Page 59 – Practical Gastro

A Case Report

Internal Biliary Fistula Secondary to Cushing’s Ulcer in a Child

July 2017 • Volume XLI, Issue 7

Allison Ta,Suchitra Hourigan,Otto Louis-Jacques

Allison Ta, MD¹ Suchitra Hourigan, MD² Otto Louis-Jacques, MD² ¹Inova Fairfax Children’s Hospital, Falls Church, VA ²Pediatric Specialists of Virginia, Fairfax, VA

INTRODUCTION

Internal biliary fistulas are abnormal communications between the extrahepatic biliary tree and another organ. These fistulas are rare disorders, typically affecting elderly patients as complications of biliary disease or, less commonly, peptic ulcer disease or cancer requiring surgical intervention. We present the case of a cholecystoduodenal fistula (CDF) secondary to a perforated duodenal ulcer in a pediatric patient with posterior fossa tumor. We discuss the success of medically treating this patient with proton pump inhibitors and subsequent resolution of the fistula.

Case Report

A 10 year-old female presented to the hospital with complaints of headache, vomiting, abnormal gait and upper extremity weakness for approximately eight months. She utilized ibuprofen or acetaminophen several times a week for her symptoms. Her past medical history was significant only for hypothyroidism.

A magnetic resonance imaging (MRI) of her brain showed a large posterior fossa tumor (measuring 8x4x3 cm). The patient was admitted to the pediatric intensive care unit (PICU) for stabilization and pre-operative planning. Dexamethasone was started on hospital day (HD) 1 and weaned post-operatively. On HD 4, she underwent surgical debulking of the tumor. On HD 8, she was started on nasoduodenal feeds and famotidine. The patient complained intermittently of epigastric pain, but otherwise had an uncomplicated initial postoperative course.

On HD 11, she became acutely hypotensive and her hemoglobin dropped from 10 to 5.1g/dL. Nasogastric (NG) tube lavage revealed brown colored fluid. She was resuscitated with packed red blood cells and fluids. Urgent esophagogastroduodenoscopy (EGD) discovered a large, non-bleeding duodenal ulcer. An orifice was seen medially within the ulcer bed (Figure 1). Biopsies taken at the time of EGD confirmed ulceration and ruled out Helicobacter infection. An abdominal computed tomography (CT) scan revealed air and contrast in a normal-appearing gallbladder, with a small communication between gallbladder and duodenum, consistent with a cholecystoduodenal fistula (Figure 2). Pediatric surgery was consulted and recommended medical management.

The patient was started on intravenous pantoprazole at 120 mg daily (roughly 1.6mg/kg/day), total parenteral nutrition and a NG tube was placed for gastric decompression. An EGD was repeated on hospital day 20 due to persistent melena. It showed the fistula surrounded by ulcerated tissue with a small amount of blood and bile flowing out of fistula. Attempts to place a clip on the edges of the ulcer bed were unsuccessful. Her proton pump inhibitor (PPI) was switched to continuous drip after which the bleeding resolved. Repeat EGD and abdominal CT on HD 36 showed a healed ulcer and closure of the fistula. The patient was transitioned to oral PPI and NG feeds were resumed. She had no further complications before transfer to a rehabilitation facility. At clinic follow-up more than three months later, there was no recurrence of bleeding.

Discussion

Internal biliary fistulas (IBF) are abnormal communications that develop between the epithelial- lined biliary tract and another organ, most commonly the gastrointestinal tract or part of the biliary tree.¹ IBF represent complications of cholelithiasis in >90% of cases.¹ Far less frequently, peptic ulcer disease, malignancy, inflammatory bowel disease or prior surgery can cause the fistula.¹ Morbidity associated with IBF is related to recurrent underlying disease, cholangitis if common bile duct is involved and/or acute gastrointestinal bleeding.²

The presentation of an IBF is often non-specific making its diagnosis difficult. Patients may complain of right lower quadrant pain or epigastric pain in setting of biliary disease and/or dyspepsia related to peptic ulcer disease.³ Fever and jaundice are seen in cases of cholangitis resulting from choledochoduodenal fistulas.^2,3 Radiologic findings of pneumobilia and/or contrast in the biliary tree on plain abdominal X-ray or contrast studies (upper GI series, abdominal CT or magnetic cholangiopancreatography [MRCP]) are suggestive of the diagnosis.^4,5

The etiology of the IBF and the stability of the patient are important in guiding management. In adults, biliary disease is commonly the cause of IBF. Definitive treatment requires cholecystectomy which allows the fistula to heal as recurrence can occur with gallstones formation.^1,5 Proton pump inhibitors are key in closure of the fistula if it is secondary to peptic ulcer disease.^3,5,6 Patients with smaller choledochoduodenal fistulas (orifice <0.5 cm) can be successfully treated medically, however surgical intervention may be necessary in case of complications from the ulcer, including uncontrolled bleeding or perforation.⁵

Given the lower incidence of gallstones and the rarity of peptic ulcer disease in children, it is not surprising that there are very few reports of IBF in children. In one case, a 6 year-old child presented with recurrent cholangitis.² MRCP revealed a choledochoduodenal fistula for which she underwent cholecystectomy, common bile duct excision and Roux- en-Y hepaticojejunostomy. The only previous report of a child with a choledochoduodenal fistula secondary to peptic ulcer disease is a 10 year-old male with a three month history of abdominal pain and non-bilious vomiting.⁴ An EGD revealed a scarred ulcer in first part of duodenum causing obstruction which was treated surgically.

This is, to our knowledge, the first report of a pediatric patient with a CDF caused by a penetrating duodenal ulcer who was successfully treated medically. Our patient had multiple risk factors that predisposed her to developing an ulcer and subsequent bleeding including prolonged use of non-steroidal anti- inflammatory drugs (NSAIDs), the peri-operative use of systemic steroids and the stress of PICU hospitalization all in the setting of a posterior fossa tumor. An important aspect of our patient’s case is the development of a peptic ulcer in the setting of a posterior fossa tumor which has been described as a Cushing’s ulcer. Harvey Cushing’s initial work in 1932 described an association between intracranial tumors or injury and the development of ulceration in the upper gastrointestinal tract.⁷ He theorized that these intracranial masses caused stimulation of the vagal nerve leading to increased gastrin predisposing patients to develop an ulcer in the esophagus, stomach or duodenum. This suggests prophylactic acid suppressant medication may be necessary.^7,8

CONCLUSION

This case highlights the successful use of acid suppressants to heal a CDF caused by a perforated duodenal Cushing’s ulcer, a complication rarely seen in children. In pediatrics, some patients are predisposed to develop peptic ulcer disease (NSAID use, steroids, posterior fossa tumors, to name a few) and should have prophylactic acid suppressant started. Hemorrhage from an ulcer can have high morbidity and aggressive treatment, including the use of continuous PPI infusion, should be initiated until bleeding is controlled.

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Dispatches From The Guild Conference, Series #6

Antiviral Therapy for Patients with Immune Active Hepatitis B – What, When and is Forever?

July 2017 • Volume XLI, Issue 7

Tatyana Kushner,

Norah Terrault

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Hepatitis B is the most common chronic viral infection in the world and leads to significant complications. Antiviral therapies currently available are highly effective in achieving viral suppression, however if and when providers can consider discontinuation of antiviral therapy continue to evolve. Increasingly, there is emphasis on treating until HBsAg loss occurs, but this means many patients will be on life-long therapy. A finite duration of therapy is attractive to patients and providers but one must consider the potential risks when stopping treatment. New data continue to inform this question and are reflected in this review.

Tatyana Kushner, MD, MSCE, Norah Terrault, MD, MPH, Department of Gastroenterology/Hepatology, University of California, San Francisco, CA

INTRODUCTION

An estimated 240 million persons are affected by chronic hepatitis B infection, making HBV the most common chronic viral infection worldwide. Forty percent of chronic hepatitis B (CHB) patients will progress to liver complications of decompensated cirrhosis and hepatocellular carcinoma (HCC), leading to 1 million deaths/year.¹ Given this tremendous disease burden, the WHO and CDC have made hepatitis B part of the viral hepatitis “elimination by 2030 initiative.

In the United States, approximately 2.2 million persons have chronic HBV, and this may be an underestimate since prevalence studies may under- sample immigrant and other high-risk populations. Over the past 35 years, it has become evident that up to 75% of persons with chronic HBV in the United States are foreign-born, and therefore despite implementation of universal vaccination in the United States, chronic hepatitis B is an ongoing public health problem in our country.²

With current therapies, hepatitis B cannot be cured, as hepatitis B virus exists as cccDNA in the hepatocyte and this serves as a reservoir, unaffected by the nucleoside analogues used to treat CHB. However, hepatitis B can be controlled with clinical benefits. Intermediate endpoints that reflect adequate disease control include sustained suppression of HBV DNA, HBeAg seroconversion in patients who are HBeAg positive at the time of initiation of treatment, reversal of hepatic fibrosis, and HBsAg loss (or appearance of hepatitis B surface antibody), the latter being the best marker of lasting immune control. Sustained viral suppression has been associated with reduced rates of cirrhosis, hepatic failure, liver cancer, and liver-related deaths.5

Recently updated guidelines from the American Association for the Study of Liver Diseases (AASLD) were published, supported by multiple systematic reviews of the literature.³ Who to treat, how to treat and when to stop were addressed in the guidelines. Importantly, the goal of HBsAg loss as an endpoint of therapy was highlighted but with discontinuation of therapy prior to HBsAg loss a possible option after careful consideration of provider and patient preferences/goals. Defining those patients in whom discontinuation of therapy is best suited is an active area of research.

Indications for Treatment in Chronic Hepatitis B

The dynamic natural history of chronic hepatitis B requires careful monitoring of patients with CHB throughout their lives. Patients who are not candidates for treatment on initial evaluation may become treatment candidates in future. Phases of infection (see Figure 1) include the HBeAg positive immune tolerant phase where there is no significant necroinflammatory activity and ALT is normal despite marked HBV DNA elevation, and the immune clearance phase characterized by active HBeAg positive hepatitis B defined by HBV DNA > 20,000 IU/mL and ALT elevated at ≥2 times the upper limit of normal (ULN). Once HBeAg is cleared, the immune control phase is characterized by inactive CHB with suppressed HBV DNA and normal ALT, although CHB reactivation can occur, and is defined by elevated HBV DNA and ALT despite HBeAg negative status. The presence of precore and basal core promoter mutations often characterizes this phase and can lead to marked elevations of HBV DNA with abnormal ALT values. In a small number of patients clearance of HBsAg occurs, although this is not common.¹ HBeAg negative immune active phases, characterized by elevated HBV DNA and ALT levels, is recommended as these phases of infection place patients at the highest risk of liver-related complications (see Figure 2). The viral load threshold advised by AASLD guidelines is HBV DNA levels of ≥ 2000 IU/mL if HBeAg negative and HBV DNA ≥ 20,000 IU/mL if HBeAg is positive, along with elevated ALT ≥2 times ULN. 3 For patients with HBV DNA near but not quite at the treatment thresholds or ALT levels at 1-2 ULN, a liver biopsy may be useful in determining whether there is sufficient necroinflammation and/or fibrosis to warrant initiation of therapy.

Treatment Options for Immune Active Hepatitis B

Providers can choose between peg-interferon alfa-2a, entecavir (ETV), tenofovir dipovoxil fumarate (TDF), and the recently approved tenofovir alafenamide (TAF) (Table 1). Antiviral agents such as lamivudine and adefovir, which have been previously recommended, are no longer indicated given significantly higher risks of resistance. Although peg-interferon has no risk of resistance and achieves the highest rates of HBsAg loss with finite duration of treatment of 12 months, its use is limited by the higher frequency of side effects and more limited applicability (its use is contraindicated in those with cirrhosis, significant psychiatric disease or cardiopulmonary disease, for example). The oral antiviral agents, ETV, TDF and TAF all have high potency and very low rates of resistance in treatment naïve patients. For nucleoside analogue experienced patients, TAF and TDF are preferred drugs (Table 1).

As mentioned, the oral antiviral drugs are generally very well tolerated. However, prolonged use of TDF has been associated with kidney and bone toxicity (specifically Fanconi’s syndrome), and therefore monitoring of renal function (and phosphate level and urine studies) as well as bone scans need to be performed annually. The recently approved drug, TAF, which has been found to be non-inferior to TDF in efficacy,^6,7 minimizes these toxicities, and therefore offers a better safety profile long-term. Entecavir is not associated with significant side affects other than rare reports of lactic acidosis in patients with decompensated cirrhosis. Thus, TAF and ETV are offer similarly high efficacy and excellent safety without the need for monitoring for toxicities.

Antiviral Treatment Discontinuation

Considerations for discontinuation of nucleos(t)ide analogue therapy differ for patients with immune active HBeAg positive versus HBeAg negative CHB.³ For patients with HBeAg positive immune active disease treated with ETV or TDF, about 20% of patients will undergo HBeAg seroconversion to HBeAb after 1 year of therapy and this percentage increases to ∼35% after 5 years of treatment. Given that HBeAg seroconversion is a key event in CHB natural history which signals an improved level of immune control and decreased risk of cirrhosis, HCC and liver-related death, the AASLD guideline recommends that persons with HBeAg-positive disease who achieve seroconversion to anti-HBe, may discontinue treatment after a period of treatment consolidation for at least 12 months. This recommendation does not apply to patients with cirrhosis, given ongoing high risk of clinical decompensation with discontinuation of antiviral therapy.

Although antiviral therapy may be discontinued, the durability of response is often not sustained, and treatment may have to be re-initiated. In patients who stop treatment with HBeAg seroconversion, studies have demonstrated virological relapse defined by HBV DNA>2000 IU/mL in up to 80% of patients.⁸ Furthermore, seroreversion back to HBeAg positive status occurs in up to 44% of patients.⁹ Thus, it is important to identify which patients are more likely to sustain virologic control. The factors most consistently associated with a durable response off treatment are younger age (<40 years) and longer duration of treatment consolidation after seroconversion (>12-15 months).¹⁰ Thus, adults under the age of 40 years with 18 months of consolidation therapy may be the best candidates for treatment discontinuation. Due to the risk of relapse and HBV flare, recommendations are to continue close monitoring of HBV DNA and ALT for at least a year after treatment withdrawal.

The AASLD guideline recommends that HBeAg negative immune active patients receive indefinite antiviral therapy, but adds that treatment discontinuation can be considered after HBsAg loss has occurred. The rationale for indefinite therapy stems from studies of treatment withdrawal that show that HBV DNA becomes elevated again in more than 90% of patients.¹¹ Clinical relapse occurs in up to 53% of patients, with the rate dependent upon how relapse is defined. Hepatitis flares and even hepatic decompensation occurred, with those with cirrhosis at highest risk.¹²

Predictors of relapse have been investigated, and similarly to HBeAg positive patients, a prolonged period of HBV DNA undetectability and low HBsAg titer are most consistently associated with less hepatitis flares and clinical relapses. A recent study showed that sustained suppression of HBV DNA for over 3 years compared to 1 year was associated with lower rates of disease relapse.¹³ Even after treatment consolidation, once treatment is discontinued, patients should be monitored closely for recurrent viremia, flares, and clinical decompensation. HBeAg-negative patients with cirrhosis are not recommended for withdrawal of antiviral therapy due to concerns of HBV flare leading to liver decompensation.

