Home 1595 From the mid-17th century there were many ...cfmedicine.com/history/pdf/Cystic Fibrosis -...

The History of CysticFibrosis by Dr JamesLittlewood OBE

1595 - 1929

The early years

1595 From the mid-17th century there were many reports of infants who may well havehad cystic fibrosis. The first description of the pancreas in a child who almost certainly died with cystic fibrosis (CF) isusually attributed to Professor Pieter Pauw (1564 -1617), the Professor of Botany and Anatomy atLeiden who wrote “On January 16th 1595, in a square leading to the Grand Canal in Treuendeel, inthe presence of Drs Treloatius, Heurnius and Trutius, I conducted an autopsy on an 11-year oldgirl said to be bewitched. She had had strange symptoms for eight years. Inside the pericardium,the heart was floating in a poisonous liquid, sea green in colour. Death had been caused by thepancreas which was oddly swollen. It was very close to the rounded side of the liver, so that onecould have thought, in touching it, that it was a scirrhous (a type of cancer with a hard and woodytexture). When it was removed the interior was found to be brightly coloured, a kind of hard whiteviscous mass. The little girl was very thin, worn out by hectic fever (a fluctuating) but persistentfever”.

Figure 2: Peiter Pauw performing an autopsy in the Anatomical Theatrein Leiden. From The Paradox of the Pancreas. Modlin IM, Kidd M (Eds).2003:280. With the author's permission.

1606 Alonso y de Los Ruyzes de Fontecha J. Diez previlegios para mugeres prenadas. LP Grande, Alcala de Henares, 1606, p 212. (figure 3) The Professor of Medicine at Henares in Spain first described the salty taste of infants with cysticfibrosis. He wrote that it was known that the fingers tasted salty after rubbing the forehead of thebewitched child (Quoted by Quinton PM. Physiological basis of cystic fibrosis: a historicalperspective. Physiol Rev 1999; 79:S3-S22). [PubMed]

Busch notes that reference to this finding could be found in the 19th century in eleven Europeanstates – in Poland, both German states, the Soviet Union, Czechoslovakia, Austria, Switzerland,Hungary, Romania, Yugoslavia and in Spain (Busch, 1987 below).

Home

Introduction

Early Years

The Thirties

The Fourties

The Fifties

The Sixties

The Seventies

The Eighties

The Nineties

Two Thousand

Mega Papers

Topics

Glossary

Abbreviations

The History of Cystic Fibrosis by Dr James Littlewood OBE

1 Copyright © cfmedicine.com 2009-2011

Figure 4: KarlFreiherr vonRokitansky. FromWikipedia.

Figure 3: The original Alonso y de Los Ruyzes deFontecha document.

1705 Schmidt. In: Book of Folk Philosophy. Chemnitz, Joh Christoph and Joh DavidStoseln.

1729 It was stated that an excessively salty taste to the skin meant a child wasbewitched. (Quoted by Taussig LM (Ed.). Cystic Fibrosis. Thieme-Stratton Inc, New York. 1984).

1813 Home Sir Everard. On the formation of fat in the intestines of living animals. PhilosTrans Royal Soc (London) 1813; 103: 146-158. Sir Everard Home (1756-1812), a pupil of John Hunter whose sister he married, was surgeon at StGeorge’s Hospital, London. He described patients who had steatorrhoea considered to be due topancreatic insufficiency.

1838 Rokitansky C von. Sections-Protokoll und Gutachen. Wien, 4.April 1838 (als Anhang) Karl Freiherr von Rokitansky (1804-1878) (figure 4) was a distinguishedViennese pathologist and described as a founder of modern pathologicalanatomy. He was one of the towering figures who made the New ViennaSchool into a world medical centre in the second half of the nineteenthcentury. His contributions were fundamental to the establishment ofpathology as a recognised science, and he himself performed more than30,000 autopsies. He was one of the few who stood by the side ofSemmelweiss in the controversy over aseptic methods. Rokitansky described the autopsy findings in a seven month gestationpremature male fetus found in a box in a cemetery in Vienna in 1834 asfollows - “Truncus foetus septimestris, in cujus abdomine intestinum ileumproxime valvulum coeci pariete convexo hiat foramina semen cannabisaequante tunicis intestine extus revolutis cincto in peritonaei cavumillincque meconium effudit”. -"In the last part of the small bowel there wasa small ileal perforation the size of a hemp seed and around the perforationthere was yellow jelly-like meconium partially fast sticking to the outside of



the bowel". Death was considered due to peritonitis secondary to the ileal perforation. Althoughthe report did not include microscopic description of the pancreas, it was macroscopically normal. Although the histology of the pancreas was not recorded, this report has been considered to be anearly or even the first description of meconium ileus in cystic fibrosis. However, it was later shownthat meconium ileus can occur in non-CF infants (Rickham et al,1965 below). Later it was therecognition of the changes in the pancreas, present in some of the many infants that came toautopsy, that led to the eventual recognition of “fibrocystic disease of the pancreas” as a specificentity by Dorothy Andersen in 1938 (below) even though the changes in the pancreas are veryvariable in severity. 1848 Pfyffer, J X. (zit bei 46): zitierend aus dem Wörterbuch derschweizerdeutschen Sprache 7 (1848).

