Seminar

Chronic pancreatitis
Joan M Braganza, Stephen H Lee, Rory F McCloy, Michael J McMahon

Lancet 2011; 377: 1184–97 Chronic pancreatitis is a progressive fibroinflammatory disease that exists in large-duct (often with intraductal
Published Online calculi) or small-duct form. In many patients this disease results from a complex mix of environmental (eg, alcohol,
March 11, 2011 cigarettes, and occupational chemicals) and genetic factors (eg, mutation in a trypsin-controlling gene or the cystic
DOI:10.1016/S0140-
fibrosis transmembrane conductance regulator); a few patients have hereditary or autoimmune disease. Pain in
6736(10)61852-1
the form of recurrent attacks of pancreatitis (representing paralysis of apical exocytosis in acinar cells) or constant
Department of
Gastroenterology
and disabling pain is usually the main symptom. Management of the pain is mainly empirical, involving potent
(J M Braganza DSc) and analgesics, duct drainage by endoscopic or surgical means, and partial or total pancreatectomy. However, steroids
Department of Radiology rapidly reduce symptoms in patients with autoimmune pancreatitis, and micronutrient therapy to correct
(S H Lee FRCR), Manchester
electrophilic stress is emerging as a promising treatment in the other patients. Steatorrhoea, diabetes, local
Royal Infirmary, Manchester,
UK; Department of Education, complications, and psychosocial issues associated with the disease are additional therapeutic challenges.
Lancashire Teaching Hospitals,
Preston, UK (R F McCloy FRCS); Introduction Definition
and University of Leeds and
Chronic pancreatitis is a progressive inflammatory Traditionally, chronic pancreatitis has been classed as
Nuffield Hospital, Leeds, UK
(Prof M J McMahon FRCS) disorder in which pancreatic secretory parenchyma is fundamentally different from acute pancreatitis—the
Correspondence to:
destroyed and replaced by fibrous tissue, eventually latter is usually characterised by restoration of normal
Dr Joan M Braganza, leading to malnutrition and diabetes. Two forms are pancreatic histology after full clinical recovery.1 However,
c/o Mrs Jenny Parr, recognised—a large-duct calcifying type1 and a small-duct acute, recurrent acute, and chronic pancreatitis are now
Core Technology Facility,
variant.2–4 The disease is uncommon in Europe and the regarded as a disease continuum.9,10 There are several
3rd Floor, Grafton Street,
Manchester M13 9NT, UK USA; its prevalence in France is 26 per 100 000 people.5 reasons for this change: recurrent acute pancreatitis can
jenny.parr@manchester.ac.uk This prevalence is not dissimilar to the middle of three develop into chronic pancreatitis;10–12 there is an overlap
estimates from Japan,6,7 but considerably lower than the in causative factors, both genetic and environmental;10,13
figure of 114–200 per 100 000 in south India.7 experimental protocols can be modified to induce each
The main symptom of chronic pancreatitis is usually condition;14 and the pancreatitis attack is stereotyped—
pain, which occurs as attacks that mimic acute pancrea- patients have severe abdominal pain and increased blood
titis or as constant and disabling pain. Despite decades of amylase, lipase, and trypsinogen.
research, treatment of chronic pancreatitis remains
mostly empirical, and thus patients are repeatedly Pathophysiology and pathology
admitted to hospital and have interventional procedures, Experimental studies since the 1950s have shown that an
which strains medical resources.8 This absence of attack of pancreatitis begins as pancreastasis,13 prevention
progress in treatment is a sign of uncertainty about how of apical exocytosis in the pancreatic acinar cell (figure 1).15
the identified causative factors lead to the disease. The acinar cell quickly releases newly synthesised enzyme
Therefore, in this Seminar we focus on the patho- via the basolateral membrane into lymphatics, by way of
physiology and pathology of chronic pancreatitis before the interstitium, and directly into the bloodstream.16 Some
describing clinical management. zymogen granules also release their stored enzyme
basolaterally.15 These events result in inflammation.17
Findings from prospective clinical studies concur with
Search strategy and selection criteria this pancreastasis–pancreatitis sequence.13,17
We searched PubMed and the Cochrane library (to August, Experimental work has pinpointed a burst of reactive
2010) for reviews on chronic pancreatitis. We used Google oxygen species (ROS) as the trigger of so-called
scholar for specific searches, with “chronic pancreatitis” as the pancreastasis18 and as the potentiator of inflammation by
key phrase combined with “epidemiology”, “pathology”, activating signalling cascades that convert the damaged
“aetiology”, “gene mutations”, “pathogenesis”, acinar cell into a factory for chemokines and cytokines.19,20
“classification”, “diagnosis”, “pancreatic function tests”, ROS serve several physiological roles, including in signal
“pancreatic imaging tests”, “treatment of pain”, “pancreatic transduction,13,21 but an excess of ROS compared with
enzyme therapy”, “micronutrient therapy”, “antioxidant antioxidant capacity (electrophilic stress) is potentially very
therapy”, “endoscopic treatment”, or “surgical treatment”. We damaging. The exocytosis blockade seems to be caused by
selected the most up-to-date articles but did not disregard disruption of the methionine trans-sulphuration pathway
commonly referenced older publications. We also examined that produces essential methyl and thiol (principally
the reference lists of identified papers and selected those that glutathione) moieties.17,22 This problem also occurs in
we judged to be relevant. Review articles and book chapters clinical acute or acute-on-chronic pancreatitis.23–25
are cited to give readers more details and references than this In patients who develop large-duct chronic pancreatitis,
Seminar can accommodate. 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
E pathways PAP/regIII
PSP/reg

