EUS in bile duct, gallbladder, and ampullary lesions

Key points

In patients with low-to-moderate clinical probability of common bile duct (CBD) stones, EUS or MRCP is recommended before endoscopic retrograde cholangiopancreatography (ERCP) is performed.
In patients with acute pancreatitis of unknown origin or right upper quadrant pain with normal transabdominal ultrasound, EUS should be considered.
In patients with a CBD stricture of unknown origin, EUS should be performed and, if inconclusive, ERCP should follow with tissue sampling via brush biopsies with possible addition of digital single-operator cholangioscopy-directed biopsies.
Gallbladder polyps larger than 5 mm in size may be investigated with EUS to determine the malignancy potential and the subsequent therapeutic approach.
Ampullary tumors can be staged with EUS. EUS is best to differentiate between early (adenoma, T1) and advanced (T2–4) tumors and to guide therapy.

GENERAL EXAMINATION CHECKLIST FOR BILIARY STONES AND TUMORS, AND AMPULLARY LESIONS

Extrahepatic ducts (dilation, stones)
Intrahepatic ducts (dilation)
Left and right liver lobes
Gallbladder
Ampulla
Pancreatic main and accessory ducts
Lymph nodes
Ascites
Portal hypertension
Vascular Involvement

EUS and biliary stones

A

Bile duct stones

Endoscopic retrograde cholangiopancreatography (ERCP) has long been considered the gold standard for diagnosing main bile duct (CBD) stones. Moreover, ERCP also allows for therapy during the same endoscopic session with extraction of CBD stones. However, ERCP is an invasive procedure and carries a substantial risk of complications, although when performed by experienced endoscopists, the adverse event and mortality rates can be reduced to under 5% and 0.1%, respectively. Furthermore, since it can be difficult to differentiate small stones from pneumobilia (air in the bile duct), a substantial proportion of ERCP procedures are completed with endoscopic sphincterotomy (ES) and balloon sweeps of the main bile duct, in order to confirm the diagnosis of choledocholithiasis. ES has a complication rate of 5% to 10%, with a current mortality being less than 1%. Long-term complications, such as stenosis and nonobstructive cholangitis, are rare occurring in approximately 10% or fewer of patients. ^,

Therefore, ERCP is no longer acceptable as a diagnostic tool for CBD stones given the risks of procedure-related complications outweigh potential benefits. However, ERCP remains the therapeutic modality of choice for extraction of CBD stones. Transabdominal ultrasonography (TUS) is a widely available, noninvasive imaging modality that should be part of the initial evaluation of any patient with clinical and/or laboratory suspicion of CBD stones. However, although TUS is very sensitive and specific for cholelithiasis, its sensitivity for the diagnosis of choledocholithiasis remains limited, even in heavily calcified CBD stones. The location and orientation of the bile duct, along with adjacent duodenal air make imaging of the distal bile duct difficult, and abdominal fat attenuates ultrasound waves making this technique less effective in obese patients.

Other imaging modalities such as multidetector CT, endoscopic ultrasonography (EUS), and magnetic resonance cholangiopancreatography (MRCP) have been effectively employed for the diagnosis of CBD stones. The sensitivity, specificity, and accuracy of helical CT range from 85% to 88%, 88% to 97%, and 86% to 94%, respectively. Nevertheless, the sensitivity of CT for detecting stones under 5 mm in size remains significantly lower than those measuring 5 mm or more. In one comparative study with MRCP and EUS, helical CT was inferior to either, although multiplanar reconstructions with multidetector CT can improve its specificity. ^, In one study, EUS had an accuracy of 94% to detect CBD stones in patients with a negative CT and intermediate to high probability of CBD stones. Therefore, EUS and MRCP remain the most accurate minimally invasive methods for diagnosing CBD stones.

