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Surgery_Schwartz. veinIMVSMVHead of pancreasDuodenumJejunumTail of pancreasStomachLiverPortal veinHead of pancreasDuodenumSMVFigure 33-1. Pancreatic anatomy as seen on computed tomography. Knowledge of the relationship of the pancreas with surrounding structures is important to ensure that injury is avoided during abdominal surgery. IMV = inferior mesenteric vein; SMA = superior mesenteric artery; SMV = superior mesenteric vein.PortalveinSplenicveinInferiormesentericveinSuperiormesentericveinSuperiormesentericveinSuperiormesentericveinInferiormesentericveinInferiormesentericveinSplenicveinSplenicveinPortalveinPortalveinFigure 33-2. Variations in portal venous anatomy. The superior mesenteric vein joins the splenic vein and then continues toward the porta hepatis as the portal vein. The inferior mesenteric vein often joins the splenic vein near its junction with the portal vein, but sometimes joins the superior mesenteric vein; or the three veins merge as a trifurcation to form the portal


Surgery_Schwartz

Surgery_Schwartz. mesenteric vein often joins the splenic vein near its junction with the portal vein, but sometimes joins the superior mesenteric vein; or the three veins merge as a trifurcation to form the portal vein.Brunicardi_Ch33_p1429-p1516.indd 143101/03/19 6:44 PM 1432SPECIFIC CONSIDERATIONSPART IIBlindaccessory duct30%60%Minor papilla10%Dorsal anlageVentral anlageVentral budLiver budLesser oraccessorypapillaGreaterpapillaFusion oftwo ductsBile ductDorsal budDuct ofsantoriniDuct ofwirsungFigure 33-3. Embryology of pancreas and duct variations. The duct of Wirsung from the ventral bud connects to the bile duct, while the duct of Santorini from the larger dorsal bud connects to the duodenum. With gut rotation, the two ducts fuse in most cases such that the majority of the pancreas drains through the duct of Wirsung to the major papilla. The duct of Santorini can persist as a blind accessory duct or drain through the lesser papilla. In a minority of patients, the ducts remain separate, and


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Surgery_Schwartz. the duct of Wirsung to the major papilla. The duct of Santorini can persist as a blind accessory duct or drain through the lesser papilla. In a minority of patients, the ducts remain separate, and the majority of the pancreas drains through the duct of Santorini, a condition referred to as pancreas divisum.tortuous. The anterior surface of the body of the pancreas is cov-ered by peritoneum. Once the gastrocolic omentum is divided, the body and tail of the pancreas can be seen along the floor of the lesser sac, just posterior to the stomach.Pancreatic pseudocysts commonly develop in this area, and the posterior aspect of the stomach can form the anterior wall of the pseudocyst, allowing drainage into the stomach. The base of the transverse mesocolon attaches to the inferior margin of the body and tail of the pancreas. The transverse mesoco-lon often forms the inferior wall of pancreatic pseudocysts or inflammatory processes, allowing surgical drainage through the transverse mesocolon.


Surgery_Schwartz

Surgery_Schwartz. and tail of the pancreas. The transverse mesoco-lon often forms the inferior wall of pancreatic pseudocysts or inflammatory processes, allowing surgical drainage through the transverse mesocolon. The body of the pancreas is anterior to the aorta at the origin of the superior mesenteric artery. The neck of the pancreas is anterior to the vertebral body of L1 and L2, and blunt anteroposterior trauma can compress the neck of the pancreas against the spine, causing parenchymal and, sometimes, ductal injury. The neck divides the pancreas into approximately two equal halves. The small portion of the pan-creas anterior to the left kidney is referred to as the tail and is nestled in the hilum of the spleen near the splenic flexure of the left colon. Awareness of these anatomic relationships is impor-tant to avoid injury to the pancreatic tail during left colectomy or splenectomy.Pancreatic Duct AnatomyAn understanding of embryology is required to appreciate the common variations in pancreatic


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Surgery_Schwartz. to avoid injury to the pancreatic tail during left colectomy or splenectomy.Pancreatic Duct AnatomyAn understanding of embryology is required to appreciate the common variations in pancreatic duct anatomy. The pancreas is formed by the fusion of a ventral and dorsal bud (Fig. 33-3). The duct from the smaller ventral bud, which arises from the hepatic diverticulum, connects directly to the common bile duct. The duct from the larger dorsal bud, which arises from the duodenum, drains directly into the duodenum. The duct of the ventral anlage becomes the duct of Wirsung, and the duct from the dorsal anlage becomes the duct of Santorini. With gut rotation, the ventral anlage rotates to the right and around the posterior side of the duodenum to fuse with the dorsal bud. The ventral anlage becomes the inferior portion of the pancreatic head and the unci-nate process, while the dorsal anlage becomes the body and tail of the pancreas. The ducts from each anlage usually fuse together in the


Surgery_Schwartz

Surgery_Schwartz. the inferior portion of the pancreatic head and the unci-nate process, while the dorsal anlage becomes the body and tail of the pancreas. The ducts from each anlage usually fuse together in the pancreatic head such that most of the pancreas drains through the duct of Wirsung, or main pancreatic duct, into the common channel formed from the bile duct and pancreatic duct. The length of the common channel is variable. In about one-third of patients, the bile duct and pancreatic duct remain distinct to the end of the papilla, the two ducts merge at the end of the papilla in another one-third, and in the remaining one-third, a true common channel is present for a distance of several millimeters. Commonly, the duct from the dorsal anlage, the duct of Santorini, persists as the lesser pancreatic duct, and sometimes drains directly into the duo-denum through the lesser papilla just proximal to the major papilla. In approximately 30% of patients, the duct of Santorini ends as a blind accessory


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Surgery_Schwartz. duct, and sometimes drains directly into the duo-denum through the lesser papilla just proximal to the major papilla. In approximately 30% of patients, the duct of Santorini ends as a blind accessory duct and does not empty into the duodenum. In 10% of patients, the ducts of Wirsung and Santorini fail to fuse.1 This results in the majority of the pancreas draining through the duct of Santorini and the lesser papilla, while the inferior portion of the pancreatic head and uncinate process drains through the duct of Wirsung and major papilla. This nor-mal anatomic variant, which occurs in one out of 10 patients, is referred to as pancreas divisum (see Fig. 33-3). In a minority of these patients, the minor papilla can be inadequate to handle the flow of pancreatic juices from the majority of the gland. This rela-tive outflow obstruction can result in pancreatitis and is some-times treated by sphincteroplasty of the minor papilla.The main pancreatic duct is usually only 2 to 3 mm in


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Surgery_Schwartz. of the gland. This rela-tive outflow obstruction can result in pancreatitis and is some-times treated by sphincteroplasty of the minor papilla.The main pancreatic duct is usually only 2 to 3 mm in diameter and runs midway between the superior and inferior borders of the pancreas, usually closer to the posterior than to the anterior surface. Pressure inside the pancreatic duct is about twice that in the common bile duct, which is thought to prevent reflux of bile into the pancreatic duct. The main pancreatic duct joins with the common bile duct and empties at the ampulla of Vater or major papilla, which is located on the medial aspect of the second portion of the duodenum. The muscle fibers around the ampulla form the sphincter of Oddi, which controls the flow of pancreatic and biliary secretions into the duodenum. Contrac-tion and relaxation of the sphincter is regulated by complex neu-ral and hormonal factors. When the accessory pancreatic duct or lesser duct drains into the


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Surgery_Schwartz. secretions into the duodenum. Contrac-tion and relaxation of the sphincter is regulated by complex neu-ral and hormonal factors. When the accessory pancreatic duct or lesser duct drains into the duodenum, a lesser papilla can be identified approximately 2 cm proximal to the ampulla of Vater.1Brunicardi_Ch33_p1429-p1516.indd 143201/03/19 6:44 PM 1433PANCREASCHAPTER 33BileductPortalveinAbdominal aortaCeliac trunkSplenic arteryDorsalpancreatic arteryGreatpancreaticarteryCaudalarteryInferiorpancreatic arteryAnterior inferiorpancreaticoduodenal arteryAnterior superiorpancreatico-duodenalarteryPosterior inferiorpancreaticoduodenal arteryPosterior superiorpancreatico-duodenalarteryGastroduodenalarteryHepatic arteryproperCommon hepaticarterySuperiormesenteric arterySpleenDuodenumFigure 33-4. Arterial supply to the pancreas. Multiple arcades in the head and body of the pancreas provide a rich blood supply. The head of the pancreas cannot be resected without devascularizing the duodenum


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Surgery_Schwartz. supply to the pancreas. Multiple arcades in the head and body of the pancreas provide a rich blood supply. The head of the pancreas cannot be resected without devascularizing the duodenum unless a rim of pancreas containing the pancreaticoduodenal arcade is preserved.Vascular and Lymphatic AnatomyThe blood supply to the pancreas comes from multiple branches from the celiac and superior mesenteric arteries (Fig. 33-4). The common hepatic artery gives rise to the gastroduodenal artery before continuing toward the porta hepatis as the proper hepatic artery. The right gastric artery branches off the gastroduodenal artery just superior to the duodenum. The gastroduodenal artery also supplies the superior pancreaticoduodenal artery which divides into the anterior and superior pancreaticoduodenal arteries. These travel inferiorly within the pancreaticoduodenal groove giving off small branches to the duodenum and head of the pancreas. The superior pancreaticoduodenal arteries join the


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Surgery_Schwartz. arteries. These travel inferiorly within the pancreaticoduodenal groove giving off small branches to the duodenum and head of the pancreas. The superior pancreaticoduodenal arteries join the inferior pancreaticoduodenal arteries to complete the arcade. The inferior pancreaticoduodenal artery is a branch off the supe-rior mesenteric artery. Therefore, it is impossible to resect the head of the pancreas without devascularizing the duodenum, unless a rim of pancreas containing the pancreaticoduodenal arcade is preserved. The inferior pancreaticoduodenal artery needs to be controlled when dissecting the head of the pancreas off the SMA during a Whipple procedure. The gastroduodenal artery travels inferiorly anterior to the neck of the pancreas and posterior to the duodenal bulb. A posterior ulcer in the duodenal bulb can erode into the gastroduodenal artery in this location. At the inferior border of the duodenum, the gastroduodenal artery then gives rise to the right gastroepiploic


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Surgery_Schwartz. ulcer in the duodenal bulb can erode into the gastroduodenal artery in this location. At the inferior border of the duodenum, the gastroduodenal artery then gives rise to the right gastroepiploic artery then can con-tinue on to join the inferior pancreaticoduodenal artery.Variations in the arterial anatomy occur in one out of five patients. The right hepatic artery, common hepatic artery, or gas-troduodenal arteries can arise from the superior mesenteric artery. In 15% to 20% of patients, the right hepatic artery will arise from the superior mesenteric artery and travel upwards toward the liver along the posterior aspect of the head of the pancreas (referred to as a replaced right hepatic artery). It is important to look for this variation on preoperative com-puted tomographic (CT) scans and in the operating room so the 2replaced hepatic artery is recognized and injury is avoided. The body and tail of the pancreas are supplied by multiple branches of the splenic artery. The splenic