ZG ZG ZG D

L ZG-L ZG-L

GC GC
RER RER ZG RER
Ph-elastase
Ph-PLA2

Nucleus Nucleus Nucleus

Constitutive MO
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 so-
called groove (paraduodenal) pancreatitis has been
identified.11 Each inflammatory attack can cause foci of
fat necrosis that seem to lead to both pseudocysts and
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) mono-
oxygenases,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 peroxi-
dase), 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 lipo-
fuscin 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
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

A B
D
H

H
D 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§

Lesions
Distribution Patchy Diffuse Diffuse Diffuse
Extent of gland Variable Total Total Total or focal
Duct system
Main duct Irregularly dilated Minimally dilated Smoothly dilated Constricted
Protein plugs All ducts Intralobular and interlobular No No
Calcifying tendency Yes No No 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 Panel 1: Causative factors
Toxic
Causes Xenobiotics
Panel 1 lists causative factors of chronic pancreatitis. In • Alcohol
adults, excluding those with cystic fibrosis, 90–95% of • Cigarette smoke
patients are regarded as having alcoholic or idiopathic • Occupational volatile hydrocarbons
disease. Infective causes are rare.52 The connection between • Drugs: valproate, phenacitin, thiazide, oestrogen,
chronic pancreatitis and drugs (eg, valproate) is mostly and azathioprine
anecdotal. Studies from Italy,53 China, and Japan54 report
Endogenous
an association with gallstones in about 30% of patients.
• Hypercalcaemia, hyperparathyroidism
• Hyperlipidaemia, lipoprotein lipase deficiency
Alcoholic
• Chronic renal failure
Alcohol has long been regarded as the leading cause of
chronic pancreatitis in Europe, the USA, Brazil, Mexico, Infection or infestation
and South Africa, and is now regarded as the main cause • HIV, mumps virus, coxsackie virus
of the disease also in Australia and South Korea.7 • Echinococcus, Cryptosporidium
However, excess alcohol was the predominant factor in Genetic*
only 34% of cases of chronic pancreatitis in a recent • CFTR mutation
multicentre study from Italy53 and in 44% of cases in an • PRSS1 mutation
audit from the USA,55 with another study reporting that • SPINK1 mutation
African-Americans are at particular risk.56 Whether these
new data reflect differences in the definition of alcoholic Obstruction of main pancreatic duct
disease55 or a genuine change in the cause of chronic • Cancer
pancreatitis is not clear.57 • Post-traumatic scarring
Experimental studies have shown that, although the • Post-duct destruction in severe attack
pancreas processes ethanol efficiently (via a non-oxidative Recurrent acute pancreatitis
route that produces fatty acid ethyl esters, and by
oxidation via the acetaldehyde pathway), its metabolites Autoimmune
injure acinar cells and activate stellate cells in vitro.42,58
Miscellaneous
However, prolonged ethanol feeding does not induce
• Gall stones
chronic pancreatitis.58,59 Hence, the finding of a latent
• After transplant
interval of 15 years or more in patients who consumed
• After irradiation
150 g or more of ethanol per day—as most recently noted
• Vascular disease
in India60—is unsurprising. Moreover, less than 10% of
people who drink alcohol in excess develop the disease.61 Idiopathic
Collectively, these findings suggest that other factors • Early or late onset
interact to amplify ethanol toxicity in vivo. • Tropical
In animal models, small doses of ethanol induce
CFTR=cystic fibrosis transmenbrane conductance regulator. PRSS1=protease serine
CYP2E1, thus increasing the toxicity from other chemicals cationic trypsinogen. SPINK1=serine protease inhibitor Kazal. *Other, less common
to which the animal is simultaneously exposed.62,63 These mutations have been described.

