Frontiers In Endoscopy, Series #44

Radiofrequency Ablation for Biliary Disease

July 2018 • Volume XLII, Issue 7
Patrick Powers,Douglas G. Adler

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Biliary RFA has emerged as a viable method for the ablation and palliation of biliary strictures, and studies suggest that endobiliary RFA is a safe and feasible technique. In this article we discuss important issues for the clinician to be aware of: Adverse events common to endobiliary RFA, the effect of chemotherapy on survival, plastic vs metal stents and the continued investigation to further elucidate the efficacy of endobiliary RFA in the management of biliary strictures.

Patrick Powers MD, Douglas G. Adler MD, FACG, AGAF, FASGE, University of Utah School of Medicine, Gastroenterology and Hepatology, Utah School of Medicine, Salt Lake City, UT

INTRODUCTION

Biliary obstruction remains a common clinical compliant, and strategies to treat this such as ERCP have been widely employed. The majority of patients with biliary obstruction harbor an underlying malignancy, most commonly pancreatic adenocarcinoma and cholangiocarcinoma. Hepatocellular carcinoma, metastatic masses or adenopathy, gallbladder carcinoma, and ampullary carcinoma are also seen frequently.1 Surgical resection is the treatment of choice, and if possible leads to better long term outcomes.2,3 However, because of the insidious and progressive nature of these malignancies, the presentation and diagnosis often occurs late in the disease and most cases are surgically unresectable. Therefore, the palliative relief of biliary obstruction has become the standard of care, and has been shown to improve quality of life.3,4

The development of self-expanding metal stents (SEMS) has been shown to give symptomatic relief and offers improved quality of life. However, tumor ingrowth, overgrowth, and stent occlusion from sludge or stones can cause stent failure, often at a median time of 6-8 months.5,6,7 While most stent occlusions are treated by placement of a new stent within the old stent, interest in other approaches has resulted in the development of endoscopic strategies to relieve stent occlusion, including photodynamic therapy (PDT) and radiofrequency ablation (RFA).

In PDT, a photosensitizer is administrated 48 hours prior to the procedure and is taken up by tumor tissue. An ERCP-directed laser fiber is passed across the malignant stricture, and apoptosis is induced via specific light wavelengths. PDT has demonstrably improved both quality of life, and outcomes in malignant biliary obstruction. The photosensitizer is believed to possibly be preferentially absorbed by malignant cells, and so it may have the advantage of causing relatively little damage to nearby non-malignant cells. 8,9,10,11

Radiofrequency Ablation

Radiofrequency ablation utilizes an electric current to induce thermal coagulative necrosis of localized tissue. The circuit is composed of either a monopolar probe coupled with a dispersive electrode placed on the skin of the patient, or a local bipolar probe. The current alternates between probes at the frequency of radio waves, typically 400-600 hertz (Hz). Tissue is a poor electrical conductor, and so as the current flows it causes the target tissue to heat up to 50-100 degrees Celsius.12 Heat causes protein denaturation, followed by cell dehydration and coagulative necrosis. The heat generated is directly proportional to the current generated, and so tissue nearest the probe experiences the greatest rise in temperature. Necrosis causes eventual dehydration and charring with loss of the conducting ions within the cells. This leads to a rise in impedance, reducing the depth to which RFA can penetrate.12,13,14 One strategy to reduce this impedance is by using pulsed RFA, which allows the tissue to cool and rehydrate between pulses, allowing the current to travel deeper into the tissue. Another strategy is to use internally cooled RFA probes. In this case, the goal is to reduce the heat gradient between the probe and the tissue while maintaining current, thereby reducing charring, and allowing deeper penetrance of adequate heat to induce coagulative necrosis.14

RFA has also been proposed to stimulate systemic antitumor immunity. Theoretically, by exposing tumor antigen with modalities such as RFA, antigen presenting cells can direct the immune system against targets that would otherwise be hidden.15,16 Further research into the field of synergistic immunomodulation with RFA is ongoing.

Percutaneous or intraoperative RFA has been historically quite successful in the management of solid tumors including liver, breast, lung, and kidney. More recently RFA has been used in the management of various gastrointestinal disorders as well including Barrett’s esophagus, gastric antral vascular ectasia, and metastatic hepatocellular carcinoma.13 First described in 2011, Habib et al. developed a bipolar catheter that could be directed via ERCP to enter the biliary tree. Since its development, several groups have investigated the safety and efficacy of RFA in biliary obstruction. Its use has been described mostly in the management of malignant biliary obstruction, both before SEMS placement, and after SEMS occlusion. Newer uses are being investigated as experience with RFA grows.

ENDOBILIARY RADIOFREQUENCY ABLATION PROCEDURE

The Habib EndoHPB catheter (Habib EndoHPB, EMcision Ltd, London, UK) is an 8Fr catheter with two 8 mm stainless electrodes separated by 6 mm. The proximal end is connected to an electrosurgical generator, where the power and duration can be adjusted. The biliary tree is accessed via standard ERCP. Opacification of the biliary tree is used to demarcate the stricture location and size, and the guidewire is directed across the stricture. The RFA catheter is then threaded over a guidewire. Energy is supplied by the generator at desired specifications (typically 5-10 watts for 90-120 seconds with a 60 second cooling period). After RFA, the biliary tree is then swept via balloon to remove debris. Depending on the size and location of the stricture, multiple RFA applications may be required, and these may be to some extent overlapping. This is usually followed by the application of SEMS. If RFA is applied to an already obstructed stent, several applications may be required.13,14

RFA FOR MALIGNANT BILIARY STRICTURES

In the vast majority of patients, RFA is used in the setting of a malignant obstruction, either prior to SEMS placement or in an occluded SEMS that has developed tumor ingrowth or overgrowth. (Figure 1)

RFA Prior to Stent Placement

The first group to look at the use of RFA prior to SEMS placement in humans was Steel et al. in 2011. In this study, a total of 21 patients underwent RFA for malignant biliary stricture by either cholangiocarcinoma or pancreatic adenocarcinoma. At 30 days, there were no mortalities, and at 90 days 16 of the initial 21 patients were alive with patent stents. This paper introduced RFA as a relatively safe modality to reduce obstruction prior to SEMS placement.17

Four additional small studies from 2013 to 2015 also investigated the safety and feasibility of RFA in malignant biliary obstruction. In a retrospective study, Alis et al. investigated obstruction secondary to cholangiocarcinoma in 17 patients. Of this group, 7 did not have successful ERCP or endobiliary RFA, although the group did not describe the technical difficulties. Of the 10 remaining patients, 30-day mortality was 0%. Two patients developed ERCP-pancreatitis. The authors concluded that RFA was a safe modality for malignant obstruction, although there was a high rate of technical failure.18 A pilot study by Figueroa-Barojas et al. looked at 20 total patients (11 with pancreatic adenocarcinoma, 7 with cholangiocarcinoma, 1 intraductal papillary mucinous neoplasm and 1 metastatic gastric cancer). All 20 patients underwent successful RFA, and complication rates were similar to rates that had been published for ERCP with stent alone. With a 0% immediate and 30-day mortality, the group concluded that RFA was a safe, and technically feasible technique for malignant obstruction.19 In a 2014 study of 12 patients, Tal et al. investigated the safety of RFA in hilar tumors (mostly Klatskin Bismuth IV), followed by placement of plastic stents. RFA was technically successful in all cases, but there was a higher frequency of complications. Hemobilia occurred in three patients between 4 and 6 weeks: one of which was spontaneous, and two, which occurred during removal of the plastic stent. Two of these cases were fatal, and one was successfully treated with a SEMS. 30 and 90-day mortality were 8.3% and 50% respectively. Given their higher mortality and complication rate than prior studies, the group reported RFA as a technically feasible technique, but one that required further investigation with large controlled trials to avoid fatal complications.20 In a 12 patient case series, Laquiere et al. investigated the safety of RFA in a relatively homogenous group of patients with extrahepatic cholangiocarcinoma. Endobiliary RFA was technically successful in all cases. Within 30 days, there was one patient with sepsis thought to be secondary to bacterial translocation, and one patient with acute cholangitis secondary to stent migration. 30-day mortality was 0%. Patients were followed to 9 months and of the 12 patents, 6 received a second RFA session, 3 of which were due to acute stent obstruction with or without acute cholangitis, 3 of which were planned to prevent re-obstruction. This study demonstrated again that RFA was a safe technique for treatment patients with malignant obstruction, and suggested that scheduled repeat session may also be effective at preventing biliary re-obstruction.21

In 2014, Dolak et al. published a retrospective, multicenter study of 58 patients undergoing a total of 84 total RFA procedures to look at safety and feasibility.22 78 procedures were performed via ERCP and 6 were performed via a percutaneous approach. The patient population had varying malignancies (51 with biliary tract cancer, 4 with pancreatic cancer, and 3 with hepatocellular cancer), and over 50% had received other treatment modalities prior to RFA. The majority had SEMS placed (35 of 58 pts), and 19 received plastic stents. 30-day mortality was 1.7%, and 90 day mortality was 19%. Within 30 days, there 5 cases of cholangitis, three cases of hemobilia, two cases of cholangiosepsis, and one case each of gallbladder empyema, hepatic coma, and newly diagnosed left bundle branch block. The patient with hepatic coma had a fatal oucome. One patient had a severe complication of liver infarct, which was thought to be secondary to thermal damage to a segmental branch of the hepatic artery. The patient with hepatic coma Median survival rates were extrapolated to 10.6 months post RFA procedure, and 17.9 months from initial diagnosis. Median stent patency was found to be 115 days in plastic stents and 218 days in metal stents. This was the largest retrospective analysis of RFA to date, and while it again demonstrated RFA as a relatively safe option, the size of the cohort allowed the authors to suggest RFA as a way to improve survival and extend stent patency in malignant biliary obstruction.

While the above studies provide data regarding the safety and feasibility of RFA for malignant obstruction, several groups have investigated whether this procedure could impact stent patency and patient survival. To this end, Sharaiha et al. compared patients receiving RFA prior to SEMS placement to patients who received SEMS alone.23 Of 66 total patients, 26 underwent RFA prior to SEMS placement, and they were matched with 40 patients treated with SEMS alone. RFA was technically successful in all attempts. There were five adverse events in both groups including 3 with abdominal pain, one with pancreatitis, and one with cholecytitis. There was no difference in adverse events between the two groups. There was no significant difference in survival rates between the two groups. However, Multivariate Cox proportional analysis showed that RFA was an independent predictor of survival, with a hazard ratio of 0.29 (95% confidence interval 0.11-0.76). The following year, the same group retrospectively studied 69 patients: 45 with cholangiocarcinoma, 19 with pancreatic cancer, 2 with gallbladder cancer, 1 with gastric cancer, and 3 with liver metastases.24 These patients all underwent RFA in addition to stent placement for malignant biliary stricture, and were compared to Surveillance, Epidemiology, and End Results (SEER) database patients. In the study group, 78% had received prior or concurrent chemotherapy, and there was a mixture of plastic stents and SEMS. In the study group, the authors described survival rates of 14.6 and 17.7 months for pancreatic and cholangiocarcinoa respectively. These were significantly improved over SEER database survival rates: 5.9 months for pancreatic cancer and 6.2 months for cholangiocarcinoma. The authors concluded that their study suggested that RFA prior to stenting can improve survival rates. However, their study was limited in its retrospective nature, and use of historical data, necessitating larger and prospective trials.

Kallis et al. (2015) performed a similar study to assess the efficacy of RFA in biliary obstruction secondary to pancreatic adenocarcinoma.25 In this study, 23 patients receiving RFA prior to SEMS were matched with 46 controls receiving SEMS alone. 30 day mortality was 0%, and adverse events were limited to one case each of hyperamylasemia and antibiotic-responsve cholangitis. Of note, the two groups were stringently matched based on demographic characteristics and chemotherapeutic regimens. The group found that there was a statistically significant difference in survival: median survival 226 days with the RFA group vs. 123.5 days in the SEMS only group. Multivariate analysis revealed that RFA afforded an early survival benefit, but this was lost after the 180 day mark. They also found that stent patency was not significantly improved with RFA, and that a majority of patients died from carcinomatosis rather than complications arising from biliary obstruction. The authors concluded that while there was a survival benefit associated with RFA, they could not necessarily connect it to improved stent patency. While their data could not adequately demonstrate improved stent patency, just 9 of 23 patients in the RFA group, and 14 of 46 patients in the control group reached the end point of stent occlusion due to mortality. The high mortality rate of these malignancies makes correlation between patency and survival inherently difficult.

Dutta et al. published a study that also looked at RFA vs stenting alone. 26 This was a smaller study, with 15 patients in the RFA arm, and 16 receiving stent alone, and compared various malignancies causing biliary obstruction. RFA median survival was 220 days vs 106.5 days in those receiving SEMS alone. Multivariate analysis was able to demonstrate a survival advantage with RFA independent of age, malignancy type, or obstruction site. Although many of the above studies were able to demonstrate statistically significant efficacy, they were limited in their retrospective nature, and small sample size.

In an attempt to combine the data from several of these smaller studies, Sofi et al. performed a meta-analysis to evaluate survival and stent patency benefits, as well as complication rates in RFA for malignant biliary strictures.27 Their study population included 505 patients from nine studies, and had patients receiving both percutaneous and endoscopic RFA. The authors found that stent patency was significantly improved by a mean of 50.6 days in the RFA group. Survival rates were significantly better as well with a median 285 days in the RFA group versus 248 days in the controls. When evaluating for adverse events, the RFA group was found to have significantly more episodes of abdominal pain, but all other common adverse events (cholangitis, acute cholecystitis, acute pancreatitis, and hemobilia) were not significantly different between the two groups. Sofi et al. concluded that while their pooled data was promising, they acknowledge the need for larger prospective trials to fully elucidate the efficacy of RFA and the correlation between stent patency and survival.

In a randomized, controlled, single-center prospective study, Yang et al. investigated the use of RFA in 65 patients with unresectable extrahepatic cholangiocarcinoma.28 The patients were randomized to RFA combined with plastic stenting, or stenting-only. Of note, patients receiving chemotherapy, and those with Bismuth types III and IV lesions were excluded from the study. All patients received endoscopic ultrasound prior to intervention to fully characterize the lesions, and had repeat RFA at a mean of 6 months after initial RFA. Adverse event rates were not significantly different between the two groups, and included 3 cases of acute cholangitis, and one each of acute pancreatitis and hemorrhage. The authors found that stent patency was significantly improved with RFA (6.8 months vs 3.4 months). Survival rates were also significantly improved in the RFA group with a mean survival of 13.2 months vs 8.3 months in the stent-only group. The authors concluded that RFA prior to stenting can significantly improve both survival and stent patency in extrahepatic cholangiocarcinoma.

