The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

1941 Beazell JM, Schmidt CR, Ivy AC. The diagnosis and treatment of achylia pancreatica. J Am Med Assoc 1941; 116:2735-2739.
This classic paper, from Professor Ivy's group, was said to initiate the modern treatment of pancreatic insufficiency. At the start, the authors state “Since the number of well studied patients are few and since oral pancreatic enzyme therapy in man is not generally considered to be of value, a view that is inconsistent with most of the results with animal experiments, we have undertaken to determine the effectiveness of oral pancreatic enzyme therapy in human patients with achylia pancreatica”.
Four patients with pancreatic insufficiency were studied in detail with estimation of faecal fat and nitrogen and also estimation of their duodenal enzymes – which were totally absent. Enzyme replacement therapy resulted in an average reduction in daily faecal nitrogen excretion of 62% (7.84 to 2.99 g) and lipids of 63.3% (74.4 to 27.3 g). All the patients gained weight (6 to 40 lbs) over 2.5 to 36 months. The authors note that Dorothy Andersen had already shown that pancreatic enzyme therapy improved the intestinal malabsorption of children with cystic fibrosis (Andersen DH. J Pediatr 1939; 15:763).

Professor AC Ivy (1893-1978) (figure 2 in main text) was a famous physiologist who, with Oldberg, discovered cholecystokinin in 1928 and apparently published some 2000 scientific articles. There was considerable discussion for many years among paediatricians as to whether pancreatic replacement therapy was worth using – some paediatricians considered that the unpleasant taste of the crude pancreatic extract did more harm than good in putting children off their food to achieve only modest improvements in absorption. However, all agreed that the introduction of the acid resistant microspheres (Pancrease and Creon) in the early Eighties represented a major advance in treatment.

 

1943 Shohl AT, May CD, Shwachman H. Studies of nitrogen and fat metabolism on infants and children with pancreatic fibrosis. J Pediatr 1943; 23:267-279.
A study of nine patients with cystic fibrosis. The striking feature of the infants with CF was the excess of nitrogen found in the faeces when normal diets were eaten, the patients remaining in negative nitrogen balance. Average weight of dried faeces/day - Normal infants 7.3 g - CF infants 33.4 g. Average nitrogen content of faeces/day - Normal infants 0.39 g - CF infants 1.7 g. Average fat content of dried faeces/day - Normal infants 3.1 g - CF infants 16.8 g. On a fat-free diet of casein hydrolysate and glucose, nitrogen retention was in the normal range and excretion normalised. The authors concluded that hydrolysed casein could be utilised in contrast to whole protein.


Subsequently feeds containing hydrolysed protein (e.g. Pregestimil) were shown by others to prove useful in improving malabsorption in some infants with CF where control of the malabsorption has proved difficult – particularly after meconium ileus operations and with cow’s milk intolerance. The concept of an elemental diet, which required less digestion, to improve absorption was also later pioneered by Jimmy Allen, a general paediatrician in Macclesfield, England (Allan JD et al, 1970 and 1973 below) and created considerable interest in the Seventies when it was almost impossible to maintain a normal nutritional state as the children became older and their chests became progressively worse.

 

1945 Andersen DH. Celiac syndrome. II. Fecal excretion in congenital pancreatic deficiency at various ages and with various diets, with discussion of optimal diet. Am J Dis Child 1945; 69:221-230.
Faecal fat was normal in 3 patients aged less than six months but increased in all patients above that age. Some infants are pancreatic sufficient for some months as was later shown by Kevin Gaskin et al in Australian screened infants with cystic fibrosis (Waters et al, 1990 below; Gaskin et al, 1991 below). Reduction of dietary fat resulted in proportionate decrease in faecal fat. Fat excretion was usually reduced by pancreatin but the effect was variable.
Various dietary combinations were tried leading to the suggestion that the optimal diet was approximately as follows: “The protein should provide 25% of the calories: the proportion of fat should be small but eggs and fat soluble vitamins should be included: the carbohydrate should be provided in part as sugar and for older infants and children part of it may be in the form of cereal starches and potato if these foods are clinically tolerated”.

 

1946 West CD, Wilson JL, Eyles R. Blood amino nitrogen levels: changes in blood amino nitrogen levels following ingestion of protein hydrolysate in infants with normal and with deficient pancreatic function. Am J Dis Child 1946; 72:251-273.
The absorption of whole protein and casein hydrolysate was compared. There was a significantly smaller rise in blood amino acids after a whole protein meal in infants with CF but similar increases in blood amino acids after casein hydrolysate in both normal and CF children. Authors suggested that substitution of the hydrolysate for whole protein should benefit CF children.


This was further confirmation of the suggestion of Shohl et al, 1943 (above) and subsequently shown to be useful in practice (Allan et al, 1970 & 1973 below and the “Allan diet”) that protein hydrolysate was better absorbed than whole protein by children with cystic fibrosis..

 

1951 Chung AW, Morales S, Snyderman SE, Lewis JM, Holt LE Jr. Studies in steatorrhoea. Effect of the level of dietary fat upon absorption of fat and other foodstuffs in idiopathic celiac disease and cystic fibrosis of the pancreas. Pediatrics 1951; 7:491-502. [PubMed]
This was an important paper as it showed that fat absorption remained proportional to the dietary intake. Thus increasing fat intake, as was done so successfully in Toronto by Douglas Crozier (Crozier 1974 below), would be likely to improve total fat absorption and thus energy absorption. However, many clinicians and patients noted that higher fat intakes increased the already unpleasant abdominal symptoms, the volume of the stools and faecal calcium loss; therefore they continued to recommend a low fat diet. In fact, many patients could not tolerate a normal fat intake due to distressing abdominal symptoms even with large doses of the relatively inefficient pancreatic enzymes which were available at the time - this was before the acid resistant microspheres, such as Pancrease and Creon, became available in the early Eighties.
The acid resistant microspheres (Pancrease and Creon) were not available generally until the early Eighties and when patients were changed onto them from the older preparations their superiority over standard preparation was immediately quite obvious to both patients and clinicians. It is no exaggeration to say that these new acid resistant enzymes revolutionised the management of the intestinal malabsorption in people with CF during the Eighties permitting most to take a normal amount of fat in their diet and so improve their energy intake and nutritional state.

