Hereditary Angioedema (HAE): Pathophysiology, Clinical Imaging, Diagnosis, and Treatment

DOI: 10.1056/NEJMcps2307935

Introduction

Hereditary Angioedema (HAE) is a rare but potentially life-threatening autosomal dominant disorder characterized by recurrent episodes of swelling in various parts of the body, including the skin, gastrointestinal tract, and upper airways. Despite its rarity, affecting approximately 1 in 50,000 individuals worldwide, the impact of HAE on patient quality of life is profound. Misdiagnosis and diagnostic delay remain common, with many patients experiencing years of symptoms before accurate identification.

This article presents a comprehensive overview of hereditary angioedema including pathophysiology, epidemiology, clinical presentation, imaging features, differential diagnosis, diagnostic work-up, treatment, and prognosis. A real clinical case of a 19-year-old male presenting with recurrent abdominal pain is integrated into the discussion, with imaging findings and figure references provided for deeper understanding.

Pathophysiology of Hereditary Angioedema

HAE arises primarily from deficiency or dysfunction of C1 esterase inhibitor (C1-INH), a member of the serpin family that regulates multiple plasma enzyme systems including the complement cascade, contact pathway, fibrinolysis, and coagulation.

Type I HAE (~85% of cases): Characterized by low levels of C1-INH.
Type II HAE (~15% of cases): Characterized by normal levels but dysfunctional C1-INH.
Type III HAE (rare): Normal quantitative and functional C1-INH, associated with mutations in coagulation factor XII or other genes.

In C1-INH deficiency, uncontrolled activation of factor XII and plasma kallikrein leads to excessive cleavage of high-molecular-weight kininogen (HMWK), generating bradykinin. Elevated bradykinin binds to B2 receptors on endothelial cells, increasing vascular permeability and leading to localized angioedema.

Epidemiology

Global prevalence: ~1:50,000 with no ethnic or gender predilection.
Onset: Typically begins in childhood, with mean age of first attack between 8–12 years.
Disease progression: Attacks often worsen during puberty.
Family history: Strong autosomal dominant inheritance, though de novo mutations occur.

Clinical Presentation

The hallmark of HAE is recurrent, non-pitting, non-pruritic swelling of subcutaneous or submucosal tissues, without urticaria.

Key clinical features:

Cutaneous swelling: Face, lips, extremities, genitalia.
Abdominal attacks: Severe cramping pain, nausea, vomiting, transient ileus; may mimic acute abdomen.
Airway edema: Laryngeal swelling occurs in ~0.9% of attacks and is life-threatening.
Prodromal symptoms: Fatigue, erythema marginatum (serpiginous rash), tingling at affected site.
Duration: Swelling lasts hours to days, resolving spontaneously if untreated.

Case Integration

A 19-year-old previously healthy male presented with recurrent diffuse abdominal pain for 10 years, now occurring every 2 weeks. Laboratory evaluation showed low C4 complement and reduced C1-INH activity (<25%), confirming HAE.

Imaging Features

Imaging is crucial when abdominal symptoms dominate.

CT findings:
- Circumferential small bowel wall thickening.
- Submucosal edema.
- Mesenteric edema.
- Moderate ascites.

Figure 1. Axial non-contrast CT. Demonstrates prominent wall thickening of proximal jejunum with mucosal hyperenhancement and mesenteric edema, consistent with HAE bowel involvement.

Figure 2. Axial non-contrast CT. Shows recurrent intestinal wall edema with free peritoneal fluid, supporting diagnosis of hereditary angioedema rather than infectious enteritis.

Unlike inflammatory bowel disease, there is no mesenteric adenopathy or mucosal ulceration.

Differential Diagnosis

HAE often mimics other causes of recurrent abdominal pain or swelling. Important differentials include:

Appendicitis / pancreatitis / bowel obstruction
Inflammatory bowel disease (Crohn’s, ulcerative colitis)
Infectious gastroenteritis
Familial Mediterranean Fever (FMF)
Eosinophilic gastroenteritis
Irritable bowel syndrome
Acute intermittent porphyria

Key distinction: absence of fever, urticaria, or inflammatory markers, plus family history and response to C1-INH replacement therapy.

