Chronic Pancreatitis (LitReview - 2009)

August 2009
A Supplement to Clinician Reviews
CME
A Case-Based Discussion of
Chronic Pancreatitis 2
Randall K. Pearson, MD
Evaluation and Diagnosis 9
Rakesh Nanda, MD
Camron Kiafar, DO
Management of Exocrine
Pancreatic Insuffciency 15
Francisco C. Ramirez, MD
Pancreatic Enzyme Therapy 20
Phillip Toskes, MD
Chronic Pancreatitis
Improving Patient Outcomes
This activity is jointly sponsored by Postgraduate Institute
for Medicine and Quadrant Medical Education.
Supported by an educational grant from
Solvay Pharmaceuticals.
Release date: August 2009
Expiration date: August 31, 2010
Estimated time to complete activity: 1.5 hours
Target Audience: Clinicians with an interest in chronic
pancreatitis.
Statement of Need: The diffculty of diagnosing patients
with mild or early chronic pancreatitis contributes to an
underdiagnosis of this condition, which is highlighted by
the fact that the delay between onset of symptoms and
diagnosis is often yearsmost particularly in patients
without a history of alcoholism. However, the serious
nature of the disease, the high risk of complications,
and the severe impact of pancreatitis-associated pain
on quality of life argue for a more concerted effort to
diagnose those with the disease. Use of pancreatic
enzyme therapy can alleviate the complications asso-
ciated with chronic pancreatitis, including malabsorp-
tion and steatorrhea, which can lead to muscle wasting.
Patients with HIV/AIDS may be at greater risk for both
chronic pancreatitis and its complications; recent data
suggest that those in the VA health care system carry
a higher risk for HIV/AIDS than do those in the general
population. It is important that physicians and other
health care professionals be aware of these conditions
and of the need to initiate appropriate and effective
interventions such as pancreatic enzyme therapy.
Educational Objectives: Upon completion of this
activity, participants will be able to successfully:
Explain the epidemiology and pathophysiology of
chronic pancreatitis.
Discuss the symptoms and diagnosis of chronic pan-
creatitis.
State the complications of pancreatic exocrine insuf-
fciency (PEI) and malabsorption.
Explain the importance of treating PEI to improve
patient outcomes.
Discuss the role of pancreatic enzyme therapy in
improving nutritional health of patients suffering from
chronic pancreatitisassociated PEI and steatorrhea,
including appropriate dosing of such therapy.
Faculty: James V. Felicetta, MD (Chair), Chairman,
Department of Medicine, Carl T. Hayden VA Medical
Center, Phoenix, Arizona; Professor of Clinical Medicine,
University of Arizona, Tucson.
Camron Kiafar, DO, FACG, Assistant Chief of Thera-
peutic Endoscopy, Department of Gastroenterology at
Carl T. Hayden VA Medical Center, Phoenix, Arizona.
Rakesh Nanda, MD, FACP, FACG, Assistant Professor
of Clinical Medicine at the University of Arizona, Tucson;
gastroenterologist on staff at Carl T. Hayden VA Medical
Center, Phoenix, Arizona.
Randall K. Pearson, MD, Associate Professor, Depart-
ment of Medicine, Division of Gastroenterology and Hep-
atology, Mayo Medical Center, Rochester, Minnesota.
Francisco C. Ramirez, MD, Professor of Clinical Medicine
at the University of Arizona College of Medicine,
Phoenix; Chief of the Division of Gastroenterology at
Carl T. Hayden VA Medical Center, Phoenix, Arizona.
Phillip Toskes, MD, Professor of Medicine, University of
Florida College of Medicine, Gainesville, Florida.
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CME Information
ChronIC PanCrEatItIs
Improving Patient outcomes through Early Intervention and treatment
viduals who are in a position to control the content of
CME activities. All relevant conficts of interest that are
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The faculty reported the following fnancial relation-
ships or relationships to products or devices they or
their spouse/life partner have with commercial interests
related to the content of this CME activity:
James V. Felicetta, MD (Chair), is a member of the
speakers bureaus of Merck, Novartis, and sanofi-
aventis.
Camron Kiafar, DO, FACG, has no fnancial arrange-
ments or affiliations with commercial or equipment
companies during the last three years.
Rakesh Nanda, MD, FACP, FACG, has no fnancial
arrangements or affliations with commercial or equip-
ment companies during the last three years.
Randall K. Pearson, MD, has no fnancial arrange-
ments or affiliations with commercial or equipment
companies during the last three years.
Francisco C. Ramirez, MD, is a member of the speak-
ers bureaus of Procter & Gamble and Takeda.
Phillip Toskes, MD, receives grant/research support
from Axcan, Eurand, Johnson & Johnson, and the
National Institutes of Health and is a member of the
speakers bureau of Axcan.
The following planners and managers, Kelly Eckert,
Linda Graham, RN, BSN, BA, Jan Hixon, RN, BSN, MA,
Trace Hutchison, PharmD, Julia Kirkwood, RN, BSN
and Jan Schultz, RN, MSN, CCMEP hereby state that
they or their spouse/life partner do not have any fnan-
cial relationships or relationships to products or devices
with any commercial interest related to the content of
this activity of any amount during the past 12 months.
Method of Participation: There are no fees for par-
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During the period August 2009 through August 31,
2010, participants must 1) read the learning objec-
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Release date: August 2009
Expiration date: August 31, 2010
Estimated time to complete activity: 1.5 hours
CHRONIC PANCREATITIS AUGUST 2009 1
This activity is supported by an educational grant from Solvay
Pharmaceuticals.
Jointly Sponsored by Postgraduate Institute for Medicine and
Quadrant Medical Education.
2 CHPON|C PANCPLAT|T|SAUGUST2009
Case: a Young Woman With PanCreatitis
A 25-year-old white woman presents with an eight-
year history of pancreatitis. She had two mild and
self-limited episodes of well characterized acute pan-
creatitis at age 17. She admitted to drinking alcohol
most weekends, sometimes bingeing, since age 16.
Her clinicians diagnosed alcoholic pancreatitis and
advised abstinence.
The woman was asymptomatic for two years. At age
20 and a junior in college, she had three more discrete
episodes of clinical acute pancreatitis. After the second
episode, an empiric cholecystectomy was performed
for possible microlithiasis, but her episodes persisted.
Her alcohol ingestion was now moderate: three to four
beers at least three days per week.
The patient was again advised to discontinue alco-
hol, and she complied. She was referred to a tertiary
care center where an endoscopic retrograde cholan-
giopancreatography with pancreatic sphincterotomies
was performed. A diagnosis of chronic pancreatitis
(CP) secondary to sphincter of Oddi dysfunction was
made. The procedure was complicated by her most se-
vere episode of acute pancreatitis, necessitating a 10-
day hospitalization.
Despite complete alcohol abstinence, the woman
had recurrent attacks of acute pancreatitis requiring
hospitalization every other month (on average) for
the next four years. Often the painful episodes lacked
biochemical evidence of acute pancreatitis (normal
amylase and lipase). For one year prior to referral to
our medical center, she has had persistent abdominal
pain in between attacks and has required hydrocodone
three days per week. The pain is epigastric with infra-
scapular radiation exacerbated by meals. There is no
evidence of glucose intolerance or history of chronic
diarrhea. She has lost 10 lb unintentionally. Her qual-
ity of life is poor; her frequent hospitalizations and
opioid use have resulted in a disability application.
Routine physical exam, blood test, and abdominal
computed tomography results are normal. An endo-
scopic ultrasound demonstrates six criteria for CP: hy-
perechoic strands and foci, parenchymal lobulation,
small shadowing calcifications in the pancreatic head,
an echogenic main duct wall, and an irregular main
duct contour. A diagnosis of idiopathic chronic pan-
creatitis (ICP) is established.
This review will focus on the natural history and
pathophysiology of CP to address questions raised by
this clinical presentation:
Why is this unlikely to be alcoholic pancreatitis?
Is this presentation, with its relatively late diagnosis
(eight years), typical?
Will understanding the natural history help us ad-
vise this patient?
Are there any insights into the mechanisms respon-
sible for idiopathic pancreatitis?
Causes of ChroniC PanCreatitis
alcoholic Chronic Pancreatitis
Long-term, excessive alcohol ingestion is the most
common cause of CP in the developed countries of the
West, accounting for 65% to 80% of all cases (Table 1).
1

Thus, the rate of CP depends on alcohol consump-
tion habits and varies from 3.5 per 100,000 to 27.4 per
100,000.
13
Up to 75% of affected individuals are men.
1

Most experts estimate that no more than 10% of chronic
alcoholics develop CP; however, epidemiologic studies
to determine environmental, dietary, or genetic cofac-
tors have been negative or inconsistent.
2,3
Several analy-
ses have suggested that concomitant cigarette smoking
increases the risk for, and accelerates the rate of, progres-
sion of alcoholic chronic pancreatitis (ACP).
4
Chronic Pancreatitis
a Case-Based Discussion
randall K. Pearson, mD
Chronicpancreatitisisaprogressiveanddestructivenecroinflammatorydisorderofthe
pancreascharacterizedbyirreversiblefibrosisoftheglandwitheventualfailureofexocrine
andendocrinefunctions.Flaresofinflammationandabdominalpainaredominantclinical
featuresearlyinitscourse.Atendstage,parenchymalandductalcalcificationsoftencoincide
withglandfailure.
Dr. Pearson is an associate professor in the department of
medicine, division of gastroenterology and hepatology, at Mayo
Medical Center, Rochester, Minnesota.
AUGUST2009CHPON|C PANCPLAT|T|S 3
The amount of ingested alcohol needed to induce
pancreatitis has not been established. However, most
experts would agree that daily ingestion must be sub-
stantial over a long period; at our center, an intake
of 80 g of pure alcohol daily for 10 years is required
for a patient to be firmly placed in the alcoholic co-
hort.
5
This equates to one bottle of wine or a six-pack
of beer daily for a decade. Cumulative lifetime intake
approaches 1000 L of pure alcohol; thus, the peak
incidence of ACP occurs in the fifth decade of life
(mean age, 44). An important epidemiologic study
from Europe demonstrated the dose effect of alcohol:
for every 20-g/day increase in consumption, there was
a 1.4-fold increase in relative risk for CP.
6

In our practice, this patients intermittent alcohol
ingestion for fewer than five years is insufficient to
make a diagnosis of ACP, although even modest al-
cohol intake accelerates disease progression and acute
flares of inflammation.
7
I believe, however, that absti-
nence was unlikely to alter significantly this patients
disabling symptoms.
idiopathic Chronic Pancreatitis
Once alcohol and the uncommon causes of CP have been
excluded, the clinician and the patient are faced with the
vexing and unsatisfactory idiopathic diagnosis, which
accounts for at least 20% of CP.
13
However, many of
these patients have identifiable genetic predispositions to
CP. The epidemiology and natural history of ICP can be
distinguished from ACP; these are two distinct cohorts,
based on age of onset and clinical presentation.
early-onset iCP
ICP presents nearly 20 years earlier (mean age of onset,
20 years) than ACP and involves both sexes equally.
5,8,9

Pain was virtually universal (96%) in the Mayo se-
ries patients
5
and is usually punctuated by episodes of
clinical acute pancreatitis early in the disease course.
Pain is moderate to severe in 80% of patients, and
they require pancreatic surgery more frequently than
alcoholics (60% vs 30%) in this series.
5

Late-onset iCP
ICP has a bimodal age distribution; the second
peak occurs in the sixth decade (median age, 56).
Approximately 50% of these patients present without
abdominal pain, and only 10% have severe pain.
5

The rate of progression to gland failure from onset
of disease, often marked by the appearance of calci-
fication on clinical radiographs, differs significantly
between the groups. In ACP, the appearance of calci-
fications averaged 8.7 years, late-onset ICP 19 years,
and early onset ICP 25 years in the Mayo series.
5