 

1952 Lavik PS, Matthews LW, Buckaloo GW, Lemm FJ, Spector S, Friedell HL. Use of I131 labelled protein in the study of protein digestion and absorption in children with and without cystic fibrosis of the pancreas. Pediatrics 1952; 10:667-676. [PubMed]
Nine controls and 5 children with CF were studied using a test meal with I131 labelled protein. Less than 6% of the ingested isotope was excreted in the faeces in non-CF children but 10-40% was excreted by children with cystic fibrosis; there was a 50% decrease in faecal loss when the CF children were on pancreatin, so failure of protein absorption due to failure of digestion was confirmed.

Shwachman commented that this study further showed that pancreatin was working as there was, even then, still some dispute as to its value in improving absorption.

 

1952 Shwachman H, Leubner H, Patterson P, Weill CC. Mucoviscidosis with partial pancreatic insufficiency. Am J Dis Child 1952; 84:763-765.[PubMed]
Previously some people with CF had escaped diagnosis as the duodenal trypsin test gave normal results. Progressive loss of pancreatic activity could be shown. Partial pancreatic insufficiency could be demonstrated by various techniques – examining duodenal fluid for various enzymes, viscosity and pH. In the discussion the need to differentiate the various causes of coeliac syndrome was stressed as some coeliac children were being falsely labelled as CF as a result of “the present interest in the cystic fibrosis”.

For many years a frequent examination question for medical students was to list the differences between coeliac disease and cystic fibrosis; just as they must know the differences between children with hypothyroidism and Down’s syndrome.
By 1952 Shwachman had obviously become cautious about using secretin intravenously for pancreatic function tests as he warns that secretin “may occasionally produce disastrous effects…..usually not a purified substance….some children are allergic to it”. So although 10 years previously Shwachman had presented a study of secretin pancreatic stimulation tests in children (Maddock et al, 1943 above), he now preferred olive oil as a stimulant and believed “The most reliable diagnostic procedure is study of the duodenal fluid” (also Gibbs et al, 1950 above).

 

1955 Harris R, Norman AP, Payne WW. The effect of pancreatin therapy on fat absorption and nitrogen retention in children with fibrocystic disease of the pancreas. Arch Dis Child 1955; 30:424-427. [PubMed]
A classic study from Dr Archie Norman’s unit at the Hospital for Sick Children, Great Ormond Street Hospital, London showing a modest improvement in the absorption of fat and nitrogen with pancreatin enzyme therapy (fat absorption increased from 46% to 71% of intake and faecal nitrogen was reduced by 50% from 23.10 gm to 10.27 gm per day).
These improvements in absorption with pancreatin are modest by present standards as with modern acid resistant enzymes many patients will achieve more than 90% absorption of ingested fat (normal being over 95%).


In the previous year Charles May had claimed that better nutritional results were obtained by the administration of a generous high protein diet without pancreatin which he believed impaired the appetite. May was asked to comment on this particular paper (Pediatric Year Book, 1955) and he mentioned the negative nitrogen balance (due to the increased energy requirement which was later established in a number of studies – Pencharz et al. J Ped Gastro Nutr 1984; 3 (Suppl 1):S147-S153 below; Buchdahl RM et al. 1988; 64:1810-1816 below). He considered that the sensible approach was to try pancreatin in adequate dosage and judge by the clinical response taking pains not to attribute the improvement in weight, which resulted from treating the chest infection, as due to the action of pancreatin. He observed that a more effective and less expensive means of pancreatic enzyme substitution therapy was sorely needed.

 

1955 di Sant’Agnese PA. Fibrocystic disease of the pancreas with normal or partial pancreatic function: current views on pathogenesis and diagnosis. Pediatrics 1955; 15:683-697. [PubMed]
Another early report of “pancreatic sufficient” patients i.e. defined as those who had sufficient remaining pancreatic function (probably around 10%) to achieve normal intestinal fat absorption without enzyme replacement therapy. On testing, six had partial pancreatic deficiency and 3 normal pancreatic function. These patients provide further evidence that the secretory activity of many and perhaps all exocrine glands, mucus producing and others, is affected rather than the clinical manifestations being due primarily to pancreatic disease and secondary malnutrition e.g. vitamin A deficiency. (See also Gibbs et al, 1950 above; Shwachman et al, 1956 below).

 

1970 Shmerling DH, Forrer JCW, Prader A. Fecal fat and nitrogen in healthy children and in children with malabsorption or maldigestion. Pediatrics 1970; 46:690-695. [PubMed]
This classic paper, from Professor Prader’s unit in Zurich, for many years provided paediatricians with the reference values for intestinal fat and nitrogen absorption in infants and children. Fat and nitrogen per day in normal infants were not more than 4.3 g (mean+/- 2SD) and 1 g respectively and for older children 3.1 g fat and 1.2 g nitrogen. The degree of steatorrhoea resulting from exocrine pancreatic insufficiency was considerably more severe than the fat malabsorption in untreated coeliac disease where between three to 13 g were excreted daily.

