FIBROCYSTIC DISEASE OF THE PANCREAS IN THENEWBORN

BY

ALBERT E. CLAIREAUXFrom the Bernhard Baron Memorial Research Laboratories, Queen Charlotte's Maternity Hospital,

and the Institute of Obstetrics and Gynaecology, University ofLondon(RECEIVED FOR PUBLICATION SEPTEMBER 1, 1955)

Fibrocystic disease of the pancreas in the newborninfant is usually recognized by the development ofintestinal obstruction as a result of meconium ileus(Andersen, 1938). According to Bodian (1952),a certain number of infants affected by fibrocysticdisease develop severe intestinal lesions during intra-uterine life. The abnormal consistence of themucus produced in the alimentary tract causesinspissation of meconium and leads to intestinalobstruction, perforation or even atresia of thebowel. In the older infant the disease is morelikely to take the form of a severe nutritionaldisorder which is liable to be complicated byrespiratory infection. In a number of patients therespiratory disorder may dominate the clinicalpicture (Farber, 1944). Intestinal obstruction israre in this group of patients, but it has beenreported by Levy (1951) and by Fisher (1954) as alate complication of fibrocystic disease.On the other hand, a congenital disorder such as

fibrocystic disease of the pancreas is liable to beundetected in the neonatal period unless it appears asmeconium ileus. Bodian (1952) states that in hisseries no children died in the first days of life withfibrocystic disease other than those with meconiumileus. He was thus unable to compare the dis-tribution of intestinal lesions in infants of this agegroup with and without meconium ileus. In thislaboratory we have examined sections of the pancreasobtained from a consecutive series of 500 necropsieson newborn infants without finding a single exampleof fibrocystic disease.

Recently, however, a case was encountered of aninfant who died from anoxia during delivery. Atpost-mortem examination severe fibrocystic diseaseof the pancreas was found and lesions were alsovisible in the liver. There was no evidence ofintestinal obstruction and the large bowel was fullof meconium. This appears to be the first recordedexample of fibrocystic disease of the pancreas withoutan intestinal lesion in a newborn infant.

Case ReportThe mother was a healthy woman aged 29 years and

this was her second pregnancy. Her first pregnancy in1953 resulted in the birth of a boy who is now alive andwell. Delivery was effected by Caesarean section at37 weeks on account of placenta praevia. She developedacute nephritis two months after delivery but recoveredfully.During the pregnancy she was quite well. She was

Group 0 Rh positive and no antibodies were present inthe serum. The haemoglobin was 12-7 g. % and redcells were 4-3 million per c.mm. A chest radiographwas normal and the Wassermann and Kahn tests werenegative. Her blood pressure was 120/90 mm. Hg andno abnormal constituents were present in the urine.No abnormality was detected at routine ante-natalexamination.

Labour began spontaneously on February 26, 1955,seven days after the estimated date of delivery. Thepatient's blood pressure had risen to 140/90 mm. Hg.The urine was still clear. The foetus presented by thevertex. A slight intrapartum haemorrhage occurredand signs of foetal distress became evident 12 hours afterthe onset of labour. The foetal heart rate fell to 80/min.and meconium was present in the liquor. On accountof the foetal distress forceps delivery was carried outunder local anaesthesia and when the cervix wasfully dilated episiotomy was performed. The headwas delivered slowly but the baby was now very limpand covered with meconium. The apex beat was notperceptible at delivery and all attempts at resuscitationfailed. The placenta weighed 624 g. and was perfectlynormal. The puerperium was uneventful.

Necropsy. The body was that of a well developedfemale infant weighing 2,975 g. No congenital abnor-mality was found on external examination.The falx and tentorium were intact. The brain was

firm and no lesion was found on slicing.The larynx, trachea and bronchi were healthy. No

free fluid was found in the pleural sacs. The lungs wereintensely congested and subpleural petechial haemor-rhages were present over their surface. There wasevidence of aspiration of liquor amnii. The heart andgreat vessels were normal.The peritoneum was healthy and no lesions were

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FIBROCYSTIC DISEASE OF THE PANCREAS IN THE NEWBORNpresent in stomach or bowel. The content of the smallintestine was yellow and semi-fluid. There was no over-distension. The colon was loaded with meconium,which was rather yellow instead of the usual dark green.The consistence of the meconium was normal. Theliver (140 g.) was large and congested. The capsule wassmooth but numerous small white flecks were seen on theliver surface just beneath. Similar flecks were seen onthe cut surface of the organ when sliced. The fleckswere again near the capsule. The gall bladder wasextremely small and narrow. It contained some yellowmucus. The bile ducts were patent.The pancreas was firm and nodular. The surface was

very irregular and on slicing greenish-white materialcould be expressed from the cut surface. This materiallooked like pus. No macrocysts were seen.The spleen was small and firm. The lymph nodes

were normal. The ovaries, tubes, uterus, thyroid,thymus, pituitary and suprarenal glands showed noabnormality.