Thus in order to determine whether to discontinue antiviral therapy, the patient and provider preferences need to be weighed against clinical considerations such as the risk of resistance and liver outcomes. In a survey of patient preferences, more than 80% of patients preferred a finite duration of therapy, when asked if they were willing to have lifelong treatment, more than 40% of patients agreed.¹³ Thus, patient preferences in discussion with their provider may help to inform the duration of treatment.

CONCLUSIONS

With currently available treatment options, CHB is controlled and not cured. Thus, a long-term treatment plan is needed in those with active disease. Tenofovir (TDF and TAF), ETV, and peg-IFN are the preferred treatment agents, as they have been shown to decrease progression of disease and disease-related complications. The endpoints of treatment are evolving, and although HBsAg loss is desirable, it is infrequently obtained with current therapies. Thus, discontinuation of therapy requires careful weighing of the risks and benefits of health outcomes, as well as patient/provider preference, with close monitoring after treatment discontinuation. Ongoing and future studies will help to define those patients with immune active disease who are best suited for discontinuation of antiviral treatment prior to achievement of HBsAg loss. Encouragingly, many new drug classes are being evaluated for CHB, and the hope is that future drug combinations will more frequently achieve HBsAg seroconversion (functional cure) with a finite treatment course.

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Nutrition Issues In Gastroenterology, Series #165

Reinfusion of Gastrointestinal Secretions – The Bedside Experience

July 2017 • Volume XLI, Issue 7

Amy Berry

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Both pancreatic enzymes and bile salts are necessary for complete absorption of dietary fat. While pancreatic enzymes are available to replace insufficient pancreatic secretion, there is no replacement for bile salts. Unabated external loss of upper intestinal secretions can result in dehydration, acid/base imbalance, electrolyte abnormalities as well as malabsorption. This article describes the reinfusion of GI secretions, various methods of reinfusion, as well as potential and significant pitfalls when embarking on this form of treatment.

Amy J. Berry, MS, RD, CNSC University of Virginia Health System, Surgical Nutrition Support Charlottesville, VA

INTRODUCTION

Successful digestion and absorption of long chain fat and fat soluble vitamins require coordinated release of adequate pancreato-biliary secretions, along with ingested nutrients. Bile, produced in the liver, flows into the right and left hepatic ducts before joining the common bile duct, where it finally enters the duodenum via the sphincter of Oddi (Figure 1).¹ Between meals, bile is shunted into the gallbladder for storage. After fat ingestion, secretin stimulates bile release from the liver, while cholecystokinin (CCK) stimulates gallbladder contraction as well as relaxation of the sphincter of Oddi. Pancreatic enzyme release is dependent on both secretin and CCK.²

Approximately 1 liter each of bile and pancreatic fluid, as well as 2-3 liters of gastric secretions are produced daily.³ However, some conditions may prevent these digestive secretions from ever reaching the small intestine, leading to malabsorption, dehydration, and electrolyte disarray (Table 1). Reinfusion of these secretions may be a viable option in select populations, e.g., those with prolonged hospitalization, high volume upper GI losses with persistent fluid and electrolyte imbalance, and imperfect absorption. To date, only case reports have been published on this practice.⁴ Bile reinfusion can be complex; for example:

1. When might a clinician consider this option?
2. How is it actually executed on in-patient units?
3. How does this work when transitioning the patient to home or a facility?

Case A
Pancreatitis with gastric outlet obstruction

PG, a 59-year-old male was transferred from an outside hospital to our service for continued management of severe gallstone pancreatitis after cholecystectomy. He was 5′ 11″ with a pre-illness weight of 88 kg (admit weight of 102 kg). He reported normal oral intake up until the time of admission for pancreatitis, however he had been NPO for 7 days prior to transfer. He was briefly placed on parenteral nutrition (PN) due to gastric outlet obstruction with prolonged NPO status, catabolic state, and lack of appropriate enteral access.

Two days after admission, a 24 Fr percutaneous endoscopic gastrostomy tube was placed with a 12 Fr jejunal extension tube (PEG/J) (Wilson-Cook; Cook Medical). Standard enteral nutrition (EN) was initiated through his j-tube, followed by PN discontinuation. The PEG was left to gravity drainage to decompress his gastric contents while continuing to feed his jejunum. PG’s gastric output was ∼1.5L over 24 hours with reported nausea and emesis. He was currently receiving 15mg of a proton pump inhibitor (PPI) suspension twice daily, via his j-tube, which was increased to 30mg twice daily. The surgical team allowed sips of clear liquids for comfort; however, his gastric output increased to 3-4 L/day. He was having difficulty tolerating the 150mL water flush through his j-tube, causing nausea and hiccups leading to emesis over his vented secretions. His gastric pH was checked to ensure PPI efficacy and confirmed to be >6. Due to the high gastric volume loss, the surgical team started replacement fluids through his j-tube using lactated ringers as 1/2 mL for each 1 mL of output from his gastric tube, run continuously. He complained of frequent “orange colored” stools, which coincided with the increase of his EN rate.

Two days after the standard EN reached goal rate, it was changed to a semi-elemental formula (Perative; Abbott Nutrition). The rationale for this change was the presumption that the external loss of pancreato-biliary secretions from gastric venting, known pancreatic damage, and his orange colored stools suggesting malabsorption. Due to his current complexity of care, with simpler methods available to stabilize fluid and electrolytes, it was deemed not the time in his course to consider GI reinfusion. After the change to the semi- elemental feeding, the patient reported firmer and color normalization of his stools.

PG required a negative pressure wound therapy vac due to dehiscence at his proximal surgical midline incision necessitating discharge to a facility for wound management, as well as ongoing dependence on intravenous volume replacement. He was changed to a nocturnal EN regimen in anticipation of discharge. His gastric output had decreased to 1-1.5L /day with small sips of clear liquids for pleasure. For volume replacement, he discharged with intravenous Lactated Ringer’s (1:1 replacement of gastric output), as well as water flushes via the j-tube. Weight on discharge was 97 kg.

Five days later, PG was readmitted with failure to thrive (FTT) and acute kidney injury (AKI) (Table 2); lipase was elevated to 6700. PG’s PPI had been stopped upon arrival at the outside facility and a standard, fiber containing formula had been substituted for the semi- elemental formula he was previously receiving. His fluid replacement was unknown, and the patient reported persistent and severe nausea/vomiting. PG required 10L of resuscitation, the PPI and semi-elemental EN were resumed. Due to his metabolic disarray and dehydration, the decision was made to start GI reinfusion through his j-tube. PG’s gastric pH was rechecked (7.9), therefore appropriate for reinfusion into the small bowel (goal gastric pH = ≥ 6 to mimic normal pH). The patient was stabilized and ready for discharge. The day prior to discharge, tubing was fashioned to shunt gastric output directly from his G-tube into his j-tube. This direct connection of gastric output to jejunal input was to occur during the day when EN was off; at night when j-tube was used for feeding, the G-tube would be left to gravity and those contents bolused into the jejunum in the morning; which varied between 400-600mL. He initially tolerated this change, and PG was discharged to the transitional care facility weighing 95 kg.

While at the transitional care facility, PG did not tolerate his G-tube being hooked directly up to his j-tube, reporting increased nausea/emesis. He also reported not seeing any fluid moving from his G-tube to his j-tube during the day. Intolerance of the large jejunal bolus of GI secretions collected overnight was now occurring. The facility was having difficulty reinfusing all of his upper GI losses. A follow up computed tomography (CT) scan showed a new peri-pancreatic fluid collection, in which a drain was placed. Over the next week, his stools became more watery and profuse and he was found to be C. Diff positive. Additionally, his glycemic control became erratic.

After 33 days, and exhibiting signs of sepsis, with increased nausea and vomiting, PG was readmitted to the hospital. Despite documentation reporting PG was receiving the majority of his goal EN on a consistent basis, he was down to 82 kg. This was presumed due to dehydration as well as his recent poor glycemic control altering his inability to fully utilize his EN. A CT scan demonstrated a recurrent retroperitoneal abscess. At this time, surgery was deemed necessary due to his persistent pancreatic fluid collection, associated fevers, and leukocytosis. Therefore, 2 months after PG’s first admission to our facility, he underwent an open necrosectomy for pancreatic abscess debridement, and 2 additional drains placed in the abscess cavity.

PG’s semi-elemental feeding was started post- operative day (POD) 1 at 20mL/hr, but he suffered from abdominal distention and discomfort when the rate was advanced. PG remained NPO at this time. Therefore, trophic EN continued for 3 days, after which slow advancement by 20mL/day commenced until goal rate was reached. PN was discussed with the surgical team during this time, but they preferred to avoid PN and continue to work on slow enteral advancement given his infectious risk and hyperglycemia. His PEG remained open to gravity, putting out 2-3L/day, with continued nausea. GI reinfusion was resumed as a bolus infusion. Unfortunately, due to his high volume losses and imprecise instruction to the nursing staff, jejunal boluses of >500mL were administered, causing the patient increased nausea and vomiting. EN advancement was further delayed as was adequate EN delivery.

At this time, one of the nurses devised a method for gravity feeding the patient’s gastric output through the j-tube using an enema bag. Biliary secretions were collected (over 4-6 hours), poured into the enema bag, hung alongside the EN, and then simply Y’d in utilizing the gravity method (Figure 2 A-D). The nurse and patient reported good tolerance to this method and patient was able to tolerate 100% reinfusion. Nocturnal EN was reattempted, but was met with intolerance. Therefore, he was discharged back to the transitional care hospital on continuous EN with gravity infusion of GI secretions. Three weeks later, the patient was able to tolerate G-tube clamping for 24 hours; one week later a clear liquid diet was restarted. Two weeks after this, his PPI was stopped. He was discharged home at 87kg. Two weeks later he followed up in surgical clinic, reporting he had stopped his nocturnal EN and was taking solid food. He had no signs or symptoms of malabsorption and weight had been stable since discharge. His feeding tube was removed in clinic.

Case B Surgical Leak

SL, a 41-year-old male, transferred to our facility for management of post-op complications. His history prior to transfer included: long term NSAID use, perforated duodenal ulcer requiring Billroth II/gastrojejunostomy and duodenal stump patch (Figure 3). On POD4 he required an exploratory laparotomy for drain dislodgement, and an additional drain placement. POD7, blood was noted in his drains. CT angiography was negative for bleeding; however, esophagogastroduodenoscopy (EGD) revealed a friable anastomosis with ulceration. POD13, he underwent an exploratory laparotomy: his anastomosis remained intact, but bile staining was found at the duodenal stump. It was at this time SL was transferred to our facility with AKI requiring continuous renal replacement therapy (CRRT), an open abdomen and ABThera wound vac. PN was started at the outside facility and was continued on admission. SL was 5′ 8″ and weighed 97.7kg.

Drainage of multiple fluid collections
Ligation of the gastroduodenal artery
Closure of a dehisced duodenal stump
Cholecystectomy
2 intraluminal drains placed to divert bile drainage
J-tube placement
Abdomen remained open

An elemental formula (Vivonex, Nestle Health Science) was started POD 1 due to loss of pancreato- biliary secretions via external drains (Figure 4 A-B) as follows:

Drain #1 (most proximal) in the hepatobiliary limb put out ∼1L/day of pancreato-biliary secretions (Figure 4 A).
Drain #2 (distal) put out ∼50mL/day (Figure 4 A-B).
The tip of drain #3 in the right upper quadrant terminated near the duodenal perf repair with minimal serosanguinous fluid (Figure 4 A)

The patient’s GI secretions (drain #1 and #2) continued to increase up to 3L/day; concurrently SL’s stool output also increased requiring a rectal management system. Prior to initiation of reinfusion, the duodenal drainage pH was confirmed to be 7.6. GI reinfusion was then initiated via j-tube on the following day by continuous pump method (continuous method of bile reinfusion required 2 feeding pumps) (Figure 5). In the case of SL, GI secretions were collected every 3 hours and transferred into an empty EN bag to be infused via pump. By utilizing a “Y” adapter, this volume was infused concurrent with EN formula into the jejunum. The combined rate of bile and EN infusion averaged between 300-400mL an hour. Although SL tolerated this volume without complaint, he was changed to a more calorie dense, semi-elemental formula (Vital 1.5, Abbott Nutrition) given his high duodenal and stool output to maximize absorption potential. Of note, it is likely he would have done well on a concentrated standard formula also.

A week after admission, SL returned to the OR for debridement of his abdominal wall and fascia, as well as abdominal closure. His AKI was resolving; he was now off CRRT. Stooling had decreased to once daily. Over the next few days, the volume of his most proximal biliary drain (#1), significantly dropped, and the secondary drain increased (determined to be a clog in drain #1). The patient continued to tolerate full GI reinfusion via pump of ∼1.5- 2L/day. A regular oral diet was started, but poor appetite and nausea prevented much intake. Discharge planning for home began, as he wanted to go home with family and not to a facility.

In preparation for the transition to home, the following simplifications were made to his EN and reinfusion regimen:

1. Trial GI reinfusion from pump to bolus. Bile was collected every 4 hours, 24/7, with reinfusion of at least 250mL (> 250mL was discarded) at each of the q 4 hour intervals (6 x/day).
2. Intravenous fluids were stopped; 100mL of 0.45% normal saline (NS) flushes before and after EN cycle was initiated with 50mL after any bile reinfusion.
3. PPI transitioned from IV to liquid suspension via jejunal tube.

The patient tolerated the changes well, and the new regimen appeared to keep SL’s electrolytes and volume status in balance. His weight was 93 kg. SL and family were educated and provided extensive written instructions, including home EN regimen, GI reinfusion, and home reconstitution of 1/2NS. However, it was noted that during the education, the patient and family asked very few questions and did not seem engaged. SL was discharged home and followed up in surgery clinic 4 days later. He reported not tolerating home EN, having increased nausea and vomiting; he was only reinfusing his bile on average of 2x/day (down from 6x/day in the hospital). He reported no BM since discharge. His weight in clinic was 79.5 kg. It was recommended he be readmitted for IV hydration; the importance of GI reinfusion was stressed. The patient declined readmission promising improved compliance at home.

One week later, SL was readmitted with FTT, nausea/vomiting, dehydration, and metabolic disarray (Table 2). SL reported not using EN, and that bile output had vastly tapered off. He was completely unable to eat due to gastric discomfort/fullness; feeling like food was “just sitting there” when he ate. He had not stooled in days. Of note, patient was on narcotics at home and only on stool softeners to relieve his constipation. SL was rehydrated and restarted on appropriate medications:

>PPI via j-tube, maximum dose BID
• Stool softeners and osmotic laxatives prn; goal = 1 stool at least every other day
>Oxycodone prn, for abdominal discomfort
>Reglan, before meals and HS to help with nausea
>50mL, 1/2 NS flush after anything administered via j-tube

His EN was changed back to continuous and bolusing of GI secretions into the j-tube every 4 hours was resumed. SL remained in the hospital 4 days tolerating regimen well. He reported less nausea; however, oral intake remained poor. His EN continued to meet his nutritional needs. EN was readjusted to a 16-hour nocturnal regimen with bolus of bile reinfused 6x/day as follows (ideally prior to any oral intake):

>250mL before and after 16 hour EN run (1800 & 1000)
>250mL ∼ 4 hours into EN infusion (before bed at 2000) and upon waking (0600)-(stop EN, infuse, resume EN)
>250mL while EN off during day (1200 & 1500)

For total of: 250mL 6x/day (1500mL); discard remaining. In addition:

Patient to use 1/2 normal saline (NS) flushes (made with 3/4 teaspoon table salt mixed with 1 liter of water- NOTE: would only have those patients prepare this mixture if you are sure they can measure correctly)
- Give 1 syringe (60mL) after medications, EN infusion, or GI secretion bolus.
- Patient to increase volume of 1/2NS bolus if oral intake of liquids decreased.

