Pancreatic Insufficiency

Etiology

EPI's etiology can be broadly classified into diseases or toxins that cause loss of functional pancreatic parenchyma, conditions that obstruct outflow and delivery of pancreatic enzymes, and anatomic changes that impede enzyme production and function stimulation. The 2 principal causes of EPI are chronic pancreatitis in adults and cystic fibrosis in children.[1] Other causes include recurrent acute pancreatitis, pancreatic neoplasms, diabetes mellitus, celiac disease, inflammatory bowel disease, bariatric surgery, HIV infection, and genetic or congenital conditions.[2][3][4] 

The Toxic-Metabolic, Idiopathic, Genetic, Autoimmune, Recurrent, and Severe Acute Pancreatitis, Obstructive classification system categorizes the causes and risk factors for chronic pancreatitis and pancreatic exocrine insufficiency.

• Toxic-metabolic causes include excessive alcohol use, tobacco smoking, hypercalcemia, hyperlipidemia, and chronic kidney disease.
• Idiopathic causes account for approximately 25% of cases and may be linked to unrecognized genetic variants.
• Genetic causes include mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, serine peptidase inhibitor Kazal-type 1 (SPINK1) gene, and hereditary pancreatitis.
• Autoimmune causes include Sjögren disease, primary biliary cirrhosis, and inflammatory bowel disease.
• Obstructive causes include congenital anomalies of the pancreatic ducts (large or small), sphincter of Oddi dysfunction, obstruction of the duct by a tumor, and posttraumatic pancreatic duct fibrosis.
• Recurrent and severe acute pancreatitis due to necrosis, vascular diseases, and radiation are also potential causes.[5] 

Alcohol use disorder is a well-recognized cause of chronic pancreatitis. In the United States, patients with heavy alcohol use have a 3-fold higher risk of developing chronic pancreatitis, and the risk is further elevated in patients with concurrent tobacco use.[6] Furthermore, EPI is associated with HIV infection and is a significant cause of chronic diarrhea in this population. Patients with HIV presenting with symptoms of diarrhea or malabsorption should be screened for EPI.[7] Another major cause of EPI, especially in children, is cystic fibrosis. Approximately 85% of patients with cystic fibrosis have EPI, which often presents soon after birth. All patients with cystic fibrosis, regardless of age, need to be tested for EPI.[8][9] 

EPI can coexist with other gastrointestinal diseases. For example, EPI is present in a small number of patients with celiac disease; however, it usually resolves with a gluten-free diet. EPI should be excluded in patients with celiac disease who remain symptomatic despite a gluten-free diet.[3][10] EPI is also not uncommon in inflammatory bowel disease. Associated autoimmunity or medications used to treat inflammatory bowel disease could precipitate pancreatitis. Both acute and chronic pancreatitis have an increased incidence among patients with inflammatory bowel disease.[11][12] 

EPI is a well-known complication of bariatric surgery, and is increasing in incidence as more of these surgeries are performed worldwide. The diagnosis of pancreatitis after bariatric surgery is confounded by altered anatomy and symptoms that overlap with postoperative complications. Many bariatric surgeries involve bypassing a portion of the gastrointestinal tract, creating malabsorption that aids in weight loss; the extent of malabsorption depends on the length of the bypassed section of intestine. This type of malabsorption needs to be differentiated from EPI.[13] 

Epidemiology

The exact prevalence of exocrine pancreatic insufficiency in the general population is unknown, as it occurs secondary to multiple conditions with varying prevalence rates.[14] EPI develops in 60% to 90% of patients diagnosed with chronic pancreatitis within 10 to 12 years of diagnosis. Chronic pancreatitis has a prevalence of 42 to 73 cases per 100,000 persons in the United States and is the most common pancreatic disorder associated with EPI. Conversely, Japan, China, and India have a prevalence of 36 to 125 cases per 100,000 persons.[14][15][16] 

In a systematic review and meta-analysis, the prevalence of EPI during hospitalization for acute pancreatitis was 62%, decreasing to 35% at follow-up. Risk of EPI was 2-fold higher in patients with severe compared to mild acute pancreatitis. Alcohol-related pancreatitis and concomitant pancreatic necrosis were additional risk factors associated with developing EPI.[17] In a prospective cohort study, results demonstrated that EPI was diagnosed in 34.1% of patients 12 months after the onset of acute pancreatitis. Factors significantly associated with EPI included recurrent or severe acute pancreatitis, preexisting diabetes, alcohol use, and idiopathic pancreatitis.[18] 

