Exocrine pancreatic insufficiency

INTRODUCTION — Exocrine pancreatic insufficiency is an under recognized complication of pancreatic disease [1-3]. While patients with advanced exocrine pancreatic insufficiency usually present with abdominal pain and steatorrhea, those with less severe insufficiency may only have mild symptoms. This topic will review the etiology, clinical manifestations, diagnosis, and management of exocrine pancreatic insufficiency. An overview of nutrient absorption, malabsorption, and the evaluation and management of exocrine pancreatic insufficiency in cystic fibrosis are discussed in detail separately. (See "Approach to the adult patient with suspected malabsorption" and "Overview of nutrient absorption and etiopathogenesis of malabsorption" and "Overview of the treatment of malabsorption in adults" and "Cystic fibrosis: Assessment and management of pancreatic insufficiency" and "Cystic fibrosis: Overview of gastrointestinal disease".)

NORMAL PANCREATIC PHYSIOLOGY — The pancreas secretes approximately 1.5 liters of enzyme-rich fluid every day for the digestion of fats, starch, and protein. Normal pancreatic juice is clear, colorless, isotonic, and alkaline. The composition of pancreatic juice differs in basal and stimulated phases. In the fasting state, pancreatic fluid is protein-rich and has a bicarbonate concentration of 80 mEq/L. Stimulation of the pancreas after a meal increases the flow of water and the bicarbonate concentration of pancreatic juice. A large volume of alkaline, enzyme-rich fluid enters the duodenum to neutralize gastric chyme for optimal digestion.

Pancreatic secretion is controlled by hormonal and neuronal mechanisms. The principal regulatory hormones are secretin and cholecystokinin (CCK). Both are tightly regulated by negative feedback mechanisms. Secretin is released from the duodenal mucosa in response to the presence of acid in the duodenum (figure 1). Secretin primarily stimulates the release of bicarbonate and water from the interlobular duct cells and causes a gradual rise in the flow of pancreatic fluid through the ducts and a typical pattern of electrolyte secretion (figure 2). As bicarbonate concentration rises to a peak concentration of 120 mEq/L, chloride concentration decreases reciprocally to maintain isotonicity. CCK is released from gut endocrine cells in response to the entry of fat and protein into the proximal intestine (figure 3). CCK acts directly and through vagal afferents to stimulate pancreatic acinar cells to release digestive proenzymes. (See "Overview of nutrient absorption and etiopathogenesis of malabsorption", section on 'Fat' and "Physiology of cholecystokinin" and "Secretin".)

ETIOLOGY AND PATHOGENESIS — Several conditions are associated with exocrine pancreatic insufficiency [4].

Chronic pancreatitis — Chronic pancreatitis is the most common cause of exocrine pancreatic insufficiency in adults. Progressive inflammatory changes in the pancreas in chronic pancreatitis results in permanent structural damage, which can lead to impairment in exocrine function. (See "Etiology and pathogenesis of chronic pancreatitis in adults", section on 'Pathogenesis'.)

Cystic fibrosis — Cystic fibrosis is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator protein. This protein regulates the transport of chloride and water across endothelial cell membranes in the lungs and exocrine glands. Approximately 80 percent of patients with cystic fibrosis also develop progressive pancreatic damage due to the blockage of ductules resulting from inspissated pancreatic secretion. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Pancreatic disease'.)

Pancreatic resection — Total or a partial resection of the pancreas may result in varying degrees of exocrine pancreatic insufficiency due to reduction of glandular tissue or postoperative pancreatic duct occlusion. Extensive denervation following lymph node dissection can result in postcibal asynchrony and decreased pancreatic stimulation. (See "Chronic complications of the short bowel syndrome in adults".)

Pancreatic duct obstruction — Atrophy of the pancreas secondary to pancreatic/ampullary tumor-induced pancreatic duct obstruction and fibrosis can lead to exocrine pancreatic insufficiency [5,6].

Shwachman-Diamond syndrome — Shwachman-Diamond syndrome is an autosomal recessive syndrome that generally presents in infancy with bone marrow failure, particularly neutropenia, and exocrine pancreatic dysfunction. (See "Shwachman-Diamond syndrome".)

