Hospital Medicine

Endoscopic therapy has become an alternative to surgery for some patients with acute recurrent pancreatitis, ie, those whose disease is caused by gallstones or other mechanical processes that can obstruct the outflow from the pancreas.

In this paper, we review the specific situations in which endoscopic therapy might be useful in patients with acute recurrent pancreatitis.

ACUTE PANCREATITIS IS MANAGED DIFFERENTLY IF IT RECURS

Recurrent acute pancreatitis is defined as more than one episode of acute pancreatitis.¹ In clinical practice, it is important to distinguish between the first and recurrent episodes of acute pancreatitis.

Most patients who have one episode of acute pancreatitis never have another one.^2,3 Therefore, for patients having an initial attack, we recommend a limited workup that includes a detailed history, laboratory evaluation, and a noninvasive imaging study such as transcutaneous ultrasonography or computed tomography.

On the other hand, people who have a second attack are at higher risk of more recurrences. Therefore, patients having recurrent attacks need a more extensive workup to determine the underlying cause. We recommend referring them to a gastroenterologist for further evaluation.

WHICH CAUSES CAN BE MANAGED ENDOSCOPICALLY?

In the Western world, 70% to 80% of cases of recurrent pancreatitis are due to either alcohol abuse or gallstone disease.^2,4 The rest are related to:

• Autoimmune disorders
• Cancer, including occult malignancies and premalignant conditions such as intraductal papillary mucinous neoplasm
• Chronic pancreatitis
• Drugs
• Heredity
• Metabolic abnormalities (hypertriglyceridemia, hypercalcemia)
• Sphincter of Oddi dysfunction
• Structural or congenital abnormalities (pancreas divisum)
• Trauma.

• Gallstone disease, including biliary microlithiasis and sludge (in patients with or without a gallbladder)
• Sphincter of Oddi dysfunction
• Pancreas divisum
• Obstruction to flow of pancreatic juice.

Endoscopy is not completely benign

Although endoscopic procedures are less invasive than surgery, they are not completely benign. They can cause anxiety and are associated with risks such as bleeding, perforation, and pancreatitis.⁵ The risks, benefits, and alternatives to these procedures should be discussed with the patient, and informed consent should be obtained before any endoscopic procedure.⁶

STONES (LARGE OR SMALL) OR SLUDGE IN PATIENTS WITH A GALLBLADDER

Gallstones can be large, but small stones (microlithiasis) and sludge are more common and therefore account for more cases of pancreatitis.

Strictly defined, microlithiasis refers to stones smaller than 2 mm in diameter in the biliary tract, whereas sludge is a suspension of biliary crystals, mucin, and cellular debris in the gallbladder or bile ducts.⁷ The terms are often used interchangeably, since the conditions often coexist and their treatment is similar.

Theories differ as to how microlithiasis or sludge can cause recurrent pancreatitis. According to one theory, the debris blocks the common channel, increasing the pancreatic intraductal pressure and leading to pancreatitis.⁸ A second theory is that small stones or biliary crystals passing through the sphincter of Oddi cause inflammation, and that repeated inflammation eventually leads to stenosis or dyskinesia of the sphincter, both of which have been associated with pancreatitis.⁹

Studies suggest that microlithiasis and sludge are common causes of recurrent pancreatitis, accounting for about two-thirds of cases according to estimates by Ros et al¹⁰ and Lee et al.¹¹

Detecting small stones and sludge

The diagnosis of microlithiasis and biliary sludge in patients with a gallbladder is based on imaging studies and bile microscopy.¹²

Transabdominal ultrasonography is the imaging study most often used for diagnosing microlithiasis. The technology and expertise for this test are widely available, and it is relatively inexpensive.

Endoscopic ultrasonography is more sensitive for detecting microlithiasis and can examine the distal common bile duct.

Bile microscopy involves obtaining bile from the second portion of the duodenum (via an endoscope or a duodenal tube) or from the bile ducts (by cannulating the common bile duct and stimulating the gallbladder with cholecystokinin). The bile sample is centrifuged and inspected microscopically under plain light and polarized light (which aids the visualization of biliary crystals). The crystals can be cholesterol monohydrate, calcium bilirubinate, or calcium carbonate.^7,13,14

Removing the gallbladder is the treatment of choice for small stones and sludge

Treatments to prevent recurrent attacks of acute pancreatitis due to microlithiasis and sludge include cholecystectomy, biliary sphincterotomy, and ursodioxycholic acid.^10,11,15

In prospective observational studies by Ros et al¹⁰ and Lee et al,¹¹ about half of the patients with recurrent pancreatitis were treated with cholecystectomy, endoscopic sphincterotomy, or ursodioxycholic acid in a nonrandomized fashion. The choice of therapy was based on the patient’s medical status and the preferences of the patient and the physician. Half the patients received no treatment. In both studies the median follow-up was 4 years. Treated patients had a significantly lower rate of recurrent attacks of pancreatitis during follow-up: less than 20% with therapy compared with more than 60% without therapy. Unfortunately, no published study has compared these three treatments head to head.

Cholecystectomy, however, is the most definitive therapy and is generally considered the treatment of choice.

Biliary sphincterotomy is an endoscopic procedure that involves cutting the sphincter of Oddi to allow the stones and sludge to pass more freely. It is as effective as cholecystectomy in preventing recurrent attacks but does not eliminate the risk of cholecystitis and cholangitis (Figure 1). For this reason, it is usually reserved for patients who cannot tolerate surgery due to comorbidities, those who refuse surgery, or those who are pregnant.¹⁶

Ursodeoxycholic acid is a reasonable alternative in patients who cannot tolerate surgical or endoscopic biliary sphincterotomy.^1,17–20 The dosage is 10 mg/kg/day, which can be in two or three divided doses. The optimal duration of treatment is not known; however, since this drug works slowly, it may need to be taken for 2 years or more. Ursodeoxycholic acid is more effective in patients with cholesterol-based stones and crystals. It is not effective for large stones (> 1 cm in diameter) or calcified stones.

STONES AFTER CHOLECYSTECTOMY

Bile duct stones can be classified as primary or secondary. A primary stone is one that remains where it was formed, whereas a secondary stone is one that has migrated from its site of formation.²¹

Some suggest that bile duct stones that are detected within 2 years of cholecystectomy originated in the gallbladder and were missed when the gallbladder was removed (and therefore are considered secondary stones), and that stones that present more than 2 years after cholecystectomy are de novo (ie, primary) stones.^22,23

In any event, stones have been found in the common bile duct in 4% to 24% of patients up to 15 years after cholecystectomy.^24–26 A fair number of these patients have no symptoms.²⁷ Risk factors for stone recurrence are lithogenic bile (ie, high concentration of cholesterol, low concentration of bile salts), biliary stasis, strictures, dilated bile ducts, and advanced age.^28–30

No role for crystal analysis after cholecystectomy

Biliary crystal analysis does not seem to have diagnostic value in patients with recurrent acute pancreatitis after cholecystectomy,³¹ because removing the gallbladder eliminates the crystals and sludge. Imaging studies are therefore the cornerstone of diagnosis.

Transabdominal ultrasonography is the most commonly used initial imaging test. However, abdominal fat and gas in the duodenum can obscure the distal common bile duct and decrease the sensitivity of this test.³²

Endoscopic ultrasonography involves positioning the transducer in the second part of the duodenum, where it can show the adjacent biliary tree without interference from digestive gas or abdominal fat.

Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasonography are both highly sensitive for detecting common bile duct stones and are recommended if they can be done without delay.

Endoscopic retrograde cholangiopancreatography (ERCP). As a rule, patients who are very likely to have gallstones are best served by proceeding directly to ERCP, a procedure that enables both imaging and treatment. However, ERCP exposes the patient to radiation and the risk of pancreatitis, so in some patients (eg, pregnant women, people who recently had acute pancreatitis), one may want to do ultrasonography first.

ERCP is the treatment of choice after cholecystectomy

The treatment of choice in patients with choledocholithiasis is ERCP with biliary sphincterotomy and stone extraction. Success at clearing the biliary tree of all stones depends on the size, number, and location of the stones, the anatomy of the digestive tract and the bile duct, and the experience of the endoscopist. At specialized centers, the rate of successful clearance with subsequent procedures is close to 100%. Large stones may require fragmentation inside the bile duct to aid their removal.³³

SPHINCTER OF ODDI DYSFUNCTION

The sphincter of Oddi, located where the bile and pancreatic ducts penetrate the wall of the duodenum, actually consists of three sphincters: the common, the biliary, and the pancreatic. Its physiologic role is to regulate the flow of bile and pancreatic juice into the duodenum and to prevent reflux into the ducts from the duodenum.³⁴ Its basal pressure is the main regulating mechanism for pancreatic and biliary secretions into the intestine, and its phasic contractile activity is closely associated with duodenal motility.

Sphincter dysfunction: Stenosis, dyskinesia

The sphincter of Oddi can obstruct the flow of bile and pancreatic juice owing either to stenosis or to dyskinesia.^35,36 Stenosis refers to structural alteration of the sphincter, probably from inflammation and subsequent fibrosis. In contrast, dyskinesia refers to a motor abnormality of the sphincter that makes it hypertonic.

Stenosis or dyskinesia can occur in the biliary sphincter, the pancreatic sphincter, the common sphincter, or any combination of the three. For example, dysfunction of the biliary sphincter can cause abnormalities in liver-associated enzyme levels and biliary-type pain, whereas pancreatic sphincter dysfunction can cause recurrent attacks of pancreatitis and pancreatic-type pain.³⁷ Elevated pancreatic sphincter pressure has been shown to correlate with increased pancreatic ductal pressure, suggesting that the sphincter plays a role in the pathogenesis of acute pancreatitis.^23,38

Sphincter pressure can be measured during ERCP, but ERCP is risky

The gold standard for the diagnosis of sphincter of Oddi dysfunction is manometry,^23,35 ie, direct measurement of sphincter pressure via a thin catheter placed inside the pancreatic or biliary sphincter during ERCP (Figure 1).

However, in patients with suspected sphincter of Oddi dysfunction, ERCP with or without manometry is associated with a high rate of complications, with pancreatitis occurring in up to 25% of cases.^39–41 Therefore, several noninvasive and provocative tests have been designed in an attempt to identify patients with this disorder. Unfortunately, none of them seems to be as sensitive and specific as manometry for diagnosing sphincter of Oddi dysfunction, and so they have not gained widespread use.

Opening the sphincter of Oddi with drugs, endoscopy, or surgery

Drug treatment of sphincter of Oddi dysfunction is based on drugs that relax smooth muscle, such as calcium channel blockers and nitrates. The treatment must be lifelong. Also, it does not improve sphincter stenosis, and only half of patients with sphincter dyskinesia respond to it. For these reasons, drug treatment of sphincter of Oddi dysfunction has not gained widespread acceptance.^36,42

Endoscopic sphincterotomy is the current standard endoscopic therapy for sphincter of Oddi dysfunction. This procedure is performed during ERCP and involves cutting the sphincter with electrocautery.

