American Pancreatic Association Practice Guidelines in ... · American Pancreatic Association Practice Guidelines in Chronic Pancreatitis Evidence-Based Report on Diagnostic Guidelines

ORIGINAL ARTICLE

American Pancreatic Association Practice Guidelinesin Chronic Pancreatitis

Evidence-Based Report on Diagnostic Guidelines

Darwin L. Conwell, MD, MS,* Linda S. Lee, MD,† Dhiraj Yadav, MD,‡ Daniel S. Longnecker, MD,§Frank H. Miller, MD,|| Koenraad J. Mortele, MD,¶ Michael J. Levy, MD,# Richard Kwon, MD,**John G. Lieb, MD,†† Tyler Stevens, MD,‡‡ Phillip P. Toskes, MD,§§ Timothy B. Gardner, MD,§

Andres Gelrud, MD,|||| Bechien U. Wu, MD,¶¶ Christopher E. Forsmark, MD,§§ and Santhi S. Vege, MD#

Abstract: The diagnosis of chronic pancreatitis remains challenging inearly stages of the disease. This report defines the diagnostic criteria usefulin the assessment of patients with suspected and established chronic pan-creatitis. All current diagnostic procedures are reviewed, and evidence-based statements are provided about their utility and limitations. Diagnosticcriteria for chronic pancreatitis are classified as definitive, probable, or in-sufficient evidence. A diagnostic (STEP-wise; survey, tomography, endos-copy, and pancreas function testing) algorithm is proposed that proceedsfrom a noninvasive to a more invasive approach. This algorithmmaximizesspecificity (low false-positive rate) in subjects with chronic abdominal painand equivocal imaging changes. Furthermore, a nomenclature is suggestedto further characterize patients with established chronic pancreatitis basedon TIGAR-O (toxic, idiopathic, genetic, autoimmune, recurrent, andobstructive) etiology, gland morphology (Cambridge criteria), and physio-logic state (exocrine, endocrine function) for uniformity across future mul-ticenter research collaborations. This guideline will serve as a baselinemanuscript that will be modified as new evidence becomes available andour knowledge of chronic pancreatitis improves.

Key Words: chronic pancreatitis, diagnosis, guidelines, evidence-based

(Pancreas 2014;43: 1143–1162)

A t the 2011 meeting of the American Pancreatic Association(APA), a chronic pancreatitis (CP) conference was held to

From the *Division of Gastroenterology, Hepatology, and Nutrition, Departmentof Internal Medicine, Ohio State University Wexner Medical Center, Columbus,OH; †Division of Gastroenterology, Hepatology, and Endoscopy, Department ofInternal Medicine, Brigham and Women's Hospital, Boston, MA; ‡Division ofGastroenterology, Hepatology, and Nutrition, Department of Internal Medicine,University of Pittsburgh Medical Center, Pittsburgh, PA; §Department of Pathol-ogy, The Geisel School of Medicine at Dartmouth, Hanover, NH; ║Depart-ment of Radiology, Northwestern University Feinberg School of Medicine,Chicago, IL; ¶Department of Radiology, Beth Israel Deaconness Hospital,Harvard Medical School, Boston, MA; #Division of Gastroenterology andHepatology, Department of Medicine, Mayo Clinic, Rochester, MN; **Di-vision of Gastroenterology, Department of Internal Medicine, University ofMichigan Health System, Ann Arbor, MI; ††Division of Gastroenterology,Department of Medicine, University of Pennsylvania, Philadelphia, PA;‡‡Department of Gastroenterology and Hepatology, Cleveland Clinic,Cleveland, OH; §§Division of Gastroenterology, Hepatology, and Nutrition, De-partment of Internal Medicine, University of Florida, Gainesville, FL; ║║Depart-ment of Gastroenterology, University of Chicago, Chicago, IL; and ¶¶Divisionof Gastroenterology, Department of Medicine, Kaiser Permanente Los AngelesMedical Center, Los Angeles, CA.Received for publication June 17, 2014; accepted September 19, 2014.Reprints: Darwin L. Conwell, MD, MS, Division of Gastroenterology,

Hepatology, and Nutrition, Ohio State University Wexner Medical Center,288A Faculty Office Tower, 410 W, 10th Ave, 2nd Floor, Columbus, Ohio43210 (e‐mail: [email protected]).

The authors declare no conflict of interest.Supplemental digital contents are available for this article. Direct URL

citations appear in the printed text and are provided in the HTML and PDFversions of this article on the journal’s Web site (www.pancreasjournal.com).

Copyright © 2014 by Lippincott Williams & Wilkins

Pancreas • Volume 43, Number 8, November 2014

Copyright © 2014 Lippincott Williams & Wilkins. Unau

review the medical literature to develop the first US practiceguideline for CP. The APA Practice Guidelines in Chronic Pancre-atitis is a 3-part evidence-based document that reviews the cur-rent literature on the diagnosis (part 1), treatment (part 2), andmanagement of complications (part 3) of CP. The objective ofthis report was to provide an initial platform on which to buildfurther evidence-based recommendations for the managementof CP as new evidence becomes available.

Chronic pancreatitis is characterized by chronic progres-sive pancreatic inflammation and scarring, irreversibly damag-ing the pancreas and resulting in loss of exocrine and endocrinefunction. It was first described in the medical literature in 1788by Sir Thomas Cawley; however, a review in the New EnglandJournal of Medicine stated that despite the “thousands of re-ports dealing with this disease, it remains an enigmatic processof uncertain pathogenesis, unpredictable clinical course, anduncertain treatment.”1 Fortunately, since that landmark publi-cation, there have been major advances in our understandingof CP pathogenesis and pathophysiology, including pancreaticfibrosis, etiologic risk factors, natural history, and associatedgenetic and epigenetic changes.2–6 Clinical diagnostic toolshave also seen considerable improvement with advances inendoscopic and radiologic imaging techniques, and the devel-opment of endoscopy-assisted pancreas function testing haswidened its clinical use.7–10 Most importantly, multicenter pro-spective randomized trials are underway using clearly definedoutcomes, including validated pain scales, cost analysis, anddisease-specific quality of life measures, to clarify the rolesof endoscopy and surgery in the management of CP and itscomplications.11–18

The clinical manifestations of CP can include abdominalpain, steatorrhea, and diabetes, as well as numerous acute andchronic complications.16,18,19 Current treatments can only pro-vide temporary pain relief and manage complications but areunable to arrest or slow the progression of this often debilitat-ing illness.13,19,20 In addition, a subset of CP patients developspancreatic adenocarcinoma, which is generally advanced at thetime of diagnosis due to the marked morphologic changes in thegland that can “mask” tumors, preventing early detection.21,22

Both basic scientists and clinical researchers are activelyinvestigating the pathogenesis of CP.23–25 The resulting advanceswill certainly improve diagnosis, management, and treatment ofCP in the future, but until then, evidence-based current practicestrategies are needed. Where there is no clear evidence, expertopinion from experienced basic scientists, gastroenterologists,therapeutic endoscopists, and surgeons, who specialize inpancreatology, must prevail. Unlike acute pancreatitis (AP),there is a paucity of practice guidelines for CP in the medicalliterature. Italian, German, and Spanish Consensus Guidelinefor Chronic Pancreatitis have recently been published, and

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Conwell et al Pancreas • Volume 43, Number 8, November 2014

both provide valuable insight into the numerous challengesfacing diagnosis and management of this complex disorder.

MATERIALS AND METHODSThe primary aim of this report was to provide current prac-

tice guidelines for CP from an evidence-based review of themedical literature and expert opinion. The development of theAPA Practice Guidelines in Chronic Pancreatitis involvedthe following steps:1. A 1-day multidisciplinary symposium, led by leaders in the

field of CP, to review the literature on CP as it pertains todiagnosis, treatment, and management of complications.The organization committee (D.L.C., S.S.V., and C.E.F.)invited participation from speakers, moderators, and thoughtleaders specializing in gastroenterology, surgery, and thera-peutic endoscopy from numerous academic centers through-out the United States.

2. The final program was approved by the APA and organizedinto 3 sessions as follows: (1) diagnostic guidelines, (2)treatment guidelines, and (3) complications and long-termmanagement.

3. Experts reviewed the medical literature and presented evi-dence pertaining to CP, epidemiology, diagnosis, treat-ment, and management of its complications.

4. Each of the 3 sessions concluded with commentary fromthought leaders summarizing the major challenges facingphysicians treating patients with CP.

5. Open discussions and breakout meetings were organized aftereach session to allow for all 2011 APA conference attendeesto participate in debate and discussion of controversial areasand to assist in the development of future practice guidelines.

6. The conference lectures were transcribed and edited by thespeakers, then reviewed and collated by session chairpersonsand moderators into aworking draft for each of the 3 sessions.

7. For recommendations, APA used the classification by theGRADE (Grading of Recommendations Assessment, Devel-opment, and Evaluation) with slight changes. The Strength ofrecommendation is either strong or conditional (weak). Fac-tors influencing strong recommendation include the qualityof evidence, presumed patient-important outcomes, and cost.Conditional recommendation denotes the variability in prefer-ences and values or more uncertainty, implying less certainty,higher cost, or resource consumption. Quality of evidence ishigh (A, further research unlikely to change confidence inthe estimate of the clinical effect), moderate (B, further re-search may change confidence), low (C, further research verylikely to impact confidence), and very low (D, an estimate ofthe effect is uncertain). However, in the GRADE approach,high-quality evidence may not translate into strong rec-ommendation, and weak evidence may result in a strongrecommendation.26

8. The conference organization committee reviewed and editedthe session drafts, compiling a working draft of the APAChronic Pancreatitis Practice Guidelines.

9. Theworking draft was submitted to independent reviewers, ex-perts in each major session area, for critique and commentary.

10. A final draft was submitted to the APA Governing Board foreditorial review.

11. After further editorial revisions, the official APA PracticeGuideline for Chronic Pancreatitis was finalized and submit-ted for peer-reviewed publication.

1144 www.pancreasjournal.com


EVIDENCE-BASED REPORT ONDIAGNOSTIC GUIDELINES

Chronic pancreatitis should be in the differential diagno-sis of a patient with typical features of epigastric pain withradiation to the back, steatorrhea, weight loss, or recurrentAP. Patients generally have known risk factors for CP such asmoderate to heavy alcohol or tobacco exposure. Because thedisease is irreversible and carries a social stigma, the diagnosisneeds to be certain (ie, definitive, probable) before labeling apatient with this chronic illness. Furthermore, clinical evalua-tion is warranted in patients with a high suspicion of diseaseto rule out pancreas carcinoma that can mimic both its clinicaland imaging presentation.

