Page 61 – Practical Gastro

Julie Nguyen,Swathi Paleti,John A. Bonino

INTRODUCTION

Nocardia is an intracellular pathogen with the potential to cause life-threatening disease, particularly in immunocompromised patients. Based on long-term data (nine years, 2000 patients), the incidence of Nocardia infection has been estimated at 0.01% in patients taking adalimumab.¹

The diagnosis of Nocardia is often limited by clinical suspicion and local expertise of the diagnostic laboratory.²

Case Description A 36 year old male with a history of Crohn’s disease, on chronic adalimumab therapy, presented to the emergency department after he sustained a forehead laceration while working in his backyard. The wound was cleansed in standard fashion and sutures placed. Later, during suture removal, he was noted to have a small single draining pustule. He was then prescribed a seven day course of oral trimethoprim-sulfamethoxazole.

Over the course of several days, he developed tender lymphadenopathy and fever prompting cessation of adalimumab and subsequent hospitalization. Wound cultures were obtained and subsequently grew Nocardia arthritidis.

Due to the development of a persistent cough, a computed tomography (CT) of his chest demonstrated multiple pulmonary nodules, some with cavitation. He was subsequently treated with a combination of intravenous (IV) trimethoprim-sulfamethoxazole and meropenem with improvement of his pustules and near complete resolution of the pulmonary nodules on subsequent imaging.

Discussion

Tumor necrosis factor (TNF) is a cytokine produced by activated monocytes, macrophages and T lymphocytes involved in cell-mediated immunity. TNF interacts with other cytokines, including interferon-delta, to generate an immune response to intracellular pathogens such as Myobacterium tuberculosis, Listeria, Histoplasma and Nocardia. Disruption of this pathway by anti-TNF medications, such as adalimumab, may increase rates of infection by such organisms.³

Nocardia are soil-borne, gram-positive, facultative intracellular bacteria. They are ubiquitous and found worldwide in dust, sand, soil and bodies of water. Respiratory transmission is presumed to be via contact with dust particles contaminated by the organism.⁴

Nocardia has a predilection for the lungs due to its ability to aerosolize, but infection may also occur via the skin or central nervous system.^5,6

Cutaneous infections typically occur through open wounds contaminated with soil. Lesions may manifest as localized abscesses and mimic infection from pyogenic bacteria. Infection may also spread to regional lymph nodes and mimic sporotrichosis.²

The laboratory diagnosis of Nocardia requires a high level of suspicion, since these organisms are slow-growing and may lead to premature disposal of cultures. Histologically, Nocardia are strictly aerobic bacteria with branching filamentous structures. Standard blood cultures are rarely found to be positive. Confirmation and speciation require specialized polymerace chain reaxtion (PCR) testing.⁴

Initial antibiotic therapy includes IV trimethoprim- sulfamethoxazole for a minimum of three weeks. After three weeks, patients without immune dysfunction may be switched to oral trimethoprim-sulfamethoxazole until infection resolution. For those who are immunocompromised, duration of treatment may be extended beyond six months.⁷

The prognosis is poor (mortality rate >50%) for immunocompromised patients with disseminated nocardiosis, even those treated with appropriate antibiotics.^5,8

CONCLUSION

Cutaenous Nocardiosis should be considered in inflammatory bowel disease patients on anti-TNF therapy presenting with atypical or difficult to treat cutaneous infections to ensure timely diagnosis and treatment.

Frontiers In Endoscopy, Series #34

Endoscopic Management of Large Duodenal Adenomas

Jeffrey H. Lee

Duodenal adenomas are often incidentally detected during routine upper endoscopies, yet data regarding effective management are scarce. With advances in endoscopic tools and techniques, duodenal adenomas are increasingly managed endoscopically. There are two main endoscopic resection techniques: endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). Compared to EMR during colonoscopy, EMR in the duodenum is much more arduous and complications are more problematic to manage. In this article, all practical points on how best to perform duodenal adenoma resection and data on follow-up are reviewed.

Duodenal adenomas are often incidentally detected during routine upper endoscopies, yet data regarding effective management are scarce. Owing to the potential for malignant transformation, duodenal adenomas should be excised whenever possible. Traditionally, surgical resection was the mainstay in removing duodenal adenomas. However, due to the anatomic location of the duodenal adenomas, surgeons often faced difficulties requiring extensive segmental resection or pancreaticoduodenectomy. With advances in endoscopic tools and techniques, duodenal adenomas are increasingly managed endoscopically. There are two main endoscopic resection techniques, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). While most endoscopists are unfamiliar with the techniques of ESD, they are well acquainted with EMR, largely from frequent necessity during colon polyp removal. Compared to EMR during colonoscopy, however, EMR in the duodenum is much more arduous and complications are more problematic to manage. In this article, all practical points on how best to perform duodenal adenoma resection and data on follow-up are reviewed.

INTRODUCTION

Duodenal adenomas may occur sporadically or as a part of familial adenomatous polyposis (FAP) syndrome. FAP patients are more likely to present with multifocal disease than patients with sporadic adenomas.¹ Adenomas in the duodenum may occur at the ampulla or non-ampullary locations. The strategy in managing ampullary adenomas is markedly different than that of non-ampullary duodenal adenomas (NADA). In this review, we will only focus on NADA.

Duodenal adenomas may progress to carcinomas, somewhat resembling the process of colon adenoma to carcinoma sequence.² Cassani et al., in a retrospective study of 213 patients at a tertiary referral cancer center, reported while there was no difference between FAP and sporadic groups with progression to new dysplasia or cancer when observed without intervention, there was a significant difference in overall survival between the FAP and sporadic groups (P < 0.001). The range of time of progression to cancer was 3-161 months.

Therefore, observation is not ideal in managing duodenal adenomas, which leaves the affected patients with two alternate options: 1. Surgical resection 2. Endoscopic management with resection and/or ablation.

Management of Large Non-Ampullary Adenomas

Surgical resection of NADA often presents challenges mainly from location of the polyps in the duodenum. Compared to operations involving the stomach or colon, the surgical approach to the duodenum is demanding as it is bordered by other major organs in the retroperitoneal space.³

The goal of surgical resection would be primary resection and anastomosis of the duodenum; however, it is often not possible to have such an outcome, either secondary to the particular location of the polyp and/or the extent of polyps, thus resulting in duodenal resection, combined with jejunal anastomosis. Furthermore, as the pancreatic duct and bile duct join at the ampulla, patients may face pancreaticoduodenectomy for NADA when the adenoma involves the medial wall near the papilla in the second portion of the duodenum. Therefore, patients and surgeons frequently choose or advocate endoscopic means of therapy for NADA. While technically facile, endoscopic ablations by argon plasma coagulation (APC) or heater probe are not suitable in most cases, because the ablative attempt would not be able to cover the entire adenomatous area owing to the size of the adenoma(s). Consequently, patients and providers resort to endoscopic resection (ER) in managing NADA. In general, there are two ER techniques; endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). There are pros and cons in each technique. EMR is technically less challenging to perform than ESD, but provides multiple segmented specimens making it impossible to assess lateral-margin status. On the other hand, ESD provides the specimens in one piece allowing accurate evaluation of lateral-margins. Even though endoscopic resection has been successfully performed by EMR or ESD for benign mucosal and early malignant tumors in various locations of the gastrointestinal tract, ESD in the duodenum should be attempted only by experts with thorough preparation and discussion of the options with the patient and surgical colleagues; such discussions should consider technical difficulty, thinness of the duodenal wall, and the risk of immediate or delayed perforation.

Endoscopic Management of Large Non-Ampullary Duodenal Adenomas

1. Endoscopic Visualization of Duodenal Adenoma and Defining the Margins for Resection

To improve visualization of adenomas in the duodenum, one may use chromoendoscopy techniques by spraying diluted methylene blue or indigo carmine. However, preparation of the solution and spraying the dye necessitate additional steps in the resection procedure. With the advent of narrow band imaging (NBI) technology, the duodenal polyps can be better detected, obviating the need to employ the coloring agents. Once the margins are clearly visualized, the planned resection margin should be marked using a hot snare or ESD knife.

2. Preparation for Endoscopic Resection

Before the initiation of ER, intubation should be considered to protect the patient’s airway as the endoscope may be repeatedly advanced into the duodenum during the resection process. Regarding solutions to inject into the submucosal layer, there are multiple candidates with varying viscosity. The higher the viscosity, the longer the submucosal lift will last. Among the most viscous solutions are hyaluronic acid and hydroxypropyl methylcellulose, which are relatively inexpensive, but not readily available in the United States. Other viscous solutions include hypertonic solutions of sodium chloride (3.0%), dextrose (20, 30, or 50%), glycerol, and albumin. Albumin is ubiquitous in hospitals, yet expensive. Normal saline solution (0.9%) is inexpensive, available, and easy to inject. Though viscous solutions are often necessary for ESD, it is not imperative to have such solutions in EMR, where saline solution mixed with epinephrine may be readily used.

3. Techniques of Endoscopic Mucosal Resection

3a. Injection-assisted EMR

In this technique, a mixture of solution is prepared by injecting 10 cc of epinephrine (1:10,000) to either 250 mL or 500 mL of normal saline. Usually, a small amount of indigo carmine or methylene blue is added to provide blue color on the sub-adenomatous base after EMR. Once the solution is prepared, 10 cc aliquots can be made using syringes. Submucosal injection is performed by advancing the injection needle at the normal mucosa near the endoscopic edge of the polyp. To avoid transmural injection, the needle should be introduced as injection is being applied. Once the submucosal bleb is created, further injection of the solution should be carried out observing continuing elevation of the mucosal layer. There is no need to raise all areas of the edge before commencing on resection. Resection can be carried out using either cut or coagulation electrocautery with a preferred setting. Most endoscopists use blended cutting (more cutting than coagulation), rather than coagulation settings. This is because of the feared complication of delayed perforation from transmural thermal injury. There are no firm recommendations where EMR should begin in terms of location; EMR may be initiated at the proximal or distal end, or right or left edges, whichever would be strategically advantageous for complete resection. In terms of snare size, 15 mm is sufficient. Use of a larger size snare increases the risk of grabbing too much tissue, including the muscularis propria layer, because the duodenal wall is quite thin and delicate. To ensure the muscularis propria layer is not involved in the resection, it is vital to loosen the snare slightly by shaking after grabbing the segment to be resected before applying electrocautery. Bleeding can usually be managed using a coagulation grasper while performing EMR. Before completing the EMR session, it is also essential to inspect the EMR base to ensure no adenomatous tissue is remaining and to prevent delayed bleeding. Any suspicious tissue or visible blood vessels in the resection base should be treated at the time of EMR. Experts of ER prefer using a coagulation grasper rather than APC for treatment of residual tissue or vessels. When APC is used, one may occasionally observe insufflation of submucosal tissue from emitted argon gas. The significance of treating the base after ER was well illustrated in the study by Lépilliez et al.; the authors reported that there was no delayed bleeding when the resected base was treated by endoscopic clipping or APC, in contrast to a 22% bleeding rate without the treatment.⁴

3b. Band Ligation-assisted EMR (EMR-L)

Although EMR-L is minimally invasive and easy to perform in the esophagus, stomach, and rectum, EMR-L should not be employed in resecting duodenal adenomas. Different from the walls of the esophagus, stomach, or rectum, the duodenal wall is very pliable and thus suctioning of the polyp to apply a band can bring the entire wall into the banding cap, resulting in perforation when resected (Figure 1). EMR-L is based on the technique of variceal band ligation. When there is a sessile or flat polyp, suction is applied to the targeted area, and subsequently a band is applied to create a pseudopolyp. Once the pseudopolyp is created, it is resected using a snare with electrocautery. In general, there are two sizes available in EMR-L kit (Duette Multi-Band Mucosectomy device, Cook Medical Inc., Winston-Salem, NC), one for the diagnostic upper endoscope and the other for the therapeutic upper scope (one to fit endoscopes with outer diameters of 9.5 to 13 mm and the other 11 to 14mm). It is important to select proper endoscope and the band ligation kit to ensure precise fitting of the device. It is recommended to place one band and immediately cut the segment, rather than placing multiple bands and cutting all banded areas in sequence. By slightly overlapping the cutting area, while avoiding injury to the muscle layer, one can avoid leaving slivers of adenomatous tissue in between the bands.

