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Treatment of Hepatitis C in Patients with Compensated and Decompensated Cirrhosis

November 2017 • Volume XLI, Issue 11
Elie Ghoulam,Nancy Reau

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Hepatitis C virus (HCV) treatment of compensated and decompensated cirrhosis differs because of the marginal hepatic function, increased mortality and high risk of complications in decompensated cirrhosis. Before the development of oral direct acting antivirals (DAAs), treating patients with decompensated cirrhosis was not an option. This article will address the management, the most recent recommended treatment and post cure monitoring of patients with compensated and decompensated HCV cirrhosis.

The course of chronic hepatitis C virus (HCV) progression can take decades and differs among individuals. Many patients are unaware of their HCV infection and some will develop only mild inflammation and fibrosis of the liver. Yet, a significant number of these patients will develop cirrhosis, decompensated cirrhosis and hepatocellular carcinoma (HCC). Many studies have shown that attaining sustained viral response (SVR) in both groups decreases all cause mortality and reduces the risk of HCC development. HCV treatment of compensated and decompensated cirrhosis differs because of the marginal hepatic function, increased mortality and high risk of complications in decompensated cirrhosis. Before the development of oral direct acting antivirals (DAAs), treating patients with decompensated cirrhosis was not an option. This article will address the management, the most recent recommended treatment and post cure monitoring of patients with compensated and decompensated HCV cirrhosis.

Elie Ghoulam MD, MS Post-Doctoral Research Fellow, Section of Hepatology, Rush University Medical Center, Chicago, IL Nancy Reau, MD Professor of Medicine Chief, Section of Hepatology, Associate Director, Solid Organ Transplantation, Rush University Medical Center, Chicago, IL

INTRODUCTION

Hepatitis C virus (HCV) was previously identified as non-A non-B hepatitis until its existence was proven in 1989.1. Hepatitis C is a contagious, blood borne, ssRNA virus and exists in multiple genotypes.2 Risk factors for acquiring include injection drug use, inadequate sterilization of medical equipment and transfusion of unscreened blood and blood products.3 HCV can also be transmitted sexually and vertically, but these modes of transmission are less efficient. Globally, 130-150 million people have HCV.3 According to the Centers for Disease Control and Prevention (CDC), an estimated 3.2 million people in the United States (USA) are living with chronic hepatitis C infection, many of whom are unaware of their infection.4 There is a high seroprevelance of HCV infection in persons born from 1945-1965, one-half of whom already had severe fibrosis or cirrhosis based on a study by Klevens et al. This data prompted the CDC to recommend one- time hepatitis C virus antibody testing in this group of people.5,6

The course of chronic HCV disease progression occurs over decades and is varied among individuals.7 Factors that impact disease progression are older age, male gender, diabetes, obesity, steatosis, iron overload, genotype 3, alcohol intake and human immunodeficiency virus (HIV) or hepatitis B (HBV) coinfection.8,9,10 Over the first 20 years of infection, most patients do not develop liver disease beyond inflammation and moderate fibrosis.10 A percentage of these patients will then progress to cirrhosis, possibly decompensated or symptomatic, and HCC.8 The chances of developing decompensated cirrhosis in the cirrhotic populations are 11.7% with a four-year survival of 50%. The risk of developing HCC is 1%-5% annually.8,11

Hepatitis C therapy has evolved significantly since first using interferon and ribavirin. This evolution has allowed the expansion of therapy to groups of individuals previously without treatment options. Although, even in the interferon era, individuals with well compensated cirrhosis could contemplate therapy, there were occasions of decompensation and significant toxicity. All-oral options have now made therapy commonplace for those with asymptomatic cirrhosis and an option to consider in those with decompensation.

The clinical benefit of viral eradication in those with advanced liver disease has been unarguably established through several long-term observational trials. Development of cirrhosis, decompensation and HCC are all considerably reduced after sustained viral response (SVR) with either interferon based or all oral direct acting antiviral (DAA) therapy. The rate of liver transplant wait-listing for HCV secondary to decompensated cirrhosis has decreased by 32% as a result of DAA therapy.12 Not only has there been demonstrable benefit to liver-related mortality, but all- cause mortality is also improved with viral eradication.13 However, clinicians still need to be aware that not all patients with cirrhosis are the same. Those with symptomatic cirrhosis (decompensated cirrhosis) are at higher risk for adverse events and drug toxicity. Historically, treatment of this group of individuals was contraindicated. As the toxicity and efficacy of therapy improved, we have been able to expand therapy to increasingly sicker patients, although the benefit of doing so remains controversial.

Recognizing Cirrhosis

Our guidance recommends staging each patient with hepatitis C.14 Cirrhosis can be quite subtle, and can easily be missed.

Cirrhosis

Cirrhosis is defined as the late stage of progressive hepatic fibrosis characterized by change of hepatic architecture and the formation of regenerative nodules.15 In its advanced stages it is considered to be irreversible, but in its earlier stages it may improve or even reverse if specific treatments aimed at the underlying etiology of liver disease are addressed.16

Signs and symptoms of cirrhosis can be nonspecific such as anorexia, weight loss, weakness, fatigue or signs and symptoms of hepatic decompensation such as jaundice, pruritus, upper gastrointestinal bleeding, abdominal distension from ascites and confusion due to hepatic encephalopathy.16

Physical findings consist of spider angiomatas, palmar erythema, gynecomastia, testicular atrophy, amenorrhea, parotid/lacrimal gland hypertrophy, Dupuytren’s contractures, clubbing and jaundice.16

Laboratory abnormalities may be striking such as elevated serum bilirubin or coagulopathy. However, laboratory findings may be subtler such as a platelet count &tl;150 or AS>ALT. Several clinical calculators can help identify those at higher risk for cirrhosis such as APRI or FIB4.17

Diagnosis

If cirrhosis is evident clinically (nodularity on imaging, splenomegaly, low platelets, ascites, encephalopathy, jaundice, etc.), no further assessment is required. However, most patients with advanced disease lack these clinical cues. Several non-invasive means have been validated to assess for fibrosis. All have diagnostic utility, yet a combination of concordant serum markers and elastography is felt to have the most reliability outside of biopsy.14

Compensated vs Decompensated Cirrhosis

Patients who develop complications of cirrhosis are considered to have decompensated cirrhosis and those who have not developed major complications are classified as having compensated cirrhosis.18 The median survival of patients with compensated cirrhosis is >12 years.18 Patients that develop varices but not variceal bleeding are still considered as having compensated cirrhosis but have a 2.1 percent increase in one-year mortality.18 Several factors can predispose to decompensation in a patient with cirrhosis. Risk factors include bleeding, infection, alcohol intake, medications, dehydration, obesity and constipation.19,20

Predictive Models

Two predictive models, the Child-Pugh classification (CP) and Model for End-Stage Liver Disease (MELD) score, are most commonly used today in attempt to predict the prognosis of cirrhotic patients. Based on clinical and laboratory information, these models have been derived from multiple studies.21,22

Child-Pugh Classification

The variables included in the CP classification are the serum albumin and bilirubin, ascites, encephalopathy and prothrombin time. The score ranges from 5 to 15. Patients with a score of 5 or 6 have Child-Pugh class A cirrhosis (well-compensated cirrhosis), those with a score of 7 to 9 have Child-Pugh class B cirrhosis (significant functional compromise) and those with a score of 10 to 15 have Child-Pugh class C cirrhosis (decompensated cirrhosis).21

The Child-Pugh classification system is not only used in staging of cirrhosis but has been found to correlate with survival of patients not undergoing surgery with decrease survival rates as you progress from Child-Pugh A to C.23 It is also associated with likelihood of developing complications of cirrhosis. Child-Pugh C patients are much more likely to develop variceal bleeding for example than Child-Pugh A.24

MELD Score

Another model to predict prognosis in patients with cirrhosis is the MELD score 22. Based on bilirubin levels, creatinine, INR and the etiology of cirrhosis, the MELD score has been adopted for use in prioritizing patients awaiting liver transplantation and has an expanding role in predicting outcomes in patients with liver disease in the non-transplantation setting as well. In January 2016, Organ Procurement and Transplantation Network Policy 9.1 (MELD Score) was updated to include serum sodium as a factor in the calculation of the MELD score 25. The MELDNa score can be calculated online.

Consider Consequences of Cirrhosis

Individuals with advanced liver disease are at risk for complications of portal hypertension and liver cancer. Once cirrhosis is recognized, it is advised to obtain abdominal imaging with ultrasonography to screen for hepatocellular cancer (HCC). If ultrasound is of poor quality, cross sectional imaging should be done.

Ascites may be clinically evident, but is not infrequently identified first on imaging done for liver cancer screening. The development of ascites carries significant impact on prognosis, decreasing expected 5-year survival to <60%. If the ascites is refractory to diuretics, associated with dilutional hyponatremia or type 2 hepatorenal syndrome (HRS), the anticipated 1-year survival is 30%.26

Several clinical algorithms exist to help identify those cirrhotics that are at higher risk for complications of portal hypertension. Those individuals with liver stiffness scores <20 kPa and serum platelet count >150,000/ mm3 are unlikely to have high-risk varices. Recently updated AASLD guidelines27 recommended performing an upper endoscopy to evaluate for gastroesophageal varices for all individuals that do not meet those criteria. If high-risk for bleeding (the presence of medium/large varices), primary prophylaxis with either non-selective beta-blockers or band ligation should be initiated.

Other routine health maintenance includes vaccinating against hepatitis A (HAV), hepatitis B, yearly influenza and avoidance of hepatotoxins. Patients with a CP score of >7 or MELD score >18 are at high risk for complications and should be co-managed by an experienced clinician.28

HCV and Genotypes and Treatment

Although pan genotypic therapy exits, the genotype of HCV remains an important variable as this may determine the efficacy and duration of therapy.14

Treatment of HCV in Patients with Compensated Cirrhosis

Individuals with HCV cirrhosis that lack symptoms (ascites, variceal bleeding, coagulopathy, jaundice, encephalopathy) are considered compensated. The Child-Pugh Class (CP) can be used to confirm prognosis. CP A is considered well compensated.29

No therapeutic agent is contraindicated in a patient with compensated cirrhosis, however certain regimens are recommended depending on genotype and treatment experience. Recommended regimens are generally prioritized due to shorter duration and the omission of ribavirin (RBV) to achieve higher efficacy. The most up to date therapeutic recommendations can be found in the American Association for the Study of Liver Disease/ Infectious Disease Society of America (AASLD/ IDSA ) guidance document.14 Table 1 summarizes the recommended and alternative, or not recommended, treatment choices for treatment naïve and treatment experienced (exposed to interferon, ribavirin or sofosbuvir) patients with cirrhosis.

Treatment of HCV with Decompensated Cirrhosis

The treatment of patients with CP class B or C cirrhosis is controversial, as most will require liver transplantation for optimal long-term survival. In patients who are not transplant candidates, the goal is to achieve SVR with the hope that there will be an improvement in clinical condition. For patients who are transplant candidates, the goals are not as straightforward. SVR before transplantation prevents re-infection of the new liver which could improve post-transplant outcomes and survival of the graft.14,30 However, viral eradication pre- transplant prevents the use of HCV exposed organs and treatment post-transplant is safe and effective.

Marginal hepatic function limits treatment options. In the era of IFN-based therapies, treatment in decompensated cirrhosis was contraindicated.31 All-oral therapy has significantly better efficacy and safety, however drug toxicity must still be considered. Although safe and effective in CP class A, protease inhibitors are not advised for those with CP class B/C cirrhosis.

Accordingly, the AASLD, IDSA and the European Association for the Study of the Liver (EASL) guidelines recommend only all-oral DAA regimens containing sofosbuvir, ledipasvir, daclatasvir and RBV as show in Table 2.31

Individuals with decompensated cirrhosis are at high risk for complications. It is advised that treatment should be performed by a highly experienced medical practitioner, preferably associated with a transplant center.14,30

Post-Cure Monitoring

It is important to recognize that although SVR substantially lowers the risk of progression or liver cancer, it does not eliminate this risk. All patients with cirrhosis, despite demonstration of regression by biopsy or non-invasive measurements, still require longitudinal follow-up. Liver cancer screening remains necessary as risk for malignancy remains. Recent analysis of a large Veterans Administration (VA) database demonstrates that age, gender and diabetes increase this risk.32

CONCLUSION

Compensated HCV cirrhosis has excellent long-term prognosis and a chance of reversal if SVR is attainable. Decompensated cirrhosis carries high risk of mortality and should be performed by highly experienced HCV providers. Early referral for transplant for patients with CTP >7 and MELD >18 is key for better patient outcomes as early treatment of HCV can prevent many life threatening complications and reduce HCC risk.

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A Case Report

A Rare Finding of Colonic Malakoplakia

October 2017 • Volume XLI, Issue 10
Jordan Orr,Mohamed Shoreibah,Ali Ahmed

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Jordan Orr, MD Mohamed Shoreibah, MD Ali Ahmed, MD The University of Alabama at Birmingham, Birmingham, AL

INTRODUCTION

Malakoplakia is a rare chronic inflammatory disease characterized by granulomatous formation from dysfunctional bacterial clearance by neutrophils and macrophages.1 Originally described in 1902, these inflammatory collections are characterized by a histiocytic infiltrate with round intracytoplasmic inclusions named Michaelis-Gutmann bodies.2 Since first discovered, the number of reported cases of malakoplakia is less than 500 in the United States.3 Malakoplakia is classically associated with the genitourinary tract but is also seen in the gastrointestinal (GI) tract, the second most common site of occurrence.4 Malakoplakia is largely an incidental finding, however colonic malakoplakia is particularly concerning because of its close association with colon adenocarcinoma.

Case Report

A 45-year-old female Jehovah’s Witness patient with a history of living donor kidney transplant (lupus nephritis) was admitted for further evaluation of a two-month history of rectal bleeding and severe symptomatic anemia resulting in weakness, tachycardia and general malaise. She denied hematemesis, melena, abdominal pain, nausea and vomiting but did report a five kilogram (11 lb) weight loss over the previous year. Her medication list included three immunosuppression drugs for her transplant (mycophenolate, tacrolimus and prednisone). Her admission labs revealed a hemoglobin (Hb) level of 6.2 gm/dL (MCV 76 fL), which decreased to 5.1 gm/dL after fluid resuscitation, and a creatinine (Cr) of 1.7 (baseline Cr 1.3). She refused red blood cell transfusion, in keeping with her religious beliefs. During her subsequent hospitalization, her hemoglobin improved with IV iron supplementation, darbepoetin alfa and limited blood draws.

