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Introduction

Chronic pancreatitis is an inflammatory disorder of the pan￾creas that leads to changes in the structure of the gland, ulti￾mately resulting in impairment of its endocrine and exocrine

functions [1]. As opposed to acute pancreatitis, where injury

to the gland is transient, the morphologic and functional

changes associated with chronic pancreatitis are irreversible

[1–3]. Because of variations in presentation, the true preva￾lence of chronic pancreatitis has been difficult to study,

although most estimates range from 0.04 to 5% [1]. The vari￾ous causes of chronic pancreatitis are discussed in detail in

Chapters 39–43.

While the gold standard for the diagnosis of chronic pancre￾atitis is histologic, such an invasive approach is not feasible for

most patients. As such, the diagnosis of chronic pancreatitis is

typically made by other tests of pancreatic structure and func￾tion [4]. Endoscopic retrograde cholangiopancreatography

(ERCP), magnetic resonance cholangiopancreatography

(MRCP), and endoscopic ultrasound (EUS) are three imaging

modalities which, over the past decade, have rapidly changed

both the diagnostic and the therapeutic approach to chronic

pancreatitis. This chapter discusses the role of each of these

modalities in the diagnosis of chronic pancreatitis.

Diagnosis

In patients with advanced disease, the diagnosis of chronic

pancreatitis can be made by virtually any available test, obvi￾ating the need for invasive testing [4,5]. Although a history of

alcohol abuse and longstanding epigastric pain coupled with

the finding of pancreatic calcifications on plain abdominal

radiography is pathognomonic of chronic pancreatitis, this

occurs in only 30% of cases [1]. The presentation of chronic

pancreatitis can be highly variable, with differing pain pat￾terns and duration; up to 20% of patients may present with

so-called “painless pancreatitis.” Indeed, some patients may

be minimally symptomatic or “presymptomatic” despite

advanced degrees of pancreatic fibrosis [6]; these patients may

often have normal laboratory and imaging studies. In this

group of individuals with so-called “early” chronic pancreati￾tis, the diagnosis may be particularly challenging [7].

Endoscopic retrograde

cholangiopancreatography

Historically, ERCP has been thought to be the most specific

and sensitive imaging technique for the diagnosis of chronic

pancreatitis [8–10]. In most studies, the sensitivity and speci￾ficity of ERCP for the diagnosis of chronic pancreatitis have

ranged from 70 to 90% and 80 to 100%, respectively

[5,11–16] (Table 49.1). Ductal abnormalities detected using

ERCP can be classified from normal to severe depending on

the appearance of the main pancreatic duct, the number of

abnormal ductal side branches identified, and the presence or

absence of additional features such as evidence of ductal

obstruction, severe dilation, or irregularity. Together, these cri￾teria comprise the Cambridge classification of pancreato￾graphic findings in chronic pancreatitis [17] (Table 49.2).

Alternating strictures with ductal dilations, also known as

the “chain-of-lakes” appearance, are pathognomonic for

chronic pancreatitis. Other common findings include a dif￾fusely dilated pancreatic duct and the presence of visible side

branches (Fig. 49.1). The sensitivity and specificity of ERCP

for the diagnosis of chronic pancreatitis are greatest when obvi￾ous, advanced ductal abnormalities such as these are present.

The sensitivity and specificity decrease as the ductal changes

477

Endoscopic retrograde

cholangiopancreatography, magnetic

resonance cholangiopancreatography,

and endoscopic ultrasound in chronic

pancreatitis

Andrew S. Ross and Irving Waxman

49

9781405146647_4_049.qxd 1/30/08 11:46 AM Page 477

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Second Edition

Edited by H. G. Beger, A. L. Warshaw, M. W. Büchler, R. A. Kozarek, M. M. Lerch, J. P. Neoptolemos,

K. Shiratori, D. C. Whitcomb, and B. M. Rau © 2008 Blackwell Publishing Limited, ISBN: 978-1-405-14664-7

become more subtle [11,18]. This is likely due to the fact that

subtle ductal abnormalities can be caused by diseases other

than chronic pancreatitis. In addition, less dramatic pancre￾atographic changes are open to a certain degree of subjectivity,

resulting in a high degree of interobserver variation in inter￾pretation [4,11].

Several additional factors may work to negatively impact

the accuracy of ERCP in the diagnosis of chronic pancreatitis.

The quality of the study may have a significant effect on diag￾nostic accuracy. A good-quality ERCP is defined as filling of

the pancreatic duct to the second generation of side branches

in the absence of a movement artifact [4,11,19]. Some have

suggested that up to one-third of all studies do not meet these

criteria [4]. In addition, many of the pancreatographic find￾ings associated with chronic pancreatitis are nonspecific.

Normal aging, pancreatic carcinoma, acute pancreatitis, and

pancreatic stent placement may produce changes similar to

those found in chronic pancreatitis [4,11,20,21]. As always,

all radiographic findings should be interpreted within the con￾text of the clinical history.

ERCP has traditionally been used to establish the diagnosis

of chronic pancreatitis in symptomatic patients with normal

abdominal radiographs and the absence of steatorrhea. In

most patients, abnormalities on ERCP correlate with func￾tional pancreatic impairment. Ductal abnormalities detected

using ERCP may or may not correlate with the degree of func￾tional pancreatic impairment. Bozkurt et al. [16] prospectively

compared ERCP findings and pancreatic function in 48

patients with an established diagnosis of chronic pancreatitis.

Pancreatic insufficiency was found in none of the patients

with a normal pancreatogram, whereas almost all of those

with markedly abnormal studies (Cambridge class III) were

found to have abnormal functional pancreatic testing.

However, some patients, especially those with early chronic

pancreatitis, have a normal pancreatogram [17]. In such cases,

where clinical suspicion remains high despite a normal ERCP,

additional diagnostic testing is warranted. Aside from the

diagnosis of chronic pancreatitis, ERCP has been used to pro￾vide a “road-map” of the pancreatic duct in patients with

severe disease or complications requiring surgery. The use of

therapeutic ERCP in chronic pancreatitis is discussed in

Chapter 53.

Despite its wide availability and high sensitivity for the diag￾nosis of chronic pancreatitis, ERCP is an invasive procedure

with a significant associated complication rate [22]. Short-term

complications including perforation, hemorrhage, infection,

cardiopulmonary problems, and pancreatitis have been

reported to occur in 5–10% of all patients undergoing the pro￾cedure, regardless of whether endoscopic sphincterotomy was

performed [22,23]. In addition, ERCP carries a 0.1–0.5% mor￾tality risk [11]. The risk of complications associated with

ERCP is closely related to operator skill and experience [22].

Given these risks, the use of other imaging modalities (such as

CHAPTER 49

478

Figure 49.1 Pancreatogram revealing a diffusely dilated main

pancreatic duct with multiple visible side branches. These findings

are consistent with severe chronic pancreatitis.

Table 49.1 Sensitivity and specificity of endoscopic retrograde

cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS)

for the diagnosis of chronic pancreatitis.

Imaging Sensitivity Specificity

technology (%) (%)

ERCP 70–90 80–100

EUS 79–87 72–91

Table 49.2 Cambridge classification of pancreatographic findings of chronic pancreatitis. (From ref. 10 with permission.)

Terminology Main pancreatic duct Duct side branches Additional features

Normal Normal None None

Equivocal Normal
3 None

Class I Normal 3 None

Class II Abnormal 3 None

Class III Abnormal 3 One or more of large cavity, filling

defects, severe dilation, or irregularity

9781405146647_4_049.qxd 1/30/08 11:46 AM Page 478

EUS and MRCP) to establish the diagnosis of chronic pancre￾atitis has greatly increased, thus relegating ERCP to a more

therapeutic role [24].

