Figure 1

Magnetic Resonance Cholangiopancreatography Images

A. Image before secretion stimulation

B. Image after secretion enhances pancreatic duct, showing pancreas divisum

Figure 2

Endoscopic Images

A. Endoscopic necrosectomy after endoscopic ultrasound-guided cystgastrostomy

B. Endoscopic view inside the necrotic cyst cavitiy prior to undertaking endoscopic debridement

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June 2008 | Back to Table of Contents

Clinical and Health Affairs

Approach to Acute, Recurrent, and Chronic Pancreatitis

By Timothy P. Kinney, M.D., and Martin L. Freeman, M.D.

Abstract
Pancreatitis can manifest as a one-time episode, recurring attacks, or chronic pain. It is caused by numerous factors ranging from alcohol consumption to gallstones to subtle obstructive causes and occult autoimmune disorders. As a result, determining the etiology and effectively treating the causes and consequences of pancreatitis can be challenging. This article reviews the diagnosis and management of acute, acute recurrent, and chronic pancreatitis, focusing on more challenging scenarios.


Like most medical disorders, pancreatitis can manifest in a variety of ways, from severe, fulminant, and life-threatening disease to ongoing or “smoldering” disease with minimal laboratory abnormalities. Some patients experience a single episode, while others can have recurrent attacks. Still others with minimal-change chronic pancreatitis may present only with intractable pain. Thus, in some patients, pancreatitis can be difficult to diagnose and treat.

Traditionally, the physician’s only options for diagnosis were laboratory tests such as amylase and lipase, and standard imaging such as ultrasound and computerized tomography (CT). Now, safe-but-sophisticated noninvasive or minimally invasive imaging of the pancreaticobiliary tree is available with secretin-stimulated magnetic resonance cholangiopancreatography (MRCP), which shows the pancreatic and bile ducts, and endoscopic ultrasound (EUS), in which an ultrasound transducer is placed on the end of a flexible peroral endoscope. Both allow for detection of subtle disease and aid in management of severe disease.1

Diagnosing Pancreatitis
Diagnosing acute pancreatitis is often straightforward, as most patients present with epigastric pain, nausea, vomiting, and dehydration. Serum amylase and lipase are almost universally elevated in patients with acute pancreatitis. The exception to this rule is longstanding chronic pancreatitis, a condition in which the patient may no longer produce a measurable biochemical response because of a “burned out” pancreas. Diagnosing subtle chronic pancreatitis can be difficult and is discussed later on.

Abdominal ultrasound, which is inexpensive and readily available, is often the first imaging test performed in patients with suspected pancreatitis. Ultrasound can show an edematous pancreas or identify pancreatic fluid collections in patients with severe disease, although bowel gas and abdominal pain associated with the exam can hinder imaging. Abdominal ultrasound is most beneficial in assessing for gallstones, which may suggest an etiology for the pancreatitis. Bile duct stones, however, are often missed by ultrasound. Duct diameter can be measured easily using ultrasound, although a dilated bile duct may or may not indicate truly obstructive pathology.

Computerized tomography can identify pancreatic edema, fluid collections, and pancreatic necrosis in patients with acute pancreatitis. Necrosis can take a few days to develop, and intravenous contrast-enhanced CT is most useful when performed 72 hours after the initial onset of symptoms. This allows time for aggressive rehydration with IV fluids and reduces the risk of contrast-induced nephropathy.2 Computerized tomography can also be used to grade the severity of pancreatitis, which can help direct patient management.3,4

Computerized tomography is also an excellent way to diagnose chronic calcific pancreatitis. However, in patients with symptoms of chronic pancreatitis, the severity seen on imaging does not always correlate with the severity of symptoms. Diagnosing patients who experience chronic pancreatic-type abdominal pain but who only have subtle or no findings on conventional imaging can be a challenge, and there is debate among experts as to which imaging modalities and criteria best establish this diagnosis. For diagnosis of “minimal change” chronic pancreatitis, EUS is the most sensitive method.5 Endoscopic ultrasound, as well as MRCP, is also useful for imaging patients with more advanced cases of pancreatitis.

