Clinical Pancreatology for Practising Gastroenterologists and Surgeons - part 6 pptx

The development of endoscopic ultra-sonography, which has a very high sensitivity for the diagnosis of chronic pancreatitis, has further limited pancre-31 Pancreatic function tests for d

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Because histology is usually not available for the

diag-nosis of chronic pancreatitis, this is based on the

demonstration of the morphologic and/or functional

changes that typically develop over time in the course of

the disease Exocrine pancreatic function is impaired

progressively as chronic pancreatitis develops Thus,

exocrine pancreatic dysfunction refers to a mild,

mod-erate, or severe reduction of exocrine pancreatic

func-tion Finally, pancreatic function becomes insufficient

to maintain normal digestive processes Exocrine

pancreatic insufficiency thus refers to the presence of

maldigestion and malabsorption of nutrients as a

con-sequence of primarily and/or secondarily impaired

ex-ocrine pancreatic function Thus the terms “exex-ocrine

pancreatic insufficiency” and “severe exocrine

pan-creatic dysfunction” are synonymous

Exocrine pancreatic dysfunction is a frequent finding

not only in chronic pancreatitis but also in most other

diseases of the exocrine and endocrine pancreas, i.e.,

cystic fibrosis, pancreatic tumors, after acute

necrotiz-ing pancreatitis and insulin-dependent diabetes

mellitus In addition, secondary exocrine pancreatic

dysfunction frequently develops after gastrointestinal

surgery (partial or total gastrectomy, duodenectomy)

Functional evaluation of the exocrine pancreas may

be important for supporting the diagnosis of pancreatic

disease in cases of inconclusive morphologic findings

on imaging methods However, the most relevant role

for functional evaluation of the pancreas is the

detec-tion of primary or secondary pancreatic insufficiency in

patients with known pancreatic disease or after

gas-trointestinal surgery in order to aid in the indication ofenzyme substitution therapy and to control the efficacy

of this therapy

Exocrine pancreatic function may be evaluated bymeans of direct methods requiring duodenal intubationand noninvasive indirect methods (Table 31.1) Theclinical usefulness of each of the available methods isrelated to factors like diagnostic accuracy, applicability

to clinical routine, and cost Direct pancreatic functiontests, mainly the secretin–cholecystokinin test, are thegold standard for evaluation of exocrine pancreaticfunction However, these tests are invasive, cumber-some, time-consuming, and expensive and thus limited

to some specialized centers Indirect pancreatic tion tests are more easily applicable to clinical routineand therefore more widely used Among these are oraland breath tests that, together with fecal fat quantifica-tion, evaluate the digestive ability of the exocrine pancreas, and fecal tests that measure the activity orconcentration of pancreatic enzymes in feces The sen-sitivity and specificity of these indirect tests are variableand lower than those of the direct tests Since the infor-mation provided by each test is different, it is important

func-to select the optimal test func-to be performed in each clinicalsituation

In patients with clinical suspicion of chronic atitis but normal imaging, only the secretin–ceruleintest is sufficiently sensitive to support the diagnosis ofthe disease The development of endoscopic ultra-sonography, which has a very high sensitivity for the diagnosis of chronic pancreatitis, has further limited

pancre-31 Pancreatic function tests for

diagnosis and staging of chronic pancreatitis, cystic fibrosis, and exocrine pancreatic insufficiency of other etiologies: which tests are necessary and how should they be performed in clinical routine?

J Enrique Domínguez-Muñoz

the clinical usefulness of direct pancreatic function

tests Conversely, the diagnosis of primary or

secondary exocrine pancreatic insufficiency and, in this

context, the indication for or control of the efficacy of

enzyme substitution therapy require a test able to detect

maldigestion It is easy to understand that in these two

clinical situations the test to be used should have a very

different sensitivity, highest in the former case, lowest

in the latter (Fig 31.1) In transitional situations, tests

with an intermediate sensitivity may be useful for the

screening of chronic pancreatitis in patients with a

compatible clinical picture and for the long-term

follow-up of patients with known chronic pancreatitis

(Fig 31.1)

Direct tests

Invasive pancreatic function tests are based on the rect measurement of pancreatic enzymes and bicarbon-ate output in samples of duodenal juice obtained afterstimulation of the gland by intravenous administration

di-of secretin and cholecystokinin (CCK) or cerulein (secretin–cholecystokinin test) Simple stimulation byintravenous secretin (secretin test) is used in the so-called endoscopic test, which is based on the mea-surement of bicarbonate concentration in endoscopy-guided aspirates of duodenal juice (see below) Finally,endogenous stimulation by a test meal (Lundh test) is

no longer used because of a lower diagnostic accuracy.Since direct pancreatic function tests are invasive,cumbersome, time-consuming, nonstandardized, andexpensive, and since the development of novel sensitiveimaging methods (i.e., endoscopic ultrasonography)has markedly improved the diagnosis of chronic pan-creatitis, the usefulness of the secretin–cholecystokinintest is nowadays limited to its use as gold standard inthe validation of new pancreatic function tests

Secretin–cholecystokinin test

Method

The secretin–cholecystokinin test protocol differsamong centers A double-lumen nasoduodenal tubeshould be placed for constant aspiration of gastric juiceand complete and fractionated collection of duodenaljuice on ice during continuous intravenous infusion ofsecretin and CCK or cerulein The protocol recom-mended by our group is summarized in Fig 31.2 Despite duodenal juice being continuously aspirated,collection may be incomplete The amount of juice losttoward the jejunum may be calculated by constant duo-denal perfusion of a nonabsorbable dilution marker,usually polyethylene glycol However, this requires atriple-lumen tube and further complicates the perfor-mance of the test

An additional problem is the variable inactivation ofpancreatic enzymes within the collected duodenal juicedespite the use of antiproteases and collection on ice.This may be overcome by the single quantification ofzinc instead of bicarbonate and enzymes Zinc secre-tion is linked to pancreatic proteases; it is easily quan-tifiable and very stable in duodenal juice Our grouphas recently demonstrated that the secretin–ceruleintest based on single quantification of zinc output is as

Table 31.1 Pancreatic function tests.

Direct tests

Secretin–cholecystokinin test

Endoscopic test

Indirect tests

Fecal fat quantification

Fecal levels of pancreatic enzymes

NBT-PABA test

Pancreolauryl test

Amino acid consumption test

Breath tests ( 13 C-labeled substrates)

HIGH

LOW

• Diagnosis of chronic pancreatitis in cases of

inconclusive morphologic changes

• Sereening of chronic pancreatitis in patients

with compatible clinical symptoms

• Long-term follow-up of patients with known

chronic pancreatitis

• Diagnosis of primary or secondary pancreatic

insufficiency

• Indication for and control of the efficacy of oral

enzyme substitution therapy

Figure 31.1 Indications for evaluation of exocrine pancreatic

function The sensitivity of the function test to be used varies

according to the indication.

C H A P T E R 3 1

accurate as the test based on quantification of

bicar-bonate and enzymes for evaluation of exocrine

pan-creatic function

Interpretation

The secretin–cholecystokinin test allows classification

of the severity of exocrine pancreatic dysfunction

(Table 31.2) The sensitivity and specificity of this test

for the diagnosis of chronic pancreatitis both exceed

90% (Table 31.3)

Endoscopic test

The endoscopic pancreatic function test has been

devel-oped in order to avoid the problems associated with the

secretin–cholecystokinin test, i.e., intubation,

dura-tion, and clinical applicability It is based on the

measurement of bicarbonate concentration and/or

pancreatic enzyme activity in samples of duodenal juice

obtained during upper gastrointestinal endoscopy after

intravenous secretin stimulation

Method

The protocol for the endoscopic pancreatic function

test is based on the following four steps

1 Standard endoscopy to the descending duodenum

with the patient under conscious sedation

2 Intravenous administration of secretin (1 U/kg or

0.2 mg/kg)

3 Endoscopic duodenal fluid collection at 0, 15, 30,

45, and 60 min after secretin injection A short version

of the test is based on the collection of duodenal juicefor only 10 min

4 Fluid analysis for bicarbonate concentration and/or

pancreatic enzyme activity

Interpretation

The peak bicarbonate concentration over 60 min islower in patients with advanced chronic pancreatitisthan in those with abdominal pain of extrapancreaticorigin Measurement of lipolytic activity in duodenaljuice collected for 10 min after intravenous secretin isalso significantly lower in patients with chronic pancre-atitis compared with patients with normal pancreas,but it is not accurate enough for routine clinical use

Calculation of bicarbonate and enzyme output

Quantification of volume, bicarbonate concentration, and

amylase, lipase and protease (trypsin, chymotrypsin,

and/or elastase) activities

Overnight fasting

Placement of a double-lumen tube under

fluoroscopic control, with the tip at the

ligament of Treitz Continuous aspiration of gastric and duodenal juice

Continuous intravenous infusion of secretin

(1 U/kg per hour) and cerulein (100 ng/kg per hour)

over 90 min

Sampling of duodenal juice in 10-min aliquots over the

last 60 min of hormone infusion

Figure 31.2 Secretin–cerulein test protocol.

Table 31.2 Severity of exocrine pancreatic dysfunction based

on the secretin–cholecystokinin test.

Normal Normal output of enzymes and

bicarbonate Mild dysfunction Secretion of enzymes and

bicarbonate ≥ 75% of the lower limit of normal

Moderate dysfunction Secretion of enzymes and

bicarbonate 30–75% of the lower limit of normal Severe dysfunction Secretion of enzymes and

bicarbonate < 30% of the lower limit of normal

Table 31.3 Mean accuracy of exocrine pancreatic function

tests for the diagnosis of chronic pancreatitis.