RFA vs PDT Prior to Stent Placement

In the only study to date to directly compare PDT to RFA prior to stent placement, Strand et al. performed a retrospective analysis of 48 patients with unresectable cholangiocarcinoma. 29Of these patients, 16 received RFA, and 32 underwent PDT, followed by either plastic stent or SEMS. The PDT group received primarily plastic stents (90.6%) whereas the RFA group received primarily uncovered SEMS (68.7%). Tumor type, and percentage of patients receiving chemotherapy were not significantly different between the two groups. Median survival rates were 9.6 months in the RFA arm, and 7.5 months in the PDT arm, which were not significantly different. In general, adverse event rates were comparable in the two arms, although stent occlusion and cholangitis were significantly increased in the RFA arm. The authors concluded that while their study was limited in its retrospective nature and small sample size, it suggested that RFA and PDT were comparable methods for the palliative treatment of unresectable cholangiocarcinoma. They also discussed the relative advantages and disadvantages between the two methods. While PDT does potentially preferentially select malignant cells, it requires a pre-treatment with photosensitizer and subsequent avoidance of sun exposure for at least 48 hours. The continued comparison between these two methods requires further, large, prospective trials.

RFA for Occluded SEMS

Pozsar et al. were the first to report the use of RFA for occluded biliary SEMS in 2011.30 In this small trial, 5 patients with occluded SEMS secondary to cholangiocarcinoma were treated with RFA. In all patients, biliary obstruction was successfully relieved without complication. The median stent patency after RFA treatment was 62 days, and the authors concluded that RFA was a relatively safe method for treating occluded SEMS. In a larger trial, Kadayifci et al. investigated the use of the RFA in 50 patients with occluded SEMS.31 In their study, patients with occluded SEMS were split into two groups. The first group had a new, plastic stent placed within the occluded stent. The second group had RFA to the occluding tissue, without subsequent stent placement. In the RFA group, only 56% had successful ablation, defined as >80% obstruction removed. In the remaining 44%, RFA was considered to have failed, and plastic stents were placed. Analysis of RFA failure found that pancreatic cancer and distal obstruction were predictive of RFA success. Survival rates were not significantly different between the two groups. However, stent patency was found to be significantly improved in the successful ablated group when compared to those with stent alone. The authors concluded that while RFA success was dependent on tumor type and location, when >80% ablation was achieved, there was a demonstrable improvement in stent patency compared to re-stenting alone.

Percutaneous Intraductal RFA

While not the focus of this review, it should be noted that percutaneous intraductal RFA has been described in the literature as a viable tool. Several studies have looked at the use of percutaneous intraductal RFA in malignant biliary strictures. In general, these groups have shown this technique to be safe and feasible. 32,33,34,35 Larger trials, such as those by Wu et al. and Cui et al., have demonstrated a significant improvement in both stent patency and survival.36,37 Their outcomes were comparable to those found in endoscopic RFA trials discussed above.

OTHER USES FOR ENDOBILIARY RFA

Ampullary Adenoma with Intraductal Extension Ampullary adenomas are typically treated successfully with endoscopic or surgical resection. However, when the adenoma extends into the biliary tree itself, it often presents a therapeutic challenge for clinicians. (Figure 2) Suarez et al. investigated the use of RFA for the treatment of ampullary adenomas with intraductal extension in a 4 patient case series.38 Three of the patients had benign ampullary adenomas, and the fourth had an ampullary adenoma with a foci of adenocarcinoma. All cases were technically feasible, and aside from a delayed biliary stricture in one patient, there were no immediate adverse events. Those with benign adenomas had no recurrence of ampullary lesions, but the patient with adenocarcinoma developed overt invasive ampullary cancer and passed away from their disease, demonstrating the limitations of this technology. Rustagi et al. investigated the use of RFA in ampullary neoplasms in a slightly larger trial of 14 patients.39 The group had mixed pathology, including two adenocarcinomas, and a mix of tubulovillous and tubular adenomas. There were also varied treatment strategies, with half receiving RFA-only, and half receiving a mix of RFA in combination with argon plasma coagulation, PDT, or electrocoagulation. Despite the heterogenous nature of the cohort, the authors reported 92% of patients with successful eradication of disease after a 16 month median follow up period. Adverse event rates were high at 43%, the majority of which were benign common bile duct strictures. These studies demonstrate that RFA has potentially beneficial applications in the management of ampullary lesions, but will require more robust, standardized trials to further elucidate its clinical utility.

Benign Biliary Strictures

As several groups reported the safety and efficacy of RFA in malignant biliary strictures, this technique was proposed by some as a means to manage benign strictures as well. Benign strictures are fairly heterogenous in nature, resulting from multiple etiologies including liver transplant, pancreaticobiliary surgery, and any condition causing chronic inflammation. The majority results in stiff fibrinous tissue, histologically far different than malignant strictures. Typically managed by dilatation and multiple stenting procedures, up to 40% of strictures are refractory to current endoscopic techniques. Hu et al. investigated the use of RFA in 9 patients with benign biliary strictures.40 All patients had successful RFA followed by balloon dilatation. No serious adverse events occurred, and all patients achieved immediate improvement or resolution of their benign strictures. There were variable follow up times, but at a median of 12.6 months, 4 patients had achieved full stricture resolution without need for further stenting. The authors concluded that RFA was a feasible and safe method for benign biliary strictures, but refrained from making conclusions on efficacy given the relatively small and heterogenous study design. Swine models are currently being developed, and further studies are needed to investigate the use of RFA in benign biliary strictures.

CONCLUSION

Biliary RFA has emerged as a viable method for the ablation and palliation of biliary strictures. Data thus far has been largely limited to retrospective analyses, but the results from these studies suggest that endobiliary RFA is a safe, and feasible technique. In unresectable malignancy, RFA may confer both survival and stent patency benefits, but further investigation is required before definitive statements can be made. Clinicians should be aware of the adverse events common to endobiliary RFA, including abdominal pain, cholangitis, acute cholecystitis, stricture formation or worsening, and hemobilia. As experience with endobiliary RFA grows, further questions remain; including the effect of chemotherapy on survival and how plastic vs metal stents may alter stent patency duration. Continued investigation with large, randomized, controlled, prospective trials is required to answer these questions and further elucidate the efficacy of endobiliary RFA in the management of biliary strictures.

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A Case Report

Gastrointestinal Bleeding Due to a Post Transplant Lymphoproliferative Disorder: A Complication of Renal Transplant

June 2018 • Volume XLII, Issue 6
Marianna Mavilia,Leon Averbukh,Michael Einstein

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Post-transplant lymphoproliferative disorder (PTLD) is a rare complication after solid organ or stem cell transplant, which is thought to be related to the immunosuppression medications used in this patient population. Although the gastrointestinal tract is a common location for proliferation, gastrointestinal bleeding (GIB) is rare in PTLD. We present a patient with history of renal transplant treated with prednisone, tacrolimus and azathioprine presenting with GIB. She was found to have multifocal jejunal B cell lymphoma. Outcomes in PTLD treated with immunosuppression reduction and chemotherapy are promising with response rates of 82-90%. Therefore, post-transplant care must include careful surveillance for PTLD.

Marianna Mavilia DO1 Leon Averbukh DO1 Michael Einstein MD2 1University of Connecticut, Department of Medicine, Farmington, CT 2Hartford Hospital, Department of Gastroenterology and Hepatology, Hartford, CT

INTRODUCTION

Post-transplant lymphoproliferative disorder (PTLD) is any proliferation of lymphocytes occurring after solid organ or allogeneic stem cell transplant due to immunosuppression (IS) therapy.1 The most common extranodal location for PTLD is in the gastrointestinal tract.2

On average, PTLD occurs in 1-3% of renal transplant cases, though percentages vary based on patient’s age, type of transplant, and IS regimen.2 There is a higher frequency of PTLD amongst patients transplanted for autoimmune etiologies.1 This is thought to be due to more intensive immunosuppression regimens used in this population.1 The presentation of PTLD is variable. B symptoms are seen in about 49% of cases.2 The initial presentation may be complications such as mass effect of tumor, gastrointestinal obstruction, perforation, or gastrointestinal bleeding (GIB).2 GIB is a rare presentation with only a few case reports to date in the literature. PTLDs were initially thought to occur within 1 year of transplant, however studies have shown that more than 70% cases occur later.1,3 Here we present a case of multifocal small bowel B cell lymphoma occurring 16 years after renal transplant. Case Description

A 48 year-old female with history of end stage renal disease secondary to membranous glomerulonephritis, with living donor renal transplant 16 years prior, presented to the emergency department with generalized abdominal pain and fatigue. She reported intermittent dark-colored stools, generalized weakness, and a 10-lb weight loss in the preceding three months. She denied use of nonsteroidal anti-inflammatory drugs, alcohol and tobacco. The patient was on prednisone 5 mg daily, tacrolimus 3 mg twice daily, and azathioprine 50mg daily for IS. She had no significant family history. Physical exam was benign except for positive occult blood on rectal exam. Laboratory workup revealed hemoglobin of 7.4 mg/dL, which was decreased from her baseline of 10 mg/dL three months prior. She also had mildly elevated BUN and creatinine at 30 mg/dL and 2.5 mg/dL respectively from a baseline creatinine of 1.4-1.6 mg/dL. Renal ultrasound with doppler was normal. Patient underwent an esophagogastroduodenoscopy and colonoscopy, which demonstrated only mild gastritis. Further workup with capsule endoscopy was positive for an ill-defined lesion in the proximal jejunum. Based on these results, the patient underwent push enteroscopy and was found to have an area of patchy inflammation with congestion and shallow ulcerations in the proximal jejunum (shown in Figure 1). Biopsy of this lesion showed focal ulceration and necrosis of the mucosa with underlying cellular infiltrate. The infiltrate was comprised mainly of large abnormal cells with scattered small lymphocytes and eosinophils (Figure 2A). The neoplastic cells were positive for CD20 (Figure 2B), CD79a (Figure 2C), PAX-5 (Figure 2D), and expressed monotypic lambda light chains (Figure 2E). The Ki-67 proliferation index was elevated at greater than 90%. The specimen was weakly positive for CD30 and negative for CD15. Due to strong suspicion for Epstein-Barr virus (EBV)-positive mucosal ulcers, EBV testing was conducted with both in situ hybridization for EBER and immunohistochemistry for EBV-LMP, though both were negative. Taken together, the above findings were consistent with monomorphic PTLD with features of diffuse large B-cell lymphoma.

The patient was subsequently referred to oncology for staging where a bone marrow biopsy was found to be normocellular with non-neoplastic lymphocytes on flow cytometry. Positron emission test/computed tomography (PET CT) demonstrated multifocal areas of intense hypermetabolism involving the GI tract including the distal gastroesophageal junction and multiple foci within the jejunum (Figure 3). There was no FDG avid lymphadenopathy. Although some bowel uptake can be physiologic, these findings were suggestive of multifocal small bowel disease given her biopsy-proven lymphoma in the jejunum.

Our patient’s IS dose was minimized with reduction of tacrolimus to 1mg twice daily and azathioprine was stopped. She was treated with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). After initiation of treatment, the patient continued to have evidence of GIB with melena and slowly dropping hematocrit. Her blood counts were monitored closely and she was transfused as needed. PET/CT was performed after 3 cycles of chemotherapy, revealing resolution of the jejunal lesions and no new areas of abnormal FDG uptake. Her blood counts stabilized as therapy progressed.

DISCUSSION

GIB in a post-transplant patient is a complicated issue. With renal transplant specifically, renal dysfunction alone increases risk of GIB 8.7-fold, as uremia and nitric oxide accumulation contribute to impaired platelet function.4 Additionally, immunosuppressive agents can lead to GIB. Steroids and tacrolimus can impair gastrointestinal epithelium, thus predisposing patients to ulceration or other mucosal injury.5 Other agents, such as azathioprine, can cause thrombocytopenia.6 As demonstrated in this case, IS also predisposes patients to the development of PTLD which can cause GIB.

The pathogenesis of PTLD is not completely understood. EBV, known to provoke malignant transformation of B cells, is a major risk factor for the development of PTLD, accounting for more than 70% of cases.3 In the absence of EBV, as in our patient, the pathogenesis is not well understood. This patient was on an intensive IS regimen with three agents, which subjected her to increased risk for PTLD. IS, used for its inhibition of T cell function to prevent graft rejection, also allows for uncontrolled lymphoproliferation with potential for malignant transformation.

Mortality rates for PTLD ranges from 50-70%,7 with five year survival rate of 53-59%.3 Those with EBV positivity carry an unfavorable prognosis.9,10 Our patient possessed features thought to be good prognosticators, including female gender and inclusion of tacrolimus or azathioprine in IS regimen.7 These specific agents have more favorable prognosis as compared to patients on other IS regimens.

Treatment of PTLD requires a balance between eliminating the malignancy while also preserving the graft, with the key being dose reduction of IS.7 This allows for the re-engagement of the natural anti-tumor actions of the immune system. However, IS reduction is only effective in 10% of cases. Rituximab alone or combined with CHOP is an alternative in high risk cases.7 R-CHOP has a response rate of 82-90%.7 Given this favorable response to treatment, early identification of PTLD is key. With increasing number of solid organ transplants, it is important to consider PTLD as a potential complication in this population.

Acknowledgements A special thank you to Dr. Hassan Dalal of the University of Connecticut Department of Pathology for providing pathologic figures for this case.

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Nutrition Issues In Gastroenterology, Series #176

Blenderized Feeding Options- The Sky’s the Limit

June 2018 • Volume XLII, Issue 6
Lisa Epp

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The use of blenderized tube feeding (BTF) continues to increase in popularity, among people of all ages, in the United States and across the globe. It will likely continue to increase in popularity as more studies are published. Clinicians have a responsibility to include assessment of BTF use in all home enteral nutrition (HEN) patients in order to provide guidance for appropriate recipe development and monitoring. This article is intended as a guide to empower clinicians to aid patients in the use of BTF.

The use of blenderized tube feeding (BTF) continues to increase in popularity, among people of all ages, in the United States and across the globe. BTF is the process in which foods and liquids are blended together and given via an enteral feeding tube. This may be in place of, or in addition to/combination with, commercially available enteral formulas. Commercial enteral formulas (CEF) have precise amounts of micronutrients and macronutrients and are prepared in a sterile fashion; unlike BTF, which is usually prepared at home in the family kitchen.