In general, the radiologic and endoscopic evaluation of apatient with suspected CP should progress from a least invasiveto more invasive approach to establish a diagnosis. A computedtomography (CT) scan of the pancreas is usually the initial im-aging modality of choice. Patients with equivocal or mild CTimaging findings or refractory symptoms may be referred tospecialized centers for additional studies such as magnetic res-onance imaging (MRI)/secretin-enhanced magnetic resonancecholangiopancreatography (MRCP) or endoscopic proceduressuch as endoscopic ultrasound (EUS), endoscopic retrograde chol-angiopancreatography (ERCP), and pancreas function testing.

The posttest probability of chronic pancreatic disease ismarkedly influenced by the clinical history, physical examina-tion, etiologic risk factor profile, and results of radiologic andendoscopic imaging tests. Despite exhaustive attempts at diag-nosis, up to 5% to 10% of patients cannot be clearly diagnosedwith certainty because of disagreement or discordance betweenimaging and endoscopic findings.

This article is the first of a 3-part guideline proposed by theAPA to assist physicians caring for individuals with suspectedCP.We review the current epidemiology, pathology, radiology, en-doscopy, and physiologic testing methods and procedures that arecurrently utilized in the evaluation of suspected CP.We present ev-idence to support a definitive diagnosis and propose a nomencla-ture that can be used at academic centers to standardize clinicalresearch reporting of data.

It is our hope that this initial document will serve as an initialplatform on which to build further evidence-based recommenda-tions as more knowledge becomes available and as our under-standing of CP pathophysiology improves.

Topic 1. Epidemiology and Risk Factors• Dhiraj Yadav, MD, University of Pittsburgh Medical Center,Pittsburgh, PA (lead discussant)

Evidence-Based Medicine Statements1. Data on population-based estimates of CP are emerging.2. A small fraction of patients progress from AP to CP.3. Alcohol and smoking are independent risk factors for CP. Both

are associated with disease progression, and their risks arelikely multiplicative.

4. The spectrum of risk factors for CP has broadened.5. Genetic discoveries are rapidly uncovering new susceptibility

factors. Knowledge of gene and gene-environment interactionsmay translate into new diagnostic and treatment paradigms.

Level of Evidence1. Conditional recommendation (level of evidence, low)2. Conditional recommendation (level of evidence, moderate)3. Strong recommendation (level of evidence, high)

© 2014 Lippincott Williams & Wilkins




TABLE 1. Incidence and Prevalence of CP in Population-Based Studies27–34

Design Population Year(s)

Incidence (per 100,000)

All Males Females

IncidenceChart review Luneberg County, Germany 1988–1995 6.4 8.2 1.9

Moravia, Czech Republic 1999 7.9 NA NAOlmsted County, Minnesota 1997–2006 4.4 5.2 3.8

Survey Japan 2007 11.9 NA NAAdministrative data Britain 1999–2000 8.6 12.4 4.8

United States 1988–2004 8.1 4.1 4.0The Netherlands 2004 8.4 11.4 5.7Allegheny County, Pennsylvania 1996–2005 7.8 8.3 7.2

PrevalenceSurvey Japan 1994 36.9 53.2 21.2Chart review Olmsted County, Minnesota 2006 41.8 51.5 33.9

NA, not available.

Pancreas • Volume 43, Number 8, November 2014 Diagnostic Guidelines in Chronic Pancreatitis

4. Conditional recommendation (level of evidence, low)5. Strong recommendation (level of evidence, moderate)

In the past 50 years, we have learned a lot about the epidemi-ology and risk factors associated with CP. Most epidemiologic datafor CP come from large case series and cross-sectional studies.Population-based data on CP are scarce due to its low incidenceand prevalence, difficulty in establishing an early diagnosis, andvariable time course for progression from AP to CP. The overall in-cidence of CP (Table 1) ranges from 4.4 to 11.9 per 100,000 peryear.27–34 The incidence is higher in men than in women by a fac-tor of 1.5 to 3. Data on prevalence of CP are even scarcer andrange from 36.9 to 41.8 per 100,000 persons.29,30

TABLE 2. Classification System for Etiology and Risk Factors for CP1

Classification for CP Etiology

Traditio

Alcohol, idiopathic, hereditary, obstructive, hyperlipidemia

TIGAR

Toxic-metabolic: alcohol, tobacco smoking, hypercalcemia, hyperlipidemiIdiopathic: early onset, late onset, tropicalGenetic mutations: PRSS1, CFTR, SPINK1, othersAutoimmune: isolated, syndromicRecurrent and severe AP-associated CP: postnecrotic (severe AP), vasculaObstructive: pancreas divisum, sphincter of Oddi disorders, duct obstructi

MANNH

M indicates multiple risk factors including:Alcohol consumption: excessive (>80 g/d), increased (20–80 g/d), moderNicotine consumptionNutritional factors: high calorie proportion of fat and protein, hyperlipidemHereditary factors: hereditary, familial, idiopathic (early onset, late onset),Efferent duct factors: pancreas divisum, annular pancreas and other conge(eg, tumors), posttraumatic pancreatic duct scars, sphincter of Oddi dys

Immunological factors: autoimmune pancreatitisMiscellaneous and rare metabolic disorders: hypercalcemia, hyperparathyr



The etiology of CP has traditionally been classified as al-cohol, hereditary, obstructive, hyperlipidemia, and idiopathic(Table 2). The TIGAR-O risk factor classification has beenproposed10 as follows: toxic-metabolic, idiopathic, genetic,autoimmune, recurrent and severe AP-associated CP, and ob-structive etiologic factors. This classification system wasdeveloped with the premise that the risk of developing CP inan individual is determined by the presence of 1 or more riskfactors. A similar MANNHEIM classification has been pro-posed that also recognizes the role of multiple etiologic factorsin disease development.35

Alcohol and smoking contribute greatly to the developmentof CP. Alcohol is the single most common etiologic factor and

0,35

nal

-O

a, chronic renal failure, medications, toxins

r disease/ischemic, postirradiationon (eg, tumor), posttraumatic pancreatic duct scars

EIM

ate (<20 g/d)

iatropicalnital abnormalities of the pancreas, pancreatic duct obstructionfunction

oidism, chronic renal failure, drugs, toxins





FIGURE 1. Pancreas with CP. The stomach is at the top, theduodenum at the lower left, and the spleen on the right with thepancreas extending from the spleen to the duodenum. The pancreasis small, probably because of atrophy. The massively dilated mainduct with a white stone is seen in the head and body of the pancreas.These are all characteristics of CP. Photo courtesy of Edward Bradley.

TABLE 3. Prevalence and Consequence From Known Genetic Mutations in CP65–75

Gene Gene Name Consequence

Prevalence, %

CommentsGeneral Population CP

PRSS1 Cationic trypsinogen Increased trypsinogen activation,decreased trypsin degradation

<0.01 2–3 Penetrance for AP (80%), CP (40%)

SPINK1 Pancreatic secretorytrypsin inhibitor

Failure of trypsin degradation 3–8 8 *Acute phase protein*Risk related to 1 or 2 mutations,another risk factor

*Risk much higher in nonalcoholic CPCTRC Chymotrypsin C Failure of trypsin degradation ≤1 3–4 Risk higher in tropical/idiopathic CPCASR Calcium sensing

receptorIncreased extracellular ionizedcalcium; increased trypsinactivation and failed trypsindegradation

10 18 May have role in alcohol-related pancreatitisor hyperparathyroidism-induced pancreatitis

CFTR Cystic fibrosistransmembraneconductance receptor

Impaired flushing of pancreaticducts leading to trypsin activation

2–3 (∆F508) 6 *Risk in pancreas sufficient patients: ~25%

5 (other) 8–9 *About one third of idiopathic CP arecompound heterozygotes

*Increased recognition of the role ofatypical/benign mutations (eg, R75Q)


accounts for 44% to 65% cases in population- and nonpopulation-based studies.36–46 Compared with the general population, thespectrum of alcohol consumption in patients with CP is clearlyshifted to the right. The prevalence of pancreatitis in the settingof alcoholism is 3 to 6 times higher when compared withnondrinkers,47 and the absolute risk of pancreatitis among heavydrinkers is 2.5% to 3%.47,48 There seems to be a threshold of 4to 5 drinks/d of alcohol consumption that clearly increases the riskof developing CP.12,48 Even at lower levels of consumption, alco-hol likely plays a disease-modifying role. Experimental data gen-erated using hyperstimulation models have demonstrated thatheavy alcohol exposure increases the susceptibility of the pan-creas to other injury49–51; and after the initiation of pancreatic in-jury, alcohol modifies the immune response.52

The association between smoking and CP is more uniformacross epidemiologic studies. Smoking is a dose-dependent co-factor for causation of CP.12,53–59 The risk of developing CP insubjects smoking less than 1 pack of cigarettes per day is 2.4(0.9–6.6) and increases to 3.3 (1.4–7.9) in those smoking morethan 1 pack per day. Overall, smokers are on average 3 timesmore likely to develop CP compared with nonsmokers (pooledrisk estimate, 2.8 [1.7–4.8]). More importantly, smoking cessa-tion reduces the risk ratio estimate for CP by about 50% from2.4 (1.8–4.2) in current smokers to 1.4 (1.1–1.9) in formersmokers.60 Similarly, early smoking cessation after clinical on-set of CP has been shown to reduce the risk of developing cal-cifications, whereas continued smoking is associated withincreased risk of disease progression.61 The risk associatedwith smoking and alcohol together is important and likely mul-tiplicative.12 Although alcohol and smoking increase the risk ofprogression individually, disease progression is more likely inthe setting of continued alcohol and smoking.62

Several genetic variations have been associated with pan-creatitis including PRSS1, PRSS2, SPINK1, CTRC, CASR, andCFTR.65–75 The role of these gene mutations in CP is becomingincreasingly recognized and better understood. It is importantto note that these genetic mutations are all primarily linked tothe trypsin pathway; the proportion of CP with known geneticmutations is small, and the association of these genetic



variations is much stronger in the nonalcoholic etiologies com-pared with alcoholic pancreatitis (Table 3). Furthermore, spe-cific mutations have been associated with varying degrees ofgenetic penetrance (80% for PRSS1), and varying risk of idio-pathic pancreatitis (CFTR), tropical pancreatitis (CTRC), andnonalcoholic CP (SPINK1).