Rates of appearance of exocrine and endocrine failure
mirror these observations (Table 2).
5,10
autoimmune Pancreatitis
This uncommon disorder, which may account for 3%
to 5% of CP, has been recognized relatively recently,
and its most common variant has a distinct histopath-
ologic pattern.
1113
Autoimmune pancreatitis is also
termed lymphoplasmacytic sclerosing pancreatitis.
The condition involves a plasma cell infiltrate around
small ducts and swirling fibrosis around ducts and
veins (storiform fibrosis), with a distinctive oblitera-
tive phlebitis. This disease presents primarily in men
(70% to 85%) in their seventh decade.
1013
A landmark
study from Japan in 2001 reported the association of
this condition with elevated levels of immunoglobulin
subtype 4 (IgG4) in the serum.
11
It is now recognized as
a systemic disease with plasma cells bearing IgG4, in-
filtrating the pancreas and other organs including bile
ducts, salivary glands, retroperitoneum, and kidneys.
Because autoimmune pancreatitis is distinct from
other forms of CP, pain and acute inflammation are
uncommon at presentation. An inflammatory mass in
the head of the pancreas causing obstructive jaundice
and mimicking pancreatic cancer is the most frequent
clinical presentation at our center. The unique respon-
siveness of autoimmune pancreatitis to systemic corti-
costeroid therapy differentiates this disorder from CP
and pancreatic cancer.
other Causes
In Asia and parts of India, the highest prevalence of
CP is observed (up to one in 830 persons).
14
This form
of CP has been called tropical pancreatitis; it is dis-
tinguished by early age of onset (mean age, 13), lack
of alcohol exposure, and rapid progression to calcific
Table 1. Causes of Chronic Pancreatitis
Data extracted from Witt H et al,
1
Etemad B et al,
2
and DiMagno
MJ et al.
3
Common frequency (%)
Alcoholic 6580
Idiopathic 1530
uncommon
Autoimmune 35
Obstructive 35
rare
Hereditary <1
Hypertriglyceridemia <1
Hyperparathyroidism <1
CHPON|C PANCPLAT|T|SA CASL-8ASLD D|SCUSS|ON
disease and gland failure.
14
Speculation about etiology
has centered on the nearly 50% rate of mutation of the
serine peptidase inhibitor, Kazal type 1 gene, SPINK1,
in these cohorts (see section on SPINK1).
Hypertriglyceridemia and hypercalcemia due to pri-
mary hyperparathyroidism are important to recognize
due to their reversibility, but they account for much
less than 1% of cases.
1-3
Pancreatic duct obstruction will lead to atrophy, fi-
brosis, ductal abnormalities, and parenchymal calcifica-
tions upstream from the block, whether the obstruction
results from neoplasia or benign strictures (eg, iatrogenic
from pancreatic duct stenting). Intraductal papillary
mucinous neoplasia, especially of the main duct, can
present in an indolent fashion with all the features of ad-
vanced CP due to tumor obstruction or secreted mucin,
including ductal and parenchymal calcification.
15
The
risk of invasive malignancy that complicates this disor-
der dictates surgical resection in a subset of patients.
Hereditary pancreatitis (HP), an autosomal domi-
nant disease that was first recognized by Comfort and
Steinberg in 1952, is rare but provides crucial insights
into the pathophysiologic mechanisms responsible for
CP.
16,17
Hereditary pancreatitis recapitulates the more
common ACP and ICP clinical presentation, with early
attacks of acute pancreatitis (often in children younger
than age 10), progression of fibrosis and ductal defects,
and chronic pain, eventuating in gland calcification
and failure.
Mutations in
the cationic tryp-
sinogen gene,
PRSS1, have been
identified as re-
sponsible for the
majority of HP
kindreds. This
discovery has in-
tensified investi-
gation of the role
of premature acti-
vation of trypsin
in the acinar cell
as critical in ini-
tiating pancreatic
injury.
18
The most
common mutation
(affecting about
50% of kindreds)
in PRSS1 is R122H
or histidine for ar-
ginine.
17,18
Figure
1 illustrates how
this gain-of-function mutation leads to autodiges-
tion by activating the enzyme cascade in the acinar
cell.
2
Recently, a transgenic mouse model expressing
mutant PRSS1 displayed both acute inflammation and
progressive fibrosis over time, reproducing the clinical
features of CP with a single amino acid substitution in
trypsin.
19
Pathogenesis of ChroniC PanCreatitis
By the time ACP is recognized clinically, both acinar
and ductal elements of the exocrine pancreas are ir-
reversibly distorted and injured. Thus, it is no surprise
that multiple theories on the cellular pathogenesis of
alcohol-mediated injury have emerged; these are sum-
marized below and in two recent reviews.
2,20

Oxidative stress. Similar to hepatocytes, acinar cells
metabolize alcohol, including an oxidative pathway,
capable of damaging lipid membranes including
lysosomes and zymogen granules. However, while
oxidative stress is almost certain to contribute to fi-
brogenesis, it has never been shown to be capable of
initiating the process.
Toxic-metabolic. Alcohol appears to be directly toxic
to acinar cells by altering cellular metabolism that
leads to accumulation of excess cytoplasmic lipid.
It is unclear whether development of a steatopan-
creatopathy (similar to findings in the liver) leads
to inflammation.
Stone and ductal obstruction. Henri Sarles pro-
Table 2. features of Chronic Pancreatitis:
idiopathic, alcoholic, and autoimmune
* Insufficient clinical data or follow-up.
Data extracted from Layer P et al
5
and Chari ST et al.
10
idiopathic alcoholic autoimmune
early-onset Late-onset
sex (m/f [%]) 44/56 56/44 72/28 83/17
at diagnosis
Median age (yr) 19 56 44 63
Pain (%) 96 54 77 20
Diabetes (%) 0 22 8 40
Exocrine failure (%) 8 22 12 *
Jaundice (%) 0 0 5 73
Calcification (%) 0 2 4 0
IgG4 increase (%) 6 6 6 71
subsequent course
(event [%]/median time [yr])
Diabetes 32/28 41/12 38/20 75/*
Exocrine failure 44/26 46/17 48/13 *
Calcification 56/25 37/19 60/09 0
PLAPSON
posed the ducts as the primary site of deranged me-
tabolism in CP, drawing a clear distinction with
acute pancreatitis, wherein activation of trypsin
in the acinar cell has been the central paradigm.
21

In this model, CP begins in the pancreatic ductal
system; alcohol directly alters the secretion, favor-
ing protein plugs and stone formation. While the
lithogenicity model clearly applies as the disease
progresses, protein plugs and obstructed ducts are
not always observed in the early stages of clinical
disease or in animal models.
necrosis-fibrosis model
Traditional models of ACP pathogenesis assumed that
the disease was chronic from the start (ie, by the time
irreversible injury and fibrosis were present).
13
The ne-
crosis-fibrosis construct postulates initiation of ACP as
an acute event with progression to a chronic irreversible
stage as the result of repeated acute injury.
20
The pro-
posed site of the acute necroinflammatory episode is the
acinar cell, with the underlying mechanism centered on
uncontrolled activation of trypsin. Clinical and experi-
mental evidence have accumulated rapidly to support
the necrosis-fibrosis model. These data include:
Hereditary pancreatitis is due most commonly to
a mutation in trypsinogen that results in a protein
with enhanced intra-acinar activation and impaired
degradation (gain of function).
18
Postmortem studies in fatal, acute alcoholic pancre-
atitis have shown no evidence of chronic changes
in the pancreas in 53% of cases.
22
A prospective study of a cohort of alcoholics dem-
onstrated that progression of ACP correlated most
closely with the frequency of recurrent clinical
acute pancreatitis.
7,23
Pancreatic fibrosis in animal models can be in-
duced by repeated episodes of necroinflammation
using a variety of methods, including supraphysi-
ologic doses of cerulein, inhibition of superoxide
dismutase, and endotoxin administration coupled
with chronic alcoholic feeding.
2427
This paradigm shift in our understanding of the initia-
tion of CP requires a reconciliation with the long-held
clinical observation that common causes of acute pan-
creatitis (eg, biliary) are self-limited and do not lead to ir-
reversible injury. The identification of pancreatic stellate
cells (PSCs) is a crucial development in understanding the
evolution of acute injury to irreversible fibrogenesis.
28
PanCreatiC steLLate CeLLs
In the liver, stellate cells are established as a key regula-
tor and source of collagen deposition in hepatic fibrosis
and progression to cirrhosis. The discovery of these
vitamin-A storing cells a decade ago in the human
Figure 1. role of trypsin activation in Pancreatitis
(A) Normal pancreas. Autoactivation of trypsin from trypsinogen within the pancreatic acinar cell zymogen granule is inhibited initially by SPINK1 and then
degraded by mesotrypsin and CTRC. This defense mechanism prevents trypsin from activating the enzyme cascade leading to autodigestion, acinar cell death,
and clinical pancreatitis. (B) Hereditary pancreatitis. Mutant PRSS1 demonstrates enhanced autoactivation kinetics and the most common mutant allele (R122H) is
less susceptible to degradation. This enhanced trypsin activity leads to intra-acinar enzyme cascade activation, autodigestion, and inflammation due to necrosis.
(C) Idiopathic pancreatitis. The effects of trypsin autoactivation in the acinar cell can also be enhanced by impaired defense mechanisms including loss of function
mutations in SPINK1 and CTRC. The mechanism by which CFTR mutations (present on ductal cells) enhance intraparenchymal activation of trypsin is not known but
may involve alterations in the balance of proteases and antiproteases due to defective trafficking (relative secretory block) or acidification effects.
AP = activation peptide; CFTR = cystic fibrosis transmembrane conductance regulator gene; CTRC = chymotrypsin C gene; PRSS1 = cationic trypsinogen gene; SPINK1 = serine protease
inhibitor, Kazal type 1 gene.
Adapted from Witt H et al.
1
a normal pancreas
hereditary
B pancreatitis
idiopathic
C pancreatitis
Trypsinogen
Trypsin
CFTR
AP
SPINK1 Mesotrypsin
CTRC

Trypsinogen
Trypsin
CFTR
AP
SPINK1 Mesotrypsin
CTRC
Trypsinogen
Trypsin
CFTR
AP
SPINK1
Mesotrypsin
CTRC
Enzyme cascade
Autodigestion Pancreatitis Autodigestion Pancreatitis
Enzyme cascade
+
pancreas was a major advance.
28
In the quiescent state,
they are triangular-shaped, perivascular cells contain-
ing lipid-laden vacuoles. Activated PSCs lose their lipid
droplets, morphologically transform into a fibroblast-
like phenotype, and migrate into periacinar regions.
Once activated, PSCs synthesize and secrete the com-
ponents of early pancreatic fibrogenesis, especially
type I and III collagen.
Considerable experimental and clinical evidence
supports a central role for these cells in generating
the excessive extracellular matrix protein essential for
initiation and progression of CP.
2,20,25,29
Furthermore,
two distinct pathways of activation have been iden-
tified linking PSC activation with alcoholic toxicity.
Proinflammatory cytokines released during acute epi-
sodes of necroinflammation have been observed to acti-
vate PSCs in vitro.
2,20
Activated PSCs are also capable of
expressing these same cytokines, setting up the milieu
for autocrine activation and perpetuation of excessive
collagen deposition after the initial injury has resolved.
Secondly, alcohol and its metabolites (especially acetal-
dehyde) activate PSCs directly and via oxidative stress
mechanisms, bypassing the need for acute injury. This
pathway of activation suggests that pancreatic fibrosis
secondary to alcohol may not be absolutely dependent
on acute inflammation. Figure 2 shows a current work-
ing model for ACP pathogenesis.
2
genetiCs anD ChroniC PanCreatitis
Recent advances in genetics have identified the follow-
ing major groups of mutations predisposing to CP:
Proteases
Serine protease 1 gene, PRSS1. As previously dis-
cussed, autosomal dominant HP is due to identifiable
gain-of-function mutations in the trypsinogen gene
in 75% of kindreds.
18,30
Because penetrance of CP in
mutation carriers is high (80%), most patients can be
readily identified by family history.
18,30
However, sub-
jects harboring a new or spontaneous mutation would
be missed. Patients younger than 25 years of age with
idiopathic acute or CP should undergo genetic testing;
Figure 2. Working model for aCP Pathogenesis
In the necrosisfibrosis concept, the acinar cell is the site of initiation. Direct toxicity of alcohol and its metabolites have a variety of effects on acinar cell function,
including increased expression of digestive enzymes, perturbed lipid metabolism, oxidant stress, and destabilized zymogen and lysosomal membranes. The net
effect is enhanced activation of trypsin and, with an appropriate trigger, enzyme cascade activation, necrosis, and inflammation. Inflammation recruits cytokines
that activate stellate cells to deposit excessive extracellular matrix. Stellate cells are also directly activated by alcohol and its metabolites, leading to further collagen
deposition and fibrosis. Finally, perturbed glandular architecture and function cause protein precipitation in the small ductules potentiating the disease process (eg,
a secretory block at the apical surface of the acinar cell).
ACP = alcoholic chronic pancreatitis; CE = cholesteryl esters; FAEE = fatty acid ethyl esters; mRNA = messenger RNA.
Adapted from Witt H et al.
1
Acinar
cell Secretory block
Ductule
Protein plug
Acetaldehyde
Oxidant stress
Stellate cell
activation
Cytokines
Necrosis
PLAPSON
in one series, 5% of this cohort had PRSS1 mutations
in the absence of a family history.
30
Chymotrypsin C gene, CTRC. A recent study found
variants in this protease to be associated with both he-
reditary and idiopathic CP.
31
The detected mutations
were loss-of-function mutations, consistent with the
role of this protease in degrading activated trypsin.
Thus, loss of CTRC would reduce trypsin-degrading
activity in the acinar cell, enhancing trypsin activity
and autodigestion.
31
Serine protease inhibitor, Kazal type 1 gene,
SPINK1. Considering the central role of trypsin acti-
vation in pancreatitis, SPINK1 is a logical candidate
gene. A potent protease inhibitor coexpressed in the
acinar cell, it is a first-line defender in the zymogen
granule against activated intrapancreatic trypsin. In
2000, a germline mutation in the coding region of
SPINK1 (N34S) was found to be strongly associated
with tropical pancreatitis (~50%) and early onset ICP
(~20%).
32,33
However, the high prevalence (~2%) of
this genetic polymorphism in the general population
suggests that this mutation predisposes rather than
causes pancreatitis. Furthermore, the mechanism
of impaired protease inhibition has been difficult
to prove; the N34S mutant is a functional inhibi-
tor.
34
Nevertheless, overexpression of native SPINK1
in transgenic models protects against pancreatitis.
35