Sensitivity (%) Specificity (%) Secretin–cholecystokinin 90 94

Although the endoscopic pancreatic function test is a

promising procedure, it is far from being the current

standard Whether the peak bicarbonate

concentra-tion, instead of output over time, is a reliable marker of

exocrine pancreatic function is questionable In fact,

most experts in this field support bicarbonate and

enzyme output and not concentration as the most

reliable marker of exocrine pancreatic function This is

due to the inverse relationship between bicarbonate

concentration and rate of juice secretion in response to

secretin In addition, the endoscopic pancreatic

func-tion test requires the endoscope to be maintained in the

duodenum for 1 hour, which is at least as

uncomfort-able for patients as nasoduodenal tubing Because of

this, pharmacologic conscious sedation is required in

the context of the endoscopic test, although the effect of

these drugs on exocrine pancreatic function has not

been specifically evaluated All these facts hinder the

clinical usefulness of the endoscopic pancreatic

func-tion test

Indirect tests

Indirect tests evaluate exocrine pancreatic function by

quantifying either the digestive ability of the gland or

levels of pancreatic enzymes in feces (Table 31.1) From

a methodologic point of view, these tests can thus be

classified as oral tests and fecal tests In oral tests, a

substrate is orally given together with a test meal

Pancreatic enzymes hydrolyze the substrate within the

duodenum; the released metabolites are absorbed from

the gut and can then be measured in serum, urine, or

breath Oral tests include the pancreolauryl test and

different breath tests, mainly using 13C-labeled

sub-strates Other tests like the NBT-PABA test and the

amino acid consumption test are no longer

commer-cially available and/or have insufficient diagnostic

ac-curacy to be recommended for clinical use

Several extrapancreatic factors are known to limit

the accuracy of oral pancreatic function tests, mainly

those interfering with normal digestion (slow gastric

emptying rate, decreased bile acid secretion) and

in-testinal absorption (inin-testinal diseases) as well as those

affecting the elimination of digestion products (renal

insufficiency) Variability in gastric rate can be avoided

to some extent by administration of metoclopramide or

any other prokineticum in the context of the test The

potential negative role of renal disturbances is avoided

by the quantification of digestion products in serum instead of urine

Fecal tests are based on the quantification of creatic enzyme concentration (elastase) or activity(chymotrypsin) in feces Enzymes are deactivated anddiluted or concentrated to a variable degree during intestinal passage, which must be taken into accountwhen interpreting test results Exocrine pancreaticfunction can also be measured indirectly in feces bymeans of fecal fat quantification The amount of fateliminated within the feces indirectly reflects fat diges-tion and therefore pancreatic lipase secretion

pan-Fecal tests

Fecal fat quantification

Fecal fat quantification using the classical Van deKamer test is the gold standard for the diagnosis ofsteatorrhea However, this test has several importantdisadvantages that limit its clinical applicability Pa-tients must eat a standard diet containing 80–120 g offat daily for five consecutive days This is an importanthandicap since the majority of patients with chronicpancreatitis are alcoholics and thus have limited com-pliance Furthermore, patients should collect the totalamount of feces produced over the last 3 days of thediet Again this is not easy for alcoholic patients A 3-day collection is needed to reduce errors and variabilitythat may occur if a shorter collection period is used.Patient compliance is not the only limitation of fecalfat quantification; so is the handling of stool samples

in the laboratory Stool samples collected over 3 daysmust be first homogenized and then processed man-ually, making this test unpleasant and cumbersome Anew methodology based on near-infrared reflectanceanalysis (NIRA) has greatly simplified the quantifica-tion of fat in stool and thus could make feasible thewide application of this test in clinical routine Never-theless, the difficulties associated with patient com-pliance remain the same

Method In our laboratory, patients are instructed to

eat a diet containing 92 g of fat for 5 days Stool fromthe last three consecutive days is collected in three dif-ferent containers The daily amount of fat excreted(g/day) is quantified based on fat concentration meas-ured by NIRA (g/100 g stool) and the total weight of the stool on each day The mean of the three values obtained is considered as the result

Interpretation Following the test protocol described

above, a fecal fat excretion below 7.5 g/day is

consid-ered normal Fat maldigestion indicating exocrine

pan-creatic insufficiency is defined by a fecal fat excretion

greater than 7.5 g/day Interpretation of the test may be

improved by keeping a record of all dietary intake over

the 5-day period In this way, fat intake can be

deter-mined and thus the fractional fat absorption can be

cal-culated It should be noted that fecal fat quantification

is a nonspecific pancreatic function test since any other

cause of maldigestion (i.e., obstructive jaundice) or

malabsorption (i.e., sprue, Crohn’s disease) may also

induce abnormal fecal fat excretion

Fecal chymotrypsin activity

Quantification of fecal chymotrypsin is a simple test

and easy to apply to the clinical routine This test is

based on the enzymatic quantification of chymotrypsin

activity in an isolated small stool sample Because of

this, fecal chymotrypsin has been widely introduced in

clinical routine as an exocrine pancreatic function test

However, chymotrypsin is variably inactivated during

intestinal passage in such a way that fecal chymotrypsin

activity does not accurately reflect pancreatic secretion

of the enzyme In addition, dilution of the enzyme in

patients with diarrhea of any etiology will also decrease

the fecal activity of the enzyme

Because of this, and in order to maintain adequate

specificity of the test, a low cut-off (3 U/g of stool) is

generally accepted as the definition of an abnormal test

Patients with fecal chymotrypsin activity of less than

3 U/g of stool are thus considered as suffering from

ex-ocrine pancreatic dysfunction, although the sensitivity

obtained with the test is too low to recommend it for

clinical practice In fact, the test is not able to detect a

single case of mild exocrine pancreatic dysfunction,

and can only detect slightly more than half of those

patients with moderate or severe dysfunction (Table

31.3)

Last but not least, orally administered exogenous

pancreatic enzymes as a treatment for exocrine

pan-creatic insufficiency interact with the determination

of chymotrypsin in stool and thus this therapy should

be interrupted for at least the 48 hours preceding

stool sample collection This is not always easy to

accomplish for patients with exocrine pancreatic

insufficiency

In conclusion, and after taking into consideration all

the aspects mentioned above, fecal chymotrypsin

quan-tification should no longer be considered adequate for evaluating exocrine pancreatic function in clinicalroutine

Fecal elastase concentration

Compared with chymotrypsin, pancreatic elastase ishighly stable during gastrointestinal transit and thefecal concentration of this enzyme correlates signifi-cantly with the amount of enzyme secreted by the ex-ocrine pancreas Furthermore, since the methodologyused to quantify this enzyme is based on human-specific monoclonal antibodies, oral enzyme substitu-tion therapy does not interfere with the test Therefore,interruption of this therapy previous to stool collection

is not needed, which is an important advantage

Method Quantification of fecal elastase is performed

in a single small stool sample by a specific enzyme immunoassay

Interpretation A fecal elastase concentration higher

than 200mg/g is considered normal Concentrationslower than 50mg/g are related to exocrine pancreaticinsufficiency Although fecal elastase quantification isnot sensitive enough to detect patients with mild ex-ocrine pancreatic dysfunction, its sensitivity in cases ofmoderate to severe dysfunction is very high, reachingvalues close to 100% The specificity of fecal elastase

is also high, only limited by dilution in cases of waterydiarrhea

Fecal elastase based on the use of human-specificmonoclonal antibodies is therefore an excellent test forthe diagnosis of exocrine pancreatic dysfunction in thecontext of chronic pancreatitis Since this test is easy toapply to the clinical routine, it may be used as a first step in the study of patients with clinically suspectedchronic pancreatic disease and for the follow-up of patients with known chronic pancreatitis In situations

of secondary exocrine pancreatic dysfunction (i.e.,after gastrointestinal surgery), fecal elastase is usefulfor evaluating pancreatic secretion but not for detect-ing maldigestion

Oral tests

Pancreolauryl test

Fluorescein dilaurate is administered orally togetherwith a standardized breakfast A pancreas-specific cholesterol ester hydrolase acts on this compound

C H A P T E R 3 1

and water-soluble fluorescein is released and absorbed

from the gut Fluorescein can thus be measured in

serum or urine after renal excretion The advantage of

this test is that it is easily applicable to the clinical

routine and can be used not only for supporting the

diagnosis of chronic pancreatitis but also for the

follow-up of patients with this disease The major

dis-advantages of the test are the limiting factors of oral

tests described above and a limited sensitivity for the

early diagnosis of chronic pancreatitis

Method The standard test requires collection of urine

over 10 hours after the ingestion of the standard

break-fast and fluorescein dilaurate The diuresis should be

in-creased by the ingestion of at least 1500 mL of water

during the test In order to compensate for the variable

intestinal absorption and renal excretion of the

sub-strate, the test should be repeated 3 days later by giving

fluorescein sodium as substrate On both test days,

urine fluorescein concentration is measured

Repetition of the test is not necessary if fluorescein

concentration is measured in serum Our group has

op-timized the serum pancreolauryl test by administering

intravenous metoclopramide just after the ingestion

of the test meal in order to avoid potential problems

related to gastric emptying In addition, intravenous

administration of secretin just before ingestion of the

test meal significantly increases the sensitivity of the test

by inducing a washout of stored pancreatic enzymes

accumulated overnight Finally, we have optimized the

measurement of serum fluorescein concentration The

optimized serum pancreolauryl test protocol is

summa-rized in Fig 31.3 Potential adverse effects of

metoclo-pramide and secretin present very rarely after a single

dose In our experience, transient mouth dryness is

ob-served occasionally after metoclopramide

administra-tion A few patients suffer from nausea after secretin,

which can be prevented by slow injection of the drug

(over 2–3 min)

Interpretation Results of the urine pancreolauryl test

are expressed as the quotient between the urine

fluores-cein concentration at day 1 (when fluoresfluores-cein dilaurate

is given as substrate) and that at day 2 (when fluorescein

sodium is given as substrate) A quotient is considered

as normal if higher than 30 and abnormal if lower than

20 Values between 20 and 30 are inconclusive

The peak serum fluorescein concentration is

consid-ered as the result of the serum test A peak greater than

4.5mg/mL indicates normal exocrine pancreatic tion Mild to moderate exocrine pancreatic dysfunc-tion is defined by a peak between 2.5 and 4.5mg/mL

func-A result below 2.5mg/mL is observed in patients withsevere pancreatic dysfunction

The accuracy of the optimized serum pancreolauryltest is much higher than the accuracy of the standardtest in urine (Table 31.3) The sensitivity of the opti-mized serum test for the diagnosis of mild exocrine pan-creatic dysfunction is 75%, and for moderate or severedysfunction is 100% False-positive results can be ob-tained in patients with gastrointestinal extrapancreaticdiseases leading to maldigestion of fluorescein dilau-rate (e.g., partial gastric resection with Billroth II anas-tomosis, obstructive jaundice) or to malabsorption ofreleased fluorescein (e.g., sprue)

13 C-substrate breath tests

Several substrates, mainly 13C-labeled, have been used

to evaluate exocrine pancreatic function by means ofbreath tests In these tests, the labeled substrate is givenorally together with a test meal After intraduodenalhydrolysis of the substrate by specific pancreatic en-zymes,13C-marked metabolites are released, absorbedfrom the gut, and metabolized within the liver As a con-sequence of hepatic metabolism, 13CO2is released and

Overnight fast Placement of an indwelling cannula in an antecubital vein

Take basal blood sample (10 mL)

Intravenous administration of secretin (1 U/kg body

weight) over 2–3 min Ingestion of the test meal (40 g of white bread, 20 g of butter, 200 mL of tea) together with 1 mmol fluorescein dilaurate spread on the bread together with the butter Intravenous metoclopramide administration (10 mg) Take blood samples (5 mL each) at 120, 150, 180 and

240 min after test meal ingestion Measurement of serum fluorescein concentration

in all samples

Figure 31.3 Optimized serum pancreolauryl test protocol.