The prevalence of EPI among patients with diabetes is generally low and usually mild to moderate in severity. In a study of 133 patients with diabetes and pancreatic insufficiency, the fecal elastase-1 assay was evaluated as a screening test; 13% had a low test result (indicating the presence of EPI). Other studies' results showed that 10% to 30% of patients with type 1 diabetes had EPI, 10% to 30% had severe EPI, and 22% to 56% had moderate EPI. In patients with type 2 diabetes, rates of EPI ranged from 5% to 46%.[19][20][21] 

Approximately 66% to 92% of patients with advanced pancreatic cancer develop EPI. Between 14% and 74% of patients with inflammatory bowel disease may also have EPI. Among patients undergoing bariatric surgery, the risk of EPI is still high despite enzymatic and nutritional supplementation.[3][13] Furthermore, the prevalence of EPI in patients with HIV infection is estimated at 26% to 45%.[22] 

Pathophysiology

Chronic pancreatitis is caused by recurrent episodes of inflammation that eventually progress to fibrosis. Consequently, both the endocrine and exocrine functions of the pancreas can be affected.[4] Proposed mechanisms include the toxic metabolic, oxidative stress, obstructive, and necrosis-fibrosis theories.[21][23] Typically, when chyme reaches the duodenum, both secretin and cholecystokinin stimulate the secretion of approximately 1.5 L of pancreatic fluid that contains pancreatic enzymes (amylase, lipase, and protease), water, and ions (bicarbonate and phosphate). These enzymes are essential to digestion in the small intestine.[6] In EPI, an insufficient amount of pancreatic enzymes reaches the small intestine.

Furthermore, pancreatic insufficiency often results from conditions that impair acinar cell function, decreasing digestive enzyme production.[24] Chronic pancreatitis, pancreatic resection, cystic fibrosis, and pancreatic cancer lead to loss of pancreatic parenchyma, causing impaired enzyme production. Tumors and ductal stenoses lead to impaired enzyme outflow. Postoperative anatomical changes (such as duodenal resection), inflammatory enteropathies (including celiac disease and inflammatory bowel disease), and somatostatinomas alter the endogenous stimulation of cholecystokinin and enteropeptidase (formerly enterokinase), interfering with the activation of digestive enzymes.[25] 

In cystic fibrosis, epithelial cells in the pancreatic ducts are affected by mutations in the cystic fibrosis transmembrane conductance regulator gene, which encodes a cyclic adenosine monophosphate-regulated anion channel. Exocrine pancreatic insufficiency results from chronic obstructive pancreatitis with progressive acinar destruction.[26][27] Additionally, decreased ductal bicarbonate secretion and decreased alkalinization of the acinar lumen may contribute to inflammation and the destruction of pancreatic ducts.[9] 

Diabetes mellitus can also lead to EPI. The pancreas is smaller in size in patients with type 1 diabetes, possibly secondary to the decreased trophic effects of insulin on acinar cells, autoimmune destruction of islet cells, and reduced pancreatic secretory function due to diabetic neuropathy.[28] Finally, EPI may result from reduced cholecystokinin secretion caused by villous atrophy in patients with celiac disease or milk protein enteropathy. Cholecystokinin levels return to normal after mucosal healing has occurred in these patients.[29]

History and Physical

EPI is a notable cause of maldigestion and malabsorption.[3] The combination of steatorrhea and insufficient dietary intake places patients at significant risk for malnutrition.[30] Malabsorption reduces the quality of life and causes serious complications.[14] Furthermore, clinical features of EPI are usually nonspecific. Symptoms include steatorrhea, abdominal discomfort, bloating, and weight loss. Additionally, malnutrition, trace element and vitamin deficiencies, metabolic bone disease (osteoporosis or osteomalacia), muscle spasms, decreased immune competence, and an increased risk of cardiovascular events frequently occur.[31] 