 

1973 DiMagno EP, Go VLW, Summerskill WHJ. Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 1973; 288:813-815. [PubMed]
This classic study of DiMagno examined the relationship between steatorrhoea and creatorrhoea and pancreatic lipase and trypsin outputs in 17 patients with chronic pancreatitis and controls. Steatorrhoea was not observed until lipase output was 10 percent or less of normal and creatorrhoea only when trypsin output had fallen to 10% of normal. These findings provided an explanation for the large reserve of enzyme output and the late appearance of steatorrhoea in chronic pancreatitis.


Eugene DiMagno (figure 6 in main text) at the Mayo Clinic was a leading expert on pancreatic disorders. These “10%” figures, so convincingly demonstrated in this beautifully clear, concise paper (less than 3 pages), were subsequently repeatedly quoted. The fact that the majority of CF infants have intestinal malabsorption from early life attests to the early onset and great severity of the pancreatic damage in many, but not all, of them.

 

1976 Stapleton FB, Kennedy J, Nousia-Arvanitakis S, Linshaw MA. Hyperuricosuria due to high-dose pancreatic extract therapy in cystic fibrosis. N Eng J Med 1976; 295:246-248. [PubMed]
A child with CF developed dysuria with a normal serum uric acid level. Hyperuricosuria in this and two people with CF was related to ingestion of large doses of pancreatin (Cotazym powder). Symptoms settled with reduction of the pancreatin intake. Later this group suggested reducing fat intake to lessen the need for high doses of pancreatic enzymes (Nousia-Arvanitakis S et al, J Pediatr 1977; 90:302-305).
Subsequent studies discussed the relationship to renal stones although with modern pancreatic enzymes the problems with hyperuricosuria seem to have regressed; however, renal stones still appear to be relatively common in people with cystic fibrosis – in one report they were present in 21% of patients (Terribile M, et al. Nephro Dial Trans 2006; 21:1870-1875). Nevertheless the clinical illness due to the renal stones are not a common occurrence in a clinic of people with CF. A report from Manchester indicated that hyperuricaemia and gout were more common in CF adults than in the general population (Horsley A et al. 2011.[PubMed]).

 

1977 Khaw KT, Adeniyi-Jones S, Gordon D, Polombo J, Suskind R. Efficacy of pancreatin preparations on fat and nitrogen absorptions in cystic fibrosis. Pediatr Res 1978; 12:437.
An early report of the marked superiority of Pancrease over currently used enzymes at the time. Pancrease consisted of acid resistant micro spheres which only released their enzymes when they reached the more alkaline environment of the upper intestine, thus protecting their active enzyme contents from destruction by the gastric acid. Viokase and Cotazym were the standard enzyme preparations in use at the time both of which were affected by gastric acid .Twelve children with CF aged eight to 14 years took Viokase four eight or 12 tablets, Cotazym two four or six capsules and Pancrease one two or three capsules per meal. All three preparations improved absorption compared with placebo but Pancrease did so at the much smaller dose. Viokase 12 capsules per meal and Pancrease 3 capsules per meal achieved 94% and 94,.8 % fat absorptiion respectively. Similarly six Cotazym and three Pancrease capsules achieved 84.2% and 89.7% fat absorption respectively.


The acid resistant microspheres were undoubtedly one of the major nutritional advances, when gradually introduced during the early Eighties allowing most patients to take a normal fat intake and hence significantly improve their energy intake. The markedly better absorption of fat and protein was shown in all subsequent trials and the reduction in the patients’ unpleasant bowel symptoms and fat intolerance in many was quite dramatic (also Weber et al, 1979 below).

 

1979 Weber AM, de Gheldere B, Roy CC, Fontaine A, Dufour OL, Morin CL, Lasalle R. Cystic Fibrosis Club Abstracts. May 1, 1979.
Second report of the new enzyme preparation Pancrease from Prof. Roy’s unit in Montreal. This enzyme preparation had a major effect on the treatment of the intestinal malabsorption in CF. The table (figure 1) shows Pancrease compared with Cotazym, the usual widely used preparation at the time, and also shows that crushing the microspheres and removing the protective effect of their pH sensitive coating markedly reduced their effect. Six children aged between 2.2 and 3.8 years were studied.

 

Fig. 1: Table comparing fat absorption with Cotazym and Pancrease.

 

1980 Holsclaw DS, Keith H. Long-term benefits of pH sensitive enteric coated enzymes in CF. Perspectives in Cystic Fibrosis. Proc. 8th International Cystic Fibrosis Congress Toronto 1980. 19a.
One of the first reports of the new acid resistant pancreatic enzyme – Pancrease. Previously discussed at the N. American Cystic Fibrosis Club by Khaw et al, 1977, Suskind et al, 1979 and Weber et al, 1979 (all above). This report provided details of longer term treatment to that already reported at the 1979 Cystic Fibrosis Club.
Twenty patients with CF were followed for 14 months. Urine uric acid decreased from 850 to 550 mg/day, diets broadened in terms of fat content, nutritional state improved and gastrointestinal symptoms diminished on between nine and 11 Pancrease capsules per day.
The obvious superiority over previous enzyme preparations was repeatedly confirmed in subsequent controlled trials (Mischler et al, 1982; Gow et al, 1981; Beverley et al, 1987 - all below).
Over 90% of the enzymatic activity of the older unprotected preparations was destroyed by the acid in the stomach; the new preparations passed through the stomach before releasing their enzyme activity.

Fig. 2: Intact Pancrease microspheres in duodenal fluid recovered from a person with CF having passed through the stomach intact. (Miller MG et al, EWGCF Jerusalem. 1985).

