1. health and fitness
2. disease

Seminar
Chronic pancreatitis
Joan M Braganza, Stephen H Lee, Rory F McCloy, Michael J McMahon
Lancet 2011; 377: 1184–97
Published Online
March 11, 2011
DOI:10.1016/S01406736(10)61852-1
Department of
Gastroenterology
(J M Braganza DSc) and
Department of Radiology
(S H Lee FRCR), Manchester
Royal Infirmary, Manchester,
UK; Department of Education,
Lancashire Teaching Hospitals,
Preston, UK (R F McCloy FRCS);
and University of Leeds and
Nuffield Hospital, Leeds, UK
(Prof M J McMahon FRCS)
Correspondence to:
Dr Joan M Braganza,
c/o Mrs Jenny Parr,
Core Technology Facility,
3rd Floor, Grafton Street,
Manchester M13 9NT, UK
[email protected]
Chronic pancreatitis is a progressive fibroinflammatory disease that exists in large-duct (often with intraductal
calculi) or small-duct form. In many patients this disease results from a complex mix of environmental (eg, alcohol,
cigarettes, and occupational chemicals) and genetic factors (eg, mutation in a trypsin-controlling gene or the cystic
fibrosis transmembrane conductance regulator); a few patients have hereditary or autoimmune disease. Pain in
the form of recurrent attacks of pancreatitis (representing paralysis of apical exocytosis in acinar cells) or constant
and disabling pain is usually the main symptom. Management of the pain is mainly empirical, involving potent
analgesics, duct drainage by endoscopic or surgical means, and partial or total pancreatectomy. However, steroids
rapidly reduce symptoms in patients with autoimmune pancreatitis, and micronutrient therapy to correct
electrophilic stress is emerging as a promising treatment in the other patients. Steatorrhoea, diabetes, local
complications, and psychosocial issues associated with the disease are additional therapeutic challenges.
Introduction
Definition
Chronic pancreatitis is a progressive inflammatory
disorder in which pancreatic secretory parenchyma is
destroyed and replaced by fibrous tissue, eventually
leading to malnutrition and diabetes. Two forms are
recognised—a large-duct calcifying type1 and a small-duct
variant.2–4 The disease is uncommon in Europe and the
USA; its prevalence in France is 26 per 100 000 people.5
This prevalence is not dissimilar to the middle of three
estimates from Japan,6,7 but considerably lower than the
figure of 114–200 per 100 000 in south India.7
The main symptom of chronic pancreatitis is usually
pain, which occurs as attacks that mimic acute pancreatitis or as constant and disabling pain. Despite decades of
research, treatment of chronic pancreatitis remains
mostly empirical, and thus patients are repeatedly
admitted to hospital and have interventional procedures,
which strains medical resources.8 This absence of
progress in treatment is a sign of uncertainty about how
the identified causative factors lead to the disease.
Therefore, in this Seminar we focus on the pathophysiology and pathology of chronic pancreatitis before
describing clinical management.
Traditionally, chronic pancreatitis has been classed as
fundamentally different from acute pancreatitis—the
latter is usually characterised by restoration of normal
pancreatic histology after full clinical recovery.1 However,
acute, recurrent acute, and chronic pancreatitis are now
regarded as a disease continuum.9,10 There are several
reasons for this change: recurrent acute pancreatitis can
develop into chronic pancreatitis;10–12 there is an overlap
in causative factors, both genetic and environmental;10,13
experimental protocols can be modified to induce each
condition;14 and the pancreatitis attack is stereotyped—
patients have severe abdominal pain and increased blood
amylase, lipase, and trypsinogen.
Search strategy and selection criteria
We searched PubMed and the Cochrane library (to August,
2010) for reviews on chronic pancreatitis. We used Google
scholar for specific searches, with “chronic pancreatitis” as the
key phrase combined with “epidemiology”, “pathology”,
“aetiology”, “gene mutations”, “pathogenesis”,
“classification”, “diagnosis”, “pancreatic function tests”,
“pancreatic imaging tests”, “treatment of pain”, “pancreatic
enzyme therapy”, “micronutrient therapy”, “antioxidant
therapy”, “endoscopic treatment”, or “surgical treatment”. We
selected the most up-to-date articles but did not disregard
commonly referenced older publications. We also examined
the reference lists of identified papers and selected those that
we judged to be relevant. Review articles and book chapters
are cited to give readers more details and references than this
Seminar can accommodate.
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Pathophysiology and pathology
Experimental studies since the 1950s have shown that an
attack of pancreatitis begins as pancreastasis,13 prevention
of apical exocytosis in the pancreatic acinar cell (figure 1).15
The acinar cell quickly releases newly synthesised enzyme
via the basolateral membrane into lymphatics, by way of
the interstitium, and directly into the bloodstream.16 Some
zymogen granules also release their stored enzyme
basolaterally.15 These events result in inflammation.17
Findings from prospective clinical studies concur with
this pancreastasis–pancreatitis sequence.13,17
Experimental work has pinpointed a burst of reactive
oxygen species (ROS) as the trigger of so-called
pancreastasis18 and as the potentiator of inflammation by
activating signalling cascades that convert the damaged
acinar cell into a factory for chemokines and cytokines.19,20
ROS serve several physiological roles, including in signal
transduction,13,21 but an excess of ROS compared with
antioxidant capacity (electrophilic stress) is potentially very
damaging. The exocytosis blockade seems to be caused by
disruption of the methionine trans-sulphuration pathway
that produces essential methyl and thiol (principally
glutathione) moieties.17,22 This problem also occurs in
clinical acute or acute-on-chronic pancreatitis.23–25
In patients who develop large-duct chronic pancreatitis,
studies in the quiescent phase of the disease show that
the composition of pancreatic fluid changes in a manner
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Seminar
Normal
Pancreastasis
Pancreatitis
Constitutive
pathways
E
PAP/regIII
PSP/reg
ZG
ZG
L
ZG
ZG-L
ZG-L
GC
RER
D
GC
RER
ZG
RER
Ph-elastase
Ph-PLA2
Nucleus
Nucleus
Nucleus
MO
Constitutive
pathway
E
E
E
MC
PMN
Foci of gland digestion
Figure 1: Schematic representation of disturbances in the pancreatic acinar cell during experimental acute pancreatitis
See text for a full description. The constitutive pathway at the basolateral pole normally transports a small fraction of newly synthesised enzyme, as do two pathways at the
apical pole. E=amylase, lipase, trypsinogen, and other precursor proteases, and pro-phospholipase A2. RER=rough endoplasmic reticulum. GC=Golgi complex. ZG=zymogen
granules. L=lysosomes. ZG-L=miniscule fraction of zymogens activated by co-localisation with lysosomal enzymes. D=centripetal dissolution of granules.