Endoscopic ultrasound

Although ERCP has high sensitivity for the diagnosis of

chronic pancreatitis, it is limited because it is only able to visu￾alize the pancreatic duct; pancreatic parenchymal changes

cannot be appreciated. As discussed previously, the diagnostic

sensitivity of ERCP for chronic pancreatitis is therefore great￾est when ductal changes consistent with severe advanced

chronic pancreatitis are present [7,11]. EUS was developed in

the 1980s as an imaging modality designed to perform high￾resolution imaging of the entire pancreas [25–27]. The use of

high-frequency transducers allows the user to detect subtle

parenchymal changes and minor ductal abnormalities in

patients with chronic pancreatitis [28,29]. In addition, the use

of EUS overcomes the major obstacles to pancreatic imaging

by transabdominal ultrasound, namely intestinal bowel gas

and fat [30].

EUS of the normal pancreas reveals a homogeneous echo￾texture that is more echogenic than the liver. The main pan￾creatic duct diameter is approximately 2.4 mm in the head,

1.8 mm in the body, and 1.2 mm in the tail. Side branches are

visible using EUS; however, they are narrow, with the greatest

diameter (0.8 mm) occurring in the head of the gland [30,31].

The diagnosis of chronic pancreatitis by EUS is based on the

presence of up to nine abnormalities of the pancreatic duct

and parenchyma [29] (Table 49.3). Ductal abnormalities

include increased wall echogenicity, irregular caliber or dila￾tion of the main pancreatic duct, dilation of side branches,

and the presence of calculi (Fig. 49.2). Parenchymal changes

include focal areas of reduced echogenicity, hyperechoic foci,

the presence of cysts, and lobular morphology (Fig. 49.3).

Studies vary with regard to the number of abnormalities

required to make the diagnosis of chronic pancreatitis by EUS,

ERCP, MRCP AND EUS IN CHRONIC PANCREATITIS

479

Table 49.3 Endoscopic ultrasound features of chronic pancreatitis. (From Ref. 32

with permission.)

Parenchymal

Focal areas of reduced echogenicity

Hyperechoic foci (3 mm diameter)

Gland size, cysts

Accentuation of lobular pattern (hypoechoic areas surrounded by hyperechoic septae)

Ductal

Increased duct wall echogenicity

Irregular caliber of main pancreatic duct

Dilation of main pancreatic duct (3 mm in head, 2 mm in body, 1 mm in tail)

Dilation of side branches

Calculi

Figure 49.2 Endoscopic ultrasound (EUS) image revealing a dilated

pancreatic duct with increased echogenicity of the duct wall. These

ductal changes are commonly seen when EUS is performed in

patients with chronic pancreatitis.

Figure 49.3 Endoscopic ultrasound (EUS) image revealing a

heterogeneous pancreas with hyperechoic foci. These findings are

consistent with the parenchymal changes often identified during EUS

performed in patients with chronic pancreatitis.

9781405146647_4_049.qxd 1/30/08 11:46 AM Page 479

although almost all require a minimum of three [7,29,32–36].

Minimal standard terminology for the description of

endosonographic changes consistent with chronic pancreatitis

has been developed [37] (Table 49.4).

The sensitivity and specificity of EUS for the diagnosis of

chronic pancreatitis (see Table 49.1) remains the subject of

much controversy. By definition, the sensitivity and specificity

of any diagnostic test are determined by comparison with the

“gold standard” test for the condition of interest. A reliable

gold standard for the diagnosis of chronic pancreatitis has not

been universally agreed [7]. The ideal gold standard for the

diagnosis of chronic pancreatitis would be pancreatic histol￾ogy, but this is clearly not feasible due to the high risk associ￾ated with pancreatic biopsy. In many studies, ERCP is chosen

as the diagnostic gold standard, although this technique is not

without its problems [7]. Chronic pancreatitis can exist in the

setting of a normal pancreatogram [4,17], a high degree of

interobserver variability exists in the interpretation of pancre￾atograms [4,38], and the ERCP changes of chronic pancreati￾tis are nonspecific [4,7,38,39].

Because of the lack of an approved gold standard diagnostic

test, EUS has been compared with several different modalities

in order to better understand its sensitivity and specificity for

the diagnosis of chronic pancreatitis. Multiple studies have

compared EUS with ERCP [7,28,29,32–36] for the diagnosis

of chronic pancreatitis. In three studies [29,32,35], both stan￾dard EUS criteria and the Cambridge classification for ERCP

were used and the results can therefore be compared with each

other directly [30]. If three endosonographic criteria are used

as a cutoff for the diagnosis of chronic pancreatitis, EUS and

ERCP agree in approximately 80% of cases [7,30]. Agreement

is highest in cases of severe advanced chronic pancreatitis.

However, in the majority of cases where the two tests disagree,

EUS demonstrated abnormalities when ERCP was normal.

The major question that has arisen is whether EUS is more

sensitive than ERCP or whether endosonographers are simply

overdiagnosing chronic pancreatitis [7,30]. The overall sensi￾tivity and specificity of EUS using ERCP as the gold standard

are 87% and 75%, respectively [29,32,35]. The sensitivity

and specificity of EUS compared with ERCP vary with respect

to the number of endosonographic criteria required to make

the diagnosis of chronic pancreatitis [30].

When pancreatic function testing is used as the comparison

gold standard for the diagnosis of chronic pancreatitis, EUS has

a sensitivity of 79% and specificity of 72% [29,32]. Agreement

was seen between the two tests in 75% of cases; however, simi￾lar to the case with ERCP, of the 25% of cases where there was

disagreement, 71% had abnormal EUS in the setting of normal

pancreatic function testing [30], again raising the issue as to

whether EUS is “overdiagnosing” chronic pancreatitis.

One small study compared pancreatic histopathology with

EUS for the diagnosis of chronic pancreatitis [40].

Histopathology was obtained by pancreatectomy or pancreatic

biopsy in 34 patients, all of whom had undergone prior EUS.

Using a threshold of three endosonographic criteria for the diag￾nosis of chronic pancreatitis, the sensitivity and specificity of

EUS were 87% and 64%, respectively. As the number of criteria

was increased, the sensitivity and specificity moved in opposite

directions. When six or more endosonographic criteria were

required to diagnose chronic pancreatitis, the sensitivity and

specificity were 43% and 91%, respectively. The results of this

study suggested that the use of four or more endosonographic

criteria (sensitivity 78%, specificity 73%) was ideal for the diag￾nosis of chronic pancreatitis [30]. While pancreatic biopsy to

obtain histopathology is highly invasive and associated with sig￾nificant operative risk, the use of EUS-guided fine-needle aspira￾tion (FNA) is less so. Although limited to cytology, the addition

of FNA has expanded the utility and diagnostic accuracy of EUS

for a variety of conditions. A single study [41] found that adding

FNA to EUS increased the negative predictive value of EUS to

CHAPTER 49

480

Table 49.4 Minimal standard terminology (MST) definitions for endoscopic ultrasound (EUS) findings in chronic

pancreatitis. (From ref. 37.)

EUS criteria for chronic pancreatitis MST definition

Hyperechoic foci Small distinct reflectors

Hyperechoic strand Small string-like hyperechoic structures

Lobular out gland margin No MST definition

Lobularity Containing lobules: rounded homogeneous areas separated by strands of another

echogenicity

Cyst Abnormal anechoic round or oval structure

Stone Hyperechoic lesion with acoustic shadowing within a duct or gallbladder

Calcification Hyperechoic lesion with acoustic shadow within a parenchymal organ or a mass

Ductal dilation No MST definition

Side-branch dilation No MST definition

Duct irregularity Coarse, uneven outline of the duct

Hyperechoic duct margins No MST definition

Atrophy No MST definition

Nonhomogeneous echo pattern No MST definition

9781405146647_4_049.qxd 1/30/08 11:46 AM Page 480

100% and the specificity to 64% when compared with ERCP as

the diagnostic gold standard. Although no standardized histo￾logic or cytologic criteria exist for the diagnosis of chronic pan￾creatitis by FNA, a scoring system was used which graded each

specimen with regard to the presence of an inflammatory cellular

infiltrate. The results of this study suggest that FNA is most help￾ful for excluding chronic pancreatitis when mild or patchy

parenchymal abnormalities with unclear significance are identi￾fied on EUS. FNA was generally well tolerated; mild acute pan￾creatitis occurred in 2 of 27 patients studied.