 

Fig. 3: The first microsphere pancreatic enzymes (Creon- upper and Pancrease - lower)

So these new acid resistant microspheres were undoubtedly one of the major advances of the decade permitting most people with CF to eat a normal amount of fat. At the time of these initial reports it was hard to imagine the profound beneficial effect the enzymes were to have on the patients’ ability to tolerate fat, improve their energy intake and maintain a reasonable nutritional state and, not least, improve their quality of life. However, when one observed the effect on people with CF their superiority over the older preparations was obvious.
One 16 year old girl wept as she recounted how her life, previously dominated by her very abnormal bowel habit, had been totally transformed by the new enzymes by allowing her to take part in normal social activities with her friends. (also Weber et al, 1979 above; Khaw et al. 1977&1979 above; Holsclaw DS & Keith H, 1980 above; Mischler et al, 1982 below; Beverley et al, 1987 below).

 

1981 Gow R, Bradbear R, Francis P, Shepherd R. Comparative study of varying regimens to improve steatorrhoea and creatorrhoea in cystic fibrosis: effectiveness of an enteric coated preparation with and without antacids and cimetidine. Lancet 1981; 2: 1071-1074. [PubMed]
This was a useful early paper further confirming the marked superiority of the recently introduced Pancrease microsphere enzymes over conventional pancreatic enzyme preparations. Ten patients were observed during four two-week treatment periods of 1). Conventional pancreatic supplements. 2). pH sensitive enteric coated microspheres (Pancrease). 3). Enteric coated microspheres (ECMP) plus cimetidine. 4). ECMP plus antacids. Significant reductions in faecal fat, nitrogen and weight occurred with the Pancrease. Additional antacids and cimetidine did not improve absorption except in those where there was still significant malabsorption when the addition of cimetidine caused significant improvement. (also Weber et al, 1979 above; Khaw et al. 1977&1979 above; Holsclaw DS & Keith H, 1980 above; Mischler et al, 1982

 

1982 Mischler EH, Parrell S, Farrell PM, Odell GB. Comparison of effectiveness of pancreatic enzyme preparations in cystic fibrosis. Am J Dis Child 1982; 136:1060-1063.[PubMed]
One of the early trials establishing the clear superiority of the new acid-resistant pH sensitive microsphere enzymes (Pancrease) over the conventional encapsulated powders (Cotazym). Ten boys in the trial experienced significantly better nitrogen and fat absorption with the enteric-coated enzyme product Pancrease. (also Weber et al, 1979 above; Khaw et al. 1977&1979 above; Holsclaw DS & Keith H, 1980 above; Gow et al, 1981 above; Beverley et al, 1987 below).below; Beverley et al, 1987 below).

 

1982 Gaskin K, Gurwitz D, Durie P, Corey M, Levison H, Forstner G. Improved respiratory prognosis in patients with cystic fibrosis with normal fat absorption. J Pediatr 1982; 100:857-862. [PubMed]
A study carried out when Kevin Gaskin from Sydney was working in Toronto. In general, patients who were pancreatic sufficient had milder clinical symptoms and a lower mean sweat chloride value (85.42+-24.43 SD meq/l) than their counterparts with steatorrhoea (102.29 +-20.4 meq/l); also their pulmonary function tests were significantly better. The maintenance of better pulmonary function, coupled with the low mortality, suggested that patients without steatorrhoea have a better prognosis.
At the time the difference was unexplained, but it was eventually shown that the “pancreatic sufficient” patients more often had ‘mild’ gene mutations – a possibility already suggested by Stern who had earlier described seven patients with “Pseudomonas bronchitis”, borderline sweat tests and normal absorption (Stern RC, et al. JAMA 1978; 239:2676-2680.[PubMed]).

 

1984 Schoni M, Kraemer R, Ruedeberg A, Lentze MJ, Mordasini RC, Riesen WF, Klay MP, Rossi E. Long-term cimetidine in children with cystic fibrosis: a randomized double-blind study. Pediatr Res 1984; 18:66-70. [PubMed]
The group from Berne having previously shown some improvement with acid suppression with cimetidine in a few patients (Helvet Paediatr 1981; 36:359-369) performed this detailed prospective, randomized double-blind study of 38 children with CF designed to evaluate the effectiveness of cimetidine (600 mg/m2) in improving fat absorption and clinical condition. They concluded that cimetidine does not improve fat absorption and has, therefore, no place and no benefit in the treatment of children with CF.


In Leeds, in contrast, we found that cimetidine seemed to improve absorption (Chalmers DM et al, Acta Paediatr Scand 1985; 74:114-117.[PubMed]) with a significant reduction in faecal fat in 17 patients. However, the acid resistant microspheres Pancrease and Creon were now available in the UK and increasingly used so, for a time, interest in acid suppression to improve the absorption with the older unprotected enzymes waned. There was a revival of interest in acid suppression, as a means of reducing the dose of enzymes, following the description of fibrosing colonopathy (Smyth et al, 1994 below), considered to be related to excessively high doses of the high strength enzymes introduced in the early Nineties. Also as oesophageal reflux became increasing recognised as a frequent and significant complication particularly in older patients (Feigelson et al, 1975 above; Scott et al, 1985 below) acid suppression was a more frequently prescribed treatment.

Prof. Martin Schoni (figure 24 in main text) from Berne has been involved in the care of people with CF and also in research since the Seventies and has published widely on the subject. Both he and Richard Kraemer were colleagues of Prof. Rossi in the Berne clinic

 

1987 Beverley DW, Kelleher J, MacDonald A, Littlewood JM, Robinson T. Comparison of four pancreatic extracts in cystic fibrosis. Arch Dis Child 1987; 62:564-568. [PubMed]
A controlled trial of ‘old’ (Pancrex V Forte) and new acid resistant enzymes (Pancrease, Creon, Pancreatin Merck – the last later marketed as Nutrizym). The study confirmed the marked superiority of the new preparations Pancrease and Creon that achieved lower abdominal symptom scores and significantly better median fat absorption (87% and 85%) and nitrogen absorption (faecal nitrogen of 1.6 and 2.1g/day) than the other two preparations Pancrex V Forte and Pancreatin Merck (Nutrizym) with fat absorptions of 74% and 81% and median faecal nitrogen of 2.9 and 2.7g/day (figure 40)..