SPINK1 knockout mice die shortly after birth with
acinar cell degeneration, confirming the importance
of this protein in pancreatitis protection as well as in
acinar cell integrity.
36
Figure 1 illustrates a conceptual
model of mutations in trypsin and its inhibitors in
the pathogenesis of acinar cell injury.
2

Cystic fibrosis transmembrane conductance reg-
ulator gene, CFTR. Cystic fibrosis (CF) is the most
common autosomal recessive disease among whites.
It is caused by mutations in CFTR, leading to defi-
cient chloride secretion.
37
More than 1000 mutations
in CFTR have been identified with a variable impact
on function of the protein.
38
When CFTR function is
severely impaired by two mutations causing near com-
plete loss of chloride channel activity (including in the
pancreatic ductal cell), overt CF is present with pan-
creatic insufficiency and chronic lung disease, which
are cardinal features contributing to premature death.
Milder impairment in CFTR function has been recog-
nized with a less severe phenotype including sufficient
pancreatic function; ironically, these CF patients are at
risk for clinical episodes of acute pancreatitis.
38
In 1998, two groups identified an almost 6-fold in-
crease in CFTR mutations in patients with ICP who oth-
erwise lacked any clinical features of CF.
39,40
Several series
have confirmed that about 20% to 25% of patients with
ICP (especially early onset) harbor at least one CFTR muta-
tion.
41,42
Some are true compound heterozygotes with two
mutated alleles, but one mutation mildly impairs CFTR
function, leaving enough residual chloride channel activ-
ity to avoid overt CF. Thus, ICP is part of a growing list of
monosyndromatic disorders due to impaired CFTR func-
tion (eg, congenital bilateral absence of the vas deferens
[male infertility] and pulmonary bronchiectasis). Given
the high rate of CFTR mutations in the general popula-
tion (~3%), a single CFTR mutation is likely to be a predis-
posing, permissive factor rather than causative for most
subjects.
41,42
genetiCs anD aLCohoLiC PanCreatitis
Attempts to link germline mutations to a risk for al-
coholic pancreatitis have been inconsistent and in-
conclusive. Increased CFTR and SPINK1 mutations in
ACP have been observed in some but not all studies.
3

Preliminary studies also suggest that CTRC loss is over-
represented in ACP.
31
A recently described polymor-
phism in the anionic trypsinogen gene, PRSS2, protects
against pancreatitis but has not been tested in suffi-
ciently large populations to know its role in the 10%
penetrance of ACP in chronic alcoholism.
43

Case: Diagnosis anD reCommenDations
Our patient was diagnosed with early-onset ICP.
Alcohol abstinence, high-dose pancreatic enzyme
supplements, and pharmacologic doses of antioxidants
did not prevent further attacks of acute pancreatitis.
After informed consent, a series of genetic tests were
performed. No disease-causing mutations in PRSS1
were identified. Screening for the 100 most common
CFTR mutations and SPINK1 showed the patient to be a
transheterozygote: CFTR 508 and SPINK1 N34S. This
combination of mixed mutations has been shown to
be overrepresented in ICP in other studies.
42
Given the long course expected with early onset ICP
and the dominance of recurrent flares of acute pancre-
atitis, the patient was referred for consideration of total
pancreatectomy with islet-cell autotransplantation.
ConCLusion
Chronic pancreatitis due to any cause is a vexing clini-
cal problem for clinicians and patients. A long delay in
diagnosis, recurrent acute pancreatitis, chronic pain, and
long-term morbidity associated with failed exocrine and
endocrine function are normal. Improved understanding
of the initial insult of necroinflammation at a biochemi-
cal and cellular level (intra-acinar activation of trypsin),
coupled with the identification of PSC as the source of
collagen deposition, should lead to more specific and ef-
fective therapies and improve long-term prognoses.
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AUGUST 2009 CHRONIC PANCREATITIS
C
hronic pancreatitis (CP) is a challenging di-
agnosis, affecting many patients for years
before being recognized. The chronic pain
associated with the disease and the poten-
tial for opioid abuse magnify the social cost, as well
as the financial burden on the family and the health
care system. Known causes range from alcohol abuse,
which is responsible for more than 80% of the CP in
North America, to heredity, although many cases are
idiopathic.
The clinicians index of suspicion determines the
aggressiveness with which the diagnosis is pursued.
From onset of symptoms to diagnosis, the average time
lag is 62 months, but for patients without a history of
alcoholism, the delay from onset of symptoms to diag-
nosis averages 81 months.
1,2
Early diagnosis with inter-
vention, including alcohol cessation when applicable,
often slows progression or reduces complications.
This article discusses symptoms that might point to-
ward a diagnosis of CP in its early stages, classic symp-
toms that present in its late stages, and the laboratory
findings and imaging studies used to diagnose CP. Two
case histories demonstrate the subtle and not-so-subtle
characteristics of the disease.
Two Typical cases
case 1: abdominal pain with weight loss
A 65-year-old man is referred by his primary care phy-
sician to a gastroenterology practice for evaluation
of chronic abdominal pain of 3 years duration. His
pain occurs daily, without relief, typically radiating
from the epigastrium to the back. Eating aggravates
the pain, and he has lost 20 lb over the preceding
6 months. He reports consuming no alcohol and no
recreational drugs. Physical examination reveals mild
temporal muscle wasting. The patient is anicteric and
has no abdominal masses or tenderness.
Laboratory data show that hemoglobin, liver func-
tion tests, electrolytes, blood glucose, glycosylated
hemoglobin, and serum amylase are normal. Esopha-
gogastroduodenoscopy (EGD), abdominal ultrasound,
and an abdominal computed tomographic (CT) scan
are also normal.
When patients present with chronic abdominal
pain and weight loss, the differential diagnosis is vast
encompassing common conditions such as CP, peptic
ulcer disease, gallstones, endocrine diseases, ischemic
bowel, and even pancreatic carcinoma. What should
be the clinicians next step?
case 2: early satiety, Diarrhea, and weight loss
A 66-year-old attorney who has atrial fibrillation and
takes warfarin for anticoagulation is referred for EGD
and colonoscopy. He has reported a loss of appetite, in-
creased frequency of bowel movements, and a weight
loss of 20 lb over 6 months. Are his symptoms sug-
gestive of CP?
pReseNTaTioN cHalleNGes
Our ability to diagnose CP in its early stages is limited:
while pancreatic function is still within physiologic
limits, there may be no symptoms other than pain
and pain is absent in more than 10% of patients with
pancreatic damage.
3
No current physiologic tests can
aid clinicians in making a definitive, early diagnosis,
and few tests help in staging the disease, especially in
its early stages. Direct pancreatic secretory assessment,
once considered a gold standard for diagnosing pan-
creatic insufficiency, is very cumbersome to perform
and is now used in very few centers.
4
Histologic test-
ing is difficult to perform safely and may not provide
reliable information regarding pancreatic function.
Confirmation of pancreatitis requires radiographic
imaging and, like initial laboratory tests, such images
often reveal no abnormality in early disease.
For these reasons, a strong clinical suspicion of early
(minimal change) CP should be pursued vigorously
with specialized testing to confirm the diagnosis.
evaluation and Diagnosis of
chronic pancreatitis
Rakesh Nanda, MD, and camron Kiafar, Do
In early chronic pancreatitis, there may be no symptoms other than pain, which is absent in more
than 10% of cases. Here, some subtle clues that should raise a clinicians index of suspicion.
Dr. Nanda is assistant professor of clinical medicine at the
University of Arizona, Tucson, and a gastroenterologist on staff at
Carl T. Hayden VA Medical Center, Phoenix.
Dr. Kiafar is assistant chief of therapeutic endoscopy in the
department of gastroenterology at Carl T. Hayden VA Medical
Center, Phoenix.
EvAluATION ANd dIAgNOSIS Of CHRONIC PANCREATITIS
10 CHRONIC PANCREATITIS AUGUST 2009
Moreover, a thorough and meticulous patient history
may be useful, particularly if it uncovers any signifi-
cant period of alcohol abuse.
siGNs aND syMpToMs
The earliest symptom of CP, abdominal pain, may be
quite variable. Its etiology is unclear and may be mul-
tifactorial, with common causes including pancreatic
or neural inflammation.
5
The classic disease triadpancreatic calcification,
diabetes mellitus, and clinically significant malab-
sorptionemerges only in advanced disease, often
accompanied by complications such as pseudocysts,
bile duct or duodenal obstruction, ascites, splenic vein
thrombosis, or pancreatic cancer, which also require
evaluation and management.
6
Frequently, more than
90% of the pancreas has been destroyed by the time
such manifestations occur.
7
classic pain patterns
The nature of the patients pain may help rule out
other common causes of abdominal discomfort, and
the patients age at presentation may provide clues as
to the etiology of the pancreatitis. The pain of heredi-
tary and tropical pancreatitis tends to present early,
between ages 10 and 30. Alcohol-related pancreatitis
usually presents between ages 30 and 50. Late-onset
idiopathic pancreatitis produces no pain in 50% of
cases, but when pain is present, it tends to emerge
between ages 50 and 70.
8

In CP, two pain patterns have been described: con-
tinuous and intermittent. When pain is intermittent,
episodes may be separated by pain-free intervals of
months or years. In one study, 44% of patients with CP
had short episodes of pain, usually less than 10 days
duration, separated by pain-free intervals of months
to years, and 56% had episodes of continuous pain,
ranging from daily to 2- to 3-days per week for at least
2 months.
9

Classically, pancreatic pain is felt in the epigastrium
or upper abdomen, with penetration to the back or
radiation to the left intercostal region. The patient may
find relief in crouching down, lying curled up in bed
with thighs pressed against the abdomen, or bending
over the edge of a chair or a bed.
10