Lisa Epp, RDN, CNSC, LD, Assistant Professor of Nutrition, Mayo Clinic College of Medicine and Science, Division of Endocrinology, Mayo Clinic, Rochester, MN

INTRODUCTION

Home enteral nutrition (HEN) is when tube feeding is given in the home setting. A publication by Mundi, et al. reported that more than 400,000 people (189,036 pediatric & 248,846 adult patients) are receiving HEN in the United States as of 2013.1 This is a significant increase from previously reported numbers in 1992, when an estimated 152,000 people were on HEN.2 In recent decades, the standard process for HEN was for a clinician to prescribe a CEF in the hospital and the patient would continue its use at home.

the last 10 years consumer demand for “natural” and organic foods has increased, and the HEN population is no exception. One study suggests that as many as 55.5% of adult HEN users use BTF in varying amounts, and 90% expressed the desire to use BTF if given adequate information.3 Yet another survey of 216 adult and pediatric Oley Foundation members indicated it could be as high as 90% in some populations, especially among children.4 The Oley Foundation is a non-profit organization that supports people at home on parenteral nutrition and/or enteral nutrition (oley.org). Adults who responded to the Oley survey indicated 65.9% use BTF.4 In a survey of 433 parents of tube fed children, 49.5% indicated they used BTF for their child.5 However, a concerning finding of this survey was that only 50% of respondents used a nutrition professional to help create recipes.5 Given that only 50% of parents are getting assistance from a nutrition professional, clinicians have a responsibility to identify those who are utilizing BTF in order to provide support and ensure HEN patients are meeting their nutrition needs.

A recent study of 212 head and neck cancer patients demonstrated that many are using BTF even when it is not prescribed.6 In this cohort, 112 received CEF, 69 patients voluntarily switched to BTF with unknown ingredients and 31 were prescribed BTF due to lack of health insurance coverage. The results showed that those using BTF did not receive adequate nutrition support and had a decrease in fat free mass. One could argue that since patients changed to BTF on their own, they did not have the clinical support or guidance needed to create nutritionally complete recipes with adequate calories. This is a prime example of why clinicians must be open to the use of BTF.

the previously mentioned surveys, common reasons given for using BTF were:

  • 1. “It’s more natural”
  • 2. “I can tolerate it better”
  • 3. “I like to eat what my family is eating”

Additionally, patients may prefer whole foods, organic, non-GMO, allergen free ingredients. Another reason for using BTF is CEF intolerance, such as reflux, constipation, diarrhea or fullness. Finally, some patients just do not have insurance coverage or adequate funds for commercial enteral formulas. BTF has the potential for allowing each patient’s nutrition needs to be met with individualized medicine.

Despite a patient’s desire to use BTF, some health care professionals hesitate to support its use. A survey of registered dietitians showed that the use of BTF is largely patient/family driven, but 28% of registered dietitians surveyed felt they needed more information about using BTF in clinical practice.7 Some clinical hesitations may include increased clinician time, potential for increased microbial contamination,8-9 increase in tube clogging and variability in nutrition composition.

At this time there is a small body of evidence that indicates that BTF may help with EN intolerance such as reflux, volume intolerance and bowel issues. With the reemergence of BTF, additional research is underway and this body is evidence is growing. In a study of 33 children, 52% of those given BTF had a reduction in gagging, 73% had a decrease in overall GI symptoms, and 57% had an increase in oral intake; no child had worsening symptoms.10 In another study, 10 children with short bowel syndrome were given formula with real food ingredients; 9 experienced an improvement in their stool habits and were able to wean off elemental formula.11 In a third study,18 infants with diarrhea were randomized to BTF vs. semi-elemental formula, and those on BTF experienced improvement in diarrhea and weight gain compared to those on semi-elemental formula.12 Lastly, a recent publication showed that children who were given BTF had decreased vomiting along with an increase in the bacterial diversity of their stool.13 These studies were all done in the pediatric population; however one study in adult patients included a group of 178 elderly individuals, 5 of which were on enteral feeding via percutaneous endoscopic gastrostomy (PEG).14 Those with a diverse diet had the healthiest gut microbiome, while those on a single formula had increased frailty.

remainder of this article is intended as a guide for clinicians wanting to help their patients utilize BTF if desired. Considerations before starting BTF:

  • Does your patient have a 14 French or greater size feeding tube?
    • Smaller tubes may work with thinner blends
  • Is the stoma mature in case the tube does become clogged?
    • A tube in a mature stoma can be changed more easily if needed
    • Some patients may benefit from BTF at initial tube placement and should be considered on a case by case basis.
  • Can your patient tolerate bolus feeding since food can only be held safely at room temperature for 2 hours?15
    • More information is needed on the use of BTF in post pyloric feeding tubes

Tools needed:

  • Commercial grade blender such as Vitamix®(vitamix.com), Blendtec® (blendtec.com) or Ninja® (ninjakitchen.com)
  • O ring syringes (Figure 1)
  • Large bore gravity bags (Figure 2)
    • Feeding pumps may not work well due to decrease in accuracy and motor failure
  • Straight bolus extension set for low profile tubes (Figure 3)
  • Bolee bag with bolink (Figure 4)
  • Nutrition professional involved
  • Plan for monitoring and evaluation

There are a variety of ways to develop BTF recipes; including using food exchanges, standard recipes or the plate method with family meals. Table 1 shows a 500 calorie recipe that is easy to double, triple or quadruple as needed to meet estimated calorie needs with balanced macronutrients. Using food exchanges makes it easy to choose foods that are available in the home to create a variety of recipes. Tables 2 and 3 provide sample standard recipes for approximately 1000 and 1600 calories. Lastly, reviewing the MyPlate Daily Checklist (choosemyplate.gov)16 is a great way to determine the number of servings of each food needed in the blend at a given calorie level.

Many children and adults use BTF due to enteral formula intolerance. Therefore, these patients may not be able to tolerate large volumes of feeding at one time. Table 4 gives examples of nutrient dense foods in each food group that may help decrease overall volume intake while still providing adequate calories. Table 5 provides options to “exchange” foods to increase the variety of the blenderized meals.

Some patients may use commercial food-based enteral formulas for some or all of their nutrition intake. See Table 6 for a variety of available products. These products may make it easier to travel or be away from home since they are shelf stable and do not require preparation, or refrigeration until opened.

is important to note that BTF is approximately 70-75% fluid. Therefore, extra fluid will likely be needed to meet hydration needs. Fluid can either be mixed into the recipes or given as boluses between feedings. It is also important to review micronutrient profiles of the recipes as homemade blends tend to be low in sodium, and salt may need to be added in some cases. A multivitamin/mineral, calcium, vitamin D or iron supplement may be needed, but should not be necessary if the recipes contain a wide variety of foods. Routine multivitamin/mineral use is not usually indicated if a variety of foods are used. Monitoring patients as they transition onto BTF is essential, and when they are tolerating goal feedings these patients should be followed in the same fashion as any other HEN patient. Labs should only be done when relevant to the clinical situation and are typically not routinely monitored.

SUMMARY

Blenderized tube feeding use has increased over the recent years, and will more than likely continue to increase in popularity as more studies are published. While patients are interested in using BTF for a variety of reasons, clinicians remain hesitant to support its use. We have a clinical responsibility to include assessment of BTF use in all HEN patients in order to provide guidance for appropriate recipe development and monitoring. This article is meant to increase awareness of the widespread use of BTF and to help empower clinicians to aid patients in its use.

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The Microbiome And Disease, Series #5

The Microbiome, Viscerosensory Signaling and Autism

June 2018 • Volume XLII, Issue 6
Daniel Frochtzwajg,Sabine Hazan

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Throughout this series we have pointed to evidence of an increasingly complex understanding of the relationship between the gut, its commensal bacterial composition, and its link to various pathological states within different organ systems. Here we will briefly discuss the emerging research that demonstrates the connection between gut microbes and the nervous and immune systems as well as how disproportional bacterial concentrations may be implicated in Autism and other neuropsychiatric ailments.

Daniel Frochtzwajg, DO, Research Assistant, Ventura Clinical Trials, Ventura, CA Sabine Hazan, MD, Gastroenterology/Hepatology/Internal Medicine Physician, CEO, Ventura Clinical Trials, CEO, Malibu Specialty Center, Ventura, CA

Throughout this series we have pointed to evidence of an increasingly complex understanding of the relationship between the gut, its commensal bacterial composition, and its link to various pathological states within different organ systems. Paramount in our articles has been a theme of holistic interconnectedness. The relationships between the gut microbiome and the disease states already discussed are not isolated but are inextricably linked. Here we will briefly discuss the emerging research that demonstrates the connection between gut microbes and the nervous and immune systems as well as how disproportional bacterial concentrations may be implicated in Autism and other neuropsychiatric ailments.

Contemporary research has shown that gastrointestinal (GI) infections lead to behavioral changes in mice and that the immune system affects mood and learning.2,5,12 In turn, depression and stress can cause changes in immune functioning.5 The former relationship, that of infection influencing behavior, was observed in a study by Lyte et al. in 1998. Researches noted increased anxiety in mice after the per-oral administration of Campylobacter jejuni, as compared to saline treated mice.11 Also of note was the lack of bacteria or pro-inflammatory cytokines found in the systemic circulation of the C. jejuni-treated mice. This finding was a springboard for the investigation of intestinal viscerosensory nerves as a possible conduit between the gut and the brain and behavioral responses. Within the gut, there are two types of viscerosensory nerves, intrinsic and extrinsic. Intrinsic nerves control motility and secretion, but do not directly convey signals to the central nervous system. Extrinsic nerves, including the vagus nerve and the spinal visceral nerves communicate with the CNS, innervate the intrinsic nerves, and contact lymphoid tissue in the subepithelium.5 To firmly establish the connection between the immune system, infection, and changes in behavior, Goehler et al. and subsequently Lyte et al. demonstrated evidence of c-Fos, an early gene product and marker of cell “activation”, in the vagal neurons of mice after inoculation with Campylobacter jejuni or Citrobacter rodentium, respectively.5,6,10 Another intestinal-CNS link was elucidated by Castex et al. in 2005. In this study, researchers noted c-Fos expression in specific brain regions in rats in response to intestinal ischemia. Furthermore, they found that intraperitoneal administration of ondansetron or perivagal capsaicin attenuated c-Fos expression, implicating 5-HT3 in the immune “activation” of the viscerosensory nerves.1 A number of other proinflammatory mediators/receptors have also been identified as possible players in the intestinal activation of vagal/spinal nerves. These include: Bradykinin, prostaglandins and leukotrienes, ATP and adenosine, vanilloid receptors, proteinase-activated receptors, and nerve growth factor (NGF).9 Vagal fibers also express toll-like receptors (TLRs), specifically TLR-4 on their surface, which is known to respond to bacterial lipopolysaccharide.7

The established paradigm demonstrating a behavioral response to intestinal bacteria, bacterial products, and mechanical stimuli logically suggests that some neuropsychiatric disorders may be, at least in part, due to derangements in the human intestinal microbiome. The relationship between irritable bowel syndrome (IBS) and depression and anxiety are widely known, and one can imagine that other intestinal insults may be responsible for various neurologic and/or psychiatric conditions and vice versa. In fact, there is evidence that predictable gut microbiome derangements may contribute to Autism Spectrum Disorder (ASD), as GI symptoms are increasingly associated with autism.3,4 Per the most recent CDC statistics, roughly 1 in 59 children are affected by ASD and the worldwide prevalence is somewhere between 1-2%; ASD is about 4 times more likely to be identified in boys as compared to girls.13 In a very recent study by Finegold et al. published in Anaerobe, researchers studied stool specimens from 33 autistic children ages 2-9 with intestinal symptoms and 13 control children without autism or GI upset. Results showed that the intestinal microbiome of autistic children with GI disease was colonized by proportionally higher counts of Clostridium perfringens. In addition to the statistically significant higher raw number of C. perfringens colony forming units, it was also noted that children with ASD harbor significantly more of the C. perfringens responsible for beta2-toxin production, as opposed to colonies producing other C. perfringens toxin genes.

Diets including specific probiotics have been shown to inhibit visceral pain caused by colonic distension.8 We have discussed the commonality in viscerosensory afferents. If alterations in diet can mediate visceral pain, it is likely that further research will lead to dietary and pharmacologic interventions aimed at the microbial disproportions associated with ASD and other neuropsychiatric illnesses.

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Dispatches From The Guild Conference, Series #13

Routine Health Maintenance and Disease Prevention in Patients with Inflammatory Bowel Disease

June 2018 • Volume XLII, Issue 6
Sean Fine,Adam S. Cheifetz

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Disease prevention and health maintenance is crucial, however patients with inflammatory bowel disease (IBD) do not receive the same rate of preventative interventions as the general population. This article highlights recommendations regarding health maintenance issues in patients with IBD including vaccinations, screening for colorectal, skin and cervical cancers, screening for osteoporosis and guidance on smoking cessation.

Disease prevention and health maintenance is crucial, however patients with inflammatory bowel disease (IBD) do not receive the same rate of preventative interventions as the general population. Vaccine preventable illnesses affect patients with IBD at a higher rate secondary to chronic illness and immunosuppression, yet many patients with IBD go unvaccinated. A lack of awareness regarding the significance of vaccinations, poor insight about the safety, and ambiguity about the gastroenterologists’ role in providing vaccinations may be contributing factors to the lower vaccination rates. Since patients with IBD often identify their gastroenterologist as their primary care provider, gastroenterologists need to specifically define and help coordinate the unique needs of these patients with other healthcare providers. This article highlights recommendations regarding health maintenance issues in patients with IBD including vaccinations, screening for colorectal, skin and cervical cancers, screening for osteoporosis and guidance on smoking cessation.

Sean Fine, MD, MS, Director, Inflammatory Bowel Disease Center, Alpert Medical School, Brown University, East Providence, RI Adam S. Cheifetz, MD, Director, Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center, Associate Professor of Medicine, Harvard Medical School. Boston, MA

INTRODUCTION

Inflammatory bowel disease is a chronic gastrointestinal disease that includes both ulcerative colitis (UC) and Crohn’s disease (CD). The course of these diseases is characterized by intermittent relapses. Agents used to manage more aggressive disease include corticosteroids, immunomodulators and biologic agents. It is now recognized that patients with IBD are at an increased risk for a number of different health issues that include infections, osteoporosis, depression, skin and colorectal cancers. The importance of health maintenance and prevention has emerged as a crucial objective in the overall delivery of care. Patients with IBD frequently have a strong relationship with their gastroenterologist and often turn to them for primary care needs and questions.1 However, data has shown that patients with IBD get less preventative and health maintenance care than non-IBD patients of the same age.2 This in part may be due to the fact that the gastroenterologists do not feel it is their job as the specialist, and the primary care physicians often feel uncomfortable managing these issues in patients who are often immunocompromised. It is therefore important for both the gastroenterologist and primary care physician to work closely together to ensure these preventive interventions are carried out properly.

Vaccinations

Though patients with IBD are at risk for infectious complications secondary to the disease and immunosuppression from medical therapy, they tend to be under vaccinated.3 The reasons for these low vaccination rates are likely multifactorial. Gastroenterologists have reported a lack of knowledge about the importance of vaccinations in this group of patients.4 Furthermore, gastroenterologist often do not have the vaccines available at their medical practice and feel it is the job of the primary care physician to administer vaccinations. Another barrier to vaccination often raised by patients is the concern of vaccines causing or exacerbating a flare. Fortunately, vaccines have not been shown to lead to flares in patients with underlying rheumatologic diseases or IBD.5,6 Patients with IBD who were given the influenza vaccine were not found to have an increased risk for disease flare within four weeks of its administration.7 Similarly, another study that included 43 patients with IBD on thiopurines did not observe any increase in disease severity attributable to vaccinations.8 Therefore, inactivated vaccinations should not be withheld from patients for the fear of causing a disease flare.

