Acta Radiologica

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Pulmonary Changes in Fibrosis of the Pancreas Thomas Rosendal To cite this article: Thomas Rosendal (1951) Pulmonary Changes in Fibrosis of the Pancreas, Acta Radiologica, 35:3-4, 233-245, DOI: 10.3109/00016925109137567 To link to this article: http://dx.doi.org/10.3109/00016925109137567

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ACTA RADIOLOGICA E I) I‘rX 1’1: 11 so (: I I:TXTE s 13 A D I o LO G I (:AS D A N IX, F E N N IX, I I E I,\’ 13T I H 0 1 , I A N d I “E, K 0 lOL. xssv

A4m€L 1951

FASC. 4

Illiring tlie past 10 to 15 y(~arstlie paeciiatric literature, partly t h a t of Switzerland (6, 9, 1 1 , 16, and 17), hiit especially that of America (2, 3, 3, 7, 13, 14, and 18) has contained a n increasing iiuniber of comniunications abont n new nosological cntity in children which begins during infancy and is known as fibrosis of tlic pancreas. I n the Scandinavian literature on the subject the disease ]ins been mentioned by . ~ I . J S E R ( 1 946) and PLENSROI~C ( 1947). The term used for this disease is to a certain degree misleading, as i t only tienotcs the changes in the pancreas: the pathological processes occurring simnltancousl,y in tlic lungs, as a rule, predominate in tlie clinical picture antl have proved fatal i n alniost a1L the cases reported. The first c.oii:rnuriicatioiis were ,211 based upon the post-mortem finclings, and where a microscopical exmiination of the pancreas only had kicri made. Irowever, that the disease is no rarity is apparent from the rise of the percentage from 1 or 2 in 1938 (5) t o 12 per cent in 1942, bnsed upon a series of post-mortem exaiiiiriations a t the Children’s Hosp’tal in I3oston (15). The total number of cases at this hospital since 1938 is 134; they have been described in two publications from Boston

in 1949 (13, 14). Thc liistological changes in the pancreas (see Figures 1 and 2) consist of blocking of the m a l l excretory ducts antl of the acini, with a thickened, often stratified secretion; tlie ducts ancl the acini are dilated, the glandular cells atropliic, ancl there is a diffuse formation of connective tissue in tlie gland, but without actual inflaniniatory changes. The islands of Langerhans remain unaffected. ~-

Subniittctl for publication, Sept. 6, 1930. From the p d i a t r i c clinic of the Municipality of Copenhagin (Director : ARNE ROTHE-METER), and t h e radiological clepartnictit of the Sundby -Hospital (Director: THOJIAH IZOSEST)AL), CoI)enliapen, Uenimrk. 1

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TIIOMAS ROPENDAL

The histological changes have h e n considered indicative of an obstruction to the flow of the external secretion of the pancreas, partly because i t is thick and viscous, partly because of fibrosis and occlusion of the small excretory ducts. Clinically, the absence of the pancreatic enzymes trypsin, lipase and amylase in the duodenal juice is the most important sign of the disease. The histological changes in the pancreas are irreversible, and the disease appears immediately a t birth or very soon after. In the former case the absence of the pancreatic secretion n-ill cause the intestinal contents, the nieconium, of the new-born baby t o be of a changed nature; the meconiiim will not, as under normal conditions, be digested by the trypsin, but will become thickened and viscous and assume a resinous consistency. Intestinal peristalsis will become ineffective, and a meconiuni ileus will develop. The connection between ineconiuiii ileus and cystic fibrous clianges were described by L A N D s m I N m as cnrly as in 1905, but only the paediatric publications of recent years refmed to above have caused this clinical picture and its association with fibrosis of the pancreas to become wellknown. When the fibrosis of the pancrtw does not manifest itself until some time after birth, the absence of pancreas trypsin and lipase will Give rise to disturbances of digestion with large, often fatty, stools of a distinctly cheesy odour, emaciation, and pronounced distension of the abdomen; the clinical picture can then only with difficulty be distinguished from coeliac disease. There is, however, the difference that the fibrosis of the pancreas gives symptoms in the coiirse of the first few months, whereas the coeliac syndrome does not appear until the second year of life. In the lungs, too, there is a change in the mechanism of secretion, with plugging of the lesser bronchi and bronchioles with a viscous, thickened secretion (see Figure 3). By a valve-action an emphysema will develop peripherally to the plugging, and atelectatic areas will also develop. Secondary infection will give rise to purulent bronchitis, peribronchial infiltration, development of small abscesses and bronchopneumonia. 1nterstitia.l fibrosis may cause a further increase in the occlusion of the bronchioles so that bronchiectases my develop. The same changes as have been mentioned in the case of the pancreas and the lungs have been found in the bile ducts, in the glands of the intestinal canal, and in the salivary glands. The pathological changes in the lungs will lead to a pertussoid type of cough, troubled respiration and cyanosis, with fever caused by the infection; the respiratory symptoms will appear in the course of the first few weeks of life. The reason that fibrosis of the pancreas has not been recognized earlier is that the respiratory symptoms dominated the clini-

