A CASE REPORT

Percutaneous Endoscopic Gastrostomy Fixation of Intrathoracic Gastric Volvulus and Giant Paraesophageal Hernia

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by Karmen Gill, David Wozny, Satinder Gill

Displacement of the stomach into the chest occurs secondary to a weakening of gastric anchoring ligaments and an enlargement of the esophageal hiatus.1 When the stomach moves above the diaphragm, patients may present with obstruction-like symptoms. These symptoms make up the Borchardt triad, signifying a surgical emergency.7 We present a 94-year-old female with displacement of the stomach who underwent laparoscopic reduction and endoscopic fixation via single PEG tube placement. Despite the patient’s age and intrathoracic extrusion, we report positive quality of life outcome. As a result, we suggest single PEG tube fixation as the least invasive solution for recurrent gastric volvulus.

 CASE PRESENTATION 

A 94-year-old female with past medical history of hypertension, asthma, and depression presented to the emergency department with shortness of breath, bloating, epigastric pain, nausea and vomiting. The patient stated she was sitting at home when her symptoms began abruptly at rest. She lives with her adult daughter who is her primary caregiver. 

Over the past year, the patient had been experiencing worsening dysphagia, food regurgitation, globus sensation, gagging without vomiting, frequent constipation and gastroesophageal reflux (GERD) symptoms. She denied similar episodes in the past and has no prior abdominal surgery or recent imaging. Her daughter reports that she maintains most of her mental capacities but does require caregiver assistance at home. 

On physical exam, the patient was acutely tender to palpation in the epigastric region without rebound tenderness. Bowel sounds were diminished in the abdomen but noted diffusely on auscultation of the chest. Cardiac auscultation was normal. Vital signs were positive for tachycardia and tachypnea. 

Chest x-ray (Figure 1) and abdominal computed tomography (CT) (Figures 2 and 3) at that time indicated a large hiatal hernia with a significantly distended stomach located above the diaphragm. The patient was admitted to the hospital where she was kept NPO, given intravenous fluid resuscitation and a nasogastric tube placed. The patient and her family were counseled on possible options to repair the defect, but they expressed reluctance given her frailty and advanced age. The patient was discharged home after four days. 

Two months later, the patient returned to the emergency room with epigastric pain, nausea and vomiting. Physical exam was nearly identical to her first admission. Chest x-ray (Figure 4) and CT abdomen and pelvis without contrast (Figures 5 and 6) at that time indicated a very large hiatal hernia with the majority of the stomach located within the mediastinum. The patient was treated, as before, with nasogastric tube and intravenous fluid resuscitation. The patient and her family opted for her to undergo gastropexy using single PEG tube placement. 

Description of the Procedure 

Percutaneous endoscopic gastrostomy (PEG) was offered to the patient as an alternative to hernia sac resection with mesh cruroplasty due to her frailty and advanced age. Endoscopic approach was preferred as the least invasive option. The endoscopic approach was attempted first, but despite multiple attempts at endoscopic reduction, trans illumination through the abdominal wall was not possible. The endoscopic reduction of gastric volvulus approach was abandoned, and the patient’s abdomen prepped for laparoscopic surgery. 

Upon laparoscopic approach, gas distended bowel loops were noted to occupy the majority of the abdomen and the patient’s large hiatal hernia was easily visualized. The entire transverse colon was incarcerated within the hiatal hernia. It was carefully grasped, and a gentle traction applied until the herniated tissue and the omentum could be fully reduced. The stomach was carefully reduced using laparoscopic grasping forceps into the abdominal cavity. The endoscope was reintroduced and the light was visualized through the abdominal wall despite a distended abdominal cavity with insufflation. The PEG tube was then placed via pull technique. 

The patient tolerated the procedure well. She was extubated in the operating room and taken to the recovery room in a stable condition. She was allowed to resume oral fluids and light diet intake from the first postoperative day and was discharged on the second postoperative day. 

Post Operative Follow Up 

Outpatient follow up occurred 20 days after the procedure. She reported complete resolution of food regurgitation. Her GERD symptoms were now episodic and nocturnal where they had been persistent. The percutaneous endoscopic gastrostomy tube was not used for feeding, and the patient continues to advance her oral intake. At the time of follow up she had resumed a near-normal diet with accommodations made to remain roughly 70% fiber free. Her bowel movements were formed and occurred once daily. 

DISCUSSION 

Hiatal hernia is a condition where a portion of the stomach lies above the esophageal hiatus, within the thoracic cavity. The most common type, sliding hiatal hernia, occurs when the lower esophageal sphincter and portion of the stomach are pulled cephalad so the esophageal hiatus contains the stomach alone.9 One rarer form of hiatal hernia is the rolling hiatal hernia which occurs when the lower esophageal sphincter remains below the esophageal hiatus and a portion of the stomach moves through the hiatus into the thoracic cavity. This condition can progress until most, or all, of the stomach enters the thoracic cavity.1 

Surgery is the treatment of choice for symptomatic large hiatal hernia. However, the timing of surgery and methodology are still in contention. One single center study of 270 patients estimated the annual probability of requiring emergency surgery of a large hiatal hernia was 1%.12 The most common symptoms patients report include GERD, early satiety, dyspnea, chest pain, dysphagia, regurgitation and anemia secondary to Cameron’s ulcers.5 Post-operative follow up has demonstrated symptom resolution of heartburn (93%), regurgitation (92%), dysphagia (81%) early satiety (79%), and chest pain (76%).12 Although surgery has proven successful option for symptom relief in these patients, some conditions can result from an enlarged esophageal hernia which require surgical intervention. 

One condition which may result from an enlarged hiatal hernia and require immediate surgical intervention is gastric volvulus. Gastric volvulus, from the Latin volvere meaning “to roll”, describes a rotation of the stomach more than 180 degrees.6 This condition is potentially life threatening with mortality rates as high as 50%10 secondary to progressive complications including hemorrhage, perforation, shock and potentially a closed loop obstruction. 

There are three subtypes of gastric volvulus classified by the stomach’s axis of rotation: mesenteroaxial, organoaxial and the combined type.7 As a hiatal hernia progresses, the chance of organoaxial volvulus increases as the stomach extrudes into the thorax and rotates around its long axis causing potential obstruction at the level of the gastroesophageal junction or at the pylorus.12 Normally, ligamentous structures keep the stomach in place. The main attachments of the stomach are the gastrophrenic, gastrocolic and gastrosplenic ligaments as well as peritoneal fixation of the duodenum. It has been suggested that a weakening of these ligaments, specifically the gastrocolic and gastrosplenic, can lead to gastric volvulus.10 

The majority of gastric volvulus, 80-90%, occur in the fifth decade of life with no reported associated to race or sex.7 The key diagnostic features of gastric volvulus are described by Borchardt’s triad of severe epigastric pain, vomiting followed by uncontrollable retching without the ability to vomit, and difficulty or inability to pass nasogastric tube.7,10,12 The Borchardt triad has been described in up to 70% of gastric volvulus cases.5 This is a potentially life-threatening condition that has been shown to progress to perforation or infarct.12

Diagnosis of hiatal hernia commonly occurs during endoscopic evaluation and can be confirmed on CT scan.12 The degree of herniation and diagnosis of chronic gastric volvulus are visualized using CT or upper GI studies. CT studies of gastric volvulus demonstrate two air fluid levels with a transition line while barium studies can show if the stomach is laying vertically or horizontally with possible migration of the gastroesophageal junction into the chest.11,12 

The correction of Grade III hiatal hernias and intrathoracic gastric volvulus requires surgical intervention. The traditional surgical therapy for gastric volvulus is based on an open approach.7,10 An analysis of paraesophageal hernia repair from the National Inpatient Sample (NIS) between 1991 and 2008 showed 91% of repairs were performed open and 9% were performed laparoscopically.12 

Endoscopic derotation of gastric volvulus has shown positive results but given the nature of this condition, derotation without fixation is considered a temporary measure.10 The technique for endoscopic derotation requires manipulation of the endoscope into a J-shape then rotating clockwise or counter clockwise. However, depending on the extent of stomach extrusion within the chest, derotation and reduction may not be possible with endoscopy alone.6 In these situations, laparoscopy can assist in stomach visualization reduction. 

Once the stomach has been returned to a near-normal anatomic position, it should be fixed in place to prevent recurrence. The two main methods of fixation are percutaneous endoscopic gastrostomy tube placement and mesh cruroplasty. Mesh cruroplasty resulted in 27% recurrence in one-year imaging despite quality-of-life improvements and four patients required repeat surgery.8 Although PEG tube placement has much smaller sample size, results have been favorable compared to mesh cruroplasty.13

One study of five patients who underwent laparoscopic correction of paraesophageal hernia with 2-point PEG fixation reported 80% returned to normal oral intake post-procedure and were discharged home within three days.11 Gastropexy with a single gastrostomy tube has been reported as sufficient management of gastric volvulus in multiple case reports.2,3,13 Only one study published in 1985 has speculated that single PEG tube fixation may have served as the site of recurrent volvulus.5 Given that both one and two PEG tubes have been efficacious in the fixation of paraesophageal hernia we suggest that one PEG tube is preferable as it halves the chance of common PEG tube complications. 

CONCLUSION 

The method of surgical correction of gastric volvulus and hiatal hernia is generally a question of patient tolerance and preference. Other studies that have shown dual PEG tube placement11 and mesh cruroplasty8 are effective treatment for gastric volvulus, but they are not without complications. The technique described in this case report is unique for the extent of intrathoracic stomach and concomitant gastric volvulus in a patient of advanced age. A small number of similar studies have been published regarding the use of single PEG tube correction of gastric volvulus.2,3,13 Based on the positive results of this study, further investigation is warranted to determine if single PEG tube fixation of gastric volvulus and intrathoracic stomach, as described in this report, is a preferred method of repair.

  1. Altorki, N. K., Yankelevitz, D., & Skinner, D. B. Massive hiatal hernias: the anatomic basis of repair. The Journal of thoracic and cardiovascular surgery. 1998; 115(4):828–835. 
  2. Bhandarkar, D. S., Shah, R., & Dhawan, P. Laparoscopic gastropexy for chronic intermittent gastric volvulus. Indian journal of gastroenterology: official journal of the Indian Society of Gastroenterology. 2001; 20(3): 111–112. 
  3. Baudet, J. S., Armengol-Miró, J. R., Medina, C., Accarino, A. M., Vilaseca, J., & Malagelada, J. R. (1997). Percutaneous endoscopic gastrostomy as a treatment for chronic gastric volvulus. Endoscopy. 1997; 29(2): 147–148. 
  4. Dellaportas, D., Papaconstantinou, I., Nastos, C., Karamanolis, G., & Theodosopoulos, T. Large Paraesophageal Hiatus Hernia: Is Surgery Mandatory? Chirurgia. 2018. 113(6): 765–771. 
  5. Eckhauser, M. L., & Ferron, J. P. The use of dual percutaneous endoscopic gastrostomy (DPEG) in the management of chronic intermittent gastric volvulus. Gastrointestinal Endoscopy. 2018; 31(5): 340–342. 
  6. Jamil, L. H., Huang, B. L., Kunkel, D. C., Jayaraman, V., & Soffer, E. E. Successful gastric volvulus reduction and gastropexy using a dual endoscope technique. Case reports in medicine. 2014; 136381. 
  7. Lee, H. Y., Park, J. H., & Kim, S. G. Chronic Gastric Volvulus with Laparoscopic Gastropexy after Endoscopic Reduction: A Case Report. Journal of gastric cancer. 2015; 15(2):147–150. 
  8. Lidor, A. O., Steele, K. E., Stem, M., et al. Long-term quality of life and risk factors for recurrence after laparoscopic repair of paraesophageal hernia. JAMA surgery. 2015; 150(5): 424–431. 
  9. El Hajj Moussa WG, Rizk SE, Assaker NC, et al. Large paraesophageal hernia in elderly patients: Two case reports of laparoscopic posterior cruroplasty and anterior gastropexy. Int J Surg Case Rep. 2019;65:189–192. 
  10. Morelli, U., Bravetti, M., Ronca, P., et al. Laparoscopic anterior gastropexy for chronic recurrent gastric volvulus: a case report. Journal of medical case reports, 2008; 2: 244. 
  11. Shehzad K, Askari A, Slesser AAP, Riaz A. A Safe and Effective Technique of Paraesophageal Hernia Reduction Using Combined Laparoscopy and Nonsutured PEG Gastropexy in High-Risk Patients. Journal of the Society of Laparoscopic & Robotic Surgeons. 2019;23(4):e2019.00041. 
  12. Lebenthal A, Waterford SD, Fisichella PM. Treatment and controversies in paraesophageal hernia repair. Front Surg. 2015; 2:13. 
  13. Xenos ES. Percutaneous endoscopic gastrostomy in a patient with a large hiatal hernia using laparoscopy. Journal of the Society of Laparoscopic & Robotic Surgeons. 2000;4(3):231–233. 

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FRONTIERS IN ENDOSCOPY, SERIES #87

The Role of ERCP in Patients with Hepatobiliary and Pancreatic Trauma

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INTRODUCTION

Abdominal trauma affects a wide range of demographics and is considered a significant cause of patient mortality. Abdominal trauma can be difficult to diagnose due to the broad presentation of patients. Many patients with abdominal trauma suffer hepatobiliary and/or pancreatic injury. ERCP is an effective diagnostic tool and treatment modality for patients that have experienced these types of injuries. This manuscript will review the endoscopic interventions of patients that present with hepatic and pancreatic trauma, with a focus on ERCP. 

Hepatic Trauma 

Blunt trauma is the most common cause of non-iatrogenic injury to the biliary system. 1 Biliary disruptions that develop secondary to trauma are a rare adverse event with an incidence rate of 4-23% among patients with hepatobiliary trauma.1,2,3 Blunt trauma to the abdomen is most commonly seen following motor vehicles accidents (MVA), but also arise from motorcycle or all-terrain vehicle (ATV) accidents, bicycle accidents, and traumatic falls. Penetrating trauma can also cause biliary duct disruptions.1,3 Penetrating traumas include gunshot wounds (GSW), explosion shrapnel penetration, and stabbing wounds with a sharp object.4 (Figure 1) 

Hepatic trauma affecting the biliary tree can be classified in a variety of ways, but the most widely accepted is the grading scale set by the American Association for the Surgery of Trauma (AAST).4 Generally, higher grades are associated with increased rates of mortality.3,5 The location of the hepatic trauma can also alter the risk factor for bile leaks and may alter the success of the treatment.6 The main bile ducts are located more centrally and are larger than the peripheral bile ducts. Centrally located hepatic traumas were associated with an increased risk of bile leaks and more difficulty recovering compared to peripherally located trauma.1 (Figure 2) 

Manifestations of Hepatobiliary Trauma 

Hepatobiliary trauma can manifest in a variety of ways depending on severity of the liver damage. Manifestations include bile leaks, hemobilia, abdominal abscesses, and bile peritonitis.2 The incidence of major bile leaks and bilomas is 4.9-16% among patients presenting with hepatic trauma.3 Bile leaks were characterized as either a type I or type II in this study. Type I bile leaks are confined to the liver, while type II bile leaks expand out of the liver due to liver capsule disruptions. Type II bile leaks are associated with an increase in hospital length of stay (LOS) as well as increased total bilirubin levels.7 Traumatic extrahepatic biliary injuries can be difficult to diagnose due to the involvement of multiple organ injuries and the deceptive presentation of trauma patients. Many times, incomplete biliary injuries present days to weeks after the initial injury and present with nausea, vomiting, jaundice, and abdominal pain. All of which are nonspecific for bile duct injuries.8,9 This combined with suboptimal imaging and rarity of traumatic bile leaks can present difficulties in diagnosing bile duct leaks.9 

In a study by Yuan et al., serum total bilirubin level greater than 2.55 mg/dL had a sensitivity of 100% and a specificity of 85.1% for predicting bile duct injury.1 Hemobilia is a less common presentation of abdominal trauma, with an incidence rate below 5%. Hemobilia presents clinically as abdominal pain, the presence of bleeding in the upper gastrointestinal tract, and jaundice, although, all three clinical presentations are only seen in 20% of patients with hemobilia.10 Abscesses are a rare adverse event and were only seen in 1/22 patients with liver related adverse events following a high grade (III-V) liver injury in one study.3 

Management of Hepatobiliary Trauma 

It has been well established that nonoperative management is indicated in hemodynamically stable patients following blunt trauma resulting in bile leaks. Laparotomy is generally performed in patients that are unstable or have experienced penetrating wounds that require exploration.11 Nonoperative treatment has been shown to decrease the need for blood transfusions and injury severity score in the nonoperative treatment group with major liver injury grades (II-V).1,12 Nonoperative treatment of blunt hepatic trauma has demonstrated a success rate between 85 and 100%.13 Nonoperative management has also been shown to significantly decrease liver related adverse events when compared to those who underwent surgical hemostasis.3,10

Endoscopic retrograde cholangiopancreatography (ERCP) has been a well-established treatment modality for the diagnosis and management of iatrogenic biliary leaks (which are almost always secondary to surgical interventions) with a success rate of 90-100%.14 There are currently no guidelines on the treatment non-iatrogenic causes of biliary leaks, but ERCP has been widely applied in this setting as well. The timing of intervention has not been well established. In a study by Desai et al., they investigated the rates of adverse events (AEs) on the timing of ERCP. AEs that were included were pancreatitis, duodenal perforation, duodenal hemorrhage, and cholangitis. Patients that had ERCP performed emergently (1 day after bile duct leak) or urgently (2-3 days after the bile leak) had a significantly higher rate of AEs than those who had ERCP done expectantly (3 or more days) after diagnosis of the bile leak.15 The authors did discuss a possible “severity bias” that describes a situation of less stable patients requiring a quicker intervention and thus are at increased risk of developing AEs. Expectant timing has also been shown to have a lower 90-day mortality rate than urgent and emergent groups.16 These findings could also have been affected by the “severity bias” phenomenon. Regardless these studies as well as previously mentioned studies on delayed bile leak presentation support a delayed intervention approach to hemodynamically stable patients presenting with nonspecific symptoms. 

ERCP techniques commonly used to treat bile duct leaks include biliary sphincterotomy, bile duct stent placement, or a combination of the two. (Figure 3) Combination therapy has been shown to have a lower rate of ERCP failure when compared to biliary stenting alone, although in practice many simply place stents as it is simple to perform and avoids the (admittedly low) risks of sphincterotomy, most notably bleeding and perforation.14 The mechanism for bile leak resolution following stent placement and/or sphincterotomy is by lowering the transpapillary pressure, making the transpapillary route of biliary drainage the path of least resistance, which leads to a decrease in resistance and reduces bile flow out of the leak itself, so that the site of the leak can then heal (as healing cannot occur while bile is flowing out of the leak site).17,16 In the study by Flumignan et al., it was determined that there was no difference in clinical success between sphincterotomy combined with biliary stenting and sphincterotomy alone.18 Some believe that high-grade leaks require stenting, whereas smaller leaks can be managed by sphincterotomy alone, but in practice this is left to the operator and most treatment is individualized.19,20 

It is not uncommon for patients to undergo exploratory laparotomy following trauma to the abdomen if severe, potentially repairable injury is suspected. This is especially true in patients that are hemodynamically unstable. One study found that 29% of patients that presented to a level 1 trauma center required an immediate operation and of those patients that required immediate operation, only 15% required emergency operation due to severe liver bleeding.21 Bala et al. found that among patients presenting with high grade liver injuries, 37.5% died in the first 24 hours. Among those who died, 75% died due to hemorrhagic shock. It is important to note that grade V injuries showed a 69% mortality rate when compared to grade III and IV.3 ERCP with sphincterotomy and stent placement is an effective treatment for patients with bile duct damage after hepatic trauma and resolves bile leaks in 90-100% of patients.2,11,14,20,21 In addition to a high success rate in diagnosing and treating bile leaks, ERCP can decrease the risk of developing strictures and cholangitis after abdominal trauma.20 

Pancreatic Trauma 

Pancreatic trauma is reported to occur in as low as 0.2%-3% of all traumas.22 Blunt trauma to the pancreas is rare due to the retroperitoneal location of the pancreas. Blunt trauma represents 37% of those reports, while penetrating trauma, such as GSW and stab wounds, make up the remaining 63%. Mortality rates for pancreatic injury range from 9-34% but have been reported as high as 64% in a site with a level 1 trauma center.22,23,28 In a study by Buitendag et al., overall mortality was 13%. A majority of the fatalities were seen in the operative group. The reasons for mortality in these patients included multiple organ injuries, sepsis, hypovolemic shock, and traumatic brain injury.24 Integrity of the main pancreatic duct is the most important factor in the mortality of patients with pancreatic injury.31,37,39 There are few studies that compare the adverse events that can occur following blunt and penetrating trauma to the pancreas. Coelho et al. found that patients with penetrating trauma were more likely to have recurrence of pancreatic pseudocysts and increased risk of developing an infection when compared to those with blunt trauma.43 

Pancreatic injuries are classified by the American Association of Surgery and Trauma on a scale of I-V on CT.25 Grades I and II include minor contusions with superficial lacerations for grade I laceration without duct injury for grade II. Grade III is a distal transection or parenchymal injury with duct injury. Grade IV is a proximal transection or parenchymal injury involving the ampulla. Grade V is “massive disruption” of the pancreatic head.25 Grade I and II injuries are generally managed without surgery, but grade III and higher are usually managed surgically.26 Grade I and II injuries are the most common pancreatic injuries and represent 80-87% of all pancreatic trauma.26,28 Takishima et al. were able to classify traumatic pancreatic injuries via ERCP. Grade I is a normal appearing pancreatic duct. Grade IIa is injury to branches of the main pancreatic duct with contrast extravasation into the parenchyma, whereas grade IIb is contrast extravasation into the retroperitoneal space. Grade IIIa is injury to the main pancreatic duct at the body or tail of the pancreas, and grade IIIb involves the head of the pancreas.27 

Manifestations of Pancreatic Trauma 

Most patients with pancreatic injury present with polytraumatic injuries due to the retroperitoneal location of the pancreas. The most common concomitant injuries included the liver and the spleen at 34% and 38%, respectively.28 Traumatic injury to the pancreas can present with non-specific abdominal pain or without pain.26 Pancreatic trauma can present with elevated serum amylase and lipase and peripancreatic hematoma.29 Serum lipase and amylase levels were also shown to increase proportionately to the grade of pancreatic injury.27 Serum lipase and amylase have shown a 100% specificity and 85% sensitivity for the prediction of traumatic pancreatic injury.30 Although other studies have failed to show this same correlation, elevated serum amylase and lipase should raise the clinical suspicion of pancreatic injury.30 Other less common adverse events of pancreatic trauma include hemorrhagic pancreatitis, pancreatic ascites, abscesses, and fistula formation.26 

Delays in the diagnosis of traumatic pancreatic duct leaks greater than 24 hours have been shown to increase pancreas-specific morbidity and mortality rates, especially in patients with pancreatic duct disruption.31 Diagnosis of a pancreatic duct leak can be confirmed via ERCP if indicated, based on findings from abdominal CT or observations made during laparotomy if the patient is not hemodynamically stable and warrants surgical exploration.32 ERCP has been shown to be a more sensitive diagnostic tool for pancreatic duct leaks when compared to CT or laparotomy and has a lower rate of adverse events.31 A study by Barkin et al. found that ERCP had a sensitivity and specificity of 100% in the diagnosis of pancreatic duct disruption.33 Another study found that CT scans alone underestimated the grade of pancreatic injury in 13% of patients, as well as missed important findings such as pancreatic head ductal disruptions due to the high fat content surrounding the head of the pancreas.29 Abdominal CT has been shown to miss the diagnosis of major pancreatic duct injury in up to 40% of patients.34 As such, ERCP is considered the gold standard for diagnosis of pancreatic duct leaks. ERCP allows for better visualization of pancreatic injury and can be a platform for simultaneous enactment of therapy to treat a wide range of pancreatic ductal injuries.27 

Management of Pancreatic Duct Injury 

Management of pancreatic trauma is dependent on whether the patient is hemodynamically stable or not.28 Patients that have abdominal trauma with comorbid hemorrhagic shock have been shown to be at increased risk of mortality.28 Conservative management of a pancreatic duct disruption consist of stenting to correct any improper drainage of pancreatic enzymes and bicarbonate, decreasing systemic inflammation, optimal nutritional support, and decreasing the exocrine secretions of the pancreas.35 This can be achieved with the use of parenteral nutrition in combination with medications like octreotide and somatostatin. 