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Surgery_Schwartz. and in the operating room so the 2replaced hepatic artery is recognized and injury is avoided. The body and tail of the pancreas are supplied by multiple branches of the splenic artery. The splenic artery arises from the celiac trunk and travels along the posterior-superior border of the body and tail of the pancreas toward the spleen. The inferior pancreatic artery usually arises from the superior mesenteric artery and runs to the left along the inferior border of the body and tail of the pancreas, parallel to the splenic artery. Three vessels run perpen-dicular to the long axis of the pancreatic body and tail and con-nect the splenic artery and inferior pancreatic artery. They are, from medial to lateral, the dorsal, great, and caudal pancreatic arteries. These arteries form arcades within the body and tail of the pancreas and account for the rich blood supply of the organ.The venous drainage of the pancreas follows a pattern similar to that of the arterial supply (Fig. 33-5). The


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Surgery_Schwartz. the body and tail of the pancreas and account for the rich blood supply of the organ.The venous drainage of the pancreas follows a pattern similar to that of the arterial supply (Fig. 33-5). The veins are usually superficial to the arteries within the parenchyma of the pancreas. There is an anterior and posterior venous arcade within the head of the pancreas. Typically, the superior vein drains directly into the portal vein just above the neck of the pancreas and is often a larger branch of the portal vein which is divided during the Whipple procedure. The posterior infe-rior arcade drains directly into the inferior mesenteric vein at the inferior border of the neck of the pancreas and this is also divided during a Whipple procedure. The anterior inferior pan-creaticoduodenal vein joins the right gastroepiploic vein and the middle colic vein to form a common venous trunk, which enters into the superior mesenteric vein. Traction on the trans-verse colon during colectomy can tear these


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Surgery_Schwartz. right gastroepiploic vein and the middle colic vein to form a common venous trunk, which enters into the superior mesenteric vein. Traction on the trans-verse colon during colectomy can tear these fragile veins, which then retract into the parenchyma of the pancreas, making control tedious. There also are numerous small venous branches com-ing from the pancreatic parenchyma directly into the lateral and posterior aspect of the portal vein. Venous return from the body and tail of the pancreas drains into the splenic vein.The lymphatic drainage from the pancreas is diffuse and widespread (Fig. 33-6). The profuse network of lymphatic Brunicardi_Ch33_p1429-p1516.indd 143301/03/19 6:44 PM 1434SPECIFIC CONSIDERATIONSPART IIBileductPortal veinLeft gastric veinSplenic veinInferior mesenteric veinMiddle colic veinAnteroinferiorpancreatico-duodenalveinAnterosuperiorpancreatico-duodenalveinPosterosuperiorpancreatico-duodenalveinRightgastroepiploicveinSuperior mesenteric


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Surgery_Schwartz. mesenteric veinMiddle colic veinAnteroinferiorpancreatico-duodenalveinAnterosuperiorpancreatico-duodenalveinPosterosuperiorpancreatico-duodenalveinRightgastroepiploicveinSuperior mesenteric veinAbdominalaortaSpleenFigure 33-5. Venous drainage from the pancreas. The venous drainage of the pancreas follows a pattern similar to the arterial supply, with the veins usually superficial to the arteries. Anterior traction on the transverse colon can tear fragile branches along the inferior border of the pancreas, which then retract into the parenchyma of the pancreas. Venous branches draining the pancreatic head and uncinate process enter along the right lateral and posterior sides of the portal vein. There are usually no anterior venous tributaries, and a plane can usually be developed between the neck of the pancreas and the portal and superior mesenteric veins.Celiaclymph nodeHepaticlymph nodePyloriclymph nodeAnteriorpancreatico-duodenallymph nodePosteriorpancreaticoduodenallymph


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Surgery_Schwartz. between the neck of the pancreas and the portal and superior mesenteric veins.Celiaclymph nodeHepaticlymph nodePyloriclymph nodeAnteriorpancreatico-duodenallymph nodePosteriorpancreaticoduodenallymph nodeSuperior mesentericlymph nodeInferiorbodySuperior body Splenic lymphnodeDuodenumSpleenFigure 33-6. Lymphatic supply to the pancreas. The lymphatic drainage from the pancreas is diffuse and widespread, which explains the high incidence of lymph node metastases and local recurrence of pancreatic cancer. The pancreatic lymphatics also communicate with lymph nodes in the transverse mesocolon and mesentery of the proximal jejunum. Tumors in the body and tail of the pancreas are often unresect-able because they metastasize to these lymph nodes. (Reproduced with permission from Bell RH, Rikkers LF, Mulholland M: Digestive Tract Surgery: A Text and Atlas. Philadelphia, PA: Lippincott Williams & Wilkins; 1996.)Brunicardi_Ch33_p1429-p1516.indd 143401/03/19 6:44 PM 1435PANCREASCHAPTER


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Surgery_Schwartz. LF, Mulholland M: Digestive Tract Surgery: A Text and Atlas. Philadelphia, PA: Lippincott Williams & Wilkins; 1996.)Brunicardi_Ch33_p1429-p1516.indd 143401/03/19 6:44 PM 1435PANCREASCHAPTER 33SpleenPancreasEsophagusCeliac ganglionRight vagus nerveLeft vagus nerveSplanchnic nervesDuodenumAbdominal aortaFigure 33-7. Innervation of the pancreas. The pancreas has a rich supply of afferent sensory fibers that travel superiorly to the celiac ganglia. Interruption of these somatic fibers with a celiac plexus block can interfere with transmission of pancreatic pain. (Reproduced with permission from Bell RH, Rikkers LF, Mulholland M: Digestive Tract Surgery: A Text and Atlas. Philadelphia, PA: Lippincott Williams & Wilkins; 1996.)vessels and lymph nodes draining the pancreas provides egress to tumor cells arising from the pancreas. This diffuse lymphatic drainage contributes to the fact that pancreatic cancer often presents with positive lymph nodes and a high incidence of local recurrence


Surgery_Schwartz

Surgery_Schwartz. tumor cells arising from the pancreas. This diffuse lymphatic drainage contributes to the fact that pancreatic cancer often presents with positive lymph nodes and a high incidence of local recurrence after resection. Lymph nodes can be palpated along the distal bile duct and posterior aspect of the head of the pan-creas in the pancreaticoduodenal groove, where the mesenteric vein passes under the neck of the pancreas, along the inferior border of the body, at the celiac axis and along the hepatic artery ascending into the porta hepatis, and along the splenic artery and vein. The pancreatic lymphatics also communicate with lymph nodes in the transverse mesocolon and mesentery of the proxi-mal jejunum. Tumors in the body and tail of the pancreas often metastasize to these nodes and lymph nodes along the splenic vein and in the hilum of the spleen.NeuroanatomyThe pancreas is innervated by the sympathetic and parasympathetic nervous systems. The acinar cells responsible for exocrine


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Surgery_Schwartz. nodes along the splenic vein and in the hilum of the spleen.NeuroanatomyThe pancreas is innervated by the sympathetic and parasympathetic nervous systems. The acinar cells responsible for exocrine secretion, the islet cells responsible for endocrine secretion, and the islet vasculature are innervated by both systems. The parasympathetic system stimulates endocrine and exocrine secretion and the sympathetic system inhibits secretion.2 The pancreas is also innervated by neurons that secrete amines and peptides, such as somatostatin, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), and galanin. The exact role of these neurons in pancreatic physiology is uncertain, but they do appear to affect both exocrine and endocrine function. The pancreas also has a rich supply of afferent sensory fibers, which are responsible for the intense pain associated with advanced pancreatic cancer, as well as acute and chronic pancreatitis. These somatic fibers travel superiorly


Surgery_Schwartz

Surgery_Schwartz. of afferent sensory fibers, which are responsible for the intense pain associated with advanced pancreatic cancer, as well as acute and chronic pancreatitis. These somatic fibers travel superiorly to the celiac ganglia (Fig. 33-7). Interruption of these somatic fibers with a celiac plexus block can stop transmission of pain sensation.HISTOLOGY AND PHYSIOLOGYThe exocrine pancreas accounts for about 85% of the pancreatic mass; 10% of the gland is accounted for by extracellular matrix, and 4% by blood vessels and the major ducts, whereas only 2% of the gland is comprised of endocrine tissue. The endocrine and exocrine pancreas are sometimes thought of as function-ally separate, but these different components of the organ are coordinated to allow an elegant regulatory feedback system for digestive enzyme and hormone secretion. This complex system regulates the type of digestion, its rate, and the processing and distribution of absorbed nutrients. This coordination is facili-tated by the


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Surgery_Schwartz. enzyme and hormone secretion. This complex system regulates the type of digestion, its rate, and the processing and distribution of absorbed nutrients. This coordination is facili-tated by the physical approximation of the islets and the exo-crine pancreas, the presence of specific islet hormone receptors on the plasma membranes of pancreatic acinar cells, and the existence of an islet-acinar portal blood system.Although patients can live without a pancreas when insu-lin and digestive enzyme replacement are administered, the loss of this islet-acinar coordination leads to impairments in diges-tive function. Although only approximately 20% of the normal pancreas is required to prevent insufficiency, in many patients undergoing pancreatic resection, the remaining pancreas is not normal, and pancreatic endocrine and exocrine insufficiency can develop with removal of smaller portions of the gland.Exocrine PancreasThe pancreas secretes approximately 500 to 800 mL per day of colorless,


Surgery_Schwartz

Surgery_Schwartz. and pancreatic endocrine and exocrine insufficiency can develop with removal of smaller portions of the gland.Exocrine PancreasThe pancreas secretes approximately 500 to 800 mL per day of colorless, odorless, alkaline, isosmotic pancreatic juice. Pan-creatic juice is a combination of acinar cell and duct cell secre-tions. The acinar cells secrete amylase, proteases, and lipases, enzymes responsible for the digestion of all three food types: carbohydrate, protein, and fat. The acinar cells are pyramid-shaped, with their apices facing the lumen of the acinus. Near the apex of each cell are numerous enzyme-containing zymogen Brunicardi_Ch33_p1429-p1516.indd 143501/03/19 6:44 PM 1436SPECIFIC CONSIDERATIONSPART IIAcinar cellsCentroacinar cellsIntercalated ductFigure 33-8. Acinar cell. Zymogen granules fuse with the apical membrane and release multiple enzymes to digest carbohydrates, proteins, and fat. (Reproduced with permission from Bloom W, Fawcett DW: A Textbook of Histology, 10th


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Surgery_Schwartz. granules fuse with the apical membrane and release multiple enzymes to digest carbohydrates, proteins, and fat. (Reproduced with permission from Bloom W, Fawcett DW: A Textbook of Histology, 10th ed. Philadelphia, PA: Saunders; 1975.)granules that fuse with the apical cell membrane (Fig. 33-8). Unlike the endocrine pancreas, where islet cells specialize in the secretion of one hormone type, individual acinar cells secrete all types of enzymes. However, the ratio of the different enzymes released is adjusted to the composition of digested food through nonparallel regulation of secretion.Pancreatic amylase is secreted in its active form and com-pletes the digestive process already begun by salivary amylase. Amylase is the only pancreatic enzyme secreted in its active form, and it hydrolyzes starch and glycogen to glucose, malt-ose, maltotriose, and dextrins. These simple sugars are trans-ported across the brush border of the intestinal epithelial cells by active transport mechanisms.