PULBIONARY CHANGES IN FIBROSIS OF THE PAKCRE-4S

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Fig. 1. Fig. 2. Pigs. 1 and 2. Micropliotographs of pancreatic tissue of child with fibrosis of the pancreas. Case I, Fig. 2 . (Magnification about 250 x .)

cal picture and resulted in death; post-mortem examinations suggested that the lung changes were the probable cause of death. I n the greater part of the literature on the subject there is a tendency t o classify the clinical picture of fibrosis of the pancreas into three types according to the time when the disease is apparent. Soon after birth it is characterized by rrieconiuni ileus, during the first few weeks of life by respiratory affection, and after the sixth month of life the disease appears j n the guise of coeliac disease complicated with chronic bronchitis. MAY and LOWE(1949) warn 11s against this tendency, stressing that the simu!taneous affection of various systems t o different and varyin? degrees will give a combination of signs, a few only of which will be dominant. This will often result in a clinical picture which cannot be classified according t o type. The following are the case records and roentgenologic findings of a child who died of the disease with respiratory signs in the seventh month of life, and of another child in whom the disease has been followed for t h e e years. C a R e 1. A girl (%J. H., case record 395/49) born a t term on January Sth, 1949. Her mother contracted syphilis in 1935 and last underwent antiluetic treatment at the University Hospital in Copenhagen in 1936. I n 1949 she had a strongly positive Wasserniann reaction. The child’s reaction was negative. The latter was the fifth of a family

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Fig. 3. Microphotogra1)li of pnlnionary tissue of child with fibrosis of the pancreas. Case I. (Magnification about 20 x .) of 5 brothcrs and sisters. Three had died :it, agc’s from 2 to 4 months, one in the course of antiluetic treatment in 1935 ancl two with pulmonary lesions in 1937 a i d 1939. The cause of death was pneumonia in both casc.s. A brother aged 5 years is alive and in good health. The fifth child, whose case record will be reported here, had been admitted to the ~)Blegdamshospitabin Copenhagen at the : L ~ Pof 2 months and had been there for 1 month with a diagnosis of ’tussis convulsia and I)i~onchopneunionia’.After a fortnight’s stay a t home, when the cough persisted, the chiltl was admitted on April 30th, 1949, t o the Paediatric Clinic of the Municipality of C!openhagen for bronchitis and dyspepsia. She was 31/2 months of age. Her general licalth was poor. There was a constant cough, dyspnoea and slight cyanosis. Numerous moist riles could be heard over the lungs, the temperature was slightly raised, and thci tliagnosis of pneumonia ancl capillary bronchitis was made. I n spite of treatment with penicillin, sulphathiazole and a steam tent the clinical picture remained dominated by the persistent cough; the teniperature became nornial, b u t clyspnoea and some cyanosis persistrtl. As the stools became increasingly frequent, semiliquid and offensive, fibrosis of the pancreas was suspected, and this was confirmed as :L specimen of duodenal juice showcd lack of pancreatic enzymes. I n spite of a fatfree, high carbohydrate and high protein diet, pancrcatin, and vitamin preparations

