SEMINAR

Seminar

Pancreatitis

R M S Mitchell, M F Byrne, J Baillie

In the past decade, our understanding of the genetic basis, pathogenesis, and natural history of pancreatitis has grown
strikingly. In severe acute pancreatitis, intensive medical support and non-surgical intervention for complications keeps
patients alive; surgical drainage (necrosectomy) is reserved for patients with infected necrosis for whom supportive
measures have failed. Enteral feeding has largely replaced the parenteral route; controversy remains with respect to use
of prophylactic antibiotics. Although gene therapy for chronic pancreatitis is years away, our understanding of the roles
of gene mutations in hereditary and sporadic pancreatitis offers tantalising clues about the disorder’s pathogenesis. The
division between acute and chronic pancreatitis has always been blurred: now, genetics of the disorder suggest a
continuous range of disease rather than two separate entities. With recognition of pancreatic intraepithelial neoplasia,
we see that chronic pancreatitis is a premalignant disorder in some patients. Magnetic resonance cholangio-
pancreatography and endoscopic ultrasound are destined to replace endoscopic retrograde cholangiopancreatography
for many diagnostic indications in pancreatic disease.

Two entities of pancreatitis exist: acute and chronic. We
discuss the pathogenesis, diagnosis, and treatment of each
type of this disorder.
Pathogenesis of acute pancreatitis
Although risk factors for acute pancreatitis have been
known for some time, the pathophysiology is only now
being elucidated. Most patients with this disorder have
minimum organ dysfunction, and recovery is uneventful.
However, 10–15% of patients develop systemic
inflammatory response syndrome (SIRS), leading to a
fulminant course with pancreatic necrosis and multiorgan
failure. SIRS seems to be caused by activation of an
inflammatory cascade mediated by cytokines,
immunocytes, and the complement system. Inflammatory
cytokines cause macrophages to migrate into tissues distant
to the pancreas, including the lungs and kidneys.
Immunocytes attracted by cytokines released from
macrophages release more cytokines, free radicals, and
nitric oxide.1,2 Some of these cytokines are implicated in
disease progression—eg, interleukin 1 and tumour necrosis
factor (TNF); interleukins 6 and 8 are useful for monitoring
course of disease.3 Administration of an antagonist of
interleukin 1 or anti-TNF has reduced severity and
improved survival in rats with acute pancreatitis.4,5
Although administration of interleukin 10 has been
similarly effective in animals,6,7 its use in patients after
endoscopic retrograde cholangiopancreatography (ERCP)
has produced conflicting results.8 Despite showing early
promise in animals and people, the platelet-activating factor
antagonist lexipafant probably has a clinically insignificant
effect on SIRS or mortality in severe acute pancreatitis.9
Inappropriate activation of the proteolytic enzyme trypsin
is thought to be the initial step in development of
pancreatitis. Trypsinogen is activated through hydrolysis of
an N-terminal peptide called trypsinogen-activating
Lancet 2003; 361: 1447–55
Division of Gastroenterology, Duke University Medical Center,
Durham, NC, USA (R M S Mitchell MBBCh, M F Byrne MD,
Prof J Baillie MBChB)
Correspondence to: Prof John Baillie, Box 3189 Duke South,
Duke University Medical Center, Durham, NC 27710, USA
(e-mail: baill001@mc.duke.edu)
peptide. In rats, this peptide has been used to localise the
site of activation of trypsinogen within the pancreatic acinar
cell to small cytoplasmic vacuoles.10,11 Several different
mechanisms prevent pancreatic autodigestion by activated
trypsin. These include: production of serine protease
inhibitor Kazal type 1 (SPINK1; also known as pancreatic
secretory trypsin inhibitor [PSTI]), which reversibly
inhibits activated trypsin; trypsin-activated trypsin-like
enzymes—eg, mesotrypsin—that degrade trypsinogen; and
bicarbonate-rich secretions, which are affected by abnormal
production of cystic fibrosis transmembrane conductance
receptor (CFTR). SPINK1 inhibits up to 20% of potential
trypsin within the pancreas in the event that trypsinogen
becomes prematurely activated. The N34S mutation in
SPINK1, identified by Chen and colleagues,12 has been
reported in people with familial pancreatitis and in children
with idiopathic chronic pancreatitis,13,14 and in 2% of
control populations.13–15 Since SPINK1 mutations are much
more common than pancreatitis, this protein probably acts
as a disease modifier, rather than causing pancreatitis by
itself.
