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Table of Contents

Published April 8, 2005

Tyler
Stevens, MD

Department of
Gastroenterology
and Hepatology

Darwin L. Conwell, MD

Department of
Gastroenterology
and Hepatology

Print Chapter

Definitions

Prevalence

Etiology

Pathophysiology

Signs and
Symptoms

Diagnosis

Therapy

Outcomes

References

Acute pancreatitis (AP) is an acute inflammatory condition of the pancreas that may extend to local and distant extrapancreatic tissues.¹ The American College of Gastroenterology (ACG) practice guidelines provide acceptable terminology for the classification of AP and its complications.² AP is broadly classified as mild or severe. Mild AP is often referred to as interstitial pancreatitis, based on its radiographic appearance. Severe AP implies the presence of organ failure, local complications, or pancreatic necrosis. Interstitial pancreatitis implies preservation of pancreatic blood supply; necrosis suggests the disruption of pancreatic blood supply with resulting ischemia.

Abdominal CT of acute pancreatitis with pseudocyst formation (arrows).

Figure 1

Different types of fluid collections develop in the setting of AP, including acute fluid collections, acute pseudocysts, and pancreatic abscesses. Acute fluid collections occur early in 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 (Figure 1). Pseudocysts typically form 4 to 6 weeks after an episode of AP. A pseudocyst that has become infected is a pancreatic abscess (Figure 2). Pancreatic abscesses may also form through encapsulation of areas of infected pancreatic necrosis. The terms pancreatic phlegmon and hemorrhagic pancreatitis are no longer used in the current ACG guidelines.

When acute pancreatitis occurs on two or more occasions (evidenced by elevation of the serum pancreatic enzymes), it is classified as acute recurrent pancreatitis. In some cases, acute recurrent pancreatitis progresses to chronic pancreatitis, implying the presence of parenchymal fibrosis and loss of glandular function.

Gallstones and alcohol are the two most common causes of AP in western countries, accounting for 80% of cases. Gallstone pancreatitis results from transient obstruction of the ampulla of Vater by small stones or edema. Clinical features include preceding biliary colic, the presence of cholelithiasis or biliary dilatation on gallbladder ultrasound, and liver function test abnormalities. Gallstone pancreatitis typically does not recur after cholecystectomy and/or endoscopic therapy (biliary sphincterotomy and stone extraction). Alcohol is the second leading cause of AP, which typically occurs after episodes of binge drinking. After recurrent episodes, most alcoholics go on to develop chronic pancreatitis (See Disease Management chapter on Chronic Pancreatitis).

Numerous less-common causes have been described (Table 1).⁴ Hypertriglyceridemia produces acute pancreatitis if triglyceride levels are above 1,000 mg/dL. Markedly elevated triglyceride levels may be encountered in the setting of diabetes, alcoholism, and inherited disorders of lipoprotein metabolism (Frederickson types I, II, and V). Hypercalcemia produces AP through calcium-mediated activation of trypsinogen and subsequent glandular autodigestion. Hypercalcemia-associated AP may occur in the setting of primary and secondary hyperparathyroidism, malignancy, and metabolic bone disease. In recent years, numerous genetic mutations have been associated with the development of acute and chronic pancreatitis. These include mutations of cationic trypsinogen (hereditary pancreatitis), serine protease inhibitor Kazal type 1 (SPINK-1), and the cystic fibrosis transmembrane regulator (CFTR) gene. Numerous case reports and case series have implicated specific medications as causes of acute pancreatitis (Table 2); however, the strength of these associations varies.

Obstruction of the pancreatic duct may produce acute or chronic pancreatitis. Specific causes of obstructive AP include ductal adenocarcinoma, ampullary tumors and polyps, neuroendocrine and cystic pancreatic tumors, and intraductal papillary mucinous tumor. Pancreatic tumors should be kept in the differential diagnosis, particularly in older patients. Occasionally, congenital abnormalities of the pancreas such as pancreas divisum and annular pancreas produce obstructive AP in adult patients.