The intensity of pain may range from mild to debili-
tating and chronic. The latter may precipitate opioid
dependence or continued alcohol abuse as a means of
providing analgesia. It is essential to assess the pains
severity and effect on the patients quality of life. It
has been suggested that, as the disease progresses and
the pancreas is destroyed, the pain may subside or
disappear altogether, while symptoms of endocrine
and exocrine insufficiency predominate.
9,11
This may
explain the findings of one study in which 45% of
alcoholic subjects had not reported having had pain
despite manifestations of CP at autopsy.
12
Malabsorption and Diabetes Mellitus
With advancing disease, patients develop exocrine in-
sufficiency and thus lose the ability to digest protein
and fat. Fat malabsorption results in steatorrhea, signi-
fied by the production of large-volume stools that tend
to be foul-smelling, greasy, and hard to flush, possibly
leaving a rim of fat in the toilet bowl. Patients may re-
port weight loss with diarrhea. There may be associated
malabsorption of vitamin B12 and fat-soluble vitamins
(A, D, E, and K), which might help an astute dietitian
diagnose the condition at an early stage, thereby allow-
ing for more effective intervention. Since malnutrition
impairs immunity, incidence of infection is likely to
rise among affected patients. In a population of veter-
ans, CP related to alcohol abuse is also associated with
drug abuse, hepatitis C viral infection, HIV/AIDS, and
cirrhosis,
13
conditions that further compromise the nu-
tritional status and overall health of the patient.
With the destruction of insulin-producing pancre-
atic cells (endocrine insufficiency), the patient may
develop diabetes mellitus. By the time the patient
manifests malabsorption and diabetes mellitus, the
pancreas has been irreversibly damaged, and the dis-
ease is in its very late stages. At that point, the third
classic sign of CP, calcification, may be apparent on
abdominal radiographs and CT scans.
DiaGNosTic TesTiNG
Although there is no single test that is diagnostic for
early CP, laboratory testing during painful episodes
may be helpful in some patients with acute exacerba-
tion of their CP, since pancreatic enzyme levels are
typically elevated more than 3 times the upper limits
of normal. However, in chronic pancreatitis, serum
concentrations of amylase and lipase may be mildly
elevated but are usually normal for the following rea-
sons: (1) significant pancreatic fibrosis frequently re-
duces the level of these enzymes within the pancreas;
and (2) CP tends to be a patchy, focal disease that
only minimally increases pancreatic enzymes in the
blood.
6
The complete blood count and electrolytes are typi-
cally normal in the absence of significant vomiting
and poor oral intake. Elevation of liver enzymes may
point to coexistent liver disease or cholestasis because
of compression of the intrapancreatic portion of the
common bile duct from edema, fibrosis, or pancreatic
cancer.
14
NANdA and kIAfAR
AUGUST 2009 CHRONIC PANCREATITIS 11
stool Tests
Steatorrhea, if suspected, can be assessed qualitatively
by Sudan staining of feces. Since the qualitative test is
fairly insensitive, unless the patient has gross steator-
rhea, it needs to be performed with the patient on a
high-fat diet. Steatorrhea also can be assessed quanti-
tatively by determining fecal fat excretion in 24 hours
with the patient following a 100-g fat diet. Such tests
are usually performed over 72 hours, with excretion of
more than 7 g of fat per day considered diagnostic of
malabsorption. (Patients with steatorrhea often excrete
more than 20 g of fat per day.) In the proper clinical
setting (typical abdominal pain), confirmation of ste-
atorrhea may be sufficient to diagnose CP.
pancreatic Function Tests
Pancreatic function tests (PFTs) can be helpful in diag-
nosing patients who experience recurrent abdominal
pain but have normal imaging and laboratory tests.
Pancreatic function tests may be indirect (ie, simple
and noninvasive) or direct (ie, invasive). Indirect tests
measure the consequences of pancreatic insufficiency.
These tests are more widely available than direct PFTs,
which are performed only at a few specialized centers.
In direct PFTs, the pancreas is stimulated through
the administration of a meal or hormonal secreta-
gogues. Shortly thereafter, the duodenal fluid is col-
lected and analyzed to quantify normal pancreatic se-
cretory content. The main problem with many direct
PFTs is their low sensitivity, especially in mild disease.
A negative PFT, therefore, should not exclude the di-
agnosis of CP (Table 1).
Measurement of fecal elastase has been found to be
helpful in evaluating pancreatic exocrine dysfunction
(malabsorption) in some studies.
15,16
Unpublished data
from the test manufacturer indicate that fecal elastase
values of less than 200 g/g suggest pancreatic insuf-
ficiency.
15
Low fecal elastase values, however, are also
seen in 25% to 30% of patients with conditions involv-
ing the small bowel, including celiac disease, Crohns
disease, cow milk protein enteropathy, bacterial over-
growth, short-bowel syndrome, and enteritis
17,18
; and in
patients with diabetes mellitus, a common complica-
tion of CP. The prevalence of low stool elastase has been
reported to be 46% in patients with type 1 diabetes and
30% in patients with type 2 diabetes.
19
Since low fecal
elastase can be seen in a variety of other small-bowel
conditions, it should be not used as a sole diagnostic
tool for CP.
Another indirect, minimally invasive test of pancre-
atic exocrine function is the pancreolauryl test (PLT),
which involves ingesting the compound fluorescein
dilaurate, a substrate for the pancreatic enzyme cho-
lesterol esterase, with a standard breakfast. Fluorescein
is then absorbed from the gut and excreted in the
urine. Enzymatic cleavage of this substrate results in
Table 1. pancreatic Function Tests
Type sensitivity (%) specificity (%)
Tubeless
Fecal elastase 78 94
Pancreolauryl 5085 82
Bentiromide
(discontinued) 85 90
Duodenal intubation test
Secretin 7589 8090
Table 2. imaging and endoscopic studies for the Diagnosis of chronic pancreatitis
Test sensitivity (%) specificity (%)
Plain abdominal X-ray NA NA
Ultrasonography 6070 8090
Contrast-enhanced
computed tomography 7590 85
Magnetic resonance
cholangiopancreatography (MRCP) 85 100
Endoscopic ultrasound (EUS) 97 60
Endoscopic retrograde cholangiopancreatography (ERCP) 7595 90
the release of fluorescein in proportion to the activ-
ity of cholesterol esterase. Measurement of fluorescein
from the serum or from a 24-hour urine collection al-
lows for a quantitative estimate of pancreatic exocrine
function. Studies have noted that the sensitivity of PLT
ranges from 85% for severe to 50% for mild pancreatic
exocrine insufficiency.
20,21
The bentiromide test was
similar in principle to the PLT but is no longer used
since the reagent has been withdrawn from the market.
In general, the usefulness of these tests is limited by
their negative results in early stages of the disease and
by their lack of availability in most centers.
Two hormones have been used to stimulate pan-
creatic secretion, cholecystokinin (CCK) and secretin.
The CCK tests measure the ability of pancreatic acinar
cells to secrete digestive enzymes, while the secretin
tests measure the ability of pancreatic ductal cells to
produce bicarbonate. Although advanced pancreatic
insufficiency involves abnormalities of both acinar
and ductal secretions, it is not known which hormone
is more sensitive for early pancreatic functional de-
cline; this is an area of ongoing debate.
Of all available PFTs, the secretin stimulation test
is probably the most studied and thus represents a
reference standard for direct PFTs.
22
There are differ-
ent versions of the test, but its basic principle requires
the continuous collection of duodenal fluid for 1 to
2 hours. The fluid is then analyzed for bicarbonate
concentration, volume, and total output. Both biologic
and synthetic porcine secretin have been used, but hu-
man synthetic secretin is now available and compares
favorably with other agents.
23

For this test, a double-lumen tube is inserted through
the patients nose and threaded into the duodenum, or
the sample is collected endoscopically.
24
A test dose
is given to determine hypersensitivity to any of the
components in the formulations. After a test dose of 0.2
mg synthetic secretin, duodenal contents are collected
before and after IV synthetic secretin, at 15-minute
intervals for 1 hour. A bicarbonate concentration of
less than 80 mEq/L in 4 aliquots represents exocrine
insufficiency (malabsorption). Unfortunately, the test
is time-consuming (requiring about 1 hour), unpleas-
ant for the patient, and neither sensitive nor specific
enough to definitively identify early CP; there is sig-
nificant overlap of values among patients with and
without CP.
20

imaging studies
In about 30% percent of patients with CP, plain abdom-
inal films reveal calcifications within the pancreatic
duct. The calcification is pathognomonic of CP and lo-
cated exclusively within the ductal system, not involv-
ing the parenchyma of the gland. Calcium deposition
Figure 1. endoscopic Ultrasound (eUs) images
EUS images (A and B) show features consistent with the diagnosis of chronic pancreatitis. The parenchyma has increased
echogenic foci, stranding with lobulation. The pancreatic duct has an irregular contour with increased echogenicity of the wall.
a B
NANdA and kIAfAR
is most commonly seen with alcoholic pancreatitis but
is also seen in hereditary and tropical forms.
Transabdominal ultrasound, CT scan, and mag-
netic resonance imaging can all assist in diagnosis
and management of CP. All of these studies may show
calcifications, ductal dilation, pancreatic enlargement,
and fluid collections (ie, pseudocysts) adjacent to the
gland. Although endoscopic retrograde cholangiopan-
creatography (ERCP) is used as a reference standard,
a contrast-enhanced CT scan of the abdomen is the
initial imaging modality of choice because it is rea-
sonably sensitive and specific at a relatively low cost
(Table 2).
ERCP has been deemed the gold standard imaging
procedure for diagnosing CP,
6
with beading of the
main pancreatic duct, stones or protein plugs within
the duct, and ecstatic side branches considered diag-
nostic. Based upon ductal changes apparent on ERCP,
the Cambridge classification system assigns patients
to 1 of 3 categories: equivocal changes (Cambridge I),
mild-to-moderate changes (Cambridge II), and con-
siderable changes (Cambridge III). One study using
this system found that no patients with normal ducts
on ERCP had functional impair-
ment, while 50% of patients with
Cambridge II changes had pancre-
atic insufficiency.
25
For patients
with suspected CP, however, mag-
netic resonance cholangiopancrea-
tography (MRCP), with or without
secretin, and endoscopic ultrasound
(EUS) have become the modalities
of choice in visualizing pancreatic
ducts. These tests provide diagnos-
tic performance similar to ERCP
26,27

without the potential complica-
tions associated with ERCP (infec-
tion, hemorrhage, perforation, and
most notably, causing or exacerbat-
ing pancreatitis). Today, ERCP is
rarely used for diagnosis alone but
may be used as part of a therapeutic
intervention.
MRCP has the unique ability to
detect biliary and pancreatic ducts
noninvasively and, when used
with IV secretin, significantly im-
proves visualization of the main
pancreatic duct as well as its side
branches.
28
Likewise, EUS has been
shown to be more sensitive than
ERCP in patients with early CP.
29

