Exocrine Pancreatic Insufficiency (EPI) Causes

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Exocrine pancreatic insufficiency (EPI) is most commonly caused by conditions affecting the pancreas, such as chronic pancreatitis, celiac disease, diabetes, and cystic fibrosis. However, people typically don't have symptoms until the condition has become advanced.

While EPI is typically caused by a condition affecting the pancreas, genetics and certain lifestyle factors may play a role in the development of EPI as well. This article will discuss the main causes of EPI and the other factors that may affect its development.

What Are Digestive Enzymes?

EPI occurs when the pancreas fails to produce important digestive enzymes. Digestive enzymes are proteins that help break down the food you eat. They include amylase (to break down carbohydrates), protease (to break down proteins), and lipase (to break down fats).

Pancreas, illustration.


Common Causes of EPI

EPI can occur in both adults and children. In adults, the main cause of EPI is chronic pancreatitis. It is estimated that as many as 8 in 10 adults with this disorder develop EPI. Pancreatitis causes inflammation and swelling of the pancreas. Over time, chronic inflammation can damage the pancreatic cells that make digestive enzymes.

Other conditions that can cause EPI include:

  • Celiac disease: This is an autoimmune disease that prevents proper nutrient absorption and digestion of gluten, a protein found in wheat, rye, and barley. The Celiac Disease Foundation estimates that about 1 in 100 people worldwide suffer from this condition. A small percentage of them suffer from EPI.
  • Cystic fibrosis: This genetic condition is the primary cause of EPI in babies and children. Children inherit the cystic fibrosis gene mutation from both parents. This condition causes thick mucus to build up in the lungs, making breathing difficult. Mucus also collects in the pancreas, which keeps digestive enzymes from reaching the small intestine.
  • Diabetes: Type 1 diabetes (in which the pancreas produces little or no insulin) and type 2 diabetes (the body doesn't use insulin properly) are often accompanied by mostly mild forms of EPI. This is thought to be due to damages in the pancreatic tissue that are caused by inflammation, affecting the production and release of digestive enzymes.
  • Inflammatory bowel disease (IBD): Chronic inflammatory bowel diseases include Crohn’s disease and ulcerative colitis. Although experts aren’t entirely sure why people with IBD can develop EPI, a malfunctioning of the immune system mainly is to blame. This may result in pancreatic damage and a lack of enzymes.
  • Pancreatic cancer: Tumors in the pancreas, which is an important organ for digestion, can damage pancreatic tissue and block pancreatic ducts. Pancreatic ducts contain pancreatic juice, which consists of a mixture of bicarbonates, water, and several enzymes. They are involved in the digestion of nutrients, particularly carbohydrates, proteins, and fat. In the absence of digestive enzymes, nutrients are unable to be broken down into smaller pieces.
  • Shwachman-Diamond syndrome (SDS): Also known as neutropenia, this inherited condition causes EPI in children. SDS is a rare, inherited bone marrow failure that produces a low number of white blood cells. It can also lead to poor growth, skeletal abnormalities, and difficulty absorbing food. This is because the cells that secrete digestive enzymes don't function properly.
  • Surgery on the digestive tract, including weight loss surgery: Surgery that changes the shape of the stomach and/or small intestine can affect how digestive enzymes are produced and released. If enzymes are not produced or released on time, they are unable to work properly.
  • Zollinger-Ellison syndrome: This is a rare condition marked by tumors called gastrinomas that form in the pancreas or the upper part of the small intestine. The tumors secrete the hormone gastrin. This causes an increase in gastric acid, leading to the formation of ulcers in the stomach and upper small intestine.

Cystic Fibrosis and EPI

Nearly 9 in 10 infants with cystic fibrosis develop EPI within the first year. The rest are at risk for developing EPI during childhood or adulthood.


Although not much is known about the role of genes in the development of EPI, recent studies have found that EPI can be caused by a mutation in the COX4I2 gene, which produces COX4 proteins. COX4 proteins play an important role in the regulation of the pancreas. Mutations in the COX4I2 gene reduce the production of COX4 proteins, which can lead to the malabsorption (difficulty digesting or absorbing nutrients from food) of fats in the digestive system.

Lifestyle Risk Factors

A risk factor is anything that increases your chances of getting a disease. Lifestyle risk factors of EPI include smoking and chronically drinking alcohol, which may worsen your symptoms of the disease. For example, excessive alcohol use can lead to inflammation of the pancreas. This may make the pancreas less effective at producing digestive enzymes, which may lead to EPI.

In addition, the severity of EPI also depends on the underlying cause. Some people will only have mild EPI and may have few (if any) symptoms. Progression, severe symptoms, and consequences (such as nutritional deficiencies and weight loss) are more likely to occur when EPI is complicated by conditions such as cystic fibrosis, inflammatory bowel disease, or pancreatic cancer.


Exocrine pancreatic insufficiency (EPI) is a rare but serious malabsorptive condition that occurs when the pancreas fails to produce important digestive enzymes. Without these enzymes, the body cannot properly digest food and absorb nutrients, particularly fat.

EPI most often occurs in people (adults) who have conditions affecting the pancreas such as chronic pancreatitis, celiac disease, diabetes, and cystic fibrosis. However, people typically don't have symptoms until the condition has become advanced. In infants and children, cystic fibrosis is the primary cause of EPI.

A Word From Verywell

The causes of EPI can vary greatly. Because there is a greater risk of malnutrition if complications of EPI progress and becomes severe, seek immediate medical attention if you experience persistent or unexplained digestive issues. Early detection and diagnosis of EPI by a doctor who specializes in gastrointestinal diseases (gastroenterologist) can lead to a better prognosis and management of the disease.

Additionally, treatment and prognosis for EPI depends on the underlying cause of the disease but can be greatly improved when drinking and smoking are decreased or eliminated completely. That said, consult with your gastroenterologist about supplementing your low-fat meals with fat-soluble vitamins (A, D, E, K), as many people with EPI are low in these vitamins. Therefore, you may need to supplement these vitamins to make sure you’re getting enough.

7 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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