Disconnected duct syndrome is a serious adverse event due to trauma to the abdomen that results in a transection of the pancreatic duct causing an accumulation of pancreatic enzymes and bicarbonate to leak into the abdominal cavity. Endoscopic transpapillary drainage has a clinical success rate of 87% of patients with disconnected pancreatic duct syndrome, but the endoscopist must be able to bridge the disruption fully with a stent for this approach to be successful.36 It is believed that this success rate is so high because this method utilizes the patient’s normal anatomy to route the drainage appropriately. Bhasin et al. have developed a proposed algorithm to evaluate patients with pancreatic duct injury. If there is suspicion of pancreatic duct leak or it is visualized on CT, then ERCP should be performed to evaluate the severity of the leak. Complete disruptions should be surgically repaired, but partial leaks can be treated with endoscopic transpapillary drainage via stenting with or without pancreatic sphincterotomy. If that treatment is unsuccessful, then the patient should be referred to surgery.37 

Recent studies have shown that ERCP can allow as many as three fourths of patients with blunt and penetrating pancreatic trauma to avoid surgery altogether.38 (Figure 4) Patients who receive ERCP greater than 72 hours after the trauma have a significantly increased rate of pancreas-related adverse events and increased hospital LOS.34 ERCP

is especially effective at treating patients with fistulae and pancreatic fluid collections following trauma.39 Transpapillary drainage via ERCP is an effective treatment as long as the pancreatic duct disruption is partial and can be bridged.39 If the disruption is complete, placement of a bridging transpapillary stent via ERCP is still possible, but has a lower success rate overall. A common adverse event in patients with pancreatic trauma is the formation of a pancreatic duct stricture, generally at the site of ductal injury itself (even if the ERCP is successful) and was seen in 4 out of the 6 patients in a study conducted by Lin et al. They also reported one fatality 3 days following the stent placement as a result of sepsis, although the death was likely due to the inciting trauma itself and not the ERCP per se.40 Kim et al. also noted that 2 patients in their series developed mild stenosis of the main pancreatic duct at a 3-month follow-up, but both were asymptomatic 1 year later.34 

Pseudocyst formation is a reported adverse events following blunt trauma to the abdomen and generally occurs weeks to months after the event itself.43 Lin et al. demonstrated the success of ERCP stenting following a distal pancreatectomy complicated by a pancreatic pseudocyst.41 Coelho et al. demonstrated a success rate of 94% for patients treated with ERCP for post-traumatic pancreatic pseudocysts.42 Rates of early adverse events were similar between blunt and penetrating trauma, but stent occlusion was only found in those patients that received ERCP after a penetrating trauma (5.8%). 

CONCLUSION 

Endoscopy is a well-established diagnostic tool that can be utilized in both biliary and pancreatic injury secondary to abdominal trauma. ERCP should be considered as a first-line treatment of hemodynamically stable patients that have suffered abdominal trauma. ERCP has a high success rate for treating biliary and pancreatic injuries. ERCP has shown a low rate of adverse events when used to treat patients with traumatic abdominal injuries. While ERCP is still considered an invasive procedure, the multifunctionality of visualizing the biliary and pancreatic duct and treating the patient outweigh the risk associated with the procedure. ERCP may be utilized in an acute and delayed setting for the treatment of biliary and pancreatic leaks. Biliary injuries specifically show a decrease in adverse events when delayed. Conversely, delays in the diagnosis of pancreatic duct injuries have shown an increase in both mortality and morbidity among trauma patients. Thus, using ERCP is an effective and efficient modality to diagnose and treat patients with traumatic pancreatic and biliary injuries. 

References 

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  • 11. Bridges A, Wilcox CM, Varadarajulu S. Endoscopic man­agement of traumatic bile leaks. Gastrointest Endosc. 2007 Jun;65(7):1081-5. doi: 10.1016/j.gie.2006.11.038. PMID: 17531646. 
  • 12. Croce MA, Fabian TC, Menke PG, Waddle-Smith L, Minard G, Kudsk KA, Patton JH Jr, Schurr MJ, Pritchard FE. Nonoperative management of blunt hepatic trauma is the treatment of choice for hemodynami­cally stable patients. Results of a prospective trial. Ann Surg. 1995 Jun;221(6):744-53; discussion 753-5. doi: 10.1097/00000658-199506000-00013. PMID: 7794078; PMCID: PMC1234706. 
  • 13. Velmahos GC, Toutouzas K, Radin R, Chan L, Rhee P, Tillou A, Demetriades D. High success with nonoperative management of blunt hepatic trauma: the liver is a sturdy organ. Arch Surg. 2003 May;138(5):475-80; discussion 480-1. doi: 10.1001/archsurg.138.5.475. PMID: 12742948. 
  • 14. Rio-Tinto R, Canena J. Endoscopic Treatment of Post- Cholecystectomy Biliary Leaks. GE Port J Gastroenterol. 2021 Jul;28(4):265-273. doi: 10.1159/000511527. Epub 2020 Dec 8. PMID: 34386554; PMCID: PMC8314759. 
  • 15. Desai A, Twohig P, Trujillo S, Dalal S, Kochhar GS, Sandhu DS. Clinical efficacy, timing, and outcomes of ERCP for management of bile duct leaks: a nationwide cohort study. Endosc Int Open. 2021 Feb;9(2):E247-E252. doi: 10.1055/a-1322-2425. Epub 2021 Feb 3. Erratum in: Endosc Int Open. 2021 Feb;9(2):C2. PMID: 33553588; PMCID: PMC7857965. 
  • 16. Adler DG, Papachristou GI, Taylor LJ, McVay T, Birch M, Francis G, Zabolotsky A, Laique SN, Hayat U, Zhan T, Das R, Slivka A, Rabinovitz M, Munigala S, Siddiqui AA. Clinical outcomes in patients with bile leaks treated via ERCP with regard to the timing of ERCP: a large multi­center study. Gastrointest Endosc. 2017 Apr;85(4):766-772. doi: 10.1016/j.gie.2016.08.018. Epub 2016 Aug 26. PMID: 27569859. 
  • 17. Yun SU, Cheon YK, Shim CS, Lee TY, Yu HM, Chung HA, Kwon SW, Jeong TG, An SH, Jeong GW, Kim JW. The outcome of endoscopic management of bile leakage after hepatobiliary surgery. Korean J Intern Med. 2017 Jan;32(1):79-84. doi: 10.3904/kjim.2015.165. Epub 2016 Jul 8. PMID: 27389530; PMCID: PMC5214721.

18. Flumignan VK, Sachdev AH, Nunes JPS, Silva PF, Pires LHB, Andreoti MM. SPHINCTEROTOMY ALONE VERSUS SPHINCTEROTOMY AND BILIARY STENT PLACEMENT IN THE TREATMENT OF BILE LEAKS: 10 YEAR EXPERIENCE AT A QUATERNARY HOSPITAL. Arq Gastroenterol. 2021 Jan-Mar;58(1):71-76. doi: 10.1590/S0004-2803.202100000-12. PMID: 33909800. 

19. Sandha GS, Bourke MJ, Haber GB, Kortan PP. Endoscopic therapy for bile leak based on a new classification: results in 207 patients. Gastrointest Endosc. 2004 Oct;60(4):567-74. doi: 10.1016/s0016-5107(04)01892-9. PMID: 15472680. 

20. Bajaj JS, Spinelli KS, Dua KS. Postoperative manage­ment of noniatrogenic traumatic bile duct injuries: role of endoscopic retrograde cholangiopancreaticography. Surg Endosc. 2006 Jun;20(6):974-7. doi: 10.1007/s00464-005- 0472-3. Epub 2006 May 11. PMID: 16738995. 

21. Velmahos GC, Toutouzas K, Radin R, Chan L, Rhee P, Tillou A, Demetriades D. High success with nonoperative management of blunt hepatic trauma: the liver is a sturdy organ. Arch Surg. 2003 May;138(5):475-80; discussion 480-1. doi: 10.1001/archsurg.138.5.475. PMID: 12742948. 

22. Gaspar BS, Ionescu RF, Bejenaru IM, Najm A, Iliescu R, Manolescu ȘL, Dumitriu B, Gheju I, Chiotoroiu A, Ene D, Georgescu TF, Jinescu G, Mehic R, Tănase C, Iordache F, Turculeţ C, Avram M, Beuran M. The Management of Pancreatic Trauma – A Continuous Challenge. Chirurgia (Bucur). 2021 Dec;116(6 Suppl):S43-S53. PMID: 35274611. 

23. Dave S, Toy FK, London S. Pancreatic Trauma. [Updated 2022 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https:// www.ncbi.nlm.nih.gov/books/NBK459365/ 

24 Buitendag JJP, Kong VY, Laing GL, Bruce JL, Manchev V, Clarke DL. A comparison of blunt and penetrating pan­creatic trauma. S Afr J Surg. 2020 Dec;58(4):218. PMID: 34096212. 

25. Moore EE, Cogbill TH, Malangoni MA, Jurkovich GJ, Champion HR, Gennarelli TA, McAninch JW, Pachter HL, Shackford SR, Trafton PG. Organ injury scaling, II: Pancreas, duodenum, small bowel, colon, and rectum. J Trauma. 1990 Nov;30(11):1427-9. PMID: 2231822. 

26. Iacono C, Zicari M, Conci S, Valdegamberi A, De Angelis M, Pedrazzani C, Ruzzenente A, Guglielmi A. Management of pancreatic trauma: A pancreatic surgeon’s point of view. Pancreatology. 2016 May-Jun;16(3):302-8. doi: 10.1016/j. pan.2015.12.004. Epub 2015 Dec 22. PMID: 26764528. 

27. Takishima T, Hirata M, Kataoka Y, Asari Y, Sato K, Ohwada T, Kakita A. Pancreatographic classification of pancreatic ductal injuries caused by blunt injury to the pancreas. J Trauma. 2000 Apr;48(4):745-51; discussion 751-2. doi: 10.1097/00005373-200004000-00026. PMID: 10780612. 

28. Cerwenka H, Bacher H, El-Shabrawi A, Kornprat P, Lemmerer M, Portugaller HR, Mischinger HJ. Management of pancreatic trauma and its consequences–guidelines or individual therapy? Hepatogastroenterology. 2007 Mar;54(74):581-4. PMID: 17523326. 

pancreatography in the treatment of traumatic pancreatic duct injury. Gastrointest Endosc. 2001 Jul;54(1):49-55. doi: 10.1067/mge.2001.115733. PMID: 11427841. 

35. Sealock RJ, Othman M, Das K. Endoscopic Diagnosis and Management of Gastrointestinal Trauma. Clin Gastroenterol Hepatol. 2021 Jan;19(1):14-23. doi: 10.1016/j.cgh.2019.09.048. Epub 2019 Oct 9. PMID: 31605872. 

36. Chen Y, Jiang Y, Qian W, Yu Q, Dong Y, Zhu H, Liu F, Du Y, Wang D, Li Z. Endoscopic transpapillary drainage in disconnected pancreatic duct syndrome after acute pancre­atitis and trauma: long-term outcomes in 31 patients. BMC Gastroenterol. 2019 Apr 16;19(1):54. doi: 10.1186/s12876- 019-0977-1. PMID: 30991953; PMCID: PMC6469079. 

37. Bhasin DK, Rana SS, Rawal P. Endoscopic retrograde pan­creatography in pancreatic trauma: need to break the mental barrier. J Gastroenterol Hepatol. 2009 May;24(5):720-8. doi: 10.1111/j.1440-1746.2009.05809.x. Epub 2009 Mar 12. PMID: 19383077. 

38. Thomson DA, Krige JE, Thomson SR, Bornman PC. The role of endoscopic retrograde pancreatography in pan­creatic trauma: a critical appraisal of 48 patients treated at a tertiary institution. J Trauma Acute Care Surg. 2014 Jun;76(6):1362-6. doi: 10.1097/TA.0000000000000227. PMID: 24854301. 

39. Bhasin DK, Rana SS, Rao C, Gupta R, Verma GR, Kang M, Nagi B, Singh K. Endoscopic management of pan­creatic injury due to abdominal trauma. JOP. 2012 Mar 10;13(2):187-92. PMID: 22406599. 

40. Lin BC, Liu NJ, Fang JF, Kao YC. Long-term results of endoscopic stent in the management of blunt major pancre­atic duct injury. Surg Endosc. 2006 Oct;20(10):1551-5. doi: 10.1007/s00464-005-0807-0. Epub 2006 Aug 1. PMID: 16897285. 

41. Lin BC, Fang JF, Wong YC, Liu NJ. Blunt pancreatic trauma and pseudocyst: management of major pancreatic duct injury. Injury. 2007 May;38(5):588-93. doi: 10.1016/j. injury.2006.11.017. Epub 2007 Feb 15. PMID: 17306266. 

42. Coelho DE, Ardengh JC, Carbalo MT, de Lima-Filho ER, Baron TH, Coelho JF. Clinicopathologic characteristics and endoscopic treatment of post-traumatic pancreatic pseu­docysts. Pancreas. 2011 Apr;40(3):469-73. doi: 10.1097/ MPA.0b013e31820bf898. PMID: 21343833.

29. Al-Thani H, Ramzee AF, Al-Hassani A, Strandvik G, El-Menyar A. Traumatic Pancreatic Injury Presentation, Management, and Outcome: An Observational Retrospective Study From a Level 1 Trauma Center. Front Surg. 2022 Jan 28;8:771121. doi: 10.3389/fsurg.2021.771121. PMID: 35155546; PMCID: PMC8831377. 

30 Mahajan A, Kadavigere R, Sripathi S, Rodrigues GS, Rao VR, Koteshwar P. Utility of serum pancreatic enzyme levels in diagnosing blunt trauma to the pancreas: a prospective study with systematic review. Injury. 2014 Sep;45(9):1384- 93. doi: 10.1016/j.injury.2014.02.014. Epub 2014 Feb 23. PMID: 24702828. 

31 Oláh A, Issekutz A, Haulik L, Makay R. Pancreatic transection from blunt abdominal trauma: early versus delayed diagnosis and surgical management. Dig Surg. 2003;20(5):408-14. doi: 10.1159/000072708. Epub 2003 Jul 31. PMID: 12900531. 

32. Jeroukhimov I, Zoarets I, Wiser I, Shapira Z, Abramovich D, Nesterenko V, Halevy A. Diagnostic Use of Endoscopic Retrograde Cholangiopancreatectography for Pancreatic Duct Injury in Trauma Patients. Isr Med Assoc J. 2015 Jul;17(7):401-4. PMID: 26357712. 

33. Barkin JS, Ferstenberg RM, Panullo W, Manten HD, Davis RC Jr. Endoscopic retrograde cholangiopancreatography in pancreatic trauma. Gastrointest Endosc. 1988 Mar- Apr;34(2):102-5. doi: 10.1016/s0016-5107(88)71272-9. PMID: 2452762. 

34. Kim HS, Lee DK, Kim IW, Baik SK, Kwon SO, Park JW, Cho NC, Rhoe BS. The role of endoscopic retrograde

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Medical Bulletin Board

Updated Standard Of Care Guidelines Point To Cairn Breath Test To Evaluate Gastric Emptying & Diagnosing Gastroparesis

 BRENTWOOD, TENNESSEE, September 14, 2023/EINPresswire.com/ – Cairn Diagnostics, an innovative leader in providing cutting-edge FDA-approved breath tests intended for routine use in diagnostic medicine, today announced the inclusion of its 13C-Spirulina Gastric Emptying Breath Test (GEBT), in recently updated American, European and International Consensus Clinical Guidelines* for evaluation of gastric emptying and diagnosis of gastroparesis (“paralysis of the stomach”) in patients ages 18 years and older. 

Gastroparesis is a debilitating disease in which the stomach empties at an abnormally slow pace and is defined by delayed gastric emptying in the absence of mechanical obstruction. It is characterized by recurrent symptoms such as nausea, vomiting, early satiety, postprandial fullness, abdominal discomfort, and pain. Gastroparesis has clinical origins arising from diabetes, hypothyroidism, nervous system disorders, autoimmune disorders, viral infections, surgery and idiopathic (unknown) reasons. 

Awareness of gastroparesis in the clinical and obesity management community is increasing, with a growing number of gastroparesis cases now resulting from drug interventions such as narcotic pain medications and popular drugs used to treat diabetes and obesity. Semaglutide, in particular, is a drug that slows gastric emptying, making patients feel full and decreasing their appetite, which helps facilitate weight loss and improves glycemic control. Semaglutide is the active ingredient in familiar drugs such as Ozempic, Wegovy and Rybelsus. If these drugs are prescribed to patients that are unknowingly predisposed to gastroparesis, or if the dosage is not carefully titrated to recommended dosage protocols, this can induce moderate to severe gastroparesis. 

Historically, clinical guidelines for diagnosis of gastroparesis have recommended using a radioactive 4-hour gastric emptying study conducted in a nuclear medicine center: a procedure known as Gastric Emptying Scintigraphy (GES). Today, clinicians and patients may alternatively choose Cairn’s innovative GEBT, a safe, non-radioactive, non-invasive, orally administered, 

 FDA-approved, and standardized test to measure rates of gastric emptying and to help diagnose gastroparesis. GEBT does not require nuclear medicine imaging equipment, specially licensed facilities or personnel, or radioactive material. The test can be administered in a clinical practice or by virtually supervised telehealth conveniently in a patient’s home. Upon receipt of a patient’s breath samples at Cairn’s CLIA Laboratory, results can be reported within 24-48 hours. GEBT is now covered by Medicare (CMS) and is commercially available in the U.S. 

“Gastroparesis affects over 5 million people in the U.S.i We have an obesity crisis (approximately 40 percent of Americans being overweight), along with high prevalence of gastroparesis in diabetics, serious gastroparesis-related adverse events associated with popular weight loss drugs, and reluctance to give deep sedation to patients scheduled for endoscopy or surgery who are taking semaglutide,” said Kerry Bush, President & COO, Cairn Diagnostics. “Given the significantly elevated gastroparesis conversation among physicians, these recently updated U.S., EU and international standard of care guidelines underscore the need for the GEBT – a more widely available method for helping to rapidly diagnose this disease and improve health outcomes.” 

GEBT provides a more convenient, timely modality for assessing gastric emptying, particularly in susceptible populations such as diabetics, idiopathic gastroparetic patients, neurologically affected patients, and tender populations where radiation is best avoided. Examples include: patients and clinicians preferring to avoid radiation (gastroparesis is 4 times more prevalent in women than men); patients needing more than one evaluation; those living in smaller and rural communities where nuclear medicine assets are unavailable; and those encountering long scheduling times (up to 3 months) for the nuclear medicine procedure in major metropolitan areas (including academic medical centers), causing delays in evaluation and diagnosis. Contrary to nuclear medicine-based GES, GEBT is always conducted in exactly the same manner over a 4-hour period per Clinical Guideline recommendations. 

GEBT was validated in FDA-approved, 

dual-labeled clinical validation studies (Mayo Clinic, Rochester) against the 4-hour radioactive Gastric Emptying Scintigraphy (GES) procedure, which is considered the conventional method of assessing gastric emptying and must be conducted in specially licensed nuclear medicine facilities.ii 

About Cairn Diagnostics 

Cairn Diagnostics provides safe, validated, standardized, FDA-approved, and conveniently administered diagnostic breath tests. The Company serves community-based practices and partners with university-based academic researchers, medical device, and pharmaceutical companies. Cairn received FDA approval for GEBT in 2015, expanded FDA approval of GEBT to include “at home” administration under virtual supervision in 2021, and inclusion in ACG and AGA Guidelines for evaluating Gastroparesis in 2022. Cairn also recently (2023) received FDA approval for a new generation of high precision gas isotope ratio mass spectrometers (GIRMS) for analyzing GEBT breath specimens making analysis, test reporting and time to diagnosis even faster. 

Cairn was also granted an exclusive CPT PLA Code (0106U) by AMA in July 2019, and received CMS (Medicare) coverage approval in July 2020. Medicare’s coverage decision for GEBT was based on the test’s “analytic and clinical validity as well as clinical utility in the diagnosis of gastroparesis.”iii The GEBT CPT code, Code Description, and Medicare payment rate was published in the National Clinical Laboratory Fee Schedule in January 2021. Cairn currently holds the intellectual property on 14 patents and one pending patent. 

For more information, visit: cairndiagnostics.com 

i. Centers for Disease Control and Prevention. Long-term Trends in Diabetes. CDC’s Div Diabetes Transl. 

ii. Szarka L, et al. A stable isotope breath test with a standard meal for abnormal gastric emptying of solids in the clinic and in research. Clinical Gastroenterology and Hepatology. June 2008; 6(6):635-643. Available at http://www.ncbi.nlm.nih. gov/pubmed/18406670 

iii. Jurisdictions JJ, JM and MolDx, Palmetto GBA, July 2020; Billing & Reimbursement – 13C-Spirulina GEBT. Accessed June 24, 2021. https://cairndiagnostics.com/billing/ 

* ACG Clinical Guideline: Gastroparesis: https://journals.lww. com/ajg/Fulltext/2022/08000/ACG_Clinical_Guideline__ Gastroparesis.15.aspx?context=FeaturedArticles&coll ectionId=2 

LILLY’S MIRIKIZUMAB HELPED PATIENTS WITH CROHN’S DISEASE ACHIEVE LONG-TERM REMISSION IN PHASE 3 TRIAL 

Mirikizumab demonstrated clinical remission and endoscopic response for patients with moderately to severely active Crohn’s disease through 52 weeks 

The study achieved the coprimary endpoints and all major secondary endpoints versus placebo 

This successful Phase 3 trial will be the basis of global regulatory submissions for Crohn’s disease 

INDIANAPOLIS, Oct. 12, 2023/PRNewswire/– Eli Lilly and Company (NYSE: LLY) announced today that mirikizumab (an investigational interleukin-23p19 antagonist) met the co-primary and all major secondary endpoints compared to placebo in VIVID-1, a Phase 3 study evaluating the safety and efficacy of mirikizumab for the treatment of adults with moderately to severely active Crohn’s disease. The double-blind, treat-through trial included mirikizumab, placebo and active control (ustekinumab) arms. 

Crohn’s disease is a form of inflammatory bowel disease (IBD) that can cause systemic inflammation manifested as abdominal pain, diarrhea, fever and weight loss. It can lead to intestinal obstruction, fibrosis and other complications. 

In VIVID-1, all patients in the active treatment arms from the 12-week induction period continued with their original therapy into the maintenance portion of the study up to Week 52. Placebo patients who did not achieve clinical response at Week 12 (nonresponders) were switched to blinded mirikizumab treatment. 