While less invasive than ERCP, EUS
provides an opportunity for the clinician to obtain
tissue samples during the same procedure if a mass
is detected. Features considered suggestive of CP on
EUS include stones (which are highly predictive), vis-
ible side branches, cysts, lobularity, an irregular main
pancreatic duct, hyperechoic foci and strands, dilation
of the main pancreatic duct, and hyperechoic margins
of the main pancreatic duct. The presence of four or
more of these features is considered to be indicative
of CP.
30
case DiscUssioN
In case 1, with help from the patients son, who ac-
companied the patient at this visit, clinicians elicit
a detailed history, which includes a long period of
alcohol abuse (about 6 beers daily for 20 years) that
ended approximately 8 years ago. Clinicians further
determine that the patient has regular, nonbloody,
formed stools.
Given the patients history of long-standing, al-
though remote, alcohol abuse, CP is a possible diag-
nosis. An EUS reveals features consistent with CP, in-
cluding a parenchyma with increased echogenic foci,
Figure 2. computed Tomography (cT) scan
The CT scan shows solitary calcification in the tail of the pancreas, which suggests
chronic calcific pancreatitis.
stranding with lobulation, a pancreatic duct with an
irregular contour, and increased echogenicity of the
wall (Figure 1).
In case 2, after much discussion, the patient dis-
closes that he had been a heavy alcohol user for 18
years, from age 12 until after he left the army. He
recalls that he stopped drinking after a severe episode
of abdominal pain that required hospitalization. At the
time, he was told he had swelling of the pancreas. He
has not consumed ethanol since that time, more than
35 years ago. A CT scan reveals solitary calcification
in the tail of the pancreas, suggesting chronic calcific
pancreatitis (Figure 2).
Both cases typify presentations of CP in which a di-
agnosis may be reached after a taking a detailed, prob-
ing history. The diagnosis of CP was not suspected ini-
tially in either case, and snapshot histories would have
missed important aspects of both patients livessuch
as significant, although remote, alcohol abuse. These
cases underscore the need for the clinician-historian to
look at the patients entire life, keeping in mind that
it is often more difficult to diagnose CP when alcohol
is not a factor.
ReFeReNces
1. Rizk MK, Gerke H. Utility of endoscopic ultrasound in pancre-
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2. Obideen K, Yakshe P, Wehbi M. Pancreatitis, chronic. eMedi-
cine Web site. http://www.emedicine.com/med/TOPIC1721.
htm. Updated June 16, 2008. Accessed June 24, 2009.
3. Lankisch PG, Lhr-Happe A, Otto J, Creutzfeldt W. Natural
course in chronic pancreatitis. Pain, exocrine and endocrine
pancreatic insuffciency and prognosis of the disease. Digestion.
1993;54(3):148155.
4. Forsmark CE. The early diagnosis of chronic pancreatitis. Clin
Gastroenterol Hepatol. 2008;6(12):12911293.
5. Dimcevski G, Sami AK, Funch-Jensen P, et al. Pain in chronic
pancreatitis: The role of reorganization in the central nervous
system. Gastroenterology. 2007;132(4):15461556.
6. Steer ML, Waxman I, Freeman S. Chronic pancreatitis. N Engl J
Med. 1995;332(22):14821490.
7. Regan PT, Malagelada JR, DiMagno EP, Glanzman SL, Go VL.
Comparative effects of antacids, cimetidine and enteric coat-
ing on the therapeutic response to oral enzymes in severe pan-
creatic insuffciency. N Engl J Med. 1977;297(16):854858.
8. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiM-
agno EP. The different courses of early- and late-onset idio-
pathic and alcoholic chronic pancreatitis. Gastroenterology.
1994;107(5):14811487.
9. Ammann RW, Muellhaupt B; Zurich Pancreatitis Study Group.
The natural history of pain in alcoholic chronic pancreatitis.
Gastroenterology. 1999;116(5):11321140.
10. Haubrich WS. Abdominal pain. In: Berk JE, Haubrich WS, eds.
Gastrointestinal SymptomsClinical Interpretation. Philadelphia,
PA: BC Decker; 1991:5052.
11. Blackstone MO. Pain in alcoholic chronic pancreatitis. Gastro-
enterology. 1999;117(4):10261028.
12. Pitchumoni CS, Glasser M, Saran RM, Panchacharam P,
Thelmo W. Pancreatic fbrosis in chronic alcoholics and non-
alcoholics without clinical pancreatitis. Am J Gastroenterol.
1984;79(5):382388.
13. Wilson NJ, Kizer KW. The VA health care system: An unrecognized
national safety net. Health Aff (Millwood). 1997;16(4):200204.
14. Mergener K, Baillie J. Chronic pancreatitis. Lancet.
1997;350(9088):13791385.
15. Keim V, Teich N, Moessner J. Clinical value of new fecal elastase
test for detection of chronic pancreatitis. Clin Lab. 2003;49(5-
6):209215.
16. Borowitz D, Baker SS, Duffy L, et al. Use of fecal elastase-1 to
classify pancreatic status in patients with cystic fbrosis. J Pedi-
atr. 2004;145(3):322326.
17. Beharry S, Ellis L, Corey M, Marcon M, Durie P. How useful is
fecal pancreatic elastase 1 as a marker of exocrine pancreatic
disease? J Pediatr. 2002;141(1):8490.
18. Nousia-Arvanitakis S. Fecal elastase-1 concentration: An in-
direct test of exocrine pancreatic function and a maker of
enteropathy regardless of cause. J Pediatr Gastroenterol Nutr.
2003;36(3):314315.
19. Czak L, Takcs T, Hegyi P, et al. Quality of life assessment after
pancreatic enzyme replacement therapy in chronic pancreati-
tis. Can J Gastroenterology. 2003;17(10):597603.
20. DiMagno EP. A perspective on the use of tubeless pancreatic
function tests in diagnosis. Gut. 1998;43(1):23.
21. Lankisch PG, Schreiber A, Otto J. Pancreolauryl test. Evaluation
of a tubeless pancreatic function test in comparison with other
indirect and direct tests for exocrine pancreatic function. Dig
Dis Sci. 1983;28(6):490493.
22. Chowdhury RS, Forsmark CE. Review article: Pancreatic func-
tion testing. Aliment Pharmacol Ther. 2003;17(6):733750.
23. Somogyi L, Ross SO, Cintron M, Toskes PP. Comparison of
biologic porcine secretin, synthetic porcine secretin, and syn-
thetic human secretin in pancreatic function testing. Pancreas.
2003;27(3):230234.
24. Stevens T, Conwell DL, Zuccaro G Jr, et al. A prospective cross-
over study comparing secretin-stimulated endoscopic and Dreil-
ing tube pancreatic function testing in patients evaluated for
chronic pancreatitis. Gastrointest Endosc. 2008;67(3):458466.
25. Bozkurt T, Braun U, Leferink S, Gilly G, Lux G. Comparison of
pancreatic morphology and exocrine functional impairment
in patients with chronic pancreatitis. Gut. 1994;35(8):1132
1136.
26. Adler DG, Baron TH, Davila RE, et al; Standards of Practice
Committee of American Society of Gastrointestinal Endoscopy.
ASGE guideline: The role of ERCP in diseases of the biliary tract
and the pancreas. Gastrointest Endosc. 2005;62(1):18.
27. Remer EM, Baker ME. Imaging of chronic pancreatitis. Radiol
Clin North Am. 2002;40(6):12291242.
28. Erturk SM, Ichikawa T, Motosugi U, Sou H, Araki T. Diffusion-
weighted MR imaging in the evaluation of pancreatic exocrine
function before and after secretin stimulation. Am J Gastroen-
terol. 2006;101(1):133136.
29. Kahl S, Glasbrenner B, Leodolter A, Pross M, Schulz HU,
Malfertheiner P. EUS in the diagnosis of early chronic pan-
creatitis: A prospective follow-up study. Gastrointest Endosc.
2002;55(4):507511.
30. Wallace MB, Hawes RH, Durkalski V, et al. The reliability of
EUS for the diagnosis of chronic pancreatitis: Interobserver
agreement among experienced endosonographers. Gastrointest
Endosc. 2001;53(3):294299.
Case: a Middle-aged Man with a history
of alCohol abuse
A 56-year-old man with a long-standing history of
alcohol abuse presents to the clinic for management
of chronic diarrhea and weight loss. He has a history
of chronic abdominal pain in the epigastric area that
has increased in intensity over the years. For the past
six to nine months, he has experienced bloating and
diarrhea that is described as foul smelling, pale, bulky,
and greasy in nature, occurs 4 to 6 times per day, and
is associated with a 10-lb weight loss in 6 months. On
physical exam, the mans height was 6'3"; his weight
was 134 lbs; and he was afebrile and well hydrated,
without stigmata of chronic liver disease. There was
no jaundice. Results of cardiovascular and lung exams
were normal. The abdomen was slightly protuberant,
with mild tenderness on deep palpation in the epigas-
tric area. No hepatosplenomegaly or intra-abdominal
masses were noted. Extremities failed to reveal any
pedal edema.
Laboratory work-up revealed a white blood cell
count of 7500/mL with normal differential; a hemo-
globin level of 12.8 g/dL; mean corpuscular volume
of 100 mm
3
; and platelet count of 210,000/mL. His
fasting serum glucose level was 100 mg/dL; his blood
urea nitrogen, creatinine, and electrolyte levels were
normal. The amylase and lipase levels were normal.
Liver enzymes showed an aspartate aminotransferase
of 54 U/L and an alanine aminotransferase of 36 U/L
with normal bilirubin and alkaline phosphatase levels.
Plain abdominal films revealed calcifications in the
midportion of the abdomen; a computed tomographic
scan of the abdomen showed that the calcifications
were located in the pancreas with atrophy of the gland
and mild dilation of the entire pancreatic duct. An en-
doscopic ultrasound showed changes compatible with
chronic pancreatitis (CP). The patients stool studies
were negative for fecal leukocytes, occult blood, and
ova and parasite. The Sudan III stain of random stools
was positive. The patient also underwent a quantitative
measurement of fecal fat while on a 100-g fat diet for
3 days and showed a fecal fat content of 50 g/day.
PanCreatiC exoCrine insuffiCienCy
The pancreas secretes about 2 L of pancreatic juice
daily; this is composed of water, bicarbonate, and en-
zymes that digest fats, proteins, and carbohydrates.
1

The pancreas normally produces more enzymes than
what is needed for the normal digestion of food, and
this is not clinically compromised until the pancreas
has lost 90% or more of its secretive capacity
2
; how-
ever, this concept has been challenged.
3
The digestive
capacity of the different enzymes is affected separately
by several intraluminal factors where degradation oc-
curs. The loss of enzymatic activity within the intes-
tinal lumen is due, among other factors, to proteolytic
degradation, acid content, and the short half-life of
some of the enzymes. Lipase is particularly vulnerable
to all these factors, which explains why maldigestion
of fat precedes, and is more severe than, carbohydrate
and protein maldigestion in the setting of exocrine
pancreatic insufficiency.
48
The main consequence of pancreatic exocrine in-
sufficiency is maldigestion and malabsorption of lip-
ids, leading to a distinct form of diarrhea character-
ized by steatorrhea, weight loss, and malnutrition.
Efficient digestion of triglycerides requires lipase, co-
lipase, and bile salts. CP involves acid-mediated lipase
inactivation and decreased secretion of lipase and
colipase. In the presence of a low luminal pH, bile
acid precipitation and mucosal dysfunction also con-
tribute to malabsorption. Fat maldigestion also leads
to malabsorption of fat-soluble vitamins (A, D, E, K).
Malabsorption of vitamin B12 also occurs, although
the clinical correlate is unknown. Steatorrhea affects
nutrition and quality of life negatively.
9
The deficiency
in micronutrients, fat-soluble vitamins, and lipopro-
Management of exocrine
Pancreatic insufficiency
francisco C. ramirez, Md
Exocrine pancreatic insufficiency is characterized by maldigestion and malabsorption of lipids,
leading to steatorrhea, weight loss, and malnutrition. Alcohol abuse is a significant risk factor,
and treatment may include pancreatic enzyme replacement.
dr. ramirez is a professor of clinical medicine at the University
of Arizona College of Medicine and chief of the division of
gastroenterology at Carl T. Hayden VA Medical Center, both in
Phoenix, Arizona.
mANAgEmENT Of ExOCRINE PANCREATIC INSuffICIENCy
teins has been associated with an increased morbid-
ity secondary to the increased risk for malnutrition-
related complications and cardiovascular (CV) events.
10

CV complications arise primarily from abnormalities
in lipid metabolism; these abnormalities are significant
contributors to atherosclerosis, although they may not
be its direct cause. Patients with alcoholic CP exhibit
significantly lower levels of total cholesterol, high-
density lipoprotein (HDL), apoprotein A1 (apoA1), and
lipoprotein(a) [Lp(a)] than controls and significantly
lower levels of cholesterol, apoA1, apoprotein B (apoB),
and Lp(a) than alcoholics who do not exhibit clinical
evidence of pancreatic or liver disease. Decreased levels
of Lp(a) have been associated with increased risk of
atherogenic CV disease. In addition, a decreased level
of HDL, which is protective against CV disease, further
increases the risk for pancreatic or liver disease.
10

Fat maldigestion is the most common manifesta-
tion of exocrine pancreatic insufficiency, although
protein (azotorrhea) and starch (amylorrhea) mal-
digestion may be rare and late occurrences in the
course of the disease. Bacterial overgrowth, which is
seen in 25% to 50% of patients with exocrine pan-
creatic insufficiency, either contributes to diarrhea or
is responsible for its persistence in patients receiving
adequate pancreatic exocrine supplementation.
1113

The exact reason for the association of bacterial
overgrowth with exocrine pancreatic insufficiency is
not well known. In patients with untreated severe
pancreatic insufficiency, bacterial overgrowth was
seen in 50% of patients.
12
In an animal model with
pancreatic duct ligation, however, pancreatic enzyme
replacement reversed bacterial overgrowth. This sug-
gests that pancreatic enzymes may have an important
role in the normalization of luminal conditions that
prevent such overgrowth.
14
Bacterial overgrowth may
also give rise to bile acid malabsorption and changes
in intestinal permeability.
1516
treatMent of PanCreatiC enzyMe
insuffiCienCy
The indications for pancreatic enzyme replacement
therapy include weight loss, more than 15 g of fe-
cal fat excretion daily while on a 100-g/day fat diet,
and steatorrhea-related relevant symptoms.
17
The role
of pancreatic enzyme replacement in persons with
asymptomatic steatorrhea of less than 15 g/day is
controversial; these patients have low circulating lev-
els of prealbumin, ferritin, and liposoluble vitamins
that normalize with pancreatic enzyme replacement.
Consequently, some observers advocate its use to pre-
vent related nutrient deficiencies.
18
nutritional Management
The nutritional management of pancreatic exocrine
insufficiency includes dietary modification, such as
limitation of fat content in the diet, and administra-
tion of liposoluble vitamins, such as calcium and vi-
tamin B12. Fat-soluble multivitamins can be admin-
istered orally using water-miscible preparations and
water-soluble forms.
19
In patients with alcoholic CP
(the most common cause of CP and pancreatic exo-
crine insufficiency), abstinence from alcohol is asso-
ciated not only with decreased pain but also with an
increase in gastric lipase that may compensate partly
for the loss of pancreatic lipase, helping fat digestion.
20