The patient and his family were much more interactive with education for home with a much higher level of interest in EN/reinfusion instructions- they wanted to go home and stay home.

Three days after discharge, patient’s family called reporting increase in stools, increase in nausea and decrease in bile output. He reported infusing all GI secretions, but reported the output had decreased to <1.5L/day. We reviewed exact EN and flush regimen over the phone; the patient had not quite received goal EN or flushes due to his abdominal discomfort. SL’s labs had been checked the day prior and were normal, showing no signs of dehydration. Due to his nausea and diarrhea, EN was changed back to a continuous regimen again. His medications were reviewed; upon discharge his PPI had been changed to an oral capsule vs. the suspension BID via jejunal tube and his antiemetic and prokinetic coverage were inadvertently left off his discharge medications; all of which were resumed.

SL was seen twice in surgery clinic over the next month; his weight maintained at 79.5 kg and he remained well hydrated with decreasing GI secretions from his drains. Three months after his first admission, his final surgical drain was removed. He was off EN, maintaining his weight, and his feeding tube was removed.

APPLICATION AND CONCLUSION

These two cases highlight clinical applications of successful GI reinfusion along with EN to provide nutrition, hydration, electrolyte balance, and improved absorption in patients with excessive loss of GI secretions, avoiding both PN/IV fluids and a central line. They also highlight the complexity of this process, as well as the potential number of mistakes and pitfalls that can easily occur along the way. A multidisciplinary team is clearly needed to achieve success. Once a patient is deemed a good candidate for GI reinfusion (Table 3 lists poor candidates), the best method needs to be determined (Table 4). In deciding on how to reinfuse, it may not only depend on whether the patient tolerates it, but whether the patient will be in a facility or at home. Ideally, GI secretions should be administered concurrent with EN for optimal pancreato-biliary secretion and nutrient mixing once a pH >6 has been verified. If it is not in the best interest for the patient to receive this therapy, there are other options for EN without reinfusion of endogenous secretions in order to maintain hydration and electrolyte balance (Table 5).

Thank you to the surgical nurses, residents and attendings who help conceptualize unique solutions for complex patients, and who are always willing to take the time to teach me. A special thanks to Joe Freeze, NP.

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A Case Report

Familial Multifocal Gastrointestinal Stromal Tumors – Critical Lessons in Identification of a Rare Disorder

June 2017 • Volume XLI, Issue 6

Paul Fitzmorris,Leona Council,Fred Weber

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Paul Fitzmorris¹ Leona Council² Fred Weber¹ 1Department of Gastroenterology and Hepatology, ²Department of Pathology, University of Alabama at Birmingham, AL

INTRODUCTION

A 50 year-old Caucasian gentleman presented with melena. Identification of multiple gastric submucosal masses and a family history of gastrointestinal stromal tumors had important clinical implications for both the patient and his asymptomatic children.

Case

A 50 year-old Caucasian gentleman with a history of gastroesophageal reflux, diabetes mellitus and basal cell carcinomas presented with melena over the past few weeks. He denied nausea, vomiting and abdominal pain.

His vitals and abdominal exam were unremarkable. Digital rectal exam revealed black, tarry stool. Hemoglobin on admission was 6.3 g/dL. Computed tomography (CT) scan revealed two infiltrating masses in the proximal stomach (Images 1 and 2).

After resuscitation, an upper endoscopy noted a large submucosal mass in the fundus and two smaller submucosal masses along the angularis. Subsequent endoscopic ultrasound described the masses as lacking a defined capsule and having irregular extension into the gastric wall with isoechoic and heterogenous areas. Fine needle aspiration revealed spindle cell tumors (CD117 positive/DOG1 negative/SMA negative cells with < 2 mitoses per 20 high powered field) (Images 3 and 4). Upon further questioning he reported that multiple first- and second-degree relatives have been diagnosed with gastrointestinal stromal tumors (GISTs).

His disease was thought to be locally advanced and he was started on neo-adjuvant imantinib. Total gastrectomy was performed several months later; small ileal and jejunal tumors, not previously seen by CT, were identified intraoperatively and resected. These additional lesions were GISTs as well, and he was placed on long-term maintenance imantinib.

A detailed family history revealed that his father, brother, paternal aunt and multiple cousins on the paternal side had previously been diagnosed with GISTs, the youngest at age 25 and the oldest at age 57. The patient underwent genetic testing, revealing him to be heterozygous for a three nucleotide deletion on exon 11 of KIT mRNA.

After his diagnosis with the germline KIT mutation, his two adult children (son and daughter) were tested and both were positive. His asymptomatic daughter was found to have a 3 cm jejunal mass on screening CT enterography and resection is planned. His son is scheduled for an EGD, colonoscopy and CT enterography.

Discussion

GISTs are rare tumors, most commonly due to sporadic mutations of the KIT gene. The annual incidence of GISTs is estimated at 10 – 20 per 1,000,000. The median age of diagnosis is 50 years of age and some literature suggests a male predisposition. Presentations may include gastrointestinal bleeding, abdominal pain and gastrointestinal outlet obstruction. GISTs may occur in the stomach (60 – 70%), small intestine (20 – 30%), colon/rectum (5%) and esophagus (<5%).¹ GISTs usually present as solitary tumors with local or locally advanced disease. Only 10% of cases are metastatic upon initial diagnosis. Multifocal disease can also be due to multiple primary tumors. The occurrence of multiple primary GISTs in adults is rare but may be under appreciated. It is almost exclusively seen in familial GIST disorders or other specific syndromes, such as Carney’s triad or type 1 neurofibromatosis.²

Familial GISTs are part of a rare autosomal dominant disorder of unknown incidence. It is due to inherited germline mutations of the KIT gene in 80% of cases and mutations of the PDGFRA gene in 10% of cases. Given how rare familial GISTs are, guidelines do not discuss when to screen for germline mutations, nor how/when to evaluate asymptomatic family members with the mutation.³ Finally, case reports have described an association between familial GISTs and other manifestations of the KIT gene mutations, including gastrointestinal dysmotility, cutaneous hyperpigmentation, urticaria pigmentosa, systemic mastocytosis and melanoma. The link between these disorders may be explained by a common progenitor cell that requires KIT activation to differentiate into interstitial cells of Cajal, gastrointestinal smooth muscle, melanocytes and mast cells.^4-8

CONCLUSIONS

When a patient is found to have multifocal GISTs or a family history of gastrointestinal stromal tumors in multiple family members, consider genetic testing for a familial GIST mutation.
For patients with a germline KIT mutations, periodic GI tract surveillance, including dedicated small bowel imaging, seems reasonable. Our patient’s asymptomatic daughter underwent a CT enterography that identified a GIST, allowing for pre-symptomatic surgical resection.
Furthermore, an annual dermatologic evaluation may be prudent. Our patient’s daughter was found to have a dysplastic nevus.

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Dispatches From The Guild Conference, Series #5

Postoperative Management of Crohn’s Disease

June 2017 • Volume XLI, Issue 6

Jana G. Hashash,

Miguel Regueiro

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The majority of patients with Crohn’s disease will require an intestinal resection at some point in their life. Postoperatively, these patients are at risk for developing recurrent Crohn’s disease and medications are often required to prevent recurrence. Here we discuss the importance of stratifying patients according to their risk of recurrence as it determines postoperative management.

Jana G. Hashash, MD, MSc, Assistant Professor of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA Miguel Regueiro, MD, AGAF, FACG, FACP, Professor of Medicine and Professor, Clinical and Translational Science, University of Pittsburgh School of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Senior Medical Lead of Specialty Medical Homes, University of Pittsburgh Medical Center, IBD Clinical Medical Director, Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh, PA

INTRODUCTION

Crohn’s disease is a chronic inflammatory condition that affects the GI tract anywhere between the mouth and the anal verge. Approximately 780,000 people in the United States carry the diagnosis of Crohn’s disease and the incidence and prevalence have been on the rise.^1,2 The majority of patients with Crohn’s disease will require an intestinal resection, most commonly an ileocecal resection. The indication for surgery is usually for medically refractory disease or complications such as strictures, abscess, fistulae, or rarely malignancy.^3,4 In a recent systematic review, it was reported that the 1 year cumulative risk of surgery for Crohn’s disease patients is estimated to be 16.3%, 33.3% at 5 years, and as high as 46.6% at 10 years.⁵

Natural Course of Postoperative Crohn’s Disease and Recurrence Rates

After a curative ileocecal resection, the prevention of Crohn’s disease recurrence remains a challenge. Recurrence in these patients usually occurs at the ileocolonic anastomosis and in the neo-terminal ileum.⁶ Studies have shown that histologic recurrence may occur as early as 1 week after surgery.⁷ Endoscopic recurrence of Crohn’s disease tends to follow with recurrence rates as high as 70-90% at 1 year after surgery in patients who do not receive postoperative Crohn’s disease medications.^6,8-12 Crohn’s disease recurrence after resection is often silent and this accounts for the lag between endoscopic and clinical recurrence, with the latter occurring later.¹³ Clinical recurrence rates, as defined by the Crohn’s disease Activity Index (CDAI), were shown to occur in 20-40% of patients at 1 year from surgery, and 35-50% by 5 years postoperatively.^6,9-11,14 It is not an uncommon scenario for patients to require yet another surgical resection once clinical symptoms ensue in the postoperative setting (i.e. clinical recurrence). A quarter (25%) of patients will require a second intestinal resection by 5 years after their initial surgery, and up to 35% of patients by 10 years.15 The indication for subsequent intestinal resection tends to be similar to the indication of the initial operation.^16-19

Surveillance of Postoperative Crohn’s Disease

The most sensitive modality for detection of postoperative Crohn’s disease is via an ileocolonoscopy which allows for the evaluation of the neo-terminal ileum mucosa. Due to the high rates of early endoscopic recurrence, it has been recommended that ileocolonoscopy is performed 6-12 months postoperatively.^13,17,20-22 This would allow for early detection and aggressive treatment of recurrent disease, if present.

Endoscopic Scoring of Postoperative Crohn’s Disease

The most widely used endoscopic scoring system was developed by Rutgeerts et al.¹¹ Although it is not validated, this score is widely used and predicts a patient’s risk for future clinical and surgical recurrence. Based on the endoscopic appearance of the neo-terminal ileum, patients are categorized into one of 5 groups; i0, i1, i2, i3, or i4 (Table 1). Patients with a score of i0 (normal appearing neo-terminal ileum) and i1 (<5 small aphthous ulcers in the neo-terminal ileum) have a low likelihood of progression to clinical or surgical recurrence in the next 5 years and are considered to be in endoscopic remission. Specifically, 85% remain in clinical remission over a 2-year time period and are considered very low risk for requiring a second operation.^11,23,24 Patients with scores of i2, i3, and i4 are at a high risk to require a second Crohn’s disease intestinal operation within the following 5 years and are designated as having endoscopic recurrence.^11,23,24

Risk Factors for Postoperative Crohn’s Disease Recurrence

There are several risk factors that have been shown to contribute to the postoperative recurrence of Crohn’s disease. These factors are classified as (1) patient- related factors, (2) disease-related factors, and (3) surgery-related factors.²⁵ The only modifiable risk factor is tobacco smoking.^26-30 Not only does smoking tobacco increase endoscopic and clinical recurrence rates, surgical rates were seen to increase by 2.5 fold.31 Recurrence rates were higher in females and those who were smoking greater than 15 cigarettes per day.^28,32 Fistulizing or penetrating Crohn’s disease and the need for prior Crohn’s disease related intestinal resection have also been shown to be strong risk factors for postoperative recurrence.³³ Data on peri-operative steroid use as a risk factor for Crohn’s disease recurrence has been inconclusive. Recently, however, a multi-centre observational study by de Barcelos et al. showed that perioperative steroid use was the only significant risk factor for early postoperative endoscopic recurrence.³⁴ A number of other disease-related risk factors have been studied as potential risk factors and these include young age at diagnosis of Crohns’ disease, young age at initial intestinal resection, and short duration of disease prior to the need for surgery.^{16,17,19,25,27,28,30,35-40} Surgical risk factors pertaining to the intestinal resection itself have been extensively studied, but all have been inconclusive in identifying strong factors for postoperative recurrence of Crohn’s disease. Variables that were explored include: length of resected bowel, width of surgical margins, type of anastomosis, perioperative complications, and presence of granulomas in the surgical specimen.^{4,24,25,28,36,39,41-44}

Medications Studied for the Management of Postoperative Crohn’s Disease

There have been many studies on the early use of different medication classes for the prevention of postoperative Crohn’s disease after resective surgery. Table 2 displays the 1 year clinical and endoscopic recurrence rates that have been reported in various randomized controlled studies of patients after an ileocecal resection and the use of immunomodulators,^45-47 nitroidimazole,^48,49 budesonide,^50,51 5-aminosalicylic acid^52-55 and placebo. The lowest endoscopic recurrence rates were seen with immunomodulators (azathioprine and 6 mercaptopurine) at 42-44%. Postoperative recurrence rates were further decreased with the widespread use of anti-tumor necrosis factors (anti-TNF) medications. Table 3 summarizes the postoperative endoscopic rates reported with these medications.^56-64 Most recently, data from the PREVENT trial⁶⁵ showed that the clinical recurrence rates in patients on infliximab was less than the rates on placebo at week 76 or less, however this difference was not statistically significant (12.9% vs 20%; p=0.097). Endoscopic recurrence rates, however, were significantly lower in patients receiving infliximab compared to placebo (22.4% vs 51.3%; p<0.001). In the POCER trial, endoscopic recurrence rates at 18 months after surgery compared those who underwent an ileocolonoscopy at 6 months after an ileocecal resection (active care arm) and who subsequently received medication escalation if needed (endoscopic ileal score ≥i2), to those patients who did not get a 6 month ileocolonoscopy (standard care arm).⁶⁶ All patients received metronidazole 400 mg by mouth twice daily for the first 3 months postoperatively. Additionally patients who were classified as high risk (smokers, penetrating disease, and/or prior intestinal resection) received azathioprine. Those who were intolerant of azathioprine were given adalimumab instead. At 18 month follow up, endoscopic recurrence rates were significantly lower amongst patients in the active care arm compared to those in the standard arm (60/122=49% vs 35/52=57%; p=0.03). It was also noted that within the high-risk active arm patients, those who received adalimumab had lower 6 month endoscopic recurrence rates when compared to those who received azathioprine (6/28=21% vs 33/73=45%).66

