# 32 - 359 Acute and Chronic Pancreatitis ### 359 Acute and Chronic Pancreatitis clinically suspected, EUS imaging is more sensitive than MDCT for the detection of pancreatic malignancy and permits fine-needle aspira­ tion/biopsy (FNA/B). Currently, EUS-guided FNA/B is the diagnostic modality of choice for the acquisition of diagnostic tissue and cyst fluid in patients with pancreatic masses and cystic lesions, respectively. Although a pancreatogram during ERCP is the most specific and sensitive test for evaluating the ductal anatomy, EUS and MRI/MRCP have largely replaced ERCP in the diagnostic evaluation of pancreatic disease to avoid the risk of complications. Therefore, ERCP is primar­ ily of therapeutic value after CT, EUS, or MRI/MRCP has detected abnormalities requiring endoscopic treatment. ERCP is the most sensi­ tive modality for the detection of bile duct stones. In the management of acute biliary pancreatitis, ERCP should not be unduly delayed in patients with high clinical suspicion of biliary obstruction. In chronic pancreatitis, ERCP abnormalities in the main pancreatic duct and side branches have been outlined by the Cambridge classification (Fig. 358-2). The presence of ductal stenosis and irregularity can make it difficult to distinguish chronic pancreatitis from pancreatic adenocarcinoma. It is important to be aware that ERCP changes interpreted as indicating chronic pancreatitis actually may be due to the effects of aging on the pancreatic duct, sequelae of a recent attack of acute pancreatitis, or changes secondary to placement of pancreatic duct stent. Pancreatic adenocarcinoma is characterized by stenosis or obstruction of either the pancreatic duct or the common bile duct; both ductal systems are often abnormal (double-duct sign). When indicated, ERCP permits acquisition of diagnostic tissue as in biopsy of ampullary lesions or biliary brushings for distal bile duct strictures. Elevated serum amy­ lase levels after ERCP have been reported in the majority of patients, and clinical pancreatitis has been reported in 5–10% of patients. Historically, pancreatic duct stents were commonly placed to prevent post-ERCP pancreatitis. Recent data, however, have revealed that the periprocedural administration of rectal indomethacin can decrease the incidence of post-ERCP pancreatitis. In a randomized multicenter study, it was demonstrated that the combination of rectal indometha­ cin with prophylactic pancreatic duct stents was more effective than indomethacin alone in preventing post-ERCP pancreatitis in high-risk patients. PART 10 Disorders of the Gastrointestinal System ■ ■TESTS OF EXOCRINE PANCREATIC FUNCTION Pancreatic function tests (Table 358-1) can be divided into the following: 1. Direct stimulation of the pancreas by IV administration of secretin followed by collection and measurement of duodenal contents: The secretin test, used to detect diffuse pancreatic disease, is based on the physiologic principle that the pancreatic secretory response is directly related to the functional mass of pancreatic tissue. In the standard assay, secretin is given IV in a dose of 0.2 μg/kg of synthetic human secretin as a bolus. Normal values for the standard secretin test are (1) volume output >2 mL/kg per h, (2) bicarbonate (HCO3 –) concentration >80 mmol/L, and (3) HCO3 – output >10 mmol/L in 1 h. The most reproducible measurement, giving the highest level of discrimination between normal subjects and patients with chronic pancreas dysfunction, appears to be the maximal bicarbonate con­ centration. A cutoff point <80 mmol/L is considered abnormal and suggestive of reduced secretory function that is most commonly observed in early chronic pancreatitis. 2. There may be a dissociation between the results of the secretin test and other tests of absorptive function. For example, patients with chronic pancreatitis often have abnormally low outputs of HCO3 – after secretin but have normal fecal fat excretion. The secretin test directly measures the secretory capacity of ductular epithelium, whereas fecal fat excretion indirectly reflects intraluminal lipolytic activity. Steatorrhea does not occur until intraluminal levels of lipase are markedly reduced, underscoring the fact that only small amounts of enzymes are necessary for intraluminal digestive activi­ ties. It must be emphasized that an abnormal secretin test result suggests that pancreatic ductal secretory function is abnormal. This is an early abnormality in chronic pancreatitis but should not be considered diagnostic and must be interpreted within the proper clinical context. 3. Measurement of fecal pancreatic enzymes such as elastase: Measure­ ment of intraluminal digestion products (i.e., undigested muscle fibers, stool fat, and fecal nitrogen) is discussed in Chap. 336. The amount of human elastase in stool reflects the pancreatic output of this proteolytic enzyme. Decreased fecal elastase-1 (FE-1) activity in stool is a test to detect severe EPI in patients with chronic pancre­ atitis and cystic fibrosis. FE-1 levels >200 μg/g are normal, levels of 100–200 μg/g are considered mild-moderate EPI, and levels <100 μg/g are severe EPI. Although the test is simple and noninvasive, it can yield false-positive results if stools are not formed and should not generally be used for the evaluation of a patient with diarrhea. Falsepositive results have also been observed in diabetes and irritable bowel syndrome. Tests useful in the diagnosis of EPI and the differential diagnosis of malabsorption are also discussed in Chaps. 336 and 359. ■ ■FURTHER READING Conwell DL et al: American Pancreatic Association practice guidelines in chronic pancreatitis: Evidence-based report on diagnostic guidelines. Pancreas 43:1143, 2014. Hart PA et al: Endoscopic pancreas fluid collection: Methods and relevance for clinical care and translational science. Am J Gastroenterol 111:1258, 2016. Petrov MS, Yadav D: Global epidemiology and holistic prevention of pancreatitis. Nat Rev Gastroenterol Hepatol 16:175, 2019. Singh VK et al: Diagnosis and management of chronic pancreatitis: A review. JAMA 322:2422, 2019. Phil A. Hart, Darwin L. Conwell, Somashekar G. Krishna Acute and Chronic Pancreatitis BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION ■ ■GENERAL CONSIDERATIONS The pancreas secretes 1500–3000 mL of isosmotic alkaline (pH >8) fluid per day containing ~20 enzymes. Pancreatic secretions provide the enzymes and bicarbonate needed to perform the major digestive activity of the gastrointestinal tract and produce an optimal pH for the function of these enzymes. ■ ■REGULATION OF PANCREATIC SECRETION Secretions from the exocrine pancreas are highly regulated by neuro­ hormonal systems in a phasic manner (cephalic, gastric, and intestinal phases). Gastric acid is the stimulus for the release of secretin from the duodenal mucosa (S cells), which stimulates the secretion of water and electrolytes from pancreatic ductal cells. Release of cholecystokinin (CCK) from the duodenal and proximal jejunal mucosa (Ito cells) is largely triggered by long-chain fatty acids, essential amino acids (tryptophan, phenylalanine, valine, methionine), and gastric acid itself. CCK evokes an enzyme-rich secretion from acinar cells in the pancreas. The parasympathetic nervous system (via the vagus nerve) exerts significant control over pancreatic secretion, particularly during the cephalic phase. Secretion evoked by secretin and CCK depends on the permissive roles of vagal afferent and efferent pathways. This is particularly true for enzyme secretion, whereas water and bicarbonate secretions are heavily dependent on the hormonal effects of secretin and to a lesser extent CCK. Also, vagal stimulation affects the release of vasoactive intestinal peptide (VIP), a secretin agonist. Pancreatic exocrine secretion is also influenced by inhibitory neuropeptides including somatostatin, pancreatic polypeptide, peptide YY, neuro­ peptide Y, enkephalin, pancreastatin, calcitonin gene–related peptides, glucagon, and galanin. Pancreatic polypeptide and peptide YY may act primarily on nerves outside the pancreas, while somatostatin acts at multiple sites. ■ ■WATER AND ELECTROLYTE SECRETION Bicarbonate is the ion of primary physiologic importance in pancreatic secretions. The ductal cells secrete bicarbonate predominantly derived from plasma (93%) more so than from intracellular metabolism (7%). Bicarbonate enters the duct lumen through the sodium bicarbonate cotransporter with depolarization caused by chloride efflux through the cystic fibrosis transmembrane conductance regulator (CFTR). Secretin and VIP bind at the basolateral surface and cause an increase in secondary messenger intracellular cyclic AMP and act on the apical surface of the ductal cells opening the CFTR to promote secretion. CCK, acting as a neuromodulator, markedly potentiates the stimula­ tory effects of secretin. Acetylcholine also plays an important role in ductal cell secretion. Intraluminal bicarbonate secreted from the ductal cells helps neutralize gastric acid, increases the solubility of fatty acids and bile acids, maintains an optimal pH for pancreatic and brush bor­ der enzymes, and prevents intestinal mucosal damage. ■ ■ENZYME SECRETION The acinar cell is highly compartmentalized for the production and secretion of pancreatic enzymes. Proteins synthesized by the rough endoplasmic reticulum are processed in the Golgi apparatus and then targeted to the appropriate site: zymogen granules, lysosomes, or other cell compartments. The zymogen granules migrate to the apical region of the acinar cell awaiting the appropriate neural or hormonal stimulatory response. The pancreas secretes amylolytic, lipolytic, and proteolytic enzymes into the duct lumen. Amylolytic enzymes, such as amylase, hydrolyze starch to oligosaccharides and the disaccharide maltose. The lipolytic enzymes include lipase, phospholipase A2, and cholesterol esterase. Bile salts inhibit lipase in isolation, but colipase, another constituent of pancreatic secretion, binds to lipase and pre­ vents this inhibition. Bile salts activate phospholipase A and choles­ terol esterase. Proteolytic enzymes include endopeptidases (trypsin, chymotrypsin), which act on internal peptide bonds of proteins and polypeptides; exopeptidases (carboxypeptidases, aminopeptidases), which act on the free carboxyl- and amino-terminal ends of pep­ tides, respectively; and elastase. The proteolytic enzymes are secreted as inactive zymogen precursors. Ribonucleases (deoxyribonucleases, ribonuclease) are also secreted. Enterokinase, an enzyme found in the duodenal mucosa (“brush border”), cleaves the lysine-isoleucine bond of trypsinogen to form trypsin. Trypsin then activates the other proteolytic zymogens and phospholipase A2 in a cascade. The nervous system initiates pancreatic enzyme secretion. The neurologic stimula­ tion is cholinergic, involving extrinsic innervation by the vagus nerve and subsequent innervation by intrapancreatic cholinergic nerves. The stimulatory neurotransmitters are acetylcholine and gastrin-releasing peptides. These neurotransmitters activate calcium-dependent second­ ary messenger systems, resulting in the release of zymogens into the pancreas duct. VIP is present in intrapancreatic nerves and potentiates the effect of acetylcholine. In contrast to other species, there are no CCK receptors on