The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

1888 Gee S. On the coeliac affection. St Bartholomew’s Hospital Report 1888; 24:17-20. Samuel Gee (1839-1911), (figure 1) was physician to St Bartholomew's Hospital and The Hospital for Sick Children, Great Ormond Street, London. In a lecture in 1887 Gee described a syndrome he termed the coeliac affection –“There is a kind of chronic indigestion which is met with in persons of all ages, yet is especially apt to affect children between one and five years old (figure 2). Signs of the disease are yielded by the fæces; being loose, not formed, but not watery; more bulky 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 food having undergone putrefaction rather than concoction". The cause of the coeliac affection was unknown until the role of gluten was described by Willem Dicke in 1950.

 

 

Fig. 1: Samuel Gee. From Wikipedia.

Fig. 2: Wasted boy with coeliac disease. From Common Disorders and Diseases of Childhood. GF Still. Oxford Medical Publications, Fifth Edition, 1927.

Eventually the two most important causes of this syndrome of the "coeliac affection" were identified as gluten-induced enteropathy, or coeliac disease as we know it today, and cystic fibrosis. Subsequently two important advances in the Fifties permitted a clear separation of these two conditions. The first was the discovery of the elevated salt content of the sweat in CF reported in 1953 by Paul di Sant’Agnese from New York (di Sant’Agnese et al, 1953 below). The second 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, 1953 below).

 

Fig. 3: Small bowel mucosa in coeliac disease showing subtotal villus atrophy.

Fig. 4: Normal small bowel mucosa.

 

Also the characteristic histological small bowel appearance of subtotal villous atrophy of gluten induced coeliac disease (figure 3) was first identified by Paulley in 1954 in laparotomy specimens from adults with idiopathic steatorrhoea (coeliac disease) (Paulley J W. Observations on the 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 bowel biopsy from an 8 year old child (Sakula J, Shiner M. Coeliac disease with atrophy of the small intestine mucosa. Lancet 1957; ii: 876-877).[PubMed] and subsequently in children by Charlotte Anderson 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 even taller than normal (figure 4).

John Walker-Smith believes that the development of the technique to perform oral small intestinal biopsy 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 I would support this view (Littlewood JM. Coeliac disease in childhood. In: Howdle PD (Ed.). Clinical Gastroenterology. International Practice and Research. Bailliere Tindall, London. 1995; 9:295-328). Paediatric subspecialities often developed on the back of a specialised investigation that a number of paediatricians learned from adult physicians. The first was obviously cardiac catheterisation by paediatric cardiologists then came various biopsy procedures including small intestinal biopsy during the Sixties and later fibreoptic endoscopy of the lungs and gastrointestinal tract.

 

1918 Still GF. Lumleian lectures on Coeliac Disease. Lancet 1918; 2:162 and Lancet 1918; 2:193.
Sir George Frederick Still (1868-1941) (figure 5):noted the majority of his cases of coeliac disease occurred in the later part of infancy, none ever beginning while the child was breast fed.

 

Fig.5: Sir George Frederick Still. From www.georgestillforum.co.uk with permission.

He had seen 17 such children amongst 14,800 hospital patients but 24 in his private practice. One of his cases had loose stools for four months at seven years and died aged seven and a half years and had excess fibrous tissue especially about the ducts suggestive of pancreatitis. He explained the presence of pancreatitis and round cell infiltration of the intestinal mucosa and submucosal in one case as an inflammatory process secondary to some functional failure of digestive secretion with resulting abnormal decomposition of food residue favouring growth 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 on coeliac disease – “On the assumption that some defect of the pancreatic secretion underlies coeliac disease, a view put forward by Dr Cheadle and others, various pancreatic extracts have been tried. I can only say that in my experience such drugs have had very little if any effect, certainly none comparable to the effect of the castor oil mixture”. So there was no suggestion that some of these children may have suffered from pancreatic abnormalities. Also the ages and outlook of the children would be against their having cystic fibrosis.

 

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 Society in 1922, recalled he had reported five children (Freeman, 1911 above) one of whom had very defective bone formation and various fractures. He had noted that “she seemed to derive more benefit from pancreatic extract than anything else”. Others at the meeting emphasised the importance of considering coeliac disease as a symptom complex rather than a specific condition although others disagreed and regarded it a distinct clinical entity.
So there was still considerable confusion regarding the specific causes of the malabsorption syndrome in childhood.