Endoscopic pancreatic sphincterotomy prevents recurrent attacks of pancreatitis in patients with pancreatic sphincter dysfunction in more than 60% of cases.^23,43–46 A potential complication is pancreatitis, which occurs more often in patients with pancreatic sphincter dyskinesia. Placing a stent in the pancreatic duct after pancreatic sphincterotomy reduces the risk of pancreatitis after ERCP.^37,47,48

Surgery. Pancreatic sphincterotomy can also be done surgically, most commonly via transduodenal pancreatic sphincteroplasty. Surgical sphincteroplasty is as effective as endoscopic sphincterotomy for preventing recurrent attacks of pancreatitis in patients with pancreatic sphincter dysfunction.⁴⁹ However, endoscopic therapy is much less invasive and remains the preferred treatment for sphincter of Oddi dysfunction in most centers with experience in this technique.⁵⁰

PANCREAS DIVISUM

Pancreas divisum is the most common congenital anomaly of the pancreatic duct. Autopsy studies show it occurs in 5% to 10% of the population.^51–53

At approximately the 5th week of gestation, there are two pancreatic buds: a ventral and a dorsal bud. The ventral bud eventually gives rise to part of the pancreatic head and uncinate process of the pancreas in the adult. The dorsal bud eventually gives rise to the rest of the pancreatic head, the pancreatic body, and the pancreatic tail. At 6 to 7 weeks of gestation, the ventral bud rotates clockwise and lies posterior to the dorsal bud. At this stage, both the dorsal and ventral pancreata have their own ducts, which do not communicate with each other. Normally, the ventral and dorsal pancreas and their ducts fuse together at 8 weeks of gestation; in people with pancreas divisum, this ductal fusion does not occur.⁵¹

The pancreas secretes 1.5 L of fluid per day. Normally, 90% to 95% of this volume drains through the major papilla. In people with pancreas divisum, 90% to 95% of the fluid drains through the minor papilla.

People with pancreas divisum are a heterogeneous group. Most have no symptoms, and their ductal anatomy is diagnosed only incidentally. However, a subgroup is prone to develop acute pancreatitis. The cause is thought to be the small diameter of the minor papilla, which poses a relative obstruction to the flow of pancreatic juice.⁵⁴ Direct support for this theory comes from a study in which investigators measured pancreatic ductal pressures in eight people with normal anatomy and six people with pancreas divisum. The pressure in the main pancreatic duct in those with pancreas divisum was significantly higher than in those with normal anatomy.⁵⁵ Additional evidence in favor of this theory is the effectiveness of treatment, which involves widening the minor papillary opening (minor papillary sphincterotomy).

Diagnosis of pancreas divisum

The diagnosis of pancreas divisum is based on imaging studies, and ERCP remains the gold standard for patients with equivocal results on noninvasive imaging. However, MRCP, especially secretin-enhanced MRCP, is as accurate as ERCP. In most cases, MRCP has replaced ERCP for the diagnosis of this condition, although a recent study suggests that MRCP is inferior to ERCP in the diagnosis of pancreas divisum.⁵⁶ We recommend secretin-enhanced MRCP for this purpose.

Computed tomography and endoscopic ultrasonography can also diagnose pancreas divisum, but their diagnostic accuracy is lower than that of ERCP and MRCP.

Minor papillary sphincterotomy

Treating recurrent pancreatitis due to pancreas divisum involves relieving the relative obstruction of the minor papilla by minor papillary sphincterotomy. This can be done surgically or endoscopically (Figure 1).

Surgery. No randomized, controlled study has yet assessed the efficacy of surgical sphincteroplasty for recurrent pancreatitis in patients with pancreas divisum. However, retrospective studies and one prospective study have been published.^57,58

In the retrospective study with the largest number of patients, Warshaw et al⁵⁷ reported their experience in 49 patients who had recurrent pancreatitis due to pancreas divisum. After surgical sphincteroplasty, the patients were followed for a mean of 53 months; 40 (82%) of the 49 patients had no further episodes of acute pancreatitis during this time.

Bradley and Stephan⁵⁸ studied 37 patients with pancreas divisum and recurrent pancreatitis.⁵⁸ After surgical sphincteroplasty, the patients were followed for a mean of 60 months; 31 of the 37 patients had no further attacks, a success rate of 84%.

Endoscopic therapy. As with surgical therapy trials, most trials of endoscopic therapy of recurrent pancreatitis in patients with pancreas divisum are small case series. In a retrospective study with one of the largest number of patients, Heyries et al⁵⁹ reported their experience with 24 patients with pancreas divisum and recurrent pancreatitis. After undergoing endoscopic minor papillary sphincterotomy, all patients were followed for a mean of 39 months, during which 22 (92%) did not have further episodes of acute pancreatitis.

In the only randomized controlled trial available, 19 patients with recurrent pancreatitis and pancreas divisum underwent either no treatment or endoscopic minor papillary sphincterotomy.⁶⁰ In the treatment group, 9 of 10 patients had no further episodes of acute pancreatitis during the 3 years of follow-up, while 6 of 9 patients who were randomized to no treatment had at least one episode.⁶⁰

Although surgical and endoscopic minor papillary sphincterotomy are equally effective, endoscopic therapy is preferred since it is less invasive, is associated with less morbidity, and costs less. It is also more convenient for patients, since it is an outpatient procedure. Surgical treatment is usually reserved for those in whom endoscopic treatment has failed or is not technically possible.

OTHER PROCESSES OBSTRUCTING THE FLOW OF PANCREATIC JUICE

Any process preventing free flow of pancreatic juice can lead to acute pancreatitis. The cause of the blockage can be around the ampulla, in the ampulla, or in the duct.⁶¹

Periampullary lesions, tumors, or polyps can press on the ampulla and cause complete or relative obstruction of the pancreatic duct with a subsequent increase in intraductal pressure and, thus, acute pancreatitis.⁶² Tumors or polyps of the ampulla, such as ampullary adenoma or carcinoma, can cause pancreatitis by directly obstructing the pancreatic duct where it opens into the duodenum.^63–66 Intraductal processes such as ductal adenocarcinoma, intraductal papillary mucinous tumor, pancreatic duct stone, and intraductal stricture due to cancer, chronic pancreatitis, or trauma can also cause pancreatitis by preventing free flow of pancreatic juice.^67–71

Although it is well known that sequelae of severe chronic pancreatitis such as ductal strictures or intraductal stones can lead to recurrent attacks of acute pancreatitis by preventing the free flow of pancreatic juice, a relationship also seems to exist between early chronic pancreatitis and recurrent acute pancreatitis.⁷² Several studies have shown that up to 50% of patients with idiopathic recurrent pancreatitis have evidence of chronic pancreatitis.^72–74 However, it is still unclear whether early chronic pancreatitis is the underlying cause of the recurrent attacks of acute pancreatitis or whether recurrent attacks of acute pancreatitis might have led to the development of chronic pancreatitis.

Diagnosis

Ampullary and periampullary neoplasms can be diagnosed endoscopically. Intraductal lesions such as strictures can be diagnosed by MRCP, especially secretin-enhanced MRCP, or by ERCP. ERCP has the additional advantage of being able to deliver treatment, ie, balloon dilation and stenting. In the case of ductal strictures, upsizing of the stents or placement of multiple stents during subsequent procedures is usually needed. Pancreatic ductal calcifications associated with chronic pancreatitis are usually radiopaque and are easily visible on plain films or computed tomography of the abdomen. Parenchymal and ductal changes of chronic pancreatitis can be diagnosed by endoscopic ultrasonography.

Treatment

The treatment is to relieve the obstruction and re-establish the free flow of pancreatic juice.

Periampullary tumors or polyps can be resected surgically or, if they involve only the mucosa, by endoscopic mucosal resection. Ampullary adenomas can be resected endoscopically. Ampullary carcinomas usually require surgical resection.

Small, nonobstructive stones in the pancreatic duct can be removed during ERCP.⁷⁵ Larger stones may need to be fragmented by extracorporeal shock wave lithotripsy to facilitate removal by ERCP.⁷⁵

Intraductal strictures should raise the suspicion of pancreatic adenocarcinoma, especially in older patients.⁶¹ In these cases, relief of the obstruction by placement of a pancreatic stent can prevent further attacks of pancreatitis until a diagnosis can be established and a more definitive treatment can be offered.

Endoscopic therapy has become an alternative to surgery for some patients with acute recurrent pancreatitis, ie, those whose disease is caused by gallstones or other mechanical processes that can obstruct the outflow from the pancreas.

In this paper, we review the specific situations in which endoscopic therapy might be useful in patients with acute recurrent pancreatitis.

ACUTE PANCREATITIS IS MANAGED DIFFERENTLY IF IT RECURS

Recurrent acute pancreatitis is defined as more than one episode of acute pancreatitis.¹ In clinical practice, it is important to distinguish between the first and recurrent episodes of acute pancreatitis.

Most patients who have one episode of acute pancreatitis never have another one.^2,3 Therefore, for patients having an initial attack, we recommend a limited workup that includes a detailed history, laboratory evaluation, and a noninvasive imaging study such as transcutaneous ultrasonography or computed tomography.

On the other hand, people who have a second attack are at higher risk of more recurrences. Therefore, patients having recurrent attacks need a more extensive workup to determine the underlying cause. We recommend referring them to a gastroenterologist for further evaluation.

WHICH CAUSES CAN BE MANAGED ENDOSCOPICALLY?

In the Western world, 70% to 80% of cases of recurrent pancreatitis are due to either alcohol abuse or gallstone disease.^2,4 The rest are related to:

• Autoimmune disorders
• Cancer, including occult malignancies and premalignant conditions such as intraductal papillary mucinous neoplasm
• Chronic pancreatitis
• Drugs
• Heredity
• Metabolic abnormalities (hypertriglyceridemia, hypercalcemia)
• Sphincter of Oddi dysfunction
• Structural or congenital abnormalities (pancreas divisum)
• Trauma.

• Gallstone disease, including biliary microlithiasis and sludge (in patients with or without a gallbladder)
• Sphincter of Oddi dysfunction
• Pancreas divisum
• Obstruction to flow of pancreatic juice.

Endoscopy is not completely benign

Although endoscopic procedures are less invasive than surgery, they are not completely benign. They can cause anxiety and are associated with risks such as bleeding, perforation, and pancreatitis.⁵ The risks, benefits, and alternatives to these procedures should be discussed with the patient, and informed consent should be obtained before any endoscopic procedure.⁶

STONES (LARGE OR SMALL) OR SLUDGE IN PATIENTS WITH A GALLBLADDER

Gallstones can be large, but small stones (microlithiasis) and sludge are more common and therefore account for more cases of pancreatitis.

Strictly defined, microlithiasis refers to stones smaller than 2 mm in diameter in the biliary tract, whereas sludge is a suspension of biliary crystals, mucin, and cellular debris in the gallbladder or bile ducts.⁷ The terms are often used interchangeably, since the conditions often coexist and their treatment is similar.

Theories differ as to how microlithiasis or sludge can cause recurrent pancreatitis. According to one theory, the debris blocks the common channel, increasing the pancreatic intraductal pressure and leading to pancreatitis.⁸ A second theory is that small stones or biliary crystals passing through the sphincter of Oddi cause inflammation, and that repeated inflammation eventually leads to stenosis or dyskinesia of the sphincter, both of which have been associated with pancreatitis.⁹

Studies suggest that microlithiasis and sludge are common causes of recurrent pancreatitis, accounting for about two-thirds of cases according to estimates by Ros et al¹⁰ and Lee et al.¹¹

Detecting small stones and sludge

The diagnosis of microlithiasis and biliary sludge in patients with a gallbladder is based on imaging studies and bile microscopy.¹²

Transabdominal ultrasonography is the imaging study most often used for diagnosing microlithiasis. The technology and expertise for this test are widely available, and it is relatively inexpensive.

Endoscopic ultrasonography is more sensitive for detecting microlithiasis and can examine the distal common bile duct.