National guidelines for age appropriate vaccinations should be implemented for patients with IBD, with special considerations given to those who are on, or planning to initiate, immunosuppressive therapy. Luckily, most patients in the United States will have received routine childhood vaccinations. For patients who need to begin treatment with immunosuppressive therapy, delaying live vaccines in order to timely start treatment will be necessary.9

All patients with IBD, regardless of immunosuppression, should receive inactivated vaccines (Table 1). The level of immunosuppression will dictate which patients should receive live vaccines. Typically, the level of immunosuppression has been broken down into “low” and “high.” Patients on low-level immunosuppression can safely receive live vaccines while those on high-level should avoid live vaccines. “Low-level” immunosuppression is defined as patients receiving a daily dose of systemic corticosteroids for ≥14 (20mg/day equivalent and within three months of stopping), methotrexate ≤0.4 mg/kg/week and within three months of stopping, azathioprine ≤3.0 mg/kg/day, and 6-mercaptopurine ≤1.5mg/kg/day and within three months of stopping.10 Patients on the typical IBD doses of methotrexate and thiopurines fall into this category. The Infectious Disease Society of America guidelines consider all patients on anti-tumor necrosis factors (anti-TNF) to have high level immunosuppression and should not receive live vaccines. These guidelines were written prior to the availability of vedolizumab and ustekinumab, but avoidance of live vaccines should likely still apply to ustekinumab. And, given the gut selectivity of vedolizumab, oral live vaccines should probably be avoided.

Inactivated Vaccinations
Influenza Vaccination

Influenza infection may result in serious life threatening illness and therefore it is recommended that all immunosuppressed patients receive the vaccine.11 Patients with IBD are felt to be at an increased risk for infection regardless of immunosuppressive treatment.12 Currently it is recommended that the injectable forms of the influenza vaccines be given, not the live attenuated nasal spray.13 Yearly vaccination is required secondary to antigenic drift of the virus in order to best provide protection. It is of value to discuss the importance of receiving the influenza vaccination with all patients with IBD because even a partial, blunted response may provide some degree of protection.14,15

Pneumococcal Vaccination

Pneumococcal pneumonia is more prevalent in patients with IBD compared to age-matched controls16 and patients with IBD who are hospitalized secondary to pneumonia tend to have worse outcomes.17 Certain risk factors such as proton pump inhibitors, anti-TNFs, narcotics, and steroids appear to increase this risk. Recent guidelines recommend that all immunosuppressed patients with IBD receive immunization against pneumococcus, ideally prior to starting immunosuppression.18 The typical vaccination schedule is to receive a single dose of PCV13 (pneumococcal conjugate vaccine), followed by the PPSV23 (pneumococcal polysaccharide vaccine) 2-12 months later. If the patient has already received the PPSV23 vaccine, then the PCV13 vaccine should be given after one year. A booster PPSV23 should be given five years after the initial vaccine and then should be given again after the age of 65 years if more than five years has passed since the prior booster (Diagram 1).16

Hepatitis A Vaccination

The incidence of hepatitis A infection (HAV) in the United States has decreased by 95% since the vaccination became available in 1995.19 Currently, the HAV vaccine is part of the recommended series of childhood vaccines. However, there still remain many unvaccinated adults. Gastroenterologists should inquire about prior vaccination to HAV. If patients are unable to recall, they can be given the vaccine again as there are no known harms of receiving a second dose series of the vaccine. The vaccine is given in a two-part regimen at zero months followed by a second dose at six months. It is not recommended to perform post-vaccination testing as there is a high rate of vaccine response and not all testing methods are reliable for detecting low, but protective anti-HAV concentrations.20

Hepatitis B Vaccination

Hepatitis B virus (HBV) infection can cause both acute and chronic liver disease and have long-term health implications. Patients with IBD are at an increased risk for HBV infection secondary to immunosuppressive therapy, surgery and blood transfusions. Understanding the HBV immunologic status for patients with IBD is of particular importance given the implications and serious repercussions immunosuppressive therapy can have on HBV reactivation.21 Testing for HBV infection or prior exposure [hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb)] in all patients with IBD is encouraged, and certainly for those who will need treatment with biologic therapy.

If not already immune, vaccination for HBV is recommended ideally at the time of IBD diagnosis, during disease remission or before starting immunosuppressive therapy.22 There are currently two single antigen HBV vaccines (Engerix and Recombivax) and one combined vaccine (Twinrix, HBV and HAV) that are indicated for the adult population.23 The typical schedule in which the vaccination should be administered is a dose at 0, 1, and 6 months with the goal to achieve Hepatitis B surface ab >10IU/L. Accelerated vaccination protocols have been established for patients traveling to endemic areas who are at high risk for HBV exposure; these schedules can be applied to patients with IBD who are not immune to HBV prior to starting immunosuppressive therapy if needed. The protocol schedule gives the vaccine at day 0, 7, 21-30, and a booster at 12 months.24 Regardless of the regimen used, serologic titers should be checked one to two months after completion of the vaccination series. If no vaccine response is seen (Hepatitis B surface ab >10IU/L), then patients should receive an additional series of either double dose HBV vaccine or the combined HAV/HBV vaccine at 0, 1, and 6 months.

Tetanus, Diphtheria, and Pertussis Vaccination

There is a five part childhood vaccination series DTaP that provides protection against diphtheria, pertussis and tetanus and a Td booster is recommended every ten years thereafter.25 Recently there has been a rise in pertussis epidemics and it is now recommended that patients between the ages of 11-64 receive one Td booster substituted by Tdap. The timing of the Tdap vaccine in patients with IBD seems to be important. In a prospective study looking at post vaccination Tdap antibody titers, patients with IBD on immunomodulator monotherapy or combination immunomodulator/anti-tumor necrosis factor (TNF) alpha therapy had decreased response rates.26 Based on this observation, the ideal time to administer the Tdap booster in patients with IBD would be prior to the initiation of immunosuppressive therapy.

Meningococcal Vaccination

Meningococcal disease can lead to serious complications such as sepsis, limb ischemia, meningitis, and rarely death. There are two serogroup B meningococcal (MenB) inactivated vaccines currently available in the United States, MenB-FHbp and MenB-4C.27 All adolescents and young adults between the ages of 16-23 should receive the vaccination. As there is no current evidence that patients with IBD are at increased risk for meningococcal infection, patients should receive the vaccination according to the Advisory Committee on Immunization Practices (ACIP) guidelines.27 The MenB-FHP is currently approved for both a two-dose series (0 and 6 months) and a three-dose series (0, 1-2, 6 months) while the MenB-4c is given in a two-dose series (0 and 6 months). Persons considered being at highest risk should be given the three dose series as it likely provides better immunogenicity. Importantly, the same vaccine must be used for all doses and are not interchangeable.

Human Papilloma Virus Vaccination

Human papilloma virus (HPV) has been clearly linked to the development of cervical cancer. Female patients with IBD have been found to have an increased risk of abnormal Papanicolaou (Pap) smears linked to HPV 16 or 18 serotypes, which has been associated with immunosuppressive therapy.28 There are currently two licensed vaccines available in the United States against HPV that include protection against serotypes 16 and 18. Gardasil comes in a quadrivalent and 9-valent form. The 9-valent vaccination covers five additional serotypes that account for 15% of cervical cancers as well as HPV serotypes 6 and 11 that cause most anogenital warts.29 The additional coverage of the 9-valent vaccine is felt to mostly provide beneficial protection to women over men. Since patients with IBD are considered to be immunocompromised, the three-dose regimen of either vaccine should be administered at 0, 1-2 and 6 months to patients aged 9-26.

Live Vaccinations Measles, Mumps, Rubella Vaccination

Since the adaptation of universal vaccination protocols, the incidence of measles, mumps and rubella (MMR) has drastically decreased in incidence.30 The vaccination is a live vaccine and is given to children around the age of one in a two-part series. If a patient with IBD is not immune to MMR, then the vaccination can be safely administered to the patient as long as there is no plan to start high-level immunosuppressive therapy within 6 weeks or high-level therapy has been discontinued for at least three months.10

Varicella Zoster

Varicella Zoster virus (VZV) is a highly contagious infection that can lead to severe disseminated disease in immunocompromised patients. Corticosteroid use in combination with immunosuppressive agents appears to be a significant risk factor for infection.31 The majority of adults have immunity to VZV either through acquisition during childhood infection or vaccination. The VZV vaccine is a live attenuated vaccine. Given the high risk for complications, all patients with IBD should have their immunity to VZV assessed (documentation of two-dose regimen, history or varicella infection, or laboratory evidence of immunity). If the patient is not immune, a two-dose vaccination series should be initiated if there is no plan to start high-level immunosuppressive therapy within six weeks or high-level therapy has been discontinued for at least three months. For patients with IBD without immunity who are on high-level immunosuppressive therapy (and who cannot stop it without risk of flare) but are at increased risk for exposure to varicella, such as health-care workers or teachers, the risk of infection needs to be weighed against receiving the vaccination.32 There is some evidence available in small case series that administration of the VZV vaccine was safe in pediatric patients who were on either thiopurines or infliximab.33

Zoster/Shingles Vaccination

Varicella Zoster virus (VZV) persists as a latent infection in sensory nerve ganglia and can reactivate, especially in immunocompromised patients, causing Herpes zoster.34 About one in three people will develop zoster in the general population. The most common side effect is postherpetic neuralgia, however immunocompromised patients may suffer from disseminated infection that can be potentially fatal.35 In 2006, the live Zoster vaccine (Zostavax) was released and recommended by the Center for Disease Control (CDC) for patients 60 years or older. This live attenuated single-dose vaccine is at least 14 times the potency of the varicella vaccine. The CDC advises that administration of the vaccine to patients on “low-doses” of methotrexate, azathioprine or 6-mercaptopurine is safe. There is limited data to suggest the vaccine is safe for patients on anti-TNF therapy36, but the CDC does not recommend its use.

Recently, an inactivated vaccine consisting of varicella zoster protein in an adjuvant system (Shingrix) was FDA approved. It has remarkable efficacy in immunocompetent individuals, reducing the risk of developing zoster by 97%.37 This vaccine is indicated for patients 50 years or older as a two-dose regimen, at month 0 followed by a second dose at 2-6 months. Although this vaccine has not been directly tested in patients with IBD on immunosuppression, its safety and efficacy has been demonstrated in patients post renal transplant on immunosuppression as well as patients with either solid tumor or hematologic malignancies receiving chemotherapy.38,39

Screening and Surveillance of Cancer
Cervical Cancer Screening

Cervical dysplasia and cancer have been linked to the oncogenic properties of the HPV virus. Fortunately, the mortality rate has drastically decreased due to the implementation of mass screening with the Pap smear.40 Screening women with IBD is of particular importance as patients on immunosuppressive therapy have been shown to be at increased risk for cervical neoplasia, particularly in relationship to thiopurines.41 Unfortunately, despite these heightened risk, patients with IBD still seem to be under vaccinated for HPV42 and do not receive adequate cervical cancer screening.43 Patients with IBD who are on immunomodulator therapy should undergo yearly Pap Smears regardless if the patient has received the HPV vaccine.44 All patients with IBD who are on chronic immunosuppressive therapy should also be considered for yearly pap screening according to the American College of Obstetrics and Gynecology.45

Colorectal Cancer Screening and Dysplasia Surveillance

Patients with UC and colonic Crohn’s disease are at an increased risk of colon cancer that is two times the risk of the general population. Risk factors for development of colon cancer and dysplasia in patients with IBD include duration and extent of disease, family history of colon cancer, primary sclerosing cholangitis (PSC) and young age at disease onset.46 All patients with IBD should have a restaging (screening) colonoscopy eight years after disease onset as disease involvement may progress over time and proximal biopsies should exclude microscopic involvement in endoscopically normal appearing areas. The extent of the disease should be based either on endoscopic or microscopic involvement, whichever reveals more extensive disease.47 Patients with UC involving and proximal to the sigmoid colon and Crohn’s patients with more than a third of the colon involved should be placed in an endoscopic surveillance protocol. The presence of limited proctitis has not been proven to be a risk factor for the development of colorectal cancer.48 Ideally, surveillance should be undertaken when disease is in remission as active disease can hinder accurate interpretation of dysplasia.49

Current guidelines recommend colonoscopies every 1-3 years depending on risk factors and decided on a patient-to-patient basis. The patients at highest risk should undergo yearly surveillance colonoscopies (Table 2). For patients who are not in the high-risk group, lengthening the surveillance interval from one year can be considered if patients have endoscopically and histologically normal mucosa on two or more surveillance colonoscopies.46 The Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients (SCENIC) guidelines recommend chromoendoscopy over white-light endoscopy with random biopsies as the preferred method of surveillance in patients with IBD. Targeted biopsies or resection (if the lesion is felt to be endoscopically resectable) should be performed if a lesion is identified with chromoendoscopy. One may also consider two biopsies from each colonic segment for histologic staging.46 If chromoendoscopy is not available or the yield is reduced by significant inflammation, poor preparation or multiple pseuodpolyps, then random biopsies with targeted biopsies of any suspicious lesion should be undertaken.

Skin Cancer Screening

The awareness of the risk of skin cancer in patients with IBD has grown overtime. Non-melanoma skin cancer (NMSC) includes both squamous cell and basal cell carcinoma. The risk of acquiring NMSC is largely associated with thiopurine use (odds ratio of 4) and not IBD alone.50 There has been conflicting evidence in regards to the ongoing risk of NMSC once thiopurine use has stopped. A large French prospective cohort study demonstrated a pronounced increase in the incidence of NMSC in patients 50 or older with prior thiopurine exposure compared to controls.51 Contrary, a study on a large cohort of Veterans Affairs patients demonstrated that the incidence of NMSC reverted back to pre-exposure levels after the thiopurine was stopped regardless of the prior exposure duration.52

While NMSC appears to be strongly correlated to thiopurine use, patients with IBD have a significantly higher incidence of melanoma compared to the general population regardless of medical therapy.53 In addition, anti-TNF agents do appear to double the risk of melanoma.54,55 Given that there is an increased risk for melanoma in patients with IBD, routine counseling on the importance of decreased sun exposure, avoidance of tanning beds, use of protective sunscreen and clothing should be performed at office visits.

Our practices recommend referrals to dermatology for all of our IBD patients to undergo screening and in order to identify the particular risk and needs of continued surveillance according to individual risk factors based on our current understanding. Given the conflicting data of thiopurine use and risk for NMSC after cessation, it seems most reasonable to continue surveillance even after cessation in patients older that 50.

