1. Classification of Acute Pancreatitis Andrzej Dąbrowski Andrzej Dąbrowski Department of Gastroenterology and Internal Medicine Medical University of Bialystok, Poland

2. Why do we need good AP classification? To improve clinical assessment of the AP To facilitate communication between treating physicians (uniformity) For better reporting of clinical studies (common platform for research)

3. Introduction – historical view Pannala R et al. Pancreas 2009, 38, 355 Nicholaes Tulp (1593-1674) of Amsterdam is credited with the first description (1652) of acute pancreatitis.

4. Introduction – historical view Pannala R et al. Pancreas 2009, 38, 355 Reginald Fitz in 1889 described 3 forms of acute pancreatitis (hemorrhagic, suppurative, and gangrenous) and proposed that fat necrosis was a sequel of severe pancreatitis

5. Introduction – historical view Frey CF, Pancreas 1986, 1, 62 1942 – Lagerlof classified pancreatitis as acute and chronic based on clinical, functional, and pathologic observations from autopsy and operative findings. Beginning in 1955, Joske, then Janowitz in 1957, Howard in 1960, and Dreiling in 1964 developed a comprehensive classification system of pancreatitis based on etiologic factors. Blumenthal and Probstein in 1959 provided a classification system based on etiology in which they then categorized 163 patients from clinical and autopsy criteria. 1963 - Marseille Classification of pancreatitis I.Acute pancreatitis II.Recurretnt acute pancreatitis III.Recurrent chronic pancreatitis IV.Chronic pancreatitis 1983 – Cambridge classification 1984 – the second Marseille symposium

6. Introduction – historical view Frey CF, Pancreas 1986, 1, 62 1983 – Cambridge classification The Cambridge group defined the severity and complications of acute pancreatitis. An attack of acute pancreatitis was defined as “mild” if there was no multisystem failure and “severe” if multisystem failure occurred and/or there were early or late, local or systemic complications. The complications identified for definition were (a) phlegmon, an inflammatory mass in and around the pancreas; (b) pseudocyst, a localized collection of fluid containing high concentrations of pancreatic enzymes within, adjacent to, or remote from the pancreas: and (c) abscess, pus in or around the pancreas.

7. Atlanta classification (1992) Bradley EL III, Arch Surg 1993, 128, 586 Definition Acute pancreatitis (AP) An acute inflammatory process of the pancreas with variable involvement of other regional tissues or remote organ systems Associated with raised pancreatic enzyme levels in blood and/or urine Severity Mild APAssociated with minimal organ dysfunction and an uneventful recovery; lacks the features of severe acute pancreatitis. Usually normal enhancement of pancreatic parenchyma on contrast-enhanced computed tomography Severe APAssociated with organ failure and/or local complications such as necrosis, abscess or pseudocyst Predicted severity Ranson score ≥3 or APACHE II score ≥8

8. Atlanta classification (1992) Bradley EL III, Arch Surg 1993, 128, 586 Definition Organ failure and systemic complications ShockSystolic blood pressure < 90 mmHg Pulmonary insufficiency Pa O 2 ≤60 mmHg Renal failureCreatinine ≥177 µmol/l or ≤2 mg/dl after rehydration Gastrointestinal bleeding 500 ml in 24 h Disseminated intravascular coagulation Platelets ≤100, 000/mm 3, fibrinogen 80 µg/l Severe metabolic disturbances Calcium ≤1·87 mmol/l or ≤7·5 mg/dl

9. Atlanta classification (1992) Bradley EL III, Arch Surg 1993, 128, 586 Definition Local complications Acute fluid collections Occur early in the course of acute pancreatitis, are located in or near the pancreas and always lack a wall of granulation of fibrous tissue. In about half of patients, spontaneous regression occurs. In the other half, an acute fluid collection develops into a pancreatic abscess or pseudocyst Pancreatic necrosis Diffuse or focal area(s) of non-viable pancreatic parenchyma, typically associated with peripancreatic fat necrosis Non-enhanced pancreatic parenchyma > 3 cm or involving more than 30% of the area of the pancreas