PAP/regIII=pancreatitis associated protein. PSP/reg=pancreatic stone protein/islet regenerating protein. MC=mast cell. PMN=polymorphonuclear cell. MO=monocyte.
Ph-PLA2=phospholipase A2 from phagocytes and mast cell. Adapted from Braganza.13
that, for uncertain reasons, facilitates protein deposits—
the precursors to calcium carbonate stones.1 (1) There is
an early increase in secretion of enzyme and calcium, but
a decrease in the serine protease inhibitor Kazal type 1
(SPINK 1), bicarbonate, and citrate.1 (2) Concentrations of
free radical oxidation products are raised in the pancreatic
fluid,26 which suggests ongoing electrophilic stress, and
in an apparent attempt to compensate, concentrations of
the natural antioxidants27 lactoferrin and mucin are
increased.1,2,28 (3) Concentrations are altered of two
secretory stress proteins29 (increased concentration of
pancreatitis associated protein [PAP]/regIII, which is
activated by electrophilic stress; and variable concentration
of pancreatic stone protein [PSP]/reg, formerly called
lithostatin;1 figure 1) that tend to form fibrous lattices
upon partial digestion by trypsin. (4) There is an increase
of GP-2, which is a secreted component of zymogen
granule membranes (analogous to the renal cast protein).30
(5) Concentrations of lysosomal enzymes are increased in
ductal fluid, and traces of trypsin appear.31 Moreover, the
methionine metabolic pathway remains fractured.32–34
On histology, the defining triad of stable disease
(irrespective of main causes or location)35 is acinar loss,
mononuclear cell infiltration, and fibrosis. The early
lesions are distributed in patches; thus, normal findings
on needle biopsy are unreliable. An unusual form of socalled groove (paraduodenal) pancreatitis has been
identified.11 Each inflammatory attack can cause foci of
fat necrosis that seem to lead to both pseudocysts and
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fibrosis.11 Nerves show breaching of the perineurium
adjacent to inflammatory foci, while the expression of
nociceptive chemicals in nerve endings is increased.36
Immunocytochemistry gives valuable insights into the
development of chronic pancreatitis. Acinar cells,
which are hyperplastic at disease outset,2 show
strong expression of cytochrome P450 (CYP) monooxygenases,37–39 as do proliferated islets of Langerhans,37–39
and hepatocytes (figure 2).37,38 After birth, CYP enzymes
are mainly located in the liver. CYP metabolises
environmental lipophilic chemicals (xenobiotics). In the
first phase, the enzyme uses ROS to hydroxylate the
substrate, which then usually undergoes second-phase
conjugation reactions, often with glutathione and
catalysed by glutathione transferases. So-called enzyme
induction might be accompanied by expansion of the
endoplasmic reticulum so that, at least initially, the cell
secretes more of its normal products. However, this
defence reaction backfires if first-phase processing (eg, by
CYP2E1, CYP1A, and CYP3A1 isoforms) produces a
reactive xenobiotic metabolite. Cell injury depends on
whether or not there is enough by way of defences to
ROS and reactive xenobiotic species: antioxidant enzymes
(including the selenium-dependent glutathione peroxidase), glutathione transferases, glutathione, and ascorbic
acid (the bioactive form of vitamin C, which can substitute
for glutathione).32,40 Immunochemistry shows that these
defence mechanisms are insufficient to meet the
increased oxidant load in acinar cells,32,37 which therefore
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show signs of electrophilic stress, such as excess lipofuscin and cytoplasmic microvesiculation.41
Fibrosis is a sign that interstitial stellate cells are
activated in chronic pancreatitis; these cells play a
central part in disease progression by regulating the
synthesis and degradation of extracellular matrix
proteins.42,43 Findings from histochemistry suggest a
causal influence of two factors—an increase in lipid
peroxidation products caused by an excess of ROS in
adjacent acini,44 and the release of mast cell
degranulation products,45 transforming growth factor β1
in particular.46 The two factors are linked in that ROS
and their oxidation products are natural activators of
mast cells.17 Activation of stellate cells is increased by
cytokines from infiltrating leucocytes and the injured
acinar cell.43 The end stage of chronic pancreatitis is
identified by loss of all secretory tissue, disappearance
of inflammatory cells, and intense fibrosis. This
A
progression resembles that from chronic active hepatitis
to liver cirrhosis.2,12,47
The table summarises the histological features of
ordinary chronic pancreatitis compared with features of
three variants in which the lesions are diffuse. The
pancreatic lesion in cystic fibrosis is a diffuse form of
chronic pancreatitis wherein inflammatory stigmata
disappear by birth,48 except in patients with mild
mutations in the cystic fibrosis transmembrane
conductance regulator gene (CFTR), who might have
recurrent attacks.49 Uniform lesions also occur upstream
of an obstructed duct1,11,48 and in autoimmune
pancreatitis.50,51 The latter can involve the whole or part
of the gland and has two subtypes. Characteristics of
the more common type-1 autoimmune pancreatitis are
a dense lymphoplasmacytic infiltrate with predominantly
IgG4+ cells, periductal swirling sclerosis, and obliterative
venulitis. In the type-2, duct-destructive form, hordes
B
D
H
D
H
A
S
A
D
50 μm
50 μm
Figure 2: Immunolocalisation of cytochrome P4503A1 in surgical material from a 27-year-old woman with calcific chronic pancreatitis
The patient drank little alcohol, smoked 40 cigarettes a day, and worked as a forecourt attendant at a car and lorry-fuelling station. (A) The pancreatectomy fragment
shows that the enzyme (brown stain) is strongly expressed in acinar cells (A) but absent from epithelium of dilated ducts (D) or expanded stroma (S). (B) The needle
biopsy fragment of the liver showed that the enzyme is strongly expressed across the liver lobule (H) and weakly expressed in bile duct epithelium (D). Reproduced
with permission from Foster et al.37
Ordinary*
Cystic fibrosis†
Obstructive‡
Autoimmune§
Distribution
Patchy
Diffuse
Diffuse
Diffuse
Extent of gland
Variable
Total
Total
Total or focal
Main duct
Irregularly dilated
Minimally dilated
Smoothly dilated
Constricted
Protein plugs
All ducts
Intralobular and interlobular No
No
Calcifying tendency
Yes
No
No
Lesions
Duct system
No
Epithelium destroyed
(Groove form)
No
No
Yes (type 2)
Neutrophils
No
No
No
Yes (type 2)
Inflammatory cells
Mononuclear
No
No
Plasmalymphacytic
Fibrosis
Mainly perilobular
Perilobular, intralobular
Perilobular, intralobular
Perilobular, intralobular, periductal
Pseudocyst
Frequent
No
No
No
*Excludes the small-duct variant (as in at least 30% of cases) wherein characteristic features are focal acinar cell damage and tubular complexes.3 Groove pancreatitis is similar
to the ordinary form, except for prominent destruction of ductal epithelium and cysts.1,11 †The earliest lesions occur in utero.48 ‡Diffuse lesions occur upstream from the
obstruction.1,11 §See text for subtypes.
