Braganza2011 PDF
Braganza2011 PDF
Braganza2011 PDF
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
ZG ZG ZG D
L ZG-L ZG-L
GC GC
RER RER ZG RER
Ph-elastase
Ph-PLA2
Constitutive MO
pathway
E
E E
MC PMN
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— fibrosis.11 Nerves show breaching of the perineurium
the precursors to calcium carbonate stones.1 (1) There is adjacent to inflammatory foci, while the expression of
an early increase in secretion of enzyme and calcium, but nociceptive chemicals in nerve endings is increased.36
a decrease in the serine protease inhibitor Kazal type 1 Immunocytochemistry gives valuable insights into the
(SPINK 1), bicarbonate, and citrate.1 (2) Concentrations of development of chronic pancreatitis. Acinar cells,
free radical oxidation products are raised in the pancreatic which are hyperplastic at disease outset,2 show
fluid,26 which suggests ongoing electrophilic stress, and strong expression of cytochrome P450 (CYP) mono-
in an apparent attempt to compensate, concentrations of oxygenases,37–39 as do proliferated islets of Langerhans,37–39
the natural antioxidants27 lactoferrin and mucin are and hepatocytes (figure 2).37,38 After birth, CYP enzymes
increased.1,2,28 (3) Concentrations are altered of two are mainly located in the liver. CYP metabolises
secretory stress proteins29 (increased concentration of environmental lipophilic chemicals (xenobiotics). In the
pancreatitis associated protein [PAP]/regIII, which is first phase, the enzyme uses ROS to hydroxylate the
activated by electrophilic stress; and variable concentration substrate, which then usually undergoes second-phase
of pancreatic stone protein [PSP]/reg, formerly called conjugation reactions, often with glutathione and
lithostatin;1 figure 1) that tend to form fibrous lattices catalysed by glutathione transferases. So-called enzyme
upon partial digestion by trypsin. (4) There is an increase induction might be accompanied by expansion of the
of GP-2, which is a secreted component of zymogen endoplasmic reticulum so that, at least initially, the cell
granule membranes (analogous to the renal cast protein).30 secretes more of its normal products. However, this
(5) Concentrations of lysosomal enzymes are increased in defence reaction backfires if first-phase processing (eg, by
ductal fluid, and traces of trypsin appear.31 Moreover, the CYP2E1, CYP1A, and CYP3A1 isoforms) produces a
methionine metabolic pathway remains fractured.32–34 reactive xenobiotic metabolite. Cell injury depends on
On histology, the defining triad of stable disease whether or not there is enough by way of defences to
(irrespective of main causes or location)35 is acinar loss, ROS and reactive xenobiotic species: antioxidant enzymes
mononuclear cell infiltration, and fibrosis. The early (including the selenium-dependent glutathione peroxi-
lesions are distributed in patches; thus, normal findings dase), glutathione transferases, glutathione, and ascorbic
on needle biopsy are unreliable. An unusual form of so- acid (the bioactive form of vitamin C, which can substitute
called groove (paraduodenal) pancreatitis has been for glutathione).32,40 Immunochemistry shows that these
identified.11 Each inflammatory attack can cause foci of defence mechanisms are insufficient to meet the
fat necrosis that seem to lead to both pseudocysts and increased oxidant load in acinar cells,32,37 which therefore
show signs of electrophilic stress, such as excess lipo- progression resembles that from chronic active hepatitis
fuscin and cytoplasmic microvesiculation.41 to liver cirrhosis.2,12,47
Fibrosis is a sign that interstitial stellate cells are The table summarises the histological features of
activated in chronic pancreatitis; these cells play a ordinary chronic pancreatitis compared with features of
central part in disease progression by regulating the three variants in which the lesions are diffuse. The
synthesis and degradation of extracellular matrix pancreatic lesion in cystic fibrosis is a diffuse form of
proteins.42,43 Findings from histochemistry suggest a chronic pancreatitis wherein inflammatory stigmata
causal influence of two factors—an increase in lipid disappear by birth,48 except in patients with mild
peroxidation products caused by an excess of ROS in mutations in the cystic fibrosis transmembrane
adjacent acini,44 and the release of mast cell conductance regulator gene (CFTR), who might have
degranulation products,45 transforming growth factor β1 recurrent attacks.49 Uniform lesions also occur upstream
in particular.46 The two factors are linked in that ROS of an obstructed duct1,11,48 and in autoimmune
and their oxidation products are natural activators of pancreatitis.50,51 The latter can involve the whole or part
mast cells.17 Activation of stellate cells is increased by of the gland and has two subtypes. Characteristics of
cytokines from infiltrating leucocytes and the injured the more common type-1 autoimmune pancreatitis are
acinar cell.43 The end stage of chronic pancreatitis is a dense lymphoplasmacytic infiltrate with predominantly
identified by loss of all secretory tissue, disappearance IgG4+ cells, periductal swirling sclerosis, and obliterative
of inflammatory cells, and intense fibrosis. This 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
*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)
most popular theory and incorporates the idea that constant pain; symptoms and signs of local complications
