Page 44 – Practical Gastro

David Pineles,Cristina Hajdu,David M. Poppers

Globally, prostate cancer is the most commonly diagnosed cancer in men.1 Radiation therapy remains a mainstay in the treatment of this disease. Radiation proctopathy is a common side effect of this treatment modality with an incidence in patients treated with brachytherapy alone estimated to range from 8 to 13%, and up to 21% in combination with other modalities.2 Radiation proctopathy typically presents with diarrhea, mucoid discharge, urgency, tenesmus, and bleeding. Argon plasma coagulation (APC) has become the primary therapeutic modality in the management of radiation injury. It is essential that physicians of all specialties (as well as others who care for these patients) be aware of the multiple complications of this therapy. More severe adverse events, notably rectal ulcers following APC therapy are not uncommon, with an incidence ranging from 3 to 16%.2

Case

A sixty seven year old man with a history of prostate cancer treated with radiation therapy one year prior presented with intermittent rectal bleeding for one and a half months. Colonoscopy revealed a small area near the dentate line characterized by slightly oozing, neovascularized tissue consistent with radiation proctopathy (Image 1). This area was treated with APC with good effect. Biopsies of this area revealed hyperplastic crypts, lamina propria fibrosis, and vascular ectasias compatible with radiation injury. Three months following treatment, the patient developed recurrent rectal bleeding. A flexible sigmoidoscopy revealed a deep, non-bleeding ulcer in the rectum (Image 3). Subsequent computed tomography enterographyand magnetic resonance imaging of the pelvis demonstrated a deep rectal ulcer with abutment of a 1.5 cm peri-prostatic abscess. The patient was followed closely over the next several months, in conjunction with colorectal surgery, with serial imaging and subsequent resolution of the periprostatic abscess and cessation of rectal bleeding.

Discussion

As more patients with prostate cancer are treated with radiation therapy the incidence of radiation proctopathy is increasing.3,4 Although argon plasma coagulation has been shown to be an effective therapy for this issue, providers must consider and discuss with patients the potential complications of this otherwise effective and generally welltolerated mode of treatment

DISPATCHES FROM THE GUILD CONFERENCE, SERIES #26

Medical Management of Post-Operative Crohn’s Disease

Abhik Bhattacharya,

Miguel Regueiro

Nearly one million people in the United States suffer from Crohn’s disease (CD), with studies showing increase in the rate of prevalence of CD from 214 per 100,000 people in 2004-2005, to 236 per 100,000 people in 2008-2009.1,2 Crohn’s disease (CD) is a chronic immune mediated inflammatory disorder of the gastrointestinal system that can involve anywhere from the mouth to the anus. Over one-half of patients with CD will have an intestinal complication of strictures, fistulas and abscesses3 and nearly 70% require surgical resections by 15 years.4 Surgery can induce remission but is not curative, as most patients undergoing an ileo-cecal resection will develop endoscopic recurrence one year after surgery.5 More importantly, these patients do not manifest symptoms (i.e. they are clinically “silent”) until another complication presents and surgery is required. Primary care physicians will often see these patients and it is important to understand the natural course and management of postoperative Crohn’s disease.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #191

Author Addendum/Correction

Carol Rees Parrish, MS, RDN, Series Editor

Diet in Non-Alcoholic Fatty Liver Disease

by Jennifer B. Miller, Zachary Henry

We regret the following oversight in our article,“Diet in Non-Alcoholic Fatty Liver Disease”, by Jennifer B. Miller and Zachary Henry, that appeared in our October 2019 issue (Volume XLIII No. 10, pp. 24-27).

Specifically, the last two bullet points on Table 1 were incorrect. Please see the corrected Table 1. Download the PDF below.

The Editors

FRONTIERS IN ENDOSCOPY, SERIES #56

A Common Bile Duct Bump

Moamen Gabr,

Pradeep Yarra,

Douglas Pleskow

We present a 36-year-old woman with right upper quadrant pain, nausea, vomiting and anorexia. Significant past medical history includes morbid obesity, status post laparoscopic sleeve gastrectomy (14 months ago) with an accompanying 70 pounds weight loss. The postoperative course was complicated by a portal vein thrombosis, which was treated with Apixaban for 3 months. She was non-complaint in her followup. The patient now presents 6 months later with these symptoms. On examination, right upper quadrant tenderness was present with negative murphy sign, Patient had normal white blood count and liver function tests. Initial evaluation included a right upper quadrant ultrasound, which showed cholelithiasis without gallbladder wall edema or pericholecystic fluid. The surgical consult agreed that there were no signs of acute cholecystitis. Computed tomography (CT) demonstrated no acute abdominal process. Cavernous transformation of the main portal vein with numerous abdominal varices was seen. Additional findings included mild splenomegaly and cholelithiasis without evidence of cholecystitis. (Figure 1) A Magnetic Resonance Venography (MRV) was performed which revealed Cavernous transformation of the main portal vein with multiple collateral vessels as well as multiple portosystemic collateral vessels within the anterior abdomen and anterior body wall. Given a suspicion for a biliary process as a source of her right upper quadrant pain, she was referred for an endoscopic retrograde cholangiopancreatography (ERCP). ERCP was performed and revealed smooth narrowing of the common bile duct on the cholangiogram (Figure 2). In order to more fully characterize the stricture a cholangioscopy was performed. Cholangioscopy revealed a smooth extrinsic compressible common bile duct mass consistent with intraductal varix (Figure 3). The decision was made to perform intraductal endoscopic ultrasound (IDUS) using the ultrasound probe. The probe was advanced in the bile duct under fluoroscopic and endoscopic guidance and revealed periductal dilated intravascular spaces compressing the distal common bile duct. (Figure 4) The patient was referred to IR for a trial of portal vein recanalization that was not successful, the patient then underwent a successful Transjugular Intrahepatic Portosystemic Shunt (TIPS) procedure. This case also showed extensive involvement of the pericholecystic, peripancreatic, intra and extra hepatic venous system causing the cavernous transformation.

DISPATCHES FROM THE GUILD CONFERENCE, SERIES #25

Managing Chronic Pancreatitis: Beyond Opioids

Neil B. Marya,

V. Raman Muthusamy

Neil B. Marya, MD, V. Raman Muthusamy MD, MAS Vatche and Tamar Manoukian Division of Digestive Disease, University of California Los Angeles, Los Angeles, CA.

Chronic pancreatitis severely impacts the quality of life for affected patients and is a major burden on the health care system. Of all of the complications associated with chronic pancreatitis, chronic pain is one of the most difficult to manage. Historically, clinicians have used opioids as part of a long-term management strategy to keep patients out of the hospital and manage pain. With the growing opioid epidemic in the United States and mounting evidence that opioids can ultimately worsen patient outcomes, clinicians should be aware of the medical, nutritional, endoscopic and surgical alternatives that are available for managing pain resulting from chronic pancreatitis. These options should increasingly be utilized in the initial treatment and management of chronic pancreatitis rather than as salvage options when increasingly high doses of opioids become ineffective.