The pathogenesis of CP can likely be summarized by a 2-hithypothesis model. In the setting of preexisting AP risk factors(genetic, metabolic, environmental), an initial first AP hit initiatesor activates the immune system, followed by post-AP, followed bycomplete recovery or progression to CP.64

In summary, population-based data on the epidemiology ofCP are emerging and improving our understanding of the epidemi-ology, risk factors, and pathogenesis of the disease. The spectrum ofrisk factors for CP has broadened. Alcohol and smoking are inde-pendent risk factors for CP and interact in a multiplicative manner.Continuous alcohol and smoking abuse are associated with diseaseprogression. Calculating attributable risk for individual risk factors





FIGURE 2. Pancreas with CP. Note the fibrosis between andsurrounding the lobules of acinar tissue. This is perilobular orinterlobular fibrosis. The fibrosis extends into the lobule at the centerand that is referred to as intralobular fibrosis. There is a chronicinflammatory infiltrate in this pancreas, best seen in the fibroustissue. Hematoxylin and eosin stain (H and E).

FIGURE 4. Atrophy and fibrosis (alcoholic CP). The amount ofcollagen (pink) is increased, especially in the left-hand panel.Note the slight dilation of ducts and the loss of acinar tissue. On theright there are 5 islets located close together because of the loss ofacinar tissue. Foci of calcification are blue. H and E.


is difficult due to the complex nature of the disease and the variabil-ity of genetic and epigenetic factors. However, it is likely that theattributable risk of alcohol for CP is approximately 40% and thatof smoking approaches 25%. Only a small fraction of patientswith AP progress to CP.46,62–64 Genetic discoveries are rapidlyunraveling new susceptibility factors, and the knowledge ofgene and gene-environment interactions will likely translate intotargeted diagnostic and treatment strategies.

Topic 2. Pathologic Definitions• Daniel S. Longnecker,MD, DartmouthMedical Center, Hanover,NH (lead discussant)

Anatomic Pathology-Based Statements1. Chronic pancreatitis is characterized by atrophy and fibrosis of

the exocrine tissue with or without chronic inflammation.2. Scarring of the parenchyma may be focal, patchy, or diffuse.3. Progressive fibrosis and atrophy may lead to exocrine insuf-

ficiency (steatorrhea) followed by endocrine insufficiency(diabetes).

4. Autoimmune pancreatitis can mimic pancreas carcinoma.

FIGURE 3. Perilobular and intralobular fibrosis. The collagen is blue.You can see the massive amounts of collagen around the lobuleand extending into the lobule. The acini are atrophic. Small ductsalong the top margin of the lobule are somewhat dilated. These areall characteristics of CP. There is less inflammatory infiltrate here thanin Fig. 2. Connective tissue stain.



Level of EvidenceThe usual level of evidence statements are generally not used

in anatomic pathology.The pathology of CP varies with etiology, but there are

changes that are present in all types. Typical changes seen atthe gross level include reduction in size of the pancreas, dilata-tion of ducts, loss of lobular pattern in areas of scarring, and thepresence of stones in the ducts (Fig. 1). Several of these fea-tures are variable and may not be seen in all cases.

Histologically, the 2 most common features of CP are lossof acinar tissue (atrophy) and fibrosis. The fibrosis may sur-round the lobules (perilobular or interlobular fibrosis) or ex-tend into the lobules of acinar tissue (intralobular fibrosis)(Figs. 2, 3). A chronic inflammatory infiltrate may be present(Fig. 2), but this feature is highly variable and disappears latein the course of CP (Fig. 3). A diagnosis of CP may be madeon the basis of atrophy and fibrosis in the absence of otherchanges. Islets often survive until late in the course of thedisease—becoming more closely spaced as acinar tissue is lost(Fig. 4). In cystic fibrosis, which may be regarded as a specialform of CP, there is dilation of ducts resulting from the abnor-mal secretions with progressive fibrosis and loss of acinar tis-sue (Fig. 5).

Chronic pancreatitis can be a patchy or localized processwith regional involvement (Fig. 6). This is best understood by

FIGURE 5. Pancreas in cystic fibrosis. Note the diffuse fibrosis, lossof acinar tissue, persistence of ducts, and some islets. The ductsare dilated and contain mucus. This is an advanced stage of cysticfibrosis in which inflammation has largely burned out. H and E.





FIGURE 6. CP can be a patchy or localized process. In the upper leftportion of this transected pancreas, there is a dilated ductsurrounded by scar tissue (fibrous tissue) with virtually complete lossof acinar lobules (white arrow). In the lower right portion of thesame transsection, there is relatively good preservation of the acinarlobules illustrating that CP can have quite localized involvement(black arrow).


considering the mechanisms of pathogenesis, in particular thenecrosis-fibrosis hypothesis, which posits that CP develops asa result of multiple episodes of AP with necrosis and scarring.This process may be patchy at first, progressing to a diffusepattern after multiple episodes. This is commonly consideredto be the mechanism in alcoholic CP, paraduodenal CP, andlikely hereditary pancreatitis. On the other hand, duct obstruc-tion can lead to progressive fibrosis and loss of acinar tissuethat may be localized or segmental, as in the presence of anobstructing neoplasm, or may be diffuse as is characteristic ofcystic fibrosis.

In a review focused on alcoholic pancreatitis, we find thestatement that “both alcoholic and nonalcoholic CP result inindistinguishable pancreatic damage.”76 A recently reported in-ternational comparison study provides evidence that the partic-ipating pathologists did not distinguish between alcoholic andobstructive CP, although they did become proficient at recog-nizing autoimmune pancreatitis (AIP) and its subtypes.77 Auto-immune pancreatitis is probably the most histologically distincttype of CP (Fig. 7). However, some expert pathologists do ob-serve characteristics that distinguish different CP etiologies,

FIGURE 7. Inflammation of pancreatic duct walls is the most distinctive fduct wall is more conspicuous. On the left there is inflammation in the dthere is severe ductitis (yellow arrow)with paraductal and interlobular fibr



thereby providing a basis for subclassification. Klöppel78

provides a histologic classification that includes alcoholic,hereditary, autoimmune, paraduodenal, and obstructive CPbased on differences in the prevalence of various criteria suchas necrosis, pseudocyst, fibrosis, duct lumen, duct contents,and duct epithelium. For example, necrosis and pseudocystare much more likely to be seen in alcoholic CP than in theother forms. However, there is clearly an overlap of most his-tologic features among all types. A universal histologic gradingand scoring system is needed to correlate clinical features withsurgical pathologic findings.

In summary, atrophy and fibrosis of the exocrine tissue arethe key features seen in CP. There may or may not be evidenceof chronic inflammation, but it is quite appropriate to refer toCP as a fibroinflammatory disease. The scarring can be focalinitially and may progress to become diffuse. The loss of acinartissue may result in exocrine insufficiency and ultimately lossof islet tissue with diabetes. Acute phase pseudocysts may per-sist in CP that has developed via the necrosis-fibrosis pathway.

Topic 3. Chronic Pancreatitis: Ultrasound andComputed Tomography• Frank H. Miller, MD, Northwestern University, Chicago, IL(lead discussant)

Evidence-Based Medicine Statements1. Ultrasound and CT are best for the late findings of CP but are

limited in the diagnosis of early or mild pancreatitis.2. Intraductal pancreatic calcifications are the most specific and

reliable sonographic and CT signs of CP.3. Computed tomography is helpful for the diagnosis of compli-

cations of CP.4. Computed tomography is helpful for diagnosis of other condi-

tions that can mimic CP.

Level of Evidence1. Conditional recommendation (level of evidence, moderate)2. Strong recommendation (level of evidence, moderate)3. Strong recommendation (level of evidence, moderate)4. Conditional recommendation (level of evidence, low)

The clinical diagnosis of CP, especially in its early stages,can be difficult and frustrating for patients and treating

eature of AIP. Although lobules can be involved, inflammation in theuct wall (white arrow) and fibrosis around the duct. On the rightosis (white arrow) and atrophy of acinar tissue (black arrow). H and E.





FIGURE 8. Ultrasound in CP. Transabdominal ultrasounddemonstrating calcifications (white arrow) in the pancreasdue to CP.

FIGURE 10. Ductal changes in CP. Dilated, beaded MPD(white arrow), and parenchymal atrophy and calcifications.


physicians. Diagnosis of CP by ultrasound and CT imaging re-lies on changes in morphology of the pancreas, easily detectedin the setting of advanced disease, but challenging in early CP.The frequent lack of histopathologic confirmation of the diag-nosis further complicates evaluation. The key findings are pa-renchymal loss (glandular atrophy), chronic inflammation, andfibrosis of the pancreas. Important ductal findings include bead-ing, dilated side-branch radicals, enlargement of the main pancre-atic duct (MPD), and dystrophic intraductal calcifications.

Transabdominal ultrasound has been used for many years toevaluate the pancreas. Although there have been improvementsin hardware and high-resolution transducers, there have notbeen any recent studies to evaluate the diagnosis of CP usingultrasound. Ultrasound is a noninvasive, inexpensive, and rapidmethod of evaluating morphological changes in the pancreas;however, considerable limitations reduce its diagnostic utility.Initially, bowel gas and the patient's body habitus may obscurethe pancreas. Assuming adequate visualization, most of trans-abdominal ultrasound findings are neither specific nor sensitivein the diagnosis of CP. The classic sonographic findings of CPare pancreatic calcifications (Fig. 8). These are seen as multipleechogenic foci in as many as 40% of patients.79 These foci mayor may not shadow based on their size and may show color Dopp-ler twinkling artifact.80 There is no correlation between exocrinefunction and the number of calcifications.81,82 Late findings seenon ultrasound include alterations of the size and echogenicityof the gland, pancreatic calcifications, pancreatic duct dilata-tion and irregularity, and biliary dilatation. Ultrasound can beused to visualize pseudocysts and complications of CP, includ-ing biliary dilatation and splenic vein thrombosis. Pancreaticparenchymal echogenicity may be normal or decreased in CP,making it an unreliable diagnostic feature.79,83,84

FIGURE 9. Computed tomography findings in CP.



