Page 77 – Practical Gastro

The Bellevue IBD clinic serves a radically different patient population than is treated in most US healthcare settings, represented in most clinical trials, or reflected in current management guidelines. Here we discuss the complexity of providing care to these individuals, areas of disparity in IBD care and resources to assist our patient population

INTRODUCTION

Bellevue Hospital Center (Bellevue), the oldest public hospital in the United States, was founded in 1736 as a six-bed infirmary utilized to quarantine ill patients. In 1811, the hospital moved to its current location on Manhattan’s east side, when New York City (NYC) purchased the Kips Bay farm and began construction of an almshouse (the “Bellevue Establishment”), consisting of two pavilions for men and women, respectively.¹ Bellevue has been known as an institution willing to serve the poor and underserved since its creation.² Currently, Bellevue is a level 1 trauma tertiary care teaching hospital in New York City’s Manhattan borough, serving as a major referral center for complex medical cases citywide.^{1, 2} It serves as the flagship for the NYC Health and Hospitals Corporation (HHC), which is the largest public healthcare delivery system in the United States, overseeing 11 acute care hospitals.³ Bellevue has been affiliated with NYU School of Medicine since 1847.

Bellevue’s mission is to provide the highest quality of care to New York’s neediest populations and to deliver health care to every patient with dignity, cultural sensitivity and compassion, regardless of ability to pay”.² There are 828 beds in operation with nearly 528,000 clinic visits, 125,000 emergency room visits, and approximately 32,000 inpatient discharges annually.¹ According to New York State healthcare center cost records from 2010, HHC hospitals provided the highest proportion of care to uninsured, self-paying patients.²

Bellevue’s patient population resides mainly in the following communities: Southern Manhattan, Northern Brooklyn, and Western Queens. The Bellevue patient population differs from that of NYC as a whole. In NYC, 63.4% of individuals are younger than age 65, while 67.1% of Bellevue’s patients are younger than age 65. The racial background of Bellevue’s patients are as follows: 40% White, 38.1% Hispanic, 21.9% Black, 15.4% Asian, and 22.5% other.^{2, 4} In addition, poverty rates of families cared for at Bellevue, especially those with children, are significantly higher than those of NYC overall. At Bellevue, 22% of families and 31% of families with children live below the federal poverty guideline. In NYC overall, these numbers are 16.7% and 24.4%, respectively.^{2, 4, 5}

Prior to implementation of the Affordable Care Act, 45% of Bellevue outpatient visits were covered through Medicaid and 31% of Bellevue outpatient visits were self-pay. This degree of poverty goes hand in hand with the difficult social circumstances facing this patient population and adds to the complexity of providing care to these individuals. In addition to facing high poverty rates, the population served by Bellevue consists of individuals with lower education levels than patients of surrounding city hospitals.

Bellevue has long offered a Gastroenterology Clinic for patients who are in need of screening, diagnostic, and/or treatment services in the area of digestive diseases. More recently, due to a growing number of patients presenting with suspected or diagnosed inflammatory bowel disease (IBD) along with the complex nature of IBD treatment, Bellevue implemented an Inflammatory Bowel Disease Clinic, specifically to serve patients with Crohn’s disease and ulcerative colitis.

IBD Epidemiology

IBD is a chronic, relapsing and remitting intestinal condition with increasing incidence worldwide. Currently, ulcerative colitis has an incidence of 2.2-19.2 cases per 100,000 person-years and Crohn?s disease has an incidence of 3.1-20.2 cases per 100,000 person-years.⁶ It is a disease of the developed world and typically affects those originating from Northern Europe and North America. The incidence and prevalence of IBD appears to be lower in Asia, the Middle East, and Central and South America, likely reflecting both genetic and environmental differences between these patient populations. While the incidence of IBD has plateaued in the Western world, areas previously unaffected by IBD are exhibiting an increase in this disease.^{7, 8} Due to the makeup of the Bellevue patient population we are now seeing more individuals presenting with Crohn?s disease and ulcerative colitis at our hospital. Few studies have evaluated the IBD phenotype of the more recently affected patient populations; however, there is no clear pattern of age at time of diagnosis, pattern of disease distribution, or severity.^{9, 10}

Areas of Disparity in IBD Care

Patients with IBD typically require close surveillance by their care providers for management of symptoms, adjustment of medication regimens, and endoscopic interventions. Moreover, individuals with this disease face unique barriers to accessing medical care that greatly impact their clinical outcomes and prognosis. Studies have shown that race and socioeconomic status weigh heavily in the type of care patients who are suffering from chronic disease states receive.¹¹ Sewell and colleagues performed a systematic review, studying the role of socioeconomic status and race and the quality of care delivered to patients with IBD. They specifically focused on differences in utilization of medical and surgical therapies, rates of adherence to therapy, clinical outcomes, access to healthcare, utilization of healthcare, patient?s individual perception and knowledge about IBD, employment rates, and medical insurance status. The authors hypothesized that patients who were non-white and of lower socioeconomic status would receive less effective and lower quality care for their IBD. The majority of studies in this review found that white patients were more likely to be treated with immunomodulators and infliximab when compared with non-white patients, despite the severity of illness being reported as similar.¹¹ The majority of studies also displayed disparities in surgical care among different racial and socioeconomic groups, with minorities and impoverished patients less likely to undergo colectomy when compared with white, affluent patients.^{11, 12} Medication compliance is a particularly important issue in the management of IBD. This review found that black patients were less likely to adhere to prescribed medications and more likely to discontinue medications if they perceived subjective improvement of symptoms. They also noted that black patients understood less about the nature of their disease.^11-15

With the increased incidence of IBD being seen among minority patients, this information is highly relevant to the Bellevue patient population.^{3, 4, 10, 11} Although studies evaluating outpatient utilization of IBD healthcare resources among different races have yielded different results, follow-up rates have been universally and unequivocally low at Bellevue. Patients have been lost to follow-up due to barriers such as difficulty paying for medications, perceived difficulty paying for visits, employment and familial obligations, and substance abuse.

Thus, the need for an IBD Clinic at Bellevue was identified not only because of the growing numbers of Bellevue patients presenting with IBD, but also due to potential barriers to care and the complexity of the diagnostic, treatment, and surveillance care required for these individuals.

IBD at Bellevue: The IBD Clinic

In late 2011, Bellevue opened the first clinic within the NYC HHC system dedicated solely to the comprehensive evaluation of patients with IBD. The IBD Clinic includes two physicians who specialize in IBD and engenders a collaborative multidisciplinary approach to the care of this patient population. The IBC Clinic works to coordinate care with all needed physicians and other healthcare professionals from other departments and divisions including: infectious diseases, general and colorectal surgery, rheumatology, endocrinology, radiology, pathology, nutrition, and psychiatry.

In terms of the IBD patient population being seen in the Bellevue system, during an 18-month span between 2012 and 2013, 218 patients were referred through the gastrointestinal clinic system with a diagnosis of Crohn’s disease or ulcerative colitis based on the ICD 9 codes 555 and 556. Since its inception, the IBD Clinic patient volume has grown steadily and currently treats 110 patients in an ongoing fashion. Most patients are referred from within the medical clinic system at Bellevue, other HHC hospitals, and by providers outside the institution after providing treatment in an acute care setting. Roughly half of the patients have ulcerative colitis and half have Crohn’s disease. Due to economic barriers, delayed diagnosis, and low health literacy, a disproportionately high percentage of our Bellevue patient population is treatment-na�ve. The IBD Clinic population consists of approximately 40% Hispanic, 25% Asian, 20% Caucasian, and 15% African/African-American patients. Since the majority of these patients are uninsured or underinsured, it became necessary for the Clinic to pioneer access to medical care that would otherwise be financially prohibitive.

IBD at Bellevue: Addressing Barriers to Care

As part of the specialized care provided by the IBD Clinic at Bellevue, several barriers to care have been identified and continue to be addressed (Figure 1). Three major factors include significant language barriers, limited support staff for the IBD Clinic, and the patients’ inability to pay for medications and other treatment needs.

First, English is not the primary language for a large proportion of the Bellevue population. For non-English speaking patients, coordinating care and gaining a true understanding of IBD and its treatment can be difficult. To help resolve potential language barriers, Bellevue offers a full phone interpretation service as well as in-person interpreters. Despite these services, gaps in communication can still occur and the IBD Clinic is exploring additional options to further address this issue.

Second, the IBD Clinic currently has limited support staff to assist with patient scheduling, phone calls, and paperwork. Moreover, patients may be scheduled for appointments without confirming their availability, resulting in a high no-show rate to the Bellevue clinics, which in turn can generate long wait times to be seen, in some cases greater than 90 days. This issue has been identified and plans are underway to address this need.

Finally, patients with IBD have significant treatment and care needs, both acute and ongoing, but many lack the financial resources to obtain their medications and other treatment services. To assist patients in this area, the IBD Clinic works with several organizations that address the needs of underserved patients.

Financial Resources for Our Patient Population

To assist patients who lack the funds to obtain the needed medications and supplies for the treatment of their IBD, the IBD Clinic has found great benefit in working with external organizations that help underserved patients. These organizations provide assistance ranging from free medications to reduced-cost ostomy supplies to assistance with insurance premiums and co-pays

(Table 1).

For example, Needy Meds (www.needymeds.org) is an organization that has been helpful in assisting our underserved patient population with access to select prescription medications. The mission of the organization is stated as follows:

“to be the best source of accurate, comprehensive and up-to-date information on programs that help people facing problems paying for medications and healthcare; to assist those in need in applying to programs; and to provide health-related education using innovative methods.”

Founded by a physician and social worker in 1997, Needy Meds assists patients who are unable to receive prescribed treatment through the hospital by providing prescriptions at a significantly reduced fee. The Needy Meds website notes a number of useful resources available to patients and providers, including a listing of reduced fee imaging centers and active governmental healthcare programs.

One such resource includes patient assistance programs (PAPs), which are typically sponsored by pharmaceutical companies and provide medications free of charge or at a significantly reduced fee for patients who earn a low to moderate income and are uninsured or underinsured. Eligibility and requirements for the programs differ by drug and all information can be viewed at www.needymeds.org.

Additionally, discount drug cards are available at needymeds.org and can be printed for patients. These drug programs typically save patients up to 80% off the listed price and can be used at over 63, 000 pharmacies nationwide. The card can be used in the following scenarios: in lieu of a patient’s insurance when there is a costly co-pay and the reduced fee is more manageable; when the plan has a high deductible; when the drug is not covered by the patient’s insurance plan; or for patients in the Medicare Part D “donut hole.” The card cannot be used in conjunction with insurance. There are no income insurance or residency requirements for use of the card. Pricing, coupons, and rebates can be found at: http://www.drugdiscountcardinfo.com/disclaimer.htm.

Other resources for the uninsured or underinsured with IBD include the Health Well Foundation, which provides financial assistance to eligible individuals to assist with co-insurance, co-pays, healthcare premiums, and deductibles for certain medications and therapies; the Osto Group, which provides ostomy supplies for the uninsured (patients pay for shipping only); and the Oley Foundation, which provides an equipment/supply exchange to patients that require total parenteral nutrition.

CONCLUSION

The Bellevue IBD Clinic serves a radically different IBD patient population than is treated in most US healthcare settings, represented in most clinical trials, or reflected in current management guidelines. To ensure the standard of care in IBD diagnosis and treatment for this underserved patient population is met, barriers to care must continue to be identified and addressed. Great progress has been made since the Bellevue IBD Clinic?s inception in 2011, and plans are underway for further expansion of this much needed clinical program for underserved patients with this complex disease.