Acute pancreatitis presents with the sudden onset of epigastric pain radiating to the back. The pain may be severe and characterized as deep and boring. Eating food worsens pain; bending forward ameliorates pain. In AP precipitated by alcohol, pain occurs from hours to days after binge drinking. Abdominal pain lasts for days and is associated with anorexia, nausea, and vomiting. 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 frequently 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 (flank ecchymosis) or Cullen (umbilical ecchymosis) signs suggestive of retroperitoneal hemorrhage, a palpable mass suggestive of a pseudocyst, panniculitis suggestive of subcutaneous fat necrosis, and dullness to percussion of lung fields suggestive of 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.

According to the ACG guidelines,² the diagnosis of AP is supported by an elevation of the serum amylase and lipase in excess of three times the upper limit of normal. These enzymes are elevated because of leakage from pancreatic acinar cells into the interstitial space and subsequent absorption into the circulation. Amylase becomes elevated within hours of the development of pain and may remain elevated for 3 to 5 days. The differential diagnosis for hyperamylasemia includes several intestinal and extraintestinal disorders (Table 3). 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 may be elevated in other conditions as well. The severity of pancreatitis does not correlate well with the magnitude of elevation of serum amylase and lipase.⁶ There is no value in following daily trends of serum amylase and lipase as they do not correlate with recovery or prognosis.

Laboratory studies to allow calculation of Ranson scores on admission and 48 hours later should be ordered. Specific abnormalities encountered in AP include hyperglycemia, hypocalcemia, leukocytosis, and mild elevations of the liver function tests. Elevation of the serum alanine aminotransferase greater than 80 U/mL is highly specific but poorly sensitive for gallstone pancreatitis.⁷ Experimental biochemical markers that may hold promise for assessing severity of disease include trypsinogen activation peptide, interleukin-6, interleukin-10, and C-reactive protein.⁸

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 frequently normal or may demonstrate ileus. A chest radiograph can detect pulmonary complications of AP such as atelectasis, pleural effusions (most commonly left-sided), or infiltrates suggestive of adult 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:

1. it detects gallstones as a potential cause, it rules out acute cholecystitis as a differential cause of pain and hyperamylasemia, and
2. it detects biliary dilatation suggestive of 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 (Figure 3).

Abdominal CT showing interstitial pancreatitis. The pancreas is irregular and ill-defined, with blurring of the peripancreatic fat planes (arrows).

Figure 3

Importantly, CT detects areas of pancreatic necrosis (Figure 4), which significantly influences subsequent management. The presence of necrosis confers a substantial increase in mortality compared with interstitial pancreatitis (Table 4). The severity of pancreatitis detected on CT may be staged based on the Balthazar system (Table 5).⁹ 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."² A CT should also be considered for those in whom a localized pancreatic complication is suspected (eg, pseudocyst, splenic vein thrombosis, splenic artery aneurysm). CT is also appropriate after resolution of AP to exclude a tumor if the cause of the attack is unclear. It is highly controversial whether intravenous contrast worsens or precipitates pancreatic necrosis, and abdominal CT should generally not be withheld on this basis.¹⁰

Endoscopic ultrasound 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 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. Operator dependence and expense limit the widespread availability of EUS and MRCP. ERCP allows identification and removal of common-bile-duct stones in suspected gallstone pancreatitis (Figure 5). Because of its invasive nature and the inherent risk of worsening pancreatitis, it should be performed only in the setting of ongoing biliary obstruction and cholangitis.

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 kept NPO, 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."² A therapeutic algorithm closely based on the ACG guidelines is shown in Figure 6.

In recent years, 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."² Many patients sequester substantial amounts of fluid into the retroperitoneal space, producing very high fluid requirements. Intravascular volume depletion may lead to tachycardia, hypotension, renal failure, hemoconcentration, and generalized circulatory collapse. More than 6 liters of fluid sequestration within the first 48 hours is considered a marker of increased severity according to the Ranson criteria (Table 6). 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.¹¹ 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 may require as much as 250 to 350 mL/hr, 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 as 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 patient-controlled analgesia should be used liberally during the attack and tapered as diet is advanced to enable prompt bowel recovery.

Nutrition support may be withheld in mild pancreatitis for several days. The ACG guidelines advise nutrition support if NPO status is maintained for longer than 5 to 7 days.² All patients with severe AP should receive nutrition 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 infectious complication rates.¹² 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 may limit the use of enteral feeding. Many patients with AP develop gastric and colonic ileus but maintain adequate small-bowel motility, permitting enteral feeding.

