Benjamin L. Cohen

Effect of Colesevelam on Liver Fat Quantified by Magnetic Resonance in Nonalcoholic Steatohepatitis: A Randomized Controlled Trial

Bile acid sequestrants (BAS) lower plasma low density lipoprotein levels and improve glycemic control. Colestimide, a BAS, has been claimed by computed tomography to reduce liver fat. Therefore, we examined the efficacy of colesevelam, a potent BAS, to decrease liver fat in patients with biopsy‐proven nonalcoholic steatohepatitis (NASH). Liver fat was measured by a novel magnetic resonance imaging (MRI) technique, the proton‐density‐fat‐fraction (PDFF), as well as by conventional MR spectroscopy (MRS). Fifty patients with biopsy‐proven NASH were randomly assigned to either colesevelam 3.75 g/day orally or placebo for 24 weeks. The primary outcome was change in liver fat as measured by MRI‐PDFF in colocalized regions of interest within each of the nine liver segments. Compared with placebo, colesevelam increased liver fat by MRI‐PDFF in all nine segments of the liver with a mean difference of 5.6% (P = 0.002). We cross‐validated the MRI‐PDFF‐determined fat content with that assessed by colocalized MRS; the latter showed a mean difference of 4.9% (P = 0.014) in liver fat between the colesevelam and the placebo arms. MRI‐PDFF correlated strongly with MRS‐determined hepatic fat content (r2 = 0.96, P < 0.0001). Liver biopsy assessment of steatosis, cellular injury, and lobular inflammation did not detect any effect of treatment. Conclusion: Colesevelam increases liver fat in patients with NASH as assessed by MRI as well as MRS without significant changes seen on histology. Thus, MRI and MRS may be better than histology to detect longitudinal changes in hepatic fat in NASH. Underlying mechanisms and whether the small MR‐detected increase in liver fat has clinical consequences is not known. (HEPATOLOGY 2012;56:922–932)

Fatigue is highly associated with poor health‐related quality of life, disability and depression in newly‐diagnosed patients with inflammatory bowel disease, independent of disease activity

Fatigue is common in Crohns disease (CD) and ulcerative colitis (UC). Data on fatigue in newly diagnosed patients are unavailable.

Myocardial infarction after microvascular head and neck reconstruction.

Objective/Hypothesis Microvascular flap transfer is a popular method for immediate reconstruction of defects in the head and neck resulting after the treatment of head and neck cancer. Head and neck cancer occurs most commonly in elderly patients with a high prevalence of heavy smoking. Surgery in this patient population is frequently prolonged and is associated with significant intraoperative blood loss. The present study seeks to identify factors contributing to perioperative myocardial infarction and to determine the best course of management.

Update on anti-tumor necrosis factor agents and other new drugs for inflammatory bowel disease

The treatment of inflammatory bowel disease (IBD)—ulcerative colitis (UC) and Crohn’s disease (CD)—has evolved beyond surgery with the introduction of biologic agents, primarily antibodies against mediators of inflammation and cell attraction. Anti-tumor necrosis factor (TNF) agents have been the first line treatment for moderate to severe ulcerative colitis and Crohn’s disease for more than 15 years. During that time much has been learnt about how best to use these agents. This review will assess the evidence on how to optimize the use of anti-TNF agents; when and how to start treatment; how to monitor treatment and when to de-escalate it; and the potential adverse effects of these drugs. New and emerging treatments such as anti-attractants, anti-interleukins, and Janus kinase (JAK) inhibitors will also be discussed.

High-Dose Infliximab Therapy in Crohn’s Disease: Clinical Experience, Safety, and Efficacy

BACKGROUND Inadequate response to infliximab [IFX] therapy in Crohns disease [CD] may necessitate dose intensification. We evaluated safety and efficacy of high-dose IFX [HD IFX] [greater than 10mg/kg every 8 weeks] in CD and characterized predictors of response to HD IFX intensification. METHODS Electronic medical records were queried for CD patients between 2010 and 2012 who received HD IFX and were reviewed for history, medications, laboratory data, efficacy, and safety. RESULTS In all, 86 patients received HD IFX for CD at doses between 10 and 22.5mg/kg every 4 to 7 weeks. In early HD IFX therapy [week 1-16], 25.8% and 59.1% experienced full and partial response, respectively. In later HD IFX therapy [week 38-100], 27.9% and 34.4% experienced full and partial response, respectively. Median serum IFX levels increased from 1.7 to 7.3 µ/mL [p = 0.017], and median C-reactive protein [CRP] values decreased from 20.5 at baseline to 4.7 mg/L after 16 weeks [p < 0.001]. Baseline CRP values were significantly elevated in the group that responded at 1-16 weeks compared with nonresponders [22.0 vs 3.5mg/L, p < 0.01]. HD IFX therapy was discontinued in 26% and 7.3% of patients for inadequate response and adverse events, respectively. Eleven cases of infection required hospitalization for a serious infection rate of 7.41 events per 100 patient-years. CONCLUSIONS HD IFX therapy may benefit CD patients who have failed standard doses of IFX. HD IFX therapy may be associated with more serious adverse events compared with standard dosing. Baseline CRP value may predict clinical response to HD IFX.

Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia.

Background:The expression and distribution of farnesoid X receptor (FXR) in colitis and colitis-associated neoplasia (CAN) is unknown. We investigated FXR expression in neoplastic and nonneoplastic tissue from ulcerative colitis (UC) patients, with or without primary sclerosing cholangitis (PSC), as well as the role of DNA methylation in FXR expression in colorectal cancer (CRC) cell lines. Methods:Samples from the right (RC) and left (LC) colon of patients with UC, with and without PSC, and with or without CAN, were stained by immunohistochemistry and scored semiquantitatively for nuclear FXR expression. FXR expression was analyzed by western blot and polymerase chain reaction (PCR) in nine different CRC cell lines before and after demethylation with 5-azacytidine. Results:In nondysplastic samples, FXR expression demonstrated a diminishing expression from proximal to distal colon (strong FXR expression: 39% RC samples vs. 14% LC samples; P = 0.007). With moderate-to-severe inflammation, FXR expression was almost always absent or weak in both UC and PSC-UC, regardless of location. With quiescent/mild inflammation, 56% of UC samples in the RC retained strong FXR expression versus 24% of PSC-UC samples (P= 0.017). FXR was absent in 72% of the neoplastic samples, with an inverse association with the grade of dysplasia. FXR expression was absent in all CRC cell lines, in some cases due to DNA methylation. Conclusions:FXR expression is inversely correlated with neoplastic progression and severity of inflammation in UC. Patients with PSC-UC have diminished FXR expression in the proximal colon compared to UC patients. This finding could contribute to the higher risk of proximal neoplasia in PSC patients.

Immunosuppression in inflammatory bowel disease: how much is too much?

Purpose of review Current treatment approaches favor the early introduction of immunomodulators and/or antitumor necrosis factor (TNF) agents. There is now strong evidence showing that combination therapy appears to be more effective than monotherapy in both ulcerative colitis and Crohns disease. However, there are concerns associated with this strategy, and eventually the following questions will emerge when discussing therapeutic options with our patients: is it safe to maintain these therapies for the long-term?; how long should we maintain therapy?; and if we decide to stop or de-escalate therapy, what strategy should we use? Recent findings During the past year new evidence regarding safety of long-term therapy with anti-TNF and immunomodulators, and predictors of relapse following therapy discontinuation have become available. Summary In this review we aim to discuss some of the safety concerns related to the use of immunosuppressive drugs used in inflammatory bowel disease, as well as the possible strategy for de-escalation or discontinuation therapy. Eventually, choosing to stop either the anti-TNF or the immunomodulator is a case-by-case decision based on the estimated risk–benefit ratio. In addition to the identified predictors of relapse after therapy discontinuation, other considerations such as long-term safety, cost, and natural history of the disease must be brought into this discussion.

State of Adult Trainee Inflammatory Bowel Disease Education in the United States: A National Survey.

Background:The fundamentals of inflammatory bowel disease (IBD) education begin during gastroenterology fellowship training. We performed a survey of gastroenterology fellowship program directors (PDs) and trainees with the aim to further examine the current state of IBD training in the United States. Methods:A 15-question PD survey and 19-question trainee survey was performed using an online platform. Results:Surveys were completed by 43/161 (27%) PDs and 160 trainees. All trainee years were equally represented. A significant proportion of trainees was unsure or believed that their inpatient (32%) or outpatient (43%) training was inadequate. Only 28% of trainees were satisfied with their current level of IBD exposure during training. Fewer than half the trainees reported comfort in the management of pouch or stoma issues, pregnant patients with IBD, or postoperative management. The proportion of PDs viewing a competency as essential for trainee education strongly correlated with trainee comfort in that area (Pearsons rho = 0.793; P < 0.01). In multivariate logistic regression, monthly IBD didactics was the only variable independently associated with satisfaction with the current level of training (odds ratio, 4.1 95% CI, 1.9–9.0). Conclusions:Over one-third of participating gastroenterology trainees did not feel “confident” or “mostly comfortable” with their level of IBD training, with varying comfort regarding different competencies in IBD management. These findings suggest that specific areas of IBD training may require additional focus during training and can provide the basis for the development of an IBD core competency curriculum.

A review of the impact of biologics on surgical complications in Crohn's disease.

Abstract:Anti–tumor necrosis factor therapy has revolutionized the treatment of Crohns disease. Despite the increased use in the past decade and a half, a majority of patients with Crohns disease with ultimately require operative management of their disease. No clear consensus has been made in the literature regarding the surgical outcomes in patients who have been exposed to anti–tumor necrosis factor therapy. This review highlights the most recent and relevant literature regarding the safety and effects of anti–tumor necrosis factor use in the perioperative period.

Review article: the intersection of mucosal pathophysiology in HIV and inflammatory bowel disease, and its implications for therapy

The immunopathology of inflammatory bowel diseases (IBD) and HIV in the gastrointestinal (GI) tract can be viewed as ends of a spectrum with IBD being associated with ‘immune excess’ and HIV with ‘immune paucity’ within the GI tract.