Magnetic resonance cholangiopancreatography can be used to establish the anatomy of the bile and pancreatic ducts and show bile duct stones and abnormalities such as pancreas divisum, pancreatic ductal dilation, or strictures. It also can provide a roadmap of the pancreatic and biliary ducts to facilitate selective cannulation and target therapy during endoscopic retrograde cholangiopancreatography (ERCP). Administration of secretin during MRCP stimulates secretion of pancreatic juices, thereby not only enhancing the imaging of the pancreatic duct but also providing functional information about the presence and severity of outflow obstruction at a stricture or at the pancreatic sphincter (Figure 1). At our center, secretin-enhanced MRCP is obtained routinely for patients with pancreatic disease and has completely supplanted diagnostic ERCP, a more invasive procedure that is associated with significant risk of complications.6

Magnetic resonance cholangiopancreatography has the advantage of being noninvasive. It is, however, limited by a lack of sensitivity and specificity for detection of small bile duct stones, microlithiasis, and small pancreatic tumors. Also, the quality of MRCP varies substantially between centers, and MRCP is contraindicated in patients with pacemakers and cerebral aneurysm clips, and those who have had injuries that leave metal fragments such as schrapnel in the body.

Although more invasive than MRCP, EUS carries minimal risk when compared with ERCP, and it is the best method for diagnosing occult pancreatic tumors including neuroendocrine tumors, intraductal papillary and mucinous neoplasia, and small adenocarcinomas. Endoscopic ultrasound is also highly sensitive for detecting occult biliary tract disease including gallstones, biliary sludge, or choledocholithiasis. Endoscopic ultrasound is a sensitive test for chronic pancreatitis and can identify intraductal pancreatic stones that may be missed by CT. The primary limitation of EUS is its lack of availability because of the shortage of well-trained endoscopists. In our institution, EUS is the procedure of choice for the initial evaluation of unexplained acute and recurrent pancreatitis; it is complementary to secretin-stimulated MRCP.

Acute Pancreatitis
Establishing an etiology for acute pancreatitis is important in order to prevent recurrent attacks. The most common etiologies—alcohol, gallstones, hypertriglyceridemia, and certain medications—can be elucidated by taking a careful history and performing basic lab and imaging studies. If the initial episode of pancreatitis doesn’t lead to necrosis or ductal damage, appropriate treatment (abstinence from alcohol, cholecystectomy, etc.) will usually result in no further pancreatic problems.

Regardless of etiology, all patients with acute pancreatitis should receive the same initial treatment, including intravenous fluids and pain management. Arguably, this is the most important and simplest treatment for early acute pancreatitis, as pancreatitis causes severe third-spacing of intravascular volume, and patients presenting with acute pancreatitis are often severely dehydrated. Patients with severe pancreatitis are at risk for acute renal failure and hypotension, which are exacerbated by intravascular dehydration. It is theorized that hemoconcentration and hypoperfusion can cause ischemia and further damage to the organ.

Predicting the severity of disease is important so that patients with poor prognostic signs are monitored closely. Although Ranson’s criteria were widely used in the past, the most accurate predictors of severity of pancreatitis are the Apache II score, presence of organ failure, and the CT severity index.3,7 Elevated serum hematocrit on presentation, indicating hemoconcentration, has recently been proposed as another predictor of poor outcome.2,8

Most patients with acute biliary pancreatitis, which is caused by obstruction of the pancreatic duct by a stone that becomes lodged at the junction of the bile and pancreatic ductal systems, will recover completely within a week or so. Although ERCP is sometimes required to clear an obstructing gallstone, the offending stone will spontaneously pass into the duodenum in more than 70% of cases.9 Some form of intervention such as cholecystectomy or at least a biliary sphincterotomy is almost always recommended for treating patients with biliary pancreatitis. Biliary pancreatitis has been shown to recur in 29% to 67% of patients who do not undergo subsequent cholecystectomy or biliary sphincterotomy.9 Routine preoperative ERCP in patients who are planning to undergo cholecystectomy is not indicated unless there is evidence of a persistent bile duct stone or cholangitis by imaging or laboratory studies. Intraductal stones can be identified at intraoperative cholangiography at the time of surgery. The stones can then be removed postoperatively. In preoperative patients with an intermediate likelihood of having retained bile duct stones, EUS or MRCP can provide further evidence of the severity of the disease and thus help physicians determine whether there is a need for ERCP.

