Exocrine pancreatic insufficiency (EPI) is a digestive condition that has a variety of possible causes. Understanding the causes can help with diagnosis and treatment.

When a person has EPI, the pancreas does not produce enough enzymes or produces defective enzymes. This can affect the body’s ability to digest food and absorb nutrients.

About 25% of EPI cases are idiopathic, which means they have no known cause.

However, several conditions and other factors can contribute to the development of EPI.

Without treatment, EPI can lead to malnutrition. Understanding the potential causes can help ensure proper diagnosis and treatment.

Here are some potential causes of EPI.

The most common cause of EPI is chronic pancreatitis, which is inflammation in the pancreas that gets progressively worse over time. The inflammation can eventually damage the pancreas, leading to EPI.

EPI affects 60% to 90% of people who have been living with chronic pancreatitis for 10 to 12 years. Chronic pancreatitis is the most common pancreatic condition in the United States, affecting 42 to 73 in 100,000 people.

Cystic fibrosis is an inherited, progressive condition. It causes chronic lung infections that eventually make breathing difficult. According to the Cystic Fibrosis Foundation, the condition affects more than 40,000 people in the United States and around 105,000 people worldwide.

In some people living with cystic fibrosis, a sticky, thick mucus forms in the lungs and the organs of the digestive tract, including the pancreas. This buildup of mucus can cause EPI to develop, leading to digestive issues.

According to a 2021 research review, nearly 90% of people with cystic fibrosis also have EPI. Cystic fibrosis is the leading cause of EPI in children.

Several other factors and health conditions can cause EPI, including:

  • autoimmune conditions such as Sjögren disease, primary biliary cirrhosis, and inflammatory bowel disease
  • chronic renal failure (the loss of kidney function)
  • hyperlipidemia (high levels of fat in the blood)
  • hypercalcemia (high levels of calcium in the blood)
  • irregularities and blockages in the pancreas
  • alcohol and tobacco use

People with diabetes may be at higher risk of developing EPI. According to a 2019 review, 30% to 50% of people with type 1 diabetes and 20% to 30% of people with type 2 diabetes also have EPI.

The review also mentions that EPI affects notable numbers of people who have the following conditions:

  • celiac disease
  • HIV
  • benign pancreatic tumor
  • pancreatic cancer

Two specific genetic mutations may make a person more susceptible to developing EPI:

  • CFTR mutations: A mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene results in insufficient production or no production of the CFTR protein.
  • SPINK1 mutations: Serine peptidase inhibitor Kazal type 1 (SPINK1) is responsible for coding a protein that the pancreas releases. A mutation in this gene has an association with hereditary pancreatitis.

Surgery in or around the pancreas can also cause EPI. According to a 2019 review, surgical procedures that can cause EPI include:

  • pediatric intestinal transplantation
  • pancreatic surgery
  • gastrointestinal surgery

Although surgery can lead to EPI in some cases, it can help improve EPI in others. Benign tumors in the pancreas can cause EPI before surgery, which means that surgical removal of the tumors may improve the condition.

Once a person has received a diagnosis of EPI, they can start treatment for it. The goal of treatment is to make sure the person receives all necessary nutrients.

Pancreatic enzyme replacement therapy (PERT) is the main treatment for EPI. PERT comes in the form of prescription pills. These pills aid digestion during meals by providing the enzymes that the pancreas is not making. People should take these pills with food.

Making dietary changes may also help treat EPI. For example, people with cystic fibrosis and EPI should eat a well-balanced diet that is high in calories and healthy fats.

A doctor may also prescribe or recommend vitamin and mineral supplements to make up for the vitamins and minerals the body is not absorbing as a result of EPI.

It is important to regularly check in with a doctor or dietitian to make sure EPI treatment is working. People should also work with a doctor to address and treat any underlying health conditions, as doing so may help improve EPI.

When a person has EPI, the pancreas does not produce enough of enzymes that are necessary for digestion of key nutrients, or it produces defective enzymes. The most common causes of EPI are chronic pancreatitis and cystic fibrosis. Other medical conditions may also lead to EPI.

Several other factors — including gene mutations, surgery side effects, and tobacco and alcohol use — can cause EPI as well.

A person with EPI can treat their symptoms with PERT, dietary changes, and vitamin and mineral supplements. Addressing the underlying condition that is causing EPI may also improve symptoms.