Nutrition Issues in Gastroenterology, Series #130

Nutrition Guidelines for Treatment of Children with Eosinophilic Esophagitis

June 2014 • Volume XXXVIII, Issue 6

Michelle Henry

Eosinophilic Esophagitis (EoE) is a chronic immune-/antigen-mediated disease characterized by clinical symptoms and histological changes induced by environmental and/or dietary triggers. Dietary intervention for EoE includes food eliminations, which can put patients at risk for poor nutrition intake. In this article, we discuss the integral role of a registered dietitian to assess growth, micronutrient intake and to provide guidance for implementing any elimination diet. Understanding typical presentations in patients with EoE help to determine nutrition risk, and target evaluation, education and regular follow-up are key.

BACKGROUND

Since the original description of eosinophilic esophagitis (EoE) in the early 1990s, a number of guidelines for the diagnosis and treatment of the disease have been developed.^1-3 EoE is defined as a chronic immune-/antigen-mediated disease of the esophagus characterized by both clinical symptoms and histological changes. Estimated prevalence of EoE is at least 56.7 in every 100,000 persons and is more common in males than females.⁴ Symptoms of EoE vary with age of presentation, from feeding refusal in infants and toddlers to dysphagia and abdominal pain in adolescents. The histological findings in patients with EoE are increased eosinophilic infiltration of the esophageal lining (>15/hpf) that is not attributable to reflux or any other cause of inflammation. At this time it is understood that EoE is a chronic disease that is not usually outgrown.

EoE and Food Allergies

Explanations of the three major categories of food allergies and intolerances are summarized in Table 1. To date, the exact pathophysiological mechanism(s) by which food allergies cause EoE are not certain, but it is likely that both IgE-mediated and non-IgE-mediated processes are involved.³ Clinical evidence supporting a role for food allergies as an underlying cause of EoE has been provided using three dietary approaches: an elemental diet, an empiric approach and a tailored diet. The elemental diet involves complete avoidance of food in lieu of taking in only elemental (amino acid-based) formula for complete nutrition (see Table 2). The empiric approach is to provide a diet free of the top six (milk, soy, egg, wheat, peanut/tree-nut, fish/shellfish), or top four (milk, soy, egg and wheat) most likely allergens with or without elemental formula supplementation. Lastly, the tailored diet is a diet that is crafted utilizing allergen test data and a detailed history for the individual, which may or may not be excluding the top known allergens, also with or without elemental formula supplementation. The benefits and challenges to each dietary approach are outlined in Table 3.

Dietary therapy was first identified as effective treatment with a diet consisting of only an elemental formula, which established a clinicopathological remission in children with EoE.^5,6 Later using an empiric approach by removing the six most common food allergens in the United States (milk, soy, wheat, egg, fish/shellfish, peanut/tree-nut) yielded similar results.⁷ Further, empiric elimination of only the top four most common food allergens (milk, soy, wheat and egg) has also proven effective.^9,10 The third commonly used diet therapy, the tailored diet, is documented to be the lesser of the effective dietary treatments, yet results in similar levels of clinicopathological remission in a smaller percentage of patients.¹¹ In comparison, the literature suggests that the elemental diet remains the most effective followed by the empiric elimination and finally the tailored diet approach.³ Taken together, these studies demonstrate the role of food antigens in the pathogenesis of EoE and a high response rate with each approach chosen. The clinician should use this information to help decide which treatment approach would be best, or most feasible, for each individual patient or family.

There are obvious practical limitations to each of the three dietary approaches. The elemental diet may pose the greatest challenge, especially for those who previously ate a regular diet. Though improvements have been made in the palatability and variety of available amino acid-based formulas (Table 2), they can also be expensive and difficult to maintain as exclusive nutrition intake. The empiric elimination diets can be hard for those with limited access to allergen-free alternatives and for families with skill and affinity for home cooking tend to report an easier transition to this diet. Tailored elimination diets may pose similar challenges as with the empiric elimination diet. Though, in some cases foods removed are more difficult to identify on food label in the tailored elimination diet, since current regulations on food labeling only require clear indication of presence of the top six allergens. Of all the dietary approaches, it is ideal to work with the patient and family to provide the guidance needed to make the changes work for them.

EoE Nutrition Risks

A number of challenges exist if any of the dietary treatments for EoE are pursued. Nutritional adequacy, medication-nutrient interactions, practical implementation challenges, and costs all play a role. Because of these potential barriers to success, the expertise of a pediatric dietitian specializing in food allergies is ideal.

Nutrition risk associated with presentation of disease differs by age of presentation. Younger patients are more likely to present with feeding difficulties, while adolescents and adults are more likely to present with dysphagia and food impactions. Table 4 delineates the most common presentations of EoE and how they may result in nutrition risk. The presenting symptoms associated with EoE may require special attention prior to initiating a dietary treatment. For example, in the case of a young child presenting with poor growth, it may be ideal to establish adequate weight gain and linear growth prior to initiating a dietary treatment of eliminating foods in the diet.

Prior to starting an elimination diet, a full diet assessment is warranted to identify inadequacies in the current diet. If any are identified, it would be important to address them within the confines of the prescribed diet. Following this, considerations for new deficiencies that may develop as a result of the prescribed diet would also need to be addressed. For example, elimination of dairy from a toddler’s diet may result in lower calcium, vitamin D, possibly vitamins A and E and fat intake. Providing education that will target replacement of key nutrients in the diet is imperative. Table 5 describes a few potential nutrients impacted by food elimination diets. Laboratory evaluation may be necessary to determine if supplementation is necessary and if so, is necessary for determining how much is needed. When prescribing supplements, the clinician must take extra care in ensuring that the supplement is also allergen free. Confirming active and inactive ingredient content of over-the-counter supplements with the manufacturer or pharmacist should be done to be sure the supplement does not contain the allergens the patient is avoiding.

Patients prescribed an elemental diet will require recommendations for the goal amount of formula to take to meet calorie, protein and micronutrient needs. In addition, recommendations for fluid and electrolyte intake should also be provided as some patients choose to concentrate the formula to combat early satiety while keeping caloric intake at goal. For example, the recommended intake of a standard complete amino acid formula will contain 20-22 mEq sodium for 1000 calories. Suppose a 20 kg child at 6 years of age is taking this formula at a goal of 65 calories/kg/day, he/she will only receive about 1.4 mEq/kg sodium where the recommended range is 2-6 mEq/kg/day. It is important to ask how the patient/family is mixing formula to ensure they are receiving the adequate macro and micronutrients.

Empiric or tailored elimination diets can pose nutrition risk if appropriate dietary substitutes are not recommended or not accepted. When removing wheat from a child’s diet, attention should be paid to sources of B-vitamins through alternative grains or wheat-free fortified grain products. If milk is removed, a dairy-free fortified alternative should be provided or a supplement identified to meet Calcium and Vitamin D needs. In some cases, an amino acid-based formula can accompany the empiric or tailored elimination diet to better meet nutrient needs.

Children with EoE may also be treated with other medical treatments such as proton-pump inhibitors for concomitant gastroesophageal reflux disease. An emerging body of data suggests that some adults may be prone to problems with calcium absorption and potential bone mineralization when on long-term proton-pump inhibitors.¹² Topical swallowed steroids carry potential, but unmeasured, risks including decreased bone mineralization.³ Thus, monitoring of adequate calcium and Vitamin D intake is important for pediatric EoE patients on these medications.

A meta-analysis of studies evaluating the nutrition risks of patients on multiple food allergy elimination diets highlighted the benefits of dietitian counseling for these patients.¹³ This analysis suggests that children with multiple food allergies are at higher risk for poor growth and inadequate vitamin and mineral intakes. Though the number of studies in this analysis was few, it does indicate that monitoring and evaluating the growth and nutrient intakes of these children is of the utmost importance.

Role of the Clinician in EoE Treatment

The clinician, (often a dietitian) plays several integral roles in the management of EoE related to instituting a therapeutic diet. This role includes providing guidance for an individualized dietary plan. Figure 1 identifies the different nutrition evaluation components for each stage in treatment. The initial evaluation should include a review of the full diet intake including actual intakes for each food group, textures preferred, possible preferences for liquids, ability to swallow pills (if multivitamin supplement needed). Objective evaluation metrics should include previous growth patterns, and any parent concerns for growth, development, or physical findings.

When dietary therapy is initiated, it is most often not the “final” diet prescription for the patient. With the direction of the allergist and gastroenterologist, foods are methodically reintroduced until the maintenance diet is reached. In some cases, patients will “fail” reintroductions, and when no additional foods or food groups will be introduced, the patient is deemed to be on their maintenance diet. Most patients are able to successfully reintroduce foods and will have a very limited number of foods removed on their maintenance diet.10 To achieve nutrition goals, the dietitian should provide dietary education for food elimination as needed, including skills for label-reading, substitutions, cooking, supplementation (vitamins, minerals and/or formula as needed) and texture modification. When providing diet education, one should consider that dietary adherence can be challenging and many of the barriers to adherence can be addressed by the dietitian and the care team.¹⁴

As the patient with untreated EoE, or EoE not yet in remission, may experience the need for softer textures, the dietitian should aim to help the patient achieve adequate intake within the confines of the skill with feeding. While this would not be a long-term issue, it is important to meet the nutrition goals in the interim to help bridge the patient to their goal feeding skill with adequate nutrient intake. Table 6 shows examples of different ways to prepare some common foods based on the patient’s ability or comfort level with textures.

In the maintenance phase, the dietitian should focus on helping the patient achieve a reasonable variety in the diet. As much as possible, the diet should be designed to help meet all macro- and micronutrient needs for growth as well as fluid and electrolyte needs, with supplementation as necessary. Patients and families should be educated in recognizing signs of disease recurrence such as increased or excessive water to drink with meals to wash food down, preference for softer foods or purees, and avoidance of social eating. These signs are important for recognizing when the disease may not be controlled and they should see their doctor for evaluation. Lastly, while in the maintenance diet phase, periodic review of the patient’s growth is important.

CONCLUSION

The clinician plays an integral role in the assessment and treatment of patients with EoE. A well versed understanding of the three dietary elimination diets used for EoE is essential. Expertise of nutrient deficiency signs and symptoms are important to guide assessment in the child with multiple food allergies. In addition, educating patients and their parents to label-read, cook with limited ingredients, and use of food substitutions are an important component of the educational process. Long-term close follow up is ideal as patients and families work through the implementation phase of elimination diets. Reevaluation of diet intakes for variety and overall nutrient intake is necessary in each stage of treatment.

Frontiers in Endoscopy, Series #11

Endoscopic Management of Pancreatic Duct Stones Via ERCP

June 2014 • Volume XXXVIII, Issue 6

Madeleine Birch,

Douglas G. Adler

Endoscopic sphincterotomy (ES) has allowed the development of interventional endoscopic procedures to remove pancreatic duct stones. These endoscopic approaches were less invasive than previously developed surgical measures to treat pancreatic duct stones and rapidly gained widespread acceptance. Other endoscopic procedures such as electrohydraulic lithotripsy, extracorporeal shock wave lithotripsy, and laser lithotripsy can be used in the removal of pancreatic duct stones. This manuscript will review the current state of the art with regards to endoscopic management of pancreatic duct stones.

INTRODUCTION AND OVERVIEW OF PANCREATIC DUCT STONES

Calcium carbonate deposition combined with inadequate pancreatic ductal drainage and/or pancreatic duct strictures in the setting of chronic pancreatitis can lead to the formation of pancreatic duct stones. (Figure 1) The formation of such stones can result in inflammation and/or obstruction of the pancreatic duct and promulgate a vicious cycle whereby stones lead to inflammation and obstruction, and ongoing obstruction can further promote the formation of pancreatic duct stones. Pancreatic stones can lead to increased intraductal pressure, enhancing the symptoms of pancreatitis, most notably pancreatic-type pain.¹ If pancreatic stones develop they can sometimes be asymptomatic. If stones cause obstruction of the pancreatic duct, pain is most often the first symptom. Pain from chronic pancreatitis is often epigastric but can often manifest anywhere in the upper abdomen, and can often radiate to the back.