 

1932 Parsons LG. Celiac disease. Rachford Memorial Lectures. Am J Dis Child 1932; 43:1293.
Leonard Parsons (1879-1950) was Professor of Paediatrics in Birmingham, UK. This is a long article describing the current situation regarding coeliac disease drawing on the author’s experience of 73 children - 21 were from the Boston Children’s Hospital “through the kindness of Dr Kenneth Blackfan”. Parsons advised against diagnosing coeliac disease unless there were more than 2 g of fat daily in the faeces – usually there was considerably more - up to 20 g; also the percentage of fat in the stools may reach 80% - the normal upper limit being 25%. There is a detailed clinical commentary with attention to the nutritional deficiencies.

The mortality of only 10.6%, in the pre-antibiotic era, suggests that there were few infants with CF included in this series. In discussing the morbid anatomy Parsons mentions that “in two or three cases some excess of fibrous tissue or small-celled infiltration around the ducts of the pancreas has been found”. However, most authors had not found pancreatic changes at autopsy in children with coeliac disease. “In celiac disease the pancreatic juice is normal because the fats in the stool are split normally; furthermore, specimens obtained by duodenal intubation have shown the presence of trypsin, amylopsin and lipase in normal amounts – when estimated by the method of McClure, Wetmore and Reynolds”. However, Parsons observed that Fanconi apparently believed “that the diastatic ferments function poorly” in coeliac disease.


So in this very detailed paper by one of the UK’s leading paediatricians, most of the discussion centred on what was almost certainly gluten induced coeliac disease; the possibility that some cases were due to pancreatic abnormality was discussed only briefly but dismissed. In later work some degree of pancreatic insufficiency was reported to occur in untreated coeliac disease but this was only temporary and considered to be due to substrate protein deficiency associated with the malnutrition (Carroccio A et al, Gut 1991; 32:796-799.[PubMed]).

 

1945 Patterson D, Pierce M, Peck E. The treatment of coeliac disease with vitamin B complex and concentrated liver. Arch Dis Child 1945; 19:99 – 110.
This paper, although not concerning CF directly, is included as Henderson 1945 (below) mentions an unsuccessful trial of this treatment in a child with cystic fibrosis. This paper reviews Patterson’s successful experience in 1943-44 in treating 26 children with coeliac disease with a regimen similar to that advocated by May et al (J Pediatr 1941; 21:17) with liver extract and vitamin B complex. The author mentions that, in the investigations of these children, fibrocystic disease of the pancreas was excluded by aspiration of the duodenal contents as recommended by Andersen & Early (Am J Dis Child 1942:63:891) – a procedure by this time established as essential in the diagnosis of cystic fibrosis and for differentiating CF from coeliac disease.

 

1953 Dicke WK, Weijers HA, van de Kamer JH. Coeliac disease. The presence in wheat of a factor having a deleterious effect in cases of coeliac disease. Acta Paediatr Scand 1953; 42:34-42. [PubMed]
Although not strictly related to CF, this was undoubtedly a major discovery and an advance in further separating coeliac disease (the aetiology of which was unknown up to this time) from CF and other causes of intestinal malabsorption. The characteristic intestinal mucosal changes of subtotal villous atrophy were not described until the late Fifties (for details see entry of Gee, 1888 above).

Willem Dicke,(1905-1962) was a Dutch paediatrician who described the central role of a “wheat factor”, which was not starch but eventually identified as gluten, in the aetiology of coeliac disease in his MD Thesis in 1952. Apparently he had believed that wheat was the injurious factor since the Thirties. The account of his numerous clinical observations and eventual collaboration with van de Kamer and Weijers, which eventually led to the discovery, is described in a fascinating article (Pioneer in the gluten free diet: Willem-Karel Dicke 1905-1962, over 50 years of gluten free diet. Van Berge-Henegouwen GP, Mulder CJJ. Gut 1993; 34:1473-1475).

In 1953, although CF had been clearly described as one cause of the coeliac syndrome, the sweat electrolyte abnormality had not been described. So the diagnosis of CF was still a problem and rested on demonstrating low trypsin levels in the duodenal fluid or faeces of a child with intestinal malabsorption. Also the characteristic subtotal villous atrophy of the small bowel in coeliac disease had not been described; this was first identified by Paulley in 1954 in full thickness specimens obtained at laparotomy from adults (Paulley J. BMJ 1954; ii: 1318). Small bowel subtotal villous atrophy was identified in vivo by per oral biopsy by Margot Shiner in 1957 (Sakula J, Shiner M. Lancet 1957; ii: 876); also Charlotte Anderson showed the small bowel changes in children with coeliac disease were reversible after gluten withdrawal (Anderson CM Arch Dis Child 1960; 35:419). (see Gee 1888 above for more details).