The study included co-primary endpoints, which were: 

Proportion of participants achieving clinical response by patient reported outcomes (PRO)* at Week 12 and clinical remission (defined as a Crohn’s Disease Activity Index [CDAI] Total Score <150) at Week 52 compared to placebo 

In the mirikizumab arm, a statistically higher proportion achieved clinical response at Week 12 and clinical remission at Week 52 compared to placebo (45.4% versus 19.6%, p<0.000001) 

Proportion of participants achieving clinical response by PRO at Week 12 and endoscopic response (defined as ≥50% reduction from 

baseline in Simple Endoscopic Score – Crohn’s Disease [SES-CD] Total Score) at Week 52 compared to placebo 

• In the mirikizumab arm, a statistically higher proportion achieved clinical response at Week 12 and endoscopic response at Week 52 compared to placebo (38.0% versus 9.0%, p<0.000001) 

In this double-blind placebo and active controlled trial – the first reported for an IL-23p19 antibody – mirikizumab achieved all individual and composite major secondary endpoints at Week 52 compared to placebo (p<0.000001). Notably, of the patients who received mirikizumab, 54.1% achieved clinical remission at Week 52 compared to 19.6% of patients who received placebo (p<0.000001). In addition, for the endpoint of clinical remission (defined as CDAI <150), mirikizumab demonstrated non-inferiority versus ustekinumab (non-inferiority margin of 10%). For the endpoint of endoscopic response (≥50% reduction from baseline in SES-CD Total Score) at Week 52, mirikizumab did not achieve superiority to ustekinumab although results with mirikizumab were numerically higher, particularly in the non-multiplicity controlled bio-failed population. 

“I’m excited by these results, which showed more than half of patients on mirikizumab achieved clinical remission as measured by CDAI at one year. Furthermore, mirikizumab demonstrated robust efficacy across subgroups and particularly in patients for whom prior biologic therapy had failed,” said Lotus Mallbris, M.D., Ph.D., senior vice president of immunology development at Lilly. “Many people are seeking relief from their uncontrolled Crohn’s disease, including those still experiencing symptoms with available therapies such as TNF inhibitors. Helping patients achieve long-term clinical remission is what inspires us to develop innovative treatments for inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis.” 

The overall safety was consistent with the known safety profile of mirikizumab. The frequency of serious adverse events was greater in placebo than mirikizumab. The most common treatment-emergent adverse events reported among patients treated with mirikizumab were COVID-19, anemia, arthralgia, headache and upper respiratory tract infection. Additional adverse events of interest reported among patients treated with mirikizumab included infections, injection-site reactions, hypersensitivity, liver enzyme elevations, depression and suicidal thoughts. No major adverse cardiac events were observed in the mirikizumab arm. 

With these data, Lilly plans to submit a marketing application for mirikizumab in Crohn’s disease to the Food and Drug Administration (FDA), followed by submissions to other regulatory agencies around the world, in 2024. Full data from the Phase 3 VIVID program will be disclosed in publications and at upcoming congresses. 

* Clinical response by PRO is defined as ≥30% decrease in stool frequency and/or abdominal pain, and neither score worse than baseline. 

About Mirikizumab 

Mirikizumab is an interleukin-23p19 antagonist that is currently indicated for the treatment of moderately to severely active ulcerative colitis (UC) in Japan, Germany, the United Kingdom and Canada. Mirikizumab selectively targets the p19 subunit of IL-23 and inhibits the IL-23 pathway. Inflammation due to over-activation of the IL-23 pathway plays a critical role in the pathogenesis of UC and Crohn’s disease. 

About Lilly 

Lilly unites caring with discovery to create medicines that make life better for people around the world. We’ve been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 51 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world’s most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer’s disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we’re motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly. com and Lilly.com/news or follow us on Facebook, Instagram, Twitter and LinkedIn. P-LLY

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LIVER DISORDERS

An Enhancing Review of Focal Liver Lesions

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Liver lesions are commonly encountered in our current practice of medicine. Focal liver lesions
encompass the cystic and solid lesions that providers may encounter. Lesions vary greatly.
Most encountered lesions are benign. These include common lesions like the hemangioma,
simple cyst, and focal nodular hyperplasia, or the rarer hepatic adenoma. If uncomplicated,
these lesions rarely need intervention. Malignant lesions are also encountered. These nefarious
lesions include hepatocellular carcinoma and cholangiocarcinoma. Though less common than
benign lesions, these malignant lesions are still frequently identified in clinical practice. Given
the plethora of liver lesions and the various methods for evaluation, it is prudent for primary
care providers and specialists alike to be familiar with this topic. This review aims to highlight
salient information regarding characteristics focal liver lesions and modalities for evaluation.

 INTRODUCTION 

Our modern practice of medicine is rich with information. The widespread use of abdominal imaging for diagnostic and screening purposes has led to an increase in the detection of liver lesions, many of which are discovered incidentally. Furthermore, advances in radiologic techniques and equipment have greatly improved the accuracy when characterizing liver lesions into benign versus malignant, fluid versus solid, or simple versus complex. It is even possible to subclassify liver lesions based on imaging features alone. 

The common use of abdominal imaging, the frequency at which liver lesions are identified, and the prevalence of chronic liver disease worldwide make it essential for all healthcare providers to have familiarity with focal liver lesions and the imaging modalities that assist with further evaluation. In this article, we begin by reviewing various imaging studies available for the detection and evaluation of focal liver lesions. We then highlight clinically relevant benign and malignant liver lesions, their epidemiology, the evaluation of the lesion, and recommendations for management. 

Diagnostic Imaging for Focal Liver Lesions 

The abundance of information collected in radiologic imaging has transformed the field of hepatology. Abdominal imaging is the cornerstone for the evaluation and management of focal liver lesions, so it is important for providers to understand key features of each modality. 

Ultrasound 

Ultrasonography is a non-invasive, readily available, and inexpensive form of abdominal imaging. Because of the high number of ultrasounds (US) performed in everyday practice, many liver lesions are first identified with this modality. These studies can provide insight into the characteristics of the lesion – including echogenicity, shape of the margins, or the presence of vascularity.1 US is particularly helpful for the differentiation between cystic lesions and solid lesions. 

The convenience, safety, and low cost of US make it a good option for screening and surveillance exams. Society guidelines recommend screening patients with cirrhosis every six months for the development of hepatocellular carcinoma (HCC) using a right upper quadrant US with an alpha-fetoprotein (AFP) level. It is important to note that these twice-yearly HCC screening guidelines extend to those infected with hepatitis B virus (HBV) with or without evidence of cirrhosis, as about 20% of patients with HBV who develop HCC will not have cirrhosis.2,3 

When a lesion is identified on traditional non-contrasted US, follow up imaging with another modality may be prudent. For example, simple asymptomatic hepatic cysts can be observed with expectant management, but complicated cysts and solid liver lesions should undergo further workup with contrast enhanced imaging. 

Contrast-Enhanced Ultrasound 

The addition of contrast to the abdominal US has improved the diagnostic capabilities when evaluating liver lesions. Contrast-enhanced US (CEUS) utilizes a gas-filled microbubble contrast agent which allows for visualization of the microcirculation of a liver lesion. The contrast allows for greater assessment for hypervascularity, which can be seen in lesions such as HCC. Similar to other imaging modalities, the pattern 

of enhancement with contrast during arterial phase followed by subsequent contrast washout is an important feature of HCC on CEUS.2 

CEUS is not as widely available in the United States as it is in European countries, largely due to the need for approval of contrast agents from the Food and Drug Administration (FDA). The FDA has currently approved the use of the contrast agent Lumason, however utilization has not yet been adopted into common clinical practice. European studies have shown that CEUS has high sensitivity (97-100%) for diagnosing HCC when lesions are >2.0 cm, which rivals that of computed tomography (CT) and magnetic resonance imaging (MRI).4 However, similar to CT and MRI, the sensitivity and accuracy decrease when lesions are <2.0 cm.4 It is worth noting that the American Association for the Study of Liver Diseases (AASLD) initially included CEUS as an acceptable imaging modality for the diagnosis of HCC, however this recommendation was removed in 2010 after data had shown false positive HCC diagnoses in patients actually affected with cholangiocarcinoma.5 

Computed Tomography 

The “triple-phase” or “triphasic” CT is one of the most helpful imaging modalities when evaluating focal liver lesions. “Triple-phase” refers to three points in time where images are captured after injection of a contrast agent. The first phase refers to the arterial phase which captures images about 30 seconds post-injection. This is followed by a portal venous phase, where images are captured after a 75 second delay from the contrast administration. The final image set captured is the delayed venous phase which occurs about 3 minutes post-contrast bolus. Studies have found that HCC can be diagnosed with >90% accuracy when a lesion is >2cm.6 This means that this technique allows many liver lesions to be diagnosed without the need for invasive biopsy. 

The AASLD and the American College of Radiology (ACR) both support the use of a standardized system for the terminology, technique, interpretation, and reporting of liver lesions suspected to be HCC. This is called the Liver Imaging Reporting and Data System (LI-RADS).7 LI-RADS categories range from LI-RADS 1, representing a lesion that is “definitely benign,” 

to LI-RADS 5 which is “definitely HCC.” It also includes categories such as “not categorizable,” “probably or definitely malignant, not necessarily HCC” and “tumor-in-vein.” Finally, there are categories that reflect treatment response after a lesion has undergone therapy, such as a lesion having “viable” tissue present, a lesion being “non-viable,” or “equivocal.”7 

Magnetic Resonance Imaging 

MRI provides detailed, non-invasive images to assist with the characterization of solid liver lesions. Similar to CT, the specific filling pattern of a lesion can often lead to a diagnosis without the need for a tissue biopsy. The LI-RADS system for the classification of HCC tumors can be applied to images obtained via MRI. 

Gadolinium-based contrast agents (GBCA) are used to enhance MR imaging. There are two hepatospecific contrast agents which have improved the sensitivity and specificity for detection of focal liver lesions: gadoxetic acid (Gd-EOB-DTPA, Eovist) and gadobutrol (Gd-BT-DO3A, Gadavist).8 These agents act to enhance functionally intact hepatocytes along with the extracellular spaces. To this end, these agents enable evaluation of the hepatic tissue perfusion and the hepatobiliary excretion.8 

Gadoxetic acid is a linear chelating GBCA that was approved for clinical use in the United States in 2008. About 50% of the contrast dose is taken up by hepatocytes and then eliminated by biliary excretion. This is in comparison to only about 3-5% of uptake seen in other non-hepatospecific contrast agents.9 Hepatobiliary phase images (i.e., images in which parenchyma is hyperintense compared to vasculature and there is excretion of contrast into the biliary system) can be acquired about 20-40 minutes after the injection of contrast, as opposed to over 1.5 hours after injection of other contrast agents.9 The unique properties of gadoxetic acid create both advantages and disadvantages to using this agent. The advantages include improved distinction between the appearance of lesions such as hepatocellular adenoma and focal nodular hyperplasia. Pitfalls include the “pseudowashout” appearance with benign lesions. This is when the brisk uptake of contrast into hepatocytes can make some hypervascular lesions (such as hemangiomas) 

seem like they are experiencing a “washout,” which would be more suggestive of a malignant lesion.9,10 

Gadobutrol is a GBCA that was approved in the United States in 2011. This agent chelates gadolinium in a macrocyclic, clam-shell-like arrangement. Gadobutrol is useful for the evaluation of possible metastatic lesions or cholangiocarcinoma. There is robust enhancement of lesions during the arterial and portal venous phases. It can also help with evaluation of the arterial and venous anatomy of the liver. Response to local therapies such as transarterial chemoembolization (TACE) or radiofrequency ablation (RFA) can also be assessed with gadobutrol. 

Nuclear Medicine Scans 

A fluorodeoxyglucose (FDG)-positron emission tomography (PET) detects metabolically active malignant cells. When evaluating solid liver lesions, this study can be useful for identifying metastatic disease or primary malignancy such as cholangiocarcinoma. Of note, the sensitivity of FDG-PET in diagnosis HCC is limited and has been reported to be between 50%-70%1, and is therefore not a preferred study for HCC evaluation. 

An additional nuclear study is the technetium- 99m sulfur colloid scan. This is a study that utilizes radioactive technetium attached to a colloid particle. These particles are extracted by cells of the reticuloendothelial system, including Kupffer cells of the liver. Focal nodular hyperplasia appears as a hot area on this uptake scan, while other lesions appear cold.11 

Benign Liver Lesions 

Each of the various lesions that occur within the liver has its own unique fingerprint of risk factors, characteristic features, and techniques for diagnosis and management. An intuitive way to categorize lesions is by globally identifying them as benign or malignant. Below, we review some of the most notable examples of benign focal lesions that providers encounter in practice. 

Cystic Lesions 

Hepatic cysts are a heterogeneous group of fluid filled lesions lined by a thin layer of fibrous tissue. These are usually asymptomatic, but if symptoms are present, they are likely the result of mass effect. 

Symptoms include abdominal pain, distension, nausea, vomiting, early satiety, or biliary obstruction. Hemorrhage of the cyst, rupture, and infection are other potential complications. Uncomplicated cysts are usually managed conservatively, though if complications or symptoms are present, or if there is concern that a lesion has potential for malignant transformation, then treatments such as aspiration, alcoholic sclerotherapy, surgical deroofing, or partial hepatectomy can be considered. 

Simple hepatic cysts are fluid-filled lesions lined with an outer layer of fibrous tissue comprised of cuboidal columnar epithelium.12 Simple cysts have an estimated prevalence of 1%12, occur four times more frequently in women than in men, and usually occur after the age of 40. Studies have not demonstrated an increased risk of cysts with the use of oral contraceptives, which is a notable difference from other focal liver lesions. They are typically asymptomatic, though patients may experience abdominal pains, early satiety, or complications such as rupture or hemorrhage of the cyst.13,14 Uncomplicated, simple cysts can be managed expectantly. 

Mucinous cystic neoplasm of the liver (MCN-L), previously known as biliary cystadenoma, is a lesion characterized by a smooth, thin-walled fibrous stroma lined by biliary-type mucus-secreting cuboidal or columnar epithelium.15 It has been reported that 1-5% of all hepatic cysts are MCN-L. The prevalence increases to 10% if only considering lesions >4 cm.16 MCN-L can be categorized into non-invasive or invasive (previously called biliary cystadenocarcinoma). Imaging can help with raising the suspicion of diagnosis of MCN-L, though ultimately the final diagnosis is made histologically. Needle biopsy is not recommended, as it has limited sensitivity and introduces the risk of seeding the tract with malignant cells if the lesion was in fact an MCN-L with invasive carcinoma.17 Surgical resection is recommended, as this provides tissue for the definitive diagnosis and serves as treatment of the lesion3,18. 

Polycystic liver disease (PCLD) is the development of multiple benign cysts within the liver. It is hypothesized that the cysts arise from aberrant formation of fetal bile ducts that lack connection to the main biliary system. This can occur through two distinct pathologic processes. The first is by inheriting an autosomal dominant genetic mutation of either PKD1 or PKD2 genes, leading to the development of autosomal dominant polycystic kidney disease (ADPKD). Another process is isolated polycystic liver disease (IPCLD), which results from mutations in the protein kinase C substrate 80K-H (PRKCSH) or SEC63 genes.19 In rare cases, significantly symptomatic PCLD or hepatic failure due to the cysts can warrant consideration for orthotopic liver transplantation (OLT). 

Hepatic Hemangioma 

Also referred to as cavernous hemangiomas, these vascular lesions are the most common benign hepatic tumor and have a prevalence of 0.7-1.5%.20,21 Prior studies suggest that they occur three to five times more often in woman than in men,22,23 however other recent data suggests that the distribution between men and women may be rather equal.24 They are most commonly diagnosed between the ages of 40-60 but can occur at any age.24 These lesions are largely asymptomatic and are typically discovered incidentally. If symptoms occur, patients may present with abdominal pains, nausea, vomiting, and earlier satiety, which is likely related to mass effect.22 A rare condition known as Kasabach-Merritt syndrome can occur in those with large hemangiomas >4cm. This syndrome is characterized by bleeding due to consumptive coagulopathy, thrombocytopenia, or disseminated intravascular coagulation.25 It has previously been postulated that hemangiomas are related to female sex hormones and oral contraceptive (OCP) use. However, case-control studies have not shown a direct correlation. Tumor growth has been shown in men, post-menopausal woman, and woman who 

do not take OCPs.26,27 

These lesions can be identified on contrast-enhanced abdominal imaging with US, CT, or MRI. Typical features include a discontinuous peripheral nodular enhancement in the early phase along with a progressive centripetal fill-in during the late phase.3,19 If the imaging is equivocal, a Technetium- 99m-labeled red blood cell scan (Tc99-m RBC scan) can be completed. These are relatively inexpensive exams, and specificity has been described as 100%.1 Given the high vascularity, biopsy is not recommended if imaging is consistent with hemangioma. Hemangiomas rarely need treatment or intervention. If a hemangioma is very large (>10 cm) or is symptomatic, then intervention can be considered. Procedures such as enucleation, RFA, cryoablation, and resection have been reported approaches to treatment.19 

Hepatocellular Adenoma 

Hepatocellular adenoma, also called hepatic adenoma, is a rare benign solid liver lesion. The prevalence is estimated to be between 0.007- 0.012% of the population.3 When the lesions occur, they are typically found in women who use OCPs. This is due to elevated estrogen levels acting as a risk factor for the development of hepatocellular adenoma. Men and women with high endogenous androgen levels, women who are on OCPs or other hormonal therapy, and those who are on anabolic androgen steroids are at increased risk.28 If a patient is diagnosed with an adenoma and is taking hormonal medications, then it is recommended that those medications be discontinued.19 Furthermore, obesity has been identified as a risk factor for the development and progression of hepatocellular adenomas.29 The exact mechanism is not clear, but it has been proposed that it may be related to increased oxidative stress from fatty liver deposition, hepatic inflammation, or from higher amount of estrogen due to adipose tissue.29 

These lesions are often discovered incidentally, though they have a greater tendency to be symptomatic than other lesions. Symptomatic patients describe epigastric or right upper quadrant abdominal pains. One of the more common complications of hepatocellular adenoma is spontaneous hemorrhage, which can occur in 11- 29% of patients.30 

Hepatocellular adenomas can be subclassified based on histology and genetics into 4 different subtypes: hepatocyte nuclear factor-1 alpha, inflammatory hepatocellular adenoma, inflammatory beta-catenin, and non-inflammatory beta-catenin. Each subtype has been associated with varying risk factors, patient population affected, and risk of complication such as rupture or malignant transformation.31 

The evaluation of a possible hepatocellular adenoma starts with obtaining multiphasic cross-sectional imaging. The use of MRI with a GBCA such as gadoxetic acid can help with differentiating hepatocellular adenomas from other benign lesions, such as focal nodular hyperplasia.3,19 MRI can often elucidate the subclass of adenoma based on imaging features. Imaging characteristics include a homogenous, well demarcated lesion with peripheral enhancement. MRI can suggest the presence of steatosis or hemorrhage depending on the density of the contrast present within the lesion.19 CT can be used though is not as informative as MRI and cannot be used to subclassify adenomas. 

Notable complications of adenomas include malignant transformation and rupture. It is estimated that up to 5% of hepatic adenomas progress to HCC.32 Spontaneous rupture of the lesion can occur in 10% of people1, however this rate may be higher in patients with symptomatic lesions. Because of the risk of complications, the management of hepatic adenomas is more aggressive than other benign liver lesions. Surgical resection of a suspected adenoma is recommended if the lesion is >5 cm. Alternatively, if the patient is a woman currently on OCPs, then OCPs can be held and repeat imaging can be obtained to look for interval decrease in size of the adenoma. Lesions <5 cm can be managed with a conservative approach, as small adenomas have rarely been complicated by rupture or transformation to HCC.19 Some experts recommend that lesions of any size be resected in men due to the risk of transformation to HCC.33 

Focal Nodular Hyperplasia 

Focal nodular hyperplasia (FNH) is the second most common benign liver tumor with a prevalence of 0.3-3%.3 They are usually discovered incidentally, but about 20-40% of patients may present with vague symptoms such as abdominal pains, 

palpable mass, hepatomegaly or weight loss.19 FNH typically occurs in women around age 30- 40, though lesions can develop in men and women of all ages.19 It was once suspected that estrogen and other female sex hormones may play a role in the development of FNH. There has been a slight correlation drawn between OCP use and FNH from prior observational studies, but modern OCPs seem to contribute very little to the development or progression of these lesions.34 There have been associations observed between FNH and other vascular anomalies such as hepatic hemangiomas and the vascular hepatic adenomas. Up to 23% of cases of FNH have concurrent hemangioma or adenoma present in the liver.35 

The exact pathogenesis of FNH is not known. It is hypothesized that the lesion starts after an injury to the portal tract. This results in the formation of arterial to venous shunts which in turn causes oxidative stress. This stress triggers hepatic stellate cells to form a characteristic central scar that is typically seen in these lesions.36,37 

It is necessary to differentiate FNH from hepatic adenoma as the management of these two lesions differ. FNH can be well-characterized by abdominal imaging. A classic feature is the “spoke wheel” central scar which can be seen on triphasic CT and GBCA enhanced MRI.38,39 Biopsy is rarely required during the workup of FNH but can be considered if the diagnosis is in question. 

The management of FNH is largely conservative. Most tumors are asymptomatic, the size remains stable or can regress, and rarely is complicated by rupture.19,40 If tumors are severely symptomatic, or if the definitive diagnosis cannot be established, then surgical resection can be considered. Pregnancy, the use of OCPs, and the use of anabolic steroids are not contraindicated when a patient has a known FNH.3 However, it is recommended that the lesion be monitored with abdominal imaging (such as US) every 2-3 years for women who wish to remain on OCPs.19 

Malignant Liver Lesions 

The liver is one of the most common sites of metastatic cancer deposits due in part to its rich blood supply. However, providers should bear in mind that primary liver malignancies are unfortunately commonly encountered in our modern practice of medicine. We now shift our discussion to two nefarious primary liver malignancies. 

