Utility of endoscopic ultrasound in pancreatitis: A review

Abstract

The close proximity of the endoscopic ultrasound probe to the pancreas results in superior spatial resolution compared to CT scan and MRI. In addition, endoscopic ultrasound (EUS) is a minimally invasive procedure that does not share the relatively high complication rate of ERCP. Due to these advantages, EUS has evolved into an important technique to assess pancreatobiliary disease. This review will discuss the role of EUS in patients with pancreatitis. The indications can be divided into acute pancreatitis and chronic pancreatitis. In acute pancreatitis, EUS is used to determine the etiology; in suspected chronic pancreatitis it is helpful to establish the diagnosis. Lastly, this review will discuss biliary pancreatitis with suspicion for persistent choledocholithiasis.

Key Words: Idiopathic pancreatitis, Acute pancreatitis, Chronic pancreatitis, Endoscopic ultrasound, Endosono-graphy, Pancreas divisum, Cholelithiasis, Microlithiasis, Choledocholithiasis, Biliary pancreatitis

INTRODUCTION

Overlying intestinal gas and the retroperitoneal location of the pancreas distant from the abdominal wall can impair the visualization of this organ with trans-abdominal ultrasound. This problem has been overcome by integrating the ultrasound probe into an endoscope in order to place it directly into the gastric and duodenal lumen. The close proximity of the endoscopic ultrasound probe to the pancreas results in high spatial resolution that is superior to that of Computer Tomography (CT) and magnetic resonance imaging (MRI). In addition, endoscopic ultrasound (EUS) is a minimally invasive procedure that does not share the relatively high complication rate of endoscopic retrograde cholangiopancreatography (ERCP). Due to these advantages, EUS has evolved into an important technique to assess pancreatobiliary disease.

This review will discuss the role of EUS in patients with pancreatitis. The indications can be divided into acute pancreatitis and chronic pancreatitis. In acute pancreatitis, EUS is used to determine the etiology; in suspected chronic pancreatitis it is helpful to establish the diagnosis. Another indication that will be discussed is biliary pancreatitis with suspicion for persistent choledocholithiasis.

ACUTE IDIOPHATHIC PANCREATITIS

The diagnosis of acute idiopathic pancreatitis (AIP) is applied when an etiology cannot be determined after the initial evaluation that includes a thorough history and physical exam, laboratory evaluation and abdominal ultrasound or CT[1-4]. In-depth evaluation of AIP using EUS often yields the diagnosis of microlithiasis, pancreatic divisum, chronic pancreatitis[1,5-7] or even neoplasm[1,4].

Occult gallstones and microlithiasis

A substantial number of patients with AIP and unexplained biliary pain turn out to have biliary sludge or small gallstones that have gone undetected by abdominal ultrasound (US) or CT. The term ‘biliary microlithiasis’ was coined to describe gallstones of < 3 mm in diameter[8-10]. Although sonographic characteristics of cholelithiasis do not differ between EUS and trans-abdominal ultrasound, EUS is more sensitive in detecting gallstones[11] due to the proximity of the endoscope tip to the gallbladder. Small gallbladder stones present as bright floating foci. Larger stones have posterior shadowing. Sludge presents as hyperechoic content within the gallbladder or bile duct (Figures 1 and 2).

Figure 1 Linear EUS of gallbladder with shadowing stone.

Figure 2 Linear EUS of gallbladder with sludge, and bright shadowing foci representing small stones.

The reported incidence of occult gallstones in patients with AIP varies widely. It ranges from 10%-73%[12-15]. Gallstones remain the most common cause of pancreatitis in patients with intact gallbladder. Therefore, it is commonly believed that the finding of microlithiasis explains the etiology of the pancreatitis. This has recently been challenged. In a study by Garg et al. Seventy-five patients with AIP were studied with duodenal bile microscopy and EUS. Initially, the cause of the recurrent pancreatitis was attributed to biliary microlithiasis in 10 of 75 patients. Eight of these 10 patients underwent cholecystectomy or endoscopic sphincterotomy yet continued to have recurrent pancreatitis flares[16] which implies that gallstones or biliary crystals were innocent bystanders in these patients. In contrast, other studies have demonstrated response to cholecystectomy[5,17], sphincterotomy[11] or ursodeoxycholic acid (UDCA)[10] in patients with microlithiasis suggesting a causal relationship.