3c. Cap-assisted EMR (EMR-C)

In this technique, an EMR cap is attached to the tip of the scope and submucosal injection is performed using an injection needle and the aforementioned solution mixture. Then, an EMR snare provided in the EMR kit (Olympus America Inc, Center Valley, Pa) is placed in the internal groove of the EMR cap, creating a loop. Next, the targeted lesion is suctioned into the cap and the snare is fastened while suction is still being applied. One caveat is, as mentioned under EMR-L section, suction should be applied with caution. Full suction is likely to bring the full thickness of the duodenal wall into the cap, resulting in perforations when resected. Therefore, it is paramount to apply a controlled suction; one-half or less of vacuum suction should be applied when EMR-C is performed in the duodenum. Furthermore, this technique should be reserved only for the experts with extensive experience in ER. Even then, a multidisciplinary approach should be employed alerting surgical colleagues before EMR-C is planned due to perforation risk.

4. Endoscopic Submucosal Dissection (ESD)

While EMR provides multiple segmented specimens, ESD allows resection of the entire segment in one piece, thus allowing clear discernment of margin involvement. In ESD, following injection of one of the aforementioned solutions under the targeted lesion, the submucosa is dissected by an electrosurgical knife. Thus, ESD allows excision of larger and deeper lesions with curative intent than can be resected by EMR. ESD, however, requires an extensive dedicated training, including repetitive practice at ex-vivo and live animal lab as well as closely supervised attempts in human cases, in order to attain competency.

Data regarding the efficacy and safety of duodenal adenoma resection are scarce. Kim et al. reported the result of their retrospective observations of 64 lesions in 62 patients who underwent endoscopic resection of duodenal subepithelial tumors in an academic setting. Injection assisted EMR was performed in 38 lesions, EMR-L in 18, and ESD in 8. The overall en bloc resection and complete ER rates were 96.9% (62/64) and 100% (64/64), respectively while complete pathologic resection was 76.6% (49/64). Ironically, ESD was independently associated with incomplete pathologic resection. Strikingly, the procedure-related bleeding and perforation rates were 6.3% and 4.7%, respectively. Follow-up data were promising showing no recurrence in patients who underwent complete ER at a median follow-up of 20 months (range 6-112 months).⁵ In the study reported by Cassani et al., 47/213 patients (14 FAPs and 33 sporadic adenomas) underwent EMR of their adenomas and 46/47 achieved endoscopically complete resection. The deep margin was positive in 4 resections (9%). Evidence of recurrence was seen in 3 patients (6%). All recurrences occurred within 1 year of EMR.

Hoteya et al. compared the outcomes of EMR and ESD in 129 endoscopic resections for NADA.⁶ The authors performed 74 ESD (49 lesions > 20 mm, and 25 lesions < 20 mm in diameter) and 55 EMR procedures. In terms of technical outcomes, the authors concluded that EMR was safer than ESD for small size NADA as perforation and delayed bleeding were significantly higher in both ESD groups than in the EMR group. The authors felt prophylactic endoscopic closure of large mucosal defects after ESD was useful in preventing the complications. Navaneethan et al. reported a systemic review on the efficacy and safety of endoscopic resection of duodenal polyps; in total, the meta-analysis included 440 patients (485 duodenal polyps) from 14 studies.⁷ The mean size of polyps ranged from 13 mm to 35 mm with 1.9% being adenocarcinoma. The majority of the polyps were sessile (92%) and located in the 2nd portion of the duodenum. EMR was successful in 93% (95%CI 89-97%) with immediate bleeding rate of 16% (95%CI 10-23%), delayed bleeding rate of 5% (95%CI 2-7%), and perforation rate of 1% (95% CI 1-3%). In addition, APC was applied post-EMR in 29% of the procedures to ensure complete eradication of the dysplastic tissue. Surgical intervention was required in 12 patients after initial EMR (3%); of which 8 cases of non-curative EMR and 4 for procedure related adverse events (3 perforations and 1 hemorrhage).

Follow-Up of Large Non-Ampullary Adenomas After Endoscopic Resection

In our hospital, we routinely keep patients for observation for 1-2 days post ER with follow-up blood counts the morning after the procedure. To protect the ER site, proton pump inhibitor is given either intravenously or by mouth.

Regarding diet, the patient is kept fasting on the day of ER. On post-operative day 1, clear liquids are given, which are advanced to full liquids for the following 2 days, and then soft diet for the ensuing 3 days.

If the patient has abdominal pain or rebound tenderness, delayed perforation should be considered and excluded. If abdominal pain persists and/or increases, computed tomography (CT) of the abdomen with oral and intravenous contrast is indicated, along with surgical consultation. If CT is indeterminate, diagnostic and/or therapeutic upper endoscopic examination is warranted. If a small perforation is noted, attempts to close it endoscopically can be made along with urgent surgical consultation.

1. Delayed Perforation

Even after successful ER, monitoring for delayed perforation is advised, especially when the duodenal adenoma is large and located in the 2nd portion of the duodenum or distal to the ampulla. Ideally, leaving a thin submucosal layer over the muscularis propria would be ideal, but is not always possible. This is even more difficult to achieve when the ER base is tethered to the muscularis propria layer by fibrotic scar tissue. Scar tissue may form from previous vigorous biopsies and/or ablative therapy by heater probe, electrocautery, or APC treatment. Therefore, if ER is planned or considered, one or two small biopsies at the periphery of the lesion would be ideal. The concern for delayed perforation should be heightened if the muscle layer is exposed and/or damaged during ER. The biliary and pancreatic enzymes may auto-digest the exposed muscle layer. Therefore, if endoscopic closure is possible, the application of clips should be attempted. However, as the duodenum is fixed in the retroperitoneum, opposing the mucosal/ submucosal defect is not straight forward. Furthermore, if a clip is placed on the muscularis propria layer, it can cause immediate perforation or enlarge a perforation that had already occurred. To divert the pancreatic enzymes and bile, one may consider placing naso- biliary and/or naso-pancreatic tubes; but placing these tubes are technically challenging and uncomfortable to patients. To circumvent this enigma after EMR/ESD of NADA, Hochberger et al. recently introduced a novel approach of placing a vacuum sponge, 2.5 cm long and 1.8 cm wide (Endo-Vac; Braun, Melsungen Germany) in the duodenum through an overtube (US Endoscopy, Mentor, Ohio, USA).⁸ Using this technique, the drainage tube connected to the sponge was externalized via the nose, and suction of approximately125 mmHg was applied. The authors also performed endoscopic closure using over-the-scope clip and endoclips immediately after EMR/ESD to reduce or eliminate the unprotected area. EGD on post-procedure day 4 showed no signs of perforation and excellent wound healing upon retrieving the sponge. Surgical management of perforations depends on the amount of time elapsed between the time of perforation and timing of surgery. Immediate surgical intervention would allow primary repair or resection of the perforated segment with primary anastomosis. However, when there is a delay in surgical management, a significant amount of bile and pancreatic secretions may collect in the retroperitoneal space, complicating the operation. At the operation, pus may be found in the retroperitoneal space during irrigation and aspiration (wash-out). In this situation, primary anastomosis is not possible; thus diverting surgical resection and anastomoses would be performed along with placement of multiple drainage tubes at the pockets of fluid collections in the retroperitoneum by consultation with interventional radiology. The recovery from this type of operation is lengthy and arduous, especially in the elderly where a long-term physical and occupational therapy would be needed.

2. Surveillance for Recurrence

In the aforementioned meta-analysis of EMR, the recurrence rate after EMR was 15% (95% CI 7-23%) over a median follow-up of 6-72 months, and endoscopic resection of recurrent polyps was successful in 62% (9%CI 37-87%).⁷ Therefore, it is crucial to provide a continuing endoscopic surveillance in this population after ER. The first esophagogastroduodenoscopy (EGD) post-EMR is usually performed in 3 months when the ER site is carefully examined for any residual lesions or early recurrence. If any residual polyp or recurrence is detected, endoscopic resection, biopsy, and/or ablative therapy may be performed. If EGD is unremarkable, it would be reasonable to perform a surveillance EGD in 1 year and then annually for several years; provided that the original adenoma(s) were absent of high-grade dysplasia or carcinoma.

Future Management of Large Duodenal Adenomas

Ichikawa et al. reported the safety and feasibility of laparoscopic and endoscopic cooperative surgery (LECS) for early non-ampullary duodenal tumors in 12 patients.⁹ In this study, 13 early duodenal lesions (10 adenocarcinomas, 2 neuroendocrine tumors, and 1 adenoma) in 12 patients were managed by LECS. All submucosal tumors were successfully resected en bloc and the defect in the duodenal wall was sutured after resection. For epithelial lesions, ESD was performed and the base of the ESD was reinforced via manual suturing. Notably, there were two intraoperative perforations in 2/11 epithelial lesions while ESD was being performed; these were successfully repaired via laparoscopic approach. The median procedure time was 322 minutes with no significant blood loss; 1 patient had minor leakage due to a pancreatic fistula.

The LECS technique emphasizes the importance of a multidisciplinary approach for this challenging task. As was previously emphasized, the most feared complication of duodenal adenoma resection is perforation. If the size of the perforation is small and surrounding mucosa and submucosal layers are available, it would be reasonable to attempt endoscopic closure using clips. However, when the size of perforation is greater than 2 cm, it would be difficult to close it by placing clips. Endoscopic suturing (ES) would be valuable in this situation, however ES is a difficult procedure to master and attain proficiency.¹⁰ While ES is being performed, more carbon dioxide can be introduced into the peritoneum, as well. It is imperative to ensure no pooling of fluid at the site of perforation, while ES is being attempted, by repositioning the patient as appropriate. Future research should focus on developing artificial tissue that can be sprayed to cover the perforation immediately (for example, such as fibrin glue or cyanoarylate);^11,12 this material would adhere to the mucosa creating instantaneous cover at the perforation.

CONCLUSION

Duodenal adenoma resection is a daunting task, which requires careful planning prior to attempted resection. The patient and the family should be invited to partner with providers in discussing therapeutic options, risks involved, and potential complications with their consequences. It would be ideal to discuss the case at multidisciplinary conference, in order to 1. find the best approach for effective treatment, and 2, seek early and active involvement of a surgeon as perforations are grave adverse events in a significant minority of patients. Following successful ER, the patient should be closely monitored for delayed complications and recurrence. Future endeavors should focus on development of effective and convenient diversion of biliary and pancreatic secretions in the duodenum, potential tissue covering/protectants and/or easier endoscopic suturing systems to solve the conundrum of endoscopic perforation management.

Nutrition Issues In Gastroenterology, Series #160

The Use of Medium-Chain Triglycerides in Gastrointestinal Disorders

Neha D. Shah,

Berkeley N. Limketkai

Medium-chain triglycerides (MCTs) are lipid molecules that are more readily absorbed and oxidized than most lipids. This unique characteristic of MCTs has led to interest in their use in the management of several gastrointestinal disorders, where MCTs have been primarily used to reduce fat malabsorption and to serve as a source of calories to optimize nutritional status. In this review, we discuss the composition of MCTs, its sources, and the roles that they potentially play in the treatment of various gastrointestinal disorders.

Structure

A fatty acid is a simple lipid molecule with a carboxylic acid group on one end and a hydrocarbon chain on the other.² The hydrocarbon chain length may range from 4 to 28 carbons and determines the classification of fatty acids: short chain (< 6 carbons), medium chain (6 to 12 carbons), long chain (13 to 21 carbons), and very long chain (≥ 22 carbons). Triglycerides are lipid molecules with three fatty acids attached to a glycerol backbone. Similar to simple fatty acids, the length of the fatty acid group determines the nomenclature of short- chain triglycerides (SCTs), medium-chain triglycerides (MCTs), and long-chain triglycerides (LCTs).

The presence of double bonds can vary within fatty acids. Saturated fatty acids do not contain any double bonds along the hydrocarbon chain, while unsaturated fatty acids do. Monounsaturated fatty acids contain a single double bond, while polyunsaturated fatty acids contain two or more double bonds. Most fatty acids can be endogenously synthesized, except for two long-chain polyunsaturated fatty acids: linoleic acid (18 carbons with 2 cis bonds at C9 and C12) and linolenic acid (18 carbons with 3 cis bonds at C9, C12, C15); these are considered essential fatty acids (EFAs) and must be obtained from the diet.

The fatty acid groups of MCTs include caproic acid, caprylic acid, capric acid, and lauric acid. Compared with LCTs, MCTs are smaller in molecular weight, water soluble, rapidly oxidized for energy, possess a lower smoke point (the temperature when volatile substances are produced and a blue-colored smoke is seen as a result of oxidation of oil) and are liquid at room temperature. MCTs only contain saturated fatty acids and therefore do not contain either of the EFAs, linoleic and linolenic acid. As MCTs do not contain EFAs, they also do not serve as a precursor to the synthesis of eicosanoids. MCTs provide fewer calories per gram than LCTs, 8.3 vs. 9.2, respectively.

