Approximately 95% of patients in Northern Europe are pancreatic insufficient due to an inadequacy of their own pancreatic enzyme secretions (Littlewood et al, 2006). These patients need to take pancreatic enzyme replacement therapy (PERT) in order to prevent the symptoms of fat malabsorption. These symptoms include frequent pale, oily and offensive stools, abdominal pain, poor growth and deficiencies of fat soluble vitamins and essential fatty acids.
Patients who present with obvious symptoms of malabsorption should be started on PERT as soon as the diagnosis of CF is made (Wolfe & Morton, 2006). Confirmation of pancreatic insufficiency should then be made by measuring faecal pancreatic elastase (Borowitz, 2005). If clinical symptoms of malabsorption are absent, pancreatic insufficiency should be confirmed before PERT is started (Littlewood et al, 2006). Faecal pancreatic elastase should also be used to monitor the onset of pancreatic insufficiency in pancreatic sufficient patients (Walkowiaket al, 2003).
There are various enzyme preparations available (Littlewood et al, 2006). The enteric coated, acid-resistant microsphere and minimicrosphere preparations are significantly more effective than the older pancreatic enzyme preparations (e.g. Pancrex V®, Cotazyme®). All pancreatic insufficient infants should be given a standard strength, acid resistant pancreatic enzyme preparation e.g. Creon®Micro, or Creon® 10,000 (see below for the dose of PERT and the method of giving the enzymes). Many factors affect the efficacy of pancreatic enzymes (e.g. the acidity in the gut and the gastrointestinal transit time) which results in a wide variability in enzyme requirements. Doses should be advised individually and re-assessed regularly by the dietitian. Educating patients about dose adjustment and the timing of PERT is essential to achieve optimal absorption and a good nutritional status.
As patients get older and their food intake increases they need to take higher doses of pancreatic enzymes. For this reason, many older adolescents and adults choose to take a higher strength enzyme preparation. These preparations (Creon® 25,000, Creon® 40,000, Pancrease HL® and Nutrizym 22®) contain up to four times the quantity of lipase of standard preparations. A number of higher strength enzymes were introduced in the UK in 1992 (some of which have since been withdrawn). In the early 1990’s a new complication, fibrosing colonopathy (stricture of the lower bowel) occurred in a number of children taking large doses of the high strength enzymes (Smyth et al, 1994). In the UK a case-control study linked fibrosing colonopathy with large doses of enzymes that contained Eudragit L30 D55 in their covering (Pancrease HL®, Nutrizym 22® and Panzytrat® 25,000), but not with Creon® 25,000, a preparation which does not contain Eudragit (Smyth et al, 1995). Conflicting results were observed in a similar case control study in the USA. Links were found between excessive intakes of high strength enzymes but not with Eudragit (FitzSimmons et al, 1997). Fibrosing colonopathy has been reviewed in detail elsewhere (Littlewood, 1999).
In view of the occurrence of fibrosing colonopathy, the UK Committee on Safety of Medicines advised that the total dose of enzymes should not usually exceed 10,000 IU lipase/kg/day (Committee on Safety of Medicines, 1995). We would also where possible use a preparation that does not contain Eudragit and therefore when Nutrizym® and Pancrease HL® preparations need to be used extra caution should be employed.
Leeds recommendations for pancreatic enzyme replacement therapy
• Use minimicrosphere preparations Creon® Micro or Creon® 10,000.
• For every breast feed or 90 -120ml infant formula give an initial dose equivalent to 2,500 IU lipase (½ scoop of Creon® Micro or ¼ capsule Creon® 10,000)
• Mix the enzyme microspheres with a small amount of expressed breast milk, formula or fruit puree and give from a spoon
• The timing of enzyme administration should be determined individually. For some absorption may be better if the enzymes are given at the beginning and towards the middle of the feed. For others towards the middle and end of the feed may be best. If the infant takes over 20 minutes to feed giving the enzymes at the beginning and towards the end may be best. Close supervision from a dietitian is essential to achieve the optimum timing
• Increase the dose gradually according to clinical symptoms, appearance of the stools and objective assessment of weight gain, growth and absorption
• Once solid food is introduced, individually titrate the enzyme dose according to the fat intake. Regular advice from a dietitian is mandatory for best results
• Aim to keep the lipase intake below 10,000 IU per kg body weight per day
Toddlers and older children
• Initial dose of 2 to 4 scoops Creon® Micro or 1 to 2 capsules of Creon® 10,000 (10,000-20,000 IU lipase) per meal. One to two scoops Creon® Micro or ½ to one capsule Creon® 10,000 with fat containing snacks
• Enzymes should be given with all fat containing foods and drinks. The dose should be worked out individually and varied according to the fat intake. Because of multiple factors affecting enzyme efficacy, dose requirements can vary widely between 500 and 4000 IU lipase per gram of fat
• Enzyme capsules should be swallowed whole at as early an age as possible and many children will manage this by three or four years, some very much earlier. If children were started on Creon® Micro as an infant they should be given a capsule preparation by four years of age, and encouraged to swallow the capsules whole. If removed from the capsules or taken from a jar, the microspheres should not be sprinkled on, or mixed with, the whole meal but should be mixed with a small amount of milk or food and given from a spoon. They should not be crushed or chewed
• The timing of enzyme administration should be worked out individually (see section on infants above)
• The dose is gradually increased until the symptoms of fat malabsorption are controlled
• Patients and parents should be encouraged to openly discuss any problems with enzyme compliance that they may have. Advice should be given to help overcome these problems
Adolescents and adults
• Newly diagnosed pancreatic insufficient adolescents and adults should be started on standard strength pancreatic enzymes as outlined above for toddlers and older children
• Once PERT is established, if high doses of enzymes are required the use of high strength enzyme preparations (e.g. Creon® 25,000 and Creon® 40,000) should be considered
Pancreatic enzyme replacement when fasting
If a patient is fasting for any period of time it is our practice to give pancreatic enzymes to prevent gut blockage. The theory is that one enzyme capsule or one to two scoops of Creon® Micro every three to four hours helps breakdown the thick sticky mucus that may block the gut and lead to distal intestinal obstruction syndrome (DIOS).
