Exocrine pancreatic insufficiency

Exocrine pancreatic insufficiency (EPI) is a condition characterized by deficiency of the exocrine pancreatic enzymes, resulting in the inability to digest food properly, or maldigestion, resulting in malabsorption ¹⁾. This inadequate digestion with nutrient and, especially, fat malabsorption occurs when intraduodenal levels of lipase fall below 5–10% of normal enzyme output ²⁾, leading to pancreatic steatorrhea, weight loss, and a potential decrease in quality of life ³⁾. Furthermore, in exocrine pancreatic insufficiency, due to cystic fibrosis (CF) or chronic pancreatitis, there is decreased bicarbonate output causing a lower intestinal pH, which precipitates bile salt acids and impairs micelle formation of fats ⁴⁾. Fat maldigestion is compounded by decreased pancreatic secretion of lipase and colipase, further dampening hydrolysis of intraluminal fat.

The cause of exocrine pancreatic insufficiency includes pancreatic and nonpancreatic causes ⁵⁾. Numerous conditions account for the cause of exocrine pancreatic insufficiency, with the most common being diseases of the pancreatic tissue including chronic pancreatitis, cystic fibrosis, and a history of extensive necrotizing acute pancreatitis.

Many diagnostic tests are available to diagnose exocrine pancreatic insufficiency, however, the criteria of choice remain unclear and the causes for a false-positive test are not yet understood.

Treatment for exocrine pancreatic insufficiency includes dietary management, lifestyle changes (i.e., decrease in alcohol consumption and smoking cessation), and pancreatic enzyme replacement therapy ⁶⁾.

Exocrine pancreatic insufficiency causes

The exocrine pancreas produces three main types of enzymes: amylase, protease, and lipase ⁷⁾. Under normal physiologic conditions, the enzymes, specifically lipase, break undigested triglycerides into fatty acids and monoglycerides, which are then solubilized by bile salts. Because the exocrine pancreas retains a large reserve capacity for enzyme secretion, fat digestion is not clearly impaired until lipase output decreases to below 10% of the normal level ⁸⁾.

A leading cause of exocrine pancreatic insufficiency is chronic pancreatitis ⁹⁾. Other pancreatic causes include a history of extensive necrotizing acute pancreatitis, pancreatic cancer, pancreatic surgery, and cystic fibrosis. Non-pancreatic causes are celiac disease, diabetes mellitus, Crohn’s disease, gastric surgery, short bowel syndrome, and Zollinger–Ellison syndrome ¹⁰⁾.

Chronic pancreatitis

Chronic pancreatitis is an ongoing inflammatory process with irreversible morphological changes to the pancreas and a gradual loss in pancreatic parenchyma. There are three major groups of mutations that account for chronic pancreatitis (PRSS1, SPINK1, and CFTR). Theories of pathogenesis include oxidative stress, toxic-metabolic derangements, loss of ductal function or obstruction, and necrosis-fibrosis ¹¹⁾.

In chronic pancreatitis, approximately 20% of patients develop exocrine pancreatic insufficiency over time as a result of progressive loss of acinar cell function ¹²⁾. Layer et al. ¹³⁾ found that the median duration from the onset of symptomatic disease to exocrine pancreatic insufficiency was significantly longer in early-onset chronic pancreatitis (median age of onset being 19.2 years) than in late-onset idiopathic chronic pancreatitis (median age of 56.2 years) or alcoholic pancreatitis (median age of 13.1 years).

Cystic fibrosis

Cystic fibrosis is an autosomal recessive disorder caused by a mutation of the gene that encodes for a chloride channel called the cystic fibrosis transmembrane conductance regulator (CFTR). In ductal epithelial cells, CFTR is highly expressed and functions to transport fluid and anions into the lumen ¹⁴⁾. Dysfunction of the CFTR gene leads to a decrease in luminal fluid volume and decreased pH, resulting in protein precipitation within the ductal lumen and loss of normal acinar cell function.