Given the ability to visualize both the pancreatic parenchyma

and duct, in addition to its excellent sensitivity and low associ￾ated procedural risk, the use of EUS for the diagnosis of chronic

pancreatitis has increased over the past decade. As such, the use

of minimal standard terminology to describe endosonographic

findings and the appropriate number of endosonographic

abnormalities required to make the diagnosis of chronic pancre￾atitis are of critical importance. The accuracy of any diagnostic

test is related to the reproducibility of its results [7]. When 11

experienced endosonographers who were blinded to the clinical

history independently evaluated previously taped examinations

for the presence of EUS criteria of chronic pancreatitis, diagnos￾tic agreement was reached at a rate comparable with other

endoscopic or radiographic tests [42]. Agreement was highest

for ductal dilatation and lobularity. As with any diagnostic test,

the clinical history is key to interpreting the results of EUS in the

diagnosis of chronic pancreatitis.

Magnetic resonance cholangio￾pancreatography

While ERCP has been associated with an incidence of acute

pancreatitis in up to 10% of individuals who undergo this

procedure [32], MRCP is able to provide high-quality imaging

of the pancreatic and biliary ducts in a noninvasive manner

[43]. Wallner et al. [44] first described MRCP in 1991. At that

time, the study was time-consuming with questionable image

quality. Over the past 15 years, however, the acquisition time

for single images has gone from 5 min to 2 s, allowing more

widespread use of this technology. In most centers, the imple￾mentation of high-quality MRCP into clinical practice has

replaced diagnostic ERCP [24].

Takehara et al. [45] first compared MRCP, specifically mag￾netic resonance pancreatography, with ERCP for the diagnosis

of chronic pancreatitis. High-quality images of the pancreatic

duct in the head, body, and tail of the gland were obtained in

70%, 64%, and 53%, respectively, of patients, all of whom

had been previously diagnosed with chronic pancreatitis based

on ERCP. Agreement between the two tests was observed in

83–92% of cases of ductal dilatation, 70–92% of cases of

ductal narrowing, and 92–100% of cases with ductal filling

defects. This study also found low interobserver variation for

most findings, although MRCP did tend to overestimate the

extent of pancreatic ductal stenosis [43,45]. Other studies

have yielded similar findings [46].

Secretin is a hormone secreted by the gastrointestinal tract

that leads to rapid secretion of a bicarbonate-rich fluid from

the exocrine pancreas [43,47]. As a result, the volume of fluid

in the pancreatic duct increases. The administration of intra￾venous secretin to improve imaging of the pancreatic duct was

first described in combination with transabdominal ultra￾sonography for the diagnosis of chronic pancreatitis [48,49].

Because of the tendency of MRCP to overestimate pancreatic

ductal stenosis, Takehara et al. [50] studied the use of secretin

stimulation during the acquisition of images in order to

improve signal intensity and imaging of the pancreatic duct in

patients suspected of having pancreatic disease. The investiga￾tors found that the use of secretin improved evaluation of the

main pancreatic duct and its side branches compared with

imaging not using secretin stimulation (Fig. 49.4). These

results have been replicated by other groups [47,51].

Since this initial study, several investigations have focussed

specifically on secretin-enhanced MRCP for the diagnosis of

chronic pancreatitis [52,53]. Manfredi et al. [52] studied this

modality in 31 patients with chronic pancreatitis. The use of

secretin increased the percentage of visible pancreatic duct

segments from 91 to 100% and side branches from 71 to

100%. Although the improved ductal visualization with

secretin was not statistically significant, the authors noted that

improved visualization of the ductal side branches may allow

earlier diagnosis of chronic pancreatitis, thus reducing the

ERCP, MRCP AND EUS IN CHRONIC PANCREATITIS

481

Figure 49.4 Secretin-stimulated magnetic resonance

cholangiopancreatography revealing a markedly dilated main

pancreatic duct with multiple visible side branches. These findings

are consistent with severe chronic pancreatitis.

9781405146647_4_049.qxd 1/30/08 11:46 AM Page 481

false-negative rate and improving the specificity of MRCP for

this diagnosis. Standardized criteria for the diagnosis of

chronic pancreatitis by MRCP have yet to be developed.

Aside from improving delineation of the pancreatic ductal

morphology, secretin-enhanced MRCP may have value in the

measurement of pancreatic exocrine function. Matos et al. [47]

performed MRCP in 10 volunteers and 13 patients with sus￾pected pancreatic disease. Pancreatograms were obtained prior

to and then at 30-s intervals following the administration of

secretin. The volume of filling within the duodenum was used

as a quantitative measure of pancreatic function. The results

were compared with ERCP and secretin stimulation testing.

The study found that the mean duodenal filling score was sig￾nificantly lower in patients with known reduced exocrine func￾tion compared with that in volunteers, thus providing the first

evidence that secretin-stimulated MRCP has the potential to

detect impaired pancreatic exocrine function. These results

have been confirmed by other investigators [52,54–56].

Direct comparisons of MRCP with EUS for the diagnosis of

chronic pancreatitis have yet to be performed. In comparison

with EUS and ERCP, MRCP is certainly the least invasive.

Secretin-stimulated MRCP has the additional advantage of

evaluating pancreatic function, an attribute not shared by EUS

or ERCP. Although not yet studied, this feature may enhance

the specificity of MRCP for the diagnosis of chronic pancreati￾tis. ERCP does not provide detailed images of the pancreatic

parenchyma; this is a potential disadvantage compared with

EUS, which has the ability to detect both ductal and parenchy￾mal abnormalities. Magnetic resonance imaging (MRI) of the

pancreas is possible at the same time as MRCP, although this

adds cost and time to the examination. The MRI findings asso￾ciated with chronic pancreatitis [57] are beyond the scope of

this chapter. Due to its minimally invasive nature and high cor￾relation with ERCP findings, MRCP is often ordered as the

first test for the diagnosis of chronic pancreatitis in cases where

advanced imaging modalities are required [52].

Diagnostic approach

The use of advanced imaging modalities such as ERCP, MRCP,

and EUS for the diagnosis of chronic pancreatitis is not

required in the majority of cases. Indeed, in many cases of

chronic alcoholic pancreatitis, the clinical history alone can be

sufficient to make the diagnosis [11]. However, in some cases,

especially early chronic pancreatitis, advanced imaging is

required. Of these three modalities, EUS likely has the greatest

ability to diagnose early disease. Although it is an invasive

diagnostic test, the complication rate associated with EUS is

less than that of ERCP and it has the ability to detect both mor￾phologic and ductal abnormalities. While MRCP is clearly the

least invasive, it is an expensive test with results that may be

center-dependent. In addition, the ability to visualize the pan￾creatic duct alone may decrease its diagnostic sensitivity for

early disease. Finally, it is the least studied of the three modali￾ties discussed in this chapter. While it is often considered the

gold standard, the high rate of procedure-related complications

associated with ERCP has limited its use in chronic pancreatitis

to the performance of therapeutic interventions.