Chronic pancreatitis (CP) is a fibro-inflammatory condition that affects the exocrine and endocrine function of the pancreas and can also cause a chronic pain syndrome that adversely impacts the lives of patients. Epidemiologic studies suggest that CP occurs more frequently in blacks than other ethnicities and is more common in men than women.^1-3 Risk factors for the development of CP include genetic mutations (such as PRSS1 and SPINK1), autoimmune conditions, obstruction of the main pancreatic duct, recurrent acute pancreatitis, smoking and chronic alcohol use. In many cases, the etiology of the recurrent pancreatitis is never identified. The incidence of CP ranges from 4 to 13 cases per 100,000 patient-years.^4-6

Although few widespread population studies have been performed, available data suggests that the incidence of CP is on the rise.⁷
In early stages of CP, patients experience recurrent symptoms consistent with acute pancreatitis (i.e. severe mid-upper abdominal pain that radiates to the back, nausea, and vomiting). If flares of inflammation persist over several years, the pancreatic tissue becomes fibrotic and calcified. Typically patients will experience symptoms consistent with CP once 15% or less of functional pancreas remains.⁸ Classic symptoms that patients with CP will experience can be separated into three categories – those related to exocrine insufficiency, those related to endocrine insufficiency and abdominal pain.

Exocrine insufficiency of the pancreas is manifested as steatorrhea, diarrhea, and poor nutrition due to malabsorption. Endocrine insufficiency is characterized by the loss of insulin-producing beta cells due to atrophy of pancreatic islets resulting in an insulin-dependent phenotype of diabetes. Chronic pain, perhaps the most significant sequelae of CP patients, severely impacts quality of life and levies major financial burdens on the health care system (estimated to be over $600 million dollars annually).⁹ Chronic pain is very prevalent in CP, occurring in 85% of patients.^10-12 Approximately 90% of patients with CP will be admitted at least once to the hospital for management of chronic abdominal pain and, on average, more than 10 times over the course of their lives.¹³

Managing pain and the other sequelae of CP can be challenging. Historically, opioids have been a cornerstone of management of CP with over 50% of patients receiving at least one prescription for an opiate during their disease process.¹⁴ Given the growing epidemic of opioid overuse and the presence of literature that suggests that opiates may not only just be ineffective for chronic pain, but may also perpetuate a cycle of chronic pain symptoms by worsening symptoms of chronic pancreatitis and changing pain thresholds, it is clear that alternative strategies must be considered when managing CP.^15,16

The goal of this review is to provide a summary of medical, nutritional, endoscopic, and surgical alternatives for the management of CP so that clinicians are aware of what options exist beyond prescribing opiates.

Medical and Nutritional Therapy

CP patients will suffer from severe post-prandial pain due to the release of cholecystokinin once a food bolus enters the duodenum. After cholecystokinin is released, the pancreas begins secreting enzymes into the gastrointestinal lumen. CP patients subsequently can develop significant pain as a result of increased pressure within the pancreatic duct (ductal hypertension) as well as effects of trypsin on nociceptive receptors surrounding the pancreas. The oxidative-stress incurred by recurrent parenchymal inflammation may also adapt the central nervous system pain receptors such that some CP patients will also develop a component of neuropathic pain that becomes independent of the pancreas.
To counteract this, physicians have a variety of tools that target specific factors contributing to pain in CP patients. Antioxidants alongside pregabalin, for example, have been shown to improve pain control for CP patients, presumably by preventing the neural changes that result in the development of neuropathic pain.^17,18 Alternatively, pancreatic enzyme replacement therapy (PERT) is useful by limiting the release of cholecystokinin in the duodenal lumen and reducing the amount of pancreatic exocrine stimulation that occurs during meals, thereby improving ductal hypertension and reducing pain. A review of randomized controlled trials studying the effect of PERT for the purpose of pain control in CP demonstrated that only pancreatic enzyme formulations that were uncoated (i.e. not acid protected) resulted in improvement in pain.^19-24 Based on these studies, it is recommended that uncoated formulations of enzymes be used to manage chronic pain and that the enzymes are administered at high doses (>25,000, United States Pharmacopeia—USP) four to eight times per day.²⁵ Patients receiving these medications must receive anti-secretory therapy (i.e. proton pump inhibitors) to avoid the non-enteric coated enzymes from being inactivated by gastric acid.

Patients suffering from symptoms of exocrine insufficiency also benefit from enzyme supplementation. Compared to CP patients where pain is the predominant symptom, patients with severe exocrine insufficiency can benefit from enteric coated formulations of PERT as the enzymes are released in the jejunum and ileum to assist with absorption. Doses of PERT are titrated based on patient weight, symptom severity, and meal size. For average sized meals, doses should range from 50,000-90,000 USP.²⁶ If patients have persistent symptoms of malabsorption, clinicians should consider upping the PERT dose and adding a proton pump inhibitor in order increase the enzyme concentration in the distal small bowel.²⁷

In conjunction with PERT, CP patients with malnutrition will often require dietary alterations and nutritional supplementation to improve malabsorption symptoms. As the natural history of CP progresses and patients limit oral intake, it is key that patients understand what to prioritize in their diet to avoid becoming malnourished. Traditionally, due to concerns of fat malabsorption, CP patients have been told to avoid fatty foods and, instead, focus on high fiber diets. We now know that fat is an essential source of energy for CP patients and, alternatively, high fiber diets have actually been shown to inhibit lipase secretion, which may worsen malabsorption.^28,29 Consultation with an experienced dietician should be considered as studies have shown that expert advice regarding nutritional supplements has been shown to improve outcomes for CP patients.³⁰ In order to maximize the effects of all of these interventions, CP patients should also be counseled to completely abstain from alcohol and to stop smoking to limit progression of disease.

Endoscopic Therapies

Over the past several of years, innovations in endoscopic technology have advanced the role of endoscopy in the management of chronic pancreatitis. Now, clinicians can rely on endoscopic therapy as a valuable and effective tool to address structural issues related to CP and to avoid or defer more invasive surgical procedures.

Pancreatic duct stones, or pancreatic calculi (PC), are an example of structural complications in CP patients that are amenable to endoscopic therapy. PC are made up of calcium carbonate (along with other minerals found in pancreatic juices) and develop in approximately 50% of CP patients.³³ These stones can obstruct the main pancreatic duct resulting in intraductal hypertension along with pain and inflammation that can accelerate the progression of parenchymal fibrosis.³⁴ Through endoscopic retrograde cholangiopancreatography (ERCP), endoscopists are able to obtain retrograde access to the main pancreatic duct. The goal of endoscopic treatment in these cases is to remove stones, resolve obstructions, and improve intraductal flow. For smaller stones this can be achieved by performing a sphincterotomy or by using extraction balloons, forceps, or baskets. In the cases where larger stones are present, lithotripsy may be required. Extracorporeal shockwave lithotripsy is a potential first step for the management of larger stones as it has shown to be cost effective. It important to note, however, that this technology is not available in all medical centers.²⁷ Alternatively, endoscopic advancements now allow for mechanical, electrohydraulic and laser lithotripsy to be performed through an endoscope. Mechanical lithotripsy involves inserting a catheter or basket into the pancreatic duct, crushing an obstructing stone, and removing the fragments from the duct. In laser or electrohydraulic lithotripsy, a smaller 10 French scope is inserted through the duodenoscope and into the pancreatic duct to direct laser or electrohydraulic treatment to obstructing stones. All of these techniques have shown efficacy in studies; however, longer term studies regarding efficacy and safety are still needed. Importantly, knowing which stones to attempt therapy on is a critical issue that is not always readily apparent. The presence of a caliber change in the pancreatic duct with dilation of the duct upstream from the stone is a useful criteria that is often utilized as an appropriate indication for treatment.