acinar cells in humans. CCK in physiologic con­ centrations contributes to pancreatic secretion by stimulating afferent vagal and intrapancreatic nerves. ■ ■AUTOPROTECTION OF THE PANCREAS Autodigestion of the pancreas is prevented by (1) the packaging of pan­ creatic proteases in the precursor (proenzyme) form, (2) intracellular calcium homeostasis (low intracellular calcium in the cytosol of the acinar cell promotes the destruction of spontaneously activated tryp­ sin), (3) acid-base balance, and (4) the synthesis of protective protease inhibitors serine protease inhibitor, Kazal type 1 (SPINK1) which can bind and inactivate ~20% of intracellular trypsin activity. Chymotryp­ sin C can also lyse and inactivate trypsin. These protease inhibitors are found in acinar cells, pancreatic secretions, and the α1- and α2-globulin fractions of plasma. Loss of any of these four protective mechanisms leads to premature enzyme activation, autodigestion, and ultimately acute pancreatitis. ■ ■ENTEROPANCREATIC AXIS AND FEEDBACK INHIBITION Pancreatic enzyme secretion is controlled, at least in part, by a negative feedback mechanism induced by the presence of active serine prote­ ases in the duodenum and nutrients in the distal small intestine. For example, perfusion of the duodenal lumen with phenylalanine (stimu­ lates early digestion) causes a prompt increase in plasma CCK levels as well as increased secretion of chymotrypsin and other pancreatic enzymes. However, simultaneous perfusion with trypsin (stimulates late digestion) blunts both responses. Conversely, perfusion of the duo­ denal lumen with protease inhibitors leads to enzyme hypersecretion. Available evidence supports the concept that the duodenum contains a peptide called CCK-releasing factor (CCK-RF) that is involved in stim­ ulating CCK release. It appears that serine proteases inhibit pancreatic secretion by inactivating a CCK-releasing peptide in the lumen of the small intestine. Thus, the integrative result of both bicarbonate and enzyme secretion depends on a feedback process for both bicarbon­ ate and pancreatic enzymes. Acidification of the duodenum releases secretin, which stimulates vagal and other neural pathways to activate pancreatic duct cells, which secrete bicarbonate. This bicarbonate then neutralizes the duodenal acid, and the feedback loop is completed. Dietary proteins bind proteases, thereby leading to an increase in free CCK-RF. CCK is then released into the blood in physiologic concentra­ tions, acting primarily through the neural pathways (vagal-vagal). This leads to acetylcholine-mediated pancreatic enzyme secretion. Proteases continue to be secreted from the pancreas until the protein within the duodenum is digested. At this point, pancreatic protease secretion is reduced to basic levels, thus completing this step in the feedback pro­ cess. Additional hormonal feedback inhibition of pancreatic enzyme secretion occurs via peptide YY and glucagon-like peptide-1 following lipid or carbohydrate exposure to the ileum. CHAPTER 359 Acute and Chronic Pancreatitis ACUTE PANCREATITIS ■ ■GENERAL CONSIDERATIONS Recent U.S. estimates indicate that acute pancreatitis is one of the most common principal gastrointestinal diagnoses, accounting for almost 300,000 hospitalizations annually. The annual incidence ranges from 15–45/100,000 persons, depending on the distribution of etiologies (e.g., alcohol, gallstones, metabolic factors, drugs; Table 359-1) and country of study. The median length of hospital stay is 4 days, with a median hospital cost of ~$6000 and a mortality of ~1%. The estimated annual cost approaches $3 billion. Hospitalization rates increase with age and are higher among African Americans. Globally, there is a steady increase in the incidence of acute pancreatitis, most promi­ nently in North America and Europe. Thus, the incidence of acute pancreatitis continues to rise and is associated with substantial health care costs. ■ ■ETIOLOGY AND PATHOGENESIS There are many causes of acute pancreatitis (Table 359-1), and the mechanisms by which each of these conditions triggers pancreatic inflammation have not been fully elucidated. Gallstones and alcohol account for 80–90% of identified cases of acute pancreatitis in the United States. Gallstones are the leading cause of acute pancreatitis in most series (30–60%). The risk of acute pancreatitis in patients with at least one gallstone <5 mm in diameter is fourfold greater than patients with larger stones. Alcohol is the second most common cause, responsible for 15–30% of cases in the United States. The incidence of pancreatitis in individuals with heavy alcohol use is surprisingly low (5/100,000), indicating that in addition to the amount of alcohol TABLE 359-1  Causes of Acute Pancreatitis Common Causes Gallstones (including microlithiasis) Heavy alcohol use Severe hypertriglyceridemia Endoscopic retrograde cholangiopancreatography (ERCP), especially after therapeutic intervention Idiopathic Uncommon Causes Drugs (azathioprine, 6-mercaptopurine, sulfonamides, estrogens, tetracycline, valproic acid, 5-aminosalicylic acid [5-ASA], dipeptidyl peptidase-4 [DPP4] inhibitors) Connective tissue disorders and thrombotic thrombocytopenic purpura (TTP) Pancreatic cancer Hypercalcemia Periampullary diverticulum Pancreas divisuma Hereditary pancreatitis Cystic fibrosis Renal failure Infections (mumps, coxsackievirus, cytomegalovirus, echovirus, parasites) Autoimmune (e.g., type 1 and type 2) Trauma (especially blunt abdominal trauma) Postoperative (abdominal and nonabdominal operations) Causes to Consider in Patients With Recurrent Bouts of Acute Pancreatitis Without an Obvious Etiology PART 10 Disorders of the Gastrointestinal System Occult disease of the biliary tree or pancreatic ducts, especially microlithiasis/ biliary sludge Alcohol abuse Metabolic: Hypertriglyceridemia, hypercalcemia Anatomic: Pancreas divisuma Pancreatic cancer Intraductal papillary mucinous neoplasm (IPMN) Hereditary pancreatitis Cystic fibrosis Idiopathic aPancreas divisum is not believed to cause acute pancreatitis in isolation of another disease precipitant. ingested, other factors affect a person’s susceptibility to pancreatic injury, such as cigarette smoking and genetic predisposition. Acute pancreatitis occurs in 5–10% of patients following endoscopic retro­ grade cholangiopancreatography (ERCP); however, this risk can be decreased with proper patient selection and the use of a prophylactic pancreatic duct stent and/or rectal nonsteroidal anti-inflammatory drugs (NSAIDs; indomethacin). Risk factors for post-ERCP pan­ creatitis include minor papilla sphincterotomy, suspected functional sphincter dysfunction (previously termed sphincter of Oddi dysfunc­ tion), prior history of post-ERCP pancreatitis, age <60 years, more than two contrast injections into the pancreatic duct, and endoscopist experience. Hypertriglyceridemia is the cause of acute pancreatitis in 1–4% of cases; serum triglyceride levels are usually >1000 mg/dL. Most patients with hypertriglyceridemic pancreatitis have undiagnosed or uncontrolled diabetes mellitus. An additional subset has an underlying derangement in lipid metabolism, probably unrelated to pancreati­ tis. Such patients are prone to recurrent episodes of pancreatitis and increased severity. Any factor (e.g., alcohol or medications, such as oral contraceptives) that causes an abrupt increase in serum triglyc­ erides can potentially precipitate a bout of acute pancreatitis. Patients with a deficiency of apolipoprotein CII have an increased incidence of pancreatitis; apolipoprotein CII activates lipoprotein lipase, which is important in clearing chylomicrons from the bloodstream. Although frequently entertained, <2% of cases of acute pancreatitis are drug related. Drugs cause pancreatitis either by a hypersensitivity reaction or by the generation of a toxic metabolite, although in some cases, it is not clear which of these mechanisms is operative (Table 359-1). Increased attention has been directed toward a potential increased risk for acute pancreatitis in patients taking glucagon-like peptide-1 recep­ tor agonists (GLP-1RA) and dipeptidyl peptidase-4 (DPP4) inhibitors. The most recent metanalysis of cardiovascular outcome trials does support an increased risk with DPP4 inhibitors, but not with GLP-1RA medications. When used for treating hyperglycemia, it is important to be conscious that >10% of individuals with diabetes will have elevated amylase or lipase levels irrespective of medication use. Pathologically, acute pancreatitis ranges from interstitial pancreatitis (pancreas blood supply maintained), which is generally self-limited, to necrotizing pancreatitis (pancreas blood supply interrupted). Autodi­ gestion is a currently accepted pathogenic theory resulting when pro­ teolytic enzymes (e.g., trypsinogen, chymotrypsinogen, proelastase) and lipolytic enzymes (such as phospholipase A2) are activated in the pancreas acinar cell compartment rather than the intestinal lumen. Several factors (e.g., endotoxins, exotoxins, viral infections, ischemia, oxidative stress, lysosomal calcium, direct trauma) are believed to facilitate premature activation of trypsin, which can activate other enzymes. Spontaneous activation of trypsin also can occur, resulting in autodigestion. ■ ■ACTIVATION OF PANCREATIC ENZYMES IN THE PATHOGENESIS OF ACUTE PANCREATITIS Several studies have suggested that pancreatitis is a disease that evolves in three phases. The initial phase is characterized by intrapancreatic digestive enzyme activation and acinar cell injury. Trypsin activation appears to be mediated by lysosomal hydrolases such as cathepsin B that become colocalized with digestive enzymes in intracellular organelles; it is currently believed that acinar cell injury is the conse­ quence of trypsin activation. The second phase of pancreatitis involves the activation, chemoattraction, and sequestration of leukocytes and macrophages in the pancreas, resulting in an enhanced intrapancre­ atic inflammatory reaction. Neutrophil depletion induced by prior administration of an antineutrophil serum has been shown to reduce the severity of experimentally induced pancreatitis. There is also evi­ dence to support the concept that neutrophils can activate trypsinogen. Thus, intrapancreatic acinar cell activation of trypsinogen could be a two-step process (i.e., an early neutrophil-independent and a later neutrophil-dependent phase). The third phase of pancreatitis is due to the effects of activated proteolytic enzymes and cytokines, released by the inflamed pancreas, on distant organs. Activated proteolytic enzymes, especially trypsin, not only digest pancreatic and peripan­ creatic tissues but also activate other enzymes such as elastase and phospholipase A2. The active enzymes and cytokines then digest cel­ lular membranes and cause proteolysis, edema, interstitial hemorrhage, vascular damage, coagulation necrosis, fat necrosis, and cellular necro­ sis in the parenchyma. Cellular injury and death result in the liberation of bradykinin peptides, vasoactive substances, and histamine that can produce vasodilation, increased vascular permeability, and edema with profound effects on other organs. The systemic inflammatory response syndrome (SIRS) and acute respiratory distress syndrome (ARDS), as well as multiorgan failure, may occur because of this