EUS technique for detecting choledocholithiasis

EUS provides excellent sonographic visualization of the extrahepatic biliary tree. Bile duct stones are shown as echodense structures ( Fig. 15.1 ) within the ampulla ( Fig. 15.2 , ) or CBD ( Fig. 15.3 ), sometimes freely moving within the duct, with or without acoustic shadowing or thickening of the bile duct wall ( Fig. 15.4 A and B; ). The accuracy of EUS was found to be higher than that of ERCP for the detection of small CBD stones with a negative predictive value exceeding 95% and specificity in ruling out the presence of CBD stones of 95% or higher in the majority of published studies ( Table 15.1 ). In addition, EUS detects bile duct sludge as well as microlithiasis ( ), often missed by other imaging modalities.

• Fig. 15.1, Radial EUS image (7.5 MHz) of common bile duct stone in a patient presenting with right upper quadrant pain and elevated transaminases.

• Fig. 15.2, Linear EUS image (7.5 MHz) of a shadowing 11 mm common bile duct stone without significant upstream ductal dilation.

• Fig. 15.3, Linear EUS image (7.5 MHz) of a shadowing 9 mm common hepatic duct stone near the hepatic duct bifurcation with mild upstream biliary ductal dilation.

• Fig. 15.4, A 45-year-old female presenting with right upper quadrant pain and elevated transaminases. (A) CT scan of the abdomen—coronal section showing a distal 5 mm common bile duct stone near the ampulla with upstream biliary duct dilation and a calcified stone in the gallbladder. (B) Linear EUS image (7.5 MHz) of the same stone in part A. Distal 5 mm common bile duct stone near the ampulla with upstream biliary duct dilation. (C) Cholangiogram (fluoroscopy image) of a common bile duct with filling defects during ERCP in a different patient. (D) Stone confirmed after biliary sphincterotomy and balloon sweeping of the common bile duct in the same patient as in part C.

TABLE 15.1

Performance of EUS in the Diagnosis of Common Bile Duct Stones

Reference (year)	Level of Evidence ^a	Number of Patients Included	Frequency of CBD Stones (%)	EUS PERFORMANCE CHARACTERISTICS
Reference (year)	Level of Evidence ^a	Number of Patients Included	Frequency of CBD Stones (%)	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Accuracy (%)
Kohut et al. (2002)	1	134	68	93	93	98	87	94
Meroni et al. (2004)	1	47	15	71	90	55	95
Liu et al. (2000)	2	139	35	98	98	100	96	99
Prat et al. (2001)	2	123	27	100	100	100	100	100
Berdah et al. (2001)	2	68	20	96	97	93	100	98
Buscarini et al. (2003)	2	463	52	98	99	99	98	97
Kohut et al. (2003)	2	55	9	75	99	100	98	98
Aubé et al. (2005)	2	45	34	94	97	94	97	96
Ney et al. (2005)	2	68	32	96	99	100	97	98
Lachter et al. (2000)	3	50	66	96	75	89	93	94
Materne et al. (2000)	3	50	26	97	88	94	93	94
Scheiman et al. (2001)	3	28	18	80	95	80	96	–
Ainsworth et al. (2004)	3	163	33	90	99	98	94	93
Kondo et al. (2005)	3	30	86	98	50	92	100	93
Dittrick et al. (2005)	3	30	37	100	84	56	100	–
Jeon et al. (2017)	3	200	83	98	80	95	89	94
Netinatsunton et al. (2016)	3	141	59	98	80	98	80
Maruta et al. (2019)	2	104	54			98

a Level 1: Technique compared with ERC + systematic ES with a very short interval between the technique and ERCP; Level 2: Technique compared with ERCP + ES if positive, and clinical and biological follow-up of at least 6 months if negative; Level 3: Technique compared with ERC or with intraoperative cholangiography.

In most EUS literature, radial-array echoendoscopes were used for assessment of choledocholithiasis. Nevertheless, the accuracy of linear-array echoendoscopes appear to be comparable to that of the radial endosonographic exam, as indicated in some series comparing EUS with ERCP plus ES, or choledochotomy with choledochoscopy ( Table 15.1 ). ^, ^, ^, ^, ^, ^, ^, ^, The advantages of radial-array echoendoscopes ( Figs. 15.1 and 15.3 ) reside in their ability to visualize the bile duct in a long section (along its main axis) without having to torque the scope. Nevertheless, it can miss hilar stones due to the distance. A linear-array echoendoscope, on the other hand, provides cross-sectional or tangential views of the bile duct but requires continuous torque to visualize the entire duct: clockwise to interrogate the bile duct from the hilum ( Fig. 15.3 ) to the papilla ( Fig. 15.2 ) and counter clockwise to interrogate the duct in the opposite direction ( Fig. 15.4 B; to ).

