Exocrine Pancreatic Insufficiency

The pancreas, named for the Greek words pan (all) and kreas (flesh), is a soft, lobulated, retroperitoneal organ that is 12-15 cm long and roughly J-shaped (like a hockey stick). It lies transversely, though a bit obliquely, on the posterior abdominal wall behind the stomach, across the lumbar (L1-2) spine (see the image below). The pancreas is prismoid in shape and appears triangular in cut section, with superior, inferior, and anterior borders as well as anterosuperior, anteroinferior, and posterior surfaces.

Pancreas anatomy.

The head of the pancreas lies in the duodenal C loop in front of the inferior vena cava (IVC) and the left renal vein (see the images below). The uncinate process is an extension of the lower (inferior) half of the head toward the left; it is of varying size and is wedged between the superior mesenteric vessels in front (the vein on the right and the artery on the left) and the aorta behind. The pancreatic head constitutes about 50% of the pancreatic parenchymal mass.

The duodenum and pancreas.

The pancreas and duodenum, posterior view.

The body and tail of the pancreas run obliquely upward to the left in front of the aorta and the left kidney. The pancreatic neck is the arbitrary junction between the head and body of the pancreas. The narrow tip of the tail of the pancreas reaches the splenic hilum in the splenorenal (lienorenal) ligament. The body and tail make up the remaining 50% of the pancreatic parenchymal mass.

The transverse mesocolon (with the middle colic vessels in it) is attached to the anterior surface of the lower (inferior) surface of the body and tail; thus, most of the gland is located in the supracolic compartment. The body and tail of the pancreas lie in the lesser sac (omental bursa) behind the stomach.

The GI tract is responsible for digesting and absorbing food.[8] Lipids provide the richest source of energy for the body, with 9 calories in every gram of fat; in comparison, carbohydrate and protein contains 4 calories per gram. Whereas protein and carbohydrate begin to undergo digestion in the stomach, triglycerides remain mostly unchanged until they reach the small intestine. Intragastric breakdown accounts for approximately 10% of total lipid digestion.[8]

The pancreatic enzymes responsible for lipid digestion are inactivated when the pH drops below 5; thus, before digestion can continue in the duodenum, the acidic contents of the stomach must be neutralized. Fortunately, the pancreas also secretes bicarbonate, which increases the pH of the duodenal contents.

The exocrine pancreas produces 3 main types of enzymes: amylase, protease, and lipase.[3] Under normal physiologic conditions, lipase breaks the undigested triglycerides into fatty acids and monoglycerides. Bile salts then solubilize these breakdown products to form micelles, which are vehicles for absorbing lipid breakdown products.[8] Normal fat digestion also depends on postprandial synchrony between delivery of nutrients to the duodenum and discharge of pancreatic enzymes.[3]

Pancreatic secretion is governed by neural and hormonal mechanisms. The hormones responsible for regulation are secretin and cholecystokinin (CCK). Secretin is secreted in response to acid in the duodenum, causing duct cells to release water and bicarbonate; CCK is secreted in response to protein and fat in the small intestine, stimulating acinar cells to release the pancreatic enzymes (see the image below).

Factors controlling release of pancreatic secretions. Image courtesy of Wikimedia Commons.

EPI is characterized by a deficiency of these exocrine pancreatic enzymes, which results in inability to digest food properly (ie, maldigestion). Because pancreatic lipase accounts for up to 90% of fat digestion, maldigestion of fat is more profound in EPI than maldigestion of proteins and carbohydrates is.[8] Because the exocrine pancreas retains a large reserve capacity for enzyme secretion,[8] fat digestion is not clearly impaired until lipase output decreases to below 10% of the normal level.[4]

Fat malabsorption precedes malabsorption of other macronutrients.[9] Bile salt precipitation and subsequent adsorption to undigested food reduces the bile salt pool, and this reduction further impairs fat digestion.[10] Undigested fat, rather than being absorbed, is excreted in the feces, leading to steatorrhea.

Another factor that contributes to pancreatic steatorrhea is the presence of neurohormonal disturbances, which result in gall bladder hypomotility and accelerated gastric and intestinal transit.[11] Malabsorption of fat-soluble vitamins A, D, E, and K may accompany EPI.

