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High mobility group box protein-1 (HMGB-1) as a new diagnostic marker in patients with acute appendicitis.

Albayrak Y, Albayrak A, Celik M, Gelincik I, Demiryılmaz I, Yildirim R, Ozogul B - Scand J Trauma Resusc Emerg Med (2011)

Bottom Line: The WBC averages of Groups 1, 2 and 3 were, respectively, 7.41+2.02 (x10⁹/L), 15.71+2.85 (x10⁹/L) and 8.51+1.84 (x10⁹/L).The average HMGB-1 level of the patients with AA was 36.92±15.43 ng/ml while the average HMGB-1 value of the healthy group was 21.71±11.36 ng/ml.The significantly higher levels of HMGB-1 in AA patients compared to healthy persons infer that HMGB-1 might be useful in the diagnosis of AA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of General Surgery and Burn Unit, Erzurum Region Education and Research Hospital, and Department of Clinical Biochemistry, Ataturk University, School of Medicine, Erzurum, Turkey. yavuzalbayrakdr@gmail.com

ABSTRACT

Background: The aim of this prospective study was therefore to evaluate the diagnostic value of preoperative serum High Mobility Group Box Protein-1 (HMGB-1) levels in patients with Acute Appendicitis (AA) who show normal white blood cell count (WBC) counts.

Method: Our study was carried out from October 2010 through November 2010 and included 20 healthy control group participants and 60 patients who presented at the emergency department of Erzurum Training and Research Hospital in Turkey with acute abdominal pain complaints, who were pathologically diagnosed with AA after laparotomy, and who agreed to participate in the study.

Results: Of the 60 patients who underwent appendectomies, 36 were male and 24 were female, and of the healthy group, 12 were male and 8 female. The age averages of the patients in Groups 1, 2 and 3 were, respectively, 31.3+15.4, 34.0+16.3 and 31.0+13.1 years. The WBC averages of Groups 1, 2 and 3 were, respectively, 7.41+2.02 (x10⁹/L), 15.71+2.85 (x10⁹/L) and 8.51+1.84 (x10⁹/L). The HMGB-1 levels for Groups 1 (healthy persons), 2 (AA patients with high WBC counts ) and 3 (AA patients with normal WBC counts) were, respectively, 21.71±11.36, 37.28+13.37 and 36.5±17.73 ng/ml. The average HMGB-1 level of the patients with AA was 36.92±15.43 ng/ml while the average HMGB-1 value of the healthy group was 21.71±11.36 ng/ml.

Conclusion: The significantly higher levels of HMGB-1 in AA patients compared to healthy persons infer that HMGB-1 might be useful in the diagnosis of AA. Use of HMGB-1, especially in patients with normal WBC counts, will reduce the number of unnecessary explorations.

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Related in: MedlinePlus

Schematic summary of the HMGB1 release and action. HMGB1 can be actively secreted by innate immune cells in response to exogenous microbial products from infection; or passively released from injured or necrotic cells.
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Figure 3: Schematic summary of the HMGB1 release and action. HMGB1 can be actively secreted by innate immune cells in response to exogenous microbial products from infection; or passively released from injured or necrotic cells.