Surgery_Schwartz

Surgery_Schwartz. starch and glycogen to glucose, malt-ose, maltotriose, and dextrins. These simple sugars are trans-ported across the brush border of the intestinal epithelial cells by active transport mechanisms. Gastric hydrolysis of protein yields peptides that enter the intestine and stimulate intestinal endocrine cells to release cholecystokinin (CCK)-releasing pep-tide, CCK, and secretin, which then stimulate the pancreas to secrete enzymes and bicarbonate into the intestine.The proteolytic enzymes are secreted as proenzymes that require activation. Trypsinogen is converted to its active form, trypsin, by another enzyme, enterokinase, which is produced by the duodenal mucosal cells. Trypsin, in turn, activates the other proteolytic enzymes. Trypsinogen activation within the pancreas is prevented by the presence of inhibitors that are also secreted by the acinar cells. A failure to express a normal tryp-sinogen inhibitor, pancreatic secretory trypsin inhibitor (PSTI), also known as serine


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Surgery_Schwartz. by the presence of inhibitors that are also secreted by the acinar cells. A failure to express a normal tryp-sinogen inhibitor, pancreatic secretory trypsin inhibitor (PSTI), also known as serine protease inhibitor Kazal type 1 (SPINK1), is a cause of familial pancreatitis. Inhibition of trypsinogen activation ensures that the enzymes within the pancreas remain in an inactive precursor state and are activated only within the duodenum. Trypsinogen is expressed in several isoforms, and a missense mutation on the cationic trypsinogen, or PRSS1, results in premature, intrapancreatic activation of trypsinogen. This accounts for about two-thirds of cases of hereditary pan-creatitis. Chymotrypsinogen is activated to form chymotrypsin. Elastase, carboxypeptidase A and B, and phospholipase are also activated by trypsin. Trypsin, chymotrypsin, and elastase cleave bonds between amino acids within a target peptide chain, and carboxypeptidase A and B cleave amino acids at the end of peptide


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Surgery_Schwartz. also activated by trypsin. Trypsin, chymotrypsin, and elastase cleave bonds between amino acids within a target peptide chain, and carboxypeptidase A and B cleave amino acids at the end of peptide chains. Individual amino acids and small dipeptides are then actively transported into the intestinal epithelial cells. Pancreatic lipase hydrolyzes triglycerides to 2-monoglyceride and fatty acid. Pancreatic lipase is secreted in an active form. Colipase is also secreted by the pancreas and binds to lipase, changing its molecular configuration and increasing its activity. Phospholipase A2 is secreted by the pancreas as a proenzyme that becomes activated by trypsin. Phospholipase A2 hydrolyzes phospholipids and, as with all lipases, requires bile salts for its action. Carboxylic ester hydrolase and cholesterol esterase hydrolyze neutral lipid substrates like esters of cholesterol, fat-soluble vitamins, and triglycerides. The hydrolyzed fat is then packaged into micelles for transport into


Surgery_Schwartz

Surgery_Schwartz. and cholesterol esterase hydrolyze neutral lipid substrates like esters of cholesterol, fat-soluble vitamins, and triglycerides. The hydrolyzed fat is then packaged into micelles for transport into the intestinal epithelial cells, where the fatty acids are reassembled and packaged inside chylomicrons for transport through the lymphatic system into the bloodstream (Table 33-1).The centroacinar and intercalated duct cells secrete the water and electrolytes present in the pancreatic juice. About 40 acinar cells are arranged into a spherical unit called an acinus. Centroacinar cells are located near the center of the acinus and are responsible for fluid and electrolyte secretion. These cells contain the enzyme carbonic anhydrase, which is needed for bicarbonate secretion. The amount of bicarbonate secreted varies with the pancreatic secretory rate, with greater concen-trations of bicarbonate being secreted as the pancreatic secre-tory rate increases. Chloride secretion varies inversely


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Surgery_Schwartz. secreted varies with the pancreatic secretory rate, with greater concen-trations of bicarbonate being secreted as the pancreatic secre-tory rate increases. Chloride secretion varies inversely with bicarbonate secretion such that the sum of these two remains constant. In contrast, sodium and potassium concentrations are kept constant throughout the spectrum of secretory rates3 (Fig. 33-9). The hormone secretin is released from cells in the duodenal mucosa in response to acidic chyme passing through the pylorus into the duodenum. Secretin is the major stimulant for bicarbonate secretion, which buffers the acidic fluid entering the duodenum from the stomach. CCK also stimulates bicarbon-ate secretion, but to a much lesser extent than secretin. CCK potentiates secretin-stimulated bicarbonate secretion. Gastrin and acetylcholine, both stimulants of gastric acid secretion, are also weak stimulants of pancreatic bicarbonate secretion.4 Truncal vagotomy produces a myriad of complex effects


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Surgery_Schwartz. secretion. Gastrin and acetylcholine, both stimulants of gastric acid secretion, are also weak stimulants of pancreatic bicarbonate secretion.4 Truncal vagotomy produces a myriad of complex effects on the downstream digestive tract, but the sum effect on the exocrine pancreas is a reduction in bicarbonate and fluid secretion.5 The endocrine pancreas also influences the adjacent exocrine pan-creatic secretions. Somatostatin, pancreatic polypeptide (PP), and glucagon are all thought to inhibit exocrine secretion.The acinar cells release pancreatic enzymes from their zymogen granules into the lumen of the acinus, and these pro-teins combine with the water and bicarbonate secretions of the centroacinar cells. The pancreatic juice then travels into small intercalated ducts. Several small intercalated ducts join to form an interlobular duct. Cells in the interlobular ducts contribute fluid and electrolytes to adjust the final concentrations of the pancreatic fluid. Interlobular ducts then


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Surgery_Schwartz. ducts join to form an interlobular duct. Cells in the interlobular ducts contribute fluid and electrolytes to adjust the final concentrations of the pancreatic fluid. Interlobular ducts then join to form about 20 secondary ducts that empty into the main pancreatic duct. Brunicardi_Ch33_p1429-p1516.indd 143601/03/19 6:44 PM 1437PANCREASCHAPTER 33Table 33-1Pancreatic enzymesENZYMESUBSTRATEPRODUCTCarbohydrate Amylase (active)Starch, glycogenGlucose, maltose, maltotriose, dextrinsProtein Endopeptidases Trypsinogen (inactive) Enterokinase Trypsin (active) Chymotrypsinogen (inactive) EnterokinaseTrypsin Chymotrypsin (active) Proelastase (inactive) EnterokinaseTrypsin Elastase (active) Exopeptidases Procarboxy peptidase A&B (inactive) Enterokinase Carboxypeptidase A&B (active)Cleave bonds between amino acidsCleave amino acids from end of peptide chainsAmino acids, dipeptides—Fat Pancreatic lipase (active) Phospholipase A2 (inactive) Trypsin Phospholipase A2 (active) Cholesterol


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Surgery_Schwartz. bonds between amino acidsCleave amino acids from end of peptide chainsAmino acids, dipeptides—Fat Pancreatic lipase (active) Phospholipase A2 (inactive) Trypsin Phospholipase A2 (active) Cholesterol esteraseTriglyceridesPhospholipaseNeutral lipids2-Monoglycerides, fatty acids——Concentration (mEq/L)18016014012010080604020 000.40.81.21.6Secretory rate (mL/min)Pancreatic juice180160140120100806040200PlasmaNaHCO3ClKNa=151.5HCO3=26.0Cl=110.0K=5.38Figure 33-9. Composition of pancreatic exocrine secretions. Greater concentrations of bicarbonate are secreted at higher secretory rates, and chloride secretion varies inversely with bicarbonate secretion. In contrast, sodium and potassium concentrations are independent of the secretory rate. (Reproduced with permission from Bro-Rasmussen F, Killmann SA, Thaysen JH: The composition of pancreatic juice as compared to sweat, parotid saliva and tears, Acta Physiol Scand. 1956 Sep 26;37(2-3):97-113.)Table 33-2Pancreatic Islet Peptide


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Surgery_Schwartz. F, Killmann SA, Thaysen JH: The composition of pancreatic juice as compared to sweat, parotid saliva and tears, Acta Physiol Scand. 1956 Sep 26;37(2-3):97-113.)Table 33-2Pancreatic Islet Peptide ProductsHORMONESISLET CELLFUNCTIONSInsulinBetaDecreases gluconeogenesis, glycogenolysis, fatty acid breakdown, and ketogenesisIncreased glycogenesis, protein synthesis and glucose uptakeGlucagonAlphaOpposite effects of insulin; increases hepatic glycogenolysis and gluconeogenesisSomatostatinDeltaInhibits secretion and action of all pancreatic and gut peptides, inhibits cell growthPancreatic PolypeptidePP or FInhibits pancreatic exocrine secretion and facilitates hepatic action of insulinAmylin (IAPP)BetaCounter-regulates insulin secretion and functionPancreastatinBetaDecreases insulin and somatostatin secretion, increases glucagon secretion, decreases exocrine secretionGhrelinEpsilonDecreases insulin secretion and actionPeptide YY (PYY)not knownIncreases insulin secretion and beta cell


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Surgery_Schwartz. secretion, increases glucagon secretion, decreases exocrine secretionGhrelinEpsilonDecreases insulin secretion and actionPeptide YY (PYY)not knownIncreases insulin secretion and beta cell growthDestruction of the branching ductal tree from recurrent inflam-mation, scarring, and deposition of stones in chronic pancreatitis eventually contributes to destruction of the exocrine pancreas and exocrine pancreatic insufficiency.Endocrine PancreasThere are nearly 1 million islets of Langerhans in the normal adult pancreas. They vary greatly in size from 40 to 900 μm. Larger islets are located closer to the major arterioles and smaller islets are embedded more deeply in the parenchyma of the pancreas. Most islets contain 3000 to 4000 cells of five major types: alpha cells that secrete glucagon, beta-cells that secrete insulin, delta cells that secrete somatostatin, epsilon cells that secrete ghrelin, and PP cells that secrete PP (Table 33-2).Insulin is the best-studied pancreatic hormone. The


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Surgery_Schwartz. that secrete insulin, delta cells that secrete somatostatin, epsilon cells that secrete ghrelin, and PP cells that secrete PP (Table 33-2).Insulin is the best-studied pancreatic hormone. The discovery of insulin in 1920 by Frederick Banting, an orthopedic Brunicardi_Ch33_p1429-p1516.indd 143701/03/19 6:44 PM 1438SPECIFIC CONSIDERATIONSPART IIsurgeon, and Charles Best, a medical student, was recognized with the awarding of the Nobel Prize in Physiology or Medicine. They produced diabetes in dogs by performing total pancreatectomy and then treated them with crude pancreatic extracts from dog and calf pancreata using techniques to prevent the breakdown of insulin by the proteolytic enzymes of the exocrine pancreas. Insulin was subsequently purified and found to be a 56-amino acid peptide with two chains, an alpha and a beta chain, joined by two disulfide bridges and a connecting peptide, or C-peptide. Proinsulin is made in the endoplasmic reticulum and then is transported to the


