Exocrine pancreatic insufficiency (EPI) is characterized by the maldigestion of macronutrients and micronutrients as a result of inadequate intraduodenal pancreatic exocrine enzyme delivery. Manifestations of EPI include steatorrhea, malnutrition, trace element and vitamin deficiency, abdominal discomfort, bloating, and metabolic bone disease, which ultimately can lead to a significant decrease in quality of life ^{1, 2} . The symptoms and manifestations of EPI are not specific and are shared with other common gastrointestinal conditions. This can lead to a lack of recognition and a lack of diagnostic testing in many patients. Even in those who are correctly diagnosed, many are not treated with appropriate dosages of pancreatic enzyme replacement therapy (PERT).

One central challenge in accurate diagnosis is the lack of a highly accurate diagnostic test for EPI. The diagnostic tests that are available are generally difficult to perform, inaccurate, or non-specific. Diagnostic testing can be directed at documenting the presence of maldigestion in general or at measuring pancreatic enzyme output directly or indirectly. The gold standard for diagnosing maldigestion, or malabsorption, has been 72-hour fecal fat testing. In this study, patients ingest a high-fat diet (of known fat content) for 5 days, with collection of stool output over the last 3 days. In the normal state, on a 100 g fat/day diet, at least 93% of dietary fat is absorbed ³ . This test is difficult or impossible in a routine clinical setting, given that it is heavily reliant on accurate recording of fat intake and stool collection over 3 days. Additionally, given this test signifies only malabsorption of fat, it does not isolate the pancreas as the cause of the abnormality. Another way to diagnose EPI is by administering some type of test meal which requires digestion by pancreatic enzymes and measuring the presence of metabolites of the test substance. The usage of these tests is not common in the US (Lundh test meal); however, they are still utilized at several sites throughout Europe. Breath tests to measure fat digestion by pancreatic lipase have a role as an alternative in the diagnosis of EPI ^{4– 6} ; however, they are not widely available and accuracy seems to be similar to the testing of fecal elastase ⁷ . Direct quantification of pancreatic ductal secretion of bicarbonate after secretin stimulation is available, but this test does not measure digestive enzyme secretion from acinar cells. Measuring enzyme output with duodenal tubes, after stimulation with the hormone cholecystokinin, is not currently performed in the US.

Unfortunately, the only currently available test for EPI is the measurement of elastase levels in stool samples ⁸ . The test is performed on a single solid or semi-solid stool sample. The test, although called fecal elastase-1, does not actually measure elastase-1, as this is transcriptionally silenced in humans ^{9, 10} . The test actually measures chymotrypsin-like elastases (CELA) 3A and 3B. Other pancreatic enzyme levels (chymotrypsin) can also be measured in stool, but these are not as stable during intestinal passage and are far less accurate. The advantages of fecal elastase measurement include lack of requirement of timed stool collection or a prerequisite for specific diet prior to testing. Moreover, it is widely accessible and can be performed while a patient is taking PERT (the assay measures human CELA3A and 3B and does not cross-react with porcine replacement products). The accuracy of the test depends on the chosen cut-off. It has reasonable sensitivity in advanced or severe EPI if a cut-off of <100 mcg/g of stool is chosen. Levels above 200 mcg/g stool are normal, and levels between 100 and 200 are indeterminate ¹¹ . Many shortcomings of this test exist and include high false positive rates dependent on cut-off levels chosen, stool consistency at the time of sampling (may be falsely low in watery stool because of dilution), and low fecal elastase in advanced age and other medical conditions such as chronic kidney disease or diabetes mellitus (DM). Therefore, the diagnosis of EPI is often heavily reliant on the identification of patients who are at increased risk and who present with suggestive clinical symptoms.