Assessment of Severity:

An important initial step in management is the assessment of severity by clinical and radiographic criteria. Although AP is usually mild, a subset of patients develops a severe course. Severe AP implies organ failure or pancreatic necrosis and carries a mortality rate of 40%. Patients with severe AP should be administered close supportive care in an intensive care unit setting. According to the ACG guidelines, severe pancreatitis is recognized on the basis of early clinical prognostic signs, evidence of organ failure, or local complications (pancreatic necrosis or abscess).² Early recognition of severe pancreatitis improves outcomes by prompting aggressive fluid resuscitation and transfer of the patient to an intensive care unit. Therefore, it is critical that early classification of severity be made for every patient admitted with AP.

Multiple clinical and radiographic severity scores have been proposed. Initially studied in patients with alcoholic acute pancreatitis, the Ranson score comprises five clinical criteria measured at admission and six measured at 48 hours (Table 6). 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 and should prompt ICU transfer and CT scan to rule out pancreatic necrosis.

The APACHE II and III scores (acute physiology, age, and chronic health evaluation) are generated from multiple parameters and are considered highly accurate.³ Furthermore, APACHE scores allow prediction of severity from the day of admission and may be recalculated on a daily basis. Unfortunately, because of the time-consuming and cumbersome nature of the APACHE evaluation, it is rarely used in clinical practice.

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 may occur through the development of large pleural effusions or adult respiratory distress syndrome. Rarely, hemorrhage into retroperitoneal tissues results in further hemodynamic compromise. Hypervigilance for these complications will result in more timely and aggressive management and improved patient outcomes.

Antibiotics:

Because superinfection of pancreatic necrosis dramatically increases the mortality rate of AP compared with sterile necrosis, a major goal in management is the prevention of infection. Some randomized trials suggest a benefit for early initiation of broad-spectrum antibiotics in preventing pancreatic infection.¹³ Antibiotics with good pancreatic tissue penetration, such as imipenem (500 mg IV every 8 hours), cefuroxime (1.5 g IV every 8 hours), or ciprofloxacin (400 mg IV every 12 hours) are favored in this setting. Potential drawbacks of prophylactic antibiotics include the development of resistant organisms and fungal infections. Although antibiotics have been shown to decrease infection rates, they have not consistently demonstrated a mortality benefit. The ACG guidelines recommend that² "in patients with necrotizing pancreatitis associated with organ failure, it is reasonable to initiate treatment with antibiotics with good spectrum of activity against aerobic and anaerobic bacteria."

Endoscopic Retrograde
Cholangiopancreatography (ERCP)
Although the ACG guidelines state that² "patients with severe pancreatitis caused by gallstones should undergo urgent ERCP," there has been much recent debate over the benefit of early endoscopic removal of common-bile-duct stones in suspected gallstone pancreatitis. There is strong evidence to suggest a benefit for ERCP with papillotomy and stone extraction in the setting of stone impaction and cholangitis.¹⁴ However, randomized trials of early ERCP in the management of all patients with suspected gallstone pancreatitis have shown conflicting results. ERCP may further exacerbate acute pancreatitis. The United Kingdom guidelines (from the British Society of Gastroenterology) advise that "severe gallstone pancreatitis in the presence of increasingly deranged liver function tests and signs of cholangitis (fever, rigors, and positive blood cultures) require an immediate and therapeutic ERCP."¹⁵ If there is only moderate suspicion of retained stones, an MRCP is a "no-risk" alternative to ERCP, with excellent sensitivity for the detection of common-bile-duct stones.

Pancreatic Necrosis
Confirmation of the diagnosis of infected pancreatic necrosis is critical because surgical management is indicated. Unfortunately, clinical and radiographic criteria are not sufficiently reliable for detecting pancreatic infection. Infection is confirmed through ultrasound- or CT-guided aspiration of areas of pancreatic necrosis or suspected pancreatic abscesses. This procedure is safe and reliable, and has been recommended for all patients with CT criteria for pancreatic necrosis and evidence of sepsis or organ failure.