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Endoscopic ultrasonography (EUS) and fine-needle aspiration

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42. Wallace MB, Hawes RH, Durkalski V et al. The reliability of EUS

for the diagnosis of chronic pancreatitis: interobserver agreement

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with MR imaging before and after secretin stimulation. Am J

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45. Takehara Y, Ichijo K, Tooyama N et al. Breath-hold MR cholan￾giopancreatography with a long-echo-train fast spin-echo

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46. Barish MA, Yucel EK, Soto JA, Chuttani R, Ferrucci JT. MR

cholangiopancreatography: efficacy of three-dimensional turbo

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47. Matos C, Metens T, Deviere J et al. Pancreatic duct: morphologic

and functional evaluation with dynamic MR pancreatography

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48. Bolondi L, Gaiani S, Gullo L, Labo G. Secretin administration

induces a dilatation of main pancreatic duct. Dig Dis Sci

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49. Glaser J, Hogemann B, Krummenerl T et al. Sonographic imaging

of the pancreatic duct. New diagnostic possibilities using secretin

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50. Takehara Y, Ichijo K, Tooyama N et al. [Enhanced delineation of

the pancreatic duct in MR cholangiopancreatography (MRCP)

with a combined use of secretin.] Nippon Igaku Hoshasen

Gakkai Zasshi 1995;55:255–6.

51. Nicaise N, Pellet O, Metens T et al. Magnetic resonance cholan￾giopancreatography: interest of IV secretin administration in the

evaluation of pancreatic ducts. Eur Radiol 1998;8:16–22.

52. Manfredi R, Costamagna G, Brizi MG et al. Severe chronic pan￾creatitis versus suspected pancreatic disease: dynamic MR

cholangiopancreatography after secretin stimulation. Radiology

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53. Manfredi R, Costamagna G, Vecchioli A, Colagrande C, Spina S,

Marano P. [Dynamic pancreatography with magnetic resonance

after functional stimulus with secretin in chronic pancreatitis.]

Radiol Med (Torino) 1998;96:226–31.

54. Cappeliez O, Delhaye M, Deviere J et al. Chronic pancreatitis:

evaluation of pancreatic exocrine function with MR pancreatog￾raphy after secretin stimulation. Radiology 2000;215:358–64.

55. Heverhagen JT, Battmann A, Kirsch M et al. Magnetic resonance

hydrometry: non-invasive quantification of the exocrine pancre￾atic function. ROFO 2002;174:291–6.

56. Punwani S, Gillams AR, Lees WR. Non-invasive quantification of

pancreatic exocrine function using secretin-stimulated MRCP.

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Introduction

In the minority of patients (i.e., 5.8–20%), chronic pancreatitis

takes a primarily painless course [1–7]. Exocrine and endocrine

insufficiency are the dominating symptoms. For the majority of

patients, however, pain is the decisive symptom, causing much

discomfort in their daily lives. Some studies have correlated the

course of pain in chronic pancreatitis with the duration of the

disease, progressing exocrine and endocrine pancreatic insuffi￾ciency, and morphologic changes such as pancreatic calcifica￾tion and duct abnormalities. Furthermore, the course of pain

has been studied following alcohol abstinence and after surgery

in some groups.

Pain decrease and duration of chronic

pancreatitis

Whether progressive parenchymal destruction of the pancreas

leads to pain decrease has been repeatedly debated [8,9].

Ammann’s group has claimed that pain decreases with increas￾ing duration of the disease [3,10,11]. In one long-term study,

85% of 145 patients with chronic pancreatitis felt no more pain

after 4.5 years (median) from onset of the disease [3]. In another

series, in which the interval between the onset of alcohol￾induced chronic pancreatitis and pain relief was compared in

surgically and nonsurgically treated patient groups, the curves

were virtually parallel: pain relief was obtained in about 50%

within 6 years and in more than 80% within 10 years from the

onset of illness [12].

The reports from Zürich are at variance with the studies from

Japan and Germany. Miyake et al. [6] found that only 48.2% of

patients with chronic pancreatitis became free of pain within 5

years, but 66–73% became free of pain after more than 5 years.

This showed that every third or fourth patient still suffered

from relapsing pain attacks even after a long observation

period. Our group reported that the incidence of relapsing pain

attacks decreased during the observation period, but more than

half of the patients (53%) still suffered from relapsing pain

attacks after more than 10 years of observation [7].

At present, the course of pain in alcoholic and idiopathic

chronic pancreatitis remains unclarified. Layer et al. [13]

investigated a group of patients with idiopathic chronic

pancreatitis who had never consumed alcoholic beverages dur￾ing their lifetime. They found that patients with early-onset

pancreatitis (under 35 years of age) have a long course of severe

pain from the start of their illness, whereas patients with late￾onset pancreatitis (over 35 years) have a mild and often painless

course. Both forms differ from alcoholic pancreatitis in having

an equal gender distribution and a much slower rate of calcifi￾cation. In contrast, our group has found that the course of pain

is the same in alcohol- and nonalcohol-induced chronic pancre￾atitis [14]. Even when we divided the nonalcoholic group into

teetotallers and patients with little alcohol consumption, and

separately compared their course of pain with alcoholics, there

were no differences concerning pain relief among the three

groups [15]. Further studies are required.

Pain decrease and progressing exocrine

and endocrine pancreatic insufficiency

The Swiss group have repeatedly observed pain decrease when

exocrine and endocrine pancreatic function declines [8–11].

Similarly, Girdwood et al. [16] have reported from South

Africa that pain decreases when exocrine pancreatic function

deteriorates.

Conversely, groups from Denmark and Germany have

reported the opposite. Thorsgaard Pedersen et al. [17] from

Copenhagen found no correlation between pain and exocrine

pancreatic function. Our group in Göttingen [7] have used the

secretin–pancreozymin test and fecal fat analysis to evaluate

exocrine pancreatic insufficiency, whereas the Swiss group had

used only indirect pancreatic function tests, i.e., chymotrypsin

measurements, to evaluate exocrine pancreatic insufficiency

[3]. We used a clear-cut grading of the severity of exocrine pan￾creatic insufficiency: mild impairment was defined as reduced

enzyme output, moderate impairment as a decreased bicarbon￾ate concentration along with reduced enzyme output but nor￾mal fecal fat excretion, and severe impairment was equated

with an abnormal secretin–pancreozymin test plus steatorrhea.

At the end of the observation period, 141 (45%) of 311 patients

with painful chronic pancreatitis had severe exocrine pancreatic

insufficiency. The majority of them (81/144, 57%) still suffered

from pain attacks.

Additionally, we studied the course of pain in correlation with

endocrine pancreatic insufficiency. Endocrine pancreatic insuffi￾ciency was classified as absent, moderate (diabetes mellitus

Natural course of chronic pancreatitis 50 Paul Georg Lankisch

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The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Second Edition

Edited by H. G. Beger, A. L. Warshaw, M. W. Büchler, R. A. Kozarek, M. M. Lerch, J. P. Neoptolemos,

K. Shiratori, D. C. Whitcomb, and B. M. Rau © 2008 Blackwell Publishing Limited, ISBN: 978-1-405-14664-7

treated only by diet with or without oral medication), and severe

(requiring insulin). At the end of the observation period, 117

(38%) patients were classified as having severe endocrine pan￾creatic insufficiency. The majority of them (69/117, 59%) still

suffered from pain attacks [7,18].

Thus, according to our results, the progression of exocrine

and endocrine pancreatic insufficiency has limited, if any,

influence on the course of pain in chronic pancreatitis.

Pain decrease and development of

morphologic changes in the pancreas

(pancreatic calcifications and/or duct

abnormalities)

The Swiss group [3,10] showed an increased incidence of pan￾creatic calcifications, which in turn was associated with pain

decrease. However, in a later survey the same group reported

regression of pancreatic calcifications in a long-term study of

patients with chronic pancreatitis [19]. Thus, the prognostic

role of pancreatic calcifications in determining the course of

pain is unclear.

Furthermore, the Swiss results are at variance with two

other studies. Malfertheiner et al. [20] found that 89% of

patients had pain despite pancreatic calcifications observed on

computed tomography, of whom 39% had very intense pain.

In our study, freedom from pain was significantly higher in the

calcification group compared with the noncalcification group.

However, the majority of patients with pancreatic calcifica￾tions (56%) still had relapsing pain attacks [7].

