Saturday, February 9, 2008

Pancreatic Enzymes Article

Pancreatic enzymes
Sue Wolfe, Kisten Tremlett, Helen White and James Littlewood. Jan, 2001. Pancreatic enzymes [online]. Seacroft and St James's University Hospitals, Leeds, UK. Available from

Virtually all CF patients (95%) require pancreatic enzyme supplements due to an inadequacy of their own pancreatic secretions (Morgan et al, 1999). Various preparations are available (Walters & Littlewood, 1996). The acid-resistant microsphere preparations (Creon 10,000, Pancrease) are significantly more effective than the older pancreatic enzyme preparations (e.g., Pancrex V and Cotazyme) (Beverley et al, 1987).

High lipase pancreatic preparations: High strength pancreatic enzyme preparations (HSPE) containing 3-5 times the quantity of lipase of standard preparations were introduced in the UK in 1992 (Creon 25,000, Pancrease HL & Nutrizym 22). The use of HSPE preparations permitted a welcome reduction in capsule dose in many patients but in others the reduction was less than expected from the substantial increase in lipase. In 1993 a new complication, fibrosing colonopathy (FC), strictures of the lower bowel, occurred in a few children taking large doses of the HSPEs (Smyth et al, 1994). By late 1994, 13 cases of FC had been identified in the UK (Littlewood & Hind, 1996). Subsequently a case-control study confirmed the association of FC with large doses of those brands of HSPE that contained the methacrylic acid copolymer Eudragit L30 D55 in their covering (the microtablets Pancrease HL and Nutrizym 22), but not with Creon 25,000, a microsphere preparation which does not contain the copolymer (Smyth et al, 1995). Subsequently FC occurred in 3 UK children taking the standard enzyme Nutrizym GR, which has contained methacrylic acid copolymer since 1993 (Jones et al, 1995; Ramsden et al, 1998). In the USA a case controlled study of 29 patients confirmed the association with high doses of HSPE preparations but not with the methacrylic acid copolymer (FitzSimmons et al, 1997), possibly due to the design of the study (Prescott & Bakowski, 1999). Fibrosing colonopathy has recently been reviewed in detail (Littlewood, 1999). Although not all are agreed on the role of methacrylic acid copolymer (Powell, 1999), In Leeds strong advice against the use of any enzyme preparations containing methacrylic copolymer Eudragit L30 D55 (i.e. the high strength pancreatic enzymes Pancrease HL, Nutrizym 22 and the standard preparation Nutrizym GR) is given. Standard preparations Creon 10,000 and Pancrease or the high strength pancreatic enzyme Creon 25,000 are recommended, none of which have been associated with fibrosing colonopathy. HSPE Creon 25,000 appears to be safe and is used to reduce the number of capsules required both for children and adults who need larger doses of enzymes, but the total daily dose of any preparation should only rarely exceed the equivalent of 10,000 IU lipase/kg/day (Littlewood, 1996). It is reassuring that there have been only 17 children with FC in the UK since 1993 and only 3 of these occurred after 1994; all 3 were very young children taking large doses of the standard strength preparation Nutrizym GR which contains relatively large quantities of methacrylic acid copolymer and is still available in the UK (Jones et al, 1995; Ramsden et al, 1998).

Recommendations for pancreatic replacement therapy - Leeds CF Unit (Littlewood & Wolfe, 2000). The Leeds recommendations are summarised as follows:

Infants ?Use microsphere or minimicrosphere preparations. ?For every 120 mls infant formula or breast milk give an initial dose of one quarter to one third of a capsule of Creon 10,000 (2500-3333 IU lipase) or one third to one half a capsule Pancrease (1666-2500 IU lipase). These doses equate to approximately 400-800 IU lipase per g of dietary fat. ?Mix the enzyme minimicrospheres with a small amount of formula or expressed breast milk or fruit puree and give from a spoon directly before the feed. ?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 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.

Older children ?Initial dose of 1 to 2 capsules of Creon 10,000 (10,000-20,000 IU lipase) or Pancrease (5,000-10,000 IU lipase) per meal and a half to one capsule with fat containing snacks. ?Some paediatric units have continued to use Creon 25,000 without problems as the Committee on Safety of Medicines advised avoiding only Pancrease HL, Nutrizym 22 and Panzytrat 25,000 for children. ?Enzymes should be given with all fat containing foods. The dose should be worked out individually, initially with the help of a dietitian, and varied according to the fat intake. Because of multiple factors affecting enzyme efficacy, dose requirements can vary widely between 500 and 4000 IU per g of fat. ?The capsules should be swallowed whole at as early an age as possible and many children will manage this by 3 or 4 years, some very much earlier. If removed from the capsules, the microspheres can be mixed with a small amount of food and administered at the start of the meal. The enzyme microspheres should not be mixed with the whole meal or crushed/chewed in the mouth. ?Enzymes are best given at the beginning or early in the meal. Half the dose is recommended at the beginning and half in the middle of the meal. ?The dose is gradually increased until the symptoms are controlled when evidence is sought that absorption has been controlled either by faecal microscopy or by measuring the 3-day faecal fat output. ?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.

Pancreatic enzyme replacement when fasting: If a patient is fasting for any period of time it is the Leeds practice to give pancreatic enzymes as prophylaxis against gut blockage. Giving one standard strength enzyme (Creon 10,000 or Pancrease) 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 in the ventilated patient Enteric coated pancreatic enzymes cannot be put down standard nasogastric and gastrostomy tubes. If a patient is unconscious and is unable to take enzymes orally it is our practice to give a powdered enzyme preparation, e.g. Pancrex V. These enzymes (approximately 0.5 g) are flushed down the tube at three to four hourly intervals. The enzymatic activity of powdered enzymes is largely destroyed in the acid environment of the stomach. Therefore, an acid blocking drug, e.g. omeprazole, should be given to try to preserve some of the enzymatic activity.

Persisting bowel symptoms despite optimal treatment: Some CF patients still have a significant degree of malabsorption despite what appears to be appropriate enzyme treatment. In these cases a full gastro-intestinal investigation should be carried out as there may be other conditions causing the problems e.g. anatomical abnormalities, infections or other gastro-intestinal abnormalities (Littlewood, 1992; Littlewood, 1995).

Constipation as the cause of recurrent abdominal pain: The detailed causes, investigations and treatment of abdominal pain in patients with CF have been described in detail (Littlewood 1995). About 10% of CF patients in our clinic have some degree of persisting abdominal symptoms, usually pain, despite adequate doses of enzymes. The most common cause of recurrent pain in these patients is often constipation. In many patients intestinal absorption is well controlled as judged by faecal fat studies, and increase in the enzyme dose only makes matters worse. An X-ray of the abdomen frequently reveals a markedly overloaded colon. This is much more severe than the usual colonic overloading common to asymptomatic patients with CF. Even with a grossly overloaded colon patients often do not complain of infrequent hard stools (i.e. constipation), the pain is often their only perceived problem. This is usually central or below the umbilicus and is often relieved by defecation and responds to regular laxatives. Initially, regular lactulose may be tried for a few weeks but in some Senokot and occasional doses of gastrografin may be necessary (O'Halloran et al, 1986). The patients total intake of lipase should be checked to ensure this is not excessive (ie: over 10,000 units/kg body weight/day). An adequate fluid intake should also be advised.