Exocrine pancreatic insufficiency is most commonly observed at birth or soon after due to in utero exocrine pancreatic damage. Waters et al. ¹⁵⁾ showed that, during newborn screening, 63% of infants with cystic fibrosis are exocrine insufficient and almost 30% of the pancreas-sufficient group will become exocrine insufficient over the next 36 months. Individuals with class IV, V, or VI mutations (less severe CFTR mutations and hence some preserved CFTR function), tend to suffer from exocrine pancreatic insufficiency later in life ¹⁶⁾. Corey et al. ¹⁷⁾ compared 1000 patients from CF clinics in Boston and Toronto and demonstrated that prolonged untreated exocrine pancreatic insufficiency is associated with a worse long-term outcome and that patients maintained on a high fat diet (100 g per day) with higher doses of exogenous pancreatic enzymes did better than those on a low fat, lower pancreatic enzyme regimen. Overall, pancreatic insufficiency requiring lifelong pancreatic exocrine replacement therapy (PERT) is found in about 85% of CF patients ¹⁸⁾.

A rare complication of PERT is seen only in patients with cystic fibrosis on very high doses of enzymes. Fitzsimmons et al. ¹⁹⁾ found that, in children with cystic fibrosis, there was a strong correlation between high daily doses of PERT and the development of fibrosing colonopathy. However, this represents a small case series published in New England Journal of Medicine in 1997, which were not biopsy proven with very few cases reported since then. Factors related to cystic fibrosis, including thick intestinal secretions, dosing of PERT, and agents in the enteric coating of the pancrelipase preparations may be the precipitating factors causing this complication ²⁰⁾. Therefore, it has been recommended that, in children and adults with cystic fibrosis, the daily dose should remain below 2500 lipase units/kg of body weight per meal or 10000 lipase units/kg of body weight per day ²¹⁾.

Post pancreatic surgery

Factors that contribute to exocrine pancreatic insufficiency following pancreatic surgery are a decrease in pancreatic tissue volume, extensive denervation following lymph node dissection, and surgically altered anatomy ²²⁾. Conditions such as pancreatic cancer, intraductal papillary mucinous neoplasms, premalignant mucinous cystic lesions, and benign tumors of the pancreas may all lead to exocrine pancreatic insufficiency via obstruction of the pancreatic duct. The degree of exocrine pancreatic insufficiency following pancreatic surgery is dependent on the extent of pancreatic resection combined with the degree of residual pancreatic parenchymal function with full manifestation of exocrine pancreatic insufficiency seen following a total pancreatectomy ²³⁾. The mechanism of exocrine pancreatic insufficiency in patients undergoing a Whipple procedure may be related to a mistiming of secreted endogenous pancreatic enzymes mixing with chyme.

Large systematic reviews report a 19–80% incidence of exocrine pancreatic insufficiency following a distal pancreatectomy ²⁴⁾; however, this wide variation may be in part a result of the different diagnostic methods employed ²⁵⁾. Post-operative incidence of exocrine pancreatic insufficiency after Whipple surgery is 56–98% ²⁶⁾. In addition, Halloran et al. ²⁷⁾ analyzed 40 patients following resection for pancreatic malignancy and found that exocrine pancreatic insufficiency was common and sustained after surgery, but was not associated with significant symptoms. These patients with newly developed exocrine pancreatic insufficiency, however, did have a tendency towards poorer quality of life.

Celiac disease

Celiac disease is a chronic inflammatory intestinal disorder that may occur in genetically predisposed people triggered by the ingestion of gluten. This disease has a United States and British prevalence of approximately 1% ²⁸⁾. In celiac disease, although exocrine pancreatic function is intrinsically normal, reduced levels of cholecystokinin release as a result of the duodenal villous atrophy, accounts for impaired gall bladder contraction and reduced exocrine pancreatic secretion ²⁹⁾.

