Observations on 205 confirmed cases of acute pancreatitis

Gut, 1965, 6, 545

Observations on 205 confirmed cases of acutepancreatitis, recurring pancreatitis, and

chronic pancreatitisHENRI SARLES, JEAN-CLAUDE SARLES, ROGER CAMATTE, RAYMONDMURATORE, MICHEL GAINI, CLAUDE GUIEN, JEAN PASTOR, AND

FRANCOISE LE ROY

From Unite de Recherches de Pathologie digestive de l'Institut Nationalde la Sante et de la Recherche medicale, H6pital Sainte-Marguerite, Marseilles

EDITORIAL SYNOPSIS Two hundred and five confirmed cases of pancreatitis have been classified.Primary calcifying pancreatitis is associated with alcoholism. Pancreatic changes are patchy andrelated to plugging of minute ducts. Cysts are frequent. Obstruction to the main pancreatic ductmay also result in chronic pancreatitis. Acute pancreatitis and acute recurrent pancreatitis areoften associated with gall stones. Acute pancreatitis rarely progresses towards the chronic form.

Since Comfort, Gambill, and Baggenstoss (1946) andGambill, Comfort, and Baggenstoss (1948) describedthe natural history of chronic relapsing pancreatitisthere has been a general tendency to group all formsof pancreatitis, from acute haemorrhagic pancreatitisto calcifying pancreatitis. as features of the sameprogressive disease. Sarles, Muratore, and Sarles(1961), however, consider that acute pancreatitishas a different aetiology from chronic pancreatitis,citing that acute pancreatitis begins at a moreadvanced age than chronic pancreatitis and thatwhile gall stones are more frequently found in theformer condition, alcoholism is more prevalent inthe latter.According to Marks and Bank (1963), the con-

ventional classification into acute, relapsing, andchronic types has minimized the importance of anaetiological approach and led to a standard medicaland surgical attack on the disease irrespective of thespecific cause in the individual patient. Littleattempt is often made to identify and eradicate thecausal factors in these patients. More recentlyFitzgerald, Fennelly, McMullin, and Boland (1963)have criticised the term 'chronic relapsing pancreat-itis' and proposed in its place that of 'chronicprogressive pancreatitis'.The term 'acute pancreatitis', recurrent pancreatitis,

and 'chronic pancreatitis' are employed withdifferent meanings by different writers. During asymposium held in Marseilles in April 1963 (1965)to discuss the clinical and pathological features ofchronic pancreatitis, clinicians and pathologists

from seven European countries met and adoptedunanimously a classification for pancreatitis whichhas been used in this paper.

ACUTE PANCREATITIS AND RELAPSING ACUTE PAN-CREATITIS In these two acute forms the pancreas isrestored to normal clinically and functionally whenthe initial cause or factors leading to the illness areeliminated.

CHRONIC PANCREATITIS AND RELAPSING CHRONICPANCREATITIS By this is meant chronic pancreatitiswith acute exacerbations. In these two chron icforms anatomical and functional changes persist inthe pancreas even if the initial cause and factorsleading to the disease are eliminated. The distinctionbetween the two groups, relapsing chronic pancreat-itis and chronic pancreatitis, is essentially clinicaland not anatomical.The purpose of this paper is to establish a cor-

relation between the histological aspects of pancreat-itis on the one hand and on the other the causes andnatural history of pancreatitis.

GROUPING OF CASES

All the patients were studied in Marseilles hospitals. Of atotal of rather more than 500 painful abdominal syn-dromes, not due to malignancy but associated withfunctional insufficiency of the pancreas, the followinggroups were selected.

1 CHRONIC PANCREATITIS WITH RADIOLOGICAL EVIDENCEOF CALCIFICATION One hundred patients presented with

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546 H. Sarles, J.-C. Sarles, R. Camatte, R. Muratore, M. Gaini, C. Guien, J. Pastor, and F. Le Roy

radiological calcification indisputably of pancreaticorigin, and in 47 of these the pancreas was examinedhistologically.

2 CHRONIC PANCREATITIS WITHOUT RADIOLOGICAL EVI-

DENCE OF CALCIFICATION Only patients who had beenoperated on and who had had a pancreatic biopsyrevealing chronic pancreatic lesions of fibrosis of theorgan and diminution of the exocrine parenchyma wereretained and numbered 15.

3 ACUTE PANCREATITIS There were 91 patients, operatedon intentionally or in error, in whom were present thelesions of acute pancreatitis-oedematous, necrotic, orhaemorrhagic. One of these patients has evolved towardsa chronic pancreatitis, and she has been finally placed inthat group. Fourteen others have had recurring acuteattacks, then have been finally cured; these are patientswith relapsing acute pancreatitis.

These very strict diagnostic criteriea have led to theelimination of more than half of our observations andhence exaggerated the relative frequency of calcifyingpancreatitis. However, the result is a group of cases ofpancreatitis in which the diagnosis was indisputable.

TESTS

In addition to a careful history and a clinical examinationthe patients with acute pancreatitis had one or moreestimations of serum amylase and repeated estimationsof blood sugar. Patients with chronic pancreatitis wereinvestigated by duodenal intubation, earlier cases withthe simple estimation of duodenal lipase, later cases bythe technique of Burton, Evans, Harper, Howat, Oleesky,Scott, and Varley (1960) using secretin (Vitrum) andpancreozymin (Boots or Vitrum). In more than half ofthe cases fat balance studies were performed over aperiod of three days. An estimation of amino-acids inurine and the serum by two-dimensional paper chromato-graphy was performed in five patients who had calcifyingpancreatitis.A sweat test was carried out according to the technique

of Hennequet, Debris, and Marie (1958) in 42 patients.For each patient there was also carried out at the samehour of the day at the same time of the year a test on thesweat of a control subject within two years of the patient'sage, and of the same sex who was free of pulmonarydisease, diabetes, and gastro-duodenal ulcer.