10. Atlanta classification (1992) Bradley EL III, Arch Surg 1993, 128, 586 Definition Local complications Acute pseudocyst Collection of pancreatic juice enclosed by a wall of fibrous or granulation tissue, which arises as a result of acute pancreatitis, pancreatic trauma or chronic pancreatitis, occurring at least 4 weeks after onset of symptoms, is round or ovoid and most often sterile; when pus is present, lesion is termed a pancreatic abscess Pancreatic abscess Circumscribed, intra-abdominal collection of pus, usually in proximity to the pancreas, containing little or no pancreatic necrosis, which arises as a consequence of acute pancreatitis or pancreatic trauma Often 4 weeks or more after onset Pancreatic abscess and infected pancreatic necrosis differ in clinical expression and extent of associated necrosis

11. Definitions for organ failure and predicted severe AP in guidelines published after 1993 GuidelineDefinitions for organ failure Definitions for severe AP UK 2005Refers to Atlanta Classification 1992 At admission Clinical assessment BMI > 30 kg/m 2 Pleural effusion APACHE score > 8 At 24-48 h Clinical assessment Glasgow score ≥3 APACHE II score > 8 Persistent organ failure for 48 h (especially if multiple and progressive) CRP > 150 mg/l Note: Organ failure present within 1 week, which resolves within 48 h, should not be considered an indicator of a severe attack of acute pancreatitis Bollen TL et al., Br J Surg 2008, 95, 6

12. Definitions for organ failure and predicted severe AP in guidelines published after 1993 GuidelineDefinitions for organ failure Definitions for severe AP ACG 2006Refers to Atlanta Classification 1992 Note: Criteria of organ failure will change in the future: gastrointestinal bleeding will undoubtedly be deleted At admission Age > 55 years BMI > 30 kg/m 2 Presence of organ failure Pleural effusion/infiltrates At 24-48 h APACHE II score ≥ 8 Serum hematocrit ≥ 44% Note: Ranson signs are no longer advocated, due to a comprehensive evaluation of 110 studies that concluded that Ranson signs provided very poor predictive power of severity of acute pancreatitis Bollen TL et al., Br J Surg 2008, 95, 6

13. Definitions of severe AP local complications need revision Bollen TL et al., Br J Surg 2008, 95, 6 Contrast-enhanced computed tomography (CT) of a patient with acute pancreatitis 30 days after onset of symptoms. The fluid collection seems to be homogeneous and encapsulated (white arrows) and could be interpreted as a pseudocyst according to the Atlanta Classification. However, at operation the collection was found to contain large amounts of necrotic debris that CT had not shown. Acute pseudocyst (Atlanta 1992) Collection of pancreatic juice enclosed by a wall of fibrous or granulation tissue, which arises as a result of acute pancreatitis, pancreatic trauma or chronic pancreatitis, occurring at least 4 weeks after onset of symptoms, is round or ovoid and most often sterile; when pus is present, lesion is termed a pancreatic abscess

14. CT findings in AP Besselink MGH et al, Pancreas 2006, 33, 331 The interobserver agreement of the Atlanta classification for categorizing peripancreatic collections in acute pancreatitis on CT is poor. The Atlanta classification should not be used to describe complications of acute pancreatitis on CT.

15. CT findings in AP Besselink MGH et al, Pancreas 2006, 33, 331 The use of the Atlanta classification on CT in necrotizing pancreatitis. A, Computed tomography scan 12 days after onset of disease. The definitions chosen for this collection were "pseudocyst" (n = 1), "pancreatic abscess" (n = 1), "pancreatic necrosis" (n = 1), and "mixture" (n = 2). B, Computed tomography scan 27 days after onset of disease. The definitions chosen for this collection were "pancreatic abscess" (n = 3) and "mixture" (n = 2). C, Computed tomography scan 31 days after onset of disease. The definitions chosen were "pancreatic necrosis" (n = 1), "pancreatic abscess" (n = 1), "pseudocyst" (n = 1), and "mixture" (n = 2).

16. Need for the revision Although the Atlanta Classification has proved useful over the following 16 years, many of the definitions proved confusing (used inconsistently) and have not been accepted or utilized by the pancreatic community (pancreatic gastroenterologists, surgeons, and radiologists).

17. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf DEFINITION OF ACUTE PANCREATITIS The clinical definition of AP, whether in the presence or absence of underlying chronic pancreatitis, requires two of the following three features: 1) abdominal pain suggestive strongly of AP, 2) serum amylase and/or lipase activity at least 3 times greater than the upper limit of normal, and 3) characteristic findings of acute pancreatitis on transabdominal ultrasonography or on CECT, which is considered to be the best, most universally available imaging modality.

18. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf CLINICAL CLASSIFICATION (1st week) DEFINITION OF SEVERITY OF ACUTE PANCREATITIS The definition of the severity of acute pancreatitis (during the first week) is based on clinical rather than morphologic parameters (thereafter; over the first week). Initially at presentation and over the first 48 hours, patients should be classified temporarily as having severe acute pancreatitis based on the presence of the persistent systemic inflammatory response syndrome (SIRS) and/or developing organ failure. Several potential risk factors of severity and measurements related to the acute pancreatitis that may reflect severity should be recorded ideally and evaluated prospectively, including age, BMI, hematocrit, APACHE II scores, and serum levels of C-reactive protein. It should be stressed that serum amylase and lipase activities, while important in the diagnosis of “acute pancreatitis,” are not of any clinical importance in defining the severity of acute pancreatitis.

19. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf O VER THE F IRST W EEK Over the first week, the distinction between non-severe old term: mild and severe acute pancreatitis depends ultimately on the development of organ failure. Non-severe acute pancreatitis is defined as the absence of organ failure or the presence of organ failure that does not exceed 48 hours in duration. The definition of severe acute pancreatitis is the persistence of organ failure that exceeds 48 hours duration (i.e., organ failure recorded at least once during each of three consecutive days). OF>48 hrsSevere AP

20. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf DEFINITION OF ORGAN FAILURE Three organ systems should be assessed to define organ failure: respiratory, cardiovascular, and renal. Organ failure is best and most easily defined in accordance with the Marshall scoring system as a score ≥2 for at least one of these three organ systems: respiratory (pO2/FIO2); renal (serum creatinine in μmol/l or mg/dl); and cardiovascular (systolic blood pressure in mm Hg). Multi-system organ failure is defined as two or more organs failing over the same 2- to 3-day period.

21. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf Marshall Scoring System FIO2 = fraction of inspired oxygen

22. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf MORPHOLOGIC IMAGING-BASED CLASSIFICATION (used AFTER the first week) This new classification proposes the use of morphologic CECT criteria to diagnose the specific type of acute pancreatitis: Acute interstitial edematous pancreatitis (IEP) Acute necrotizing pancreatitis. A.Presence/absence and site(s) of necrosis, 3 subtypes: normal pancreatic parenchyma enhancement with peripancreatic fluid collections (fat necrosis) one or more focal areas of nonenhancing pancreatic parenchyma with peripancreatic fluid collections without peripancreatic fluid collections B. Evidence for the presence/absence of infection (FNA, gas within nonenhancing retroperitoneal tissue)

23. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf NECROTIZING PANCREATITIS Pancreatic Parenchyma: About 80% of patients with necrotizing pancreatitis have a variable extent of pancreatic parenchymal necrosis on CECT. The extent of necrosis is quantified in three categories: 50% of the total pancreatic parenchyma. The presence of pancreatic parenchymal non-enhancement differentiates necrotizing pancreatitis from IEP. gland enlargement on CECT minimal diffuse localized

24. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf NECROTIZING PANCREATITIS Peripancreatic Tissues: The presence or absence of necrosis in the peripancreatic tissues is more difficult to evaluate by CECT, especially early in the course of the disease. While the presence or absence of necrosis in the peripancreatic tissues is not always possible to diagnose definitively with CECT, CECT may suggest the presence of peripancreatic necrosis by the presence of “thickening” of the paracolic gutters and of the base of the small bowel mesentery, fat stranding and involvement of the anterior pararenal spaces, or especially the presence of non-homogeneous fluid collections containing solid components in one or more areas.

25. Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf Characteristics of Necrosis: The relative amount of liquid vs semi-solid components within areas of necrosis varies with the time since onset of necrotizing pancreatitis. As time evolves, the initially solid necrosis liquefies by a process of liquefaction necrosis. Complete resolution of necrosis (weeks to months later) may occur through liquefaction necrosis and eventual reabsorption of the liquefaction. In some patients, complete reabsorption may never occur. If resorption does not take place, the area of liquefaction necrosis may persist as an area of walled-off pancreatic necrosis (WOPN; organized necrosis, necroma, or pancreatic sequestration) without symptoms or may cause pain or mechanical obstruction of the duodenum and/or bile duct. solid necrosis <1 week semi-solid necrosis (PNPFC) >4 weeks liquefied necrosis (WOPN) liquefaction (no resorption)

26. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf NECROTIZING PANCREATITIS Infection: Depending on the stage of the necrosis (primarily solid, semi-solid, or liquefaction) and the organism(s) involved, the infected necrosis will have varying amounts of suppuration (pus). In the later stages of infected necrosis, the content may be predominantly pus (in addition to some solid components) as the process of liquefaction necrosis matures. “Pancreatic abscess” according to the Atlanta Classification in 1992 is a “localized collection of purulent material without significant necrotic material;” most agree that the latter Atlanta definition of “pancreatic abscess” is an exceedingly uncommon finding in necrotizing pancreatitis. The current imaging-based classification does not use the term “pancreatic abscess” in order to avoid this confusion.

27. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf Both acute IEP and necrotizing pancreatitis can be associated with PANCREATIC AND PERIPANCREATIC FLUID COLLECTIONS

28. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf ACUTE PERIPANCREATIC FLUID COLLECTIONS (APFCs) (1st 4 weeks after onset of IEP) a. Sterile b. Infected These fluid collections arise in patients with IEP, have no solid components, and result from parenchymal and/or peripancreatic inflammation in the absence of necrosis. Resolve spontaneously within 6 weeks 40%, 80% if <6 cm; communication with pancreatic duct seen in 70%. They exist predominantly adjacent to the pancreas, have no definable wall, and are confined by the normal peripancreatic fascial planes, primarily the anterior pararenal fascia. APFCs arise presumably from rupture of the main duct or a small peripheral pancreatic ductal side branch or they result from local edema related to the pancreatic inflammation and have no connection with the ductal system. Old term: acute fluid collections

29. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf POST-NECROTIC PANCREATIC/PERIPANCREATIC FLUID COLLECTIONS a. Sterile b. Infected Fluid collections arising in patients with acute necrotizing pancreatitis are termed PNPFCs to distinguish them from APFCs and pseudocysts. PNPFCs contain both fluid and necrotic contents to varying degrees. In PNPFCs, a continuum exists from the initial solid necrosis to liquefaction necrosis, depending on duration of the disease since onset. PNPFC may or may not have a connection with the pancreatic ductal system. Necrosis PNPFC (necrosis+fluid) WOPN (infected or sterile) late stage Old term: acute fluid collections

30. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf PANCREATIC PSEUDOCYST Non-infected Pseudocysts on CECT become defined >4 weeks after onset of pancreatitis as a well-circumscribed (clearly evident wall; capsule), usually round or oval, homogeneous fluid collection surrounded by a well- defined wall with no solid necrotic debris within the fluid collection. Pseudocysts develop from an APFC that persists for >4 weeks after onset of pancreatitis. Prior to 4 weeks, these collections are categorized as APFC. Old term: pancreatic pseudocyst

31. Revision of the Atlanta classification of AP Acute Pancreatitis Classification Working Group. Revision of the Atlanta classification of acute pancreatitis (3 rd revision). www. pancreasclub.com/resources/AtlantaClassification.pdf PANCREATIC PSEUDOCYST Infected (suppurative) Determination of presence or absence of infection in a pancreatic pseudocyst is also potentially important. An infected pancreatic pseudocyst contains purulent liquid without an associated solid component (necrosis). This definition differentiates pseudocyst from infected PNPFC and infected WOPN. As with all peripancreatic fluid collections, image-guided FNA with Gram stain and culture or the presence of extraluminal gas are necessary to confirm the pre-interventional diagnosis of infection. Old term: pancreatic abscess

33. Acute pancreatitis has been described for the first time by: A.Reginald Fitz B.David Dreiling C.Nicholaes Tulp D.Hippokrates of Kos What is the uncommon complication of acute pancreatitis: A.Respiratory B.Renal C.Cardiovascular D.Gastrointestinal bleeding The true statement about acute peripancreatic fluid collections is: A.Fluid collections arising in patients with acute necrotizing pancreatitis, but not in patients with acute interstitial edematous pancreatitis. B.Have no solid components, and result from parenchymal and/or peripancreatic inflammation in the absence of necrosis. C.Become defined >4 weeks after onset of pancreatitis as a well-circumscribed, usually round or oval, homogeneous fluid collection surrounded by a well-defined wall with no solid necrotic debris within the fluid collection. D.Contain both fluid and necrotic contents to varying degrees.