Page 51 – Practical Gastro

David M. Schwartzberg,H. Tarik Kirat,Feza H. Remzi

David M. Schwartzberg MD, H. Tarik Kirat MD, Feza H. Remzi MD FACS FASCRS Department of Surgery, Inflammatory Bowel Disease Center, New York University Langone Health, New York, NY

INTRODUCTION

Chronic intestinal inflammation caused by Crohn’s disease (CD) has been associated with malignant transformation into aggressive forms of small bowel adenocarcinoma. The overall incidence of small bowel adenocarcinoma is less than 2%.^1,2 Signet ring cell carcinoma (SRCC) is an aggressive subtype and is associated with poor differentiation and a poor survival, often presenting as T4 lesions in Crohn’s patients.³ Mid-small bowel CD is difficult to survey and subtle symptomatology maybe the only clue in deciding between biologic therapy or surgical intervention. Before deciding on medical therapy, including a number of possible biologic therapies, malignancy must be ruled out, or surgical resection must be offered.⁴

We report a case of SRCC in a patient with long-standing Crohn’s disease who was suspected to have increasing symptoms secondary to Crohn’s ileitis. Escalation of medical therapy failed to control his symptoms and operative intervention was ultimately required. Pathology revealed a poorly differentiated, pT4aN2M1 SRCC adenocarcinoma in the setting of active Crohn’s disease. This case highlights the importance of considering malignant transformation of the small intestine in the setting of long-standing inflammatory bowel disease.

Case Report

A 63-year-old male with a 32-year history of Crohn’s disease presented with increasing abdominal pain, fatigue, weight loss and intolerance to solid food. Historically he had been treated with budesonide and mesalamine only requiring sporadic corticosteroid tapers. Recent colonoscopy revealed a scarred ileocecal valve, which prompted initiation of infliximab. Ileal thickening (to 16.9mm) was noted on computed tomography (CT) ordered for persistent symptoms despite two months of infliximab treatment (Image 1). Aggressive inpatient therapy failed to control his symptoms and surgical intervention was recommended. Peritoneal implants were noted on the anterior abdominal wall; frozen section was positive for mucinous adenocarcinoma. En bloc resection was performed (Image 2). His final pathology showed a poorly differentiated, pT4N2M1 signet ring cell carcinoma measuring 23 cm in length. Mismatch repair was stable. There was metastatic lymph node spread (12 of 15 lymph nodes), lymphovascular and perineural invasion, omental and peritoneal metastasis. CDX2, CK20 and CK7 stains were positive. The surrounding bowel was consistent with active Crohn’s disease.

Discussion

This case describes malignant transformation of the ileum to an aggressive form of small bowel adenocarcinoma, signet ring cell carcinoma, in a patient with long-standing Crohn’s disease. The subtype of SRCC is rare with only one other case arising in the presence of Crohn’s disease.8 SRCC originate from undifferentiated stem cells and are mucin secreting tumors with an abundance of intracellular mucin that peripherally displaces the nucleus.2 SRCC is most commonly found in the stomach and colon, with small bowel SRCC only occurring in 1.1% of reported cases. It is generally associated with poor-differentiation and T4 lesions with a reported 5-year overall survival of 16.1%.^2,3

Overall, small bowel adenocarcinoma is uncommon, and its symptoms non-specific. Its association with Crohn’s disease, however, increases the risk 40 to 60-fold relative to the general population.^1,6 Though adenocarcinoma is rare, and the exact mechanism of malignant degeneration unknown, malignancy must be ruled out prior to escalating medical therapy, especially in patients with long-standing CD.⁶

Surveillance of CD is possible in upper and lower gastrointestinal disease. Small bowel disease is often difficult to access endoscopically, thus location of disease must factor into the treatment algorithm. The aggressive nature of small bowel adenocarcinoma, specifically SRCC, should be considered when small bowel CD fails to improve with escalating medical therapy, or long-standing disease becomes increasingly worrisome. Surgical resection may be the only opportunity for cure, and it must be considered to be diagnosed.¹¹.

An Uncommon Complication of a Motor Vehicle Accident, Diagnosed via ERCP

David T. Chao,Victoria O’Connor,Karl K. Kwok

Cholecystocolonic fistulas are a rare complication of gallstone disease that are typically incidentally discovered intraoperatively while patients are undergoing cholecystectomy. We present a case of an incidental finding of a cholecystocolonic fistula diagnosed unequivocally while undergoing endoscopic retrograde cholangiopancreaticography to evaluate a biliary stricture that developed after a motor vehicle accident.

David T. Chao, MD¹ Victoria O’Connor, MD² Karl K. Kwok, MD¹ ¹Department of Gastroenterology ²Department of Surgical Oncology Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA

INTRODUCTION

Cholecystoenteric and cholecystocolonic fistulas are uncommon complications of gallstone disease. Symptoms are often absent or subtle and nonspecific, and abdominal imaging may fail to identify the presence of the fistula. Consequently, the majority of patients are diagnosed intraoperatively creating a difficult dilemma for the surgeon.

Case Report

A 61-year-old woman with no significant medical history was a restrained passenger in a motor vehicle accident with rollover approximately one year prior to presentation. She was discharged from the emergency room in stable condition after evaluation did not reveal any evidence of blunt force trauma.

Approximately eight months after the motor vehicle accident, the patient presented to an outside hospital with painless jaundice. She was otherwise asymptomatic, denying diarrhea, abdominal pain, nausea, and vomiting. Emphysematous cholecystitis was diagnosed on computed tomography (CT) scan of her abdomen with pericholecystic inflammatory changes, gallbladder wall thickening, air within the gallbladder lumen, and intrahepatic pneumobilia. No gallstones were noted. The patient underwent an endoscopic retrograde cholangiopancreatography (ERCP) which revealed a common bile duct stricture, that was brushed and stented. Bile duct brushings revealed atypical cells.

Re-evaluation of her common bile duct stricture with endoscopic ultrasound (EUS) and repeat ERCP was recommended. During EUS, the gallbladder was identified with some difficulty, after repeated imaging of the expected area of the gallbladder based on anatomical landmarks. Additionally, the distal bile duct appeared to have a discrete hypoechoic mass lesion, which was sampled with fine needle aspiration.

On cholangiogram, abnormal pooling of contrast into a tubular structure not obviously representative of the diseased gallbladder was noted (Figure 1). Although there were initial concerns of a spontaneous perforation, the contrast disappeared in less than 30 seconds, and could not be located. Repeat cholangiogram demonstrated antegrade contrast flow first into the gallbladder, then into the descending colon, sigmoid colon, and rectum (Figure 2), which was consistent with a cholecystocolonic fistula.

The patient underwent combined surgical repair of the cholecystocolonic fistula, as well as pancreaticoduodenectomy. Final pathologic diagnosis revealed no evidence of malignancy.