Table: Main histological features of chronic pancreatitis subtypes (at diagnosis in stable disease)
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of neutrophils infiltrate the wall of the duct, accompanied
by lymphocytes and plasma cells.51
Causes
Panel 1 lists causative factors of chronic pancreatitis. In
adults, excluding those with cystic fibrosis, 90–95% of
patients are regarded as having alcoholic or idiopathic
disease. Infective causes are rare.52 The connection between
chronic pancreatitis and drugs (eg, valproate) is mostly
anecdotal. Studies from Italy,53 China, and Japan54 report
an association with gallstones in about 30% of patients.
Alcoholic
Alcohol has long been regarded as the leading cause of
chronic pancreatitis in Europe, the USA, Brazil, Mexico,
and South Africa, and is now regarded as the main cause
of the disease also in Australia and South Korea.7
However, excess alcohol was the predominant factor in
only 34% of cases of chronic pancreatitis in a recent
multicentre study from Italy53 and in 44% of cases in an
audit from the USA,55 with another study reporting that
African-Americans are at particular risk.56 Whether these
new data reflect differences in the definition of alcoholic
disease55 or a genuine change in the cause of chronic
pancreatitis is not clear.57
Experimental studies have shown that, although the
pancreas processes ethanol efficiently (via a non-oxidative
route that produces fatty acid ethyl esters, and by
oxidation via the acetaldehyde pathway), its metabolites
injure acinar cells and activate stellate cells in vitro.42,58
However, prolonged ethanol feeding does not induce
chronic pancreatitis.58,59 Hence, the finding of a latent
interval of 15 years or more in patients who consumed
150 g or more of ethanol per day—as most recently noted
in India60—is unsurprising. Moreover, less than 10% of
people who drink alcohol in excess develop the disease.61
Collectively, these findings suggest that other factors
interact to amplify ethanol toxicity in vivo.
In animal models, small doses of ethanol induce
CYP2E1, thus increasing the toxicity from other chemicals
to which the animal is simultaneously exposed.62,63 These
results might rationalise the old observation that there is
no threshold for the pancreatic toxicity of ethanol,1 but
recent data suggest there is a threshold at 60 g per day.55
Moreover, CYP2E1 is the main pathway that metabolises
ethanol upon chronic excessive ingestion,63 but this
pathway releases ROS.64
Idiopathic
60–70% of cases of chronic pancreatitis in India and
China are labelled as idiopathic, as are around half the
cases in Japan.7 Tropical pancreatitis is a form of
idiopathic pancreatitis that affects young people and
has a propensity to diabetes and large calculi.65 This
disease is mainly reported in developing countries of
Asia, Africa, and Central America, where severe
malnutrition and cyanogenic glycosides in cassava
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Panel 1: Causative factors
Toxic
Xenobiotics
• Alcohol
• Cigarette smoke
• Occupational volatile hydrocarbons
• Drugs: valproate, phenacitin, thiazide, oestrogen,
and azathioprine
Endogenous
• Hypercalcaemia, hyperparathyroidism
• Hyperlipidaemia, lipoprotein lipase deficiency
• Chronic renal failure
Infection or infestation
• HIV, mumps virus, coxsackie virus
• Echinococcus, Cryptosporidium
Genetic*
• CFTR mutation
• PRSS1 mutation
• SPINK1 mutation
Obstruction of main pancreatic duct
• Cancer
• Post-traumatic scarring
• Post-duct destruction in severe attack
Recurrent acute pancreatitis
Autoimmune
Miscellaneous
• Gall stones
• After transplant
• After irradiation
• Vascular disease
Idiopathic
• Early or late onset
• Tropical
CFTR=cystic fibrosis transmenbrane conductance regulator. PRSS1=protease serine
cationic trypsinogen. SPINK1=serine protease inhibitor Kazal. *Other, less common
mutations have been described.
(manioc) were implicated. The classic description of
tropical pancreatitis was from Kerala, south India;66
however, hospital admission statistics revealed a decline
in the disease by six times between 1962 and 1987,66
without a change in cassava consumption. Instead, the
decline coincided with the introduction of electricity in
this province, which removed the dependence on
traditional lighting (see below). At present, tropical
pancreatitis accounts for just 3·8 % of cases of chronic
pancreatitis in India.60
Other toxic causes
Cigarette smoke has emerged as a strong independent
risk factor for chronic pancreatitis;55,67 the link was verified
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by inhalation toxicology experiments.68,69 A case-control
study from the UK identified occupational volatile
hydrocarbons as another independent risk factor.70 This
connection is upheld by descriptive studies from Chennai,
India,71 and Soweto, South Africa,72 which also reported
regular contact with kerosene or paraffin, respectively, in
cookers, heaters, or lamps in patients with chronic
pancreatitis (potentially relevant to Kerala, see above).
Toxic damage to the pancreas by petrochemicals has been
documented in lower vertebrates.40 Moreover, the simplest
animal model of chronic pancreatitis, which develops via
an acute phase, involves just one parenteral injection of
dibutyltin (which has many industrial uses) and the injury
is amplified by alcohol.73
All these findings reinforce the pathological evidence
(figure 2) that the pancreas is a versatile but also
vulnerable xenobiotic-metabolising organ.40 Inhaled
xenobiotics that survive the pulmonary circulation would
pose the biggest threat (figure 2A) by striking the
pancreas directly via its rich arterial supply.
