Chapter 47 Enzyme Supplementation
The exocrine pancreas has great reserve capacity; consequently, the clearly recognizable signs of failure emerge only when up to 90% of the exocrine gland tissue has been compromised. Replacement therapy with enzyme supplementation is then needed to compensate for the lack of endogenous enzyme production.1
Pancreatic enzyme replacement therapy was first attempted in human medicine at the turn of the twentieth century and it was shown that nutritional status could be significantly improved with such therapies. One challenge to this therapy is the sensitivity of pancreatic enzymes to gastric acid. Amylase and lipase are the most susceptible and are destroyed at a pH below 4.5. Trypsin can withstand a pH of 3.5, thus remaining unaffected by most pH conditions in the stomach. In humans, only 17% of ingested lipase can be recovered intact from the duodenum.2 To improve passage of pancreatic enzymes through the acidic environment of the stomach, pharmaceutical companies have developed porcine, enteric-coated pancreatic enzyme preparations. The manufacturing process must be gentle to ensure that enzymes are not destroyed. Although much is already known about pancreatic enzyme supplementation, modern replacement therapy has significant room for improvement. Despite adequate enzyme supplementation, digestion capacity does not return to normal in humans or dogs with exocrine pancreatic insufficiency (EPI). Only a small portion of the orally administered enzyme is delivered intact and functional to the small intestine.1 For maximum digestive efficiency, pancreatic enzyme preparations should be formulated to (a) protect acid-labile enzyme from gastric inactivation, (b) provide concomitant gastric emptying of the enzyme with the ingested meal, and (c) deliver maximal enzyme activity to the proximal duodenum. To fulfill these criteria, formulation of a sustained-release preparation of pancreatic extract that releases enzymes over a prolonged period of time to a site favorable for their function would be highly desirable. Unfortunately, this preparation is not yet commercially available.3
The gastric-emptying rates of nondisintegrating forms of enzyme have been reported in several studies. Early studies reported that particles reduced to a size of 2 mm or less are emptied rapidly from the canine stomach.4 More recently, however, in normal dogs and in one dog with EPI, the majority of multiunit preparations (diameter, 1 to 1.7 mm) have been shown to remain in the canine stomach for up to 8 hours before being emptied into the duodenum by the interdigestive migrating motility complex.5 The majority of pancreatic enzymes prepared in granule form obviously would never be emptied from the stomach simultaneously with food. Even a reduction of granule size to 0.3 mm had no clear effect on the gastric-emptying time of these preparations. It can be concluded, therefore, that smaller granules (<0.3 mm) will be needed to optimize gastric emptying of multiple-unit preparations in pancreatic replacement enzyme therapy. It should be recognized, however, that this could aggravate existing problems in manufacturing associated with granulation and particle coating.3 In humans with chronic pancreatitis or cystic fibrosis, encapsulated enteric-coated microspheres and mini-microspheres (diameter <1.7 mm) are considered the enzyme treatment of choice. Even so, full recovery from the catabolic state of EPI with enzyme replacement therapy is never achieved in all patients.6
To study the effect of different enzyme preparations in the treatment of dogs with EPI, experimental studies were carried out in two dogs with cranial jejunal cannulation.7 Food was supplemented with commercial enzyme preparations in the following sequences: powder, granules, capsules, enteric-coated tablets, and finely chopped raw pig pancreas. Jejunal ingesta were sampled at 30-minute intervals for 6 hours after feeding. Protease, amylase, and lipase activities were determined in jejunal samples and in feces. The control subjects comprised 14 healthy dogs and one subclinical EPI dog. This dog had approximately 90% pancreatic atrophy, but did not yet have clinical signs of maldigestion. In normal dogs and in the EPI dog, the highest lipase activities in the jejunal samples were achieved using raw pig pancreas. Powder achieved the second highest activities, but the other commercial porcine enzyme preparations yielded activities that were only one-tenth of those attained with the raw pancreas. Raw pancreas and commercial enzyme preparations increased the activities of proteases and amylase well beyond those found in the jejunum of the subclinical EPI dog. With the commercial powder preparation and with the raw pancreas, jejunal enzyme activity was detected immediately after feeding. Capsules and granules delayed the appearance of jejunal enzymatic activity by 1 to 2 hours and enteric-coated tablets by 5 hours. It should be noted that measuring enzymatic activity in feces was not reliable for evaluating the potency of pancreatic enzyme preparations added to food. Lipase activity was seldom found in the colon, and amylase and protease activities showed substantial variation.