cascade producing local and distant effects. Several genetic factors can increase the susceptibility and/or modify the severity of pancreatic injury in acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis. The major genetic susceptibility factors center on the control of trypsin activity within the pancreatic acinar cell, in part because they were identified as candidate genes linked to intrapancreatic trypsin control. Six genetic variants have been identified as being associated with susceptibility to pancreatitis. The genes that have been identified include (1) cationic trypsinogen gene (PRSS1), (2) SPINK1, (3) the cystic fibrosis transmembrane conductance regulator gene (CFTR), (4) the chymotrypsin C gene (CTRC), (5) the calcium-sensing receptor (CASR), and (6) claudin-2 (CLDN2). Among these variants, only PRSS1 mutations are sufficient to precipitate acute pancreatitis in the absence of other risk factors, whereas the other variants are disease modifiers. Investigations for other genetic variants are in progress, so it is expected this list will be expanded in the future. APPROACH TO THE PATIENT Abdominal Pain Abdominal pain is the major symptom of acute pancreatitis. Pain may vary from mild discomfort to severe, constant, and incapacitat­ ing distress. Characteristically, the pain, which is steady and boring in character, is located in the epigastrium region and may radiate to the back, chest, flanks, and lower abdomen. Nausea, vomiting, and abdominal distention due to gastric and intestinal hypomotility are also frequent complaints. Physical examination frequently reveals a distressed and anxious patient. Low-grade fever, tachycardia, and hypotension are com­ mon. Shock is not unusual and may result from (1) hypovolemia secondary to exudation of blood and plasma proteins into the retroperitoneal space; (2) increased formation and release of kinin peptides, which cause vasodilation and increased vascular perme­ ability; and (3) systemic effects of proteolytic and lipolytic enzymes released into the circulation. Jaundice occurs infrequently; when present, it may be a consequence of extrinsic compression due to peripancreatic edema, a pancreatic head mass, or intraductal obstruction from a common bile duct stone or sludge. Erythema­ tous skin nodules (“pancreatic panniculitis”) due to subcutaneous fat necrosis are possible, but rarely occur. There are pulmonary findings in 10–20% of patients, including basilar rales, atelectasis, and pleural effusion, the latter most frequently left-sided. Abdomi­ nal tenderness and muscle rigidity are present to a variable degree, but compared with the intense pain, these signs may be less impres­ sive. Bowel sounds are usually diminished or absent. An enlarged pancreas from an acute fluid collection, walled-off necrosis, or a pseudocyst may be palpable in the upper abdomen later in the course of the disease (i.e., 4–6 weeks). A faint blue discoloration around the umbilicus (Cullen’s sign) may occur as the result of hemoperitoneum, and a blue-red-purple or green-brown discol­ oration of the flanks (Turner’s sign) reflects tissue breakdown of hemoglobin from severe necrotizing pancreatitis with hemorrhage; both findings are rare but reflect an increased clinical severity. ■ ■LABORATORY DATA Serum amylase and lipase values greater than three times the upper limit of normal are strongly supportive of the diagnosis if alternate etiologies, including gut perforation, ischemia, and infarction, are excluded. However, it should be noted that there is no correlation between the severity of pancreatitis and the degree of serum lipase and amylase elevations or serial trends. After 3–7 days, even with continu­ ing evidence of pancreatitis, total serum amylase values tend to return to normal. However, pancreatic lipase levels may remain elevated for 7–14 days. It should be recognized that amylase elevations in serum and urine occur in many conditions other than pancreatitis (see Chap. 358, Table 358-2). Importantly, patients with acidemia (arterial pH ≤7.32) may have spurious elevations in serum amylase. This finding explains why patients with diabetic ketoacidosis may have marked ele­ vations in serum amylase without any other evidence of acute pancre­ atitis. On the other hand, serum amylase levels can be spuriously low in severe hypertriglyceridemia. Serum lipase activity increases in parallel with amylase activity and is more specific than amylase, making it the preferred test. A serum lipase measurement can be instrumental in dif­ ferentiating a pancreatic or nonpancreatic cause for hyperamylasemia. Leukocytosis (15,000–20,000 leukocytes/μL) occurs frequently. Patients with more severe disease may show hemoconcentration with hematocrit values >44% and prerenal azotemia (elevated blood urea nitrogen [BUN]) resulting from loss of plasma into the retroperito­ neal space and peritoneal cavity. In fact, one study reported that a combination of admission BUN and a change in BUN at 48 h was a strong predictor of mortality (area under the curve [AUC] 0.91). Hemoconcentration may be the harbinger of more severe disease, whereas azotemia is a significant risk factor for mortality. Hypergly­ cemia is common and is due to multiple factors, including decreased insulin release, increased glucagon release, and increased output of adrenal glucocorticoids and catecholamines. Hypocalcemia occurs in ~25% of patients, and its pathogenesis is incompletely understood. Although earlier studies suggested that the response of the parathy­ roid gland to a decrease in serum calcium is impaired, subsequent observations have failed to confirm this phenomenon. Intraperitoneal saponification of calcium by fatty acids in areas of fat necrosis occurs occasionally, with large amounts (up to 6.0 g) dissolved or suspended in ascitic fluid. Such “soap formation” may also be significant in patients with pancreatitis, mild hypocalcemia, and little or no obvious ascites. Hyperbilirubinemia (serum bilirubin >4.0 mg/dL) occurs in ~10% of patients. However, jaundice is usually transient, and serum bilirubin levels return to normal in 4–7 days. Serum alkaline phosphatase and transaminase levels may also be transiently elevated and parallel serum bilirubin values. Elevations of alanine aminotransferase (ALT) >3× the upper limit of normal are strongly associated with a gallstone etiology in patients with acute pancreatitis. Approximately 5–10% of patients have hypoxemia (arterial PO2 ≤60 mmHg), which may herald the onset of ARDS. Finally, the electrocardiogram is occasionally abnormal in acute pancreatitis with ST-segment and T-wave abnormalities simulat­ ing myocardial ischemia. An abdominal ultrasound is recommended as the initial diagnostic imaging modality and is most useful for evaluating gallstones and com­ mon bile duct dilation. CHAPTER 359 The Revised Atlanta Criteria have clearly outlined the morpho­ logic features of acute pancreatitis on computed tomography (CT) scan as follows: (1) interstitial pancreatitis, (2) necrotizing pancreati­ tis, (3) acute pancreatic fluid collection, (4) pancreatic pseudocyst, (5) acute necrotic collection (ANC), and (6) walled-off necrosis (WON) (Table 359-2 and Fig. 359-1). Radiologic studies useful in the diagnosis of acute pancreatitis are discussed in Chap. 358 and listed in Table 358-1. Acute and Chronic Pancreatitis ■ ■DIAGNOSIS Any severe acute pain in the abdomen or back should raise the pos­ sibility of acute pancreatitis. The diagnosis is established by two of the following three criteria: (1) typical abdominal pain in the epigastrium that may radiate to the back, (2) threefold or greater elevation in serum lipase and/or amylase, and (3) confirmatory findings of acute pancre­ atitis on cross-sectional abdominal imaging. Although not required for diagnosis, markers of severity may include hemoconcentration (hematocrit >44%), admission azotemia, SIRS, and signs of organ fail­ ure (Table 359-3). The differential diagnosis should include the following disorders: (1) perforated viscus, especially peptic ulcer; (2) acute cholecystitis and biliary colic; (3) acute intestinal obstruction; (4) mesenteric vascular occlusion; (5) renal colic; (6) inferior myocardial infarction; (7) dissect­ ing aortic aneurysm; (8) connective tissue disorders with vasculitis; (9) pneumonia; and (10) diabetic ketoacidosis. It may be difficult to differ­ entiate acute cholecystitis from acute pancreatitis, because an elevated serum amylase may be found in both disorders. Pain of biliary tract origin is more right sided or epigastric than periumbilical or left upper quadrant and can be more severe; ileus is usually absent. Ultrasound is helpful in establishing the diagnosis of cholelithiasis and cholecystitis. Intestinal obstruction due to mechanical factors can be differentiated from pancreatitis by the history of crescendo-decrescendo pain, find­ ings on abdominal examination, and CT of the abdomen showing changes characteristic of anatomic obstruction. Acute mesenteric vas­ cular occlusion is usually suspected in elderly debilitated patients with leukocytosis, abdominal distention, and bloody diarrhea, confirmed by CT or magnetic resonance angiography. Vasculitides secondary to sys­ temic lupus erythematosus and polyarteritis nodosa may be confused with pancreatitis, especially because pancreatitis may develop as a com­ plication of these diseases. Diabetic ketoacidosis is often accompanied TABLE 359-2  Revised Atlanta Definitions of Morphologic Features of Acute Pancreatitis   DEFINITION COMPUTED TOMOGRAPHY FEATURES Types of Acute Pancreatitis Interstitial pancreatitis Acute inflammation of the pancreatic parenchyma and peripancreatic tissues, but without recognizable tissue necrosis Necrotizing pancreatitis Inflammation associated with pancreatic parenchymal and/or peripancreatic necrosis Morphologic Features Acute pancreatic fluid collection Peripancreatic fluid associated with interstitial edematous pancreatitis with no associated peripancreatic necrosis. This term applies only to areas of peripancreatic fluid seen within the first 4 weeks after onset of interstitial edematous pancreatitis and without the features of a pseudocyst. Pancreatic pseudocyst An encapsulated collection of fluid with a well-defined wall usually outside the pancreas with minimal or no necrosis. This usually occurs >4 weeks after onset of interstitial edematous pancreatitis. Acute necrotic collection (ANC) A collection containing variable amounts of both fluid and necrosis associated with necrotizing pancreatitis; the necrosis can involve the pancreatic parenchyma and/or the peripancreatic tissues. Walled-off necrosis (WON) A mature, encapsulated collection of pancreatic and/or peripancreatic necrosis that has developed a well-defined inflammatory wall. WON usually occurs >4 weeks after onset of acute necrotizing pancreatitis. PART 10 Disorders of the Gastrointestinal System Source: Data from P Banks et al: Gut 62:102, 2013. by abdominal pain and elevated total serum amylase levels, thus closely mimicking acute pancreatitis; however, the serum lipase level is often not elevated in diabetic ketoacidosis, and pancreas imaging is normal. ■ ■CLINICAL COURSE, DEFINITIONS, AND CLASSIFICATIONS The Revised Atlanta Criteria define (1) phases of acute pancreatitis, (2) severity of acute pancreatitis, and (3) radiographic definitions, as outlined