From the The Dictionary of the Swiss-German Language -"If it tastes salty when someone iskissed on the brow, then this person is hexed” (bewitched).

1857 Rochholz EL. Alemannisches Kinderlied und Kinderspiel aus der Schweiz, In theAlmanac of Children’s Songs and Games from Switzerland: Leipzig. JJ Weber, 1857.p280. “The child will soon die whose brow tastes salty when kissed”. Yet another widely used quotationindicating that a salty taste on the skin indicated a poor prognosis with the implication that thechild may have had cystic fibrosis.

1888 Gee S. On the coeliac affection. St Bartholomew’s Hospital Report 1888; 24:17-20. Samuel Gee (1839-1911), (figure 5) was physician to St Bartholomew's Hospital and The Hospitalfor Sick Children, Great Ormond Street, London. In a lecture in 1887 Gee described a syndromehe termed the coeliac affection –“There is a kind of chronic indigestion which is met with inpersons of all ages, yet is especially apt to affect children between one and five years old (figure6). Signs of the disease are yielded by the fæces; being loose, not formed, but not watery; morebulky than the food taken would seem to account for; pale in colour, as if devoid of bile; yeasty,frothy, an appearance probably due to fermentation; stinking, stench often very great, the foodhaving undergone putrefaction rather than concoction". The cause of the coeliac affection wasunknown until the role of gluten was described by Willem Dicke in 1950.

Figure 5: Samuel Gee. FromWikipedia.

Figure 6: Wasted boy with coeliac disease.From Common Disorders and Diseases ofChildhood. GF Still. Oxford MedicalPublications, Fifth Edition, 1927.

Eventually the two most important causes of this syndrome of the "coeliac affection" wereidentified as gluten-induced enteropathy, or coeliac disease as we know it today, and cysticfibrosis. Subsequently two important advances in the Fifties permitted a clear separation of thesetwo conditions. The first was the discovery of the elevated salt content of the sweat in CF reportedin

1953 by Paul di Sant’Agnese from New York (di Sant’Agnese et al, 1953 below). Thesecond was Willem Dicke’s discovery of the central role of “a factor in wheat” (gluten)in the aetiology of coeliac disease reported in his MD Thesis in 1950 (Dicke et al, 1953below).

Figure 7: Small bowel mucosain coeliac disease showing

Figure 8: Normal small bowelmucosa.



subtotal villous atrophy.

Subsequently the characteristic histological small bowel appearance of subtotal villous atrophy ofgluten induced coeliac disease (figure 7) was first identified by Paulley in 1954 in laparotomyspecimens from adults with idiopathic steatorrhoea (coeliac disease) (Paulley J W. Observations onthe aetiology of idiopathic steatorrhoea. Jejunal and Lymph node biopsies. BMJ 1954; 173:1318-1321 [PubMed] and then in 1957 by Margot Shiner, in specimens obtained by per oral small bowelbiopsy from an 8 year old child (Sakula J, Shiner M. Coeliac disease with atrophy of the smallintestine mucosa. Lancet 1957; ii: 876-877) [PubMed] and subsequently in children by CharlotteAnderson in 1960 (Anderson et al, Arch Dis Child 1960; 35:419-427 below). [PubMed] In contrast,the intestinal villi are of normal height in people with CF – in some we found them to be eventaller than normal (figure8). John Walker-Smith believes that the development of the technique to perform oral small intestinalbiopsy in childhood was the real beginning of paediatric gastroenterology (Walker-Smith JA.Historic notes in pediatric gastroenterology. J Pediatr Gastroenterol Nutr 1997; 25: 316) and Iwould support this view Littlewood JM. Coeliac disease in childhood. In: Howdle PD (Ed.). ClinicalGastroenterology. International Practice and Research. Bailliere Tindall, London. 1995; 9:295-328). Paediatric subspecialties often developed on the back of a specialised investigation that anumber of paediatricans learned from adult physicians. The first was obviously cardiaccatheterisation by paediatric cardiologists then came various biopsy procedures including smallintestinal biopsy during the Sixties and later fibreoptic endoscopy of the lungs and gastrointestinaltract.

1900 Arraga A, Vinas M. Sclerosis of the pancreas accompanied by chronicgastroenteritis. Arch Med Enfant Paris 1900; i: 1497-1500. Ten children with gastroenteritis were found at autopsy to have histological changes in thepancreas with inflammation causing sclerosis with possible blockage of the main pancreatic duct ofWirsung.