C H A P T E R 3 1

thereafter eliminated with expired air (Fig 31.4) The

amount of 13CO2expired, which indirectly reflects

ex-ocrine pancreatic function, can be measured by means

of mass spectrometry or infrared analysis

Most substrates used in breath tests, among them

mixed13C-triglyceride, cholesteryl 13C-octanoate,13

C-hiolein, and 13C-triolein, are hydrolyzed by pancreatic

lipase In this way pancreatic function breath tests

should be seen as fat digestion tests and thus considered

as an alternative to fecal fat quantification

The only breath test that has been optimized is the

mixed13C-triglyceride (13C-MTG) breath test In our

experience, this is the optimal substrate for the

diagno-sis of fat maldigestion and thus the 13C-MTG breath

test has been developed as a simple alternative to fecal

fat quantification

Method According to the protocol developed by our

group, a total of 250 mg of 13C-MTG is spread on a

solid test meal containing 16 g of fat Before the meal

(basal sample) and in 30-min intervals for 6 hours after

ingestion of the meal, breath samples are collected in

10-mL tubes A single dose of a prokineticum (i.e.,

metoclopramide) is given orally 20–30 min before the

meal in order to avoid potential problems related to

gastric emptying The amount of 13CO2 in breath

samples is measured by mass spectrometry The result

of the test is expressed as the total amount of recovered

13CO2over the 6 hours

Interpretation A13CO2below 58% indicates the

pres-ence of fat maldigestion, with a sensitivity and ity higher than 90% The test is also highly accurate for the diagnosis of maldigestion in clinical situations

specific-of secondary exocrine pancreatic insufficiency, such

as partial or total gastrectomy or duodenectomy.The13C-MTG breath test is a simple, noninvasive,and accurate method for the diagnosis of exocrine pan-creatic insufficiency It is easily applicable to the clinicalroutine and can be repeated as often as necessary In thisway, the utility of the test is not only limited to the diag-nosis of exocrine pancreatic insufficiency but can also

be extended to control of the efficacy of oral enzymesubstitution therapy in these patients Therefore, the

13C-MTG breath test may play a relevant role in themanagement of patients with maldigestion secondary

to chronic pancreatitis, cystic fibrosis, pancreatic cer, and after acute necrotizing pancreatitis or gastric orduodenal surgery

can-Summary

A wide variety of tests are nowadays available for the evaluation of exocrine pancreatic function The secretin–cholecystokinin test is still the gold standard,but its use is presently limited to the evaluation of newfunction tests in specialized centers Quantification ofpancreatic zinc output as a single marker may simplifythe clinical applicability of this direct test

The optimized serum pancreolauryl test is the mostsensitive tubuless pancreatic function test and probably

13 C-substrate

13 CO2

13 CO2

13 C-metabolites

Figure 31.4 Basis of pancreatic

function breath tests.

Domínguez-Muñoz JE, Martínez S, Leodolter A, Malfertheiner P Quantification of pancreatic zinc output as pancreatic function test: making the secretin–caerulein test

applicable to clinical practice Pancreatology 2004;4:57–

Lembcke B Present and future of breath test in the diagnosis

of pancreatic insufficiency In: P Malfertheiner, JE

Dominguez-Muñoz, HU Schulz, H Lippert (eds) Diagnostic Procedures in Pancreatic Disease Berlin: Springer-Verlag,

1997: 261–271.

Lembcke B, Grimm K, Lankish PG Raised fecal fat

concentra-tion is not valid indicator of pancreatic steatorrhea Am J Gastroenterol 1987;82:526–531.

Lembcke B, Braden B, Caspary WF Exocrine pancreatic insufficiency: accuracy and clinical value of the uniformly labeled 13C-hiolein breath test Gut 1996;39:668–74.

Leodolter A, Kahl S, Domínguez-Muñoz JE, Gerard C, Glasbrenner B, Malfertheiner P Comparison of two tube- less function tests in the assessment of mild to moderate

exocrine pancreatic insufficiency Eur J Gastroenterol Hepatol 2000;12:1335–1338.

Löser C, Möllgaard A, Fölsch UR Faecal elastase 1: a novel, highly sensitive and specific tubeless pancreatic function

Malfertheiner P, Büchler M Correlation of imaging and

function in chronic pancreatitis Radiol Clin North Am

Gas-Stein J, Jung M, Sziegoleit A, Zeuzem S, Caspary F, Lembcke

B Immunoreactive elastase 1: clinical evaluation of a new

noninvasive test of pancreatic function Clin Chem 1996;

Ventrucci M, Cipolla A, Ubalducci GM, Roda A, Roda E

13 C-labelled cholesteryl octanoate breath test for assessing

pancreatic exocrine insufficiency Gut 1998;42:81–87.

the most appropriate for the screening of chronic

pan-creatitis in patients with clinical suspicion of the

dis-ease The urine pancreolauryl test can no longer be

recommended because of its low sensitivity and the

need to repeat the test twice three days apart

Fecal elastase quantification is the most adequate

fecal test It is clearly more accurate than fecal

chy-motrypsin for evaluation of exocrine pancreatic

func-tion and is easy to apply to the clinical routine

Therefore, fecal elastase may be applied as a first step in

the study of patients with suspected chronic

pancreati-tis and to aid in the differential diagnosis of chronic

diarrhea Fecal chymotrypsin activity is a

nonsensi-tive pancreatic function test and can no longer be

considered for clinical routine

The13C-MTG breath test appears to be an accurate

alternative to fecal fat quantification for the diagnosis

of maldigestion of any etiology This is a simple and

noninvasive method, easily applicable to the clinical

routine, that can be repeated as frequently as needed

and that is useful for the diagnosis of maldigestion as

well as for optimization of enzyme substitution therapy

in patients with primary or secondary exocrine

pan-creatic insufficiency

Recommended reading

DiMagno EP, Go VLW, Summerskill HJ Relations between

pancreatic enzyme outputs and malabsorption in severe

pancreatic insufficiency N Engl J Med 1973;288:813–815.

Domínguez-Muñoz JE Noninvasive pancreatic function

tests In: MW Büchler, H Friess, W Uhl, P Malfertheiner

(eds) Chronic Pancreatitis: Novel Concepts in Biology and

Therapy Oxford, Berlin: Blackwell Publishing, 2002:

225–232.

Domínguez-Muñoz JE, Malfertheiner P Optimized serum

pancreolauryl test for differentiating patients with and

without chronic pancreatitis Clin Chem 1998;44:869–

875.

Domínguez-Muñoz JE, Pieramico O, Büchler M,

Malfertheiner P Clinical utility of the serum pancreolauryl

test in diagnosing and staging of chronic pancreatitis Am J

Gastroenterol 1993;88:1237–1241.

Domínguez-Muñoz JE, Hyeronimus C, Sauerbruch T,

Malfertheiner P Fecal elastase test: evaluation of a new

noninvasive pancreatic function test Am J Gastroenterol

1995;90:1834–1837.

In the initial stages of chronic pancreatitis, which

generally last about 5 or 6 years, the disease is

charac-terized by attacks of abdominal pain that recur at

vari-able intervals during which the patient is pain-free

When the disease is more advanced, the pain tends to

disappear, either spontaneously or following surgery,

but other symptoms or complications may develop that

can alter the course of the disease In this chapter

we discuss the role of the physician in management of

this disease, particularly as regards follow-up and

complications

What to do in the follow-up

The clinical onset of chronic pancreatitis most

com-monly occurs when the patient is in his thirties or

for-ties A typical patient with chronic pancreatitis is a male

who is employed in a job that requires heavy labor

and who generally (70–80% of cases) drinks alcohol

to excess In Italy, alcohol is by far the most frequent

etiologic factor, present in 75–80% of patients with

chronic pancreatitis who have an average daily

con-sumption of 120–140 g of pure alcohol Thus, the first

and most important task for the physician is to

con-vince the patient to stop drinking alcohol, informing

him that if he does not do so there is little or no chance

that his condition will improve, and that he may well

also develop unpleasant complications It should also

be explained that if he ceases to drink, the attacks may

become less frequent and eventually disappear

Unfor-tunately, not all patients quit drinking, some resuming

once a painful attack has subsided (Table 32.1)

A majority of individuals with chronic pancreatitis

also smoke, and so another duty of the physician is topersuade the patient to quit this habit as well, eventhough it has not been clearly demonstrated that smok-ing has a pathogenetic role in chronic pancreatitis orthat it can negatively influence progression of the disease

Pain, the most important symptom in chronic creatitis, particularly in its initial stage, must be care-fully assessed and monitored in each patient If thefrequency and intensity of the painful attacks are re-duced by cessation of alcohol ingestion, the attacks arelikely to eventually disappear, generally within the first

pan-5 or 6 years of the disease; for these patients, surgical intervention is not indicated Among our patients,roughly 50% fall into this category If, on the contrary,the frequency and intensity of the painful attacks in-crease or remain high, surgery or, for a few selected patients, endoscopic intervention should certainly beconsidered, which is the case for about 50% of our patients For most of the patients who undergo surgery, this generally occurs within 5 or 6 years of clinical onset

It is important to study exocrine and endocrine creatic function from the initial stages of the disease,both to support the clinical diagnosis of chronic pan-creatitis and to guide its treatment In studies that uti-lized duodenal intubation and prolonged maximalpancreatic stimulation, we showed that exocrine pan-creatic function is impaired in almost all patients withchronic pancreatitis, starting in the initial stages of thedisease, at which point the functional impairment isgenerally mild or moderate Although duodenal intu-bation is the more sensitive means of assessing exocrinepancreatic function, it is time-consuming and trouble-some and is no longer used in clinical practice At pre-

pan-32 Follow-up of patients with chronic

pancreatitis: what to do and which complications can be expected

Lucio Gullo and Raffaele Pezzilli

not stop drinking, often do not keep their scheduled appointments but may show up only after an attack

of severe pain

In the nonalcoholic forms of chronic pancreatitis(about 20–30% of cases), the most important measure

is to determine the cause of the disease and to eliminate

it, which usually leads to improvement in the clinicalpicture With regard to the follow- up, the measures areessentially the same as those for alcoholic pancreatitis.The patient with advanced chronic pancreatitis, whohas had the disease for longer than 5 or 6 years, gener-ally presents with different clinical problems In the ma-jority of studies on chronic pancreatitis, it is reportedthat pain, the principal clinical manifestation in theearly stages of the disease, is generally no longer present

in the more advanced stages The patient may have hadsurgery for the pancreatitis, or the pain may have resolved on its own Those for whom pain continues

to be a significant problem are generally either thosewho continue to drink, and for these patients it is diffi-cult to find a definitive solution for the pain, or they arepatients who have developed a complication, mostoften a pseudocyst We should mention, however, that

in one study pain has been reported to be frequent even

in advanced stages of the disease

In the advanced stages of chronic pancreatitis, ally after 8–10 years from clinical onset, exocrine pancreatic insufficiency may become severe (< 10% ofnormal enzyme production) and steatorrhea develops,necessitating the administration of pancreatic extracts

gener-It is very important to establish the correct daily dose ofthe extracts, which must be adequate to prevent the loss

of fat in the feces; a dose of 30 000 U per meal is ally sufficient If steatorrhea does not disappear com-pletely, this dose can be increased In patients withgastric acid hypersecretion it can be helpful to adminis-ter H2blocking agents or proton pump inhibitors withthe extracts in order to prevent their inactivation bygastric acid Steatorrhea develops in about 50–60% ofpatients with advanced chronic pancreatitis

gener-In advanced stages of chronic pancreatitis, usuallyafter 7 or 8 years from clinical onset, diabetes can de-velop as a result of the destruction of islet cells by pan-creatic fibrosis It usually starts in a mild form that istreatable with oral antidiabetic agents or low doses ofinsulin but often progresses to a more severe form withhigher insulin requirements The complications of dia-betes due to chronic pancreatitis are similar to those ofprimary diabetes In particular, we studied the fre-

sent, it has been substituted by indirect tests of

pancre-atic function that often show normal results when

the chronic pancreatitis is mild We now use the fecal

elastase test, which has good sensitivity particularly

in patients who have moderate or severe pancreatic

insufficiency

Patients who have mild or moderate pancreatic

insufficiency do not have steatorrhea and therefore do

not require the use of pancreatic extracts However,

some authors have advocated the use of extracts in

patients with mild to moderate insufficiency as well,

for the purpose of preventing attacks of pain In this

regard, various studies have been carried out but the

re-sults have been conflicting, possibly due to the different

types of enzyme preparations that have been used The

preparations that seemed to be useful in preventing

at-tacks of pain were those administered in tablet form

Endocrine pancreatic function is generally normal in

the initial phases of chronic pancreatitis and clinically

evident diabetes usually appears in the advanced stages

of the disease, generally 8–10 years after onset Thus, in

the early stages of the disease blood glucose

determina-tion and a glucose tolerance test every 6–12 months are

generally sufficient for monitoring endocrine function

For optimal management of patients with chronic

pancreatitis, especially in the initial stages of the

dis-ease, it is essential to have frequent follow-up visits, at

least once every 6 or 12 months This serves to monitor

the frequency of episodes of pain as well as the

appear-ance of other disturbappear-ances, and especially to determine

whether the patient has stopped drinking Many

pa-tients quit drinking alcohol and these same individuals

generally keep their appointments for follow-up visits

Others, who are typically heavier drinkers and who do

Table 32.1 What to do in follow-up.