Seventy-seven patients were interrogated about theirdietary intake, if possible in the presence of their family,by a dietitian trained specially for the work, who,applying the tables of Tremolieres, Serville, and Jacquot(1956), calculated the mean dietary and alcohol intakeof these patients. On the same day the same dietitian alsointerrogated two normal subjects within two years ofage and of the same sex and of comparable professionand of the same racial origin to act as controls.A laparotomy was undertaken on 76 patients with

chronic pancreatitis (Lamy, Sarles, and Bricot, 1963;Sarles and Mercadier, 1960). During operation cholangio-graphy was performed and at least six radiographs taken.During operations pancreatography of the canal of

Wirsung, either by direct puncture or after excision of thetail of the pancreas or more rarely after duodenotomy,necessitated taking from four to eight additional films,using image intensification and transmitted by closedcircuit television in the operating theatre. In no casehas any ill result been observed following the instillationof 35% diodone into the pancreatic duct. In five patientssplenoportography was carried out by transplenicpuncture a few days before operation and in seven caseslymphangiography was performed.

RESULTS

PRIMARY CALCIFYING PANCREATITIS Into this groupfall patients (100 cases; 93 men, seven women) whopresented with calcification in the duct of Wirsungeither in the larger branches or in the finer peripheralducts, with the exception of one patient classified asa pancreatitis secondary to cancer.

Aetiology The mean age (Fig. 1) at the firstpainful crisis in the 93 patients who presented withpain was 38-4 years (S.D. = 18, range 22 to 67).Fifty-five patients were interrogated about theireating habits (Table I). Only one patient was a totalabstainer and only five were accustomed to drinking

Ages

80o

70.

60.

50.

30.

20.

A.P. P.C.

..

*-

..10000-00....

_....

.:::. .

:

FIG. 1. The age distribution at which the acute episode ofhaemorrhagic or oedematous pancreatitis (A.P.) and thefirst attack of chronic calcifying pancreatitis (P.C.) tookplace.

I

000 00

. . 0 0 000 0

. 0

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Observations on 205 confirmed cases of acute pancreatitis, recurring pancreatitis, and chronic pancreatitis 547

TABLE IDIETARY INTAKE OF 55 PATIENTS WITH

PRIMARY CALCIFYING PANCREATITIS AND TWOCONTROL GROUPS

55 Calcifying 55 Controls A 55 Controls BPancreatitis

Protein 119' 104 107(44-378) (51-229) (55-259)

PC > A PC > Bp = 0 0034 p = 0-0582

Fat 125 99 106(49-378) (35-217) (54-240)

PC > A PC > Bp = 0 0034 p = 0-0078

Carbohydrates 425 430 436(119-849) (203-1,041) (148-945)

n.s. n.s.p = 0443 p = 0443

3,316 3,049 3,021(1,255-7,968) (1,380-6,475) (1,903-6.945)

n.s. n.s.p = 0 1003 p = 0-582

Alcohol 175 74 72(0-550) (0-300) (0-393)

PC > A PC > Bp = 0 00003 p = 0 00003

'The values in italics are the means in grams and calories per day;the values in parenthesis are the range. Significance is calculated bythe sign test.

less than 50 g. of alcohol a day. A gall bladder stonewas found in two cases. Two cases came from thesame family, an uncle and nephew. In the youngerofthese two patients we were unable to find abnormalaminoaciduria.

Clinicalfeatures These are presented in Table II.A sweat test was carried out in 42 patients and in anumber of identical and comparable controls(Table III).

TABLE IIISWEAT TESTS IN PATIENTS WITH CALCIFYING

PANCREATITIS AND IN CONTROLS

Sodium Sodium PotassiumChloride (38 cases) (38 cases)(42 cases)

Calcifying m = 56 m = 69pancreatitis S.D. = 23.49 S.D. = 24-10Controls m 42 m = 51

S.D.= 1195 S.D.= 16Probability for PC > C for PC > C

p = 0 0007 p = 0-0007Significance is calculated by the sign test.

m = 7S.D. = 1-6m = 8

S.D.= 2-33for C >PCp = 0 0594

Histology A histological study was carried outin 47 patients: once on necropsy material, 17 timeson larger sections obtained at partial pancreatec-tomy, and 29 times on biopsy specimens taken duringoperation (Table IV). A characteristic feature of theanatomical lesions, at least at the onset of thedisease, was the irregularity of their distribution.One of our patients presented a normal pancreaswith the exception of a small area, about 1-5 cm. indiameter, in which there was intense sclerosis with adiminution of exocrine parenchyma and a dilatationof the ducts which contained calculi. This patho-logical area related to the duct of Santorini whichdilated, the duct of Wirsung being normal.

In the later stages the lesions were diffuse but theseverity varied from one area to another (Fig. 2). Thejuxtaposition of normal and pathological areaswas seen only in those cases in which the duct ofWirsung remained normal. As soon as it dilatedlesions were found diffusely throughout the gland

3LE IICLINICAL FEATURES OF 100 PATIENTS WITH PRIMARY CALCIFYING PANCREATITIS

No. of CasesClinical Feature

Pain

Loss of weightJaundice

Portal hypertension

Complications

Carbohydrate metabolism (studied in 78 cases)

Fat balance (performed in 48 patients)

4

PresentAbsentRecurrent (lasting from two hours to 10 days separated by intervals of8 days to 35 years)DailySited in the mid epigastriumSited in the backSited in the right hypochondriumSited in the left hypochondriumPartially relieved by bending forward

In 34 patients following the painful crises, lasting from two to eight daysin 33, or more than one month in threeHaematemesisMelaenaPulmonary tuberculosisAddiction to morphineArteritis of the lower limbsAlcoholic cirrhosis of the liverPulmonary abscessGout cured after pancreatico-jejunal anastomosisTrue diabetesDiminution of glucose toleranceNormal glucose toleranceHypoglycaemia without any suggestive clinical symptomsSteatorrhoea from 5 5 to 50 g. per day over three-day period

937

76

177956442958100

72943

I

232419217



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TABLE IVHISTOLC

Sclerosis 0

++++

DiffuseIntralobularPerilobular

Sclerolipomatosis 0-4++

Inflammation 0-+++

Exocrine Absent orparenchyma poor

Little or noreduction

Islets of NormalLangerhans Diminished

IncreasedDiscreteislets

Canalicular 0dedifferentiation +of the acini ± +

Ductules Absent onsectionNormalDilatedMucous plugs

Larger ducts Absent onsectionNormalDilatedCavities with-out continuousliningPlugs

)GYPrimaryCalcifyingPancreatitis(47 cases)

2418239

3137416

38922

25

171416

85

21139

3351816

5189

PrimaryInflammatoryPancreatitis(4 cases)

0

44444

44

4

4

4

31

16

distal to the obstruction. The localization of focallesions appeared to correspond to the areas suppliedby the ducts of variable calibre.