Management of Postoperative Crohn’s Disease – Technical Review and Guidelines

Recently, the American Gastroenterological Association (AGA) published a technical review on the management of postoperative Crohn’s disease.⁶⁷ This review addressed clinical questions pertaining to the different management strategies for postoperative Crohn’s disease patients and their role in reducing recurrence. For instance, this review addressed if routine early pharmacologic prophylaxis was superior to endoscopy- guided treatment in reducing long-term recurrence in postoperative Crohn’s disease patients. Another question related to the comparative effectiveness of the different medications used amongst Crohn’s disease patients who are receiving early postoperative pharmacological prophylaxis. Similarly, comparative effectiveness of the different medications used to decrease endoscopic recurrence in patients who already developed postoperative asymptomatic endoscopic recurrence. Additionally, this review compared whether routine endoscopic monitoring at 6-12 months postoperatively is superior to no endoscopic monitoring.⁶⁷ This technical review informed AGA Guidelines for the management of postoperative Crohn’s disease.⁶⁸ (Table 4) The authors provide two approaches to patients with postoperative Crohn’s disease (Figures 1, 2). Based on individuals’ risk factors, patients are stratified in to groups to aid physicians in their further management. Some physicians prefer to practice the ‘watchful waiting’ approach, while other physicians are more proactive and initiate medications postoperatively for prophylaxis and secondary prevention of recurrent Crohn’s disease. Despite the published algorithms, deciding the best option for patients often remains a dilemma. It is the authors’ personal practice to initiate postoperative Crohn’s disease prophylaxis to prevent recurrence. Almost all patients receive a medication postoperatively, whether using an immunomodulator or combination therapy with a biologic agent and an immunomodulator. Depending on a patient’s risk factors, he/she is categorized in to a low-risk, moderate-risk, or high-risk group (Figure 1). All patients regardless of their group will receive an ileocolonoscopy for surveillance of endoscopic recurrence, 6-12 months postoperatively. The authors stratify patients into risk categories when approaching postoperative management. Low risk patients include those who are undergoing their first intestinal resection for a short stricture and those who have had long standing disease (>10 years). Patients in the low risk group are not administered medications, however, if there is evidence of recurrent Crohn’s disease (ileal score of ≥i2), treatment with an immunomodulator and/or anti-TNF is initiated. Otherwise, they would remain off of any medications, but should continue to have surveillance colonoscopies every 1-3 years. Patients who are in the moderate risk group are those who are undergoing their first intestinal resection for a long stricture (>10 cm) or for inflammatory Crohn’s disease and who have had disease for shorter than 10 years. Patients in this moderate risk group start thiopurines in the postoperative setting +/- metronidazole. While the authors still believe there is a role for immunomodulators in patients not previously receiving this type of medication, there has been a recent trend to only use thiopurines in combination with biologics rather than monotherapy. Nonetheless, we still use immunomodulators for this moderate risk group naïve to treatment, but escalate to an anti-TNF if there is evidence of subsequent recurrence. Patients in the high-risk group include those with penetrating disease, more than 2 intestinal resection surgeries, and who are smokers. In these high-risk patients, we recommend a combination of an immunomodulator with anti-TNF. Whether therapeutic drug monitoring of biologic therapy would allow for monotherapy anti- TNF (without an immunomodulator) for postoperative Postoperative Management of Crohn’s Disease Crohn’s disease management is unknown. Another approach to the management of postoperative Crohn’s disease is to stratify patients by risk of recurrence but utilize endoscopic recurrence to guide therapy (Figure 2).⁶⁶ In this approach, patients are separated in to a high-risk group and a low risk group for recurrence where only patients in the high-risk group would receive Crohn’s disease medications. The medication of choice is a thiopurine agent, but in cases of thiopurine intolerance, anti-TNF medications are used instead. Again, similar to the algorithm in Figure 1, all patients would undergo an ileocolonoscopy at 6 months postoperatively, and depending on evidence of endoscopic recurrence, medication escalation is made. Of note, the authors of POCER have also reported the potential for fecal calprotectin as a surrogate marker for Crohn’s disease recurrence and may be a noninvasive method to measure recurrence.⁶⁹

CONCLUSION

The majority of patients with Crohn’s disease will require an intestinal resection at some point in their lifetime. Postoperative management of these patients remains a challenge. It is important to identify high- risk patients who exhibit risk factors for recurrence and to aggressively treat these patients to prevent or ameliorate recurrence of their Crohn’s disease. All patients regardless of their risk should have an ileocolonoscopy 6-12 months postoperatively to initiate or adjust medications in cases of endoscopic recurrence (ileal score ≥i2). The authors provide the algorithm that they utilize in their practice when approaching postoperative Crohn’s disease patients (Figure 1).

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Nutrition Issues In Gastroenterology, Series #164

Essential Fatty Acid Deficiency

June 2017 • Volume XLI, Issue 6

Kris M. Mogensen

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Essential fatty acid deficiency (EFAD) may occur in both the inpatient and outpatient setting. Patients with malabsorptive disorders as a result of pancreatic insufficiency or massive bowel resection are at risk, and it is important to recognize that other patient populations may develop EFAD. A relatively new risk factor for EFAD is the shortage of intravenous fat emulsions in those requiring parenteral nutrition. This article provides a brief review of the role of essential fats, identifies those at risk, the clinical signs and symptoms associated with EFAD, as well as prevention and treatment recommendations.

Kris M. Mogensen MS, RD-AP, LDN, CNSC Team Leader Dietitian Specialist, Department of Nutrition, Brigham and Women’s Hospital, Boston, MA

INTRODUCTION

Essential fatty acid deficiency (EFAD) is rare in healthy adults and children who consume a varied diet with adequate intake of essential fatty acids, linoleic acid (LA) and alpha-linolenic acid (ALA). Clinicians should be aware of the risk of EFAD in specific populations that may suffer from malabsorption syndromes, or have other reasons that severely limit fat intake, absorption, or metabolism. A recent concerning trend in the United States (US) is the increasing incidence of parenteral nutrition (PN) product shortages, including vitamins and minerals, but also lipid injectable emulsion (ILE, formerly known as intravenous fat emulsion or IVFE).¹ This has led to new populations at risk for EFAD, and clinicians must be aware of these shortages and the risks posed to patients dependent on PN.

Role of Fats

Fat is an essential component in the diet, whether it part of an oral diet, an enteral nutrition formula, or part of a PN admixture. The human body needs fat stores to cushion organs and provide insulation for temperature regulation. The fat depot can be used for energy during times of starvation, although it is important to recognize that some tissues in the body (brain and red blood cells) rely solely on glucose for energy as fat cannot be metabolized to create glucose. Dietary fat is not only an energy source through oxidation, it is also required to facilitate absorption of fat-soluble vitamins in the small bowel.²

Fat has important roles at the cellular level as it is an essential part of cell membranes. The cell membrane is composed of phospholipids, which are sensitive to chemical signaling. Consuming diverse types of fat (e.g., omega-3 fatty acids vs. omega-6 fatty acids) will allow incorporation of different types of fat into the cell membrane, modifying the response to a number of metabolic processes including inflammation, controlling gene expression in the cell, and cellular protein production. A recent review by Calder provides a more detailed discussion of these processes.³

Fats are composed of triglycerides, containing a glycerol backbone with three fatty acids that vary in length and number of double bonds. Fatty acids can be classified based on their length, with short chain fatty acids having 2-4 carbon atoms, medium chain fatty acids having 6-12 carbon atoms, and long-chain fatty acids having 12-24 carbon atoms. Fatty acids are further classified by the number of double bonds: saturated fats – 0, monounsaturated fats – 1, and polyunsaturated fats ≥ 2. Humans generally consume enough fat in the diet to meet all fatty acid requirements; the EFAs are those that cannot be synthesized as humans lack the enzymes required.^2-5

Fat Digestion, Absorption, and Metabolism

Digestion and absorption is a complex process. Understanding normal digestion and absorption of fat helps to identify risk factors for EFAD in patients with gastrointestinal (GI) diseases. Digestion of fat starts in the mouth with salivary lipase; when food enters the stomach there is exposure to gastric lipase, although this primarily digests medium- and short-chain fatty acids. As chyme is released from the stomach into the duodenum, fat is emulsified by bile, while pancreatic lipase and colipase digests fat into free fatty acids and monoglycerides that are packaged into micelles (∼ 200 times smaller than emulsion droplets). The micelles transport the free fatty acids and monogylcerides to the brush border of the distal jejunum and ileum for absorption. Once inside the enterocyte, monoglycerides and fatty acids are resynthesized into triglycerides with cholesterol, fat-soluble vitamins, and phospholipids into chylomicrons. Chylomicrons are transported via the lymphatic system to the liver, adipose, and muscle for additional metabolism and/or storage.^2,4

Within the cell, fatty acids are metabolized through desaturation and elongation. When considering the essential fatty acids, ALA (an omega-3 fatty acid) is metabolized preferentially over LA (an omega-6 fat); when either fat is not available or limited, oleic acid (an omega-9 fat) is metabolized.⁵ Interestingly, most reports of EFAD are of LA deficiency, with little comment of ALA deficiency.

Risk factors for EFAD

When fat intake, digestion, absorption, and/or metabolism are impaired, there is risk of EFAD.

Patients with GI disorders are at high risk for EFAD because of potential impairment of pancreatic enzyme secretion or diseased small bowel preventing normal absorption of fat (see Table 1). Siguel and Lerman evaluated 47 patients with chronic intestinal disease (25 Crohn’s disease, 11 with ulcerative colitis, 7 with short bowel syndrome, and 4 with celiac disease) and compared them to 57 healthy controls. Using biochemical measures of EFAD, the authors found that the patients with GI diseases had significantly lower levels of fatty acids and biochemical evidence of EFAD.⁶ Jeppesen and colleagues evaluated 112 patients with GI disorders (including Crohn’s disease, ulcerative colitis, bowel resection, celiac disease, radiation enteritis, and cholestatic liver disease) by conducting fecal fat analysis and serum levels of LA. The authors found that those with higher degrees of malabsorption had lower LA levels.⁷

Cystic fibrosis (CF) is a risk factor for EFAD. There are approximately 30,000 patients in the U.S. with CF and 70,000 worldwide.8 Although this is a small number of patients, they may be seen by nutrition support clinicians given the intensive nutritional needs of this population. Pancreatic insufficiency is present in varying degrees in most patients with CF.⁸ Strandvik et al evaluated 110 CF patients taking a normal diet; only 15 had no evidence of pancreatic insufficiency. Presence of EFAD was evaluated using biochemical measures. The authors found that serum concentrations of LA and docosahexaenoic acid were significantly lower in patients who had severe CF transmembrane conductance regulator mutations, suggesting that the deficiency was associated with abnormal EFA metabolism.⁹ Patients with other causes of pancreatic insufficiency or impairment are also at risk for EFAD. There is very little reported in the literature on prevalence of EFAD in patients with acute or chronic pancreatitis, but one must consider pancreatitis to be a risk factor if pancreatic insufficiency is present.

There are clinical conditions where fat delivery is restricted. For example, patients dependent on PN who have an allergy to ILE and cannot receive it will be at risk for EFAD. PN-dependent patients with significant hypertriglyceridemia (e.g., triglyceride levels > 400 mg/dL) also have ILE restricted to decrease the risk of pancreatitis. Patients who follow extremely low-fat diets may also be at risk for EFAD, including patients with chyle leaks, who must be maintained on very low fat diets for ≥ 3 weeks.^10-12 A small study of patients undergoing Roux-en-Y gastric bypass versus patients who have undergone adjustable gastric banding showed transient signs of EFAD.¹³ Carnitine is important in fat metabolism; deficiency may contribute to development of EFAD.¹⁴ Ahmad and colleagues found that maintenance hemodialysis patients with signs of EFAD showed partial correction with L-carnitine supplementation alone.¹⁵ Shortages of ILE are a relatively new risk for EFAD. The American Society for Parenteral and Enteral Nutrition (ASPEN) has published patient care guidelines in the event of ILE shortage on the ASPEN Website on the Product Shortage page (http://www. nutritioncare.org/public-policy/product-shortages/).¹⁶

Clinical Manifestations of EFAD

Patients with EFAD may exhibit both physical and biochemical evidence of deficiency (see Table 2). For patients with known risk factors, clinicians need to monitor for evidence of EFAD.

As stated above, in the absence of adequate ALA and LA, oleic acid is metabolized to mead acid (also known as eicosatrieonic acid [triene]). There is also reduced production of arachidonic acid (also known as eicosatetraenoic acid [tetraene]). An elevated triene:tetraene ratio demonstrates that more mead acid than arachidonic acid is being produced, suggestive of EFAD. A ratio > 0.2 (some suggest > 0.4) is diagnostic of EFAD.⁵ An elevated triene:tetraene ratio will manifest before any other signs or symptoms of EFAD.

There are non-specific biochemical changes that should raise suspicion of EFAD in at-risk patients. Richardson and Sgoutas monitored four patients receiving PN and found elevations in serum aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase that paralleled a rise in triene:tetraene ratio with duration of fat-free PN. The authors noted the same pattern with serum triglyceride levels. All improved with the addition of ILE.¹⁷ Alterations in liver function tests have been attributed to mitochondrial dysfunction that occurs with EFAD.¹⁸ Press and colleagues noted that patients with EFAD had altered platelet aggregation.¹⁹

Physical manifestations of EFAD are often present in the skin. Close examination of the skin may reveal many nutritional deficiencies, including B vitamins, vitamin C, and zinc, as well as EFAD. Much of what is known about the physical manifestations of EFAD come from early case reports in the 1970s and 1980s.^10,17,19-24 Patients who complain of a dry, scaly rash, who also have an underlying disease associated with fat malabsorption, should raise clinical concerns of EFAD and prompt further investigation. It is important to recognize that zinc deficiency can also present as a dry, scaly rash and patients with malabsorption and chronic diarrhea may present with both EFAD and zinc deficiency.

Prevention of EFAD

Adequate fat provision is the starting point to prevent EFAD. At least 10% of total energy delivery should come from polyunsaturated fat, and 2%-4% of calories from LA. Once high-risk patients are identified, an appropriate nutrition plan can be developed. Patients dependent on PN can develop EFAD in 10 days without appropriate fat provision, but most reports are after 4 weeks of fat-free PN.⁵ For patients receiving PN with a standard, soybean oil based ILE, the minimum amount of fat to prevent EFAD is 100g (500mL of 20% ILE) per week.²⁴ ILE products comprised of only soybean oil contain 50% LA.¹⁸ Smoflipid® (Fresenius Kabi, Lake Zurich, IL) is an ILE that contains a blend of soybean oil, medium chain triglycerides, olive oil, and fish oil that was introduced to the US market in 2016. ClinOleic 20% (Baxter Corporation, Mississauga, ON; not available in the U.S.) is a blend of olive oil and soybean oil (see Table 3). With either of the new ILEs, clinicians need to calculate the amount of LA infused to ensure adequate provision of LA.²⁵ Table 4 summarizes EFAD prevention strategies.

Cycling of PN may also be beneficial to meet fatty acid requirements. Since human adipose tissue is 10% LA, the fat depot may be a significant source of EFAs. When PN is cycled, insulin secretion and lipogenesis are reduced during the time when PN is off or when hypocalorically feeding, allowing for some mobilization of LA from the fat depot;^18,26 adequate fat stores are needed for this to be effective.

With the advent of new ILE products, clinicians may have questions about the ability to use these products to meet EFA requirements. Gramlich and colleagues reported on three obese patients requiring prolonged PN because of complications of GI surgery.¹⁸ All three patients started with standard, soybean oil based ILE, then transitioned to ClinOleic 20% and/or Smoflipid® throughout their prolonged course of PN. All had PN cycled for at least part of their time on PN. Although two of the three patients had mildly elevated mead acid (triene) levels by the end of their PN courses, all had normal triene-tetraene ratios. Patients likely met EFA needs with their ILE, but cycling of PN and their own adipose tissue may have provided some EFAs as well. It will be important for clinicians to report outcomes with these new ILE products in underweight patients with little fat stores.