Hepatocellular Carcinoma 

HCC is one of the more common cancers worldwide. It is the fourth leading cause of cancer death worldwide,41 accounting for 75% of primary malignant tumors of the liver.42 The largest risk factor for the development of HCC is the presence of cirrhosis; about 1-6% of patients with cirrhosis develop HCC each year.1 Additional risk factors for the development of HCC include those with a history of chronic HBV or HCV (hepatitis C virus), alcohol use, hormonal treatments, metabolic liver disease, those who smoke, and those exposed to environmental or occupational carcinogens.1 

Current guidelines suggest that patients with cirrhosis or chronic HBV with or without cirrhosis undergo HCC screening every 6 months with an abdominal ultrasound with AFP serology.43 Patients with cirrhosis who are found to have a liver lesion of >1 cm on screening US should undergo further diagnostic imaging. This similarly applies to those who have lesions found incidentally on other abdominal imaging, those with a rising AFP in the absence of an identified liver lesion on ultrasound, and in those for whom there is strong clinical suspicion for HCC.44 Triphasic CT or MRI should be performed; the preferred study should depend on a center’s availability of radiologic expertise. Characteristic findings of HCC include enhancement during the arterial phase, followed by washout in the portal venous phase. An enhancing capsule may also be seen on the portal venous or delayed phases.45,46 When present, these findings are highly sensitive and specific for HCC. When these typical features of HCC are not present, and the diagnosis is still in question, then an image-guided biopsy of the lesions can be considered. This decision should be made cautiously, as there is potential risk of seeding tumor through the biopsy tract.1 

Several therapeutic options exist after diagnosis of HCC. TACE is a procedure that directs chemotherapy directly to a lesion with the intent of shrinking tumor size. Radioembolization and systemic chemotherapy can similarly be utilized to reduce tumor burden. Curative treatments include RFA, hepatic resection, or OLT. These can be 

curative and have a 5-year survival rate >50%.3 It is important to carefully choose candidates for OLT. The Milan criteria establish guidelines to help with selection of those who may benefit from treatment of their HCC by OLT. A patient is considered to be within the criteria if they have the following: one lesion ≥2 cm but ≤5 cm; or up to three lesions, each ≥1 cm but ≤3 cm.47 

Cholangiocarcinoma 

Cholangiocarcinoma (CCA) is a malignancy of the biliary tract. It accounts for approximately 25% of primary liver tumors.48 Most cases of CCA are sporadic, though risk factors for development include a medical history of primary sclerosing cholangitis (PSC), choledochal cysts, Caroli’s diseases, biliary papillomatosis, or infection with liver flukes such as Opisthorchis viverrini and Clonorchis sinensis.1,48,49 CCA lesions are subclassified by anatomic location: intrahepatic CCA (ICCA), perihilar CCA (PCCA), or distal CCA (DCCA).48 

The diagnosis of CCA can be challenging, as clinical symptoms and lab testing can be nonspecific. Patients may present with abdominal pains and loss of appetite, along with characteristic “B symptoms” such as fatigue, weight loss, and night sweats. Tumor markers can be helpful if elevated, as a carbohydrate antigen (CA19-9) level greater than 100 U/mL has been shown to have sensitivity and specificity of >80% in patients with concomitant PSC.50 Significantly elevated levels of CA 19-9 (≥ 1000 U/mL) have been associated with metastatic ICCA.48 In most scenarios, however, markers such as CA19-9, AFP, and cancer embryonic antigen (CEA) lack sensitivity and specificity. Imaging with CT or MRI can be very helpful with diagnosing CCA. Imaging may reveal hepatic capsular retractions, encasement of vasculature that may lead to lobar atrophy, and biliary ductal dilation due to obstruction. If a lesion is identified, biopsy should be obtained for definitive diagnosis, as it can be difficult to differentiate CCA from metastatic disease.51 

Prognosis for patients diagnosed with CCA is poor. Treatment options include resection if possible. However, it is important to note that recurrence can occur in up to 62% of patients after 26 months of follow up, and median survival time is 36 months.52 For patients with inoperable tumors, the current recommended chemotherapy includes gemcitabine plus cisplatin.53 

CONCLUSION 

Focal liver lesions are commonly encountered in the clinical practice of both the general internist and the subspecialist. The relatively high prevalence combined with the widespread use of abdominal imaging has led to increasing detection of lesions. The lesions range greatly in significance, from benign “incidentalomas” to advanced malignancies. It is therefore prudent for a practitioner to have a sturdy knowledge base so that one can appropriately evaluate, manage, or refer when a lesion in found. 

References 

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25. Liu X, Yang Z, Tan H, et al. Giant liver hemangioma with adult Kasabach-Merritt syndrome. Medicine (United States). 2017;96(31). doi:10.1097/ MD.0000000000007688 

26. Lehmann FS, Beglinger C, Schnabel K, Terracciano L. Progressive development of diffuse liver hemangiomatosis. J Hepatol. 1999;30(5). doi:10.1016/S0168- 8278(99)80152-4 

27. Gemer O, Moscovici O, Ben-Horin CLD, Linov L, Peled R, Segal S. Oral contraceptives and liver hemangioma: A case-control study. Acta Obstet Gynecol Scand. 2004;83(12). doi:10.1111/j.0001-6349.2004.00551.x 

28. Martin NM, Abu Dayyeh BK, Chung RT. Anabolic steroid abuse causing recurrent hepatic adenomas and hemorrhage. World J Gastroenterol. 2008;14(28). doi:10.3748/ wjg.14.4573 

29. Bunchorntavakul C, Bahirwani R, Drazek D, et al. Clinical features and natural history of hepatocellular adenomas: The impact of obesity. Aliment Pharmacol Ther. 2011;34(6). doi:10.1111/j.1365-2036.2011.04772.x 

30. Erdogan D, Busch ORC, van Delden OM, ten Kate FJW, Gouma DJ, van Gulik TM. Management of spontaneous haemorrhage and rupture of hepatocellular adenomas. A single centre experience. Liver International. 2006;26(4). doi:10.1111/j.1478-3231.2006.01244.x 

31. Semaan A, Branchi V, Marowsky AL, et al. Incidentally detected focal liver lesions-a common clinical management dilemma revisited. Anticancer Res. 2016;36(6). 

32. Colli A, Fraquelli M, Massironi S, Colucci A, Paggi S, Conte D. Elective surgery for benign liver tumours. Cochrane Database of Systematic Reviews. 2007;(1). doi:10.1002/14651858.CD005164.pub2 

33. Oldhafer KJ, Habbel V, Horling K, Makridis G, Wagner KC. Benign Liver Tumors. Visc Med. 2020;36(4). doi:10.1159/000509145 

34. Scalori A, Tavani A, Gallus S, la Vecchia C, Colombo M. Oral contraceptives and the risk of focal nodular hyperplasia of the liver: A case-control study. Am J Obstet Gynecol. 2002;186(2). doi:10.1067/mob.2002.120277 

35. Mathieu D, Zafrani ES, Anglade MC, Dhumeaux D. Association of focal nodular hyperplasia and hepatic hemangioma. Gastroenterology. 1989;97(1). doi:10.1016/0016- 5085(89)91429-7 

36. Sato Y, Harada K, Ikeda H, et al. Hepatic stellate cells are activated around central scars of focal nodular hyperplasia of the liver-a potential mechanism of central scar formation. Hum Pathol. 2009;40(2). doi:10.1016/j.humpath.2008.04.024 

37. Roncalli M, Sciarra A, Tommaso L di. Benign hepatocellular nodules of healthy liver: focal nodular hyperplasia and hepatocellular adenoma. Clin Mol Hepatol. 2016;22(2). doi:10.3350/cmh.2016.0101 

38. Huppertz A, Haralda S, Kraus A, et al. Enhancement of focal liver lesions at gadoxetic acid-enhanced MR imaging: Correlation with histopathologic findings and spiral CT-initial observations. Radiology. 2005;234(2). doi:10.1148/radiol.2342040278 

39. Grazioli L, Morana G, Kirchin MA, Schneider G. Accurate differentiation of focal nodular hyperplasia from hepatic adenoma at gadobenate dimeglumine-enhanced MR imaging: Prospective study. Radiology. 2005;236(1). doi:10.1148/radiol.2361040338 

40. Kuo YH, Wang JH, Lu SN, et al. Natural course of hepatic focal nodular hyperplasia: A long-term follow-up study with sonography. Journal of Clinical Ultrasound. 2009;37(3). doi:10.1002/jcu.20533 

41. Kanwal F, Singal AG. Surveillance for Hepatocellular Carcinoma: Current Best Practice and Future Direction. Gastroenterology. 2019;157(1). doi:10.1053/j.gastro.2019.02.049 

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43. Marrero JA, Ahn J, Rajender Reddy K, Americal College of Gastroenterology. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol. 2014;109(9). doi:10.1038/ajg.2014.213 

44. Marrero JA, Welling T. Modern Diagnosis and Management of Hepatocellular Carcinoma. Clin Liver Dis. 2009;13(2). doi:10.1016/j.cld.2009.02.007 

45. Kambadakone AR, Fung A, Gupta RT, et al. LI-RADS technical requirements for CT, MRI, and contrast-enhanced ultrasound. Abdominal Radiology. 2018;43(1):56-74. doi:10.1007/s00261-017-1325-y 

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NUTRITION REVIEWS IN GASTROENTEROLOGY

Nutrition Care for Patients with Upper GI Malignancies: Part 1 – Head and Neck Cancer

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Patients with head and neck cancer (HNC) often present to their first oncology appointment with malnutrition. The various HNC treatments frequently exacerbate their malnutrition; if patients are not malnourished initially, they are at high risk for developing it while undergoing treatments. Practitioners who are able to navigate through nutrition related side effects of treatment can play a key role in helping patients successfully complete their therapy and recover to a state of good health. During the recovery phase, as side effects eventually subside, patients may require assistance to transition back to their normal diet and lifestyle. This article will review the background of HNC, the nutrition-related side effects of treatments, and it will provide recommendations for providers to guide their patients through various treatment complications.

 INTRODUCTION

Globally there are an estimated 900,000 new cases of head and neck cancer (HNC) and 400,000 deaths from this disease annually.1 Approximately 3% of malignancies in the United States are diagnosed as HNC.1 Common risk factors associated with HNC include Human papillomavirus infection (HPV), smoking, alcohol use, and the Epstein-Barr virus.1 

Head and neck cancers originate in the oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, or the major salivary glands.2 Due to the location of these cancers, a tumor can impede patients’ ability to chew or swallow leading to decreased dietary intake. When this is the case, patients may present with malnutrition to an initial oncology evaluation; 25-50% of patients present with involuntary weight loss.3 Cancer treatments such as surgery or radiation, that target the tumor site, as well as the systemic side effects of chemotherapy and immunotherapy make eating/ drinking more difficult for HNC patients and thus, increase the risk of sarcopenia, frailty and malnutrition.4,5 The purpose of this review is to provide guidance to clinicians on how to help HNC patients navigate treatment symptoms to improve outcomes and quality of life (QoL).

Nutrition Related Side Effects

Maintaining good nutritional status throughout HNC treatment, by preventing weight loss, plays an important role in ensuring optimal outcomes.3,6,7 Patients often need assistance coping with the side effects that occur with HNC treatments. The Registered Dietitian Nutritionist (RDN) is vital to help patients subsist despite the side effects that develop. Sarcopenia is a skeletal muscle disorder characterized by low muscle strength, quality, quantity, and function.4 HNC patients are more prone to sarcopenia than some other cancers due to swallowing disabilities from the primary tumor, comorbidities associated with HNC risk factors (habitual drinking/smoking, old age), and cancerinduced catabolism.4 Sarcopenia is associated with reduced overall survival.5 This may be due to the fact that patients with low skeletal muscle mass experience more toxicities of cisplatin and radiotherapy, thus necessitating dose reductions and breaks from treatment.8 Frailty is a cumulative decline across multiple physiologic systems leading to increased risk of adverse health outcomes; it is preventable and/ or treatable with nutrition and physical activity interventions.9,10 If frailty and malnutrition are not reversed, and patients remain malnourished during treatments, they are at high risk of body tissue catabolism and wound healing disorders.10 Odynophagia and mucositis are common injuries of radiation and chemotherapy, with up to 89% of patients reporting mucositis.3,11,12 Although variable, odynophagia onset often arises during the 3rd week of radiation therapy (RT).13 Soft, smooth, and moist foods pass more easily through the inflamed oral cavity and throat, opposed to hard or crunchy foods that feel like “grit” and often irritate mucosal sores. Acidic foods (citrus foods and vinegars) also irritate mouth sores and should be avoided.

Oral care is important for patients with mucositis; a salt water and baking soda rinse should be encouraged (Table 1).13 Mouthwashes that contain topical anesthetics combined with an antacid suspension and/or diphenhydramine, with or without nystatin, may be prescribed to help patients manage the pain of mucositis.14 Some patients require pain medications prior to meals in order to consume a diet.3 Patients receiving fluorouracil, paclitaxel and docetaxel are at high risk of mucositis.13 One means to reduce the incidence of mucositis is to reduce the blood flow to the mouth, and thus the chemo-toxic medication, by having patients melt ice chips in their mouth for 10-15 minutes before, during, and 10-15 minutes after infusion of fluorouracil; this is not recommended for those with tumors within the oral cavity.14 The combination of chemotherapy and RT can increase the duration and severity of mucositis, though narrowed RT treatment fields reduce affected areas.3,15

Xerostomia results from damage to the parotid glands and it is reported to be the most common side effect of HNC therapies with one study reporting an incidence of 93%.12,13,16 Xerostomia contributes to dysphagia and decreased oral intake resulting in malnutrition.17 Patients with xerostomia should carry fluids with them and learn to sip often. Alternating between bites of foods and sips of liquids, and adding broths, gravies, and sauces to moisten foods will help patients consume more food. As with odynophagia and mucositis, those with xerostomia should maintain good oral hygiene to reduce their risk of dental caries.3 Alcohol-containing beverages and mouthwashes have a drying effect that exacerbates xerostomia and should be avoided.3 Alcohol free mouthwash can be used throughout the day.3,18 Dysphagia is caused by the tumor placement, surgery or deconditioning.13,19 It affects ≤ 30% of patients prior to treatment, but the incidence increases to 38-46% after treatment.20 Altered swallowing can lead to aspiration, pneumonia, pneumonitis, atelectasis, empyema, bronchitis, acute lung injury and adult respiratory distress syndrome.21 Any suspicion of dysphagia should trigger an immediate referral to a speech language pathologist (SLP) who will perform a swallow evaluation and make recommendations for food consistency and fluid viscosity; recommended texture modifications are based on the International Dysphagia Diet Standardization Initiative (IDDSI).22 Table 2 highlights the IDDSI system. 

To maintain swallow function through treatment, HNC patients are encouraged to eat solid foods as much as possible. Patients should focus on eating soft/moist or pureed, high protein, high calorie foods. Frequent, small meals (every 2 hours), opposed to 3 large meals daily, are often better tolerated. Oral nutrition supplements can help to bridge gaps between calories/protein consumed and estimated nutrition needs. 

Dysgeusia is a cancer treatment side effect plaguing up to 76% of patients undergoing combined modality treatment.23 Simple interventions to combat dysgeusia are to avoid metallic silverware and use a mouth rinse/brushing prior to eating.24 Radiation therapy often results in ageusia which can continue for weeks to months post RT, but will slowly start to return to a “new normal” for each patient.23 Dysgeusia/ageusia inhibits appetite. Patients with some taste sensation can enhance food flavor with heavy seasonings.24 The tart flavor is sensed more easily so using lemon flavored foods or vinegar marinades/dressings may help patients who are not plagued by mucositis.25 

Nausea/vomiting – Patients receiving emetogenic chemotherapy agents will likely experience nausea/ vomiting.12 Up to 50-80% of patients may report nausea at some point during HNC treatment.23 Nausea can lead to dehydration, electrolyte imbalances (with vomiting), and malnutrition.23 Patients with mild to moderate nausea may tolerate small, frequent meals. Those with more severe nausea often require antiemetic medications to control their nausea and allow for oral intake. Warm foods tend to be odorous and trigger nausea more than cold or room temperature foods, thus cold foods may be better tolerated when nauseous is a problem.26 A common cause for nausea/vomiting is delayed gastric emptying. Avoidance of foods that are slow to empty from the stomach (e.g., high fat/ fried or high fiber) is recommended.27 Also, head elevation for at least 30 minutes after eating can help to prevent nausea.13

Nutrition Screening and Assessment 

All oncology patients should be screened for risk of malnutrition using a valid screening tool; screening should be repeated throughout the treatments.13 Both the Malnutrition Screening Tool (MST) and the Patient-Generated Subjective Global Assessment (PG-SGA) are validated for outpatients.28,29 The MST is relatively quick to administer, though the PG-SGA is recommended for cancer patients.30 Table 3 highlights the criteria for each screening tool. All patients found to have risk for malnutrition should be referred to the RDN for a complete assessment and interventions. 

Head and neck cancer patients typically have high calorie, protein and fluid needs, often requiring 35-40 kcal/kg/day and 1.5 g protein/ kg/day.13 Patients with severe malnutrition, or protracted nausea and vomiting, may be at risk of refeeding syndrome or Wernicke’s encephalopathy with initiation of nutrition interventions; cautious introduction of calories with multivitamins and thiamine supplementation may be warranted. Close monitoring by the RDN should continue until the therapies are completed and the patients are nutritionally stable; for some patients this may mean long term follow-up with a dietitian.31 In particular, a RDN certified as an oncology nutrition specialist (CSO) is trained to help navigate nutrition related side effects that cancer patients may encounter. 

Enteral Nutrition 

Treatment for HNC is rigorous and given the importance of maintaining proper nutrition during and after treatment, enteral nutrition (EN) may be necessary. While many providers prefer for patients to meet their nutrition needs without EN, some will benefit from a prophylactic enteral feeding tube placed beyond the affected area. Table 4 outlines the National Comprehensive Cancer Network guidelines on timing for enteral feeding tube placement.31 

A standard, polymeric EN formula is appropriate for patients with HNC requiring EN. The use of immunonutrition in HNC patients appears to reduce the severity of mucositis, however more research is needed before guidelines are developed.10,13,32,33 Study results of elemental diets in patients with HNC did not show significant benefit and therefore is not recommended.32 

Patients receiving EN can experience a variety of intolerance complications. The RDN can help to manage these complications in order to maximize EN tolerance to meet the patient’s nutrition needs. 

Nausea/vomiting – First, test for improved tolerance by reducing the EN formula volume and rate of infusion. Next, evaluation for constipation as it can trigger nausea/vomiting symptoms. In severe cases, when adjustments to the EN regimen do not improve symptoms, then use of prokinetic agents, such as metoclopramide or erythromycin, may increase gastric motility and, in-turn, alleviate nausea.21 Diarrhea is defined as stool volume greater than 500 mL every 8 hours or greater than 3 bowel movements (BM) per day for 2 consecutive days.21 When receiving EN, one liquid BM daily is not diarrhea. It is important to evaluate the possible causes of the diarrhea and not simply blame the EN. Table 5 lists possible causes of diarrhea. Once infection and fecal impaction are ruled out, patients can start an anti-diarrheal medication to help control stool output. The RDN can evaluate the patient and make recommendations for adjustments to the EN regimen.21 

Constipation – Common causes of constipation are dehydration, insufficient or excess fiber intake, and the use of narcotic pain medications. Evaluation of hydration status with strict attention to intake and output data will help elucidate whether dehydration is contributing to constipation; ensure that the patient is receiving at least 1 mL of fluid per calorie and producing at least 1 liter of urine per 24 hours.21 If the patient is adequately hydrated, then the RDN can evaluate the fiber content of the enteral formula and make recommendations for adjustments. 

Survivorship

HNC patients are at risk for chronic, nutrition-related complications throughout their treatments. Weight loss in the weeks/months post treatment are a sign of compromised nutritional status and should be addressed as decreased nutritional status increases mortality risk and reduces QoL.34 Long-term follow-up with a RDN is beneficial to help manage nutrition intake in the setting of the treatment side effects. Additionally, the RDN can help patients to transition from EN, or oral supplements, back to a more normal diet while closely monitoring weight, strength, and physical function. 

CONCLUSION 

HNC and its treatments can be harrowing, often leaving patients with physical disfigurements and long-term nutrition complications. Providers must arm themselves with the knowledge necessary to identify patients at nutritional risk, and the tools to help patients meet their nutritional needs, in order to successfully complete and recover from the treatments. In a perfect world, a patient would be able to eat throughout their treatments. However, that often is not the case so providers must be cognizant of the proper timing for EN access to bridge all nutritional gaps. The RDN will provide diet counseling, troubleshoot EN intolerances, and assist patients with their transition back to an oral diet when possible. The side effects of HNC treatments can be long lasting; awareness that treatment completion does not mean the patient will quickly progress back to their normal diet is important. An understanding of the salient issues and readiness to help patients navigate nutrition-related consequences of cancer treatments will improve clinical outcomes and help HNC patients lead a more fulfilling life.

References 

  1. Stenson KM. Epidemiology and risk factors for head and neck cancer. In Brockstein BE, Sha S eds. UpToDate. UpToDate; 2022. Access 11/4/2022. www.uptodate.com 
  2. Brockstein BE, Stenson KM, Song S. Overview of treat­ment for head and neck cancer. In Posner MR, Fried MP, Brizel DM, Shah S, eds. UpToDate. UpToDate; 2022. Access 11/4/2022. http://www.uptodate.com 
  3. Maghami E, Ho A. Multidisciplinary Care for the Head and Neck Cancer Patient. Springer, Durant, CA, 2018;187-208. 

Takenaka Y, Takemoto N, Oya R, et al. Prognostic impact of sarcopenia in patients with head and neck cancer treated with surgery or radiation: A meta-analysis. Plos 

One. 2021; https:/doi.org/16:e0259288. 

5. Findlay M, White K, Stapleton N, et al. Is sarcopenia a predictor of prognosis for patients undergoing radiother­apy for head and neck cancer? A meta-analysis. Clinical Nutrition. 2021;40:1711-1718. 

6. Ravasco P, Monteiro-Grillo I, Vidal PM, et al. Impact of Nutrition on Outcome: A Prospective Randomized Controlled Trial in Patients with Head and Neck Cancer Undergoing Radiotherpy. Head & Neck: Journal for the Sciences and Specialties of the Head and Neck. 27(8), 659-668. 

7. Tan SE, Satar NFA, Majid HA. Effects of Immunonutrition in Head and Neck Cancer Patients Undergoing Cancer Treatment – A Systemic Review. Frontiers in Nutrition. 2022;9:821924. 

8. de Bree R, van Beers MA, Schaeffers A. Sarcopenia and its impact in head and neck cancer treatment. Curr Opin Otolaryngol Head Neck Surg. 2022;30:87-93. 

9. de Bree R, Meerkerk C, Halmos G, et al. Measurement of sarcopenia in head and neck cancer patients and its associ­ation with frailty. Frontiers in Oncology. 2022;12:884988. 

10. Dewansigh P, Bras L, ter Beek L, et al. Malnutrition risk and frailty in head and neck cancer patients: coexistent but distinct conditions. European Archives of Oto-Rhino- Larngology. 2022. https://doi.org/10.1007/s00405-022- 07728-6. 

11. Pacheco R, Cavacas MA, Mascarenhas P, et al. Incidence of Oral Mucositis in Patients Undergoing Head and Neck Cancer Treatment: Systematic Review and Meta- Analysis. Med. Sci. Forum. 2021;5(1):23.

12. Orell H, Schwab U, Saarilahti K, et al. Nutritional Counseling for Head and Neck Cancer Patients Undergoing (Chemo) Radiotherapy – A Prospective Randomized Trial. Frontiers in Nutrition. 2019;6:1-12. 

13. Coble Voss A, Williams V. Oncology Nutrition for Clinical Practice, 2nd edition. Academy of Nutrition and Dietetics, Chicago, IL, 2021;472-485. 

14. Leser M, Ledesma N, Bergerson S, et al. Oncology Nutrition for Clinical Practice. Academy of Nutrition and Dietetics, Chicago, IL, 2013;268. 

15. Galloway T, Amdur RJ. Management and preventions of complications during initial treatment of head and neck cancer. In Posner MR, Brockstein BE, Brizel DM, Deschler DG eds. UpToDate. UpToDate;2023. Access 3/14/2023. https://www.uptodate.com. 

16. Schulz RE, Bonzanini LIL, Ortigara GB, et al. Prevalence of hyposalivation and associated factors in survivors of head and neck cancer treated with radiotherapy. Journal of Applied Oral Science. 2021;29:e20200854. 

17. Nuchit S, Lam-ubol A, Paemuang W, et al. Alleviation of dry mouth by saliva substitutes improved swallowing ability and clinical nutritional status of post-radiotherapy head and neck ancer patients: a randomized controlled trial. Supportive Care in Cancer. 2020;28:2817-2828. 

18. Recipes to Help with Sore Mouth or Throat. Oncology Nutrition: Educational Handouts and Resources. Academy of Nutrition and Dietetics. 2021. 

19. Mercandante S, Aielli F, Adile C, et al. Prevalence of oral mucositis, dry mouth, and dysphagia in advanced cancer patients. Support Care Cancer. 2015;23:3249-3255. 

20. Kristensen MB, Isenring E, Brown B. Nutrition and swal­lowing therapy strategies for patients with head and neck cancer. Nutrition. 2020;69:110548. 

21. Gottschlich MM. The A.S.P.E.N. Nutrition Support Core Curriculum: A Case Based Approach – The Adult Patient. The American Society for Parenteral and Enteral Nutrition, Silver Spring, MD, 2007; 247-252. 