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
(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
Genetic
Normally, if trypsinogen becomes prematurely activated
within the pancreas, it is inhibited by SPINK1 and then
self-destructs or is degraded by trypsin-activated pro-
teases;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 degradation-
resistant 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-of-
function 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
1188
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.
Ductal theory
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 auto-
immune 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. How-
ever, in chronic pancreatitis electrophilic stress from
toxic metabolites—and, thereby, recurrent pancrea-
stasis—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
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 distri-
bution.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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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
Attacks of apparent
acute pancreatitis A Early
Pain
Complications
• Bile duct stricture
• Duodenal stricture
• Vascular stricture
Clinical • Portal hypertension B Intermediate Cause
criteria • Pseudocyst
• Pancreatic fistula
• Pancreatic ascites
• Rare, eg, colonic
stricture C End stage
1 endocrine
2 exocrine
Pancreatic failure 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 Ordinary chronic pancreatitis has a high mortality
pointer for diagnosis of chronic pancreatitis in these rate—nearly 50% within 20–25 years of disease onset,12
patients, as is meteorism in patients whose pain has led to as a result of complications of an attack, coexisting
dependence on narcotic analgesics (figure 4). An epigastric disease, or the effects of alcoholism. Patients with
swelling suggests a pseudocyst, inflammatory mass, or chronic pancreatitis have an increased risk of pancreatic
cancer. Patients with multisystem involvement usually cancer,93 which accounts for 3% of deaths.86 Although
have the autoimmune form of chronic pancreatitis. 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
Panel 2: Pain in chronic pancreatitis pancreatitis also does not affect long-term survival.95
Caused by the disease
Diagnosis
Active inflammation*
Routine laboratory tests might reveal incipient diabetes,
Altered nociception type-1 hyperlipidaemia, or hypercalcaemia in patients
• Neurogenic inflammation* with suspected chronic pancreatitis. If type-1 auto-
• Visceral nerve sensitisation* immune disease is a possibility, serology will show
• Central nerve sensitisation raised concentrations of γ-globulin, IgG (IgG4 pre-
• Psychological dominantly), and various antibodies, including anti-
Hypertension lactoferrin, anti-carbonic anhydrase, rheumatoid factor,
• Ductal or tissue via increased cholecystokinin and anti-nuclear antibody.50,51 An abnormal liver function
profile suggests alcoholic liver disease, non-alcoholic
Tissue ischaemia
steatohepatitis,96 sclerosing cholangitis,50,51,96 metastases
Caused by complications from superimposed pancreatic cancer, gallstones, or,
• Inflammatory mass in head of gland most commonly, constriction of the intrapancreatic bile
• Obstruction of bile duct or duodenum duct, which occurs early in autoimmune pancreatitis,50,51
• Pseudocyst but is late otherwise.47
• Cancer of the pancreas Confirmation of the diagnosis of (non-calcific) chronic
pancreatitis is by histology of a wedge biopsy or resected
Caused by treatment specimen of pancreas. However, this is impractical. A
• Opiate gastroparesis or constipation reduction in bicarbonate with or without enzyme
Caused by unrelated problems content of duodenal aspirates after intubation and
• Peptic ulcer hormonal stimulation (by secretin with or without CCK
• Gall stones or its analogue caerulein), and abnormalities in the
• Mesenteric ischaemia pancreatic duct system on endoscopic retrograde
• Small-bowel stricture cholangiopancreatography (ERCP) are the most efficient
• Somatic (eg, surgical scar) alternative diagnostic techniques—with the former
substantially better at detecting small-duct disease than
*Mast cell degranulation products and hydrogen sulphide are potential mediators
(see text).
the latter.2,4 However, the secretory test is available in
only a few centres worldwide (and whether or not an

A 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.