Digestion and Absorption

The length of the fatty acid influences the process of its digestion and absorption within the gastrointestinal tract. The entry of triglycerides as LCTs from the stomach into the duodenum stimulates the enteric secretion of the hormone cholecystokinin (CCK) and pancreatic enzymes from the pancreas. CCK promotes further release of bile from the gallbladder to help emulsify the triglycerides into smaller fat droplets to maximize its digestion.3,4 Pancreatic lipase then cleaves the fatty acid chains from the triglycerides to form individual fatty acid molecules that then aggregate into micelles. Micelles are absorbed into the enterocytes along the intestinal brush border via passive diffusion or are shuttled by fatty acid transporters. Once in the enterocytes, the fatty acids are transported into the endoplasmic reticulum, reconverted into triglycerides, and packaged into chylomicrons.

The chylomicrons are released via exocytosis, enters and travels through the lymphatic system and eventually, drains into the subclavian vein to reach the bloodstream. In the intracellular space, long-chain fatty acids bind to carnitine for transport into the mitochondria for subsequent B-oxidation. In carnitine deficiency states that contribute to severe protein malnutrition (e.g., chronic malabsorption, small bowel obstruction, starvation), these long-chain fatty acids cannot be efficiently utilized and instead lead to accumulation of unoxidized fatty acids and impairment of ureogenesis, ketogenesis, and gluconeogenesis.⁵ Clinical sequelae may include hepatic steatosis, hepatomegaly, myopathy, and altered mental status.

By contrast, MCT digestion is rapid and simple. MCTs do not stimulate CCK secretion.^3,4 MCT absorption occurs via passive diffusion along the gastrointestinal tract into the portal system bound to albumin. No further packaging or modification of the MCT molecules is required. Moreover, MCTs are not dependent on the carnitine acyltransferase system for transport into the mitochondria for B-oxidation.⁵ This provides the ability for more rapid metabolism of MCTs and improved utilization even in states of protein deficiency (Table 1).

Sources

Most fats and oils of animal and plant origin contain LCTs (e.g., fish, avocado, nuts, seeds, corn, peanut, safflower, and soybean oil). By contrast, natural sources of MCTs include coconut oil and palm kernel oil, although these oils also contain LCTs. Commercial MCT formulations may either be comprised of naturally- derived MCT oil, 100% synthetic MCT oil (produced from medium-chain fatty acids that are hydrolyzed from coconut or palm kernel oil, purified, and then re- esterified onto a glycerol backbone), physical mixtures (blend of MCTs and LCTs), or structured lipids⁶ (Table 2). Structured lipids are synthetic lipid molecules with a mix of medium-chain and/or long-chain fatty acids attached to a glycerol backbone. In the clinical setting, it is not uncommon for healthcare professionals to tell their patients to use coconut oil to obtain MCTs. However, depending on the circumstance, this may worsen fat malabsorption due to the LCT content. Semi- elemental and elemental enteral formulas typically include MCTs to minimize need for digestion prior to absorption, although LCTs may also be included as a source of EFAs (Table 3). Clinical applications may include malabsorption disorders from pancreatic insufficiency or severe small bowel disease.

Dosage

Excessive intake of oral MCT oil has been associated with gastrointestinal distress, such as abdominal discomfort, cramping, gassiness, bloating, and diarrhea. A tablespoon (15 mL) of MCT oil contains 14 grams of fat and 115 calories. A maximum daily dose of 50-100 grams has been suggested for improved gastrointestinal tolerance; this is equivalent to 4-7 tablespoons (60-100 mL) per day (56-98 grams of fat and 460-805 calories).¹ The daily dose of MCTs should be increased as tolerated to the maximum daily dose, while equally dividing the dose across all meals. The MCTs can be easily mixed into a variety of foods and beverages. If MCTs are used in cooking, the temperature should be kept below 150° C (302° F) to reduce risk of its oxidation, otherwise the flavor of the food could be affected.¹ A tablespoon of MCT oil can also be administered through a feeding tube using a syringe along with a 30 ml water flush before and after its administration (See Table 4). In the severely fat-restricted patient, a source of EFAs will need to be provided in the diet along with MCT supplementation to prevent EFA deficiency. MCT oil does not require a prescription. Although MCTs possess unique characteristics, it is not considered to be a panacea and its use is intended to be administered along with other therapies to treat a disorder.¹

Use in Gastrointestinal Disorders
Pancreatic Insufficiency

Pancreatic insufficiency is characterized by a disruption in the exocrine function of the pancreas, which may result in decreased synthesis and/or release of pancreatic enzymes that normally assist in digestion of nutrients in the small bowel, particularly dietary LCTs. It may arise in acute or chronic pancreatitis, cystic fibrosis and as a consequence of pancreatic resection. The primary intervention for pancreatic insufficiency is pancreatic enzyme replacement therapy, and occasionally, acid- suppression therapy. There are limited studies at this time investigating the impact of oral MCT oil in pancreatic insufficiency. However, as MCTs do not require pancreatic enzymes for digestion, it is reasonable to consider them as a source of supplemental calories in these patients if needed.⁴

In chronic pancreatitis, there is interest in using MCTs to help reduce post-prandial pain. A small study of 8 adult pancreatic enzyme-sufficient patients with chronic pancreatitis found that consumption of an elemental enteral formula containing MCTs (69% of the total fat content; 9.8 grams per can), at least 3 times per day for 10 weeks, and <e; 20 grams of fat from the diet per day, resulted in minimal increases in serum CCK levels and a significant reduction in post-prandial abdominal pain.⁷ A study of 17 children with cystic fibrosis found no difference in absorption rates between a polymeric enteral formula (Isocal) with pancreatic enzyme replacement and elemental enteral formula (Peptamen) containing MCTs without enzyme replacement.⁸

Chyle Leaks

Chyle is a turbid or milk-colored fluid that primarily consists of LCT-containing chylomicrons and lymphatic fluid. Chyle originates in the small bowel where chylomicrons are formed and absorbed into the lymphatic system via the lacteals. Chyle then passes through the lymphatic system and enters the venous circulation via the thoracic duct. An obstruction or injury to the lymphatic system may result in a chyle leak into the pleural, pericardial, or peritoneal space. Common causes of chyle leaks include neoplasia, infection, radiation, and trauma.

The nutritional management of a chyle leak may initially include consumption of a fat-restricted or a fat-free diet, elemental enteral nutrition with MCTs, or a high-protein diet with MCT supplementation.^9,10

These interventions should only be used for the short term (approximately 2 weeks), as there is a risk of developing EFA deficiency with prolonged restriction of dietary LCTs. Once the chyle leak is closed, foods can be gradually re-introduced into the diet. If the chyle leak continues to persist despite these interventions, then parenteral nutrition is indicated. With parenteral nutrition, there is no need to restrict intravenous lipid emulsions, as they completely bypass the gastrointestinal tract and lymphatic system.

Three cases have been reported on the successful use of oral and/or nasogastric enteral feeding with MCTs for chylous fistulas that developed after neck dissections.¹¹ The patients had closure of their fistulas after two weeks on MCTs. In a retrospective review of 245 patients that underwent pancreatoduodenectomy or a total pancreatectomy, 40 patients who developed a chyle leak were placed on an MCT-containing enteral formula until they were able to transition to a fat free diet with oral MCT supplementation.¹² All patients experienced a decrease in chyle output without requiring surgical intervention or parenteral nutrition.

Short Bowel Syndrome

Short bowel syndrome (SBS) is defined by a significant anatomic (or functional) reduction in small bowel length, thus leading to compromise in the digestive and absorptive capacity of the small bowel. Significant malabsorption observed in these patients often manifest as diarrhea, unintentional weight loss, and fluid and electrolyte disturbances. The rationale behind the use of MCTs in SBS is to provide calories that are efficiently absorbed with minimal need for prior digestion.

At this time, there are only a few early case reports that have demonstrated potential benefit of MCTs in SBS. One case involved a 65 year-old woman with 76 cm of jejunum, 20 cm of terminal ileum, and an intact colon, who was admitted for chronic diarrhea and unintentional weight loss 3 years after extensive bowel resection for adhesions.¹³ Another case involved a 69-year-old man with 120 cm of remaining small bowel (mostly jejunum), who was admitted with chronic diarrhea and unintentional weight loss 2 years after his extensive bowel resection due to mesenteric thrombosis.13 Fecal fat excretion was elevated in both patients when given a LCT-rich regular diet or enteral formula. When switched to a sole MCT-containing enteral formula, fecal fat excretion was reduced and the patients experienced weight gain. Both patients afterwards were placed on a fat-restricted (LCTs) diet for 8-10 months that was supplemented with MCT.

The influence of bowel anatomy on the benefits of MCTs is yet unclear, although early studies suggest that the presence of an intact colon plays a significant role. In a randomized cross-over study of 19 SBS patients (9 without a colon; 10 with a colon), participants were initially administered high fat diets with either LCTs alone or an equal mixture of LCTs and MCTs in which the source of the MCT was either a MCT-containing margarine or MCT oil.¹⁴ When switched from the LCT to LCT-MCT diets, patients with an intact colon had no difference in fecal volume, while those without a colon had an increase in fecal volume. Interestingly, patients with a colon also experienced an increase in fat and overall energy absorption on the LCT-MCT diet, although those without a colon only had a marginal increase in fat absorption and no improvement in overall energy absorption. The study investigators suggest that the colon serves as a major organ for absorption of the water-soluble MCTs, similar to short-chain fatty acids and unlike the insoluble LCTs. The lack of improvement in energy absorption among those with ileostomies and jejunostomies was attributed to increased carbohydrate and protein loss. The use of MCTs can be considered in the management of patients with SBS and an intact colon.

Potential Use in Other Disorders

Due to their integral role in physiologic function, MCTs may have potential benefit in several non-gastrointestinal disorders. A discussion of these benefits is beyond the scope of this review, although we present a few unique examples of MCT use in diverse conditions.

Obesity

Due to its influence on thermogenesis and satiety, MCTs have been proposed to reduce obesity by increasing energy expenditure, reducing food intake and decreasing fat deposition in adipose tissue.^15,16 A systematic review and meta-analysis of 13 randomized controlled trials in healthy adults showed that when compared with LCTs, MCTs reduced body weight, waist and hip circumference, total body fat, total subcutaneous fat and visceral fat.¹⁷ Serum lipid levels did not differ.

Cardiovascular Disease

In cardiovascular disease, MCTs have been proposed to reduce hyperlipidemia based on observations that indigenous populations with high consumption of coconut flesh have low incidence of cardiovascular disease. However, a review of 8 clinical trials and 13 observational studies on the effect of coconut oil consumption on cardiovascular risk indicated that there is not enough evidence to support this practice.¹⁸

Alzheimer’s Disease

In mild to moderate Alzheimer’s disease, MCTs have been investigated to improve cognition based on the theory that decreased glucose metabolism in the brain may result in cognitive and memory impairment, so using MCTs as an alternative energy source as ketones for the brain should potentially counteract this impairment. Small studies have shown modest improvement in memory recall after consumption of MCT.19

Epilepsy

The ketogenic diet, which is a high fat, low carbohydrate diet, is often used as a treatment for refractory childhood epilepsy. A Cochrane review of the traditional ketogenic diet for epilepsy concluded that the use of the diet appears promising in treatment of epilepsy, but further studies are needed.²⁰ While the ketogenic diet often consists of LCTs, the use of MCTs in the ketogenic diet may be more appealing due to their greater potential to yield ketones for rapid oxidation. The MCT-rich ketogenic diet would additionally require less fat in favor of more carbohydrates to afford greater variety in the diet. However, a randomized trial of 145 pediatric patients with refractory epilepsy found no difference in efficacy between the MCT diet and the traditional ketogenic diet.²¹

CONCLUSION

MCTs possess unique characteristics of digestion, absorption, and oxidation that lead to great interest in their use in the management of gastrointestinal disorders. The facile absorption of MCTs without the need for bile or pancreatic enzymes makes them a good source of calories in the setting of malabsorption and steatorrhea from diseases, such as pancreatic or bile insufficiency. Due to their ability to bypass the lymphatic system, MCTs can also serve as a lipid source for patients with chyle leaks. As MCTs do not contain EFAs, supplementation with EFA containing vegetable oils will be necessary after 3 weeks to avoid deficiency.10 Although studies are limited, MCTs may be considered as a supplemental calorie source either alone, or as part of an enteral product, in certain gastrointestinal disorders.