22. International Dysphagia Diet Standardisation Initiative. The IDDSI Framework. Accessed March 16, 2023. https://iddsi.org/Framework. 

23. Martini S, Iorio GC, Arcadipane F, et al. Prospective assessment of taste impairment and nausea during radio­therapy for head and neck cancer. Medical Oncology. 2019;36:44. 

24. Dellafiore F, Bascape B, Baroni I, et al. What is the rela­tions between dysgeusia and alterations of the nutritional status? A metanarrative analysis of integrative review. Acta Biomed. 2021;92(2):e2021023.

25. Donald M. A matter of taste: alteration in patients with cancer. British Journal of Nursing. 2022;31(13). 

26. Nausea and Vomiting. Oncology Nutrition: Educational Handouts and Resources. Academy of Nutrition and Dietetics. 2021. 

27. Gropper SS, Smith JL, Groff JL. 2. In: Advanced Nutrition and Human Metabolism. Thomson Wadsworth, Belmont, CA, 2005:39. 

28. Ferguson, M, Capra S, Bauer J, et al. Malnutrition Screening Tool. Nutrition. 1999;15:458-464. 

29. PG-SGA. Patient-Generated Subjective Global Assessment. Accessed March 16, 2023. https://pt-global. org/pt-global/. 

30. Serón-Arbeloa C, Labarta-Monzón L, Puzo-Foncillas J, et al. Malnutrition Screening and Assessment. Nutrients. 2022 Jun 9;14(12):2392. https://doi.org/10.3390/ nu14122392. 

31. NCCN Guidelines Version 3.2021 Head and Neck Cancers. National Comprehensive Cancer Network web­site. Accessed 10/26/2021. https://www.nccn.org. 

32. Tanaka Y, Shimokawa T, Harada K. Effectiveness of elemental diets to prevent oral mucositis associated with cancer therapy: A meta-analysis. Clinical Nutrition ESPEN. 2022;49:172-180. 

33. Zheng X, Kaili Y, Wang G. Effects of immunonutrition on chemoradiotherapy patients: A systemic review and meta-anaylsis. JPEN. 2020;44(5):768-778. 

34. Zaid ZA, Neoh MK, Daud ZAM, et al., Weight Loss in Post-Chemoradiotherapy Head and Neck Cancer Patients. Nutrients. 2022;14:548. 

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MEDICAL BULLETIN BOARD

U.S. Fda Approves Subcutaneous Administration of Takeda’s Entyvio® (Vedolizumab) for Maintenance Therapy in Moderately to Severely Active Ulcerative Colitis 

 ENTYVIO Is the Only FDA-Approved Ulcerative Colitis Biologic That Offers the Choice of Intravenous or Subcutaneous Maintenance Therapy 

OSAKA, Japan and CAMBRIDGE, Massachusetts, September 27, 2023 – Takeda (TSE:4502/ NYSE:TAK) announced that the U.S. Food and Drug Administration (FDA) has approved a subcutaneous (SC) administration of ENTYVIO® (vedolizumab) for maintenance therapy in adults with moderately to severely active ulcerative colitis (UC) after induction therapy with ENTYVIO intravenous (IV).1 ENTYVIO SC is expected to be available in the U.S. as a single-dose pre-filled pen (ENTYVIO Pen) by the end of October. Additionally, a Biologics License Application for an investigational SC administration of ENTYVIO for the treatment of adults with moderately to severely active Crohn’s disease is currently under review by the FDA. 

“With the FDA approval of subcutaneous ENTYVIO, patients and physicians who want ENTYVIO’s clinical profile along with flexibility of administration now have two choices for maintenance treatment for adults with moderate to severe ulcerative colitis,” said Brandon Monk, senior vice president, head, U.S. Gastroenterology Business Unit, Takeda. “Takeda is committed to meeting the varied medical needs, circumstances and personal preferences of people living with UC as they progress in their lifelong journey with the disease. ENTYVIO is the only FDA-approved biologic for maintenance therapy in ulcerative colitis offering the option of either intravenous or subcutaneous administration.” 

The approval of this new route of administration for ENTYVIO is based on the VISIBLE 1 study (SC UC Trial). VISIBLE 1 was a Phase 3, randomized, double-blind, placebo-controlled trial that assessed the safety and efficacy of an SC formulation of ENTYVIO as maintenance therapy in adult patients with moderately to severely active UC who achieved clinical response* at Week 6 following two doses of open-label vedolizumab intravenous therapy at Weeks 0 and 2.1 A total of 162 patients were randomized at Week 6 in a double-blind fashion (2:1) to one of the following regimens: ENTYVIO SC 108 mg or placebo by subcutaneous injection every 2 weeks. Eligible patients included patients who had demonstrated an inadequate response to, loss of response to, or intolerance to at least one 12-week regimen of azathioprine or 6-mercaptopurine, induction with a tumor necrosis factor (TNF) blocker, or corticosteroids. The primary endpoint was clinical remission at Week 52, which was defined as a total Mayo score of ≤2 and no individual subscore >1. 

“The VISIBLE 1 trial demonstrated that ENTYVIO SC can provide physicians with an additional administration option for achieving remission in their moderate to severe ulcerative colitis patients. Since its approval in 2014, ENTYVIO has continued to build a robust safety and efficacy profile. I appreciate now having a subcutaneous administration option that provides a clinical profile consistent with ENTYVIO IV while also giving me and my appropriate UC patients a choice of how they receive their maintenance therapy,” said Bruce Sands, M.D., M.S., Chief of the Dr. Henry D. Janowitz Division of Gastroenterology at the Icahn School of Medicine at Mount Sinai. Dr. Sands is a paid consultant of Takeda Pharmaceuticals U.S.A., Inc. He has not been compensated for media work. 

A statistically significant proportion of patients receiving ENTYVIO SC 108 mg maintenance therapy administered every 2 weeks achieved clinical remission** compared to patients receiving placebo (46% vs. 14%; p<0.001) at Week 52.1 In clinical studies, the ENTYVIO SC safety profile was generally consistent with the known safety profile of ENTYVIO IV, with the addition of injection site reactions (including injection site erythema, rash, swelling, bruising and hematoma) as an adverse reaction for ENTYVIO SC. The most common adverse reactions reported with 

ENTYVIO IV (incidence ≥3% and ≥1% higher than placebo) were nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities. 

*Clinical response is defined as a reduction in complete Mayo score of ≥3 points and ≥30% from baseline with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point.1 

**Clinical remission is defined as a complete Mayo score of ≤2 points and no individual subscore >1 point at Week 52.1 

Takeda does not expect a material impact on the full year consolidated reported forecast for the year ending March 31, 2024 (Fiscal Year 2023), as a result of this approval. 

About ENTYVIO® (vedolizumab) 

Vedolizumab is a biologic therapy and is approved for intravenous (IV) and subcutaneous (SC) administration (approvals vary by market).1,2 Vedolizumab SC has been granted marketing authorization in the United States, European Union and more than 50 countries (vedolizumab SC is not currently approved for Crohn’s disease in the U.S.). Vedolizumab IV has been granted marketing authorization in more than 70 countries, including the United States and European Union. Globally, vedolizumab IV and SC have more than one million patient years of exposure to date.3 Vedolizumab is a humanized monoclonal antibody designed to specifically antagonize the alpha4beta7 integrin, inhibiting the binding of alpha4beta7 integrin to intestinal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but not vascular cell adhesion molecule 1 (VCAM-1).4 MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract.5 The alpha4beta7 integrin is expressed on a subset of circulating white blood cells.4 These cells have been shown to play a role in mediating the inflammatory process in ulcerative colitis and Crohn’s disease.4,6,7 By inhibiting alpha4beta7 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.4 

  1. ENTYVIO (vedolizumab) Prescribing Information. Takeda Pharmaceuticals U.S.A., Inc. 
  2. ENTYVIO Summary of Product Characteristics (SmPC). Available at: https://www.ema.europa.eu/en/documents/product-information/entyvio-epar-product-information_en.pdf. Last updated: April 2023. Last accessed: August 2023. 
  3. Data on file. Takeda Pharmaceuticals. 
  4. Soler D, Chapman T, Yang LL, et al. J Pharmacol Exp Ther. 2009;330(3):864-875. 
  5. Briskin M, Winsor-Hines D, Shyjan A, et al. Am J Pathol. 1997;151:97 110. 
  6. Eksteen B, Liaskou E, Adams DH. Inflamm Bowel Dis. 2008;14:1298 1312. 
  7. Wyant T, Fedyk E, Abhyankar B. J Crohns Colitis. 2016;10(12):1437-1444. doi:10.1093/ecco-jcc/jjw092. 

Takeda’s Commitment to Gastroenterology 

With this latest milestone, Takeda continues to demonstrate a commitment to meeting the very real needs of those living with gastrointestinal (GI) diseases. We believe that GI and liver diseases are life-disrupting conditions. Beyond a fundamental need for effective treatment options, we understand that improving patients’ lives also depends on their needs being recognized. With nearly 30 years of experience in gastroenterology, Takeda has made significant strides in addressing patient needs with treatments for inflammatory bowel disease (IBD), acid-related diseases, short bowel syndrome (SBS) and motility disorders. We are making significant strides toward closing the gap on new areas of unmet need. Together with researchers, patient groups and more, we are working to advance scientific research and clinical medicine in GI. 

About Takeda 

Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience, and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. 

For more information, visit: 

takeda.com 

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NUTRITION REVIEWS IN GASTROENTEROLOGY

Micronutrient Considerations for Celiac Disease

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While the benefit of a gluten-free diet to promote healing in individuals with celiac disease is clear, it is critical for providers to consider the micronutrient fluctuations that are associated with this conditionand its dietary treatment. Nutritional deficiencies of micronutrients are frequently found in untreated or newly diagnosed celiac disease often as a byproduct of malabsorption. Deficiencies may persist even after strict adherence to a gluten-free diet related to lower nutrient profiles of gluten-free grains and gluten-free products and possibly concurrent dietary restrictions. Micronutrients of concern that may or may not require supplementation include vitamin D, calcium, vitamin B12, folate, and iron. A team approach, including a dietitian specializing in celiac disease, is necessary to ensure micronutrient needs are met on an ongoing basis. This review will summarize considerations for monitoring and supplementation of micronutrients of concern for those adherent to a gluten-free diet.

 INTRODUCTION 

Celiac disease (CeD) is a genetically-mediated autoimmune disease in which gluten causes damage to the small intestine, resulting in interference of nutrient absorption.1 At this time, the only treatment for CeD is strict avoidance of gluten, a protein found in wheat, barley, and rye.2 Gluten triggers a reversible inflammatory process in the small bowel mucosa, which may induce diarrhea, steatorrhea, constipation, bloating, nausea, vomiting, and/or weight loss in individuals with CeD.1 Once a gluten-free diet (GFD) is initiated, the bowel begins to heal, and most individuals report resolution of symptoms. Despite symptom improvement, a strict GFD must be maintained for life to prevent ongoing damage.3 A strict GFD can restore the histology of the small bowel in 95% of children within two years, whereas 34% and 66% of adults experience mucosal recovery after two and five years, respectively.1 

Nutritional deficiencies of micronutrients are frequently found in untreated or newly diagnosed CeD.2 Long-term consequences of mucosal damage and inflammation include malabsorption of nutrients such as calcium, vitamin D, iron, vitamin B12, folic acid, and zinc, which increases the risk for osteoporosis, anemia, and stunted growth.1 The degree of malabsorption depends on the length of time before the CeD diagnosis and the degree of intestinal mucosal injury.2 Moreover, development and/or persistence of symptoms, such as diarrhea and vomiting, may result in decreased total intake and may impact the quality of the diet, further increasing this risk. Parallel restrictions of lactose avoidance and vegan/vegetarian diets may exacerbate the risk for deficiencies and subsequent comorbidities. In a cross-sectional age and gender matched study of Spanish adults, the individuals with CeD on a GFD for >1 year had a deficient intake of folate, vitamin E, vitamin D, iodine, and calcium.4 Women with CeD also had lower iron intake than the women in the control group.4 Additionally, a cross-sectional study of 20 individuals with CeD and 39 healthy controls showed significant differences in serum and dietary folate levels.5 Specifically, the folate, B6, and B12 values were lower in the diet of the individuals on a GFD compared to the healthy controls.5 

Gluten free (GF) products tend to also have lower iron and B vitamins as well as other nutrients, such as calcium, zinc, and magnesium. As the FDA enriches wheat products back to the natural nutrient value of the wheat grain,6 a wheat-based diet is inherently rich in iron, fiber, and B complex vitamins. Food products such as GF breads, pastas, and cereals are not required to be enriched by the FDA.6 Lee and colleagues found that by adding only GF whole grains to a typical GFD, the overall nutrient value improved, specifically with increases in thiamin, iron, calcium, and folate.7 

While the benefit of adhering to a GFD to promote healing in individuals with CeD is clear, it is critical for clinicians to consider the micronutrient fluctuations that are associated with this condition and its medically required dietary pattern. This review will summarize considerations for monitoring and supplementation of micronutrients of concern for those adherent to a GFD. 

Nutrient-Specific Recommendations 

Through discussions with our specialist providers at the Celiac Disease Center at Columbia University, we developed guidelines based on current evidence along with our clinical experience and judgment. Typically ordered nutrient labs include iron studies, folate, vitamin B12, and vitamin D. There is no consensus on the optimal timing for a dual x-ray absorptiometry (DEXA) scan to evaluate bone mineral density (BMD) in CeD, whether at diagnosis or during follow up.2 

For a newly diagnosed CeD patient who just started a GFD: 

Pediatric: we recommend ordering the typical nutrient labs after 4-6 months on a GFD. 

Adult: we recommend ordering the typical nutrient labs at the CeD diagnosis and annually for monitoring. However, if nutrient labs are low at diagnosis, we generally recommend rechecking labs in 3-6 months. 

If usual food intake shows nutritional inadequacies that cannot be alleviated through improved eating habits to meet the Recommended Dietary Allowances (RDA), the dietitian should recommend a GF multivitamin/mineral (MVM).8 If nutrient deficiencies are found through lab work, clinicians should consider recommending a MVM or nutrient-specific supplementation (Table 1, Table 2). A prenatal MVM is recommended for all pregnant or lactating individuals.9 

Vitamin D 

Vitamin D plays an important role in promoting bone health, both through hormonal regulation of bone remodeling and calcium absorption.2 Vitamin D deficiency is common in CeD, which may be due to villous atrophy, fat malabsorption, and possibly reduced dairy intake secondary to lactose intolerance.2 In addition, much of the bone loss in CeD is related to secondary hyperparathyroidism, which is likely caused by vitamin D deficiency and can only be partially reversed with a GFD.2 Verma studied 60 newly diagnosed pediatric patients and found a significant increase in vitamin D levels as well as BMD and bone mass content after 6 months on a GFD.10 

Vitamin D can be obtained through sunlight, supplements, and food.11 The skin makes vitamin D when it is exposed to sunlight; amounts vary based on the time of day, season, geographical 

latitude, skin pigmentation, and other factors.12 Food sources include fatty fish, such as salmon, mackerel, and tuna.11,12 Vitamin D is added to milk and other dairy products, orange juice, and fortified cereals.11,12 However, GF cereals may not be fortified. Cheese and egg yolks naturally contain small amounts of vitamin D.11,12 Many of these sources are animal-based and therefore, individuals following vegan or vegetarian dietary plans must be counseled on strategies to incorporate plant-based vitamin D sources, such as fortified dairy alternatives.11,12 

There are two types of vitamin D supplements: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol).13 The primary source of vitamin D2 is plants, and D2 can be manufactured 

synthetically, whereas vitamin D3 is synthesized in the skin after exposure to the sun.13 Both forms are well-absorbed in the small bowel.11 Vitamin D supplements should ideally be taken with a meal and the full amount can be taken at one time.12 Many calcium supplements also contain vitamin D. Although the body needs vitamin D to absorb calcium, a vitamin D supplement does not need to be taken at the same time as a calcium supplement.12 Note that individuals may not need supplementation over the summer months if increased exposure to sunlight is expected. 

Calcium 

Calcium is an essential mineral for development and maintenance of bone integrity.12 Calcium is  also part of teeth constitution and enables blood to clot, muscles to contract, and the heart to beat.12 The body cannot produce its own calcium, so sufficient dietary intake is critical.12 If calcium intake is insufficient, calcium is taken from the bones.12 Additionally, mucosal damage in CeD impairs calcium absorption, which can lead to impaired bone health. Initially, lactose intolerance may occur related to impaired release of lactase enzyme from the damaged mucosa, which may further limit dairy intake. However, this lactose intolerance is likely to resolve with mucosal healing. Pediatric patients with untreated CeD are at risk of short stature and constitutional delay of puberty.1 Nonetheless, a 2022 meta-analysis concluded that the GFD was associated with higher bone mineral content and BMD in children and adolescents with CeD.14 Calcium-rich foods include dairy (milk, yogurt, cheese), fortified milk substitutes (soy, nut, pea), kale, and salmon.15 

It is important to note that absorption from calcium is highest with doses of 500 mg or less.15 Therefore, calcium intake, from food or supplements, should be spread out throughout the day for maximum absorption. The bioavailability of calcium from dairy products and fortified foods is 30%.15 The presence of oxalic acid and phytic acid in plants reduces calcium absorption.15 Foods such as milk, broccoli, kale, and cabbage have an absorption rate of 27% while spinach, collard greens, sweet potatoes, and beans have an absorption rate of 5%.15 Nevertheless, when individuals consume a variety of foods, the interactions with oxalic or phytic acid likely have minimal or negligible nutritional consequences.15 Absorption of dietary calcium is also reduced to a small extent by intakes of caffeine and phosphorus and to a greater extent by insufficient vitamin D status.15 

Dietitians are necessary to assess dietary intake because serum calcium is an unreliable marker for calcium status.15 Calcium supplementation may be recommended if dietary calcium is inadequate or if malabsorption is suspected. If supplementation is recommended, calcium citrate is often the supplement of choice. Calcium citrate can be taken with or without food, is more easily absorbed, and causes fewer symptoms of gas, bloating, and constipation than calcium carbonate.15 Calcium citrate is also recommended for individuals who are taking acid suppressants as the calcium citrate is better absorbed even in a lower acid environment than calcium carbonate.15 However, calcium citrate supplements only contain approximately 20% calcium.15 Therefore, in order to reach daily requirements, individuals may need to take more of the calcium citrate supplement. 

Vitamin B12 

Vitamin B12 is required for proper red blood cell formation, neurological function, and DNA synthesis.16 Vitamin B12 is absorbed primarily in the ileum.2 Possible reasons for deficiency in CeD, although not well-established, include terminal ileal involvement, pancreatic insufficiency, and competition for vitamin B12 by undesirable bacteria in SIBO.2 

Vitamin B12 is naturally found in animal products, including fish, meat, poultry, eggs, milk, and milk products.16 Therefore, individuals following vegan diet plans must be counseled on strategies to incorporate plant-based vitamin B12 sources, such as fortified nutritional yeast and dairy alternatives.16 

Absorption of vitamin B12 is dose dependent.16 The estimated bioavailability from food varies because absorption decreases drastically when the availability of intrinsic factor is at capacity (at 1–2 mcg of vitamin B12).16 Bioavailability also varies by the type of food source; it appears to be about three times higher in dairy products compared to meat, fish, and poultry.16 The bioavailability from dietary supplements is about 50% higher than that from food sources.16 Gastric acid inhibitors (proton pump inhibitors and histamine 2-receptor antagonists) used to treat gastroesophageal reflux disease and peptic ulcer disease may interfere with vitamin B12 absorption from food by slowing the release of gastric acid into the stomach.16 

Vitamin B12 administered parenterally as a prescription medication through intramuscular injections may be considered for severe deficiency, neurologic features, or ongoing malabsorption.2 Clinicians should assess for intake of supplements, herbals, and energy drinks, which may be sources of vitamin B12.

Folate 

Folate is a B vitamin that is naturally present in some foods whereas folic acid is the form of vitamin B9 that is used in fortified foods and most dietary supplements.17 Folate deficiency is common in CeD likely related to malabsorption, lower folate content of GF grains, and the lack of fortification/ enrichment of GF products.7 Folate is found in a wide variety of foods, including vegetables, especially dark green leafy vegetables, fruits and fruit juices, nuts, beans, peas, seafood, eggs, dairy products, meat, poultry, and grains.17 Spinach, liver, asparagus, and Brussels sprouts are among the foods with the highest folate levels.17 Dietitians should assess for a lack of variety and inadequate intake of GF whole grains in the diet as studies have shown improvement in folate levels with the inclusion of GF whole grains.7 

At least 85% of folic acid is estimated to be bioavailable when taken with food, whereas only about 50% of folate naturally present in food is bioavailable.17 When consumed without food, nearly 100% of supplemental folic acid is bioavailable.17 Given the risk of neural tube defects related to low folate levels, a prenatal MVM with folic acid is recommended for all females of child-bearing age through pregnancy and lactation.17 

Iron 

Iron is an essential mineral for carrying oxygen in the hemoglobin of red blood cells.18 Iron also supports the body’s metabolism, growth, development, cellular functioning and synthesis of some hormones and connective tissue.18 Iron deficiency is common in newly diagnosed CeD due to malabsorption, but iron deficiency discovered further along into the GFD warrants additional investigation to determine the etiology. 

Dietary iron is in the form of heme or non-heme iron.18 Heme iron comes from animal sources, such as meat, fish, and poultry and is most readily absorbed by the body.18 Non-heme iron is found in plant-based foods, such as fruits, vegetables, beans and nuts and has a lower bioavailability.18 Strategies to increase absorption of iron include cooking with a cast iron skillet and consuming heme iron sources or vitamin C along with non-heme iron sources to enhance the absorption of the non-heme iron.18 

Fortified foods are recommended for children between ages 1-2 to ensure iron stores are repleted as prenatal iron stores are exhausted by 6 months.18 Pediatric diets commonly fall short of adequate iron intake and most GF pediatric chewable supplements do not contain iron. Special attention should be paid to toddlers who drink milk in excess of 24 oz per day due to possible interference with iron absorption. 

Frequently used forms of iron in supplements include ferrous and ferric iron salts, such as ferrous sulfate, ferrous gluconate, ferric citrate, and ferric sulfate.18 Ferrous iron in dietary supplements is more bioavailable than ferric iron.18 It is important to note that supplements containing 25 mg iron or more can reduce zinc absorption and plasma zinc concentrations so these levels should be monitored.18 Calcium might interfere with the absorption of iron, although this effect has not been definitively established and the effect is expected to be mitigated by a typical mixed western diet.18 Nevertheless, some experts suggest taking individual calcium and iron supplements at different times of the day to maximize absorption.18 

Although high doses of supplemental iron (45 mg/day or more) are often used to replete iron stores in iron deficiency, it is important to consider that they may cause gastrointestinal side effects, such as nausea and constipation.18 Other forms of supplemental iron, such as heme iron polypeptides, carbonyl iron, iron amino-acid chelates, and polysaccharide-iron complexes, might have fewer gastrointestinal side effects than ferrous or ferric salts.18 Iron infusion is recommended if there is failure or intolerance of oral iron in the setting of persistent iron deficiency anemia. Because proton pump inhibitors reduce production of gastric acid, they can reduce iron absorption as well. Therefore, consider that individuals with iron deficiency on proton pump inhibitors can have suboptimal responses to iron supplementation.18 

CONCLUSION 

A GFD prescription should include standard nutritional guidance emphasizing naturally GF whole foods such as fruits, vegetables, dairy, meat, seafood, nuts, seeds, and legumes for a sound nutritional base.2 The addition of naturally GF 

whole grains or pseudocereals, such as amaranth and quinoa, provides the fiber, B vitamins, and minerals (calcium, iron, magnesium) missing when gluten is removed.2 

Research has indicated that micronutrient deficiencies are common at the time of diagnosis and even after initiation and adherence to a GFD. Deficiencies may be attributed to malabsorption from villous atrophy, lower nutrient profiles of GF grains and GF products, as well as additional dietary restrictions. Routine monitoring of at-risk vitamin and mineral levels should be part of comprehensive follow-up for patients with CeD. A patient-centered team approach including consultation and regular follow up with a specialist dietitian will ensure optimal outcomes. 