Autoimmune
Autoimmune pancreatitis (2–4% of cases57) can be part
of a multisystem disease (type 1) or can affect the
pancreas alone (type 2).50,51 Aberrant human leucocyte
antigen DR-1 expression on pancreatic ductal cells
might present autoantigens to lymphocytes. Proposed
pancreas-specific antigens include lactoferrin,28 carbonic
anhydrase, SPINK1, and a peptide that is present in
acinar cells that has homology to aminoacid sequences
in the plasminogen-binding protein of Helicobacter pylori74
(which might represent molecular mimicry)51 and also
in ubiquitin–protein ligase74 (a cofactor for steroid
hormone receptors and an important peptide in the
intracellular protein degradation pathway).75
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Idiopathic chronic pancreatitis is associated with a
mutation in the CFTR gene.80,82,83 Patients can have one
abnormal recessive allele, but possession of two confers
a 40 times increased risk of developing idiopathic chronic
pancreatitis, which rises to 500 times in patients who
also have a SPINK1 mutation.83 Some patients with
apparent idiopathic chronic pancreatitis who have CFTR
mutations have an atypical form of cystic fibrosis.80 Three
overlooked aspects of CFTR function have been reviewed
recently.32 CFTR is present in the luminal pole of acinar
cells where it might facilitate membrane recycling and
exocytosis, like it does elsewhere. CFTR transports
bicarbonate and glutathione—which facilitate the
solubility of mucins in secretions—across the luminal
membrane of ductal cells adjacent to the centroacinar
space. CFTR is inactivated by electrophilic stress but is
protected by thiols and ascorbic acid. Moreover, CFTR is
mislocalised to the cytoplasm of ductal cells in patients
with chronic pancreatitis; this misplacement is corrected
in autoimmune disease by steroids, which also reduce
inflammation, restore bicarbonate and enzyme secretion,
and regenerate acinar cells.84
Mutations in CFTR and SPINK1 have also been
described in patients with hypertriglyceridaemia or
hyperparathyroidism who develop pancreatitis.32 At
present, molecular deficits that contribute to chronic
pancreatitis have been identified in less than 10% of
alcoholic chronic pancreatitis and around 50% of
cases overall.79
Pathogenesis
There is no agreement as to how these diverse causative
factors lead to chronic pancreatitis. There are many
hypotheses about the pathogenesis of the disease,43 which
fall into five main categories.
Genetic
Ductal theory
Normally, if trypsinogen becomes prematurely activated
within the pancreas, it is inhibited by SPINK1 and then
self-destructs or is degraded by trypsin-activated proteases;31 the potent inhibitor gluthathione is available if
all else fails.76 Hereditary pancreatitis is a rare condition
that is caused by a gain-of-function mutation (autosomal
dominant, 80% penetrance) in the cationic trypsinogen
gene (PRSS1),9,10,42 which produces a degradationresistant form of trypsin.77 A transgenic mouse model
of chronic pancreatic injury has proved this link.78 The
PRSS1 mutation is not associated with alcoholic or
tropical chronic pancreatitis.79 By contrast, a loss-offunction mutation in SPINK1 is strongly associated
with idiopathic disease79–82 but is thought to be a
predisposing or modifying factor rather than being
directly causative.42,79,80 Mutations in other genes that
could increase the threat from trypsin have also been
described,79 as has a loss-of-function mutation in the
PRSS2 gene (encoding anionic trypsinogen), which
protects against pancreatitis.79,80
One hypothesis suggests that ducts are the primary target
of the disease: theories centre on the primacy of calcifying
protein deposits (protein plug hypothesis),1 stagnation of
pancreatic juice, reflux of noxious bile and duodenal juice
(facilitated by passage of gallstones), and primary autoimmune attack.
Acinar theory
Another hypothesis suggests that acini are the primary
target: alcohol is thought to injure acinar cells directly
(toxic metabolite hypothesis) or by increasing the cell’s
sensitivity to cholecystokinin (CCK) or via CYP2E1, while
also activating stellate cells, especially in the presence of
endotoxin.42,58 Another suggestion is that the disease is
caused by cyanide toxicity of the pancreas.
Two-hits theory
Two so-called hits are additionally suggested as causing
the disease: variations include a duct-to-acinar sequence,
vice versa, or double acinar hits. The last of these is the
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most popular theory and incorporates the idea that
recurrent necrosis leads to periductal fibrosis.11 The first
attack of pancreatitis is taken to represent autodigestion
caused by unregulated trypsin activity in the acinar cell. If
this attack is severe enough to recruit macrophages
(sentinel acute pancreatitis event hypothesis), subsequent
damage to the gland (by alcohol or electrophilic stress)
leads to fibrosis via macrophage-primed stellate cells.
Electrophilic stress theory
The electrophilic stress theory is the pancreatic equivalent
of paracetamol or carbon tetrachloride hepatotoxicity,
which results from insufficient protection by glutathione
against electrophilic attack (via CYP) on key
macromolecules—not least, enzymes in the methionine
trans-sulphuration pathway towards glutathione. However, in chronic pancreatitis electrophilic stress from
toxic metabolites—and, thereby, recurrent pancreastasis—develops over many years as a result of repetitive
exposures to multiple xenobiotics.41 Previous dietary
insufficiency of micronutrients, especially methionine
and ascorbic acid, facilitates the problem.41,85 The diversion
of free radical oxidation products into the interstitium
causes mast cells to degranulate, leading to inflammation,
activation of nociceptive axon reflexes, and fibrosis.41 The
realisation that compromised availability of methyl and
thiol (glutathione) moieties underlies chronic pancreatitis
has allowed an extension of the electrophilic stress
concept to chronic pancreatitis that is associated with
gene mutations.32 Thus, the daily exposure of acinar cells
to traces of trypsin in people with PRSS1 or SPINK1
mutations is expected to strain glutathione reserves. Of
particular note, those with a CFTR mutation would be
left vulnerable not only to pancreastasis but also to
intraductal calcifying protein plugs (large duct disease)
when the residual CFTR protein is immobilised by
electrophilic stress.32
constant pain; symptoms and signs of local complications
of the disease (eg, pseudocyst, obstruction of adjacent
organs, or vascular thrombosis); or complaints that suggest
exocrine or endocrine pancreatic failure, or both, by which
stage pancreatic calculi are often present. These features
form the basis for the most recent classification system
(figure 3).47 In alcoholic disease, the interval from first
attack to steatorrhoea (signifying >95% loss of acini) is
around 13 years, which is substantially shorter than in
early-onset idiopathic disease12,86 or hereditary pancreatitis
(≥26 years).12 Pancreatic calculi appear earliest in tropical
pancreatitis,65 and earlier in alcoholic than idiopathic
disease.86 Diabetes might precede, begin at the same time
as, or start after steatorrhoea.65,88
Pain is the over-riding symptom in all but 10–15% of
cases of chronic pancreatitis; these cases are usually elderly
patients with idiopathic disease12,86 or patients with
autoimmune pancreatitis who might present with
steatorrhoea, diabetes, or jaundice.50,51 The pain is wearying
and occurs in episodes that last about 1 week, or is constant.