Unlike patients with mild or moderate biliary pancreatitis, patients with severe pancreatitis and retained bile-duct stones have been shown to benefit from early ERCP, defined in research trials as within 72 hours of presentation. Four randomized controlled trials have compared early ERCP with no intervention in patients with biliary pancreatitis.9-12 Data from these studies support early ERCP for patients with severe disease and those with ascending cholangitis to remove a retained bile-duct stone.

The use of antibiotics, especially for severe pancreatitis, is widespread, although the evidence supporting this therapy is very limited. A recent meta-analysis of several randomized controlled trials did not support the routine use of antibiotics in severe pancreatitis unless there is evidence of cholangitis or infected pancreatic necrosis.13,14 Differentiating between these disorders and pancreatitis, however, can be very difficult, as all can manifest with fever and leukocytosis.

For patients with acute injury, resting the pancreas by fasting and providing fluids and electrolytes is standard practice during the initial days following presentation. When the patient begins to show improvement in nausea and pain, slow reintroduction of nourishment can be initiated and increased as tolerated. For patients with severe pancreatitis or for whom a protracted NPO period is expected, early introduction of nutrition is indicated. Whenever possible, enteral feeding is preferable to parenteral nutrition because of maintenance of the barrier between gut and circulation, and because of lower complication and infection rates. If oral or nasojejunal feeding is not tolerated, parenteral nutrition should be considered.

For patients experiencing ongoing pain for several weeks and low-level pancreatic enzyme elevation despite fasting and total parenteral nutrition, ERCP with placement of a transpapillary pancreatic stent can allow for rapid resolution of persistent smoldering pancreatitis. Such patients may have relatively mild disease without significant or dramatic findings on CT scan, but upon refeeding attempts they persistently relapse with pain and elevation of pancreatic enzymes. Placement of a transpapillary stent can interrupt and hasten resolution of the process, regardless of the underlying etiology. Data supporting this approach, however, are limited to a single study reporting 90% efficacy.15

Patients with severe necrotizing pancreatitis need careful monitoring for complications such as infected necrosis, hemosuccous pancreaticus, or multiorgan failure. These patients often require the expertise of multiple specialists including those from intensive care, interventional endoscopy, interventional radiology, and surgery. Pancreatic necrosectomy, once the realm of the surgeon, can be performed endoscopically through the gastric or duodenal wall (Figure 2). Although a grossly infected necrosis in a critically ill patient typically is treated with open surgical debridement, less-invasive procedures such as laparoscopic or endoscopic debridement can be performed in certain patients. If the necrosis persists for several weeks and becomes liquified, percutaneous drainage with very large bore catheters and aggressive flushing can be considered. This, however, can lead to external pancreatic fistulas. Management of these complex patients is best performed at centers with advanced expertise in pancreatic disease.

“Unexplained” Pancreatitis
Conventional methods will reveal no clear etiology for 10% to 30% of patients with acute recurrent pancreatitis.16 These patients are often labeled as having “idiopathic” pancreatitis. The term “unexplained” may be more appropriate, as the diagnosis of “idiopathic pancreatitis” should be reserved for pancreatitis for which the etiology remains unidentified after a truly exhaustive workup.

If a careful history and imaging including transabdominal ultrasound and thin-cut contrast-enhanced pancreatic protocol CT do not produce a diagnosis, further evaluation should be considered, especially if the pancreatitis is severe or has recurred more than once. The type of evaluation needed for these patients can vary widely even among expert centers. Endoscopic retrograde cholangiopancreatography, which was traditionally used to diagnose occult bile duct stones or other disorders of the biliary tree, is now being replaced by newer, less-invasive imaging techniques, in particular MRCP and EUS. These techniques can precisely identify pancreatic pathology, which is the most common source of otherwise unexplained pancreatitis. In the context of recurrent or unexplained pancreatitis, ERCP should now be relegated to therapy that is focused on the exact etiology of the pancreatitis.

