Complement Deficiency

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

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

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.

 

Indications for Testing

Laboratory Testing

  • Initial testing
    • Testing for classical (CH50) and alternative (AH50) pathways
    • May also include mannose-biding lectin (MBL) testing depending on the clinical presentation
  • Further testing based on disease presentation and initial testing
  • 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
  • Genetics
    • Most disorders are inherited as autosomal recessive disorders
    • X-linked – properdin 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

  • Associated with frequent, recurrent disseminated infections
  • May present as an autoimmune disease (eg, SLE, nephritis)
  • Presentation is similar among the various complement component dysfunctions – refer to tables below for details about each pathway
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 Level 4a 2003180
Method: Radioimmunoassay

Complement Component 5 0050156
Method: Quantitative Radial Immunodiffusion

Complement Component Level 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 Level (B-1H) 2009416
Method: Quantitative Radial Immunodiffusion

Complement Factor I 2009382
Method: Quantitative Radial Immunodiffusion

Guidelines

Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar B, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM, Sullivan K, Tang ML. 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 FA, Bernstein L, Khan DA, Ballas ZK, Chinen J, Frank MM, Kobrynski LJ, Levinson AI, Mazer B, Nelson RP, Orange JS, Routes JM, Shearer WT, Sorensen RU, 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 MR, Kallenberg CG. The complement system in systemic autoimmune disease. J Autoimmun. 2010; 34(3): J276-86. PubMed

Grumach AS, 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]

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

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

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

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

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

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Last Update: August 2016