Liu et al prospectively evaluated 89 consecutive patients who presented with symptoms of acute pancreatitis with trans-abdominal ultrasound, CT, or both. ERCP was performed in all patients with confirmed or suspected biliary pancreatitis. EUS was performed in patients suspected of having idiopathic pancreatitis. Of the 18 patients classified as idiopathic pancreatitis who underwent EUS, 14 had stones that were between 1 and 9 mm in size which was confirmed by cholecystectomy. Three had concomitant choledocholithiasis confirmed by ERCP[17].

Another study retrospectively evaluated 31 patients with AIP who underwent EUS 2-3 wk after resolution of symptoms[5]. Five of 31 patients had microlithiasis diagnosed by EUS (n = 3), or by bile microscopy after EUS (n = 2). All 5 patients underwent cholecystectomy and remained asymptomatic during the follow-up period. Sludge was found on pathology examination in all 5 gallbladders. Gallstones or sludge were not diagnosed in any of the other 26 subjects during the follow-up period.

In summary, EUS is an effective modality in diagnosing microlithiasis and may strengthen the indication for a subsequent intervention. Treatment with cholecystectomy, endoscopic sphincterotomy or ursodeoxycholic acid may reduce recurrent attacks of pancreatitis[10,11]. However, it remains debatable how intensively we have to search for occult gallstones. Statistically, gallstones remain by far the likeliest cause of unexplained recurrent pancreatitis in patients with intact gallbladders. The morbidity of laparoscopic cholecystectomy is very low, and one could argue that this procedure is justified regardless of the findings of cross sectional imaging.

Pancreas divisum

Pancreas divisum is a common congenital malformation. The prevalence is estimated at 5%-10% in a Western population[18]. This abnormality is characterized by lack of connection between the dorsal and ventral pancreatic ducts due to incomplete fusion of the pancreatic buds during embryologic development. As a result, the ventral duct drains only a small portion of the pancreas via the major papilla, whereas the dorsal pancreatic duct drains the majority of the pancreas via the minor papilla. The small size of the minor papilla in relation to the drainage volume may lead to relative outflow obstruction. Since only a minority of patients with pancreas divisum becomes symptomatic, it has been suggested that symptomatic disease requires additional factors leading to minor papilla stenosis. Symptomatic patients present with recurrent acute pancreatitis, chronic pancreatitis, or chronic abdominal pain without evidence of pancreatitis. Pancreas divisum has been implicated in as much as 20% of patients with AIP[12]. Patients with discrete episodes of acute pancreatitis commonly improve after ERCP with minor papillotomy, whereas the results are less favorable for those with chronic pancreatitis or chronic abdominal pain[19] .

ERCP is the gold standard for the diagnosis of pancreas divisum but poses a risk of post procedure pancreatitis. Small series suggest that EUS enables a fairly reliable diagnosis of pancreas divisum and may therefore present an alternative to ERCP with minimal complication rate[5,7,20,21]. Different EUS-criteria have been used: Bhutani et al suggest that the absence of a "stack sign" may be useful in determining the diagnosis. The stack sign is obtained by positioning a radial echoendoscope in the long position with the transducer in the duodenal bulb. The balloon is then inflated and advanced snugly into the apex of the bulb. From this position, the bile duct and the pancreatic duct can be seen running parallel through the pancreatic head. In six patients with known pancreas divisum that underwent EUS, the stack sign was found in only two patients. Of the two patients with presence of a stack sign, one had a ventral duct that was markedly dilated, and the other patient had an unusually large ventral pancreas[20]. Tandon et al used different sonographic criteria. The authors required direct visualization of the dorsal duct coursing to the duodenal wall, and excluded patients with a sonographically visible ventral pancreatic duct. The authors feel that their criteria will exclude some cases of pancreas divisum and many cases of "incomplete pancreas divisum," but may be more specific as compared to the absence of a stack sign[5]. Lai et al suggests that evaluation using a linear-array echoendoscope is possible. The main pancreatic duct can be followed continuously from the major papilla into the pancreatic body. The duct can be seen crossing a sonographic border between the ventral and dorsal pancreas. Absence of this feature suggests pancreas divisum. In the retrospective study, of the 78% who had adequate visualization of the pancreatic duct, sensitivity, specificity, positive and negative predictive values for EUS were 95%, 97%, 86%, and 99%, respectively[21].

