Acute Phase Proteins - Acute Phase Reactants

Diagnosis

Indications for Testing

• Inflammation or infection not explained by other etiology
  • Except for CRP, these markers are predominantly used in research settings

Clinical Background

Plasma proteins termed acute phase proteins or reactants are involved in the innate system response to inflammation, tissue injury or malignancy.  During inflammatory processes, the plasma concentration of these acute phase proteins increases or decreases by ≥50%.

Classification

• Human plasma acute phase proteins

  Human Plasma Acute Phase Proteins
  Positive Acute Phase Proteins*
  Complement system	C2, C3, C4, C5, C9, factor B, C1 inhibitor, C4b-BP, mannose-BP, B-2-glycoprotein-1
  Coagulation system	Fibrinogen, plasminogen, urokinase, protein S, vitronectin, PAI-1, alpha-2-antiplasmin, antithrombin 3
  Antiproteases	Alpha-1-antitrypsin, alpha-1-antichymotrypsin, pancreatic secretory trypsin inhibitor, inter-alpha-trypsin inhibitor, alpha-2 macroglobulin
  Binding proteins	Ceruloplasmin, haptoglobin, hemopexin, LPS-BP, mannose-BP
  Proteins involved in inflammatory response	Secreted phospholipase A2, IL-IRA, GM-CSF, cytokines (interleukins), tumor necrosis factor
  Others	Serum amyloid A, C-reactive protein, alpha-1 acid glycoprotein, fibronectin, ferritin, angiotensinogen, hepcidin
  Negative Acute Phase Proteins**
  Albumin, transferrin, alpha 2-HS-glycoprotein, alpha fetoprotein, thyroxine-BP, IGF-1, factor XII, retinol binding protein, transthyretin, transcortin
  * Increase in response to inflammation ** Decrease in response to inflammation

Pathophysiology

• Most acute phase reactants are synthesized in the hepatocytes
  • Not elevated in functional disturbances
  • Usually not elevated in stable chronic diseases
  • Strongly elevated in bacterial infections, juvenile arthritis, tumors, Crohn disease, surgery, polymyalgia rheumatica, systemic vasculitis, burns, fractures
  • Negligible elevation in arthralgia, myalgia, back pain

Selected Acute Phase Proteins

• Alpha-1 acid glycoprotein
  • Function – immunomodulatory activity that may reduce collateral damage caused by inflammation
  • Regulation – proinflammatory cytokines, including interleukin 1 (IL-1), interleukin 6 (IL-6), chemokines (IL-8) and glucocorticoids
• Pentraxin
  • C-reactive protein (CRP)
    • Functions
      • May increase a thousandfold in response to inflammation and infection
      • Acts as an opsonin for bacteria, parasites and immune complexes
        • Can act as an activator of classic complement pathway
      • Elevated in many disease states, including coronary artery disease, infections, vasculitis, acute phase of connective tissue diseases, malignancy
  • Amyloid
    • Functions
      • Apolipoproteins that associate with HDL3
      • Enhances binding capacity of HDL3 to hepatocytes
      • Elevated in malignancy
  • Haptoglobin
    • Functions
      • Binds free hemoglobin released from erythrocytes
      • Involved in inflammation, infections and malignancy
  • Ceruloplasmin
    • Functions
      • Globulin involved in release of iron into plasma cells
      • Serum antioxidant
      • Modulates inflammatory response
      • Elevated in pregnancy, high estrogen conditions, infections, cirrhosis, malignancy, hyperthyroidism, and rheumatoid arthritis (RA)
• Cytokines
  • Functions
    • Major activators of acute phase proteins are IL-1 and IL-6
    • Mediators between leukocytes; 18 identified interleukins with varying effects
  • Interleukin-1-beta
    • Production – activated macrophages
    • Functions – wide variety of biological actions
      • Stimulates expression of IL-2 receptors
      • Stimulates production and secretion of IL-2
    • In synergy with tumor necrosis factor alpha, elevated interleukin-1-beta is seen in the following
      • Septic shock
      • Cerebrospinal fluid
        • Meningitis
        • Multiple sclerosis
  • Interleukin-6
    • Function – involved in B-cell differentiation into plasma cells
      • Usually not detected in normal serum, plasma, cerebral spinal fluid (CSF) or joint fluid
    • Elevated levels occur in the following
      • Inflammatory processes
        • Infections (endotoxemia)
        • Connective tissue disease
      • Alcoholic cirrhosis
      • Chronic renal failure
      • Central nervous system inflammation (increased CSF levels)
        • Bacterial meningitis
        • CNS involvement in systemic lupus erythematosus (SLE)
      • RA (increased synovial fluid levels)
  • Interleukin-2
    • Production – activated T-cells
    • Also known as
      • T-cell growth factor
      • Thymocyte simulation factor
      • Thymocyte mitogenesis factor
      • T-cell replacing factor
      • Killer-helper factor
    • Function – most notable immunologic function is the activation, proliferation and promotion of T-cells, B-cells and NK-cells
    • Decreased IL-2 production associated with
      • SLE
      • Hodgkin lymphoma
      • Lepromatous leprosy
      • HIV/AIDS
      • Common variable immunodeficiency
      • Chronic mucocutaneous candidiasis 
  • Interleukin-8
    • Production – activated macrophages
    • Function – pro-inflammatory cytokine and chemoattractant for neutrophils
    • Elevated in many inflammatory processes – infections, connective tissue diseases

Tumor Necrosis Factor (TNF-α, Cachectin)

• Production – mononuclear phagocytes
• Functions
  • Activation of T-cells 
  • Pyrogenicity and endotoxemia
  • Mitogenic effects on fibroblasts 
  • Resorption of bone and cartilage
  • Activation of neutrophil function 
  • Decreased activity of several enzymes involved in lipid metabolism
  • Decreased synthesis of hepatic protein
  • Cachexia
• Regulation
  • IL6R, IL1R and IL2RA interleukin receptors
  • Granulocyte monocyte-colony stimulating factor
  • MYC and FOS genes
  • Epidermal growth factor

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Cytokine Panel, TH1 by MAFD 0051408 Method: Quantitative Multiplex Bead Assay	Limited clinical use
Cytokine Panel, TH2 by MAFD 0051518 Method: Quantitative Multiplex Bead Assay	Limited clinical use
Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, 12 Cytokines 0051540 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use
Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interferon gamma 0051574 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use
Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 1 beta 0051580 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use
Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 2 0051571 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use
Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 2 Receptor (Soluble) 0051572 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use
Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 4 0051576 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use
Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 5 0051577 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use
Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 6 0051581 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use
Alpha-1-Antitrypsin 0050001 Method: Quantitative Immunoturbidimetry	Limited clinical use
Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, TH1 Cytokines 0051558 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use
Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, TH2 Cytokines 0051562 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use
Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Monokines 0051566 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use
Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, Monokines 0051587 Method: Cell Culture/Multiplex Bead Assay	Limited clinical use
Interleukin-1-Receptor-Associated Kinase-4 (IRAK-4) Deficiency Screen 0051393 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use
Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies 0095899 Method: Quantitative Flow Cytometry	Test includes percentage and absolute counts for CD2, CD3 (total T-cells), HLA-DR, CD4 (helper T-cells), CD45RA (naive helper T-cells), CD45RO (memory helper T-cells), CD8 (suppressor T-cells), CD19 (B-cells ), NK cells, and  CD4:CD8 ratio Limited clinical use
Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 8 0051582 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use
Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Tumor Necrosis Factor alpha 0051583 Method: Cell Culture/Quantitative Multiplex Bead Assay	Limited clinical use