below. Phases of Acute Pancreatitis  Two clinical phases of acute pan­ creatitis have been defined, early (<2 weeks) and late (>2 weeks), which primarily describe the hospital course of the disease. In the early phase of acute pancreatitis, which lasts 1–2 weeks, severity is defined by clini­ cal parameters rather than morphologic findings. Most patients exhibit SIRS, and if this persists, patients are predisposed to organ failure. Three organ systems should be assessed to define organ failure: respi­ ratory, cardiovascular, and renal. Organ failure is defined as a score of 2 or more for one of these three organ systems using the modified Marshall scoring system. Persistent organ failure (>48 h) is the most important clinical finding regarding the severity of the acute pancreati­ tis episode. CT imaging is usually not needed or recommended during the first 48 h of admission in acute pancreatitis. The late phase is characterized by a protracted course of illness and may require imaging to evaluate for local complications. The critical clinical parameter of severity, as in the early phase, is persistent organ failure. These patients may require supportive measures such as renal dialysis, ventilator support, or need for supplemental nutrition. The radiographic feature of greatest importance to recognize in this phase is the development of necrotizing pancreatitis on CT imaging. Necrosis is associated with prolonged hospitalization and, if infected, may require intervention (percutaneous, endoscopic, or, rarely, surgical). Severity of Acute Pancreatitis  Three classes of severity have been defined: mild, moderately severe, and severe. Mild acute pancreatitis is Pancreatic parenchyma enhancement by IV contrast agent and without peripancreatic necrosis Lack of pancreatic parenchymal enhancement by IV contrast agent and/or presence of findings of peripancreatic necrosis (see below—ANC and WON) Occurs in the setting of interstitial pancreatitis Homogeneous collection with fluid density Confined by normal peripancreatic fascial planes No definable wall encapsulating the collection Adjacent to pancreas (no intrapancreatic extension) Well circumscribed, usually round or oval Homogeneous fluid density No solid component Well-defined wall; that is, completely encapsulated Maturation usually requires >4 weeks after onset of acute interstitial pancreatitis Occurs in the setting of acute necrotizing pancreatitis Heterogeneous and nonliquid density of varying degrees in different locations (some appear homogeneous early in their course) No definable wall encapsulating the collection Location—intrapancreatic and/or extrapancreatic Heterogeneous with liquid and nonliquid density with varying degrees of loculations (some may appear homogeneous) Well-defined wall; that is, completely encapsulated Location—intrapancreatic and/or extrapancreatic Maturation usually requires >4 weeks after onset of acute necrotizing pancreatitis without local complications or organ failure. Most patients with inter­ stitial acute pancreatitis have mild pancreatitis. In mild acute pancre­ atitis, the disease is self-limited, usually within 3–7 days after onset. Oral intake can be resumed if the patient is hungry, has normal bowel function, and is without nausea and vomiting. Typically, a clear or full liquid diet has been recommended for the initial meal; however, a lowfat solid diet is advised early in mild acute pancreatitis. Moderately severe acute pancreatitis is characterized by transient organ failure (i.e., it resolves in <48 h) or local or systemic complica­ tions in the absence of persistent organ failure. These patients may or may not have necrosis but may develop a local complication such as a fluid collection, which often requires a prolonged hospitalization >1 week. As with mild acute pancreatitis, the mortality rate for these patients remains low. Severe acute pancreatitis is characterized by persistent organ failure (>48 h), involving one or more organs. A CT scan or magnetic reso­ nance imaging (MRI) should be obtained to assess for necrosis and/ or complications. If a local complication is encountered, management is dictated by clinical symptoms, evidence of infection, the maturity of fluid collection, and clinical stability of the patient. Prophylactic antibiotics are no longer recommended for severe acute pancreatitis. Imaging in Acute Pancreatitis  Two types of pancreatitis are recognized on imaging as interstitial or necrotizing based on pancreatic perfusion. CT imaging with IV contrast is best evaluated 3–5 days into hospitalization if patients are not responding to supportive care to assess for local complications such as necrosis. Recent studies report the overutilization of CT imaging within 72 h for acute pancreatitis, including those with a mild severity of disease. The Revised Atlanta Cri­ teria outline the terminology for local complications and fluid collec­ tions along with a CT imaging template to guide reporting of findings. Local morphologic features are summarized in Table 359-2. Interstitial pancreatitis occurs in 90–95% of admissions for acute pancreatitis and is characterized by diffuse gland enlargement, homogenous contrast enhancement, and mild inflammatory changes or peripancreatic A B C D FIGURE 359-1  Evolution of changes of acute necrotizing pancreatitis on computed tomography (CT). A. CT scan of the abdomen without IV contrast performed on admission for a patient with acute gallstone pancreatitis, showing mild peripancreatic stranding. B. Contrast-enhanced CT scan of the abdomen performed on the same patient 1 week after admission shows extensive intrapancreatic necrosis, evidenced by the lack of contrast enhancement in the pancreatic body with minimal enhancement noted at the distal most aspect of the pancreatic tail. C. Contrast-enhanced CT scan of the abdomen performed on the same patient 2 weeks after admission demonstrates a semiorganized, heterogeneous fluid collection, referred to as an acute necrotic collection. On this image, a small area of viable pancreatic parenchyma is seen at the tail of the pancreas. D. Contrast-enhanced CT scan of the abdomen performed on the same patient 5 weeks after admission demonstrates a well-encapsulated fluid collection, essentially replacing the pancreas, referred to as walled-off necrosis. stranding. Symptoms generally resolve with a week of hospitalization. Necrotizing pancreatitis occurs in 5–10% of acute pancreatitis admis­ sions and may not evolve until after several days of hospitalization. It is characterized by lack of pancreatic parenchymal enhancement by intravenous contrast agent and/or presence of peripancreatic necrosis. The natural history of pancreatic and peripancreatic necrosis is vari­ able because it may remain solid or liquefy, remain sterile or become infected, and persist or resolve over time. Importantly, those with only extrapancreatic necrosis have a more favorable prognosis than patients with pancreatic necrosis (with or without extrapancreatic necrosis). CT identification of local complications, particularly necrosis, is critical in patients who are not responding to therapy because patients with necrosis are at the greatest risk of mortality (Figs. 359-1 and 359-2). The median prevalence of organ failure is >50% in necrotizing pancreatitis and is slightly higher in infected versus sterile necrosis. With singleorgan system failure, the mortality is 3–10%, but increases to nearly 50% with multiorgan failure. ■ ■ACUTE PANCREATITIS MANAGEMENT The management of patients with acute pancreatitis from the time of diagnosis in the emergency ward to hospital discharge is briefly reviewed, highlighting salient features based on severity and complica­ tions. It is important to recognize that 85–90% of cases of acute pancre­ atitis are self-limited and subside spontaneously, usually within 3–7 days after onset, and do not exhibit organ failure or local complications. The management of acute pancreatitis begins in the emergency ward. After a diagnosis has been confirmed, early and aggressive fluid resuscitation is critical. Additionally, intravenous analgesics are administered, severity is assessed, and a search for etiologies that may CHAPTER 359 Acute and Chronic Pancreatitis impact acute care is begun. Patients who do not respond to aggressive fluid resuscitation in the emergency ward should be considered for admission to a step-down or intensive care unit for further intensive monitoring and management, including hemodynamic monitoring and management of organ failure, if present. Fluid Resuscitation and Monitoring Response to Therapy  The most important treatment intervention for acute pancreatitis is early, intravenous fluid resuscitation to prevent systemic complications from the secondary systemic inflammatory response. The patient is initially made NPO to minimize nutrient-induced stimulation of the pancreas and is given intravenous narcotic analgesics to control abdominal pain and supplemental oxygen (as needed). Lactated Ringer’s solution has been shown to decrease systemic inflammation (lower C-reactive protein levels from admission) and may be a better crystalloid than normal saline. Aggressive intravenous fluids have historically been promoted including an initial bolus of approximately 15–20 mL/kg (1050–1400 mL), followed by 2–3 mL/kg per h (200–250 mL/h), to maintain urine output >0.5 mL/kg per hour. However, a recent randomized controlled trial demonstrated that this hydration strategy is associated with an increased risk of fluid overload (based on signs or symptoms) compared to a less aggressive strategy (10 mL/kg bolus, followed by 1.5 mL/kg per h) without an improve­ ment in clinical outcomes. Irrespective of the initial fluid management strategy, serial bedside evaluations are required every 6–8 h to assess vital signs, oxygen saturation, and change in physical examination to optimize fluid resuscitation. A targeted resuscitation strategy with measurement of hematocrit and BUN every 8–12 h is recommended to ensure the adequacy of fluid resuscitation and monitor response TABLE 359-3  Severity Assessment of Acute Pancreatitis Risk Factors for Increased Severity • Age >60 years • Obesity, BMI >30 kg/m2 • Comorbid disease (based on Charlson comorbidity index) Markers of Severity at Admission or Within 24 h • SIRS—defined by presence of 2 or more criteria: • Core temperature <36° or >38°C • Heart rate >90 beats/min • Respirations >20/min or PCO2 <32 mmHg • White blood cell count >12,000/μL, <4000/μL, or 10% bands • APACHE II (≥8 at 24 h) • Hemoconcentration (hematocrit >44%) • Admission BUN (>20 mg/dL) • BISAP score (≥3 present) • (B) BUN >25 mg/dL • (I) Impaired mental status • (S) SIRS: ≥2 of 4 present • (A) Age >60 years • (P) Pleural effusion • Organ failure (Modified Marshall score) (≥1 present): • Cardiovascular: systolic BP <90 mmHg, heart rate >130 beats/min • Pulmonary: PaO2 <60 mmHg • Renal: serum creatinine >2.0 mg/dL Markers of Severity during Hospitalization • Elevated C-reactive protein (CRP) (variable thresholds >100 mg/L reported) • Persistent organ failure (≥48 h) • Pancreatic or extrapancreatic necrosis PART 10 Disorders of the Gastrointestinal System Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; BISAP, Bedside Index of Severity in Acute Pancreatitis; BMI, body mass index; BP, blood pressure; BUN, blood urea nitrogen; SIRS, systemic