The Hepatic Response to Severe Injury

  • M. G. Jeschke
  • D. N. Herndon


After severe injury, such as thermal injury, a variable degree of liver injury is present and it is usually related to the severity of the thermal injury. Fatty changes, a very common finding, are per se reversible and their significance depends on the cause and severity of accumulation [1]. However, autopsies of burned children who died have shown that fatty liver infiltration was associated with increased bacterial translocation, liver failure, and endotoxemia, thus delineating the crucial role of the liver during the post-burn response [2]–[4]. In a recent study in 102 children, 41 females and 61 males with a total body burn size of 58 ±2% and third degree burns in 45 ± 2 %, we found that liver size and weight significantly increased during the first week post-burn (+85 ±5%), peaked at 2 weeks post-burn (+126 ± 19%), and was increased by +89 ± 10% at discharge. At 6, 9, and 12 months the liver weight was increased by 40 – 50 % compared to predicted liver weight. In addition, liver protein synthesis was impaired for a 6-month period with a shift from constitutive hepatic proteins to acute phase proteins [5]. Liver enzymes were significantly elevated over the first 3 weeks post-burn, normalizing over time. These findings indicate that the hepatic acute phase response perseveres for a longer time period than previously thought [5, 6].


Hepatocyte Growth Factor Acute Phase Protein Acute Phase Response Recombinant Human Growth Hormone Hepatocyte Growth Factor Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Linares HA (1988) Autopsy findings in burned children. In: Carvajal HF, Parks DH (eds) Burns in Children: Pediatric Burn Management. Year Book Medical Pub, ChicagoGoogle Scholar
  2. 2.
    Barret JP, Jeschke MG, Herndon DN (2001) Fatty infiltration of the liver in severely burned pediatric patients: autopsy findings and clinical implications. J Trauma 51:736–739PubMedGoogle Scholar
  3. 3.
    Barrow RE, Hawkins HK, Aarsland A, et al (2005) Identification of factors contributing to hepatomegaly in severely burned children. Shock 24:523–528PubMedCrossRefGoogle Scholar
  4. 4.
    Barrow RE, Mlcak R, Barrow LN, Hawkins HK (2004) Increased liver weights in severely burned children: comparison of ultrasound and autopsy measurements. Burns 30:565–568PubMedCrossRefGoogle Scholar
  5. 5.
    Jeschke MG, Mlcak RP, Herndon DN (2007) Morphologic changes of the liver after a severe thermal injury. Shock (in press)Google Scholar
  6. 6.
    Jeschke MG, Barrow RE, Herndon DN (2004) Extended hypermetabolic response of the liver in severely burned pediatric patients. Arch Surg 139:641–647PubMedCrossRefGoogle Scholar
  7. 7.
    Jeschke MG, Low JF, Spies M, et al (2001) Cell proliferation, apoptosis, NF-kappaB expression, enzyme, protein, and weight changes in livers of burned rats. Am J Physiol Gastrointest Liver Physiol 280:G1314–1320PubMedGoogle Scholar
  8. 8.
    Steller H (1995) Mechanisms and genes of cellular suicide. Science 267:1445–1449PubMedCrossRefGoogle Scholar
  9. 9.
    Teplitz C (1996) The pathology of burns and the fundamentals of burn wound sepsis. In: Herndon D (ed) Total Burn Care, 1st edn. WB Saunders, Philadelphia, pp 45–50Google Scholar
  10. 10.
    Wolf SE, Ikeda H, Matin S, et al (1999) Cutaneous burn increases apoptosis in the gut epithelium of mice. J Am Coll Surg 188:10–16PubMedCrossRefGoogle Scholar
  11. 11.
    Carlson DL, Lightfoot E Jr, Bryant DD, et al (2002) Burn plasma mediates cardiac myocyte apoptosis via endotoxin. Am J Physiol Heart Circ Physiol 282:H1907–1914PubMedGoogle Scholar
  12. 12.