DISCUSSION

Cholecystocolonic fistula is a communication which originates from the gallbladder and extends typically to the proximal transverse colon at the hepatic flexure. It is the second most common cholecystoenteric fistula after cholecystoduodenal fistulas.¹ Women appear to be more affected than men in a 2.47:1 ratio with the majority of patients diagnosed when they are 60 to 70 years old.² However, cases have been described in patients younger than 40 years old and thus the diagnosis should be considered in all age groups.

Often considered a late sequelae of gallstone disease, cholecystocolonic fistulas complicate approximately 1 in 1000 cases of acute cholecystitis.³ They are thought to develop secondary to chronic inflammation involving the gallbladder wall from cholelithiasis that cause pressure necrosis, erosion, and eventual fistulization. Cholecystocolonic fistulas have also been associated with peptic ulcer disease, malignancy, and abdominal trauma.⁴ A review of 231 published cases of cholecystocolonic fistulas found an increased association with gallbladder cancer.²

The diagnosis is typically made incidentally, since patients with cholecystocolonic fistulas are either asymptomatic or develop symptoms insidiously. If symptoms are present, patients will most commonly complain of chronic watery diarrhea secondary to bile salt malabsorption.² Diversion of bile salts directly into the colon bypasses the terminal ileum, which disrupts enterohepatic circulation of bile salts and reduces absorption of vitamin K. Other nonspecific symptoms may include abdominal pain, nausea, vomiting, jaundice, and fevers. When symptoms develop more acutely, cholecystocolonic fistulas may present with large bowel obstruction (secondary to gallstones >2.5cm causing luminal obstruction in the distal or sigmoid colon).^5,6,2 Laboratory testing may reveal cholestatic liver chemistry elevations or coagulopathy that corrects with parenteral vitamin K administration. Standard diagnostic imaging including CT, magnetic resonance imaging (MRI), and ultrasound have poor sensitivity may not reveal presence of a cholecystocolonic fistula 50% of patients.⁷ The presence of pneumobilia in conjunction with an elevated protime in a patient presenting with diarrhea should raise suspicion for the presence of a cholecystocolonic fistula.⁷

Treatment is surgical and typically consists of a cholecystectomy en bloc with partial colectomy followed by either primary repair of the colonic wall defect or primary anastomosis of the colon. Formation of a diverting end ileostomy may be needed, but is generally not required in patients with good nutritional status who undergo tension-free anastomosis without serious intra-operative deviations from the planned operation. As cases of cholecystocolonic fistula are often times not detected pre-operatively in patients undergoing cholecystectomy, incidental discovery of a cholecystocolonic fistula presents surgeons with the intraoperative challenge of performing a much more complex operation than initially planned.

In conclusion, cholecystocolonic fistula is a rare complication of gallstone disease that should be considered in the differential diagnosis of unexplained chronic watery diarrhea, particularly in patients with known cholelithiasis. In this case, a pre-operative cholangiogram helped definitively define the disease process that was otherwise rather subtle on cross sectional imaging. Without evidence of gallstone disease on abdominal imaging, we suspect the patient may have developed her biliary stricture and cholecystocolonic fistula from abdominal trauma sustained during the motor vehicle accident.

Frontiers In Endoscopy, Series #48

Hemospray for Gastrointestinal Bleeding: Technology Status Update

Babatunde Olaiya,

Douglas G. Adler

A simple to use hemostatic agent such as a hemostatic powder may potentially impact the endoscopic management of gastrointestinal bleeding, especially in lesions less amenable to conventional endoscopy. This paper aims to describe the efficacy and safety of Hemospray (Cook Medical, Winston Salem NC) in the management of gastrointestinal bleeding.

Babatunde Olaiya MD, MPH, MPP¹ Douglas G. Adler MD, FACG, AGAF, FASGE² ¹Marshfield Clinic, Marshfield, Wisconsin ²University of Utah School of Medicine, Salt Lake City, UT

INTRODUCTION

Mortality due to upper gastrointestinal bleeding (UGIB) has declined significantly in the last two decades, largely attributable to improved endoscopic practices.¹ A similar downward trend has been observed in lower gastrointestinal bleeding (LGIB).² Nonetheless, gastrointestinal bleeding (GIB) is still a major cause of morbidity and mortality in the United States with significant associated healthcare costs. UGIB accounts for about 300,000 hospital admissions yearly with a case fatality rate of 2-3%.^1,2 Case fatality rate in LGIB is 1.47% with a two fold increase in patients greater than 75 years old.²

Endoscopic hemostasis remains first line treatment for GIB. While conventional endoscopic methods including injectable agents, thermal treatments, argon plasma coagulation (APC), hemostatic clips and other therapies are effective, they often require high level of endoscopic expertise which may not be readily available. Furthermore, these modalities often require precise localization of the bleeding source and may be less effective in patients experiencing large mucosal bleeds, difficult to access lesions or in severe bleeding. Even with high level of endoscopic expertise, rebleeding risk with conventional endoscopic methods is about 5%.³

Overview of Hemospray

Hemospray is a hemostatic powder developed for endoscopic therapy of GI bleeding. (Figure 1) Unlike conventional endoscopic methods, Hemospray is non-contact, non-thermal and non-traumatic. It also doesn’t require specific lesion targeting to secure hemostasis, although if possible direct spraying of the compound on the lesion is preferable.

According to the manufacturer, Hemospray is metabolically inert, presumably nontoxic and doesn’t contain any human or animal allergens. On contact with blood, Hemospray induces hemostasis by absorbing water and forming a mechanical and adhesive barrier over the bleeding site. It causes a dose dependent reduction in median recalcification and clotting time of whole blood, rapidly producing hemostasis.^{^43-45} Hemospray is not absorbed by the body and no long-term effects due to ingestion have been documented to date.

Hemospray was first studied in porcine models to control surgically created high-pressure spurting arterial bleeds.⁷ Hemostasis was achieved successfully in all study animals as compared to none in control animals. A pilot study of 20 people with peptic ulcer bleeding closely followed and hemostasis was achieved in 95% of cases.⁸ These initial results have prompted the evaluation of Hemospray for endoscopic hemostasis in a wide array of bleeding disorders in the upper and lower gastrointestinal tract.^8-16

Primary Hemostasis
Peptic Ulcer Disease

Gastrointestinal bleeding is common in peptic ulcer disease (PUD), accounting for more than 7 in 10 hospitalizations amongst PUD patients annually.¹⁷ (Figure 2 and Figure 3) About a tenth of those with severe bleeding die, a higher risk of death observed in patients with high risk stigmata (active bleeding, non-bleeding visible vessel) and/or duodenal ulcers.^4,17-19 While conventional endoscopic methods are often highly effective, some lesions are not easily amenable to conventional therapy due to difficulties in endoscope positioning, surrounding tissue friability or fibrosis, or other factors. This was evident in a recent large national study that observed that 7% of PUD patients with high risk stigmata did not receive any endoscopic therapy, with lesions deemed to be too large for endoscopic approaches being a frequently cited reason.²⁰

Hemospray has been used successfully both as monotherapy and in conjunction with conventional methods in controlling bleeding due to PUD.^8,9,21,22 Sung et al. used Hemospray monotherapy on 20 patients with Forrest 1a and 1b ulcers and reported immediate hemostasis in 95% of patients.⁸ Hemostasis was not secured in one patient who had a psuedoaneurysm and eventually required arterial embolization. Rebleeding occurred in 2 patients within 72 hours but there was no active bleeding on repeat endoscopy.