The ability of either echoendoscope to visualize intrahepatic stones remains low due to the distance from the tip of the scope and the presence of several intervening structures. In addition, stones impacted at the level of the papilla can be missed unless full visualization of the duct at its insertion into the duodenal wall is possible. This ampullary view can be difficult to obtain in some cases from the duodenal bulb, where deep insertion into the second part of the duodenum followed by slow withdrawal with the tip of the scope in full upward deflection could help bring the ampulla to view and stabilize the scope within the duodenal sweep ( D). It is also recommended to instill water in the second part of the duodenum particularly when the radial-array echoendoscope is being utilized to improve acoustic coupling of the periampullary area. At least one study demonstrated improved capability to visualize the very distal bile duct and the pancreatic–biliary junction with a linear-array echoendoscope compared to a radial-array echoendoscope. A few variations to the technique to examine the main bile duct with a linear-array echoendoscope ^, can be adopted based on the patient’s body habitus and variations in the upper gastro-intestinal anatomy.

The use of EUS, MRCP, and ERCP in the management of choledocholithiasis

MRCP is a noninvasive, radiation-free imaging modality and is more accurate than CT ( Fig. 15.4 A) for the diagnosis of choledocholithiasis ( Table 15.2 ). ^, The disadvantages of this technique include the limited spatial resolution, the difficulty of diagnosing CBD stones in the periampullary region, lack of availability in some areas, need for operator’s experience to interpret findings, and the high cost. Moreover, MRCP is contraindicated in patients with metallic hardware such as MRI-incompatible pacemakers or cerebral aneurysm clips and is difficult to conduct in claustrophobic patients or patients who are unable to hold their breath for a period of time. EUS offers higher spatial resolution than MRCP (0.1 vs 1–1.5 mm), and its sensitivity for detecting choledocholithiasis does not vary with the stone size such as MRCP. Thus, it is not surprising that stones missed by MRCP are usually always smaller than 10 mm ^, and that the sensitivity of MRCP decreased to approximately 65% for diagnosing stones smaller than 5 mm. ^, In a systematic review, the sensitivity of MRCP in detecting CBD stones was 90% with a specificity of 95%. The diagnostic performance of EUS has been evaluated in two meta-analyses including 3532 and 2673 patients. ^, The pooled sensitivity and specificity of EUS were 89% to 94% and 94% to 95%, respectively. The evidence for the use of MRCP for the diagnosis of CBD stones has been examined in a systematic review of 10 studies and was shown to provide a high sensitivity (range 80% to 100%) and specificity (range 83% to 98%). In comparative studies of the two technologies, EUS was found to be either superior ^, or equivalent ^, ^, ^, to MRCP for the diagnosis of choledocholithiasis. A comparative meta-analysis reported the odds to detect CBD stones being higher with EUS compared to MRCP (162.5 vs 79, P = .008) and this was primarily related to the higher sensitivity of EUS (97% vs 87%, P = .006). Another meta-analysis and two systematic reviews ^, comparing EUS and MRCP for depicting CBD stones showed a high diagnostic performance for both modalities. Although no statistically significant differences were found between the two modalities, there was a trend toward higher sensitivity and specificity for EUS compared to MRCP. This was especially obvious in the context of small stones causing acute biliary pancreatitis. A recent Cochrane systematic review demonstrated both EUS and MRCP have a high diagnostic accuracy to identify CBD stones with no significant difference between the two modalities. Nevertheless, the choice between these two techniques should depend on others factors such as resource availability, operator experience, and cost. A recent Endoscopy Society guideline from the United States reflects a similar perspective on the two modalities.