Other — Patients with gastrinoma (Zollinger-Ellison syndrome) may develop exocrine pancreatic insufficiency due to inactivation of pancreatic enzymes by gastric acid. Small bowel mucosal disease (eg, celiac disease, Crohn disease) can result in decreased cholecystokinin release, which in turn can result in reduced pancreatic secretion. Patients with a history of complex foregut surgery (Roux-en-Y gastric bypass, pancreaticoduodenectomy, duodenal switch, etc) are also at moderate risk for exocrine pancreatic insufficiency. Loss of the pylorus, dumping syndrome, and motility disorders following surgery may result in asynchrony as delivery of pancreatic enzymes may not match the delivery of the meal in the upper intestine. Other rare causes of exocrine pancreatic insufficiency include hereditary hemochromatosis, which results in progressive iron deposition in the pancreas. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis" and "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency" and "Physiology of cholecystokinin".)

CLINICAL MANIFESTATIONS

Asymptomatic/mild symptoms — Patients with mild exocrine pancreatic insufficiency may be asymptomatic or have mild abdominal discomfort and bloating with normal-appearing bowel movements.

Moderate to severe symptoms — Advanced exocrine pancreatic insufficiency results in maldigestion of fat and protein and weight loss. Overt steatorrhea does not occur until approximately 90 percent of glandular function has been lost [7]. Patients with steatorrhea report loose, greasy, foul-smelling stools that are difficult to flush. Other symptoms include bloating, cramping, and increased flatulence. Although clinically symptomatic vitamin deficiency is rare, metabolic bone disease and impaired night vision have been observed in patients with chronic pancreatitis [8,9]. (See "Approach to the adult patient with suspected malabsorption".)

LABORATORY FINDINGS — Patients with severe exocrine pancreatic insufficiency have elevated levels of fecal fat. Fat malabsorption predisposes patients to deficiencies of the fat soluble vitamins A, D, E, and K [10,11]. Rarely, patients may also have vitamin B12 deficiency because a reduction in intestinal pH adversely affects the transfer of vitamin B12 from R protein to intrinsic factor [12,13]. (See "Approach to the adult patient with suspected malabsorption" and "Chronic pancreatitis: Clinical manifestations and diagnosis in adults" and "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Pancreatic insufficiency'.)

IMAGING FINDINGS — Cross-sectional imaging (computed tomography scan, magnetic resonance imaging, and endoscopic ultrasound) cannot identify exocrine pancreatic insufficiency but can identify underlying pancreatic diseases. In patients with chronic pancreatitis, abdominal imaging may demonstrate calcifications, ductal dilatation, enlargement of the pancreas, and peripancreatic fluid collections. Patients with advanced chronic pancreatitis, cystic fibrosis, Shwachman-Diamond syndrome, and advanced hemochromatosis may have evidence of pancreatic atrophy.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of exocrine pancreatic insufficiency includes other causes of chronic diarrhea and steatorrhea. These include small intestinal bacterial overgrowth, celiac disease, and giardiasis. Exocrine pancreatic insufficiency can be distinguished from these causes based on history and laboratory studies.

●Small intestinal bacterial overgrowth – Patients with small intestinal bacterial overgrowth (SIBO) present with nonspecific symptoms of bloating, flatulence, abdominal discomfort, or steatorrhea. The diagnosis of SIBO is established by a carbohydrate breath test (eg, glucose or lactulose breath test) or jejunal aspirate culture.

●Celiac disease – Patients with celiac disease can present with chronic diarrhea or steatorrhea but have elevated celiac serologies (IgA anti-tissue transglutaminase antibody). Some patients with celiac disease may have secondary exocrine pancreatic insufficiency that resolves with mucosal inflammation on a gluten-free diet. (See "Diagnosis of celiac disease in adults", section on 'Diagnostic approach' and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Gastrointestinal manifestations'.)

●Giardiasis – Giardia duodenalis is a protozoan parasite capable of causing epidemic or sporadic diarrheal illness. Acute and chronic giardiasis can cause diarrhea, malaise, abdominal cramps, and weight loss. The diagnosis of giardiasis can be established with antigen detection assays, nucleic acid detection assays, or stool examination. (See "Giardiasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

The differential diagnosis for other causes of chronic diarrhea is broad and is discussed in detail separately. (See "Approach to the adult with chronic diarrhea in resource-abundant settings".)

DIAGNOSIS

Diagnostic approach — The diagnosis of exocrine pancreatic insufficiency should be suspected in patients with chronic diarrhea/steatorrhea and chronic abdominal pain. Exocrine pancreatic insufficiency should also be suspected in patients with milder symptoms of bloating with overt morphological abnormalities on pancreatic imaging that are suggestive of chronic pancreatitis (eg, calcifications and/or main pancreatic duct dilation).