Osteoporosis and Osteopenia

Patients with IBD are at increased risk for bone mineral disorders including osteopenia and osteoporosis. The reported prevalence of osteoporosis in patients with IBD is estimated to be as high as 40% and more subtle degrees of decreased bone mineral density can be seen in 70% of patients with IBD.56 There are certain risk factors that lead to accelerated bone mineral loss. Patients with IBD who have one or more of the following risk factors should undergo screening with Dual-energy X-ray absorptiometry (DEXA): corticosteroid use more than three months or repeated use, history of low trauma-fracture, post-menopausal women, and males older than 50.57 Other risk factors to consider are chronic inflammation, active smoking, and malnutrition. If osteoporosis is found then referral to the patient’s PCP, endocrinologist or rheumatologist should be made for consideration of bisphosphonate therapy. Vitamin D levels should be checked at regular intervals and adequate calcium intake (1000mg/day) is recommended for all patients with IBD.58

Smoking

It is important to assess for tobacco use and provide cessation counseling to all patients with IBD given the overall health implications. Despite the observation that smoking may be protective against UC, practitioners should still encourage cessation, but caution the patient about the potential for flare. More importantly, Crohn’s patients should be advised that it is absolutely crucial to stop smoking. There is good evidence that patients with Crohn’s who smoke are at an increased risk of flare and smoking cessation lessens the risk.59 Furthermore, smoking is associated with increased steroid exposure, greater risk for surgery and increased risk of post-operative recurrence.60,61 There are a number of support systems that practitioners can refer patients to that include telephone based, mobile applications, and support group programs to help achieve cessation. Furthermore, medical therapy options that have been shown to be beneficial in smoking cessation include Nicotine replacement therapy, varenicline and bupropion.62

CONCLUSION

Inducing and maintaining remission for patients with IBD still remains the primary goal. However, the importance of health maintenance and prevention has emerged as a crucial objective in the overall delivery of care. Providers should take an active role in maintaining the wellness of patients and preventing any future adverse events. The role of the gastroenterologist should be as the principal physician closely managing the care with other health care professionals to ensure the patients are up to date with age appropriate vaccinations, cancer screening, screening for osteoporosis, and smoking cessation.

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A Case Report

Esophageal Dieulafoy Lesion – A Rare Cause of Upper Gastrointestinal Bleeding

May 2018 • Volume XLII, Issue 5
Tehseen Haider,Harish Guddati,Hilary Hertan

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Tehseen Haider, MD1 Harish Guddati, MD2 Hilary Hertan, MD, FACG2 1Department of Medicine, 2Department of Gastroenterology, Montefiore Medical Center, Wakefield Division, Bronx, NY

INTRODUCTION

Named after French surgeon Georges Dieulafoy, Dieulafoy lesions are uncommon but important causes of acute gastrointestinal (GI) bleeding which can be massive and life threatening.1 Dieulafoy lesions are known to occur anywhere in GI tract but are rarely reported in the esophagus and lower GI tract. Diagnosed endoscopically, they are amenable to treatment but pose a threat of rebleeding after the first intervention. We present a case of 91 year-old female with acute upper GI bleeding due to an esophageal Dieulafoy lesion.

Case Report

A 91 year-old African American woman presented with acute left upper extremity pain to emergency department (ED). She was taken to the operating room (OR) for acute limb ischemia. She experienced an episode of hematemesis in the post anesthesia care unit (PACU) with 300 ml of coffee ground aspirate in the nasogastric (NG) tube. She was transferred to intensive care unit (ICU) for hypovolemic shock and respiratory failure. Laboratory studies were significant for drop in hemoglobin from her baseline of 13.6 g/dL to 10.6 g/dL in 12 hours, indicating acute blood loss anemia. Emergent bedside esophagogastroduodenoscopy (EGD) showed coffee ground material in the stomach, necessitating lavage. A single, ectatic blood vessel with stigmata of recent bleeding was visualized in the lower third of the esophagus (Figure 1). The vessel was injected with four cc of 1:10,000 solution of epinephrine, and one hemostatic clip was placed to prevent recurrent bleeding (Figures 2 & 3). She was monitored in the ICU for recurrent bleeding, but she remained stable afterwards with no further rebleeding.

DISCUSSION

Dieulafoy lesions are a rare cause of acute nonvariceal GI bleeding, responsible for approximately 1.5% of acute upper GI bleeding.2 They can be associated with massive, life threatening bleeding. Initially reported in the stomach only, Dieulafoy lesion have been known to occur elsewhere in GI tract and extraintestinal locations. Most of these lesions, 75-90%, occur in the stomach, generally along the lesser curvature, within five cm of the gastro-esophageal junction. Rarely they can occur in small bowel (around 14-18%) and even more rarely in esophagus (roughly 8%)3,4,5

A Dieulafoy lesion is a congenital arteriovenous malformation which bleeds in arterial pulsatile fashion. Unlike normal arteries which go through narrowing of their caliber as they approach the mucosa, the Dieulafoy is a “caliber persistent artery” maintaining its caliber through the submucosa to the mucosa.4 The caliber of artery is in the range of 1-3 mm, which is approximately 10 times the normal caliber of mucosal capillaries. The mechanism of bleeding is erosion secondary to pulsations of the artery, rather than primary ulceration of mucosa. The mechanism and processes by which the artery maintains its caliber and tortuosity is largely unknown.3 Bleeding is mostly seen in men with comorbidities such as hypertension, cardiovascular disease, chronic kidney disease, diabetes mellitus or alcohol abuse.4 Endoscopy is the diagnostic modality of choice. On endoscopy, it appears as a stream of arterial blood emanating from mucosa. A nonbleeding Dieulafoy lesion appears as a raised nipple or visible vessel without an associated ulcer. The diagnosis rates for initial endoscopy range from 49% to 63%, and repeat endoscopy is often required (6%) due to intermittent bleeding.6 Repeat endoscopy timed as close as possible to a rebleeding event is crucial for the diagnosis. Endoscopic criteria for diagnosis of a Dieulafoy lesion has been established and includes (i) active arterial oozing/spurting from a small defect in the mucosa, (ii) visualization of a small vessel protruding from normal mucosa, (iii) fresh blood clot adherent to a defect of normal mucosa.7

Endoscopy is the mainstay of treatment. Multiple modalities can be utilized including mechanical therapy such as band ligation, hemoclip placement, thermocoagulation, cyanoacrylate injection, epinephrine or ethanolamine injection. Injection monotherapy has a high initial success rate, however there seems to be a high rate of rebleeding. In a retrospective analysis a rebleeding rate of 55% was reported with injection therapy. Combination therapy with injection followed by heater probe thermocoagulation is preferred. Doppler ultrasound can be used to confirm ablation of a Dieulafoy lesion by documenting the absence of blood flow following intervention.8 In view of unknown pathophysiology, there is little evidence to support acid suppression therapy to prevent rebleeding. If endoscopy fails, angiography is used as diagnostic intervention as in other causes of GI bleeding.9 Rebleeding is treated with repeat endoscopic hemostasis, angiographic embolization or surgical wedge resection of the lesion. The long-term rate of rebleeding is low once a Dieulafoy lesion is completely eradicated.

CONCLUSION

Dieulafoy lesions are one of the lesser known cause of massive upper GI bleeding with the stomach being the most common site. This condition can be encountered in any age group. Early endoscopy is essential to identify the source of bleeding and manage it appropriately. It is important to involve gastroenterology, critical care, interventional radiology and surgery in the management of these patients.

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Dispatches From The Guild Conference, Series #12

Inflammatory Bowel Disease in the Older Patient

May 2018 • Volume XLII, Issue 5
Sara Lewin,Uma Mahadevan

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Older patients with IBD require special attention due to comorbidity, polypharmacy, functional status, and increased risk of infection and malignancy compared to younger IBD patients. Medication interactions, prevention of infection and management of comorbidities may require closer monitoring to determine therapeutic response and to ensure adequate safety of medical therapy for IBD. In this article, we discuss the importance of developing a treatment strategy for older patients with IBD focused on restoration of normal bowel function and improved quality of life, avoidance of hospitalization and unnecessary surgery and minimizing long-term risk of therapies.

Sara Lewin, MD, Clinical Fellow, Division of Gastroenterology Uma Mahadevan, MD, Professor of Medicine, Division of Gastroenterology, University of California San Francisco, San Francisco, CA

INTRODUCTION

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic conditions characterized by inflammation of the gastrointestinal tract. The peak incidence of IBD occurs in the second to fourth decades of life.1 Although IBD is often thought of as a disease of the young, the incidence of IBD in older patients has been reported to be 10-15%. As the global population ages and the overall incidence of inflammatory bowel disease increases, the number of older patients who are diagnosed with IBD and the number of aging patients diagnosed with IBD when they were younger will increase considerably.1 With current estimates that 10-30% of patients with IBD are over the age of 60,3 the anticipated growth of older patients with IBD introduce distinct challenges and considerations in the care of this patient population.

Epidemiology and Pathophysiology

Older patients with IBD, also termed “elderly” or “geriatric,” typically defined as ≥60 years of age, comprise a heterogeneous group due to a wide range of medical co-morbidities and functional status. Older-onset ulcerative colitis is more common than older-onset Crohn’s disease, and older men have higher incidence rates of IBD than older women.4

Genetics and family history appear to have less influence on the development of older-onset IBD when compared to younger populations suggesting other factors at play.5 As the immune system ages, age-related T-cell impairment and decline in T-cell production can lead to a relative immunodeficiency. This immunodeficiency predisposes older patients to gastrointestinal infections, but immune dysregulation with advancing age also leads to the increased production of pro-inflammatory cytokines, which are implicated in the development of inflammatory diseases.6 In addition to immune dysregulation, current theories of IBD pathogenesis suggest that alterations in the intestinal microbiome may trigger the development of IBD.7 The composition of the intestinal microbiota also evolves with aging, with less overall diversity characterized by decrease in anaerobes, such as bifidobacteria, and increase in enterobacteria. These changes in the microbiota are hypothesized to be caused by changes in diet, mobility, intestinal motility, increased use of antibiotics associated with aging.8 Frailty is also associated with decreased microbiota diversity compared to non-frail older individuals.9

Clinical Presentation

Clinicians experience more difficulty diagnosing IBD in older patients, leading to misdiagnosis and delayed diagnosis. 60% of older patients with CD are initially misdiagnosed, compared to 15% of younger patients.10 The clinical presentation of IBD in older patients may be confused with infectious (such as Clostridium difficile), ischemic, radiation, non-steroidal anti-inflammatory drug-induced, or diverticular-associated enterocolitis.11 Older-onset IBD patients present with more subtle disease compared to younger adults. They more frequently present with isolated colonic inflammation (61.9% vs. 36.7% in younger adults) and less frequently present with small bowel involvement or upper gastrointestinal disease (38.1% vs. 63.3% in adults). 12 In CD, older patients are more likely to present with rectal bleeding without profound diarrhea, abdominal pain, fever, or weight loss.4 Additionally, older-onset CD patients more often have isolated colonic disease without penetrating disease, a phenotype similar to UC.3 In UC, older patients are more likely to present with left-sided colitis rather than ulcerative proctitis or pancolitis, and often have milder symptoms of abdominal pain and rectal bleeding than younger patients.12 Extraintestinal manifestations of IBD (e.g., arthritis, erythema nodosum, pyoderma gangrenosum, apthous stomatitis, uveitis) are less common in patients diagnosed with IBD at an older age.13 Progression of disease, such as extension of ulcerative proctitis to left-sided colitis, or the development of penetrating disease, is less common in older-onset IBD.13

Outcomes and Complications of IBD

Despite having milder disease and less progression, older patients with IBD are less likely to utilize IBD-specific outpatient care14 and more likely to be hospitalized for IBD.15 A study of IBD patients in a Swedish National Registry found that older patients with IBD are less likely to have IBD-specific outpatient healthcare and more likely to have IBD-related hospitalizations and intestinal surgeries.16 It has been hypothesized that increased hospitalizations and surgeries in older IBD patients may be related to reluctance to use corticosteroid-sparing immunomodulator and biologic medications in older patients due to other comorbid conditions and risk of complications.17 Older age is an independent risk factor for hospital mortality in IBD-related hospitalizations.20 Lastly, older patients who undergo surgery for IBD have longer post-operative length of hospital stay19 and may have increased post-operative mortality.20

Older patients with IBD are also at increased risk for serious infection regardless of treatment type,18 though use of immunosuppression, disease activity and use of narcotics also increase the risk of serious infection in older IBD patients. Due to immunosenescence, older patients with IBD are at increased risk for infection, including zoster infection.21 Immunization (with inactive vaccines for patients on immunosuppresive therapies) for influenza and pneumonia are recommended for all older patients with IBD. Zoster vaccination is also recommended for all individuals 60 and older. A new, inactive vaccine for herpes zoster (Shingrix, GlaxoSmithKline), with >90% reduction in shingles incidence, is now commerically available and is likely safe in immunosuppressed patients with IBD.22

Patients with IBD are at a two- to three-fold increased risk of developing a venous thromboembolism (VTE). This risk increases significantly with age; there is a 20% increased risk of a venous thromboembolism for each increased decade in age.23 There are no specific guidelines for VTE prevention in older IBD patients, though smoking cessation, weight reduction in obese patients, and mobilization in the hospital, at home, and during long-distance travel should be encouraged.24

The most well-recognized risk factors for the development of colorectal cancer in inflammatory bowel disease are duration and extent of disease.25 Based on these established risk factors, it is plausible that patients diagnosed with IBD at an older age would be at lower risk for IBD-associated colorectal cancer given shorter duration of disease and typically less extensive involvement. However, cohort studies from Hong Kong and the Netherlands have found that older-onset IBD is associated with a shorter time to the development of colon dysplasia and colorectal cancer.26,27 While this may represent sporadic disease, earlier colonoscopy for colon cancer surveillance than guidelines suggest (e.g., eight years after diagnosis) in elderly-onset IBD is advisable.

Management

The general approach to treatment in elderly-onset IBD is no different than in the younger IBD population. Treatment goals should focus on inducing and maintaining remission, preventing disease-related and treatment-related complications, and optimizing quality of life. The therapeutic choices may be more challenging in older IBD patients due to different disease phenotype, patient comorbidities, and concern for polypharmacy. Additionally, older patients with IBD are often excluded from clinical studies, particularly randomized control trials for IBD therapeutics. The paucity of efficacy and safety data specifically pertaining to older IBD patients, further complicates treatment decisions.