TABLE 15.2

Performance of MRCP in the Diagnosis of Common Bile Duct Stones

Reference (year)	Level of Evidence ^a	Number of Patients	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Accuracy (%)
Gautier et al. (2004)	2	99	96	99	–	–	–
Aubé et al. (2005)	2	45	88	97	93	93	–
Topal et al. (2003)	2	315	95	100	100	98
Mofidi et al. (2008)	2	49	100	96	–	–	–
Scaffidi et al. (2009)	2	120	88	72	87	72	83
Cervi et al. (2000)	3	60	100	94	–	–	–
Demartines et al. (2000)	3	70	100	96	93	100	–
Stiris et al. (2000)	3	50	88	94	97	81	–
Materne et al. (2000)	3	50	91	94	88	95	92
Scheiman et al. (2001)	3	28	40	96	66	88	–
Kim et al. (2002)	3	121	95	95	–	–	95
Taylor et al. (2002)	3	146	98	89	84	99	–
Griffin et al. (2003)	3	115	84	96	91	93	92
Ainsworth et al. (2004)	3	163	87	97	95	93	–
Kondo et al. (2005)	3	30	88	75	96	50	86
Ausch et al. (2005)	3	773	94	98	80	99	–
Hallal et al. (2005)	3	29	100	91	50	100	92
Makary et al. (2005)	3	64	94	98	94	98	–
Moon et al. (2005)	3	32	80	83	89	71	81
De Waele et al. (2007)	3	104	83	98	91	95	94
Norero et al. (2008)	3	125	97	74	89	90	90
Richard et al. (2013)	3	70	27	83	36	77	69
Badger et al. (2016)	3	527	90	86	97	60	–

a Level 1 : Technique compared with ERC + systematic ES with a very short interval between the technique and ERCP; Level 2 : Technique compared with ERCP + ES if positive, and clinical and biological follow-up of at least 6 months if negative; Level 3 : Technique compared with ERC or with intraoperative cholangiography.

The use of noninvasive imaging modalities has resulted in a considerable reduction in the number of inappropriate ERCPs. ^, One meta-analysis comparing an EUS-guided ERCP strategy with an ERCP-only strategy found that the use of EUS significantly reduced the risk of overall complications (relative risk 0.35) by safely avoiding ERCP in 67% of patients. Whether or not an EUS or MRCP would be necessary prior to ERCP depends on the pre-test probability of having a stone in the CBD. Patients suspected of having choledocholithiasis on clinical and laboratory criteria and/or US can be grouped into risk groups, ranging from low to intermediate to high risk. ^, ^,

Patients in the high-risk group include those with CBD stone on transabdominal US, clinical ascending cholangitis and bilirubin >4 mg/dL. When considering all published studies, the proportion of high-risk patients who actually have CBD stones was less than 80% (66% to 78%), ^, ^, ^, whereas fewer than 40% of patients classified as being at intermediate (also called moderate) risk had choledocholithiasis (19% to 44%). ^, ^, ^, Most experts agree that ERCP could be performed as a first-line approach in patients at high risk of CBD stones, ^, ^, although it may be impossible to avoid unnecessary ERCP procedures altogether. EUS as a first-line approach in patients in the high-risk category could still be performed if available to exclude a stone or to evaluate other causes of biliary symptoms. ^, ^, Moreover, EUS confirming CBD stones would justify the use of aggressive techniques, such as pre-cut endoscopic sphincterotomy, if needed. A study reported an EUS-first approach followed by ERCP based on EUS findings reduced the need for ERCP by 40% with no increased risk of recurrent stones in the group where ERCP was deferred. However, there is still no consensus on the routine use of EUS in such cases. Practically, the best approach is probably to perform EUS followed by ERCP with stone extraction ( Fig. 15.4 C and D) or stent placement during the same endoscopic session if a stone is found on EUS. ^,

Intermediate-risk patients include those who present with symptoms compatible with biliary origin, along with liver test abnormalities or dilated CBD on TUS. The consensus in this group of patients is to consider EUS (or MRCP) as the first-line diagnostic approach (after TUS). ^, ^, This approach was evaluated in the context of laparoscopic cholecystectomy in a series of 300 patients. Choledocholithiasis were found on preoperative EUS in 19% of the intermediate risk, and on ERCP in 78% of the high risk.