In patients with well-established chronic pancreatitis or underlying pancreatic disease, a clinical diagnosis can be made based on the patient's symptoms. However, if the diagnosis is unclear or in those without well-established pancreatic disease, we begin with an indirect test of pancreas function (fecal elastase-1) to establish the diagnosis of exocrine pancreatic insufficiency. Response to a therapeutic trial of pancreatic enzymes should not be relied upon to diagnose exocrine pancreatic insufficiency in patients with nonspecific symptoms as the response may be due to placebo effect and result in delays in diagnosis [4].

Indirect pancreatic function tests — Indirect tests measure the consequence of exocrine insufficiency (maldigestion). Indirect tests are simpler, easier to perform, and less expensive as compared with direct pancreas function tests. Their main role is in diagnosis of advanced exocrine pancreatic insufficiency. They are much less sensitive as compared with direct tests for diagnosis of earlier stages of exocrine pancreatic insufficiency. Other disadvantages include false positive results with non-pancreatic gastrointestinal diseases and the need for stool collection.

Fecal elastase-1 — Fecal elastase is the most sensitive and specific indirect test of pancreatic function, and the most widely available and commonly performed pancreatic function test in clinical practice. Fecal elastase-1 is an enzymatic product of pancreatic secretion that remains relatively stable during transport through the gastrointestinal tract. There is a direct correlation in pancreatic elastase-1 concentrations in pancreatic fluid and stool [14,15]. Fecal elastase-1 must be performed on a semi-solid or solid stool specimen. Watery diarrhea may dilute the fecal specimen and produce false-positive results. This limitation can be ameliorated by lyophilizing (concentrating) the stool sample [16].

Fecal elastase-1 <200 mcg/g is considered abnormal. Levels <100 mg/g of stool are more consistent with EPI, while levels of 100 to 200 mg/g of stool are indeterminate for exocrine pancreatic insufficiency. The sensitivity of fecal elastase-1 for mild, moderate, and severe exocrine pancreatic insufficiency in patients with chronic pancreatitis are 63, 100, and 100 percent, respectively. Fecal elastase has a specificity of 93 percent in patients with exocrine pancreatic insufficiency [14,17-19]. Exogenous pancreatic enzyme replacement therapy does not alter fecal elastase test results.

Other — Other tests are not routinely used to measure pancreatic function.

Fecal chymotrypsin — Fecal chymotrypsin is also an enzymatic product of pancreatic secretion that can be used to detect pancreatic insufficiency. However, chymotrypsin has a lower sensitivity and specificity for exocrine pancreatic insufficiency as compared with fecal elastase-1 [20]. The sensitivity of fecal chymotrypsin for mild to moderate and advanced pancreatic insufficiency is 49 and 85 percent, respectively [21]. Chymotrypsin is variably affected during intestinal transport and may be diluted in the presence of concomitant diarrhea. Since chymotrypsin is present in commercially available enzymes, patients must stop exogenous enzymes for two days prior to testing.

Serum trypsinogen — Serum trypsinogen is an inexpensive and widely available test that reflects pancreatic acinar cell mass [22,23]. Serum trypsinogen has a high sensitivity for advanced exocrine pancreatic insufficiency when trypsinogen levels are less than 20 ng/mL [24]. However, the test has low sensitivity for diagnosing less severe exocrine pancreatic insufficiency when trypsinogen levels are between 20 and 29 ng/mL. In addition, serum trypsinogen is not specific for exocrine pancreatic insufficiency and levels rise with acute pancreatitis and abdominal pain of nonpancreatic origin [22,23].

Direct pancreatic function tests — Direct pancreatic function tests are the most sensitive diagnostic tests for exocrine pancreatic insufficiency [25]. They involve stimulation of the pancreas through the administration of hormonal secretagogues after which duodenal fluid is collected and analyzed to directly quantify pancreatic secretory content (ie, enzymes and bicarbonate). Limitations include the lack of standardization of testing protocol and normal ranges, limited availability of expertise needed to perform the test, and poor patient tolerance [20,26]. Cholecystokinin (CCK) and secretin have both been used to stimulate pancreatic secretion [27-29]. However, it is unclear which secretagogue offers the best sensitivity for early pancreatic insufficiency. Studies evaluating the performance of direct pancreas function tests in patients with established chronic pancreatitis on imaging have demonstrated a sensitivity of 72 to 94 percent [25,30-39].

Secretin test — Direct pancreas function testing using secretin stimulation measures the ability of ductal cells to produce bicarbonate.

