Biochemistry Pancreatitis Case File

Biochemistry Pancreatitis Case File

Eugene C.Toy, MD, William E. Seifert, Jr., PHD, Henry W. Strobel, PHD, Konrad P. Harms, MD

❖ CASE 19

A 40-year-old obese female presents to the emergency center with complaints of worsening nausea, vomiting, and abdominal pain. Her pain is located in the midepigastric area and right upper quadrant. She reports a subjective fever and denies diarrhea. Her pain is presently constant and sharp in nature but previously was intermittent and cramping only after eating “greasy” foods. On examination she has a temperature of 37.8°C (100°F) with otherwise normal vital signs. She appears ill and in moderate distress. She has significant midepigastric and right upper-quadrant tenderness. Some guarding is present but no rebound. Her abdomen is otherwise soft with no distention and active bowel sounds. Laboratory values were normal except for increased liver function tests, white blood cell count, and serum amylase. Ultrasound of the gallbladder revealed numerous gallstones and a thickening of the gallbladder wall. A surgery consult was immediately sought.

◆ What is the most likely diagnosis?

◆ What is the role of amylase in digestion?

ANSWERS TO CASE 19: PANCREATITIS

Summary: 40-year-old female with history of intermittent right upper-quadrant pain worsening after “greasy” meals and now with constant midepigastric pain, nausea, and vomiting with elevated liver function tests and amylase.

◆ Diagnosis: Gallstone pancreatitis.

◆ Role of amylase: Enzyme for carbohydrate metabolism, used to digest glycogen and starch.

CLINICAL CORRELATION

Acute pancreatitis is an inflammatory process in which pancreatic enzymes are activated and cause autodigestion of the gland. In the United States, alcohol use is the most common cause, and episodes are often precipitated by binge drinking. The next most common cause is biliary tract disease, usually passage of a gallstone into the common bile duct. Hypertriglyceridemia is also a common cause, and that occurs when serum triglyceride levels are greater than 1000 mg/dL, as is seen in patients with familial dyslipidemias or diabetes. When patients appear to have “idiopathic” pancreatitis, that is, no gallstones are seen on ultrasound, and no other predisposing factor can be found, biliary tract disease is still the most likely cause: either biliary sludge (microlithiasis), or sphincter of Oddi dysfunction. Abdominal pain is the cardinal symptom of pancreatitis, and it is often severe, typically in the upper abdomen with radiation to the back. The pain is often relieved by sitting up and bending forward and is exacerbated by food. Patients also commonly have nausea and vomiting, also precipitated by oral intake. The treatment includes nothing by mouth, intravenous hydration, pain control, and monitoring for complications.

APPROACH TO AMYLASE AND CARBOHYDRATE METABOLISM

Objectives

1. Be aware of the role of amylase in carbohydrate metabolism.

2. Understand the cause for increased amylase in pancreatitis.

3. Understand why conservative treatment (intravenous [IV] fluids, NPO, pain medication, and possibly a nasogastric tube) is effective in treatment of this condition.

Definitions

α-Amylase: An endosaccharidase that catalyzes the hydrolysis of α(1→4) glycosidic bonds present in glycogen and starch. It is present in both saliva and pancreatic digestive juice. (See Figure 25-1b in Case 25 for a diagram showing the α(1→4) glycosidic bonds in starch.)

Endosaccharidase: An enzyme that randomly hydrolyzes glycosidic bonds within polysaccharides.

Lipase: An enzyme that hydrolyzes the ester linkage between a fatty acid and glycerol in a triglyceride.

Pancreas: A major endocrine and exocrine organ located behind the stomach. It secretes pancreatic juice into the duodenum to neutralize the effluent from the stomach and supply digestive enzymes. It also synthesizes and secretes the hormones insulin, glucagon, and somatostatin into the bloodstream from cells within the islets of Langerhans.

Zymogen: A proenzyme; an inactive precursor of an enzyme stored in secretory granules. After secretion, the zymogen is activated by cleavage of certain peptide bonds either by low pH or by other enzymes.

DISCUSSION

The pancreas is a major exocrine organ that synthesizes and secretes digestive enzymes. It also produces and secretes NaHCO3 to neutralize the acidic effluent from the stomach. The pancreas also has an important endocrine role because it synthesizes and secretes the hormones insulin, glucagon, and somatostatin into the bloodstream from cells within its islets of Langerhans.

The exocrine gland is divided into small globules that are drained by an intralobular duct. The intralobular ducts feed into the interlobular duct, which is joined to the main pancreatic duct. The pancreatic duct joins with the common bile duct (usually) in the hepatopancreatic ampulla, which exits into the duodenum. The secretory unit of the pancreas consists of the acinus and the intercalated duct. The epithelial cells of the intercalated duct have high concentrations of the enzyme carbonic anhydrase, which generates HCO3 − from CO2 and H2O for neutralization 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 acetylcholine 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 α-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 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 acinar 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.

α-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 α(1→4) 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. α-Amylase hydrolyzes dietary starch and glycogen to glucose, maltose, maltotriose, and an oligosaccharide referred to as the α-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′- and 3′-positions to produce free fatty acids and β-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 α-amylase and lipase are stored in the pancreas as the active enzymes, they are important blood markers to help diagnose acute pancreatitis. The serum level of α-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 α-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 gallstones will resolve on their own, and therefore conservative treatment modalities 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 efficacy of nasogastric suction in the treatment of mild to moderate acute pancreatitis.

COMPREHENSION QUESTIONS

[19.1] Prior to a race, many marathon runners will try to increase their glycogen concentrations by loading up with foods with a high starch content, such as pasta. α-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, amylopectinlike structure with long outer chains. Which of the following enzymes would most likely be deficient?

A. α-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 breastfed 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–D) 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

Answers

[19.1] D. α-Amylase hydrolyzes α(1→4) glycosidic bonds present in starch (amylose and amylopectin) in a random fashion leaving primarily the disaccharide maltose, the trisaccharide maltotriose, and an oligosaccharide known as the α-limit dextrin, which is composed of 6 to 8 glucose residues with one or more α(1→6) glycosidic bonds. Galactose and fructose are not present in starch.

[19.2] B. Amylopectin is plant starch that has some α(1→6) 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 α(1→6) branch points.

[19.3] E. Neither hormone sensitive lipase nor lipoprotein lipase is a digestive enzyme. The patient’s 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

❖ The pancreas is a large exocrine organ that has a role in the digestion of food as well as an endocrine organ which secretes insulin, somatostatin, and glucagon.

❖ 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.

❖ The three major breakdown products of amylase are maltose, maltotriose, and α-dextrins. Enzymes in the brush border of the intestines continue to digest the carbohydrates.

References

Greenberger NJ, Toskes PP. Acute and chronic pancreatitis. In: Fauci AS, Braunwald E, Kasper KL, et al., eds. Harrison’s Principles of Internal Medicine, 14th ed. New York: McGraw-Hill, 1998. 

Hopfer U. Digestion and absorption of basic nutritional constituents. In: Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations, 5th ed. New York: Wiley-Liss, 2002. 

Kumar V, Cotran RS, Robbins SL. Robbins Basic Pathology, 7th ed. Philadelphia, PA: W.B. Saunders, 2003. 

Marino CS, Gorelick FS. Pancreatic and salivary glands. In: Boron WF, Boulpaep EL, eds. Medical Physiology: A Cellular and Molecular Approach. Philadelphia, PA: W.B. Saunders, 2003.

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