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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 2  |  Issue : 4  |  Page : 143-151

Prediction of severity outcomes in acute pancreatitis: An odyssey in eternal evolution


Institute of Gastroenterology, Hepatobiliary Sciences and Transplantation, SRM Institute for Medical Science, Chennai, Tamil Nadu, India

Date of Submission15-Sep-2022
Date of Decision18-Sep-2022
Date of Acceptance28-Sep-2022
Date of Web Publication13-Oct-2022

Correspondence Address:
Rohan Yewale
Institute of Gastroenterology, Hepatobiliary Sciences and Transplantation, SRM Institute for Medical Science, Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ghep.ghep_24_22

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  Abstract 


Acute pancreatitis (AP) is one of the most frequently encountered gastrointestinal emergencies in clinical practice. It has a wide clinical spectrum and a natural history which varies significantly from patient to patient as well as between two distinct episodes in a single patient. Severe AP often causes considerable morbidity and mortality with a substantial financial burden on the health-care system. The natural course and severity manifestations of AP gradually unfold and can be defined only after the initial 48–72 h of symptom onset. Early identification of patients at high risk for developing a severe course of the disease is crucial for preventing organ failure and death. A vast number of clinical, laboratory, and radiological markers and scoring systems which can predict severity outcomes of AP during this early phase, are described in literature. With a recent exploration of molecular genetics, gut microbiome analysis, and advent of artificial intelligence-derived models, these markers and scoring systems are undergoing constant evolution. Unlike the universally accepted Revised Atlanta classification for defining the severity of AP, there is no uniform consensus on the use of any particular marker or scoring system for early prediction of AP severity. Our review briefly summarizes the available literature on the early prediction of severity outcomes in AP and highlights a few recent advances in this field.

Keywords: Acute pancreatitis, artificial intelligence, gut-microbiome, markers, molecular genetics, morbidity, mortality, prediction, scoring systems, severity


How to cite this article:
Yewale R, Chand N, Ramakrishna BS. Prediction of severity outcomes in acute pancreatitis: An odyssey in eternal evolution. Gastroenterol Hepatol Endosc Pract 2022;2:143-51

How to cite this URL:
Yewale R, Chand N, Ramakrishna BS. Prediction of severity outcomes in acute pancreatitis: An odyssey in eternal evolution. Gastroenterol Hepatol Endosc Pract [serial online] 2022 [cited 2022 Nov 27];2:143-51. Available from: http://www.ghepjournal.com/text.asp?2022/2/4/143/358476




  Introduction Top


Acute pancreatitis (AP) is an acute inflammatory condition of the pancreas which can involve peripancreatic tissue and various remote organ systems. The worldwide incidence of AP is continuously on the rise with a general range of 20–40 per 100,000 population.[1],[2] It has a diverse etiological spectrum and natural history which varies from patient to patient as well as from episode to episode within a single patient. AP also harbors a wide clinical spectrum with mild, uncomplicated self-limiting pancreatic/peri-pancreatic inflammation at one end and persistent organ failure with or without local or systemic complications on the other end. Despite recent advances in gastroenterology, AP continues to be associated with substantial mortality, morbidity, and health-care resource utilization. Although 80% of AP patients have mild disease, nearly one-fifth end up with a severe course with an overall disease-specific mortality of 10%–20% despite all medical, endoscopic and/or surgical interventions.[3]


  Defining the Severity of Acute Pancreatitis Top


For nearly two decades, the clinically based 1992 Atlanta classification system formed the reference point for defining and classifying the severity of AP. Severe AP was defined on the basis of fulfillment of criteria for organ failure and/or local complications such as necrosis, abscess, or pseudocyst. However, it had several drawbacks such as ambiguous definitions for local complications and discordance between reported severity and patient-related clinical outcomes.[4] A decade later, a landmark multi-center study in the UK reported that “persistent” organ failure for more than 48 h in the 1st week of AP is strongly associated with the risk of death or local complications.[5] Subsequently, many other studies concluded that organ failure was central to the definition of severe AP as it reflects the systemic effects of pancreatic injury. In 2012, two new classifications systems of AP severity emerged; (i) Determinant-Based Classification of AP severity (DBC) and (ii) Revised Atlanta Classification 2012 (RAC).[6],[7] The DBC uses 2 main determinants of mortality in AP, i.e., persistent organ failure (systemic) and infected pancreatic/prepancreatic necrosis (local), to classify patients into four categories-mild, moderate, severe, and critical AP.[6]

