Acute Pancreatitis The incidence of acute pancreatitis (AP) has increased during the past 20 years. AP is responsible for more than 300,000 hospital admissions annually in the United States. Most patients develop a mild and self-limited course; however, 10% to 20% of patients have a rapidly progressive inflammatory response associated with prolonged length of hospital stay and significant morbidity and mortality. Patients with mild pancreatitis have a mortality rate of less than 1% but, in severe pancreatitis, this increases up to 10% to 30%.[3] The most common cause of death in this group of patients is multiorgan dysfunction syndrome. Mortality in pancreatitis has a bimodal distribution; in the first 2 weeks, also known as the early phase, the multiorgan dysfunction syndrome is the final result of an intense inflammatory cascade triggered initially by [4] pancreatic inflammation. Mortality after 2 weeks, also known as the late period, is often caused by septic complications.
Pathophysiology The exact mechanism whereby predisposing factors such as ethanol and gallstones produce pancreatitis is not completely known. Most researchers believe that AP is the final result of abnormal pancreatic enzyme activation inside acinar cells. Immunolocalization studies have shown that after 15 minutes of pancreatic injury, both zymogen granules and lysosomes colocalize inside the acinar cells. The fact that zymogen and lysosome colocalization occurs before amylase level elevation, pancreatic edema, and other markers of pancreatitis are evident suggests that colocalization is an early step in the pathophysiology and not a consequence of pancreatitis. In addition, the inflammatory response seen in AP can be prevented if acinar cells are pretreated with cathepsin B inhibitors. In vivo studies have also shown that cathepsin B knockout mice have a significant decrease in the severity of pancreatitis.[2] Intra-acinar pancreatic enzyme activation induces autodigestion of normal pancreatic parenchyma. In response to this initial insult, acinar cells release proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukins (IL)-1, 2, and -6, and anti-inflammatory mediators such as IL-10 and IL-1 receptor antagonist. These mediators do not initiate pancreatic injury but propagate the response locally and systemically. As a result, TNF-α, IL-1, and IL-7, neutrophils, and macrophages are recruited into the pancreatic parenchyma and cause the release of more TNF- α, IL-1, IL-6, reactive oxygen metabolites, prostaglandins, platelet-activating factor, and leukotrienes. The local inflammatory response further aggravates the pancreatitis because it increases the permeability and damages the microcirculation of the pancreas. In severe cases, the inflammatory response causes local hemorrhage and pancreatic necrosis. In addition, some of the inflammatory mediators released by neutrophils aggravate the pancreatic injury because they cause pancreatic enzyme [5] activation. The inflammatory cascade is self-limited in approximately 80% to 90% of patients. However, in the remaining patients, a vicious cycle of recurring pancreatic injury and local and systemic inflammatory reaction persists. In a small number of patients, there is a massive release of inflammatory mediators to the systemic circulation. Active neutrophils mediate acute lung injury and induce the adult distress respiratory syndrome frequently seen in patients with severe pancreatitis. The mortality seen in the early phase of pancreatitis is the result of this persistent inflammatory response. A summary of the inflammatory cascade seen in AP is shown in Figure 56-6.
FIGURE 56-6 Pathophysiology of severe acute pancreatitis. The local injury induces the release of TNF-α and IL-1. Both cytokines produce further pancreatic injury and amplify the inflammatory response by inducing the release of other inflammatory mediators, which cause distant organ injury. This abnormal inflammatory response is responsible for the mortality seen during the early phase of acute pancreatitis.
Risk Factors Gallstones and ethanol abuse account for 70% to 80% of AP cases. In pediatric patients, abdominal blunt trauma and systemic diseases are the two most common conditions that lead to pancreatitis. Autoimmune and drug-induced pancreatitis should be a differential diagnosis in patients with rheumatologic conditions such as systemic lupus erythematosus and Sjögren's syndrome.
Biliary or Gallstone Pancreatitis Gallstone pancreatitis is the most common cause of AP in the West. It accounts for 40% of U.S. cases. The overall incidence of AP in patients with symptomatic gallstone disease is 3% to 8%. It is seen more frequently in women between 50 and 70 years of age. The exact mechanism that triggers pancreatic injury has not been completely understood, but two [6] theories have been proposed. In the obstructive theory, pancreatic injury is the result of excessive pressure inside the pancreatic duct. This increased intraductal pressure is the result of continuous secretion of pancreatic juice in the presence of pancreatic duct obstruction. The second, or reflux, theory proposes that stones become impacted in the ampulla of Vater and form a common channel that allows bile salt reflux into the pancreas. Animal models have shown that bile salts cause direct acinar cell necrosis because they increase the concentration of calcium in the cytoplasm; [2] however, this has never been proven in humans.