Treatment of EFAD

If EFAD is identified, the clinician must first consider the cause. For patients taking an oral diet, take a careful diet history and determine adequacy of EFA intake. Counsel patients with known fat malabsorption to consume foods rich in EFAs, including condiments made with oils that have high EFA content (Table 5), such as mayonnaise and margarine made with soybean oil, and spreads such as sunflower seed butter (see Table 5). For those with pancreatic insufficiency, evaluate adequacy of pancreatic enzyme replacement.

For PN-dependent patients, recalculate the fat content of the PN prescription and determine how much LA is being provided. Although 100g soybean oil based ILE per week should be adequate to prevent EFAD, patients may need more to treat pre-existing EFAD. Unfortunately, there are no dosing guidelines to help determine how much more ILE to administer. If the patient is receiving only 4% of calories from LA, the clinician could consider increasing to 6% of calories from LA for a defined period of time (e.g., 2-4 weeks) and then recheck the triene:tetraene ratio. PN-dependent patients may also be at risk for carnitine deficiency and should be evaluated and treated if deficient.

For PN-dependent patients who cannot reliably receive ILE (e.g., patients with severe hypertriglyceridemia), topical oils may be a source of essential fats (Table 6). Use of topical oils to treat EFAD may be worth trying, but clinicians must recognize that this method may not be effective. In some cases, provision of ILE (particularly for those patients who must follow an extremely low fat diet, for example, those with a chyle leak) is the best way to treat EFAD.

Monitoring

There are little data to guide monitoring of EFA status. Standard monitoring practices for long-term PN patients suggest checking a fatty acid panel at least once or twice per year. Clinicians may want to monitor at-risk patients more closely, for example every 3-4 months. Clinicians must maintain a high level of suspicion of EFAD for patients who are at risk and should monitor for physical signs of deficiency that may prompt biochemical evaluation. For patients who require prolonged fat restriction, first conduct a careful physical examination to evaluate for signs or symptoms of EFAD. Check a triene:tetraene ratio if there is concern for EFAD or if the patient is malnourished. If there is no concern for EFAD at the baseline clinical evaluation, check a triene:tetraene ratio after four weeks of extreme fat restriction.

CONCLUSIONS¹

Although EFAD is rare in the US, there are patient populations at risk for developing this deficiency including malabsorption disorders, those following highly fat restrictive diets, PN-dependent patients with restricted fat delivery due to inability to tolerate ILE (e.g., allergy or hypertriglyceridemia), or ILE product shortage. New ILE products coming to the market may reduce the risk of product shortage, and may be tolerated by those patients with adverse reactions to standard ILE products. At risk patients should be monitored closely for signs and symptoms of EFAD as biochemical changes indicative of EFAD will occur before clinical signs and symptoms appear.

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Inflammatory Bowel Disease: A Practical Approach, Series #101

Clostridium Difficile Infection in Inflammatory Bowel Disease An Updated Review

June 2017 • Volume XLI, Issue 6

Arun Swaminath

The incidence and severity of Clostridium difficile infection (CDI) is rising, primarily due to a new and virulent strain. Unlike patients in the general population, those with IBD who acquire C. difficile tend to be younger, have less antibiotic exposure and have more community-acquired infections. Given the high burden of CDI in IBD patients who have an acute IBD flare, all patients should be tested for CDI. Treatment of CDI focuses on antibiotics, however, in IBD patients, attention is required regarding immunosuppression during treatment. The aim of this paper is to review the most updated information on CDI in IBD including the epidemiology, pathogenesis, clinical presentation, risk factors, diagnosis and treatment guidelines.

The incidence and severity of Clostridium difficile infection (CDI) is rising, primarily due to a new and virulent strain. The impact of CDI on patients with inflammatory bowel disease (IBD) should not go unrecognized since this is a high risk patient population. Unlike patients in the general population, those with IBD who acquire C. difficile tend to be younger, have less antibiotic exposure and have more community-acquired infections. The clinical presentation of CDI in IBD is also unique compared to the general population. Given the high burden of CDI in IBD patients who have an acute IBD flare, all patients should be tested for CDI. Treatment of CDI focuses on antibiotics, however, in IBD patients, attention is required regarding immunosuppression during treatment. The aim of this paper is to review the most updated information on CDI in IBD including the epidemiology, pathogenesis, clinical presentation, risk factors, diagnosis and treatment guidelines.

Andrew A. Nguyen, DO¹ Angelica Nocerino, MD¹ Dana J. Lukin, MD, PhD² Arun Swaminath, MD3 ¹Resident, Department of Internal Medicine, Lenox Hill Hospital, Hofstra Northwell School of Medicine, New York, NY ²Assistant Professor, Department of Gastroenterology and Liver Diseases, Montefiore Medical Center, Albert Einstein College, Bronx, NY 3Associate Professor, Department of Gastroenterology, Lenox Hill Hospital, Hofstra Northwell School of Medicine, New York, NY

INTRODUCTION

Clostridium difficile (C. difficile) is an obligate, anaerobic, gram-positive, spore-forming bacillus that is associated with pseudomembranous colitis and the clinical spectrum ranges from asymptomatic carriage to severe colitis, sepsis and death.¹ In the United States (US), it is becoming an increasing health concern as its incidence is on the rise. C. difficile recently surpassed methicillin resistant Staphylococcus aureus (MRSA) as the most common hospital acquired infection in the US.² In addition, in 2014, deaths from CDI were greater than those associated with HIV infection.³ CDI is higher amongst females, whites and the elderly; however, CDI in IBD patients is also increasing.^4,5

In IBD patients, CDI may be more prevalent in ulcerative colitis (UC) than Crohn’s disease (CD).⁶ Patients with IBD complicated by CDI have higher mortality and resource utilization, including increased hospitalization, longer length of stay and higher inpatient morbidity.^7-10 In addition, CDI complicating IBD may lead to an increase in the need for surgical intervention. 8 Thus, it is important to evaluate CDI and its role in the IBD community.

Epidemiology of CDI

CDI is a major cause of morbidity and mortality worldwide and in the US in particular. In 1978, C. difficile was first recognized as a major cause of antibiotic related colitis. Since then the incidence and severity of CDI has increased with a particular rise in the past decade. From 2000 to 2006, the number of hospitalizations secondary to CDI nearly doubled in the general population in the US, with a reported annual incidence of 300,000 hospitalizations and an annual healthcare cost of 4.8 billion dollars.^11,12 In 2011, there were over 450,000 cases of CDI, resulting in approximately 30,000 deaths.¹³ The incidence of hospitalizations, however, minimizes the true prevalence of CDI, as community acquired infections are also on the rise and account for nearly 27% of all C. difficile related infections.¹⁴

The emergence of a highly virulent C. difficile strain (BI/NAP1/027) serves as a predictor of disease severity and risk of mortality.¹⁵ This strain, which is group B1 (restriction-endonuclease analysis), type NAP1 (North American PFGE type 1) and ribotype 027 (polymerase chain reaction), is resistant to fluoroquinolones and has been shown to produce larger amounts of toxin than other C. difficile strains.^14,16 This is due to a mutation of the regulatory tcdC gene and the production of C. difficile transferase, an ADP-ribosylating binary toxin.¹⁷ One in vivo study compared a reference C. difficile strain in mice to the B1/NAP1/027 strain and found that the B1/NAP1/027 strain has at least 11 different antigenic epitopes compared to the reference strain, with less susceptibility to antibody neutralizations. Furthermore, it exhibits a lower dose needed for virulence compared to the reference strain.¹⁸

Patients with IBD have an increased risk and higher incidence of CDI compared to the general population.^5,19 In a retrospective analysis of nationwide inpatient admissions for CDI in those with IBD, CDI prevalence in the general population had an incidence of 4.5 per 1000. CDI was higher among those with UC (37.3 per 1000) and CD (10.9 per 1000).⁶ A second population study examined the rate of hospitalizations of IBD patients in the US and discovered a similar incidence of CDI, with a rate of 2.8% in UC and 1% in CD.¹⁹ Compared to patients with CD and CDI, those with UC and CDI also had higher rates of surgery (10.4% vs. 8%), and higher mortality rates (5% vs. 3%).20 Two recent meta-analyses confirm higher rates of both colectomy and mortality in IBD patients with CDI with a more significant effect in UC.^21,22 Although the reason for the increase in incidence of CDI and disease severity among those with UC as compared to CD remains unclear, it is hypothesized that colonic involvement, seen more frequently in patients with UC, may be an attributable risk factor.¹⁰ Interestingly, there was a geographical variation of CDI, with more hospitalizations and higher mortality rates seen in the Northeast region of the US as compared to the Southwest region.²³ The prevalence of asymptomatic and community acquired CDI among the IBD population is also on the rise. Clayton et al. compared 122 individuals with IBD to 99 individuals without IBD and discovered that 8.2% of the IBD population is colonized with C. difficile, as compared to 1% of the general population.²⁴

CDI appears to have a more aggressive disease course in IBD patients. Ananthakrishnan et al. examined 124,570 hospitalizations among those with CDI and IBD, CDI alone and IBD alone. Patients with IBD and CDI had greater mortality (4.2%) than those with CDI alone (3.7%) or IBD alone (0.5%).²⁰ Furthermore, the length of hospital stay was longer in the those with CDI and IBD (7 days) as compared to CDI alone (5 days) and IBD alone (4 days).²⁰ Those with IBD are also more likely to suffer from CDI recurrence, with rates as high as 40% as compared to only 20% of those without IBD.²⁵ Up to 35% of UC patients had a colectomy one year after diagnosis of CDI, as compared to 9.9% in those without IBD.²⁶

Pathogenesis

C. difficile can be transmitted via fecal-oral route by ingestion of spores. It is easily spread, as it can persist on fomites for several months. Both toxin and non-toxin strains exist though only the toxic strains are associated with disease.²⁷ Most C. difficile strains produce toxin A and toxin B, which are products of tcdA and tcdB genes. Strains producing one or both toxins are able to cause disease, while strains producing both toxins are the most virulent.¹⁷ Toxin A, an enterotoxin, binds to intestinal epithelial cells, subsequently damaging intestinal villous tips and the tight junctions between the epithelial cells.¹⁸ Toxin B, a cytotoxin, plays a role in promoting neutrophil chemotaxis, and the activation of the cytokine cascade, including tumor necrosis factor (TNF), interleukin (IL)-6, IL IL-8, IL-1Β, leukotrienes B4 and interferon-y. This creates a pro-inflammatory state in the mucosa of the intestine, leading to diarrhea, ulceration and the formation of pseudomembranes.²⁸

The natural gut microbiota plays a major role in the defense against CDI, as it stimulates the mucosal immune system and aids in the transformation of secondary bile acids known to inhibit C. difficile germination.³⁰ Distinct changes within the intestinal microbiome have been associated with CDI, including increases in the relative abundance of Proteobacteraciae and Verrucomicrobiota with corresponding decreases in Enterococcaceae, Leuconostocacaea, Prevotellaceae and Spirochaetaceae.³¹ A decrease in endogenous gut diversity can, therefore, weaken barrier defenses and predispose to CDI. Although the etiology of IBD is unknown, it is theorized that environmental factors and genetics trigger an immune response against the natural bowel flora.³² Subsequently, this leads to chronic inflammation of the intestinal mucosa and a decrease in microbiota diversity.³³ It is well known that the ileum plays a major role in the active reabsorption of bile acids, which has a role in inhibiting C. difficile germination. In patients whose terminal ileum is affected by Crohn’s disease, the chronic inflammation can result in the destruction of the sodium/bile acid co-transporting polypeptides located on the ileal enterocytes, which subsequently results in malabsorption of bile acids, and may predispose to CDI.^27,34 Genetics may also play a role. Polymorphisms in the IL-4 receptor gene and TNF receptor superfamily member 14 can be associated with IBD and may also increase susceptibility to CDI.35,36 These factors may explain the increased risk of CDI in those with IBD.

Presentation

Clinically, C. difficile has a wide range of expression, from asymptomatic carrier to toxic megacolon and colonic perforation. Typical diarrhea, nausea, vomiting, abdominal pain, fever and leukocytosis characterize CDI. CDI can mimic IBD flares often making it difficult for physicians to distinguish the two, and thus it is always recommended that all patients with IBD who present with a flare be tested for CDI. CDI might present as bloody diarrhea in IBD patients, which may not be commonly seen in the general population, affected by C. difficile.

Post-operative IBD patients may be at higher risk of developing CDI than those without a surgical history. The risk can be seen as early as the first 90 days after surgery but can also occur years later.^37,38 CDI may manifest as an increase in ileostomy output, and may present as pouchitis in those with an ileal pouch.³⁹ CDI enteritis, a relatively rare entity, occurs almost exclusively in post-operative patients. Roughly half of cases occur in IBD patients and is associated with a high mortality rate.⁴⁰ Thus the absence of a colon should not preclude the evaluation for CDI. Antibiotics prior to surgery have been shown to increase the risk of CDI.⁴¹ Furthermore, it is thought that those who develop CDI immediately post-operative may have had undiagnosed CDI of the colon prior to surgery that subsequently migrates to the small bowel. It has also been shown that the flora of the small bowel mimics colonic flora after colectomy increasing the risk of CDI.³⁸

Endoscopically there exists a key difference between those with CDI and concomitant IBD and those with CDI alone. While pseudomembranes can be seen in up to 60% of those with CDI in the general population, pseudomembranes may not be as common in those with IBD. In a retrospective multi-center study performed in 20 centers in Europe and Israel by Ben-Horin et al, 93 IBD patients with a diagnosis of CDI underwent lower endoscopy. Endoscopic pseudomembranes were seen in only 13% of patients. In those patients who were found to have pseudomembranes, fever was also commonly present.⁴² In another retrospective study of 24 patients with IBD and CDI, pseudomembranes were not seen endoscopically or histologically in any of the patients.⁴³ It is theorized that in IBD the colon is chronically damaged and cannot mount an adequate local inflammatory response to form pseudomembranes. Another hypothesis is that immunomodulators themselves affect the inflammatory cascade in a way that leads to an absence of pseudomembranes.^29,44

RISK FACTORS

Traditionally, antibiotic use, in particular clindamycin, fluoroquinolones and broad-spectrum cephalosporin, is considered to be the most common risk factor for CDI. The loss of microbial diversity from antibiotic use creates an optimal environment that predisposes patients to CDI. In the general population CDI is the etiology in up to 55% of cases of antibiotic associated colitis.^44,45 Other risk factors for CDI include older age, residence in long term care facilities, hospitalization, immunosuppression, chronic kidney disease, gastric acid suppression through proton pump inhibitor use, surgery of the gastrointestinal tract and malignancy.⁴⁶

IBD patients constitute a unique risk group as they tend to be young individuals with a history of outpatient- acquired infections and overall less antibiotic exposure compared to the general population.⁴⁴ Population studies have demonstrated that up to 40% of CDI in IBD had no prior antibiotic exposure and that 76% of cases were diagnosed in the outpatient setting.43,47 Multiple studies have also found that colonic involvement is an important risk factor for CDI in IBD.^43,44 In one single center study, Issa et al. found that up to 91% of patients with IBD who were diagnosed with CDI had colonic involvement.⁴³ A second population study demonstrated that those who had IBD with colonic involvement had a 3.5 times higher incidence of CDI compared to those whose inflammatory disease only affected the small bowel.⁶

CDI is also associated with high rates of colectomy and mortality amongst patients with IBD.^21,22 Studies have shown an incidence of CDI ranging from 10 % to 18.3% in patients who underwent an ileal pouch-anal anastomosis.^41,48 Ananthakrishnan et al. analyzed the occurrence colectomy and/or death within 180 days of CDI in a retrospective multi-institution database of IBD patients. Approximately 20 percent of patients met this endpoint at a median of 31 days and predictors of severe outcomes included albumin <3 g/dL (HR 2.97), hemoglobin <9 mg/dL (HR 2.51), age >65 (HR 2.14) and serum creatinine >1.5 g/dL.⁴⁹

In comparison to the general population, use of proton pump inhibitor medications has been reported to be lower in IBD patients with CDI than in non-IBD patients with CDI.⁵⁰ Furthermore, Ananthakrishnan et al. found that 25(OH)-Vitamin D levels differed significantly amongst IBD patients with and without CDI (20.4 vs. 27.1, respectively) and levels below 20 ng/mL were associated with an odds ratio of 2.27 for CDI.⁵¹

The use of immunomodulators is also an important risk factor that should be well recognized. Issa et al. reported that 78% of patients with IBD and CDI were on immunosuppressive medication, including azathioprine, 6-mercaptopurine, methotrexate and infliximab.43 Schneeweiss et al. analyzed 10,662 IBD patients and discovered that those on steroids were three times more likely to acquire CDI as compared to those on other immunosuppressant agents.⁵² In this study the use of infliximab did not increase risk of CDI, which is in contrast to the RECIDIVISM study, which discovered that infliximab, and not adalimumab, was associated with increased recurrence of CDI compared to adalimumab.⁵⁰ Lastly, analysis of the Food And Drug Administration Adverse Events Reporting System showed an increased incidence of CDI amongst patients receiving therapy with vedolizumab, but not with anti-TNF biologics.⁵³ Based on these studies, steroids appeared to increase the risk of CDI, but there have been inconsistent findings regarding the risk of biologics.