Surgery_Schwartz

Surgery_Schwartz. with two chains, an alpha and a beta chain, joined by two disulfide bridges and a connecting peptide, or C-peptide. Proinsulin is made in the endoplasmic reticulum and then is transported to the Golgi complex, where it is packaged into granules and the C-peptide is cleaved off. There are two phases of insulin secretion. In the first phase, stored insulin is released. This phase lasts about 5 minutes after a glucose challenge. The second phase of insulin secretion is a longer, sustained release due to ongoing production of new insulin. beta-cell synthesis of insulin is regulated by plasma glucose levels, neural signals, and the paracrine influence of other islet cells. The diagnosis of diabetes is made by using oral and intravenous (IV) glucose tolerance tests. Oral glucose not only enters the bloodstream but also stimulates the release of enteric hormones such as gastric inhibitory peptide (also known as glucose-dependent insulinotropic polypeptide or GIP), glucagon-like peptide-1


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Surgery_Schwartz. the bloodstream but also stimulates the release of enteric hormones such as gastric inhibitory peptide (also known as glucose-dependent insulinotropic polypeptide or GIP), glucagon-like peptide-1 (GLP-1), and CCK that augment the secretion of insulin and are therefore referred to as incretins. As a result, oral glucose is a more vigorous stimulus to insulin secretion than IV glucose. In the oral glucose tolerance test (OGTT), the patient is fasted overnight, and a basal glucose value is determined. Forty g/m2 or 75 g of glucose is given orally over 10 minutes. Blood samples are taken every 30 minutes for 2 hours. Normal values and criteria for diabetes vary by age, but essentially all values should be <200 mg/dL, and the 120-minute value should be <140 mg/dL.Insulin secretion by the beta-cell is also influenced by plasma levels of amino acids such as arginine, lysine, leucine, and free fatty acids. Glucagon, GIP, GLP-1, and CCK stimulate insulin release, while somatostatin, amylin,


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Surgery_Schwartz. is also influenced by plasma levels of amino acids such as arginine, lysine, leucine, and free fatty acids. Glucagon, GIP, GLP-1, and CCK stimulate insulin release, while somatostatin, amylin, and pancreastatin inhibit insulin release.6 Cholinergic fibers and alpha-sympa-thetic fibers stimulate insulin release, while beta-sympathetic fibers inhibit insulin secretion.Insulin’s glucoregulatory function is to inhibit endogenous (hepatic) glucose production and to facilitate glucose transport into cells, thus lowering plasma glucose levels. Insulin also inhibits glycogenolysis, fatty acid breakdown, and ketone formation, and stimulates protein synthesis. There is a considerable amount of functional reserve in insulin secretory capacity. If the remaining portion of the pancreas is healthy, about 80% of the pancreas can be resected without the patient becoming diabetic.7 In patients with chronic pancreatitis, or other conditions in which much of the gland is diseased, resection of a smaller


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Surgery_Schwartz. 80% of the pancreas can be resected without the patient becoming diabetic.7 In patients with chronic pancreatitis, or other conditions in which much of the gland is diseased, resection of a smaller fraction of the pancreas can result in pancreatogenic, or type 3c diabetes (Table 33-3).Insulin receptors are dimeric, tyrosine kinase–containing transmembrane proteins that are located on all cells. Insulin defi-ciency (seen in type 1 and type 3c diabetes) results in an overex-pression or upregulation of insulin receptors, which causes an enhanced sensitivity to insulin in muscle and adipocytes (and therefore increases the risk of insulin-induced hypoglycemia). Type 2 diabetes is associated with a downregulation of insulin receptors and relative hyperinsulinemia, with resulting insulin resistance. Some forms of diabetes are associated with selected impairments of hepatic or peripheral insulin receptors, such as pancreatogenic or type 3c diabetes (T3cDM) or maturity-onset diabetes of the


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Surgery_Schwartz. Some forms of diabetes are associated with selected impairments of hepatic or peripheral insulin receptors, such as pancreatogenic or type 3c diabetes (T3cDM) or maturity-onset diabetes of the young (MODY).Glucagon is a 29-amino-acid, single-chain peptide that promotes hepatic glycogenolysis and gluconeogenesis and counteracts the effects of insulin through its hyperglycemic action. Glucose is the primary regulator of glucagon secretion, as it is with insulin, but it has an inhibitory rather than stimulatory effect. Glucagon release is stimulated by hypoglycemia and by the amino acids arginine and alanine. GLP-1 inhibits glucagon secretion in vivo, and insulin and somatostatin inhibit glucagon Table 33-3Clinical and laboratory findings in types of diabetes mellitusPARAMETERTYPE 1TYPE 2TYPE 3C IDDMNIDDMPancreatogenicKetoacidosisCommonRareRareHyperglycemiaSevereUsually mildMildHypoglycemiaCommonRareCommonPeripheral insulin sensitivityNormal or increasedDecreasedIncreasedHepatic insulin


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Surgery_Schwartz. 3C IDDMNIDDMPancreatogenicKetoacidosisCommonRareRareHyperglycemiaSevereUsually mildMildHypoglycemiaCommonRareCommonPeripheral insulin sensitivityNormal or increasedDecreasedIncreasedHepatic insulin sensitivityNormalNormal or decreasedDecreasedInsulin levelsLowHighLowGlucagon levelsNormal or highNormal or highLowPP levelsNormal or low (late)HighLowGIP levelsNormal or lowNormal or highLowGLP-1 levelsNormalNormal or highNormal or highTypical age of onsetChildhood or adolescenceAdulthoodAnyAbbreviations: IDDM = insulin dependent diabetes mellitus; NIDDM = non–insulin-dependent diabetes mellitus; PP = pancreatic polypeptide; GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide 1.Reproduced with permission from Slezak LA, Andersen DK: Pancreatic resection: effects on glucose metabolism, World J Surg. 2001 Apr;25(4):452-460.Brunicardi_Ch33_p1429-p1516.indd 143801/03/19 6:44 PM 1439PANCREASCHAPTER 33secretion in a paracrine fashion within the islet. The same


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Surgery_Schwartz. on glucose metabolism, World J Surg. 2001 Apr;25(4):452-460.Brunicardi_Ch33_p1429-p1516.indd 143801/03/19 6:44 PM 1439PANCREASCHAPTER 33secretion in a paracrine fashion within the islet. The same neural impulses that regulate insulin secretion also regulate glucagon secretion, so that the two hormones work together in a balance of actions to maintain glucose levels. Cholinergic and alpha-sympathetic fibers stimulate glucagon release, while beta-sympathetic fibers inhibit glucagon release.8 In pancreatogenic or type 3c diabetes, glucagon responsiveness to a fall in blood glucose is lost, thereby increasing the risk for hypoglycemia.Although originally isolated from the hypothalamus, somatostatin is a peptide that is now known to have a wide ana-tomic distribution, not only in neurons but also in the pancreas, gut, and other tissues. It is a highly conserved peptide hormone, as it is found in lower vertebrates, and is now realized to be of fundamental importance in regulatory


Surgery_Schwartz

Surgery_Schwartz. but also in the pancreas, gut, and other tissues. It is a highly conserved peptide hormone, as it is found in lower vertebrates, and is now realized to be of fundamental importance in regulatory processes throughout the body. One gene encodes for a common precursor that is dif-ferentially processed to generate tissue-specific amounts of two bioactive products, somatostatin-14, and somatostatin-28. These peptides inhibit endocrine and exocrine secretion and affect neurotransmission, GI and biliary motility, intestinal absorption, vascular tone, and cell proliferation.Five different somatostatin receptors (SSTRs) have been cloned and the biologic properties of each are different.9 The hexapeptide and octapeptide analogues such as octreotide bind only to SSTR2, SSTR3, and SSTR5. These analogues have a longer serum half-life, and their potent inhibitory effect has been used clinically to treat both endocrine and exocrine disor-ders. For example, octreotide has been shown to decrease


Surgery_Schwartz

Surgery_Schwartz. have a longer serum half-life, and their potent inhibitory effect has been used clinically to treat both endocrine and exocrine disor-ders. For example, octreotide has been shown to decrease fistula output and speed the time it takes for enteric and pancreatic fistulas to close.10Endocrine release of somatostatin occurs during a meal. The major stimulant is probably intraluminal fat. Acidification of the gastric and duodenal mucosa also releases somatostatin in isolated perfused organ preparations. Acetylcholine from the cholinergic neurons inhibits somatostatin release.Pancreatic polypeptide (PP) is a 36-amino-acid, straight-chain peptide discovered by Kimmel in 1968 during the process of insulin purification. Protein is the most potent enteral stimu-lator of PP release, closely followed by fat, whereas glucose has a weaker effect.11 Hypoglycemia, whether or not it is insulin induced, strongly stimulates PP secretion through cholinergic stimulation.12 Phenylalanine, tryptophan, and


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Surgery_Schwartz. by fat, whereas glucose has a weaker effect.11 Hypoglycemia, whether or not it is insulin induced, strongly stimulates PP secretion through cholinergic stimulation.12 Phenylalanine, tryptophan, and fatty acids in the duodenum stimulate PP release, probably by inducing CCK, GIP, and secretin release. Vagal stimulation of the pancreas is the most important regulator of PP secretion. In fact, vagotomy eliminates the rise in PP levels usually seen after a meal. This can be used as a test for the completeness of a surgical vagot-omy or for the presence of diabetic autonomic neuropathy.PP has been shown to inhibit choleresis (bile secretion), gallbladder contraction, and secretion by the exocrine pan-creas. However, PP’s most important role is in glucose regu-lation through its regulation of hepatic insulin receptor gene expression. A deficiency in PP secretion due to proximal pan-createctomy, severe chronic pancreatitis, or cystic fibrosis, is associated with diminished hepatic insulin


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Surgery_Schwartz. hepatic insulin receptor gene expression. A deficiency in PP secretion due to proximal pan-createctomy, severe chronic pancreatitis, or cystic fibrosis, is associated with diminished hepatic insulin sensitivity due to reduced hepatic insulin receptor availability.13 This effect is reversed by PP administration.14Recent studies have shown that a fifth islet peptide, ghre-lin, is secreted from a distinct population of islet cells, called epsilon cells.15,16 Ghrelin also is present in the gastric fundus in large amounts and stimulates growth hormone secretion via growth hormone releasing hormone release from the pituitary. It is an orexigenic, or appetite-stimulating, peptide the plasma levels of which are increased in obesity. Ghrelin has also been shown to block insulin effects on the liver, and inhibits the beta-cell response to incretin hormones and glucose.17 Therefore, ghrelin secretion from and within the islet may modulate the responses of other islet cells to nutrient and


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Surgery_Schwartz. liver, and inhibits the beta-cell response to incretin hormones and glucose.17 Therefore, ghrelin secretion from and within the islet may modulate the responses of other islet cells to nutrient and hormonal stimuli.In addition to the five main peptides secreted by the pan-creas, there are a number of other peptide products of the islet cells, including amylin, peptide YY (PYY), and pancreastatin, as well as neuropeptides such as VIP, galanin, and serotonin. Amylin or islet amyloid polypeptide (IAPP) is a 37-amino-acid polypeptide that is predominantly expressed by the pancreatic beta-cells, where it is stored along with insulin in secretory granules.18 The function of IAPP seems to be the modulation or counterregulation of insulin secretion and function. Pancre-astatin is a recently discovered pancreatic islet peptide prod-uct that inhibits insulin, and possibly somatostatin release, and augments glucagon release.19,20 In addition to this effect on the endocrine pancreas,