Diabetes mellitus

Diabetes mellitus can predispose to exocrine pancreatic insufficiency and, conversely, longstanding exocrine pancreatic insufficiency can be associated with diabetes ³⁰⁾. In diabetes, there are several possible causes which can account for exocrine pancreatic insufficiency – the lack of the trophic action of insulin (and potentially of glucagon and somatostatin) on acinar cells, autoimmune damage of islet cells, causing destruction of both endocrine and exocrine tissue, and decreased exocrine pancreatic secretion as a complication of diabetic neuropathy ³¹⁾. Therefore, the lack of insulin production and the autoimmunity in type I diabetes explain the higher observed prevalence of exocrine pancreatic insufficiency compared to those with type II diabetes (about 60% vs. 30%) ³²⁾. In addition, a recent article by Soave et al. ³³⁾ showed that the lower the immunoreactive trypsinogen levels at birth in newborns with cystic fibrosis, reflecting more severe exocrine pancreatic disease in utero, the earlier in life they developed cystic fibrosis-related endocrine disease (diabetes).

All infants

Based on the study by Lebenthal and Lee ³⁴⁾ indicating that the duodenal fluid of newborns and infants contained no amylase and negligible lipase at least for the first month of life, all healthy term infants are exocrine pancreatic insufficient. Normally, this is compensated for by amylase and lipase present in breastmilk. However, in formula-fed infants, exocrine pancreatic insufficiency would be expected. In fact, a recent study by Martin et al. ³⁵⁾ confirmed that formula-fed preterm infants had impaired fatty acid absorption evident through 6 or more weeks postnatal age compared to breastmilk-fed infants, and this is consistent with limited pancreatic lipase production by the pancreas ³⁶⁾. Thus, all infants, both term and preterm, represent the largest population of individuals with exocrine pancreatic insufficiency. The clinical implications of developmental pancreatic insufficiency in non-breast-fed infants is unknown, but may play a role in early nutrient deficits in critically ill newborns such as the preterm infant.

Exocrine pancreatic insufficiency symptoms

Symptoms of exocrine pancreatic insufficiency can include steatorrhea (clay-colored, loose, greasy, foul-smelling large stools), abdominal discomfort, bloating, and weight loss. Although floating stools are often thought of being indicative of steatorrhea, they are not; rather sticking to the toilet bowl is a more specific sign.

Exocrine pancreatic insufficiency diagnosis

A multitude of tests for exocrine pancreatic insufficiency have been developed over the past several decades and classified as direct versus indirect measures of exocrine pancreatic function. However, many of these have poor sensitivity or specificity (e.g. serum trypsin levels, qualitative stool fat) and/or are available at only limited centers such as with the 13C mixed triglyceride (13C-MTG) breath test.

72-hour fecal fat test

The gold standard has been the 72-hour stool collection while the patient consumes a diet containing 100 g of fat per day. Fat malabsorption is diagnosed at > 7 g of fat per 100 g of stool per day, with severe steatorrhea at ≥ 15 g per day ³⁷⁾. Unfortunately, this test is time-consuming and not easily tolerated due to bloating, abdominal discomfort, flatulence, and worsening steatorrhea. Additionally, errors can occur in stool collections and recording of fat intake ³⁸⁾. Diseases that impact mucosal fatty acid uptake, such as Crohn’s disease, bacterial overgrowth, and short bowel syndrome, can cause abnormal values despite normal exocrine pancreatic function. However, the 72-hour stool collection has served to measure the effectiveness of PERT in exocrine pancreatic insufficiency ³⁹⁾ for United States Food and Drug Administration (FDA) approval of PERTs.