recurrent necrosis leads to periductal fibrosis.11 The first of the disease (eg, pseudocyst, obstruction of adjacent
attack of pancreatitis is taken to represent autodigestion organs, or vascular thrombosis); or complaints that suggest
caused by unregulated trypsin activity in the acinar cell. If exocrine or endocrine pancreatic failure, or both, by which
this attack is severe enough to recruit macrophages stage pancreatic calculi are often present. These features
(sentinel acute pancreatitis event hypothesis), subsequent form the basis for the most recent classification system
damage to the gland (by alcohol or electrophilic stress) (figure 3).47 In alcoholic disease, the interval from first
leads to fibrosis via macrophage-primed stellate cells. attack to steatorrhoea (signifying >95% loss of acini) is
around 13 years, which is substantially shorter than in
Electrophilic stress theory early-onset idiopathic disease12,86 or hereditary pancreatitis
The electrophilic stress theory is the pancreatic equivalent (≥26 years).12 Pancreatic calculi appear earliest in tropical
of paracetamol or carbon tetrachloride hepatotoxicity, pancreatitis,65 and earlier in alcoholic than idiopathic
which results from insufficient protection by glutathione disease.86 Diabetes might precede, begin at the same time
against electrophilic attack (via CYP) on key as, or start after steatorrhoea.65,88
macromolecules—not least, enzymes in the methionine Pain is the over-riding symptom in all but 10–15% of
trans-sulphuration pathway towards glutathione. How- cases of chronic pancreatitis; these cases are usually elderly
ever, in chronic pancreatitis electrophilic stress from patients with idiopathic disease12,86 or patients with
toxic metabolites—and, thereby, recurrent pancrea- autoimmune pancreatitis who might present with
stasis—develops over many years as a result of repetitive steatorrhoea, diabetes, or jaundice.50,51 The pain is wearying
exposures to multiple xenobiotics.41 Previous dietary and occurs in episodes that last about 1 week, or is constant.
insufficiency of micronutrients, especially methionine It starts in the epigastrium and moves through to the dorsal
and ascorbic acid, facilitates the problem.41,85 The diversion spine or localises to the left hypochondrium, radiating to
of free radical oxidation products into the interstitium the left infrascapular region. The pain is sometimes
causes mast cells to degranulate, leading to inflammation, associated with nausea and vomiting and can be partially
activation of nociceptive axon reflexes, and fibrosis.41 The eased by sitting up and leaning forward or by application of
realisation that compromised availability of methyl and local heat or other counterirritants to the dorsal spine or
thiol (glutathione) moieties underlies chronic pancreatitis epigastrium. The pain can be so severe that patients fear
has allowed an extension of the electrophilic stress food and lose weight. Most,12,86,89 but not all,88 studies have
concept to chronic pancreatitis that is associated with reported that pain diminishes markedly once the disease
gene mutations.32 Thus, the daily exposure of acinar cells burns out (which suggests that viable acini are a prerequisite
to traces of trypsin in people with PRSS1 or SPINK1 for pancreatic pain). However, by then patients often have
mutations is expected to strain glutathione reserves. Of become addicted to narcotic analgesics, which could cause
particular note, those with a CFTR mutation would be them to lose their jobs, homes, or families.88,90
left vulnerable not only to pancreastasis but also to Panel 2 lists factors that might contribute to pain in
intraductal calcifying protein plugs (large duct disease) patients with chronic pancreatitis:36 mast cell degranulation
when the residual CFTR protein is immobilised by products and hydrogen sulphide are plausible mediators
electrophilic stress.32 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 Attacks of apparent
acute pancreatitis A Early
incorporates the other theories while noting that Pain
pancreatic ischaemia can aggravate the disease.43
Complications
Clinical features • Bile duct stricture
• Duodenal stricture
Alcoholic chronic pancreatitis presents in the fourth or • Vascular stricture
fifth decade of life and mainly affects men.86 Idiopathic Clinical • Portal hypertension B Intermediate Cause
criteria • Pseudocyst
disease has early-onset (second decade) and late-onset • Pancreatic fistula
(sixth decade) forms, which have equal gender distri- • Pancreatic ascites
bution.12,86 Hereditary disease manifests at around 10 years87 • Rare, eg, colonic
stricture C End stage
and tropical pancreatitis at between 20 and 30 years,65 1 endocrine
whereas the more common type-1 form of autoimmune 2 exocrine
disease affects men in the sixth decade.51 Pancreatic failure 3 both
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
because of non-compliance (eg, in patients who misuse 2 years in patients with intraductal calculi;138 however,
alcohol) or a large cyst or pseudocyst;125 otherwise, lithotripsy can occasionally precipitate acute pancrea-
symptom control was achieved by choline supplements to titis.133 Thoracoscopic splanchnicectomy can provide good
boost methyl supply.32 Moreover, micronutrient therapy initial pain relief, but pain recurs by 15 months in more
has no effect on painful conditions that might be than 50% of patients.139