Alcohol abstinence may improve fat malabsorption by
an indirect mechanism, (ie, by an increase in the se-
cretion of gastric lipase). It is not known whether this
increase is clinically significant and sufficient to pre-
vent fat malabsorption and steatorrhea.
21
The finding that the lipolytic activity of pancreatic
enzyme replacements is higher when replacements
are taken with high- rather than low-fat diets has
led to questions about the benefit of a low-fat diet.
22

Other dietary modifications include low volume and
frequent meals that avoid difficult-to-digest food, as
well as the use of medium-chain triglycerides (MCTs),
which do not require enzymatic breakdown for absorp-
tion. However, MCTs are primarily used for supple-
menting calories in patients with weight loss and to
reduce steatorrhea in patients with a poor response to
pancrelipase.
17

Pancreatic enzyme replacement
The cornerstone of treatment of pancreatic exocrine
insufficiency is the exogenous replacement of lipase.
To understand the requirements for exogenous oral
pancreatic replacement, it is important to review exo-
crine secretion by a healthy pancreas in response to
nutrients.
23
In the fasting state, pancreatic secretion
follows an interdigestive cyclical pattern, which de-
Fat maldigestion is the most
common manifestation of exocrine
pancreatic insufficiency, although
protein (azotorrhea) and starch
(amylorrhea) maldigestion may
be rare and late occurrences in the
course of the disease.
RAmIREz
pends on upper gastrointestinal motility.
24
The mean
secretion of lipase during the interdigestive period is
about 1000 U/min,
4,2526
the maximal postprandial
enzyme output is between 3000 to 6000 U/min, and
2000 to 4000 U/min are secreted for a longer period
of time.
4,26
Since lipase is the major deficiency, 30,000
IU or more need to be ingested with each meal to
end or prevent steatorrhea. It is crucial, however, to
understand the equivalence/conversion between IU
and units used in different countries (in the US, USP
[US Pharmacopeia] units; in Europe, PhEur [European
Pharmacopoeia] units). Thus, since 1 IU is equivalent
to 3 USP units of lipase activity, 30,000 IU is equivalent
to 90,000 USP units. Remembering this difference is
essential for avoiding undertreatment of patients.
27
(A
conversion dose of the three different enzyme contents
in the pancrelipase preparations include: 1 PhEur unit
of amylase = 4.15 USP units of amylase; 1 PhEur unit of
lipase = 1 USP unit of lipase, and 1 PhEur unit of pro-
tease = 62.5 USP units of protease.
28,29
) Since the goal
of exocrine pancreatic insufficiency treatment is to re-
place lipase, the decision about which formulation to
use should be based primarily on the lipase activity
content. Keep in mind that the lipase replacement goal
may be difficult to achieve because of gastric acid se-
cretion, nonparallel gastric emptying, and proteolytic
inactivation of lipase.
The timing of administration of the pancreatic en-
zymes may affect therapeutic efficacy. Adequate mix-
ing of food with the pancreatic enzymes and optimal
intestinal motility are crucial for satisfactory fat diges-
tion.
30,31
A commonly reported mistake is giving the
enzymes before meals rather than with meals, which
increases mixing the enzymes with the chyme. One
recommendation is to administer one quarter of the
dose after the first bites of the meal, one half during
the meal, and the remaining quarter with the last few
bites.
27
A prospective, randomized, three-way crossover
study found that enzyme replacement therapy appears
to be more efficacious when enzymes are administered
with meals or just after meals rather than before eat-
ing.
32
The study did not use a quantitative fecal bal-
ance to assess the response, however.
27
Changes in
malabsorption can be measured using the coefficient
of fat absorption (CFA). CFA = dietary fat (g/day)
fecal fat (g/day)/dietary fat (g/day) x 100%. The normal
fecal fat amount while on a 100-g fat diet is less than
7%. The CFA may be used to calculate this percentage,
but it is more important to follow up on the response
to therapy and to assess the efficacy of the formula-
tions compared with placebo or other medication. The
diagnosis of exocrine pancreatic insufficiency is based
on demonstration of more than 7% of ingested fat in
the stool, using a 3-day stool collection, while ingest-
ing 100 g of fat per day for 3 days. This results in a
CFA of 95% (within normal limits).
Pancreatic enzyme replacement formulations
Two major pancreatic enzyme (pancrelipase) formu-
lations are available: uncoated or conventional and
enteric-coated microencapsulated.
28
The former are
susceptible to excessive inactivation by gastric acid
(pancreatic lipase is irreversibly inactivated at pH lev-
els of less than 4), which is further enhanced by de-
creased bicarbonate pancreatic secretion.
20
Although
uncoated pancreatic enzyme replacement is effective
in reducing steatorrhea, fat digestion and absorption
do not normalize in most patients.
3337
To avoid this,
one may increase the dose to counteract the loss. This
high-dose pancrelipase replacement may be associated
with adverse effects, including diarrhea and flatulence,
as well as hyperuricosuria in children because of the
high purine content in the formulations. Alternatively,
one may increase the gastric pH by concomitant use
of bicarbonate, histamine 2 (H2) receptor antagonists,
or proton pump inhibitors.
34,3840
Because no head-to-
head comparisons of bicarbonate, H2 receptor antago-
nists, or proton pump inhibitors have been performed,
the superiority of any one of these medications has
not been established.
41
The pH effect (pH greater than
4) in the duodenum must last at least 90 minutes to
allow time for the enzyme to act and to prevent its
destruction.
33
Combination therapy does not seem to
be superior to enteric-coated preparations administered
alone, however.
42

The enteric-coated formulations allow delivery of the
enzymes into the small intestine where they are released
only when the pH is greater than 5.5. In most studies,
but not all, enteric-coated formulations are superior to
uncoated preparations in improving fat digestion.
3437

The use of microspheres provides the theoretical advan-
In patients with alcoholic CP,
abstinence from alcohol is
associated not only with decreased
pain but also with an increase in
gastric lipase that may compensate
partly for the loss of pancreatic
lipase, helping fat digestion.
mANAgEmENT Of ExOCRINE PANCREATIC INSuffICIENCy
tage of allowing a better mixing with the chyme, but
the size of the microspheres seems to have an impact
on the rate of gastric emptying. Smaller microspheres
(1.0 to 1.2 mm in diameter) are associated with a 25%
higher therapeutic benefit than larger microspheres (1.8
to 2 mm),
43
but their effect is similar to minimicro-
spheres (0.7 to 1.2 mm).
44
Enteric-coated microspheres
have higher therapeutic efficacy as measured by CFA,
body weight, stool frequency, and stool character, as
well as abdominal pain.
45
The use of acid-suppressant
drugs with enteric-coated pancreatin microspheres has
been reported to be beneficial in patients with cystic
fibrosis.
4647
Proton pump inhibitors can be used in pa-
tients with incomplete response to even enteric-coated
minimicrospheres.
48
In addition, bowel decontamina-
tion, supplementation of bile acids, and probiotics may
be required to lessen the inflammatory response in the
intestine, and to allow optimal efficacy of the pancreatic
enzyme replacements in controlling clinical signs and
symptoms of pancreatic insufficiency.
16

Case: diagnosis and reCoMMendations
The patient has CP, which, most likely, is alcoholic in
origin. He already has symptomatic exocrine pancre-
atic insufficiency that is manifested by malabsorption,
steatorrhea, and malnutrition. Management should in-
clude counseling about alcohol abstinence to prevent
further damage to the pancreas and other organs (and,
perhaps, to decrease malabsorption by a theoretical
increase in gastric lipase). The patient may need refer-
ral to a substance abuse program to help him achieve
abstinence.
Additionally, this patient should be evaluated and
monitored by a nutritionist, who will counsel him
about caloric needs while he is being treated for exo-
crine pancreatic insufficiency. Finally, since the patient
has significant steatorrhea, pancreatic enzyme replace-
ment must be instituted. Treatment with any enteric-
coated formulation, which will avoid polypharmacy
and may improve adherence, is recommended. It is
important to emphasize the timing of administration
with meals. The choice of formulation should be based
on the lipase activity of the pancreatic extract and the
number of units needed (1 IU is approximately equal
to 3 USP units) to improve the steatorrhea. In this pa-
tient, supplementation with water-miscible, fat-soluble
vitamins may be required as well.
gauging resPonse to theraPy
The response to treatment of exocrine pancreatic insuf-
ficiency traditionally is measured clinically by weight
(gain or absence of loss) and improvement in the ste-
atorrhea-related symptoms. However, these measure-
ments may not be completely accurate. More objective
tests, such as the 13C-mixed triglyceride breath test,
have been shown to be abnormal in patients with mal-
nutrition, even though clinical response to pancreatic
enzyme replacement appeared to be adequate.
18
Thus,
an evaluation of fat digestion and absorption in re-
sponse to therapy may be desirable.
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the course of pancreatic dysfunction in alcoholic pancreatitis.
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20 CHRONIC PANCREATITISAUGUST2009
Case: a Middle-aged Man
with abdoMinal Pain
A 45-year-old white man presents to the emergency
room with unrelenting abdominal pain that radiates
to the back. He has low-grade fever, nausea, and vom-
iting. His medical history shows chronic pancreatitis
(CP) that was diagnosed by a computed tomographic
(CT) scan two years earlier. More recently, he reports
bloating and distention, as well as a 20-lb weight loss
during the last three months.
The patient has been a bartender for 10 years. He
has four to six drinks per day, smokes two packs of
cigarettes daily, and takes three to five oxycodones
daily.
The patients physical exam shows a man in acute
distress: pulse, 100 beats/min; blood pressure, 149/95
mm Hg; temperature, 100.4F (38C); respiration rate,
20 breaths/min (regular); body mass index, 20th per-
centile. An abdominal exam reveals diffuse tender-
ness; there is no rebound tenderness.
His laboratory tests show the following:
Complete blood count: white blood cell count,
10,000/mm
3
; hemoglobin, 11.58 g/dL; platelets,
280,000/mm
3
; and hematocrit, 36%.
Triglycerides, 138 mg/dL.
Serum electrolytes and creatinine: sodium, 148
mmol/L; potassium, 4 mmol/dL; glucose, 150 mg/
dL; calcium, 7.5 mg/dL; and creatinine, 1.6 mg/dL
Pancreatic enzymes: serum amylase, 125 U/L;
serum lipase, 100 U/L.
Liver tests: albumin, 2.6 g/dL; bilirubin, 1.2 mg/dL;
aspartate aminotransferase, 100 IU/L; and alanine
aminotransferase, 70 IU/L.
A CT scan reveals CPscattered calcifications, at-
rophy of the pancreas, and dilation of the main
pancreatic duct.
ChroniC PanCreatitis:
diagnosis and treatMent
The number of hospital admissions for acute pancreati-
tis and CP is increasing worldwide. In a recent British
study, age-standardized hospital admission rates for
acute pancreatitis between 1989 to 1990 and 1999
to 2000 rose by 43%, while those for CP increased
100%.
1
The dynamics of CP are also changing. While
worldwide CP is largely related to alcohol abuse in sus-
ceptible patients, CP is occurring more frequently in
people who dont drink.
2
Some patients develop CP and exocrine pancreatic
insufficiency (EPI) after one attack of acute pancreatitis
from either gallstone disease or endoscopic retrograde
cholangiopancreatograpy (ERCP)induced acute pan-
creatitis.
3
In one study, 34 patients who had recov-
ered from biliary or post-ERCP acute pancreatitis were
evaluated five years later; the participants had had one
attack of acute pancreatitis and were symptom-free at
follow-up.
3
The findings showed that 65% of patients
had exocrine insufficiency, and 35% had endocrine
insufficiency. In addition, patients quality of life was
significantly impaired. (It is important to appreciate
that CPas documented by atrophy on an abdominal
CT scan, calcifications in the pancreas, or enlargement
of the main pancreatic ductmay lead to EPI in about
40% of patients, based on the authors clinical experi-
Pancreatic enzyme therapy:
improving nutritional health of
Patients with exocrine Pancreatic
insufficiency and steatorrhea
Phillip toskes, Md
Pancreaticenzymetherapyimprovesqualityoflifeformostpatientswithexocrinepancreatic
insufficiency,althoughsteatorrheamaynotresolve.Manyclinicianswhotreatpatientswith
chronicpancreatitisrecommendearlyuseofpancreaticfunctiontests,leadingtoprompt
treatmentwithpancreaticenzymetherapy.
dr. toskes is professor of medicine, at the University of Florida
College of Medicine in Gainesville.
AUGUST2009CHRONIC PANCREATITIS 21
ence. However, an abnormal CT scan
does not mean that the patient has EPI
but that the patient has CP.)
diagnosing exocrine Pancreatic
insufficiency
These remarkable data are challenging
clinicians to understand when and how
pancreatic enzyme therapy should be
used in CP patients. According to many
clinicians who take care of CP patients,
enzyme therapy is greatly underused. It
is important to evaluate patients for EPI
by using pancreatic function tests.
Exocrine pancreatic insufficiency
is caused by a generalized reduction
in pancreatic enzyme production and
delivery, leading to severe impairment
in fat absorption. Patients with EPI
manifest lethargy, weakness, and abdominal pain.
Consequences of exocrine pancreatic insufficiency are
listed in Table 1.
4
Serum trypsinogen and fecal elas-
tase tests are easy to perform, noninvasive, and conve-
nient.
5,6
Serum trypsinogen lower than 20 ng/mL and
fecal elastase lower than 100 mg/g stool strongly indi-
cate severe EPI.
5,6
Using these simple tests will identify
not only patients who have pancreatitis but also those
who have the severe damage that characterizes EPI.
Both tests are widely available at many commercial
laboratories. It behooves the clinician to embrace these
tests and to use them to manage severe EPI. In one
study of patients with alcoholic CP, exocrine insuffi-
ciency occurred at a mean of 5.65 years after diagnosis
and was nearly universal in patients with disease for
longer than 10 years.
7