In addition to pain, pancreatic duct stones can be the cause of other symptoms such as pancreatic duct obstruction and severe acute pancreatitis.² Surgical or endoscopic measures are often used in the management and treatment of pancreatic duct stones. The primary goal of these procedures is to remove the stone(s) in order to relieve pain and restore the patency of the pancreatic duct.³

This manuscript will review the current state of the art with regards to endoscopic management of pancreatic duct stones.

Sphincterotomy and Balloon Extraction

In order to facilitate the removal of pancreatic duct stones, a pancreatic sphincterotomy is typically the first therapeutic maneuver performed after pancreatic cannulation and deep guidewire access to the main pancreatic duct have been obtained. (Figure 2) This procedure can be done using a needle-knife sphincterotome (usually over a pancreatic duct stent) or with a standard sphincterotome passed over a guidewire. Both are equally effective and safe. A standard sphincterotome is most commonly used. In a study performed of 1,000 patients by Choi and Lehman, complications in patients who underwent pancreatic sphincterotomy procedures included acute pancreatitis (2-7%), bleeding (0-2%), perforation (< 1%), and delayed stenosis of the pancreatic sphincter orifice (up to 10%) were reported, arguing for the overall safety of the procedure.2

Following pancreatic sphincterotomy, the most common first step when attempting to remove pancreatic duct stones is simple balloon extraction in a manner analogous to that used during ERCP to remove common bile duct stones. (Figure 3) An occlusion balloon is inserted into the duct until it reaches an optimal location proximal to the stone. The balloon is then inflated to an appropriate size and used to sweep the pancreatic duct, dragging stones and debris through the duct, out the sphincterotomy, and into the duodenal lumen.

Compared to other stone extraction techniques such as basket extraction and lithotripsy, balloon extraction is considered to be the safest and easiest to perform. Unlike basket extraction, an extraction balloon has little to no chance of becoming impacted in the pancreatic duct because it can be deflated. Removal of pancreatic duct stones with occlusion balloons usually works best in patients with small stones and/or pancreatic duct debris. Balloons may fail clinically if they are popped or torn on the sharp or jagged edges of pancreatic duct stones and may be of limited value in patients whose stones are above difficult pancreatic duct strictures.2

Concomitant Pancreatic Duct Stricture Therapy

The successful removal of pancreatic duct stones is often predicated on the absence of significant ductal strictures. Other key factors include the size and number of stones, the absence of impacted stones, and the location of the stones within the pancreatic duct.⁴ If ductal strictures interfere with stone extraction, endoscopic balloon dilation (EBD) of the stricture itself can be performed. Dilation of the pancreatic duct (either by balloon or passage dilators) followed by stone extraction can be performed in a single session in many patients.⁵

Endoscopic balloon dilation requires guidewire passage across the stricture, which can be difficult (or impossible) in very tight strictures.⁶ In addition, endoscopic catheters may not always be able to traverse pancreatic duct strictures, especially if they are highly angulated.⁷ In a study by Brand et al., the use of the 7-Fr Soehendra Stent Retriever used as a dilator when conventional endoscopic balloon dilation was unsuccessful was evaluated. Successful dilation of the tight strictures was accomplished in all of the patients.⁸ If a pancreatic duct stricture is intractable, proximal stones may not be able to be removed endoscopically.

Basket Extraction

In addition to balloon extraction, basket extraction is a standard method for removal of pancreatic duct stones. A basket catheter or Dormia basket is commonly used, although a variety of baskets are available from multiple vendors. No single basket has been identified as being ideal. A basket catheter is typically made of nitinol wires. A wide range of sizes is available, with basket diameters of 1-3cm being most commonly employed. A wire connecting the tip of the basket to the handle of the device allows the basket to be opened and closed. Modern stone extraction catheters are typically double lumen, one lumen to extract the stone, and the second to accommodate a guidewire, although some single lumen devices are still available.⁹

Baskets may be designed to simply trap stones or may also be considered lithotripters i.e. baskets that are able to both capture and crush stones in the duct itself prior to attempts at removal. Lithotripter baskets typically have braided wires for additional tensile strength and to reduce the risk of wire breakage during lithotripsy.

Non-lithotripter baskets can be used to trap and drag stones through the pancreatic duct and out to the duodenal lumen through the pancreatic sphincterotomy. (Figure 4) In practice, non-lithotripter baskets are uncommonly used for pancreatic duct stone removal given the risk of basket entrapment (either above a stricture, after stone capture, or both). After the stone has been trapped inside the basket, a metal coil (which may be advanced over a Teflon sheath or may simply serve as the sheath itself) is advanced to the base of the basket and the basket/stone complex is withdrawn into the sheath, crushing the stone and releasing the stone fragments from the basket into the duct as the lumen of the basket functionally disappears.¹⁰ The basket can then be reopened to capture and/or crush more stones and stone fragments as needed.

In a retrospective review of 69 patients by Thomaset al., endoscopic clearance of pancreatic ductal stones was successful in 90-97% of patients when basket extraction and mechanical lithotripsy were combined with pancreatic sphincterotomy. Of those 69 patients, there was a complication rate of 11.6% (8/69 patients). Of the eight patients that experienced complications, 37.5% had single stones, while 62.5% had multiple stones, suggesting that more involved duct clearance procedures were associated with a higher rate of pancreatitis. Seven patients experienced complications concerning a trapped or broken basket. Wire fracture of the basket occurred during mechanical lithotripsy in four patients. One patient experienced a pancreatic duct leak following the procedure. Complications were successfully treated with endoscopic measures including electrohydraulic lithotripsy, stenting, per-oral Soehendra lithotripsy, and extracorporeal lithotripsy.¹⁰

In a study by Hintze and Adler, 60 patients had pancreatic ductal stones large enough to require mechanical lithotripsy before removal. Three patients experienced traction wire fracture during the procedure. In 2 patients the use of a shorter metal sheath allowed for immediate resolution and continuation of the procedure. Extracorporeal shock wave lithotripsy was performed on 1 patient in order to successfully remove the stone.¹¹ In a retrospective study of 53 patients by Smitset et al., pancreatic ductal stones were fragmented using mechanical lithotripsy in 4 patients. Eight patients underwent extracorporeal shock wave lithotripsy. A pancreatic stent was placed in 28 patients. Small stones were removed with a balloon-tipped catheter. Dormia-type baskets were used to extract larger stones. If balloon and/or basket extraction techniques were unsuccessful, a nasopancreatic drain or pancreatic stent was inserted beyond the stone to allow for sufficient drainage. After a mean follow-up of 33 months, stone removal was successful in 79% of patients.¹²

In a study by Farnbacher et al., 125 patients with pancreatic ductal stones were retrospectively analyzed. Successful removal of ductal stones was achieved in 85% of patients. Eleven patients (8.8%) underwent mechanical lithotripsy procedures to fragment the stones before subsequent removal. There were no significant complications experienced in lithotripsy procedures. Patients that experienced stones larger that 12 mm, stones in the tail of the pancreas, or multiple stones (2 or more) required more extensive therapeutic measures before removal could be accomplished.¹³

Pancreatoscopy, while not used directly during mechanical lithotripsy of pancreatic duct stones, can be used to identify the specific locations of pancreatic duct stones prior to inserting a basket into the pancreatic duct if the location of the stones is unclear on pancreatography.¹⁴ Pancreatoscopy can also be used to confirm duct clearance after stone extraction. (Figure 5)

Unlike extraction balloons, which can almost always be removed from the duct without difficulty (whether the balloon is working or has failed), stone retrieval baskets can become impacted within the pancreatic duct. Basket impaction can occur via several mechanisms, the most common of which is if the stone/basket complex cannot fit through the duct and be withdrawn to the duodenum. This situation is common if the pancreatic duct contains strictures, especially fibrotic strictures. Furthermore, if the ductal stones are too dense to be crushed, traction wires can fracture during attempted mechanical lithotripsy, creating a non-functioning basket with part or all of a stone still inside. Fractured traction wires can make the basket impossible to close and/or remove by pulling it back through the duct.¹⁵ In a multi-center study cited by Hlaing, a complication rate of 11.6% was associated with mechanical lithotripsy of pancreatic duct stones, often due to basket failure and/or impaction.¹⁶

Basket impaction in the pancreatic duct can be treated by the use of a Soehendra lithotripter cable (to destroy the stone/basket complex and allow basket removal) or via EHL or laser lithotripsy to try to break up the stone in the basket (theoretically allowing the empty basket to then be removed from the pancreatic duct), although the latter two devices may be very difficult to use in this situation. The actual incidence of basket impaction in the pancreatic duct is unknown as these events are likely underreported in the literature.

In a study by Sasahira et al., basket extractions in 10 patients with main pancreatic duct stones of 5 mm or less were observed. There was one case of temporal basket impaction. The basket was easily removed after the stone was released from the basket. A sphincterotomy extension was performed and the stone was successfully extracted after a second attempt. In 5 patients a nitinol basket catheter was successfully used to remove ductal stones. A basket catheter was used to initially extract stones in the remaining 5 patients. A balloon catheter sweep was performed to remove any residual stones. A pancreatic stent was temporally placed in all 10 patients.⁹ In a study by Thomas et al., 69 patients with pancreatic stones underwent endoscopic intervention. A complication rate of 0.8-5.9% associated with mechanical lithotripsy was reported. Extraction baskets broke in 7 patients, traction wires fractured in 4 patients, and basket handles broke is 5 patients. The basket impactions were successfully resolved using EHL and extracorporeal shock wave lithotripsy (ESWL).¹⁰

Electrohydraulic Lithotripsy

Electrohydraulic Lithotripsy (EHL) can be applied to pancreatic ductal stones in order to facilitate endoscopic removal. EHL applies high-energy shock waves to small areas.¹⁷ The technique uses a wire to generate a spark in a fluid filled duct. The spark generates a shock wave that propagates through the fluid and can fracture stones. EHL requires pancreatoscopy to perform, both to access and visualize the stones in question. EHL is directly applicable to pancreatic duct stone extraction as this procedure can be used to fragment stones that are too dense to be successfully fragmented using mechanical lithotripsy or that have failed attempts at balloon extraction.