The ACG guidelines differentiate necrotizing pancreatitis with and without clinical improvement.² Patients with evidence of slow clinical improvement may be managed expectantly, without needle aspiration; however, "in the absence of clinical improvement, guided percutaneous aspiration should be performed." Other authors have concurred, with an expectant approach to pancreatic necrosis with supportive care and prophylactic antibiotics before consideration of percutaneous aspiration.¹⁶ This approach is reasonable if the patient is hemodynamically stable and has not developed significant organ failure or septic syndrome. It is important to obtain a surgical consultation before consideration of this procedure, given the possible need for surgical debridement.

Surgical Management:

Surgical management of AP is indicated in two clinical settings: infected pancreatic necrosis and gallstone pancreatitis.¹⁷ In the setting of infected pancreatic necrosis, resection of all devitalized pancreatic and surrounding tissue is performed. Multiple reexplorations, continuous irrigation, or laparostomy formation may be required for adequate debridement. Recent studies suggest that a delayed approach to surgical debridement improves outcomes by allowing time for adequate separation of necrotic and vital areas.²¹ Surgical necrosectomy is clearly indicated in the setting of infected necrosis; however, its benefit in sterile necrosis is controversial. Cholecystectomy is indicated to prevent recurrence of gallstone pancreatitis. In mild disease, an early cholecystectomy performed during the same hospitalization is favored. In severe gallstone pancreatitis, cholecystectomy may be delayed until clinical improvement or performed at the time of necrosectomy.

Idiopathic Acute Pancreatitis:

Ten percent of cases of acute pancreatitis are idiopathic (IAP). Potential underlying causes of "idiopathic" pancreatitis include biliary microlithiasis, sphincter of Oddi dysfunction, and undiagnosed genetic defects. Biliary microlithiasis has been implicated as a common cause of IAP.¹⁸ Recurrent acute episodes of pancreatitis may develop in the absence of gallstones on ultrasound, with or without elevated liver enzymes. Repeat ultrasound examinations may eventually reveal biliary sludge or small stones. The finding of cholesterol monohydrate or calcium bilirubinate crystals on microscopic biliary analysis after cholecystokinin stimulation strongly supports the diagnosis of microlithiasis; however, it is not completely sensitive. Laparoscopic cholecystectomy prevents recurrence in patients with IAP and should be considered in all patients with acute recurrent pancreatitis of unclear cause.¹⁹ Endoscopic sphincterotomy or stone dissolution therapy with ursodiol (8 to 10 mg/kg/day, in two divided doses) are valid options in patients with high surgical risk. Stone dissolution therapy is effective only for noncalcified, cholesterol-monohydrate stones less than 1 cm in diameter.

ERCP may be helpful in elucidating the cause of IAP. ERCP allows the detection of ampullary tumors, mucinous ductal ectasia, common-bile-duct stones, pancreas divisum, and pancreatic ductal adenocarcinoma. Biliary manometry allows the diagnosis of sphincter of Oddi dysfunction. ERCP is most strongly indicated in patients who are older than age 40 to rule out neoplasia. MRCP is a safer alternative to ERCP for detection of diseases of the pancreatic duct; however, it is less sensitive for small-duct processes, and does not allow inspection of the ampulla or functional assessment of the sphincter of Oddi. Genetic screening for cationic trypsinogen, SPINK-1, or CFTR gene mutations may be considered in some patients with IAP, although positive results are unlikely to change management.

There are no published guidelines for the approach to recurrent IAP. Laparoscopic cholecystectomy, ERCP/MRCP, and genetic screening each have their advocates as the initial step in the diagnostic workup. Most authors do not favor extensive evaluation for the first episode of IAP, as it does not recur in most patients after the first episode; however, CT after resolution is probably reasonable for excluding pancreatic cancer. It is best to individually tailor the diagnostic approach based on patient characteristics. We favor a laparoscopic cholecystectomy in any patient who develops a second episode of IAP. One suggested approach to the patient with idiopathic recurrent acute pancreatitis is demonstrated in Figure 7.

Mortality rates for hospitalized patients vary from 5-10% in most series. In patients with interstitial pancreatitis, mortality is close to zero. Mortality is substantially increased in necrotizing pancreatitis (10% for sterile, 30% for infected necrosis) (Table 4).

Return to Medicine Index

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