minimalchange chronic pancreatitis6gut1992;33: 1566-1571 minimalchangechronicpancreatitis tnwalsh,j...

6Gut 1992;33: 1566- 1571

Minimal change chronic pancreatitis

T N Walsh, J Rode, B A Theis, R C G Russell

AbstractIn patients with severe abdominal pain, ofpancreatic origin, there are a few with minimalor equivocal findings on pancreatic investiga-tion and in whom the aetiology of their pan-

creatic disease is elusive. The findings andoutcome in 16 of these patients (four men and12 women) who underwent resection are

reported. Pancreatic imaging showed minimalor equivocal findings in all 16; pancreas

divisum was present in five. All were managedconservatively at first but resection was

required for progression ofsymptoms. A drain-age procedure was performed initially in fivepatients but relief of pain was at best transitorybefore further surgery was required. Partialresection was needed in 12, of whom eightrequired subsequent completion pancreatec-tomy and four had a one stage total resection.Nine patients are currently pain free afterresection or are very much improved, while sixare no better and one patient has died from an

unrelated cause. Histology of resected speci-mens showed chronic inflammatory changesaccompanied by subtle non-inflammatorychanges in all but one. These changes includeduct proliferation, duct complex formation,adenomatous nodules, and acinar cell atrophy,the significance of which is unclear. Thesefindings suggest a syndrome ofminimal macro-scopic and radiological change chronic pan-

creatitis with pain as its chief clinical featureand a distinct histology, the aetiology of whichis unclear. It seems that there is a distinctsyndrome of minimal change pancreatitis,among the group of patients which presentswith the clinical features of chronic pan-

creatitis.(Gut 1992; 33: 1566-1571)

Departments of Surgeryand Pathology, TheMiddlesex Hospital,LondonT N WalshJ RodeB A TheisR C G RussellCorrespondence to:Mr R C G Russell, ConsultantSurgeon, The MiddlesexHospital, Mortimer Street,London W1N 8AA.

Accepted for publication23 March 1992

Established pancreatic pain is characteristic - thepain is deep and gnawing with prolonged andsevere exacerbations; it is situated to the left ofthe midline and when severe passes round or

through to the back; it is aggravated by eating;the epigastrium is tender and movement makesthe discomfort worse. Analgesics relieve onlytemporarily and opiates seem to aggravate thepain over a period of time. This pain is oftenassociated with gross morphological disease,which, when removed, cures the pain, butoccasionally investigation of the pancreas showsonly minor morphological changes. It is acceptedthat pancreatic pain correlates poorly with mor-

phology, be it by gross inspection, by histologicalexamination, or by imaging.

Ihse has suggested that pain may be associatedwith the dynamics of the disease rather than witha static situation.' Recent investigation has sug-gested that intraductal pressures are higher2 in

patients with painful chronic pancreatitis. Aclose correlation has been found between tissue

pressure and pain in these patients.' A furtherdynamic concept is that of pancreatitis associatedneuritis. Beger et al have reported a comparativeincrease in the number of nerves in inflammatorypancreatic tissue, together with round cell in-filtration and striking disintegration of the peri-neurium.4 They suggested that loss of function ofthe perineural barrier allowed an influx of inflam-matory mediators or active pancreatic enzymes,and they recently showed an increase in neuro-peptidase substance P and calcitonin gene relatedpeptide within sensory nerve fibres in patientswith chronic pancreatitis.

In this paper attention has been paid to a groupof patients with characteristic pancreatic pain ofsufficient severity to necessitate operative inter-vention, near normal pancreatic ducts, andnormal morphology on ultrasound scan andcomputed tomography, yet who, on histologicalexamination, have the subtle histological changesof duct proliferation, duct complex formation,adenomatous nodules, acinar cell atrophy, andacinar cell vacuolation.

Patients and methodsBetween 1976 and 1989, 486 patients with adiagnosis of chronic pancreatitis were referredfor a surgical opinion. Forty three had a charac-teristic history of pancreatic disease, often withacute attacks associated with a rise in serumamylase, and in all respects with a similar clinicalpresentation to the other patients referred, yet oninvestigation were found to have minimal mor-phological changes in the pancreas on the basis ofa pancreatogram, and ultrasound or computedtomography. On the basis of clinical criteria, thatis failure to improve as a result of outpatientmanagement with analgesics, enzyme replace-ment, and abstinence from alcohol, and inpatienttreatment on at least three occasions with paren-teral nutrition and intestinal rest, 16 patientsunderwent resection of their pancreas.