In a small study by Kwek et al. comparing the effectiveness of Hemospray monotherapy to conventional modalities, initial hemostasis was achieved in 90% (9/10) and 100% (10/10) of cases respectively.⁹ In the Hemospray group, 7 of 10 patients had duodenal ulcers and initial hemostasis was achieved in 6 of these. Of note, case of Hemospray failure involved a patient with a Forrest 1b posterior duodenal wall ulcer. Hemostasis was eventually achieved with conventional endoscopy. Cahyadi et al. recorded immediate hemostasis with Hemospray in 18 patients with PUD related bleeding whose lesions were deemed not amenable to endoscopy (due to difficult anatomical situation or diffuse bleeding without definite source.) or after conventional endoscopic failure.²² Similarly, Smith et al. reported success in a report of 5 patients who were treated with Hemospray as second line after the failure of conventional endoscopy.²¹

Hemospray has been used as an adjunct to conventional endoscopic methods to control PUD bleeding. Sinha et al. used Hemospray in addition to Adrenaline (8 cases) and Hemospray in addition to Adrenaline with clips or thermal devices (12 cases).²³ Immediate hemostasis was achieved 95% (19/20) of cases. The failure case occurred in the group that had Hemospray, Adrenaline with clips/thermal devices and hemostasis was secured by embolization to the gastroduodenal artery.

Tumor Bleeding

Gastrointestinal tumor bleeding accounts for 2.6 – 5% of UGIB.24-27 Bleeding is the initial symptom of gastrointestinal tumor in about half of cases making late stage presentation a common phenomenon.²⁴ Compared to other causes of UGIB, mortality in gastrointestinal tumor is quite high regardless of endoscopic therapy likely reflecting the severity of the underlying disease.^24,28 However, endoscopic hemostasis is pivotal to managing tumor bleeding and has been shown to reduce the need for blood transfusions or emergent surgery, often acting as a therapeutic bridge to palliative surgery, radiation or chemotherapy.^29-31 Rebleeding after endoscopic treatment is however very high in tumor bleeding.

Bleeding due to gastrointestinal tumor may be diffuse and lack a specific target for endoscopic hemostasis. Furthermore, tumor bleeding often arises from ulcerated or friable mucosa, potentially limiting the use of mechanical or contact hemostatic methods. As such, a non-contact, non-thermal option like Hemospray may be a good option for providing at least short-term hemostasis. Pittayanon et al. evaluated the effectiveness of Hemospray in 88 patients with tumor bleeding in a large multicenter study.³² Over 70% were stage 4 tumors and 50 were located in the upper gastrointestinal tract. Hemostasis was achieved with Hemospray in 98% of cases. Definite hemostatic treatment i.e. embolization, chemotherapy, radiotherapy and surgery was associated with improved survival after Hemospray treatment. In smaller studies, immediate hemostasis with Hemospray on bleeding due to upper gastrointestinal tumor ranged from 93 to 100%.^22,33-35

Variceal Upper Gastrointestinal Bleeding

Acute variceal bleeding (AVB) is a leading cause of death in cirrhotic patients, with mortality rates as high as 24% at 6 weeks.^36,37 While gastroduodenal ulcers coexist in a quarter of patients, variceal bleeding accounts for over 50% of UGIB in cirrhotic patients.^38,39 Per conventional endoscopy, sclerotherapy and variceal band ligation (VBL) are frequently utilized to treat bleeding esophageal varices, the latter having superior effects on reducing rebleeding, mortality and fewer esophageal strictures.⁴⁰ The combination of VBL with pharmacologic agents demonstrates even better effects on achieving hemostasis and reducing rebleeding than VBL alone.⁴¹ Nonetheless, failure to control bleeding occurs in up to 10% of patients with acute variceal bleeds.⁴²

There is emerging evidence on the efficacy of Hemospray in controlling acute variceal bleeding. In a single arm prospective trial, Ibrahim et al. used Hemospray monotherapy in 30 patients with confirmed AVB. Over 80% of varices were in the esophagus and more than half were actively bleeding.⁴³ With the exception of one patient who required the use of two Hemospray devices due to continued bleeding, others required just one application and immediate hemostasis was achieved in all patients at initial endoscopy.⁴³ In another study by Ibrahim et al., 100% hemostasis was achieved in all nine patients with AVB treated with Hemospray monotherapy.⁴⁴ Ibrahim et al. also studied 86 cirrhotic patients with AVB in a multicenter randomized trial. The study observed that patients who had immediate treatment with Hemospray within 2 hours of admission followed by elective endoscopy treatment at 24 hours had significantly better survival rates at 6 weeks compared to those who had elective endoscopy alone. These patients also had lower rates of rebleeding and need for rescue endoscopy.⁴⁵

Lower Gastrointestinal Bleeding

Lower gastrointestinal bleeding (LGIB) is about a fifth as common as UGIB and more prevalent in patients older than 65 years.⁴⁶ While acute LGIB often resolves spontaneously with supportive care, about 25- 40% of cases warrant direct endoscopic therapeutic intervention.^47,48 Conventional endoscopic treatment modalities are often effective at achieving hemostasis. However, in a few cases, bleeding persists warranting the need for other hemostatic options.⁴⁹

Hemospray use in LGIB has been less frequently reported; however some studies have reported on its efficacy in achieving initial hemostasis. (Figure 4) Ivekovic et al. reported the successful use of Hemospray in a patient with spurting post polypectomy bleeding that did not respond to clipping.⁵⁰ Similarly, Soulellis et al. also achieved hemostasis with Hemospray in two patients with post-polypectomy bleeding after failure of thermal and mechanical therapy.⁵¹ In a case series, Granata et al. treated four patients with severe LGIB due to ischemic colitis with Hemospray.⁵² All four patients were hypotensive and on antithrombotic therapy at presentation. Mean ulcer diameter was quite large at 32 mm. Hemostasis was achieved in all four patients. Less common causes of LGIB in which hemostasis was successfully achieved with Hemospray includes stercoral ulceration, cytomegalovirus induced bleeding, post proctocolectomy bleeding and diclofenac-induced lower GI bleed.^13-16