Pancreatic enzyme replacement with enteral tube feeds
Pancreatic enzymes should be taken with all elemental or polymeric fat-containing enteral tube feeds. The dose is worked out on an individual basis taking the type, fat content and rate of administration of the feed into consideration. If the feed is to be infused over a long period of time e.g. overnight only a small does of enzymes may be needed (Kerrin et al, 2000). This is partly because of the stimulation of gastric lipase (Armand et al, 2004) which will help to digest the fat in the feed as it is infused overnight. In practice a starting dose of one to two capsules of the patient’s usual enzyme preparation is given at the start and at the end of the feeding. The dose is then titrated against symptoms rather than the fat content of the feed. If bolus feeds are being given or the feed is being infused over a short period of time larger enzyme doses may be required due to the faster rate of fat infusion.
Pancreatic enzyme replacement in patients who cannot swallow e.g. the ventilated patient
Enteric coated pancreatic enzymes cannot be put down standard nasogastric and gastrostomy tubes. If a patient is unable to take enzymes orally, it is our practice to give a powdered enzyme preparation, e.g. Pancrex V® powder. Powdered enzymes (approximately 0.5 g) should be flushed down the tube at three to four hourly intervals. If the patient is also receiving enteral feeds the dose and frequency of administration may need to be increased. The enzymatic activity of powdered enzymes is largely destroyed in the acid environment of the stomach. An acid blocking drug e.g. omeprazole, should be given to try to preserve some of the enzymatic activity.
If a patient has symptoms suggestive of malabsorption despite what appears to be an adequate enzyme dose and method of administration, assessment of other factors affecting PERT should be carried out.
• The enzyme dose should be tailored to the fat content of the meal or snack (Lowdon et al, 1998). The patient’s knowledge of enzyme titration according to dietary fat intake should be assessed
• The timing and method of taking the enzyme capsules should be reviewed. The variable mixing of enzymes with the meal in the stomach and rate of leaving the stomach suggests that a trial of varying the timing of taking the enzymes through the meal may improve absorption in individual patients (Taylor et al, 1999)
• Practical considerations such as enzyme storage and stock rotation should be discussed. Enzyme preparations that are past their use by date or that have been stored at extremes of temperature may have lost some or most of their activity
• Consideration should be given to changing to another brand of enzyme that because of different formulation, in the same dose, may result in an improvement in symptoms and absorption
• Drugs to reduce gastric acid e.g. H2 antagonists and proton pump inhibitors may improve absorption in some patients (Francisco et al, 2002; Proesmans & De Boeck, 2003)
• Patient adherence to the dose and method of taking enzymes may be an important factor in poor control and should be discussed
The importance of the role of an experienced CF dietitian to discuss the practical details of treatment in such circumstances cannot be over emphasised.
Persisting bowel symptoms despite optimal treatment
A few patients with CF still have significant bowel symptoms despite malabsorption being adequately controlled. It is important that these persisting symptoms are investigated and a full gastro-intestinal investigation should be carried out to rule out other causes of the symptoms e.g. anatomical abnormalities, infections or other gastro-intestinal abnormalities (Littlewood et al, 2006). Coeliac disease occurs more frequently in patients with CF than in the general population
Constipation as the cause of recurrent abdominal pain
The detailed causes, investigations and treatment of abdominal pain in patients with CF are described in detail elsewhere (Littlewood, 1995). We find that the most common cause of recurrent pain in these patients is constipation. In some patients intestinal absorption is well controlled as judged by faecal fat studies, and therefore indiscriminately increasing the enzyme dose may only make matters worse.
An X-ray of the abdomen frequently reveals a markedly overloaded colon and pain is often the only reported symptom. This is usually central or below the umbilicus and is often relieved by defaecation and responds to regular laxatives. Ensuring an adequate fluid intake is also important.
• In Northern Europe, 95% of patients require pancreatic enzyme replacement therapy
• The dose of enzymes should be worked out individually and titrated against the fat content of the food/drink being taken to achieve optimal absorption
• If symptoms of malabsorption persist despite optimising enzyme therapy a detailed review by a CF specialist dietitian is mandatory and there should be an assessment of other factors that either reduce the effectiveness of PERT or cause malabsorption and/or abdominal pain
• Patients presenting with obvious malabsorption should be started on PERT immediately
• Ideally doses should be kept below 10,000 IU lipase/kg body weight/day
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