The etiology of EPI can be classified into pancreatic and nonpancreatic causes.[12, 13]

Pancreatic causes

These include the following:

• Chronic pancreatitis (the most common cause of EPI) - This condition has a number of possible causes, but the end result is a metabolic insult to the pancreatic exocrine cells that leads to necrosis, fibrosis and loss of function (see the image below).

  Residual islets in dense fibrous stroma secondary to loss of exocrine pancreatic tissue in chronic pancreatitis (hematoxylin-eosin stain, medium magnification). Image courtesy of Dr. Rose Anton.

• Acute pancreatitis - A literature review by Huang et al found that during first admission for acute pancreatitis (ie, the time between the commencement of oral refeeding and discharge) in 370 patients, exocrine pancreatic insufficiency (EPI) had a pooled prevalence of 62%. At follow-up (1 month or more following discharge for a first attack of acute pancreatitis) in 1795 patients, the pooled prevalence of EPI was 35%. The investigators also found at follow-up that compared with mild acute pancreatitis, the pooled prevalence for EPI was twice as great for severe acute pancreatitis (21% vs 42%, respectively).[14]

• Cystic fibrosis - In this condition, reduced chloride transport in the pancreas leads to reduced water content of secretions, precipitation of proteins, and plugging of ductules and acini, preventing the pancreatic enzymes from reaching the gut; autodigestion of the pancreas occasionally leads to pancreatitis.

• Obstructions of the pancreatic duct (eg, from pancreatic cancer or ampullary tumors) - These hinder pancreatic exocrine secretions from reaching the gut.

• Shwachman-Diamond syndrome (SDS) - This is a rare autosomal recessive disorder characterized by EPI, bone marrow dysfunction, leukemia predisposition, and skeletal abnormalities.[15, 16]

• Diabetes - A study by Yatchenko et al suggested that EPI in type 2 diabetes mellitus derives from the effects of high insulin levels on pancreatic acinar cells. The investigators found evidence that high insulin concentrations impact naïve acinar cells via the activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1) pathways, leading to activation of the endoplasmic reticulum–stress unfolded protein response (UPR).[17]

Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel (see the image below) and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces.

Defective protein transmembrane conductance regulator (CFTR) in cystic fibrosis.

Nonpancreatic causes

Celiac disease

Celiac disease (secondary to decreased pancreatic stimulation) leads to EPI in about one third of patients and may be an unrecognized cause of treatment failure.

Crohn disease

Crohn disease is associated with pancreatic autoantibodies that lead to impaired pancreatic exocrine function.

Autoimmune pancreatitis

Autoimmune pancreatitis is often caused by immunoglobulin G4 (IgG4)-related disease and can progress to EPI.[18]

Zollinger-Ellison syndrome

Zollinger-Ellison syndrome can produce EPI through acid inactivation of pancreatic enzymes; it is corrected by controlling the acid secretion

GI and pancreatic surgical procedures

Any such procedures that lead to loss of postprandial synchrony, decreased pancreatic stimulation, and loss of pancreatic parenchyma can cause EPI.[19] A study by Huddy et al found that EPI contributes to postoperative morbidity in patients who undergo esophagectomy.[20]  Using multivariate analysis, a study by Dhar et al indicated that in patients with chronic pancreatitis who undergo duodenum-sparing head resection or pancreaticoduodenectomy to relieve abdominal pain, EPI and narcotic requirement are the only predictors of the need for revision surgery.[21]

A study by Okano et al suggested that following pancreatectomy, a remnant pancreatic volume of under 24 mL is the only independent predictor of postoperative EPI. The study included 227 patients.[22]

However, a study by Hallac et al indicated that in patients who undergo distal pancreatectomy, the chance of developing de-novo exocrine pancreatic insufficiency (EPI) is greater in those with an underlying obstructive pancreatic pathology and in individuals who present with a history of acute pancreatitis. The investigators found that new-onset EPI arose in 38 of 324 patients (11.7%), while EPI existed preoperatively in 22 (6.8%) of patients, suggesting that patients set to undergo pancreatectomy may not uncommonly have preexisting EPI.[23]