1904 Bramwell B. Pancreatic infantilism: remarkable improvement (growth of body andsexual development) as a result of the administration of pancreatic extract. TransMedico-chi Soc Edin 1904; 23; 162. Clinical Studies 1904; 2:348-352. Edinburgh. R and RClark. Byron Bramwell notes the previously described association of chronic diarrhoea and arrested bodydevelopment. He describes a boy aged 18 years who was the size of one aged 11 years, whosesize and sexual development responded to one drachm of “Armour’s liquor pancreaticus” and onedrachm of glycerine extract of “steapsin” three times daily. Bramwell writes that “After carefullystudying the case I came to the conclusion that the diarrhoea was due to defective metabolism inthe upper part of the gastrointestinal tract: and I suggested that it was probably due to disease ordefective action of the pancreas”. Pancreatic secretion was shown to be defective by demonstrating undigested fat in the stool, by alow phosphoric acid content of the urine after administration of milk and by Sahli’s test ofdigesting a glutoid capsule surrounding iodoform and demonstrating the released iodine in thesaliva. Bramwell published six other papers on “pancreatic infantilism” between 1902 and 1915 at variousEdinburgh meetings and certainly some of these appeared to be recording progress of the samepatient. In this present report Bramwell writes – “I claim that there is a distinct variety or form ofinfantilism which is due to disease of the pancreas and that this, the pancreatic form of infantilism,as I have ventured to term it, can be cured by administration of pancreatic extract. I consider thatit is a distinct clinical entity – a disease which has not hitherto been recognised or described”. Sothis is probably an early description of cystic fibrosis as a distinct clinical entity! Leonard Parsonsconsidered, almost certainly incorrectly, that some of these cases were examples of coeliac disease(Parsons, 1935 below; comment by Rentoul, 1904 below). Admittedly their length of survival isagainst their having CF although it is possible they had an atypical form caused by milder geneticmutations.

1904 Thomson J. Exhibition of patients: two cases of infantilism. Trans Med ChirgEdinburgh 1904; 23:165-166. Dr John Thomson of Edinburgh "exhibited two cases of infantilism accompanied by severedyspepsia and diarrhoea of many years' duration, and probably due to some morbid condition ofthe pancreas". One a man aged 24 years was the height of a boy aged nine years (51.5 inches),he had weak muscles and a tumid abdomen. He had been well until severe influenza at the age of11 years was followed by intractable diarrhoea. There was very slow growth and a wide variety oftreatments were of little value. A similar young man aged 17 years (height on 49.5 inches - theaverage height of an 8 year old boy) was pre-pubertal and had chronic diarrhoea. The diarrhoea inboth these patients was considered to be pancreatic in origin and the clinical features similar tothose patients of Dr Bramwell (1904 above) but no evidence to support this assumption waspresented.

1904 Rentoul JL. Pancreatic infantilism. Brit Med J 1904; 2:1694-1695. A patient apparently diagnosed by Dr Rentoul of Lisburn, Co Antrim, thanks to Byron Bramwell’sprevious descriptions of pancreatic infantilism (Bramwell, 1904 above). Rentoul described a girlaged 18 years with severe growth retardation so she looked more like a nine year old and alsohad a swollen abdomen. There had been lifelong chronic diarrhoea that responded impressively topancreatic extract with improved growth and signs of puberty but whose bowel symptoms relapsed



Figure 8 Karl Landsteiner

when this was withdrawn. In four months she gained 9.5 lbs in weight and gained 2 inches inheight. Also on pancreatin she was “bright happy and willing for any work”! "The cases reported above by Bramwell 1904, Thomson, 1904 and this of Rentoul could have hadShwachman-Diamond syndrome (Shwachman et al, 1964 below) or congenital lipase deficiency(Sheldon W. Arch Dis Child 1964; 39:268-271); [PubMed] Ligumsky M et al. Gut 1990; 31:1416-1418) [PubMed] as chest involvement did not seem to be a significant feature and also the age ofpresentation was far beyond the likely survival age of a child with CF at that time.

1905 Landsteiner K. Intestinalobstruction from thickenedmeconium. Zentralbl Allg Pathol1905; 16:903-907.This was the first description of aninfant with meconium ileus to beaccompanied by a description of theassociated pancreatic histologicalchanges. The pancreas showed anincrease in inter and intra lobularconnective tissue and round cellinfiltration and markedly dilated ducts.Landsteiner suggested that lack ofpancreatic secretion had caused thethickening of the meconium. Hementions another infant where thepancreas was normal but there was nosecretion of bile. "> The report is considered to be thefirst to suspect that microscopicchanges in the pancreas could interferewith secretions and digestion ofmeconium and thus result in bowel

obstruction. Oppenheimer & Esterly, the distinguished N. American pathologists, regard this as thefirst report of meconium ileus (1975, below). Karl Landsteiner (1868-1943) (figure 8a) was a Viennese pathologist who worked first in Viennathen from 1922 in the United States. He described the blood iso-agglutinins in 1900 and the bloodgroups in 1901 for which he received the Nobel Prize in 1930.

1907 Lockhart-Mummery P. Prolapse of the rectum in children, with fifty cases. Brit MedJ 1907; 2:812. A common disorder among children, writes Mr. Lockhart-Mummery a distinguished Londonsurgeon, “especially that class which attends the surgical practice at a children’s hospital”. He hadseen examples of the usually quoted causes of rectal prolapse (phimosis, stone in the bladder,colonic polyps, etc) to be rare but chronic diarrhoea, wasting and general weakness to be common– particularly the removal of fat from around the rectum in such cases.