Thomas et al. reported retrospective results in 69 patients with pancreatic stones. Two patients with large stones that proved difficult to remove underwent EHL. Stone clearance was successful in both procedures without any complications of pancreatitis associated.¹⁰ Attwell et al. performed a study of 46 patients undergoing various methods of endoscopic stone removal. EHL was performed in 85% of patients. Stone clearance and reduction of pain was successfully obtained in 74%.¹⁸

Craigie et al. reported on 10 patients with stones in the head of the pancreas underwent EHL. Intraductual stones were fragmented and successfully removed in all patients. There were no reported complications associated with EHL or stone extraction procedures.¹⁹

Studies on EHL have generally been small, single center, and retrospective in nature. In a study by Howell et al., 6 patients underwent EHL to fragment pancreatic duct stones. EHL was used as initial therapy in 1 patient. In 5 patients, EHL was used after other endoscopic clearance procedures were unsuccessful. Of note, balloon dilation of pancreatic duct strictures was performed in the same procedure to facilitate the entire procedure. After EHL was completed, balloon catheters and baskets were used to remove the stone fragments. Ductal clearance was successfully achieved in 50% of patients. Improved drainage and symptom relief was obtained in 100% of patients. No complications associated with EHL were observed.²⁰

In a small series by Tanaka et al., two patients with large pancreatic ductal stones lodged in the head of the pancreas underwent EHL. The stones were successfully fragmented and optimal ductal flow was restored.²¹

In a case study by Papachristou et al., a patient with a pancreatic stone measuring 15.5×11.1×6.4 mm underwent various endoscopic procedures. EHL was performed after failed attempts of balloon extraction, balloon dilation, and mechanical lithotripsy. Using EHL, the stone was successfully fragmented and removed using balloon and basket extraction devices.¹⁷

Laser Lithotripsy

Laser lithotripsy procedures can be used to facilitate removal of difficult pancreatic stones, although there is relatively little clinical data on the efficacy of this technique. Laser lithotripsy, like EHL, requires a pancreatoscope to both directly identify stones and to serve as a conduit for a laser fiber. In laser lithotripsy, a laser pulse is used to pulverize the stone making extraction measures more successful. GI lasers or lasers designed for urology can be used for laser lithotripsy. Stones fragmented by laser lithotripsy can then be removed from the pancreatic duct via baskets and/or balloons.

In a study by Alatawi et al., five patients with pancreatic stones were treated with laser lithotripsy using a holmium YAG (yttrium aluminum garnet) laser All patients had previously undergone unsuccessful ERCP treatments. After stone fragmentation, stone retrieval was performed using a dormia basket or balloon catheter. Stone extraction was successful in all five patients. No complications associated with laser lithotripsy procedures were reported.²²

In a small prospective study by Maydeo et al., 4 patients with pancreatic stones underwent laser lithotripsy when removal by basket or balloon catheters failed. Pancreatic stones were fragmented in 100% of patients followed by complete clearance via ERCP. No complications associated with laser lithotripsy or ERCP were reported.²³

In a case report Hlaing et al., laser lithotripsy was used to assist in removing a basket that had become impacted in the pancreatic duct after entrapment of a pancreatic duct stone. During a mechanical lithotripsy procedure, the basket wires fractured and the basket became entrapped in the pancreatic duct. The pancreatic stone was fractured via laser lithotripsy. The basket and stone fragments could be successfully removed after laser lithotripsy.²⁴

Extracorporeal Shock Wave Lithotripsy

Extracorporeal show wave lithotripsy (ESWL) is a non-invasive treatment for pancreatic duct stones. ESWL can be used to fragment stones using an externally applied shock wave pulse. A water filled cushion can be placed externally adjacent to the target area, or ESWL can be administered to a patient that is partially immersed in water. Sedation, epidural anesthesia, or general anesthesia can be used in patients undergoing ESWL depending on local institutional protocols. ESWL is generally used if the patient has many stones or if previous endoscopic measures have failed.

In a study performed by Ong et al., 250 patients underwent ESWL after chronic pancreatitis was confirmed via ERCP, conventional ultrasound, endoscopic ultrasound, or computed tomography scans. Multiple stones were reported in 87% of patients. Only 13% of patients had single stones. Stones in the head of the pancreas were seen in 98% of patients with multiple stones. After the stones were fragmented with ESWL, the pieces were removed with a dormia basket and/or balloon extraction via ERCP. Complete clearance of associated stones was achieved in 60% of patients and partial clearance occurred in 24% of patients, illustrating how even the most aggressive treatments can sometimes fail to allow duct clearance. Complications associated with ESWL occurred in 6% of patients. Pain during ESWL was the most common complication reported. Mild bleeding during ERCP occurred in three patients. No complications of acute pancreatitis associated with ESWL or stone extraction procedures were reported.²⁵

Farnbacher et al. retrospectively analyzed 125 patients with pancreatic duct stones. Eighty-two patients had multiple stones. Successful stone clearance was achieved in 85% of patients. Stone clearance was achieved in 11 patients by mechanical lithotripsy and 114 patients by ESWL followed by ERCP. ESWL was performed in patients in whom stone clearance was unsuccessful via ERCP.²⁶

In a retrospective study by Hiromu et al., 80 patients with pancreatic stones underwent ESWL. Forty-five patients underwent pancreatic stenting prior to ESWL treatment. Stone fragmentation was achieved in 91% of patients who underwent stenting prior to ESWL therapy and in 80% of patients who did not undergo stenting prior to ESWL therapy. Stone fragmentation was successful in 89% of patients while symptom relief was observed in 88% of patients regardless of stent placement. A complication rate of 7% was seen in patients who had pancreatic stents and 17% in patients who had no pancreatic stent. Complications included rare pancreatitis and cholangitis.²⁷

CONCLUSIONS

A variety of endoscopic treatments are available for pancreatic duct stones. For small pancreatic duct stones and/or debris, balloon catheters and basket extraction devices can be used to extract stones. For larger or difficult pancreatic duct stones, a combined approach of basket/balloon extraction with more extensive measures such as electrohydraulic lithotripsy, laser lithotripsy, and/or extracorporeal shockwave lithotripsy can be used. Some patients will fail all endoscopic techniques; in these patients, surgery is still an option. Endoscopic approaches to treating pancreatic duct stones has an acceptable rate of adverse events and is now considered first line therapy.

Fellows' Corner

An Unusual Cause of Acute Pancreatitis

Josephine Ni,Octavia Pickett-Blakely

A 19-year-old man with one previous episode of pancreatitis presented with abdominal pain, nausea and vomiting for two days. He presented one month previously with similar symptoms to another institution and was diagnosed with acute pancreatitis based on an abdominal CT scan and an elevated lipase. He was managed conservatively with NPO, analgesia and IV ﬂuids and ultimately discharged. Two days prior to the current admission he developed constant epigastric pain with radiation to the back. This was accompanied by nausea and non-bloody, non-bilious vomiting. He denied diarrhea, melena, or hematochezia. He endorsed drinking five drinks per weekend in the past, but stated that his last drink was 3 months prior to admission.

Laboratory studies were significant for a lipase of 209 U/L with normal liver-associated enzymes tests, and a normal white blood cell count. Triglycerides, ANA, and IgG-4 were all within normal limits.

CT scan of the abdomen and pelvis with contrast showed mild stranding and ﬂuid adjacent to the pancreas consistent with mild uncomplicated pancreatitis. The gallbladder was unremarkable without findings of cholecystitis or cholelithiasis.

An MRCP was then performed and showed a normal pancreas and bile ducts; however, there was new mild segmental dilation of the proximal jejunum with suggestion of segmental mild wall thickening distally.

An anterograde push enteroscopy was performed to evaluate the abnormal small bowel seen on MRCP and showed severe, circumferential erythema, edema, friability, and ulcerated mucosa with exudate extending circumferentially from the duodenal bulb to the proximal-mid jejunum. Multiple biopsies were taken of the small bowel and stomach.

QUESTIONS

What is the differential diagnosis?
Are there associations between this condition and pancreatitis?
What are the causes of pancreatitis in patients with this condition?
How would you treat this condition in this patient?

Discussion

The pathology from the small bowel biopsies showed small bowel mucosa with severe acute and chronic inflammation consistent with Crohn’s disease, and his episodes of acute pancreatitis were thought to be due to peri-pancreatic duct inflammation caused by Crohn’s involvement of the duodenum.

Although extraintestinal manifestations of IBD are well described and relatively common, acute pancreatitis is a rare extraintestinal manifestation. In a retrospective cohort study, the prevalence of pediatric and adult patients with acute pancreatitis as the initial presenting symptom of IBD was 2.17% (10 of 460 pediatric patients) and 0.06% (2 of 3500 patients), respectively.

(1) The most common etiologies of pancreatitis in patients with Crohn’s disease are gallstones, alcohol, and purine analogs.(2) However, Crohn’s disease of the duodenum was found in a retrospective cohort study of 48 patients to be a risk factor for acute pancreatitis in 7 patients (15% of the cases of pancreatitis). (2) Although the pathophysiology of duodenal Crohn’s causing acute pancreatitis has not been well-studied, it has been theorized that small bowel inflammation can cause both papillitis and the reflux of pancreatic contents into the pancreatic duct. (3) Thus, Crohn’s disease of the duodenum should be considered in the differential diagnosis in individuals with acute pancreatitis, particularly in younger patients whose work-up has otherwise been unrevealing.

This patient is currently doing well on a steroid taper with plans to initiate infliximab therapy at his next clinic visit.

A Case Report

Acute Hepatitis – Do Not Forget About Hepatitis E

Peter S. Francisco,Stephen M. J. Hoffman

Introduction

Hepatitis E (HEV) is a single stranded, non-enveloped RNA virus that can infect both humans and animals through fecal-oral contamination. Once infected, the incubation period can range from 2 to 8 weeks. Symptoms include myalgias, arthalgias, weakness, vomiting, jaundice, pruritus, clay-colored stools and dark urine. These symptoms can accompany elevation of liver enzymes such as transaminases, bilirubin, alkaline phosphatase and gammaglutamyltransferase. Patients infected with hepatitis E can potentially progress to fulminant hepatic failure.¹ Recently, in the United States, cases of suspected drug-induced hepatitis were ultimately deemed secondary to a hepatitis E infection.⁶ We present the case of a patient with suspected drug-induced hepatitis determined to have acute hepatitis E infection.

CASE

A 47-year-old Middle Eastern male, without significant medical history, was sent by his primary care physician (PCP) to the emergency department for evaluation. The visit with his PCP was initiated due to upper respiratory symptoms, including sinus congestion, rhinorrhea, postnasal drip and cough. He was started on medications for suspected infection, including azithromycin.

The patient subsequently had fevers and nausea with episodes of bilious emesis. Trimethoprim/ sulfamethoxazole was substituted for the azithromycin but he continued to get worse. He admitted to anorexia with approximately 10-15 pounds of unintended weight loss. He also experienced dark urine, clay-colored stools and abdominal bloating with fevers.

There was no history of exposure to herbal products, over the counter medications (including acetaminophen) or excessive vitamin use. During his trip to Bangladesh two months ago, he described a one-week history of an acute diarrheal illness.

On physical exam, scleral icterus was noted. His liver size was 12cm in the right mid-axillary line to percussion and he did not have asterixis on exam.

Laboratory tests and imaging studies revealed an aspartate aminotransferase (AST) of 1,172; alanine aminotransferase (ALT) of 2,203; alkaline phosphatase (ALP) of 239; total bilirubin of 10.4; direct bilirubin of 7.4; prothrombin time (PT) of 13.6; international normalized ratio (INR) of 1.11 on admission. His acetaminophen level was undetectable. His hepatitis profile showed prior exposure to hepatitis A but no exposure to hepatitis B or C. Hepatitis E serology was still pending upon discharge. Abdominal ultrasound showed a heterogenous pattern of the liver consistent with hepatocellular disease. There was normal flow within the hepatoportal veins on Doppler views.

The patient did well clinically through the rest of his hospital course. The etiology was presumed to be antibiotic-induced hepatotoxicity at the time of discharge. However, after discharge, his hepatitis E serology came back positive for acute hepatitis.

DISCUSSION

Although hepatitis E is found worldwide, the continents of Africa, Central America and Asia have the highest prevalence.¹ The incidence of HEV in rural

Bangladesh fluctuates with the highest occurrence

during the monsoon season because of extensive water contamination.^2,3 The virus has even been known to cause severe acute hepatitis leading to fulminant liver failure.^4,5 High morbidity and mortality has resulted in pregnant woman with HEV and decompensation of patients with underlying cirrhosis.^4,5

Treatment for acute Hepatitis E is mainly supportive since the virus is cleared spontaneously in immunocompetent patients.¹ Hepatitis E is being identified more in developed countries, such as the United States, which should alert doctors to consider the virus as a potential etiology of abnormal liver enzymes in patients with significant hepatic injury.