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 Seminar

endoscopic secretory test is as good is unclear).97

A B
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, Figure 5: Examples of ultrasound and multidetector images in patients with chronic pancreatitis
which also shows duodenal filling by pancreatobiliary (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)
secretions99 and is more accurate than standard MRCP in and a pseudocyst at the tail of the pancreas (short arrow).
identifying small-duct disease;100 endoscopic ultrasound
(EUS),101,102 which identifies both parenchymal and ductal A B
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 Figure 6: Examples of three-dimensional magnetic resonance cholangiopancreatogram and endoscopic
will generate many false positive outcomes and cause ultrasound in patients with chronic pancreatitis
distress to the patient.2 Figure 7 presents a sequential (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
scheme for diagnosis of the disease, on the basis of pancreatic duct in the head of pancreas (arrowed) consistent with mild chronic pancreatitis: the distal common
whether or not the secretin test is available. This scheme bile duct appears normal (arrow head).
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 disease, for which there are no serum markers), a
tropical pancreatitis. This stepwise approach is therapeutic trial of steroids or histology (of core biopsy or
unnecessary in a patient who presents with fatty stools resected specimen), or both might be needed.50,51
after a long history of pancreatitis attacks or pain. In this There are two difficult diagnostic issues that must be
event, any of the following tests is probably sufficient for addressed. First, how can one distinguish between an
diagnosis: acid steatocrit (high value) on a spot stool inflammatory mass of ordinary chronic pancreatitis, focal
sample (which obviates the need for the traditional 3-day autoimmune disease, and pancreatic adenocarcinoma
faecal fat test);105 faecal elastase (low);105 recovery in expired with upstream chronic pancreatitis? Raised IgG
air of ¹³C (low) from a ¹³C-labelled mixed triglyceride concentrations can occur in all three settings and existing
load;106 or serum trypsinogen (low).4 However, a CT scan tumour markers are not specific enough to distinguish
is needed to identify the disease type. between them, although new molecular markers are being
Imaging tests show distinctive changes in type-1 developed.108 EUS or MDCT-guided core biopsy can be
autoimmune pancreatitis. Both ultrasound and MDCT used to confirm autoimmune pancreatitis, or a simple
typically show a diffusely enlarged sausage-shaped gland needle biopsy might identify tumour cells. ¹⁸F-fluoro-
(figure 5). ERCP shows long or multiple strictures of the deoxyglucose PET with CT facilitates the identification of
pancreatic duct and sometimes a long stricture in the cancer,104 but increased uptake is also a feature of
distal bile duct or sclerosing cholangitis.50,51 Findings autoimmune pancreatitis (as is increased uptake of
from one study suggest that MRCP cannot replace ERCP gallium).50,51 A pancreatectomy specimen might have to be
for the diagnosis of autoimmune disease.107 These used as the final diagnostic test, as it is for detecting an
imaging features are sufficient to make the diagnosis in a intraductal papillary mucinous tumour in a patient who
patient with an increased concentration of IgG4 in serum. has suspected idiopathic large-duct disease.109 Second,
If diagnostic doubt exists (as in a patient with type-2 should the clinician start a search for genetic mutations?