Ascertain whether the patient has stopped drinking

In nonalcoholic forms, determine the cause and eliminate it

Evaluate pain; if the attacks are frequent, consider surgery or,

in select patients, endoscopy

Assess exocrine and endocrine pancreatic function; if

impaired, treat accordingly

Assess for complications and treat accordingly

Activity limitations and dietetic rules: this is pertinent mainly

to patients with severe steatorrhea or advanced diabetes

Arrange for check-up visits at least every 6–12 months, when

possible, with a specialist in pancreatic diseases

quency of diabetic retinopathy in chronic pancreatitis

and found that it is similar to that of patients with type

I diabetes Diabetes develops in about 50–60% of

patients with advanced chronic pancreatitis

Another task for the physician responsible for

pa-tients with chronic pancreatitis is to educate them

re-garding their diet Prior to onset of the disease these

patients are often hearty eaters and drinkers In the

early stages of the disease, when steatorrhea and

dia-betes are not yet present, there is no need for particular

dietetic measures; it is important, however, that the diet

be well balanced and that it meets the nutritional needs

of the individual It is generally advised to reduce fat

intake, although there is no clear evidence that this is

useful Obviously, if there is decreased glucose

toler-ance, carbohydrate and sugar intake should be

re-duced In more advanced stages of the disease, when

steatorrhea may be present, the diet should be

hyper-caloric but, other than a reduction of fat intake, the

patient should not be subjected to other restrictions

unless diabetes is also present

Regarding restrictions on activity, none should be

imposed except in the case of patients who have severe

steatorrhea or advanced diabetes; if their job entails

heavy labor, they should be advised to seek less

strenuous employment

Complications

Of the various complications that can develop in the

course of chronic pancreatitis, pseudocysts and

steno-sis (generally mild) of the retropancreatic portion of the

common bile duct are the most frequent Several less

common ones can also be encountered (Table 32.2)

Pancreatic pseudocysts

Pseudocysts most commonly develop during the initial

stages of chronic pancreatitis; their reported frequency

varies from study to study, but they are fairly frequent,

occurring in about 25–30% of cases In surgical series

their frequency is higher (about 50–60%) Most often

pseudocysts present as a single lesion, but sometimes

two or more can be seen; their size is variable, they are

often symptomatic (persistent pain being the most

frequent symptom), and they are occasionally

com-plicated by rupture or infection In our experience, in

the great majority of cases the pseudocysts derive from

C H A P T E R 3 2

dilated ducts, and thus are true cysts; as they dilate, the epithelial lining can be lost, at which point they nolonger appear to be true cysts Among our patients withchronic pancreatitis, postnecrotic pseudocysts are rare,the main reason being that we see few patients (about10%) who have had an acute necrotic attack

As far as treatment is concerned, if the pseudocystsare asymptomatic and without complications they can

be left untreated, but repeat ultrasound is mended every 6–12 months to control their size If theybecome painful or develop a complication, treatmentbecomes obligatory Years ago the only treatment available was surgery; more recently this has beenabandoned in favor of endoscopic intervention.Another possibility in the treatment of painfulpseudocysts in chronic pancreatitis is the administra-tion of octreotide, a synthetic analog of somatostatin,which causes the cysts to shrink and eventually disap-pear We have shown that this treatment (100mg every

re8 hours) is effective mainly when the cysts do not municate with the Wirsung duct and if the drug is ad-ministered when their size is increasing When thesecriteria are met, the pain disappears completely and definitively after 3–4 days of octreotide treatment,

com-as the cysts begin to shrink in size; the cysts then appear completely after 6–8 weeks of treatment

dis-We would like to point out that size alone is not anindication for treatment Although it has been a guidingprinciple that cysts of greater than 5–6 cm in diametershould be treated, we feel that if the cysts are asympto-matic treatment is not necessary, regardless of their

Table 32.2 Complications, associated diseases, and

mortality in chronic pancreatitis.

size We have followed several patients whose cysts

have been larger than 5 or 6 cm and stable in size for

many years, during which they have also been

pain-free; we believe that intervention is not necessary in

these cases Generally speaking, once cysts are treated

they are no longer problematic

Stenosis of the retropancreatic common bile duct

Stenosis of the distal portion of the common bile duct is

a complication seen in both initial and advanced stages

of chronic pancreatitis and can be observed in up to

40–50% of cases; it is generally mild and does not

ob-struct the flow of bile The stenosis is caused by

pancre-atic fibrosis in the area of the duct It can contribute to a

generally mild and transient (lasting 3–10 days) form of

jaundice that can occur during attacks of pain, when

the already stenotic bile duct is compressed by

pancre-atic edema This transient jaundice during attacks of

abdominal pain occurs in about 30–40% of cases

In about 5–10% of the patients with chronic

pancre-atitis the jaundice persists and requires treatment It is

due to complete obstruction of the retropancreatic

common bile duct, most often by pancreatic fibrosis,

although sometimes it is due to compression of the

duct by a cyst of the pancreatic head or, more rarely, by

cancers of the pancreatic head, which can complicate

chronic pancreatitis In these cases, it is necessary to

perform a choledochojejunostomy A stent is

some-times placed endoscopically, but these tend to become

occluded, and the procedure is often complicated by the

development of cholangitis; for this reason, it should

only be used in carefully selected cases, such as in

pa-tients awaiting surgery or in those who present a high

surgical risk

Pancreatic cancer

Many studies have been published on the risk of

pan-creatic cancer in patients with chronic pancreatitis, but

results have been conflicting: some have concluded that

there is a risk, others that there is not or that it is very

low We believe that chronic pancreatitis is a risk factor

for pancreatic cancer but that this risk is low, on the

order of 1–3% Lowenfels et al reported a cumulative

risk of pancreatic cancer in subjects with chronic

pancreatitis who were followed for 10 and 20 years

after the diagnosis of pancreatitis of 1.8 and 4%

respectively

The risk of pancreatic cancer has been reported to bevery much higher in patients with hereditary chronic

pancreatitis Lowenfels et al have shown that the

esti-mated cumulative risk of pancreatic cancer to age 70years in patients with this disease approaches 40%.Extrapancreatic cancer

Patients with chronic pancreatitis have a high incidence(10–15%) of extrapancreatic cancer, the commonestsites being the upper and lower airways as well as thegastrointestinal tract The reason for this increased incidence is not clear, but the abuse of tobacco and alcohol in these patients is thought to be responsible.Splenic vein thrombosis

While splenic vein thrombosis is well known as a plication of chronic pancreatitis, its incidence is not.Bradley reported an incidence of 2% among his pa-tients with this disease In our experience, the incidencehas been a little higher (about 5%) Thrombosis of thesplenic vein is due to involvement of the vein by thechronic inflammatory process in the pancreas It can result in the development of gastric or esophagealvarices; although there are no precise data regardingthe frequency with which these varices bleed, the percentage is generally low

com-PseudoaneurysmThis is a rare complication of chronic pancreatitis, seen

in about 2–3% of cases It usually occurs in associationwith pancreatic pseudocysts, the mechanism of forma-tion being erosion of an expanding pseudocyst into anearby artery The vessels most commonly involved arethe splenic, gastroduodenal, pancreaticoduodenal, andhepatic arteries Pancreatic pseudoaneurysms causebleeding that may be slow and intermittent or acute andmassive Treatment is necessary even if they are not ac-tively bleeding because untreated pseudoaneurysmshave a very high mortality rate Bleeding can be suc-cessfully controlled by arteriographic transcatheterembolization or surgery

Duodenal obstructionThis complication occurs in about 4–5% of patientswith chronic pancreatitis It is generally due to marked

fibrosis of the head of the pancreas that involves the

duodenum or to a pseudocyst; treatment consists of

surgery for the former and endoscopic drainage or

sur-gical treatment for the latter

Pancreatic fistula

Pancreatic fistulas are a rare complication of chronic

pancreatitis (2–3%) External fistulas generally

develop after surgical procedures on the pancreas or

after attacks of necrotic pancreatitis Internal

pan-creatic fistulas are generally due to rupture of the main

pancreatic duct or leakage from a pseudocyst The

main complications of internal fistulas are pancreatic

ascites or pleural effusions

Treatment consists of fasting, parenteral nutrition,

octreotide (100mg every 8 hours), or endoscopic stent

placement; if the fistula persists surgery is indicated

Pancreatic abscess

This is a rare complication that involves only about

2–3% of patients with chronic pancreatitis The

ab-scess often develops at the site of a previous pseudocyst

Treatment with antibiotics is generally unsuccessful,

leaving surgery as the only viable alternative

Alcoholic liver disease

Based on clinical studies, it was long believed that in

pa-tients with chronic alcoholic pancreatitis the damage

from alcohol was limited to the pancreas and that liver

involvement was rare However, with histologic studies

of the liver we and others have shown that a high

per-centage of these patients have alcoholic damage to the

liver as well In particular, in a study done on surgical

biopsies of the liver taken from 50 patients with chronic

alcoholic pancreatitis undergoing surgery for

pancre-atitis, we showed that 22 (44%) had associated

alcoholic liver disease; of these 22, 13 had alcoholic

hepatitis, 7 cirrhosis, and 2 steatosis The percentage

of alcoholic liver disease in this series of patients

was similar to that found in the general alcoholic

population

We have seen that patients with chronic alcoholic

pancreatitis who develop hepatic disease are most often

those who drink larger quantities of alcohol (> 200 g of

pure alcohol daily) and for a longer period of time (> 20

years) It is therefore important that patients with

chronic alcoholic pancreatitis, especially those whosealcohol consumption is to the above-described extent,are periodically monitored with liver function andimaging tests for early recognition and timely treat-ment of any associated liver disease

Cardiovascular lesionsSeveral investigators have reported an increased frequency of vascular lesions in patients with chronicpancreatitis, but while some have assumed that this was simply a coincidence, others have suggested that acausal relationship may exist In a study of 54 patientswith chronic pancreatitis (mean age 44 years, range26–66), we found evidence of vascular involvement in

18 (33%) of the patients and in 5 (9%) of the controls

In particular, we found electrocardiographic signs ofcoronary artery disease in eight patients, as well as peripheral signs and symptoms of obliterative athero-sclerotic disease in the lower extremities in 12 patients

No significant differences in the prevalence of the majorvascular risk factors were noted between patients withvascular lesions and those without, or between the pa-tients and the control subjects

In another study, we showed that in 57 patients withchronic pancreatitis there was radiologic evidence ofaortic calcification in 35 (41.4%), but only in 12 of 40(30%) smoker controls Interestingly, these patientshad a mean age of 44 years (range 26–59), whereas inthe general population aortic calcifications are rarelyseen in persons under the age of 50–60 years None ofthese patients with chronic pancreatitis had conditionsassociated with atherosclerosis, such as diabetes, arterial hypertension, obesity, or hyperlipidemia Itshould be mentioned that aortic calcification is associ-ated with a marked increase in risk of death by cardio-vascular disease These two studies indicate that,compared with the general population, patients withchronic pancreatitis have more frequent cardiovascu-lar lesions and the lesions tend to develop at an earlierage; the reason for these findings is not clear

MortalityAll the studies published on mortality in chronic pan-

creatitis have concluded that it is high Ammann et al in

their study of 245 patients with chronic pancreatitis reported that 86 (35%) died; the mean age at death was 54 years in 54 patients with alcoholic pancreatitis

C H A P T E R 3 2

lence of aortic calcification in chronic pancreatitis Am J Gastroenterol 1996;91:759–761.