Computed tomography is considered by many to be thebest initial imaging test for CP.84–87 It is widely available andallows for comprehensive detailed evaluation of the pancreas.Despite marked improvements in CT, including the develop-ment of multiple detector computed tomography (MDCT),there have not been any recent studies evaluating the sensitivityor specificity for CP. The classical CT findings in CP are dilatationof the pancreatic duct, pancreatic calcifications, and parenchymalatrophy.84–87 A retrospective study from the Mayo Clinic pub-lished in 1989 studied 56 patients with documented CP (Fig. 9).88

A dilated pancreatic duct and secondary radicals were the mostcommon findings seen in 68% of patients (Fig. 8).88 Intraductal cal-cifications were seen in as many as 50% of patients (Fig. 10).88

These were scattered or clustered, focal, or diffuse. Calcificationsdevelop from deposition of calcium carbonate in inspissatedintraductal protein plugs. Calcifications, however, are associatedwith advanced or severe CP (Fig. 11).89 Other findings includepancreatic parenchymal atrophy (54%), although this is variableand the pancreas can even be enlarged (30%) or normal in appear-ance (7%), making the diagnosis difficult (Fig. 12).88 Unfortu-nately, parenchymal atrophy is neither sensitive nor specific andcan be seen as a normal aging process. Many patients may havea normal-appearing pancreas on CT despite severe exocrinedysfunction. Other CT findings include MPD dilatation and di-lated secondary radicals. The MPD is classically beaded and ir-regular; however, the main duct may also be regularly contoured.Computed tomography is especially helpful in identifying compli-cations of CP, including pseudocysts, portosplenic venous throm-bosis, collaterals and arterial pseudoaneurysms, and pancreatico-pleural fistulas.84–87 Computed tomography is especially helpfulbecause it can exclude other causes of abdominal pain or weightloss besides CP. In the literature, studies evaluating the CT





FIGURE 11. Calcifications in CP. Intraductal and parenchymalcalcifications (white arrow) in CP.

FIGURE 13. Duct penetrating sign in mass-forming CP.Distinguishing CP from cancer can be difficult in mass formingCP. Visualization of the pancreas duct as it penetrates the mass(white arrow and circle) on MRI favors a diagnosis of CP. ERCP andbiopsy suggested adenocarcinoma, but surgical pathology Whipplespecimen confirmed CP.


features of CP are from the 1980s. Since then, vast improvementsin CT technology, including multidetector CT, multiple-phaseimaging after contrast enhancement, and thinner collimation, haveundoubtedly improved the sensitivity of the diagnosis of CP. Re-evaluation of CP using CT is long overdue.84

It is important to distinguish CP from cancer using imag-ing studies; however, this is not always possible.90–92 Featuresthat favor CP is intraductal or parenchymal calcifications, lackof obstructing mass, irregular dilatation of the pancreatic duct,and relatively limited atrophy of the gland. The presence of aduct-penetrating sign, which is a dilated duct or branches thatpenetrate an apparent mass, favors CP (Fig. 13).90 Features fa-voring cancer include pancreatic duct dilatation with associ-ated mass at the site of obstruction with associated atrophy ofthe pancreas, vascular invasion, and metastases.

In summary, CT is useful as an initial radiologic test, ishelpful to visualize calcifications and duct abnormalities, andexcludes other non-CP etiologies for pain or weight loss. In ad-dition, ultrasound and CT are best for the late findings of CPbut have limitations, especially in the early diagnosis of mildto CP. Imaging is quite helpful for the diagnosis of complica-tions of CP.

Topic 4. MRI Imaging• Koenraad J. Mortele, MD, Beth Israel Deaconess MedicalCenter, Boston, MA (lead discussant)

Evidence-Based Medicine Statements1. Compared with ultrasound and CT, MRI is a more sensitive

imaging tool for the diagnosis of CP.

FIGURE 12. Computed tomography can appear normal in CP.Computed tomography image shows typical pancreaticappearance without calcifications or radiologic evidence to suggestCP. Follow-up MRI/MRCP showed markedly abnormal MPDand side branches.



2. Ductal abnormalities are very specific and reliable MRI signsof CP.

3. Signal intensity changes in the pancreas, seen on MRI, mayprecede ductal abnormalities and suggest early CP.

4. Stimulation of the pancreas using intravenous (IV) secretinmay improve the diagnostic accuracy in the detection of ductaland parenchymal abnormalities seen in CP.

Level of Evidence1. Conditional recommendation (level of evidence, moderate)2. Conditional recommendation (level of evidence, low)3. Conditional recommendation (level of evidence, low)4. Conditional recommendation (level of evidence, low)

Chronic pancreatitis leads to irreversible parenchymal andductal changes in the pancreas.93 Magnetic resonance imagingmay be able to provide an early diagnosis of CP so patients can betreated early on or patients can be applied treatment optionsthat may prevent progression.94 The diagnosis of early CP typi-cally relies on the presence of clinical symptoms, pancreaticexocrine function testing (the criterion standard), and imaging.95

Magnetic resonance imaging is highly sensitive and specific tomake the diagnosis of CP by evaluating both parenchymal andductal changes, especially in patients with more advanced CP.96

However, MRI can also help in the diagnosis of early CP by eval-uating the exocrine response of both the ducts and parenchymaafter hormonal stimulation of the gland using IV secretin.97–101

When applying a standard MRI/MRCP protocol, radiolo-gists should look, from a ductal perspective, for changes thatare induced by the periductal fibrosis, the resultant duct ectasia,and obstructed outflow. These changes of side-branch abnormali-ties, main duct dilation, and strictures or presence of intraductalstone and intraparenchymal cyst formation can be graded usingthe Cambridge classification (Fig. 14). In addition to evaluatingthe ductal changes, MRI is also very sensitive to detect parenchy-mal abnormalities; what radiologists specifically should lookfor is subtle signal intensity decreases within the gland, especiallyon fat-suppressed T1-weighted images.102 It is very important to re-alize that these parenchymal abnormalities may precede the ductalabnormalities. Therefore, CT or ultrasound may be falsely neg-ative in the detection of early CP because of their lack of detect-ing subtle ductal abnormalities. These tests fail to depict theseparenchymal changes that are only detected with MRI. Anotherimportant conventional MRI feature of CP is the delayed anddiminished enhancement of the gland after gadolinium chelatesadministration. Therefore, in summary for conventional MRI/





FIGURE 14. Classic CP ductal changes. Cambridge 4 (minor main pancreas ductal abnormalities with side-branch changes, left) andCambridge 5 (major main pancreas ductal changes, right) in CP.


MRCP, the parenchymal features of CP include, in addition toatrophy (Fig. 15), abnormal decreased signal intensity on thefat-suppressed T1-weighted images (Fig. 16) and delayed andlimited enhancement after contrast administration (Fig. 17).

As mentioned previously, one could currently explorethe MRI appearances of early CP after hormonal stimulationof the pancreas, using IV secretin, and look for new or im-proved detection of ductal and parenchymal abnormalities(Fig. 18).103 One's primary assessment in evaluating the pancreaswith secretin-enhanced MRCP should focus on the pancreaticduct compliance, which defines a normal distention (of ap-proximately 1 mm) of the ducts after secretin stimulation andthen a recovery of the duct diameter to baseline (10 minutes af-ter IV secretin injection). Several investigators have evaluatedthe time to peak MPD dilation after IV secretin stimulation todifferentiate a normal pancreas from a pancreas in patientswho have CP. Patients with early CP may have completely nor-mal conventional MRCP/MRI studies, and only the secretinstimulation will depict the mild abnormal pancreatic ductalcompliance.104 Furthermore, one should also evaluate the IVsecretin-augmented MRCP images for increased number ofside branches or new recognition of side branches and evaluatethe exocrine pancreatic function by assessing the productionand excretion of bicarbonate and fluid by the gland. The lattercan be evaluated both quantitatively and semiqualitatively.Semiqualitatively, one can apply a rudimentary grading systemthat evaluates the filling of the duodenal and jejunal loops ofbowel after stimulation.105,106 A much more accurate way is to ac-tually measure the exact amount of fluid that gets produced by

FIGURE 15. Glandular atrophy. Sequential (right to left) contrast-enhanduct in CP.



the gland using a multislice fast T2-weighted sequence and a verysimple mathematical model. Measuring the signal intensity ofthe fluid and the 3-dimensional area of fluid before and after thestimulation of the pancreas with IV secretin allows measuringhow much fluid is being produced by the gland over time andcan provide a flow rate chart. This quantitative model has beenused successfully to evaluate the exocrine fluid flow rate in pa-tients with CP before and after secretin administration.

Lastly, some future MRI applications are on the horizon thatmay have immediate impact on the way we image patients withCP. The more universal use of high field strength magnets now al-lows for increased signal-to-noise in the pancreas, and using thosehigh field strength magnets, we can depict more subtle abnormal-ities in the pancreas compared with lower field strength magnets.Perfusion MRI explores that fact that the pancreas in patientswith CP has decreased and delayed enhancement and aims todetect subtle alterations in pancreatic parenchymal perfusion.107

Diffusion-weighted MRI measures the restriction of freeBrownian motion (diffusion) of water molecules in the gland.The more fibrosis there is, the more likely there will be less dif-fusion of water molecules (the latter is measured as apparentdiffusion coefficient); therefore, apparent diffusion coefficientvalues will be lower in patients with CP than in normal patients.Exploiting this idea, one can actually evaluate the gland usingdiffusion MRI after IV secretin stimulation and enhance thesensitivity to depict subtle abnormalities in diffusion restrictionand separate normal patients from those with early CP.108,109

In summary, MRI is a great tool to detect ductal and paren-chymal changes in CP patients, both at baseline or after

ced MRI showing glandular atrophy and dilation of main pancreas





FIGURE 16. Low T1 signal. MRI displaying decreased pancreas signal intensity on T1-weighted images (lower right and left). No major CPchanges observed on CT (upper left) or MRCP (upper right).


stimulation with IV secretin.110–113 The complexity of the disease,however, remains challenging and limits the accuracy of MRI.Ductal changes may be preceded by parenchymal changes andvice versa.114 Additional findings can only be detected if onestimulates the gland with IV secretin. There probably is a need foran EUS-like MRI-based staging system, which does not exist atthis point, combining the ductal changes with the parenchymalchanges and with the findings after IV secretin stimulation.115–120

FIGURE 17. Delayed contrast enhancement. Precontrast and postcontr



Topic 5. Endoscopic Ultrasound• Michael J. Levy, MD, Mayo Clinic Rochester, Rochester, MN(lead discussant)

Evidence-Based Medicine Statements1. The ideal threshold number of EUS criteria necessary to diag-

nose CP has not been firmly established, but the presence of

ast MRI showing delayed contrast enhancement of pancreas.