PULMONARY CIIAKQES IN FIBROSIS OF THE PAKCREAS

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Fig. 4. Ci~soI. Aged 31/2 trioiiths. Marked eriiphysenia most conspicuous on the left side with displacement of the niediastinurn a i d the heart t o the right,

Fig. 5 . Case 1. Aged 41/, nionths. Eniphysenia of the left lung with displacement of the riietliastiiiuiii to thc right and increased lung markings around the hilus on either side. together with petiidliti treatment ant1 repeated blood transfusions, the child became worse. After 2 months treatment she was extrctrir4y cmaciated and cyanotic. Thrrr was considerable clyspnow and persistent cough. She died on July lst, 1949. At post-mortem examination a t the Municipal Hospital of Copenhagen the microscopicd examination of thc. pancreas (Figures 1 antl 2) showed a diffuse, interstitial fibrosis with increase of the inter- antl intralobular connective tissue. Scattered round cells were seen in the connective tissue, but there were no inflarnniatory infiltration. Retention of the secretion in the acini, and a few dilated excretory ducts were noted. The secretion

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l'lf0,MAS ROSENDAL

Fig. 6. Case 11. Aged 6 months. Opacity over the left half of the diaphragm. in the latter was in the form of round or oval - in some parts stratified - corpuscles. The glandular epithelium was in parts atrophic; in many glands i t had been shed. The lungs (Figure 3) revealed a severe, purulcnt bronchitis with scattered atelectases, eniphysenia, and small peribronchitic pneumonias. The liver and the spleen were hyperaeniic. The other organs showed no abnormality. The lungs had been repeatedly exainined roentgenologically b u t the changes had not heen recognized. When the films a c r e re-examined, the first ones taken showed a marked emphysema (Figure 4) which was most conspicuous on the left side, with downward displacement of the diaphragm a i t t l displacement of the heart to the right. The mediastilium was also displaced to the right, and in front of the dorsal spine air-containing pulmonary tissue of the left lung could b(>dibtinctly observed. I n subsequent films (Fig. 5 ) the lung markings had become diffusely increased. Considerable emphysema persisted.

C n s e Z 1 . l A boy (T. V., case record 71/50), born a t term on April 24th, 1947. The younger of 2 children. A sister died 2'i2 months old in the paediatrical department of the Sundby Hospital, Copenhagen, of malignant gastro-enteritis; microscopical exaniinatioii of the pancreas was not carritd out a t the post-mortem examination. The mother stated t h a t the child had been coughing from birth. The patient has been admitted 3 times to the Paediatric Department of the oSundby Hospital));the first time for 14 months in 1947-48, the second time for 1 month in 1919, and the third time after January, 1950. H e was first admitted at the age of 6 months ~

The author is indebted t o Chief Physician, Dr. C. FRIDERICHSEN, for the use of this case history. 1

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Fig. 7. Case 11. Aged 15 months. 1)rnse hilus shadows.

lmause of chronic bronchitis from which he had been suffering from the age of 1 month. On aclniission, he was suffering from catarrh, cough and troubled respiration. He was not exhausted. His state of nutrition was above the average. The borders of the lungs were expanclccl; rhonchi and rilles were present. Soon after athission it was noted that the stools were large, greyish and of a cheesy oclour, and this - in connection with the patient’s chronic bronchitis - aroused the suspicion of fibrosis of the pancreas. -4sample of duodenal juice was secured, and the exntriination showed no trypsin activity, slight lipase, and only a trace of amylase activity; on the basis of these findings the diagnosis of fibrosis of the pancreas was made. He was treated with a fat-free, high carbohydrate and high protein diet, vitamins and pancreatin. In the course of this treatment the stools b t w m e more normal in appearance, and whilst his weight had previously remained unchanged i t now increased, This treatment has been continued (luring the past 2l/, years. The disease has chiefly been characterized by a persistent infection of the respiratory tract with cough and febrile remissions, caused by pneunionic processes which have been treated by sulphathiazole and penicillin. The treatment has been carried out in the patient’s home; he has been re-admitted to hospital only by reason of the constant arid troublesome pulmonary symptoms. 1)uring his last stay in hospital this pear he was dyspnoeic, slightly cyanotic, thin, slender and without any subcutaneous adipose tissue; typical cyanotic clubbed fingers had developed. One obtained the impression that the pulmonary signs had increased. The developerit of the changes in the lungs ran be followed in a series of roentgenograms taken from October, 1947, to March, 1950. I n the first examination (Figure 6) a small opacity can be seen over the left half of the diaphragm, indicative of atelectasis or pneumonia. I n 1948 the hilus sliaciows had become large and dense, and the markings of the lungs more distinct basally (Figure 7). I n 1949 and 1990 (Figures 8,