During the Sixties small bowel biopsy gradually became more generally available in the UK. In Leeds we offered a service to Yorkshire paediatricians from 1968 (Littlewood JM. Coeliac Disease in Childhood. In: Howdle PD (ed.): Coeliac Disease. London: Bailliere Tindal, 1996:295-328) and ultimately in our unit performed over 1000 jejunal biopsies, in later years using the fibreoptic endoscope method.
The accurate diagnosis of gluten induced coeliac disease was of great importance in the evaluation of children with malabsorption syndrome and thus in the differential diagnosis of cystic fibrosis. With the availability of both jejunal biopsies and sweat tests in the Sixties, predictably, children who had both CF and coeliac disease were described (Hide and Burman, 1969 below); later children with CF were reported who also had intestinal mucosal damage due to cow’s milk protein intolerance (Hill et al, 1989 below).
So during the late Fifties and Sixties, with the introduction the sweat test and the jejunal biopsy, CF and coeliac disease could be diagnosed confidently in the majority of cases in centres where the two investigations were available and reliable.

 

1960 Anderson CM. Histologic changes in duodenal mucosa in coeliac disease: Reversibility during treatment with wheat gluten free diet. Arch Dis Child 1960; 35:419-427. [PubMed]
This is the first report of peroral duodenal biopsy in 17 children with coeliac disease; 11 of whom were re-biopsied after taking a gluten free diet when all had improved histology. Eventually it would become practice, in patients considered to have coeliac disease, to re-biopsy to ensure the intestinal mucosa had recovered and at some stage later to re-challenge with gluten powder to ensure the gluten intolerance was permanent before committing the patient to a lifetime gluten free diet.
This report was some three years after the first reports of per oral intestinal biopsy in adults by Margot Shiner (Sakula J, Shiner, M. Lancet 1957; ii: 876) and the first in children.
It is an important paper both with regard to the management of coeliac disease and also important in improving the means of clearly differentiating between cystic fibrosis and coeliac disease; also rarely the coexistence of the two conditions could be identified (Hide & Burman, 1969 below). This recently introduced technique of per-oral duodenal biopsy permitted a positive diagnosis of coeliac disease for the first time (see comment on Samuel Gee,1888 above). The technique gradually became more generally available at major centres throughout the UK during the Sixties. Note the author of this paper is Charlotte Anderson – not Dorothy Andersen – the spelling is confused in more than one publication – even by the editor of a leading paediatric journal!!

 

Fig. 6: Charlotte Anderson.

Charlotte M Anderson (1915-2002) (figure 6) was the first woman to be appointed a Professor of Paediatrics in the United Kingdom. She qualified in 1945 and after hospital jobs in Melbourne she worked at the Hospital for Sick Children at Great Ormond Street, London and at the Institute of Child Health at the University of Birmingham. Her work with British colleagues on the role of gluten in coeliac disease (Anderson CM et al. Coeliac disease gastrointestinal studies and the effect of wheat flour. Lancet 1952; i: 836-842. [PubMed]) was carried out at much the same time as that of Dicke and colleagues in Holland, and helped to establish her international renown. She started the first Australian cystic fibrosis clinic in 1953 in Melbourne and published widely on both CF and paediatric gastroenterology. She became Professor of Paediatrics at the University of Birmingham and director of the Institute of Child Health in 1968. I was fortunate to hear her speak at the Samuel Gee 1988 Coeliac Centenary Meeting at St Bartholomew’s in London and to talk with her and Margot Shiner (the first person to perform per oral intestinal biopsy) over lunch time sandwiches.

 

1969 Hide DW, Burman D. An infant with both cystic fibrosis and coeliac disease. Arch Dis Child 1969; 44:533-535. [PubMed]
The first convincing description of both coeliac disease and CF in a marasmic infant from David Burman’s paediatric unit in Bristol. The sweat test was re-checked when the infant was thriving and was strongly positive. In addition to the abnormal jejunal biopsy, which showed subtotal villus atrophy, the infant reacted violently when challenged with gluten at the age of a year.