Acknowledgements 

We are grateful for the contributions of Cecilia Chen and our colleagues at the Celiac Disease Center, including Dr. Jacqueline Jossen, Dr. Amy DeFelice, Dr. Peter Green, Dr. Benjamin Lebwohl, Dr. Suzanne Lewis, Dr. Suneeta Krishnareddy, Dr. Randi Wolf, and Dr. Marcella Walker. 

References 

  1. Aljada B, Zohni A, El-Matary W. The Gluten-Free Diet for Celiac Disease and Beyond. Nutrients. 2021; 13(11):3993. 
  2. Dennis M, Lee AR, Mccarthy T. Nutritional Considerations of the Gluten-Free Diet. Gastroenterology Clinics of North America. 2019;48(1):53–72. 
  3. Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet. 2018;391(10115):70-81. 
  4. Ballestero-Fernández C, Varela-Moreiras G, Úbeda N, et.al. Nutritional Status in Spanish Adults with CD Following a Long- Term Gluten-Free Diet Is Similar to Non-Celiac. Nutrients. 2021;13(5):1626. 
  5. Valente FX, Campos Tdo N, Moraes LF, et. al. B vitamins related to homocysteine metabolism in adults celiac disease patients: a cross-sectional study. Nutr J. 2015;14:110. 
  6. FDA – National Research Council (US) Subcommittee on the Tenth Edition of the Recommended Dietary Allowances. Recommended Dietary Allowances: 10th Edition. Washington (DC): National Academies Press (US); 1989. 
  7. Lee AR, Ng DL, Dave E, et. al. The effect of substituting alternative grains in the diet on the nutritional profile of the gluten-free diet. J Hum Nutr Diet. 2009 Aug;22(4):359-63. 
  8. Academy of Nutrition and Dietetics. RECOMMENDATIONS SUMMARY. Evidence Analysis Library. https://www.andeal. org/template.cfm?template=guide_su12ry&key=2102. Published 2023. Accessed February 15, 2023. 
  9. Office of dietary supplements – multivitamin/mineral supplements. NIH Office of Dietary Supplements. https://ods.od.nih. gov/factsheets/MVMS-HealthProfessional/. Published October 11, 2022. Accessed February 15, 2023. 
  10. Verma A, Lata K, Khanna A, et al. Study of effect of gluten-free diet on vitamin D levels and bone mineral density in celiac disease patients. J Family Med Prim Care. 2022;11(2):603-607. 
  11. Office of dietary supplements – vitamin D. NIH Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/vitamind-healthprofessional/#h2. Published August 12, 2022. Accessed February 15, 2023. 
  12. Calcium/vitamin D requirements, Recommended Foods & Supplements. Bone Health & Osteoporosis Foundation. May 24, 2023. Accessed July 30, 2023. https://www.bonehealthandosteoporosis.org/patients/treatment/calciumvitamin-d/. 
  13. Alayed Albarri EM, Sameer Alnuaimi A, Abdelghani D. Effectiveness of vitamin D2 compared with vitamin D3 replacement therapy in a primary healthcare setting: a retrospective cohort study. Qatar Med J. 2022;2022(3):29. 
  14. Oliveira DDC, da Silva DCG, Kawano MM, de Castro CT, Pereira M. Effect of a gluten-free diet on bone mineral density in children and adolescents with celiac disease: Systematic review and meta-analysis Crit Rev Food Sci Nutr. 2022;1-11.  Office of dietary supplements – calcium. NIH
  15. Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/Calcium- HealthProfessional/#h2. Published October 6, 2022. Accessed February 15, 2023. 
  16. Office of dietary supplements – vitamin B12. NIH Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/ VitaminB12-HealthProfessional/#h2. Published December 22, 2022. Accessed February 15, 2023. 
  17. Office of dietary supplements – folate. NIH Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/Folate- HealthProfessional/. Published November 30, 2022. Accessed February 15, 2023. 
  18. Office of dietary supplements – iron. NIH Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/Iron- HealthProfessional/. Published April 5, 2022. Accessed February 15, 2023. 

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FRONTIERS IN ENDOSCOPY

EUS-Guided Choledochoduodenostomy: Current Role and Status

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 There are a variety of conditions which may lead to biliary obstruction, usually as a result of malignancy. Endoscopic retrograde cholangiopancreatography (ERCP) is usually highly successful in relieving biliary obstruction via stent placement in these patients, but can fail if the ampulla is not reachable due to gastric outlet obstruction (GOO).1,2,3,4 The 2nd portion of the duodenum/papilla can become infiltrated by invasive malignancy, which can also hamper efforts at deep biliary cannulation.1-2,4 Up to 80% of biliary obstruction cases are due to pancreatic cancer, followed by duodenal cancer, cholangiocarcinoma, metastatic disease, and ampullary cancer.4,5,6,7,8,9,10,11 To a lesser degree, biliary obstruction can also occur with benign conditions such as choledochal cysts, chronic pancreatitis, and post-cholecystectomy biliary strictures.12 

Percutaneous biliary drainage (PTBD) and surgery are the traditional methods for biliary drainage when ERCP is not possible or has failed.13 However, surgical biliary bypass is associated with high morbidity and costs when compared to endoscopic therapy.2,13 While PTBD is effective, it is associated with significant adverse events including fistulas, bleeding, and abscess formation.2 Moreover, external drains frequently require exchanges and can significantly impact a patient’s quality of life.13 As a result, EUS-guided choledochoduodenostomy has emerged as another option to manage biliary obstruction in these cases. 

Development of EUS-Guided Choledochoduodenostomy (EUS-CDS) 

Giovanni et al. first reported EUS-CDS in 2001.14 EUS-CDS is thought to be an easier procedure for draining biliopancreatic tumors.7 Moreover, the rate of tumor ingrowth may be lower as the biliary stricture is not traversed15and a fistula is formed away from the tumor.5,15 While earlier studies suggested EUS guided biliary drainage (EUS-BD) offered greater stent patency than endoscopic transpapillary stenting (ETS), more recent studies 

demonstrate similar clinical efficacy, with shorter procedure time and decreased incidence of post-procedural pancreatitis in EUS-CDS.15,16 

There are two primary approaches to EUS-BD: hepatogastrostomy (EUS-HGS) and EUS- CDS.11 EUS-HGS targets the intrahepatic bile ducts from the stomach, but as there is a thick wall to penetrate, stent deployment can be technically difficult.17 Movement of the liver during breathing may lead to inward stent migration and additional risks include bile leak, biloma, and gastric perforation.17,18 Furthermore, procedural time with EUS-HGS is usually longer as there are more manipulations with the guidewire.18 In EUS-CDS, the extrahepatic biliary ducts are accessed in a transmural manner via the duodenal bulb. The thinner duodenal wall facilitates puncture and abuts the bile duct with minimal respiratory influence.17 It is important to note that stent deployment in the duodenal bulb can be technically challenging because of a relatively unstable endoscope position and small space between the echoendoscope tip and duodenal wall.6 

EUS-CDS was initially performed with plastic stents and while inexpensive, it was prone to bile leaks.5,6 Due to small luminal diameter, there was also an increased risk of early stent occlusion.6,15,19 Since patency decreased after 3 months, the stents were designed to be easily removed and exchanged as needed.19 

The next innovation in EUS-CDS development was the use of covered metal stents. Because of expandability, fully covered or partially covered self-expanding metal stents (SEMS) can potentially seal the gap between fistula and stent better than plastic stents, thus minimizing bile leakage.13,20 (Figure 1) When compared with plastic stents, SEMS offered larger diameters (8-10mm vs. 7-10Fr), which increased the duration of stent patency.20 However, an issue that has been noted is the rate of stent migration, since tubular SEMS have no antimigration system.6,20 Furthermore, while SEMS possesses an adequate diameter for effective biliary drainage, the ends of the stent may lead to tissue injury and bleeding in the duodenum and/or the biliary tree.6 

The advent of the lumen apposing metal stent (LAMS) enabled creation of anastomoses to drain entities such as pancreatic fluid collections and the gallbladder.21 Prior biliary drainage techniques were 

performed without dedicated accessories, so the emergence of LAMS was soon applied to drainage of biliary obstruction.1 The 6mm x 8mm LAMS, 8mm x 8mm LAMS, and the 10mm x10mm LAMS are used most frequently for biliary drainage (in an off-label manner). The choice of stent size is largely determined by operator preference, taking into account the size of the bile duct and the luminal access point.1,8,13 As the LAMS diameter ranges from 6mm to potentially 10mm, this provided better drainage compared to PTBD catheters and the flanges prevent migration.10 LAMS greatly simplified the technique for EUS-CDS, but in this form, several steps are still required to properly place the stent.6 

EC-LAMS: The Current Approach for EUS-Guided Choledochoduodenostomy 

While there is high clinical success for EUS-CDS, there is also a relatively high rate of associated adverse events and a small but definite mortality risk (0.4%) which may reflect the learning curve.22 This has led to the development of dedicated accessories for EUS-CDS.22 Electrocautery Enhanced LAMS (EC-LAMS) span two gastrointestinal lumens using an electrocautery enhanced cutting tip, so tract dilation is not required, nor is even the use of a guidewire as the stent placement can be performed via the freehand technique.23 EC-LAMS eliminates 

device exchanges and has markedly increased efficiency of EUS-CDS.8 

Under endosonographic guidance, a needle (frequently 19-gauge) is used to puncture the extrahepatic bile duct via the duodenal bulb.24 Bile is aspirated, and contrast is injected to create a cholangiogram and confirm the location under fluoroscopy. Either a 0.025” or 0.035” guidewire is then passed into the bile duct. The needle is removed, and the EC-LAMS system is passed over the guidewire and once at the duodenal wall, current is used to advance the system into the bile duct through the duodenal wall and the bile duct wall. The distal flange is deployed under endosonographic and/or fluoroscopic guidance and the proximal flange is deployed under endoscopic guidance. A second stent can be placed on the non-perpendicular axis of the LAMS into the bile duct to prevent the wall from collapsing into the inner flange after biliary decompression, if desired.23 Wire placement was recommended before the ability to recapture the LAMS, to prevent misdeployment.13 However, in experienced hands, wire access is not always necessary, and the entire procedure can be performed via a freehand technique to save time and increase efficiency.4 (Figures 2-7) 

Compared to multi-stage process, EC-LAMS decreases adverse events, procedural time, and 

fluoroscopy exposure.13 It is worth noting that post-ERCP pancreatitis can affect eligibility for curative surgery for advanced pancreatic disease, but EUS-guided procedures avoid manipulation of the papilla entirely and, by and large, do not cause post-procedure pancreatitis. Thus, some sources suggest that EUS-CDS should be evaluated as a primary procedure for stenting biliary obstruction, disease staging, and tissue sampling, although at most centers ERCP remains first-line therapy.4 

Risks and Adverse Events 

Despite the benefits of EUS-CDS, there are immediate and delayed adverse events which are important to acknowledge. 

With regard to LAMS, there is the possibility of misdeployment, dislodgement, as well as duodenal perforation, and bleeding.1,22 Reintervention is most commonly required for stent obstruction secondary to disease progression, food impaction, sump syndrome (accumulation of debris in the common bile duct (CBD) distal to the anastomosis in a side-to-side choledochoduodenostomy), stent migration, LAMS dysfunction, and cholangitis.1,6,13,22 It is thought that smaller stent diameter (6mm/8mm) may be more prone to clogging than a larger bore stent (10mm).6 Moreover, the distal flange can kink in the bile duct after decompression, resulting 

in stent occlusion and cholangitis.6 Thus, many sources recommend LAMS placement may be best in patients with a dilated CBD i.e. > 10-15mm to allow for safer opening of the distal flange.10,13 

In regard to fully covered self-expanding metal stents (FC-SEMS), early adverse events include cholangitis, cholecystitis, liver abscess, and peritonitis.15,22,24,25 Migration is a frequent reason for reintervention, seen in approximately 20% of cases, followed by food impaction, tumor ingrowth, stent dysfunction, and to lesser degree, infections.22,24,25 

Early adverse events following plastic stent placement include bile peritonitis, hemobilia, and pneumoperitoneum.26 Delayed adverse events include stent occlusion and migration.5,26 Da Silva et al. reported a particularly severe case of two double pigtail stents migrating from the duodenal bulb into the abdominal cavity, requiring surgical management. This led to concerns regarding the challenging nature of plastic stent positioning and placement.11 

Vanella et al. advocated for dividing LAMS dysfunction into categories to standardize research, evaluate pathogenesis of the dysfunction, and develop rescue strategies.3 Type 1 dysfunction is sump syndrome, managed with transpapillary stent placement. Type 2 dysfunction is stone impaction (type 2a) or food impaction (type 2b), both of which are treated with balloon extraction. Type 3 

dysfunction is LAMS invasion on the biliary side (3a) or duodenal side (3b), treated by placing double pigtail stents or SEMS through the LAMS. Type 4 dysfunction is LAMS migration, which can be managed by replacing the LAMS through the same fistula, creating a new EUS-CDS, or other methods of EUS-BD. Type 5 dysfunction exists when the malignant biliary obstruction occurs concurrently with a GOO, compromising EUS-CDS patency. The ideal situation would be to resolve the GOO via EUS-guided gastroenterostomy. However, if this does not work, percutaneous transpapillary stenting or EUS-HGS are additional options.3 

Comparison Studies 

Biliary drainage procedures have evolved over time and several studies have evaluated these different techniques. In a retrospective cohort study, Sawas et al. evaluated EUS-CDS (via LAMS and SEMS) vs. PTBD in 86 patients. There was similar technical success (100% in EUS-CDS vs. 96.6% PTBD), but EUS-CDS carried greater clinical success (84.6% vs. 62.1% in PTBD) and had lower adverse event rate (14.3% vs. 29.3% in PTBD). There was no significant difference in survival between the 2 groups and the re-intervention rate was significantly lower with EUS-CDS vs. PTBD (10.7% vs. 77.6%, p<0.001).10 

Furthermore, in a retrospective cohort analysis by Kawakabu et al. comparing optimal drainage 

technique, 26 patients underwent EUS-CDS and 56 patients underwent ETS with covered metal stents. Clinical success was similar between the two groups (96.2% in EUS-CDS vs. 98.2% in ETS, p=0.54), however adverse events occurred in 26.9% of those with EUS-CDS compared to 35.7% of those with ETS. While these figures appear high, the study involved a small sample size and most adverse events were milder cases of pancreatitis, abdominal pain, and fevers. This study suggests that when managing distal malignant biliary obstruction (MDBO) caused by non-pancreatic cancer, there is similar success and efficacy between EUS-CDS and ETS, but the former reduces risk of pancreatitis.15 Notably, this study was conducted among centers with extensive experience in interventional EUS. As EUS-CDS may not be feasible if the required expertise is not available, ERCP is the most commonly used technique, given the widespread availability and good clinical success rate. 

De Benito Sanz and colleagues conducted a retrospective study of 57 patients comparing LAMS to SEMS among patients undergoing EUS-CDS. There was 95% technical success in each cohort and similar clinical success (LAMS 94.7% vs. SEMS 100%, p= NS). There was a 5.4% mild adverse event rate for the LAMS cohort compared to a 10% mild adverse event rate with SEMS and a 5.4% serious adverse event rate requiring surgical management for bile leak in the LAMS cohort versus 5% serious adverse event rate requiring surgery in those with SEMS (p=0.71). Overall, there were equivalent results among the two stent types, however SEMS were more affordable and didn’t require as dilated a CBD, while EC-LAMS allowed a simpler insertion process. The authors concluded that choice of therapy depended on center expertise, cost of treatment, and safety concerns.22 

There was further refinement of the LAMS technique as demonstrated by the multicenter retrospective analysis by El Chafic et al., where EUS-CDS was successfully completed with EC-LAMS in 64/67 patients with technical success 95.5%. A plastic/metal stent was placed through the lumen of the LAMS in 78.1% of patients to maintain a non-perpendicular LAMS orientation into the bile duct and prevent the bile duct wall from collapsing into the inner flange after decompression. Biliary re-intervention for obstruction was required in 7 patients. The authors determined that EC-LAMS could be performed with high clinical and technical success and inserting an axis-orienting plastic stents through the lumen of the LAMS may reduce the need for biliary re-interventions.23 

Fugazza et al. conducted a multicenter retrospective analysis of EUS-CDS using LAMS in patients with MDBO after failed ERCP. Centers with low and high experience in placing LAMS 

for EUS-CDS were evaluated. The single stage technique was used in 89.7% of low-experience centers, compared with 98% of high-experience centers. Similarly, guidewire was utilized in 10.3% of low-experience centers, versus 2% of high-experience centers (p=0.004). There was similar technical success among the cohorts, which was associated with shorter procedures and larger CBD size. The authors concluded that the study findings provided evidence for reproducibility of EUS-CDS for challenging cases of MDBO among a wide variety of centers.9 

A retrospective study by Wei et al. examined EUS-CDS for MDBO using EC-LAMS and several metrics were evaluated. Technical success with 6mm EC-LAMS was similar to that of 8-10mm EC-LAMS, but higher adverse event rates (OR 3.71, p=0.008) and reintervention rates (OR 6.17, p=0.019) were seen in the 6mm LAMS cohort due to stent occlusion and cholangitis. Due to orientation of EC-LAMS in the duodenal bulb, the luminal opening can become occluded with debris. A larger diameter EC-LAMS may circumvent this, but placement can be challenging due to the flange size. An additional observation from this study was that indwelling EC-LAMS did not hinder surgery in patients that subsequently underwent pancreaticoduodenectomy.4 

CONCLUSION 

Both benign and malignant conditions can lead to biliary obstruction, but when ERCP fails, a few good options are available. Surgical management is associated with significant cost and morbidity and while percutaneous approaches with external drains are highly effective, these may lead to fistulas and negatively affect quality of life. EUS-CDS provides an alternative means of biliary decompression with decreased mortality and incidence of pancreatitis. LAMS increased efficiency of the procedure and ongoing refinement of the technique will address other adverse events which are encountered (i.e., stent occlusion and cholangitis). While factors such as cost of treatment and technical expertise may influence the adoption of this practice, for patients with MDBO and failed ERCP or those in whom ERCP is not technically possible, the results thus far have been promising and the procedure is entering more widespread practice. 

References 

2 Artifon EL, Loureiro JF, Baron TH, Fernandes K, Kahaleh M, Marson FP. Surgery or EUS-guided choledochoduodenostomy for malignant distal biliary obstruction after ERCP failure. Endosc Ultrasound. 2015 Jul-Sep;4(3):235-43. doi: 10.4103/2303-9027.163010. PMID: 26374583; PMCID: PMC4568637. 

3 Vanella G, Bronswijk M, Dell’Anna G, Voermans RP, Laleman W, Petrone MC, van Malenstein H, Fockens P, Arcidiacono PG, van der Merwe S, van Wanrooij RLJ. Classification, risk factors, and management of lumen apposing metal stent dysfunction during follow-up of endoscopic ultrasound-guided choledochoduodenostomy: Multicenter evaluation from the Leuven-Amsterdam-Milan Study Group. Dig Endosc. 2023 Mar;35(3):377-388. doi: 10.1111/den.14445. Epub 2022 Nov 9. PMID: 36177532. 

4 On W, Paranandi B, Smith AM, Venkatachalapathy SV, James MW, Aithal GP, Varbobitis I, Cheriyan D, McDonald C, Leeds JS, Nayar MK, Oppong KW, Geraghty J, Devlin J, Ahmed W, Scott R, Wong T, Huggett MT. EUS-guided choledochoduodenostomy with electrocautery-enhanced lumen-apposing metal stents in patients with malignant distal biliary obstruction: multicenter collaboration from the United Kingdom and Ireland. Gastrointest Endosc. 2022 Mar;95(3):432-442. doi: 10.1016/j.gie.2021.09.040. Epub 2021 Oct 9. PMID: 34637805. 

5 Yamao, K., Bhatia, V., Mizuno, N., Sawaki, A., Ishikawa, H., Tajika, M., Hoki, N., Shimizu, Y., Ashida, R., & Fukami, N. (2008). EUS-guided choledochoduodenostomy for palliative biliary drainage in patients with malignant biliary obstruction: Results of long-term follow-up. Endoscopy, 40(4), 340–342. PMID: 18389451 

6 Tsuchiya T, Teoh AYB, Itoi T, Yamao K, Hara K, Nakai Y, Isayama H, Kitano M. Long-term outcomes of EUS-guided choledochoduodenostomy using a lumen-apposing metal stent for malignant distal biliary obstruction: a prospective multicenter study. Gastrointest Endosc. 2018 Apr;87(4):1138-1146. doi: 10.1016/j.gie.2017.08.017. Epub 2017 Aug 24. PMID: 28843583 

7 Jacques J, Privat J, Pinard F, Fumex F, Chaput U, Valats JC, Cholet F, Jezequel J, Grandval P, Legros R, Lepetit H, Albouys J, Napoleon B. EUS-guided choledochoduodenostomy by use of electrocautery-enhanced lumen-apposing metal stents: a French multicenter study after implementation of the technique (with video). Gastrointest Endosc. 2020 Jul;92(1):134-141. doi: 10.1016/j.gie.2020.01.055. Epub 2020 Feb 19. PMID: 32084411. 

8 Jacques J, Privat J, Pinard F, Fumex F, Valats JC, Chaoui A, Cholet F, Godard B, Grandval P, Legros R, Kerever S, Napoleon B. Endoscopic ultrasound-guided choledochoduodenostomy with electrocautery-enhanced lumen-apposing stents: a retrospective analysis. Endoscopy. 2019 Jun;51(6):540-547. doi: 10.1055/a-0735-9137. Epub 2018 Oct 22. PMID: 30347424. 1 Kunda R, Pérez-Miranda M, Will U, Ullrich S, Brenke D, Dollhopf M, Meier M, Larghi A. EUS-guided choledochoduodenostomy for malignant distal biliary obstruction using a lumen-apposing fully covered metal stent after failed ERCP. Surg Endosc. 2016 Nov;30(11):5002-5008. doi: 10.1007/s00464-016-4845-6. Epub 2016 Mar 11. PMID: 26969661. 

9 Fugazza A, Fabbri C, Di Mitri R, Petrone MC, Colombo M, Cugia L, Amato A, Forti E, Binda C, Maida M, Sinagra E, Repici A, Tarantino I, Anderloni A; i-EUS Group. EUS-guided choledochoduodenostomy for malignant distal biliary obstruction after failed ERCP: a retrospective nationwide analysis. Gastrointest Endosc. 2022 May;95(5):896- 904.e1. doi: 10.1016/j.gie.2021.12.032. Epub 2022 Jan 4. PMID: 34995640. 

10 Sawas T, Bailey NJ, Yeung KYKA, James TW, Reddy S, Fleming CJ, Marya NB, Storm AC, Abu Dayyeh BK, Petersen BT, Martin JA, Levy MJ, Baron TH, Bun Teoh AY, Chandrasekhara V. Comparison of EUS-guided choledochoduodenostomy and percutaneous drainage for distal biliary obstruction: A multicenter cohort study. Endosc Ultrasound. 2022 May-Jun;11(3):223-230. doi: 10.4103/EUS-D-21- 00031. PMID: 35102902; PMCID: PMC9258024. 

