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Histopathology ofAcute Pancreatitis

Downloaded from https://onlinelibrary.wiley.com/doi/ by Universität Bern, Wiley Online Library on [22/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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Histopathology Related toEtiologic Factors andPathophysiologic Mechanisms

Acute pancreatitis with a fat necrosis pattern is most often associated with alcohol abuse and gallstone disease. The only difference between the two etiologic factors on the resulting morphologic changes seems to be the disease severity, since biliary pancreatitis usually follows a mild course as compatible with interstitial pancreatitis, while alcoholic pancreatitis is a severe necrotizing disease. Rare causative factors are metabolic or drug- associated processes, and familial- hereditary or circulatory failurerelated conditions.

The pathophysiologic mechanisms that lead to sudden autodigestive fat necrosis in the human pancreas are still unidentified or hypothetical. Based on findings in experimental pancreatitis it has been suggested that disruption of intracellular compartmentalization leads to an intracellular enzyme activation by lysosomal hydrolases with subsequent acinar cell damage [18,19]. However, acinar cell necrosis has not yet been convincingly proven as the initial histologic lesion in acute human pancreatitis caused by the most common etiologic factors[20]. It must therefore be assumed that etiologic factors such as alcohol abuse and gallstone disease lead to a functional rather than a structural acinar cell damage, which results in a sudden and uncontrolled release of digestive enzymes from the acinar cells into the adjacent interstitial tissue [20]. It is possible that among the released proenzymes lipase plays an important role, because it is one of the few pancreatic enzymes that does not require activation [21,22] and may therefore directly cause the liquefaction necrosis of interstitial fat cells. Whether fat necrosis depends on the action of lipase alone or the combined action of lipase plus other enzymes, such as phospholipase A2, is not known, but it is likely that several proenzymes as well as cytokines become activated by fat- cell necrosis and may then help to destroy adjacent tissues and trigger the inflammatory process that determines the severity of the clinical course.

Another pathophysiologic theory related to the fat necrosis pattern, which rests on the frequent association of gallstone disease with pancreatitis, is the duct obstruction–bile reflux theory (based on Opie’s common channel theory)[23]. It postulates that temporary obstruction of the common bile duct and the main pancreatic duct by a gallstone (or tumor tissue or inspissated secretions as in cystic fibrosis)[24] causes increased intraductal pressure and/or ampullary incontinence, with duodenopancreatic and bile reflux. This in turn activates pancreatic proenzymes, which leak from small ducts into the interstitial space. However, despite the obvious clinical

association between gallstone migration and pancreatitis, definite functional and histologic proof of the ductalobstruction pathogenesis is, thus far, lacking in human acute pancreatitis.

Acute pancreatitis with necrosis of the duct epithelium is associated with prolonged circulatory failure. In this case the tissue hypoxia in the pancreas seems to injure especially the medium- sized interlobular ducts and cause its necrosis. In addition, there could be an autoactivation of trypsinogen within the duct lumen, as the ducts are found to be filled with dense pancreatic secretions and neutrophil granulocytes [14]. This could be due to a stasis of pancreatic juice, which became viscous and sluggish because of a general slowdown of secretory processes in the exocrine pancreas, because of a severe circulatory failure. Since we saw a comparable picture in a case of familial pancreatitis, it may be speculated that a similar duct damage as in prolonged circulatory failure may occur due to mutation- related changes of the trypsinogen molecule (e.g., by PRSS1 mutations) allowing its uncontrolled premature activation[25].

In acute pancreatitis with acinar cell necrosis and without any significant autodigestive interstitial necrosis, there seems to be a direct cytotoxic damage to the acinar cells by microorganism such as mumps virus or bacterial agents.

Unsolved Questions

There are several unsolved questions in acute pancreatitis, but the most important one concerns its pathogenesis and pathophysiology. It is not known how etiologic factors such as alcohol abuse, gallstone disease, hypercalcemia, or circulatory failure lead to premature digestion in the pancreas. Moreover, the pathophysiologic concepts currently discussed usually refer to experimental pancreatitis models [18,26,27]. Although these models have markedly improved our knowledge on pathogenetic mechanisms in acute pancreatitis, it must be emphasized that none of these models is fully comparable to what is seen in humans.

