Pancreatic enzyme therapy in cystic fibrosis

When cystic fibrosis (CF) of the pancreas was first described by the Swiss pediatrician Guido Fanconi in 1936 [1] and the American Dorothy Andersen in 1938 [2], it was the pancreatic failure and its corresponding pathology that were the dominant features of the reports. Affected children failed to thrive and usually died from pneumonia (often staphylococcal) in the first year of life, before chronic pulmonary disease and bronchiectasis had time to develop. Now, 70 years later, when the mean life-span of CF patients approaches 40 years [3] and the majority are now being managed by adult pulmonologists, in our preoccupation with control of chronic pulmonary infection, we can easily underestimate the importance of pancreatic insufficiency.

Do all CF patients need enzymes?

In CF populations of Northern European descent, the great majority have little or no exocrine pancreatic function after the first year of life, although in Southern Europe, and elsewhere, up to 50% of CF patients retain sufficient pancreatic function, often throughout life, and do not need pancreatic enzyme-replacement therapy (PERT). There are now more than 2000 known mutations in the CFTR gene, most of them obviously rare, but the best clinical genotype–phenotype correlations are in respect of pancreatic function. Pancreatic insufficiency correlates only poorly with a tendency to more-severe pulmonary disease and it cannot be assumed that pancreatic-sufficient patients will have a better prognosis.

How much?

The recent review by Heubi reported some new developments in PERT [4]. It was noted that current preparations are derived from hog pancreas, and enzyme activity present at the time of manufacture deteriorates with duration and conditions of storage. To ensure that the stated levels of lipase and protease activity are valid at the end of the products’ shelf-life, all manufacturers overfill the capsules and the extent of overfilling varies a little from batch to batch. In a study performed in my own departmental laboratories more than a decade ago, we found that, in one instance, the lipase content was approximately twice the claimed amount [5]. Precise dosage is, therefore, impossible. However, this variation, while unacceptable for ordinary pharmaceuticals, may not be so important in this case because the in vivo performance of administered enzymes in CF varies according to the composition of the diet in a particular meal, gastric acid secretion, patterns of gastric emptying, the release characteristics of the enteric coating, the pH at different levels of the small and large intestine, the contribution (if any) of residual pancreatic function, bile acid composition and concentration [6], and an important, but often forgotten, effect of impaired absorption of the fatty acid products of triglyceride digestion by the CF gut mucosa [7,8]. Dosage ‘requirements’ are, therefore, inevitably approximate. It is recommended that the total daily intake of lipase should not exceed 10,000 units per kg bodyweight, divided between meals and snacks. If evidence of steatorrea and significant abdominal symptoms are still present when this dose has been reached, it is unlikely that increasing will produce any benefit, and further investigations are recommended to exclude coexisting disorders.

Nevertheless, the waning potency of pancreatic enzymes over time (particularly lipase and protease, which do not degrade at the same rate) has come to the attention of regulatory authorities on both sides of the Atlantic, and manufacturers are under pressure to supply improved products. One approach, adopted by the USA company Altus, has been to develop ‘artificial’ mixes of bacterial enzymes in a stable crystalline form, and clinical trials are underway. Eurand, based in Italy, which produces hog pancreas products currently marketed in the USA as Ultrase^® (Axcan, Quebec, Canada) and in Europe as Pancrease^® (Cilag, Switzerland) and Nutrizyme^® (Merck, Darmstadt, Germany), has improved its product stability and has embarked on clinical trials of the new preparation under its own name. These trials were reviewed by Heubi [4].

A novel approach has been to add recombinant human milk bile salt-stimulated lipase, which is acid resistant and, therefore, unaffected by gastric acid, to conventional hog pancreas therapy. The Swedish company Arexis, which is now owned by Biovitrum, has supported clinical trials, and early studies have reported improved fat absorption [9].

How much is too much?

One of the pressures toward a formulation with a more predictable enzyme activity has been the fear of overdose, particularly of protease, because of its proven association with fibrosing colonopathy [10]. Some of the affected children were being administered up to ten-times the recommended upper dose of enzymes, which we now know to be safe and effective. Fibrosing colonopathy has been exceptionally described in a very young infant with CF who had never been exposed to exogenous enzymes after surgery for neonatal meconium ileus [11]. Presumably, this was due to rapid transit of endogenous enzymes from a still-functioning pancreas into the colon without an intervening ileo–caecal valve, but it underlines the fact that the intestines of people with CF are not normal; enhanced absorption of small (Na⁺) and large (amino acid) molecules is well known [12]. A recent paper showed that some pancreatic enzymes are translocated across the intestinal mucosa in rats [13], but it is not known if this absorption is enhanced in CF, although evidence of enzyme damage across the whole thickness of the intestine in fibrosing colonopathy suggests that this might be the case. Furthermore, markers of intestinal inflammation are increased in the stools of CF patients [14] and recent work has shown that protease activation of receptor 2 is a major factor in intestinal inflammation [15]. Therefore, there is good reason to continue to prescribe enzymes with restraint. Since the unhappy experience of fibrosing colonopathy in the 1990s and the subsequent, almost universal, observation of an upper dose limit, enzyme-related instances of the condition have almost disappeared, and it may join retrolental fibroplasia in premature infants as a historical example of an iatrogenic disorder caused by overdose of a ‘natural’ product. While I was preparing this commentary, notice came of another possible problem with current PERT. Canadian researchers have found, as an incidental discovery, that urine from CF children taking enteric-coated pancreatic enzymes contained significantly more phthalates than urine from controls. A number of different phthalates are widely used as plasticisers in packaging and in medical and medicinal products, including pancreatic enzymes marketed by Solvay (Creon^®), Axcan (Ultrase), Organon (Cotazyme^®) and Cilag (Pancrease). Few relevant toxicity studies appear to have been conducted and none of them shed much light on whether the levels of phthalates found in the CF children are likely to be harmful. There is absolutely no evidence to indicate that patients taking enzyme products containing phthalates are at risk, but a warning has been sounded and no doubt the pharmaceutical industry will be going back to the drawing board to deal with this latest issue [16]. In the meantime, clinicians are advised that there is no need to change current prescriptions.

Financial & competing interests disclosure

The author has been an ad hoc independent advisor to several companies marketing pancreatic enzymes during the past 30 years. Between 1997 and 1999, JA Dodge was a paid consultant to Scandipharm, an American company who were taken over by Axcan (Canada), at which point his consultancy was terminated. The author has no financial interests in any pharmaceutical company. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.