FIGURE 18. Secretin MRCP. Serial sequential images (A–D) of pancreas displaying ductal and duodenal filling changes after secretinadministration.


5 or more and 2 or less strongly suggests or refutes the diag-nosis of CP.

2. The EUS features of CP are not necessarily pathologic andmay occur as a normal aging, as a normal variant, or dueto nonpathologic asymptomatic fibrosis in the absence ofendocrine or exocrine dysfunction.

3. The relatively poor interobserver agreement (IOA) for EUS CPfeatures limits the diagnostic accuracy and overall utility ofEUS for diagnosing CP.

Level of Evidence1. Strong recommendation (level of evidence, low)2. Strong recommendation (level of evidence, low)3. Strong recommendation (level of evidence, moderate)

Endoscopic ultrasound is an often used diagnostic tool forevaluating CP due to the ability to visualize subtle alterationsin pancreatic structure before other imaging modalities andfunctional tests are abnormal. Although the EUS sensitivity isenhanced as one lowers the necessary number of criteria for di-agnosis, the already poor specificity further decreases, oftenleading to unnecessary and often risky interventions. Somehave even performed total pancreatectomy and auto-islet celltransplant for pain secondary to presumed CP, only to find nor-mal histology in the resected specimen.

The EUS diagnosis is based on ductal and parenchymalcriteria described by the International Working Group using min-imum standard terminology, and the criteria have been linked todistinct pathologic correlates identified on histological examina-tion (Fig. 19).121–123 Although the minimum standard terminologysystem classically lists 9 potentially abnormal features, others alsoconsider 2 additional features including an enlarged pancreasand narrowing of the pancreatic duct. The number of EUS criterianeeded to diagnose CP varies among endosonographers and insti-tutions (Table 4).

The ideal threshold number of EUS criteria necessary todiagnose CP has not been firmly established. For patients withno pancreatic pathology and those with severe CP, EUS pro-vides reliable and accurate diagnosis. However, the diagnosisis seldom in doubt for such patients. Endoscopic ultrasound



offers the greatest potential to impact patient care in personswith early or mild CP; however, it is in this subset of patientsthat results are most uncertain and unreliable. Previously, therewas broad agreement that the presence of 5 or more features re-liably establishes the diagnosis of CP and that absence of allfeatures reliably excludes CP.121,124

However, given that some EUS features are actually physio-logic and others pathologic, the 5 criteria threshold may not be ap-propriate. It has been suggested that the presence of 1 to 2 EUSfeatures should be regarded as a normal gland and that the pres-ence of 3 to 4 criteria may indicate early or mild CP. DiagnosingCP based solely on minimal EUS criteria, with otherwise negativeor inconclusive findings, is strongly discouraged. It is impor-tant to correlate the EUS findings with clinical, structural,and functional analyses in this group of patients with possibleearly or indeterminate disease.

Pancreatic injury is a progressive process that leads to in-creasing structural abnormalities and functional deficits over time.The degree of injury necessary to designate CP is not clearly de-fined. Although exocrine pancreatic insufficiency in the form ofsteatorrhea does not typically occur until 70% to 90% or moreof functional capacity is lost, the occurrence, timing, and severityof disease manifestations greatly vary. Our goal was to accuratelydiagnose early CP to allow effective intervention to positively in-fluence the natural disease course. However, there is a paucity ofdata confirming the impact of any currently available therapiesor interventions. Efforts to enhance early diagnosis are typicallyassociated with overdiagnosis and decreased diagnostic specific-ity. Given the limited impact of early interventions and risk of de-livering unnecessary and risky care, most set test parameters tofavor a greater positive predictive value at the cost of a somewhatdelayed diagnosis.

Many have questioned the predictive value of individualEUS criteria and suggested their respective predictive valuesmay differ significantly. Rajan et al125 evaluated 120 patientswithout evidence of pancreatic disease who underwent EUSfor a nonpancreaticobiliary indication. They identified at least1 parenchymal and/or ductal EUS abnormality in 28% of pa-tients, with a trend toward increasing numbers of abnormal fea-tures with ages younger than 40 years (23%), 40 to 60 years





FIGURE 19. Selected CP EUS criteria. EUS morphologic features of CP. A, Hyperechoic foci and strands. B, Lobularity. C, Dilated, irregularpancreatic duct. D, Hyperechoic duct margin. E, Calcified, shadowing stones. Reprinted from Conwell and Wu,9 Copyright @ 2012,with permission from Elsevier.


(25%), and older than 60 years (39%) (P = 0.13). Hyperechoicstranding (n = 22) was the most common finding in all agegroups. They concluded that ductal or parenchymal calculi,duct narrowing, duct dilatation, or the presence of more than3 features seemed to be the most specific features for diagnosingCP regardless of age. Others have reported similar findings.123,126

The Rosemont classification was developed from a con-sensus conference that included 32 internationally recognized

TABLE 4. EUS Criteria for CP and Histological Correlates91–93

EUS Criteria for CP and Histological Correlates

EUS Criteria Histological CorrelateParenchymal featuresHyperechoic foci Focal fibrosisHyperechoic strands Bridging fibrosisLobular contour Interlobular fibrosisCysts Cyst/pseudocyst

Ductal FeaturesMain duct dilatation, mm >3 head, >2 body, >1 tailDuct irregularity Focal dilatation/narrowingHyperechoic margins Periductal fibrosisVisible side branches Side branch dilationStones Calcified stones



endosonographers.127 Participants defined each EUS CP crite-rion and applied these features in a manner that was felt to op-timize the diagnostic accuracy. Major and minor criteria weredeveloped and subdivided into major A and major B becauseof a perceived difference in predictive accuracy. Parenchymalmajor A criteria included hyperechoic foci with shadowingand well-circumscribed lobularity, and the only ductal majorA criteria was MPD calculi. The only parenchymal major Bcriteria was lobularity with honeycombing. Minor parenchymalcriteria were cysts, stranding, nonshadowing hyperechoic foci,and lobularity with noncontiguous lobules. Minor ductal criteriawere dilated ducts (body ≥3.5 mm and tail ≥1.5 mm), irregularMPD contour, dilated side branches 1 mm or more, andhyperechoic duct margin. The diagnosis of CP based on theRosemont Classification was consistent if one of the followingwas present: (a) 1 major A feature + ≥3 minor features, (b) 1 majorA feature + major B feature, and (c) 2 major A features. All othercombinations of features were categorized as suggestive, indetermi-nate, or normal. Although this classification system represents animportant step forward due to the use of weighted criteria, theirfindings were based solely on expert opinion.

It is uncertain that EUS features are pathologic, normal age-related findings, normal anatomic variants, or due to nondiagnosticasymptomatic fibrosis in the absence of endocrine or exocrinedysfunction.125 Such asymptomatic fibrosis has been reportedin alcoholism, advanced age, male gender, obesity, and cigarettesmoking. These features have been associated with abnormal pan-creatic imaging and histology in patients without evidence of






CP and are reported in as many as 60% of alcoholics withoutclinical evidence of CP. Although some of these patients mayhave mild disease destined to increase in severity over time, thelifetime risk of CP in alcoholics is only 2% to 5%, far less thanthe presence of fibrosis alone. Endoscopic ultrasound findingsmust be interpreted with caution due to the inability to distinguishthis clinically and metabolically benign asymptomatic fibrosisfrom true CP.

One of the greatest limitations in the use of EUS for evaluat-ing CP is the relatively poor IOA. Wallace et al122 studied the in-terpretations from 11 expert endosonographers, blinded to clinicalinformation, who evaluated videotaped examinations for thepresence of 9 CP criteria among 33 patients with CP. Althoughagreement was good in 2 features, duct dilatation (κ = 0.6) andlobularity (κ = 0.51), agreement was poor for the other 7 fea-tures (κ < 0.4). There was moderate overall agreement for thefinal diagnosis of CP (κ = 0.45). Topazian et al128 assessed IOAfor interpretation of EUS in persons at high risk for pancreaticcancer using recorded video clips and found similar results.

In summary, although EUS is an important diagnostic toolfor evaluatingmany gastrointestinal and nongastrointestinal disor-ders, the same may not be true for suspected CP. Despite ad-vances in EUS technology and training, there has been nomeaningful progress in EUS-based diagnosis since initial reports.The limitations of EUS are greatest for patients within the early/indeterminate CP and definite CP diagnostic range (>2 to <5).Definitive diagnosis in this vulnerable patient population must in-clude pancreas function testing and advanced radiologic imagingsuch as MRI and secretin-enhanced MRCP. Further study isneeded to refine the definitions of EUS features of CP, to deter-mine the relative predictive value of each feature, to establish anideal threshold number of criteria, and to consider the compositeresults in a manner that optimizes their diagnostic and prognosticutility. We must also improve our understanding of the impact offactors such as aging, obesity, and smoking on imaging. Anymeaningful advance in the use of EUS will mandate broader re-producibility in image interpretation and improved IOA. If weare to error in the use of EUS, we should do so in a manner thatfavors more stringent diagnostic criteria to avoid overdiagnosisand delivery of unnecessary and potentially risky therapies. Thisapproach will lead to failed diagnosis in some patients but is fa-vored given the current lack of reliably effective therapies.

Topic 6. Endoscopic RetrogradeCholangiopancreatography• Richard Kwon, MD, MS, University of MichiganMedical Cen-ter, Ann Arbor, MI (lead discussant)

Evidence-Based Medicine Statements1. Endoscopic retrograde pancreatogram (ERP) is rarely used for

diagnostic purposes.2. The correlation between the Cambridge criteria and histology

is highest in advanced CP.3. Multiple confounders limit the interpretation of ductal changes

by Cambridge criteria.