Another question that is still to be solved relates to the severity of acute pancreatitis. It is not yet known which factors govern the mechanisms that decide the extent of autodigestion and thus lead either to a mild or severe course of the disease.

A final question is how the criteria that define the Atlanta 2012 classification[1] and are solely based on radiologic[6] and clinical features relate to the morphologic findings in acute pancreatitis? Table17.1 therefore tries to summarize and correlate the most important criteria of the Atlanta 2012 classification with the histopathologic changes that can be seen in conventional acute pancreatitis.

References

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1 Banks PA, Bollen TL, Dervenis C etal. Classification of

acute pancreatitis-

- 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013;62(1):102–111.

2 Bradley EL, 3rd. A clinically based classification system for

acute pancreatitis: summary of the international symposium on acute pancreatitis, Atlanta 1992. Arch Surg 1993;128:586–590.

3 Klöppel G. Acute pancreatitis. Semin Diagn Pathol

2004;21:221–226.

4 Klöppel G. Pathology of severe acute pancreatitis. In:

Bradley EL, ed. Acute Pancreatitis: Diagnosis and Therapy. NewYork: Raven Press, 1994: 35–46.

5 Klöppel G, von Gerkan R, Dreyer T. Pathomorphology of

acute pancreatitis. Analysis of 367 autopsy cases and 3 surgical specimens. In: Gyr KE, Singer MV, Sarles H, eds. Pancreatitis—

Concepts and Classification. Amsterdam:

Elsevier, 1984: 29–35.

6 Murphy KP, O’Connor OJ, Maher MM. Updated imaging

nomenclature for acute pancreatitis. Am J Roentgenol 2014;203(5):W464–469.

7 Sugawa G, Walt AJ. Endoscopic retrograde

pancreatography in the surgery of pancreatic pseudocysts. Surgery 1979;86:639–647.

8 Traverso LW, Tomkins RK, Urrea PT, Longmire WP.

Surgical treatment of chronic pancreatitis: twenty-

two

years’ experience. Ann Surg 1979;190:312–317.

9 Detlefsen S, Sipos B, Feyerabend B, Klöppel G.

Fibrogenesis in alcoholic chronic pancreatitis: the role of tissue necrosis, macrophages, myofibroblasts and cytokines. Mod Pathol 2006;19:1019–1026.

10 Klöppel G, Maillet B. Chronic pancreatitis: evolution of

the disease. Hepato-

11 Klöppel G, Maillet B. The morphological basis for the

Gastroenterology 1991;38(5):408–412.

evolution of acute pancreatitis into chronic pancreatitis. Virchows Arch [A] Pathol Anat 1992;420:1–4.

12 Ammann RW, Muellhaupt B. Progression of alcoholic

acute to chronic pancreatitis. Gut 1994;35:552–556.

13 Ammann RW, Heitz PU, Klöppel G. Course of alcoholic

chronic pancreatitis: a prospective clinicomorphological long- term study. Gastroenterology 1996;111(1):224–231.

14 Foulis AK. Histological evidence of initiating factors in

acute necrotising pancreatitis in man. J Clin Pathol 1980;33:1125–1131.

15 Kimura W, Ohtsubo K. Clinical and pathological features

of acute interstitial pancreatitis in the aged. Int J Pancreatol 1989;5:1–9.

16 Klöppel G, Detlefsen S, Feyerabend B. Fibrosis of the

pancreas: the initial tissue damage and the resulting pattern. Virchows Arch 2004;445:1–8.

17 Howard JM, Howard J, Idezuki Y, Ihse I, Prinz R. The

broad spectrum of pancreatitis, with etiologic considerations: a clinical overview from around the world. Surgical Diseases of the Pancreas, Vol. 3. Baltimore, MD: Williams & Wilkins, 1998: 157–197.

18 Bialek R, Willemer S, Arnold R, Adler G. Evidence of

intracellular activation of serine proteases in acute cerulein-

induced pancreatitis in rats. Scand J

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19 Steer ML, Perides G. Pathogenesis: how does acute

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Muñoz JE, ed. Clinical Pancreatology for Practising Gastroenterologists and Surgeons. Malden, MA: Blackwell, 2005: 10–26.