Mesalamine

5-aminosalicylic (5-ASA) agents are widely used for treatment of mild to moderate ulcerative colitis and may also be used for treatment of Crohn’s colitis.28 Over 80% of patients with IBD diagnosed after age 60 are treated with 5-ASA agents.4 5-ASA can be taken orally, with several formulations requiring dosing multiple times per day or with multiple pills for each dose.29 Topical 5-ASA therapies include suppositories, which can treat inflammation in the distal 10 cm of the rectum, and enemas, which can theoretically treat inflammation distal to the splenic flexure. In the older IBD patient, several factors can influence adherence to medical therapy. Cost of medications, concern for side effects, difficulties with pill size and number, difficulty with enema and suppository administration, and complex dosing schedules all can affect adherence to medical therapy.30

Although 5-ASA agents are generally considered to have an excellent safety profile, side effects and adverse reactions can occur. The most common adverse reactions include nausea and vomiting, headache, and rash. Nephrotoxicity, which is typically due to interstitial nephritis, is rare but clinically important, with a mean occurrence of 0.26% per patient-year. The incidence of nephrotoxicity appears to be idiosyncratic, as it has not been found to be related to formulation, dosing, or duration of 5-ASA therapy.31 As many older patients with IBD may have comorbid chronic kidney disease or risk factors for the development of renal insufficiency (e.g., diabetes mellitus, hypertension), renal function should be monitored closely before and during treatment.31

Corticosteroids

Corticosteroids are effective in establishing but not maintaining remission in moderate to severe IBD. Despite this, 30-40% of older IBD patients are on maintenance therapy with systemic corticosteroids.33,34 Long-term corticosteroid use is associated with many adverse effects, which are more frequent and severe in the geriatric population. Adverse effects include osteoporotic-related fractures, serious and opportunistic infections, altered mental status and delirium, precipitating or exacerbating diabetes mellitus and hypertension, and development of cataracts and glaucoma.35,36 Budesonide, a newer corticosteroid with formulations targeting both the small intestine and the colon, possesses some safety advantage to conventional corticosteroids, such as prednisone. Budesonide has extensive first-pass metabolism in the liver, leading to fewer systemic adverse effects and increased tolerability in patients. However, cost and lack of insurance coverage may limit use and corticosteroids may still be required for induction of remission in more severe disease activity.17

Immunomodulators: Thiopurines and Methotrexate

Some patients who are unable to achieve disease remission with oral mesalamine may be treated with thiopurine agents (such as azathioprine or 6-mercaptopurine) or methotrexate for maintenance therapy in IBD. In older patients with IBD, use of thiopurines and methotrexate is quite uncommon, (6% and 1%, respectively in one retrospective study33), potentially due to concern for adverse effects associated with these agents.

Use of thiopurines can lead to leukopenia and elevated liver enzymes, though testing for thiopurine methyltransferase genetics and/or enzyme activity prior to initiation of thiopurine therapy can help to identify those at highest risk for leukopenia.37 Acute pancreatitis is also associated with thiopurine use.38 Thiopurine use has been associated with increase risk of lymphoma, with a median age of onset of 60.39 Thiopurine use is also associated with an increased risk of non-melanoma skin cancer,40 with risk increasing with age.

Common side effects of methotrexate use include nausea, fatigue, stomatitis and rash. Rarely, hepatotoxicity can occur; liver enzymes should be monitored routinely. Methotrexate appears to be safe in older patients. Renal function, rather than advancing age itself, predicts development of toxicity, and should be taken into consideration when initiating and monitoring methotrexate therapy.41 Folic acid supplementation is recommended to prevent methotrexate-associated hepatic and gastrointestinal hepatotoxicity as well as associated folate deficiency.41

Biologic Therapies

Biologic agents, including tumor necrosis factor alpha (TNF-.), integrin and interleukin antagonists, are effective treatments for moderate to severe UC and CD. Although TNF-. agents have been in use for over a decade, use in the elderly IBD population is infrequent, possibly due to lack of safety data in this population or concern for side effects associated with these therapies.17

Anti-TNF agents may be less effective in older patients, as older IBD patients are more likely to be primary non-responders compared to younger IBD patients. Older IBD patients on anti-TNF therapy also have higher rates of IBD-associated hospitalizations, surgeries and serious infections compared to younger IBD patients.43

Anti-TNF use is associated with increased risk of serious infection that may be even higher in older patients with IBD and may lead to earlier discontinuation of anti-TNF compared to younger IBD patients.44 The increased risk of infection is most pronounced in combination therapy when anti-TNF and thiopurine agents are given concurrently. Live vaccines should not be given to patients on anti-TNF therapy and inactive vaccines may be less effective in patients receiving anti-TNF therapy. The combination of inadequate immune response and non-adherence to vaccination increases the risk of infection in the vulnerable older IBD patient population. Anti-TNF therapy has also been associated with worsening congestive heart failure, and is contraindicated in New York Heart Association Class III and IV heart failure,45 which is more likely to be a comorbid condition in older patients with IBD. There is also an increased risk of lymphoma with use of anti-TNF agents, particularly with combination therapy, and long-term combination therapy should be avoided in individuals 65 and older.17,39 The risk of both non-melanoma and melanoma skin cancers are increased in patients taking anti-TNF, and they should undergo regular dermatologic skin examinations.46

The administration of anti-TNF agents, which are given as an infusion (infliximab) or as a self-administered injection (adalimumab, certolizumab-pegol, golimumab), may provide logistical challenges for the older patient with IBD, who may have difficulty with transportation to infusion centers, with venous access, with self-administration of injectable agents due to poor dexterity and decreased visual acuity, and with adherence to a complex dosing schedule.47

Vedolizumab is a gut-selective monoclonal antibody that inhibits a4?7 integrin to block lymphocyte trafficking to the intestinal endothelium that is used for moderate to severe UC and CD. Vedolizumab has an excellent safety profile, with no increased risk of serious infection and low rates of malignancy in the general IBD population.48 The safety profile of vedolizumab in older patients with IBD, has not been extensively studied, though preliminary data suggests that vedolizumab is low risk for use in older patients with IBD,49 and may be a preferred treatment choice for moderate to severe IBD due to its low lymphoma and infection risk.

Ustekinumab

Ustekinumab is a monoclonal antibody against IL-12 and IL-23, initially approved for the use in psoriasis, but now is approved for use in moderate to severe CD. Clinical trials of ustekinumab in Crohn’s disease have also demonstrated an excellent safety profile with no increased risk of adverse events compared to placebo.50 There is a paucity of data regarding safety of ustekinumab in the older IBD population, but studies of ustekinumab use in older psoriasis patients have demonstrated favorable safety profile,51 and may also be a preferred treatment choice for older patients with Crohn’s disease.

Similar to anti-TNF agents, older patients with IBD on vedolizumab or ustekinumab may have difficulty with adherence to intravenous (IV) infusions and self-administered subcutaneous injections with complex dosing schedules. In general, immunosuppressive regimens should be minimized or avoided, if possible, in patients with multiple poorly controlled comorbidities, poor functional status, severe malnutrition, and cognitive decline. However, older IBD patients with minimal or well-controlled comorbidities with excellent cognitive, nutritional, and functional status are suitable candidates for immunosuppressive therapy if clinically indicated.

Drug-drug interactions

Older patients with IBD are prescribed an average of nine routine medications to manage their IBD and other comorbid conditions. Nearly one-third of medication regimens in older patients with IBD have major drug-drug interactions.34 (Table 1.) Careful review for drug-drug interactions with IBD medications should be considered prior to introducing a new medication. As 5-ASA agents are the most common medications used in older patients with IBD, drug-drug interactions with mesalamine agents are common, including with non-steroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors, histamine blocker, and warfarin use. Corticosteroids have many drug-drug interactions, including increased risk of tendon rupture when taken with fluoroquinolones, and increased risk of hypokalemia when taken with thiazide and loop diuretics. Allopurinol and angiotensin-converting-enzyme (ACE) inhibitors use may increase myelotoxicity when given with thiopurines and thiopurines may decrease the anticoagulation effect of warfarin. NSAIDs, aspirin, thiazide diuretics, and penicillin may inhibit renal excretion of methotrexate, leading to increased risk of methotrexate toxicity. Antibiotics given as treatment for and management of complications of IBD, such as metronidazole, have an increased risk of neuropathy when given with statins, and ciprofloxacin has the potential to increase the anticoagulation effects of warfarin.52 Biologic therapies have not been associated with significant drug-drug interactions with other common medications.53

In order to minimize drug-drug interactions, all providers caring for older patients with IBD, including gastroenterologists and primary care providers, should review the patient’s medication regimen carefully. Factors to consider include determining if there is an appropriate indication for the drug, that is effective for its intended condition, and that the dosage and directions are correct and practical given the patient’s comorbidities and functional limitations. Other considerations include ensuring that there are no significant drug-drug interactions or drug-disease interactions, that the duration of therapy is acceptable, and that the cost of the patient’s medical regimen compared to alternatives of equal usefulness is minimized.

CONCLUSION

Older patients with IBD require special attention due to comorbidity, polypharmacy, functional status, and increased risk of infection and malignancy compared to younger IBD patients. Medication interactions, prevention of infection, and management of comorbidities may require closer monitoring to determine therapeutic response and to ensure adequate safety of medical therapy for IBD. Although the side effects and risks of corticosteroids are well-known, many older IBD patients are maintained on long-term corticosteroid use, which should be avoided in favor of other corticosteroid-sparing agents. A treatment strategy for older patients with IBD should be focused on restoration of normal bowel function and improved quality of life, avoiding hospitalization and unnecessary surgery, and minimizing long-term risk of therapies.

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Frontiers In Endoscopy, Series #43

Endoscopic Mucosal Resection (EMR)

May 2018 • Volume XLII, Issue 5
Constantine Melitas,Serge A. Sorser,Douglas G. Adler

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Removal of large colon polyps can put patients at risk for procedure complications and inadequate resection of the lesion. Endoscopic mucosal resection (EMR) is a well-described technique that is safe and predominantly used for removal of larger lesions (> 1cm) of the gastrointestinal tract, which are limited to the superficial layers such as the mucosa and submucosa. In this article, we discuss several EMR techniques, each with their own indications,risks, and benefits.

Constantine Melitas, MD, Gastroenterology and Hepatology Fellow, Michigan State University College of Human Medicine, Providence, Providence Park Hospitals, Southfield, MI Serge A. Sorser, MD, Clinical Assistant Professor, Gastroenterology and Hepatology, Michigan State University College of Human Medicine, Providence, Providence Park Hospitals, Southfield, MI Douglas G. Adler, MD, FACG, AGAF, FASGE, Division of Gastroenterology and Hepatology, Utah School of Medicine, Salt Lake City, UT

INTRODUCTION/BACKGROUND

Removal of large colon polyps can put patients at risk for procedure complications and inadequate resection of the lesion. Endoscopic mucosal resection (EMR) is a well-described technique that is safe and predominantly used for removal of larger lesions (> 1cm) of the gastrointestinal tract, which are limited to the superficial layers such as the mucosa and submucosa. EMR can be used to remove benign, premalignant, and early (T1N0) malignant lesions, which can prevent the need for surgical intervention. To perform EMR, patient selection is critical for optimal outcomes. Patients should be selected if concern for an invasive lesion is low, based on lesion size, and if polyp features are of low complication risk. Also, patients who do not meet these criteria but are poor surgical candidates may also benefit from EMR. There are several EMR techniques, each with their own indications, risks, and benefits. Lesions may either be taken out whole (i.e. en bloc) or by removing them in segments (i.e. piecemeal). It has been studied that lesions greater than 1.5 or 2 cm should be removed piecemeal to reduce the risk of perforation.1-5

Techniques

There are three main techniques for EMR: injection, cap, and band ligation. Underwater EMR is a more recent technique, which also is performed by some endoscopists.

Injection-assisted EMR is a technique that involves injection of a substance under the mucosa to separate the mucosa from the submucosa to allow for resection of the lesion without penetration into the deeper layers of the GI tract in an attempt to decrease the risk of perforation. This also allows for removal of lesions en bloc, depending on the size of the lesion. It is important to inject and lift the proximal side of the lesion first as if this is not done, the lesion may be distorted into a position that is away from the endoscope obstructing visualization and placing it in an unfavorable position for resection. Nonlifting of a lesion can be a predictor of deeper invasion and is not indicated for removal through EMR.1,6-8 However, nonlifting can also occur if the lesion has previously manipulated or intervened upon. If nonlifting is thought to be due to prior manipulation of the lesion, EMR may be attempted.9

After the lesion is adequately lifted, resection is then performed using a snare with electrocautery. (Figure 1) If the lesion size is not amenable to removal en bloc, it may be removed piecemeal by systematically beginning at one margin and working across the entire lesion. The endoscopist must take great care to ensure islets of residual tissue are not left as these may become difficult to remove. Prior to removal of each portion of the polyp, the portion to be ensnared should be lifted away from the mucosa to further help prevent injury to the muscularis propria. Resection should be continued until the muscularis propria has been exposed. Remnants of adenomatous tissue can be removed with conventional methods for polypectomy such as forceps or snares, however the remnant tissue may also be treated with argon plasma coagulation (APC), alternative forms of monopolar coagulation, or may be fulgrated.