Material expressed from the pancreas was examinedbacteriologically. Smears showed numerous pus cellsbut no organisms. All cultures were sterile.

Histology. The pancreas showed a great increase inconnective tissue with a marked atrophy of the acinartissue. The degree of pathological change varied greatlyfrom lobule to lobule. In some lobules the acini hadalmost completely disappeared and in these areas thegland was composed of enormously dilated ducts filledwith amorphous, slightly eosinophil debris and poly-morphonuclear leucocytes (Fig. 1). In some places theduct walls had undergone necrosis and pools of inspis-sated secretion had formed. The ducts were surroundedby dense fibrous tissue. It was presumably the materialfrom these dilated ducts which was expressed when thepancreas was cut during post-mortem examination.Elsewhere the destructive process was less severe. Theacinar tissue was still recognizable and in a very fewareas appeared almost normal. The islets of Langerhansshowed no change. Even in the less affected lobules,however, many acini were distended and filled witheosinophilic material which had the appearance ofinspissated secretion (Fig. 2). The affected structureswere surrounded by fibrous tissue which was infiltratedwith lymphocytes and mononuclear cells. There waslittle evidence of necrosis in these areas, but again

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FIG. 1.-Pancreas x 250. Grossly distended pancreatic duct filled FIG. 2.-Pancreas x 250. Dilated acini filled with inspissatedwith acidophil debris and polymorphonuclear leucocytes. The secretion. There is pronounced periacinar fibrosis but less evidencesmaller ducts are surrounded by proliferated fibrous tissue. (All of inflammatory cell infiltration in this area.

sections stained with haematoxylin and eosin.)

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ARCHIVES OF DISEASE IN CHILDHOODinfiltration with polymorphonuclear leucocytes wasobserved.The liver showed focal biliary cirrhosis (Fig. 3). The

portal tracts chiefly affected were those immediatelybeneath the capsule and corresponding to the white flecksobserved on macroscopic examination. Elsewhere,especially toward the centre of the organ, the bile ductsand portal tracts had a normal appearance. In thecirrhotic areas there was proliferation of small bile ductsand an increase in the fibrous tissue stroma in the portaltracts. The bile ducts were distended and containedsome amorphous material which stained brick-red withhaematoxylin and eosin (Fig. 4). The material wasprobably inspissated mucus. The portal tracts wereinfiltrated with polymorphonuclear leucocytes andlymphocytes and mononuclear cells.The lumen of the gall bladder was filled with thick

mucus. The lining cells were of the tall columnar type.The wall was congested and fibrosed and no dilatedmucous glands were seen.The lungs were slightly expanded as a result of exces-

sive aspiration of liquor amnii. Many alveoli andalveolar ducts contained cornified cells. The lungs werecongested. The bronchi in the lung roots showed anabnormality of the mucous glands (Fig. 5). These glands

FIG. 3.-Liver x 100. Focal biliary cirrhosis. The portal tractsshow prolifet-ation of small bile ducts, increase in fibrous tissue and

infiltration with inflammatory cells.

were distended with inspissated secretion. The bronchialepithelium had a normal appearance.The parotid gland appeared normal. The sub-

mandibular salivary glands showed moderate dilatationof groups of acini which contained mucus. The ductscontained mucous secretion. The changes were notsevere. No sections were taken from the sublingualglands.

Sections were examined from the stomach, duodenum,ileum and colon. The gastric mucosa showed fairlysevere post-mortem change. A few glands were dis-tended with thick mucus, but they were the exception.Some of Brunner's glands in the duodenum were dilatedand contained inspissated mucus, but the lesion was notpronounced. The ileum showed post-mortem change ofthe mucosa. A few dilated glands were present. Themucous membrane of the colon was healthy. Thevilli appeared normal. Many goblet cells containedmucus, but there was no glandular dilatation (Fig. 6).The spleen, kidneys and suprarenal glands showed no

pathological change.Discuission

This infant obviously had severe fibrocysticdisease of the pancreas. The criteria laid down by

FIG. 4.-Liver x 250. Portal tract showing distended bile ductscontaining acidophil secretion. There is an increase in fibrous tissuewhich is infiltrated with polymorphonuclear leucocytes and lympho-

cytes.