While chronic pancreatitis (CP) is the most well-known cause of EPI, other common etiologies include cystic fibrosis, pancreatic cancer, and pancreatic resection for benign or malignant disease. Less commonly known are a number of additional conditions which may also have EPI as a consequence ¹² . Because of an increase in morbidity associated with this condition, and mortality correlated with malnutrition ¹³ , therapy has been targeted to replace or augment underlying exocrine enzyme deficiency by oral PERT. The principles of PERT are to supply a level of enzyme sufficient to aid in adequate digestion and absorption of fat and fat-soluble vitamins, leading to improvement in signs and symptoms associated with EPI ¹⁴ . However, given the complexity associated with optimal dosing of PERT, due to variability in both an individual’s meal fat content and residual pancreatic function, there still remains inconsistency amongst medical professionals over optimal administration and potential benefit. The aim of this review is to identify patients who are at high risk for the development of EPI, analyze symptoms and consequences of this syndrome, review rationale for enzyme replacement, and examine evidence-based protocols for treatment optimization.

Symptoms of EPI develop when approximately 90% of the exocrine function of the pancreas is lost, with manifestations that include steatorrhea (often without diarrhea), abdominal bloating, weight loss, various vitamin deficiencies, and metabolic bone disease. Although patients with EPI may not digest fat, protein, and carbohydrates efficiently, malabsorption of fat appears to be the most clinically impactful. There are a number of reasons for this, including the susceptibility of lipase to inactivation and alternative mechanisms for protein and carbohydrate digestion. Ongoing fat malabsorption leads to nutritional deficiencies of fat-soluble vitamins (A, D, E, and K) along with possible deficiencies of calcium, folic acid, magnesium, thiamine, and zinc. As a result of decreased absorption of vitamin D, patients with EPI are at high risk of developing osteopenia or osteoporosis due to decreased bone mineral density ^{37, 38} . The prevalence of overall osteopathy (osteopenia and osteoporosis) is more than 60% in patients with CP, with one in four patients having osteoporosis ³⁹ . As a result, initial and serial bone mineral density testing should be done in all patients with EPI, along with baseline evaluation of nutritional status and periodic measurements of fat-soluble vitamins ( Table 1).

Treatment of EPI consists of providing activated digestive enzymes to the duodenum during the prandial and post-prandial period. In normal health, most fat and fat-soluble vitamin absorption occurs in the duodenum, with significantly less in the jejunum. The human pancreas in healthy adult subjects is estimated to produce at least 900,000 USP units of lipase with every meal. This amount is actually significantly more than is necessary for relatively normal digestion of fats, and it is estimated approximately 10% of this is required to have adequate digestion of nutrients. This would suggest at least 90,000 USP units of lipase would need to be prescribed with each meal. When prescribing PERT, however, the full 90,000 USP units of lipase may not be required given that many patients retain some residual secretion of lipase from the pancreas. In addition, there may be a compensatory increase in gastric lipase secretion of variable degree, which may also provide some improvement in digestion. Despite these considerations, a minimal starting dosage of at least 40,000 to 50,000 USP units of lipase with each meal and half with snacks is recommended ( Table 2). If there is concern for inadequate response, the dosage can be adjusted to 90,000 USP units with each meal, or more if needed.

Enzyme supplements need to be administered during the meal. A typical regimen is to divide the pills so that they are taken during both the early and the late portion of the meal (e.g. half of the pills after a few bites, and the rest of the pills as the final few bites are ingested). Clinical effectiveness is best determined by the demonstration of steatorrhea improvement, but this is rarely feasible. Instead, improvements in visible steatorrhea, fat-soluble vitamin levels, nutritional indices (e.g. retinol-binding protein), muscle strength, and quality of life provide surrogate measures of success. In those patients who seem to be failing therapy, the most common indication is non-compliance (sometimes owing to cost), wrong timing of ingestion, or inadequate dosage.

In some individuals, an inadequate response to PERT can also be due to inactivation of lipase by gastric acid. This is particularly an issue when using the non-enteric-coated oral PERT preparation, which requires simultaneous acid-reducing agents to be taken. Some data suggest that acid-reducing agents might even increase the overall efficacy of enteric-coated enzyme formulations, allowing them to be released from their pH-sensitive delivery systems more proximally in the small intestine, where fat absorption normally occurs ⁴⁰ . In those who continue to fail PERT therapy and/or lose weight, consideration should be given to alternative diagnoses including small intestinal bacterial overgrowth ^{41, 42} , the development of secondary pancreatic or non-pancreatic malignancy, or an unrelated condition such as celiac disease.