inflammatory response syndrome. to therapy, noting that a less aggressive resuscitation strategy may be sufficient in milder forms of pancreatitis. Importantly, a rising BUN during hospitalization is associated not only with inadequate hydration but also higher in-hospital mortality. A decrease in hematocrit and BUN during the first 12–24 h is strong evidence that an adequate volume of fluids is being administered. Adjustments in fluid resuscitation may be required in patients with cardiac, pulmonary, or renal disease. Assessment of Severity and Hospital Triage  Severity of acute pancreatitis should be determined in the emergency ward to assist in A B C FIGURE 359-2  Imaging features of a pancreaticopleural fistula secondary to acute pancreatitis. A. Pancreaticopleural fistula: pancreatic duct leak on endoscopic retrograde cholangiopancreatography. Pancreatic duct leak (arrow) demonstrated at the time of retrograde pancreatogram in a patient with exacerbation of alcoholinduced acute pancreatitis. B. Pancreaticopleural fistula: computed tomography (CT) scan. Contrast-enhanced CT scan (coronal view) with arrows showing fistula tract from pancreatic duct disruption in the pancreatic pleural fistula. C. Pancreaticopleural fistula: chest x-ray. Large pleural effusion in the left hemithorax from a disrupted pancreatic duct. Analysis of pleural fluid revealed elevated amylase concentration. (Courtesy of Dr. K.J. Mortele, Brigham and Women’s Hospital; with permission.) patient triage to a regular hospital ward, step-down unit, or intensive care unit. The Bedside Index of Severity in Acute Pancreatitis (BISAP) incorporates five clinical and laboratory parameters obtained within the first 24 h of hospitalization (Table 359-3)—BUN >25 mg/dL, impaired mental status (Glasgow coma scale score <15), SIRS, age >60 years, and pleural effusion on radiography—that can be useful in assessing severity. The presence of three or more of these factors was associated with substantially increased risk for in-hospital mortal­ ity among patients with acute pancreatitis. In addition, an elevated hematocrit and admission BUN are also associated with more severe acute pancreatitis. Incorporating these indices with the overall patient response to initial fluid resuscitation in the emergency ward can be useful in triaging patients to the appropriate hospital acute care setting. In general, patients with lower BISAP scores, hematocrit, and admission BUN levels tend to respond to initial management and can be safely triaged to a regular hospital ward for ongoing care. If SIRS is not present at 24 h, the patient is unlikely to develop organ failure or necrosis. Conversely, patients with persistent SIRS at 24 h or underly­ ing comorbid illnesses (e.g., chronic obstructive pulmonary disease, congestive heart failure) should be considered for a step-down unit setting if available. Patients with higher BISAP scores and elevations in hematocrit and admission BUN who do not respond to initial fluid resuscitation and exhibit evidence of respiratory failure, hypotension, or organ failure should be considered for direct admission to an inten­ sive care unit. Special Considerations Based on Etiology  A careful history, review of medications, selected laboratory studies (liver profile, serum triglycerides, serum calcium), and abdominal ultrasound are recom­ mended in the emergency ward to assess for etiologies that may impact acute management. An abdominal ultrasound is the initial imaging modality of choice and will evaluate the gallbladder, common bile duct, and pancreatic head. GALLSTONE PANCREATITIS  Patients with evidence of ascending chol­ angitis (including sepsis with evidence of biliary obstruction on labo­ ratory or imaging studies) should undergo ERCP within 24–48 h of admission. Patients with gallstone pancreatitis are at increased risk of recurrence, and consideration should be given to performing a chole­ cystectomy during the same admission in mild acute pancreatitis. An alternative for patients who are not surgical candidates would be to perform an endoscopic biliary sphincterotomy before discharge. HYPERTRIGLYCERIDEMIA  Serum triglycerides >1000 mg/dL are asso­ ciated with acute pancreatitis. Initial therapy should focus on the treat­ ment of hyperglycemia with intravenous insulin, which often corrects hypertriglyceridemia. In contrast to the standard nutritional manage­ ment of acute pancreatitis, patients should remain fasting for the initial 24–36 h to promote the resolution of severe triglyceride elevations. Adjunct therapies may also include heparin or plasmapheresis, but there is no compelling evidence these measures improve clinical outcomes. Outpatient therapies include control of diabetes if present, administration of lipid-lowering agents, weight loss, and avoidance of drugs that elevate lipid levels. Other potential etiologies that may impact acute hospital care include hypercalcemia and post-ERCP pancreatitis. Treatment of hyper­ parathyroidism or malignancy is effective at reducing serum calcium. Pancreatic duct stenting and/or rectal indomethacin administration are effective at decreasing the risk of pancreatitis after ERCP. Drugs that cause pancreatitis should be discontinued. Multiple drugs have been implicated, but only about 30 have been rechallenged (Class 1A) and found to be causative. Nutritional Therapy  A low-fat solid diet can be administered to subjects with mild acute pancreatitis once they are able to eat. Enteral nutrition should be considered 2–3 days after admission in subjects with more severe pancreatitis instead of total parenteral nutrition (TPN). Enteral feeding maintains gut barrier integrity, limits bacterial translocation, is less expensive, and has fewer complications than TPN. While there may be physiologic advantages of jejunal feeding, gastric feeding is safe, and the benefits of jejunal over gastric feeding remain under investigation. Management of Local Complications (Table 359-4)  Patients exhibiting signs of clinical deterioration despite aggressive fluid resus­ citation and hemodynamic monitoring should be assessed for local complications, including necrosis, pseudocyst formation, pancreas duct disruption, peripancreatic vascular complications, and extrapan­ creatic infections. A multidisciplinary team approach is recommended, including gastroenterology, surgery, interventional radiology, and intensive care specialists; consideration should be made for transfer to a tertiary pancreas center of excellence if these services are not available. NECROSIS  The management of necrosis requires a multidisciplinary team approach. Percutaneous fine-needle aspiration of necrosis with Gram stain and culture was previously performed to evaluate for infected pancreatic necrosis in those with sustained leukocytosis, fever, or organ failure. However, the current use of this technique varies depending on institutional preference, with many abandoning this diagnostic test to avoid potentially contaminating an otherwise sterile collection, particularly when culture results will not lead to a clinical decision to de-escalate antimicrobial therapy. Even though there is currently no role for prophylactic antibiotics in necrotizing pancreatitis, empiric antibiotics should be considered in those with clinical decom­ pensation. Prophylactic antibiotics do not lead to improved survival and may promote the development of opportunistic fungal infections. Repeated CT or MRI imaging should also be considered with any change in clinical course to monitor for complications (e.g., thrombo­ ses, hemorrhage, abdominal compartment syndrome). In general, sterile necrosis is most often managed conservatively unless complications arise. Once a diagnosis of infected necrosis is established and an organism identified, targeted antibiotics should be instituted. Pancreatic drainage and/or debridement (necrosectomy) should be considered for definitive management of infected necrosis, but management decisions are ultimately influenced by the clinical response since almost two-thirds of patients respond to antibiotic treatment with or without drainage. Symptomatic local complications as outlined in the Revised Atlanta Criteria typically require definitive therapy. A step-up approach (percutaneous or endoscopic transgastric/ transduodenal drainage followed, if necessary, by endoscopic or, rarely, surgical necrosectomy) is the current treatment paradigm. Random­ ized trials have reported advantages to an initial endoscopic approach compared to an initial surgical necrosectomy approach in patients requiring intervention for symptomatic WON. Taken together, a more conservative approach to the management of infected pancreatic necrosis has evolved under the close supervision of a multidisci­ plinary team. If conservative therapy can be safely implemented, it is TABLE 359-4  Complications of Acute Pancreatitis Local Pancreatic/peripancreatic fluid collections (Table 359-2):   Acute necrotic collection (sterile or infected)   Walled-off necrosis (sterile or infected)   Pancreatic pseudocyst Disruption of main pancreatic duct or secondary branches Pancreatic ascites Chylous ascites (secondary to disruption of lymphatic ducts) Involvement of contiguous organs by necrotizing pancreatitis (e.g., colon perforation) Splanchnic thromboses (splenic vein, superior mesenteric vein, and/or portal vein) Gastric outlet obstruction Biliary obstruction (jaundice) Systemic Pulmonary   Pleural effusion   Atelectasis   Mediastinal fluid   Pneumonitis   Acute respiratory distress syndrome Cardiovascular   Hypotension   Hypovolemia   Nonspecific ST-T changes in electrocardiogram simulating myocardial CHAPTER 359 infarction   Pericardial effusion Hematologic   Disseminated intravascular coagulation Gastrointestinal hemorrhage   Peptic ulcer disease   Erosive gastritis   Hemorrhagic pancreatic necrosis with erosion into major blood vessels   Variceal hemorrhage secondary to splanchnic thrombosis Renal   Oliguria (<300 mL/d)   Azotemia   Renal artery and/or renal vein thrombosis   Acute tubular necrosis Metabolic   Hyperglycemia   Hypertriglyceridemia   Hypocalcemia   Encephalopathy   Sudden blindness (Purtscher’s retinopathy) Central nervous system   Psychosis   Fat emboli Fat necrosis   Subcutaneous tissues (erythematous nodules)   Bone   Miscellaneous (mediastinum, pleura, nervous system) Acute and Chronic Pancreatitis recommended to do so for 4–6 weeks to allow the pancreatic collec­ tions to either resolve or evolve to develop a more organized boundary (i.e., to “wall off”) since interventions are generally safer and more technically straightforward. PSEUDOCYST  The incidence of pseudocyst is low, and most acute collections resolve over time. Less than 10% of patients have persis­ tent fluid collections after 4 weeks that would meet the definition of a pseudocyst. Only symptomatic collections require intervention with endoscopic or surgical drainage. PANCREATIC DUCT DISRUPTION  Pancreatic duct disruption may present with symptoms of increasing abdominal pain or shortness of breath in the setting of an enlarging fluid collection resulting in pan­ creatic ascites (ascitic fluid has high amylase level). Diagnosis can be confirmed on magnetic resonance cholangiopancreatography (MRCP) or ERCP. Placement of a bridging pancreatic stent for at least 6 weeks is >90% effective at