RAC system scores above DBC as it recognizes two distinct phases (i.e., early and late) in the natural course of AP with the late phase limited to patients with moderate-to-severe disease.[7],[8] The early phase spans the 1st 1–2 weeks from the onset of symptoms and the late phase begins at 2 weeks and beyond. While systemic inflammatory response syndrome (SIRS) and resultant organ failure dominate the early phase, the late phase is characterized by local complications of necrosis, pancreatic and/or peri-pancreatic fluid collections, and superadded infections. The RAC provides clear definitions for interstitial and necrotizing pancreatitis and associated local complications. It emphasizes that severe AP can be defined solely by the presence of “persistent” organ failure.[7] Since pancreatic necrosis is a critical determinant in DBC, it mandates the performance of a contrast-enhanced computed tomography (CT) scan of the abdomen in all patients with AP for accurate categorization of severity. This is considered inessential in mild AP, which more often than not, has a self-limiting course. The timeline of various severity classification systems of AP is briefly summarized in [Table 1]. As the dominant focus of this review is on early “predictors” of the severity of AP, the severity classification systems and definition of various local and systemic complications of AP are not discussed in further detail henceforth.
Table 1: Timeline of severity classification systems of acute pancreatitis

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  Rationale for Prediction of Severity Top


Over the years, our understanding of the natural history of AP has evolved tremendously. It is, now, well recognized that while local complications of AP are associated with variable morbidity; mortality in AP is mainly determined by the presence of persistent organ failure. About 10%–20% of patients with AP may develop necrosis of the pancreatic or/and peri-pancreatic tissue. This subset of patients often end up with a complex, undulating, protracted clinical course with prolonged hospitalization and considerable morbidity and mortality. Infection of pancreatic necrosis is a notorious complication in the natural history of severe AP associated with a mortality rate as high as 30%.[9] There is an abrupt rise in mortality rate as the grade of pancreatitis progresses from mild to severe. Two peaks of mortality have been recognized in severe AP.[10] About 50% of deaths occur during the early phase within the first 2 weeks and can be attributed to the cytokine storm leading to SIRS and resultant organ failure. The second peak in mortality occurs much later owing to complications of severe AP such as pancreatic/peri-pancreatic necrosis, infections, and secondary multiorgan dysfunction syndrome.[7],[11] The primary objective of predicting the severity of AP and outlining the phase of disease from the onset of pain is for guiding clinicians in triage, appropriate goal-directed patient management, and prognostication.

The natural course and severity manifestations of AP gradually unfold and can be defined only after the initial 48–72 h of symptom onset. As previously discussed, the persistence of organ failure for >48 h, is inherent in the definition of severe AP.[7] Clinical judgment alone for the prediction of severe outcomes in the very early phase of AP (i.e., first 48 h of symptom onset), although highly specific, lacks sensitivity. Thus, markers and scoring systems which can aid clinicians in the prediction of disease severity in this initial window period have gained consistent attention over the years.

Mild AP usually has a self-limiting course and does not require any specific treatment apart from nil per oral, pain management, and parenteral fluid resuscitation for a few days.[12] Severe AP, on the other hand, has a tumultuous, unpredictable course which needs an individualized, expectant, phase-directed, multi-disciplinary management approach in a tertiary center equipped with resources for such a level of care. Such patient's attenders often need to be counseled and logistically prepared in the initial stages itself for the possibility of prolonged hospitalization, need for critical care, and mortality. The rationale for early prediction of severity in AP cannot, thus, be emphasized enough.

We often tend to confuse between markers or modalities for severity “diagnosis” with those for severity “prediction.” Although there are multiple criteria and modalities for defining the former, there are quite evident lacunae in translational research on the later. Recent guidelines, reviews, and studies recommend the following severity predictors at admission/during the initial 24–48 h to be useful, albeit when combined with appropriate clinical judgment. For discussion purpose, they can be classified into clinical characteristics or patient factors, laboratory markers, radiological criteria, and scoring systems. The last section of our review briefly highlights a few recent advances and newly proposed markers for early prediction of severity outcomes of AP.