In 1996, Whitcomb and colleagues16 identified the third
exon of the cationic trypsinogen gene on chromosome 7q35
as the gene that causes hereditary pancreatitis. This
disorder is autosomal dominant, and 80% of individuals
with the susceptibility gene develop recurrent acute
pancreatitis; all those with penetrance (about 80%) develop
chronic pancreatitis, and up to 40% of those with
hereditary pancreatitis could go on to develop pancreatic
cancer.17,18 The clinical and pathological features of these
patients are identical to those of individuals with sporadic
pancreatitis. The first mutation identified consisted of an
arginine to histidine substitution at codon 122 (R122H);
this mutation causes a conformational change in the
Search strategy and selection criteria
We did a Medline search of reports published in English, with
the keywords acute pancreatitis, chronic pancreatitis,
hereditary pancreatitis, idiopathic pancreatitis, CFTR, SPINK,
cationic trypsinogen, pancreatic cancer. We reviewed the
Cochrane database with respect to enteral versus parenteral
feeding in acute pancreatitis. To evaluate treatments for acute
and chronic pancreatitis, we concentrated on data from
prospective randomised clinical trials.

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SEMINAR
3-dimensional structure of the trypsinogen-SPINK1
complex and might impair activity of the SPINK1 defence
mechanism against activated trypsin.16,19 Further
mutations—eg, A16V, K23R, N291, N29T, R122C—have
been identified in close proximity to the cationic trypsinogen
gene, which seem to confer susceptibility to hereditary
pancreatitis. These gene defects could enhance trypsin
activity by promotion of autoactivation of trypsinogen or
reduction of degradation of active trypsin.16,20 Many of these
mutations have been noted in patients with idiopathic
chronic pancreatitis that has no obvious hereditary
basis.16,21–25
Risk factors and presentation of acute
pancreatitis
Acute pancreatitis is an acute inflammatory process of the
pancreas, with variable involvement of peripancreatic tissues
and remote organ systems.26 A range of morphological
findings exists, from interstitial oedema in mild disease to
confluent areas of necrosis and haemorrhage in severe
disease. In severe acute pancreatitis, multiorgan failure is the
usual cause of early death. Local complications of severe
disease include pseudocyst, abscess, and pseudoaneurysm
formation. Although overall mortality of acute pancreatitis
ranges from 2% to 10%,27 in 80% of patients the disorder is
mild and self-limiting, with minimum mortality. In severe
disease, however, the mortality rate can be as high as 25% in
the presence of infected pancreatic necrosis.28 Sepsis is the
usual cause of late mortality in severe acute pancreatitis.
Gallstones are the leading cause of acute pancreatitis in
developed countries; including microlithiasis, gallstones can
account for more than 90% of cases worldwide. Alcohol
abuse is typically cited as a close second to gallstones;
however, whether acute alcoholic pancreatitis ever arises in
the absence of chronic injury to the gland is hotly debated.
Infrequent—but not rare—causes of the disorder include:
drug reaction (usually idiosyncratic); pancreatic and
ampullary tumours; hypertriglyceridaemia; hypercalcaemia
(almost always due to hyperparathyroidism); hypothermia;
congenital anomalies of pancreatic and biliary anatomy (eg,
choledochocele); trauma (including iatrogenic damage,
such as ERCP); and infectious or parasitic organisms. Rare
causes include bites of certain spiders, scorpions, and the
Gila Monster lizard. Cases without obvious cause are
referred to as idiopathic. The roles of sphincter of Oddi
dysfunction, pancreas divisum, and bile crystals or sludge
are less clear. Advances in radiology and intensive medical
management have led to a shift away from early surgery for
pancreatic necrosis to treatment of local complications by
endoscopic29 or percutaneous30 methods, which is
considered by some—including us—to have improved
survival.31
Diagnosis of acute pancreatitis
Diagnosis of acute pancreatitis can be difficult, as shown by
the many cases diagnosed at autopsy.32 The clinical history
of upper-abdominal pain and vomiting are characteristic of
several acute disorders. The signs of Cullen and Grey-
Turner (periumbilical and flank bruising, respectively) are
rare, and can arise in any disease that causes retroperitoneal
haemorrhage. A rise in concentration of serum amylase is
expected in acute pancreatitis, but this increase is not always
seen. Although normoamylasaemia has been said to arise in
up to 30% of cases, by definition, the denominator cannot
be known. We feel that normoamylasaemic pancreatitis
probably arises in fewer than 10% of cases, some of which
undoubtedly show the rapid urinary clearance of amylase
and missed (transient) amplification of serum amylase.
Combination of the serum amylase value with results of
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either CT or ultrasound of the pancreas and biliary tree
leads to the correct diagnosis in 81–95% of patients.33,34
Amplification of time from onset of pain to measurement,35
alcohol as the primary causal factor,36 and presence of
hypertriglyceridaemia37 all reduce the sensitivity of serum
amylase estimation.
