Acute_Pancreatitis

Acute pancreatitis is a common condition, with lethal potential. Incidence varies widely, due to differences in geographic and aetiological factors; additionally affected by the precision with which the diagnosis is made, but it can be as high as 79.8 per 100,000 per year [1]. The incidence of acute pancreatitis in the UK appears to be rising. This is certainly true in Scotland [2] and appears also to be the case in the South of England [3-4]. Incidence ranges in the UK from 150 to 420 cases per million population [2, 4]. Gallstones and alcohol are commonly reported as the main causative agents, increasing use of the latter being implicated in the recent rise in incidence of acute pancreatitis in Scotland [2]. Approximately 20% of cases of acute pancreatitis are severe; although the overall mortality of all cases of acute pancreatitis is 4-6%, this increases to 17-39% in the severe subgroup [5-8]. This mortality is biphasic, with deaths in the first two weeks or so being attributed to systemic inflammatory response syndrome, whereas those in the later phase, being related to infection. Pancreatic necrosis begins to develop within days of symptom onset, but does not often become infected before the third week [9]. Overall at least a third of cases of severe pancreatitis complicated by pancreatic necrosis will become infected [10]. In those cases where infected necrosis is detected, surgery has a vital role to play in survival as cases left untreated have almost 100% mortality [11]. Acute pancreatitis initially comprises of series of complex cascading events, all of which, start in the pancreatic acinar cells. The critical initiating event is the intracellular activation of pancreatic zymogens, which result in autodigestion of pancreas. Trypsinogen, a serine protease, is now thought to be the first enzyme to be activated [12-15]. Subsequently, other digestive proenzymes are cleaved and activated. The pancreas has a variety of mechanisms to prevent intracellular zymogen activation and subsequent autodigestion. However, in acute pancreatitis, these protective mechanisms are no longer effective or are overwhelmed [12-15]. Recent works have endorsed the critical role of calcium in the acinar cell injury. Rise in intracellular calcium and disruption of acinar cell signalling is associated with acinar cell vacuolization and the intracellular Trypsinogen activation events that occur in early acute pancreatitis [16-20]. Acinar cell damage leads to local inflammatory response but the inflammatory mediators also spill over into general circulation. The severity of an attack of acute pancreatitis appears to be determined by the magnitude of the resultant systemic inflammatory response [21]. Acute pancreatitis has the least predictable course of any digestive disease. It is widely recognised that the close observation of patients with acute pancreatitis and clinical monitoring should focus on the assessment of intravascular volume (e.g. physical examination, urine output, and acid-base status) and pulmonary function status (e.g. hypoxemia) [22]. There is evidence that early and aggressive fluid management may result in the resolution of organ failure and that this early resolution of organ failure is associated with a reduced risk of mortality from acute pancreatitis [23]. It has been recommended that patients with severe acute pancreatitis be managed in a critical care setting, since this facilitates optimisation of fluid status and cardio-respiratory parameters [23-24]. Identifying this cohort of patients who require critical care support is vital to rationalise health care resources, since it would not be feasible or appropriate to manage all patients with acute pancreatitis in such an environment. Because it is important to predict the severity of the disease as early as possible in order to optimize the therapy and to prevent organ dysfunction and local complications, several scores such as Ranson, Glasgow and Acute Physiology And Chronic Health Evaluation (APACHE II) scores have been used [22, 25-27]. New serum markers have emerged and their ability to provide additional information on the severity of the disease has been evaluated. But none of them provide an accurate estimate of the severity of the disease in the first 24 hours and therefore, have potential weaknesses. Since acute pancreatitis is an immunological response to the injury [28-29], we postulate that peripheral blood leukocytes would harbour specific markers of progression of disease which would help to identify patients who are at higher risk of developing complications in the first 24 hours of the disease onset. Acute pancreatitis presents with diagnostic and treatment challenges. Modern scientific research into