Alcohol-Induced Injury Excessive ethanol consumption is the second most common cause of AP worldwide. It accounts for 35% of cases and is more prevalent in young men (30 to 45 years of age) than in women. However, only 5% to 10% of patients who drink alcohol develop AP. Factors that contribute to ethanol-induces pancreatitis include heavy ethanol abuse (>100 g/day for at least 5 years), smoking, and genetic predisposition. As compared with nonsmokers, the relative risk of alcohol-induced pancreatitis in smokers is 4.9.[7]
Alcohol has a number of deleterious effects in the pancreas. It triggers proinflammatory pathways such as nuclear factor κB (NF-κB), which increase the production of TNF-α and IL-1. It also increases the expression and activity of caspases. Caspases are proteases that mediate apoptosis. In addition, alcohol decreases pancreatic perfusion, induces sphincter of [8] Oddi spasm, and obstructs pancreatic ducts through the precipitation of proteins inside the ducts.
Anatomic Obstruction Abnormal flow of pancreatic juice into the duodenum can result in pancreatic injury. AP has been described in patients with pancreatic tumors, parasites, and congenital defects. Pancreas divisum is an anatomic variation present in 10% of the population. Its association with AP is controversial. Patients with this variation have a 5% to 10% lifetime risk of developing AP caused by relative outflow obstruction through the minor papilla. Endoscopic retrograde cholangiopancreatography (ERCP) with minor papillotomy and stenting may be beneficial for such patients. Infrequent anatomic obstructions that have been associated with AP include Ascaris lumbricoides infection and annular pancreas. Although pancreatic cancer is not uncommon, patients with pancreatic cancer usually do not develop AP.
Endoscopic Retrograde Cholangiopancreatography–Induced Pancreatitis AP is the most common complication after ERCP, occurring in up to 5% of patients. AP occurs more frequently in patients who have undergone therapeutic procedures as compared with diagnostic procedures. It is also more common in patients who have had multiple attempts of cannulation, sphincter of Oddi dysfunction, and abnormal visualization of the secondary pancreatic ducts after contrast injection. The clinical course is mild in 90% to 95% of patients.[8]
Drug-Induced Pancreatitis Up to 2% of AP cases are caused by medications. The most common agents include sulfonamides, metronidazole, erythromycin, tetracyclines, didanosine, thiazides, furosemide, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), azathioprine, 6-mercaptopurine, 5-aminosalicylic acid, sulfasalazine, valproic acid, and acetaminophen. More recently, antiretroviral agents used for the treatment of AIDS have been implicated in AP.
Metabolic Factors Hypertriglyceridemia and hypercalcemia can also lead to pancreatic damage. Direct pancreatic injury can be induced by triglyceride metabolites. It is more common in patients with type I, II, or V hyperlipidemia. It should be suspected in patients with a triglyceride level higher than 1000 mg/dL. A triglyceride level higher than 2000 mg/dL confirms the diagnosis. Hypertriglyceridemia secondary to hypothyroidism, diabetes mellitus, and alcohol does not typically induce AP. Hypercalcemia is postulated to induce pancreatic injury through the activation of trypsinogen to trypsin and intraductal precipitation of calcium, leading to ductal obstruction and subsequent attacks of pancreatitis. Approximately 1.5% to 13% [8] of patients with primary hyperparathyroidism develop AP.
Miscellaneous Conditions Blunt and penetrating abdominal trauma can be associated with AP in 0.2% and 1% of cases, respectively. Prolonged intraoperative hypotension and excessive pancreatic manipulation during abdominal surgery can also result in AP. Pancreatic ischemia in association with acute pancreatic inflammation can develop after splenic artery embolization. Other rare causes include scorpion venom stings and perforated duodenal ulcers.
Clinical Manifestations The cardinal symptom of AP is epigastric and/or periumbilical pain that radiates to the back. Up to 90% of patients have nausea and/or vomiting that typically does not relieve the pain. The nature of the pain is constant; therefore, if the pain disappears or decreases, another diagnosis should be considered. Dehydration, poor skin turgor, tachycardia, hypotension, and dry mucous membranes are commonly seen in patients with AP. Severely dehydrated and older patients may also develop mental status changes.
The physical examination of the abdomen varies according to the severity of the disease. With mild pancreatitis, the physical examination of the abdomen may be normal or reveal only mild epigastric tenderness. Significant abdominal distention, associated with generalized rebound and abdominal rigidity, is present in severe pancreatitis. Note the nature of the pain described by the patient may not correlate with the physical examination or the degree of pancreatic inflammation. Rare findings include flank and periumbilical ecchymosis (Grey Turner and Cullen's signs, respectively). Both are indicative of retroperitoneal bleeding associated with severe pancreatitis. Patients with concomitant choledocholithiasis or significant edema in the head of the pancreas that compresses the intrapancreatic portion of the common bile duct can present with jaundice. Dullness to percussion and decreased breathing sounds in the left or, less commonly, in the right hemithorax suggest pleural effusion secondary to AP.