Serum lipase concentration rises within 4–8 h of an
episode of acute pancreatitis, peaks at 24 h, and returns to
normal after 8–14 days,38 making it a useful diagnostic
method in patients presenting late (eg, >24 h from onset of
pain). Lipase estimation is also more sensitive than that of
amylase in alcohol-induced acute pancreatitis. Although
amplification of serum lipase concentration is not specific to
this disorder, a value greater than three times the upper limit
of normal excludes most non-pancreatic causes. Other
pancreatic enzymes, such as P-isoamylase, macroamylases,
immunoreactive trypsinogen, and elastase are generally not
considered useful for diagnosis of acute pancreatitis.
Establishment of severity
Prediction of the severity of an attack at the time of
admission can be difficult. Several prognostic scoring
systems, with clinical, laboratory, and radiological criteria,
have been proposed.39–41 Failure of pancreatic parenchyma
to enhance during the arterial phase of intravenous contrast-
enhanced CT indicates necrosis, which predicts a severe
attack, especially if more than 50% of the gland is involved.
The so-called Balthazar Score predicting severity of acute
pancreatitis is based on CT appearances, including presence
or absence of necrosis.42 Development of the Atlanta
Classification for severity has allowed comparison between
trials and methodologies, and a more rational approach to
prediction of severity. This classification defines severe acute
pancreatitis on the basis of standard clinical manifestations,
a score of 3 or more with Ranson criteria, or a score of 8 or
more with APACHE II criteria, and evidence of organ
failure and intrapancreatic pathological findings—ie,
necrosis or interstitial pancreatitis.43 Other markers, such as
obesity, concentration of serum C-reactive protein (CRP),
neutrophil elastase, pancreatitis-associated peptide,
interleukins 6, 8, 1, 10, and soluble TNF receptors, could
have use in early prediction of severity. CRP concentration
has independent prognostic value. A peak of more than
210 mg/L on day 2–4, or more than 120 mg/L at the end of
the first week, could be as predictive as the multiple factor
scoring systems.44 Urinary trypsinogen activation peptide,
which is released during activation of trypsinogen to trypsin,
has been shown to accurately predict severity of acute
pancreatitis 24 h after onset, and might be an appropriate
single marker for severity assessment in clinical practice.45
Treatment strategies in acute pancreatitis
Enteral nutrition
Patients with mild acute pancreatitis can usually begin oral
refeeding within a few days of onset of their pain. In severe
disease attributable to reduced oral intake and presence of a
catabolic state, poor nutrition is a common and serious
problem.43,46–48 Early nutritional support may aid recovery.49
One of the goals of this therapy is to avoid stimulation of the
pancreas.50 Traditionally, this goal has been achieved by
total parenteral nutrition; however, this method is
expensive, and carries a risk of sepsis and metabolic
disturbances.49,51 Enteral feeding has been shown to be safe,
as effective as total parenteral nutrition, and well tolerated in
severe acute pancreatitis.52,53 Enteral nutrition is less
expensive than parenteral feeding, helps to maintain
mucosal function, and limits absorption of endotoxins and
cytokines from the gut.54,55 Pancreatic stimulation can be
avoided by placement of the enteral feeding tube distal to
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the Treitz ligament. Unfortunately, proximal migration of
the feeding tube and subsequent pancreatic stimulation can
aggravate acute pancreatitis, and severe ileus preventing
enteral feeding is common in the early stages of disease.56
Partial ileus (manifest by reduced but not absent bowel
sounds) should not be deemed a contraindication to enteral
feeding; in this setting, patients frequently tolerate
continuous low-volume nasojejunal infusion. In our
institution, we favour laparoscopic or combined endo-
scopic-radiologic jejunostomy tube placement once patients
have shown that they can tolerate nasoenteral feedings for
5–7 days. Results of a randomised study of nasogastric
versus nasojejunal feeding in severe acute pancreatitis
suggested that nasogastric feeding may also be safe, since
little difference in pain, analgesic requirements, serum CRP
concentrations, or clinical outcome was reported between
the two methods.57 Enteral feeding by nasojejunal tube or
percutaneous jejunostomy has largely replaced total
parenteral nutrition in the management of patients with
severely catabolic acute pancreatitis.58
Antibiotics
Use of antibiotics in severe acute pancreatitis remains
contentious: there is concern that their routine use is leading
to a rise in drug-resistant or unusual organisms in
pancreatic sepsis, and possibly even increased mortality
when antibiotics are used inappropriately.59 Results of
studies in the 1970s showed no benefit from routine
antibiotic prophylaxis.60–62 However, the studies were
probably underpowered, because patients with mild acute
pancreatitis, who have a low morbidity and mortality, were
included. In severe disease, secondary infection of necrotic
pancreatic parenchyma is the leading cause of late mortality
(figure 1).63
In the past decade, three randomised studies comparing
antibiotics with no antibiotics in acute necrotising
pancreatitis have been done. Pederzoli and colleagues64
randomly allocated 74 patients with necrotising pancreatitis
from six centres in Italy either imipenem 0·5 g every 8 h for
2 weeks or no antibiotic. Oral antibiotics were used after the
2-week period if recovery was prolonged. In the imipenem
group, a significant reduction in pancreatic and non-
pancreatic sepsis was noted, but not in surgical intervention,
multiorgan dysfunction, or death. In a Finnish study,65
60 patients with acute necrotising pancreatitis were ran-
domly allocated cefuroxime 4·5 g daily or no antibiotic. A
significant reduction in septic complications and death was
seen in the antibiotic group. However, two patients in the
no antibiotic group died very early in the course of their
Figure 1: Contrast-enhanced helical abdominal CT scan
showing severe necrotising pancreatitis
Courtesy of Erik Paulson, Duke University Medical Center.