Rebleeding

Rebleeding after endoscopic hemostasis is an independent predictor of mortality in both UGIB and LGIB.^3,4,53 Endoscopic findings that are predictive of rebleeding include active bleeding at the time of endoscopy, large ulcer size, posterior duodenal location and lesser gastric curve location.⁵⁴ Various strategies have been proposed to reduce the risk of rebleeding including avoiding epinephrine monotherapy and the use of dual conventional therapy. Rebleeding occurs in 10 -20% of cases despite use of dual therapy.⁵⁵

Studies show rebleeding rates after Hemospray to be highly variable, typically ranging between 15 and 49%.^{9,21-23,35,56-58} This variability may be explained by heterogeneity of study populations, studies with small sample size and different modalities of Hemospray use. Certain factors are associated with an increased risk of rebleeding when Hemospray is used for endoscopic hemostasis. When Hemospray was used as a treatment modality for patients whose ulcers were deemed not amenable to conventional methods i.e. large ulcers or lesions at historically difficult locations to treat, rebleeding rates after initial hemostasis was as high as 49% after 7 days.²² Rebleeding also appears to be higher when Hemospray is used as salvage therapy i.e. after failure of conventional therapy as compared to primary hemostatic method.²² Similar to conventional modalities, rebleeding rates are much higher when Hemospray is used to treat spurting arterial bleeding (Forrest 1a ulcers).^9,21,23 However, when treating actively bleeding ulcers, Hemospray may have a higher risk of rebleeding as compared to conventional methods.⁹ In fact, at least one study suggests that Hemospray not be used as monotherapy for spurting arterial bleeds due to high risk of rebleeding.⁵⁶

Safety Issues/Adverse Effects

Despite the benefits of Hemospray or hemostatic powders, there are potential safety issues and reports of adverse events. When Hemospray is used before other hemostatic modalities, there is a risk of obscuring the boundaries of a lesion making it more difficult to implement other hemostatic options if they are needed.⁵⁹ Furthermore, there is a risk of catheter obstruction if the delivery device comes into contact with blood. Per the manufacturer, no more than 3 devices (60g) of Hemospray are to be used in a single patient. Hemospray is not absorbed by the gastrointestinal tract so there is a risk of colonic impaction at higher doses. Up to 150g of Hemospray was utilized in the study by Sung et al., without any report of colonic obstruction.⁸ Biliary obstruction after treatment of a post sphincterectomy bleed treated by Hemospray use has been documented.⁶⁰ Patency was restored by irrigation and prodding the orifice open with a sphincterotome tip.

Due to its pressurized contents, Hemospray is associated with a risk of bowel perforation and embolization. Hagel et al. documented an 8cm gastric wall perforation after Hemospray was used for a patient with ischemic colitis who presented with melena and generalized peritonitis after total colectomy.⁶¹ Similarly, visceral perforation after Hemospray application has been documented in two other studies although it was unclear if this was directly related to Hemospray use.^62,63 Hemospray is not currently recommended for primary treatment of variceal bleeding due to the theoretical risk of embolization, although this can be performed in an off-label manner. It is thought that the pressurized contents of Hemospray may overcome the low pressure venous system. However, this adverse event has not been recorded in studies where Hemospray was used for variceal bleeding.^43-45

CONCLUSION

Hemospray has potential advantages over conventional methods in the control of gastrointestinal bleeding. It has high primary hemostasis rates in both variceal and non-variceal upper gastrointestinal bleeding. Limited studies also demonstrate high primary hemostasis rates in LGIB. Beyond this, it is simple to use and does not require a high level of endoscopist expertise. It also appears to have a good safety profile, only very few studies documenting serious adverse effects. Hemospray also has some limitations. Despite high primary hemostasis rates, it appears to have higher rates of rebleeding if used to treat spurting arterial bleeding or large, difficult to reach ulcers. It is a single use product and cannot be reused in the same patient if rebleeding occurs at a later date. Furthermore, if the device becomes clogged during endoscopy, further use is impossible and another device needs to be used. Going forward, there is need for larger studies to define the optimal role and cost effectiveness of Hemospray in the management of gastrointestinal bleeding.

Inflammatory Bowel Disease: A Practical Approach, Series #105

Vaccinations for Patients with Inflammatory Bowel Disease: An Updated Review

Manisha Apte,

Jason Reich,

Francis A. Farraye

Patients with Inflammatory Bowel Disease (IBD) are at an increased risk for infectious complications due to the immune disturbance inherent with disease pathophysiology and immunosuppressive therapies. This review highlights vaccinations for patients with IBD, suggestions for increasing vaccination rates in your practice and new changes in practice guidelines.

INTRODUCTION

Patients with Inflammatory Bowel Disease (IBD) are a patient population where a focus on increasing preventative health care measures is needed.¹ The pathophysiology of IBD involves the activation of a systemic inflammatory process with release of cytokines and other inflammatory mediators.² As a result, patients with IBD are at an increased risk of infections due to their altered immune system; further complicating this is the fact that many patients with IBD are treated medically with immunosuppressive therapies, increasing risk of infection.³ For instance, a retrospective cohort study demonstrated patients with IBD are at increased risk for pneumonia, a risk further increased with steroids and opioids.⁴ Immunosuppressive therapies for IBD includes agents such as 6-mercaptopurine (6-MP), azathioprine, methotrexate and tofacitinib. In addition, biologic agents including infliximab, adalimumab, certolizumab, golimumab, vedolizumab and ustekinumab are being used more frequently, while corticosteroids continue to be used in acute flare management.⁵ Infectious complications are an important cause for hospitalization in IBD patients.⁶ With these heightened risks, it is important to understand the best practices in vaccinating patients with IBD, both before and after therapy is initiated. This article will discuss current guidelines for vaccination recommendations in patients with IBD and review how to implement a vaccination process in your practice.

Vaccination and Disease Activity

A growing body of literature has served as the basis of current expert recommendations on how and when to vaccinate patients with IBD, and has concluded that vaccinating IBD patients is not associated with a flare in disease activity.^7,8

Defining Immunosuppression in Patients with IBD

Patients with IBD on immunosuppressive agents are considered to have either low or high levels of immunosuppression depending on their medications. High levels of immunosuppression include those on treatment of daily steroid therapy with doses equivalent or greater than 20 mg of prednisone for 14 days or more, treatment with anti-TNF agents, ustekinumab, tofacitinib as well as patients with severe protein calorie malnutrition. Patients receiving 20 mg of prednisone or less for less than 14 days, those receiving methotrexate less than or equal to 0.4 mg/kg per week, and those on azathioprine less than or equal to 3 mg/kg per day or 6-mercaptopurine less than or equal to 1.5 mg/kg per day are considered to have low levels of immunosuppression.^9,10

Vaccination Recommendations
Live Vaccines
Varicella

In general, IBD patients should be immunized with live attenuated vaccines at a minimum of 6 weeks before starting immunosuppressant therapy.1 Before initiating immunosuppressive therapy for IBD, the Advisory Committee on Immunization Practices (ACIP)¹¹ recommends confirming immunity for varicella. If a history of vaccination cannot be confirmed or if they are not shown to be immune serologically, the 2013 Infectious Diseases Society of America (IDSA guidelines) recommend administration of the live varicella vaccine prior to immunosuppression.⁹

