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

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 Lab 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 of Automated Core Laboratory, ARUP Laboratories
Contributor

References

Additional Resources