Accuracy of circulating histones in predicting persistent organ failure and mortality in patients with acute pancreatitis

Abstract

Background: Early prediction of acute pancreatitis severity remains a challenge. Circulating levels of histones are raised early in mouse models and correlate with disease severity. It was hypothesized that circulating histones predict persistent organ failure in patients with acute pancreatitis.

Methods: Consecutive patients with acute pancreatitis fulfilling inclusion criteria admitted to Royal Liverpool University Hospital were enrolled prospectively between June 2010 and March 2014. Blood samples were obtained within 48 h of abdominal pain onset and relevant clinical data during the hospital stay were collected. Healthy volunteers were enrolled as controls. The primary endpoint was occurrence of persistent organ failure. The predictive values of circulating histones, clinical scores and other biomarkers were determined.

Results: Among 236 patients with acute pancreatitis, there were 156 (66·1 per cent), 57 (24·2 per cent) and 23 (9·7 per cent) with mild, moderate and severe disease respectively, according to the revised Atlanta classification. Forty-seven healthy volunteers were included. The area under the receiver operating characteristic (ROC) curve (AUC) for circulating histones in predicting persistent organ failure and mortality was 0·92 (95 per cent c.i. 0·85 to 0·99) and 0·96 (0·92 to 1·00) respectively; histones were at least as accurate as clinical scores or biochemical markers. For infected pancreatic necrosis and/or sepsis, the AUC was 0·78 (0·62 to 0·94). Histones did not predict or correlate with local pancreatic complications, but correlated negatively with leucocyte cell viability (r = -0·511, P = 0·001).

Conclusion: Quantitative assessment of circulating histones in plasma within 48 h of abdominal pain onset can predict persistent organ failure and mortality in patients with acute pancreatitis. Early death of immune cells may contribute to raised circulating histone levels in acute pancreatitis.

Fig. 1

Proposed role of extracellular histones in acute pancreatitis. After injury caused by pancreatic toxins, the pancreas (primarily pancreatic acinar cells) releases damage-associated molecular pattern molecules including extracellular histones. The released extracellular histones and other inflammatory mediators stimulate resident immune cells to release more proinflammatory cytokines/chemokines. Once released into the circulation, the circulating histones activate polymorphonuclear neutrophils (PMNs) and facilitate neutrophil extracellular trap (NET) formation. Apoptotic and necrotic neutrophils and NETs release more histones and inflammatory mediators, which further stimulate PMN infiltration and NET formation. Stimulated PMNs, NET components, circulating histones and other inflammatory mediators cause distant organ dysfunction, such as acute respiratory distress syndrome or even multiple organ dysfunction syndrome (MODS). MODS in turn causes excessive release of circulating histones and other inflammatory mediators, triggering a vicious cycle of uncontrolled MODS, coagulation and death. TLR, Toll-like receptor; NLRP, NOD-like receptor family, pyrin domain-containing; IL, interleukin; TNF, tumour necrosis factor; MPO, myeloperoxidase; NE, neutrophil elastase

Fig. 2

Flow chart showing patient selection

Fig. 3

Comparison of circulating histone levels measured within 24 h of admission: a healthy volunteers and patients with acute pancreatitis on admission; b patients with persistent organ failure occurring in less than 24 h versus 24 h or more. Median values (bold line), i.q.r. (box), and range (error bars) including outliers (circles) are shown. *P < 0·050 versus each other group (Mann–Whitney U test)

Fig. 4

Comparison of receiver operating characteristic (ROC) curves for prediction of persistent organ failure since admission: a circulating histones within 24 h versus C-reactive protein (CRP) within 24 h or at 48 h; b circulating histones within 24 h versus urea within 24 h or at 48 h. Dotted line is the ROC reference line