Sclerosis was absent in two cases only and presentin 45 cases, in eight associated with sclerolipomatosis.Inflammation was absent or insignificant (smallareas of lymphocytic infiltration) in 38 cases. It wasmarked by an increased number of inflammatorycells in nine cases.

Pancreatic and peripancreatic oedema can beseen when a laparotomy is done during or shortlyafter a crisis, especially when the pancreas is lessseverely affected. During a painful crisis oedemamay compress the common duct in its intrapancreaticcourse and lead to icterus. Even when the exocrineparenchyma is much destroyed it is remarkable tobe able to identify normal acini and see an almostintact lobule in juxtaposition to very markedsclerosis. The most frequent and characteristicfeature is 'canalicular dedifferentiation of the acini'flattening of the epithelial cells surrounding thecentral lumen which is more or less dilated. This

FIG. 2. in calcifying pancreatitis, the lesions vary verymuch from one lobule to the next. Some lobules are almostintact; others show complete canalicular dedifferentiationand canalicular dilatation; sclerosis.

appearance was observed in 39 but was absent ineight cases (Fig. 2).The endocrine parenchyma varies tremendously.

It was reduced or absent in 17 cases and apparentlyincreased in 14 cases (Fig. 3). In 16 cases onlyisolated islets were present. We have not been ableto correlate the presence of endocrine tissue withdisturbance of glucose metabolism.Some small ducts were well seen on biopsy in 38

cases, in only three of which were these normal. In35 cases they were dilated, the epithelium oftenhaving features of mucinous cells. In 18 cases thesmall ducts contained a substance either amorphousor disposed concentrically with some epithelialdebris (Fig. 4). Topographically these plugs werefrequently found in small ductules but might beobserved in the acini. The large ducts were seen in32 cases. In three they were normal and in 18 theywere dilated. In nine cases we saw cavities withoutcontinuous walls in the pancreatic tissue with inplaces epithelial debris attached to the wall. Thesecavities appear to be dilated ducts lined with verylargely altered epithelium. Abnormal precipitates



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FIG. 3. Cakifying pancreatitis showing very numerous

islets of Langerhans; a transitional appearance between

these and the dilated acini.

FIG. 4. Calcifying pancreatitis showing a tiny muco-protein plug in a canaliculus. Small plugs in dilated aciniadjoining it.

were noted 16 times in the larger ducts. Rarely theypresent the appearances of massive calcification. Theepithelium can be absolutely normal. It can also bechanged with mucoid degeneration or with zonesof epidermal metaplasia or more or less completedesquamation. No correlation exists between thedilatation of the peripheral ducts and that of theduct of Wirsung. In two cases in which the duct ofWirsung was normal on pancreatography thereexisted foci of acino-canalicular dilatation. Nor doesthere exist a correlation between the level of excretionof sodium chloride in the sweat and the type of thehistological lesion.The calcified precipitates can be slight, in the

smaller peripheral ducts or in the larger ones, formingcalculi in the duct of Wirsung (Fig. 5) or one of itsdilated branches. Stones were always present in theducts. The peripheral localization of calcification isoften associated with calculi of the duct of Wirsung.We never saw a primary lithiasis of the duct ofWirsung. In five cases calcification appeared one tothree years after anatomical examination hadrevealed acino-canalicular dilatation and foci ofsclerosis.

In a single case we found a cancer of the pancreasassociated with a diffuse calcifying pancreatitis oflong standing, and we have classified in the sectionof pancreatitis secondary to an obstruction asecond case of cancer of the pancreas associated withcalcification.

Pancreatography In 55 pancreatographies theduct of Wirsung was normal on 13 occasions anddilated in 42 cases, always due to obstruction whichwas twice as often a stenosis (Figs. 6 and 7) as acollection of stones (Fig. 8). The narrowed segmentlies generally in the region of the head, more oftenin the isthmus, and sometimes it is multiple (twostrictures). Stenosis of the duct of Wirsung is notthe initial cause of the disease for it is absent whenhistological lesions are still localized to restrictedareas surrounded by normal tissue. When stenosisexists the intraductal pressure is always raised atoperation.

Pancreatography reveals frequent cyst formation.In 53 cases explored at operation 26 patients hadpseudo-cysts. On 11 occasions there were extra-pancreatic cysts of considerable size (Fig. 10), fourof which were suppurating. In 16 cases there weresmall intrapancreatic cysts varying from 1 to 4 cm.in diameter (Figs. 6 and 9). The cysts may be singleor multiple and can communicate with the pancreaticduct or be detached from it. Three of our patientshad a large extrapancreatic pseudo-cyst at the onset,the rest of the pancreas being apparently normal atthis time, but two or three years later these patientshad developed calcifying pancreatitis. In 17 of 80



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FIGS. 5a and b. Calcifying pancreatitis: grossly dilatedduct containing a mucoprotein plug. The epithelium islittle changed.

FIG. 5a

FIG. 5b



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-.- .......-

FIG. 6. Calcifying pancreatitis: pancreatography during Fl . 7. Calcifying pancreatitis: cholangiography andoperation by direct puncture ofthe duct of Wirsung. A cyst pancreatography during operation by direct injection intowhich does not communicate with the duct has been the ducts show dilatation of the main bile duct and of theindependently outlined by injection. The duct is seen above canal of Wirsung distal to a short stenosis in the head ofit in the region ofthe spine. The duodenum has been outlined the pancreas. As a rule the extent of the narrowing of theat a perfusion pressure of 50 cm. of water. The duct of common bile duct is greater than in this case.Wirsung is dilated. A very narrow stricture is present in theterminal part of the duct.