Bile microscopy involves obtaining bile from the second portion of the duodenum (via an endoscope or a duodenal tube) or from the bile ducts (by cannulating the common bile duct and stimulating the gallbladder with cholecystokinin). The bile sample is centrifuged and inspected microscopically under plain light and polarized light (which aids the visualization of biliary crystals). The crystals can be cholesterol monohydrate, calcium bilirubinate, or calcium carbonate.^7,13,14

Removing the gallbladder is the treatment of choice for small stones and sludge

Treatments to prevent recurrent attacks of acute pancreatitis due to microlithiasis and sludge include cholecystectomy, biliary sphincterotomy, and ursodioxycholic acid.^10,11,15

In prospective observational studies by Ros et al¹⁰ and Lee et al,¹¹ about half of the patients with recurrent pancreatitis were treated with cholecystectomy, endoscopic sphincterotomy, or ursodioxycholic acid in a nonrandomized fashion. The choice of therapy was based on the patient’s medical status and the preferences of the patient and the physician. Half the patients received no treatment. In both studies the median follow-up was 4 years. Treated patients had a significantly lower rate of recurrent attacks of pancreatitis during follow-up: less than 20% with therapy compared with more than 60% without therapy. Unfortunately, no published study has compared these three treatments head to head.

Cholecystectomy, however, is the most definitive therapy and is generally considered the treatment of choice.

Biliary sphincterotomy is an endoscopic procedure that involves cutting the sphincter of Oddi to allow the stones and sludge to pass more freely. It is as effective as cholecystectomy in preventing recurrent attacks but does not eliminate the risk of cholecystitis and cholangitis (Figure 1). For this reason, it is usually reserved for patients who cannot tolerate surgery due to comorbidities, those who refuse surgery, or those who are pregnant.¹⁶

Ursodeoxycholic acid is a reasonable alternative in patients who cannot tolerate surgical or endoscopic biliary sphincterotomy.^1,17–20 The dosage is 10 mg/kg/day, which can be in two or three divided doses. The optimal duration of treatment is not known; however, since this drug works slowly, it may need to be taken for 2 years or more. Ursodeoxycholic acid is more effective in patients with cholesterol-based stones and crystals. It is not effective for large stones (> 1 cm in diameter) or calcified stones.

STONES AFTER CHOLECYSTECTOMY

Bile duct stones can be classified as primary or secondary. A primary stone is one that remains where it was formed, whereas a secondary stone is one that has migrated from its site of formation.²¹

Some suggest that bile duct stones that are detected within 2 years of cholecystectomy originated in the gallbladder and were missed when the gallbladder was removed (and therefore are considered secondary stones), and that stones that present more than 2 years after cholecystectomy are de novo (ie, primary) stones.^22,23

In any event, stones have been found in the common bile duct in 4% to 24% of patients up to 15 years after cholecystectomy.^24–26 A fair number of these patients have no symptoms.²⁷ Risk factors for stone recurrence are lithogenic bile (ie, high concentration of cholesterol, low concentration of bile salts), biliary stasis, strictures, dilated bile ducts, and advanced age.^28–30

No role for crystal analysis after cholecystectomy

Biliary crystal analysis does not seem to have diagnostic value in patients with recurrent acute pancreatitis after cholecystectomy,³¹ because removing the gallbladder eliminates the crystals and sludge. Imaging studies are therefore the cornerstone of diagnosis.

Transabdominal ultrasonography is the most commonly used initial imaging test. However, abdominal fat and gas in the duodenum can obscure the distal common bile duct and decrease the sensitivity of this test.³²

Endoscopic ultrasonography involves positioning the transducer in the second part of the duodenum, where it can show the adjacent biliary tree without interference from digestive gas or abdominal fat.

Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasonography are both highly sensitive for detecting common bile duct stones and are recommended if they can be done without delay.

Endoscopic retrograde cholangiopancreatography (ERCP). As a rule, patients who are very likely to have gallstones are best served by proceeding directly to ERCP, a procedure that enables both imaging and treatment. However, ERCP exposes the patient to radiation and the risk of pancreatitis, so in some patients (eg, pregnant women, people who recently had acute pancreatitis), one may want to do ultrasonography first.

ERCP is the treatment of choice after cholecystectomy

The treatment of choice in patients with choledocholithiasis is ERCP with biliary sphincterotomy and stone extraction. Success at clearing the biliary tree of all stones depends on the size, number, and location of the stones, the anatomy of the digestive tract and the bile duct, and the experience of the endoscopist. At specialized centers, the rate of successful clearance with subsequent procedures is close to 100%. Large stones may require fragmentation inside the bile duct to aid their removal.³³

SPHINCTER OF ODDI DYSFUNCTION

The sphincter of Oddi, located where the bile and pancreatic ducts penetrate the wall of the duodenum, actually consists of three sphincters: the common, the biliary, and the pancreatic. Its physiologic role is to regulate the flow of bile and pancreatic juice into the duodenum and to prevent reflux into the ducts from the duodenum.³⁴ Its basal pressure is the main regulating mechanism for pancreatic and biliary secretions into the intestine, and its phasic contractile activity is closely associated with duodenal motility.

Sphincter dysfunction: Stenosis, dyskinesia

The sphincter of Oddi can obstruct the flow of bile and pancreatic juice owing either to stenosis or to dyskinesia.^35,36 Stenosis refers to structural alteration of the sphincter, probably from inflammation and subsequent fibrosis. In contrast, dyskinesia refers to a motor abnormality of the sphincter that makes it hypertonic.

Stenosis or dyskinesia can occur in the biliary sphincter, the pancreatic sphincter, the common sphincter, or any combination of the three. For example, dysfunction of the biliary sphincter can cause abnormalities in liver-associated enzyme levels and biliary-type pain, whereas pancreatic sphincter dysfunction can cause recurrent attacks of pancreatitis and pancreatic-type pain.³⁷ Elevated pancreatic sphincter pressure has been shown to correlate with increased pancreatic ductal pressure, suggesting that the sphincter plays a role in the pathogenesis of acute pancreatitis.^23,38

Sphincter pressure can be measured during ERCP, but ERCP is risky

The gold standard for the diagnosis of sphincter of Oddi dysfunction is manometry,^23,35 ie, direct measurement of sphincter pressure via a thin catheter placed inside the pancreatic or biliary sphincter during ERCP (Figure 1).

However, in patients with suspected sphincter of Oddi dysfunction, ERCP with or without manometry is associated with a high rate of complications, with pancreatitis occurring in up to 25% of cases.^39–41 Therefore, several noninvasive and provocative tests have been designed in an attempt to identify patients with this disorder. Unfortunately, none of them seems to be as sensitive and specific as manometry for diagnosing sphincter of Oddi dysfunction, and so they have not gained widespread use.

Opening the sphincter of Oddi with drugs, endoscopy, or surgery

Drug treatment of sphincter of Oddi dysfunction is based on drugs that relax smooth muscle, such as calcium channel blockers and nitrates. The treatment must be lifelong. Also, it does not improve sphincter stenosis, and only half of patients with sphincter dyskinesia respond to it. For these reasons, drug treatment of sphincter of Oddi dysfunction has not gained widespread acceptance.^36,42

Endoscopic sphincterotomy is the current standard endoscopic therapy for sphincter of Oddi dysfunction. This procedure is performed during ERCP and involves cutting the sphincter with electrocautery.

Endoscopic pancreatic sphincterotomy prevents recurrent attacks of pancreatitis in patients with pancreatic sphincter dysfunction in more than 60% of cases.^23,43–46 A potential complication is pancreatitis, which occurs more often in patients with pancreatic sphincter dyskinesia. Placing a stent in the pancreatic duct after pancreatic sphincterotomy reduces the risk of pancreatitis after ERCP.^37,47,48

Surgery. Pancreatic sphincterotomy can also be done surgically, most commonly via transduodenal pancreatic sphincteroplasty. Surgical sphincteroplasty is as effective as endoscopic sphincterotomy for preventing recurrent attacks of pancreatitis in patients with pancreatic sphincter dysfunction.⁴⁹ However, endoscopic therapy is much less invasive and remains the preferred treatment for sphincter of Oddi dysfunction in most centers with experience in this technique.⁵⁰

PANCREAS DIVISUM

Pancreas divisum is the most common congenital anomaly of the pancreatic duct. Autopsy studies show it occurs in 5% to 10% of the population.^51–53

At approximately the 5th week of gestation, there are two pancreatic buds: a ventral and a dorsal bud. The ventral bud eventually gives rise to part of the pancreatic head and uncinate process of the pancreas in the adult. The dorsal bud eventually gives rise to the rest of the pancreatic head, the pancreatic body, and the pancreatic tail. At 6 to 7 weeks of gestation, the ventral bud rotates clockwise and lies posterior to the dorsal bud. At this stage, both the dorsal and ventral pancreata have their own ducts, which do not communicate with each other. Normally, the ventral and dorsal pancreas and their ducts fuse together at 8 weeks of gestation; in people with pancreas divisum, this ductal fusion does not occur.⁵¹

The pancreas secretes 1.5 L of fluid per day. Normally, 90% to 95% of this volume drains through the major papilla. In people with pancreas divisum, 90% to 95% of the fluid drains through the minor papilla.

People with pancreas divisum are a heterogeneous group. Most have no symptoms, and their ductal anatomy is diagnosed only incidentally. However, a subgroup is prone to develop acute pancreatitis. The cause is thought to be the small diameter of the minor papilla, which poses a relative obstruction to the flow of pancreatic juice.⁵⁴ Direct support for this theory comes from a study in which investigators measured pancreatic ductal pressures in eight people with normal anatomy and six people with pancreas divisum. The pressure in the main pancreatic duct in those with pancreas divisum was significantly higher than in those with normal anatomy.⁵⁵ Additional evidence in favor of this theory is the effectiveness of treatment, which involves widening the minor papillary opening (minor papillary sphincterotomy).

Diagnosis of pancreas divisum

The diagnosis of pancreas divisum is based on imaging studies, and ERCP remains the gold standard for patients with equivocal results on noninvasive imaging. However, MRCP, especially secretin-enhanced MRCP, is as accurate as ERCP. In most cases, MRCP has replaced ERCP for the diagnosis of this condition, although a recent study suggests that MRCP is inferior to ERCP in the diagnosis of pancreas divisum.⁵⁶ We recommend secretin-enhanced MRCP for this purpose.

Computed tomography and endoscopic ultrasonography can also diagnose pancreas divisum, but their diagnostic accuracy is lower than that of ERCP and MRCP.

Minor papillary sphincterotomy

Treating recurrent pancreatitis due to pancreas divisum involves relieving the relative obstruction of the minor papilla by minor papillary sphincterotomy. This can be done surgically or endoscopically (Figure 1).

Surgery. No randomized, controlled study has yet assessed the efficacy of surgical sphincteroplasty for recurrent pancreatitis in patients with pancreas divisum. However, retrospective studies and one prospective study have been published.^57,58

In the retrospective study with the largest number of patients, Warshaw et al⁵⁷ reported their experience in 49 patients who had recurrent pancreatitis due to pancreas divisum. After surgical sphincteroplasty, the patients were followed for a mean of 53 months; 40 (82%) of the 49 patients had no further episodes of acute pancreatitis during this time.

Bradley and Stephan⁵⁸ studied 37 patients with pancreas divisum and recurrent pancreatitis.⁵⁸ After surgical sphincteroplasty, the patients were followed for a mean of 60 months; 31 of the 37 patients had no further attacks, a success rate of 84%.

Endoscopic therapy. As with surgical therapy trials, most trials of endoscopic therapy of recurrent pancreatitis in patients with pancreas divisum are small case series. In a retrospective study with one of the largest number of patients, Heyries et al⁵⁹ reported their experience with 24 patients with pancreas divisum and recurrent pancreatitis. After undergoing endoscopic minor papillary sphincterotomy, all patients were followed for a mean of 39 months, during which 22 (92%) did not have further episodes of acute pancreatitis.