Unusual Causes of Abdominal Pain, #4

Unusual Causes of Abdominal Pain

Kristen Pontiff,Brannon Alberty

CASE

A 4 year old female was referred to the pediatric gastroenterology clinic with intermittent postprandial nausea and abdominal pain with varying location. The episodes, each lasting 3-5 days, have occurred several times over the past couple of years and have gradually worsened over the past few months. The parents deny that she vomits old food. Chart review reveals a waxing and waning presence of splenomegaly on abdominal exam. Prior workup by her pediatrician included a normal complete blood count (CBC) and rapid streptococcus test. Epstein-Barr virus (EBV) titers demonstrated prior infection, but were not consistent with current infection. Splenic ultrasound demonstrated an 11.2 cm spleen (normal < 9 cm) with no other focal abnormality noted. On presentation, physical examination revealed a soft, non-tender, non-distended abdomen with bowel sounds appreciated in all four quadrants. Her spleen was located in left lower quadrant. She was then sent for a computed tomography (CT) scan of the abdomen and pelvis with contrast.

ANSWER AND DISCUSSION

Wandering spleen is the displacement of the spleen from its usual position in the left upper quadrant secondary to elongation of the pedicle. The etiology is usually congenital absence or malformation of gastrosplenic or splenorenal ligaments. In adults, wandering spleen is seen in women of childbearing age secondary to hormonal changes and resulting lax abdominal musculature. Wandering spleen in children is rare and can be associated with torsion or infarct on presentation. This demonstrates the importance of high suspicion as well as the necessity of swift action. More common presentations can include nonspeciﬁc lower abdominal pain associated with back pain, nausea, vomiting and flatulence. Diagnosis can be made via ultrasound with Doppler or contrast enhanced CT. Our patient’s CT scan demonstrated ectopic positioning of a normal sized spleen in the left ﬂank, with soft tissue opacity in the left upper abdomen. A central area of increased density within the left upper abdomen was presumably related to rotation of the splenic pedicle. A possible calcified phlebolith within the splenic vein was also noted. We diagnosed the patient with wandering spleen and referred her for surgical evaluation. Splenopexy is ideal if no hemorrhage, phlebolith or other compromise to blood supply is demonstrated. Splenectomy is undertaken if the patient demonstrates infarction, potential for infarction with acute torsion or signs of frank necrosis. Splenectomy was performed secondary to a mass noted intraoperatively. Pathology later revealed benign pancreatic tissue with focal infarct. Our patient has been well to date with no further recurrence of abdominal pain since her procedure. Management of the asplenic patient includes vaccination for pneumococcus, hemophilus influenzae type B (if not already immunized fully), meningococcal group C and yearly influenza vaccine.

Antibiotic prophylaxis is given to asplenic pediatric patients to prevent sepsis and additionally instructed to seek immediate medical attention if fever develops. She was also advised to avoid contact with dogs secondary to increase in risk of canine associated bacteremias causing sepsis in asplenic patients.

Endoscopy: Opening New Eyes, Series #8

Trace Element Supplementation and Monitoring in the Adult Patient on Parenteral Nutrition

Cassandra Pogatschnik

Often overlooked by medical providers, trace elements are essential nutrients for the long-term parenteral nutrition (PN) patient. They play a significant role in human metabolism and can lead to serious complications when deficient or in excess. Individual trace element regimens are determined by patient presentation, organ dysfunction, inflammation, and patient history. In this article we emphasize awareness of the complexity of trace elements and the understanding that careful monitoring of trace element status can improve patient success on PN.

Introduction

As an integral and often life sustaining therapy, parenteral nutrition (PN) enables absorption of nutritive constituents while bypassing the gastrointestinal (GI) tract. Macronutrients sustain an individual calorically; electrolytes allow for proper electrical charge and cellular space fluid distribution; and micronutrients allow for efficient human metabolism. Often overlooked by clinicians, trace elements regulate metabolism as enzymatic cofactors that transport substrates across cell membranes.^1,2 In the United States five of nine essential trace elements are supplemented in PN. Routine addition and adjustment of chromium, copper, manganese, selenium and zinc are based upon laboratory levels, where appropriate, as well as physical and clinical symptoms of deficiency and toxicity. Specific populations, including the severely malnourished, patients with high enteral losses and those on long term home PN, require trace element monitoring.

Trace Element History

Since PN’s birth in the 1960s and its introduction to the home setting in the early 1970s, trace elements’ importance was recognized. In 1977 an expert nutrition panel from the Nutritional Advisory Group of the American Medical Association (NAG-AMA) devised the first trace element guidelines which were submitted to the Food and Drug Administration (FDA) in 1978 and were subsequently published in the Journal of American Medicine in 1979.^3,4 (See Table 1) At that time it was encouraged that single formulations of individualized trace elements be available for easier adjustment and removal as necessary.4,5 Selenium was established as essential in 1979 when supplementation eradicated Keshan Disease (a congestive cardiomyopathy caused by a combination of dietary deficiency of selenium and the presence of a mutated strain of Coxsackie virus characterized by heart failure and pulmonary edema). This prompted selenium’s inclusion, and supported copper dosage reduction (based on copper balance studies in long-term PN patients) in the 1982 trace element review.4 Despite numerous expert panel reviews, studies, and proposals, the FDA has not yet approved a new multi-trace element formulation, a delay that may prove hazardous in some patients.³ One recent investigation performed autopsies on 8 PN dependent patients for an average duration of 14 years who had received the NAG-AMA trace element formulation. The autopsies revealed excessive tissue concentrations of chromium, copper, and manganese, which supported the need for change in multi-trace formulations today.⁶

Monitoring Trace Elements

With optimal doses under debate, PN drug shortages, a growing long-term PN population, variability of patients’ conditional requirements, and questionable laboratory testing, the task of monitoring home PN patient’s micronutrient status is difficult. Trace element lab samples are difficult to collect, handle, and are extremely susceptible to contamination, making them an infrequent and expensive physician order.² When obtained, trace element results must be interpreted with caution as some are affected by inflammatory states.² If the clinician is uncertain, but suspects an inflammatory or infectious process (such as active Crohn’s, etc.) may be present, while there are no data to support this practice, checking a C-reactive protein might be considered (See Table 2). Measurements of serum and plasma levels have demonstrated to be less indicative of body stores or nutrient adequacy in those receiving PN.6 Decreased laboratory levels may actually reflect redistribution versus true deficiency.⁷

Though whole blood and serum markers have shown unimpressive correlation to tissue levels,² they allow clinical establishment of patient baseline and trends. Suggestion for monitoring varies per clinician and home nutrition support program, however, it is suggested that trace elements be repeated at least annually. Upon trace element shortage (particularly when an individual supplement is omitted) or patient history of deficiency or toxicity, studies may be repeated every three months until levels and/or clinical symptoms improve. They may be repeated more frequently based upon clinical judgment. It is essential that clinicians confirm laboratory findings with both clinical and physical characteristics of deficiency and toxicity (See Table 3).

Chromium

Chromium is a transitional metal that is biologically active in the trivalent phase.² Considered an essential trace element due to its regulatory properties and decline with age, chromium gets incorporated into a chromodulin or “glucose tolerance factor,” promoting insulin action in peripheral tissue and reducing insulin requirements.^2,8 Transported by transferrin and albumin, it competes with iron for binding sites on transferrin.^2,8 Hemochromatosis is thought to be associated with both chromium deficiency and glucose intolerance.⁸ Deficiency symptoms include hyperglycemia, hyperlipidemia,⁸ neuropathy,⁹ and in rare cases encephalopathy.¹⁰ It is important to note, that additional chromium supplementation will not improve hyperglycemia if it is already being adequately supplemented.² No toxicities have been reported in adults;^3,9 however expert concerns arise from accumulation of high levels of chromium in the sera and tissue overtime. It has been proposed that efficient chromium dosing may be provided from alternate ingredient contamination, such as 70% dextrose solutions used for compounding PN formulations.³ Current recommended dosage of 10-15 mcg/day may be overestimated and new recommendations may be as low as 0.14-0.87 mcg/day.3 Removal from formulations may be preferred in patients with renal insufficiency as it is excreted most readily through urine.^2,3,7,8 No satisfactory test has been discovered for measurement of chromium; however, with improved analytical measurements and quality controls, serum chromium can be measured more accurately. The best way to capture deficiency may be to monitor glucose response to chromium.¹¹

Copper

Copper allows for erythrocyte synthesis, absorption and use of iron, phospholipid formation, and improves connective tissue integrity.^2,12 Transcuprein and albumin transport copper to the liver where it is incorporated into ceruoplasmin, which transports copper to peripheral tissues. Sixty to ninety-five percent of circulating copper is present in this form. Copper is not present in the blood due to poor solubility and must be drawn as a serum lab draw. Revealed during significant deficiency, and in patients with compromised GI tract with high enteric losses,¹³ symptoms include, leukopenia, hypochromic and normocytic anemia with depressed reticulocyte count.^2,10 If left untreated, patients may present with gait difficulty, resembling Vitamin B12 deficiency,^4,13 connective tissue disorders, blood vessel defects, osteoporosis, and cardiac disease.¹² Menkes Disease is defined as copper accumulation in the intestinal mucosa, which inhibits transportation of copper to the liver and tissue resulting in true deficiency, and in rare cases, causing degenerative brain disorders, severe mental retardation and in few instances, death.¹⁰ One case report revealed severe copper deficiency after a three-month intravenous multi-trace holiday due to intravenous product shortage.¹³ The multi-trace contained 0.5 mg copper/day, of which the patient received 5 days/week. Upon removal, the patient was supplemented with an oral multivitamin/mineral supplement containing 15 mg copper/day; of which she only took 1-2 doses/week due to GI intolerance. She presented with fatigue, lower extremity edema, WBC 3.1K, hemoglobin 6.5 g/dL and hematocrit of 21.3%. The patient was subsequently admitted and underwent a neurological exam and GI work-up, both of which were negative. Further labs concluded copper deficiency (Cu <3 mcg/dL, ceruloplasmin <3 mg/dL, and normal Zn of 61 mcg/dL). The patient was started on 6 mg oral copper for 1 week, 4 mg oral copper for 2 weeks, and then dosage was decreased to 2 mg/day. Two months later intravenous multi-trace was again available and was added back to the PN. Within two months all laboratory studies had normalized. Copper deficiency can manifest as early as eight to ten weeks upon withholding supplementation and with adequate repletion, can reverse hematological changes in one to two weeks.13 A case report by Spiegel et al. also demonstrated copper deficiency (confirmed by both lab and bone marrow biopsy) and pancytopenia eight weeks after intravenous copper removal.¹⁴ Repletion with copper sulfate improved the patient’s hematological and copper studies; however, the patient expired from cardiac tamponade. Interestingly no reports of human myocardial deaths caused by copper deficiency have been reported, however copper deficient rats have developed fatal cardiac diseases (ruptured arterial aneurysms and hemorrhagic pericardial tamponade) thought to be attributed to copper’s effect on elastin and collagen synthesis.¹⁴ As a trace element that is almost exclusively excreted through the bile, cholestasis can lead to copper toxicity, and toxicity can cause hepatocellular damage, accumulation and cirrhosis.^2,10 Blaszyk et al. studied long-term PN patients’ hepatic tissue copper levels and compared them to patients with alternative drug induced cholestasis. Results concluded that PN patients who had significant cholestasis accumulated high levels of hepatic copper and found that PN therapy duration alone was independent of copper toxicity.¹⁵ Renal failure and neurological disorders have also been associated with copper toxicity.² Current recommended dose is 0.5-1.5 mg/day,12 with 1 mg/day being provided in multi-trace formulations.³ The American Society for Enteral and Parenteral Nutrition (ASPEN) most recently proposed a dosage decrease to 0.3-0.5 mg/ day.³ It is suspected that requirements may increase by 0.4-0.5 mg/day in persistent malabsorptive states^12,13 and that a decrease in dosage to 0.15 mg/d or removal altogether may be required in cholestasis.¹⁶ Of note, it is necessary to monitor patients with such minute dosages as they have demonstrated pancytopenia at six weeks.⁹ Elevated bilirubin of 10.9 mg/dL and liver biopsy revealing mild steatosis, early fibrosis, and cholestasis prompted intravenous copper removal in another case report by Fuhrman et al.¹⁷ Fifteen months after removal, the patient required monthly red cell transfusions accompanied by WBC and platelet decline. Nineteen months after the copper holiday, bone marrow biopsy proved suspicion for copper deficiency etiology. Dosage of 1mg/day was again supplemented, copper levels rose and neutropenia and thrombocytopenia dramatically improved, resulting in a break from transfusions. Subsequently serum copper became elevated and was again removed. Three months later patient developed severe copper deficiency correlating again with neutropenia, thrombocytopenia, anemia, and again necessitating red cell transfusions. As a result of this experience Fuhrman et al. monitors serum copper quarterly and supplements 1 mg copper thrice weekly.¹⁷ Though serum copper and ceruloplasmin do not have high correlation with actual tissue accumulation, it is extremely important to monitor with the onset of clinical symptoms (see above). Autopsies have demonstrated copper accumulation in both liver and kidney without reflection in laboratory status.^6.9 Smoking, pregnancy, and contraception were found to alter levels.^10.11