Fecal elastase test

The pancreas produces pancreatic elastase 1, which is a highly stable enzyme during intestinal transit ⁴⁰⁾. This proteolytic enzyme can be measured in a fecal sample by an enzyme-linked immunosorbent assay ⁴¹⁾. Because pancreatic elastase is highly stable during intestinal transit, the fecal concentration correlates well with exocrine pancreatic secretion ⁴²⁾. Diagnostic testing using fecal elastase has some advantages over other tests because it does not require a timed stool collection or special diet, has a high negative predictive value, and has a high sensitivity in moderate to severe exocrine pancreatic insufficiency when formed stools are analyzed ⁴³⁾. The reference range of less than 200 μg/g feces can be applied to both children and adults for the diagnosis of exocrine pancreatic insufficiency ⁴⁴⁾. Some consider values less than 100 μg/g feces as diagnostic of exocrine pancreatic insufficiency, with fecal elastase values between 100 and 200 μg/g to be indeterminate and difficult to interpret ⁴⁵⁾.

In mild to moderate exocrine pancreatic insufficiency, diagnostic testing using fecal elastase has a lower sensitivity (as low as 30%) and specificity, possibly resulting in an underestimation of exocrine pancreatic insufficiency ⁴⁶⁾. In childhood, however, fecal elastase is a useful noninvasive screening test for exocrine pancreatic insufficiency, demonstrating a negative predictive value of 99% for ruling out exocrine pancreatic insufficiency ⁴⁷⁾. Since fecal elastase is measured as a concentration in stool, watery stools will almost invariably result in low elastase values being measured and thus this non-invasive, pancreatic function test should be performed in a clinical setting where exocrine pancreatic insufficiency is suspected and a formed stool can be analyzed. This has replaced the more cumbersome 72-hour fecal fat test. In addition, PERTs do not have to be stopped for fecal elastase testing since the porcine enzymes do not cross react with the human fecal elastase antibody.

Laboratory studies

A complete laboratory evaluation is required not only to diagnose exocrine pancreatic insufficiency but also to determine the extent of the malabsorption and assess manifestations of the underlying disease, if present.

Blood tests

These can include the following:

• Complete blood count (CBC). A complete blood count (CBC) may reveal microcytic anemia due to iron deficiency or macrocytic anemia due to vitamin B-12 or folate malabsorption. Serum iron, vitamin B-12, and folate concentrations may help establish the diagnosis of exocrine pancreatic insufficiency. Prothrombin time (PT) may be prolonged because of malabsorption of vitamin K, a fat-soluble vitamin. A study by Lindkvist et al found that serum nutritional markers (eg, magnesium, albumin, prealbumin) can be used to determine the probability of exocrine pancreatic insufficiency in patients with chronic pancreatitis ⁴⁸⁾.
• Antigliadin and antiendomysial antibodies. Serum levels of antigliadin and antiendomysial antibodies can be used to help diagnose celiac sprue. The serum immunoglobulin A (IgA) level can be assessed to rule out IgA deficiency.
• Malabsorption can involve electrolyte imbalances such as hypokalemia, hypocalcemia, hypomagnesemia, and metabolic acidosis. Protein malabsorption may cause hypoproteinemia and hypoalbuminemia. Fat malabsorption can lead to low serum levels of triglycerides, cholesterol, and alpha- and beta-carotene. The Westergren erythrocyte sedimentation rate (ESR) may provide a clue to an underlying autoimmune disease.

Stool tests

Determination of fecal elastase and chymotrypsin (2 proteases produced by the pancreas) can be used to try to distinguish between pancreatic causes and intestinal causes of malabsorption.

