Early identification of severe forms of AP is essential for successful management of affected patients. Unfortunately, early reliable and sensitive predictive markers of severity are not at hand for application in clinical practice beyond popular multifactorial scores [22,23,24]. Moderately severe-to severe acute pancreatitis is believed to be the result of a multifactorial process that involves tissue necrosis, hydrolytic enzyme activation, release of inflammatory cytokines, generation of reactive oxygen species and synthesis of bioactive lipid mediators. In addition, some of these events take place in extra-pancreatic organs and none of them, by its own, is directly linked to the severity of the disease. Of note, pancreas-derived mediators that proved valuable for severity prediction in experimental animals have failed to predict the future course of pancreatitis when applied to human disease. The concomitant activation of different local and systemic processes explains the need for multifactorial scoring systems developed to predict the severity of AP, including Ranson criteria, APACHE-II or BISAP [5].
Fatty acid chlorohydrins are halogenated lipids generated by the action of hypochlorous acid on unsaturated fatty acids [10]. Although absent in control conditions, they can be released to the bloodstream during AP due to the combined effect of high lipase and MPO activities. Since this combination is characteristic of severe pancreatic/peripancreatic damage and enhanced systemic response, the presence of fatty acid chlorohydrins could only be expected to occur under the simultaneous activation of both hydrolytic and inflammatory processes that, when combined, are associated with the progression from mild to severe AP. Importantly, a number of pro-inflammatory activities have also been reported for fatty acid chlorohydrins, including the induction of P-selectin and the activation of macrophages [9, 25].
The value of lipid metabolites as indicators of increased severity of AP has been progressively recognized. There are also some clues that point to an active role of lipid mediators in the progression of mild to severe AP, in particular on the systemic effects that may lead to organ failure. Obesity or increased intra-abdominal fat is associated with severe AP, possibly through a mechanism related to the lipotoxic action of unsaturated fatty acids released by the effect of lipase on triglycerides of visceral adipocytes. In a series of elegant experiments, Navina et al. [26] demonstrated the pathogenic role of unsaturated fatty acids released during pancreatitis on inflammation, necrosis, multisystem organ failure and mortality. The measurement of chlorohydrins of fatty acids is a further step on this direction since the presence of these molecules indicates that, in addition to the effects of hydrolytic enzymes released by the pancreas, the inflammatory microenvironment required for the halogenation of fatty acids becomes relevant in distant organs. Even when these reactions are only relevant in local scenarios, the plasma levels of OAC are ultimately related to increased severity of AP and to multiorgan failure. The experimental study in rats indicates that release of OAC depends on the action of lipase following a kinetic similar to that observed for oleic acid, whereas its final course seems to be related to the hepatic uptake of free fatty acids [9]. Chlorinated fatty acids have been reported to be catabolized by hepatocytes through ω-oxidation and subsequent β-oxidation and their final products are rapidly excreted in urine [27]. Altogether it suggests that OAC could be a useful prognostic parameter but only in the initial stages of acute pancreatitis.
Our results in human patients confirm the expectations generated in experimental studies and show the value of OAC in predicting the course and outcome of AP. OAC was particularly accurate in predicting persistent organ failure and mortality, the most important outcome variables in AP. Our data reveal that levels of OAC measured on admission allow for discriminating the different degrees of severity to be developed on the progression of the disease in the long run, which should have a direct impact on the clinical management of these patients. According to our data, OAC concentrations higher than 32.4 nM are associated with severe AP, while a cutoff value of 7.5 distinguishes mild from moderate and severe disease.
Like many other studies focusing on research of prognostic biochemical markers, our study also has a number of methodological and technical limitations. The study includes patients from two hospitals, but, as expected, the number of patients in moderate and severe groups was significantly lower than in mild group. Therefore, out of 59 patients with AP only 13 had severe pancreatitis and 16 moderately severe. Although the results obtained allow to discriminate between these three groups with a good statistical level, there is no doubt that more studies with a much higher number of patients need to be done. Anyway, OAC was very accurate to detect severity and was compared with preexisting predictors of severity that were applied to the same sample showing a lower accuracy. On the other hand, the generation of OAC through the incorporation of the HOCl to the 9,10 double bond of oleic acid results in the formation of two isomeric chlorohydrins (the 9-chloro, 10-OTMS 18:0 chlorohydrin and the 9-OTMS, 10-chloro 18:0 chlorohydrin). These compounds are not separated by the GC column and, although this limitation may have little impact on the overall results of our study, we have to acknowledge that our data indicate the sum of the two isomers. In addition, it must be taken into account that, although the measure of OAC by gas chromatography/mass spectrometry is too complex and slow to be applied to clinical practice, ELISA tests similar to those for prostaglandins and other lipid metabolites can be easily developed allowing for much faster measurements of OAC. Availability of faster and easier assays methods will make easier to confirm our results in larger samples of patients. In this line, although these encouraging results have been obtained from two independent cohorts of patients from two different and geographically remote hospital centers, they should be validated in larger cohort studies performed by other groups. In case of similar results, OAC would be, by far, the most accurate early predictor of severe acute pancreatitis ever described.