In a large meta-analysis by de La Iglesia-Garcia et al. ⁴³ , treatment with PERT in patients with CP improved both fat and protein absorption. Additionally, PERT was seen to improve symptoms of abdominal pain, flatulence, and stool consistency. Although similar results were not seen in a previous Cochrane review ⁴⁴ , this may have been because only two relevant studies were included at the time. In the more recent meta-analysis of 14 randomized controlled trials (RCTs), PERT appears to have clear nutritional and symptomatic benefit in patients with EPI.

The therapeutic effects of PERT appear to go beyond the resolution of steatorrhea and weight loss alone. In a large prospective longitudinal cohort study in patients with CP, EPI has been shown to be an independent risk factor for mortality ⁴⁵ . Although the impact of PERT was not directly assessed in this study, an analysis of CP patients who were receiving PERT following pancreatic surgery showed improved survival ⁴⁵ . Similarly, improved survival outcomes have been shown in multiple large cohort studies in patients using PERT following pancreatic cancer surgery ^{46– 48} . Quality of life has also been assessed; however, no long-term RCTs exist for this outcome. Nevertheless, in one open label 51-week extension of a previous double blind RCT of PERT in the treatment of EPI, quality of life was seen to significantly improve from baseline ⁴⁹ . Significant data also exist on the benefit of PERT in pancreatic cancer. Of note, one recent population-based analysis demonstrated improved survival in pancreatic cancer patients receiving PERT, in which survival time more than doubled ⁵⁰ . This benefit of PERT was equivalent to the survival advantage of receiving chemotherapy or undergoing surgery for pancreatic cancer.

The benefits in treatment of EPI have led to practice guideline recommendations for the use of PERT in patients with CP, pancreatic cancer, and pancreatic surgery ²⁷ . However, most analyses suggest a majority of patients in these groups are either not treated or treated with inadequate dosages. In a European survey study of patients with EPI due to CP or pancreatic cancer, one-quarter of patients took three or fewer capsules a day and more than two-thirds of patients reported ongoing symptoms of steatorrhea ⁵¹ . Similarly, in a Dutch national survey of patients with CP and EPI, the median initiating daily dosage was suboptimal (four capsules daily, 25,000 USP units of lipase each), and a majority of patients reported ongoing gastrointestinal symptoms of EPI including steatorrhea and weight loss ⁵² . More recently, in a US population-based analysis, 6.5% of patients with CP received any testing for EPI, 30.4% received a prescription for PERT, and only 10% received a minimally effective dose ⁵³ . Likewise, in a similar analysis of patients with pancreatic cancer, only 1.9% of patients had testing for EPI and 22% received a prescription for PERT, with only 5.5% receiving an adequate dose ⁵⁴ . Ultimately, these studies highlight that despite the common association of EPI with CP and pancreatic cancer, diagnostic testing is rarely performed, treatment with PERT is infrequent, and, if utilized, the dosage amounts are frequently inadequate.

EPI is frequently an unrecognized consequence of benign and malignant pancreatic disease, leading to various consequences such as abdominal discomfort, steatorrhea, malnutrition, sarcopenia, osteoporosis, weight loss, reduced quality of life, and diminished survival. Despite these rather severe outcomes, the diagnosis and management of EPI is suboptimal, which underscores the importance of awareness in high-risk patients, appropriate use of diagnostic testing, and understanding of treatment goals and strategies. However, current literature suggests that patients who are at high risk of developing EPI do not undergo testing or are not treated with adequate dosages. This review highlights the need for increased efforts in awareness of EPI and more widespread implementation of effective diagnoses and treatment optimization when managing patients with PERT.