For low-risk patients, who typically have no biliary symptoms or liver test abnormalities, and have no CBD dilatation on TUS, no further examination is necessary in this case. We suggest an algorithm to investigate patients with suspected choledocholithiasis based on their risk stratification ( Fig. 15.5 ).

• Fig. 15.5, An algorithm for the management of patients with suspected choledocholithiasis.

The utilization of EUS was associated with potential financial advantages as a first-line strategy in cost-effectiveness studies. In a prospective study of 485 patients suspected of having CBD stones where EUS was always performed regardless of the risk classification, the mean cost for patients managed by the EUS-based strategy was significantly lower than that for patients who had ERCP. In another study, the EUS-guided ERCP strategy resulted in 14% reduction in ERCP procedures, and was associated with significant cost savings. Other studies have found that EUS was the most cost-effective strategy in the intermediate-risk group, whereas in the high-risk group with a probability of CBD stones above 50%, the most cost-effective approach was an ERCP-first approach. ^, ^, ^, ^, In patients with acute biliary pancreatitis, an economic evaluation also concluded that EUS-first strategy was associated with lower costs, fewer procedures, and complications. This was especially obvious in patients with severe acute pancreatitis. Finally, a randomized study comparing EUS and ERCP during the same endoscopic session versus EUS and ERCP in two separate sessions for the management of choledocholithiasis showed that the average procedure time and days of hospitalization were significantly reduced in the first group resulting in significant reductions in total costs.

Two adjunct ultrasound-based techniques have been described in the past: extraductal catheter probe EUS (EDUS) and intraductal ultrasonography (IDUS). Two studies have shown the diagnostic accuracy of a radial EDUS is comparable to that of a linear-array EUS. ^, Other studies have demonstrated that the sensitivity of MRCP, ERCP, and IDUS for the diagnosis of choledocholithiasis were 80%, 90%, and 95%, respectively, with the addition of IDUS to ERCP increasing the diagnostic accuracy and decreasing the recurrence rate (13% to 3%) for CBD stones, after endoscopic clearance. These techniques require expertise and are currently exclusive to a few endoscopy centers of excellence.

In summary, EUS is the ideal and superior alternative to cholangiography for the evaluation of choledocholithiasis, selecting only those patients confirmed to have CBD stones at ERCP. MRCP can be utilized as an alternative when there are contraindications to sedation, or when EUS is not available. ERCP should be avoided, if biliary EUS is normal, ^, unless symptoms persist or recur during follow-up. Ideally, EUS and ERCP should be combined in a single endoscopic session whenever possible to reduce risks of repeated sedation and to minimize costs. When this approach is not feasible, high-risk patients could be managed with an ERCP-first approach.

B

Gallstones

Transabdominal ultrasound (TUS) is an excellent modality for the diagnosis of cholelithiasis, with exceedingly high sensitivity and specificity, but its performance is limited in smaller-size stones and large body habitus. Because of its value in diagnosing small CBD stones, EUS has also been evaluated for detecting cholelithiasis ( Figs. 15.6 to 15.8 ; ). EUS can influence the management of patients with biliary pain and normal initial imaging with TUS or CT. ^, For example, Thorboll et al. studied patients with a normal TUS but with suspected gallstones based on clinical grounds and detected cholelithiasis in 18/35 patients (52%).

• Fig. 15.6, (A) Radial EUS image (7.5 MHz) demonstrating a shadowing gallbladder (GB) stone. (B) Radial EUS image (7.5 MHz) demonstrating a shadowing gallbladder (GB) stone and common bile duct (CBD) with a biliary plastic stent in the same patient as in part A. (C) Linear EUS image (7.5 MHz) demonstrating a shadowing gallbladder stone and sludge in a different patient.

• Fig. 15.7, Linear EUS image (7.5 MHz) of a multiple small shadowing gallstones.

• Fig. 15.8, (A and B) Linear EUS images (7.5 MHz) of extensive gallbladder (GB) sludge.