 

Fig. 4: Percentage fat absorption vs. type/brand of enzyme. With permission of BMJ publishing Group.

 

Undoubtedly the introduction of these new enzymes was one of, some would say the, major advance in clinical care during the decade (also Weber et al, 1979 above; Khaw et al. 1977&1979 above; Holsclaw DS & Keith H, 1980 above; Gow et al, 1981 above; Mischler EH et al. 1982 above). The percentage intestinal fat absorption of 380 new referrals to our CF Centre for assessment between 1980 and 1992 shows many patients had inadequate control of their intestinal malabsorption at the time of referral but with a tendency to improve (which when analysed was significant) in those referred in the later years when the new enzymes were increasingly prescribed by referring consultants (figure 41 in main text).

 

1990 Walters MP, Kelleher J, Gilbert J, Littlewood JM. Clinical monitoring of steatorrhoea in cystic fibrosis. Arch Dis Child 1990; 65:99-102. [PubMed]
When compared with chemical faecal fat assays and steatocrit the simple microscopy method was highly sensitive (97%) and only three of 80 patients with steatorrhoea would have been missed using this technique. All patient with severe steatorrhoea (> 60 mmol fat/day) were clearly identified (figures 5 & 6). This method is still used in the Leeds CF Centre and gives some indication as to the success of the enzyme replacement therapy as chemical estimations of faecal fat are rarely done unless as part of a research project. This unfortunate as severe fat malabsorption may be present without significant abdominal symptoms and conversely severe symptoms may be present without there being steatorrhoea - a situation which would not respond to increasing the enzyme dose as, unfortunately, does occur on occasion.

 

Fig.5: Faecal neutral fat - microscopy vs. chemical analysis. With permission of BMJ Publishing Group.

Fig. 6: Fat droplets in faecal sample under microscope

1991 Morrison G, Morrison JM, Redmond AOR, Byers CA, McCormack KJ, Dodge JA, Guilford SA, Bowden MW. Comparison between a standard pancreatic supplement and a high enzyme preparation. Aliment Pharmacol Ther 1992; 6:549-555. [PubMed]
First of a number of reports showing new “high strength” enzymes were effective. This study compared the relative effectiveness of a standard pancreatic enzyme supplement ('Creon'), and a new high strength preparation ('Pancrease HL') containing about 3 times the lipase and more than 5 times the protease activity. Capsule dosage was adjusted to a ratio of approximately 3 Creon to 1 Pancrease HL to provide similar intakes of lipase. Fat balances showed that absorption of fat did not change significantly on conversion to the new high-lipase product, and the coefficient of absorption of total energy was similarly maintained. The coefficient of protein absorption was significantly enhanced with the high enzyme preparation (P < 0.01), which may explain the reported subjective improvement in stool odor. No adverse effects were recorded. Patient acceptability of the new compound was high; the great reduction in the number of capsules required at each meal was cited by all patients as the reason for their preference.
Later reports associated fibrosing colonopathy with the use of Pancrease HL but not with the new high strength Creon 25,000.(Smyth et al, 1994) which some considered due to the presence of the copolymer, eudragit, in the covering of all the new high strength enzymes other than Creon 25,000.

 

1991 Gaskin K, Waters D, Dorney S, Gruca M, O'Halloran M, Wilcken B. Assessment of pancreatic function in screened infants with cystic fibrosis. Pediatr Pulmonol 1991; Suppl 7:69-71. [PubMed]
Previously these authors reported that 37% of infants with CF diagnosed by neonatal screening with the dried blood spot immunoreactive trypsin assay were pancreatic sufficient (Waters et al, 1990 above). However, 34 of the 78 infants had pancreatic function tests an average 2.3 years after diagnosis, thus it was possible that the percentage with neonatal pancreatic sufficiency was even underestimated, due to the loss of pancreatic function with time in some infants. To assess this hypothesis the authors assessed pancreatic function at the time of diagnosis in a further 20 infants since the completion of the previous study. Results of fecal fat determinations and/or pancreatic stimulation tests indicated that no less than 10 (50%) of these infants have pancreatic sufficiency. Combining these results with those of the previous study, 31 of 64 patients (48%) have pancreatic sufficiency at this early age. The authors monitored the progression of pancreatic disease in the 39 children with pancreatic sufficiency recognized to date. Eleven have developed pancreatic insufficiency and require enzyme replacement therapy. Five others have shown further improvement of colipase secretion with age.
So the authors confirmed their previous conclusion that the dried blood immunoreactive trypsin screening program for cystic fibrosis does recognize patients with pancreatic sufficiency and at diagnosis nearly half their patients were in this category. To date, 28% of patients with pancreatic sufficiency have demonstrated a variable decline in pancreatic function with age.

Fig. 7: Some of the Sydney CF doctors in 1998. Peter Cooper (paediatrician), Kevin Gaskin (paediatrician), visitor (Jim Littlewood) and Peter Bye (respiratory physician).

In this study there were a surprisingly large number of infants who were pancreatic sufficient (48%) and this is quite different from our experience of screened infants with CF over the last 30 years in Leeds, although, of course, the frequency will depend on the mutations which the infants have. For example of the last 15 screened infants with CF in Leeds only 2 were pancreatic sufficient (Wolfe et al. J Cyst Fibros 2005; 4(S1):S94).