Similar to pancreatic duct stones, main pancreatic duct strictures (PDS) are obstructive complications of CP that cause chronic pain by preventing drainage of the main pancreatic duct and increasing intraductal pressures. The first step in managing a newly identified pancreatic duct stricture is to rule out underlying malignancy. This can be done non-invasively by obtaining a magnetic resonance imaging (MRI) or computerized tomography (CT) scan of the pancreas or invasively by endoscopic ultrasound with fine needle aspiration. Once malignancy has been ruled out, management of symptomatic benign strictures can be pursued. The goal of treatment in these cases is decompress the pancreatic duct by relieving the obstruction and improving pain. In current practice, treatment of CP strictures occurs via three techniques: pancreatic sphincterotomy, stricture dilation, and stenting. Execution of these maneuvers is effective in sustaining pain relief in 32%-68% of cases.^35,36While pancreatic sphincterotomy and dilation are well-established steps in the management of PDS, research is currently focusing on how to best maximize the benefit of endoscopic interventions by studying different stenting practices. There is a longer track record of research supporting the use of plastic stents in CP patients with strictures, however, newer data suggests that fully covered self-expanding metal stents (FC-SEMS) placed across PDS can improve ductal patency and keep patients asymptomatic longer. One study demonstrated that 89% of patients that were followed for more than 38 months after metal stent placement for PDS remained asymptomatic.³⁷ Future studies confirming the safety, efficacy and cost benefits of FC-SEMS over plastic stents will be important in making this standard practice.

In addition to strictures of the pancreatic duct, up to 46% of CP patients will develop strictures of the common bile duct their disease course.³⁸Strictures often occur secondary to pancreatic parenchymal edema and progressively worsening fibrosis. Patients presenting with biliary strictures may be jaundiced or even have symptoms of cholangitis. Similar to PDS, biliary strictures must be first be investigated for possible malignancy; once that has been ruled out, patients can be considered for endoscopic treatment. Endoscopists can choose to place multiple plastic stents across the biliary strictures or opt for the placement of a FC-SEMS. A recent randomized controlled trial, however, suggests that compared to placing plastic stents, placement of FC-SEMS results in increased rates of stricture resolution while requiring fewer procedures.³⁹

For patients where no focal anatomical changes can be attributed as a cause of recurrent pancreatic-type pain, celiac nerve blocks (CNB) or celiac neurolysis can be considered. During a CNB procedure, an endoscopist uses an echoendoscope to directly inject a steroid-anesthetic mixture into a celiac ganglion or the area around the celiac axis if no ganglion is seen. Celiac neurolysis is a similar procedure; however, the injection is a mixture of alcohol and an anesthetic and this mixture has not typically been utilized in patients with benign pancreatic disease. For CP patients with chronic pain, CNB is effective in 50-60% of cases; however, additional treatments will likely be required as the treatment effect often diminishes over the course of a few months.^40,41

A final complication of CP that can be managed endoscopically are pancreatic pseudocysts. Pancreatic pseudocysts are walled-off, encapsulated collections of pancreatic fluid that are commonly seen in both acute pancreatitis and CP. Unlike in acute pancreatitis, most CP pseudocysts do not often resolve spontaneously. However, they also do not tend to cause many symptoms. If pseudocysts in CP cause symptoms due to mass effect on nearby organs or because they become infected, treatment is warranted. The goal of endoscopic treatment in these causes is to drain the cyst and have it collapse and ultimately resolve. Endoscopic drainage techniques have been shown to be successful in resolving pseudocysts in up to 90% of cases and also improve quality of life for CP patients. Compared to surgical or percutaneous drainage, endoscopic approaches have been associated with less procedural risk, decreased hospitalizations, and costs.^42-45 Endoscopic drainage of pseudocysts can be performed by a transmural approach (if the pseudocyst is near the stomach or duodenum) or by a transpapillary approach (if the pseudocyst has a direct communication to the pancreatic duct). Endoscopic transmural drainage of pseudocysts has been made simpler by the development of lumen apposing metal stents and these stents have become the primary method of endoscopic therapy of pancreatic fluid collections. Using a single device specifically created for this aim, these stents are able to puncture the cyst and connect the cyst cavity to the lumen of the GI tract to facilitate drainage. By simplifying this process, endoscopists have achieved success rates comparable to surgery while significantly reducing procedure times and cost.

Surgical Management

In cases of CP where less invasive treatment strategies have failed, surgical management can be considered. Surgical treatment of chronic pancreatitis can be broken down into drainage procedures, resection procedures, and combined drainage/resection procedures.

Surgical drainage procedures are indicated in CP patients with refractory, chronic pain who have evidence of a persistently obstructed and distended (> 6 mm) main pancreatic duct or occasionally in CP patients who are found to have a disconnected pancreatic duct. Surgical management in these cases involves bringing a loop of jejunum up to the pancreas and creating a direct anastomosis with the dilated pancreatic duct to facilitate drainage. This procedure is known a lateral pancreaticojejunostomy (also often referred to as a Puestow procedure). Pancreaticojejunostomies are effective (providing initial pain relief in 90% of cases) and safe (mortality of 0-4%).^48-51 Despite achieving high rates of pain relief initially, 40% of CP patients will eventually require hospitalization after surgery for pain management and, potentially, additional procedures such as pancreatic resection will be necessary. Finally, although this technique is advantageous in that no gland is resected, as many as 25% of CP patients will develop glandular dysfunction and become insulin dependent after surgery, despite the lack of resection of the gland.^51,52

When CP patients are experiencing pain but the main pancreatic duct is not dilated, pancreatic resection procedures are considered. Other situations where a surgeon may choose a resection procedure includen if a CP patient has a focal lesion which may represent malignancy or if the patient has had an attempt at a drainage procedure in the past which has failed. There are three main types of surgical resections that are utilized for CP patients based on what parts of the pancreatic parenchyma are most diseased/involved.

For the majority of CP patients, chronic inflammatory changes are focused at the head of the pancreas. The preferred surgical procedure in this setting is a pancreaticoduodenectomy (also known as a Whipple procedure) or a duodenal preserving pancreatic head resectiton (Beger procedure). For cases where the majority of the body and the tail of the pancreas are calcified a distal pancreatectomy is performed. In this procedure, the distal pancreas (neck, body and tail) is resected, while the pancreas head and uncinate process are preserved. Finally, a complete resection of the pancreas (i.e. total pancreatectomy) is indicated in CP patients who are found to have extensive main-duct intraductal papillary mucinous neoplasms or hereditary pancreatitis due to the significant risk of malignant transformation within the entire gland. All of these resection procedures are associated with good initial pain relief. As would be expected, to varying degrees, each surgery is associated with post-operative morbidity as well as significant rates of endocrine insufficiency. For example, following total pancreatectomy, patients will develop insulin-dependent diabetes that can be very difficult to manage. To improve post-operative glycemic control, surgeons have utilized auto-islet cell transplantation (where the pancreas is removed, emulsified, purified to extract islet cells and then injected back into the patient). Studies of auto-islet cell transplantation demonstrate promising results; however, this procedure is available only in expert centers and can be very expensive.^53-63 It also appears to be less efficacious in patients with more advanced disease, in whom fewer available islet cells are available for extraction.
Finally, combined resection/drainage procedures, like the Frey procedure, are often performed in patients with a dilated pancreatic duct associated with an enlarged pancreatic head. During a Frey procedure, the affected areas of the pancreatic head are cored out and a lateral pancreaticojejunostomy is performed. Compared with standard drainage procedures, combined procedures such as the Frey procedure are associated with improved long-term pain relief.⁶⁴

CONCLUSION

This review has covered the management strategies of chronic pancreatitis that exist beyond opioid prescription – medical/nutritional therapy, endoscopic therapy, and surgical treatment. It is key that clinicians are aware of alternatives to opiates for the management of CP. Opiates should not be considered a long-term solution to pain management in CP as they may be a driver towards the development of centrally-mediated neuropathic pain. The development of this centrally-mediated pain is believed to result in reduced efficacy of subsequent endoscopic and surgical treatments. With advances in available medical, surgical and endoscopic therapy, clinicians have even more options available to them to better manage CP and should utilize these approaches earlier in managing pain associated with CP. The next steps in optimizing the management of CP is to gain a better understanding of which specific scenarios would benefit from endoscopic management versus surgical management. Future trials directly comparing these different techniques and combination therapies will be vital in providing direction to clinicians managing these patients.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #191

Diet in Non-Alcoholic Fatty Liver Disease

Jennifer B. Miller,

Zachary Henry

Carol Rees Parrish, MS, RDN, Series Editor

Jennifer B. Miller, MD, GI Fellow, University of Virginia Division of Gastroenterology and Hepatology Zachary Henry, MD, MSc, Assistant Professor, University of Virginia Division of Gastroenterology and Hepatology, Charlottesville, VA.