    Carlson DL, Willis MS, White DJ, Horton JW, Giroir BP (2005) Tumor necrosis factor-alpha-induced caspase activation mediates endotoxin-related cardiac dysfunction. Crit Care Med 33:1021–1028PubMedCrossRefGoogle Scholar
  13. 13.
    Horton JW, Maass DL, Ballard-Croft C (2005) Rho-associated kinase modulates myocardial inflammatory cytokine responses. Shock 24:53–58PubMedCrossRefGoogle Scholar
  14. 14.
    Lightfoot E Jr, Horton JW, Maass DL, White DJ, McFarland RD, Lipsky PE (1999) Major burntrauma in rats promotes cardiac and gastrointestinal apoptosis. Shock 11:29–34PubMedGoogle Scholar
  15. 15.
    Baron P, Traber LD, Traber DL, et al (1994) Gut failure and translocation following burn and sepsis. J Surg Res 57:197–204PubMedCrossRefGoogle Scholar
  16. 16.
    Ikeda H, Suzuki Y, Suzuki M, et al (1998) Apoptosis is a major mode of cell death caused by ischaemia and ischaemia/reperfusion injury to the rat intestinal epithelium. Gut 42:530–537PubMedCrossRefGoogle Scholar
  17. 17.
    Noda T, Iwakiri R, Fujimoto K, Matsuo S, Aw TY (1998) Programmed cell death induced by ischemia-reperfusion in rat intestinal mucosa. Am J Physiol 274:G270–276PubMedGoogle Scholar
  18. 18.
    Ramzy PI, Wolf SE, Irtun O, Hart DW, Thompson JC, Herndon DN (2000) Gut epithelial apoptosis after severe burn: effects of gut hypoperfusion. J Am Coll Surg 190:281–287PubMedCrossRefGoogle Scholar
  19. 19.
    Beg AA, Finco TS, Nantermet PV, Baldwin AS Jr (1993) Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation. Mol Cell Biol 13:3301–3310PubMedGoogle Scholar
  20. 20.
    Bellas RE, FitzGerald MJ, Fausto N, Sonenshein GE (1997) Inhibition of NF-kappa B activity induces apoptosis in murine hepatocytes. Am J Pathol 151:891–896PubMedGoogle Scholar
  21. 21.
    Jeschke MG, Einspanier R, Klein D, Jauch KW (2002) Insulin attenuates the systemic inflammatory response to thermal trauma. Mol Med 8:443–450PubMedGoogle Scholar
  22. 22.
    Jeschke MG, Herndon DN, Vita R, Traber DL, Jauch KW, Barrow RE (2001) IGF-I/BP-3 administration preserves hepatic homeostasis after thermal injury which is associated with increases in no and hepatic NF-kappa B. Shock 16:373–379PubMedCrossRefGoogle Scholar
  23. 23.
    Jeschke MG, Herndon DN, Wolf SE, et al (1999) Recombinant human growth hormone altersacute phase reactant proteins, cytokine expression, and liver morphology in burned rats. J Surg Res 83:122–129PubMedCrossRefGoogle Scholar
  24. 24.
    Brealey D, Karyampudi S, Jacques TS, et al (2004) Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol 286:R491–497PubMedGoogle Scholar
  25. 25.
    Brealey D, Singer M (2003) Mitochondrial Dysfunction in Sepsis. Curr Infect Dis Rep 5: 365–371PubMedCrossRefGoogle Scholar
  26. 26.
    Davies NA, Cooper CE, Stidwill R, Singer M (2003) Inhibition of mitochondrial respiration during early stage sepsis. Adv Exp Med Biol 530:725–736PubMedGoogle Scholar
  27. 27.
    Singer M, Brealey D (1999) Mitochondrial dysfunction in sepsis. Biochem Soc Symp 66: 149–166PubMedGoogle Scholar
  28. 28.