The faecal pancreatic elastase is now a convenient and reliable way of determining pancreatic function and following the progress of pancreatic function in these infants. The lesson here is that not all newborns with CF require enzyme replacement therapy so it is important to make sure there is evidence of pancreatic insufficiency before commencing enzymes - in practice easily done with a faecal elastase measurement and a small specimen of stool for fat microscopy (Walters et al, 1990 above). The faecal elastase test is also reliable indicator of pancreatic function even when the infant is taking enzyme replacement therapy - in this respect it differs from faecal trypsin and chymotrypsin.

 

1998 Lowden J, Goodchild MC, Ryley HC, Doull I. Maintenance of growth in cystic fibrosis despite reduction in pancreatic enzyme supplementation. Arch Dis Child 1998; 78:377-378. [PubMed]
This study from Cardiff, in the post-fibrosing colonopathy era, further supported the view that children with CF in the UK were taking unnecessarily large doses of pancreatic enzymes. Fifteen children with CF on a mean enzyme intake equivalent to 18,300 IU lipase/kg/day were able to reduce their enzyme supplements to a mean of 8,647 U lipase/kg/day. There were no changes in energy or fat intake but significant increases in weight, height and weight for height.

Many UK patients were taking considerably more enzymes supplements than the equivalent of 10,000 U lipase/kg/day advised as a result of the occurrence of fibrosing colonopathy (Mehta A. Lancet 2001;358:1547-1548). This study from Cardiff supported this and confirmed that in some patients the doses were not required.

Fig. 8: Iolo Doull.

Dr Iolo Doull (Fig. 45.2) followed Mary Goodchild as the Director of the Cardiff Paediatric CF centre. He became heavily involved with CF care and research in the UK and Europe, also in the development and running of a shared care network for children with CF in most of Wales.

 

2004  Konstan MW, Stern RC, Trout JR, Sherman JM, Eigen H, Wagener JS, Duggan C, Wohl ME, Colin P. Ultrase MT12 and Ultrase MT20 in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: safety and efficacy. Aliment Pharm Ther 2004; 20:1365-1371.[PubMed]

Patients receiving the Ultrase MT12 and Ultrase MT20 experienced a mean fat and protein absorption 79.4% and 83.8%, and 87.3% and 88.6%, respectively. No adverse events related to study drug were reported. This study further supports the use of enzymes to treat pancreatic insufficiency in cystic fibrosis. Excellent fat and protein absorption was achieved with minimal adverse events and safe doses.

This was one of the studies demanded by the FDA on pancreatic enzymes following the appearance of fibrosing colonopathy in 1994. The relative importance of the polymer coating of the enzymes and the high doses of lipase and other components has never been agreed. Both these enzymes contain the copolymer covering but this does not seem to be a major problem unless very large doses are used. It is also reassuring that there does not seem to be a group of patients with subclinical colonic damage.

 

2006 Littlewood JM, Wolfe SP, Conway SP. Diagnosis and treatment of intestinal malabsorption in cystic fibrosis. Pediatr Pulmonol 2006; 41:35-49. [PubMed]
Detailed review of the present management of malabsorption based on some 25 years experience at the Regional Paediatric CF Centre in Leeds. We have been very fortunate in Leeds in having a number of outstanding paediatric dietitians since Anita MacDonald (now Chief Dietitian at Birmingham Children’s Hospital) played a major part in building up the Regional Paediatric CF Unit at St James’s during the Eighties.
Sue Wolfe, the present chief paediatric dietitian, (figure 42 in main text) and Alison Morton (see Conway et al, 2000 above) chief dietitian on the adult CF unit, at St James’s Leeds have made a major contribution to the nutritional aspects of CF and now have vast practical and research experience. Much of our nutritional and gastrointestinal work was in collaboration with members of Professor Monty Losowsky's University Department of Medicine in St James's where there was a very productive collaboration between the adult gastroenterologists and our CF team. Particular mention going to the late Dr Jerry Kelleher the chief biochemist and his colleague Mr Mike Walters.

 

2003 Proesmans M, De Boeck K. Omeprazole, a proton pump inhibitor, improves residual steatorrhoea in cystic fibrosis patients treated with high dose pancreatic enzymes. Eur J Pediatr 2003; 162:760-763. [PubMed]
The results of 15 patients (3 girls and 12 boys) with confirmed steatorrhoea during the control evaluation were analysed. Median age was 8.7 years (range 3.5-15.9 years). Median daily lipase intake was 13,500 U/kg per day (range 10,000-22,000 U/kg per day). During treatment with omeprazole, median faecal fat loss (g fat/day) decreased from 13 g (quartiles 11.5-16.5 g/day) to 5.5 g (quartiles 4.9-8.1 g/day) (P<0.01). The same improvement was noted when fat absorption was calculated: 87% (quartiles 81-89%) without versus 94% (quartiles 90-96%) with omeprazole (P<0.001). So omeprazole improves fat digestion and absorption in cystic fibrosis patients with residual faecal fat loss despite maximal pancreatic enzyme substitution.

A useful study showing a definite improvement in absorption using omeprazole for acid suppression.

 

2004 Borowitz D, Baker SS, Duffy L, Baker RD, Fitzpatrick L, Gyamfi J, Jarembek K. Use of fecal elastase-1 to classify pancreatic status in patients with cystic fibrosis. J Pediatr 2004; 145:322-326. [PubMed]
Intestinal fat absorption and faecal elastase-1 (FE-1) were compared in subjects with CF at 33 CF centers. The authors concluded that FE-1 is an accurate, easily obtained screening test to classify pancreatic status in patients with CF. This information is important for prognostication, treatment, and to avoid misclassification in clinical research. They suggested that measurement of FE-1 should become a standard of care for patients with CF.

