Practice Essentials
Exocrine pancreatic insufficiency (EPI) is a condition characterized by deficiency of exocrine pancreatic enzymes, resulting in the inability to digest food properly, or maldigestion. The etiology of EPI includes pancreatic and nonpancreatic causes (see Etiology). [1, 2]
The exocrine pancreas produces three main types of enzymes: amylase, protease, and lipase, which are responsible for the digestion of carbohydrates, protein, and fat. [3] Under normal physiologic conditions, lipase breaks undigested triglycerides into fatty acids and monoglycerides, which are then solubilized by bile salts (see Pathophysiology). Because exocrine pancreas retains a large reserve capacity for enzyme secretion, fat digestion is not clearly impaired until lipase output decreases to below 10% of the normal level. [4]
The diagnosis of EPI is largely clinical. [5] It may go undetected because the signs and symptoms are similar to those of other gastrointestinal (GI) diseases [6] or because signs and symptoms are not always evident, due to dietary restrictions (see Presentation and Differential Diagnosis). [7]
Signs of exocrine pancreatic insufficiency
Major symptoms of EPI include steatorrhea (oily stool) and weight loss. Although steatorrhea is the most common symptomatic complaint, sometimes the stool can be watery, reflecting the osmotic load received by the intestine.
Workup in exocrine pancreatic insufficiency
Blood tests
These can include the following:
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Complete blood count (CBC)
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Antigliadin and antiendomysial antibodies - To rule out celiac disease
Stool tests
Determination of fecal elastase (a protease produced by the pancreas) can be used to support the diagnosis of EPI.
Malabsorption tests
These can include the following:
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Fat absorption tests
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D-xylose test
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Carbohydrate absorption test
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Bile salt absorption test
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Schilling test
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13C-D-xylose breath test
Pancreatic function tests
These can include the following:
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Direct testing - Secretin test, cholecystokinin (CCK) test, secretin-CCK test
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Indirect testing - Qualitative fecal fat analysis, fecal elastase level analysis
Abdominal imaging
Abdominal imaging can help in identifying features of chronic pancreatitis, which is the most common cause of EPI.
Management of exocrine pancreatic insufficiency
Management strategies for EPI include the following:
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Lifestyle modifications - Eg, avoidance of fatty foods, limitation of alcohol intake, cessation of smoking, and consumption of a well-balanced diet
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Vitamin supplementation - Primarily the fat-soluble vitamins A, D, E, and K
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Pancreatic enzyme replacement therapy (PERT)
PERT is the basis of treatment for EPI; the endpoints of treatment are normalization of gut absorption and correction of nutritional deficiencies. The typical indications for initiating PERT are progressive weight loss and steatorrhea.
Anatomy
The pancreas, named for the Greek words pan (all) and kreas (flesh), is a soft, lobulated, retroperitoneal organ that is 12-15 cm long and roughly J-shaped (like a hockey stick). It lies transversely, though a bit obliquely, on the posterior abdominal wall behind the stomach, across the lumbar (L1-2) spine (see the image below). The pancreas is prismoid in shape and appears triangular in cut section, with superior, inferior, and anterior borders as well as anterosuperior, anteroinferior, and posterior surfaces.
The head of the pancreas lies in the duodenal C loop in front of the inferior vena cava (IVC) and the left renal vein (see the images below). The uncinate process is an extension of the lower (inferior) half of the head toward the left; it is of varying size and is wedged between the superior mesenteric vessels in front (the vein on the right and the artery on the left) and the aorta behind. The pancreatic head constitutes about 50% of the pancreatic parenchymal mass.
The body and tail of the pancreas run obliquely upward to the left in front of the aorta and the left kidney. The pancreatic neck is the arbitrary junction between the head and body of the pancreas. The narrow tip of the tail of the pancreas reaches the splenic hilum in the splenorenal (lienorenal) ligament. The body and tail make up the remaining 50% of the pancreatic parenchymal mass.
The transverse mesocolon (with the middle colic vessels in it) is attached to the anterior surface of the lower (inferior) surface of the body and tail; thus, most of the gland is located in the supracolic compartment. The body and tail of the pancreas lie in the lesser sac (omental bursa) behind the stomach.