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FIBROCYSTIC DISEASE OF THE PANCREAS IN THE NEWBORN

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FiG. 5.-Lung x 100. Portion of wall of major bronchus showingdilatation of mucous gland which is packed with secretion. Thegland on tte right is emptying viscid mucus into the bronchial lumen.

Bodian (1952) were all present. There was anexcessive quantity of abnormal secretion, atrophy ofexocrine tissue and a fibroblastic reaction andfibrosis of the stroma. Some pancreatic lobuleswere much more severely affected than others andthis is characteristic of the disease. In some areasthere was almost complete fibrosis with disappear-ance of exocrine parenchyma and in others onlymild dilatation of the acini was found. However,the pancreas in this case presented some ratherunusual features. The lesion was very far advancedat this stage of development and the presence of suchlarge numbers of polymorphonuclear leucocytes wasmost extraordinary. Farber (1944) found largemononuclear cells and evidence of lymphocyticinfiltration in some of his material, but 'neithernecrosis nor acute inflammatory changes wereencountered'. Inflammatory infiltration was nota feature of the series reported by Bodian (1952).Both necrosis and severe inflammatory reactionoccurred in this pancreas. The ducts were enor-mously distended with inspissated secretion andmany were packed with polymorphs. The ductwalls were also necrosed.

FIG. 6.-Colon x 150. Mucous membrane is healthy. Many of thegoblet cells in the epithelium contain mucus, but there is no glandular

dilatation.

The cause of this inflammatory reaction is obscure.All attempts at recovering an organism failed.Bodian (1952) suggested that retained secretion maycause pressure atrophy of the exocrine tissue andduring this process intracellular substances areliberated. These substances are believed to beirritant and produce a fibroblastic reaction andfibrosis. If such a process does occur it mayexplain the inflammatory changes in this case.

This question of inflammatory change is alsoconnected with the development of the pancreaticlesion in its early stages. Farber (1944) found onlyinspissated material in the small ducts and acini,and no evidence of fibrosis in the early stage offibrocystic disease. Di Sant' Agnese (1955), on theother hand, examined biopsy material from apatient suffering from fibrocystic disease. Thispatient still had normal pancreatic enzymes in hisduodenal juice. In his case the pancreatic aciniand islets were entirely normal, but there was anincrease in fibrous tissue and an inflammatoryreaction was present in the stroma. It is, of course,impossible to come to any conclusion on suchslender evidence, but it may be that an inflammatory

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ARCHIVES OF DISEASE IN CHILDHOOD

reaction plays a greater part in the development ofthe early pancreatic lesion in some patients than hasbeen suspected.The pancreatic and other lesions in fibrocystic

disease have hitherto been regarded as the result ofabnormal mucus production, i.e., mucosis. Recently,however, Di Sant' Agnese, Darling, Perera and Shea(1953) have shown that there is an increase in thequantity of electrolytes in the sweat of patientssuffering from fibrocystic disease. The sweatglands show no histological change, but are saidto be constantly affected in this condition. Itwould seem, therefore, that exocrine glands otherthan those producing mucus are affected and theexact pathogenesis of the histological lesions inthe pancreas and elsewhere still awaits elucidation.The liver and gall bladder showed typical changes.

The gall bladder was small and fibrosed. It con-tained only thick mucus. The bile ducts werepatent but narrow. No dilated glands were seen.The liver changes were striking. They werecharacteristically subcapsular in distribution andwere very scanty in sections taken from the centreof the liver. They consisted of plugging of smallbile ducts in the portal tracts with strongly acido-phil secretion. There was proliferation of small bileducts and a great increase in fibrous tissue in theaffected portal tracts. The inspissated secretion hadled to dilatation of these small ducts with resultingatrophy to the surrounding liver parenchyma, whichhad been replaced by fibrous tissue. The appear-ance was that of biliary cirrhosis which was pre-dominantly focal in distribution. It is possible thatthis type of lesion plays a part in the development ofliver cirrhosis reported by Webster and Williams(1953) in older children with fibrocystic disease.Inflammatory cell infiltration was also a feature ofthe lesions in the portal tracts and again thepolymorphonuclear leucocyte played a prominentpart. The density of the cellular infiltration in boththe pancreas and the liver was quite exceptional.The absence of any severe lesion in the intestinal