Idiopathic acute pancreatitis (IAP) is an important clinical entity where the cause for acute pancreatitis can be challenging to identify despite an exhaustive workup. The prevalence of IAP is as high as 25% and poses a diagnostic dilemma with paramount clinical implications to identify a treatable cause to help reduce recurrent episodes of acute pancreatitis and associated complications, as well as reduce the risk of progression to chronic pancreatitis and its associated morbidity. Studies ^, have shown the most common identifiable etiologies include biliary (30% to 40%), followed by chronic pancreatitis and occult malignancy with a small percentage related to congenital pancreatic duct anomalies. Guidelines for the evaluation of this disease have endorsed the use of EUS as an effective tool to uncover underlying pancreatic or biliary pathology.

Biliary disease can the result from biliary sludge or microlithiasis undetected by other imaging techniques ( Fig. 15.8 ) and remains the most common cause of pancreatitis in patients with intact gallbladder. An older large series of 168 patients with IAP were referred for EUS which identified gallbladder sludge or very small stones in 40% of patients, with or without associated CBD stones that had been missed by other examinations. Yusoff et al. reported that EUS established a presumptive diagnosis in 31% of 201 patients with a single episode of IAP, the most frequent causes in those with in situ gallbladders being chronic pancreatitis and biliary sludge. A systematic review evaluating the role of EUS in idiopathic pancreatitis showed a high diagnostic yield, especially in patients with a single idiopathic episode, and in patients with recurrent episodes and gallbladder in situ. A cost analysis study identified EUS as the most cost-effective initial test in the evaluation of IAP when compared with other strategies including ERCP with manometry and bile aspiration, and laparoscopic cholecystectomy. Recent studies ^, have demonstrated the ability of EUS to identify an etiology in the majority of patients (up to 67%) with IAP with no increased risk of complications. A recently published systematic review and meta-analysis reported a diagnostic accuracy of 59% in identifying an etiology. Studies ^, have also demonstrated the superiority of EUS over MRCP (including secretin-enhanced MRCP) and ERCP with a systematic review and meta-analysis . confirming these findings (diagnostic accuracy = 64% EUS vs 34% MRCP). MRCP, however, was found to have a higher diagnostic accuracy for identifying pancreas divisum. Nevertheless, pancreas divisum ^, is yet to be established as a direct cause for acute pancreatitis and biliary disease was the primary etiology identified in almost all studies. A large multicenter prospective study (Pancreatitis of Idiopathic origin: Clinical added value of endoscopic UltraSonography [PICUS]) is currently underway and expected to help establish the role of EUS in evaluating IAP. At this time, an EUS-based strategy appears to be the best initial approach to evaluate patients with IAP because of its minimal invasiveness and high diagnostic accuracy in identifying gallbladder sludge and stones, pancreatic diseases, and occult malignancy. In patients with multiple unexplained attacks, particularly in patients post-cholecystectomy and normal pancreatic duct anatomy, ERCP with empiric biliary endoscopic sphincterotomy should be considered after negative EUS results.

Summary

EUS is the most effective method for confirming the presence or absence of CBD stones. Its utility in avoiding unnecessary ERCP has been validated in patients at low or moderate risk of CBD stones. MRCP can probably be used as an alternative to EUS if available and there are no contraindications. EUS remains the preferred diagnostic test in the setting of acute pancreatitis where biliary stones can be very small and missed on MRCP. For patients at high risk of CBD stones, ERCP ± ES/balloon sweep (in case CBD stones were found on cholangiography) can be considered as the first-line approach; however, if EUS is available and can be performed during the same endoscopic session prior to ERCP, it would be optimal. EUS is now a well-established modality after TUS for the diagnosis of gallbladder stones and sludge in patients with unexplained right upper quadrant pain, and also in those with IAP.

DIAGNOSTIC CHECKLIST

CBD or gallstone
- Hyperechoic mobile structure with or without acoustic shadowing
Associated signs
- Dilation of extrahepatic ducts and/or cystic duct
- Thickening of the gallbladder and/or bile duct wall
- Thickening of the ampulla
- Pericholecystic fluid

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