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Surgery_Schwartz. discovered pancreatic islet peptide prod-uct that inhibits insulin, and possibly somatostatin release, and augments glucagon release.19,20 In addition to this effect on the endocrine pancreas, pancreastatin inhibits pancreatic exocrine secretion.21 PYY is structurally related to PP and was initially found in hormone-secreting “L” cells of the small intestine, where it colocalizes with GLP-1. Recently, PYY has been local-ized to the islets22 where it appears to regulate insulin secretion through an autocrine mechanism.Islet DistributionThe beta-cells are generally located in the central portion of each islet and make up about 70% of the total islet cell mass. The other cell types are located predominantly in the periphery. The delta cells are least plentiful, making up only 5%; the 〈-cells make up 10%, and the PP cells make up 15%.23 In contrast to the acinar cells that secrete the full gamut of exocrine enzymes, the islet cells seem to specialize in the secretion of predominantly one


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Surgery_Schwartz. make up 10%, and the PP cells make up 15%.23 In contrast to the acinar cells that secrete the full gamut of exocrine enzymes, the islet cells seem to specialize in the secretion of predominantly one hormone. However, individual islet cells can secrete mul-tiple hormones. For example, the beta-cells secrete both insulin and amylin, which counter regulates the actions of insulin. In reality, more than 20 different hormones are secreted by the islets, and the exact functions of this milieu are very complex. There is diversity among the islets depending on their location within the pancreas. The beta and delta cells are evenly distrib-uted throughout the pancreas, but islets in the head and uncinate process (ventral anlage) have a higher percentage of PP cells and fewer alpha cells, whereas islets in the body and tail (dorsal anlage) contain the majority of alpha cells and few PP cells. This is clinically significant because pancreatoduodenectomy removes 95% of the PP cells in the


Surgery_Schwartz

Surgery_Schwartz. islets in the body and tail (dorsal anlage) contain the majority of alpha cells and few PP cells. This is clinically significant because pancreatoduodenectomy removes 95% of the PP cells in the pancreas. This may partially explain the higher incidence of glucose intolerance after the Whipple procedure compared to a distal pancreatectomy with an equivalent amount of tissue resected. In addition, chronic pan-creatitis, which disproportionately affects the pancreatic head, is associated with PP deficiency and pancreatogenic diabetes.24 The relative preponderance of alpha cells in the body and tail of the pancreas explains the typical location of glucagonomas.ACUTE PANCREATITISDefinition, Incidence, and EpidemiologyAcute pancreatitis is an inflammatory disorder of the pancreas that is characterized by edema and, when severe, necrosis. It is a common and challenging disease that can develop local and systemic complications. As such, it ranges from a mild, self-limiting inflammation of the


Surgery_Schwartz

Surgery_Schwartz. by edema and, when severe, necrosis. It is a common and challenging disease that can develop local and systemic complications. As such, it ranges from a mild, self-limiting inflammation of the pancreas to severe and critical disease characterized by infected pancreatic necrosis, multiple Brunicardi_Ch33_p1429-p1516.indd 143901/03/19 6:44 PM 1440SPECIFIC CONSIDERATIONSPART IITable 33-4Etiologies of acute pancreatitisAlcoholBiliary tract diseaseHyperlipidemiaHereditaryHypercalcemiaTrauma External Surgical Endoscopic retrograde cholangiopancreatographyIschemia Hypoperfusion Atheroembolic VasculitisPancreatic duct obstruction Neoplasms Pancreas divisum Ampullary and duodenal lesionsInfectionsVenomDrugsIdiopathicReproduced with permission from Townsend CM, Sabiston DC: Sabiston’s Textbook of Surgery: the biological basis of modern surgical practice, 16th ed. Philadelphia, PA: Saunders/Elsevier; 2000.organ failure, and a high mortality.25 The traditional view is that acute pancreatitis


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Surgery_Schwartz. of Surgery: the biological basis of modern surgical practice, 16th ed. Philadelphia, PA: Saunders/Elsevier; 2000.organ failure, and a high mortality.25 The traditional view is that acute pancreatitis completely resolves with no morphological, functional, or symptomatic sequelae. But necrotizing pancreati-tis can leave significant scarring, strictures, and impairment of exocrine and endocrine pancreatic function. The overall clinical outcome has improved over recent decades, even in the absence of specific treatments that target outcome-determining patho-physiology, probably because of a more standardized approach to diagnosis, monitoring, and management.Acute pancreatitis is the most common inpatient princi-pal gastrointestinal discharge diagnosis in the United States (274,119 in 2009), with an increasing incidence (30% since 2000) and is associated with the highest aggregate inpatient costs at 2.6 billion dollars per year.26 The crude mortality rate of 1 per 100,000 population ranks


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Surgery_Schwartz. an increasing incidence (30% since 2000) and is associated with the highest aggregate inpatient costs at 2.6 billion dollars per year.26 The crude mortality rate of 1 per 100,000 population ranks it as the 14th most common overall and the 9th most common noncancer cause of gastrointestinal deaths. Worldwide, the incidence of acute pancreatitis ranges from 5 to 80 per 100,000 population, with the highest incidence recorded in Finland and the United States.27 The incidence of acute pancreatitis also shows significant variation related to the prevalence of etiological factors and ethnicity. The annual inci-dence of acute pancreatitis in Native Americans is 4 per 100,000 population; in whites, it is 5.7; and in blacks it is 20.7.28 Smok-ing is an independent risk factor for acute pancreatitis.29EtiologyMany factors are causally related to the onset of acute pan-creatitis, but the mechanism is often poorly understood. The most common causes are gallstones and alcohol (Table 33-4),


Surgery_Schwartz

Surgery_Schwartz. factors are causally related to the onset of acute pan-creatitis, but the mechanism is often poorly understood. The most common causes are gallstones and alcohol (Table 33-4), accounting for up to 80% of cases, but it is not uncommon to diagnose acute pancreatitis in the absence of these etiological factors (“idiopathic acute pancreatitis”), and it is important that a systematic approach is taken to the identification of other, less common and potentially modifiable factors. The median age at index presentation of acute pancreatitis varies with etiology: with alcoholand drug-induced pancreatitis presenting in the third or fourth decade compared with gallstone and trauma in the sixth decade. The gender difference is probably more related to etiology: in males alcohol is more often the cause while in females it is gallstones.GallstonesEvidence that passage of a gallstone is related to the onset of acute pancreatitis comes from the characteristic transient derangement of liver function


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Surgery_Schwartz. while in females it is gallstones.GallstonesEvidence that passage of a gallstone is related to the onset of acute pancreatitis comes from the characteristic transient derangement of liver function tests and the high retrieval rate of gallstones from feces within 10 days of an attack of acute pancreatitis compared with those without acute pancreatitis (88% vs. 11%).30 The mechanism by which small gallstones cause acute pancreatitis in migrating through to the duodenum is not clear. Opie made the seminal observation of a gallstone impacted in the sphincter of Oddi in two fatal cases of acute pancreatitis, which lead to the “common channel” hypothesis. It was proposed that this allowed bile to reflux into the pancre-atic duct, but this cannot be reliably reproduced in experimen-tal models. Another proposal was that transient incompetence caused by the passage of a stone through the sphincter might allow duodenal fluid and bile to reflux into the pancreatic duct, but this is not supported


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Surgery_Schwartz. proposal was that transient incompetence caused by the passage of a stone through the sphincter might allow duodenal fluid and bile to reflux into the pancreatic duct, but this is not supported by the failure of this to commonly occur after endoscopic sphincterotomy. A third possibility is that acute pancreatitis is due to the gallstone obstructing the pancreatic duct and leading to ductal hypertension. It has been postulated that this backpressure might lead to minor ductal dis-ruption, extravasation of pancreatic juice into the less alkaline interstitium of the pancreas, and promotion of enzyme activa-tion. When gallstones and other etiological factors cannot be identified, there is still the possibility of finding microlithiasis, seen as birefringent crystals, on bile microscopy.31 This occult microlithiasis is probably responsible for up to half of those with idiopathic acute pancreatitis.AlcoholAlcohol ingestion is associated with acute pancreatitis, and sus-tained alcohol


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Surgery_Schwartz. This occult microlithiasis is probably responsible for up to half of those with idiopathic acute pancreatitis.AlcoholAlcohol ingestion is associated with acute pancreatitis, and sus-tained alcohol ingestion is associated with recurrent acute pan-creatitis and development of chronic pancreatitis in susceptible individuals who have been drinking for more than a decade. The type of alcohol consumed is less important than the amount consumed (typically 100–150 grams per day) and the pattern of drinking. It is common for patients with alcohol-associated acute pancreatitis to have a history of excess alcohol consumption prior to the first attack. There are several mechanisms by which ethanol causes acute pancreatitis by acting on the acinar and stellate cells.32 The acinar cell metabolizes ethanol by oxidative and nonoxidative pathways, and exhibits changes that predis-pose the cell to autodigestive injury, necroinflammation, and cell death. The stellate cells are activated on exposure to


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Surgery_Schwartz. by oxidative and nonoxidative pathways, and exhibits changes that predis-pose the cell to autodigestive injury, necroinflammation, and cell death. The stellate cells are activated on exposure to ethanol to a myofibroblast phenotype, stimulating synthesis of proinflam-matory mediators and cytokines. Ethanol causes a brief secretory increase followed by inhibition. The secretory burst coupled with ethanol induced spasm of the sphincter of Oddi probably incites acute pancreatitis. Ethanol also induces ductal permeability, which allows prematurely activated enzymes to cause damage to the pancreatic parenchyma. Ethanol also increases the protein content of pancreatic juice and decreases bicarbonate levels and trypsin inhibitor concentration. The formation of protein plugs may also contribute by causing an obstructive element to pancre-atic outflow, more often seen in chronic pancreatitis.Brunicardi_Ch33_p1429-p1516.indd 144001/03/19 6:44 PM 1441PANCREASCHAPTER 33Figure 33-10. Schema of


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Surgery_Schwartz. causing an obstructive element to pancre-atic outflow, more often seen in chronic pancreatitis.Brunicardi_Ch33_p1429-p1516.indd 144001/03/19 6:44 PM 1441PANCREASCHAPTER 33Figure 33-10. Schema of key loco-regional pathophysiological events in the pancreas and intestine and how they interact to drive the severity and outcome of acute pancreatitis. (Adapted with permission from Flint RS, Windsor JA: The role of the intestine in the pathophysiology and management of severe acute pancreatitis, HPB (Oxford). 2003;5(2):69-85.)IatrogenicAcute pancreatitis can occur due to trauma to the ducts or parenchyma after surgical procedures, including biopsy, bile duct exploration, distal gastrectomy, and splenectomy. As the pancreas is susceptible to ischemia, it can also occur second-ary to splanchnic hypoperfusion with cardiopulmonary bypass, cardiac transplant, hemorrhagic shock, and major trauma. The most common iatrogenic cause is ERCP in which acute pancre-atitis occurs after about 5% to 10%