Mentions: HMGB1 (previously designated HMG1 or amphoterin) [12] is not a new protein. It was discovered > 30 years ago as a nuclear DNA-binding protein and was initially named for its characteristic rapid electrophoretic mobility in polyacrylamide gels [13]. HMGB1 is a cytokine that can be released by activated monocytes, macrophages, neutrophils and platelets, and in turn mediates inflammation and enhanced cell motility. Extracellular HMGB1 acts as a late mediator of inflammation. Tracey and collaborators detected HMGB1 in the serum of septic patients [14] and found that application of anti-HMGB1 antibodies reversed established sepsis [15]. In macrophages and neutrophils, HMGB-1 also induces the production of proinflammatory cytokines such as TNF, interleukin (IL)-1a and -1b, IL6 and macrophage inflammatory protein 1 (MIP1) [10,14,16]. During the inflammatory process, HMGB1 migration to organs/tissue sites induces various inflammatory cytokines including TNF-α, IL-1α, IL-1β, IL-1RA, IL-6, IL-8, MIP-1α and MIP-1β, thereby promoting chronic inflammation [17,18]. HMGB1 has been suggested to serve as a pro-inflammatory cytokine [19] and it has many organ-specific biological functions including induction of fever, anorexia, and weight loss, as well as cytokine production in the brain, acute lung injury and production of pro-inflammatory cytokines/mediators in the lungs, promotion of translocation in the gut, induction of arthritis and joint inflammation, modulation of heart rhythm and bactericidal effects [20]. Extracellular HMGB1 translocation during inflammatory responses leads to significantly increased in vivo serum levels in patients with arthritis, sepsis, disseminated intravascular coagulation and other inflammatory disorders [14,21-24]. Increased levels of HMGB-1 have been found following myocardial ischemia, in cerebral ischemia subjects [25] and in chronic kidney disease patients, where this elevation correlates well with inflammatory markers in the synovial fluid as well as with a reduction in glomerular filtrate [26]. When compared to healthy controls, HMGB-1 concentrations in plasma and lung epithelial lining fluid were increased in patients with acute lung injury and acute respiratory distress (ARDS) [27]. In one study, the circulating blood of patients with pneumonia and with pneumonia combined with serious sepsis showed greatly elevated levels of HMGB-1 [28]. In addition, patients with low hepatic fibrosis also showed elevated serum levels of HMGB-1 [29]. In our study, higher HMGB-1 levels were found in AA patients with high WBC counts and with normal WBC counts than in the healthy group. This condition can be explained by the action of HMGB-1, which is a proinflammatory cytokine secreted by the neutrophils, monocytes and macrophages throughout the inflammatory processes involved in AA. Gaini, et al., in the study comparing bacteraemic and non-bacteraemic patients, have determined significantly higher levels of HMGB-1, and have also shown that the increase in HMGB-1 levels correlated with other pro-inflammatory indicators (WBC, CRP and neutrophils). At the conclusion of this study, they have asserted that the high levels of HMGB-1 in bacteraemic patients may be related to the pro-inflammatory role of HMGB-1 [30]. There is a possible mechanism which is the increase of serum HMGB-1 levels in patients with acute appendicitis. HMGB-1, is secreted by stimulated macrophages/monocytes in the late stage of inflammation, may be produced and released by macrophages/monocytes in response to inflammatory mediators. In acute appendicitis, it is conceivable that the release of humoral mediators from the excessive activated macrophages/monocytes may lead to remote organ injury. As the released HMGB-1 can cause the development of inflammation,[31]. release of HMGB1 from activated macrophages/monocytes may participate in tissue inflammation in acute appendicitis [32]. Post infection release and effects of HMGB-1 have been schematized in Figure 3. For these reasons, serum levels of HMGB-1 rise during acute appendicitis. Kosai, et al., have shown that WBC count is correlated with the increase of HMGB-1 in bacterial pneumonia patients co-infected with influenza [33]. In our study, we have also determined a correlation between an increase in HMGB-1 levels and WBC counts in acute appendicitis. However, our study has also shown that in acute appendicitis, an increase in HMGB-1 levels may occur even when there is no increase in WBC numbers. These findings have shown that HMGB-1 serum levels may be used in the diagnosis of acute appendicitis as a non-invasive indicator. HMGB-1 levels are already known to rise during infections or sepsis [14,21,22,28,30-33], but the key result from the current study is that HMGB-1 levels of the AA group with normal WBC counts were significantly higher than those of the healthy group. This shows that HMGB-1 can help to discriminate AA and that it might provide a diagnosis for patients who present with suspected AA, but have normal WBC counts.