  Clinical Predictors Top


This is the earliest step and often an undervalued tool in the prediction of AP severity. It involves a comprehensive history elicitation and careful, periodic general and systemic clinical assessment. (a) Etiology of acute pancreatitis: It is debatable whether etiology of AP determines its severity. In a systematic review comparing the severity of hypertriglyceridemia-induced AP to that of AP from other etiologies, five studies reported that the former led to more severe episodes of AP, while two other studies did not report of any such difference. It is noteworthy though that the severity assessment criteria and study designs were heterogeneous across the studies included in this review.[13] Some other patient factors described for severity prediction are (b) advanced age (>55 years), (c) obesity (body mass index [BMI] >30 kg/m2), (d) presence of comorbidities (based on Charlson's comorbidity index), and (e) systemic inflammatory response syndrome (defined by two or more of the following criteria: Pulse >90/min, respiratory rate >20/min or PaCO2 <32 mmHg, temperature >38° centigrade and whole blood cell count >12,000 or <4000/mm3 or >10% band forms). In a previous study, mortality in AP patients with persistent, transient, and no SIRS was reported as 25%, 8%, and <1%, respectively.[14] Persistent tachycardia in an afebrile state despite adequate fluid resuscitation and palliation of pain is an ominous sign and quite often a harbinger of progression to severe disease, according to the authors personal experience. A recent meta-analysis of 19 studies concluded that a BMI between 25 and 30 kg/m2 increases the risk of severe AP alone, while a BMI >30 kg/m2 increases the risk of severity as well as mortality in AP. The same analysis also reported that a BMI <18.5 kg/m2 carries an almost two times higher risk of mortality in comparison with normal BMI.[15] Factors such as advanced age, weight loss, and comorbidities are more pronounced in the prediction of severity when superimposed on a background of chronic pancreatitis.[16]


  Laboratory Predictors Top


Serum lipase

It is well known that the height of elevation of pancreatic enzymes amylase and lipase do not correlate with the severity of AP. However, in pediatric AP, it was reported that a 7-fold elevation in lipase predicted severe disease with a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 85%, 56%, 46%, and 89%, respectively.[17]

Hematocrit

A rise in blood hematocrit closely reflects the degree of cytokine-induced third-space loss of intravascular fluid. A previous study reported that a hematocrit >44% had a sensitivity of 72% on admission and 94% after 24 h in detecting organ failure.[18] However, the reported hematocrit cut off value to predict severe AP varies across different studies as it majorly depends on a dynamic processes such as hydration status and timing of blood sampling. Thus, instead of absolute cut off values, failure of rise in hematocrit in the first 24 h of admission predicts a good prognosis.[19]

C-reactive protein

C-reactive protein (CRP) is an acute-phase reactant produced by hepatocytes after stimulation by interleukin (IL)-6 and IL-1. A recent study concluded that an interval change in CRP is a comparable measure to absolute CRP in the prognostication of AP severity and a rise of >90 mg/dL from admission or an absolute value of >190 mg/dL at 48 h predicts severe disease with the greatest accuracy.[20] A recent Cochrane review showed that CRP had no role in the prediction of pancreatic necrosis.[21] Most guidelines, however, suggest a cut off value of >150 mg/dl at 48 h as a predictor of severe outcomes.[22]

Blood urea nitrogen/Serum creatinine

Several scoring systems incorporate blood urea nitrogen (BUN) as one of the important parameters for the prediction of mortality in AP. Similar to hematocrit, BUN also provides information on changes in intravascular volume status due to initial third-space loss and adequacy of subsequent volume resuscitation. In a large multi-center observational study, it was reported that for every 5 mg/dL rise in BUN during the first 24 h, the age- and gender-adjusted odds ratio (OR) for mortality increased by 2.2.[23] A prospective study involving 129 patients with AP concluded that pancreatic necrosis was more frequent in patients with serum creatinine >1.8 mg/dL in the first 48 h of admission.[24]

Pro-calcitonin

This is a pro-peptide acute phase reactant which accurately predicts organ failure with a reported sensitivity of 86% and specificity of 95% within the first 24 h of symptom onset.[25] Another systematic review reported that procalcitonin accurately predicted infected pancreatic necrosis in patients with confirmed pancreatic necrosis.[26]

Polymorphonuclear elastase

This is a neutrophil-derived enzyme which rises very early in AP and has the potential to distinguish mild from severe AP.[27]

Urinary trypsinogen-activated peptide

Premature intrapancreatic activation of trypsin during AP results in the release of urinary trypsinogen activated peptide (uTAP). Early rise within 12 h of admission and ability to predict severe AP with a PPV of 80% and NPV of nearly 100% are its main advantages over other predictive markers. A cut off value >30 nmol/L correlates well with pancreatic necrosis, SIRS, and sepsis.[28] In a meta-analysis of six studies, the pooled sensitivity and specificity of uTAP for predicting severity of AP at the time of admission, at a cut off value of 35 nmol/L, was 71% and 75%, respectively (area under the receiver operating curve (AUC) =0.83, diagnostic OR = 8.86, 95% confidence interval (CI = 3.70–20.33).[29]

Cytokines

Various cytokines are released during the process of premature trypsin activation in AP. These are partly responsible for the extravasation of fluid into the third space and trigger a cascade of SIRS and organ failure. Some of these are IL-6, IL-17, IL-23, TNF-alpha, phospholipase A2, and carboxypeptidase-B.[30],[31],[32],[33] However, their widespread use is limited by lack of concrete evidence based on large-scale studies and availability of methods to measure these markers.