In the only randomized controlled trial available, 19 patients with recurrent pancreatitis and pancreas divisum underwent either no treatment or endoscopic minor papillary sphincterotomy.⁶⁰ In the treatment group, 9 of 10 patients had no further episodes of acute pancreatitis during the 3 years of follow-up, while 6 of 9 patients who were randomized to no treatment had at least one episode.⁶⁰

Although surgical and endoscopic minor papillary sphincterotomy are equally effective, endoscopic therapy is preferred since it is less invasive, is associated with less morbidity, and costs less. It is also more convenient for patients, since it is an outpatient procedure. Surgical treatment is usually reserved for those in whom endoscopic treatment has failed or is not technically possible.

OTHER PROCESSES OBSTRUCTING THE FLOW OF PANCREATIC JUICE

Any process preventing free flow of pancreatic juice can lead to acute pancreatitis. The cause of the blockage can be around the ampulla, in the ampulla, or in the duct.⁶¹

Periampullary lesions, tumors, or polyps can press on the ampulla and cause complete or relative obstruction of the pancreatic duct with a subsequent increase in intraductal pressure and, thus, acute pancreatitis.⁶² Tumors or polyps of the ampulla, such as ampullary adenoma or carcinoma, can cause pancreatitis by directly obstructing the pancreatic duct where it opens into the duodenum.^63–66 Intraductal processes such as ductal adenocarcinoma, intraductal papillary mucinous tumor, pancreatic duct stone, and intraductal stricture due to cancer, chronic pancreatitis, or trauma can also cause pancreatitis by preventing free flow of pancreatic juice.^67–71

Although it is well known that sequelae of severe chronic pancreatitis such as ductal strictures or intraductal stones can lead to recurrent attacks of acute pancreatitis by preventing the free flow of pancreatic juice, a relationship also seems to exist between early chronic pancreatitis and recurrent acute pancreatitis.⁷² Several studies have shown that up to 50% of patients with idiopathic recurrent pancreatitis have evidence of chronic pancreatitis.^72–74 However, it is still unclear whether early chronic pancreatitis is the underlying cause of the recurrent attacks of acute pancreatitis or whether recurrent attacks of acute pancreatitis might have led to the development of chronic pancreatitis.

Diagnosis

Ampullary and periampullary neoplasms can be diagnosed endoscopically. Intraductal lesions such as strictures can be diagnosed by MRCP, especially secretin-enhanced MRCP, or by ERCP. ERCP has the additional advantage of being able to deliver treatment, ie, balloon dilation and stenting. In the case of ductal strictures, upsizing of the stents or placement of multiple stents during subsequent procedures is usually needed. Pancreatic ductal calcifications associated with chronic pancreatitis are usually radiopaque and are easily visible on plain films or computed tomography of the abdomen. Parenchymal and ductal changes of chronic pancreatitis can be diagnosed by endoscopic ultrasonography.

Treatment

The treatment is to relieve the obstruction and re-establish the free flow of pancreatic juice.

Periampullary tumors or polyps can be resected surgically or, if they involve only the mucosa, by endoscopic mucosal resection. Ampullary adenomas can be resected endoscopically. Ampullary carcinomas usually require surgical resection.

Small, nonobstructive stones in the pancreatic duct can be removed during ERCP.⁷⁵ Larger stones may need to be fragmented by extracorporeal shock wave lithotripsy to facilitate removal by ERCP.⁷⁵

Intraductal strictures should raise the suspicion of pancreatic adenocarcinoma, especially in older patients.⁶¹ In these cases, relief of the obstruction by placement of a pancreatic stent can prevent further attacks of pancreatitis until a diagnosis can be established and a more definitive treatment can be offered.

Endoscopic therapy has become an alternative to surgery for some patients with acute recurrent pancreatitis, ie, those whose disease is caused by gallstones or other mechanical processes that can obstruct the outflow from the pancreas.

In this paper, we review the specific situations in which endoscopic therapy might be useful in patients with acute recurrent pancreatitis.

ACUTE PANCREATITIS IS MANAGED DIFFERENTLY IF IT RECURS

Recurrent acute pancreatitis is defined as more than one episode of acute pancreatitis.¹ In clinical practice, it is important to distinguish between the first and recurrent episodes of acute pancreatitis.

Most patients who have one episode of acute pancreatitis never have another one.^2,3 Therefore, for patients having an initial attack, we recommend a limited workup that includes a detailed history, laboratory evaluation, and a noninvasive imaging study such as transcutaneous ultrasonography or computed tomography.

On the other hand, people who have a second attack are at higher risk of more recurrences. Therefore, patients having recurrent attacks need a more extensive workup to determine the underlying cause. We recommend referring them to a gastroenterologist for further evaluation.

WHICH CAUSES CAN BE MANAGED ENDOSCOPICALLY?

In the Western world, 70% to 80% of cases of recurrent pancreatitis are due to either alcohol abuse or gallstone disease.^2,4 The rest are related to:

• Autoimmune disorders
• Cancer, including occult malignancies and premalignant conditions such as intraductal papillary mucinous neoplasm
• Chronic pancreatitis
• Drugs
• Heredity
• Metabolic abnormalities (hypertriglyceridemia, hypercalcemia)
• Sphincter of Oddi dysfunction
• Structural or congenital abnormalities (pancreas divisum)
• Trauma.

• Gallstone disease, including biliary microlithiasis and sludge (in patients with or without a gallbladder)
• Sphincter of Oddi dysfunction
• Pancreas divisum
• Obstruction to flow of pancreatic juice.

Endoscopy is not completely benign

Although endoscopic procedures are less invasive than surgery, they are not completely benign. They can cause anxiety and are associated with risks such as bleeding, perforation, and pancreatitis.⁵ The risks, benefits, and alternatives to these procedures should be discussed with the patient, and informed consent should be obtained before any endoscopic procedure.⁶

STONES (LARGE OR SMALL) OR SLUDGE IN PATIENTS WITH A GALLBLADDER

Gallstones can be large, but small stones (microlithiasis) and sludge are more common and therefore account for more cases of pancreatitis.

Strictly defined, microlithiasis refers to stones smaller than 2 mm in diameter in the biliary tract, whereas sludge is a suspension of biliary crystals, mucin, and cellular debris in the gallbladder or bile ducts.⁷ The terms are often used interchangeably, since the conditions often coexist and their treatment is similar.

Theories differ as to how microlithiasis or sludge can cause recurrent pancreatitis. According to one theory, the debris blocks the common channel, increasing the pancreatic intraductal pressure and leading to pancreatitis.⁸ A second theory is that small stones or biliary crystals passing through the sphincter of Oddi cause inflammation, and that repeated inflammation eventually leads to stenosis or dyskinesia of the sphincter, both of which have been associated with pancreatitis.⁹

Studies suggest that microlithiasis and sludge are common causes of recurrent pancreatitis, accounting for about two-thirds of cases according to estimates by Ros et al¹⁰ and Lee et al.¹¹

Detecting small stones and sludge

The diagnosis of microlithiasis and biliary sludge in patients with a gallbladder is based on imaging studies and bile microscopy.¹²

Transabdominal ultrasonography is the imaging study most often used for diagnosing microlithiasis. The technology and expertise for this test are widely available, and it is relatively inexpensive.

Endoscopic ultrasonography is more sensitive for detecting microlithiasis and can examine the distal common bile duct.

Bile microscopy involves obtaining bile from the second portion of the duodenum (via an endoscope or a duodenal tube) or from the bile ducts (by cannulating the common bile duct and stimulating the gallbladder with cholecystokinin). The bile sample is centrifuged and inspected microscopically under plain light and polarized light (which aids the visualization of biliary crystals). The crystals can be cholesterol monohydrate, calcium bilirubinate, or calcium carbonate.^7,13,14

Removing the gallbladder is the treatment of choice for small stones and sludge

Treatments to prevent recurrent attacks of acute pancreatitis due to microlithiasis and sludge include cholecystectomy, biliary sphincterotomy, and ursodioxycholic acid.^10,11,15

In prospective observational studies by Ros et al¹⁰ and Lee et al,¹¹ about half of the patients with recurrent pancreatitis were treated with cholecystectomy, endoscopic sphincterotomy, or ursodioxycholic acid in a nonrandomized fashion. The choice of therapy was based on the patient’s medical status and the preferences of the patient and the physician. Half the patients received no treatment. In both studies the median follow-up was 4 years. Treated patients had a significantly lower rate of recurrent attacks of pancreatitis during follow-up: less than 20% with therapy compared with more than 60% without therapy. Unfortunately, no published study has compared these three treatments head to head.

Cholecystectomy, however, is the most definitive therapy and is generally considered the treatment of choice.

Biliary sphincterotomy is an endoscopic procedure that involves cutting the sphincter of Oddi to allow the stones and sludge to pass more freely. It is as effective as cholecystectomy in preventing recurrent attacks but does not eliminate the risk of cholecystitis and cholangitis (Figure 1). For this reason, it is usually reserved for patients who cannot tolerate surgery due to comorbidities, those who refuse surgery, or those who are pregnant.¹⁶

Ursodeoxycholic acid is a reasonable alternative in patients who cannot tolerate surgical or endoscopic biliary sphincterotomy.^1,17–20 The dosage is 10 mg/kg/day, which can be in two or three divided doses. The optimal duration of treatment is not known; however, since this drug works slowly, it may need to be taken for 2 years or more. Ursodeoxycholic acid is more effective in patients with cholesterol-based stones and crystals. It is not effective for large stones (> 1 cm in diameter) or calcified stones.

STONES AFTER CHOLECYSTECTOMY

Bile duct stones can be classified as primary or secondary. A primary stone is one that remains where it was formed, whereas a secondary stone is one that has migrated from its site of formation.²¹

Some suggest that bile duct stones that are detected within 2 years of cholecystectomy originated in the gallbladder and were missed when the gallbladder was removed (and therefore are considered secondary stones), and that stones that present more than 2 years after cholecystectomy are de novo (ie, primary) stones.^22,23

In any event, stones have been found in the common bile duct in 4% to 24% of patients up to 15 years after cholecystectomy.^24–26 A fair number of these patients have no symptoms.²⁷ Risk factors for stone recurrence are lithogenic bile (ie, high concentration of cholesterol, low concentration of bile salts), biliary stasis, strictures, dilated bile ducts, and advanced age.^28–30

No role for crystal analysis after cholecystectomy

Biliary crystal analysis does not seem to have diagnostic value in patients with recurrent acute pancreatitis after cholecystectomy,³¹ because removing the gallbladder eliminates the crystals and sludge. Imaging studies are therefore the cornerstone of diagnosis.

Transabdominal ultrasonography is the most commonly used initial imaging test. However, abdominal fat and gas in the duodenum can obscure the distal common bile duct and decrease the sensitivity of this test.³²

Endoscopic ultrasonography involves positioning the transducer in the second part of the duodenum, where it can show the adjacent biliary tree without interference from digestive gas or abdominal fat.

Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasonography are both highly sensitive for detecting common bile duct stones and are recommended if they can be done without delay.

Endoscopic retrograde cholangiopancreatography (ERCP). As a rule, patients who are very likely to have gallstones are best served by proceeding directly to ERCP, a procedure that enables both imaging and treatment. However, ERCP exposes the patient to radiation and the risk of pancreatitis, so in some patients (eg, pregnant women, people who recently had acute pancreatitis), one may want to do ultrasonography first.

ERCP is the treatment of choice after cholecystectomy

The treatment of choice in patients with choledocholithiasis is ERCP with biliary sphincterotomy and stone extraction. Success at clearing the biliary tree of all stones depends on the size, number, and location of the stones, the anatomy of the digestive tract and the bile duct, and the experience of the endoscopist. At specialized centers, the rate of successful clearance with subsequent procedures is close to 100%. Large stones may require fragmentation inside the bile duct to aid their removal.³³

SPHINCTER OF ODDI DYSFUNCTION

The sphincter of Oddi, located where the bile and pancreatic ducts penetrate the wall of the duodenum, actually consists of three sphincters: the common, the biliary, and the pancreatic. Its physiologic role is to regulate the flow of bile and pancreatic juice into the duodenum and to prevent reflux into the ducts from the duodenum.³⁴ Its basal pressure is the main regulating mechanism for pancreatic and biliary secretions into the intestine, and its phasic contractile activity is closely associated with duodenal motility.