Dispatches From The Guild Conference, Series #1

Practical Use of Therapeutic Drug Monitoring of Anti-TNF Therapy in IBD

Konstantinos Papamichail,

Adam S. Cheifetz

Anti-tumor necrosis factor therapy has revolutionized the care of inflammatory bowel disease. However, 10-30% of IBD patients show no initial clinical benefit to anti-TNF therapy and over 50% after an initial response lose response over time. Therapeutic drug monitoring can better explain and guide the management of patients with a loss of response to anti-TNF therapy. This review will focus on the role of TDM in guiding therapeutic decisions in IBD.

Some of this primary non-response and the majority of the secondary loss of response is due to sub-therapeutic drug concentrations and/or the development of anti-drug antibodies. Therapeutic drug monitoring (TDM) can better explain and guide the management of patients with a loss of response to anti-TNF therapy (reactive TDM). Reactive TDM has also been proven to be more cost-effective compared to empiric dose escalation of anti-TNF therapy based only on symptoms. Preliminary data demonstrate that proactive TDM with drug titration to a target concentration applied in patients showing clinical benefit can optimize anti-TNF therapy efficacy and cost. This review will focus on the role of TDM in guiding therapeutic decisions in IBD.

INTRODUCTION

Anti-tumor necrosis factor (TNF) therapy is the cornerstone of the treatment of patients with moderate to severe Crohn’s disease (CD) and ulcerative colitis (UC).¹ Nevertheless, up to 30% of patients with inflammatory bowel disease (IBD) show no initial clinical benefit to anti-TNF therapy (primary non-responders) and over 50% lose response within the first year of therapy.^2,3 Mechanisms underlying these undesired therapeutic outcomes involve pharmacokinetic or pharmacodynamic issues. The first are associated with inadequate drug concentrations due to the development of anti-drug antibodies or an increased non-immune drug clearance, while the latter are related to a non-TNF driven inflammatory process.2,3

Numerous exposure-response relationship studies have demonstrated that higher serum anti-TNF drug concentrations are associated with favorable objective therapeutic outcomes during both induction and maintenance therapy (Table 1).^4-24 On the other hand, low or undetectable drug concentrations are linked to anti- drug antibodies formation and treatment failure.3,25-27 These data suggest that in addition to “treating-to- target’ we should also be ‘treating-to-trough’ and that early proactive optimization of anti-TNF therapy may achieve better long-term therapeutic outcomes.

Therapeutic drug monitoring (TDM), defined as the evaluation of serum drug concentrations and anti-drug antibodies, has rationalized the management of IBD patients who lose response to anti-TNF therapy and improved therapeutic decision making. Reactive TDM allows for more individualized treatment (personalized medicine) when a secondary loss of response occurs. Moreover, it better directs care and prevents unnecessary drug exposure in patients who are unlikely to respond to more anti-TNF therapy.³

Preliminary data show that proactive TDM with drug titration to a target trough concentration applied in patients in clinical response or remission can improve the efficacy and potentially cost-effectiveness of anti- TNF therapy.^28,29 Proactive TDM may also be useful to better guide therapeutic decisions in other clinical scenarios, such as re-introduction of anti-TNF therapy after a drug holiday³⁰ or discontinuation of anti-TNF therapy in patients achieving deep remission.^31,32 This review will focus on the practical role of TDM of anti- TNF therapy in clinical practice.

Reactive TDM

Reactive TDM can better explain and guide the management of loss of response to anti-TNF therapy in IBD and has been proven to be more cost-effective than standard-of-care.^33-35 Patients with sub-therapeutic or undetectable drug concentrations and no anti-drug antibodies benefit more from escalation of treatment (by increasing the dose or decreasing the interval) compared to those switched to another anti-TNF agent.36 Moreover, higher drug concentrations after dose escalation are associated with re-capturing clinical response and improved clinical outcomes.^37-39 On the contrary, patients with therapeutic or supra-therapeutic drug concentrations benefit more when changing out of class to a drug with a different mechanism of action, as there is probably a shift to non-TNF driven disease.³⁶ A recent study showed that infliximab and adalimumab trough concentration of >3.8 and >4.5 µg/mL, respectively, measured at the time of loss of response distinguished patients who had a better long- term outcome from alternative therapies compared to those who escalated the anti-TNF therapy or switched to another anti-TNF agent.40 However, considering the lower response rate to a subsequent biologic, the limited pharmacological options, and the lack of a clear drug threshold, in practice we typically dose optimize to drug concentrations of >10-15µg/mL before stopping infliximab or adalimumab. On the other hand, patients with high anti-drug antibodies do better when switched to another anti-TNF rather than further dose escalation.36 Vande Casteele and colleagues, showed that patients with antibodies to infliximab >9.1 U/ml when loss of response occurred had a 3.6 times higher risk to fail a subsequent infliximab dose optimization.⁸ There are several laboratories that offer TDM and it is critically important to understand the assay and how the antibodies are recorded (Table 2). A proposed treatment algorithm for using reactive TDM for anti-TNF therapy is shown in Figure 1.

Proactive TDM

Recent data demonstrate that proactive TDM can optimize efficacy and potentially cost of anti-TNF therapy.^28,29 An observational study from our center was the first to show significantly greater infliximab durability in IBD patients in clinical remission who underwent proactive TDM and dose optimization to a therapeutic trough concentration of 5 to 10µg/mL when compared to patients receiving empiric dose escalation and/or reactive TDM.²⁸ Subsequently, the landmark Trough Concentration Adapted Infliximab Treatment (TAXIT) trial demonstrated that proactive TDM to a target concentration of 3-7µg/mL was associated with less need for rescue therapy and a higher rate of detectable drug concentrations compared to clinically- based dosing.29 Moreover, this randomized controlled trial showed that during the initial optimization phase dose escalation in patients with CD and a suboptimal infliximab concentration significantly increased the number of patients in clinical remission with a concomitant decrease in CRP levels.²⁹ A proposed treatment algorithm for using proactive TDM for anti- TNF therapy is shown in Figure 2.

Though the above studies relate to patients in the maintenance phase of anti-TNF therapy, exposure- response relationship studies show that higher drug concentrations during, or early after, the induction phase are associated with improved therapeutic outcomes (Table 1). These data imply that early optimization, even during induction therapy, may better optimize the efficacy of anti-TNF therapy. In fact, moderate to severely active patients with significant inflammatory burden are likely to benefit the most from proactive TDM as they have an increased drug clearance which predisposes to lower drug concentrations and development of anti-drug antibodies. Although clinically relevant drug thresholds can vary based on the assay used and the therapeutic outcome of interest, we typically aim for post-induction concentrations > 10 µg/mL both for infliximab and adalimumab.

Another aspect of proactive TDM is to guide treatment de-escalation in patients with supra- therapeutic drug concentrations through dose reduction, interval prolongation and/or withdrawal of an immunomodulator (IMM). The rationale for this treatment de-escalation is to potentially maximize both safety and cost-effectiveness of anti-TNF therapy. In our study, 15% of patients either stopped or de-escalated infliximab therapy based on TDM without any negative impact on their long-term clinical outcomes.²⁸ Similarly, 27% of patients in the TAXIT trial underwent dose de-escalation resulting in a significant reduction of treatment costs without any deterioration of remission rates.²⁹ Another study showed that the great majority (90%) of patients with trough concentration >8µg/ mL who de-escalated infliximab therapy to a target concentration of a 3 to 7µg/mL remained in deep remission after a median follow up of 8 months.41 Recently, a prospective study of 80 consecutive patients with IBD in clinical remission demonstrated that a TDM-based de-escalation approach was superior to blind adjustments of infliximab therapy based on symptoms and CRP.⁴²

Regarding IMM withdrawal as a de-escalating therapeutic strategy, our study showed that drug retention was similar between patients in clinical remission on mono- or combo-therapy who achieved an infliximab concentration of ≥5µg/mL, suggesting that “optimized monotherapy’ is feasible in this group of patients.²⁸ This is in line to another study which demonstrated that in patients receiving combination therapy, those with infliximab trough concentration ≥5µg/mL at the time of IMM discontinuation have a decreased risk for dose escalation, IBD-related surgery and drug cessation due to loss of response.⁴³ Furthermore, it was previously shown that although patients who continued to receive combination therapy had higher median trough infliximab concentration and lower CRP levels than those who discontinued IMM, no clear clinical benefit of combo-therapy was observed beyond 6 months.⁴⁴

Another potential role of proactive TDM is when anti-TNF therapy needs to be discontinued for reasons other than loss of response or adverse event (e.g. pregnancy, patient preference, health insurance issues) as preliminary evidence suggests that low or undetectable drug concentrations at the time of drug discontinuation are associated with sustained clinical remission after anti-TNF withdrawal.^31,32 Subsequently, when re-starting anti-TNF therapy after a drug holiday, a recent retrospective study showed that the absence of antibodies to infliximab and detectable infliximab trough concentrations after the first dose were associated with fewer infusion reactions and a better long-term response, respectively.³⁰

TDM Assays

There are several assays available for TDM of anti-TNF therapy, and currently none of them can be considered as the gold standard (Table 2).^45-57 The choice of assay in clinical practice typically depends on cost, local availability and physician’s preference and expertise. Recent data suggests that commonly used assays are generally comparable regarding drug concentrations, in contrast to anti-drug antibodies that still largely depend on the analytical properties of the assay used (Table 2). Consequently, clinically relevant thresholds of low or high titer anti-drug antibodies can vary among the currently available assays, making it difficult to compare results across studies. It is important to understand the assay used to avoid misinterpretations and erroneous therapeutic decisions, particularly as anti- drug antibodies can be reported in various ways that may make titers appear high and clinically significant when, in fact, they are not (Table 2). Recent data suggest that a new era in TDM is imminent as accurate, affordable, and easily accessible point-of-care testing and software- decision support tools that will incorporate a predictive pharmacokinetic model based on patient and disease characteristics are already underway.⁵⁸

Limitations

Before TDM can be widely applied into everyday clinical practice there are still several barriers that have to be overcome. These include out-of-pocket cost and health insurance reimbursement issues, time lag from collecting a serum sample to the result of the test, accurate interpretation and application of the results based on the assay used, and the optimal timing of serum sampling. Furthermore, additional data from well-designed prospective studies with a long-term follow up concerning all available biologics during both maintenance and induction therapy are urgently needed.

Despite these limitations, TDM appears to improve outcomes and the care of patients with IBD. A panel consisting of members of the Building Research in Inflammatory Bowel Disease Globally research alliance (BRIDGe; www.BRIDGeIBD.com), and recognized leaders in the field of TDM in IBD has recently published recommendations that helps clinicians on the appropriate timing and best way to interpret and respond to TDM results depending on the specific clinical scenario.⁵⁹

CONCLUSION

A TDM-based therapeutic strategy is likely to emerge as the new standard-of-care of utilizing biologics in IBD. Numerous studies demonstrate the association of adequate drug concentrations and improved clinical outcomes including objective measures of inflammation. Reactive TDM better directs care in those patients losing response to anti-TNF and is more cost-effective than empiric dose escalation. Additionally, although data are still limited, proactive, rather than reactive, TDM may prove even more effective in optimizing biologic therapies and the treatment of IBD. Nevertheless, before a TDM-based therapeutic approach can be widely implemented in clinical practice, several barriers should be first overcome regarding the type and cost of the assay used, optimal time of serum sampling and intinterpretation and application of the results.

Funding

K.P. received a fellowship grant from the Hellenic Group for the study of IBD.

Potential Competing Interests

K.P.: nothing to disclose; A.S.C: received consultancy fees from AbbVie, Janssen, UCB, Takeda, Prometheus, Miraca laboratories and Pfizer.

Introduction To A New Series: Dispatches From The Guild Conference

Dispatches from the GUILD Conference 2017

Uma Mahadevan

The Gastrointestinal Updates in Inflammatory Bowel and Liver Disease (GUILD) Conference is an annual CME conference held in Maui, Hawaii every February. Offering world class faculty, cutting edge interactive clinical sessions and workshops, the GUILD inaugural conference was held February 19- 22, 2017. The objective of the meeting is to provide the most up-to-date and practical information on the management of inflammatory bowel disease (IBD) and viral hepatitis, the two areas of our field that change at the most rapid pace, in an interactive and collegial environment.

