Complement

Why Get Tested?

To determine whether deficiencies or abnormalities in complement system proteins are contributing to increased infections or increased autoimmune activity; to help monitor the activity and treatment of autoimmune diseases and immune complex-related diseases (Complement deficiencies may comprise between 1 and 10% of all primary immunodeficiencies.)

When To Get Tested?

When you have recurrent microbial (usually bacterial) infections, unexplained inflammation or edema, or symptoms related to an autoimmune disorder; periodically to help monitor a known acute or chronic condition that affects the complement system

Sample Required?

A blood sample drawn from a vein in your arm

Test Preparation Needed?

None

What is being tested?

The complement system consists of almost 60 proteins, approximately 30 of which are circulating blood proteins that work together to promote immune and inflammatory responses. Complement tests measure the amount or activity of complement proteins in the blood.

The complement system's principal role is to help identify, destroy and remove foreign pathogens like bacteria and viruses, as well as damaged "self" materials (e.g., cells and proteins). The complement system is so named because it “complements” or aids the natural body defenses, such as antibodies. So, the complement system is also activated when the body makes antibodies, whether against itself or foreign invaders. The body makes antibodies against its own tissues that it thinks are foreign (autoantibodies) in various autoimmune diseases.

The complement system is part of the body's innate immune system. Unlike the acquired immune system, which produces antibodies that target and protect against specific threats, the innate immune system is non-specific and can quickly respond to foreign substances. It does not require previous exposure to an invading microbe or offending substance and does not maintain a memory of previous encounters.

There are nine primary complement proteins that are designated C1 through C9. These components, in addition to the remaining proteins, work together in a cascade-like approach by activating, amplifying, breaking apart, and forming protein complexes that respond to infections, "non-self" tissues (e.g., transplants), dead cell debris (e.g., from apoptosis), or inflammation.

The complement cascade consists of 3 separate pathways that may be activated to converge in a final common pathway. The pathways include the "classical pathway" (including components C1qrs, C2, C4), the "alternative pathway" (including components C3, factor B, properdin), and the "lectin pathway" (a.k.a. mannan-binding lectin [MBL]). The end result of all three activation pathways is the same – the formation of the membrane attack complex (MAC). Complement activation causes several things to happen ("complement cascade"):

The MAC binds to the surface of each microbe, abnormal cell, or substance that has been targeted for destruction. It creates a lesion (hole) in the membrane wall and causes lysis, which is destruction of the cell by letting the contents out – like piercing a water-filled balloon.
It increases the permeability of blood vessels, allowing infection-fighting white blood cells (WBCs) to move out of the bloodstream and into tissues.
It attracts WBCs to the site of the infection.
It stimulates phagocytosis, a process in which microbes are engulfed by macrophages and neutrophils and killed.
It also labels immune complexes with complement components so that WBCs will engulf them and clear them out of the blood.

Complement tests measure the amount or the function (activity) of complement proteins in the blood. Complement components may be measured individually or together to determine whether the system is functioning normally. C3 and C4 are the most frequently measured complement proteins. Total complement activity can be measured if a healthcare practitioner suspects a deficiency that is not measured by C3 or C4. The CH50 functional test measures the function of the complete classical complement pathway, mediated by components C1 – C9. If this measurement is outside the normal range, then each of the nine different complement levels can be measured individually to look for hereditary or acquired deficiencies.

Common Questions

How is it used?

Complement tests, most commonly C3 and C4, are used to determine whether deficiencies or abnormalities in the complement system are causing, or contributing to, a person's disease or condition. Total complement activity (CH50) may be ordered to look at the integrity of the entire classical complement pathway. Other complement components are ordered as needed to look for deficiencies.

Complement testing may be used to:

Help diagnose the cause of recurrent microbial infections (such as Streptococcus pneumoniae, Neisseria meningitides, Neisseria gonorrhea), angioedema, or inflammation
Help diagnose and monitor the activity and treatment of acute or chronic autoimmune diseases such as lupus (systemic lupus erythematosus or SLE) and rheumatoid arthritis
Monitor immune complex-related diseases and conditions such as glomerulonephritis (a kidney disorder), serum sickness, and vasculitis

When is it ordered?

Complement testing may be ordered when a person has unexplained inflammation or edema or symptoms of an autoimmune disorder such as lupus. It may also be ordered when a healthcare practitioner suspects that someone may have an immune complex-related condition and wants to check the status of the person's complement system.

Individual complement components may be ordered when the total complement activity (CH50, sometimes called CH100) is abnormal to help determine which of the components are deficient or abnormal. C3 and C4 levels are the most frequently ordered, but others, such as C1 inhibitor, may be ordered when other deficiencies are suspected. C3 and C4 are often ordered together as the relative levels are often important.