20 Klöppel G, Dreyer T, Willemer S, Kern HF, Adler G.

Human acute pancreatitis: its pathogenesis in the light of immunocytochemical and ultrastructural findings in acinar cells. Virchows Arch [A] Pathol Anat 1986;409:791–803.

21 Schmitz- Moormann P, Wedel RV, Agricola B,

Himmelmann GW. Studies of lipase induced fat necrosis in rats. Pathol Res Pract 1978;163:93–108.

22 Creutzfeldt W, Schmidt H, Bockus HL. Etiology and

pathogenesis of pancreatitis. In: Gastroenterology, Vol. 3. Philadelphia: Saunders, 1976: 1005–1019.

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pancreas and to fat necrosis. Am J Med Sci 1901;121:27–43.

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pathogenesis of acute biliary pancreatitis. Surgery 1980;88:118–25.

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how does acute pancreatitis develop? In: Clinical Pancreatology for Practising Gastroenterologists and Surgeons. Malden, MA: Blackwell, 2005: 10–26.

27 Buchholz I, Nagel F, Klein AP etal. The impact of

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170

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Severity Classification ofAcute Pancreatitis

John A. Windsor

Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand

Introduction

The accurate classification of acute pancreatitis severity is important because it will “improve communication and advance our understanding of the disease and its management” [1]. When specific treatments become available for clinical trials in acute pancreatitis “an inclusive clinical classification system will assume increasing importance” [2]. Systems for classifying severity will continue to evolve with new scientific knowledge and for this reason they are best considered “working” classifications. The aim of this chapter is to outline the reasons for classifying severity, review the systems currently available, and identify aspects for further improvement.

Reasons forClassifying theSeverity ofAcute Pancreatitis

Classification systems are valuable in clinical and research settings, to assist communication between clinicians, patient monitoring and allocation to clinical studies, auditing of clinical outcomes, and comparison between centres (Table18.1). Some of these reasons are best met by predicting severity, rather than by classifying severity, although these are sometimes confused[3– 5]. When the ultimate disease severity needs to be anticipated ahead of time, prediction of severity is required. When the severity needs to be defined at a particular time point, classification of severity is required. In this way prediction is about the future and classification is about the present and the past. Prediction is usually required early in the disease course, whereas classification can be useful at any time during the disease course.

Severity Classification Systems

The first severity classification system for acute pancreatitis was published in 1983 [6], followed by the widely used original Atlanta classification in 1993 [7], which was a clinically based classification system that defined a binary approach: mild and severe disease. While there has never been difficulty in identifying patients with mild and uncomplicated acute pancreatitis, this is not so for severe disease. Nor is it so for patients with non- mild acute pancreatitis who represent a heterogenous group with varying severity and outcomes that were not captured by the original Atlanta classification.

Two systems for classifying the severity of acute pancreatitis were introduced about a decade ago and have replaced the original Atlanta classification (Table18.2): the “determinant- based classification” (DBC) in 2012 with four categories of severity [8] and the “revised Atlanta classification” (RAC) in 2013with three grades of severity[9]. It has been suggested that DBC and RAC are “equivalent” and “comparable and complementary”[3,4], but there a “few differences”[10] worth noting (Table18.3). There have also been questions about which is the more valid, which has higher utility, and which should be used [11]. A number of studies have compared the validity of the DBC and RAC classification systems (Table18.4). Most of the studies have been from single tertiary centers and subject to selection bias.

The DBC defines severe AP on the basis of either persistent organ failure (without infected pancreatic necrosis) or infected pancreatic necrosis (without persistent organ failure). The RAC defines severe AP on the basis of persistent organ failure alone, with infected pancreatic necrosis a diagnostic criterion for the moderately severe grade[9]. The explanation given for this was that “infected necrosis without persistent organ failure . .. has a lesser

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

Approach toSeverity Classification Depends onthe Setting 171

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Table18.1 The reasons forclassifying theseverity ofacute

pancreatitis.

Related to clinical decision-

Related to research decision-

Denotes reason that is more appropriate for prediction than

classification systems.

Table18.2 Classifications forthe severity ofacute pancreatitis.