Measles, Mumps and Rubella

Vaccinating for measles, mumps and rubella (MMR) is typically accomplished in early childhood so a majority of patients with IBD are already immune. If patients have not been vaccinated or have negative serologies, MMR should be administered prior to initiating immunosuppressant therapies.¹² ACIP guidelines give attention to growing outbreaks of these preventable illnesses in the United States, including mumps.¹³ Patients determined to be at increased risk are recommended to receive an additional, third dose through the MMR vaccination.¹¹

Herpes Zoster

The incidence of herpes zoster virus reactivation is roughly 3 to 13/1000 person years and increases in patients who are receiving combination therapy, including anti-tumor necrosis factor alpha (TNF-a) with azathioprine and/or steroids.^14,15 Two retrospective studies demonstrated that patients on thiopurines or a combination of thiopurines and TNF antagonists had an increased risk of developing herpes zoster.¹⁶ Previous ACIP guidelines recommended all immunocompetent patients receive the live-attenuated vaccine Zostavax at age 60. IBD patients aged 60 or older should receive this vaccine before initiating immunosuppressant therapies given the risks of administering live vaccines to immunosuppressed patients.¹¹ However, patients with IBD considered to have a low level of immunosuppression fit a safety profile that still allow for vaccination.⁸

Recent data suggests that vaccinating patients with Zostavax while on anti-TNF therapy is relatively safe, as the use of these medications alone was not associated with increased incidence of vaccine related infection.18 Additionally, administration of the live zoster vaccine was associated with a significant reduction in the risk of developing shingles.¹⁷ Therefore, expert opinion recommends shared decision making with patients on anti-TNF agents, as well as an individual case review before offering the live vaccine.⁸ Potential barriers to vaccinating IBD patients against herpes zoster have recently been reduced with the new inactivated vaccine for herpes zoster, Shingrix (reviewed below). The recent Food and Drug Administration (FDA) approval of Shingrix has allowed for a review of vaccination guidelines.¹⁹

Inactivated Vaccines Herpes Zoster

Shingrix, a two-dose, inactivated vaccine against herpes zoster, was approved by the FDA in 2017 for adults aged 50 years or older (Table 2). Phase I and Phase II trials of Shingrix suggested that the effectiveness of the vaccines would wane a full 19 years after administration.17 The ACIP and CDC now recommend this vaccine to all immunocompetent adults aged 50 years or older instead of the live Zostavax vaccine, and also approving it for immunocompetent adults irrespective of prior Zostavax administration.¹⁸ With the prospect of a safe inactivated vaccine for healthy individuals against herpes zoster, additional studies are needed in immunosuppressed patients, including those with IBD. Studies demonstrating the efficacy and safety of Shingrix in hematologic malignancies and renal transplant patients offer the impetus to complete studies in immunocompromised patients with IBD.²⁰

Hepatitis A Virus

Patients in developed nations, including the United States, are at a lower risk of contracting hepatitis A virus (HAV) infection, but patients with IBD should still be vaccinated with the HAV vaccine if they are not immune.

Patients on anti-TNFs have a statistically significant decreased response to HAV vaccine compared to those not treated (p=0.001); however, the rate of seroconversion was still notably high in the anti-TNF group with a rate of 92.4% (85/92) compared to 99.1% (324/327) in the non-treatment group.²¹

Patients diagnosed with IBD should be tested for HAV immunity and should receive the routine two-dose series administered at 0 and 6 months if they are not immune. ⁵ The 2018 ACIP guidelines does not address immunosuppressed patients in its HAV guidelines, although prior ACIP recommendations noted this inactivated vaccine is safe to administer such populations.¹

Hepatitis B Virus

The prevalence of hepatitis B virus (HBV) is similar in patients with IBD and the general population.²² The ACIP recommends that patients with IBD who are not immune to HBV receive the vaccination series, even after initiating immunosuppressant therapy. The most commonly administered vaccine for HBV is a recombinant formulation that consists of the HBV surface antigen (HBsAg) administered in three doses. A newer vaccine, Heplisav-B, a single-antigen HepB vaccine with a immunostimulatory adjuvant, was approved by the FDA in 2018 for use in adults ≥18 years old.²³ This vaccine generates a strong serologic response in adults (95%), although long-term implications on safety have yet to be studied.²⁴ The ability to generate antibodies depends on a robust T-cell response and for B cells to proliferate and differentiate into anti-HBs-secreting plasma cells.²⁵ While these immune system components are fully functional in healthy individuals, patients with IBD have immune alterations and further suppression when on therapy. A lower antibody titer response may be seen in older age adults and the use of anti-TNF treatments.^26,27 When vaccinating patients on anti-TNF therapy, we ideally recommend vaccinating prior to initiation of therapy.²⁸

Influenza

The ACIP recommends patients receive the inactivated or recombinant influenza vaccination (available in trivalent or quadrivalent forms) annually to target the evolving viral strain.²⁹ Patients with IBD have a lower serologic response to this inactivated vaccine and this response is worse in those on immunosuppressant therapy.^30,31 There are no recommendations for an additional booster.³² Current ACIP guidelines allow for vaccinating IBD patients already on immunosuppressant therapies. There is improved serologic response to a higher-dose trivalent or quadrivalent dose, a reliable option for the elderly.¹¹

Pneumococcal Pneumonia

Two vaccines are available for pneumococcal pneumonia (Table 3), the 23-valent polysaccharide (Pneumovax; PPSV23) and the 13-valent conjugate vaccine (Prevnar; PCV13). The ACIP recommends immunosuppressed patients receive a two-dose vaccination series.

PPSV23 is a polysaccharide vaccine that depends on B-cell immune response. This humoral immune response creates specific antibodies (IgM and IgG) that target 23 pneumococcal bacterial strains. IgM memory cells are primarily responsible for targeting the bacteria.³⁴ Since IBD patients have lower circulating levels of IgM B cells due to their altered immune function, and deficient spleen function, their response to the vaccine may be suboptimal.³⁵

Patients with IBD had lower circulating antibodies after receiving PPSV23, with patients on combination therapy having a decreased immune response.³⁶ Per the 2018 ACIP guidelines, adults aged ≥19 years with anatomical or functional asplenia, cerebrospinal fluid leak, or cochlear implant or who are immunocompromised should receive PCV13 and then PPSV23 at least 8 weeks after.¹¹ We recommend that patients with IBD receive these vaccines at initial diagnosis of IBD.³⁷ They should then receive an additional PPSV23 booster at least five years after their first dose as long as they received their initial PPSV23 before they turn 65 years of age. If a patient has already received PPSV23, PCV13 should be administered 1 year later.

