Pancreatic Disorders

ACUTE PANCREATITIS

Definitions

Acute pancreatitis (AP) is an inflammatory condition of the pancreas that can extend to extrapancreatic tissues. AP is broadly classified as mild or severe. Mild AP is often referred to as interstitial pancreatitis, based on its radiographic appearance. The pancreatic blood supply is preserved in interstital pancreatitis. Severe AP implies organ failure, local complications, or pancreatic necrosis. There is disruption of the pancreatic blood supply in necrotizing pancreatitis, with resulting ischemia.

Different types of fluid collections develop in the setting of AP. Acute fluid collections occur early in the course of AP in the peripancreatic areas and are not encapsulated by a fibrous wall. Acute pseudocysts are well-developed collections of pancreatic juice encapsulated by a nonepithelialized wall of granulation tissue (Fig. 1). Pseudocysts typically form 4 to 6 weeks after an episode of AP. A pseudocyst that has become infected is a pancreatic abscess. Pancreatic abscesses can also form through encapsulation of areas of infected pancreatic necrosis. The terms pancreatic phlegmon and hemorrhagic pancreatitis are no longer used in the current American College of Gastroenterology (ACG) guidelines.

Figure 1 Abdominal computed tomography scan of acute pancreatitis.

Pseudocyst formation can be noted (arrowheads).

When acute pancreatitis occurs on two or more occasions, it is classified as acute recurrent pancreatitis. In some cases, acute recurrent pancreatitis progresses to chronic pancreatitis, characterized by parenchymal fibrosis and loss of exocrine function.

Prevalence

The yearly incidence of AP in the United States is approximately 17 new cases per 100,000 popuation. Acute pancreatitis results in more than 100,000 hospitalizations per year. Eighty percent of cases of AP are mild; the remaining 20% are severe. Approximately 2000 patients per year die from complications related to AP.

Etiology

Gallstones and alcohol are the two most common causes of AP in Western countries, accounting for 80% of cases. Gallstone (biliary) pancreatitis results from transient obstruction of the ampulla of Vater by small stones or crystals (microlithiasis). Clinical features suggesting biliary pancreatitis include preceding biliary colic, the presence of cholelithiasis or biliary dilation on gallbladder ultrasound, and liver function test abnormalities. Biliary pancreatitis typically does not recur after cholecystectomy or endoscopic therapy (biliary sphincterotomy and stone extraction). Alcohol is the second leading cause of AP. Acute recurrent pancreatitis from alcohol often leads to chronic pancreatitis.

Numerous less-common causes have been described (Box 1). Hypertriglyceridemia produces acute pancreatitis if triglyceride levels are above 1000 mg/dL. Markedly elevated triglyceride levels may be encountered in the setting of diabetes, alcoholism, and inherited disorders of lipoprotein metabolism (Fredrickson types I, II, and V). Hypercalcemia produces AP through calcium-mediated activation of trypsinogen and subsequent glandular autodigestion. Hypercalcemia-associated AP can occur in the setting of primary and secondary hyperparathyroidism, malignancy, and metabolic bone disease. Certain medications (e.g., sulfa drugs, 6-mercaptopurine, didanosine, furosemide, and valproate) have also been implicated as causes of acute pancreatitis.

Obstruction of the pancreatic duct can produce acute or chronic pancreatitis. Causes of obstructive AP include ductal adenocarcinoma, ampullary tumors and polyps, neuroendocrine and cystic pancreatic tumors, and intraductal papillary mucinous tumors. Congenital abnormalities such as pancreas divisum and annular pancreas can also result in obstructive AP in adult patients.

Pathophysiology

The pathogenesis of AP has been studied extensively using animal models. Although different etiologies produce distinct inciting events, the final common pathway is premature activation of enzymes. Ordinarily, pancreatic proenzymes become activated on release within the duodenum. Pancreatitis results when activation of pancreatic enzymes occurs early within the acinar cells, producing autodigestion of the pancreas and surrounding tissues. Exposure of trypsinogen to lysosomal enzymes such as cathepsin B has been shown as a mechanism for early trypsin activation.

Signs and Symptoms

Acute pancreatitis manifests with the sudden onset of epigastric pain radiating to the back. The pain may be severe and worsens after meals. Abdominal pain can last for days and is associated with anorexia, nausea, and vomiting. In alcohol-related AP, pain occurs from hours to days after binge drinking. Most patients present to the emergency department. However, occasional patients manage their symptoms at home by minimizing oral intake for a few days.