Level of Evidence1. Strong recommendation (level of evidence, moderate)2. Strong recommendation (level of evidence, moderate)3. Strong recommendation (level of evidence, low)

With the widespread availability of cross-sectional imaging(CT and MRI) and EUS, ERPs are rarely, if ever, used to diagnoseCP, and instead, they have largely been relegated to a therapeutic



procedure. Endoscopic retrograde pancreatogram had been utilizedto identify ductal abnormalities or obstructions, to clarify ductalanatomy before surgical intervention, and to confirm the patency ofpostsurgical anastomoses, including pancreaticojejunostomies.129

Now recent guidelines, published by the American Societyfor Gastrointestinal Endoscopy (ASGE) in 2006, recommendthat ERP should be reserved for patients in whom the diagnosisstill remains unclear after pancreatic function testing (PFT) orother noninvasive (CTor MRI) or less invasive imaging studies(EUS) have been performed.130

The diagnosis of CP by ERP is made on the basis of changesin the MPD and side branches, requiring a quality pancreatogramto most accurately delineate the ductal anatomy.131 Contrastshould be injected through the length of the pancreatic ductto the tail, as well as into the secondary branches while avoidingacinarization of contrast.131 It is also important to avoid intra-ductal air bubbles and movement artifact, which will contributeto misinterpretation of the pancreatogram.

The most accepted criteria for scoring ductal changes onpancreatograms are the Cambridge criteria131 (Fig. 20A), whichgrade pancreatograms from normal or equivocal to mild, moder-ate or severe CP based on main duct and side-branch abnormali-ties (Fig. 20B–E). Main duct abnormalities include dilation,narrowing, strictures, filling defects, and leaks or cavities. Identi-fication of these abnormalities can be subjective as their defini-tions are not clear. Average normal main duct diameters were3.6, 2.7, and 1.6 mm in the head, body, and tail respectively,131

although the upper limited normal may be as high as 6.5, 5, and3 mm in the head, body, and tail, respectively.131–133Main duct di-lation is either general (involving more than two thirds of the mainduct) or local (less than two thirds of the ducts). Severe dilationwas defined as being more than 1 cm. Side-branch abnormalitiesinclude decreased number, shortened length, and dilated ornarrowed caliber; however, the criteria to distinguish normalfrom abnormal are not clearly defined.

There are several limitations that account for the decline inthe use of ERP for diagnostic purposes. The ERP procedure is in-vasive and carries a risk of postprocedure complications, includ-ing AP. Endoscopic retrograde pancreatogram can be operatordependent, and the interpretation of pancreatograms is subjectto interobserver variability.134 Moreover, pancreatograms allowvisualization of the ductal anatomy only, without any parenchy-mal imaging. Other potential confounders to interpretation ofpancreatograms include age-related ductal changes,131,135–137

post-AP ductal changes,138,139 and Pancreatic IntraepithelialNeoplasia (PanIN)-related branch duct changes,140,141 which areindistinguishable from ductal changes related to CP.

The experts at the Cambridge conference admitted thatpancreatography “does not imply coincidence with the severityof disease pathology or functional status.”131 A recent study of31 patients who underwent both ERCP and pancreatic resectionshowed a correlation between the Cambridge criteria and histol-ogy in 74% (n = 23).142 This correlation between pancreatogramand histology was higher in patients with moderate and markeddisease (77%) by ERP than those with normal, equivocal, or mildchanges (67%).142 In a postmortem study of 69 patients withoutCP, pancreatic duct abnormalities on pancreatograms led to a di-agnosis of CP in 81% of the patients (minimal 37%, moderate33%, severe 11%). Therefore, considering ductal abnormalitiesalone can lead to amisdiagnosis of CP.137 In correlation with othertests, there is good correlation between ERP and MRCP.143,144

The correlation with PFT may be modest, particular with earlydisease,145,146 and is the subject of a later discussion.

In summary, ERP can yield useful diagnostic informationthough it is rarely used as a diagnostic modality in CP. The





FIGURE 20. Cambridge Criteria (normal - severe). Retrograde pancreatograms exhibiting various stages of change in pancreatic duct foradvancing. Reprinted from Axon et al,131 Copyright @ 1984, with permission from BMJ Publishing Group.


correlation of abnormalities on pancreatogram with histologyand function is higher in advanced disease than early disease.

Topic 7. Indirect Pancreatic Function Testing• John G. Lieb, II, MD, University of Pennsylvania, Philadelphia,PA (lead discussant)

Evidence-Based Medicine Statements1. Indirect PFTs generally are sensitive for steatorrhea and useful

in quantifying the degree of exocrine insufficiency.2. Indirect PFTs are moderately sensitive and specific for diag-

nosing advanced CP but are less so for diagnosing early CP.3. The fecal elastase assay, the polyclonal assay more than the

monoclonal, can be limited in specificity, especially if the stoolsample is watery and/or in the presence of small bowel disease.

4. Fecal chymotrypsin may be useful in detecting compliancewith exogenous pancreatic enzyme supplementation.



5. Fecal fat assays are sensitive for steatorrhea but are of limitedutility due to the cumbersome nature of patient collection andlaboratory handling of samples. In addition, strict adherenceto dietary recommendations for several days is required.

Level of Evidence1. Conditional recommendation (level of evidence, low)2. Conditional recommendation (level of evidence, strong)3. Conditional recommendation (level of evidence, low)4. Conditional recommendation (level of evidence, low)5. Conditional recommendation (level of evidence, moderate)

Indirect PFTs, such as serum trypsinogen, fecal elastase,and fecal fat measurements, do not require direct hormonalstimulation of the pancreas.145 Typically, indirect PFTs are sen-sitive only for late CP (when steatorrhea is already present).146

Thus, they are best used to quantify the degree of insufficiency





FIGURE 21. Traditional secretin PFT with Dreiling tube.


in established CP, rather than diagnosing CP.147 For example,indirect PFTs are modestly sensitive and specific even for ad-vanced CP.148–150 In general, indirect tests of pancreatic func-tion should always be accompanied by cross-sectional CT orMRI imaging studies to rule out malignancy.

In rare circumstances when direct PFT may not be avail-able or tolerated, indirect PFTs may be used to assist in the diag-nosis of CP. In this setting, it is crucial to understand thecharacteristics of the type of assay being used (serum trypsin byradioimmunoassay (RIA) vs enzyme-linked immunosorbant as-say (ELISA) and monoclonal vs polyclonal fecal elastase assays)and whether the patient has complied with pretesting preparations(high-fat diet for fecal fat measurement, etc). Laboratory factorsalso play a role, for example, a fecal elastase test should be per-formed on a solid stool sample to avoid falsely positive results.153

Serum amylase and lipase measurement should not be entirelydiscounted as a potentially useful indirect test of pancreatic func-tion, especially if they have a low value.154–157

Typically when performing indirect tests to diagnose CP, thereference values should likely meet a more stringent thresholdthan when performed in patients with established/obvious CP. Inthis setting, at least 2 indirect PFTs, sampling different substrates(blood, stool), should be performed. For example, a serum trypsinmeasured by RIA of less than 20 pg/dL158 and a fecal elastase lessthan 50 μg/dL stool by monoclonal antibody in the same patientare probably diagnostic of CP, although further study is neededin this area. Classic false-positive fecal elastase measurements(low levels) occur in small bowel bacterial overgrowth and waterystool.159,160 Conversely, classic false-negative serum trypsin mea-surements (normal/high levels) occur when performed in the

FIGURE 22. Endoscopic pancreatic function test.



setting of AP inflammation.161 In the absence of other supportingevidence, intermediate indirect PFT results (monoclonal fecalelastase 50–200 μg/dL or trypsin 20-29 pg/dL by RIA) shouldbe interpreted with caution when used to diagnose CP. A poly-clonal fecal elastase may be a better test162; however, the mono-clonal assay is currently better standardized, yet some largeultrasound commercial reference laboratories reflexively usethe polyclonal assay. Newer methods such as 13C-MTG triglyc-eride breath testing, although shown to be sensitive and spe-cific in select tertiary referral centers,163,164 have not yet beenuniversally adopted in the United States.

Fecal fat measurement alone is highly nonspecific and inisolation cannot diagnose CP. Exocrine pancreatic insuffi-ciency (steatorrhea) in the setting of established CP is cur-rently defined as more than 7 g of fat per 24 hours measuredby a 72-hour fecal fat test.165 This reference value is validonly in the appropriate clinical context; small bowel bacterialovergrowth and celiac sprue/short gut and inflammatorybowel disease have been excluded. A positive qualitative fe-cal fat (more than 6 droplets per high power field), which isa fairly insensitive test for steatorrhea,166,167 or monoclonalfecal elastase (<50 μg/dL) under similar circumstances wouldalso support the diagnosis of exocrine insufficiency. Fecal chy-motrypsin is currently only available through 1 company in theUnited States; however, because it detects porcine pancreaticelastase, it may be useful to evaluate patient compliance withexogenous pancreatic enzyme supplementation.170

The role of tests of endocrine function such as a serumpancreatic polypeptide level, other than traditional definitionsof diabetes such as a hemoglobin A1C, a fasting glucose, or





FIGURE 23. New Dreiling tube.


glucose tolerance test, has not been well characterized in the as-sessment of CP, and these endocrine tests are probably neithersensitive nor specific for CP but may serve as outcome mea-sures worthy of further investigation.169,170

Topic 8. Direct Pancreatic Function Tests• Linda S. Lee, MD, Brigham and Women's Hospital, Boston,MA (lead discussant)

Evidence-Based Statements1. Direct PFTs have high sensitivity for detecting late CP but

lower sensitivity (70%–75%) for early CP.2. The traditional secretin and cholecystokinin (CCK) PFTs

performed with the oroduodenal tube pancreas fluid collec-tion are highly accurate but require fluoroscopy for confir-mation of tube placement and are not widely utilized.

3. The endoscopic PFT (ePFT) has good correlation with the tra-ditional Dreiling PFT.

Level of Evidence1. Strong recommendation (level of evidence, low)2. Strong recommendation (level of evidence, moderate)3. Strong recommendation (level of evidence, moderate)

Direct PFTs have a long history, from traditional testing dat-ing back to the early 1900s to newer techniques, including the en-doscopically assisted and the purely endoscopic methods. DirectPFT may be limited by, among other factors, false positives forat least several months after a bout of AP and false negatives insome patients who have early CP. Direct PFT is capable of detect-ing secretory dysfunction in patients with at least 30% pancreasdamage and therefore has a high sensitivity for late CP, but itcertainly will miss patients with less severe pancreatic damage.

