Dietary management and lifestyle changes
Fat malabsorption is the predominant cause of the symptoms of pancreatic steatorrhea resulting in weight loss as well as deficiencies of fat-soluble vitamins A, D, E, and K. In patients with chronic pancreatitis, a low fat diet has been the recommendation in order to minimize the pain of this disease and, in conjunction with PERT, to effectively treat steatorrhea. However, in patients with CF, a high fat diet in conjunction with increased amounts of PERTs has been shown to improve the associated CF lung disease and thus low fat diets are no longer advocated in this disease. Fat soluble vitamins A, D, E, and K should be supplemented if indicated, and taken with PERT [
54]. Consulting a dietitian is helpful to assess nutritional adequacy [
55]. In addition, smoking has been proven to be a risk factor in acute pancreatitis, chronic pancreatitis, pancreatic cancer [
56], and to be associated with reduced exocrine pancreatic function [
57]. Therefore, smoking and alcohol cessation is recommended in EPI due to chronic pancreatitis.
Pancreatic enzyme replacement therapy
The elimination of malabsorption, reduction of maldigestion-related symptoms, and the prevention of malnutrition-related morbidity and mortality is the goal for PERT [
55]. This is most evident in CF, where prior to the availability of PERT, infants died within the first year of life. Prior to 2010, pancreatic enzymes were not FDA regulated and had variable consistency of activity. As a result, in 2010, the FDA mandated approval of all prescribed formulations of PERT. It should be noted that the clinical trials were relatively small (less than 40 subjects) and tested in subjects who were known to respond to PERTs. All pancreatic enzyme preparations are extracts from porcine pancreas (pancrelipase) and are available in preparations encapsulated in mini-microspheres or microtablets, which vary in particle size and pH-related release kinetics [
58]. Enteric-coated pancreatic microspheres are designed to be acid resistant and pH-sensitive to protect lipase from denaturation by gastric acid. Unfortunately, confusion has arisen due to the many different dosage strengths of PERTs [
59] (Table
1).
Table 1
Current Food and Drug Administration (FDA) approved pancreatic enzyme replacement therapies (PERTs)
Creon | 3000; 6000; 12,000; 24,000; 36,000 |
Zenpep | 3000; 5000; 10,000; 15,000; 20,000; 25,000 |
Pancreaze | 4200; 10,500; 16,800; 21,000 |
Ultresa | 13,800; 20,700; 23,000 |
Viokase | 10,440; 20,880 (requires acid suppression) |
Pertzye | 8000; 16,000 |
Enteric-coated pancreatic enzymes are most effective at a pH > 6. However, in patients with CF, the duodenal pH is < 6 [
60]. The use of acid-suppression medications can increase gastric pH levels and theoretically improve the efficacy of PERT and decrease EPI symptoms [
61,
62]. Current data may suggest a trial of acid blockers in patients with CF who have refractory steatorrhea [
61‐
65]. However, a recent retrospective study demonstrated no improvement of the coefficient of fat absorption (72-hour fecal fat test) when using a proton pump inhibitor in pediatric patients with CF [
66].
Uncoated exogenous pancreatic enzymes, such as Viokase (Aptalis Pharma), are thought to mix well with intragastric nutrients and rapidly release high duodenal lipase amounts for fat digestion [
58]. The addition of acid-suppression medications is required to prevent degradation of non-enteric coated pancreatic enzymes [
58]. Only non-enteric pancreatic enzymes have been shown to improve the pain in a subset of patients with chronic pancreatitis. The use of unprotected exogenous enzymes in combination with enteric-coated enzymes has previously been recommended for the treatment of refractory EPI [
58,
67]; however, Kalnins et al. [
68] showed no improvement in nutrient digestion (fecal fat, energy, and nitrogen output) when unprotected pancreatic enzymes were added to the conventional enteric-coated enzymes in 14 pediatric patients with CF.
Dosing and frequency of PERT administration
Dosing and frequency of administration are difficult aspects of PERT treatment since different enteric-coated microspheres are not bioequivalent in vitro [
69‐
71], and there are not enough clinical studies between preparations to define in vivo bioavailability. In these in vitro studies, the preparations varied in dissolution time (49–71 min half-life time) and in optimum pH (pH 5.0–5.8).