To share our learning with the gastroenterology community at large, we introduce our new series based on discussions held at GUILD, beginning with the following article, “Practical Use of Therapeutic Drug Monitoring of Anti-TNF Therapy in IBD”.

We look forward to providing informative and educational articles covering IBD and Viral Hepatitis in Practical Gastroenterology over the following months.

For more information on the GUILD Conference visit: guildconference.com

A Case Report

A Case of Significant Gastrointestinal Involvement in Granulomatosis with Polyangiitis

Erin Tompkins,Matthew Robles,Mark Cumings

Granulomatosis with polyangiitis (GPA) is a rare, autoimmune condition usually presenting with pulmonary and renal involvement. There are not many reports of gastrointestinal involvement and even fewer cases of disseminated disease. We present a case of biopsy-proven, active gastrointestinal GPA throughout the stomach, small intestine and colon. Patients may present with diffuse abdominal pain, making the diagnosis difficult. We suggest that unidentified or inadequately managed gastrointestinal involvement in GPA is a potentially serious condition. This disease manifestation must be maintained in the differential in at-risk patients with gastrointestinal symptoms, and appropriate imaging should be considered when clinical suspicion warrants.

CPT Erin Tompkins MD¹ CPT Matthew Robles, DO¹ Mark Cumings, MD² ¹Madigan Army Medical Center Department of Internal Medicine, Tacoma, WA ²Providence St. Peter Hospital, Olympia, WA

INTRODUCTION

Granulomatosis with polyangiitis (GPA) is a rare autoimmune condition usually presenting with pulmonary and renal involvement.^1,2 The prevalence of this condition is 3 in 100,000 people in the United States.^1,3 There are numerous studies documenting cerebral, cutaneous and cardiac manifestations, however, few reports of gastrointestinal involvement exist.^1,4,5 Even in patients with known GPA, abdominal symptoms are significantly more likely to represent common underlying etiologies rather than the vasculitis itself. GPA has been included in a group of systemic vasculitides that have been described as “great masqueraders” due to the ability of this condition to manifest itself in ways that differ widely from their more typical presentation.² For this reason, it is important to consider GPA when evaluating patients with a history of GPA who have abdominal complaints after more common etiologies have been ruled out. Here we discuss a case of GPA where both the upper and lower gastrointestinal tract demonstrated active vasculitis.

CASE

A 38-year-old woman presented with several months of postprandial periumbilical abdominal pain. Accompanying symptoms included anal pain upon defecation, fatigue, malaise, night sweats, weight loss, arthralgias and decreased oral intake. Her medical history was significant for granulomatosis with polyangiitis, manifested by pulmonary, renal, sinus and ocular involvement, in remission for three years and off of therapy. Her exam was notable for abdominal tenderness, supraclavicular lymphadenopathy, and a perianal ulceration. Initial workup was concerning for new onset anemia and a positive fecal occult blood test. Upon admission, upper endoscopic and colonoscopic evaluations were performed. Patchy erythematous mucosa, with erosions, was identified in the gastric body, antrum, duodenum, terminal ileum and descending colon; a large ulceration was seen in the splenic flexure.

With the exception of the ileal biopsies, neutrophilic infiltration and reactive capillary endotheliitis without granulomata, consistent with active gastrointestinal GPA, was noted pathologically. Additionally, left anterior cervical lymph node biopsy revealed low- grade follicular lymphoma, which was also noted in the terminal ileum. She was treated with high-dose glucocorticoids with pending transition to rituximab.

DISCUSSION

This is a rare case of gastrointestinal GPA in a young female with multiple organ system involvement. GPA is an ANCA-associated vasculitis, and most commonly presents with upper respiratory, pulmonary and renal manifestations, as seen in our patient.^1,4 Cutaneous, ocular and nervous system manifestations are less common but still described regularly.^1,2 Gastrointestinal involvement is not commonly seen.^1,6 Often, these cases are discovered after an extensive evaluation culminating in endoscopic evaluation with confirmatory pathology. Most of the described cases of intestinal involvement have been noted intraoperatively during bowel perforation repair. Given the potential severity of unidentified or inadequately managed gastrointestinal involvement in GPA, this disease manifestation must be considered in at-risk patients with gastrointestinal symptoms. Appropriate endoscopic workup with biopsies should be performed when clinical suspicion warrants. Missing a diagnosis of gastrointestinal GPA can have a serious impact on morbidity or mortality of the patient as life-threatening consequences, such as bowel ischemia and perforation, are potential complications.^5,6 Early recognition and management are paramount for appropriate patient care.

A Case Report

A Rare Cause of Abdominal Pain in Plain Sight

Jordan Orr,Basem Alkurdi

Visceral angioedema, swelling of the soft tissues and organs of the abdominal cavity leading to signi cant gastrointestinal symptoms, is a rare adverse reaction associated with the use of an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. While several cases of ACEI-induced visceral angioedema have been reported, only one case of ARB-induced visceral angioedema exists. We report a unique case of ARB-induced visceral angioedema from the use of irbesartan and discuss the management and clinical importance of visceral angioedema.

Jordan Orr, MD Basem Alkurdi, MD, The University of Alabama at Birmingham, AL

INTRODUCTION

Angioedema is the classic adverse drug reaction of an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) that manifests as swelling of the face, tongue and lips and can be potentially life threatening. Even though universally recognized, this adverse reaction is rare with a defined incidence of 0.1% to 0.7% of patients taking an ACEI.¹ An even less frequent manifestation of angioedema is visceral angioedema which is characterized by swelling of the soft tissues and organs of the abdominal cavity leading to significant gastrointestinal symptoms. Visceral angioedema is classically associated with ACE inhibitors however it is also rarely observed with the use of ARBs. Only 28 cases of ACEI induced visceral angioedema have been reported in literature from 1980-2010 and the reported cases of ARB induced visceral angioedema are even less frequent.^1,2

Case Presentation

A 59-year-old female presented to the emergency department at a community hospital with complaints of severe cramping periumbilical abdominal pain with radiation to the lower abdomen. Her history was significant for diverticulitis, gastroesophageal reflux disease and multiple abdominal surgeries including Nissen fundoplication, cholecystectomy, hysterectomy, appendectomy and sigmoid resection for suspected ischemic colitis. Her pain was associated with bloating and severe nausea without vomiting. Computed tomography (CT) of the abdomen and pelvis was suggestive of small bowel obstruction with surrounding edema. She was admitted to the hospital and ultimately underwent exploratory laparotomy. Intraoperative findings revealed a normal small bowel without evidence of ischemia or adhesions. Serial CT scans throughout her hospitalization displayed successive resolving free fluid, small bowel wall thickening and stranding in the surrounding mesentery with resolution of findings by hospital day three (Figure 1, 2, 3). Without a diagnosis and symptomatically improved, she was discharged and referred to the gastroenterology clinic at our tertiary medical care center. She again presented with symptoms of abdominal pain and nausea, similar to her initial presentation despite normal vital signs, abdominal exam and laboratory work up. Review of her recent hospital course revealed her home medications, including irbesartan, had been held while hospitalized. This coincided with her resolving CT findings. Her irbesartan was discontinued and, at one-month follow up, she was asymptomatic, confirming the diagnosis of ARB induced visceral angioedema.

Discussion

Visceral angioedema is a rare cause of abdominal pain. The presenting gastrointestinal symptoms of visceral angioedema can be broad (abdominal pain, cramping, colicky pain, nausea, vomiting, diarrhea) and are often mistaken for a surgical abdomen.³ In fact, it is not uncommon for the patient presenting to the emergency department with visceral angioedema to undergo surgical exploration due to the degree of symptoms and radiologic findings.⁴ CT images of visceral angioedema classically display thickening, dilation and straightening of the small bowel with preservation of luminal transit.³ Other potential etiologies of these radiographic findings include small-bowel ischemia, superior mesenteric and portal vein thrombosis, radiation, vasculitidies, Crohn’s disease, hemorrhage, pneumatosis or ulceration, thus making the radiological diagnosis of visceral angioedema increasingly difficult.³ The pathogenesis of ACEI-induced angioedema is well described and felt to be due to the accumulation and potentiation of bradykinin, the molecule that evades degradation by angiotensin converting enzyme inhibition. This abnormal accumulation of bradykinin causes overwhelming vasodilation and increased permeability leading to the observed edema.^1,2 The pathogenesis of ARB-induced visceral angioedema, however, is not well understood. It is conceivable that ARBs also lead to bradykinin accumulation by the feedback-induced increase in angiotensin II levels in plasma, however further investigation is needed to help explain the phenomenon of ARB induced angioedema.² A high degree of suspicion is needed to diagnose visceral angioedema. Once recognized, the symptoms of visceral angioedema often resolve in as little as 48 hours if the offending medication is removed.¹ Unfortunately, many patients suffer from prolonged symptoms from unrecognized visceral angioedema. One study reported a median of 10 months elapsed between onset of visceral angioedema and withdrawal of the ACEI, and many cases are reported of patients with visceral angioedema who took an ACEI for years before the cause of their symptoms was diagnosed.¹ In patients who have experienced any degree of angioedema, clinicians should be careful about switching a patient from an ACEI to an ARB. Recurrent angioedema has been reported to occur in 1.5% to 10% of patients after changing medication classes. Recurrent visceral angioedema has also been reported after switching from an ACEI to an ARB.² It is recommended that clinicians wait a period of four weeks after discontinuing an ACEI and starting an ARB so that residual ACEI induced angioedema is not mistaken for new ARB induced angioedema.²

This rare but important cause of abdominal pain can be easily overlooked without a careful review of the medication list however recognition of this process and discontinuation of the provoking medication will save the patient from unnecessary diagnostic evaluation and intervention and bring timely symptomatic relief.

Inflammatory Bowel Disease: A Practical Approach, Series #100

Fecal Microbiota Transplantation for Recurrent or Refractory Clostridium difficile Infection in IBD

Yao-Wen Cheng,

Monika Fischer

A recent multicenter study demonstrated safety and efficacy of fecal microbiota transplant (FMT) for the treatment of recurrent or refractory CDI in IBD patients with cure rates comparable to the general population. Here we discuss the impact of FMT on underlying IBD and its position in the treatment paradigm.

Over the past decade, the incidence of Clostridium difficile infection (CDI) has more than doubled. Fecal microbiota transplant (FMT) has emerged as a guideline-based treatment for recurrent and refractory disease. However, the role of FMT for the treatment of CDI in patients with underlying inflammatory bowel disease (IBD) is controversial despite higher CDI-related complication rates in this population including mortality, colectomy, and recurrent infection. A recent multicenter study demonstrated safety and efficacy of FMT for the treatment of recurrent or refractory CDI in IBD patients with cure rates comparable to the general population, but questions still remain regarding the impact of FMT on underlying IBD and its position in the treatment paradigm.