surgery is yet to come up with an ideal prognostic system to differentiate between mild and severe attacks and also with effective treatment for the early phase of this disease; notably moderation of SIRS. Surgical debridement has a role in the second phase to remove pancreatic infection, which still is high risk even in the specialist centres. Assessing the severity of acute pancreatitis is an important initial step in the management of these patients. An ideal prognostic system/marker doesn’t exist, and current approaches fall short of what is needed when dealing with individual patients. It has been 35 years since Ranson et al. [25] showed that it was possible to stratify patients with acute pancreatitis according to their risk of dying. Since then, there have been thousands of articles promoting hundreds of prognostic markers and systems. The fact that very few of these have actually found place in the clinical practice goes on to show that we still haven’t found what we are looking for. An ideal or desirable detection scoring system/biomarker should: * Have high sensitivity and positive prediction value (PPV). * Be able to predict necrosis early (<48 hours) * Be performed rapidly (<4 hrs) * Be available in most hospitals * Be relatively inexpensive * Be objective and not observer-dependent [30]. The extent to which different clinical, laboratory and radiological detection methods satisfy these requirements vary greatly and show distinct limitations peculiar to each individual system. APACHE II (Acute Physiology and Chronic Health Evaluation II) is a classification system designed to measure the severity of a disease for acutely unwell adult patients [27]. In the prediction of mortality for acute pancreatitis, it has been analysed in various studies and has been found to have a sensitivity of 65-81%, specificity of 77-91%, PPV of 23-69% and NPV of 86-99% [31]. Some studies have found a significant association of APACHE II with mortality, but conflicting results were found within these as well [32-34]. Moreover, it relies very heavily on age. Infact, a 76-year-old (6 points) would require very little physiologic disruption to be classified in the category of ‘severe acute pancreatitis’ (>8 points). This has been one of the arguments all along of defined number of APACHE II points when the age is high. Hence, the need for more accurate predictors of mortality. Ranson’s Criteria were initially introduced in 1974 for the assessment of severity of acute pancreatitis [25]. It is an objective indicator of diseases severity and is particularly useful at the two ends of the scale. Pancreatitis is mild when the score is ≤2, whereas pancreatitis is severe when the score is >6. The correlation of severity of disease or development of necrosis in patients with a score of 3-5 (which is a common occurrence) is deficient [35-36]. Moreover, the system requires the completion of 11 measurements, which necessitates a total of 48 hrs of observation for proper evaluation [37]. Although a modification of the Ranson’s scoring was introduced by Blamey et al [38], the overall sensitivity of these numeric systems in the initial staging of an attack of pancreatitis remains 65%, with specificity of 70%, PPV of 20-63% and NPV of 86-94% [31]. Some studies have found conflicting results between patients who died compared with those who survived [25, 30, 39-40]. The Glasgow Criteria were originally presented in 1978 [41] and the original system used 9 data elements. This was subsequently modified to 8 data elements, by the removal of the contribution of transaminase levels (either AST-SGOT or ALT-SGPT >100 U/l) [38]. The Glasgow criteria have been analysed in multiple studies and the sensitivity was found to be 94%, specificity 28%, PPV 18-66% and NPV 86-100% [31]. The score, however, is not valid for repeated measurements beyond 48 hrs and like Ranson’s criteria, has not been validated for use in children. Other scoring systems like, Mortality Probability Model (MPM) [42] and APACHE III [43] (a modified version of APACHE II including the prior site of health care- i.e. hospital floor, emergency room etc. – and additional physiological parameters – urine output, blood urea nitrogen, albumin, bilirubin, glucose) at 96 hrs have been calculated and brought forward but without creating much influence on the current clinical practice. Unlike clinical scores, radiological scores are based on local anatomic changes in the pancreatic and peripancreatic tissues. Contrast-enhanced CT scans can be used to assess pancreatic necrosis, since loss of perfusion consequent upon necrosis results in a reduced enhancement. In 1985, Balthazar et al [44] proposed a scoring system for the grading of disease severity based on the CT findings. The