When an acute or chronic condition has been diagnosed, complement testing may be used to help give a rough idea of the severity of the condition with the assumption that the severity is linked to the decrease in complement levels. Complement testing may also be ordered occasionally when a healthcare practitioner wants to monitor the current activity of a condition.

What does the test result mean?

Complement levels may be decreased due to increased consumption (because of increased activation) or, more rarely, a hereditary deficiency. Hereditary deficiency in one of the complement proteins will usually lead to a high frequency of recurrent microbial infections. Decreased complement levels also are associated with an increased risk of developing an autoimmune disease. Both C3 and C4 levels are typically depressed in lupus while C3 alone is low in septicemia and infections caused by fungi or parasites such as malaria.

If the deficiency is due to an underlying acute or chronic condition, complement levels will usually return to normal if the underlying condition can be resolved.

Decreased complement activity may be seen with:

Recurrent microbial infections (usually bacterial)
Autoimmune diseases, including lupus and rheumatoid arthritis
Hereditary angioedema
Acquired angioedema
Various types of kidney disease, including glomerulonephritis, lupus nephritis, membranous nephritis, and IgA nephropathy as well as kidney transplant rejection
Cirrhosis
Hepatitis
Malnutrition
Septicemia, shock
Serum sickness (immune complex disease)

Complement protein levels are usually increased, along with other unrelated proteins called acute phase reactants, during acute or chronic inflammation. These all usually return to normal when the underlying condition is resolved. However, complement proteins are rarely measured in these conditions, compared to the widely ordered C-reactive protein (CRP), and the relevance of their measurement in these situations is not reviewed here.

Increased complement activity may also be seen with:

Cancer (leukemia, Hodgkin lymphoma, sarcoma)
Ulcerative colitis
Thyroiditis
Acute myocardial infarction
Sarcoidosis
Juvenile rheumatoid arthritis

Is there anything else I should know?

Increased and decreased complement levels will not tell a healthcare practitioner what is wrong with a patient, but they can give an indication that the immune system is involved with a condition.

What are the other parts of the innate immune system?

It includes:

The phagocytic system (white blood cells, including neutrophils and monocytes/macrophages), whose function is to ingest and digest invading microbes
Inflammatory mediators produced by various cells, including basophils, mast cells, and eosinophils
Natural killer (NK), B and T cells that are specialized lymphocytes that kill some tumors cells, microorganisms, and cells that have been infected by viruses
Acute phase reactants and cytokines, which are a group of soluble proteins that can cause changes in the growth of many cells, including the white blood cells that produce them

View Sources

Sources Used in Current Review

2018 review performed by Kimia Sobhani, PhD, Director, Core labs, Cedars-Sinai Medical Center.

(January 29, 2014) V.M. Holers. Complement and its receptors: new insights into human disease. Available online at https://www.ncbi.nlm.nih.gov/pubmed?term=24499275. Accessed on 5/28/18.

(October 17, 2012) B. Nilsson. Complement Diagnostics: Concepts, Indications, and Practical Guidelines. Available online at https://www.hindawi.com/journals/jir/2012/962702/. Accessed on 5/28/2018.

(March 26, 2018) R.A. Schwartz. Complement Deficiencies. Available online at https://emedicine.medscape.com/article/135478-overview. Accessed on 5/28/2018.

(August 17, 2012) J. Charchaflieh. The Role of Complement System in Septic Shock. Available online at https://www.hindawi.com/journals/jir/2012/407324/. Accessed on 5/28/2018.

Sources Used in Previous Reviews

Thomas, Clayton L., Editor (1997). Taber's Cyclopedic Medical Dictionary. F.A. Davis Company, Philadelphia, PA [18th Edition].

Pagana, Kathleen D. & Pagana, Timothy J. (2001). Mosby's Diagnostic and Laboratory Test Reference 5th Edition: Mosby, Inc., Saint Louis, MO.

Biology of the Immune System. The Merck Manual of Medical Information--Home Edition, Section 16. Immune Disorders, Chapter 167 [On-line information]. Available online at http://www.merck.com/mrkshared/mmanual_home/sec16/167.jsp.

The Complement System. The Merck Manual of Diagnosis and Therapy, Section 12, Immunology; Allergic Disorders, Chapter 146. Biology Of The Immune System [On-line information]. Available online at http://www.merck.com/pubs/mmanual/section12/chapter146/146d.htm.

Kovacs, B. (2001 November 17). Complement. MedlinePlus Health Information, Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003456.htm.

Kovacs, B. (2001 October 6, Updated). C4 level. MedlinePlus Health Information, Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003354.htm.

Kovacs, B. (2001 November 17, Updated). Complement component 3 (C3). MedlinePlus Health Information, Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003539.htm.

