m Exocrine Pancreatic Insufficiency: An Overview

Exocrine Pancreatic Insufficiency: An Overview

Dr. Ashni Dharia 1, Dr. Charmi Bhanushali 2

Abstract

Exocrine Pancreatic Insufficiency (EPI) is identified by the insufficiency of exocrine pancreatic enzymes resulting in malabsorption. Patients with mild EPI maybe asymptomatic or have mild abdominal discomfort and bloating while advanced EPI results in steatorrhea and weight loss. The causes can be divided into pancreatic and extra-pancreatic origin. Pancreatic causes include chronic pancreatitis, cystic fibrosis, pancreatic tumors, and pancreatic resection. Extra-pancreatic causes include diabetes, IBD, celiac disease, etc.There are various direct and indirect tests available to diagnose EPI, with indirect ones such as the concentration of fecal elastase beingmost commonly used. However, the gold standard test for diagnosis is a72-hour fecal fat test.Treatment for pancreatic exocrine insufficiency includes lifestyle modifications, dietary consultation, and a structured assessment of nutritional status. The mainstay remains pancreatic enzyme replacement therapy, which is administered in the form of enteric-coated minimicrospheres during meals. Keywords: chronic pancreatitis, malabsorption, fecal elastase, pancreatic enzyme replacement therapy

Introduction

Exocrine pancreatic insufficiency (EPI) is identified by the insufficiency of exocrine pancreatic enzymes.[1, 2] Inadequate digestion occurs when intra-duodenal levels of lipase fall below 5–10% of normal enzyme output, which is the threshold required for normal digestion.[3] EPI presents with non-specific symptoms similar to other gastrointestinal diseases and can lead to clinical presentations and biochemical modifications, which can result in life-threatening conditions and decrease the quality of life. Abdominal distress, loose bulky stools, and malnutrition form a part of the clinical presentations of EPI. The biochemical modifications are related to impaired breakdown and absorption of fats and fat-soluble micronutrients. In simple terms, EPI leads to maldigestion and malabsorption.[1,2] Malnutrition, which occurs because of malabsorption, leads to weight loss and contributes to future cardiovascular events. In addition, malnutrition can cause alterations in the bone density.[5] EPI is also an independent risk factor for death in patients with chronic pancreatitis.[4] Mild EPI may have no clinical manifestations but can significantly affect the nutritional condition of patients.[6] Therefore, it is important that symptoms like flatulence, abdominal cramps, and nutritional deficiencies are identified in patients at-risk of EPI and are diagnosed and treated appropriately. 1,2 General Medicine, TNMC & Nair Hospital, Mumbai Corresponding Author: Dr. Charmi Bhanushali, General Medicine, TNMC & Nair Hospital, Mumbai. Email:charmi.bhan@gmail.com

Prevalence

The prevalence of exocrine pancreatic insufficiency in the population is unknown.[1] The causes can be divided into pancreatic and extra-pancreatic origin.

Chronic pancreatitis is the most common pancreatic disease associated with EPI.[7] It is reported in 60-90 percent patients 10-15 years after diagnosis.[8] It occurs as a result of progressive inflammatory changes resulting in permanent damage of the acinar cell function. EPI is seen in >75 percent of newborns born with cystic fibrosis; an autosomal recessive disorder caused by a mutation of the gene that encodes for Cystic Fibrosis Transmembrane conductance Regulator (CFTR).[9] The mutation results in the production of inspissated pancreatic secretions that cause blockade of tubules which results in progressive pancreatic damage. EPI is also seen with acute pancreatitis, autoimmune pancreatitis, pancreatic adenocarcinoma, and resective pancreatic surgery.

Among extra-pancreatic causes, EPI is commonly seen in patients with Diabetes Mellitus Type 1 & 2. It is caused by various factors such as lack of the trophic action of acinar cells, autoimmune damage of islet cells, decreased exocrine pancreatic secretion as a complication of diabetic neuropathy, and microvascular damage induced pancreatic fibrosis.[10] It is also seen with inflammatory bowel disease, celiac disease, gastric resection, Sjogren syndrome, and heart failure patients.[1]

Pathophysiology

Physiologic digestive process requires pancreat-

ic stimulation, synthesis, and release of digestive enzymes by pancreatic acinar cells, enzyme transportation through the duct system, and synchronized mixing of the pancreatic secretions with ingested food. [11] Failure to function adequately at any of these levels can lead to EP1. Hence the etiology can be divided into: (1) Loss of pancreatic parenchyma seen in chronic pancreatitis, cystic fibrosis, and pancreatic tumors. (2) Asynchrony seen in diabetes, IBD, and gastric resection. (3) Obstruction of the main pancreatic duct seen in pancreatic and ampullary tumors. (4) Acid-mediated inactivation of pancreatic enzymes (Zollinger-Ellison syndrome).[12]

Diagnosis

There are two categories of tests to diagnose EPI: direct and indirect. Direct tests directly estimate the production of pancreatic secretions. Direct tests have superior sensitivity but are invasive and tedious. On the contrary, indirect tests analyze the effect of exocrine insufficiency i.e., estimate the quantitative change in pancreatic secretion. These tests are cheaper and easier to perform than the direct pancreatic function tests.[1]