Physical examination often reveals systemic signs such as fever, tachycardia, and hypotension. Abdominal examination reveals epigastric tenderness, with localized guarding and rebound. Sluggish or absent bowel sounds indicate coexisting ileus. Less-frequent findings signal complications, including Grey Turner’s (flank ecchymosis) or Cullen’s (umbilical ecchymosis) signs suggesting retroperitoneal hemorrhage, a palpable mass suggesting a pseudocyst, panniculitis suggesting subcutaneous fat necrosis, and dullness to percussion of lung fields suggesting pleural effusion. The differential diagnosis of upper gastrointestinal bleeding in acute pancreatitis includes erosion of a pseudocyst into the splenic artery (hemosuccus pancreaticus) or bleeding from gastric varices that arise secondary to splenic vein thrombosis.

Diagnosis

The diagnosis of AP is supported by an elevation of the serum amylase and lipase levels in excess of three times the upper limit of normal. These enzyme levels are elevated because of leakage from pancreatic acinar cells into the interstitial space and subsequent absorption into the circulation. The amylase level becomes elevated within hours of the development of pain and can remain elevated for 3 to 5 days. The differential diagnosis for hyperamylasemia includes intestinal obstruction, visceral perforation, tubo-ovarian abscess, renal failure, and salivary gland disease. Macroamylasemia is a condition in which amylase is chronically elevated because of its binding to an abnormal serum protein, leading to delayed clearance. Serum lipase has higher specificity for pancreatic disease, but its level may be elevated in other conditions as well. The severity of pancreatitis does not correlate well with the magnitude of elevation of the serum amylase and lipase levels. There is no value in following daily trends of serum amylase and lipase levels because they do not correlate with recovery or prognosis.

Laboratory abnormalities encountered in AP include hyperglycemia, hypocalcemia, leukocytosis, and mild elevations of liver function test results. Elevation of the serum alanine aminotransferase level to greater than 80 U/mL is highly specific and poorly sensitive for biliary pancreatitis. An elevated hematocrit at admission is now recognized as an important marker of severity in AP.

Simple plain films of the chest and abdomen are appropriate for the initial radiographic assessment of AP. An abdominal radiograph is helpful for excluding other causes of acute abdominal pain, such as obstruction and perforation. In AP, the abdominal radiograph is typically normal or might demonstrate ileus. A chest radiograph can detect pulmonary complications of AP such as atelectasis, pleural effusions (most commonly left-sided), or infiltrates suggesting acute respiratory distress syndrome.

Although transabdominal ultrasound is poorly reliable for imaging the pancreas itself, it is the best initial radiographic test for the evaluation of mild AP because it detects gallstones as a potential cause, it rules out acute cholecystitis as a differential cause of pain and hyperamylasemia, and it detects biliary dilation, which suggests the need for early endoscopic retrograde cholangiopancreatography (ERCP).

Contrast-enhanced computed tomography (CT) of the abdomen is the preferred test for evaluating severe pancreatitis and detecting complications. CT features in interstitial pancreatitis include homogenous contrast enhancement; diffuse or segmental pancreatic enlargement; irregularity, heterogeneity, and lobularity of the pancreas; and obliteration of the peripancreatic fat planes. CT detects areas of pancreatic necrosis (Fig. 2), which significantly influences subsequent management. The presence of necrosis predicts a substantial increase in mortality compared with interstitial pancreatitis. A CT should not be routinely ordered for all patients with AP; however, the ACG practice guidelines state that “a dynamic contrast-enhanced CT is recommended at some point beyond the first 3 days in severe acute pancreatitis (on the basis of a high APACHE score or organ failure) to distinguish interstitial from necrotizing pancreatitis.” It is unlikely that intravenous contrast worsens or precipitates pancreatic necrosis, and abdominal CT should generally not be withheld on this basis. A CT may also be considered for those in whom a localized pancreatic complication is suspected (e.g., pseudocyst, splenic vein thrombosis, splenic artery aneurysm). A CT is also appropriate 4 to 6 weeks after resolution of AP to exclude a tumor if the cause of the attack is unclear.

Figure 2 Computed tomography appearance of necrotizing pancreatitis.

The image on the left is before contrast. The image on the right is after contrast. The lack of contrast enhancement of the entire gland suggests areas of necrosis.

Endoscopic ultrasound (EUS) and magnetic resonance cholangiopancreatography (MRCP) are emerging as potentially valuable tests in the evaluation of AP. Both are helpful in detecting stones in the common bile duct and in directly assessing the pancreatic parenchyma. Magnetic resonance imaging is similar or superior to contrast CT in its ability to stage AP and detect necrosis and complications, and it does not require intravenous contrast.

