Complement Deficiency

Primary Authors: Delgado, Julio, MD, MS. Hill, Harry R., MD.

  • Key Points
  • Diagnosis
  • Algorithms
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Content

The complement system is a complex system of proteins that play a role in host defense and inflammation response by acting as a cascade involving three pathways - classical (CP), alternative (AP), and lectin (LP). Each pathway is initiated by distinct mechanisms. Deficiency of any of the proteins in these pathways may lead to recurrent infections (with encapsulated organisms, in particular) or inappropriate inflammatory responses. Inherited deficiencies are uncommon, but acquired deficiencies, due to a variety of etiologies, are much more common.

Initial evaluation for suspected complement deficiency should include testing for both the CP (using the CH50 method) and AP (using the AH50 method) pathways but may also include testing for the LP pathway (using mannose binding lectin [MBL]), depending on the clinical circumstance. Results from the initial evaluation guide secondary testing for complement deficiency.

Clinical presentation is similar among the various complement component dysfunctions. Refer to tables below for details about each pathway.

Indications for Testing

  • Recurrent pyogenic infections (especially meningococcal meningitis, Streptococcus pneumoniae)
  • Angioedema without urticaria
  • Autoimmune disorders (eg, cryoglobulinemic vasculitis, renal or ophthalmic disorders)

Laboratory Testing

  • Initial testing for suspected complement deficiency
    • Testing for both the classical (CH50) and alternative (AH50) pathways
    • May also include mannose-biding lectin (MBL) testing depending on the clinical circumstance
  • Further testing based on disease presentation and enzyme activity levels
  • Circulating immune complexes – may be useful for disease monitoring

The complement system provides an innate defense mechanism against pathogenic organisms.

Epidemiology

  • Prevalence – 2% of immunodeficiency disorders relate to complement deficiency

Pathophysiology

  • Complement system consists of plasma enzymes, regulatory proteins, and proteins activated in cascading fashion, resulting in cell lysis
  • In humans, most active complement components are synthesized early in fetal life
    • C1 – produced by cells in gut columnar epithelium
    • C4 and C2 – produced by macrophages in primary organs
    • C3 – produced by hepatic parenchymal cells
    • C5 – produced in fetal lung, liver, intestine
  • Complement activation can occur via three different pathways – classic, mannose-binding lectin (MBL), and alternative
    • C3 cleavage by each pathway leads to activation of C5, C6, C7, C8, C9
    • Pathways converge into a final terminal pathway

Clinical Presentation

Indications for Laboratory Testing

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

Complement Activity Enzyme Immunoassay, Total 0050198
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations

Does not evaluate individual components of the alternative pathway

Complement activation can occur during blood draw (rare)

Follow Up

Refer to Key Points

Complement Activity, Alternative Pathway (AH50) 2005373
Method: Semi-Quantitative Radial Immunodiffusion

Limitations

Does not evaluate individual components of the alternative pathway

Complement activation can occur during blood draw (rare)

Follow Up

Refer to Key Points

Mannose Binding Lectin 0051692
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Limitations

Does not evaluate individual components of the alternative pathway

Complement activation can occur during blood draw (rare)

Follow Up

Refer to Key Points

Anti-C1q Antibody, IgG 2007601
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations

Not all patients with lupus nephritis will be positive for C1q antibodies

C1q antibodies are not specific for lupus

Complement Component 2 0050148
Method: Quantitative Radial Immunodiffusion

Complement Component 3 0050150
Method: Quantitative Immunoturbidimetry

Limitations

C3 is an acute phase reactant and may also be elevated early in inflammation or infection

Complement Component 4 0050155
Method: Quantitative Immunoturbidimetry

Complement Components 3 and 4 0050149
Method: Quantitative Immunoturbidimetry

Complement Component 4A 2003180
Method: Radioimmunoassay

Complement Component 5 0050156
Method: Quantitative Radial Immunodiffusion

Complement Component 6 0099072
Method: Quantitative Radial Immunodiffusion

Complement Factor B 0051720
Method: Quantitative Radial Immunodiffusion

Complement C3 Nephritic Factor 2009380
Method: Qualitative Immunofixation Electrophoresis 