High mobility group box protein-1 (HMGB-1) as a new diagnostic marker in patients with acute appendicitis.

Albayrak Y, Albayrak A, Celik M, Gelincik I, Demiryılmaz I, Yildirim R, Ozogul B - Scand J Trauma Resusc Emerg Med (2011)

Schematic summary of the HMGB1 release and action. HMGB1 can be actively secreted by innate immune cells in response to exogenous microbial products from infection; or passively released from injured or necrotic cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3094252&req=5

Figure 3: Schematic summary of the HMGB1 release and action. HMGB1 can be actively secreted by innate immune cells in response to exogenous microbial products from infection; or passively released from injured or necrotic cells.
Mentions: HMGB1 (previously designated HMG1 or amphoterin) [12] is not a new protein. It was discovered > 30 years ago as a nuclear DNA-binding protein and was initially named for its characteristic rapid electrophoretic mobility in polyacrylamide gels [13]. HMGB1 is a cytokine that can be released by activated monocytes, macrophages, neutrophils and platelets, and in turn mediates inflammation and enhanced cell motility. Extracellular HMGB1 acts as a late mediator of inflammation. Tracey and collaborators detected HMGB1 in the serum of septic patients [14] and found that application of anti-HMGB1 antibodies reversed established sepsis [15]. In macrophages and neutrophils, HMGB-1 also induces the production of proinflammatory cytokines such as TNF, interleukin (IL)-1a and -1b, IL6 and macrophage inflammatory protein 1 (MIP1) [10,14,16]. During the inflammatory process, HMGB1 migration to organs/tissue sites induces various inflammatory cytokines including TNF-α, IL-1α, IL-1β, IL-1RA, IL-6, IL-8, MIP-1α and MIP-1β, thereby promoting chronic inflammation [17,18]. HMGB1 has been suggested to serve as a pro-inflammatory cytokine [19] and it has many organ-specific biological functions including induction of fever, anorexia, and weight loss, as well as cytokine production in the brain, acute lung injury and production of pro-inflammatory cytokines/mediators in the lungs, promotion of translocation in the gut, induction of arthritis and joint inflammation, modulation of heart rhythm and bactericidal effects [20]. Extracellular HMGB1 translocation during inflammatory responses leads to significantly increased in vivo serum levels in patients with arthritis, sepsis, disseminated intravascular coagulation and other inflammatory disorders [14,21-24]. Increased levels of HMGB-1 have been found following myocardial ischemia, in cerebral ischemia subjects [25] and in chronic kidney disease patients, where this elevation correlates well with inflammatory markers in the synovial fluid as well as with a reduction in glomerular filtrate [26]. When compared to healthy controls, HMGB-1 concentrations in plasma and lung epithelial lining fluid were increased in patients with acute lung injury and acute respiratory distress (ARDS) [27]. In one study, the circulating blood of patients with pneumonia and with pneumonia combined with serious sepsis showed greatly elevated levels of HMGB-1 [28]. In addition, patients with low hepatic fibrosis also showed elevated serum levels of HMGB-1 [29]. In our study, higher HMGB-1 levels were found in AA patients with high WBC counts and with normal WBC counts than in the healthy group. This condition can be explained by the action of HMGB-1, which is a proinflammatory cytokine secreted by the neutrophils, monocytes and macrophages throughout the inflammatory processes involved in AA. Gaini, et al., in the study comparing bacteraemic and non-bacteraemic patients, have determined significantly higher levels of HMGB-1, and have also shown that the increase in HMGB-1 levels correlated with other pro-inflammatory indicators (WBC, CRP and neutrophils). At the conclusion of this study, they have asserted that the high levels of HMGB-1 in bacteraemic patients may be related to the pro-inflammatory role of HMGB-1 [30]. There is a possible mechanism which is the increase of serum HMGB-1 levels in patients with acute appendicitis. HMGB-1, is secreted by stimulated macrophages/monocytes in the late stage of inflammation, may be produced and released by macrophages/monocytes in response to inflammatory mediators. In acute appendicitis, it is conceivable that the release of humoral mediators from the excessive activated macrophages/monocytes may lead to remote organ injury. As the released HMGB-1 can cause the development of inflammation,[31]. release of HMGB1 from activated macrophages/monocytes may participate in tissue inflammation in acute appendicitis [32]. Post infection release and effects of HMGB-1 have been schematized in Figure 3. For these reasons, serum levels of HMGB-1 rise during acute appendicitis. Kosai, et al., have shown that WBC count is correlated with the increase of HMGB-1 in bacterial pneumonia patients co-infected with influenza [33]. In our study, we have also determined a correlation between an increase in HMGB-1 levels and WBC counts in acute appendicitis. However, our study has also shown that in acute appendicitis, an increase in HMGB-1 levels may occur even when there is no increase in WBC numbers. These findings have shown that HMGB-1 serum levels may be used in the diagnosis of acute appendicitis as a non-invasive indicator. HMGB-1 levels are already known to rise during infections or sepsis [14,21,22,28,30-33], but the key result from the current study is that HMGB-1 levels of the AA group with normal WBC counts were significantly higher than those of the healthy group. This shows that HMGB-1 can help to discriminate AA and that it might provide a diagnosis for patients who present with suspected AA, but have normal WBC counts.

