Hidehiro Sawa

Significant increase of serum high-mobility group box chromosomal protein 1 levels in patients with severe acute pancreatitis.

Objective: Multiple organ failure because of systemic inflammatory response in the early phase and sepsis in the late phase is the main contributor to high mortality in severe acute pancreatitis (SAP). High-mobility group box chromosomal protein 1 (HMGB1) was recently identified as a potent proinflammatory mediator and increases in various pathological conditions such as sepsis. The aim of this study was to investigate contributions of HMGB1 in SAP. Methods: We measured serum HMGB1 concentrations by an enzyme-linked immunosorbent assay in 45 patients with SAP at the time of admission. Furthermore, relationship between their serum HMGB1 levels and clinical factors was analyzed. Results: The mean value of serum HMGB1 levels was significantly higher in patients with SAP (5.4 ± 1.3 ng/mL) than that in healthy volunteers (1.7 ± 0.3 ng/mL). Serum HMGB1 levels were significantly positively correlated with the Japanese severity score and Glasgow score. Serum HMGB1 levels were significantly positively correlated with lactate dehydrogenase, C-reactive protein, and total bilirubin. The HMGB1 levels were higher in patients with organ dysfunction and infection during the clinical course. The HMGB1 levels in nonsurvivors were higher than those in survivors. Serum HMGB1 levels gradually declined after the admission. Conclusions: Serum HMGB1 levels were significantly increased in patients with SAP and were correlated with disease severity. These results suggest that HMGB1 may act as a key mediator for inflammation and organ failure in SAP.

Significant elevation of serum interleukin-18 levels in patients with acute pancreatitis

BackgroundWe have reported that peripheral lymphocyte reduction due to apoptosis is linked to the development of subsequent infectious complications in patients with severe acute pancreatitis and that Th1 (helper T cell type 1)/Th2 (helper T cell type 2) balance tends to cause Th1 suppression in experimental severe acute pancreatitis. It has been reported that interleukin (IL)-18 is a cytokine produced from Kupffer cells and activated macrophages, and that IL-18 acts on Th1 cells and in combination with IL-12 strongly induces production of interferon-γ. However, the role of IL-18 in acute pancreatitis has not yet been fully understood.MethodsSerum IL-18 concentrations were determined by an enzyme-linked immunosorbent assay in 43 patients with acute pancreatitis at the time of admission. The relationships with etiology, pancreatic necrosis, severity, blood biochemical parameters on admission, infection, and organ dysfunction during the clinical course and prognosis were analyzed.ResultsSerum IL-18 levels in patients with acute pancreatitis (656 ± 11pg/ml) were significantly higher than those in healthy volunteers (126 ± pg/ml). Serum IL-18 levels were significantly positively correlated with the Ranson score and Japanese severity score. Among the blood biochemical parameters on admission, base excess and total protein were significantly negatively correlated with serum IL-18 levels. Moreover, the CD4/CD8 rate of lymphocytes, serum IL-6 levels, and serum IL-8 levels were significantly positively correlated with serum IL-18 levels. On day 7 after admission, the CD4/CD8 rate of lymphocytes and the rate of CD4-positive lymphocytes were significantly positively correlated with serum IL-18 levels. Furthermore, serum IL-18 levels in patients with hepatic dysfunction (980 ± 25pg/ml) were significantly higher than those without hepatic dysfunction (464 ± 8pg/ml). Serum IL-18 levels were not related to infection or prognosis. Elevation of serum IL-18 levels continued during 4 weeks after admission.ConclusionsThese results suggest that serum IL-18 levels are significantly elevated and are correlated with severity in patients with acute pancreatitis and that IL-18 may be closely related to helper T cell response and hepatic dysfunction in this disease.

Increased levels of soluble triggering receptor expressed on myeloid cells-1 in patients with acute pancreatitis.