Unfortunately there is no mention of long term outlook of these children that may have suggestedsome may have had CF; however, the fact that the average age was 2.56 years perhaps indicatedthat prior to 1907 most children that had a prolapse due to CF would have already died. Also in1907 death in early childhood from gastroenteritis was relatively common as was malnutrition andwasting.Subsequently rectal prolapse was described as a feature of CF (Kulczycki & Shwachman, 1958below). The lack of fat around the rectum, as suggested by Lockhart-Mummery, is obviouslyrelevant in CF for when this is restored with appropriate pancreatic enzyme treatment thetendency to rectal prolapse diminishes – usually completely.

In over 600 people with CF I only recall one teenage girl who still complained of rectal prolapseoccasionally. However, one wonders if persistence of this embarrassing problem is under-reportedas was later found to be the case with urinary incontinence in people with cystic fibrosis(Cornacchia et al, 2001 below). (Illustration of severe rectal prolapse in Kulczycki & Shwachman,1958 below).

1908 Herter CA. On infantilism from chronic intestinal infection. MacMillan, New York.1908:18. Christian Archibald Herter (1865-1910) from New York was a pathologist and an expert onmetabolism. He described “intestinal infantilism due to chronic intestinal infection causing anunsuitable intestinal bacterial flora resulting in excessive putrefaction and chronic intoxication ofthe neuromuscular system" – subsequently known as Herter’s Disease. This appeared to be the same clinical condition as Samuel Gee had described in 1888. Somechildren did well for the first year or so then developed chronic gastrointestinal symptoms andsigns and growth problems, steatorrhoea and altered faecal bacterial flora. There were no post-mortems so the state of the pancreas was unknown. The fact that Herter’s cases were aged eight,nine, four, three and nine and a half years makes it very unlikely they had CF, as few children withCF survived to these ages at that time, and so they were more likely to have had coeliac disease.

1909 Heubner O. Serious digestive insufficiency of children beyond infancy. JahrbKinderh 1909; 70:667-700. Johan O L Heubner (1843-1926) was Professor of Paediatrics in Berlin and Leipzig. He studied



Figure 9:SirArchibaldGarrod.

Figure 10: Sir GeorgeFrederick Still. From

infant nutrition and warned against the prolonged sterilisation of milk. He described the infantileform of idiopathic steatorrhoea – subsequently this became known as Heubner-Herter disease(Herter, 1908 above). He also isolated meningococci from the spinal fluid and described syphiliticendarteritis of the cerebral vessels.

1911 Freeman RG. The intestinal infantilism of Herter. Am J Dis Child 1911; 2:332-339. Freeman discusses Herter’s 1908 cases (Herter, 1908 above) and notes recent attention has beengiven to classifying the different types of “dwarfs” described as intestinal (Herter) hepatic(Coutley), and pancreatic (Bramwell). The discussion implies that Herter described a specificcondition which is unlikely to be the case. Freeman describes four patients, aged between twoyears five months and four years six months with chronic gastrointestinal symptoms two of whomimproved with pancreatic extract – “Have good appetite, take food eagerly but have the largepoorly digested movements with a great waste of fat”. There were no post-mortems as all fourchildren gradually improved and appeared to survive which makes CF an unlikely diagnosis.

1912 Garrod AE, Hurtley WH. Congenital familial steatorrhoea. Q J Med1912; 6:242-258. Sir Archibald Garrod (1857-1936) (figure 9 was a London physician and an expertin inborn errors of metabolism. He succeeded Sir William Osler as Regius Professorof Medicine at Oxford and wrote his famous “The Inborn Errors of Metabolism” in1931. Garrod notes that the term “steatorrhoea” was first employed by Kunzmannin 1824 to designate the passage of liquid fat in the stools but later, ratherconfusingly, the term was applied by Sir James Erasmus Wilson (1809-1884) adistinguished London dermatologist, to the disease of the skin commonly known asseborrhoea! Garrod reviews the details of previously published families some ofwhose children had steatorrhoea and died of pneumonia suggesting a recessiveinheritance. The present report describes a well-grown child aged eight years who “passedgrease” from the bowel – a sign very suggestive of pancreatic insufficiency. He wasthe second of five children of whom only two survived – one had died of