Occult neoplasm

It has been estimated that pancreatic neoplasms cause pancreatitis at some point in the disease course in up to 7 percent of patients[22]; however, they are a rare differential diagnosis in patients with AIP.

Mujica et al surveyed 19 physicians regarding 45 patients who presented with acute pancreatitis prior to a diagnosis of a neoplasm. The patients had a mean number of 2 episodes of acute pancreatitis prior to the diagnosis of neoplasm. The mean time to diagnosis of the neoplasm after the initial episode was 34 wk. The majority of patients were diagnosed using conventional cross-sectional imaging, whereas only 3 patients in the series were diagnosed using EUS[22].

Albeit rare, it has been suggested that pancreatic malignancy should be suspected in patients with unexplained pancreatitis who are older than 40 years of age[23]. EUS is superior to CT in detecting small pancreatic neoplasms[24,25], however, inflammatory changes during a pancreatitis flare may decrease the image quality. Therefore, cross-sectional imaging and/or EUS should be repeated after the resolution of the acute attack.

Single episode of idiopathic pancreatitis

The utility of an evaluation with EUS after a single episode of unexplained pancreatitis is not well studied and remains unclear[4]. In a small series by Tandon et al, EUS found an etiology in 7 of 14 patients with a single episode of idiopathic pancreatitis (3 microlithiasis, 1 pancreas divisum, 3 alcoholic chronic pancreatitis). The diagnosis changed in only 1 patient[23] during the follow-up period. A series reported by Yusoff et al included 201 patients with a single episode of acute pancreatitis. A presumptive diagnosis was made after EUS in 31%; chronic pancreatitis and sludge were the most common diagnoses in those with a gallbladder, whereas chronic pancreatitis and pancreatic divisum were the most prevalent diagnoses in patients who had a prior cholecystectomy[6].

Although these studies suggest a high yield of EUS in patients with a single episode of unexplained pancreatitis, some skepticism remains. Only 20%-50% of patients will have recurrent symptoms[26] following the initial attack. Furthermore, it is difficult to be sure about the causal relationship of an abnormal EUS finding after a single episode of pancreatitis. Pancreas divisum, for example, is common in the general population, and may be a coincidental finding rather than the cause of the pancreatitis. Even microlithiasis may be a harmless bystander[16]. As discussed in detail in a later paragraph, the diagnosis of chronic pancreatitis with EUS is problematic due to lack of specificity in early stages. In our opinion, further studies are necessary before advocating EUS for every patient after a single episode of idiopathic pancreatitis.

CHRONIC PANCREATITIS

The diagnosis of chronic pancreatitis (CP) can be challenging. The normal pancreas has a homogeneous fine granular echo-pattern (salt and pepper appearance), with a thin and regular main pancreatic duct. Certain sonographic changes can be observed in patients with CP. In an attempt to develop diagnostic scores for the EUS-diagnosis of chronic pancreatitis, "EUS criteria" have been developed. These were first described by Jones et al[27], and later refined by Wiersema et al[28]. The criteria can be divided into pancreatic duct findings and parenchymal findings. Parenchymal findings include hyperechoic foci, hyperechoic strands, lobularity, heterogeneity, shadowing calcifications, and cysts. Pancreatic duct findings include dilation (> 4 mm in the head, > 3 mm in the body, > 2 mm in the tail), irregularity, hyperechoic duct margins, and visible side-branches (Table 1, Figures 3,4,5 and 6). Multiple studies have evaluated the ability of EUS to diagnose CP using the above criteria. In a prospective, blinded study by Sahai et al, 126 patients who were admitted for abdominal pain underwent ERCP followed by EUS performed by a blinded operator. ERCP diagnosis of CP was based on Cambridge Criteria. EUS sensitivity was uniformly greater than 85% when the diagnosis of CP was based on the presence of fewer than three criteria, but the specificity was less than 60%. Specificity increased as the number of criteria increased and was greater than 85% when more than five criteria were used. "Moderate to severe chronic pancreatitis" was unlikely (NPV > 85%) when fewer than three criteria were present[29]. When criteria that can easily be detected by other imaging methods (ductal dilation, calcification, and cysts) were excluded, the number of parenchymal EUS criteria remained an independent predictor of CP[29].