Because EPI has multiple possible causes and is not usually recorded as a medical statistic, its prevalence and demographics cannot be established with certainty at present. In a German-based study, one of the most common causes of EPI had an age-adjusted prevalence of 8 per 100,000 for males and 2 per 100,000 for women; these numbers are probably relatively close to the prevalence of EPI in most developed countries. No other reliable data are currently available.[24]

The natural history and progression of EPI depend on the underlying etiology. For example, patients with autoimmune pancreatitis or cystic fibrosis may progress to almost complete insufficiency, whereas those with alcohol-induced EPI may recover from or at least halt the progression of pancreatic insufficiency if they abstain from alcohol. Even with complete loss of exocrine function, however, protease and lipase supplements are effective in restoring normal digestion of dietary nutrients.

A prospective, longitudinal cohort study by de la Iglesia et al indicated that in patients with chronic pancreatitis, EPI is an independent risk factor for cardiovascular events, with the incidence rate ratio for such events in patients with EPI compared with those without being 3.67. In addition, the odds ratio for cardiovascular events in individuals with a combination of EPI and diabetes mellitus was higher than for EPI patients without diabetes.[25]

A study by Vujasinovic et al indicated that in patients with chronic pancreatitis, EPI is an independent risk factor for nephrolithiasis. The investigators found that the adjusted hazard ratio (aHR) for kidney stones in chronic pancreatitis patients with EPI is 4.95. Male sex and an increase in body mass index (BMI) were also determined to be risk factors for stone formation, the aHRs being 4.51 and 1.16, respectively.[26]

The major symptoms of exocrine pancreatic insufficiency (EPI) include steatorrhea and weight loss. The most common symptomatic complaint is steatorrhea, which is fatty diarrhea, but sometimes the stool can be watery, reflecting the osmotic load received by the intestine.

Steatorrhea is the result of fat malabsorption and is characterized by pale, bulky, and malodorous stools. These stools often float on top of the toilet water with oily droplets and are difficult to flush.

Weight loss and fatigue are common and may be pronounced; however, patients may compensate by increasing their caloric consumption, and as a result, weight loss from malabsorption may be masked. The weight loss may be compounded by an underlying disease involving the intestine (eg, celiac disease or Crohn disease).

Flatulence and abdominal distention are caused by bacterial fermentation of unabsorbed food substances, which releases gaseous products such as hydrogen and methane. Flatulence often causes uncomfortable abdominal distention and cramps.

Edema may result from hypoalbuminemia caused by chronic protein malabsorption; loss of protein into the intestinal lumen can cause peripheral edema. With severe protein depletion, ascites may develop.

Anemia resulting from malabsorption can be either microcytic (related to iron deficiency) or macrocytic (related to vitamin B-12 deficiency). Anemia may also be associated with the underlying disease causing EPI. For instance, iron deficiency anemia is often a manifestation of celiac disease. Ileal involvement in Crohn disease or ileal resection can cause megaloblastic anemia due to vitamin B-12 deficiency.

Bleeding disorders are usually a consequence of vitamin K malabsorption and subsequent hypoprothrombinemia. Ecchymosis usually is the manifesting symptom, though melena and hematuria may occur on occasion.

Metabolic bone disease caused by vitamin D deficiency can result in osteopenia or osteomalacia. In severe cases, bone pain and pathologic fractures occur with low calcium levels leading to secondary hyperparathyroidism.

Neurologic manifestations can result from electrolyte disturbances (eg, hypocalcemia and hypomagnesemia) and can lead to tetany. Malabsorption of certain vitamins can cause generalized motor weakness (pantothenic acid and vitamin D), peripheral neuropathy (thiamine), loss of a sense of vibration and position (cobalamin), night blindness (vitamin A), or seizures (biotin).

Signs of weight loss, muscle wasting, and loss of subcutaneous fat are often noted.

On abdominal examination, orthostatic hypotension may be present. The abdomen may be distended, and bowel sounds may be hyperactive. In severe hypoproteinemia, ascites may be present. Peripheral edema may be observed.

On dermatologic examination, pale skin may reflect anemia. Ecchymoses due to vitamin K deficiency may be apparent. Dermatitis herpetiformis, erythema nodosum, and pyoderma gangrenosum may be noted. Pellagra, alopecia, or seborrheic dermatitis may be present. Examination of the mouth may reveal cheilosis, glossitis, or aphthous ulcers.