Malabsorption tests

These can include the following:

• Fat absorption tests. See 72-hour fecal fat test above.
• D-xylose test. If the 72-hour fecal fat collection results demonstrate fat malabsorption, the D-xylose test is used to document the integrity of the intestinal mucosa. D-xylose is readily absorbed in the small intestine. Approximately half of the absorbed D-xylose is excreted in urine without being metabolized. If absorption of D-xylose is impaired by either a luminal factor (eg, bacterial overgrowth) or a reduced or damaged mucosal surface area (eg, from surgical resection or celiac disease), urinary excretion will be lower than normal. Cases of pancreatic insufficiency usually result in normal urinary excretion because absorption of D-xylose is still intact.
• Carbohydrate absorption test. A simple sensitive test for carbohydrate malabsorption is the hydrogen breath test, in which patients are given an oral solution of lactose ⁴⁹⁾. In cases of lactase deficiency, colonic organisms digest the unabsorbed lactose, which results in an elevated hydrogen content in the expired air. Bacterial overgrowth or rapid transit also can cause an early rise in breath hydrogen, in which case it is necessary to use glucose instead of lactose to make a diagnosis. However, 18% of patients are hydrogen nonexcretors, in whom the hydrogen breath test will yield false-negative test results.
• Bile salt absorption test. The bile salt breath test can determine the integrity of bile salt metabolism. The patient is given an oral conjugated bile salt, such as glycine cholic acid with the glycine radiolabeled in the carbon position. The bile salt is deconjugated and subsequently metabolized by bacteria. If interrupted enterohepatic circulation (eg, from bacterial overgrowth, ileal resection, or disease), a radioactively labeled elevated breath carbon dioxide level will be noted.
• Schilling test. Malabsorption of vitamin B-12 may occur as a consequence of an intrinsic factor deficiency (eg, from pernicious anemia or gastric resection), pancreatic insufficiency, bacterial overgrowth, ileal resection, or disease. The 3-stage Schilling test can often help differentiate these conditions.
• C¹³-D-xylose breath test. A study by Hope et al suggested that small intestinal malabsorption in chronic alcoholism may be identified by means of a C¹³-D-xylose breath test ⁵⁰⁾. The investigators evaluated this test in 14 alcoholics, compared the results with those obtained from untreated celiac disease patients and healthy control subjects, and correlated the breath test findings with the morphologic findings from the duodenal mucosa. In this study, absorption of C¹³-D-xylose was significantly less in the alcoholic patients than in healthy control subjects, whereas the time curve of C¹³-D-xylose absorption in the alcoholics was similar to that in the untreated celiac patients ⁵¹⁾. In addition, although few changes were observed on light microscopy in the alcoholics, morphologic pathology (primarily reduced surface area of microvilli) was observed on electron microscopy in the majority of the patients.

Pancreatic function tests

These can include the following:

• Direct testing – Secretin test, cholecystokinin (CCK) test, secretin-CCK test
• Indirect testing – Qualitative fecal fat analysis, fecal elastase and fecal chymotrypsin level analysis

Pancreatic function can be measured directly by using endoscopy or the Dreiling tube method after stimulation with secretin or cholecystokinin (CCK). Direct pancreatic function testing is the most sensitive approach to assessment of exocrine pancreatic function and is usually performed at specialized centers ⁵²⁾. Various methods have been developed ⁵³⁾.

Direct testing

Whereas the cholecystokinin (CCK) test measures the ability of the acinar cells to secrete digestive enzymes, the secretin test measures the ability of the ductal cells to secrete bicarbonate. Although both tests yield abnormal results in advanced exocrine pancreatic insufficiency, it is not known which of the 2 secretagogues offers better sensitivity for early exocrine pancreatic insufficiency. In uncertain cases, both cholecystokinin (CCK) and secretin tests may be ordered.

Secretin test

In the secretin test, porcine or human synthetic secretin is given in doses ranging from 0.5 to 5 clinical units (CU)/kg. Duodenal fluid is continuously collected in 15-minute aliquots for 1 hour. The fluid is analyzed for bicarbonate concentration, volume, and total bicarbonate output.

A bicarbonate concentration lower than 80 mEq/L in all 4 aliquots represents exocrine insufficiency. A peak bicarbonate cutoff of 90 mEq/L has been advocated by some investigators. A peak bicarbonate concentration lower than 50 mEq/L is indicative of severe exocrine insufficiency. When the bicarbonate concentration is equivocal, volume and total bicarbonate output are used as secondary diagnostic parameters.