Because of continued rectal bleeding and profound anemia she underwent endoscopic evaluation. Esophagogastroduodenoscopy (EGD) revealed a normal upper gastrointestinal (GI) tract without any source of bleeding. Colonoscopy revealed a large pedunculated polyp (2-3 cm, adenoma) in the proximal transverse colon and multiple small to large polyps (1-2.5 cm) in the remaining colon. Additionally, the mucosa in the rectosigmoid colon appeared nodular. Internal hemorrhoids were also found and was presumed to be the source of her lower GI bleed. Routine hematoxylin and eosin (H&E) stain of the colonic biopsies revealed numerous intramucosal macrophages with some showing nuclear changes compatible with Michaelis- Gutmann bodies, consistent with malakoplakia (Figure 1, Figure 2).

She remained hemodynamically stable following endoscopy, with improvement of her hemoglobin and resolution of her acute kidney injury, and was discharged from the hospital. Empiric antibiotic therapy (levofloxacin and azithromycin) was initiated as an outpatient upon biopsy result findings. Repeat colonoscopy four months after initial evaluation revealed normal appearing ascending and transverse colon, unlike previous colonoscopy, with a small sessile descending polyp (tubular adenoma). Infectious work up was negative for rhodococcus, tropheryma whipplei, mycobacterium tuberculosis, Epstein-Barr virus, and cytomegalovirus, however she was found to have high blood levels of BK virus by PCR. It was recommended that she return for surveillance colonoscopy in 12 months.

Discussion

Colonic malakoplakia, first reported by Terner and Lattes in 1965, is a rare manifestation of this chronic inflammatory condition.4 Malakoplakia can be seen throughout the entire GI tract and gives the gross appearance of mucosal plaques or nodules that are tan to yellow.4,5 This appearance gives rise to its name as it is derived from the classic Greek work “malacos” meaning soft and “placos” meaning plaque.5 These lesions can cause abdominal pain, diarrhea, hemorrhage and obstruction, however they are largely asymptomatic and rarely diagnosed clinically.3 Diagnosis is established histologically by determining the presence of large “Hansemann macrophages” which contain the Michaelis-Gutmann inclusions.1

The pathogenesis of malakoplakia is not well understood, but it has been proposed to be the result of an unusual infectious organism, an abnormal or altered immune response or an abnormal macrophage response due to defective lysosomal function.4 Escherichia coli has been identified as the most common bacterial pathogen, found in over 90% of affected patients, however other chronic bacterial infections, such as Proteus mirabilis, Staphylococcus aureus, Klebsiella spp, Mycobacterium Tuberculosis and Shigella boydii, have also been observed in malakoplakia.1,4 Malakoplakia has also been reported in association with coliform bacteria in patients on chemotherapy and Rhodococcus equi in patients with acquired immunodeficiency syndrome.5 Malakoplakia is closely associated with an impaired immune response, specifically organ transplant patients receiving immunosuppression to prevent organ rejection. Approximately 40% of malakoplakia cases that did not involve the urinary tract were associated with immunosuppression.6 Colonic malakoplakia has been reported in three cases with liver transplant, one case with cardiac transplant and five cases with kidney transplant from 1994-2010.1 Most significantly, malakoplakia is associated with colon adenocarcinoma. A review found 95 published cases of colonic malakoplakia, 24 of which had coexistent colonic adenocarcinoma.4 An early report found an association between malakoplakia of the GI tract and colorectal carcinoma in more than 30% of patients examined, however it appears to be an incidental finding in close proximity to the carcinoma in a majority of cases.5 Malakoplakia is also rarely associated with colonic adenoma, as seen in our case.2 It is unclear if malakoplakia is a precursor to tumor or if it is an inflammatory response in conjunction with tumor.5 Currently there are no additional recommended guidelines for colon cancer screening or surveillance.

Treatment for malakoplakia is not fully understood, but case reports demonstrate successful treatment with ciprofloxacin and lowering immune suppression. [6]

The significance of malakoplakia, a seemingly incidental finding, is not fully understood; however it is important to monitor patients with colonic malakoplakia because of its close relationship with colon adenocarcinoma.

Acknowledgements

We would like to thank Leona Council, MD, Assistant Professor, Division of Anatomic Pathology/Department of Pathology at The University of Alabama at Birmingham and Jessica Tracht, MD for providing expert opinion and pathology microphotographs.

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A Special Article

A Practical Approach to Managing Inpatient Acute Severe Ulcerative Colitis

October 2017 • Volume XLI, Issue 10
Stephanie O. Eschete,Kara M. De Felice

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Hospitalized acute severe ulcerative colitis patients require a multidisciplinary team approach with a focus on early escalation of medical therapy and early surgical consultation. This review aims to provide a practical approach on the treatment of inpatient acute severe ulcerative colitis.

Stephanie O. Eschete, PA-C, Kara M. De Felice, MD Louisiana State University Health Science Center, Department of Gastroenterology, New Orleans, LA

INTRODUCTION

Acute severe ulcerative colitis (UC) is a medical emergency requiring hospitalization and a multidisciplinary team approach involving a gastroenterologist and colorectal surgeon. North American UC cohort studies report that 18 to 25% of patients with UC will experience at least one flare requiring hospitalization.1,2

Severe UC is defined as having six or more bloody stools per day, tachycardia, fever, anemia (hemoglobin <10g/dL), and elevated erythrocyte sedimentation rate (ESR >30).1

Intravenous (IV) corticosteroids are the initial treatment for inpatient acute severe UC, however only two-thirds of patients will respond.3 Predictors of nonresponse to IV corticosteroids are persistence of bloody stools and an elevated CRP on day 3 (≥8 stools/day or 3-8 stool/day plus CRP > 45 mg/L).4 Up to 30% of patients admitted with an acute severe UC flare will require a colectomy. Early medical treatment and surgical consultation have been shown to decrease mortality rates in these patients.3

The purpose of this review is to provide a practical approach (Figure 1.) for the management of inpatient acute severe UC.

Day 1

On initial presentation, the patient should be hemodynamically resuscitated as appropriate.

1. Stool Evaluation for Infectious Pathogens

Patients should have stool samples assayed for Clostridium difficile (C. difficile) and cultured for bacterial pathogens. Patients with inflammatory bowel disease (IBD) concomitantly infected with C. difficile have longer hospitalizations, increase need for colectomy, and higher mortality rates.5 The stool sample should be collected first, and if clinical suspicion for C. difficile infection is high, prophylactic oral vancomycin may be initiated. Oral vancomycin should be discontinued if C. difficle is negative. Routine use of antibiotics in the absence of infectious colitis is inappropriate.6

2. Laboratory Evaluation

On admission, labs should include complete blood count (CBC), basic metabolic panel (BMP), and albumin. C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) should be ordered to assess disease severity. Some patients may have a normal CRP despite having severe inflammation on endoscopy.

In preparation for possible biologic therapy, one should test for tuberculosis (QuantiFERON-TB Gold and chest x-ray), hepatitis B (hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody), and human immunodeficiency virus (HIV antibody). Some of these tests require several days to result; therefore, it is best to draw them on admission.

3. Abdominal Radiograph

Patients should have a baseline plain abdominal radiograph on admission to help identify conditions that require immediate surgical attention such as megacolon, pneumatosis intestinalis, and perforation. If the patient’s clinical course changes at any time throughout the hospitalization, it is important to repeat the abdominal radiograph and compare it to the initial film.

4. Endoscopic Evaluation

A flexible sigmoidoscopy with biopsies should be done within the first 48 hours to assess disease severity and biopsy for cytomegalovirus (CMV). A bowel preparation and full colonoscopy is unnecessary in the acute setting and can increase the risk for megacolon and perforation.7

Biopsies for CMV should be done in the center of the ulceration. The gold standard for diagnosis is immunohistochemistry. CMV is considered significant if more than five inclusion bodies per high power field is seen. The preferred treatment for CMV colitis is IV ganciclovir.8

5. Diet

Patients should be allowed a normal diet throughout their hospitalization. There has been no evidence that complete bowel rest or total parenteral nutrition (TPN) improves inflammation or changes disease outcomes.9 If a normal diet is not tolerated, enteral nutrition is indicated.

6. Deep Venous Thrombus Prophylaxis

Hospitalization and active inflammation increase an UC patient’s risk for deep venous thrombosis (DVT). In a meta-analysis of eight randomized controlled trials, there was no significant increase in bleeding in patients treated with heparin during hospitalization for acute UC flares.10 Therefore, despite having bloody stools, all hospitalized UC patients should receive DVT prophylaxis.

7. First Line Medical Therapy

IV corticosteroids (40 mg/day) should be initiated on admission. Studies have shown that there is no evidence to support increasing methylprednisolone beyond 60 mg/day and the benefits do not outweigh the risks when increasing the dose beyond 40 mg/day.3

Patients who fail to respond to IV corticosteroids by day 3, have poor outcomes and should be evaluated for surgery or rescue medical therapy. Steroid nonresponse is defined as ≥8 stools/day or 3-8 stools/day plus CRP > 45 mg/L on day 3.4

8. Medications to Avoid and/or Stop During Hospitalization

Aminosalicylates have been shown to cause paradoxical colitis in 3% of patients and therefore should be discontinued on admission.11 Non-steroidal anti- inflammatory drugs (NSAIDs) can cause ulcers, increase risk for gastrointestinal bleeding, and can exacerbate flares and should be avoided.12

Narcotics increase morbidity and mortality in IBD patients.13 It can also increase a patient’s risk for megacolon. Narcotics are best avoided. Anti-diarrheals can also alter colonic motility and have no role in the treatment of UC.

Day 2
1. Clinical Assessment and Laboratory Evaluation

Clinical response should be assessed based on the trend in the number of stools, blood in stools, and CRP.

2. Colorectal Surgery Consultation

Early colorectal surgery consultation is important. Surgery should be considered as an equal option to rescue medical therapy in a patient who is not responding to IV corticosteroids. Early discussions about all possible options (medical versus surgical) between the patient, colorectal surgeons, and gastroenterologists will ensure optimal patient care.

Day 3
1. Clinical Assessment and Laboratory Evaluation

On day 3, response to IV corticosteroids will help to determine if rescue (medical or surgical) therapy is needed. Those patients that are responding to IV corticosteroids as defined by less than 8 stools per day with an appropriate downtrend in CRP can be switched to oral prednisone (40 mg daily). These patients should be discharged on oral prednisone (40 mg daily) with close outpatient gastroenterology follow up (preferably within one week). At follow up, maintenance therapy should be initiated (biologic and/or immunomodulator) and prednisone should be tapered.

Patients who fail to respond to IV corticosteroids by day 3, as defined by ≥8 stools/day or 3-8 stool/day plus CRP > 45 mg/L, should consider rescue medical therapy versus surgery.4

2. Rescue Medical Therapy

Either IV cyclosporine or infliximab is an appropriate choice as rescue therapy for patients who are failing IV corticosteroids and should be given on days 3-5.14 The choice of medication depends on the center’s expertise. Response should be assessed within 5-7 days after receiving rescue medical therapy.15 If no clinical response by day 7, surgery is indicated.

Patients who respond to IV cyclosporine should be switched to oral thiopurines for maintenance therapy.16 Combination therapy with a biologic may be required. Patients who respond to a single infusion of infliximab should complete induction doses at week 2 and week 6 followed by maintenance therapy every 8 weeks. Combination therapy with an immunomodulator should be considered.17

Low albumin levels and elevated CRP have been associated with lower infliximab serum levels due to rapid drug clearance.18 Studies have also found that infliximab is lost in the stool in the setting of severe inflammation resulting in lower serum infliximab levels.19 Therefore, higher and more frequent doses of infliximab may be required in patients with acute severe UC with elevated CRP levels and hypoalbuminemia. A recent retrospective study found that accelerated infliximab dosing (infliximab 5mg/kg, 3 doses within a median of 24 days) was associated with lower rates of colectomy compared to standard infliximab induction doses (infliximab 5mg/kg at week 0, 2, and 6).20

3. Surgical Management

Indications for surgery include toxic megacolon, perforation, massive bleeding, nonresponse to IV corticosteroids by day 3, and nonresponse to rescue medical therapy with cyclosporine or infliximab. The surgery of choice is a total colectomy with end- ileostomy and Hartmann’s pouch.21 An ileal pouch-anal anastomosis can be considered three to six months after the initial colectomy.

CONCLUSION

All patients with acute severe UC flares requiring hospitalization should receive IV corticosteroids on admission. C. difficile infection is common and should be treated with oral vancomycin. An early multidisciplinary team approach is critical to ensure optimal patient outcomes. Early rescue medical therapy or surgery is indicated if patients do not respond to IV corticosteroids by day 3. Other biologics have not been thoroughly studied as rescue medical therapies. Future research should aim to characterize the use of other biologic and biosimilar agents in the setting of an acute severe ulcerative colitis flare requiring hospitalization.

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Frontiers In Endoscopy, Series #39

Prognostic Biomarkers in Pancreatic Ductal Adenocarcinoma

October 2017 • Volume XLI, Issue 10
Valerie Gausman,Tamas Gonda

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Pancreatic ductal adenocarcinoma (PDAC) carries significant morbidity and mortality and remains one of the most difficult malignancies to treat. Individual patient and tumor factors need to be taken into account to provide an optimal, personalized approach. In this review, we highlight established and novel biomarkers that have the potential to be used as prognostic biomarkers in PDAC and some that may be used to guide therapeutic decisions. We briefly review some blood based biomarkers but focus on those that are tissue based and may be identified and characterized in pancreatic cancer biopsies.

Valerie Gausman, MD, Resident, Department of Medicine, NYU School of Medicine, New York, NY Tamas Gonda, MD, Assistant Professor of Medicine, Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY

INTRODUCTION

Despite major advances in the therapies of many solid tumors, survival in pancreatic ductal adenocarcinoma (PDAC) has not improved.1 Delayed diagnosis, aggressive biology and marked chemoresistance have all contributed to this disappointing trend. Prognostic biomarkers inform of a likely cancer outcome (disease recurrence, progression or death) independent of type of treatment. A biomarker is predictive if there is a difference in treatment effect for biomarker positive patients compared to biomarker negative patients. General prognostic markers, not specific to a defined therapeutic regimen, can be useful in distinguishing which patients are at higher risk of a poor outcome and should therefore be managed more aggressively. While large gene expression panels have been identified for use in prognostication of other malignancies and some have been linked to therapeutic response, few such markers have been well characterized in pancreatic cancer and even fewer have been used in clinical practice. We provide an overview of the most promising markers and those that may be closest to clinical use.

