Organ failure and (peri)pancreatic necrosis are two key factors that are causally associated with the severity of AP. A large number of investigations demonstrated a statistically significant association between a wide array of factors and the severity of acute pancreatitis, such as prolonged hospitalization and need for intervention, but the relationships are non-causal[22, 23]. Therefore, the early and accurate prediction of organ failure is particularly important in the treatment of SAP patients. The widely adopted guidelines of the International Association of Pancreatology and the American Pancreatic Association recommend the persistent (lasting≥48 h) SIRS as early markers to predict the development of organ failure . However, despite a reasonably good sensitivity of 50-95%, SIRS has a lower specificity of 75% [25, 26]. Several clinical scores can also be exploited to predict the development of organ failure in AP, such as APACHE II, BISAP score and SOFA score, which are involved multiple parameters and are somewhat cumbersome to use. Single laboratory markers (including IL-6, CRP, and procalcitonin) can also be used as a sensitive marker, but the guidelines emphasize the need for a repeated clinical assessment [24, 28, 29]. At present, no single laboratory marker can be recommended for the early prediction of the development of OF in AP. Recent studies showed that angiopoietin-2(a marker of vascular leak syndrome) or serum urokinase-type plasminogen activator receptor (uPAR) can be applied as a marker in predicting persistent organ failure. Unfortunately, the detections of these indicators are not widely used so far and is difficult to obtain in clinical practice. It is necessary to find early and appropriate markers of organ failure, which can help doctors identify critically ill patients and allow for the proper allocation of intensive care resources in time.
BAs are physiological detergent molecules synthesized from cholesterol in the liver. Dietary intake stimulates Bile acids into the intestines and then they can facilitate the absorption of dietary lipids and vitamins in the intestines.Over the past few decades, many studies have suggested that bile acids are signalling molecules that regulate lipid, glucose and energy metabolism which are predominately mediated by bile acid-activated FXR and TGR5[8, 9, 14, 33]. When the homeostasis of BAs is broken or the signaling pathway is impaired, it can lead to a variety of metabolic disorders or inflammatory diseases [14, 33]. At present, circulating TBA can be used as a marker for diagnosing hepatobiliary diseases, and has been widely used in clinical work[16, 34]. Besides, some studies have reported that circulating TBA can predict the occurrence of colorectal cancer[35, 36] and pancreatic cancer. However, there are few researches in the field of critical illness or AP involving BAs.
The results of our study shown that 54 (18.43%) patients with AP had a D7 TBAmax ≥ 10 μmol/L within 7 days after admission, and the increase of circulating TBA was not only observed in biliary AP, but also in hypertriglyceridemic and alcoholic AP. Further research revealed that the incidence of OF in the HTBA group was significantly higher than that in the NTBA group, and the AP severity classification in the HTBA group was more serious than that in the NTBA group. We performed a stratified analysis at multiple time points, and in addition we repeated the comparative analysis after biliary AP was excluded, thereby further verifying the reliability of the results. The pancreatic necrosis rate, PCD rate and mortality in the HTBA group were higher than those in the NTBA group according to the D7 TBAmax values. All of the above results indicated that the increase in circulating TBA in AP patients was not related to the etiology, and the AP patients with HTBA had a worse prognosis.
The pathophysiological mechanism of AP complicated with OF is that pancreatitis per se (sterile inflammation) causes the release of a large number of inflammatory mediators leading to primary (early) OF or infected pancreatic necrosis leads to the secondary (late) OF . Cholestasis is a common complication of sepsis. Hao et al. showed that the amplified plasma levels of BAs are important for the prediction of sepsis-associated mortality. They proved that bile acids activate the NLRP3 inflammasome via promoting calcium influx. Their research also depicted that the FXR-bile acid axis involves in the regulation of cholestasis-associated sepsis, which can be mediated by the negative regulation of NLRP3 inflammasome via the direct binding of FXR to NLRP3 and caspase 1 in macrophages [38, 39]. Maleszka et al. reported that circulating TBA on the first day of AP could be used to discriminate the biliary AP from the other etiologies. The cut-off values of 4.7 mol/L, with a diagnostic accuracy of 85%. However, circulating TBA had nothing to do with the severity of AP . On the contrary, in this present study, we found that the levels of circulating TBA were closely related to the severity of AP, and logistic analysis suggested that circulating D7 HTBAmax was an independent risk factor for AP complicated with organ failure. Our results are somewhat different from those of Maleszka et al. The reasons for the differences may be in the following aspects: first, in their study, the values of circulating TBA were continuously monitored for three days after AP onset, while the time span of our test was longer; secondly, the sample sizes of two groups were relatively small in our study, which is prone to bias; finally, our center is a SAP tertiary referral center in which our patients are more serious.
In recent years, the pathophysiological mechanisms of BAs and its receptors in diseases were elucidated in some researches. Iracheta-Vellve A et al. manifested that agonists of FXR and TGR5 (OCA, INT-767 and INT-777) can reduce the expression of inflammatory cytokine in animal models of alcoholic liver disease by inhibiting macrophage inflammation through activation of protein kinase A induced by cyclic adenosine monophosphate (cAMP). This mechanism was confirmed in TGR5 ligand ameliorating the immunity of intestinal mucosa in experimental colitis . Moreover, in the pancreas, local accumulation of BAs molecules could inhibit autophagy of pancreatic acinar cells through FXR, leading to the increasing of apoptosis and necrotic apoptosis . Our team previously found that the administration of INT-777 could protect AP in mice and improve pancreatic acinar cell necrosis . Based on the above studies, we hypothesize that the imbalance of BAs, which may lead to the disorder in BAs metabolism and inflammatory response, thus affecting the organ function. Especially after a certain period of standardized treatment, the circulating TBA levels are still higher than normal during the observation period, which deserves our attention. However, the specific mechanism of increased circulating TBA levels associated with organ failure remains unclear which needs further study.
Our study reports for the first time that circulating TBA levels in the early stage of AP patients are associated with the development of organ failure. This can help clinicians identify patients whom are at risk of organ failure in the early stage of AP (within 14 days), so as to treat them promptly and reduce the mortality rate. In addition, the detection of circulating TBA has been widely used, exerting multiple effects of the same indicator. However, our research also has some limitations. First, this is a single-center retrospective study with a small sample size and further research with larger sample sizes is needed. Moreover, our observation marker, TBAmax, was the highest value of circulating TBA within 7 days of admission. Long monitoring time span may cause some bias to the results. Finally, our study cannot completely rule out the effects of liver injury and drug application on circulating TBA.