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A Primer on Exocrine Pancreatic Insufficiency, Fat Malabsorption, and Fatty Acid Abnormalities
Samer Alkaade, MD and Ashley A. Vareedayah, MD
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A Primer on Exocrine Pancreatic Insufficiency, Fat Malabsorption, and Fatty Acid Abnormalities

Samer Alkaade, MD and Ashley A. Vareedayah, MD
Exocrine Pancreatic Insufficiency
Exocrine pancreatic insufficiency (EPI) is a condition characterized by deficiency of exocrine pancreatic enzymes, resulting in the inability to properly digest fats, carbohydrates, and proteins.10,11 The most common cause of EPI is chronic pancreatitis (CP), followed by cystic fibrosis (CF), which is the most common cause of EPI in children.6 EPI is also associated with a variety of conditions, including pancreatic cancer, pancreatic and gastric surgery, diabetes mellitus, Crohn’s disease, Zollinger-Ellison syndrome, and Celiac sprue.6,9

EPI commonly leads to fat malabsorption and can manifest as a wide spectrum of symptoms, including steatorrhea (fatty, frothy, loose, greasy, foul-smelling stools), weight loss, abdominal discomfort, and abdominal bloating.6,12 The enzymatic digestion of carbohydrates and proteins may also be affected by EPI. Deficiency of amylase and protease in EPI is typically masked by the multiple other sources of these enzymes (salivary, gastric, and small intestine).10,12 Therefore, adequate digestion of proteins and carbohydrates is usually maintained, even with complete loss of pancreatic function. As a result, these insufficiencies are generally not clinically significant in EPI.10,13 Conversely, extrapancreatic sources for fat digestion by gastric lipase and lingual lipase are unable to compensate for pancreatic lipase deficiency in EPI.6,8,12 The clinical manifestations of fat malabsorption with EPI are, therefore, generally noted earlier than clinical manifestations due to deficiencies of other pancreatic enzymes.10 The management of EPI includes dietary and lifestyle modifications (eg, smoking cessation, limiting or avoiding alcoholic drinks, and limiting dietary fat intake), as well as pancreatic enzyme replacement therapy (PERT); vitamin supplementation may also be necessary.9

EPI is often under-diagnosed because of its wide spectrum of symptoms. The exact incidence and prevalence of EPI is difficult to determine, due to its multiple causes, and because it is not typically recorded as a medical statistic. The prevalence of CP, the leading cause of EPI, is higher in men than women and is estimated to be approximately 50 per 100,000 persons.14,15 EPI is estimated to occur in 30% to 40% of individuals with CP.6 The age- and sex-adjusted prevalence of CP as measured by a study of the population of 100,000 inhabitants in Olmsted County, Minnesota was 41.76 (95% CI, 30.21-53.32) per 100,000 person-years in 2006, with an age-adjusted prevalence in women of 33.88 per 100,000 person-years (95% CI, 19.65-48.10) compared with 51.45 per 100,000 person-years for men (95% CI, 32.37-70.55).14 The incidence of EPI, as measured in this study (1977-2006), was observed to be 4.05 per 100,000 person-years (95% CI, 3.27-4.83), and was also higher in men than women (5.21 vs 3.11 per 100,000 person-years).14

Excess alcohol consumption is a common cause of CP, as alcohol is toxic to the pancreatic acinar cells.6 In a well-designed multicenter study conducted in the United States (North American Pancreatic Study 2 [NAPS2]), very heavy alcohol consumption, defined as consuming 5 or more drinks per day, was associated with a more than 3-fold increase in the risk of developing chronic pancreatitis (OR, 3.10; 95% CI, 1.87-5.14; P <.001). Notably, among heavy drinkers who were also heavy smokers, defined by a greater than 35 pack-year history of smoking, the risk of developing  CP was further elevated 13-fold compared with heavy drinkers who were nonsmokers (OR, 13.41; 95% CI, 5.23-34.4; P <.001).16 Alcohol intake was thought to be the causative factor in CP among 44.5% of patients, with other factors including genetics, autoimmune conditions, and other causes accounting for the remaining cases.17 These results were replicated in another multicenter Italian study that identified alcohol as a causative factor in 34% of CP cases, with multiple other causes  accounting for the remaining 66% of cases.18