Treatment

Supportive Care

The primary goals of therapy in AP are meticulous supportive care and prevention of pancreatic necrosis, infection, and organ failure. The primary treatment is pancreatic rest and analgesia. Patients should be given nothing by mouth, and intravenous fluids should be given with careful attention to volume status. The ACG guidelines state, “all patients should receive close supportive care including pain control, fluid resuscitation, and nutritional support.” A therapeutic algorithm closely based on the ACG guidelines is shown in (Fig. 3).

Figure 3 Approach to the management of acute pancreatitis.

This algorithm is based on the practice guidelines from the American College of Gastroenterology. CT, computed tomography; US, ultrasound.

The importance of vigorous hydration to optimize outcomes has been increasingly recognized. The ACG guidelines stress, “Patients with evidence of significant third-space losses require aggressive fluid resuscitation.” Many patients sequester substantial amounts of fluid into the retroperitoneal space, producing very high fluid requirements. Intravascular volume depletion can lead to tachycardia, hypotension, renal failure, hemoconcentration, and generalized circulatory collapse. More than 6 L of fluid sequestration within the first 48 hours is considered a marker of increased severity, according to the Ranson criteria (Box 2). Patients with evidence of hemoconcentration resulting from intravascular water loss appear to be at increased risk for the development of pancreatic necrosis and organ failure. In addition to maintenance fluid requirements, the amount sequestered should be monitored and replaced with isotonic fluids such as normal saline, with a goal of euvolemia and hemodilution. Some patients require as much as 250 to 350 mL/hour, particularly in the early phases of AP. Of course, the aggressiveness of fluid replacement must be tempered in the presence of underlying cardiac or renal disease.

Oral intake should be severely limited initially and then carefully advanced as pain subsides and hunger returns. Carbohydrate-containing foods are best for early refeeding because they do not stimulate the pancreas as much as fat- and protein-containing foods. A nasogastric tube is necessary only in the presence of vomiting or ileus. Intravenous narcotics by injection or by patient-controlled analgesia should be used liberally during the attack and tapered as the diet is advanced to enable prompt bowel recovery.

The ACG guidelines advise nutritional support if NPO status is maintained for longer than 5 to 7 days. All patients with severe AP should receive nutritional support because of the inherently high level of stress and hypercatabolism. Nasojejunal feeding past the ligament of Treitz does not stimulate the pancreas and is preferred over parenteral feeding because of decreased infection complication rates. Studies have shown improved humoral and cellular immunity, decreased systemic inflammatory response, and decreased bacterial translocation for enteral feeding compared with parenteral nutrition. The presence of a severe intestinal ileus or delay in tube placement can limit the use of enteral feeding. Many patients with AP develop gastric and colonic ileus but maintain adequate small bowel motility for enteral feeding.

Assessment of Severity

An important initial step in management is the assessment of severity by clinical and radiographic criteria. Severe AP implies organ failure or pancreatic necrosis and carries a mortality rate of 10%. According to the ACG guidelines, severe pancreatitis is recognized on the basis of early clinical prognostic signs, evidence of organ failure, or local complications. Early recognition of severe pancreatitis improves outcomes by prompting aggressive fluid resuscitation and transfer of the patient to an intensive care unit.

Several clinical and radiographic severity scores have been proposed. The Ranson score was developed for alcoholic AP and comprises five clinical criteria measured at admission and six clinical criteria measured at 48 hours (see Box 2). The criteria measured at admission reflect the local inflammatory effects of pancreatic enzymes; those measured at 48 hours represent the later systemic effects. Three or more Ranson criteria predict a severe course and increased mortality. The APACHE II and III scores (acute physiology, age, chronic health evaluation) are generated from multiple parameters and are considered highly accurate. APACHE scores allow prediction of severity from the day of admission and may be recalculated on a daily basis. Unfortunately, the APACHE score is rarely used in clinical practice because of its time-consuming and cumbersome nature.

In addition to formal scoring systems, patients should be followed closely for other markers of increased severity, including signs of hemodynamic instability or organ failure. Respiratory failure can occur through the development of large pleural effusions or acute respiratory distress syndrome. Rarely, hemorrhage into retroperitoneal tissues results in further hemodynamic compromise. Extra vigilance for these complications will result in more timely and aggressive management and improved patient outcomes.