Table 1 EUS criteria of chronic pancreatitis.

Parenchymal criteria	Pancreatic ductal criteria
Hyperechoic foci	Dilation (4 mm in head, 3 mm in body, 2 mm in tail)
Hyperechoic strands	Irregularity
Lobularity	Hyperechoic duct margins
Heterogeneity	Visible branch ducts
Shadowing calcifications	Intraductal stones
Cysts

Figure 3 Linear EUS showing a shadowing stone within the pan-creatic duct (PD STONE).

Figure 4 Linear trans-gastric EUS of the pancreas showing parench-ymal calcifications (CALC) causing dilatation of the upstream pancreatic duct (PD).

Figure 5 Linear trans-gastric EUS showing a small pancreatic cyst (labeled with mea-surement markers).

Figure 6 Linear EUS of pancreatic body with echoge-nic strands and lobularity.

There are nuances that need to be considered when using the above score. Firstly, the role of ERCP as a diagnostic "gold-standard" is debatable[30]. Thus, it is difficult to determine whether EUS is over-diagnosing pancreatic disease based on minimal changes or whether ERCP is a false negative in those with abnormal EUS findings but normal ERCP. In a study by Kahl et al[31], 32 patients with abnormal EUS but normal initial pancreatogram developed findings of CP on repeat ERCP after a median follow-up of 18 mo suggesting that EUS findings may precede ERCP findings. The sensitivity to diagnose chronic pancreatitis was 100% for EUS, but only 81% for ERCP.

Another concern when using an EUS scoring system to diagnose CP is that not all criteria may be equally important. For example, the presence of intraductal calcifications or parenchymal calcifications alone may be diagnostic of CP even in the absence of other criteria[30]. Age related changes in the pancreas may also affect the diagnostic threshold. The pancreatic duct becomes progressively wider with a hyperechoic wall with increased age. Another aspect to consider is interobserver variability of different criteria. Wiersema et al[28] found excellent interobserver agreement among 3 experienced endosonographers reading individual criteria of CP. There was 88% interobserver agreement on presence of echogenic foci, 94% agreement on focally reduced echogenicity, 94% agreement on lobular gland pattern, 83% agreement on the main pancreatic duct echogenicity, and 94% agreement on main pancreatic duct irregularity. On the contrary, Wallace et al[32] could not confirm these optimistic results. EUS-exams on 33 patients with suspected CP and 12 controls without suspected CP were videotaped by 3 experienced endosonographers. Eleven expert endosonographers, who were blinded to clinical information, independently evaluated the examinations for the presence of CP and were asked to rank the importance of individual EUS features. There was moderately good interobserver agreement in the final diagnosis of CP (Kappa = 0.45).

Interobserver agreement was good for the individual criteria "ductal dilation" and "lobularity" but was poor for the other 7 criteria. The presence of stones was regarded as the most predictive feature of CP by all endosonographers, followed by visible side branches, cysts, lobularity, irregular main pancreatic duct, hyperechoic strands, main pancreatic duct dilation and main duct hyperechoic margins[32].

In our opinion, the early diagnosis of CP remains problematic due to lack of specificity and the presence of interobserver variability. The overall interpretation of the experienced endosonographer may be more valuable than a diagnosis based on a scoring system.

Only a few studies have evaluated the utility of biopsy in addition to EUS for the diagnosis of CP. One small study suggested that fine needle aspiration may improve the negative predictive value but not the specificity of EUS[33], however this study was limited by the small number of patients without chronic pancreatitis. Out of 37 patients, 31 had chronic pancreatitis. Only 4 patients had normal EUS findings, 3 without and one with chronic pancreatitis (negative predictive value of 75%). The negative predictive value was improved to 100% by FNA-cytology. In our opinion, it is difficult to draw conclusions based on such small numbers. Another study found that EUS-guided core biopsies with a Trucut needle was poor at diagnosing CP[34].