BLOOD OR SERUM BASED BIOMARKERS
Established Serum Based Biomarkers

There are few established and widely clinically used biomarkers for PDAC compared to other malignancies. Carbohydrate antigen 19-9 (CA 19-9), or sialyl Lewis antigen, is the only biomarker recommended by the National Comprehensive Cancer Network guidelines in the evaluation of PDAC. Its role in carcinogenesis may be related to its association with an increased adherence of cancer cells to endothelial cells through E-selectin,2 In addition to its well-known role in the diagnosis of PDAC, higher levels of pre-operative CA 19-9 have been shown to be correlated with advancing stage,3 less resectability,4,5 and decreased survival.6-8 However, its sensitivity is limited due to 10% of the population being non-secretors of CA 19-9 and its specificity limited due to its secretion by normal biliary epithelium.7

Other commonly used pre-operative laboratory markers include carcinoembryonic antigen (CEA), an intercellular adhesion glycoprotein normally present in very low levels in the blood, lactate dehydrogenase (LDH), an enzyme involved in sugar metabolism and C-reactive protein (CRP), an acute phase reactant. Compared to normal levels, elevated LDH,9 CEA,10,11 and CRP12,13 have all been shown to be independent unfavorable prognostic factors of survival. However, similar to CA 19-9, these laboratory markers are limited in their specificity. Table 1 highlights the accuracy of these markers in distinguishing resectability and prognosticating survival.

Blood or Serum Based
Biomarkers in Development

The value of serum-based markers is their less invasive approach and ability to collect multiple samples for various analyses. The most notable serum-based markers currently under investigation include circulating tumor cells, circulating tumor DNA and microRNAs and are summarized in Table 2.

Metastatic spread is commonly perceived to be one of the latest steps in the progression of cancer; however, the presence of circulating tumor cells (CTCs) in early stages as well as in pre-invasive lesions have challenged this. CTCs are cancer cells that are shed off the primary or metastatic tumor and can travel through the blood stream, potentially leading to new metastasis. A meta-analysis has revealed that the presence of CTCs in PDAC corresponds with worse progression- free and overall survival.41 A recent study found that cytokeratin-expressing CTCs, but not mesenchymal- like CTCs, had prognostic utility, highlighting the importance of phenotypic identification of CTCs.42 The CellSearch system is the only FDA-approved CDC detection technology (since 2004), but it is expensive, requires a complicated enrichment step, has a long detection time, low sensitivity and does not allow for isolation of CTCs for further molecular analyses. Thus, new detection modalities are being investigated including line confocal microscopy, surface-enhanced Raman spectroscopy (SERS), new enrichment technologies and fluorescence in situ hybridization (FISH).43,44

Cell-free DNA (cfDNA) is another minimally invasive potential sample source that is also referred to as a liquid biopsy. These are small fragments of DNA that are released after cellular necrosis or apoptosis and circulate in the bloodstream; when they are released from tumor cells, they are called circulating tumor DNA (ctDNA). ctDNA is, on its own, a negative prognostic marker,45 and it can also be used to identify genetic mutations which can further prognosticate survival in PDAC.46 One study looking at ctDNA in a variety of early and late stage malignancies found that ctDNA was detectable in some patients without detectable CTCs (but not vice versa), suggesting that these biomarkers are separate entities.47

The majority of the human genome is made up of non-coding RNA molecules, which are not transcribed into proteins, but have been shown to play a major role in regulating gene expression. MicroRNAs (miRNAs) are small (18-25 nucleotide) single stranded transcripts of non-coding RNA, which are highly stable and can act as tumor suppressors or oncogenes depending on their dysregulation. Nearly 100 miRNAs are differentially expressed in pancreatic cancer and they have been analyzed in human blood, bile, pancreatic juice, pancreatic cysts and stool. miR-21 is commonly considered an oncogene as many of its targets are tumor suppressors such as programmed cell death 4 (PDCD4) and PTEN. A large number of studies have identified miR-21 as a strong negative prognostic marker of survival in PDAC. A meta-analysis of 11 studies found tissue miR-21 levels to be strongly associated with reduced survival.48 In the serum, high levels of miR-21 have also been shown to be correlated with low survival and decreased time to recurrence.49,50 Conveniently, miR-21 has been found to be elevated early in pancreatic carcinogenesis. Up-regulation of miR-21 in precursor lesions such as intraductal papillary mucinous neoplasms (IPMN) and pancreatic intraepithelial neoplasia (PanIN) is also associated with a worse prognosis.48 A large supportive study analyzing miRNA levels in PDAC revealed high expression of miR-21 and miR-31 with low expression of miR-375 were associated with poor overall survival following surgical resection.51

HOX Transcript Antisense RNA (HOTAIR) is a powerful predictor of metastasis and poor prognosis in multiple cancers. It is a non-coding RNA that works via histone modifications to decrease the expression of multiple genes. In PDAC, high HOTAIR expression has been shown to be associated with decreased survival and more aggressive tumors (those that extend to lymph nodes and beyond the pancreas).52 HOTAIR has also shown potential to be quantified in salivary samples.53

TISSUE BASED BIOMARKERS
High Quality Pancreatic Tumor Biopsies

There have been marked recent advances in the ability to obtain high quality histologically intact core biopsies from pancreatic cancer and this shift will likely allow a far greater use of tissue based biomarkers. Although few studies have evaluated different biopsy techniques and needle designs side-by-side, it is apparent that the newer generation “core” fine needle biopsies (FNB) will provide far better quality and quantity specimens than the first-generation fine needle aspirations (FNA). Several studies have demonstrated that the overall diagnostic accuracy of FNA and FNB is similar (92.5- 94.8% vs. 90-98.3%, respectively).35-37 In some studies, FNB required a significantly lower number of needle passes and was associated with greater accuracy at onsite cytology.37 However, more recent studies have found similar overall diagnostic accuracy and per path diagnostic accuracy.38

In addition to the comparable and possibly superior accuracy, the main objective when using a core biopsy is to obtain histologically intact tumor architecture and greater tumor volume. Figure 1A-C demonstrates three of the new FNB needles and an example of a pancreatic cancer specimen obtained through FNB. There are multiple ways to perform tissue acquisition and no certain needle size has shown clear superiority. It appears that both the tumor biology and architecture, as well as the endoscopic position may determine the most successful method. Therefore, we recommend individualizing this approach. Negative suction in the needle may be created by withdrawing the stylet during tissue acquisition (“slow pull technique” associated with lowest suction force), by dry suction (attaching the needle to a syringe that contains a 10-50 ml of vacuum column) or by wet suction (preloading the needle with saline prior to attaching the syringe to create negative suction).39,40 We recommend examining the specimen obtained by a low suction force method and if the material is minimal, attempt a higher suction method as second line. However, in hard fibrotic tumors (either based on expected histology such as sarcomas or NETs or by feel during the procedures), a higher suction force method would be reasonable to try first and only switch to a lower suction method if the aspirate is overwhelmingly bloody.

Handling of core biopsy specimens is possibly as important to acquiring high quality and quantity tissue as needle design. Perhaps the most reliable way of examining the specimen is by expelling the needle content on a glass slide. In our practice, we expel the tissue in a serpentine manner to allow visual examination of the entire content. Often, white materials can be seen interspersed with the red coagulum and these may be highest yield for diagnostic tissue. We use one of these suspected microcores to generate a smear for on site evaluation and for cytologic evaluation. Given that cytologic details such as nuclear and cytoplasmic details are often better preserved in CytoLyt, it remains important to have some material in this preservative. In addition, the quality of nucleic acid isolated from tissue material is somewhat better from CytoLyt than from formalin fixed material. The remainder, and the majority, of the microcores are placed in formalin. As shown in Figure 1D, the formalin-processed cell blocks often yield significant areas of intact tissue.

Prognostic Markers

Tissue-based markers harbor the benefit of being more specific to the tumor tissue, but at the expense of requiring more invasive collection techniques. Immunohistochemical (IHC) analysis is a widely- used process utilized to visualize specific molecular markers and identify their distribution in clinical tissue specimens. Though these markers may be useful in patients who undergo surgical resection, investigations are still needed to discern if there is prognostic value to these biomarkers in pre-operative brush or biopsy specimens. Perhaps the best characterized treatment predictive biomarker is human equilibrative nucleoside transporter 1 (hENT1). hENT1, ribonucleotide reductase subunit 1 and 2 (RRM1, RRM2), and excision repair cross-complementing gene-1 (ERCC1) are vital for cellular transport and DNA synthesis and are frequently implicated as poor prognostic factors in various malignancies.14 In one multivariate analysis, high expression of RRM2 and ERCC1, but not the others, were associated with worse recurrence-free survival (RFS) and overall survival (OS).14 Another study found low hENT1 expression to be associated with poor RFS and OS.15 As hENT1 plays a major role in the internalization of Gemcitabine by pancreatic cancer cells, the primary role of hENT1 is as a predictive marker to Gemcitabine chemotherapy, for which there is more data available. Table 3 summarizes the data for hENT1 and other tissue-based markers as prognostic markers for survival in PDAC.

Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein which undergoes epigenetic silencing in pancreatic adenocarcinoma, but is often strongly expressed at the interface between the tumor and stroma by stromal fibroblasts.16 Supporting data suggest this interaction is important for tumor progression, metastasis and chemoresistance. Stromal SPARC expression is observed in all disease stages suggesting early expression is critical for tumor progression.17 Strong stromal SPARC expression in patients with well to moderately differentiated cancer who underwent surgical resection was associated with decreased overall survival when compared to patients with no SPARC expression.17,18 Furthermore, patients with diffuse stromal SPARC expression extending beyond the peri-tumoral region had a significantly worse prognosis.19 Most reports of cytoplasmic SPARC expression by malignant pancreatic cells have shown no prognostication value.17 Some studies have found no prognostic benefit in observational cohorts, but only a strong predictive association in patients who were treated with gemcitabine.20 Elevated SPARC mRNA expression has similarly been found to be a negative prognostic marker for PDAC survival and can be beneficial in that this analysis can be run on samples that are too small for IHC, such as from pre-operative fine needle aspiration.21 Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, thus facilitating tumor growth and progression. In IHC analysis, staining for VEGF is mainly demonstrated within the cytoplasm and cell membrane of cancer cells. Increased VEGF expression has been associated with a poor prognosis, including lower survival and increased lymphatic vessel invasion and lymph node metastasis.22-24 Similar to SPARC and hENT1, there are therapies targeted against VEGF, so it also has potential as a predictive marker.

Smad4 is a tumor suppressor gene involved in mediating transforming growth factor beta (TGF-B). As evidenced by its alternative name, DPC4 (deleted in pancreatic carcinoma, locus 4), loss or inactivation of Smad4 is seen in ∼50% of PDAC25 and leads to increased cellular proliferation by upregulating the progression from G1-S in the cell cycle. Loss of Smad4 expression has frequently been shown to be associated with reduced survival in PDAC.8,26 Interestingly, one study discordantly demonstrated that low expression of Smad4 was associated with improved overall survival and importantly, pancreatic resection only benefited (via longer survival) tumors who had lost Smad4 expression.27

KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is a GTPase that activates proteins required for propagation of growth factors and other cell signaling receptors. Overall, KRAS mutations have correlated with a reduction in survival.8,28,29 Interestingly, the different mutational subtypes show varying duration of survival, with wild type GGT (glycine) converted to GAT (aspartate) being the most common and the only one to be prognostic of poor survival.8,28 Additionally, mutational analysis performed for these KRAS mutations can be performed with quantitative polymerase chain reaction (PCR) which is cheaper and faster than other sequencing methods and uses less DNA data, making it easier to perform multiple molecular analyses on the same sample.28

Perhaps the most exciting development of cancer therapy in the last few years has been the remarkable progress of the use of immunotherapy. Despite the success seen in several solid malignancies (melanoma, lung cancer, urological cancers), response rates have been minimal in pancreatic cancer. However, an immune response is present in pancreatic cancer and emerging strategies to turn on this immune response or identify tumors with an immune sensitive phenotype are promising. Parallel to these efforts, there is increasing evidence that the native immune response in pancreatic cancer is predictive of treatment outcomes. Immunohistochemical analyses that identify T cell populations and myeloid cells in pancreatic cancer,30 or the level of expression of negative checkpoint regulators (NCR)31,32 have already demonstrated prognostic value. These markers may also serve as important predictors of response to immunotherapies in the future.

Smad4, hENT1 and SPARC possess another benefit as biomarkers, in that they have been shown to be effectively assessed on pre-operative biopsy specimens.19,27,33,34 Since quantitative PCR of VEGF and KRAS has also been shown to be accurate, there may be a role for these biomarkers during the pre-operative assessment with the smaller samples associated with biopsies.

Treatment Predictive Markers

There are various imaging modalities involved in the diagnosis and staging of PDAC including computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), and endoscopic retrograde cholangiopancreatography (ERCP). The roles of these modalities have changed over time, but the relative importance of EUS greatly increased with the advent of EUS-guided fine needle aspiration (EUS- FNA) over 20 years ago. Though limited by relative invasiveness and operator variability, it has been demonstrated to have excellent sensitivity (91-100%) and specificity (94-100%) for the diagnosis of PDAC.54

While many tissue-based biomarkers show promise in the evaluation of PDAC, most of these studies have relied on surgically resected material, which comprise less than 20% of all patients diagnosed with this disease. As EUS-FNA technology continues to improve, including the ability to obtain more histologically intact core biopsies with new needles and improved visibility with the use of contrast-enhancement and elastography, the clinical utility of these biopsies broadens. Though not yet in widespread use, we can reliably perform immunohistochemistry analyses to identify prognostic and predictive markers such as hENT1, VEGF and microRNAs on these tissue samples pre- operatively.33,55-57 Unfortunately, truly targeted therapies in pancreatic cancer are not yet available, but as our understanding of the biology of cancer evolves, it is important that our tissue acquisition methods improve and are ready for “prime time.”

One could imagine that a combination of currently available and previously discussed biomarkers may help in the selection of therapies, but only if our ability to evaluate them in pancreatic cancer biopsies can be validated. There a few emerging examples of clinical trials that require specific markers in biopsies. Pegylated recombinant human hyaluronidase (PEGPh30) is an enzyme that has been shown to potentiate chemotherapy in PDAC by removing excess hyaluronic acid from the tumor microenvironment. A phase 1b trial of PEGPh30 in combination with Gemcitabine as first line therapy in metastatic disease demonstrated a good safety profile and promising therapeutic benefit.58 There are several ongoing clinical trials of PEGPh30; participation not only requires histologically confirmed PDAC, but frequently also evaluation of PEGPh30 expression in biopsies.