    Klein D, Schubert T, Horch RE, Jauch KW, Jeschke MG (2004) Insulin treatment improves hepatic morphology and function through modulation of hepatic signals after severe trauma. Ann Surg 240:340–349PubMedCrossRefGoogle Scholar
  29. 29.
    Cano N, Gerolami A (1983) Intrahepatic cholestasis during total parenteral nutrition. Lancet 1:985PubMedCrossRefGoogle Scholar
  30. 30.
    Bolder U, Jeschke MG, Landmann L, et al (2006) Heat stress enhances recovery of hepatocyte bile acid and organic anion transporters in endotoxemic rats by multiple mechanisms. Cell Stress Chaperones 11:89–100PubMedCrossRefGoogle Scholar
  31. 31.
    Bolder U, Ton-Nu HT, Schteingart CD, Frick E, Hofmann AF (1997) Hepatocyte transport of bile acids and organic anions in endotoxemic rats: impaired uptake and secretion. Gastroenterology 112:214–225PubMedCrossRefGoogle Scholar
  32. 32.
    Hurd T, Lysz T, Dikdan G, McGee J, Rush BF Jr, Machiedo GW (1988) Hepatic cellular dysfunction in sepsis: an ischemic phenomenon? Curr Surg 45:114–116PubMedGoogle Scholar
  33. 33.
    Jeschke MG, Bolder U, Chung DH, et al (2007) Gut mucosal homeostasis and cellular mediators after severe Thermal trauma, the effect of insulin-like growth factor-I in combination with insulin-like growth factor binding protein-3. Endocrinology 148:354–362PubMedCrossRefGoogle Scholar
  34. 34.
    Huang W, Ma K, Zhang J, et al (2006) Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312:233–236PubMedCrossRefGoogle Scholar
  35. 35.
    Moshage H (1997) Cytokines and the hepatic acute phase response. J Pathol 181:257–266PubMedCrossRefGoogle Scholar
  36. 36.
    Baumann H, Gauldie J (1994) The acute phase response. Immunol Today 15:74–80PubMedCrossRefGoogle Scholar
  37. 37.
    Hiyama DT, von Allmen D, Rosenblum L, Ogle CK, Hasselgren PO, Fischer JE (1991) Synthesis of albumin and acute-phase proteins in perfused liver after burn injury in rats. J Burn Care Rehabil 12:1–6PubMedCrossRefGoogle Scholar
  38. 38.
    Finnerty CC, Herndon DN, Przkora R, et al (2006) Cytokine expression profile over time in severely burned pediatric patients. Shock 26:13–19PubMedCrossRefGoogle Scholar
  39. 39.
    De Maio A, Mooney ML, Matesic LE, Paidas CN, Reeves RH (1998) Genetic component in the inflammatory response induced by bacterial lipopolysaccharide. Shock 10:319–323PubMedCrossRefGoogle Scholar
  40. 40.
    Kishimoto T, Taga T, Akira S (1994) Cytokine signal transduction. Cell 76:253–262PubMedCrossRefGoogle Scholar
  41. 41.
    Gilpin DA, Hsieh CC, Kuninger DT, Herndon DN, Papaconstantinou J (1996) Effect of thermal injury on the expression of transcription factors that regulate acute phase response genes: the response of C/EBP alpha, C/EBP beta, and C/EBP delta to thermal injury. Surgery 119:674–683PubMedCrossRefGoogle Scholar
  42. 42.
    Alam T, An MR, Papaconstantinou J (1992) Differential expression of three C/EBP isoforms in multiple tissues during the acute phase response. J Biol Chem 267:5021–5024PubMedGoogle Scholar
  43. 43.
    Siebenlist U, Franzoso G, Brown K (1994) Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol 10:405–455PubMedCrossRefGoogle Scholar
  44. 44.