Tetanus and Diphtheria

The tetanus and diphtheria vaccine (Tdap) should be administered to all patients with IBD every 10 years, as per ACIP recommendations.¹ A meta-analysis assessing IBD patient response to this vaccine has revealed no conclusive results on immune response and seroconversion.³⁸ Patients receiving combination therapies or single biologics were found to have significantly decreased response, and, should therefore ideally receive Tdap before starting immunomodulators, particularly when used in combination with anti-tumor necrosis factor alpha agents.^39,40

Meningococcal

Neisseria meningitides infection poses a risk of meningitis; young adults are especially vulnerable due to their proximity to other individuals in colleges and the military. The 2018 ACIP guidelines recommends young adults aged 16-23 should be vaccinated. Given the vaccine is inactivated, patients with IBD in this age group are also recommended to receive the vaccine even if they are on immunosuppressive therapies. This however remains a conditional recommendation, as there have been few evidence-based studies to support this action.^8,39 There are multiple vaccine options against Neisseria, which cover different serotypes. The conjugate Menactra, Menveo and polysaccharide Menomune act against serogroups A, C, W, and Y, while Bexero and Trumenba only cover serogroup B (MenB) with a two-dose or three-dose series, respectively.⁸ As MenB is the prevalent serogroup observed in meningitis cases in the United States, the vaccine series targeting it is recommended for adolescents.⁴⁰

HPV

The human papillomavirus (HPV) is the strongest risk factor for cervical cancer, which is the second most common cause of cancer in women worldwide.⁴² Additionally, it is also associated with penile, vulvar, vaginal, anal and oropharnygeal cancers. Specific HPV genotypes are associated with both low and high-grade cervical dysplasia on cytology.⁴³ There are two vaccines available that protect against HPV types 6, 11, 16 and 18-the former two genotypes are associated with low grade dysplasia and the latter two are associated with cervical cancer.⁴⁴ The bivalent vaccination protects against types 16 and 18 while the quadrivalent targets all four types.

As an inactivated vaccine, the quadrivalent form (Gardasil) is given in three doses at 0, 2 and 6 months, respectively for males and females aged 16-26.¹¹ Additional recommendations from 201811 guidelines now also include children aged 9-15, who can instead receive two doses 6 months apart. On October 5, 2018 the FDA approved Gardasil for adults aged 27 through 45. We await updated recommendations from the ACIP.⁴⁵ In measuring serologic response to this vaccine, 94% of IBD patients who received three doses, seroconverted to all four types of the virus, which was a similar response to rates previously documented in healthy individuals.⁴⁶

Implementation

It is important to note that despite vaccination schedule guidelines, there is no current consensus on who is responsible for coordinating and administering vaccinations. Surveys of gastroenterologists and family practitioners revealed that the majority of physicians believe the responsibility to ensure vaccine completion lies with the patient [41.7%] and the family physician [32.3%]. Furthermore, this survey revealed that significant predictors of vaccine completion were annual vaccination review by family physician (odds ratio [OR] = 1.82) or gastroenterologist [OR = 1.72], current steroid use [OR = 1.28], and current or prior treatment with biologics [OR = 1.42].⁴⁷ An understanding of how to implement a vaccination program is therefore necessary. New innovative approaches to aid clinicians and patients alike have been developed and introduced to improve vaccination rates amongst IBD patients. One example is the utilization of electronic medical records to create smart phrases, which can be auto-populated in notes or letters to patients to include completed and overdue vaccinations;¹ these templates can be used whenever a patient is seen in the office so that it is always updated. The Crohn’s and Colitis Foundation and Cornerstones have developed useful checklists for office use. If offices carry vaccines, it is efficient to use this template and administer the vaccine before a patient leaves the appointment. Utilizing nurses has also been demonstrated to increase vaccination rates.⁴⁸ For practices that do not stock vaccines, or have limited resources to administer vaccinations, an alternative approach is to prescribe vaccines for patients to receive at a local pharmacy. Pharmacy resources can prevent delays to vaccination and have the added benefit of offering more flexible hours and vaccine availability.⁴⁸ Finally, the success of implementing a vaccination program rests on shared decision-making with patients. Office visits should include educational components to emphasize the importance of vaccines and patients should be kept up to date on recommended scheduling. If patients are not seen regularly, then patient portals can be utilized with routine automated messages to remind patients of preventative health care tasks.¹

CONCLUSION

This review highlights current guidelines for vaccinating patients with IBD, including implications of the recent FDA approval of the new herpes zoster vaccine, the two-dose hepatitis B vaccine and new recommendations for the HPV vaccine. Vaccinating IBD patients is an important focus within the broader preventative care sphere, especially prior to initiating immune-modulating therapies. The optimal time to review vaccination schedules are when patients with IBD are seen for their initial gastroenterology visits. While live vaccines should generally be administered on these early visits if not already given, recommendations vary for inactivated vaccines and primarily differ on age; supporting data included here generally favor administration at any time, with minimal risk to patients on immunosuppressant therapy. The vaccinations discussed in this review article are imperative given the elevated risk patients with IBD are at for contracting infectious diseases. Further work to improve vaccinations rates in this population includes clarifying whether the gastroenterologist or primary care physician is primarily responsible for this task. Educating physicians in both fields will help spread knowledge on current guidelines and is an area for improvement in preventative care of IBD patients.

Liver Disorders, Series #10

Alcoholic Hepatitis: A Review

Navroop Nagra,

Robert Hu,

Gaurav Singhvi

Alcoholic Hepatitis (AH) is an acute clinical entity characterized by jaundice and coagulopathy occurring in individuals with a history of heavy alcohol use. It is associated with a high mortality rate, as treatment options available to date have been underwhelming. In this review we discuss AH with an emphasis on potential future treatment options.

Navroop Nagra MD, Peace Health Southwest Medical Center, Vancouver, WA Robert Hu, University of Pennsylvania, Philadelphia, PA Gaurav Singhvi, MD Olive View/UCLA Medical Center, Sylmar, CA

INTRODUCTION

Alcoholic Hepatitis (AH) is an acute clinical entity characterized by jaundice and coagulopathy occurring in individuals with a history of heavy alcohol use. It is associated with a high mortality rate, as treatment options available to date have been underwhelming.^1,2,3,4 In this review we discuss AH with an emphasis on potential future treatment options.