Non-alcoholic fatty liver disease (NAFLD) is quickly becoming one of the leading causes of end stage liver disease, and many physicians will encounter these patients in the clinical setting. It has been proven that a hypercaloric diet, loaded with high fructose corn syrup is directly correlated with the amount of fatty deposition in the liver. A 7-10% weight loss has been associated with a decrease in liver fat content and improvement in liver fibrosis. Therefore, the goal of treating these patients should be weight loss. This can be achieved with exercise, which alone has proven to be advantageous for the NAFLD patient, in concert with dietary change. Diets that reduce carbohydrates, especially high fructose corn syrup, and increase anti-oxidants have a positive impact on NAFLD. The following review highlights the epidemiology, pathogenesis, and treatment goals for patients with NAFLD.

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of end-stage liver disease and is considered the third-most common indication for liver transplantation in the United States.^1,2 The term NAFLD encompasses the spectrum of fatty liver diseases including non-NASH fatty liver (NNFL), nonalcoholic steatohepatitis (NASH), and NASH cirrhosis. NAFLD is defined by the presence of ≥ 5% hepatic steatosis, confirmed by imaging or histology, and lack of secondary causes of hepatic fat accumulation.³ A meta-analysis of over eight million patients estimated that the overall global prevalence of NAFLD diagnosed by imaging was 25.24%.⁴ The prevalence of NAFLD has been reported to be higher in patients with metabolic syndrome, and autopsy data indicates that NASH is at least six times more prevalent in obese patients compared to lean patients.⁵ NAFLD is present in 65% of persons with Class I or II obesity (BMI 30-39.9 kg/m2) and 85% of persons with a BMI ≥ 40 kg/m.4,6 NAFLD is strongly linked to both insulin resistance and cardiovascular disease and is considered to be the hepatic manifestation of the metabolic syndrome.^7,8 With the increasing prevalence of metabolic syndrome and consequently the NAFLD population, there is an urgency to identify efficacious management strategies, as these patients are at risk to develop complications of end stage liver disease.

Pathophysiology of NAFLD

The cornerstone of our current understanding of the progression of hepatic steatosis to NASH fibrosis was described by Day and colleagues as the “2-hit” phenomenon. This hypothesis proposed that accumulation of fat in the liver is followed by an oxidative stress state resulting in liver injury/inflammation and resultant scarring i.e. fibrosis.⁷ In the hepatocyte mitochondria, free fatty acids undergo a process of oxidation, esterification and synthesis into phospholipids and cholesterol esters, which are exported from the liver as very low density lipoprotein. Accumulation of hepatic fat can overwhelm the above described process. This hepatic fat accumulation can occur by different mechanisms including delivery from the intestine as chylomicrons, delivery from lipolysis through the action of lipase on insulin resistant adipocytes and thirdly, de novo lipogenesis.⁹ A recent study revealed that patients with higher hepatic fat content derive a greater proportion of liver fat from de novo lipogenesis, compared to matched controls. Interestingly, specific components of the modern American diet, specifically high fructose corn syrup, have been shown to augment the amount of hepatic de novo lipogenesis in patients with NAFLD.⁶

Therapies for NAFLD

The prognosis of a patient with NAFLD is variable, and determining that patient’s risk for liver related morbidity is essential to gauge therapeutic intervention. Ekstedt et al. performed a thirty-three year cohort study evaluating 229 biopsy proven NAFLD patients, which found that patients with NAFLD had an increased mortality compared with the referenced population (HR 1.29, CI 1.04-2.15, P=0.02). The causes of death in patients with NAFLD included cardiovascular disease (41%), non-gastrointestinal malignancy (19%) and hepatocellular carcinoma (5%). Those patients with baseline fibrosis stage 3 or 4 (per biopsy) had the worst prognosis.10 Given the complex underlying physiology of NAFLD, there are many potential targets for therapeutic drugs. Unfortunately, medical therapies up to now have been unsuccessful in reversing fibrosis and have only been marginally effective at improving the underlying components of NAFLD – steatosis, inflammation, and balloon cell degeneration.¹¹

Weight reduction in patients with NAFLD leads to a decrease in liver fat content, serum liver enzymes, and hepatic inflammation; it may also improve fibrosis.³ A 7%-10% reduction in body weight results in improvement in histological findings including lobular inflammation and hepatocyte ballooning.¹² Small decreases in body weight equate to more substantial decreases in liver fat, and the method by which a patient loses weight is irrelevant.¹³ In a prospective trial of 293 patients on a low-fat hypocaloric diet, 750 kcal/d less than their daily energy needed, a greater than 10% weight loss resulted in a reduced fibrosis score of at least 1 point in 13 of 16 (81%) patients with baseline fibrosis.¹⁴ This study along with many others supports the fact that weight loss is independently linked to an improvement in histological outcomes in patients with NAFLD.
It is important to also recognize that physical activity, independent of weight loss, can improve fatty liver disease by reducing hepatic fat content. Studies have shown that exercise improves the body’s peripheral sensitivity to insulin. This decreases the action of lipase, resulting in less adipocyte lipolysis and less delivery of free fatty acids to the liver. Exercise has also been shown to decrease the amount of de novo lipogenesis in patients dedicated to an exercise program.¹⁵ Therefore, in addition to encouraging patients to follow a healthy diet, clinicians should also encourage dedicated exercise programs to maximize potential impact on NAFLD as well as metabolic syndrome in general.

Specific Diets in NAFLD

Lifestyle modifications have shown proven benefit in patients with NAFLD. Accomplishing weight loss can occur through healthy dietary modifications that decrease calories and result in a net negative energy balance. In order to achieve this, expert opinion recommends patients should undergo a multidisciplinary approach, which includes education by a registered dietitian nutritionist. Overall, there are limited data to support one particular diet over another for NAFLD due to small numbers of patients in lifestyle studies. In addition, a recent large trial suggested that a patient’s response to a particular diet may be based upon individualized factors as of yet unidentified and predicting success is more difficult than previously thought.¹⁶ However, we will present current data below to support our recommendations for lifestyle modification in patients with NAFLD.