FIG. 8. Calcifying pancreatitis: pancreatography bydirect puncture of the duct during operation. Dilated duct,obstruction being caused by a collection of easily seenpancreatic calculi. The duodenum was filled at a pressure of25 cm. of water.

FIG. 9. Calcifying pancreatitis: normal duct of Wirsung.Two intrapancreatic cysts. The duodenum filled at a normalpressure.



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552 H. Sarkes, J.-C. Sarles, R. Camatte, R. Muratore, M. Gaini, C. Guien, J. Pastor, and F. Le Roy

FIG. 11. Calcifying pancreatitis: transparietal spleno-portography reveals compression ofthe splenic vein anteriorto the spine.

a.- iFIG. 10. Cakicfying pancreatitis: cholangiography by gallbladder puncture during operation. Direct injection of avoluminous extrapancreatic cvst which traverses thediaphragm to lie in the thorax.

cholangiographies the bile duct was normal but in61 cases a quite typical appearance existed ofretraction of the retropancreatic bile duct leading toa normal patent sphincter of Oddi (Fig. 7). In twocases incomplete stenosis at the upper border ofthe pancreas was present. In only three cases wasbile seen to reflux from the biliary into the pancreaticpassages. Further, in one case no reflux was seenon cholangiograms taken early in the operation butit was seen later after the surgeon had removedcalculi from the duct of Wirsung.

Splenoportography This was done on five occas-ions and showed obstruction of the splenic vein infour patients, caused by compression (Fig. 11) inthree instances and by thrombosis in one (Fig. 12).Lymphangiography was done in cases showingcompression of the retropancreatic lymphatics withretrograde stasis and dilatation of the peripheral

.. ... :III AXioi. f

FIG. 12. Calcifying pancreatitis: transparietal spleno-portography. Thrombosis of splenic and portal veins withrevascularization of the liver by collateral vessels.

lymphatic trunks. Lymphatic obstruction wasalways incomplete.

CHRONIC PANCREATITIS SECONDARY TO OBSTRUCTIONIN THE DUCT OF WIRSUNG In three cases, two menand one woman, the diagnosis of Vaterian stenosiswas confirmed by histological examination of abiopsy specimen obtained at operation and on twooccasions at necropsy. None of the patients was analcoholic. In no case was there associated biliarylithiasis.The symptoms always resembled those of biliary

rather than pancreatic disease, painful crises in theepigastrium and in the right hypochondrium lastingfor some hours, recurring and accompanied in twocases by rigors with fever as high as 40°C. and



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followed by recurring icterus. The lesions (Fig. 13aand b) are very similar: an inflammatory fibrosis intwo cases, but fibrosis with no inflammation in theother, this being more prominent in the region of thehead of the pancreas and surrounding the ducts.In two of the patients there co-existed a cholestaticcirrhosis of the liver, the lesions of the liver beingmuch more intense than those of the pancreas.One woman presented at the age of 52 years with a

severe attack of acute pancreatitis, confirmed atexploratory laparotomy, after which she hadrepeated attacks of pancreatitis. At a secondoperation a stone was found in the gall bladder whichhad escaped recognition at the first operation. Thehead of the pancreas appeared to be normal but inthe region of the isthmus the pancreas was replacedby cartilaginous cicatricial tissue. In the region ofthis scar the canal of Wirsung was completelyobliterated, but in the tail of the pancreas the ductwas widely dilated. The scar compressed both thecommon bile duct and the portal vein. Histologically

at the junction of the head and the body of thepancreas there was a ring of sclerosis containing norecognizable acinar tissue which completely sur-rounded the duct of Wirsung which was lost in thistissue. At the tail of the pancreas the sclerosisremained severe and dense with little inflammationand the exocrine parenchyma was non-existent with-out any acino-canalicular dilatation. A number ofisolated islets of Langerhans remained in sclerotictissue.Three patients, one man and two women, had

chronic pancreatitis as the sequel to a slowly growingcarcinoma. The first two had been operated onseveral times during the three years that their illnesslasted. The successive laparotomies for biliary andpancreatic anastomoses had permitted the taking ofrepeated pancreatic biopsies which had alwaysshown lesions of benign pancreatitis. At necropsyin two cases diffuse fatty sclerotic lesions, bothextra and intralobular, were found, leaving quitelarge areas of parenchymatous tissue separated by

FIG. 13a FiG. 13b

FIG. 13. Chronic pancreatitis and Vaterian stenosis: (a) section in the region of the duct of Wirsung and ofthe commonbile duct reveals diffuse sclerosis and periductal inflammation; (b) a second section made distally shows that the lesionsare not present.



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areas of necrosis. There existed in addition a hyper-plastic proliferation of the ducts. In the region ofthe head of the pancreas the sclero-lipomatosis wasmost intense, the pancreatic tissue meagre, and therewas neoplastic compression of the duct of Wirsung.The third patient presented with cancer of the bodyof the pancreas obstructing the duct of Wirsungwhich was dilated. The distal branches containedcalcium deposits but none were found proximallyin the head or in the region of the tumour.One of our patients had a quasi-experimental

chronic pancreatitis after ligature of the duct ofWirsung in the course of a gastrectomy for ulcer ofthe second part of the duodenum.

PRIMARY INFLAMMATORY PANCREATITIS Four pati-ents, three women and one man, age of onset57, 59, 61 and 73 years, belong to this group.Onepatient had gall stones. Nonewas an alcoholic.

There was a progressive development of the disease,without crises, marked by a progressive loss ofweight and steatorrhoea. Pain, which was presentin only two cases, was quite atypical and lesssevere than in other types of pancreatitis. Onepatient presented with obstructive jaundice whichdid not disappear after biliary drainage. One womanpresented during two years with an undulating feverresembling biucellosis which did not respond toantibiotics. In two cases death terminated cachexiaover a period of one to three years. Necropsyallowed us to eliminate cancer as a cause. In twoother cases, in the course of which surgical inter-vention allowed us to take multiple biopsies of thepancreas, spontaneous clinical cure took place andwas accompanied by the complete disappearance ofsteatorrhoea.