resolving the leak with or without parenteral nutri­ tion and octreotide. Nonbridging stents are less effective (25–50%) but may be useful in combination with parenteral nutrition and octreotide prior to surgical evaluation. PERIVASCULAR COMPLICATIONS  Perivascular complications may include splenic vein thrombosis with gastric varices and pseudoaneu­ rysms, as well as portal and superior mesenteric vein thromboses. Gastric varices rarely bleed but can be life-threatening. Similarly, life-threaten­ ing bleeding from a ruptured pseudoaneurysm can be diagnosed and treated with mesenteric angiography and embolization. EXTRAPANCREATIC INFECTIONS  Hospital-acquired infections occur in up to 20% of patients with acute pancreatitis. Patients should be con­ tinually monitored for the development of pneumonia, urinary tract infection, and line infection. Continued culturing of urine, monitoring of chest x-rays, and routine changing of intravenous lines are important during hospitalization. Follow-Up Care  Hospitalizations for moderately severe and severe acute pancreatitis can be prolonged and last weeks to months and often involve periods of intensive care unit admission and outpatient reha­ bilitation or subacute nursing care. Follow-up evaluation should assess for development of diabetes, exocrine pancreatic insufficiency, recur­ rent cholangitis, or infected fluid collections. As mentioned previously, cholecystectomy should be performed during the initial hospitalization for acute gallstone pancreatitis with mild clinical severity. For patients with necrotizing gallstone pancreatitis, the timing of cholecystectomy needs to be individualized. PART 10 Disorders of the Gastrointestinal System ■ ■RECURRENT ACUTE PANCREATITIS Approximately 25% of patients who have had an attack of acute pancre­ atitis will experience a recurrence. The two most common etiologic fac­ tors are alcohol and cholelithiasis. In patients with recurrent pancreatitis without an obvious cause, the differential diagnosis should consider occult biliary tract disease, including microlithiasis, hypertriglyceri­ demia, pancreatic cancer, and hereditary pancreatitis (Table 359-1). In one small series, up to two-thirds of patients with recurrent acute pan­ creatitis without an initially apparent cause had occult gallstone disease attributed to microlithiasis. Genetic defects as in hereditary pancreatitis and cystic fibrosis mutations can result in recurrent pancreatitis. Other diseases of the biliary tree and pancreatic ducts that can cause acute pancreatitis include choledochocele; ampullary tumors; pancreas divi­ sum; and pancreatic duct stones, stricture, and tumors. Approximately 2–4% of patients with pancreatic cancer present with acute pancreatitis. ■ ■PANCREATITIS IN PATIENTS WITH AIDS The incidence of acute pancreatitis is theoretically increased in patients with AIDS for two reasons: (1) the high incidence of infec­ tions involving the pancreas such as infections with cytomegalovirus, Cryptosporidium, and the Mycobacterium avium complex; and (2) the frequent use of medications such as pentamidine, trimethoprimsulfamethoxazole, and protease inhibitors. The incidence has been markedly reduced due to advances in therapy, including the disuse of didanosine (Chap. 208). CHRONIC PANCREATITIS AND EXOCRINE PANCREATIC INSUFFICIENCY ■ ■PATHOPHYSIOLOGY Chronic pancreatitis is a disease process characterized by irreversible damage to the pancreas, in contrast to the reversible changes noted in acute pancreatitis (Table 359-4). The events that initiate and then per­ petuate the inflammatory process in the pancreas are becoming more clearly understood. Irrespective of the mechanism of injury, it is apparent that stellate cell activation leads to cytokine expression and production of extracellular matrix proteins that contribute to acute and chronic inflammation and collagen deposition in the pancreas. This condition is defined by the presence of histologic abnormalities, including chronic inflammation, fibrosis, and progressive destruction (atrophy) of both exocrine and endocrine tissue. A number of etiologies have been associ­ ated with chronic pancreatitis resulting in the cardinal manifestations of the disease such as abdominal pain, steatorrhea, weight loss, diabetes mellitus, and, less commonly, pancreatic cancer (Table 359-5). Even in individuals in whom alcohol is believed to be the primary cause of chronic pancreatitis, other factors are likely required for the development and progression of disease, which explains why not all heavy consumers of alcohol develop pancreatic disease. Importantly, there is a strong association between smoking and chronic pancreatitis. Cigarette smoke leads to an increased susceptibility to pancreatic auto­ digestion and predisposes to dysregulation of duct cell CFTR function. Smoking is an independent, dose-dependent risk factor for chronic pancreatitis and recurrent acute pancreatitis. Both continued alcohol and smoking exposure are associated with disease progression, includ­ ing pancreatic fibrosis and calcifications. Characterization of pancreatic stellate cells (PSCs) has added insight into the underlying cellular responses behind development of chronic pancreatitis. Specifically, PSCs are believed to play a role in maintaining normal pancreatic architecture that shifts toward fibrogenesis in those who develop chronic pancreatitis. It is believed that alcohol or additional stimuli lead to matrix metalloproteinase–mediated destruction of nor­ mal collagen in pancreatic parenchyma, which later allows for pancreatic TABLE 359-5  Classification of Chronic Pancreatitis: The TIGAR-O System Toxic-metabolic Alcoholic Tobacco smoking Hypercalcemia Hyperlipidemia (hypertriglyceridemia) Chronic renal failure Idiopathic Early onset Late onset Tropical Genetic Cationic trypsinogen (PRSS1) Cystic fibrosis transmembrane conductance regulator gene (CFTR)a Calcium-sensing receptor (CASR)a Chymotrypsin C gene (CTRC)a Pancreatic secretory trypsin inhibitor gene (SPINK1)a Autoimmune Type 1 autoimmune pancreatitis (associated with IgG4-related disease) Type 2 autoimmune pancreatitis (idiopathic duct-centric chronic pancreatitis) Recurrent and severe acute pancreatitis Postnecrotic (severe acute pancreatitis) Recurrent acute pancreatitis Vascular diseases/ischemia Radiation induced Obstructive Pancreas divisuma Duct obstruction (e.g., tumor) Preampullary duodenal wall cysts Posttraumatic pancreatic duct strictures aThese conditions are believed to be disease modifiers that require additional factors to cause chronic pancreatitis. Abbreviations: TIGAR-O, toxic-metabolic, idiopathic, genetic, autoimmune, recurrent and severe acute pancreatitis, obstructive. remodeling. Proinflammatory cytokines, tumor necrosis factor α (TNF-α), interleukin 1 (IL-1), and interleukin 6 (IL-6), as well as oxidant com­ plexes, can induce PSC activity with subsequent new collagen synthesis. In addition to being stimulated by cytokines, oxidants, or growth factors, PSCs also possess transforming growth factor β (TGF-β)–mediated selfactivating autocrine pathways that may explain disease progression in chronic pancreatitis even after removal of noxious stimuli. ■ ■ETIOLOGIC CONSIDERATIONS Among adults in the United States, heavy alcohol use is the most com­ mon cause of clinically apparent chronic pancreatitis. As many as 25% of adults in the United States with chronic pancreatitis have the idiopathic form, including a subset of patients who do not develop clinical manifes­ tations until later in life (referred to as idiopathic late-onset chronic pan­ creatitis). Recent investigations have indicated that up to 15% of patients with chronic pancreatitis previously classified as having idiopathic pan­ creatitis may have an underlying genetic predisposition (Table 359-5). The prototypical genetic defect was identified in the cationic tryp­ sinogen gene (PRSS1) by studying several large families with chronic pancreatitis. Additional pathogenic and nonpathogenic mutations have been identified in this gene. The defect prevents the destruction of prematurely activated trypsin and allows it to be resistant to the intracellular protective effect of trypsin inhibition. It is hypothesized that this continual activation of digestive enzymes within the gland leads to acute injury and, finally, chronic pancreatitis. Since the initial discovery of the PRSS1 mutation defect, other genetic disease modifiers have been identified (Table 359-5). The CFTR gene functions as a cyclic AMP–regulated chloride channel. In patients with cystic fibrosis, the high concentration of macromolecules can block the pancreatic ducts. It must be appreciated, however, that there is a great deal of heterogeneity in relationship to the CFTR gene defect. More than 1700 putative mutations of the CFTR gene have been identified. The large number and different classes of CFTR mutations have hampered attempts to elucidate the relationship between the genotype and pancreatic manifestations. The ability to detect CFTR mutations has led to the recognition that the clinical spec­ trum of the disease is broader than initially thought. Studies have clari­ fied the association between mutations of the CFTR gene and another monosymptomatic form of cystic fibrosis (i.e., chronic pancreatitis). It is estimated that in patients with idiopathic pancreatitis, the frequency of a single CFTR mutation is 11 times the expected frequency and the frequency of two mutant alleles is 80 times the expected frequency. In these studies, patients were adults when the diagnosis of pancreatitis was made; none had any clinical evidence of pulmonary disease, and sweat test results were not diagnostic of cystic fibrosis. The prevalence of such mutations is unclear, and further studies are needed. In addi­ tion, the therapeutic and prognostic implication of these findings with respect to managing pancreatitis remains to be determined. CFTR mutations are common in the general population, so it is unclear whether the CFTR mutation alone can lead to pancreatitis as an auto­ somal recessive disease. A study evaluated 39 patients with idiopathic chronic pancreatitis to assess the risk associated with these mutations. Patients with two CFTR mutations (compound heterozygotes) dem­ onstrated CFTR function at a level between that seen in typical cystic fibrosis and cystic fibrosis carriers and had a 40-fold increased risk of pancreatitis. The presence of a separate genetic mutation (N34S SPINK1) increased the risk 20-fold. A combination of two CFTR muta­ tions and an N34S SPINK1 mutation increased the risk of pancreatitis 900-fold. Knowledge of the genetic defects and downstream alterations in protein expression has led to the development of novel therapies in children with cystic fibrosis that potentiate the CFTR channel, result­ ing in improvement in lung function, quality of life, and weight gain. Some studies have shown that use of CFTR modulators may reduce the frequency of acute pancreatitis in heterozygous carriers. Table 359-5 lists other recognized causes of chronic pancreatitis. ■ ■AUTOIMMUNE PANCREATITIS (TABLE 359-6) Autoimmune pancreatitis (AIP) refers to a form of chronic pancre­ atitis with distinct histopathology and several unique differences in TABLE 359-6  Comparison of the Autoimmune Pancreatitis (AIP) Subtypes   TYPE 1 AIP TYPE 2 AIP Age at