Hereditary Angioedema - C1-INH Deficiency

Hereditary angioedema (HAE) is an episodic swelling disease associated with the deficiency or malfunction of complement 1 esterase inhibitor (C1-INH). In contrast to acquired angioedema, which is a secondary process, HAE is associated with genetic variations. Initial laboratory assessment involves testing for C1-INH levels, complement 4 (C4) levels, functional C1-INH activity, and possibly C1q levels.

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Diagnosis

Indications for Testing

  • Recurrent angioedema in the absence of urticaria of
    • Subcutaneous tissues
    • Systemic organs
    • Mouth, larynx, or pharynx
  • Family history of angioedema
  • Unexplained episode of laryngeal edema

Laboratory Testing

  • Initial testing
    • Complement 1 esterase inhibitor (C1-INH), complement 4 (C4)
      • Decreased levels suggest hereditary angioedema
      • Confirm with repeat testing of C1-INH and C4
      • If family history present, consider functional testing for typing
    • Functional C1-inhibitor activity
      • Assists with determination of hereditary angioedema type
    • Consider C1q testing when family history is absent
      • Later age of onset and low C1q suggest acquired angioedema
      • Early age of onset and normal C1q suggest familial angioedema
    • If all results are normal
      • Repeat C4, C1-INH testing during attack
      • Consider other types of angioedema (eg, autoimmune disorder)
  • Genetic testing – not necessary for diagnosis

Differential Diagnosis

  • Cutaneous edema
    • Allergic urticaria/angioedema
    • Drug-induced angioedema (eg, angiotensin-converting enzyme [ACE] inhibitors, nonsteroidal anti-inflammatory drugs [NSAIDs])
    • Contact dermatitis
    • Acquired angioedema
    • Urticarial vasculitis associated with angioedema
    • Idiopathic or cold-induced angioedema
    • Cellulitis
    • Parasitic infection (eg, Trichinella spp)
    • Autoimmune conditions
  • Laryngeal edema – peritonsillar abscess

Background

Epidemiology

  • Incidence – 1/50,000
  • Age
    • Congenital form – usually occurs in childhood
    • Acquired form – onset occurs later
  • Sex – M:F, equal

Risk Factors

  • Genetics
  • Pressure applied to an extremity
  • Stress
  • Ingested estrogens, pregnancy
  • Lymphoproliferative disorder

Inheritance

  • Autosomal dominant inheritance
    • 25% are de novo variants
  • Variants in SERPING1 gene

Classification

  • Hereditary angioedema (HAE) types
    • Type 1 – low complement 1 esterase inhibitor (C1-INH) level and low function (85%)
      • If C1q is also low, suspect acquired angioedema
    • Type 2 – normal C1-INH  level but low function (15%)
    • Type 3 (familial angioedema) – normal C1-INH  and normal function (rare)

Pathophysiology​

  • C1-INH
    • Multispecific, protease inhibitor
    • Regulates the enzymes of the complement, coagulation, fibrinolytic, and kinin-forming systems, including
      • C1r and C1s subunits of activated first component of complement
      • Activated Hageman factor (factor XIIa) and Hageman factor fragments
      • Activated plasma thromboplastin antecedent (PTA or factor XIa)
      • Prekallikrein (Fletcher factor)
      • Plasmin
    • Possible disorders associated with C1-INH include
      • HAE
        • Hereditary quantitative deficiency or qualitative defect in C1-INH
        • Deficiency of functionally active component may lead to life-threatening angioedema
      • Acquired C1-INH deficiency
        • Qualitative defect in C1-INH
        • Associated with a variety of diseases, including lymphoid malignancies

Clinical Presentation

  • Symptoms typically begin in childhood, worsen in puberty, and have an unpredictable course throughout adulthood
  • Transient, recurrent attacks of nonpruritic, deep-seated swelling of various tissues occur throughout the body without the presence of urticaria
    • Typically involves arms, legs, hands, trunk, face, mouth, larynx, airway, genitals, and tongue
  • Gastrointestinal tract often involved, with recurrent episodes of cramping, abdominal pain, nausea, and emesis (most frequent presenting complaint in children)
  • Most frequent cause of death is airway obstruction secondary to laryngeal edema
  • Presence of autoimmune diseases (especially glomerulonephritis) is higher in these patients
  • Typical and predictable course
    • Many attacks, preceded by prodrome (tingling sensation)
    • Swelling gradually increases over the first 24 hours, then gradually subsides over the next 48-72 hours

ARUP Laboratory Tests

Primary Tests

Aid in diagnosis of hereditary angioedema (HAE)

Test for C1-esterase inhibitor (C1-INH) levels and complement 4 (C4) levels

Panel includes C1-INH, C1-INH functional, complement component 4

Aid in the diagnosis of C1q deficiency

Related Tests

Diagnose hereditary angioedema (HAE)

Monitor response to therapy

Aid in diagnosis of HAE

Monitor response to therapy

Rule out a complement deficiency

Follow-up test for complement activity screening when CH50 is low or absent and AH50 is normal and high suspicion remains for complement deficiency

Rule out complement component 3 deficiency

Medical Experts

Contributor

Genzen

Jonathan R. Genzen, MD, PhD
Associate Professor of Clinical Pathology, University of Utah
Chief Operations Officer: Medical Director, Automated Core Laboratory, ARUP Laboratories
Contributor

References

Additional Resources