The cap-assisted technique also begins with injection of a solution in the submucosal space similar to the injection-assisted technique. However, a cap is placed at the end of the endoscope to allow for suction of the entire lesion or portion of the lesion into the cap. An electrocautery device, such as a hot snare, is placed in position prior to the retraction of the lesion into the cap and is used to resect the retracted portion of the lesion. There are caps available, which include an electrocautery device, most commonly a snare, attached to them. This process is repeated until the lesion is fully resected. The caps that are available are plastic and are cylindrical in order to fit on the end of the endoscope similar to caps used for variceal band ligation.10

Ligation-assisted EMR is a technique that does not require an injection into the submucosal space. As in cap assisted, a cap is placed over the end of the endoscope. However, the cap used with this technique is equipped with band ligation. The lesion is retracted into the cap by the use of suction. A band is then deployed onto the lesion to ligate the portion to be resected. An electrocautery device is subsequently used to resect the ligated area.11,12 The EMR band ligator allows for passage of a snare through the working channel of the endoscope without removal of the band ligating cap. The cap is typically equipped with six bands. (Figure 2)

The underwater technique is performed by filling the GI tract with water, which theoretically allows the lesion to elevate itself or float. It has been hypothesized that this enables the lesion to separate itself from the deeper layers of the GI tract and therefore theoretically allow for resection with less risk of injury or perforation.13 This method however has been thought to have a decreased risk of seeding malignant cells into the deeper layers of the mucosa after resection. Furthermore, it has been postulated that this technique may also decrease the fibrosis formation at the resection area making recurrent lesions easier to manipulate.9 As fibrosis makes lifting a lesion much more difficult, the underwater technique has been found to be valuable and beneficial in treating lesions which have been previously manipulated.6,14-20

Injectable Solutions

Several solutions are available for injection into the submucosal space to help prevent injury to the deeper layers of the GI tract with EMR. Normal saline is the most commonly used solution, is readily available, and is inexpensive, however, it dissipates after only a few minutes. Dissipation of the lift can be managed with repeating the injection, which is a common occurrence, especially when removing large lesions. Solutions such as hyaluronic acid, hydroxypropyl methylcellulose, succinylated gelatin, glycerol, and fibrinogen containing solutions have all been found to last longer than normal saline.21-27 Hyaluronic acid is also inexpensive but is not readily available in the U.S. In several trials with which have compared hyaluronic acid to normal saline, it has been concluded that hyaluronic acid sustains a more effective lift. Hyaluronic acid has been found to be the solution that sustains a lift for the longest duration of all currently available solutions.28 Hydroxypropyl methylcellulose however is a readily available solution and has a good duration of lift but has been found to have a risk of tissue damage at the injection site.29,30 Succinylated gelatin is readily available and inexpensive but is mainly used for colonic lesions > 20 mm as it has been found to assist in removing lesions in piecemeal fashion.31

Other endoscopic tools and techniques are available to further assist the endoscopist to identify the lesion margins. Chromoendoscopy is one modality, which involves staining the colonic mucosa with a topical solution to help delineate the lesion in its entirety. Solutions that have been used include methylene blue, toluidine blue, Lugol’s solution, Congo red, phenol red, and indigo carmine. Another tool that can be used is narrow band imaging (NBI) which is a mode that most high definition endoscopes are now equipped with and which enhances the mucosal surface without the need for dyes. The wavelengths that make up white light have been found to have different penetration abilities. Blue light has been shown to penetrate only the superficial layers of the colon while red light penetrates into the deeper layers. NBI therefore uses blue light wavelengths to reveal the superficial vasculature of the mucosa, which helps identify the lesion easier.32 Along with these tools, other helpful solutions may be added to the solution used to lift the lesion to be resected. Epinephrine (1:100,000 – 1:200,000) is sometimes added to the solution to theoretically decrease the risk of post polypectomy bleeding by means of vasoconstriction of the feeding vessels. However, this has the potential side effects of epinephrine use, such as severe hypertension, tachycardia, arrhythmias, and intestinal ischemia, which are all rare complications but are well documented when epinephrine is absorbed systemically.33-36 Other very helpful additives to a solution are methylene blue and indigo carmine. These additives significantly assist in delineating the margins of the lesion as it stains the underlying mucosa blue without affecting the color of the lesion itself, highlighting the margins. This staining may also help identify the muscularis propria and therefore can help prevent perforation.37,38

Efficacy

In the esophagus, EMR can be used for removal of superficial malignancies as well as Barrett’s associated high-grade dysplasia and intramucosal carcinoma.39-41 For Barrett’s associated neoplasia, EMR may be used as a solitary modality to remove neoplastic lesions or may be used in conjunction with ablative techniques to remove large segments of Barrett’s. A recent study which evaluated the efficacy of complete resection of Barrett’s and its associated neoplasia through EMR, found that neoplasia with high risk characteristics, such as submucosal invasion, poor differentiation, lymphatic or vascular infiltration, was completely eradicated in 98.8% of patients.41 Recurrence rates in this study were found to be very low (1.4%) for both neoplastic and highly dysplastic lesions. Studies have compared cap-assisted and ligation-assisted techniques for removal of Barrett’s associated neoplasia and it has been shown that the ligation-assisted technique slightly decreases the time of the procedure, however both techniques were found to be equally efficacious and had similar rates of adverse events.42

Studies that have evaluated EMR with radiofrequency ablation for Barrett’s have shown remission of neoplasia and metaplasia in 90% of patients 5 years after treatment. In these prospective studies, EMR was first performed on the visible abnormalities and was followed up by circumferential radiofrequency ablation 4-6 weeks after the initial treatment.43

EMR can also be used to remove superficial squamous cell carcinoma (SCC) in the esophagus. Many studies have evaluated the efficacy of EMR on SCC, which have seen a recurrence rate of as low as 0.3% in lesions smaller than 20 mm.40

In the stomach, endoscopic submucosal dissection, or ESD, is most commonly used for gastric cancer as it has been found to be associated with lower recurrence rates when compared to EMR (0.7% vs 6.4% respectively), however, EMR and ESD for early gastric cancer have been found to have similar overall survival rates.44 Due to the lower recurrence rate, ESD is the preferred method for removal of gastric cancer, when available, as it also carries the benefit of histologic evaluation of the margins of the removed lesion 45 (ref 45). EMR does not have this benefit, especially when lesions are removed piecemeal. Gastric carcinoids that are less than 1 cm can also be resected with EMR, however ESD again is the preferred modality as it has also been shown to reduce local recurrence rates in this setting.46,47

Several non-ampullary lesions have been resected with EMR, however in the duodenum, the risk of bleeding and perforation are the highest due to its thin walls. There are several studies that have quoted success rates of up to 96% in removal of these lesions, however as previously mentioned, many of these studies have reported a higher risk of complications.48-51

The colon is largely the most common area of the gastrointestinal tract where EMR is used and is typically performed using the injection-assisted technique. One recent study has shown that local recurrence rates for removal of flat lesions are as low as 3% when removed en bloc but up to 20% when removed in piecemeal.52 After endoscopic retreatment of these areas, with APC, EMR, or both, recurrence rate was 21%, however eradication rate of 91.4% was eventually achieved with an average of 1.2 retreatment sessions. Another large study revealed a recurrence rate of 16% at 4 months and a 4% recurrence rate at 16 months.52 The majority of recurrences in these patients were managed endoscopically and through the results, a timeframe for follow-up colonoscopy after a lesion was removed via EMR was proposed. It was proposed that patients with lesions greater than 15 mm and removed piecemeal, should have colonoscopy repeated in 6-12 months to evaluate for recurrence.51,53 Interestingly, when injection-assisted EMR has been compared to under water EMR, it was found that recurrent lesions were removed significantly better by using the underwater technique (88.9% vs 31.8%).14 A prospective study with polyps ranging from 20 – 100 mm removed via en bloc or piecemeal had an overall recurrence rate of 4.2% after a mean of 30 months. Recurrence was most commonly seen in patients with polyps greater than 40 mm.18 However, in another recent study with a mean polyp size of 30mm, invasive adenocarcinoma was found in 6 polyps (3.4%), 5 of which were successfully treated with EMR.20

As previously mentioned, colonic lesions that do not lift with injection into the submucosal space should not be lifted as this likely indicates invasion into the deeper layers of the bowel wall.1,6-8 However, if a lesions’ inability to lift is thought to be due to fibrosis secondary to a previous intervention, it has been found that these lesions are amenable for removal via EMR.9

As in the esophagus, other techniques may be used as an adjunct to EMR for removal of colonic adenomatous lesions. Several other techniques have been used with EMR, such as biopsy forceps or snare to ablate or remove residual tissue. Interestingly, this adjunctive technique has been found to increase the risk of recurrent lesions.52

Adverse Events

The most common adverse events associated with EMR are bleeding, perforation, and strictures. The most common overall complication is bleeding. Clinically significant bleeding rates can be seen in 11-22% of cases with removal of colonic lesions greater than 20mm.17,54 About one third of these patients may need endoscopic intervention to establish hemostasis. Conventional endoscopic methods for hemostasis are used in this setting.54 Risk factors for clinically significant post-EMR bleeding include size of the lesion, Paris classification (0-IIa and Is), and tubulovillous or villous histology.17

Luckily, colonic perforation with EMR is rare and occurs in less than 1% of cases.1,6,18,55 Signs of injury to the muscularis propria include a whitish or grey central circular area surrounded by the blue staining of the submucosal layer (if a staining additive has been used). This is also known as the “target” sign.56 As with perforations in the colon through other methods, small defects may be controlled with the use of endoclips, however larger perforations often require surgical intervention.56-59

Bleeding secondary to gastric EMR can be seen in up to 11.5% of cases and is also managed through conventional hemostatic techniques.60,61,62 Bleeding rates in the duodenum have similar risk as in the stomach for lesions less than 3cm but have been reported in up to 58% of cases with larger lesions.49-63 The risk of perforation in the stomach is low (<1%) likely due to the increased thickness of the stomach wall.64 Few studies have been performed which have evaluated the risk of perforation in the duodenum and report a risk of less than 2%, however the risk is believed to be higher given the thin duodenal walls, therefore it is advised that EMR in the duodenum should be performed with caution.63

In the esophagus, adverse events are overall much lower than in the colon. Unlike the colon, the most common adverse effect in the esophagus is stenosis and can widely range between 6-88% of cases according to several studies.41,65,66-70 Strictures can occur after removal of large mucosal resections, circumferential resections, or resection of multiple lesions but can be treated similarly to strictures of any alternative etiology with esophageal dilation.41,67,70 Bleeding can also occur in the esophagus and has been observed in about 1.2% of patients.71-76 Perforation in the esophagus is also seen less often and has been reported as low as less than 0.5% in the setting of an experienced endoscopist who routinely uses EMR.41,60,66,76-83 In comparison to ESD, EMR has been associated with a significantly lower rate of perforation.40

CONCLUSION/SUMMARY

EMR is a very helpful and safe endoscopic technique for removal of larger premalignant and early-stage malignant lesions of the gastrointestinal tract. Prior to the consideration of EMR, it is critical that the lesion selection is appropriate. Close endoscopic evaluation to delineate lesion margins, size (>1 cm), and identification of lesion depth are imperative. EUS can be used, if needed, to stage the lesion and further identify the depth of mucosal involvement. Many endoscopists have found it helpful to lift the lesion with a staining solution or mark the periphery of the lesion with cautery such as argon plasma coagulation or with the tip of a hot snare to further define the lesion margins and extent to be resected. Adjunctive techniques may be used along with EMR to further remove or ablate residual tissue. Lesions greater than 1.5 or 2 cm should be removed piecemeal. However, close follow-up colonoscopy, especially if the lesion is removed piecemeal as this poses a higher risk for recurrence. The most common adverse event is bleeding and if the lesion is deemed to be high risk, preventative measures or conventional hemostatic methods should be taken if post-resection bleeding occurs. Endoscopists performing EMR should be knowledgeable and skilled in treating possible adverse events associated with EMR.

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A Case Report

Necrotizing Rash Associated with Autoimmune Hepatitis

April 2018 • Volume XLII, Issue 4
Lili Loni Barsky,Yaw A. Adjepong

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Background:
An unfamiliar skin eruption often prompts an immediate referral to dermatology, when more thorough evaluation may be warranted first. We describe a case where an unusual skin lesion was the first observed sign of an underlying gastrointestinal illness.

Clinical Case:
A previously well male presented with a burning skin rash.
Physical examination revealed multiple desquamating lesions. Serologic evaluation showed elevations in liver enzymes, international normalized ratio, antinuclear antibody, anti-smooth muscle antibody and gammaglobulin titers, thrombocytopenia and C4 hypocomplementemia. Skin biopsy revealed epidermal necrosis and diffuse lymphocytic infiltrate. Liver biopsy showed interface hepatitis. Upon initiation of steroids, the skin lesions and abnormal liver enzymes resolved.

Conclusion:
The clinical findings and response to steroids confirmed autoimmune hepatitis. This case highlights the importance and challenge the internist faces in distinguishing between primary dermatoses and cutaneous manifestations of gastrointestinal disease.

Lili Loni Barsky, MD Yaw A. Adjepong, MD, MPH, PhD Yale University/Bridgeport Hospital, Bridgeport, CT

Case Presentation

A49-year-old previously well male presented with a three-week history of multiple burning and peeling skin lesions. These lesions initially appeared on his right palm and fingers and subsequently spread diffusely. His review of systems was otherwise negative. The man denied any recent changes in soaps, lotions or detergents, trauma, known allergies, insect bites, heat or chemical exposure or sick contacts. He did not take any medications, vitamins or supplements. The patient immigrated to the United States from South America ten years ago but had not traveled since. He worked in construction but always wore gloves. He most recently engaged in sexual intercourse four years ago with one female partner, with intermittent condom use. He denied any history of sexually transmitted infection. He admitted to consuming two beers weekly for the past eight years as well as a remote history of marijuana use, but he denied use of tobacco or other recreational drugs.

On admission, the patient was afebrile and hemodynamically stable. His physical examination revealed multiple small, coalescing, desquamating, vesiculopustural lesions with surrounding erythema (Figure 1), in a scattered distribution on the bilateral palms, left elbow, scalp and bilateral ears. The mouth, groin and soles were spared. Nikolsky sign was negative.

Laboratory evaluation showed an elevated alanine aminotransferase of 100, aspartate aminotransferase of 571, alkaline phosphatase of 184, hyperbilirubinemia of 1.5, hypoalbuminemia of 2.7, increased international normalized ratio of 1.56 and thrombocytopenia of 18,000. He also had elevated antinuclear antibody (ANA) and anti-smooth muscle antibody (ASMA) titers of 1:320, hypergammaglobulinemia and C4 hypocomplementemia. Titers were negative for the viral hepatidites, rapid plasma reagin, human immunodeficiency virus, human T-cell lymphotropic virus, Babesia, Ehrlichia, double stranded deoxyribonucleic acid, Ro, cryoglobulins, porphyrins, glucose-6-phosphate dehydrogenase, rheumatoid factor, celiac panel and the anti-neutrophil cytoplasmic, cardiolipin, topoisomerase-1, histone and mitochondrial antibodies. The urine drug screen, gonorrhea screen and blood and skin cultures were negative. Skin biopsy revealed confluent epidermal necrosis with increased dermal mucin (Figure 2a) and diffuse perivascular and periadnexal lymphocytic infiltrate (Figure 2b), with no deposition on direct immunofluorescence (DIF). Liver biopsy demonstrated interface hepatitis. The patient was initiated on steroids, and his skin lesions and abnormal liver enzymes resolved after four months.

Case Discussion

The presence of elevated liver transaminases, ANA and ASMA titers and hypergammaglobulinemia in conjunction with liver biopsy finding of interface hepatitis and response to steroids all verify the diagnosis of autoimmune hepatitis (AIH).1 While other dermatological conditions may be considered, they do not embody the clinicopathologic characteristics of this patient’s skin lesions. While the skin’s histological findings could suggest Rowell’s syndrome,2 the positive ANA titer was the only major criterion for the condition fulfilled in this case. Also, the lack of deposition on DIF and atypical clinical appearance for any of the subtypes excluded cutaneous lupus erythematosus. Perivascular and periadnexal lymphocytic infiltration can also be observed in polymorphous light eruption (PLE), Jessner’s lymphocytic infiltration of the skin and reticular erythematosus mucinosis (REM).3 However, these differentials were excluded by the atypical clinical appearance, presence of mucin deposition and high ANA titer. The patient’s skin eruption was attributed to a cutaneous manifestation of his underlying AIH.