Complement Factor H (B1H) 2009416
Method: Quantitative Radial Immunodiffusion

Complement Factor I 2009382
Method: Quantitative Radial Immunodiffusion

Additional Tests Available

Complement Component 3A 2003304
Method: Radioimmunoassay

Comments

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

Raji Cell Immune Complex Assay 0050302
Method: Quantitative Flow Cytometry

Immune Complex Panel 0050667
Method: Quantitative Flow Cytometry/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments

Panel includes C1Q Binding Assay and Raji Cell Immune Complex Assay

Complement Component 1Q Level 0099130
Method: Radial Immunodiffusion

Comments

Aids in diagnosis of C1q deficiency

Complement Component 7 0099073
Method: Quantitative Radial Immunodiffusion

Comments

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

Complement Component 8 0099074
Method: Quantitative Radial Immunodiffusion

Comments

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

Complement Component 9 0099076
Method: Quantitative Radial Immunodiffusion

Comments

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

Complement Component 1, Functional 0099078
Method: Quantitative Hemolytic Assay

Comments

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

Complement Component 6 Functional 0099131
Method: Quantitative Hemolytic Assay

Complement Component 7 Functional 0099121
Method: Quantitative Hemolytic Assay

Complement Component 8 Functional 0099133
Method: Hemolytic Assay

Complement Component 9 Functional 0099120
Method: Quantitative Hemolytic Assay

C1-Esterase Inhibitor 0050140
Method: Quantitative Nephelometry

C1-Esterase Inhibitor Functional 0050141
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

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

Comments

Panel includes C1-esterase inhibitor, C1-esterase inhibitor functional, and complement component 4

C1q Binding Assay 0050301
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments

Detect circulating immune complexes (CIC)

Not a first-line test for determining CIC activity 

Guidelines

Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley M, Cunningham-Rundles C, Etzioni A, Franco J, Gaspar B, Holland S, Klein C, Nonoyama S, Ochs H, Oksenhendler E, Picard C, Puck J, Sullivan K, Tang M. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014; 5: 162. PubMed

General References

Bonilla F, Bernstein L, Khan D, Ballas Z, Chinen J, Frank M, Kobrynski L, Levinson A, Mazer B, Nelson R, Orange J, Routes J, Shearer W, Sorensen R, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, Joint Council of Allergy, Asthma and Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005; 94(5 Suppl 1): S1-63. PubMed

Chen M, Daha M, Kallenberg C. The complement system in systemic autoimmune disease. J Autoimmun. 2010; 34(3): J276-86. PubMed

Grumach A, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014; 61(2): 110-7. PubMed

Immune Deficiency Foundation. Towson, MD [Accessed: Nov 2015]

Lipsker D, Hauptmann G. Cutaneous manifestations of complement deficiencies. Lupus. 2010; 19(9): 1096-106. PubMed

Locke B, Dasu T, Verbsky J. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014; 46(2): 154-68. PubMed

Mayilyan K. Complement genetics, deficiencies, and disease associations. Protein Cell. 2012; 3(7): 487-96. PubMed

Nilsson B, Ekdahl K. Complement diagnostics: concepts, indications, and practical guidelines. Clin Dev Immunol. 2012; 2012: 962702. PubMed

Pettigrew D, Teuber S, Gershwin E. Clinical significance of complement deficiencies. Ann N Y Acad Sci. 2009; 1173: 108-23. PubMed

Wen L, Atkinson J, Giclas P. Clinical and laboratory evaluation of complement deficiency. J Allergy Clin Immunol. 2004; 113(4): 585-93; quiz 594. PubMed

Medical Reviewers

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Last Update: January 2016