The most used indirect test for exocrine pancreatic function analyses is fecal elastase-1 levels. Pancreatic elastase-1 is a highly stable enzyme and is not degraded in the intestines.[13] Hence, its fecal level, which is measured by an enzyme-linked immunosorbent assay, is closely related to the exocrine pancreatic secretion. This test does not require a timed stool collection or a special diet. In children, this test has a negative predictive value of 99% for ruling out EPI. In addition, it has a highlevel sensitivity in cases of moderate to severe EPI.[3, 14] One drawback of this test is that only formed stools can be analyzed. Watery stools change the fecal elastase concentration and will show lower values.[15,16]

A test for serum trypsinogen levels is another indirect test. Serum levels of trypsinogen are related to the pancreatic acinar cell mass. However, it is not specific for EPI. It has a favorable specificity for advanced EPI but low sensitivity for mild insufficiency. Hence, it is not practically used in the clinical setting.[1,16,17]

Chymotrypsin is another product of pancreatic secretion. It is measured in fecal samples. However, the test for chymotrypsin is less useful compared to that of FE-1.[1]

The gold standard test is the 72-hour fecal fat test. The patient consumes a diet containing 100 g of fat per day and his stool is collected for 72 hours. A CFA (Coefficient of fat absorption) is calculated which denotes the percentage of fat that is absorbed. The diagnosis of fat malabsorption is established at > 7 g of fat per 100 g of stool per day. However, the practicality of this test is restricted, as it is extremely tedious and susceptible to errors in stool collection. The results are also influenced by other conditions like Crohn’s disease, bacterial overgrowth, and short bowel syndrome, which also affect the mucosal fatty acid intake.[1,2,3] The most sensitive diagnostic tests for the diagnosis of EPI are the direct pancreatic function tests. The principle behind these tests is that the pancreas is stimulated with hormonal secretagogues, and the duodenal fluid is collected. The enzymes and bicarbonate levels of this fluid are measured. This directly gives us a measure of the pancreatic function.[1,2,3,18]

A panel of serum nutritional markers (e.g. - Hemoglobin, albumin, retinol-binding protein levels) and pancreatic imaging tests (e.g. - Computed Tomography scan, Endoscopic Ultrasound, Endoscopic Retrograde Cholangiopancreatography) can aid in the diagnosis of EPI.[11]

Management

The primary goal for treatment of EPI is to reinstitute normal digestion to maintain adequate nutrition and prevent disease progression. It includes lifestyle modifications such as alcohol abstinence, cessation of smoking, enzyme replacement therapy, consumption of a well-balanced normal fat diet, and structured follow up to assess nutrition.[19] Deficiency of fat-soluble vitamins A, D, E, and K can occur due to malabsorption and hence should be supplemented if indicated.

Pancreatic Enzyme Replacement Therapy (PERT)is the cornerstone of the treatment. It is administered as enteric-coated minimicrospheres in patients with EPI to compensate for the lack of enzyme secretion required for the physiological digestion process and prevent malabsorption. The pancreatic enzyme preparations are extracts prepared from the porcine pancreas.[1] They are consumed along with meals and mixed in the stomach with the chyme but are protected from acid degradation by an enteric coating. They are then released into the duodenum where the acid-resistant coating dissolves in the duodenum’s alkaline environment, releasing the enzymes at the optimum point for digestion and absorption. The optimal pH for enzyme activation in the duodenum is <6, hence some may require a trial of acid-suppressing agents in patients who continue to experience symptoms of EPI despite high doses of PERT.[19] The APC-recommended PERT starting dose for adults is 25,000-40,000 units of lipase. If there is an insufficient response to the initial dose, it should be titrated up to a maximum of 75,000-80,000 units of lipase per meal.It is essential to check gastrointestinal symptoms and nutritional parameters such as anthropometry, body weight, and Vit A, D, E, K, B12, and iron levels

at baseline and then annually after starting PERT.[9] The effectiveness of PERT is assessed clinically by improvement in stool consistency, fat-soluble vitamin levels, and gain in body weight and anthropometric parameters. In a patient with suspected EPI with a known history of pancreatic disease, PERT can be indicated empirically without further testing. Improvement in the condition would be both diagnostic for EPI as well as therapeutic. Along with this, it is essential to refer to a dietician for nutritional assessment and counseling for all patients of EPI. If PERT is ineffective, then non-compliance, inadequate dosage, acid denaturation of enzymes, and other causes of maldigestion should be considered such as lactose intolerance, enteric bacterial infection, giardiasis, small intestinal bacterial overgrowth, biliary disease colitis, celiac disease, short bowel syndrome, and Crohn’s disease should be suspected.[20]

Conclusion

EPI has a detrimental effect on the nutritional status of patients with pancreatic and extra-pancreatic disorders. However, it is often undiagnosed in the early stages. To address this problem, it is important that the physicians look out for symptoms in at-risk individuals and agree on the same methods for diagnosis. This is important because there has been a change in the diagnostic approach for EPI from the undependable qualitative stool test and the time-consuming 72-hour fecal fat collection, to a more sensitive, but less specific, fecal elastase test. This has been particularly useful in mild to moderate EPI. In addition, there are also various studies with different recommendations for dosing of exogenous pancreatic enzymes and there is confusion over the time of intake of these supplements. Therefore, there is a need to refine the currently available treatment options for EPI.[3] In some cases, empirical treatment of EPI might be considered, for example- when despite negative test results for EPI, classic symptoms and nutritional deficiencies are present in patients with known pancreatic disease. Moreover, the clinical significance of EPI in conditions such as diabetes, smoking, and aging is an untrodden path and requires more research.[2]

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