Determinant- based classification[8]

Mild No (peri)pancreatic necrosis and no

Moderate Sterile (peri)pancreatic necrosis and/or

Severe Infected (peri)pancreatic necrosis or

Critical Infected (peri)pancreatic necrosis and

Revised Atlanta classification[9]

Mild No organ failure and no local or

Moderately Severe transient organ failure and/or

Severe Persistent organ failure (single or

making

Triage of patients regarding initial treatment intensity

Transfer of patients to specialist unit or intensive care

Tracking trajectory of patient’s clinical course

Treatment (e.g., ERCP, enteral nutrition)

Audit of outcome

Allocation of patients to trial arm

Analysis of interventions

organ failure

transient organ failure

persistent organ failure

systemic complications

local or systemic complications or exacerbations of preexisting comorbidities

multiple)

Table18.3 Key differences between theDBC andRAC

classification systems.

Severity classification

systems

DBC

Criteria

Exacerbation of comorbid disease Not

Infected (peri)pancreatic necrosis without persistent organ failure

Infected (peri)pancreatic necrosis with persistent organ failure

DBC: determinant- based classification; RAC: revised Atlanta classification.

category RAC grade

included

Severe Moderately

Critical Severe

Moderately severe

severe

Given the significant advances in the management of infected pancreatic necrosis, fueled by technology developments and the seminal randomized trials from the Dutch Acute Pancreatitis group[22], it is reasonable to ask how important infected necrosis still is as a determinant of mortality. Open necrosectomy, which is responsible for new-

onset organ failure and increased mortality, has been superseded by the “step- up approach.” The original meta- analysis [14] has recently been repeated using data from the modern era and it has confirmed that infected pancreatic necrosis has become less important as a determinant of mortality (publication pending). This change has virtually abolished the second peak of the bimodal mortality curve, which was previously attributed to infected pancreatic necrosis [23]. In the nationwide prospective cohort study from 26 hospitals in Spain it was found that infected pancreatic necrosis correlated with high morbidity and had a mortality comparable to sterile necrotizing pancreatitis[24].

mortality rate than infected necrosis with persistent organ failure.” Thus, the principle difference between the DBC and RAC is the importance attributed to infected pancreatic necrosis. In some studies patients with infected pancreatic necrosis without persistent organ failure have been shown to have a similar outcome to those with severe acute pancreatitis [12,13]. These findings are consistent with the meta- analysis of 14 studies which was the basis for the DBC[14]. This demonstrated that infected (peri)pancreatic necrosis and persistent organ failure were independent and virtually equivalent determinants of mortality. It was for this reason that the DBC included infection of pancreatic necrosis in the severe category.

Approach toSeverity Classification Depends onthe Setting

In a peripheral hospital the incidence of severe and critical acute pancreatitis is low and the fundamental clinical decision is whether the patient is going to develop sufficiently severe acute pancreatitis to warrant transfer to a tertiary center. In this setting a binary classification system (non- severe vs. severe) might well suffice. In a tertiary center the requirements are different and the incidence of severe and critical acute pancreatitis higher. In this setting there is value in having more than two categories of severity. With different

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Table18.4 Studies that compared thedeterminant- based classification (DBC) andrevised Atlanta classification (RAC) systems fromthe

same dataset.

Ref Setting Study design Key findings

Nawaz (2013) 3 Tertiary (SC)

Acevedo-

Chen (2015) 15 Tertiary (SC)

Mircea (2015) 16 Tertiary (SC)

Xu (2015) 17 Tertiary (SC)

Guo (2105) 18 Tertiary (SC)

Kadiyala (2016) 4 Tertiary (SC)

Bansal (2016) 19 Tertiary (SC)

Fernandes (2016) 20 Tertiary (SC)

Zubia(2016)

Piedra (2014) 12 Tertiary (SC)

Olaskoaga

Pittsburgh

Spain

Nanjing

Bucharest

Lanzhou

Chengdu

Boston

Birmingham

Portugal

21 Tertiary (MC)

Spain etc.

Retrospective (prospective database)

Retrospective Similar for clinical outcomes, although RAC has slight

Retrospective Similar distribution and outcomes. Recommended

Prospective No significant difference between RAC and DBC.