diagnosis, mean Seventh decade Fifth decade Male sex 75% 50% Serum IgG4 elevation ~66% ~25% Other organ involvement 50% Noa Histologic findings:       Lymphoplasmacytic   Infiltration ++ ++   Periductal inflammation ++ ++   Storiform fibrosis ++ +   Obliterative phlebitis ++ +   Granulocytic epithelial – +++ lesion (GEL)   IgG4 tissue staining Abundant (≥10 cells/hpf) Scant (<10 cells/hpf) Response to steroids ~100% ~100% Risk for relapse Moderate to high (20–60%) Low (<10%) Associated with IgG4-RD Yes No aInflammatory bowel disease is seen in ~10–20% of patients with idiopathic ductcentric chronic pancreatitis but may also occur in type 1 AIP. Abbreviations: hpf, high-power field; IgG4-RD, IgG4-related disease. Source: Reproduced with permission from PA Hart: Reviews in basic and clinical gastroenterology and hepatology. Gastroenterology 149:39, 2015. CHAPTER 359 the clinical phenotype. Currently, two subtypes of AIP are recognized, type 1 AIP and idiopathic duct-centric chronic pancreatitis (IDCP, also referred to as type 2 AIP). Type 1 AIP is identified as the pancre­ atic manifestation of a multiorgan syndrome currently referred to as IgG4-related disease (Chap. 380). The characteristic histopathologic findings of type 1 AIP include lymphoplasmacytic infiltrate, storiform fibrosis, and abundant IgG4 cells. IDCP is histologically defined by the presence of granulocytic infiltration of the duct wall (termed a granulocytic epithelial lesion [GEL]) but without IgG4-positive cells. Type 1 AIP is often associated with involvement of other organs in the setting of IgG4-related disease, including bilateral submandibular gland enlargement, characteristic renal lesions, retroperitoneal fibrosis, and stricturing of the extrapancreatic biliary tree. In contrast, IDCP is a pancreas-specific disorder that is associated with inflammatory bowel disease in ~10% of patients. AIP is not a common cause of idiopathic recurrent acute pancreatitis. Acute and Chronic Pancreatitis Jaundice, weight loss, and new-onset diabetes are the most common presenting symptoms. Elevated serum IgG4 levels are supportive of the diagnosis (elevated in two-thirds of patients with type 1 AIP) but have a low positive predictive value when used in isolation of other clinical findings. CT imaging demonstrates abnormalities in the majority of patients with either diffuse or focal enlargement during active disease, unless the gland is atrophic due to previous disease (Fig. 359-3). The presence of an inflammatory rim, termed a capsule sign, is highly specific (but not sensitive) for AIP. ERCP or MRCP reveals strictures in the bile duct in more than one-third of patients with AIP, including some patients with isolated intrahepatic bile duct strictures (type 1 AIP only), which can mimic primary sclerosing cholangitis, and is referred to as IgG4-related sclerosing cholangitis (previously termed IgG4-associated cholangitis). The Mayo Clinic HISORt criteria provide a helpful mnemonic to remember the key diagnostic features of this disease, including (1) histology; (2) imaging; (3) serology (elevated serum IgG4 levels); (4) other organ involvement; and (5) response to glucocorticoid therapy. These diagnostic criteria have been harmonized with those from other countries to develop the International Consensus Diagnostic Criteria for AIP, which are the most comprehensive criteria. Glucocorticoids have shown efficacy in alleviating symptoms, decreasing the size of PART 10 Disorders of the Gastrointestinal System A B FIGURE 359-3  Imaging features of the pancreatic parenchyma in a patient with type 1 autoimmune pancreatitis on computed tomography (CT). A. Contrast-enhanced CT scan of the abdomen demonstrates diffuse pancreatic enlargement and a hypoechoic rim (capsule sign) in a patient who presented with jaundice. The serum IgG4 level was elevated to 942 mg/dL (reference range 4–86 mg/dL), so the patient was diagnosed with definitive type 1 autoimmune pancreatitis. B. Contrast-enhanced CT scan of the abdomen following a treatment course with high-dose steroids demonstrates return to normal size of the pancreas, reappearance of normal lobulations along the margin, and absence of the hypoechoic rim. the pancreas, and reversing histopathologic features in patients with AIP. Patients typically respond dramatically to glucocorticoid therapy within a 2- to 4-week period. Prednisone is usually administered at an initial dose of 40 mg/d for 4 weeks followed by a taper of the daily dosage by 5 mg per week based on monitoring of clinical parameters. Relief of symptoms, liver biochemistries, and abnormal imaging of the pancreas and bile ducts are followed to assess for treatment response. A poor response to glucocorticoids should raise suspicion of an alternate diagnosis, such as pancreatic cancer. A prior multicenter international study examined >1000 patients with AIP. Clinical remission was achieved in 99% of type 1 AIP and 92% of type 2 AIP patients with steroids. However, disease relapse occurred in 31 and 9% of patients with type 1 and type 2 AIP, respectively. Patients with multiple relapses have been managed with immunomodulators (e.g., azathioprine, 6-mercaptopurine, or mycophenolate mofetil) with variable success. Management with B-cell depletion therapy (e.g., rituximab) is likely the most effective treatment option for patients with recurrent relapses with other therapies under investigation. The appearance of interval cancers following a diagnosis of AIP is uncommon. Clinical Features of Chronic Pancreatitis  Patients with chronic pancreatitis primarily seek medical attention due to abdominal pain or symptoms of maldigestion. The abdominal pain may be variable in loca­ tion, severity, and frequency. The pain can be constant or intermittent with pain-free intervals. Eating may exacerbate the pain, leading to a fear of eating with consequent weight loss. The spectrum of abdominal pain ranges from mild to quite severe, with narcotic dependence as a frequent consequence. There is often a disparity between the reported severity of abdominal pain and the physical findings, which primarily consist of nonfocal abdominal tenderness. Patients with chronic abdominal pain may or may not experience symptoms of maldigestion, such as chronic diarrhea, steatorrhea, and/or weight loss. Fat-soluble vitamin deficien­ cies are increasingly recognized. Importantly, there is an exceedingly high prevalence of metabolic bone disease in chronic pancreatitis, with ~65% of patients having either osteopenia or osteoporosis. Patients with chronic pancreatitis have impaired quality of life and develop significant morbidity, requiring frequent health encounters. The diagnosis of early or mild chronic pancreatitis can be challeng­ ing because there is no accurate biomarker for the disease. In contrast to acute pancreatitis, the serum amylase and lipase levels are usually not strikingly elevated in chronic pancreatitis. Rather, low serum pancreatic enzyme levels are moderately specific for a diagnosis of chronic pancre­ atitis but have poor sensitivity. Elevation of serum bilirubin and alkaline phosphatase may indicate cholestasis secondary to common bile duct stricture caused by chronic inflammation or fibrosis. The cumulative prevalence of exocrine pancreatic insufficiency is >80%. The presence of overt steatorrhea in a patient with chronic pancreatitis is highly sug­ gestive of this complication. However, in those with milder symptoms, additional testing, such as a random fecal elastase-1 level (on a formed stool specimen) may be needed to confirm the diagnosis of exocrine pancreatic insufficiency. The radiographic evaluation of a patient with suspected chronic pancreatitis usually proceeds from a noninvasive to more invasive approach. Abdominal CT imaging (Fig. 359-4) is the initial modality of choice, followed by MRI, endoscopic ultrasound, and pancreas function testing. In addition to excluding a pseudocyst and pancreatic cancer, CT imaging may show calcifications, dilated pancre­ atic or biliary ducts, or an atrophic pancreas. Although abdominal CT scanning and MRI greatly aid in the diagnosis of pancreatic disease, the diagnostic test with the best sensitivity is the direct pancreatic function test using secretin. The secretin test becomes abnormal when ≥60% of the pancreatic exocrine function has been lost and usually correlates well with the onset of chronic abdominal pain. The role of endoscopic ultrasonography (EUS) in diagnosing early chronic pancreatitis is still evolving. A total of nine endosonographic features have been described in chronic pancreatitis. The presence of five or more features is consid­ ered diagnostic of chronic pancreatitis. EUS is not a specific enough test for detecting early chronic pancreatitis alone (Chap. 358) and may show positive features in patients with diabetes, patients with a his­ tory of cigarette smoking, or even in normal aging individuals. Recent data suggest that EUS can be combined with endoscopic pancreatic function testing (EUS-ePFT) during a single endoscopy to screen for chronic pancreatitis in patients with chronic abdominal pain. Diffuse calcifications noted on plain film of the abdomen usually indicate sig­ nificant damage to the pancreas and are pathognomonic for chronic pancreatitis. While patterns of calcification are not specific for an etiol­ ogy, patients with tropical pancreatitis (often associated with a SPINK1 mutation) characteristically have bulky calcifications. Complications of Chronic Pancreatitis  There are a number of disease-related complications from chronic pancreatitis in addition to the aforementioned abdominal pain and exocrine pancreatic insufficiency (Table 359-7). The lifetime prevalence of chronic pancreatitis–related diabetes exceeds 80%. Although most patients develop hyperglycemia due to insulin deficiency caused by loss of islet cells, diabetic ketoaci­ dosis and diabetic coma are uncommon. Likewise, end-organ damage (retinopathy, neuropathy, nephropathy) is also uncommon. Nondia­ betic retinopathy may be due to vitamin A and/or zinc deficiency. Osteoporosis and osteopenia are increasingly recognized in chronic pancreatitis and likely related to a combination of shared risk factors (e.g., alcohol use, cigarette smoking), vitamin D deficiency, and detri­ mental effects on the bone from chronic inflammation. Gastrointesti­ nal bleeding may occur from peptic ulceration, gastritis, a pseudocyst A B C D FIGURE 359-4  Distribution of imaging features of chronic pancreatitis on computed tomography (CT). Distinct features of chronic pancreatitis are seen on selected images from contrast-enhanced CT scans of the abdomen from four unique patients, including the following. A. Numerous punctate calcifications involving the pancreatic parenchyma in the head and body. B. A moderate-sized calculus visualized in the pancreatic duct with associated ductal dilation. C. Significant pancreatic duct dilation and adjacent parenchymal atrophy secondary to a pancreatic duct stricture (which is not well seen on this scan). D. A large unilocular, encapsulated cyst in the tail of the pancreas consistent with a pseudocyst from prior pancreatitis. Note adjacent pancreatic parenchymal atrophy. eroding into the duodenum, arterial bleeding into the pancreatic duct (hemosuccus pancreaticus), or ruptured varices secondary to splenic vein