Objective:To determine the contribution of triggering receptor expressed on myeloid cells (TREM)-1 in acute pancreatitis (AP). Design:Prospective study. Setting:General intensive care unit at Kobe University Hospital. Patients:Forty-eight patients with AP and seven patients as control. Interventions:None. Measurements and Main Results:We measured serum concentrations of soluble TREM-1 (sTREM-1) at the time of admission by enzyme-linked immunoadsorbent assay. Serum sTREM-1 levels increased significantly in AP (63 ± 11 pg/mL) and correlated with Ranson score (R = .628, p < .001) and Acute Physiology and Chronic Health Evaluation II score (R = .504, p < .001). Serum TREM-1 levels were higher in patients with early organ dysfunction (which occurred within 7 days after onset) than those without early organ dysfunction (101 ± 19 vs. 25 ± 4 pg/mL, p < .001). Incidences of early organ dysfunction in patients whose serum sTREM-1 levels were ≤40 and >40 pg/mL were 17% and 83%, respectively (p < .001). The usefulness of serum sTREM-1 in detecting early organ dysfunction was superior to that of C-reactive protein, interleukin-6, interleukin-8, Ranson score, and Acute Physiology and Chronic Health Evaluation II score. Serum sTREM-1 levels decreased with resolution of early organ dysfunction. Conclusions:Serum sTREM-1 levels were significantly increased and correlated with disease severity and early organ dysfunction in patients with AP. Serum sTREM-1 level may be a useful marker for early organ dysfunction in AP.

Immunosuppression in patients with severe acute pancreatitis.

BackgroundIn severe acute pancreatitis (SAP), immunologic impairment in the early phase may be linked to subsequent infectious complications. In this study, immunologic alterations in patients with SAP were analyzed, and immunologic parameters related to infectious complications were clarified.MethodsA total of 101 patients with SAP were analyzed retrospectively. Various immunologic parameters on admission were analyzed and compared between the infection group and noninfection group during SAP. Furthermore, chronologic change in the lymphocyte count was investigated, and its utility for predicting infection was compared with conventional scoring systems.ResultsSerum immunoglobulin G (IgG), serum IgM, lymphokine-activated killer cell activity, and natural killer cell activity were low, and the incidence of abnormally low values was 50.0%, 65.0%, 45.5%, and 42.4%, respectively. Serum complement factor 3 was significantly negatively correlated with the APACHE II score. The lymphocyte count was decreased below the normal range, and was significantly negatively correlated with the APACHE II score. CD4-, CD8-, and CD20-positive lymphocyte counts were below the normal range, and CD4- and CD8-positive lymphocyte counts were significantly lower in the infection group. The lymphocyte count on day 14 after admission was significantly lower in the infection group and was more useful for predicting infection than conventional scoring systems.ConclusionsImmunosuppression occurs from the early phase in SAP, and quantitative impairment of lymphocytes, mainly T lymphocytes, may be closely related to infectious complications during SAP. CD4- and CD8-positive lymphocyte counts on admission and the lymphocyte count on day 14 after admission may be useful for predicting infection.

Role of Toll-Like Receptor 4 in the Pathophysiology of Severe Acute Pancreatitis in Mice

PurposeMultiple organ dysfunction and infection are major contributors to the high mortality associated with severe acute pancreatitis (SAP). Toll-like receptor 4 (TLR4) recognizes the lipopolysaccharide of gram-negative bacilli and is involved in inflammatory response and host defense. We examined the effects of TLR4-deficiency in SAP in mice.MethodsClosed duodenal loop-induced pancreatitis was induced in C3H/HeN (wild-type) and C3H/HeJ (TLR4-deficient) mice. We compared the severity of pancreatitis, liver and kidney dysfunction, and bacterial translocation to the pancreas between the two types of mice 12 h after the induction of SAP.ResultsThe severity of pancreatitis was similar in the two types of mice. The TLR4-deficient mice had significantly lower serum levels of aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine; significantly lower serum levels of interleukin-1 and tumor necrosis factor; reduced apoptosis of the liver and kidney; and a significantly higher rate of positive gram-negative bacterial cultures of the pancreas. TLR4 protein expression in the liver, kidney, and small intestine was increased 4 h after the induction of SAP, and decreased 12 h after the induction of SAP.ConclusionsTLR4 is implicated in the mechanism of organ dysfunction and bacterial translocation in SAP, and TLR4 may trigger the inflammatory response and function defensively against infection.