In addition, from many other cancer treatment algorithms, we know that understanding changes in tumor biology following a first line treatment regimen is critical. Recent phase II trials of a VEGF inhibitor, Vatalinib59 and nab-paclitaxel60 as individual second line therapies in advanced PDAC have demonstrated a favorable survival outcome in some patients; however, serum-based biomarkers did not correlate with response and the predictive value of tissue-based biomarkers (SPARC) were inconclusive due to small sample size. With high quality biopsies, we can expect that most trials, and increasingly, the standard of practice, will emphasize the need for post-treatment biopsies.

CONCLUSION

This review focused on biomarkers that can be used to prognosticate outcome in PDAC, independent of treatment strategy. There are a multitude of potential biomarkers in the literature, but many are limited by specificity, heterogeneity of disease, difficulty in obtaining adequate samples and conflicting results. Also, the majority of the tissue-based biomarkers have been studied in resection specimens, and these patients only account for a minority of most PDAC cohorts. The most promising tissue biomarkers include hENT1, SPARC, Smad4, and VEGF as they may be valuable in the pre-operative period and may additionally have predictive value in guiding individualized pancreatic cancer therapy. The novel serum-based markers are also valuable due to their minimally invasive approach and foundation for genetic analysis. As both endoscopic methods to obtain high quality biopsy specimens and the molecular understanding of pancreatic cancer advances, it is likely that these and many other biomarkers will enter into routine clinical practice. It is increasingly important to obtain the highest quality tumor biopsies at the time of diagnostic procedures and assure that sufficient tumor tissue material is available for molecular and immunohistochemical analysis.

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Stuck on You – A Familial Tale of Eosinophilic Esophagitis

September 2017 • Volume XLI, Issue 9
Michael Root,Marianna Papademetriou,David M. Poppers

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Michael Root, Medical Student, MS4. Marianna Papademetriou, MD, Fellow. David M. Poppers, MD, PhD, Clinical Associate Professor of Medicine. Division of Gastroenterology, NYU Langone Health New York University School of Medicine, New York, NY

INTRODUCTION

Eosinophilic esophagitis (EoE) is an IgE-mediated allergic condition of the esophagus characterized by dense eosinophilic infiltrates. The prevalence of EoE has been increasing over the last few decades and has become an important entity encountered by primary care physicians, gastroenterologists and allergists.1 An association with atopic conditions suggests that EoE may be driven by both genetic and environmental factors, including food-related exposures.2 Here, we present two cases of EoE in adult brothers with an update on the known genetic involvement in this disease.

Case Report

An 18 year-old male with allergic rhinitis and food allergies presented with abdominal pain, foul-smelling bowel movements and weight loss for one year. Esophagogastroduodenoscopy (EGD) revealed linear furrows throughout the esophagus (Figures 1a and b). Biopsies demonstrated eosinophilia up to 150 per high-power field (HPF) consistent with eosinophilic esophagitis (EoE). Serum allergen testing indicated an elevated serum IgE (380 IU/ml) and multiple food sensitivities. The patient was initially placed on a proton pump inhibitor (PPI) and scheduled for a repeat EGD to assess response and confirm the suspected EoE diagnosis. In the interim, the patient began experiencing dysphagia primarily to liquids but also to solids. Repeat EGD showed unchanged linear furrows in the mid and proximal esophagus (Figures 1c and d), however biopsies showed significant reduction in eosinophilia to 22/HPF. The patient’s symptoms improved after an 8-week PPI course and he has not required further treatment with topical steroids.

His brother is a 36 year-old with a history of gastroesophageal reflux disease (GERD) and one year history of progressive dysphagia to solids. He has no known allergies or atopic conditions. On initial EGD, the esophageal mucosa appeared normal (Figures 1e and f); however, biopsies yielded eosinophilia up to 150/HPF, concerning for EoE. His serum allergen panel was negative with a mildly elevated IgE (163 IU/ml). The patient completed an 8-week PPI course with improvement in dysphagia but has not undergone a follow-up EGD at the time of this manuscript. He is being followed by an allergist and primary care physician for further evaluation of potential food- triggers.

Discussion

Esinophilic esophagitis is an increasingly prevalent condition encountered by various health care providers. Until recently, the entity has been poorly understood and this has led to delayed diagnosis and treatment increasing the risk of complications including esophageal strictures.3 Understanding the heterogeneous clinical presentation and underlying patient demographics and risk factors, principally family history and association with atopic conditions, is crucial for timely and accurate diagnosis.

Here we describe two adult male siblings who presented with symptomatic EoE within the same year. Both were diagnosed with a high burden of eosinophilia on endoscopic biopsies, with some differences in the details of their clinical presentations and serologic and endoscopic findings. One patient demonstrated classic endoscopic findings of linear esophageal furrows with a history of atopic disease (food allergies and allergic rhinitis), whereas his sibling had a normal appearing esophagus and no history of atopy. The patients presented in the second and fourth decades of life, respectively, illustrating the delayed diagnosis and varying latency periods of disease manifestation seen in the adult population.

Studies support a heritable component in EoE with recurrence risk ratios (RRR) in first-degree relatives of patients ranging from 10-64 compared to the general population, which is a stronger relationship than that observed in other atopic diseases such as asthma.4 The RRRs were found to be highest in brothers (64) and fathers (42.9) of probands, compared to sisters and mothers.4 However, research on the relative contribution of genetics and environment to this condition is limited. Alexander et al. provides insight through analysis of nuclear family and twin cohorts of EoE probands. The authors estimate that the combined gene-environment heritability for the nuclear family cohort was 72% with common environment accounting for most of the observed variation.4 Furthermore, dizygotic twins had a significantly higher frequency of EoE than non-twin siblings, which suggests not only the importance of a shared environment but also the timing of early life exposures that may influence genetically-susceptible family members.4 In a population-based study, findings support an increased risk in first degree relatives but extend their analysis to include more distant relatives. Both second-degree relatives and first cousins showed an increased odds ratio (OR) of concordant disease, supporting the role of a heritable component in family members less likely to share common environments.5

Clinically, the heterogeneity of presentation as well as symptom overlap with more common conditions such as GERD have proven roadblocks to timely and accurate diagnosis of EoE. As discussed, our two patients presented with different clinical presentations in terms of disease latency, symptoms, and endoscopic appearance. While prior studies have not shown a statistically significant difference in signs and symptoms, endoscopic appearance, or atopic status between familial and sporadic EoE patients, our case study suggests there may be more variability within the familial EoE population than previously recognized.6

Despite different clinical presentations, the histopathologic similarity between the two patients presented here is consistent with reports of a genomic “EoE transcriptome” that may be conserved across EoE patients regardless of sex, age, or atopic/allergic status.7 The eotaxin-3 (eosinophil-specific chemoattractant) gene has been identified as a highly over-expressed gene in the transcriptome, with end-organ eosinophilia being strongly correlated with both eotaxin-3 mRNA levels as well as disease severity.7 The gene expression profile also differed from patients with chronic esophagitis, including GERD, highlighting a potentially unique downstream pathway for diagnosis and treatment of EoE.

According to the 2013 ACG Practice Guidelines, the first step in management of suspected EoE is an 8-week PPI trial followed by repeat EGD to assess clinical and histological response. A lack of PPI- response is consistent with EoE but a positive response places a patient in a category known as PPI-responsive esophageal eosinophilia (PPI-REE), requiring the physician to rule out GERD as a possible cause of this eosinophilia.8 Interestingly, in our two patients, both had clinical responses to an 8-week PPI trial, one of whom also showed endoscopic evidence of response with significantly reduced esophageal eosinophilia.

There is growing evidence that PPI-REE is not a separate clinical entity, but rather lies within the spectrum of patients with EoE. Patients with EoE and PPI-REE not only share the same demographics, clinical presentations, and endoscopic characteristics, but also have indistinguishable downstream immuno- histochemical profiles of certain inflammatory markers, including eotaxin-3.9 Furthermore, these same markers were useful in identifying EoE patients compared to controls with GERD or dysphagia.9 The strict cutoff of persistent eosinophilia ≥15/HPF for failing a PPI trial also blurs the distinction between these two entities. Strictly speaking, our patient would qualify as a failed responder despite clinical improvement and drastic reduction in esophageal eosinophilia, which is not uncommon in patients with typical EoE presentations. As such, there is growing support to reclassify PPI-REE as a subtype of EoE in which a PPI trial is a safe and effective first-line therapy rather than a diagnostic test.10

In conclusion, EoE represents an increasingly important condition to recognize in various clinical settings. Proper diagnosis and treatment can reduce the risk of long-term consequences such as esophageal strictures, and is also useful for family members who may have yet-undiagnosed disease. New insights into the genetic susceptibility and importance of early life exposures support a complex pathogenesis of this disease, of which our understanding is improving. Our case study adds to the growing body of evidence to support a familial inheritance of EoE while simultaneously highlighting the diverse clinical presentations that create additional challenges for healthcare providers.

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A Special Article

Real-Time Radiographic Identification of Contrast Consistency in Modified Barium Swallow Studies: An Alternative Technique

September 2017 • Volume XLI, Issue 9
Rupert K. Hung,Jamie Muhly,Mamie Gao,Gary Gong,Martin Auster

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Contrast agents of varying consistency, ranging from thin liquids to solids, are utilized in modified barium swallow (MBS) studies, typically without real-time radiographic labeling. We describe a method for identifying the contrast consistency using radiographic labels during each fluoroscopy sequence. Two cases demonstrating the utility of the radiographic labels in clinical practice are described in detail. Our labeling method is an easily implemented and cost-effective technique to promote increased accuracy. Real-time labeling of sequential MBS studies facilitate assessment on sequential studies and for different RIS/PAC systems and will reduce ambiguities and misinterpretations.

Rupert K. Hung, MD1 Jamie Muhly, MS CCC-SLP1 Mamie Gao, MS42 Gary Gong, MD PhD1 Martin Auster, MD, MBA1 1Johns Hopkins Medical Institutions, Baltimore Maryland 2Texas Tech University Health Sciences Center, Odessa, TX.

INTRODUCTION

Oropharyngeal dysphagia is a potential complication of numerous neurologic and muscular diseases including stroke, multiple sclerosis, Parkinson’s disease, dementia and myositis and may also arise through structural compression such as by head and neck cancers.1,2,3 Presently, modified barium swallow (MBS), or video fluoroscopic swallow study (VFSS), is the modality of choice in evaluating this type of dysphagia. This study utilizes different consistencies of contrast (thin liquid, nectar, honey, pudding and solids) to assess oral, pharyngeal and epiglottic dysfunction that may lead to the development of aspiration events with resulting pneumonia.4 In current clinical practice, multiple consistencies are imaged in succession as a patient may tolerate ingestion of one consistency but not another. This information is vital for the speech language pathologist (SLP) to determine appropriate dysphagia treatment plans and to accurately prescribe nutritional recommendations in order to prevent aspiration and malnutrition.5 Typically, identification of the administered consistency is provided verbally at the time of imaging or post-procedurally through either hand-written notes, post procedure annotations of images or, less commonly, through audio recording. Real-time radiographic labeling at the time of imaging displaying the consistency administered is typically absent. Despite the advantages of annotating the MBS exam to reduce ambiguity and potential miscommunications, its use is not common practice. Lack of real-time labeling by the examining radiologist may be due to perceived reductions in efficiency, increased work burden and cost of implementation. Furthermore, lack of adequate labeling for any individual study may be seen as inconsequential. With serial swallowing evaluations that are commonly performed in the setting of acute stroke to assess for neuromuscular recovery, the importance of reliable communication between the various consistencies administered becomes even more critical.

The volume of serial swallowing studies has progressively increased over the past decades due to more frequent assessments for dysphagia in patients with acute stroke, myositis and progressive neuromuscular diseases.1 As significant improvements in swallowing function may be rapid in some patients, correct identification of improvement compared to previous studies is important in preventing unnecessary invasive interventions such as placement of a long-term percutaneous endoscopic gastrostomy (PEG) tube or nasogastric tube (NGT), or initiation of total parenteral nutrition (TPN). This further highlights the importance of a reliable radiographic labeling technique.

With more frequent indications of serial assessment, regular labeling of the contrast consistency administered will enhance interdisciplinary communication and create less ambiguity and greater ease in evaluating both retrospective and serial studies, particularly if the studies are performed by different members of the healthcare team or from outside referrals.We therefore detail an alternative technique for the examining radiologist to provide real-time radiographic identification at the time of imaging of the contrast consistency administered.

Materials and Methods

Labels denoting different contrast consistencies using radiopaque alloy letters by Pb Markers, an online company specializing in custom-made markers, were created. Each label measured approximately 2 x 1 inches and cost $10 USD to procure. The labels were then reversibly attached by Velcro pads to a painter’s stick measuring 20 x 1.5 inches. One end of the painter’s stick displays the contrast consistency that is administered, and the other end holds the unused labels (Figure 1). At the beginning of each consistency trial of the swallowing study, the examining radiologist passes the end of the painter’s stick with the appropriate Pb label between the patient and the image intensifier. This provides radiographic identification of the contrast consistency in real-time at the time of imaging.

RESULTS
Case 1. Use of Radiographic Labels in Clinical Practice

A 77-year-old woman with a history notable for gastroesophageal reflux disease and diabetes, but without history of dysphagia, undergoes an MBS study (Figure 2). Panels 2A-2D show the placement of the radiographic labels prior to administration of the contrast material. Panels 2E-2H show the pharyngeal phase of swallowing with the contrast material corresponding to the labels on the upper panel. This swallowing study revealed grossly adequate oropharyngeal swallowing function with all contrast consistencies administered, without laryngeal penetration or aspiration. Notably, without adequate labeling of each consistency, one cannot reliably distinguish the contrast consistencies from fluoroscopic appearance alone.

Case 2. Improved Efficiency with Radiographic Labeling in Serial Evaluations

A 59 year-old male, hospitalized due to severe burn, underwent an MBS study which revealed pharyngeal deficits resulting in aspiration on initial assessment. Figure 3A and B show the initial swallowing assessment with thin and nectar liquids without any radiographic labeling at the time of imaging. A follow-up evaluation was completed one week later (Figure 3C and D). Non real-time labeling made it difficult to distinguish changes using different contrast consistencies on initial study as well as serial studies. With more frequent indications for serial assessment, as in this case study, real time labeling of contrast consistency will enhance interdisciplinary communication and create less ambiguity in evaluating both retrospective and serial studies from the same or different institutions.

DISCUSSION

We presented two cases where real-time radiographic labeling facilitated diagnostic evaluation by providing accurate and unambiguous identification of the contrast consistencies administered. Presently, the identification of the contrast consistency administered during fluoroscopy is typically provided verbally at the time of imaging between members of the healthcare team and annotated post-procedurally through hand-written, audio or digital means. Current practices may be prone to errors stemming from misinterpretations between team members at the time of imaging, and erroneous recall occurring post-procedurally due to delays in annotation.

