of stomach acid entering the duodenum. The acinus is a cluster of acinar cells that are grouped around the intercalated duct. The acinar cells are specialized epithelial cells that synthesize and secrete the 20 or so enzymes that will be used to digest the macromolecules in the lumen of the intestine. Most of the digestive enzymes, particularly those used to degrade proteins, are synthesized as zymogens or proenzymes that must be activated. These proenzymes are synthesized on ribosomes on the rough endoplasmic reticulum. They are then transported to the Golgi apparatus and are sequestered in zymogen granules until they are secreted. Storing these inactive enzymes in zymogen granules protects the acinar cell from digesting itself. Secretion of these zymogens is regulated by cholecystokinin receptors and muscarinic acetyl- choline receptors. The proenzymes are activated in the intestine, usually by the action of trypsin. There are some enzymes that are synthesized and stored as the active enzymes in the zymogen granules. These include a-amylase, carboxyl ester lipase, lipase, colipase, RNase, and DNase. Acute pancreatitis is a result of anatomical changes that arise from two events. The first is the autodigestion of the acinar cells by inappropriate activation of the pancreatic enzymes (especially trypsinogen) within the cell. The second is CLINICAL CASES 173 the cellular injury response that is mediated by proinflammatory cytokines. The mechanisms by which the digestive enzymes become activated within the acinar cell are unclear. However, such inappropriate activation of pancreatic enzymes leads to destruction of the acinar cell and surrounding fat deposits, and it weakens the elastic fibers of the blood vessels, resulting in leakage. Obstruction of the main pancreatic duct as a result of a gallstone lodged in or near to the hepatopancreatic ampulla can result in acute pancreatitis. One theory is that obstruction increases the pressure in the main pancreatic duct. The increase in pressure causes interstitial edema, which impairs the blood flow to the acinus. The lack of blood flow leads to ischemic injury of the aci- nar cell, resulting in release of the digestive enzymes into the interstitial space. How this leads to premature activation of the proenzymes stored in the acinar cell is unclear. a-Amylase and lipase are two digestive enzymes that are synthesized and stored in the acinar cell as the active enzymes. Amylase is an endosaccharidase that catalyzes the hydrolysis of the \u3b1(1\u21924) glycosidic bonds that form the main polymeric backbone of the polysaccharides starch and glycogen. Present in both saliva and pancreatic juice, it is the pancreatic form of the enzyme that breaks down most of the dietary polysaccharides. \u3b1-Amylase hydrolyzes dietary starch and glycogen to glucose, maltose, maltotriose, and an oligosac- charide referred to as the \u3b1-limit dextrin. Pancreatic lipase is the primary digestive enzyme for the breakdown of triglycerides. It acts on triglycerides to hydrolyze the fatty acyl ester bonds. Lipase is specific for the ester bonds in the 1\u2032- and 3\u2032-positions to produce free fatty acids and \u3b2-monoacylglycerols. Pancreatic lipase is strongly inhibited by bile acids and therefore requires the presence of colipase, a small protein that binds to the lipase and activates it. Since both \u3b1-amylase and lipase are stored in the pancreas as the active enzymes, they are important blood markers to help diagnose acute pancreati- tis. The serum level of \u3b1-amylase will increase in the first 12 hours following the onset of acute pancreatitis. During the next 48 to 72 hours, the levels will usually fall back to normal values. Serum lipase levels also rise, but they remain elevated after the \u3b1-amylase levels have returned to normal and may take 7 to 10 days to normalize. Most cases (85 to 90 percent) of acute pancreatitis that are caused by gall- stones will resolve on their own, and therefore conservative treatment modal- ities are appropriate. These include pain management with analgesics, administration of intravenous fluids to maintain the intravascular volume and electrolyte balance, as well as removal of oral alimentation to decrease the secretion of pancreatic juice. Nasogastric suction has also been used to decrease gastrin release from the stomach and to eliminate gastric emptying into the duodenum. However, controlled trials have not demonstrated the effi- cacy of nasogastric suction in the treatment of mild to moderate acute pancreatitis. 174 CASE FILES: BIOCHEMISTRY COMPREHENSION QUESTIONS [19.1] Prior to a race, many marathon runners will try to increase their glyco- gen concentrations by loading up with foods with a high starch content, such as pasta. \u3b1-Amylase secreted by the pancreas will digest the starch into which of the following major products? A. Amylose, amylopectin, and maltose B. Glucose, galactose, and fructose C. Glucose, sucrose, and maltotriose D. Limit dextrins, maltose, and maltotriose E. Limit dextrins, lactose, and sucrose [19.2] A 3-month-old infant presents with hepatosplenomegaly and failure to thrive. A liver biopsy reveals glycogen with an abnormal, amylopectin- like structure with long outer chains. Which of the following enzymes would most likely be deficient? A. \u3b1-Amylase B. Branching enzyme C. Debranching enzyme D. Glycogen phosphorylase E. Glycogen synthase [19.3] A 3-year-old Caucasian female presents with chronic diarrhea and a failure to thrive. Stools were oily. History reveals that she was breast- fed and had no problems until she was weaned. Which of the enzymes would be expected to be deficient following stimulation with secretin? A. Cholesteryl esterase B. Gastric lipase C. Hormone sensitive lipase D. Lipoprotein lipase E. Pancreatic lipase Match the following enzymes (A\u2013D) to the products yielded. A. Sucrose and lactose B. Glucose and fructose C. Glucose and galactose D. Glucose [19.4] Lactase [19.5] Sucrase [19.6] Maltase CLINICAL CASES 175 176 CASE FILES: BIOCHEMISTRY Answers [19.1] D. \u3b1-Amylase hydrolyzes \u3b1(1\u21924) glycosidic bonds present in starch (amylose and amylopectin) in a random fashion leaving primarily the disaccharide maltose, the trisaccharide maltotriose, and an oligosac- charide known as the \u3b1-limit dextrin, which is composed of 6 to 8 glucose residues with one or more \u3b1(1\u21926) glycosidic bonds. Galactose and fructose are not present in starch. [19.2] B. Amylopectin is plant starch that has some \u3b1(1\u21926) branch points, but not as many as normal glycogen. Glycogen, which has an amylopectin-like structure, has fewer branch points than normal glycogen and would be less soluble within the cell. A deficiency in the branching enzyme will introduce fewer \u3b1(1\u21926) branch points. [19.3] E. Neither hormone sensitive lipase nor lipoprotein lipase is a diges- tive enzyme. The patient\u2019s symptoms are consistent with an inability to absorb triglycerides, which would eliminate cholesteryl esterase from consideration. Since the patient did not have any problems while being breast-fed, then the most likely enzyme to be deficient is pancreatic lipase, since gastric lipase is most active on short chain triglycerides, such as those that are found in breast milk. [19.4] C. Lactase breaks down lactose into glucose and galactose. [19.5] B. Sucrase breaks down sucrose into glucose and fructose. [19.6] D. Maltase and isomaltase convert maltose and isomaltose into glucose. BIOCHEMISTRY PEARLS \u2756 The pancreas is a large exocrine organ that has a role in the diges- tion of food as well as an endocrine organ which secretes insulin, somatostatin, and glucagon. \u2756 Acute pancreatitis occurs from autodigestion of the acinar cells by inappropriate activation of the pancreatic enzymes (especially trypsinogen) within the cell, leading to cellular injury mediated by proinflammatory cytokines.