Retrospective (prospective database)

Retrospective RAC and DBC were similar for outcomes

Prospective observational

DBC and RAC comparable for predicting ICU admission, ICU length of stay, and mortality. The RAC was better at predicting hospital stay and DBC better for predicting the need for intervention

No significant differences in the distribution and outcomes between the two classifications, but very low incidence of severe and critical categories

RAC and DBC comparable in relation to longclinical prognosis, major complications, and clinical interventions. Critical category very high risk and distinct from severe category in DBC

advantage for hospital length of stay and DBC for ICU admission and length of stay. DBC easier to use

combining RAC and DBC

Mortality similar and distribution of severity marginally different

The RAC and DBC were essentially equivalent in predicting mortality, need for admission to the ICU, ICU length of stay, and hospital length of stay. Paucity of critical category, limited utility. Neither classification accounts for multisystem persistent organ failure, the strongest predictor of mortality

The RAC and DBC perform equally well. DBC critical category associated with doubled mortality risk, ICU stay and need for drainage or surgery greater than RAC, with definite implications for prognosis

Proposed a modified DBC for only ICU patients. Superior to DBC and RAC for mortality. Similar to DBC for morbidity and superior to RAC. Severe DBC category separated into two groups: transient organ failure with infected local complications and persistent organ failure and no infected local complications

term

ICU: intensive care unit.

treatment options available there is the need to accurately allocate patients to research arms and to tailor treatments to individual patients, it is desirable to have distinct and homogeneous patient subgroups to study and treat. For instance, if there were a new treatment for organ failure to be tested it would confound interpretation of outcomes if all patients were included with organ failure, even if this contained those who would respond promptly (e.g., transient organ failure), those who might not respond (e.g., persistent organ failure), and those who cannot respond (e.g., no organ failure).

Further, if the purpose of a treatment were to reverse established organ failure it would be necessary to exclude patients with transient organ failure. If the purpose were to prevent the development of persistent organ failure it would be necessary to include patients with transient organ failure. These examples indicate that while a binary classification is probably sufficient for those in primary and secondary care settings, more categories are required in the tertiary setting. Tailoring the severity classification needs to be tested, particularly in the secondary setting.

Conclusions 173

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Table18.5 Modified determinant- based classification (DBC) system for patients admitted to intensive care with organ failure[21]. Note

that patients with mild acute pancreatitis are not included. Source: Adapted from [21].

Parameters

Group Organ failure Infected necrosis Mortality Intensive care LOS Interventions

1 TOF No 2% Short −

2 TOF Ye s 6.6% Long +

3 POF No 41% Short −

4 POF Ye s 59% Long +

TOF: transient organ failure; POF: persistent organ failure; LOS: length of stay.

The use of severity classification has also been studied in the intensive care unit setting. In 2016 a modified DBC was recommended following a large prospective study involving 46intensive care units [21] and subsequently validated [25,26]. Four groups were defined (Table 18.5), with mild acute pancreatitis excluded as these patients are not admitted to ICU. These studies provide compelling evidence that the severe category of AP, as defined by the DBC, represents two distinct subgroups. Patients with local complications (infected pancreatic necrosis, abdominal hemorrhage, and intestinal perforation), but without persistent organ failure (“group2”) have a high morbidity but low mortality. In contrast, patients with persistent organ failure but without local complications (“group3”) have a high mortality but relatively low morbidity.

These studies also confirmed that patients with critical acute pancreatitis (“group4”) had a clinically and statistically different clinical course in regard to morbidity and mortality. Others have questioned the utility of this category because of its relatively infrequency[4], while in other series it is associated with a significantly higher mortality and is endorsed[13,19,26]. The critical category has more clinical relevance in the ICU setting[27] (31% of patients with 54% mortality)[25] than in the tertiary hospital setting (1% of patients with 61% mortality) [26]. In the Spanish study [21] only 2.2% (37/1655) had critical AP but a mortality of 54%, compared with 39% with a mortality of 5.8% (97/1655) for severe AP. The time to oral feeding (median 24.2 vs.

9.4days), need for invasive treatment (100 vs. 39.2%), admission to intensive care unit (97.3 vs. 53.6%), and hospital stay (median 88 vs. 34.2days) were all significantly increased in patients with critical acute pancreatitis.

While the setting is important in regard to the approach to severity classification, there are other factors that might be considered including the quality of the evidence base, method used for development, the validity and ease of use.