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TIIOMAS ROSENDAL

Pig. 8. Case 11. Aged 2 years. Eniphysenia, large and dense hilus shadows with incrcitsctl lung niarkings.

9 and lo), the changes have beconic inotx conspic~io~is, are still progressing and appear as a symnietrical, diffuse increase of t tit. Iring niarkings, radiating from the eii1;irgetl hilus shadows. I n addition there is unit'oimi emphysema of both lungs; the heart is normal in appearance.

I n these two cases the clinical picture has been characterized by persistent respiratory symptoms which have been refractory to treatment. The large stools aroused the suspic*ionof fibrosis of the pancreas, and the diagnosis was confirmed by exaininntion of the duodenal juice. With our present knowledge the changes in the liings, demonstrated by means of roentgenologic examination, coulc 1 also have assisted in the diagnosis in each case. They follow the type of change found in fibrosis of the pancreases described by ATTWOOD and SARGENT (1942), BAYLIN (1944), and NEUIIAUSER (1946). The first case affords an example of the early changes seen when various degrees of obstruction of the bronchi give rise t o emphysema, and before inflarnmatory changes have occurred. The emphysema manifests itself by n displacement of the diaphragm and may, when unilateral, cause considerable displacement of the heart

PULMONARY CHANQES I N FIBROSIS OP TIIE PANCREAS

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Fig. 9. Case 11. Aged 2 years arid 9 months. Emphysema, large and very dense hilus shadows; greatly increased lung markings.

and of the iiiediastinum, thus resembling a pneumothorax. As already rnentioned, the plugging of the bronchi niay also give rise to atelectasis; this may be lobar. In the second case the development of the pathological changes in the lungs niay readily be followed; in addition to emphysema and atelectatic areas there are inflammatory changes with peribronchitic infiltration and pneiiinonic foci. Characteristic of this stage is the completely uniform, diffuse increase of the lung markings, decreasing towards the periphery. Jenerally, these pulmonary changes will be considered as signs of bronvhiectasis, and in Case I1 the clinical picture is suggestive thereof. It was, howcver, not possible t o make a definite roentgenological diagnosis; the llatient’s condition did not permit bronchography. I n the cases reported 111 the literature the same was the case: the patients have been too exhausted by respiratory symptoms to undergo bronchography. MAY and LOWEhave thus only performed bronchography in 8 out of 134 cases,

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THOMAS ROSENDAL

Fig. 10. Case 11. Aged 3 years. Enipliysema, very large and dense hilus shadows, and a greatly diffused increase of the lung markings.

and bronchiectases were demonstrated in one case only. The fact that

ANDERSENhas ascertained the presence of bronchiectases in 15 cases in a series of 44 children, suggests that it is of quite frequent occurrence. Though the features of roentgenograms of the lungs mentioned above are not absolutely typical of fibrosis of the pancreas, they may, however, make such a diagnosis possible, and it is, therefore, important to be familiar with this picture when roentgenograms of children with pulmonary catarrhal affections are examined. The disease has proved t o be hereditary (13). The history of the first case seems to indicate that the two siblings who died at ages of 2 and 4 months respectively may have had the same disease, and a similar supposition may be made in Case 11. On the basis of an examination of the familial occurrence of the 134 cases of fibrosis of the pancreas collected a t the Children’s Hospital in

