Acute Phase Proteins - Acute Phase Reactants

Diagnosis

Indications for Testing

  • Inflammation or infection not explained by other etiology

Laboratory Testing 

  • C-reactive protein
  • Other 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 esterase inhibitor, C4b-BP, mannose-BP, B-2-glycoprotein-1

    Coagulation system

    Fibrinogen, plasminogen, urokinase, protein S, vitronectin, plasminogen activator inhibitor-1 (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 binding protein (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, (eg, interleukin 1 (IL-1), interleukin 6 (IL-6), chemokines (IL-8), glucocorticoids)
  • Pentraxins
    • C-reactive protein (CRP)
      • Functions
        • May increase a thousand fold in response to inflammation and infection
        • Acts as an opsonin for bacteria, parasites, immune complexes
          • Can act as an activator of classic complement pathway
        • Elevated in many disease states (eg, 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, 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, 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
    • 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
        • 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, NK cells
      • Decreased IL-2 production associated with
    • Interleukin-8
      • Production – activated macrophages
      • Function – proinflammatory cytokine, 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
Test Name and Number Recommended Use Limitations Follow Up
C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Use in clinical scenarios associated with inflammation (autoimmune disease, connective tissue disease, rheumatoid arthritis, or sepsis)

Do not order for CVD risk assessment; use CRP high sensitivity 

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Alpha-1-Acid Glycoprotein 0050002
Method: Quantitative Nephelometry

Limited clinical use

Haptoglobin 0050280
Method: Quantitative Immunoturbidimetry

Limited clinical use

Tumor Necrosis Factor - alpha 0051539
Method: Quantitative Multiplex Bead Assay

Limited clinical use

Cytokine Panel 12 0051394
Method: Quantitative Multiplex Bead Assay

Limited clinical use

Cytokine Panel, Monokines 0051524
Method: Quantitative Multiplex Bead Assay

Limited clinical use

Interleukin 1 beta 0051536
Method: Quantitative Multiplex Bead Assay

Limited clinical use

Interleukin 2 Receptor (CD25), Soluble 0051529
Method: Quantitative Multiplex Bead Assay

Limited clinical use

Interleukin 2 0051588
Method: Quantitative Multiplex Bead Assay

Limited clinical use

Interleukin 6 0051537
Method: Quantitative Multiplex Bead Assay

Limited clinical use

Interleukin 8 0051538
Method: Quantitative Multiplex Bead Assay

Limited clinical use

Alpha-1-Antitrypsin 0050001
Method: Quantitative Immunoturbidimetry

Limited clinical use

Cytokine Panel, TH1 0051408
Method: Quantitative Multiplex Bead Assay

Limited clinical use

Cytokine Panel, TH2 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 (CD25), 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

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

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

Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 10 0051578
Method: Cell Culture/Quantitative Multiplex Bead Assay

Limited clinical use

Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 13 0051579
Method: Cell Culture/Quantitative Multiplex Bead Assay

Limited clinical use