Causes of Exocrine Pancreatic Insufficiency
Digestive HealthExocrine Pancreatic Insufficiency
Explore This Topic

Causes of Exocrine Pancreatic Insufficiency

Causes of Exocrine Pancreatic Insufficiency
Ben Bryant/Getty Images
By
and
Updated on March 24, 2025
by

Exocrine pancreatic insufficiency (EPI) is a condition that results in a shortage of key digestive enzymes needed to digest fats, proteins, and starches. The most common causes of EPI are health conditions that affect the pancreas, including chronic pancreatitis, diabetes, and cystic fibrosis and other conditions such as celiac.

Lifestyle habits, such as drinking large amounts of alcohol, and rare genetic conditions can also increase the risk of EPI as they can affect pancreatic function.

Here’s what to know about the causes and risk factors for exocrine pancreatic insufficiency.

Chronic Pancreatitis

In adults, chronic pancreatitis is the most common cause of EPI.

 Chronic pancreatitis causes damage to the cells that make critical digestive enzymes amylase, protease, and lipase.

According to a review published in 2024, about 42 to 73 out of every 100,000 people in the United States have chronic pancreatitis.

 Of these, around 8 in 10 who have chronic pancreatitis develop EPI.

The two most common causes of acute pancreatitis are heavy alcohol use and gallstones, accounting for around 80 percent of people with the disease.

 Regularly drinking large amounts of alcohol can damage the pancreas over time as well as impede fat digestion and lead to chronic pancreatitis.

 Gallstones may block the channel through which digestive enzymes travel — the pancreatic duct — causing acute gallstone pancreatitis. With this condition, the enzymes start digesting the tissue of the pancreas, triggering inflammation.

Other, less common reasons for an increased risk of chronic pancreatitis include:

  • Autoimmune pancreatitis, in which the immune system accidentally attacks otherwise healthy tissue in the pancreas.

     Autoimmune diseases linked to EPI include Sjögren’s syndrome, inflammatory bowel disease (IBD), and primary biliary cirrhosis.

  • An infection, such as mumps, Coxsackie virus, CMV, herpes simplex virus (HSV), hepatitis B, human immunodeficiency virus (HIV), and SARS-CoV-2, salmonella, Legionella, and other viral, bacterial, fungal, or parasitic infections

  • High calcium or triglyceride levels in the blood, which can interfere with digestive enzymes, though the exact mechanism is unknown

  • Certain medications

Pancreatic Cancer and Tumors

Pancreatic cancer results when uncontrolled cell growth leads to the development of malignant tumors in the pancreas.

The pancreas consists of two types of tissue: exocrine tissue, which makes digestive enzymes and endocrine tissue, which produces hormones like insulin. Around 95 in 100 pancreatic cancers start in the exocrine tissue.

EPI is common in people with pancreatic cancer and may occur due to:

  • A tumor directly blocking the pancreatic duct (the main channel through which digestive enzymes leave the pancreas)
  • Scarring in the pancreas, which reduces the amount of healthy tissue available to make these enzymes
  • Surgery to treat cancer or a tumor, which can involve removing some pancreatic tissue that plays a role in making these enzymes
Having chronic pancreatitis may increase a person’s risk of pancreatic cancer, and having pancreatic cancer is a risk factor for long-term pancreas inflammation.

Cystic Fibrosis

Cystic fibrosis (CF) is a chronic, progressive genetic disorder that causes thickened mucus to form in your lungs, pancreas, and other organs in the body, and can affect the ability to breathe over time.

 CF is the leading cause of EPI in babies and children.

Usually, mucus that lines organs and body cavities is slick and slippery. However, with CF, the thick mucus clogs the airways and plugs up tubes and passageways in the body, causing blockages, scarring, and fluid-filled lumps called cysts that stop organs from working properly.

Sticky mucus can block the digestive enzymes produced in the pancreas from reaching the small intestine, resulting in EPI.

According to the Cystic Fibrosis Foundation Patient Registry, cystic fibrosis affects close to 40,000 people in the United States,

 and around 85 percent of them have EPI, often shortly after birth.

Rare Genetic Conditions

Genetic syndromes or disorders that can lead to EPI include:

  • Johanson-Blizzard Syndrome (JBS) EPI occurs from birth in almost all children with JBS, a rare genetic disorder that also causes an abnormally shaped nose and teeth. Reduced nutrient absorption due to EPI usually affects intellectual development and physical growth in children with JBS.

     
  • Pearson Syndrome This very rare genetic condition impacts the bone marrow and the cells that make different types of blood cells. Pearson syndrome’s effects on the pancreas may include EPI or difficulties in producing hormones like insulin that might lead to increased diabetes risk.