In conclusion, current data do not support a role of EUS-guided biopsies in the diagnosis of CP. In addition to their questionable diagnostic value, pancreatic biopsies carry a potential risk of post-procedure pancreatitis.

CP makes the detection of pancreatic cancer more difficult. In a series of 282 patients with pancreatic mass (210 with adenocarcinoma), a lower sensitivity for EUS-FNA was observed in patients with CP (more than 4 EUS-criteria) than in those without CP (73.9% vs 91.3%). Patients with CP required more EUS-FNA passes to establish a diagnosis versus those without CP (5 vs 2)[35].

In summary, the diagnosis of CP remains challenging. EUS criteria have been established. Although these criteria are highly sensitive, they lack specificity in early stages. EUS is accurate in ruling out CP if no pancreatic abnormalities are found and in diagnosing CP if multiple criteria are present. However, a wide grey zone remains for patients with minimal to moderate findings.

CP decreases the sensitivity of EUS-FNA in the evaluation of pancreatic masses.

BILIARY PANCREATITIS AND CHOLEDOCHOLITHIASIS

In most patients with biliary pancreatitis, the causal gallstone has already passed. This makes it difficult to identify those patients in whom ERCP with sphincterotomy may be beneficial. In this context, EUS may provide a minimally invasive modality to diagnose or exclude choledocholithiasis. A review of five studies by Verma et al evaluating the efficacy of different modalities in diagnosing choledocholithiasis found an aggregated sensitivity of EUS of 0.93, a specificity of 0.96, a positive predictive value of 0.93, and a negative predictive value of 0.96. There was no statistical difference between MRCP and EUS[36]. In a study by Lui et al[37], 100 patients admitted for acute pancreatitis were evaluated with trans-abdominal ultrasound, EUS, and ERCP. EUS was found to be as sensitive as ERCP in the detection of choledocholithiasis, but with a lower complication rate.

Arguedas et al proposed a decision analysis model in evaluating biliary pancreatitis. Cost-effectiveness of strategies involving observation, intraoperative cholangiography, EUS, MRCP, and ERCP was evaluated. The results demonstrated that the choice of strategy is strongly influenced by the pretest probability of choledocholithiasis. If cost-minimization is the goal, observation with intraoperative cholangiography at the time of cholecystectomy is preferred in patients considered at "low risk" for choledocholithiasis. EUS is cost effective in patients at "intermediate risk" and ERCP is the preferable strategy in patients at "high-risk". There was no utility for MRCP in this model, as EUS was less costly[38]. Scheiman et al[39], also suggested that there is no role for MRCP for biliary pancreatitis in centers where EUS is available.

Sugiyama et al prospectively evaluated 35 patients with suspected acute biliary pancreatitis. All patients underwent trans-abdominal ultrasound, CT, EUS, and ERCP. The severity of pancreatitis was graded using APACHE II scores. EUS and ERCP were significantly more sensitive in the detection of CBD stones than trans-abdominal ultrasound and CT. ERCP and EUS were equivalent in CBD stone detection. Based on the severity of the pancreatitis, 20 of 35 ERCP were determined to be potentially avoidable[38].

In summary, EUS is both sensitive and specific in the detection of common bile duct stones and has a considerably lower complication rate than ERCP. While patients with high likelihood of cholelithiasis should undergo ERCP directly, EUS may enable selective use of ERCP in those with intermediate likelihood[1,3,7,10,38,39].

CONCLUSION

EUS is helpful in the evaluating patients with AIP and in diagnosing CP. In patients with AIP, EUS enables the diagnosis of occult cholelithiasis, pancreas divisum, chronic pancreatitis or an occult neoplasm. While EUS may be more sensitive than ERCP in diagnosing CP, the specificity is limited in early stages. In biliary pancreatitis, EUS allows accurate detection of common bile duct stones and can be used to select patients who will benefit from ERCP.