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SEMINAR
illness, and 76% of patients in the no antibiotic group
received an antibiotic at some point during their admission,
factors that could have skewed results. In the smallest of the
three studies, Delcenserie and colleagues66 randomly
allocated 23 consecutive patients ceftazidime, amikacin,
and metronidazole, or no antibiotic. The incidence of
sepsis—but not mortality—was reduced in the antibiotic
group. Results of a meta-analysis of these trials confirmed a
reduction in mortality in patients with severe acute
pancreatitis treated with antibiotics.67
Buchler and colleagues68 reported that of ten different
antibiotics tested, only imipenem, ofloxacin, and
ciprofloxacin showed adequate tissue penetration and
bactericidal properties to be useful in infected pancreatic
necrosis. Bassi and co-workers59 later randomly allocated
60 patients with necrotising acute pancreatitis either
intravenous pefloxacin 400 mg twice daily or intravenous
imipenem 500 mg three times daily, starting within 120 h of
diagnosis and continuing for 2 weeks. Pancreatic—but not
extrapancreatic—sepsis was reduced in the imipenem
group, but mortality did not differ greatly between the two
groups. The importance of early initiation of antibiotics is
unclear, but in a study, early imipenem-cilastatin therapy
seemed to substantially reduce the need for surgery and the
overall number of major organ complications. Mortality was
also lowered, but did not differ significantly.69 An alternative
strategy for prevention of translocation of bacteria from the
gut into the pancreatic bed is selective decontamination:
conclusive data are absent, but some preliminary results
have been reported from animals70 and work in human
beings.71 At present, the standard of care dictates that
patients with acute pancreatitis complicated by necrosis
should receive a prophylactic, broad-spectrum antibiotic,
typically imipenem.
Therapeutic endoscopy in acute pancreatitis and its
complications
Of four prospective randomised trials that have been
reported, the two most methodologically sound showed
benefit from early ERCP for bile-duct clearance in acute
gallstone (biliary) pancreatitis.72,73 Urgent ERCP is usually
reserved for patients with acute cholangitis or progressive
jaundice, to keep the yield at a maximum and thereby keep
the number of unnecessary procedures to a minimum.
Pseudocysts complicate acute pancreatitis in fewer than 5%
of cases. Pseudocysts are peripancreatic fluid collections
that develop a wall that does not have an epithelial layer;
they take 4–6 weeks to mature. Pseudocyst fluid usually has
high amylase concentrations and low amounts of tumour
markers, such as CA19-9 and carcinoembryonic antigen. If
acute pseudocysts are uncomplicated, asymptomatic, and
not increasing in size on serial imaging, to withhold
intervention is preferable, since many of these pseudocysts
will resolve spontaneously. Otherwise, endoscopic,
percutaneous, or surgical drainage is indicated.
Reported success rates for endoscopic pseudocyst
drainage vary between 70% and 94%.74,75 Predrainage
ERCP to define pancreatic ductal anatomy is advisable.
Endoscopic transpapillary stent placement is a treatment
option when communication is shown between the
pseudocyst and the pancreatic duct.76 Contraindications to
endoscopic drainage of pancreatic pseudocysts include
presence of an abscess or necrotic tissue within the cyst (a
necroma), gastric or duodenal varices, coagulopathy, and
excessive thickness (>1 cm) of the cyst wall. Use of endo-
scopic ultrasound to define safe access for endotherapy
reduces the risk of life-threatening complications. Newer
echoendoscopes allow direct pseudocyst drainage without
the need for a separate endoscopic procedure.77
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Figure 2: Peroperative photograph showing the abdominal
incision for necrosectomy
Courtesy of Douglas Tyler, Duke University Medical Center.