On neurologic examination, motor weakness, peripheral neuropathy, or ataxia may be present. The Chvostek sign or the Trousseau sign may be noted as a consequence of hypocalcemia or hypomagnesemia.

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

Blood tests

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 EPI. 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 EPI in patients with chronic pancreatitis.[27]

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.

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.

Stool tests

Determination of fecal elastase (a protease that is produced by the pancreas and that remains intact in the stool) can be used to support the clinical diagnosis of EPI.

Tests of malabsorption

A full malabsorption workup is required to differentiate EPI from other causes of malabsorption. Such a workup may include a number of tests, as follows.

Fat absorption tests

A fat absorption test is usually the first one ordered because there are many disease processes that can result in fat malabsorption. For quantitative measurement of fat absorption, a 72-hour fecal fat collection is often performed and is considered the standard. Qualitative tests include the acid steatocrit test and Sudan III stain of stool, but these tests are less reliable.

Patients are instructed to consume a normal amount (80-100 g/day) of fat before and during the collection. On the basis of this level of intake, fecal fat excretion in healthy individuals should be less than 7 g/day.

The current standard for measuring fat malabsorption is the coefficient of fat absorption (CFA),[12] which is the percentage of absorbed fat in the diet. Normally, the CFA is approximately 90%. The various diseases that can give rise to EPI will produce different degrees of pancreatic insufficiency and, hence, different CFAs. For example, cystic fibrosis often results in a CFA lower than 40%, which typically increases to more than 80% with therapy.

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.[28, 29] 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.

13C-D-xylose breath test

A study by Hope et al suggested that small intestinal malabsorption in chronic alcoholism may be identified by means of a13 C-D-xylose breath test.[30] 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 of13 C-D-xylose was significantly less in the alcoholic patients than in healthy control subjects, whereas the time curve of13 C-D-xylose absorption in the alcoholics was similar to that in the untreated celiac patients.[30] 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 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.[6] Various methods have been developed.[31]

Direct testing

Whereas the 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 EPI, it is not known which of the 2 secretagogues offers better sensitivity for early EPI. In uncertain cases, both 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.

CCK test

Use of a 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-CCK test

Many pancreatic research centers use the combined secretin-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.[32] In addition, measurement of fecal elastase 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 owing to dilution by watery stools.[6] The typical findings in EPI 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 13C-mixed triglyceride breath test (TGBT) in the diagnosis of EPI in chronic pancreatitis. However, the TGBT appeared to be more accurate than the FE-1 test in operated patients with chronic pancreatitis.[33]

Abdominal imaging (see the image below) can help in identifying features of chronic pancreatitis, which is the most common cause of EPI. Because fat maldigestion is not evident until pancreatic lipase secretion falls below 10% of normal, some patients with confirmed chronic pancreatitis may not have the signs and symptoms of EPI.

Complete replacement of the pancreas with cystic disease and intrahepatic biliary dilation caused by extrinsic compression of the common bile duct. Note also the renal cysts and masses. This patient had exocrine pancreatic insufficiency. Image courtesy of Wikimedia Commons.

 A study by Saad et al indicated that in pediatric patients, a smaller pancreas parenchymal volume on magnetic resonance imaging (MRI) serves as a marker for exocrine and endocrine pancreatic dysfunction. The likelihood that exocrine pancreatic dysfunction would be diagnosed by endoscopic pancreatic function testing (ePFT) or fecal elastase testing was found to be greater in children whose pancreas parenchymal volume was reduced by 5 mL, the odds ratios (ORs) for such diagnosis in ePFT and fecal elastase testing both being 1.16. For the subset of patients without acute pancreatitis, the ORs were 1.29 and 1.23, respectively.[34]

Management approaches to exocrine pancreatic insufficiency (EPI) include the following[12, 35] :

• 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 EPI 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

PERT is the basis of treatment of EPI[36, 37] ; the endpoints of treatment are normalization of gut absorption and correction of nutritional deficiencies. The typical indications for initiating PERT are progressive weight loss and steatorrhea.