FIGURE 24. Liguory drainage tube (Burton method).



Sensitivity of the traditional Dreiling tube test for early CP de-creases to 70% to 75%.147,171,172

The original secretin-stimulated direct PFTwas performedwith the Dreiling tube and popularized at the University ofFlorida (Fig. 21). This test is highly accurate and measures ductcell function. This double lumen, 26F oroduodenal tube withboth gastric and duodenal ports is introduced using fluoros-copy guidance. The patient's oropharynx is medicated withtopical anesthesia. Under fluoroscopic guidance, the weightedtip of the Dreiling tube is swallowed and advanced close tothe ligament of Treitz and the tapered radiopaque portion ofthe tube is positioned at the pylorus. Low, constant suction isapplied to collect duodenal fluid at 0, 15, 30, 45, and 60 minutesafter an IV bolus injection of secretin, and the fluid is analyzedfor pH, volume, and bicarbonate concentration. Drawbacks of thisprocedure may include patient discomfort, need for fluoroscopy,and limited availability of the traditional Dreiling tubes. Pa-tients with nausea, gastroparesis, and pyloric stenosis pose achallenge to performing this procedure.

Another direct PFT is the CCK PFT developed at the MayoClinic, which is a dual tube technique using 2 double lumen tubesfor perfusion and aspiration of both gastric and duodenal contents.This test measures acinar cell function. This test incorporates amarker perfusion system to account for the amount of gastricand duodenal fluid that is “lost” or escapes aspiration into the dis-tal small bowel lumen to accurately calculate the total pancreaticenzyme secretory output. Disadvantages of this procedure includelimited availability of the special “dual tube” system, need forfluoroscopy, utilization of a PEG/mannitol marker, and need forcontinuous IV CCK infusion during the duration of the test.173

Combining secretin and CCK injection does not seem to yield im-proved results, and in fact, peak bicarbonate concentration over1 hour is the best correlate to histologic findings.

Several endoscopic variations of pancreas function testinghave been developed.174–180 The pure ePFT developed at theCleveland Clinic allows the patient to be moderately sedated,typically with a long-acting benzodiazepine and narcotic, forthe upper endoscopy while pancreas fluid is suctioned via the up-per esophagogastroduodenoscopy (EGD) or EUS endoscope.175

After IV bolus injection of secretin (0.2 μg/kg), duodenal fluid isaspirated from the duodenal bulb. When performing ePFT, it is im-portant to completely aspirate gastric secretions to avoid contamina-tion of duodenal fluid by the acidic gastric contents. Placing thepatient at a 30-degree angle or in Trendelenburg position preventsdistal migration and loss of duodenal fluid. It is also very importantto aspirate and discard approximately 2 to 4 mL of duodenal fluidbefore each collection to rinse residual gastric fluid from the suctionchannel. For the full 1-hour test, normal peak bicarbonate level isgreater than or equal to 80 mEq/L. The shortened screening testuses a peak bicarbonate cut point of 75 meq/L. Advantages of thistest include its simplicity, universal availability of upper





FIGURE 25. Correlation of EUS and PFT with pancreas fibrosis. There is moderate correlation of EUS and ePFT to pancreatic fibrosis.Reprinted from Albashir et al,187 Copyright @ 2010, with permission from the Nature Publishing Group.


endoscopy, and lack of need for fluoroscopy. Althoughmodest se-dation does not affect ePFT results, the impact of heavy sedationand/or general anesthesia on ePFT results is unclear and may con-found function test result interpretation.176 There is good correla-tion between the traditional Dreiling test and the ePFT test (Fig. 22).

A newer disposable latex-free version of the Dreiling tubecan also be endoscopically placed over a guide wire withfluoroscopic assistance (Fig. 23), whereas the Liguory tube(Frank Burton method) can be advanced over a wire during upperendoscopy without fluoroscopy.179 The disposable Liguory tubehas a pigtail tip with side ports at the end (Fig. 24). After theplacement of the tube, the patient is transferred to the recoveryareawhere secretin is administered and PFT is performed. The av-erage time for endoscopic Dreiling tube placement is approxi-mately 10 minutes in combination with 2 minutes of fluoroscopytime. Intraductal PFT performed during ERCP requires cannula-tion of the pancreatic duct followed by injection of secretin, andaspiration of pancreatic secretions fromwithin the pancreatic ductfor approximately 15 minutes. After secretin injection, the bi-carbonate level in pancreas fluid continues to rise and doesnot plateau for about 15 to 30 minutes (Fig. 22). Therefore,timing of aspirations is critical for accurate functional assess-ment. A recent study comparing intraductal PFT during ERCPto the standard Dreiling test reported a 20% specificity and 80%sensitivity for the intraductal test.180

In summary, the 1-hour ePFT and Dreiling tube collec-tion methods are the nonhistologic criterion standards for diag-nosis of early CP. A shortened 30- to 45-minute ePFT test maybe used to screen for CP. In practice, patients referred with

FIGURE 26. Diagnostic accuracy of EUS, ePFT, or combined EUS/ePFT. Afor early CP. Reprinted from Albashir et al,187 Copyright @ 2010, with p



chronic abdominal pain undergoing evaluation for early CPmay undergo screening for CP using EUS combined with theshortened 45-minute ePFT to assess for both structural and func-tional changes of CP. Because the 45-minute test has slightlylower specificity than the full 1-hour test, patients with borderlineresults should undergo a full 1-hour PFTwith the endoscopic orDreiling tube method.

Topic 9. Correlation of Imaging and FunctionWith Histology• Tyler Stevens, MD, Cleveland Clinic, Cleveland, OH (lead

discussant)

Evidence-Based Medicine Statements1. As structural severity worsens in CP, exocrine function

declines.2. Both EUS and PFT results correlate with fibrosis in CP.3. A combined approach (eg, EUS/ePFT) could improve detec-

tion of minimal change CP (MCCP).

Level of Evidence1. Strong recommendation (level of evidence, moderate)2. Conditional recommendation (level of evidence, low)3. Conditional recommendation (level of evidence, low)

Mild exocrine insufficiency is frequently present in mildand severe CP, and progressive structural fibrosis is reflectedin exocrine function decline. However, this relationship is not lin-ear, and imaging and PFT results are not perfectly concordant.

combined EUS/ePFT may be the most accurate means of accessingermission from the Nature Publishing Group.





FIGURE 27. STEP-wise algorithm approach to diagnosis of CP.Step 1: survey—data review, risk factors, CT imaging. Step 2:tomography—pancreas protocol CT scan, MRI/secretin-enhancedMRCP. Step 3: endoscopy—EUS (standard criteria). Step 4: pancreasfunction—Dreiling, ePFT. Step 5: ERCP (with intent for therapeuticintervention).




Multiple studies have shown suboptimal concordance of ERCPand PFT results, with the greatest discrepancy in mild disease.In 1 example, the concordance rate for secretin PFT and ERCPin noncalcific CP was only 47%.181 Endoscopic ultrasound isnow favored over ERCP for the endoscopic diagnosis of CPdiagnosis due to increased safety and the ability to evaluate boththe ductal and parenchymal architecture. As with ERCP, similardiscordance has been seen between EUS criteria and PFT results.The overall concordance rates between EUS and secretin PFTrange from 48% to 70% in 3 past studies comparing EUS andsecretin PFT.180,182,183 In 302 patients undergoing a combinedEUS and secretin endoscopic PFT, a moderate correlation wasobserved between peak bicarbonate concentration and EUSscore (r = −0.59).180

Only a few recent studies evaluating ERCP, EUS, and PFThave incorporated histological reference standards. Two studiescompared secretin and cholecystokinin PFT results with histo-logical fibrosis. Twenty-five patients underwent a PFT beforesurgery for painful CP.184 A discriminative analysis revealedmoderate correlations of certain PFT parameters (eg, peak bicar-bonate and trypsin concentrations) with specific histologicalfeatures (eg, atrophy, small duct dilation). Weaker correlationswere observed between other parameters. Another study com-pared PFT results with pancreatic histology in 108 patients un-dergoing a variety of abdominal surgeries.172 Most patients hadsurgery done for nonpancreatic indications (eg cholecystec-tomy) that included performance of a wedge biopsy of the pan-creas. A significant correlation (r = 0.59) was observedbetween the overall PFT and histological rating scales.

Three recent studies185–187 have compared preoperativeEUS criteria with histology in patients undergoing pancreaticresections or operative biopsy, using the pancreatic fibrosis scoreof Ammann et al.36 These studies differ in the patient populations(CP vs pancreatic masses) disease severity (minimal change vscalcific) and the fibrosis score cut point used to diagnose CP.The overall correlation coefficients for EUS versus fibrosis scoresrange from 0.40 to 0.85, suggesting a moderate to very good cor-relation. The sensitivity and specificity estimates for EUS com-pared with the histological reference standard range from 83%to 91% and 80% to 100%, respectively. Another study reportedpreoperative EUS results in 50 patients undergoing total pancrea-tectomy with autologous islet cell transplant.188 One to 3 wedgebiopsies were obtained for histological examination before enzy-matic digestion of the gland for islet cell isolation. The histologi-cal findings of fibrosis, atrophy, or inflammation were consideredindividually diagnostic of CP. This study was less encouraging forEUS as a diagnostic test. Compared with histology, the area underthe receiver operating characteristics curve was only 0.593, in-dicating poor discrimination. Furthermore, the negative andpositive predictive values were poor even when the EUS cutpoint was optimized for each.

It is controversial whether EUS or PFT is most sensitivefor detecting early CP. It is clear that some patients with signif-icant structural changes have preserved exocrine function,whereas others have minimal or no EUS features and mightstill have an abnormal PFT indicating early CP. In a recentstudy, EUS and/or a secretin endoscopic PFTwere done in 25patients within 1 year of resection or open biopsy.187 Twelvepatients had both tests done and had histological fibrosis indi-cating CP. Correlations for EUS and ePFTwere 0.72 and 0.57,respectively (Fig. 25). Of these, all 25 had either an abnormalEUS or ePFT, indicating 100% sensitivity of the combined ap-proach (Fig. 26). Although the sample size is small, these re-sults imply that combining structural with function testingmay optimize the detection of MCCP.