Gullo L, Ventrucci M, Tomassetti P, Migliori M, Pezzilli R.

Fecal elastase 1 determination in chronic pancreatitis Dig Dis Sci 1999;44:210–213.

Gullo L, Tomassetti P, Migliori M, Casadei R, Marrano D Do early symptoms of pancreatic cancer exist that can allow an

earlier diagnosis? Pancreas 2001;22:210–213.

Hansen TH, Laursen M, Christensen E et al Chronic atitis and extrapancreatic cancer Int J Pancreatol 1995;

pancre-18:235–240.

Hayakawa T, Kondo T, Shibata T, Sugimoto Y, Kitagawa M Chronic alcoholism and evolution of pain and prognosis in

chronic pancreatitis Dig Dis Sci 1989;34:33–38.

Karlson BM, Ekbom A, Josefsson S et al The risk of

pan-creatic cancer following pancreatitis: an association due

fac-of 240 patients Gastroenterology 1988;96:1165–1172 Lowenfels AB, Maisonneuve P, Cavallini G et al Pancreatitis and the risk of pancreatic cancer N Engl J Med 1993;

328:1433–1437.

Lowenfels AB, Maisonneuve P, DiMagno EP et al Hereditary pancreatitis and the risk of pancreatic cancer J Natl Cancer Inst 1997;89:442–446.

Miyake H, Harada H, Kunichik K, Ochi K, Kimura I Clinical

course and prognosis of chronic pancreatitis Pancreas

1987;2:378–385.

Pradeep B, Sonnenberg A Pancreatitis is a risk factor for

pan-creatic cancer Gastroenterology 1995;109:247–251.

Saed ZA, Ramirez FC, Hepps KS Endoscopic stent placement

for internal and external pancreatic fistulas ogy 1993;105:1213–1217.

Gastroenterol-Segal I, Parekh D, Lipschitz J et al Treatment of pancreatic

ascites and external pancreatic fistulas with a long-acting

somatostatin analogue Digestion 1993;54:53–58 Woods MS, Traverso LW, Kozarek RA et al Successful treat-

ment of bleeding pseudoaneurysms of chronic pancreatitis.

Pancreas 1995;10:22–26.

and 66 years in 32 with nonalcoholic pancreatitis In a

study by Levy et al of 240 patients with chronic

pan-creatitis, of whom 210 were drinkers, it was reported

that after a mean of 20 years from the clinical onset of

the disease, 57 patients (23.7%) were dead and that the

average age at the time of death was 52 years

The mortality rate for chronic alcoholic pancreatitis

is higher than it is for idiopathic or other forms of

chronic pancreatitis; as would be expected, among

patients with alcoholic pancreatitis the mortality rate

is higher for those who continue to drink The main

causes of death for these patients are cardiovascular

disease, hepatic cirrhosis, extrapancreatic or

pan-creatic cancer, postoperative complications,

com-plications of chronic pancreatitis or of diabetes, and

alcoholism In general, less than 20% of deaths are

directly related to chronic pancreatitis

Recommended reading

Ammann RW, Akovbiantz A, Largiader F, Schueler G Course

and outcome of chronic pancreatitis Longitudinal study of

a mixed medical–surgical series of 245 patients

Gastroen-terology 1984;86:820–828.

Bender JS, Bouwman DL, Levison MA et al Pseudocysts and

pseudoaneurysms: surgical strategy Pancreas 1995;10:

143–145.

Bradley EL III The natural history of splenic vein thrombosis

due to chronic pancreatitis: indications for surgery Int J

Pancreatol 1987;2:87–92.

Gullo L, Barbara L Treatment of pancreatic pseudocysts with

octreotide Lancet 1991;338:540–541.

Gullo L, Stella A, Labriola E et al Cardiovascular lesions in

chronic pancreatitis A prospective study Dig Dis Sci

1982;27:716–722.

Gullo L, Barbara L, Labò G Effect of cessation of alcohol

use on the course of pancreatic dysfunction in alcoholic

pancreatitis Gastroenterology 1988;95:1063–1068.

Gullo L, Parenti M, Monti L, Pezzilli R Diabetic retinopathy

in chronic pancreatitis Gastroenterology 1990;98:1577–

1581.

Gullo L, Casadei R, Campione O, Grigioni W, Marrano D

Alcoholic liver disease in alcoholic chronic pancreatitis:

a prospective study Ital J Gastroenterol 1995;27:69–

72.

Gullo L, Tassoni U, Mazzoni G, Stefanini F Increased

Chronic pancreatitis is an inflammatory, often painful

dis-ease of the exocrine pancreas that leads to exocrine

insuf-ficiency Its incidence is about 8.2 new cases per 100 000

inhabitants per year in western Europe Complications

encountered in chronic pancreatitis include biliary

(10–30%) and duodenal (10–25%) obstruction and, as

the disease progresses, maldigestion and diabetes mellitus

However, the most disturbing complication of chronic

pancreatitis is abdominal pain Surgical management is

often indicated in cases with medically intractable pain

and this has also repercussions on the economic

manage-ment of these patients Three typical pain profiles that

occur during the evolution of chronic pancreatitis have

been described: (i) repeated episodes of acute

pancreati-tis (acinar necrosis) in early stages; (ii) spontaneous

last-ing pain relief in association with severe pancreatic

dysfunction in the late stage of uncomplicated chronic

pancreatitis; and (iii) persistent severe pain (or frequent

recurrent episodes of pain) usually in association with

local complications such as pseudocysts, ductal

hyper-tension or extrapancreatic complications such as partial

obstruction of the common bile duct, peptic ulcer, and

opiate addiction Clearly, the actual pathophysiology of

abdominal pain remains elusive and several hypotheses

have been postulated over the last few years

At present, pancreatic and extrapancreatic

mecha-nisms are implicated in the development of pain in

chronic pancreatitis

Pancreatic causes of pain

Acute inflammation of the pancreas

Acute inflammation is readily apparent when there is

severe abdominal pain and tenderness, elevation ofserum amylase and lipase, and evidence of acute pan-creatic inflammation on computed tomography Thecauses are likely to be the same as for inflammation associated with acute pancreatitis, involving activatedenzymes and other injurious substances

Increased pressure in the pancreatic ducts and tissueIntrapancreatic ductal pressure might be related topancreatic secretion itself and to the presence of an ob-struction in the pancreatic duct Therefore, many inves-tigators have related the origin of pain to increasedpressure in the pancreatic ducts and tissue This ductalhypertension hypothesis as an explanation for pain inchronic pancreatitis is derived from observations thatdecompression of a dilated pancreatic duct or pseudo-cyst frequently relieves pain in patients with chronicpancreatitis Pancreatic enzyme supplementation mayalso relieve pain in some patients with chronic pan-creatitis It is believed that the beneficial effect of pan-creatic enzymes is explained by regulation involvingcholecystokinin-mediated feedback between pancreat-

ic exocrine secretion and the activity of proteases in the lumen of the small intestine According to this hypothesis, administration of enzymes reduces hyper-cholecystokininemia in patients with chronic pancre-atitis, thus resulting in less stimulation of the pancreasand subsequently lowered intraductal pressure andpain Interestingly, different studies have shown thatprogressive pancreatic insufficiency, which appearsseveral years after the first diagnosis, is often associatedwith a reduction in, and sometimes complete relief of,pain in patients with chronic pancreatitis, thus indicat-ing that disease progression might “burn out” the pan-creas itself, as mentioned before In contrast, we have to

33 Conservative treatment of pain in

chronic pancreatitis: guidelines for clinical routine

Pierluigi Di Sebastiano, Markus A Weigand, Jörg Köninger, Fabio F di Mola, Helmut Friess, and Markus W Büchler

consider that often pain in chronic pancreatitis is not

related to the consumption of food, and even pain

intensity, radiation, and duration are not constant In

addition, other studies have calculated that around

30% of the patients treated with decompressive

surgery exhibit recurrent attacks of pain On one hand,

when patients are pain-free after surgery, this could

often be due to the reduction of alcohol ingestion or to

progressive pancreatic insufficiency At present, the

relationship between pancreatic parenchymal pressure

and pain in chronic pancreatitis is still controversial

Neurogenic inflammation

Recent concepts have focused on the possible

involve-ment of the nervous system in chronic pain and the

in-flammatory process in chronic pancreatitis Supporting

this fascinating hypothesis, Keith et al postulated that

neural and perineural alteration might be important in

the pathogenesis of pain in chronic pancreatitis They

demonstrated that pain severity correlated with the

duration of alcohol consumption, pancreatic

calcifica-tion and, more interestingly, with the percentage of

eosinophil number in the perineural infiltrate, but not

with duct dilatation

A subsequent study demonstrated that there is an

increase in both number and diameter of pancreatic

nerve fibers in the course of chronic pancreatitis

compared with normal pancreas Also, there is an

altered pattern of intrinsic and possibly extrinsic

innervation of the pancreas in chronic pancreatitis,

leading to upregulation of neuropeptides such as

sub-stance P and calcitonin gene-related peptide Because

both of these peptides are generally regarded as pain

transmitters, these findings provided evidence that

changes in pancreatic nerves themselves might be

in-volved in the long-lasting pain syndrome in chronic

pancreatitis

Another interesting finding of these studies was the

observation of close contacts between neuronal

struc-tures and immune cells in chronically inflamed

pan-creas, which led to the concept that neuroimmune

mechanisms play a role in the pathogenesis of chronic

pancreatitis and the accompanying abdominal pain To

confirm this interesting hypothesis, in a subsequent

report the presence of growth-associated protein

(GAP)-43, an established marker of neuronal plasticity,

correlated with individual pain scores in patients with

chronic pancreatitis

Extrapancreatic causes of pain

Bile duct stenosis and duodenal stenosis due to sive pancreatic fibrosis and inflammation are often considered putative extrapancreatic causes of pain.However, only a few authors are in accordance withthis belief Recently, Becker and Mischke described apathologic condition named “groove pancreatitis” in19.5% of 600 patients with chronic pancreatitis Thisform of chronic pancreatitis is characterized by the for-mation of a scar plate between the head of the pancreasand the duodenum Scars in the groove lead to compli-cations also determined by the topography: distur-bance in the motility of the duodenum, stenosis of theduodenum, and tubular stenosis of the common bileduct, which occasionally leads to obstructive jaundice.These alterations might be responsible for severalsymptoms present in chronic pancreatitis and also forpostprandial pain, probably due to compression of several critical structures, such as nerves and ganglia, present between the pancreatic head and the duodenum

exten-Characteristics of pain in chronic pancreatitis

Pain is the leading symptom in chronic pancreatitis andshould be treated to improve quality of life and to pre-vent excessive weight loss in these patients Pain can bemild, moderate, or severe and increase or decrease overtime Multifactorial elements are involved and this mayexplain why all patients do not respond to the sametreatment modality