The correlation between pain and pancreatic duct changes or

pressure in the duct system is also not clear. Ebbehøj et al.

[21,22] measured pancreatic tissue fluid pressure percuta￾neously or intraoperatively and found a significant correlation

with pain in patients with chronic pancreatitis but not with the

results of endoscopic retrograde cholangiopancreatography

(ERCP), i.e., regional pressure tended to be highest in the region

of the pancreas with the largest but not the smallest duct diam￾eter. Jensen et al. [23] found no correlation between pancreatic

duct changes and pain. Warshaw et al. [24] found that 2 of 10

patients, 1 year after lateral pancreaticojejunostomy, had no

pain relief despite a patent anastomosis detected by ERCP.

Two investigations have confirmed the nonparallelism between

pancreatic duct changes and pain relief. Malfertheiner et al. [20]

found severe pain in only 62% of patients who had advanced

pancreatic duct changes demonstrated by ERCP. We found no

significant correlation between pancreatic duct abnormalities

detected by ERCP and pain in 88 patients with chronic pancre￾atitis [7]. Severe pancreatic duct abnormalities, as defined by the

Cambridge classification [25], were present in 42 patients, but

only 16 (31%) of these became free of pain. Despite a normal

pancreatic duct in 14 patients, 10 (71%) suffered from persisting

pain [7].

Thus, morphologic changes such as pancreatic calcifications

or pancreatic duct abnormalities are not necessarily helpful in

determining the prognosis of chronic pancreatitis or predict￾ing the course of pain. Recently it has been shown that smok￾ing has an effect on the natural course of the disease since it

increases the risk of pancreatic calcification in late-onset but

not early-onset idiopathic chronic pancreatitis [26].

Pain decrease and alcohol abuse

Since alcoholism is the leading etiologic factor in chronic pan￾creatitis, several studies have investigated whether alcohol

abstinence influences pain or progression of the disease. Sarles

and Sahel [27] reported that 50% of their patients with

chronic pancreatitis experienced pain relief when alcohol

abuse was discontinued, whereas Trapnell [28] reported a fig￾ure of 75%.

Two other investigations have confirmed that abstinence can

be helpful. Miyake et al. [6] demonstrated pain relief in 60% of

their patients who discontinued or reduced alcohol intake,

whereas spontaneous pain relief was seen in only 26% of the

group who continued drinking. In another study, 66 (31%) of

214 patients with alcoholic chronic pancreatitis were motivated

to stop drinking [7]. Pain relief was obtained in only 52% of

these patients, whereas spontaneous relief in alcoholics was

seen in 37%. Thus, alcohol abstinence in every second patient

with chronic pancreatitis will probably lead to some improve￾ment of pain, but why exactly abstinence helps in some cases

but not others remains to be investigated.

Pain decrease and interventional

procedures

Interventional procedures for pain treatment in chronic pancre￾atitis include fragmentation of stones by extracorporeal shock￾wave lithotripsy (ESWL), endoscopic stone extraction, and

bridging of pancreatic strictures by stent applications. Reports of

the effect of these procedures on pain are controversial and con￾trolled studies are lacking. A large Japanese study of 555 patients

who underwent ESWL for pancreatic stones reported a success

rate of 92.4% (fragmentation of stones) and a complete stone

clearance rate after ESWL alone or in combination with inter￾ventional endoscopy of 72.6%. Symptom relief was achieved in

91.1% of the patients. Complications developed in 6.3% of the

patients, including acute pancreatitis in 5.4%. A total of 504

patients were followed up for a mean of 44.3 months, during

which 122 (22%) suffered stone recurrence (mean time to recur￾rence, 25.1 months); 22 (4.1%) required surgery [29]. In another

series from Japan, a total of 117 patients with pancreatic stones

underwent ESWL and endoscopic treatment. Immediate pain

relief was achieved in 97% and complete removal of stones in

56%. During long-term follow-up over 3 years, 70% of the

patients continued to be asymptomatic [30]. These results are at

variance with a smaller German study in 80 patients with chronic

pancreatitis, in whom ESWL was always followed by a further

NATURAL COURSE OF CHRONIC PANCREATITIS

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CHAPTER 50

486

endoscopic procedure. Treatment success was defined as com￾plete clearance of the main pancreatic duct or partial clearance

that allowed implantation of a pancreatic stent. Successful treat￾ment was more frequent in patients with solitary stones. The

mean duration of follow-up was 40 (range 24–92) months. Pain

relief and necessity for further analgesia was independent of

ESWL results [31] (Table 50.1). Thus, in this study pancreatic

drainage by ESWL and endoscopy had almost no effect on pain

in chronic pancreatitis in the long term [32].

The effect of pancreatic stents on pain in chronic pancreatitis

is even more controversial. Patients undergoing pancreatic duct

stent placement for disrupted ducts, isolated strictures, pancreas

divisum, and hypertensive pancreatic sphincters showed subse￾quent ductal changes consistent with chronic pancreatitis in

36%, even though 72% of these patients had a normal initial

pancreatogram [33]. Furthermore, patients with preoperative

endoscopic pancreatic stenting had frequent postoperative com￾plications, mostly septic, and a prolonged hospital stay [34].

A surgical review of the pitfalls and liminations of stenting in

chronic pancreatitis reported that the indications for surgery

in patients with a pancreatic stent were severe abdominal pain

in 100%, relapsing pain attacks in 77%, and necrotizing pan￾creatitis in 14%. Before being selected for surgery, 4.5 ERCPs

and 3.7 stent exchanges were performed per patient. Thus, from

the surgical point of view, endoscopic pancreatic duct stenting

in chronic pancreatitis seems not to be indicated because of a

low success rate and a substantial risk of complications [35].

The latter results are in sharp contrast to a long-term out￾come study of pancreatic stenting in severe chronic pancreati￾tis in 100 patients from Belgium. The majority (70%) of

patients who responded to pancreatic stenting remained pain￾free after definitive stent removal. However, a significantly

higher restenting rate was observed in patients with chronic

pancreatitis and pancreas divisum [36]. Obviously, the results

are also different in special subgroups. Endoscopic stenting of

biliary strictures in chronic pancreatitis provided an excellent

short-term but only moderate long-term result in another

study from Germany. Patients without calcifications of the

pancreatic head benefit from biliary stenting. However,

patients with calcifications had a 17-fold increased risk of fail￾ure during the course of a 12-month follow-up [37].

Of special interest is a recent prospective randomized trial

that compared endoscopic with surgical treatment of chronic

pancreatitis. Endoscopic treatment included pancreatic sphinc￾terotomy in all and additional stenting of the pancreatic duct in

33 (52%) patients. Mean duration of stent treatment was 16

(range 12–27) months, and stents were exchanged six times

(range 4–9). Surgical treatment included pancreatic resection in

61 (80%) and drainage procedures in 15 (20%) patients.

Although the short-term effects were similar, the results after

5 years of follow-up showed a comparatively low rate of patients

with complete absence of abdominal pain. However, the results

for surgery were significantly better than for endotherapy

(Table 50.2) [38]. The study has been criticized for the random￾ization, which was agreed to by only 51.4% of the patients.

For the time being, reports of treatment of chronic pancre￾atitis using ERCP by removal or destruction of stones, place￾ment of stents, and dilation of strictures suggest that both

immediate and long-term pain relief are possible. No con￾trolled studies support the generalizability of this finding or

the merit of this approach compared with other management

strategies. Studies of this area would be of value [39].

Pain decrease and surgery

During the course of the disease, every second to fourth patient

needs surgical treatment because of pain and/or organ compli￾cations, such as pancreatic pseudocysts [3,7]. The choice of

surgical procedure depends on the special circumstances of

each patient. However, it is unclear to what extent surgical

treatment influences the course of pain since the different stud￾ies cannot be compared for the following reasons.

• The definition of freedom from pain was often vague, and

pain symptoms were usually not measured. Measurement on

an analog scale is recommended [18].