The clinical diagnosis of steatorrhea and EPI is
reached relatively late in the course of pancreatitis.
Because pancreatic function tests often are not per-
formed in patients with CP demonstrated by CT, many
patients who may have had EPI but not severe diarrhea
or weight loss are not started on pancreatic enzyme
therapy. The utilization of serum trypsinogen and fe-
cal elastase tests should allow for quicker detection of
EPI and more aggressive use of pancreatic enzymes.
A recent study suggests that steatorrhea may occur at
an earlier age than previously thought and may have
important nutritional consequences.
8
Dumasy and
colleagues studied 60 patients with well-established
CP, most of whom had advanced disease; 18 patients
(30%) had clinical signs and symptoms suggestive of
steatorrhea, and 42 did not.
8
The authors used a test,
the acid steatocrit, not commonly performed in the
United States, to demonstrate steatorrhea. Many non-
symptomatic patients had an abnormal acid steatocrit;
these test results suggested that steatorrhea is much
more common in patients with advanced CP than has
been suspected, especially if CP has been present for
more than 10 years.
Too many clinicians wait to consider enzyme treat-
ment until after the patient shows severe diarrhea
and weight loss. I believe that practice must change.
Pancreatic function tests, such as serum trypsinogen
and fecal elastase, should be used to define deficiency
of pancreatic function, which can be restored with the
use of pancreatic enzymes.
Every patient diagnosed with CP should be eval-
uated for EPI at least once a year if he or she does
not manifest symptoms of diarrhea, steatorrhea, and
weight loss. If these symptoms are present, both the
serum trypsinogen and fecal elastase tests should be
performed. If elastase is less than 100 mg/g stool or
the trypsinogen is less than 20 ng/mL, the patient
should begin taking pancreatic enzymes. Too many
patients are allowed to deteriorate before ezymes are
prescribed. After enzymes are started, clinicians should
follow their patients progress by assessing weight gain,
general well-being, and other health parameters. An
international study (for which data are being analyzed)
compared both tests in patients with demonstrated el-
evation of quantitative fecal fat. I anticipate that the
findings will define the relative merits of serum tryp-
sinogen and fecal elastase in documenting EPI.
Pancreatic enzyme issues
Proof of efficacy and safety of pancreatic enzyme
preparations have not been required because these
agents were used for many years before the New Drug
Application (NDA) process at the Food and Drug
table 1. Consequences of exocrine Pancreatic
insufficiency
deficiency outcome
Vitamin A Night blindness
Vitamin D Osteomalacia, hypocalcemia
Vitamin E Neuropathy, hemolytic anemia
Vitamin K Coagulopathy
Fat malabsorption Weight loss
Hypoproteinemia Edema
Carbohydrate malabsorption Bloating, diarrhea
Source: Pezzilli R.
4
PANCREATIC ENZYME THERAPY
22 CHRONIC PANCREATITISAUGUST2009
Administration (FDA) was instituted. In April 2004, the
FDA reported that currently marketed enzyme prepara-
tions varied greatly in their composition, enzymatic
activities, formulation, stability, and bioavailability.
9

These variations in product content led to highly
variable enzyme preparation quality and potentially
inconsistent clinical results. The FDA mandated that
new randomized controlled trials must be submitted
as part of NDAs for any pancreatic enzyme marketed
in the United States. All pancreatic enzyme prepara-
tions must meet certain standards, including delivery
of enzymes to the proximal small bowel; demonstrated
improvement of fat absorption in patients with cys-
tic fibrosis; demonstrated increased fat absorption in
adult patients with chronic pancreatitis and EPI; and
loss of no more than 15% of activity within a year.
9

Manufacturers are required to provide safety and ef-
ficacy data for the enzyme products. If these mandates
are met, the overfilling that has been practiced with
pancreatic enzyme preparations no longer would be
needed. Because of overfilling, the exact quantity of
each enzyme and its stability has been difficult to as-
certain. Waljee and associates recently conducted a sys-
tematic review of the design and results of randomized
parallel trials of pancreatic enzyme supplements in CP
patients with steatorrhea.
10
A computer-assisted search
of MEDLINE and EMBASE identified relevant studies.
Of 619 articles found in the literature, 20 potentially
relevant articles were identified; four manuscripts met
inclusion criteria. No studies performed head-to-head
comparisons of supplements. Important differences
in patient population, study endpoint, study design,
pancreatic enzyme dosage, and measurement of coef-
ficient of fat absorption (CFA) were present across tri-
als, which precluded comparison of different agents.
All studies quantified steatorrhea by CFA. Because the
studies were short term, no data could be obtained on
weight gain or weight loss while patients were on the
supplements. All studies were randomized and double-
blind, and had appropriate patient follow up.
Waljee and associates concluded that enzyme sup-
plementation is more likely than placebo to improve
CFA, but fat malabsorption remained abnormal.
10

Enzyme supplementation improved fat absorption in
all patients in the studies, but the values for mean CFA
or fecal weight remained abnormal, which indicated
that steatorrhea was not abolished.
The finding that enzyme supplementation improves
CFA compared with placebo, but may not completely
abolish steatorrhea, should have been expected. Because
of the paucity of data in the literature, the FDA was
correct in determining that pancreatic enzyme supple-
mentation data were insufficient. It was appropriate to
suggest, therefore,
that new random-
ized controlled
trials should be
conducted. Too
often, a patients
diagnosis is based
on a CT-scan ab-
normality with
no evidence of
functional defi-
ciency. Indeed, in
one study, all 64
patients with CP
were thought to
have EPI and were
taking pancreatic
enzyme prepara-
tions prior to the run-in phase.
11
However, when quanti-
tative stool fats were measured, only 27 patients had in-
creased fecal fat excretion. It should be noted that most
randomized trials of pancreatic enzyme supplementa-
tion are only 14 days long, which may not be adequate
to assess the impact of supplementation on weight gain.
Additionally, the trials may not be long enough to as-
sess the safety and tolerability of these supplements,
although long-term labeled trials would meet this need.
The recommended dose of pancreatic enzyme supple-
mentation, certainly in children, should not be more
than 10,000 units of lipase per kg. Higher doses of pan-
creatic enzyme supplementation are associated with a
10-fold increase in fibrosing colonopathy.
12

In reality, management of patients with steatorrhea
secondary to EPI can be carried out quite well with a
good pancreatic enzyme preparation, usually in a two-
capsule dose with each meal.
It is preferable to administer a proton pump inhibi-
tor with a nonenteric-coated enzyme preparation.
2

The data do not support more frequent dosing than
with each meal, especially in adult patients with EPI.
13

With this approach, diarrhea will decrease remark-
ably in most patients, along with less bloating and
pain, improved weight gain, increased strength, and
less lethargy. Data from the few reports of individuals
who did not have cystic fibrosis but who were thought
to develop fibrosing colonopathy are quite rare and
not convincing to me. In my large pancreatitis referral
practice, I have never observed this complication in
an adult who did not have cystic fibrosis. Side effects
of pancreatic enzymes are quite uncommon; most pa-
tients tolerate these preparations well (Table 2).
14

All pancreatic enzyme formulations, both those
now in use and new formulations, must be approved
table 2. side effects of
Pancreatic enzymes
Folic acid deficiency
Hyperuricemia
Allergy to pork
Hypersensitivity following
inhalation
Abdominal pain
Constipation
Colonic strictures
Source: Lebenthal E, et al.
14
TOSKES
AUGUST2009CHRONIC PANCREATITIS 23
by the FDA before April 2010. In May 2009, the FDA
approved a pancrelipase delayed-release capsule for
treatment of EPI.
15
In a randomized, double-blind,
crossover trial of 32 patients with cystic fibrosis, pan-
crelipase was significantly more effective than placebo
on the primary endpoint of CFA. At least four other
pancrelipase products are marketed under different
names; because these products predated modern FDA
regulations, they, too, must now be approved to re-
main on the market.
16
The newly approved capsules
will contain the precise amount of lipase specified on
the label. Pancreatic enzyme product capsules typi-
cally used to be overfilled based on manufacturing
standards that allowed a range of lipase content from
90% to 165% of label claims. The FDAs new ruling
requires a zero overfill target.
16