Treatment strategy against infection : clinical outcome of continuous regional arterial infusion, enteral nutrition, and surgery in severe acute pancreatitis

BackgroundIn severe acute pancreatitis (SAP), infectious complications are the main contributors to high mortality. Since 1995, we have performed continuous regional arterial infusion of protease inhibitor and antibiotics (CRAI) and enteral nutrition (EN) as prevention therapies against infection. When infected pancreatic necrosis was proven, surgical intervention was adapted. The aim of this study was to investigate the clinical outcome of these treatments.MethodsWe examined the relationship between the historical change of treatment strategy and clinical outcome. We divided 84 patients with acute necrotizing pancreatitis into two groups, CRAI (−) and CRAI (+), and compared the outcome. We divided 145 patients with SAP into two groups, EN (−) and EN (+), and compared the outcome. We also analyzed the outcome of surgical treatment.ResultsIn the CRAI (+) group, the incidence of infection, the frequency of surgery, and the mortality rate were lower than those in CRAI (−) group: 34% versus 51%, 27% versus 63% (P < 0.05), and 37% versus 54%, respectively. In the EN (+) group, the frequency of surgery and the mortality rate were lower than those in the EN (−) group: 23% versus 32% and 19% versus 35% (P < 0.05), respectively. These improvement effects were manifest in stage 3 (9 ≤ Japanese Severity Score ≤ 14). Treatment outcome of necrosectomy for infected pancreatic necrosis was still poor. Bleeding and abscess–gut fistula were postoperative life-threatening complications.ConclusionsCRAI and EN may improve the clinical outcome of SAP, reducing infection and averting pancreatic surgery.

Long-term outcome of severe acute pancreatitis

BACKGROUND/PURPOSE This study was undertaken to evaluate the post-discharge outcome of severe acute pancreatitis (SAP) and to clarify the prognostic factors for poor outcome. METHODS In 45 patients, recurrence of acute pancreatitis (AP), transition to chronic pancreatitis (CP), and development of diabetes mellitus (DM) were evaluated. Relationships of the outcome with the findings on admission and the presence/absence of alcohol intake were analyzed. RESULTS The mean follow-up period was 56+/-6 months. Recurrence of AP was noted in 19% of the patients. The recurrence rate was higher in patients with necrotizing pancreatitis than in those without this feature. C-reactive protein and white blood cell (WBC) count were higher in patients with recurrence of AP. Transition to CP was noted in 22% of patients. The transition rate was higher in those with alcoholic SAP than in those with biliary SAP. In patients with transition to CP, the WBC count, hematocrit, Ranson score, and Japanese severity score were higher, and base excess (BE) was lower, compared with these features in patients without this transition. Development of DM was noted in 39% of patients. Blood glucose and BE were higher in patients who developed DM than in those who did not. CONCLUSIONS The degree of inflammation and pancreatic necrosis found on admission for SAP may be related to the recurrence of AP. Alcoholic SAP in which the disease is very severe may contribute to the transition to CP. Patients with impaired glucose tolerance readily develop DM after SAP.

Prediction of early death in severe acute pancreatitis

BackgroundIn severe acute pancreatitis (SAP), it is clinically important at the time of admission to predict the likelihood of early death. This investigation aimed to clarify the factors predicting early death in SAP.MethodsEarly death was defined as death within 10 days after disease onset. Prediction factors for early death were evaluated from data obtained on admission from 93 patients with SAP, and the characteristics of patients who died early were analyzed.ResultsBetween the early-death and early-survival groups, significant factors were base excess (BE), serum creatinine (Cr), blood sugar, serum glutamate oxaloacetic transaminase, and serum calcium. Multivariate analysis revealed that BE was an independent prediction factor for early death. The early-death rate in patients with BE < −5.5 mEq/l and Cr ≥ 3.0 mg/dl was 31% and 36%, respectively. The combination of BE and Cr raised the positive predictive value to 50%, and was equally able to predict early death as the Japanese Severity Score (JSS), which was the most useful of the three conventional scoring systems used. All early-death patients had pancreatic necrosis, and their JSS was ≥15 (stage 4). Characteristically, early-death patients had lactate dehydrogenase (LDH) > 1300 IU/l, or they had serious preexisting comorbidities.ConclusionsAs a single parameter, BE was most useful for predicting early death. The combination of BE and Cr could predict early death as well as the JSS. An extreme rise of LDH and serious preexisting comorbidity may also be risk factors for early death.