Resection was performed as a primary pro-cedure in 11 patients and after a duct drainageoperation in five (Table), all of whom hadpancreas divisum. Drainage was by accessoryduct sphincteroplasty in four of the five patientswith divisum, the fifth patient had an endoscopicsphincterotomy of the accessory ampulla. Fourpatients who had a distal pancreatectomy (75%)also had a pancreatojejunostomy Roux en Y tothe divided end of the pancreas. In all, 12patients have had a total pancreatectomy (in eightofwhom it was performed as a staged procedure)and four patients have had a partial pancreatec-tomy (two of whom have had a distal resectionand two a resection of the pancreatic head). Ofthe 14 patients undergoing resection of the headof the pancreas, either as a total pancreatectomyor as a partial resection, 12 had a duodenumpreserving resection of the head, one had a

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Operative procedures performed on 16 patients with minimal change pancreatitis

Outcome No First procedure Second procedure Third procedure

One stage total 1 Duodenumresection preserving total

pancreatectomy3 Sphincteroplasty Duodenum preserving

total pancreatectomyTwo stage total 4 Distal resection Duodenum preservingresection resection of head

1 Duodenum Distal resectionpreserving resectionof head

1 Sphincteroplasty Distal resection Duodenumpreserving resectionof head

1 Sphincterotomy Duodenum preserving Distal resectionresection of head

1 Distal resection PancreatoduodenectomyPartial resection 1 Duodenum

preserving resectionof head

1 Pylorus preservingresection of head

2 Distal resection

pylorus preserving pancreatectomy, and one a

pancreatoduodenectomy. All patients have beenfollowed up by the authors in a pancreatic clinicand assessed at six monthly intervals.

HISTOLOGYAfter routine formalin fixation, the pancreaticresection specimens were cut serially intoapproximately 3 mm thick sagittal slices. Thesewere numbered consecutively to facilitate sub-sequent identification of any area affected bypathological changes. After macroscopic inspec-tion either all or representative slices were

paraffin processed. Selected cases were receivedfresh immediately after the resection at whichtime the main pancreatic duct was injected with a

radio-opaque dye. Assessment ofthe distributionof the dye after radiography and by macroscopicand microscopic examination allowed the diag-nosis of variants of the ductal drainage pattern ofthe gland. Only paraffin blocks of tissue sampledat random were available from cases early in theseries. Paraffin blocks were cut at 4 um intervals.Sections were stained with haematoxylin andeosin, for the general neural and neuroendocrinemarker protein gene product 9-5 (PGP 9.5) forvisualisation ofganglion cells, nerves, and neuro-

endocrine cells including islet cell tissue; forpancreatic polypeptide to highlight the embryo-logical ventral derived portion of the pancreas;and if thought contributory for diagnosis, for thepolypeptide hormones and transmitter sub-stances insulin, somatostatin, glucagon, gastrin,calcitonin, calcitonin gene related peptide, andserotonin. The presence or absence of theseneuroendocrine markers was noted and dif-ferences with the rest of the group documented.

Histology was performed in all cases by a singlepathologist (JR) with a special interest in earlychanges in chronic pancreatitis.

Results

PATIENT DETAILS

There were four men and 12 women. The mean

age at onset was 25.5 years (range 14-30) for menand 32 years (range 14-48) for women while themean age at surgery was 32 years (range 26-36)

for men and 40 years (range 19-51) for women.The only potential aetiological factor was thepresence of pancreas divisum in five and exces-sive alcohol intake in one patient. Two patientsfelt that their symptoms dated from an attack ofmumps and one from a flu like illness as ateenager.

Seven patients had a psychiatric assessmentbefore surgery, and all were considered to benormal. Assessment of the other nine by thesurgical team was considered to have beennormal in seven, while one patient was thought'depressive' and another 'inadequate.' It wasdifficult, however, to determine if these traitspreceded or followed the onset of symptoms.

PANCREATIC IMAGINGAll 16 patients underwent endoscopic retrogradecholangiopancreatography (ERCP). Pancreasdivisum was identified in five; one being associ-ated with delayed emptying while another hadminor side duct changes. Of the other 1 1, sevenwere reported as showing minor or equivocal sidebranch abnormalities and four as normal studies.

Ultrasound was performed in all 16 patients,six of whom were reported as showing mildchanges - confined to the head in three, to the tailin two, and diffuse in one. No abnormality wasdetected in the remaining 10 patients.The pancreatic appearances were considered

to be within normal limits in the four patientswho had a computed tomogram.