Diagnosis

Diagnosis of CDI in IBD patients is the same as the diagnosis in the general population. Multiple diagnostic modalities are available, including cell cytotoxicity assays, enzyme immunoassay (EIA) for toxin (tcdA and tcdB), culture, glutamate dehydrogenase (GDH) detection, nucleic acid amplification tests (NAAT) and multi-step algorithms. Regardless of the modality chosen, testing should only be performed on diarrheal stool as testing on formed stool can decrease the specificity of diagnosis confusing a carrier with an active infection.⁵⁴ The gold standard for the diagnosis of CDI is stool culture for toxin which requires growing C. difficile and an additional step to detect the presence of toxin. This test is time and labor intensive, taking up to 48 hours for results.⁵⁵ Thus, rapid testing is commonly preferred. One such test is GDH detection via EIA, however, GDH is present in both toxigenic and non- toxigenic strains, therefore, testing for GDH requires an additional modality that detects toxin. Due to the complexity and time sensitivity of CDI diagnosis, many have suggested multistep algorithms for rapid diagnosis.^25,54,55 Multistep algorithms involve a two-step process, initially using a highly sensitive test to screen for CDI that is reflexively followed by a highly specific test to confirm the diagnosis. Detection of GDH has a high negative predictive value and is commonly used as the first step in many proposed multistep algorithms. One systematic review found that diagnosis with multistep algorithms using PCR for toxin or single step PCR on liquid stools may have the best outcome (multistep: sensitivity 0.68-1.00 and specificity 0.92- 1.00; single step: sensitivity 0.86-0.92 and specificity 0.94-0.97).⁵⁶ Thus, EIA for GDH and toxin or PCR for tcdB gene seem to be the most commonly applied tests in clinical practice.

The American College of Gastroenterology guidelines recommend screening for CDI in IBD patients who are hospitalized for a flare and IBD patients who develop diarrhea when disease activity was previously in remission or have risk factors for CDI.⁵⁷ Colonoscopy is not commonly used in the diagnosis of CDI in the general population, as there are other less invasive modalities available. However, in the IBD population, colonoscopy may be used more frequently as presentation of CDI and IBD can be similar but its value in differentiating the two may be limited. Nevertheless it is important to remember that the typical findings of pseudomembranes are not commonly found in IBD patients and the histologic findings may be difficult to differentiate from IBD.⁴³ Computed tomography scans may aid in the diagnosis of CDI if typical features of CDI are present (i.e. nodular haustral thickening or the accordion pattern), however, this test is also limited by a lack of specificity.⁵⁸

Treatment

Treatment of CDI is based on the severity of CDI, defined as mild to moderate (leukocytosis with white blood cell count <15,000 cells/µL and serum creatinine level <1.5 times the premorbid level), severe (leukocytosis with a white blood cell count of ≥15,000 cells/µL or a serum creatinine level ≥1.5 times the premorbid level, serum albumin <3 g/dL) or severe complicated (hypotension or shock, ileus, megacolon).^54,57 In addition, whether the diagnosis is a primary event or a recurrence also determines the course of treatment.

There are three antibiotics that are recommended in the treatment of CDI among the general population, including metronidazole, vancomycin and fidaxomicin. Metronidazole is the drug of choice for mild to moderate CDI, whereas, vancomycin is preferred in severe CDI.⁵⁴ Previous studies have shown that in severe and complicated CDI metronidazole has a higher rate of treatment failures.⁵⁶ In addition, metronidazole may be inferior to vancomycin despite the severity of disease suggesting vancomycin should be the first choice in the treatment of CDI.^59,60

Fidaxomicin is the most recently approved antibiotic for the treatment of primary and first recurrence CDI. It was introduced in 2011 when Louie et al. showed that the rates of cure with fidaxomicin were non-inferior to the rates of cure with vancomycin.⁶¹ In addition, fidaxomicin was associated with a significantly lower rate of recurrent CDI.⁶² Unfortunately, the use of fidaxomicin is limited by its high cost.6⁶³3

Fecal microbiota transplantation (FMT) has a role in CDI. FMT changes the bacterial composition of the gut microbiota, and has been associated with resolution of CDI symptoms.⁶⁴ FMT is 70-91% effective in achieving cure after initial treatment and 89-98% effective in overall cure.^65-67 Systematic reviews have found an 89.7%-92% cure rate of recurrent CDI after FMT.^68,69 There are no randomized controlled trials assessing the role of FMT in primary non-recurrent CDI, however, Lagier et al. conducted an open label, nonrandomized, prospective study assessing early (within one week of infection) FMT via nasogastric infusion with fresh stool in primary CDI that showed a significant reduction in mortality.⁷⁰ Unfortunately, the route (oral vs. endoscopic), stool preparation (fresh vs. frozen), amount of stool infusate and donor characteristics have not been standardized.

Monoclonal antibodies to C. difficile toxin are now available to decrease CDI recurrence when part of the initial treatment algorithm.⁷¹ There are two monoclonal antibodies that have been evaluated in the prevention of recurrent CDI, actoxumab and bezlotoxumab, which bind and neutralize C. difficile toxins A and B, respectively. Wilcox et al. conducted two multi- center randomized, double blind, placebo-controlled trials (MODIFY I and MODIFY II) with participants with either primary CDI or recurrent CDI who were treated with standard of care antibiotics (vancomycin, metronidazole or fidaxomicin) for 10-14 days. They found that the rate of recurrent CDI was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% vs. 28%; 95% CI -15.9 to -4.3; P<0.001; MODIFY II: 16% vs. 26%; 95% CI -15.5 to -4.3; P<0.001) and significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% vs. 28%; 95% CI -17.4 to -5.9; P<0.001; MODIFY II: 15% vs. 26%; 95% CI -16.4 to -5.1; P<0.001).⁷² The original MODIFY I trial included an actoxumab alone arm, however, this arm was discontinued after planned interim analysis did not show efficacy. The rates of recurrent infection were lower in both groups that received bezlotoxumab compared to the placebo group. Approximately, 20% of participants included in the study were immunocompromised, however, supplementary material do not distinguish the defining characteristics of those subjects. Bezlotoxumab’s role in the treatment of IBD patients with CDI is undefined.

Management of CDI in IBD

The management of CDI in IBD patients is difficult as the symptoms cannot be attributed to either IBD flare or CDI alone. Many patients with IBD are immunocompromised often due to treatment with immunomodulators or biologics making the choice of treatment difficult. In a non-IBD population hospitalized with CDI, use of corticosteroids within 2 weeks of diagnosis has been associated with a two-fold increase in mortality.73 De-escalation of corticosteroid dose may lessen the severity of an active CDI.⁴³ Patients with IBD and a concomitant CDI treated with immunomodulators and antibiotics had poorer outcomes than those treated with antibiotics alone. This was based on 155 patients (antibiotics: n = 51 vs. antibiotics and immunomodulators: n =104).⁷⁴ In contrast, Lukin et al. recently performed a multi-center retrospective cohort study of 157 patients with IBD and CDI that assessed immunosuppressive medications on the clinical outcome in this patient population. They found a marked increase in serious outcomes (i.e. death, sepsis, colectomy) among patients who did not have an escalation of IBD therapy within 90 days of CDI suggesting a subpopulation of IBD with CDI where CDI is a marker of disease severity.⁷⁵ This concept is supported by the data from Ananthakrishnan et al, but goes further in suggesting that a specific subpopulation of patients with CDI and IBD could be harmed if IBD therapy is not escalated.¹⁰

No prospective studies have been performed to assess the antibiotic preference of CDI in IBD patients, however, as CDI in IBD is high risk and a complicated disease, it is reasonable to consider vancomycin as first line treatment in these patients.⁵⁹ This group may also be ideal to benefit from toxin B antibody during initial treatment, though no studies in IBD patients have yet been performed.

There is a growing consensus that FMT may be used in the treatment of CDI in UC patients. A systematic review of 17 articles that assessed FMT in IBD found 15 IBD patients (8 UC and 7 CD) with CDI who were treated with FMT. There was outcome data for 12/15 with resolution of CDI when treated with FMT based on negative stool sample enterotoxin. However, only 11/12 patients had reduction or complete resolution of diarrhea.⁷⁶ Another multicenter retrospective series that assessed FMT for CDI treatment in immunocompromised patients included 36 patients with IBD. In the IBD patients, they found resolution of CDI in 86% of patients after a single FMT and an overall cure rate of 94%.⁶⁶ In a prospective study examining FMT for the treatment of refractory CDI by Hamilton et al., 14 of 43 study patients were reported to have UC.⁷⁷ While no subgroup analysis is provided, all UC patients were reported to have improved from CDI after FMT. A more recent prospective study reported cure rates of 79% after first FMT and 90% overall in IBD patients undergoing FMT for CDI.78 In this study, treatment failure was associated with hypoalbuminemia. Additionally, the durability of FMT within IBD patients appears to be less than in the general population. In a small pediatric study in recurrent CDI, analysis of the fecal microbiome in patients both with and without IBD resembled that of the donor immediately following FMT but the microbiome in patients with IBD returned to a signature resembling that before FMT after 6 months.⁷⁹ Lastly, the possibility of FMT-related adverse effects, including exacerbation of IBD, remains uncertain.^66,80 Thus, there may be benefit in treatment of CDI in IBD patients with FMT; however, larger studies need to be performed to assess FMTs efficacy and potential adverse effects in IBD patients with CDI.

In 2013, the American College of Gastroenterology put forth guidelines for the management of C. difficile infection, which include recommendations for patients with IBD.⁵⁷ These guidelines emphasize that CDI must be suspected in all IBD patients hospitalized for or presenting for outpatient evaluation of a presumed disease flare, including patients with ileal pouch following total proctocolectomy. While there is low- quality evidence currently available to guide IBD treatment at the time of CDI, these guidelines advocate for the simultaneous empiric treatment of CDI and IBD while awaiting the results of diagnostic testing. Maintenance of ongoing immunosuppressive therapy is recommended during active CDI, but escalation of therapy is advised only after appropriate treatment of the infection for 72 hours. Further, high quality prospective studies are needed to inform future treatment guidelines.

CONCLUSION

CDI is an increasing health concern due to the virulence of B1/NAP1/027 strain with prevalence increasing in both the hospital and community setting. CDI is particularly important in IBD patients as it complicates the disease course and increases morbidity and mortality. CDI in IBD can be difficult to diagnose as it can mimic or complicate IBD flares and does not classically present in the same manner as the general population, such as increased asymptomatic carriage and community acquired CDI and a decrease in frequency of pseudomembranes in the IBD population. All patients with IBD who have an acute flare of their disease should be tested for CDI. There are multiple antibiotics available in the treatment of CDI; however, oral vancomycin may be the preferred agent in IBD patients. FMT and monoclonal antibodies to toxin B are two newly proposed modalities to aid in the treatment of CDI, however, their role in CDI and IBD is currently unclear. Immunosuppression in IBD patients with CDI can also be difficult to manage, however, a recent study has shown that there may be a benefit to corticosteroids and biologics after antibiotic treatment for CDI. There is a developing body of information regarding CDI in IBD management, however, further studies are still required to establish a standard of care and management.

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A Case Report

An Uncommon Cause of Dysphagia in a 35 Year Old Male

May 2017 • Volume XLI, Issue 5

Carmelo Blanquicett,Terence Dunn,Arjun Nanda,Frederick Weber

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Typical causes of intermittent esophageal dysphagia in a young person include eosinophilic esophagitis, esophageal dysmotility and esophageal rings. We report a 35-year-old male with a one year history of intermittent dysphagia to solid foods. After the endoscopic removal of a food bolus, a barium swallow revealed extrinsic compression of the proximal esophagus. Computed tomography angiogram revealed an aberrant right subclavian artery (ARSA) coursing behind the esophagus, suggesting the diagnosis of dysphagia lusoria. Although rare, dysphagia lusoria represents an important consideration in the differential diagnosis of intermittent esophageal dysphagia in a young adult.

Carmelo Blanquicett, MD, PhD¹ Terence Dunn, MD¹ Arjun Nanda, MD,² Frederick Weber, MD² ¹Department of Internal Medicine, ²Dept of Gastroenterology and Hepatology, University of Alabama at Birmingham, AL

INTRODUCTION

In young adults, esophageal dysphagia is most commonly attributed to eosinophilic esophagitis, strictures, motility disorders or neurological injury. Occasionally symptoms can result from extrinsic compression from mediastinal masses, vascular structures or surgical changes. We present the case of a 35-year-old male who presented with complaints of intermittent esophageal dysphagia and was found to have dysphagia lusoria. Although uncommon, it is important to consider this diagnosis when evaluating patients with dysphagia.

CASE REPORT

A 35-year-old Caucasian male was admitted to our institution after he presented to the emergency department with the sensation of food stuck in his chest for two days following the consumption of pork. He reported a one-year history of intermittent solid- food dysphagia with episodes typically resolving by “?coughing up”? and regurgitating the food bolus. He denied choking, aspiration, associated dyspnea, difficulty initiating a swallow or odynophagia. He denied tiring upon chewing or focal weakness. His weight had been unchanged, and he denied any prior tobacco use. He underwent an esophagogastroduodenoscopy (EGD) with esophageal biopsies two months prior to presentation at an outside facility and was placed on empiric proton pump inhibitor (PPI) therapy without clinical benefit. Biopsies did not reveal evidence of eosinophils. His past medical history included chronic tension headaches but he denied a history of atopy or asthma.

