Pancreatic Insufficiency

Etiology

The 2 principal causes of exocrine pancreatic insufficiency are chronic pancreatitis in adults and cystic fibrosis in children. Other causes include- acute pancreatitis, pancreatic tumors, diabetes mellitus, celiac disease, inflammatory bowel disease, bariatric surgery, human immunodeficiency virus (HIV)/acquired immunodeficiency disease (AIDS), and genetic and congenital causes.[1][2][3]  

The Toxic-Metabolic, Idiopathic, Genetic, Autoimmune, Recurrent, and Severe Acute Pancreatitis, Obstructive (TIGAR-O) classification system was developed to categorize causes and risk factors of chronic pancreatitis and pancreatic exocrine insufficiency.[4] 

• The toxic-metabolic causes include alcohol, tobacco smoking, hypercalcemia, hyperlipidemia, and chronic renal failure.
• Idiopathic causes are responsible for approximately 25% of causes, and recently it is related to genetic defects.
• The genetic defects may include CFTR mutations, SPINK1 mutations, and hereditary pancreatitis.
• The autoimmune causes include pancreatitis associated with Sjogren syndrome, primary biliary cirrhosis, and inflammatory bowel disease.
• There is recurrent and severe acute pancreatitis, including recurrent acute pancreatitis, post-necrotic, vascular diseases, and post-radiation.
• Obstructive causes include congenital anomalies of pancreatic ducts (large or small ducts), sphincter of Oddi dysfunction, obstruction of the duct by a tumor, and post-traumatic pancreatic duct fibrosis.

Alcohol excess is a well-recognized cause of chronic pancreatitis. In the United States, heavy drinkers have a triple risk of developing chronic pancreatitis, and the risk is further increased in drinkers who are also heavy smokers.[5] The pancreas is one of the primary organs affected by cystic fibrosis. About 85% of cystic fibrosis patients have EPI, usually acquired soon after birth. All patients, regardless of age, need to be tested for EPI.[6][7] EPI could present in a small number of patients with celiac disease; however, it usually resolves after dietetic control. EPI should be excluded in patients with celiac disease who remain symptomatic despite a gluten-free diet.[2][8] 

EPI is not uncommon in inflammatory bowel disease. It could result from disease activity (autoimmune changes) or secondary to medications used in the treatment. Both acute and chronic pancreatitis have increased incidence among inflammatory bowel disease patients.[9][10] EPI is a well-known complication after bariatric surgery and could impose an important entity due to the increasing number of such surgeries worldwide. Altered anatomy and intersecting symptoms with the surgery itself make distinction difficult. Bariatric surgery includes bypassing a portion of the gastrointestinal tract; the extent of malabsorption depends on the length of the part removed.[11] EPI has been associated with HIV infection and is considered an important cause of chronic diarrhea in patients with HIV. Screening for EPI should be performed in patients with HIV presenting with chronic diarrhea.[12]

Epidemiology

The exact prevalence of exocrine pancreatic insufficiency in the population is unknown. It occurs secondary to multiple causes with varying prevalence.[13] EPI is prevalent in about 60% to 90% of patients diagnosed with chronic pancreatitis within 10 to 12 years of diagnosis. Chronic pancreatitis occurs in about 42 to 73 per 100,000 of the population in the United States and is considered to be the most common pancreatic disorder associated with pancreatic insufficiency, and this could be compared to 36 to 125 per 100,000 of the population in Japan, China, and India.[13][14][15] 

A study of the prevalence of EPI in patients admitted with acute pancreatitis found in more than half (62%) of patients, reducing over follow up to 35%. The risk of EPI in those patients was higher when alcohol was the etiology. The risk of EPI was doubled in severe compared to mild acute pancreatitis.[16] The prevalence of EPI among diabetic patients is low and usually mild to moderate. In a study of 133 patients with diabetes in whom pancreatic insufficiency was evaluated using the fecal elastase-1 (FE-1) assay as a screening test, 13% had a low FE-1. Other studies showed that in type 1 diabetes, 10% to 30% had severe and 22% to 56% had a moderate EPI, while in type 2 diabetes, 5% to 46% had EPI.[17][18][19] About 66% to 92% of patients with advanced pancreatic cancer get EPI. Between 14% and 74% of patients with irritable bowel disease might suffer from EPI. Among patients undergoing bariatric surgery, the risk of EPI is still high despite enzymatic and nutritional supplements.[2][11] The prevalence of EPI in patients with HIV/AIDS is estimated to be between 26% to 45%.[20] 