Cholecystokinin test

Use of a cholecystokinin (CCK) receptor agonist (eg, cerulein) as a hormonal stimulant provides information on pancreatic enzyme-secreting capacity. Two endoscopic tubes are placed: (1) a single-lumen gastric tube and (2) a double-lumen duodenal tube. The gastric tube continuously collects and discards gastric fluid to prevent acidification of the duodenum. One duodenal lumen continuously collects duodenal drainage fluid, whereas the other is used for administration of a mannitol-saline solution containing a nonabsorbable marker (polyethylene glycol [PEG]).

An accurate determination is made of enzyme concentration, enzyme output, and fluid volume on the basis of recovery of the PEG marker. Measurement of perfusion markers requires a specialized laboratory.

Secretin-cholecystokinin test

Many pancreatic research centers use the combined secretin-cholecystokinin (CCK) test, which allows simultaneous assessment of ductal and acinar secretory capacity. Many dosing regimens have been used for this test. The 2 hormones are administered, and the concentration and output of both bicarbonate and pancreatic enzymes are evaluated.

Indirect testing

Pancreatic function can also be measured indirectly. Qualitative fecal fat analysis via microscopic examination of random stool samples is used as a screening test only ⁵⁴⁾. In addition, measurement of fecal elastase and fecal chymotrypsin levels may serve as an indirect indicator of pancreatic function; however, sensitivity is limited to moderate or severe disease, and the result can be falsely positive as a result of dilution by watery stools ⁵⁵⁾. The typical findings in exocrine pancreatic insufficiency are increased fecal fat and decreased enzymes.

A prospective study by González-Sánchez et al suggested that with regard to sensitivity, specificity, and positive and negative predictive values, results from the fecal elastase-1 (FE-1) test are similar to those from the C¹³-mixed triglyceride breath test in the diagnosis of exocrine pancreatic insufficiency in chronic pancreatitis. However, the triglyceride breath test appeared to be more accurate than the FE-1 test in operated patients with chronic pancreatitis ⁵⁶⁾.

Abdominal imaging

Abdominal imaging can help in identifying features of chronic pancreatitis, which is the most common cause of exocrine pancreatic insufficiency.

Exocrine pancreatic insufficiency treatment

Management approaches to exocrine pancreatic insufficiency include the following ⁵⁷⁾:

• Lifestyle modifications (eg, avoidance of fatty foods, limitation of alcohol intake, cessation of smoking, and consumption of a well-balanced diet)
• Vitamin supplementation (primarily the fat-soluble vitamins A, D, E, and K)
• Pancreatic enzyme replacement therapy (PERT), which is the therapeutic mainstay

Long-term monitoring of patients with exocrine pancreatic insufficiency should focus on the following 2 issues:

• Correction of nutritional deficiencies
• Treatment of causative diseases (when possible); such treatment will vary according to the specific disease present

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 pancreatic enzyme replacement therapy (PERT), to effectively treat steatorrhea. However, in patients with cystic fibrosis, a high fat diet in conjunction with increased amounts of pancreatic enzyme replacement therapies (PERTs) has been shown to improve the associated cystic fibrosis 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 pancreatic enzyme replacement therapy (PERT) ⁵⁸⁾. Consulting a dietitian is helpful to assess nutritional adequacy ⁵⁹⁾. In addition, smoking has been proven to be a risk factor in acute pancreatitis, chronic pancreatitis, pancreatic cancer ⁶⁰⁾, and to be associated with reduced exocrine pancreatic function ⁶¹⁾. Therefore, smoking and alcohol cessation is recommended in exocrine pancreatic insufficiency 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 pancreatic enzyme replacement therapy (PERT) ⁶²⁾. This is most evident in cystic fibrosis, where prior to the availability of pancreatic enzyme replacement therapy (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 pancreatic enzyme replacement therapy (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 ⁶³⁾. 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 (Table 1) ⁶⁴⁾.