Yao-Wen Cheng¹ Monika Fischer² ¹Resident, Department of Medicine, Indiana University School of Medicine 2Assistant Professor, Division of Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN

INTRODUCTION

Clostridium difficile infection (CDI) is the most prevalent cause of nosocomial infectious diarrhea in developed countries.¹ Over the past decade its incidence has doubled,^2,3 a phenomenon attributed to the emergence of an epidemic strain of C. difficile known as North American pulsed-field type 1, PCR ribotype 027 (NAP1/BI/027),⁴ an accelerated toxin producer associated with greater disease severity, higher relapse rates, and significant mortality.5 Its financial burden on the healthcare system is estimated to be up to $3.2 billion annually in the United States.⁶ The impact of CDI on patients with inflammatory bowel disease (IBD) is even more pronounced. Over the past decade, the incidence of CDI has doubled in Crohn’s disease (CD) and tripled in ulcerative colitis (UC).⁷ More importantly, the prevalence of CDI in the IBD population (CDI-IBD) is estimated to be 2.5 to 8-fold higher than the general population, with a 10% lifetime chance of infection.^8-10 In 2007, 2.9% of all IBD hospitalizations in the US were complicated by CDI.¹¹ Beyond the alarming rise of CDI incidence disproportionate to the general population, hospital admissions for CDI-IBD result in worse outcomes when compared with CDI alone or IBD alone. In-hospital mortality is four to six times greater for patients admitted for CDI-IBD compared to IBD alone.^12,13 Furthermore, patients with CDI-IBD have a twenty-fold increase in colectomy rate compared to patients with IBD alone,¹¹ and six times greater colectomy rate compared to patients with CDI alone.¹² Length of hospital stay and costs associated with hospitalization are also significantly higher when CDI- IBD is compared to IBD or CDI-related admissions.^12,13

Fecal microbiota transplant (FMT) has emerged as a highly effective therapy for recurrent CDI.¹⁴ There is also strong evidence that FMT is safe and rarely associated with adverse events even within immunosuppressed populations.^15-17 Treatment guidelines published in 2013 by the American College of Gastroenterology recommend FMT for the third CDI recurrence.¹⁸ This is predicated on treatment success rates surpassing 90% for recurrent and refractory CDI after just one FMT delivered via colonoscopy to the ascending colon or cecum.^19,20 Fecal microbiota transplant via other routes have also demonstrated efficacy rates of roughly 85% when delivered through nasoduodenal tube^21,22 or via enema.^23,24 More recent studies suggest a role for FMT in hospitalized patients with severe and severe-complicated CDI; cure rates are as high as 88% after a single FMT25 and over 90% when utilized in a sequential manner.^26,27

Despite the disproportionately high incidence and poor outcomes associated with CDI in patients with IBD, only a handful of studies have described outcomes after FMT therapy in this population. Among IBD patients on immunosuppressive therapy (N=36), Kelly and colleagues demonstrated CDI resolution in 86% of patients after a single FMT, with an overall cure of 94%.²⁸ More recently, Khoruts et al. showed patients with IBD were more likely to fail a single FMT and that immunosuppressive therapy did not influence the outcome.²⁹ In their study, a single colonoscopic FMT cleared CDI from 74% of patients with IBD compared to 92% of patients without IBD (P = 0.0018). A multicenter study on the use of FMT specifically in IBD patients with recurrent or refractory CDI, the largest study on this subject to date, had the primary goal of assessing treatment success rates for CDI in this unique population, and to describe secondary outcomes pertaining to safety and effect on IBD disease activity.30

Methods

In this retrospective study, patients from seven medical centers with a history of IBD and recurrent or refractory CDI were treated with FMT delivered via colonoscopy or sigmoidoscopy. Protocols for donor selection and stool processing were performed as outlined by the Fecal Microbiota Transplantation Working group.³¹ IBD activity and severity was assessed based on the judgement of the treating physician, endoscopic findings, and clinical disease activity scores. Results of these assessments were recorded at 1 month pre-FMT, at the time of FMT, and 3 months post-FMT. Changes in IBD clinical course after FMT were categorized by the treating physician as improved, no change, or worsened.

Outcomes of CDI Treatment

A total of 67 patients were included, 35 with CD, 31 with UC, and 1 with indeterminate colitis among which 64% were being treated with immunosuppressive agents at time of FMT. All patients in this group had a history of recurrent or refractory CDI with an average of four episodes. The majority of patients (94%) were previously treated with vancomycin. The indication for FMT was recurrent CDI in 80% and severe or severe-complicated CDI in 9%. Overall, 79% were treated successfully after one single FMT, while 90% achieved success after a maximum of three FMTs. The only independent predictor for a repeat FMT was low serum albumin concentration.

Impact of FMT on IBD

Seventy-six percent of this CDI-IBD population had endoscopic evidence of active IBD during FMT. After 3 months, the majority of patients were “doing well”; the IBD clinical course had improved in 46.3% and went unchanged in 35.8% of patients. Clinical disease activity score (Harvey-Bradshaw index) was available for 23 CD patients and decreased significantly from a mean of 7 pre-FMT to 2 post-FMT (P = 0.004). However, a significant minority of patients (17.9%) had worsening of their IBD clinical course. Among those patients considered to be worse, three had extensive colitis at the time of FMT and were hospitalized for an IBD flare in the ensuing 2 weeks post-FMT, but responded promptly to a short course (10-30 days) of systemic steroids. Two patients proceeded to colectomy within 1 month, both for severe Crohn’s colitis and therapy-refractory CDI. Two other ulcerative colitis patients underwent proctocolectomy, but were noted to be negative for CDI by PCR at the time of surgery. Nineteen patients were started on a new IBD therapy during the 12 week follow up period.

Overall, 12% (8/67) of patients experienced a serious adverse event (SAE), two of which were IBD flares requiring hospitalization. Only one patient experienced an SAE directly attributable to FMT; this immunocompromised CD patient in clinical and endoscopic remission at the time of FMT, developed a flare 1-week post-FMT and was found to have active inflammation and CMV-positive cells on subsequent colonic biopsies. CMV could have been transmitted through the stool transplant; neither the donor nor recipient was tested for CMV prior to the FMT. Notably, no other infectious complications related to FMT were reported.

How Will FMT Change the Treatment Paradigm For CDI-IBD?

This study demonstrated the efficacy of FMT as an adjunct to medical therapy for the treatment of CDI in the IBD population. It reaffirms success previously documented in case series28,29,32 and derives a cure rate comparable to the general population. The majority of patients had an improved or unchanged IBD course post-FMT, but a significant minority developed an IBD flare or had worsening disease activity. These findings are consistent with a previous study on immunocompromised patients where 14% of patients in the IBD subset experienced an IBD exacerbation after FMT.28 More recently, Khoruts et al. reported that 25% of IBD patients had a flare requiring systemic steroid therapy after FMT.29 Importantly, a majority of these patients had severe colonic inflammation at the time of FMT. Given the considerable portion of patients who experienced an IBD flare post-FMT, the authors adopted the practice of increasing anti- inflammatory/immunosuppressive therapy in patients with severe underlying colitis to mitigate the risk of post-FMT IBD flare. In another study, Chin and colleagues administered FMT to 35 CDI-IBD patients primarily via oral capsules.³³ While FMT was well tolerated by all patients, a large portion (54%) required therapy escalation for IBD after FMT. Interestingly, two patients developed de novo disease in the form of perianal fistula and abscess post-FMT. The cause of post-FMT IBD flare and worsening disease activity is unknown. Conceivably, the flares could be precipitated by Clostridium difficile infection itself versus natural IBD progression, and/or an immune reaction triggered by FMT administration. Prospective studies on temporal changes in the gut microbiota composition are needed to gain mechanistic insights.

Patients with IBD have multiple risk factors for CDI including dysbiotic gut flora and higher rates of exposure to immunosuppressive medications, antibiotics, and hospitalization, which collectively lead to conspicuously worse morbidity and mortality outcomes.^34,35 Yet, patients with CDI-IBD are treated under the same guidelines as their non-CDI counterparts. There is a role for a more aggressive treatment methodology. Mounting evidence supports the use of vancomycin in CDI-IBD as first line therapy even for non-severe CDI. In one study, patients with UC and non-severe CDI had fewer readmissions and shorter length of stay when treated with vancomycin-containing regimens than those with metronidazole alone.³⁶ Lower rates of colectomy were reported when CDI-IBD patients were treated with oral vancomycin.³⁷ There is a need for CDI disease severity stratification specific to the IBD population. Both elevated white blood cell count (WBC) and serum albumin concentration below 3g/dL are characteristic of severe disease and independently associated with colectomy and death in the general population.³⁸ In the CDI-IBD population, serum albumin below 3g/dL was associated with a three-fold increase in the primary outcomes of colectomy and death, irrespective of the white blood cell count.³⁹

There are improved outcomes in CDI-IBD patients after usage of vancomycin even for non-severe cases. The severity of disease may possibly be masked by the concurrent use of immunosuppressive medications and delayed recognition of CDI due to the similarities in patient symptomatology during an IBD flare and CDI. Further, delay in recognition of CDI severity even after colonoscopy may be due to the lower frequency of pseudomembranous colitis in CDI-IBD patients. Fifty percent of non-IBD patients with CDI have pseudomembranous disease,⁴⁰ but only 13% of patients with CDI-IBD in a large cohort study had pseudomembranes identified during colonoscopy.⁴¹ Pseudomembranes, as a marker of disease severity in non-IBD patients, did not have an association with length of stay or adverse clinical outcomes in this set of CDI-IBD patients.⁴¹ These factors may result in suboptimal treatment, which is further exacerbated by declining response rates to metronidazole even in non- severe patients. Initial CDI response to metronidazole was >90% in 1983,⁴² but have now dropped to roughly 50%.⁴³

There may be a role for earlier positioning of FMT for the treatment of CDI in the IBD population even though current evidence for FMT in the treatment of IBD without concurrent CDI is weak at best.⁴⁴ Rates of admission for CDI recurrence are much higher for patients with IBD (8.7%) versus the general population (0.1%).⁷ However, there still appears to be unpredictability in the response to FMT in the IBD population. Our patients also had variable responses in IBD activity after FMT therapy with 17.9% citing worse symptoms. The variable clinical courses of IBD after FMT could well be explained by a “donor effect,” which has been raised after a recent randomized controlled trial using FMT to treat patients with mild to moderate UC, documented a particular donor being particularly effective at inducing remission in these patients.⁴⁵ Fluctuations in the composition of commensal organisms occur over time,⁴⁶ combined with the idiosyncratic response to therapy due to the heterogeneity of recipients’ underlying IBD, may explain why only some patients have improved IBD activity after FMT. Prospective, longitudinal studies are required to determine the optimal timing for FMT in the treatment of CDI-IBD, to ensure the best outcomes while curtailing worsening IBD activity post-FMT.

CONCLUSION

Current data suggest that FMT for the treatment of recurrent or refractory CDI is effective and safe in patients with inflammatory bowel disease. The overall cure rate in CDI-IBD patients is comparable to non- IBD patients, however IBD patients may need more than one FMT for cure. While the majority of CDI- IBD patients’ clinical course improves following FMT, some remain unchanged despite CDI clearance and a significant minority may experience an IBD flare. Hospitalizations related to CDI-IBD portend much higher rates of mortality, colectomy, and hospital length of stay compared with CDI or IBD alone, therefore FMT may need to be considered earlier on in this population. To effectively treat these patients and decide where to position FMT in the treatment paradigm, further studies of FMT on CDI and IBD outcomes are needed.

Nutrition Issues In Gastroenterology, Series #159

Medicare Coverage for Home Parenteral An Oxymoron Nutrition What Does it Take to Qualify For HPN

Penny Allen

In this second part of a two part series on Medicare policy for HPN, we examine real life Medicare HPN referrals, discuss how to assess if a patient/beneficiary qualifies for coverage, and provide suggestions for alternative options when no coverage for home infusion therapy is provided.

Penny Allen, RD, CSNC National Director, Nutrition Support Lead for Medicare Clearance, Parenteral Nutrition, AxelaCare Health Solutions

Physicians and healthcare providers charged with caring for patients requiring home parenteral nutrition (HPN) face increasing pressure to discharge patients earlier from the acute setting. Patients with gastrointestinal (GI) disorders or GI/nutritional complications from cancer treatments and other conditions may require continuation of parenteral nutrition (PN) therapy in the home setting. As the population of Medicare eligible beneficiaries grows, it is often a surprise at the time of discharge that many Medicare patients do not have coverage for HPN and the related medically necessary infusion therapies under the current Medicare system. In this second part of a 2 part series on Medicare policy for HPN, we examine real life Medicare HPN referrals, discuss how to assess if a patient/beneficiary qualifies for coverage, and provide suggestions for alternative options when no coverage for home infusion therapy is provided.

INTRODUCTION

A 67 year old female patient with Stage III ovarian cancer presents with a partial small bowel obstruction and intractable nausea and vomiting; she is referred to a home infusion provider for home parenteral nutrition (HPN) on a Friday afternoon. The patient has Medicare as her primary insurance along with a supplemental policy. The physician and case manager are told:

“I am sorry, your patient does not have coverage for HPN under Medicare.”

In last month’s edition, the current (and very outdated) Medicare parenteral nutrition (PN) policy was reviewed, along with a call to action to support the Medicare Infusion Site of Care Act which would provide more meaningful infusion benefits for Medicare beneficiaries.¹ In this article, real life referral case studies will be reviewed. Guidance for the clinician trying to obtain the appropriate supporting documentation to meet coverage criteria for a beneficiary requiring HPN will be provided (see Table 1 for clinical conditions that are unlikely or will not be covered by Medicare). For a review of policy details, see last month’s issue with reference tables and checklist.