Histological study was carried out on two casesby biopsy and two cases after necropsy. Microscopyshowed marked sclerosis (Fig. 14), not condensed,with scattered areas infiltrated with mononuclearcells and even focal agglomeration of pyknoticpolynuclear cells. This sclerosis was diffuse in threecases with no evidence of any parenchymatousstructure other than a few canaliculi and endocrineislets. In the fourth case it formed scattered or widelyseparated foci interspersed with zones of necrosis inwhich there remained several acinar rests. This isanalogous to a acute hepatic necrosis at the stageof connective tissue proliferation.

Sclerolipomatosis was a feature of three cases.The duct of Wirsung was normal in three cases anddilated distal to a stenosis situated in the region ofthe neck in the fourth. The common bile ductpresented an appearance identical to that of the ductof Wirsung. Biochemically there appeared to bemarked exocrine pancreatic deficiency with steator-

f~~~~~~~~FIG. 14. Primary inflammatory pancreatitis: completedestruction of exocrine pancreas. The islets alone remainin the midst of dense inflammatory sclerotic tissue.

rhoea and a constant increase in the gamma globulinto the level of 40% and an absence of abnormalitiesof glucose tolerance. Blood cultures were negative.In two persons immune antibodies against thepancreas were sought but none were found.

CHRONIC PANCREATITIS Three cases were difficultto classify.Two cases, both in men, are interesting, because

they manifested lesions which we think character-istic of calcifying pancreatitis, particularly themultiple features of canalicular dedifferentiation ofthe acini, the mucous plugs, and the dilated ducts.But these two patients did not present radiologicalcalcification. Both died a short time after surgicalintervention on the fifth day and in the secondmonth respectively.A man of 29 years presented with five recurrences

of obstructive jaundice without pain or fever, lastingfrom 48 hours to eight weeks. In the course ofsurgical intervention cholangiography showed in thelower part of the common duct, for about 1 cm.proximal to the sphincter of Oddi, a gap 1 cm. long



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Observations on 205 confirmed cases ofacute pancreatitis, recurring pancreatitis, and chronic pancreatitis 555

FIG. 15. In this patient, the pancreas is normal with the sole exception of one lobule. In this lobule the smallest ductscontain protein plugs such as are found in calcifying pancreatitis.

reducing the lumen of the bile duct but not com-

pletely obstructing it. This led to an erroneous

diagnosis of cancer of the common bile duct and a

duodeno-pancreatectomy was performed. The speci-men showed that the pancreas was normal with theexception of a single pathological lobule situated incontact with the common bile duct which it was

deforming. In this region there existed a peri- andintralobular sclerosis, acinar dedifferentiation, andthe smallest ducts contained protein plugs such asare found in calcifying pancreatitis (Fig. 15). Theduct of Wirsung was normal.

ACUTE PANCREATITIS AND ACUTE RECURRING

PANCREATITIS There were 90 cases.Aetiology The mean age was 517 years (range

22 to 73; S.D. 12 8). In 54 men mean age was 50 9years and in 36 women it was 54-7 years. Gall stoneswere found in 46 cases (51 %). Amongst these caseswith stone there were 22 men of mean age 513years and 24 women of mean age 55 4 years. Gallstones were present therefore in about 60% of thewomen with pancreatitis and 407% of the men.The stones were present in the gall bladder in 37cases and in nine cases in both gall bladder and thecommon bile duct. In one case a stone was wedgedat the ampulla of Vater. Two patients, neither ofwhom had gall stones, had been treated by corti-

TABLE VDIETARY INTAKE OF 22 PATIENTS WITH ACUTE

PANCREATITIS

AcutePancreatitis(22 Patients)

22 Controls(Group A)

22 Controls(Group B)

Protein 93' 103 100(52-147) (68-135) (50-158)

n.s. n.s.p = 0-262 p 0-43

Fat 99 86 90(60-19) (63-120) (45-140)

n.s. n.s.p = 0- 143 p = 0 416

Carbohydrate 353 416 465(170-541) (220-708) (270-831)

p = 0-067 p = 0-067Calories without 2,670 2,860 3,090alcohol (1,924-3,961) (1,910-3,928) (1,926-5,000)

p = 0-584 p = 0-262Alcohol 93 S7 50

(0-245) (0-285) (0-221)AP>A AP>Bp = 0-002 p = 0-008

'The values in italics are the means in grams and calories per day;the values in parenthesis are the range. Significance is calculated by thesign test.

costeroids for respectively three and six months,one for leukaemia, the other for Addison's disease.Acute pancreatitis occurred in a women of 35 yearsin the eighth month ofpregnancy and in another caseafter normal delivery. There were no gallstones in



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these two cases. In 39 cases (43 %) no causal factorcould be discovered. A pre-existing diabetes wasfound only twice. Twenty-two patients had adietetic enquiry (Table V).

Clinicalfeatures These are presented in Table VI.Of the 67 patients who survived, 14 presented with

recurring painful episodes of acute relapsingpancreatitis. They comprised six with bile ductstone in whom surgical removal led to a definitivecure and six cases with necrotic cysts difficult todiagnose, the evolution of which appeared to besufficient to explain the pain. Two patients presentedwith recurrent pain without our being able toascertain a cause. Of the 39 patients followed formore than two years, clinical cure was observed inall either spontaneously or after treatment of thecyst or common duct stones. Only one patient whohad acute pancreatitis progressed to chronicpancreatitis, in which group she is classified. Nopatient developed calcification.

TABLE VIFREQUENCY OF THE CLINICAL MANIFESTATIONSIN 90 PATIENTS WITH ACUTE PANCREATITIS

Frequency(%)

PainPain referred to backVomitingParalytic ileusDyspnoeaShockTransient hypertensionTemperature exceeding 38 C.MeteorismModerate guardingRigidityJaundice

1005467581044136072491517

Pathological anatomy There was oedematouspancreatitis in 18 cases and acute necrotic haemor-rhagic pancreatitis in 72 cases. Frank infection of thelesion supervened in 14 cases. Fourteen patientsdeveloped a necrotic pseudocyst as a sequel. Thiswas situated in 11 cases in the epigastrium, in one itwas situated in the right iliac fossa, and in two casesin the left iliac fossa.