  Radiological Predictors Top


A landmark, retrospective study more than two decades ago reported that early evidence of pleural effusion on a simple chest X-ray was seen in 84.2% with severe AP in comparison with 8.6% of patients with mild AP.[34] Pleural effusion forms an integral component of the universally accepted Bedside Index of Severity in AP (BISAP) score for the prediction of severity of AP.[35] Cross-sectional imaging modalities such as CT scan and magnetic resonance imaging (MRI) are invaluable in detecting severity and complications of AP. However, radiological severity correlates such as pancreatic necrosis usually manifest after 48–72 h of symptom onset and attain peak accuracy at the end of the 1st week. Another practical problem often faced in clinical practice is the presence of acute kidney injury as one of the manifestations of SIRS and organ failure in AP. Thus, a contrast CT scan of the abdomen may not be feasible in all patients with suspected severe AP. All withstanding, the various CT-based criteria of severe AP, possess high accuracy in predicting the hospitalization period, surgical treatment, infection, and mortality in AP.[36] Besides, several studies have emphasized the value of individual findings on radiological imaging namely pleural effusion, skeletal muscle mass and density, visceral adipose tissue, and mean muscle attenuation as predictors of severity and complications of AP. Few studies have shown that radial endoscopic ultrasound can predict AP severity and prognosis in acute biliary pancreatitis by detecting features such as diffuse parenchymal edema, peri-parenchymal plastering, peri-pancreatic edema, and diffuse retroperitoneal free fluid accumulation.[37] Other imaging modalities such as transabdominal ultrasound, contrast ultrasound, MRI, although helpful in diagnosing complications of severe AP, have a limited role in the early prediction of severity. The CT-based grading system of Balthazar and CT Severity Index for defining the severity and prognosticating AP are described in [Table 2].[38]
Table 2: Computed tomography grading system of acute pancreatitis[36]

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  Severity Scoring Systems Top


A variety of scoring systems based on clinical features, laboratory markers, and imaging characteristics have been described over the years to predict severe AP.[35],[38],[39],[40],[41],[42],[43],[44],[45] These are briefly enumerated along with their specific characteristics in [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]. An ideal predictor or severity determinant is a characteristic or a marker which manifests or can be evaluated within the 1st 24–48 h after the onset of symptoms and has a high PPV. Conversely, most of the markers/scoring systems described in literature rather possess good specificity and high NPV. Majority of them, therefore, find relevance in research settings and clinical trials rather than day-to-day practice.
Table 3: Ranson score[39]

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Table 4: Acute Physiology and Chronic Health Evaluation II[40]

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Table 5: Bedside index of severity in acute pancreatitis score[35]

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Table 6: Harmless acute pancreatitis score[41]

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Table 7: Glasgow-Imrie score[42]

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Table 8: PANC-3 score[43]

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Table 9: Japanese severity score[44]

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Table 10: DeBanto score (acute pancreatitis in children)[45]

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  Novel Predictors of Severity Top


C-reactive protein/albumin ratio

In a retrospective study by Kaplan et al., it was found that an admission CRP/albumin ratio at a cut off >16.28 was a significant marker in prediction of mortality in AP with a 92.1% sensitivity and 58% specificity. Further, a 1 unit rise in the ratio resulted in 1.52 times increase in mortality risk.[46]

Neutrophil-lymphocyte ratio, red cell distribution width, platelet lymphocyte ratio

A large retrospective study concluded that red cell distribution width (RDW), platelet lymphocyte ratio, and neutrophil-lymphocyte ratio along with BUN had good predictive value for severe AP and RDW had an added predictive value for mortality.[47]

Soluble suppression of tumorigenicity 2

This is a novel protein receptor for IL-33 responsible for IL-33/soluble suppression of tumorigenicity 2 (sST2) pathway-mediated T-helper (Th)-2 immune response. A recent study showed that sST2 may be used as a novel inflammatory marker in predicting AP severity by regulating the function and differentiation of IL-33/sST-2-mediated Th1 and Th2 lymphocytes in AP homeostasis.[48]

Serum cortisol

A prospective study found that serum cortisol outperformed other novel cardiovascular, inflammatory, and neurohumoral biomarkers (copeptin, pro-atrial natriuretic peptide, pro-adrenomedullin) and had a significant discriminative value for the prediction of mild and severe AP with an AUC = 0.78.[49]