RESPONSE TO SURGERYSixteen patients underwent pancreatic resection- in 11 as a primary procedure and after unsuc-cessful drainage in five.

DrainageNo patient who underwent a drainage procedurehad lasting relief of their pain and all went on torequire resection within two years.

Partial resectionTwelve patients have had a partial pancreatec-tomy. Recurrence of symptoms necessitated asubsequent completion pancreatectomy in eight,leaving only four currently with partial pan-createctomy. Two of these had a distal pan-createctomy, both ofwhom had a good responseto surgery, while one had a duodenum preservingresection ofthe head and now has mild symptomsthat are easily controlled by occasional anal-gesics, and one had a pylorus preserving resec-tion of the head without much relief.

Case reports

CASE 1A 35 year old woman was referred in 1982 with afour year history of intermittent epigastric pain,precipitated by alcohol and fatty foods. Her pastmedical history was unremarkable and heralcohol intake occasional. An ERCP was normalbut ultrasound questioned changes in the head ofthe pancreas. The pain progressed and in 1983 an80% distal pancreatectomy was carried out.

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Walsh, Rode, Theis, Russell

Histology showed some mild intralobular inflam-mation as well as inspissated protein in someducts. These was marked acinar atrophy with fatvacuolation duct complex formation andadenomatous nodules. These changes were seenin both anlages.

After her operation she was symptom free forone year but then pain that was unresponsive toconservative management recurred. A duo-denum preserving completion pancreatectomywas performed; histological changes in the headwere identical. She has been completely well andwithout symptom during her 53 months' followup.

Total pancreatectomyBecause of the disappointment with staged pro-cedures, four patients had a duodenum preserv-ing total pancreatectomy as a sole resection. Thiswas performed in three patients with pancreasdivisum after a previous accessory ductsphincteroplasty and in one non-divisum patientas her only operation.

CASE 2A 40 year old woman was referred with a two yearhistory of left upper quadrant pain which wasconstant, with exacerbations radiating to theback, and associated with vomiting, diarrhoea,and weight loss of 6 kg. Her past medical historywas significant in that she suffered from theautoimmune diseases of Sj0gren's, hypo-thyroidism and rheumatoid arthritis. She did notdrink alcohol. ERCP showed pancreas divisumbut the ducts were grossly normal. Accessoryduct sphincteroplasty was carried out in 1984.This was followed by an eight month period ofpain relief but symptoms returned and necessi-tated four inpatient admissions over the next 18months. In 1986, a duodenum preserving totalpancreatectomy was performed. Histologyshowed foci of fat vacuolation of the acini withacinar atrophy and duct conversion. Thesechanges were confined to the dorsal anlage. She iscurrently very much better and has not requiredhospital admission since her operation.

CASE 3A 29 year old woman was referred with a historyof epigastric pain radiating to the back andaggravated by food. This seemed to follow anattack of mumps in childhood. In her pastmedical history the only feature of note wasGilbert's disease and a family history of diabetes.She initially had a good response to enzymetreatment and to coeliac block but both responsesfaded after three to six months. The pain becameunbearable, and in 1989 a duodenum preservingtotal pancreatectomy was performed. Histologyshowed foci of fat vacuolation of the acini with anincrease in centro-acinar cells and duct conver-sion. These foci were not confined to any oneregion of the pancreas.

She had complete relief of symptoms for thenext year but then developed a bile duct strictureat the distal end requiring a chole-dochoduodenostomy. She is currently workingfull time and has minimal symptoms.

Pancreas divisumThe five patients with pancreas divisum initiallyunderwent a drainage procedure (sphinctero-plasty in four and endoscopic sphincterotomy inone) with variable periods of pain relief. Progres-sion of symptoms, however, necessitated pan-creatic resection in all. This was duodenumpreserving in three, and a distal resection fol-lowed by completion pancreatectomy in two.Current pain status in this subgroup is improvedin four and the same in one.