pneumonia at seven months, one at six weeks with convulsions and the third at eleven monthswith measles and bronchopneumonia. The parents were first cousins. The boy’s stools contained“large quantities of liquid fat which solidified on cooling to form a plate around the faecal mass.Liquid fat escaped involuntarily from the anus at times”. A variety of investigations suggestedthere was no overall defect of pancreatic secretion “as a whole” suggesting “an inborn errorhitherto undescribed” – suggesting “that in congential steatorrhoea some agent which facilitatesabsorption is, in like manner (to alkaptonuria), wanting”. He suggested “An error of fat absorptionaccompanied by, but not dependent on, a limitation of the power to split fats”.Despite the family history, the overall progress, normal growth, lack of respiratory problems,presence of tryptic digestion are against this child having CF, but could indicate he had “congentiallipase deficiency”, a condition later described by Sir Wilfred Sheldon, paediatrician at GreatOrmond Street, London (Arch Dis Child 1964; 39:268-71) in two families, each with two affectedchildren. Sheldon’s patients had severe steatorrhoea and a tendency for oil to ooze from the anus,but satisfactory growth, absent or low pancreatic lipase but normal amylase and proteolyticenzymes in the pancreatic juice. (Also Garrod AE. Congenital family steatorrhoea. BMJ 1920; i:249-264).

1914 Poynton FJ, Armstrong RR, Nabarro DN. Contribution to study of a group of casesof recurrent diarrhoea in childhood. Brit J Child 1914; 11:145-155 and 193 –201. While studying the chronic diarrhoeas of childhood the authors noted marked increase ininterlobular fibrous tissue of the pancreas, particularly surrounding the ducts, in one of their fatalcases of “coeliac disease” – it is likely that this child had cystic fibrosis. The authors suggested twofactors in the aetiology of the disease – a possible infection and the appearance of the coeliacaffection symptoms as sequelae to the pancreatic damage.

1918 Still GF. Lumleian lectures on Coeliac Disease. Lancet 1918; 2:162 and Lancet1918; 2:193. Sir George Frederick Still (1868-1941) (figure 10) noted the majority of his cases of coeliacdisease occurred in the later part of infancy, none ever beginning while the child was breast fed.He had seen

17 such children amongst 14,800 hospital patients but 24 in hisprivate practice. One of his cases had loose stools for fourmonths at seven years and died aged seven and a half yearsand had excess fibrous tissue especially about the ductssuggestive of pancreatitis. He explained the presence ofpancreatitis and round cell infiltration of the intestinal mucosaand submucosal in one case as an inflammatory processsecondary to some functional failure of digestive secretion withresulting abnormal decomposition of food residue favouringgrowth of harmful bacteria. This child is not mentioned in his classic paediatric textbook“Common Disorders and Diseases of Childhood” 1927 edition.The only brief mention of the pancreas is in the chapter oncoeliac disease – “On the assumption that some defect of thepancreatic secretion underlies coeliac disease, a view putforward by Dr Cheadle and others, various pancreatic extracts



www.georgestillforum.co.ukwith permission.

Figure 11: SirFrederick Banting.From Wikipedia.

have been tried. I can only say that in my experience suchdrugs have had very little if any effect, certainly nonecomparable to the effect of the castor oil mixture”. So there wasno suggestion that some of these children may have suffered

from pancreatic abnormalities. Also the ages and outlook of the children would be against theirhaving cystic fibrosis.

1919 Passini F. Pankreaserkrankung als Ursache des Nichtgedeihens von Kindern.(Pancreatic disease as a cause of failure to thrive in children) Deutsche Med Wschr1919; 45: 851-853. Passini described pancreatic disease in an infant aged two months with nutritional failure and largestools. The pancreatic histology was typical of that subsequently described in cystic fibrosis; healso described a sibling aged nine months who had a small pancreas with cystic changes in theacini and a reduction in the islets of Langerhans. Another infant aged 18 months showed wideningof the pancreatic ducts and a necrotic parenchyma. All died of bronchopneumonia and presumablyhad cystic fibrosis.

Martin Bodian (1952 below), pathologist at the Hospital for Sick Children, Great Ormond Street,London and other authors (for example Wolman 1942), considered that Passini was the first tosuggest and prove the presence of a definite abnormality of the pancreas in some cases ofsteatorrhoea which he differentiated from Herter’s disease – chronic intestinal infantilism possiblydue to some disturbed bacterial situation in the gut (Herter, 1908 above).

1920 Miller R, Perkins H. Congenital steatorrhoea. Q J Med 1920; 14:1-9. Miller described a child with the clinical features of CF who died at home following a dentalextraction. There was 52 percent of fat in the stools but there was no autopsy. Later Millerreviewed the post mortem findings of some previous cases and concluded that the excessive fatloss in the stools was due to enteritis and must be due to a digestive fault, probably a defectiveaction of bile salts (Miller R. Lancet 1921; i: 743; Miller R. Arch Pediat 1923; 40:88).