Pain in chronic pancreatitis is usually elicited by theactivation of specific nociceptive receptors (nocicep-

tors) and is thus referred to as nociceptive pain

How-ever, it may also result from injury to sensory fibers or

from damage to the central nervous system itself pathic pain) Inflammation due to neural activity is called neurogenic inflammation In healthy conditions,

(neuro-nociceptors in the pancreas are silent and are not activated by noxious stimulation In chronic pancreati-tis, however, inflammation, ischemia, elevated pres-sures, and release of substances such as prostaglandins,bradykinin, leukotrienes, and substance P sensitize no-ciceptors to the generation of action potentials and in-duce nociceptive pain In addition, pain is also based onneuropathic changes such as proliferation of unmyeli-nated nerve fibers, destruction of the perineurium, neur-

C H A P T E R 3 3

al edema, and damage to nerve fibers Thus, nociceptive

pain and neurogenic inflammation in chronic

pancreati-tis provide the rationale for medical, analgesic, and

antiinflammatory treatment In the beginning, patients

should be examined for obvious abnormalities and

extrapancreatic causes of pain Surgical intervention

should seriously be considered if long-term use of potent

opioids is required for pain relief, before the

develop-ment of narcotic addiction In addition, surgery is

recommended if pain no longer responds to analgesics

or if complications in adjacent organs occur

Conservative treatment of pain

Abstinence from alcohol

The first step in managing pain in chronic pancreatitis

consists of the complete avoidance of alcohol Alcohol

abstinence can achieve pain relief in up to 50% of

pa-tients, but its effect seems to be restricted to patients

with mild or moderate disease

Analgesics

The treatment of pain in chronic pancreatitis is

per-formed according to the three-step ladder of the World

Health Organization for the relief of cancer pain (Fig

33.1) The first step is for mild to moderate pain and

consists of nonopioid analgesics The second step is for

moderate to severe pain and a nonopioid analgesic is

combined with a mild opioid, which is titrated untilpain relief is satisfactory The third step is for severepain and requires the use of a potent opioid such asmorphine Adjuvant drugs like tricyclic antidepres-sants may be used at each step on the ladder However,

as already mentioned above, when pain treatment

in chronic pancreatitis requires the long-term use

of potent opioids, surgical intervention should be considered

Although the application of reasonable levels ofanalgesics is the first-line therapy for pain in chronicpancreatitis, there are no randomized studies compar-ing different drugs for pain therapy in chronic pancre-atitis Regular application of analgesic drugs should bepreferred to drug intake on demand in order to provideconsistent analgesia Pain intensity should be regularlyestimated by visual analog scale and the lowest drugdose for sufficient pain relief prescribed Pain therapyshould be coordinated and provided by one physician

to avoid overprescription and to reduce the risk ofabuse or addiction

Acetaminophen (paracetamol) and metamizol

According to a consensus report from the German Society of Gastroenterology, acetaminophen ormetamizol are the drugs of first choice for pain treat-ment in chronic pancreatitis Acetaminophen is a drugwith good analgesic and antipyretic properties andminimal adverse effects In particular, no relevant gas-trointestinal adverse effects of the drug in the recom-

Mild opioids Tramadol Tilidin/naloxone (Dihydro)codeine Dextropropoxyphene

Adjuvant drugs (tricyclic antidepressants, anticonvulsants, and steroids) Physiotherapy, psychotherapy

Surgery and other interventional procedures

Potent opioids Morphine Buprenorphine Transdermal patches

of fentanyl and buprenorphine

Change in opioids or application mode Treatment of opioid-induced advevse effects

Neurolytic procedures

Figure 33.1 World Health

Organization analgesic ladder for

cancer pain adapted for pain

management in chronic pancreatitis.

COX, cyclooxygenase; NSAIDs,

nonsteroidal antiinflammatory drugs.

mended dose is known Acetaminophen may also have

synergistic effects with other nonopioid analgesics

Metamizol has potent analgesic and antipyretic

effects and is the standard nonopioid analgesic in

many countries In addition to its analgesic properties,

metamizol also has spasmolytic effects, which can be

beneficial for pain treatment in chronic pancreatitis A

major adverse effect of metamizol is the risk of

agranulo-cytosis Because of this, metamizol is not approved in the

USA and UK When metamizol is used on a regular basis,

a white blood cell count has to be performed regularly

Unfortunately, acetaminophen and metamizol have

only weak inhibitory activity against cyclooxygenase

(COX) and therefore possess no antiinflammatory

effects Since inflammation is a major cause of the

nociceptive and neuropathic pain during chronic

pancreatitis, antiinflammatory analgesic agents may be

beneficial under these conditions

Nonsteroidal antiinflammatory drugs

Nonsteroidal antiinflammatory drugs (NSAIDs), withthe exception of aspirin, inhibit COX-1 and COX-2 in

a reversible manner and thus provide consistent sia and antiinflammatory action In addition, they haveantipyretic properties NSAIDs are recommended asfirst-line drugs for the treatment of nociceptive pain(Table 33.1)

analge-Although the inhibition of inflammation by NSAIDs

is an attractive hypothesis because (neurogenic) mation is a key pathogenic factor in chronic pancreati-tis, there are no studies confirming the superiority ofantiinflammatory analgesics in chronic pancreatitis.Therefore, the potential adverse effects of NSAID treatment must be balanced with the potential benefits.The adverse effects of NSAIDs range from trivial, such

inflam-as skin irritation or dyspepsia, to life-threatening, such

as gastric ulceration and renal toxicity In addition

Table 33.1 Drug overview for the management of pain in chronic pancreatitis.

Dosing interval Maximum Drug class Generic name Single dose (mg) (hours) dosage (mg) COX-2 selectivity*

Nonacidic nonopioid Acetaminophen 500–1000 6 4000 (6000)

Transdermal fentanyl 25–50 mg/hour (48)–72 Transdermal 35–52.5 mg/hour 72 buprenorphine

antidepressants Clomipramine 20–50–100 24 In the morning Mild stimulating

* The 80% inhibitory concentration ratios of COX-2 relative to COX-1 in human whole blood assays (Warner et al 1999).

† Highest dosage only approved for treatment of acute pain.

COX, cyclooxygenase; NSAIDs, nonsteroidal antiinflammatory drugs.

to direct nephrotoxicity, patients with reduced

glomerular filtration rate (especially when already

taking diuretics), cirrhosis, and heart failure may be

seriously affected by NSAIDs Risk factors for

gas-trointestinal bleeding include old age, cirrhosis, and

coagulation and platelet disorders Thus, due to these

adverse effects of NSAIDs, acetaminophen or

metami-zol may be the safer drugs for long-term use in chronic

pancreatitis, at least in at-risk patients If NSAIDs are

used on a regular basis, proton pump inhibitors should

be added

COX-2 inhibitors

Recent data demonstrate that COX-2 is overexpressed

in chronic pancreatitis and correlates with the stage of

disease and diabetes mellitus These data point to the

treatment of pain in chronic pancreatitis with selective

COX-2 inhibitors such as celecoxib, rofecoxib, and

valdecoxib However, the contribution of the

constitu-tive COX-1 enzyme to pronocicepconstitu-tive pools of

prostaglandins should not be discounted Therefore,

under certain conditions COX-2-selective drugs are

suspected to be less analgesic than unselective COX

in-hibitors such as diclofenac In addition, treatment with

COX-2-selective analgesics turned out to be a

double-edged sword Although studies indicate a lower

inci-dence of ulcer complications/symptomatic ulcers and a

decreased rate of lower gastrointestinal clinical events

with coxib treatment of rheumatoid arthritis compared

with nonselective NSAIDs, the total incidence of

non-gastrointestinal serious adverse events was increased

In particular, renal adverse events, blood pressure,

an-nualized myocardial infarction rate, and mortality

were higher with coxib use Thus, the potential benefits

of COX-2-selective inhibitors have to be weighed

against potential harm Because gastric ulcer

complica-tions are only reduced but not eliminated by selective

COX-2 inhibitors, proton pump inhibitors cannot

al-ways be omitted when patients are treated with these

drugs At present, COX-2 inhibitors are not approved

for pain treatment in chronic pancreatitis

Opioids

If no sufficient pain relief is achieved by nonopioid

analgesics, mild opioids should be added (Table 33.1)

Treatment with opioids can be started with

immediate-release formulations in order to titrate the opioid, and

later can be continued with depot preparations to

reduce the frequency of administration Nausea andvomiting either settle with time or can be treated withstandard antiemetics In case of constipation laxativesmay be prescribed

Morphine is the standard potent opioid However,injection of morphine increases constriction of thesphincter of Oddi, resulting in a 10–15 fold elevation inpressure in the common bile duct This may worsenpain symptoms in chronic pancreatitis In contrast, fentanyl is much less likely to cause this problem andbuprenorphine has no undesireable effect on the biliarytract Transdermal fentanyl and buprenorphine are effectively absorbed from a patch by the transdermalroute, with a long duration of onset and offset suitablefor providing stable blood levels over days

Adjuvant drugsPatients with chronic pancreatitis may often be depressed due to their pain syndrome In addition, tricyclic antidepressants are classical drugs for treat-ment of neuropathic pain Therefore, the addition oftricyclic antidepressants as adjuvant therapy is helpful

in many cases Depending on the patient’s condition, either a sedating (amitriptyline) or a mild stimulating(clomipramine) tricyclic antidepressant has to be prescribed

According to recent data for treatment of pain in betic neuropathy, anticonvulsants are now frequentlyrecommended as drugs of first choice for neuropathicpain In particular, gabapentin is now widely used for this indication Gabapentin should be started in low doses such as 100 mg t.i.d and daily increased to

dia-300 mg t.i.d or higher

Secretory inhibitionInhibition of gastric acid secretion by proton pump in-hibitors such as omeprazole and pantoprazole leads to

a higher duodenal pH and might therefore lessen stimulus-driven pancreatic secretion In addition, patients with chronic pancreatitis show an enhancedrisk of duodenal ulcer formation Although no formalstudies have demonstrated the effectiveness of protonpump inhibitors, they are used in many institutions especially when NSAIDs are used, because this ap-proach is relatively easy and safe