Manganese

Manganese is a cofactor in many enzymatic systems and has roles in bone formation and metabolism of carbohydrates and cholesterol.¹⁸ This enzyme is involved in fatty acid and protein synthesis as well as melanin and dopamine production.¹⁹ After oxidation in its trivalent form, manganese is bound to transmanganin and is successfully deposited in the liver, skin, and skeletal muscle.² Deficiency has not been well detected;² however weight loss, transient dermatitis, and occasional nausea and vomiting have correlated with low manganese levels.¹⁰ Intravenous manganese administration is recommended at 60-100 mcg/day while standard multi-trace formulations contain 500-800 mcg/day. Toxicity has been reported in patients receiving long term PN. Manganese has been shown to accumulate in the basal ganglia resulting in neurotoxicity^2,9 and Parkinson’s like symptoms, hallucinations, and agitation.¹⁰ Manganese toxicity may also be associated with liver toxicity and hepatic cholestasis.^9,20 Laboratory levels often take five to six months to decrease when elevated.² One case reported an ongoing elevation of whole blood manganese for 369 days after complete removal of manganese; the patient had cholestatic disease.⁹ It has been recommended that manganese dosage be held in patients with hepatic dysfunction and cholestasis as it is almost exclusively excreted through bile;² however there is no evidence to support that manganese must be removed from PN in the setting of transient elevations of bilirubin in an acute care setting –this is not to say that evidence may be forthcoming, but clinical monitoring of these patients is essential. One study in Japan demonstrated that 55 mcg/day sustained serum manganese levels; with this evidence ASPEN supports dosage lowering to 55 mcg/day to prevent toxicity.³

Though lower than the US formulations, European dosing is 265 mcg/day and toxicity continues to exist.³ Whole blood manganese (a better representative of tissue manganese versus serum), found to be present in 60-80% of erythrocytes^2,9 may be drawn annually and more often in patients with hepato-biliary dysfunction and/or in patients exhibiting clinical signs and symptoms of deficiency and toxicity (See Table 3).

Selenium

Selenium is needed to synthesize selenocysteine, which aids in glutathione peroxidase that serves as an antioxidant, protecting cell membranes from lipid peroxidases, and free radicals. Selenium also drives endocrine enzyme function, which regulates thyroid hormone and metabolizes vitamin C.^2,21 Deficiency symptoms include macrocytic anemia, skeletal muscle pain and tenderness, arrhythmia, whitened nail beds, and loss of hair and skin pigmentation.^2,21 The development of Keshan disease (see trace element history above) is due to severe selenium deficiency, which is characterized by severe cardiomyopathy that is often irreversible or fatal.^2,4,21 Unfortunately most patients are extremely deficient prior to the appearance of clinical and physical symptoms;²¹ hence laboratory testing can be done prophylactically. The usual dose of selenium in PN is 20-60 mcg/day; however consensus is that needs are actually increased to 60-100 mcg/day.^3,9 Selenium requirements are elevated in malabsorptive states⁹ and increased dosage is controversial in critically ill, septic, and burn patients.³ Although rare,²² selenium toxicity is likely to appear when levels are tenfold higher than normal.²¹ Toxicity may cause oxidative cell and tissue death. Symptoms may include hair loss, brittle nails,²¹ skin changes, decay of teeth, and neurogenic abnormalities.¹⁰ Selenium laboratory studies lack correlation to actual selenium storage and likely reflect acute changes between tissues.⁹ Some professionals feel that erythrocyte glutathione peroxidase activity could be more reflective of selenium storage however; further studies are warranted.^9,11

Zinc

Zinc is a metalloenzyme that has roles in immune function, stress response, wound healing, and glucose control. As a cofactor, zinc also aids in the metabolism of macronutrients. Transported by plasma protein and albumin, >85% is stored in the skeletal muscle and smaller amounts in the bone, skin, liver, pancreas, kidney, and prostate.^23,24 Zinc deficiency can appear rapidly, within 14 days to 3 months of supplementation holiday,^23,24 and is often related to prolonged severe malnutrition, high enteric losses, and/or thiazide diuretic use.¹⁰ Deficiency characteristics are detectable once levels are severely low, often present with physical signs: acrodermatitis enteropathica, alopecia, hair pigmentation changes, stomatitis, glossitis, perioral ulcers, and periungual lesions.^23,24 Clinical symptoms often entail delayed wound healing, delayed sexual maturation, reduction of taste sensitivity, poor night vision and impaired immunity.¹⁰ Standard dosage administered through PN is 2.5-5 mg/day. Patient with high GI loss may require 12-17 mg/liter lost,^3,24 with a proposed upper limit of 50 mg/day.¹⁰ Some clinicians proactively supplement 10 mg/day for patients at high risk for deficiency.10 ASPEN does not have an adjustment they would like to make at this time; however, per Shike et al. average zinc dose given was 7.6 mg/day to maintain adequate zinc status, adequate for 90% of the patient population.¹² They supplemented 6.7 mg/day versus 9 mg/day in their non-short bowel as opposed to short bowel patients.¹² Rare toxicities have been detected, often expressed as dysfunction of neutrophils and lymphocytes² and have been associated with urinary tract infections.²⁵ Zinc laboratory studies have questionable accuracy as zinc is tightly regulated and reserved in the blood until supply is scarce; hence zinc deficiency may be caught late.⁹

Summary

Trace elements are essential in providing adequate PN formulations in long-term PN patients. Though infused in minute quantities, trace elements have a significant role in health and well being. However, if not carefully monitored in these patients, they can have detrimental effects. It is vital that clinicians who care for these patients understand dosages available, patients’ conditional requirements, anticipate where potential toxicities and deficiencies might occur and

the importance of dosage adjustment as appropriate. As most laboratory measures are unsatisfactory, assessment of the entire clinical picture is critical in determining the best plan of care. Develop a plan for scheduled monitoring, and if faced with product shortage, see the ASPEN website for suggestions: http://www. nutritioncare.org/news/parenteral_nutrition_trace_ element_product_shortage_considerations.

Endoscopy: Opening New Eyes, Series #8

Hemospray™ in Gastrointestinal Bleeding

Kirsten Regalia,

Alan Barkun

In this article we discuss the use of Hemospray™ (TC-325, Cook Medical Inc., Winston-Salem, NC, USA), a novel, highly adsorptive nanopowder made from a proprietary inorganic mineral blend. It has some distinct advantages over conventional endoscopic hemostatic modalities as it is easy to use and appears relatively safe and efficacious for various causes of both upper and lower gastrointestinal bleeding. It is currently licensed in Europe, Hong Kong and Canada for endoscopic hemostasis of non-variceal upper gastrointestinal bleeding and is undergoing Food and Drug Association evaluation in the United States.

Introduction

A cute upper and lower gastrointestinal bleeding are common medical emergencies with high rates of morbidity and mortality.¹ Various endoscopic hemostatic treatment modalities exist including injection, thermal and mechanical therapies. These methods have limitations, as they all require technical expertise and, in most, direct tissue contact with the bleeding vessel.² Thermal and ligation devices, such as clips, are limited by the need for en face positioning, possible difficulties in deployment and potential complications such as bleeding and perforation. Furthermore, these techniques do not provide rapid enough hemostasis in the case of massive bleeding.^3,4

Application of a hemostatic powder to the bleeding site obviates the need for direct contact of an instrument with the vessel or mucosa. Hemospray™ (TC-325, Cook Medical Inc., Winston-Salem, NC, USA) is a novel, highly adsorptive nanopowder made from a proprietary inorganic mineral blend. It contains no human or animal proteins, botanicals or allergens and is nontoxic.² It is currently licensed in Europe, Hong Kong and Canada for endoscopic hemostasis of non-variceal upper gastrointestinal bleeding^5,6 and is undergoing Food and Drug Association (FDA) evaluation in the United States (US) for similar use. It is currently only FDA approved for external traumatic uses.^7,8

Hemospray Application
Technique and Mechanism of Action

The Hemospray delivery device consists of a powder canister (which contains approximately 20 grams of TC-325 hemostatic powder), a compressed carbon dioxide propellant and a delivery catheter that is introduced through the working channel of the endoscope. Hemospray is deployed through a 7-Fr or 10-Fr catheter in short bursts (each of which contains an average of 1 to 5 grams of powder). When the powder contacts blood, it absorbs water and forms a gel, which acts both cohesively and adhesively to create a stable mechanical barrier that covers the actively bleeding site. Hemospray is neither absorbed nor metabolized by mucosal tissue and the covering formed by the powder eventually sloughs from the lesion and is eliminated via the gastrointestinal tract.^6,9,10 In vitro experiments, whereby Hemospray was added to the plasma of healthy and factor-deficient patients, suggested that Hemospray may also activate the coagulation cascade and platelet function, thereby facilitating local hemostasis.¹¹ However, these preliminary findings require confirmatory studies.

Safety and Efficacy in Animal Models

Hemostatic powders have been used efficaciously for hemorrhage control in battlefield trauma patients. Swine model studies have raised concerns about the safety of these agents when used to externally pack open vascular injuries. Local and distant thrombi, transmural vessel damage and neurovascular changes have been described with use of WoundStat (a topical hemostatic agent made of smectite granules) in swine model studies.^12,13 While these safety concerns have caused some hesitancy about the use of hemostatic powders in humans with gastrointestinal bleeding, the animal studies involved extreme vascular injury from surgically transected vessels in which the hemostatic material was firmly packed into the wounds, and therefore could have predisposed to thrombus formation.

In a swine model study by Giday et al., 6 animals underwent gastrotomy and creation of a looped vascular bundle, which was placed into the stomach lumen.² On subsequent endoscopy the transplanted vascular bundle was punctured using a needle-knife to create Forrest grade Ia (pulsatile) or Ib (oozing) bleeding gastric lesions. Hemospray was then applied. Initial hemostasis was achieved in all animals and there were no signs of re-bleeding at post-procedure day 9. There was no hemostatic powder identified grossly in any stomach specimens, nor was there histologic evidence of powder or thrombosis in any local or systemic tissue samples.