At the time of our evaluation, he was handling his oral secretions and had no complaints of dyspnea or choking. His vital signs and physical examination, including a comprehensive cardiovascular and head, eyes, ears, nose and throat (HEENT) exam were unremarkable. Laboratory studies were within normal limits. After glucagon was administered in the emergency room without clinical improvement, a large food bolus was successfully removed endoscopically from the proximal esophagus. The underlying mucosa appeared friable but no strictures or rings were visualized.

Post-endoscopy esophagram revealed a smooth narrowing at the pharyngoesophageal junction consistent with a cricopharyngeal bar. More significantly, there was extrinsic compression of the proximal esophagus distally (Figure 1). A computed tomography (CT) angiography of the chest demonstrated an aberrant right subclavian artery (ARSA) passing posteriorly to the esophagus resulting in compression of the posterior aspect of the thoracic esophagus (Figure 2). These findings, in conjunction with the patient?s history, suggested the diagnosis of dysphagia lusoria. The patient was referred to vascular surgery clinic for consideration of surgical correction. A reconstruction of the CT images was performed as shown in Figure 3.

DISCUSSION

Dysphagia lusoria results from a congenital abnormality in the development of the aortic arch and its branches causing extrinsic compression of the esophagus. In the majority of cases, the causative vessel is an ARSA originating from a left-sided aortic arch, but persistent right-sided aortic arch with aberrant left subclavian artery has also been described.¹ The ARSA originates from the proximal portion of the descending thoracic aorta with three possible anatomic positions: posterior to the esophagus (80%), between the esophagus and trachea (15%) and anterior to the trachea (5%).² This abnormal course led to the term lusorian artery from the Latin lusus naturae or “?freak of nature”?. The prevalence of a lusorian artery has been estimated at 0.4% to 0.7% among the general population.¹ Patients with Down Syndrome commonly have vascular anomalies, and the incidence of ARSA in these patients has be reported in up to 39%.³ Based on retrospective data, only 30-40% of individuals with ARSA develop symptoms of dysphagia in their lifetime.¹ Without intervention, progressive worsening of symptoms may occur via proposed mechanisms such as age-related loss of esophageal or arterial compliance and aortic elongation. ²

Depending on the severity of the symptoms, the approach to management varies. In mild cases, behavioral modification strategies, including smaller bites with more thorough chewing, can be adopted.⁴ Adjunctive PPI therapy may also improve symptoms. In more severe cases, a surgical approach is warranted. Options include open surgical repair with ligation of the aberrant subclavian artery and anastomosis to the ipsilateral carotid artery or a combined surgical and endovascular (hybrid) approach using stenting as well as carotid-to-subclavian bypass grafting.⁵ High success rates, with complete resolution of symptoms, have been reported in patients who underwent surgery.^5,6 We recommended our patient undergo surgical evaluation, given his history of recurrent dysphagia with impaction, in order to address the degree to which his symptoms had progressed.

In summary, dysphagia lusoria represents a rare clinical manifestation of a somewhat uncommon vascular anomaly and should be considered in the evaluation of intermittent esophageal dysphagia in a young adult.

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Dispatches From The Guild Conference, Series #4

Rheumatologic Complications of Inflammatory Bowel Diseases

May 2017 • Volume XLI, Issue 5

Arthur Kavanaugh,Abha Goyal Singh

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Beyond gastrointestinal symptoms and complications, IBD is a systemic disease that is frequently accompanied by extraintestinal manifestations (EIM) involving virtually every organ in the body. Rheumatologic extraintestinal manifestations and complications are common, presenting as peripheral arthritis and/or axial arthritis which can add to the detrimental impact that IBD has on affected patients in terms of pain, quality of life and functional status. Here we discuss the importance of a high index of suspicion and early treatment, which may decrease healthcare burden.

Rheumatologic manifestations are the most common extra-intestinal complications in patients with inflammatory bowel disease (IBD), and have been reported to occur among 6-46% of IBD patients. The immunopathophysiology may relate to aberrant lymphocyte trafficking from the inflamed gut into the articular synovium as well as extra-articular tissues, especially the entheses. There are multiple potential clinical presentations including peripheral arthritis, spinal or axial arthritis and enthesitis. Peripheral arthritis accompanied IBD may be oligo-articular or polyarticular, with the former occurring more early in the disease course, and sometimes transitioning to the latter. Much of data relevant to the treatment of peripheral arthritis related to IBD comes from the literature on the treatment of psoriatic arthritis (PsA) with peripheral arthritis. Treatment options include disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX), sulfasalazine, leflunomide and apremilast. Among biologic agents, tumor necrosis factor inhibitors (TNFi) have the longest and largest clinical data supporting their substantial efficacy. The most relevant data concerning the treatment of spinal, also called axial, arthropathies comes from studies of patients with ankylosing spondylitis (AS). While non-steroidal anti-inflammatory agents (NSAIDs) and specific cyclooxygenase 2 (COX2) inhibitors are effective in both peripheral and axial arthritis, their use in IBD must take into account their potential effects on the bowel. While DMARDs are ineffective for axial arthritis, TNFi are highly effective. IL-17 inhibitors, which have recently been shown effective in PsA and AS, would not be a good choice for IBD related arthritis as they can have a detrimental effect on bowel inflammation.

Arthur Kavanaugh, MD¹, Abha Goyal Singh, MD² ¹Professor of Medicine Director, Center for Innovative Therapy Division of Rheumatology, Allergy and Immunology, ²Assistant Professor of Medicine, Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, CA

INTRODUCTION

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, are chronic autoimmune diseases of the gastrointestinal tract that affect over 1.6 million Americans, with a rising global incidence and prevalence.1 These diseases cause significant morbidity, with frequent hospitalizations, surgery, and use of corticosteroids and immunosuppressive medications. Annual direct and indirect healthcare costs of IBD are estimated between $14.6-31.6 billion, with over 50% attributable to hospitalization-related costs. Beyond gastrointestinal symptoms and complications, IBD is a systemic disease that is frequently accompanied by extraintestinal manifestations (EIM) involving virtually every organ in the body. Extraarticular manifestations can add to the detrimental impact that IBD has on affected patients in terms of pain, quality of life and functional status.

Among extraintestinal manifestations of IBD, those affecting the musculoskeletal system are among the most common, and have been reported in several series to affecting from 6 to 46% patients.^2,3 Indeed, from a rheumatology standpoint, IBD-associated arthritis, or ‘enterpathic arthritis’, has been considered to be within the family of conditions grouped under the title ‘spondyloarthropathies’ (SpA). Also included within this category are psoriatic arthritis (PsA), ankylosing spondylitis (AS) and reactive arthritis. There is growing understanding of the immunopathophysiology of these conditions, highlighting common alterations in the immune and inflammatory responses common to diseases with potentially diverse clinical manifestations. In addition, there are increasing therapeutic options for patients with SpA, with some agents more or less effective for specific manifestations. A number of agents used to treat SpA have also shown efficacy in IBD, highlighting some common aspects of immune dysregulation across these conditions.

Epidemiology

Joint involvement is the most common extraintestinal manifestation of IBD, affecting up to 46% of patients.^2,3 In addition to non-inflammatory arthralgias without actual swollen joints, seen in 8-30% of patients, inflammatory arthritis of the spine (also called axial disease) or the peripheral joints have been clearly demonstrated. Early reports classified peripheral arthropathies into type I pauciarticular (four or fewer peripheral joints) or type II polyarticular (five or more peripheral joints involved). More recent work has shown that patients may present early with fewer joints involved and over time evolve into a polyarticular phenotype. In addition to peripheral arthritis, patients may have axial arthritis. Such patients typically present with inflammatory back pain, generally defined as pain that occurs in younger adults (e.g. less than 40 years of age), is worse in the morning, improves with use and responds clinically to non-steroidal anti-inflammatory drug (NSAID) therapy. Another area of inflammation common to SpA conditions is enthesitis. Entheses are areas where tendons, ligaments and joint capsules insert into bone. Inflammation at the entheses is not only common, but may be an early and perhaps etiopathogenically relevant aspect of SpA, including IBD related arthritis. While musculoskeletal involvement most often develops following the diagnosis of IBD, in a small subset of patients (<5%) articular symptoms may precede IBD. Risk factors for articular manifestations among IBD patients have been suggested to include a family history of IBD, appendectomy, cigarette smoking and the presence of other extraintestinal manifestations such as erythema nodosum or pyoderma gangrenosum.⁴ Patients with extensive colitis (rather than proctitis) patients with colonic Crohn’s disease have been suggested to be more likely to develop articular EIMs.

As more effective therapies have become available for the treatment of peripheral arthritis, axial arthritis and enthesitis, early recognition has become even more important. Some signs and symptoms that could prompt consideration of inflammatory musculoskeletal involvement in an IBD patient include chronic (e.g more than three months) back pain, peripheral joint pain and swelling, enthesial tenderness and dactylitis (swelling of an entire digit due to abundant arthritis and tenosynovitis).⁵

Pathophysiology

Rheumatologic manifestations in patients with IBD have been hypothesized to be due to articular and peri- articular homing of activated intestinal lymphocytes; these data suggest the presence of a ‘gut-joint axis’.⁶ In patients with IBD, lymphocytes of various subtypes may access articular sites using multiple adhesion molecules and their counter receptors. In addition to aberrant lymphocyte homing, dysbiosis, or an alteration in the diversity of gut microbiota, may be another shared pathophysiological mechanism between IBD and IBD- associated arthritis.

Clinical Presentation and Diagnosis
Peripheral Arthropathies

Peripheral arthritis in IBD typically presents as inflammatory arthritis, with joint pain and swelling. Traditionally, IBD-associated arthritis had been considered to be generally non-erosive and non- destructive; however, there is the possibility that these considerations were tautologic, and therefore this may not be an accurate distinction.^3,4,5

Early reports classified peripheral arthropathies into so-called type I pauciarticular (four or fewer peripheral joints) or type II polyarticular (five or more peripheral joints involved) (Table 1). More recent work has shown that patients may present early with fewer joints involved and over time evolve into a polyarticular phenpotype. The most important distinction is the number of joints involved. Patients with oligoarticular disease are more likely to have a more favorable prognosis over time. In contrast, those with polyarticular disease, either at onset or later in the disease course, are more likely to suffer impaired functional status and quality of life. IBD associated arthritis, as a SpA related condition, is distinct from rheumatoid arthritis that could also occur in IBD patients. Supporting this are the lack of correlation between IBD arthritis and antibodies to citric citrullinated peptides (anti-CCP).⁶

Axial Arthritis

Axial involvement is a common feature of IBD- associated arthritis. The prototypical symptom is inflammatory back pain; other features of ankylosing spondylitis have been clearly demonstrated in patients with arthritis associated with IBD.^3,4,5 These are more frequently observed in patients with Crohn’s disease (5-22%), as compared to ulcerative colitis (2- 6%).

Inflammatory back pain is characterized by insidious onset of back pain, lasting more than three months, associated with morning stiffness and improvement with exercise. Ankylosing spondylitis has been traditionally diagnosed based on a combination of inflammatory back pain symptoms, limitation of spinal flexion (Schober’s test) and reduced chest expansion and X-ray imaging showing bilateral sacroiliitis grade ≥2 or unilateral sacroiliitis grade 3-4. There appears to be a genetic association between ankylosing spondylitis and IBD. Approximately 5-10% patients with ankylosing spondylitis develop IBD, and up to 70% patients may have microscopic evidence of gut inflammation; likewise, about 5-10% patients with IBD may develop ankylosing spondylitis.⁶ The presence of an elevated C-reactive protein and serum and/or fecal calprotectin in patients with ankylosing spondylitis has been shown to have modest accuracy as a screening strategy to identify potential ankylosing spondylitis patients with gut inflammation. Most patients with ankylosing spondylitis are HLA-B27 positive. Patients with IBD and axial arthritis have a rate of HLA-B27 positivity far above the general population (∼50%) but lower than those patients with AS. Regarding the diagnosis of axial inflammatory arthritis, magnetic resonance imaging (MRI) is often considered the gold standard. Changes on plain X-ray are more specific for the diagnosis of AS, but are less sensitive.

Other Musculoskeletal Extraintestinal Manifestations of IBD

Besides peripheral and axial arthropathies, enthesitis, tenosynovitis and dactylitis are commonly observed, particularly if highly sensitive imaging techniques such as ultrasound are utilized.⁵

Rheumatic Complications in IBD

While osteoporosis is not perhaps strictly an extraintestinal manifestaition of IBD, it is indeed a frequently observed complication, occurring in about 14-42% patients.^3,4 It is multifactorial, and related to a number of factors including intestinal malabsorption due to active disease or surgical resections, recurrent exposure to corticosteroids, and the local and systemic effects of chronic systemic inflammation. National guidelines suggest screening IBD patients with conventional risk factors for osteoporosis with dual energy X-ray absorptiometry.

Treatment

Arthritis can be functionally limiting in patients with IBD, and hence warrants attention and treatment in symptomatic patients.

Much of the data relevant to the treatment of peripheral arthritis related to IBD comes from the literature on the treatment of psoriatic arthritis (PsA) with peripheral arthritis. Treatment options include disease modifying anti-rheumatic drugs (DMARDs), including methotrexate (MTX), sulfasalazine, leflunomide and apremilast. Among biologic agents, tumor necrosis factor inhibitors (TNFi) have the longest and largest clinical data supporting their substantial efficacy. The most relevant data concerning the treatment of spinal, also called axial, arthropathies comes from studies of patients with ankylosing spondylitis. While NSAIDs and specific cyclooxygenase 2 (COX2) inhibitors are effective in both peripheral and axial arthritis, their use in IBD must take into account their potential effects on the bowel. Short courses (less than two weeks) of NSAIDs, particularly, COX-2 inhibitors may be used in patients with IBD.⁷ However, caution should be exercised since NSAIDs may exacerbate underlying IBD. In a large prospective cohort study of 791 patients with IBD in clinical remission at baseline, frequent use of NSAIDs ≥5 times per month was associated with 1.7 times higher risk of flare of Crohn’s disease, but not of ulcerative colitis; less frequent use was not associated with risk of IBD exacerbation.⁸ In a meta-analysis of 7 studies with 344 patients with IBD, about 14.4% patients treated with NSAIDs experienced exacerbation of gastrointestinal symptoms.⁹

While DMARDs are ineffective for axial arthritis, TNFi are highly effective. IL-17 inhibitors, which have recently been shown effective in PsA and AS, would not be a good choice for IBD related arthritis as they can have a detrimental effect on bowel inflammation.

Given the considerable overlap in IBD and rheumatic diseases, the concept a multi-disciplinary approach in a combined gastroenterology-rheumatology clinical has been explored. In a prospective study of 269 IBD patients with joint pain, Canigliaro and colleagues observed that a diagnosis of enteropathic arthritis was made in 50.5% of IBD patients with joint pain. These patients had peripheral arthropathies in 53%, axial arthropathies in 20.6% and both peripheral and axial arhropathies in 26.4% patients. These patients had higher prevalence of other EIMs and received more anti-TNF treatment compared with IBD patients without enteropathic arthritis.¹⁰ The mean diagnostic delay of 5.2 years was revealed in these patients; however, with the creation of a combined clinic there was a considerable decline in diagnostic delay.