We believe that adoption of a system in which the examining radiologist labels the contrast consistencies in real-time at the time of imaging would improve efficiency and reduce ambiguity and potential errors from miscommunication. Use of hand-written, audio or digital annotations do not always accompany the fluoroscopic images, leading to delays in assessment, particularly during retrospective reviews. It is interesting to note that some audio recordings do not become part of the patient’s electronic medical record (EMR) but are stored on a separate disc or on a dysphagia work station (DWS). Lack of adequate identification of the consistencies administered may also lead to ambiguity and potentially incorrect assessments of swallowing function by the healthcare team. This can result in improper recommendations for the patient that can have disastrous consequences for the patient including aspiration pneumonia, and decreased quality of life.4,5 Furthermore, lack of labeling may limit the utility of studies for future educational and research purposes.

The advantage of radiographic labeling in real-time is its intrinsic inclusion into the fluoroscopic images, reducing ambiguity associated with an unlabeled MBS study.

The advantages of real time labeling of MBS studies are particularly evident in serial evaluations for dysphagia. Retrospective review of the fluoroscopic images obtained from earlier studies may also be important for proper assessment of interval changes in swallowing function of the patient. As serial evaluations may be performed by different members of the healthcare team, proper communication of the contrast consistency administered in each trial is paramount to the proper nutritional and therapeutic recommendations made by the SLP.4 Common concerns to our method of real-time labeling includes the perception of decreased efficiency, the possibility of additional radiation exposure to the patient and operator and potential cost of constructing the radiographic labels. In our clinical practice, efficiency of the MBS studies was largely unchanged, and patients were not exposed to any significant additional radiation due to the same length of the exam. Furthermore, the operator is at no point in the direct radiation field due to the extended reach provided by the painter’s stick that is carrying the radiopaque labels. In terms of costs of implementation, the materials used to assemble our radiographic labels were inexpensive and readily bought from local or online retailers.

When the initial study of our burn patient was retrospectively reviewed for assessment of interval changes, there were significant ambiguities regarding which contrast consistencies were administered with each trial as more fluoroscopic sequences were obtained than the consistencies administered. Correct pairing of the contrast consistencies with their respective fluoroscopic videos was performed only after contact between the SLP and radiologist who were present at the time of the original study. The inefficiencies and ambiguities observed in this case would have been further accentuated in patients with more numerous studies and unlabeled trials, further highlighting the importance of regular labeling technique.

Consistent identification of contrast consistency may not be routinely performed due to perceptions that labeling increased work burden and reduces efficiency, and that lack of labeling has few adverse consequences. Implementation of our method is inexpensive and potentially may enhance communication between operators and reviewers of the examination. There are other methods that may be used to identify the contrast consistency at the time of examination, including audio recordings and annotations that are not universally utilized in current clinical practice.

CONCLUSION

We describe an alternative, easily implemented and cost-effective technique to provide real-time labeling of contrast consistencies administered during modified barium swallow studies. Consistent and adequate identification of contrast consistencies will reduce ambiguities stemming from poor labeling technique. Implementation of the method described above may lead to improved interdisciplinary communication, increased patient care and safety and may facilitate further education and research. A more detailed study of comparing our labeling technique with other institutions, would help validate its importance to the dysphagia patient.

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Dispatches From The Guild Conference, Series #8

Liver Cancer – From Detection to Treatment

September 2017 • Volume XLI, Issue 9
Michael P. Curry,Sentia Iriani

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Hepatocellular carcinoma continues to be a signi cant cause of morbidity and mortality in patients with chronic liver disease. Among both men and women in the United States, death due to liver cancer has increased at the highest rate of all cancers in the past decade. Despite the improvements in imaging and therapeutics, only tumors diagnosed in early stages effectively respond to treatment. Loco-regional therapies, surgical resection and transplantation allow for improved survival. For patients with advanced stage disease, there is a need for novel and effective therapies. Here we discuss prevention, diagnosis and treatment of HCC.

Michael P. Curry, MD, Director of Hepatology, Beth Israel Deaconess Medical Center, Associate Professor of Medicine, Harvard Medical School, Boston, MA, Sentia Iriani, MD, Hepatology Fellow, Beth Israel Deaconess Medical Center, Boston, MA

EPIDEMIOLOGY

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. The majority of disease burden occurs in Asia and sub-Saharan Africa due to endemic hepatitis B (HBV).1 In the United States, the incidence of HCC has more the doubled over the past two decades and is increasing. This is largely due to the growing number of patients with advanced liver disease from hepatitis C virus (HCV) infection and the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). HCC has a strong male preponderance with a male to female ratio estimated to be 2.4. Among both men and women in the United States, death due to liver cancer has increased at the highest rate of all cancers in the past decade.2 Worldwide, HBV accounts for 54% of all HCC in adults and almost all childhood HCC cases. HCV is the major risk factor for HCC in Europe and North America.3 Hepatocellular carcinoma is 15 to 20 times higher in persons infected with HCV as compared with those without HCV, and most occur in patients with advanced fibrosis or cirrhosis. Cirrhosis is an important risk factor for the development of HCC and approximately one third of patients with cirrhosis will develop HCC over their lifetime.4 Roughly 30-40% of cases of HCC in Western countries occur in patients without HBV or HCV. These cases are related to alcohol, hemochromatosis, alpha- 1-antitrypsin deficiency, autoimmune hepatitis and possibly NAFLD, given the associations between and increased risk of HCC with obesity and diabetes.

Prevention

There are limited effective strategies proven to reduce the risk of HCC. Infant vaccination against HBV has proven to be the most successful preventive strategy for HCC and has been associated with the most dramatic reduction in the incidence of HCC in children ages 6-14 years.5 The use of antiviral therapy in chronic HBV has also been associated with reduction in HCC development.6 Historically, achieving a sustained virologic response (SVR) in patients with HCV infection using interferon has resulted in a decreased risk of future HCC across all stages of liver disease including cirrhosis.7 There is some controversy about the risk of HCC in HCV patients who have been treated with direct acting antiviral (DAA) therapy. Some studies suggest an increased risk of HCC recurrence and de novo HCC in patients with HCV cirrhosis treated with DAA.88 The use of HMG-coA-reductase inhibitors (“statins”) has been associated with a reduction in the risk of HCC in a meta-analysis of observational studies and randomized trials.9 Two meta-analyses have demonstrated an inverse relationship between coffee consumption and HCC supporting a reduced risk of liver cancer among individuals with and without a history of liver disease.10,11 Lastly, the use of metformin has been associated with a reduced risk of HCC in patients with diabetes.

Surveillance

The American Association for Study of Liver Disease (AASLD), the European Association for Study of the Liver (EASL) and the Asian Pacific Association for the Study of the Liver (APASL) recommend surveillance for HCC for patients at high risk of HCC development in order to detect tumors at an early stage when they are amenable to curative therapy. The rationale for surveillance is based on data from a randomized study comparing outcomes in HBV patients assigned to screening ultrasound (US) and alpha-fetoprotein (AFP) every 6 months versus no surveillance. In the surveillance group, HCC was detected at an earlier stage and curative treatment successfully resulted in a 37% reduction in mortality. Additional non-randomized studies of screening for HCC in cirrhosis support the role of surveillance for an earlier diagnosis, potential curative therapies and improvement in overall survival (Table 1).12

Despite these guidelines, surveillance is underutilized. In a study of patients diagnosed with HCC between 2005 and 2011, only 20% had undergone surveillance. Nineteen percent of patients had unrecognized cirrhosis, 20% had unrecognized liver disease, 38% lacked surveillance orders and 3% failed despite surveillance orders.13 A more recent study performed in the Veterans Administration health service showed that only 53.5% of patients had received surveillance in the two years prior to HCC diagnosis. However, only 23.1% of patients with NAFLD related HCC received surveillance as compared with 51.8% of HCV-related and 47.4% of alcohol-related HCC suggesting that more work needs to be done educating physicians on the correlation between NAFLD cirrhosis and HCC.14 In order to improve the effectiveness of HCC surveillance, there will need to be improved recognition of liver cirrhosis in all at risk populations and initiation and compliance with surveillance.

Diagnosis

Hepatocellular carcinoma develops in the background of a field defect of either viral infection or advanced fibrosis or cirrhosis.15 Hepatocarcinogenesis should be considered as a continuum with dedifferentiation from regenerative nodule through dysplastic nodule to early and subsequently overt HCC. Unlike regenerative and dysplastic nodules, which have portal and arterial blood supply, unpaired hepatic arteries solely supply HCC.16 This results in the characteristic vascular pattern on arterial enhancement and portal venous phase washout on cross sectional multiphase imaging. In 2005, the AASLD and EASL panel of experts adopted a new HCC radiological algorithm, which has been validated. The diagnostic accuracy of a single dynamic technique showing intense arterial uptake followed by “washout” of contrast in the venous- delayed phases has been demonstrated. Non-invasive diagnosis was established by one imaging technique in nodules above 2 cm showing the HCC radiological hallmark and two coincidental techniques with nodules of 1-2 cm in diameter (computed tomography (CT) and magnetic resonance imaging (MRI)). Recent updated AASLD guidelines have proposed that one imaging technique (CT or MRI) showing the HCC radiological hallmark suffices for diagnosing tumors of 1-2 cm in diameter.17 For tumors that meet radiological criteria, biopsy is no longer indicated. However, liver biopsy is recommended by AASLD, EASL and the National Comprehensive Cancer Network (NCCN) for nodules > 1cm if radiological criteria are not present on multiphasic imaging. The NCCN guideline also allows for repeat cross sectional imaging at a 3-month interval for nodules between 1-2cm to determine if the tumor characteristics have changed.3,17,18

Histological assessment of tissue obtained by needle biopsy of a nodule allows for assessment using a number of techniques to establish the diagnosis of HCC. The presence of an increase in clear to cytoplasm (N:C) ratio and degree of cellular atypia can provide clues to the presence of HCC. Disruption of the normal reticulin pattern adds additional evidence. The use of immunohistochemical assessment to demonstrate positive staining for HepPar1 and polyclonal CEA can establish origin of the cells and lastly the use of glypican 3, gluthamine synthase and heat shock protein 7 which are relatively sensitive for HCC can help in the definitive diagnosis.

Staging

Clinical staging of HCC is an essential part of the evaluation to assess prognosis and to guide therapeutic interventions. Numerous staging systems have been developed and are employed. The Chinese University Prognostic index (CUPI) and the Cancer of the Liver Italian Program (CLIP) have been validated, include prognosis based on tumor stage and sub-classify patients at advanced stages of liver cancer.19,20 The Japanese Integrated Staging (JIS) has been modified to include the biomarkers AFP, AFPL-3 and des- gamma-carboxy prothrombin (DCP).21 While there is no worldwide consensus as to which system should be used, the AASLD and EASL recommend use of the Barcelona-Clinic Liver Cancer (BCLC) staging system. The BCLC divides patient into 5 stages (0, A, B, C and D) according to established prognostic variables and allocates therapies based on tumor stage, functional capacity and degree of liver dysfunction.

Treatment

Treatment of HCC requires that due consideration be given to the tumor burden, stage of liver disease and the patient’s performance status. This is best assessed by a multidisciplinary team approach that includes hepatologists, surgeons, oncologists, radiologists and interventional radiologists, pathologists and radiation oncologists.

Surgical resection and liver transplantation are the mainstays of HCC treatment as they offer the best outcomes in patients with early disease stage and afford patients a five-year survival of 60-80%. Liver resection is the treatment of choice for patients with non-cirrhotic HCC. Improved outcomes for patients with cirrhosis and HCC has occurred as a result of refinements in surgical technique and appropriate selection of candidates. Some selection criteria to enroll appropriate patients for liver resection include a hepatic venous pressure gradient (HVPG) of < 10mmHg and a platelet count of > 100,000.mm3. Adjuvant and neo-adjuvant therapies have not been conclusively shown to decrease the risk of or recurrence of de-novo tumor in patients undergoing surgical resection for HCC.

Loco-regional therapy is considered first line treatment for patients not suitable for surgical resection. Additionally, this therapy may be utilized by transplant programs to “bridge” patients to transplantation or to downstage patients who are outside acceptable criteria for liver transplantation. Loco-regional therapies include local ablation of the tumor by chemical or thermal destruction, chemoembolization with conventional chemoembolization or drug eluting beads and radio embolization. Radiofrequency ablation (RFA) and transarterial chemotherapy are most commonly used for loco-regional therapy of HCC (Table 3). Percutaneous ethanol injection (PEI) and RFA are suggested for patients with BCLC stage A disease and tumors up to 3 cm. Transarterial chemoembolization (TACE) is the recommended treatment for intermediate stage HCC. Conventional TACE (cTACE) and drug eluting bead TACE (deb-TACE) are both used in patients with intermediate stage disease. Deb-TACE is better tolerated, however cTACE may offer better long term results. Radioembolization can be used in patients with intermediate stage disease who do not respond to, or have contraindications to TACE. It can also be applied in the setting of portal vein thrombosis or tumor thrombosis.

Liver transplantation (LT) is considered for patients with compromised liver function and small multifocal tumors or single tumors of modest size. Liver transplantation has the added advantage of curing the tumor as well as the underlying liver cirrhosis. However, in the equitable distribution of liver grafts, patients receiving liver transplantation for HCC should have the same outcome in as those patients undergoing liver transplantation for non-HCC indications. The Milan criteria, proposed in 1996, established the tumor size and number criteria for patients with HCC that demonstrated a similar survival as compared to non- HCC liver transplant recipients.22,23 Several other sets of criteria have been published and are utilized to select suitable candidates with HCC for liver transplantation in different geographic locations around the globe (Table 2).