1922 Banting FG, Best CH. Internal secretion of the pancreas. J Lab Clin Med 1922; VII:251-266.

The work reported in this classic paper eventually led to a Nobel Prizein 1923 for Banting and Macleod, in whose Toronto laboratory thework was done. Frederick Banting (1891-1941) (figure 11) was aCanadian orthopaedic surgeon who became an assistant in physiologyin Ontario where he worked in Richard McLeod’s laboratory withCharles Best, a medical student. It was here, after many ups anddowns and arguments and with the help of Bertram Collip, a highlytrained biochemist (to extract the insulin) that they eventuallyproduced and tried the insulin on a diabetic patient in 1922. The paper begins –“The hypothesis underlying this series ofexperiments was first formulated by one of us in November 1920(Banting was then assistant in Physiology at Western University,London, Ontario) while reading an article dealing with the relation ofthe isles of Langerhans to diabetes (Barron M: The relation of theislets of Langerhans to diabetes with special reference to cases ofpancreatic lithiasis. Surg Gynec Obstetr 1920; xxxi :437-448).Fromthe passage in the article which gives a resume of degenerativechanges in the acini of the pancreas following ligation of the ducts,the idea presented itself that since the acinous but not the islandtissue degenerates after this operation, advantage might be taken of

this fact to prepare an active extract of the islet tissue. The subsidiary hypothesis was thattrypsinogen or its derivatives was antagonistic to the internal secretion of the gland. The failures ofother investigators in this much worked field were thus accounted for”.The authors concluded from their experiments that –“intravenous injections of extract from dog’spancreas, removed from 7 to 10 weeks after ligation of the ducts, invariably exercises a reducinginfluence upon the percentage sugar of the blood and the amount of sugar excreted in the urine”

This medical classic is a “good read” and one of the most significant medical papers of the 20thcentury as also is Moses Barron's paper that gave him the idea (above). It is included here notonly for its historical interest but also for its relevance to CF as the majority of those affected willeventually develop CF related diabetes in adult life. Although the Islets of Langerhans in CF arefunctioning adequately through childhood in most patients, despite their severe exocrine pancreaticinsufficiency, they are eventually destroyed resulting in the majority of adults with CF developingdiabetes mellitus. Efforts to prevent the slow destruction of the pancreas and prevent or delay theonset of CF related diabetes will surely become an area of research as more people survive todevelop this complication which has an adverse effect both on their prognosis and quality of life.

1922 Freeman RG. Celiac disease. Arch Pediatr 1922; 39:378. Rowland Freeman of New York, in a discussion on celiac disease at the American Pediatric Societyin 1922, recalled he had reported five children (Freeman, 1911 above) one of whom had verydefective bone formation and various fractures. He had noted that “she seemed to derive morebenefit from pancreatic extract than anything else”. Others at the meeting emphasised theimportance of considering coeliac disease as a symptom complex rather than a specific conditionalthough others disagreed and regarded it a distinct clinical entity.



Figure 12: Histology ofthe pancreas.

So there was still considerable confusion regarding the specific causes of the malabsorptionsyndrome in childhood.

1923 Schick B, Wagner R. Über eine Verdauungsstörung jenseits des Säuglingsalters.(Atrophia pluriglandularis digestiva). Ztschr f Kinder 1923; 35:263-274. A description of a disturbance of digestion after infancy due to "multiple glandular atrophies". Achild aged 16 months is described with atrophy of the pancreas in addition to “atrophy of otherdigestive glands and organs of internal secretion”. Also four other patients with similar featureswere described. Oedema was a particular feature in some. The authors suggested that in someinfants with coeliac disease it was “an anatomically proved fact that glands of internal secretionwhich are in close relationship to digestion are primarily atrophic” and coined the term “atrophicapluriglandularis digestiva” (Hess & Saphir, 1935. below).

1923 Wilson JR, DuBois RO. Report of a fatal case of keratomalacia in an infant withpostmortem examination. Am J Dis Child 1923; 26:431-446. A female infant aged five months died 18 days after admission. She had been fed almost entirelyon diluted condensed milk and was severely wasted. There was severe keratomalacia andeventually perforation of the left cornea. At autopsy microscopic examination showed extensivechanges in many organs including the lungs, salivary glands and pancreas. There wereinflammatory lesions in the lachrymal and salivary glands. The pancreas (figure 12) showed keratinisation in certain ducts, many epithelial lined cyst likecavities, a marked inflammatory process and extensive fibrosis. The lungs also showedkeratinisation of the epithelium a marked peribronchitis, bronchiectatic cavities and abscesses. Theauthors observed - “To the mechanical effect of desquamated keratinized epithelium we areinclined to attribute the pancreatic cysts and bronchiectasis”. This is an interesting paper as Dorothy Andersen, who described CF in 1938 (below), for manyyears considered the pancreatic lesions and intestinal malabsorption to be primary and the othersystemic effects to be the result of the vitamin A deficiency which, for example, caused secondarysquamous conversion of the lining respiratory epithelium. It seems almost certain that the presentinfant had CF with severe secondary vitamin A deficiency.

1924 Clarke C, Hadfield G. Congenital pancreatic diseasewith infantilism. Q J Med 1924; 17:358 - 364. A girl aged four years was admitted to the General Hospital inBristol, UK in 1921 with fatty diarrhoea from birth. She wasundersized, under weight, passed large bulky unformed andobviously fatty stools. She had never been jaundiced although theliver was greatly enlarged. She died from bronchopneumoniaseven weeks later. Two of her eight siblings had died in infancy ofbronchopneumonia. At autopsy there were miliary lung abscesses,atrophy and fibrosis of the pancreas - a shrunken looking deadwhite fatty mass occupied the position of the pancreas and theliver showed high grade fatty infiltration. “Histology of thepancreas yielded a striking but indirect confirmation of modernexperimental and clinical knowledge of the function of thepancreatic islet tissue”. Histology of the pancreas was typical of that subsequentlydescribed in cystic fibrosis (similar to that reported by Davie 1938,below).

