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Background: In acute pancreatitis (AP), disorders of the coagulation-fibrinolysis system are closely related to the severity of the AP and to organ dysfunctions. We previously reported that plasma tissue factor (TF) levels were elevated in patients with AP, particularly in cases of alcoholic AP with pancreatic necrosis. Tissue factor pathway inhibitor (TFPI) is a key regulator of the extrinsic coagulation pathway, but plasma TFPI levels in AP have not yet been determined., Methods: Plasma TFPI concentrations were measured by enzyme-linked immunosorbent assay in 44 patients with AP on admission. The relationships between AP severity, pancreatic necrosis, organ dysfunction, infection, and prognosis were analyzed., Results: Plasma TFPI levels were increased in AP patients compared with healthy volunteers. Plasma TFPI levels in severe AP were greater than those in mild AP. Plasma TFPI levels significantly correlated with Ranson score, APACHE II score, and Japanese severity score. Plasma TFPI levels in patients with pancreatic necrosis were greater than those in patients without pancreatic necrosis. Plasma TFPI levels in patients with organ dysfunction were greater than those in patients without organ dysfunction. In patients with pancreatic necrosis, the TF/TFPI ratios in non-survivors were lower than those in survivors. Moreover, the mortality rates in patients with TF/TFPI ratios > or = 2.0 were lower than those in patients with TF/TFPI ratios < 2.0., Conclusions: Plasma TFPI levels were significantly increased in patients with AP, and the elevation was markedly related to the severity, pancreatic necrosis and organ dysfunctions. The imbalance of TF and TFPI may influence the disease state and thereby the prognosis in AP.

Mild acute pancreatitis (AP) is rarely complicated by infection, and the value of prophylactic antibiotics is questionable. We report a case of mild AP complicated by infection, which developed within 1 week after the onset. A 66-year-old woman was referred to our hospital where a diagnosis of mild AP was made, based on laboratory data and computed tomography (CT) findings. She was managed conservatively with fluid resuscitation, intravenous antibiotics, and protease inhibitor. Her general condition improved initially, but a high fever redeveloped on hospital day 3. On hospital day 7, a repeat CT scan showed a peripancreatic fluid collection with gas, indicating peripancreatic abscess. A drainage operation was performed, and the organism cultured from the abscess was Escherichia coli. Her postoperative course was uneventful. We report this case to stress that infection may develop even in mild AP, and even in the early phase.

Background: The Japanese severity score (JSS) for acute pancreatitis was revised in 2008. As special therapies for severe acute pancreatitis (SAP), continuous regional arterial infusion of protease inhibitor and antibiotics (CRAI) and enteral nutrition (EN) are now utilized in Japan. We investigated the usefulness of the new JSS and the indications for CRAI and EN based on the new JSS., Methods: We assessed the new JSS in 138 patients with SAP according to the previous Japanese criteria. Usefulness of the new JSS for the prediction of mortality rates was compared with conventional scoring systems by receiver-operator characteristic curve analysis. We analyzed the relationship between the new JSS and prognosis in patients with and without CRAI and EN, respectively., Results: Forty-five patients (33%) were assessed as having mild acute pancreatitis, and 93 patients (67%) were assessed as having SAP. Their mortality rates were 7 and 40%, respectively. The area under the curve for the prediction of mortality rates with the new JSS was 0.822 and was the highest among conventional scoring systems. In patients with new JSS >or= 6, the mortality rate was lower in patients with CRAI than in patients without CRAI (P = 0.129). In patients with new JSS >or= 4, the mortality rate was lower in patients with EN than in patients without EN (P = 0.016)., Conclusions: The new JSS is useful and easier to use for the prediction of prognosis compared to the conventional scoring systems. EN was effective in reducing the mortality rate in patients with a new JSS >or= 4.

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.

Background: In 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., Methods: Early 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., Results: Between 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 >or= 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 >or= 15 (stage 4). Characteristically, early-death patients had lactate dehydrogenase (LDH)>1300 IU/l, or they had serious preexisting comorbidities., Conclusions: As 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.

Background: In 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., Methods: We 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., Results: In 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 < or = Japanese Severity Score < or = 14). Treatment outcome of necrosectomy for infected pancreatic necrosis was still poor. Bleeding and abscess-gut fistula were postoperative life-threatening complications., Conclusions: CRAI and EN may improve the clinical outcome of SAP, reducing infection and averting pancreatic surgery.

Background/purpose: Sepsis due to infected pancreatic necrosis is the most serious complication in the late phase of severe acute pancreatitis (SAP). Bacterial translocation from the gut is thought to be the main cause of pancreatic infection. The possibility has recently been reported that selective digestive decontamination (SDD) and enteral nutrition (EN) may alleviate the complications and reduce the mortality rate in patients with SAP. We analyzed the treatment outcome of SDD and EN in patients with SAP., Methods: We divided 90 patients with SAP into three groups: SDD(-)EN(-),group A; SDD(+)EN(-), group B; and SDD(+)EN(+), group C. Clinical outcome was analyzed retrospectively. The effect of SDD was compared in groups A and B, and the effect of EN was compared in groups B and C., Results: The background of patients was not significantly different between the groups. SDD reduced the incidence of organ dysfunction (from 70% to 59%) and the mortality rate (from 40% to 28%), but the differences were not significant. EN reduced the incidence of infected pancreatic necrosis (from 31% to 24%) and the frequency of surgery for pancreas (from 28% to 18%), and further reduced the mortality rate (from 28% for SDD to 16%), but the differences were not significant. The peripheral lymphocyte count was significantly increased in patients with EN., Conclusions: SDD and EN did not significantly affect the treatment outcome in SAP. However, the results in this study raise the possibility that SDD and EN may decrease the complications and reduce the mortality rate in SAP. The efficacy of SDD and EN for SAP should be evaluated in a randomized controlled trial.

We report a rare case of pancreaticobronchial fistula caused by chronic pancreatitis. A 46-year-old man with a history of chronic alcoholic pancreatitis was referred to us for investigation of dyspnea and bloody sputum. Chest radiography showed a bilateral pneumonia-like shadow, with severe atelectasis in the left lower lung field. Abdominal computed tomography showed a huge pancreatic pseudocyst in the left upper abdomen. The pseudocyst extended as a soft mass from the retroperitoneum into the posterior mediastinum with gas. The pancreatic amylase level in the sputum was 57,500 IU/l. The organism cultured from the sputum was Pseudomonas aeruginosa. Based on these findings, we diagnosed a pancreaticobronchial fistula created by the infected pseudocyst penetrating directly through the dome of the diaphragm to the bronchial tree. External drainage of the infected pseudocyst improved the patient's respiratory condition, allowing him to undergo distal pancreatectomy and splenectomy. Thereafter, he did not suffer any further symptoms.

Purpose: Multiple 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., Methods: Closed 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., Results: The 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., Conclusions: TLR4 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.

Background: In 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., Methods: A 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., Results: Serum 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., Conclusions: Immunosuppression 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.

Background: Coagulative 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., Methods: We 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., Results: Plasma 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., Conclusions: Plasma 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.

Background: We 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-gamma. However, the role of IL-18 in acute pancreatitis has not yet been fully understood., Methods: Serum 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., Results: Serum 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., Conclusions: These 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.