Serum macrophage migration inhibitory factor is an early marker of pancreatic necrosis in acute pancreatitis.

OBJECTIVE: To determine if 24-hour blood concentrations of macrophage migration inhibitory factor (MIF), soluble CD14, and CD163 receptors could predict complications associated with acute pancreatitis (AP). SUMMARY BACKGROUND DATA: Soluble receptor proteins derived from the macrophage-monocyte lineage potentiate the inflammatory cytokine response early in AP. Understanding the temporal expression of these molecules could afford better measures for therapeutic intervention. METHODS: Patients with AP (amylase >5 times normal) were recruited within 24-hour of onset of pain. Peripheral blood was analyzed for MIF, sCD163, and sCD14 levels and levels correlated with CRP, APACHE-II score, and clinical disease severity (Atlanta criteria); subclassified as multiorgan dysfunction (MOF), pancreatic necrosis (PN >30% on contrast CT), and death. RESULTS: In total, 64 patients with AP (severe, 19: 8 had MOF alone, 7 both PN and MOF, 2 PN without MOF, and 2 single-organ failures with local septic complications) were recruited. Both sCD14 and MIF concentrations were elevated in patients with severe attacks (P = 0.004 and P < 0.001 respectively), and patients who developed MOF (P = 0.004 and P < 0.001). However, only serum MIF was significantly raised in patients who subsequently developed PN (median, 92.5 ng/mL; IQR, 26-181 vs. 31.1 ng/mL; IQR, 5-82, P < 0.001), independently of MOF (P = 0.01). Multivariate analysis demonstrated serum MIF as an independent predictor of PN (P = 0.01; OR = 2.73; 95% CI, 2.72-2.74). CONCLUSION: The prognostic utility of 24-hour plasma MIF concentration in predicting PN has major clinical and healthcare resource implications. Its mechanistic pathway may afford novel therapeutic interventions in clinical disease by using blocking agents to ameliorate the systemic manifestations of AP.

Soluble CD14 receptor expression and monocyte heterogeneity but not the C-260T CD14 genotype are associated with severe acute pancreatitis.

OBJECTIVE: Soluble CD14 is derived from a membrane glycoprotein, and it enhances endothelial cytokine responses to lipopolysaccharide. We studied the role of soluble CD14 in the pathogenesis of the systemic inflammatory response associated with acute pancreatitis, to determine whether altered expression was due to a functional C-260T polymorphism in the CD14 promoter gene or altered monocyte heterogeneity. DESIGN: Prospective case-matched study. SETTING: Tertiary pancreatic treatment unit in the United Kingdom. SUBJECTS: Patients with pancreatitis and controls. INTERVENTIONS: DNA from 117 patients with pancreatitis (34 severe) and 263 controls underwent CD14 genotyping using restriction fragment length polymorphism-polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: Peripheral venous blood samples at 24 and 72 hrs after the onset of abdominal pain were analyzed for sCD14 levels. Isolated peripheral blood mononuclear cells were phenotyped for CD14/CD16 receptor expression using immunofluorescence flow cytometry. Disease severity was assessed using Atlanta criteria, Acute Physiology Scores, and C-reactive protein.Soluble CD14 levels were higher in severe (24-hr median, 66.6 ng/mL; 72-hr median, 72.2 ng/mL) compared with mild attacks (24-hr median, 50.7 ng/mL; 72-hr median, 49.7 ng/mL, p < .001), although the latter was similar to controls (median, 51 ng/mL). Furthermore, soluble CD14 levels correlated with Acute Physiology Scores (p < .001) and C-reactive protein (p = .01).Peripheral blood mononuclear cells CD14++ (p = .008), CD14+/16+ (p = .003), and CD16++ (p = .015) receptor densities were all increased in severe attacks at 24 hrs. Early CD14+/16+ receptor density correlated with sCD14 (p < .001), Acute Physiology Scores (p < .001), and C-reactive protein (p = 0.006). The CD14 genotype prevalence in acute pancreatitis was similar to controls and failed to correlate with any variables studied. CONCLUSIONS: Increased soluble CD14 expression is associated with the systemic inflammatory response to acute pancreatitis and an expansion of the proinflammatory CD14+/CD16+ monocyte subset. Its targeted disruption may afford some benefit in preventing the development of systemic complications.

Intestinal hypoperfusion contributes to gut barrier failure in severe acute pancreatitis.

Intestinal barrier failure and subsequent bacterial translocation have been implicated in the development of organ dysfunction and septic complications associated with severe acute pancreatitis. Splanchnic hypoperfusion and ischemia/reperfusion injury have been postulated as a cause of increased intestinal permeability. The urinary concentration of intestinal fatty acid binding protein (IFABP) has been shown to be a sensitive marker of intestinal ischemia, with increased levels being associated with ischemia/reperfusion. The aim of the current study was to assess the relationship between excretion of IFABP in urine, gut mucosal barrier failure (intestinal hyperpermeability and systemic exposure to endotoxemia), and clinical severity. Patients with a clinical and biochemical diagnosis of acute pancreatitis were studied within 72 hours of onset of pain. Polyethylene glycol probes of 3350 kDa and 400 kDa were administered enterally, and the ratio of the percentage of retrieval of each probe after renal excretion was used as a measure of intestinal macromolecular permeability. Collected urine was also used to determine the IFABP concentration (IFABP-c) and total IFABP (IFABP-t) excreted over the 24-hour period, using an enzyme-linked immunosorbent assay technique. The systemic inflammatory response was estimated from peak 0 to 72-hour plasma C-reactive protein levels, and systemic exposure to endotoxins was measured using serum IgM endotoxin cytoplasmic antibody (EndoCAb) levels. The severity of the attack was assessed on the basis of the Atlanta criteria. Sixty-one patients with acute pancreatitis (severe in 19) and 12 healthy control subjects were studied. Compared to mild attacks, severe attacks were associated with significantly higher urinary IFABP-c (median 1092 pg/ml vs. 84 pg/ml; P < 0.001) and IFABP-t (median 1.14 microg vs. 0.21 microg; P = 0.003). Furthermore, the control group had significantly lower IFABP-c (median 37 pg/ml; P = 0.029) and IFABP-t (median 0.06 microg; P = 0.005) than patients with mild attacks. IFABP correlated positively with the polyethylene glycol 3350 percentage retrieval (r = 0.50; P < 0.001), CRP (r = 0.51; P < 0.001), and inversely with serum IgM EndoCAb levels (r = -0.32; P = 0.02). The results of this study support the hypothesis that splanchnic hypoperfusion contributes to the loss of intestinal mucosal integrity associated with a severe attack of pancreatitis.