In a randomized controlled animal trial, 10 swine were randomized to endoscopic treatment with Hemospray or sham (through endoscopic monitoring only) after operative creation of gastric arterial bleeding.¹⁴ Initial hemostasis was achieved in all animals treated with Hemospray while those in the sham treatment group all succumbed to uncontrolled hemorrhage. Durable hemostasis up to 24 hours post-treatment was observed in 80% of the treatment group. There was no evidence of foreign body granuloma or embolization in the lung or brain at necropsy in any of the treatment animals sacrificed one week later.

Clinical Applications of Hemospray

A review of the literature using PubMed and Ovid up to February 2014 showed various clinical applications of Hemospray in both upper and lower gastrointestinal bleeding (summarized in Table 1).

Upper Gastrointestinal Bleeding
Various Causes of Upper GI Bleeding¹

A multicenter, international SEAL (Survey to Evaluate the Application of Hemospray in the Luminal Tract) cohort study assessed the use of Hemospray in nonvariceal upper gastrointestinal bleeding in 10 pilot sites across Europe.¹⁵ A total of 63 patients were treated with Hemospray as either primary monotherapy (in 55 patients) or combination second-line therapy (in 8 patients). The etiology of the bleeding was gastroduodenal ulcer in 48% of patients, with the remaining etiologies attributable to various other nonvariceal causes. Primary hemostasis was achieved in 85% of patients who received Hemospray monotherapy, the remainder required additional endoscopic hemostatic adjuvant interventions or angiographic embolization. Of the patients for whom initial hemostasis was achieved with Hemospray monotherapy, 15% developed re-bleeding within 7 days. Of the 8 patients treated with Hemospray when standard endoscopic therapies had failed, all 8 (100%) achieved hemostasis with Hemospray. However, 25% of these patients re-bled within 7 days. There were a total of 4 deaths within 7 days, none of which was due to bleeding. Of the patients with peptic ulcer bleeding, 36% failed to achieve either primary or sustained hemostasis with Hemospray. This is higher than expected when compared to published data from controlled studies in ulcer bleeding, but likely attributable at least in part to patient selection. While this was an uncontrolled, solely observational study with no set protocol for Hemospray use, it provides some insight into the efficacy and safety of Hemospray in non-variceal upper gastrointestinal bleeding.

Peptic Ulcer Bleeding

In a prospective, single-arm pilot clinical study by Sung et al., consecutive adults with confirmed peptic ulcer bleeding (Forrest class Ia or Ib) were treated with Hemospray.¹⁰ The majority of ulcers (70%) were located in the duodenum, while 30% were in the stomach. Routine second-look endoscopy at 72 hours post-treatment and phone follow-up at 30 days were performed in all participants. Of the 20 total patients in the study (18 men, mean age of 60 years), acute hemostasis was achieved in 95% (19/20) of patients. The one patient for whom Hemospray failed had a pseudoaneurysm that required arterial embolization (the only patient with Forrest Ia ulcer bleeding). Two patients had recurrent bleeding within 72 hours (detected clinically by hemoglobin drop), but neither had active bleeding identified at repeat endoscopy. There were no major adverse events, mortality, or treatment-related adverse events (including systemic embolization, bowel obstruction or allergic reaction) during the 30-day follow-up period. At the routine second-look endoscopy at 72 hours, Hemospray had been eliminated from the stomach and duodenum in all patients. All patients at follow-up endoscopy had clean-based ulcers, and had received high-dose proton pump inhibition co-administration.

Portal Hypertensive Bleeding
Esophageal Variceal Bleeding

A prospective, non-randomized pilot study by Ibrahim et al. evaluated the efficacy of Hemospray in 9 patients with acute esophageal variceal bleeding: 3 with active hemorrhage and 6 with stigmata of recent bleeding.¹⁶ The application of Hemospray produced hemostasis in all patients, and a second dose was required in only one case. Follow-up endoscopy was performed at 24 hours post-intervention in all patients, at which time hemostatic powder had been eliminated from the upper gastrointestinal tract in all patients, and the entire cohort then underwent elective variceal band ligation. No cases of recurrent bleeding or Hemospray-related adverse events were reported. These findings highlight Hemospray as a potential bridge to definitive therapy (either transjugular intrahepatic portosystemic shunt [TIPS] or band ligation) in acute esophageal variceal bleeding, especially in cases when immediate hemostasis is otherwise difficult to achieve. Currently, Hemospray is not recommended for use in variceal hemorrhage by the manufacturer due to theoretical concerns about possible systemic embolization.³

Gastric Variceal Bleeding

There are two case reports describing the use of Hemospray in gastric variceal bleeding, both after injection therapy with N-butyl-2-cyanoacrylate (Histoacryl™) with lipiodol failed. In one of the patients, it served as a bridge to TIPS, and in the other it was definitive therapy as TIPS was contraindicated due to underlying cardiomyopathy.^17,18

Portal Hypertensive Gastropathy

Hemospray has been used successfully in 3 patients with diffuse bleeding from portal hypertensive gastropathy.⁶

Patients on Antithrombotic Therapy

Antithrombotic therapy (ATT) includes antiplatelet therapy and anticoagulants and can give rise to life-threatening gastrointestinal hemorrhage. Holster et al. evaluated the relative efficacy of Hemospray in patients with bleeding on ATT (n = 8) compared with those without ATT (n = 8).¹⁹ Successful initial hemostasis was achieved in all 8 (100%) of the non-ATT patients and in 5/8 (63%) of the patients on ATT (p = 0.20). For the 3 patients on ATT for whom Hemospray failed, 2 had spurting arterial bleeds controlled with subsequent clipping and the other patient required angiography with coil embolization. Re-bleeding within 7 days was observed in 5 of the 16 patients (3 in the ATT group and 2 in the non-ATT group). In 2 of the 3 ATT cases, Hemospray had been applied to spurting arterial vessel bleeding, and in both of the non-ATT cases, Hemospray had been applied for peptic ulcer related arterial bleeds. No deaths occurred up to 30 days after Hemospray application in either group.

Malignant Tumor Bleeding

Both primary and metastatic tumors of the gastrointestinal tract are at risk of bleeding. Bleeding from malignancy can be induced by tumor necrosis and is often diffuse and widespread.²⁰ Conventional endoscopic hemostatic therapies (such as heater probe, electrocautery and argon plasma coagulation [APC]) are associated with high rates of recurrent bleeding compared to other non-malignant causes of gastrointestinal bleeding.²¹ Chen et al. described 5 cases in which Hemospray was used to treat upper gastrointestinal bleeding due to gastroduodenal tumors.²² Hemospray was successful in achieving immediate and sustained hemostasis in 4 of the 5 patients, but failed in a patient with severe metastatic disease and disseminated intravascular coagulation. In a study by Leblanc et al., 5 patients with active upper gastrointestinal bleeding due to malignancies of the esophagus, stomach or pancreas were treated with Hemospray.²⁰ Hemospray was used as first-line therapy in 4 of the 5 patients, and as rescue therapy in the fifth for persistent bleeding despite placement of hemostatic clips. Immediate hemostasis was successful in all 5, with recurrent bleeding in 2 patients. Figure 1 shows a gastric tumor with diffuse bleeding prior to the use of Hemospray. Figure 2 shows complete hemostasis of the same lesion following the application of Hemospray.

Post-Therapeutic Intervention Bleeding

Hemospray has been used in 12 patients who developed upper gastrointestinal bleeding after therapeutic endoscopic interventions.20 Bleeding occurred after esophageal endoscopic mucosal resection (EMR) in 5 patients, after duodenal EMR in 4 patients, after ampullary resection in 2 patients and after biliary sphincterotomy in 1 patient. Lesion diameter ranged from 10 mm to 90 mm. Hemospray was used as initial therapy in 8 of these patients and as rescue therapy (after standard hemostatic therapy failed) in 4 patients. Recurrent bleeding was suspected but not confirmed on repeat endoscopy 48 hours after Hemospray application in two of the 12 patients. No recurrent bleeding occurred in any of the 12 patients during follow-up at 7 days and 30 days post-treatment. In the only published U.S. case report of Hemospray, a young patient with a metal biliary stent placed for malignant biliary obstruction developed a bleeding duodenal ulcer from stent migration.⁸ Because of its location and anatomic distortion, conventional endoscopic hemostatic interventions failed and the patient continued to bleed despite gastroduodenal artery embolization. An investigational device exemption was approved for use of Hemospray, and hemostasis was finally achieved. The patient was discharged home 6 days later with no further bleeding episodes.

Lower Gastrointestinal Bleeding

Lower gastrointestinal bleeding accounts for 20-40% of acute gastrointestinal bleeding cases. This type of bleeding can be massive and therefore requires prompt and durable hemostasis. Conventional hemostatic modalities include clips and thermal coagulation.⁹ The role of Hemospray in lower gastrointestinal bleeding has recently been studied. In a multi-center European case series by Holster et al., nine patients with active lower gastrointestinal bleeding of various causes (post-9 patients (22%) within 7 days. Both of these patients polypectomy, colorectal anastomosis, rectal ulcer, were on aspirin and had initial pulsatile arterial bleeds. diverticular, proctitis and cecal adenocarcinoma) were Successful hemostasis was eventually achieved in these treated with Hemospray, either as initial or salvage patients with clip placement and arterial embolization. therapy.⁹ Immediate hemostasis was successful in all Soulellis et al. were the first group to report 9 patients (100%), but re-bleeding occurred in 2 of the additional clinical uses of Hemospray.²³ Indications included post-polypectomy bleeding, after conventional hemostatic therapy with clips, thermal probe, and epinephrine injection had failed. Hemospray was also used successfully in a left-sided colonic Dieulafoy’s lesion after clip placement and epinephrine injection failed. Lastly, the investigators also reported its use in radiation proctopathy after argon plasma coagulation caused more bleeding. Granata et al. described a single case report of Hemospray application for refractory cecal ulcer bleeding in a patient with influenza A (H1N1) virus who was being treated with extracorporeal membrane oxygenation for respiratory failure.²⁴ Re-bleeding had occurred after initial hemostasis with fibrin glue injection, whereas rescue therapy with Hemospray resulted in durable hemostasis.