Diagnosis

Diagnostic algorithm includes:

Screening test: Serum C4 (low during and between attacks).
Confirmatory tests:
- Quantitative C1-INH levels.
- Functional C1-INH activity assay.
Genetic testing: Indicated for suspected Type III or equivocal cases.

Treatment

On-demand therapy (acute attacks):

C1-INH replacement (plasma-derived or recombinant).
Icatibant (bradykinin B2 receptor antagonist).
Ecallantide (kallikrein inhibitor, requires medical supervision).
Fresh frozen plasma (second-line if specific drugs unavailable).

Short-term prophylaxis:

Pre-procedural administration of C1-INH concentrate.
Short courses of danazol or stanozolol pre-surgery.

Long-term prophylaxis:

C1-INH concentrate (IV or SC).
Lanadelumab (monoclonal antibody against kallikrein).
Berotralstat (oral kallikrein inhibitor).
Danazol (limited by side effects: weight gain, acne, hirsutism, hypertension, dyslipidemia).

In the presented case, financial limitations restricted access to first-line therapies, so danazol 200 mg weekly was initiated with good response after 6 months.

Prognosis

With modern therapy, life expectancy approaches normal.
Untreated, mortality from laryngeal edema can reach 30%.
Quality of life depends on attack frequency and treatment accessibility.
Long-term androgen therapy requires monitoring for metabolic and hepatic toxicity.

Quiz

Q1. Which of the following best explains the pathophysiology of hereditary angioedema (HAE)?

A. Mast cell degranulation leading to histamine release
B. Uncontrolled bradykinin production due to C1-INH deficiency
C. Autoimmune attack on vascular endothelium
D. Elevated IgE-mediated hypersensitivity

Q2. What is the most dangerous complication of HAE?

A. Cutaneous swelling
B. Abdominal pain
C. Laryngeal edema
D. Arthralgia

Q3. Which laboratory finding supports the diagnosis of HAE type I?

A. Elevated C4 and normal C1-INH
B. Low C4 and low quantitative C1-INH
C. Normal C4, reduced C1-INH activity
D. Elevated C1q

Q4. Which of the following drugs is NOT effective for acute HAE attacks?

A. Icatibant
B. Ecallantide
C. Plasma-derived C1-INH
D. Antihistamines

Q5. Which therapy is most appropriate for long-term prophylaxis in patients with frequent HAE attacks?

A. Lanadelumab
B. Antihistamines
C. Corticosteroids
D. Antibiotics

Answer & Explanation

1. Answer: B. Explanation: HAE is bradykinin-mediated, not histamine-mediated.

2. Answer: C. Explanation: Laryngeal edema occurs in ~0.9% of attacks and can be fatal.

3. Answer: B. Explanation: Type I HAE has low C1-INH levels and low C4.

4. Answer: D. Explanation: Antihistamines are ineffective because HAE is bradykinin-mediated, not histamine-mediated.

5. Answer: A. Explanation: Lanadelumab is an FDA-approved monoclonal antibody for prophylaxis.

References

[1] M. Cicardi and H. Grumach, “Hereditary angioedema: epidemiology, clinical manifestations, and diagnosis,” N Engl J Med, vol. 382, pp. 1136–1148, 2020.
[2] W. C. Longhurst and B. Zuraw, “New treatments for hereditary angioedema: an update,” Allergy Asthma Proc., vol. 41, no. 3, pp. 180–187, 2020.
[3] B. Zuraw et al., “Pathophysiology of bradykinin-mediated angioedema,” J Allergy Clin Immunol., vol. 141, no. 5, pp. 1491–1503, 2018.
[4] H. Bork et al., “Hereditary angioedema: new findings concerning symptoms, affected organs, and course,” Am J Med., vol. 119, no. 3, pp. 267–274, 2019.
[5] M. Maurer et al., “The international WAO/EAACI guideline for the management of hereditary angioedema,” Allergy, vol. 73, pp. 1575–1596, 2022.
[6] I. Busse et al., “Long-term safety and efficacy of lanadelumab for hereditary angioedema prevention,” Allergy Clin Immunol Pract., vol. 8, no. 5, pp. 1728–1739, 2020.
[7] P. Banerji et al., “Berotralstat for the prevention of hereditary angioedema attacks,” N Engl J Med, vol. 384, pp. 1131–1140, 2021.

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