The effect of the two uncoated enzyme supplements—raw chopped pancreas and porcine pancreatic powder preparation—were compared in a long-term clinical study.8 The study included 76 dogs with an EPI diagnosis: 40 dogs were fed powdered enzymes and 36 dogs were fed raw chopped pancreas. When comparing the prevalence of clinical signs, there were no significant differences between the two groups. The study showed that in practice, the prescription of one of these supplements was largely based on economics and practicality. The raw chopped pancreas was only one-fourth as expensive, but practical difficulties, mainly in availability, handling, and storing, were considerable compared with powdered enzyme supplements. The most common source of raw chopped pancreas was from pigs (72%), followed by cattle (19%) and lambs or reindeer (9%). The mean amount of raw chopped pancreas was 87 g/meal. It has been shown that raw pancreas can be stored frozen for several months prior to feeding. All dogs treated with powdered enzyme supplements were fed the same product (Viokase V, Fort Dodge Laboratories, IA), and the mean amount was 3 g/meal. No correlation was found between body weight and amount of enzyme fed.
Because raw chopped pancreas is not available in many countries, powder enzyme supplementation is the most common treatment for dogs and cats with EPI. Widely accepted treatment recommendations for dogs include feeding of a dose of 1 to 2 tsp of powdered pancreatic extract per 20 kg body weight at each meal.9 For cats, a starting dose of 0.5 to 1 tsp should be administered with each meal. Enzymes should be mixed with food 20 minutes before feeding. Thereafter, pet owners are counseled to decrease the dose of pancreatic enzymes based on their pet’s initial response. Most dogs require at least 1 tsp of enzymes per meal. Little additional improvement was observed after doubling or quadrupling this dose in EPI dogs with experimental pancreatic ductal ligation.10 Side effects of porcine pancreatic extracts are rare, but it has been reported that high doses of pancreatic enzyme supplements can cause oral bleeding in dogs with EPI. Oral bleeding can be successfully managed by dose reduction in most dogs.11
Numerous attempts have been made to increase the efficacy of enzyme supplementation in dogs. Antacids or histamine H2-receptor antagonists have been recommended in the therapeutic regimen to reduce gastric acid–induced destruction of orally administered enzyme. This practice is, however, costly and does not necessarily increase the efficacy of pancreatic enzyme supplementation.9,12 In humans, a double-blind, placebo-controlled crossover study was conducted to measure the effect of acid suppression (ranitidine or omeprazole) on fat absorption in patients with cystic fibrosis. No overall significant improvement in fat absorption could be demonstrated with adjuvant therapy.13 Concurrent oral administration of bile salts and preincubation of the meal with pancreatic enzymes for 20 to 30 minutes before feeding also did not improve the response.14
Besides porcine pancreatic extracts, bacterial lipase has been reported to be effective in correcting steatorrhea in dogs with experimental EPI.15 Bacterial lipase is secreted by Burkholderia plantarii during fermentation. It is resistant to acid denaturation and protease digestion and does not require colipase activation for lipolytic activity. Bacterial lipase maintains activity even in the presence of bile acids. The effects of bacterial lipase were compared with those of a powdered porcine pancreatic enzyme preparation (Viokase powder, A.H. Robins Co., Richmond, VA) in alleviating steatorrhea in EPI dogs. The results of that study revealed that correcting steatorrhea required 75 times more porcine lipase than bacterial lipase by weight (240 mg vs. 18 mg). Improved fat absorption with use of bacterial lipase does not, however, improve absorption of the other nutrients, and thus, proteases and amylase are still necessary to correct protein and carbohydrate malabsorption, if present. These studies further showed that in using bacterial or porcine lipase to treat dogs with experimental EPI, a high-fat and high-protein diet improved fat absorption more efficiently than a low-fat, low-protein diet.
Enzyme preparations of vegetable origin have also been launched alongside ordinary pancreatins; these are extracted from molds or contain a protein-cleaving papain from the tropical papaya tree. Nevertheless, preparations obtained from an animal (porcine) pancreas have been demonstrated to be the ideal replacement enzymes and can in no case be replaced by vegetable ferments.16 An experimental study in dogs has, however, shown that fungal lipase may prove to be useful in treating dogs with EPI.17
3 Heinämäki J. Formulation and radiological imaging of oral solid drug products intended for the treatment of exocrine pancreatic insufficiency in dogs. Helsinki, Finland: Thesis, Yliopistopainos; 1991.
13 Francisco MP, Wagner MH, Sherman JM, et al. Ranitidine and omeprazole as adjuvant therapy to pancrelipase to improve fat absorption in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2002;35:79–83.
15 Suzuki A, Mizumoto A, Rerknimitr R, et al. Effect of bacterial or porcine lipase with low- or high-fat diets on nutrient absorption on pancreatic-insufficient dogs. Gastroenterology. 1999;116:431–437.