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.

Tabs Content

Clinical Overview

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
  - Lymphoproliferative disorders (lymphoma, B-cell and T-cell lymphomas)
  - Autoimmune disease
  - Neoplasia
- 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 Lab Tests

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

C-1-Esterase Inhibitor Panel 0050139
Method: Immunoturbidimetry/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Nephelometry

Recommended Use

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

Complement Component 1Q Level 0099130
Method: Radial Immunodiffusion

Recommended Use

Aid in the diagnosis of C1q deficiency

Medical Experts

Genzen, Jonathan R., MD, PhD, Laboratory Section Chief, Clinical Chemistry, and Medical Director, Automated Core Laboratory, at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Peterson, Lisa K., PhD, D(ABMLI), Medical Director, Immunology, at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

References

Guidelines

Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C, Fay AC, Longhurst HJ, Morrison L, Price A, Price M, Watters D. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005; 139(3): 379-94. PubMed
Boyle RJ, Nikpour M, Tang ML. Hereditary angio-oedema in children: a management guideline. Pediatr Allergy Immunol. 2005; 16(4): 288-94. PubMed
Castaldo AJ. Hereditary angioedema: a current state-of-the-art review, IX: the US Hereditary Angioedema Association: a message from the president. Ann Allergy Asthma Immunol. 2008; 100(1 Suppl 2): S47-8. PubMed
Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Zuraw B, Aygoeren-Pürsün E, Craig T, Binkley K, Hebert J, Ritchie B, Bouillet L, Betschel S, Cogar D, Dean J, Devaraj R, Hamed A, Kamra P, Keith PK, Lacuesta G, Leith E, Lyons H, Mace S, Mako B, Neurath D, Poon M, Rivard G, Schellenberg R, Rowan D, Rowe A, Stark D, Sur S, Tsai E, Warrington R, Waserman S, Ameratunga R, Bernstein J, Björkander J, Brosz K, Brosz J, Bygum A, Caballero T, Frank M, Fust G, Harmat G, Kanani A, Kreuz W, Levi M, Li H, Martinez-Saguer I, Moldovan D, Nagy I, Nielsen EW, Nordenfelt P, Reshef A, Rusicke E, Smith-Foltz S, Späth P, Varga L, Xiang ZY. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010; 6(1): 24. PubMed
Zuraw BL, Bernstein JA, Lang DM, Craig T, Dreyfus D, Hsieh F, Khan D, Sheikh J, Weldon D, Bernstein DI, Blessing-Moore J, Cox L, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller DE, Spector SL, Tilles SA, Wallace D, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013; 131(6): 1491-3. PubMed
Zuraw BL, Banerji A, Bernstein JA, Busse PJ, Christiansen SC, Davis-Lorton M, Frank MM, Li HH, Lumry WR, Riedl M, US Hereditary Angioedema Association Medical Advisory Board. US Hereditary Angioedema Association Medical Advisory Board 2013 recommendations for the management of hereditary angioedema due to C1 inhibitor deficiency. J Allergy Clin Immunol Pract. 2013; 1(5): 458-67. PubMed

General References

Banerji A. Hereditary angioedema: classification, pathogenesis, and diagnosis. Allergy Asthma Proc. 2011; 32(6): 403-7. PubMed

Bork K, Gül D, Hardt J, Dewald G. Hereditary angioedema with normal C1 inhibitor: clinical symptoms and course. Am J Med. 2007; 120(11): 987-92. PubMed

Bork K. Hereditary angioedema with normal C1 inhibitor activity including hereditary angioedema with coagulation factor XII gene mutations. Immunol Allergy Clin North Am. 2006; 26(4): 709-24. PubMed

Cicardi M, Johnston DT. Hereditary and acquired complement component 1 esterase inhibitor deficiency: a review for the hematologist. Acta Haematol. 2012; 127(4): 208-20. PubMed

Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med. 2009; 15(2): 69-78. PubMed

Ebo DG, Verweij MM, De Knop KJ, Hagendorens MM, Bridts CH, De Clerck LS, Stevens WJ. Hereditary angioedema in childhood: an approach to management. Paediatr Drugs. 2010; 12(4): 257-68. PubMed

Frank MM. 8. Hereditary angioedema. J Allergy Clin Immunol. 2008; 121(2 Suppl): S398-401; quiz S419. PubMed

Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet. 2012; 379(9814): 474-81. PubMed

Tse K, Zuraw BL. Recognizing and managing hereditary angioedema. Cleve Clin J Med. 2013; 80(5): 297-308. PubMed

Testing Algorithms

C1-INH Deficiency Testing Algorithm

Read more about C1-INH Deficiency Testing Algorithm

Content Review:

November 2017

Last Update: June 2019

Hereditary Angioedema - C1-INH Deficiency

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Risk Factors

Inheritance

Classification

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

C1-INH Deficiency Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Hereditary Angioedema - C1-INH Deficiency. ARUP Consult^©. Retrieved August 19, 2019, from: https://arupconsult.com/content/hereditary-angioedema

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Hereditary Angioedema - C1-INH Deficiency

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Risk Factors

Inheritance

Classification

Pathophysiology​

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

C1-INH Deficiency Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult

Pathophysiology