    Yao J, Mackman N, Edgington TS, Fan ST (1997) Lipopolysaccharide induction of the tumor necrosis factor-alpha promoter in human monocytic cells. Regulation by Egr-1, c-Jun, and NF-kappaB transcription factors. J Biol Chem 272:17795–17801PubMedCrossRefGoogle Scholar
  45. 45.
    Fey G, Gauldie J (1990) The Acute Phase Response of the Liver in Inflammation. W.B. Saunders, PhiladelphiaGoogle Scholar
  46. 46.
    Rothschild MA, Oratz M, Schreiber SS (1988) Serum albumin. Hepatology 8:385–401PubMedCrossRefGoogle Scholar
  47. 47.
    Livingston DH, Mosenthal AC, Deitch EA (1995) Sepsis and multiple organ dysfunction syndrome: a clinical-mechanistic overview. New Horiz 3:257–266PubMedGoogle Scholar
  48. 48.
    Selzman CH, Shames BD, Miller SA, et al (1998) Therapeutic implications of interleukin-10 in surgical disease. Shock 10:309–318PubMedCrossRefGoogle Scholar
  49. 49.
    Yin MJ, Yamamoto Y, Gaynor RB (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 396:77–80PubMedCrossRefGoogle Scholar
  50. 50.
    Tracey KJ, Fong Y, Hesse DG, et al (1987) Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330:662–664PubMedCrossRefGoogle Scholar
  51. 51.
    Tracey KJ, Lowry SF, Fahey TJ 3rd, et al (1987) Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog. Surg Gynecol Obstet 164:415–422PubMedGoogle Scholar
  52. 52.
    Alexander HR, Doherty GM, Buresh CM, Venzon DJ, Norton JA (1991) A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice. J Exp Med 173:1029–1032PubMedCrossRefGoogle Scholar
  53. 53.
    Pruitt JH, Copeland EM, 3rd, Moldawer LL (1995) Interleukin-1 and interleukin-1 antago nism in sepsis, systemic inflammatory response syndrome, and septic shock. Shock 3: 235–251PubMedCrossRefGoogle Scholar
  54. 54.
    Czura CJ, Yang H, Tracey KJ (2003) High mobility group box-1 as a therapeutic target downstream of tumor necrosis factor. J Infect Dis 187(Suppl 2):S391–396PubMedCrossRefGoogle Scholar
  55. 55.
    Lotze MT, Tracey KJ (2005) High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 5:331–342PubMedCrossRefGoogle Scholar
  56. 56.
    Wang H, Bloom O, Zhang M, et al (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251PubMedCrossRefGoogle Scholar
  57. 57.
    Wang H, Yang H, Czura CJ, Sama AE, Tracey KJ (2001) HMGB1 as a late mediator of lethal systemic inflammation. Am J Respir Crit Care Med 164:1768–1773PubMedGoogle Scholar
  58. 58.
    Benigni F, Atsumi T, Calandra T, et al (2000) The proinflammatory mediator macrophage migration inhibitory factor induces glucose catabolism in muscle. J Clin Invest 106:1291–1300PubMedGoogle Scholar
  59. 59.
    Calandra T (2003) Macrophage migration inhibitory factor and host innate immune responses to microbes. Scand J Infect Dis 35:573–576PubMedCrossRefGoogle Scholar
  60. 60.
    Calandra T, Echtenacher B, Roy DL, et al (2000) Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 6:164–170PubMedCrossRefGoogle Scholar
  61. 61.
    Calandra T, Froidevaux C, Martin C, Roger T (2003) Macrophage migration inhibitory factor and host innate immune defenses against bacterial sepsis. J Infect Dis 187(Suppl 2):S385–390PubMedCrossRefGoogle Scholar
  62. 62.
    Roger T, David J, Glauser MP, Calandra T (2001) MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 414:920–924PubMedCrossRefGoogle Scholar
  63. 63.