Pathophysiology

Under normal circumstances, when the chyme arrives at the duodenum, both secretin and cholecystokinin are released, leading to the secretion of about 1.5 L/day of pancreatic juice containing pancreatic enzymes (amylase, lipase, and protease), water, and ions (bicarbonate and phosphate). These enzymes are responsible for most of the digestive work in the small intestine.[5] It is often thought that a loss of 90% of pancreatic function is required before overt exocrine insufficiency occurs; however, this is not well supported by current studies.[21] Chronic pancreatitis is a condition affecting the pancreas where recurrent inflammation results in a replacement of pancreatic tissue by fibrosis; consequently, both endocrine and exocrine functions of the pancreas could be affected.[3] There are multiple theories for the pathogenesis of chronic pancreatitis, including toxic metabolic theory, oxidative stress theory, obstructive theory, and necrosis-fibrosis hypothesis.[19][22]

In cystic fibrosis, epithelial cells in pancreatic ducts could be affected by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cAMP-regulated anion channel. Exocrine pancreatic insufficiency results from chronic obstructive pancreatitis.[23][24] Also, decreased ductal bicarbonate secretion and the resulting decreased alkalization of the acinar lumen might enhance inflammation and the destruction of pancreatic ducts.[7] Diabetes mellitus can lead to EPI. It has been noted that the pancreas is smaller in size in patients with type 1 diabetes. This could be secondary to the lack of trophic effect of insulin on acinar cells, autoimmune destruction of islet cells, and reduced pancreatic secretory function due to diabetic neuropathy.[25] EPI might result from reduced cholecystokinin secretion caused by villous atrophy in celiac disease or milk protein enteropathy patients. Cholecystokinin levels come back to normal after mucosal healing.[26]

History and Physical

Pancreatic insufficiency is an important cause of maldigestion and malabsorption.[2] The combination of steatorrhea and insufficient dietary intake puts patients at significant risk for malnutrition.[21] It can lead to multiple clinical manifestations, causing poor quality of life and potentially serious complications.[13] Clinical features of exocrine pancreatic insufficiency are usually non-specific. These include steatorrhea, abdominal discomfort, bloating, and weight loss. Additionally, malnutrition, trace element and vitamin deficiency, metabolic bone disease (osteoporosis or osteomalacia), muscle spasms, decreased immune competence, and an increased risk of cardiovascular events frequently occur.[27] Steatorrhea is the most frequent sign of EPI; it is recognized when the fat content of stool is more than 7g/day and given that the diet includes 100 g of fat a day. Fat malabsorption requires at least a 5% to 10% fall in pancreatic lipase and trypsin levels.[28] Following bariatric surgery, patients might present with steatorrhea, weight loss, maldigestion, and malabsorption, which are pathognomonic for EPI and make diagnosis challenging.[11]

Evaluation

Exocrine pancreatic insufficiency can be classified into mild, moderate, or severe. Mild insufficiency occurs with reduced secretion of one or two enzymes with preserved bicarbonate and normal fecal fat. Moderate insufficiency includes the above with impaired bicarbonate secretion. Severe insufficiency occurs when all of the above plus steatorrhea.[3] Exocrine pancreatic insufficiency can be suspected in patients with suggestive symptoms and clinical history. However, this differs between patients depending on the severity of insufficiency and its cause. To confirm the diagnosis, laboratory and radiological evaluation would be required.[29] 

Two categories of tests are recognized: direct and indirect tests. Direct tests such as the secretin-cholecystokinin stimulation test and endoscopic pancreatic function test. The two tests evaluate the pancreatic secretive function, and while they are sensitive and specific, they are invasive, expensive, and time-consuming, limiting their use in clinical practice. On the other hand, indirect tests such as fecal, breath, and blood tests assess the implications of EPI. Despite being less sensitive and specific, they are more feasible and less expensive.[13][29] The gold standard test for diagnosing EPI is the 72-hour fecal fat quantification and determination of the coefficient for fat absorption; however, its use is limited by unacceptance for both patient and laboratory.[30] 

Fecal elastase-1 (FE-1) is considered a reliable, non-invasive, and less time-consuming test to evaluate EPI. It is not affected by enzyme replacement as well. Such advantages make it a popular test in screening for EPI.[31] However, it is affected by dilution in watery diarrhea.[32] An FE-1 of less than 15 mcg/g feces is highly sensitive and specific for detecting EPI in patients with chronic pancreatitis; however, intermediate levels (15 to 200 mcg/g feces) are less sensitive and might require using more sensitive tests to confirm the diagnosis. Moreover, FE-1 levels are not reliable in EPI detection in post-pancreatic resection patients.[33] Fecal chymotrypsin might be of benefit to evaluate compliance with pancreatic enzyme therapy. its value is limited due to intestinal degradation and less availability in laboratories.[32][34]