Surgery_Schwartz

Surgery_Schwartz. hypoperfusion with cardiopulmonary bypass, cardiac transplant, hemorrhagic shock, and major trauma. The most common iatrogenic cause is ERCP in which acute pancre-atitis occurs after about 5% to 10% of procedures, and in many series, it is the third most common identified etiological fac-tor. The risk of post-ERCP acute pancreatitis is increased if the contrast agent is infused repeatedly under high pressure by the endoscopist and in patients with sphincter of Oddi dysfunction. Recent evidence demonstrates that the risk can be decreased with prophylactic rectal nonsteroidal drugs,33 and this may be a better strategy than prophylactic pancreatic duct stenting.34Hereditary PancreatitisHereditary pancreatitis is an autosomal dominant disorder usually related to mutations of the cationic trypsinogen gene (PRSS1). Mutations in this gene cause premature activation of trypsinogen to trypsin and causes abnormalities of ductal secre-tion, both of which promote acute pancreatitis. Mutations in


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Surgery_Schwartz. gene (PRSS1). Mutations in this gene cause premature activation of trypsinogen to trypsin and causes abnormalities of ductal secre-tion, both of which promote acute pancreatitis. Mutations in the SPINK1 protein, which blocks the active binding site of trypsin, is likely to also have a role in predisposing to acute pancreatitis. Variations in penetration and phenotype are common, and there are many other mutations that have become implicated. Mutant enzymes activated within acinar cells can overwhelm the first line of defense (pancreatic secretory trypsin inhibitor) and resist backup defenses (e.g., proteolytic degradation, enzyme Y, and trypsin itself) allowing activated mutant cationic trypsin to trig-ger the entire zymogen activation cascade.35TumorsA pancreatic or periampullary tumor should be considered in patients with idiopathic acute pancreatitis, especially in those over 50 years old. Approximately 1% to 2% of patients with acute pancreatitis have a pancreatic tumor, and an


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Surgery_Schwartz. should be considered in patients with idiopathic acute pancreatitis, especially in those over 50 years old. Approximately 1% to 2% of patients with acute pancreatitis have a pancreatic tumor, and an episode of acute pancreatitis can be the first clinical indicator. Cross-sectional imaging after the resolution of the acute pancreatitis is required.HyperlipidemiaPatients with types I and V hyperlipoproteinemia can experience episodes of abdominal pain, and these often occur in association with marked hypertriglyceridaemia. Lipase is thought to liberate toxic fatty acids into the pancreatic microcirculation, leading to microcirculatory impairment and ischemia. Dietary modifica-tions and drug treatment are used to lower triglycerides.DrugsIsolated cases of acute pancreatitis have been associated with exposure to certain drugs, such as thiazide diuretics, furosemide, estrogen replacement therapy, and steroid therapy in children. In addition, certain chemotherapy agents and anti-immune


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Surgery_Schwartz. with exposure to certain drugs, such as thiazide diuretics, furosemide, estrogen replacement therapy, and steroid therapy in children. In addition, certain chemotherapy agents and anti-immune drugs have been associated with acute pancreatitis, and lipid-based drugs or solutions, such as propofol, have been shown to cause acute pancreatitis.PathophysiologyAcute pancreatitis occurs in various degrees of severity, the determinants of which are multifactorial. The generally prevalent belief today is that pancreatitis begins with the activation of diges-tive zymogens inside acinar cells, which cause acinar cell injury. Studies suggest that the ultimate severity of the resulting pancre-atitis may be determined by the events that occur subsequent to acinar cell injury.36 These include inflammatory cell recruitment and activation, as well as generation and release of cytokines and other chemical mediators that cause systemic inflammation and multiple organ dysfunction/failure (Figure


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Surgery_Schwartz. cell recruitment and activation, as well as generation and release of cytokines and other chemical mediators that cause systemic inflammation and multiple organ dysfunction/failure (Figure 33-10).Precipitating EventsIn 1896, Chiari proposed that pancreatitis was due to the premature, intrapancreatic activation of digestive enzymes, resulting in “auto-digestion” of the organ. Since then the Brunicardi_Ch33_p1429-p1516.indd 144101/03/19 6:44 PM 1442SPECIFIC CONSIDERATIONSPART IIFigure 33-11. Schematic representation of the acinar cell events in acute pancreatitis. When acinar cells are pathologically stimulated, their lysosomal (L) and zymogen (Z) contents colocalize, and consequently trypsinogen is activated to trypsin by cathepsin B. Increased cytosolic calcium is required for colocalization. Once trypsin has permeabilized the contents of the cytosol, cathepsin B and other contents of these colocalized organelles are released. Once in the cytosol, cathepsin B activates apoptosis


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Surgery_Schwartz. Once trypsin has permeabilized the contents of the cytosol, cathepsin B and other contents of these colocalized organelles are released. Once in the cytosol, cathepsin B activates apoptosis by causing cytochrome c to be released from the mitochondria. Activation of PKC results in a sudden activation of nuclear factor kappa beta (NFκβ), which in turn triggers the release of cytokines that attract inflammatory response cells that mediate local and systemic inflammation cascades.intra-acinar activation of zymogens has been demonstrated consistently in multiple animal models of acute pancreatitis and is considered a key precipitating event.37,38 The key role of trypsin activation in acute pancreatitis has gained additional support from recent studies showing that mice lacking trypsinogen-7 (the isoform of trypsinogen that is activated during acute pancreatitis in mice) have significantly less pancreatic injury during acute pancreatitis39 and that intra-acinar expression of active trypsin


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Surgery_Schwartz. isoform of trypsinogen that is activated during acute pancreatitis in mice) have significantly less pancreatic injury during acute pancreatitis39 and that intra-acinar expression of active trypsin causes pancreatitis in mice.40 The role of trypsin activation in the pathophysiology of acute pancreatitis has also been suggested by clinical studies. Hereditary pancreatitis is associated with mutations that lead to elevated intracellular trypsin activation,41 and activation of trypsinogen causes clinical pancreatitis.42Significant progress has been made in understanding the mechanisms by which injurious stimuli lead to intra-acinar activation of trypsinogen and autodigestion of the gland (Figure 33-11). Under physiologic conditions, several protective mechanisms have evolved to prevent autodigestion of the pancreas by these enzymes. This includes synthesis of enzymes as inactive precursors, separation of the site of production, and activation of the enzymes and presence of trypsin


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Surgery_Schwartz. autodigestion of the pancreas by these enzymes. This includes synthesis of enzymes as inactive precursors, separation of the site of production, and activation of the enzymes and presence of trypsin inhibitors in the pancreas. It is thought that acute pancreatitis occurs when these protective mechanisms are overwhelmed with erroneously activated enzymes, causing injury. It has been shown that intra-acinar activation of trypsinogen goes hand-in-hand with inhibition of acinar secretion.43,44 Furthermore, with injurious stimuli the zymogens responsible for initiating the disease are not secreted outside, but colocalize with cytoplasmic vacuoles that contain lysosomal enzymes such as cathepsin B45 that activate trypsinogen. Thus, inhibition of cathepsin B by pharmacological inhibitors46 or by genetic deletion of cathepsin B eliminates trypsin activation and decreases the severity of pancreatitis in animal models.47 What leads to the colocalization of zymogens and lysosomal hydrolases is


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Surgery_Schwartz. genetic deletion of cathepsin B eliminates trypsin activation and decreases the severity of pancreatitis in animal models.47 What leads to the colocalization of zymogens and lysosomal hydrolases is unclear, but injurious stimuli leading to sustained cytosolic calcium increase have been indicted. Blocking this calcium increase prevents colocalization and activation of trypsin, and it decreases injury due to pancreatitis.48 Based on these data, pre-ERCP supplementation of magnesium, a natural antagonist of calcium, is currently being evaluated as a strategy to decrease post-ERCP pancreatitis.49 Recent work has led to the novel hypothesis that the lysosomal hydrolase cathepsin B activates trypsinogen to trypsin within the colocalization vacuoles. Trypsin then permeabilizes these colocalization vacuoles causing the release of cathepsin B into the cytosol. Once in the cytosol, cathepsin B initiates apoptotic cell death by permeabilizing mitochondrial membranes, which allows cytochrome C to


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Surgery_Schwartz. vacuoles causing the release of cathepsin B into the cytosol. Once in the cytosol, cathepsin B initiates apoptotic cell death by permeabilizing mitochondrial membranes, which allows cytochrome C to be released into the cytosol. This initiates the apoptotic cascade and results in the apoptotic death of the acinar cells50 (see Figure 33-11).Intrapancreatic EventsAlthough intra-acinar events initiate acute pancreatitis, events occurring subsequent to acinar cell injury determine the severity of pancreatitis. Activated neutrophils are attracted and activated in the pancreas releasing superoxide (the respiratory burst) and proteolytic enzymes (cathepsins, elastase, and collagenase) that cause further pancreatic injury. In addition, macrophages release cytokines (including tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1, IL-2, IL-6, and IL-8) that mediate local and systemic inflammation.38These inflammatory mediators cause an increased pancre-atic vascular permeability, leading


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Surgery_Schwartz. (TNF-α) and interleukins (IL-1, IL-2, IL-6, and IL-8) that mediate local and systemic inflammation.38These inflammatory mediators cause an increased pancre-atic vascular permeability, leading to hemorrhage, edema, and Acinar cell deathTo pancreatic ductTrypsinogenCathepsin BActive trypsinEarly stagesLeaky colocalizedorganellesColocalizationSustainedRise in Ca2+PKC activationInsultSystemic in‘ammationRelease of cytokinesand chemokinesRecruitment ofin‘ammatory cellsLater stagesNF–KBactivationLocal injury: PancreatitisZLBrunicardi_Ch33_p1429-p1516.indd 144201/03/19 6:44 PM 1443PANCREASCHAPTER 33Figure 33-12. Computed tomography scan showing well perfused interstitial edematous acute pancreatitis of the neck and tail of the pancreas with a confluent area of necrosis of the pancreatic body. The pancreas is surrounded by fluid, inflammation, and possible peripancreatic fat necrosis.Table 33-5Local complications of acute pancreatitisCONTENT ACUTE (<4 WEEKS, NO DEFINED WALL)CHRONIC (>4


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Surgery_Schwartz. The pancreas is surrounded by fluid, inflammation, and possible peripancreatic fat necrosis.Table 33-5Local complications of acute pancreatitisCONTENT ACUTE (<4 WEEKS, NO DEFINED WALL)CHRONIC (>4 WEEKS, DEFINED WALL)NO INFECTIONINFECTIONNO INFECTIONINFECTIONFluidAcute pancreatic fluid collection (APFC)Infected APFCPseudocystInfected pseudocystSolid ± fluidAcute necrotic collection (ANC)Infected ANCWalled off necrosis (WON)Infected WONReproduced with permission from Windsor JA, Petrov MS: Acute pancreatitis reclassified, Gut. 2013 Jan;62(1):4-5.microthrombi. Fluid may collect in and around the pancreas. The failure of the pancreatic microcirculation, a feature of more severe acute pancreatitis, results in pancreatic hypoperfusion and necrosis. Acute inflammation of the pancreatic parenchyma and peripancreatic tissues, but with no recognizable necrosis, is termed interstitial edematous pancreatitis.25 When necrosis is present, as evidenced by pancreatic hypoperfusion with contrast CT,