Previously, it was theorized that a hypercaloric diet leading to increased delivery of fat to the liver was the primary driver of NAFLD. To investigate this theory, Kechangias et al.. explored the effects of a four week hypercaloric diet in the form of fast-food on intrahepatic triglyceride concentrations and noted an increase in intrahepatic triglyceride content by 1.1-2.8% and an increase in serum ALT levels from 22 U/I to 69 U/I.17 Hypercaloric diets also appear to increase fasting hepatic glucose output and increase hepatic insulin resistance index by almost two-fold, suggesting both these mechanisms contribute to the development of NAFLD.¹⁸

A growing body of evidence suggests that specific macronutrients (carbohydrates) may have a more profound effect on fatty liver disease. Macronutrients in the portal vein can be as high as ten times greater than that of the systemic circulation, and therefore the liver is in the direct line of fire.² High fructose corn syrup, a predominant component of the western diet, is extensively metabolized in the liver and is thought to be a dominant driver of NAFLD by means of de novo lipogenesis. It has been shown to increase intrahepatic fat accumulation and also cause a decrease in hepatic lipid oxidation.⁶ Americans ingest between 15-25% of their total daily calories from refined sugars; the most commonly consumed sugar is high fructose corn syrup.² Le et al. compared the effects of seven days of hypercaloric feeding with high-fructose corn syrup on healthy male offspring of parents with and without diabetes mellitus (DM), but with no history of NAFLD. After seven days of a high fructose corn syrup diet, intrahepatic triglyceride concentrations increased by 79% in the male offspring of parents with DM and 76% in the control group.¹⁹ In a second study, Sevastianova et al. studied the effects of short term carbohydrate overfeeding (“candy diet” including 1000 extra carbohydrate kilocalories/day) on liver fat in sixteen overweight patients for three weeks and found that carbohydrate overfeeding increased weight by 2% and liver fat by 27%. When the same cohort of patients were then restricted to a hypocaloric diet for a six month period, they lost 4% of their body weight, and liver fat content decreased by 25%. The authors then took the study a step further by measuring the lipogenic index, i.e., the ratio of saturated fatty acids to unsaturated fatty acids as a marker of de novo lipogenesis. The authors found that three days of high-carbohydrate feeding stimulated de novo lipogenesis by increasing the lipogenic index in measured VLDL triglycerides.¹³ The ability of high fructose corn syrup to instigate de novo lipogenesis seems to be a substantial part of the development of NAFLD. Based on this data, clinicians and registered dietitian nutritionists should encourage patients with NAFLD to eliminate high fructose corn syrup from their diet.

Conversely, polyunsaturated fats have gained positive attention. This can be explained by the fact that polyunsaturated fatty acids upregulate genes responsible for the expression of proteins associated with fatty acid oxidation and decreased hepatic fat accumulation. Furthermore, polyunsaturated fats downregulate the genes responsible for the expression of proteins that boost hepatic fat.⁶ The complexity of diet and its composition should be carefully reviewed by not only the clinician and patient, but also between the patient and registered dietitian nutritionist. The goal of dietary counseling should be to eliminate those components that are worsening the patient’s liver fat content and potentially adding those macronutrients which may down regulate the accumulation of fat in the liver and the inflammatory process that ensues.

The Mediterranean Diet (MD), which is high in polyunsaturated fats, consists of eating primarily fresh fruits, olive oil, nuts, fish, white meat and legumes in moderation and limiting red meat and sweets. This diet has both anti-oxidant and anti-inflammatory properties and was first noted to decrease risk of cardiovascular disease and diabetes mellitus in the 1960s.²⁰ In regards to NAFLD, a study of overweight/obese patients showed that patients with a low adherence to the MD had a prevalence of NAFLD at 96.5% and those with high adherence to the MD had a NAFLD prevalence of 71.4%, P<0.001.20 Other studies have also suggested a similar benefit of the MD on NAFLD, and hence the European Association for the Study of the Liver guidelines have encouraged the MD for management of NAFLD; however, many of these studies were limited by population based study designs, and so further investigations are needed to solidify the efficacy of this diet in NAFLD management.²⁰

CONCLUSION

Non-alcoholic fatty liver disease is quickly becoming the most prominent liver disease in the world and mirrors the ongoing global epidemic of obesity. In an effort to manage this growing problem, clinicians need to counsel patients on lifestyle modifications with the goal of a 7-10% reduction in total body weight. The bottom line when focusing on dietary intervention in patients with NAFLD is that dietary changes that result in weight loss are beneficial, regardless of the specific dietary modifications undertaken. However, there may be added benefits in those diets that decrease the amount of high fructose corn syrup, increase polyunsaturated fats, and decrease the inflammatory state of NAFLD via antioxidant nutrients such as those found in the Mediterranean diet. Finally, to help clinicians with the management of these patients it is very important to consider referring them to a registered dietitian nutritionist and exercise physiologist or trainer as lifestyle changes are very difficult to undertake alone and require persistence and constant reinforcement.

FROM THE LITERATURE

Effects of Opioids on Esophageal Function

It has previously been demonstrated that there is an association between chronic opioid use and esophageal motor dysfunction characterized by esophagogastric junction outflow obstruction, distal esophageal spasm, achalasia III and possibly jackhammer esophagus. To characterize the influence of different opioids and doses on esophageal dysfunction, a retrospective review of 225 patients prescribed oxycodone, hydrocodone, or tramadol for greater than 3 months and who completed high-resolution manometry from 2012 to 2017 was carried out.

Demographic and manometric data were extracted from a prospectively maintained motility database. Frequency of opioid-induced esophageal dysfunction (OIED), defined as distal esophageal spasm, esophagogastric junction outflow obstruction, achalasia type III or jackhammer esophagus on high-resolution manometry, was compared among different opioids. The total 24-hour opioid doses for oxycodone, hydrocodone, and tramadol were converted to a morphine equivalent for dose effect analysis.

OIED was present in 24% (55 of 225) of opioid users. OIED was significantly more prevalent with oxycodone or hydrocodone use, compared with tramadol (31% vs. 28% vs. 12%), and for oxycodone alone vs. oxycodone with acetaminophen (43% vs. 21%), there was no difference in OIED for patients taking hydrocodone alone vs. hydrocodone with acetaminophen. Patients with OIED were taking a higher median 24-hour opioid dose than those without OIED (45 vs. 30 mg).

It was concluded that OIED is more prevalent in patients taking oxycodone or hydrocodone, compared with tramadol. There is a greater likelihood of OIED developing with higher doses. Reducing the opioid dose or changing to tramadol may reduce OIED in opioid users.

Snyder, D., Crowell, M., Horsley-Silva, J., et al. “Opioid-Induced Esophageal Dysfunction: Differential Effects f Type and Dose.” American Journal of Gastroenterology 2019; Vol. 114, pp. 1464-1469.

Murray H. Cohen, DO, “From the Literature” Editor, is on the Editorial Board of Practical Gastroenterology.

FROM THE LITERATURE

Safety of Proton Pump Inhibitor Therapy

To confirm tolerance of proton pump inhibitor (PPI) therapy with long-term treatment, an adequately powered, randomized trial was carried out, performing a 3 x 2 partial factorial, double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease, randomly assigned to groups, given pantoprazole 40 mg daily (n = 8791), or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily with aspirin 100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone.

Data was collected on development of pneumonia, C. difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow up.

There was no statistical significant difference between the pantoprazole and placebo groups in safety events, except for enteric infections (1.4% vs. 1.0%) in the placebo group (OR 1.33). For all other safety outcomes, proportions were similar between groups, except for C. difficile infection, which was approximately twice as common in the pantoprazole vs. the placebo group, although there were only 13 events and the difference was not considered statistically significant.

It was concluded that in a large placebo-controlled, randomized trial, pantoprazole therapy is not associated with any adverse events when used for 3 years, with the possible exception of an increased risk of enteric infections.

Moayyedi, P., Eikelbloom, J., Bosch, J., et al for the COMPASS Investigators. “Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin.” Gastroenterology 2019; Vol. 157, pp. 682-691.