Referral 1

Partial small bowel obstruction due to ovarian cancer

1. Possible “Situation” in Medicare policy that HPN would be covered? (All “Situations” referred to in the following referral scenarios are quoted verbatim from Medicare policy).
Situation D^1,2
“The beneficiary has complete mechanical small bowel obstruction where surgery is not an option”
2. Assessment
Since the beneficiary only has a “partial” obstruction, she does not meet Situation D exactly so Medicare deems this a “moderate abnormality”.²
3. Required for coverage for a “moderate abnormality”:

a. Situation G and H criteria (See Part I of this series for detail).^1,2

b. Estimated length of need for HPN documented in the medical record by the attending physician, must be at least 3 months.²

c. A thoroughly documented tube feeding trial. (See Part I of this series for detail).^1,2

Referral 2

Patient diagnosed with short bowel syndrome (SBS), requiring PN and supplemental hydration after a mesenteric infarct and small bowel resection leaving 3 feet (90 cm) of small intestine. Surgery was 3 weeks ago. Patient has Medicare with a supplemental plan that will only cover the 20% patient copay if Medicare pays for the therapy.

1. Possible “Situation” in the Medicare policy where HPN is covered?
Situation A^1,2
“The beneficiary has undergone recent (within the past 3 months) massive small bowel resection leaving less than or equal to five feet of small bowel beyond the ligament of Treitz”
2. Assessment
Patient may meet criteria for Situation A if objective documentation in the medical record supports the initial information provided at time of referral.
3. Required documentation in medical record for Medicare HPN coverage:

a. Need surgical reports clearly stating there is < 5 feet (150 cm) of small bowel remaining beyond the ligament of Treitz.² and

b. Length of need for HPN must be documented in the medical record and must be greater than 90 days.²

Referral 3

Patient referred for HPN with diagnosis of weight loss, intractable nausea and vomiting due to chemotherapy and treatments for pancreatic cancer.

1. Possible “Situation(s)” in the Medicare policy where HPN is covered?

Unless there is a diagnosis of complete obstruction of the small intestine (Situation D), malabsorption (Situation E), or a motility disorder (Situation F) with the objective documentation required that supports any one of those Situations, it is highly unlikely there is coverage for HPN. Medicare will only cover HPN when there is a permanent impairment to the small intestine. Weight loss, malnutrition, nausea and vomiting are not covered conditions under the current policy; therefore in the majority of cases, cancer and cancer related complications requiring PN are usually not covered in the home setting.
2. Assessment
a. Review full medical record for any other possible covered Situations (A-F, G and H).^{1, 2}

b. Check for a major medical secondary insurance policy with PN benefits.

c. Explore other options such as PN coverage in a skilled nursing facility, patient self- pay capability, or the hospital pays the HPN provider a per diem rate (if the hospital understands the value of getting the patient out of the hospital bed and into a less costly site of care).

d. Check Part D benefits for partial coverage of PN formula understanding that the patient will have a daily copay for pump and supplies.

Referral 4

Patient is s/p gastric bypass procedure over 5 years ago with subsequent multiple abdominal surgeries and complications. Patient has been unable to tolerate oral intake and has lost over 200 lbs., and now weighs 105 lbs. She presents with significant malnutrition including multiple nutritional deficiencies. PN has been initiated, and case management would like her discharged as soon as possible. Due to longstanding disabilities, she has a Medicare replacement plan that follows Medicare PN policy; it also has exclusion criteria for weight loss surgery and complications.

1. Possible “Situation(s)” in the medical policy where HPN is covered?

Unless there is a diagnosis of SBS (Situation A or B); bowel rest for pancreatitis, enterocutaneous fistula or severe Crohn’s flare (Situation C); a complete obstruction of the small intestine (Situation D), malabsorption (Situation E), or motility disorder (Situation F) along with objective documentation required to support any one of these Situations, it is highly unlikely there is coverage for HPN. Medicare will only cover HPN when there is a permanent impairment to the small intestine. Weight loss and malnutrition are not covered conditions under the current Medicare policy and this patient’s insurance plan (which follows the Medicare PN policy) also excludes coverage for complications due to weight loss surgeries.
2. Assessment
a. Review medical record thoroughly for any conditions that may be deemed a “moderate abnormality” if the exact criteria for Situations A-F are not met.

b. Consider an enteral feeding trial if possible (see Part I of this series).¹

c. Check if patient has a major medical secondary policy with HPN benefits.

d. Explore other options such as PN coverage in a skilled nursing facility, patient self- pay capability, or the hospital pays a HPN provider a per diem rate

Care providers should shop for best competitive rate among HPN providers as applicable.

e. Check Part D benefits for partial coverage of PN formula (understanding that the patient will have a daily copay for pump and supplies).

f. Check to see if an outpatient infusion center would consider providing PN for a specific number of days/week. Not ideal or convenient for the patient due to the length of time to administer PN. Medicare replacement plans can vary greatly in regards to coverage.
3. Requirements for coverage if there is a “moderate abnormality” as defined by Medicare:
See Part I of this series.^{1, 2}
“Beneficiaries who do not meet criteria A-F must meet criteria 1-2 (modification of diet and pharmacologic intervention) PLUS criteria G and H below:
- G. The beneficiary is malnourished (10% weight loss over 3 months or less and serum albumin less than or equal to 3.4 gm/dl), and
- H. A disease and clinical condition has been documented as being present and it has not responded to altering the manner of delivery of appropriate nutrients (e.g., slow infusion of nutrients through a tube with the tip located in the stomach or jejunum).”

Referral 5

Patient with chronic pancreatitis and malabsorption referred for HPN. The case manager wants a discharge today and the patient has Medicare and a Blue Cross secondary insurance plan.

1. Possible “Situation(s)” in the Medicare policy where HPN is covered?
Situation C
Includes three scenarios under “bowel rest” category, one of which is symptomatic pancreatitis with or without pseudocyst:
“The beneficiary requires bowel rest for at least 3 months and is receiving intravenously 20-35 cal/kg/day for treatment of symptomatic pancreatitis with/without pancreatic pseudocyst, severe exacerbation of regional enteritis, or a proximal enterocutaneous fistula where tube feeding distal to the fistula isn’t possible”.^1,2
2. Assessment
Patient has the possibility for coverage under Medicare for HPN. Conduct a thorough medical chart review to assess if the documentation exists to support criteria for “symptomatic pancreatitis with or without pseudocyst,” i.e., cannot only have a history of pancreatitis, the pancreatitis must be the active problem causing the patient to require PN, and it must be documented that bowel rest is indicated. The words “bowel rest” must be in the medical record, even if NPO (nil per os) status is documented. If documentation does not exist, therapy is expected to be < 3 months, or the patient is not on bowel rest; the secondary Blue Cross (BC) insurance should be investigated concurrently to ascertain if there is coverage under the BC policy if HPN is not covered under Medicare. If the patient is eligible for HPN benefits, and the patient does not meet Medicare criteria, then Medicare would still need to be billed for a specific type of denial code in order to bill the Blue Cross plan.
3. Required documentation in medical record for Medicare HPN coverage:

a. Statement in medical record by attending physician that bowel rest is required for greater than 3 months.²

b. PN prescription provides 20-35 cal/ kg of actual body weight/day, or there is documentation from the attending physician in the record explaining why calories fall outside of the range.²

c. Diagnosis must be symptomatic pancreatitis (not a history of pancreatitis).²

Referral 6

Patient with longstanding SBS for years, previously on HPN and weaned off. After 6 months with no PN, the patient is admitted to the hospital in acute renal failure with weight loss, electrolyte abnormalities and a high output ileostomy. The patient turned 65 years old during the time off PN and now has Medicare with a supplemental insurance policy. The medical team has started the patient on PN in the hospital, corrected the fluid and electrolyte abnormalities and brought renal status back to baseline. They would like the patient to go home on PN and supplemental hydration.

1. Possible “Situation(s)” in the Medicare policy where HPN is covered?
Situation A^1,2
“The beneficiary has undergone recent (within the past 3 months) massive small bowel resection leaving less than or equal to 5 feet of small bowel beyond the ligament of Treitz, or”
Situation B^1,2
“The beneficiary has a short bowel syndrome that is severe enough that the beneficiary has net gastrointestinal fluid and electrolyte malabsorption such that on an oral intake of 2.5-3 liters/day the enteral losses exceed 50% of the oral/ enteral intake and the urine output is less than 1 liter/day”
2. Assessment
If a patient has been off PN for greater than 60 days, Medicare deems this a “break in service” and the patient must be requalified all over again. This patient does have SBS, but if the records reveal there have been no new bowel resections in the last 90 days, then Situation A is not an option–the surgery which left the patient with < 5 feet (150cm) of small intestine was over 3 months ago. The entire medical record should be reviewed to assess if the objective information is available to meet Situation ^B.

Medicare does not cover hydration therapy; therefore supplemental hydration would not be covered.³
3. Required documentation in medical record for Medicare HPN coverage:
a. Diagnosis of short bowel syndrome.

b. Statement of length of need for HPN by the attending physician (must be > 3 months).

c. Lab records: abnormal electrolytes upon admission to the hospital.

d. An intake and output (I & O) flow chart documenting:
- Oral/enteral intake of 2.5-3.0 liters/day
- > 50% of the above intake as output/ enteral losses (i.e., > 1250-1500 mL/day), and
- Urine output must be < 1 liter (It is advantageous to minimize IV fluid intake during the 24 hour time period the I & O is documented, so as not to increase urine output over what it would be at home).
4. Challenges with Situation B:
a. Electronic medical record I & O charts often do not demonstrate clear delineation of IV intake vs. oral/enteral intake. If not clearly documented all I & O should be done manually so the results are accurate and easy to interpret in preparation for future audits with CMS.

b. If the patient was given multiple liters of intravenous fluids at the time of admission, urine output may initially be greater than 1 liter, which would not meet Medicare’s criteria. Once the patient is stabilized, a detailed I & O should be repeated to allow for a more true assessment of a lower urine output in the setting of short bowel syndrome if the patient were on an oral/ enteral diet only.

c. Many patients who are ill cannot consume 2.5-3 liters orally or enterally, however, under Medicare policy, there is no exception to this, so if the patient cannot consume (or infuse enterally) at least 2500 mL, then there would be no coverage under Situation B.
5. Options for provision of supplemental hydration:
a. Self-pay pricing for supplemental hydration (healthcare providers and patients should shop around for best pricing if possible).

b. Determine if a higher volume PN solution is possible and would meet the patient’s needs. Stability of a more dilute PN solution may be an issue, but there are options to address this.

c. Patient goes to an outpatient infusion center (usually Monday-Friday operations) where Medicare would pay for the infusion.

d. Check for additional major medical policies where hydration (and PN) is usually a covered benefit.

e. During open enrollment periods (October- December), the patient has the option to select another type of Medicare plan which covers home infusion, understanding they may need home infusion for the long term and benefits under straight Medicare are limited. Medicare.gov lists options per zip code for the individual beneficiary.

Referral 7

69 year old female with SBS with < 6 feet of small bowel (exact amount not quantified in the medical record) and one-third of the distal colon remaining. She has been able to maintain the low end of ideal body weight range, but has had multiple admissions for dehydration. Patient cannot maintain urine output > 800mL/day; when more fluid is consumed, stool output increases. Creatinine levels have been slowly rising with levels ranging between 1.3 to 1.5mg/dl. When the patient gets admitted for dehydration and receives IV fluids, the creatinine drops to 1.1-1.2. The patient requires IV hydration at home to protect renal function and the physicians are asking why this is not possible.

1. Possible “Situation(s)” where HPN or intravenous hydration may be covered?

Unfortunately, Medicare simply does not cover hydration in the home.³

Options for the patient would be self-pay or when allowed to change Medicare plans (October -December is open enrollment), investigate alternative Medicare Advantage plans in the patient’s geographic area that cover home infusion therapy (including hydration and/or PN). Although inconvenient, hydration therapy is covered by Medicare in an outpatient infusion clinic (see above options for provision of supplemental hydration under Referral 6).
2. Assessment
Since the patient does have SBS, Situations A or B may be potential options. Situation A would require an operative report clearly stating how much small bowel is remaining. If a resection resulted in < 5 feet of small intestine beyond the ligament of Treitz, and the resection was in the last 3 months-then there would be coverage.

If not, we are left with Situation B. If the patient is subsequently admitted again for dehydration, the above guidance and recommendations listed in Referral 6 for Situation B should be followed. This should occur in the institutional setting to ensure clear documentation in the medical record (i.e., the legal document).

With Situations A, B and D in the Medicare PN policy, the calorie range provision (i.e., PN must provide 20-35 calories/kg of actual body weight) is not required, so if the physician documents clearly what the patient needs are due to her SBS, a more dilute PN prescription may be covered which could meet her fluid and electrolyte needs.