Case Conclusion

When faced with an unusual desquamative diffuse skin rash as described here, the primary care physician may rush to consult dermatology, when instead a more comprehensive systemic evaluation should be pursued. Such an abnormal skin finding can actually be the first indication of something systemic. This case highlights the importance and challenge presented to the primary care physician in distinguishing between primary dermatoses and cutaneous manifestations of gastrointestinal disease.

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A Special Article

Hepatitis C Screening Among Baby Boomers at Risk for Hepatitis B

April 2018 • Volume XLII, Issue 4
Rotimi R. Ayoola,Sebastian Larion,David Poppers,Renee Williams

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The Centers for Disease Control (CDC) recommends that baby boomers (adults born between 1945-1965) be screened for hepatitis C (HCV). Patients with HCV are at increased risk of co-infection with hepatitis B (HBV). In this article, we investigate HCV screening rates in a baby boomer cohort with chronic HBV or at high-risk for HBV infection from a large healthcare system.

Background and Aims: The Centers for Disease Control (CDC) recommends that baby boomers (adults born between 1945-1965) be screened for hepatitis C (HCV). Patients with HCV are at increased risk of co-infection with hepatitis B (HBV). We investigated HCV screening rates in a baby boomer cohort with chronic HBV or at high-risk for HBV infection from a large healthcare system.

Methods:
We conducted a retrospective cohort analysis of 792 baby boomers, evaluated at New York Langone (NYU) from 2012-2017 with chronic HBV or at high-risk for HBV infection. CDC guidelines were used to assess whether a patient was considered at high-risk for HBV infection. Medical history including hepatitis serology was extracted from electronic health records. Multiple logistic regression was used to identify clinical risk factors independently associated with HCV screening.

Results:
Among 792 patients, 419 (52.9%) were screened. Multivariate regression of factors significant (P< .05) on univariate analysis revealed that health insurance, end-stage renal disease (ESRD), chronic liver disease (CLD), diabetes mellitus (DM) and current alcohol use were each independently associated with HCV screening. The strongest predictors of HCV screening were ESRD (OR: 3.346; 95% CI: 1.688-6.634) and CLD (OR: 3.027; 95% CI: 2.102-4.359), while DM (OR: 0.680; 95% CI: 0.497-0.930) was associated with a decreased likelihood of prior screening.

Conclusion:
In a retrospective study of patients at NYU, the baby boomer cohort with chronic HBV or at high-risk for HBV infection are not being adequately screened for HCV. Improvement in HCV screening should be strongly encouraged by all healthcare systems.

Rotimi R. Ayoola, MD1 Sebastian Larion, MD2 David Poppers, MD3 Renee Williams, MD3 1Department of Medicine, New York University Langone Health, Brooklyn, NY 2Department of Medicine, Augusta University, Augusta, GA 3Department of Medicine, Division of Gastroenterology, New York University Langone Health, New York, NY

INTRODUCTION

Hepatitis C virus (HCV) is a major public health issue in the United States and worldwide. It is one of the leading causes of cirrhosis and hepatocellular carcinoma (HCC) and the most common indication for liver transplantation in the United States.1 From 2003 to 2010 an estimated 2.2-3.2 million Americans were chronically infected with HCV, with a high proportion of people unaware of their infection (estimates range from 45-85%).2,3 Studies show that 76% of people diagnosed with HCV infection in the United States are in the “baby boomer” cohort (those born between 1945 and 1965).

Given the strong incidence of HCV within this birth cohort, in 2012 the Centers for Disease Control and Prevention (CDC) recommended one- time testing for HCV in baby boomers without specific HCV risk factors.3,4 Application of current guidelines for risk-based screening would result in an estimated 25% of the US adult population being tested. 5 Initial evaluation should include a standard anti-HCV antibody serologic test, with a reactive result followed by a confirmatory nucleic acid test or polymerase chain reaction for HCV ribonucleic acid. One-time testing of baby boomers has been estimated to identify 800,000 infections, with subsequent treatment and management potentially avoiding up to 120,000 HCV-related deaths.6

Screening rates in this birth cohort in patients with chronic hepatitis B virus (HBV) or in those at high-risk for HBV infections have not been well documented. HCV and HBV patients share common risk factors (intravenous drug use, hemodialysis treatment and human immunodeficiency virus infection). About 2-10% of HCV-positive patients are found to be positive for HBV surface antigen, and 5-20% of patients with HBV are found to be anti-HCV positive.7-11 Per CDC criteria, all individuals in the birth cohort should be screened for HCV regardless of specific risk factors, yet a better understanding of screening rates in patients with chronic HBV or at high-risk for HBV infection is needed (Table 1). A greater awareness of HCV screening failures could potentially lead to improved screening rates, better HCV and HBV management practices and patient care.

In this study, we report HCV screening rates and independent clinical factors associated with screening adherence in a diverse birth cohort patient population with chronic HBV or at high- risk for HBV infection.

MATERIALS AND METHODS

A retrospective analysis was performed using electronic medical records (EMR) of patients presenting at New York Langone Health between 2012 and 2017 with chronic HBV or at high-risk for contracting HBV infection. Patients were considered at high-risk for contracting HBV infection if they had a medical comorbidity or activity that was classified as high-risk by CDC criteria (Table 1).4 Medical conditions were identified using ICD-10 classification and patients were randomly selected to be included in the study. Patients were excluded from the study if they were not born between 1945 and 1965 and did not have one of the documented risk factors for HBV infection or a history of chronic HBV infection.

Patient information was obtained from the EMR by individual chart review and entered into a password-protected, HIPPA-compliant and de-identified REDCap repository (Vanderbilt University, Nashville, TN). Patient demographics and clinical history were compared between a cohort of patients who were screened for HCV versus a cohort of patients who were not screened for HCV. Screening was considered to have been performed if HCV serology was listed in the EMR (either positive or negative for HCV antibody). Results are presented as frequencies or percentages, with categorical variables compared using chi- square and continuous variables compared using two-sided Student’s t-test or Mann-Whitney U test, as appropriate. Covariates found significant on univariate analysis were inputted into a multiple logistic regression with HCV serology listed as the binary dependent variable. The Hosmer- Lemeshow statistic was used to assess model calibration. Statistical analysis was performed using SigmaPlot v10.2 (Systat Software, San Jose, CA). The Institutional Review Board of New York University Langone Health approved this study.

RESULTS

A total of 1,100 high-risk patients were evaluated in the initial data set, of which 792 were born between 1945 and 1965 and included in the final study (Figure 1). Patient demographics for the entire study cohort are listed in Table 2, showing that most patients were older (mean age: 61.7 years), male (63.9%) and overweight (median BMI: 27.4 kg/ m2). The study population was socio-economically diverse with 51.9% of respondents reporting non- white ethnicity and 43.6% lacking private health insurance.

High-risk medical conditions for the study population are listed in Table 3. Diabetes mellitus (DM) (46.3%; median hemoglobin A1c: 6.4%; 25- 75th quartiles: 5.6-7.7%), chronic kidney disease (CKD) (43.7%) and high-risk sexual behavior (27.2%) were the most commonly reported comorbidities. End-stage liver disease (ESLD) was present in 12.9% of patients with 9.2% listed for liver transplant with median Model for End- Stage Liver Disease (MELD) score of 13 (25-75th quartiles: 9-21). A total of 37 (4.7%) patients died during the data collection period, including 13 (1.6%) from liver-related etiologies. Most patients (75.8%) had two or more high-risk conditions, while 39.6% had 3 or more conditions. Importantly, a history of intravenous drug use (2.8%) or alcoholic hepatitis (3.2%) was reported in only small subset of these patients. Other medical comorbidities are listed in Table 4. Cardiovascular risk factors such as hypertension (58.0%), hyperlipidemia (42.9%) and a history of tobacco use (40.2%) were highly prevalent in our patient population. Primary care physicians evaluated a total of 29.4% of patients at least annually, while a gastroenterologist evaluated 26.4% of patients at least yearly.

A total of 419 patients (52.9%) were screened for HCV while 373 patients (47.1%) were not screened. Univariate analysis revealed that patients who were screened for HCV more frequently had private health insurance (58.0% vs 54.7%; P=0.004; Table 2), history of intravenous drug use (4.1% vs 1.3%; P=0.035; Table 3) or were currently using alcohol (35.1% vs 25.0%; Table 4). Patients who were screened were more likely to have a significant liver history including chronic liver disease (CLD) (44.9% vs 22.0%; P<0.001; Table 4) or ESLD (18.4% vs 6.7%; P<0.001; Table 3). Patients with HCV screening also presented with a higher rate of renal pathology including CKD (50.4% vs 36.2%; P<0.001) and end-stage renal disease (ESRD) (44.9% vs 29.2%; P<0.001), and less frequently with DM (40.3% vs 53.1%; P<0.001; Table 3).

Multivariate regression of factors significant (P<0.05) on univariate analysis revealed that health insurance, ESRD, CLD, ESLD, DM and current alcohol use were each independently associated with HCV screening (Model 1; Table 5). The strongest predictors of HCV screening were ESRD (OR: 3.346; 95% CI: 1.688-6.634) and CLD (OR: 3.027; 95% CI: 2.102-4.359), while DM (OR: 0.680; 95% CI: 0.497-0.930) was associated with a decreased likelihood of prior screening. The Hosmer-Lemeshow statistic was not significant (P=.215), indicating that the regression fit the data. Using more restrictive modeling where only the most significant (P<0.01; Model 2) factors were inputted into the multivariate analysis, there was no appreciable change in the study findings, suggesting that intravenous drug use and alcoholic hepatitis do not change the likelihood of HCV screening.

In addition, patients who were not screened for HCV were less frequently vaccinated against hepatitis A (12.8% vs 76.1%; P<0.001) or HBV (6.3% vs 42.9%; P=0.009). These patients were less likely to utilize health care resources such as annual primary care evaluation (19.8% vs 38.0%; P<0.001), emergency department visits (26.0% vs 39.4%), or a gastroenterology specialist consultation (13.4% vs 38.0%; P<0.001). Listing for liver transplant was also less likely (5.1% vs 12.9%; P<0.001) in patients who were not screened for HCV, despite no difference in MELD score between groups (median: 13 vs 12: P=0.763). All-cause mortality (6.9% vs 2.1%; P=0.003) and liver-related mortality (2.6% vs 0.5%; P=0.042) were significantly increased in patients who were screened for HCV.

DISCUSSION

Despite CDC recommendations concerning practice management guidelines for HCV and HBV, baby boomers with chronic HBV or at high- risk for HBV infection are not being adequately screened for HCV. These patients are also less frequently vaccinated for other conditions such as hepatitis A or HBV, less likely to utilize primary care or specialty services and less likely to be listed for liver transplant.

Most individuals are unaware of their HCV and HBV infection status.12 This study retrospectively evaluated HCV screening patterns in a diverse, birth cohort in the New York area, which revealed a screening non-adherence rate (52.9%) more than twice that reported in a previous study.13 This study also identified socioeconomic risk factors such as insurance status that were independently associated with reduced HCV screening. These patients were also less likely to utilize health care resources such as primary care or gastroenterology subspecialist services. Patients who were not screened for HCV were also significantly less likely to be listed for liver transplant, despite no differences in MELD score between patient groups. Thus, socioeconomic factors can impair access to appropriate medical care, often resulting in non-adherence with HBV and HCV practice management guidelines and adverse patient outcomes. Larger studies with longer patient follow-up are needed in order to assess whether socioeconomic factors in the at- risk HBV birth cohort results in increased all-cause or liver-related mortality. Due to the 2012 CDC recommendations on HBV screening, the New York State legislation enacted a public health law in 2014 that requires all health care providers to offer HCV screening. Thus, hepatitis screening and virus detection are expected to improve.14,15

HBV and HCV co-infection is frequent due to shared risk factors and modes of transmission such as intravenous drug use. Previous studies have demonstrated that HBV/HCV co-infected patients carry a greater risk of advanced liver disease, cirrhosis and hepatocellular carcinoma in comparison to monoinfected patients.11,16 Early detection and treatment of HBV and HCV could potentially prevent progression of liver disease, decrease the need for liver transplantation and reduce the risk for overall liver disease-related morbidity and mortality.17,18 With only 52.9% of eligible patients appropriately screened for HCV, our study identifies a substantial potential area of improvement in practice management that could significantly improve patient care. However, increasing patient and clinician awareness of viral liver disease continues to pose challenges, which may be attributed to a number of factors in our diverse study population including lack of physician emphasis and knowledge regarding current screening recommendations, cultural barriers and socioeconomic elements constraining access to appropriate medical care.19

Few studies have focused on HBV and HCV screening and vaccination rates in at-risk HBV patients in the baby boomer cohort.

Viral hepatitis serology is frequently completed in order to properly manage chronic HBV infection. Despite the low rate of screening in our high-risk cohort, HCV screening is performed even less frequently in the general birth cohort. One 2004- 2008 study of the commercially-insured birth cohort population in New York estimated an HCV screening rate of 17.6%.20 Another study examining hospitalized patients reported that only 35% of eligible patient underwent HCV screening.15 Certainly, while the presence of chronic HBV or risk factors for HBV infection contribute to the differences in screening, it is important to note that screening rates for both the general and high-risk population remain low.

This study was subject to several limitations. Retrospective reviews of EMR data are limited by the ability to extract relevant data from the patient record. It is possible that patients were screened by outside providers or primary care facilities that were not accessible in the EMR, raising the possibility that true HCV screening rates are underestimated. Another possibility is that appropriate screening was indeed performed, but not accurately listed in the patient EMR. Although the CDC recommends one-time HCV screening in all individuals born between 1945- 1965 regardless of risk, clinical judgment and cognitive bias may often direct screening practices. Other potential biases include selection bias and errors in patient sampling. However, these biases are believed to be mitigated by the size of our sample population. Patients also may not know their complete medical history or choose not to divulge their behaviors to the attending physician, resulting in the underestimation of the high-risk patient population. For example, disclosure of past or current intravenous drug use is often not disclosed or under-reported. With recent reports of HCV infections tripling between 2010 and 2015, with highest rates among 20-29 year-old users of illicit substances, it is even more important to thoroughly review and document a patient’s medical history.4 Lastly, during the study one of the academic hospitals in our health system underwent a change in EMR and information on some patients could therefore not be obtained. One subject that remains to be explored is how to improve HCV screening awareness and specific barriers to screening.

CONCLUSION

This study reveals that HCV screening in patients in the birth cohort with chronic HBV or at high- risk for HBV infection remains low despite CDC practice recommendations. Due to the fact that HBV/HCV co-infection is not uncommon and may lead to more rapid progression to advanced liver disease compared to monoinfection, including HCC, it remains imperative to properly screen these individuals to allow for early recognition and management. Greater emphasis should be placed on increasing physician awareness of CDC guidelines advocating for one-time HCV screening of people born between 1945-1965, particularly those with chronic HBV or at high risk for infection. However, challenges remain to identify methods that improve physician adherence with these recommendations.

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