Percutaneous drainage is done under ultrasound or CT
guidance, and is useful to drain symptomatic peripancreatic
fluid collections, non-communicating pseudocysts, and
abscesses. Although endoscopic therapy is an option,
especially for patients unfit for surgery, data from our
institution suggest that an operative approach is preferable
for pseudocysts that communicate with the pancreatic
duct.78 Surgery is also preferred when diagnosis of a
pseudocyst is in doubt (eg, possible cystic neoplasm), when
the pseudocyst is complex, and to manage fistulae. We are
not aware of any randomised trial comparing endoscopic
treatment with percutaneous or surgical decompression for
pancreatic pseudocysts.
Timing of surgery after acute pancreatitis
In patients with mild gallstone pancreatitis, many surgeons
choose to do cholecystectomy during the same admission to
avoid risk of recurrence. In severe acute pancreatitis,
cholecystectomy is typically delayed to allow resolution of
the inflammatory process and await improvement in the
patient’s nutritional state. Increasingly, only those with a
high likelihood of choledocholithiasis undergo precho-
lecystectomy ERCP. If an intraoperative cholangiogram
shows a possible stone in the common bile duct, this stone
is dealt with by next-day ERCP. Laparoscopic bile-duct
exploration for stones avoids the need for subsequent
ERCP, but is time-consuming and has not gained
widespread acceptance. Opinion on timing of surgery to
debride non-viable pancreas (necrosectomy) after acute
pancreatitis is clearly changing, at least in the USA. In our
institution, for example, necrosectomy is usually reserved
for persistently febrile patients who fail to respond to broad-
spectrum antibiotics with or without percutaneous drainage
of fluid collections over 72 h or more (figure 2).
Post-ERCP pancreatitis
Pancreatitis complicates ERCP in 3% to more than 40% of
cases:79,80 risk is dependent on patients’ factors, such as age,
female sex, diameter of the common bile duct, previous
post-ERCP pancreatitis, and technical factors, such as
performance of biliary or pancreatic sphincterotomy or
manometry, balloon dilation of the biliary sphincter,
difficult (traumatic) cannulation, repeated injections into
the pancreatic duct, and skill of the operator.79–81 A widely
used classification of post-ERCP complications was
proposed by Cotton.82 According to this classification, mild
post-ERCP pancreatitis results in a hospital stay of
1–3 nights, moderate disease needs 4–10 nights, and severe
disease leads to admission for more than 10 nights, or any
surgical or radiological intervention, or death. About 90%
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of cases are mild. In a large multicentre study, Freeman and
colleagues83 reported that 5·7% of outpatients needed
admission for complications of ERCP (mostly pancreatitis):
of these, 79% developed pain within 6 h of the procedure.
Post-ERCP pancreatitis has a similar clinical picture to
acute pancreatitis from other causes. How can post-ERCP
pancreatitis be recognised before the patient is sent home?
Narcotic analgesia used for endoscopy sedation frequently
masks early signs and symptoms of the disease. Serum
markers, such as 4-h amylase,84 interleukins 6
and 10,85 and serum and urinary trypsinogen 2 and
trypsinogen 2 ␣1 antitrypsin complex,86 have all proved
helpful in identification of post-ERCP pancreatitis in
clinical studies. However, at present, none of these markers
is in widespread use for prediction of disease.
Trials assessing use of pharmacological agents in
prevention of post-ERCP pancreatitis have been largely
disappointing. So far, only somatostatin,87 gabexate,88
octreotide,89 interleukin 10,90 and nafamostat have shown
any benefit, although most of the studies remain to be
validated elsewhere.
Cause and presentation of chronic pancreatitis
Chronic pancreatitis is characterised by permanent damage
of structure, function, or both because of progressive
inflammation.91 The early stage of the disease is
distinguished by recurrent bouts of acute pancreatitis,
followed—generally many years later—by progressive
pancreatic exocrine and endocrine insufficiency and
sometimes calcification. In most patients, pain is the
dominant symptom.92 Complications include pseudocyst
formation, pancreatic stones and strictures, biliary
strictures, duodenal stenosis, portal hypertension with
varices, and an amplified risk of pancreatic cancer.93,94 In
countries in Europe, around 70% of cases of chronic
pancreatitis are thought to be caused by alcohol abuse. Less
common causes include autoimmune disease, hypertriglyc-
eridaemia, hyperparathyroidism, tropical pancreatitis,
pancreas divisum, obstruction of the pancreatic duct by
tumour, and genetic abnormalities.95 The remaining patients
(10–30%) are classified as idiopathic.96,97 Chronic
pancreatitis usually presents in the 5–7th decades of life, but
some patients present before the age of 30 years.92
Historically, the progressive pancreatic failure of cystic
7p22.3
p
7p11.2
7q11.22
q
CFTR
7q31.2
7q36.3
Figure 3: Artist’s impression of the cystic fibrosis
transmembrane conductance regulator gene on human
chromosome 7q31
Reprinted with permission of the US Department of Energy Human
Genome Program from http://www.ornl.gov/hgmis.