Sphincter dysfunction: Stenosis, dyskinesia

The sphincter of Oddi can obstruct the flow of bile and pancreatic juice owing either to stenosis or to dyskinesia.^35,36 Stenosis refers to structural alteration of the sphincter, probably from inflammation and subsequent fibrosis. In contrast, dyskinesia refers to a motor abnormality of the sphincter that makes it hypertonic.

Stenosis or dyskinesia can occur in the biliary sphincter, the pancreatic sphincter, the common sphincter, or any combination of the three. For example, dysfunction of the biliary sphincter can cause abnormalities in liver-associated enzyme levels and biliary-type pain, whereas pancreatic sphincter dysfunction can cause recurrent attacks of pancreatitis and pancreatic-type pain.³⁷ Elevated pancreatic sphincter pressure has been shown to correlate with increased pancreatic ductal pressure, suggesting that the sphincter plays a role in the pathogenesis of acute pancreatitis.^23,38

Sphincter pressure can be measured during ERCP, but ERCP is risky

The gold standard for the diagnosis of sphincter of Oddi dysfunction is manometry,^23,35 ie, direct measurement of sphincter pressure via a thin catheter placed inside the pancreatic or biliary sphincter during ERCP (Figure 1).

However, in patients with suspected sphincter of Oddi dysfunction, ERCP with or without manometry is associated with a high rate of complications, with pancreatitis occurring in up to 25% of cases.^39–41 Therefore, several noninvasive and provocative tests have been designed in an attempt to identify patients with this disorder. Unfortunately, none of them seems to be as sensitive and specific as manometry for diagnosing sphincter of Oddi dysfunction, and so they have not gained widespread use.

Opening the sphincter of Oddi with drugs, endoscopy, or surgery

Drug treatment of sphincter of Oddi dysfunction is based on drugs that relax smooth muscle, such as calcium channel blockers and nitrates. The treatment must be lifelong. Also, it does not improve sphincter stenosis, and only half of patients with sphincter dyskinesia respond to it. For these reasons, drug treatment of sphincter of Oddi dysfunction has not gained widespread acceptance.^36,42

Endoscopic sphincterotomy is the current standard endoscopic therapy for sphincter of Oddi dysfunction. This procedure is performed during ERCP and involves cutting the sphincter with electrocautery.

Endoscopic pancreatic sphincterotomy prevents recurrent attacks of pancreatitis in patients with pancreatic sphincter dysfunction in more than 60% of cases.^23,43–46 A potential complication is pancreatitis, which occurs more often in patients with pancreatic sphincter dyskinesia. Placing a stent in the pancreatic duct after pancreatic sphincterotomy reduces the risk of pancreatitis after ERCP.^37,47,48

Surgery. Pancreatic sphincterotomy can also be done surgically, most commonly via transduodenal pancreatic sphincteroplasty. Surgical sphincteroplasty is as effective as endoscopic sphincterotomy for preventing recurrent attacks of pancreatitis in patients with pancreatic sphincter dysfunction.⁴⁹ However, endoscopic therapy is much less invasive and remains the preferred treatment for sphincter of Oddi dysfunction in most centers with experience in this technique.⁵⁰

PANCREAS DIVISUM

Pancreas divisum is the most common congenital anomaly of the pancreatic duct. Autopsy studies show it occurs in 5% to 10% of the population.^51–53

At approximately the 5th week of gestation, there are two pancreatic buds: a ventral and a dorsal bud. The ventral bud eventually gives rise to part of the pancreatic head and uncinate process of the pancreas in the adult. The dorsal bud eventually gives rise to the rest of the pancreatic head, the pancreatic body, and the pancreatic tail. At 6 to 7 weeks of gestation, the ventral bud rotates clockwise and lies posterior to the dorsal bud. At this stage, both the dorsal and ventral pancreata have their own ducts, which do not communicate with each other. Normally, the ventral and dorsal pancreas and their ducts fuse together at 8 weeks of gestation; in people with pancreas divisum, this ductal fusion does not occur.⁵¹

The pancreas secretes 1.5 L of fluid per day. Normally, 90% to 95% of this volume drains through the major papilla. In people with pancreas divisum, 90% to 95% of the fluid drains through the minor papilla.

People with pancreas divisum are a heterogeneous group. Most have no symptoms, and their ductal anatomy is diagnosed only incidentally. However, a subgroup is prone to develop acute pancreatitis. The cause is thought to be the small diameter of the minor papilla, which poses a relative obstruction to the flow of pancreatic juice.⁵⁴ Direct support for this theory comes from a study in which investigators measured pancreatic ductal pressures in eight people with normal anatomy and six people with pancreas divisum. The pressure in the main pancreatic duct in those with pancreas divisum was significantly higher than in those with normal anatomy.⁵⁵ Additional evidence in favor of this theory is the effectiveness of treatment, which involves widening the minor papillary opening (minor papillary sphincterotomy).

Diagnosis of pancreas divisum

The diagnosis of pancreas divisum is based on imaging studies, and ERCP remains the gold standard for patients with equivocal results on noninvasive imaging. However, MRCP, especially secretin-enhanced MRCP, is as accurate as ERCP. In most cases, MRCP has replaced ERCP for the diagnosis of this condition, although a recent study suggests that MRCP is inferior to ERCP in the diagnosis of pancreas divisum.⁵⁶ We recommend secretin-enhanced MRCP for this purpose.

Computed tomography and endoscopic ultrasonography can also diagnose pancreas divisum, but their diagnostic accuracy is lower than that of ERCP and MRCP.

Minor papillary sphincterotomy

Treating recurrent pancreatitis due to pancreas divisum involves relieving the relative obstruction of the minor papilla by minor papillary sphincterotomy. This can be done surgically or endoscopically (Figure 1).

Surgery. No randomized, controlled study has yet assessed the efficacy of surgical sphincteroplasty for recurrent pancreatitis in patients with pancreas divisum. However, retrospective studies and one prospective study have been published.^57,58

In the retrospective study with the largest number of patients, Warshaw et al⁵⁷ reported their experience in 49 patients who had recurrent pancreatitis due to pancreas divisum. After surgical sphincteroplasty, the patients were followed for a mean of 53 months; 40 (82%) of the 49 patients had no further episodes of acute pancreatitis during this time.

Bradley and Stephan⁵⁸ studied 37 patients with pancreas divisum and recurrent pancreatitis.⁵⁸ After surgical sphincteroplasty, the patients were followed for a mean of 60 months; 31 of the 37 patients had no further attacks, a success rate of 84%.

Endoscopic therapy. As with surgical therapy trials, most trials of endoscopic therapy of recurrent pancreatitis in patients with pancreas divisum are small case series. In a retrospective study with one of the largest number of patients, Heyries et al⁵⁹ reported their experience with 24 patients with pancreas divisum and recurrent pancreatitis. After undergoing endoscopic minor papillary sphincterotomy, all patients were followed for a mean of 39 months, during which 22 (92%) did not have further episodes of acute pancreatitis.

In the only randomized controlled trial available, 19 patients with recurrent pancreatitis and pancreas divisum underwent either no treatment or endoscopic minor papillary sphincterotomy.⁶⁰ In the treatment group, 9 of 10 patients had no further episodes of acute pancreatitis during the 3 years of follow-up, while 6 of 9 patients who were randomized to no treatment had at least one episode.⁶⁰

Although surgical and endoscopic minor papillary sphincterotomy are equally effective, endoscopic therapy is preferred since it is less invasive, is associated with less morbidity, and costs less. It is also more convenient for patients, since it is an outpatient procedure. Surgical treatment is usually reserved for those in whom endoscopic treatment has failed or is not technically possible.

OTHER PROCESSES OBSTRUCTING THE FLOW OF PANCREATIC JUICE

Any process preventing free flow of pancreatic juice can lead to acute pancreatitis. The cause of the blockage can be around the ampulla, in the ampulla, or in the duct.⁶¹

Periampullary lesions, tumors, or polyps can press on the ampulla and cause complete or relative obstruction of the pancreatic duct with a subsequent increase in intraductal pressure and, thus, acute pancreatitis.⁶² Tumors or polyps of the ampulla, such as ampullary adenoma or carcinoma, can cause pancreatitis by directly obstructing the pancreatic duct where it opens into the duodenum.^63–66 Intraductal processes such as ductal adenocarcinoma, intraductal papillary mucinous tumor, pancreatic duct stone, and intraductal stricture due to cancer, chronic pancreatitis, or trauma can also cause pancreatitis by preventing free flow of pancreatic juice.^67–71

Although it is well known that sequelae of severe chronic pancreatitis such as ductal strictures or intraductal stones can lead to recurrent attacks of acute pancreatitis by preventing the free flow of pancreatic juice, a relationship also seems to exist between early chronic pancreatitis and recurrent acute pancreatitis.⁷² Several studies have shown that up to 50% of patients with idiopathic recurrent pancreatitis have evidence of chronic pancreatitis.^72–74 However, it is still unclear whether early chronic pancreatitis is the underlying cause of the recurrent attacks of acute pancreatitis or whether recurrent attacks of acute pancreatitis might have led to the development of chronic pancreatitis.

Diagnosis

Ampullary and periampullary neoplasms can be diagnosed endoscopically. Intraductal lesions such as strictures can be diagnosed by MRCP, especially secretin-enhanced MRCP, or by ERCP. ERCP has the additional advantage of being able to deliver treatment, ie, balloon dilation and stenting. In the case of ductal strictures, upsizing of the stents or placement of multiple stents during subsequent procedures is usually needed. Pancreatic ductal calcifications associated with chronic pancreatitis are usually radiopaque and are easily visible on plain films or computed tomography of the abdomen. Parenchymal and ductal changes of chronic pancreatitis can be diagnosed by endoscopic ultrasonography.

Treatment

The treatment is to relieve the obstruction and re-establish the free flow of pancreatic juice.

Periampullary tumors or polyps can be resected surgically or, if they involve only the mucosa, by endoscopic mucosal resection. Ampullary adenomas can be resected endoscopically. Ampullary carcinomas usually require surgical resection.

Small, nonobstructive stones in the pancreatic duct can be removed during ERCP.⁷⁵ Larger stones may need to be fragmented by extracorporeal shock wave lithotripsy to facilitate removal by ERCP.⁷⁵

Intraductal strictures should raise the suspicion of pancreatic adenocarcinoma, especially in older patients.⁶¹ In these cases, relief of the obstruction by placement of a pancreatic stent can prevent further attacks of pancreatitis until a diagnosis can be established and a more definitive treatment can be offered.

Acute myocardial infarction (MI) portends important and substantial consequences. Angioplasty or fibrinolytic therapy to open the blocked coronary artery is proven to improve the patient’s chances of surviving without consequent morbidity or death. But the diagnosis is not always straightforward. The presentation of acute MI can vary widely, and a number of other conditions—many of them equally serious emergencies—can mimic its symptoms, electrocardiographic signs, and biomarker patterns.

In an attempt to improve the accuracy of the diagnosis of MI, a multinational task force met in 1999 under the auspices of the European Society of Cardiology and the American College of Cardiology. The goal was to develop a simple, clinically oriented definition of MI that could be widely adopted. A document was created and published simultaneously in 2000 in the European Heart Journal and the Journal of the American College of Cardiology.¹ These organizations updated their paper in 2007 with a new definition of acute MI to account for advances in diagnosis and management.²

In this article we will review the new definition and how to make the diagnosis of acute MI today. Specifically, the updated definition includes:

• Subtypes of acute MI
• Imaging tests supporting the diagnosis
• Biomarker thresholds after percutaneous coronary intervention or bypass grafting.