Elevation of plasma tissue factor levels in patients with severe acute pancreatitis

BackgroundCoagulative disorders are known to occur in severe acute pancreatitis (SAP), and they are related to its severity and organ dysfunctions. Tissue factor (TF) is a transmembrane glycoprotein that activates the extrinsic pathway of the blood coagulation cascade. Plasma TF levels increase in patients with sepsis and acute coronary syndrome. However, plasma TF levels in SAP have not yet been reported.MethodsWe measured plasma TF antigen levels by enzyme-linked immunosorbent assay in 36 patients with acute pancreatitis at the time of admission. The relationships between their plasma TF levels and various factors (severity, etiology, pancreatic necrosis, organ dysfunction, and prognosis) were analyzed. The utility of plasma TF as a clinical marker was evaluated.ResultsPlasma TF levels significantly increased in patients with SAP compared with healthy volunteers and drinkers, respectively. Plasma TF level in alcoholic SAP with pancreatic necrosis was significantly higher than that in alcoholic SAP without pancreatic necrosis or that in nonalcoholic SAP with pancreatic necrosis. The incidence of an abnormally high level of plasma TF was 63.6% in alcoholic SAP with pancreatic necrosis. The area under the ROC curve of plasma TF for detection of pancreatic necrosis in alcoholic SAP was 0.773 and was superior to those of Japanese severity score and lactate dehydrogenase.ConclusionsPlasma TF levels were elevated in patients with SAP, particularly in those with alcoholic SAP with pancreatic necrosis, suggesting that TF may be closely related to the development of pancreatic necrosis in alcoholic SAP and that the plasma TF level may be a useful marker for it.

Protective Effects of Vascular Endothelial Growth Factor on Intestinal Epithelial Apoptosis and Bacterial Translocation in Experimental Severe Acute Pancreatitis

Objectives: Bacterial translocation (BT) plays an important role in systemic complications in severe acute pancreatitis (SAP). We recently demonstrated that accelerated apoptosis of intestinal mucosa might have a role in BT. Effects of vascular endothelial growth factor (VEGF) on intestinal epithelial cell apoptosis and BT were investigated in SAP. Methods: Severe acute pancreatitis was induced by retrograde injection of sodium deoxycholate into the biliopancreatic duct in rats. Recombinant rat VEGF (2 &mgr;g) was injected, and SAP was immediately induced. Eight hours after the induction, serum amylase/lipase levels and apoptosis of ileal mucosa were evaluated. After 18 hours, the villous height of ileum was examined. After 22 hours, hematocrit, pancreatic water content, BT to the mesenteric lymph nodes, plasma plasminogen activator inhibitor 1 levels, and microvessel density in the small intestine were investigated. Results: Amylase/lipase levels were significantly elevated in SAP, but VEGF did not affect them. Apoptosis of ileal mucosa was accelerated in SAP, and VEGF significantly reduced the apoptosis. Villous height was significantly decreased in SAP, and VEGF significantly improved it. Vascular endothelial growth factor did not affect the hematocrit or pancreatic water content. Bacterial translocation occurred in the SAP group, and VEGF significantly prevented that. Plasminogen activator inhibitor 1 levels were significantly elevated in SAP, and VEGF significantly improved the elevation. Microvessel counts were significantly reduced in SAP, and VEGF significantly increased them. Conclusion: These results suggest that VEGF inhibits intestinal epithelial cell apoptosis and subsequent BT in SAP.