Future Developments

The differences between classification systems represent an opportunity for further improvement, and some research priorities have been published[29]. In the editorial accompanying the DBC publication it was pointed out that there are severity determinants other than infected pancreatic necrosis and organ failure, including obesity, diabetes, and genetic predisposition, and if incorporated might have improved the DBC [2]. All three classifications (DBC, RAC, and modified DBC) fail to account for patients with “early severe” acute pancreatitis and organ failure on admission, which is a particularly challenging subgroup with a high mortality risk[30–33]. This suggests that the timing of the onset of organ failure might be factored into an improved classification system [34]. Incorporating different aspects of organ dysfunction/failure may also help, including the duration, number, combination, and sequence of the organs affected [35]. Data on these dimensions may allow more accurate classification of patients with severe and critical acute pancreatitis. Increased stratification, beyond the four categories of the modified DBC, has been suggested because of the multiple therapeutic goals (in addition to reducing mortality) and the desire to personalize treatment[36]. A “two- step approach” that distinguishes single and multiple persistent organ failure and includes 13 severity categories has been reported and requires prospective validation. Further improvements in severity classification might go beyond these clinically defined determinants to incorporate biomarkers that more accurately define severity.

Conclusions

Classifying the severity of acute pancreatitis is important for the clinical care of patients and for research purposes. The RAC and DBC have been in use for over a decade, we know they perform reasonably well. We

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also know that predicting (and not classifying) the severity of acute pancreatitis is required in the community and secondary care settings because the key decision is whether a patient needs to be transferred or not. In the tertiary setting, especially in the ICU setting, the modified DBC should become the preferred approach, noting that it would be helpful to move away from numbered groups to clinical descriptors (e.g., 0 = mild, 1 = moderate, 2 = moderately severe, 3 = severe, and 4 = critical)[21]. These are clinically distinct subgroups of patients which when classified accurately will improve the delivery of care to these patients and the study design for testing new treatments. Advances in the care of patients with acute pancreatitis will require

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improvements on current methods for classifying severity. Ultimately, these improvements will come from the discovery of early biomarkers of severity that accurately reflect the key real- time changes in the pancreas and distant organs. For now, we are reliant on clinical indicators related to the presence of organ failure and infected local complications for the RAC, DBC, and modified DBC. The differences between the classifications provide opportunities for further research to improve the accuracy and utility of severity classification. This includes determining how best to tailor severity classification to setting (e.g., secondary or tertiary hospital) and purpose (e.g., clinical management or research).

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Clinical Assessment andBiochemical Markers toObjectify Severity andPrognosis

Bettina M. Rau1 and Claus Schäfer

Department of General, Visceral, and Thoracic Surgery, Hospital of Neumarkt, Neumarkt in der Oberpfalz, Germany

Department of Internal Medicine II, Hospital of Neumarkt, Neumarkt in der Oberpfalz, Germany

Introduction

Among the inflammatory digestive disorders acute pancreatitis continues to challenge physicians as the least and most difficult one to predict in terms of clinical course and outcome. Ever since the first classification system of acute pancreatitis was established in Marseille in 1965 [1] the definition of “severe” disease has been linked to disease- specific complications with an increased risk of mortality [2–5]. Stratification of severity is required for targeting individual patients for interventions against evolving complications or for referral to specialist centers on the one hand and for comparing patients for scientific purposes or recruitment into clinical trials, on the other. The type and clinical relevance of a complication rendering the course of acute pancreatitis as “severe” has been the subject of continuous development and changes. New insights into pathomechanism and natural course of acute pancreatitis, development of laboratory variables and diagnostic imaging procedures as well as novel therapeutic approaches have strongly influenced definitions and classification systems and continue to do so.

Historical Perspectives: Approaches toSeverity Assessment

Attempts to stratify severity and prognosis date back to the second half of the last century and have been driven by major advances in new imaging procedures and laboratory tests. The development of serum amylase measurement in 1929[6] w as the first step toward a non invas ive diagnosis of acute pancreatitis and subsequently showed

that in the majority of patients a mild course with uneventful recovery was the rule rather than the exception. Supported by the development of intensive care treatment and more restrictive indications for surgical treatment in patients with clinically severe disease, interest in prognostic assessment has gained considerable headway since the 1960s. Attempts to define objective criteria for assessing disease severity and prognosis were pioneered by John Ranson in NewYork[7] and Clement Imrie in Glasgow[8] in the 1970s, which found widespread application in the pancreatic community.

