Hepatic Acute-Phase Response (APR) in Trauma

• Hepatic acute-phase response (APR) in trauma — what rises, what falls, and why it matters
  • What it is?
    • Within hours of significant injury:
      • IL-6 (with TNF-α / IL-1) shifts hepatocyte transcription toward acute-phase proteins (APPs):
        • Away from constitutive proteins
      • This fuels host defense:
        • Opsonization, complement, coagulation control, metal sequestration:
          • But distorts common labs

Protein	Kinetics after trauma	Key functions	Clinical pearls
CRP	↑ at 6–8 h; peak 48–72 h; t½ ≈ 19 h	Opsonin; complements classical/lectin pathways	Tracks inflammatory burden; falls promptly as inflammation resolves (good trend marker).
Serum amyloid A (SAA)	↑ within 4–6 h; very high amplitude	HDL remodeling; leukocyte recruitment	Rises earlier/higher than CRP; very sensitive to tissue injury.
Fibrinogen	↑ Day 2–3	Coagulation substrate; fibrin matrix for repair	Drives ESR; hyperfibrinogenemia promotes thrombosis risk.
Haptoglobin	↑ 24–48 h	Binds free Hb; antioxidant	Low in hemolysis despite APR (consumption).
Hepcidin	↑ within hours–24 h	Decreases ferroportin → hypoferremia	Mechanism of anemia of inflammation; ferritin may be high despite low iron.
Ferritin	↑ 24–48 h	Iron storage/sequestration	High ferritin doesn’t mean iron repletion in APR.
Complement (C3, C4), MBL	↑ 24–72 h	Opsonization, pathogen lysis	Low levels suggest consumption or hepatic failure.
α1-antitrypsin	↑ 24–48 h	Serine protease inhibition; tissue protection	Deficiency predisposes to unchecked proteolysis.
α1-acid glycoprotein (orosomucoid)	↑ 24–48 h	Modulates immune response; drug binding	Increases binding of basic drugs → lower free fraction.
Ceruloplasmin	↑ 24–48 h	Copper transport; oxidase activity	Oxidative defense; explains ↑ serum copper.
LPS-binding protein (LBP)	↑ 12–24 h	Presents LPS to CD14/TLR4	Often elevated after trauma even without infection.
PAI-1	↑ early	Inhibits fibrinolysis	Favors microthrombosis; part of trauma-induced coagulopathy spectrum.

• Procalcitonin (PCT):
  • Rises after major trauma but is not hepatic:
    • It’s produced systemically (notably in bacterial sepsis):
      • Helpful to distinguish sterile inflammation vs secondary infection (trajectory matters)

Protein	Why it falls	Practical read
Albumin	Reprioritized synthesis + capillary leak	Not a nutrition marker in acute illness; low from redistribution/APR.
Prealbumin (Transthyretin)	Short t½ (≈2 d) + reprioritization	Falls quickly; still APR-sensitive, not pure nutrition.
Transferrin	Iron sequestration program	Falls early; contributes to hypoferremia.
Retinol-binding protein	Reprioritization	Declines with inflammation.
Antithrombin, Protein C/S	Consumption + reduced synthesis	Pro-thrombotic tilt; watch in TIC/ICU patients.

How this maps onto trauma phases

• Ebb (0 to 24 hours): 
  • Catecholamines / cortisol surge
  • TNF-α / IL-1 spark response
  • IL-6 begins hepatic switch
• Flow – catabolic (days 1–7): 
  • CRP / SAA peak
  • Fibrinogen, complement, haptoglobin, hepcidin rise
  • Albumin / transferrin / prealbumin fall
  • Plasminogen Activator Inhibitor-1 (PAI-1):
    • Favors impaired fibrinolysis
• Flow – anabolic (weeks): 
  • APR tapers
  • APPs normalize as repair predominates:
    • IL-10 / TGF-β tone higher

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High-yield clinical pearls for surgery/ICU

• CRP trend > single value:
  • Expect a 48 to 72 hour peak post-op:
    • A secondary rise suggests infection / collection
• Hepcidin / ferritin pattern:
  • Low iron, low transferrin, high ferritin = anemia of inflammation:
    • Avoid reflex iron unless functional deficiency is proven
• Coagulation:
  • ↑ fibrinogen and PAI-1 tilt toward thrombosis:
    • Combine with VTE prophylaxis early unless contraindicated
• Drug dosing:
  • ↓ albumin raises free acidic drugs (e.g., phenytoin)
  • ↑ α-1-acid glycoprotein (AGP) / orosomucoid lowers free basic drugs (e.g., lidocaine)
  • Monitor levels / clinical effect
• Nutrition metrics:
  • Albumin / prealbumin reflect inflammation, not intake:
    • Use calorie / protein delivery, nitrogen balance, indirect calorimetry or functional metrics instead

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Selected references

• Gabay C, Kushner I. Acute-phase proteins and systemic response to inflammation. N Engl J Med. 1999.
• Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003.
• Heinrich PC, et al. Interleukin-6-type cytokine signaling in hepatocytes. Biochem J. 2003.
• Castell JV, Andus T. IL-6 and the acute-phase response. Biochem J. 1991/1992.
• Ganz T, Nemeth E. Hepcidin and iron homeostasis in inflammation. Nat Rev Immunol. 2015.
• Marnell L, Mold C, Du Clos TW. CRP and host defense. Immunol Res. 2005.
• Meisner M. Procalcitonin—biochemistry and clinical diagnosis. 2010 (monograph).