CASE 4A 42 year old woman was referred with a nineyear history of intermittent epigastric pain cul-minating in a presentation to hospital where adiagnosis ofacute pancreatitis was recorded. Thepain then became continuous, radiating throughto the back and associated with nausea andvomiting. Her alcohol intake was unremarkable.ERCP showed pancreas divisum. Accessory ductsphincterotomy was performed with immediateimprovement in symptoms. Her symptomsrecurred, however, and one year later a duo-denum preserving total pancreatectomy wascarried out. Histology showed inflammatorychanges of the parenchyma with periductalfibrosis and inspissated protein in the dilatedductules, as well as the subtle changes ofthe acinisuch as acinar atrophy and an increase in thecentro-acinar cells. These changes were confinedto the dorsal anlage.Her symptoms were well controlled for some

time but she has had two subsequent admissionsfor pain since. She currently works full time, andhas regained all her lost weight but requires mildopiates for intermittent pain.

PANCREATIC HISTOLOGYThe histological features of the resectedspecimens were often subtle and out of propor-tion to stated clinical case history. Many of thesechanges did not affect the gland diffusely butrather focally and had to be examined with care.

In a number of cases (7) when the acinar cellsappeared atrophied compared with normalglands (Fig 1) the zymogen granule content wasreduced and, in addition, the cytoplasm wasoften finely vacuolated (Fig 2).

Evidence of chronic inflammation, such aslymphocytic cell infiltrate and intralobular orperiductal fibrosis, was faint but was detected in11 cases by careful examination. Focal ductaldilatation was observed in eight cases; in sevencases inspissated protein plugs were identified inthe inflammed region of the gland. Areas ofaggregated dilated ductules of varying calibreembedded in otherwise unremarkable exocrinepancreatic parenchyma were not uncommon(Fig 3). These foci or 'ductular complexes' givethe impression of resulting from ductular pro-liferation but retention oftheir lobular configura-tion belies their origin from transformed acinarcells assuming acinar features.

Acinar cell nodules were observed in four cases(Fig 4). These are well demarcated areas com-posed of acinar cells possessing a paleeosinophilic cytoplasm devoid of zymogen

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Figure 1: Normal pancreas sho(curved arrows) and intercollati

Figure 2: Abnormal acini seen(arrows).

Figure 3: Duct complex forma,for pain.

granules and small dense nuclei. On close sec- In eight specimens focal metaplasia of acinartioning most of these nodules were found in close cells to cells with features of ductular or centro-association with islet cell tissue. The surrounding acinar cells was found (Fig 6). These metaplasticexocrine pancreatic tissue is unremarkable. cells seem to replace partly the acinar cells andStaining for a range of neurotransmitter sub- seem to 'take over' the acinus.stances showed calcitonin gene related peptide inthree cases (Fig 5).

DiscussionThe presence of a near normal pancreas atoperation in conjunction with normal imagingcasts doubt on the presence of significant disease,yet this study shows definite histological changesin 15 of the 16 patients in whom histologicalassessment was undertaken. It is accepted thatthe earliest changes in chronic pancreatitis aresubtle histological findings and normal imag-

~ mFiing. 6As the disease progresses, changes may beF qi4 ^:'.hX. | i. ffi ffi s identified on imaging, although symptoms range

from minimal discomfort to severe chronic or8' relapsing pain.6 In this syndrome, the morpho-

logical change is out of proportion to the severityof the pain.

Histological features of the normal pancreas0. E 1 and the severely diseased gland are well des-

*-Aik" ''l ilcribed but reports on the earliest changes inchronic pancreatitis are scant. Norohna et al

wving normal acini (short arrows) with centro-acinar cells described the changes seen in the pancreaticed ductules (arrow). structure of asymptomatic alcoholics and which

were considered as presaging chronic pancre-atitis.' These included cytoplasmic fat inclu-sions, decreased zymogen granules, nucleardistortion, dilated endoplasmic reticulum, mito-chondrial abnormalities, and increased numbersof lysosomes. In symptomatic patients, furtherchanges have been described such as enlarge-ment of acinar cells, osmiophillic bodies, andmitochondrial aberrations while ductule cellsshow dilated ER and prominent lysosomes.'The most frequent findings in our series of

patients were periductal fibrosis, duct dilatation,*42';7 intralobular inflammation, and diffuse chronic

inflammatory changes. Of considerable interest3.s i @_ in those cases where there was no evidence of

inflammation was the finding of ductular cells'taking over' the acini (Fig 6). There seemed tobe a progression from atrophy of the acini, to anincrease in centro-acinar cells, to duct complex

in minimal change pancreatitis with cytoplasmic vacuolation formation, and ultimately dilatation of theductules. This has been described by some as theresponse of centro-acinar cells to obstruction.'`