1925 Mautner H. The Herter-Heubner digestive insufficiency. Klin Wchnschr 1925; 4:164 A child with recurrent diarrhoea from the age of one year died from pneumonia at three years.There was high grade degeneration of the exocrine pancreas with the alveoli distended and filledwith eosin rich secretion; the islets of Langerhans were intact. There was an enormous fatty liverand acute lobular pneumonia. History and pancreatic findings were very suggestive of cystic fibrosis.

1925 Burghard E. Pankeaserkrankungen im Säuglingsalter. (Disease of the pancreas ininfancy). Klin Wschr 1925; 4:2305-2306. An infant who had failure to thrive and up to six foul fatty stools daily died at ten months withbronchitis and pneumonia. Pancreatic histology showed cystic degeneration and increase ininterlobular connective tissue that was typical of cystic fibrosis. 1926 Thoenes F. Familial pancreatic insufficiency. Monatsschr Kinderheilkd 1926; 34:398-400. A child aged one year and six months passed oily stools – “diese butterstuhle” regarded by AdolfSchmidt as pathognomonic of pancreatic insufficiency in adults. The parents were cousins and onesibling was retarded and another had died of pneumonia.The character of the stools – particularly “oil”, or “butterstuhle” – is emphasised by some laterauthors as being very suggestive of pancreatic disease. leakage of oil from the anus is alsovirtually diagnostic of pancreatic insufficiency. 1926 Gross F. Pancreatic atrophy in infancy and childhood. Jahrb F Kinder 1926; 112:251-257. An infant aged three months with cachexia and bronchitis diagnosed as Heubner-Herter disease(infantile coeliac disease 1908, 1909 above) died of pneumonia. At autopsy there was pancreaticatrophy with replacement by fat and an increase in the number of islets. The cases wherepancreatic disease seems to have been a major factor are reviewed; in particular the author drawsattention to a paper by Nakamura. Untersuchungen uber das Pankreas bei foten, neugeborenen,kinder und im pubertatsalter. Virch Arch 1924; 253-286.



Figure 13: Sir AlexanderFlemming. Fromscotlandvacations.comwith permission.

Figure 14: Sir Howard

1927 Lehndorff H, Mautner H. Die Coeliakie. Herter’s intestinal infantilism, Heubner’ssevere intestinal insufficiency beyond infancy. In Kraus F, et al. eds. Ergebnisse derinneren Medizin: Kinderheilkunde 1927; 31:456-593. This long very detailed 137 page chapter starts with six pages of references and an historicalreview of Herter’s intestinal infantilism and Heubner’s so-called severe digestive insufficiencyfollowing infancy. The authors consider that Gee’s name should be attached to the condition inview of his 1888 description (Gee 1888, above) and consider the term coeliac disease (Coeliakie inGerman) to be the best term. The bulk of the chapter consists of a compendium of cases with their clinical details. Thepancreatic findings are described – a case is described with lymphocytic infiltration of the stroma,distended glandular alveoli with reduction in the size of the glandular epithelial cells but filled withSudan positive granules – the islets of Langerhans seem enlarged but are normal. The changes areconsidered to be secondary to the poor nutritional state. (The histology does not appearsuggestive of CF and the cases described would have been unlikely to survive at that time hadthey had cystic fibrosis). The authors concluded “The outcome of our work confirms that numerous investigations of manyauthors have failed to discover the origin of coeliac disease. The development and the cure stillpresent unanswered problems. The symptomatology however appears to us so well worked outthat one is justified to think of coeliac disease as a clinically sharply defined independentsyndrome”. A view which others were to question over the next decade.

1927 Socknick A, Thoenes F. Familial pancreatic insufficiency, a contribution topancreatic pathology in early childhood. Jahr Kinderheilk 1927; 115:315. The authors tried to rely on a clinical differentiation of between coeliac disease and pancreaticinsufficiency. In the former they found marked fat loss in the stool, slight protein intolerance,neuropathy, short stature, hydrolability, marked carbohydrate intolerance and increasedperistalsis; in the latter, pancreatic insufficiency, there were “butter stools”, marked proteinintolerance, no neuropathy or dwarfism, hydrostability, good carbohydrate tolerance and normalgut motility.This appears to be a reasonable separation of coeliac disease and pancreatic steatorrhoea onclinical grounds although growth problems are a major feature of cystic fibrosis.