♦ Autoimmune Pancreatitis
Autoimmune dysfunction is increasingly recognized as a cause of acute and recurrent pancreatitis.17 Autoimmune pancreatitis is challenging to diagnose and can sometimes be detected by measuring quantitative IgG4 levels in the serum, by biopsy of the papilla during endoscopy with specialized immunohistochemical staining, or by characteristic findings on imaging including CT, MRCP, or EUS. Autoimmune pancreatitis can be associated with other autoimmune diseases such as ulcerative colitis. Recognition is important because it generally responds to corticosteroid treatment. It can also mimic pancreatic cancer and lead to unnecessary surgery.

♦ Microlithiasis and Occult Gallstones
The prevalence and ideal treatment of biliary sludge, microlithiasis, and occult gallstones in patients with acute and unexplained pancreatitis are unknown.18 These patients generally have intact gallbladders and may or may not manifest with liver enzyme abnormalities. Conventional imaging techniques such as CT or transabdominal ultrasound may reveal layering sludge in the gallbladder. Bile analysis may be performed directly on bile-duct aspirates obtained using ERCP. However, for a patient with an intact gallbladder, it may be more prudent to consider empiric laparoscopic cholecystectomy rather than the more risky ERCP. Endoscopic ultrasound is probably the most sensitive test for occult biliary sludge or microlithiasis.

Endoscopic retrograde cholangiopancreatography with empiric biliary sphincterotomy without cholecystectomy for suspected microlithiasis-associated pancreatitis may be appropriate for certain patients, especially elderly ones who are poor surgical candidates and for whom there is a strong suspicion of biliary tract disease. The effectiveness of endoscopic biliary sphincterotomy in preventing future episodes of acute biliary pancreatitis has been demonstrated in several studies.19,20 These uncontrolled case studies show a reduction in the frequency of pancreatitis attacks, although recurrent bile-duct stones and cholecystitis were not prevented. However, ERCP with empirical biliary sphincterotomy can be overused, and in patients without true biliary disease this approach may cause as much pancreatitis as it cures, especially if done using conventional techniques in patients who really have sphincter of Oddi dysfunction.

♦ Sphincter of Oddi Dysfunction
Sphincter of Oddi dysfunction is believed to be an important cause of acute recurrent pancreatitis, and may account for up to one-third of otherwise unexplained cases.21,22 In the majority of cases, effective treatment of sphincter of Oddi dysfunction now incorporates pancreatic as well as biliary sphincterotomy. The diagnosis of sphincter of Oddi dysfunction is usually established by performing manometry of the pancreatic and biliary sphincter, with basal pressures measuring greater than 40mmHg.23 Contrary to popular belief, sphincter of Oddi manometry, as it is currently performed with aspirating catheters, poses no additional risk beyond standard ERCP in these patients. It is important to emphasize that pancreatic stent placement significantly reduces the incidence of post-ERCP pancreatitis in this high-risk group and virtually eliminates the risk of severe pancreatitis. In a randomized controlled trial, incidence of postprocedural pancreatitis was reduced from 27% to 7% with pancreatic stent placement.24 Consistent and safe placement of pancreatic stents requires substantial expertise, as equipment and techniques used for stenting in patients with sphincter of Oddi dysfunction are very different from those used for treating patients with biliary disease. Failure to place a pancreatic stent in a high-risk patient can lead to severe pancreatitis, and conventional use of stents can result in damage to a previously normal duct. With advanced expertise, safe and successful pancreatic stent placement can be done in nearly every patient for whom it is indicated.

♦ Pancreas Divisum
Pancreas divisum, which is present in approximately 7% of the general population, is the most common congenital abnormality of the pancreas.25 Pancreas divisum can be diagnosed with ERCP, MRCP, or EUS—all of which will show an absent or small ventral pancreatic duct that does not communicate with the dorsal duct and a prominent dorsal duct draining entirely through the minor papilla. There is some controversy about whether pancreas divisum is a cause of acute recurrent pancreatitis; however, the majority of evidence suggests that dorsal duct outflow obstruction at the minor papilla can be the etiology of both acute and chronic pancreatitis.26 Patients with divisum have an increased prevalence of pancreatitis, and autopsy studies have shown chronic pancreatitis isolated to the dorsal pancreas in these individuals. Endoscopic therapy for pancreas divisum includes minor papillotomy and short-term stenting of the dorsal pancreatic duct, which can be very challenging. Minor papillotomy is more effective for preventing recurrences of pancreatitis than treating intractable pain.