---1-1 R .t In other areas ductular complexes were identified(Fig 3) which have been variously described asthe attempt to repair the pancreas by regenera-tion of the ductal system through hypertrophyand hyperplasia" or alternatively, they mayrepresent dedifferentiation of the acinar cell."

nv.' -, Similar lesions have been experimentallyT'R,:; ,p, . ;>t; induced and are thought by some to be fore-

runners of certain pancreatic cancers.',*|! .,jp,;,,,*;tld8^gArt,Al;'~4;_ In some specimens there were circumscribed

areas of acinar cells devoid of zymogen granules,f i; t >w<;* 3 % ~~~~changes described as acinar cell nodules or acinar

nodular hyperplasia.'4 Similar lesions have beenexperimentally induced in the rat given azaserineand are thought to develop into acinar celladenomata and acinar cell carcinomas. lMost ofthese were found in close association with isletcell tissue but we have also seen them in associ-

tion (arrows) in an otherwise unremarkable pancreas resected ation with islet cell tumours. Hormonal influ-ences may therefore play a role in their genesis. It

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Walsh, Rode, Theis, Russell

is unlikely that these lesions are a forerunner ofacinar cell carcinoma in the human, given theirfrequency in the normal pancreas and the rarityof acinar carcinoma in the pancreas.The cause of pain in chronic pancreatitis is

unclear but it is emerging that several mecha-

Figure 4: Acinar cell nodule (arrows) in close association with an islet ofLangerhan's (curvedarrows) in a painful but otherwise unremarkable pancreas.

Figure 5: Focal positive staining (arrows) for calcitonin gene-related peptide (CGRP). Theimmunoreactive cells were identified as metaplastic ductular and centro-acinar cells inadjacent sections stained with (haematoxylin and eosin).

Figure 6: Duct proliferation with partial replacement ofthe acini by ductular and centro-acinar cell metaplasia (arrows).

nisms are involved. A close correlation has beendescribed between pain and pancreatic tissuepressure.2 A drop in tissue pressure after surgerycorresponded with relief of pain, and a rise inpressure was shown in those with recurrence ofsymptoms. Intraduct pressures are higher inpatients with dilated ducts,'6 and are higher inpatients with painful pancreatitis than in those inwhom it is painless.23 Less than 50% of patientswith chronic pancreatitis, however, have dilatedducts. 7 Furthermore, the outcome ofdrainage inpatients with normal calibre pancreatic ducts isunsatisfactory suggesting that in the absenceof duct dilatation, pain must have anotheraetiology. `Nerve entrapment in scar tissue has been

suggested as a cause but the disappointing resultsof nerve section undermines this view.'9 Pancre-atitis associated neuritis has been described byBeger et al who reported an increase in thenumber of nerves in inflammatory pancreatictissue with round cell infiltration and disintegra-tion of the perineurium.4 They proposed thatbreakdown of the perineural barrier allowedinflux of inflammatory mediators or active pan-creatic enzymes. They have also described anincrease in substance P, a powerful mediator ofpain and inflammation, and calcitonin generelated peptide within sensory nerve fibres inpatients with chronic pancreatitis. Ihse postu-lated that both mechanisms may in fact worktogether with high tissue pressures facilitatinginflux of inflammatory cell mediators into thecell.'More recently attention has been focused on

the complex interaction of multiple neuro-transmitter substances in the periphery andcentrally.20 A cocktail of mediators derived fromnerves, immune cells, fibroblasts etc, is thoughtto be involved.2122 Staining of pancreatic tissuefrom patients with advanced changes of pancre-atitis has shown an increase in both neural andendocrine elements with a marked immuno-reactivity for serotonin in the islet tissue, withinthe epithelium of proliferated ductiles, in singlenerve fibres of larger nerves, and within mark-edly proliferated small nerve elements (J Rode,unpublished observations). When specimens ofminimal change pancreatitis were stained for awide range of neurotransmitter substances, themost significant finding was the presence ofcalcitonin gene related peptide in the proliferatedductule cells. It is not known whether calcitoningene related peptide produces pain directly or byinhibiting the degradation of substance P.23

It is suggested that patients with minimalchange pancreatitis have suffered a significantmorphological injury at cellular level such thatthe pain mechanisms associated with the para-crine and neurocrine systems have been damagedand trigger changes in the nerves which give riseto the pain stimulus. It seems that these changesare diffuse and unrelated to changes in mainpancreatic duct pressure as illustrated by theineffectiveness of drainage procedures in thesepatients. Similarly, partial resection, especially ifthe head of the pancreas is retained, seems lesssuccessful than total ablation.The management of these patients is primarily

conservative as illustrated by operative interven-

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Minimal change chronic pancreatitis 1571

tion in only 16 of the 43, but when operation isindicated surgical resection is preferred to drain-age, and logically total resection is preferable topartial resection because of the diffuse changeswithin the pancreas.