TROPONIN: BETTER THAN CK, BUT NOT PERFECT

The original 2000 paper¹ and the 2007 update² featured the use of the cardiac biomarker troponin, which is considerably more sensitive and specific for heart damage than total creatine kinase (CK) or its isoform, CK-MB.

The new, more-sensitive biomarker-based definition of MI resulted in more cases of MI being diagnosed, and this has attracted the attention and scrutiny of many, especially population scientists and interventional cardiologists.³ This change has caused some controversy, especially when dealing with small rises in troponin following percutaneous coronary intervention.

In addition, some confusion over terminology remains. For example, the phrase “troponin leak” is often used to describe cases in which serum troponin levels rise but there is no MI. However, most experts believe that a rise and fall in troponin is due to true myocardial cell death. Troponin I and T are such large molecules that they cannot “leak” from a cardiac cell unless there has been irreparable cellular damage—that is, cell death.

Creatine kinase still has a role

In some cases, CK and CK-MB may be helpful in determining the acuity of myocardial necrosis, but their use will vary by institution. These biomarkers typically rise 2 to 4 hours after the initial event and fall within 24 to 48 hours, whereas troponin levels stay elevated for days or weeks. Thus, the presence of troponin without CK and CK-MB in the right clinical context may indicate a past MI that is no longer acute.

INFARCTION: CELL DEATH DUE TO ISCHEMIA

MI is myocardial cell death due to prolonged ischemia. Under the microscope, it can be categorized as coagulation necrosis in which ghost-like cell structures remain after hypoxic insult (typical of most MIs) or contraction band necrosis with amorphous cells that cannot contract anymore, the latter often a hallmark of excessive catecholamine damage or reperfusion injury. Apoptosis occurs in the heart but is technically not considered necrosis and is thought not to be associated with elevated troponin levels.^6,7

In experiments in animals, cell death can occur as little as 20 minutes after coronary artery occlusion, although completion of infarction is thought to take 2 to 4 hours. The time to infarct completion may be longer in patients with collateral circulation or when the culprit coronary artery has intermittent (“stuttering”) occlusion. Preconditioning of myocardial cells with intermittent ischemia can also influence the timing of myocardial necrosis by protecting against cell death to some extent. Alteration in myocardial demand can influence the time required for completion of infarction either favorably or unfavorably; hence, reducing myocardial demand is beneficial in acute MI.

Three pathologic phases of MI

MI can be categorized pathologically as acute, healing, or healed.

Acute MI. In the first 6 hours after coronary artery occlusion, coagulation necrosis can be seen with no cellular infiltration. After 6 hours, polymorphonuclear leukocytes infiltrate the infarcted area, and this may continue for up to 7 days if coronary perfusion does not increase or myocardial demand does not decrease.

Healing MI is characterized by mononuclear cells and fibroblasts and the absence of polymorphonuclear leukocytes. The entire healing process takes 5 to 6 weeks and can be altered by coronary reperfusion.

Healed MI refers to scar tissue without cellular infiltration.

CLINICAL FEATURES VARY WIDELY

Sir William Osler said, “Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.”⁸

Just so, patients with acute MI display a wide variety of presentations, from no symptoms (about 25%) to severe, crushing chest pain. Discomfort may occur in the upper back, neck, jaw, teeth, arms, wrist, and epigastrium. Shortness of breath, diaphoresis, nausea, vomiting, and even syncope may occur. Unlike in acute aortic dissection, the discomfort is not usually maximal at its onset: it builds up in a crescendo manner. It is not usually changed by position, but can lessen in intensity upon standing. The discomfort in the chest is deep and visceral, and typically not well localized. A pressure sensation, air hunger, or “gas buildup” can be described. The only symptom may be shortness of breath or severe diaphoresis. The symptoms can last from minutes to hours and can be relieved by sublingual nitroglycerin. Atypical or less-prominent symptoms may make the diagnosis more difficult in the elderly, patients with diabetes mellitus, and women.

The physical examination during acute MI usually finds no clear-cut distinguishing features. The patient may appear pale and diaphoretic, and the skin cool to the touch. Heart sounds are generally soft. A fourth heart sound may be audible. Blood pressure may be low, but it can vary widely. Tachycardia, particularly sinus tachycardia, and pulmonary edema are poor prognostic signs.

In view of the wide variation in presentations, the history and physical findings can raise the suspicion of acute MI, but sequential electrocardiograms and measurements of biomarkers (troponin) are always necessary.

ELECTROCARDIOGRAPHY: NECESSARY BUT NOT SUFFICIENT

ST-elevation MI vs non-ST-elevation MI

Changes in the ST segment can be very dynamic, making sequential tracings very useful. Rhythm disturbances and heart block are also more likely to be recorded when using sequential readings.

Pitfalls to electrocardiographic diagnosis

Prior MI. Q waves or QS complexes, when the Q wave is sufficiently wide (≥ 0.03 msec) or deep (≥ 1 mV), usually indicate a previous MI. However, many nuances that further raise or lower the suspicion for previous MI need to be considered. These are beyond the scope of this brief review but are available in the 2007 update.

Right ventricular infarction often requires the use of right-sided leads, which may reveal ST elevation in V₄R.

ECHOCARDIOGRAPHY IF THE DIAGNOSIS IS IN DOUBT

Echocardiography is an excellent way to assess wall-motion abnormalities. In the absence of any wall-motion abnormality, a large ST-elevation MI is unlikely. A large wall-motion abnormality would verify the probability of ongoing acute MI and thus would help with rapid decision-making.

Furthermore, echocardiography can help determine the likelihood that the patient has aortic dissection or pulmonary embolism, either of which can mimic acute MI but requires very different treatment.

CLINICAL CLASSIFICATION OF ACUTE MI

The new classification scheme of the different types of MI is shown in Table 4.

The new classification scheme does not include myocardial necrosis from mechanical manipulation of the heart during open heart surgery, from cardioversion, or from toxic drugs.

As clinicians are aware, it is not unusual to see elevated biomarker levels in a host of conditions unrelated to acute myocardial ischemia or MI. The new classification of acute MI is most helpful in this regard. It will likely be even more helpful in guiding treatment and management when new ultrasensitive troponin assays are widely introduced into clinical practice.

The new classification also negotiates the controversy regarding elevated biomarker levels following percutaneous coronary intervention. In brief, elevation of biomarkers is not entirely avoidable even with a successful percutaneous coronary intervention, and furthermore, there is no scientific cutoff for biomarker elevations. So, by arbitrary convention, the troponin level must rise to more than three times the 99th percentile upper reference limit to make the diagnosis of type 4a MI. A separate type 4b MI is ascribed to angiographic or autopsy-proven stent thrombosis.

The new guidelines also suggest that troponin values be more than five times the 99th percentile of the normal reference range during the first 72 hours following coronary artery bypass graft surgery (CABG) when considering a CABG-related MI (type 5). Whenever new pathologic Q waves appear in territories other than those identified before the procedure, MI should be considered, especially if associated with elevated biomarkers, new wall-motion abnormalities, or hemodynamic instability.

Thus, the diagnosis of acute MI now has widely accepted global criteria that distinguish various types of acute MI that occur under multiple circumstances. It is expected that describing the type of acute MI according to the new criteria will further enhance our understanding of the event, its proper management, and its prognosis.

Acute myocardial infarction (MI) portends important and substantial consequences. Angioplasty or fibrinolytic therapy to open the blocked coronary artery is proven to improve the patient’s chances of surviving without consequent morbidity or death. But the diagnosis is not always straightforward. The presentation of acute MI can vary widely, and a number of other conditions—many of them equally serious emergencies—can mimic its symptoms, electrocardiographic signs, and biomarker patterns.

In an attempt to improve the accuracy of the diagnosis of MI, a multinational task force met in 1999 under the auspices of the European Society of Cardiology and the American College of Cardiology. The goal was to develop a simple, clinically oriented definition of MI that could be widely adopted. A document was created and published simultaneously in 2000 in the European Heart Journal and the Journal of the American College of Cardiology.¹ These organizations updated their paper in 2007 with a new definition of acute MI to account for advances in diagnosis and management.²

In this article we will review the new definition and how to make the diagnosis of acute MI today. Specifically, the updated definition includes:

• Subtypes of acute MI
• Imaging tests supporting the diagnosis
• Biomarker thresholds after percutaneous coronary intervention or bypass grafting.

TROPONIN: BETTER THAN CK, BUT NOT PERFECT

The original 2000 paper¹ and the 2007 update² featured the use of the cardiac biomarker troponin, which is considerably more sensitive and specific for heart damage than total creatine kinase (CK) or its isoform, CK-MB.

The new, more-sensitive biomarker-based definition of MI resulted in more cases of MI being diagnosed, and this has attracted the attention and scrutiny of many, especially population scientists and interventional cardiologists.³ This change has caused some controversy, especially when dealing with small rises in troponin following percutaneous coronary intervention.

In addition, some confusion over terminology remains. For example, the phrase “troponin leak” is often used to describe cases in which serum troponin levels rise but there is no MI. However, most experts believe that a rise and fall in troponin is due to true myocardial cell death. Troponin I and T are such large molecules that they cannot “leak” from a cardiac cell unless there has been irreparable cellular damage—that is, cell death.

Creatine kinase still has a role

In some cases, CK and CK-MB may be helpful in determining the acuity of myocardial necrosis, but their use will vary by institution. These biomarkers typically rise 2 to 4 hours after the initial event and fall within 24 to 48 hours, whereas troponin levels stay elevated for days or weeks. Thus, the presence of troponin without CK and CK-MB in the right clinical context may indicate a past MI that is no longer acute.

INFARCTION: CELL DEATH DUE TO ISCHEMIA

MI is myocardial cell death due to prolonged ischemia. Under the microscope, it can be categorized as coagulation necrosis in which ghost-like cell structures remain after hypoxic insult (typical of most MIs) or contraction band necrosis with amorphous cells that cannot contract anymore, the latter often a hallmark of excessive catecholamine damage or reperfusion injury. Apoptosis occurs in the heart but is technically not considered necrosis and is thought not to be associated with elevated troponin levels.^6,7

In experiments in animals, cell death can occur as little as 20 minutes after coronary artery occlusion, although completion of infarction is thought to take 2 to 4 hours. The time to infarct completion may be longer in patients with collateral circulation or when the culprit coronary artery has intermittent (“stuttering”) occlusion. Preconditioning of myocardial cells with intermittent ischemia can also influence the timing of myocardial necrosis by protecting against cell death to some extent. Alteration in myocardial demand can influence the time required for completion of infarction either favorably or unfavorably; hence, reducing myocardial demand is beneficial in acute MI.

Three pathologic phases of MI

MI can be categorized pathologically as acute, healing, or healed.

Acute MI. In the first 6 hours after coronary artery occlusion, coagulation necrosis can be seen with no cellular infiltration. After 6 hours, polymorphonuclear leukocytes infiltrate the infarcted area, and this may continue for up to 7 days if coronary perfusion does not increase or myocardial demand does not decrease.

Healing MI is characterized by mononuclear cells and fibroblasts and the absence of polymorphonuclear leukocytes. The entire healing process takes 5 to 6 weeks and can be altered by coronary reperfusion.

Healed MI refers to scar tissue without cellular infiltration.