It starts in the epigastrium and moves through to the dorsal
spine or localises to the left hypochondrium, radiating to
the left infrascapular region. The pain is sometimes
associated with nausea and vomiting and can be partially
eased by sitting up and leaning forward or by application of
local heat or other counterirritants to the dorsal spine or
epigastrium. The pain can be so severe that patients fear
food and lose weight. Most,12,86,89 but not all,88 studies have
reported that pain diminishes markedly once the disease
burns out (which suggests that viable acini are a prerequisite
for pancreatic pain). However, by then patients often have
become addicted to narcotic analgesics, which could cause
them to lose their jobs, homes, or families.88,90
Panel 2 lists factors that might contribute to pain in
patients with chronic pancreatitis:36 mast cell degranulation
products and hydrogen sulphide are plausible mediators
of the pancreatic component.91,92 The intensity of the pain
contrasts with the absence of specific signs in
Multiple-cause theory
The final hypothesis states that different causative factors
lead to damage via different pathways: this concept
incorporates the other theories while noting that
pancreatic ischaemia can aggravate the disease.43
Clinical features
Alcoholic chronic pancreatitis presents in the fourth or
fifth decade of life and mainly affects men.86 Idiopathic
disease has early-onset (second decade) and late-onset
(sixth decade) forms, which have equal gender distribution.12,86 Hereditary disease manifests at around 10 years87
and tropical pancreatitis at between 20 and 30 years,65
whereas the more common type-1 form of autoimmune
disease affects men in the sixth decade.51
Presenting features of chronic pancreatitis usually fall
into one of four groups: apparent acute or recurrent acute
pancreatitis (the true diagnosis of chronic pancreatitis is
suspected when attacks recur after cholecystectomy);
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Clinical
criteria
Attacks of apparent
acute pancreatitis
Pain
A Early
Complications
• Bile duct stricture
• Duodenal stricture
• Vascular stricture
• Portal hypertension
• Pseudocyst
• Pancreatic fistula
• Pancreatic ascites
• Rare, eg, colonic
stricture
B Intermediate
Pancreatic failure
Cause
C End stage
1 endocrine
2 exocrine
3 both
Figure 3: Proposal for a clinically based classification system for
chronic pancreatitis
For example, a patient may be described as having chronic pancreatitis
(idiopathic), stage B, bile duct.47
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uncomplicated disease. Erythema ab igne is a useful
pointer for diagnosis of chronic pancreatitis in these
patients, as is meteorism in patients whose pain has led to
dependence on narcotic analgesics (figure 4). An epigastric
swelling suggests a pseudocyst, inflammatory mass, or
cancer. Patients with multisystem involvement usually
have the autoimmune form of chronic pancreatitis.
Panel 2: Pain in chronic pancreatitis
Caused by the disease
Active inflammation*
Altered nociception
• Neurogenic inflammation*
• Visceral nerve sensitisation*
• Central nerve sensitisation
• Psychological
Hypertension
• Ductal or tissue via increased cholecystokinin
Tissue ischaemia
Caused by complications
• Inflammatory mass in head of gland
• Obstruction of bile duct or duodenum
• Pseudocyst
• Cancer of the pancreas
Caused by treatment
• Opiate gastroparesis or constipation
Caused by unrelated problems
• Peptic ulcer
• Gall stones
• Mesenteric ischaemia
• Small-bowel stricture
• Somatic (eg, surgical scar)
*Mast cell degranulation products and hydrogen sulphide are potential mediators
(see text).
A
Ordinary chronic pancreatitis has a high mortality
rate—nearly 50% within 20–25 years of disease onset,12
as a result of complications of an attack, coexisting
disease, or the effects of alcoholism. Patients with
chronic pancreatitis have an increased risk of pancreatic
cancer,93 which accounts for 3% of deaths.86 Although
the risk of pancreatic cancer is especially high in patients
with hereditary pancreatitis,87 they do not have a higher
mortality risk than the general population.94 Autoimmune
pancreatitis also does not affect long-term survival.95
Diagnosis
Routine laboratory tests might reveal incipient diabetes,
type-1 hyperlipidaemia, or hypercalcaemia in patients
with suspected chronic pancreatitis. If type-1 autoimmune disease is a possibility, serology will show
raised concentrations of γ-globulin, IgG (IgG4 predominantly), and various antibodies, including antilactoferrin, anti-carbonic anhydrase, rheumatoid factor,
and anti-nuclear antibody.50,51 An abnormal liver function
profile suggests alcoholic liver disease, non-alcoholic
steatohepatitis,96 sclerosing cholangitis,50,51,96 metastases
from superimposed pancreatic cancer, gallstones, or,
most commonly, constriction of the intrapancreatic bile
duct, which occurs early in autoimmune pancreatitis,50,51
but is late otherwise.47
Confirmation of the diagnosis of (non-calcific) chronic
pancreatitis is by histology of a wedge biopsy or resected
specimen of pancreas. However, this is impractical. A
reduction in bicarbonate with or without enzyme
content of duodenal aspirates after intubation and
hormonal stimulation (by secretin with or without CCK
or its analogue caerulein), and abnormalities in the
pancreatic duct system on endoscopic retrograde
cholangiopancreatography (ERCP) are the most efficient
alternative diagnostic techniques—with the former
substantially better at detecting small-duct disease than
the latter.2,4 However, the secretory test is available in
only a few centres worldwide (and whether or not an
B
Figure 4: Clinical features in chronic pancreatitis
(A) Erythema ab igne across the upper abdomen in a young patient with recurrent pancreatitis despite cholecystectomy for multiple gallstones (vertical scar). (B) Plain
abdominal radiograph shows heavy calcification in the pancreatic head (arrow) and a loaded colon in a patient with abdominal distension who was addicted to opiates.