THE LANCET • Vol 361 • April 26, 2003 • www.thelancet.com

Rights were not granted to include this
image in electronic media. Please refer
to the printed journal.
Figure 4: Artist’s impression of the cystic fibrosis
transmembrane conductance regulator protein
Reprinted with permission of The McGraw-Hill Companies. Taken from
Lewis R. Human genetics: concepts and applications. Dubuque:
Wm C Brown, 1994.
fibrosis has been judged a separate entity from chronic
pancreatitis, but in terms of genetic predisposition, some
cases of the disease might represent a forme fruste of cystic
fibrosis (see below).
Pathogenesis of chronic pancreatitis
Mutations in the CFTR gene, identified in 1989, have been
associated with chronic pancreatitis (figure 3).98,99 CFTR
mutations cause impairment of cyclic AMP (cAMP)-
regulated chloride channels of various organs, leading to
inspissated secretions and blockage of ductal systems (figure
4). As well as the F508del mutation, more than 1000 other
mutations of CFTR of varying severity are described
(http://www.genet.sickkids.on.ca/cftr/). Some of the so-
called mild mutations, such as R117H, cause pulmonary
disease of reduced severity: patients with this mutation are
generally pancreatic sufficient and have greatly improved
survival compared with the typical cystic fibrosis
phenotype.100 In the same issue of the New England Journal
of Medicine in 1998, two independent groups reported
an increased incidence of CFTR mutations in patients
with chronic pancreatitis compared with controls.98,99 In
134 patients with disease of mixed cause, Sharer and
colleagues99 noted 13·4% of patients with chronic
pancreatitis carried one common CFTR mutation
compared with 5·3% of controls. A 5T allele in intron 8,
which reduces amounts of functional CFTR by decreasing
mRNA levels, was seen twice as commonly as expected.
Cohn and co-workers98 studied 27 patients with idiopathic
pancreatitis and recorded common CFTR mutations in ten
(37%), including one patient with two mutant alleles. None
of the patients in either study fulfilled present criteria for
diagnosis of phenotypic cystic fibrosis.101
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Patients with a compound heterozygote (severe/mild-
variable) genotype for CFTR seem to be at greatest risk for
pancreatitis, whereas their lung function is protected by
residual CFTR function from the mild-variable
mutation.102,103 In young patients with idiopathic chronic
pancreatitis, the combination of two CFTR mutations and
one SPINK1 mutation has been described.104 Because
SPINK1 is present in acinar cells and CFTR in ductal
epithelium, these genes could affect susceptibility to chronic
pancreatitis independently.105 However, intrapancreatic
protease activation attributable to the SPINK1 mutation
could contribute to pathogenesis of CFTR-related
pancreatitis.104
Diagnosis of chronic pancreatitis
Imaging
Because of the difficulty of obtaining pancreatic tissue for
histological analysis in vivo, chronic pancreatitis is usually
diagnosed by pancreatic imaging with or without dynamic
tests of exocrine function. ERCP remains the gold standard
for diagnosis and staging of the disease. With sensitivity in
various series of 75–95%, and a specificity of 90% or more,
ERCP has been the most sensitive imaging tool for
diagnosing chronic pancreatitis during the past
30 years. However, it is invasive and carries significant
morbidity (3% to ⭓40%) and mortality (0·1–1·0%).
Magnetic resonance cholangiopancreatography (MRCP),
with or without secretin stimulation,106 is proving a useful
alternative to ERCP in many circumstances (figure 5). With
magnetic resonance technology, the pancreatic ductal
anatomy and peripancreatic fluid collections are seen with
heavily T2-weighted images; with different settings, with or
without MRI contrast medium, the parenchyma can be
assessed.107
Quality, sensitivity, and specificity of MRCP varies
greatly between centres, and depends not only on the type
of scanner but also on the interest and skill of the operator.
At present, most clinicians use MRCP as an alternative to
ERCP, helical CT scanning, or both in selected cases. We
predict that in the near future, MRCP will be used in place
of ERCP for most diagnostic reasons.
Endoscopic ultrasound has emerged as a sensitive
imaging technique in chronic pancreatitis. Wiersema and
colleagues prospectively assessed several pancreatic ductal
and parenchymal abnormalities seen at ultrasound
compared with clinical, laboratory, and ERCP findings.108
Eight features on ultrasound were indicative of chronic
pancreatitis: if three or more were present, sensitivity,
specificity, and accuracy of endoscopic ultrasound was
Figure 5: Normal magnetic resonance cholangiopancreatogram
The gallbladder, biliary tree and main pancreatic duct are clearly visible.