thrombosis. Jaundice, cholestasis, and biliary cirrhosis may occur from the chronic inflammatory reaction around the intrapancreatic portion of the common bile duct. Twenty years after the diagnosis of chronic calcific pancreatitis, the cumulative risk of pancreatic cancer is 4%. Patients with hereditary PRSS1 or tropical pancreatitis have an increased risk for pancreatic cancer compared to other forms of chronic pancreatitis. TREATMENT Chronic Pancreatitis There are currently no therapies to reverse or delay the disease pro­ gression of chronic pancreatitis, so management is primarily focused on screening for and management of disease-related complications. STEATORRHEA The treatment of steatorrhea with pancreatic enzyme replacement therapy is conceptually straightforward, yet complete correction of steatorrhea is uncommon. Enzyme therapy usually brings diarrhea under control and restores absorption of fat to an acceptable level TABLE 359-7  Complications of Chronic Pancreatitis Chronic abdominal pain Exocrine pancreatic insufficiency Diabetes mellitus Splanchnic venous thrombosis Metabolic bone disease (osteoporosis) Biliary stricture and/or biliary cirrhosis Pancreatic duct stricture Pseudocyst Pancreatic cancer Malnutrition, micronutrient deficiencies CHAPTER 359 Acute and Chronic Pancreatitis and affects weight gain. Thus, pancreatic enzyme replacement is the cornerstone of therapy. In treating steatorrhea, it is important to use a potent pancreatic formulation that will deliver sufficient lipase into the duodenum to correct maldigestion and decrease steatorrhea. For adult patients with exocrine pancreatic insufficiency, it is generally recommended to start at a dosage of 25,000–50,000 units of lipase taken during each meal; however, the dose may need to be increased up to 100,000 units of lipase depending on the response in symp­ toms, nutritional parameters, and/or pancreas function test results (although rarely used for this purpose). Additionally, some may require acid suppression with proton pump inhibitors to optimize the response to pancreatic enzymes. Monitoring nutritional parameters such as fat-soluble vitamins, zinc levels, body weight, and periodic bone mineral density measurement should be considered. ABDOMINAL PAIN The management of pain in patients with chronic pancreatitis is challenging due to the complex mechanisms of pancreatitis-related pain. Recent meta-analyses have shown no consistent benefit of enzyme therapy at reducing pain in chronic pancreatitis. Pain relief experienced by patients treated with pancreatic enzymes may be due to improvements in dyspepsia from maldigestion. One shortterm randomized trial showed that pregabalin could decrease pain in chronic pancreatitis and lower pain medication requirement. Other studies using antioxidants have yielded mixed results. Endoscopic treatment of chronic pancreatitis pain may involve sphincterotomy, pancreatic duct stenting, stone extraction, and drainage of a pancreatic pseudocyst. Therapy directed to the pan­ creatic duct would seem to be most appropriate in the setting of a dominant stricture, especially if there is an obstructing intraductal stone. The use of endoscopic stenting for patients with chronic pain has not been investigated in controlled trials. It is now appreci­ ated that significant complications can occur from stenting (e.g., stent migration, stent occlusion, and stent-induced pancreatic duct strictures). Recent guidelines recommend considering celiac plexus block for treatment of pain in chronic pancreatitis, but recommen­ dations were conditional with very low quality of evidence. Celiac plexus block has not been rigorously studied for chronic pancreati­ tis and does not provide durable pain relief. It can provide relief in some selected patients, but the a priori identification of those who will respond is difficult. In patients with pancreatic duct dilation, ductal decompression with surgical therapy has been the therapy of choice. Among such patients, 80% seem to obtain immediate relief; however, at the end of 3 years, one-half of the patients have recur­ rence of pain. Two randomized prospective trials comparing endo­ scopic to surgical therapy for chronic pancreatitis demonstrated that surgical therapy was superior to endoscopy at decreasing pain and improving quality of life in selected patients with dilated ducts and abdominal pain. This would suggest that chronic pancreatitis patients with dilated ducts and pain should be considered for surgi­ cal intervention. A recent randomized controlled trial suggests that early surgical intervention may provide superior pain relief in the short term compared to a conservative, nonoperative approach. The role of preoperative stenting prior to surgery as a predictor of response has yet to be proven. Total pancreatectomy with or without autologous islet cell trans­ plantation has been used in highly selected patients with chronic pancreatitis and abdominal pain refractory to conventional therapy. However, some patients will continue to have pain postoperatively, illustrating the complex nature of pain in this patient population. Patients who benefit most from total pancreatectomy have a shorter duration of symptoms and lower pain medication requirements. The role of this procedure remains to be fully defined but may be an option in lieu of ductal decompression surgery or partial pancreatic resection in patients with intractable, painful, small-duct disease or hereditary pancreatitis. PART 10 Disorders of the Gastrointestinal System ■ ■HEREDITARY PANCREATITIS Hereditary pancreatitis (PRSS1) is a rare form of pancreatitis with early age of onset that is typically associated with familial aggregation of cases. A genome-wide search using genetic linkage analysis identified the hereditary pancreatitis gene on chromosome 7. Mutations in ion codons 29 (exon 2) and 122 (exon 3) of the cationic trypsinogen gene (PRSS1) cause an autosomal dominant form of pancreatitis. The codon 122 mutations lead to a substitution of the corresponding arginine with another amino acid, usually histidine. This substitution, when it occurs, eliminates a fail-safe trypsin self-destruction site necessary to eliminate trypsin that is prematurely activated within the acinar cell. These patients have recurring episodes of acute pancreatitis. Patients frequently develop pancreatic calcification, diabetes mellitus, and ste­ atorrhea; in addition, they have an increased incidence of pancreatic cancer with a cumulative incidence of ~10%. A previous natural history study of hereditary pancreatitis in >200 patients from France reported that abdominal pain started in childhood at age 10 years, steatorrhea developed at age 29 years, diabetes at age 38 years, and pancreatic can­ cer at age 55 years. Abdominal complaints in relatives of patients with hereditary pancreatitis should raise the question of pancreatic disease. ■ ■PANCREATIC ENDOCRINE TUMORS Pancreatic endocrine tumors are discussed in Chap. 89. OTHER CONDITIONS ■ ■ANNULAR PANCREAS When the ventral pancreatic anlage fails to migrate correctly to make contact with the dorsal anlage, the result may be a ring of pancreatic tissue encircling the duodenum. Such an annular pancreas may cause intestinal obstruction in the neonate or adult. Symptoms of postpran­ dial fullness, epigastric pain, nausea, and vomiting may be present for years before the diagnosis is entertained. The radiographic findings are symmetric dilation of the proximal duodenum with bulging of the recesses on either side of the annular band, effacement but not destruc­ tion of the duodenal mucosa, accentuation of the findings in the right anterior oblique position, and lack of change on repeated examina­ tions. The differential diagnosis should include duodenal webs, tumors of the pancreas or duodenum, duodenal ulcer, regional enteritis, and adhesions. Patients with annular pancreas have an increased incidence of pancreatitis and peptic ulcer. Because of these and other potential complications, the treatment for refractory symptoms is surgical. Retrocolic duodenojejunostomy is the procedure of choice, although some surgeons advocate Billroth II gastrectomy, gastroenterostomy, and vagotomy. ■ ■PANCREAS DIVISUM Pancreas divisum is present in 7–10% of the population and occurs when the embryologic ventral and dorsal pancreatic anlagen fail to fuse, so that pancreatic drainage is accomplished mainly through the accessory minor papilla. Pancreas divisum is the most common congenital anatomic variant of the human pancreas. Current evidence indicates that this anomaly does not predispose to the development of pancreatitis in the majority of patients. However, the combination of pancreas divisum and a small accessory orifice can result in dorsal duct obstruction. The challenge is to identify this subset of patients with dorsal duct pathology. Cannulation of the dorsal duct by ERCP is tech­ nically challenging and associated with a very high risk of post-ERCP pancreatitis, so patients with pancreatitis and pancreas divisum should likely be treated with conservative measures. In many of these patients, pancreatitis is idiopathic and unrelated to the pancreas divisum. Endo­ scopic or surgical intervention is indicated if pancreatitis recurs and no other cause can be found. It should be stressed that the ERCP/MRCP appearance of pancreas divisum (i.e., a small-caliber ventral duct with an arborizing pattern) may be mistaken as representing an obstructed main pancreatic duct secondary to a mass lesion. ■ ■MACROAMYLASEMIA In macroamylasemia, amylase circulates in the blood in a polymer form too large to be easily excreted by the kidney. Patients with this condition demonstrate an elevated serum amylase value and a low uri­ nary amylase value. The presence of macroamylase can be documented by chromatography of the serum. The prevalence of macroamylasemia is 1.5% of the nonalcoholic general adult hospital population. Usu­ ally, macroamylasemia is an incidental finding and is not related to disease of the pancreas or other organs. Macrolipasemia has now been documented in patients with cirrhosis or non-Hodgkin’s lymphoma. In these patients, the pancreas appeared normal on ultrasound and CT examination. Lipase was shown to be complexed with immunoglobulin A. Thus, the possibility of both macroamylasemia and macrolipasemia should be considered in patients with elevated blood levels of these enzymes. Acknowledgment This chapter represents a revised version of chapters by Drs. Norton J. Greenberger (deceased), Phillip P. Toskes (deceased), Peter A. Banks, and Bechien Wu that were in previous editions of Harrison’s. ■ ■FURTHER READING Crockett SD et al: American Gastroenterological Association Insti­ tute guideline on initial management of acute pancreatitis. Gastroen­ terology 154:1096, 2018. De-Maderia E et al: Aggressive or moderate fluid resuscitation in acute pancreatitis. N Engl J Med 387:989, 2022. Forsmark CE et al: Acute pancreatitis. N Engl J Med 375:1972, 2016. Gardner TB et al: ACG clinical guideline: Chronic pancreatitis. Am J Gastroenterol 115:322, 2020. Hart PA et al: Recent advances in autoimmune pancreatitis. Gastro­ enterology 149:39, 2015. Petrov MS, Yadav D: Global epidemiology and holistic prevention of pancreatitis. Nat Rev Gastroenterol Hepatol 16:175, 2019. Vege SS, Chari ST: Chronic pancreatitis. N Engl J Med 386:869, 2022.