tract was rather surprising. Occasional mucousglands in the stomach, duodenum and ileum were-found and these were full of inspissated mucus.Most glands, however, were quite normal apartfrom rather severe post-mortem change. The colonwas heavily loaded with light yellow meconium.This was probably the result of poor biliary secretionand no bile was seen in the gall bladder at necropsy.The consistence of the meconium seemed normaland some had passed through the anal sphincterinto the liquor during delivery. This would seemto suggest that the development of meconium ileusis not only dependent on the presence of a severe

pancreatic lesion, but also on the disorder ofmucus production throughout the alimentary tract.This infant shows that severe pancreatic andliver changes can be present at birth in the absenceof comparable lesions in the alimentary tract.Hitherto, cases of fibrocystic disease in the neonatalperiod have been associated with meconium ileus.In this condition the ileum is grossly distended aboveand is hypertrophied round inspissated meconiumbelow. The colon is empty and is extremelynarrow. By contrast in the present case the ileumwas of normal calibre and the colon was full of softmeconium.The changes in the salivary glands were slight.

Unfortunately the sublingual salivary glands werenot sectioned. As usual the parotid glands showedno change. The submandibular glands showedsome retention of mucus secretion in the acini andthe ducts were full of mucus. There was noatrophy of acinar tissue and no fibrosis.

In the respiratory tract the mucous glands of themajor bronchi were dilated. The glands were filledwith mucus but were not cystic. The changes wereminimal and similar to those reported by Nashand Smith (1952). Their significance is doubtful.There was no doubt that the infant died from the

effects of anoxia just before delivery. The foetalheart rate had slowed to 80/min. just after intra-partum haemorrhage occurred. The infant passedmeconium into the liquor and there was histologicalevidence in the lungs of excessive aspiration ofliquor amnii. The intrapartum haemorrhage wasprobably the result of a premature separation of theplacenta which was sufficient to interfere with theoxygenation of the infant.

It is interesting to speculate on the course of thedisease if the infant had survived the hazards ofdelivery. The absence of alimentary tract lesionsmakes it unlikely that intestinal obstruction wouldhave occurred during the neonatal period. Thechanges in the respiratory tract were very slight andwould probably not have been sufficient to encouragethe development of infection. The pancreaticlesions were severe and as they are progressivewould have led to a very severe nutritional distur-bance which would have been soon recognizable.The relationship between focal biliary cirrhosisin the newborn and the development of multilobularcirrhosis in the older child with fibrocystic diseaseis not yet known. It is possible that the lattercondition is not solely the result of malnutrition andprotein deficiency.

SummaryA case of fibrocystic disease of the pancreas in an

infant who died during delivery is reported.

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FIBROCYSTIC DISEASE OF THE PANCREAS IN THE NEWBORN 27Typical lesions were present in the pancreas and

liver. Mild changes were found in the sub-mandibular salivary gland and in the mucousglands of the main bronchi and in some of themucous glands of the alimentary tract.

There was no evidence of meconium ileus andthe meconium was of normal consistence.An unusual feature of the lesions in the pancreas

was the intense inflammatory reaction. The inflam-matory cells were mainly polymorphonuclearleucocytes. A brisk inflammatory reaction was alsopresent in the portal tracts in the liver.

I am indebted to Professor J. McLure Browne foraccess to clinical records and to Mr. E. Clark of thislaboratory for the photomicrographs.

REFERENCES

Andersen, D. H. (1938). Amer. J. Dis. Child., 56, 344.Bodian, M. (1952). Fibrocystic Disease of the Pancreas. London.Di Sant' Agnese, P. A. (1955). Pediatrics, 15, 683.

Darling, R. C., Perera, G. A. and Shea, E. (1953). Ibid.,12, 549.

Farber, S. (1944). Arch. Path. (Chicago), 37, 238.Fisher, 0. D. (1954). Archives of Disease in Childhood, 29, 262.Levy, E. (1951). Ibid., 26, 335.Nash, F. W. and Smith, J. F. (1952). Ibid., 27, 73.Webster, R. and Williams, H. (1953). Ibid., 28, 343.

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