Recurrence after Liver Transplantation

Although many single center studies have shown excellent post-transplant outcome for HCC using Milan or modestly expanded criteria for patient selection, registry data that reflect more global experience with liver transplantation have continued to show inferior results with HCC compared to non-HCC indications. There is an urgent need to identify reliable factors that can predict recurrence of HCC so that these patients can be excluded from liver transplantation. MacDonald et al. analyzed 11 pre-transplant recipient and donor variables in 1074 patients with HCC meeting Milan criteria to detect association with post-liver transplant tumor recurrence or mortality.24 Recurrence of HCC was seen in 6% of patients. Univariate analysis identified AFP at listing and at last time point prior to transplantation was associated with higher rate of recurrence. The last AFP prior to liver transplantation was associated with disease recurrence. The optimal cut off of last AFP was a value of > 300ng/dL with the highest odds ratio (OR) for HCC recurrence of 2.52.24, A model has been developed and independently validated to predict recurrence of HCC based on pre transplant characteristics. The AFP model contains 3 independent pre- transplant predictors of tumor recurrence (tumor size, tumor number and AFP level at the time of listing for liver transplant). A score calculated by addition of points for each variable can differentiate patients a low (= 2 points) and high risk (>2 points) of recurrence and survival after transplantation (Table 4).25,26

Systemic Therapies

Sorafenib is currently the only approved first line systemic therapy for the treatment of advanced HCC not amenable to surgical resection. This drug has shown survival benefits of three months.27 A subsequent trial demonstrated that sorafenib was associated with over survival (OS) times of > 20 months.28 Regorafenib, a second line multi-kinase inhibitor, has been shown to prolong survival in patients with advanced stage HCC that has progressed despite sorafenib.29 A number of immunotherapies are currently in clinical trial for patients with HCC. Nivolumab has demonstrated efficacy in providing durable responses in both regorafenib naïve and experienced patients with HCC.30

CONCLUSION

Hepatocellular carcinoma continues to be a significant cause of morbidity and mortality in patients with chronic liver disease. Despite the improvements in imaging and therapeutics, only tumors diagnosed in early stages effectively respond to treatment. Surveillance rates for HCC are low due to unrecognized cirrhosis. Loco- regional therapies, surgical resection and transplantation allow for improved survival. For patients with advanced stage disease, there is a need for novel and effective therapies.

Dispatches From The Guild Conference, Series #8

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Therapeutic Drug Monitoring in Inflammatory Bowel Disease – A Practical Guide

September 2017 • Volume XLI, Issue 9
Adarsh K. Varma,Nirmal Kaur,Seymour Katz

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Adarsh K. Varma, M.D., Attending Physician, Division of Gastroenterology and Hepatology, Henry Ford Health System Nirmal Kaur, MD, Director, Inflammatory Bowel Disease Center, Division of Gastroenterology and Hepatology, Henry Ford Health System, Seymour Katz, MD, FACP, MACG, Clinical Professor of Medicine, Director of NYU IBD Outreach Program, New York University School of Medicine, New York, NY

BACKGROUND

Tumor necrosis factor ? alpha (TNF-a) antagonist therapy is highly effective for the treatment of Crohn’s disease and ulcerative colitis, broadly termed inflammatory bowel disease (IBD). While this class of medication has revolutionized the field of IBD therapy, up to 30% of patients show no benefit when treated with a TNF-a antagonist, and another 40% lose response over time within one year of treatment.1 Therapeutic drug monitoring has emerged as a method to optimize treatment with TNF-a antagonists by guiding treatment decisions, increasing the long term durability of the medications, and maximizing the likelihood of a sustained clinical benefit with significantly fewer occurrences of secondary loss of response.2

Therapeutic drug monitoring with TNF-a antagonists involves measuring serum drug levels and anti-drug antibodies, and maintaining drug levels within a specific therapeutic window. The concept of therapeutic drug monitoring is not new, and is applied to solid organ transplant patients receiving immunosuppression with medications such as cyclosporine or tacrolimus, and to septic patients receiving antibiotics such as vancomycin and gentamycin.3,4 The main principle of therapeutic drug monitoring is to maintain patients within a specific therapeutic window, as high concentrations of drug may result in increased toxicity, low concentrations will be ineffective, and for TNF-a antagonists, low concentrations risk resulting in drug antibody formation as well.2

The TNF-a antagonists for which multiple studies have demonstrated the benefit of therapeutic drug monitoring in IBD include infliximab and adalimumab. Studies date back to 2003, and delineate that higher serum concentrations of infliximab and adalimumab are associated with more durable response, sustained clinical outcomes, decreased need for colectomy, and improved patient outcomes.5-8

Numerous studies have shown that higher serum drug concentrations of TNF-a antagonists are associated with improved patient outcomes.2 Furthermore, studies have also demonstrated that low or undetectable drug concentrations are linked to anti-drug antibody formation and are ineffective for achieving clinical remission.9-12

Types of Assays

Many different anti-drug antibody assays are available, and the detection of these antibodies is more variable than serum laboratory assays for drug concentrations. The available types of assays include the Enzyme-Linked Immunosorbent Assay (ELISA), Radioimmunoassay (RIA), Homogeneous Mobility Shift Assay (HMSA), Electro-chemi-luminescence immunoassay (ECLISA), and Functional assay. The ELISA and RIA anti-drug antibody assays are affected by the presence of drug, and these assays can give inaccurate results if there are drug concentrations present in the serum. The antibody assays that are not affected by the drug levels, termed drug-tolerant assays, are more expensive.13

How is Drug Monitoring Utilized in Clinical Practice?

Therapeutic drug monitoring can be performed reactively or proactively. Reactive testing involves testing the patient at the time of disease relapse or after a drug reaction has occurred. Proactive testing involves optimizing the dose of the drug within a therapeutic window to achieve clinical efficacy.1

Serum drug levels are measured as trough levels, as most studies of anti-TNF-a drug levels have tested trough levels, and as drug trough levels roughly correlate with activity of most drugs. The drug trough level is measured prior to intravenous infusion of infliximab, or prior to subcutaneous injection of adalimumab. Serum drug levels (non-trough) are generally measured during the maintenance phase of treatment for patients, after the induction phase.1

Algorithm 1 is a reactive testing algorithm, and this algorithm delineates steps to take if faced with a patient with worsening inflammatory bowel disease while on maintenance dosing of infliximab or adalimumab. These patients have demonstrated objective evidence of continued inflammation with elevated C-reactive protein (CRP) levels, fecal calprotectin levels, abnormal imaging studies, and/or endoscopy corroborating persistent inflammation secondary to inflammatory bowel disease despite adherence to infliximab or adalimumab.

The steps are as follows: first, a drug trough level is measured. If the patient has a therapeutic trough level as defined by a serum infliximab concentration > 3 µg/mL or adalimumab concentrations > 5 µg/mL, this patient should be switched to a different drug class with a separate mechanism of action or surgical intervention should be considered. If the patient has a sub-therapeutic drug trough concentration as defined by a serum infliximab concentration < 3 µg/mL or adalimumab concentration < 5 µg/mL, this patient should have an anti-drug antibody level measured, and most assays will perform this testing. If the anti-drug antibody level is negative, the patient will benefit from an increase in the dose of drug, acceleration of the interval between infusions, addition of an immunomodulatory medication, or transition to a different anti-TNF-a agent. If the patient has an anti-drug antibody level that is positive, the patient should be switched to a different anti-TNF-a agent or a different drug class; other causes of persistent inflammation should be investigated as well.

Reactive testing has been shown to be more cost effective than empiric dose adjustments, and it allows clinicians to understand if a patient is likely to benefit from dose escalation, or if the patient should be switched to another drug class altogether.

Currently, there are no guidelines when therapeutic drug monitoring should be performed, but the BRIDGe group (Building Research in IBD Globally) has issued the following recommendations: therapeutic drug monitoring should be conducted at the end of induction in patients with primary non-response, for patients with secondary loss of response, for patients who are on maintenance therapy and who are responding, and for patients restarting treatment after a drug holiday. The utility of testing at the end of induction in patients who are already responding to anti-TNF-a therapy is uncertain.14,15

Proactive Drug Monitoring

Proactive therapeutic drug monitoring entails optimization of drug to a specific therapeutic window. Proactive testing has been demonstrated to improve patient outcomes, and the available medical literature demonstrates benefits of proactive testing in the maintenance phase of treatment for patients.2 A pilot observational study of 48 patients demonstrated that a proactive approach more frequently identified patients with low trough concentrations, and resulted in a greater probability of remaining on infliximab, increasing the long term durability of the medication. Proactive therapeutic monitoring has also been shown to improve symptom scores, CRP levels, and decreases the need for rescue therapy.16

Central to the proactive strategy for IBD is the TAXIT trial, which was a one year randomized controlled trial at a tertiary referral center including 263 adults. These patients were split into two groups, with medication dosing adjusted based upon clinical features (reactive) or trough concentrations of infliximab (proactive). At the start of the trial all patients were dose optimized to a drug concentration of 3-7 µg/mL, and then 123 of the patients had dosing adjusted based upon their clinical features and CRP levels, which is the current standard of care, and 128 patients had dosing adjusted during maintenance to a therapeutic window of 3-7 µg/mL.17

The primary outcomes for this trial were measured at one year. At that time, no significant difference was seen in the primary end point for this study (Figure 1), which compared clinical remission between the two groups, likely due to two reasons: (1) at the start of the study, all patients regardless of treatment group were dose optimized, and (2) these patients were only followed for one year. Notably, by the end of one year, the curves begin to separate, and one could infer that they would separate even further over time, with higher relapse-free survival in patients who underwent proactive therapeutic drug monitoring.17

A number of secondary endpoints in this trial favored proactive drug monitoring for patients receiving infliximab: (1) patients receiving proactive treatment did not need rescue therapy as often as the clinical group (7% vs 17.3%, p = 0.004); (2) more patients in the proactive group maintained trough concentrations within the therapeutic window (74% vs. 17.3%, p < 0.001); (3) fewer patients had undetectable trough concentrations (OR 3.7; p < 0.001); and (4) costs were similar between both groups.17

A separate study by Cheifetz and colleagues from the BridgeIBD group followed patients being treated with infliximab for more than ten years, with a goal therapeutic window between 5-10 µg/mL (Figure 2A).16 Over time, proactive therapeutic drug monitoring maintained patients on infliximab for more than ten years, versus the patients undergoing reactive monitoring, many of whom appeared to demonstrate loss of response by ten years. In this same trial (Figure 2B),16 patients who attained a trough concentration of greater than 5 µg/mL fared much better than those patients who had low levels of drug, or patients receiving the standard of care. Notably, by the end of ten years most of these patients had lost response to infliximab.14,16

In clinical practice, algorithm 2 can be followed to proactively dose-optimize patients to a therapeutic window for infliximab and adalimumab. The steps are as follows: first a trough concentration is measured. If the drug trough concentration is undetectable, and anti-drug antibody level should be measured. If the anti-drug antibody level is detectable, the patient’s anti- TNF-a drug should be discontinued. If the anti-drug antibody is undetectable, the patient’s dose of anti- TNF-a drug should be increased or the interval between doses should be accelerated. If the patient’s drug trough concentration is sub-therapeutic, the patient’s dose of drug should be increased or the interval between doses should be accelerated. If the patient has a therapeutic drug concentration of infliximab between 3-10 µg/mL or adalimumab between 5-10 µg/mL, no dose adjustments are necessary. And lastly, if the patient has an infliximab of adalimumab concentration greater than 10 µg/mL, the dose of drug should be decreased or the interval between doses should be decelerated.14

The optimal therapeutic window is not completely known. Data exists for a goal trough of 3-7 µg/mL, while other data suggests a level of 5-10 µg/mL for infliximab and adalimumab.14 During the maintenance phase for stable patients, for infliximab, a trough level of 5 µg/mL or higher has been associated with clinical remission. For deep remission, a trough level of greater than 8 µg/mL could provide benefit. For adalimumab, clinical remission was seen at or above a level of 5 µg/ mL, and deep remission was seen at or above 8 µg/mL.8,17,21-26

Since guidelines regarding therapeutic drug monitoring are not yet available, the optimal therapeutic windows are unknown; patients with particularly severe disease may warrant a higher therapeutic window than a patient with mild disease.

Contributing Clinical Factors

There are multiple factors that play into the pharmacology of monoclonal antibodies, particularly regarding clearance. The presence of anti-drug antibodies is associated with higher drug clearance and worsened clinical outcomes. Addition of an immune-modulator such as thiopurine or methotrexate has demonstrated benefit, by reducing anti-drug antibody formation and increasing drug concentrations. Factors associated with poor outcomes include severe disease, high CRP levels, low albumin, and higher baseline TNF-a concentrations. Furthermore, patients with severe disease demonstrated a faster rate of drug clearance, via proteolytic catabolism by the reticuloendothelial system.27 Clearance is also increased in patients with higher body mass index and male gender.14,18

Economic Considerations

Data strongly show that reactive drug monitoring is more cost-effective than empiric dose escalation. Reactive testing prevents over-prescribing high doses of biologics. One study calculated associated costs over the course of one year, and reactive testing was found to be approximately $5,000 less per year than empiric dose escalation for patients. Moreover, the reactive testing in the algorithm previously provided allows for more accurate management for patients with secondary loss of response.23 Another study that looked at costs of over- prescribing high doses of infliximab without drug monitoring found that costs to patients were reduced by 56% when reactive testing was performed, versus empiric dose escalation. Notably, the drug assay used was inexpensive and thus cost effective.20

CONCLUSION

S For practical use, the following is recommended: knowledge of the test performed by one’s institution, whether the antibody assay is affected by drug concentrations, and the cost of testing would all be prudent. Understanding the therapeutic algorithms would increase the likelihood of improved outcomes and cost-effective care. Utilization of web-based resources to tailor therapy (http://www.bridgeibd.com/ anti-tnf-optimizer) to optimize outcomes for patients would be ideal as well.

Reactive testing is clearly beneficial as has been shown herein. With more research and time, proactive testing may become more widely utilized. Consider proactive testing after induction and following patients at least once per year during maintenance to ensure they are within the therapeutic window and do not develop a secondary loss of response.

Questions that remain to be answered include: is there a safety benefit to dose-reduction for patients with supra-therapeutic drug levels? Should drug monitoring be individualized to each patient, or should therapeutic windows be generalized to specific patient populations? Should more aggressive disease phenotypes warrant higher therapeutic windows? As many of these assays involve significant cost, determination of appropriate utilization is paramount. And lastly but importantly, will assays be different for other biologic agents including novel therapies such as vedolizumab, ustekinumab and biosimilars? Further research will certainly be warranted to address these questions.

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Frontiers In Endoscopy, Series #38

Endoscopic Management of Esophagorespiratory Fistulas

September 2017 • Volume XLI, Issue 9
Judith Staub,Douglas G. Adler

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Esophagorespiratory fistulas (ERFs) are pathologic communications between the esophagus and any portion of the respiratory tract. ERFs lead to recurrent aspiration that can cause lethal pulmonary infections and significantly decrease quality of life for patients. Treatment of ERFs has been shown to not only improve dysphagia and aspiration, but also lead to increased survival times. While there is limited outcome data to guide clinical decision-making, the purpose of this review is to describe the current literature that supports the various endoscopic techniques utilized to manage ERFs.

Judith Staub MD, Douglas G. Adler MD, FACG, AGAF, FASGE, Division of Gastroenterology and Hepatology, Utah School of Medicine, Salt Lake City, UT I.