As mentioned above, application of high-dose creatic enzymes reduces hypercholecystokininemia in

pan-C H A P T E R 3 3

patients with chronic pancreatitis and thus may reduce

pancreatic secretion and pain Six studies and one

metaanalysis investigating the effects of pancreatic

en-zyme therapy for pain in chronic pancreatitis have been

performed, with controversial results Only two studies

using enzyme preparations in tablet form, which are

be-lieved to release pancreatic enzymes in the duodenum,

showed a benefit Thus, the role of pancreatic enzymes

in reducing pain in chronic pancreatitis remains

con-troversial However, because high-dose pancreatic

enzyme therapy carries only minor risks and may

some-times be helpful in pain management in chronic

pan-creatitis, a 6–8 week trial with preparations releasing

enzymes in the duodenum seems to be worth trying

Octreotide, a somatostatin analog, strongly inhibits

pancreatic secretion Although some patients may

show some pain relief with high doses of octreotide,

most patients do not Since octreotide injections are

painful and expensive and the effects very

controver-sial, octreotide is not recommended for general use in

chronic pancreatitis

Other treatment options

The pancreas is innervated by sympathetic,

parasym-pathetic, motor, and sensory fibers The sensory fibers

transmitting pain travel from the pancreas without

synapsing in the splanchnic nerves to the dorsal root,

transversing the celiac plexus and the sympathetic

chain Thus, blocking these nerve fibers anywhere

along this path may theoretically provide pain relief in

chronic pancreatitis

Celiac plexus block is achieved with 25 mL of 50%

alcohol on each side, which should be preceded by a

positive diagnostic block with long-acting local

anes-thetics at least 1 day before However, the results of this

procedure have been disappointing Leung et al found

that 12 of 23 patients with chronic pancreatitis had

initially complete, and six patients partial, pain relief

with celiac plexus block However, the mean pain-free

interval was only 2 months and repeated blocks were

ineffective

The role of transcutaneous electrical nerve

stimula-tion, often used in other pain syndromes, is not yet

determined for pain in chronic pancreatitis In cases

of severe pain in chronic pancreatitis which do not

respond to medical or surgical therapy, celiac plexus

block or transthoracic splanchniectomy or individual

therapeutic options such as epidural local anesthetics

or intrathecal administration of opioids via a neous infusion pump should be discussed However,conservative treatment is not always successful in pa-tients with chronic pancreatitis Pain that significantlyreduces the quality of life, especially if it requires mor-phine on a regular basis, may represent an indicationfor surgical treatment Surgery for chronic pancreatitis

subcuta-is indicated in patients with pain refractory to medicalmeasures It can be performed with low mortality and morbidity and pain relief is achieved in the vast majority of patients

Conclusions

For decades, physicians have been trying different proaches to the problem of pain in chronic pancreatitis.There is still disagreement about the mechanisms thatcontribute to the generation of pain and about the bestmethod of managing pain in chronic pancreatitis.Earlier pain hypotheses, for example those postulat-ing increased intraductal and intraparenchymal pres-sure or postprandial pancreatic hyperstimulation bydecreased enzyme secretion and insufficient function-ing of the so-called negative feedback mechanism, arenow seriously questioned as reliable explanations ofabdominal pain in patients with chronic pancreatitis

ap-In the last 10 years we have learned about the role ofaltered nerve patterns in the inflamed pancreas and theoverproduction of different neuromediators in the enlarged pancreatic nerves In the light of these con-siderations, it is now clear that we must explore thepathophysiology of pain generation in order to developnew drugs to control pain in chronic pancreatitis In ad-dition, the lack of a good animal model of chronic pan-creatitis remains a limiting factor in understanding thecomplete cascade of event that generate and sustain thelong-lasting pain syndrome in the natural history ofchronic pancreatitis

Based on current knowledge there are no gold standards for the therapy of chronic pancreatic pain Amultidisciplinary approach based on individual painhistory is recommended

Recommended reading

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C H A P T E R 3 3

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Duodenum-preserving resection of the head of the pancreas in patients

with severe chronic pancreatitis Surgery 1985;97:467–

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Pancreatic Surgery New York: Springer-Verlag, 1993:

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Bockman DE, Buchler M, Malfertheiner P, Beger HG

Analy-sis of nerves in chronic pancreatitis Gastroenterology

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Brown A, Hughes M, Tenner S, Banks PA Does pancreatic

enzyme supplementation reduce pain in patients with

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Chronic pancreatitis is a progressive disease without a

curative treatment Therapeutic efforts have therefore

centered on palliative treatment of pain, which is

present in about 90% of cases Abdominal pain is the

predominant symptom of chronic pancreatitis that

initially brings most of the patients to the physician’s

attention

The typical epigastric pain radiating to the back is

common, but any type of abdominal pain may occur

Pain is often worsened by eating or by the supine

posi-tion The pain presents a heterogeneous pattern, from

relapsing episodes to persistent pain of varying

inten-sity The usual pattern is initial episodes of acute

abdominal pain and recurrent episodes of acute

“non-biliary” pancreatitis; with progression of the disease

the attacks become more frequent and severe,

ultima-tely culminating in continuous pain requiring narcotic

analgesic and frequent hospital admissions In some

patients the pain improves with time, particularly

dur-ing the end stage of the disease, which often coincides

with deterioration of pancreatic function A small

pro-portion of patients have painless disease or minimal

pain throughout the course of their illness, and in these

the clinical emphasis is usually on endocrine or

exocrine insufficiency

Pathogenesis of pain in

chronic pancreatitis

The pathogenesis of pancreatic pain is often

multifac-torial and may vary at different stages of the disease,

explaining why not all patients respond to the same

treatment These factors may include the following

• Increased pancreatic parenchymal pressures ment syndrome) secondary to increased ductal pressureresulting from outflow obstruction caused by strictures,pancreatic stone, or compressing pseudocyst and to re-duced parenchymal compliance caused by fibrosis

(compart-• Inflammatory infiltration with fibrotic encasement

of sensory nerves, and a neuropathy characterized byboth increased number and size of intrapancreatic sen-sory nerves and by inflammatory injury to the nervesheaths allowing exposure of the neural elements totoxic substances such as activated pancreatic enzymes,calcitonin gene-related peptide, and substance P

• Pancreatic ischemia secondary to lack of compliance

of the pancreatic gland that impairs blood flow leading

to hypoxia and acidosis

• Release of oxygen-derived free radicals associatedwith a round cell inflammatory response and tissuedamage Oxidative stress is responsible for mediatingpain especially during acute exacerbations of chronicpancreatitis

• Complications such as pseudocysts

Endoscopic treatment of pain in chronic pancreatitis

The history of the endoscopic management of chronicpancreatitis begins in November 1976, when Cremerperformed the first pancreatic sphincterotomy to treat

an impacted pancreatic stone in the major papilla thatwas causing acute cholangitis Subsequent historicalsteps in this field include pancreatic stenting in 1985and extracorporeal shock-wave lithotripsy (ESWL) forpancreatic stones in 1987

34 Endoscopic treatment of pain in

chronic pancreatitis: really useful or only feasible?

Guido Costamagna and Andrea Tringali

When major pain episodes due to chronic

pancreati-tis cannot be controlled by acceptable maintenance

analgesics, intervals of narcotics, or reasonable and

brief period of hospitalization, interventional therapy

can be justified Whether immediate treatment can

change the natural history of progressive loss of

ex-ocrine and endex-ocrine function is still not known, even

though experimental and clinical evidence suggests

that early ductal decompression may be beneficial in

modulating the outcome of chronic pancreatitis

Selection of candidates for endoscopic pancreatic

duct drainage

In addition to standard laboratory tests and routine

plain films of the pancreatic area for detection of

pancreatic calcifications, magnetic resonance imaging

(MRI) is currently the noninvasive modality of choice

for selection of patients who might benefit from

endoscopic treatment Intravenous administration of

secretin, which stimulates the secretion of fluid and

bicarbonate, enhances visualization of the pancreatic

ducts and acts as an endogenous contrast medium, a

technique known as secretin-enhanced magnetic

reso-nance cholangiopancreatography (S-MRCP) It gives

appropriate information on the presence of downstream

ductal obstruction or a cystic lesion and on pancreatic

exocrine function by quantification of duodenal filling

S-MRCP provides a diagnostic pancreatogram with

which to identify those patients with a single

obstruc-tion in the head of the pancreas caused by an impacted

ductal stone or a fibrotic stricture (or both) Those cases

with Cremer type IV chronic pancreatitis are the best

candidates for endotherapy

Pancreatic sphincterotomy

Endoscopic pancreatic sphincterotomy is generally

performed as the first step toward improving access to

the pancreatic duct before pancreatic stone extraction

or endoprosthesis insertion Minor papilla

sphinctero-tomy may be needed in up to 20% of patients in cases of

dominant dorsal duct anatomy (complete or

incom-plete pancreas divisum or ansa pancreatica) In a subset

of patients, pancreatic sphincterotomy by itself may be

sufficient to resolve papillary stenosis causing upstream

dilatation and/or to extract small nonobstructive

of mild pancreatitis (1.8–9%), bleeding (1.3–3.6%),cholangitis (0–4.3%) and, in rare cases, retroduodenalperforation (0.6%)

Endoscopic manometry using a variety of techniqueshas yielded conflicting results when sphincter of Oddiand main pancreatic duct pressures in patients withchronic pancreatitis were compared with controls Inpatients with chronic pancreatitis, sphincter of Oddifunction varied from normal to gross disturbances ofbasal and phasic contractions Laugier and colleaguesobserved a significantly increased pressure response ofthe sphincter of Oddi and pancreatic duct to secretinstimulation in patients with early disease when com-pared with advanced disease associated with pan-creatic duct dilatation These changes may beconstrued as evidence of increased volume responseswith early disease The role of increased viscosity ofpancreatic juice in chronic pancreatitis and the hypoth-esis that protein plugs may impact on the sphincterleading to obstruction and pain is yet to be confirmed The results of pancreatic sphincterotomy alone in thetreatment of chronic pancreatitis was retrospectivelyassessed in 55 patients followed for a median time of

16 months (range 3–52): 34 patients (62%) reportedsignificant improvement in their pain assessed using a

numeric rating scale (P< 0.01)

Endoscopic treatment could be regarded as the initialmanagement of choice for patients with early-onset(before the age of 35) idiopathic chronic pancreatitis

In our clinic, 11 patients with pain due to early-onsetchronic pancreatitis were treated by endoscopicsphincterotomy (major and/or minor papilla) andstone extraction One patient had a dominant pancre-atic duct stricture on the head and underwent pan-creatic stenting; the other cases were treated bypancreatic sphincterotomy (major and/or minor papil-la) with or without stone extraction after ESWL Sevenpatients (64%) remained free of pain relapses after amean follow-up of 6.5 years (range 3–9.5) Causes ofrecurrent pain included stenosis of the pancreaticsphincterotomy, new pancreatic stricture formation,pancreatic stone migration, and pancreatic stent occlusion All these complications were successfully