Courtesy of Erik Paulson, Duke University Medical Center.
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80%, 86%, and 86%, respectively. Results of subsequent
studies have confirmed these criteria in idiopathic recurrent
pancreatitis109 and in high-risk groups, in which presence of
pancreatic calcifications, number of criteria present, and
history of alcohol abuse were also independently predictive
of chronic pancreatitis.110 However, detection of subtle
changes by endoscopic ultrasound might lead to
overdiagnosis of the disease.
The overall sensitivity of CT in diagnosis of chronic
pancreatitis is 75–90%. It is especially useful for detection of
focal pancreatic enlargement, parenchymal atrophy,
calcification, pancreatic ductal dilatation, and pseudocysts.
CT can also detect complications of chronic pancreatitis,
including portal and splenic vein thrombosis, gastric varices,
splenic enlargement, fluid collections, and biliary
obstruction. Although transabdominal ultrasound is
inexpensive and easily available, it is insensitive for detec-
tion of early disease. However, it is an excellent method for
imaging fluid collections, such as pseudocysts, which are
generally aspirated or drained under ultrasound guidance.
Pancreatic function tests
Aspiration and assay of duodenal contents after pancreatic
stimulation by secretin-cholecystokinin or a Lundh test
meal is judged by some the gold standard for diagnosis of
pancreatic exocrine insufficiency. Critics of dynamic testing
say that it rarely alters management: by the time a patient
has grossly abnormal dynamic testing, their chronic
pancreatitis is usually obvious clinically and radiologically.
A niche role for dynamic testing could be investigation of
patients with suspected minimum-change pancreatitis, for
which subtle loss of exocrine function might suggest
pancreatic injury not yet apparent on conventional imaging.
Since standardisation of pancreatic function tests is difficult,
these tests are rarely used outside major centres. Non-
invasive tests, such as the bentiromide (PABA) test, faecal
fat determination, and measurement of faecal pancreatic
enzymes such as elastase and chymotrypsin, are limited by
difficulties in collection, insensitivity for early chronic
pancreatitis, and the occurrence of false-positive results.
Pancreatic endocrine dysfunction is a late event in this
disease; investigation beyond fasting blood glucose
estimation and a glucose tolerance test has not proved
clinically relevant.
Treatment of chronic pancreatitis
The natural history of chronic pancreatitis is of episodic or
intractable abdominal pain, and progressive exocrine and
endocrine insufficiency. Pain is the main complaint of most
patients with the disease,111 although a few with late-onset
idiopathic chronic pancreatitis are fortunate enough never
to have pain.97,112 Some patients with alcohol-induced
disease gain pain relief as their pancreas progressively
atrophies. Development or worsening of pain in chronic
pancreatitis could signal the presence of complications, such
as pseudocysts or biliary, duodenal, or colonic strictures.113
Chronic pancreatitis has been suggested to diminish over
time, with relief of symptoms. To most clinicians managing
the disease, the reality is that it is continuous but patients
get used to their pain episodes and more adept at managing
them without emergency room visits or admissions.
Pain management
Although the pathogenesis of pain in chronic pancreatitis is
incompletely understood, it has been attributed in varying
amounts to: increased intraductal pressure (so-called
pancreatic hypertension); perineural inflammation (so-
called pancreatic neuropathy); increased visceral
nocioception; space occupying lesions, eg, a pseudocyst or
1452
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pseudoaneurysm; an associated motility disorder; or
development of malignancy. Amman and colleagues114
identified two different patterns of pain in a cohort of
patients with alcoholic chronic pancreatitis: short episodes
(<10 days) with long pain-free periods in between; and
chronic persistent pain. Patients with chronic persistent
pain had complications of chronic pancreatitis—eg,
pseudocyst formation or biliary obstruction—and all
underwent surgery. None of the patients with short episodes
of pain needed surgery. Many patients with chronic
pancreatitis and pain come to surgery for resection, ductal
drainage procedures, or management of complications such
as pseudocysts. Unfortunately, surgery is no guarantee of
pain relief, especially in those patients who have become
narcotic-dependent.
Use of pancreatic enzymes for pain relief remains
controversial; trials of non-enteric-coated enzyme
preparations have generally produced better results than
have those of enteric-coated preparations,115,116 particularly
in patients with predominantly small duct disease.
Pancreatic enzyme supplements with snacks and meals and
avoidance of dietary fat and alcohol are still the main
lifestyle modifications we recommend to patients with
chronic pancreatitis. Coeliac plexus neurolysis (chemical
destruction of the nerve plexus) has proved disappointing,
especially in young adults and in patients who have
previously undergone surgery.117 Endoscopic ultrasound-
guided coeliac plexus neurolysis, with steroids
(triamcinolone) and local anaesthetic (bupivacaine) rather
than absolute alcohol, seems safer and more effective than
the CT-guided alternative.118 In skilled hands, thoracoscopic
sympathectomy can be very effective for intractable pain.