DISCUSSION

The most important group is that of primary chroniccalcifying pancreatitis, which represents almost a

fifth of the cases of pancreatic insufficiency not dueto cancer. This frequency is in conformity with thatwhich is met in the United States (Comfort et al.,1946; Gambill et al., 1948; Howard and Jordan,1960) and in South Africa (Marks and Bank, 1963).It is very different from that met in England (Howat,

1965), in Czechoslovakia (Herfort, 1965), inSwitzerland (Haemmerli and Schmid, 1965), or inthe Argentine (Morel, 1963). On the whole thefrequency of calcifying pancreatitis in the westernworld appears to parallel the consumption ofalcohol.

This group of calcifying pancreatitis as we havedefined it excludes pancreatic calcification secondaryto an obstruction of the duct of Wirsung (one case),j uvenile familial pancreatitis, and hyperpara-thyroidism which we ourselves have not met. Thecharacteristics of the group are the preponderantincidence in men, the onset in middle adult life, andthe progressive evolution of the disease oftenpunctuated by painful acute recurring crises.Anatomically a characteristic feature is the irregu-larity of distribution of the lesions so long as theduct of Wirsung is not involved. The initial lesion asseen on microscopy is perhaps obstruction of thefiner pancreatic ducts by a gel which seems torepresent the precursor of calcification. Distal tothis lesion the ducts and the acini are dilated.Sclerosis is at first localized to the region where theducts are obstructed, then, as soon as the duct ofWirsung is involved, it diffuses throughout theorgan to become a veritable cirrhosis. Thanks tohistological verification of these lesions the diagnosisof calcifying pancreatitis has been made early, aslong as one to three years before the appearance ofradiological calcification, in five of our patients.Thus we consider that the disease presents withcharacteristic anatomical lesions before the appear-ance of calcification; that is why we associate withthis group observations D.1, D.2, and D.3. In D.3,the focus of chronic pancreatitis was so localized,as small as a grain of wheat, that no clinicalsymptoms would have ensued had not the commonbile duct been compressed.The connexion of primary calcifying pancreatitis

with pseudo-cysts of the pancreas deserves to beemphasized. In a previous report (Sarles, Martin,Camatte, and Sarles, 1963) we have shown thatextrapancreatic pseudo-cysts of a solitary characterhave the same aetiological and pathological featuresas those seen in calcifying pancreatitis. Meticuloushistological study of the wall of these cysts allowsus to conjecture that they arise not following anacute necrosis of the pancreas but by distension anda blowing out of foci of localized acino-canaliculardilatation which we have described with eventualrupture into the peripancreatic tissues. Quite differ-ent are the necrotic pseudocysts seen as a feature ofacute pancreatitis.The illness does not appear to be due to the

scarring of several successive attacks of acutepancreatitis as is the tryptic pancreatitis of Becker



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(1957). In spite of the intensity of the pain whichmay be present in the first attack, none of thesepatients has begun the illness by a dramatic abdomin-al lesion with shock such as would make one thinkof acute pancreatitis. Calcifying pancreatitis begins,at an average, some 13 years sooner than acutepancreatitis. The mean age of onset of the diseasesis respectively 38-4 and 517 years. In none of ourcases have we found signs of a parathyroid tumour.Neither have we met cases corresponding to thefamilies which Gross, Ulrich, and Maher (1962) andHardy (1965) described.Almost all of our patients were alcoholics. The

mean consumption of alcohol of those in whom itcould be measured by interrogation with accuracywas more than two times greater than that ofcontrols of the same age and the same sex taken atrandom. Like Howard and Jordan (1960) andMarks and Bank (1963) we think that alcoholismplays a determining role. Our dietectic enquiryshows us that far from consuming less proteinthan normal controls our patients have eatensignificantly more. The consumption of fat wasalso increased, though the total calorie value ofthe diet remains very much the same. Thoughalcohol is an important cause, it is not truly theinitial cause of the illness. Indeed neither theclinical evolution nor age nor sex distribution norpathological anatomy allow us to separate thepatients having a low consumption of alcohol fromthose in whom the consumption is raised. One cantherefore put forward a hypothesis that alcoholuncovers a more frequently occurring dormantdefect. This hypothesis would accord with thefinding by Ludin and Scheidegger (1941) whoperformed necropsies with minute dissection andradiography of the pancreas and found that pancrea-tic calcification occurred in 5 5% of cases, the greatmajority of which had no clinical symptoms orfeatures. It is possible that protein insufficiencyfound by Zuidema (1960) and Shaper (1960) playsthe same precipitating relationship to pancreatitisin the underdeveloped countries as it does to hepaticdisease.The acino-canalicular dilatations are reminiscent

of certain features of mucoviscidosis. This leads usto ask, as do Koch and Bohn (1963), if there doesnot exist a hereditary basis for the disease. Sweattests have been positive in 11 of 42 patients. Thecomparison of 42 patients with 42 controls of thesame age and sex has shown us that the excretionof chloride and sodium is significantly higher inour patients than in controls. The sweat test inadults has, however, been criticized so much thattoo much stress should not be laid on these results.An adrenal insufficiency could not explain these

differences. We give these facts without drawingany conclusion about the very complicated problemof adult mucoviscidosis. Another argument infavour of a genetic factor is the finding of calcifyingpancreatitis in families. It is not a matter of largefamilies with numerous cases but two cases in thesame family, uncle and nephew in our patients, twobrothers (Leger, Perrotin, Detrie, Lebel, Meyer,and Lemaigre, 1962), father and daughter (Fitz-gerald et al., 1963), mother and daughter (Koch andBohn, 1963). Geevarghese, Pillai, and Pitchumoni(1963) found in 100 cases of calcifying pancreatitisthree families in which two brothers, a father anda son, and a brother and a sister were affected.The group of chronic pancreatitis secondary to

obstruction of the flow of pancreatic juice is muchless homogeneous. In spite of the intensity of thelesions of these patients pancreatic calcification hasbeen seen only in one case.