In summary, rheumatologic extraintestinal manifestations and complications are common in patients with inflammatory bowel disease, presenting as peripheral arthritis and/or axial arthritis. These may or may not be related to IBD disease activity, but can cause considerable impairment of quality of life. A high index of suspicion and early treatment may decrease healthcare burden.

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Frontiers In Endoscopy, Series #36

Current Practice Patterns for Esophageal Stenting in Malignancy – A Web-Based Survey of Endoscopists Who Place Self Expanding Metal Stents

May 2017 • Volume XLI, Issue 5

Harshit S. Khara

David L. Diehl, MD reports consulting role with Boston Scientific and Olympus America. Douglas G. Adler, MD reports consulting role with Boston Scientific. David L. Diehl, MD¹ Jessica McKee, DO¹ Amir N. Rezk, MD¹ Douglas G. Adler, MD² Kimberly Fairley, DO¹ Harshit S. Khara, MD¹ ¹Geisinger Medical Center, Danville, PA ²Huntsman Cancer Center, University of Utah, Salt Lake City, UT

Background
The practice of placing self-expanding metal stents (SEMS) for esophageal cancer remains non-standardized regarding patient selection, timing, type, duration, and adverse event management.

Aims
To understand current practice patterns of SEMS placement and unmet needs by experts.

Methods
An 18-item on-line survey evaluated practices and preferences for SEMS by experienced advanced endoscopists (gastroenterologists and surgeons). Questions investigated stent types and sizes, methods and timing of deployment, perceived problems and unmet needs of currently available SEMS, and other issues.
Results 46 (22%) physicians responded. 51% made the decision to proceed with SEMS; 49% did after oncology request. 86% use SEMS prior to neoadjuvant treatment; 29% routinely remove SEMS at the end of radiation. 89% still observe feeding tube use instead of SEMS. Fluoroscopic placement was used by 74%. Endoscopic tumor palliation is uncommonly done (17%). Larger diameters (22-23mm) are used most commonly (59%); 52% have used SEMS < 18mm. Problems with SEMS included migration (62%), reflux (49%) and pain (56%) which infrequently requires SEMS removal. Tumor overgrowth/ingrowth was seen by 29%.

All respondents agreed that there was need for improvement of available SEMS. 62% expressed an interest in biodegradable SEMS and 60% felt that having a stent with anti-reflux functionality would be of benefit. Other unmet needs for SEMS included less radial force (51%) and better conformation to the GE junction angle (36%).

Conclusions
The use of esophageal SEMS remains non-standardized in clinical practice. Common themes regarding current usage were found. There are unmet needs regarding current stent technology.

INTRODUCTION

Dysphagia is the most common presenting symptom in patients with advanced esophageal cancer (EC). Difficulty managing oral secretions and eating solid food has a significant negative impact on their quality of life. In the current clinical environment, there is an understanding of the risks and benefits of self-expanding metal stents (SEMS) for malignant dysphagia, with most patients having excellent clinical outcomes and serious adverse events being relatively uncommon.¹ In addition, the clinical characteristics of patients who may need SEMS has changed with the widespread use of neoadjuvant treatment regimens for patients with locally advanced EC. The practice of placing esophageal SEMS remains non-standardized with regards to issues such as patient selection, timing of SEMS placement, type of SEMS placement in a given clinical situation, duration of SEMS placement, and management of SEMS-induced adverse events. To analyze trends in esophageal SEMS, we conducted a web-based survey to better understand the practice patterns of physicians who place SEMS and to poll their opinions about unmet needs in this clinical space.

Methods

An 18-item survey instrument was designed to evaluate current practices and preferences for SEMS. Questions were designed to not focus on any particular brand of stent, but general preferences in stent selection and clinical scenarios when stents are used. In addition, the survey questions were designed to try to elicit endoscopist’s perceptions of unmet needs given the current stent technology. The survey was uploaded to an on-line survey service (Survey Monkey, Palo Alto, CA), and went live for a 12-week period from December 2014-February 2015. The survey asked respondents questions regarding technical issues involving stent types and sizes, methods of deployment, and clinical issues regarding which patients received stents and when this occurred in the continuum of their care. Respondents were also questioned on their use of other palliative modalities in the treatment of dysphagia associated with EC. In addition, respondents were asked to elaborate on what they perceive as problems and unmet needs of currently available SEMS (See appendix for the entire survey instrument). Respondents were not paid for their participation.

This survey was sent to endoscopists and surgeons throughout the United States. Physicians who were involved in advanced endoscopy training were identified from the ASGE listing of advanced endoscopy programs.2 Surgeons who place esophageal stents were identified from esophageal stent sales data obtained from stent manufacturers. These physicians were included and contacted by email. An introductory message was sent to each physician along with the link to the survey. Completion of the survey signified implied consent for participation in the study. Our study was completely accomplished by survey and there was no other interaction with the subjects; i.e. there was no patient contact and no patient risk. IRB approval was obtained prior to commencing this study.

Results

The on-line survey was sent to 208 physicians, and 46 (22%) responded (Table 1). There were 39 gastroenterologists and 7 surgeons. 91% had an academic practice, while 9% identified themselves as being in private practice (with 7% in private practice but having an association with a gastroenterology fellowship). Regarding the initial decision to proceed SEMS placement, 49% physicians placed SEMS after multidisciplinary EC management team discussion; 51% made the decision to proceed with SEMS autonomously. 86% of practitioners have placed SEMS prior to neoadjuvant treatment, and 37% will schedule a planned removal at the end of radiation therapy. 89% of respondents observed placement of gastric or jejunal feeding tubes for nutrition instead of SEMS. The use of endoscopic tumor ablation instead of stenting was reported in 38% of respondents.

The majority of providers (74%) utilized fluoroscopy for SEMS placement while 26% used only endoscopic guidance for SEMS placement. Larger stent diameters (22 or 23mm) are used most commonly (59%) while 39% prefer the 18mm stent and only 2% of providers use stents less than 18mm (Figure 2). The 16 mm or smaller stents were used for indications of a very tight obstruction, pain from previous stent, pediatric application, or placement in the cervical esophagus (Figure 3).

Problems reported with SEMS included migration (62%), reflux related to use at the GE junction (49%) and problematic pain after placement (56%) (Figure 4). 91% of respondents have had the experience of having to remove a stent within a month of placement due to intractable pain; however, in general stent removal was required infrequently (Table 1). Stent migration was encountered by 62% of respondents, and tumor overgrowth / ingrowth by 29% (Figure 4).

All of the respondents agreed that there was need for improvement on the available SEMS. The majority of endoscopists expressed an interest in biodegradable SEMS (62%) and felt that having a stent with anti-reflux functionality would be of benefit (60%). Other unmet needs for SEMS in the United States included the need for stents with less radial force (51%) and stents that conform better to the angle of the GE junction (36%) (Figure 5).

DISCUSSION

Self-expanding esophageal metal stents are in widespread use and allow patients to achieve rapid palliation of dysphagia from a variety of benign and malignant causes.³ Despite this, the use of these devices remains nonstandardized in clinical practice. We undertook a survey to evaluate usage of, and perceptions about these devices in current gastroenterology practice. We present here the results of this survey to provide insight into the prevailing practice patterns of gastroenterologists who commonly place esophageal SEMS. A variety of E-SEMS have been developed for the palliation of malignant dysphagia and there may be a variety of factors influencing how endoscopists select a particular stent. Tumor length and position, the presence or absence of a fistula, potential airway compromise in the setting of proximal stenosis and personal preference may all influence the endoscopist’s choice. The use of smaller esophageal stent diameters to try to decrease post-treatment pain has been advocated,⁴ however most of our respondents continue to use the largest stent diameters (59% use 22 or 23mm stents, 39% use 18mm), and only 2% used stents smaller than 18mm. A prospective randomized study compared 18mm versus 23mm SEMS.⁵ Adverse effects were seen in both groups, but the type of incidents were somewhat different, with more migration, stent occlusion, and need for repeat endoscopy in the small diameter groups and more bleeding and esophagorespiratory fistulas in the large diameter group. The use of smaller diameter stents (16 mm or less) has been utilized in patients with very tight strictures in a limited number of studies. Kucera et al.⁶ compared small caliber SEMS (10mm-16mm) to large caliber SEMS (>18mm). Stent- related pain was decreased although migration during therapy was increased 5.5 fold. There was comparable dysphagia reduction when the two different stent types were compared.

Chest pain in patients after SEMS placement was described by more than half of respondents (56%). The exact cause of pain after SEMS deployment is not clear and is likely multifactorial, including radial force, axial force (resulting in pressure against the esophagus from the ends of the stent), GERD, primary tumor pain, and other factors. The optimal radial force for SEMS has not been determined, and it is likely variable in different patients. Half of respondents felt that having stents with less radial force may be beneficial in decreasing pain after placement.

It has been reported that up to 79% of esophageal cancer patients are malnourished even before treatment begins.⁷ One study of 138 patients with GEJ EC found that “individualized goal-directed dietary counseling” could almost completely allow avoidance of SEMS as well as external feeding tubes. Dysphagia resolved after the first cycle of chemotherapy, and an SEMS was required in only one patient.⁸ Among respondents to the survey, 89% observe use of surgical jejunostomy or gastrostomy, which may reflect referring physician’s lack of faith in the inability of an esophageal stent to allow the patient to maintain their nutritional status orally. The belief that SEMS would make feeding tubes unnecessary has not been fully realized and the presence of an external tube is a constant reminder to the patient of their diagnosis.9⁹

The emergence of neoadjuvant chemoradiation therapy as a preferred approach to treatment of esophageal cancer has introduced another large change in the landscape of the use of SEMS. Data is mixed on whether the use of SEMS in the neoadjuvant setting leads to negative outcomes,^1,10,11 or does not.^9,12-15 Eighty six percent of the respondents do use SEMS in the neo-adjuvant setting, and many (33%) indicated that removal is scheduled routinely at or near the end of the radiation treatment. The decision as to which patients should receive SEMS prior to neoadjuvant treatment may be made by the endoscopist (51% of respondents) or by a multidisciplinary oncology treatment panel (49%). The interventional endoscopist would be well-advised to discuss stent placement with a multidisciplinary oncology group prior to placement depending on institutional practices.

60% of respondents felt that having a stent with anti-reflux functionality would be of benefit. A stent with anti-reflux technology was previously available in the United States and decreased reflux symptoms after placement,¹⁶ but technical problems led to the device being withdrawn from the market. A newer stent with an anti-reflux valve (EndoMAXX EVT, Merit Medical, South Jordan, UT) has been used clinically in Europe with encouraging results. A prospective randomized study is currently under way in the United States (EVOLVE Study, # NCT02159898) to assess the usefulness of the EndoMAXX EVT stent.¹⁷

About a third of respondents (36%) felt that there may be some benefit to having stents that conform better to the geometry of the GE junction. The tumor histology of malignant esophageal obstruction has changed from predominantly squamous cell carcinoma, most commonly located in the mid esophagus, to adenocarcinoma with a distal esophageal or gastroesophageal junction (GEJ) location. Straight stents are not always positioned optimally at the GEJ location, and in rare cases may obstruct if they are impacted against gastric or esophageal lumen (Figure 6).

A majority of respondents (62%) felt that one of the unmet needs in the field was having biodegradable SEMS available for use. This technology could theoretically improve issues related to stent migration, post-deployment pain, and conformation to the GEJ, if the optimal specifications could be engineered into the stent. A biodegradable stent made from polydioxanone (ELLA-CS, Hradec Kralove, Czech Republic) has been available in Europe and the UK since at least 2008. A number of studies have been done for both malignant and non-malignant esophageal strictures.¹⁸ This device is not FDA approved for use in the United States. Biodegradable stents may play a role in the management of refractory benign strictures,^19,20 and their use has been included in the treatment algorithm of refractory strictures.²¹ Newer technology may utilize magnesium compounds as the biodegradable scaffolding.²²

Thirty eight percent of respondents use ablative techniques as an alternative to SEMS in some cases of malignant dysphagia. In the past, APC, Nd:YAG laser, photodynamic therapy (PDT) and a specialized bipolar cautery ablation probe (BICAP Tumor Probe, Circon USA) all saw some use for treating esophageal obstruction.^23-26 All techniques required specialized equipment and expertise, and usage essentially ceased shortly after SEMS were introduced. Recently, a renewed interest in cryoablation has led to a number of advanced endoscopists using this treatment as a palliative approach for obstructing esophageal cancer.²⁶ It may be a good option in the neoadjuvant setting, if studies demonstrate that one or two endoscopic ablation sessions are all that is required for palliation of dysphagia until the chemoradiation effect opens the esophageal lumen.

Endoscopists who place SEMS may not have further interaction with that patient, as their care is transitioned to medical, radiation and surgical oncologists. Stent- related problems may occur without the knowledge of the endoscopist. As a result, these other care-givers may develop a negative perception of SEMS, and try to avoid their use, particularly in the neo-adjuvant setting. The experience of even a single patient having a stent- related problem is often enough to make an oncologist or surgeon avoid referring patients for SEMS in the future. This may lead to underuse of SEMS in patients that could in fact benefit from them.

Esophageal SEMS have in the past and continue to play an important role in the management of malignant dysphagia. There is a large amount of data showing that these devices are safe in both the palliative and neoadjuvant treatment settings. Technical and clinical success rates with esophageal SEMS are high.

Physicians who place SEMS should have a realistic view of their benefits and the potential short- comings of these devices. Close collaboration between interventional endoscopists and oncology care providers is important so that treatment plans for patients with malignant esophageal obstruction can be optimized. In this way, the largest number of patients who might benefit from this technology can receive it.

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INTRODUCTION

Case Report

Discussion

CONCLUSION

INTRODUCTION

Indications for Treatment in Chronic Hepatitis B

Treatment Options for Immune Active Hepatitis B

Antiviral Treatment Discontinuation

CONCLUSIONS

INTRODUCTION

Case A Pancreatitis with gastric outlet obstruction

Case B Surgical Leak

APPLICATION AND CONCLUSION

INTRODUCTION

Case

Discussion

CONCLUSIONS

INTRODUCTION

Natural Course of Postoperative Crohn’s Disease and Recurrence Rates

Surveillance of Postoperative Crohn’s Disease

Endoscopic Scoring of Postoperative Crohn’s Disease

Risk Factors for Postoperative Crohn’s Disease Recurrence

Medications Studied for the Management of Postoperative Crohn’s Disease

Management of Postoperative Crohn’s Disease – Technical Review and Guidelines

CONCLUSION

INTRODUCTION

Role of Fats

Fat Digestion, Absorption, and Metabolism

Risk factors for EFAD

Clinical Manifestations of EFAD

Prevention of EFAD

Treatment of EFAD

Monitoring

CONCLUSIONS1

INTRODUCTION

Epidemiology of CDI

Pathogenesis

Presentation

RISK FACTORS

Diagnosis

Treatment

Management of CDI in IBD

CONCLUSION

INTRODUCTION

CASE REPORT

DISCUSSION

INTRODUCTION

Epidemiology

Pathophysiology

Clinical Presentation and Diagnosis Peripheral Arthropathies

Axial Arthritis

Other Musculoskeletal Extraintestinal Manifestations of IBD

Rheumatic Complications in IBD

Treatment

INTRODUCTION

Methods

Results

DISCUSSION

Case A
Pancreatitis with gastric outlet obstruction

CONCLUSIONS¹

Clinical Presentation and Diagnosis
Peripheral Arthropathies