Subsequently children with both conditions were reported also by Goodchild MC, et al. Arch Dis Child 1973; 48:684-691.[PubMed]; Katz AJ et al, Pediatrics 1976; 57:715-721.[PubMed]). Later studies have shown a slight increase in incidence of coeliac disease in people with cystic fibrosis (Valetta EA, Mastella G. Acta Paediatr Scand 1989; 78:784-785 below).

 

1973 Goodchild MC, Nelson R, Anderson CM. Cystic fibrosis and coeliac disease: coexistence in two children. Arch Dis Child 1973; 48:684-691. [PubMed]
Beautifully documented cases from Mary Goodchild and Charlotte Anderson from Birmingham, one of the few major CF and paediatric gastroenterological centres in the UK at the time. There are impressive photographs and weight charts showing dramatic response to withdrawal of dietary gluten. Useful advice “that cystic fibrosis may predispose to the development of coeliac disease". The association of the two conditions was first reported by Hide & Burman, 1969 (above).
Jejunal biopsy is a useful investigation in the occasional child with CF who presents with unusual features and who fails to thrive as well as expected. The authors’ advice to avoid attributing every problem to the CF is very sound and particularly apt in these days of sub-specialisation.. For example, in a later study of CF infants poor weight progress with treatment for the CF was shown to be due to small bowel mucosal damage from cow’s milk protein intolerance (Hill et al, 1989 below)
Mary Goodchild eventually became Director of the Cardiff Paediatric CF Centre and Bob Nelson subsequently developed the Paediatric CF Centre in Newcastle, UK

 

1989 Valletta EA, Mastella G. Incidence of celiac disease in a cystic fibrosis population. Acta Paediatr Scand 1989; 78:784-785. [PubMed]
Since the first report of coexistence of coeliac disease (CD) and CF in the same patient (Hide & Burman, 1969 above), isolated reports appeared of children with the two conditions. These authors report five patients with CD in a CF population of 1100 subjects – an incidence of 1 in 220. The most recent report is of the two conditions in a 56 year old man (Lampert S et al, Zeitschrift fur Gastroenterolgie 2007; 45:612-614). Recently CF has been shown to be risk factor for the development of coeliac disease which was present in 2.13% of patients (Walkowiak J et al. Acta Biochem Pol 2010; 57:115-118. [PubMed]

 

2009 Fluge G. Olesen HV. Gilljam M. Meyer P. Pressler T. Storrösten OT. Karpati F. Hjelte L. Co-morbidity of cystic fibrosis and celiac disease in Scandinavian cystic fibrosis patients. J Cyst Fibros 2009; 8:198-202. [PubMed] Transglutaminase-IgA (TGA), endomysium-IgA (EMA) and total IgA in serum were measured in 790 CF patients (48% females, 86% with pancreatic insufficiency). Six patients were diagnosed with CD prior to the study, all receiving a gluten-free diet. Patients with elevated TGA (>50 Units/mL) and a positive EMA test were offered a gastroscopy obtaining mucosal biopsies from the duodenum. RESULTS: Four new cases of CD were diagnosed. Two additional patients had positive serological tests, but normal biopsies. In total, 10 cases of CD (1.2%, 1:83) indicate a prevalence rate about three times higher than the general prevalence of CD in Norway and Sweden.

A further report showing slight increase in the incidence of coeliac disease in people with CF in Scandinavia.

 

2010 Davidson A, Martinez A, MacMahon V, Gonzalez T, Lillquist Y, Jemkins S et al. Cystic fibrosis and celiac disease:TTG screening results indicate a common association. Pediatr Pulmonol 2010; Suppl 33:418 (Poster 549).
Unpublished data from 2010 NACFC Baltimore. Tissue trans-glutaminase (tTG) screening of 114 CF patients aged 1-18 years. Seven had elevated tTG levels - serological diagnosis of CD in 7/114 (6%) and small bowel biopsy confirmed in 4/114 (3.5%) at time of writing - greater than expected in the general population.

 

2010 Walkowiak J, Blask-Osipa A, Lisowska A, Oralewska B, Pogorzelski A, Cichy W et al. Cystic fibrosis is a risk factor for celiac disease. Acta Biochem Pol 2010; 57:115-118.[PubMed]

The genetic predisposition to coeliac disease is similar in CF as in the general population but cystic fibrosis appears to be a risk factor for the development of coeliac disease.