In the pancreatitis of Vaterian stenosis, the lesionsare very circumscribed (pericanalicular sclerosispredominating in the region of the head of thepancreas and diminishing peripherally). The pan-creatic symptoms are much less marked than thebiliary symptoms (Sarles and Guigou, 1951). Theinterest of this type of pancreatitis is that Vaterianstenosis provides the sole indication for sphinctero-tomy.

Pancreatitis secondary to cancers of slow develop-ment are very difficult to diagnose. As Bimstingl(1959) has emphasized, sometimes a meticulouslycareful necropsy is necessary to uncover the cancer.The inflammatory and destructive histological lesionsand the inexorable progress are very similar to whatone sees in the group of inflammatory pancreatitis.In one of our patients at least it was thought thatdeath had occurred more from the pancreatitis thanthe cancer at the end of three years. A secondpatient died from a severe post-transfusionalhepatitis. Case B.7 is a rarity, in that pancreaticcalcification was present in the dilated ducts distalto the cancer.The group of primary chronic inflammatory

pancreatitis possessed certain features in common;an evolution with little pain, significant steatorrhoea,often an age of onset quite elderly, a preponderanceof women (three women to one man), and anelevation of the gamma globulins in excess of 40%.It is very difficult to distinguish this group fromcancer. In two of our cases the diagnosis was madeat necropsy and in two cases by symptomatic andfunctional cure. In spite of a variable evolution thelesions are very similar; they are marked by thespread throughout the pancreas of a intenselydestructive sclerosis of inflammatory characterwithout the irregular localization seen in calcifying



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558 H. Sarles, J.-C. Sarles, Roger Camatte, R. Muratore, M. Gaini, C. Guien, J. Pastor, and F. Le Roy

pancreatitis (group 1). The impossibility of findingan infectious agent or an autoimmune factor, theevolution towards death or complete cure suggeststhat this group is not homogeneous.Whereas the three preceding groups of chronic

pancreatitis were characterized, as Fitzgerald et al.(1963) have said, by a progressive evolution thegroup of acute pancreatitis that we have defined ischaracterized by either a fatal outcome or resolution(Sarles and Camatte, 1963). Howard and Jordan(1960) have noted that alcoholic pancreatitis evolvesoften in a progressive manner punctuated byrecurrences and that pancreatitis associated withgall stones is frequently cured.The feature of resolution appears to us not to be

bound to the presence of biliary stone but to theacute character of pancreatitis, pancreatic oedema,or acute haemorrhagic pancreatitis. Although acutepancreatitis not associated with stone representsabout the half of this group, one only of our patientshad evolved towards a true chronic pancreatitis.The healing of the pancreatic necrosis had lead to astenosis of the duct of Wirsung, responsible for thesclerosis distal to it. A similar case has been observedby Leger, Poirier, Dubost, Premont, and Boutelier(1962).The food intake of patients with acute pancreat-

itis as assessed by our enquiry does not differmarkedly from that of controls of the same age andsex. The intake of alcohol is increased, but two ofour patients drank no alcohol and eight weredrinking less than 50 g. in a day. Fourteen of ourcases of acute pancreatitis could be classified asrelapsing; in six the pancreatitis had led to a pseudo-cyst which in turn was responsible for the recurringpainful episodes. Following surgical intervention toextirpate the pseudo-cysts, the patients who survivedoperation were cured. Eight other patients presentedalso with relapsing acute pancreatitis. In six patientsgall stones in the common bile duct had been over-looked. Surgical intervention to remove these stonesleads to complete cure without further relapse. Intwo we found no apparent cause for the recurringpains but these pains did not continue for longerthan one year.The evolution of relapsing acute pancreatitis

towards resolution allows us to separate thesecases from true chronic pancreatitis. The pro-found differences which separate acute fromchronic pancreatitis, both clinical and functional,have been correlated with a study of the anatomicallesions. This has confirmed that there does notexist 'all the transitions from haemorrhagic pancreat-itis which kills in a few hours to the most progressivelesions of calcifying pancreatitis' but that there aredifferent entities with different clinical features, a

different aetiology, and different anatomical features.This rarity of acute pancreatitis progressing

towards chronic pancreatitis deserves to beemphasized.

SUMMARY

Analysis of three groups of proved pancreatitisshowed that of 100 cases of chronic pancreatitiswith radiological calcification, 93 were in men, sevenin women, and the mean age at onset was 38-4 years(22 to 67). The mean consumption of alcohol wasmore than twice that of controls but at least onepatient was a total abstainer. The consumption offat and protein was also increased. The meanexcretion of Na+ and Cl- sweat was significantlyhigh. Several family cases in the important statisticsfavoured the hypothesis of a more frequentlyoccurring dormant defect revealed by nutritionaldisorders. The most characteristic anatomicallesions were irregularity of their distribution at theonset of the disease; flattening of the epithelialcells surrounding a dilated lumen; plugs in dilatedducts, ductules, or even acini; sclerosis; frequencyof pseudocyst of various sizes; the illness notappearing to be due to the scarring of severalsuccessive attacks of acute pancreatitis. The pan-creatography done in 51 cases revealed dilatation in42, always due to obstruction (stenosis or collectionof stones), and cholangiography, the rarity of biliarystones and of bilio-pancreatic reflux but the frequencyof a typical narrowing of the recropancreatic bileduct.

Fifteen patients without radiological evidence ofcalcification operated on with pancreatic biopsyrevealing fibrosis and diminution of the exocrineparenchyma. In eight cases the pancreatitis was dueto an obstruction of the duct of Wirsung (threeVaterian stenosis, one cicatricial occlusion of theduct after an acute haemorrhagic pancreatitis, threeslow growing cancers, one surgical ligature of theduct of Wirsung). None had dilatation of the acinior small ducts. Only one developed pancreaticstones.Four patients had an intensely destructive

sclerosis of inflammatory character without theirregular localization or the acinocanalicular dilat-ation seen in the calcifying pancreatitis. The clinicalcourse was marked by evolution with little pain,fever, elevation of the gamma globulin. Two patientsdied and two cases appeared to be cured sympto-matically and functionally. No cause was found.Three cases seemed to represent the initial lesion

of a calcifying pancreatitis.In 90 cases of acute pancreatitis, gall stones were

found in 46 cases; 18 had oedematous pancreatitis,



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Observations on 205 confirmed cases of acute pancreatitis, recurring pancreatitis, anid chronic pancreatitis 559

72 haemorrhagic pancreatitis, and 23 patients diedat the first attack. On the 67 who survived, 14presented with recurring episodes of acute relapsingpancreatitis. Only one patient progressed to chronicpancreatitis due to cicatricial obstruction of theduct of Wirsung. The rarity of proved acute pan-creatitis progressing towards chronic pancreatitisdeserves to be emphasized.