     
  • Schwachman-Diamond Syndrome Around 1 in 80,000 newborn infants are born with this syndrome, which causes inadequate levels of white blood cells, as well as EPI and problems with bone growth. Children with Schwachman-Diamond syndrome tend to produce more pancreatic enzymes as they age.

  • Zollinger-Ellison Syndrome This causes the growth of gastric-acid-producing tumors in the small intestine or pancreas, known as gastrinomas. Zollinger-Ellison syndrome is typically diagnosed between 20 and 50 years of age.

     While the pancreas may make enough digestive enzymes, the increased acid levels can destroy the enzymes before they can support digestion.

     
  • Short Bowel Syndrome This is a loss of function in part of the bowel that occurs in people who have undergone surgery to remove part of the bowel.

Pancreatic and Gastrointestinal (GI) Surgeries

People with pancreatic cancer who undergo surgery to remove part or all of the pancreas often have an increased risk of EPI.

 Researchers estimate that around 40 to 80 percent of people who undergo a gastrectomy, or surgical removal of the stomach, as a treatment for cancer, can develop EPI.

A study published in 2022 found that EPI developed, on average, in 9.3 percent of people who underwent bariatric surgery, with 10.3 percent of those who had a Roux-en-Y gastric bypass and 4.2 percent of those with a gastric sleeve going on to have EPI.

Other Conditions Associated With EPI

Other conditions, including diabetes, celiac disease, and inflammatory bowel disease, are more likely in people with EPI and can also increase the risk of EPI. This is known as a bidirectional relationship.

Diabetes

Diabetes develops when either the pancreas doesn’t make enough insulin to process glucose from the bloodstream, or the body’s cells are resistant to the insulin produced by the pancreas. This results in high blood sugar levels. While people with either type 1 or type 2 diabetes can develop EPI, virtually everyone with diabetes that results from pancreatic diseases including pancreatitis, has EPI.

EPI can also occur in types 1 and 2 diabetes for reasons including:

  • A faulty insulin response potentially leading to a smaller pancreas
  • Diabetes potentially causing increased inflammation in the pancreas that damages tissue
  • Scarring in the pancreas’ exocrine tissue, which may apply to over one-half of all people with types 1 and 2 diabetes

Celiac Disease

Celiac disease occurs when gluten, a protein in grains like wheat and rye, triggers an autoimmune reaction that damages gut tissue. People with celiac disease need to avoid consuming gluten for the rest of their lives, as it can interfere with nutrient absorption.

Without treatment, celiac disease can cause a range of long-term issues including EPI.

 One analysis suggested that this might be due to the damaged gut lining not sending the right hormonal signals to trigger digestive enzyme release. The review found that study participants who started out with EPI and celiac disease were less likely to have EPI after following a gluten-free diet than those who didn’t eliminate gluten.

Inflammatory Bowel Disease (IBD)

Another potential cause of EPI is inflammatory bowel disease (IBD), a group of conditions (including Crohn’s disease and ulcerative colitis) in which the immune system attacks tissue in the digestive system.

However, not much data is available on the link between IBD and EPI, and many studies are conflicting, according to a review published in 2022.

Research suggests that antibodies (proteins the immune system produces) may attack the pancreas in around one-third of people with Crohn’s disease, implying that digestive changes might impact how the pancreas works, or that damaged gut tissue may send out fewer hormones to trigger the release of digestive enzymes.

The Takeaway

  • The main causes of EPI in adults are chronic pancreatitis and pancreatic cancer, while the most common cause in children is cystic fibrosis.
  • Surgery to remove part or all of the pancreas can also lead to EPI. Other causes include rare genetic or inherited conditions, diabetes, inflammatory bowel disease, and celiac disease.
  • If you notice greasy, clay-colored, foul-smelling stools; digestive pain; gas; bloating; or unexpected weight loss, speak to your doctor. These are possible signs and symptoms of EPI and its related causes.