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 Seminar

When providing treatment to control the pain

Suspected chronic associated with chronic pancreatitis, the patient’s fears
pancreatitis
and misconceptions about the disease should be
Positive
addressed sympathetically. Time should be spent
Plain radiograph for calculi
discussing the disease with the patient at the first clinic
Negative visit, with particular attention paid to circumstances
Positive
Multidetector CT surrounding the first attack. Patients should be advised
Negative to avoid alcohol and cigarettes, although there is no
Suspected small-duct Large-duct
evidence that abstinence from alcohol slows the disease
disease disease and the effect of alcohol on pain is debated.67,89 A dietary
assessment should be done (see later). Where warranted,
No Secretin test available? the help of a psychologist or pain therapy specialist
Yes should be sought, and the primary-care practitioner
Positive
must also be briefed on treatment strategy. Continuity of
Secretin test care is important to gain the patient’s trust and to
Negative
Positive minimise the risk of addiction to narcotics.
Magnetic resonance
cholangiopancreatography
after secretin stimulation Analgesics
Regular analgesics are superfluous in patients with
Negative
sporadic attacks but are needed in those with background
Positive pain. Use of analgesics should broadly follow WHO
Endoscopic ultrasound
guidelines for cancer pain.110 Briefly, analgesic
Negative
Reconsider other diagnoses Chronic
treatment begins with paracetamol or a non-steroidal
Re-test at intervals pancreatitis anti-inflammatory drug, or both, followed by a mild
Therapeutic trial of opioid such as tramadol, perhaps coupled with a
micronutrients?
neuroleptic antidepressant. Narcotic analgesics should
Figure 7: Algorithm for the diagnosis of chronic pancreatitis
be avoided if possible. A simple pain diary with a 10 cm
visual analogue scale is useful, as is a baseline quality-of-
life assessment. Analgesia devices to deliver morphine
A recent review gives valuable guidance.80 PRSS1 mutation that are controlled by the patient should not be used,
testing for diagnostic purposes is acceptable in even in an attack. Such drugs can worsen pain by
symptomatic young individuals or in those with a family inducing mast cell degranulation111 and (possibly thereby17)
history of pancreatitis, but counselling and clinical follow- cause gastroparesis4 and constipation (figure 4).
up are needed if the result is positive. There is no indication
for SPINK1 mutation testing. At present there is no Steroids and enzyme therapy
rationale for CFTR mutation testing in the setting of Treatment with steroids is associated with rapid relief
pancreatitis alone. Instead, a sweat test should be done if of symptoms in autoimmune pancreatitis.50,51 The
atypical cystic fibrosis is suspected, and patients should be starting dose is 30–40 mg per day of prednisolone,
referred to a specialist clinic when sweat chloride which is tapered over 3 months while monitoring
concentration is borderline (40–59 mmol/L) or abnormal serum IgG concentrations and imaging findings. Long-
(>60 mmol/L). However, the vulnerability of CFTR to term maintenance with 5·0–7·5 mg per day of
electrophilic stress potentially explains both false positive prednisolone is recommended to prevent relapses.50
sweat tests and abnormal nasal potential difference studies Recurrences, which typically occur in type-1 disease,95
in a variety of conditions (eg, severe malnutrition).32 favour the development of pancreatic calculi.112
In patients with small-duct disease, pancreatic acinar
Treatment cells are suggested to be under constant stimulation by
Treatment goals CCK because subnormal delivery of pancreatic proteases
The goals of treatment for chronic pancreatitis are to into the duodenum allows improved survival of a CCK-
relieve acute or chronic pain, calm the disease process to releasing peptide from the duodenal mucosa.4 Hence,
prevent recurrent attacks, correct metabolic consequences the following potential treatments have been successfully
such as diabetes or malnutrition, manage complications tested:4 oral pancreatic enzymes (non-enteric coated, two
when they arise, and address psychosocial problems. trials), subcutaneous octreotide (one trial), and oral
Endoscopic treatment, surgery, or both, are only needed dosing with the CCK-A receptor antagonist loxiglumide
when optimum medical treatment fails to relieve pain (one trial). However, this issue is contentious,113,114 and the
(figure 8) and to deal with specific complications (figure 3). explanation that these measures “allow the pancreas to
A detailed discussion of complications is beyond the rest”4 is at odds with the finding that the exocytosis
scope of this Seminar. 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 Painful chronic pancreatitis

pathways in the CNS36 or by ameliorating electrophilic

stress (see later).115 Non-narcotic analgesia
Alcohol and cigarette avoidance
Dietary assessment Exclude non-pancreatic pain Treatment
Micronutrient therapy Psychosocial issues Conservative treatment for 10 weeks effective
Micronutrient therapy is designed to supply methyl and Micronutrient treatment
Pancreatic enzyme treatment Treatment
thiol moieties that are essential for the exocytosis not
apparatus (figure 1) while protecting it against effective
electrophilic attack, as by CYP-derived ROS or reactive
xenobiotics species (figure 2).32 Findings from six
Large–duct disease Small–duct disease
clinical trials have reported that micronutrient therapy
controls pain and curbs attacks in patients with chronic
pancreatitis.116–122 Of these trials, three were Pancreatic mass No mass
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 Treatment
Cyst or pseudocyst Solid mass Endoscopic or surgical
power (80%) to detect a difference between treatment duct drainage effective
and placebo was from Delhi:122 after 6 months’ treatment
(which included pancreatic enzymes in all patients)
Treatment
there was a greater reduction in the number of painful Suspected Suspected not
days per month and in the use of analgesic tablets in autoimmune cancer effective
pancreatitis
the treatment group than in the placebo group;
Treatment
substantially more patients became pain free, and not effective Neural Treatment
biochemical markers of electrophilic stress were Trial of steroids manipulation* effective

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 micro-
nutrient 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 treat-
ment 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
Endoscopic CT guided or endoscopic Treatment
drainage ultrasound-guided biopsy not
effective
Treatment Treatment Cancer Doubt
effective effective confirmed persists
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 pancrea-
titis.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 pancrea-
tectomy, 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 conser-
vative 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
www.thelancet.com Vol 377 April 2, 2011

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.
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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