“NUTRIENTS:
Parenteral nutrition solutions containing little or no amino acids and/or carbohydrates would be covered only in situations A, B or D discussed in the Parenteral Nutrition – Policy Article A total caloric daily intake (parenteral, enteral and oral) of 20-35 cal/kg/day is considered sufficient to achieve or maintain appropriate body weight. The ordering physician must document in the medical record the medical necessity for a caloric intake outside this range in an individual beneficiary. This information must be available on request”.²

Referral 8

68 year old obese female with enterocutaneous fistula and wound vac referred for home PN. PN prescription provides 17 calories/kg actual body weight/day. Patient has Medicare for primary insurance and an American Association of Retired Persons (AARP) Medicare supplement policy.

1. Possible “Situation(s)” in the medical policy where HPN is covered?
Situation C^1,2
“The beneficiary requires bowel rest for at least 3 months and is receiving intravenously 20 -35 cal/kg/day for treatment of symptomatic pancreatitis with/without pancreatic pseudocyst, severe exacerbation of regional enteritis, or a proximal enterocutaneous fistula where tube feeding distal to the fistula is not possible”
2. Assessment
This patient has a chance at Medicare coverage under Situation C depending on a number of variables.

Required documentation in the medical record for Medicare HPN coverage:

a. Diagnosis of enterocutaneous fistula in the medical record.²

b. Statement by attending physician that bowel rest is required for at least 3 months. Medicare specifically defers to the language of “bowel rest” not “NPO”.²

c. PN prescription must provide 20-35 cal/kg of actual body weight/day. If not, documentation from the attending physician explaining why calories fall outside of the range must be in the medical record.²

d. Statement that tube feeding distal to the fistula is not possible (a fistulagram or other objective study is helpful, but not mandated by the policy).²

CONCLUSION

Until new laws are passed and coverage for home infusion/PN becomes more meaningful under Medicare, healthcare providers must carefully assess the need for HPN therapy. Referrals for homecare should be made as early as possible to allow for thorough examination and review of medical documentation and allow for the possibility that Medicare may require additional testing. This will help ensure that the beneficiary will have coverage for HPN and is not at risk for denial of payment should an audit determine that coverage criteria was not met, potentially leaving the patient and family with a significant bill in the future.

All healthcare providers involved in the care of patients requiring HPN and related therapies should develop a stronger understanding of the Medicare reimbursement system in order to advocate for the needs of this challenging patient population. Failing to do this may prevent patients from having access to life sustaining nutrition support and could also expose them to significant financial harm. Given these risks, clinicians would be well advised to carefully document the clinical necessity of HPN, backed up by objective evidence and testing, along with an estimated length of need for the therapy for all patients going home on PN- -as if they needed to meet Medicare criteria. Patients who currently have private insurance may eventually transition to Medicare and supporting documentation will be required for a successful transition and continuation of HPN therapy. More information regarding the Medicare Home Infusion Site of Care Act can be found at nhia.org.

Frontiers In Endoscopy, Series #33

Endoscopic Bariatric Interventions in the Management of Obesity: The Era of Non-Surgical Management

Vivek Kaul

In this article we discuss bariatric endoscopy, a newly developing field in the management of obesity by inducing weight loss associated with a minimal complication profile. Although some therapies currently remain under FDA evaluation and trials, the emergence of endoscopic bariatric therapies holds a promising future.

Truptesh H. Kothari MD, MS Paridhi Malik MD Shivangi Kothari MD Vivek Kaul MD Division of Gastroenterology – Hepatology, University of Rochester Medical Center, Rochester NY

Obesity is defined as a complex metabolic disease of fat accumulation associated with increased risk to health. Body Mass Index (BMI) is a measure to classify obesity in adults. It is a calculated by dividing a person’s weight in kilograms by the square of his height in meters (Kg/m²). According to the World Health Organization, obesity is defined as individuals with a BMI ≥ 30. Further categorization of obesity is done based on the severity of BMI over 30. Class I refers to BMI of 30-34.9, Class II refers to BMI 35-39.9, and Class III refers to BMI over 40.¹ Recent statistics from a National Health and Nutrition Examination Survey (NHANES) in 2013-2014 reveal that 32.7% of adults in the U.S above the age of 20 are overweight (BMI 25-30), 37.9% are obese, and 7.7% are severely obese with BMI of more than 40.² The reported average BMI in the year 2000 was 30 whereas it is 33.6 in 2016.

The behavioral risk factor surveillance system is an ongoing nation-wide telephone-based survey, which is conducted by the CDC. The most recent results of this study in 2015 reveals a total of 19 states with obesity rates between 25% and 30% along with four states (Alabama, Louisiana Mississippi, and West Virginia) with a prevalence of Obesity upwards of 35% of the population.³ Obesity carries a major risk to an individual’s health with 55% increase in mortality, 70% increase in coronary artery disease, 75% increase in stroke risk and a 400% increase in diabetes risk. Obesity and being overweight accounts for about 2.8 million preventable deaths annually and certainly has become a global epidemic.⁴

Current management of obesity includes a range of interventions from lifestyle modifications and medical therapy to invasive surgical procedures (Figure 1). Weight loss is the major lifestyle modification used in controlling obesity; however, it has proven to show only moderate improvement in obesity. “An alternative approach to managing obesity is pharmacotherapy, which is considered useful as an adjunct to lifestyle modifications. This approach results in weight loss by an additional 3 to 9% in comparison to the lifestyle modification alone”.⁵ Although anti-obesity medications assist in achieving good weight loss results, they carry a high risk of relapse and weight gain. Bariatric surgery is considered in individuals who fail to improve with lifestyle modifications and/or medications. It is also recommended for those with BMI > 40 Kg/m² or, BMI of 35 Kg/m² or more with comorbid conditions such as hypertension and type 2 diabetes. Some of the most commonly performed surgical weight loss procedures are Roux-en-Y gastric bypass, sleeve gastrectomy, and gastric banding. Several endoscopic (non-surgical) options have emerged for obesity management in the last decade.

Although Bariatric surgery remains an efficient and durable option for obesity management, less than 1% patients undergo bariatric surgery. The low usage of the surgery may be attributed to surgical cost, patient preference, access to care, and the mortality- morbidity associated with this procedure. Some of the major complications reported after a surgical bariatric procedure are luminal obstruction, anastomotic leak, marginal ulcer, gastrointestinal bleeding, wound related complications, and pulmonary embolism. The complication rates of bariatric surgical procedures remain high at 17%.⁶ The high complication rates of surgery led to the need for developing a less invasive alternative that reduces morbidity and can provide quick access to patient care. This gap in the management options has led to the evolution of bariatric endoscopy. Bariatric Endoscopy is a newly developing field in the management of obesity by inducing weight loss associated with a minimal complication profile.

Endoscopic bariatric interventions are classified based on site of intervention and can be either a Gastric or a Small Bowel intervention. Gastric interventions include space-occupying devices such as intragastric balloons, TransPyloric Shuttle, and Full Sense Device along with Aspiration therapy and Gastroplasty techniques. These devices work via different mechanisms to induce early satiety, including increasing the stimulation of mechanical and chemical receptors in the gastric tract, delaying gastric emptying and reducing luminal accommodation thus limiting food intake by inducing early satiety (Table 1).

Small bowel interventions interfere with nutritional absorption by various mechanisms depending on the technique (Table 2). Of note, currently, none of the small bowel endoscopic bariatric interventions discussed are FDA approved or commercially available in the USA.

Clinical evaluation of the Orbera device was performed in a prospective randomized controlled, comparative clinical study using 125 subjects in the treatment group and 130 subjects in the control group with BMI of 30 – 40 Kg/m2. The treatment group underwent Orbera placement followed by removal after six months. Both groups participated in a twelve-month behavioral modification program. The effectiveness of the study was measured with two co-primary endpoints. This included first, the mean percent excess weight loss (EWL) at nine months (3 months after the balloon was removed) and secondly, if >30% of Orbera-treated subjects achieved significantly greater (>15% estimated weight loss) weight loss over the mean %EWL of the control group. The study did not meet its first co-primary endpoints as the mean %EWL did not meet the 95% lower bound confidence interval, although the study did satisfy the second co- primary endpoint with 45.6% Orbera treated patients exceeding 15% mean EWL over the control subjects. Total body weight loss in the Orbera group was noticed to be a mean of 10.2% and 9.1% at 6 and 9 months after balloon insertion respectively. Significant weight loss was observed within the Orbera group as compared to the control group with a mean % excess weight loss with ideal weight defined as BMI of 25. It was found to be 38.4% at month 6, 34.6% at month 9, 29% at month 12 as compared to 12.1%, 12.3% and 11.1% in the control group with a p-value of <0.001. % Total body weight loss of 10.2, 9.1, 7.6 % in the Orbera and 3.3, 3.4, 3.1 % in the control group at 6, 9 and 12 months after the insertion of the balloon with a p-value of <0.001. Secondary effectiveness of the intervention was measured by the impact of treatment on comorbid conditions such as Hypertension, Type 2 Diabetes and dyslipidemia at months 6, 9 and 12. It was noticed that both groups experienced a comparable decrease in the severity of the comorbid conditions, which may be as a result of a common factor in both groups such as diet and exercise. P-values were not statistically significant to prove a difference between the Orbera and control group when comparing the decrease in severity of hypertension, diabetes and dyslipidemia. Orbera pivotal trial revealed that patients could expect to achieve three times the weight loss at six months as compared to diet and exercise alone, majority of which is lost in the first three months (Figure 2.a., 2.b., 2.c.).

A longitudinal and interventional study was performed in obese patients over six months after placement of an intragastric balloon aimed to study the effect of the treatment on lung function, BMI, and DXA parameters. It was noted that lung volumes were significantly reduced at six months after balloon placement. A drop in BMI was also noticed from 39.1 Kg/m2 to 34.5 Kg/m2. Considerable improvement in body fat distribution was also reported using DXA measurements of body fat.⁷

A randomized clinical study was performed to evaluate the safety and efficacy of the ReShape dual balloon system (DBS) by comparing two groups of patients: one with DBS treatment along with diet and exercise and one that was a control group with diet and exercise only (Figure 3). The study included a total of 326 individuals with 187 in the DBS group and 139 in the control group. The BMI of the targeted patient population was between 30-40 Kg/m⁷. The study revealed a significant effect in the DBS group as compared to control. The effectiveness was measured using two co-primary endpoints. The first primary endpoint was defined by the percent excess weight loss (%EWL) and the second primary endpoint measured if more than 35% achieved a 25% EWL in the treatment group at 24 weeks when the dual balloon system was retrieved. This pivotal trial successfully met both the co-primary endpoints. It was found that the weight loss was more than double as compared to the control group along with a %EWL of 25.1% in the DBS group (intention-to-treat). This is significantly greater than the control group with a %EWL of 11.3%. The second primary endpoint was also met as there was a 49.1% difference in the treatment group who achieved a 25% EWL, this was considerably over the 35% response rate.⁸

A prospective study of 150 patients was performed in patients who regained weight post-Roux-en-Y gastric bypass (RYGB) surgery. The targeted patient population included patients with Gastrojejunal anastomosis (stoma) aperture larger than 15mm. This study aimed to recognize the long-term benefits of management of dilated anastomosis aperture post-RYGB using an endoscopic procedure called Transoral Outlet Reduction (TORe). The study focused on trending weight loss at 3, 6, 12, 24, and 36 months after completion of the TORe procedure. It was reported that a weight loss of 9 to 11 kg and a BMI loss of 3 Kg/m² was achieved as a result. This was as a result of a decrease in aperture size from 24.1 + 1mm to 9.0 + 0.2mm. The adverse effects were limited to abdominal pain in 4% patients, gastrointestinal bleeding in 3.3% and nausea in 2.0%. It was shown that a greater reduction in anastomotic aperture was associated with a greater post-procedural weight reduction.⁹ TORe, being less invasive, is a safe and reliable alternative in the treatment of post-surgical complications of RYGB.

Obesity is one of the leading health problems in the United Status today and is becoming very challenging to manage. Despite numerous management options varying from lifestyle modifications to bariatric surgery, obesity remains a problem unsolved. It comes with its wide array of comorbidities increasing the financial burden of this widespread epidemic even further. As a result, it has become one of the top priorities in today’s healthcare. Endoscopic techniques allow for the management of obesity in a less-invasive manner and help prevent the associated risks of the bariatric surgical procedures. It also allows for a holistic approach to manage obesity with endoscopic intervention being the primary tool complemented by its behavioral modification program and comprehensive follow-up strategies. Although some of the therapies currently remain under FDA evaluation and trials, the emergence of endoscopic bariatric therapies holds a promising future in the way obesity will be managed. This is indeed a revolutionary step towards medical and surgical management of obesity.