●Traditional test – The traditional direct pancreas function test requires fluoroscopic placement of an oroduodenal collection tube (eg, Dreiling tube) with gastric and duodenal ports (image 1). After a test dose (0.2 mcg) of synthetic secretin, a full dose (0.2 mcg/kg) is administered as an intravenous bolus. Duodenal fluid is continuously collected in 15-minute aliquots for one hour. Fluid is analyzed for bicarbonate concentration, volume, and total bicarbonate output. A bicarbonate concentration less than 80 mEq/L in all of the four aliquots is diagnostic of exocrine pancreatic insufficiency [40]. Severe exocrine pancreatic insufficiency is characterized by a peak bicarbonate concentration less than 50 mEq/L. Total volume and bicarbonate output have been used as secondary diagnostic parameters when bicarbonate concentration is equivocal. However, bicarbonate output and fluid volume are notoriously inaccurate measures because of the incomplete recovery of duodenal fluid. A shortened collection period has also been evaluated but has significantly lower accuracy in diagnosing pancreatic insufficiency as compared with the standard one-hour collection [41,42].

●Endoscopic test – Endoscopically-assisted and purely endoscopic pancreatic function test are performed under sedation and are better tolerated as compared with tradition direct pancreas function test [43]. In endoscopically-assisted pancreas function tests, an endoscopically placed Dreiling or Liguory tube is used for duodenal fluid collection. In contrast, in purely endoscopic pancreas function testing, duodenal fluid is collected through the endoscope into a specimen trap.

The protocol for the secretin endoscopic pancreatic function test is similar to the traditional secretin test protocol. Duodenal aspirates are obtained 0, 15, 30, 45, and 60 minutes after administration of secretin; however, aspiration at 30 to 45 minutes can simplify the test and appears to be sufficient for screening [44]. A peak bicarbonate concentration <80 mEq/L is considered abnormal for the one-hour method. A cutoff of 75 mEq/L is used for the shortened test. The secretin endoscopic pancreatic function test method replicates the well-known pancreatic secretory patterns observed with collection tubes (figure 4) and is comparable in accuracy to the traditional secretin test [45-47]. In one retrospective study that included 25 patients with chronic pancreatitis, the sensitivity and specificity of endoscopic secretin pancreas function testing for chronic pancreatitis was 86 and 67 percent, respectively [48]. Standard doses of sedation do not appear to decrease pancreas secretion, but caution in interpretation of abnormal results is needed when large amounts of analgesia are needed for endoscopy [49].

Intraductal collection of secretin-stimulated pure pancreatic juice at the time of endoscopic retrograde cholangiopancreatography has also been evaluated as an alternative to standard secretin testing because it permits simultaneous evaluation of pancreatic structure and function. However, studies of intraductal secretin tests have yielded mixed results and the procedure carries the risk of acute pancreatitis [50-53].

CCK test — Use of CCK receptor agonist (eg, cerulein) as a hormonal stimulant provides information on the enzyme secretory capacity of the pancreas. However, thresholds for lipase concentrations have not been well established and results from studies have been conflicting [54-56]. Traditionally, this test requires the placement of two tubes: a double-lumen duodenal tube and a single-lumen gastric tube [29]. The gastric tube continuously collects and discards gastric fluid to prevent acidification of the duodenum. One duodenal lumen continuously collects duodenal drainage fluid. The other lumen perfuses a mannitol-saline solution with a non-absorbable marker (polyethylene glycol [PEG]). An accurate determination is made of enzyme concentration, enzyme output, and fluid volume based upon recovery of the PEG marker. CCK pancreas function test has also been performed endoscopically [55].

●Breath tests – Breath tests for exocrine pancreatic insufficiency involve the oral administration of 13C-marked substrates with a test meal [57,58]. These substrates are hydrolyzed within the intestinal lumen in proportion to the amount of pancreatic lipase activity. The hydrolyzed products are absorbed and metabolized, and eventually released across the pulmonary endothelium as 13CO2. Mass spectrometry or infrared analysis is used to quantify 13CO2. Like other indirect tests, breath tests quantify fat malabsorption and are therefore nonspecific and inaccurate for the diagnosis of mild exocrine pancreatic insufficiency. In the United States, breath tests have not been approved for diagnosis of exocrine insufficiency.

●Secretin-enhanced diffusion weighted magnetic resonance imaging – Secretin-enhanced magnetic resonance cholangiopancreatography also allows timed assessments of duodenal filling, which provides an estimation of pancreatic exocrine function. Secretin stimulates both pancreatic ductal secretion of water and pancreatic blood flow. Diffusion weight magnetic resonance imaging (MRI) permits detection of the mobility of water molecules and increased capillary blood flow in pancreatic parenchyma. The apparent diffusion coefficient is a calculated measure that integrates both diffusion and perfusion. Studies are needed to compare diffusion weighted MRI with direct pancreatic function tests [59,60].

