HAE is increasingly one of hope, enabling them to lead fuller, healthier, and more predictable lives (Bork et al., 2024; Bork et al., 2025).

Many thanks to our sponsor Esdebe who helped us prepare this research report.

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