• Not all patients received the same surgical treatment for the

same indication. Several authors do not recommend perform￾ing an indicated resection in alcoholics because of the difficult

postoperative treatment of diabetes mellitus in these patients

[40,41].

• Although continued alcohol abuse distinctly worsens the

effect of surgical treatment [42–44], it is still difficult to deter￾mine whether postoperative deterioration results from chronic

pancreatitis or continued alcohol abuse, or from the surgical

treatment.

Table 50.1 Long-term effect on pain in 80 patients with chronic

pancreatitis treated with extracorporeal shock wave lithotripsy.

(From ref. 31 with permission.)

Successful Unsuccessful

treatment treatment

(N
43) (N
37) P value

Considerable or

complete pain relief 34 (79%) 27 (73%) 0.75

No further analgesia

necessary 27 (63%) 16 (43%) 0.23

Table 50.2 Five years follow-up of abdominal pain in a prospective

randomized trial comparing endoscopic with surgical treatment for

chronic pancreatitis. (From ref. 38 with permission.)

Abdominal Endotherapy Surgery

pain (N
64) (N
76) P value

Complete absence 14.3% 36.9% 0.002

Partial relief 50.8% 49.3% NS

No success 34.9% 13.8% NS

NS, not significant.

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NATURAL COURSE OF CHRONIC PANCREATITIS

487

Evaluation of pain differs very much during the course of the

observation period. Independent of the surgical procedure,

postoperative results show that freedom from pain will be

obtained in up to 90% of patients over several years of follow￾up (Table 50.3) [7,45–78]. However, persistence of freedom

from pain has been reported differently. Taylor et al. [79]

(Table 50.4) clearly showed that pain increases during the

course of a longer follow-up. In contrast, Martin et al. [72]

showed that freedom from pain may persist over 5 years of fol￾low-up after pylorus-preserving pancreaticoduodenectomy for

chronic pancreatitis (Fig. 50.1). Whether this difference is due

to the different mode of operation remains to be clarified.

Table 50.3 Freedom from pain after different surgical procedures on the pancreas for chronic pancreatitis.*

Median Pain relief

Reference Surgical procedure observation time N (%)

Way et al. [45] Drainage/resection ~5 years 37 64

Lankisch et al. [46] Drainage/resection 2.5 years 40 60

Mangold et al. [47] Partial duodenopancreatectomy 1 year 8 months 44 73

Total duodenopancreatectomy 2 years 10 months 18 91

Partial left-sided resection 3 years 5 months 37 60

Subtotal left-sided resection 2 years 10 months 17 83

Proctor et al. [48] Pancreaticojejunostomy 11 months 22 50

Rosenberger et al. [49] Resection 6 years 67 69

Nonresective procedures 6 years 40 50

Lankisch et al. [50] Pancreaticojejunostomy 3 years 1 month 17 76

Resection 3 years 1 month 22 64

Prinz and Greenlee [51] Pancreaticojejunostomy 6 years 1 month to 91 35

7 years 11 months

Sato et al. [52] Pancreaticojejunostomy 6.5 years 38 68

Left-sided resection 6.5 years 14 79

Whipple’s operation 6.5 years 9 67

Gall et al. [53] Whipple’s operation, pancreatic duct occlusion 1 year 67 93

Morrow et al. [54] Pancreatic duct drainage 4–13 years 46 46

40–80% left-sided resection 4–13 years 21 33

80–95% left-sided resection 4–13 years 8 100

Drainage 6 years 46 80

Subtotal pancreatectomy 7 years 21 24

Sato et al. [55] Left-sided resection 6 months 21 91

Whipple’s operation 6 months 11 55

Pancreaticojejunostomy 6 months 43 91

Bradley [56] Lateral pancreaticojejunostomy 5 years 9 months 46 28

Caudal pancreaticojejunostomy 5 years 9 months 18 17

Cooper et al. [57] Total pancreatectomy 1.5 years 83 72

Frick et al. [58,59] Left-sided resection 6.5 years 74 50

Partial duodenopancreatectomy 6.5 years 62 45

Total duodenopancreatectomy 6.5 years 22 55

Drainage 4 years 7 months 156 48

Lambert et al. [60] Duodenum-preserving total pancreatectomy 9 years 5 months 14 64

Rossi et al. [61] Whipple’s operation 6 months 61 72

2 years 44 61

5 years 33 61

10 years 18 61

15 years 6 83

Mannell et al. [62] Drainage/resection 8.5 years 100 77

Stone et al. [63] Whipple’s operation 6 years 2 months 15 53

Total duodenopancreatectomy 9 years 1 month 15 27

Beger et al. [64] Duodenum-preserving pancreatic head resection 3 years 8 months 128 77

Peiper and Köhler [65] Resection 10 51 79

Drainage 10 24 65

Beger and Büchler [66] Duodenum-preserving pancreatic head resection 3.5 years 141 77

Lankisch et al. [7] Drainage/resection 6 years 70 57

Adams et al. [67] Lateral pancreaticojejunostomy 6 years 4 months 62 42

Frey and Amikura [68] Local pancreatic head resection with 6 months 50 34

longitudinal pancreaticojejunostomy

(Continued)

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In a study of 207 patients with alcoholic chronic pancreatitis

(91 without and 116 with surgical treatment for pain relief),

Ammann et al. [12] discussed the pain pattern of chronic

pancreatitis and its surgical implications. In this study, chronic

pain was typically associated with local complications (mainly

pseudocysts), which were positively relieved by a single drainage

procedure in approximately two-thirds of patients. Additional

surgery was required for late pain recurrence in 39 patients, pri￾marily symptomatic cholestasis. All patients achieved complete

pain relief in advanced chronic pancreatitis. The authors con￾clude that, in their experience, relief of chronic pain regularly fol￾lows selective surgery tailored to the presumptive pain cause or

occurs spontaneously in uncomplicated advanced chronic pan￾creatitis.

Course of exocrine pancreatic

insufficiency

Exocrine pancreatic insufficiency does not play a major prognos￾tic role. Occasionally, massive steatorrhea leading to cachexia

and susceptibility to infection has prognostic significance.

Median Pain relief

Reference Surgical procedure observation time N (%)

Hakaim et al. [103] Different operations: 5 years 2 months 50 30

pancreatic duct drainage (56%)

left-sided resection (20%)

cyst drainage (24%)

Büchler et al. [69] Duodenum-preserving pancreatic head resection 6 months 15 40

Pylorus-preserving Whipple’s operation 6 months 16 75

Fleming and Williamson [70] Total pancreatectomy 3.5 years 40 79

Izbicki et al. [71] Duodenum-preserving pancreatic head resection:

Beger’s procedure 1.5 years 20 95

Frey’s procedure 1.5 years 22 94

Martin et al. [72] Pylorus-preserving pancreaticoduodenectomy 5 years 3 months 45 92

Stapleton and Williamson [73] Proximal pancreaticoduodenectomy: 4.5 years 52 80

pylorus-preserving (N
45)

Whipple’s operation (N
7)

Amikura et al. [104] Pancreaticojejunostomy 6 months 69 75

Pancreaticojejunostomy plus pancreatic head 6 months 11 90

resection

Left-sided resection 6 months 37 80

Whipple’s operation 6 months 13 65

Rumstadt et al. [74] Whipple’s operation 8 years 4 months† 134 66

Traverso and Kozarek [75] Whipple’s operation 3.5 years 47 76

Total pancreatectomy 3.5 years 10 76

Beger et al. [105] Duodenum-preserving pancreatic head resection 5 years 8 months† 303 88

Berney et al. [76] Different procedures of pancreas resection 6 years 4 months 68 62

Jimenez et al. [106] Whipple’s operation 3 years 5 months 33 53

Pylorus-preserving pancreatic head resection 3 years 5 months 39 40

Sakorafas et al. [77] Whipple’s operation 6 years 7 months 66 67

White et al. [78] Total pancreatectomy 6 months 24 82

Nealon and Matin [107] Pancreaticojejunostomy 6 years 9 months 124 86

Left-sided resection 6 years 9 months 29 67

Pancreatic head resection (duodenum-preserving 6 years 9 months 46 91

or pylorus-preserving)

Sakorafas et al. [108] Left-sided resection 6 years 8 months 31 49

Hutchins et al. [109] Left-sided resection 2 years 10 months 84 48

* Only reports of “total freedom from pain” were included. Further stages of postoperative improvement (e.g., partial freedom from pain) were not

considered. Closure of literature search, December 2005.

