The Use of Pancreatic Enzyme Replacement Therapy in Patients With a Diagnosis of Chronic Pancreatitis and Pancreatic Cancer in the US Is Infrequent and Inconsistent

Chris E. Forsmark; Gong Tang; Hongzhi Xu; Marie Tuft; Steven J. Hughes; Dhiraj Yadav


Aliment Pharmacol Ther. 2020;51(10):958-967. 

In This Article

Abstract and Introduction


Background: Patients with chronic pancreatitis or pancreatic cancer commonly develop exocrine pancreatic insufficiency, and may not be adequately treated with pancreatic enzyme replacement therapy (PERT).

Aims: To estimate the frequency of diagnostic testing for exocrine insufficiency, and appropriate use of PERT, in a commercially insured population in the US.

Methods: We utilised a nationally representative administrative database representing 48.67 million individuals in over 80 US healthcare plans to assess testing for and treatment of exocrine insufficiency in patients who received a diagnosis of chronic pancreatitis (n = 37 061) or pancreatic cancer (n = 32 461) from 2001 to 2013. We identified the details of any testing for exocrine insufficiency and PERT use. We defined appropriate PERT use as a dosage of ≥120 000 USP units of lipase daily. Multiple logistic regression was used to identify predictors of appropriate use of PERT.

Results: In patients with chronic pancreatitis, 6.5% had any testing for exocrine insufficiency, 30.4% filled a prescription for PERT, and 8.5% were prescribed an adequate dose. In those with pancreatic cancer, 1.9% had testing for exocrine insufficiency, 21.9% filled a prescription for PERT, and 5.5% were prescribed an adequate dose. Number of comorbidities, testing for exocrine insufficiency, pancreatic surgery and duration of enrolment were independent predictors for use and appropriate dosing.

Conclusions: Testing for exocrine insufficiency, and appropriate dosing of PERT in patients with chronic pancreatitis or pancreatic cancer, is infrequent and inconsistent in an insured US population. Efforts are needed to educate medical providers on the best practices for managing exocrine pancreatic insufficiency in these patients.


Exocrine pancreatic insufficiency, defined as maldigestion due to inadequate delivery of pancreatic digestive enzymes, can occur in a variety of clinical settings. The most common cause is chronic pancreatitis, and steatorrhea occurs when more than 90% of pancreatic exocrine capacity is lost.[1] The prevalence of exocrine pancreatic insufficiency ranges from 35% to 75%, with the highest risk in those with chronic pancreatitis due to alcohol (usually with coexistent smoking) and with longer disease duration.[2–6] Exocrine insufficiency is almost universal in those with chronic pancreatitis due to cystic fibrosis, and is relatively common in many genetic causes of chronic pancreatitis.[7] Exocrine insufficiency may occur prior to, after, or at the same time as diabetes due to the pancreatic disease (pancreaticogenic or Type 3c diabetes).[8]

A second major cause of exocrine pancreatic insufficiency is pancreatic malignancy, both pancreatic ductal adenocarcinoma and main duct intraductal papillary mucinous neoplasm. In both, obstruction of the main pancreatic duct can prevent pancreatic enzymes from reaching the duodenum. Approximately 70% of all cases of pancreatic cancer are in the head of the pancreas, and are associated with both main pancreatic duct obstruction and upstream parenchymal pancreatic atrophy. Studies in patients with unresectable pancreatic cancer note exocrine insufficiency in 50%-90%.[9,10] In those with resectable pancreatic cancer (approximately one in five patients), exocrine insufficiency is found in 40%-50% on average, but this increases to approximately 75% after surgery.[8–11] Pancreatic surgery is also an independent risk factor for exocrine insufficiency, even if not performed for chronic pancreatitis or pancreatic cancer.[12] A number of other conditions may also be associated with exocrine pancreatic insufficiency,[13] including up to 25% of patients after a single episode of acute pancreatitis.[14]

The consequences of exocrine pancreatic insufficiency can be substantial, and include weight loss, sarcopenia, malnutrition, fat-soluble vitamin deficiency, metabolic bone disease and others.[6,15] Osteoporosis is found in around 25% of those with chronic pancreatitis, and osteopenia in an additional 40%.[6,16] This is associated with an increased risk of fractures.[6,17,18] These patients may develop pancreaticogenic diabetes (termed Type 3cDM), and the maldigestion and malnutrition associated with concomitant exocrine insufficiency makes control of blood sugar more difficult and increases the risk of episodes of hypoglycaemia.[8] The consequences of exocrine insufficiency in patients with pancreatic cancer include acceleration of weight loss and sarcopenia, reduced ability to tolerate chemotherapy or surgery, and possibly increased mortality. Sarcopenia is closely associated with exocrine insufficiency in patients with pancreatic cancer,[19] and is a predictor of increased morbidity and mortality in patients with pancreatic cancer.[20,21] Pancreatic enzyme replacement therapy (PERT) may be an independent predictor of prolonged survival after pancreatic cancer surgery.[22]

Accurate estimates of the prevalence of exocrine pancreatic insufficiency in patients with pancreatic cancer or chronic pancreatitis are difficult, given that no simple diagnostic test exists. While 72-hour faecal fat analysis can document the presence of steatorrhoea, it does not prove the presence of exocrine pancreatic insufficiency. In addition, an accurate 72-hour stool collection for fat is difficult outside of a clinical research centre. Measurement of faecal elastase-1 is used most commonly, but lacks sensitivity and specificity.[23] In addition, patients with exocrine pancreatic insufficiency may have significant steatorrhoea but not complain of diarrhea, making it difficult to use the results of a therapeutic trial as a diagnostic test.[15] The normal pancreas produces a minimum of 900 000 USP (United States Pharmacopeia) units of lipase with a normal meal. It has been suggested that 10% of this amount will correct steatorrhoea and produce near normal digestion and absorption.[1,15] It may not be necessary to supplement with 90 000 USP units of lipase with each meal, as there may be residual pancreatic secretion, and gastric lipase may partially compensate for reductions in pancreatic lipase. A typical starting dose would be 40 000–50 000 USP units with each meal,[15] but several European survey studies show many patients receive far less[24,25] or do not receive PERT at all.[26] No systematic analysis of the use of PERT for patients with chronic pancreatitis or pancreatic cancer has been performed in the US, so we attempted to estimate the frequency of appropriate use of PERT in an insured population in the US.