Steatorrhea is the most common manifestation of EPI and is diagnosed when the fat content of the stool exceeds 7 g/day, while on a diet that incorporates 100 g/day of fat. Fat malabsorption is defined by a decrease in pancreatic lipase and trypsin levels of at least 5% to 10%.[32] Following bariatric surgery, patients may present with steatorrhea, weight loss, maldigestion, and malabsorption related to surgery, but these symptoms are also pathognomonic for EPI, making diagnosis challenging.[13]

Evaluation

Exocrine pancreatic insufficiency is classified as mild, moderate, or severe. Mild insufficiency occurs with reduced secretion of 1 or 2 pancreatic enzymes, preserved bicarbonate, and normal fecal fat. Moderate insufficiency is defined by reduced enzyme secretion with impaired bicarbonate secretion. Severe insufficiency occurs when enzyme and bicarbonate secretion are reduced and steatorrhea is present.[4] The presentation of exocrine pancreatic insufficiency varies among patients depending on the severity of the insufficiency and its underlying cause. Laboratory and radiologic evaluation are required to confirm the diagnosis.[33] 

Two categories of diagnostic tests are recognized: direct and indirect tests. Although direct tests are sensitive and specific, they are invasive, expensive, and time-consuming, which limits their use in clinical practice. Conversely, indirect tests such as fecal, breath, and blood tests assess the clinical sequelae of EPI. Despite being less sensitive and specific, they are more feasible and less expensive.[14][33]  

Direct Tests

Direct tests include the secretin-cholecystokinin stimulation test and the endoscopic pancreatic function test. These tests evaluate pancreatic secretory function by stimulating pancreatic enzyme production by administering secretin or cholecystokinin, then collecting duodenal fluid to quantify bicarbonate and enzyme production. During the secretin-cholecystokinin stimulation test, a tube is inserted from the nose into the duodenum, and duodenal fluid is aspirated serially over 1 to 2 hours. An alternative to the secretin-cholecystokinin stimulation test is the endoscopic pancreatic function test, which can retrieve duodenal fluid samples endoscopically 45 to 60 minutes after intravenous secretin injection. The endoscopic pancreatic function test is a highly sensitive diagnostic tool that can confirm the diagnosis of EPI in borderline cases.[34] 

Indirect Tests

The gold standard test for diagnosing steatorrhea is the 72-hour fecal fat quantification and determination of the fat absorption coefficient; however, testing is limited by the tedious and time-consuming nature of stool collection, as patients must collect and refrigerate their stool for 72 hours.[35] Fecal elastase-1 (FE-1) is considered a reliable, noninvasive, and less time-consuming test to evaluate EPI. This test measures the proportion of fecal elastase secreted into the duodenum that survives intestinal transit. Fecal elastase serves as a surrogate measure of pancreatic enzyme output. FE-1 is not affected by pancreatic enzyme replacement. Such advantages make it a popular test in EPI screening.[36] However, the test can be confounded by dilution in watery diarrhea, and thus, should be performed on semi-solid or solid stool.[37] A FE-1 test result of less than 200 μg/g feces is considered abnormal. Less than 100 μg/g feces suggests pancreatic insufficiency, whereas less than 50 μg/g feces is specific for severe EPI.[25][38][39][25] However, FE-1 levels are unreliable for EPI detection in patients after pancreatic resection.[40] 

Fecal chymotrypsin may be of benefit when evaluating compliance with pancreatic enzyme therapy. The test's value is limited due to intestinal degradation and lack of laboratory availability.[37][41] Notably, serum pancreatic enzymes are not a reliable diagnostic tool for pancreatic insufficiency. However, serum trypsinogen can be a useful marker for EPI. A serum level below 20 ng/mL is sensitive for pancreatic steatorrhea.[42][43]

The 13C-mixed triglyceride breath test measures fat digestion by pancreatic lipase. After the patient ingests a fatty meal containing radiolabeled carbon-13, the body digests the meal, and the radiolabeled carbon is released as 13CO2, which is then exhaled. Breath testing quantifies exhaled 13CO2 and can aid in the diagnosis of EPI. While this test is as sensitive as fecal elastase, it is not widely available.[31][34] Furthermore, testing for nutritional deficiencies by measuring serum magnesium, fat-soluble vitamins (A, E, D, and K), and lipoproteins can support the diagnosis of EPI and monitor response to treatment.[33] Moreover, secretin-stimulated magnetic resonance cholangiopancreatography can assess for pancreatic structural abnormalities in response to secretin administration. However, this test has a low sensitivity (69%) with limited supporting evidence for use in EPI diagnosis.[4] 