TABLE 5. Diagnostic Evidence for CP Diagnosis

Evidence Criteria

Definitive evidence (any of the following) Moderate/marked pancreas imaging morphology (ie, ductal andparenchymal abnormalities)

Pancreatic calcificationsHistologic confirmation

Probable evidence (abnormal imaging/suggestive history+ abnormal physiology)

Mild pancreas imaging morphologyorRecurrent pseudocyst/pancreatitisplusAbnormal pancreas physiology (secretin test, diabetes, steatorrhea)

Insufficient evidence Equivocal pancreas imaging morphologyorAbdominal pain with any of the following:No history of pancreatitis (lipase < 3� upper limit of normal (ULN)Normal imagingFamily history of pancreatitisPrior ERCP with pancreatic duct stentingPresence of TIGAR-O risk factors (smoking, alcohol)

Evidence should be interpreted in a patient with history and physical examination suspicious for CP such as abdominal pain, history of AP, steatorrhearesponsive to pancreatic enzyme replacement therapy, heavy alcohol or smoking history, and genetic risk factors of family history.


In summary, the overall correlation of EUS and PFT withhistology seems to be in the moderate to very good range. Thestudies comparing EUS and PFT with histology have signifi-cant limitations. Most were done using a highly selected sampleof patients undergoing planned pancreatic surgery. The studiesare heavily weighted with severe disease, which may falsely ele-vate sensitivity (ie, spectrum bias). In addition, not all patientsundergoing the EUS or PFT go on to receive a histologicaldiagnosis, which produces verification bias. The use of wedgepancreatic biopsies in some studies may lead to sampling bias.A combined EUS/ePFTapproach may bemost useful for the eval-uation of patients with chronic abdominal pain and suspectedearly or MCCP.

TABLE 6. Pancreas Morphology Imaging Grade (I–IV)34

Ultrasound

Equivocal (I) Mild (II

Same as CT Same as C

CT/MRI scan 1 of the following: main ductenlarged (2–4 mm), slightgland enlargement, heterogenousparenchyma, small cavities(<10 mm), irregular ducts,focal pancreatitis, increasedechogenicity of main duct wall,irregular head/body contour

≥2 of the following:main duct (2–4 menlargement, heterparenchyma, smal(<10 mm), irregufocal AP, increasedof main duct wall,head/body contour

EUS (0–9 criteriastandard criteria)

0–2 3–4

MRCP/ERCP <3 Abnormal side-branchchanges

≥3 Abnormal side-bchanges



Summary of Diagnostic Guidelines in CP• Darwin L. Conwell, MD, MS, Ohio State University WexnerMedical Center, Columbus, OH (lead discussant)

Confirming a diagnosis of CP is clear in highly suspiciouspatients (recurrent pancreatitis, alcohol or smoking abuse) withsteatorrhea, weight loss, and marked/moderate morphologicchanges in the gland. The diagnosis of CP still remains chal-lenging in early stages (equivocal and mild morphologic orphysiologic changes) of the disease.9,10 These patients shouldnot be classified as having CP until definitive diagnostic featuresare evident. Our guidelines propose a diagnostic algorithm thatproceeds from a noninvasive to more invasive diagnostic

) Moderate (III) Marked (IV)

T Same as CT Same as CT

enlargedm), glandogenousl cavitieslar ducts,echogenicityirregular

Cannot distinguishfrom mild

Moderate changes plus ≥1of the following: large cavities(>10 mm), gland enlargement,intraductal filling defects/calculi,duct obstruction, strictureor gross irregularity

≥5

ranch Abnormal main duct;>3 abnormal sidebranches

Moderate changes plus;1 of the following:obstruction, fillingdefects, severeirregularity/dilationof main duct





TABLE 9. CP Case Studies

Diagnosis case 1: insufficient evidence. A 35-year-old woman withchronic narcotic requiring abdominal pain. A CT scan is normalwithout evidence of a pancreas mass. MRI/secretin-enhancedMRCP is normal. Pain is similar to ERCP-induced pancreatitispain. No history of pancreatitis before or after resolution ofERCP-induced AP. Stool fecal elastase is >500 μg/g on a solidsample. Tertiary referral center EUS has 3 criteria, and ePFT hasa peak bicarbonate of 83 meq/L.Diagnosis: chronic abdominal pain syndrome

Diagnosis case 2: probable evidence. A 56-year-old male smokerwith history of alcohol abuse 10 years earlier who presents withintermittent abdominal pain and mild lipase enzyme elevations to2� ULN. Computed tomography scan is negative for pancreasmass. Fecal elastase is 225 μg/g on a solid stool sample. MRI showsdecreased T1 signal, and secretin-enhanced MRCP reveals a fewprominent side branches. EUS shows 4 criteria, and ePFT has apeak bicarbonate of 69 meq/L.Diagnosis: chronic alcohol-induced pancreatitis, imaging grade II,physiology stage B

Diagnosis case 3: definitive evidence. A 33-year-old woman withacute onset of severe AP. No prior history or use of alcohol or drugs.Computed tomography scan consistent with interstitial pancreatitiswithout a pancreas mass. Her father had a pancreaticojejunostomywhen he was 25 years old for recurrent pancreatitis. Further testingreveal mildly elevated glucose to 150 and glycohemoglobin in7.5 mg/dL. Genetic testing revealed PRSS1 mutation. Patientwas followed for several months and continued to have recurrentpancreatitis and nonnarcotic requiring abdominal pain. MRI had alow T1 signal, and secretin-enhanced MRCP revealed a mildlyirregular main pancreas duct with multiple side-branch dilations.Total pancreatectomy with autologous islet transplant wasperformed. Final pathology reveled inflammation, fibrosis, andatrophy consistent with CP.Diagnosis (before total pancreatectomy with islet transplantation(TPIAT)): chronic genetic (PRSS1)-induced pancreatitis, imaginggrade III, physiology stage D

Diagnosis case 4: definitive evidence. A 18-year-old female collegefreshman presents to emergency department with acute onset of

TABLE 7. Pancreas Physiology Stage35

Stage Physiologic Definition

A Normal secretory, exocrine, and endocrine functionB Secretory dysfunction (abnormal secretin stimulation test)C Exocrine insufficiency (abnormal fecal elastase, steatorrhea,

low serum trypsin)D Endocrine insufficiency (abnormal fasting glucose,

glycohemoglobin, glucose tolerance test)E Both C and DX Not classified/unknown


approach (Fig. 27A–B). This algorithm maximizes specificity(low false-positive rate) in subjects with chronic abdominal painand equivocal imaging changes. The diagnosis of CP is madebased on definitive criteria. All patients with suspected CP shouldhave a dedicated pancreatic protocol CT scan or MRI/MRCP torule out pancreas carcinoma.

Our guidelines define the diagnostic evidence for CP as de-finitive, probable, and insufficient based on current knowledgeof the natural history of the disease (Table 5). Without sufficientevidence, patients should not be mislabeled as having CP, whenin fact they may have chronic abdominal pain syndrome anda remote history of ERCP-induced pancreatitis or ductal changes.Given there is no current therapy to alter disease progression, it isbetter to error on the side of not labeling the patient with CP. Inmost cases, longitudinal follow-up is recommended with serialimaging and physiologic testing in equivocal/mild cases with in-sufficient evidence of CP until definitive evidence is apparent.

Once a diagnosis of CP is confirmed, our guidelines rec-ommend a comprehensive characterization of CP in regards toetiology (TIGAR-O; see Table 2), morphology (modified fromMannheim group, Table 6), and physiologic state (Table 7). In anattempt to standardize research studies across centers, a nomencla-ture is proposed (Table 8). To conclude, case studies are presented

abdominal pain, nausea, and vomiting. Amylase and lipase are both>3� ULN; liver function test (LFT)s are normal. Computedtomography imaging suggests focal inflammation and fullnessof pancreas. MRI scan is suggestive of AIP with focal dilationof pancreatic tail in region of parenchymal inflammation. EUSconfirms findings on cross-sectional imaging; there is no evidencefor a mass. Periampullary biopsies and staining for IgG4 arenegative. Serum IgG4 is normal. Fecal elastase >500 μg/g.Patient abdominal pain requiring narcotics to control, intractableto 5 weeks of steroids and 1 week hospitalization for pancreaticrest (nothing by mouth (NPO)). Repeat MRI and EUS confirmprevious findings with persistent focal dilation of distal duct;fine needle aspiration (FNA) biopsy was nondiagnostic. Distalpancreatectomy recommended for intractable pain and concern offocal duct dilation. Pathology revealed ductcentric lymphopasmacyticinfiltration suggestive of AIP; IgG4 staining is negative.Diagnosis: chronic autoimmune pancreatitis, imaging grade IV,physiology stage A

TABLE 8. APA CP Nomenclature

In an attempt to combine the latest diagnostic criteria into a workingnomenclature that incorporates etiology, morphology, andphysiologic status, we propose the following nomenclature forCP once probable or definitive evidence is present:

Chronic (TIGAR-O etiology – induced) pancreatitis +MANNHEIM/Cambridge imaging grade (normal [0] – marked[IV])+ physiology stage (A, B, C, D, E, X)

Examples:Nomenclature example 1: chronic toxic (alcohol, smoking)-inducedpancreatitis, imaging grade III, physiology stage C – alcoholand smoking risk factors, ductal abnormalities on imaging withexocrine insufficiency as measured by fecal elastase, fecal fat orserum trypsinNomenclature example 2: chronic genetic (PRSS1mutation)-inducedpancreatitis, imaging grade II, physiology stage E genetic risk factors,mild imaging changes with both exocrine (as above) and endocrineinsufficiency as measured by glycohemoglobin, fasting glucoseor glucose tolerance testNomenclature example 3: chronic severe acute (pancreaticnecrosis)-induced pancreatitis, imaging grade II, physiologystage A sequelae of necrotizing pancreatitis with mild ductalchanges and preserved glandular function



to emphasize salient features of the proposed diagnostic evalua-tion (Table 9).

It is our intent that this manuscript serve as a baseline “work-ing document” that will be modified as new evidence becomesavailable and our knowledge of CP improves.

REFERENCESReferences are available online at: http://links.lww.com/MPA/A335.





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