1190
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Seminar
endoscopic secretory test is as good is unclear).97
Moreover, ERCP for diagnosis has largely been
abandoned in favour of magnetic resonance
cholangiopancreatography (MRCP) because ERCP can
precipitate pancreatitis in up to 4% of patients.9
There is no non-invasive test that can substitute for the
hormonal test for chronic pancreatitis.2 By contrast,
sophisticated imaging methods have rapidly developed,
such that the traditional ultrasound scan to visualise the
pancreas itself is virtually obsolete (but see figure 5). The
repertoire of imaging techniques is impressive:
multidetector CT (MDCT; figure 5); MRI;97 MRCP
(figure 6), which provides excellent images of the main
pancreatic duct98 but not always of the side-branch
changes as shown by ERCP; secretin-enhanced MRCP,
which also shows duodenal filling by pancreatobiliary
secretions99 and is more accurate than standard MRCP in
identifying small-duct disease;100 endoscopic ultrasound
(EUS),101,102 which identifies both parenchymal and ductal
alterations (figure 6; now classified as the Rosemont
criteria),102 but which is observer-dependent and tends to
overdiagnose the disease;67 diffusion-weighted MRI;103
and PET.104 The last two imaging techniques have not
been properly assessed in chronic pancreatitis, whereas
the role of EUS continues to advance.
No investigation algorithm is suitable worldwide,
because much depends on available resources and
expertise, but a battery of tests should not be used for
diagnosis of suspected chronic pancreatitis because this
will generate many false positive outcomes and cause
distress to the patient.2 Figure 7 presents a sequential
scheme for diagnosis of the disease, on the basis of
whether or not the secretin test is available. This scheme
recognises that an abdominal radiograph will show
pancreatic calculi (nearly 100% specificity; figure 4) in at
least 30% of patients overall and in most patients with
tropical pancreatitis. This stepwise approach is
unnecessary in a patient who presents with fatty stools
after a long history of pancreatitis attacks or pain. In this
event, any of the following tests is probably sufficient for
diagnosis: acid steatocrit (high value) on a spot stool
sample (which obviates the need for the traditional 3-day
faecal fat test);105 faecal elastase (low);105 recovery in expired
air of ¹³C (low) from a ¹³C-labelled mixed triglyceride
load;106 or serum trypsinogen (low).4 However, a CT scan
is needed to identify the disease type.
Imaging tests show distinctive changes in type-1
autoimmune pancreatitis. Both ultrasound and MDCT
typically show a diffusely enlarged sausage-shaped gland
(figure 5). ERCP shows long or multiple strictures of the
pancreatic duct and sometimes a long stricture in the
distal bile duct or sclerosing cholangitis.50,51 Findings
from one study suggest that MRCP cannot replace ERCP
for the diagnosis of autoimmune disease.107 These
imaging features are sufficient to make the diagnosis in a
patient with an increased concentration of IgG4 in serum.
If diagnostic doubt exists (as in a patient with type-2
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A
B
Figure 5: Examples of ultrasound and multidetector images in patients with chronic pancreatitis
(A) Transabdominal ultrasound scan showing a uniformly swollen, hypoechoic pancreas (arrowed), typical of
autoimmune pancreatitis. (B) Multidetector CT showing pancreatic calculi in an atrophic pancreas (long arrow)
and a pseudocyst at the tail of the pancreas (short arrow).
A
B
Figure 6: Examples of three-dimensional magnetic resonance cholangiopancreatogram and endoscopic
ultrasound in patients with chronic pancreatitis
(A) Three-dimensional magnetic resonance cholangiopancreatogram shows a minimally dilated biliary tree and
moderately dilated irregular main pancreatic duct. (B) Endoscopic ultrasound scan shows a minimally dilated
pancreatic duct in the head of pancreas (arrowed) consistent with mild chronic pancreatitis: the distal common
bile duct appears normal (arrow head).
disease, for which there are no serum markers), a
therapeutic trial of steroids or histology (of core biopsy or
resected specimen), or both might be needed.50,51
There are two difficult diagnostic issues that must be
addressed. First, how can one distinguish between an
inflammatory mass of ordinary chronic pancreatitis, focal
autoimmune disease, and pancreatic adenocarcinoma
with upstream chronic pancreatitis? Raised IgG
concentrations can occur in all three settings and existing
tumour markers are not specific enough to distinguish
between them, although new molecular markers are being
developed.108 EUS or MDCT-guided core biopsy can be
used to confirm autoimmune pancreatitis, or a simple
needle biopsy might identify tumour cells. ¹⁸F-fluorodeoxyglucose PET with CT facilitates the identification of
cancer,104 but increased uptake is also a feature of
autoimmune pancreatitis (as is increased uptake of
gallium).50,51 A pancreatectomy specimen might have to be
used as the final diagnostic test, as it is for detecting an
intraductal papillary mucinous tumour in a patient who
has suspected idiopathic large-duct disease.109 Second,
should the clinician start a search for genetic mutations?
1191
Seminar
Suspected chronic
pancreatitis
Plain radiograph for calculi
Positive
Negative
Multidetector CT
Positive
Negative
Suspected small-duct
disease
No
Large-duct
disease
Secretin test available?
Yes
Positive
Secretin test
Magnetic resonance
cholangiopancreatography
after secretin stimulation
Positive
Negative
Analgesics
Negative
Endoscopic ultrasound
Negative
Positive
Reconsider other diagnoses
Re-test at intervals
Therapeutic trial of
micronutrients?
Chronic
pancreatitis
Figure 7: Algorithm for the diagnosis of chronic pancreatitis
A recent review gives valuable guidance.80 PRSS1 mutation
testing for diagnostic purposes is acceptable in
symptomatic young individuals or in those with a family
history of pancreatitis, but counselling and clinical followup are needed if the result is positive. There is no indication
for SPINK1 mutation testing. At present there is no
rationale for CFTR mutation testing in the setting of
pancreatitis alone. Instead, a sweat test should be done if
atypical cystic fibrosis is suspected, and patients should be
referred to a specialist clinic when sweat chloride
concentration is borderline (40–59 mmol/L) or abnormal
(>60 mmol/L). However, the vulnerability of CFTR to
electrophilic stress potentially explains both false positive
sweat tests and abnormal nasal potential difference studies
in a variety of conditions (eg, severe malnutrition).32
Treatment
Treatment goals
The goals of treatment for chronic pancreatitis are to
relieve acute or chronic pain, calm the disease process to
prevent recurrent attacks, correct metabolic consequences
such as diabetes or malnutrition, manage complications
when they arise, and address psychosocial problems.
Endoscopic treatment, surgery, or both, are only needed
when optimum medical treatment fails to relieve pain
(figure 8) and to deal with specific complications (figure 3).
A detailed discussion of complications is beyond the
scope of this Seminar.