† Median values.

Table 50.4 Percentage of patients who became free from pain

6 months, 2 years, and 5 years after different surgical procedures

for chronic pancreatitis. (From ref. 79 with permission.)

Whipple’s Left-sided

Follow-up operation Pancreaticojejunostomy resection

Alcohol-induced

pancreatitis

6 months 82 87 60

2 years 74 53 39

5 years 71 54 26

Idiopathic

pancreatitis

6 months 50 80 77

2 years 50 60 46

5 years 33 60 20

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Whether exocrine pancreatic function deteriorates during the

course of the disease is disputed. Ammann et al. [3] found that

severe exocrine pancreatic insufficiency developed within 5.65

years (median) in 122 (86.6%) of 145 patients, whereas

Thorsgaard Pedersen et al. [17] observed no significant changes

in exocrine pancreatic insufficiency in their patients during an

observation period of 4 years. We found no change in the

degree of severity of exocrine pancreatic insufficiency in 66

(46.2%) patients, but a deterioration in 61 (42.6%) patients.

Functional improvement was even seen in 16 (11.2%) of our

patients, several of whom no longer required pancreatic enzyme

substitution. Several other studies have furnished evidence of

functional improvement in cases of exocrine pancreatic insuffi￾ciency in chronic pancreatitis [6,80–82]. Improvement was

observed in patients who stopped drinking and/or where

exocrine pancreatic insufficiency was moderate and not severe

prior to conservative and/or surgical treatment [7].

Course of endocrine pancreatic

insufficiency

Whereas almost all patients with chronic pancreatitis have

exocrine pancreatic insufficiency to some degree at the time of

diagnosis, this is not the case for endocrine pancreatic insuffi￾ciency. We found moderate to severe endocrine pancreatic

insufficiency in 335 patients with chronic pancreatitis, includ￾ing 24 patients with painless chronic pancreatitis; 260 (78%)

suffered from diabetes and 133 (40%) needed insulin treat￾ment. After almost 10 years of observation, the incidence of

diabetes had increased 10-fold in only 28 (8%) patients.

However, even after this long observation period, 75 (22%)

patients (i.e., every fifth patient) still had no diabetes [7].

In a large prospective cohort study, Malka et al. [83] com￾pared patients who underwent elective pancreatic surgery with

those who never underwent surgical treatment. The prevalence

of diabetes mellitus did not increase in the surgical group overall,

but was higher 5 years after distal pancreatectomy compared

with pancreaticoduodenectomy, pancreatic drainage, or cystic,

biliary, or digestive drainage. There were no differences between

the other surgical procedures. Pancreatic drainage did not pre￾vent the onset of diabetes mellitus. The risk seemed to be largely

caused by progression of the disease, because it increased by

more than threefold after the onset of pancreatic calcifications.

Endocrine complications may play a major prognostic role, espe￾cially after surgical treatment of chronic pancreatitis, because of

possible hypoglycemia [84]. Hypoglycemia frequently occurs

after subtotal left-sided pancreatic resection [41] and may con￾tribute to an unfavorable prognosis.

The frequency of some complications of diabetes mellitus sec￾ondary to chronic pancreatitis has been studied. Earlier investi￾gations showed that diabetic retinopathy is a rare complication

of pancreatogenic diabetes, with an occurrence rate of 7.4–18%

[85–87]. Gullo et al. [88] have shown that the risk of retinopa￾thy and the characteristics of this complication in patients with

chronic pancreatitis and secondary diabetes are the same as for

patients with type 1 diabetes. About half of the patients studied

in both groups had retinopathy; this was background, minimal,

or mild to moderate without impairment of visual function. The

only significant difference was the longer duration of diabetes in

patients with retinopathy compared with those without this

complication. A longer observation time may explain the higher

frequency of diabetic retinopathy in this study [88] compared

with the earlier investigations [85–87]. Similarly, Tiengo et al.

[89] and Couet et al. [90] found retinopathy in 31% and 41%,

respectively, of patients with chronic pancreatitis. Furthermore,

in 1995, Levitt et al. [91] showed that microvascular complica￾tions (retinopathy, nephropathy) in pancreatic diabetes and

insulin-dependent diabetes mellitus are equally common and

severe.

Nondiabetic retinal lesions and retinal function abnormalities

(increased threshold of dark adaptation, difficulty with night

vision) are also common in patients with chronic pancreatitis,

even in the absence of steatorrhea compared with healthy con￾trols [92]. Electrocardiographic evidence of ischemic heart disease

was found twice as frequently in genetic diabetics compared with

pancreatic diabetes (37% vs. 18%) [93]. Diabetic neuropathy

was reported in about 30% of patients with chronic pancreatitis

(no control group) [94].

Finally, lower extremity arterial disease occurred in 25.3% of

patients with chronic pancreatitis and had the same prevalence

and distribution as in idiopathic pancreatitis [95]. Whether

these complications have major prognostic significance has not

yet been investigated.

Course of complications of chronic

pancreatitis

The list of complications in chronic pancreatitis includes pan￾creatic pseudocysts and abscesses; stenosis of the common bile

NATURAL COURSE OF CHRONIC PANCREATITIS

489

10

0

2

3

4

5

6

8

9

7

1

Pain score

Preoperative 6 months 1 year 2 years 5 years

Time

Figure 50.1 Long-term improvement in pain in patients undergoing

pylorus-preserving pancreaticoduodenectomy for chronic

pancreatitis. (From ref. 72 with permission.)

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CHAPTER 50

490

duct, duodenum, and colon; development of pleural ascites;

and gastrointestinal bleeding. All these complications surely

have severe implications for the prognosis of the disease.

However, since these have not been investigated in larger stud￾ies, their exact influence on the outcome of the disease is

uncertain and they are therefore not discussed here.

Course of pancreatic and extrapancreatic

carcinomas in chronic pancreatitis

In clinical studies, the incidence of pancreatic carcinoma in

patients with chronic pancreatitis has been reported as varying

from 1.4 to 2.7% [3,7,17,96,97]. A multicenter historical cohort

study of 2015 subjects with chronic pancreatitis involved clinical

centers in six countries [98]. The cumulative risk of pancreatic

carcinoma in these patients, who were followed for at least

2 years, increased noticeably, and 10 and 20 years after the diag￾nosis of chronic pancreatitis was 1.8 and 4%, respectively (Fig.

50.2) [98]. Thus, the risk of pancreatic carcinoma was signifi￾cantly elevated in patients with chronic pancreatitis, and thus

chronic pancreatitis has to be included in the precanceroses [98].

Unfortunately, it is very difficult to diagnose pancreatic car￾cinoma in chronic pancreatitis. Carcinoma of the pancreas should

certainly be suspected in a patient with chronic pancreatitis if

there is increasing abdominal discomfort, progressive weight

loss, jaundice, and radiologic evidence including nodularity of

the duodenal sweep.

Extrapancreatic carcinomas in chronic pancreatitis are not

rare events and have been reported with varying incidence,

from 3.9 to 12.5% [6,7,17,97,99]. In some of these and other

studies [6,7,97,100], a considerable number of extrapancre￾atic carcinomas involving the upper respiratory tract (oral

cavity, larynx, bronchial tree) have been observed. Since alco￾hol abuse is the dominating etiology of chronic pancreatitis,

and because many alcoholics probably smoke, extrapancreatic

carcinomas involving the upper respiratory tract may reflect

the consequences of another habit abuse.