Case: diagnosis and reCoMMendations
The patient is admitted to the hospital for pain control
and management of nausea. He improves quickly and
is told to see his primary care provider (PCP) is within
two weeks. He is discharged after 48 hours.
The patients PCP confirms that the patient is back
to his normal baseline of chronic abdominal pain for
several days of each week. However, the PCP notes that
the patient is requesting increasing amounts of narcot-
ics and continues to have bloating, abdominal pain,
remarkable abdominal distention, and weight loss.
The PCP refers the patient to a gastroenterologist,
who obtains a serum trypsinogen, which is very low (ie,
less than 5 ng/mL), and a fecal elastase, which is also
very low (36 mg/g). Both of these tests indicate severe
EPI. Fat-soluble vitamins are measured (normal ranges
are in parentheses), showing 25-hydroxy vitamin D,
16 (30 to 80 mg/mL); vitamin E, alpha tocopherol, 15
(5.5 to 18 mg/L), and gamma tocopherol, 1.2 (0 to 6
mg/L); and carotene, 11 (20 to 40 mg/dL). Prealbumin
is 11 (20 to 40 mg/dL), reflecting malnutrition.
The gastroenterologist prescribes a pancreatic en-
zyme preparation, two capsules with each meal; 1,200
mg calcium with vitamin D twice daily; and a diet
of high protein, moderate fat, and moderate carbo-
hydrates.
ConClusion
Pancreatic enzyme treatment leads to a better quality
of life, even though, in most patients, steatorrhea is not
completely abolished. If a patient with EPI does not
respond to pancreatic enzymes within two weeks, the
clinician should consider other possibilities, such as
small-intestine bacterial overgrowth due to GI surgery,
hypomotility of the intestine from chronic abdomi-
nal pain, or frequent use of narcotics.
17
Patients with
these conditions may need both pancreatic enzymes
and antibiotics before diarrhea and steatorrhea can be
managed effectively.
referenCes
1. Tinto A, Lloyd DAJ, Kang JY, et al. Acute and chronic pancre-
atitisdiseases on the rise: a study of hospital admissions in
England 1989/90- 1999/2000. Aliment Pharmacol Ther. 2002;
16(12):20972105.
2. Gupta V, Toskes PP. Diagnosis and management of chronic pan-
creatitis. Postgrad Med J. 2005;81(958):491497.
3. Symersky T, van Hoorn B, Masclee AA. The outcome of long-
term follow-up of pancreatic function after recovering from
acute pancreatitis. JOP. 2006:7(5):447453.
4. Pezzilli R. Chronic pancreatits: maldigestion, intestinal ecol-
ogy and intestinal infammation. World J Gastroenterol.
2009;15(14):16731676.
5. Jacobsen DG, Curington C, Connery K, Toskes PP. Trypsin-like
reactivity immunoreactivity as a test for pancreatic insuffcien-
cy. N Engl J Med. 1984:310(20):13071309.
6. Muench R, Ammann R. Fecal immunoreactive lipase: a
new tubeless pancreatic function test. Scand J Gastroenterol.
1992:27(4):289294.
7. Lser C, Mllgaard A., Flsch UR. Fecal elastase 1: a novel,
highly sensitive, and tubeless pancreatic function test. Gut.
1997:39(4):580586.
8. Dumasy V, Delhaye M, Cotton F, Deviere J. Fat malabsorp-
tion screening in chronic pancreatitis. Am J Gastroenterol.
2004;99(7):13501354.
9. Food and Drug Administration. FDA requires pancreatic ex-
tract manufacturers to submit marketing applications. Avail-
able at www.fda.gov/NewsEvents/Newsroom/PressAnnounce-
ments/2004/ucm108289.htm. Accessed July 3, 2009.
10. Waljee AK, Dimagno MJ, Wu BU, Schoenfeld PS, Cornwell DL.
Systematic review: pancreatic enzyme treatment of malabsorp-
tion associated with chronic pancreatitis. Aliment Pharmacol
Ther. 2009;29(3):235246.
11. Safdi M, Bekal PK, Martin S, Saeed ZA, Burton F, Toskes PP. The
effects of oral pancreatic enzymes (Creon 10 capsule) on steat-
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subjects with chronic pancreatitis. Pancreas. 2006;33(2):156162.
12. FitzSimmons SC, Burkhart GA, Borowitz D, et al. High-dose pan-
creatic-enzyme supplements and fbrosing colonopathy in chil-
dren with cystic fbrosis. N Engl J Med. 1997;336(18):12831289.
13. Domnguez-Muoz JE, Iglesias-Garcia J, Iglesias-Rey M, Fiquei-
ras A, Vilario-Insua M. Effect of the administration schedule
on the therapeutic effcacy of oral pancreatic enzyme supple-
ments in patients with exocrine pancreatic insuffciency: a ran-
domized, three-way cross-over study. Aliment Pharmacol Ther.
2005;21(8):9931000.
14. Lebenthal E, Rolston DD, Holsclaw DS Jr. Enzyme therapy for
pancreatic insuffciency: present status and future needs. Pan-
creas. 1994;9(1):112.
15. Barclay L. FDA approves Creon delayed release capsules for pan-
creatic insuffciency. Published May 7, 2009. Available at www.
medscape.com/viewarticle/702489. Accessed July 9, 2009.
16. Phend C. FDA formally approves creon pancrelipase. Published
May 1, 2009. Available at www.medpagetoday.com/Product
Alert/Prescriptions/14021. Accessed July 9, 2009.
17. Lembcke B, Kraus B, Lankisch PG. Small intestinal function in
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151.
1. Long-term, excessive alcohol ingestion is the most common cause of
chronic pancreatitis (CP) in the developed countries of the West.
a.True b.False
2. Cigarette smoking may increase the risk for, and accelerates the rate of,
progression of alcoholic CP.
a.True b.False
3. Early-onset idiopathic CP (ICP) differs from late-onset ICP in the
following way:
a.Approximately50%ofearly-onsetpatientspresent
withoutabdominalpain.
b.Themajorityoflate-onsetpatientshaveseverepain.
c.Late-onsetICPpeaksintheseventhdecade(medianage,66).
d.Painismoderatetoseverein80%ofpatientswithearly-onsetICP.
4. The mean age of onset of alcoholic CP is:
a.30 c.65
b.44 d.58
5. Which of the following statements is true regarding genetic mutations
predisposing to CP?
a.ArecentstudyfoundvariantsinchymotrypsinCtobeassociatedwith
onlyhereditaryCP.
b.Thehighprevalence(~2%)ofserineproteaseinhibitor,Kazaltype1,
inthegeneralpopulationsuggeststhatitpredisposestoratherthan
causespancreatitis
c.MilderimpairmentinCFTRfunctionmeansthataffectedcysticfibrosis
patientsareatlessriskforclinicalepisodesofacutepancreatitis
d.ThemajorityofpatientswithidiopathicCP(especiallyofearlyonset)
harboratleastoneCFTRmutation
6. In diagnosing CP in its early stages, clinicians should recognize that:
a.Painispresent,tosomedegree,inallpatients.
b.Painmaybeabsentinmorethan10%ofpatients.
c.Directpancreaticsecretoryassessmentremainsthegold
standardfordiagnosingpancreaticinsufficiency.
d.Radiographicimagingconfirmspancreatitisinearlystages
ofthedisease.
7. In the proper clinical setting (typical abdominal pain), confirmation of
steatorrhea may be sufficient to diagnose CP.
a.True b.False
8. Which of the following statements about imaging and endoscopic testing
for CP is true?
a.Themostsensitivetestisaplainabdominalx-ray.
b.Endoscopicultrasoundisthemostspecifictest.
c.Acontrast-enhancedCTscanoftheabdomenistheinitialimaging
modalityofchoicebecauseitisreasonablysensitiveandspecificat
arelativelylowcost.
d.Magneticresonancecholangiopancreatographycannotdetectpancre-
aticductsnoninvasively.
9. Pancreatic exocrine insufficiency is characterized by:
a. Thepancreaslosingmorethan90%ofitssecretivecapacity.
b. Maldigestionoffatresultingfromcarbohydrateandproteinmaldiges-
tion.
c. Maldigestionandmalabsorptionoflipids,leadingtodiarrheacharac-
terizedbysteatorrhea,weightloss,andmalnutrition.
d. Proteinandstarchmaldigestionoccurringearlyinthediseasecourse.
10. The nutritional management of pancreatic enzyme insufficiency includes
high-volume meals.
a.True b.False
11. Pancreatic enzyme replacement requires that:
a. 30,000IUormorelipasebeingestedwitheachmealtoendorpre-
ventsteatorrhea.
b. 20,000USPormorelipasebeingestedwitheachmealtoendorpre-
ventsteatorrhea.
c. 30,000IUormoreamylasebeingestedwitheachmealtoendorpre-
ventsteatorrhea.
d. Enzymesbegivenbeforemeals.
12. With regard to pancreatic enzyme replacement formulations, uncoated
microencapsulated formulations are susceptible to excessive inactiva-
tion by gastric acid.
a.True b.False
13. The clinical diagnosis of exocrine pancreatic insufficiency (EPI):
a. isreachedrelativelyearlyinthecourseofchronic
pancreatitis.
b. invariablyinvolvesseverediarrhea.
c. invariablyinvolvesweightloss.
d. includeslethargy,weakness,andabdominalpain.
14. According to an analysis of pancreatic enzyme supplements conducted
by Waljee and colleagues:
a. enzymesupplementationimprovedfatabsorptioninpatientsinall
studies.
b. valuesformeancoefficientoffatabsorptionreachednormalrange.
c. valuesforfecalweightreachednormalrange.
d. onlyfourstudiesconductedhead-to-headcomparisonsofdifferent
supplements.
15. Regarding use of pancreatic enzyme supplements:
a. Sideeffectsarecommon.
b. Aprotonpumpinhibitorshouldbeadministeredwithanon
enteric-coatedenzymepreparation.
c. Thedatasupportprescribingpancreaticenzymesupplements
witheachmeal,plusanadditionaldoseatbedtime,inadults
withalcoholicchronicpancreatitis.
d. Steatorrheaiscompletelyabolishedinmostpatients.
5691-ES-34
To apply for continuing medical education credit, read
this self-study supplement and complete the posttest and
evaluationonthenextpage.Yourposttest/evaluationmustbe
postmarked or faxed prior to August 31, 2010. Participants
must attain a minimum score of 70% to receive continuing
medicaleducationcredit.Acertificateverifyingyourcreditwill
bemailedtoyouwithinthreeweeksofreceipt.
Select the single best answer for each of the following questions and mark your answer on the answer form.
CME Test: Chronic Pancreatitis
EvaluaTion FoRM
ChRoniC PanCREaTiTis Project ID: 5691-ES-34
To assist us in evaluating the effectiveness of this activity and to make recommendations for future educational offerings, please take a few minutes to complete this
evaluation form. You must complete this evaluation form to receive acknowledgment for completing this activity.
1 = Strongly Disagree 2 = Disagree 3 = Neutral 4 = Agree 5 = Strongly Agree
Posttest Answer Key
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Early-onset idiopathic chronic pancreatitis affects men and women equally.
1 2 3 4 5
A CT scan revealing a pancreatic mass in the head of the pancreas may
indicate a diagnosis of autoimmune pancreatitis.
1 2 3 4 5
Currently there are no physiological tests available to aid in making a
definitive, early diagnosis of pancreatitis.
1 2 3 4 5
Patients with acute pancreatitis due to biliary obstruction are not at risk
for progression to chronic pancreatitis.
1 2 3 4 5
To avoid nutritional deterioration, early screening for fat malabsorption
should be recommended in all patients with chronic pancreatitis.
1 2 3 4 5
The heavy exposure to alcohol resulting in alcoholic chronic pancreatitis may
be many years, even decades, prior to the onset of symptomatic disease.
1 2 3 4 5
All currently available pancreatic enzyme preparations must complete the
new drug application process and be approved by the FDA no later than
May 2010 to remain on the market.
1 2 3 4 5
Extent to Which Program Activities Met the Identified
Objectives
After completing this activity, I am now better able to:
Explain the epidemiology and pathophysiology of chronic pancreatitis.
1 2 3 4 5
State the complications of pancreatic exocrine insufficiency (PEI) and
malabsorption.
1 2 3 4 5
Discuss the symptoms and diagnosis of chronic pancreatitis.
1 2 3 4 5
Explain the importance of treating PEI to improve patient outcomes.
1 2 3 4 5
Discuss the role of pancreatic enzyme therapy in improving nutritional health
of patients suffering from chronic pancreatitisassociated PEI and steatorrhea,
including appropriate dosing of such therapy.
1 2 3 4 5
Impact of the Activity
Name one thing you intend to change in your practice as a result of completing this activity:

Please list any topics you would like to see addressed in future educational activities:

Additional comments about this activity:

Follow-up
As part of our continuous quality improvement effort, we conduct postactivity follow-up surveys to assess the impact of our
educational interventions on professional practice. Please indicate if you would be willing to participate in such a survey:
o Yes, I would be interested in participating in a follow-up survey.
o No, Im not interested in participating in a follow-up survey.
If you wish to receive acknowledgment for completing this activity, please complete the posttest by selecting
the best answer to each question, complete this evaluation verification of participation, and fax to: (303) 790-4876.
Overall Effectiveness of the Activity
The content presented:
Was timely and will influence how I practice.
1 2 3 4 5
Enhanced my current knowledge base.
1 2 3 4 5
Addressed my most pressing questions.
1 2 3 4 5
Provided new ideas or information I expect to use.
1 2 3 4 5
Addressed competencies identified by my specialty.
1 2 3 4 5
Avoided commercial bias or influence.
1 2 3 4 5
Request for Credit
Name Degree
Organization Specialty
Address City, State, ZIP
Telephone Fax Email
Signature Date
For Physicians Only
I certify my actual time spent to complete this educational activity to be:
o I participated in the entire activity and claim 1.5 credits. o I participated in only part of the activity and claim _____ credit.
Project ID: 5691-ES-34
To what extent do you agree with the following statements? (Please circle the appropriate number on the scale.)

Chronic Pancreatitis (LitReview - 2009)

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August 2009

A Supplement to Clinician Reviews

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