severity of pancreatitis is divided into 5 distinct groups, from A to E. Most patients with severe acute pancreatitis (SAP) exhibit one or more pancreatic fluid collections and are classified as grades D or E according to the Balthazar score. Furthermore, when the score is >5, this is defined as SAP on the CT severity index (CTSI) – a development of the Balthazar score in which is included the pancreatic necrosis. Even in these cases, as with the clinical scores, the commonly used radiological scores are particularly useful in predicting survival in the absence of peripancreatic fluid collections (Balthazar score) or collections/pancreatic necrosis (CTSI), but when these abnormalities are present, the scores may miss up to 50-59% of patients who eventually die from the disease [31]. From the above mentioned facts, it is evident that there is no one most reliable predictor of mortality and all scores and parameters seem to show a good NPV but a relatively low PPV. The ability to confidently exclude a large cohort of patients with a low risk of mortality is of value in the management of patients with acute pancreatitis. However, all scoring systems and prognostic factors suffer from a low PPV and patients scoring highly on such parameters do not necessarily progress to a fatal outcome. Much effort has been directed to develop a single, simple, rapid, affordable and reliable laboratory test for the prediction of severity and to monitor disease progression. So far, several single biological parameters, which represent important steps in the pathophysiology of acute pancreatitis, have been evaluated, and several tests have been developed. Trypsinogen Activation Peptide (TAP) is the most studied activation peptide in acute pancreatitis. It is specifically related to the onset of acute pancreatitis and therefore, seem to be a good marker for it [45-47]. It is rapidly cleared by the kidneys and excreted into the urine [48], so that its detection in urine is easier than in serum. However, 30% of all patients with acute pancreatitis have normal TAP values in urine on admission [45]. Similarly, urinary TAP has not been able to predict mild pancreatitis following ERCP [49]. Two multicenter studies investigated the predictive value of urinary TAP [46, 50]. The American study showed a very high sensitivity of 100% and a specificity of 85% within 48 hrs, while the European trial demonstrated a sensitivity of only 58% and a specificity of 73% within 24 hrs after the onset of symptoms. Likelihood ratios for a positive urinary TAP assay at 48 hrs showed a small increase in the positive likelihood of severe acute pancreatitis from 20% to 35% [51]. This finding may limit the clinical usefulness of urinary TAP measurements for the prediction of disease severity. The general accuracy of TAP alone does not qualify for clinical decision-making. The elevated TAP concentration in severe cases decreases quickly in serum and within 72 hrs in urine, so that the prognostic accuracy declines rapidly [45-47, 50]. Moreover, the TAP-ELISA is still too complex and too expensive to be used as a routine test in everyday practice. In patients with acute pancreatitis, elevated Tumour Necrosis Factor (TNF) levels have been well documented [52]. However, TNF measurements are inconsistent even in severe disease because of intermittent release and rapid clearance by the liver before it reaches the general circulation. The importance of Interleukin-6 (IL-6) in the acute phase response has been confirmed by the observation that it stimulates the synthesis of acute phase proteins, including C reactive protein (CRP), from hepatocytes in vitro and in vivo [53-54]. Its concentrations peak already 24 hrs after the onset of the disease, but decrease to baseline within 4 days [55]. A large series of patients with acute pancreatitis confirmed that IL-6 levels on admission correlate well with the subsequent course of pancreatitis [56]. But due to its rapid decline, IL-6 does not seem to be a useful marker for monitoring disease progression. Similarly, Interleukin-8 (IL-8) levels have been shown to increase even earlier than IL-6, with a peak detected 12 hours after the onset of acute pancreatitis [57]. However, similar to IL-6, IL-8 decreases rapidly within 3-5 days [58] and consequently, disease progression cannot be recorded with these markers. The most famous acute-phase reactant and most commonly used serum parameter for the staging of acute pancreatitis is C-Reactive Protein (CRP). The importance of CRP in predicting severity of acute pancreatitis has been shown in numerous clinical studies over the past years [59-61]. Increased levels of CRP are a direct effect of hepatocytes stimulation by cytokine release. This also explains the