Socioeconomic situation in chronic

pancreatitis

Some attention has been paid to the socioeconomic situation of

patients with chronic pancreatitis. Gastard et al. [101] found that

one out of two male patients continued to work normally, despite

pain or diabetes, while one out of three was regarded as unfit for

regular work, being totally incapacitated or absent from work

for more than 3 months a year. The figures improved after 15

years due to the death of patients with severe forms of the dis￾ease; at this stage, 68% of the patients were working regularly,

while 6% were totally incapacitated. Thorsgaard Pedersen et al.

[17] found a decline during an observation period of 5 years

(median). Only 15 (40%) of their 38 surviving patients still

worked, whereas the remaining were either on prolonged sick￾leave or retired. Miyake et al. [6] reported that while 63 (71%) of

their 89 patients continued to work, almost all the other patients,

who were either retired or who suffered socioeconomically, con￾tinued their alcohol abuse. In our study [7], the incidence of

unemployed patients increased from 3 to 15% and that of the

retired from 3 to 25% during an observation period of about

11 years. Almost half of the retirements were due to chronic

pancreatitis.

Mortality in chronic pancreatitis

Data on the mortality rate in chronic pancreatitis are difficult to

interpret since etiology and mean observation times vary from

study to study. Three studies with a comparatively similar obser￾vation time (median 6.3–9.8 years) revealed a general death rate

of 28.8–35%, but the death rate related to chronic pancreatitis

was only 12.8–19.8% [3,6,7]. Continued alcohol abuse after

conservative treatment and/or surgery has been associated with

significantly lower survival rates (Fig. 50.3) [3,6,7,40,41,70].

Prognosis of chronic pancreatitis

The prognosis of chronic pancreatitis is independent of con￾servative or surgical treatment. A multicenter investigation in

6

5

3

2

1

4

Cumulative incidence of pancreatic cancer (%)

5 10 15 20

Years after diagnosis of pancreatitis

(1160)

(599)

(244)

(64)

Figure 50.2 Cumulative incidence of pancreatic cancer in 1552

subjects with chronic pancreatitis with a minimum of 2 years’

follow-up. The vertical lines represent 95% confidence intervals;

numbers in parentheses are the subjects at risk. One additional case

of cancer developed after 25 years of follow-up. (From ref. 98 with

permission.)

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NATURAL COURSE OF CHRONIC PANCREATITIS

491

seven hospitals in six countries including 2015 patients with

chronic pancreatitis showed that the mortality rate was 3.6-

fold higher than in patients without pancreatitis. The 10-year

survival rate was 70% and the 20-year survival rate 45%,

compared with 93% and 65%, respectively, in patients with￾out pancreatitis.

The following risk factors have been found.

1 Medium or high age at the time of diagnosis: the mortality

rate in patients of medium or high age was 2.3-fold and 6.3-

fold, respectively, higher than in patients with chronic pancre￾atitis in whom the disease was diagnosed before age 40 years.

2 Consistent alcohol abuse: hazard ratio 1.6.

3 Smoking: hazard ratio 1.4.

4 Liver cirrhosis: hazard ratio 2.5.

5 Neither gender nor surgical history had any influence on

prognosis of the disease [102].

Outlook

It will not have escaped the attention of the reader that up to

now there have been only a few well-performed and valid

studies, and even some of these have produced partly diverg￾ing results. More controlled studies with a larger number of

patients than any single center can undertake are necessary.

This means we have to consider our resources and work out

common criteria for the diagnosis of chronic pancreatitis and

follow-up of its course. Hence, this chapter is not only an

up-to-date survey of studies on the natural course of chronic

pancreatitis but also an appeal to the readership to embark

upon this task.

References

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diagnostische Verfahren bei der chronisch-rezidivierenden und

chronischen Pankreatitis. Schweiz Med Wochenschr 1970;100:

1180–9.

2. Ammann RW, Hammer B, Fumagalli I. Chronic pancreatitis in

Zurich, 1963–1972. Clinical findings and follow-up studies of

102 cases. Digestion 1973;9:404–15.

3. Ammann RW, Akovbiantz A, Largiadèr F, Schueler G. Course

and outcome of chronic pancreatitis. Longitudinal study of a

mixed medical-surgical series of 245 patients. Gastroenterology

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4. Gullo L, Costa PL, Labò G. Chronic pancreatitis in Italy.

Aetiological, clinical and histological observations based on 253

cases. Rendic Gastroenterol 1977;9:97–104.

5. Goebell H. Beginn und Entwicklung der chronischen

Pankreatitis. Internist 1986;27:172–4.

6. Miyake H, Harada H, Kunichika K, Ochi K, Kimura I. Clinical

course and prognosis of chronic pancreatitis. Pancreas

1987;2:378–85.

7. Lankisch PG, Löhr-Happe A, Otto J, Creutzfeldt W. Natural

course in chronic pancreatitis. Pain, exocrine and endocrine pan￾creatic insufficiency and prognosis of the disease. Digestion 1993;

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8. Ammann R. Die chronische Pankreatitis. Zur Frage der

Operationsindikation und Beitrag zum Spontanverlauf der chro￾nisch-rezidivierenden Pankreatitis. Dtsch Med Wochenschr

1970;95:1–7.

9. Ammann R. Die Behandlung der chronischen Pankreatitis. Dtsch

Med Wochenschr 1970;95:1234–5.

10. Ammann RW, Largiadèr F, Akovbiantz A. Pain relief by surgery

in chronic pancreatitis? Relationship between pain relief, pancre￾atic dysfunction, and alcohol withdrawal. Scand J Gastroenterol

1979;14:209–15.

11. Ammann R. Klinik, Spontanverlauf und Therapie der chroni￾schen Pankreatitis. Unter spezieller Berücksichtigung der

Nomenklaturprobleme. Schweiz Med Wochenschr 1989;119:

696–706.

12. Ammann RW, Muellhaupt B, Zurich Pancreatitis Study Group.

The natural history of pain in alcoholic chronic pancreatitis.

Gastroenterology 1999;116:1132–40.

13. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ,

DiMagno EP. The different courses of early- and late-onset idio￾pathic and alcoholic chronic pancreatitis. Gastroenterology

1994;107:1481–7.

14. Lankisch PG, Seidensticker F, Löhr-Happe A, Otto J, Creutzfeldt

W. The course of pain is the same in alcohol- and nonalcohol￾induced chronic pancreatitis. Pancreas 1995;10:338–41.

15. Lankisch PG, Seidensticker F, Löhr-Happe A, Creutzfeldt W. The

course of pain is the same in alcoholics, alcohol consumers, and

teetotalers [Abstract]. Pancreas 1996;13:446.

16. Girdwood AH, Marks IN, Bornman PC, Kottler RE, Cohen M.

Does progressive pancreatic insufficiency limit pain in calcific

pancreatitis with duct stricture or continued alcohol insult? J Clin

Gastroenterol 1981;3:241–5.

17. Thorsgaard Pedersen N, Andersen BN, Pedersen G,

Worning H. Chronic pancreatitis in Copenhagen. A retrospective

study of 64 consecutive patients. Scand J Gastroenterol 1982;17:

925–31.

50

0

100

Percentage

0 10 20 30 40

Years after onset of the disease

Figure 50.3 Cumulative survival curve for 230 patients with

alcoholic chronic pancreatitis (solid line) and 105 patients with

nonalcoholic chronic pancreatitis (dashed line) (P
0.0001). The

mean age of onset of the disease (i.e., first pancreatitis-related

symptoms) was 37  9 (mean  SD) years in patients with alcoholic

chronic pancreatitis and 39  17 years in patients with nonalcoholic

chronic pancreatitis. (From ref. 7 with permission.)

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