CLINICAL FEATURES VARY WIDELY

Sir William Osler said, “Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.”⁸

Just so, patients with acute MI display a wide variety of presentations, from no symptoms (about 25%) to severe, crushing chest pain. Discomfort may occur in the upper back, neck, jaw, teeth, arms, wrist, and epigastrium. Shortness of breath, diaphoresis, nausea, vomiting, and even syncope may occur. Unlike in acute aortic dissection, the discomfort is not usually maximal at its onset: it builds up in a crescendo manner. It is not usually changed by position, but can lessen in intensity upon standing. The discomfort in the chest is deep and visceral, and typically not well localized. A pressure sensation, air hunger, or “gas buildup” can be described. The only symptom may be shortness of breath or severe diaphoresis. The symptoms can last from minutes to hours and can be relieved by sublingual nitroglycerin. Atypical or less-prominent symptoms may make the diagnosis more difficult in the elderly, patients with diabetes mellitus, and women.

The physical examination during acute MI usually finds no clear-cut distinguishing features. The patient may appear pale and diaphoretic, and the skin cool to the touch. Heart sounds are generally soft. A fourth heart sound may be audible. Blood pressure may be low, but it can vary widely. Tachycardia, particularly sinus tachycardia, and pulmonary edema are poor prognostic signs.

In view of the wide variation in presentations, the history and physical findings can raise the suspicion of acute MI, but sequential electrocardiograms and measurements of biomarkers (troponin) are always necessary.

ELECTROCARDIOGRAPHY: NECESSARY BUT NOT SUFFICIENT

ST-elevation MI vs non-ST-elevation MI

Changes in the ST segment can be very dynamic, making sequential tracings very useful. Rhythm disturbances and heart block are also more likely to be recorded when using sequential readings.

Pitfalls to electrocardiographic diagnosis

Prior MI. Q waves or QS complexes, when the Q wave is sufficiently wide (≥ 0.03 msec) or deep (≥ 1 mV), usually indicate a previous MI. However, many nuances that further raise or lower the suspicion for previous MI need to be considered. These are beyond the scope of this brief review but are available in the 2007 update.

Right ventricular infarction often requires the use of right-sided leads, which may reveal ST elevation in V₄R.

ECHOCARDIOGRAPHY IF THE DIAGNOSIS IS IN DOUBT

Echocardiography is an excellent way to assess wall-motion abnormalities. In the absence of any wall-motion abnormality, a large ST-elevation MI is unlikely. A large wall-motion abnormality would verify the probability of ongoing acute MI and thus would help with rapid decision-making.

Furthermore, echocardiography can help determine the likelihood that the patient has aortic dissection or pulmonary embolism, either of which can mimic acute MI but requires very different treatment.

CLINICAL CLASSIFICATION OF ACUTE MI

The new classification scheme of the different types of MI is shown in Table 4.

The new classification scheme does not include myocardial necrosis from mechanical manipulation of the heart during open heart surgery, from cardioversion, or from toxic drugs.

As clinicians are aware, it is not unusual to see elevated biomarker levels in a host of conditions unrelated to acute myocardial ischemia or MI. The new classification of acute MI is most helpful in this regard. It will likely be even more helpful in guiding treatment and management when new ultrasensitive troponin assays are widely introduced into clinical practice.

The new classification also negotiates the controversy regarding elevated biomarker levels following percutaneous coronary intervention. In brief, elevation of biomarkers is not entirely avoidable even with a successful percutaneous coronary intervention, and furthermore, there is no scientific cutoff for biomarker elevations. So, by arbitrary convention, the troponin level must rise to more than three times the 99th percentile upper reference limit to make the diagnosis of type 4a MI. A separate type 4b MI is ascribed to angiographic or autopsy-proven stent thrombosis.

The new guidelines also suggest that troponin values be more than five times the 99th percentile of the normal reference range during the first 72 hours following coronary artery bypass graft surgery (CABG) when considering a CABG-related MI (type 5). Whenever new pathologic Q waves appear in territories other than those identified before the procedure, MI should be considered, especially if associated with elevated biomarkers, new wall-motion abnormalities, or hemodynamic instability.

Thus, the diagnosis of acute MI now has widely accepted global criteria that distinguish various types of acute MI that occur under multiple circumstances. It is expected that describing the type of acute MI according to the new criteria will further enhance our understanding of the event, its proper management, and its prognosis.

Acute myocardial infarction (MI) portends important and substantial consequences. Angioplasty or fibrinolytic therapy to open the blocked coronary artery is proven to improve the patient’s chances of surviving without consequent morbidity or death. But the diagnosis is not always straightforward. The presentation of acute MI can vary widely, and a number of other conditions—many of them equally serious emergencies—can mimic its symptoms, electrocardiographic signs, and biomarker patterns.

In an attempt to improve the accuracy of the diagnosis of MI, a multinational task force met in 1999 under the auspices of the European Society of Cardiology and the American College of Cardiology. The goal was to develop a simple, clinically oriented definition of MI that could be widely adopted. A document was created and published simultaneously in 2000 in the European Heart Journal and the Journal of the American College of Cardiology.¹ These organizations updated their paper in 2007 with a new definition of acute MI to account for advances in diagnosis and management.²

In this article we will review the new definition and how to make the diagnosis of acute MI today. Specifically, the updated definition includes:

• Subtypes of acute MI
• Imaging tests supporting the diagnosis
• Biomarker thresholds after percutaneous coronary intervention or bypass grafting.

TROPONIN: BETTER THAN CK, BUT NOT PERFECT

The original 2000 paper¹ and the 2007 update² featured the use of the cardiac biomarker troponin, which is considerably more sensitive and specific for heart damage than total creatine kinase (CK) or its isoform, CK-MB.

The new, more-sensitive biomarker-based definition of MI resulted in more cases of MI being diagnosed, and this has attracted the attention and scrutiny of many, especially population scientists and interventional cardiologists.³ This change has caused some controversy, especially when dealing with small rises in troponin following percutaneous coronary intervention.

In addition, some confusion over terminology remains. For example, the phrase “troponin leak” is often used to describe cases in which serum troponin levels rise but there is no MI. However, most experts believe that a rise and fall in troponin is due to true myocardial cell death. Troponin I and T are such large molecules that they cannot “leak” from a cardiac cell unless there has been irreparable cellular damage—that is, cell death.

Creatine kinase still has a role

In some cases, CK and CK-MB may be helpful in determining the acuity of myocardial necrosis, but their use will vary by institution. These biomarkers typically rise 2 to 4 hours after the initial event and fall within 24 to 48 hours, whereas troponin levels stay elevated for days or weeks. Thus, the presence of troponin without CK and CK-MB in the right clinical context may indicate a past MI that is no longer acute.

INFARCTION: CELL DEATH DUE TO ISCHEMIA

MI is myocardial cell death due to prolonged ischemia. Under the microscope, it can be categorized as coagulation necrosis in which ghost-like cell structures remain after hypoxic insult (typical of most MIs) or contraction band necrosis with amorphous cells that cannot contract anymore, the latter often a hallmark of excessive catecholamine damage or reperfusion injury. Apoptosis occurs in the heart but is technically not considered necrosis and is thought not to be associated with elevated troponin levels.^6,7

In experiments in animals, cell death can occur as little as 20 minutes after coronary artery occlusion, although completion of infarction is thought to take 2 to 4 hours. The time to infarct completion may be longer in patients with collateral circulation or when the culprit coronary artery has intermittent (“stuttering”) occlusion. Preconditioning of myocardial cells with intermittent ischemia can also influence the timing of myocardial necrosis by protecting against cell death to some extent. Alteration in myocardial demand can influence the time required for completion of infarction either favorably or unfavorably; hence, reducing myocardial demand is beneficial in acute MI.

Three pathologic phases of MI

MI can be categorized pathologically as acute, healing, or healed.

Acute MI. In the first 6 hours after coronary artery occlusion, coagulation necrosis can be seen with no cellular infiltration. After 6 hours, polymorphonuclear leukocytes infiltrate the infarcted area, and this may continue for up to 7 days if coronary perfusion does not increase or myocardial demand does not decrease.

Healing MI is characterized by mononuclear cells and fibroblasts and the absence of polymorphonuclear leukocytes. The entire healing process takes 5 to 6 weeks and can be altered by coronary reperfusion.

Healed MI refers to scar tissue without cellular infiltration.

CLINICAL FEATURES VARY WIDELY

Sir William Osler said, “Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.”⁸

Just so, patients with acute MI display a wide variety of presentations, from no symptoms (about 25%) to severe, crushing chest pain. Discomfort may occur in the upper back, neck, jaw, teeth, arms, wrist, and epigastrium. Shortness of breath, diaphoresis, nausea, vomiting, and even syncope may occur. Unlike in acute aortic dissection, the discomfort is not usually maximal at its onset: it builds up in a crescendo manner. It is not usually changed by position, but can lessen in intensity upon standing. The discomfort in the chest is deep and visceral, and typically not well localized. A pressure sensation, air hunger, or “gas buildup” can be described. The only symptom may be shortness of breath or severe diaphoresis. The symptoms can last from minutes to hours and can be relieved by sublingual nitroglycerin. Atypical or less-prominent symptoms may make the diagnosis more difficult in the elderly, patients with diabetes mellitus, and women.

The physical examination during acute MI usually finds no clear-cut distinguishing features. The patient may appear pale and diaphoretic, and the skin cool to the touch. Heart sounds are generally soft. A fourth heart sound may be audible. Blood pressure may be low, but it can vary widely. Tachycardia, particularly sinus tachycardia, and pulmonary edema are poor prognostic signs.

In view of the wide variation in presentations, the history and physical findings can raise the suspicion of acute MI, but sequential electrocardiograms and measurements of biomarkers (troponin) are always necessary.

ELECTROCARDIOGRAPHY: NECESSARY BUT NOT SUFFICIENT

ST-elevation MI vs non-ST-elevation MI

Changes in the ST segment can be very dynamic, making sequential tracings very useful. Rhythm disturbances and heart block are also more likely to be recorded when using sequential readings.

Pitfalls to electrocardiographic diagnosis

Prior MI. Q waves or QS complexes, when the Q wave is sufficiently wide (≥ 0.03 msec) or deep (≥ 1 mV), usually indicate a previous MI. However, many nuances that further raise or lower the suspicion for previous MI need to be considered. These are beyond the scope of this brief review but are available in the 2007 update.

Right ventricular infarction often requires the use of right-sided leads, which may reveal ST elevation in V₄R.

ECHOCARDIOGRAPHY IF THE DIAGNOSIS IS IN DOUBT

Echocardiography is an excellent way to assess wall-motion abnormalities. In the absence of any wall-motion abnormality, a large ST-elevation MI is unlikely. A large wall-motion abnormality would verify the probability of ongoing acute MI and thus would help with rapid decision-making.

Furthermore, echocardiography can help determine the likelihood that the patient has aortic dissection or pulmonary embolism, either of which can mimic acute MI but requires very different treatment.

CLINICAL CLASSIFICATION OF ACUTE MI

The new classification scheme of the different types of MI is shown in Table 4.

The new classification scheme does not include myocardial necrosis from mechanical manipulation of the heart during open heart surgery, from cardioversion, or from toxic drugs.

As clinicians are aware, it is not unusual to see elevated biomarker levels in a host of conditions unrelated to acute myocardial ischemia or MI. The new classification of acute MI is most helpful in this regard. It will likely be even more helpful in guiding treatment and management when new ultrasensitive troponin assays are widely introduced into clinical practice.

The new classification also negotiates the controversy regarding elevated biomarker levels following percutaneous coronary intervention. In brief, elevation of biomarkers is not entirely avoidable even with a successful percutaneous coronary intervention, and furthermore, there is no scientific cutoff for biomarker elevations. So, by arbitrary convention, the troponin level must rise to more than three times the 99th percentile upper reference limit to make the diagnosis of type 4a MI. A separate type 4b MI is ascribed to angiographic or autopsy-proven stent thrombosis.