chronological delay of increased CRP levels compared to IL-6 and IL-8 concentrations, with peak levels occurring 48-96 hrs after symptom onset. Pezzilli et al [58] found the highest sensitivity and specificity for predicting severity of acute pancreatitis for IL-6 and IL-8 on days 1 and 2, while on day 3 CRP surpassed both of these mediators. This is due to the relative rapid decrease of the two cytokines. Although, CRP is a valuable parameter for predicting severity of acute pancreatitis more than 48 hrs after the onset of the disease and for monitoring disease progression, it does not help with prediction within the first 48 hours of the disease onset. Serum Amyloid A (SAA) proteins constitute a family of apolipoproteins mainly synthesized in liver in response to cytokines [62]. SAA has been found to be of similar value for the discrimination between edematous and necrotizing pancreatitis as CRP [63-64]. However, SAA was less accurate than CRP in predicting infection, multi-organ failure and death. Moreover, in contrast to CRP, SAA does not have an accepted cut-off value. The European Multicenter trial [64] was able to demonstrate that SAA distinguishes mild from severe acute pancreatitis already at the onset of the disease and that this difference was significant for the whole observation period of 5 days. However, the other trial could not demonstrate the early predictive value of SAA [63]. It is very clear from the discussion above that despite the proliferation of scoring systems and biochemical parameters for grading acute pancreatitis, there is still no one single system/biomarker which is completely reliable in accurately predicting the severity of the disease within the first 48 hrs. One method to identify new potential markers is to map out those genes which are uniquely expressed during the disease process. Recently, investigators have measured gene expression of the pancreas in experimental pancreatitis and have identified several novel genes which are likely to be important in the development and severity of acute pancreatitis [65-66]. Ji et al utilized microarrays to identify genes commonly induced in rat pancreatic acinar cells within 1-4 hrs in two in vivo models (caerulein and taurocholate) and observed that a complex programme of gene expression was rapidly initiated early in the course of the disease [65]. Their data suggested a model in which early signalling events led to activation of transcription factors which regulated the expression of specific cellular and secreted molecules. These secreted factors were hypothesized to be useful prognostic indices for the disease. Similarly, some researchers have identified genes likely to be involved in the endogenous self-protection mechanisms in acute pancreatitis using experimental animal models [67]. While others have studied changes in the population of leukocytes in pancreatitis and have emphasized on a pathogenetic role of immune system in the development of acute pancreatitis [68]. Although the early acinar cell expression is important for the subsequent severity of acute pancreatitis and could provide insight into the mechanisms involved in the initiation of acute pancreatitis [65], obtaining pancreatic tissue to analyse acinar cell gene expression is not a practical option in human patients. To date, no one has actually studied the role of blood derived inflammatory cells as markers for pancreatic inflammation. We postulate that the response to pancreatitis and potentially the prognostic indicator of disease severity, rests in the peripheral blood leukocytes. These are the cells which mediate the immunologic reaction to pancreatitis. The genetic map of these leukocytes during the disease has not been looked into before. Recently, Bluth et al looked into the gene expression profiles in cells of peripheral blood to identify new molecular markers of acute pancreatitis using microarray technology and concluded that pancreatitis related genes are induced in cells outside the pancreas – in peripheral blood mononuclear cells during necrotizing pancreatitis [69]. It should not be surprising that such genes are induced since these genes were originally identified from inflamed pancreatic tissue which likely already had similar peripheral blood mononuclear cells infiltrating them. We hypothesize that the peripheral blood leukocytes can serve as a ‘reporter function’ as biomarkers of acute pancreatitis, and as such would express unique genes during pancreatitis. Further, these cells represent an easily accessible, non-invasive source of material. This easy availability of blood leukocytes to provide reporter function for solid organ disease will likely prove useful in pancreatitis. 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