Many patients with chronic pancreatitis become addicted to
narcotic analgesics; such patients benefit from management
in a dedicated pain clinic. Non-narcotic modulators of
chronic pain, such as gabapentin, and selective serotonin
reuptake inhibitors (eg, paroxetine), should be considered
in difficult-to-manage pain syndromes associated with
chronic pancreatitis.
Exocrine and endocrine insufficiency
A reduction in pancreatic enzyme output to less than 10%
of normal is usually needed for maldigestion to occur.119 To
ensure that an adequate dose of pancreatic enzymes reaches
the duodenum, gastric acid must be suppressed by an H2-
receptor antagonist or proton-pump inhibitor. Enzyme
supplements which have high lipase concentrations are
effective, but have been associated with fibrosing small-
bowel disease (diaphragm disease) and fibrosing
colonopathy, especially in children with cystic fibrosis.120,121
Diabetes, usually insulin-dependent, eventually develops in
30–50% of patients with chronic pancreatitis,112 and can be
difficult to manage, particularly in the presence of
continuing alcohol use and maldigestion.
Non-surgical versus surgical approaches to complications
of chronic pancreatitis
Symptomatic pseudocysts complicating chronic pancreatitis
rarely resolve spontaneously.122 Management of pseudocysts
should be multidisciplinary. If the pseudocyst
communicates with the pancreatic ductal system, surgery
could be the best option. If endoscopy if preferred,
transpapillary drainage might be effective,76 although in
practice results are variable and less predictable than
the transgastric or transduodenal approach. If no
communication is present between the pseudocyst and the
pancreatic duct, endoscopic or percutaneous drainage
frequently leads to resolution. Endoscopic clearance of
main pancreatic duct stones and dilation of ductal strictures
THE LANCET • Vol 361 • April 26, 2003 • www.thelancet.com

Normal PanIN-1A PanIN-1B
tall columnar mucinous cells nuclear changes
flat papillary growth
Figure 6: PanIN progression series
PanIN 3 lesions are papillary and show budding and necrosis of clusters of epithelial cells. Reprinted from Clinical Cancer Research 2000; 6: 2969–72,
with permission.
might have beneficial long-term results in some patients.123
About 50% of patients with chronic pancreatitis will
undergo surgery at some stage in their disease for pain
management or to manage their complications.96,124 In many
cases, however, despite apparent technical success, no
measurable improvement is seen in quality of life.125
Chronic pancreatitis and risk of pancreatic
cancer
Chronic pancreatitis, especially the hereditary form, has
long been deemed a risk factor for development of
pancreatic cancer. Traditional teaching holds that the
disease is responsible for fewer than 5% of all pancreatic
adenocarcinomas.126 However, this figure will probably be
revised upwards as our understanding of the genetic basis of
chronic pancreatitis and pancreatic cancer increases. The
PanIN (pancreatic intraepithelial neoplasia) classification
has been proposed to unify the various previous
classifications of malignant precursors of pancreatic ductal
adenocarcinoma (http://www.path.jhu. edu/pancreas).
There are three categories: PanIN 1, 2, and 3. The
classification describes a progression of lesions from mildly
to strikingly atypical. PanIn 3 lesions can have an associated
mass, although there is no invasion of the basement
membrane (figure 6). All stages of PanIN lesion have been
reported in chronic pancreatitis:127,128 these are presumed to
be potential sites for future cancer development. To identify
PanIn 3 lesions might be possible with endoscopic
ultrasound before development of frank malignancy.
Clinicians are, at present, suggesting that patients with
established chronic pancreatitis undergo endoscopic
ultrasound every year with fine-needle aspiration cytology
or biopsy of suspicious masses in the pancreatic-duct wall.
Those with dysplastic lesions or carcinoma in situ should be
offered surgical resection as prophylaxis against developing
what is presently an almost 100% fatal cancer. The logistics
of providing yearly ultrasound for every patient with chronic
pancreatitis are staggering, but to think that such screening
might reduce the death toll from pancreatic
adenocarcinoma is exciting.
Conflict of interest statement
None declared.
Acknowledgments
RMSM’s advanced endosopy fellowship is supported by an unrestricted
grant from Boston Scientific. The sponsor had no role in study design, data
collection, data analysis, data interpretation, or writing of the report.
THE LANCET • Vol 361 • April 26, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
Jennifer Parsons Brumbaugh, MA
PanIN-2 PanIN-3
mitoses, luminal nuclei
papillae lack stromal core
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