1192
When providing treatment to control the pain
associated with chronic pancreatitis, the patient’s fears
and misconceptions about the disease should be
addressed sympathetically. Time should be spent
discussing the disease with the patient at the first clinic
visit, with particular attention paid to circumstances
surrounding the first attack. Patients should be advised
to avoid alcohol and cigarettes, although there is no
evidence that abstinence from alcohol slows the disease
and the effect of alcohol on pain is debated.67,89 A dietary
assessment should be done (see later). Where warranted,
the help of a psychologist or pain therapy specialist
should be sought, and the primary-care practitioner
must also be briefed on treatment strategy. Continuity of
care is important to gain the patient’s trust and to
minimise the risk of addiction to narcotics.
Regular analgesics are superfluous in patients with
sporadic attacks but are needed in those with background
pain. Use of analgesics should broadly follow WHO
guidelines for cancer pain.110 Briefly, analgesic
treatment begins with paracetamol or a non-steroidal
anti-inflammatory drug, or both, followed by a mild
opioid such as tramadol, perhaps coupled with a
neuroleptic antidepressant. Narcotic analgesics should
be avoided if possible. A simple pain diary with a 10 cm
visual analogue scale is useful, as is a baseline quality-oflife assessment. Analgesia devices to deliver morphine
that are controlled by the patient should not be used,
even in an attack. Such drugs can worsen pain by
inducing mast cell degranulation111 and (possibly thereby17)
cause gastroparesis4 and constipation (figure 4).
Steroids and enzyme therapy
Treatment with steroids is associated with rapid relief
of symptoms in autoimmune pancreatitis.50,51 The
starting dose is 30–40 mg per day of prednisolone,
which is tapered over 3 months while monitoring
serum IgG concentrations and imaging findings. Longterm maintenance with 5·0–7·5 mg per day of
prednisolone is recommended to prevent relapses.50
Recurrences, which typically occur in type-1 disease,95
favour the development of pancreatic calculi.112
In patients with small-duct disease, pancreatic acinar
cells are suggested to be under constant stimulation by
CCK because subnormal delivery of pancreatic proteases
into the duodenum allows improved survival of a CCKreleasing peptide from the duodenal mucosa.4 Hence,
the following potential treatments have been successfully
tested:4 oral pancreatic enzymes (non-enteric coated, two
trials), subcutaneous octreotide (one trial), and oral
dosing with the CCK-A receptor antagonist loxiglumide
(one trial). However, this issue is contentious,113,114 and the
explanation that these measures “allow the pancreas to
rest”4 is at odds with the finding that the exocytosis
apparatus is already paralysed in an attack (figure 1) and
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Seminar
hindered thereafter.32 Other explanations might be that
such treatments act by blunting an effect of CCK on pain
pathways in the CNS36 or by ameliorating electrophilic
stress (see later).115
Micronutrient therapy
Micronutrient therapy is designed to supply methyl and
thiol moieties that are essential for the exocytosis
apparatus (figure 1) while protecting it against
electrophilic attack, as by CYP-derived ROS or reactive
xenobiotics species (figure 2).32 Findings from six
clinical trials have reported that micronutrient therapy
controls pain and curbs attacks in patients with chronic
pancreatitis.116–122 Of these trials, three were
descriptive116–118 and three were placebo-controlled.119–122
However, the different ways of expressing outcome
precludes a meta-analysis.123 The study with the highest
power (80%) to detect a difference between treatment
and placebo was from Delhi:122 after 6 months’ treatment
(which included pancreatic enzymes in all patients)
there was a greater reduction in the number of painful
days per month and in the use of analgesic tablets in
the treatment group than in the placebo group;
substantially more patients became pain free, and
biochemical markers of electrophilic stress were
lowered by active treatment.
Studies from Manchester, UK, suggested that the
micronutrient therapy formulation should include
methionine and vitamin C,124 with the need for selenium
assessed by measuring blood concentrations. Vitamin E
and β carotene were included in the first trial because
there was no commercial preparation that did not include
them,119 and three of the other five trials also used this
protocol.116,121,122 Improvement, as judged by the number of
attacks, admission episodes, pain diaries, pain intensity,
or permutations and combinations of these factors,
occurred by 10–12 weeks.119,121,122 In the UK, the micronutrient therapy preparation Antox (Pharma Nord,
Morpeth, UK) is a convenient means of dosing because it
contains all the desired items. A starting regimen of two
tablets of Antox three times per day provides daily doses
of 2·88 g methionine (but up to 4 g might initially be
needed in some patients),125 720 mg vitamin C, 300 μg
organic selenium, and 210 mg vitamin E (which is
unnecessary until steatorrhoea develops).126 This treatment has no significant side-effects now that β carotene
has been withdrawn because of cosmetic problems:125
one patient (of >300) developed schizophrenia when on
4 g of methionine daily but, of note, this patient had a
strong family history of psychiatric disease.125
Patients should also be given dietary advice on
antioxidant-rich foods to aid the long-term management
of the disease. It should be stressed that culinary
practices—eg, frying vegetables at high temperature (as
in south India41)—could compromise the bioavailability of
antioxidants, notably of ascorbic acid.32 Blood monitoring
is essential to ensure that plasma and erythrocyte
www.thelancet.com Vol 377 April 2, 2011
Painful chronic pancreatitis
Non-narcotic analgesia
Alcohol and cigarette avoidance
Dietary assessment
Psychosocial issues
Micronutrient treatment
Pancreatic enzyme treatment
Treatment
not
effective
Large–duct disease
Small–duct disease
Pancreatic mass
Cyst or pseudocyst
No mass
Suspected
autoimmune
pancreatitis
Treatment
not
effective
Suspected
cancer
Treatment
not effective
Neural
manipulation*
Trial of steroids
Treatment
effective
CT guided or endoscopic
ultrasound-guided biopsy
Treatment
effective
Treatment
effective
Endoscopic or surgical
duct drainage
Solid mass
Endoscopic
drainage
Treatment
effective
Exclude non-pancreatic pain
Conservative treatment for 10 weeks
Cancer
confirmed
Doubt
persists
Treatment
effective
Treatment
not
effective
Pancreatectomy
Figure 8: Algorithm for the management of painful chronic pancreatitis
Note that the solid mass in autoimmune pancreatitis is often in the head of pancreas and suggests cancer,
but that ducts are usually constricted. *Procedures include thoracic splanchnicectomy, coeliac plexus block,
and neurostimulation.