    Bierhaus A, Humpert PM, Morcos M, et al (2005) Understanding RAGE, the receptor for advanced glycation end products. J Mol Med 83:876–886PubMedCrossRefGoogle Scholar
  64. 64.
    Peyroux J, Sternberg M (2006) Advanced glycation endproducts (AGEs): pharmacological inhibition in diabetes. Pathol Biol (Paris) 54:405–419PubMedCrossRefGoogle Scholar
  65. 65.
    Rong LL, Gooch C, Szabolcs M, et al (2005) RAGE: a journey from the complications of diabetes to disorders of the nervous system-striking a fine balance between injury and repair. Restor Neurol Neurosci 23:355–365PubMedGoogle Scholar
  66. 66.
    Wendt T, Harja E, Bucciarelli L, et al (2006) RAGE modulates vascular inflammation and ath erosclerosis in a murine model of type 2 diabetes. Atherosclerosis 185:70–77PubMedCrossRefGoogle Scholar
  67. 67.
    Foell D, Wittkowski H, Vogl T, Roth J (2007) S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 81:28–37PubMedCrossRefGoogle Scholar
  68. 68.
    Jeschke MG, Barrow RE, Herndon DN (2000) Recombinant human growth hormone treatment in pediatric burn patients and its role during the hepatic acute phase response. Crit Care Med 28:1578–1584PubMedCrossRefGoogle Scholar
  69. 69.
    Schwander JC, Hauri C, Zapf J, Froesch ER (1983) Synthesis and secretion of insulin-like growth factor and its binding protein by the perfused rat liver: dependence on growth hormone status. Endocrinology 113:297–305PubMedCrossRefGoogle Scholar
  70. 70.
    Aarsland A, Chinkes D, Wolfe RR (1996) Contributions of de novo synthesis of fatty acids to total VLDL-triglyceride secretion during prolonged hyperglycemia/hyperinsulinemia in normal man. J Clin Invest 98:2008–2017PubMedCrossRefGoogle Scholar
  71. 71.
    Aarsland A, Chinkes D, Wolfe RR, et al (1996) Beta-blockade lowers peripheral lipolysis in burn patients receiving growth hormone. Rate of hepatic very low density lipoprotein triglyceride secretion remains unchanged. Ann Surg 223:777–789PubMedCrossRefGoogle Scholar
  72. 72.
    Takala J, Ruokonen E, Webster NR, et al (1999) Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 341:785–792PubMedCrossRefGoogle Scholar
  73. 73.
    Jeschke MG, Herndon DN, Wolf SE, et al (2000) Hepatocyte growth factor modulates the hepatic acute-phase response in thermally injured rats. Crit Care Med 28:504–510PubMedCrossRefGoogle Scholar
  74. 74.
    Seth A, Gonzalez FA, Gupta S, Raden DL, Davis RJ (1992) Signal transduction within the nucleus by mitogen-activated protein kinase. J Biol Chem 267:24796–24804PubMedGoogle Scholar
  75. 75.
    Guillen MI, Gomez-Lechon MJ, Nakamura T, Castell JV (1996) The hepatocyte growth factor regulates the synthesis of acute-phase proteins in human hepatocytes: divergent effect on interleukin-6-stimulated genes. Hepatology 23:1345–1352PubMedCrossRefGoogle Scholar
  76. 76.
    Pierzchalski P, Nakamura T, Takehara T, Koj A (1992) Modulation of acute phase protein synthesis in cultured rat hepatocytes by human recombinant hepatocyte growth factor. Growth Factors 7:161–165PubMedGoogle Scholar
  77. 77.
    Michalopoulos GK, DeFrances MC (1997) Liver regeneration. Science 276:60–66PubMedCrossRefGoogle Scholar
  78. 78.
    Michalopoulos GK, Appasamy R (1993) Metabolism of HGF-SF and its role in liver regenera tion. Exs 65:275–283PubMedGoogle Scholar
  79. 79.