Pathophysiology
The GI tract is responsible for digesting and absorbing food. [8] Lipids provide the richest source of energy for the body, with 9 calories in every gram of fat; in comparison, carbohydrate and protein contains 4 calories per gram. Whereas protein and carbohydrate begin to undergo digestion in the stomach, triglycerides remain mostly unchanged until they reach the small intestine. Intragastric breakdown accounts for approximately 10% of total lipid digestion. [8]
The pancreatic enzymes responsible for lipid digestion are inactivated when the pH drops below 5; thus, before digestion can continue in the duodenum, the acidic contents of the stomach must be neutralized. Fortunately, the pancreas also secretes bicarbonate, which increases the pH of the duodenal contents.
The exocrine pancreas produces 3 main types of enzymes: amylase, protease, and lipase. [3] Under normal physiologic conditions, lipase breaks the undigested triglycerides into fatty acids and monoglycerides. Bile salts then solubilize these breakdown products to form micelles, which are vehicles for absorbing lipid breakdown products. [8] Normal fat digestion also depends on postprandial synchrony between delivery of nutrients to the duodenum and discharge of pancreatic enzymes. [3]
Pancreatic secretion is governed by neural and hormonal mechanisms. The hormones responsible for regulation are secretin and cholecystokinin (CCK). Secretin is secreted in response to acid in the duodenum, causing duct cells to release water and bicarbonate; CCK is secreted in response to protein and fat in the small intestine, stimulating acinar cells to release the pancreatic enzymes (see the image below).
EPI is characterized by a deficiency of these exocrine pancreatic enzymes, which results in inability to digest food properly (ie, maldigestion). Because pancreatic lipase accounts for up to 90% of fat digestion, maldigestion of fat is more profound in EPI than maldigestion of proteins and carbohydrates is. [8] Because the exocrine pancreas retains a large reserve capacity for enzyme secretion, [8] fat digestion is not clearly impaired until lipase output decreases to below 10% of the normal level. [4]
Fat malabsorption precedes malabsorption of other macronutrients. [9] Bile salt precipitation and subsequent adsorption to undigested food reduces the bile salt pool, and this reduction further impairs fat digestion. [10] Undigested fat, rather than being absorbed, is excreted in the feces, leading to steatorrhea.
Another factor that contributes to pancreatic steatorrhea is the presence of neurohormonal disturbances, which result in gall bladder hypomotility and accelerated gastric and intestinal transit. [11] Malabsorption of fat-soluble vitamins A, D, E, and K may accompany EPI.
Etiology
The etiology of EPI can be classified into pancreatic and nonpancreatic causes. [12, 13]
Pancreatic causes
These include the following:
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Chronic pancreatitis (the most common cause of EPI) - This condition has a number of possible causes, but the end result is a metabolic insult to the pancreatic exocrine cells that leads to necrosis, fibrosis and loss of function (see the image below).
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Acute pancreatitis - A literature review by Huang et al found that during first admission for acute pancreatitis (ie, the time between the commencement of oral refeeding and discharge) in 370 patients, exocrine pancreatic insufficiency (EPI) had a pooled prevalence of 62%. At follow-up (1 month or more following discharge for a first attack of acute pancreatitis) in 1795 patients, the pooled prevalence of EPI was 35%. The investigators also found at follow-up that compared with mild acute pancreatitis, the pooled prevalence for EPI was twice as great for severe acute pancreatitis (21% vs 42%, respectively). [14]
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Cystic fibrosis - In this condition, reduced chloride transport in the pancreas leads to reduced water content of secretions, precipitation of proteins, and plugging of ductules and acini, preventing the pancreatic enzymes from reaching the gut; autodigestion of the pancreas occasionally leads to pancreatitis.
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Obstructions of the pancreatic duct (eg, from pancreatic cancer or ampullary tumors) - These hinder pancreatic exocrine secretions from reaching the gut.
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Diabetes - A study by Yatchenko et al suggested that EPI in type 2 diabetes mellitus derives from the effects of high insulin levels on pancreatic acinar cells. The investigators found evidence that high insulin concentrations impact naïve acinar cells via the activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1) pathways, leading to activation of the endoplasmic reticulum–stress unfolded protein response (UPR). [17]
Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel (see the image below) and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces.