glutathione levels have increased and that concentrations
of the prescribed micronutrients are not excessive,
because this would compromise the physiological roles of
ROS.127,128 Very recent reports indicate the need to keep
track of blood homocysteine, and concentrations of
vitamins (B6, B12, folic acid) that serve as cofactors of
enzymes that govern homocysteine removal—either by
facilitating its transmethylation back to methionine, or by
ensuring its passage along the transsulphuration pathway
towards glutathione.32,34,41,129 Of particular interest, elevated
homocysteine has been recorded in people at Soweto
(South Africa) who drank more than 100 g alcohol per day
for many years130—a group that is traditionally regarded
as being at high risk of chronic pancreatitis.55
Treatment for 10 weeks is recommended before any
invasive procedure in patients with chronic pancreatitis,
to calm the disease process. Full treatment is usually
needed for 6 months, followed by a gradual dose reduction
guided by biochemical data and patients’ symptoms.125 We
recorded treatment failure in 10% of patients, usually
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Seminar
because of non-compliance (eg, in patients who misuse
alcohol) or a large cyst or pseudocyst;125 otherwise,
symptom control was achieved by choline supplements to
boost methyl supply.32 Moreover, micronutrient therapy
has no effect on painful conditions that might be
misdiagnosed as chronic pancreatitis (unpublished); once
validated, this finding could form the basis for a therapeutic
trial when the diagnosis remains equivocal after full
testing (figure 7). Finally, there is increasing evidence to
support the idea that a daily micronutrient supplement
might abort the development of chronic pancreatitis in
groups or even populations at risk of the disease.32,130
Micronutrient treatment is better at controlling pain
and improving quality of life than conventional
treatment.131 Moreover, long-term micronutrient
treatment might curb disease progression.82 Excluding
typical autoimmune pancreatitis, which can be treated
with steroids, micronutrient treatment has been effective
irrespective of cause (including mutations in PRSS1,118
CFTR,82 and SPINK182), disease duration,131 or ductal
anatomy (large-duct calcifying or small-duct disease),
and also when there is an inflammatory calcified mass.132
By contrast, the antioxidants allopurinol and curcumin
have been ineffective for treatment of chronic pancreatitis
in clinical trials.32 Two multicentre trials of Antox are
in progress (Current Controlled Trials numbers
ISRCTN21047731 and ISRCTN44912429).
Treatment of steatorrhoea and diabetes
The treatment of pancreatic steatorrhoea usually begins
with 30 000 IU of lipase per meal in an acid-resistant
enzyme preparation. In patients who do not respond to
this treatment, a low-fat diet (50–75 g per day), dose
increase, gastric proton-pump inhibitor, or a combination
thereof should be recommended.67 A check on fat-soluble
vitamin status is advisable.126 The main aim in the
treatment of diabetes in patients with chronic pancreatitis
is to prevent hypoglycaemia caused by deficiency of
glucagon; simple insulin regimens are preferable.
Endoscopic treatment
Of the many potential indications for endoscopic
treatment of chronic pancreatitis,133 two are undisputed.
First, EUS can be used to facilitate transmural drainage of
pseudocysts that are not connected to the pancreatic duct
system, and endoscopically placed transpapillary stents in
the duct are useful when they do134 or when a duct leak
leads to pancreatic ascites or pleural effusion.135 Second,
endoscopic stenting of the bile duct is a useful temporary
measure in patients with a distal duct stricture.
Limited comparative data suggest that surgery is more
effective136 and has a more durable effect in controlling
pain137 than endoscopic dilatation or stenting of the
pancreatic duct. Findings from a randomised clinical
trial showed that extracorporeal shock-wave lithotripsy
with or without endoscopic clearance of stone fragments
was equally effective at reducing pain over the subsequent
1194
2 years in patients with intraductal calculi;138 however,
lithotripsy can occasionally precipitate acute pancreatitis.133 Thoracoscopic splanchnicectomy can provide good
initial pain relief, but pain recurs by 15 months in more
than 50% of patients.139
Surgery
Historically, around 50% of patients with chronic
pancreatitis referred to surgical clinics require an operation
compared with around 25% on long-term follow-up in a
specialist medical clinic.88 Micronutrient treatment seems
to substantially reduce the need for surgery.82,125,132 The
objectives of surgery are to decompress obstructed ducts
(to relieve pain) and at the same time to preserve pancreatic
tissue as well as adjacent organs (to preserve function),
while recognising that the head of the pancreas constitutes
the so-called pacemaker of chronic pancreatitis. The
simplest operation—lateral pancreaticojejunostomy—
provides immediate pain relief in many patients but pain
tends to recur with the passage of time. Distal pancreatectomy, like pancreaticojejunostomy, does not address the
problem of disease in the head of the pancreas, which can
continue to deteriorate. Moreover, distal pancreatectomy
can result in removal of the functionally most active part of
the gland. Pancreaticoduodenectomy gives good pain
relief, but is a major operation. It is indicated in groove
pancreatitis if there is duodenal obstruction or when
neoplasia cannot be ruled out preoperatively.140
Duodenum-preserving head resection combined, when
appropriate, with lateral pancreaticojejunostomy has
been a major advance: only 8·7% of patients continued to
have pancreatic pain at a median of 5·7 years follow-up,
whereas 93% of patients had pancreatic pain
preoperatively.141 The operation was simplified by carving
out an inverted cone from the pancreatic head, allowing
the cavity and the distal duct to drain into a jejunal loop,
thus removing the complex mass of obstructed ducts and
inflammatory tissue that frequently lies within the head
of the gland.142 A further simplification made this
operation suitable for patients in whom there was little in
the way of duct dilatation: a so-called ice-cream scoop is
taken out of the pancreatic head to leave a thin rim of
pancreas laterally and posteriorly. Pain improved in
55% of patients after 41 months of follow-up.143
A precise assessment of the merits of the different
operations for painful chronic pancreatitis has been
confounded by an absence of agreement about
indications for surgery, details of the surgical
techniques, and methods used to measure outcomes.144
However, there is no doubt that the safety of conservative operations (eg, lateral pancreaticojejunostomy
combined with limited excision of the head of the
gland) has improved: operative mortality, about 5% with
traditional resection of the head of pancreas, has fallen
to 0–3% and morbidity has been halved.145 There seems
to be little if any advantage to be gained from total
pancreatectomy with islet transplant.146
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Seminar
Conclusions
Chronic pancreatitis remains a challenging disease.
Resective surgery continues to be the definitive treatment
for persistent pain, but is not ideal in a chronic
inflammatory process. Micronutrient treatment might
offer a viable alternative.
Contributors
All authors participated in writing this Seminar. All authors saw and
approved the final manuscript.
22
23
24
25
26
Conflicts of interest
We declare that we have no conflicts of interest.
Acknowledgments
We thank Prof J R Foster for the microphotographs (figure 2).
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