A literature review by de la Iglesia-García et al indicated that PERT can be effective against EPI and malnutrition associated with chronic pancreatitis. The investigators found PERT-associated improvement in the coefficient of fat absorption (CFA), as well as in serum nutritional parameters, GI symptoms, and quality of life. It was also determined that PERT’s efficacy may be increased through the use of higher enzyme doses and enteric-coated enzymes, the administration of therapy during food, and the suppression of acid.[38]

Similarly, a study by Erchinger et al indicated that in chronic pancreatitis patients with EPI, PERT diminishes fecal energy and fat loss, with the investigators finding that this reduction reached significance on a maximum PERT dose of 75,000 U per meal.[39]

Approved agents

The pancreatic enzyme products (PEPs) used for PERT are extracts of porcine pancreas that contain all 3 pancreatic enzymes (ie, amylase, protease, and lipase) in varying proportions. However, it is lipase that plays the paramount role in therapy. The following 6 PEPs have been approved by the US Food and Drug Administration (FDA) for the treatment of maldigestion in patients whose bodies do not produce sufficient pancreatic enzymes:

• Creon (Abbott Laboratories, North Chicago, IL)

• Zenpep (Eurand Pharmaceuticals, Yardley, PA)

• Pancreaze (Janssen Pharmaceuticals, Titusville, NJ)

• Ultresa (Aptalis Pharma US, Birmingham, AL)

• Viokace (Aptalis Pharma US, Birmingham, AL)

• Pertzye (Digestive Care, Bethlehem, PA)

These PEPs are not interchangeable. For example, Viokace, unlike the other 5 products, lacks an enteric coating and must be taken with a proton pump inhibitor.

Because exogenous pancreatic enzymes should exert their action on the ingested meal and because gastric emptying of nutrients should occur in parallel with pancreatic enzymes reaching the duodenum, PEPs are administered together with meals and snacks. When a sufficient enzyme concentration is delivered into the duodenal lumen simultaneously with a meal, fat absorption is enhanced.

PEP dosing for PERT is based on the content of lipase units (see Table 1 below). The pancreatic lipase replacement dose should be adjusted on the basis of body weight, clinical symptoms, and stool fat content. Several days should be allowed between dose adjustments.

Table 1. Lipase Content of Currently Available Pancreatic Enzyme Products (Open Table in a new window)

The total daily dose is based on the assumption that the patient will have about 3 meals/day and 2-3 snacks/day, with half the mealtime dose given with a snack. Lipase doses larger than 2500 units/kg/meal (or dosages exceeding 10,000 units/kg/day) should be used with caution and only when supported by documentation of 3-day fecal fat measures. Lipase doses larger than 6000 units/kg/meal are associated with colonic stricture and should be reduced.

Dosing for pancreatic insufficiency is as follows:

• Initial oral lipase dose, 500 units/kg/meal

• Lipase dose range, 500-2500 units/kg/meal

• Maximum lipase dosage, 10,000 units/kg/day or 4000 units per gram of fat daily

Dosing for pancreatic insufficiency due to chronic pancreatitis or pancreatectomy is as follows:

• Oral lipase dose, 72,000 units/meal with consumption of at least 100 g of fat daily

• Alternatively, lower initial lipase doses (500 units/kg/meal) with individualized dose titration may be considered

In a double-blind, randomized, multicountry, placebo-controlled, parallel-group trial enrolling 54 patients aged 18 years or older with confirmed EPI due to chronic pancreatitis or pancreatic surgery, Whitcomb et al found that Creon delayed-release 12,000–lipase unit capsules were effective in treating fat and nitrogen maldigestion, with a treatment-emergent adverse event rate similar to that of placebo.[40]

In an open-label extension of this study, the investigators determined that pancrelipase was well tolerated over 6 months and resulted in statistically significant weight gain and reduced stool frequency in patients with EPI due to chronic pancreatitis or pancreatic surgery who were previously managed with standard PERT.[41]

Toskes et al carried out a randomized, double-blind, dose-response, crossover study in which the effect of Zenpep on the coefficient of fat absorption was investigated with a placebo run-in (7-9 days) and 2 treatment periods (9-11 days) consisting of a high dose (7 × 20,000 lipase units/day) and a low dose (7 × 5000 lipase units/day).[42] The results suggested that chronic pancreatitis patients with EPI benefit from a low dose, whereas a high dose might be needed for patients with more severe EPI.