Several countries have recommended different doses of PERT. The Australasian Pancreatic Club [
72], The Italian Association for the Study of the Pancreas [
8], and The Spanish Pancreatic Club [
73] recommend 25,000–50,000 lipase units per main meal in adults. Unfortunately, the evidence for these recommendations is relatively weak as emphasized by The Australasian Pancreatic Club in their recent study on the management of pancreatic exocrine insufficiency [
72]. In addition, a study from the Netherlands by Sikkens et al. [
74] found that 70% (
n = 161) of the patients with EPI caused by chronic pancreatitis were under-treated and reported steatorrhea-related symptoms, despite PERT (median enzyme intake of 6 capsules, 25,000 lipase units per day). These differences in recommendations demonstrate the significant confusion over dosing and administration amongst medical practitioners.
Likewise, there is no consensus over frequency of PERT administration. In 1977, DiMagno et al. [
75] demonstrated that administration of PERT during a meal was as effective as hourly administration over the day to decrease steatorrhea. Other recommendations based on several reviews are to take 50% of the exogenous pancreatic enzymes at the beginning of the meal and 50% half-way through [
76], pancreatic enzymes during or immediately following the meal [
77], or lastly, 25% of the enzymes with the first bite, 50% during the meal, and 25% with the last bite [
78]. In addition, a recent randomized three-way crossover study of 24 patients using 40,000 lipase units per meal compared three different administration schedules with PERT before meals, during meals, or after meals using the
13C-MTG breath test to measure fat absorption [
79]. The percentage of patients who normalized fat digestion was 50%, 54%, and 63%, respectively. Thus, no statistically significant differences were found between different administration schedules, however, they did recommend giving PERT during or after meals.
In a patient with suspected EPI with a known history of pancreatic disease, empiric therapy with PERTs may be indicated without formal testing. A clear response would be both diagnostic for EPI as well as therapeutic. In addition, if there is a poor response to PERT, one should consider concurrent gastrointestinal comorbidities such as lactose intolerance, enteric bacterial infection, parasites (especially giardia), small intestinal bacterial overgrowth, biliary disease (cholestasis), colitis, celiac disease, short bowel syndrome, and Crohn’s disease [
80]. Other reasons could be insufficient dosing, lack of compliance, inadequate timing of PERT administration, and poor diet (Table
2).
Table 2
Treatment strategies for lack of response to pancreatic enzyme replacement therapy (PERT)
• Increase dosage | |
• Check compliance with the patient | |
• Add acid inhibitor | |
• Consider adding enzymes during and towards end of meal | |
• Consider microspheres, possibly adding a rapid release enzyme preparation | |
• Look for evidence of concurrent gastrointestinal disorder | |
PERT should be taken with the first bite of a meal and consider adding extra enzymes during or towards the end of the meal. Thus, if consumption of a meal is less than 15 min, all enzymes can be taken at the beginning of the meal; for a 15- to 30-minute meal, we suggest taking half the enzyme capsules with the first bite and the other half in the middle of the meal; for more than 30 minutes, we recommend taking one third at the beginning, one third in the middle and one third at the end. The rationale for taking pancreatic enzymes throughout the meal is to mimic the action of our own endogenous pancreatic enzymes, where secretion from the gland occurs throughout a meal. Specifically, the more food that is ingested and/or the grater the amount of fat in the diet, the higher the amount of endogenous pancreatic enzyme secretion; thus, the number of PERT capsules consumed should reflect this. Table
3 gives a suggested clinical overview of PERT dosing for different age groups [
17,
19,
80].
Table 3
Pancreatic enzyme replacement therapy (PERT) suggested dosing in different age groups
Infant | 2000–4000 units/120 mL formula or breastmilk |
Child age < 4 years | 1000 units/kg/meal 500 units/kg/snack |
Child age ≥ 4 years | 500 units/kg/meal 250 units/kg/snack |
Adult starting dose | 50,000 units/meal 25,000 units/snack |
Adult maximum dose | 150,000 units/meal 70,000 units/snack |