PULMONARY CIIANQES IN FIBROSIS OF THE PANCREAS

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Boston it has been shown t o be a recessive inheritance (13), and it can thus be taken for granted that 25 per cent of the children in a family will develop fibrosis of the pancreas when the disease occurs in one of the children. The etiology of the disease is unknown. Most authors agree in attributing the causc of the occurrence of the symptoms t o a n obstruction to the flow of the changed secretion in the pancreas and ia the mucous glands of the bronchi, and the simultaneous change in the secretions of the two organs suggests a common causation. Various hypotheses based on infection, incomplete resorption of nutriments, and disturbance of the autonomic nervous system have not helped in a recognition of the pathogenesis. A particularly interesting supposition was p u t forward in 1948 by BAGGEMTOSS ;mi co-workers to the effect that the cause of the pliysicd change in the cxteriial secretion of the pancreas could be attributed t o a suspended secretin-formation in the duodenal wall. This hypothesis is based on experiments which BAGGENSTOSS and co-workers made on dogs ~+-ithexperimental fistula of the pancwas, arid in which no pancreatic secretion was obtained after injection of a duodenal extract from a child who had died of fibrosis of the pancreas. However, this one experiment only has been made in support of the theory, and in any case would only explain tlie changes in the pancreatic secretion. So far, the prognosis of the disease is bad, and no cases have been reported in which the children have survived for more than 14ljZyears. But whereas previously they all died during babyhood, it is now possible t o improve the condition of the respiratory tract by means of penicillin inhalations anti to improve the disturbance of digestion by diet. The patient’s life has thus been prolonged. S IJ M M A 11 Y Based on the 1iter;itur.e on fibrosis of tlie I)ancreas in children a brief account is given of the clinical picture arid the pathogenesis. Two cases are reported; in the first case the disease was followed up until the patient died in the seventh niontli of life, antl in the second in which the child is still alive, it has been followed for 3 years. I n both cases the clinical picture was characterized by respiratory symptoms; the changes observed in the roentgenograms of the lungs are described. The early changes are characterized by the presence of a localized, unilateral einphysenia; later a cliffuse increase of the lung ninrkings and enlargement of the hilus appears. These signs indicate bronchitis and peribronchitis, as well as bronchial plugging, hronchiectasis antl miirked einphysenia.

ZU SAMM E N F A S S U N G An Hand der Litcratur iiber Pankreas-Fibrose 1)ei Kindern wird ein kurzer Bericht uber das klinischti Hild iind die Pathogenese gegeben. Zwei Falle werden mitgeteilt: im

244

THOMAS ROSENDAL

ersten Falle wurde die Krankhcit in ihrciii Verlauf bis zum Tode tles Patienten ini 7. Lebensmonat verfolgt. Im andereii Fall?, in den1 das Kind noch lebt, wurde die Kranklicit 3 Jahre lang beobachtet. In beitlen Fallen wurde das klinische Bild von Krankheitserscheinungen an den Atmungsorganen bcherrscht. Es werden die Verandcrungen, die auf den Rontgenbildern der Lungen beoljachtet wurden, beschrieben. Dic ersten Vcri tiderungen sind gekennzeichnet durch das vorhandene umschriebene und einseitige Emphysem. Spater zeigt sich eine diffuse Zunahnie der Lungenzeichnung und einc Verpriisscrung der Lungenwurzel. Diese Zeichrn sind der Ausdruck fur Bronchitis und Pcribronchitis und ebenso fur Bronchialvcrstopfung, Bronchiektasie und deutliches Emphysem.

RESUME En se basant sur les donnkes tle la litdraturc I’auteur donne un court a p e r p clu tableau clinique et de la pathoghie de la fibrosc du pancreas chez leu enfants. I1 en relate deux cas: dans le preinic.r on put suivre le coups de la malatlie jusq’au moment oh l’enfant mourut, 1’Bgc de sclh mois; dans le second, oh le patient est encore en vie, l’observation a dti: poursuivie peiiilimt trois ans. Dans l’un e t l’autre cas le tableau clinique est caract&& par des syniptGniw respiratoircs; l’auteur ddcrit lcs lesions observ&cs s u p les radiographies tles pounions. Les altdrations du debut se traduisent par la prksence d’un emphys6me localis&, unilatCra1; plus tard on voit apparaitre un rcnforcement diffus du dessin pulmonaire et tin Clargissement des hiles. Ce sont 1h lcs signes tl’une bronchite e t pdribronchite, ainsi qiic ceux d’un encombrenicnt des bronches, d’uiie bronchcctasie et d’un cniphysixme ni:irqui..