REFERENCES

Becker, V. (1957). Sekretionstudien am Pankrease. Thieme, Stuttgart.Birnstingi, M. (1959). A study of pancreatography. Brit. J. Surg., 47,

128-139.Burton, P., Evans, D. G., Harper, A. A., Howat, H. T., Oleesky, B.,

Scott, J. E., and Varley, H. (1960). A test of pancreatic functionin man based on the analysis of duodenal contents afteradministration of secretin and pancreozymin. Gut, 1, 111-124.

Comfort, M. W., Gambill, E. E., and Baggenstoss, A. H. (1946).Chronic relapsing pancreatitis; a study of twenty-nine caseswithout associated disease of the biliary or gastro-intestinaltract. Gastroenterology, 6, 239-285, 376-408.

Fitzgerald, 0. and P., Fennelly, J., McMullin, J. P., and Boland, S. J.(1963). A clinical study of chronic pancreatitis. Gut, 4, 193-216.

Gambill, E. E., Comfort, M. W., and Baggenstoss, A. H. (1948).Chronic relapsing pancreatitis: an analysis of 27 cases associ-ated with disease of the biliary tract. Gastroenterology, 11, 1-33.

Geevarghese, P. J., Pillai, V. K., Pitchumoni, C. S. and (1963). Theaetiopathogenesis of chronic relapsing pancreatitis. Proc. 2ndWld Congr. Gastroent., pp. 153-155. Karger, Basel and NewYork.

Gross, J. B., Ulrich, J. A., and Maher, F. T. (1962). Further observ-ations on the hereditary form of pancreatitis. In Ciba Found-ation Symposium on the Exocrine Pancreas, edited by A. V. S.de Reuck and M. A. Cameron, pp. 278-309. Churchill, London.

Haemmerli, Y., and Schmid, M. (1965). In Symposium of Marseilles,April, 1963, pp. 58-74. (see Symposium of Marseilles).

Hardy, M. (1965). In Symposium of Marseilles, April, 1963, pp. 189-216. (see Symposium of Marseilles).

Hennequet, A., Debris, P., and Marie, J. (1958). La test de la sueurpar injection intradermique d'un parasympathicomimetiquede synthese, Sem. H6p. Paris, 34, 883-885.

Herfort, K. (1965). In Symposium of Marseilles, April, 1963, pp. 35-45. (see Symposium of Marseilles).

Howat, H. (1965). In Symposium of Marseilles, 1963, pp. 31-34. (seeSymposium of Marseilles).

Howard, J. M., and Jordan, G. L. (1960). Surgical Diseases of thePancreas. Lippincott, Philadelphia.

Koch, W., and Bohn, H. (1963). Vorkommen von Pankreatopathiemit Verkalkung in Familien mit Mucoviscidosis. Proc. 2ndWld Congr. Gastroent., pp. 147-152. Karger, Basel and NewYork., Vol. IV.

Lamy, J., Sarles, J. C., and Bricot, R. (1963). A propos du traitmentchirurgical des pancreatites chroniques de l'adulte. Ibid., pp.738-743.

Leger, L., Perrotin, J., Detrie, Ph., Lebel, M., Meyer, J., and Lemaigre,G. (1962). Pancr6atites chroniques familiales. A propos delesions similaires observees chez deux freres. Presse med., 70,1257-1260.

Poirier, A., Dubost, C., Premont, M., and Boutelier, P. (1962).La pancr6atite chronique 6tape ultime de la pancr6atite aigue.En faveur de l'unicit6 de la pancr6atite. Ibid., 70, 2095-2098.

Ludin, M., and Scheidegger, S. (1941). Uber Pankreaskonkremente(Rontgenologisch-pathologisch-anatomische Untersuchungen).Klin. Wschr., 20, 690-694.

Marks, I. N., and Bank, S. (1963). The aetiology, clinical features anddiagnosis of pancreatitis in the south western Cape. S. Afr.med. J., 37, 1039-1053.

Morel, C. J. L. (1963). Pancreatitis Cronical. Lopez, Beunos-Aires.Sarles, H., and Camatte, R. (1963). Pancreatites Aigues. Masson, Paris.

and Guigou, C. (1951). Pancr6atites et papillites chroniquesprimitives. Sem. Hop. Paris, 27, 3266-3276.Martin, M., Camatte, R., and Sarles, J. C. (1963). Le demem-brement des pancr6atites: les pseudokystes des pancr6atitesaigues et des pancreatites chroniques. Presse me'd., 71, 237-240.and Mercadier, M. (1960). Les Pancreatites Chroniques del'Adulte. L'Expansion Scientifique Francaise, Paris.Muratore, R., and Sarles, J. C. (1961). Itude anatomique despancr6atites chroniques de l'adulte. Sem. Hop. Paris, 37,1507- 1522.

Shaper, A. G. (1960). Chronic pancreatic disease and protein mal-nutrition. Lancet, 1, 1223-1224.

Symposium of Marseilles, April 1963. (1965). Etiology and patho-logical anatomy of chronic pancreatitis. Bibl. gastroent.(Basel).

Tremolieres, J., Serville, Y., and Jacquot, R. (1956). Manuel tlment-aire d'e'limentation Humaine, vol. 3. Pratique de l'Alimentation.Iditions Sociales Francaises, Paris.

Zuidema, P. J. (1960). Cirrose en calcificatie von de pancreas bijpatienten mit wanvoding. T. Gastro-ent., 3, 77-80.



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Observations on 205 confirmed cases of acute pancreatitis