Treatment / Management

Treatment of exocrine pancreatic insufficiency includes preventing malnutrition-related complications and improving the patients' quality of life. Documentation of body weight and body mass index along with anthropometric measurements, dual-energy x-ray absorptiometry scan, and screening for nutritional deficiencies (albumin; international normalized ratio; vitamins A, D, E, and K; B vitamins; and folate levels) should be performed for all patients diagnosed with EPI at diagnosis and at least annually to assess the response to pancreatic enzyme replacement therapy (PERT) and disease status.[5][33][34] PERT is recommended to treat EPI and associated malnutrition and malabsorption. Effectiveness is enhanced by increasing the dose, using enteric-coated formulations, suppressing gastric acid, and administering the medication during meals.[40] Treatment of the underlying etiology of EPI is important, and patients should undergo lifestyle counseling that includes abstinence from alcohol, smoking cessation, and dietary modifications in the form of small, frequent meals and avoidance of indigestible foods. Patients with EPI should also be advised to supplement with fat-soluble vitamins.[6][44](A1)

PERT is the primary treatment of EPI.[45] A combination of pancreatic enzymes (lipase, amylase, and protease) prevents malabsorption and restores the normal physiologic digestive process. The enteric coating of the enzymatic supplement protects from gastric acidity, allowing for dissolution in the duodenum in response to an alkaline pH. Due to decreased bicarbonate secretion, some patients may require gastric acid suppression to dissolve the enteric coat. Histamine-2 receptor antagonists or proton-pump inhibitors are needed for patients taking non–enteric-coated formulations to protect the enzymes from gastric acidity.[33] The dose varies depending on the severity of EPI and the individual patient's needs.

The typical starting dose of PERT is 500 units of lipase/kg/meal (eg, 40,000 units of lipase for a patient weighing 80 kg), with a half-dose administered with snacks. The dose can be titrated according to response to 75,000 to 90,000 lipase units per meal. The most common adverse effects are nausea, bloating, and abdominal pain, which may be similar to symptoms associated with EPI. In cases that do not improve despite dose escalation, gastric acid suppression and excluding other superimposed causes for symptoms should be considered.[5][33] PERT can treat EPI in cystic fibrosis with cautious dose increases adjusted for energy consumption.[26] Replacement therapy improves survival and quality of life among patients with pancreatic cancer for both resectable and nonresectable tumors by addressing malnutrition and associated complications.[35][46]

Dietary modifications include a low- to moderate-fat diet with frequent, small meals and avoidance of a very low-fat diet. Patients benefit from a dietitian consultation to review and formulate diet plans.[33][47] Finally, stem cell technology, which induces pluripotent stem cells to differentiate into pancreatic exocrine cells, shows promise but remains under investigation.[47] (B3)

Differential Diagnosis

Exocrine pancreatic insufficiency is often underdiagnosed due to its broad and nonspecific presentation. Symptoms often overlap with those of functional gastrointestinal disorders.[6][33] A comprehensive approach, including obtaining a thorough history, performing a physical examination, and obtaining laboratory investigations, is essential for a timely and accurate diagnosis. Conditions that may be confused with EPI include malabsorption syndromes (such as celiac disease), inflammatory bowel disease, irritable bowel syndrome, microscopic colitis, small intestinal bacterial overgrowth, and giardiasis.[22]

Prognosis

Prognosis depends on the underlying etiology of pancreatic exocrine insufficiency and proper management of symptoms through enzyme replacement therapy, dietary modification, and nutrient supplementation. 

Complications

Untreated EPI can lead to malnutrition and associated complications that impair quality of life and shorten life expectancy. For example, approximately 65% of patients diagnosed with chronic pancreatitis have either osteoporosis or osteopenia. Untreated EPI reduces quality of life due to persistent symptoms, decreased work capacity, and financial strain. Increased morbidity and mortality are due to malnutrition and cardiovascular complications.[33]