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Surgery_Schwartz. and peripancreatic tissues, but with no recognizable necrosis, is termed interstitial edematous pancreatitis.25 When necrosis is present, as evidenced by pancreatic hypoperfusion with contrast CT, it is termed necrotizing pancreatitis (Figure 33-12). The updated morphological definitions and the contrast enhanced CT criteria for the diagnosis of the local complications of acute pancreatitis are in the revised Atlanta statement51 and summa-rized in Table 33-5.52Systemic EventsAn important aspect of the pathophysiology of acute pancre-atitis is the mechanism by which events occurring in the pan-creas induce systemic inflammation and multiorgan failure. The NFκB-dependent inflammatory pathway is an important mechanism (see Figure 33-11). Activation of NFκB parallels trypsin activation in acute pancreatitis but appears to be inde-pendent of it, as it occurs in trypsin knockout mice.39 Sustained calcium increase, which leads to trypsinogen activation, is criti-cal for NFκB activation since


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Surgery_Schwartz. pancreatitis but appears to be inde-pendent of it, as it occurs in trypsin knockout mice.39 Sustained calcium increase, which leads to trypsinogen activation, is criti-cal for NFκB activation since attenuation of cytosolic calcium abrogates NFκB activation.53 Once activated, NFκB regulates synthesis of multiple cytokines and chemokines, leading to recruitment of various inflammatory cells that then magnify and propagate systemic inflammation.54 The infiltrating neutrophils can also further augment the pancreatic injury.55,56 Inhibition of many of these cytokines have led to reduced local and systemic injury in animal models of acute pancreatitis. But these results did not translate to clinical improvement.57 New strategies are required to reduce the systemic inflammatory response.58-60Organ failure can develop at any stage of acute pancreati-tis, associated with an overwhelming proinflammatory response early, or later secondary to the development of infected local complications. The


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Surgery_Schwartz. failure can develop at any stage of acute pancreati-tis, associated with an overwhelming proinflammatory response early, or later secondary to the development of infected local complications. The drivers of the systemic response are poorly understood, although factors include the elaboration of proin-flammatory cytokines, and it appears that mesenteric lymph, bypassing the liver and containing these constituents, may con-tribute to the development of organ failure61 (see Figure 33-10). The development of pancreatic necrosis, the breakdown of the intestinal barrier, and the suppression of the immune response through the compensatory inflammatory response contribute to the development of infected pancreatic necrosis, the incidence of which peaks in the third to fourth week. This is usually asso-ciated with deterioration in the patient’s condition and may be associated with the late development of the systemic inflam-matory response syndrome (SIRS) and multiorgan dysfunction


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Surgery_Schwartz. is usually asso-ciated with deterioration in the patient’s condition and may be associated with the late development of the systemic inflam-matory response syndrome (SIRS) and multiorgan dysfunction syndrome/failure (MODS/F).Organ failure is scored using the Marshall or Sequential Organ Failure Assessment (SOFA) systems (Table 33-6). The three organ systems most frequently involved are cardiovas-cular, respiratory, and renal. Multiple organ failure is defined as two or more organs registering two or more points on these scoring systems.51 Monitoring organ failure over time and in response to treatment is important in the care and timing of intervention in these patients.Management of Acute PancreatitisGeneral Considerations. The management of acute pancre-atitis covers a wide spectrum of severity. All patients with sus-pected acute pancreatitis should be admitted to hospital. Those with mild acute pancreatitis usually remain in hospital for less than a week, while those with severe


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Surgery_Schwartz. severity. All patients with sus-pected acute pancreatitis should be admitted to hospital. Those with mild acute pancreatitis usually remain in hospital for less than a week, while those with severe and critical acute pan-creatitis may require many weeks or months of intensive treat-ment. The risk of mortality reflects this spectrum of severity. The risk is less than 1% for those with mild disease, increasing to around 10% for those with moderate disease, but for severe (20–40%) and critical (>50%) disease the mortality risk is much higher. The earlier identification of these high-risk categories and their transfer to specialized centers is an important priority of management.62The management of acute pancreatitis is multidisciplinary, and it is important that this is coordinated care plan is carefully supervised.63 The essential requirements for the management Brunicardi_Ch33_p1429-p1516.indd 144301/03/19 6:44 PM 1444SPECIFIC CONSIDERATIONSPART IITable 33-6Sequential organ failure


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Surgery_Schwartz. is carefully supervised.63 The essential requirements for the management Brunicardi_Ch33_p1429-p1516.indd 144301/03/19 6:44 PM 1444SPECIFIC CONSIDERATIONSPART IITable 33-6Sequential organ failure assessment (SOFA) score in acute pancreatitis 01234Respiration (PaO2FIO2) (mmHg)>400≤400≤300≤200 with respiratory support≤100 with respiratory supportCoagulation Platelets (xl01 per μL)>150≤150≤100≤50≤20Liver Bilirubin (μmol/L)<2020–3233–101102–204>204Cardiovascular HypotensionNo hypotensionMAP <70 mmHgDopamine ≤5 or dobutamine (any dose)aDopamine >5 or epi ≤0.1a or norepi ≤0.1aDopamine >15 or epi >0.1a or norepi >0.1aCentral nervous system Glasgow coma score1513–1410–126–9<6Kidney Creatinine (μmol/L) or urine output<110110–170171–299300–440 or <500 mL/day>440 or <200 mL/dayaAdrenergic agents administered for at least 1 h (doses given in μg/kg per min). A score of 2 or more in any two systems indicates the presence of multiple organ failure.Abbreviations: MAP =


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Surgery_Schwartz. mL/dayaAdrenergic agents administered for at least 1 h (doses given in μg/kg per min). A score of 2 or more in any two systems indicates the presence of multiple organ failure.Abbreviations: MAP = mean arterial pressure; Epi = epineptvine; Norepi = norepinephrine.of acute pancreatitis are accurate diagnosis, appropriate triage, high-quality supportive care, and monitoring for and treatment of complications.64DiagnosisThe diagnosis of acute pancreatitis requires the patient to pres-ent with abdominal pain consistent with acute pancreatitis (acute onset of a severe constant epigastric pain that often radiates through to the mid back) and the elevation of serum amylase or lipase (>3 times upper limit of normal). Imaging (usually by contrast-enhanced CT scanning) is only required for the diagnosis of acute pancreatitis when these diagnostic criteria are not met.51 Because of the many causes of hyperamylasemia, it is important to use either the pancreatic isoenzyme of amylase or


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Surgery_Schwartz. the diagnosis of acute pancreatitis when these diagnostic criteria are not met.51 Because of the many causes of hyperamylasemia, it is important to use either the pancreatic isoenzyme of amylase or lipase.63The serum amylase concentration increases almost imme-diately with the onset of disease and peaks within several hours and remains elevated for 3 to 5 days.64 There is no correlation between the extent of serum amylase elevation and severity of pancreatitis; in fact, a milder form of acute pancreatitis is often associated with higher levels of serum amylase compared with that in a more severe form of the disease. It is important to note that hyperamylasemia can also occur in association with other diseases. For example, it can occur in a patient with small bowel obstruction, perforated duodenal ulcer, or other intra-abdominal inflammatory conditions. In contrast, a patient with acute pancreatitis can have a normal serum amylase level, for several different reasons. In patients with


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Surgery_Schwartz. duodenal ulcer, or other intra-abdominal inflammatory conditions. In contrast, a patient with acute pancreatitis can have a normal serum amylase level, for several different reasons. In patients with hyperlipidemia, values might appear to be normal because of interference with chemical determination of serum amylase by lipids. In some cases, urinary clearance of pancreatic enzymes from the circu-lation increases during pancreatitis, meaning that urinary levels may be more sensitive than serum levels. For these reasons, it is recommended that amylase concentrations also be measured in the urine. Urinary amylase levels usually remain elevated for several days after serum levels have returned to normal. In patients with severe pancreatitis associated with significant necrosis, the pancreas may not have the capacity to release large amounts of enzymes into the circulation. With more severe dis-ease, there is also hemoconcentration from third space fluid loss, and this can affect the serum


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Surgery_Schwartz. not have the capacity to release large amounts of enzymes into the circulation. With more severe dis-ease, there is also hemoconcentration from third space fluid loss, and this can affect the serum concentration of amylase.The clinical signs of acute pancreatitis include abdominal tenderness, often with signs of peritonitis in the upper abdomen. Rarely, pancreatic fluid and bleeding from the pancreas into the retroperitoneum may result in a bruise-like discoloration around the umbilicus (Cullen’s sign) or in the flanks (Grey Turner’s sign). Another rare sign is tetany as a result of hypocalcaemia. In addition to hemoconcentration, patients with acute pancreati-tis often have azotemia with elevated blood urea nitrogen and creatinine levels, hyperglycemia, and hypoalbuminemia.Pain ManagementPain is the cardinal symptom of acute pancreatitis, and its relief is a clinical priority. There is a lack of high-quality evidence to guide the choice of analgesic. Because of unpredictable


Surgery_Schwartz

Surgery_Schwartz. is the cardinal symptom of acute pancreatitis, and its relief is a clinical priority. There is a lack of high-quality evidence to guide the choice of analgesic. Because of unpredictable absorption, analgesia should be administered intravenously, at least at the outset and before oral intake has been established. Those with mild pain can usually be managed with a nonsteroidal anti-inflammatory drugs (e.g., metamizole 2 g/8 h IV), while those with more severe pain are best managed with opioid analgesia (e.g., buprenorphine 0.3 mg/4 h IV). Administration of buprenorphine, pentazocine, procaine hydrochloride, and meperidine are all of value in controlling abdominal pain. Morphine is to be avoided because of its potential to cause sphincter of Oddi spasm.Predicting SeverityWhereas classification relates to the present or past severity of acute pancreatitis, prediction is about the future and ultimate severity and outcome of the patient. Accurately predicting acute


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Surgery_Schwartz. classification relates to the present or past severity of acute pancreatitis, prediction is about the future and ultimate severity and outcome of the patient. Accurately predicting acute Brunicardi_Ch33_p1429-p1516.indd 144401/03/19 6:44 PM 1445PANCREASCHAPTER 33Table 33-7Ranson’s prognostic signs of pancreatitisCriteria for acute pancreatitis not due to gallstonesAt admissionDuring the initial 48 h Age >55 y Hematocrit fall >10 points WBC >16,000/mm3 BUN elevation >5 mg/dL Blood glucose >200 mg/dL Serum calcium <8 mg/dL Serum LDH >350 IU/L Arterial PO2 <60 mmHg Serum AST >250 U/dL Base deficit >4 mEq/L Estimated fluid sequestration >6 LCriteria for acute gallstone pancreatitisAt admissionDuring the initial 48 h Age >70 y Hematocrit fall >10 points WBC >18,000/mm3 BUN elevation >2 mg/dL Blood glucose >220 mg/dL Serum calcium <8 mg/dL Serum LDH >400 IU/L Base deficit >5 mEq/L Serum AST >250 U/dL Estimated fluid sequestration >4 LNote: Fewer than three positive criteria predict