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Y, Nakazawa Y, et al. Pressure of papillary zone andpancreatic main duct in patients with chronic pancreatitis inthe early state. ScandJ Gastroenterol 1988; 23: 501-6.

3 Ebboh0j N, Borly L, Bulow J, Rasmussen SG, Madsen P.Evaluation of pancreatic tissue fluid pressure and pain inchronic pancreatitis - a longitudinal study. ScandJ Gastro-enterol 1990; 25: 462-6.

4 Beger HG, Buchler M, Bittner R. The duodenum preservingresection of the head of the pancreas (DPRHP) in patientswith chronic pancreatitis and an inflammatory mass in thehead - an alternative surgical technique to the Whippleoperation. Acta Chir Scand 1990; 156: 309-15.

5 Gyr KE, Singer MV, Sarles H. Pancreatitis: concepts andclassification. Amsterdam: Excerpta Medica, 1984.

6 Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984;25: 756-9.

7 Axon ATR. Endoscopic retrograde cholangiopancreatographyin chronic pancreatitis. Cambridge classification. RadiolClin North Am 1989; 27: 39-50.

8 Norohna M, Dreiling DA, Bordalo 0. Sequential changesfrom minimal pancreatic inflammation to advanced alcoholicpancreatitis. Z Gastroenterol 1983; 21: 666-73.

9 Tasso F, Stemmelin N, Searles H, et al. Comparative morpho-metric study of the human pancreas in its normal state and inprimary chronic calcifying pancreatitis. Biomedicine 1973;18: 134-44.

10 Porta EA, Stein AA, Patterson P. Ultrastructural changes ofthe pancreas and liver in cystic fibrosis. Am J Clin Pathol1964:42:451-65.

11 Norohna M, Bordalo 0, Dreiling DA. Alcohol and thepancreas II. Pancreatic morphology of advanced alcoholicpancreatitis. AmJ Gastroenterol 1981; 76: 120-4.

12 Bockman DE, Boydston WR, Parsa I. Architecture of humanpancreas: implications for early changes in pancreaticdisease. Gastroenterology 1983; 85: 55-61.

13 Takahashi M, Arai H, Kokubo T, Furukawa F, Kurata Y, ItoN. An ultrastructural study of precancerous and cancerouslesions of the pancreas in Syrian hamsters induced byN-nitrosobis (2-oxopropyl) amine. Gan No Rinsho 1980; 71:825-3 1.

14 Oertel JE. The pancreas: non-neoplastic alterations. AmJ SurgPathol 1989; 13 (suppl 10): 50-65.

15 Longnecker DS, Curphey TJ. Adenocarcinoma of thepancreas in azaserine-treated rats. Cancer Res 1975; 35:2249-58.

16 Bradley EL. Pancreatic duct pressures in chronic pancreatitis.AmJ3Surg 1982; 144: 313-6.

17 Sato T, Miyashita E, Matsuno S, Yamauchi H. The role ofsurgical treatment of chronic pancreatitis. Ann Surg 1986;203: 266-71.

18 Way LW, Gadacz T, Goldman L. Surgical treatment ofchronic pancreatitis. AmJ Surg 1974; 127: 202-9.

19 White TT, Slavotinek AH. Results of surgical treatment ofchronic pancreatitis: report of 142 cases. Ann Surg 1979; 189:217-24.

20 Buchler M, Weihe E, Friess H, Malfertheiner P, Bockman E,Muller S, et al. Changes in peptidergic innervation in chronicpancreatitis. Pancreas 1992; 7: 183-92.

21 Weihe E. Neuropeptides in primary sensory neurones. In:Zenker W, Neuhuber W, eds. The primary afferent neurone -a survey of recent morpho-functional aspects. New York:Plenum Press, 1990.

22 Lotz M, Vaughan JH, Carson DA. Effect of neuropeptides onthe production of inflammatory cytokines by humanmonocytes. Science 1988; 241: 1218-21.

23 Nyberg F, Legrevos P, Terenius L. Modulation of endo-peptidase activity by calcitonin gene-related peptide: amechanism affecting substance P action? Biochimie 1988; 70:65-8.


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