Molecular genetics

A recent study from China suggested the integration of conventional biomarkers and genome-wide cell-free (cf) DNA methylation markers for accurate prediction of severity of AP. This group formulated an expanded predictive model based on 12 conventional biomarkers (red blood cell count, absolute lymphocyte count, mean hemoglobin, serum chloride, globulin level, uric acid, estimated glomerular filtration rate, serum creatinine, absolute neutrophil count, triglyceride, BUN, and RDW) and 59 cfDNA methylation markers which improved severe AP prediction sensitivity to 92.2% with an AUC = 0.96.[50]

Fatty liver

α–1 antitrypsin is a glycoprotein that is mainly synthesized by the liver. It can play a significant anti-inflammatory effect by affecting a wide range of inflammatory cells. A recent study showed that liver steatosis significantly inhibits α–1 antitrypsin levels in mice and human models of AP. This in turn reduces the level of serum α–1 antitrypsin and leads to excessive activation of inflammation.[51] Thus, a chronic proinflammatory state in fatty liver patients may aggravate the course of AP. In an unpublished study by the authors of this review, the influence of fatty liver on the severity and clinical outcome of AP was assessed in 100 consecutive hospitalized patients with AP. It was found that the severity of pancreatitis was significantly higher in patients with hepatic steatosis (objectively assessed on CT scan of the abdomen) in comparison with those without it (P < 0.05). In addition, the prevalence of local complications, organ failure, requirement of intensive care unit admission, and mortality were significantly higher in AP patients with fatty liver.

Oro-intestinal microbiome

Very recently, a large, multi-center, prospective translational study (NCT04777812) initiated patient recruitment for assessing the effect of oro-intestinal microbiome on the course, severity, and outcome of patients with AP. The study proposes to obtain buccal and rectal swabs within 72 h of admission for AP for DNA extraction and microbiome analysis using 3rd generation sequencing for 16S rRNA and metagenomic sequencing.[52]

Few other recently proposed markers for severity prediction in AP are serum irisin (a novel hormone secreted by skeletal myocytes and fat tissue in the presence of inflammation), hepcidin, thrombopoietin, d-dimer, circulating endothelial progenitor cells, signaling profile of blood leukocytes, immature granulocytes, and certain specific markers of oxidative stress among various others.[53],[54],[55] Research on most of these markers is still in infancy and beyond the scope of our review.


  Artificial Intelligence - A Renewed Approach to Severity Prediction Top


Of late, there has been particular interest and enthusiasm in the integration of artificial intelligence (AI) models in diagnostic and prognostic gastroenterology. The early achievable severity index (EASY-app) is the latest AI model developed by the Hungarian pancreatic study group for early prediction of severity in AP. Machine learning (ML) models helped in identifying predictors from an international cohort of 1184 patients and a validation cohort of 3543 patients. Six predictors namely respiratory rate, body temperature, abdominal muscular reflex, gender, age, and glucose level were identified and integrated into an algorithm which can predict the severity of AP on admission using an easy-to-use web application with an AUC of 0.81 ± 0.033.[56] A couple of studies compared the accuracy of ML models with the Acute Physiology and Chronic Health Evaluation (APACHE) II score in predicting the severity of AP. In both of these studies, the ML models outperformed the accuracy of APACHE II in predicting severe AP (AUC 0.92 vs. 0.63, 0.82 vs. 0.74).[57],[58]

In summary, most of the scoring systems and models rely on data from two different points in time after admission, rendering them futile in triage settings in the emergency room. A few of these scoring systems although comprehensive, are quite cumbersome for calculation of predicted severity. The future seems exciting as we await results from recently proposed studies and conduction of further trials determining the role of gut microbiome in predicting outcomes of AP. Molecular genetics is another niche area which needs further exploration for the identification of specific DNA methylation markers of early severity prediction. AI and ML derived models, too are expected to play a significant role for predicting severity outcomes in the very early stages of AP. Evidence needs to be concrete and validated across diverse geographical strata and different etiologies of AP before the renowned pancreatic societies can provide standard clinical practice guidelines on early predictors of severity outcomes in AP. At present, CRP >150 mg/dL at 48 h and BISAP score ≥3 on admission remain the most popular and widely accepted predictors of severe AP worldwide. Finally, it is essential to understand that the diverse pool of markers and scoring systems with predictive potential described in literature, are just supplementary clinical aids. The significance of alert, judicious, periodic clinical assessment in the early phase of AP cannot be underestimated.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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