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Surgery_Schwartz. mg/dL Blood glucose >220 mg/dL Serum calcium <8 mg/dL Serum LDH >400 IU/L Base deficit >5 mEq/L Serum AST >250 U/dL Estimated fluid sequestration >4 LNote: Fewer than three positive criteria predict mild, uncomplicated disease, whereas more than six positive criteria predict severe disease with a mortality risk of 50%.Abbreviations: AST = aspartate transaminase; BUN = blood urea nitrogen; LDH = lactate dehydrogenase; PO2 = partial pressure of oxygen; WBC = white blood cell count.Data from Ranson JHC. Etiological and prognostic factors in human acute pancreatitis: a review. Am J Gastroenterol. 1982;77:633 and from Ranson JH, Rifkind KM, Roses DF, et al. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet. 1974;139:69.pancreatitis severity is important in making triage decisions about whether a patient should be transferred to a tertiary hospital or an intensive care unit and in making decisions about fluid therapy and whether an ERCP is


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Surgery_Schwartz. important in making triage decisions about whether a patient should be transferred to a tertiary hospital or an intensive care unit and in making decisions about fluid therapy and whether an ERCP is indicated, as well as other issues.65 There is a very long history of attempts to find prognostic or predictive markers that accurately stratify the risk, with the most widely used being the Ranson’s criteria (Table 33-7) or modified Glasgow criteria. Both use clinical and biochemical parameters scored over the first 48 hours of admission. When there are three or more positive criteria, the disease is considered “predicted severe.” There are many other approaches to predicting severity. At 24 hours after admission an APACHE II score of 8 or more or a serum C-reactive protein level of >150 mg/dL has a similar accuracy in predicting severity as Ranson’s criteria.66 The more recently proposed Bedside Index for Severity of Acute Pancreatitis (BISAP) is calculated from blood urea nitrogen (> 25


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Surgery_Schwartz. has a similar accuracy in predicting severity as Ranson’s criteria.66 The more recently proposed Bedside Index for Severity of Acute Pancreatitis (BISAP) is calculated from blood urea nitrogen (> 25 mg/dL), impaired mental status (GCS <15), presence of systemic inflammatory response syndrome, age >60 years, and pleural effusion. Although it has the advantage of simplicity and can be performed within the first 24 hours of admission, it performed no better than other predictors.67 The presence of SIRS also has prognostic significance.68 There remains some controversy as to how important obesity is as a risk factor for severe and critical acute pancreatitis.69 Another approach has been taken in seeking to predict those with the “harmless acute pancreatitis score”70 using three factors that can be determined on admission: absence of rebound tenderness or guarding, normal hematocrit, and normal serum creatinine. The accuracy of this approach appears to be over 90% and triages most patients


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Surgery_Schwartz. be determined on admission: absence of rebound tenderness or guarding, normal hematocrit, and normal serum creatinine. The accuracy of this approach appears to be over 90% and triages most patients away from intensive care.Unfortunately, these and many other single and combined predictors of severity have an accuracy of around 70%66. This means that there is misclassification error of 30% that limits the value in predicting the severity of acute pancreatitis in indi-vidual patients. In the absence of any new biomarkers of pancre-atitis severity, making better use of existing predictors through sequencing tests, combining tests, or using artificial neural network methodologies has shown some promise.71 Scoring systems should augment clinical judgment, but not replace it.64 Over the first 2 to 3 days the clinician must be alert to patients with an elevated BUN or creatinine and/or persistent SIRS after adequate fluid resuscitation because these patients are at risk of developing severe


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Surgery_Schwartz. to 3 days the clinician must be alert to patients with an elevated BUN or creatinine and/or persistent SIRS after adequate fluid resuscitation because these patients are at risk of developing severe acute pancreatitis.64Classification of SeverityAccurately classifying or staging acute pancreatitis severity is important for clinical decision-making, communication, and enrolment into trials. The wide spectrum of pancreatitis severity was not captured in the previous binary classifica-tions (mild or severe). The key determinants of severity are local complications (absent, sterile, or infected) and systemic complications (absent, transient organ failure, persistent organ failure).25,72 Two classification systems have recently been proposed: the three grades (mild, moderately severe, and severe) of the Revised Atlanta Criteria (RAC)51 and the four categories (mild, moderate, severe, critical) of the Determi-nants Based Classification (DBC)73 (Table 33-8). The DBC Table 33-8Definitions for


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Surgery_Schwartz. of the Revised Atlanta Criteria (RAC)51 and the four categories (mild, moderate, severe, critical) of the Determi-nants Based Classification (DBC)73 (Table 33-8). The DBC Table 33-8Definitions for the classification of acute pancreatitis severity according to Revised Atlanta Classification11 and the Determinants Based Classification14. (Transient organ failure has a duration of <48 hours, persistent organ failure has duration of >48 hours.)Determinant Based Classification (2012)Revised Atlanta Classification (2013)MildNo local complicationNo systemic complicationNo local complicationNo systemic complicationModerateSterile local complication and/orTransient organ failureLocal or systemic complications without persistent organ failureorexacerbation of preexisting comorbiditySevereinfected local complicationorPersistent organ failurePersistent organ failure (single or multiple)CriticalInfected local complication and Persistent organ failure-Brunicardi_Ch33_p1429-p1516.indd


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Surgery_Schwartz. local complicationorPersistent organ failurePersistent organ failure (single or multiple)CriticalInfected local complication and Persistent organ failure-Brunicardi_Ch33_p1429-p1516.indd 144501/03/19 6:44 PM 1446SPECIFIC CONSIDERATIONSPART IITable 33-9The Modified Determinant Based Classification (MDBC) (Acevedo) of acute pancreatitis severity compared with the Revised Atlanta Classification (RAC) and Determinants Based Classification (DBC). Note that the DBC has a narrower definition for local complications than RAC, leading to a slightly broader range of mild acute pancreatitis in this table.RACMild(No OF, No LC)Moderately severe(TOF and/or LC)Severe(POF)DBCMild(No OF, No LC)Moderate(TOF and/or SN)Severe(POF or IN)Critical(POF and IN)MDBC ExcludedGroup 1(TOF and/or SN)Group 2(IN without POF)Group 3(POF without IN)Group 4(POF and IN)Abbreviations: OF = organ failure; LC = local complication; TOF = transient organ failure; POF = persistent organ failure; SN = sterile necrosis; IN


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Surgery_Schwartz. POF)Group 3(POF without IN)Group 4(POF and IN)Abbreviations: OF = organ failure; LC = local complication; TOF = transient organ failure; POF = persistent organ failure; SN = sterile necrosis; IN = infected necrosis.was developed on the principle of casual inference, derived by meta-analysis, and refined by an international multidis-ciplinary process,73 and both classifications have been inde-pendently validated, which suggests that they are broadly equivalent. More recently a prospective multicenter study has modified the DBC to address the ongoing issue that patients considered to have severe acute pancreatitis represent several subgroups with different morbidity, mortality, and interven-tion profiles74 (Table 33-9).The classification of patient severity is helpful in tracking the clinical trajectory of a patient, and it can be applied on a daily or more frequent basis. It can also be used in retrospect for audit purposes.Determining EtiologyThe history of alcohol ingestion must be


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Surgery_Schwartz. trajectory of a patient, and it can be applied on a daily or more frequent basis. It can also be used in retrospect for audit purposes.Determining EtiologyThe history of alcohol ingestion must be ascertained and preferably confirmed with blood ethanol levels. Gallstones should be investigated by ultrasonography. A gallstone etiology is more likely in females over the age of 50 with an elevation of alkaline phosphatase (>300 iu/L), alanine transferase (>100 iu/L), and amylase (>4000 iu/L). In the absence of gallstones and alcohol, a systematic approach to the identification of another factor will include taking a history of drugs, trauma, ERCP, infection, and measuring serum triglycerides, calcium, and others (see Table 33-4).Fluid ResuscitationFluid therapy to restore and maintain circulating blood volume is the most important intervention in the early management of acute pancreatitis75. However, a recent systematic review has shown that the evidence base for fluid therapy is


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Surgery_Schwartz. circulating blood volume is the most important intervention in the early management of acute pancreatitis75. However, a recent systematic review has shown that the evidence base for fluid therapy is scant,76 and most recommendations are based on expert opinion.64 It is not known which fluid to give, how aggressively to adminis-ter it, or what goal to use to guide and monitor the response to it. While there are proponents for vigorous fluid therapy (5–10 mL per kilogram per hour), especially in the first 24 hours, and for specific resuscitation goals,77 it is prob-ably best to resuscitate with a balanced crystalloid and aim to restore normal blood volume, blood pressure, and urine output. In one study, lactated Ringer’s solution was supe-rior to normal saline in reducing the systemic inflammatory response.78 Caution needs to be exercised in those with car-diac and renal disease and in the elderly, where the risks of over-resuscitation are greater.Nutritional SupportIn contrast to


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Surgery_Schwartz. inflammatory response.78 Caution needs to be exercised in those with car-diac and renal disease and in the elderly, where the risks of over-resuscitation are greater.Nutritional SupportIn contrast to analgesia and fluid therapy, there is a sound evidence base for nutritional support in acute pancreatitis. It is no longer acceptable to “rest the pancreas” by avoiding enteral nutrition, now the mainstay of nutritional support.79 Parenteral nutrition is now known to be more expensive, riskier, and not more effective than enteral nutrition and should only be offered if the patient’s calculated nutritional requirements cannot be achieved by the enteral route. Early initiation of enteral nutrition (within the first 24 hours of admission) is not superior to delaying an oral diet until 72 hours.80 If this is not tolerated over 48 to 72 hours, then nasogastric tube feedings can be started and increased in step-wise fashion over 2 to 3 days.81 The tube can be advanced to the jejunum, by


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Surgery_Schwartz. hours.80 If this is not tolerated over 48 to 72 hours, then nasogastric tube feedings can be started and increased in step-wise fashion over 2 to 3 days.81 The tube can be advanced to the jejunum, by endoscopy or fluoroscopy, if there is evidence of feeding intolerance. A delay in commencing enteral nutrition may contribute to the development of intestinal ileus and feeding intolerance, but aggressive early enteral feeding, particularly before adequate resuscitation, may put the patient at risk of nonocclusive mesenteric ischemia. There is no evidence to support the use of elemental or immune-enhancing formulas over standard polymeric formulas.82 In predicted mild acute pancreatitis the recommencement of oral fluids and then food was delayed until resolution of abdominal pain and normalization of serum levels of amylase, but it appears safe to allow patients to resume intake ad libitum (i.e., patient-controlled nutrition). If after 3 to 5 days there is evidence of feeding


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Surgery_Schwartz. and normalization of serum levels of amylase, but it appears safe to allow patients to resume intake ad libitum (i.e., patient-controlled nutrition). If after 3 to 5 days there is evidence of feeding intolerance, tube feeding should be commenced.Cross-Sectional ImagingIt may be necessary to perform a CT scan to diagnose acute pancreatitis in patients who are severely ill or in those presenting with undifferentiated abdominal pain. But there is no advantage in using CT scanning to predict the severity of acute pancreatitis.51,63 The primary purpose of cross-sectional imaging is the diagnosis of local complications; in particular, the development and extent of pancreatic necrosis and the different collections (see Table 33-5). CT scanning is also important to guide the insertion of percutaneous drains, now assuming a greater role in the management of the local complications (discussed later). Magnetic resonance imaging (MRI) is superior to CT scanning in detecting any solid content