Nonpancreatic causes
Celiac disease
Celiac disease (secondary to decreased pancreatic stimulation) leads to EPI in about one third of patients and may be an unrecognized cause of treatment failure.
Crohn disease
Crohn disease is associated with pancreatic autoantibodies that lead to impaired pancreatic exocrine function.
Autoimmune pancreatitis
Autoimmune pancreatitis is often caused by immunoglobulin G4 (IgG4)-related disease and can progress to EPI. [18]
Zollinger-Ellison syndrome
Zollinger-Ellison syndrome can produce EPI through acid inactivation of pancreatic enzymes; it is corrected by controlling the acid secretion
GI and pancreatic surgical procedures
Any such procedures that lead to loss of postprandial synchrony, decreased pancreatic stimulation, and loss of pancreatic parenchyma can cause EPI. [19] A study by Huddy et al found that EPI contributes to postoperative morbidity in patients who undergo esophagectomy. [20] Using multivariate analysis, a study by Dhar et al indicated that in patients with chronic pancreatitis who undergo duodenum-sparing head resection or pancreaticoduodenectomy to relieve abdominal pain, EPI and narcotic requirement are the only predictors of the need for revision surgery. [21]
A study by Okano et al suggested that following pancreatectomy, a remnant pancreatic volume of under 24 mL is the only independent predictor of postoperative EPI. The study included 227 patients. [22]
However, a study by Hallac et al indicated that in patients who undergo distal pancreatectomy, the chance of developing de-novo exocrine pancreatic insufficiency (EPI) is greater in those with an underlying obstructive pancreatic pathology and in individuals who present with a history of acute pancreatitis. The investigators found that new-onset EPI arose in 38 of 324 patients (11.7%), while EPI existed preoperatively in 22 (6.8%) of patients, suggesting that patients set to undergo pancreatectomy may not uncommonly have preexisting EPI. [23]
Epidemiology and Prognosis
Because EPI has multiple possible causes and is not usually recorded as a medical statistic, its prevalence and demographics cannot be established with certainty at present. In a German-based study, one of the most common causes of EPI had an age-adjusted prevalence of 8 per 100,000 for males and 2 per 100,000 for women; these numbers are probably relatively close to the prevalence of EPI in most developed countries. No other reliable data are currently available. [24]
The natural history and progression of EPI depend on the underlying etiology. For example, patients with autoimmune pancreatitis or cystic fibrosis may progress to almost complete insufficiency, whereas those with alcohol-induced EPI may recover from or at least halt the progression of pancreatic insufficiency if they abstain from alcohol. Even with complete loss of exocrine function, however, protease and lipase supplements are effective in restoring normal digestion of dietary nutrients.
A prospective, longitudinal cohort study by de la Iglesia et al indicated that in patients with chronic pancreatitis, EPI is an independent risk factor for cardiovascular events, with the incidence rate ratio for such events in patients with EPI compared with those without being 3.67. In addition, the odds ratio for cardiovascular events in individuals with a combination of EPI and diabetes mellitus was higher than for EPI patients without diabetes. [25]
A study by Vujasinovic et al indicated that in patients with chronic pancreatitis, EPI is an independent risk factor for nephrolithiasis. The investigators found that the adjusted hazard ratio (aHR) for kidney stones in chronic pancreatitis patients with EPI is 4.95. Male sex and an increase in body mass index (BMI) were also determined to be risk factors for stone formation, the aHRs being 4.51 and 1.16, respectively. [26]
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Complete replacement of the pancreas with cystic disease and intrahepatic biliary dilation caused by extrinsic compression of the common bile duct. Note also the renal cysts and masses. This patient had exocrine pancreatic insufficiency. Image courtesy of Wikimedia Commons.
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Residual islets in dense fibrous stroma secondary to loss of exocrine pancreatic tissue in chronic pancreatitis (hematoxylin-eosin stain, medium magnification). Image courtesy of Dr. Rose Anton.
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Pancreas anatomy.
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The duodenum and pancreas.
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The pancreas and duodenum, posterior view.
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Factors controlling release of pancreatic secretions. Image courtesy of Wikimedia Commons.
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Defective protein transmembrane conductance regulator (CFTR) in cystic fibrosis.