L I TI?It A T U R E 1. ATTWOOD, C. J. and SARGENT, W. H.: Cystic Fibrosis of the Pancreas With Observations on the Roentgen Appearanc(x of the Associated Pulmonary Lesion. Radiology 39 (1942), 417. 2. ASDERSEN,DOROTHY: Cystic Fibrosis of the Pancreas and I t s Relation to CtBliac Disease. Am. J. Dis. Child. SG ( 1 938), 344. 3. BAGGENSTOSS, 8. H., M. A. POWER :~ti(lJ. H. GRINDLAY: Pibrocystic Diseases of the Pancreas With no Sccretin in the Intestinal Mucosa. Gastroenterologia 8 (1948), 208. 4. BAYLIN,G. J.: Pulmonary Changes in Chronic Cystic Pancreatic Disease. Am. J. Roentgcnol. 62 (1944), 303. 5. BLACKFAN, K. D. and C. I>. MAY: Inhpissation of Secretion, Dilatation of the Ducts and -4cini, Atrophy and Fibrosis of the Pancreas in Infants. A Clinical Note, J. Pediat. 13 (1938), 627. 6. FAXCONI, C. E., UEHLINGER and C. KSAUSER:Das Coeliakiesyndrom bei angeborener zystischer Pankreasfibroniatose uiid Bronchiektasien. Wien. med. Wschr. 1936, 763. 7. FARRER, S.: Pathologic Changes Ashociated With Pancreatic Insufficiency in E h l y Life. Arch. Path. 37 (1944), 238. 8. FLEXSBORG, E. WINCE: Oni den haakaldte kongenite cystiske pancreasfibrose. Nord. Med. 39 (1948), 1674. 9. GLASZMAKN,E.: Dysporia entero-broncho-pancreatica congenita familiaris. Zystische Pankreasfibrose. Eine klinihche Vorlesung. Ann. paediat. 166 (1946), 289. 10. KAIJSER,KURTand C. W. LUNDQIJIST: Korigenital cystisk pancreasfibros. Nord. Med. 38 (1946), 2361.

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11. KSALTER, C.: Zwei Fiille von Coeliakic 1x4 angel?. zyst. Pankreasfibrose und kong. Uronchiektasirn. Iiiaug. Uiss. Ziirich 1935. 12. IIASDSTEISER, K.: ~)iirniverhclilussdurch cingetlicktes Meconiuni. .kllg. h t h . 11. path. t2n:it. 16 (l!)W), 903. 13. LOWE, C. hI., C. L). MAY a i d 8. REED:Fibrosis of the Pancreas in Infants ant1 Children: d St:ttistical Stutlv of Hereditarv and Clinical Features. Ani. J. Uis. Cliilcl. 7s (1949), 349. 1L MAY, C. L). and C. M. T,o\re: Fibrosis of thc Paiicrcas in Infants anti Chilclrrn. J. Pediat. 34 (1949), 663. 15. ? ~ E V H A U S E R ,K . H. I).: Roentgen Changtls Associat,cd with Pancreatic Insufficiency In Eitrly Life. Radiology 46 (1946), 319. 16. RISIKER,l'.: I)ysporii~ entero-broiicho-I,;iiicrc;ltica coiigenita, fmiiliaris. Zystische Piiiicreasfibrose. E'ii,ttiologisch-ariatoniisclicr Tril. Anri. Imctliat. 166 (1946), 314. 17. Wrssrxn, H. ant1 11. IT. h L L 1 S i : E R : The fimdihre kongenitale zystischc Pankreasfibrose init Hrorrc,liit,ktasieii. Helvet. piidiiit. :icta, yo]. 1, 1945/46. 18. \ V ~ ~ r , ~ s \ v o i v r iF. r , I\.: Fihrocystic Didcase of tht: Pancrrns. Am. J . hl. Sc. 212 ( l W i ) , 351.