Epidemiology

The true incidence and prevalence of AH is difficult to define, as is the amount and duration of alcohol use needed to cause AH.⁵ Most individuals present between the age of 40 and 50. Typically, they have a history of using more than 100g/day over a time period of two decades.⁷ AH is more prevalent in men given their higher tendency to abuse alcohol. Binge drinking also increases the risk of AH.⁴ In patients with severe AH, the short-term mortality can be as high as 45%.^5,6

Pathophysiology

Oxidative stress and increased gut permeability are two major mechanisms triggering hepatic inflammation leading to AH.^6,8,9 By products of alcohol metabolism via the two major pathways lead to the formation of free radicals and increased oxidative stress. Alcohol is reduced to acetaldehyde and acetate by the enzymes alcohol dehydrogenase and acetaldehyde dehydrogenase, respectively. These enzymes convert NAD to NADH. An increased NADH/NAD ratio leads to the suppression of gluconeogenesis, increased fatty acid (FA) oxidation, and fatty infiltration.^10,11 Alcohol increases the activity of cytochrome P-4502E1, which also produces free radicals. Decreased levels of glutathione make the liver even more prone to oxidative stress.^11,12 The release of free radicals leads to the activation of inflammatory cytokines (TNF-α, IL-1 and IL-6 ), which in turn causes hepatic inflammation. Chronic alcohol use also leads to severe gut dysfunction due to intestinal bacterial overgrowth and the disruption of the tight junctions of the epithelial cells of the gut mucosa.^13,14,15 These changes increase the permeability of the gut and cause a leakage of bacteria and endotoxins into the blood stream. Increased levels of bacterial lipopolysaccharides (LPS) cause an activation of inflammatory cytokines, eventually leading to hepatic necrosis and inflammation.16 (Table 1.)

Clinical Presentation

Symptoms of AH tend to be nonspecific and variable.⁶ Elevated bilirubin is considered characteristic of AH.¹⁷ Other findings include fever, right upper quadrant abdominal pain, anorexia, and abdominal distension due to ascites. Severe cases may present with hepatic encephalopathy. Renal failure due to hepatorenal syndrome (HRS) and bleeding due to coagulopathy can also be seen.^18,19 Features of chronic liver disease such as spider angiomata, gynecomastia, and proximal muscle wasting are common. Alcohol withdrawal causing tremors, seizures, delirium, and coma can complicate matters. Lab abnormalities include elevated bilirubin, mild leukocytosis with neutrophilic predominance, elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT), anemia, thrombocytopenia, and elevated international normalized ratio (INR). AST/ALT levels are typically below 500 mg/dl with an AST/ALT ratio that is more than two being characteristic of AH. This is attributed to a deficiency of pyridoxal 5′-phosphate in alcoholics, which is required for the enzymatic activity of ALT.^17,21 Reversal of this ratio should lead to the workup for other etiologies of hepatitis.

DIAGNOSIS

The diagnosis of AH is a clinical one.⁶ A medical history should be obtained in detail with an emphasis on the amount and duration of alcohol intake. Some patients may not have been drinking for a few weeks prior to presentation but may still have AH. This history, in conjunction with lab findings, helps to make the diagnosis. Other etiologies of acute hepatitis need to be ruled out if the clinical features and labs are inconsistent with AH. Although liver biopsy is not routinely indicated, it is recommended if there is a doubt about the diagnosis and an alternate diagnosis is suspected. Pathology shows ballooning hepatocytes, Mallory-Denk bodies, severe fibrosis (usually micronodular, but sometimes mixed macro- and micronodular) starting from the central vein and extending into the portal triad, and neutrophilic infiltration.²⁰

Scoring Systems in AH

Various scoring systems have been developed for AH in order to assist in determining the severity and prognosis, and to guide treatment. The Maddrey discriminant function (DF) score and model for end-stage liver disease (MELD) score are the most commonly utilized.^14,23,24 Other less commonly used ones are the Glasgow alcoholic hepatitis score (GAHS), alcoholic hepatitis histology score (AHHS), and Lille score. DF uses the prothrombin time (PT) and bilirubin levels with the equation to calculate the score being: 4.6 x [prothrombin time (sec) – control prothrombin time (sec)]) + (serum bilirubin). Patients with a DF ≥32 have an almost 50% short term mortality (severe AH) and may benefit from glucocorticoid treatment.²⁵ Individuals with a DF< 32 will not benefit from steroids. MELD score is typically used for prioritization of liver transplant and to predict mortality in cirrhotic patients, but it has also been used in predicting prognosis in AH. It takes the creatinine, total bilirubin, and INR into account. An increase in the MELD score of ≥2 points in the first week of hospitalization may independently predict mortality.22 MELD ≥ 21 has a 75% sensitivity and specificity in predicting 3 months mortality (20%).²⁸ GAHS uses age, serum bilirubin, blood urea nitrogen, prothrombin time, and peripheral white blood cell count. This multivariable scoring system also predicts mortality in AH. Patients with a DF ≥32 and GAH score ≥9 had higher survival rates after receiving steroids.²⁶ AHHS score requires a liver biopsy, which as previously mentioned is not performed routinely for AH. It also predicts severity and 90-day mortality in AH. The stage of fibrosis, degree of neutrophilic infiltration, and type of bilirubinostasis are the major variables predicting severity and prognosis.^27,28 A high stage of fibrosis and presence of bilirubinostasis favors a poor outcome. A higher degree of neutrophilic infiltration and the presence of megamitochondria represents an early stage of hepatocellular injury and represents a favorable prognosis.^29,30,31 The Lille score helps to identify the response to glucocorticoids. It uses the decrease in bilirubin after one week of glucocorticoid treatment as a marker of response. The score is calculated one week after steroid initiation. Scores of more than 0.45 predict a poor prognosis with 6-month survival rate of less than 25%.³² Glucocorticoids should be stopped in patients who are steroid non-responders (score ≥ 0.56).

Treatment

Treatment of AH with steroids and pentoxifylline has been the mainstay for many years. The importance of nutritional support cannot be understated. It is also vital that the virtues of abstinence be stressed to patients. Resources such as alcoholics anonymous should be utilized. The feasibility of early transplant, even in those who are actively drinking, continues to be studied and is advocated by some. There are also many other novel treatments being looked at. While none are ready for widespread usage at this time, they do provide for some potentially exciting opportunities in the future.

Nutrition

Most patients with AH have nutritional deficiencies and protein calorie malnutrition.³⁶ Randomized controlled trials have come to different conclusions in regards to the role and survival benefit of enteral nutrition, but poor nutritional status is associated with worse outcomes in AH. All patients should get a calorie count and should receive enough calorie supplementation to meet their needs. Protein intake does not need to be restricted.³³ The enteral route is preferred since it maintains gut mucosal integrity, decrease the risk of bacterial translocation, and is cost-effective.^34,35

Steroids

Treatment with glucocorticoids is indicated in severe AH (DF≥32) or hepatic encephalopathy.^43,44,45 Glucocorticoids decrease the levels of TNF and IL8, ultimately decreasing inflammation.^46,47 Prednisolone is the steroid of choice since it does not require conversion to any active metabolites in the liver,48 although it is contraindicated in renal failure, active gastrointestinal bleeding, uncontrolled hyperglycemia, acute pancreatitis, psychosis, and infection.^49,50 Prednisolone 40 mg/day orally is given for four weeks, followed by a gradual taper over the next two weeks in patients who are steroid responders.²⁵ Response to steroids is determined by the Lille score, calculated one week after the start of steroids.