FRONTIERS IN ENDOSCOPY, SERIES #55

Pancreatic Duct Strictures: Evaluation and Management

Mohit Girotra

Douglas G. Adler MD, FACG, AGAF, FASGE, Series Editor

Jodie A. Barkin, MD Instructor in Medicine Jamie S. Barkin, MD MACP MACG AGAF FASGE Professor of Medicine Enrico Souto, MD, Assistant Professor of Clinical Medicine Mohit Girotra, MD FACP Assistant Professor of Clinical Medicine, University of Miami Miller School of Medicine, Miami, FL

INTRODUCTION

Accurate classification, diagnosis and management of pancreatic duct (PD) strictures can pose significant challenges to the treating endoscopists for a variety of reasons, including previously limited diagnostic options, compounded by the underlying disease processes which led to the stricture. The roles of endoscopic intervention are to first evaluate the stricture to firmly exclude a malignant etiology, and second, to provide interventional options aimed at ductal decompression, most commonly for pain relief. In benign disease such as that caused by chronic pancreatitis (CP), PD stones may form independently or be associated with a CP stricture. This may lead to clinical symptoms due to ductal obstruction further complicating the clinical picture. Furthermore, traumatic pancreatic injury related strictures sometimes have leaks associated with them, leading to recurrent collections, which are by themselves difficult to manage.

The primary aim of this review is to provide a concise differential diagnosis of the etiologies of PD strictures and to understand the diagnostic and therapeutic endoscopic management options. Secondary aims include exploring the management options for the secondary processes that can be associated with PD strictures, including PD stones, leaks and collections. Lastly we will explore the role of surgery for these disease processes.

The Importance of Anatomy

To appropriately understand the PD anatomy, and plan any pancreatic endotherapy, it is imperative to dive into the embryology of the pancreas. The pancreas arises from 2 endodermal outpouchings (called “buds”) from the primitive duodenum. The small ventral bud forms the inferior (lower) portions of the head/uncinate, whereas the majority of the pancreas including the superior (upper) portions of head/uncinate, as well as the body and tail arise from the dorsal bud. The duct from the distal portion (body/tail) of the dorsal bud unites with the ventral bud duct to form the main PD (of Wirsung), and the residual proximal duct (head) of dorsal bud remains as the accessory PD (of Santorini). The normal anatomy allows the majority of the pancreas to be drained via a single duct, which opens at the ampulla of Vater. The presence of variant ductal anatomy, including pancreas divisum or ansa, is important to consider before planning any pancreatic endotherapy. If the dorsal duct does not unite with the ventral duct in the pancreatic head, pancreas divisum results, where the majority of pancreatic secretions drain via the minor ampulla.
Defining location of the stricture is critical to formulating an effective management strategy. Location in either the dorsal or the ventral duct, in relationship to dorsal-ventral confluence, may influence the initial ductal access approach, via either the major or minor papilla. Furthermore, anatomic location of the stricture in the main PD should be distinctly defined as in head, genu, body, or tail, with the knowledge that strictures more distal in the duct may be more challenging to manage endoscopically, via the traditional transpapillary approach.

Etiologies of PD Strictures

PD strictures can be categorized into three main etiologic groups: malignant, autoimmune, and benign, i.e. secondary to acute pancreatitis (AP), CP, or trauma. The algorithm to determine its etiology begins with a meticulous history and physical examination, followed by cross sectional imaging with computed tomography (CT), magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP), or EUS, or any combination of these modalities, to accurately evaluate the pancreatic anatomy, parenchyma and the ductal system.¹ It is noteworthy at the outset that EUS is the only modality allowing tissue acquisition, making it most optimal in the diagnostic algorithm of PD strictures.
PD strictures secondary to malignancy can either directly involve the duct or extrinsically compress the duct due to mass effect. Primary pancreatic ductal adenocarcinoma can obstruct the main PD (MPD) and cause symptoms of AP or exocrine pancreatic insufficiency (EPI). Approximately 2% of patients with “newly-diagnosed” CP may have underlying pancreatic malignancy.² Moreover, up to 10% of patients with intraductal papillary mucinous neoplasms (IPMNs), which are pre-malignant lesions, may be initially incorrectly diagnosed with CP.³ Patients over the age of 40 years, with an unexplained attack of AP need be screened for underlying pancreatic malignancy.^4,5 Hence, careful diagnostic workup should be pursued in those with high clinical suspicion for malignancy, and especially in patients over 40 years old who have unexplained AP and/or EPI.^4,5
Autoimmune pancreatitis (AIP) and Immunoglobulin G4 (IgG4) related sclerosing cholangitis (IgG4-SC) may lead to PD strictures, and IgG4-SC may also lead to biliary strictures. In addition to the typical features of AIP on cross-sectional imaging of the pancreas or endoscopic ultrasound (EUS) showing diffuse glandular enlargement or a discrete mass, PD strictures can result from AIP. PD strictures associated with AIP may cause diffuse irregular MPD narrowing, may be long (> 1/3 length of MPD) and lack upstream MPD dilation (MPD size < 5mm).^6-11 In these cases, EUS-guided pancreatic parenchymal biopsy may be performed to confirm AIP on histology and to exclude malignancy. EUS-guided parenchymal biopsy has a sensitivity of approximately 80% for diagnosis of AIP via histology alone, but does carry a minimal resultant risk of AP from performance of parenchymal biopsy.¹²

The most common benign etiology of PD strictures is CP. Importantly, even in likely benign strictures associated with CP, malignancy should be ruled out with the appropriate diagnostic workup. Dominant MPD strictures in CP are defined by having at least one of the following criteria: upstream MPD dilation ≥ 6mm, prevention of contrast medium outflow next to a 6 French catheter placed upstream from the stricture, or abdominal pain with continuous infusion of 1 liter of saline over 12 to 24 hours via a nasopancreatic catheter placed upstream from the stricture.^4,13 Clinically, dominant PD strictures causing ductal obstruction result in pain or superimposed episodes of acute on chronic pancreatitis.5 While CP itself may lead to strictures, resultant PD stones may further perpetuate damage. In a large, multicenter cohort of over 1000 patients with CP and MPD obstruction managed with pancreatic endotherapy, PD strictures accounted for the most common etiology (47%), while PD stones led to 18%; and a combination of stricture and stones accounted for an additional 32%.¹⁴Mechanistically, PD stones are thought to obstruct the PD leading to increased PD pressure, causing inflammatory cascade activation resulting in further fibrosis.15 Similarly, PD strictures can cause the same ductal hypertension and activate the same inflammatory cascade.15 Other causes of benign PD strictures may include trauma, as well as iatrogenic triggers from placement of a PD stent, instrumentation during endoscopic retrograde cholangiopancreatography (ERCP), or surgery, particularly at an anastomosis after pancreatic surgery.

Imaging of Pancreatic Strictures

There is a clear role for cross-sectional imaging in the evaluation and non-invasive management of patients with CP, and possible PD strictures. CT with dedicated pancreatic protocol is currently the first-line recommended imaging modality for evaluation of the pancreatic parenchyma by the European guidelines.⁴ CT with pancreatic protocol has the benefit of being highly sensitive for detection of parenchymal calcifications and specifically masses.^4,5 CT does, however, have the drawback of repeated radiation exposure, which needs to be considered over time for this chronic condition. Further, CT, while beneficial for the parenchyma, is not as efficacious as MRCP for evaluation of the ductal systems of the pancreas and biliary tree. MRCP has excellent performance characteristics for delineation of ductal abnormalities including strictures, dilation, and intra-ductal stones.^16,17 Given the reliability of MRCP findings and the fact that MRCP is noninvasive, ERCP has largely shifted to primarily a therapeutic procedure offering the endoscopist the modality to intervene upon the findings of noninvasive imaging technologies, often including EUS.
EUS is utilized to evaluate both the pancreatic parenchyma and PD. EUS can diagnose the presence of CP using, for example, the expert-consensus based Rosemont Classification, which is a combination of features including the presence of parenchymal lobularity, hyperechoic foci and strands, and honeycombing, as well as PD changes including calculi, tortuosity, dilation, and hyperechoic PD walls.18 EUS for diagnosis of CP is limited however by varying degrees of interobserver agreement.^19,20 EUS has the added benefit of tissue sampling when indicated, and is particularly useful if malignancy, and in some cases AIP, is suspected for both imaging diagnosis and tissue acquisition (Figure 1A, B). A meta-analysis of 33 studies of 4,984 patients from 1997 to 2009 estimated the sensitivity of EUS with malignant cytology to be 85% and specificity of 98% for detection of solid pancreatic neoplasms.²¹ These figures are likely to improve over time as imaging technologies and EUS needles for tissue acquisition via fine needle aspiration for cytology or fine needle biopsy for histology continue to advance.