misdiagnosed as chronic pancreatitis (unpublished); once
validated, this finding could form the basis for a therapeutic Surgery
trial when the diagnosis remains equivocal after full Historically, around 50% of patients with chronic
testing (figure 7). Finally, there is increasing evidence to pancreatitis referred to surgical clinics require an operation
support the idea that a daily micronutrient supplement compared with around 25% on long-term follow-up in a
might abort the development of chronic pancreatitis in specialist medical clinic.88 Micronutrient treatment seems
groups or even populations at risk of the disease.32,130 to substantially reduce the need for surgery.82,125,132 The
Micronutrient treatment is better at controlling pain objectives of surgery are to decompress obstructed ducts
and improving quality of life than conventional (to relieve pain) and at the same time to preserve pancreatic
treatment.131 Moreover, long-term micronutrient tissue as well as adjacent organs (to preserve function),
treatment might curb disease progression.82 Excluding while recognising that the head of the pancreas constitutes
typical autoimmune pancreatitis, which can be treated the so-called pacemaker of chronic pancreatitis. The
with steroids, micronutrient treatment has been effective simplest operation—lateral pancreaticojejunostomy—
irrespective of cause (including mutations in PRSS1,118 provides immediate pain relief in many patients but pain
CFTR,82 and SPINK182), disease duration,131 or ductal tends to recur with the passage of time. Distal pancrea-
anatomy (large-duct calcifying or small-duct disease), tectomy, like pancreaticojejunostomy, does not address the
and also when there is an inflammatory calcified mass.132 problem of disease in the head of the pancreas, which can
By contrast, the antioxidants allopurinol and curcumin continue to deteriorate. Moreover, distal pancreatectomy
have been ineffective for treatment of chronic pancreatitis can result in removal of the functionally most active part of
in clinical trials.32 Two multicentre trials of Antox are the gland. Pancreaticoduodenectomy gives good pain
in progress (Current Controlled Trials numbers relief, but is a major operation. It is indicated in groove
ISRCTN21047731 and ISRCTN44912429). pancreatitis if there is duodenal obstruction or when
neoplasia cannot be ruled out preoperatively.140
Treatment of steatorrhoea and diabetes Duodenum-preserving head resection combined, when
The treatment of pancreatic steatorrhoea usually begins appropriate, with lateral pancreaticojejunostomy has
with 30 000 IU of lipase per meal in an acid-resistant been a major advance: only 8·7% of patients continued to
enzyme preparation. In patients who do not respond to have pancreatic pain at a median of 5·7 years follow-up,
this treatment, a low-fat diet (50–75 g per day), dose whereas 93% of patients had pancreatic pain
increase, gastric proton-pump inhibitor, or a combination preoperatively.141 The operation was simplified by carving
thereof should be recommended.67 A check on fat-soluble out an inverted cone from the pancreatic head, allowing
vitamin status is advisable.126 The main aim in the the cavity and the distal duct to drain into a jejunal loop,
treatment of diabetes in patients with chronic pancreatitis thus removing the complex mass of obstructed ducts and
is to prevent hypoglycaemia caused by deficiency of inflammatory tissue that frequently lies within the head
glucagon; simple insulin regimens are preferable. of the gland.142 A further simplification made this
operation suitable for patients in whom there was little in
Endoscopic treatment the way of duct dilatation: a so-called ice-cream scoop is
Of the many potential indications for endoscopic taken out of the pancreatic head to leave a thin rim of
treatment of chronic pancreatitis,133 two are undisputed. pancreas laterally and posteriorly. Pain improved in
First, EUS can be used to facilitate transmural drainage of 55% of patients after 41 months of follow-up.143
pseudocysts that are not connected to the pancreatic duct A precise assessment of the merits of the different
system, and endoscopically placed transpapillary stents in operations for painful chronic pancreatitis has been
the duct are useful when they do134 or when a duct leak confounded by an absence of agreement about
leads to pancreatic ascites or pleural effusion.135 Second, indications for surgery, details of the surgical
endoscopic stenting of the bile duct is a useful temporary techniques, and methods used to measure outcomes.144
measure in patients with a distal duct stricture. However, there is no doubt that the safety of conser-
Limited comparative data suggest that surgery is more vative operations (eg, lateral pancreaticojejunostomy
effective136 and has a more durable effect in controlling combined with limited excision of the head of the
pain137 than endoscopic dilatation or stenting of the gland) has improved: operative mortality, about 5% with
pancreatic duct. Findings from a randomised clinical traditional resection of the head of pancreas, has fallen
trial showed that extracorporeal shock-wave lithotripsy to 0–3% and morbidity has been halved.145 There seems
with or without endoscopic clearance of stone fragments to be little if any advantage to be gained from total
was equally effective at reducing pain over the subsequent pancreatectomy with islet transplant.146
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