Table 1. Current Food and Drug Administration (FDA) approved pancreatic enzyme replacement therapies (PERTs)

Brand	Units of lipase
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

[Source ⁶⁵⁾ ]

Enteric-coated pancreatic enzymes are most effective at a pH > 6. However, in patients with cystic fibrosis, the duodenal pH is < 6 ⁶⁶⁾. The use of acid-suppression medications can increase gastric pH levels and theoretically improve the efficacy of pancreatic enzyme replacement therapy (PERT) and decrease exocrine pancreatic insufficiency symptoms ⁶⁷⁾. Current data may suggest a trial of acid blockers in patients with cystic fibrosis who have refractory steatorrhea ⁶⁸⁾. 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 cystic fibrosis ⁶⁹⁾.

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 ⁷⁰⁾. The addition of acid-suppression medications is required to prevent degradation of non-enteric coated pancreatic enzymes ⁷¹⁾. 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 exocrine pancreatic insufficiency ⁷²⁾; however, Kalnins et al. ⁷³⁾ 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 cystic fibrosis.

Dosing and frequency of pancreatic enzyme replacement therapy administration

Dosing and frequency of administration are difficult aspects of pancreatic enzyme replacement therapy (PERT) treatment since different enteric-coated microspheres are not bioequivalent in vitro ⁷⁴⁾ 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 pancreatic enzyme replacement therapy (PERT). The Australasian Pancreatic Club ⁷⁵⁾, The Italian Association for the Study of the Pancreas ⁷⁶⁾ and The Spanish Pancreatic Club ⁷⁷⁾ 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 ⁷⁸⁾. In addition, a study from the Netherlands by Sikkens et al. ⁷⁹⁾ found that 70% (n = 161) of the patients with exocrine pancreatic insufficiency caused by chronic pancreatitis were under-treated and reported steatorrhea-related symptoms, despite pancreatic enzyme replacement therapy (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 pancreatic enzyme replacement therapy (PERT) administration. In 1977, DiMagno et al. ⁸⁰⁾ demonstrated that administration of pancreatic enzyme replacement therapy (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 ⁸¹⁾, pancreatic enzymes during or immediately following the meal ⁸²⁾, or lastly, 25% of the enzymes with the first bite, 50% during the meal, and 25% with the last bite ⁸³⁾. 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 pancreatic enzyme replacement therapy (PERT) before meals, during meals, or after meals using the 13C-MTG breath test to measure fat absorption ⁸⁴⁾. 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 pancreatic enzyme replacement therapy (PERT) during or after meals.

In a patient with suspected exocrine pancreatic insufficiency with a known history of pancreatic disease, empiric therapy with pancreatic enzyme replacement therapy (PERT)s may be indicated without formal testing. A clear response would be both diagnostic for exocrine pancreatic insufficiency as well as therapeutic. In addition, if there is a poor response to pancreatic enzyme replacement therapy (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 ⁸⁵⁾. Other reasons could be insufficient dosing, lack of compliance, inadequate timing of pancreatic enzyme replacement therapy (PERT) administration, and poor diet (Table 2).

Table 2. Treatment strategies for lack of response to pancreatic enzyme replacement therapy (PERT)

Treatment strategies
• 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

[Source ⁸⁶⁾ ]

Pancreatic enzyme replacement therapy (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 pancreatic enzyme replacement therapy (PERT) capsules consumed should reflect this. Table 3 gives a suggested clinical overview of pancreatic enzyme replacement therapy (PERT) dosing for different age groups ⁸⁷⁾.

Table 3. Pancreatic enzyme replacement therapy (PERT) suggested dosing in different age groups

Age group	Units of lipase
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

[Source ⁸⁸⁾ ]