Management Strategies for Pancreatic Duct Strictures

There are multiple tools in the armamentarium to approach PD strictures including medical, endoscopic, and surgical options. Perhaps the easiest strictures to manage are those caused by AIP or IgG4-SC, in which treatment is primarily medical with steroid administration.^5,6 Medical therapy in CP should be focused on removal of any potential offending agents, such as alcohol and smoking in an effort to minimize further damage, and use of pancreatic enzyme replacement therapy in those who have EPI,^5,22 which may additionally help with pain as well. It is important to remain cognizant that not all PD strictures need treatment, and endoscopic techniques should be reserved for carefully selected symptomatic patients, where expected benefits outweigh the risks of pancreatic endotherapy.

Traditional Endoscopic Techniques

Endoscopically, ERCP with use of it associated devices and technologies are the mainstay of pancreatic endotherapy. The initial endoscopic approach to PD strictures is often pancreatic sphincterotomy, followed by guidewire passage through the stricture and then stricture dilation followed by placement of a PD stent. These techniques result in good overall technical success.^15,23,24 Stricture dilation can be performed with either balloon or bougie dilators, as well as with the Soehendra stent retriever as a rescue option if the dilator cannot traverse the stricture.^4,25 Dilation alone, without stenting, is not recommended based on the most recent ASGE guidelines, as dilation alone is not typically effective for these tight and resilient PD strictures.⁵

Endoscopic ductal stenting can be performed in strictures that involve either short or long segments of PD. Current ASGE guidelines recommend the use of plastic stents for MPD strictures, which can be either a single large caliber stent or multiple smaller caliber stents placed in a side-by-side configuration.⁵ Stent size selection should be at least as large as the PD diameter and long enough to traverse the stricture while not going far beyond the strictured area to minimize collateral damage to the PD.²⁶ There are no published trials to date evaluating placement of a single larger diameter (10 French) plastic stent compared to placement of multiple side-by-side smaller diameter plastic stents for PD stricture therapy.5 Stents may become occluded over time and require replacement, which can be done on a scheduled basis every 2-3 months or as needed based on return of symptoms. While both methods have been studied, there is no clear head-to-head comparison favoring one schedule over another.^15,27,28 Stenting may be pursued for a number of months to years for therapy. When stents are placed, larger diameter 10 French plastic stents resulted in significantly fewer hospitalizations for abdominal pain than plastic stents of 8.5 French diameter or less.²⁹ When dilation and stenting are performed in PD strictures without the presence of intraductal stones, abdominal pain decreased in 65 to 84% of CP patients.^23,30 The long-term efficacy of PD stenting for relief of pain in CP appears to be in the range of 52% to 90% with less than 30% of patients requiring surgery.^24,31,32 Predictors of good clinical outcomes to nonsurgical interventions in painful CP are obstructive ductal calcifications located in the pancreatic head, short disease duration, and low frequency of pain attacks prior to the planned intervention.³³

From a technical perspective, placement of multiple side-by-side stents may be challenging depending on patient ductal anatomy. While stenting has traditionally been performed with plastic stents, fully covered metal stents may be used as well, and are an emerging field of investigation. A 2014 systematic review of 5 studies of 80 patients with chronic pancreatitis revealed comparable technical success rates for refractory PD strictures using multiple plastic stents (94.7%) compared to fully covered self-expandable metal stents (FCSEMS) (100.0%; p=ns), comparable stent migration rates (10.5% vs 8.6%), and comparable pain relief rates (84.2% vs 85.2%).³⁴ There was, however, a 26.2% reported complication rate in the metal-stents group and no reported complications with plastic stents. Notably, sample size was low in both groups (19 patients in plastic stents vs. 61 patients with metal stents). When complications occur, they are most commonly pain, mild pancreatitis and stent migration, but may also include stent occlusion, infection, bleeding, perforation and stone formation.5 Further, placement of any type of stent may induce periductal damage and scarring leading to development of further strictures.^35,36

Two recent studies have raised concern over the long-term outcomes of FCSEMS for benign pancreatic strictures. In a study of 10 patients followed for 35 months after 3 months of FCSEMS stent placement, the rate of recurrent stricture was 38%.³⁷ Further, in a second study of 15 patients followed for 15.9 months with refractory PD strictures secondary to chronic pancreatitis, there was a 27% rate of new stricture development secondary to placement of the metal stent itself.³⁸ At this time, the jury is still out, and choice of pancreatic stent should be made with caution, based on provider expertise on a case-by-case basis. The exception is pancreatic cancer induced biliary strictures causing biliary obstruction, in which guidelines recommend use of uncovered self-expanding metal stents for palliation, if life expectancy is greater than 6 months in unresectable patients.^39-41

In patients in whom PD access cannot be achieved via ERCP with a transpapillary approach, EUS-guided PD access and drainage is feasible. EUS can then guide traditional transpapillary drainage (rendezvous technique where the PD is punctured with needle under EUS guidance, and a guidewire is placed into the PD and then passed through the papilla), or EUS can be used to provide transmural drainage into the stomach or duodenum.^1,42-44 Lastly, in patients who have a peri-pancreatic fluid collection associated with a stricture such as in the case of patients with ductal trauma, endoscopic drainage of only the collection will not fix the ductal leak, giving rise to the fluid collection. Endoscopic drainage of the collection can be attempted using a transpapillary approach or using EUS guidance for drainage using a transgastric or transduodenal approach.¹ In these cases, similar to patients with bile leaks due to bile duct injury, endoscopic therapy to address the stricture preferably with stenting to decrease the ductal pressure gradient is necessary to prevent re-accumulation of the peri-pancreatic fluid collection after initial drainage (Figure 1C, D).

Moreover, patients with post-surgical anastomotic strictures may present a completely different set of challenges for the endoscopists, including identification and intubation of afferent limb, and later identification and cannulation of pancreatico-jejunal (P-J) anastomosis. The etiologies of P-J stricture may be benign post-surgical changes or inflammation, or recurrence of malignancy. EUS may have a role in this situation to assist in identification of the PD and sometimes perform rendezvous or direct drainage of the PD.

New Endoscopic Technologies

Intraductal pancreatoscopy previously was limited in its technological abilities with cumbersome systems of mother-daughter scopes and low overall image quality. The newest platform is the SpyGlass DS™, single-operator, single-use cholangiopancreatoscopy system (Boston Scientific, Natick, Massachusetts, USA), which provides high-quality images to guide diagnostic and therapeutic interventions. Digital pancreatoscopy can directly image a stricture to assist with determination of malignant potential, take small biopsies as opposed to conventional brushings, and may enable therapeutics especially for stone removal with targeted endoscopic lithotripsy.⁴⁵ Pancreatoscopy may further characterize the etiology of indeterminate PD strictures and pathology, including main duct intraductal papillary mucinous neoplasms and malignancy both by endoscopic appearance and improved sampling via biopsy with sensitivities of up to 91%.^46-48 With increased time on the market, we can expect larger series in the future to further evaluate the impact of this technology on pancreatobiliary pathology.