There is an age-dependent negative linear correlation between patient age at symptomatic disease onset of CP and time to development of EPI; there is a shorter time to development of EPI in late-onset CP or alcohol-induced pancreatitis compared with patients with early-onset CP. Approximately 20% of patients with CP develop EPI over time, as this disease is characterized by the progressive loss of acinar cell function.19 As expected, the prevalence of EPI increases with disease duration—between 5 and 10 years after diagnosis of CP, more than half of patients will develop EPI.9,20

Approximately 90% of patients with CF have EPI.21 Estimates of prevalence for CF vary greatly, with estimates of less than 40 per 100,000 persons, and some studies reporting a much lower prevalence.22 In patients with insulin-dependent diabetes mellitus, EPI may occur in up to 43% of patients; severity is mild to moderate, with 1% requiring therapy.6

EPI has numerous etiologies, which are typically classified into one of two categories: pancreatic and non-pancreatic. Pancreatic causes include CP, CF, pancreatic duct obstruction, pancreatic surgery, and the rare Shwachman-Diamond syndrome.6,9,10,13 Conditions leading to EPI are shown in Table 16,10,12,13. Nonpancreatic conditions associated with EPI include celiac disease, Crohn’s disease, Zollinger-Ellison syndrome, and gastrointestinal surgery.6,9

The most common cause of EPI is CP, which is characterized by an initial pancreatic insult leading to progressive tissue damage and pancreatic fibrosis.6,7 The destruction of pancreatic tissue in CP affects both exocrine and endocrine functions; CP leads to EPI and also loss of endocrine pancreatic function in later stages of disease.8,10 Other than alcohol use (described previously), common factors associated with CP include smoking, genetic predisposition, severe necrotizing pancreatitis, autoimmune pancreatitis, obstruction of the pancreatic duct, and idiopathic causes.23,24

CF is another potential cause of EPI.19 CF is an autosomal recessive disease caused by mutations in the gene that encodes the CF transmembrane conductance regulator (CFTR) protein. CFTR protein dysfunction results in reduced chloride and bicarbonate transport and malfunction/deregulation of other transporters across epithelial cells.13 The most common sites of disease manifestation include epithelial secretory tissues (respiratory tract and pancreatic duct epithelium), where CFTR protein dysfunction results in pulmonary and pancreatic dysfunction. With regard to EPI, reduced chloride/bicarbonate transport in the pancreas leads to reduced water content of secretions entering the ductal lumen, and highly concentrated secretions obstruct the pancreatic ducts and acini, preventing pancreatic enzymes from being secreted and emptied into the small intestine.13 Sustained obstruction can lead to pancreatic tissue destruction, or autodigestion, due to retained proteolytic enzymes.6

Tumors that obstruct the main pancreatic duct (ie, periampullary tumors, pancreatic head cancer, or benign tumors) can also lead to EPI.6 Pathophysiology in this case include replacement of pancreatic tissue by tumor cells in the head of the pancreas, and as tumors grow, normal  pancreatic tissue is lost in the head of the pancreas. In addition, chronic obstructive pancreatopathy develops in the remaining part of the pancreas, which manifests as pancreatic duct dilation and pancreatic atrophy, leading to the development of EPI.25 Following surgical resection of pancreatic tumors, patients may continue to experience clinical symptoms of EPI due to exocrine dysfunction of the residual part of the pancreas.3

Unlike EPI in patients with CP and CF, decreased stimulation and production of endogenous pancreatic lipase as seen in celiac disease, Crohn’s disease, or Shwachman-Diamond syndrome occurs without glandular destruction.6 Zollinger-Ellison syndrome involves a non-pancreatic etiology of EPI characterized by acid-mediated inactivation of pH-sensitive pancreatic enzymes in acidic duodenal environments despite normal pancreatic secretions.3,12 Patients with diabetes mellitus may develop EPI in part as a result of disturbances in acinar-islet interactions. Although these patients may also experience EPI-related clinical symptoms, cases of EPI in this population are generally mild to moderate.3,6

Surgery, such as gastrectomy, gastric bypass, extensive small bowel surgery, and other gastrointestinal surgeries can affect the postprandial synchrony between the delivery of gastric contents to the duodenum and the discharge of pancreatic and biliary secretions. Additionally, gastrointestinal surgeries can cause motility disorders, which decrease “contact time” of food within the gastrointestinal tract, and result in decreased stimulation and secretion of pancreatic enzymes.6 Motility disorders related to EPI can be self-exacerbating, and if left untreated, patients with EPI may develop rapid gastric emptying with faster small intestinal transit. These changes hamper digestion and absorption and reduce pancreatic enzyme activity.6

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