INTRODUCTION

Esophagorespiratory fistulas (ERFs) are pathologic communications between the esophagus and any portion of the respiratory tract. ERFs lead to recurrent aspiration that can cause lethal pulmonary infections and significantly decrease quality of life for patients.1,2 Treatment of ERFs has been shown to not only improve dysphagia and aspiration, but also lead to increased survival times.3 While there is limited outcome data to guide clinical decision-making, the purpose of this review is to describe the current literature that supports the various endoscopic techniques utilized to manage ERFs.

II. ETIOLOGY

ERFs are classically divided into two broad categories, acquired and congenital, of which congenital are more common.4 Acquired ERFs can be further subdivided into benign and malignant. Benign ERFs can be iatrogenic and caused by luminal procedures such as bronchoscopy, endotracheal intubation, gastrointestinal endoscopy, or as a complication of esophageal stent placement.5,6,7 Esophageal inflammation and diverticulum are other known benign causes of ERF.4

Malignant ERFs are a devastating complication of esophageal, lung cancer, large B-cell lymphoma, neuroendocrine tumors, and other tumors.8 They are associated with lower patient survival times and clinical success rates when compared to patients with benign fistulas. Balazs described the incidence of fistulas in patients with esophageal cancer to be between 0.9 and 22%, but these may occur more frequently than documented given their difficult diagnosis at the end stage of malignant disease.1,2 ERFs in malignancy are usually a complication of disease progression and nearly half of patients with ERF have metastatic disease at the time of diagnosis.9 Palliative oncologic treatments including chemotherapy and radiation are not thought to directly cause ERF. Instead, they lead to ERF formation either by increasing survival times or decreasing tumor burden without leaving necessary tissue to maintain patency of the lumen.1,2

ERFs can be located at any point along the esophagus and respiratory tract. ERF in the proximal and mid-esophagus are most common. Fisutlae in the proximal esophagus have been shown to be the most difficult to manage and associated with the most adverse events and shortest survival time, while patients with distal ERF have the longest survival.8 Patients with mid-esophageal fistulae have intermediate survival. This may reflect the anatomic proximity of the proximal esophagus to the trachea, allowing for widespread contamination of both lung fields on aspiration.

III. NON-ENDOSCOPIC MANAGEMENT OF ERF
A. Operative Management

Operative management such as esophageal bypass with reconstruction, thoracotomy with direct suture closure, and esophageal defect with pedicled soft tissue flap interposition are treatment options in select patients, although these are all major surgical undertakings.10,11 For patients with acquired, non-malignant ERF, surgical options may provide the best opportunity for full recovery in good operative candidates. The choice of surgical technique is dependent on the etiology, size, and location of the fistula. Pre-operative requirements such as Eastern Cooperative Oncology Group (ECOG) status of 0-2 and lack of metastatic disease make surgery prohibitive for many patients with malignant ERF.9 Indeed, the vast majority of patients with malignant ERF are poor surgical candidates at the time of presentation and other palliative and therapeutic interventions are typically considered.

B. Concurrent Chemoradiotherapy (CCRT)

Historically, the presence of a malignant ERF was considered a relative contraindication for CCRT, but recent evidence has demonstrated significantly increased survival with CCRT in esophageal squamous cell carcinoma (SCC) complicated by ERF.12 Koike et al. studied the effect of 5-fluorouracil and cisplatin combined with full dose radiotherapy in patients with esophageal cancer complicated by malignant ERF. They found complete closure of esophago-mediastinal fistulae in 3/3 patients but only 4/13 patients with esophago-respiratory fistula achieved clinical success. A more recent study showed that CCRT combined with enteral nutrition can achieve promising improvement and closure of malignant fistulae.13

IV. ENDOSCOPIC MANAGEMENT
A. Bronchoscopy Monotherapy

Some patients may have contraindications to endoscopic management such as non-passable esophageal obstruction by tumor.14 Several studies have demonstrated successful endotracheal or endobronchial stent placement with improvement in clinical symptoms.14,15,16 However, the anatomical complexity of the respiratory system makes airway stenting a more challenging procedure compared to esophageal stenting. In addition to multiple branch points, different airway locations vary in their diameter, thickness, and nearby anatomic structures. These factors require that different airway stents are utilized according to the size and location of the malignant ERF.14

B. Esophageal Monotherapy
a. Esophageal Stents

The first stents to treat ERFs were rigid plastic tubes and were associated with a variety of complications and these older stents are now obsolete.17 Esophageal intubation in the form of self-expanding metal stents (SEMS) was first introduced in the 1980s for palliation of esophageal stenosis, and is currently the gold standard for endoscopic management of malignant ERFs.18 Advantages of SEMS include their ability to be constrained to small diameters on a delivery catheter, thus largely eliminating the need for pre-insertion dilatation.19 (Figure 1)

SEMS may be or fully covered or partially covered. Partially covered stents have the advantage of anchoring and embedding into the esophageal wall making them less prone to migration, but are susceptible to tumor ingrowth.20 In contrast, covered stents have higher rates of migration, but have been shown to have better palliation because of decreased need for re-intervention secondary to recurrent dysphagia.21 Covered stents are more easily retrieved. Thus, stent choice depends on the expected risks of stent migration or tumor overgrowth for the particular patient.

The literature reports high technical success rates defined by complete ERF closure following esophageal stent placement of nearly 100%.17 Adverse events have been reported in as many as 40% of patients but are generally minor.8 Complications of stent placement in ERF include aspiration, malposition, migration, ERF progression, and perforation.22 Stent migration is a common complication with a rate of 25 to 32% and may be secondary to insufficient expansion, tumor shrinkage due to chemo or radiation therapy, lack of a stenosis to help anchor the stent, or stent malposition.23

b. Over-the-Scope Clips

Endoscopically placed clips are an established method of sealing ERF. Through-the-scope clip (TTS) technology has been available for over 10 years and most endoscopists now have access to over-the-scope clips (OTSC), which are much larger than TTS clips.24 The OTSC system consists of a nitinol alloy clip that is equipped with teeth. The clip is preloaded on an applicator cap and mounted on the endoscope tip. The OTSC devices are available in several different sizes and configurations. OTSC have been used to treat ERFs due to their ability to grasp more tissue and provide greater compressive force.25,26 They have been generally used for treatment of small defects.27 Large ERF may be difficult to close by any method, including OTSC devices.

The OTSC method has lower therapeutic efficacy for closing fistulae when compared to esophageal perforations and leaks.27,28 The main barrier for successful sealing of ERF with OTSC is the ability to completely approximate the borders of the defect and suction damaged tissue inside the cap because ERF often have fibrotic and retracted rims. However, there are studies showing promise for treating ERFs with OTSC in conjunction with other interventions. A recent multicentre retrospective study examined 5 patients with OTSClips alone or in combination with esophageal stents, airway stents, or with stents and endoscopic sutures.8 One patient in this study had OTSC monotherapy and did not achieve clinical success. The remaining four patients with combination therapy achieved technical and clinical success in 4/4 patients. Additionally, evolving OTSC technology such as the Padlock Clip show promise for improved efficacy of these devices to treat ERFs.26,28

c. Atrial Septal Defect (ASD) and Ventricular Septal Defect (VSD) Occluders

A novel method for endoscopic closure of ERF is the use of ASD and VSD occlusion devices. These devices have been used for percutaneous closure of cardiac septal defects since the 1970s with a goal of inducing an endothelial response and closure of the defect.29 The device typically consists of two nitinol, self- expanadable, polyester coated discs connected by a thin waist that is compressed inside a loaded catheter. The two discs have different diameters after deployment.

The first reported successful closure of an ERF with a VSD occluder device was performed in 2006 after a patient with non-malignant ERF had failed other endoscopic options.30 Since then, ASD occluder devices have also been utilized with varying clinical success.31,32 The device is placed by maneuvering a guide wire endoscopically with fluoroscopic assistance into the fistula orifice from the esophageal side, and threading the wire through the hypopharynx such that both ends come out of the mouth. The occluder is then threaded through either orifice and deployed with one disc on either side of the fistula.

The most significant complication reported from use of ASD and VSD occluders is device migration to the airway, which may occur from incorrectly sized devices, physiologic esophageal peristalsis, extrusion by external source, or enlargement of the fistula.33,34 These patients often present with severe cough from bronchial obstruction by the device or pneumonia. Jiang describes a theoretical solution to this problem by using an endotracheal approach and placing the larger, distal disc in the esophagus.35 The structural design of the device favors its permanence. As it anchors into the fistula, it stimulates an inflammatory response and promotes granulation tissue and re-epithelialization over the device.

d. Parallel Airway and Esophageal Stenting

Combined placement of stents in both the esophagus and the tracheobronchial tree is another endoscopic method that has been utilized for treatment of benign and malignant ERF.36,37,38 (Figure 2) This method may be advantageous in circumstances in which there is concern for airway compression by an expanding esophageal stent, or in patients with combined symptoms of dysphagia, aspiration, and dyspnea. The stents are similar to those for monotherapy and include SEMs and airway Y stents or self-expanding metallic airway stents.38 The procedure is typically performed under general anesthesia, with airway stenting often performed first due to the small risk of airway compression by the expanding esophageal stent.39 A retrospective analysis by Schweigert demonstrated complete seal of malignant ERF in 9/9 patients using the parallel stent technique without anesthesia related complications.36 Five out of nine were able to have additional chemo or radiation therapy and 7/9 were able to return home. A more recent, larger study by Wlodarczyk examined 31 patients with malignant ERF and documented technical success in 100% of patients.39 Only 4 patients required re-intervention because of fistula recurrence, and nearly all patients achieved improvement in degree of dyspnea and dysphagia.

The most feared complications of dual stenting for ERFs are massive bleeding and respiratory compromise.38,39,40 The close proximity of the parallel stents may lead to pressure necrosis causing bleeding and, in rare cases, death. Binkert reported pressure necrosis when Gianturco-Rösch Z stents were used, as a result of tissue erosion at sites where stent struts were in direct opposition causing bleeding from the esophageal venous plexus. Wlodarczyk reported bleeding events in 7/31 patients with malignant ERF.39 A more recent study of 8 patients treated with dual stent placement, however, demonstrated similar adverse events to esophageal monotherapy without any major complications.8

The American College of Chest Physician Guidelines reports a grade C recommendation for stenting of both the esophagus and tracheobronchial tree to achieve the best results for symptom relief.41 Increased survival time in patients that received dual stenting for malignant ERF compared to airway stenting alone has been demonstrated in a larger, prospective study.36

e. Other Methods

Other methods that have been utilized for closure of ERF include fibrin glue, sutures, polyglycolic acid sheets, and argon plasma coagulation. Typically, these methods are used in conjunction with the aforementioned endoscopic techniques to promote direct closure of the fistula. Evidence for their use alone is limited but encouraging.

Fibrin glue is made of thombin and fibrinogen. With the addition of calcium and factor XIII, thrombin converts fibrinogen to fibrin and stimulates scar formation at the fistula site.42 Most of the literature on the use of fibrin glue for ERF comes from the pediatric population, where it is used for endoscopic management of congenital ERF. In select pediatric patients it has been shown to reduce morbidity and recurrence when compared to open approaches or alternative endoscopic techniques.42 Data is more sparse in the literature with regards to adult patients, however a study by Lippert et al identified 26 patients with fistulas in the esophagus treated with fibrin glue.43 Nine of these patients achieved success with fibrin glue alone, while the remaining 17 patients required either additional endoscopic therapy with stents or surgical intervention. A case report of a patient with a small, benign ERF secondary to mechanical ventilation demonstrated complete healing of the fistula after bronchoscopic administration of fibrin glue.44

Argon plasma coagulation (APC) functions by creating coagulation-induced inflammation/granulation along the fistula. Again, this method has been used in conjunction with other endoscopic methods to promote fistula closure. A case report from 2001 demonstrated complete closure of a benign ERF using APC with the addition of endoscopic sutures.45

The use of polyglycolic acid (PGA) sheets is another novel technique that has been described in recent case reports to promote complete closure of ERF. PGA sheets are bio-absorble synthetic polymers that are typically used to enhance the strength of sutures during surgical procedures and to prevent delayed perforation.46 A case report by Han describes complete closure of a post- operative fistula by endoscopically placing PGA sheets over the lesion and securing with endoclips and fibrin glue.47 The use of PGA sheets in this case increased the area of healthy mucosa available, thereby avoiding the need to clip inflamed tissue. Another case report by Tsujii describes utilizing PGA sheets as a scaffold inserted within an esophago-mediastinal fistula, then securing with fibrin glue.46 On re-imaging, the fistula was replaced by granulation tissue. A case report by Matsuura describes complete closure a large, post- esophagectomy ERF after repeated interventions with PGA sheets and fibrin glue.48 A report by Kinoshita demonstrated complete closure of an ERF secondary to Bechet’s disease with 10 repeated applications of PGA sheets combined with fibrin glue and endoclips. None of the above case reports described serious adverse events.49 Although based on limited data and requiring repeated applications, PGA sheets present a promising method to completely close benign or malignant ERF. V.

CONCLUSION

Benign and malignant ERFs pose both a technical and clinical challenge to today’s practitioners. Advances in endoscopic technique have broadened the tools available to allow for improved quality of life for patients suffering from the devastating effects of ERFs. Although the various endoscopic techniques pose different adverse events, an experienced clinician may select the appropriate intervention to maximize the risks/benefits of the procedure based on the size, location, and etiology of the fistula.

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Nutrition Issues In Gastroenterology, Series #167

Seeking Enteral Autonomy with Teduglutide

September 2017 • Volume XLI, Issue 9
Andrew P. Copland,Brian Behm,Carol Rees Parrish

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Patients with short bowel syndrome (SBS) often struggle to maintain nutrition and hydration status. Using a combination of diet and pharmacotherapies, partial or full enteral autonomy may be achievable over time as the bowel adapts. There are select groups that cannot achieve autonomy with conventional therapy, but with augmentation of the absorptive capacity of their existing small bowel, autonomy may be feasible and quality of life significantly improved. With the approval of the GLP-2 analog intestinotrophic agent teduglutide, adaptation and intestinal absorption enhancement is possible. This article describes the course of 7 patients on maximal conventional SBS therapy who achieved either enteral autonomy or significant improvements in nutritional status, stool and urine output, and quality of life after initiation of teduglutide.

Andrew P. Copland MD, Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Brian Behm MD, MS, Associate Professor of Medicine, Division of Gastroenterology and Hepatology, Carol Rees Parrish MS, RD, Nutrition Support Specialist, University of Virginia Health System, Digestive Health Center, Charlottesville, VA

INTRODUCTION

Short bowel syndrome (SBS) causes severe malabsorption most often due to significant resection or defunctionalized segments of the small intestine. It presents an extremely difficult challenge for clinicians and is a life altering condition for patients. Despite aggressive management of SBS with dietary modification and gut slowing agents, the use of parenteral nutrition (PN) is often required to maintain adequate nutrition and hydration. Resource utilization and healthcare costs for the necessary care of short bowel patients are high and our current healthcare system does not lend itself to the time needed in caring for these patients.