Bottom Line: The WBC averages of Groups 1, 2 and 3 were, respectively, 7.41+2.02 (x10⁹/L), 15.71+2.85 (x10⁹/L) and 8.51+1.84 (x10⁹/L).The average HMGB-1 level of the patients with AA was 36.92±15.43 ng/ml while the average HMGB-1 value of the healthy group was 21.71±11.36 ng/ml.The significantly higher levels of HMGB-1 in AA patients compared to healthy persons infer that HMGB-1 might be useful in the diagnosis of AA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of General Surgery and Burn Unit, Erzurum Region Education and Research Hospital, and Department of Clinical Biochemistry, Ataturk University, School of Medicine, Erzurum, Turkey. yavuzalbayrakdr@gmail.com

ABSTRACT

Background: The aim of this prospective study was therefore to evaluate the diagnostic value of preoperative serum High Mobility Group Box Protein-1 (HMGB-1) levels in patients with Acute Appendicitis (AA) who show normal white blood cell count (WBC) counts.

Method: Our study was carried out from October 2010 through November 2010 and included 20 healthy control group participants and 60 patients who presented at the emergency department of Erzurum Training and Research Hospital in Turkey with acute abdominal pain complaints, who were pathologically diagnosed with AA after laparotomy, and who agreed to participate in the study.

Results: Of the 60 patients who underwent appendectomies, 36 were male and 24 were female, and of the healthy group, 12 were male and 8 female. The age averages of the patients in Groups 1, 2 and 3 were, respectively, 31.3+15.4, 34.0+16.3 and 31.0+13.1 years. The WBC averages of Groups 1, 2 and 3 were, respectively, 7.41+2.02 (x10⁹/L), 15.71+2.85 (x10⁹/L) and 8.51+1.84 (x10⁹/L). The HMGB-1 levels for Groups 1 (healthy persons), 2 (AA patients with high WBC counts ) and 3 (AA patients with normal WBC counts) were, respectively, 21.71±11.36, 37.28+13.37 and 36.5±17.73 ng/ml. The average HMGB-1 level of the patients with AA was 36.92±15.43 ng/ml while the average HMGB-1 value of the healthy group was 21.71±11.36 ng/ml.

Conclusion: The significantly higher levels of HMGB-1 in AA patients compared to healthy persons infer that HMGB-1 might be useful in the diagnosis of AA. Use of HMGB-1, especially in patients with normal WBC counts, will reduce the number of unnecessary explorations.

Show MeSH
Related in: MedlinePlus