 

 

2004 Konstan MW, Stern RC, Trout JR, Sherman JM, Eigen H, Wagener JS, Duggan C, Wohl ME, Colin P. Ultrase MT12 and Ultrase MT20 in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: safety and efficacy. Aliment Pharm Ther 2004; 20:1365-1371. [PubMed]
Patients receiving the Ultrase MT12 and Ultrase MT20 experienced a mean fat and protein absorption 79.4% and 83.8%, and 87.3% and 88.6%, respectively. No adverse events related to study drug were reported. This study further supports the use of enzymes to treat pancreatic insufficiency in cystic fibrosis (if this needed support!). The authors consider that excellent fat and protein absorption was achieved with minimal adverse events and safe doses.

This was one of the studies demanded by the FDA on pancreatic enzymes following the appearance of fibrosing colonopathy in 1994. The relative importance of the polymer coating of the enzymes and the high doses of lipase and other components has never been agreed. Both these enzymes contain the copolymer covering but this does not seem to be a major problem unless very large doses are used. It is also reassuring that there does not seem to be a group of patients with subclinical colonic damage.

 

 

2006 Kalnins D, Ellis L, Corey M, Pencharz PB, Stewart C, Tullis E, Durie PR. Enteric-coated pancreatic enzyme with bicarbonate is equal to standard enteric-coated enzyme in treating malabsorption in cystic fibrosis. J Pediatr Gastroenterol Nutr 2006; 42:256-261.[PubMed]
To compare the efficacy of an enteric-coated buffered pancreatic enzyme containing 1.5 mEq of bicarbonate per capsule with a conventional enteric-coated enzyme capsule in cystic fibrosis patients with signs or symptoms of moderate to severe malabsorption. The authors found that In the doses used, nutrient absorption of patients taking the buffered preparation offered no advantage over a conventional preparation.

The addition of bicarbonate or acid suppressing drugs was recommended to protect the active enzymes from gastric acid before the acid resistant enzymes became available in the early Eighties. With the introduction of the acid resistant microspheres (e.g. Pancrease and Creon) acid suppression was required infrequently and only recommended if malabsorption was difficult to control even with doses equivalent to 10,000IU lipase/kg/day.

 

Fig. 9: Daina Kalnins

 

Daina Kalnins (figure 9) is Academic and Clinical Specialist Dietitian, Respiratory Medicine Manager, Clinical Dietetics at the Hospital for Sick Children in Toronto, Ontario. In addition to many research publications on CF she has co-authored several books on nutrition, including The Hospital for Sick Children’s Better Food for Kids and Better Baby Food, which won The International Cookbook Revue Award (2001).

 

2009 Löhr JM, Hummel FM, Pirilis KT, Steinkamp G, Körner A, Henniges F. Properties of different pancreatin preparations used in pancreatic exocrine insufficiency. Eur J Gastroenterol Hepatol 2009; 21:1024-1031. [PubMed]
Measurements of size, surface, acid resistance, release of enzymes, pharmacokinetics and batch consistency were undertaken. available pancreatin preparations vary widely with respect to investigated parameters, which may have consequences for facilitating optimal digestion.

2011 Littlewood JM, Connett GJ, Sander-Struckmeier S, Henniges F. Creon 40,000 Study Group. A 2-year post-authorization safety study of high-strength pancreatic enzyme replacement therapy (pancreatin 40,000) in cystic fibrosis. Expert Opin Drug Saf 2011; 10:197-203.[PubMed]
At the request of the Medicines and Healthcare Regulatory Agency and in agreement with the appropriate authorities, an observational, multi-center, non-interventional, post-authorization safety study of high-strength pancreatic enzymes was conducted. RESEARCH DESIGN AND METHODS: Patients with exocrine pancreatic insufficiency due to cystic fibrosis (CF) who had previously taken high doses of pancreatic enzymes received pancreatin 40,000 capsules (Creon 40,000 Minimicrospheres, Abbott GmbH, Hanover, Germany) as part of their normal treatment for up to 2 years. Initial doses were calculated to match previous established doses in lipase units, with adjustment if required. MAIN OUTCOME MEASURES: Safety focused on serious suspected adverse drug reactions. Maldigestion symptoms and body weight were also monitored. Patients were managed according to general guidelines common to all major CF units in the UK, although minor variations were expected. The coefficient of fat absorption was not assessed as this was a safety rather than an efficacy study.

RESULTS: Sixty-four patients were enrolled at nine UK centers. Two deaths occurred during the study, which were considered unrelated to therapy by investigators. There were no further serious suspected adverse drug reactions related to pancreatin 40,000 and no cases of fibrosing colonopathy. Daily lipase doses were reduced by 11% after switching to pancreatin 40,000. Maldigestion symptoms improved and mean body weight increased from baseline to last observation (mean + 6.1 kg in patients < 18 years old). We concluded there were no safety concerns were identified with pancreatin 40,000 therapy for up to 2 years. Daily lipase doses were not increased when switching to pancreatin 40,000

The association of fibrosing colonopathy (FC) with the introduction of the high strength pancreatic enzymes in the early Nineties resulted in some apprehension when Creon 40,000, an even higher strength enzyme, was introduced. However, FC has never been associated with any preparation of Creon possibly because the preparation does not contain the copolymer Eudragit in the covering. It was to be expected therefore that Creon 40,000 would be well tolerated as it was.

 

2011 Caras S, Boyd D, Zipfel L, Sander-Struckmeier S. Evaluation of Stool Collections to Measure Efficacy of PERT in Subjects With Exocrine Pancreatic Insufficiency. J Pediatr Gastroenterol Nutr 2011; 53:634-640. [PubMed]

The aim of this study was to was to investigate sparse stool sample collection as an alternative to very unpopular complete 72-hour collection for measurement of stool fat in subjects with exocrine pancreatic insufficiency (EPI). Percentage fat (PF) data from sparse stool samples were compared with 72-hour coefficient of fat absorption (CFA) values. Twelve subjects provided samples for this analysis. Multiple-sample PF values <=30% were greatly predictive for CFA values >=80%, as shown by positive predictive value, sensitivity, and specificity values >=0.89, with high accuracy (AUCs >=0.93).