Serum pancreatic enzymes are not considered a reliable tool to diagnose pancreatic insufficiency. However, only serum trypsinogen could be used as a useful marker for EPI. A serum level below 20 ng per milliliter was sensitive to pancreatic steatorrhea.[35][36] A replacement for the previously used Secretin-cholecystokinin stimulation test is the endoscopic pancreatic function test (ePFT), which can evaluate pancreatic secretion through quantification of bicarbonate concentration in samples retrieved endoscopically from the duodenum 45 to 60 minutes after intravenous Secretin injection. It is a highly sensitive test and can be used to confirm the diagnosis of EPI in borderline cases.[37] 

Breath tests measure fat digestion by pancreatic lipase. The test depends on quantifying the recovery rate of 13 CO2 over 6 hours after a meal, which contains 250 mg of 13C-MTG. It can be used to diagnose EPI, but while equally sensitive to fecal elastase, it is not widely available.[27][37] Testing for nutritional deficiencies such as magnesium, fat-soluble vitamins (A, E, D, and K), and lipoproteins can support the diagnosis of EPI and monitor treatment.[29] Secretin-stimulated magnetic resonance cholangiopancreatography (S-MRCP) could be considered the most appropriate morphological test for EPI assessment. It could be used as an indicator of pancreatic function. However, it has a low sensitivity (69%) with limited supporting evidence for use in EPI diagnosis.[3] 

Treatment / Management

Treatment for exocrine pancreatic insufficiency includes avoiding malnutrition-related complications and improving the patient's 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 D, A, and E level, vitamins B and folate) should be performed for all patients diagnosed with EPI at presentation and at least every year to assess the response to replacement therapy and progression of the disease.[4][29][37] (B3)

Pancreatic enzyme replacement therapy is recommended to treat EPI and resultant malnutrition. it could be enhanced by increasing doses, enteric coating, gastric acid suppression, and proper administration during meals.[33] There is a need to treat the underlying cause of EPI and lifestyle advice, including abstinence from alcohol, smoking cessation, and dietary modifications in the form of small frequent meals and avoidance of indigestible foods. Also, the supplementation of fat-soluble vitamins if required.[5] (A1)

Pancreatic enzyme replacement therapy (PERT) is the main treatment of EPI. A combination of pancreatic enzymes (lipase, amylase, and protease) prevents malabsorption and restores the normal physiological digestive process. The enteric coating of the enzymatic supplement provides protection from gastric acidity and dissolves afterward in the duodenum in response to alkaline PH. Some patients might require reducing gastric acidity in the case of reduced bicarbonate secretion to dissolve the enteric coat.[29] 

The dose needed for enzyme replacement differs between patients depending on the severity of the deficiency and individual needs. Moreover, high doses of supplements don't come without complications, so the lowest effective dose should be used. The current recommendation is 25,000 to 40,000 units of lipase taken with meals or half with snacks, then titrated according to response to a maximum of 75,000 to 90,000 units of lipase per meal. In case of poor response, gastric acid suppression and excluding other potential causes for symptoms should be considered.[4][29]

Dietetic management includes advice about keeping a normal diet as possible, along with small frequent meals, avoidance of fat restriction, and very high fiber diets. A referral is recommended to a dietician for a review of dietetic history along with anthropometric measures, plus counseling and support.[29][38] EPI in cystic fibrosis can be treated by pancreatic enzyme replacement with cautious dosage increments in line with energy consumption.[23] Evidence suggests that replacement therapy improves survival among pancreatic cancer patients for both operable and non-operable tumors.[39][30] A promising approach is the use of stem cell technology. It includes pluripotent stem cells to produce pancreatic exocrine cells, but it is still under research.[38] (B3)

Differential Diagnosis

Usually, exocrine pancreatic insufficiency is underdiagnosed due to the broad and non-specific presentation. Symptoms can easily be confused with functional gastrointestinal disorders.[5][29] vA comprehensive approach with the analysis of history and investigations is essential to reach an accurate diagnosis. conditions that might be confused with EPI include malabsorption syndromes (such as celiac disease), inflammatory bowel disease, irritable bowel syndrome, microscopic colitis, intestinal bacterial overgrowth, and giardiasis.[20]

• Biliary obstruction
• Celiac disease
• Giardiasis
• Malabsorption syndromes
• Inflammatory bowel disease
• Intestinal bacterial overgrowth
• Irritable bowel syndrome
• Microscopic colitis
• Zollinger-Ellison syndrome

Prognosis

Long-term prognosis depends on proper management and monitoring of pancreatic insufficiency. Patients are at risk of potentially serious complications if not treated properly. The treatment provides a good chance for the relief of symptoms and a better quality of life.

Complications

If no treatment is provided for exocrine pancreatic insufficiency, patients become exposed to complications related to fat malabsorption and malnutrition, reducing the quality of life. Almost 65% of patients diagnosed with chronic pancreatitis have either osteoporosis or osteopenia. Reduced quality of life due to persistent symptoms, reduced ability to work, and resultant financial troubles. Increased morbidity and mortality due to malnutrition and cardiovascular complications.[29]