Resources We Trust

EDITORIAL SOURCES
Everyday Health follows strict sourcing guidelines to ensure the accuracy of its content, outlined in our editorial policy. We use only trustworthy sources, including peer-reviewed studies, board-certified medical experts, patients with lived experience, and information from top institutions.
Resources
  1. Exocrine Pancreatic Insufficiency (EPI). Cleveland Clinic. June 10, 2021.
  2. Exocrine Pancreatic Insufficiency (EPI). National Pancreas Foundation.
  3. Han C et al. Management of chronic pancreatitis: recent advances and future prospects. Therapeutic Advances in Gastroenterology. February 24, 2024.
  4. Pancreatitis. Cleveland Clinic. January 12, 2023.
  5. Exocrine Pancreatic Insufficiency (EPI). Loma Linda University.
  6. Pancreatitis. Mayo Clinic. September 23, 2023.
  7. Autoimmune pancreatitis. Mayo Clinic. December 16, 2023.
  8. Ghodeif AO et al. Pancreatic Insufficiency. StatPearls. January 16, 2023.
  9. Pancreatitis and Infected Pancreatic Necrosis. Johns Hopkins. February 17, 2023.
  10. Causes of Chronic Pancreatitis. Stanford Medicine.
  11. What Is Pancreatic Cancer? American Cancer Society. February 5, 2024.
  12. Pancreatic Cancer. Cedars Sinai.
  13. Roeyen G et al. Expert opinion on management of pancreatic exocrine insufficiency in pancreatic cancer. ESMO Open. February 3, 2022.
  14. About Cystic Fibrosis. Cystic Fibrosis Foundation.
  15. Cystic Fibrosis. Cleveland Clinic. May 1, 2024.
  16. Johanson-Blizzard Syndrome. National Organization for Rare Disorders. December 13, 2016.
  17. Pearson Syndrome. Boston Children’s Hospital.
  18. Shwachman-Diamond syndrome. MedlinePlus. March 1, 2020.
  19. Zollinger-Ellison syndrome. Mayo Clinic. November 5, 2024.
  20. Whitcomb DC et al. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatic Insufficiency: Expert Review. Gastroenterology. November 1, 2023.
  21. Singh VK et al. Less common etiologies of exocrine pancreatic insufficiency. World Journal of Gastroenterology. October 21, 2017.
  22. Stern L et al. Perioperative management of pancreatic exocrine insufficiency-evidence-based proposal for a paradigm shift in pancreatic surgery. HPB (Oxford). January 2024.
  23. Kwon JY et al. Exocrine pancreatic insufficiency after bariatric surgery. Pancreatology. November 1, 2022.
  24. Richardson A et al. Acute pancreatitis and diabetes mellitus: a review. The Korean Journal of Internal Medicine. December 4, 2020.
  25. Radlinger B et al. Exocrine Pancreatic Insufficiency in Type 1 and Type 2 Diabetes. Current Diabetes Reports. April 1, 2020.
  26. What is Celiac Disease? Celiac Disease Foundation.
  27. Jiang C et al. Exocrine Pancreatic Insufficiency Is Common in Celiac Disease: A Systematic Review and Meta-Analysis. Digestive Diseases and Sciences. August 1, 2023.
  28. Massironi S et al. Systematic review—pancreatic involvement in inflammatory bowel disease. Alimentary Pharmacology & Therapeutics. May 3, 2022.
Meet Our Experts
See Our Editorial PolicyMeet Our Health Expert Network

Yuying Luo, MD

Medical Reviewer

Yuying Luo, MD, is an assistant professor of medicine at Mount Sinai West and Morningside in New York City. She aims to deliver evidence-based, patient-centered, and holistic care for her patients.

Her clinical and research focus includes patients with disorders of gut-brain interaction such as irritable bowel syndrome and functional dyspepsia; patients with lower gastrointestinal motility (constipation) disorders and defecatory and anorectal disorders (such as dyssynergic defecation); and women’s gastrointestinal health.

She graduated from Harvard with a bachelor's degree in molecular and cellular biology and received her MD from the NYU Grossman School of Medicine. She completed her residency in internal medicine at the Icahn School of Medicine at Mount Sinai, where she was also chief resident. She completed her gastroenterology fellowship at Mount Sinai Hospital and was also chief fellow.

See full bio

Ashley Welch

Author

Ashley Welch has more than a decade of experience in both breaking news and long-form storytelling. She is passionate about getting to the crux of the latest scientific studies and sharing important information in an easy-to-digest way to better inform decision-making. She has written about health, science, and wellness for a variety of outlets, including Scientific American Mind, Healthline, New York Family, Oprah.com, and WebMD.

She served as the health editor for CBSNews.com for several years as a reporter, writer, and editor of daily health news articles and features. As a former staff member at Everyday Health, she covered a wide range of chronic conditions and diseases.

Welch holds a bachelor's degree from Fordham University and a master's degree from the Craig Newmark Graduate School of Journalism at the City University of New York, where she studied health and science reporting. She enjoys yoga and is an aspiring runner.

See full bio

Adam Felman

Author
Adam is a freelance writer and editor based in Sussex, England. He loves creating content that helps people and animals feel better. His credits include Medical News Today, Greatist, ZOE, MyLifeforce, and Rover, and he also spent a stint as senior updates editor for Screen Rant.

As a hearing aid user and hearing loss advocate, Adam greatly values content that illuminates invisible disabilities. (He's also a music producer and loves the opportunity to explore the junction at which hearing loss and music collide head-on.)

In his spare time, Adam enjoys running along Worthing seafront, hanging out with his rescue dog, Maggie, and performing loop artistry for disgruntled-looking rooms of 10 people or less.

See full bio
See Our Editorial PolicyMeet Our Health Expert Network