The authors concluded that sparse stool sampling for percentage fat analysis appears to be a valid, practical alternative to 72-hour CFA determination and has potential as a screening tool in clinical practice to identify both suboptimal dosing in subjects with EPI receiving pancreatic enzyme replacement therapy (PERT) and substantial fat malabsorption in subjects not receiving PERT.

This is a very useful paper for practical management of the intestinal malabsorption in the clinic although obviously not suitable for research. Unfortunately, in the UK, it is now rare for any objective measure of fat absorption to be made in CF patients to check the adequacy of their pancreatic enzyme replacement therapy. In Leeds for many years simple microscopy of a small sample of stool was evaluated and used as a regular screen to ensure that gross fat malabsorption was not present (Walters MP, et al, Clinical monitoring of steatorrhoea in cystic fibrosis. Arch Dis Child 1990; 65:99-102. above with figures). Also if there were abdominal complaints demonstrating the absence of obvious steatorrhea would avoid unnecessarily increasing the dose of pancreatic enzymes but instead would lead to a search for other causes of the symptoms. So these screening tests are very useful and a significant improvement on symptoms and signs alone. Unfortunately, apparently due to financial cuts, even faecal microscopy has been abandoned in the Leeds CF centre.

In my opinion failure to make some regular simple semi-quantitative measure of absorption such as simple faecal microscopy represents suboptimal treatment and is the reason, in an audit of 17 specialist CF centres in the UK, so many patients were receiving considerably more than the recommended total dose of enzymes (10,000 IU lipase/kg/day) as a result of merely responding to abdominal symptoms by increasing the dose (Mehta A. Further comments on the fibrosing colonopathy study. Lancet 2001; 358:1547-1548).

 

 


2015 Woestenenk JW, van der Ent CK, Houwen RH. Pancreatic Enzyme Replacement Therapy and Coefficient of Fat Absorption in Children and Adolescents with Cystic Fibrosis. J Pediatr Gastroenterol Nutr. 2015 Mar 11. [Epub ahead of print] [PubMed]
There are few details of the daily practice regarding PERT and the resulting coefficient of fat absorption (CFA) are known. The authors therefore recorded the PERT and CFA in a large cohort of pancreatic insufficient pediatric CF patients. 1,719 completed 3-day dietary food records, including the pancreatic enzyme intake registrations, and 1,373 CFA assessments of 224 CF patients, aged 0 - 17 years. The clinical characteristics, PERT, expressed as an intake of lipase unit (LU)/g fat/day and LU/kg/day, and the CFA were described for the group as a whole, and separately for those on enteral tube feeding. Cross-sectional relationship between the CFA and the LU/g fat/day and LU/kg/day were determined for each year of age. The authors also addressed the effect of the interventions done in patients with CFA outcomes <85%.
The LU/g fat/day was relatively stable throughout the age groups, while the LU/kg/day fell markedly with age. The median CFA in the 17 age groups varied between 86% and 91%, however, with a CFA below 85% in 325/1,373 (24%) of the measurements.No relationship was found between PERT and CFA. The patients with persistent CFA <85% had significant lower z-scores weight-for-age, and weight-for-height (p 0.01) than those with CFA ≥85%.
In this study population, no correlation between an enzyme dosage and the degree of fat malabsorption was found. However a CFA below 85% was found in 24% of the measuremen
 
- This data appears to be from Dr Woestenenk's Thesis, University of Utrecht, "Dietary Intake and body growth in cystic fibrosis". The findings confirm previous work in this area that many children and adolescents had an energy intake below that traditionally recommended although higher than healthy cintrols. It seems to be more prudent to advise calorie intake slightly above age specific intake with individual adjustments as necessary. There was an enormous variation in the need for pancreatic enzyme therapy with no clear correlation between the coefficient of fat absorption and pancreatic enzyme dosages. The advise to consider each patient individually is very sound and confirmed by this very interesting and extensive study (Dietary Intake and body growth in cystic firbosis. J W Woestenenk. The full version of the thesis is available on iinternet)

 


2015 Kashirskaya NY; Kapranov NI; Sander-Struckmeier S; Kovalev V.
Safety and efficacy of Creon micro in children with exocrine pancreatic insufficiency due to cystic fibrosis.  J Cyst Fibros 2015; 14(2):275-81 [PubMed] 

Pancreatic enzyme replacement therapy is the foundation of nutritional management for exocrine pancreatic insufficiency (EPI). METHODS: A 3-month, open-label, multicentre study in Russia assessing safety, efficacy, and ease-of-use of Creon() Micro (5000 lipase units/spoon) in children aged 1 month to <4 years with EPI due to cystic fibrosis. Efficacy assessments included growth parameters. RESULTS: All 40 subjects (mean age 26.5 months) completed treatment. Adverse events occurred in 40% of the subjects (most commonly respiratory tract infection [15%], frequent bowel movements [8%], rhinitis, stomatitis, nasopharyngitis, and diarrhoea [all 5%]), none were serious or led to discontinuation. After 3 months, mean+/-SD increases from baseline z-scores were height/length-for-age 0.13+/-0.48, weight-for-age 0.20+/-0.39, and BMI-for-age 0.29+/-0.65. Treatment was rated 'easy' to administer by 95% caregivers and acceptance 'good'/'very good' by 90%.
Creon Micro was well tolerated. Growth development parameters increased over the 3-month treatment period. Treatment was considered easy to use and acceptance was good.