During the early 1980s intraoperative findings revealed

morphological features such as presence and extent

localof necrosis[9,10] and infection of necrosis [11) showing an excellent correlation with systemic severity and outcome. Flanked by the introduction of contrast- enhanced computed tomography (CE- CT) and percutaneous guided fine- needle- aspiration (FNA) nonoperative assessment of these complications became possible and assigned morphology- based severity stratification a predominant role. Hence, imaging procedures have become indispensable for assessment of severity in acute pancreatitis and an integral part of new classification systems[2–4] and treatment algorithms[5,12–16] alike.

After almost two decades of mainly morphology-

based severity stratification the role of systemic aspects in terms of onset, severity, and persistence of pancreatitisrelated organ failure was recognized as a central determinant of severity [17–29]. Moreover, early and persisting multiorgan dysfunction syndrome (MODS) has been found to outweigh morphological factors such as necrosis and even infection of necrosis as far as nonsurvival is concerned[20,29].

Dynamics ofOrgan Failure 177

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Dynamics ofOrgan Failure

The prognostic role of early pancreatitis- associated organ failure was already recognized during the early 1970s. Objective measurement of pulmonary failure by arterial oxygen pressure or renal failure by serum creatinine had become available and had been integrated into prognostic multiparameter scoring systems according to Ranson[7] and Imrie[8]. However, it took another three decades until pancreatologists realized that the occurrence of a temporary single organ failure does not necessarily indicate a life- threatening disease. Specific aspects such as onset, severity, and persistence of organ failure have gained special attention in the past two decades.

Early Organ Failure

The role of “early” organ failure, defined as failure of one or more organ systems within the first 3days after onset of acute pancreatitis/hospital admission was first described by Isenmann etal. in 2001[17]. The presence of “early” single or multiple organ failure leads to a significant increase in mortality up to 56% irrespective of whether necrosis is sterile or infected [17–19,21,22]. Early multiple organ failure represents an important risk

factor for death and even seems to outweigh local morphological complications such as extent or infection of necrosis[20,29].

Persistent Organ Failure

The dynamics of organ failure in terms of response/resolution or nonresponse/persistence despite intensive care treatment has been identified as another major determinant of complications and death. In many pro- and retrospective studies resolution of organ failure within the first week of the disease resulted in mortality rates close to zero, whereas mortality rates rose to 55% if organ failure persisted beyond the first week[22–25,27]. Moreover, organ failure nonresponding to intensive care treatment closely correlates with the development of pancreatic infections and death[26,28,29].

There is little doubt that organ failure is one of the most important determinants of prognosis and mortality in acute pancreatitis. The revised Atlanta classification of 2012 [3] and the international multidisciplinary “Determinant- based classification” of 2012[4]) therefore defined organ failure as a central criterion to differentiate up to four severity groups of acute pancreatitis (Table19.1).

Table19.1 (a) Definition of three grades of severity in acute pancreatitis according to the

revised Atlanta classification 2012. Source:[3]/BMJ Publishing Group Ltd.

* Mild acute pancreatitis: ● no organ failure

● no local or systemic complications

* Moderately severe acute pancreatitis:

* Severe acute pancreatitis: persistent organ failure >48 h

(b) Definition of four grades of severity in acute pancreatitis according to the “Determinant- based classification” 2012. Source: Adapted from[4].

* Mild acute pancreatitis:

* Moderate acute pancreatitis:

* Severe acute pancreatitis:

* Critical acute pancreatitis:

● organ failure that resolves within 48 h

(transient organ failure)

and/or

● local or systemic complications

without persistent organ failure

● single organ failure

● multiple organ failure

● no organ failure

● no peri- /intrapancreatic necrosis

● organ failure that resolves within 48 h

(transient organ failure)

and/or

● sterile peri- /intrapancreatic necrosis

● persistent organ failure >48 h

● infected peri- /intrapancreatic necrosis

● persistent organ failure >48 h

and

● infected peri- /intrapancreatic necrosis

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