C H A P T E R 3 4

retreated endoscopically The frequency of

hospitaliza-tion before and 1, 3, and 6 years after endoscopic

treat-ment was significantly reduced

In selected cases, such as early stage of chronic

creatitis and early-onset idiopathic chronic

pan-creatitis, pancreatic sphincterotomy in the absence of

pancreatic duct stricture and dilation can be proposed

as a treatment for reducing the frequency of pain and

recurrence of pancreatitis Patients with an attack of

“nonbiliary” pancreatitis are studied with S-MRCP

and those who show signs of initial chronic pancreatitis

(side-branch dilation, tortuous pancreatic duct)

under-go clinical follow-up In cases of a second attack of

pan-creatitis within 1–2 years pancreatic sphincterotomy

can be proposed

ESWL of pancreatic stones

Approximately one-third of patients with chronic

pan-creatitis have pancreatic stones and half of these will

have the main portion of their stone burden within the

main duct in the pancreatic head or body Successful

en-doscopic stone extraction after pancreatic

sphinctero-tomy depends on the size (< 10 mm), number (< 3), and

pancreatic location (head or body) of the stones, and

may not be possible if strictures are present or if thestones are impacted in the ductal wall ESWL is neces-sary to fragment stones prior to endoscopic extraction

in 36–44% of patients with chronic pancreatitis.ESWL-related complications (organ damage oracute pancreatitis) are rare (0–12.5%) and mortalitywas absent in the largest published series and in our ex-perience (300 pancreatic ESWL) Mild adverse effects

of ESWL include petechiae on the skin in the area ofshock-wave penetration, and in the gastric antrum.The best fragmentation of pancreatic stones is ob-tained using a two-dimensional radiologic targetingsystem under conscious sedation or general anesthesia

In two series where ultrasound was used to localize the stones, the fragmentation rate was much lower Incases where calcified pancreatic stones are present, radiologic targeting is easy and ESWL can be per-formed as a first procedure before therapeutic endo-scopic retrograde cholangiopancreatography (ERCP).Results from the literature show that ESWL and en-dotherapy achieve stone fragmentation in 54–100% ofcases, complete duct clearance in 44–74%, and com-plete or partial pain relief in 48–85% after a mean follow-up of 7–40 months; surgery is necessary due topersistence or recurrence of pain in 3–20% of patients(Table 34.1)

Table 34.1 Results of extracorporeal shock-wave lithotripsy (ESWL) and endotherapy for chronic calcific pancreatitis.

Complete Complete or Need for

No of Fragmentation clearance partial pain surgery Mean follow-up

ESWL and endotherapy

* Patients with complete pain relief during follow-up.

NA, not addressed.

Early outcome of pancreatic ESWL in combination

with interventional endoscopy has been prospectively

evaluated After a mean follow-up of 7 months, there

was a significant decrease in pancreatic duct diameter

(P < 0.001) and pain score (P < 0.0001); weight gain

occurred in 68% of patients and several

quality-of-life scores improved significantly Improvement in

pain score was also correlated with weight gain,

de-crease in pancreatic duct diameter, and nonalcoholic

etiology

A large retrospective study analyzed 114 patients

with pancreatic stones treated by ESWL and

endother-apy The authors assessed the criteria for success of

treatment and univariate analysis showed that

middle-aged patients, an early stage of chronic pancreatitis,

and distal location of stones were significantly

asso-ciated with a higher rate of treatment success and pain

relief Stones located in the pancreatic tail are usually

less symptomatic because of frequent parenchymal

at-rophy A statistically significant decrease in pain score

(P = 0.001), yearly hospitalizations for pancreatitis

(P= 0.001), and monthly use of narcotic medications

was found after a mean follow-up of 2.4 years in

another retrospective study focused on ESWL and

endotherapy for chronic pancreatitis

For patients with calcified stones but without a tight

stricture and with residual exocrine function as shown

on diagnostic S-MRCP, ESWL alone is a possible

first-line treatment, endotherapy being considered in cases

where this approach is not successful The hypothesis is

that after ESWL, pancreatic juice and fragments can

pass spontaneously through the intact sphincter with

relief of ductal obstruction Two Japanese groups have

examined the results of this approach, with preliminary

results similar to those of ESWL in association with

endotherapy

Much of the available information on ESWL and

en-dotherapy for the treatment of pain in chronic

pancre-atitis come from retrospective studies New prospective

trials are warranted to confirm the good results of

pancreatic ESWL

Pancreatic stenting

The main indication for endoscopic placement of a

pancreatic stent in chronic pancreatitis is the presence

of a dominant ductal stricture, defined as high grade of

narrowing with one of the following characteristics:

• induction of pancreatic duct dilation (≥ 6 mm);

• prevention of contrast medium outflow alongside a

Early complications of pancreatic stenting in chronicpancreatitis include acute pancreatitis (3.9–39%) andbleeding (3.9%) Late complications include stent clog-ging (20%), stent migration (10%), pain recurrence orbouts of pancreatitis, and possibly infection Technicalsuccess of pancreatic stenting in the course of ERCP ishigh (96–100%), with immediate pain relief in 82–94%

of cases; this improvement lasts for 6 months in 74% oftreated patients Results are summarized in Table 34.2.Mean pancreatic stent patency is 12 months (range2–38) and symptomatic stent exchange is suggested in-stead of prophylactic therapy In fact pancreatic stents,even when clogged, may function as a wick aroundwhich pancreatic juice can drain, sometimes for years.After stent removal, morphologic resolution of thepancreatic stricture is uncommon, but improvement ofpain can be obtained even without stricture calibration.For example, after stent removal in 29/93 patients(53%) after a mean period of stenting of 15.7 months,73% of these patients remained pain-free without astent during a mean follow-up of 3.8 years

As described for pancreatic sphincterotomy andESWL, pancreatic stenting is also more effective in thetreatment of pain in chronic pancreatitis especially incases with a shorter history of symptomatic chronicpancreatitis Thus early endoscopic ductal drainage inchronic pancreatitis is advisable When endoscopictreatment of pain in chronic pancreatitis is not effective

or the need for stent exchange becomes too frequent,surgery is the alternative treatment

Recently, a prospective randomized trial comparedthe outcome of endotherapy and surgery in the treat-ment of chronic pancreatitis Initial success rates weresimilar for both groups, but at 5-year follow-up com-plete absence of pain was more frequent after surgery(37% vs 14%) while the rate of partial relief was simi-lar (49% vs 51%) Increase in body weight was greater

by 20–25% in the surgical group, while new-onset

dia-C H A P T E R 3 4

betes developed with similar frequency in both groups.

According to these data, surgery is superior to

en-dotherapy for long-term pain reduction in patients

with painful chronic pancreatitis Because of its low

de-gree of invasiveness, endotherapy can be offered as a

first-line treatment, with surgery being performed in

cases of failure or recurrence

New technique:

EUS-guided pancreaticogastrostomy

In cases of obstruction or rupture of the main pancreatic

duct or when surgical reconstruction precludes access

to the duodenal papillae, a new technique has been

described for draining the pancreatic duct through an

endoscopically created fistula to the digestive tract,

under echographic and fluoroscopic guidance The

endoscopically created pancreaticogastrostomy is

en-larged by balloon dilatation or a diathermic sheath, and

kept open by a 6–10 Fr stent Three of four patients with

chronic pancreatitis treated by endoscopic ultrasound

(EUS)-guided pancreaticogastrostomy had satisfactory

relief of pain at a median follow-up of 1 year Results of

this technique are preliminary but promising Future

wider experience in tertiary centers specialized in

bil-iopancreatic therapeutic endoscopy are expected

Endoscopic drainage of

pancreatic pseudocyst

In the setting of chronic pancreatitis, symptomatic

pseudocysts are commonly seen in association withstones or strictures and these also need to be addressed Pancreatic pseudocysts may complicate the course ofchronic pancreatitis in 20–40% of cases, and less than10% will resolve spontaneously

Pseudocysts communicating with the main creatic duct are amenable to transpapillary drainage

pan-In the absence of a communication with the pancreaticduct, transmural drainage (cystgastrostomy or cyst-duodenostomy) can be performed under endoscopiccontrol where there is visible bulging of the pseudocystinto the wall of the stomach or duodenum With the advent of large-channel linear echoendoscopes, trans-mural drainage is feasible even in the absence ofpseudocyst bulging when the gut lumen is more than

1 cm away from the pseudocyst

The indications for pseudocyst drainage are the ence of pain, cyst enlargement, or complications (gas-trointestinal and biliary obstruction, vascular occlusion,spontaneous infection, fistula formation with pleuralcavity or adjacent viscera) Complex pseudocysts thatare multiseptated, associated with necrosis, or asso-ciated with a totally disrupted main pancreatic duct areless amenable to endoscopic management Asympto-matic pseudocysts can be safely observed with carefulfollow-up using computed tomography (CT) or MRI.Pain related to pseudocysts can be relieved after endoscopic drainage with satisfactory results: clinicalresolution of the cyst was observed in 86% of patients after transmural drainage and 84% of patientstreated with transpapillary drainage Complications ofpseudocyst drainage are present in 10% of patients En-doscopic cystenterostomy is associated with a higher

pres-Table 34.2 Results of stent therapy of main pancreatic duct strictures in chronic pancreatitis.

No of diameter Early pain patency resolution surgery follow-up

* Planned stent exchange every 2 months.

† Elective stent removal after a median time of 6 months.

NA, not addressed.

complication rate than transpapillary drainage The

major complications reported are bleeding,

retroperi-toneal leakage, and infection

Endoscopic drainage of the pancreatic

duct in chronic calcifiyng pancreatitis

Figures 34.1–34.5 show the stages in endoscopic

drainage of the pancreatic duct to alleviate chronic

calcifying pancreatitis

EUS-guided celiac plexus

block/neurolysis

Pancreatic pain is predominantly transmitted through

the celiac plexus and the splanchnic nerve Celiac ganglion injection with alcohol or steroids has beenperformed percutaneously under CT guidance or sonographically (EUS) for patients still suffering aftersuccessful surgical or endoscopic drainage of the pan-creatic duct, indicating that the mechanism of pain inthese patients is not related to ductal obstruction Therole of EUS-guided celiac ganglion block is similar topercutaneous celiac block but it has the advantage ofnot having to traverse the aorta or the lumbar muscula-ture with its associated risk (paraplegia) and discom-fort In addition, bacteria within the stomach may betranslocated into the retroperitoneum during endo-scopic transgastric blocks

Injection of anesthetics and/or corticosteroids fortemporary block is termed celiac plexus block (CPB)while injection of absolute ethanol that permanentlydestroys the plexus is called celiac plexus neurolysis(CPN) EUS-guided CPB /CPN was described in 1996;the procedure can be performed in 10 min under con-scious sedation

A prospective randomized comparison of EUS- andpercutaneous CT-guided CPB for managing the pain ofchronic pancreatitis showed that EUS-guided CPB pro-vided more persistent pain relief than CT-guided blockand was the preferred technique among the subjectsstudied The effect of EUS-guided CPB with bupivacaineand triamcinolone has been prospectively assessed in 90patients with chronic pancreatitis and pain unrespon-sive to current treatment options Benefit was limited:significant pain relief was obtained in 55% of patientsafter 4 and 8 weeks of follow-up; persistent pain reliefbeyond 12 and 24 weeks was observed in 26% and 10%

of patients, respectively Three patients (3%) enced diarrhea after EUS-guided CPB that resolved

experi-C H A P T E R 3 4

Figure 34.1 Magnetic resonance cholangiopancreatography

shows marked dilation of the main pancreatic duct with

obstructive stone in the head.

Figure 34.2 Radiograph shows

pancreatic calcifications before (left)

and after (right) extracorporeal

shock-wave lithotripsy.