Cautionary note and CompliCations

A recent review suggested that because the Hemospray powder only binds to actively bleeding sites, its short contact time on the lesion may limit its use as monotherapy and may contribute to re-bleeding. Feared complications of Hemospray use include bowel obstruction, systemic embolization and perforation. There have been no reports of bowel obstruction to date. Due to fear of systemic embolization, the manufacturers do not recommend use of Hemospray in variceal bleeding (where theoretically the powder could enter the venous circulation and embolize). However, some authors report that the outflow pressure of the device (when used correctly) is 12 mmHg, which should be less than intravariceal pressures, suggesting the embolization risk may be overstated.²³ In the available published literature where Hemospray was used in esophageal and gastric varices, there was no clinical evidence of systemic embolization. There has been only one reported case of perforation after endoscopic application of Hemospray in a patient with active portal hypertensive gastropathy-related bleeding. It was unclear whether the perforation was a result of endoscopy itself or directly due to the application of Hemospray.6 This potential risk is related to the requisite carbon dioxide pressure used during application, which is approximately 12 mmHg with the catheter 1 to 2 cm from the target lesion, but reaches 55 mmHg if the catheter is incorrectly placed in direct contact with the mucosa.²³

There is one report of Hemospray causing transient biliary obstruction when applied to a bleeding biliary orifice after sphincterotomy done for biliary stone removal. Biliary patency was restored with water irrigation and prodding open of the papillotomy orifice, but caution is recommended when applying Hemospray near small orifices adjacent to bowel lumen, such as a biliary or pancreatic sphincterotomy site.²⁵ In one case series, a female patient experienced abdominal pain after each burst of Hemospray application that resolved on its own post-procedure.⁹ Device-related complications have included clumping of the powder within the catheter when the biopsy port is exposed to a moist or wet environment and transient adherence of the endoscope to the mucosa.^8,15

Summary

Hemospray has some distinct advantages over conventional endoscopic hemostatic modalities. It is easy to use and appears relatively safe and efficacious for various causes of both upper and lower gastrointestinal bleeding. Based on the limited available studies, it may have reduced efficacy in spurting arterial ulcer bleeds and in patients on ATT, primarily due to delayed re-bleeding that may exceed the residency time of the product more so than failure to achieve initial immediate hemostasis. In fact, Hemospray may be the most effective product available today in achieving immediate hemostasis. Unfortunately, Hemospray has not been compared in head-to-head controlled comparisons with conventional hemostatic therapies and hence the relative efficacy of this treatment is unknown. Hemospray has been

successfully used in combination with other therapeutic modalities in some cases, and when lightly applied, the mucosal topography is preserved.

Its greatest applicability is as rescue therapy in massive hemorrhage when other therapies fail, or as a bridge to more definitive therapy (such as transferring the patient to a more specialized center, application in the context of a marked coagulopathy or in active variceal bleeding as a bridge to TIPS or band ligation under more controlled conditions). It may also be particularly adapted in diffusely bleeding lesions that involve large surface areas, especially in malignant bleeding in which the noncontact application may be particularly advantageous. While Hemospray appears promising as an adjunctive endoscopic hemostatic agent, prospective, controlled studies and resulting cost-effective analyses are urgently needed before more specific recommendations can be made regarding its use in patients with gastrointestinal bleeding.

A Case Report

Intrahepatic-Ductal Papillary Mucinous Neoplasm: A Real Disease Entity

April 2014 • Volume XXXVIII, Issue 4

Megha Kothari,Matthew Grossman,Gregory Haber

INTRODUCTION

A rare and recently emerging papillary subtype of biliary intraductal neoplasms is intraductal pancreatic mucinous neoplasm of the bile duct (B-IPMN). B-IPMNs have histological and clinicopathological resemblance to pancreatic IPMNs. These rare tumors represent approximately 8.3-29.9% of all biliary neoplasms and more likely to occur in males between the ages of 39 and 71. Patients most commonly experience abdominal discomfort (65%), jaundice (39%) and weight loss (35%), which are related to mass effect. In comparison to pancreatic IPMN, B-IPMN have a greater malignancy potential, 83% vs. 30%. However, they harbor a favorable outcome with aggressive surgical resection.

Case Presentation

A 67 year-old Chinese female was referred to our center with recurrent right upper quadrant abdominal pain and intermittent fevers over the past year, worsening in the last month. Her history included a cholecystectomy 16 years ago for symptomatic gallstones. The patient’s labs were within normal limits, except for an elevated carcinoembryonic antigen (CEA) level of 206 ng/ml (normal range 0-3 ng/ml). An initial abdominal ultrasound revealed a markedly dilated common bile duct (CBD) to approximately 3 cm. Magnetic resonance cholangiopancreatography (MRCP) confirmed intra and extra-hepatic duct dilatation with a fusiform CBD measuring 2.8 cm (Image 1 and 2). No intrahepatic bile duct or CBD calculi were identified. Marked saccular dilatation of intra-hepatic bile ducts was seen in the lateral segment of the left lobe (segments 2 and 3). No pancreatic mass or pancreatic ductal abnormality was noted. An endoscopic retrograde cholangiopancreatography (ERCP) with direct cholangioscopy (Spyglass, Boston Scientific) was performed. The ampulla was noted to have a classic “fish-mouth” appearance – patulous with viscous mucin extravasating from the os. ERCP revealed papillary mucosal changes in the left intrahepatic duct near the saccular dilatation (Image 3). Multiple cold-forcep biopsies were taken from the area. Pathology noted fibrous tissue with mild epithelial atypia. No carcinoma was identified. Given the findings, there was concern for an underlying papillary mucinous neoplasm and the patient was then referred for a left hepatectomy with resection of the common bile duct. Surgical pathology revealed a biliary intraductal papillary mucinous neoplasm (B-IPMN) with moderate epithelial dysplasia involving the left hepatic duct and periductal branches (Images 4-7).

Discussion

Biliary intraductal neoplasms are found to occur as either intra or extrahepatic lesions. A rare and recently emerging papillary subtype of biliary intraductal neoplasms is IPMN of the bile duct (B-IPMN). The two known subtypes are flat and papillary type.¹ However, B-IPMN have histological and clinicopathological resemblance to pancreatic IPMN. This is believed to be in part due to parallel embryological developments of the pancreatic and bile ducts from the hepato-pancreatic bud of the foregut.² B-IPMN differ from other biliary mucinous cystic neoplasms; they lack ovarian-like stroma and growth tends to occur along the biliary ducts, without confined cyst formation.³

These rare tumors represent approximately 8.329.9% of all biliary neoplasms.⁴ The wide range is likely due to variations in classification of B-IPMN.⁴ In a retrospective study of resected cholangiocarcinomas, Chu et al. found that B-IPMN are more frequently encountered in males between the ages of 39 and 71.⁴ A high correlation of B-IPMN is observed in patients with a history of choledocholithiasis, infections, pancreatic injury and biliary hyperplasia thus potentially defining some of the risk factors.¹ These lesions are thought to develop from stem cells of the bile ductules, lining of biliary epithelium glands or epithelium of peribiliary glands.⁵

Although very little is known regarding the molecular pathogenesis of the B-IPMN, the idea of microsatellite instability has been postulated. Susan at el. extracted DNA samples from B-IPMN lesions, invasive cholangiocarcinoma and normal tissue to find high occurrence microsatellite instability, particularly in B-IPMN. Importantly, they noted that the patterns of allelic shifts were different between relatively benign IPMN and invasive cholangiocarcinoma lesions, indicating a high level of genetic heterogeneity in these neoplasms.⁶ This variation may in part contribute to their difference of varying malignant potentials.

B-IPMN exhibit mucosal spread along the bile duct lumen and cause mucin hypersecretion, often resulting in polypoid or sessile growths;^3,5 therefore, ducts may exhibit marked dilatation. Tumors are often confined within the dilated part of the bile ducts.³ Occasionally, hepatic parenchymal atrophy has been observed due to long-standing elevated ductal pressures, resulting in partial obstruction.⁵ This may be accompanied by compensatory hypertrophy of a “normal” hepatic lobe.⁵ However, mass effect related symptoms may not always be present with B-IPMN. Symptoms usually appear when a mass enlarges to cause pressure on the liver capsule.⁵ Lim at al. reported that the most common symptom presentations are abdominal discomfort (65%), jaundice (39%) and weight loss (35%).⁷

In comparison to pancreatic IPMN, B-IPMN had a greater malignancy potential, 83% vs. 30%.² B-IPMN range from benign to malignant based on histological criteria. One classification scheme categorizes the tumors as adenomas, borderline tumors, carcinoma in situ or carcinomas.¹ Another classification system is based on histology and genetic expression, which has significant roles in carcinogenesis and tumor invasion. Histologically, B-IPMN can be classified as intestinal, pancreatico-biliary, gastric or oncocytic; while gene expression is classified as MUC1, MUC2, and MUC5 genes.¹ Higashi et al. found that MUC1 expression and the absence of MUC2 correlated with increased aggressiveness and subsequently a poor outcome in pancreatic ductal adenocarcinomas. Subsequently, isolated MUC2 and MUC5 expression poses a more favorable outcome for B-IPMNs.^1,5,8

Ultrasound and MRCP are the initial non-invasive studies for assessment of IPMN lesions. It is important to note that ERCP fails to delineate intraductal papillary changes along the ductal border; thus, cholangioscopy and/or intraductal ultrasonography (IDUS) are the most sensitive and specific modalities for diagnosing and localizing papillary tumors. The presence of a large amount of viscous mucin within the duct can make cholangiogram imaging difficult. Cholangioscopy proves to be better than IDUS to diagnose the extent of tumor.⁹

A recent case report presented a large B-IPMN, which was resected via a right sided trisectionectomy and caudate lobectomy.¹⁰ The authors note that complete surgical resection usually has a favorable prognosis; therefore, aggressive surgery needs to be recommended regardless of tumor size and extent.¹⁰ Favorable prognosis of B-IPMN is likely due to the theory that these tumors do not aggressively invade the bile duct wall unless there is transformation to tubular adenocarcinoma or mucinous adenocarcinoma.¹¹

CONCLUSION

In conclusion, B-IPMN are rare neoplasms which harbor a favorable outcome with aggressive surgical resection. Biliary mucinous cystic neoplasm, mass-forming type intrahepatic cholangiocarcinoma with choledochal cysts and recurrent pyogenic cholangitis with choledocholithiasis are among the differentials for B-IPMN lesions.⁹ However, biliary IPMN should be considered when bile duct dilatation and hepatic parenchymal atrophy is seen. This area warrants further investigation to devise a classification system and treatment options.

Unusual Causes of Abdominal Pain, #3

Unusual Causes of Abdominal Pain

April 2014 • Volume XXXVIII, Issue 4

George W. Meyer

CASE

A 44 year old man presents with a complaint of episodic abdominal pain and fever beginning at age 27. He emigrated to the United States as a young adult from his home in Catania, Sicily. Typically these episodes last roughly 24 hours and occur monthly but have recently increased in frequency. Right shoulder pain, 1-2 hours before the onset of his symptoms, would occasionally precede sudden, severe subxiphoid stabbing pain radiating to the back. Progression would include generalized abdominal pain. The associated fever would last 6-12 hours; there is no vomiting but diarrhea has occurred. When evaluated in the emergency department (ED) his white blood cell count (WBC) and erythrocyte sedimentation rate (ESR) were both elevated. Although resolution of the fever and pain occur within 24 hours, these events cause exhaustion for the next 24 hours. A therapeutic trial was initiated.

Answer and Discussion

Familial Mediterranean Fever (FMF), inherited by autosomal recessive means, affects mostly those whose families have come from around the Mediterranean Sea, such as Sephardic Jews, Armenians, Turks, North Africans and Arabs. Greeks and Italians are less often affected. Most of those who suffer with this disorder develop symptoms in their first decade and 90% are symptomatic by the age of 20. The typical patient will develop sudden onset of fever and abdominal pain (sterile peritonitis), which may last 1-3 days and resolve spontaneously. They may also have pleuritis, synovitis, pericarditis, a skin rash that looks like erysipelas, or orchitis. The abdominal exam may simulate acute peritonitis (guarding, rebound tenderness, rigidity and ileus), leading to exploratory surgery. Abnormal lab results may include elevated WBC, ESR, and CRP. Treatment with colchicine is dramatic in ~75% of patients (fewer than 1 episode in 6 months), usually 0.6 mg per day but as high as 1.8 mg may be needed daily. At least half of non responders were noncompliant patients. The major complication of untreated FMF is amyloidosis (AA type), which may develop after several decades. Differential diagnosis, to be especially considered if the patient does not respond to colchicines, should include: tumor necrosis factor receptor-1-associated periodic syndrome (TRAPS), hyper-IgD syndrome, Muckle-Wells syndrome, and familial cold autoinflammatory syndrome. Genetic testing for FMF is available but is not very sensitive.