11 da Silva RRR, Facanali Junior MR, Brunaldi VO, Otoch JP, Rocha ACA, Artifon ELA. EUS-guided choledochoduodenostomy for malignant biliary obstruction: A multicenter comparative study between plastic and metallic stents. Endosc Ultrasound. 2023 Jan-Feb;12(1):120-127. doi: 10.4103/EUS-D-21-00221. PMID: 36861511; PMCID: PMC10134915. 

12 Park DH, Jang JW, Lee SS, Seo DW, Lee SK, Kim MH. EUS-guided biliary drainage with transluminal stenting after failed ERCP: predictors of adverse events and long-term results. Gastrointest Endosc. 2011 Dec;74(6):1276-84. doi: 10.1016/j.gie.2011.07.054. Epub 2011 Oct 1. PMID: 21963067. 

13 Anderloni, A., Fugazza, A., Troncone, E., Auriemma, F., Carrara, S., Semeraro, R., Maselli, R., Di Leo, M., D’Amico, F., Sethi, A., & Repici, A. (2019). Single-stage EUS-guided choledochoduodenostomy using a lumen-apposing metal stent for malignant distal biliary obstruction. Gastrointestinal Endoscopy, 89(1), 69–76. PMID: 30189198 

14 Giovannini M, Moutardier V, Pesenti C, Bories E, Lelong B, Delpero JR. Endoscopic ultrasound-guided bilioduodenal anastomosis: a new technique for biliary drainage. Endoscopy. 2001 Oct;33(10):898-900. doi: 10.1055/s-2001- 17324. PMID: 11571690 

15 Kawakubo K, Kawakami H, Kuwatani M, Kubota Y, Kawahata S, Kubo K, Sakamoto N. Endoscopic ultrasound-guided choledochoduodenostomy vs. transpapillary stenting for distal biliary obstruction. Endoscopy. 2016 Feb;48(2):164-9. doi: 10.1055/s-0034-1393179. Epub 2015 Oct 30. PMID: 26517848 

16 Hamada T, Isayama H, Nakai Y, Kogure H, Yamamoto N, Kawakubo K, Takahara N, Uchino R, Mizuno S, Sasaki T, Togawa O, Matsubara S, Ito Y, Hirano K, Tsujino T, Tada M, Koike K. Transmural biliary drainage can be an alternative to transpapillary drainage in patients with an indwelling duodenal stent. Dig Dis Sci. 2014 Aug;59(8):1931-8. doi: 10.1007/s10620-014-3062-1. Epub 2014 May 20. PMID: 24839917 

17 Khashab MA, Messallam AA, Penas I, Nakai Y, Modayil RJ, De la Serna C, Hara K, El Zein M, Stavropoulos SN, Perez-Miranda M, Kumbhari V, Ngamruengphong S, Dhir VK, Park DH. International multicenter comparative trial of transluminal EUS-guided biliary drainage via hepatogastrostomy vs. choledochoduodenostomy approaches. Endosc Int Open. 2016 Feb;4(2):E175-81. doi: 10.1055/s-0041- 109083. Epub 2016 Jan 15. PMID: 26878045; PMCID: PMC4751013. 

18 Minaga K, Ogura T, Shiomi H, Imai H, Hoki N, Takenaka M, Nishikiori H, Yamashita Y, Hisa T, Kato H, Kamada H, Okuda A, Sagami R, Hashimoto H, Higuchi K, Chiba Y, Kudo M, Kitano M. Comparison of the efficacy and safety of endoscopic ultrasound-guided choledochoduodenostomy and hepaticogastrostomy for malignant distal biliary obstruction: Multicenter, randomized, clinical trial. Dig Endosc. 2019 Sep;31(5):575-582. doi: 10.1111/den.13406. Epub 2019 May 29. PMID: 30908711. 

19 Donelli G, Guaglianone E, Di Rosa R, Fiocca F, Basoli A. Plastic biliary stent occlusion: factors involved and possible preventive approaches. Clin Med Res. 2007 Mar;5(1):53- 60. doi: 10.3121/cmr.2007.683. PMID: 17456835; PMCID: PMC1855334. 

20 Song TJ, Hyun YS, Lee SS, Park DH, Seo DW, Lee SK, Kim MH. Endoscopic ultrasound-guided choledochoduodenostomies with fully covered self-expandable metallic stents. World J Gastroenterol. 2012 Aug 28;18(32):4435-40. doi: 10.3748/wjg.v18.i32.4435. PMID: 22969210; PMCID: PMC3436062. 

21 Binmoeller KF, Shah J. A novel lumen-apposing stent for transluminal drainage of nonadherent extraintestinal fluid collections. Endoscopy. 2011 Apr;43(4):337-42. doi: 10.1055/s-0030-1256127. Epub 2011 Jan 24. PMID: 21264800. 

22 de Benito Sanz M, Nájera-Muñoz R, de la Serna-Higuera C, Fuentes-Valenzuela E, Fanjul I, Chavarría C, García- Alonso FJ, Sanchez-Ocana R, Carbajo AY, Bazaga S, Perez-Miranda M. Lumen apposing metal stents versus tubular self-expandable metal stents for endoscopic ultrasound-guided choledochoduodenostomy in malignant biliary obstruction. Surg Endosc. 2021 Dec;35(12):6754-6762. doi: 10.1007/s00464-020-08179-y. Epub 2020 Nov 30. PMID: 33258038. 

23 El Chafic AH, Shah JN, Hamerski C, Binmoeller KF, Irani S, James TW, Baron TH, Nieto J, Romero RV, Evans JA, Kahaleh M. EUS-Guided Choledochoduodenostomy for Distal Malignant Biliary Obstruction Using Electrocautery- Enhanced Lumen-Apposing Metal Stents: First US, Multicenter Experience. Dig Dis Sci. 2019 Nov;64(11):3321- 3327. doi: 10.1007/s10620-019-05688-2. Epub 2019 Jun 7. PMID: 31175495. 

24 Nakai Y, Isayama H, Kawakami H, Ishiwatari H, Kitano M, Ito Y, Yasuda I, Kato H, Matsubara S, Irisawa A, Itoi T. Prospective multicenter study of primary EUS-guided choledochoduodenostomy using a covered metal stent. Endosc Ultrasound. 2019 Mar-Apr;8(2):111-117. doi: 10.4103/eus. eus_17_18. PMID: 30168480; PMCID: PMC6482602. 

25 Kuraoka N, Hara K, Okuno N, Kuwahara T, Mizuno N, Shimizu Y, Niwa Y, Terai S. Outcomes of EUS-guided choledochoduodenostomy as primary drainage for distal biliary obstruction with covered self-expandable metallic stents. Endosc Int Open. 2020 Jul;8(7):E861-E868. doi: 10.1055/a- 1161-8488. Epub 2020 Jun 16. PMID: 32617390; PMCID: PMC7297614. 

26 Hara K, Yamao K, Niwa Y, Sawaki A, Mizuno N, Hijioka S, Tajika M, Kawai H, Kondo S, Kobayashi Y, Matumoto K, Bhatia V, Shimizu Y, Ito A, Hirooka Y, Goto H. Prospective clinical study of EUS-guided choledochoduodenostomy for malignant lower biliary tract obstruction. Am J Gastroenterol. 2011 Jul;106(7):1239-45. doi: 10.1038/ ajg.2011.84. Epub 2011 Mar 29. PMID: 21448148. 

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Fundamentals of ERCP

Fundamentals of ERCP Image Interpretation

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INTRODUCTION

Successful cannulation of the desired duct and safely carrying out any necessary interventions are the primary goals in ERCP. It is also important to obtain the best possible images, accurately interpret these images, and document the findings in the procedure report. There are common, avoidable mistakes or errors that occur while performing ERCP. These include poor technique, misinterpretation of variant anatomy and artifacts, and failure to recognize adverse events, especially perforation.1 Many of the image interpretation errors arise with less commonly encountered anatomic variants of the biliary and the pancreatic ducts.2 Most ERCP malpractice lawsuits arise after adverse events such as pancreatitis, perforations, and severe infections. These lawsuits are difficult to defend if the procedure was not indicated or if there was a failure to adequately document the justification for the risk of the procedure.3,4 Therefore, all ERCP procedures should include documentation of appropriate and acceptable indications and detailed descriptions of the findings and the interventions. Images should be correctly interpreted, and any adverse events recognized and treated early. Capturing and saving images assists in “telling the story” of the entire procedure, illustrating the interventions performed, documenting the absence of adverse events or early recognition of adverse events. The images and the report should be congruent. As will be described in this article, fluoroscopy can be utilized to assist in correctly positioning the duodenoscope, identifying the major and the minor papilla, and selectively cannulating the duct of choice. 

Proper Use of Fluoroscopy and Safety Measures 

Every endoscopist performing ERCP should have a basic understanding of the fluoroscopy equipment, proper settings, and safety measures.5 Common errors, mistakes, and pitfalls in ERCP imaging are summarized in Table 1. It is not uncommon that the endoscopist will be required to directly operate the fluoroscopy equipment and therefore should have a good working understanding of how to generate and correctly interpret adequate fluoroscopic images in a safe manner. A helpful publication from the American Society for Gastrointestinal Endoscopy (ASGE) reviews in detail radiation and fluoroscopy safety in endoscopy.6 

There are several different types of fluoroscopy units, but ERCP is performed in most centers with a portable C-arm unit, although some high-volume centers have so-called fixed table units. The principles, however, are the same. An X-ray beam is passed from the X-ray source or cathode that is usually located below the fluoroscopy table or bed upward through the patient. An image intensifier or receiver unit receives the beam and generates the images. The X-ray beams may deflect causing scatter resulting in increased radiation exposure. There is increased scatter in obese patients. The image intensifier should always be placed as close to the patient as possible without contacting the patient or interfering with the ability to move the table or the fluoroscope. Typically, placing the image intensifier 1-2 inches above the patient is ideal for good image quality without excess magnification or increased scatter. The ALARA principle (As Low as Reasonably Achievable) should always be followed to limit the exposure to the patient and the staff. 

Endoscopists and assistants should always wear thyroid shields, lead glasses, and lead aprons that fully cover their body. Adding a lead skirt or drape around the fluoroscopy unit can help prevent scatter and reduce excess exposure as can clear lead shields positioned between the fluoroscopy unit and the endoscopy staff. Increased fluoroscopy time increases cancer risk to the patient, endoscopist and all staff present at the procedure. Angulation of the beam and magnification all increase radiation exposure to patients and staff. 

Physician-controlled fluoroscopy may result in reduced radiation exposure compared to utilizing an X-ray technician.7 There are clinical determinants that may predict longer fluoroscopy times and, hence, greater overall exposure, such as patient obesity, mechanical lithotripsy, needle knife use, and malignant biliary obstruction.8 With more ERCP experience, fluoroscopy time is typically shorter.9 Radiation time should, if possible, be noted, recorded, and compared with published benchmarks to ensure excess fluoroscopy time is not being utilized and to make it a goal to reduce exposure time as much as possible. It may be helpful to turn off the auto save mode of the fluoroscopy unit to avoid excess images to review at the conclusion of a case. Selected images should be saved and sent for permanent storage in the local picture archiving and communication system (PACS). The images saved should include the scout film and final film, and those images documenting the complete biliary tree or pancreatic duct as well as images that identify distinct findings or interventions. 

Room Design and Patient Position 

The room design, type of fluoroscopy equipment, and position of the patient and the monitors are all important for a successful procedure. This also helps ensure the comfort and safety of all in the room, including proper and healthy ergonomics for the endoscopist. The position of the fluoroscope and the position of the patient also affect the anatomic appearance as well as filling and drainage of the ducts of interest. Most ERCPs are performed with the patient in the prone or semi-prone position where the papilla is better positioned for the design of the duodenoscope and for most endoscopist’s natural scoping position. Most endoscopists position the biliary tree to the left side of the image as would correspond to the patient’s right side if the patient were supine and viewed from the front and how CT and MRI images are typically saved and reviewed. However, with the patient prone, this would not be consistent with how the image was acquired. Therefore, some endoscopists prefer the right corresponding to a posterior view when the patient is prone (see Figures 1 and 2 – page 26). I.e., most ERCP images are consistent with an anterior-to-posterior view, but some prefer a posterior-to-anterior view. 

Supine positioning of the patient may be necessary in certain cases such as: extreme obesity, poor neck mobility, an open abdomen, altered anatomy, or the need to perform a laparoscopic-assisted ERCP. With a patient in the supine position, many endoscopists look at the endoscopy and fluoroscopy monitoring screens with their back towards the patient. With this positioning, the endoscopist must maintain significant rightward torque on the duodenoscope. This can be accomplished with the aid of an assistant, if needed, while the endoscopist is facing away from the patient. 

The Importance and Utility of the Scout Film 

The baseline fluoroscopic image is also termed the “scout film” and it should be reviewed and saved routinely. The scout film serves several important purposes. The scout film confirms that the fluoroscopy equipment is functioning properly, ensures a properly focused field of view and position or orientation, demonstrated the initial bowel gas pattern (prior to insufflation) and verifies that the images can be saved (see Figures 3 and 4). The fluoroscopy image should be adjusted as needed to ensure the spine is vertically oriented, or close to it, and that there is a focused field of view that encompasses the expected area of interest (either biliary tree, pancreatic duct, or both). Such a proper focused field of exam, employing alternate angles of view, and the judicious use of magnification can reduce radiation exposure and interpretation errors in ERCP (see Figure 5). The scout film also identifies any impairment of the view of the duct or ducts. 

Artifacts during ERCP are common. Overlying objects such as EKG leads, wires from the pulse oximeter, blood pressure cuff, or IV lines that need to be moved out of the examination field will be revealed during the scout film. Excess bowel gas, retained contrast, the presence of any internal hardware or prosthesis including clips, coils, or percutaneous drains (see Figures 6 and 7) that may or may not interfere with the view or need to be taken into consideration should also be noted. Spinal hardware usually does not obscure the view of the biliary tree but may require some adjustment of the fluoroscopy angle (see Figures 8–12). Calcifications should be recognized. These may include calcified hemangiomas of the liver (see Figure 13), porcelain gallbladder (see Figures 14 and 15), calcific pancreatitis, phleboliths, renal lithiasis, or calcified lymph nodes to name a few. Overlying bowel gas and retained contrast (see Figures 16 and 17) can interfere with image creation, produce shadows, and can lead to misinterpreted images. When evaluating the scout film, careful notation should be made of the appearance of the diaphragm, bowel gas pattern, stomach, and the liver edge prior to any intervention. Pre-procedure and post-procedure scout films should always be obtained to look for, and, if needed, document the presence or absence of free air. 

It should be recognized that undue pressure from the endoscope or catheters can distort ductal anatomy as well as increase the risk of adverse events. Contrast material outside the ductal systems from prior contrast imaging studies or inadvertent extraductal injection should be appreciated. Under filling of the ducts or unintentional injection of air can also result in misinterpreted images. Oblique and lateral images can be helpful in showing abnormalities, variants of anatomy, or artifacts. Analog, as opposed to digital, fluoroscopic units will, in general, produce poorer images (see Figure 18). Misinterpretation of images is, unfortunately, very common but having a routine and following basic principles will reduce such errors. 

The Role Of Contrast Media 

In the context of ERCP, there is some debate about whether to use full-strength or diluted contrast media. Commonly, the initial cannulation begins with diluted contrast (typically half-strength). Then, after cannulation of the CBD an early cholangiogram is achieved (see Figure 19) some switch to full-strength contrast if necessary for better delineation of the biliary tree or pancreatic duct. Dilute contrast, however, is best for the detection of small stones, especially in patients with dilated ducts.10 (see Figure 20). Prior to the routine use of guidewire cannulation techniques, dilute contrast was often favored due to the belief that if inadvertent pancreatic duct cannulation was achieved, there would be less risk of post-ERCP pancreatitis. This notion has been discarded. 

Full-strength contrast is favored by some endoscopists for detection of strictures in the bile duct or in the pancreatic duct and when needing to clearly visualize the biliary and pancreatic duct anatomy. Prior to cannulation, all catheters should be flushed with contrast to eliminate air bubbles. If air bubbles are inadvertently introduced they can produce artifacts that can interfere with image interpretation. 

Using Fluoroscopy to Achieve Proper Scope Postion for Finding the Papilla and Successful Cannulation 

During ERCP, the scope tip is generally positioned below and lateral to the 12th rib, at about the level of the L2 vertebral body or between L2 and L3 vertebrae. This is considered the “usual position.” The body of the pancreas typically crosses the spine at the L1-L2 vertebrae. Understanding the scope position in the duodenum relative to the spine and ribs can help reveal a hidden or difficult to identify major papilla or when locating the minor papilla. Sometimes the major papilla is partially or totally obscured by an overlying duodenal fold and is not easily identified. It may be helpful to advance the duodenoscope into the deep second portion of the duodenum and then slowly withdraw it into the usual position just below the 12th rib between the L2 and L3 vertebrae. The major papilla is then typically found in this location, though gentle lifting of folds with a catheter or sphincterotome may be needed in some situations. 

For bile duct cannulation, the scope tip will typically have a “hockey stick” configuration (see Figures 21 and 22), whereas when cannulation of the pancreatic duct is desired, the scope tip is usually in a flatter position if not advanced to the long position (see Figure 23). For minor papilla cannulation, the scope is usually initially best positioned in a longer position with the tip more proximal in the duodenum. Once the PD is cannulated via the minor papilla, the duodenoscope can be reduced though this may risk loss of scope position. Once the CBD or PD are cannulated deeply, the scope position can typically be maintained (see Figures 24 and 25). Knowing the typical and expected anatomic position of the major papilla on fluoroscopy can also aid ERCP procedures in patients with surgically altered anatomy (see Figures 26–29). 

Utilizing Fluoroscopy to Maximize the Preferred Guidewire Cannulation 

Guidewire cannulation is now commonly employed during ERCP, and the use of injection during cannulation is much less frequently performed than it was in the past. Knowing the angle of both the bile duct and the pancreatic duct can assist in selective cannulation of the duct of choice. When CBD cannulation is desired, but the PD is inadvertently cannulated with the guidewire, the so-called “double wire technique” is a very useful and often successful method to achieve selective CBD cannulation (see Figure 30). The initial guidewire is left in the PD and a second guidewire is loaded into the sphincterotome (see Figure 31). Positioning the duodenoscope in the “hockey stick” position and observing a separation of the CBD and PD with a properly bowed sphincterotome under endoscopic and fluoroscopic guidance can also aid in selective cannulation of the CBD. 

Some have suggested that the first cholangiogram should be performed with the catheter or sphincterotome in the upper bile duct just below the confluence to prevent the inadvertent flushing of debris and stones or stone fragments from the distal extrahepatic duct into the intrahepatic ducts, although others prefer to inject distally first11 (see Figure 30). 

Body Position Effect on Duct Filling and Injection Tips 

Opacification of the biliary tree is, to some extent, dependent on gravity, and contrast media is denser than bile; therefore, the dependent ducts will fill preferentially. Whether the patient is in the semi-prone position or in the supine position will therefore determine which ducts are more dependent and will fill first. In the standard ERCP prone or semi-prone position the left ducts and anterior duct of the right lobe will fill first whereas in the supine position the right posterior ducts will fill first (see Figures 33 and 34). 

When using a balloon catheter, contrast should initially be injected with the balloon deflated. This will allow air bubbles or debris within the intrahepatic system to be flushed into the extrahepatic duct. The size of the balloon catheter selected should match the size of the duct to ensure appropriate occlusion and retention of contrast above the balloon and to facilitate a complete occlusion cholangiogram of the intrahepatic ducts (see Figure 35). 

In the semi-prone position, the left hepatic duct system is more dependent and fills earlier than the right ducts. In this position, the common bile duct is more posterior to the common hepatic duct and will fill earlier than the distal common bile duct. Furthermore, the cystic duct also generally courses posteriorly to the common hepatic duct with the anterior portion of the gallbladder filling first. With low-pressure contrast injections, there may be difficulty filling the right hepatic duct. If there is runoff into the gallbladder, the bile duct may be poorly opacified early. Balloon occlusion injection below the confluence will help fill the right hepatic ducts. Continuing to inject with the balloon inflated and moving distally in the duct can help delineate the distal duct. If the patient is moved into a more left lateral position, the right duct drains more preferentially. With the patient in the supine position, the right ducts are in a more dependent position and will fill preferentially as does the posterior gallbladder. Historically, if delayed biliary drainage was suspected, patients were placed supine with their head up though this is not commonly performed in the modern era. 

Balloon Sweeping and Proper Visualization of the Ducts 

Contrast injection is continued while slowly sweeping the duct with an occlusion balloon to remove biliary sludge, stones, or debris. Spot images can be captured and saved of the inflated balloon at the confluence (see Figure 36) then at the mid-bile duct, and finally in the distal CBD just above the papilla (see Figure 33). The mid-portion of the bile duct is commonly obscured by the duodenoscope and can be better visualized by gently pushing the duodenoscope into a long position with counterclockwise torque with care not to lose duct access (see Figure 38). Having a guidewire deep into the biliary tree and locked with an accessory locking device attached to the duodenoscope, use of elevator closure, or pinching the catheter or guidewire with the little finger of the endoscopist’s left hand reduces the risk of losing biliary access during this maneuver. Alternatively, the fluoroscopy C-arm can be rotated to expose the duct; but pushing the duodenoscope to the long position is typically more time efficient. Complete opacification of the biliary tree, including the intrahepatic ducts, can be performed to avoid missing intrahepatic stones, strictures, and anatomic variants. An exception to this may include cases of overt cholangitis where there is a genuine concern for the risk of precipitation of hepatic abscesses with high pressure injection. 

Discerning Bile Duct Stones Versus Air Bubbles or Pneumobilia 

Air introduced into the biliary or the pancreatic ducts can be problematic in that it can mimic stones, and both bubbles and stones are true “filling defects.” Air bubbles are commonly 2-5 mm in size, symmetrically round, and tend to cluster together or conform to the shape of the duct (see Figure 38). Tilting the patient may assist the endoscopist in distinguishing air bubbles from stones as the air bubbles usually rise in the duct with such maneuvers and bile duct stones will sink. However, floating stones do occur and can be misinterpreted as bubbles. This can result in missed identification of stones.12 Bubbles can also be long and tubular. Aside from stones and air bubbles, a filling defect may also be indicative of clots, tumor, or an intraductal parasite such as Ascaris. 

It is important to note that the use of imaging to identify stones or masses has its limitations. Dilute contrast may be best for visualization of small bile duct stones, especially in patients with dilated bile ducts.13 By paying close attention to early images on the initial contrast injection, the endoscopist can reduce the chance of missing stones. 

Larger and more dense radiopaque stones are easier to identify than smaller stones (see Figures 39–41). It is important to remember small stones can be missed in the distal bile duct at the papilla and may not be retrieved or extracted on balloon sweeps if the balloon slips past the stones without engaging them. Balloon occlusion cholangiogram and serial duct sweeps are the most effective technique for ensuring complete duct clearance (see Figure 42). Failure to perform multiple sweeps with an adequate balloon size relative to the duct size may result in inadequate clearance of the duct. The risk of inadequate duct clearance can be increased in patients with a dilated bile duct, in the presence of pneumobilia, following lithotripsy, and when a guidewire or stent is in the pancreatic duct (see Figure 43). 