The goal of autonomy from PN facilitates avoiding both complications of SBS as well as those of PN such as line infections and vascular thrombosis. Successful enteral autonomy is achieved by enlisting a multifaceted approach including: dietary modification to initiate and stimulate intestinal adaptation, fluid management, and pharmacotherapy. The goal of this approach is to gradually decrease (or eliminate) a patient’s dependence on intravenous fluids and PN. The introduction of intestinal mucosal trophic agents such as the glucagon- like peptide 2 (GLP-2) analog, teduglutide, has added another facet to this approach. Incorporating the strategic use of trophic agents such as teduglutide may reduce or eliminate PN requirements in previously PN- dependent patients.

Endogenous GLP-2 is a locally active hormone secreted from the terminal ileum/proximal colon promoting crypt cell growth and reducing enterocyte apoptosis, while also stimulating intestinal blood flow. Early research demonstrated that exogenous GLP-2 stimulated growth of the intestinal mucosa, which led to enhanced fluid and nutrient absorption. Clinical trials of the GLP-2 analog, teduglutide, demonstrated improved intestinal function in short bowel patients. The first randomized control trial performed to evaluate the efficacy of teduglutide in SBS showed a significant decrease in dependence on parenteral support over a 24- week period.1 The 28-week extension of this trial (52 total weeks of treatment) demonstrated that over 50% of patients had a 20% or more decrease in PN dependence.2 In a subsequent 2 year open-label extension trial, an even more significant reduction in total PN volume was described in patients treated with teduglutide with 15% (13/88) patients enrolled achieving full enteral autonomy.3

The following illustrates our institution’s experience with 7 cases where strategic use of teduglutide was utilized for short bowel patients on otherwise maximal therapy. Patient initials have been changed to protect patient confidentiality.

Case 1

WS is a 66 y/o female with a history of SBS as a result of mesenteric ischemia. Her GI anatomy consists of 105cm of normal proximal small bowel terminating in an end jejunostomy. She was unable to maintain adequate hydration status 18 months post-op from bowel resection with significant ostomy output making enteral feeding quite difficult. She was initiated on teduglutide after maximizing the use of high dose codeine. She was long past the hypersecretory phase. Over the initial 3 months of teduglutide therapy, she successfully transitioned from nightly IV hydration fluids to nocturnal oral rehydration therapy infused via a gastrostomy tube. Her urine output increased significantly during this time indicating improved hydration and her stool output became much more manageable. Over the first year of therapy with teduglutide, WS was able to gradually reduce nightly hydration via gastrostomy; 13 months after initiating teduglutide she was succeeding with oral nutrition and hydration alone. She now has enteral autonomy, her gastrostomy is removed, and she relies on careful management of her PO diet in addition to gut slowing agents, which we were also able to wean. She now volunteers at the hospital and exercises at the gym 3 times a week.

WS stands as an example for the potential for using intestinal growth factors such as teduglutide to free patients from the use of PN, IV fluids, and augmentation of nutrient absorption via gastrostomy. She also highlights the usefulness of gastrostomy tubes in this patient population. With careful management, many patients with significant malabsorption can be managed quite well by a combination of enteral feedings (or oral rehydration) instilled slowly through a nasogastric or gastrostomy tube via a pump. This can be a very effective tool in patients who are unable to wean from PN or IV fluids, and/or tolerate sufficient PO intake. See Box 1.

Case 2

LP is a 31 y/o gentleman with a history of SBS as a result of necrotizing enterocolitis as a child. His GI anatomy consists of 30cm of normal proximal small bowel anastomosed to 50cm of distal colon. Prior to starting teduglutide, he was transitioned from PN to a regimen of nocturnal enteral feeding via PEG in addition to nightly IV fluids. This was sufficient for him to maintain a marginal weight and urine output. Escalation of gut slowing agents was somewhat limited by a history of bowel obstruction. After initiation of teduglutide at a standard dose, he had a significant improvement in his weight over the initial 6 months of therapy. While his weight stabilized at his goal, he was able to decrease the amount of tube feeding required to maintain this weight in addition to oral intake. His urine output gradually improved to over 1L daily with a decreased IV fluid requirement. He has been maintained on teduglutide for 3 years and continues on a stable regimen at or around his goal weight. As his strength increased, he began working longer hours and started an exercise program. We had to increase his enteral feedings overnight to compensate for his higher energy expenditure.

LP experienced no significant side effects from initiation of teduglutide. Three years into therapy, he was admitted for 7 days for symptomatic small bowel obstruction. This was managed conservatively and required no surgical intervention. He was subsequently restarted on ? dose teduglutide 2 weeks after discharge, which he tolerated well and then progressed back to full dose. During this brief period, he experienced increased stool output and mild weight loss, so his nutrition support was adjusted as needed. See Box 2.

Case 3

JF is a 48 y/o female with a distant history of Roux-en-Y gastric bypass now with SBS as a result of a volvulus followed by significant bowel ischemia. Her GI anatomy consists of Roux-en-Y gastric bypass anatomy to small bowel to colon via an ileocolic anastomosis. She had been on PN for 7 years. However, because of a history of multiple line infections, it was decided to hold her PN, optimize gut slowing, and enlist intense diet and hydration instruction. She did well at first, but difficulty with adherence ultimately resulted in precipitous weight loss and significant fat-soluble vitamin deficiency. We then admitted her for a nocturnal enteral feeding trial with concurrent 72 hour fecal fat collection to determine if she had sufficient absorptive capacity. However her fecal fat wasting was profound so further enteral feeding was abandoned. She was restarted on PN and gradually made improvements in both her weight and hydration status. She was then started on teduglutide. She had a history of lower extremity edema prior to teduglutide initiation, but did not require titration of her diuretics during the first few months of therapy. She currently has manageable stool output and is on chronic narcotics for pain, but no additional gut slowing agents.

Initiation of teduglutide has resulted in improved weight gain and hydration status over the first 5 months of therapy and resolution of her lower extremity edema. This case is significantly complicated by the pre- existing Roux-en-Y gastric bypass anatomy, which requires particular attention to the risks of vitamin deficiency. Non-adherence played a partial role as well. Fluid retention is a known risk of teduglutide and may require careful observation for rapid weight gain and/or edema during the initiation weeks to months after starting therapy in those who are sensitive to fluid overload. As of this writing, she has reached her goal weight, and we are planning to decrease PN from 7 to 6 days, giving her a night off PN every week. See Box 3.

Case 4

MS is a 47 y/o gentleman with a history of SBS as a result of mesenteric ischemia secondary to thrombosis. His GI anatomy consists of approximately 200cm of small bowel terminating in an end-ileostomy. There is a suggestion of dilated, defunctionalized bowel on small bowel imaging. Although he has a significant amount of colon, it is not in continuity. Prior to starting teduglutide, he attempted discontinuation of his PN with dramatic weight loss and high ostomy output with attempts at increased PO. He was admitted for a combination SBS diet and nocturnal enteral feeding trial using a nasogastric tube concurrent with a 72-hour fecal fat collection and demonstrated significant malabsorption with high ostomy output despite high dose gut slowing agents. He had also experienced stomal stenosis, which required dilation. He was initiated on a half- dose of teduglutide because of the stomal stenosis and demonstrated a robust response while on a combination of PO intake with no change in his PN solution. His weight improved over 3 months nearing his goal weight and his ostomy output required decreasing doses of gut slowing agents. Over the subsequent few months, he experienced more discomfort around the stenosis of his end ileostomy altering his oral intake and worsening his ostomy output due to outflow diarrhea. A decision was made to revise this site with plan for placement of the colon back in continuity with the small bowel in an effort to facilitate improved enteral absorption and fluid management and possibly permit weaning of PN. See Box 4.

Case 5

CR is a 50 y/o female with a history of SBS as a result of surgery and radiation therapy for cervical cancer. Multiple surgeries for mechanical bowel obstruction resulted in her GI anatomy consisting of 45cm of viable small bowel and an additional 35cm of irradiated, defunctionalized bowel anastomosed to the colon with the sigmoid colon terminating in an end ostomy. Prior to starting teduglutide, CR was unable to reach her goal weight or control her stool output despite PN for nutrition support and attempts at gut slowing. CR has had a great deal of difficulty adhering to medication/ nutrition regimens and tracking her urine and stool outputs. Her clinical course has also been complicated by line infection. After initiation of teduglutide, her weight has remained relatively stable and she has tolerated a gradual tapering of her PN from 4 days/ week to 1L of IV fluids plus electrolytes and vitamins 3 days weekly. While she has not reached her goal weight, her current nutrition support strategy with IV fluids is lower risk relative to PN, and the current regimen, in combination with gut slowing and SBS diet, has been sufficient to maintain hydration and meets her preferences. See Box 5.

Case 6

KJ is a 57 y/o male with longstanding Crohn’s disease with prior small bowel resections in 1991 and 2001 with approximately 50% of the small bowel remaining. The patient also underwent liver transplantation in 2008 due to nodular regenerative hyperplasia. In 2012, he developed increasing GI symptoms in the setting of colonic pneumatosis. While the etiology of pneumatosis was never identified, and despite resolution on subsequent imaging, his GI symptoms did not return to baseline. PN and IV fluids were required to maintain hydration and adequate urine output. Attempts at tapering IV fluids led to reduced urine output and worsening renal function and 2 episodes of nephrolithiasis. The patient was started on teduglutide in June 2013. The patient had a significant reduction in stool volume after initiation; slower improvement in weight and urine output followed, and IV fluids were reduced 4 months later. By month 16 the patient was off IV fluids and was maintaining adequate hydration with oral intake alone. No changes in post-transplant medications were necessary, and he has enjoyed traveling both nationally and internationally without incident. See Box 6.

Case 7

NN is a 54 y/o male with SBS related to Crohn’s disease with multiple prior small bowel and colon resections with resultant transverse colostomy. His last surgery was in March 2016 at which time he underwent an ileocolic resection due to anastomotic stricturing. Postoperatively he struggled with high ostomy output, weight loss, and difficulty with hydration. Small bowel imaging showed approximately 100cm of small bowel remaining, and stool testing showed significant malabsorption with 97g of fat per 24 hours (normal 2-7g). He was initiated on PN in December 2016, but developed a line-related infection shortly after initiation. Teduglutide was initiated in February 2017; weight increased significantly after initiation and he was able to wean off parenteral support in July 2017. See Box 7.

DISCUSSION

Living with SBS is extremely challenging for patients, not only as a result of the short bowel and associated diarhea in particular,4 but also from the labor-intensive regimens that include careful meal planning, medication adherence, coordination of PN/IV fluids and enteral feedings from preparation to delivery to administration. All of these factors have a great impact on quality of life for patients with SBS. Anything clinicians can do to ease this burden is a worthy goal. This requires focusing on issues that are most important to patients. Interventions that decrease side effects of SBS are extraordinarily meaningful to patients-for example, one of our patients reported the following after initiating codeine for gut slowing instead of the loperamide he was previously using:

“I awoke at 4:30am and went fishing with the TPN hanging on my back. Bathroom once on the way there and once again at 2:30! That’s incredible!” and later, “with the decrease in my diarrhea on the codeine, I was able to take 2 hours off my usual 9 hour trip up to Virginia as I did not have to find a bathroom nearly as often!!”

The use of intestinotrophic agents such as teduglutide can play a vital role in improving patient quality of life by helping to manage core issues in SBS to include improving nutritional status, limiting stool/ostomy output, and decreasing dependence on parenteral support.

Careful patient selection is essential to maximizing the benefits of trophic agents while minimizing the risks. Gastrointestinal dysplasia and cancer are contraindications to teduglutide therapy given concern for the trophic effects on a potential malignancy. A history of biliary disease or pancreatitis is another. It should be clear that patients should maximize other potential therapies5-8 before initiating teduglutide given the significant cost. Following this, a careful discussion with the patient regarding the risks and potential benefits should be undertaken and reasonable goals set. It may not be possible for a short bowel patient to discontinue PN due to teduglutide therapy, but it may be reasonable to hope for fewer days of PN each week or significantly shorter infusion times, less diarrhea, and an increase in overall well-being.

Finally, it is crucial to keep in mind (and express to patients) that trophic agents such as teduglutide are not a substitute for a comprehensive SBS program, but rather an adjunct to this program.

Weaning from PN

The weaning of parenteral support can be a daunting task for short bowel patients, particularly those who have struggled in the past to maintain weight and hydration. We typically begin this process once a patient has stabilized at or near their goal weight, unless clinical course accelerates our decision (multiple septic episodes, unwieldy stool output on maximum anti-diarrheal/anti-secretory agents, etc.). For patients on PN, we make stepwise decreases in total fluid volume and macronutrient content (Table 1). Weekly labs are followed closely as are patient’s weights, stool output, and urine output, particularly in patients who attempt to increase their PO intake to compensate for decreased PN support, which may make stool output increasingly difficult to manage. This frequently requires the escalation or addition of anti-diarrheal agents such as loperamide or codeine.8 A subset of patients is unable to increase their PO intake successfully without uncontrolled stool output. Our experience has suggested that many of these patients can still work toward enteral autonomy through the use of a gastrostomy tube using a pump for nightly feedings at a decreased, but continuous rate for 8-12 hours. However, prior to placing permanent access, a nasogastric nocturnal feeding trial with concurrent 72- hour fecal fat collection is undertaken to ensure we do not drive stool output higher than manageable and to ensure absorption is adequate. Similarly, some patients succeed with an enteral backpack for daytime use to infuse enteral feeding or oral rehydration solutions. The portability of the enteral backpack is often a key to success and quality of life in these patients. A small subset of patients is unable to achieve enteral autonomy. This is most commonly the case in patients with severely foreshortened bowel, defunctionalized remaining bowel, or short bowel in the context of bariatric surgeries. Rather than a change in the above process, these patients often require a change in goals of weaning. For many patients, even one or two nights off of PN per week is very meaningful for their quality of life and often helps facilitate vacations and social functions. A similarly worthwhile alternative goal might be attempting to reduce total weekly PN in favor of IV fluids to support hydration, which has a more favorable risk profile particularly with regards to line infection.

CONCLUSION

Successful management of the challenges SBS patients face requires systematic and strategic intervention. It is important to avoid “throwing the kitchen sink” at patients to prevent overtreatment (which can act to drive stool output further), but also result in unnecessary healthcare costs. This article demonstrates how diet, hydration, and medication selection, including the judicious use of intestinotrophic agents, all play an integral role in the complex management of SBS. See Table 2 for additional resources for clinicians. References

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