1927 De Lange C. Cirrhosis of pancreas and liver in infant. Am J Dis Child 1927; 34:372-383 Cornelia de Lange, famous for her description of the syndrome of multiple congenital anomalieswhich bears her name, described the third child of healthy parents who was jaundiced from the7th day of life and admitted to hospital aged six weeks weighing only 2200 gm. The child appearedatrophic with peeling skin and hepatosplenomegaly and died two days later. At autopsy thepancreas showed a great increase in connective tissue and round cells but “excretory ductsshowed nothing of importance”. Some islets were of abnormal size and sclerotic. The liver showedbile thrombi and evidence of obstruction. The heart and lungs were normal.It is difficult to accept that this infant definitely had CF, but there was neonatal obstructivejaundice and histological abnormalities of the pancreas and so CF would be a definite possibility.

1929 Kornblith BA, Otani S. Meconium ileus withcongenital stenosis of the main pancreatic duct. Am J Path1929; 5:249 - 261.Stenosis of the proximal end of Wirsung’s duct (the mainpancreatic duct) was found in an infant with meconium ileus whodied aged five days. There was marked increase in the stroma ofthe pancreas; the acini were atrophic and many areas replacedby connective tissue. The main duct was extremely widenedwhich suggested a congenital anomaly of duct development as acause of the pancreatic fibrosis which was present.Almost certainly CF in view of the pancreatic changes and themeconium ileus (Dodd, 1936 below; Landsteiner, 1905 above aresimilar).

1929 Flemming A. "On the antibacterial action of culturesof a penicillium, with special reference to their use in theisolation of B. influenza." Br J Exp Pathol 1929; 10: 226–36.

Alexander Flemming (1881-1955) (figure 13) was a Scottishbacteriologist, working at St Mary’s Hospital, London, whosediscovery of penicillin (1928) prepared the initial step towards thehighly effective practice of antibiotic therapy for infectiousdiseases.

In 1945 Fleming shared the Nobel Prize for Physiology or Medicinewith Ernst Boris Chain (1906-1979) and Howard Walter Florey(1898-1968) who both (from 1939) were responsible for carryingforward Fleming's initial observation by further isolation,purification, testing, and quantity production of penicillin

In 1940 a report was issued describing how penicillin had beenfound to be a chemotherapeutic agent capable of killing sensitive



Florey

Figure 15: Ernst BorisChain

Figure 16: ErnestDuchesne. FromWikipedia.

germs in the living body. Thereafter great efforts were made,with government assistance, to enable sufficient quantities of thedrug to be made for use in World War II to treat servicemen withwar wounds. Penicillin became available for a few patients with CF in the USAin 1943 and the results were reported by Paul di Sant’Agnese(1944 below) – prior to this virtually all children with CF died ininfancy or early childhood from Staphylococcal pneumonia andmalnutrition.

It is noteworthy that Flemming failed to develop his 1929discovery – this was done over 10 years later by Florey andChain. Nor was Flemming the first to observe the antibacterialeffects of moulds. Ernest Duchesne (1874 –1912) (figure 14 wasa French physician who noted that certain moulds kill bacteria. Hemade this discovery thirty-two years before Alexander Flemingobserved the antibiotic properties of penicillin, a substancederived from those moulds, but his research went unnoticed.Duchesne entered l'Ecole du Service de Santé Militae de Lyon(the Military Health Service School of Lyon) in 1894. Duchesne'sthesis, “Contribution à l’étude de la concurrence vitale chez lesmicro-organismes: antagonisme entre les moisissures et lesmicrobes” (Contribution to the study of vital competition in micro-organisms: antagonism between moulds and microbes), that hesubmitted in 1897 to get his doctorate degree, was the first studyto consider the therapeutic capabilities of moulds resulting fromtheir anti-microbial activity. Duchesne had made hisbreakthrough by observing how the Arab stable boys at the armyhospital kept their saddles in a dark and damp room to encouragemould to grow on them. When he asked why, they told him thatthe mould helped to heal the saddle sores on the horses.Intrigued, Duchesne prepared a solution of the mould andinjected it into a series of diseased guinea pigs. All recovered. In a series of meticulous experiments, Duchesne studied theinteraction between Escherichia coli and Penicillium glaucum,showing that the latter was able to completely eliminate theformer in a culture containing only these two organisms. He alsoshowed that an animal inoculated with a normally lethal dose oftyphoid bacilli would be free of the disease if the animal was alsoinoculated with Penicillium glaucum. Unfortunately, as he wasonly 23 years old and unknown, the Institut Pasteur did not evenacknowledge receipt of his dissertation! He urged more researchbut unfortunately his army service, after getting his degree,prevented him from doing any further work.

Considerable attention has been allotted to penicillin as before theavailability of penicillin few infants with CF survived infancy. Itwas the introduction of penicillin and later other antibiotics which

was the main development that permitted survival beyond infancy.

top

Copyright © cysticfibrosismedicine.com and cfmedicine.com 2009-2011



Home 1595 From the mid-17th century there were many ...cfmedicine.com/history/pdf/Cystic Fibrosis -...

Documents

Transcript of Home 1595 From the mid-17th century there were many ...cfmedicine.com/history/pdf/Cystic Fibrosis -...