Adequate Views and Sizing of Ducts 

It is important to adjust the endoscope position, and, if necessary, the fluoroscope itself to ensure that the entire duct of interest is visualized. For therapeutic interventions, it is important to know how to estimate the size of lesions, stones, and strictures. The size of stones and of the duct itself will influence the decision regarding removal techniques. These decisions include the size of sphincterotomy needed, the need for balloon sphincteroplasty, the size of any balloon or retrieval basket that may be needed. Knowing the insertion tube outer diameter of the duodenoscope is one of the easiest and quickest ways to estimate sizes. These vary by manufacturers and if pediatric or therapeutic duodenoscope from 7.5 mm to 12.1 mm.14 The most prevalent Olympus TJF190 therapeutic duodenoscope has an 11.3 mm outer insertion tube diameter while the Pentax duodenoscopes vary from 10.8 to 12.1 mm. Both the currently available single use disposable duodenoscopes also have outer insertion tube diameters of 11.3 mm.15 The endoscope diameter can serve as a “ruler” to compare any object to during the procedure. Large stones are considered those greater than 10 mm, so stones greater than the outer insertion diameter of the duodenoscope are, by definition, large stones (see Figure 41). 

Contrast streaming artifacts can occur when contrast flows along the dependent wall of a dilated duct. This may give the illusion of a normal duct caliber. However, obtaining a balloon occlusion cholangiogram will confirm the true duct size. Small periductal lymphatics sometimes fill with contrast especially during difficult cannulations in the setting of a tight stricture or if mucosal tears or false passages are created. 

Contrast filling of a duodenal diverticulum can sometimes cause confusion and obscure the view of the distal bile duct. The presence of an ampullary diverticulum should be noted during inspection of the papilla and subsequent filling of the diverticulum with contrast should be avoided if possible. Refluxed contrast filling of the duodenal bulb is common and may be mistaken for a partially filled gallbladder (see Figure 44). Excessive air in the stomach may make it difficult to pass the duodenoscope beyond the pylorus or difficult to maintain the proper scope position during ERCP maneuvers. A large “J shaped” stomach can also make it difficult to traverse the pylorus. Decompressing the stomach with suction and rotating the patient into a more left lateral position may help in this situation. Contrast refluxing backwards into the stomach or excessive air in the stomach may interfere with the interpretation of the pancreatogram due to overlying dye. 

Normal Bile Duct and Liver Anatomy 

Biliary anatomy can be quite variable.16 The extrahepatic bile duct is typically approximately 7-12 cm in length17 (see Figure 1). The portion of the bile duct below the cystic duct and above the papilla is, by convention, termed the common bile duct (CBD). The portion above the cystic duct and below the confluence of the right and left hepatic ducts is called the common hepatic duct (CHD) (see Figure 32). By convention, the distal CBD is that portion above the papilla and the proximal CBD is the portion nearest the liver. 

Duct diameters vary widely. In general, duct diameters are 1mm for each decade of life, until about age 60, in patients with an intact gallbladder. An easy rule of thumb is “7-11” where a CBD in a patient with an intact gallbladder of 7 mm or greater is considered dilated, and one that is 11 mm or greater post-cholecystectomy is dilated.18 Patients above age 60 may experience physiologic bile duct dilation in the absence of injury or illness. A large ultrasound (US) study found that the bile duct increased 0.4 mm/per year over age 50 and suggested a bile duct over 8.5 mm in an elderly individual would be considered abnormally dilated. However, there are some discrepancies between US and cholangiographic measures of bile duct diameter. Fluoroscopically, the bile duct also typically arises from the papilla at around the level of L2-L3 vertebrae and courses superiorly rightward into the liver (see Figure 45). 

Understanding the segments of liver and their relation to the branches of the biliary tree and anatomic variations is also important. In the Couinard classification of liver anatomy, there are 8 segments of the liver. Each segment is distinct with biliary drainage that parallels the portal drainage and can be defined by CT, MRI, and ERCP19,20 (see Figure 46). The most common hepatic ductal anatomy is a left hepatic duct (LHD) joining a confluence of the right posterior sectoral duct (RPSD) and right anterior hepatic duct (RAHD). The RPSD typically drains segments VI and VII, the RAHD segments VIII and V, and the LHD and its branches segments drain segments I, II, III and IV. 

Recognizing Biliary Tree Variants 

The most common biliary tree anatomic variants involve the RPSD.21 One of the most common is the RPSD coming off the LHD before its confluence with the RAHD (see Figures 47 and 48) and is present in about 15% of patients. In this variant the RPSD commonly passes above the portal vein creating a hump-like appearance before it crosses to its typical horizontal crossing. This is usually, but not always, posterior to the vertically coursing RAHD (see Figure 49). The next most common variant is when the RPSD does not pass the RAHD posteriorly, but it drains into the right side of the RAHD (see Figure 50). A segmental or accessory right hepatic duct that drains into the CHD or the cystic duct (CD) is also quite common. Rather than a typical bifurcation at the confluence; a trifurcation or triple confluence (triunion) of the proximal ducts is also relatively common (see Figures 51–53). Uncommon variants of the biliary tree include a CHD that may appear absent with a low union of the right and left hepatic ducts (see Figure 54). RPSD variants include an accessory LHD draining into the right anterior duct while the RPSD drains into the left accessory duct and left hepatic duct coming off the RAHD (see Figure 55). 

The cystic duct origin can be quite variable and may originate from any part of the biliary tree. Normally the CD arises from the CHD, defining the CBD below (see Figures 56 and 46). There are three common CD variants: a low CD insertion characterized by the CD fusing with the distal CBD (see Figures 57 and 58) and a CD that parallels the CHD (see Figure 59). An uncommon CD variant includes high insertion of the CD into the CHD (see Figure 60). Noting and alerting surgeons to the cystic duct variants can be quite helpful prior to cholecystectomy. The hepatic artery may cross over the bile duct and produce an indentation on the CBD that can mimic a stricture or tumor.

Biliary cysts, choledochocysts, and choledochoceles can cause confusion and misinterpretation on cholangiograms. The Todani classification (Table 2) is the commonly used system for classification of bile duct cysts. Type I cysts are the most common (90%) and have three variations. Type Ia is dilation of the entire extrahepatic bile duct (see Figures 61 and 62). 

Type Ib is focal dilation of the extrahepatic bile duct (see Figure 63). Type III is a dilation of the extrahepatic bile duct within the duodenal wall (a.k.a. a choledochocele), and is typically treated via biliary sphincterotomy. Type IV cysts are the second most common. Type V, also known as Caroli’s disease, involves multiple dilations or cysts of the intrahepatic ducts only.

Most often, the gallbladder is somewhat pear-shaped. However, it can have an hourglass shape, have septations, or have a Phrygian cap that folds over the gallbladder. The location of the gallbladder can be variable: high or intrahepatic, low, “left sided,” congenitally absent, or multiple. 

Normal Pancreatic Duct and Variants 

The pancreatic duct (PD) is formed by the fusion of the dorsal and ventral pancreatic anlagen in utero. The dorsal duct (Duct of Santorini) and the ventral duct (Duct of Wirsung) merge, with the main pancreatic duct usually emptying at the major papilla. The minor papilla is found superior and lateral to the major papilla. The CBD and the PD usually join before entering the papilla, typically within 2-3 mm of the papilla, with CBD usually superior to the PD and closer to the duodenal wall. The pancreas itself usually lies between the T12 and L2 vertebrae with the mid-body of the pancreas over L1 (see Figure 64). The PD varies in length from about 9 cm to 15 cm. It is typically 4 mm in diameter in the head, 2-3 mm in diameter in the body and 1-2 mm in diameter in the tail. Like the CBD, it may be longer and larger in diameter with increased age. The duct typically has an ascending course before crossing over the spine, but it may be more horizontal, sigmoid shaped, or descending in course and contour. A looped duct can be present as well (a.k.a. ansa pancreatica). Sometimes a pancreatic duct branch may ascend to the duct of Santorini or descend to the uncinate portion of the pancreas. 

Congenital variants of the pancreaticobiliary tree include anomalous pancreaticobiliary duct union or junction; pancreas divisum, annular pancreas, an Ansa variant (Ansa pancreatica) (see Figure 65). Very rarely the pancreatic duct can be bifid or trifid 22 (see Figure 66). 

Pancreas divisum, where the dorsal and ventral pancreatic ducts fail to fuse in utero, is relatively common. Pancreas divisum can be complete or incomplete (see Figure 67). It is estimated to be present in 5-12% of all adults. It is usually easily recognized when the ventral duct is completely opacified and there is failure to opacify the dorsal or main pancreatic duct. Pancreas divisum can be confirmed by opacifying the dorsal duct at the minor papilla, though this is often unnecessary and may increase the risk of pancreatitis or adverse events. On the other hand, over injection of the ventral duct in divisum can cause acinar filling especially if divisum was not anticipated. A Santorinicele is a small cystic dilation of the dorsal pancreatic duct at the minor papilla in pancreas divisum. When present the duct of Santorini may be dilated23,24 (see Figure 68). 

Annular pancreas is a rare congenital anomaly. When present, the pancreas partially or completely encircles the duodenum. It will have a characteristic appearance of the pancreatic duct encircling the duodenum and often the duodenoscope before heading out to the body and tail of the pancreas (see Figures 69 and 70). Pancreas divisum coexists in as many as 45% of adults with annular pancreas. It is estimated that at least 1/3 of these individuals may suffer chronic pancreatitis25,26 (See Figure 71). 

Bile Duct Strictures And Tumors 

A contracted biliary sphincter may mimic a stricture or distal CBD stone. Transient narrowing or tapering of the distal duct in the absence of upstream ductal dilation argues against the presence of a true stricture. However, both benign and malignant strictures are commonly encountered during ERCP. Distinguishing between the two can be difficult at times and such strictures are commonly termed indeterminate. There are several possible causes of biliary strictures.27 Intrahepatic duct or CHD dilation is more common in malignant strictures but whether the stricture is smooth in contour or irregular does not adequately distinguish etiology.28 Malignant strictures tend to be much longer and irregular with shelf-like edges (see Figure 72). Strictures from ampullary cancers tend to be short and smooth (see Figure 73). Extrinsic compression from tumors or adenopathy can result in marked biliary ductal dilation (see Figure 75). Post-liver transplant strictures are usually short and often smooth but may be asymmetric or have a shelf-like margin as well (See Figure 76). Pancreatic cancer in the head of the pancreas causes the most common malignant biliary stricture, usually a severe distal stenosis 2-4cm long (see Figures 77–84). Iatrogenic strictures commonly include post anastomotic after liver transplantation or bile duct resection and post cholecystectomy bile duct injuries (BDI). Stones can occur above anastomotic strictures (see Figures 87–96). 

Whenever a biliary stricture is noted and a clear, benign underlying cause is not suspected, sampling should be performed that should include brushings for cytology and/or biopsy. Digital cholangioscopy with direct visualization and directed biopsies have higher yields than brushing alone. 

Primary sclerosing cholangitis is characterized by the presence of focal or multifocal strictures, pruning or rarefaction of the biliary tree, ductal irregularities, beading or saccular dilations of the intrahepatic ducts commonly alternating with segmental strictures29 (see Figures 97–101). Secondary sclerosing cholangitis also can be seen (see Figures 102–107). 

The Bismuth-Corlette classification has been the most widely used system for bile duct tumors and benign strictures with a modification used for main hepatic duct injury. However, its prognostic value has been called into question in more recent years30 (see Table 3). 

Bismuth Type IV lesions extend to and involves both the right and left hepatic ducts to the second order hepatic ducts; and is commonly referred to as a Klatskin tumor (see Figure 108). Treatment of Klatskin tumor is rarely surgical and requires bilateral stenting (see Figure 109). Bismuth Type V lesions produce a stricture involving both the common bile duct and the cystic duct.31 Cholangiocarcinoma is more accurately classified as intraductal iCCA, perihilar pCCA or distal dCCA.32 A complete occlusion cholangiogram of the biliary tree should be obtained and documented in cases of known or suspected biliary malignancies or PSC (see Figures 110 and 111). Careful delineation and documentation of the extent of ductal involvement with high quality cholangiograms is important for treatment decisions especially surgical candidacy. Not only is digital cholangioscopy often warranted to obtain directed biopsies for confirmatory diagnosis but is often requested by the surgeon preoperatively (see Figure 112). 

Bile Duct Injuries (BDI) and Leaks 

At the time of ERCP, it is critical to recognize any biliary or pancreatic duct injury, extravasation, leaks, and perforations. It is important to clearly visualize and document the sites of any leaks and/or bile duct injuries (BDI) prior to making decisions on treatment options. Many leaks and BDI are readily apparent on cholangiogram. When a post-surgical bile leak or BDI is suspected to have occurred but is not clearly seen, then a balloon occlusion cholangiogram can be performed. Common areas for bile leaks to occur in the biliary tree are in the cystic duct remnant following cholecystectomy (see Figures 113–117), the CHD region (see Figure 117), the duct of Luschka (see Figure 118) or in low lying, right sided, proximal intrahepatic ducts that overlie the gallbladder fossa. 

Careful attention should be paid to avoid confusing the cystic duct stump with the hepatic duct in cases of post-cholecystectomy stenosis. Stenosis in the biliary tree, consistent with BDI, following cholecystectomy is usually at the level of the CHD. This is often complete and difficult to pass even with a small diameter hydrophilic guidewire. A common mistake is confusing the CD stump and an occluded CHD and then repeatedly pushing a guidewire into the cystic duct stump. The two ducts are commonly superimposed on fluoroscopy, so changing the angle or axis of fluoroscopy may be necessary to distinguish the two.

The Strasberg classification of bile duct injuries is a widely used system to define the injuries by the location33 (see Table 4). Type E is an injury to the main hepatic duct that is further classified according to the Bismuth system34 (See Figures 119 –123). 

Penetrating trauma to biliary tree is rare, but can be seen in patients with hepatic gunshot wounds (see Figure 124). 

There are rare reports of portal vein (PV) cannulation as the PV runs parallel to the CBD.35 Resistance to guidewire or catheter placement, rapid disappearance of contrast, and opacification of the PV branches may be clues to PV cannulation.36 PV cannulation most commonly occurs in patients with cholangiocarcinoma or other malignancy that weakens the biliary wall and allows communication between the biliary tree and the portal venous system. 

Pancreatic Duct Strictures, Injuries, and Leaks 

Pancreatic duct strictures are common in patients with chronic pancreatitis (see Figure 125), pancreatic cancer, and patients with prior pancreatic surgery who have ductal anastomoses (see Figures 126 and 127). PD leaks, disruption, or a disconnected PD may occur from severe acute pancreatitis with necrosis or after pancreatic surgery (see Figures 128 and 129). PD injury can also occur because of ERCP. Traumatic injuries to pancreas can occur, most commonly following blunt force trauma such as in motor vehicle accidents. PD injuries from trauma are relatively uncommon, occurring in only about 2% blunt trauma cases. Most blunt trauma injuries to the pancreas occur in the junction of the body and tail, where the gland is compressed against the spine posteriorly, causing a crush injury and resulting in partial or complete pancreatic duct transection.37 Penetrating injuries to the pancreas from gunshots or stab wounds are more common than blunt trauma injuries. A classification of PD injuries associated with ERCP that is commonly utilized by endoscopists is described by Takishima38 (see Table 5 and Figure 130). 

Duodenal and Ductal Injuries and Perforations 

Duodenal injuries are a risk of ERCP. The endoscopist should be familiar with the Stapfer classification of duodenal perforations39 (see Table 6). Type 1 is endoscopy related and invariably requires surgery carrying a substantial risk of morbidity and mortality. The best outcome 

in a type I perforation is when this is identified and intervened upon early.40 Type II is the most common and is a periampullary perforation often related to sphincterotomy and may be treated with endoscopic clips or by placing a covered metal biliary stent. Type III is a ductal or duodenal perforation caused by endoscopic instruments but not a guidewire. Type III is less common but can require surgery. Type IV is the presence of retroperitoneal air due to a guidewire puncture. Types II and IV duodenal perforations rarely require surgery. Being aware of and avoiding each of these perforations as well as recognizing their appearance both endoscopically and fluoroscopically are key to early endoscopic or surgical intervention and better patient outcomes.41 

All endoscopists performing ERCP and advanced endoscopic therapeutic interventions must be familiar with and comfortable recognizing free air on fluoroscopy (see Figures 131 and 132). If a perforation is suspected, an upright chest X-ray should be done immediately as this is more sensitive than an abdominal X-ray for the detection of free air. Free air under the diaphragm is easily seen on an upright chest X-ray (see Figures 133 and 134). Rigler’s sign is present when both sides of bowel wall are well defined due to free intra-abdominal air adjacent to gas-filled loops of bowel.42 Sometimes only a subtle triangle of free air can be visible outside the bowel wall as a sign of pneumoperitoneum. 

SUMMARY 

The keys to avoiding imaging pitfalls and mistakes during ERCP are to routinely perform a pre-procedure scout film, always obtain high-quality balloon occlusion cholangiograms and pancreatograms with adequate filling and visualizations of the entire biliary tree (or pancreatic duct if indicated). Strictures should be recognized, well defined, and sampled. All images should be reviewed in real time as well as after the procedure, with selected images saved that “tell the story” of the exam, findings, and interventions. Detailed descriptions of the findings including of variant anatomy, and interventions should also be documented in the ERCP report. Adverse events should be recognized early and treated appropriately. 

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FROM THE PEDIATRIC LITERATURE

Eosinophilic Esophagitis in Children with Inflammatory Bowel Disease 

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 Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal condition likely caused by multiple factors, including genetic susceptibility, immune dysfunction, and microbiome abnormalities. IBD typically is divided into three types: Crohn disease, ulcerative colitis, and inflammatory bowel disease unclassified. Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus associated with eosinophilic infiltration. EoE can have an allergic component although EoE also can be associated with IBD suggesting a common inflammatory pathway for the two disorders. Minimal data is available regarding the occurrence of IBD and EoE in children, and the authors of this Italian study looked for such an association using a retrospective, case-control, multicenter study of children with IBD. 

All new cases of IBD in children from 2009 to 2021 were included in the study. Included patients had standard medical information recorded, and the diagnosis of IBD was based on clinical, endoscopic, histologic, and radiographic findings defined by the Porto Criteria. All EoE cases were diagnosed using European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) criteria. Each pediatric patient under 18 years of age with IBD and EoE was compared to 3 children with IBD alone and 3 children with EoE alone. Patients with IBD and EoE had disease activity monitored by follow-up clinic visits performed 6, 12, and 24 months after IBD diagnosis. Follow up information included the need for corticosteroids use in patients with IBD, clinical relapse in patients with EoE, need for hospitalization, and need for escalation of medical therapy. 

No significant difference was found regarding sex, age at diagnosis, and family history of EoE or IBD between the 3 groups. A total of 11 pediatric patients with both IBD and EoE existed in the study group of 3,090 patients with IBD (prevalence 0.35%). The majority of patients (five children) with both IBD and EoE were diagnosed with EoE after IBD with a mean time between diagnoses of 22 ± 10.1 months. Patients with both IBD and EoE were statistically more likely to have IgE-mediated food allergies compared to patients who had IBD alone. No statistical difference was noted for reactive airway disease or eczema. 

When patients with both IBD and EoE were compared to patients with IBD alone, no difference was seen regarding IBD type, disease location, inflammatory marker testing results, and treatment. Patients with IBD alone were statistically more likely to have abdominal pain as a presenting symptom compared to patients with both IBD and EoE (P=0.04). Epigastric pain was statistically more common as a presenting symptom in patients with EoE alone compared to patients with both IBD and EoE (P=0.001). Approximately 64% of patients with both IBD and EoE had dysphagia as a presenting symptom with the rest of this patient group having no symptoms to suggest EoE. There were no other clinical differences between patients with EoE alone and patients with both IBD and EoE. There was no statistical difference between patients regarding esophageal eosinophilic infiltration (i.e., number of eosinophils per high-power field) between patients with EoE alone and patients with both IBD and EoE. 

The number of patients who needed therapy escalation was significantly higher in patients with IBD alone compared to patients with both IBD and EoE during follow up at 12 months (P=0.04) and 24 months (P=0.04). Patients with IBD alone also were significantly more likely to require systemic steroids and require hospitalization compared to patients with EoE alone and patients with both IBD and EoE. Patients with both IBD and EoE had significantly higher erythrocyte sedimentation rates at follow up compared to patients with EoE alone. 

This study appears to show that patients with a combination of IBD and EoE may present with less severe IBD as evidenced by a decreased use 

of systemic steroids and less hospitalizations. However, the number of patients with both IBD and EoE was small in this study, and further research is needed to confirm these findings. 

A Cause of Infant Colic? 

Infant colic is commonly seen in general pediatric clinics, and patients with such symptoms often are referred to pediatric gastroenterologists due to concerns of gastroesophageal reflux disease causing colic. However, the etiology of colic is unclear. The authors of this study from Turkey evaluated infant circadian rhythm disruption to see if this aspect was a potential cause of colic. 

All included study infants were born between 37-42 weeks of age. Case and control infants were evaluated at 6 weeks of age to see if they had colic using the Wessel criteria defined as crying for at least 3 hours per day for at least 3 days per week. The subsequent study consisted of two parts. In the first stage, parents of all enrolled infants were given a questionnaire for information about infant medical history, parental coping techniques, parental smoking history, parental sleep history, potential circadian rhythm disorders in the family, and parental history of headaches and migraines. The second stage consisted of parents collecting infant 24-hour urine samples via urine bags as well as cotton swab buccal mucosa RNA specimens. Urine samples were obtained twice daily for two days (11 AM and 11 PM) and were tested for cortisol, serotonin, and 6-sulphatoxymelatonin (i.e., a melatonin metabolite) levels by ELISA testing. Buccal mucosa samples underwent quantitative analysis for H3f3b mRNA levels using real-time PCR as the H3f3b gene is involved with sleep regulation. 

A total of 215 infants qualified for the study, and 95 infants completed the study which was comprised of 46 patient cases and 49 controls. No difference between the two groups regarding demographics was present except for a significantly higher birth weight in the colic group. No infant in the study had undergone physical abuse. Infants with colic had significantly more sound and light sensitivity, defecation difficulty, and waking frequency while having significantly less total daily sleep and sleep period duration compared to controls. Mothers of infants with colic had a significantly more waking frequency while having significantly less total sleep. Mothers of infants with colic also had significantly more headaches and migraines although no such effect was seen in the fathers. 

A significant difference in melatonin levels obtained between day and night was noted in the control group suggesting the control group had a normal circadian rhythm. No such finding was present in the colic group suggesting an impaired circadian rhythm. No difference in cortisol levels was present between groups. Serotonin levels were noted to be significantly higher at night in the colic group. H3f3b mRNA levels were significantly higher in control infants compared to infants with colic regardless of samples being obtained during the day or night. 

These results demonstrate potential risk factors for infant colic that may work in an aggravating fashion. Such risk factors include impaired infant circadian rhythms as evidenced by urine and mRNA biomarkers, maternal history of sleep impairment, and maternal history of headaches and migraines. The authors bring up the compelling idea that infant colic could be a type of migraine. Although these study results are intriguing, they need to be evaluated in other settings including other countries with lower smoking rates. 

Aloi M, D’Arcangelo G, Rossetti D, Bucherini S, Felici E, Romano C, Martinelli M, Dipasquale V, Lionetti P, Oliva S. Occurrence and Clinical Impact of Eosinophilic Esophagitis in a Large Cohort of Children with Inflammatory Bowel Disease. Inflamm Bowel Dis 2023; 29: 1057-1064. 

Egeli T, Tufekci K, Ural C, Durur D, Erdogan F, Cavdar Z, Genc S, Keskinoglu P, Duman N, Ozkan H. A New Perspective on the Pathogenesis of Infantile Colic: Is Infantile Colic a Biorhythm Disorder? J Pediatr Gastroenterol Nutr 2023; 77: 171-177. 

John Pohl, M.D., Book Editor, is on the Editorial Board of Practical Gastroenterology 

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