♦ Pancreatitis Caused by Occult Neoplasm
Perhaps the most important and easily missed cause of unexplained acute pancreatitis is occult neoplastic disease. Ampullary tumors and larger pancreatic tumors can be diagnosed with conventional techniques including CT scan and ERCP. These modalities, however, lack sensitivity for small pancreatic tumors, particularly islet cell or other neuroendocrine tumors and adenocarcinomas measuring less than 2 cm, which are the very tumors that are most important to detect as they generally are surgically resectable at this stage. Endoscopic ultrasound is essential for identifying these small tumors and is substantially more sensitive than CT.

♦ Rare Causes of Pancreatitis
Type III choledochal cysts, annular pancreas, anomalous pancreaticobiliary junction, and pancreatic intraductal parasites have all been reported to cause acute or recurrent pancreatitis. These may be diagnosed by EUS, MRCP, or ERCP and can occasionally benefit from endoscopic intervention, which usually consists of biliary and pancreatic sphincterotomy.

Chronic Pancreatitis
Finding unexpected signs of chronic pancreatitis in a patient with symptoms of acute or recurrent pancreatitis is not uncommon. Some patients may present with chronic pain as the only manifestation of disease. These patients may have a normal or nonspecific CT scan; but further investigation with EUS may reveal moderate-to-severe chronic pancreatitis, sometimes with small intraductal stones or strictures and sometimes with only subtle changes in the appearance of the pancreatic parenchyma. CFTR, cationic trypsinogen, SPINK-1, and other gene mutations have been associated with acute and chronic pancreatitis. The clinical utility of looking for these genetic markers in sporadic cases is limited, however.

Endoscopic pancreatic sphincterotomy, stone extraction, stricture dilation and stenting, and drainage of pancreatic fluid collections and pseudocysts can all play a role in the treatment of patients with chronic pancreatitis and may reduce the incidence of recurrent flare-ups and chronic pain.27,28 A substantial number of these patients, however, fail to respond to even the most aggressive endoscopic therapy and may suffer from severe intractable abdominal pain. These patients are usually relegated to chronic pain management, which is often unsatisfactory, and may suffer from severe disability in what would otherwise be the prime of their lives.

A novel approach to treating these patients, which was developed at the University of Minnesota and is performed there routinely, is total pancreatectomy with autologous islet cell transplantation. Total pancreatectomy generally has been avoided because of the severity of resultant diabetes. The development of the process to isolate and transplant back the patient’s own islet cells via the portal vein has allowed patients to benefit from definitive pain relief with prevention or minimized risk of subsequent diabetes.29 Recently, the world’s first minimally invasive total pancreatectomy with autologous islet cell transplant was performed at the University of Minnesota using laparoscopic and da Vinci robotic surgical techniques.

Summary
The etiology of acute pancreatitis can be elucidated in the majority of patients by taking a careful history and doing basic lab work and imaging studies. In patients with severe acute pancreatitis and those who clearly have biliary obstruction because of gallstones, conventional ERCP with biliary sphincterotomy is well-indicated. Aggressive hydration with intravenous fluids is the simplest but perhaps the most important initial step in managing patients with acute pancreatitis, as most patients with pancreatitis will recover with conservative management. The approach to treating patients with severe pancreatitis and pancreatic necrosis should be multidisciplinary, involving critical care, therapeutic endoscopy, surgery, and interventional radiology. In most patients with otherwise unexplained pancreatitis, an exhaustive workup that includes secretin-enhanced MRCP and EUS will establish the diagnosis and etiology. Advanced techniques such as sphincter of Oddi manometry should be considered for remaining patients. Because of the inherent risks associated with ERCP, it should be primarily used therapeutically for recurrent pancreatitis, with attempts to establish diagnosis whenever possible by less-invasive means. MM

Timothy Kinney is an assistant professor of medicine at the University of Minnesota and director of endoscopy at Hennepin County Medical Center. Martin Freeman is a professor of medicine at the University of Minnesota and co-director of the Minnesota Pancreas and Liver Center.
 
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