Pentoxifylline

Pentoxifylline acts by inhibiting phosphodiesterase and decreasing the levels of TNF.^37,38 It is known to decrease the incidence of HRS in AH.^39,40,41 The studies and trials conducted to date, including the STOPAH study, have concluded that pentoxifylline has no impact on mortality in AH. It may be used as an alternative therapy in patients with severe AH in whom steroids are contraindicated or in patients with renal failure.⁴² It is not recommended in patients who are steroid non-responders. The combined use of pentoxifylline and steroids has not demonstrated a mortality benefit and is not recommended.⁴²

Liver Transplant

Liver transplant is considered in those with severe AH who have failed medical management. Studies have shown a significant long-term mortality benefit in patients who underwent liver transplantation. Six month and two-year survival were significantly higher in patients who received early liver transplant despite being active drinkers upon presentation.⁵² Most transplant centers require a minimum of six months of abstinence before considering liver transplant. Given that severe AH carries a high mortality, many patients do not survive long enough to meet this criterion. Although early liver transplant in AH has good outcomes, patient selection is very difficult. Alcohol relapse after transplantation is a challenge, and it is therefore no surprise that ethical and sociocultural factors play a big role. More studies are needed in order to create better criteria for transplant eligibility.

Granulocyte Colony Stimulating Factor (G-CSF)

G-CSF acts by mobilizing the hematopoietic stem cells that cause liver regeneration.^53,54 It also increases the bactericidal activity of neutrophils.^57,58 Studies have shown that G-CSF leads to the production of CD34⁺ stem cells and induces proliferation of hepatic progenitor cells which can lead to liver regeneration.^55,56 This leads to decreased infections, improved DF score, and increased three month survival.⁵⁹ The studies conducted so far have only compared GCSF with pentoxifylline or with normal controls not receiving any pharmacological treatment. None of the studies have compared outcomes with patients on steroids. The treatment may improve survival in patients who are steroid ineligible or steroid refractory, but this needs to be further researched.

Extra Corporal Liver Support

Various biologic and non-biologic liver support systems are being developed and studied in AH. Extracorporeal cellular therapy (ELAD) is a biologic system that uses liver cells (C3Acells). These cells have anti-inflammatory and antioxidative properties that help regenerate the liver.^60,61,62 Non-biologic liver support devices use the concepts of plasma exchange and albumin dialysis. Some examples of such devices are single pass albumin dialysis (SPAD), molecular adsorbent recirculating system (MARS), and fractionated plasma separation and adsorption (PROMETHEUS). MARS therapy has been shown to decrease serum bilirubin and serum creatinine. It also leads to clearance of hepatic encephalopathy.⁶³ The favorable effects of albumin dialysis in patients with severe AH suggest that the procedure used alone or in combination with other pharmacological therapies may play a role in the future. However, prior to being used further it has to be proven to be effective in well-designed randomized controlled trials, especially in terms of improving both short- and long-term survival.⁶⁴ The outcome of ELAD depends on the severity of AH and organ dysfunction. Patients with acute renal failure, severe coagulopathy, age >50 and MELD >28 have worse outcomes with ELAD.⁶² ELAD can work as a bridge therapy for liver transplant in younger patients who do not have renal failure or severe coagulopathy.

N Acetyl Cysteine (NAC)

N Acetyl cysteine acts by replenishing glutathione levels, which tend to be depleted in AH. NAC alone is not an effective treatment for AH.^65,66,67 That being said, the combined use of NAC and steroids decreases the risk of infections and hepatorenal syndrome. Combination therapy also decreases short term mortality but has no long-term survival benefit.⁶⁸ Further studies are needed before making the combination therapy of NAC and steroids a standard of care in AH.

Stool Transplant / Fecal Microbiota Transplant (FMT)

Studies looking at healthy donor fecal microbiota transplant (FMT) have shown improved survival at one year in steroid ineligible patients.⁶⁹ In one trial, patients with severe alcoholic hepatitis were transplanted for seven continuous days with the goal of modulating patient gut bacteria. Microbiota analysis was subsequently performed, with similar profile found between donors and recipients at the one-year mark. Immune Modulation One potential therapy target is chemokines. These molecules, especially CCL20,⁷⁰ play an important role in alcoholic hepatitis due to upregulation. Targeting this molecule, along with IL8, is being studied in order to see if a safe and effective therapy may be developed. Secukinamab is an anti IL-17a monoclonal antibody, currently used for rheumatoid arthritis, that may play a role in AH.⁷ IL-10, anti-osteoponin, and anti-TNF agents are also being looked at to see if they might be effective against AH. Osteoponin is an extracellular protein matrix that is highly expressed in alcoholic hepatitis and may be a good potential target for treatment as well.⁷²

Granulacytapheresis

This is a technique in which granulocytes and monocytes are removed from patient blood. It is well tolerated, may be beneficial in steroid non-responders, and is under further study in AH patients.⁷³

CONCLUSION

Alcoholic hepatitis is a relatively common condition that can have deadly consequences for patients, and is burdensome for society at large given the loss of productivity and costs that are associated with it. Fortunately, research continues to elucidate the pathophysiology of the disease and this may potentially lead to new breakthroughs in treatment. Novel treatments such as FMT deserve further study, as does early transplantation. Despite these advances, nutrition and abstinence are two relatively simple interventions that need to be the cornerstone of any treatment regimen going forward.

Aspen Announces Publication of the Guidebook on Enteral Medication Administration

SILVER SPRING, MD – The American Society for Parenteral and Enteral Nutrition (ASPEN) announced the publication of the Guidebook on Enteral Medication Administration, a critical resource for healthcare providers managing patients who receive medications through their feeding tubes.

Upper Gastrointestinal Bleeding with Oral Anticoagulants

To compare the incidence of hospitalization for upper gastrointestinal bleeding in patients using individual anticoagulants with and without PPI cotherapy and to determine variation according to underlying gastrointestinal bleeding risk, a retrospective cohort study in Medicare beneficiaries was carried out between January 1, 2011 and September 30, 2015. The agents studied included apixaban, dabigatran, rivaroxaban, or warfarin, with or without PPI cotherapy.

Misoprostol and Aspirin-Induced Small Bowel Bleeding

A double-blind, randomized, placebo-controlled trial was carried out to determine whether misoprostol can heal small bowel ulcers in patients with small bowel bleeding who require continuous aspirin therapy. The study was prospective among 84 aspirin users who required continued aspirin therapy in Hong Kong and Japan.

Antibiotic Resistance in H. Pylori Infection

A systematic review and meta-analysis was carried out to assess the distribution of H. pylori resistance to commonly used antibiotics and to measure the association between antibiotic resistance and treatment failure.

Diverticular Hemorrhage and Anticoagulants