In a randomized, placebo-controlled PERT withdrawal study evaluating the efficacy and safety of Pancreaze in cystic fibrosis patients with EPI, Trapnell et al found that the agent effectively improved fat absorption and protein absorption in these patients without giving rise to unexpected adverse events.[43]

A study examining the use of endoscopic therapy in patients with chronic pancreatitis determined that although this therapy is most useful in patients with pancreatic duct stones and dilation and should be used as first-line treatment for those patients, it cannot be recommended as the treatment of choice for all patients with chronic pancreatitis.[44]

Investigational therapy

Liprotamase is a biologically engineered nonporcine PERT agent that has been advocated for the treatment of EPI associated with cystic fibrosis and pancreatectomy. In January 2011, the FDA withheld approval of the drug, citing the need for further study.

In a subsequently published phase III 12-month open-label trial designed to assess the safety, tolerability, and long-term nutritional effects of liprotamase in 215 patients with cystic fibrosis and EPI aged 7 years and older, Borowitz et al reported that treatment with a mean of 5.5 capsules of liprotamase per day during meals and snacks for up to 12 months was safe and well tolerated and was associated with age-appropriate growth and weight gain or weight maintenance.[45]

Guidelines concerning the diagnosis, etiology, and management of pancreatic exocrine insufficiency (PEI) were voted on by pancreatic specialists at the 2019 Annual Meeting of the Pancreatic Society of Great Britain and Ireland and published in 2021. Some, but not all, of the recommendations are listed below[46] :

• The FE-1 test is recommended as a suitable first-line PEI exam, despite the fact that the gold-standard diagnostic test for PEI is considered to be the coefficient of fat absorption
• If a diagnosis of PEI is unclear, it can be supported by employing positive markers of malnutrition, including clinical history, anthropometric measurements, or serum micronutrient levels (such as magnesium, vitamin E, and retinol-binding protein/vitamin A); when diagnosing PEI, however, do not consider these markers in isolation
• It is recommended that PERT commence at a dose of at least 50,000 units lipase with meals and 25,000 units lipase with snacks; if this is ineffective, dose adjustment by the patient should be encouraged
• Patients should spread pancreatic enzyme consumption throughout a meal
• Patients should avoid diets that are very high in fiber, but restriction of dietary fat is not routinely recommended
• No significant complications are associated with PERT
• PERT’s efficacy is impacted by acid and temperature; if PERT is ineffective, a proton pump inhibitor can boost its usefulness, but if, after addition of the inhibitor, one of the PERT agents is still not effective, it is recommended that a trial be conducted of an alternative PERT preparation
• With limited evidence suggesting an association between long-term use of very–high-dose PERT and fibrosing colonopathy in children with cystic fibrosis, doses in this population should be restricted to 10,000 units lipase/kg/day

The goals of pharmacotherapy are to improve the digestion and absorption of nutrients, to reduce morbidity, and to prevent complications.

Class Summary

Pancreatic enzyme products (PEPs) are a combination of porcine-derived amylases, lipases and proteases and are used to treat exocrine pancreatic insufficiency (EPI). They mimic digestive enzymes secreted by the pancreas and act in the duodenum and proximal small intestine. They catalyze the hydrolysis of starches into dextrins and short-chain sugars such as maltose and maltriose; fats into monoglycerides, glycerol, and free fatty acids; and proteins into peptides and amino acids.

Creon, Pancreaze, Pertzye, Ultresa, Viokace, Zenpep are the only PEPs that have been approved by the US Food and Drug Administration (FDA) for marketing in the United States.[47, 48]

Pancrelipase (Creon, Pancreaze, Pertzye, Ultresa, Viokace, Zenpep)

With the exception of Viokace, all PEPs have enteric coatings and are used to treat EPI due to cystic fibrosis or other conditions. Viokace is used in combination with a proton pump inhibitor to treat pancreatic insufficiency due to chronic pancreatitis or pancreatectomy.

The PEPs are not interchangeable. When a patient is switched to a new PEP, the dose must be started at a similar amount of lipase units and then titrated according to patient response. It may take 1-2 weeks for the patient to adjust to new PEP dose, which can vary.