The new guidelines also suggest that troponin values be more than five times the 99th percentile of the normal reference range during the first 72 hours following coronary artery bypass graft surgery (CABG) when considering a CABG-related MI (type 5). Whenever new pathologic Q waves appear in territories other than those identified before the procedure, MI should be considered, especially if associated with elevated biomarkers, new wall-motion abnormalities, or hemodynamic instability.

Thus, the diagnosis of acute MI now has widely accepted global criteria that distinguish various types of acute MI that occur under multiple circumstances. It is expected that describing the type of acute MI according to the new criteria will further enhance our understanding of the event, its proper management, and its prognosis.

Things are what they are

To the Editor: I finished residency in 1996. I’m not sure this qualifies me to respond to Dr. Lansdale’s article, but I will anyway. In 12 years, I have witnessed what he describes, even though I work in a not-for-profit military hospital (medical center). Yet I am uncertain that things are worse than they were then, even though it seems like the house staff spend thrice the time typing on a keyboard in the team room than they do at the bedside. Things are what they are. Patients are living longer—I have seen this with my own eyes. Some of them are seeing children graduate, get married, and have babies and spending final holidays with other loved ones. I often feel a sense of helplessness at exactly the sort of obstacles to true excellence Dr. Lansdale points out. However, in the spirit of evidence-based medicine, it remains to be established that spending less time touching the patient doesn’t reduce nosocomial infections. We were putting Swan-Ganz catheters in 12 years ago, and I am pretty sure in retrospect we were hurting patients—we don’t do that much any more. When I struggle with these difficulties and I try to figure out how to emulate my mentors from what seems like a better time, I remember what my mom told me when I was a second-grader: “Just do your best, and no one will fault you.” While I understand burnout, I think a more productive approach would be to redouble efforts at preserving humanistic traditions, valuable clinical skills, and a sense of what we were, rather than to retreat.

Things are what they are

To the Editor: I finished residency in 1996. I’m not sure this qualifies me to respond to Dr. Lansdale’s article, but I will anyway. In 12 years, I have witnessed what he describes, even though I work in a not-for-profit military hospital (medical center). Yet I am uncertain that things are worse than they were then, even though it seems like the house staff spend thrice the time typing on a keyboard in the team room than they do at the bedside. Things are what they are. Patients are living longer—I have seen this with my own eyes. Some of them are seeing children graduate, get married, and have babies and spending final holidays with other loved ones. I often feel a sense of helplessness at exactly the sort of obstacles to true excellence Dr. Lansdale points out. However, in the spirit of evidence-based medicine, it remains to be established that spending less time touching the patient doesn’t reduce nosocomial infections. We were putting Swan-Ganz catheters in 12 years ago, and I am pretty sure in retrospect we were hurting patients—we don’t do that much any more. When I struggle with these difficulties and I try to figure out how to emulate my mentors from what seems like a better time, I remember what my mom told me when I was a second-grader: “Just do your best, and no one will fault you.” While I understand burnout, I think a more productive approach would be to redouble efforts at preserving humanistic traditions, valuable clinical skills, and a sense of what we were, rather than to retreat.

Things are what they are

To the Editor: I finished residency in 1996. I’m not sure this qualifies me to respond to Dr. Lansdale’s article, but I will anyway. In 12 years, I have witnessed what he describes, even though I work in a not-for-profit military hospital (medical center). Yet I am uncertain that things are worse than they were then, even though it seems like the house staff spend thrice the time typing on a keyboard in the team room than they do at the bedside. Things are what they are. Patients are living longer—I have seen this with my own eyes. Some of them are seeing children graduate, get married, and have babies and spending final holidays with other loved ones. I often feel a sense of helplessness at exactly the sort of obstacles to true excellence Dr. Lansdale points out. However, in the spirit of evidence-based medicine, it remains to be established that spending less time touching the patient doesn’t reduce nosocomial infections. We were putting Swan-Ganz catheters in 12 years ago, and I am pretty sure in retrospect we were hurting patients—we don’t do that much any more. When I struggle with these difficulties and I try to figure out how to emulate my mentors from what seems like a better time, I remember what my mom told me when I was a second-grader: “Just do your best, and no one will fault you.” While I understand burnout, I think a more productive approach would be to redouble efforts at preserving humanistic traditions, valuable clinical skills, and a sense of what we were, rather than to retreat.

The current system is nuts

To the Editor: To add to what Dr. Lansdale said, advances in outpatient management and what one can do in “day surgery” have reshaped medicine. Medicine is now more of an outpatient enterprise. Hospitals have contracted to take care of only the sickest. Many things have been lost, including much of the fabric and texture of medicine. There are few of us left who are trained to do primary care, or willing to do it…

…For any provider, it is uneconomic to round on one or two patients. Hospitalists, who are often last year’s residents, try to manage sicker and more complex medical patients, whom they don’t know well. Emergency rooms are overflowing with primary care patients who go there in frustration and for urgent care, since there are not enough primary care physicians. The most expensive place is being used for basic care, and these patients are now seen by less adequately trained mid-level personnel, with reimbursements hugely in excess of what office visits generate…

…Most of us really do know how to practice economically, use resources appropriately, and manage our patients effectively. We are simply not being allowed to do so, or not paid for it when we do. In one word, the current system is nuts.

Before it is too late, and it may already be so, we need to restructure the system. That means rebuilding it around an outpatient model where doctors are paid and really rewarded for performance, and not for how many patients they see in a day…

The current system is nuts

To the Editor: To add to what Dr. Lansdale said, advances in outpatient management and what one can do in “day surgery” have reshaped medicine. Medicine is now more of an outpatient enterprise. Hospitals have contracted to take care of only the sickest. Many things have been lost, including much of the fabric and texture of medicine. There are few of us left who are trained to do primary care, or willing to do it…

…For any provider, it is uneconomic to round on one or two patients. Hospitalists, who are often last year’s residents, try to manage sicker and more complex medical patients, whom they don’t know well. Emergency rooms are overflowing with primary care patients who go there in frustration and for urgent care, since there are not enough primary care physicians. The most expensive place is being used for basic care, and these patients are now seen by less adequately trained mid-level personnel, with reimbursements hugely in excess of what office visits generate…

…Most of us really do know how to practice economically, use resources appropriately, and manage our patients effectively. We are simply not being allowed to do so, or not paid for it when we do. In one word, the current system is nuts.

Before it is too late, and it may already be so, we need to restructure the system. That means rebuilding it around an outpatient model where doctors are paid and really rewarded for performance, and not for how many patients they see in a day…

The current system is nuts

To the Editor: To add to what Dr. Lansdale said, advances in outpatient management and what one can do in “day surgery” have reshaped medicine. Medicine is now more of an outpatient enterprise. Hospitals have contracted to take care of only the sickest. Many things have been lost, including much of the fabric and texture of medicine. There are few of us left who are trained to do primary care, or willing to do it…

…For any provider, it is uneconomic to round on one or two patients. Hospitalists, who are often last year’s residents, try to manage sicker and more complex medical patients, whom they don’t know well. Emergency rooms are overflowing with primary care patients who go there in frustration and for urgent care, since there are not enough primary care physicians. The most expensive place is being used for basic care, and these patients are now seen by less adequately trained mid-level personnel, with reimbursements hugely in excess of what office visits generate…

…Most of us really do know how to practice economically, use resources appropriately, and manage our patients effectively. We are simply not being allowed to do so, or not paid for it when we do. In one word, the current system is nuts.

Before it is too late, and it may already be so, we need to restructure the system. That means rebuilding it around an outpatient model where doctors are paid and really rewarded for performance, and not for how many patients they see in a day…

The good old days weren't that good

To the Editor: Dr. Lansdale's stroll down memory lane reminiscing about the “good old days” brought back lots of memories (I graduated from medical school 10 years before Dr. Lansdale) but is of absolutely no help with today's medical challenges…

…Most of the physicians working in the trenches today did not set our current health care policies, and most of us will not change them either. That will only come from those we elect to go to Washington. I can vote responsibly, but I would not be very good in Washington. Until things change, it is my responsibility to learn the rules of engagement and care for my patients the best I can within the system we have. Like the waiter in the restaurant, I didn't set the table, I'm just trying to clean up the mess. Today's medical students and residents don't want to or will not work the hours we did 20 or 30 years ago, and I don't blame them. Maybe they will have a lower divorce rate, live longer, and practice medicine longer than our current retiring physicians…

…Dr. Lansdale worries about infection in the hospital, where handwashing between patients is abysmal. I can't do anything about my peers' handwashing habits, but I can wash my own hands. Don't like retrospective review for quality measures? We all know what is best for CHF and AMI patients, but studies show that less than 50% of our patients get the care we know is best. Physicians have always done a better job when somebody is watching. More oversight is coming. Get used to it…

…I am a hospital guy. As long as patients, medical students, and residents need me, I'll be a hospital guy.

The good old days weren't that good

To the Editor: Dr. Lansdale's stroll down memory lane reminiscing about the “good old days” brought back lots of memories (I graduated from medical school 10 years before Dr. Lansdale) but is of absolutely no help with today's medical challenges…

…Most of the physicians working in the trenches today did not set our current health care policies, and most of us will not change them either. That will only come from those we elect to go to Washington. I can vote responsibly, but I would not be very good in Washington. Until things change, it is my responsibility to learn the rules of engagement and care for my patients the best I can within the system we have. Like the waiter in the restaurant, I didn't set the table, I'm just trying to clean up the mess. Today's medical students and residents don't want to or will not work the hours we did 20 or 30 years ago, and I don't blame them. Maybe they will have a lower divorce rate, live longer, and practice medicine longer than our current retiring physicians…

…Dr. Lansdale worries about infection in the hospital, where handwashing between patients is abysmal. I can't do anything about my peers' handwashing habits, but I can wash my own hands. Don't like retrospective review for quality measures? We all know what is best for CHF and AMI patients, but studies show that less than 50% of our patients get the care we know is best. Physicians have always done a better job when somebody is watching. More oversight is coming. Get used to it…

…I am a hospital guy. As long as patients, medical students, and residents need me, I'll be a hospital guy.

The good old days weren't that good

To the Editor: Dr. Lansdale's stroll down memory lane reminiscing about the “good old days” brought back lots of memories (I graduated from medical school 10 years before Dr. Lansdale) but is of absolutely no help with today's medical challenges…

…Most of the physicians working in the trenches today did not set our current health care policies, and most of us will not change them either. That will only come from those we elect to go to Washington. I can vote responsibly, but I would not be very good in Washington. Until things change, it is my responsibility to learn the rules of engagement and care for my patients the best I can within the system we have. Like the waiter in the restaurant, I didn't set the table, I'm just trying to clean up the mess. Today's medical students and residents don't want to or will not work the hours we did 20 or 30 years ago, and I don't blame them. Maybe they will have a lower divorce rate, live longer, and practice medicine longer than our current retiring physicians…

…Dr. Lansdale worries about infection in the hospital, where handwashing between patients is abysmal. I can't do anything about my peers' handwashing habits, but I can wash my own hands. Don't like retrospective review for quality measures? We all know what is best for CHF and AMI patients, but studies show that less than 50% of our patients get the care we know is best. Physicians have always done a better job when somebody is watching. More oversight is coming. Get used to it…

…I am a hospital guy. As long as patients, medical students, and residents need me, I'll be a hospital guy.

We're chart doctors now

To the Editor: Dr. Lansdale appears to have jumped from the frying pan into the fire. In clinical medicine he will quickly find out that the quality of patient care has become nearly irrelevant. The quality of the medical record (chart) is all that matters to insurance companies, bean counters, and government agencies. I have been a primary care internist in private practice for 29 years. Instead of taking care of patients, I now spend most of my time taking care of charts. I'm a chart doctor.