There are several technical considerations of using digital pancreatoscopy, of which endoscopist must remain cognizant. First, based on the width of the probe, the PD must be dilated to > 4mm, and have a relatively non-tortuous course in the head of pancreas, to allow safe passage of the probe (Figure 2C, D). The probe should be advanced over a long guidewire, traditionally 0.035-inch x 450 cm long, which can then be removed once the scope is stabilized within the duct, so as to not interfere with visualization.⁴⁵ Additionally, even with favorable caliber and contour of PD, stones downstream to the stricture may have to be managed first (as discussed below), pancreatic sphincterotomy may need to be initially performed to facilitate MPD access, and strictures may require dilation to allow passage of the probe for full characterization of the stricture as well as management of upstream stones/pathology.^45,49 Last, it is of utmost importance to remember that there is an associated increased risk of post-ERCP pancreatitis (PEP) when performing pancreatoscopy secondary to pancreatic manipulation, and appropriate PEP prophylaxis measures should be utilized.⁵⁰

Additional newer technology for PD stricture evaluation includes confocal laser endomicroscopy (CLE). CLE uses a low-power laser light which is focused on a single point to create a microscopic field of view, with the goal of creating real-time digital histology to enable the operator to characterize the nature of lesions.⁵¹ Use of intravenous fluorescein sodium as a contrast agent may enhance CLE image quality. The current CLE mini-probe available for pancreatobiliary disorders is the CholangioFlex miniprobe (Mauna Kea Technologies, Paris, France), and is passed through the working channel of the endoscope. Needle based systems are also available for cystic and mass lesions. It was initially utilized for evaluation of indeterminate biliary strictures, first applying the Miami Classification and subsequently the Paris Classification systems.^52-54 However, no such rubric exists for evaluation of PD strictures. Small case series and studies have shown promise for probe-based CLE in the evaluation of PD strictures but larger studies will need to be performed to further progress this technology.55-59 If CLE is proven to be useful in PD stricture evaluation on a larger scale, standardized classification systems specifically for PD strictures will need to be established as most work to date has focused on biliary stricture classification.

Pancreatic Ductal Stones

PD stones occur in approximately 50% of CP patients, and can be located in both the parenchyma and PD.¹⁴ Classically, removal of PD stones is performed with ERCP with a retrograde approach to the PD. PD stones are usually more difficult to manage than biliary stones, given their shape/morphology, high calcium and protein content resulting in harder stones, and the small caliber and usually tortuous contour of the PD in CP patients (Figure 2A, B). Once cannulation of the MPD is achieved, stones in the MPD can be removed using small balloons, retrieval baskets, or perhaps forceps. Pancreatic sphincterotomy may assist in removal of larger stones and debris.¹⁵ In addition to conventional ERCP with mechanical stone extraction, larger stones (usually those over 5mm in size) or stones impacted in a stricture or in a side branch PD may be difficult to remove and require either endoscopic or extracorporeal shock wave lithotripsy (ESWL) for management.^45,60-64 Endoscopic techniques of stone fragmentation include electrohydraulic lithotripsy (EHL), which may be targeted using pancreatoscopy, and laser lithotripsy.^45,63,64 (Figure 3A-D). The specific performance, indications, efficacy, risks and benefits of each of these techniques are outside of the scope of this manuscript.
Surgical Approach to Pancreatic Strictures While endoscopy is the preferred initial approach for patients with symptomatic benign PD strictures, in patients who fail endoscopic interventions, surgery should be considered.^4,60 Surgically, there are multiple options depending on stricture location, presence of additional parenchymal disease and stricture etiology. Surgical interventions can be divided into resection procedures, drainage procedures, or a combination thereof.65 These include drainage procedures, i.e. the Puestow or Frye procedures as lateral pancreatico-jejunostomies, and resection procedures including a traditional Whipple procedure primarily for disease confined to the head or proximal pancreas, a central or distal pancreatectomy, a total pancreatectomy, and most recently, a total pancreatectomy with islet cell autotransplantation to minimize the risk of post-operative diabetes.

When comparing endoscopic interventions to surgery specifically for painful CP, both methods appear to have suboptimal results, likely due to the complex nature of chronic pain in CP.^4,66-69 A 2015 Cochrane Database systematic review and meta-analysis comparing endoscopic (excluding any trials with ESWL) and surgical interventions for painful CP included two randomized controlled trials of 111 total patients showing significantly higher proportion of patients with pain relief in the surgical arm at both medium (2-5 years; Relative risk 1.62; 95% CI 1.22-2.15) and long-term (≥ 5 years; Relative risk 1.56; 95% CI 1.18-2.05) follow up.^65-67 In this Cochrane review, surgery also resulted in improved medium-term quality of life and preserved exocrine pancreatic function; however, this effect was not durable at 5 years. Given the small number of patients in the two studies included, there were no differences in morbidity and mortality between the two arms but the review authors noted that the sample size was underpowered to detect such differences. In fact, in multiple other studies, surgical intervention for CP seems to carry substantially higher rates of morbidity and mortality compared to endoscopic interventions for CP (morbidity surgery 18-53% vs. endoscopy 3-9%; mortality surgery 0-5% vs. endoscopy 0-0.5%).^{4,14,61,70-73}

The Caveat: Post-ERCP Pancreatitis

Post-ERCP pancreatitis (PEP) is the most common and feared complications of ERCP, with an incidence of 3-10% in large series.^74,75 When planning ERCP for biliary access, PD cannulation is inadvertent; however, when PD cannulation is the goal of the procedure, the endoscopist must be increasingly mindful of PEP risk. Strategies to minimize PEP risk should be employed per protocol in all patients undergoing ERCP with intention of PD cannulation, unless there is a contraindication. The current strategy is a trifecta of intravenous fluid hydration (preferably with lactated ringer’s solution), rectal indomethacin, and PD stenting.^39,76-80 Specifically, placement of a 3-French or 5-French, short, plastic stent can decrease PEP risk (^{39, 81}). Interestingly, CP may actually confer a slight relative protection against PEP; however, a recent large study showed a PEP incidence of 4.5% in CP patients compared to 4.8% in non-CP patients.73,82,83 Decisions on any interventions in this patient population or others should be made carefully after a clear discussion of risks, benefits, and alternatives with the patient.

CONCLUSIONS

PD strictures and upstream stones remain challenging for endoscopists to manage. There are, however, continually emerging diagnostic and therapeutic tools, techniques and procedural refinements at the endoscopist’s disposal to approach these complex disease processes. The physician must always remember to exclude underlying malignancy, and subsequently move on to the perhaps far more daunting task of managing PD strictures and stones oftentimes associated with painful CP. While surgery remains an option in especially difficult cases and specifically for those with refractory painful CP, endoscopic management now includes a panacea of options to provide both short and long-term therapies. Careful discussion with the patient of risks, benefits, and alternatives should be had regarding all appropriately indicated diagnostic and therapeutic options in these often challenging cases, but fear not, for the future is bright.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #187

The POTS (Postural Tachycardia Syndrome) Epidemic: Hydration and Nutrition Issues

June 2019 • Volume XLIII, Issue 6

John K. DiBaise,

Tisha Lunsford,

Lucinda A. Harris