Diagnosis The cornerstone of the diagnosis of AP are the clinical findings plus an elevation of pancreatic enzyme levels in the plasma. A threefold or higher elevation of amylase and lipase levels confirms the diagnosis. Amylase's serum half-life is shorter as compared with lipase. In patients who do not present to the emergency department within the first 24 or 48 hours after the onset of symptoms, determination of lipase levels is a more sensitive indicator to establish the diagnosis. Lipase is also a more specific marker of AP because serum amylase levels can be elevated in a number of conditions, such as such as peptic ulcer disease, mesenteric ischemia, salpingitis, and macroamylasemia. Patients with AP are typically hyperglycemic; they can also have leukocytosis and abnormal elevation of liver enzyme levels. The elevation of alanine aminotransferase levels in the serum in the context of AP confirmed by high pancreatic enzyme levels has a positive predictive value of 95% in the diagnosis of acute biliary pancreatitis.[6]
Imaging Studies Although simple abdominal radiographs are not useful to diagnose pancreatitis, they can help rule out other conditions, such as perforated ulcer disease. Nonspecific findings in patients with AP include air-fluid levels suggestive of ileus, cutoff colon sign as a result of colonic spasm at the splenic flexure, and widening of the duodenal C loop caused by severe pancreatic head edema. The usefulness of ultrasound to diagnose pancreatitis is limited by intra-abdominal fat and increased intestinal gas as a result of the ileus. Nevertheless, this test should always be ordered in patients with AP because of its high sensitivity (95%) in diagnosing gallstones. Combined elevation of liver transaminase and pancreatic enzyme levels, and the presence of gallstones on ultrasound, have an even higher sensitivity (97%) and specificity (100%) for diagnosing acute biliary pancreatitis. Contrast-enhanced computed tomography (CT) is currently the best modality to evaluate the pancreas, especially if the study is performed using a multidetector CT scanner. The most valuable contrast phase to evaluate the pancreatic parenchyma is the portal venous phase (65 to 70 seconds after contrast injection), which allows evaluation of the viability of the pancreatic parenchyma amount of peripancreatic inflammation and presence of intra-abdominal free air or fluid collections. Noncontrast CT scanning may also be of value in the setting of renal failure by identifying fluid collections and/or extraluminal air.[9] Abdominal magnetic resonance imaging (MRI) is also useful to evaluate the extent of necrosis, inflammation, and presence of free fluid. However, its cost and availability, and the fact that patients requiring imaging are critically ill and need to be in intensive care units, limit its applicability in the acute phase. Although magnetic resonance cholangiopancreatography (MRCP) is not indicated in the acute setting of AP, it has an important role in the evaluation of patients with unexplained or recurrent pancreatitis because it allows complete visualization of the biliary and pancreatic duct anatomy. In addition, IV administration of secretin increases pancreatic duct secretion, which causes a transient distention of the pancreatic duct. For example, secretin MRCP is useful in patients with AP and no evidence of a predisposing condition to rule out pancreas divisum, intraductal papillary mucinous neoplasm (IPMN), or the presence of a small tumor in the pancreatic duct.[9] In the setting of gallstone pancreatitis, endoscopic ultrasound (EUS) may play an important role in the evaluation of persistent choledocholithiasis. Several studies have shown that routine ERCP for suspected gallstone pancreatitis reveals no evidence of persistent obstruction in most cases and may actually worsen symptoms because of manipulation of the gland. EUS has been proven to be sensitive for identifying choledocholithiasis; it allows for examination of the biliary tree
and pancreas with no risk of worsening the pancreatitis. In patients in whom persistent choledocholithiasis is confirmed by EUS, ERCP can be used selectively as a therapeutic measure.
Assessment of Severity of Disease The earliest scoring system designed to evaluate the severity of AP was introduced by Ranson and colleagues in 1974.[10] It predicts the severity of the disease based on 11 parameters obtained at the time of admission and/or 48 hours later. The mortality rate of AP directly correlates with the number of parameters that are positive. Severe pancreatitis is diagnosed if three or more of the Ranson criteria are fulfilled. The main disadvantage is that it does not predict the severity of disease at the time of the admission because six parameters are only assessed after 48 hours of admission. Ranson's score has a low positive predictive value (50%) and high negative predictive value (90%). Therefore, it is mainly used to rule out severe pancreatitis or predict the risk of mortality.[11] The original scoring symptom designed to predict the severity of the disease and its modification for acute biliary pancreatitis are shown in Boxes 56-1 and 56-2.
Box 56-1 Ranson's Prognostic Criteria for Gallstone Pancreatitis At presentation • Age >70 yr • Blood glucose level >220 mg/dL • WBC >18,000 cells/mm3 • Lactate dehydrogenase level >400 IU/liter • Aspartate aminotransferase level >250 IU/liter After 48 hours of admission • Hematocrit[*]: Decrease >10% • Serum calcium level 5 mEq/L • Blood urea nitrogen level[†]: Increase >2 mg/dL • Fluid requirement >4 liters • Pao2: Not available Ranson score ≥3 defines severe pancreatitis. * As compared with admission value.
Box 56-2 Ranson's Prognostic Criteria for Nongallstone Pancreatitis At presentation • Age >55 yr • Blood glucose level >200 mg/dL • WBC >16,000 cells/mm3 • Lactate dehydrogenase level >350 IU/L • Aspartate aminotransferase >250 IU/L After 48 hours of admission • Hematocrit[*]: Decrease >10% • Serum calcium level 4 mEq/L • Blood urea nitrogen level[†]: Increase >5 mg/dL • Fluid requirement >6 liters • Pao2