    Zarnegar R (1995) Regulation of HGF and HGFR gene expression. EXS 74:33–49PubMedGoogle Scholar
  80. 80.
    Ohira H, Miyata M, Kuroda M, et al (1996) Interleukin-6 induces proliferation of rat hepatocytes in vivo. J Hepatol 25:941–947PubMedCrossRefGoogle Scholar
  81. 81.
    Humbel RE (1990) Insulin-like growth factors I and II. Eur J Biochem 190:445–462PubMedCrossRefGoogle Scholar
  82. 82.
    Huang KF, Chung DH, Herndon DN (1993) Insulin-like growth factor 1 (IGF-1) reduces gut atrophy and bacterial translocation after severe burn injury. Arch Surg 128:47–53PubMedGoogle Scholar
  83. 83.
    Strock LL, Singh H, Abdullah A, Miller JA, Herndon DN (1990) The effect of insulin-like growth factor I on postburn hypermetabolism. Surgery 108:161–164PubMedGoogle Scholar
  84. 84.
    Jeschke MG, Herndon DN, Barrow RE (2000) Insulin-like growth factor I in combination with insulin-like growth factor binding protein 3 affects the hepatic acute phase response and hepatic morphology in thermally injured rats. Ann Surg 231:408–416PubMedCrossRefGoogle Scholar
  85. 85.
    Jeschke MG, Barrow RE, Herndon DN (2000) Insulinlike growth factor I plus insulinlike growth factor binding protein 3 attenuates the proinflammatory acute phase response in severely burned children. Ann Surg 231:246–252PubMedCrossRefGoogle Scholar
  86. 86.
    Jeschke MG, Barrow RE, Suzuki F, Rai J, Benjamin D, Herndon DN (2002) IGF-I/IGFBP-3 equilibrates ratios of pro-to anti-inflammatory cytokines, which are predictors for organ function in severely burned pediatric patients. Mol Med 8:238–246PubMedGoogle Scholar
  87. 87.
    Jeschke MG, Klein D, Bolder U, Einspanier R (2004) Insulin attenuates the systemic inflam matory response in endotoxemic rats. Endocrinology 145:4084–4093PubMedCrossRefGoogle Scholar
  88. 88.
    Jeschke MG, Rensing H, Klein D, et al (2005) Insulin prevents liver damage and preserves liver function in lipopolysaccharide-induced endotoxemic rats. J Hepatol 42:870–879PubMedCrossRefGoogle Scholar
  89. 89.
    Jeschke MG, Klein D, Herndon DN (2004) Insulin treatment improves the systemic inflammatory reaction to severe trauma. Ann Surg 239:553–560PubMedCrossRefGoogle Scholar
  90. 90.
    Herndon DN, Nguyen TT, Wolfe RR, et al (1994) Lipolysis in burned patients is stimulated by the beta 2-receptor for catecholamines. Arch Surg 129:1301–1304PubMedGoogle Scholar
  91. 91.
    Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR (2001) Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 345:1223–1229PubMedCrossRefGoogle Scholar
  92. 92.
    Barrow RE, Wolfe RR, Dasu MR, Barrow LN, Herndon DN (2006) The use of beta-adrenergic blockade in preventing trauma-induced hepatomegaly. Ann Surg 243:115–120PubMedCrossRefGoogle Scholar
  93. 93.
    Morio B, Irtun O, Herndon DN, Wolfe RR (2002) Propranolol decreases splanchnic triacylglycerol storage in burn patients receiving a high-carbohydrate diet. Ann Surg 236:218–225PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media Inc. 2007

Authors and Affiliations

  • M. G. Jeschke
    • 1
  • D. N. Herndon
    • 2
  1. 1.Department of Surgery, Shriners Hospital for ChildrenGalveston Burns UnitGalveston
  2. 2.Department of SurgeryShriners Hospitals for ChildrenGalvestonUSA

Personalised recommendations