ESTABLISHING THE ETIOLOGY — Once functional tests have established the diagnosis of exocrine pancreatic insufficiency, it is necessary to determine the underlying etiology (table 1). In patients in whom the history can often clearly point to the underlying etiology, we do not perform additional evaluation in the absence of worrisome clinical features (eg, new onset of steatorrhea with weight loss). Historical clues that may be indicative of a specific etiology include a history of cystic fibrosis, chronic pancreatitis, and gastric/small bowel/pancreatic resection. In patients with new onset steatorrhea and weight loss, we perform an abdominal computerized tomography scan or endoscopic ultrasound to rule out pancreatic ductal adenocarcinoma. (See 'Etiology and pathogenesis' above.)

Exocrine pancreatic insufficiency may also be associated with celiac disease, gastrinoma, and liver disease. Additional testing for these conditions should be performed in patients with a history or physical examination findings suggestive of these disorders. (See "Diagnosis of celiac disease in adults", section on 'Diagnostic approach' and "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis", section on 'Diagnosis'.)

MANAGEMENT — The mainstay of management in patients with symptoms of maldigestion and steatorrhea due to exocrine pancreatic insufficiency is administration of exogenous pancreatic enzymes. Patients with exocrine pancreatic insufficiency are also at risk for deficiencies of fat-soluble vitamins and other micronutrients, and bone disease. Prevention and monitoring for these complications are discussed separately. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency", section on 'Management' and "Overview of the treatment of malabsorption in adults" and "Chronic pancreatitis: Management", section on 'Management of pancreatic insufficiency'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic pancreatitis and pancreatic exocrine insufficiency".)

SUMMARY AND RECOMMENDATIONS

●Etiology and pathogenesis – Exocrine pancreatic insufficiency results from loss of pancreatic parenchyma (eg, chronic pancreatitis), inadequate pancreatic stimulation (eg, pancreatic surgical resection), pancreatic duct obstruction, or pancreatic enzyme inactivation (eg, gastrinoma) (table 1). (See 'Etiology and pathogenesis' above.)

●Clinical features  

•Patients with mild exocrine pancreatic insufficiency may be asymptomatic or have mild abdominal discomfort and bloating with normal-appearing bowel movements. Overt steatorrhea does not occur until approximately 90 percent of glandular function has been lost. Advanced exocrine pancreatic insufficiency results in maldigestion of fat and protein and weight loss. Patients with steatorrhea report loose, greasy, foul-smelling stools that are difficult to flush. Other symptoms include bloating, cramping, and increased flatulence. (See 'Clinical manifestations' above.)

•Patients with severe exocrine pancreatic insufficiency have elevated levels of fecal fat. Malabsorption of the fat-soluble vitamins (A, D, E, K) and vitamin B12 may also occur. (See 'Laboratory findings' above.)

●Imaging findings – In patients with chronic pancreatitis, calcifications, ductal dilatation or atrophy of the pancreas may be detected on abdominal imaging. Patients with advanced chronic pancreatitis, cystic fibrosis, Shwachman-Diamond syndrome, and advanced hemochromatosis may have pancreatic atrophy on imaging. (See 'Imaging findings' above.)

●Diagnosis – The diagnosis of exocrine pancreatic insufficiency should be suspected in patients with underlying conditions associated with exocrine insufficiency, and who have postprandial cramping abdominal pain, bloating, chronic diarrhea, or steatorrhea. Exocrine pancreatic insufficiency should also be suspected in patients with milder symptoms of bloating with morphological abnormalities on pancreatic imaging that are suggestive of chronic pancreatitis (eg, calcifications and/or main pancreatic duct dilation). In patients with well-established chronic pancreatitis or underlying pancreatic disease, a clinical diagnosis can be made based on the patient's symptoms. However if the diagnosis is unclear or in those without well-established pancreatic disease, we begin with an indirect test of pancreas function (fecal elastase-1) to establish the diagnosis of exocrine pancreatic insufficiency. (See 'Diagnostic approach' above.)

●Determining the underlying etiology – Once a diagnosis of exocrine pancreatic insufficiency is made, it is necessary to determine the underlying etiology (table 1). In patients in whom the history can clearly point to the underlying etiology, we do not perform additional evaluation in the absence of worrisome clinical features (eg, new onset of steatorrhea with weight loss). In patients with new onset steatorrhea and weight loss, we perform an abdominal CT scan or endoscopic ultrasound to rule out pancreatic ductal adenocarcinoma. (See 'Establishing the etiology' above.)