(1999 January 29, Updated). How Does the Immune System Work? [13 paragraphs]. National Institute of Allergy and Infectious Diseases, National Institutes of Health [On-line information]. Available online at http://www.niaid.nih.gov/publications/autoimmune/work.htm.

ARUP's Guide to Clinical Laboratory Testing (CLT) [On-line information].
Complement Activity Enzyme Immunoassay, Total.
Complement Component 2.
Complement Component 3.
Complement Component 4.
Complement Component 5.
Complement Factor B.

Peng, S. (2005 April 20, Updated). Complement component 3 (C3). MedlinePlus Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003539.htm. Accessed on 4/10/07.

Peng, S. (2005 April 20, Updated). Complement. MedlinePlus Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003456.htm. Accessed on 4/10/07.

Liszewski, M. K, et. al. (2002 June 7). Innate Immunity: The Complement System. Medscape from ACP Medicine Online [On-line information]. Available online at http://www.medscape.com/viewarticle/534974. Accessed on 4/10/07.

(© 2007). Complement Disorders - Complement Activity. ARUP Consult [On-line information]. Available online at http://www.arupconsult.com/Topics/Infectious_Disease/Chronic/Complement_Activity.html. Accessed on 4/10/07.

Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 4th ed. Burtis CA, Ashwood ER, Bruns, D eds. St. Louis: Elsevier Saunders; 2006.

Henry's Clinical Diagnosis and Management by Laboratory Methods. 21st ed. McPherson R, Pincus, M, eds. Saunders Elsevier: 2007.

Harrison's Principles of Internal Medicine. 16th edition Kasper, Braunwald, Fauci, Hauser, Long, Jameson, eds. McGraw-Hill: 2005.

Borigini, M. and Zieve, D. (Updated 2009 February 3). Complement. MedlinePlus Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003456.htm. Accessed September 2010.

(© 1995-2010). Unit Code 8174: Complement C3, Serum. Mayo Clinic Mayo Medical Laboratories [On-line information]. Available online at http://www.mayomedicallaboratories.com/test-catalog/Overview/8174. Accessed September 2010.

Delgado, J. et. al. (Updated 2010 June). Complement Deficiency. ARUP Consult [On-line information]. Available online at http://www.arupconsult.com/Topics/ComplementDeficiency.html?client_ID=LTD. Accessed September 2010.

Chaganti, R. K. and Schwartz, R. (Updated 2009 July 9). Complement Deficiencies. eMedicine [On-line information]. Available online at http://emedicine.medscape.com/article/135478-overview. Accessed September 2010.

Delves, P. (Revised 2008 September). Complement System. Merck Manual for Healthcare Professionals [On-line information]. Available online at http://www.merck.com/mmpe/sec13/ch163/ch163d.html?qt=complement&alt=sh. Accessed September 2010.

Gupta, R. et. al. (Updated 2009 April 21). Complement-Related Disorders. eMedicine [On-line information]. Available online at http://emedicine.medscape.com/article/136368-overview. Accessed September 2010.

Henry's Clinical Diagnosis and Management by Laboratory Methods. 21st ed. McPherson R, Pincus M, eds. Philadelphia, PA: Saunders Elsevier: 2007, Pp 850, 855-861.

MedlinePlus Medical Encylopedia. Complement. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003456.htm. Accessed March 2014.

MedlinePlus Medical Encyclopedia. Complement component 3 (C3). Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003539.htm. Accessed March 2014.

MedlinePlus Medical Encyclopedia. Complement component 4. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003354.htm. Accessed March 2014.

ARUP Consult. Complement Deficiency. Available online at http://www.arupconsult.com/Topics/ComplementDeficiency.html#tabs=0. Accessed March 2014.

National Jewish Health Complement Laboratory. Complement: The Immune System's Most Aggressive Mechanism Against Infection. Available online at http://www.nationaljewish.org/professionals/clinical-services/diagnostics/adx/about-us/lab-expertise/complement/. Accessed March 2014.

University of Rochester Medical Center. Complement C3 (Blood). Available online at http://www.urmc.rochester.edu/encyclopedia/content.aspxContentTypeID=167&ContentID=complement_c3_blood. Accessed March 2014.

Healthline. Complement Test. Written by Ann Peitrangelo. Published on June 4, 2012. Available online at http://www.healthline.com/health/complement#Overview. Accessed March 2014.

Glovsky MM, Ward PW, Johnson KJ. Complement determinations in human disease. Ann Allergy Asthma Immunol. 2004; 93:513-523.

Speth C, Prodinger WM, Wurzner R, et al. Complement. Chapter 33 in Fundamental Immunology. William E Paul. Philadelphia:Lippincott-Williams-Wilkins. 2008, Pg 1048.

LabCorp

Find a Lab

Search Tests